Most recent papers:

• The role of microRNAs involved in PI3‐kinase signaling pathway in colorectal cancer.
  Saeed Noorolyai, Ahad Mokhtarzadeh, Elham Baghbani, Milad Asadi, Amir Baghbanzadeh Kojabad, Mahsa Maleki Mogaddam, Behzad Baradaran.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2- microRNAs have a very crucial role in tumorgenesis and prevention of cancer, which play a significant role in influencing various factors through different signaling pathways. microRNAs can act as tumor suppressors and oncomirs in this cancer through phosphoinositide 3‐kinase/AKT signaling pathway. Abstract In recent decades, cancer has been one of the most important concerns of the human community, which affects human life from many different ways, such as breast, lung, colorectal, prostate, and other cancers. Colorectal cancer is one of the most commonly diagnosed cancers in the world that has recently been introduced as the third leading cause of cancer deaths in the world. microRNAs have a very crucial role in tumorgenesis and prevention of cancer, which plays a significant role with influencing various factors through different signaling pathways. Phosphoinositide 3 (PI3)‐kinase/AKT is one of the most important signaling pathways involved in the control and growth of tumor in colorectal cancer, through important proteins of this pathway, such as PTEN and AKT, that they can perform specific influence on this process. Our effort in this study is to collect microRNAs that act as tumor suppressors and oncomirs in this cancer through PI3‐kinase/AKT signaling pathway. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27415   open full text
• DDIT3 regulates cementoblast mineralization by isocitrate dehydrogenase 1 through nuclear factor‐κB pathway.
  Xiayi Liu, Hualing Sun, Miao Yu, Jie Liu, Beining Yang, Yanru Wu, Jiawei Wang.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2- In this study, we reported the decreased expression of DDIT3 during cementogenic mineralization, as well as the inhibitory effect of DDIT3 to cementogenic mineralization. In addition, we showed that DDIT3 can regulate isocitrate dehydrogenase 1 through the nuclear factor‐κB pathway. Abstract DDIT3 is of great importance in endoplasmic reticulum stress and is involved in many inflammatory diseases and mineralization processes. The cementum protects teeth from periodontitis and provides attachment for Sharpey's fibers of the periodontal ligament. However, the effect of DDIT3 on cementoblast differentiation remains largely unknown. In this study, we found that DDIT3 was suppressed during cementoblast differentiation. Knockdown of DDIT3 increased the messenger RNA (mRNA) and protein levels of several key osteogenic markers in vitro, including alkaline phosphatase, runt‐related transcription factor 2, and osteocalcin (OCN). In addition, isocitrate dehydrogenase 1 (IDH1) was increased during cementoblast differentiation, and knockdown of DDIT3 increased the protein and mRNA levels of IDH1. Furthermore, inhibition of IDH1 could partially reduce the effect of DDIT3 on cementoblast differentiation. The DDIT3 knockdown activated nuclear factor‐κB (NF‐κB) transcriptional activity and upregulated the expression of p‐p65 and p‐IκBα. The increased osteogenic differentiation ability and IDH1 expression, as induced by the DDIT3 knockdown, could be partially turned over by the addition of NF‐κB inhibitor BAY 11–7082. Overall, our data clarified that DDIT3 suppresses cementoblast differentiation through IDH1, via the NF‐κB pathway. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27811   open full text
• Ranolazine prevents pressure overload‐induced cardiac hypertrophy and heart failure by restoring aberrant Na+ and Ca2+ handling.
  Jiali Nie, Quanlu Duan, Mengying He, Xianqing Li, Bei Wang, Chi Zhou, Lujin Wu, Zheng Wen, Chen Chen, Dao Wu Wang, Katherina M. Alsina, Xander H.T. Wehrens, Dao Wen Wang, Li Ni.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2 In this study, we revealed the effect of ranolazine to attenuate pressure overload‐induced cardiac hypertrophy and heart failure in mice by reducing Na+ accumulation and Ca 2+ overload, normalizing SR leak. The Ca 2+‐dependent Ca 2+/calmodulin (CaM)/CaMKII/MEF2D and CaM/CaMKII/calcineurin/nuclear factor of activated T‐cells hypertrophic pathways and endoplasmic reticulum (ER) stress were triggered by pressure overload and were inhibited by ranolazine. Abstract Background Cardiac hypertrophy and heart failure are characterized by increased late sodium current and abnormal Ca2+ handling. Ranolazine, a selective inhibitor of the late sodium current, can reduce sodium accumulation and Ca 2+ overload. In this study, we investigated the effects of ranolazine on pressure overload‐induced cardiac hypertrophy and heart failure in mice. Methods and Results Inhibition of late sodium current with the selective inhibitor ranolazine suppressed cardiac hypertrophy and fibrosis and improved heart function assessed by echocardiography, hemodynamics, and histological analysis in mice exposed to chronic pressure overload induced by transverse aortic constriction (TAC). Ca2+ imaging of ventricular myocytes from TAC mice revealed both abnormal SR Ca 2+ release and increased SR Ca 2+ leak. Ranolazine restored aberrant SR Ca 2+ handling induced by pressure overload. Ranolazine also suppressed Na + overload induced in the failing heart, and restored Na +‐induced Ca 2+ overload in an sodium‐calcium exchanger (NCX)‐dependent manner. Ranolazine suppressed the Ca 2+‐dependent calmodulin (CaM)/CaMKII/myocyte enhancer factor‐2 (MEF2) and CaM/CaMKII/calcineurin/nuclear factor of activated T‐cells (NFAT) hypertrophy signaling pathways triggered by pressure overload. Pressure overload also prolonged endoplasmic reticulum (ER) stress leading to ER‐initiated apoptosis, while inhibition of late sodium current or NCX relieved ER stress and ER‐initiated cardiomyocyte apoptosis. Conclusions Our study demonstrates that inhibition of late sodium current with ranolazine improves pressure overload‐induced cardiac hypertrophy and systolic and diastolic function by restoring Na+ and Ca 2+ handling, inhibiting the downstream hypertrophic pathways and ER stress. Inhibition of late sodium current may provide a new treatment strategy for cardiac hypertrophy and heart failure. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27791   open full text
• Effect of PLK1 inhibition on cisplatin‐resistant gastric cancer cells.
  Zihao Chen, Yanling Chai, Ting Zhao, Ping Li, Lihua Zhao, Fang He, Yu Lang, Jing Qin, Hongping Ju.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2 This study aims to investigate the effect of polo‐like kinase 1 (PLK1) inhibition on cisplatin (DDP)‐resistant gastric cancer (GC) cells. Together, our experimental results illustrated that the DDP resistance of GC cells might be associated with the aberrant overexpression of PLK1. PLK1 inhibition, including si‐PLK1 and BI2536 treatment, could restore the chemosensitivity of drug‐resistant SGC‐7901/DDP cells and enhance the efficacy of DDP, revealing the potential value of PLK1 inhibition in GC chemotherapy. Abstract Objective This study aims to investigate the effect of polo‐like kinase 1 (PLK1) inhibition on cisplatin (DDP)‐resistant gastric cancer (GC) cells. Methods: The transcriptional level of PLK1 was measured by quantitative reverse‐transcription polymerase chain reaction. Expressions of PLK1 and its downstream mediators as well as autophagy‐related protein LC3 I/LC3 II were detected by western blot. An 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay and 5‐ethynyl‐2′‐deoxyuridine immunofluorescent staining were conducted to evaluate the cell viability and replication activity separately. Flow cytometry was carried out to determine the cell cycle status. The GFP‐LC3 vector contributed toward tracking the formation and aggregation of autophagosomes. Results: Drug‐resistant SGC‐7901/DDP cells showed insignificant changes in all phases after DDP treatment, including DNA replication, cell proliferation, cell cycle, and apoptosis, whereas DDP could significantly improve the autophagy level of SGC‐7901/DDP as well as PLK1expression. By downregulating the expression of PLK1, both BI2536 andsi‐PLK1 enhanced SGC‐7901/DDP sensitivity to DDP, suppressing the proliferation and autophagy as well as improving the apoptosis rate. PLK1 inhibition also resulted in the repression of cell division regulators CDC25C and cyclin B1. Conclusion: Together, our experimental results illustrated that the DDP resistance of GC cells might be associated with the aberrant overexpression of PLK1. PLK1 inhibition, including si‐PLK1 and BI2536 treatment, could restore the chemosensitivity of drug‐resistant SGC‐7901/DDP cells and enhance the efficacy of DDP, revealing the potential value of PLK1 inhibition in GC chemotherapy. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.26777   open full text
• Novel effects of sphingosylphosphorylcholine on the apoptosis of breast cancer via autophagy/AKT/p38 and JNK signaling.
  Di Ge, Jia Gao, Lina Han, Ying Li, Hong‐Hong Liu, Wan‐Cheng Yang, Fen Chang, Jing Liu, Mei Yu, Jing Zhao.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2- Sphingosylphosphorylcholine (SPC) could induce apoptosis through c‐Jun N‐terminal kinase (JNK) signaling in MDA‐MB‐231 cells. An antagonistic signaling about autophagy/AKT/p38 was activated to inhibit JNK signaling and subsequent apoptosis by SPC. Though evoking autophagy/AKT/p38 pathways that anatagonize apoptosis, SPC eventually led to cell apoptotic death. Abstract Sphingosylphosphorylcholine (SPC), an important lipid mediator in blood, inhibits the proliferation and migration of various cancer cells. However, its effect as a cell‐specific sphingolipid in breast cancer cells is still unknown. Here, we showed that SPC promoted autophagy and apoptosis in triple‐negative breast cancer MDA‐MB‐231 cells. Autophagy worked as a negative regulator of apoptosis‐induced by SPC. Mechanistically, SPC mediated apoptosis via activating c‐Jun N‐terminal kinase (JNK). Meanwhile, p38MAPK (p38) and protein kinase B (PKB or AKT) signaling pathways were also activated to inhibit apoptosis, suggesting that SPC could evoke multiple signaling pathways to modulate cell apoptosis. In addition, the crosstalk between autophagy, p38, AKT and JNK is that autophagy, p38, and AKT attenuated the JNK. AKT and p38 were in the downstream of autophagy, which is autophagy/AKT/p38 signaling evoked by SPC to antagonize JNK signaling and subsequent apoptosis. Although the pathways that antagonize apoptosis were evoked, the cells eventually reached apoptosis by SPC. Therefore, the combination with pharmacological autophagy inhibitors would be a more effective therapeutic strategy for eliminating breast cancer cells by SPC. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27802   open full text
• Protective effect of microRNA‐224 on acute lower extremity ischemia through activation of the mTOR signaling pathway via CHOP in mice.
  Yang‐Xi Chen.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2- MicroRNA‐224 could alleviate the occurrence and development of acute lower extremity ischemia (ALEXI) in mice through activation of the mammalian target of rapamycin (mTOR) signaling pathway by downregulating C/EBP homologous protein (CHOP). Abstract Acute lower extremity ischemia (ALEXI) is known worldwide as an urgent condition, occurring when there is an abrupt interruption in blood flow into an extremity. This study aims to investigate whether microRNA‐224 (miR‐224) affects the ALEXI mice and the underlying mechanism. The miR‐224 expression and C/EBP homologous protein (CHOP), mammalian target of rapamycin (mTOR), translation initiation factor 4E‐binding protein 1 (4E‐BP1), and phosphoprotein 70 ribosomal protein S6 kinase (p70S6K) messenger RNA (mRNA), as well as protein expressions, were determined. The target gene of miR‐224 was also verified by using a luciferase reporter gene assay. The vascular endothelial cells from the ALEXI mice were transfected with miR‐224 mimics, miR‐224 inhibitors, or small‐interfering RNA against CHOP. Cell proliferation was assessed using a 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The cell cycle distribution along with the cell apoptosis were both evaluated by using a flow cytometry. The muscle fibers of the lower extremities found in the ALEXI mice were evidently swollen and rounded, presenting with a remarkably narrowed gap. The positive CHOP expression increased in ALEXI mice than normal mice, while the miR‐224 expression and mTOR, 4E‐BP1, and p70S6K mRNA, as well as the protein expression, decreased. Luciferase reporter gene assay validated that the miR‐224 gene directly targeted CHOP. MiR‐224 facilitated cell proliferation but inhibited cell apoptosis; by contrast, CHOP increased cell apoptosis. Moreover, the cells transfected along with miR‐224 mimic exhibited a lower CHOP expression as well as increased mTOR, 4E‐BP1, and p70S6K expression. Our study provided evidence that miR‐224 could alleviate the occurrence and development of ALEXI in mice through activation of the mTOR signaling pathway by downregulating CHOP. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27550   open full text
• Biogenic nanoselenium particles activate Nrf2‐ARE pathway by phosphorylating p38, ERK1/2, and AKT on IPEC‐J2 cells.
  Xiao Xiao, Deguang Song, Yuanzhi Cheng, Yuhan Hu, Fengqin Wang, Zeqing Lu, Yizhen Wang.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2- Our data demonstrated that biogenic nanoselenium (BNS) particles activated Nrf2‐ARE pathway through p38, extracellular signal‐regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT) mediated‐phosphorylation of nuclear factor (erythroid‐derived‐2)‐like 2 (Nrf2) to improve the antioxidant function of intestinal epithelial cells. Abstract As the intestinal epithelium is vulnerable to oxidative stress because of frequent enterocyte renewal and continuous exposure to exogenous agents, it is meaningful to figure out how the epithelial cells exert antioxidant function. We previously synthesized a novel biogenic nanoselenium (BNS) particles and proved that BNS could effectively improve intestinal antioxidative function through activating Nrf2‐ARE pathway. The objective of the present study was to investigate the mechanism by which BNS activate Nrf2‐ARE pathway on the physiological function of intestinal epithelial cells. In the present study, we demonstrated that treatment of IPEC‐J2 cells with BNS particles not only elevated the levels of downstream proteins of nuclear factor (erythroid‐derived‐2)‐like 2 (Nrf2) such as heme oxygenase‐1 and NQO‐1 in a time‐dependent manner which started to weaken at 12 hr after treatment but also significantly activated Nrf2, mitogen‐activated protein kinase (MAPK), and protein kinase B (AKT) pathway in a time‐dependent manner within 24 hr. BNS particles significantly increased the content of phosphorylated‐Nrf2, without evident influence on the level of Kelch‐like ECH‐associated protein 1 (Keap1). Moreover, BNS also induced the activation of p38, extracellular signal‐regulated kinase 1/2 (ERK1/2), c‐Jun N‐terminal kinase, and AKT while phosphorylating Nrf2. Using specific protein kinase inhibitors, we found that the Nrf2‐phosphorylating and antioxidative effects of BNS particles were abolished when p38, ERK1/2, and AKT were significantly inhibited. Overall, our data demonstrated that BNS particles activated Nrf2‐ARE pathway through p38, ERK1/2, and AKT mediated‐phosphorylation of Nrf2 to improve the antioxidant function of intestinal epithelial cells - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27773   open full text
• Prospect of mesenchymal stem cells in therapy of osteoporosis: A review.
  Leili Aghebati‐Maleki, Sanam Dolati, Reza Zandi, Ali Fotouhi, Majid Ahmadi, Ali Aghebati, Mohammad Nouri, Seyed Kazem Shakouri, Mehdi Yousefi.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2- Stem cell therapy has been recommended as a probable therapeutic approach for patients with osteoporosis. Even though the concept of stem cell‐based therapy for osteoporosis has suggested substantial attention over the years, no clinical trial has been published in humans. The cell studies on the basis of osteoporosis are primarily attentive on osteoclastic activity and bone resorption procedures; at that point on osteoblastogenesis, and in recent times on the differentiation probable of mesenchymal stem cells. In this review, we have summarized the therapeutic role of stem cell‐based strategy in osteoporosis. Abstract Osteoporosis is a systemic skeletal disease associated with reduced bone strong point that results in raised fracture risk, with decreased bone strength, leading to reduced bone mineral density and poor bone quality. It is the most common in older females but some men are also at high risk. Although considered as a predictable result of aging, it is can be avoidable and treatable. The existing treatment of osteoporosis mainly contains antiresorptive and anabolic agents. In spite of these improvements, concerns around unusual side‐effects of antiresorptive drugs, and the lack of perfect confirmation in maintenance of their long‐standing effectiveness is bring about many patients not receiving these drugs. Over the years, the stem cell‐based therapy has attained substantial clinical consideration because of its potential to treat numerous diseases. The stem cell therapy has been recommended as a probable therapeutic approach for patients with osteoporosis. Even though the concept of stem cell‐based therapy for osteoporosis has caught substantial attention, no clinical trial has been published on humans. The cell studies based on osteoporosis are primarily focused on osteoclastic activity and bone resorption procedures. Earlier, it was on osteoblastogenesis and in recent times, on the differentiation probable of mesenchymal stem cells. In this review, we have summarized the therapeutic role of stem cell‐based strategy in osteoporosis. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27833   open full text
• Trehalose inhibits cell proliferation and amplifies long‐term temozolomide‐ and radiation‐induced cytotoxicity in melanoma cells: A role for autophagy and premature senescence.
  Giulia Allavena, Barbara Del Bello, Paolo Tini, Nila Volpi, Giuseppe Valacchi, Clelia Miracco, Luigi Pirtoli, Emilia Maellaro.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2- Trehalose, a natural disaccharide, inhibits short‐term cell proliferation and, even more, colony‐forming capacity in melanoma cells. Moreover, trehalose magnifies temozolomide (TMZ)‐ and irradiation (IR)‐induced cytotoxicity in the long term. Two different cell responses are induced by trehalose: a remarkable autophagy in melanoma cells (A375) sensitive to TMZ‐ and IR‐induced apoptosis, and premature senescence in melanoma cells (SK‐Mel‐28) resistant to apoptosis and less prone to autophagy. Abstract Cutaneous melanomas frequently metastasize to the brain, with temozolomide (TMZ) plus radiotherapy (RT) offering little control of these lesions. We tested whether trehalose, a natural glucose disaccharide proved to induce autophagy, could enhance the effect of TMZ and ionizing radiation (IR). In two melanoma cell lines (A375 and SK‐Mel‐28), which greatly differ in chemosensitivity and radiosensitivity, trehalose significantly inhibited short‐term cell proliferation and also enhanced IR‐induced cytostasis. Interestingly, in TMZ‐resistant SK‐Mel‐28 cells, trehalose was more effective than TMZ, and combined trehalose + TMZ further reduced cell proliferation. In long‐term experiments, colony‐forming capacity was dramatically reduced by trehalose, and even more by combined trehalose + TMZ or trehalose + IR. In resistant SK‐Mel‐28 cells, although growth was inhibited most with trehalose + TMZ + IR‐6 Gy combined treatment, it is notable that trehalose + TMZ treatment was also very effective. Along with a direct antiproliferative effect, two further mechanisms may explain how trehalose potentiates TMZ‐ and IR‐induced effects: the remarkable trehalose‐stimulated autophagy in A375 cells, which were sensitive to TMZ‐ and IR‐induced apoptosis; and the notable trehalose‐stimulated premature senescence in SK‐Mel‐28 cells, which were resistant to apoptosis and less prone to autophagy. In normal melanocytes, trehalose induced a minor autophagy and cell proliferation inhibition, without affecting cell viability; moreover, when trehalose was used in combination with TMZ, the slight TMZ‐induced cytotoxicity was not significantly reinforced. Together, our results suggest that trehalose, a safe nutrient supplement able to cross the blood–brain barrier, is a promising candidate, worthy to be further explored in vivo, to augment the therapeutic efficacy of TMZ and RT in melanoma brain metastases. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27838   open full text
• Identification of dysregulated miRNAs in triple negative breast cancer: A meta‐analysis approach.
  Leimarembi Devi Naorem, Mathavan Muthaiyan, Amouda Venkatesan.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2- The study adopted meta‐analysis using the robust rank aggregation method to integrate miRNA expression profiling datasets of triple negative breast cancer. A meta‐signatures of six significantly dysregulated miRNAs (hsa‐miR‐135b‐5p, hsa‐miR‐18a‐5p, hsa‐miR‐9‐5p, hsa‐miR‐522‐3p, hsa‐miR‐190b, and hsa‐miR‐449a) were identified from different studies and have high prediction accuracy. Abstract Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor clinical outcomes and lack of approved targeted therapy. Dysregulated microRNAs (miRNAs) have been considered a promising biomarker, which plays an important role in the tumorigenesis of human cancer. Due to the increase in miRNA profiling datasets of TNBC, a proper analysis is required for studying. Therefore, this study used meta‐analysis to amalgamate ten miRNA profiling studies of TNBC. By the robust rank aggregation method, metasignatures of six miRNAs (4 upregulated: hsa‐miR‐135b‐5p, hsa‐miR‐18a‐5p, hsa‐miR‐9‐5p and hsa‐miR‐522‐3p; 2 downregulated: hsa‐miR‐190b and hsa‐miR‐449a) were obtained. The gene ontology analysis revealed that target genes regulated by miRNAs were associated with processes like the regulation of transcription, DNA dependent, and signal transduction. Also, it is noted from the pathway analysis that signaling and cancer pathways were associated with the progression of TNBC. A Naïve Bayes‐based classifier built with miRNA signatures discriminates TNBC and non‐TNBC samples in test data set with high diagnostic sensitivity and specificity. From the analysis carried out by the study, it is suggested that the identified miRNAs are of great importance in improving the diagnostics and therapeutics for TNBC. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27839   open full text
• LINC00707 contributes to hepatocellular carcinoma progression via sponging miR‐206 to increase CDK14.
  Janfei Tu, Zhongwei Zhao, Min Xu, Minjiang Chen, Qiaoyou Weng, Jiangmei Wang, Jiansong Ji.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2- We observed that long intergenic nonprotein‐coding RNA 707 (LINC00707) was increased in hepatocellular carcinoma (HCC) cells and LINC00707 silence was able to greatly repress HCC progression, and the correlation between LINC00707 and mciroRNA‐206 (miR‐206) was validated in our research and downregulation of LINC00707 increased miR‐206 expression in HCC cells. Then, cyclin‐dependent kinase 14 (CDK14) was predicted as a target of miR‐206 and the correlation between them was proved in our study. In conclusion, our data implied that LINC00707/miR‐206/CDK14 axis participated in HCC development and LINC00707 might be a biomarker for HCC. Abstract Recently, increasing numbers of long noncoding RNAs (lncRNAs) have been found to be aberrantly expressed in various cancers. However, the roles of lncRNAs in hepatocellular carcinoma (HCC) progression is largely unknown. In our current study, we identified that long intergenic nonprotein‐coding RNA 707 (LINC00707) was remarkably elevated in HCC cells, indicating that LINC00707 was involved in HCC development. Subsequently, LINC00707 was significantly decreased in HepG2 and Huh7 cells. The in vitro functional assays demonstrated that knockdown of LINC00707 significantly reduced HCC cell proliferation, induced cell apoptosis, and blocked the cell cycle progression. In addition, HCC cell migration and invasion was also greatly inhibited by downregulation of LINC00707. Increasing evidence has indicated that lncRNAs can act as molecular sponges of microRNAs. Currently, we observed that microRNA‐206 (miR‐206) was dramatically inhibited in HCC cells and LINC00707 can modulate HCC development through sponging miR‐206. The binding correlation between LINC00707 and miR‐206 was confirmed by dual‐luciferase reporter assay, RNA pull down and RNA immunoprecipitation assay in our study. Moreover, cyclin‐dependent kinase 14 (CDK14) was predicted as a target of miR‐206 and we found that miR‐206 suppressed CDK14 levels in HCC cells. Finally, in vivo assays were used and it was proved that silence of LINC00707 can restrain HCC development through modulating miR‐206 to upregulate CDK14. In conclusion, it was implied that LINC00707 can lead to HCC progression through sponging miR‐206 and modulating CDK14. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27737   open full text
• Immunoresolvents in asthma and allergic diseases: Review and update.
  Ramin Lotfi, Alireza Rezaiemanesh, Seyed Hamidreza Mortazavi, Ali Gorgin Karaji, Farhad Salari.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2- Asthma and allergic diseases are inflammatory conditions developed by excessive reaction of the immune system against normally harmless environmental substances. Essential fatty‐acids‐derived immunoresolvents, namely, lipoxins, resolvins, protectins, and maresins are anti‐inflammatory compounds that are believed to have protective and beneficial effects in inflammatory disorders, including asthma and allergies. Abstract Asthma and allergic diseases are inflammatory conditions developed by excessive reaction of the immune system against normally harmless environmental substances. Although acute inflammation is necessary to eradicate the damaging agents, shifting to chronic inflammation can be potentially detrimental. Essential fatty‐acids‐derived immunoresolvents, namely, lipoxins, resolvins, protectins, and maresins, are anti‐inflammatory compounds that are believed to have protective and beneficial effects in inflammatory disorders, including asthma and allergies. Accordingly, impaired biosynthesis and defective production of immunoresolvents could be involved in the development of chronic inflammation. In this review, recent evidence on the anti‐inflam]matory effects of immunoresolvents, their enzymatic biosynthesis routes, as well as their receptors are discussed. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27836   open full text
• Gene polymorphisms and serum levels of TL1A in patients with rheumatoid arthritis.
  Zhi‐Chao Yuan, Jia‐Min Wang, Lin‐Chong Su, Wang‐Dong Xu, An‐Fang Huang.
  Journal of Cellular Physiology. November 29, 2018
  --- - |2- 1. TNF‐like ligand 1A (TL1A) gene polymorphisms correlated with RA. 2. TL1A protein concentrations were elevated in RA patients. 3. TL1A may play important roles in RA. Abstract Recent findings showed elevated expression of tumor necrosis factor (TNF)‐like ligand 1A (TL1A) in rheumatoid arthritis (RA) patients and arthritis mice. However, whether TL1A gene polymorphisms may correlate with RA susceptibility needs to be discussed. This case‐control study was performed on 350 RA patients and 556 healthy subjects to identify TL1A genetic variants (rs3810936, rs6478109, and rs7848647) and their possible association with TL1A levels, susceptibility to and severity of RA. Odds ratio and 95% confidence interval were calculated to represent the correlation between TL1A polymorphisms and RA. The TL1A serum levels were evaluated. Results showed that frequencies of TC, TT + TC genotypes of rs3810936, rs7848647 in RA patients were significantly lower in RA patients compared with controls. Patients with C allele showed more severe disease course (disease activity index: erythrocyte sedimentation rate, rheumatoid factor) than in carriers of T allele. However, the allele or genotype frequencies of rs6478109 were not associated with RA. In addition, TL1A genetic variants conferred higher TL1A levels in RA patients compared with controls. In conclusion, these findings indicated an association between TL1A rs3810936, rs7848647 variation and the susceptibility of RA in a sample of Chinese individuals, and TL1A may correlate with severity of RA. - 'Journal of Cellular Physiology, EarlyView. '

  November 29, 2018   doi: 10.1002/jcp.27834   open full text
• The novel relationship between Sirt3 and autophagy in myocardial ischemia–reperfusion.
  Yitian Zheng, Binhao Shi, Mengqing Ma, Xiaoqin Wu, Xianhe Lin.
  Journal of Cellular Physiology. November 28, 2018
  --- - |2- The signal pathways in Sirt3‐mediated autophagy when myocaridal ischemia–reperfusion (I/R) happened. We tend to find the novel relationship between Sirt3 and autophagy when myocardial I/R happened. Abstract Class III histone deacetylases (HDACs) belong to the proteasome family, comprising seven family members identified in mammalian cells, identified Sirt1–Sirt7. As an important member of HDACs, Sirt3 is hotly debated for its multiple functions. It was reported that Sirt3 got involved in the alleviation of multiple diseases, including myocardial infarction, neuron ischemia, hypertrophy, and diabetic myopathy. Through regulating many cellular mechanisms, such as apoptosis, autophagy, and clearance of reactive oxygen species (ROS), Sirt3 played an important role in the alleviation of myocardial ischemia–reperfusion injury. Nowadays Sirt3‐induced autophagy was indicated to be involved in the process of the development of myocardial ischemia–reperfusion injury. Sirt3 could both activate and inhibit autophagy process by activating different downstream signal pathways, such as Sirt3–AMP‐activated protein kinase pathway, Sirt3–Foxo3a pathway, and Sirt3–superoxide dismutase–mitochondrial ROS pathway. Whereas the Sirt3‐induced autophagy in different phases of myocardial ischemia–reperfusion has not been systematically illustrated. In this review, we summarized the regulated mechanisms found in these years and listed the updated research about the relationship between Sirt3 and autophagy which are both positive and negative during myocardial ischemia–reperfusion phase. We anticipated that we may controlled the activation of autophagy by regulating the concentration of Sirt3 in myocyte. By maintaining a proper expression of autophagy in different phases of myocardial ischemia–reperfusion, we could reduce the morbidity of patients with myocardial infarction apparently in the future. - 'Journal of Cellular Physiology, EarlyView. '

  November 28, 2018   doi: 10.1002/jcp.27329   open full text
• EW‐7197 prevents ulcerative colitis‐associated fibrosis and inflammation.
  Maryam M. Binabaj, Fereshteh Asgharzadeh, Amir Avan, Farzad Rahmani, Atena Soleimani, Mohammad R. Parizadeh, Gordon A. Ferns, Mikhail Ryzhikov, Majid Khazaei, Seyed M. Hassanian.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Here, we investigate the potential therapeutic effects of EW‐7197 in a murine model of ulcerative colitis. Our results suggest that EW‐7197 has potentially useful therapeutic properties against colitis, with clinically translational potential of inhibiting key pathological responses of inflammation and fibrosis in patients with colitis. Abstract EW‐7197 is a transforming growth factor‐β type I receptor kinase inhibitor with potential anti‐inflammatory and antifibrotic properties. Here, we investigate the potential therapeutic effects of EW‐7197 in a murine model of ulcerative colitis. EW‐7197 attenuated the colitis disease activity index by improving rectal bleeding, body weight, and degree of stool consistency. EW‐7197 also reduced colorectal tissue damage and the colon histopathological score by reducing crypt loss, mucosal damage, and tissue inflammation. Moreover, EW‐7197 appeared to ameliorate the inflammatory and fibrotic responses by reducing oxidative stress, reducing submucosal edema and inflammatory cell infiltration, downregulating proinflammatory and pro‐fibrotic genes, and inhibiting excessive collagen deposition in inflamed and fibrotic ulcerative colitis tissues. These results suggest that EW‐7197 has potentially useful therapeutic properties against colitis, with clinically translational potential of inhibiting key pathological responses of inflammation and fibrosis in patients with colitis. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27823   open full text
• Poly (3‐hydroxybutyrate‐co‐3‐hydroxyvalerate) improved osteogenic differentiation of the human induced pluripotent stem cells while considered as an artificial extracellular matrix.
  Fatemeh Sadat Hosseini, Fatemeh Soleimanifar, Amir Aidun, Seyedeh Elnaz Enderami, Ehsan Saburi, Hadi Zare Marzouni, Mohammad‐Mehdi Khani, Arash Khojasteh, Abdolreza Ardeshirylajimi.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- ‐The pluripotent stem cells produced from the patient and the nanofibrous polymeric scaffold that can be completely degraded in the body and its produced monomers could be also usable and are the best options for this implant. ‐In this study, electrospun PHBV nanofibers were fabricated and characterized and then osteogenic differentiation of the human iPSCs was investigated while cultured on PHBV scaffold. ‐MTT, alkaline phosphatase activity, calcium content, gene expression, and western blot evaluations were confirmed osteogenic differentiation of the human iPSCs increased significantly when grown on PHBV nanofibers. Abstract Cocell polymers can be the best implants for replacing bone defects in patients. The pluripotent stem cells produced from the patient and the nanofibrous polymeric scaffold that can be completely degraded in the body and its produced monomers could be also usable are the best options for this implant. In this study, electrospun poly (3‐hydroxybutyrate‐co‐3‐hydroxyvalerate) (PHBV) nanofibers were fabricated and characterized and then osteogenic differentiation of the human‐induced pluripotent stem cells (iPSCs) was investigated while cultured on PHBV scaffold. MTT results showed that cultured iPSCs on PHBV proliferation were increased compared to those cultured on tissue culture polystyrene (TCPS) as the control. Alkaline phosphatase (ALP) activity and calcium content were also significantly increased in iPSCs cultured on PHBV compared to the cultured on TCPS under osteogenic medium. Gene expression evaluation demonstrated that Runx2, collagen type I, ALP, osteonectin, and osteocalcin were upregulated in iPSCs cultured on PHBV scaffold in comparison with those cultured on TCPS for 2 weeks. Western blot analysis have shown that osteocalcin and osteopontin expression as two major osteogenic markers were increased in iPSCs cultured on PHBV scaffold. According to the results, nanofiber‐based PHBV has a promising potential to increase osteogenic differentiation of the stem cells and iPSCs‐PHBV as a cell‐co‐polymer construct demonstrated that has a great efficiency for use as a bone tissue engineered bioimplant. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27807   open full text
• Antibody–drug conjugates (ADCs) for cancer therapy: Strategies, challenges, and successes.
  Meghdad Abdollahpour‐Alitappeh, Majid Lotfinia, Tohid Gharibi, Jalal Mardaneh, Behrouz Farhadihosseinabadi, Pegah Larki, Babak Faghfourian, Koushan Sineh Sepehr, Kazem Abbaszadeh‐Goudarzi, Ghasem Abbaszadeh‐Goudarzi, Behrooz Johari, Mohammad Reza Zali, Nader Bagheri.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Third‐generation antibody–drug conjugates are more effective, showing lower levels of unconjugated monoclonal antibodies, more‐stable linkers, improved pharmacokinetic properties, and safety profiles. Abstract Targeted delivery of therapeutic molecules into cancer cells is considered as a promising strategy to tackle cancer. Antibody–drug conjugates (ADCs), in which a monoclonal antibody (mAb) is conjugated to biologically active drugs through chemical linkers, have emerged as a promising class of anticancer treatment agents, being one of the fastest growing fields in cancer therapy. The failure of early ADCs led researchers to explore strategies to develop more effective and improved ADCs with lower levels of unconjugated mAbs and more‐stable linkers between the drug and the antibody, which show improved pharmacokinetic properties, therapeutic indexes, and safety profiles. Such improvements resulted in the US Food and Drug Administration approvals of brentuximab vedotin, trastuzumab emtansine, and, more recently, inotuzumab ozogamicin. In addition, recent clinical outcomes have sparked additional interest, which leads to the dramatically increased number of ADCs in clinical development. The present review explores ADCs, their main characteristics, and new research developments, as well as discusses strategies for the selection of the most appropriate target antigens, mAbs, cytotoxic drugs, linkers, and conjugation chemistries. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27419   open full text
• CtIP promotes G2/M arrest in etoposide‐treated HCT116 cells in a p53‐independent manner.
  Hongyu Chen, Jin Shan, Dandan Chen, Ruoxi Wang, Wenjing Qi, Hailong Wang, Yueshuang Ke, Wenguang Liu, Xianlu Zeng.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- CtIP can modulate the etoposide sensitivity of HCT116 cells by promoting G2/M phase arrest, which mainly through the ATR‐Chk1‐CDC25C pathway rather than the p53‐p21/GADD45a pathway. Abstract Acquired resistance to cytotoxic antineoplastic agents is a major clinical challenge in tumor therapy; however, the mechanisms involved are still poorly understood. In this study, we show that knockdown of CtIP, a corepressor of CtBP, promotes cell proliferation and alleviates G2/M phase arrest in etoposide (Eto)‐treated HCT116 cells. Although the expression of p21 and growth arrest and DNA damage inducible α (GADD45a), which are important targets of p53, was downregulated in CtIP‐deficient HCT116 cells, p53 deletion did not affect G2/M arrest after Eto treatment. In addition, the phosphorylation levels of Ser317 and Ser345 in Chk1 and of Ser216 in CDC25C were lower in CtIP‐deficient HCT116 cells than in control cells after Eto treatment. Our results indicate that CtIP may enhance cell sensitivity to Eto by promoting G2/M phase arrest, mainly through the ATR‐Chk1‐CDC25C pathway rather than the p53‐p21/GADD45a pathway. The expression of CtIP may be a useful biomarker for predicting the drug sensitivity of colorectal cancer cells. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27824   open full text
• Long noncoding RNA LINC00460 promotes carcinogenesis via sponging miR‐613 in papillary thyroid carcinoma.
  Li Feng, Bin Yang, Xiao‐Di Tang.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- The present study first demonstrated that the expression of long intergenic noncoding RNA 460 (LINC00460) was upregulated in papillary thyroid carcinoma (PTC) tissues and cell lines. And the elevation of LINC00460 was correlated with advanced tumor–node–metastasis (TNM) stage and lymph node metastasis. Our results also revealed that the oncogene LINC00460 promoted PTC progression via partly regulating miR‐613/sphingosine kinase 2 (SphK2) axis. These findings suggested that the LINC00460/miR‐613/SphK2 might act as a novel therapeutic target for the treatment of PTC. Abstract Long intergenic noncoding RNA 460 (LINC00460) has been identified as a critical regulator for multiple types of cancers. However, the biological role and underlying mechanism in human papillary thyroid carcinoma (PTC) still remain unclear and need to be uncovered. This study was aimed to ascertain the biological role and molecular mechanism of LINC00460 in PTC progression. Our findings revealed that the level of LINC00460 was significantly upregulated in PTC tissues and cell lines, which was positively correlated with advanced tumor–node–metastasis (TNM) stage and lymph node metastasis. Cellular experiments exhibited that knockdown of LINC00460 decreased proliferative, migratory, and invasive abilities of PTC cells. Mechanism assays noted that knockdown of LINC00460 suppressed cell proliferation, migration, and invasion, and inhibited expression of sphingosine kinase 2 (SphK2, a target of miR‐613) in PTC cells, at least in part, by regulating miR‐613. These findings suggested that LINC00460 could function as a competing endogenous RNA to regulate SphK2 expression by sponging miR‐613 in PTC. Targeting LINC00460 could be a promising therapeutic strategy for patients with PTC. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27799   open full text
• Intersectin‐Cdc42 interaction is required for orderly meiosis in porcine oocytes.
  Xiaoyan Li, Min Gao, Yongfu He, Bo Xiong, Honglin Liu, Ling Gu.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Our findings support a model where intersectins, through the interaction with Cdc42, modulates the assembly of meiotic apparatus and actin polymerization, consequently ensuring the orderly meiotic progression during porcine oocyte maturation. Abstract Intersectins (ITSNs) have been shown to act as adaptor proteins that govern multiple cellular events via regulating Cdc42 activity. However, it remains to be determined whether the ITSN‐Cdc42 pathway is functional in porcine oocytes. To address this question, we used a small molecule, ZCL278, to selectively disrupt the ITSN2‐Cdc42 interaction. In the present study, we find that porcine oocytes exposed to ZCL278 are unable to completely progress through meiosis. Meanwhile, the spindle defects and chromosomal congression failure are frequently detected in these oocytes. In support of this, we observed the accumulated distribution of vesicle‐like ITSN2 signals around the chromosome/spindle region during porcine oocyte maturation. In addition, our results also showed that inhibition of the ITSN‐Cdc42 interaction impairs the actin polymerization in porcine oocytes. In summary, the findings support a model where ITSNs, through the interaction with Cdc42, modulates the assembly of meiotic apparatus and actin polymerization, consequently ensuring the orderly meiotic progression during porcine oocyte maturation. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27510   open full text
• PCNA and JNK1‐Stat3 pathways respectively promotes and inhibits diabetes‐associated centrosome amplification by targeting at the ROCK1/14‐3‐3σ complex in human colon cancer HCT116 cells.
  Yu Cheng Lu, Pu Wang, Jie Wang, Ronald Ma, Shao Chin Lee.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- The study shows the power of functional proteomic analysis in the delineation of cell signal transduction. Understanding of the mechanisms underlying the diabetes‐associated centrosome amplification is beneficial for the development of intervention protocols for the control of centrosome amplification and its consequences (ie., cancer development) in diabetes. Abstract We have recently reported that type 2 diabetes promotes centrosome amplification via enhancing the expression, biding, and centrosome translocation of rho‐associated coiled‐coil containing protein kinase 1 (ROCK1)/14‐3‐3σ complex in HCT116 cells. In the functional proteomic study, we further investigated the molecular pathways underlying the centrosome amplification using HCT116 cells. We found that treatment of HCT116 cells with high glucose, insulin, and palmitic acid triggered the centrosome amplification and increased the expressions of proliferating cell nuclear antigen (PCNA), nucleophosmin (NPM), and 14‐3‐3σ. Individual knockdown of PCNA, NPM, or 14‐3‐3σ inhibited the centrosome amplification. Knockdown of PCNA inhibited the treatment‐increased expression of ROCK1, whereas knockdown of ROCK1 did not affect the PCNA expression. High glucose, insulin, and palmitic acid also increased the expressions of c‐Jun N‐terminal kinase‐1 (JNK1) and signal transducer and activator of transcription 3 (Stat3), individual knockdown of which upregulated the treatment‐increased expression of 14‐3‐3σ and promoted the centrosome amplification. In contrast, overexpression of JNK1 inhibited the centrosome amplification. Knockdown of Stat3 enhanced the centrosome translocation of 14‐3‐3σ. Moreover, we showed that knockdown of JNK1 inhibited the treatment‐increased expression of Stat3. Knockdown of PCNA, JNK1, or Stat3 did not have an effect on NPM and vice versa. In conclusion, our results suggest that PCNA and JNK1‐Stat3 pathways respectively promotes and feedback inhibits the centrosome amplification by targeting at the ROCK1/14‐3‐3σ complex, and NPM serves as an independent signal for the centrosome amplification. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27813   open full text
• CircRNA ZNF609 functions as a competitive endogenous RNA to regulate FOXP4 expression by sponging miR‐138‐5p in renal carcinoma.
  Yunhe Xiong, Jiabin Zhang, Chao Song.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Our research indicates that circRNA ZNF609 (circ‐ZNF609) functions as a competitive endogenous RNA to regulate forkhead box P4 expression by sponging microRNA‐138‐5p has great significance in the pathogenesis of renal carcinoma. Therefore, further study of circRNA may have clinical implications for future diagnosis and treatment of renal carcinoma and other diseases. Abstract Circular RNA (circRNA) play important roles in the pathological processes of many diseases. By analyzing the results of the GSE100186 chip, we found that the expression of circRNA ZNF609 (circ‐ZNF609) was significantly increased in renal cell carcinoma. Recently, there are studies showing that circ‐ZNF609 can regulate cell proliferation and invasion ability of various cells. In this study, we investigated whether circ‐ZNF609 may affect cell invasion and proliferation in renal carcinoma. Quantitative reverse transcription polymerase chain reaction was performed to detect the expression of circ‐ZNF609 in renal carcinoma cell lines and renal epithelial cells. The direct interaction between microRNA‐138‐5p (miR‐138‐5p) and forkhead box P4 (FOXP4) or circ‐ZNF609 was confirmed by luciferase reporter assay and RNA immunoprecipitation assay. We use Cell Counting Kit‐8, 5‐ethynyl‐2′‐deoxyuridine, and Matrigel assays to assess the effect of miR‐138‐5p or circ‐ZNF609 on cell proliferation or invasion ability. And we found that circ‐ZNF609 is significantly increased in renal carcinoma cell lines. In addition, the high expression of circ‐ZNF609 promotes cell proliferation and invasion ability. In short, our current study reveals the role of the circ‐ZNF609/miR‐138‐5p/FOXP4 regulatory network in renal carcinoma and provides a new perspective for the pathogenesis of renal carcinoma. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27744   open full text
• Active vitamin D regulates macrophage M1/M2 phenotypes via the STAT‐1‐TREM‐1 pathway in diabetic nephropathy.
  Xiaoliang Zhang, Yu Zhao, Xiaodong Zhu, Yinfeng Guo, Ying Yang, Yuteng Jiang, Bicheng Liu.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2 Vitamin D can inhibit macrophage transition to the M1 phenotype through the STAT‐1/TREM‐1 pathway. Abstract Aim Imbalance of M1/M2 macrophages phenotype activation is a key point in diabetic nephropathy (DN). This study aimed to investigate whether active vitamin D (VD) suppresses macrophage transition to the M1 phenotype via inhibiting the high glucose‐induced STAT‐1 phosphorylation to reduce TREM‐1 expression. Methods In vivo, pathological changes in kidney tissue were detected and the expression of CD68 TREM‐1, STAT‐1, M1 makers, and M2 makers were acquired in renal tissue of patients with DN and 18w DN rats. In vitro, RAW 264.7 cells were incubated in the presence of high glucose with or without VD. Silencing and overexpression of TREM‐1 and silencing and activate of STAT‐1 were explored to elucidate the underlying mechanism. The expression of TREM‐1 and STAT‐1 and the changes of macrophage phenotype were examined separately by western blot and immunofluorescence staining. Results (a) Expression of TREM‐1, p‐STAT‐1, and M1 markers (iNOS and TNF‐α) were increased and positively correlated in kidneys from patients with DN. (b) In DN rats, the enlargement of glomerular surface area, expansion of glomerular mesangial matrix, the expression of CD68, TREM‐1, p‐STAT‐1, and M1 marker (iNOS) were significantly increased in comparison with the normal control group, whereas above changes were markedly decreased in the diabetic group treated with the VD group. (c) In vitro, VD significantly decreased high glucose‐induced CD68, TREM‐1, p‐STAT‐1, and M1 marker (iNOS) expression. However, above‐mentioned effects of VD are abolished when TREM‐1 is overexpressed or STAT‐1 is activated. Reductions in STAT‐1 expression decreased the TREM‐1 expression. Conclusion VD can inhibit macrophage transition to the M1 phenotype through the STAT‐1/TREM‐1 pathway. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27450   open full text
• Molecular interaction of NFκB and NICD in monocyte–macrophage differentiation is a target for intervention in atherosclerosis.
  Ambika Binesh, Sivasithamparam Niranjali Devaraj, Devaraj Halagowder.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Inhibition of NFκB regulated notch intracellular domain (NICD), which, in turn, downturned macrophage differentiation. Inhibition of both NFκB–NICD is a potential target for intervention in early stage of atherosclerosis (monocyte to macrophage differentiation), to prevent the furtherance of disease. Abstract The activation of two transcription factors, NFκB and NICD (notch intracellular domain), plays a crucial role in different stages of atherosclerotic disease progression, from early endothelial activation by modified lipids like oxidized low‐density lipoprotein (oxyLDL) to the imminent rupture of the atherosclerotic plaque. Inflammatory mediators and the notch pathway proteins were upregulated in atherogenic diet‐induced rats and the same was confirmed by the differentiation of monocyte to macrophage on exposure to oxyLDL. The inflammatory transcription factor NFκB and the notch signaling transcription factor NICD were analysed for their molecular interaction in monocyte to macrophage differentiation. Inhibition of NFκB by dexamethasone in monocyte to macrophage differentiation resulted in a concomitant downregulation of NICD, whereas inhibition of NICD by N‐(N‐[3, 5‐difluorophenacetyl])‐l‐alanyl)‐S‐phenylglycine t‐butyl ester (DAPT), a γ–secretase inhibitor, did not significantly influence the expression of NFκB, but downregulated macrophage differentiation. These findings revealed that NFκB inhibition using dexamethasone regulated NICD, which turned down macrophage differentiation. Thus, inhibition of both NFκB–NICD is a potential target for intervention in atherosclerosis. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27458   open full text
• G protein‐coupled receptor 119 is involved in RANKL‐induced osteoclast differentiation and fusion.
  Hyun‐Ju Kim, Hye‐Jin Yoon, Ji‐Wan Park, Xiangguo Che, Xian Jin, Je‐Yong Choi.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- G protein‐coupled receptor 119 (GPR119) activation inhibits osteoclastogenesis and fusion induced by receptor activator of nuclear factor‐κB ligand (RANKL). GPR119 may become a new target for the treatment of bone‐erosive diseases characterized by increased osteoclast number. Abstract G protein‐coupled receptor 119 (GPR119) is known to be a promising therapeutic target for type 2 diabetes. Recently, it has been reported that the GPR119 agonist increases bone mineral density in an animal model of diabetes, suggesting that GPR119 may play a key role in bone metabolism. In this study, we investigated the functional role of GPR119 in receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclast formation. We found that the GPR119 expression was markedly increased in preosteoclasts and then downregulated in mature osteoclasts. Activation of GPR119 with AS1269574, a potent selective agonist for GPR119, inhibited the generation of multinuclear osteoclasts from bone marrow‐derived macrophages. Confirming this observation, targeted silencing of GPR119 using short hairpin RNA abrogated the AS1269574‐mediated suppressive effect on osteoclast formation. GPR119 activation attenuated the expression of c‐Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and blocked RANKL‐stimulated phosphorylation of IκBα, c‐Jun N‐terminal protein kinase (JNK), and extracellular signal‐regulated kinase (ERK) but not p38. In addition, GPR119 activation suppressed preosteoclast fusion by downregulating the expression of the dendritic cell‐specific transmembrane (DC‐STAMP), a molecule that is essential for cell–cell fusion in osteoclast formation. Furthermore, ectopic expression of DC‐STAMP restored AS1269574‐mediated inhibition of osteoclast fusion. Taken together, our findings demonstrate that GPR119 plays a negative role in osteoclast differentiation and fusion induced by RANKL, and therefore may represent a potential target for bone resorption‐associated diseases. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27805   open full text
• MicroRNA: A new player in response to therapy for colorectal cancer.
  Mostafa Sarvizadeh, Ziba V. Malekshahi, Ebrahim Razi, Hossein Sharifi, Nousin Moussavi, Mohsen Taghizadeh.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2 Abstract Colorectal cancer (CRC) is one of the important malignancies that result in cancer‐related deaths worldwide. Multiple lines of evidence have indicated that different responses to therapy in CRC cells led to the failure of the current therapies. Hence, identification of the underlying cellular and molecular pathways involved in the emergence of different responses from CRC cells could contribute to finding and designing new therapeutic platforms to overcome the present limitations. Among the various targets involved in CRC pathogenesis, microRNAs (miRNAs) have key roles in many signaling pathways that are associated with the initiation and progression of CRC. Increasing evidence has confirmed that miRNAs as epigenetic regulators could play critical roles in the response (resistance or sensitivity) to therapy. Cancer stem cells are well‐known players in resistance to therapy in CRC. They have been shown to play significant roles via inhibition and activation of many miRNA networks. Hence, miRNAs could be involved in the resistance and sensitivity of therapy in CRC cells via affecting different mechanisms, such as activation of cancer stem cells. Here, we summarized the role of various miRNAs in response to therapy of CRC cells. Moreover, we highlighted the roles of these molecules in the function of cancer stem cells, which are known as important players in the resistance to therapy in CRC. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27806   open full text
• Downregulation of microRNA‐592 protects mice from hypoplastic heart and congenital heart disease by inhibition of the Notch signaling pathway through upregulating KCTD10.
  Xue‐Feng Pang, Xue Lin, Jian‐Jun Du, Ding‐Yin Zeng.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- This study demonstrates that downregulation of miR‐592 prevents CHD and hypoplastic heart by inhibition of the Notch signaling pathway via negatively binding to KCTD10. Abstract Evidence has demonstrated that the microRNA (miR) may play a significant role in the development of congenital heart disease (CHD). Here, we explore the mechanism of microRNA‐592 (miR‐592) in heart development and CHD with the involvement of KCTD10 and Notch signaling pathway in a CHD mouse model. Cardiac tissues were extracted from CHD and normal mice. Immunohistochemistry staining was performed to detect positive expression rate of KCTD10. A series of inhibitor, activators, and siRNAs was introduced to verified regulatory functions for miR‐592 governing KCTD10 in CHD. Furthermore, the effect of miR‐592 on cell proliferation and apoptosis was also investigated. Downregulated positive rate of KCTD10 was observed in CHD mice. Downregulation of miR‐592 would upregulate expression of KCTD10 and inhibit the activation of Notch signaling pathway, thus promote cell proliferation. This study demonstrates that downregulation of miR‐592 prevents CHD and hypoplastic heart by inhibition of the Notch signaling pathway via negatively binding to KCTD10. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27190   open full text
• α‐2‐Macroglobulin induces the shedding of microvesicles from cutaneous wound myofibroblasts.
  Alexandra Laberge, Akram Ayoub, Syrine Arif, Sébastien Larochelle, Alain Garnier, Véronique J. Moulin.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- α‐2‐Macroglobulin positively regulates microvesicle shedding through the activation of low‐density lipoprotein receptor‐related protein‐1 on myofibroblasts. Abstract Microvesicles (MVs) are recognized as an important class of cell‐to‐cell messengers. Although the properties of MVs are increasingly documented, the mechanisms regulating MV biogenesis remain debated. Myofibroblasts are a key cellular component of wound healing and have been shown to produce MVs upon stimulation with serum. However, the mediator(s) responsible for the observed effect of serum on MV release have yet to be identified. To isolate the molecule(s) of interest, serum proteins were sequentially separated using chromatography, selective precipitation, and electrophoresis. MV production was assessed throughout the purification and after stimulation of myofibroblasts with two potent purified molecules. α‐2‐Macroglobulin (A2M) was thereby found to dose‐dependently stimulate MV release. We confirmed the presence of the A2M receptor, low‐density lipoprotein receptor‐related protein‐1 (LRP1), on myofibroblasts. Inhibition of LRP1 resulted in a significant decrease in MV production. Together, our results suggest that A2M positively regulates MV shedding through the activation of LRP1 on myofibroblasts. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27794   open full text
• Central adiponectin induces trabecular bone mass partly through epigenetic downregulation of cannabinoid receptor CB1.
  Hua Jiang, Yuwei Wu, Paloma Valverde, Dana Murray, Jin Tang, Qi Yao, Qianqian Han, Jin Zhang, Lan Zhang, Lei Sui, Yin Tang, Qisheng Tu, Jake Chen.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- 1.Globular adiponectin (gAPN) enhanced expression levels of various histone deacetylases (HDACs), especially HDAC5. 2.Chromatin immunoprecipitation assays revealed HDAC5 bound to the transcriptional start site 2 (TSS2) region of the CB1 promoter. 3.Our study identified a possible novel central APN‐HDAC5‐CB1 signaling mechanism that promotes peripheral bone formation through epigenetic regulation of hypothalamic CB1 expression. Abstract Central adiponectin (APN) in either the globular (gAPN) or full‐length forms decreases sympathetic tone and increases trabecular bone mass in mice through the hypothalamus. It is known that cannabinoid type‐1 (CB1) receptors are expressed in the hypothalamic ventromedial nucleus and participate in energy metabolism by controlling sympathetic activity. However, whether central APN could influence endocannabinoid signaling through CB1 receptor to regulate bone metabolism has not been characterized. Here we demonstrate that gAPN downregulated CB1 expression in embryonic mouse hypothalamus N1 cells in vitro. gAPN intracerebroventricular (icv) infusions also decreased hypothalamic CB1 expression and bone formation parameters in APN‐knockout (APN‐KO) and wild‐type mice. Most importantly, mice pretreated with icv infusions with the CB1 receptor agonist arachidonyl‐2′‐chloroethylamine or antagonist rimonabant attenuated or enhanced respectively central APN induction of bone formation. We then investigated whether epigenetic signaling mechanisms were involved in the downregulation of hypothalamic CB1 expression by gAPN. We found gAPN enhanced expression levels of various histone deacetylases (HDACs), especially HDAC5. Furthermore, chromatin immunoprecipitation assays revealed HDAC5 bound to the transcriptional start site transcription start site 2 region of the CB1 promoter. In summary, our study identified a possible novel central APN‐HDAC5‐CB1 signaling mechanism that promotes peripheral bone formation through epigenetic regulation of hypothalamic CB1 expression. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27460   open full text
• A novel infram deletion in MSH6 gene in glioma: Conversation on MSH6 mutations in brain tumors.
  Zeinab Deris Zayeri, Maryam Tahmasebi Birgani, Javad Mohammadi Asl, Davood Kashipazha, Mohammadreza Hajjari.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2 1. Making a connection between the genetic profiles and the evolved pathways and therapeutic approaches enhance our vision in estimating the results beyond the treatment. 2. our patients revealed a homozygous pattern for a novel 9 base‐pare deletion at the 912–914 codon on exon 4 of the MSH6 gene. 3. In temozolomide (TMZ)‐resitance cases, it is suggested to use complementary strategies Abstract Objective and background Histological and molecular information and biopsy help in the diagnosis of the type and grade of tumors and increase the value of estimation of the biological behavior of tumors. In this study, we focused on a consanguineous Iranian Family with high prevalence of brain tumors in their pedigree and reviewed the literature on MSH6 mutations in brain tumors and the treatment responses focused on Gliomas. Method We chose a family with a high prevalence of brain tumor in their pedigree. We studied the proband's neuroimaging and brain proton magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), biopsy result, and whole‐genome sequencing. Result The neuroimaging and brain proton MRS reported a lesion in the right frontoparietal. The MRI revealed a large enhancible heterogenous mass in the right temporo‐fronto‐parieto‐occipital lobes with involvement of corpus callosum which was suggestive of glioma. The patient revealed a homozygous pattern for a novel 9 base‐pare deletion at the 912–914 codon on exon 4 of the MSH6 gene. Discussion We discuss several studies on MSH6 mutations in brain tumors and we discuss treatment responses in MSH6 mutations and the studies conducted to sensitize chemotherapy and radiotherapy resistance brain tumors to face this subject efficiently. Conclusion Patients should be evaluated for MMR mutation before chemo and radiotherapy, and it is valuable to follow‐up these mutations during the treatment too. In temozolomide (TMZ)‐resitance cases, it is suggested to use complementary strategies such as using HDACis and a combination of a STAT3 Inhibitor and an mTOR inhibitor, BER inhibition mechanism, and PARP‐1 inhibitor. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27759   open full text
• Identification of functional lncRNAs in atrial fibrillation by integrative analysis of the lncRNA‐mRNA network based on competing endogenous RNAs hypothesis.
  Cheng Qian, Hang Li, Danqi Chang, Baozhu Wei, Yanggan Wang.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- In this study, we identified eight functional long noncoding RNAs (lncRNAs) for atrial fibrillation based on competing endogenous RNA (ceRNA) hypothesis. These eight lncRNAs showed a good diagnostic power for atrial fibrillation (AF) and could be used as potential biomarkers Abstract A mounting body of evidence has suggested that long noncoding RNAs (lncRNAs) play critical roles in human diseases by acting as competing endogenous RNAs (ceRNAs). However, the functions and ceRNA mechanisms of lncRNAs in atrial fibrillation (AF) remain to date unclear. In this study, we constructed an AF‐related lncRNA‐mRNA network (AFLMN) based on ceRNA theory, by integrating probe reannotation pipeline and microRNA (miRNA)‐target regulatory interactions. Two lncRNAs with central topological properties in the AFLMN were first obtained. By using bidirectional hierarchical clustering, we identified two modules containing four lncRNAs, which were significantly enriched in many known pathways of AF. To elucidate the ceRNA interactions in certain disease or normal condition, the dysregulated lncRNA‐mRNA crosstalks in AF were further analyzed, and six hub lncRNAs were obtained from the network. Furthermore, random walk analysis of the AFLMN suggested that lncRNA RP11‐296O14.3 may function importantly in the pathological process of AF. All these eight lncRNAs that were identified from previous steps (RP11‐363E7.4, GAS5, RP11‐410L14.2, HAGLR, RP11‐421L21.3, RP11‐111K18.2, HOTAIRM1, and RP11‐296O14.3) exhibited a strong diagnostic power for AF. The results of our study provide new insights into the functional roles and regulatory mechanisms of lncRNAs in AF, and facilitate the discovery of novel diagnostic biomarkers or therapeutic targets. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27819   open full text
• Cardiovascular complications and related risk factors underlying opium consumption.
  Reyhaneh T. Ebdali, Seyyedeh Samaneh Tabaee, Samira Tabaei.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Opium might have deleterious influences on cardiovascular events. As a result, people need to be trained with regard to the adverse effects of opium on cardiovascular events. It may cause hypertension, dyslipidemia, and hormonal abnormalities. Abstract Opium is considered as the second most abused addictive compound in worldwide. It seems that one of the causes for common consumption of opium in many countries is a traditional belief, even among medical personnel, through which opium might have advantageous influences on cardiovascular events and be beneficial in controlling hypertension, dyslipidemia, and diabetes. According to several investigations, it is thought that opium not only has no beneficial effects on cardiovascular events, but it might have deleterious influences on these settings. As a result, people need to be trained with regard to the adverse effects of opium on cardiovascular events. In this review, we try to go through the understanding of the effects of opium cardiovascular disorders and related complications such as blood pressure, blood sugar, lipid circumstances, and finally atherosclerosis. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27780   open full text
• Inhibition of miR‐124 improves neonatal necrotizing enterocolitis via an MYPT1 and TLR9 signal regulation mechanism.
  Yiyu Yin, Zhenfang Qin, Xiaobing Xu, Xu Liu, Huaxin Zou, Xiaole Wu, Junhua Cao.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2 miR‐124 was a promoter of necrotizing enterocolitis (NEC), which promotes the intestine cell apoptosis and inflammatory cell infiltration through the inhibition of Toll‐like receptor 9 (TLR9) expression by targeting rho‐associated coiled‐coil‐containing protein kinase 1 (ROCK1). Abstract Backgrounds Necrotizing enterocolitis (NEC) was one of the main causes of morbidity and mortality in neonates. Our objective was to detect the mechanism of miR‐124 in small bowel tissues of NEC. Methods Hematoxylin and eosin (H&E) staining was used to detect the repair of the damaged tissues in rat NEC model. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to evaluate the cell apoptosis level in intestinal tissue. Reverse transcription polymerase chain reaction (RT‐PCR) was used to detect the messenger RNA (mRNA) expression level of miR‐124, Rho‐associated coiled‐coil‐containing protein kinase 1 (ROCK1), myosin phosphatase target subunit 1 (MYPT1), and Toll‐like receptor 9 (TLR9) in NEC tissues and IEC‐6 cells. Luciferase reporter assay was used to verify whether ROCK1 is a direct target of miR‐124. Results miR‐124 was overexpressed in the NEC tissues, while ROCK1 and MYPT1 was downregulated in the NEC tissues. Inhibition of miR‐124, suppressed the intestinal cell apoptosis and promoted the expression of ROCK1 and MYPT1. What is more, overexpression of miR‐124 could inhibit the expression of ROCK1, TLR9, and MYPT1. Luciferase assay confirmed that miR‐124 can regulate the transcriptional activity of ROCK1 through binding its 3′‐UTR region. Conclusion miR‐124 was a promoter of NEC, which promotes the intestine cell apoptosis and inflammatory cell infiltration through the inhibition of TLR9 expression by targeting ROCK1. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27691   open full text
• MicroRNA‐99b suppresses human cervical cancer cell activity by inhibiting the PI3K/AKT/mTOR signaling pathway.
  Yong‐Jie Li, Yue Wang, Yi‐Ying Wang.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- These results indicate that miR‐99b attenuates the migration and invasion of human cervical cancer cells through downregulation of the phosphatidylinositol 3‐kinase/protein kinase B/mechanistic target of rapamycin signaling pathway, which provides a therapeutic approach for cervical cancer treatment. Abstract Cervical cancer is common cancer among women with high morbidity. MicroRNAs (miRs) are involved in the progression and development of cervical cancer. This study aimed to explore the effect of miR‐99b‐5p (miR‐99b) on invasion and migration in cervical cancer through the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway. The microarray‐based analysis was used to screen out differentially expressed miRNAs. Expression of miR‐99b, PI3K, AKT, mTOR, and ribosomal protein S6 kinase (p70S6K) was determined in both cervical cancer tissues and paracancerous tissues. Next, alteration of miR‐99b expression in cervical cancer was conducted to evaluate levels of PI3K, AKT, mTOR, p70S6K matrix metallopeptidase 2, epithelial cell adhesion molecule, and intercellular adhesion molecule 1, as well as the effect of miR‐99b on cell proliferation, invasion, migration, cell cycle distribution, and apoptosis. The results demonstrated that miR‐99b expression was decreased and levels of PI3K, AKT, mTOR, and p70S6K were elevated in cervical cancer tissues. More important, overexpressed miR‐99b repressed the PI3K/AKT/mTOR signaling pathway, inhibited cell proliferation, invasion, and migration, blocked cell cycle entry, and promoted apoptosis in cervical cancer. These results indicate that miR‐99b attenuates the migration and invasion of human cervical cancer cells through downregulation of the PI3K/AKT/mTOR signaling pathway, which provides a therapeutic approach for cervical cancer treatment. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27645   open full text
• Altered plasma proteins released from platelets and endothelial cells are associated with human patent ductus arteriosus.
  Hai‐Tao Hou, Xi‐Zhang, Jun Wang, Li‐Xin Liu, Jian‐Feng Zhang, Qin Yang, Guo‐Wei He.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Ductus arteriosus closure involves functional and structural remodeling, controlled by many factors and we for the first time demonstrate six key differential plasma proteins in human patent ductus arteriosus patients using proteomic technology and present a model to illustrate the constriction and closure of ductus arteriosus. Those proteins are closely related to platelet activation and coagulation cascades, complement mannan‐binding‐lectin, and other systemic signaling pathways. Our findings for the first time indicate that the differential proteins involved in different pathways may play key roles in the nonclosure of the ductus arteriosus in humans and may be developed as biomarkers for diagnosis. All those findings may be served as the basis of understanding the etiology and pathogenesis of patent ductus arteriosus. Abstract Patent ductus arteriosus is the third most common congenital heart disease and resulted from the persistence of ductal patency after birth. Ductus arteriosus closure involves functional and structural remodeling, controlled by many factors. The changes in plasma protein levels associated with PDA closure are not known. Here we for the first time demonstrate six key differential plasma proteins in human patent ductus arteriosus patients using proteomic technology and present a model to illustrate the constriction and closure of ductus arteriosus. Differentially expressed proteins were analyzed by using isobaric tags for relative and absolute quantification and validated by enzyme‐linked immunosorbent assay in new samples. The proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD008568. We found 74 upregulated and 98 downregulated proteins in the plasma of patients with PDA. Five decreased proteins (platelet factor 4, fibrinogen, von Willebrand factor, collagen, and mannose binding lectin‐associated serine protease‐2) and one increased protein (fibronectin) may increase the risk of patent ductus arteriosus. Those proteins are closely related to platelet activation and coagulation cascades, complement mannan‐binding‐lectin, and other systemic signaling pathways. Our findings for the first time indicate that the differential proteins involved in different pathways may play key roles in the nonclosure of the ductus arteriosus in humans and may be developed as biomarkers for diagnosis. All those findings may be served as the basis of understanding the etiology and pathogenesis of patent ductus arteriosus. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27433   open full text
• The possible role of bacteria, viruses, and parasites in initiation and exacerbation of irritable bowel syndrome.
  Aref Shariati, Fateme Fallah, Ali Pormohammad, Ali Taghipour, Hossein Safari, Alireza salami chirani, Sahar Sabour, Mahmood Alizadeh‐Sani, Taher Azimi.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Irritable bowel syndrome (IBS) is a prolonged and disabling functional gastrointestinal disorder with the incidence rate of 18% in the world. The pathophysiology of the IBS is hardly understood, whereas several possible mechanisms, such as visceral hypersensitivity, irregular gut motility, abnormal brain–gut relations, and the role of infectious agents, are implicated in initiation and development this syndrome. It appears that the main obligatory pathogens correspond with the IBS disease. Abstract Irritable bowel syndrome (IBS) is a prolonged and disabling functional gastrointestinal disorder with the incidence rate of 18% in the world. IBS could seriously affect lifetime of patients and cause high economic burden on the community. The pathophysiology of the IBS is hardly understood, whereas several possible mechanisms, such as visceral hypersensitivity, irregular gut motility, abnormal brain–gut relations, and the role of infectious agents, are implicated in initiation and development of this syndrome. Different studies demonstrated an alteration in B‐lymphocytes, mast cells (MC), T‐lymphocytes, and cytokine concentrations in intestinal mucosa or systemic circulation that are likely to contribute to the formation of the IBS. Therefore, IBS could be developed in those with genetic predisposition. Infections’ role in initiation and exacerbation of IBS has been investigated by quite several clinical studies; moreover, the possible role of some pathogens in development and exacerbation of this disease has been described. It appears that the main obligatory pathogens correspond with the IBS disease, Clostridium difficile, Escherichia coli, Mycobacterium avium subspecies paratuberculosis, Campylobacter concisus, Campylobacter jejuni, Chlamydia trachomatis, Helicobacter pylori, Pseudomonas aeruginosa, Salmonella spp, Shigella spp, and viruses, particularly noroviruses. A number of pathogenic parasites (Blastocystis, Dientamoeba fragilis, and Giardia lamblia) may also be involved in the progression and exacerbation of the disease. Based on the current knowledge, the current study concludes that the most common bacterial, viral, and parasitic pathogens may be involved in the development and progression of IBS. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27828   open full text
• Cell fate regulation by reticulon‐4 in human prostate cancers.
  Hu Zhao, Weipeng Su, Changyan Zhu, Tengyue Zeng, Shunliang Yang, Weizhen Wu, Dong Wang.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Our results showed that reticulon‐4 (RTN4) was downregulated and targeted by miR‐148a‐3p, and inhibited prostate cancer cell proliferation by inducing cell cycle arrest and senescence, suggesting that RTN4 may be an important molecular event linked to prostate cancer. Abstract Reticulon‐4 (RTN4), a reticulon family protein localized in the endoplasmic reticulum, is reported to be involved in multiple physiological processes like neuroendocrine secretion and membrane trafficking in neuroendocrine cells. Previous studies have presented a great potential of RTN4 for the treatment of autoimmune‐mediated demyelinating diseases and spinal cord injury regeneration. While interaction with Bcl‐2 and Bcl‐2‐like family in apoptosis modulation implicated its possible role in various human cancers. However, the investigation of this gene in prostate cancer is mainly ignored. Here in our current study, we focused on its role in prostate cancer and found that RTN4 DNA copy numbers were higher in prostate cancer than normal prostate gland while its RNA and protein expressions were relatively lower. Chromosomal neighbor gene EML6 had similar expression patterns with RTN4 in prostate cancer tissues and cell lines, and further research found that they could be both targeted by miR‐148a‐3p. Lentivirus‐mediated RTN4 overexpression potently inhibited DU145 and LNCaP cells proliferation. Cell cycle was blocked in G2/M phase and significant cell senescence was observed in RTN4 overexpressed prostate cancer cells. Finally, interaction networks in the normal prostate gland and cancer tissues further revealed that RTN4 maybe phosphorylated by MAPKAPK2 and FYN at tyrosine 591 and serine 107, respectively. All these results implied that RTN4 might somehow participate in prostate tumor progression, and this elicits possibility to develop or identify selective agents targeting RTN4 for prostate cancer therapy. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27704   open full text
• Effects of nebulized N­‐acetylcystein on the expression of HMGB1 and RAGE in rats with hyperoxia‐­induced lung injury.
  Junying Qiao, Lixia Chen, Xianjie Huang, Feifei Guo.
  Journal of Cellular Physiology. November 27, 2018
  --- - "\nHigh mobility group box 1 (HMGB1) and receptor for advanced glycation end product (RAGE) were involved in the pathogenesis of hyperoxia‐induced lung injury, inhalation of N‐acetylcysteine might alleviate hyperoxia‐induced lung injury by regulating the expression of HMGB1 and RAGE. \n\n\n\n\n\n\nAbstract\n\nObjective\nTo investigate the role of high mobility group box 1 (HMGB1) and receptor for advanced glycation end product (RAGE) in the lungs of hyperoxia‐induced rats and the effect of N‐­acetlycystein (NAC).\n\n\nMethods\nA model of hyperoxic lung injury was established, rats in the NAC intervention, and control, hyperoxia group were given nebulized NAC aerosol, nebulized same volume of saline once a day for 7 consecutive days, respectively. Wet/dry (\nW/\nD) ratio of the lungs was determined to evaluate the edema of the lung tissues. Conventional hematoxylin–eosin (HE) staining was used to observe the pathological changes of lung tissues. Immunohistochemical staining was used to investigate the expression of HMGB1 and RAGE in the lung tissues. Quantitative reverse‐transcription polymerase chain reaction and western blot analysis were used to measured the changes in the messenger RNA (mRNA) and protein expression of HMGB1 and RAGE, respectively.\n\n\nResults\nWeight gain of the rats in the hyperoxia group was significantly slower than that in the control group and intervention group (p < 0.05). HE staining results showed lung tissues in the hyperoxia group were severely damaged compared with control group. W/D ratio in hyperoxia group was significantly higher than that in control group and intervention group (p < 0.05). Protein and mRNA expression of HMGB1 and RAGE in the hyperoxia group were significantly higher than control group and intervention group (p < 0.05).\n\n\nConclusion\nHMGB1 and RAGE were involved in the pathogenesis of hyperoxia‐induced lung injury, inhalation of NAC might alleviate hyperoxia‐induced lung injury by regulating the expression of HMGB1 and RAGE.\n" - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27724   open full text
• Cholinergic activity regulates the secretome of epicardial adipose tissue: Association with atrial fibrillation.
  Marinela Couselo‐Seijas, Jose N. López‐Canoa, Rosa M. Agra‐Bermejo, Esther Díaz‐Rodriguez, Angel L. Fernandez, Jose M. Martinez‐Cereijo, Dario Durán‐Muñoz, Susana B. Bravo, Alba Velo, Laila González‐Melchor, Xesus A. Fernández‐López, Jose L. Martínez‐Sande, Javier García‐Seara, Jose R. González‐Juanatey, Moises Rodriguez‐Mañero, Sonia Eiras.
  Journal of Cellular Physiology. November 27, 2018
  --- - "\n\n\nMuscarinic receptor type 3 is upregulated after adipogenesis.\nEpicardial fat from atrium or ventricles express this receptor and contain cholinergic activity.\nEpicardial fat‐released proteins after cholinergic activity as possible predictors of postoperative AF\n\n\n\n\n\nAbstract\nBotulinum toxin injection on epicardial fat, which inhibits acetylcholine (ACh) release, reduced the presence of atrial fibrillation (AF) in patients after heart surgery. Thus, we wanted to study the profile of the released proteins of epicardial adipose tissue (EAT) under cholinergic activity (ACh treatment) and their value as AF predictors. Biopsies, explants, or primary cultures were obtained from the EAT of 85 patients that underwent open heart surgery. The quantification of muscarinic receptors (mAChR) by real‐time polymerase chain reaction or western blot showed their expression in EAT. Moreover, mAChR Type 3 was upregulated after adipogenesis induction (p < 0.05). Cholinergic fibers in EAT were detected by vesicular ACh transporter levels and/or acetylcholinesterase activity. ACh treatment modified the released proteins by EAT, which were identified by nano‐high‐performance liquid chromatography and TripleTOF analysis. These differentially released proteins were involved in cell structure, inflammation, or detoxification. After testing the plasma levels of alpha‐defensin 3 (inflammation‐involved protein) of patients who underwent open heart surgery (\nn = 24), we observed differential levels between the patients who developed or did not develop postsurgery AF (1.58 ± 1.61 ng/ml vs. 6.2 ± 5.6 ng/ml; \np < 0.005). The cholinergic activity on EAT might suggest a new mechanism for studying the interplay among EAT, autonomic nervous system dysfunction, and AF." - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27723   open full text
• Knockdown of NEAT1 repressed the malignant progression of glioma through sponging miR‐107 and inhibiting CDK14.
  Yingwei Zhen, Yang Nan, Shewei Guo, Longzhou Zhang, Ge Li, Saichao Yue, Xianzhi Liu.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- We found that inhibition of nuclear paraspeckle assembly transcript 1 (NEAT1) repressed glioma development via sponging miR‐107. The correlation between NEAT1 and miR‐107 was validated in our study, and cyclin dependent kinase 14 (CDK14) was targeted by miR‐107 by using bioinformatics analysis. All these data revealed that NEAT1/miR‐107/CDK14 axis was involved in glioma development Abstract Aberrant expressions of long noncoding RNAs (lncRNAs) contribute to carcinogenesis via regulating tumor suppressors or oncogenes. LncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been recognized as an oncogene to promote tumor progression of many cancers. However, the function of NEAT1 in glioma remains poorly discovered. Currently, we focused on the role of NEAT1 in glioma. Here, we found that NEAT1 was greatly upregulated in glioma cells compared with normal human astrocytes (NHAs). Meanwhile, miR‐107 was significantly downregulated in glioma cell lines. Then, we observed that knockdown of NEAT1 suppressed the growth and invasion of glioma cells including U251 and SW1783 cells. Reversely, overexpression of NEAT1 dramatically induced glioma cell survival, increased cell colony formation, and promoted cell invasion ability. Subsequently, bioinformatics analysis was performed to predict the correlation between NEAT1 and miR‐107. Moreover, it was revealed that NEAT1 could modulate miR‐107 via serving as an endogenous sponge of miR‐107. The direct binding correlation between NEAT1 and miR‐107 was validated in our study. In addition, cyclin dependent kinase 14 (CDK14) was predicted as an messenger RNA target of miR‐107 and the association between them was confirmed in our research. Moreover, we implied that NEAT1 demonstrated its biological functions via regulating miR‐107 and CDK14 in vivo. In summary, our findings indicated that NEAT1/miR‐107/CDK14 axis participated in glioma development. NEAT1 could act as a significant prognostic biomarker in glioma progression. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27727   open full text
• c‐Met inhibition is required for the celecoxib‐attenuated stemness property of human colorectal cancer cells.
  Yueh‐Ming Lin, Chien‐Chang Lu, Yi‐Ping Hsiang, Shu‐Chuan Pi, Chih‐I Chen, Kung‐Chuan Cheng, Hsiao‐Lin Pan, Pei‐Hsuan Chien, Yun‐Ju Chen.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- This is the first report that elucidates the mechanism underlying celecoxib‐inhibited cancer stem cell (CSC). c‐Met is identified as a critical factor for the CSC property of colorectal cancer cells. Abstract Cyclooxygenase‐2 (COX‐2) is frequently overexpressed and enhances colorectal cancer (CRC) tumorigenesis, including cancer stem cell (CSC) regulation. Accordingly, nonsteroidal anti‐inflammatory drugs (NSAIDs), inhibiting COX‐1/2 activity, are viewed as potential drugs for CRC treatment. Accumulated evidence indicates that celecoxib has the most potency for antitumor growth among NSAIDs and the underlying mechanism is only partly dependent on COX‐2 inhibition. However, the potency of these NSAIDs on CSC inhibition is still not known. In this study, we found that among these NSAIDs, celecoxib has the most potency for CSC inhibition of CRC cells, largely correlating to inhibition of c‐Met, not COX‐2. Further analysis reveals that c‐Met activity was required for basal CSC property. Silence of c‐Met blocked whereas overexpression of c‐Met enhanced the celecoxib‐inhibited CSC property. Collectively, these results not only first elucidate the mechanism underlying celecoxib‐inhibited CSC but also indicate c‐Met as a critical factor for the CSC property of CRC cells. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27701   open full text
• Preparation of adriamycin gelatin microsphere‐loaded decellularized periosteum that is cytotoxic to human osteosarcoma cells.
  Chuan Chen, Jianghui Dong, Hong Chen, Xin Wang, Jin Mei, Liping Wang, Cory J Xian.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- The effectiveness of these two scaffolds in killing human osteosarcoma cells was tested by evaluating cell viability overtime of the cancer cells cultured with the scaffolds. In summary, a gelatin/decellularized periosteum‐based biologic scaffold material was designed aiming for local delivery of chemotherapy drugs for osteosarcoma, with the results showing ability of the scaffolds in sustaining release of the cancer drug and in suppressing growth of the cancer cells in vitro Abstract The purpose of this study was to develop a novel approach to treat bone osteosarcoma using a multipurpose scaffold aiming for local drug delivery. The slowly releasing microspheres was designed to deliver the chemotherapy drug adriamycin (ADM) and a decellularized (D) periosteum scaffold (which is known to be able to promote bone regeneration) was used to carry these microspheres. D‐periosteum was obtained by physical and chemical decellularization. Histological results showed that the cellular components were effectively removed. The D‐periosteum showed an excellent cytocompatibility and the ability to promote adhesion and growth of fibroblasts. Two kinds of slowly releasing microspheres, adriamycin gelatin microspheres (ADM‐GMS) and adriamycin poly (dl‐lactide‐co‐glycolide) gelatin microspheres (ADM‐PLGA‐GMS), were prepared and anchored to D‐periosteum, resulting in two types of drug‐releasing regenerative scaffolds. The effectiveness of these two scaffolds in killing human osteosarcoma cells was tested by evaluating cell viability overtime of the cancer cells cultured with the scaffolds. In summary, a gelatin/decellularized periosteum‐based biologic scaffold material was designed aiming for local delivery of chemotherapy drugs for osteosarcoma, with the results showing ability of the scaffolds in sustaining release of the cancer drug and in suppressing growth of the cancer cells in vitro. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27753   open full text
• Embryo quality, and not chromosome nondiploidy, affects mitochondrial DNA content in mouse blastocysts.
  Ying Jing, Li Li, Yuan‐Yuan Li, Ying‐Chun Ouyang, Qing‐Yuan Sun, Cui‐Lian Zhang, Rong Li.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Mitochondria prematurely replicate in blastocysts from aged women and in nondiploidy blastocysts, which have decreased developmental potential. Here, we show that the cytoplasmic quality, and not chromosome ploidy, causes premature mitochondrial biogenesis in early embryo development. Abstract It has been shown recently that there is premature mitochondria biosynthesis in blastocysts from older women whose egg or embryo quality is poor and that aneuploid blastocysts also have a high number of mitochondrial DNA (mtDNA) copies. Whether nondiploidy/aneuploidy or reduced egg or embryo quality causes premature mitochondrial biosynthesis is not known. This study constructed haploid, diploid, triploid, and tetraploid blastocysts by parthenogenetic activation, intracytoplasmic sperm injection with one or two sperm heads, blastomere electrofusion, respectively, and generated reduced cytoplasm quality embryos from diabetic mouse and in vitro fertilization of aged oocytes, and examined whether nondiploidy or reduced cytoplasm quality causes premature mitochondrial biosynthesis. MtDNA numbers of each blastocyst from different models were tested by absolute quantitative real‐time polymerase chain reaction. It was found that mtDNA content in preimplantation embryos was not associated with their chromosome ploidy, while mtDNA copy numbers in embryos with suboptimal quality were increased. Therefore, it might be the reduced cytoplasmic quality, and not chromosome nondiploidy, that causes premature mitochondria biosynthesis in blastocysts. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27713   open full text
• miR‐142‐3p as tumor suppressor miRNA in the regulation of tumorigenicity, invasion and migration of human breast cancer by targeting Bach‐1 expression.
  Behzad Mansoori, Ali Mohammadi, Mehri Ghasabi, Solmaz Shirjang, Razeieh Dehghan, Vahid Montazeri, Uffe Holmskov, Tohid Kazemi, Pascal Duijf, Morten Gjerstorff, Behzad Baradaran.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2 Our results revealed that miR‐142‐3p could target Bach‐1in breast cancer cells leading to the reduction of EMT‐related proteins and reduced cell proliferation, invasion, and migration. The results also demonstrated that miR‐142‐3p could regulate important tumor suppressor miRNAs in breast cancer cells. The results suggest that miR‐142‐3p could be a good candidate for the targeted therapy of breast cancer, especially for the invasive type. Abstract Background Breast cancer is the most common type of cancer among women, and despite improved treatments, it remains a major challenge. However, improved mechanistic insight may lead to novel therapeutic strategies. miR‐142‐3p belongs to the miR‐142 family and is involved in pathogenesis and metastasis of various types of malignancies by targeting several important messenger RNAs (mRNAs) including Bach‐1. This is especially true for breast cancer, where Bach‐1 is involved in the metastatic spread by deregulation of metastasis‐associated genes. Methods In this study, we collected 24 breast cancer tissues with 24 adjusted normal tissues to measure the expression levels of miR‐142‐3p and Bach‐1 mRNA using quantitative reverse‐transcription polymerase chain reaction (qRT‐PCR) and IHC. miR‐142‐3p targeting of Bach‐1 expression in MCF‐7 and MDA‐MB‐468 breast cancer cells was evaluated using bioinformatics, qRT‐PCR and western blot analyses. The cellular proliferation, invasion, and migration were assessed by MTT, transwell matrigel and wound healing assay and the EMT‐associated proteins C‐X‐C chemokine receptor type 4 (CXCR‐4), matrix metalloproteinase‐9 (MMP9), and vascular endothelial growth factor receptor (VEGFR) were analyzed by western blot analysis. Also, the expression levels of tumor suppressors including miR‐330, miR‐145, and miR‐34a were estimated by qRT‐PCR. Results Analysis of paired specimens of primary malignant and normal tissues showed that miR‐142‐3p was downregulated, while Bach‐1 mRNA and protein both were overexpressed in the breast cancer tumors. This inverse relationship was confirmed by cell line experiments demonstrating that miR‐142‐3p expression reduced Bach‐1 mRNA levels. Furthermore, replacement of miR‐142‐3p could inhibit the proliferation, invasion, and migration in breast cancer potentially by targeting of Bach‐1 mRNA and subsequent inhibition of CXCR4, MMP9, and VEGFR protein expressions. In addition, induction of miR‐142‐3p could upregulate tumor suppressor miRNAs, including miR‐330, miR‐145, and miR34a. Conclusion For the first time, our results revealed that miR‐142‐3p could target Bach‐1in breast cancer cells leading to the reduction of EMT‐related proteins and reduced cell proliferation, invasion, and migration. The results also demonstrated that miR‐142‐3p could regulate important tumor suppressor miRNAs in breast cancer cells. In conclusion, our results suggest that miR‐142‐3p could be a good candidate for the targeted therapy of breast cancer, especially for the invasive type. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27670   open full text
• A novel multidimensional signature predicts prognosis in hepatocellular carcinoma patients.
  Song Wang, Jian‐Hua Zhang, Huan Wang, Lu Yang, Shuai Hong, Bo Yu, Jin‐Cheng Guo, Jing Liu, Yan‐Bing Zhu.
  Journal of Cellular Physiology. November 27, 2018
  --- - "\nUsing bioinformatics analysis methods including Cox’s proportional hazards regression analysis, the random survival forest algorithm, Kaplan–Meier and receiver operating characteristic curve analysis, we mined the gene expression profiles of 469 hepatocellular carcinoma (HCC) patients from The Cancer Genome Atlas (n = 379) and Gene Expression Omnibus (GSE14520; \nn = 90) public database and found a prognostic protein‐coding gene‐microRNA signature that predicts survival in patients with HCC patients. The signature has a bright clinical significance to be a potential prognostic biomarker.\n\n\n\n\n\nAbstract\nThe abnormal expression of microRNAs (miRNAs) or protein‐coding genes (PCGs) have been found to be associated with the prognosis of hepatocellular carcinoma (HCC) patients. Using bioinformatics analysis methods including Cox’s proportional hazards regression analysis, the random survival forest algorithm, Kaplan–Meier, and receiver operating characteristic (ROC) curve analysis, we mined the gene expression profiles of 469 HCC patients from The Cancer Genome Atlas (n = 379) and Gene Expression Omnibus (GSE14520; \nn = 90) public database. We selected a signature comprising one protein‐coding gene (PCG; DNA polymerase μ) and three miRNAs (hsa‐miR‐149‐5p, hsa‐miR‐424‐5p, hsa‐miR‐579‐5p) with highest accurate prediction (area under the ROC curve [AUC] = 0.72; \nn = 189) from the training data set. The signature stratified patients into high‐ and low‐risk groups with significantly different survival (median 27.9 vs. 55.2 months, log‐rank test, \np < 0.001) in the training data set, and its risk stratification ability were validated in the test data set (median 47.4 vs. 84.4 months, log‐rank test, \np = 0.03) and an independent data set (median 31.0 vs. 46.0 months, log‐rank test, \np = 0.01). Multivariable Cox regression analysis showed that the signature was an independent prognostic factor. And the signature was proved to have a better survival prediction power than tumor–node–metastasis (TNM) stage (AUC\nsignature = 0.72/0.64/0.62 vs. AUC\nTNM = 0.65/0.61/0.61; \np < 0.05). Moreover, we validated the expression of these prognostic genes from the PCG‐miRNA signature in Huh‐7 cell by real‐time polymerase chain reaction. In conclusion, we found a signature that can predict survival of HCC patients and serve as a prognostic marker for HCC." - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27818   open full text
• Human breast cancer decellularized scaffolds promote epithelial‐to‐mesenchymal transitions and stemness of breast cancer cells in vitro.
  Gang Liu, Biao Wang, Shubin Li, Qin Jin, Yanfeng Dai.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- In our study, human breast cancer biopsies were decellularized by the detergent technique with sodium lauryl ether sulfate (SLES) solution for the first time. Scaffolds seeded with MCF‐7 cells demonstrated the process of cell recellularization in vitro, with increased cell migration, proliferation, and epithelial‐to‐mesenchymal transition (EMT) process. When treated with 5‐fluorouracil (5‐Fu), the expressions of stem cell markers, including Oct4, Sox2, and CD49F, were maximally maintained in the recellularized scaffold with decreased apoptosis rates compared with monolayer cells. Abstract Breast cancer, with unsatisfactory survival rates, is the leading cause of cancer‐related death in women worldwide. Recent advances in the genetic basis of breast cancer have benefitted the development of gene‐based medicines and therapies. Tissue engineering technologies, including tissue decellularizations and reconstructions, are potential therapeutic alternatives for cancer research and tissue regeneration. In our study, human breast cancer biopsies were decellularized by a detergent technique, with sodium lauryl ether sulfate (SLES) solution, for the first time. And the decellularization process was optimized to maximally maintain tissue microarchitectures and extracellular matrix (ECM) components with minimal DNA compounds preserved. Histology analysis and DNA quantification results confirmed the decellularization effect with maximal genetic compounds removal. Quantification, immunofluorescence, and histology analyses demonstrated better preservation of ECM components in 0.5% SLES‐treated scaffolds. Scaffolds seeded with MCF‐7 cells demonstrated the process of cell recellularization in vitro, with increased cell migration, proliferation, and epithelial‐to‐mesenchymal transition (EMT) process. When treated with 5‐fluorouracil, the expressions of stem cell markers, including Oct4, Sox2, and CD49F, were maximally maintained in the recellularized scaffold with decreased apoptosis rates compared with monolayer cells. These results showed that the decellularized breast scaffold model with SLES treatments would help to simulate the pathogenesis of breast cancer in vitro. And we hope that this model could further accelerate the development of effective therapies for breast cancer and benefit drug screenings. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27630   open full text
• Identification of hsa‐mir‐34a, hsa‐mir‐124, and hsa‐mir‐204 as signatures for cataract.
  Ying‐Li Wei, Hao Sun.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Three key microRNAs (miRNAs) related to cataract pathogenesis are identified, and the corresponding target genes and transcription factors are also analyzed. Moreover, the potential functions of the target genes are revealed. The results in the study may contribute to the targeted therapy of cataract through miRNAs. Abstract Cataract, one of the common age‐related diseases that remains the leading cause of blindness worldwide. There have been studies pertaining to microRNA (miRNA) effects on cataract pathogenesis. However, the results were different from each other due to the influence of sequencing platform, sample selection, filter conditions, and so on. This study aims to explore the key miRNAs underlying the pathogenesis of cataract and find prevention and treatment methods. First, six representative cataract miRNA datasets are selected and the key miRNAs are determined. The target genes of these key miRNAs are predicted using the TargetScan software, and then, the functional enrichment and transcription factor binding analysis of these target genes are completed, respectively. Three signature miRNAs associated with cataract are finally identified. Among them, hsa‐mir‐34a seems to be significantly upregulated, while hsa‐mir‐124 and hsa‐mir‐204 are significantly downregulated. The target genes of the signature miRNAs are mainly enriched in hsa04015:Rap1 signaling pathway, hsa04142:lysosome, and hsa04360:axon guidance, indicating that these pathways may be the crucial metabolic pathways. To summarize, three key miRNAs related to cataract pathogenesis are identified, and the corresponding target genes and transcription factors are also analyzed. Moreover, the potential functions of the target genes are revealed. The results of this study may contribute to the targeted therapy of cataract through miRNAs. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27741   open full text
• Comparative study of laparoscopic‐assisted and open total gastrectomy for Siewert Types II and III adenocarcinoma of the esophagogastric junction.
  Jianchu Wang, Jin‐Cheng Wang, Bin Song, Xu‐Dong Dai, Xiao‐Yu Zhang.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2 Abstract Background The potential advantages of laparoscopic‐assisted total gastrectomy (LATG) compared with open total gastrectomy (OTG) for Siewert Types II and III adenocarcinoma of the esophagogastric junction (AEJ) are not very clear. Thus, the aim of this study was to investigate the surgical outcomes and potential advantages of LATG for Siewert Types II and III AEJ. Methods The clinical data of 75 patients (32 for LATG and 43 for OTG) with Siewert II or III AEJ from August 2009 to February 2014 were analyzed retrospectively. Patients were followed up by telephone or out‐patient examination till August 2015. Results Two groups of patients were successfully performed with no perioperative death. The mean operation time was 3.23 ± 0.35 hr in LATG group, longer than the OTG group 2.83 ± 0.51 hr. The mean intraoperative bleeding was 122.7 ± 50.6 ml, less than the OTG group 219.2 ± 85.2 ml. The analgesics use was 3.00 ± 0.67 times in the LATG group, less than the OTG group 3.43 ± 1.03 times. The gastrointestinal function recovery time was 2.69 ± 0.46 days in the LATG group, shorter than the OTG group 3.42 ± 0.86 days. The mean postoperative hospital stay was 12.94 + 2.76 days in the LATG group, less than the OTG group 14.57 + 2.35 days (p < 0.05). Conclusions LATG and OTG had no significant difference for Siewert II and III AEJ in terms of radical resection and tumor recurrence, but LATG is worthy to be promoted with less bleeding, less postoperative pain, faster recovery of gastrointestinal function, and shorter hospital stay. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27777   open full text
• SP1, MYC, CTNNB1, CREB1, JUN genes as potential therapy targets for neuropathic pain of brain.
  Xue‐Tao Yan, Yong Xu, Xiao‐Li Cheng, Xiang‐Hu He, Yu Wang, Wen‐Zhong Zheng, Ying Zhao, Hu Chen, Yan‐Lin Wang.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Our results suggested a potential application of SP1, MYC, CTNNB1, CREB1, and JUN genes as prognostic biomarkers in the clinical management of neuropathic pain, and two most important signaling pathways, immune response and reception reactions, were found to be closely related to the occurrence and development of neuropathic pain. The more specific mechanism of these genes with the brain tissue related to neuropathic pain stimulation needs further research. Abstract Neuropathic pain (NP) may cause serious brain diseases, but the genes associated with the metabolic pathway and transcript factors of NP remain unclear. This study is aimed to identify the therapy target genes for NP and to investigate the metabolic pathways and transcript factors associated with NP. The differentially expressed genes of three brain tissues (nucleus accumbens, periaqueductal gray, and prefrontal cortex) dealt with NP stimulation were analyzed. Besides, The Database for Annotation, Visualization, and Integrated Discovery and Tfacts datasets were used in the analysis of the genes related to the metabolic pathway and transcript factors of the brain. Eight genes were found to coexpress in all three tissues. A functional enrichment analysis showed that the upregulated genes were mostly enriched in pathways as inflammatory response, calcium‐mediated signaling, cytokine‐cytokine receptor interaction, and extracellular matrix (ECM)‐receptor interaction, whereas the downregulated genes were mostly enriched in pathways as phospholipid metabolic processes, positive regulation of protein kinase B signaling, and metabolism of xenobiotics by cytochrome P450. Finally, 135 and 98 transcript factors genes were upregulated and downregulated, among which SP1, MYC, CTNNB1, CREB1, JUN were identified as the most critical genes because the number of up‐ and downregulated gene ranked at the top. In conclusion, the pathways of immune response and cytokine‐cytokine receptor interaction were determined as the main metabolic pathways of NP affecting the brain, and SP1, MYC, CTNNB1, CREB1, JUN genes were recognized as the most enriched genes in this process, which may provide evidence for the diagnosis and treatment research of neuropathic pain. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27413   open full text
• Synergistic anticancer action of quercetin and curcumin against triple‐negative breast cancer cell lines.
  Sai Kundur, Amrita Prayag, Priyanga Selvakumar, Hung Nguyen, Lloyd McKee, Clairissa Cruz, Asha Srinivasan, Sunday Shoyele, Ashakumary Lakshmikuttyamma.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Women with the breast cancer type 1 susceptibility protein (BRCA1) mutation and loss of BRCA1 expression are reported to have an increased risk of triple‐negative breast cancer (TNBC). We detected that quercetin and curcumin dose‐dependently enhanced BRCA1 expression. Quercetin and curcumin appeared to induce BRCA1 promoter histone acetylation. Our present study concluded that the combination treatment of quercetin and curcumin acts synergistically to induce anticancer activity against TNBC cells by modulating tumor suppressor genes. Abstract Women with the breast cancer type 1 susceptibility protein (BRCA1) mutation and loss of BRCA1 expression are reported to have an increased risk of triple‐negative breast cancer (TNBC). Targeting BRCA1 modulation might offer a therapeutic option to treat TNBC patients. Our studies detected that BRCA1 is poorly expressed in TNBC cell lines and highly expressed in ER+ breast cancer cell lines. To modulate BRCA1 expression, we tested two different dietary components to find out if any would induce tumor suppressor genes. We detected that quercetin and curcumin dose‐dependently enhanced the BRCA1 expression. Further, a synergistic action of quercetin and curcumin was observed in modulating the BRCA1 level and in inhibiting the cell survival and migration of TNBC cell lines. Quercetin and curcumin appeared to induce BRCA1 promoter histone acetylation. Furthermore, BRCA1 knockdown induced cell survival and cell migration in ER + cells were significantly decreased by the combined treatment of quercetin and curcumin. Our present study concluded that the combination treatment of quercetin and curcumin acts synergistically to induce anticancer activity against TNBC cells by modulating tumor suppressor genes. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27761   open full text
• Induced pluripotent stem cell‐derived extracellular vesicles: A novel approach for cell‐free regenerative medicine.
  Behnaz Taheri, Masoud Soleimani, Sedigheh Fekri Aval, Elahe Esmaeili, Zahra Bazi, Nosratollah Zarghami.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- Extracellular vesicles contribute to the therapeutic effect of the stem cells, including stimulation of organ repair. The discovery of induced pluripotent stem cells represented a promising source for autologous extracellular vesicles generation to use in regenerative medicine. Abstract In recent years, induced pluripotent stem cells (iPSCs) have been considered as a promising approach in the field of regenerative medicine. iPSCs can be generated from patients’ somatic cells and possess the potential to differentiate, under proper conditions, into any cell type. However, the clinical application of iPS cells is restricted because of their tumorigenic potential. Recent studies have indicated that stem cells exert their therapeutic benefit via a paracrine mechanism, and extracellular vesicles have been demonstrated that play a critical role in this paracrine mechanism. Due to lower immunogenicity, easier management, and presenting no risk of tumor formation, in recent years, researchers turned attention to exosomes as potential alternatives to whole‐cell therapy. Application of exosomes derived from iPSCs and their derived precursor provides a promising approach for personalized regenerative medicine. This study reviews the physiological functions of extracellular vesicles and discusses their potential therapeutic benefit in regenerative medicine. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27775   open full text
• Glucagon attenuates lipid accumulation in cow hepatocytes through AMPK signaling pathway activation.
  Yu Li, Hongyan Ding, Jihong Dong, Sajid Ur Rahman, Shibin Feng, Xichun Wang, Jinjie Wu, Zhe Wang, Guowen Liu, Xiaobing Li, Xinwei Li.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- The ketotic cows displayed hepatic lipid metabolic disorder and high blood concentration of glucagon. The present study indicates that glucagon activates the AMPK signalling pathway to increase lipid oxidation and VLDL assembly and decrease lipid synthesis in cow hepatocytes, thereby reducing liver fat accumulation. Abstract The ketotic cows displayed hepatic lipid metabolic disorder and high blood concentration of glucagon. Importantly, adenosine monophosphate‐activated protein kinase (AMPK) signaling pathway plays an important role in the hepatic lipid homeostasis. Therefore, the aim of this study was to investigate the effect of glucagon on AMPK pathway and its underlying mechanism on lipid metabolism in cow hepatocytes. Cow hepatocytes were cultured and treated with glucagon and AMPK inhibitor (BML‐275). The results showed that glucagon significantly promoted the expression of glucagon receptor and increased the phosphorylation level and activity of AMPKα. Activated AMPKα increased the expression level and transcriptional activity of peroxisome proliferator‐activated receptor α, which further increased the expression of fatty acid oxidation genes and lipid oxidation. Furthermore, activated AMPKα inhibited the expression level and transcriptional activity of sterol regulatory element binding protein‐1c and carbohydrate response element binding protein, which decreased the expression of lipogenic genes, thereby decreasing lipid synthesis. In addition, glucagon also increased the expression of very‐low‐density lipoprotein (VLDL) assembly to export intracellular triglycerides (TG). Consequently, the content of intracellular TG was significantly decreased in cow hepatocytes. These results indicate that glucagon activates the AMPK signaling pathway to increase lipid oxidation and VLDL assembly and decrease lipid synthesis in cow hepatocytes, thereby reducing liver fat accumulation. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27258   open full text
• Comparative transcriptome analysis reveals PERP upregulated during Salmonella Enteritidis challenge in laying ducks.
  Yu Zhang, Tian‐tian Gu, Yang Chen, Yu Huang, Jinping Du, Lizhi Lu, Guo‐qiang Zhu, Qi Xu, Guo‐hong Chen.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2- The PERP overexpression resulted in an increased induction of p53, MDM2, caspase‐3, and Bcl‐2 during SE infection in dGCs, whereas an opposite trend was observed with PERP knockdown. Duck PERP, as a negative regulator, was involved in the ovarian local immune niche through a p53 signaling pathway that promoted cell apoptosis, as well as SE adhesion and invasion during SE infection. Abstract Salmonella Enteritidis (SE) can be transmitted to eggs through cecum or the ovary from infected layers and causes food poisoning in humans. The mechanism of cecal transmission has been extensively studied. However, the mechanism and route of transovarian transmission of SE remain unclear. In this study, the ducks were orally inoculated with SE, and the ovarian follicles and stroma were collected to detect SE infection. The immune responses were triggered and the innate and adaptive immune genes (TLR4, NOD1, AvβD7, and IL‐1β) were upregulated significantly during the SE challenge. Moreover, the ovary tissues (small follicle and stroma) of susceptible and resistant–laying ducks were performed by RNA sequencing. We obtained and identified 23 differentially expressed genes (DEGs) between susceptible and resistant–laying ducks in both small follicle and stroma tissues ( p < 0.05). The DEGs were predominately identified in the p53 signaling pathway. The expression of key genes (p53, MDM2, PERP, caspase‐3, and Bcl‐2) involved in the signaling pathway was significantly higher in granulosa cells (dGCs) from SE‐infected ducks than those from uninfected ducks. Moreover, the overexpression of PERP resulted in further induction of p53, MDM2, caspase‐3, and Bcl‐2 during SE infection in dGCs. Whereas, an opposite trend was observed with the knockdown of PERP. Besides, it is further revealed that the PERP could enhance cell apoptosis, SE adhesion, and SE invasion in SE‐infected dGCs overexpression. Altogether, our results demonstrate the duck PERP involved in the ovarian local immune niche through p53 signaling pathway in dGCs challenged with SE. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27790   open full text
• The role of nitric oxide signaling in renoprotective effects of hydrogen sulfide against chronic kidney disease in rats: Involvement of oxidative stress, autophagy and apoptosis.
  Mohammad Khabbaz Shirazi, Asaad Azarnezhad, Mohammad Foad Abazari, Mansour Poorebrahim, Pegah Ghoraeian, Nima Sanadgol, Hanieh Bokharaie, Sahar Heydari, Amin Abbasi, Sahra Kabiri, Maryam Nouri Aleagha, Seyed Ehsan Enderami, Amir Savar Dashtaki, Hassan Askari.
  Journal of Cellular Physiology. November 27, 2018
  --- - |2 Abstract The interplay between H2S and nitric oxide (NO) is thought to contribute to renal functions. The current study was designed to assess the role of NO in mediating the renoprotective effects of hydrogen sulfide in the 5/6 nephrectomy (5/6 Nx) animal model. Forty rats were randomly assigned to 5 experimental groups: (a) Sham; (b) 5/6 Nx; (c) 5/6Nx+sodium hydrosulfide‐a donor of H 2S, (5/6Nx+sodium hydrosulfide [NaHS]); (d) 5/6Nx+NaHS+ L‐NAME (a nonspecific nitric oxide synthase [NOS] inhibitor); (e) 5/6Nx+NaHS+aminoguanidine (a selective inhibitor of inducible NOS [iNOS]). Twelve weeks after 5/6 Nx, we assessed the expressions of iNOS and endothelial NOS (eNOS), oxidative/antioxidant status, renal fibrosis, urine N‐acetyl‐b‐glucosaminidase (NAG) activity as the markers of kidney injury and various markers of apoptosis, inflammation, remodeling, and autophagy. NaHS treatment protected the animals against chronic kidney injury as depicted by improved oxidative/antioxidant status, reduced apoptosis, and autophagy and attenuated messenger RNA (mRNA) expression of genes associated with inflammation, remodeling, and NAG activity. Eight weeks Nω‐nitro‐l‐arginine methyl ester ( L‐NAME) administration reduced the protective effects of hydrogen sulfide. In contrast, aminoguanidine augmented the beneficial effects of hydrogen sulfide. Our finding revealed some fascinating interactions between NO and H 2S in the kidney. Moreover, the study suggests that NO, in an isoform‐dependent manner, can exert renoprotective effects in 5/6 Nx model of CKD. - 'Journal of Cellular Physiology, EarlyView. '

  November 27, 2018   doi: 10.1002/jcp.27797   open full text
• Global estimate of gastric cancer in Helicobacter pylori–infected population: A systematic review and meta‐analysis.
  Ali Pormohammad, Naser Mohtavinejad, Pourya Gholizadeh, Hossein Dabiri, Alireza Salimi Chirani, Ali Hashemi, Mohammad Javad Nasiri.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- The frequency of gastric cancer (GC) among H. pylori–infected population varied markedly across countries. The highest rate of GC was observed in H. pylori–infected individuals from Asian countries. The frequency of GC was relatively high in H. pylori–infected population in the world. However, the eradication of H. pylori might be a promising strategy for GC prevention, especially in high‐risk populations such as Asian countries. There is information regarding the rates of gastric cancer (GC) in different populations and the important role of Helicobacter pylori in GC development; however, no comprehensive study has yet been performed to investigate the prevalence of GC in H. pylori–infected patients. PubMed, Embase, and Cochrane Library through January 1, 2000 were searched without language restrictions. Quality of included studies was assessed with a critical appraisal checklist recommended by the Joanna Briggs Institute. All of the analyses were conducted using Comprehensive Meta‐Analysis Software Version 2.0 and Stata 14.0. Forty‐four studies from 17 countries were included. The pooled frequency of GC was 17.4% (95% confidence interval: 16.4–18.5) in H. pylori–infected population. The frequency of GC among H. pylori–infected population varied markedly across countries. The highest rate of GC was observed in H. pylori–infected individuals from Asian countries. The frequency of GC was relatively high in H. pylori–infected population in the world. However, the eradication of H. pylori might be a promising strategy for GC prevention, especially in high‐risk populations such as Asian countries. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1208-1218, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27114   open full text
• Role and translational implication of galectins in arthritis pathophysiology and treatment: A systematic literature review.
  Francesca Salamanna, Francesca Veronesi, Antonio Frizziero, Milena Fini.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Galectins are members of the animal lectin family that bind to the β‐galactoside‐containing carbohydrate moieties of glycoconjugates. This descriptive systematic literature review summarizes in vitro, in vivo, and clinical studies that analyzed and examined the role and mechanism of action of galectins in arthritis to highlight and clarify their possible translation implication. Manipulation of certain galectins can suppress or aggravate disease symptoms in arthritis animal models, demonstrating the therapeutic potential of galectins for the treatment of rheumatoid arthritis and osteoarthritis. Galectins are members of the animal lectin family that bind to the β‐galactoside‐containing carbohydrate moieties of glycoconjugates. They seem to have an important role in the pathophysiology of several diseases, including arthritis. Osteoarthritis (OA) and rheumatoid arthritis (RA) are chronic conditions with few or no available therapies. In this context, galectins could provide a novel opportunity, but the precise role and mechanism of their involvement in arthritis are still not fully understood. This descriptive systematic literature review summarizes in vitro, in vivo, and clinical studies that analyzed and examined the role and mechanism of action of galectins in arthritis to highlight and clarify their possible translation implication. This review yielded promising evidence that individual galectins, in particular galectin‐1, ‐3, and ‐9, could play positive or negative roles in the pathogenesis of arthritis, especially in RA and OA. It also emphasized the cell‐dependent role of these galectins. This is particularly true for galectin‐1, which was shown to have a protective anti‐inflammatory role in RA, while it seemed to be associated with cartilage degeneration in OA. In summary, this review underlined that manipulation of certain galectins can suppress or aggravate disease symptoms in arthritis animal models, demonstrating the therapeutic potential of galectins for the treatment of RA and OA. Nevertheless, despite the fact that galectin therapy and therapies acting on galectin expression seem to be an interesting and important opportunity for research, we highlighted that further investigation is necessary to carefully evaluate their potential clinical implications in arthritis. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1588-1605, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27026   open full text
• A cellular perspective of adipogenesis transcriptional regulation.
  Walid Kuri‐Harcuch, Cristina Velez‐delValle, Alfredo Vazquez‐Sandoval, Claudia Hernández‐Mosqueira, Veronica Fernandez‐Sanchez.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- In this review, we examine the research bearing on the control of adipose cell differentiation, some of it dating back to the early days when Howard Green and his group described the preadipocyte cell lines 3T3‐L1 and 3T3 F442A and also concentrated our attention on research published during the last few years, emphasizing data described to regulate adipose differentiation, outside of those that are part of the canonical adipogenic transcriptional cascade. Adipose cells store lipids in the cytoplasm and signal systemically through secretion of adipokines and other molecules that regulate body energy metabolism. Differentiation of fat cells and its regulation has been the focus of extensive research since the early 1970s. In this review, we had attempted to examine the research bearing on the control of adipose cell differentiation, some of it dating back to the early days when Howard Green and his group described the preadipocyte cell lines 3T3‐L1 and 3T3‐F442A during 1974–1975. We also concentrated our attention on research published during the last few years, emphasizing data described on transcription factors that regulate adipose differentiation, outside of those that were reported earlier as part of the canonical adipogenic transcriptional cascade, which has been the subject of ample reviews by several groups of researchers. We focused on the studies carried out with the two preadipocyte cell culture models, the 3T3‐L1 and 3T3‐F442A cells that have provided essential data on adipose biology. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1111-1129, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27060   open full text
• A review of the molecular mechanisms of hyperglycemia‐induced free radical generation leading to oxidative stress.
  Habib Yaribeygi, Stephen L. Atkin, Amirhossein Sahebkar.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Studies have shown that many of the diabetes complications result from excessive free radical generation and oxidative stress, and it has been shown that chronic hyperglycemia is a potent inducer for free radical production, generated through several pathways and triggering multiple molecular mechanisms. An understanding of these processes may help us to improving our preventive or therapeutic strategies. In this review, the major molecular pathways involved in free radical generation induced by hyperglycemia are described. Abstract The prevalence of diabetes is growing worldwide with an increasing morbidity and mortality associated with the development of diabetes complications. Free radical production is a normal biological process that is strictly controlled and has been shown to be important in normal cellular homeostasis, and in the bodies response to pathogens. However, there are several mechanisms leading to excessive free radical production that overcome the normal protective quenching mechanisms. Studies have shown that many of the diabetes complications result from excessive free radical generation and oxidative stress, and it has been shown that chronic hyperglycemia is a potent inducer for free radical production, generated through several pathways and triggering multiple molecular mechanisms. An understanding of these processes may help us to improving our preventive or therapeutic strategies. In this review, the major molecular pathways involved in free radical generation induced by hyperglycemia are described. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1300-1312, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27164   open full text
• The potential prognostic and therapeutic application of tissue and circulating microRNAs in cervical cancer.
  Malihe Hasanzadeh, Mehraneh Movahedi, Marzieh Rejali, Faezeh Maleki, Mehrdad Moetamani‐Ahmadi, Sima Seifi, Zeinab Hosseini, Majid Khazaei, Forouzan Amerizadeh, Gordon A. Ferns, Majid Rezayi, Amir Avan.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Exosomes and microRNAs. Exosomes contain genetic information of their cellular source, and circulate throughout body, indictaing its values as noninvasive biomarkers. Abstract Cervical cancer (CC) is a common malignancy in women and a major cause of cancer‐related mortality globally. Some novel biomarkers may enable the early diagnosis and monitoring of CC. MicroRNAs (miRNAs) are small noncoding RNAs that control gene translation at a posttranscriptional level. Hence the deregulation of these molecules can cause many diseases. There appears to be an association between aberrant miRNA expression and CC, but the molecular mechanisms involved in the development of CC remain unknown. The upregulation of some circulating miRNAs, for example, miRNA‐20a, miRNA‐203, miRNA‐21, miRNA‐205, miRNA‐218, and miR‐485‐5, as well as tissue‐specific miRNAs, for example, miR‐7, miR‐10a, miR‐17‐5p, miR‐135b, miR‐149, and miR‐203 have been found in patients with CC. There is also growing evidence for the importance of miRNAs in the development of drug resistance. This review therefore highlights recently published preclinical and clinical investigation performed on tissue specific and circulating miRNAs, as potential biomarkers for the detection of patients at early stages of CC, in the prediction of prognosis, and monitoring of their response to therapy. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1289-1294, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27160   open full text
• Anticancer properties of tocotrienols: A review of cellular mechanisms and molecular targets.
  Marina Montagnani Marelli, Monica Marzagalli, Fabrizio Fontana, Michela Raimondi, Roberta Manuela Moretti, Patrizia Limonta.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Vitamin E TTs have gained interest due to their health benefits in chronic diseases. In particular, TTs were reported to exert significant antitumor activity in a wide range of cancer cells, by counteracting cell growth or proliferation, metastasis and angiogenesis. Recent studies pointed out that TTs exert a synergistic antitumor effect on cancer cells when given in combination with either standard antitumor agents or natural compounds with anticancer activity. These results, together with the safety of TT administration in healthy subjects, suggest that these compounds might represent a new chemopreventive or anticancer treatment strategy. Clinical trials aimed at confirming this antitumor activity of TTs are needed. Vitamin E is composed of two groups of compounds: α‐, β‐, γ‐, and δ‐tocopherols (TPs), and the corresponding unsaturated tocotrienols (TTs). TTs are found in natural sources such as red palm oil, annatto seeds, and rice bran. In the last decades, TTs (specifically, γ‐TT and δ‐TT) have gained interest due to their health benefits in chronic diseases, based on their antioxidant, neuroprotective, cholesterol‐lowering, anti‐inflammatory activities. Several in vitro and in vivo studies pointed out that TTs also exert a significant antitumor activity in a wide range of cancer cells. Specifically, TTs were shown to exert antiproliferative/proapoptotic effects and to reduce the metastatic or angiogenic properties of different cancer cells; moreover, these compounds were reported to specifically target the subpopulation of cancer stem cells, known to be deeply involved in the development of resistance to standard therapies. Interestingly, recent studies pointed out that TTs exert a synergistic antitumor effect on cancer cells when given in combination with either standard antitumor agents (i.e., chemotherapeutics, statins, “targeted” therapies) or natural compounds with anticancer activity (i.e., sesamin, epigallocatechin gallate (EGCG), resveratrol, ferulic acid). Based on these observations, different TT synthetic derivatives and formulations were recently developed and demonstrated to improve TT water solubility and to reduce TT metabolism in cancer cells, thus increasing their biological activity. These promising results, together with the safety of TT administration in healthy subjects, suggest that these compounds might represent a new chemopreventive or anticancer treatment (i.e., in combination with standard therapies) strategy. Clinical trials aimed at confirming this antitumor activity of TTs are needed. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1147-1164, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27075   open full text
• Cell communication by tunneling nanotubes: Implications in disease and therapeutic applications.
  Rahul Mittal, Elisa Karhu, Jay‐Shing Wang, Stefanie Delgado, Ryan Zukerman, Jeenu Mittal, Vasanti M. Jhaveri.
  Journal of Cellular Physiology. November 20, 2018
  --- - | A schematic representation of various cellular cargoes transported by tunneling nanotubes (TNTs). nanotubes Abstract Intercellular communication is essential for the development and maintenance of multicellular organisms. Tunneling nanotubes (TNTs) are a recently recognized means of long and short distance communication between a wide variety of cell types. TNTs are transient filamentous membrane protrusions that connect cytoplasm of neighboring or distant cells. Cytoskeleton fiber‐mediated transport of various cargoes occurs through these tubules. These cargoes range from small ions to whole organelles. TNTs have been shown to contribute not only to embryonic development and maintenance of homeostasis, but also to the spread of infectious particles and resistance to therapies. These functions in the development and progression of cancer and infectious disease have sparked increasing scrutiny of TNTs, as their contribution to disease progression lends them a promising therapeutic target. Herein, we summarize the current knowledge of TNT structure and formation as well as the role of TNTs in pathology, focusing on viral, prion, and malignant disease. We then discuss the therapeutic possibilities of TNTs in light of their varied functions. Despite recent progress in the growing field of TNT research, more studies are needed to precisely understand the role of TNTs in pathological conditions and to develop novel therapeutic strategies. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1130-1146, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27072   open full text
• Liposomal nanocarriers for statins: A pharmacokinetic and pharmacodynamics appraisal.
  Anis Askarizadeh, Alexandra E. Butler, Ali Badiee, Amirhossein Sahebkar.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2 Abstract Statins, inhibitors of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase, are a well‐known class of drug with beneficial therapeutic effects in cardiovascular disease and lipid disorders and have potential use against cancer. However, the bioavailability of statins is hampered due to low aqueous solubility and rapid metabolism. To improve pharmacokinetic profiles of statins, development of drug delivery systems is promising. Hence, the use of liposomes for selective delivery of statins to a selected site or for bioavailability enhancement is an effective strategy to increase statin therapeutic effects. Moreover, liposomal delivery can reduce the required dose of statins especially in terms of antitumor effects. Liposomes, because of their unique properties and biphasic and amphiphilic nature, have attracted much interest and can be considered as a suitable choice for delivery of both hydrophilic and lipophilic statins. In this review article, we focus on liposomes and evaluate the effects of different liposomal delivery systems, based on differences in size, phospholipid composition, circulation half‐life, and cholesterol content, on statin function. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1219-1229, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27121   open full text
• Regulation of tumor angiogenesis by microRNAs: State of the art.
  Nasser H. Goradel, Nejad Mohammadi, Hamed Haghi‐Aminjan, Bagher Farhood, Babak Negahdari, Amirhossein Sahebkar.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- This review focuses on tumor angiogenesis regulation by microRNAs and the mechanism underlying this regulation. MicroRNAs (miRNAs, miRs) are small (21–25 nucleotides) endogenous and noncoding RNAs involved in many cellular processes such as apoptosis, development, proliferation, and differentiation via binding to the 3′‐untranslated region of the target mRNA and inhibiting its translation. Angiogenesis is a hallmark of cancer, which provides oxygen and nutrition for tumor growth while removing deposits and wastes from the tumor microenvironment. There are many angiogenesis stimulators, among which vascular endothelial growth factor (VEGF) is the most well known. VEGF has three tyrosine kinase receptors, which, following VEGF binding, initiate proliferation, invasion, migration, and angiogenesis of endothelial cells in the tumor environment. One of the tumor microenvironment conditions that induce angiogenesis through increasing VEGF and its receptors expression is hypoxia. Several miRNAs have been identified that affect different targets in the tumor angiogenesis pathway. Most of these miRNAs affect VEGF and its tyrosine kinase receptors expression downstream of the hypoxia‐inducible Factor 1 (HIF‐1). This review focuses on tumor angiogenesis regulation by miRNAs and the mechanism underlying this regulation. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1099-1110, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27051   open full text
• PD‐1/PD‐L1 immune checkpoint: Potential target for cancer therapy.
  Fatemeh K. Dermani, Pouria Samadi, Golebagh Rahmani, Alisa K. Kohlan, Rezvan Najafi.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- In this review, we highlight a brief overview of the molecular and biochemical events that are regulated by the PD‐1 and PD‐L1 interaction in various cancers. Abstract Recent studies show that cancer cells are sometimes able to evade the host immunity in the tumor microenvironment. Cancer cells can express high levels of immune inhibitory signaling proteins. One of the most critical checkpoint pathways in this system is a tumor‐induced immune suppression (immune checkpoint) mediated by the programmed cell death protein 1 (PD‐1) and its ligand, programmed death ligand 1 (PD‐L1). PD‐1 is highly expressed by activated T cells, B cells, dendritic cells, and natural killer cells, whereas PD‐L1 is expressed on several types of tumor cells. Many studies have shown that blocking the interaction between PD‐1 and PD‐L1 enhances the T‐cell response and mediates antitumor activity. In this review, we highlight a brief overview of the molecular and biochemical events that are regulated by the PD‐1 and PD‐L1 interaction in various cancers. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1313-1325, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27172   open full text
• Mesenchymal stem cells as the game‐changing tools in the treatment of various organs disorders: Mirage or reality?
  Faroogh Marofi, Ghasem Vahedi, Ali hasanzadeh, Sadegh Salarinasab, Pishva Arzhanga, Bahareh Khademi, Majid Farshdousti Hagh.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Recently a growing attention in scientific community has been gathered on potential application of mesenchymal stem cells (MSCs) in various fields of medicine. Various useful properties of MSCs including tropism toward tumor/injury site(s), weakly immunogenic, production of anti‐inflammatory molecules, and safety against normal tissues have made them prone for regenerative medicine, targeted therapy and treating injured tissues, and immunological abnormalities. Abstract Recently a growing attention in scientific community has been gathered on potential application of mesenchymal stem cells (MSCs) in various fields of medicine. Owing to the fact that they can be easily isolated from different sources, and simply proliferated in large quantities while keeping their original biological characteristics, they can be successfully used as cell‐based therapeutics. Engineering MSCs and other type of stem cells to be carriers of therapeutic agents is a new tactic in the targeted gene and cell therapy of cancers and degenerative diseases. Various useful properties of MSCs including tropism toward tumor/injury site(s), weakly immunogenic, production of anti‐inflammatory molecules, and safety against normal tissues have made them prone for regenerative medicine, targeted therapy and treating injured tissues, and immunological abnormalities. In this review, we introduce latest advances, methods, and applications of MSCs in gene therapy of various malignant organ disorders. Additionally, we will cover the problems and challenges which researchers have faced with when trying to translate their basic experimental findings in MSCs research to clinically applicable therapeutics. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1268-1288, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27152   open full text
• The viral approach to breast cancer immunotherapy.
  Atefeh Arab, Nima Behravan, Atefeh Razazn, Nastaran Barati, Fatemeh Mosaffa, Jessica Nicastro, Roderick Slavcev, Javad Behravan.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- This manuscript discusses the latest findings regarding viral vectors designed for fighting breast cancer Despite years of intensive research, breast cancer remains the leading cause of death in women worldwide. New technologies including oncolytic virus therapies, virus, and phage display are among the most powerful and advanced methods that have emerged in recent years with potential applications in cancer prevention and treatment. Oncolytic virus therapy is an interesting strategy for cancer treatment. Presently, a number of viruses from different virus families are under laboratory and clinical investigation as oncolytic therapeutics. Oncolytic viruses (OVs) have been shown to be able to induce and initiate a systemic antitumor immune response. The possibility of application of a multimodal therapy using a combination of the OV therapy with immune checkpoint inhibitors and cancer antigen vaccination holds a great promise in the future of cancer immunotherapy. Display of immunologic peptides on bacterial viruses (bacteriophages) is also increasingly being considered as a new and strong cancer vaccine delivery strategy. In phage display immunotherapy, a peptide or protein antigen is presented by genetic fusions to the phage coat proteins, and the phage construct formulation acts as a protective or preventive vaccine against cancer. In our laboratory, we have recently tested a few peptides (E75, AE37, and GP2) derived from HER2/neu proto‐oncogene as vaccine delivery modalities for the treatment of TUBO breast cancer xenograft tumors of BALB/c mice. Here, in this paper, we discuss the latest advancements in the applications of OVs and bacterial viruses display systems as new and advanced modalities in cancer immune therapeutics. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1257-1267, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27150   open full text
• MicroRNA‐10b expression predicts long‐term survival in patients with solid tumor.
  Yi Zhang, Li‐Juan Wang, He‐Quan Yang, Rong Wang, Hua‐Jun Wu.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2 Abstract Background Numerous studies have evaluated the significance of the microRNA‐10b (miR‐10b) in the development and progression of many cancers. Their findings revealed that increased expression of miR‐10b is associated with unfavorable prognosis in patients with cancer. Results A total of 1,834 patients from 19 studies were included in this study. A significantly shorter overall survival was observed in patients with increased expression of miR‐10b (hazard ratio [HR] = 1.99, 95% confidence interval [CI]: 1.51–2.61). Statistical significance was also observed in subgroup meta‐analysis stratified by the cancer type, cutoff value, analysis type, and sample size. Also, patients with a high expression level of miR‐10b had a poorer disease‐free survival rate (HR = 1.18, 95% CI: 1.05–1.33). In addition, the pooled odds ratios (ORs) showed that increased miR‐10b was also associated with positive lymph node metastasis (OR = 2.09, 95% CI: 1.45–3.03), distant metastasis (OR = 2.40, 95% CI: 1.57–3.67), tumor size (OR = 3.86, 95% CI: 2.25–6.64), and poor clinical stage (OR = 5.02, 95% CI: 3.37–7.47). Materials and Methods A systematic literature search was conducted on a number of electronic databases, including PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Springer, Google Scholar, and Gene expression omnibus. We retrieved the relevant articles to examine the association between the miR‐10b expression levels and patients’ prognosis. The meta‐analysis was conducted using the RevMan 5.2 software and Stata SE12.0 software. Conclusions High miR‐10b expression was correlated with poor clinical outcome, which indicated the potential clinical use of miR‐10b as a molecular biomarker for cancer, particularly in assessing prognosis for patients with cancers. Further studies should be performed to verify the clinical utility of miR‐10b in human solid tumors. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1248-1256, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27138   open full text
• Therapeutic potency of Wnt signaling antagonists in the pathogenesis of prostate cancer, current status and perspectives.
  Mehran Pashirzad, Mojtaba Shafiee, Majid Khazaei, Hamid Fiuji, Mikhail Ryzhikov, Saman Soleimanpour, AmirReza Hesari, Amir Avan, Seyed Mahdi Hassanian.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Suppression of Wnt canonical or noncanonical signaling pathways via Wnt biological or pharmacological antagonists is a potentially novel therapeutic approach for patients with prostate cancer. This review summarizes the role of Wnt signaling inhibitors in the pathogenesis of prostate cancer for a better understanding and hence a better management of this disease. Abstract Prostate cancer is a major cause of cancer‐related death in males. Wnt/β‐catenin signaling plays a critical role in the pathogenesis of this disease by regulating angiogenesis, drug resistance, cell proliferation, and apoptosis. Suppression of Wnt canonical or noncanonical signaling pathways via Wnt biological or pharmacological antagonists is a potentially novel therapeutic approach for patients with prostate cancer. This review summarizes the role of Wnt signaling inhibitors in the pathogenesis of prostate cancer for a better understanding and hence a better management of this disease. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1237-1247, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27137   open full text
• The prognostic and therapeutic values of long noncoding RNA PANDAR in colorectal cancer.
  Mahdi Rivandi, Alireza Pasdar, Leila Hamzezadeh, Amir Tajbakhsh, Sima Seifi, Mehrdad Moetamani‐Ahmadi, Gordon A. Ferns, Amir Avan.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Schematic representation of mechanisms of PANDAR in colorectal cancer. PANDAR could promote metastasis via EMT pathway on the other hand, it could regulate cell proliferation. PANDAR inhibits apoptosis by bax‐caspase 3 pathway. Abstract Long noncoding RNAs (lncRNAs) consist of 200 nucleotide sequences that play essential roles in different processes, including cell proliferation, and differentiation. There is evidence showing that the dysregulation of lncRNAs promoter of CDKN1A antisense DNA damage‐activated RNA (PANDAR) leads to the development and progression in several cancers including colorectal cancer, via p53‐dependent manner. This suggests that these lncRNAs may be of value as prognostic indices and a therapeutic target, as a high expression of lncRNAs PANDAR is associated with poor prognosis. Furthermore, modulating lncRNAs PANDAR has been reported to induce apoptosis and inhibit the tumor growth through modulation of cell cycle and epithelial‐mesenchymal transition (EMT) pathway. The aim of the current review was to provide an overview of the prognostic and therapeutic values of lncRNAs PANDAR in colorectal cancer - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1230-1236, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27136   open full text
• Stem cell‐based therapy for Parkinson’s disease with a focus on human endometrium‐derived mesenchymal stem cells.
  Saeid Bagheri‐Mohammadi, Mohammad Karimian, Behrang Alani, Javad Verdi, Rana Moradian Tehrani, Mahdi Noureddini.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Parkinson’s disease (PD) as an increasing clinical syndrome is a multifunctional impairment. Till now, there is a lack of eligible treatment for PD, and stem cells therapy recently has been considered for PD treatment. Human stem cell technology especially human endometrium‐derived stem cells (HEDSCs) have made advancement as a therapeutic source for PD. Abstract Parkinson’s disease (PD) as an increasing clinical syndrome is a multifunctional impairment with systemic involvement. At present, therapeutic approaches such as l‐3,4‐dihydroxy‐phenylalanine replacement therapy, dopaminergic agonist administration, and neurosurgical treatment intend to relieve PD symptoms which are palliative and incompetent in counteracting PD progression. These mentioned therapies have not been able to replace the lost cells and they could not effectively slow down the relentless neurodegenerative process. Till now, there is a lack of eligible treatment for PD, and stem cells therapy recently has been considered for PD treatment. In this review, we demonstrate how human stem cell technology especially human endometrium‐derived stem cells have made advancement as a therapeutic source for PD compared with other treatments. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1326-1335, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27182   open full text
• Heat shock protein 70: A promising therapeutic target for myocardial ischemia–reperfusion injury.
  Yan‐Jun Song, Chong‐Bin Zhong, Xian‐Bao Wang.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- During myocardial ischemia–reperfusion (I/R), HSP70 is overexpressed and exerts numerous cardioprotective effects against I/R injury. In this review, we highlight these protective effects of HSP70, elucidate the mechanisms involved, and provide several HSP70‐driven therapeutic potentials against myocardial I/R injury. In summary, it is considered that HSP70 is a promising therapeutic target against myocardial I/R injury. Acute myocardial infarction is a major cause of death worldwide. The most important therapy for limiting ischemic injury and infarct size is timely and efficient myocardial reperfusion treatment, which may instead induce cardiomyocyte necrosis due to myocardial ischemia–reperfusion (I/R) injury. Heat shock protein 70 (HSP70), a stress‐inducible protein, is overexpressed during myocardial I/R. The induced HSP70 is shown to regulate several intracellular proteins (e.g., transcription factors, enzymes, and apoptosis‐related proteins) and signaling pathways (e.g., c‐Jun N‐terminal kinase pathway and extracellular‐signal‐regulated kinase 1/2 pathway), forming a complicated network that contributes to reducing reactive oxygen species accumulation, improving calcium homeostasis, inhibiting cellular apoptosis, thereby enhancing the stress adaption of myocardium to I/R injury. In addition, the extracellular HSP70, which is released from injured cardiomyocytes during I/R, acts as a proinflammatory mediator that results in cell death, while the intracellular HSP70 exerts antiinflammatory effects by suppressing proinflammatory signaling pathways. Notably, HSP70 is induced and contributes to the cardioprotection in several types of preconditioning and postconditioning. Meanwhile, it is shown that the cardioprotective effectiveness of preconditioning‐induced HSP70 (e.g., hyperthermia preconditioning‐induced HSP70) can be impaired by certain pathological conditions, such as hyperlipidemia and hyperglycemia. Thus, we highlight the widespread cardioprotective involvement of HSP70 in preconditioning and postconditioning and elucidate how HSP70‐mediated cardioprotection is impaired in these pathological conditions. Furthermore, several therapeutic potentials of HSP70 against myocardial I/R injury and potential directions for future studies are also provided in this review. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1190-1207, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27110   open full text
• Therapeutic potential of A2 adenosine receptor pharmacological regulators in the treatment of cardiovascular diseases, recent progress, and prospective.
  Amirhossein Bahreyni, Amir Avan, Mohammad Shabani, Mikhail Ryzhikov, Hamid Fiuji, Saman Soleimanpour, Majid Khazaei, Seyed Mahdi Hassanian.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Regulation of A2 adenosine receptor signaling via specific and novel pharmacological regulators is a potentially novel therapeutic approach for a better understanding and hence a better management of cardiovascular diseases (CVDs). This review summarizes the role of pharmacological A2 adenosine receptor regulators in the pathogenesis of CVDs. Abstract Adenosine and its analogs are of particular interest as potential therapeutic agents for treatment of cardiovascular diseases (CVDs). A2 adenosine receptor subtypes (A2a and A2b) are extensively expressed in cardiovascular system, and modulation of these receptors using A2 adenosine receptor agonists or antagonists regulates heart rate, blood pressure, heart rate variability, and cardiovascular toxicity during both normoxia and hypoxia conditions. Regulation of A2 adenosine receptor signaling via specific and novel pharmacological regulators is a potentially novel therapeutic approach for a better understanding and hence a better management of CVDs. This review summarizes the role of pharmacological A2 adenosine receptor regulators in the pathogenesis of CVDs. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1295-1299, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27161   open full text
• The clinical importance of CD4+CD7− in human diseases.
  Saeed Mohammadian Haftcheshmeh, Amir Tajbakhsh, Mohaddese Kazemi, Seyed‐Alireza Esmaeili, Fatemeh Mardani, Mostafa Fazeli, Amirhossein Sahebkar.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- In this review, we first focus on the clinical importance of CD4+CD7− T cells in human disease and also explain the possible function of these cells. Secondly, we also investigate if the CD4 +CD7− T cells are resistant to apoptosis. The CD7 antigen is a member of the immunoglobulin superfamily that expresses on the surface of all thymocytes, a majority of mature T cells, and also natural killer cells. Interestingly, under physiological and different pathological conditions, the loss of CD7 antigen occurred in the subset of CD4+ memory T cells. Various functions have been proposed for CD7, including its role in the activation and intercellular adhesiveness of T cells. Several studies indicate that the number of CD4+CD7− T cells increases in diseases such as chronic inflammation and T‐cell malignancies, these being skin inflammatory lesions. Therefore, this can be useful for the diagnosis of cancer cells, especially with reference to blood origin, treatment monitoring, and establishment of new therapies. Therefore, a comprehensive review could be useful to increase our knowledge about the clinical importance of these cells in human disease. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1179-1189, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27099   open full text
• Evidence of curcumin and curcumin analogue effects in skin diseases: A narrative review.
  Yunes Panahi, Omid Fazlolahzadeh, Stephen L. Atkin, Muhammed Majeed, Alexandra E. Butler, Thomas P. Johnston, Amirhossein Sahebkar.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Curcumin, a natural polyphenolic and yellow pigment obtained from the spice turmeric, has strong antioxidative, anti‐inflammatory, and antibacterial properties; due to these properties, curcumin has been used as a remedy for the prevention and treatment of skin aging and disorders such as psoriasis, infection, acne, skin inflammation, and skin cancer and curcumin has protective effects against skin damage caused by chronic ultraviolet B radiation. One of the challenges in maximizing the therapeutic potential of curcumin is its low bioavailability, limited aqueous solubility, and chemical instability; in this regard, the present review is focused on recent studies concerning the use of curcumin for the treatment of skin diseases, as well as offering new and efficient strategies to optimize its pharmacokinetic profile and increase its bioavailability. Curcumin, a natural polyphenolic and yellow pigment obtained from the spice turmeric, has strong antioxidative, anti‐inflammatory, and antibacterial properties. Due to these properties, curcumin has been used as a remedy for the prevention and treatment of skin aging and disorders such as psoriasis, infection, acne, skin inflammation, and skin cancer. Curcumin has protective effects against skin damage caused by chronic ultraviolet B radiation. One of the challenges in maximizing the therapeutic potential of curcumin is its low bioavailability, limited aqueous solubility, and chemical instability. In this regard, the present review is focused on recent studies concerning the use of curcumin for the treatment of skin diseases, as well as offering new and efficient strategies to optimize its pharmacokinetic profile and increase its bioavailability. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1165-1178, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27096   open full text
• Exercise ameliorates high‐fat diet‐induced impairment of differentiation of adipose‐derived stem cells into neuron‐like cells in rats.
  Hisashi Kato, Hidemasa Minamizato, Hideki Ohno, Yoshinobu Ohira, Tetsuya Izawa.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- High‐fat diet (HFD) impaired the differentiation potential of adipose‐derived stem cells (ADSCs) into neuron‐like cells, which was accompanied by increases in apoptotic activity and oxidative stress. Importantly, exercise training ameliorated the HFD‐induced impairment of neurogenesis in ADSCs. Thus, the adipose tissue microenvironment could influence the differentiation potential of ADSCs, a source of autologous stem cell therapy. Adipose‐derived stem cells (ADSCs) can differentiate into neurons under particular conditions. It remains largely unknown whether this differentiation potential is affected by physical conditions such as obesity, which modulates the functions of adipose tissue. In this study, we determined the impact of either a 9‐week high‐fat diet (60% fat; HFD) or 9‐week exercise training on the differentiation potential of ADSCs into neuron‐like cells in male Wistar rats. Rats were randomly assigned to a normal diet‐fed (ND‐SED) group, HFD‐fed (HFD‐SED) group, or exercise‐trained HFD‐fed group (HFD‐EX). After a 9‐week intervention, ADSCs from all groups differentiated into neuron‐like cells. Expression of neuronal marker proteins (nestin, βIII‐tubulin, and microtubule‐associated protein 2 [MAP2]) and the average length of cell neurites were lower in cells from HFD‐SED rats than in other groups. Instead, protein expression of COX IV and Cyt‐c, the Bax/Bcl‐2 and LC3‐II/I ratio, and the malondialdehyde level in culture medium were higher in cells from HFD‐SED rats. No significant difference between ND‐SED and HFD‐EX rats was observed, except for the average length of cell neurites in MAP2. Thus, HFD impaired the differentiation potential of ADSCs into neuron‐like cells, which was accompanied by increases in apoptotic activity and oxidative stress. Importantly, exercise training ameliorated the HFD‐induced impairment of neurogenesis in ADSCs. The adipose tissue microenvironment could influence the differentiation potential of ADSCs, a source of autologous stem cell therapy. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1452-1460, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26957   open full text
• Wogonoside impedes the progression of acute myeloid leukemia through inhibiting bone marrow angiogenesis.
  Binyan Lin, Kai Zhao, Dawei Yang, Dongsheng Bai, Yan Liao, Yuxin Zhou, Zhou Yu, Xiaoxuan Yu, Qinglong Guo, Na Lu.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Wogonoside inhibits bone marrow angiogenesis in acute myeloid leukemia (AML) patients. Wogonoside inhibits angiogenesis via JAK‐STAT3 signaling. Wogonoside would be a promising drug for relapsed and resistant AML patients. Decreasing bone marrow (BM) microvessel density and circulating angiogenic cytokine levels are promising strategies for the treatment of relapsed and resistant acute myeloid leukemia (AML). Previous studies have reported that wogonoside could inhibit the progression of AML and suppress angiogenesis in a solid tumor, but the correlation of these two effects was ignored. In this research, we determined whether wogonoside could inhibit angiogenesis in this hematologic malignancy. We found that wogonoside could inhibit tumor growth and progression, and prolong the survival of nude mice inoculated with U937/MDR. Besides, reducing BM angiogenesis might cause therapeutic effect against resistant AML. Therefore, coculture between AML cells and BM stromal cells was established to imitate their crosstalk. Then, the effect of wogonoside on BM angiogenesis was tested in vitro and in vivo. We found that wogonoside could suppress microvessel formation in the chicken chorioallantoic membrane assay model and matrigel plug assay. The mechanism research revealed that wogonoside could block the JAK2‐STAT3 pathway in AML cells and stromal cells to break their positive feedback. We detected several cytokines related to AML or angiogenesis and found that secreted interleukin‐8 was a significant angiogenic cytokine to induce BM angiogenesis. These findings supported that new diagnostics and promising treatment strategies could be developed in relapsed and resistant AML patients. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1913-1924, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27067   open full text
• Prolonged lipopolysaccharide exposure induces transient immunosuppression in BV2 microglia.
  Krishna Sundar Twayana, Namrata Chaudhari, Palaniyandi Ravanan.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- In vitro endotoxin treatment on BV2 microglia cells has similar results, that is, cells become hyporesponsive to stimuli, even after repeated exposure to lipopolysaccharide for months. Immunosuppressed cells reversing back to normal immunoresponsive proves plasticity of these central nervous system macrophages. Nature has enabled them to have such plastic nature to be adapted themselves first and continue the immunosurveillance to protect neuronal cells that are comparatively fragile and vulnerable to inflammatory stress. And endogenously high inhibitor of apoptotic proteins expression enables them to cope up with continual exposure to stimuli without compromising the viability. Continuous pre‐exposure of immune cells to low level of inflammatory stimuli makes them hyporesponsive to subsequent exposure. This pathophysiological adaptation; known as endotoxin tolerance is a general paradigm behind several disease pathogenesis. Current study deals with this immunosuppression with respect to BV2 microglia. We attempted to investigate their immune response under prolonged endotoxin exposure and monitor the same upon withdrawal of the stimuli. BV2 microglia cells were maintained under continual exposure of lipopolysaccharide (LPS) for weeks with regular passage after 72 hr (prolonged LPS exposed cells [PLECs]). PLECs were found to be immunosuppressed with diminished expression of proinflammatory cytokines (IL6, IL1β, TNF‐α, and iNOS) and production of nitric oxide, as compared to once LPS exposed cells. Upon remaintenance of cells in normal media without LPS exposure (LPS withdrawal cells [LWCs]), the induced immunosuppression reversed and cells started responding to inflammatory stimuli; revealed by significant expression of proinflammatory cytokines. LWCs showed functional similarities to never LPS exposed cells (NLECs) in phagocytosis activity and their response to anti‐inflammatory agents like dexamethasone. Despite their immunoresponsiveness, PLECs were inflamed and showed higher autophagy rate than NLECs. Additionally, we investigated the role of inhibitor of apoptotic proteins (IAPs) in PLECs to understand whether IAPs aids in the survival of microglial cells under stress conditions. Our results revealed that cIAP1 and cIAP2 are induced in PLECs which might play a role in retaining the viability. Furthermore, antagonism of IAPs has significantly induced cell death in PLECs suggesting the role of IAPs in microglial survival under stress condition. Conclusively, our data suggest that continuous exposure of BV2 microglia cells to LPS results in transient immunosuppression and indicates the involvement of IAPs in retaining their viability under inflammatory stress. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1889-1903, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27064   open full text
• Intratumor lactate levels reflect HER2 addiction status in HER2‐positive breast cancer.
  Lorenzo Castagnoli, Egidio Iorio, Matteo Dugo, Ada Koschorke, Simona Faraci, Rossella Canese, Patrizia Casalini, Patrizia Nanni, Claudio Vernieri, Massimo Di Nicola, Daniele Morelli, Elda Tagliabue, Serenella M. Pupa.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- The purpose of this study was to identify a reliable, noninvasive, and novel biomarker associated with HER2 addiction that reflects the susceptibility to HER2‐specific therapy. Our results provide experimental and relevant support for the preclinical and clinical association between HER2 addiction/trastuzumab susceptibility and intratumor levels of lactate, a key metabolic player in cancer progression that is upregulated early in the development of malignancies. Through molecular and metabolic analyses, we found a statistically significant association among HER2 transcript levels, intratumor lactate levels and response to therapy, thus paving the way for the utilization of Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy as a powerful and independent tool to better tailor anti‐HER2 therapies and improve the outcomes of all patients with HER2‐positive BC. Despite different molecular tumor profiles indicate that human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) levels mirror HER2 addiction and trastuzumab benefit in HER2‐positive breast cancer (BC), the identification of noninvasive clinical predictors of trastuzumab sensitivity remains an unmet clinical need. In the current study, we investigated whether intratumor lactate levels reflect HER2 addiction and, in turn, trastuzumab susceptibility. Accordingly, the gene expression profiles of transgenic murine BC cell lines expressing the human d16HER2 variant (HER2‐addicted) or human full‐length HER2 (WTHER2; HER2‐nonaddicted) revealed a significant enrichment of glycolysis‐related gene pathways in HER2‐addicted cells. We studied the metabolic content of 22 human HER2‐positive BC by quantitative nuclear magnetic resonance spectroscopy and found that those cases with higher lactate levels were characterized by higher HER2 transcript levels. Moreover, gene expression analyses of HER2‐positive BC samples from a TCGA data set revealed a significant enrichment in glycolysis‐related pathways in high/HER2‐addicted tumors. These data were confirmed by metabolic analyses of human HER2‐positive BC cell lines with high or low HER2 transcript levels, which revealed significantly more active glycolytic metabolism in high HER2 transcript than in low HER2 transcript cells. Overall, our results provide evidence for noninvasive intratumor lactate detection as a potential metabolic biomarker of HER2 addiction and trastuzumab response suggesting the possibility to use in vivo imaging to assess lactate levels and, in turn, select HER2‐positive BC patients who are more likely to benefit from anti‐HER2 treatments. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1768-1779, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27049   open full text
• MicroRNA‐150 contributes to ischemic stroke through its effect on cerebral cortical neuron survival and function by inhibiting ERK1/2 axis via Mal.
  Hui Lv, Jie Li, Yu‐Qin Che.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- The key findings of this study support the notion that miR‐150 under‐expression‐mediated direct promotion of Mal protects CNN functions through the activation of ERK1/2 axis, and underscore the concept that miR‐150 may represent a novel pharmacological target for ischemic stroke intervention. Ischemic stroke, caused by the blockage of blood supply, is a major cause of death worldwide. For identifying potential candidates, we explored the effects microRNA‐150 (miR‐150) has on ischemic stroke and its underlying mechanism by developing a stable middle cerebral artery occlusion (MCAO) rat model. Gene expression microarray analysis was performed to screen differentially expressed genes associated with MCAO. We evaluated the expression of miR‐150 and Mal and the status of ERK1/2 axis in the brain tissues of MCAO rats. Then the cerebral cortical neurons (CCNs) were obtained and introduced with elevated or suppressed miR‐150 or silenced Mal to validate regulatory mechanisms for miR‐150 governing Mal in vitro. The relationship between miR‐150 and Mal was verified by dual luciferase reporter gene assay. Besides, cell growth and apoptosis of CCNs were detected by means of MTT assay and flow cytometry analyses. We identified Mal as a downregulated gene in MCAO, based on the microarray data of GSE16561. MiR‐150 was over‐expressed and negatively targeted Mal in the brain tissues obtained from MCAO rats and their CCNs. Increasing miR‐150 blocked the ERK1/2 axis, resulting in an inhibited cell growth of CNNs but an enhanced apoptosis. Furthermore, MiR‐150 inhibition was observed to have effects on CNNs as opposed to those inhibited by miR‐150 promotion. The key findings of this study support the notion that miR‐150 under‐expression‐mediated direct promotion of Mal protects CNN functions through the activation of the ERK1/2 axis, and underscore the concept that miR‐150 may represent a novel pharmacological target for ischemic stroke intervention. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1477-1490, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26960   open full text
• Hippo pathway functions as a downstream effector of AKT signaling to regulate the activation of primordial follicles in mice.
  Liao‐Liao Hu, Tie Su, Rui‐Chen Luo, Yue‐Hui Zheng, Jian Huang, Zhi‐Sheng Zhong, Jing Nie, Li‐Ping Zheng.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Our study provided direct evidence to highlight the role of Hippo signaling in regulating follicle development and indicated that AKT functions as an upstream regulator of Hippo pathway in primordial follicle activation. Our results help to further clarify the molecular mechanism of the maintenance of primordial follicles pool and suggest a new therapeutic strategy for prevention and treatment of female infertility. Clarifying the molecular mechanisms by which primordial follicles are initiated is crucial for the prevention and treatment of female infertility and ovarian dysfunction. The Hippo pathway has been proven to have a spatiotemporal correlation with the size of the primordial follicle pool in mice in our previous work. But the role and underlying mechanisms of the Hippo pathway in primordial follicle activation remain unclear. Here, the localization and expression of the core components were examined in primordial follicles before and after activation. And the effects of the Hippo pathway on primordial follicle activation were determined by genetically manipulating yes‐associated protein 1 (Yap1), the key transcriptional effector. Furthermore, an AKT specific inhibitor (MK2206) was added to determine the interaction between the Hippo pathway and AKT, an important signaling regulator of ovarian function. Results showed that the core components of the Hippo pathway were localized in both primordial and primary follicles and the expression levels of them changed significantly during the initiation of primordial follicles. Yap1 knockdown suppressed primordial follicle activation, while its overexpression led to the opposite trend. MK2206 downregulated the ratio of P‐MST/MST1 and upregulated the ratio of P‐YAP1/YAP1 significantly, whereas Yap1‐treatment had no influence on AKT. In addition, YAP1 upregulation partially rescued the suppression of the primordial follicle activation induced by MK2206. Our findings revealed that the Hippo‐YAP1 regulates primordial follicular activation, which is mediated by AKT signaling in mice, thus providing direct and new evidence to highlight the role of Hippo signaling in regulating ovarian follicles development. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1578-1587, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27024   open full text
• Caveolin enhances hepatocellular carcinoma cell metabolism, migration, and invasion in vitro via a hexokinase 2‐dependent mechanism.
  Fang Chai, Yan Li, Keyi Liu, Qiang Li, Hongzhi Sun.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Caveolin‐1 (CAV‐1) increased hexokinase 2 (HK2) expression. CAV‐1 enhances glycolysis, invasion, and metastasis in hepatocellular carcinoma cells via a HK2‐dependent mechanism. The development and progression of hepatocellular carcinoma (HCC) have been associated with abnormal cellular metabolism. Gene Expression Profiling Interactive Analysis RNA sequencing data revealed caveolin‐1 (CAV‐1) and hexokinase 2 (HK2) messenger RNA (mRNA) were significantly upregulated in human HCC compared with normal tissues, and high HK2 expression was associated with significantly poorer overall survival in HCC ( p < 0.05). CAV‐1 and HK2 mRNA and protein expression were upregulated and positively correlated in 42 fresh human HCC tissues compared with tumor‐adjacent normal tissues. Overexpression of CAV‐1 or HK2 in SMMC‐7721 and HepG2 HCC cells enhanced glucose and lactate metabolism and increased cell migration and invasion in transwell assays; knocking down CAV‐1 or HK2 had the opposite effects. Overexpression of CAV‐1 increased HK2 expression; overexpression of HK2 did not affect CAV‐1 expression. Knocking down HK2 partially reversed the ability of CAV‐1 to promote cellular metabolism, invasion, and migration in HCC, indicating CAV‐1 enhances glycolysis, invasion, and metastasis in HCC cells via HK2‐dependent mechanism. Further studies of the function and relationship between CAV‐1 or HK2 expression are warranted to explore the potential of these proteins as metabolic targets for the treatment of HCC. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1937-1946, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27074   open full text
• Mutual regulation between IGF‐1R and IGFBP‐3 in human corneal epithelial cells.
  Rossella Titone, Meifang Zhu, Danielle M. Robertson.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Here we report that the insulin‐like growth factor binding protein‐3 (IGFBP‐3) mediates nuclear translocation of insulin‐like growth factor type 1 receptor (IGF‐1R) in response to stress. This occurs via SUMOylation by SUMO 2/3. This is the first study to show a direct relationship between IGF‐1R and IGFBP‐3 in the maintenance of corneal epithelial homeostasis. The insulin‐like growth factor type 1 receptor (IGF‐1R) is part of the receptor tyrosine kinase superfamily. The activation of IGF‐1R regulates several key signaling pathways responsible for maintaining cellular homeostasis, including survival, growth, and proliferation. In addition to mediating signal transduction at the plasma membrane, in serum‐based models, IGF‐1R undergoes SUMOylation by SUMO 1 and translocates to the nucleus in response to IGF‐1. In corneal epithelial cells grown in serum‐free culture, however, IGF‐1R has been shown to accumulate in the nucleus independent of IGF‐1. In this study, we report that the insulin‐like growth factor binding protein‐3 (IGFBP‐3) mediates nuclear translocation of IGF‐1R in response to growth factor withdrawal. This occurs via SUMOylation by SUMO 2/3. Further, IGF‐1R and IGFBP‐3 undergo reciprocal regulation independent of PI3k/Akt signaling. Thus, under healthy growth conditions, IGFBP‐3 functions as a gatekeeper to arrest the cell cycle in G0/G1, but does not alter mitochondrial respiration in cultured cells. When stressed, IGFBP‐3 functions as a caretaker to maintain levels of IGF‐1R in the nucleus. These results demonstrate mutual regulation between IGF‐1R and IGFBP‐3 to maintain cell survival under stress. This is the first study to show a direct relationship between IGF‐1R and IGFBP‐3 in the maintenance of corneal epithelial homeostasis. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1426-1441, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26948   open full text
• Norepinephrine stimulation downregulates the β2‐adrenergic receptor–nitric oxide pathway in human pulmonary artery endothelial cells.
  Wande Yu, Yue Gu, PeiP Chen, Jie Luo, Pengfei Liu, Yuelin Chao, Shao‐Liang Chen, Hang Zhang.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- These data provide a novel mechanism for norepinephrine (NE)‐decreased endothelium‐derived nitric oxide and NE‐induced human pulmonary artery endothelial cells proliferation that leads to pulmonary hypertension associated with left heart disease (PH‐LHD), suggesting a potential therapeutic target for PH‐LHD. Background Norepinephrine (NE)‐mediated vasoconstriction plays an important role in pulmonary hypertension associated with left heart disease (PH‐LHD). However, the role of NE‐mediated endothelial cell dysfunction in the pathogenesis of PH‐LHD remains to be elucidated. Methods and Results An enzyme‐linked immunosorbent assay showed that the NE concentration in the plasma of patients with PH‐LHD was higher and the nitrate–nitrite concentration was lower than those in the control group. NE treatment decreased phospho‐Ser633‐eNOS and β2‐adrenergic receptor (β2‐AR) levels in the membrane of human pulmonary artery endothelial cells (HPAECs) analysed by western blot analysis. Consistently, fluorescence microscopy and flow cytometry showed that nitric oxide (NO) production was also decreased in HPAECs. Coimmunoprecipitation confirmed a direct interaction between β2‐AR and endothelial NO synthase (eNOS). Overexpression of β2‐AR attenuated the decline in phospho‐Ser633‐eNOS and NO production. Additionally, the expression of phospho‐Ser633‐eNOS and β2‐AR was decreased in human pulmonary artery endothelium. Finally, our results indicate that NE stimulated HPAEC proliferation, which was blocked by protein kinase A inhibitor or protein kinase B (PKB–AKT) inhibitor. Conclusions These data provide a novel mechanism for NE‐decreased endothelium‐derived NO and NE‐induced HPAEC proliferation that leads to PH‐LHD, suggesting a potential therapeutic target for PH‐LHD. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1842-1850, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27057   open full text
• Carvacrol induces mitochondria‐mediated apoptosis via disruption of calcium homeostasis in human choriocarcinoma cells.
  Whasun Lim, Jiyeon Ham, Fuller W. Bazer, Gwonhwa Song.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- In this study, we demonstrated that carvacrol exertes antiproliferative effects through suppression of phosphoinositide 3‐kinase–protein kinase B and mitogen‐activated protein kinase signaling, generating oxidative stress and altering calcium homeostasis mediated by mitochondrial dysfunction in human choriocarcinoma JAR and JEG3 cells. Therefore, carvacrol has a possibility as a novel therapeutic agent or supplement for the treatment of choriocarcinoma patients. Carvacrol is a monoterpenoid phenol present in the oils of various plants including Origanum vulgare (oregano) or Origanum majorana (marjoram). For a long time, it has been used as spice in foods because of its antimicrobial properties. Additionally, it appears to have anticancer effects against some cancer but this has not been well studied. Therefore, we conducted various assays to confirm the effects of carvacrol on choriocarcinoma cell lines (JAR and JEG3). Our results indicate that carvacrol has antiproliferative properties and induces apoptosis, resulting in increased expression of proapoptotic proteins. Additionally, carvacrol disrupted the mitochondrial membrane potential and induced calcium ion overload in the mitochondrial matrix in both JAR and JEG3 cells. Furthermore, carvacrol generated oxidative stress and lipid peroxidation in both JAR and JEG3 cells. Moreover, carvacrol‐suppressed phosphoinositide 3‐kinase–protein kinase B and extracellular signal–regulated kinase 1/2 mitogen‐activated protein kinase (MAPK) signal transduction whereas expression of phosphor‐P38 and c‐Jun N‐terminal kinase MAPK was increased. Together, our results indicate that carvacrol may be a possible new therapeutic agent or supplement for the control of human choriocarcinomas. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1803-1815, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27054   open full text
• The predictive value of a preoperative systemic immune‐inflammation index and prognostic nutritional index in patients with esophageal squamous cell carcinoma.
  Hongdian Zhang, Xiaobin Shang, Peng Ren, Lei Gong, Ashique Ahmed, Zhao Ma, Rong Ma, Xianxian Wu, Xiangming Xiao, Hongjing Jiang, Peng Tang, Zhentao Yu.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- (a) The preoperative high systemic immune‐inflammation index (SII) and low prognostic nutritional index (PNI) are powerful indicators of aggressive biology and poor prognosis for patients with esophageal squamous cell carcinoma (ESCC). (b) Combination of SII and PNI (coSII–PNI) clearly classified ESCC patients into three independent groups before surgery. (c) The coSII–PNI can enhance the accuracy of prognosis. Growing evidence indicates that systemic inflammation response and malnutrition status are correlated with survival in certain types of solid tumors. The aim of this study is to evaluate the association between the systemic immune‐inflammation index (SII) and prognostic nutritional index (PNI) and overall survival (OS) in patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. A consecutive series of 655 patients with resected ESCC who underwent esophagectomy were enrolled in the retrospective study. The preoperative SII was defined as platelet × neutrophil/lymphocyte counts. The PNI was calculated as albumin concentration (g/L) + 5 × total lymphocyte count (109/L). The optimal cut‐off values of SII, neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and PNI were determined by receiver operating characteristic analysis. Survival analysis was performed using the Kaplan–Meier method with a log‐rank test, followed by a multivariate Cox proportional hazards model. A high SII was significantly related to tumor size, histological type, invasion depth, and TNM stage (p < 0.05). A low PNI was significantly associated with age, tumor size, invasion depth, lymph node metastasis, and TNM stage (p < 0.05). Univariate analysis revealed that age, smoking history, tumor size, invasion depth, lymph node metastasis, SII, NLR, PLR, and PNI were predictors of OS (p < 0.05). Multivariate analysis identified age (p = 0.041), tumor size (p = 0.016), invasion depth (p < 0.001), lymph node metastasis (p < 0.001), SII (p = 0.033), and PNI (p = 0.022) as independent prognostic factors correlated with OS. There was a significant inverse relationship between the SII and PNI (r = 0.309; p < 0.001). The predictive value increased when the SII and PNI were considered in combination. Our results demonstrate that the preoperative high SII and low PNI are powerful indicators of aggressive biology and poor prognosis for patients with ESCC. The combination of SII and PNI can enhance the accuracy of prognosis. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1794-1802, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27052   open full text
• Irisin promotes cardiac progenitor cell‐induced myocardial repair and functional improvement in infarcted heart.
  Yu Tina Zhao, Jianguo Wang, Naohiro Yano, Ling X. Zhang, Hao Wang, Shouyan Zhang, Gangjian Qin, Patrycja M. Dubielecka, Shougang Zhuang, Paul Y. Liu, Y. Eugene Chin, Ting C. Zhao.
  Journal of Cellular Physiology. November 20, 2018
  --- - "\nThese results indicate that Irisin promoted Nkx2.5+ cardiac progenitor cell (CPC)‐induced cardiac regeneration and functional improvement and that Irisin serves as a novel therapeutic approach for stem cells in cardiac repair. MI: myocardial infarction. \n\n\n\n\n\nIrisin, a newly identified hormone and cardiokine, is critical for modulating body metabolism. New evidence indicates that irisin protects the heart against myocardial ischemic injury. However, whether irisin enhances cardiac progenitor cell (CPC)‐induced cardiac repair remains unknown. This study examines the effect of irisin on CPC‐induced cardiac repair when these cells are introduced into the infarcted myocardium. Nkx2.5+ CPC stable cells were isolated from mouse embryonic stem cells. Nkx2.5\n+ CPCs (0.5 × 10\n6) were reintroduced into the infarcted myocardium using PEGlylated fibrin delivery. The mouse myocardial infarction model was created by permanent ligation of the left anterior descending (LAD) artery. Nkx2.5\n+ CPCs were pretreated with irisin at a concentration of 5 ng/ml in vitro for 24 hr before transplantation. Myocardial functions were evaluated by echocardiographic measurement. Eight weeks after engraftment, Nkx2.5\n+ CPCs improved ventricular function as evident by an increase in ejection fraction and fractional shortening. These findings are concomitant with the suppression of cardiac hypertrophy and attenuation of myocardial interstitial fibrosis. Transplantation of Nkx2.5\n+ CPCs promoted cardiac regeneration and neovascularization, which were increased with the pretreatment of Nkx2.5\n+ CPCs with irisin. Furthermore, irisin treatment promoted myocyte proliferation as indicated by proliferative markers Ki67 and phosphorylated histone 3 and decreased apoptosis. Additionally, irisin resulted in a marked reduction of histone deacetylase 4 and increased p38 acetylation in cultured CPCs. These results indicate that irisin promoted Nkx2.5\n+ CPC‐induced cardiac regeneration and functional improvement and that irisin serves as a novel therapeutic approach for stem cells in cardiac repair." - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1671-1681, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27037   open full text
• NKCC1 promotes EMT‐like process in GBM via RhoA and Rac1 signaling pathways.
  Haiwen Ma, Tao Li, Zhennan Tao, Long Hai, Luqing Tong, Li Yi, Iruni R. Abeysekera, Peidong Liu, Yang Xie, Jiabo Li, Feng Yuan, Chen Zhang, Yihan Yang, Haolang Ming, Shengping Yu, Xuejun Yang.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- There are some highlights in this paper: 1. An ion channel that is critical to tumor invasion is proposed. 2. This Ion cotransporters promoted epithelial‐mesenchymal transition process in glioma. 3. An intermediate mechanism for regulating epithelial–mesenchymal transition is proved. Glioblastoma is the most common and lethal primary intracranial tumor. As the key regulator of tumor cell volume, sodium‐potassium‐chloride cotransporter 1 (NKCC1) expression increases along with the malignancy of the glioma, and NKCC1 has been implicated in glioblastoma invasion. However, little is known about the role of NKCC1 in the epithelial‐mesenchymal transition‐like process in gliomas. We noticed that aberrantly elevated expression of NKCC1 leads to changes in the shape, polarity, and adhesion of cells in glioma. Here, we investigated whether NKCC1 promotes an epithelial–mesenchymal transition (EMT)‐like process in gliomas via the RhoA and Rac1 signaling pathways. Pharmacological inhibition and knockdown of NKCC1 both decrease the expressions of mesenchymal markers, such as N‐cadherin, vimentin, and snail, whereas these treatments increase the expression of the epithelial marker E‐cadherin. These findings indicate that NKCC1 promotes an EMT‐like process in gliomas. The underlying mechanism is the facilitation of the binding of Rac1 and RhoA to GTP by NKCC1, which results in a significant enhancement of the EMT‐like process. Specific inhibition or knockdown of NKCC1 both attenuate activated Rac1 and RhoA, and the pharmacological inhibitions of Rac1 and RhoA both impair the invasion and migration abilities of gliomas. Furthermore, we illustrated that NKCC1 knockdown abolished the dissemination and spread of glioma cells in a nude mouse intracranial model. These findings suggest that elevated NKCC1 activity acts in the regulation of an EMT‐like process in gliomas, and thus provides a novel therapeutic strategy for targeting the invasiveness of gliomas, which might help to inhibit the spread of malignant intracranial tumors. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1630-1642, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27033   open full text
• mTOR inhibitor INK128 attenuates dextran sodium sulfate‐induced colitis by promotion of MDSCs on Treg cell expansion.
  Guoping Shi, Dan Li, Jing Ren, Xiaojing Li, Tingting Wang, Huan Dou, Yayi Hou.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Mammalian target of rapamycin inhibitor INK128 attenuates dextran sodium sulfate–induced colitis by promotion of myeloid‐derived suppressor cells on regulatory T‐cell expansion. Accumulating evidence has shown that mammalian target of rapamycin (mTOR) pathway and myeloid‐derived suppressor cells (MDSCs) are involved in pathogenesis of inflammatory bowel diseases (IBDs). INK128 is a novel mTOR kinase inhibitor in clinical development. However, the exact roles of MDSCs and INK128 in IBD are unclear. Here, we showed that the INK128 treatment enhanced the resistance of mice to dextran sodium sulfate (DSS)–induced colitis and inhibited the differentiation of MDSCs into macrophages. Moreover, interferon (IFN)‐α level was elevated in INK128‐treated colitis mice. When stimulated with IFN‐α in vitro, MDSCs showed a superior immunosuppression activity. Of note, the regulatory T cells (Tregs) increased but Th1 cells decreased in INK128‐treated colitis mice. These results indicate that mTOR inhibitor INK128 attenuates DSS‐induced colitis via Treg expansion promoted by MDSCs. Our work provides a new evidence that INK128 is potential to be a therapeutic drug on DSS‐induced colitis via regulating MDSCs as well as maintaining Treg expansion. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1618-1629, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27032   open full text
• LncRNA AK077216 promotes RANKL‐induced osteoclastogenesis and bone resorption via NFATc1 by inhibition of NIP45.
  Chuan Liu, Zhen Cao, Yun Bai, Ce Dou, Xiaoshan Gong, Mengmeng Liang, Rui Dong, Hongyu Quan, Jianmei Li, Jingjin Dai, Fei Kang, Chunrong Zhao, Shiwu Dong.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Lnc‐AK077216 promotes the expression of NFATc1 via suppressing NIP45 expression, thereby promoting RANKL‐induced osteoclast differentiation and function. Osteoclasts derived from the monocyte/macrophage hematopoietic lineage regulate bone resorption, a process balanced by bone formation in the continual renewal of the skeletal system. As dysfunctions of these cells result in bone metabolic diseases such as osteoporosis and osteopetrosis, the exploration of the mechanisms regulating their differentiation is a priority. A potential mechanism may involve long noncoding RNAs (lncRNAs), which are known to regulate various cell biology activities, including proliferation, differentiation, and apoptosis. The expression of the lncRNA AK077216 (Lnc‐AK077216) is significantly upregulated during osteoclastogenesis identified by microarray and verified by qPCR. Up‐ and downregulation of Lnc‐AK077216, respectively promotes and inhibits osteoclast differentiation, bone resorption, and the expression of related genes on the basis of tartrate‐resistant acid phosphatase staining, qPCR, and western blot results. In addition, Lnc‐AK077216 suppresses NIP45 expression and promotes the expression of NFATc1, an essential transcription factor during osteoclastogenesis. Besides, it was found that the expression of Lnc‐AK077216 and Nfatc1 is upregulated, whereas Nip45 expression is downregulated in bone marrow and spleen tissues of ovariectomized mice. The results suggest that Lnc‐AK077216 regulates NFATc1 expression and promotes osteoclast formation and function, providing a novel mechanism of osteoclastogenesis and a potential biomarker or a new drug target for osteoporosis. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1606-1617, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27031   open full text
• MiR‐24‐3p regulates cell proliferation and milk protein synthesis of mammary epithelial cells through menin in dairy cows.
  Cao Qiaoqiao, Honghui Li, Xue Liu, Zhengui Yan, Meng Zhao, Zhongjin Xu, Zhonghua Wang, Kerong Shi.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2 MiR‐24‐3p negatively modulates the expression of MEN1/menin in mammary epithelial cells by targeting the 3 'UTR of MEN1. MiR‐24‐3p plays regulatory role of cell proliferation and milk protein synthesis in mammary epithelial cells through cooperatively acting with menin. Abstract MiR‐24‐3p, a broadly conserved, small, noncoding RNA, is abundantly expressed in mammary tissue. However, its regulatory role in this tissue remains poorly understood. It was predicted that miR‐24‐3p targets the 3′ untranslated region (3′‐UTR) of multiple endocrine neoplasia type 1 (MEN1), an important regulatory factor in mammary tissue. The objective of this study was to investigate the function of miR‐24‐3p in mammary cells. Using a luciferase assay in mammary epithelial cells (MAC‐T), miR‐24‐3p was confirmed to target the 3′‐UTR of MEN1. Furthermore, miR‐24‐3p negatively regulated the expression of the MEN1 gene and its encoded protein, menin. miR‐24‐3p enhanced proliferation of MAC‐T by promoting G1/S phase progression. MiR‐24‐3p also regulated the expression of key factors involved in phosphatidylinositol‐3‐kinase/protein kinase B/mammalian target of rapamycin and Janus kinase/signal transducer and activators of transcription signaling pathways, therefore controlling milk protein synthesis in epithelial cells. Thus, miR‐24‐3p appears to act on MAC‐T by targeting MEN1. The expression of miR‐24‐3p was controlled by MEN1/menin, indicating a negative feedback loop between miR‐24‐3p and MEN1/menin. The negatively inhibited expression pattern of miR‐24‐3p and MEN1 was active in mammary tissues at different lactation stages. The feedback mechanism is a new concept to further understand the lactation cycle of mammary glands and can possibly to be manipulated to improve milk yield and quality. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1522-1533, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27017   open full text
• Role of STAT signaling and autocrine action of chemokines during H2O 2 induced HTR‐8/SVneo trophoblastic cells invasion.
  Priyanka Banerjee, Ankita Malik, Sudha Saryu Malhotra, Satish Kumar Gupta.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- H2O2 (a reactive oxygen species) at 25 μM concentration increases human HTR‐8/SVneo cells invasion. The underlying mechanism of H2O2‐mediated increase in HTR‐8/SVneo cells invasion depends on increased MMP‐9/TIMP‐1 ratio, and secretion of IL‐8 and MIP‐1β via activation of STAT signaling. During pregnancy, regulated generation of reactive oxygen species (ROS) is important for activation of signaling pathways and placentation. In the current study, the effect of H2O2 on invasion of HTR‐8/SVneo cells, a human extravillous trophoblast cell line, is investigated. Treatment of HTR‐8/SVneo cells for 24 hr with H 2O2 (25 µM) leads to a significant increase in invasion without affecting cell proliferation, viability, and apoptosis. Concomitantly, a significant increase in the matrix metalloproteinase‐9 (MMP‐9)/tissue inhibitor of metalloproteinases‐1 (TIMP‐1) ratio is observed. Further, significant increase in phosphorylation of signal transducer and activator of transcription 1 (STAT‐1) and STAT‐3 (both at ser727 residue) is observed on treating HTR‐8/SVneo cells with 25 µM of H2O2 accompanied by an increase in the secretion of interleukin‐8 (IL‐8) and macrophage inflammatory protein‐1β (MIP‐1β). A significant decrease in H2O2‐mediated invasion of HTR‐8/SVneo cells and reduced expression of IL‐8 and MIP‐1β accompanied by decrease in MMP‐9/TIMP‐1 ratio are observed on inhibiting STAT‐1 and STAT‐3 by small interfering RNA (siRNA). Inhibition of STAT‐1 activity by fludarabine and STAT‐3 activity by Stattic also leads to a decrease in H2O2‐mediated increase in HTR‐8/SVneo cell invasion. Inhibition of IL‐8 and MIP‐1β by siRNA also leads to a significant decrease in both basal and H2O2‐mediated invasion. Interestingly, inhibition of MIP‐1β by siRNA leads to a significant reduction in H2O2‐mediated increase in IL‐8. However, no significant effect of IL‐8 silencing on H2O2‐mediated MIP‐1β expression was observed. From the above results, it can be concluded that H2O2 activates STAT signaling, MIP‐1β & IL‐8 secretion and increases MMP‐9/TIMP‐1 ratio leading to an increased invasion of HTR‐8/SVneo cells without affecting their viability. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1380-1397, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26934   open full text
• Hypoxic conditioned medium derived from bone marrow mesenchymal stromal cells protects against ischemic stroke in rats.
  Run‐Hao Jiang, Chen‐Jiang Wu, Xiao‐Quan Xu, Shan‐Shan Lu, Qing‐Quan Zu, Lin‐Bo Zhao, Jun Wang, Sheng Liu, Hai‐Bin Shi.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Conditioned medium constitutes a therapeutic effect on stroke. Paracrine actions of bone marrow mesenchymal stromal cell are enhanced by hypoxic preconditioning. Apoptosis and neovascularization are involved in this beneficial effect. In recent years, studies have shown that the secretome of bone marrow mesenchymal stromal cells (BMSCs) contains many growth factors, cytokines, and antioxidants, which may provide novel approaches to treat ischemic diseases. Furthermore, the secretome may be modulated by hypoxic preconditioning. We hypothesized that conditioned medium (CM) derived from BMSCs plays a crucial role in reducing tissue damage and improving neurological recovery after ischemic stroke and that hypoxic preconditioning of BMSCs robustly improves these activities. Rats were subjected to ischemic stroke by middle cerebral artery occlusion and then intravenously administered hypoxic CM, normoxic CM, or Dulbecco modified Eagle medium (DMEM, control). Cytokine antibody arrays and label‐free quantitative proteomics analysis were used to compare the differences between hypoxic CM and normoxic CM. Injection of normoxic CM significantly reduced the infarct area and improved neurological recovery after stroke compared with administering DMEM. These outcomes may be associated with the attenuation of apoptosis and promotion of angiogenesis. Hypoxic preconditioning significantly enhanced these therapeutic effects. Fourteen proteins were significantly increased in hypoxic CM compared with normoxic CM as measured by cytokine arrays. The label‐free quantitative proteomics analysis revealed 163 proteins that were differentially expressed between the two groups, including 107 upregulated proteins and 56 downregulated proteins. Collectively, our results demonstrate that hypoxic CM protected brain tissue from ischemic injury and promoted functional recovery after stroke in rats and that hypoxic CM may be the basis of a potential therapy for stroke patients. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1354-1368, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26931   open full text
• Src mediates TGF‐β‐induced intraocular pressure elevation in glaucoma.
  Teruhisa Tsukamoto, Kentaro Kajiwara, Shigeyuki Nada, Masato Okada.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Src kinase is involved in TGF‐β‐induced elevation of intraocular pressure in glaucoma. Src regulates TGF‐β2‐induced changes in the contractile and adhesive characteristics of trabecular meshwork cells, and ECM deposition. Glaucoma, a progressive and irreversible optic neuropathy, is one of the leading causes of vision impairment worldwide. Elevation of intraocular pressure (IOP) due to transforming growth factor‐β (TGF‐β)‐induced dysfunction of the trabecular meshwork is a risk factor for glaucoma, but the underlying molecular mechanisms remain elusive. Here, we show that Src kinase is involved in TGF‐β‐induced IOP elevation. We observed that dasatinib, a potent Src inhibitor, suppressed TGF‐β2‐induced IOP in rat eyes. Mechanistic analyses in human trabecular meshwork cells showed that TGF‐β2 activated Src signaling and concomitantly increased cytoskeletal remodeling, cell adhesion, and extracellular matrix (ECM) accumulation. Src was activated via TGF‐β2‐induced upregulation of the Src scaffolding protein CasL, which mediates the assembly of focal adhesions, cytoskeletal remodeling, and ECM deposition. Activation of Src suppressed the expression of tissue plasminogen activator, thereby attenuating ECM degradation. Furthermore, the Src inhibitor ameliorated TGF‐β2‐induced changes in the contractile and adhesive characteristics of trabecular meshwork cells, and ECM deposition. These findings underscore the crucial role of Src activity in TGF‐β‐induced IOP elevation and identify Src signaling as a potential therapeutic target in glaucoma. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1730-1744, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27044   open full text
• Deletion of Axin1 in condylar chondrocytes leads to osteoarthritis‐like phenotype in temporomandibular joint via activation of β‐catenin and FGF signaling.
  Yachuan Zhou, Bing Shu, Rong Xie, Jian Huang, Liwei Zheng, Xuedong Zhou, Guozhi Xiao, Lan Zhao, Di Chen.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- We have generated Axin1 conditional knockout (KO) mice by targeting aggrecan‐expressing condylar cartilage cells in the temporomandibular joint (TMJ). The Axin1 conditional KO mice showed TMJ osteoarthritis (OA)‐like phenotype, probably through activation of β‐catenin and fibroblast growth factor (FGF) signaling. Osteoarthritis (OA) in the temporomandibular joint (TMJ) is a degenerative disease in the adult, which is characterized by the pathological degeneration of condylar cartilage. Axin1 plays a critical role in the regulation of cartilage development and homeostasis. To determine the role of Axin1 in TMJ tissue at the adult stage, we generated Axin1Agc1ER mice, in which Axin1 was deleted in aggrecan‐expressing chondrocytes at 2 months of age. Histology, histomorphometry, and immunostaining analyses were performed using TMJ tissues harvested from 4‐ and 6‐month‐old mice after tamoxifen administration. Total RNA isolated from TMJ cartilage of 6‐month‐old mice was used for gene expression analysis. Progressive OA‐like degeneration was observed in condylar cartilage in Axin1 knockout (KO) mice with loss of surface continuity and the formation of vertical fissures. In addition, reduced alcian blue staining in condylar cartilage was also found in Axin1 KO mice. Immunostaining and reverse transcription quantitative polymerase chain reaction (qRT‐PCR) assays revealed disturbed homeostasis in condylar cartilage with increased expressions of MMP13 and Adamts5 and decreased lubricin expression in Axin1‐deficient chondrocytes. Less proliferative cells with increased hypertrophic and apoptotic activities were presented in the condylar cartilage of Axin1Agc1ER KO mice. As a scaffolding protein, the deletion of Axin1 stimulated not only the β‐catenin but also the fibroblast growth factor (FGF) signaling via extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2) activation. The qRT‐PCR results showed an increased expression of Fgfr1 in Axin1 KO cartilage. Overall, the deletion of Axin1 in condylar chondrocytes altered the β‐catenin and FGF/ERK1/2 signaling pathways, thus cooperatively contribute to the cartilage degeneration. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1720-1729, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27043   open full text
• Effects of carnitine palmitoyltransferases on cancer cellular senescence.
  Lihuan Guan, Yixin Chen, Yongtao Wang, Huizhen Zhang, Shicheng Fan, Yue Gao, Tingying Jiao, Kaili Fu, Jiahong Sun, Aiming Yu, Min Huang, Huichang Bi.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- This study revealed that carnitine palmitoyltransferase 1C (CPT1C) knockdown exhibited the strongest impact on cell growth arrest and senescence, lipid change and accumulation, and mitochondrial dysfunction among all members of the CPT family. In addition, only knocking down CPT1C could downregulate the protein expression of c‐Myc and cyclin D1 and upregulate the cell cycle inhibitor p27 significantly, which contributes to the potential molecular mechanism of CPT1C knockdown‐induced cellular senescence. The carnitine palmitoyltransferase (CPT) family is essential for fatty acid oxidation. Recently, we found that CPT1C, one of the CPT1 isoforms, plays a vital role in cancer cellular senescence. However, it is unclear whether other isoforms (CPT1A, CPT1B, and CPT2) have the same effect on cellular senescence. This study illustrates the different effects of CPT knockdown on PANC‐1 cell proliferation and senescence and MDA‐MB‐231 cell proliferation and senescence, as demonstrated by cell cycle kinetics, Bromodeoxyuridine incorporation, senescence‐associated β‐galactosidase activity, colony formation, and messenger RNA (mRNA) expression of key senescence‐associated secretory phenotype factors. CPT1C exhibits the most substantial effect on cell senescence. Lipidomics analysis was performed to further reveal that the knockdown of CPTs changed the contents of lipids involved in mitochondrial function, and lipid accumulation was induced. Moreover, the different effects of the isoform deficiencies on mitochondrial function were measured and compared by the level of radical oxygen species, mitochondrial transmembrane potential, and the respiratory capacity, and the expression of the genes involved in mitochondrial function were determined at the mRNA level. In summary, CPT1C exerts the most significant effect on mitochondrial dysfunction‐associated tumor cellular senescence among the members of the CPT family, which further supports the crucial role of CPT1C in cellular senescence and suggests that inhibition of CPT1C may represent as a new strategy for cancer treatment through the induction of tumor senescence. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1707-1719, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27042   open full text
• Implication of basal lamina dependency in survival of Nrf2‐null muscle stem cells via an antioxidative‐independent mechanism.
  Yusei Takemoto, Shoya Inaba, Lidan Zhang, Kazutake Tsujikawa, Akiyoshi Uezumi, So‐ichiro Fukada.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Muscle regeneration ability of Nrf2‐null mice is normal. However, in a basal lamina–disrupted model, Nrf2‐null mice exhibited remarkable regeneration defects without increased levels of reactive oxidative species in muscle stem cells Nuclear factor erythroid 2–related factor 2 (Nrf2) is a master regulator for the induction of antioxidative genes and plays roles in diverse cellular functions. The roles of Nrf2 in muscle regeneration have been investigated, and both important and unimportant roles of Nrf2 for muscle regeneration have been reported. Here, using aged Nrf2‐null and Nrf2–dystrophic double‐null mice, we showed nonsignificant phenotypes in the muscle regeneration ability of Nrf2‐null mice. In contrast with these results, strikingly, almost all Nrf2‐null muscle stem cells (MuSCs) isolated by fluorescence‐activated cell sorting died in vitro of apoptosis and were not rescued by antioxidative reagents. Although their proliferation was still impaired, the Nrf2‐null MuSCs attached to myofibers activated and divided normally, at least in the first round. To elucidate these discrepancies of MuSCs behaviors, we focused on the basal lamina, because both in vivo and single myofiber culture allow MuSCs within the basal lamina to become activated. In a basal lamina–disrupted model, Nrf2‐null mice exhibited remarkable regeneration defects without increased levels of reactive oxidative species in MuSCs, suggesting that the existence of the basal lamina affects the survival of Nrf2‐null MuSCs. Taken together, these results suggest that the basal lamina compensates for the loss of Nrf2, independent of the antioxidative roles of Nrf2. In addition, experimental conditions might explain the discrepant results of Nrf2‐null regenerative ability. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1689-1698, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27040   open full text
• Protective effects of ex‐527 on cerebral ischemia–reperfusion injury through necroptosis signaling pathway attenuation.
  Sara Nikseresht, Fariba Khodagholi, Abolhassan Ahmadiani.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- The selective and potent inhibitor of Sirt1, ex‐527, reduces the infarction volume of ischemic brains and improves the survival rate. Treatment with ex‐527 effectively abolishes the elevation of the critical regulators of necroptosis. Ex‐527 relieves ischemia‐induced perturbation of necroptosis‐associated metabolic enzyme activity downstream. Necroptosis, a novel type of programmed cell death, is involved in ischemia–reperfusion‐induced brain injury. Sirtuin 1 (Sirt1), as a well‐known member of histone deacetylase class III, plays pivotal roles in inflammation, metabolism, and neuron loss in cerebral ischemia. We explored the relationship between Sirt1 and the necroptosis signaling pathway and its downstream events by administration of ex‐527, as a selective and potent inhibitor of Sirt1, and necrostatin‐1 (nec‐1), as a necroptosis inhibitor, in an animal model of focal cerebral ischemia. Our data showed different patterns of sirt1 and necroptosis critical regulators, including receptor‐interacting protein kinase 3 and mixed lineage kinase domain–like protein gene expressions in the prefrontal cortex and the hippocampus after ischemia–reperfusion. We found that ex‐527 microinjection reduces the infarction volume of ischemic brains and improves the survival rate, but not stroke‐associated neurological deficits. Additionally, treatment with ex‐527 effectively abolished the elevation of the critical regulators of necroptosis, whereas necroptosis inhibition through nec‐1 microinjection did not influence Sirt1 expression levels. Our data also demonstrated that the ex‐527 relieves ischemia‐induced perturbation of necroptosis‐associated metabolic enzymes activity in downstream. This study provides a new approach to the possible neuroprotective potential of ex‐527 orchestrated by necroptosis pathway inhibition to alleviate ischemia–reperfusion brain injury. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1816-1826, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27055   open full text
• Exercise protects against diabetic cardiomyopathy by the inhibition of the endoplasmic reticulum stress pathway in rats.
  Wang Chengji, Fan Xianjin.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Exercise training improves diabetic cardiomyopathy and heart function by decreasing the cardiac myocyte ER stress and subsequent myocardial apoptosis.This is an important finding because ER stress is one of the underlying mechanisms of diabetic complications. Thus, exercise training may significantly contribute to complication prevention in diabetes, which shows an intensity effect. Our findings reveal a novel mechanism of the effect of exercise in the management of diabetic cardiomyopathy. To explore the protective effect of exercise training on the injury of myocardium tissues induced by streptozotocin (STZ) in diabetic rats and the relationship with endoplasmic reticulum stress (ERS), the male sprague‐dawley (SD) rats were fed with high‐fat and high‐sugar diet for 4 weeks, followed by intraperitoneal injection of STZ, 40 mg/kg, to establish a diabetes model, and then 10 rats were randomly selected as diabetes mellitus (DM) controls and 20 eligible diabetic rats were randomized into two groups: low‐intensity exercise training (n = 10) and high‐intensity exercise training (n = 10). After 12 weeks of exercise training, rats were killed and serum samples were used to determine cardiac troponin‐I (cTn‐I). Myocardial tissues were sampled for morphological analysis to detect myocardial cell apoptosis, and to analyze protein expression of glucose‐regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and caspase‐12. Different intensities (low and high) significantly reduced serum cTn‐I levels compared with the DCM group (p < 0.01), and significantly reduced the percentage of apoptotic myocardial cells and improved the parameters of cardiac function. Hematoxylin and eosin and Masson staining indicated that exercise training could attenuate myocardial apoptosis. Additionally, exercise training significantly reduced GRP78, CHOP, and cleaved caspase‐12 protein expression in an intensity‐dependent manner. These findings suggest that exercise appeared to ameliorate diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress‐induced apoptosis in diabetic rats. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1682-1688, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27038   open full text
• Gastrin‐releasing peptide receptor gene silencing inhibits the development of the epithelial–mesenchymal transition and formation of a calcium oxalate crystal in renal tubular epithelial cells in mice with kidney stones via the PI3K/Akt signaling pathway.
  Xin‐Fang Wang, Bei‐Hao Zhang, Xiao‐Qing Lu, Rui‐Qiang Wang.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Gastrin‐releasing peptide receptor gene silencing suppresses the development of the epithelial–mesenchymal transition (EMT) and formation of a calcium oxalate crystal in renal tubular epithelial cells (TECs) of kidney stones through the inactivation of the PI3K/Akt signaling pathway. Between 1% and 15% of people are globally affected by kidney stones, and this disease has become more common since the 1970s. Therefore, this study aims to investigate the effects of gastrin‐releasing peptide receptor (GRPR) gene silencing via the PI3K/Akt signaling pathway on the development of the epithelial–mesenchymal transition (EMT) and formation of a calcium oxalate crystal in renal tubular epithelial cells (TECs) of kidney stones. A total of 70 clean and healthy C57BL/6J mice were assigned into the normal ( n = 10) and kidney stones groups ( n = 60). The underlying regulatory mechanisms of GRPR were analyzed in concert with the treatment of shGRPR‐1, LY294002, and shGRPR‐1 + LY294002 in TECs isolated from mice with kidney stones. A series of experiments were conducted for the measurement of urinary oxalate and urinary calcium, the renal calcium salt deposition, the positive rate of GRPR, the expressions of renal TECs related genes and calcium oxalate regulation related genes, and the growth of calcium crystals induced by cells. After treatment of shGRPR‐1 and shGRPR‐1 + LY294002, levels of urinary oxalate and urinary calcium in the serum, as well as positive rate of GRPR, became relatively low, levels of E‐cadherin enhanced, whereas levels of Akt, PI3K, GRPR, extents of PI3K and Akt phosphorylation, α‐SMA, Vimentin and FSP‐1, OPN, MCP‐1, and CD44 decreased and a number of crystals reduced. Taken together, we conclude that GRPR gene silencing suppresses the development of the EMT and formation of the calcium oxalate crystal in renal TECs of kidney stones through the inactivation of the PI3K/Akt signaling pathway. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1567-1577, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27023   open full text
• Combination therapy with KRAS siRNA and EGFR inhibitor AZD8931 suppresses lung cancer cell growth in vitro.
  Habib Zarredar, Shadi Pashapour, Khalil Ansarin, Majid Khalili, Roghayyeh Baghban, Safar Farajnia.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- In this study, we try to understand that if we knock down some important genes like the Kirsten rat sarcoma oncogene (KRAS) and the epidermal growth factor receptor (EGFR) family in lung cancer cell lines, we could control proliferation and development of these cancer cells. Lung cancer is a leading cause of cancer‐related deaths worldwide, with less than a 5‐year survival rate for both men and women. Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma oncogene (KRAS) signaling pathways play a critical role in the proliferation and progression of various cancers, including lung cancer. Genetic studies have shown that amplification, over‐expression, or mutation of EGFR is an early and major molecular event in many human tumors. KRAS mutation is a negative factor in various cancer, including non‐small‐cell lung cancer, and complicates therapeutic approaches with adjuvant chemotherapy and anti‐EGFR directed therapies. This article is dedicated to evaluating the synergistic effect of a novel EGFR inhibitor AZD8931 and KRAS small interfering RNA (siRNA) on the proliferation and apoptosis of lung adenocarcinoma cancer cells. A549 lung cancer cells were treated with KRAS siRNA and the EGFR inhibitor alone or in combination. The cytotoxic effects of KRAS siRNA and te EGFR inhibitor were determined usingMTT assay, and induction of apoptosis was determined by FACS analysis. Suppression of KRAS, Her‐2, and EGFR expression by treatments was measured by qRT‐PCR and western blotting. KRAS siRNA and the EGFR inhibitor significantly reduced the proliferation of A549 cells as well as KRAS and EGFR mRNA levels 24 hr after treatment. The results also indicated that the silencing of KRAS and EGFR has synergistic effects on the induction of apoptosis on the A549 cells. These results indicated that KRAS and EGFR might play important roles in the progression of lung cancer and could be potential therapeutic targets for treatment of lung cancer. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1560-1566, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27021   open full text
• Inhibition of JNK and p38 MAPK‐mediated inflammation and apoptosis by ivabradine improves cardiac function in streptozotocin‐induced diabetic cardiomyopathy.
  Guangfeng Zuo, Xiaomin Ren, Xuesong Qian, Peng Ye, Jie Luo, Xiaofei Gao, Junjie Zhang, Shaoliang Chen.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2 (a) The JNK and p38 MAPK protein levels in heart tissues after intramyocardial injection of lentiviruses carrying shRNA targeting JNK (LV‐JNK shRNA) and p38 MAPK (LV‐p38 MAPK shRNA). (b,c) Proinflammatory cytokine mRNA and protein expression were significantly decreased in diabetic mice treated with LV‐JNK shRNA and LV‐p38 MAPK shRNA. Column figure shows the difference in mRNA and protein expression. (d) TUNEL staining of heart tissues in each group. Inflammation plays a critical role in the development of diabetic cardiomyopathy (DCM), which has been identified as a major predisposing factor for heart failure in diabetic patients. Previous studies indicated that ivabradine (a specific agent for heart rate [HR] reduction) has anti‐inflammatory properties, but its role in DCM remains unknown. This study investigated whether ivabradine exerts a therapeutic effect in DCM. C57BL/6J mice were injected intraperitoneally with streptozotocin (STZ) to induce diabetes; then administered with ivabradine or saline (control). After 12 weeks, the surviving mice were analyzed to determine the cardioprotective effect of ivabradine against DCM. Although treatment with ivabradine did not affect blood glucose levels, it attenuated tumor necrosis factor‐α, interleukin‐1β, and interleukin‐6 messenger RNA (mRNA) expression, inhibited c‐Jun N‐terminal kinase (JNK) and p38 mitogen‐activated protein kinase (p38 MAPK) activation, reduced histological abnormalities, myocardial apoptosis and collagen deposition, and improved cardiac function in the diabetic mice. Interestingly, the anti‐inflammatory and antiapoptotic properties of ivabradine, but not its inhibitory effect on JNK and p38 MAPK, were observed in high‐glucose‐cultured neonatal rat ventricular cardiomyocytes. Attenuating inflammation and apoptosis via intramyocardial injection of lentiviruses carrying short hairpin RNA targeting JNK and p38 MAPK validated that the anti‐inflammatory and antiapoptotic effects of ivabradine were partly attributed to JNK and p38 MAPK inactivation in diabetic mice. In summary, these data indicate that ivabradine‐mediated improvement of cardiac function in STZ‐induced diabetic mice may be partly attributed to inhibition of JNK/p38 MAPK‐mediated inflammation and apoptosis, which is dependent on the reduction in HR. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1925-1936, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27070   open full text
• Identification of key gene modules and pathways of human glioma through coexpression network.
  Tianming Shi, Jianchun Chen, Jing Li, Bing‐Yin Yang, Qiao‐Lin Zhang.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Glioma causes great harm to people worldwide. Systemic coexpression analysis of this disease could be beneficial for the identification and development of new prognostic and predictive markers in the clinical management of glioma. In this study, we extracted data sets from GEO (Gene Expression Omnibus) data set by using “glioma” as the keyword. Then, a coexpression module was constructed with the help of WGCNA (Weighted Gene Coexpression Network Analysis) software. Besides, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the genes in these modules. As a result, the critical modules and target genes were identified. Eight coexpression modules were constructed using the 4,000 genes with a high expression value of the total 141 glioma samples. The result of the analysis of the interaction among these modules showed that there was a high scale independence degree among them. The GO and KEGG enrichment analyses showed that there was a significant difference in the enriched terms and degree among these eight modules, and module 5 was identified as the most important module. Besides, the pathways it was enriched in, hsa04510: Focal adhesion and hsa04610: Complement and coagulation cascades, were determined as the most important pathways. In summary, module 5 and the pathways it was enriched in, hsa04510: Focal adhesion and has 04610: Complement and coagulation cascades, have the potential to serve as biomarkers for glioma patients. Glioma causes great harm to people worldwide. Systemic coexpression analysis of this disease could be beneficial for the identification and development of new prognostic and predictive markers in the clinical management of glioma. In this study, we extracted data sets from the Gene Expression Omnibus data set by using “glioma” as the keyword. Then, a coexpression module was constructed with the help of Weighted Gene Coexpression Network Analysis software. Besides, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the genes in these modules. As a result, the critical modules and target genes were identified. Eight coexpression modules were constructed using the 4,000 genes with a high expression value of the total 141 glioma samples. The result of the analysis of the interaction among these modules showed that there was a high scale independence degree among them. The GO and KEGG enrichment analyses showed that there was a significant difference in the enriched terms and degree among these eight modules, and module 5 was identified as the most important module. Besides, the pathways it was enriched in, hsa04510: Focal adhesion and hsa04610: Complement and coagulation cascades, were determined as the most important pathways. In summary, module 5 and the pathways it was enriched in, hsa04510: Focal adhesion and has 04610: Complement and coagulation cascades, have the potential to serve as biomarkers for patients with glioma. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1862-1870, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27059   open full text
• The effect of high‐fat diet and inhibition of ceramide production on insulin action in liver.
  Piotr Zabielski, Jarosław Daniluk, Hady Razak Hady, Adam R. Markowski, Monika Imierska, Jan Górski, Agnieszka U. Blachnio‐Zabielska.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Hepatic insulin resistance induced by high‐fat diet resulted from an increase in synthesis rate of ceramide and diacylglycerol (DAG). Myriocin treatment improved insulin sensitivity, which was accompanied by a decrease in the synthesis rate and content of ceramide and DAG. Liver, as one of the most important organs involved in lipids and glucose metabolism, is perceived as a key tissue for pharmacotherapy of insulin resistance (IRes) and type 2 diabetes. Ceramides (Cer) are biologically active lipids, which accumulation is associated with the induction of muscle IRes. We sought to determine the role of intrahepatic bioactive lipids production on insulin action in liver of insulin‐resistant rats and after myriocin administration. The experiments were conducted on male Wistar rats divided into three groups: Control, fed high‐fat diet (HFD), and fed HFD and treated with myriocin (HFD/Myr). Before sacrifice, the animals were infused with a [U‐13C]palmitate to calculate lipid synthesis rate by means of tracer incorporation technique in particular lipid groups. Liver Cer, diacylglycerols (DAG), acyl‐carnitine concentration, and isotopic enrichment were analyzed by LC/MS/MS. Proteins involved in lipid metabolism and insulin pathway were analyzed by western blot analysis. An OGTT and ITT was also performed. HFD‐induced IRes and increased both the synthesis rate and the content of DAG and Cer, which was accompanied by inhibition of an insulin pathway. Interestingly, myriocin treatment reduced synthesis rate not only of Cer but also DAG and improved insulin sensitivity. We conclude that the insulin‐sensitizing action of myriocin in the liver is a result of the lack of inhibitory effect of lipids on the insulin pathway, due to the reduction of their synthesis rate. This is the first study showing how the synthesis rate of individual lipid groups in liver changes after myriocin administration. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1851-1861, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27058   open full text
• MicroRNA‐590‐5p functions as a tumor suppressor in breast cancer conferring inhibitory effects on cell migration, invasion, and epithelial–mesenchymal transition by downregulating the Wnt–β‐catenin signaling pathway.
  Jin Gao, Shao‐Rong Yu, Yuan Yuan, Li‐Li Zhang, Jian‐Wei Lu, Ji‐Feng Feng, Sai‐Nan Hu.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- This study provides evidence suggesting that the transfection of overexpressed miR‐590‐5p can act to alleviate the effects of breast cancer demonstrating an ability to inhibit the processes of cell proliferation, migration, and invasion as well as epithelial–mesenchymal transition by suppressing the expression of paired‐like homeodomain transcription factor 2 and activation of the Wnt–β‐catenin pathway. Abstract Breast cancer remains one of the foremost primary causes of female morbidity and mortality worldwide. During the current study, the effect of miR‐590‐5p and paired‐like homeodomain transcription factor 2 (PITX2) on proliferation, invasion, migration, and epithelial–mesenchymal transition (EMT) of human breast cancer via the Wnt–β‐catenin signaling pathway was investigated. Breast cancer–related genes and related signaling pathways were obtained from KEGG database. The PITX2 regulatory microRNA was predicted. To define the contributory role by which miR‐590‐5p influences the progression of breast cancer, the interaction between miR‐590‐5p and PITX2 was explored; the proliferation, invasion, and migration abilities as well as the tumor growth and metastasis in nude mice were detected following the overexpression or silencing of miR‐590‐5p. PITX2 was determined to share a correlation with breast cancer and miR‐590‐5p was selected for further analysis. PITX2, Wnt‐1, β‐catenin, N‐cadherin, and vimentin all displayed higher levels, while miR‐590‐5p and E‐cadherin expression were lower among breast cancer tissues than in the adjacent normal tissue. After overexpression of miR‐590‐5p or si‐PITX2, the expression of E‐cadherin was markedly increased, decreases in the expression of Wnt‐1, β‐catenin, N‐cadherin, and vimentin, as well as inhibited cell proliferation, invasion, migration, metastasis, and EMT were observed. This study provides evidence suggesting that the transfection of overexpressed miR‐590‐5p can act to alleviate the effects of breast cancer demonstrating an ability to inhibit the processes of cell proliferation, migration, and invasion as well as EMT by suppressing the expression of PITX2 and activation of the Wnt–β‐catenin pathway. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1827-1841, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27056   open full text
• Licochalcone D directly targets JAK2 to induced apoptosis in human oral squamous cell carcinoma.
  Ji‐Hye Seo, Hyun Woo Choi, Ha‐Na Oh, Mee‐Hyun Lee, Eunae Kim, Goo Yoon, Seung‐Sik Cho, Seon‐Min Park, Young Sik Cho, Jung‐Il Chae, Jung‐Hyun Shim.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Our results demonstrated that LCD inhibited the kinase activity of JAK2, soft agar colony formation, and the proliferation of HN22 and HSC4 cells. LCD also induced mitochondrial apoptotic events such as altered mitochondrial membrane potential and reactive oxygen species production and, LCD increased expression of apoptosis‐associated proteins in oral squamous cell carcinoma cells. These results indicate that the anticancer effect of LCD is due to the direct targeting of JAK2 kinase. Licochalcone (LC) families have been reported to have a wide range of biological function such as antioxidant, antibacterial, antiviral, and anticancer effects. Although various beneficial effects of LCD were revealed, its anticancer effect in human oral squamous cancer has not been identified. To examine the signaling pathway of LCD’s anticancer effect, we determined whether LCD has physical interaction with Janus kinase (JAK2)/signal transducer and activator of transcription‐3 (STAT3) signaling, which is critical in promoting cancer cell survival and proliferation. Our results demonstrated that LCD inhibited the kinase activity of JAK2, soft agar colony formation, and the proliferation of HN22 and HSC4 cells. LCD also induced mitochondrial apoptotic events such as altered mitochondrial membrane potential and reactive oxygen species production. LCD increased the expression of apoptosis‐associated proteins in oral squamous cell carcinoma (OSCC) cells. Finally, the xenograft study showed that LCD significantly inhibited HN22 tumor growth. Immunohistochemical data supported that LCD suppressed p‐JAK2 and p‐STAT3 expression and induced cleaved‐caspase‐3 expression. These results indicate that the anticancer effect of LCD is due to the direct targeting of JAK2 kinase. Therefore, LCD can be used for therapeutic application against OSCC. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1780-1793, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27050   open full text
• LncRNA PVT1 regulates VEGFC through inhibiting miR‐128 in bladder cancer cells.
  Cui Yu, Liu Longfei, Wang Long, Zeng Feng, Jinbo Chen, Li Chao, Liu Peihua, Zu Xiongbing, Chen Hequn.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- PVT1 might play a critical role in bladder cancer tumorigenesis via miR‐218 and VEGFC. PVT1 could be a new biomarker for bladder cancer diagnosis and therapy. Long noncoding RNA PVT1 is considered to be an oncogene in multiple cancers. Our previous studies indicated that PVT1 levels were higher in bladder cancer tissue and correlated with clinical progression and poor prognosis in bladder cancer patients. A bioinformatics analysis showed that PVT1 may regulate VEGFC expression through miR‐128 as a competing endogenous RNA (ceRNA). In this study, we demonstrated that PVT1 expression levels affect the proliferation and migration ability of bladder cancer cells. Moreover, PVT1 knockdown significantly decreased the proliferation capacity of bladder cancer cells in nude mice. Luciferase assays and RNA‐binding protein immunoprecipitation were performed to investigate the potential mechanism of ceRNAs in the regulation of PVT1 and VEGFC. The results showed that the increased number of PVT1 transcripts interacted directly with miR‐128 to decrease miR‐128 binding to the VEGFC 3′‐untranslated region. This effect suppressed VEGFC mRNA degradation by miR‐128. In conclusion, these results indicated that PVT1 might play a critical role in bladder cancer tumorigenesis via miR‐218 and VEGFC. Therefore, PVT1 could be a new biomarker for bladder cancer diagnosis and therapy. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1346-1353, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26929   open full text
• Long non‐coding RNA LINC00152 promotes cell growth and invasion of papillary thyroid carcinoma by regulating the miR‐497/BDNF axis.
  Zhihui Sun, Xun Guo, Mingcui Zang, Peisong Wang, Shuai Xue, Guang Chen.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2 Long intergenic non‐coding RNA 152 (LINC00152) was reported to be tightly linked to tumorigenesis and progression in multiple cancers. However, its biological role and modulatory mechanism in papillary thyroid carcinoma (PTC) has not been elucidated. In this study, we determined the expression levels of LINC00152 in PTC tissues and cell lines by quantitative real time polymerase chain reaction (qRT‐PCR). Cell proliferation, colony formation, migration, and invasion were measured by a Cell Counting Kit‐8 assay, colony formation analysis, wound healing, and transwell invasion assay, respectively. A luciferase reporter assay and qRT‐PCR were used to determine whether LINC00152 interacts with miR‐497 directly. We established a xenograft mouse model to examine the underlying molecular mechanism and effect of LINC00152 on tumor growth in vivo. We found that LINC00152 expression was significantly increased in PTC tissues and derived cell lines. LINC00152 knockdown significantly inhibited proliferation, colony formation, migration, and invasion in vitro, and impaired tumor growth in vivo. We revealed that LINC00152 functioned as a competing endogenous RNA to the miR‐497 sponge, downregulating its downstream target brain‐derived neurotrophic factor (BDNF), which is an oncogene in thyroid cancer. These findings suggest that LINC00152 is responsible for PTC cell proliferation and invasion and exerts its function by regulating the miR‐497/BDNF axis. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1336-1345, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26928   open full text
• Estrogen‐related receptor γ negatively regulates osteoclastogenesis and protects against inflammatory bone loss.
  Hyun‐Ju Kim, Bo Kyung Kim, Boram Ohk, Hye‐Jin Yoon, Woo Youl Kang, Seungil Cho, Sook Jin Seong, Hae Won Lee, Young‐Ran Yoon.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Our findings identify orphan nuclear receptor ERRγ as a novel negative regulator of osteoclastogenesis and further reveals its protective role on inflammatory bone loss in vivo. Estrogen‐related receptor γ (ERRγ) is an orphan nuclear receptor that plays an important role in various metabolic processes under physiological and pathophysiological conditions. Here, we report that ERRγ functions as a negative regulator in receptor activator of nuclear factor κΒ ligand (RANKL)–induced osteoclast differentiation. We observed that ERRγ was strongly expressed in osteoclast precursors, bone marrow–derived macrophages (BMMs) while its expression was significantly reduced by RANKL during osteoclastogenesis. Overexpression of ERRγ in BMMs suppressed the formation of multinucleated osteoclasts and attenuated the induction of c‐Fos and nuclear factor of activated T cells c1, which are critical modulators in osteoclastogenesis. Similarly, the treatment of ERRγ agonists, N‐(4‐(diethylaminobenzylidenyl)‐N'‐(4‐hydroxybenzoyl)‐hydrazine (DY131) or GSK4716, also inhibited osteoclast generation and the expression of these key modulators. On the other hand, shRNA‐mediated knockdown of ERRγ accelerated the formation of bone‐resorbing cells and the expression of osteoclastogenic markers. Forced expression of ERRγ blocked RANKL‐stimulated phosphorylation of the nuclear factor κB (NF‐κB) inhibitor IκBα and suppressed NF‐κB transcriptional activity induced by RANKL or the NF‐κB subunit p65. Furthermore, by employing a pharmacological approach, we showed that the ERRγ agonist DY131 protected against inflammatory bone loss induced by lipopolysaccharide in vivo. Together, our findings reveal that ERRγ is a pivotal regulator in RANKL‐mediated osteoclastogenesis and suggest that ERRγ may have potential as a therapeutic target for pathological bone loss. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1659-1670, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27035   open full text
• Antioxidant effect of human placenta hydrolysate against oxidative stress on muscle atrophy.
  Dong‐ho Bak, Jungtae Na, Song I Im, Chang Taek Oh, Jeom‐Yong Kim, Sun‐Kyu Park, Hae Jung Han, Joon Seok, Sun Young Choi, Eun Jung Ko, Seog‐Kyun Mun, Suk‐Won Ahn, Beom Joon Kim.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Human placental hydrolysate required for the regulation of oxidative stress through the control of Mstn expression by nuclear factor‐κB, mitochondrial quality control, and autophagy process, leading to improved muscle atrophy. Sarcopenia, which refers to the muscle loss that accompanies aging, is a complex neuromuscular disorder with a clinically high prevalence and mortality. Despite many efforts to protect against muscle weakness and muscle atrophy, the incidence of sarcopenia and its related permanent disabilities continue to increase. In this study, we found that treatment with human placental hydrolysate (hPH) significantly increased the viability (approximately 15%) of H2O2‐stimulated C2C12 cells. Additionally, while H2O2‐stimulated cells showed irregular morphology, hPH treatment restored their morphology to that of cells cultured under normal conditions. We further showed that hPH treatment effectively inhibited H2O2‐induced cell death. Reactive oxygen species (ROS) generation and Mstn expression induced by oxidative stress are closely associated with muscular dysfunction followed by atrophy. Exposure of C2C12 cells to H2O2 induced abundant production of intracellular ROS, mitochondrial superoxide, and mitochondrial dysfunction as well as myostatin expression via nuclear factor‐κB (NF‐κB) signaling; these effects were attenuated by hPH. Additionally, hPH decreased mitochondria fission–related gene expression (Drp1 and BNIP3) and increased mitochondria biogenesis via the Sirt1/AMPK/PGC‐1α pathway and autophagy regulation. In vivo studies revealed that hPH‐mediated prevention of atrophy was achieved predominantly through regulation of myostatin and PGC‐1α expression and autophagy. Taken together, our findings indicate that hPH is potentially protective against muscle atrophy and oxidative cell death. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1643-1658, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27034   open full text
• Circular RNA circRNA_15698 aggravates the extracellular matrix of diabetic nephropathy mesangial cells via miR‐185/TGF‐β1.
  Wei Hu, Qing Han, Lei Zhao, Li Wang.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- circRNA_15698/miR‐185/TGF‐β1 promoted the extracellular matrix (ECM) related proteins synthesis. Circular RNAs (circRNAs) are a novel type of noncoding RNAs that modulate the pathogenesis of multiple diseases. Nevertheless, the role of circRNAs in diabetic nephropathy (DN) pathogenesis is still ambiguous. In the current study, our team aims to investigate the expression profiles of circRNAs in DN and identify the function of circRNA on mesangial cells. CircRNAs microarray analysis revealed dysregulated circRNA in db/db DN mice, and circRNA_15698 was validated to be upregulated in both db/db mice and mouse mesangial cells (SV40‐MES13) that were exposed to high glucose (25 mM) using real‐time polymerase chain reaction. Loss‐of‐functional experiments showed that circRNA_15698 knockdown significantly inhibited the expression levels of collagen type I (Col. I), collagen type IV (Col. IV), and fibronectin. Moreover, the cellular localization of circRNA_15698 was mainly in the cytoplasm. Bioinformatics tools and luciferase reporter assay confirmed that circRNA_15698 acted as a ‘sponge’ of miR‐185, and then positively regulated the transforming growth factor‐β1 (TGF‐β1) protein expression, suggesting a circRNA_15698/miR‐185/TGF‐β1 pathway. Further validation experiments validated that circRNA_15698/miR‐185/TGF‐β1 promoted extracellular matrix (ECM)‐related protein synthesis. In summary, our study preliminarily investigates the role of circRNAs in mesangial cells and ECM accumulation, providing a novel insight for DN pathogenesis. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1469-1476, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26959   open full text
• Nine hub genes as the potential indicator for the clinical outcome of diabetic nephropathy.
  Xiaoping Song, Min Gong, Yanping Chen, Hui Liu, Jun Zhang.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- In this study, a total of nine genes were found to have an important function in the occurrence and development of DN, among which six were reported earlier, and the result was further verified in this study. More important, the three remaining genes, VAV1, LCK, and PLK1, were identified as novel and had the potential to serve as the predictive indicator in the diagnosis and treatment of DN, which still needs further research. Diabetic nephropathy (DN) is one of the most serious and dangerous chronic complications caused by diabetes mellitus, and the identification and development of novel biomarkers could be beneficial for the diagnosis and prognosis of DN patients. This study focused on researching the differently expressed pattern of the DN samples from glomeruli and tubulointerstitium. Significance analysis of microarrays (SAM) was used to identify differentially regulated genes in 44 microdissected human kidney samples. Functional enrichment analysis was used to analyze the functions these genes are mostly enriched in. Besides, protein–protein interaction (PPI) network was used to select the hub genes that were associated with DN. The gene expression pattern of DN samples from glomeruli and tubulointerstitium was found to be quite different. It showed that the recurrence rate of DN originating from glomeruli and control samples was lower than that from tubulointerstitium and control samples. A total of 332 differentially expressed genes were identified between glomeruli tissues and tubulointerstitium tissues. PPI network analysis was performed on these 332 genes. Finally, nine hub genes were selected as the most potential biomarkers in the occurrence of DN. In conclusion, a total of 332 genes were found to be related to DN, and these genes were found to be mostly enriched in pathways such as immunity, inflammatory, and vascular pathways. Three genes VAV1, LCK, and Plk had the potential to serve as indicators for the occurrence and development of DN in clinical management. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1461-1468, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26958   open full text
• Downregulated microRNA‐488 enhances odontoblast differentiation of human dental pulp stem cells via activation of the p38 MAPK signaling pathway.
  Dan Yu, Xue Zhao, Jin‐Zhang Cheng, Di Wang, Hui‐Hui Zhang, Guang‐Hong Han.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Downregulation of miR‐488 promotes odontoblastic differentiation of human dental pulp stem cells (hDPSCs) by targeting mitogen‐activated protein kinases 1 (MAPK1) through the p38 MAPK signaling pathway, paving the basis for further study about hDPSCs. Human dental pulp stem cells (hDPSCs) are primarily derived from the pulp tissues of permanent third molar teeth. They were widely used in human bone tissue engineering. It was previously indicated that microRNA (miR) expressions are closely associated with hDPSCs development. However, the specific effect of miR‐488 on hDPSCs still remains unclear. In this study, we aimed to investigate effects of miR‐488 on the differentiation of hDPSCs into odontoblast cells through the p38 mitogen‐activated protein kinases (MAPK) signaling pathway by binding to MAPK1. The hDPSCs were isolated and cultured in vitro. Dual‐luciferase reporter gene assay was performed to test the relationship between MAPK1 (p38) and miR‐488. Reverse transcription quantitative polymerase chain reaction and western blot analysis were used to detect the mRNA and protein expressions of p38 MAPK signaling pathway‐related genes (MAPK1, Ras, and Mitogen‐activated protein kinase kinase 3/6 [MKK3/6]), along with expressions of dentin Sialophosphoprotein (DSPP), alkaline phosphatase (ALP), and osteonectin (OCN). ALP staining and alizarin red staining were conducted to detect ALP activity and degree of mineralization. Initially, we found that MAPK1 was the target gene of miR‐488. Besides, downregulation of miR‐488 was observed to stimulate the p38 MAPK signaling pathway and to increase the messenger RNA and protein expressions of DSPP, ALP, and OCN. Furthermore, ALP activity and formation of a mineralized nodule in hDPSCs were enhanced upon downregulation of miR‐488. The aforementioned findings provided evidence supporting that downregulation of miR‐488 promotes odontoblastic differentiation of hDPSCs through the p38 MAPK signaling pathway by targeting MAPK1, paving the basis for further study about hDPSCs. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1442-1451, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26950   open full text
• Preparation of superparamagnetic iron oxide/doxorubicin loaded chitosan nanoparticles as a promising glioblastoma theranostic tool.
  Leila Gholami, Mohsen Tafaghodi, Bita Abbasi, Majid Daroudi, Reza Kazemi Oskuee.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Illustration of ACSD nanoparticles (NPs) preparation by the ionic gelation method, and subsequent hypothetical scheme of ACSD NPs internalization. Theranostic nanoparticles (NPs) are promising for opening new windows toward personalized disease management. Using a single particle capable of both diagnosis and drug delivery, is the major benefit of such particles. In the present study, chitosan NPs were used as a dual action carrier for doxorubicin (DOX; chemotherapeutic agent) and superparamagnetic iron oxide nanoparticles (SPIONs; imaging agent). SPIONs and DOX were loaded at different concentrations within poly‐l‐arginine‐chitosan‐triphosphate matrix (ACSD) using the ionic gelation method. NPs’ size were in the range of 184.33 ± 4.4 nm. Drug release analysis of DOX loaded NPs (NP‐DOX) showed burst release at pH 5.5 (as in tumor environment) and slow release at pH 7.4 (physiological condition), demonstrating pH‐sensitive drug release profile. NP‐DOX internalization was confirmed by flowcytometry and fluorescent microscopy. Uptake process results were corroborated by accumulation of drug in the intracellular space. Iron content was evaluated by inductively coupled plasma and prussian blue staining. In vitro magnetic resonance imaging (MRI) showed a decline in T 2 relaxation times by increasing iron concentration. MRI analysis also confirmed uptake of NPs at the optimum concentration in C6 glioma cells. In conclusion, ACSD NPs could be utilized as a promising theranostic formulation for both diagnosis and treatment of glioblastoma. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1547-1559, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27019   open full text
• TBX18 transcription factor overexpression in human‐induced pluripotent stem cells increases their differentiation into pacemaker‐like cells.
  Armita M. Gorabi, Saeideh Hajighasemi, Hossein A. Tafti, Amir Atashi, Masoud Soleimani, Nasser Aghdami, Ali K. Saeid, Vahid Khori, Yunes Panahi, Amirhossein Sahebkar.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- In this in vitro study, the effect of T‐box 18 gene expression in human‐induced pluripotent‐stem‐cell‐derived cardiomyocytes to induce pacemaker‐like cells was examined. Background The discovery of gene‐ and cell‐based strategies has opened a new area to investigate novel approaches for the treatment of many conditions caused by cardiac cell failure. The TBX18 (T‐box 18) transcription factor is considered as a prominent factor in the sinoatrial node (SAN) formation during the embryonic development. In this in vitro study, the effect of TBX18 gene expression on human‐induced pluripotent‐stem‐cell‐derived cardiomyocytes (hiPS‐CMs) to induce pacemaker‐like cells was examined. Methods The human‐dermal‐fibroblast‐derived iPSCs were transfected using chemical, physical, and Lentiviral methods of TBX18 gene delivery during differentiation into cardiomyocytes (CMs). After the differentiation process through small‐molecule‐based temporal modulation of the Wnt signaling pathway, the hiPSC‐CMs were analyzed using the real‐time polymerase chain reaction, immunocytochemistry, immunofluorescence, whole‐cell patch‐clamp recording, and western blotting to investigate the accuracy of differentiation and identify the effect exerted by TBX18. Results The hiPS‐CMs showed spontaneous beating and expressed specific markers of cardiac cells. The lentiviral‐mediated TBX18 delivery was the most efficient method for transfection. The results showed the increment in Connexin 43 expression among untransfected hiPS‐CMs, whereas this protein was significantly downregulated followed by TBX18 overexpression. TBX18‐hiPSCMs were detected with pacemaker cell features. Conclusions It was demonstrated that the TBX18 gene is able to conduct hiPSCs to differentiate into pacemaker‐like cells. The TBX18 gene delivery seems to have the potential for the development of biological pacemakers; however, more investigations are still needed to assess its usefulness to fix arrhythmic conditions with SAN failure basis. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1534-1546, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27018   open full text
• ESM‐1 promotes adhesion between monocytes and endothelial cells under intermittent hypoxia.
  Haili Sun, Huina Zhang, Kun Li, Hao Wu, Xiaojun Zhan, Fang Fang, Yanwen Qin, Yongxiang Wei.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Intermittent hypoxia (IH), the key property of obstructive sleep apnea, is closely associated with endothelial dysfunction. Endothelial‐cell‐specific molecule‐1 (ESM‐1, Endocan) is a novel, reported molecule linked to endothelial dysfunction. The aim of this study is to evaluate the effect of IH on ESM‐1 expression and the role of ESM‐1 in endothelial dysfunction. ESM‐1 is significantly upregulated by HIF‐1α/vascular endothelial growth factor pathway under IH in endothelial cells, playing a role in enhancing adhesion between monocytes and endothelial cells, which might be a potential target for IH‐induced endothelial dysfunction. Intermittent hypoxia (IH), the key property of obstructive sleep apnea (OSA), is closely associated with endothelial dysfunction. Endothelial‐cell‐specific molecule‐1 (ESM‐1, Endocan) is a novel, reported molecule linked to endothelial dysfunction. The aim of this study is to evaluate the effect of IH on ESM‐1 expression and the role of ESM‐1 in endothelial dysfunction. We found that serum concentration of ESM‐1, inter‐cellular adhesion molecule‐1 (ICAM‐1), and vascular cell adhesion molecule‐1 (VCAM‐1) is significantly higher in patients with OSA than healthy volunteers (p < 0.01). The expression of ESM‐1, hypoxia‐inducible factor‐1 alpha (HIF‐1α), and vascular endothelial growth factor (VEGF) was significantly increased in human umbilical vein endothelial cells (HUVECs) by treated IH in a time‐dependent manner. HIF‐1α short hairpin RNA and vascular endothelial growth factor receptor (VEGFR) inhibitor inhibited the expression of ESM‐1 in HUVECs. ICAM‐1 and VCAM‐1 expressions were significantly enhanced under IH status, accompanied by increased monocyte–endothelial cell adhesion rate ( p < 0.001). Accordingly, ESM‐1 silencing decreased the expression of ICAM‐1 and VCAM‐1 in HUVECs, whereas ESM‐1 treatment significantly enhanced ICAM‐1 expression accompanied by increasing adhesion ability. ESM‐1 is significantly upregulated by the HIF‐1α/VEGF pathway under IH in endothelial cells, playing a critical role in enhancing adhesion between monocytes and endothelial cells, which might be a potential target for IH‐induced endothelial dysfunction. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1512-1521, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27016   open full text
• Exosome‐encapsulated miR‐6089 regulates inflammatory response via targeting TLR4.
  Donghua Xu, Meiyan Song, Chunxiang Chai, Jinghua Wang, Chengwen Jin, Xiaodong Wang, Min Cheng, Shushan Yan.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- TLR4 is a direct target for miR‐6089. MiR‐6089 regulates the generation of IL‐6, IL‐29, and TNF‐α by targetedly controlling the TLR4 signaling. Exosome‐encapsulated microRNAs (miRNAs) have been identified as potential biomarkers in autoimmune diseases. However, little is known about the role of exosome‐delivered miRNAs in rheumatoid arthritis (RA). In this study, we investigated the profile of specific exosomal miRNAs by microarray analysis of serum exosomes from three patients with RA and three healthy controls. Quantitative real‐time PCR (qRT‐PCR) was performed to validate the aberrantly expressed exosomal miRNAs. A total of 20 exosome‐encapsulated miRNAs were identified to be differently expressed in the serum of patients with RA compared with controls. Interestingly, we found that exosome‐encapsulated miR‐6089 was significantly decreased after validation by qRT‐PCR in serum exosomes from 76 patients with RA and 20 controls. Besides, miR‐6089 could inhibit lipopolysaccharide (LPS)‐induced cell proliferation and activation of macrophage‐like THP‐1 cells. TLR4 was a direct target for miR‐6089. MiR‐6089 regulated the generation of IL‐6, IL‐29, and TNF‐α by targetedly controlling TLR4 signaling. In conclusion, exosome‐encapsulated miR‐6089 regulates LPS/TLR4‐mediated inflammatory response, which may serve as a novel, promising biomarker in RA. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1502-1511, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27014   open full text
• Sex differences in murine cardiac pathophysiology with hyperoxia exposure.
  Jennifer L. Rodgers, Lydia E. Rodgers, Zhi Tian, Diane Allen‐Gipson, Siva K. Panguluri.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Hyperoxia is a common intervention in ICU. It is known that sex differences do exist in cardiovascular physiology, and this manuscript describes the sex differences in hyperoxia induced cardiac pathophysiology. Hyperoxia (>90% oxygen) is commonly implemented in mechanically ventilated patients. Reports suggest that hyperoxia is directly associated with in‐hospital mortality in ventilated patients. Certain studies also show that mortality in women undergoing mechanical ventilation is significantly higher than that in men. Additionally, females are predisposed to certain cardiac electrophysiological risks, including QTc prolongation. In this study, we assessed the impact of hyperoxia in male and female mice (C57BL/6J) at age 8–10 weeks. On completion of either hyperoxia or normoxia exposures, physical, hemodynamic, biochemical, functional, electrophysiological, and molecular assessments were conducted. Hyperoxia‐exposed mice lost a significant amount of body mass, compared with normoxia controls, in both sexes. However, while both genders developed brady‐arrhythmia after hyperoxia exposure, female mice exhibited significantly reduced heart rates compared with males, with significantly elevated RR intervals. Additionally, 50% mortality was observed in females, whereas no mortality was reported in males. Furthermore, unlike in male mice, we observed no hypertrophy upon hyperoxia exposure in female mice. We reported that both hyperoxia‐treated male and female mice exhibit significant hyperdynamic left ventricular ejection fraction, which is marked by % ejection fraction > 70 compared with the normoxia controls. We also noted significant reductions in stroke volume and cardiac output in both mice with hyperoxia. Surface ECG also demonstrated that hyperoxia exposure significantly augments RR, PR, QRS, QTc, and JT intervals in both sexes. Molecular analysis of left ventricular tissue demonstrated dysregulation of potassium ion channels in hyperoxia‐treated males and females. In summary, we determined that sex differences are present with 72 hr hyperoxia exposure. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1491-1501, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27010   open full text
• Inhibitory role of large intergenic noncoding RNA‐ROR on tamoxifen resistance in the endocrine therapy of breast cancer by regulating the PI3K/Akt/mTOR signaling pathway.
  Peng‐Wei Lu, Lin Li, Fang Wang, Yuan‐Ting Gu.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Our study demonstrated that silencing lincRNA‐ROR could increase the sensitivity of BC MAD‐MB‐231 cells to TAM by suppressing the activation of P13K/Akt/mTOR signaling pathway. Breast cancer (BC) is the second‐leading cause of central nervous system metastases among severe malignancies. This study aimed at investigating the underlying mechanism by which large intergenic noncoding RNA‐regulator of reprogramming (lincRNA‐ROR) affects the tamoxifen (TAM) resistance of BC cells by regulating the PI3K/Akt/mTOR signaling pathway. Immortalized human mammary epithelial cell line (MCF10A) and BC cell lines (MCF‐7, MDA‐MB‐231, T47D, BCAP‐37, and ZK‐75‐1) were cultured, and BC tissues and adjacent normal breast tissues were collected from 152 BC patients. LincRNA‐ROR expression in tissues and cells were detected using reverse transcription quantitative polymerase chain reaction. RNA interference was used to silence lincRNA‐ROR in MDA‐MB‐231 cells, and then the cell proliferation and apoptosis were detected by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay and annexin‐V and propidium iodide (PI) double staining respectively. The expression of apoptosis‐related proteins and PI3K/Akt/mTOR signaling pathway–related proteins was measured by performing western blot assay. The BC tissues and cells presented a higher expression of lincRNA‐ROR. MAD‐MB‐231 cells exhibited the highest lincRNA‐ROR expression. After lincRNA‐ROR silencing, MAD‐MB‐231 cells showed decreased proliferation, and increased sensitivity to TAM. Besides, the apoptosis‐promoting effect of TAM on MAN‐MB‐231 cells significantly increased. The expression of PI3K/Akt/mTOR signaling pathway–related proteins and the PI3K/Akt/mTOR signaling pathway were repressed by TAM after silencing lincRNA‐ROR. Our study demonstrated that silencing lincRNA‐ROR could increase the sensitivity of BC MAD‐MB‐231 cells to TAM by suppressing the activation of P13K/Akt/mTOR signaling pathway. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1904-1912, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27066   open full text
• Anticancer effects of echinacoside in hepatocellular carcinoma mouse model and HepG2 cells.
  Ying Ye, Yanan Song, Juhua Zhuang, Guoyu Wang, Jing Ni, Wei Xia.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Echinacoside (ECH) could attenuate diethylnitrosamine‐induced hepatocellular carcinoma (HCC) in mice, and exerted antiproliferative and proapoptotic functions on HepG2 HCC cell line. ECH exerted its antitumor activity via decreasing TREM2 expression and phosphoinositide 3‐kinase/AKT signaling. Echinacoside (ECH) is a phenylethanoid glycoside extracted from a Chinese herbal medicine, Cistanches salsa. ECH possesses many biological properties, including anti‐inflammation, neural protection, liver protection, and antitumor. In the current study, we aimed to explore the effects of ECH on hepatocellular carcinoma (HCC) and the underlying mechanisms. The results showed that ECH could attenuate diethylnitrosamine (DEN)‐induced HCC in mice, and exerted antiproliferative and proapoptotic functions on HepG2 HCC cell line. ECH exposure in HepG2 cells dose‐dependently reduced the phosphorylation of AKT (p‐AKT) and enhanced the expression of p21 (a cell cycle inhibitor) and Bax (a proapoptotic protein). Furthermore, ECH significantly suppressed insulin‐like growth factor‐1‐induced p‐AKT and cell proliferation. These data indicated that phosphoinositide 3‐kinase (PI3K)/AKT signaling was involved in the anti‐HCC activity of ECH. Gene set enrichment analysis results revealed a positive correlation between the PI3K pathway and triggering receptors expressed on myeloid cells 2 (TREM2) expression in HCC tissues. ECH exposure significantly decreased TREM2 protein levels in HepG2 cells and DEN‐induced HCC. Furthermore, ECH‐mediated proliferation inhibition and AKT signaling inactivation were notably attenuated by TREM2 overexpression. In conclusion, ECH exerted its antitumor activity via decreasing TREM2 expression and PI3K/AKT signaling. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1880-1888, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27063   open full text
• Chibby is a weak regulator of β‐catenin activity in gastric epithelium.
  Feng‐Qian Li, Luis Chiriboga, Margaret A. Black, Ken‐Ichi Takemaru, Robert D. Raffaniello.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Chibby (Cby) is a 14‐kDa protein that inhibits β‐catenin localization to the nucleus and represses β‐catenin‐induced transcriptional activity. Cby expression was decreased in gastric cancer (GC) tissue and Cby expression altered β‐catenin localization in cultured GC cells. However, Cby did not affect cell proliferation rates or β‐catenin‐induced protein expression. The canonical Wnt–β‐catenin pathway is important in normal development. Mutations in β‐catenin or proteins involved with regulating its phosphorylation or localization result in its nuclear accumulation where it activates its target genes and stimulates cell proliferation. This pathway is dysregulated in many different types of cancer, including gastric cancer (GC). Chibby (Cby) is a 14‐kDa protein that inhibits β‐catenin localization to the nucleus and represses β‐catenin‐induced transcriptional activity. In the current study, we examined the expression and function of Cby in normal and cancerous human gastric tissue. Reverse‐transcription polymerase chain reaction and immunohistochemistry revealed that Cby is expressed in human stomach and localized to glandular elements. Immunohistochemical staining intensity of Cby was decreased in GC tissue when compared with normal gastric epithelium. In AGS cells, a human gastric carcinoma cell line, Cby expression was low. Stable AGS cell transfectants overexpressing Cby were prepared. Cby overexpression did not affect proliferation rates or β‐catenin levels. However, confocal microscopy and subcellular fractionation studies revealed that Cby overexpression resulted in a small decrease in nuclear β‐catenin. Moreover, Cby overexpression caused a molecular weight shift in nuclear β‐catenin and resulted in decreased β‐catenin signaling in AGS cells as measured by the TopFlash assay. However, Cby overexpression did not affect c‐Myc protein levels. To conclude, Cby expression was decreased in GC samples and Cby expression altered β‐catenin localization in cultured GC cells. However, Cby did not affect cell proliferation rates or β‐catenin‐induced protein expression. Cby may be involved in the early events in the pathogenesis of GC. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1871-1879, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27062   open full text
• Circulating exosomal CPNE3 as a diagnostic and prognostic biomarker for colorectal cancer.
  Bo Sun, Yiming Li, Yiming Zhou, Tien Khee Ng, Chao Zhao, Qiaoqiang Gan, Xiaodong Gu, Jianbin Xiang.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Exosomal Copine III (CPNE3) levels are associated with the tumor extent and may serve as a diagnostic biomarker in patients with colorectal cancer (CRC). Combining measurement of exosomal CPNE3 in plasma with carcinoembryonic antigen (CEA) may further improve the diagnostic accuracy. The high exosomal CPNE3 level was a reliable indicator for worse disease‐free survival (DFS) and overall survival (OS). Exosomal proteins are emerging as relevant diagnostic and prognostic biomarkers for cancer. This study was aimed at illustrating the clinical significance of exosomal Copine III (CPNE3) purified from the plasma of colorectal cancer (CRC) patients. The CPNE3 expression levels in CRC tissues were analyzed by real‐time PCR, western blot, and immunohistochemistry. Plasma exosomes were isolated to examine the CPNE3 level using ELISA. Pearson’s correlation analysis was performed to investigate the CPNE3 levels between CRC tissues and matched plasma samples. Receiver operating characteristic curve analysis was developed to measure the diagnostic performance of exosomal CPNE3. The Kaplan–Meier method and Cox's proportional hazards model were utilized to determine statistical differences in survival times. CPNE3 showed increased expressions in the CRC tissues. A moderately significant correlation was found between CPNE3 expression in CRC tissues by immunohistochemistry and matched serum exosomal CPNE3 expression by ELISA (r = 0.645,(r = 0.645, p < 0.001). < 0.001). Exosomal CPNE3 yielded a sensitivity of 67.5% and a specificity of 84.4% in CRC at the cutoff value of 0.143 pg per 1ug1 ug exosome. Combined data from carcinoembryonic antigen and exosomal CPNE3 achieved 84.8% sensitivity and 81.2% specificity as a diagnostic tool. CRC patients with lower exosomal CPNE3 levels had substantially better disease‐free survival (hazard ratio [HR], 2.9; 95% confidence interval [CI]: 1.3–6.4; p = 0.009) = 0.009) and overall survival (HR, 3.4; 95% CI: 1.2–9.9; p = 0.026) = 0.026) compared with those with higher exosomal CPNE3 levels. Exosomal CPNE3 show potential implications in CRC diagnosis and prognosis. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1416-1425, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26936   open full text
• Venom of the Phoneutria nigriventer spider alters the cell cycle, viability, and migration of cancer cells.
  Natália Barreto dos Santos, Amanda Pires Bonfanti, Thomaz Augusto Alves da Rocha‐e‐Silva, Pedro Ismael da Silva, Maria Alice da Cruz‐Höfling, Liana Verinaud, Catarina Rapôso.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Phoneutria nigriventer venom (PnV) decreases viability of brain and cervix tumor, but not of nontumor cells. PnV decreases the viability of glioma cells primarily by modulating the cell cycle, while the viability of glioblastoma cells is reduced mainly by inducing death. PnV delays migration of tumor cells and decreases invasiveness. The mechanisms of cancer involve changes in multiple biological pathways. Multitarget molecules, which are components of animal venoms, are therefore a potential strategy for treating tumors. The objective of this study was to screen the effects of Phoneutria nigriventer spider venom (PnV) on tumor cell lines. Cultured human glioma (NG97), glioblastoma (U‐251) and cervix adenocarcinoma (HeLa) cells, and nontumor mouse fibroblasts (L929) were treated with low (14 µg/ml) and high (280 µg/ml) concentrations of PnV, and analyzed through assays for cell viability (thiazolyl blue tetrazolium blue), proliferation (carboxyfluorescein succinimidyl ester), death (annexin V/propidium iodide [Pi]), the cell cycle (Pi), and migration (wound healing and transwell assay). The venom decreased the viability of U‐251 cells, primarily by inducing cell death, and reduced the viability of NG97 cells, primarily by inhibiting the cell cycle. The migration of all the tumor cell lines was delayed when treated with venom. The venom significantly affected all the tumor cell lines studied, with no cytotoxic effect on normal cells (L929), although the nonglial tumor cell (HeLa) was less sensitive to PnV. The results of the current study suggest that PnV may be composed of peptides that are highly specific for the multiple targets involved in the hallmarks of cancer. Experiments are underway to identify these molecules. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1398-1415, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26935   open full text
• Nicotine downregulates microRNA‐200c to promote metastasis and the epithelial–mesenchymal transition in human colorectal cancer cells.
  Zhou Lei, Yang Xiaomin, Huang He, Chen Jian, Xu Xiaowu.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2 1) Cigarette smoking was independently associated with poorer survival, regardless of American Joint Committee on Cancer stage. 2) Nicotine progressively decreased microRNA (miR)‐200c expression in a time‐ and dose‐dependent manner in colorectal cancer (CRC) cells. 3) Nicotine promoted proliferation, migration, and invasion and the epithelial–mesenchymal transition in CRC cells, though overexpression of miR‐200c abrogated these nicotine‐induced effects. Background Cigarette smoking is the most well‐established risk factor for colorectal cancer (CRC). However, the mechanisms of smoking‐associated colorectal carcinogenesis are poorly understood. Methods The effects of prediagnosis tobacco use on clinical characteristics, overall survival (OS), and recurrence‐free survival (RFS) were analyzed in 396 patients with CRC. Associations between smoking status and OS and RFS were evaluated using Cox’s proportional hazards regression. Furthermore, the effects of nicotine on the CRC cell lines SW620 and HT‐29 were evaluated using in vitro assays. Results “Ever smoking” was associated with elevated serum carcinoembryonic antigen, American Joint Committee on Cancer T category, metastasis, and poorer OS and RFS in patients with CRC (OS: hazard ratio [HR] = 1.74, 95% confidence interval [CI], 1.07–2.81, p = 0.025; RFS: HR = 1.66, 95% CI: 1.18–2.34, p = 0.004). MicroRNA (miR)‐200c was downregulated in CRC and tumor‐adjacent tissues from ever smokers compared with the corresponding tissues from never smokers with CRC. Nicotine inhibited miR‐200c expression in a dose‐ and time‐dependent manner in SW620 and HT‐29 CRC cell lines. Nicotine induced cell proliferation, migration, and invasion and promoted the epithelial–mesenchymal transition in SW620 and HT‐29 cells, and these effects were attenuated by overexpression of miR‐200c. Conclusion Our findings support the adverse effects of prediagnosis cigarette smoking on prognosis and clinical behavior in CRC. We demonstrate a novel oncogenic mechanism by which nicotine promotes growth and metastasis in CRC by downregulating miR‐200c. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1369-1379, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.26933   open full text
• Rosmarinic acid inhibits nicotine‐induced C‐reactive protein generation by inhibiting NLRP3 inflammasome activation in smooth muscle cells.
  Yang Yao, Junjun Mao, Shouzhu Xu, Lei Zhao, Lihui Long, Lin Chen, Dongmin Li, Shemin Lu.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- (1) Rosmarinic acid plays a protective role in nicotine‐induced atherosclerosis. (2) Rosmarinic acid downregulates nicotine‐induced C‐reactive protein expression by inhibiting ROS‐mediated NLRP3 inflammasome activation in rat vascular smooth muscle cells. Atherosclerosis is widely known to be a chronic inflammatory disease. C‐reactive protein (CRP), an important inflammatory factor, plays an essential role in the pathogenesis of atherosclerosis. Nicotine, the main addictive component of cigarette, has been shown to induce the production of CRP. The aim of this study was to investigate the effect of rosmarinic acid (RA), a polyphenol with antiinflammatory activity, on nicotine‐induced elevation of CRP in vascular smooth muscle cells (VSMCs). We found that pretreatment of VSMCs with RA attenuated nicotine‐induced expression of CRP in a time‐ and dose‐dependant manner. In addition, RA also inhibited the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome and reactive oxygen species (ROS) production resulting from nicotine treatment in VSMCs. To confirm these findings in vivo, we constructed a nicotine‐induced atherosclerosis rat model. RA did not significantly reduce the serum nicotine level of the rats, whereas it significantly decreased the levels of serum lipids, including concentrations of cholesterol, triglycerides, and low‐density lipoprotein cholesterol, and the serum level of CRP. RA also led to diminished nicotine‐induced activation of NLRP3 inflammasome and elevation in the CRP level in the aortic tissue of the model rats. The results of this study suggested a protective role of RA in nicotine‐induced atherosclerosis by inhibiting the ROS–NLRP3 inflammasome–CRP axial, and RA therefore represented a potential effective therapeutic approach to atherosclerosis, in particular for those who smoke. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1758-1767, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27046   open full text
• Ameloblastin attenuates RANKL‐mediated osteoclastogenesis by suppressing activation of nuclear factor of activated T‐cell cytoplasmic 1 (NFATc1).
  Wichida Chaweewannakorn, Wataru Ariyoshi, Toshinori Okinaga, Yuko Fujita, Kenshi Maki, Tatsuji Nishihara.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Ameloblastin (Ambn) suppresses receptor activator of nuclear factor kappa‐B ligand (RANKL)‐induced osteoclastogenesis in three specific pathways; inhibition of JNK and p38 mitogen‐activated protein kinase (MAPK)‐mediated c‐Fos activation, calcium oscillation and cAMP‐response element‐binding protein (CREB)‐mediated nuclear factor of activated T cells cytoplasmic 1 (NFATc1) upregulation, and B‐lymphocyte‐induced maturation protein‐1 (Blimp1)‐mediated negative regulation of osteoclastogenesis Ameloblastin (Ambn) is an extracellular matrix protein and member of the family of enamel‐related gene products. Like amelogenin, Ambn is mainly associated with tooth development, especially biomineralization of enamel. Previous studies have shown reductions in the skeletal dimensions of Ambn‐deficient mice, suggesting that the protein also has effects on the differentiation of osteoblasts and/or osteoclasts. However, the specific pathways used by Ambn to influence osteoclast differentiation have yet to be identified. In the present study, two cellular models, one based on bone marrow cells and another on RAW264.7 cells, were used to examine the effects of Ambn on receptor activator of nuclear factor kappa‐B ligand (RANKL)‐induced osteoclastogenesis. The results showed that Ambn suppresses osteoclast differentiation, cytoskeletal organization, and osteoclast function by the downregulation of the number of tartrate‐resistant acid phosphatase (TRAP)‐positive multinucleated osteoclasts, actin ring formation, and areas of pit resorption. The expression of the osteoclast‐specific genes TRAP, MMP9, cathepsin K, and osteoclast stimulatory transmembrane protein (OC‐STAMP) was abolished in the presence of Ambn, while that of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), the master regulatory factor of osteoclastogenesis, was also attenuated by the downregulation of c‐Fos expression. In Ambn‐induced RAW264.7 cells, phosphorylation of cAMP‐response element‐binding protein (CREB), c‐Jun N‐terminal kinase (JNK), and p38 mitogen‐activated protein kinase (p38 MAPK), but not extracellular signal‐regulated kinase 1/2 (ERK1/2), was reduced. Calcium oscillation was also decreased in the presence of Ambn, suggesting its involvement in both RANKL‐induced osteoclastogenesis and costimulatory signaling. B‐lymphocyte‐induced maturation protein‐1 (Blimp1), a transcriptional repressor of negative regulators of osteoclastogenesis, was also downregulated by Ambn, resulting in the elevated expression of v‐maf musculoaponeurotic fibrosarcoma oncogene family, protein B (MafB), B‐cell lymphoma 6 (Bcl6), and interferon regulatory factor‐8 (Irf8). Taken together, these findings suggest that Ambn suppresses RANKL‐induced osteoclastogenesis by modulating the NFATc1 axis. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1745-1757, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27045   open full text
• CircHIPK3 promotes proliferation and invasion in nasopharyngeal carcinoma by abrogating miR‐4288‐induced ELF3 inhibition.
  Zhaoyang Ke, Fei Xie, Chaopan Zheng, Daishi Chen.
  Journal of Cellular Physiology. November 20, 2018
  --- - |2- Our findings demonstrated that circular homeodomain interacting protein kinase 3 (circHIPK3) facilitated nasopharyngeal carcinoma (NPC) progression through protecting E74‐like ETS transcription factor 3 (ELF3) from microRNA (miR)‐4288‐mediated silencing, which suggested that the circHIPK3‐miR‐4288‐ELF3 regulatory loop might be a potential target for NPC prevention. Circular RNAs (circRNAs) are reported to regulate the development and progression of multiple cancers. However, the functions of circRNAs in nasopharyngeal carcinoma (NPC) are unclear. In this study, we identified that circular homeodomain interacting protein kinase 3 (circHIPK3) was highly expressed in NPC tissues and cell lines. Moreover, we found that circHIPK3 expression levels could act as a prognostic marker in NPC patients. We showed that circHIPK3 silence repressed NPC cell proliferation, migration, and invasion in vitro. In addition, circHIPK3 depletion dramatically repressed tumor growth and metastasis in vivo. Mechanistically, we revealed circHIPK3 as a competing endogenous RNA of microRNA (miR)‐4288 that targets E74‐like ETS transcription factor 3 (ELF3) in NPC cells. We found that miR‐4288 inhibition reversed the effects of circHIPK3 silence on NPC cells. Furthermore, rescue assays also indicated that circHIPK3 promoted the malignant behaviors of NPC cells via enhancing ELF3 expression by suppressing the miR‐4288 levels. In conclusion, our findings demonstrated that circHIPK3 facilitated NPC progression through protecting ELF3 from miR‐4288‐mediated silencing, which suggested that the circHIPK3‐miR‐4288‐ELF3 regulatory loop might be a potential target for NPC prevention. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1699-1706, February 2019. '

  November 20, 2018   doi: 10.1002/jcp.27041   open full text
• Prognostic value of pretreatment systemic immune‐inflammation index in patients with gastrointestinal cancers.
  Yi Zhang, Shibu Lin, Xianjin Yang, Rong Wang, Lingyan Luo.
  Journal of Cellular Physiology. October 24, 2018
  --- - |2 Abstract Background Numerous studies have reported the relationship between systemic immune‐inflammation index (SII) and prognosis in gastrointestinal (GI) cancers, but no consensus has been reached. We aimed to systematically evaluate the prognostic value of SII in patients with GI cancers. Methods Relevant published papers regarding the prognostic value of SII in patients with GI cancers were obtained from a number of electronic databases. The overall hazard ratios and the corresponding 95% confidence intervals (95% CIs) were calculated using a fixed or random effects model to assess the relationship between SII and prognosis through Stata SE 12.0. Results A total of 24 eligible published articles with 9,626 patients were included. From the pooled results, we found that high SII indicated worse overall survival (OS) in patients with GI cancers (HR = 1.52, 95%CI: 1.29–1.74). And patients with high SII had poorer disease‐free survival (HR: 2.28, 95% CI: 1.46–3.10), time to recurrence (HR: 1.70, 95% CI: 1.11–2.30), and recurrence‐free survival (HR: 1.60, 95% CI: 1.19–2.00) when compared with those with low SII values. Conclusions SII might serve as a noninvasive and powerful tool for predicting survival outcome in patients with GI cancers. - Journal of Cellular Physiology, EarlyView.
  

  October 24, 2018   doi: 10.1002/jcp.27373   open full text
• Thrombin cleavage of osteopontin controls activation of hepatic stellate cells and is essential for liver fibrogenesis.
  Guangying Cui, Jianing Chen, Zhongwen Wu, Haijun Huang, Lin Wang, Yan Liang, Ping Zeng, Jiezuan Yang, Toshimitsu Uede, Hongyan Diao.
  Journal of Cellular Physiology. October 23, 2018
  --- - |2- Abstract Liver biopsy is the current reliable way of evaluating liver fibrosis. However, no specific sera biomarker could be applied in clinical diagnosis. As the pivotal role of osteopontin (OPN) reported in numerous liver diseases, thrombin‐cleaved OPN (Thr‐OPN) exposes an integrin‐binding motif that promoted biological functions. Herein, we investigated the potential of Thr‐OPN in liver fibrosis. Using patient samples, mouse models and hepatic stellate cells (HSCs), we analyzed the involvement of Thr‐OPN in liver fibrosis. The result showed that, first, Thr‐OPN level was significantly higher in patients with liver cirrhosis than that in patients with chronic hepatitis B and healthy controls. Thr‐OPN level was positively correlated with liver fibrosis degree in clinical samples. Then in mouse models, it showed a similar correlation between hepatic Thr‐OPN levels and liver fibrosis degree. Thr‐OPN peptides exacerbated liver fibrosis in OPN‐deficient mice, whereas the neutralization of Thr‐OPN alleviated liver fibrosis in wild‐type mice. Furthermore, when compared with full‐length OPN (FL‐OPN), Thr‐OPN exhibited a greater ability to promote HSC activation, proliferation, and migration via mitogen‐activated protein (MAP) kinase and nuclear factor (NF)‐κB pathways. In conclusion, Thr‐OPN, not FL‐OPN, was critically involved in the exacerbation of liver fibrosis by α9 and α4 integrins via MAP kinase and NF‐κB signaling pathway, thus representing a novel diagnostic biomarker and treatment target for liver cirrhosis. - Journal of Cellular Physiology, EarlyView.
  

  October 23, 2018   doi: 10.1002/jcp.27571   open full text
• Tumor suppressors BTG1 and BTG2: Beyond growth control.
  Laurensia Yuniati, Blanca Scheijen, Laurens T. Meer, Frank N. Leeuwen.
  Journal of Cellular Physiology. October 23, 2018
  --- - |2- Abstract Since the identification of B‐cell translocation gene 1 (BTG1) and BTG2 as antiproliferation genes more than two decades ago, their protein products have been implicated in a variety of cellular processes including cell division, DNA repair, transcriptional regulation and messenger RNA stability. In addition to affecting differentiation during development and in the adult, BTG proteins play an important role in maintaining homeostasis under conditions of cellular stress. Genomic profiling of B‐cell leukemia and lymphoma has put BTG1 and BTG2 in the spotlight, since both genes are frequently deleted or mutated in these malignancies, pointing towards a role as tumor suppressors. Moreover, in solid tumors, reduced expression of BTG1 or BTG2 is often correlated with malignant cell behavior and poor treatment outcome. Recent studies have uncovered novel roles for BTG1 and BTG2 in genotoxic and integrated stress responses, as well as during hematopoiesis. This review summarizes what is currently known about the roles of BTG1 and BTG2 in these and other cellular processes. In addition, we will highlight the molecular mechanisms and biological consequences of BTG1 and BTG2 deregulation during cancer progression and elaborate on the potential clinical implications of these findings. - Journal of Cellular Physiology, EarlyView.
  

  October 23, 2018   doi: 10.1002/jcp.27407   open full text
• Growth arrest‐specific 5 attenuates cisplatin‐induced apoptosis in cervical cancer by regulating STAT3 signaling via miR‐21.
  Tingting Yao, Rongbiao Lu, Jun Zhang, Xingyu Fang, Li Fan, Chunxian Huang, Rongchun Lin, Zhongqiu Lin.
  Journal of Cellular Physiology. October 23, 2018
  --- - |2- Abstract Cervical cancer is the most common cause of female cancer‐related mortality worldwide. Decreased expression of long noncoding RNA growth arrest‐specific 5 (GAS5) is found in human cervical cancer tissues and associated with poor prognosis. However, the studies on associations between GAS5 level and malignant phenotypes, as well as sensitivity to chemotherapeutic drug in cervical cancer cells are limited. In this study, overexpression of GAS5 in cervical cancer cells resulted in prohibited cell proliferation and colony formation, which were promoted by siGAS5. Enhanced GAS5 increased cell percentage in the G0/G1 phase and decreased cells percentage in the S phase, whereas reduced expression did not. The malignant behaviors of cervical cancer cells, manifested by cell migration and invasion, could be weakened by the GAS5 overexpression and enhanced by siGAS5. Furthermore, in cisplatin‐induced cell, overexpression of GAS5 reduced cells viability and enhanced apoptosis, whereas in cells transfected with siGAS5, apoptosis eliminated. We have reported the upregulation of microRNA‐21 (miR‐21) and its oncogenetic roles in cervical cancer previously. In this study, we found the negative relationship between the GAS5 and miR‐21. Moreover, the decrease of miR‐21 associated proteins phosphorylated STAT3 and E2F3 was seen in GAS5 overexpressed cells, both of which could be increased by siGAS5. The GAS5 deficiency also reduced miR‐21 target proteins TIMP3 and PDCD4 expressions. Taken together, the GAS5 expression level is inversely associated with malignancy, but positively associated with sensitivity to cisplatin‐induced apoptosis, suggesting that GAS5 could be a biomarker of cisplatin‐resistance in clinical therapy of human cervical cancer. - Journal of Cellular Physiology, EarlyView.
  

  October 23, 2018   doi: 10.1002/jcp.27647   open full text
• GLUT12 expression and regulation in murine small intestine and human Caco‐2 cells.
  Eva Gil‐Iturbe, Rosa Castilla‐Madrigal, Jaione Barrenetxe, Ana Cristina Villaro, María Pilar Lostao.
  Journal of Cellular Physiology. October 23, 2018
  --- - "\nAbstract\nGLUT12 was cloned from the mammary cancer cell line MCF‐7, but its physiological role still needs to be elucidated. To gain more knowledge of GLUT12 function in the intestine, we investigated GLUT12 subcellular localization in the small intestine and its regulation by sugars, hormones, and intracellular mediators in Caco‐2 cells and mice. Immunohistochemical methods were used to determine GLUT12 subcellular localization in human and murine small intestine. Brush border membrane vesicles were isolated for western blot analyses. Functional studies were performed in Caco‐2 cells by measuring α‐methyl‐d‐glucose (αMG) uptake in the absence of sodium. GLUT12 is located in the apical cytoplasm, below the brush border membrane, and in the perinuclear region of murine and human enterocytes. In Caco‐2 cells, GLUT12 translocation to the apical membrane and α‐methyl‐\nd‐glucose uptake by the transporter are stimulated by protons, glucose, insulin, tumor necrosis factor‐α (TNF‐α), protein kinase C, and AMP‐activated protein kinase. In contrast, hypoxia decreases GLUT12 expression in the apical membrane. Upregulation of \nTNF‐α and hypoxia‐inducible factor‐1α (\nHIF‐1α) genes is found in the jejunal mucosa of diet‐induced obese mice. In these animals, GLUT12 expression in the brush border membrane is slightly decreased compared with lean animals. Moreover, an intraperitoneal injection of insulin does not induce GLUT12 translocation to the membrane, as it occurs in lean animals. GLUT12 rapid translocation to the enterocytes’ apical membrane in response to glucose and insulin could be related to GLUT12 participation in sugar absorption during postprandial periods. In obesity, in which insulin sensitivity is reduced, the contribution of GLUT12 to sugar absorption is affected." - Journal of Cellular Physiology, EarlyView.
  

  October 23, 2018   doi: 10.1002/jcp.27231   open full text
• Zic1 mRNA is transiently upregulated in subcutaneous fat of acutely cold‐exposed mice.
  Jessica Perugini, Laura Bordoni, Wiebe Venema, Samantha Acciarini, Saverio Cinti, Rosita Gabbianelli, Antonio Giordano.
  Journal of Cellular Physiology. October 21, 2018
  --- - "\nAbstract\nIn the mammalian adipose organ cold exposure not only activates typical brown adipose tissue, but also induces browning, that is the formation of thermogenic multilocular adipocytes in white, or predominantly white, adipose depots such as subcutaneous fat. Unlike typical brown adipocytes, newly formed thermogenic adipocytes have been reported not to express the gene zinc finger of the cerebellum 1 (Zic1). Here, a time course approach enabled us to document a significant increase in \nZic1 messenger RNA in inguinal subcutaneous fat from acutely (24 hr) cold‐exposed mice, which was paralleled by an increase in multilocular and paucilocular uncoupling protein 1‐positive adipocytes and in parenchymal noradrenergic innervation. This transient, depot‐specific molecular signature was associated not to \nZic1 promoter demethylation, but to chromatin remodeling through an H3K9me3 histone modification. These findings challenge the notion that \nZic1 is exclusively expressed by typical brown adipocytes and suggest its involvement in brown adipocyte precursor differentiation and/or white‐to‐brown adipocyte transdifferentiation." - Journal of Cellular Physiology, EarlyView.
  

  October 21, 2018   doi: 10.1002/jcp.27301   open full text
• Pancreatic endocrine‐like cells differentiated from human umbilical cords Wharton’s jelly mesenchymal stem cells using small molecules.
  Sharath Belame Shivakumar, Dinesh Bharti, Raghavendra Baregundi Subbarao, Ju‐Mi Park, Young‐Bum Son, Imran Ullah, Yong‐Ho Choe, Hyeong‐Jeong Lee, Bong‐Wook Park, Sung‐Lim Lee, Gyu‐Jin Rho.
  Journal of Cellular Physiology. October 21, 2018
  --- - |2- Abstract Following success of pancreatic islet transplantation in the treatment of Type I diabetes mellitus, there is a growing interest in using cell‐based treatment approaches. However, severe shortage of donor islets–pancreas impeded the growth, and made researchers to search for an alternative treatment approaches. In this context, recently, stem cell–based therapy has gained more attention. The current study demonstrated that epigenetic modification improves the in vitro differentiation of Wharton’s jelly mesenchymal stem cells (WJMSCs) into pancreatic endocrine‐like cells. Here we used two histone deacetylase (HDAC) inhibitors namely trichostatin A (TSA) and TMP269. TSA inhibits both class I and II HDACs whereas TMP269 inhibits only class IIa HDACs. WJMSCs were differentiated using a multistep protocol in a serum‐free condition with or without TSA pretreatment. A marginal improvement in differentiation was observed after TSA pretreatment though it was not significant. However, exposing endocrine precursor‐like cells derived from WJMSCs to TMP269 alone has significantly improved the differentiation toward insulin‐producing cells. Further, increase in the expression of paired box 4 (PAX4), insulin, somatostatin, glucose transporter 2 (GLUT2), MAF bZIP transcription factor A (MAFA), pancreatic duodenal homeobox 1 (PDX‐1), and NKX6.1 was observed both at messenger RNA and protein levels. Nevertheless, TMP269‐treated cells secreted higher insulin upon glucose challenge, and demonstrated increased dithizone staining. These findings suggest that TMP269 may improve the in vitro differentiation of WJMSCs into insulin‐producing cells. - Journal of Cellular Physiology, EarlyView.
  

  October 21, 2018   doi: 10.1002/jcp.27184   open full text
• TRPM4 channel is involved in regulating epithelial to mesenchymal transition, migration, and invasion of prostate cancer cell lines.
  Alfredo I. Sagredo, Eduardo A. Sagredo, Victor Pola, César Echeverría, Rodrigo Andaur, Luis Michea, Andrés Stutzin, Felipe Simon, Katherine Marcelain, Ricardo Armisén.
  Journal of Cellular Physiology. October 21, 2018
  --- - |2- Abstract Transient Receptor Potential Melastatin 4 (TRPM4) is a Ca2+‐activated and voltage‐dependent monovalent cation channel, which depolarizes the plasma cell membrane, thereby modulating Ca2+ influx across Ca2+‐permeable pathways. TRPM4 is involved in different physiological processes such as T cell activation and the migration of endothelial and certain immune cells. Overexpression of this channel has been reported in various types of tumors including prostate cancer. In this study, a significant overexpression of TRPM4 was found only in samples from cancer with a Gleason score higher than 7, which are more likely to spread. To evaluate whether TRPM4 overexpression was related to the spreading capability of tumors, TRPM4 was knockdown by using shRNAs in PC3 prostate cancer cells and the effect on cellular migration and invasion was analyzed. PC3 cells with reduced levels of TRPM4 (shTRPM4) display a decrease of the migration/invasion capability. A reduction in the expression of Snail1, a canonical epithelial to mesenchymal transition (EMT) transcription factor, was also observed. Consistently, these cells showed a significant change in the expression of key EMT markers such as MMP9, E‐cadherin/N‐cadherin, and vimentin, indicating a partial reversion of the EMT process. Whereas, the overexpression of TRPM4 in LnCaP cells resulted in increased levels of Snail1, reduction in the expression of E‐cadherin and increase in their migration potential. This study suggests a new and indirect mechanism of regulation of migration/invasion process by TRPM4 in prostate cancer cells, by inducing the expression of Snail1 gene and consequently, increasing the EMT. - Journal of Cellular Physiology, EarlyView.
  

  October 21, 2018   doi: 10.1002/jcp.27371   open full text
• MiR302c, Sp1, and NFATc2 regulate interleukin‐21 expression in human CD4+CD45RO+ T lymphocytes.
  Hassan El‐Said, Mohammad Fayyad‐Kazan, Rabab Aoun, Nada Borghol, Najwa Skafi, Redouane Rouas, Luc Vanhamme, Mohamad Mourtada, Mohamad Ezzeddine, Arsène Burny, Hussein Fayyad‐Kazan, Bassam Badran.
  Journal of Cellular Physiology. October 21, 2018
  --- - |2- Abstract Interleukin‐21 (IL‐21) is a cytokine with potent regulatory effects on different immune cells. Recently, IL‐21 has been contemplated for use in the treatment of cancers. However, the molecular mechanisms regulating human IL‐21 gene expression has not yet been described. In this study, we initially studied the promoter region and identified the transcription start site. We thereafter described the essential region upstream of the transcription start site and showed the in vivo binding of NFATc2 and SP1 transcription factors to this region, in addition to their positive role in IL‐21 expression. We also studied the role of microRNAs (miRNAs) in regulating IL‐21 expression. We, thus, established the miRNA profile of CD4+CD45RO+ versus CD4+CD45RA+ isolated from healthy volunteers and identified a signature composed of 12 differentially expressed miRNAs. We showed that miR‐302c is able to negatively regulate IL‐21 expression by binding directly to its target site in the 3′‐untranslated region. Moreover, after using fresh human CD4‐positive T cells, we observed the high acetylation level of histone H4, an observation well in line with the already described high expression of IL‐21 in CD4+CD45RO+ versus CD4+CD45RA+ T cells. Altogether, our data identified different molecular mechanisms regulating IL‐21 expression. - Journal of Cellular Physiology, EarlyView.
  

  October 21, 2018   doi: 10.1002/jcp.27151   open full text
• CSC‐3436 inhibits TWIST‐induced epithelial–mesenchymal transition via the suppression of Twist/Bmi1/Akt pathway in head and neck squamous cell carcinoma.
  Ying‐Ju Lai, Wan‐Nien Yu, Sheng‐Chu Kuo, Chi‐Tang Ho, Chao‐Ming Hung, Tzong‐Der Way, Chiung‐Tong Chen.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer deaths worldwide, especially in male. With poor prognosis, significant portions of patients with HNSCC die due to cancer recurrence and tumor metastasis after chemotherapy and targeted therapies. The HNSCC FaDu cell ectopic expression of Twist, a key transcriptional factor of epithelial–mesenchymal transition (EMT), which triggers EMT and results in the acquisition of a mesenchymal phenotype, was used as the cell model. Our results demonstrated that treatment with newly synthesized 2‐(3‐hydroxyphenyl)‐5‐methylnaphthyridin‐4‐one (CSC‐3436), a flavonoid derivative, elicited changes in its cell morphology, upregulated E‐cadherin messenger RNA and protein expression, downregulated N‐cadherin, vimentin, and CD133 (a marker associated with tumor‐initiating cells) in FaDu‐pCDH‐Twist cells. Moreover, CSC‐3436 exposure reduced B cell‐specific Moloney murine leukemia virus integration site 1 (Bmi1) expression regulated by Twist and further suppressed the direct co‐regulation of E‐cadherin by Twist and Bmi1. Interestingly, CSC‐3436 reduced EMT, cancer stemness, and migration/invasion abilities through the inhibition of the Twist/Bmi1‐Akt/β‐catenin pathway. Most importantly, our findings provided new evidence that CSC‐3436 played a crucial role in therapeutic targeting to Bmi1 and its molecular pathway in HNSCC, and it will be valuable in prognostic prediction and treatment. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27589   open full text
• miR‐335‐5p induces insulin resistance and pancreatic islet β‐cell secretion in gestational diabetes mellitus mice through VASH1‐mediated TGF‐β signaling pathway.
  Xu‐Wen Tang, Qing‐Xin Qin.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Multiple studies have reported different methods in treating gestational diabetes mellitus (GDM); however, the relationship between miR‐335‐5p and GDM still remains unclear. Here, this study explores the effect of miR‐335‐5p on insulin resistance and pancreatic islet β‐cell secretion via activation of the TGFβ signaling pathway by downregulating VASH1 expression in GDM mice. The GDM mouse model was established and mainly treated with miR‐335‐5p mimic, miR‐335‐5p inhibitor, si‐VASH1, and miR‐335‐5p inhibitor + si‐VASH1. Oral glucose tolerance test (OGTT) was conducted to detect fasting blood glucose (FBG) fasting insulin (FINS). The OGTT was also used to calculate a homeostasis model assessment of insulin resistance (HOMA‐IR). A hyperglycemic clamp was performed to measure the glucose infusion rate (GIR), which estimated β‐cell function. Expressions of miR‐335‐5p, VASH1, TGF‐β1, and c‐Myc in pancreatic islet β‐cells were determined by RT‐qPCR, western blot analysis, and insulin release by ELISA. The miR‐335‐5p mimic and si‐VASH1 groups showed elevated blood glucose levels, glucose area under the curve (GAUC), and HOMA‐IR, but a reduced GIR and positive expression of VASH1. Overexpression of miR‐335‐5p and inhibition of VASH1 contributed to activated TGFβ1 pathway, higher c‐Myc, and lower VASH1 expressions, in addition to downregulated insulin and insulin release levels. These findings provided evidence that miR‐335‐5p enhanced insulin resistance and suppressed pancreatic islet β‐cell secretion by inhibiting VASH1, eventually activating the TGF‐β pathway in GDM mice, which provides more clinical insight on the GDM treatment. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27406   open full text
• Circular RNA in cardiovascular disease.
  M‐Ashraf Altesha, Tiffany Ni, Afaan Khan, Kexiang Liu, Xiufen Zheng.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Circular RNA (circRNA) are endogenous transcripts that display differential expression across species, developmental stages, and pathologies. Their lack of free ends confers increased stability when compared with linear transcripts, making them ideal candidates for future diagnostic biomarkers and therapeutic interventions. Increasing evidence has implicated circRNA in the pathogenesis of multiple cardiovascular diseases. In this paper, we summarize current understanding of circRNA biogenesis, properties, expression profiles, detection methods, functions, and their implication in cardiac pathologies including/ischemia reperfusion injury, myocardial infarction, cardiac senescence, cardiac fibrosis, cardiomyopathy, cardiac hypertrophy and heart failure, atherosclerosis, coronary artery disease, and aneurysm. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27384   open full text
• Strategies to target energy metabolism in consensus molecular subtype 3 along with Kirsten rat sarcoma viral oncogene homolog mutations for colorectal cancer therapy.
  Gang Wang, Jun‐Jie Wang, Pei‐Hao Yin, Ke Xu, Yu‐Zhu Wang, Feng Shi, Jing Gao, Xing‐Li Fu.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Alterations in cellular energy metabolism play a critical role in colorectal cancer (CRC), which has been identified as the definition of consensus molecular subtypes (CMSs), and CMS3 tumors exhibit energy metabolism signatures along with Kirsten rat sarcoma viral oncogene homolog (KRAS)‐activating mutations. This review summarizes the relationship between CMS3 tumors associated with mutated KRAS and energy metabolism in CRC, especially for the dysregulated energy metabolism that affects tumor cell proliferation, invasion, and migration. Furthermore, this review concentrates on the role of metabolic genes and factors and signaling pathways, which coupled with a primary energy source connected with the CMS3 associated with mutated KRAS, induce metabolic alterations. The strategies to target energy metabolism for the metabolic alterations in mutated KRAS CRC are also introduced. In conclusion, dysregulated energy metabolism has a close relationship with mutated KRAS in CMS3 tumors. Therefore, selective inhibitors or agents against metabolic targets or KRAS signaling may be clinically useful for CMS3 tumor treatment through a personalized approach for patients with cancer. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27388   open full text
• Wnt lipidation: Roles in trafficking, modulation, and function.
  Vahid Hosseini, Christian Dani, Mohammad Hossein Geranmayeh, Fatemeh Mohammadzadeh, Saeed Nazari Soltan Ahmad, Masoud Darabi.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract The Wnt signaling pathway consists of various downstream target proteins that have substantial roles in mammalian cell proliferation, differentiation, and development. Its aberrant activity can lead to uncontrolled proliferation and tumorigenesis. The posttranslational connection of fatty acyl chains to Wnt proteins provides the unique capacity for regulation of Wnt activity. In spite of the past belief that Wnt molecules are subject to dual acylation, it has been shown that these proteins have only one acylation site and undergo monounsaturated fatty acylation. The Wnt monounsaturated fatty acyl chain is more than just a hydrophobic coating and appears to be critical for Wnt signaling, transport, and receptor activation. Here, we provide an overview of recent findings in Wnt monounsaturated fatty acylation and the mechanism by which this lipid moiety regulates Wnt activity from the site of production to its receptor interactions. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27570   open full text
• Behçet’s disease: An immunogenetic perspective.
  Arash Salmaninejad, Mohammad Reza Zamani, Arezoo Gowhari Shabgah, Seyedmojtaba Hosseini, Fatemeh Mollaei, Nayyerehalsadat Hosseini, Amirhossein Sahebkar.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2 Abstract Behçet’s disease (BD) is a chronic and rare multisystemic disorder defined by autoimmunity and inflammatory characteristics, manifested by ocular lesions, recurrent genital and oral ulcers, skin symptoms and arthritis as well as neurological, intestinal, and vascular involvement. Despite the unknown cause of BD, there is some strong documentation for immunological, genetic, environmental, and infectious factors playing a role in the pathogenesis of BD. While the nature of the genetic variants remains unidentified, many genetic risk factors are considered to contribute to BD susceptibility. Along with human leukocyte antigen gene encoding B*51 (HLA‐B*51) and areas including the major histocompatibility complex class I, genome‐wide association studies have recognized numerous other BD susceptibility genes including those encoding interleukin (IL)‐10, IL‐12 receptor β 2 (IL‐12RB2), IL‐23 receptor (IL‐23R), C‐C chemokine receptor 1 gene, signal transducer and activator of transcription 4 (STAT4), endoplasmic reticulum aminopeptidase (ERAP1), and genes encoding killer cell lectin‐like receptor family members (KLRC4‐KLRK1). It is believed that BD could be considered as a disorder lying in between autoimmune and autoinflammatory syndromes. The positive responses to classical immunosuppressive agents like azathioprine and cyclosporine and involvement of autoantigens in the initiation of the disorder are the main BD features that reflect the autoimmune nature of the disorder. In this review, we address recent findings on the role of common cytokines, antibodies and immunogenetic factors in BD. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27576   open full text
• Pancreatic resident endocrine progenitors demonstrate high islet neogenic fidelity and committed homing towards diabetic mice pancreas.
  Abhay Srivastava, Nidheesh Dadheech, Mitul Vakani, Sarita Gupta.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Pancreatic progenitors have been explored for their profound characteristics and unique commitment to generate new functional islets in regenerative medicine. Pancreatic resident endocrine progenitors (PREPs) with mesenchymal stem cell (MSC) phenotype were purified from BALB/c mice pancreas and characterized. PREPs were differentiated into mature islet clusters in vitro by activin‐A and swertisin and functionally characterized. A temporal gene and protein profiling was performed during differentiation. Furthermore, PREPs were labeled with green fluorescent protein (GFP) and transplanted intravenously into streptozotocin (STZ) diabetic mice while monitoring their homing and differentiation leading to amelioration in the diabetic condition. PREPs were positive for unique progenitor markers and transcription factors essential for endocrine pancreatic homeostasis along with having the multipotent MSC phenotype. These cells demonstrated high fidelity for islet neogenesis in minimum time (4 days) to generate mature functional islet clusters (shortest reported period for any isolated stem/progenitor). Furthermore, GFP‐labeled PREPs transplanted in STZ diabetic mice migrated and localized within the injured pancreas without trapping in any other major organ and differentiated rapidly into insulin‐producing cells without an external stimulus. A rapid decrease in fasting blood glucose levels toward normoglycemia along with significant increase in fasting serum insulin levels was observed, which ameliorated the diabetic condition. This study highlights the unique potential of PREPs to generate mature islets within the shortest period and their robust homing toward the damaged pancreas, which ameliorated the diabetic condition suggesting PREPs affinity toward their niche, which can be exploited and extended to other stem cell sources in diabetic therapeutics. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27568   open full text
• Cyclooxygenase‐2 in cancer: A review.
  Nasser Hashemi Goradel, Masoud Najafi, Eniseh Salehi, Bagher Farhood, Keywan Mortezaee.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Cyclooxygenase‐2 (COX‐2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo‐ and radiotherapy. COX‐2 is released by cancer‐associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX‐2 induces cancer stem cell (CSC)‐like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. COX‐2 mediated hypoxia within the TME along with its positive interactions with YAP1 and antiapoptotic mediators are all in favor of cancer cell resistance to chemotherapeutic drugs. COX‐2 exerts most of the functions through its metabolite prostaglandin E2. In some and limited situations, COX‐2 may act as an antitumor enzyme. Multiple signals are contributed to the functions of COX‐2 on cancer cells or its regulation. Members of mitogen‐activated protein kinase (MAPK) family, epidermal growth factor receptor (EGFR), and nuclear factor‐κβ are main upstream modulators for COX‐2 in cancer cells. COX‐2 also has interactions with a number of hormones within the body. Inhibition of COX‐2 provides a high possibility to exert therapeutic outcomes in cancer. Administration of COX‐2 inhibitors in a preoperative setting could reduce the risk of metastasis in cancer patients. COX‐2 inhibition also sensitizes cancer cells to treatments like radio‐ and chemotherapy. Chemotherapeutic agents adversely induce COX‐2 activity. Therefore, choosing an appropriate chemotherapy drugs along with adjustment of the type and does for COX‐2 inhibitors based on the type of cancer would be an effective adjuvant strategy for targeting cancer. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27411   open full text
• Runx2 is required for postnatal intervertebral disc tissue growth and development.
  Lifan Liao, Hua Jiang, Yunshan Fan, Ronald S. Lu, Changli Wei, Takeshi Takarada, Shisheng He, Di Chen.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Runx2 plays an essential role in embryonic disc tissue development in mice. However, the role of runt‐related transcription factor 2 (Runx2) in postnatal disc tissue growth and development has not been defined. In the present studies, we generated Runx2 conditional knockout (KO) mice (Runx2Agc1ER), in which Runx2 was deleted in Aggrecan‐expressing cells in disc tissue at postnatal 2‐weeks of age. We then analyzed changes in disc tissue growth and development using histology and immunohistochemical methods in 3‐month‐old mice. We found that large vacuolated notochordal cells were accumulated in the nucleus pulposus (NP) in Runx2 KO mice. The growth plate cartilage tissue in the disc was thicker in Runx2 KO mice. We also found a significant upregulation of Indian hedgehog (Ihh) expression in the cells in NP cells and in annulus fibrosus cells of Runx2 KO mice. These results demonstrated that Runx2 may play an important role in postnatal disc tissue development through interacting with Ihh signaling. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27410   open full text
• Homogentisic acid induces morphological and mechanical aberration of ochronotic cartilage in alkaptonuria.
  Giulia Bernardini, Gemma Leone, Lia Millucci, Marco Consumi, Daniela Braconi, Ottavia Spiga, Silvia Galderisi, Barbara Marzocchi, Cecilia Viti, Giovanna Giorgetti, Pietro Lupetti, Agnese Magnani, Annalisa Santucci.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Alkaptonuria (AKU) is a disease caused by a deficient homogentisate 1,2‐dioxygenase activity leading to systemic accumulation of homogentisic acid (HGA), that forms a melanin‐like polymer that progressively deposits onto connective tissues causing a pigmentation called “ochronosis” and tissue degeneration. The effects of AKU and ochronotic pigment on the biomechanical properties of articular cartilage need further investigation. To this aim, AKU cartilage was studied using thermal (thermogravimetry and differential scanning calorimetry) and rheological analysis. We found that AKU cartilage had a doubled mesopore radius compared to healthy cartilage. Since the mesoporous structure is the main responsible for maintaining a correct hydrostatic pressure and tissue homoeostasis, drastic changes of thermal and rheological parameters were found in AKU. In particular, AKU tissue lost its capability to enhance chondrocytes metabolism (decreased heat capacity) and hence the production of proteoglycans. A drastic increase in stiffness and decrease in dissipative and lubricant role ensued in AKU cartilage. Multiphoton and scanning electron microscopies revealed destruction of cell–matrix microstructure and disruption of the superficial layer. Such observations on AKU specimens were confirmed in HGA‐treated healthy cartilage, indicating that HGA is the toxic responsible of morphological and mechanical alterations of cartilage in AKU. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27416   open full text
• Helvolic acid attenuates osteoclast formation and function via suppressing RANKL‐induced NFATc1 activation.
  Kai Chen, Yu Yuan, Ziyi Wang, Dezhi Song, Jinmin Zhao, Zhen Cao, Junhao Chen, Qiang Guo, Li Chen, Jennifer Tickner, Jiake Xu.
  Journal of Cellular Physiology. October 20, 2018
  --- - "\nAbstract\nExcessive osteoclast formation and function are considered as the main causes of bone lytic disorders such as osteoporosis and osteolysis. Therefore, the osteoclast is a potential therapeutic target for the treatment of osteoporosis or other osteoclast‐related diseases. Helvolic acid (HA), a mycotoxin originally isolated from Aspergillus fumigatus , has been discovered as an effective broad‐spectrum antibacterial agent and has a wide range of pharmacological properties. Herein, for the first time, HA was demonstrated to be capable of significantly inhibiting receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclastogenesis and bone resorption in vitro by suppressing nuclear factor of activated T cells 1 (NFATc1) activation. This inhibition was followed by the dramatically decreased expression of NFATc1‐targeted genes including \nCtr (encoding calcitonin receptor), \nAcp5 (encoding tartrate‐resistant acid phosphatase [TRAcP]), \nCtsk (encoding cathepsin K), \nAtp6v0d2 (encoding the vacuolar H+ ATPase V0 subunit d2 [V‐ATPase‐d2]) and \nMmp9 (encoding matrix metallopeptidase 9) which are osteoclastic‐specific genes required for osteoclast formation and function. Mechanistically, HA was shown to greatly attenuate multiple upstream pathways including extracellular signal‐regulated kinase (ERK) phosphorylation, c‐Fos signaling, and intracellular Ca\n2+ oscillation, but had little effect on nuclear factor‐κB (NF‐κB) activation. In addition, HA also diminished the RANKL‐induced generation of intracellular reactive oxygen species. Taken together, our study indicated HA effectively suppressed RANKL‐induced osteoclast formation and function. Thus, we propose that HA can be potentially used in the development of a novel drug for osteoclast‐related bone diseases." - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27385   open full text
• The role of sphingosine 1 phosphate in coronary artery disease and ischemia reperfusion injury.
  Aynaz Mihanfar, Hamid Reza Nejabati, Amir Fattahi, Zeinab Latifi, Masoud Pezeshkian, Abbas Afrasiabi, Naser Safaie, Ahmad Reza Jodati, Mohammad Nouri.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Coronary artery disease (CAD) is a common cause of morbidity and mortality worldwide. Atherosclerotic plaques, as a hallmark of CAD, cause chronic narrowing of coronary arteries over time and could also result in acute myocardial infarction (AMI). The standard treatments for ameliorating AMI are reperfusion strategies, which paradoxically result in ischemic reperfusion (I/R) injury. Sphingosine 1 phosphate (S1P), as a potent lysophospholipid, plays an important role in various organs, including immune and cardiovascular systems. In addition, high‐density lipoprotein, as a negative predictor of atherosclerosis and CAD, is a major carrier of S1P in blood circulation. S1P mediates its effects through binding to specific G protein‐coupled receptors, and its signaling contributes to a variety of responses, including cardiac inflammation, dysfunction, and I/R injury protection. In this review, we will focus on the role of S1P in CAD and I/R injury as a potential therapeutic target. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27353   open full text
• Signatures of altered long noncoding RNAs and messenger RNAs expression in the early acute phase of spinal cord injury.
  Zhongju Shi, Guangzhi Ning, Bin Zhang, Shiyang Yuan, Hengxing Zhou, Bin Pan, Jiahe Li, Zhijian Wei, Fujiang Cao, Xiaohong Kong, Shiqing Feng.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Spinal cord injury (SCI) is a highly severe disease and it can lead to the destruction of the motor and sensory function resulting in temporary or permanent disability. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nt that play a critical role in central nervous system (CNS) injury. However, the exact roles of lncRNAs and messenger RNAs (mRNAs) in the early acute phase of SCI remain to be elucidated. We examined the expression of mRNAs and lncRNAs in a rat model at 2 days after SCI and identified the differentially expressed lncRNAs (DE lncRNAs) and differentially expressed mRNAs (DE mRNAs) using microarray analysis. Subsequently, a comprehensive bioinformatics analysis was also performed to clarify the interaction between DE mRNAs. A total of 3,193 DE lncRNAs and 4,308 DE mRNAs were identified between the injured group and control group. Classification, length distribution, and chromosomal distribution of the dysregulated lncRNAs were also performed. The gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to identify the critical biological processes and pathways. A protein−protein interaction (PPI) network indicated that IL6, TOP2A, CDK1, POLE, CCNB1, TNF, CCNA2, CDC20, ITGAM, and MYC were the top 10 core genes. The subnetworks from the PPI network were identified to further elucidate the most significant functional modules of the DE mRNAs. These data may provide novel insights into the molecular mechanism of the early acute phase of SCI. The identification of lncRNAs and mRNAs may offer potential diagnostic and therapeutic targets for SCI. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27560   open full text
• Circ‐U2AF1 promotes human glioma via derepressing neuro‐oncological ventral antigen 2 by sponging hsa‐miR‐7‐5p.
  Guoxiong Li, Min Huang, Yingqian Cai, Yuantao Yang, Xinlin Sun, Yiquan Ke.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract The prognosis for human glioma, a malignant tumor of the central nervous system, is poor due to its rapid growth, genetic heterogeneity, and inadequate understanding of its underlying molecular mechanisms. Circular RNAs composed of exonic sequences, represent an understudied form of noncoding RNAs (ncRNAs) that was discovered more than a decade ago, function as microRNA sponges. We aimed to assess the relationship between circ‐U2AF1 (CircRNA ID: hsa_circ_0061868) and hsa‐mir‐7‐5p and examine their effects on proliferation, apoptosis, and the metastatic phenotype of glioma cells regulated by neuro‐oncological ventral antigen 2 (NOVA2). We found that the expression levels of circ‐U2AF1 and NOVA2 were upregulated, while hsa‐miR‐7‐5p was downregulated in human glioma tissues and glioma cell lines. Our data and bioinformatic analysis indicated the association of these molecules with glioma grade, a positive correlation between circ‐U2AF1 and NOVA2 expression levels and a negative correlation of hsa‐miR‐7‐5p with both circ‐U2AF1 and NOVA2, respectively. In addition, silencing of circ‐U2AF1 expression resulted in increased hsa‐miR‐7‐5p expression and decreased NOVA2 expression both in vitro and in vivo. Luciferase assay confirmed hsa‐miR‐7‐5p as a direct target of circ‐U2AF1 and NOVA2 as a direct target of hsa‐miR‐7‐5p. Functionally, silencing of circ‐U2AF1 inhibits glioma development by repressing NOVA2 via upregulating hsa‐miR‐7‐5p both in vitro and in vivo. Thus, we assumed that circ‐U2AF1 promotes glioma malignancy via derepressing NOVA2 by sponging hsa‐miR‐7‐5p. Taken together, we suggest that circ‐U2AF1 can be a prognostic biomarker and the circ‐U2AF1/hsa‐miR‐7‐5p/NOVA2 regulatory pathway may be a novel therapeutic target for treating gliomas. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27591   open full text
• Upregulation of long noncoding RNA XIST is associated with poor prognosis in human cancers.
  Ji‐Long Liu, Wen‐Qian Zhang, Miao Zhao, Ming‐Yu Huang.
  Journal of Cellular Physiology. October 20, 2018
  --- - "\nAbstract\nGrowing evidence from recent studies has shown that the X‐inactive specific transcript (XIST), a well‐known long noncoding RNA involved in early embryonic development, is aberrantly regulated in various human cancers. However, the prognostic value of XIST in cancers remains uncharacterized. In this study, we searched PubMed, Web of Science, and Embase to collect all relevant studies, and a meta‐analysis was performed to explore the association of XIST expression with overall survival (OS) and clinicopathological parameters. We demonstrated that high XIST expression was associated with poor OS (hazard ratio = 1.76; 95% confidence intervals [CI], 1.56–1.98; p < 0.001). In addition, increased XIST expression was found to be associated with lymph node metastasis (odds ratio [OR] = 2.06; 95% CI, 1.46–1.90; \np < 0.001), distant metastasis (OR = 2.93; 95% CI, 2.00–4.28; \np < 0.001), tumor size (OR = 2.66; 95% CI, 1.86–3.81; \np < 0.001), poor differentiation (OR = 1.45; 95% CI, 1.00–2.10; \np = 0.049), and advanced tumor stage (OR = 3.35; 95% CI, 2.25–5.00; \np < 0.001), but not with age (OR = 0.82; 95% CI, 0.59–1.15; \np = 0.251) or gender (OR = 0.92; 95% CI, 0.70–1.19; \np = 0.512). Our meta‐analysis showed that XIST may be a useful common biomarker for predicting prognosis in patients with cancer." - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27400   open full text
• Prenatal exposure to valproate induces sex‐, age‐, and tissue‐dependent alterations of cholesterol metabolism: Potential implications on autism.
  Veronica Cartocci, Claudia Tonini, Tiziana Di Pippo, Florenzia Vuono, Sara Schiavi, Maria Marino, Viviana Trezza, Valentina Pallottini.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Here, we investigated the protein network regulating cholesterol metabolism in the liver and brain of adolescent and adult male and female rats prenatally exposed to valproate (VPA), a well validated experimental model of autism spectrum disorders (ASD). We were aimed at studying whether prenatal VPA exposure affected the proteins involved in cholesterol homeostasis in a sex‐dependent manner. To this aim the protein network of cholesterol metabolism, in term of synthesis and plasma membrane trafficking, was analyzed by western blot in the liver and different brain areas (amygdala, cerebellum, cortex, hippocampus, nucleus accumbens, and dorsal striatum) of adolescent and adult male and female rats prenatally exposed to VPA. Our results show that physiological sex‐dependent differences are present both in the liver and in brain of rats. Interestingly, VPA affects specifically the brain in an age‐ and region‐specific manner; indeed, cerebellum, cortex, hippocampus and nucleus accumbens are affected in a sex‐dependent way, while this does not occur in amygdala and dorsal striatum. Overall, we demonstrate that each brain area responds differently to the same external stimulus and males and females respond in a different way, suggesting that this could be related to the diverse incidences, between the sexes, of some neurodevelopmental pathologies such as autism, which displays a 3:1 male to female ratio. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27218   open full text
• Heat stress induces distinct responses in porcine cumulus cells and oocytes associated with disrupted gap junction and trans‐zonal projection colocalization.
  Chao Yin, Jie Liu, Bin He, Longfei Jia, Yabin Gong, Huiduo Guo, Ruqian Zhao.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Cumulus cells (CCs), the granulosa cells surrounding the oocytes, play critical roles in oocytes maturation through intercellular communication by extending trans‐zonal projections (TZPs) to contact oocytes via gap junctions (GJs). The adverse effect of heat stress (HS) on oocyte maturation has been well documented, whereas the HS responses of CCs and the oocytes in association with GJ/TZP colocalization remain unclear. In this study, porcine cumulus‐oocyte complexes (COCs) were subjected to HS at 41.5°C for 24 hr during in vitro maturation. Cumulus expansion was impaired and oocyte quality was reduced with lower survival rate, polar body extrusion rate, and early embryo developmental potentials. CCs and oocytes isolated from COCs demonstrated distinct responses to HS. The messenger RNA abundance of heat shock protein‐related genes and mitochondrial DNA‐encoded genes, together with ATP content, were significantly increased in CCs, yet decreased in oocytes, despite activation of caspase 3 detected in both CCs and oocytes. Similar changes were observed when denuded oocytes and isolated CCs subjected to HS separately, except mitochondria reactive oxygen species (mROS). In heat‐stressed COCs, mROS was significantly increased only in oocytes. However, when isolated CCs and denuded oocytes were heat‐stressed separately, mROS was significantly increased only in CCs. Moreover, F‐actin, a TZP marker, and its colocalization with a GJ protein connexin‐45, were significantly reduced in heat‐exposed COCs. These results indicate that HS induces distinct responses in porcine CCs and oocytes in association with disrupted GJ and TZP colocalization. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27277   open full text
• Colorectal cancer invasiveness in vitro: Predominant contribution of neonatal Nav1.5 under normoxia and hypoxia.
  R. Mine Guzel, Kazim Ogmen, Kristina M. Ilieva, Scott P. Fraser, Mustafa B. A. Djamgoz.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract Functional expression of voltage‐gated Na+ channels (VGSCs) occurs in human carcinomas and promotes invasiveness in vitro and metastasis in vivo. Both neonatal and adult forms of Nav1.5 (nNav1.5 and aNav1.5, respectively) have been reported to be expressed at messenger RNA (mRNA) level in colorectal cancer (CRCa) cells. Here, three CRCa cell lines (HT29, HCT116 and SW620) were studied and found to express nNav1.5 mRNA and protein. In SW620 cells, adopted as a model, effects of gene silencing (by several small interfering RNAs [siRNAs]) selectively targeting nNav1.5 or aNav1.5 were determined on (a) channel activity and (b) invasiveness in vitro. Silencing nNav1.5 made the currents more “adult‐like” and suppressed invasion by up to 73%. Importantly, subsequent application of the highly specific, general VGSC blocker, tetrodotoxin (TTX), had no further effect. Conversely, silencing aNav1.5 made the currents more “neonatal‐like” but suppressed invasion by only 17% and TTX still induced a significant effect. Hypoxia increased invasiveness and this was also blocked completely by siRNA targeting nNav1.5. The effect of hypoxia was suppressed dose dependently by ranolazine, but its effect was lost in cells pretreated with nNav1.5‐siRNA. We conclude that (a) functional nNav1.5 expression is common to human CRCa cells, (b) hypoxia increases the invasiveness of SW620 cells, (c) the VGSC‐dependent invasiveness is driven predominantly by nNav1.5 under both normoxic and hypoxic conditions and (d) the hypoxia‐induced increase in invasiveness is likely to be mediated by the persistent current component of nNav1.5. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27399   open full text
• Necrosis and necroptosis in germ cell depletion from mammalian ovary.
  Govind R. Chaudhary, Pramod K. Yadav, Anil K. Yadav, Meenakshi Tiwari, Anumegha Gupta, Alka Sharma, Kankshi Sahu, Ashutosh N. Pandey, Ajai K. Pandey, Shail K. Chaube.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract The maximum number of germ cells is present during the fetal life in mammals. Follicular atresia results in rapid depletion of germ cells from the cohort of the ovary. At the time of puberty, only a few hundred (<1%) germ cells are either culminated into oocytes or further get eliminated during the reproductive life. Although apoptosis plays a major role, necrosis as well as necroptosis, might also be involved in germ cell elimination from the mammalian ovary. Both necrosis and necroptosis show similar morphological features and are characterized by an increase in cell volume, cell membrane permeabilization, and rupture that lead to cellular demise. Necroptosis is initiated by tumor necrosis factor and operated through receptor interacting protein kinase as well as mixed lineage kinase domain‐like protein. The acetylcholinesterase, cytokines, starvation, and oxidative stress play important roles in necroptosis‐mediated granulosa cell death. The granulosa cell necroptosis directly or indirectly induces susceptibility toward necroptotic or apoptotic cell death in oocytes. Indeed, prevention of necrosis and necroptosis pathways using their specific inhibitors could enhance growth/differentiation factor‐9 expression, improve survivability as well as the meiotic competency of oocytes, and prevent decline of reproductive potential in several mammalian species and early onset of menopause in women. This study updates the information and focuses on the possible involvement of necrosis and necroptosis in germ cell depletion from the mammalian ovary. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27562   open full text
• Downregulation of SPIN90 promotes fibroblast activation via periostin‐FAK‐ROCK signaling module.
  Eunae You, Yun‐Hyun Huh, Jieun Lee, Panseon Ko, Jangho Jeong, Seula Keum, Jaegu Kim, Ahreum Kwon, Woo Keun Song, Sangmyung Rhee.
  Journal of Cellular Physiology. October 20, 2018
  --- - "\nAbstract\nAlterations in mechanical properties in the extracellular matrix are modulated by myofibroblasts and are required for progressive fibrotic diseases. Recently, we reported that fibroblasts depleted of SPIN90 showed enhanced differentiation into myofibroblasts via increased acetylation of microtubules in the soft matrix; the mechanisms of the underlying signaling network, however, remain unclear. In this study, we determine the effect of depletion of SPIN90 on FAK/ROCK signaling modules. Transcriptome analysis of \nSpin90 KO mouse embryonic fibroblasts (MEF) and fibroblasts activated by TGF‐β revealed that \nPostn is the most significantly upregulated gene. Knockdown of \nPostn by small interfering RNA suppressed cell adhesion and myofibroblastic differentiation and downregulated FAK activity in \nSpin90 KO MEF. Our results indicate that SPIN90 depletion activates FAK/ROCK signaling, induced by \nPostn expression, which is critical for myofibroblastic differentiation on soft matrices mimicking the mechanical environment of a normal tissue." - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27600   open full text
• Long noncoding RNA OPA‐interacting protein 5 antisense transcript 1 upregulated SMAD3 expression to contribute to metastasis of cervical cancer by sponging miR‐143‐3p.
  Xing Chen, Dongsheng Xiong, Huichun Yang, Liya Ye, Shuangshuang Mei, Jinhong Wu, Shanshan Chen, Xianwen Shang, Kai Wang, Lingfei Huang.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2 Abstract Objectives SMAD3 is pivotal in the biology functions of various tumors. This study is aiming to study the relationship among SMAD3, long noncoding RNAs (lncRNAs) OPA‐interacting protein 5 antisense transcript 1 (OIP5‐AS1), and miR‐143‐3p, and their effects on cervical cancer. Methods In our research, real‐time polymerase chain reaction and western blot assay were conducted to detect the expression level of messenger RNA and protein in tumor tissues and cells. Transfection of lncRNA OIP5‐AS1, miR‐143‐3p, or SMAD3 was performed to investigate their potential effects on the function of cell as well as the relationship among them in cervical cell lines via 3‐(4,5‐dimethylthiazolyl‐2)‐2,5‐diphenyltetrazolium bromide) together with transwell assays or dual‐luciferase reporter assay respectively. Results SMAD3, lncRNA OIP5‐AS1 expression is significantly enhanced in cervical cancer tissues and cell lines, but miR‐143‐3p was inhibited. LncRNA OIP5‐AS1 is demonstrated to mediate the physiological process of cervical cancer cells. Moreover, silencing SMAD3 via siRNA suppressed cell number, viability, migration and invasion, whereas overexpression of OIP5‐AS1 promoted these abilities. Furthermore, lncRNA OIP5‐AS1 exert its function via sponging miR‐143‐3p to regulate SMAD3 expression. Conclusions LncRNA OIP5‐AS1 promoted SMAD3 expression via mediating miR‐143‐3p to promote migration and invasion of cervical cancer cells. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27336   open full text
• YAP regulates periodontal ligament cell differentiation into myofibroblast interacted with RhoA/ROCK pathway.
  Yao He, Hui Xu, Zichao Xiang, Hongyou Yu, Li Xu, Yongwen Guo, Ye Tian, Rui Shu, Xianrui Yang, Chaoran Xue, Mengyuan Zhao, Yiruo He, Xianglong Han, Ding Bai.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2- Abstract During orthodontic tooth movement (OTM), periodontal ligament cells (PDLCs) receive the mechanical stimuli and transform it into myofibroblasts (Mfbs). Indeed, previous studies have demonstrated that mechanical stimuli can promote the expression of Mfb marker α‐smooth muscle actin (α‐SMA) in PDLCs. Transforming growth factor β1 (TGF‐β1), as the target gene of yes‐associated protein (YAP), has been proven to be involved in this process. Here, we sought to assess the role of YAP in Mfbs differentiation from PDLCs. The time‐course expression of YAP and α‐SMA was manifested in OTM model in vivo as well as under tensional stimuli in vitro. Inhibition of RhoA/Rho‐associated kinase (ROCK) pathway using Y27632 significantly reduced tension‐induced Mfb differentiation and YAP expression. Moreover, overexpression of YAP with lentiviral transfection in PDLCs rescued the repression effect of Mfb differentiation induced by Y27632. These data together suggest a crucial role of YAP in regulating tension‐induced Mfb differentiation from PDLC interacted with RhoA/ROCK pathway. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27312   open full text
• MiR‐128‐3p accelerates cardiovascular calcification and insulin resistance through ISL1‐dependent Wnt pathway in type 2 diabetes mellitus rats.
  Xin‐Yong Wang, Xian‐Zhao Zhang, Feng Li, Qing‐Rong Ji.
  Journal of Cellular Physiology. October 20, 2018
  --- - |2 Abstract Vascular calcification is highly prevalent in patients with type 2 diabetes mellitus (T2DM), one of the most common chronic diseases with high morbidity and mortality. In recent years, microRNAs have been widely reported as potential biomarkers for the diagnosis and treatment of T2DM. We hypothesized that miR‐128‐3p is associated with cardiovascular calcification and insulin resistance (IR) in rats with T2DM by targeting ISL1 via the Wnt pathway. Microarray analysis was adopted to identify differentially expressed genes related to T2DM. T2DM models were induced in rats. Blood samples from normal and T2DM rats were used to detect islet β‐cell function, islet sensitivity, and calcium content. Next, islet tissues were obtained to identify the expression of miR‐128‐3p, ISL1, and the Wnt signaling pathway‐ and apoptosis‐related genes. Finally, apoptosis of islet β‐cells was determined by flow cytometry. Through microarray analysis of GSE27382 and GSE23343, ISL1 was found to be downregulated in T2DM. In blood samples from T2DM rats, basic biochemical indicators, IR, and calcium content were increased, and islet sensitivity and islet β‐cell function were decreased. Furthermore, upregulation of miR‐128‐3p and ISL1 gene silencing promoted the expression of Wnt‐1, β‐catenin, GSK‐3β, and Bax and the phosphorylation of β‐catenin and GSK‐3β, inhibited c‐fos, PDX‐1, and Bcl‐2 expression, and enhanced cell apoptosis. The key findings of our study demonstrate that miR‐128‐3p aggravates cardiovascular calcification and IR in T2DM rats by downregulating ISL1 through the activation of the Wnt pathway. Thus, miR‐128‐3p may serve as a potential target for the treatment of T2DM. - Journal of Cellular Physiology, EarlyView.
  

  October 20, 2018   doi: 10.1002/jcp.27300   open full text
• Combination therapy for the treatment of pancreatic cancer through hyaluronic acid‐decorated nanoparticles loaded with quercetin and gemcitabine: A preliminary in vitro study.
  Carla Serri, Vincenzo Quagliariello, Rosario Vincenzo Iaffaioli, Sabato Fusco, Gerardo Botti, Laura Mayol, Marco Biondi.
  Journal of Cellular Physiology. October 18, 2018
  --- - |2- Abstract Combination chemotherapy by means of two or more drugs is prone to suppressing or discouraging the inception of multidrug resistance, exploiting the fact that diverse drugs act in different points of the cellular cycle of amplifying tumor cells. For example, the combination of gemcitabine (GMC) with quercetin (QCT) showed a synergistic effect in inhibiting the migration of pancreatic cancer cells. Consequently, herein GMC and QCT have been loaded within biodegradable nanoparticles (NPs) based on poly(lactic‐co‐glycolic acid), externally decorated with hyaluronic acid (HA; viz., PPHA NPs), which plays a major role in drug targeting to tumors due to its ability to specifically interact with CD44 receptor, that is overexpressed in many tumors. The produced HA‐decorated NPs loaded with GMC and QCT showed an improved cytotoxicity and cellular uptake toward two cell lines of pancreatic ductal adenocarcinoma, namely Mia‐PaCa‐2 and PANC‐1, compared with both the bare drugs and the drugs loaded in NPs which do not expose HA on the surface. HA‐decorated NPs were also able to improve the anti‐inflammatory properties of QCT, therefore leading to a decrease of interleukin cellular levels in both cell lines, preliminarily stimulated with lipopolysaccharides. This result is of special interest also considering the crucial role of interleukins in progression, metastatic processes, and drug resistance of human pancreas cancer cells. - Journal of Cellular Physiology, EarlyView.
  

  October 18, 2018   doi: 10.1002/jcp.27297   open full text
• Metformin inhibits mTOR–HIF‐1α axis and profibrogenic and inflammatory biomarkers in thioacetamide‐induced hepatic tissue alterations.
  Fahaid Al‐Hashem, Suliman Al‐Humayed, Shaimaa N. Amin, Samaa S. Kamar, Soheir S. Mansy, Sarah Hassan, Lubna O. Abdel‐Salam, Mohamed Abd Ellatif, Mohammed Alfaifi, Mohamed A. Haidara, Bahjat Al‐Ani.
  Journal of Cellular Physiology. October 18, 2018
  --- - |2- Abstract The potential inhibitory effect of the antidiabetic and anti‐inflammatory drug, metformin on thioacetamide (TAA)‐induced hepatotoxicity associated with the inhibition of mammalian target of rapamycin (mTOR)–hypoxia‐inducible factor‐1α (HIF‐1α) axis has not been investigated before. Therefore, we tested whether metformin can protect against liver injuries including fibrosis induced by TAA possibly via the downregulation of mTOR–HIF‐1α axis and profibrogenic and inflammatory biomarkers. Rats either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being killed after 10 weeks (model group) or were pretreated with metformin (200 mg/kg) daily for 2 weeks before TAA injections and continued receiving both agents until the end of the experiment, at Week 10 (protective group). Using light and electron microscopy examinations, we observed in the model group substantial damage to the hepatocytes and liver tissue such as collagen deposition, infiltration of inflammatory cells, and degenerative cellular changes with ballooned mitochondria that were substantially ameliorated by metformin. Metformin also significantly ( p < 0.05) inhibited TAA‐induced HIF‐1α, mTOR, the profibrogenic biomarker α‐smooth muscle actin, tissue inhibitor of metalloproteinases‐1, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), alanine aminotransferase (ALT) and aspartate aminotransferase in harvested liver homogenates and blood samples. In addition, a significant ( p < 0.01) positive correlation between hypoxia scoring (HIF‐1α) and the serum levels of TNF‐α ( r = 0.797), IL‐6 ( r = 0.859), and ALT ( r = 0.760) was observed. We conclude that metformin protects against TAA‐induced hepatic injuries in rats, which is associated with the inhibition of mTOR–HIF‐1α axis and profibrogenic and inflammatory biomarkers; thus, may offer therapeutic potential in humans. - Journal of Cellular Physiology, EarlyView.
  

  October 18, 2018   doi: 10.1002/jcp.27616   open full text
• Characterizing the three‐dimensional organization of telomeres in papillary thyroid carcinoma cells.
  Paola Caria, Tinuccia Dettori, Daniela Virginia Frau, Daniel Lichtenzstejn, Fabiana Pani, Roberta Vanni, Sabine Mai.
  Journal of Cellular Physiology. October 17, 2018
  --- - |2- Abstract The relationship between the three‐dimensional (3D) nuclear telomere architecture and specific genetic alterations in papillary thyroid carcinoma (PTC), in particular in cancer stem‐like cells (CSLCs), has not yet been investigated. We isolated thyrospheres containing CSLCs from B‐CPAP, K1, and TPC‐1 PTC‐derived cell lines, representative of tumors with different genetic backgrounds within the newly identified BRAFV600E‐like PTC subgroup, and used immortalized normal human thyrocytes (Nthy‐ori 3.1) as control. We performed quantitative fluorescence in situ hybridization, 3D imaging, and 3D telomere analysis using TeloView software to examine telomere dysfunction in both parental and thyrosphere cells. Among the 3D telomere profile, a wide heterogeneity was observed, except for telomere intensity. Our findings indicate that CSLCs of each cell line had longer telomeres than parental cells, according to telomere intensity values, which correlate with telomere length. Indeed, the thyrosphere cells had lower numbers of lower‐intensity telomeres (≤5,000 arbitrary fluorescent units, a.u.), compared with parental cancer cells, as well as parental control cells, (p < 0.0001). The B‐CPAP thyrospheres showed a decreased number of higher intensity telomeres (>17,000 a.u.) than K1 and TPC‐1 cells, as well as control cells (p < 0.0001). By selecting PTC‐derived cell lines with different genetic backgrounds characteristic of BRAFV600E‐like PTC subgroups, we demonstrate that thyrosphere cells with BRAFV600E and TP53 mutations show shorter telomeres than those harboring RET/PTC or BRAFV600Eand wild‐type TP53. Hence, our data reveal a trend towards a decrease in telomere shortening in CSLCs, representing the early cancer‐promoting subpopulation, as opposed to parental cells representing the tumor bulk cells. - Journal of Cellular Physiology, EarlyView.
  

  October 17, 2018   doi: 10.1002/jcp.27321   open full text
• The competing endogenous circular RNA ADAMTS14 suppressed hepatocellular carcinoma progression through regulating microRNA‐572/regulator of calcineurin 1.
  Changlong Song, Dianqiu Li, Hongyu Liu, Hongyan Sun, Zhen Liu, Lirong Zhang, Yu Hu.
  Journal of Cellular Physiology. October 14, 2018
  --- - "\nAbstract\nEmerging evidence have discovered that circular RNAs (circRNAs) may serve as diagnostic or tumor promising biomarkers. This study aimed to investigate how circular RNA ADAMTS14 (circADAMTS14) regulates microRNA‐572/\nregulator of calcineurin 1(miR‐572/\nRCAN1) in hepatocellular carcinoma (HCC). The expression profiles of circRNA/microRNA (mRNA) between HCC tissues and paired adjacent tissues were analyzed via microarray analysis. The expressions of circADAMTS14, miR‐572, and \nRCAN1 were measured by real‐time polymerase chain reaction (PCR). The protein expression level of \nRCAN1 in HCC cells was detected by western blot. The viability and apoptosis levels of HCC cell lines were measured by the cell counting Kit‐8 (CCK‐8) assay and fluorescence‐activated cell sorter. The invasiveness and migration of cells were detected based on the transwell and wound‐healing assay, respectively. The dual‐luciferase reporter assays were used to reveal circADAMTS14 and \nRCAN1 as a potential target of miR‐572, which was predicted by TargetScan and miRBase. The effect of circADAMTS14 on HCC cells was demonstrated by tumor formation in nude mice in vivo. CircADAMTS14 and \nRCAN1 were lowly expressed in HCC clinical specimens and cell lines using microarrays and qRT‐PCR, but miR‐572 inversely. Our study further verified the direct interaction between circADAMTS14 and \nRCAN1 with miR‐572 via the dual‐luciferase reporter gene assay. Overexpressed circADAMTS14 and \nRCAN1 induced apoptosis of HCC cells and inhibited cell proliferation and invasion. But overexpressed miR‐572 could decrease apoptosis of HCC cells and promote proliferation and invasion. In vivo, circADAMTS14 inhibited the tumor growth, correlated positively with the protein expression levels of \nRCAN1. Our results demonstrated that circADAMTS14 might suppress HCC progression through regulating miR‐572/\nRCAN1 as the competing endogenous RNA." - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.26764   open full text
• Lipopolysaccharide‐induced proliferation and glycolysis in airway smooth muscle cells via activation of Drp1.
  Lixin Zhang, Cui Ma, Xiaoying Wang, Siyu He, Qian Li, Yutian Zhou, Ying Liu, Min Zhang, Xiufeng Yu, Xijuan Zhao, Fei Li, Da‐ling Zhu.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract Abnormal airway smooth muscle cells (ASMCs) proliferation is an important pathological process in airway remodeling contributes to increased mortality in asthma. Mitochondrial dynamics and metabolism have a central role in the maintenance of the cell function. In this study, lipopolysaccharide (LPS)‐induced ASMCs proliferative model was used to investigate the effect of mitochondria on the proliferation of ASMCs and the possible mechanism. We used cell and molecular biology to determine the effect of dynamin‐related protein 1 (Drp1) on LPS‐mediated ASMCs cell cycle progression and glycolysis. The major findings of the current study are as follows: LPS promoted an increased mitochondrial fission and phosphorylation of Drp1 at Ser616 (p‐Drp1 Ser616). LPS‐induced ASMCs proliferation and cell cycle progression, which was significantly inhibited application of Drp1 RNA interfering. Glycolysis inhibitor 2‐deoxyglucose (2‐DG) depressed ASMCs proliferative process induced by LPS stimulation. LPS caused mitochondrial metabolism disorders and aerobic glycolysis in a dependent on Drp1 activation. These results indicated that Drp1 may function as a key factor in asthma airway remodeling by mediating ASMC proliferation and cell cycle acceleration through an effect on mitochondrial metabolic disturbance. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27605   open full text
• Genome‐wide CRISPR‐Cas9 viability screen reveals genes involved in TNF‐α‐induced apoptosis of human umbilical vein endothelial cells.
  Meng Cai, Sitao Li, Yunfei Shuai, Jie Li, Jieqiong Tan, Qiyi Zeng.
  Journal of Cellular Physiology. October 14, 2018
  --- - "\nAbstract\nTumor necrosis factor α (TNF‐α), a pivotal cytokine in sepsis, protects the host against pathogens by promoting an inflammatory response while simultaneously inducing apoptosis of the vascular endothelium. Unfortunately, inhibitors targeting certain components of the TNF‐α signaling pathway to reduce cellular apoptosis have failed to translate into clinical applications, partly due to the adverse effects of excessive immunosuppression. In an attempt to discover potential targets in the TNF‐α signaling pathway to modulate moderate inflammation and apoptosis during the development of sepsis, we performed a pooled genome‐wide CRISPR/Cas9 knockout screen in human umbilical vein endothelial cells (HUVECs). Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), B‐cell lymphoma 2 (BCL2), Bcl2‐associated death promoter (BAD), and NLR family member X1 (NLRX1) deficiencies were identified as the effective genetic suppressors of TNF‐α cytotoxicity on a list of candidate regulators. CRISPR‐mediated \nNLRX1 knockout conferred cellular resistance to challenge with TNF‐α, and NLRX1 could be induced to colocalize with mitochondria following TNF‐α stimulation. Thus, our work demonstrates the advantage of genome‐scale screening with Cas9 and validates NLRX1 as a potential modulator of TNF‐α‐induced vascular endothelial apoptosis during sepsis." - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27595   open full text
• Identification of TAF1, HNF4A, and CALM2 as potential therapeutic target genes for liver fibrosis.
  Dong Ji, Guo‐Feng Chen, Jin‐Cheng Wang, Li‐Hua Cao, Fengmin Lu, Xiao‐Xin Mu, Xiao‐Yu Zhang, Xiao‐Jie Lu.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract The molecular mechanism of liver fibrosis caused by hepatitis C virus (HCV) is not clear. The aim of this study is to understand the molecular mechanism of liver fibrosis induced by HCV and to identify potential therapeutic targets for hepatic fibrosis. We analyzed gene expression patterns between high liver fibrosis and low liver fibrosis samples, and identified genes related to liver fibrosis. We identified TAF1, HNF4A, and CALM2 were related to the development of liver fibrosis. HNF4A is important for hepatic fibrogenesis, and upregulation of HNF4A is an ideal choice for treating liver fibrosis. The gene expression of CALM2 is significantly lower in liver fibrosis samples than nonfibrotic samples. TAF1 may serve as a biomarker for liver fibrosis. The results were further validated by an independent data set GSE84044. In summary, our study described changes in the gene expression during the occurrence and development of liver fibrosis. The TAF1, HNF4A, and CALM2 may serve as novel targets for the treatment of liver fibrosis. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27579   open full text
• A pH‐sensitive luminal His‐cluster promotes interaction of PAM with V‐ATPase along the secretory and endocytic pathways of peptidergic cells.
  Vishwanatha K. Rao, Gerardo Zavala, Abhijit Deb Roy, Richard E. Mains, Betty A. Eipper.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract The biosynthetic and endocytic pathways of secretory cells are characterized by progressive luminal acidification, a process which is crucial for posttranslational modifications and membrane trafficking. This progressive fall in luminal pH is mainly achieved by the vacuolar‐type‐H+ ATPase (V‐ATPase). V‐ATPases are large, evolutionarily ancient rotary proton pumps that consist of a peripheral V1 complex, which hydrolyzes ATP, and an integral membrane V0 complex, which transports protons from the cytosol into the lumen. Upon sensing the desired luminal pH, V‐ATPase activity is regulated by reversible dissociation of the complex into its V1 and V0 components. Molecular details of how intraluminal pH is sensed and transmitted to the cytosol are not fully understood. Peptidylglycine α‐amidating mono‐oxygenase (PAM; EC 1.14.17.3), a secretory pathway membrane enzyme which shares similar topology with two V‐ATPase accessory proteins (Ac45 and prorenin receptor), has a pH‐sensitive luminal linker region. Immunofluorescence and sucrose gradient analysis of peptidergic cells (AtT‐20) identified distinct subcellular compartments exhibiting spatial co‐occurrence of PAM and V‐ATPase. In vitro binding assays demonstrated direct binding of the cytosolic domain of PAM to V1H. Blue native PAGE identified heterogeneous high‐molecular weight complexes of PAM and V‐ATPase. A PAM‐1 mutant (PAM‐1/H3A) with altered pH sensitivity had diminished ability to form high‐molecular weight complexes. In addition, V‐ATPase assembly status was altered in PAM‐1/H3A expressing cells. Our analysis of the secretory and endocytic pathways of peptidergic cells supports the hypothesis that PAM serves as a luminal pH‐sensor, regulating V‐ATPase action by altering its assembly status. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27528   open full text
• Ovarian cancer stem cell: A potential therapeutic target for overcoming multidrug resistance.
  Aynaz Mihanfar, Javad Aghazadeh Attari, Iraj Mohebbi, Maryam Majidinia, Mojtaba Kaviani, Mehdi Yousefi, Bahman Yousefi.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract The cancer stem cell (CSC) model encompasses an advantageous paradigm that in recent decades provides a better elucidation for many important biological aspects of cancer initiation, progression, metastasis, and, more important, development of multidrug resistance (MDR). Such several other hematological malignancies and solid tumors and the identification and isolation of ovarian cancer stem cells (OV‐CSCs) show that ovarian cancer also follows this hierarchical model. Gaining a better insight into CSC‐mediated resistance holds promise for improving current ovarian cancer therapies and prolonging the survival of recurrent ovarian cancer patients in the future. Therefore, in this review, we will discuss some important mechanisms by which CSCs can escape chemotherapy, and then review the recent and growing body of evidence that supports the contribution of CSCs to MDR in ovarian cancer. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.26768   open full text
• Induction of apoptotic but not autophagic cell death by Cinnamomum cassia extracts on human oral cancer cells.
  Ching‐Han Yu, Shu‐Chen Chu, Shun‐Fa Yang, Yih‐Shou Hsieh, Chih‐Yi Lee, Pei‐Ni Chen.
  Journal of Cellular Physiology. October 14, 2018
  --- - "\nAbstract\nCinnamomum cassia has been widely studied in different fields to reveal its antidiabetic, antidepressive, antiviral, anti‐inflammatory, antiosteoporotic, and anticancer effects. Its antimalignant activities have been explored in lung cancer, breast cancer, colorectal cancer, and even oral cancer, but the detailed signaling mechanism and effects of this plant on animal models need to be clarified. In the current study, \nC. cassia extract (CCE) was used to investigate the antitumorigenesis mechanism in vitro and in vivo. The major constituents of CCE used in this study were coumarin, cinnamic acid, and cinnamic aldehyde. CCE reduced the viability, number, and colony formation of human oral cancer cells, and induced their apoptosis. Caspase‐3 activation, Bcl‐2 reduction, and phosphatidylserine inversion were involved in CCE‐stimulated apoptosis. CCE also enhanced the expression of autophagic markers, including acidic vesicular organelle, microtubule‐associated protein 1 light chain 3‐I, autophagy‐related protein 14, rubicon, and p62. The combined treatment of CCE and caspase inhibitor significantly restored mitochondrial membrane potential (Δ\nψ\nm) and cell viability. However, the combined treatment of CCE and autophagy inhibitor further reduced the cell viability indicating that autophagy might be a survival pathway of CCE‐treated SASVO3 cells. In contrast, CCE treatment for 12 days did not adversely affect SASVO3 tumor‐bearing nude mice. CCE also elicited dose‐dependent effects on the decrease in tumor volume, tumor weight, and Ki‐67 expression. These results suggested that CCE showed the potential for the complementary treatment of oral caner." - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27338   open full text
• Resveratrol restores sensitivity of glioma cells to temozolamide through inhibiting the activation of Wnt signaling pathway.
  Hua‐Chao Yang, Jun‐Yi Wang, Xing‐Yao Bu, Bin Yang, Bang‐Qing Wang, Sen Hu, Zhao‐Yue Yan, Yu‐Shuai Gao, Shuang‐Yin Han, Ming‐Qi Qu.
  Journal of Cellular Physiology. October 14, 2018
  --- - "\nAbstract\nMalignant gliomas are aggressive primary neoplasms that originate in the glial cells of the brain or the spine with notable resistance to standard treatment options. We carried out the study with the aim to shed light on the sensitization of resveratrol to temozolomide (TMZ) against glioma through the Wnt signaling pathway. Initially, glioma cell lines with strong resistance to TMZ were selected by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Then, the glioma cells were subjected to resveratrol, TMZ, Wnt signaling pathway inhibitors, and activators. Cell survival rate and inhibitory concentration at half maximum value were detected by MTT, apoptosis by flow cytometry, and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling staining, in vitro proliferation by hanging drop method and β‐catenin translocation into nuclei by TOP/FOP‐FLASH assay. The expressions of the Wnt signaling pathway‐related and apoptosis‐related factors were determined by western blot analysis. Nude mice with glioma xenograft were established to detect tumorigenic ability. Glioma cell lines T98G and U138 which were highly resistant to TMZ were selected for subsequent experiments. Resveratrol increased the efficacy of TMZ by restraining cell proliferation, tumor growth, and promoting cell apoptosis in glioma cells. Resveratrol inhibited Wnt2 and β‐catenin expressions yet elevated GSK‐3β expression. Moreover, the Wnt signaling pathway participates in the sensitivity enhancing of resveratrol to TMZ via regulating \nO\n6‐methylguanine‐DNA methyltransferase (MGMT) expression. Resveratrol sensitized TMZ‐induced glioma cell apoptosis by repressing the activation of the Wnt signaling pathway and downregulating MGMT expression, which may confer new thoughts to the chemotherapy of glioma." - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27409   open full text
• Probiotics importance and their immunomodulatory properties.
  Bahman Yousefi, Majid Eslami, Abdolmajid Ghasemian, Parviz Kokhaei, Amir Salek Farrokhi, Narges Darabi.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract Mammalian intestine contains a large diversity of commensal microbiota, which is far more than the number of host cells. Probiotics play an insecure and protective role against the colonization of intestinal pathogenic microbes and increase mucosal integrity by stimulating epithelial cells. Probiotics have innate capabilities in many ways, including receptor antagonism, receptor expression, binding and expression of adapter proteins, expression of negative regulatory signal molecules, induction of microRNAs, endotoxin tolerance, and ultimately secretion of immunomodulatory proteins, lipids, and metabolites to modulate the immune system. Probiotic bacteria can affect homeostasis, inflammation, and immunopathology through direct or indirect effects on signaling pathways as immunosuppressant or activators. Probiotics suppress inflammation by inhibiting various signaling pathways such as the nuclear factor‐κB (NF‐κβ) pathway, possibly related to alterations in mitogen‐activated protein kinases and pattern recognition receptors pathways. Probiotics can also inhibit the binding of lipopolysaccharides to the CD14 receptor, thereby reducing the overall activation of NF‐κβ and producing proinflammatory cytokines. Some effects of modulation by probiotics include cytokine production by epithelial cells, increased mucin secretion, increased activity of phagocytosis, and activation of T and natural killer T cells, stimulation of immunoglobulin A production and decreased T cell proliferation. Intestinal microbiota has a major impact on the systemic immune system. Specific microbiota controls the differentiation of cells in lamina propria, in which Th17 cells secrete interleukin 17. The presence of Th17 and Treg cells in the small intestine is associated with intestinal microbiota, with the preferential Treg differentiation and the absence of Th17 cells, possibly reflecting alterations in the lamina propria cytokines and the intestinal gut microbiota. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27559   open full text
• SEMA3B‐AS1‐inhibited osteogenic differentiation of human mesenchymal stem cells revealed by quantitative proteomics analysis.
  Chen Zhang, Yun Zhu, Yugang Liu, Xiguang Zhang, Qiaoning Yue, Li Li, Yatang Chen, Sheng Lu, Zhaowei Teng.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract Human mesenchymal stem cells (hMSCs) are fibroblastoid multipotent adult stem cells with capacities of differentiation into osteoblasts and chondrocytes and show great potential in new bone formation and bone repair‐related clinical settings, such as osteoporosis. Long noncoding RNAs (lncRNAs) have been demonstrated to play important roles in various biological processes. Here, we report an antisense lncRNA SEMA3B‐AS1 regulating hMSCs osteogenesis. SEMA3B‐AS1 is proximal to a member of the semaphorin family Sema3b. Overexpression of SEMA3B‐AS1 using the lentivirus system markedly inhibits the proliferation of hMSCs and meanwhile reduces osteogenic differentiation. Using a comprehensive proteomic technique named isobaric tag for relative and absolute quantitation, we found that SEMA3B‐AS1 significantly alters the process of osteogenesis through downregulating the expression of proteins involved in actin cytoskeleton, focal adhesion, and extracellular matrix–receptor interaction, while increasing the expression of proteins in the spliceosome. Collectively, we find that SEMA3B‐AS1 is a target for controlling osteogenesis of hMSCs. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.26776   open full text
• EA15, MIR22, LINC00472 as diagnostic markers for diabetic kidney disease.
  Yan‐Zhe Wang, Ding‐Yu Zhu, Xin‐Miao Xie, Miao Ding, Yong‐Lan Wang, Lin‐Lin Sun, Nan Zhang, E. Shen, Xiao‐Xia Wang.
  Journal of Cellular Physiology. October 14, 2018
  --- - "\nAbstract\nThis study aimed to investigate the molecular mechanisms of diabetic kidney disease (DKD) and to explore new potential therapeutic strategies and biomarkers for DKD. First we analyzed the differentially expressed changes between patients with DKD and the control group using the chip data in Gene Expression Omnibus (GEO) database. Then the gene chip was subjected to be annotated again, so as to screen long noncoding RNAs (lncRNAs) and study expression differences of these lncRNAs in DKD and controlled samples. At last, the function of the differential lncRNAs was analyzed. A total of 252 lncRNAs were identified, and 14 were differentially expressed. In addition, there were 1,629 differentially expressed messenger RNAs (mRNAs) genes, and proliferation and apoptosis adapter protein 15 (PEA15), \nMIR22, and long intergenic nonprotein coding RNA 472 (\nLINC00472) were significantly differentially expressed in DKD samples. Through functional analysis of the encoding genes coexpressed by the three lncRNAs, we found these genes were mainly enriched in type 1 diabetes and autoimmune thyroid disease pathways, whereas in Gene Ontology (GO) function classification, they were also mainly enriched in the immune response, type I interferon signaling pathways, interferon‐γ mediated signaling pathways, and so forth. To summary, we identified \nEA15, \nMIR22, and \nLINC00472 may serve as the potential diagnostic markers of DKD." - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27539   open full text
• Integrated bioinformatic analysis reveals YWHAB as a novel diagnostic biomarker for idiopathic pulmonary arterial hypertension.
  Tao Wang, Xuan Zheng, Ruidong Li, Xintian Liu, Jinhua Wu, Xiaodan Zhong, Wenjun Zhang, Yujian Liu, Xingwei He, Wanjun Liu, Hongjie Wang, Hesong Zeng.
  Journal of Cellular Physiology. October 14, 2018
  --- - "\nAbstract\nIdiopathic pulmonary arterial hypertension (IPAH) is a severe cardiovascular disease that is a serious threat to human life. However, the specific diagnostic biomarkers have not been fully clarified and candidate regulatory targets for IPAH have not been identified. The aim of this study was to explore the potential diagnostic biomarkers and possible regulatory targets of IPAH. We performed a weighted gene coexpression network analysis and calculated module‐trait correlations based on a public microarray data set (GSE703) and six modules were found to be related to IPAH. Two modules which have the strongest correlation with IPAH were further analyzed and the top 10 hub genes in the two modules were identified. Furthermore, we validated the data by quantitative real‐time polymerase chain reaction (qRT‐PCR) in an independent sample set originated from our study center. Overall, the qRT‐PCR results were consistent with most of the results of the microarray analysis. Intriguingly, the highest change was found for YWHAB, a gene encodes a protein belonging to the 14‐3‐3 family of proteins, members of which mediate signal transduction by binding to phosphoserine‐containing proteins. Thus, \nYWHAB was subsequently selected for validation. In congruent with the gene expression analysis, plasma 14‐3‐3β concentrations were significantly increased in patients with IPAH compared with healthy controls, and 14‐3‐3β expression was also positively correlated with mean pulmonary artery pressure (\nR\n2 = 0.8783; \np < 0.001). Taken together, using weighted gene coexpression analysis, \nYWHAB was identified and validated in association with IPAH progression, which might serve as a biomarker and/or therapeutic target for IPAH." - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27381   open full text
• Diagnostic, prognostic, and therapeutic potency of microRNA 21 in the pathogenesis of colon cancer, current status and prospective.
  Amirhossein Bahreyni, Melika Rezaei, Afsane Bahrami, Majid Khazaei, Hamid Fiuji, Mikhail Ryzhikov, Gordon A. Ferns, Amir Avan, Seyed Mahdi Hassanian.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract Aberrant microRNA (miR) expression is implicated in multiple human malignancies. miR‐21, acting as a proto‐oncogene, is involved in a variety of cellular processes and tumorigenesis and is frequently overexpressed in some cancer types. Several tumor suppressors, metastatic, and apoptotic genes have been identified as miR‐21 targets, including Ras homolog gene family member B, PTEN, Sprouty2, programmed cell death 4, Integrin‐β4, and E‐cadherin thereby regulating tumor growth, invasion, and metastasis. There is a growing evidence that miR‐21 expression is associated with clinical outcomes in patients with colorectal cancer (CRC). In this review, we summarize the potential diagnostic, prognostic, and therapeutic values of miR‐21 in CRC progression for a better understanding and hence a better management of this disease. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27580   open full text
• Snake venoms promote stress‐induced senescence in human fibroblasts.
  Anna Lewinska, Aleksandra Bocian, Vladimir Petrilla, Jagoda Adamczyk‐Grochala, Karolina Szymura, Wiktoria Hendzel, Edyta Kaleniuk, Konrad K. Hus, Monika Petrillova, Maciej Wnuk.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract Snake venoms are widely studied in terms of their systemic toxicity and proteolytic, hemotoxic, neurotoxic, and cytotoxic activities. However, little is known about snake‐venom‐mediated effects when used at low, noncytotoxic concentrations. In the current study, two human fibroblast cell lines of different origin, namely WI‐38 fetal lung fibroblasts and BJ foreskin fibroblasts were used to investigate snake‐venom‐induced adaptive response at a relatively noncytotoxic concentration (0.01 µg/ml). The venoms of Indochinese spitting cobra ( Naja siamensis), western green mamba ( Dendroaspis viridis), forest cobra ( Naja melanoleuca), and southern copperhead ( Agkistrodon contortrix) were considered. Snake venoms promoted FOXO3a‐mediated oxidative stress response and to a lesser extent DNA damage response, which lead to changes in cell cycle regulators both at messenger RNA and protein levels, limited cell proliferation and migration, and induced cellular senescence. Taken together, we have shown for the first time that selected snake venoms may also exert adverse effects when used at relatively noncytotoxic concentrations. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27382   open full text
• The vacuolated morphology of chordoma cells is dependent on cytokeratin intermediate filaments.
  Lauren Resutek, Adam H. Hsieh.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract Notochordal cells (NCs), characterized by their vacuolated morphology and coexpression of cytokeratin and vimentin intermediate filaments (IFs), form the immature nucleus pulposus (NP) of the intervertebral disc. As humans age, NCs give way to mature NP cells, which do not possess a vacuolated morphology and typically only express vimentin IFs. In light of their concomitant loss, we investigated the relationship between cytosolic vacuoles and cytokeratin IFs, specifically those containing cytokeratin‐8 proteins, using a human chordoma cell line as a model for NCs. We demonstrate that the chemical disruption of IFs with acrylamide, F‐actin with cytochalasin‐D, and microtubules with nocodazole all result in a significant (p < 0.001) decrease in vacuolation. However, vacuole loss was the greatest in acrylamide‐treated cells. Examination of the individual roles of vimentin and cytokeratin‐8 IFs in the existence of vacuoles was accomplished using small interfering RNA–mediated RNA interference to knock down either vimentin or cytokeratin‐8 expression. Reduction of cytokeratin‐8 expression was associated with a less‐vacuolated cell morphology. These data demonstrate that cytokeratin‐8 IFs are involved in stabilizing vacuoles and that their diminished expression could play a role in the loss of vacuolation in NCs during aging. A better understanding of the NCs may assist in preservation of this cell type for NP maintenance and regeneration. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.26809   open full text
• LINC01433 promotes hepatocellular carcinoma progression via modulating the miR‐1301/STAT3 axis.
  Haijin Huang, Yan‐Zhi Bu, Xiao‐Yu Zhang, Juan Liu, Li‐Yao Zhu, Yong Fang.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract Long noncoding RNAs (lncRNAs) have been demonstrated to play significant roles in hepatocellular carcinoma (HCC) tumor progression. LINC01433 has been implicated in the progression of lung cancer. However, its biological role in HCC remains poorly understood. In our current study, we focused on the detailed mechanism of LINC01433 in HCC development. First, it was exhibited that LINC01433 was remarkably elevated in HCC cells, which indicated that LINC01433 was involved in HCC. Then, knockdown of LINC01433 was able to restrain HCC cell proliferation and cell colony formation and greatly induced cell apoptosis. On the contrary, overexpression of LINC01433 promoted HCC cell proliferation, increased cell colony formation, and enhanced cell invasion capacity. Subsequently, we found that miR‐1301 was remarkably decreased in HCC cells, and it can serve as a target of LINC01433 according to bioinformatics analysis. In addition, the binding correlation between them was validated by performing RNA pull‐down experiments and RIP assay. Moreover, STAT3 was predicted and validated as a target of miR‐1301, and it was shown that miR‐1301 mimics significantly suppressed STAT3 in HCC cells. Finally, in vivo models were established, and the results demonstrated that silencing of LINC01433 could repress HCC development through modulating miR‐1301 and STAT3. Taken together, these results indicated in our study that LINC01433 participated in HCC progression through modulating the miR‐1301/STAT3 axis and it might act as a novel biomarker in HCC diagnosis and treatment. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27366   open full text
• Interferon‐stimulated gene 15 enters posttranslational modifications of p53.
  Yang Wang, Qi Ding, Yu‐Chen Lu, Shi‐Yang Cao, Qing‐Xue Liu, Lei Zhang.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2 Abstract The tumor suppressor protein p53 is a central governor of various cellular signals. It is well accepted that ubiquitination as well as ubiquitin‐like (UBL) modifications of p53 protein is critical in the control of its activity. Interferon‐stimulated gene 15 (ISG15) is a well‐known UBL protein with pleiotropic functions, serving both as a free intracellular molecule and as a modifier by conjugating to target proteins. Initially, attentions have historically focused on the antiviral effects of ISG15 pathway. Remarkably, a significant role in the processes of autophagy, DNA repair, and protein translation provided considerable insight into the new functions of ISG15 pathway. Despite the deterministic revelation of the relation between ISG15 and p53, the functional consequence of p53 ISGylation appears somewhat confused. More important, more recent studies have hinted p53 ubiquitination or other UBL modifications that might interconnect with its ISGylation. Here, we aim to summarize the current knowledge of p53 ISGylation and the differences in other significant modifications, which would be beneficial for the development of p53‐based cancer therapy. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27347   open full text
• Tyrosine phosphorylation of HDAC3 by Src kinase mediates proliferation of HER2‐positive breast cancer cells.
  Jaesung Seo, Garam Guk, Seung‐Ho Park, Mi‐Hyeon Jeong, Ji‐Hoon Jeong, Ho‐Geun Yoon, Kyung‐Chul Choi.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract The role of histone deacetylase 3 (HDAC3) is to repress the expression of various genes by eliminating acetyl group from histone. Thus, the regulation of HDAC3 activity is essential to maintain cellular homeostasis. In this study, we found that HDAC3 interacts with c‐Src kinase. However, the interaction between HDAC3 and c‐Src was previously reported, it has still been ambiguous whether c‐Src phosphorylates HDAC3 and affects the function of HDAC3. First, we confirmed that HDAC3 directly binds to c‐Src, and c‐Src identified to interact with C‐terminal domain (277–428 a.a.) of HDAC3. c‐Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild‐type c‐Src increases HDAC3 activity, but not mutant c‐SrcK298M (kinase inactive form). When these tyrosine residues are all substituted for alanine residues, the deacetylase activity of mutant HDAC3 was abolished. In addition, a proliferation of HER2‐positive breast cancer cells expressing phosphorylation deficient mutant HDAC3 is decreased in comparison with control cells. Thus, our findings suggested that phosphorylation of HDAC3 by c‐Src kinase regulates the HDAC3 activity and the proliferation of breast cancer cells. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27378   open full text
• Cinnamaldehyde regulates H2O 2‐induced skeletal muscle atrophy by ameliorating the proteolytic and antioxidant defense systems.
  Nirmaljeet Kaur, Prachi Gupta, Vikram Saini, Sandeep Sherawat, Sanjeev Gupta, Anita Dua, Vinod Kumar, Elisha Injeti, Ashwani Mittal.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract Skeletal muscle atrophy/wasting is associated with impaired protein metabolism in diverse physiological and pathophysiological conditions. Elevated levels of reactive oxygen species (ROS), disturbed redox status, and weakened antioxidant defense system are the major contributing factors toward atrophy. Regulation of protein metabolism by controlling ROS levels and its associated catabolic pathways may help in treating atrophy and related clinical conditions. Although cinnamaldehyde (CNA) enjoys the established status of antioxidant and its role in ROS management is reported, impact of CNA on skeletal muscle atrophy and related pathways is still unexplored. In the current study, the impact of CNA on C2C12 myotubes and the possible protection of cultured cells from H 2O 2‐induced atrophy is examined. Myotubes were treated with H 2O 2 in the presence and absence of CNA and the changes in the antioxidative, proteolytic systems, and mitochondrial functions were scored. Morphological analysis showed significant protective effects of CNA on length, diameter, and nuclei fusion index of myotubes. The evaluation of biochemical markers of atrophy; creatine kinase, lactate dehydrogenase, succinate dehydrogenase along with the study of muscle‐specific structural protein (i.e., myosin heavy chain‐fast [MHCf] type) showed significant protection of proteins by CNA. CNA pretreatment not only checked the activation of proteolytic systems (ubiquitin‐proteasome E3‐ligases [MuRF1/Atrogin1]), autophagy [Beclin1/LC3B], cathepsin L, calpain, caspase), but also prevented any alteration in the activities of antioxidative defense enzymes (catalase, glutathione‐ S‐transferase, glutathione‐peroxidase, superoxide dismutase, glutathione reductase). The results suggest that CNA protects myotubes from H 2O 2‐induced atrophy by inhibiting/resisting the amendments in proteolytic systems and maintains cellular redox‐balance. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27348   open full text
• Exploring and comparing of the gene expression and methylation differences between lung adenocarcinoma and squamous cell carcinoma.
  Yang Yang, Meng Wang, Bao Liu.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract Lung cancer is one of the most frequently diagnosed malignant tumors and the main reason for cancer‐related death around the world, whereas nonsmall cell lung cancer that consists two subtypes: lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) is responsible for an estimated 85% of all lung cancers. The current study aimed to explore gene expression and methylation differences between LUAD and LUSC. EdgeR was used to identify differentially regulated genes between normal and cancer in the LUAD and LUSC extracted from The Cancer Genome Atlas (TCGA), respectively, whereas SAM was used to find genes with differential methylation between normal and cancer in the LUAD and LUSC, respectively. Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed to analyze the function which these genes enriched in. A total of 391 genes with opposite methylation patterns in LUAD and LUSC and four functional pathways were obtained (false discovery rate (FDR) < 0.1). These pathways mainly included fat digestion and absorption, phenylalanine metabolism, bile secretion, and so on, which were related to the airframe nutrition metabolic pathway. Moreover, two genes CTSE (cathepsin E) and solute carrier family 5 member 7 (SLC5A7) were also found, among which CTSE was overexpressed and hypomethylated in LUAD corresponding to normal lung tissues, whereas SLC5A7 showed the opposite in LUAD. In conclusion, this study investigated the differences between the gene expression and methylation patterns in LUAD and LUSC, and explored their different biological characteristics. Further understanding of these differences may promote the discovery and development of new, accurate strategies for the prevention, diagnosis, and treatment of lung cancer. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27240   open full text
• MiR‐208b regulates cell cycle and promotes skeletal muscle cell proliferation by targeting CDKN1A.
  Jian Wang, Chengchuang Song, Xiukai Cao, Hui Li, Hanfang Cai, Yilei Ma, Yongzhen Huang, Xianyong Lan, Chuzhao Lei, Yun Ma, Yueyu Bai, Fengpeng Lin, Hong Chen.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract Skeletal muscle is the most abundant tissue in the body. The development of skeletal muscle cell is complex and affected by many factors. A sea of microRNAs (miRNAs) have been identified as critical regulators of myogenesis. MiR‐208b, a muscle‐specific miRNA, was reported to have a connection with fiber type determination. However, whether miR‐208b has effect on proliferation of muscle cell was under ascertained. In our study, cyclin‐dependent kinase inhibitor 1A (CDKN1A), which participates in cell cycle regulation, was predicted and then validated as one target gene of miR‐208b. We found that overexpression of miR‐208b increased the expression of cyclin D1, cyclin E1, and cyclin‐dependent kinase 2 at the levels of messenger RNA and protein in cattle primary myoblasts in vivo and in vitro. Flow cytometry showed that forced expression of miR‐208b increased the percentage of cells at the S phase and decreased the percentage of cells at the G0/G1 phase. These results indicated that miR‐208b participates in the cell cycle regulation of cattle primary myoblast cells. 5‐Ethynyl‐20‐deoxyuridine and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays showed that overexpression of miR‐208b promoted the proliferation of cattle primary myoblasts. Therefore, we conclude that miR‐208b participates in the cell cycle and proliferation regulation of cattle primary skeletal muscle cell through the posttranscriptional downregulation of CDKN1A. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27146   open full text
• Alteration of cellular and immune‐related properties of bone marrow mesenchymal stem cells and macrophages by K562 chronic myeloid leukemia cell derived exosomes.
  Nazli Jafarzadeh, Zohreh Safari, Majid Pornour, Naser Amirizadeh, Mehdi Forouzandeh Moghadam, Majid Sadeghizadeh.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract Leukemic cells can impact the bone marrow niche to create a tumor‐favorable microenvironment using their secreted factors. Little knowledge is available about immunosuppressive and tumor‐promoting properties of chronic myeloid leukemia derived exosomes in bone marrow stromal components. We report here that K562‐derived exosomes can affect the gene expression, cytokine secretion, nitric oxide (NO) production, and redox potential of bone marrow mesenchymal stem cells (BM‐MSCs) and macrophages. Human BM‐MSCs and mouse macrophages were treated with K562‐derived exosomes. Our results demonstrated that the expression of the genes involved in hematopoietic developmental pathways and immune responses, including C‐X‐C motif chemokine 12 (Cxcl12), Dickkopf‐related protein 1 (DKK1), wnt5a, interleukin 6 (IL‐6), transforming growth factor‐beta, and tumor necrosis factor‐alpha (TNF‐alpha), changed with respect to time and exosome concentration in BM‐MSCs. The TNF‐alpha level was higher in exosome‐treated BM‐MSCs compared with the control. Exosome treatment of BM‐MSCs led to an increased production of NO and a decreased production of reactive oxygen species (ROS) in a time‐ and concentration‐dependent manner. We have shown that K562‐derived exosomes induce overexpression of IL‐10 and TNF‐alpha and downregulation of iNOS transcript levels in macrophages. The enzyme‐linked immunosorbent assay results showed that TNF‐alpha and IL‐10 secretions increased in macrophages. Treatment of macrophages with purified exosomes led to reduced NO and ROS levels. These results suggest that K562‐derived exosomes may alter the local bone marrow niche toward a leukemia‐reinforcing microenvironment. They can modulate the inflammatory molecules (TNF‐alpha and NO) and the redox potential of BM‐MSCs and macrophages and direct the polarization of macrophages toward tumor‐associated macrophages. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27142   open full text
• MicroRNA‐133b suppresses bladder cancer malignancy by targeting TAGLN2‐mediated cell cycle.
  Feng Zhao, Liu‐Hua Zhou, Yu‐Zheng Ge, Wen‐Wen Ping, Xin Wu, Zhong‐Le Xu, Min Wang, Zuo‐Liang Sha, Rui‐Peng Jia.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- Abstract MicroRNAs (miRNAs), a group of small noncoding RNAs, are widely involved in the regulation of gene expression via binding to complementary sequences at 3′‐untranslated regions (3′‐UTRs) of target messenger RNAs. Recently, downregulation of miR‐133b has been detected in various human malignancies. Here, the potential biological role of miR‐133b in bladder cancer (BC) was investigated. In this study, we found the expression of miR‐133b was markedly downregulated in BC tissues and cell lines (5637 and T24), and was correlated with poor overall survival. Notably, transgelin 2 (TAGLN2) was found to be widely upregulated in BC, and overexpression of TAGLN2 also significantly increased risks of advanced TMN stage. We further identified that upregulation of miR‐133b inhibited glucose uptake, invasion, angiogenesis, colony formation and enhances gemcitabine chemosensitivity in BC cell lines by targeting TAGLN2. Additionally, we showed that miR‐133b promoted the proliferation of BC cells, at least partially through a TAGLN2‐mediated cell cycle pathway. Our results suggest a novel miR‐133b/TAGLN2/cell cycle pathway axis controlling BC progression; a molecular mechanism which may offer a potential therapeutic target. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27288   open full text
• Arsenic trioxide inhibits the differentiation of fibroblasts to myofibroblasts through nuclear factor erythroid 2‐like 2 (NFE2L2) protein and the Smad2/3 pathway.
  Lingzhi Zhong, Haojie Hao, Deyun Chen, Qian Hou, Ziying Zhu, Wenjun He, Sujing Sun, Mengli Sun, Meirong Li, Xiaobing Fu.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2 Background Tissue contraction and the extracellular matrix deposition are part of the pathogenesis of hypertrophic scars. The transcriptional factor NFE2L2 inhibits fibroblast differentiation in idiopathic pulmonary fibrosis and promotes myofibroblast dedifferentiation. Our previous study showed that the transcription factor NFE2L2 was strongly induced on treatment with arsenic trioxide (ATO). Objective The present study sought to investigate the effect of ATO on myofibroblast formation to determine its potential role in hypertrophic scar treatment. Methods Small interfering RNA against NFE2L2 was used on treatment with ATO in human skin myofibroblasts. The expression levels of fibrosis markers were assessed by reverse transcription polymerase chain reaction, western blot, and immunofluorescence staining. The transforming growth factor‐β1 (TGF‐β1)/Smad2/3 signaling was detected by western blot. A rabbit ear model was used to evaluate the antifibrotic role of ATO. Results At the cellular level, ATO abolished fibroblast differentiation in response to TGF‐β1. ATO reduced TGF‐β1‐induced reactive oxygen species accumulation through increased expression of the antioxidant gene HO‐1 in fibroblasts. In addition, ATO promoted the nuclear translocation of NFE2L2 and inhibited the phosphorylation of Smad2/3. In the rabbit ear model, ATO prevented the progression of hypertrophic scar formation. Conclusions This study provides the first evidence implying that ATO inhibits the formation of myofibroblasts in vivo and in vitro and provides a possible treatment for hypertrophic scars. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27073   open full text
• Peroxisome proliferator‐activated receptor γ modulates renal crystal retention associated with high oxalate concentration by regulating tubular epithelial cellular transdifferentiation.
  Shujue Li, Yu Lan, Wenzheng Wu, Xiaolu Duan, Zhenzhen Kong, Wenqi Wu, Guohua Zeng.
  Journal of Cellular Physiology. October 14, 2018
  --- - |2- The differentiated phenotype of renal tubular epithelial cell exerts significant effect on crystal adherence. Peroxisome proliferator‐activated receptor γ (PPARγ) has been shown to be critical for the regulation of cell transdifferentiation in many physiological and pathological conditions; however, little is known about its role in kidney stone formation. In the current study, we found that temporarily high oxalate concentration significantly decreased PPARγ expression, induced Madin Darby Canine Kidney cell dedifferentiation, and prompted subsequent calcium oxalate (CaOx) crystal adhesion in vitro. Furthermore, cell redifferentiation after the removal of the high oxalate concentration, along with a decreasing affinity to crystals, was an endogenic PPARγ‐dependent process. In addition, the PPARγ antagonist GW9662, which can depress total‐PPARγ expression and activity, enhanced cell dedifferentiation induced by high oxalate concentration and inhibited cell redifferentiation after removal of the high oxalate concentration. These effects were partially reversed by the PPARγ agonist 15d‐PGJ2. Similar results were observed in animals that suffered from temporary hyperoxaluria followed by a recovery period. The active crystal‐clearing process occurs through the transphenotypical morphology of renal tubular epithelial cells, reflecting cell transdifferentiation during the recovery period. However, GW9662 delayed cell redifferentiation and increased the secondary temporary crystalluria‐induced crystal retention. This detrimental effect was partially reversed by 15d‐PGJ2. Taken together, our results revealed that endogenic PPARγ activity plays a vital regulatory role in crystal clearance, subsequent crystal adherence, and CaOx stone formation via manipulating the transdifferentiation of renal tubular epithelial cells. - Journal of Cellular Physiology, EarlyView.
  

  October 14, 2018   doi: 10.1002/jcp.27102   open full text
• Cover Image, Volume 233, Number 12, December 2018.
  May Chammaa, Agnes Malysa, Carlos Redondo, Hyejeong Jang, Wei Chen, Gerold Bepler, Rodrigo Fernandez‐Valdivia.
  Journal of Cellular Physiology. October 12, 2018
  --- - - Journal of Cellular Physiology, Volume 233, Issue 12, Page i-i, December 2018.
  

  October 12, 2018   doi: 10.1002/jcp.27479   open full text
• Table of Contents, Editor's Choice, Highlights.
  
  Journal of Cellular Physiology. October 12, 2018
  --- - - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9031-9042, December 2018.
  

  October 12, 2018   doi: 10.1002/jcp.27478   open full text
• DL‐3‐n‐butylphthalide alleviates vascular cognitive impairment by regulating endoplasmic reticulum stress and the Shh/Ptch1 signaling‐pathway in rats.
  Xiao‐Li Niu, Xin Jiang, Guo‐Dong Xu, Gui‐Min Zheng, Zhi‐Peng Tang, Nan Yin, Xiu‐Qin Li, Yan‐Yan Yang, Pei‐Yuan Lv.
  Journal of Cellular Physiology. October 11, 2018
  --- - |2 Abstract Background DL‐3‐n‐butylphthalide (NBP) has been approved to be effective in improving cognitive deficits. The aim of the current study was to determine whether NBP protects against cognitive deficits in a rat model of vascular dementia (VD) induced by chronic cerebral hypoperfusion (CCH) by regulating the sonic hedgehog (Shh)/patched1 (Ptch1) pathway and endoplasmic reticulum stress (ERS)‐related markers. Methods Adult male Sprague‐Dawley rats were subjected to permanent bilateral occlusion of the common carotid arteries (2VO) to established the model of VD. These rats were randomly divided into five groups: sham, model, NBP30 (30 mg/kg), NBP 60 (60 mg/kg), and NBP 120 (120 mg/kg) groups. The Morris water maze test was used to assess for cognitive function at 4 weeks after operation. Results NBP significantly alleviated spatial learning and memory impairment, and inhibited the loss of neurons in the CA1 region of the hippocampus. Western blot analysis and real‐time quantitative polymerase chain reaction analysis revealed that plasticity‐related synaptic markers and the Shh/Ptch1 pathway significantly increased in the NBP treated groups, while ERS‐related markers decreased. Conclusion The results of the current study prove that the Shh/Ptch1 pathway plays an essential role in the model of VD. NBP had protective effects on cognitive impairment induced by CCH. This mechanism was associated with ERS and the Shh/Ptch1 pathway. Meanwhile, the Shh/Ptch1 pathway and ERS may interact with each other. - Journal of Cellular Physiology, EarlyView.
  

  October 11, 2018   doi: 10.1002/jcp.27332   open full text
• Chrysin leads to cell death in endometriosis by regulation of endoplasmic reticulum stress and cytosolic calcium level.
  Soomin Ryu, Fuller W. Bazer, Whasun Lim, Gwonhwa Song.
  Journal of Cellular Physiology. October 10, 2018
  --- - |2- Abstract Chrysin is a natural compound derived from honey, propolis, or passion flowers and has many functional roles, such as antiinflammatory and antiangiogenesis effects. Although endometriosis is a benign gynecological disease, there is a need to identify the pathology and develop a therapy for endometriosis. Elucidating the biological mechanism of chrysin on endometriosis will improve the understanding of endometriosis. In this study, we confirmed the apoptotic effects of chrysin in human endometriotic cells using End1/E6E7 (endocervix‐derived endometriotic cells) and VK2/E6E7 (vaginal mucosa‐derived epithelial endometriotic cells). The results showed that chrysin suppressed the proliferation of endometriosis and induced programmed cell death through changing the cell cycle proportion and increasing the cytosolic calcium level and generation of reactive oxygen species. In addition, chrysin activated endoplasmic reticulum (ER) stress by stimulating the unfolded protein response proteins, especially the 78‐kDa glucose‐regulated protein–PRKR‐like ER kinase (PERK)–eukaryotic translation initiation factor 2α (eIF2α) pathway in both endometriotic cell lines. Furthermore, chrysin inactivated the intracellular phosphoinositide 3‐kinase (PI3K)/protein kinase B (PKB, also known as AKT) signaling pathway in a dose‐dependent manner. Collectively, the results of this study indicated that chrysin induced programmed cell death by activating the ER stress response and inactivating the PI3K signaling pathways in human endometriotic cells. - Journal of Cellular Physiology, EarlyView.
  

  October 10, 2018   doi: 10.1002/jcp.26770   open full text
• Long noncoding RNA Gm6135 functions as a competitive endogenous RNA to regulate toll‐like receptor 4 expression by sponging miR‐203‐3p in diabetic nephropathy.
  Ting‐Ting Ji, Ya‐Kun Wang, Ying‐Chun Zhu, Cong‐Pu Gao, Xiao‐Ying Li, Ji Li, Feng Bai, Shou‐Jun Bai.
  Journal of Cellular Physiology. October 08, 2018
  --- - |2- Abstract We aim to explore the relationship between Gm6135 and diabetic nephropathy. We detected the relative expression levels of Gm6135 and toll‐like receptor 4 (TLR4) in diabetic nephropathy mice and high‐glucose‐cultured mouse mesangial cells SV40‐MES‐13 by the quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) and western blot detection. Cell proliferation and apoptosis were detected after small interfering RNA (siRNA) interference or plasmid overexpression of Gm6135/TLR4, and bioinformatics method was used to predict and screen miR‐203 as an intermediate factor. Through dual‐luciferase reporter gene, RNA pull‐down, qRT‐PCR, and western blot, the binding relationship between Gm6135, miR‐203‐3p, and TLR4 was confirmed. The possibility of the competing endogenous RNA mechanism was demonstrated by cell localization assays and rip assays. Finally, the proliferation of mouse mesangial cells SV40‐MES‐13 was detected after mimics and inhibitor of microRNA, which were reversed with TLR4 overexpression and siRNA. The results showed that the relative expression levels of Gm6135 and TLR4 in the kidney and high‐glucose‐cultured mouse mesangial cells of diabetic nephropathy mice increased significantly. Overexpression or downregulation of Gm6135/TLR4 significantly affected the proliferation and apoptosis of mouse mesangial cells. Gm6135 upregulates TLR4 by competitively binding to miR‐203‐3p. - Journal of Cellular Physiology, EarlyView.
  

  October 08, 2018   doi: 10.1002/jcp.27412   open full text
• The imbalance of Th17/Treg axis involved in the pathogenesis of preeclampsia.
  Shadi Eghbal‐Fard, Mehdi Yousefi, Hanieh Heydarlou, Majid Ahmadi, Simin Taghavi, Aliakbar Movasaghpour, Farhad Jadidi‐Niaragh, Bahman Yousefi, Sanam Dolati, Mohammad Hojjat‐Farsangi, Reza Rikhtegar, Mohammad Nouri, Leili Aghebati‐Maleki.
  Journal of Cellular Physiology. October 02, 2018
  --- - "\nAbstract\n\nProblem\nInappropriate activation of the immune system, particularly the imbalance of T‐helper type 17 (Th17)/regulatory T (Treg) cells is thought to play considerable roles in preeclampsia (PE). To investigate the probable effects of the adaptive immune system in the pathophysiology of PE, we analyzed the dynamic changes of Th17/Treg cells, cytokines profile, and transcription pattern of Th17/Treg‐related genes and microRNAs (miRNAs) in 50 women suffering from PE in comparison with 50 healthy pregnant women.\n\n\nMethods\nExpressions of cytokines, specific transcription factors, and related miRNAs were measured by real‐time polymerase chain reaction (PCR). Enzyme‐linked immunosorbent assay (ELISA) was used to test the interleukin (IL)‐17, IL‐23, IL‐6, and IL‐10 and transforming growth factor β in serum and supernatant of peripheral blood mononuclear cells (PBMCs). The frequency of Th17 and Treg cells were determined by flow cytometry.\n\n\nResults\nPE patients exhibited a decreased number of Treg cells (p = 0.006), while Th17 cells were increased (\np = 0.004). Forkhead box P3 and \nIL‐10 mRNA expressions were reduced (\np = 0.0001 and 0.0028, respectively), while expressions of retinoic acid receptor‐related orphan nuclear receptor γt, IL‐17, IL‐23, and IL‐6 were enhanced (\np < 0.0001, 0.0018, 0.0014, and 0.027, respectively). ELISA results also showed increased levels of IL‐6, IL‐17, and IL‐23 (\np = 0.022, 0.0005, 0.0081, respectively), and decreased levels of IL‐10 in the supernatant of PBMCs of PE patients compared with control group (\np = 0.0011). There was significant upregulation of miR‐106b and miR‐326 (\np = 0.0048 and 0.028, respectively) in PE patients in comparison with the control group.\n\n\nConclusions\nThese findings suggest that imbalance of Th17/Treg cells, regulated possibly via microRNAs, may be involved in the pathogenesis of PE, emphasizing on the importance of these cells in feto‐maternal immune cross‐talk.\n" - Journal of Cellular Physiology, EarlyView.
  

  October 02, 2018   doi: 10.1002/jcp.27315   open full text
• Dual‐specificity phosphatase 6 deletion protects the colonic epithelium against inflammation and promotes both proliferation and tumorigenesis.
  Katia Beaudry, Marie‐Josée Langlois, Amélie Montagne, Sébastien Cagnol, Julie C. Carrier, Nathalie Rivard.
  Journal of Cellular Physiology. October 01, 2018
  --- - "\nAbstract\nThe Ras/mitogen‐activated protein kinase (MAPK) pathway controls fundamental cellular processes such as proliferation, differentiation, and apoptosis. The dual‐specificity phosphatase 6 (DUSP6) regulates cytoplasmic MAPK signaling by dephosphorylating and inactivating extracellular signal‐regulated kinase (ERK1/2) MAPK. To determine the role of DUSP6 in the maintenance of intestinal homeostasis, we characterized the intestinal epithelial phenotype of \nDusp6 knockout (KO) mice under normal, oncogenic, and proinflammatory conditions. Our results show that loss of Dusp6 increased crypt depth and epithelial cell proliferation without altering colonic architecture. Crypt regeneration capacity was also enhanced, as revealed by ex vivo \nDusp6 KO organoid cultures. Additionally, loss of Dusp6 induced goblet cell expansion without affecting enteroendocrine and absorptive cell differentiation. Our data also demonstrate that \nDusp6 KO mice were protected from acute dextran sulfate sodium‐induced colitis, as opposed to wild‐type mice. In addition, \nDusp6 gene deletion markedly enhanced tumor load in \nApc\nMin/+ mice. Decreased DUSP6 expression by RNA interference in HT29 colorectal cancer cells enhanced ERK1/2 activation levels and promoted both anchorage‐independent growth in soft agar as well as invasion through Matrigel. Finally, \nDUSP6 mRNA expression in human colorectal tumors was decreased in advanced stage tumors compared with paired normal tissues. These results demonstrate that DUSP6 phosphatase, by controlling ERK1/2 activation, regulates colonic inflammatory responses, and protects the intestinal epithelium against oncogenic stress." - Journal of Cellular Physiology, EarlyView.
  

  October 01, 2018   doi: 10.1002/jcp.27420   open full text
• Cover Image, Volume 233, Number 11, November 2018.
  Tingru Pan, Xueyuan Hu, Tianqi Liu, Zhe Xu, Na Wan, Yiming Zhang, Shu Li.
  Journal of Cellular Physiology. October 01, 2018
  --- - - Journal of Cellular Physiology, Volume 233, Issue 11, Page i-i, November 2018.
  

  October 01, 2018   doi: 10.1002/jcp.27284   open full text
• Table of Contents, Editor's Choice, Highlights.
  
  Journal of Cellular Physiology. October 01, 2018
  --- - - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8399-8407, November 2018.
  

  October 01, 2018   doi: 10.1002/jcp.27285   open full text
• Proinflammatory macrophages impair skeletal muscle differentiation in obesity through secretion of tumor necrosis factor‐α via sustained activation of p38 mitogen‐activated protein kinase.
  Xueqiang Wang, Daina Zhao, Yajuan Cui, Shemin Lu, Dan Gao, Jiankang Liu.
  Journal of Cellular Physiology. September 28, 2018
  --- - |2 Obesity is associated with skeletal muscle loss and impaired myogenesis. Increased infiltration of proinflammatory macrophages in skeletal muscle is noted in obesity and is associated with muscle insulin resistance. However, whether the infiltrated macrophages can contribute to obesity‐induced muscle loss is unclear. In this study, we investigate macrophage and muscle differentiation markers in the quadriceps (QC), gastrocnemius, tibia anterior, and soleus muscles from obese mice that were fed a high‐fat diet for 16 weeks. Then, we examined the effect and mediator of macrophage‐secreted factors on myoblast differentiation in vitro. We found markedly increased levels of proinflammatory macrophage markers (F4/80 and CD11c) in the QC muscle compared with the other three muscle groups. Consistent with the increased levels of proinflammatory macrophage infiltration, the QC muscle also showed a significant reduction in the expression of muscle differentiation makers MYOD1 and myosin heavy chain. In in vitro studies, treatment of C2C12 myoblasts with Raw 264.7 macrophage‐conditioned medium (CM) significantly promoted cell proliferation and inhibited myoblast differentiation. Neutralization of tumor necrosis factor α (TNF‐α) in Raw 264.7 macrophage CM reversed the reduction of myoblast differentiation. Finally, we found that both macrophage CM and TNF‐α induced sustained activation of p38 mitogen‐activated protein kinase (MAPK) in C2C12 myoblasts. Together, our findings suggest that the increased infiltration of proinflammatory macrophages could contribute toward obesity‐induced muscle loss by secreting inflammatory cytokine TNF‐α via the p38 MAPK signaling pathway. - Journal of Cellular Physiology, EarlyView.
  

  September 28, 2018   doi: 10.1002/jcp.27012   open full text
• Microbiota‐derived lipopolysaccharide retards chondrocyte hypertrophy in the growth plate through elevating Sox9 expression.
  Xin Cheng, Pei‐Zhi Li, Guang Wang, Yu Yan, Ke Li, Beate Brand‐Saberi, Xuesong Yang.
  Journal of Cellular Physiology. September 28, 2018
  --- - |2- Abstract Accumulating data show that the cytotoxicity of bacterial lipopolysaccharides (LPS) from microbiota or infection is associated with many disorders observed in the clinics. However, it is still obscure whether or not embryonic osteogenesis is affected by the LPS exposure during gestation. Using the early chicken embryo model, we could demonstrate that LPS exposure inhibits chondrogenesis of the 8‐day chicken embryos by Alcian Blue‐staining and osteogenesis of 17‐day by Alcian Blue and Alizarin Red staining. Further analysis of the growth plates showed that the length of the proliferating zone (PZ) increases whereas that of the hypertrophic zone (HZ) decreased following LPS exposure. However there is no significant change on cell proliferation in the growth plates. Immunofluorescent staining, western blot analysis, and quantitive polymerase chain reaction revealed that Sox9 and Col2a1 are highly expressed at the messenger RNA level and their protein products are also abundant. LPS exposure causes a downregulation of Runx2 and Col10a1 expression in 8‐day hindlimbs, and a suppression of Runx2, Col10a1, and Vegfa expression in 17‐day phalanges. Knocking down Sox9 in ATDC5 cells by small interfering RNA transfection lead to the expression reduction of Col2a1, Runx2, and Col10a1, implying the vital role of Sox9 in the process of LPS‐induced delay in the transition from proliferating chondrocytes to hypertrophic chondrocytes in the growth plate. In the presence of LPS, the antioxidant defense regulator nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is highly expressed, and the activities of superoxide dismutase 1 (SOD1), SOD2, and glutaredoxin rise in 17‐day phalanges and ADTC5 cells. Simultaneously, an increase of intracellular ROS is observed. When Nrf2 expression was knocked down in ATDC5 cells, the expressions of Sox9, Col2a1, Runx2, Col10a1, and Vegfa were also going down as well. Taken together, our current data suggest that LPS exposure during gestation could restrict the chondrocytes conversion from proliferating to hypertrophic in the growth plate, in which LPS‐induced Sox9 plays a crucial role to trigger the cascade of downstream genes by excessive ROS production and Nrf2 elevation. - Journal of Cellular Physiology, EarlyView.
  

  September 28, 2018   doi: 10.1002/jcp.27025   open full text
• Curcumin attenuates proangiogenic and proinflammatory factors in human eutopic endometrial stromal cells through the NF‐κB signaling pathway.
  Indrajit Chowdhury, Saswati Banerjee, Adel Driss, Wei Xu, Sherifeh Mehrabi, Ceana Nezhat, Neil Sidell, Robert N. Taylor, Winston E. Thompson.
  Journal of Cellular Physiology. September 27, 2018
  --- - |2- Abstract Endometriosis is a chronic gynecological inflammatory disorder in which immune system dysregulation is thought to play a role in its initiation and progression. Due to altered sex steroid receptor concentrations and other signaling defects, eutopic endometriotic tissues have an attenuated response to progesterone. This progesterone‐resistance contributes to lesion survival, proliferation, pain, and infertility. The current agency‐approved hormonal therapies, including synthetic progestins, GnRH agonists, and danazol are often of limited efficacy and counterproductive to fertility and cause systemic side effects due to suppression of endogenous steroid hormone levels. In the current study, we examined the effects of curcumin (CUR, diferuloylmethane), which has long been used as an anti‐inflammatory folk medicine in Asian countries for this condition. The basal levels of proinflammatory and proangiogenic chemokines and cytokines expression were higher in primary cultures of stromal cells derived from eutopic endometrium of endometriosis (EESC) subjects compared with normal endometrial stromal cells (NESC). The treatment of EESC and NESC with CUR significantly and dose‐dependently reduced chemokine and cytokine secretion over the time course. Notably, CUR treatment significantly decreased phosphorylation of the IKKα/β, NF‐κB, STAT3, and JNK signaling pathways under these experimental conditions. Taken together, our findings suggest that CUR has therapeutic potential to abrogate aberrant activation of chemokines and cytokines, and IKKα/β, NF‐κB, STAT3, and JNK signaling pathways to reduce inflammation associated with endometriosis. - Journal of Cellular Physiology, EarlyView.
  

  September 27, 2018   doi: 10.1002/jcp.27360   open full text
• Blockade of NEAT1 represses inflammation response and lipid uptake via modulating miR‐342‐3p in human macrophages THP‐1 cells.
  Lei Wang, Jing‐Wen Xia, Zun‐Ping Ke, Bing‐Hong Zhang.
  Journal of Cellular Physiology. September 27, 2018
  --- - |2- Abstract Atherosclerosis has been recognized as a chronic inflammation process induced by lipid of the vessel wall. Oxidized low‐density lipoprotein (ox‐LDL) can drive atherosclerosis progression involving macrophages. Recently, long noncoding RNAs (lncRNAs) have been reported to play critical roles in atherosclerosis development. In our current study, we focused on the biological roles of lncRNA NEAT1 in atherosclerosis progress. Here, we found that ox‐LDL was able to trigger human macrophages THP‐1 cells, a human monocytic cell line, apoptosis in a dose‐dependent and time‐dependent course. In addition, we observed that NEAT1 was significantly increased in THP‐1 cells incubated with ox‐LDL and meanwhile miR‐342‐3p was greatly decreased. Then, NEAT1 was silenced by transfection of small interfering RNA (siRNA) of NEAT1 into THP‐1 cells. As exhibited, CD36, oil‐red staining levels, total cholesterol (TC), total cholesterol (TG) levels and THP‐1 cell apoptosis were obviously repressed by knockdown of NEAT1. Furthermore, inhibition of NEAT1 contributed to the repression of inflammation in vitro. Interleukin 6 (IL‐6), IL‐1β, cyclooxygenase‐2 (COX‐2) and tumour necrosis factor‐alpha (TNF‐α) protein levels were remarkably depressed by NEAT1 siRNA in THP‐1 cells. By using bioinformatics analysis, miR‐342‐3p was predicted as a downstream target of NEAT1 and the correlation between them was confirmed in our study. Moreover, overexpression of miR‐342‐3p could also greatly suppress inflammation response and lipid uptake in THP‐1 cells. Knockdown of NEAT1 and miR‐342‐3p mimics inhibited lipid uptake in THP‐1 cells. In conclusion, we implied that blockade of NEAT1 repressed inflammation response through modulating miR‐342‐3p in human macrophages THP‐1 cells and NEAT1 may offer a promising strategy to treat atherosclerotic cardiovascular diseases. - Journal of Cellular Physiology, EarlyView.
  

  September 27, 2018   doi: 10.1002/jcp.27340   open full text
• Notch‐1 signaling activation sustains overexpression of interleukin 33 in the epithelium of nasal polyps.
  G. Chiappara, S. Sciarrino, C. Di Sano, S. Gallina, R. Speciale, F. Lorusso, S. Di Vincenzo, C. D’Anna, A. Bruno, M. Gjomarkaj, E. Pace.
  Journal of Cellular Physiology. September 27, 2018
  --- - "\nAbstract\n\nBackground\nAlterations in the nasal epithelial barrier homeostasis and increased interleukin 33 (IL‐33) expression contribute to the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP).\n\n\nAims\nAs Notch‐1 signaling is crucial in repair processes of mucosa, the current study assessed Notch‐1/Jagged‐1 signaling and IL‐33 in the epithelium of nasal polyps biopsies from allergic (A‐CRSwNP; \nn = 9) and not allergic (NA‐CRSwNP; \nn = 9) subjects by immunohistochemistry. We also assessed, in a model of nasal epithelial cells, the effects of stimulation of Notch‐1 with Jagged‐1 on the expression of IL‐33 (by flow cytometry, immunofluorescence, and immunocytochemistry), Jagged‐1 (by flow cytometry), and p‐CREB transcription factor (by western blot analysis).\n\n\nResults\nEx vivo (a) in normal epithelium, the expression of Notch‐1 and IL‐33 were higher in NA‐CRSwNP than in A‐CRSwNP; (b) in metaplastic epithelium, the expression of Notch‐1, Jagged‐1, and IL‐33 were higher in NA‐CRSwNP than in A‐CRSwNP; (c) in hyperplastic epithelium, the expression of Notch‐1, Jagged‐1, and IL‐33 were higher in A‐CRSwNP than in NA‐CRSwNP; and (d) in basal epithelial cells, no differences were observed in the expression of Jagged‐1, IL‐33, and Notch‐1. The expression of Notch‐1 significantly correlated with the expression of IL‐33. In vitro, stimulation of Notch‐1 with Jagged‐1 induced the expression of (a) Jagged‐1; (b) IL‐33; and (c) p‐CREB transcription factor. The inhibitor of Notch‐1, DAPT, reduced all the effects of Jagged‐1 on nasal epithelial cells.\n\n\nConclusions\nThe data herein provided support, for the first time, a putative role of Notch‐1/Jagged‐1 signaling in the overexpression of IL‐33 in the epithelium of nasal polyps from patients with CRSwNP.\n" - Journal of Cellular Physiology, EarlyView.
  

  September 27, 2018   doi: 10.1002/jcp.27237   open full text
• Ewing‐like sarcoma: An emerging family of round cell sarcomas.
  Samuele Renzi, Nathaniel D. Anderson, Nicholas Light, Abha Gupta.
  Journal of Cellular Physiology. September 26, 2018
  --- - "\nAbstract\nEwing‐like sarcomas are an emerging subgroup of small round blue cell sarcomas that share various degrees of morphological, immunohistochemical, molecular, and clinical similarity with Ewing sarcoma. Despite these similarities, Ewing‐like sarcomas lack the pathognomonic molecular hallmark of Ewing sarcoma: A translocation between a gene of the RNA‐binding TET family (EWSR1 or \nFUS) with a gene of the ETS‐transcription family (\nFLI1, \nERG, \nETV1, \nETV4, or \nFEV). Recently, increased use of modern molecular methods based on next‐generation sequencing have enabled the identification of distinct subgroups within this previously uncharacterized group of Ewing‐like sarcomas based on the discovery of novel molecular driving events. The focus of this review is to provide an update on the main subcategories of Ewing‐like sarcomas discovered to date: \nCIC‐rearranged sarcomas, \nBCOR‐rearranged sarcomas, sarcomas with a rearrangement between \nEWSR1 and a non‐ETS family gene, and the substantial fraction of tumors which remain uncharacterized by molecular methods. There is increasing evidence that these tumors represent stand‐alone entities with unique characteristics rather than simply a subgroup of Ewing sarcoma; thus, the question of the best therapeutic approach for these often aggressive sarcomas remains of primary importance. Ultimately, large collaborative efforts will be necessary to better determine the characteristics of this rare, heterogeneous family of tumors." - Journal of Cellular Physiology, EarlyView.
  

  September 26, 2018   doi: 10.1002/jcp.27558   open full text
• Raloxifene attenuates oxidative stress and preserves mitochondrial function in astrocytic cells upon glucose deprivation.
  Diego J. Vesga‐Jiménez, Oscar Hidalgo‐Lanussa, Eliana Baez‐Jurado, Valentina Echeverria, Ghulam Md Ashraf, Amirhossein Sahebkar, George E. Barreto.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Oxidative stress and mitochondrial dysfunction induced by metabolic insults are both hallmarks of various neurological disorders, whereby neuronal cells are severely affected by decreased glucose supply to the brain. Likely injured, astrocytes are important for neuronal homeostasis and therapeutic strategies should be directed towards improving astrocytic functions to improve brain's outcome. In the present study, we aimed to assess the actions of raloxifene, a selective estrogen receptor modulator in astrocytic cells under glucose deprivation. Our findings indicated that pretreatment with 1 µM raloxifene results in an increase in cell viability and attenuated nuclei fragmentation. Raloxifene's actions also rely on the reduction of oxidative stress and preservation of mitochondrial function in glucose‐deprived astrocytic cells, suggesting the possible direct effects of this compound on mitochondria. In conclusion, our results demonstrate that raloxifene's protective actions might be mediated in part by astrocytes in the setting of a metabolic insult. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27481   open full text
• TGF‐β1‐PML SUMOylation‐peptidyl‐prolyl cis–trans isomerase NIMA‐interacting 1 (Pin1) form a positive feedback loop to regulate cardiac fibrosis.
  Di Wu, Di Huang, Liang‐Liang Li, Ping Ni, Xiu‐Xian Li, Bing Wang, Yan‐Na Han, Xiao‐Qi Shao, Dan Zhao, Wen‐Feng Chu, Bai‐Yan Li.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Transforming growth factor‐β (TGF‐β) signaling pathway is involved in fibrosis in most, if not all forms of cardiac diseases. Here, we evaluate a positive feedback signaling the loop of TGF‐β1/promyelocytic leukemia (PML) SUMOylation/Pin1 promoting the cardiac fibrosis. To test this hypothesis, the mice underwent transverse aortic constriction (3 weeks) were developed and the morphological evidence showed obvious interstitial fibrosis with TGF‐β1, Pin1 upregulation, and increase in PML SUMOylation. In neonatal mouse cardiac fibroblasts (NMCFs), we found that exogenous TGF‐β1 induced the upregulation of TGF‐β1 itself in a time‐ and dose‐dependent manner, and also triggered the PML SUMOylation and the formation of PML nuclear bodies (PML‐NBs), and consequently recruited Pin1 into nuclear to colocalize with PML. Pharmacological inhibition of TGF‐β signal or Pin1 with LY364947 (3 μM) or Juglone (3 μM), the TGF‐β1‐induced PML SUMOylation was reduced significantly with downregulation of the messenger RNA and protein for TGF‐β1 and Pin1. To verify the cellular function of PML by means of gain‐ or loss‐of‐function, the positive feedback signaling loop was enhanced or declined, meanwhile, TGF‐β‐Smad signaling pathway was activated or weakened, respectively. In summary, we uncovered a novel reciprocal loop of TGF‐β1/PML SUMOylation/Pin1 leading to myocardial fibrosis. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27357   open full text
• 2‐Methoxyestradiol attenuates chronic‐intermittent‐hypoxia‐induced pulmonary hypertension through regulating microRNA‐223.
  Shengyu Hao, Liyan Jiang, Cuiping Fu, Xu Wu, Zilong Liu, Jieqiong Song, Huan Lu, Xiaodan Wu, Shanqun Li.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Pulmonary hypertension (PH) is prevalent in patients with obstructive sleep apnea (OSA) syndrome, and coexistence of PH and OSA indicates a worse prognosis and higher mortality. Chronic intermittent hypoxia (CIH) is the key pathogenesis of OSA. Also, microRNA‐223 (miR‐223) plays a role in the regulation of CIH‐induced PH process. However, the detailed mechanism of CIH inducing PH is still unclear. This study aimed to investigate the pathological process of CIH associated PH and explore the potential therapeutic methods. In this study, adult Sprague–Dawley rats were exposed to CIH or normoxic (N) conditions with 2‐methoxyestradiol (2‐Me) or vehicle treatment for 6 weeks. The results showed that 2‐Me treatment reduced the progression of pulmonary angiogenesis in CIH rats, and alleviated proliferation, cellular migration, and reactive oxygen species formation was induced by CIH in pulmonary artery smooth muscle cells (PASMCs). CIH decreased the expression of miR‐223, whereas 2‐Me reversed the downregulation of miR‐223 both in vivo and in vitro. Furthermore, the antiangiogenic effect of 2‐Me observed in PASMCs was abrogated by miR‐223 inhibitor, while enhanced by miR‐223 mimic. These findings suggested that miR‐223 played an important role in the process of CIH inducing PH, and 2‐Me might reverse CIH‐induced PH via upregulating miR‐223. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27363   open full text
• Curcumin induces concentration‐dependent alterations in mitochondrial function through ROS in C2C12 mouse myoblasts.
  Tianzheng Yu, Jacob Dohl, Falicia Elenberg, Yifan Chen, Patricia Deuster.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Curcumin exhibits antioxidant properties in normal cells where the uptake is low, unlike in tumor cells where uptake is high and curcumin increases reactive oxygen species (ROS) production and cell death. Mitochondria are the main source and primary target of cellular ROS. We hypothesized that curcumin would regulate cellular redox status and mitochondrial function, depending on cell sensitivity and/or curcumin concentration in normal cells. We examined the differences between low and high concentrations of curcumin, with specific attention focused on ROS levels, mitochondrial function, and cell viability in mouse C2C12 myoblast under normal and simulated conditions of diabetes. Cells incubated with high concentrations of curcumin (10–50 μM) resulted in decreased cell viability and sustained robust increases in ROS levels. Mechanistic studies showed that increased ROS levels in cells incubated with 20 μM curcumin induced opening of mitochondrial permeability transition pores and subsequent release of cytochrome c, activation of caspases 9 and 3/7, and apoptotic cell death. Low concentrations of curcumin (1–5 μM) did not affect cell viability, but induced a mild increase in ROS levels, which peaked at 2 hr after the treatment. Incubation with 5 μM curcumin also induced ROS‐dependent increases in mitochondrial mass and membrane potential. Finally, pretreatment with 5 μM curcumin prevented high glucose‐induced oxidative cell injury. Our study suggests that mitochondria respond differentially depending on curcumin concentration‐dependent induction of ROS. The end result is either cell protection or death. Curcumin may be an effective therapeutic target for diabetes and other mitochondrial diseases when used in low concentrations. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27370   open full text
• Distinct Tie2 tyrosine phosphorylation sites dictate phenotypic switching in endothelial progenitor cells.
  Vahid Siavashi, Seyed Mahdi Nassiri, Reza Rahbarghazi, Zahra Mohseni, Ali Mohammad Sharifi.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Angiogenesis is a regulated process involving the proliferation, migration, and remodeling of different cell types particularly mature endothelial and their progenitor cells, nominated as endothelial progenitor cells (EPCs). Tie2/Tek is a tyrosine kinase receptor expressed by endothelial cells that induces signal transduction pathways involved in endothelial biology. To address the potential importance of the various tyrosine residues of Tie2 in EPC development, we generated a series of Tie2 tyrosine mutated (Y1106F, Y1100F, and Y1111F) EPCs and then assess the biological features of these cells. Clonogenic, tubulogenic, proliferative, migratory, and functional properties of these cells were analyzed. Next, GFP‐positive EPCs containing Tie2 tyrosine mutations were systemically transplanted into sublethaly irradiated mice to analyze the potency of these cells for marrow reconstitution. We found that mutation in the Tie2 tyrosine 1106 residue directed EPCs toward a mature endothelial phenotype, which was associated with augmented tubulogenic and migratory properties, and increased phosphorylation of the active site (tyrosine 992) as well as increased vascular perfusion in the in vivo Matrigel plug assay. Moreover, transplantation of 1106 Tie2 mutant EPCs failed to reconstitute the bone marrow after myeloablation, whereas transplantation of EPCs with the 1100 or 1111 Tie2 tyrosine mutation resulted in bone marrow engraftment, leading to improved survival of recipient mice. Our findings demonstrate that the tyrosine 1106 residue in Tie2 plays a key role to maintain the stemness features of EPCs. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27349   open full text
• HDAC8 regulates canonical Wnt pathway to promote differentiation in skeletal muscles.
  Luca Ferrari, Cinzia Bragato, Loredana Brioschi, Marco Spreafico, Simona Esposito, Alex Pezzotta, Fabrizio Pizzetti, Artal Moreno‐Fortuny, Gianfranco Bellipanni, Antonio Giordano, Paola Riva, Flavia Frabetti, Paola Viani, Giulio Cossu, Marina Mora, Anna Marozzi, Anna Pistocchi.
  Journal of Cellular Physiology. September 24, 2018
  --- - "\nAbstract\nHistone deacetylase 8 (HDAC8) is a class 1 histone deacetylase and a member of the cohesin complex. HDAC8 is expressed in smooth muscles, but its expression in skeletal muscle has not been described. We have shown for the first time that HDAC8 is expressed in human and zebrafish skeletal muscles. Using RD/12 and RD/18 rhabdomyosarcoma cells with low and high differentiation potency, respectively, we highlighted a specific correlation with \nHDAC8 expression and an advanced stage of muscle differentiation. We inhibited HDAC8 activity through a specific PCI‐34051 inhibitor in murine C2C12 myoblasts and zebrafish embryos, and we observed skeletal muscles differentiation impairment. We also found a positive regulation of the canonical Wnt signaling by HDAC8 that might explain muscle differentiation defects. These findings suggest a novel mechanism through which HDAC8 expression, in a specific time window of skeletal muscle development, positively regulates canonical Wnt pathway that is necessary for muscle differentiation." - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27341   open full text
• Long noncoding RNA SNHG12 promotes the progression of cervical cancer via modulating miR‐125b/STAT3 axis.
  Xue‐J. Jin, Xiang‐J. Chen, Zhi‐F. Zhang, Wen‐S. Hu, Rong‐Y. Ou, Shi Li, Ji‐S. Xue, Lu‐L. Chen, Yan Hu, Hua Zhu.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Increasing evidence showed that long noncoding RNAs (lncRNAs) played an important role in the occurrence and development of tumors. To date, lncRNA small nucleolar RNA host gene 12 (SNHG12) has revealed an oncogenic role in various tumors. However, the role of SNHG12 in cervical cancer is still unclear. Therefore, we focused on the biological function and molecular mechanism of SNHG12 in the tumorigenesis of cervical cancer. In this study, the expression of miR‐125b was observably downregulated in cervical cancer cells. Meanwhile, the expression of SNHG12 was obviously upregulated in cervical cancer cell lines (HeLa, SiHa, Caski, C4‐1, and C33A) compared with the immortalized cervical epithelial cells. The further assay showed that miR‐125b was a target of SNHG12 in cervical cancer. Moreover, a negative relationship between miR‐125b and SNHG12 was found in cervical cancer. In addition, SNHG12 inhibition restrained the proliferation, migration, and invasion of cervical cancer cells. Meanwhile, miR‐125b mimics repressed the expression of signal transducer and activator of transcription 3 (STAT3). The further assay showed that STAT3 was a target of miR‐125b in cervical cancer. In addition, sh‐STAT3 repressed the migration and invasion of cervical cancer cells. Furthermore, it showed that miR‐125b inhibitors reversed STAT3 expression restrained by the reduction of SNHG12 expression. In general, SNHG12 modulated STAT3 by sponging miR‐125b in cervical cancer and played an important role in the development of cervical cancer. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27403   open full text
• Autophagy participates in cyst breakdown and primordial folliculogenesis by reducing reactive oxygen species levels in perinatal mouse ovaries.
  Tu Zhihan, Mu Xinyi, Li Qingying, Gao Rufei, Zhang Yan, Chen Xuemei, Geng Yanqing, Wang Yingxiong, He Junlin.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract The reserve of primordial follicles, which serves all oocytes for the female reproductive lifespan, is established a few days after birth in mice. During this process, more than half of the oocytes are primarily eliminated by apoptosis. Autophagy, the conserved intracellular process maintaining cellular homeostasis, serves as a protective mechanism for oocyte survival. In the current study, we speculate a new role for autophagy during primordial folliculogenesis. Active autophagy was observed in perinatal ovaries from 16.5 days post coitus to 3 days post parturition. The inhibition of autophagy by 3‐methyladenine (3‐MA) increased the number of cyst oocytes and delayed follicle formation in vivo and in organ cultures. Furthermore, the reactive oxygen species (ROS) level was elevated in ovaries treated with 3‐MA, while N‐acetylcysteine, an oxidant, alleviated the inhibitory effect of 3‐MA on primordial folliculogenesis. Additionally, the expression of growth differentiation factor 9 and transforming growth factor β1, which regulates follicle activation, was decreased after 3‐MA treatment. These data suggest that the physiological level of autophagy in perinatal ovaries regulates germ cell cyst breakdown and primordial follicle assembly by ROS clearance and exerts extensive effects on further follicular development. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27367   open full text
• The pathogenesis of thyroid autoimmune diseases: New T lymphocytes – Cytokines circuits beyond the Th1−Th2 paradigm.
  Qian Li, Bin Wang, Kaida Mu, Jin‐An Zhang.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Autoimmune thyroid disease (AITD) is one of the most common organ‐specific autoimmune disorders. It mainly manifests as Hashimoto's thyroiditis (HT) and Graves’ disease (GD). HT is characteristic of hypothyroidism resulting from the destruction of the thyroid while GD is characteristic of hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor‐specific stimulatory autoantibodies. T lymphocytes and their secretory cytokines play indispensable roles in modulating immune responses, but their roles are often complex and full of interactions among distinct components of the immune system. Dysfunction of these T cells or aberrant expressions of these cytokines can cause the breakdown of immune tolerance and result in aberrant immune responses during the development of AITDs. This review summarizes recently identified T subsets and related cytokines and their roles in the pathogenesis of AITDs with the hope to provide a better understanding of the precise roles of notably identified T subsets in AITDs and facilitate the discovery of functional molecules or novel immune therapeutic targets for AITDs. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27180   open full text
• Deglycosylation of epithelial cell adhesion molecule affects epithelial to mesenchymal transition in breast cancer cells.
  Xue Liu, Liu Yang, Dandan Zhang, Tingjiao Liu, Qiu Yan, Xuesong Yang.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract The transmembrane glycoprotein epithelial cell adhesion molecule (EpCAM) is overexpressed in most epithelial cancers including breast cancer, where it plays an important role in cancer progression. Previous study has demonstrated that knockdown of EpCAM inhibits breast cancer cell growth and metastasis via inhibition of the Ras/Raf/ERK signaling pathway and matrix metallopeptidase‐9 (MMP‐9). Although glycosylation is believed to be associated with the function of EpCAM, the contribution of N‐glycosylation to this function remains unclear. We constructed the N‐glycosylation mutation plasmid of EpCAM and used it to treat breast cancer cells. Loss of N‐glycosylation at all three sites EpCAM had no effect on its level of expression or membrane localization. However, mutation at glycosylation sites significantly reduced the ability of EpCAM to promote epithelial to mesenchymal transition in breast cancer. N‐glycosylation mutation of EpCAM led to decrease phosphorylation of Raf, ERK, and Akt, and inhibited the Ras/Raf/ERK and PI3K/Akt signaling pathways. Furthermore, we demonstrated that N‐glycosylation mutation of EpCAM‐mediated invasion and metastasis of breast carcinoma cells required the downregulation of MMP‐9 via inhibition of these two signaling pathways. Our results identified the characteristics and function of EpCAM glycosylation. These data could illuminate molecular regulation of EpCAM by glycosylation and promote our understanding of the application of glycosylated EpCAM as a target for breast cancer therapy. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27256   open full text
• PCSK9: A novel inflammation modulator in atherosclerosis?
  Zhi‐Han Tang, Tao‐Hua Li, Juan Peng, Jie Zheng, Ting‐Ting Li, Lu‐Shan Liu, Zhi‐Sheng Jiang, Xi‐Long Zheng.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Proprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the secretory serine protease family. It binds to low‐density lipoprotein receptor (LDLR) for endocytosis and lysosome degradation in the liver, resulting in an increasing in circulating LDL‐cholesterol (LDL‐c) level. Since a PCSK9 induced increase in plasma LDL‐c contributes to atherosclerosis, PCSK9 inhibition has become a new strategy in preventing and treating atherosclerosis. However, in addition to the effect of PCSK9 on elevating blood LDL‐c levels, accumulating evidence shows that PCSK9 plays an important role in inflammation, likely representing another major mechanism for PCSK9 to promote atherosclerosis. In this review, we discuss the association of PCSK9 and inflammation, and highlight the specific effects of PCSK9 on different vascular cellular components involved in the atherosclerotic inflammation. We also discuss the clinical evidence for the association between PCSK9 and inflammation in atherosclerotic cardiovascular disease. A better understanding of the direct association of PCSK9 with atherosclerotic inflammation might help establish a new role for PCSK9 in vascular biology and identify a novel molecular mechanism for PCSK9 therapy. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27254   open full text
• Angiotensin (1–7) inhibits arecoline‐induced migration and collagen synthesis in human oral myofibroblasts via inhibiting NLRP3 inflammasome activation.
  Yuehua You, Yun Huang, Dan Wang, Yang Li, Guozhen Wang, Siyi Jin, Xintao Zhu, Bin Wu, Xinya Du, Xu Li.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Arecoline induces oral submucous fibrosis (OSF) via promoting the reactive oxygen species (ROS). Angiotensin (1–7) (Ang‐(1–7)) protects against fibrosis by counteracting angiotensin II (Ang‐II) via the Mas receptor. However, the effects of Ang‐(1–7) on OSF remain unknown. NOD‐like receptors (NLRs) family pyrin domain containing 3 (NLRP3) inflammasome is identified as the novel mechanism of fibrosis. Whereas the effects of arecoline on NLRP3 inflammasome remain unclear. We aimed to explore the effect of Ang‐(1–7) on NLRP3 inflammasome in human oral myofibroblasts. In vivo, activation of NLRP3 inflammasomes with an increase of Ang‐II type 1 receptor (AT1R) protein level and ROS production in human oral fibrosis tissues. Ang‐(1–7) improved arecoline‐induced rats OSF, reduced protein levels of NADPH oxidase 4 (NOX4) and the NLRP3 inflammasome. In vitro, arecoline increased ROS along with upregulation of the angiotensin‐converting enzyme (ACE)/Ang‐II/AT1R axis and NLRP3 inflammasome/interleukin‐1β axis in human oral myofibroblasts, which were reduced by NOX4 inhibitor VAS2870, ROS scavenger N‐acetylcysteine, and NOX4 small interfering RNA (siRNA). Furthermore, arecoline induced collagen synthesis or migration via the Smad or RhoA‐ROCK pathway respectively, which could be inhibited by NLRP3 siRNA or caspase‐1 blocker VX‐765. Ang‐(1–7) shifted the balance of RAS toward the ACE2/Ang‐(1–7)/Mas axis, inhibited arecoline‐induced ROS and NLRP3 inflammasome activation, leading to attenuation of migration or collagen synthesis. In summary, Ang‐(1–7) attenuates arecoline‐induced migration and collagen synthesis via inhibiting NLRP3 inflammasome in human oral myofibroblasts. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27267   open full text
• The miR‐15a/16 gene cluster in human cancer: A systematic review.
  Ting Liu, Zhenru Xu, Daming Ou, Jing Liu, Ji Zhang.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract MicroRNAs (miRNAs) are an important class of endogenous small noncoding single‐stranded RNAs that suppress the expression of their target genes through messenger RNA (mRNA) degradation to inhibit transcription and translation. MiRNAs play a crucial regulatory role in many biological processes including proliferation, metabolism, and cellular malignancy. miR‐15a/16 is an important tumor suppressor gene cluster with a variety of factors that regulate its transcriptional activity. It has been discovered that a relative reduction of miR‐15a/16 expression in various cancers is closely related to the occurrence and progression of tumors. miR‐15a/16 takes part in a wide array of biological processes including tumor cell proliferation, apoptosis, invasion, and chemoresistance by binding to the 3′‐untranslated region of its target gene's mRNA. In this review, we will examine the complex regulatory network of miR‐15a/16 gene expression and its biological functions in human cancers to further elucidate the molecular mechanisms of its antitumor effects. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27342   open full text
• Potentiating apoptosis and modulation of p53, Bcl2, and Bax by a novel chrysin ruthenium complex for effective chemotherapeutic efficacy against breast cancer.
  Souvik Roy, Anweshan Sil, Tania Chakraborty.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Breast cancer is the most frequent cause of cancer in women. In the current study, transition metal ruthenium was complexed with flavonoid chrysin to evaluate the chemotherapeutic potential of this compound in Michigan Cancer Foundation‐7 (MCF‐7) human mammary cancer cell line and 7,12‐dimethylbenz(α)anthracene‐induced mammary cancer in female Sprague–Dawley rats. The characterizations of the complex were accomplished through UV–visible, NMR, IR, Mass spectra, and XRD techniques and antioxidant activity was assessed by DPPH, FRAP, and ABTS methods. In vitro studies included cell viability, cell cycle analysis, DNA fragmentation, and marker analysis by western blot analysis and found that complex treatment suppressed cell growth‐induced cell cycle arrest and enhanced the induction of apoptosis in cancer cells. Moreover, complex treatment modulated signaling pathways including mTOR, VEGF, and p53 in the MCF‐7 cells. Acute and subacute toxicity was performed in rats to determine the therapeutic doses. Breast cancer in rats was initiated by the administration of 7,12‐dimethylbenz(α)anthracene (0.5 mg/100 g body weight) via single tail vein injection. The histopathological analysis after 24 weeks of carcinogenesis study depicted substantial repair of hyperplastic lesions. Immunohistochemical analysis revealed upregulation of Bax and p53 and downregulation of Bcl2 proteins and TUNEL assay showed an increase in apoptotic index in ruthenium–chrysin‐treated groups as compared to the carcinogen control. Our findings from the in vitro and in vivo study support the continued investigation of ruthenium–chrysin complex possesses a potential chemotherapeutic activity against breast cancer and was efficient in reducing hyperplastic lesions in the mammary tissues of rats by inducing apoptosis. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27287   open full text
• 1,7‐Bis(4‐hydroxyphenyl)‐1,4‐heptadien‐3‐one induces lung cancer cell apoptosis via the PI3K/Akt and ERK1/2 pathways.
  Jiangjiang Fan, Mingsheng Wu, Jian Wang, Dongmei Ren, Jian Zhao, Guotao Yang.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract 1,7‐Bis(4‐hydroxyphenyl)‐1,4‐heptadien‐3‐one (EB30) is a diarylheptanoid‐like compound isolated from Viscum coloratum. This curcumin analog exhibits significant cytotoxic activity against HeLa, SGC‐7901, and MCF‐7 cells. However, little is known about the anticancer effects and mechanisms of EB30 in human lung cancer. The current study reports that EB30 significantly reduced the cell viability of A549 and NCI‐H292 human lung cancer cells. Further examination revealed that EB30 not only induced cell cycle arrest and promoted the generation of reactive oxygen species (ROS) but also induced cell apoptosis through the intrinsic and extrinsic signaling pathways. Furthermore, EB30 upregulated the expression levels of p‐ERK1/2 and p‐P90RSK, whereas downregulating the phosphorylation of Akt and P70RSK. Cell viability was further inhibited by the combination of EB30 with LY294002 (a specific PI3K inhibitor) or U0126 (a MEK inhibitor). The current study indicates that EB30 is a potential anticancer agent that induces cell apoptosis via suppression of the PI3K/Akt pathway and activation of the ERK1/2 pathway. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27364   open full text
• Tannic acid protects against experimental acute lung injury through downregulation of TLR4 and MAPK.
  Ayyanar Sivanantham, Dhamotharan Pattarayan, Ramalingam Bethunaickan, Amrita Kar, Santanu Kar Mahapatra, Rajesh K. Thimmulappa, Rajaguru Palanichamy, Subbiah Rajasekaran.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2 Abstract Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) remain a major cause of morbidity and mortality in critically ill patients, and no specific therapies are still available to control the mortality rate. Thus, we explored the preventive and therapeutic effects of tannic acid (TA), a natural polyphenol in the context of ALI. We used in vivo and in vitro models, respectively, using lipopolysaccharide (LPS) to induce ALI in mice and exposing J774 and BEAS‐2B cells to LPS. In both preventive and therapeutic approaches, TA attenuated LPS‐induced histopathological alterations, lipid peroxidation, lung permeability, infiltration of inflammatory cells, and the expression of proinflammatory mediators. In addition, in‐vitro study showed that TA treatment could reduce the expression of proinflammatory mediators. Further studies revealed that TA‐dampened inflammatory responses by downregulating the LPS‐induced toll‐like receptor 4 (TLR4) expression and inhibiting extracellular‐signal‐regulated kinase (ERK)1/2 and p38 mitogen‐activated protein kinase (MAPK) activation. Furthermore, cells treated with the inhibitors of ERK1/2 (PD98059) and p38 (SB203580) mitigated the expression of cytokines induced by LPS, thus suggesting that ERK1/2 and p38 activity are required for the inflammatory response. In conclusion, TA could attenuate LPS‐induced inflammation and may be a potential therapeutic agent for ALI‐associated inflammation in clinical settings. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27383   open full text
• Prognostic value of aberrantly expressed methylation gene profiles in lung squamous cell carcinoma: A study based on The Cancer Genome Atlas.
  Chundi Gao, Jing Zhuang, Chao Zhou, Ke Ma, Minzhang Zhao, Cun Liu, Lijuan Liu, Huayao Li, Fubin Feng, Changgang Sun.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Currently, research on genome‐scale epigenetic modifications for studying the pathogenesis of lung cancer is lacking. Aberrant DNA methylation, as the most common and important modification in epigenetics, is an important means of regulating genomic function and can be used as a biomarker for the diagnosis and prognosis of lung squamous cell carcinoma (LUSC). In this paper, methylation information and gene expression data from patients with LUSC were extracted from the TCGA database. Univariate and multivariate COX analyses were used to screen abnormally methylated genes related to the prognosis of LUSC. The relationship between key DNA methylation sites and the transcriptional expression of LUSC‐related genes was explored. A prognostic risk model constructed by four abnormally methylated genes (VAX1, CH25H, AdCyAP1, and Irx1) was used to predict the prognosis of LUSC patients. Also, the methylation levels of the key gene IRX1 are significantly correlated with the prognosis and correlated with the methylation of the site cg09232937 and cg10530883. This study is based on high‐throughput data mining and provides an effective bioinformatics basis for further understanding the pathogenesis and prognosis of LUSC, which has important theoretical significance for follow‐up studies on LUSC. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27389   open full text
• Dynamics changes in the transcription factors during early human embryonic development.
  Rasoul Godini, Hossein Fallahi.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Development of an embryo from a single cell, zygote, to multicellular morulae requires activation of hundreds of genes that were mostly inactivated before fertilization. Inevitably, transcription factors (TFs) would be involved in modulating the drastic changes in gene expression pattern observed at all preimplantation stages. Despite many ongoing efforts to uncover the role of TFs at the early stages of embryogenesis, still many unanswered questions remained that need to be explored. This could be done by studying the expression pattern of multiple genes obtained by high‐throughput techniques. In the current study, we have identified a set of TFs that are involved in the progression of the zygote to blastocyst. Global gene expression patterns of consecutive stages were compared and differences documented. Expectedly, at the early stages of development, only a few sets of TFs differentially expressed while at the later stages hundreds of TFs appear to be upregulated. Interestingly, the expression levels of many TFs show an oscillation pattern during development indicating a need for their precise expression. A significant shift in gene expression was observed during the transition from four‐ to eight‐cell stages, an indication of zygote genome activation. Additionally, we have found 11 TFs that were common in all stages including ATF3, EN1, IFI16, IKZF3, KLF3, NPAS3, NR2F2, RUNX1, SOX2, ZBTB20, and ZSCAN4. However, their expression patterns did not follow similar trends in the steps studied. Besides, our findings showed that both upregulation and active downregulation of the TFs expression is required for successful embryogenesis. Furthermore, our detailed network analysis identified the hub TFs for each transition. We found that HNF4A, FOXA2, and EP300 are the three most important elements for the first division of zygote. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27386   open full text
• USP49 inhibits ischemia–reperfusion‐induced cell viability suppression and apoptosis in human AC16 cardiomyocytes through DUSP1–JNK1/2 signaling.
  Wei Zhang, Yangyang Zhang, Hengbing Zhang, Qian Zhao, Zheng Liu, Yawei Xu.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Dual‐specificity protein phosphatases (DUSP) also known as mitogen‐activated protein kinase (MAPK) phosphatases (MKPs) can dephosphorylate MAPKs, including extracellular signal‐regulated kinase, c‐Jun N‐terminal kinase (JNK), and p38. DUSP1‐mediated JNK dephosphorylation has been found to play an antiapoptotic role against cardiac ischemia–reperfusion (I/R) injury. However, the regulation of DUSP1–JNK pathway remains unclear. In the current study, ubiquitin‐specific peptidase 49 (USP49) expression in human AC16 cardiomyocytes following I/R injury was measured by real‐time polymerase chain reaction and western blot analysis. Cell viability, apoptosis, the Bax, Bcl‐2, and DUSP1 expression, and the activity of MAPKs in AC16 cardiomyocytes following indicated treatment was measured by CCK‐8, flow cytometry, and western blot analysis. The direct interaction between USP49 and DUSP1 was measured by coimmunoprecipitation and ubiquitination analysis. The effect of USP49 on apoptosis and JNK activity in rat cardiomyocytes following I/R injury was also measured by TUNEL and western blot analysis. Here, we found that USP49 expression was time‐dependently increased in AC16 cardiomyocytes following I/R. I/R‐induced cell apoptosis and JNK1/2 activation both in in vivo and in vitro reversed by USP49 overexpression in AC16 cardiomyocytes. Inhibiting JNK1/2 activation significantly inhibited USP49 knockdown‐induced the cell viability inhibition, apoptosis and the JNK1/2 activation in AC16 cardiomyocytes. Moreover, USP49 positively regulated DUSP1 expression through deubiquitinating DUSP1. Overall, our findings establish USP49 as a novel regulator of DUSP1–JNK1/2 signaling pathway with a protective role in cardiac I/R injury. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27390   open full text
• Long noncoding RNA NEAT1 modulates cell proliferation and apoptosis by regulating miR‐23a‐3p/SMC1A in acute myeloid leukemia.
  Chen Zhao, Shanshan Wang, Yang Zhao, Feng Du, Weiyao Wang, Peng Lv, Ling Qi.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract The aim of this study was to determine the function of the NEAT1/miR‐23a‐3p/SMC1A axis in cell proliferation and apoptosis in acute myeloid leukemia (AML). Microarray analysis was used to screen differentially expressed lncRNAs/miRNAs/mRNAs in primary AML cells. The expression of nuclear paraspeckle assembly transcript 1 (NEAT1), miR‐23a‐3p, and structural maintenance of chromosome 1 alpha (SMC1A) in primary AML cells and THP‐1 cells were measured by quantitative real‐time polymerase chain reaction (qRT‐PCR). A Cell Counting Kit‐8 (CCK‐8) assay was used to analyze proliferation. Cell cycle progression and apoptosis were examined by flow cytometry. RNA immunoprecipitation (RIP) and dual‐luciferase assays were performed to determine the correlation between miR‐23a‐3p and NEAT1 or SMC1A. The qRT‐PCR illustrated that NEAT1 and SMC1A expression was decreased but that miR‐23a‐3p expression was increased in primary AML cells and THP‐1 cells compared with that in normal cells. The RIP assay and dual‐luciferase assay revealed the targeting relationship between miR‐23a‐3p and NEAT1 or SMC1A. The CCK‐8 assay showed that the overexpression of NEAT1 and SMC1A or repression of miR‐23a‐3p inhibited cell proliferation. Flow cytometry showed that the upregulation of NEAT1 and SMC1A or repression of miR‐23a‐3p promoted apoptosis and affected the cell cycle. NEAT1 repressed the expression of miR‐23a‐3p, and therefore promoted SMC1A, which in turn suppressed myeloid leukemia cell proliferation and enhanced apoptosis. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27393   open full text
• Basolateral presence of the proinflammatory cytokine tumor necrosis factor ‐α and secretions from adipocytes and macrophages reduce intestinal sugar transport.
  Rosa Castilla‐Madrigal, Eva Gil‐Iturbe, Neira Sáinz, María J. Moreno‐Aliaga, María Pilar Lostao.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- We have previously demonstrated in Caco‐2 cells that tumor necrosis factor‐α (TNF‐α) inhibits sugar uptake, acting from the apical membrane, by decreasing the expression of the Na+‐glucose cotransporter SGLT1 in the brush border membrane. The goal was to investigate the hypothesis that TNF‐α from abdominal adipose tissue (adipocytes and macrophages) would decrease sugar and amino acid transport acting from the basolateral membrane of the enterocytes. TNF‐α placed in the basal compartment of Caco‐2 cells decreased α‐methyl‐ d‐glucose (αMG) and glutamine uptake. The apical medium derived from these Caco‐2 cells apically placed in another set of cells, also reduced sugar and glutamine transport. Reverse‐transcription polymerase chain reaction analysis demonstrated upregulation of TNF‐α, IL‐1β, and MCP1 expression in Caco‐2 cells exposed to basal TNF‐α. Similarly, αMG uptake was inhibited after Caco‐2 cells were incubated, in the basal compartment, with medium from visceral human mesenchymal stem cells‐derived adipocytes of overweight individuals. The apical medium collected from those Caco‐2 cells, and placed in the upper side of other set of cells, also decreased sugar uptake. Basal presence of medium derived from lipopolysaccharide‐activated macrophages and nonactivated macrophages decreased αMG uptake as well. Diet‐induced obese mice showed an increase in the visceral adipose tissue surrounding the intestine. In this physiological condition, there was a reduction on αMG uptake in jejunal everted rings. Altogether, these results suggest that basolateral TNF‐α, which can be produced by adipocytes and macrophages during obesity, would be able to activate TNF‐α and other proinflammatory proteins expression in the small intestine and diminish intestinal sugar and amino acids transport. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27216   open full text
• Trastuzumab‐monomethyl auristatin E conjugate exhibits potent cytotoxic activity in vitro against HER2‐positive human breast cancer.
  Meghdad Abdollahpour‐Alitappeh, Majid Lotfinia, Nader Bagheri, Koushan Sineh Sepehr, Mahdi Habibi‐Anbouhi, Farzad Kobarfard, Saeed Balalaie, Alireza Foroumadi, Ghasem Abbaszadeh‐Goudarzi, Kazem Abbaszadeh‐Goudarzi, Mohsen Abolhassani.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2- Abstract Targeted therapy using specific monoclonal antibodies (mAbs) conjugated to chemotherapeutic agents or toxins has become one of the top priorities in cancer therapy. Antibody–drug conjugates (ADCs) are emerging as a promising strategy for cancer‐targeted therapy. In this study, trastuzumab, a humanized monoclonal anti‐HER2 antibody, was reduced by dithiothreitol and conjugated to the microtubule‐disrupting agent monomethyl auristatin E (MMAE) through a valine‐citrulline peptide linker (trastuzumab‐MC‐Val‐Cit‐PABC‐MMAE [trastuzumab‐vcMMAE]). After conjugation, ADCs were characterized by using UV–vis, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE), and flow cytometry. The antitumor activity of the ADC was evaluated in breast cancer cells in vitro. In addition, ADCs were further characterized using purification by the protein A chromatography, followed by assessment using apoptosis and MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide) assays. Hydrophobic interaction chromatography was used to determine drug‐to‐antibody ratio species of ADCs produced. Our finding showed that approximately 5.12 drug molecules were conjugated to each mAb. H2L2, H2L, HL, H2, H, and L forms of ADCs were detected in nonreducing SDS‐PAGE. The binding of trastuzumab‐vcMMAE to HER2‐positive cells was comparable with that of the parental mAb. The MTT assay showed that our ADCs induced significant cell death in HER2‐positive cells, but not in HER2‐negative cells. The ADCs produced was a mixture of species, unconjugated trastuzumab (14.147%), as well as trastuzumab conjugated with two (44.868%), four (16.886%), six (13.238%), and eight (10.861%) molecules of MMAE. These results indicated that MMAE‐conjugated trastuzumab significantly increases the cytotoxic activity of trastuzumab, demonstrating high affinity, specificity, and antitumor activity in vitro. Trastuzumab‐vcMMAE is an effective and selective agent for the treatment of HER2‐positive breast tumors. - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27085   open full text
• Gene expression of TWIST1 and ZBTB16 is regulated by methylation modifications during the osteoblastic differentiation of mesenchymal stem cells.
  Faroogh Marofi, Ghasem Vahedi, Saeed Solali, Mohammadreza Alivand, Sadegh Salarinasab, Milad Zadi Heydarabad, Majid Farshdousti Hagh.
  Journal of Cellular Physiology. September 24, 2018
  --- - |2 Abstract Background Osteoblastic differentiation of mesenchymal stem cells (MSCs) is the principal stage during the restoration and regeneration of bone tissue. Epigenetic modifications such as DNA methylation play a key role in the differentiation process of stem cells. In this study, the methylation status of the promoter region of ZBTB16 and Twist1 genes and their role in controlling osteoblastic differentiation in MSCs was investigated during the osteoblastic differentiation of MSCs. Methods The MSCs were cultured under standard conditions and differentiated into the osteoblasts. We had three treatment groups including 5‐azacytidine (methylation inhibitor), metformin (Twist‐inhibitor), and procaine (Wnt/β‐catenin inhibitor) and a non‐treated group (control). Methylation level of DNA in the promoter regions was monitored by methylation specific‐quantitative polymerase chain reaction (PCR). Also, the mRNA levels of key genes in osteoblastic differentiation were measured using real‐time PCR. Results ZBTB16 gene expression was upregulated, and promoter methylation was decreased. For Twist1 messenger RNA (mRNA) level decreased and promoter methylation increased during osteoblastic differentiation of MSCs. 5‐Azacytidine caused a significant reduction in methylation and increased the mRNA expression of ZBTB16 and Twist1. Metformin repressed the Twist1 expression, and therefore osteoblastic differentiation was increased. On the opposite side, procaine could block the WNT/β‐catenin signaling pathway, as a consequence the gene expression of key genes involved in osteoblastic differentiation was declined. Conclusion We found that methylation of DNA in the promoter region of ZBTB16 and Twist1 genes might be one of the main mechanisms that controlling the gene expression during osteoblastic differentiation of MSCs. Also, we could find an association between regulation of Twist1 and ZBTB16 genes and osteoblastic differentiation in MSCs by showing the relation between their expression and some key genes involved in osteoblastic differentiation. In addition, we found a connection between the Twist1 expression level and osteoblastic differentiation by using a Twist‐inhibitor (metformin). - Journal of Cellular Physiology, EarlyView.
  

  September 24, 2018   doi: 10.1002/jcp.27352   open full text
• Cholesterol burden in the liver induces mitochondrial dynamic changes and resistance to apoptosis.
  Mayra Domínguez‐Pérez, Arturo Simoni‐Nieves, Patricia Rosales, Natalia Nuño‐Lámbarri, Mónica Rosas‐Lemus, Verónica Souza, Roxana U. Miranda, Leticia Bucio, Salvador Uribe Carvajal, Jens U. Marquardt, Daekwan Seo, Luis E. Gomez‐Quiroz, María Concepción Gutiérrez‐Ruiz.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Non‐alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of histopathological changes ranging from non‐inflammatory intracellular fat deposition to non‐alcoholic steatohepatitis (NASH), which may progress into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma. Recent data suggest that impaired hepatic cholesterol homeostasis and its accumulation are relevant to the pathogenesis of NAFLD/NASH. Despite a vital physiological function of cholesterol, mitochondrial dysfunction is an important consequence of dietary‐induced hypercholesterolemia and was, subsequently, linked to many pathophysiological conditions. The aim in the current study was to evaluate the morphological and molecular changes of cholesterol overload in mouse liver and particularly, in mitochondria, induced by a high‐cholesterol (HC) diet for one month. Histopathological studies revealed microvesicular hepatic steatosis and significantly elevated levels of liver cholesterol and triglycerides leading to impaired liver synthesis. Further, high levels of oxidative stress could be determined in liver tissue as well as primary hepatocyte culture. Transcriptomic changes induced by the HC diet involved disruption in key pathways related to cell death and oxidative stress as well as upregulation of genes related to glutathione homeostasis. Impaired liver function could be associated with a decrease in mitochondrial membrane potential and ATP content and significant alterations in mitochondrial dynamics. We demonstrate that cholesterol overload in the liver leads to mitochondrial changes which may render damaged hepatocytes proliferative and resistant to cell death whereby perpetuating liver damage. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27474   open full text
• Upregulation of lncRNA DGCR5 correlates with better prognosis and inhibits bladder cancer progression via transcriptionally facilitating P21 expression.
  Chen Fang, Wei He, Tianyuan Xu, Jun Dai, Le Xu, Fukang Sun.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Mounting studies show that long noncoding RNAs (lncRNAs) could affect human cancer progression, including bladder cancer (BCa). LncRNA DiGeorge syndrome critical region gene 5 (DGCR5) has been proven to be involved in lung cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. However, the function of DGCR5 in BCa remains largely unknown. Here, we found that DGCR5 expression was significantly downregulated in BCa tissues compared with adjacent normal tissues. Higher expression of DGCR5 predicted higher survival rate in BCa patients. Functional experiments indicated that DGCR5 overexpression markedly inhibited that proliferation, colony formation, and cell‐cycle progression in BCa cells. Furthermore, ectopic expression of DGCR5 led to decreased BCa cell migration, invasion, and epithelial–mesenchymal transition while promoting apoptosis. In vivo xenograft assay also illustrated that DGCR5 overexpression inhibited BCa growth. In the mechanism, we found that DGCR5 interacted with AT‐rich interaction domain 1A (ARID1A), a chromatin remodeling protein, to promote P21 transcription. Knockdown of P21 could significantly rescue the suppressed proliferation, migration, and invasion of BCa cells by DGCR5 overexpression. In summary, our study demonstrated that DGCR5 transcriptionally promotes P21 expression to suppress BCa progression. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27356   open full text
• Hypoxia induces ZEB2 in podocytes: Implications in the pathogenesis of proteinuria.
  Krishnamurthy Nakuluri, Dhanunjay Mukhi, Rajkishor Nishad, Moin A. Saleem, Sathish Kumar Mungamuri, Ram K. Menon, Anil Kumar Pasupulati.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract The glomerular filtration barrier (GFB) plays a critical role in ensuing protein free urine. The integrity of the GFB is compromised during hypoxia that prevails during extreme physiological conditions. However, the mechanism by which glomerular permselectivity is compromised during hypoxia remains enigmatic. Rats exposed to hypoxia showed a decreased glomerular filtration rate, podocyte foot‐processes effacement, and proteinuria. Accumulation of hypoxia‐inducible factor‐1α (HIF1α) in podocytes resulted in elevated expression of zinc finger E‐box binding homeobox 2 (ZEB2) and decreased expression of E‐ and P‐cadherin. We also demonstrated that HIF1α binds to hypoxia response element localized in the ZEB2 promoter. Furthermore, HIF1α also induced the expression of ZEB2‐natural antisense transcript, which is known to increase the efficiency of ZEB2 translation. Ectopic expression of ZEB2 induced loss of E‐ and P‐cadherin and is associated with enhanced motility of podocytes during hypoxic conditions. ZEB2 knockdown abrogated hypoxia‐induced decrease in podocyte permselectivity. This study suggests that hypoxia leads to activation of HIF1α–ZEB2 axis, resulting in podocyte injury and poor renal outcome. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27387   open full text
• Genetics and rheumatoid arthritis susceptibility in Iran.
  Shahla Korani, Mitra Korani, Alexandra E. Butler, Amirhossein Sahebkar.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Rheumatoid arthritis (RA) is an autoimmune disorder with a number of risk factors, including both genetic and environmental. A number of RA risk associated genomic loci has been identified. In this review, we summarize the association of genetic factors with RA reported in population studies in Iran. No significant association was found between the majority of genetic factors identified in other populations and risk for RA in the Iranian subjects. This conflicting result could be due to the ethnic differences and diversity that are present in Iran. We conclude that there is a need to investigate larger groups of Iranian subjects, encompassing different regions of Iran, to either prove or refute these initial findings. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27379   open full text
• Melatonin and cancer: From the promotion of genomic stability to use in cancer treatment.
  Bagher Farhood, Nasser Hashemi Goradel, Keywan Mortezaee, Neda Khanlarkhani, Masoud Najafi, Amirhossein Sahebkar.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Cancer remains among the most challenging human diseases. Several lines of evidence suggest that carcinogenesis is a complex process that is initiated by DNA damage. Exposure to clastogenic agents such as heavy metals, ionizing radiation (IR), and chemotherapy drugs may cause chronic mutations in the genomic material, leading to a phenomenon named genomic instability. Evidence suggests that genomic instability is responsible for cancer incidence after exposure to carcinogenic agents, and increases the risk of secondary cancers following treatment with radiotherapy or chemotherapy. Melatonin as the main product of the pineal gland is a promising hormone for preventing cancer and improving cancer treatment. Melatonin can directly neutralize toxic free radicals more efficiently compared with other classical antioxidants. In addition, melatonin is able to regulate the reduction/oxidation (redox) system in stress conditions. Through regulation of mitochondrial nction and inhibition of pro‐oxidant enzymes, melatonin suppresses chronic oxidative stress. Moreover, melatonin potently stimulates DNA damage responses that increase the tolerance of normal tissues to toxic effect of IR and may reduce the risk of genomic instability in patients who undergo radiotherapy. Through these mechanisms, melatonin attenuates several side effects of radiotherapy and chemotherapy. Interestingly, melatonin has shown some synergistic properties with IR and chemotherapy, which is distinct from classical antioxidants that are mainly used for the alleviation of adverse events of radiotherapy and chemotherapy. In this review, we describe the anticarcinogenic effects of melatonin and also its possible application in clinical oncology. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27391   open full text
• Identification of a novel cell cycle‐related gene signature predicting survival in patients with gastric cancer.
  Lan Zhao, Longyang Jiang, Linxiu He, Qian Wei, Jia Bi, Yan Wang, Lifeng Yu, Miao He, Lin Zhao, Minjie Wei.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Gastric cancer (GC) is one of the most fatal cancers in the world. Thousands of biomarkers have been explored that might be related to survival and prognosis via database mining. However, the prediction effect of single gene biomarkers is not specific enough. Increasing evidence suggests that gene signatures are emerging as a possible better alternative. We aimed to develop a novel gene signature to improve the prognosis prediction of GC. Using the messenger RNA (mRNA)‐mining approach, we performed mRNA expression profiling in a large GC cohort (n = 375) from The Cancer Genome Atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) was performed, and we recovered genes related to the G2/M checkpoint, which we identified with a Cox proportional regression model. We identified a set of five genes (MARCKS, CCNF, MAPK14, INCENP, and CHAF1A), which were significantly associated with overall survival (OS) in the test series. Based on this five‐gene signature, the test series patients could be classified into high‐risk or low‐risk subgroups. Multivariate Cox regression analysis indicated that the prognostic power of this five‐gene signature was independent of clinical features. In conclusion, we developed a five‐gene signature related to the cell cycle that can predict survival for GC. Our findings provide novel insight that is useful for understanding cell cycle mechanisms and for identifying patients with GC with poor prognoses. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27365   open full text
• A genetic variant in CDKN2A/2B locus was associated with poor prognosis in patients with esophageal squamous cell carcinoma.
  Niloofar Ghobadi, Mehrane Mehramiz, Soodabeh ShahidSales, Arezou Rezaei Brojerdi, Kazem Anvari, Majid Khazaei, Majid Rezayi, Mohammad Sadegh Khorrami, Mona Joudi‐Mashhad, Hassan Ramshini, Saeideh Ahmadi‐Simab, Ali Moradi, Seyed Mahdi Hassanian, Majid Ghayour‐Mobarhan, Mohammad Taher Boroushaki, Gordon A. Ferns, Amir Avan.
  Journal of Cellular Physiology. September 21, 2018
  --- - "\nAbstract\nEsophageal squamous cell carcinoma (ESCC) is among the leading causes of cancer related death. Despite of extensive efforts in identifying valid cancer prognostic biomarkers, only a very small number of markers have been identified. Several genetic variants in the 9p21 region have been identified that are associated with the risk of multiple cancers. Here, we explored the association of two genetic variants in the 9p21 region, CDKN2A/B, rs10811661, and rs1333049 for the first time in 273 subjects with, or without ESCC. We observed that the patients with ESCC had a higher frequency of a TT genotype for rs10811661 than individuals in the control group, and this polymorphism was also associated with tumor size. Moreover, a CC genotype for the rs1333049 polymorphism was associated with a reduced overall survival (OS) of patients with ESCC. In particular, patients with a CC (rs1333049) genotype had a significantly shorter OS (CC genotype: 34.5 ± 8.9 months vs. CG+GG: 47.7 ± 5.9 months; \np value = 0.03). We have also shown the association of a novel genetic variant in CDKN2B gene with clinical outcome of patients with ESCC. Further investigations are warranted in a larger population to explore the value of emerging markers as a risk stratification marker in ESCC." - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27310   open full text
• The genetic factors contributing to hypospadias and their clinical utility in its diagnosis.
  Marjan Joodi, Forouzan Amerizadeh, Seyed Mahdi Hassanian, Marjan Erfani, Majid Ghayour‐Mobarhan, Gordon A. Ferns, Majid Khazaei, Amir Avan.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Hypospadias is among the most common congenital malformations in male neonates. It results from abnormal penile and urethral development, but is a multifactorial disorder that is highly heterogeneous, with several genetic and environmental determinants. Monogenic and chromosomal abnormalities are present in approximately 30% of cases, although the genetic factors contributing to hypospadias remain unknown in 70% of cases. While defects in androgen synthesis can lead to this malformation, mutational analyses have shown several genes, such as sonic hedgehog, fibroblast growth factors, bone morphogenetic proteins, homeobox genes, and the Wnt family, are involved in the normal development of male external genitalia. Mutations in the genes of penile development (e.g., HOX, FGF, Shh) and testicular determination (e.g., WT1, SRY), luteinizing hormone receptor, and androgen receptor have also been proposed to be implicated in hypospadias. Here we review the recent advances in this field and discuss the potential genes that could determine the risk of hypospadias. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27350   open full text
• Curcumin: A naturally occurring autophagy modulator.
  Abolfazl Shakeri, Arrigo F. G. Cicero, Yunes Panahi, Mohammad Mohajeri, Amirhossein Sahebkar.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Autophagy is a self‐degradative process that plays a pivotal role in several medical conditions associated with infection, cancer, neurodegeneration, aging, and metabolic disorders. Its interplay with cancer development and treatment resistance is complicated and paramount for drug design since an autophagic response can lead to tumor suppression by enhancing cellular integrity and tumorigenesis by improving tumor cell survival. In addition, autophagy denotes the cellular ability of adapting to stress though it may end up in apoptosis activation when cells are exposed to a very powerful stress. Induction of autophagy is a therapeutic option in cancer and many anticancer drugs have been developed to this aim. Curcumin as a hydrophobic polyphenol compound extracted from the known spice turmeric has different pharmacological effects in both in vitro and in vivo models. Many reports exist reporting that curcumin is capable of triggering autophagy in several cancer cells. In this review, we will focus on how curcumin can target autophagy in different cellular settings that may extend our understanding of new pharmacological agents to overcome relevant diseases. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27404   open full text
• Iturin A‐like lipopeptides from Bacillus subtilis trigger apoptosis, paraptosis, and autophagy in Caco‐2 cells.
  Haobin Zhao, Xiaoguang Xu, Shuzhen Lei, Dongyan Shao, Chunmei Jiang, Junling Shi, Yawen Zhang, Li Liu, Shuzhen Lei, Hui Sun, Qingsheng Huang.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract This study revealed that iturin A‐like lipopeptides produced by Bacillus subtillis induced both paraptosis and apoptosis in heterogeneous human epithelial colorectal adenocarcinoma (Caco‐2) cells. Autophagy was simultaneously induced in Caco‐2 cells treated with iturin A‐like lipopeptides at the early stage and inhibited at the later stage. A western blot analysis showed that the lipopeptides induced apoptosis in Caco‐2 cells via a mitochondrial‐dependent pathway, as indicated by upregulated expression of the apoptotic genes bax and bad and downregulated expression of the antiapoptotic gene bcl‐2. The induction of paraptosis in Caco‐2 cells was indicated by the occurrence of many cytoplasmic vacuoles accompanied by endoplasmic reticulum (ER) dilatation and mitochondrial swelling and dysfunction. ER stress also occurred with significant increases in reactive oxygen species and Ca2+ levels in cells. Autophagy was detected by a transmission electron microscopy analysis and by upregulated expression of LC3‐II and downregulated expression of LC3‐I. The inhibition of autophagy at the later stage was shown by upregulated expression of p62. This study revealed the capability of iturin A‐like B. subtilis lipopeptides to simultaneously execute antitumor potential via multiple pathways. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27377   open full text
• Laminar shear stress‐provoked cytoskeletal changes are mediated by epigenetic reprogramming of TIMP1 in human primary smooth muscle cells.
  Rodrigo A. da Silva, Célio Jr da C. Fernandes, Geórgia da S. Feltran, Anderson M. Gomes, Amanda Fantini Andrade, Denise C. Andia, Maikel P. Peppelenbosch, Willian F. Zambuzzi.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2 Abstract Whereas endothelial responses to shear stress are well‐characterized, the cell physiological effects of shear stress in smooth muscle cells (SMCs) remain largely obscure. As SMCs are directly challenged by shear stress after endothelial denuding injury following procedures such as angioplasty or endarterectomy, characterization of these responses represents an important scientific question. Hence we decided to contrast cytoskeletal reorganization, epigenetic reprogramming, signaling transduction, and changes in miRNA (miRs) profiles in primary human aortic smooth muscle cells (AoSMCs) between unstressed cells and cells exposed to shear stress. We observed that shear stress‐provoked reorganization of the actin cytoskeleton in an apparently Cofilin‐dependent fashion and which related to altered integrin signaling, apparently caused by remodeling of the extracellular matrix. The latter appeared a downstream effect of increased expression of matrix metalloproteinases and downregulation of tissue metalloproteinase inhibitor 1 (TIMP1) protein levels. In turn, these effects related to shear stress‐provoked changes in expression and nuclear localization of the epigenetic regulators demethylases TET1, TET2, DNMT1, DNMT3A and DNMT3B, HDAC6, and SIRT1. Accordingly, TIMP1 promotor CpG hypomethylation was a prominent effect, and resulted in a significant increase in TIMP1 transcription, which may also have related increased expression of miRs involved in modulating TIMP1 translation. Thus epigenetic‐reprogramming of TIMP1 emerges as critical element in smooth muscle responses to mechanical signals and as epigenetic machinery is amendable to pharmacological manipulation, this pathway may have important clinical consequences. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27374   open full text
• Exercise rescues the immune response fine‐tuned impaired by peroxisome proliferator‐activated receptors γ deletion in macrophages.
  Loreana Sanches Silveira, Helena Angélica Pereira Batatinha, Angela Castoldi, Niels Olsen Saraiva Câmara, Willian T. Festuccia, Camila Oliveira Souza, José Cesar Rosa Neto, Fábio Santos Lira.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2 Abstract Background Exercise is a powerful tool for prevention and treatment of many conditions related to the cardiovascular system and also chronic low‐grade inflammation. Peroxisome proliferator‐activated receptors γ (PPARγ) exerts an import role on the regulation of metabolic profile and subsequent inflammatory response, especially in macrophages. Purpose To investigate the effects of 8‐week moderate‐exercise training on metabolic and inflammatory parameters in mice with PPARγ deficiency in myeloid cells. Methods Twelve‐week old mice bearing PPARγ deletion exclusively in myeloid cells (PPARγlox/lox Lys Cre −/+, knockout [KO]) and littermate controls (PPARγlox/lox Lys Cre −/−, wild type [WT]) were submitted to 8‐week exercise training (treadmill running at moderate intensity, 5 days/week). Animals were evaluated for food intake, glucose homeostasis, serum metabolites, adipose tissue and peritoneal macrophage inflammation, and basal and stimulated cytokine secretion. Results Exercise protocol did not improve glucose metabolism or adiponectin concentrations in serum of KO mice. Moreover, the absence of PPARγ in macrophages exacerbated the proinflammatory profile in sedentary mice. Peritoneal cultured cells had higher tumor necrosis factor‐α (TNF‐α) secretion in nonstimulated and lipopolysaccharide (LPS)‐stimulated conditions and higher Toll‐4 receptor (TLR4) gene expression under LPS stimulus. Trained mice showed reduced TNF‐α content in adipose tissue independently of the genotype. M2 polarization ability was impaired in KO peritoneal macrophages after exercise training, while adipose tissue‐associated macrophages did not present any effect by PPARγ ablation. Conclusion Overall, PPARγ seems necessary to maintain macrophages appropriate response to inflammatory stimulus and macrophage polarization, affecting also whole body lipid metabolism and adiponectin profile. Exercise training showed as an efficient mechanism to restore the immune response impaired by PPARγ deletion in macrophages. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27333   open full text
• Stromal vascular fraction cells plus sustained release VEGF/Ang‐1‐PLGA microspheres improve fat graft survival in mice.
  Yucang He, Xiaofang Yu, Zhuojie Chen, Liqun Li.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Autologous fat transplantation is increasingly applied in plastic and reconstructive surgery. Stromal vascular fraction cells (SVFs) combined with angiogenic factors, such as VEGF (vascular endothelial growth factor A) and Ang‐1 (angiogenin‐1), can improve angiogenesis, which is a critical factor for graft survival. However, direct transplant with such a mixture is insufficient owing to the short half‐life of angiogenic factors. In this study, we evaluated whether a double sustained release system of VEGF/ANG‐1‐PLGA (poly (lactic‐co‐glycolic acid)) microspheres plus SVFs can improve angiogenesis and graft survival after autologous fat transplantation. VEGF/ANG‐1‐PLGA‐sustained release microspheres were fabricated by a modified double emulsion–solvent evaporation technique. Human aspirated fat was mixed with SVF suspension plus VEGF/ANG‐1 sustained release microspheres (Group C), SVF suspension (Group B) alone, or Dulbecco’s modified Eagle’s medium as the control (Group A). Eighteen immunocompromised nude mice were injected with these three mixtures subcutaneously at random positions. After 8 weeks, the mean volume of grafts was greater in the SVFs plus VEGF/ANG‐1‐PLGA group than in the control and SVFs groups (1.08 ± 0.069 ml vs. 0.62 ± 0.036 ml, and 0.83 ± 0.059 ml, respectively). Histological assessments showed that lower fibrosis, but greater microvascular density in the SVFs plus VEGF/ANG‐1‐PLGA group than in the other groups, though the SVFs group also had an appropriate capillary density and reduced fibrosis. Our findings indicate that SVFs plus VEGF/ANG‐1‐PLGA‐sustained release microspheres can improve angiogenesis and graft survival after autologous fat transplantation. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27368   open full text
• Ephrin A1 promotes proliferation of bovine endometrial cells with abundant expression of proliferating cell nuclear antigen and cyclin D1 changing the cell population at each stage of the cell cycle.
  Whasun Lim, Hyocheol Bae, Fuller W. Bazer, Gwonhwa Song.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Ephrin A1 has a role in a variety of biological events, including cell proliferation, differentiation, migration, and angiogenesis. Ephrin A1 expression is abundant in trophoblasts and endometrial cells during the implantation period; however, its intracellular activities have not yet been reported in bovine endometrial (BEND) epithelial cells. The aim of this study was to identify the functional role of ephrin A1 in BEND cells, which have served as a good model system for investigating the regulation of signal transduction following treatment with interferon‐τ (IFNT) in vitro. Supplementation of ephrin A1 to BEND cells increased cell proliferation and increased levels of proliferating cell nuclear antigen and cyclin D1 protein in BEND cell nuclei. To investigate intracellular mechanisms regulated by ephrin A1, we performed Western blot analysis focused on mitogen‐activated protein kinase (MAPK) and phosphoinositide 3‐kinase (PI3K) signaling, which are significantly involved in the successful maintenance of pregnancy. Ephrin A1 dose‐dependently increased phosphorylation of extracellular signal‐regulated kinases (ERK)1/2, c‐Jun N‐terminal kinases (JNK), P38, protein kinase B (AKT), P70S6K, S6, and cyclin D1, and the activated proteins were suppressed by pharmacological inhibitors including wortmannin (a PI3K inhibitor), U0126 (an ERK1/2 inhibitor), and SP600125 (a JNK inhibitor). Among ephrin A1 receptors, abundant expression of EPHA2 and EPHA4 messenger RNA was detected in BEND cells by reverse transcription polymerase chain reaction analysis. Furthermore, tunicamycin‐induced endoplasmic reticulum (ER) stress was inactivated by ephrin A1 treatment of BEND cells. Our findings suggest that ephrin A1 promotes the development of BEND cells and likely enhances uterine capacity and maintenance of pregnancy by activating MAPK and PI3K signaling cascades and by restoring ER stress. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27275   open full text
• Molecular mechanisms involved in the protective effect of pituitary adenylate cyclase‐activating polypeptide in an in vitro model of amyotrophic lateral sclerosis.
  Grazia Maugeri, Agata G. D’Amico, Daniela M. Rasà, Concetta Federico, Salvatore Saccone, Giovanna Morello, Valentina Cognata, Sebastiano Cavallaro, Velia D’Agata.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Based on transcriptional profiles of motor cortex samples, in a previous work, we were able to classify two subgroups of sporadic ALS (SALS) patients, named SALS1 and SALS2. A further meta‐analysis study has revealed sixteen drug targets commonly deregulated in SALS2 and superoxide dismutase 1 (SOD1) G93A mice. The identified candidate drug targets included pituitary adenylate cyclase‐activating polypeptide (PACAP), epidermal growth factor receptor (EGFR) and matrix metallopeptidase‐2 (MMP‐2). By using a motor neuron‐like hybrid cell line (NSC‐34) expressing human SOD1 G93A as an in vitro model of ALS, here we investigated the functional correlation among these three genes. Our results have shown that PACAP increases cell viability following serum deprivation. This effect is induced through EGFR transactivation mediated by protein kinase A stimulation. Furthermore, EGFR phosphorylation activates mitogen‐activated protein kinases/extracellular signal‐regulated kinases 1 and 2 survival signaling pathway and increases MMP‐2 expression, significantly reduced by serum starvation. These results suggest that a deeper characterization of mechanisms involved in PACAP/EGFR/MMP‐2 axis activation in G93A SOD1 mutated neurons may allow identifying new targets for ALS therapy. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27328   open full text
• Teeth‐derived stem cells: A source for cell therapy.
  Ghazaleh Baniebrahimi, Razieh Khanmohammadi, Fatemeh Mir.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2 Abstract Cell therapy is one of the important therapeutic approaches in the treatment of many diseases such as cancer, degenerative diseases, and cardiovascular diseases. Among various cell types, which could be used as cell therapies, stem cell therapy has emerged as powerful tools in the treatment of several diseases. Multipotent stem cells are one of the main classes of stem cells that could originate from different parts of the body such as bone marrow, adipose, placenta, and tooth. Among several types of multipotent stem cells, tooth‐derived stem cells (TDSCs) are associated with special properties such as accessible, easy isolation, and low invasive, which have introduced them as a good source for using in the treatment of several diseases such as neural injuries, liver fibrosis, and Cohrn’s disease. Here, we provided an overview of TDSCs particular stem cells from human exfoliated deciduous teeth and clinical application of them. Moreover, we highlighted molecular mechanisms involved in the regulation of dental stem cells fate. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27270   open full text
• Positive feedback loop of lncRNA LINC01296/miR‐598/Twist1 promotes non‐small cell lung cancer tumorigenesis.
  Lijuan Xu, Bin Wei, Hongxia Hui, Yuan Sun, Yangqing Liu, Xiaojuan Yu, Jian Dai.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Emerging evidence has illustrated the vital roles of long noncoding RNAs (lncRNAs) in human cancers. However, the role of lncRNAs in non‐small cell lung cancer (NSCLC) is still elusive and poorly understood. In the current study, our team conducted extensive experiments to identify the role of long intergenic nonprotein coding (LINC01296) on NSCLC tumorigenesis. The results illustrated that the elevated LINC01296 expression in NSCLC tissue specimens and cell lines were closely correlated with the poor prognosis of patients with NSCLC. Functional studies revealed that LINC01296 knockdown silenced by small interfering RNAs inhibited proliferation, accelerated apoptosis in vitro, and impaired tumor growth in vivo. Mechanical studies showed that INC01296 harbored miR‐598, acting as a microRNA “sponge.” Besides, miR‐598 targeted the 3′‐UTR of Twist1. Interestingly, transcription factor Twist1 could bind with the promoter of INC01296 and activate its transcriptional level. In summary, we conclude that INC01296/miR‐598/Twist1 constitutes a positive feedback loop to promote the tumorigenesis of NSCLC, providing a novel insight and a valuable therapeutic strategy. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27235   open full text
• Glucocorticoids reduce chemotherapeutic effectiveness on OSCC cells via glucose‐dependent mechanisms.
  Antonio Celentano, Michael McCullough, Nicola Cirillo.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Synthetic corticosteroids are routinely administered during the treatment of several diseases, including malignancies. However, recent evidence suggests that corticosteroids may have tumor‐promoting effects, particularly in epithelial neoplasms. Our aim was to assess the role of the recently characterized cancer‐associated glucocorticoid (GC) system in the resistance to chemotherapy of oral malignant keratinocytes. Human malignant oral keratinocyte cell lines H314/H357/H400/BICR16/BICR56 were tested with: two chemotherapeutic agents, doxorubicin (DOXO) and 5‐fluorouracil (5‐FU), as well as hydrocortisone (HC), adrenocorticotropic hormone (ACTH), 5‐pregnen‐3‐beta‐ol‐20‐one‐16‐alfa‐carbonitrile (PCN), and two glucose uptake inhibitors, Fasentin and WZB. Both DOXO and 5‐FU induced apoptosis in a dose‐dependent and time‐dependent manner. HC administration (100 nM) reduced the effectiveness of both chemotherapeutic agents to a variable extent in all 5 oral squamous cell carcinoma cell lines. ACTH also reduced the effectiveness of DOXO on 2 cell lines tested (H357 and BICR56). The glucose uptake inhibitors Fasentin and WZB were able to partially block the increased resistance to the cytotoxic drugs induced by HC. In summary, we have demonstrated, for the first time, the importance of cortisol on oral cancer cells ability to proliferate and combat the effectiveness of chemotherapeutic agents. This effect appears to be glucose dependent. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27227   open full text
• In vivo microscopic and optical coherence tomography classification of neurotrophic keratopathy.
  Leonardo Mastropasqua, Mario Nubile, Manuela Lanzini, Roberta Calienno, Harminder S. Dua.
  Journal of Cellular Physiology. September 21, 2018
  --- - |2- Abstract Neurotrophic keratopathy (NK) is a rare degenerative corneal disorder characterized by instability of epithelial integrity with consequent epithelial defects that can worsen up to persistent epithelial defects with stromal melting and ulceration. The pathogenesis of NK springs from a variable degree of damage to the trigeminal nerve plexus, leading to a reduction or total loss of corneal sensitivity. Mackie classification (1995) distinguishes three stages of NK, based on the severity of clinical presentation. The technological innovations in corneal diagnostic imaging allow clinicians to accurately study the morphometry and morphology of corneal structure with microscopic resolution. In this study, 45 patients affected by NK at different stages underwent in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS‐OCT) with particular attention to analyze subbasal nerve plexus fibers and the stromal structure. At the light of IVCM and AS‐OCT observations, we propose a different staging of NK with respect to the Mackie's classification that takes into account the severity of subbasal nerve fibers damage and the extension in depth of stromal ulceration; this classification better defines, at the time of diagnosis, the cellular and structural alterations in the affected corneas, with possible prognostic and therapeutic values in the management of NK. - Journal of Cellular Physiology, EarlyView.
  

  September 21, 2018   doi: 10.1002/jcp.27345   open full text
• Pyruvate dehydrogenase kinase 1 contributes to cisplatin resistance of ovarian cancer through EGFR activation.
  Meng Zhang, Qing Cong, Xiao‐Yan Zhang, Ming‐Xing Zhang, Ying‐Ying Lu, Cong‐Jian Xu.
  Journal of Cellular Physiology. September 19, 2018
  --- - |2- Abstract Patients with ovarian cancer frequently develop acquired drug resistance after the long‐term chemotherapy, leading to disease progression. Enhanced epithelial–mesenchymal transition (EMT) has been implicated in chemoresistance of ovarian cancer cells; however, the molecular mechanisms involved are largely undefined. Pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, has been recognized as a gatekeeper of the Warburg effect, a hallmark of cancer. In this study, the function of PDK1 in cisplatin resistance of ovarian cancer in terms of growth and EMT was investigated. PDK1 was upregulated in cisplatin‐resistant ovarian cancer cells. PDK1 knockdown in resistant cells led to increased sensitivity to cisplatin‐induced cell death and apoptosis. PDK1 downregulation also reversed the EMT and cell motility in cisplatin‐resistant cells. In a mouse xenograft model, tumors derived from PDK1‐silenced ovarian cancer cells exhibited decreased tumor growth and EMT compared with control after the cisplatin treatment. Mechanistically, PDK1 overexpression led to increased phosphorylation of EGFR, and blocking EGFR kinase activity by erlotinib reversed cisplatin resistance induced by PDK1 overexpression. Furthermore, in patients with ovarian cancer, higher PDK1 and p‐EGFR levels were associated with chemoresistance. These results supported that PDK1 contributes to chemoresistance of ovarian cancer by activating EGFR. Therefore, PDK1 may serve as a promising target to combat chemoresistance of ovarian cancer. - Journal of Cellular Physiology, EarlyView.
  

  September 19, 2018   doi: 10.1002/jcp.27369   open full text
• Association of the genetic polymorphisms in immunoinflammatory microRNAs with risk of ischemic stroke and subtypes in an Iranian population.
  Hassan Darabi, Arash Salmaninejad, Mohamad Ehsan Jaripour, Mahmoud reza Azarpazhooh, Majid Mojarrad, Ariane Sadr‐Nabavi.
  Journal of Cellular Physiology. September 19, 2018
  --- - "\nAbstract\nStroke is one of the most common type of cerebrovascular disease threatening human health and life with high mortality, disability, and morbidity. Ischemic stroke (IS) is determined to be a complex disease containing a group of heterogeneous disorders with various environmental and genetic risk factors. This study evaluated the polymorphisms of microRNAs involved in inflammatory routes leading to stroke in an Iranian population. This study evaluated the associations of hsa‐mir‐608 C/G rs4919510, hsa‐mir‐499 A/G rs3746444, and hsa‐mir‐145 C/T rs190323149 polymorphisms in precursor miRNAs with the risk of IS. These microRNA polymorphisms were analyzed in 470 patients with IS and 489 control subjects. The TOAST criteria was applied for IS subtypes classification. The frequency of the allele G of hsa‐mir‐499/rs3746444 A/G revealed significant association with IS in comparison with controls (\np < 0.0001, OR = 1.838, 95% CI = 1.406–2.401). Increased IS risks were associated with hsa‐mir‐499/ rs3746444 A/G genotypes in diverse genetic model (homozygote comparison: \np = 0.004, OR = 2.136, 95% CI = 1.269–3.597; heterozygote comparison: \np = 0.029, OR = 1.373, 95% CI = 1.033–1.825). Statistical analysis in IS subtypes showed that cardio‐embolic patients compared with other subtypes (large artery atherosclerosis and lacunar) had higher frequency of G allele (LAA vs. CEI, \np = 0.017; LAC vs. CEI, \np = 0.009), AG genotype (LAA vs. CEI, \np = 0.016; LAC vs. CEI, \np = 0.013). Nevertheless, this study did not find any association between the alleles and genotypes of mir‐608 C/G rs4919510 SNP and IS, respectively (\np > 0.05). The current investigation provided verification that hsa‐mir‐499 rs3746444 A/G polymorphism may be associated with a significantly increased risk of IS in an Iranian population.\n" - Journal of Cellular Physiology, EarlyView.
  

  September 19, 2018   doi: 10.1002/jcp.27159   open full text
• Melatonin and pancreatic cancer: Current knowledge and future perspectives.
  Omid Reza Tamtaji, Naghmeh Mirhosseini, Russel J. Reiter, Morteza Behnamfar, Zatollah Asemi.
  Journal of Cellular Physiology. September 19, 2018
  --- - |2 Abstract Pancreatic cancer has a high mortality rate due to the absence of early symptoms and subsequent late diagnosis; additionally, pancreatic cancer has a high resistance to radio‐ and chemotherapy. Multiple inflammatory pathways are involved in the pathophysiology of pancreatic cancer. Melatonin an indoleamine produced in the pineal gland mediated and receptor‐independent action is the pancreas and other where has both receptors. Melatonin is a potent antioxidant and tissue protector against inflammation and oxidative stress. In vivo and in vitro studies have shown that melatonin supplementation is an appropriate therapeutic approach for pancreatic cancer. Melatonin may be an effective apoptosis inducer in cancer cells through regulation of a large number of molecular pathways including oxidative stress, heat shock proteins, and vascular endothelial growth factor. Limited clinical studies, however, have evaluated the role of melatonin in pancreatic cancer. This review summarizes what is known regarding the effects of melatonin on pancreatic cancer and the mechanisms involved. - Journal of Cellular Physiology, EarlyView.
  

  September 19, 2018   doi: 10.1002/jcp.27372   open full text
• New advances of lncRNAs in liver fibrosis, with specific focus on lncRNA–miRNA interactions.
  Er‐Bao Bian, Zhi‐Gang Xiong, Jun Li.
  Journal of Cellular Physiology. September 19, 2018
  --- - |2- Abstract Noncoding RNAs (ncRNAs) were initially thought to be transcriptional byproducts. However, recent advances of ncRNAs research have increased our understanding of the importance of ncRNA in gene regulation and disease pathogenesis. Consistent with these developments, liver fibrosis research is also experiencing rapid growth in the investigation of links between ncRNAs and the pathology of this disease. The initial focus was on studying the function and regulation mechanisms of microRNAs (miRNAs). However, recently, elucidation of the mechanisms of long noncoding RNAs (lncRNAs) and lncRNA‐mediated liver fibrosis has just commenced. In this review, we emphasize on abnormal expression of lncRNAs in liver fibrosis. Furthermore, we also discuss that the interaction of lncRNAs with miRNAs is involved in the regulation of the expression of protein‐coding genes in liver fibrosis. Recent advances in understanding dysregulated lncRNAs expression and the lncRNAs–miRNAs interaction in liver fibrosis will help for developing new therapeutic targets and biomarkers of liver fibrosis. - Journal of Cellular Physiology, EarlyView.
  

  September 19, 2018   doi: 10.1002/jcp.27069   open full text
• MicroRNA‐363 inhibits angiogenesis, proliferation, invasion, and migration of renal cell carcinoma via inactivation of the Janus tyrosine kinases 2–signal transducers and activators of transcription 3 axis by suppressing growth hormone receptor gene.
  Jie Zhu, Da‐Qing Zhu, Yu Zhang, Qi‐Ming Liu, Peng‐Chao Wang, Hong‐Zhao Li, Xin Ma, Xu Zhang.
  Journal of Cellular Physiology. September 19, 2018
  --- - |2- Abstract Renal cell carcinoma (RCC) is the most common malignancy involving the kidneys and a major cause of cancer mortality. The involvement of microRNA (miRNA) expression in the tumorigenesis and progression of RCC has been previously highlighted. Therefore, we conducted this study to investigate whether microRNA‐363 (miR‐363) affects the development of RCC via the Janus tyrosine kinases (JAK2)–signal transducers and activators of transcription (STAT) axis by targeting the growth hormone receptor (GHR), by observing the changes that occurred in the RCC and the normal adjacent tissues of patients with RCC. RCC cells were transfected with a series of miR‐363 mimic, miR‐363 inhibitor, or small interfering RNA against GHR to determine the influence of miR‐363 on the expression of GHR and JAK2–STAT3 axis‐related genes with the use of reverse transcription quantitative polymerase chain reaction and Western blot analysis. The angiogenesis, viability, invasion, and migration of cells were evaluated by means of in vitro angiogenesis, 3‐(4,5)‐dimethylthiahiazo (‐z‐y1)‐3,5‐di‐phenytetrazoliumromide (MTT), wound‐healing, and Transwell assays. The results revealed reduced miR‐363 expression and elevated GHR expression in RCC. It was also found that miR‐363 altered the activation of the JAK2–STAT3 axis through the inhibition of GHR. Cells treated with the miR‐363 inhibitor presented with increased capillary vessels, cell viability, invasion, and migration, whereas it was on the contrary in the RCC cells with overexpressed miR‐363. These results implicated that the overexpression of miR‐363 could specifically bind to GHR to downregulate the expression of GHR, which, in turn, inactivates the JAK2–STAT3 axis, thereby influencing the angiogenesis, cell invasion, and migration abilities in RCC. - Journal of Cellular Physiology, EarlyView.
  

  September 19, 2018   doi: 10.1002/jcp.27020   open full text
• MiR‐499 regulates myoblast proliferation and differentiation by targeting transforming growth factor β receptor 1.
  Jiyao Wu, Binglin Yue, Xianyong Lan, Yanhuan Wang, Xingtang Fang, Yun Ma, Yueyu Bai, Xingshan Qi, Chunlei Zhang, Hong Chen.
  Journal of Cellular Physiology. September 19, 2018
  --- - |2- Abstract MicroRNAs (miRNAs or miRs) are small noncoding RNAs that play critical roles in muscle cell proliferation and differentiation via post‐transcriptional regulation of gene expression. Here, based on our previous high‐throughput sequencing results, we evaluated miRNA‐499 (miR‐499) functions during myoblast proliferation and differentiation. In addition, we analyzed miR‐499 expression profiles and characterized the associated functional roles. MiR‐499 is known to be a skeletal muscle fiber‐type‐associated miRNA. However, its roles in skeletal myoblast proliferation and differentiation are poorly understood. MiR‐499 overexpression promoted C2C12 cell proliferation and significantly attenuated C2C12 cell myogenic differentiation. Furthermore, miR‐499 inhibition enhanced C2C12 cell proliferation and suppressed C2C12 cell differentiation. Using dual‐luciferase reporter assays and western blot analysis, we confirmed that miR‐499 targeted transforming growth factor β receptor 1 (TGFβR1), a known regulator of skeletal myoblast development. Additionally, our RNA interference analysis, in which TGFβR1 was downregulated, showed that TGFβR1 significantly promoted the differentiation of C2C12 cells and inhibited their proliferation. - Journal of Cellular Physiology, EarlyView.
  

  September 19, 2018   doi: 10.1002/jcp.26903   open full text
• Chloride channel‐3 mediates multidrug resistance of cancer by upregulating P‐glycoprotein expression.
  Qi Chen, Xueqiang Liu, Zhesi Luo, Shisi Wang, Jialin Lin, Zheng Xie, Mengge Li, Chunmei Li, Hua Cao, Qingsong Huang, Jianwen Mao, Bin Xu.
  Journal of Cellular Physiology. September 19, 2018
  --- - |2- Abstract Chloride channel‐3 (ClC‐3), a member of the ClC family of voltage‐gated Cl− channels, is involved in the resistance of tumor cells to chemotherapeutic drugs. Here, we report a new mechanism for ClC‐3 in mediating multidrug resistance (MDR). ClC‐3 was highly expressed in the P‐glycoprotein (P‐gp)‐dependent human lung adenocarcinoma cell line (A549)/paclitaxel (PTX) and the human breast carcinoma cell line (MCF‐7)/doxorubicin (DOX) resistant cells. Changes in the ClC‐3 expression resulted in the development of drug resistance in formerly drug‐sensitive A549 or MCF‐7 cells, and drug sensitivity in formerly drug‐resistant A549/Taxol and MCF‐7/DOX cells. Double transgenic MMTV‐PyMT/CLCN3 mice with spontaneous mammary cancer and ClC‐3 overexpression demonstrated drug resistance to PTX and DOX. ClC‐3 expression upregulated the expression of MDR1 messenger RNA and P‐gp by activating the nuclear factor‐κB (NF‐κB)‐signaling pathway. These data suggest that ClC‐3 expression in cancer cells induces MDR by upregulating NF‐κB‐signaling‐dependent P‐gp expression involving another new mechanism for ClC‐3 in the development of drug resistance of cancers. - Journal of Cellular Physiology, EarlyView.
  

  September 19, 2018   doi: 10.1002/jcp.27402   open full text
• Slug mediates myofibroblastic differentiation to promote fibrogenesis in buccal mucosa.
  Chih‐Yuan Fang, Shih‐Min Hsia, Pei‐Ling Hsieh, Yi‐Wen Liao, Chih‐Yu Peng, Ching‐Zong Wu, Kuan‐Chou Lin, Lo‐Lin Tsai, Cheng‐Chia Yu.
  Journal of Cellular Physiology. September 19, 2018
  --- - |2- Abstract Epithelial–mesenchymal transition (EMT) has been implicated in fibrogenesis and carcinogenesis; however, the exact role of EMT‐inducer Slug in the progression of precancerous oral submucous fibrosis (OSF) has not been investigated. In the current study, we showed that the expression of Slug was upregulated in OSF tissues and associated with various myofibroblast markers. After silence of Slug in fibrotic buccal mucosal fibroblasts (fBMFs), the elevated myofibroblast activities and fibrosis markers were all downregulated. Our data revealed that arecoline, an areca nut alkaloid, increased the expression of Slug in normal BMFs, and inhibition of Slug successfully prevented the arecoline‐induced myofibroblast activation. Additionally, overexpression of Slug in BMFs stimulated the activities of myofibroblasts, indicating that upregulation of Slug by arecoline contributes to the myofibroblast transdifferentiation. Most importantly, Slug was able to bind to the E‐box of type I collagen, leading to increased expression of type I collagen. Altogether, this study demonstrated the abnormal elevation of Slug in OSF and its significance in arecoline‐induced fibrogenesis. Moreover, downregulation of Slug could be a potential target for OSF remedy via suppression of myofibroblast activities and type I collagen. - Journal of Cellular Physiology, EarlyView.
  

  September 19, 2018   doi: 10.1002/jcp.27418   open full text
• Efficient penetration of Scp01‐b and its DNA transfer abilities into cells.
  Ming Zhang, Xueli Zhao, Jingping Geng, Huiting Liu, Fanhui Zeng, Yanyan Qin, Jason Li, Changbai Liu, Hu Wang.
  Journal of Cellular Physiology. September 19, 2018
  --- - |2- Abstract The in vivo application potential of viral‐based gene delivery approaches is hindered by a risk of insertional oncogenesis. Of the many delivery methods, cell‐penetrating peptides (CPP)‐based delivery has good biocompatibility and biodegradability. However, low efficiency is still the disadvantage of CPPs‐based nucleic acid transfection, and delivery efficiency may vary from different CPPs. Here, we describe Scp01‐b, as a new CPP, which can enter cultured cell lines and primary cultured cells examined by fluorescence microscopy and quantitative assay, the internalization process is a concentration, temperature, and incubation time‐dependent manner. Scp01‐b does not insert into the membrane directly and its uptake is mediated through endocytosis pathway. Moreover, Scp01‐b could mediate the uptake of plasmid DNA into the Caski and HSC‐T6 cells, and we noted that Scp01‐b‐mediated transfection efficiency was nearly the same with traditional liposome (TurboFectin)‐mediated transfection. These findings suggest that Scp01‐b can act as a useful tool for non‐viral‐based delivery in further application such as reprogramming and gene editing. - Journal of Cellular Physiology, EarlyView.
  

  September 19, 2018   doi: 10.1002/jcp.27392   open full text
• LncRNA CRNDE promotes hepatocellular carcinoma cell proliferation, invasion, and migration through regulating miR‐203/ BCAT1 axis.
  Degang Ji, Chengwei Jiang, Lirong Zhang, Na Liang, Tiechao Jiang, Bin Yang, Haiying Liang.
  Journal of Cellular Physiology. September 19, 2018
  --- - "\nAbstract\n\nObjective\nTo investigate the impact of long noncodingRNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) on hepatocellular cancer (HCC) cell propagation, invasion, and migration by mediating miR‐203/\nBCAT1 axis.\n\n\nMethods\nMicroarray analysis was based on 25 pairs of HCC cancerous tissues and adjacent tissues. The expression levels of CRNDE, miR‐203, and BCAT1 in HCC tissues were analyzed by quantitative real‐time polymerase chain reaction (qRT‐PCR). The liver cell line L‐02 and HCC cell lines HepG2 and Huh‐7 were utilized to assess the regulatory effects of CRNDE and miR‐203 on HCC progression in vitro. Western blot was used to qualify BCAT1 protein expression level. Cell proliferation and apoptosis were evaluated using CCK‐8 and flow cytometry analysis, whereas cell invasion and migration assay were performed by the Transwell assay. The relationship among CRNDE, miR‐203, and \nBCAT1 was validated by dual luciferase assay. Tumor Xenograft study was established to verify the pathological effect of CRNDE on HCC development in vivo.\n\n\nResults\nThe expression levels of the CRNDE and BCAT1 were upregulated in HCC tissues and cells, whereas miR‐203 was downregulated in HCC. Knockdown of CRNDE or miR‐203 overexpression would inhibit HCC cell propagation and metastasis, and induced cell apoptosis. Moreover, miR‐203 was negatively correlated with CRNDE, the same as miR‐203 with \nBCAT1. Dual luciferase assay showed that miR‐203 was an inhibitory target of CRNDE, and \nBCAT1 was directly targeted by miR‐203 as well.\n\n\nConclusion\nLncRNA CRNDE could enhance HCC tumorgenesis by sponging miR‐203 and mediating BCAT1. LncRNA CRNDE might facilitate HCC cell propagation, invasiveness, and migration through regulating miR‐203/\nBCAT1 axis.\n" - Journal of Cellular Physiology, EarlyView.
  

  September 19, 2018   doi: 10.1002/jcp.27396   open full text
• The metabolic and molecular mechanisms of hyperammonaemia‐ and hyperethanolaemia‐induced protein catabolism in skeletal muscle cells.
  Hannah Crossland, Kenneth Smith, Philip J. Atherton, Daniel J. Wilkinson.
  Journal of Cellular Physiology. August 24, 2018
  --- - |2- Hyperammonaemia and hyperethanolaemia are thought to be driving factors behind skeletal muscle myopathy in liver disease, that is, cirrhosis. Despite this, the singular and combined impacts of ethanol‐ and ammonia‐induced protein catabolism are poorly defined. As such, we aimed to dissect out the effects of ammonia and ethanol on muscle catabolism. Murine C2C12 myotubes were treated with ammonium acetate (10 mM) and ethanol (100 mM) either alone or in combination for 4 hr and/or 24 hr. Myotube diameter, muscle protein synthesis and anabolic and catabolic signalling pathways were assessed. In separate experiments, cells were cotreated with selected inhibitors of protein breakdown to assess the importance of proteolytic pathways in protein loss with ammonia and ethanol. Ammonia and ethanol in combination resulted in a reduction in myotube width and total protein content, which was greater than the reduction observed with ammonia alone. Both ammonia and ethanol caused reductions in protein synthesis, as assessed by puromycin incorporation. There was also evidence of impairments in regulation of protein translation, and increased protein expression of markers of muscle protein breakdown. Myotube protein loss with ammonia plus ethanol was not affected by autophagy inhibition, but was completely prevented by proteasome inhibition. Thus, combined ammonia and ethanol incubation of C2C12 myotubes exacerbated myotube atrophy and dysregulation of anabolic and catabolic signalling pathways associated with either component individually. Ubiquitin proteasome‐mediated protein breakdown appears to play an important role in myotube protein loss with ethanol and ammonia. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9663-9673, December 2018.
  

  August 24, 2018   doi: 10.1002/jcp.26881   open full text
• MicroRNA‐16 functions as a tumor‐suppressor gene in oral squamous cell carcinoma by targeting AKT3 and BCL2L2.
  Xi Wang, Guang‐hui Li.
  Journal of Cellular Physiology. August 22, 2018
  --- - |2 Aberrant expressions of microRNAs have been reported to be strongly associated with the progression and prognosis of various tumors, including oral squamous cell carcinoma (OSCC). Recent studies on miRNA expression profiling have suggested that microRNA‐16 (miR‐16) may be dysregulated in OSCC. However, the tumorigenic roles and mechanisms of miR‐16 in OSCC are still largely unknown. In this study, we demonstrated that miR‐16 was specifically downregulated in both OSCC patients and cancer cell lines. In addition, functional roles of miR‐16 in vitro suggested that the miR‐16 mimic inhibited cell proliferation and induced apoptosis, whereas miR‐16 inhibitor displayed the opposite effects. Luciferase reporter assay and correlation analysis showed that AKT3 and BCL2L2 were directly targeted by miR‐16 and were inversely expressed with miR‐16 in OSCC. Moreover, restoration of AKT3 and BCL2L2 expression could partially reverse the cell proliferation inhibition and apoptosis induction caused by miR‐16. In xenograft nude mice, miR‐16 mimics decreased the expression of AKT3 and BCL2L2 and reduced the tumors volumes and weights, whereas the miR‐16 inhibitor exhibited adverse effects in the derived xenografts. In conclusion, the findings suggested that miR‐16 functions as a tumor suppressor miRNA to inhibit cell proliferation and induce apoptosis in OSCC through decreasing the oncogenes AKT3 and BCL2L2 and that miR‐16 could be a potential therapeutic target for OSCC. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9447-9457, December 2018.
  

  August 22, 2018   doi: 10.1002/jcp.26833   open full text
• Peroxidase expression is decreased by palmitate in cultured podocytes but increased in podocytes of advanced diabetic nephropathy.
  Eugene Lee, Hyun Soon Lee.
  Journal of Cellular Physiology. August 21, 2018
  --- - |2- High levels of serum free fatty acids (FFAs) are associated with lipotoxicity and type 2 diabetes. Palmitic acid (PA) is the predominant circulating saturated FFA. PA induces mitochondrial superoxide and hydrogen peroxide (H2O 2) generation in cultured podocytes. To elucidate the role of PA in antioxidant defense systems in diabetic nephropathy (DN), cultured podocytes were exposed to 250 μM PA for 1–24 hr, and protein expressions of catalase, peroxiredoxins (Prxs), and glutathione peroxidase (GPx) were examined by western blot analysis. PA induced an early transient increase in the Prx1, Prx2, and GPx1 levels in podocytes, but not catalase. Long‐term exposure of PA to podocytes significantly decreased the protein levels of Prx1, Prx2, GPx1, and catalase. Coincubation of PA‐treated cells with oleic acid, however, restored the expression of these proteins. In advanced human diabetic glomeruli, H2O2 generation was elevated as shown by increased fluorescence of dichlorofluorescein. Strong immunostaining for Prx1, Prx2, GPx1, and catalase was observed in the podocytes of advanced human DN, wherein transforming growth factor‐β1 staining was also positive. These results suggest that podocytes are susceptible to PA‐induced oxidative damage with impaired peroxidase activity and that peroxidases have futile antioxidant effects in the podocytes in the late stages of DN. Given this, PA‐induced podocyte injury via inadequate peroxidase response to H2O2 appears to play an important role in the pathogenesis of DN. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9060-9069, December 2018.
  

  August 21, 2018   doi: 10.1002/jcp.26875   open full text
• Methylation‐independent ITGA2 overexpression is associated with poor prognosis in de novo acute myeloid leukemia.
  Xin‐Yue Lian, Wei Zhang, De‐Hong Wu, Ji‐Chun Ma, Jing‐Dong Zhou, Zhi‐Hui Zhang, Xiang‐Mei Wen, Zi‐Jun Xu, Jiang Lin, Jun Qian.
  Journal of Cellular Physiology. August 21, 2018
  --- - |2- Previous studies have been indicated that integrin α2 (ITGA2) may be important in cell migration, invasion, survival, and angiogenesis. However, the correlation between ITGA2 expression and acute myeloid leukemia (AML) is still unclear. Real‐time quantitative polymerase chain reaction was carried out to analyze ITGA2 messenger RNA level. Methylation‐specific polymerase chain reaction (PCR) and bisulfite sequencing PCR were performed to detect the methylation of ITGA2 promoter. ITGA2 expression was significantly upregulated in 134 de novo AML patients compared with 33 controls (p = 0.007). ITGA2high group had markedly lower complete remission (CR) rate than ITGA2low group (p = 0.011). Furthermore, the overall survival in ITGA2high patients was significantly shorter than ITGA2low patients throughout AML cohort, non–acute promyelocytic leukemia (APL) and cytogenetic normal‐AML (p = 0.001, 0.002, and 0.044, respectively). Multivariate analysis confirmed that ITGA2 overexpression served as an independent prognostic factor in both whole‐cohort AML patients (p = 0.018) and non‐APL AML patients (p = 0.021). Besides, ITGA2 expression level was significantly decreased in AML patients after CR (p = 0.011), and was returned at the time of relapse phase (p = 0.021). Moreover, unmethylated ITGA2 promoter was identified in normal controls, leukemia cell lines, and primary leukemia cells with low or high ITGA2 expression. In conclusions, methylation‐independent ITGA2 overexpression is associated with poor prognosis in AML. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9584-9593, December 2018.
  

  August 21, 2018   doi: 10.1002/jcp.26866   open full text
• Peptidyl‐prolyl cis–trans isomerase NIMA interacting 1 regulates skeletal muscle fusion through structural modification of Smad3 in the linker region.
  Rabia Islam, Heein Yoon, Hye‐Rim Shin, Han‐Sol Bae, Bong‐Soo Kim, Won‐Joon Yoon, Kyung‐Mi Woo, Jeong‐Hwa Baek, Yun‐Sil Lee, Hyun‐Mo Ryoo.
  Journal of Cellular Physiology. August 21, 2018
  --- - |2- Myoblast fusion is critical for muscle growth, regeneration, and repair. We previously reported that the enzyme peptidyl‐prolyl cis–trans isomerase NIMA interacting 1 (Pin1) is involved in osteoclast fusion. The objective of this study was to investigate the possibility that Pin1 also inhibits myoblast fusion. Here, we show the increased number of nuclei in the Pin1+/− mice muscle fiber compared to that in wild‐type mice. Moreover, we show that low dose of the Pin1 inhibitor dipentamethylene thiuram monosulfide treatment caused enhanced fusion in C2C12 cells. The R‐Smads are well‐known mediators of muscle hypertrophy and hyperplasia as well as being substrates of Pin1. We found that Pin1 is crucial for maintaining the stability of Smad3 (homologues of the Drosophila protein, mothers against decapentaplegic (Mad) and the Caenorhabditis elegans protein Sma). Our results show that serine 204 within Smad3 is the key Pin1‐binding site during inhibition of myoblast fusion and that both the transforming growth factor‐β receptor and extracellular signal‐regulated kinase (ERK)‐mediated phosphorylation are required for the interaction of Pin1 with Smad3. These findings suggest that a precise level of Pin1 activity is essential for regulating myoblast fusion during myogenesis and muscle regeneration. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9390-9403, December 2018.
  

  August 21, 2018   doi: 10.1002/jcp.26774   open full text
• Inhibition of smoothened in breast cancer cells reduces CAXII expression and cell migration.
  Giuditta Guerrini, Mattia Criscuoli, Irene Filippi, Antonella Naldini, Fabio Carraro.
  Journal of Cellular Physiology. August 21, 2018
  --- - |2 Breast cancer (BC) relapse and metastasis are the leading cause of death and, together with drug resistance, keep mortality still high. The Hedgehog (Hh) pathway is expressed during embryogenesis, organogenesis and in adult tissue homeostasis and its aberrant activation is often associated with cancer. Carbonic anhydrase (CA) enzymes are important during development; they play a key role in controlling several cellular mechanisms, such as pH regulation, survival, and migration, and they are aberrantly expressed in cancer. The goal of this study was to investigate the interplay between the Hh pathway and CAXII in terms of BC cell migration. We here demonstrated that smoothened (SMO) silencing resulted in a reduction of CAXII expression at mRNA and protein level. This led to a decrease in cell migration, which was restored when cells were treated with an SMO agonist, Sag dihydrochloride (SAG), but not when cells were cotreated with SAG and the CAs inhibitor Acetazolamide. This suggested that the ability of SAG to promote cell migration was impaired when CAXII was inhibited. The reduction was also confirmed within hypoxic and inflammatory microenvironment, typical of BC, indicating a key role of the Hh pathway in controlling CAXII expression. Our results may contribute to further understand the physiology of BC cells and indicate that the Hh pathway controls BC cell migration and cell invasion also through CAXII, with important implications in identifying novel therapeutic targets. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9799-9811, December 2018.
  

  August 21, 2018   doi: 10.1002/jcp.26947   open full text
• Cancer metastasis versus stem cell homing: Role of platelets.
  Hojjat Naderi‐Meshkin, Naghmeh Ahmadiankia.
  Journal of Cellular Physiology. August 13, 2018
  --- - |2- Abstract One of the major obstacles in achieving a successful stem cell therapy is insufficient homing of transplanted cells. To overcome this obstacle, understanding the underlying mechanisms of stem cell homing is of obvious importance. Central to this review is the concept that cancer metastasis can be viewed as a role model to build up a comprehensive concept of stem cell homing. In this novel perspective, the prosurvival choices of the cancerous cells in the bloodstream, their arrest, extravasation, and proliferation at the secondary site can be exploited in favor of targeted stem cell homing. To date, tumor cells have been found to employ a wide variety of strategies to promote metastasis. One of these strategies is through their ability to activate platelets and subsequently activated platelets serve cancer cell survival and metastasis. Accordingly, in the first part of this review the roles of platelets in cancer metastasis as well as stem cell homing are discussed. Next, we provide some lessons learned from cancer metastasis in favor of developing strategies for improvement of stem cell homing with emphasis on the role of platelets. Based on direct or indirect evidence from metastasis, strategies such as manipulation of stem cells to enhance interaction with platelets, preconditioning–pretreatment of stem cells with platelets in vitro, and coinjection of both stem cells and platelets are proposed to improve stem cell homing. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9167-9178, December 2018.
  

  August 13, 2018   doi: 10.1002/jcp.26937   open full text
• Therapeutic potential of microRNAs in osteoporosis function by regulating the biology of cells related to bone homeostasis.
  Wenhua Zhao, Gengyang Shen, Hui Ren, De Liang, Xiang Yu, Zhida Zhang, Jinjing Huang, Ting Qiu, Jingjing Tang, Qi Shang, Peiyuan Yu, Zixian Wu, Xiaobing Jiang.
  Journal of Cellular Physiology. August 05, 2018
  --- - |2- MicroRNAs (miRNAs) are novel regulatory factors that play important roles in numerous cellular processes through the posttranscriptional regulation of gene expression. Recently, deregulation of the miRNA‐mediated mechanism has emerged as an important pathological factor in osteoporosis. However, a detailed molecular mechanism between miRNAs and osteoporosis is still not available. In this review, the roles of miRNAs in the regulation of cells related to bone homeostasis as well as miRNAs that deregulate in human or animal are discussed. Moreover, the miRNAs that act as clusters in the biology of cells in the bone microenvironment and the difference of some important miRNAs for bone homeostasis between bone and other organs are mentioned. Overall, miRNAs that contribute to the pathogenesis of osteoporosis and their therapeutic potential are considered. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9191-9208, December 2018.
  

  August 05, 2018   doi: 10.1002/jcp.26939   open full text
• Tumor‐associated macrophages and epithelial–mesenchymal transition in cancer: Nanotechnology comes into view.
  Roghayyeh Vakili‐Ghartavol, Reza Mombeiny, Arash Salmaninejad, Seyed Mahdi Rezayat Sorkhabadi, Reza Faridi‐Majidi, Mahmoud Reza Jaafari, Hamed Mirzaei.
  Journal of Cellular Physiology. August 05, 2018
  --- - |2 Tumor‐associated macrophages (TAMs) are an important component of the leukocytic infiltrate of the tumor microenvironment. There is persuasive preclinical and clinical evidence that TAMs induce cancer inanition and malignant progression of primary tumors toward a metastatic state through a highly conserved and fundamental process known as epithelial–mesenchymal transition (EMT). Tumor cells undergoing EMT are distinguished by increased motility and invasiveness, which enable them to spread to distant sites and form metastases. In addition, besides becoming resistant to apoptosis and antitumor drugs, they also contribute to immunosuppression and get a cancer stem‐cell like phenotype. Here, we will focus on selected molecular pathways underlying EMT—in particular, the role of TAMs in the induction and maintenance of EMT—and further discuss how the targeting of TAMs through the application of nanotechnology tools allows the development of a whole new range of therapeutics. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9223-9236, December 2018.
  

  August 05, 2018   doi: 10.1002/jcp.27027   open full text
• The MicroRNA‐326: Autoimmune diseases, diagnostic biomarker, and therapeutic target.
  Golamreza Jadideslam, Khalil Ansarin, Ebrahim Sakhinia, Shahriar Alipour, Farhad Pouremamali, Alireza Khabbazi.
  Journal of Cellular Physiology. August 05, 2018
  --- - |2- MicroRNAs (miRNAs) are uniquely regulated in healthy, inflamed, activated, cancerous, or other cells and tissues of a pathological state. Many studies confirm that immune dysregulation and autoimmune diseases with inflammation are correlated with various miRNA expression changes in targeted tissues and cells in innate or adaptive immunity. In this review, we will explain the history and classification of epigenetic changes. Next, we will describe the role of miRNAs changes, especially mir‐326 in autoimmunity, autoinflammatory, and other pathological conditions. A systematic search of MEDLINE, Embase, and Cochrane Library was presented for all related studies from 1899 to 2017 with restrictions in the English language. In recent years, researchers have concentrated on mostly those roles of miRNA that are correlated with the inflammatory and anti‐inflammatory process. Latest studies have proposed a fundamental pathogenic role in cancers and autoinflammatory diseases. Studies have described the role of microRNAs in autoimmunity and autoinflammatory diseases, cancers, and so on. The miRNA‐326 expression plays a significant role in autoimmune and other types of diseases. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9209-9222, December 2018.
  

  August 05, 2018   doi: 10.1002/jcp.26949   open full text
• Cellular senescence: Molecular mechanisms and pathogenicity.
  Wenqiang Wei, Shaoping Ji.
  Journal of Cellular Physiology. August 05, 2018
  --- - |2- Cellular senescence is the arrest of normal cell division. Oncogenic genes and oxidative stress, which cause genomic DNA damage and generation of reactive oxygen species, lead to cellular senescence. The senescence‐associated secretory phenotype is a distinct feature of senescence. Senescence is normally involved in the embryonic development. Senescent cells can communicate with immune cells to invoke an immune response. Senescence emerges during the aging process in several tissues and organs. In fact, increasing evidence shows that cellular senescence is implicated in aging‐related diseases, such as nonalcoholic fatty liver disease, obesity and diabetes, pulmonary hypertension, and tumorigenesis. Cellular senescence can also be induced by microbial infection. During cellular senescence, several signaling pathways, including those of p53, nuclear factor‐κB (NF‐κB), mammalian target of rapamycin, and transforming growth factor‐beta, play important roles. Accumulation of senescent cells can trigger chronic inflammation, which may contribute to the pathological changes in the elderly. Given the variety of deleterious effects caused by cellular senescence in humans, strategies have been proposed to control senescence. In this review, we will focus on recent studies to provide a brief introduction to cellular senescence, including associated signaling pathways and pathology. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9121-9135, December 2018.
  

  August 05, 2018   doi: 10.1002/jcp.26956   open full text
• Hyaluronidase2 (Hyal2) modulates low shear stress‐induced glycocalyx impairment via the LKB1/AMPK/NADPH oxidase‐dependent pathway.
  Hongfeng Yang, Linlin Zhu, Yuelin Chao, Yue Gu, Xiangquan Kong, Mingxing Chen, Peng Ye, Jie Luo, Shaoliang Chen.
  Journal of Cellular Physiology. August 05, 2018
  --- - |2- The endothelium glycocalyx layer (ECL), presents on the apical surface of endothelial cells, creates a barrier between circulating blood and the vessel wall. Low shear stress (LSS) may accelerate the degradation of the glycocalyx via hyaluronidase2 (Hyal2) and then alter the cell polarity. Yet the liver kinase B1 (LKB1) signaling pathway plays an important role in regulating cell polarity. However, the relationship between LKB1 and glycocalyx during LSS is not clear. In the current study, we demonstrate that LSS attenuates LKB1 and AMP‐activated protein kinase activation as well as activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47phox) and Hyal2 in the human umbilical vein endothelial cell (HUVEC). Pretreatment with 5‐Aminoimidazole‐4‐carboxamide1‐β‐D‐ribofuranoside (AICAR), or diphenyleneiodonium (DPI chloride) and transfection with LKB1 overexpression vector and p47phox small interfering RNA downregulated LSS‐induced Hyal2 activation. By coimmunoprecipitation, we discovered the existence of p47phox/Hyal2 complex. LSS induced the dissociation of p47phox/Hyal2 complex, which was inhibited by LKB1 overexpression and AICAR. Furthermore, knockdown of Hyal2 performed a positive feedback on LKB1 activity. In addition, we also show that LSS enhanced LKB1 translocation from the cytosol to the nucleus. Taken together, these data indicate that Hyal2 regulates LSS‐induced injury of the glycocalyx via LKB1/AMPK/NADPH oxidase signaling cascades. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9701-9715, December 2018.
  

  August 05, 2018   doi: 10.1002/jcp.26944   open full text
• Identification of key genes and pathways associated with osteogenic differentiation of adipose stem cells.
  Xinyuan Zhao, Minlu Liang, Xiaona Li, Xiaoling Qiu, Li Cui.
  Journal of Cellular Physiology. August 05, 2018
  --- - |2 Adipose stem cells (ASCs) are considered a great alternative source of mesenchymal stem cells (MSCs) and have shown great promise on tissue engineering and regenerative medicine applications, including bone repair. However, the underlying mechanisms regulating the osteogenic differentiation of ASCs remain poorly known. Gene expression profiles of GSE63754 and GSE37329 were downloaded from gene expression omnibus database. R software and Bioconductor packages were used to compare and identify the differentially expressed genes (DEGs) before and after ASC osteogenic differentiation. The common significant DEGs between GSE63754 and GSE37329 were then subjected to gene ontology (GO) enrichment analysis, ingenuity pathway analysis (IPA), and protein–protein interactions (PPIs) networks analysis. One of the central node genes FOXO1 was selected for further investigation. A total of 142 up‐ and 69 downregulated genes were aberrantly expressed in both GSE63754 and GSE37329. GO analysis revealed that these DEGs were associated with extracellular matrix organization, proteinaceous extracellular matrix, and Wnt‐protein binding. IPA analysis showed that canonical pathways, such as FXR/RXR activation, adipogenesis pathway, and LXR/RXR activation, were involved in regulating osteogenic differentiation of ASCs. A total of three subnetworks and 39 nodes were identified with PPI network and MCODE plugin. Moreover, suppression of one central node gene FOXO1 inhibited the osteogenic differentiation of ASCs. Our study provides a registry of genes and pathways that play important roles in regulating osteogenic differentiation of ASCs, which might have potential therapeutic applications in bone regeneration and bone tissue engineering. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9777-9785, December 2018.
  

  August 05, 2018   doi: 10.1002/jcp.26943   open full text
• Establishment and characterization of a telomerase‐immortalized porcine bronchial epithelial cell line.
  Xing Xie, Yuan Gan, Maoda Pang, Guoqing Shao, Lei Zhang, Beibei Liu, Qi Xu, Haiyan Wang, Yanyan Feng, Yanfei Yu, Rong Chen, Meng Wu, Zhenzhen Zhang, Lizhong Hua, Qiyan Xiong, Maojun Liu, Zhixin Feng.
  Journal of Cellular Physiology. August 05, 2018
  --- - |2 Primary porcine bronchial epithelial cells (PBECs) are an ideal model to study the molecular and pathogenic mechanisms of various porcine respiratory pathogens. However, the short lifespan of primary PBECs greatly limit their application. Here, we isolated and cultured primary PBECs and established immortalized PBECs by transfecting primary PBECs with the pEGFP‐hTERT recombinant plasmid containing human telomerase reverse transcriptase (hTERT). Immortalized PBECs (hTERT‐PBECs) retained the morphological and functional features of primary PBECs as indicated by cytokeratin 18 expression, telomerase activity assay, proliferation assays, karyotype analysis, and quantitative reverse‐transcriptase polymerase chain reaction. Compared to primary PBECs, hTERT‐PBECs had higher telomerase activity, extended replicative lifespan, and displayed enhanced proliferative activity. Moreover, this cell line is not transformed in vitro and does not exhibit a malignant phenotype in vivo, suggesting that it can be safely used in further studies. Besides, hTERT‐PBECs were susceptible to swine influenza virus of H3N2 subtype and porcine circovirus type 2. In conclusion, the immortalized hTERT‐PBECs represent a valuable in vitro model, which can be widely used in the study of porcine respiratory pathogenic infections. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9763-9776, December 2018.
  

  August 05, 2018   doi: 10.1002/jcp.26942   open full text
• Exogenous hydrogen sulfide attenuates the development of diabetic cardiomyopathy via the FoxO1 pathway.
  Peng Ye, Yue Gu, Yan‐Rong Zhu, Yue‐Lin Chao, Xiang‐Quan Kong, Jie Luo, Xiao‐Min Ren, Guang‐Feng Zuo, Dai‐Min Zhang, Shao‐Liang Chen.
  Journal of Cellular Physiology. August 05, 2018
  --- - |2+ Background Previous studies have suggested that exogenous hydrogen sulfide can alleviate the development of diabetic cardiomyopathy (DCM) by inhibiting oxidative stress, inflammation, and apoptosis. However, the underlying mechanism is not fully understood. Nuclear expression and function of the transcription factor Forkhead box protein O (FoxO1) have been associated with cardiovascular diseases, and thus, the importance of FoxO1 in DCM has gained increasing attention. This study was designed to investigate the interactions between hydrogen sulfide (H2S) and nuclear FoxO1 in DCM. Methods Diabetes was induced in adult male C57BL/6J mice by intraperitoneal injection of streptozotocin and was treated with H2S donor sodium hydrosulfide for 12 weeks. The H9C2 cardiomyoblast cell line and neonatal rat cardiomyocytes (NRCMs) were treated with the slow‐releasing H2S donor GYY4137 before high‐glucose (HG) exposure with or without pretreatment with the Akt inhibitor MK‐2206 2HCl. Changes in FoxO1 protein phosphorylation and subcellular localization were determined in H9C2 cells, NRCMs, and cardiac tissues from normal and diabetic mice. Cardiac structure and function in the diabetic mice were evaluated by echocardiography and histological analysis and compared with those in control animals. Results The echocardiographic and histopathological data indicated that exogenous H2S improved cardiac function and attenuated cardiac hypertrophy and myocardial fibrosis in diabetic mice. H2S also improved HG‐induced oxidative stress and apoptosis in cardiac tissue and NRCMs. In addition, H2S induced FoxO1 phosphorylation and nuclear exclusion in vitro and in vivo, and this function was not inhibited by MK‐2206 2HCl. Alanine substitution mutation of three sites in FoxO1‐enhanced FoxO1 transcriptional activity, and subsequent treatment with exogenous H2S could not prevent HG‐induced nuclear retention. Conclusions Our data indicate that H2S is a novel regulator of FoxO1 in cardiac cells and provide evidence supporting the potential of H2S in inhibiting the progression of DCM. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9786-9798, December 2018.
  

  August 05, 2018   doi: 10.1002/jcp.26946   open full text
• Berberine attenuates pulmonary arterial hypertension via protein phosphatase 2A signaling pathway both in vivo and in vitro.
  Jie Luo, Yue Gu, Pengfei Liu, Xiaomin Jiang, Wande Yu, Peng Ye, Yuelin Chao, Hongfeng Yang, Linlin Zhu, Ling Zhou, Shaoliang Chen.
  Journal of Cellular Physiology. August 05, 2018
  --- - |2- Excessive proliferation, migration, and antiapoptosis of pulmonary artery (PA) smooth muscle cells (PASMCs) underlies the development of pulmonary vascular remodeling. The innervation of the PA is predominantly sympathetic, and increased levels of circulating catecholamines have been detected in pulmonary arterial hypertension (PAH), suggesting that neurotransmitters released by sympathetic overactivation may play an essential role in PAH. However, the responsible mechanism remains unclear. Here, to investigate the effects of norepinephrine (NE) on PASMCs and the related mechanism, we used 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide, the proliferating cell nuclear antigen and the cell counting kit‐8 assay to evaluate the proliferation of PASMCs, Boyden chamber migration, and wound‐healing assays to assess migration and western blot analysis to investigate protein expression. We demonstrated that the phosphorylation level of the protein phosphatase 2A (PP2A) catalytic subunit (Y307) was higher in PAH patients and PAH models than in controls, both in vivo and in vitro. In addition, NE induced the proliferation and migration of PASMCs, which was attenuated by berberine (BBR), a Chinese herbal medicine, and/or PP2A overexpression. PP2A inhibition worsened NE‐induced PAH and could not be reversed by BBR. Thus, PP2A is critical in driving PAH, and BBR may alleviate PAH via PP2A signaling pathways, thereby offering a potential therapeutic option for PAH. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9750-9762, December 2018.
  

  August 05, 2018   doi: 10.1002/jcp.26940   open full text
• Infection‐associated epigenetic alterations in gastric cancer: New insight in cancer therapy.
  Sadegh Fattahi, Mohadeseh Kosari‐Monfared, Elham Ghadami, Monireh Golpour, Parastoo Khodadadi, Mohammad Ghasemiyan, Haleh Akhavan‐Niaki.
  Journal of Cellular Physiology. August 04, 2018
  --- - |2- Gastric cancer risk is higher for malignancies motivated by bacterial and viral infections. Epigenetic abnormalities including DNA methylation, histone modifications, and noncoding RNAs are important regulatory key players in gastric cancer development in infected patients. Epigenetic memory restoration is an extremely interesting phenomenon which should be considered in therapeutic approaches. In vitro and in vivo antiviral treatments in combination with epigenetic therapeutic strategies along with standard chemotherapy revealed promising outcomes in gastric cancer prevention and treatment. This review summarizes our current understanding of the gastric cancer infections and epigenetic alterations caused by these agents. We focus on studies highlighting recent advances in epigenetic restoration by target specific drugs and present also a comprehensive overview of effective antiviral drug treatments against gastric cancer. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9261-9270, December 2018.
  

  August 04, 2018   doi: 10.1002/jcp.27030   open full text
• Ferritinophagy/ferroptosis: Iron‐related newcomers in human diseases.
  Mingzhu Tang, Zhe Chen, Di Wu, Linxi Chen.
  Journal of Cellular Physiology. August 04, 2018
  --- - |2- Nuclear receptor coactivator 4 mediated ferritinophagy is an autophagic phenomenon that specifically involves ferritin to release intracellular free iron. Ferritinophagy is implicated in maintaining efficient erythropoiesis. Notably, ferritinophagy also plays a central role in driving some pathological processes, including Parkinson’s disease (PD) and urinary tract infections. Some evidence has demonstrated that ferritinophagy is critical to induce ferroptosis. Ferroptosis is a newly nonapoptotic form of cell death, characterized by the accumulation of iron‐based lipid reactive oxygen species. Ferroptosis plays an important role in inhibiting some types of cancers, such as hepatocellular carcinoma, pancreatic carcinoma, prostate cancer, and breast cancer. Conversely, the activation of ferroptosis accelerates neurodegeneration diseases, including PD and Alzheimer’s disease. Therefore, in this review, we summarize the regulatory mechanisms related to ferritinophagy and ferroptosis. Moreover, the distinctive effects of ferritinophagy in human erythropoiesis and some pathologies, coupled with the promotive or inhibitory role of tumorous and neurodegenerative diseases mediated by ferroptosis, are elucidated. Obviously, activating or inhibiting ferroptosis could be exploited to achieve desirable therapeutic effects on diverse cancers and neurodegeneration diseases. Interrupting ferritinophagy to control iron level might provide a potentially therapeutic avenue to suppress urinary tract infections. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9179-9190, December 2018.
  

  August 04, 2018   doi: 10.1002/jcp.26954   open full text
• Demethoxycurcumin: A naturally occurring curcumin analogue with antitumor properties.
  Mahdi Hatamipour, Mahin Ramezani, Sayyed Abolghasem Sajadi Tabassi, Thomas P. Johnston, Mahnaz Ramezani, Amirhosein Sahebkar.
  Journal of Cellular Physiology. August 04, 2018
  --- - |2- The eradication of cancer in a patient remains an elusive challenge despite advances in early detection and diagnosis, chemo‐ and immunotherapy, pinpoint radiation treatments, and expert surgical intervention. Although significant gains have been made in our understanding of cancer cell biology, a definite cure for most cancers does not exist at present. Thus, it is not surprising that the research and medical communities continue to explore the importance and therapeutic potential of natural products in their multimodality cancer treatment approach. Curcuminoids found in turmeric are one such class of natural products that have been extensively investigated for their potential to halt the progression of cancer cell proliferation and, more important, to stop metastasis from occurring. In this review, we examine one curcuminoid (demethoxycurcumin [DMC]) largely because of its increased stability and better aqueous solubility at physiological pH, unlike the more well‐known curcuminoid (curcumin), which is largely unabsorbed after oral ingestion. The present review will focus on the signaling pathways that DMC utilizes to modulate the growth, invasion, and metastasis of cancer cells in an effort to provide enhanced mechanistic insight into DMC’s action as it pertains to brain, ovarian, breast, lung, skin, and prostate cancer. Additionally, this review will attempt to provide an overview of DMC’s mechanism of action by modulating apoptosis, cell cycle, angiogenesis, metastasis, and chemosensitivity. Lastly, it is hoped that increased understanding will be gained concerning DMC’s interactive role with microRNA‐551a, 5′ adenosine monophosphate‐activated protein kinase, nuclear factor‐κB, Wnt inhibitory factor‐1, and heat shock protein 70 to affect the progression of cancer. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9247-9260, December 2018.
  

  August 04, 2018   doi: 10.1002/jcp.27029   open full text
• Monocyte‐to‐HDL‐cholesterol ratio as a prognostic marker in cardiovascular diseases.
  Shiva Ganjali, Antonio M. Gotto, Massimiliano Ruscica, Stephen L. Atkin, Alexandra E. Butler, Maciej Banach, Amirhossein Sahebkar.
  Journal of Cellular Physiology. August 04, 2018
  --- - |2- Inflammation and lipid accumulation are two basic hallmarks of atherosclerosis as a chronic disease. Inflammation not only is a local response but can also be considered as a systemic process followed by an elevation of inflammatory mediators. Monocytes are a major source of proinflammatory species during atherogenesis. In atherosclerosis, modified low‐density lipoproteins (LDLs) are removed by macrophages; these are recruited in the vessel wall, inducing the release of inflammatory cytokines in inflamed tissue. Hence, inflammatory cholesterol ester‐loaded plaque is generated. High‐density lipoprotein‐cholesterol (HDL‐C) exhibits antiatherosclerotic effects by neutralizing the proinflammatory and pro‐oxidant effects of monocytes via inhibiting the migration of macrophages and LDL oxidation in addition to the efflux of cholesterol from these cells. Furthermore, HDL plays a role in suppressing the activation of monocytes and proliferation–differentiation of monocyte progenitor cells. Thus, accumulation of monocytes and reduction of HDL‐C may participate in atherosclerosis and cardiovascular diseases (CVD). Given that the relationship between the high number of monocytes and low HDL‐C levels has been reported in inflammatory disorders, this review focused on understanding whether the monocyte‐to‐HDL ratio could be a convenient marker to predict atherosclerosis development and progression, hallmarks of CV events, instead of the individual monocyte count or HDL‐C level. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9237-9246, December 2018.
  

  August 04, 2018   doi: 10.1002/jcp.27028   open full text
• The role of ErbB3 binding protein 1 in cancer: Friend or foe?
  Dang Quan Nguyen, Dinh Hoa Hoang, Thanh Thao Nguyen Vo, Vu Huynh, Lucy Ghoda, Guido Marcucci, Le Xuan Truong Nguyen.
  Journal of Cellular Physiology. August 04, 2018
  --- - |2- ErbB3, a member of the epidermal growth factor receptor family, reportedly plays an essential role in the regulation of cancer progression and therapeutic resistance. Numerous studies have indicated that ErbB3 binding protein 1 (Ebp1), a binding partner for ErbB3, plays an important regulatory role in the expression and function of ErbB3, but there is no agreement as to whether Ebp1 also has an ErbB3‐independent function in cancer and how it might contribute to tumorigenesis. In this review, we will discuss the different functions of the two Ebp1 isoforms, p48 and p42, that may be responsible for the potentially dual role of Ebp1 in cancer growth. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9110-9120, December 2018.
  

  August 04, 2018   doi: 10.1002/jcp.26951   open full text
• Analysis of pro‐ and anti‐inflammatory cytokine gene variants and serum cytokine levels as prognostic markers in breast cancer.
  Raman Preet Kaur, Kanika Vasudeva, Heena Singla, Raja Paramjeet Singh Benipal, Preeti Khetarpal, Anjana Munshi.
  Journal of Cellular Physiology. August 04, 2018
  --- - |2- The aim of current study was to evaluate the genetic variation in all the genes encoding pro‐ and anti‐inflammatory cytokines in association with breast cancer development in patients from Malwa region of Punjab. The importance of the levels of interleukin (IL)‐17, tumor necrosis factor, interferon γ, IL‐10, IL‐6, IL‐4, and IL‐2 with respect to clinicopathological data, prognosis, and disease‐free survival was also determined in these patients. Two hundred and fifty female breast cancer patients and 250 age‐matched controls were screened for variations in cytokine‐encoding genes using global screening array microchip and PCR‐RFLP. The level of cytokines was estimated in 150 patients and 60 age‐matched controls using BD™ Cytometric Bead Array (CBA) Human Th1/Th2/Th17 cytokine kit by BD Accuri flow cytometer. The difference in cytokine levels was evaluated by Mann–Whitney test. No significant variation in the genes encoding various cytokines was found between patients and controls. Out of the seven cytokines evaluated, the levels of IL‐6 and IL‐17a were found to be significantly high in patients in comparison with controls ( p = 0.001 and 0.02, respectively). The elevated levels of these cytokines are also associated significantly with poor outcome. We did not find any specific variation in the genes encoding various cytokines between patients and controls. However, there was a significant difference in the serum levels of IL‐6 and IL‐17a between patients and controls, and the elevated levels of these two cytokines associated significantly with poor outcome in breast cancer patients and, therefore, can be used as prognostic markers. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9716-9723, December 2018.
  

  August 04, 2018   doi: 10.1002/jcp.26901   open full text
• STAC3 incorporation into skeletal muscle triads occurs independent of the dihydropyridine receptor.
  Marta Campiglio, Mehmet M. Kaplan, Bernhard E. Flucher.
  Journal of Cellular Physiology. August 02, 2018
  --- - |2- Excitation‐contraction (EC) coupling in skeletal muscles operates through a physical interaction between the dihydropyridine receptor (DHPR), acting as a voltage sensor, and the ryanodine receptor (RyR1), acting as a calcium release channel. Recently, the adaptor protein SH3 and cysteine‐rich containing protein 3 (STAC3) has been identified as a myopathy disease gene and as an additional essential EC coupling component. STAC3 interacts with DHPR sequences including the critical EC coupling domain and has been proposed to function in linking the DHPR and RyR1. However, we and others demonstrated that incorporation of recombinant STAC3 into skeletal muscle triads critically depends only on the DHPR but not the RyR1. On the contrary, here, we provide evidence that endogenous STAC3 incorporates into triads in the absence of the DHPR in myotubes and muscle fibers of dysgenic mice. This finding demonstrates that STAC3 interacts with additional triad proteins and is consistent with its proposed role in directly or indirectly linking the DHPR with the RyR1. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9045-9051, December 2018.
  

  August 02, 2018   doi: 10.1002/jcp.26767   open full text
• Exercise activates the hypothalamic S1PR1–STAT3 axis through the central action of interleukin 6 in mice.
  Vagner R. R. Silva, Thayana O. Micheletti, Carlos K. Katashima, Luciene Lenhare, Joseane Morari, Alexandre Moura‐Assis, José C. Lima‐Júnior, Juliana A. Camargo, Gabriela R. Passos, Rodrigo S. Gaspar, Licio A. Velloso, Mario J. Saad, Adelino S. R. da Silva, Leandro P. Moura, Dennys E. Cintra, José R. Pauli, Eduardo R. Ropelle.
  Journal of Cellular Physiology. July 31, 2018
  --- - |2 Hypothalamic sphingosine‐1‐phosphate receptor 1 (S1PR1), the G protein–coupled receptor 1 of sphingosine‐1‐phosphate, has been described as a modulator in the control of energy homeostasis in rodents. However, this mechanism is still unclear. Here, we evaluate the role of interleukin 6 (IL‐6) associated with acute physical exercise in the control of the hypothalamic S1PR1–signal transducer and activator of transcription 3 (STAT3) axis. Acute exercise session and an intracerebroventricular IL‐6 injection increased S1PR1 protein content and STAT3 phosphorylation in the hypothalamus of lean and obese mice accompanied by a reduction in food consumption. Transcriptome analysis indicated a strong positive correlation between Il‐6 and S1pr1 messenger RNA in several tissues of genetically diverse BXD mice strains and humans, including in the hypothalamus. Interestingly, exercise failed to stimulate the S1PR1–STAT3 axis in IL‐6 knockout mice and the disruption of hypothalamic‐specific IL‐6 action blocked the anorexigenic effects of exercise. Taken together, our results indicate that physical exercise modulates the S1PR1 protein content in the hypothalamus, through the central action of IL‐6. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9426-9436, December 2018.
  

  July 31, 2018   doi: 10.1002/jcp.26818   open full text
• Small molecule inhibitor RepSox prevented ovariectomy‐induced osteoporosis by suppressing osteoclast differentiation and bone resorption.
  Liangwei Mei, Wenhua Sang, Zhenzhong Chen, Lin Zheng, Kangtao Jin, Chao Lou, Wenjun Huang, Dengwei He.
  Journal of Cellular Physiology. July 30, 2018
  --- - |2- Osteoporosis (OP) is a serious metabolic disease that, due to the increased number or function of osteoclasts, results in increased bone brittleness and, therefore, fragile fracture. Some recent studies report the importance of the transforming growth factor β (TGFβ) pathway in bone homeostasis. RepSox is a small molecule inhibitor of TGFβRI that has a wide range of potential application in clinical medicine, except OP. The aim of our study is to evaluate the effects of RepSox on the differentiation and bone resorption of osteoclasts in vitro and in vivo in an ovariectomy (OVX)‐induced OP model. An initial analysis showed TGFβRI messenger RNA expression in both bone samples and bone cells. In the in vitro study, RepSox inhibited the receptor activator of nuclear factor κB ligand (RANKL)‐induced osteoclast differentiation and bone resorption activity. Real‐time polymerase chain reaction (PCR) analysis showed that RepSox suppressed osteoclastic marker gene expression in both dose‐dependent and time‐dependent manners. In addition, RepSox did not affect osteoblast differentiation, migration or osteoblastic‐specific gene expression in vitro. Furthermore, western blot analysis indicated the underlying mechanisms of the RepSox suppression of osteoclastogenesis via the Smad3 and c‐Jun N‐terminal kinase/activator protein‐1 (JNK/AP‐1) signaling pathways. Finally, our animal experiments revealed that RepSox prevented OVX‐induced bone loss in vivo. Together, our data suggest that RepSox regulates osteoclast differentiation, bone resorption, and OVX‐induced OP via the suppression of the Smad3 and JNK/AP‐1 pathways. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9724-9738, December 2018.
  

  July 30, 2018   doi: 10.1002/jcp.26914   open full text
• Deficiency of fibroblast growth factor 2 (FGF‐2) leads to abnormal spermatogenesis and altered sperm physiology.
  Lucía Saucedo, Regina Rumpel, Cristian Sobarzo, Dietmar Schreiner, Gudrun Brandes, Livia Lustig, Mónica Hebe Vazquez‐Levin, Claudia Grothe, Clara Marín‐Briggiler.
  Journal of Cellular Physiology. July 27, 2018
  --- - |2- In previous studies, we described the presence of fibroblast growth factor 2 (FGF‐2) and its receptors (FGFRs) in human testis and sperm, which are involved in spermatogenesis and in motility regulation. The aim of the present study was to analyze the role of FGF‐2 in the maintenance of sperm physiology using FGF‐2 knockout (KO) mice. Our results showed that in wild‐type (WT) animals, FGF‐2 is expressed in germ cells of the seminiferous epithelium, in epithelial cells of the epididymis, and in the flagellum and acrosomal region of epididymal sperm. In the FGF‐2 KO mice, we found alterations in spermatogenesis kinetics, higher numbers of spermatids per testis, and enhanced daily sperm production compared with the WT males. No difference in the percentage of sperm motility was detected, but a significant increase in sperm concentration and in sperm head abnormalities was observed in FGF‐2 KO animals. Sperm from KO mice depicted reduced phosphorylation on tyrosine residues (a phenomenon that was associated with sperm capacitation) and increased acrosomal loss after incubation under capacitating conditions. However, the FGF‐2 KO males displayed no apparent fertility defects, since their mating with WT females showed no differences in the time to delivery, litter size, and pup weight in comparison with WT males. Overall, our findings suggest that FGF‐2 exerts a role in mammalian spermatogenesis and that the lack of FGF‐2 leads to dysregulated sperm production and altered sperm morphology and function. FGF‐2‐deficient mice constitute a model for the study of the complex mechanisms underlying mammalian spermatogenesis. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9640-9651, December 2018.
  

  July 27, 2018   doi: 10.1002/jcp.26876   open full text
• CerS6 regulates cisplatin resistance in oral squamous cell carcinoma by altering mitochondrial fission and autophagy.
  Shengjiao Li, Yangou Wu, Yunpeng Ding, Miao Yu, Zexin Ai.
  Journal of Cellular Physiology. July 27, 2018
  --- - |2 Chemoresistance remains a challenge in the effective treatment of solid tumors, including oral squamous cell carcinoma (OSCC). Mitochondrial dynamics and autophagy have recently been implicated in the chemoresistance of cancer cells. The neutralization of ceramide is also associated with multidrug resistance, and ceramide synthase 6 (CerS6) is known to induce apoptosis. However, whether CerS6 regulates chemoresistance in OSCC is not clearly understood. Therefore, we investigated the role of CerS6 in the susceptibility of OSCC cells to cisplatin. In this study, we observed that cisplatin‐resistant OSCC cells process lower levels of fission‐state mitochondria and cell apoptosis than cisplatin‐sensitive cells, and autophagy was activated in cisplatin‐resistant OSCC cells. We found lower CerS6 expression in cisplatin‐resistant OSCC cells. Overexpression of CerS6 with lentivirus‐encoded CerS6 complementary DNA in cisplatin‐resistant OSCC cells increased cisplatin sensitivity. Overexpression of CerS6 enhanced mitochondrial fission and apoptosis and attenuated cisplatin‐induced autophagy in cisplatin‐resistant OSCC cells. Further investigation indicated that CerS6 might function through altering calpain expression to enhance cisplatin sensitivity. Cisplatin‐resistant OSCC cells xenografted onto a nude mouse model confirmed that CerS6 enhanced cisplatin chemotherapy sensitivity to reduce tumor volume. These data indicate that CerS6 could mediate an effective response to cisplatin in chemoresistant OSCC. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9416-9425, December 2018.
  

  July 27, 2018   doi: 10.1002/jcp.26815   open full text
• Effect of microRNA‐186 on oxidative stress injury of neuron by targeting interleukin 2 through the janus kinase‐signal transducer and activator of transcription pathway in a rat model of Alzheimer’s disease.
  Dong‐Mei Wu, Xin Wen, Yong‐Jian Wang, Xin‐Rui Han, Shan Wang, Min Shen, Shao‐Hua Fan, Juan Zhuang, Zi‐Feng Zhang, Qun Shan, Meng‐Qiu Li, Bin Hu, Chun‐Hui Sun, Jun Lu, Gui‐Quan Chen, Yuan‐Lin Zheng.
  Journal of Cellular Physiology. July 11, 2018
  --- - |2 Recent studies have proposed that microRNAs (miR) function as novel diagnostic and prognostic biomarkers and therapeutic targets in Alzheimer’s disease (AD), a common disease among the elderly. In the current study, we aim to explore the effect of miR‐186 on oxidative stress injury of neuron in rat models of AD with the involvement of the interleukin‐2 (IL2) and the Janus kinase/signal transducers and activators of transcription (JAK–STAT) pathways. AD rat models were established, and dual‐luciferase reporter assay and online software were used to confirm the targeting relationship between miR‐186 and IL2. Immunohistochemistry was used evaluating the positive rate of IL2. Afterward, to define the role of miR‐186 in AD, miR‐186, IL2, and JAK–STAT related protein (JAK2, STAT3) expressions were quantified. Cell proliferation was measured by 3‐(4,5‐dimethylthiazol‐2‐yl)2,5‐diphenyl tetrazolium bromide, and cell apoptosis was detected by flow cytometry. We observed downregulated miR‐186 and IL2 and upregulated JAK–STAT signaling pathway related genes in AD. The overexpression of miR‐186 was shown to significantly promote cell proliferation while suppressing cell apoptosis along with the expression of the IL2 and JAK–STAT signaling pathway related protein. Collectively, the key findings obtained from the current study define the potential role of miR‐186 as an inhibitor of AD development by downregulation of IL2 through suppression of the JAK–STAT signaling pathway. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9488-9502, December 2018.
  

  July 11, 2018   doi: 10.1002/jcp.26843   open full text
• Differentiated adipose‐derived stem cell cocultures for bone regeneration in RADA16‐I in vitro.
  Huifang Yang, Nanrui Hong, Hsiaowei Liu, Jieda Wang, Yan Li, Shuyi Wu.
  Journal of Cellular Physiology. July 11, 2018
  --- - |2- Craniofacial defects can cause morbidness. Adipose‐derived stem cells (ADSCs) have shown great promise for osteogeneration and vascularization; therefore cocultures of differentiated ADSCs are explored to increase bone and vessel formation. In this study, ADSCs were induced into osteogenic ADSCs (os‐ADSCs) and endothelial ADSCs (endo‐ADSCs) cells, which were then cocultured in variable proportions (os‐ADSCs/endo‐ADSCs = 2:1, 1:1, 1:2). The os‐ADSCs in a ratio of 1:1 expressed more ALP, RUNX2 and COL‐I, whereas VEGF, vWF and CD31 were upregulated in the endo‐ADSCs of this group. Next generation RNA sequencing (RNA‐seq) was performed to evaluate the molecular mechanisms of cocultured ADSCs. The os‐ADSCs and endo‐ADSCs interacted with each other during osteogenic and angiogenic differentiation, especially at the ratio of 1:1, and were regulated by vascular‐related genes, cell‐mediated genes, bone‐related genes and the transforming growth factor β signaling pathway (TGF‐β), mitogen‐activated protein kinase signaling pathway (MAPK) and wnt signaling pathway (Wnt). Angptl4, apoe, mmp3, bmp6, mmp13 and fgf18 were detected to be up‐regulated, and cxcl12 and wnt5a were down‐regulated. The results showed that the gene expression levels were consistent with that in RNA‐seq. The cells were then seeded into self‐assembling peptide RADA16‐I scaffolds as cocultures (1:1) and monocultures (ADSCs, os‐ADSCs, endo‐ADSCs). The results showed that the cells of all groups grew and proliferated well on the scaffolds, and the cocultured group exhibited better osteogeneration and vascularization. In conclusion, cocultured os‐ADSCs and endo‐ADSCs at the ratio of 1:1 showed strong osteogenic and angiogenic differentiation. There is a great potential for osteogenesis and vascularization by 3D culturing cells in a 1:1 ratio in self‐assembling peptide RADA16‐I scaffolds, which requires evaluation for bone regeneration in vivo. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9458-9472, December 2018.
  

  July 11, 2018   doi: 10.1002/jcp.26838   open full text
• Stable overexpression of p130/E2F4 affects the multipotential abilities of bone‐marrow‐derived mesenchymal stem cells.
  Xiwen Zhang, Jianxiao Chen, Airan Liu, Xiuping Xu, Ming Xue, Jingyuan Xu, Yi Yang, Haibo Qiu, Fengmei Guo.
  Journal of Cellular Physiology. July 10, 2018
  --- - |2- Bone‐marrow‐derived mesenchymal stem cells (MSCs) have great potential in transplantation medicine due to their multiple advantages. However, the controlled differentiation of MSCs is one of the key aspects of effective clinical transplantation. Growing evidence suggests that the cell cycle plays an important role in regulating differentiation, while p130 and E2F4 are key to cell cycle checkpoints. The aim of the study is to evaluate the effects and mechanism of p130/E2F4 on the multidifferentiation of MSCs. Our data showed that the transduction efficiencies of p130 or E2F4 mediated by lentiviral vectors were 80.3%–84.4%. p130 and E2F4 mRNA expression was significantly higher in MSC‐p130 and MSC‐E2F4 cells than in MSC normal control (NC) cells. Similar results were also observed for p130 and E2F4 protein expression. After osteogenic or adipogenic differentiation, the G1 phase was significantly delayed in the MSC‐p130 and MSC‐E2F4 groups compared with that in the MSC‐NC group. However, the G1 phase in the MSC‐p130 and MSC‐E2F4 groups did the opposite after chondrogenic differentiation. Moreover, overexpressing p130 or E2F4 significantly improved osteogenic differentiation while inhibiting adipogenic and chondrogenic differentiation of mouse MSCs (mMSCs). Moreover, overexpressing p130 or E2F4 significantly improved migration but not proliferation of mMSCs. Our data suggest that cell cycle regulation may be involved in p130/E2F4‐mediated changes in the multipotential abilities of bone‐marrow‐derived mMSCs. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9739-9749, December 2018.
  

  July 10, 2018   doi: 10.1002/jcp.26926   open full text
• Epithelial‐to‐mesenchymal transition and cancer stem cells contribute to breast cancer heterogeneity.
  Deli Hong, Andrew J. Fritz, Sayyed K. Zaidi, Andre J. Wijnen, Jeffrey A. Nickerson, Anthony N. Imbalzano, Jane B. Lian, Janet L. Stein, Gary S. Stein.
  Journal of Cellular Physiology. July 03, 2018
  --- - |2 Breast cancer is the most common cancer in women, and accounts for ~30% of new cancer cases and 15% of cancer‐related deaths. Tumor relapse and metastasis are primary factors contributing to breast cancer‐related deaths. Therefore, the challenge for breast cancer treatment is to sustain remission. A driving force behind tumor relapse is breast cancer heterogeneity (both intertumor, between different patients, and intratumor, within the same tumor). Understanding breast cancer heterogeneity is necessary to develop preventive interventions and targeted therapies. A recently emerging concept is that intratumor heterogeneity is driven by cancer stem cells (CSCs) that are capable of giving rise to a multitude of different cells within a tumor. Studies have highlighted linkage of CSC formation with epithelial‐to‐mesenchymal transition (EMT). In this review, we summarize the current understanding of breast cancer heterogeneity, links between EMT and CSCs, regulation of EMT by Runx transcription factors, and potential therapeutic strategies targeting these processes. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9136-9144, December 2018.
  

  July 03, 2018   doi: 10.1002/jcp.26847   open full text
• Endometrial pinopode biomarkers: Molecules and microRNAs.
  Fahimeh Zamani Rarani, Fatemeh Borhani, Bahman Rashidi.
  Journal of Cellular Physiology. July 03, 2018
  --- - |2 Ultrastructural changes on the apical surface of the luminal epithelium of the uterus are known as pinopodes. Their morphology in species and in special species is associated with different results about size, duration, and percentage of surface area covered by pinopodes. The content of pinopodes is different in rodents and humans. In mice and rats pinopodes have many vacuoles and no organelle that extends to the actin stalk above the microvilli. Human pinopodes do not have a large vacuole and contain the golgi complex, a rough endoplasmic reticulum, secretory vesicles, and mitochondria that extend from the entire cell surface. It has been suggested that pinopodes are good markers of endometrial receptivity and implantation window. There are several molecular markers related to the presence of pinopodes, including integrins, leukemia inhibiting factor (LIF), l‐selectin, HOXA10, glutaredoxin, glycodelinA, heparin‐binding epidermal growth factor, mucins, and microRNAs (miRNAs). Multiple lines of evidence have indicated that miRNAs could affect the expression of LIF and pinopodes in the endometrium and these molecules play key roles in implantation window processes. Here, we have summarized the morphology and function of pinopodes. Moreover, we have highlighted several molecules in relation to pinopodes that could be used as biomarkers. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9145-9158, December 2018.
  

  July 03, 2018   doi: 10.1002/jcp.26852   open full text
• High prevalence of serum IgG antibodies reacting to specific mimotopes of BK polyomavirus, a human oncogenic polyomavirus, in patients affected by uveal melanoma.
  Ilaria Bononi, Elisa Mazzoni, Silvia Pietrobon, Elena Torreggiani, Marika Rossini, Sara Violanti, Paolo Perri, Mauro Tognon, Fernanda Martini.
  Journal of Cellular Physiology. July 03, 2018
  --- - |2 The uveal melanoma (UM) is the most common human intraocular tumor. The BK polyomavirus (BKPyV) is a small DNA tumor virus whose footprints have been detected in different human cancers. BKPyV has oncogenic potential. Indeed, BKPyV, when inoculated into experimental animals, induces tumors of different histotypes, whereas in vitro, it transforms mammalian cells, including human cells from distinct tissues. In this investigation, the association between UM and BKPyV was studied employing indirect enzyme‐linked immunosorbent assays (ELISAs) using synthetic peptides that mimic BKPyV viral capsid 1 (VP1) antigens. Indirect ELISAs were used to detect serum IgG antibodies against this polyomavirus with oncogenic potential in samples from patients with UM and controls, represented by healthy subjects (HS). It was found that serum samples from patients with UM had a higher prevalence of BKPyV antibodies, 85% (51/60), compared with that detected in HS1, 62% (54/87), and HS2, 57% (68/120). The different prevalence of BKPyV antibodies detected in UM versus the two control groups, HS1 and HS2, is statistically significant (p < 0.005). Our immunologic data suggest a significantly higher prevalence of antibodies against BKPyV VP1 epitopes in serum samples from patients with UM compared with HS. These results indicate an association between UM and BKPyV, suggesting that this small DNA tumor virus may be a cofactor in the UM onset or progression. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9052-9059, December 2018.
  

  July 03, 2018   doi: 10.1002/jcp.26771   open full text
• Study on the mechanism behind lncRNA MEG3 affecting clear cell renal cell carcinoma by regulating miR‐7/RASL11B signaling.
  Hongchao He, Jun Dai, Ran Zhuo, Juping Zhao, Haofei Wang, Fukang Sun, Yu Zhu, Danfeng Xu.
  Journal of Cellular Physiology. July 03, 2018
  --- - |2 The goal of this research was to study the relationships between maternally expressed gene 3 (MEG3), microRNA‐7 (miR‐7), and RASL11B, and explore their influence on the progression of clear cell renal cell carcinoma (CCRCC). Microarray analysis was conducted using the data provided by The Cancer Genome Atlas. The expression levels of MEG3 and miR‐7 in CCRCC and adjacent tissue samples were ascertained by quantitative real‐time polymerase chain reaction (qRT‐PCR). The cell proliferation activity was unmasked by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, and cell apoptosis and cell cycle were investigated by flow cytometry. A dual luciferase reporter assay was used to verify target relationships. Wound healing assay and transwell assay were used to detect cell migration and invasion ability. Decreased MEG3 expression was observed in CCRCC tissues and cells. Overexpression of MEG3 accelerated apoptosis; inhibited cell proliferation, migration and invasion; and induced G0/G1 phase cell cycle arrest in CCRCC. MiR‐7, directly binding to MEG3, was overexpressed in the CCRCC tissues and could inhibit the apoptosis and promote the migration and invasion of CCRCC cells. RASL11B, lowly expressed in CCRCC, was a target of miR‐7. After the overexpression of RASL11B, G0/G1 phase cell cycle arrest was induced; cell apoptosis was promoted; and the proliferation, invasion, and migration of CCRCC cells were inhibited. MEG3 could up‐regulate RASL11B to inhibit the cell proliferation, invasion, and migration; induce G0/G1 cell cycle arrest; and promote cell apoptosis by suppressing miR‐7 in CCRCC. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9503-9515, December 2018.
  

  July 03, 2018   doi: 10.1002/jcp.26849   open full text
• The role of hypoxia‐inducible factor‐2 alpha in angiogenesis.
  Christina Befani, Panagiotis Liakos.
  Journal of Cellular Physiology. July 03, 2018
  --- - |2- Angiogenesis is a key enabling feature of mammalian embryonic development and tumor progression, which provides oxygen and nutrients that are required for vessel growth and tumor cell growth, respectively. Hypoxia is a driver of this phenomenon and is considered to be one of the most potent initiators of angiogenesis both in vitro and in vivo through stabilization of the transcription factors, hypoxia‐inducible factor‐1 and ‐2 (HIF‐1 and HIF‐2). Although these proteins are highly homologous, emerging evidence suggests that they have unique transcriptional targets and differential impact on angiogenesis. Although HIF‐1α is the best known and widely described isoform, recent studies suggest that HIF‐2α is a critical regulator of physiological and pathophysiological angiogenesis and, at least, the similiarly important as HIF‐1α. Indeed, HIF‐2α has been shown to regulate multiple aspects of angiogenesis, including cell proliferation, migration, maturation of blood vessels, and metastasis. In this review, we focus on recent insights into HIF‐2α expression, activation, and function under hypoxic and nonhypoxic conditions. We also summarize the current knowledge on the crosstalk between HIF‐2 and angiogenesis, describing reported phenotypical changes of HIF‐2α genetic models and HIF‐2 target genes implicated in angiogenesis. Finally, we provide a survey of recent pharmacologic strategies to specifically target HIF‐2 activity. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9087-9098, December 2018.
  

  July 03, 2018   doi: 10.1002/jcp.26805   open full text
• Nucleolin protects against doxorubicin‐induced cardiotoxicity via upregulating microRNA‐21.
  Hui Sun, Zhongyi Tong, Yeqing Fang, Bimei Jiang, Pengfei Liang, Yuting Tang, Yuanbin Li, Yanyang Wu, Xianzhong Xiao.
  Journal of Cellular Physiology. July 03, 2018
  --- - |2 Nucleolin is a multifunctional protein and participates in many important biological processes. Our previous study found that nucleolin protects the heart against myocardial ischemia–reperfusion injury. In this study, we aimed to investigate the role of nucleolin in doxorubicin (DOX)‐induced cardiotoxicity. The expression pattern of nucleolin in hearts subjected to DOX injury was investigated, and we found that administration of DOX induced nucleolin expression significantly in vivo and in vitro. Gene transfection and RNA interference approaches were used in cardiomyocytes to investigate the function of nucleolin. Nucleolin overexpression protects cardiomyocytes against DOX‐induced injury. Nucleolin‐ablated cardiomyocytes become susceptible to the injury induced by DOX. The hearts of cardiac‐myocyte‐specific nucleolin transgenic mice are more resistant to DOX injury. Furthermore, nucleolin upregulates microRNA(miRNA)‐21 expression in vivo and in vitro, and the miRNA‐21 inhibitor negates the protective effect of nucleolin against injury induced by DOX. These results have demonstrated that nucleolin is involved in the regulation of DOX‐induced cardiac injury and dysfunction via the regulation of miRNA‐21 expression, and may be a novel therapeutic target for DOX‐induced cardiotoxicity. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9516-9525, December 2018.
  

  July 03, 2018   doi: 10.1002/jcp.26854   open full text
• C6 ceramide motivates the anticancer sensibility induced by PKC412 in preclinical head and neck squamous cell carcinoma models.
  Yanyan Zhu, Chaojie Wang, Yun Zhou, Ning Ma, Jianwei Zhou.
  Journal of Cellular Physiology. July 03, 2018
  --- - |2 The purpose of this study was to evaluate the anti–head and neck squamous cell carcinoma (anti‐HNSCC) cell activity by C6 ceramide and multikinase inhibitor PKC412. Experiments were performed on HNSCC cell lines (SQ20B and SCC‐9) and primary human oral carcinoma cells. Results showed that PKC412 inhibited HNSCC cell proliferation without provoking apoptosis activation. Cotreatment of C6 ceramide significantly augmented PKC412‐induced lethality in HNSCC cells. PKC412 decreased Akt–mammalian target of rapamycin (mTOR) activation in HNSCC cells, facilitated with cotreatment of C6 ceramide. In contrast, exogenous expression of a constitutively active Akt restored Akt–mTOR activation and attenuated lethality by the cotreatment. We propose that Mcl‐1 is a primary resistance factor of PKC412. The cytotoxicity of PKC412 in HNSCC cells was potentiated with Mcl‐1 short hairpin RNA knockdown, but was attenuated with Mcl‐1 overexpression. Intriguingly, C6 ceramide downregulated Mcl‐1 in HNSCC cells. In vivo, PKC412 oral administration inhibited SQ20B xenograft tumor growth in severe combined immunodeficient mice. The antitumor activity of PKC412 was further sensitized with coadministration of liposomal C6 ceramide. Together, we suggest that PKC412 could be further studied as a promising anti‐HNSCC strategy, alone or in combination with C6 ceramide. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9437-9446, December 2018.
  

  July 03, 2018   doi: 10.1002/jcp.26831   open full text
• Cistanche deserticola polysaccharide attenuates osteoclastogenesis and bone resorption via inhibiting RANKL signaling and reactive oxygen species production.
  Dezhi Song, Zhen Cao, Zaibing Liu, Jennifer Tickner, Heng Qiu, Chao Wang, Kai Chen, Ziyi Wang, Shiwu Dong, Jiake Xu.
  Journal of Cellular Physiology. July 03, 2018
  --- - |2- Osteoporosis is a metabolic disease characterized by osteopenia and bone microstructural deterioration. Osteoclasts are the primary effector cells that degrade bone matrix and their abnormal function leads to the development of osteoporosis. Reactive oxygen species (ROS) accumulation during cellular metabolism promotes osteoclast proliferation and differentiation, therefore, playing an important role in osteoporosis. Cistanche deserticola polysaccharide (CDP) possesses antitumor, anti‐inflammatory, and antioxidant activity. However, the impact of CDP on osteoclasts is unclear. In this study, tartrate‐resistant acid phosphatase staining, immunofluorescence, reverse transcription‐polymerase chain reaction, and western blot analysis were utilized to demonstrate that CDP inhibited osteoclastogenesis and hydroxyapatite resorption. In addition, CDP also inhibited the expression of osteoclast maker genes including Ctsk, Mmp9, and Acp5 and had no effect on receptor activator of nuclear factor κB (RANK) expression. Mechanistic analyses revealed that CDP increases the expression of antioxidant enzymes to attenuate RANKL‐mediated ROS production in osteoclasts and inhibits nuclear factor of activated T cells and mitogen‐activated protein kinase activation. These results suggest that CDP may represent a candidate drug for the treatment of osteoporosis caused by excessive osteoclast activity. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9674-9684, December 2018.
  

  July 03, 2018   doi: 10.1002/jcp.26882   open full text
• Only a subpopulation of mouse sperm displays a rapid increase in intracellular calcium during capacitation.
  Guillermina M. Luque, Tomas Dalotto‐Moreno, David Martín‐Hidalgo, Carla Ritagliati, Lis C. Puga Molina, Ana Romarowski, Paula A. Balestrini, Liza J. Schiavi‐Ehrenhaus, Nicolas Gilio, Dario Krapf, Pablo E. Visconti, Mariano G. Buffone.
  Journal of Cellular Physiology. June 28, 2018
  --- - |2- Mammalian sperm must undergo a functionally defined process called capacitation to be able to fertilize oocytes. They become capacitated in vivo by interacting with the female reproductive tract or in vitro in a defined capacitation medium that contains bovine serum albumin, calcium (Ca2+), and bicarbonate (HCO3−). In this work, sperm were double stained with propidium iodide and the Ca2+ dye Fluo‐4 AM and analyzed by flow cytometry to determine changes in intracellular Ca2+ concentration ([Ca2+]i) in individual live sperm. An increase in [Ca2+]i was observed in a subpopulation of capacitated live sperm when compared with noncapacitated ones. Sperm exposed to the capacitating medium displayed a rapid increase in [Ca2+]i within 1 min of incubation, which remained sustained for 90 min. These rise in [Ca2+]i after 90 min of incubation in the capacitating medium was evidenced by an increase in the normalized median fluorescence intensity. This increase was dependent on the presence of extracellular Ca2+ and, at least in part, reflected the contribution of a new subpopulation of sperm with higher [Ca2+]i. In addition, it was determined that the capacitation‐associated [Ca2+]i increase was dependent of CatSper channels, as sperm derived from CatSper knockout (CatSper KO) or incubated in the presence of CatSper inhibitors failed to increase [Ca2+]i. Surprisingly, a minimum increase in [Ca2+]i was also observed in CatSper KO sperm suggesting the existence of other Ca2+ transport systems. Altogether, these results indicate that a subpopulation of sperm increases [Ca2+]i very rapidly during capacitation mainly due to a CatSper‐mediated influx of extracellular Ca2+. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9685-9700, December 2018.
  

  June 28, 2018   doi: 10.1002/jcp.26883   open full text
• RUMI is a novel negative prognostic marker and therapeutic target in non–small‐cell lung cancer.
  May Chammaa, Agnes Malysa, Carlos Redondo, Hyejeong Jang, Wei Chen, Gerold Bepler, Rodrigo Fernandez‐Valdivia.
  Journal of Cellular Physiology. June 28, 2018
  --- - |2- Recent comprehensive next‐generation genome and transcriptome analyses in lung cancer patients, several clinical observations, and compelling evidence from mouse models of lung cancer have uncovered a critical role for Notch signaling in the initiation and progression of non–small‐cell lung cancer (NSCLC). Notably, Rumi is a “protein O‐glucosyltransferase” that regulates Notch signaling through O‐glucosylation of Notch receptors, and is the only enzymatic regulator whose activity is required for both ligand‐dependent and ligand‐independent activation of Notch. We have conducted a detailed study on RUMI’s involvement in NSCLC development and progression, and have further explored the therapeutic potential of its targeting in NSCLC. We have determined that Rumi is highly expressed in the alveolar and bronchiolar epithelia, including club cells and alveolar type II cells. Remarkably, RUMI maps to the region of chromosome 3q that corresponds to the major signature of neoplastic transformation in NSCLC, and is markedly amplified and overexpressed in NSCLC tumors. Notably, RUMI expression levels are predictive of poor prognosis and survival in NSCLC patients. Our data indicates that RUMI modulates Notch activity in NSCLC cells, and that its silencing dramatically decreases cell proliferation, migration, and survival. RUMI downregulation causes severe cell cycle S‐phase arrest, increases genome instability, and induces late apoptotic–nonapoptotic cell death. Our studies demonstrate that RUMI is a novel negative prognostic factor with significant therapeutic potential in NSCLC, which embodies particular relevance especially when considering that, while current Notch inhibitory strategies target only ligand‐dependent Notch activation, a large number of NSCLCs are driven by ligand‐independent Notch activity. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9548-9562, December 2018.
  

  June 28, 2018   doi: 10.1002/jcp.26858   open full text
• Aerobic exercise, but not metformin, prevents reduction of muscular performance by AMPk activation in mice on doxorubicin chemotherapy.
  Edson A. Lima, Luís G. O. Sousa, Alexandre Abilio Teixeira, Andrea G. Marshall, Nelo E. Zanchi, José C. Rosa Neto.
  Journal of Cellular Physiology. June 28, 2018
  --- - |2- Doxorubicin (DOX) is a chemotherapy agent widely used in clinical practice, and it is very efficient in tumor suppression, but the use of DOX is limited by a strong association with the development of severe muscle atrophy and cardiotoxicity effects. Reversion or neutralization of the muscular atrophy can lead to a better prognosis. Recent studies have proposed that the negative effect of DOX on skeletal muscle is linked to its inhibition of AMP‐activated protein kinase (AMPk), a key mediator of cellular metabolism. On the basis of this, our goal was to evaluate if aerobic exercise or metformin treatment, activators of AMPk, would be able to attenuate the deleterious effects on skeletal muscle induced by the DOX treatment. C57BL6 mice received either saline (control) or DOX (2.5 mg/kg body weight) intraperitoneally, twice a week. The animals on DOX were further divided into groups that received adjuvant treatment in the form of moderate aerobic physical exercise (DOX+T) or metformin gavage (300 mg/body weight/day). Body weight, metabolism, distance run, muscle fiber cross‐sectional area (CSA), and protein synthesis and degradation were assessed. We demonstrated that aerobic training, but not metformin, associated with DOX increased the maximal aerobic capacity without changing muscle mass or fiber CSA, rescuing the muscle fatigue observed with DOX treatment alone. This improvement was associated with AMPk activation, thus surpassing the negative effects of DOX on muscle performance and bioenergetics. In conclusion, aerobic exercise increases AMPk activation and improved the skeletal muscle function, reducing the side effects of DOX. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9652-9662, December 2018.
  

  June 28, 2018   doi: 10.1002/jcp.26880   open full text
• HOXA11‐AS promotes the growth and invasion of renal cancer by sponging miR‐146b‐5p to upregulate MMP16 expression.
  Feng‐Qiang Yang, Jian‐Qiu Zhang, Jiang‐Jiang Jin, Chong‐Yi Yang, Wei‐Jie Zhang, Hai‐Ming Zhang, Jun‐Hua Zheng, Ze‐Ming Weng.
  Journal of Cellular Physiology. June 28, 2018
  --- - |2- Recently, increasing studies showed that long noncoding RNAs (lncRNAs) play critical roles in tumor progression. However, the function and underlying mechanism of HOMEOBOX A11 antisense RNA (HOXA11‐AS) on renal cancer remain unclear. In the current study, our data showed that the expression of HOXA11‐AS was significantly upregulated in clear cell renal cell carcinoma (ccRCC) tissues and cell lines. High HOXA11‐AS expression was associated with the advanced clinical stage, tumor stage, and lymph node metastasis. Function assays showed that HOXA11‐AS inhibition significantly suppressed renal cancer cells growth, invasion, and ETM phenotype. In addition, underlying mechanism revealed that HOXA11‐AS could act as a competing endogenous RNA (ceRNA) that repressed miR‐146b‐5p expression, which regulated its downstream target MMP16 in renal cancer. Taken together, our findings suggested that HOXA11‐AS could promote renal cancer cells growth and invasion by modulating miR‐146b‐5p–MMP16 axis. Thus, our findings suggested that HOXA11‐AS could serve as potential therapeutic target for the treatment of renal cancer. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9611-9619, December 2018.
  

  June 28, 2018   doi: 10.1002/jcp.26864   open full text
• NLRP3 inflammasome mediates chronic intermittent hypoxia‐induced renal injury implication of the microRNA‐155/FOXO3a signaling pathway.
  Xu Wu, Su Chi Chang, Jifu Jin, Wenyu Gu, Shanqun Li.
  Journal of Cellular Physiology. June 28, 2018
  --- - |2- Chronic intermittent hypoxia (CIH), as the foremost pathophysiological change of obstructive sleep apnea (OSA), contributes to continued deterioration in renal function. Nucleotide‐binding domain like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex that triggers innate immune responses to infection and cell stress through activation of caspase‐1 and maturation of inflammatory pro‐interleukin‐1β cytokine. Emerging evidence indicates that inhibition of the NLRP3 inflammasome ameliorates renal injury. Nevertheless, it is uncertain whether NLRP3 inflammasome participates in CIH‐induced renal injury. The molecular mechanisms modulating NLRP3 inflammasome activation remain to be elucidated. Compared with wild‐type mice, NLRP3 knockout mice dramatically protected them from kidney injury, as indicated by the restoration of creatinine levels, lessened histopathological alterations, and the suppression of macrophages infiltration stained with F4/80. NLRP3 deficiency notably reversed CIH‐induced oxidative stress (malondialdehyde and superoxide dismutase), concomitantly with the abrogated apoptosis‐related proteins and proinflammatory signaling pathway. Consistently, NLRP3‐deficient tubular cells remarkably inhibited reactive oxygen species generation and NLRP3 inflammasome activation. Furthermore, our study revealed that microRNA‐155 (miR‐155) was augmented in the renal tissue and HK‐2 cells exposed to CIH. In addition, we investigated the role of miR‐155 in the regulation of NLRP3 inflammasome. Inhibition of miR‐155 suppressed the CIH‐induced NLRP3 inflammasome activation in renal tubular cells, whereas overexpression of miR‐155 promoted oxidation and enhanced NLRP3 pathway. Collectively, we demonstrated that miR‐155 might be a positive‐regulator of NLRP3 pathway by inhibiting the targeted FOXO3a gene. These results established a link between the miR‐155/FOXO3a pathway and the NLRP3 inflammasome, suggesting pharmacological blockage of NLRP3 as a potential therapeutic strategy for OSA‐associated chronic kidney disease. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9404-9415, December 2018.
  

  June 28, 2018   doi: 10.1002/jcp.26784   open full text
• Fibroblasts and mesenchymal stem cells: Two sides of the same coin?
  Mathangi Soundararajan, Suresh Kannan.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2 Mesenchymal stem/stromal cells (MSCs) have gained considerable popularity owing to the vast possibilities and lack of ethical constraints and risks normally associated with other stem cells, such as embryonic stem cells. However, they are morphologically indistinguishable from fibroblasts. This review aims to assess the similarities and differences between the two cell types, and the possible relationship between them. We found that the two cells seem almost identical with respect to their surface immunophenotype, proliferation, and differentiation capacities and even, to an extent, their gene expression profiles and immunomodulatory capacities. There are some differences in capability between the two cells, with MSCs being more efficient than fibroblasts. Even so, the similarities are so striking, that, if we were to follow the current criteria provided by the International Society for Cellular Therapy, fibroblasts ought to be named as MSCs. One promising marker is their DNA methylation profiles. Nonetheless, without any other marker to differentiate between the cells in the first place, it would be difficult to find a definitive marker. Interestingly, the differences observed between the two cells have also been observed between young and old MSCs. This also seems to be true of certain cell surface markers. Therefore, it is possible that fibroblasts are in fact aged MSCs and that the two cells are the same. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9099-9109, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26860   open full text
• Adipokines, adiposity, and bone marrow adipocytes: Dangerous accomplices in multiple myeloma.
  Emma V. Morris, Claire M. Edwards.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2- Obesity has become a global epidemic influencing the establishment and progression of a wide range of diseases, such as diabetes, cardiovascular disease, and cancer. In 2016, International Agency for Research on Cancer reported that obesity is now associated with 13 different cancers, one of which is multiple myeloma (MM), a destructive cancer of plasma cells that predominantly reside in the bone marrow. Obesity is the accumulation of excess body fat, which causes metabolic, endocrine, immunologic, and inflammatory‐like changes. Obesity is usually associated with an increase in visceral and/or subcutaneous fat; however, an additional fat depot that also responds to diet‐induced changes is bone marrow adipose tissue (BMAT). There have been several studies over the past few decades that have identified BMAT as a key driver in MM progression. Adipocytes secrete numerous adipokines, such as leptin, adiponectin, resistin, adipsin, and visfatin, which when secreted at normal controlled levels have protective properties. However, in obesity these levels of secretion change, coupled with an increase in adipocyte number and size causing a profound and lasting effect on the bone microenvironment, contributing to MM cell growth, survival, and migration as well as potentially fueling bone destruction. Obesity is a modifiable risk factor making it an attractive option for targeted therapy. This review discusses the link between obesity, monoclonal gammopathy of undetermined significance (a benign condition that precedes MM), and myeloma, and the contribution of key adipokines to disease establishment and progression. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9159-9166, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26884   open full text
• Enhancing developmental rate and quality of mouse single blastomeres into blastocysts using a microplatform.
  Farshid Yekani, Mohammad Fazel‐Tabar, Reza Kowsari‐Esfahan, Philippe Renaud, Hanieh Kavand, Fereshteh Esfandiari, Mahnaz Azarnia, Leila Montazeri, Hossein Baharvand.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2- The present work reports the beneficial effects of using a microplatform on the development of mouse single blastomeres (SBs) to the blastocyst stage. Development of blastocysts from SBs separated from two‐ and four‐cell stage embryos (two‐ and four‐cell SBs) can provide a valuable supply both for couples who use fertility‐assisted techniques and farm animals. As a step forward, we introduce three chips that provide the possibility of culturing SBs separately, in groups, and in the vicinity of the intact embryo (co‐culture), while each well of the chips is assigned to an isolated SB. Two‐ and four‐cell SBs co‐cultured with intact embryos showed 97.1% and 76.6% developmental rates and up to 34.1% and 49.1% growth relative to the microdroplet method (control). We examined the quality of developed blastocysts by assessing the total cell number, the number of inner cell mass (ICM) according to the octamer‐binding transcription factor 4 marker (OCT4), and trophectoderm (TE). Co‐culture of SBs with an intact embryo in a chip with nanoscale culture medium volume also increased the cell population of the developed embryo. The ICM:TE ratio, which is the most important blastocyst quality parameter, also indicated that developed two‐cell SBs have a higher degree of similarity to intact embryos despite fewer numbers of total cells. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9070-9076, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26879   open full text
• Role of IL‐6‐mediated expression of NS5ATP9 in autophagy of liver cancer cells.
  Hongping Lu, Ming Han, Xiaoxue Yuan, Kelbinur Tursun, Yu Zhang, Yaru Li, Zhongshu Li, Shenghu Feng, Li Zhou, Zhipeng Pan, Qi Wang, Kai Han, Shunai Liu, Jun Cheng.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2+ This study aimed to investigate the relationship between interleukin‐6 (IL‐6) and NS5ATP9 in autophagy of liver cancer cells. Autophagy is one of the important regulators of the replication of hepatitis C virus and the survival of tumors. IL‐6 is a multifunctional cytokine that plays an important role in autophagy and development of many kinds of tumors. However, the role of IL‐6 in autophagy has not been fully explored. A previous study had shown that a novel gene, NS5ATP9, could modulate autophagy. The present study demonstrated that human IL‐6 recombinant protein induced autophagy of HepG2 cells. Conversely, autophagy decreased after IL‐6 was silenced or neutralized with monoclonal antibody against human IL‐6. In addition, NS5ATP9 was upregulated by IL‐6 via nuclear factor–kappaB activation, as detected by Western blot. Further studies indicated that the induction of autophagy by IL‐6 could be attenuated by silencing NS5ATP9. Interestingly, the expression of NS5ATP9, in turn, resulted in the upregulation of IL‐6. In conclusion, IL‐6 could induce autophagy by expressing NS5ATP9, while NS5ATP9 upregulated IL‐6 levels in turn, which further induced autophagy. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9312-9319, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26343   open full text
• PMLIV overexpression promotes TGF‐β‐associated epithelial–mesenchymal transition and migration in MCF‐7 cancer cells.
  Yu Liu, Jia‐Xin Wang, Di Huang, Bing Wang, Liang‐Liang Li, Xiu‐Xian Li, Ping Ni, Xing‐Li Dong, Wei Xia, Chun‐Xiao Yu, Wan‐Lu Xu, Wen‐Feng Chu, Dan Zhao.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2- The epithelial–mesenchymal transition (EMT) is a key event associated with metastasis and dissemination in breast tumor pathogenesis. Promyelocytic leukemia (PML) gene produces several isoforms due to alternative splicing; however, the biological function of each specific isoform has yet to be identified. In this study, we report a previously unknown role for PMLIV, the most intensely studied nuclear isoform, in transforming growth factor‐β (TGF‐β) signaling‐associated EMT and migration in breast cancer. This study demonstrates that PMLIV overexpression promotes a more aggressive mesenchymal phenotype and increases the migration of MCF‐7 cancer cells. This event is associated with activation of the TGF‐β canonical signaling pathway through the induction of Smad2/3 phosphorylation and the translocation of phospho‐Smad2/3 to the nucleus. In this study, we report a previously unknown role for PMLIV in TGF‐β signaling‐induced regulation of breast cancer‐associated EMT and migration. Targeting this pathway may be therapeutically beneficial. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9575-9583, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26862   open full text
• Cleavage of caspase‐12 at Asp94, mediated by endoplasmic reticulum stress (ERS), contributes to stretch‐induced apoptosis of myoblasts.
  Jing Song, Qiang Zhang, Shuai Wang, Fang Yang, Zhenggang Chen, Quanjiang Dong, Qiuxia Ji, Xiao Yuan, Dapeng Ren.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2- Mechanical overloading can lead to skeletal muscle damage instead of remodeling. This is attributed to the excessive apoptosis of myoblasts, mechanism of which remains to be elucidated. The present study aimed to investigate the involvement of endoplasmic reticulum stress (ERS) and caspase‐12 in mediating the stretch‐induced apoptosis of myoblasts. Myoblast apoptosis was evaluated by Hoechst staining, DNA fragmentation assay, Annexin V binding, and propidium iodide staining, as well as caspase‐3 and poly‐ADP‐ribose polymerase 1 cleavage. First, our results showed that apoptosis was elevated in a time‐dependent manner when myoblasts were subjected to cyclic mechanical stretch (CMS) for 12, 24, and 36 hr. Concomitantly, CMS triggered the ERS and caspase‐12 cleavage; ERS inhibitor GSK 2606414 suppressed the CMS‐induced cleavage of caspase‐12 and myoblast apoptosis. Silencing caspase‐12 attenuated the apoptosis of myoblasts under CMS. Furthermore, CMS‐induced myoblast apoptosis was partially recovered by overexpressing wild‐type caspase‐12 in caspase‐12‐silenced myoblasts. In contrast, overexpressing mutant caspase‐12 (D94N), which cannot be cleaved into the active caspase‐12 fragments, failed to accomplish the same effect. Finally, C2C12 overexpressing truncated caspase‐12 segment (TC‐casp12‐D94), which starts from Asp94 and ends at Asn419, underwent apoptosis under both static and stretched conditions. Interestingly, C2C12 myoblasts seemed to be resistant to stretch‐induced apoptosis upon low‐serum‐induced differentiation. In conclusion, our study provided evidence that caspase‐12 cleavage at Asp94, induced by ERS under mechanical stimuli, is the key molecule in initiating the stretch‐triggered apoptosis of myoblasts. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9473-9487, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26840   open full text
• ΔFosB regulates rosiglitazone‐induced milk fat synthesis and cell survival.
  Xuefeng Wei, Hui Li, Guangwei Zhao, Jiameng Yang, Lihui Li, Yongzhen Huang, Xianyong Lan, Yun Ma, Linyong Hu, Huiling Zheng, Hong Chen.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2+ Rosiglitazone induces adipogenesis in adipocyte and regulates cell survival and differentiation in number of cell types. However, whether PPARγ regulates the synthesis of milk fat and cell survival in goat mammary gland remains unknown. Rosiglitazone strongly enhanced cellular triacylglycerol content and accumulation of lipid droplet in goat mammary epithelial cells (GMEC). Furthermore, ΔFosB decreased the expression of PPARγ at both mRNA and protein levels, and rosiglitazone‐induced milk fat synthesis was abolished by ΔFosB overexpression. ΔFosB reduced milk fat synthesis and enhanced saturated fatty acid concentration. Rosiglitazone increased the number of GMEC in G0/G1 phase and inhibited cell proliferation, and these effects were improved by overexpression of ΔFosB. ΔFosB was found to promote the expression of Bcl‐2 and suppress the expression of Bax, and protected GMEC from apoptosis induced by rosiglitazone. Intracellular calcium trafficking assay revealed that rosiglitazone markedly increased intracellular calcium concentration. ΔFosB protected GMEC from apoptosis induced by intracellular Ca2+ overload. ΔFosB increased MMP‐9 gelatinolytic activity. SB‐3CT, an MMP‐9 inhibitor, suppressed the expression of Bcl‐2, and increased intracellular calcium levels, and this effect was abolished by ΔFosB overexpression. SB‐3CT induced GMEC apoptosis and this effect was inhibited by ΔFosB overexpression. These findings suggest that ΔFosB regulates rosiglitazone‐induced milk fat synthesis and cell survival. Therefore, ΔFosB may be an important checkpoint to control milk fat synthesis and cell apoptosis. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9284-9298, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26218   open full text
• Oxidative stress regulates autophagy in cultured muscle cells of patients with chronic obstructive pulmonary disease.
  Fares Gouzi, Marine Blaquière, Matthias Catteau, François Bughin, Jonathan Maury, Emilie Passerieux, Bronia Ayoub, Jacques Mercier, Maurice Hayot, Pascal Pomiès.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2- The proteolytic autophagy pathway is enhanced in the lower limb muscles of patients with chronic obstructive pulmonary disease (COPD). Reactive oxygen species (ROS) have been shown to regulate autophagy in the skeletal muscles, but the role of oxidative stress in the muscle autophagy of patients with COPD is unknown. We used cultured myoblasts and myotubes from the quadriceps of eight healthy subjects and twelve patients with COPD (FEV1% predicted: 102.0% and 32.0%, respectively; p < 0.0001). We compared the autophagosome formation, the expression of autophagy markers, and the autophagic flux in healthy subjects and the patients with COPD, and we evaluated the effects of the 3‐methyladenine (3‐MA) autophagy inhibitor on the atrophy of COPD myotubes. Autophagy was also assessed in COPD myotubes treated with an antioxidant molecule, ascorbic acid. Autophagosome formation was increased in COPD myoblasts and myotubes (p = 0.011; p < 0.001), and the LC3 2/LC3 1 ratio (p = 0.002), SQSTM1 mRNA and protein expression (p = 0.023; p = 0.007), BNIP3 expression (p = 0.031), and autophagic flux (p = 0.002) were higher in COPD myoblasts. Inhibition of autophagy with 3‐MA increased the COPD myotube diameter (p < 0.001) to a level similar to the diameter of healthy subject myotubes. Treatment of COPD myotubes with ascorbic acid decreased ROS concentration (p < 0.001), ROS‐induced protein carbonylation (p = 0.019), the LC3 2/LC3 1 ratio (p = 0.037), the expression of SQSTM1 (p < 0.001) and BNIP3 (p < 0.001), and increased the COPD myotube diameter (p < 0.001). Thus, autophagy signaling is enhanced in cultured COPD muscle cells. Furthermore, the oxidative stress level contributes to the regulation of autophagy, which is involved in the atrophy of COPD myotubes in vitro. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9629-9639, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26868   open full text
• P2Y12 shRNA treatment decreases SGC activation to relieve diabetic neuropathic pain in type 2 diabetes mellitus rats.
  Shouyu Wang, Zilin Wang, Lin Li, Lifang Zou, Yingxin Gong, Tianyu Jia, Shanhong Zhao, Huilong Yuan, Liran Shi, Shuangmei Liu, Bing Wu, Zhihua Yi, Hui Liu, Yun Gao, Guilin Li, Jan M. Deussing, Man Li, Chunping Zhang, Shangdong Liang.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2- Diabetic neuropathic pain is a common complication of type 2 diabetes mellitus (DM). Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in neuropathic pain through the release of proinflammatory cytokines. The P2Y12 receptor is expressed in SGCs of the DRG. In this study, our aim was to investigate the role of the P2Y12 receptor on the pathological changes in diabetic neuropathic pain. The present study showed that diabetic neuropathic pain increased mechanical and thermal hyperalgesia in type 2 DM model rats. The results showed that the expression levels of P2Y12 messenger RNA (mRNA) and protein in DRG SGCs were increased in DM model rats compared with control rats. Glial fibrillary acidic protein (GFAP) and interleukin‐1β (IL‐1β) expression levels in the DRG were increased in DM rats. Upregulation of GFAP is a marker of SGC activation. Targeting the P2Y12 receptor by short hairpin RNA (shRNA) decreased the upregulated expression of P2Y12 mRNA and protein, coexpression of P2Y12 and GFAP, the expression of GFAP, IL‐1β, and tumor necrosis factor‐receptor 1 in the DRG of DM rats, and relieved mechanical and thermal hyperalgesia in DM rats. After treatment with the P2Y12 receptor shRNA, the enhancing integrated OPTICAL density (IOD) ratios of p‐P38 MAPK to P38 mitogen activated protein kinase (MAPK) in the DM rats treated with P2Y12 shRNA were significantly lower than that in the untreated DM rats. Therefore, P2Y12 shRNA treatment decreased SGC activation to relieve mechanical and thermal hyperalgesia in DM rats. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9620-9628, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26867   open full text
• A new copper ionophore DPMQ protects cells against ultraviolet B irradiation by inhibiting the TRPV1 channel.
  Kuo‐Feng Huang, Kuo‐Hsing Ma, Yu‐Chien Hung, Liang‐Chuan Lo, Kuo‐Chen Lin, Pei‐Shan Liu, Ming‐Kuan Hu, Sheau‐Huei Chueh.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2- Copper is more likely than iron to generate reactive oxygen species (ROS) in a redox reaction due to its higher electrochemical reactivity. This study examined the effect of a newly synthesized Cu2+ binding compound, (E)‐2‐(4‐(dimethylamino)phenylimino)methyl)quinolin‐8‐ol (DPMQ), on ultraviolet B (UVB) irradiation–induced cytotoxicity in human dermal fibroblasts. DPMQ induced Cu2+ influx as effectively as disulfiram, a Cu2+ ionophore anticancer drug. However, disulfiram induced ROS generation, mitochondrial dysfunction, and apoptosis in fibroblasts in a Cu2+‐dependent manner, whereas DPMQ was not only nontoxic, but protected cells against UVB irradiation–induced apoptosis in a Cu2+‐independent manner. UVB irradiation induced a Ca2+‐dependent increase in ROS generation, a decrease in Nrf2 levels, and activation of the mitochondrial apoptotic pathway, and these effects were prevented by DPMQ, which also increased Nrf2 nuclear translocation in a Cu2+‐independent manner. UVB irradiation activated 12‐lipoxygenase and 12‐hydroxyeicosatetraenoic acid (12‐HETE), a product of 12‐lipoxygenase, activated the TRPV1 channel. DMPQ did not act as a Ca2+ chelator, but inhibited the cytosolic Ca2+ increase induced by 12‐HETE or capsaicin, but not that induced by bradykinin or ATP. Blockade of Ca2+ influx by pharmacological inhibition or silencing of the TRPV1 channel or chelation of cytosolic Ca2+ inhibited the UVB irradiation–induced Nrf2 reduction, ROS generation, mitochondrial dysfunction, and apoptosis. Taken together, our results suggest that Ca2+ influx via the TRPV1 channel is responsible for UVB irradiation–induced cytotoxicity and that DPMQ protects cells against UVB irradiation by inhibiting the TRPV1 channel and stabilizing Nrf2, and could thus be a potentially useful compound for the treatment of free radical‐induced diseases. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9594-9610, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26861   open full text
• Zerumbone inhibits epithelial‐mesenchymal transition and cancer stem cells properties by inhibiting the β‐catenin pathway through miR‐200c.
  Fatemeh Karimi Dermani, Razieh Amini, Massoud Saidijam, Mona Pourjafar, Sahar Saki, Rezvan Najafi.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2- Colorectal cancer (CRC) is one of the most lethal and rampant human malignancies in the world. Zerumbone, a sesquiterpene isolated from subtropical ginger, has been found to exhibit an antitumor effect in various cancer types. However, the effect of Zerumbone on the biological properties of CRC, including epithelial‐mesenchymal transition (EMT) and cancer stem cells (CSCs) has not been fully elucidated. Here, we investigated the inhibitory action of Zerumbone on the EMT process, CSC markers, and the β‐catenin signaling pathway in the presence or absence of miR‐200c. The effect of Zerumbone on HCT‐116 and SW‐48 cells viability was examined by 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide assay. The effects of Zerumbone on EMT‐related genes, CSCs markers, cell migration, invasion, sphere‐forming, and β‐catenin signaling pathway were explored. To evaluate the role of miR‐200c in anticancer effects by Zerumbone, miR‐200c was downregulated by LNA‐anti‐miR‐200c. Zerumbone significantly inhibited cell viability, migration, invasion, and sphere‐forming potential in HCT‐116 and SW‐48 cell lines. Zerumbone significantly suppressed the EMT and CSC properties as well as downregulated the β‐catenin. Silencing of miR200c reduced the inhibitory effects of Zerumbone on EMT and CSCs in CRC cells. These data indicated that Zerumbone may be a promising candidate for reducing the risk of CRC progression by suppressing the β‐catenin pathway via miR‐200c. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9538-9547, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26874   open full text
• Influence of all‐trans retinoic acid on sperm metabolism and oxidative stress: Its involvement in the physiopathology of varicocele‐associated male infertility.
  Rocco Malivindi, Vittoria Rago, Daniela De Rose, Maria Clelia Gervasi, Erika Cione, Giampiero Russo, Marta Santoro, Saveria Aquila.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2 The mechanisms by which varicocele affects fertility remain undetermined. Vitamin A (all‐trans retinoic acid [ATRA]) is required for fertility and normal spermatogenesis; however, the mechanisms driving its action are not defined yet. Previously, we demonstrated in varicocele sperm a reduced RARα expression and that ATRA influence sperm performance. To further define vitamin A significance in male gamete and in the physiopathology of varicocele, we tested for the first time ATRA action on human sperm metabolism and antioxidant defense systems. Evaluating triglycerides content and lipase activity, in normal sperm ATRA had a lipid lowering effect, which was not observed in varicocele sperm. The modulation of the glucose‐6‐phosphate dehydrogenase activity, concomitantly with a reduction of the glucose content, highlight an ATRA role on glucose metabolism. ATRA induced the superoxide dismutase (SOD) and glutathione transferase activities, while it reduced the malondialdehyde and reactive oxygen species (ROS) production both in healthy and varicocele sperm. Interestingly, SOD1 and SOD2 have been localized in the acrosome and midpiece, glutathione‐ S‐transferase omega 2 (GSTO2) in the acrosome, equatorial, and subacrosomial regions. SOD1, SOD2, and GSTO2 levels were significantly lower in varicocele with respect to healthy sperm. Herein, we discovered that ATRA treatment was able to reprogram sperm metabolism toward that of the capacitation status. The retinol protected human sperm from ROS damage enhancing the antioxidant enzymes activity, providing evidence toward the efficacy of vitamin A as therapeutic tool in improving sperm quality. These novel findings further confirm the importance of vitamin A in male fertility adding new insights into the retinoids complex biological framework. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9526-9537, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26872   open full text
• BMAL1 and CLOCK proteins in regulating UVB‐induced apoptosis and DNA damage responses in human keratinocytes.
  Yang Sun, Peiling Wang, Hongyu Li, Jun Dai.
  Journal of Cellular Physiology. June 26, 2018
  --- - |2- A diverse array of biological processes are under circadian controls. In mouse skin, ultraviolet ray (UVR)‐induced apoptosis and DNA damage responses are time‐of‐day dependent, which are controlled by core clock proteins. This study investigates the roles of clock proteins in regulating UVB responses in human keratinocytes (HKCs). We found that the messenger RNA expression of brain and muscle ARNT‐like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) genes is altered by low doses (5 mJ/cm2) of UVB in the immortalized HaCat HKCs cell line. Although depletion of BMAL1 or CLOCK has no effect on the activation of Rad3‐related protein kinases–checkpoint kinase 1–p53 mediated DNA damage checkpoints, it leads to suppression of UVB‐stimulated apoptotic responses, and downregulation of UVB‐elevated expression of DNA damage marker γ‐H2AX and cell cycle inhibitor p21. Diminished apoptotic responses are also observed in primary HKCs depleted of BMAL1 or CLOCK after UVB irradiation. While CLOCK depletion shows a suppressive effect on UVB‐induced p53 protein accumulation, depletion of either clock gene triggers early keratinocyte differentiation of HKCs at their steady state. These results suggest that UVB‐induced apoptosis and DNA damage responses are controlled by clock proteins, but via different mechanisms in the immortalized human adult low calcium temperature and primary HKCs. Given the implication of UVB in photoaging and photocarcinogenesis, mechanistic elucidation of circadian controls on UVB effects in human skin will be critical and beneficial for prevention and treatment of skin cancers and other skin‐related diseases. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9563-9574, December 2018.
  

  June 26, 2018   doi: 10.1002/jcp.26859   open full text
• Gut microbiota‐derived endotoxin enhanced the incidence of cardia bifida during cardiogenesis.
  Jing Zhang, Guang Wang, Jia Liu, Lin‐rui Gao, Meng Liu, Chao‐jie Wang, Manli Chuai, Yongping Bao, Ge Li, Rui‐man Li, Yu Zhang, Xuesong Yang.
  Journal of Cellular Physiology. June 22, 2018
  --- - |2+ Cytotoxicity and inflammation‐associated toxic responses could be induced by bacterial lipopolysaccharides (LPS) in vitro and in vivo, respectively. However, the mechanism involved in LPS‐induced cardiac malformation in prenatal fetus is still unknown. In this study, we demonstrated that LPS was induced in gut microbiota imbalance mice, and next, LPS exposure during gastrulation in the chick embryo increased the incidence of cardia bifida. Gene transfection and tissue transplantation trajectory indicated that LPS exposure restricted the cell migration of cardiac progenitors to primary heart field in gastrula chick embryos. In vitro explant allograft of GFP‐labeled anterior primitive streak demonstrated that LPS treatments could inhibit cell migration. A similar observation was also obtained from the cell migration assay of scratch wounds using primary culture of cardiomyocytes or H9c2 cells. In the embryos exposed to LPS, expressions of Nkx2.5 and GATA5 were disturbed. These genes are associated with cardiomyocyte differentiation when heart tube fusion occurs. Furthermore, pHIS3, C‐caspase3 immunohistological staining indicated that cell proliferation decreased, cell apoptosis increased in the heart tube of chick embryo. Meanwhile, in vivo, pHIS3 immunohistological staining and Hochest/PI staining also draw the similar conclusions. The LPS exposure also caused the production of excess ROS, which might damage the cardiac precursor cells of developing embryos. At last, we showed that LPS‐induced cardia bifida could be partially rescued through the addition of antioxidants. Together, these results reveal that excess ROS generation is involved in the LPS‐induced defects in heart tube during chick embryo development. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9271-9283, December 2018.
  

  June 22, 2018   doi: 10.1002/jcp.26175   open full text
• Serum C‐reactive protein in the prediction of cardiovascular diseases: Overview of the latest clinical studies and public health practice.
  Amir Avan, Seyedeh Belin Tavakoly Sany, Majid Ghayour‐Mobarhan, Hamid Reza Rahimi, Mohammad Tajfard, Gordon Ferns.
  Journal of Cellular Physiology. June 22, 2018
  --- - |2- Cardiovascular disease is the most common cause of morbidity and mortality globally. Epidemiological studies using high‐sensitivity assays for serum C‐reactive protein have shown a consistent association between cardiovascular disease risk and serum C‐reactive protein concentrations. C‐reactive protein is a biomarker for inflammation, and has been established in clinical practice as an independent risk factor for cardiovascular disease events. There is evidence that serum C‐reactive protein is an excellent biomarker of cardiovascular disease and is also an independent and strong predictor of adverse cardiovascular events. Further characterization of the impact and influence of lifestyle exposures and genetic variation on the C‐reactive protein response to cardiovascular disease events may have implications for the therapeutic approaches to reduce cardiovascular disease events. This review summarizes the studies that have examined the association between serum C‐reactive protein and the risk of cardiovascular disease. We also discuss the impact of independent factors and C‐reactive protein genetic polymorphisms on baseline plasma C‐reactive protein levels. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8508-8525, November 2018.
  

  June 22, 2018   doi: 10.1002/jcp.26791   open full text
• Potential role of microRNAs in the regulation of adipocytes liposecretion and adipose tissue physiology.
  Giulia Maurizi, Lucia Babini, Lucio Della Guardia.
  Journal of Cellular Physiology. June 22, 2018
  --- - |2+ Adipose tissue is a dynamic endocrine organ playing a pivotal role in metabolism modulation. Adipocytes differentiation requires a highly orchestrated series of changes of gene expression in precursor cells. At the same time, white mature adipocytes are plastic cells able to reversibly transdifferentiate toward fibroblast‐like cells via the liposecretion process, returning back to a non‐committed status of the cells. In particular, adipose tissue microenvironment along with external signaling molecules such as adipokines, cytokines and growth factors can regulate adipocytes physiology through complex molecular networks. MicroRNAs (miRNAs), a type of non‐coding RNA, acting as fine regulators of biological processes and their expression is sensible to the environment and cellular status changes. MiRNAs are thought to play a pivotal role in regulating the physiology of adipose tissue as well as in the development of obesity and associated metabolic disturbances, although the underlying mechanisms have not been identified so far. Elucidating the molecular mechanisms orchestrating adipose tissue biology is required to better characterize obesity and its associated diseases. In this respect, the review aims to analyze the microRNAs potentially involved in adipogenesis highlighting their role in the process of liposecretion, adipocyte proliferation, and adipokines secretion. The role of microRNAs in the development of obesity and obesity‐associated disorders is also discussed. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9077-9086, December 2018.
  

  June 22, 2018   doi: 10.1002/jcp.26523   open full text
• Network analysis of hippocampal neurons by microelectrode array in the presence of HIV‐1 Tat and cocaine.
  Taha Mohseni Ahooyi, Masoud Shekarabi, Emilie A. Decoppet, Dianne Langford, Kamel Khalili, Jennifer Gordon.
  Journal of Cellular Physiology. June 22, 2018
  --- - |2+ HIV‐associated neurocognitive disorders affecting greater than 30% of patients are caused by HIV‐1 infection of the CNS, and in part, include neurotoxic effects of the viral transactivator of transcription, Tat protein. In addition to increasing the risk for becoming HIV infected, cocaine abuse enhances the neuropathogenic impacts of HIV‐1. To investigate the outcome of Tat and cocaine interference in the hippocampal neuronal network, cross‐rank‐corrlation was employed to develop a systematic framework to assess hippocampal neurons behavior cultured on multielectrode arrays. Tat and cocaine differentially disturbed neuronal spiking rates, amplitude, synchronous activity, and oscillations within the hippocampal neuronal network via potentiation of inhibitory neurotransmission. The Tat‐mediated impairment of neuronal spiking was reversible by removal of Tat, which restored neuronal activity. The presence of astrocytes co‐cultured with neuronal networks diminished the effects of Tat and cocaine on neuron function suggesting a role for astrocytes in stabilizing neuronal behavior and increasing neuronal spontaneous activities such as bursting amplitude, frequency, and wave propagation rate. Taken together, our studies indicate that the HIV protein Tat and cocaine impair hippocampal neuronal network functioning and that the presence of astrocytes alleviates network dysfunction pointing to a newly discovered pathway through which ionic homeostasis is maintained by neuron‐glial crosstalk in the CNS. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9299-9311, December 2018.
  

  June 22, 2018   doi: 10.1002/jcp.26322   open full text
• EGFL7: Master regulator of cancer pathogenesis, angiogenesis and an emerging mediator of bone homeostasis.
  Guoju Hong, Vincent Kuek, Jiaxi Shi, Lin Zhou, Xiaorui Han, Wei He, Jennifer Tickner, Heng Qiu, Qiushi Wei, Jiake Xu.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2 Epidermal growth factor‐like domain‐containing protein 7 (EGFL7), a member of the epidermal growth factor (EGF)‐like protein family, is a potent angiogenic factor expressed in many different cell types. EGFL7 plays a vital role in controlling vascular angiogenesis during embryogenesis, organogenesis, and maintaining skeletal homeostasis. It regulates cellular functions by mediating the main signaling pathways (Notch, integrin) and EGF receptor cascades. Accumulating evidence suggests that Egfl7 plays a crucial role in cancer biology by modulating tumor angiogenesis, metastasis, and invasion. Dysregulation of Egfl7 has been frequently found in several types of cancers, such as malignant glioma, colorectal carcinoma, oral and oesophageal cancers, gastric cancer, hepatocellular carcinoma, pancreatic cancer, breast cancer, lung cancer, osteosarcoma, and acute myeloid leukemia. In addition, altered expression of miR‐126, a microRNA associated with Egfl7, was found to play an important role in oncogenesis. More recently, our study has shown that EGFL7 is expressed in both the osteoclast and osteoblast lineages and promotes endothelial cell activities via extracellular signal‐regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3), and integrin signaling cascades, indicative of its angiogenic regulation in the bone microenvironment. Thus, understanding the role of EGFL7 may provide novel insights into the development of improved diagnostics and therapeutic treatment for cancers and skeletal pathological disorders, such as ischemic osteonecrosis and bone fracture healing. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8526-8537, November 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26792   open full text
• Circulating microRNAs as diagnostic and therapeutic biomarkers in gastric and esophageal cancers.
  Leila Jamali, Roghayeh Tofigh, Sara Tutunchi, Ghodratollah Panahi, Fatemeh Borhani, Saeedeh Akhavan, Parisa Nourmohammadi, Sayyed M.H. Ghaderian, Milad Rasouli, Hamed Mirzaei.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2 Gastric and esophageal cancers are as main cancers of the gastrointestinal (GI) tract, which are associated with poor diagnosis and survival. Several efforts were made in the past few decades to finding effective therapeutic approaches, but these approaches had several problems. Finding new biomarkers is a critical step in finding new approaches for the treatment of these cancers. Finding new biomarkers that cover various aspects of the diseases could provide a choice of suitable therapies and better monitoring of patients with these cancers. Among several biomarkers tissue specific and circulating microRNAs (miRNAs) have emerged as powerful candidates in the diagnosis of gastric and esophageal cancers. MiRNAs are small noncoding single‐stranded RNA molecules that are found in the blood and regulate gene expression. These have numerous characteristics that make them suitable for being used as ideal biomarkers in cancer diagnosis. Research has indicated that the level and profile of miRNA in serum and plasma are very high. They are potentially noninvasive and sensitive enough to detect tumors in their primary stages of infection. Multiple lines of evidence indicate that the presence, absence, or deregulation of several circulating miRNAs (i.e., let‐7a, miR‐21, miR‐93, miR‐192a, miR‐18a, and miR‐10b for gastric cancer, and miR‐21, miR‐375, miR‐25‐3p, miR‐151a‐3p, and miR‐100‐3p for esophageal cancer) are associated with initiation and progression of gastric and esophageal cancers. The aim of this review is to highlight the recent advances in the roles of miRNAs in diagnosis and treatment of gastric and esophageal cancers. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8538-8550, November 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26850   open full text
• Transdifferentiation of human gingival mesenchymal stem cells into functional keratinocytes by Acalypha indica in three‐dimensional microenvironment.
  Dinesh Murugan Girija, Mangathayaru Kalachaveedu, Suresh Ranga Rao, Rajasekaran Subbarayan.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2 Gingival tissue is reportedly a promising, easily accessible, abundant resource of mesenchymal stem cells (MSC) for use in various tissue engineering strategies. Human gingival MSC (HGMSCs) were successfully isolated from gingival tissue and characterized. To analyze in a two‐dimensional form, HGMSCs were cultured with basal medium and induced with 25 µg/ml of Acalypha indica. Quantitative real‐time polymerase chain reaction (qPCR) and western blot analysis showed the presence of keratinocyte‐specific markers, including cytokeratin‐5 and involucrin. To further assess its capability for stratification akin to human keratinocytes, HGMSCs were encapsulated in a HyStem®‐HP Cell Culture Scaffold Kit and cultured in the presence of A. indica. Calcein AM staining indicated that the HyStem®‐HP Scaffold Kit has excellent biocompatibility. Immunofluorescence and qPCR analysis revealed the presence of keratinocyte‐specific markers. The study concluded that the three‐dimensional microenvironment is a novel method for inducing epidermal differentiation of HGMSCs to engineer epidermal substitutes with the help of A. indica, which provides an alternative strategy for skin tissue engineering. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8450-8457, November 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26807   open full text
• Promotion of the prehierarchical follicle growth by postovulatory follicles involving PGE2–EP2 signaling in chickens.
  Xin Lin, Xingting Liu, Changquan Guo, Mengqi Liu, Yuling Mi, Caiqiao Zhang.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2 The postovulatory follicle (POF) in birds is an enigmatic structure, the function of which remains largely unknown. Previous studies on chickens have shown that removal of POFs leads to the postponement of oviposition and the disturbance of broody behavior. One suggestion is that POFs may secrete some crucial hormones or cytokines to act on reproductive organs. However, such secretions and their specific target organs remain to be identified. Here, we investigate the putative functions of POFs in promoting the development of prehierarchical follicles in chickens and explore the possible signaling mechanisms controlling these processes. Results show that POFs express steroidogenic acute regulatory protein (STAR), cholesterol side‐chain cleavage enzyme (CYP11A1), cyclooxygenase 1 (COX1), and COX2 in granulosa cells (GCs), and, most notably, that POF1 produces more prostaglandin E2 (PGE2) or prostaglandin F2α than do the F1 follicle or the other POFs. Using coculture systems, we also found that POF1 or GCs from POF1 (POF1‐GCs) significantly promote the proliferation of theca externa cells of small white follicles (SWFs, one phase of the prehierarchical follicle). Treatment with PGE2 significantly facilitates theca externa cell proliferation in SWFs. This POF‐stimulating effect on SWF growth was prevented by treatment with indomethacin (COX inhibitor) or TG6‐10‐1 (PGE2 type 2 receptor [EP2] antagonist). Therefore, POF1 may secrete PGE2 to stimulate the progression of SWF by PGE2–EP2 signaling. These results indicate that POF1 may serve as a transient supplementary endocrine gland in the chicken ovary that stimulates the development of the prehierarchical follicles through PGE2–EP2 signaling. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8984-8995, November 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26844   open full text
• Establishment of an in vitro organoid model of dermal papilla of human hair follicle.
  Abhishak C. Gupta, Shikha Chawla, Ashok Hegde, Divya Singh, Balaji Bandyopadhyay, Chandrasekharan C. Lakshmanan, Gurpreet Kalsi, Sourabh Ghosh.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2 Human hair dermal papilla (DP) cells are specialized mesenchymal cells that play a pivotal role in hair regeneration and hair cycle activation. The current study aimed to first develop three‐dimensional (3D) DP spheroids (DPS) with or without a silk–gelatin (SG) microenvironment, which showed enhanced DP‐specific gene expression, resulting in enhanced extracellular matrix (ECM) production compared with a monolayer culture. We tested the feasibility of using this DPS model for drug screening by using minoxidil, which is a standard drug for androgenic alopecia. Minoxidil‐treated DPS showed enhanced expression of growth factors and ECM proteins. Further, an attempt has been made to establish an in vitro 3D organoid model consisting of DPS encapsulated by SG hydrogel and hair follicle (HF) keratinocytes and stem cells. This HF organoid model showed the importance of structural features, cell–cell interaction, and hypoxia akin to in vivo HF. The study helped to elucidate the molecular mechanisms to stimulate cell proliferation, cell viability, and elevated expression of HF markers as well as epithelial–mesenchymal crosstalks, demonstrating high relevance to human HF biology. This simple in vitro DP organoid model system has the potential to provide significant insights into the underlying mechanisms of HF morphogenesis, distinct molecular signals relevant to different stages of the hair cycle, and hence can be used for controlled evaluation of the efficacy of new drug molecules. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 9015-9030, November 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26853   open full text
• Extracellular vesicles derived from human embryonic stem cell‐MSCs ameliorate cirrhosis in thioacetamide‐induced chronic liver injury.
  Soura Mardpour, Seyedeh‐Nafiseh Hassani, Saeid Mardpour, Forough Sayahpour, Massoud Vosough, Jafar Ai, Nasser Aghdami, Amir Ali Hamidieh, Hossein Baharvand.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2+ Various somatic tissue‐derived mesenchymal stromal cells (MSCs) have been considered as an attractive therapeutic tool for treatment of liver diseases in which the secretion of soluble factors or extracellular vesicles (EVs) is the most probable mechanism. The experimental application of human embryonic stem cell‐derived MSC (ES‐MSC) increased rapidly and showed promising results, in vitro and in vivo. However, possible therapeutic effects of human ES‐MSC and their EVs on Thioacetamide (TAA)‐induced chronic liver injury have not been evaluated yet. Our data indicated that human ES‐MSC can significantly suppress the proliferation of peripheral blood mononuclear cells compared to bone marrow (BM)‐MSC and adipose (AD)‐MSC. Moreover, ES‐MSC increased the secretion of anti‐inflammatory cytokines (i.e., TGF‐β and IL‐10) and decreased IFN‐γ, compared to other MSCs. ES‐MSC EVs demonstrated immunomodulatory activities comparable to parental cells and ameliorated cirrhosis in TAA‐induced chronic rat liver injury, that is, reduction in fibrosis and collagen density, necrosis, caspase density, portal vein diameter, and transaminitis. The gene expression analyses also showed upregulation in collagenases (MMP9 and MMP13), anti‐apoptotic gene (BCL‐2) and anti‐inflammatory cytokines (TGF‐β1 and IL‐10) and down‐regulation of major contributors to fibrosis (Col1α, αSMA, and TIMP1), pro‐apoptotic gene (BAX) and pro‐inflammatory cytokines (TNFα and IL‐2) following treatment with ES‐MSC and ES‐MSC‐EV. These results demonstrated that human ES‐MSC and ES‐MSC EV as an off‐the‐shelf product, that needs further assessment to be suggested as an allogeneic product for therapeutic applications for liver fibrosis. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9330-9344, December 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26413   open full text
• Recombinant human hepatocyte growth factor provides protective effects in cerulein‐induced acute pancreatitis in mice.
  Mayrel Palestino‐Dominguez, Mario Pelaez‐Luna, Roberto Lazzarini‐Lechuga, Ignacio Rodriguez‐Ochoa, Veronica Souza, Roxana U. Miranda, Benjamín Perez‐Aguilar, Leticia Bucio, Jens U. Marquardt, Luis Enrique Gomez‐Quiroz, Maria Concepcion Gutierrez‐Ruiz.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2+ Acute pancreatitis is a multifactorial disease associated with profound changes of the pancreas induced by release of digestive enzymes that lead to increase in proinflammatory cytokine production, excessive tissue necrosis, edema, and bleeding. Elevated levels of hepatocyte growth factor (HGF) and its receptor c‐Met have been observed in different chronic and acute pancreatic diseases including experimental models of acute pancreatitis. In the present study, we investigated the protective effects induced by the recombinant human HGF in a mouse model of cerulein‐induced acute pancreatitis. Pancreatitis was induced by 8 hourly administrations of supramaximal cerulein injections (50 µg/kg, ip). HGF treatment (20 µg/kg, iv), significantly attenuated lipase content and amylase activity in serum as well as the degree inflammation and edema overall leading to less severe histologic changes such as necrosis, induced by cerulein. Protective effects of HGF were associated with activation of pro‐survival pathways such as Akt, Erk1/2, and Nrf2 and increase in executor survival‐related proteins and decrease in pro‐apoptotic proteins. In addition, ROS content and lipid peroxidation were diminished, and glutathione synthesis increased in pancreas. Systemic protection was observed by lung histology. In conclusion, our data indicate that HGF exerts an Nrf2 and glutathione‐mediated protective effect on acute pancreatitis reflected by a reduction in inflammation, edema, and oxidative stress. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9354-9364, December 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26444   open full text
• High folate intake contributes to the risk of large for gestational age birth and obesity in male offspring.
  Kaipeng Xie, Ziyi Fu, Hui Li, Xiaohong Gu, Zhiyong Cai, Pengfei Xu, Xianwei Cui, Lianghui You, Xing Wang, Lijun Zhu, Chenbo Ji, Xirong Guo.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2+ Folate supplementation is recommended before and during early pregnancy to prevent neural tube defects, but the effect of red blood cell (RBC) folate on large for gestational age (LGA) is still unknown. We performed a nested case‐control study including 542 LGA cases and 1,084 appropriate for gestational age (AGA) controls to examine the association of RBC folate concentrations with risk of LGA. Then, male offspring of dams fed basic folic acid (2 mg/kg, control) or 10‐fold folic acid (20 mg/kg, HFol) diet before and during pregnancy were used to explore the effect of high folate intake on birth weight and long‐term effects. We observed higher RBC folate concentrations in the cases compared to controls (p = 0.039). After adjustment for maternal age, BMI at enrollment, gestational weeks at enrollment, gestational weeks at delivery and infant gender, higher RBC folate levels were significantly associated with increased risk of LGA (Ptrend = 0.003). Interestingly, male offspring of HFol dams showed the higher birth weight, elevated levels of post loading blood glucose at 9 and 13 weeks post‐weaning and increased triglyceride (TG) and total cholesterol (TC) levels at 17 weeks post‐weaning. Furthermore, we observed that high folate intake increased the proliferation and differentiation of adipose cells. Our results suggest that maternal high folate intake confers the risk of LGA birth and accelerates the development of obesity in male offspring. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9383-9389, December 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26520   open full text
• A multi‐method evaluation of the effects of Inflammatory cytokines (IL‐1β, IFN‐γ, TNF‐α) on pancreatic β‐cells.
  Kaipeng Xie, Bo Xu, Yuqing Zhang, Minjian Chen, Yinwen Ji, Jie Wang, Zhenyao Huang, Kun Zhou, Yankai Xia, Wei Tang.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2+ We aimed to explore the effects of Inflammatory cytokines (IL‐1β, IFN‐γ, TNF‐α) on pancreatic β‐cells. CCK‐8 assay showed that the cell viability decreased after 24 hr treatment of TNF‐α, 48 hr of IFN‐γ, and 84 hr of IL‐1β. EdU assay illustrated that after 24 hr treatment, there were significantly reduced EdU‐labeled red fluorescence cells in TNF‐α group while not in IFN‐γ and IL‐1β groups. Flow Cytometry results displayed that TNF‐α and IFN‐γ groups increased apoptosis while IL‐1β group did not. Cell apoptosis results found that there was an increase in the S‐phase population of IL‐1β and TNF‐α groups, however, there was no significant difference in cell cycle between IFN‐γ group and the control. TEM images showed that there were reduction in the number of granules and mitochondria in IL‐1β and IFN‐γ groups, in particular paucity of insulin granules and mitochondria in TNF‐α group. Radioimmunoassay results presented that TNF‐α inhibited glucose‐induced insulin secretion, while there were no significant changes in IL‐1β and IFN‐γ groups when compared with the control. Metabolomic analysis found amino acid metabolism and Krebs cycle were the most robust altered metabolism pathways after inflammatory cytokines treatments. Overall, the altered amino acid metabolism and Krebs cycle metabolism might be important mechanisms of TNF‐α induced mouse pancreatic β‐cells dysfuction. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9375-9382, December 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26518   open full text
• ADAM17 participates in the protective effect of paeoniflorin on mouse brain microvascular endothelial cells.
  Haifang Wang, Shuhui Ma, Jing Li, Miaomiao Zhao, Xueping Huo, Jingying Sun, Lijun Sun, Jun Hu, Qinshe Liu.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2+ Paeoniflorin (PF), the most abundant active ingredient of traditional Chinese herbal medicine Paeoniae Radix, has been recognized as a potential neuroprotectant due to its remarkable efficacy on mitigating cerebral infarction and preventing the neurodegenerative diseases. However, the precise mechanisms of PF remain incompletely understood. In this study, we first provided evidence for the protective effect of PF on hydrogen peroxide‐induced injury on mouse brain microvascular endothelial bEnd.3 cells, and for transactivation of the epidermal growth factor receptor (EGFR) signal induced by PF, suggesting that EGFR transactivation might be involved in the beneficial role of PF. Next, by detecting the phosphorylation of a disintegrin and metalloprotease 17 (ADAM17) at Thr 735 and performing loss‐of‐function experiments with the ADAM17 inhibitor and ADAM 17‐siRNA, we showed that PF‐induced transactivation of EGFR and downstream ERKs and AKT signaling pathways were dependent on ADAM17. Furthermore, PF‐induced phosphorylation of ADAM17 and the EGFR transactivation were inhibited by the inhibitors of adenosine A1 receptor (A1R) or Src kinase that were applied to cells prior to PF treatment, implying the involvement of A1R, and Src in the activation of ADAM17. Finally, PF reduced the cell surface level of TNF‐receptor 1 (TNFR1) and increased the content of soluble TNFR1 (sTNFR1) in the culture media, indicating that PF might enhance the shedding of sTNFR1. Taken together, we conclude that A1R and Src‐dependent activation of ADAM17 participates in PF‐induced EGFR transactivation and TNFR1 shedding on mouse brain microvascular endothelial cells, which may contributes to the neuroprotective effects of PF. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9320-9329, December 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26308   open full text
• Effect of restriction vegan diet's on muscle mass, oxidative status, and myocytes differentiation: A pilot study.
  Daniela Vanacore, Giovanni Messina, Stefania Lama, Giuseppe Bitti, Pasqualina Ambrosio, Giancarlo Tenore, Antonietta Messina, Vincenzo Monda, Silvia Zappavigna, Mariarosaria Boccellino, Ettore Novellino, Marcellino Monda, Paola Stiuso.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2+ This study was conceived to evaluate the effects of three different diets on body composition, metabolic parameters, and serum oxidative status. We enrolled three groups of healthy men (omnivores, vegetarians, and vegans) with similar age, weight and BMI, and we observed a significant decrease in muscle mass index and lean body mass in vegan compared to vegetarian and omnivore groups, and higher serum homocysteine levels in vegetarians and vegans compared to omnivores. We studied whether serum from omnivore, vegetarian, and vegan subjects affected oxidative stress, growth and differentiation of both cardiomyoblast cell line H9c2 and H‐H9c2 (H9c2 treated with H2O2 to induce oxidative damage). We demonstrated that vegan sera treatment of both H9c2 and H‐H9c2 cells induced an increase of TBARS values and cell death and a decrease of free NO2− compared to vegetarian and omnivorous sera. Afterwards, we investigated the protective effects of vegan, vegetarian, and omnivore sera on the morphological changes induced by H2O2 in H9c2 cell line. We showed that the omnivorous sera had major antioxidant and differentiation properties compared to vegetarian and vegan sera. Finally, we evaluated the influence of the three different groups of sera on MAPKs pathway and our data suggested that ERK expression increased in H‐H9c2 cells treated with vegetarian and vegan sera and could promote cell death. The results obtained in this study demonstrated that restrictive vegan diet could not prevent the onset of metabolic and cardiovascular diseases nor protect by oxidative damage. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9345-9353, December 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26427   open full text
• Over‐expression of DEC1 inhibits myogenic differentiation by modulating MyoG activity in bovine satellite cell.
  Yongzhen Huang, Xinsheng Lai, Linyong Hu, Chuzhao Lei, Xianyong Lan, Chunlei Zhang, Yun Ma, Li Zheng, Yue‐Yu Bai, Fengpeng Lin, Hong Chen.
  Journal of Cellular Physiology. June 19, 2018
  --- - |2+ Differentiated embryo chondrocyte 1 (DEC1), a member of basic‐helix‐loop‐helix transcription factor Bhlhe40, also called stimulated by retinoic acid 13, STRA13, plays an important role in the regulation of adipogenesis, tumorigenesis, peripheral circadian output, response to hypoxia, and development of metabolic syndrome. Previous studies suggested that DEC1 was involved in skeletal muscle development; however, its precise role in myoblast differentiation has not been determined. In the present study, we showed that DEC1 expressed ubiquitously in different bovine tissues and was down‐regulated in differentiated bovine satellite cells. Expression of muscle specific transcription factors (Myf5, MyoD, MyoG, and MHC) was significantly down‐regulated when DEC1 was over‐expressed by both CoCl2‐simulated hypoxia and Adenovirus‐mediated transduction in bovine satellite cells. Consistent with that, promoter analyses via luciferase reporter assay also revealed that overexpression of bovine DEC1 could inhibit MyoG promoter activity. In conclusion, overexpression of DEC1 blocked myogenesis by inhibiting MyoG promoter activity in bovine. Our results provided a new mechanism for the muscle growth, which would contribute to increase cattle meat productivity. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9365-9374, December 2018.
  

  June 19, 2018   doi: 10.1002/jcp.26471   open full text
• Is the secret for a successful aging to keep track of cancer pathways?
  Donatella Tramontano, Francesca De Amicis.
  Journal of Cellular Physiology. June 15, 2018
  --- - |2 A successful aging could be gained by life satisfaction, social functioning, or psychological resources and, definitely, by increasing resistance to diverse age‐related pathologies. Nowadays, cancer can be considered an age‐related disease since the incidence of most cancers increases with age, rising more rapidly beginning in midlife. Although adults with extended longevity are less likely to develop cancer, it is now emerging that aging and cancer share common molecular links, and thus targeting these mechanisms may be suitable to treat multiple disorders, for the prolonging of healthy aging. At present, one of the cornerstones of antiaging is hormone‐replacement therapy to treat diseases associated with a state of age‐related sex‐hormone deficiency in women and men; however, many studies question the relationship of hormone replacement to cancer recurrence. Here, we discuss signaling and metabolic molecular crossroad linking aging and cancer. This is useful to argue about the current knowledge of prolongevity and druggable targets and to motivate specific intervention strategies that could modify practices of the aging population, activating multiple longevity pathways but keeping track of cancer pathways, thereby potentially preserving health status. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8467-8476, November 2018.
  

  June 15, 2018   doi: 10.1002/jcp.26825   open full text
• The key genes underlying pathophysiology association between the type 2‐diabetic and colorectal cancer.
  Wen‐Fang Peng, Feng Bai, Kan Shao, Li‐Sha Shen, Hui‐Hua Li, Shan Huang.
  Journal of Cellular Physiology. June 15, 2018
  --- - |2+ Although diabetes mellitus (DM) is reported as an independent risk factor for colorectal cancer (CRC) in many researches, the underlying pathophysiology is still unclear. We investigated the differentially expressed genes (DEGs) for the diabetes and CRC to reveal the underlying pathophysiological association between the type 2‐diabetic (T2D) and CRC. Gene expression profiles for T2D (GSE55650), CRC (GSE8671), and Metformin treated cell lines (GSE67342) were downloaded from GEO database. The DEGs between T2D samples and their control samples were identified with t‐test and variance analysis. After cluster analysis and functional enrichment analysis, protein‐protein interaction (PPI) network was constructed to find potential genes for diabetes and CRC in Metformin's treatment. Totally, we identified 583 overlapped genes, 169 common DEGs, and 414 independent DEGs between T2D and CRC samples. The common genes contained 89 up‐regulated (DEGs1) and 80 down‐regulated genes (DEGs3); and independent DEGs contained 270 down‐regulated genes (DEGs4) in diabetes and 144 down‐regulated genes (DEGs2) in CRC. In enrichment analysis, the Ribosome pathway was significantly enriched by the independent DEGs. The common genes were mainly enriched in some inflammatory related pathways. Two target genes of Metformin were significantly interacted with six hub genes (HADHB, NDUFS3, TAF1, MYC, HNFF4A, and MAX) with significant changes in expression values (P < 0.05, t‐test). To summary, it is suggested that the six hub genes might play important roles in the process of Metformin treatment for diabetes and CRC. However, specific pathology remains to be further studied. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8551-8557, November 2018.
  

  June 15, 2018   doi: 10.1002/jcp.26440   open full text
• Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas.
  Eleonora Sementino, Craig W. Menges, Yuwaraj Kadariya, Suraj Peri, Jinfei Xu, Zemin Liu, Richard G. Wilkes, Kathy Q. Cai, Frank J. Rauscher, Andres J. Klein‐Szanto, Joseph R. Testa.
  Journal of Cellular Physiology. June 15, 2018
  --- - |2 Malignant mesothelioma (MM) is a therapy‐resistant cancer arising primarily from the lining of the pleural and peritoneal cavities. The most frequently altered genes in human MM are cyclin‐dependent kinase inhibitor 2A (CDKN2A), which encodes components of the p53 (p14ARF) and RB (p16INK4A) pathways, BRCA1‐associated protein 1 (BAP1), and neurofibromatosis 2 (NF2). Furthermore, the p53 gene (TP53) itself is mutated in ~15% of MMs. In many MMs, the PI3K–PTEN–AKT–mTOR signaling node is hyperactivated, which contributes to tumor cell survival and therapeutic resistance. Here, we demonstrate that the inactivation of both Tp53 and Pten in the mouse mesothelium is sufficient to rapidly drive aggressive MMs. PtenL/L;Tp53L/L mice injected intraperitoneally or intrapleurally with adenovirus‐expressing Cre recombinase developed high rates of peritoneal and pleural MMs (92% of mice with a median latency of 9.4 weeks and 56% of mice with a median latency of 19.3 weeks, respectively). MM cells from these mice showed consistent activation of Akt–mTor signaling, chromosome breakage or aneuploidy, and upregulation of Myc; occasional downregulation of Bap1 was also observed. Collectively, these findings suggest that when Pten and Tp53 are lost in combination in mesothelial cells, DNA damage is not adequately repaired and genomic instability is widespread, whereas the activation of Akt due to Pten loss protects genomically damaged cells from apoptosis, thereby increasing the likelihood of tumor formation. Additionally, the mining of an online dataset (The Cancer Genome Atlas) revealed codeletions of PTEN and TP53 and/or CDKN2A/p14ARF in ~25% of human MMs, indicating that cooperative losses of these genes contribute to the development of a significant proportion of these aggressive neoplasms and suggesting key target pathways for therapeutic intervention. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8952-8961, November 2018.
  

  June 15, 2018   doi: 10.1002/jcp.26830   open full text
• Mesenchymal stromal cells from amniotic fluid are less prone to senescence compared to those obtained from bone marrow: An in vitro study.
  Nicola Alessio, Caterina Pipino, Domitilla Mandatori, Pamela Di Tomo, Angela Ferone, Marco Marchiso, Mariarosa A.B. Melone, Gianfranco Peluso, Assunta Pandolfi, Umberto Galderisi.
  Journal of Cellular Physiology. June 15, 2018
  --- - |2 Mesenchymal stromal cells (MSCs) are considered to be an excellent source in regenerative medicine. They contain several cell subtypes, including multipotent stem cells. MSCs are of particular interest as they are currently being tested using cell and gene therapies for a number of human diseases. They represent a rare population in tissues; for this reason, they require, before being transplanted, an in vitro amplification. This process may induce replicative senescence, thus affecting differentiation and proliferative capacities. Increasing evidence suggests that MSCs from fetal tissues are significantly more plastic and grow faster than MSCs from bone marrow. Here, we compare amniotic fluid mesenchymal stromal cells (AF‐MSCs) and bone marrow mesenchymal stromal cells (BM‐MSCs) in terms of cell proliferation, surface markers, multidifferentiation potential, senescence, and DNA repair capacity. Our study shows that AF‐MSCs are less prone to senescence with respect to BM‐MSCs. Moreover, both cell models activate the same repair system after DNA damage, but AF‐MSCs are able to return to the basal condition more efficiently with respect to BM‐MSCs. Indeed, AF‐MSCs are better able to cope with genotoxic stress that may occur either during in vitro cultivation or following transplantation in patients. Our findings suggest that AF‐MSCs may represent a valid alternative to BM‐MSCs in regenerative medicine, and, of great relevance, the investigation of the mechanisms involved in DNA repair capacity of both AF‐MSCs and BM‐MSCs may pave the way to their rational use in the medical field. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8996-9006, November 2018.
  

  June 15, 2018   doi: 10.1002/jcp.26845   open full text
• Lumichrome inhibits osteoclastogenesis and bone resorption through suppressing RANKL‐induced NFAT activation and calcium signaling.
  Chuan Liu, Zhen Cao, Wen Zhang, Jennifer Tickner, Heng Qiu, Chao Wang, Kai Chen, Ziyi Wang, Renxiang Tan, Shiwu Dong, Jiake Xu.
  Journal of Cellular Physiology. June 15, 2018
  --- - |2 The dynamic balance between bone resorption and bone formation is crucial to maintain bone mass. Osteoclasts are key cells that perform bone resorption while osteoblasts and osteocytes function in bone formation. Osteoporosis, a bone metabolism disease characterized by bone loss and degradation of bone microstructure, occurs when osteoclastic bone resorption outstrips osteoblastic bone synthesis. The interaction between receptor activator of nuclear factor κB ligand (RANKL) and RANK on the surface of bone marrow macrophages promotes osteoclast differentiation and activation. In this study, we found that lumichrome, a photodegradation product of riboflavin, inhibits RANKL‐induced osteoclastogenesis and bone resorption as determined by tartrate‐resistant acid phosphatase staining, immunofluorescence, reverse transcription‐polymerase chain reaction, and western blot. Our results showed that lumichrome represses the expression of osteoclast marker genes, including cathepsin K (Ctsk) and Nfatc1. In addition, lumichrome suppressed RANKL‐induced calcium oscillations, NFATc1, NF‐κB, and MAPK signaling activation. Moreover, lumichrome promoted osteoblast differentiation at an early stage, as demonstrated by upregulated expression of osteoblast marker genes Alp, Runx2, and Col1a1. We also found that lumichrome reduces bone loss in ovariectomized mice by inhibiting osteoclastogenesis. In summary, our data suggest the potential of lumichrome as a therapeutic drug for osteolytic diseases. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8971-8983, November 2018.
  

  June 15, 2018   doi: 10.1002/jcp.26841   open full text
• Sideroxylin (Callistemon lanceolatus) suppressed cell proliferation and increased apoptosis in ovarian cancer cells accompanied by mitochondrial dysfunction, the generation of reactive oxygen species, and an increase of lipid peroxidation.
  Sunwoo Park, Whasun Lim, Wonsik Jeong, Fuller W. Bazer, Dongho Lee, Gwonhwa Song.
  Journal of Cellular Physiology. June 15, 2018
  --- - |2+ Sideroxylin is a C‐methylated flavone isolated from Callistemon lanceolatus and exerts antimicrobial activity against Staphylococcus aureus. However, the anticancer effects of sideroxylin and its intracellular signaling mechanisms have not yet been identified. Results of our study showed that sideroxylin decreased cell proliferation and increased apoptosis, causing DNA fragmentation, depolarization of the mitochondrial membrane, the generation of reactive oxygen species, and an increase of lipid peroxidation in ovarian cancer cells (ES2 and OV90 cells). Additionally, sideroxylin activated the phosphorylation of ERK1/2, JNK, P38, and MAPK proteins and the use of LY294002, U0126, SB203580, and SP600125 to block their phosphorylation, respectively, in ES2 and OV90 cells. Collectively, the results of present study indicated that sideroxylin was a novel therapeutic agent to combat the proliferation of ovarian cancer cells through the induction of mitochondrial dysfunction and the activation of PI3 K and MAPK signal transduction. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8597-8604, November 2018.
  

  June 15, 2018   doi: 10.1002/jcp.26540   open full text
• LINC00968 functions as an oncogene in osteosarcoma by activating the PI3K/AKT/mTOR signaling.
  Gang Liu, Dongtang Yuan, Peng Sun, Weidong Liu, Peng‐Fei Wu, Huan Liu, Guang‐Yang Yu.
  Journal of Cellular Physiology. June 15, 2018
  --- - |2+ Osteosarcoma is recognized as a malignant tumor in the skeletal system. Long non‐coding RNAs (lncRNAs) have been exhibited to play crucial roles in osteosarcoma development. Our current study focused on the biological effects and mechanism of LINC00968 in osteosarcoma pathogenesis. We observed that LINC00968 was dramatically elevated in osteosarcoma cells including U2OS, MG63, Saos‐2, SW1353, and 143‐B cells compared to human osteoblast cell line hFOB. Silence of LINC00968 inhibited osteosarcoma cell growth and proliferation in vitro. Reversely, overexpression of LINC00968 promoted osteosarcoma cell survival and cell colony formation ability in Saos‐2 and 143‐B cells. In addition, LINC00968 was able to induce osteosarcoma cell migration and invasion through up‐regulating MMP‐2 and MMP‐9 protein levels. The phosphoinosmde‐3‐kinase/Protein Kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway has been reported to participate in several cancer types. Here, in our study, we found that PI3K/AKT/mTOR pathway was involved in osteosarcoma progression. Knockdown of LINC00968 inactivated PI3K/AKT/mTOR signaling pathway in vitro. Subsequently, in vivo tumor xenografts were established using 143‐B cells to investigate whether LINC00968 can induce osteosarcoma development in vivo. Consistently, it was indicated that inhibition of LINC00968 significantly inhibited osteosarcoma progression in vivo. Taken these together, in our research, LINC00968 could be provided as a novel prognostic biomarker and therapeutic target in osteosarcoma diagnosis and treatment. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8639-8647, November 2018.
  

  June 15, 2018   doi: 10.1002/jcp.26624   open full text
• MiR‐128‐1‐5p regulates tight junction induced by selenium deficiency via targeting cell adhesion molecule 1 in broilers vein endothelial cells.
  Tingru Pan, Xueyuan Hu, Tianqi Liu, Zhe Xu, Na Wan, Yiming Zhang, Shu Li.
  Journal of Cellular Physiology. June 15, 2018
  --- - |2 Vein endothelial cells (VECs) constitute an important barrier for macromolecules and circulating cells from the blood to the tissues, stabilizing the colloid osmotic pressure of the blood, regulating the vascular tone, and rapidly changing the intercellular connection, and maintaining normal physiological function. Tight junction has been discovered as an important structural basis of intercellular connection and may play a key role in intercellular connection injuries or vascular diseases and selenium (Se) deficiency symptoms. Hence, we replicated the Se‐deficient broilers model and detected the specific microRNA in response to Se‐deficient vein by using quantitative real time‐PCR (qRT‐PCR) analysis. Also, we selected miR‐128‐1‐5p based on differential expression in vein tissue and confirmed its target gene cell adhesion molecule 1 (CADM1) by the dual luciferase reporter assay and qRT‐PCR in VECs. We made the ectopic miR‐128‐1‐5p expression for the purpose of validating its function on tight junction. The result showed that miR‐128‐1‐5p and CADM1 were involved in the ZO‐1‐mediated tight junction, increased paracellular permeability, and arrested cell cycle. We presumed that miR‐128‐1‐5p and Se deficiency might trigger tight junction. Interestingly, miR‐128‐1‐5p inhibitor and fasudil in part hinder the destruction of the intercellular structure caused by Se deficiency. The miR‐128‐1‐5p/CADM1/tight junction axis provides a new avenue toward understanding the mechanism of Se deficiency, revealing a novel regulation model of tight junction injury in vascular diseases. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8802-8814, November 2018.
  

  June 15, 2018   doi: 10.1002/jcp.26794   open full text
• Long noncoding ribonucleic acid NKILA induces the endoplasmic reticulum stress/autophagy pathway and inhibits the nuclear factor‐k‐gene binding pathway in rats after intracerebral hemorrhage.
  Jiaoying Jia, Mingming Zhang, Qi Li, Qian Zhou, Yugang Jiang.
  Journal of Cellular Physiology. June 12, 2018
  --- - |2 Long noncoding RNAs (lncRNAs) have emerged as an important class of molecules that have been associated with brain function and neurological disease, but the expression profiles of lncRNAs after intracerebral hemorrhage (ICH) remain to be elucidated. In this study, we determined the expression pattern of nuclear factor‐k‐gene binding (NF‐kB) interacting lncRNA (NKILA) after ICH and examined its respective effects on the endoplasmic reticulum stress (ERS)/autophagy pathway, hippocampal neuron loss, and the NF‐kB pathway after type VII collagenase‐induced ICH in rats. The regulatory mechanisms of NKILA were investigated by an intraperitoneal injection of small interfering (siRNA) against NKILA into rats after ICH. NKILA inhibition mediated by siRNA against NKILA was shown to significantly reduce ERS and autophagy, activate the NF‐kB pathway, decrease neurological deficits, brain edema, and injury, and induce blood–brain barrier breakdown, further leading to hippocampal neuron loss and the production of inflammation cytokines. Taken together, the demonstration that NKILA induces the ERS/autophagy pathway and inhibits the NF‐kB pathway after ICH supports the concept that NKILA functions as a novel target that is required for the attenuation of brain injuries after ICH. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8839-8849, November 2018.
  

  June 12, 2018   doi: 10.1002/jcp.26798   open full text
• Calcium: A novel and efficient inducer of differentiation of adipose‐derived stem cells into neuron‐like cells.
  Farjam Goudarzi, Heidar Tayebinia, Jamshid Karimi, Elahe Habibitabar, Iraj Khodadadi.
  Journal of Cellular Physiology. June 05, 2018
  --- - |2 This study comparatively investigated the effectiveness of calcium and other well‐known inducers such as isobutylmethylxanthine (IBMX) and insulin in differentiating human adipose‐derived stem cells (ADSCs) into neuronal‐like cells. ADSCs were immunophenotyped and differentiated into neuron‐like cells with different combinations of calcium, IBMX, and insulin. Calcium mobilization across the membrane was determined. Differentiated cells were characterized by cell cycle profiling, staining of Nissl bodies, detecting the gene expression level of markers such as neuronal nuclear antigen (NeuN), microtubule associated protein 2 (MAP2), neuron‐specific enolase (NSE), doublecortin, synapsin I, glial fibrillary acidic protein (GFAP), and myelin basic protein (MBP) by quantitative real‐time polymerase chain reaction (quantitative real‐time polymerase chain reaction (qRT‐PCR) and protein level by the immunofluorescence technique. Treatment with Ca + IBMX + Ins induced neuronal appearance and projection of neurite‐like processes in the cells, accompanied with inhibition of proliferation and halt in the cell cycle. A significantly higher expression of MBP, GFAP, NeuN, NSE, synapsin 1, doublecortin, and MAP2 was detected in differentiated cells, confirming the advantages of Ca + IBMX + Ins to the other combinations of inducers. Here, we showed an efficient protocol for neuronal differentiation of ADSCs, and calcium fostered differentiation by augmenting the number of neuron‐like cells and instantaneous increase in the expression of neuronal markers. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8940-8951, November 2018.
  

  June 05, 2018   doi: 10.1002/jcp.26826   open full text
• Application of induced pluripotent stem cell and embryonic stem cell technology to the study of male infertility.
  Javad Amini Mahabadi, Hamed Sabzalipour, Hassan Hassani Bafrani, Seyed Mohammad Gheibi Hayat, Hossein Nikzad.
  Journal of Cellular Physiology. June 05, 2018
  --- - |2 Stem cells (SCs) are classes of undifferentiated biological cells existing only at the embryonic, fetal, and adult stages that can divide to produce specialized cell types during fetal development and remain in our bodies throughout life. The progression of regenerative and reproductive medicine owes the advancement of respective in vitro and in vivo biological science on the stem cell nature under appropriate conditions. The SCs are promising therapeutic tools to treat currently of infertility because of wide sources and high potency to differentiate. Nevertheless, no effective remedies are available to deal with severe infertility due to congenital or gonadotoxic stem cell deficiency in prepubertal childhood. Some recent solutions have been developed to address the severe fertility problems, including in vitro formation of germ cells from stem cells, induction of pluripotency from somatic cells, and production of patient‐specific pluripotent stem cells. There is a possibility of fertility restoration using the in vitro formation of germ cells from somatic cells. Accordingly, the present review aimed at studying the literature published on the medical application of stem cells in reproductive concerns. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8441-8449, November 2018.
  

  June 05, 2018   doi: 10.1002/jcp.26757   open full text
• Long noncoding RNA FAM83H‐AS1 exerts an oncogenic role in glioma through epigenetically silencing CDKN1A (p21).
  Yong‐Yan Bi, Gang Shen, Yong Quan, Wei Jiang, Fulin Xu.
  Journal of Cellular Physiology. June 05, 2018
  --- - |2 Gliomas are the commonest and most aggressive primary malignant tumor in the central nervous system. Long noncoding RNAs (lncRNAs) have been identified to act as crucial regulators in multiple biological processes, including tumorigenesis. FAM83H antisense RNA1 (FAM83H‐AS1) has been uncovered to be dysregulated in several cancers. However, the biological role of FAM83H‐AS1 in glioma still needs to be investigated. Currently, our findings indicated that FAM83H‐AS1 was upregulated in glioma tissues and cell lines and high level of FAM83H‐AS1 was associated with poor prognosis of glioma. Loss‐of‐function assays demonstrated that silenced FAM83H‐AS1 obviously suppressed cell proliferation via regulating the cell‐cycle distribution and cell apoptosis rate, and mechanistic experiments revealed that FAM83H‐AS1 could epidemically silence CDKN1A expression through recruiting EZH2 to the promoter of CDKN1A, thereby influencing the cell cycle and proliferation. Collectively, our findings suggested that FAM83H‐AS1 participated in the progression of glioma and might act as a potential therapeutic target and prognosis biomarker for human glioma. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8896-8907, November 2018.
  

  June 05, 2018   doi: 10.1002/jcp.26813   open full text
• ARHGAP21 as a master regulator of multiple cellular processes.
  Lucas R. O. Rosa, Gabriela M. Soares, Leonardo R. Silveira, Antonio C. Boschero, Helena C. L. Barbosa‐Sampaio.
  Journal of Cellular Physiology. June 01, 2018
  --- - |2 The cellular cytoskeleton is involved with multiple biological processes and is tightly regulated by multiple proteins and effectors. Among these, the RhoGTPases family is one of the most important players. RhoGTPAses are, in turn, regulated by many other elements. In the past decade, one of those regulators, the RhoGAP Rho GTPase Activating Protein 21 (ARHGAP21), has been overlooked, despite being implied as having an important role on many of those processes. In this paper, we aimed to review the available literature regarding ARHGAP21 to highlight its importance and the mechanisms of action that have been found so far for this still unknown protein involved with cell adhesion, migration, Golgi regulation, cell trafficking, and even insulin secretion. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8477-8481, November 2018.
  

  June 01, 2018   doi: 10.1002/jcp.26829   open full text
• A minireview of E4BP4/NFIL3 in heart failure.
  Bharath Kumar Velmurugan, Ruey‐Lin Chang, Shibu Marthandam Asokan, Chih‐Fen Chang, Cecilia‐Hsuan Day, Yueh‐Min Lin, Yuan‐Chuan Lin, Wei‐Wen Kuo, Chih‐Yang Huang.
  Journal of Cellular Physiology. June 01, 2018
  --- - |2 Heart failure (HF) remains a major cause of morbidity and mortality worldwide. The primary cause identified for HF is impaired left ventricular myocardial function, and clinical manifestations may lead to severe conditions like pulmonary congestion, splanchnic congestion, and peripheral edema. Development of new therapeutic strategies remains the need of the hour for controlling the problem of HF worldwide. Deeper insights into the molecular mechanisms involved in etiopathology of HF indicate the significant role of calcium signaling, autocrine signaling pathways, and insulin‐like growth factor‐1 signaling that regulates the physiologic functions of heart growth and development such as contraction, metabolism, hypertrophy, cytokine signaling, and apoptosis. In view of these facts, a transcription factor (TF) regulating the myriad of these signaling pathways may prove as a lead candidate for development of therapeutics. Adenovirus E4 promoter‐binding protein (E4BP4), also known as nuclear‐factor, interleukin 3 regulated (NFIL3), a type of basic leucine zipper TF, is known to regulate the signaling processes involved in the functioning of heart. The current review discusses about the expression, structure, and functional role of E4BP4 in signaling processes with emphasis on calcium signaling mechanisms, autocrine signaling, and insulin‐like growth factor II receptor–mediated processes regulated by E4BP4 that may regulate the pathogenesis of HF. We propose that E4BP4, being the critical component for the regulation of the above signaling processes, may serve as a novel therapeutic target for HF, and scientific investigations are merited in this direction. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8458-8466, November 2018.
  

  June 01, 2018   doi: 10.1002/jcp.26790   open full text
• Isoform‐specific effects of transforming growth factor β on endothelial‐to‐mesenchymal transition.
  Harika Sabbineni, Arti Verma , Payaningal R. Somanath.
  Journal of Cellular Physiology. June 01, 2018
  --- - |2 Endothelial‐to‐mesenchymal transition (EndMT) was first reported in the embryogenesis. Recent studies show that EndMT also occurs in the disease progression of atherosclerosis, cardiac and pulmonary fibrosis, pulmonary hypertension, diabetic nephropathy, and cancer. Although transforming growth factor β (TGFβ) is crucial for EndMT, it is not clear which isoform elicits a predominant effect. The current study aims to directly compare the dose‐dependent effects of TGFβ1, TGFβ2, and TGFβ3 on EndMT and characterize the underlying mechanisms. In our results, all three TGFβ isoforms induced EndMT in human microvascular endothelial cells after 72 hr, as evidenced by the increased expression of mesenchymal markers N‐cadherin and α‐smooth muscle actin as well as the decreased expression of endothelial nitric oxide synthase. Interestingly, the effect of TGFβ2 was the most pronounced. At 1 ng/ml, only TGFβ2 treatment resulted in significantly increased phosphorylation (activation) of Smad2/3 and p38‐MAPK and increased expression of mesenchymal transcription factors Snail and FoxC2. Intriguingly, we observed that treatment with 1 ng/ml TGFβ1 and TGFβ3, but not TGFβ2, resulted in an increased expression of TGFβ2, thus indicating that EndMT with TGFβ1 and TGFβ3 treatments was due to the secondary effects through TGFβ2 secretion. Furthermore, silencing TGFβ2 using small interfering RNA blunted the expression of EndMT markers in TGFβ1‐ and TGFβ3‐treated cells. Together, our results indicate that TGFβ2 is the most potent inducer of EndMT and that TGFβ1‐ and TGFβ3‐induced EndMT necessitates a paracrine loop involving TGFβ2. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8418-8428, November 2018.
  

  June 01, 2018   doi: 10.1002/jcp.26801   open full text
• Time‐dependent contribution of BMP, FGF, IGF, and HH signaling to the proliferation of mesenchymal stroma cells during chondrogenesis.
  Jennifer Fischer, Natalie Knoch, Tanja Sims, Nils Rosshirt, Wiltrud Richter.
  Journal of Cellular Physiology. June 01, 2018
  --- - |2 Early loss of up to 50% of cells is common for in vitro chondrogenesis of mesenchymal stromal cells (MSC) in pellet culture, reducing the efficacy and the tissue yield for cartilage engineering. Enhanced proliferation could compensate for this unwanted effect, but relevant signaling pathways remain largely unknown. The aim of this study was to identify the contribution of bone morphogenetic protein (BMP), fibroblast growth factor (FGF), insulin‐like growth factor (IGF), and hedgehog (HH) signaling toward cell proliferation during chondrogenesis and investigate whether a further mitogenic stimulation is possible and promising. Human MSC were subjected to chondrogenesis in the presence or absence of pathway inhibitors or activators up to Day 14 or from Days 14 to 28, before proliferation, DNA and proteoglycan content were quantified. [3H]‐thymidine incorporation revealed arrest of proliferation on Day 3, after which cell division was reinitiated. Although BMP signaling was essential for proliferation throughout chondrogenesis, IGF signaling was relevant only up to Day 14. In contrast, FGF and HH signaling drove proliferation only from Day 14 onward. Early BMP4, IGF‐1, or FGF18 treatment neither prevented early cell loss nor allowed further mitogenic stimulation. However, application of the HH‐agonist purmorphamine from Day 14 increased proliferation 1.44‐fold (p < 0.05) and late BMP4‐application enhanced the DNA and proteoglycan content, with significant effects on tissue yield. Conclusively, a differential and phase‐dependent contribution of the four pathways toward proliferation was uncovered and BMP4 treatment was promising to enhance tissue yield. Culture forms less prone to size limitations by nutrient/oxygen gradients and a focus on early apoptosis prevention may be considered as the next steps to further enhance chondrocyte formation from MSC. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8962-8970, November 2018.
  

  June 01, 2018   doi: 10.1002/jcp.26832   open full text
• SIRT1 inhibits TGF‐β‐induced endothelial‐mesenchymal transition in human endothelial cells with Smad4 deacetylation.
  Zhen Li, Fei Wang, Siyuan Zha, Qing Cao, Jing Sheng, Shuyan Chen.
  Journal of Cellular Physiology. June 01, 2018
  --- - |2 Endothelial‐mesenchymal transition (EndMT) plays a pivotal role in organ fibrosis. This study examined the effect of SIRT1 on transforming growth factor beta (TGF‐β)‐induced EndMT in human endothelial cells (ECs) and its probable molecular mechanism. We assessed EndMT by immunofluorescence staining, quantitative real‐time polymerase chain reaction, Western blotting, and migration and invasion assays. Adenovirus was used to overexpress or knockdown SIRT1 in ECs. The regulatory relationship between SIRT1 and Smad4 was analyzed by coimmunoprecipitation assay. We found that SIRT1 was decreased in TGF‐β‐induced EndMT, and SIRT1 inhibited TGF‐β‐induced EndMT through deacetylating Smad4. Our findings suggest that SIRT1 has an important role in inhibiting EndMT by regulating the TGF‐β/Smad4 pathway in human ECs and, thus, protecting against fibrosis. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 9007-9014, November 2018.
  

  June 01, 2018   doi: 10.1002/jcp.26846   open full text
• PTBP1 promotes the growth of breast cancer cells through the PTEN/Akt pathway and autophagy.
  Xu Wang, Yang Li, Yan Fan, Xinmiao Yu, Xiaoyun Mao, Feng Jin.
  Journal of Cellular Physiology. June 01, 2018
  --- - |2 Invasion and migration is the hallmark of malignant tumors as well as the major cause for breast cancer death. The polypyrimidine tract binding, PTB, protein serves as an important model for understanding how RNA binding proteins affect proliferation and invasion and how changes in the expression of these proteins can control complex programs of tumorigenesis. We have investigated some roles of polypyrimidine tract binding protein 1 (PTBP1) in human breast cancer. We found that PTBP1 was upregulated in breast cancer tissues compared with normal tissues and the same result was confirmed in breast cancer cell lines. Knockdown of PTBP1 substantially inhibited tumor cell growth, migration, and invasion. These results suggest that PTBP1 is associated with breast tumorigenesis and appears to be required for tumor cell growth and maintenance of metastasis. We further analyzed the relationship between PTBP1 and clinicopathological parameters and found that PTBP1 was correlated with her‐2 expression, lymph node metastasis, and pathological stage. This will be a novel target for her‐2(+) breast cancer. PTBP1 exerts these effects, in part, by regulating the phosphatase and tensin homolog‐phosphatidylinositol‐4,5‐bisphosphate 3‐kinase/protein kinase B (PTEN‐PI3K/Akt) pathway and autophagy, and consequently alters cell growth and contributes to the invasion and metastasis. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8930-8939, November 2018.
  

  June 01, 2018   doi: 10.1002/jcp.26823   open full text
• Triose‐phosphate isomerase is a novel target of miR‐22 and miR‐28, with implications in tumorigenesis.
  Saife Niaz Lone, Raihana Maqbool, Fazl Q. Parray, Mahboob Ul Hussain.
  Journal of Cellular Physiology. June 01, 2018
  --- - |2 Aerobic glycolysis is the hallmark of many cancer cells that results in a high rate of adenosine triphosphate (ATP) production and, more importantly, biosynthetic intermediates, which are required by the fast‐growing tumor cells. The molecular mechanism responsible for the increased glycolytic influx of tumor cells is still not fully understood. In the present study, we have attempted to address the above question by exploring the role of the glycolytic enzyme, triose‐phosphate isomerase (TPI), in the cancer cells. The western blot analysis of the 30 human colorectal cancer samples depicted higher post‐transcriptional expression of TPI in the tumor tissue relative to the normal tissue. In addition, we identified two novel microRNAs, miR‐22 and miR‐28, that target the TPI messenger RNA (mRNA) and regulate its expression. miR‐22 and the miR‐28 showed significant inverse expression status viz‐a‐viz the expression of the TPI. The specificity of the miR‐22/28 regulation of the TPI mRNA was confirmed by various biochemical and mutagenic assays. Moreover, the hypoxia conditions resulted in an increased expression of the TPI protein, with a concomitant decrease in miR‐22/28. The physiological significance of the TPI and miR‐22/28 interaction for the glycolytic influx was confirmed by the l‐lactate production in the HCT‐116+/+ cells. Overall, our data demonstrate the novel microRNA mediated post‐transcriptional regulation of the TPI glycolytic enzyme, which may be one of the possible reasons for the increased glycolytic capacity of the tumor cells. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8919-8929, November 2018.
  

  June 01, 2018   doi: 10.1002/jcp.26821   open full text
• In vivo antivascular endothelial growth factor treatment induces corneal endothelium apoptosis in rabbits through changes in p75NTR–proNGF pathway.
  Magda Gharbiya, Alice Bruscolini, Marta Sacchetti, Pamela Rosso, Valentina Carito, Marco Segatto, Elena Fico, Paola Tirassa, Alessandro Lambiase.
  Journal of Cellular Physiology. June 01, 2018
  --- - |2 Intravitreal injection (IVT) of antivascular endothelial growth factor (anti‐VEGF) agents is widely used for the treatment of retinal vascular diseases. Recently, the injection of anti‐VEGF agents in the ocular anterior chamber has been proposed for the treatment of neovascular glaucoma and potential side effects on the corneal structures have been investigated with contrasting results. Increasing evidence has demonstrated that VEGF inhibition is associated with cellular apoptotic changes and that this effect may be mediated by alterations in nerve growth factor (NGF) pathway. In this study, we demonstrated that anterior chamber injection (IC), but not IVT injection of two different anti‐VEGF agents, aflibercept and ranibizumab, affects rabbit corneal endothelium in terms of survival and apoptosis and is associated with changes in endothelial expression of NGF precursor (proNGF) and p75 neurotrophin receptor (p75NTR) receptor. We observed an increase in corneal endothelial cell incorporation of trypan blue and expression of cleaved‐caspase 3 (c‐Casp3), p75NTR, and RhoA after IC injection of both anti‐VEGF drugs when compared with the vehicle. Our results showed that apoptosis induction by aflibercept was more pronounced when compared with that of ranibizumab. Aflibercept also mediated a significant increase in endothelial expression of proNGF when compared with the vehicle. In line with these data, IC administration of both anti‐VEGF agents induced the activation of apoptotic signals in endothelial cells, including an increase in c‐Casp3, decrease in Bad Ser 112 phosphorylation, and unbalance of AKT phosphorylation. These results demonstrated that administration of anti‐VEGF in the anterior chamber of rabbit affects endothelial cell survival by inducing apoptosis through alteration of NGF pathway. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8874-8883, November 2018.
  

  June 01, 2018   doi: 10.1002/jcp.26806   open full text
• MALAT1 via microRNA‐17 regulation of insulin transcription is involved in the dysfunction of pancreatic β‐cells induced by cigarette smoke extract.
  Qian Sun, Hui Xu, Junchao Xue, Qianlei Yang, Chao Chen, Ping Yang, Aohan Han, Qingyun Tu, Jiachun Lu, Xiaohua Gao, Quanyong Xiang, Qizhan Liu.
  Journal of Cellular Physiology. June 01, 2018
  --- - |2 Cigarettes contain various chemicals with the potential to influence metabolic health. Exposure to cigarette smoke causes a dysfunction in pancreatic β‐cells and impairs insulin production. However, the mechanisms for cigarette smoke‐induced reduction of insulin remain largely unclear. Data from 558 patients with diabetes showed that, with smoking pack‐years, homeostatic model assessment (HOMA)‐β (a method for assessing β‐cell function) decreased and that HOMA of insulin resistance increased. For β‐cells (MIN6), cigarette smoke extract (CSE) increased the levels of thioredoxin‐interacting protein (TXNIP) and the long noncoding (lnc)RNA, metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1), and downregulated the levels of the transcription factor, mafA, and microRNA (miR)‐17. MALAT1, one of four lncRNAs predicted to regulate miR‐17, was knocked down by small interfering RNA (siRNA). For these cells, an miR‐17 mimic inhibited TXNIP and enhanced the production of insulin. Knockdown of MALAT1 induced an increase in miR‐17, which suppressed TXNIP and promoted the production of insulin. In the sera of patients with diabetes who smoked, there were higher MALAT1 levels and lower miR‐17 levels than in the sera of nonsmokers. Thus, CSE inhibits insulin production by upregulating TXNIP via MALAT1‐mediated downregulation of miR‐17, which provides an understanding of the processes involved in the reduced β‐cells function caused by cigarette smoke. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8862-8873, November 2018.
  

  June 01, 2018   doi: 10.1002/jcp.26800   open full text
• Elevated transforming growth factor β signaling activation in β‐actin‐knockout mouse embryonic fibroblasts enhances myofibroblast features.
  Xin Xie, Piergiorgio Percipalle.
  Journal of Cellular Physiology. May 31, 2018
  --- - |2 Signaling by the transforming growth factor‐β (TGF‐β) is an essential pathway regulating a variety of cellular events. TGF‐β is produced as a latent protein complex and is required to be activated before activating the receptor. The mechanical force at the cell surface is believed to be a mechanism for latent TGF‐β activation. Using β‐actin null mouse embryonic fibroblasts as a model, in which actin cytoskeleton and cell‐surface biophysical features are dramatically altered, we reveal increased TGF‐β1 activation and the upregulation of TGF‐β target genes. In β‐actin null cells, we show evidence that the enhanced TGF‐β signaling relies on the active utilization of latent TGF‐β1 in the cell culture medium. TGF‐β signaling activation contributes to the elevated reactive oxygen species production, which is likely mediated by the upregulation of Nox4. The previously observed myofibroblast phenotype of β‐actin null cells is inhibited by TGF‐β signaling inhibition, while the expression of actin cytoskeleton genes and angiogenic phenotype are not affected. Together, our study shows a scenario that the alteration of the actin cytoskeleton and the consequent changes in cellular biophysical features lead to changes in cell signaling process such as TGF‐β activation, which in turn contributes to the enhanced myofibroblast phenotype. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8884-8895, November 2018.
  

  May 31, 2018   doi: 10.1002/jcp.26808   open full text
• Two controls of cell proliferation underlie cancer relapse.
  Arthur B. Pardee, Chiang J. Li.
  Journal of Cellular Physiology. May 31, 2018
  --- - |2+ Much progress has been made in understanding the basis of cancer. Current therapies can effectively shrink tumors. But they frequently relapse, metastasize to other locations, and are lethal. Effective therapies are very much needed for preventing this relapse. Creation of a eukaryotic organism commences with one original stem cell, a fertilized egg, which multiplies and differentiates. Mutations of normal stem cells can produce cancer stem cells (CSC). These cells may resist chemotherapy, proliferate, and produce new tumors. Human chorionic gonadotrophin (hCG) is composed of two proteins (alpha and beta) that bind to the cell membrane and activate a number of intracellular pathways. hCG has been shown to activate the proliferation of cancer stem cells. Cyclin dependent regulation of the adult cells is created in normal differentiation and replaces the hCG regulation of stem cells. To selectively kill the cancer stem cells conventional cancer therapies could be followed with a therapy based on inactivating human chronic gonadotrophin (HCG). For example chemically modified prostaglandins like RU486 prevent binding of the unmodified steroid to hCG and inactivate hCG. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8437-8440, November 2018.
  

  May 31, 2018   doi: 10.1002/jcp.26597   open full text
• The imbalance of circulating T helper subsets and regulatory T cells in patients with LRBA deficiency: Correlation with disease severity.
  Gholamreza Azizi, Abbas Mirshafiey, Hassan Abolhassani, Reza Yazdani, Alireza Ghanavatinejad, Farshid Noorbakhsh, Nima Rezaei, Asghar Aghamohammadi.
  Journal of Cellular Physiology. May 28, 2018
  --- - |2 Patients with lipopolysaccharides responsive beige‐like anchor protein (LRBA) deficiency suffer from a variety of immunological abnormalities. In the current study, we investigated the role of T helper (Th) cell subsets and regulatory T (Treg) cells and their related cytokines and transcription factors in the immune dysregulation of LRBA deficiency. The study population comprised of 13 LRBA‐deficient patients and 13 age‐ and sex‐matched healthy controls (HCs). Th subsets and Treg were examined by flow cytometry. The expression of determinant cytokines (interferon‐γ [IFN‐γ], interleukin [IL]‐17, IL‐22, and IL‐10), and cell subset–specific transcription factors were evaluated before and after proliferation and activation stimuli. The frequencies of Th1, Th1‐like Th17 and Th22 cells along with the expression of T‐box transcription factor (TBET) and runt‐related transcription factor 1 (RUNX1) were significantly increased in patients with LRBA. Moreover, IFN‐γ and IL‐22 production in LRBA‐deficient CD4+ T cells were elevated after lymphocyte stimulation, particularly in patients with enteropathy. However, CD4+CD25+FoxP3+CD127− cells were significantly decreased in LRBA‐deficient patients compared with those of HCs, particularly in patients with autoimmunity. There was a negative correlation between the frequencies of CD4+CD25+FoxP3+CD127− cells and Th1‐like Th17 cells in LRBA‐deficient patients, and an overlapping phenotype of autoimmunity and enteropathy were observed in ~70% of patients. The frequency of Th17 cells was lower in patients with enteropathy, while Th1‐like Th17 cells were higher than in those without enteropathy. Our findings demonstrated an imbalance in Th subsets, mainly in Th1‐like Th17 and Treg cells and their corresponding cytokines in LRBA deficiency, which might be important in the immunopathogenesis of autoimmunity and enteropathy. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8767-8777, November 2018.
  

  May 28, 2018   doi: 10.1002/jcp.26772   open full text
• Interaction of CacyBP/SIP with NPM1 and its influence on NPM1 localization and function in oxidative stress.
  Sara Rosińska, Anna Filipek.
  Journal of Cellular Physiology. May 28, 2018
  --- - |2 Calcyclin (S100A6) binding protein/Siah‐1 interacting protein (CacyBP/SIP) is mainly a cytoplasmic protein; however, some literature data suggested its presence in the nucleus. In this work we examined more precisely the nuclear localization and function of CacyBP/SIP. By applying mass spectrometry, we have identified several nuclear proteins, among them is nucleophosmin (NPM1), that may interact with CacyBP/SIP. Subsequent assays revealed that CacyBP/SIP forms complexes with NPM1 in the cell and that the interaction between these two proteins is direct. Interestingly, although CacyBP/SIP exhibits phosphatase activity, we have found that its overexpression favors phosphorylation of NPM1 on S125. In turn, the RNA immunoprecipitation assay indicated that the altered CacyBP/SIP level has an impact on the amount of 28S and 18S rRNA bound to NPM1. The overexpression of CacyBP/SIP resulted in a significant increase in the binding of 28S and 18S rRNA to NPM1, whereas silencing of CacyBP/SIP expression decreased 28S rRNA binding and had no effect on the binding of 18S rRNA. Further studies have shown that under oxidative stress, CacyBP/SIP overexpression alters NPM1 distribution in cell nuclei. In addition, staining for a nucleolar marker, fibrillarin, revealed that CacyBP/SIP is indispensable for maintaining the nucleolar structure. These results are in agreement with data obtained by western blot analysis, which show that upon oxidative stress the NPM1 level decreases but that CacyBP/SIP overexpression counteracts the effect of stress. Altogether, our results show for the first time that CacyBP/SIP binds to and affects the properties of a nuclear protein, NPM1, and that it is indispensable for preserving the structure of nucleoli under oxidative stress. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8826-8838, November 2018.
  

  May 28, 2018   doi: 10.1002/jcp.26797   open full text
• Key genes and functional coexpression modules involved in the pathogenesis of systemic lupus erythematosus.
  Shushan Yan, Weijie Wang, Guohong Gao, Min Cheng, Xiaodong Wang, Zengyan Wang, Xiufen Ma, Chunxiang Chai, Donghua Xu.
  Journal of Cellular Physiology. May 28, 2018
  --- - |2 We performed a systematic review of genome‐wide gene expression datasets to identify key genes and functional modules involved in the pathogenesis of systemic lupus erythematosus (SLE) at a systems level. Genome‐wide gene expression datasets involving SLE patients were searched in Gene Expression Omnibus and ArrayExpress databases. Robust rank aggregation (RRA) analysis was used to integrate those public datasets and identify key genes associated with SLE. The weighted gene coexpression network analysis (WGCNA) was adapted to identify functional modules involved in SLE pathogenesis, and the gene ontology enrichment analysis was utilized to explore their functions. The aberrant expressions of several randomly selected key genes were further validated in SLE patients through quantitative real‐time polymerase chain reaction. Fifteen genome‐wide gene expression datasets were finally included, which involved a total of 1,778 SLE patients and 408 healthy controls. A large number of significantly upregulated or downregulated genes were identified through RRA analysis, and some of those genes were novel SLE gene signatures and their molecular roles in etiology of SLE remained vague. WGCNA further successfully identified six main functional modules involved in the pathogenesis of SLE. The most important functional module involved in SLE included 182 genes and mainly enriched in biological processes, including defense response to virus, interferon signaling pathway, and cytokine‐mediated signaling pathway. This study identifies a number of key genes and functional coexpression modules involved in SLE, which provides deepening insights into the molecular mechanism of SLE at a systems level and also provides some promising therapeutic targets. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8815-8825, November 2018.
  

  May 28, 2018   doi: 10.1002/jcp.26795   open full text
• The promise of stem cell markers in the diagnosis and therapy of epithelial dysplasia and oral squamous cell carcinoma.
  Farnaz Mohajertehran, Amirhossein Sahebkar, Reza Zare, Nooshin Mohtasham.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2 Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancer. Epithelial dysplasia is often initiated in the cells and cell nuclei adjacent to the epithelial cell membrane. Reduced cell–cell adhesions enable cancer cells to detach from the tumor and disseminate to other organs. The mutations in epithelial dysplasia markers such as E‐cadherin and epithelial cell adhesion molecules (CD326) can lead to proliferation, growth and survival of the tumor cells and persistence of numerous malignancies that play a key role in epithelial dysplasia of OSCC. Accordingly, these genes can be considered prognostic markers or potential therapeutic targets for the tailored management of patients with OSCC. The gene expression profile of OSCC stem cells indicates a differential pattern that facilitates establishing a cell signature. Owing to the highly tumorigenic behavior of cancer stem cells and the role of these cells in tumor differentiation, treatment resistance, relapse, and metastasis, we reviewed the role of stem cell markers in epithelial dysplasia and OSCC. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8499-8507, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26789   open full text
• Mcl‐1 targeting could be an intriguing perspective to cure cancer.
  Anna De Blasio, Renza Vento, Riccardo Di Fiore.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2 The Bcl‐2 family, which plays important roles in controlling cancer development, is divided into antiapoptotic and proapoptotic members. The change in the balance between these members governs the life and death of the cells. Mcl‐1 is an antiapoptotic member of this family and its distribution in normal and cancerous tissues strongly differs from that of Bcl‐2. In human cancers, where upregulation of antiapoptotic proteins is common, Mcl‐1 expression is regulated independent of Bcl‐2 and its inhibition promotes senescence, a major barrier to tumorigenesis. Cancer chemotherapy determines various kinds of responses, such as senescence and autophagy; however, the ideal response to chemotherapy is apoptosis. Mcl‐1 is a potent oncogene that is regulated at the transcriptional, posttranscriptional, and posttranslational levels. Mcl‐1 is a short‐lived protein that, in the NH2 terminal region, contains sites for posttranslational regulation that can lead to proteasomal degradation. The USP9X Mcl‐1 deubiquitinase regulates Mcl‐1 and the levels of these two proteins are strongly correlated. Mcl‐1 has three splicing variants (the antiapoptotic protein Mcl‐1L and the proapoptotic proteins Mcl‐1S and Mcl‐1ES), each contributing toward apoptosis regulation. In cancers responsible for the most deaths in the world, the presence of Mcl‐1 is associated with malignant cell growth and evasion of apoptosis. Mcl‐1 is also one of the key regulators of cancer stem cells’ self‐renewal that contributes to tumor survival. A great number of indirect and selective Mcl‐1 inhibitors have been produced and some of these have shown efficacy in several clinical trials. Thus, therapeutic manipulation of Mcl‐1 can be a useful strategy to combat cancer. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8482-8498, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26786   open full text
• Bone marrow mesenchymal stem cell donors with a high body mass index display elevated endoplasmic reticulum stress and are functionally impaired.
  Baris Ulum, Hikmet Taner Teker, Aysun Sarikaya, Gunay Balta, Baris Kuskonmaz, Duygu Uckan‐Cetinkaya, Fatima Aerts‐Kaya.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2 Bone marrow mesenchymal stem cells (BM‐MSCs) are promising candidates for regenerative medicine purposes. The effect of obesity on the function of BM‐MSCs is currently unknown. Here, we assessed how obesity affects the function of BM‐MSCs and the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) therein. BM‐MSCs were obtained from healthy donors with a normal (<25) or high (>30) body mass index (BMI). High‐BMI BM‐MSCs displayed severely impaired osteogenic and diminished adipogenic differentiation, decreased proliferation rates, increased senescence, and elevated expression of ER stress–related genes ATF4 and CHOP. Suppression of ER stress using tauroursodeoxycholic acid (TUDCA) and 4‐phenylbutyrate (4‐PBA) resulted in partial recovery of osteogenic differentiation capacity, with a significant increase in the expression of ALPL and improvement in the UPR. These data indicate that BMI is important during the selection of BM‐MSC donors for regenerative medicine purposes and that application of high‐BMI BM‐MSCs with TUDCA or 4‐PBA may improve stem cell function. However, whether this improvement can be translated into an in vivo clinical advantage remains to be assessed. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8429-8436, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26804   open full text
• Chronic phosphodiesterase type 5 inhibition has beneficial effects on subcutaneous adipose tissue plasticity in type 2 diabetic mice.
  Daniela Fiore, Daniele Gianfrilli, Silvia Cardarelli, Fabio Naro, Andrea Lenzi, Andrea M. Isidori, Mary A. Venneri.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2 Different adipose tissue (AT) depots are associated with multiple metabolic risks. Phosphodiesterase type 5 (PDE5) is involved in adipocyte physiology and PDE5 inhibition may affect adipogenesis and ameliorate white AT quality. The aim of this study is to investigate the distribution of AT and the composition of the stroma‐vascular fraction (SVF) of subcutaneous AT (SAT) in type 2 diabetic mice after prolonged treatment with a PDE5 inhibitor, Sildenafil. 18 db/db mice were treated with Sildenafil or vehicle for 12 weeks. AT distribution was monitored and SAT was processed for isolation of SVF by flow cytometry. Sildenafil induced an overall reduction in AT, mainly in visceral AT (VAT), compared with SAT. In Sildenafil‐treated mice, the mean change in body weight from baseline positively correlated with VAT, but not with SAT. Characterization of SVF of SAT showed an increase in the frequency of M2 macrophages and endothelial cells in treated mice. Sildenafil improved the maintenance of SAT homeostasis and distribution. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8411-8417, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26796   open full text
• Zafirlukast promotes insulin secretion by increasing calcium influx through L‐type calcium channels.
  Hyeon‐Jeong Hwang, Kyoung‐Su Park, Jang Hyun Choi, Lucio Cocco, Hyun‐Jun Jang, Pann‐Ghill Suh.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2+ The zafirlukast has been reported to be anti‐inflammatory and widely used to alleviate the symptoms of asthma. However, its influence on insulin secretion in pancreatic β‐cells has not been investigated. Herein, we examined the effects of zafirlukast on insulin secretion and the potential underlying mechanisms. Among the cysteinyl leukotriene receptor 1 antagonists, zafirlukast, pranlukast, and montelukast, only zafirlukast enhanced insulin secretion in a concentration‐dependent manner in both low and high glucose conditions and elevated the level of [Ca2+]i, further activating Ca2+/calmodulin‐dependent protein kinase II (CaMKII), protein kinase B (AKT), and extracellular signal‐regulated kinase (ERK) signaling. These effects were nearly abolished by the L‐type Ca2+ channel antagonist nifedipine, while treatment with thapsigargin, a sarco/endoplasmic reticulum Ca2+ ATPase inhibitor, did not have the same effect, suggesting that zafirlukast primarily induces the entry of extracellular Ca2+ rather than intracellular Ca2+ from the endoplasmic reticulum. Zafirlukast treatment resulting in a significant drop in glucose levels and increased insulin secretion in C57BL/6J mice. These findings will contribute to an improved understanding of the side effects of zafirlukast and potential candidate for a therapeutic intervention in diabetes. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8701-8710, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26750   open full text
• Excessive training induces molecular signs of pathologic cardiac hypertrophy.
  Alisson L. da Rocha, Giovana R. Teixeira, Ana P. Pinto, Gustavo P. Morais, Luciana da C. Oliveira, Larissa Gaioto de Vicente, Lilian E. C. M. da Silva, José R. Pauli, Dennys E. Cintra, Eduardo R. Ropelle, Leandro P. de Moura, Rania A. Mekary, Ellen C. de Freitas, Adelino S. R. da Silva.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2 Chronic exercise induces cardiac remodeling that promotes left ventricular hypertrophy and cardiac functional improvement, which are mediated by the mammalian or the mechanistic target of rapamycin (mTOR) as well as by the androgen and glucocorticoid receptors (GRs). However, pathological conditions (i.e., chronic heart failure, hypertension, and aortic stenosis, etc.) also induce cardiac hypertrophy, but with detrimental function, high levels of proinflammatory cytokines and myostatin, elevated fibrosis, reduced adenosine monophosphate‐activated protein kinase (AMPK) activation, and fetal gene reactivation. Furthermore, recent studies have evidenced that excessive training induced an inflammatory status in the serum, muscle, hypothalamus, and liver, suggesting a pathological condition that could also be detrimental to cardiac tissue. Here, we verified the effects of three running overtraining (OT) models on the molecular parameters related to physiological and pathological cardiac hypertrophy. C57BL/6 mice performed three different OT protocols and were evaluated for molecular parameters related to physiological and pathological cardiac hypertrophy, including immunoblotting, reverse transcription polymerase chain reaction, histology, and immunohistochemistry analyses. In summary, the three OT protocols induced left ventricle (LV) hypertrophy with signs of cardiac fibrosis and negative morphological adaptations. These maladaptations were accompanied by reductions in AMPKalpha (Thr172) phosphorylation, androgen receptor, and GR expressions, as well as by an increase in interleukin‐6 expression. Specifically, the downhill running–based OT model reduced the content of some proteins related to the mTOR signaling pathway and upregulated the β‐isoform of myosin heavy‐chain gene expression, presenting signs of LV pathological hypertrophy development. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8850-8861, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26799   open full text
• Long non‐coding RNA FEZF1‐AS1 promotes breast cancer stemness and tumorigenesis via targeting miR‐30a/Nanog axis.
  Zhi Zhang, Liwei Sun, Yixuan Zhang, Guanming Lu, Yongqiang Li, Zhongheng Wei.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2+ Long non‐coding RNAs (lncRNAs) have been verified to modulate the tumorigenesis of breast cancer at multiple levels. In present study, we aim to investigate the role of lncRNA FEZF1‐AS1 on breast cancer‐stem like cells (BCSC) and the potential regulatory mechanism. In breast cancer tissue, lncRNA FEZF1‐AS1 was up‐regulated compared with controls and indicated poor prognosis of breast cancer patients. In vitro experiments, FEZF1‐AS1 was significantly over‐expressed in breast cancer cells, especially in sphere subpopulation compared with parental subpopulation. Loss‐of‐functional indicated that, in BCSC cells (MDA‐MB‐231 CSC, MCF‐7 CSC), FEZF1‐AS1 knockdown reduced the CD44+/CD24− rate, the mammosphere‐forming ability, stem factors (Nanog, Oct4, SOX2), and inhibited the proliferation, migration and invasion. In vivo, FEZF1‐AS1 knockdown inhibited the breast cancer cells growth. Bioinformatics analysis tools and series of validation experiments confirmed that FEZF1‐AS1 modulated BCSC and Nanog expression through sponging miR‐30a, suggesting the regulation of FEZF1‐AS1/miR‐30a/Nanog. In summary, our study validate the important role of FEZF1‐AS1/miR‐30a/Nanog in breast cancer stemness and tumorigenesis, providing a novel insight and treatment strategy for breast cancer. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8630-8638, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26611   open full text
• TANK‐binding kinase 1 and Janus kinase 2 play important roles in the regulation of mitogen‐activated protein kinase phosphatase‐1 expression after toll‐like receptor 4 activation.
  Eunji Kim, Ju Y. Yoon, Jongsung Lee, Deok Jeong, Jae G. Park, Yo H. Hong, Ji H. Kim, Adithan Aravinthan, Jong‐Hoon Kim, Jae Y. Cho.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2 Inflammation is a response that protects the body from pathogens. Through several inflammatory signaling pathways mediated by various families of transcription factors, such as nuclear factor‐κB (NF‐κB), activator protein‐1 (AP‐1), interferon regulatory factors (IRFs), and signal transducers and activators of transcription (STATs), various inflammatory cytokines and chemokines are induced and inflammatory responses are boosted. Simultaneously, inhibitory systems are activated and provide negative feedback. A typical mechanism by which this process occurs is that inflammatory signaling molecules upregulate mitogen‐activated protein kinase phosphatase‐1 (MKP1) expression. Here, we investigated how kinases regulate MKP1 expression in lipopolysaccharide‐triggered cascades. We found that p38 and c‐Jun N‐terminal kinase (JNK) inhibitors decreased MKP1 expression. Using specific inhibitors, gene knockouts, and gene knockdowns, we also found that tumor necrosis factor receptor‐associated factor family member‐associated nuclear factor κB activator (TANK)‐binding kinase 1 (TBK1) and Janus kinase 2 (JAK2) are involved in the induction of MKP1 expression. By analyzing JAK2‐induced activation of STATs, STAT3‐specific inhibitors, promoter binding sites, and STAT3−/− cells, we found that STAT3 is directly linked to TBK1‐mediated and JAK2‐mediated induction of MKP1 expression. Our data suggest that MKP1 expression can be differentially regulated by p38, JNK, and the TBK1–JAK2–STAT3 pathway after activation of toll‐like receptor 4 (TLR4). These data also imply crosstalk between the AP‐1 pathway and the IRF3 and STAT3 pathways. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8790-8801, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26787   open full text
• Spheroids from adipose‐derived stem cells exhibit an miRNA profile of highly undifferentiated cells.
  A. Barbara Di Stefano, Federica Grisafi, Marta Castiglia, Alessandro Perez, Luigi Montesano, Alessandro Gulino, Francesca Toia, Daniele Fanale, Antonio Russo, Francesco Moschella, Angelo A. Leto Barone, Adriana Cordova.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2 Two‐dimensional (2D) cell cultures have been extensively used to investigate stem cell biology, but new insights show that the 2D model may not properly represent the potential of the tissue of origin. Conversely, three‐dimensional cultures exhibit protein expression patterns and intercellular junctions that are more representative of their in vivo condition. Multiclonal cells that grow in suspension are defined as “spheroids,” and we have previously demonstrated that spheroids from adipose‐derived stem cells (S‐ASCs) displayed enhanced regenerative capability. With the current study, we further characterized S‐ASCs to further understand the molecular mechanisms underlying their stemness properties. Recent studies have shown that microRNAs (miRNAs) are involved in many cellular mechanisms, including stemness maintenance and proliferation, and adipose stem cell differentiation. Most studies have been conducted to identify a specific miRNA profile on adherent adipose stem cells, although little is still known about S‐ASCs. In this study, we investigate for the first time the miRNA expression pattern in S‐ASCs compared to that of ASCs, demonstrating that cell lines cultured in suspension show a typical miRNA expression profile that is closer to the one reported in induced pluripotent stem cells. Moreover, we have analyzed miRNAs that are specifically involved in two distinct moments of each differentiation, namely early and late stages of osteogenic, adipogenic, and chondrogenic lineages during long‐term in vitro culture. The data reported in the current study suggest that S‐ASCs have superior stemness features than the ASCs and they represent the true upstream stem cell fraction present in adipose tissue, relegating their adherent counterparts. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8778-8789, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26785   open full text
• NEAT1 upregulates TGF‐β1 to induce hepatocellular carcinoma progression by sponging hsa‐mir‐139‐5p.
  Jianfei Tu, Zhongwei Zhao, Min Xu, Xiaojie Lu, Liu Chang, Jiansong Ji.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2+ Increasing evidence has shown that the lncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) play important roles in cell proliferation, migration, and invasion in various tumors. In our current study, we concentrated on the biological mechanisms of NEAT1 in hepatocellular carcinoma (HCC) development. It was found that NEAT1 was significantly increased in human HCC cell lines including Hep3B, LM3, MHCC97L, SK‐hep1, and HepG2 cells compared to the normal human liver cell line LO2. Meanwhile, we observed that hsa‐miR‐139‐5p was greatly decreased in HCC cells, which suggested a negative correlation between NEAT1 and hsa‐mir‐139‐5p. In addition, NEAT1 downregulation can restrain HCC cell growth, migration, and invasion. Consistently, overexpression of hsa‐mir‐139‐5p exerted a similar phenomenon. Dual‐luciferase reporter assay, RIP assay, and RNA pull‐down assay confirmed that NEAT1 can function as a ceRNA by sponging hsa‐mir‐139‐5p. In addition, TGF‐β1 was identified as a downstream target of hsa‐mir‐139‐5p and hsa‐mir‐139‐5p overexpression was able to suppress TGF‐β1 levels. Furthermore, it was indicated that TGF‐β1 inhibition can inhibit HCC cell growth, migration, and invasion ability. Taken these together, we speculated that NEAT1 can modulate TGF‐β1 expression by sponging hsa‐mir‐139‐5p in HCC. These data indicates that targeting the NEAT1/hsa‐mir‐139‐5p/TGF‐β1 axis could be a new strategy for HCC. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8578-8587, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26524   open full text
• The immunomodulatory effects of adipose‐derived mesenchymal stem cells and mesenchymal stem cells‐conditioned medium in chronic colitis.
  Maryam Heidari, Sedigheh Pouya, Kaveh Baghaei, Hamid Asadzadeh Aghdaei, Saeed Namaki, Mohammad Reza Zali, Seyed Mahmoud Hashemi.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2 Inflammatory bowel disease (IBD) as a chronic recurrent disorder is characterized by mucosal immune response dysregulation, which is more prevalent in the youth. Adipose‐derived mesenchymal stem cells (ADMSCs) are the multipotent cells that can be effective in immune response regulation via cell–cell interaction and their secretions. In this study, the effects of ADMSCs and mesenchymal stem cell‐conditioned medium (MSC‐CM) were evaluated on dextran sulfate sodium (DSS)‐induced colitis in mice. Chronic colitis was induced in female C57BL/6 mice using 2% DSS in drinking water for three cycles; there were 4 days of DSS‐water administration that was followed by 7 days of DSS‐free water, in a cycle. ADMSCs, 106 cells per mouse, were injected intraperitoneally (IP), whereas the MSC‐CM injection was also performed six times from the last day of DSS in Cycle 1. Clinical symptoms were recorded daily. The colon pathological changes, cytokine levels, and regulatory T (Treg) cell percentages were then analyzed. After receiving ADMSCs and MSC‐CM in colitis mice, the clinical symptoms and disease activity index were improved and the survival rate was increased. The histopathological examination also showed tissue healing in comparison with the nontreated group. In addition, the increased level of transforming growth factor beta, increased percentage of Treg cells, increased level of interleukin (IL)‐10, and decreased level of IL‐17 were observed after the treatment. This study showed the regulatory effects of ADMSCs and MSC‐CM on inflammatory responses. Therefore, the use of ADMSCs and MSC‐CM can be introduced as a new and effective therapeutic approach for patients with colitis. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8754-8766, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26765   open full text
• Umbelliprenin shows antitumor, antiangiogenesis, antimetastatic, anti‐inflammatory, and immunostimulatory activities in 4T1 tumor‐bearing Balb/c mice.
  Mohsen Rashidi, Ahad Khalilnezhad, Davar Amani, Hamidreza Jamshidi, Ahad Muhammadnejad, Ali Bazi, Seyed Ali Ziai.
  Journal of Cellular Physiology. May 24, 2018
  --- - |2 Umbelliprenin (UMB) has shown various pharmacological properties in vitro. We investigated the antineoplastic and immunostimulatory effects of UMB in 4T1 mammary‐tumor‐bearing mice. Two‐hundred microliter of UMB (12.5 mg/ml) was intraperitoneally administrated to healthy and tumor‐bearing female Balb/c mice for a period of 18 days. Data was analyzed using GraphPad Prism 5 software for Windows (version 5, La Jolla, CA). UMB caused a significant decrease in tumor size (P < 0.01). Serum interferon gamma (IFNγ) was augmented in both healthy and tumor‐bearing animals (P < 0.01), and IL‐4 declined in healthy animals (P < 0.01) treated with UMB. Expressions of Ki‐67, VEGF, CD31, MMP2, MMP9, VCAM1, and NF‐κB were significantly decreased in tumors from UMB‐treated animals (P < 0.001), whereas E‐Cadherin and TNFR1 expressions were markedly increased (P < 0.001). The rates of liver and lung metastases in UMB‐administrated animals were smaller compared to the control. UMB can potently inhibit tumor growth, angiogenesis, metastasis, and inflammation and potentiate an antitumor immune response in vivo. However, further investigations are required to evaluate the UMB mechanisms of action in cancerous cells. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8908-8918, November 2018.
  

  May 24, 2018   doi: 10.1002/jcp.26814   open full text
• Articular cartilage protection in Ctsk‐/‐ mice is associated with cellular and molecular changes in subchondral bone and cartilage matrix.
  Fabiana N. Soki, Ryu Yoshida, David N. Paglia, Le T. Duong, Marc F. Hansen, Hicham Drissi.
  Journal of Cellular Physiology. May 21, 2018
  --- - |2+ Osteoarthritis (OA) is a degenerative disease and a major cause of chronic disability in aging individuals. Cathepsin K (CatK), encoded by the Ctsk gene, has been implicated in the pathogenesis of pycnodysostosis and osteoporosis. The use of a selective inhibitor of CatK was recently shown to delay OA progression in rabbits. However, the cellular mechanisms underlying these protective effects remain unexplored. We examined articular cartilage maintenance and joint bone remodeling using Ctsk null mice (Ctsk‐/‐) which underwent destabilization of the medial meniscus (DMM). We found that Ctsk‐/‐ mice displayed delayed remodeling of subchondral and calcified cartilage by osteoclasts and chodroclasts respectively in DMM‐induced osteoarthritis. While WT mice displayed a more severe OA phenotype than Ctsk‐/‐ mice at 16 weeks, higher subchondral bone volume and lower trabecular spacing were also observed in surgically‐induced OA joints of Ctsk‐/‐ mice. However, no differences were seen in non‐surgical controls. During OA progression, TRAP+ osteoclast numbers were increased in both WT and Ctsk‐/‐ mice. However, Ctsk‐/‐ mice had fewer physis‐derived chondroclasts than WT when OA was present. These data suggest that CatK may differentially regulate chondroclastogenesis in the growth plate. Targeted PCR arrays of RNA harvested from laser captured osteoclasts in the subchondral bone and chondroclasts in the growth plate demonstrated differential expression of Atp6v0d2, Tnfrsf11a, Ca2, Calcr, Ccr1, Gpr68, Itgb3, Nfatc1, and Syk genes between WT and Ctsk‐/‐ mice at 8‐ and 16‐weeks post‐DMM. Our data provide insight into the cellular mechanisms by which cathepsin K deletion delays OA progression in mice. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8666-8676, November 2018.
  

  May 21, 2018   doi: 10.1002/jcp.26745   open full text
• Effect of estradiol on fibroblasts from postmenopausal idiopathic carpal tunnel syndrome patients.
  Yoshiaki Yamanaka, Kunitaka Menuki, Takafumi Tajima, Yasuaki Okada, Kenji Kosugi, Yukichi Zenke, Akinori Sakai.
  Journal of Cellular Physiology. May 21, 2018
  --- - |2+ Fibrosis of the subsynovial connective tissue (SSCT) is a characteristic finding in patients with idiopathic carpal tunnel syndrome (CTS). Idiopathic CTS frequently occurs in postmenopausal women; therefore, female steroid hormones, especially estrogens, may be involved in its development. In this study, we evaluated the effect of the estradiol on the expression of genes and proteins related to fibrosis of SSCT fibroblasts from patients with idiopathic CTS. This study included 10 postmenopausal women (mean age 76 years). Fibroblasts derived from SSCT were treated with estradiol (10−4–10−12 M), and the expression levels of TGF‐β‐responsive genes were evaluated. The relationships between the expression of untreated estrogen receptor α (ERα) and ERβ and changes in gene expression due to estradiol treatment were examined by quantitative real‐time polymerase chain reaction. The effects of 10−4 M estradiol on collagen type I (Col1) and collagen type III (Col3) protein expression levels were also evaluated by fluorescent staining. The relationships between ERα/β and Col1/3 expression were evaluated by immunohistochemical staining. The reduction in Col1A1 mRNA expression due to estradiol treatment was positively correlated with ERα expression (r = 0.903, p < 0.01). At the protein level, expression of Col1 and Col3 were down‐regulated. These results indicated that ERα‐mediated signaling may be involved in the regulation of Col1A1, and its regulatory effect may be dependent on the ERα expression level. The accurate evaluation of ERα expression level in the SSCT of individual patients with idiopathic CTS might guide the effective use of new estrogen replacement therapy. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8723-8730, November 2018.
  

  May 21, 2018   doi: 10.1002/jcp.26752   open full text
• Effects of δ‐tocotrienol on ochratoxin A—induced nephrotoxicity in rats.
  Sara Damiano, Luigi Navas, Patrizia Lombari, Serena Montagnaro, Iris M. Forte, Antonio Giordano, Salvatore Florio, Roberto Ciarcia.
  Journal of Cellular Physiology. May 18, 2018
  --- - |2+ Ochratoxin A (OTA), is a natural contaminant of the food chain worldwide involved in the development of different type of cancers in animals and humans. Several studies suggested that oxidative damage might contribute to increase the cytotoxicity and carcinogenicity capabilities of OTA. The aim of this study was to evaluate the possible protective effect of δ‐tocotrienol (Delta), a natural form of vitamin E, against OTA‐induced nephrotoxicity. Male Sprague–Dawley rats were treated with OTA and/or Delta by gavage for 14 days. Our results shown that OTA treatment induced the increase of reactive oxigen species production correlated to a strong reduction of Glomerular Filtration Rate (GFR) and absoluted fluid reabsorption (Jv) with conseguent significant increase in blood pressure. Consistent, we noted in the kidney of rats treated with OTA, an increase in malondialdheyde and dihydroethidium production and a reduction of the activity of the catalase, superoxide dismutase, and glutathione peroxidase. Conversly, in the rat group subjected to the concomitant treatment OTA plus Delta, we observed the restored effect, compared the OTA treatment group, on blood pressure, GFR, Jv, and all activities of renal antioxidant enzymes. Finally, as far as concern the tissue damage induced by OTA and measured evaluating fibronectin protein levels, we observed that in OTA plus Delta group this effect is not restored. Our findings releval that a mechanism underlying the renal toxicity induced by OTA is the oxidative stress and provide a new rationale to use a Delta in order to protect, at least in part, against OTA‐induced nephrotoxicity. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8731-8739, November 2018.
  

  May 18, 2018   doi: 10.1002/jcp.26753   open full text
• Let‐7e inhibits TNF‐α expression by targeting the methyl transferase EZH2 in DENV2‐infected THP‐1 cells.
  Yingke Zhang, Qianqian Zhang, Lian Gui, Yan Cai, Xiaohong Deng, Cheukfai Li, Qi Guo, Xiaoshun He, Junqi Huang.
  Journal of Cellular Physiology. May 16, 2018
  --- - |2+ Tumor necrosis factor α (TNFα), an important inflammatory cytokine, is associated with dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), a severe pathological manifestation of dengue virus (DENV) infection. However, the regulatory mechanism of microRNA on TNFα is currently unknown. Our study showed that the TNFα expression increased immediately and then later decreased, while a marked increase for the miRNA let‐7e was detected in dengue virus type 2 (DENV2)‐infected peripheral blood mononuclear cells (PBMCs). From this study, we found that let‐7e was able to inhibit TNFα expression, but bioinformatics analysis showed that the enhancer of zeste homolog 2 (EZH2) was the potential direct target of let‐7e instead of TNFα. EZH2 methyl transferase can produce H3K27me3 and has a negative regulatory role. Using a dual‐luciferase reporter assay and Western blotting, we confirmed that EZH2 was a direct target of let‐7e and found that siEZH2 could inhibit TNFα expression. In the further study of the regulatory mechanism of EZH2 on TNFα expression, we showed that siEZH2 promoted EZH1 and H3K4me3 expression and inhibited H3K27me3 expression. More importantly, we revealed that siEZH2 down‐regulated NF‐κB p65 within the nucleus. These findings indicate that the let‐7e/EZH2/H3K27me3/NF‐κB p65 pathway is a novel regulatory axis of TNFα expression. In addition, we determined the protein differences between siEZH2 and siEZH2‐NC by iTRAQ and found a number of proteins that might be associated with TNFα. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8605-8616, November 2018.
  

  May 16, 2018   doi: 10.1002/jcp.26576   open full text
• Inhibitory effects of tubeimoside I on synoviocytes and collagen‐induced arthritis in rats.
  Zhenzhou Liu, Lin Zhou, Xuemei Ma, Shengnan Sun, Haiwen Qiu, Hui Li, Jiake Xu, Mei Liu.
  Journal of Cellular Physiology. May 15, 2018
  --- - |2+ Advancements in rheumatoid arthritis (RA) therapies have shown considerable progresses in the comprehension of disease. However, the development of new potential medicines with relative safety and efficacy continues and natural compounds have been considered as alternatives or complementary agents to gain immense attractions. Tubeimoside I (TBMS I), a main triterpenoid saponin isolated from Bolbostemma paniculatum, has been reported to possess antiviral and anticancer effects. However, its effect on RA remains unknown. Here, we investigated the therapeutic effect of TBMS I in collagen‐induced arthritis (CIA) rats and explored its underlying mechanism. Our results showed that TBMS I treatment efficaciously ameliorated inflammation and joint destruction of rats with CIA. In vitro studies revealed that TBMS I suppressed the production of pro‐inflammatory cytokines including IL‐1β, IL‐6, IL‐8 and TNFα, and downregulated the expression of MMP‐9. In addition, TBMS I attenuated the destructive phenotypes of FLS of CIA rats including inhibiting proliferation and reducing migration rate. Further mechanistic analysis demonstrated that TBMS I suppressed TNFα‐induced activations of NF‐κB and MAPKs (p38 and JNK) leading to the downregulation of pro‐inflammatory cytokines, which was beneficial to the anti‐proliferative and anti‐migratory activities of FLS cells. Taken together, TBMS I has a great potential to be developed into a novel therapeutic agent for the treatment of RA. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8740-8753, November 2018.
  

  May 15, 2018   doi: 10.1002/jcp.26754   open full text
• Multiple phosphorylation sites on γ‐tubulin are essential and contribute to the biogenesis of basal bodies in Tetrahymena.
  Ewa Joachimiak, Maria Jerka‐Dziadosz, Łucja Krzemień‐Ojak, Ewa Wacławek, Katarzyna Jedynak, Paulina Urbanska, Wojciech Brutkowski, Hanna Sas‐Nowosielska, Hanna Fabczak, Jacek Gaertig, Dorota Wloga.
  Journal of Cellular Physiology. May 15, 2018
  --- - |2+ The mechanisms that regulate γ‐tubulin, including its post‐translational modifications, are poorly understood. γ‐Tubulin is important for the duplication of centrioles and structurally similar basal bodies (BBs), organelles which contain a ring of nine triplet microtubules. The ciliate Tetrahymena thermophila carries hundreds of cilia in a single cell and provides an excellent model to specifically address the role of γ‐tubulin in the BBs assembly and maintenance. The genome of Tetrahymena contains a single γ‐tubulin gene. We show here that there are multiple isoforms of γ‐tubulin that are likely generated by post‐translational modifications. We identified evolutionarily conserved serine and threonine residues as potential phosphosites of γ‐tubulin, including S80, S129, S131, T283, and S360. Several mutations that either prevent (S80A, S131A, T283A, S360A) or mimic (T283D) phosphorylation were conditionally lethal and at a higher temperature phenocopied a loss of γ‐tubulin. Cells that overproduced S360D γ‐tubulin displayed phenotypes consistent with defects in the microtubule‐dependent functions, including an asymmetric division of the macronucleus and abnormalities in the pattern of BB rows, including gaps, fragmentation, and misalignment. In contrast, overexpression of S129D γ‐tubulin affected the orientation, docking, and structure of the BBs, including a loss of either the B‐ or C‐subfibers or the entire triplets. We conclude that conserved potentially phosphorylated amino acids of γ‐tubulin are important for either the assembly or stability of BBs. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8648-8665, November 2018.
  

  May 15, 2018   doi: 10.1002/jcp.26742   open full text
• NEAT1 contributes to breast cancer progression through modulating miR‐448 and ZEB1.
  Xing Jiang, Yong Zhou, Ai‐Jun Sun, Jun‐Li Xue.
  Journal of Cellular Physiology. May 15, 2018
  --- - |2+ Breast cancer is a kind of common female cancers. Increasing evidence has exhibited that lncRNAs exert a crucial role in breast cancer. So far, the mechanism of lncRNAs in breast cancer is still not well established. In our current study, we focused on the biological role of lncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) in breast cancer. We observed that NEAT1 levels were significantly increased in human breast cancer cells including MCF‐7, MDA‐MB‐453, MDA‐MB‐231, and SKBR3 cells compared to normal mammary epithelial cells MCF‐10A while miR‐448 was decreased. We found that downregulation of NEAT1 was able to inhibit the growth of breast cancer cells and miR‐448 mimic exerted the similar function. Bioinformatics analysis and dual luciferase reporter assays confirmed the negative correlation between NEAT1 and miR‐448 in vitro. In addition, ZEB1 was predicted as a novel mRNA target of miR‐448. Overexpression of NEAT1 can induce breast cancer cell growth, migration, and invasion by inhibiting miR‐448 and upregulating ZEB1. It was demonstrated that NEAT1 can increase ZEB1 levels while miR‐448 mimic can repress ZEB1. It was speculated in our study that NEAT1 can serve as a competing endogenous lncRNA (ceRNA) to modulate ZEB1 by sponging miR‐448 in breast cancer. To conclude, we uncovered that NEAT1 participated in breast cancer progression by regulating miR‐448 and ZEB1. NEAT1 can be provided as a vital biomarker in breast cancer diagnosis and treatment therapy. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8558-8566, November 2018.
  

  May 15, 2018   doi: 10.1002/jcp.26470   open full text
• Zinc mitigates renal ischemia‐reperfusion injury in rats by modulating oxidative stress, endoplasmic reticulum stress, and autophagy.
  Najet Hadj Abdallah, Anna Baulies, Ahlem Bouhlel, Mohamed Bejaoui, Mohamed A. Zaouali, Safa Ben Mimouna, Imed Messaoudi, José C. Fernandez‐Checa, Carmen García Ruiz, Hassen Ben Abdennebi.
  Journal of Cellular Physiology. May 15, 2018
  --- - |2+ Oxidative stress is a major factor involved in the pathogenesis of renal ischemia/reperfusion (I/R). Exogenous zinc (Zn) was suggested as a potent antioxidant; however, the mechanism by which it strengthens the organ resistance against the effects of reactive oxygen species (ROS) is not yet investigated. The present study aims to determine whether acute zinc chloride (ZnCl2) administration could attenuate endoplasmic reticulum (ER) stress, autophagy, and inflammation after renal I/R. Rats were subjected to either sham operation (Sham group, n = 6), or 1 hr of bilateral ischemia followed by 2 hr of reperfusion (I/R groups, n = 6), or they received ZnCl2 orally 24 hr and 30 min before ischemia (ZnCl2 group, n = 6). Rats were subjected to 1 hr of bilateral renal ischemia followed by 2 hr of reperfusion (I/R group, n = 6). Our results showed that ZnCl2 enhances renal function and reduces cytolysis (p < 0,05). In addition, it increased significantly the activities of antioxidant enzymes (SOD, CAT, and GPX) and the level of GSH in comparison to I/R (p < 0,05). Interestingly, ZnCl2 treatment resulted in significant decreased ER stress, as reflected by GRP78, ATF‐6,p‐eIF‐2α, XPB‐1, and CHOP downregulaion. Rats undergoing ZnCl2 treatment demonstrated a low expression of autophagy parameters (Beclin‐1 and LAMP‐2), which was correlated with low induction of apoptosis (caspase‐9, caspase‐3, and p‐JNK), and reduction of inflammation (IL‐1ß, IL‐6, and MCP‐1) (p < 0,05). In conclusion, we demonstrated the potential effect of Zn supplementation to modulate ER pathway and autophagic process after I/R. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8677-8690, November 2018.
  

  May 15, 2018   doi: 10.1002/jcp.26747   open full text
• Downregulated expression of microRNA‐329 inhibits apoptosis of nigral dopaminergic neurons by regulating CDKN2D expression via the FoxO3a signaling pathway in rats with Parkinson's disease.
  Yuan‐Yuan Liu, Yi‐Nan Zhang, Qing‐Shan Yang.
  Journal of Cellular Physiology. May 15, 2018
  --- - |2+ Parkinson's disease (PD) is a common neurodegenerative disorder due to the loss of dopaminergic neurons in the substantia nigra. This study focuses on the effect of microRNA‐329 (miR‐329) on nigral dopaminergic neurons in a rat model of PD via the FoxO3a signaling pathway by binding to CDKN2D. Brain tissues from the substantia nigra were taken from the rats in two groups. TUNEL staining was used to observe tyrosine hydroxylase (TH)‐positive neurons. Nigral dopaminergic neurons were randomized into the normal, blank, negative control (NC), miR‐329 mimics, miR‐329 inhibitors, small interfering (siRNA)‐CDKN2D, and miR‐329 inhibitors + siRNA‐CDKN2D groups. Expressions of miR‐329, CDKN2D, FoxO3a, AKT, caspase‐3 and Bcl‐2 were determined using RT‐qPCR and western blotting. Apoptosis rate of nigral dopaminergic neurons in 7 groups was determined by flow cytometry. Compared with the blank and NC groups, the miR‐329 mimics group showed increased miR‐329 and caspase‐3 expressions as well as decreased expressions of CDKN2D, FoxO3a, AKT, and Bcl‐2, the siRNA‐CDKN2D group indicated enhanced expressions of caspase‐3 and declined expressions of CDKN2D, FoxO3a, AKT, and Bcl‐2, and the miR‐329 inhibitors group revealed decreased miR‐329 and caspase‐3 expressions and increased expressions of CDKN2D, FoxO3a, AKT, and Bcl‐2. The apoptosis rate of nigral dopaminergic neurons was significantly increased in the miR‐329 mimics and siRNA‐CDKN2D groups, but was decreased in the miR‐329 inhibitors group. Our data suggested that downregulated miR‐329 could inhibit apoptosis of nigral dopaminergic neurons in a rat model of PD by upregulating the expression of CDKN2D via the activation of the FoxO3a signaling pathway. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8617-8629, November 2018.
  

  May 15, 2018   doi: 10.1002/jcp.26608   open full text
• Unexpected regulation pattern of the IKKβ/NF‐κB/MuRF1 pathway with remarkable muscle plasticity in the Daurian ground squirrel (Spermophilus dauricus).
  Yanhong Wei, Lingchen Gong, Weiwei Fu, Shenhui Xu, Zhe Wang, Jie Zhang, Er Ning, Hui Chang, Huiping Wang, Yunfang Gao.
  Journal of Cellular Physiology. May 15, 2018
  --- - |2+ As a typical hibernator, the Daurian ground squirrel (Spermophilus dauricus) spends considerable time in a state of reduced activity with prolonged fasting. Despite this, they experience little muscle atrophy and have thus become an interesting anti‐disuse muscle atrophy model. The IKKβ/NF‐κB signaling pathway is significant to muscle atrophy due to the protein degradation resulting from the upregulation of the E3 ubiquitin ligase MuRF1. The current study showed that the IKKβ/NF‐κB signaling pathway and MuRF1 maintained relatively steady mRNA and protein expression levels, with little muscle atrophy observed in the soleus (slow‐twitch, SOL) or extensor digitorum longus (fast‐twitch, EDL) during hibernation (HIB); however, mRNA expression significantly increased in the SOL and EDL muscle during interbout arousal (IBA), as did the MuRF1 mRNA level in the SOL and MuRF1 protein level in the EDL. Interestingly, the expressions of p50 and MuRF1 significantly increased during HIB in the gastrocnemius (mixed muscle, GAS) and showed moderate atrophy, but dramatically decreased during IBA. Elevated IKKβ and p50 mRNA and protein expression in the cardiac muscle (CM) during HIB did not accompany increased MuRF1 expression or muscle wasting. Importantly, almost all increased or decreased indicators in the tested tissues recovered to pre‐hibernation levels after HIB. This is the first study to report on the unexpected regulation of the IKKβ/NF‐κB/MuRF1 pathway with remarkable muscle plasticity in Daurian ground squirrels during hibernation. Furthermore, we found that different types of muscles exhibited different strategies to cope with prolonged hibernation‐induced disuse muscle atrophy. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8711-8722, November 2018.
  

  May 15, 2018   doi: 10.1002/jcp.26751   open full text
• Effects of bone marrow mesenchymal stem cells transfected with Ang‐1 gene on hyperoxia‐induced optic nerve injury in neonatal mice.
  Fang‐Yu Liu, Guang‐Wu Li, Chang‐Hua Sun, Sha Chen, Jun‐Fei Cao, Qian‐Qian Ma, Sheng‐Yun Fang.
  Journal of Cellular Physiology. May 15, 2018
  --- - |2+ Optic nerve injury triggered retinal ganglion cell (RGC) death and optic nerve atrophy lead to visual loss. Bone marrow mesenchymal stem cells (BMSCs) are stromal cells, capable of proliferating and differentiating into different types of tissues. This aims of this study is to investigate the role of BMSCs transfected with angiopoietin‐1 (Ang‐1) in optic nerve injury induced by hyperoxia in a neonatal mice model. Ang‐1 overexpression vector was constructed and used to transfect BMSCs. Reverse transcription‐quantitative polymerase chain reaction was performed to detect Ang‐1 expression in BMSCs. The hyperoxia‐induced optic nerve injury model was established. The optic nerves at 6–7 mm posterior to the eyeball were extracted, and were treated with luxol fast blue staining, immunohistochemistry, immunofluorescence, and transmission electron microscopy to examine the effects of Ang‐1‐modified BMSCs on optic nerve injury induced by hyperoxia. The mice in the Ang‐1 + BMSCs and BMSCs groups showed remarkably improved myelin sheaths of nerve fibers compared to the hyperoxia saline group. The positive expression and integrated optic density of Ang‐1 in the Ang‐1 + BMSCs group were significantly higher compared to the air control, hyperoxia saline and BMSCs groups. The number and diameter of myelinated nerve fibers, the diameter of axons and the thickness of myelin sheath in the air control and Ang‐1 + BMSCs groups were higher compared to the hyperoxia saline group. Our study provides evidence supporting that Ang‐1‐modified BMSCs may have preventive and therapeutic effects on hyperoxia‐induced optic nerve injury in neonatal mice. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8567-8577, November 2018.
  

  May 15, 2018   doi: 10.1002/jcp.26501   open full text
• Endocytosed factor V is trafficked to CD42b+ proplatelet extensions during differentiation of human umbilical cord blood‐derived megakaryocytes.
  Jacqueline M. Gertz, Kelley C. McLean, Beth A. Bouchard.
  Journal of Cellular Physiology. May 15, 2018
  --- - |2+ Plasma‐ and platelet‐derived factor Va are essential for thrombin generation catalyzed by the prothrombinase complex; however, several observations demonstrate that the platelet‐derived cofactor, which is formed following megakaryocyte endocytosis and modification of the plasma procofactor, factor V, is more hemostatically relevant. Factor V endocytosis, as a function of megakaryocyte differentiation and proplatelet formation, was assessed by flow cytometry and microscopy in CD34+ hematopoietic progenitor cells isolated from human umbilical cord blood and cultured for 12 days in the presence of cytokines to induce ex vivo differentiation into megakaryocytes. Expression of an early marker of megakaryocyte differentiation, CD41, endocytosis of factor V, and the percentage of CD41+ cells that endocytosed factor V increased from days 6 to 12 of differentiation. In contrast, statistically significant decreases in expression of the stem cell marker, CD34, and in the percentage of CD34+ cells that endocytosed factor V were observed. A statistically significant increase in the expression of CD42b, a late marker of megakaryocyte differentiation, was also observed over time, such that by Day 12, all CD42b+ cells endocytosed factor V and expressed CD41. This endocytosed factor V was trafficked to proplatelet extensions and was localized in a punctate pattern in the cytoplasm consistent with its storage in α‐granules. In conclusion, loss of CD34 and expression of CD42b define cells capable of factor V endocytosis and trafficking to proplatelet extensions during differentiation of megakaryocytes ex vivo from progenitor cells isolated from umbilical cord blood. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8691-8700, November 2018.
  

  May 15, 2018   doi: 10.1002/jcp.26749   open full text
• Curcumin alleviates ischemia reperfusion‐induced late kidney fibrosis through the APPL1/Akt signaling pathway.
  Chen Hongtao, Fan Youling, Huang Fang, Peng Huihua, Zhong Jiying, Zhou Jun.
  Journal of Cellular Physiology. May 09, 2018
  --- - |2+ As a major cause of renal failure, transient renal ischemia and reperfusion induce both acute kidney injury and late fibrosis, which are the common pathological manifestations of end‐stage renal disease. Curcumin is a biologically active polyphenolic compound found in turmeric. Increasing evidence has demonstrated that curcumin has a protective action against renal fibrosis, whereas mechanisms underlying the anti‐fibrosis role of curcumin remain poorly defined. Here, we found that APPL1, an important intracellular binding partner for AdipoR, was involved in the pathogenesis of acute injury or fibrosis and was significantly upregulated by curcumin in a mouse model of ischemia reperfusion‐induced late kidney fibrosis. Moreover, Akt signaling was the specific signaling pathway identified downstream of APPL1 in the pathogenesis of fibrosis. Our in vitro experiment demonstrated that curcumin alleviates ischemia reperfusion‐induced late kidney fibrosis via the APPL1/Akt pathway. These data are helpful for understanding the anti‐fibrosis mechanism of curcumin in the pathogenesis of AKI‐induced late fibrosis. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8588-8596, November 2018.
  

  May 09, 2018   doi: 10.1002/jcp.26536   open full text
• Generation of hematopoietic cells from mouse pluripotent stem cells in a 3D culture system of self‐assembling peptide hydrogel.
  Wei Shan, Binsheng Wang, Yulin Xu, Xia Li, Xue Li, Huafang Wang, Yu Lin, Ruxiu Tie, Qianhao Zhao, Jinyong Wang, Weiyan Zheng, Yongxian Hu, Jimin Shi, Xiaohong Yu, He Huang.
  Journal of Cellular Physiology. January 31, 2018
  --- - |2+ Abstract In vitro generation of HSCs from pluripotent stem cells (PSCs) can be regarded as novel therapeutic approaches for replacing bone marrow (BM) transplantation without immune rejection or graft versus host disease(GVHD). To date, many differentiation approaches have been evaluated in terms of directing PSCs toward different hematopoietic cell types, yet, low efficiency and no function restrict the further hematopoietic differentiation study, our research aim to develop a three dimention (3D) hematopoietic differentiation approach that serve as recapitulation of embryonic development in vitro to a degree of complexity not achievable in a two dimention (2D) culture system. We first found that mouse PSCs could be efficiently induced to hematopoietic differentiation with expression of hematopoietic makers such as c‐kit, CD41 and CD45 within self‐assembling peptide hydrogel. Colony‐forming cells assay results suggested mPSCs could differentiated into multipotential progenitor cells and 3D induction system derived hematopoietic colonies owned potential of differentiating into lymphocyte cells. In addition, in vivo animal transplantation experiment showed that mPSCs(CD45.2) could embedded into NOD/SCID mice(CD45.1) with about 3% engraftment efficiency after 3 weeks transplantation. This study demonstrated that we developed the 3D induction approach that could efficiently promoted the hematopoietic differentiation of mPSCs in vitro and obtained the multipotential progenitors that possessed the short‐term engraftment potential. This article is protected by copyright. All rights reserved - 'Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-. '

  January 31, 2018   doi: 10.1002/jcp.26509   open full text
• The Importance of miRNAs and Epigenetics in Acute Lymphoblastic Leukemia Prognosis.
  Reza Ranjbar, Ansar Karimian, Masoud aghai, Mehdi Tourani, Seyed Mostafa Mir, Javid Sabour, Farhad Jadidi, Bahman Yousefi.
  Journal of Cellular Physiology. January 31, 2018
  --- - |2+ Abstract Acute lymphoblastic leukemia (ALL), one of the most common malignant human disorders, originates in different important genetic lesions in T‐cell or B‐cell progenitors. ALL is a malignant lymphoid progenitor with peak prevalence in children (2–5 years). The rate of survival when one is suffering from ALL depends on various agents including the age of the patient, responses to anti‐leukemic therapy, and cell biology. miRNAs and epigenetics are important regulatory factors in the expression of genes. miRNAs are noncoding RNA with inhibitory effectors on specific mRNA. Patterns of DNA methylation are profoundly changed in ALL by epigenetic mechanisms. The deciphering of miRNA and the epigenetic pathogenesis in ALL could revolutionize response to the therapy and outcome, and create an enormous promise for novel approaches to reduce the toxic side‐effects of intensive leukemia. Hence, pathogenetic miRNAs and epigenetics leading to the initiation and the progression of ALL are summarized in this review. This article is protected by copyright. All rights reserved - Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-.
  

  January 31, 2018   doi: 10.1002/jcp.26510   open full text
• Neural Regulation of Bone Remodeling: Identifying Novel Neural Molecules and Pathways Between Brain and Bone.
  Shishu Huang, Zhenxia Li, Yunhui Liu, Dashuang Gao, Xinzhou Zhang, Jin Hao, Fan Yang.
  Journal of Cellular Physiology. January 27, 2018
  --- - |2+ Abstract The metabolism and homeostasis of skeletal system has historically been regarded to be associated with the endocrine system. However, such view has been expanded with the recognition of several neural pathways playing important roles in the regulation of bone metabolism via central relays. In particular, bone metabolism and homeostasis has been reported to be precisely modulated by the central neural signaling. Initiated by the finding of leptin, the axis of neural regulation on bone expands rapidly. Semaphorin‐plexin system play an important role in the crosstalk between osteoclasts and osteoblasts, a complex system has also been identified and includes neuropeptide Y and cannabinoids. These findings facilitate our understanding of the central neuropeptides and neural factors in the modulation of bone metabolism and homeostasis, and these neuronal pathways also represent an area of research scenario that identifies the novel regulation between brain and bone. These regulatory mechanisms correlate with other homeostatic networks and demonstrate a more intricate and synergetic bone biology than previously envisioned. As such, this review summarizes the current knowledge of the neural regulation of bone metabolism and homeostasis as well as its role in skeletal diseases, and discusses the emerging challenges presented in this field. This article is protected by copyright. All rights reserved - 'Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-. '

  January 27, 2018   doi: 10.1002/jcp.26502   open full text
• Inhibition of glycolytic metabolism in glioblastoma cells by Pt3glc combinated with PI3K inhibitor via SIRT3‐mediated mitochondrial and PI3K/Akt‐MAPK pathway.
  Gang Wang, Xing‐Li Fu, Jun‐Jie Wang, Rui Guan, Yan Sun, Shing‐shun Tony To.
  Journal of Cellular Physiology. January 16, 2018
  --- - |2+ ABSTRACT Glioblastoma multiforme (GBM) is the most malignant and aggressive glioma with abnormal expression of genes that mediate glycolytic metabolism and tumor cell growth. Petunidin‐3‐O‐ glucoside (Pt3glc) is a kind of anthocyanin in the red grape and derived beverages, representing the most common naturally occurring anthocyanins with a reduced incidence of cancer and heart diseases. In this study, whether Pt3glc could effectively regulate glycolysis to inhibit GBM cell was investigated by using the DBTRG‐05MG cell lines. Notably, Pt3glc displayed potent anti‐proliferative activity and significantly changed the protein levels related to both glycolytic metabolism and GBM cell survival. The expression of the pro‐apoptotic protein Bax was increased with concomitant reduction on the levels of the anti‐apoptotic protein Bcl‐2 and caspase‐3 activity. Furthermore, the levels of survival signaling proteins, such as Akt and p‐Akt (Scr473), ERK and phospho‐ERK, were significantly decreased by Pt3glc in combination with the PI3K inhibitor of LY294002. Most importantly, the levels of SIRT3 and phosphorylated p53 were also down‐regulation, indicating that Pt3glc combinated with PI3K inhibitor could induced GBM cell death may act via the SIRT3/p53‐mediated mitochondrial and PI3K/Akt‐ERK pathways. Our findings thus provide rational evidence that the combination of Pt3glc with PI3K inhibitor, which target alternative pathways in GBM cells, may be a useful adjuvant therapy in glioblastoma treatment. This article is protected by copyright. All rights reserved - 'Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-. '

  January 16, 2018   doi: 10.1002/jcp.26474   open full text
• HIV‐1 increases extracellular amyloid‐beta levels through neprilysin regulation in primary cultures of human astrocytes.
  Marta Martínez‐Bonet, M Ángeles Muñoz‐Fernández, Susana Álvarez.
  Journal of Cellular Physiology. January 11, 2018
  --- - |2+ Abstract Since the success of combined antiretroviral therapy, HIV‐1‐infected individuals are now living much longer. This increased life expectancy is accompanied by a higher prevalence of HIV‐1 associated neurocognitive disorders. Rising too is the incidence in these patients of pathological hallmarks of Alzheimer's disease such as increased deposition of amyloid beta protein (Aβ). Although neurons are major sources of Aβ in the brain, astrocytes are the most numerous glial cells, therefore, even a small level of astrocytic Aβ metabolism could make a significant contribution to brain pathology. Neprilysin (NEP) is a decisive/crucial regulator of Aβ levels. We evaluated the effects of HIV‐1 on Aβ deposition and the expression and activity of NEP in primary human astrocytes. Specifically, no differences in intracellular amyloid deposits were found between infected and control cells. However, primary cultures of infected astrocytes showed more extracellular Aβ levels compared to controls. This was accompanied by reduced expression of NEP and to a significant decrease on its activity. These results indicate that the presence of HIV‐1 in the brain could contribute to the increase of the total burden of cerebral Aβ. This article is protected by copyright. All rights reserved - 'Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-. '

  January 11, 2018   doi: 10.1002/jcp.26462   open full text
• Muscle‐derived Satellite Cells for Treating Type 1 Diabetes in Rats (Rattus norvegicus).
  Yu Ren, Hefei Wang, Si Ha, Xingsheng Zhao, Xiao Wang, Yu Lan, Xiaoling Liu.
  Journal of Cellular Physiology. January 10, 2018
  --- - |2+ Abstract Diabetes mellitus(DM) is a complicated metabolic disease, with the fundamental treatment nowadays being diet control, insulin injections, slet or pancreas transplantation, which is limited because exogenous insulin injections fail to simulate normal insulin secretion in islet beta cells successfully and islet transplantation lacks organ donors. So far, stem cells with highly self‐renewal and multi‐directional differentiation potential have become a new hope for the treatment of diabetes. In this research, rat Muscle‐derived satellite cells *MDSCs*were separated and cultivated in vitro and inducted into insulin‐producing cells with observation and identification using dithizone staining and so on. T1D rat model was built with Streptozocin(STZ), then MDSCs and induced insulin‐producing cells from MDSCs labeled by Dil were transplanted respectively. Transplantation of MDSCs (group 1) and the induced insulin‐producing cells (group 2) into streptozotocin (STZ)‐induced diabetic rats resulted in lower blood glucose, lower urine glucose, higher body weight, higher glucose tolerance and less water intake and urine output than control rats (P < 0.05). Among the male rats, the blood glucose levels of 50% of group 1 rats were <16.7 mmol/L, and 40% of group 2 rats yielded similar results (P < 0.01). Among the female rats, the blood glucose levels of 66.67% of group 1 rats were <16.7 mmol/L, and 33.33% of group 2 rats showed similar blood glucose levels (P < 0.01). Histological examination revealed that the transplanted cells reached the pancreas and repaired damaged tissues. The above research conclusions provide theoretical basis, cell selection and good prospect for the treatment of diabetes. This article is protected by copyright. All rights reserved - 'Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-. '

  January 10, 2018   doi: 10.1002/jcp.26437   open full text
• Differential mechanisms of adenosine‐ and ATPγS‐induced microvascular endothelial barrier strengthening.
  Róbert Bátori, Sanjiv Kumar, Zsuzsanna Bordán, Mary Cherian‐Shaw, Anita Kovács‐Kása, Justin A. MacDonald, David J. R. Fulton, Ferenc Erdődi, Alexander D. Verin.
  Journal of Cellular Physiology. December 22, 2017
  --- - |2+ Abstract Maintenance of the endothelial cell (EC) barrier is critical to vascular homeostasis and a loss of barrier integrity results in increased vascular permeability. While the mechanisms that govern increased EC permeability have been under intense investigation over the past several decades, the processes regulating the preservation/restoration of the EC barrier remain poorly understood. Herein we show that the extracellular purines, adenosine (Ado) and ATPγS can strengthen the barrier function of human lung microvascular EC (HLMVEC). This ability involves protein kinase A (PKA) activation and decreases in myosin light chain 20 (MLC20) phosphorylation secondary to the involvement of MLC phosphatase (MLCP). In contrast to adenosine, ATPγS‐induced PKA activation is accompanied by a modest, but significant decrease in cAMP levels supporting the existence of an unconventional cAMP‐independent pathway of PKA activation. Furthermore, ATPγS‐induced EC barrier strengthening does not involve the Rap guanine nucleotide exchange factor 3 (EPAC1) which is directly activated by cAMP, but is instead dependent upon protein kinase A‐anchor protein 2 (AKAP2) expression. We also found that AKAP2 can directly interact with the myosin phosphatase‐targeting protein MYPT1 and that depletion of AKAP2 abolished ATPγS‐induced increases in transendothelial electrical resistance (TER). Adenosine‐induced strengthening of the HLMVEC barrier required the coordinated activation of PKA and EPAC1 in a cAMP‐dependent manner. In summary, ATPγS‐induced enhancement of the EC barrier is EPAC1‐independent and is instead mediated by activation of PKA which is then guided by AKAP2, in a cAMP‐independent mechanism, to activate MLCP which dephosphorylates MLC20 resulting in reduced EC contraction and preservation. This article is protected by copyright. All rights reserved - 'Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-. '

  December 22, 2017   doi: 10.1002/jcp.26419   open full text
• Effects of shRNA‐mediated Silencing of PSMA7 on Cell Proliferation and Vascular Endothelial Growth Factor Expression via the Ubiquitin‐Proteasome Pathway in Cervical Cancer.
  Chen‐Chen Ren, Li Yang, Ling Liu, Yan‐Nan Chen, Guo‐Mei Cheng, Xiao‐An Zhang, Hui Liu.
  Journal of Cellular Physiology. December 16, 2017
  --- - |2+ ABSTRACT This study aims to evaluate the effects of PSMA7 silencing on cervical cancer (CC) cell proliferation and vascular endothelial growth factor (VEGF) expression through the ubiquitin‐proteasome (UPP) pathway. CC tissue (n = 43) and normal tissues (n = 27) were first collected from patients. Human CC cell line (SiHa) and human normal cervical epithelial cells (H8) were obtained and classified into the normal, blank, negative control (NC), PSMA7‐shRNA1 and PSMA7‐shRNA2 groups. Hybridization in situ was used to detect the expressions of wild‐type and mutant p53 proteins. Immunofluorescence assay was carried out to test the activity of 20S proteasomes. RT‐qPCR and Western blotting were both performed to determine the expressions of PSMA7, ubiquitin, P27, P53 and VEGF in sample tissues and cells. MTT assay was used analyze cell proliferation rates, and flow cytometry to analyze cell cycle and apoptotic rate. Compared with normal tissue, CC tissues had increased expression levels of PSMA7, ubiquitin, p53, VEGF as well as increased the activity of 20S proteasomes, but exhibited a decrease in p27 expression. Compared with the blank and NC groups, the PSMA7‐shRNA1 and PSMA7‐shRNA2 groups all had decreased expression levels of PSMA7, ubiquitin, p53 and VEGF as well as decreased cell proliferation, 20S proteasomes activity and cell number in the S phase, increased p27 expression, cell apoptosis and cell number in the G0/G1 phase. Our study demonstrates that PSMA7 silencing can suppress CC cell proliferation and VEGF expression in addition to promoting cell apoptosis through inhibition of the UPP signaling pathway. This article is protected by copyright. All rights reserved - 'Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-. '

  December 16, 2017   doi: 10.1002/jcp.26408   open full text
• LncRNA XIST regulates myocardial infarction by targeting miR‐130a‐3p.
  Tao Zhou, Guowei Qin, Liehong Yang, Daokang Xiang, Suining Li.
  Journal of Cellular Physiology. December 11, 2017
  --- - |2+ Abstract The study was employed to probe long non‐coding RNA X‐inactive specific transcript RNA (lncRNA XIST) expression profile and its influence on cell cycle, proliferation and apoptosis in myocardial cells. We also aimed to explore the possible meditating relationship between XIST, PDE4D and miR‐130a‐3p. Gene differential analysis was carried out using Human LncRNA Microarray V3.0. Quantitative real‐time PCR (qRT‐PCR) was used to test mRNA expressions of XIST, miR‐130a‐3p and PDE4D in normal cells and post‐myocardial infarction (MI) cells. Western blot was applied to determine the protein expression profile of PED4D. Changes in viability and cell cycle/apoptosis of post‐MI myocardial cells after silencing of XIST or PDE4D were investigated by MTT assay and flow cytometry, respectively. The targeting relationship between miR‐130a‐3p and XIST, PDE4D in myocardial cells were verified by dual luciferase reporter assay. Simulated MI environment was constructed by performing anoxic preconditioning in normal cells to probe the influence of XIST on myocardial cell apoptosis. XIST and PDE4D were overexpressed in post‐MI myocardial cells, while miR‐130a‐3p was underexpressed in post‐MI myocardial cells. High‐expressed XIST and PDE4D both promoted myocardial cell apoptosis. High‐expressed XIST also inhibited myocardial cell proliferation. XIST down‐regulated miR‐130a‐3p and PDE4D was a direct target of miR‐130a‐3p. LncRNA XIST promotes MI by targeting miR‐130a‐3p. MI induced by PDE4D can be reversed by miR‐130a‐3p. This article is protected by copyright. All rights reserved - 'Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-. '

  December 11, 2017   doi: 10.1002/jcp.26327   open full text
• Eucalyptol Protects Lungs against Bacterial Invasion through Attenuating Ciliated Cell Damage and Suppressing MUC5AC Expression.
  Na Yu, Yi‐Tian Sun, Xin‐Ming Su, Miao He, Bing Dai, Jian Kang.
  Journal of Cellular Physiology. December 07, 2017
  --- - |2+ Abstract This study was conducted to investigate whether Eucalyptol plays a role in influencing bacterial growth in cigarette smoke exposed lungs. Rats were exposed to air (control) and cigarette smoke (smoking) in presence and absence of Eucalyptol (260 mg/day). Morphological analysis of lung structures and status of airway mucous production were observed under a microscope. Pathological changes of ciliated columnar epithelium in airways were examined using transmission electron microscopy. MUC5AC protein and mRNA expression in bronchoalveolar lavage fluid (BALF) and lungs were determined. Application of Eucalyptol reduced pulmonary bullae formation and airway mucus overproduction in the smoke exposed lungs. Treatment with Eucalyptol attenuated ciliated cell damage in cigarette smoke exposed lungs. Bacterial colonies of lungs were obviously lower in the Eucalyptol treated rats than that in the smoking rats (P < 0.01). Treatment with Eucalyptol reduced the counts of bacterial colonization residing in the challenged lungs (P < 0.01). Application of Eucalyptol not only decreased MUC5AC protein expression in BALF and tobacco‐exposed lungs but also suppressed its mRNA expression in the lungs (all P < 0.05). Intervention of Eucalyptol benefits elimination of bacterial organisms from tobacco exposed lungs through attenuating ciliated cell damage and suppressing MUC5AC expression in the lungs. This article is protected by copyright. All rights reserved - 'Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-. '

  December 07, 2017   doi: 10.1002/jcp.26359   open full text
• Retraction: Wang, L., Ma, X., Yan, L., Wang, T., Wen, J. and Mi, G., LncRNA SNHG1 negatively regulates miR‐145a‐5p to enhance NUAK1 expression and promote cancer cell metastasis and invasion in nasopharyngeal carcinoma. J Cell Physiol. Accepted Author Manuscript. doi:10.1002/jcp.26340.
  
  Journal of Cellular Physiology. December 07, 2017
  --- - |2+ Abstract The above article from the Journal of Cellular Physiology, published online on 7 December 2017 in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the authors, the journal Editor in Chief, Gary Stein, and Wiley Periodicals, Inc. The withdrawal has been agreed due to the article being submitted for publication without the consent of the authors’ instructor. - Journal of Cellular Physiology, Volume 0, Issue ja, -Not available-.
  

  December 07, 2017   doi: 10.1002/jcp.26340   open full text
• PACAP and PAC1R are differentially expressed in motor cortex of amyotrophic lateral sclerosis patients and support survival of iPSC‐derived motor neurons.
  Gabriele Bonaventura, Rosario Iemmolo, Agata G. D'Amico, Valentina La Cognata, Erminio Costanzo, Mario Zappia, Velia D'Agata, Francesca L. Conforti, Eleonora Aronica, Sebastiano Cavallaro.
  Journal of Cellular Physiology. October 20, 2017
  Amyotrophic lateral sclerosis (ALS) is a fatal and disabling neurodegenerative disease characterized by upper and lower motor neurons depletion. In our previous work, comprehensive genomic profiling of 41 motor cortex samples enabled to discriminate controls from sporadic ALS patients, and segregated these latter into two distinct subgroups (SALS1 and SALS2), each associated with different deregulated genes. In the present study, we focused our attention on two of them, Pituitary Adenylate Cyclase‐Activating Polypeptide (PACAP) and its type 1 receptor (PAC1R), and validated the results of the transcriptome experiments by quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR), immunohistochemistry and Western blot analysis. To assess the functional role of PACAP and PAC1R in ALS, we developed an in vitro model of human induced pluripotent stem cells (iPSC)‐derived motor neurons and examined the trophic effects of exogenous PACAP following neurodegenerative stimuli. Treatment with 100 nm PACAP was able to effectively rescue iPSC‐derived motor neurons from apoptosis, as shown by cell viability assay and protein dosage of the apoptotic marker (BAX). All together, these data suggest that perturbations in the PACAP‐PAC1R pathway may be involved in ALS pathology and represent a potential drug target to enhance motor neuron viability. 1) Two distinct subgroups (SALS1 and SALS2) of sporadic Amyotrophic lateral sclerosis exist and are characterized by different deregulated genes and pathways; 2) Pituitary Adenylate Cyclase‐Activating Polypeptide (PACAP) and its type 1 receptor (PAC1R) are differentially expressed in the two subgroups; 3) PACAP rescues iPSC‐derived motor neurons from apoptosis; and 4) Perturbations in the PACAP‐PAC1R pathway may be involved in ALS pathology.

  October 20, 2017   doi: 10.1002/jcp.26182   open full text
• Functional role of mesenchymal stem cells in the treatment of chronic neurodegenerative diseases.
  Debora Lo Furno, Giuliana Mannino, Rosario Giuffrida.
  Journal of Cellular Physiology. October 20, 2017
  Mesenchymal stem cells (MSCs) can differentiate into not only cells of mesodermal lineages, but also into endodermal and ectodermal derived elements, including neurons and glial cells. For this reason, MSCs have been extensively investigated to develop cell‐based therapeutic strategies, especially in pathologies whose pharmacological treatments give poor results, if any. As in the case of irreversible neurological disorders characterized by progressive neuronal death, in which behavioral and cognitive functions of patients inexorably decline as the disease progresses. In this review, we focus on the possible functional role exerted by MSCs in the treatment of some disabling neurodegenerative disorders such as Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Parkinson's Disease. Investigations have been mainly performed in vitro and in animal models by using MSCs generally originated from umbilical cord, bone marrow, or adipose tissue. Positive results obtained have prompted several clinical trials, the number of which is progressively increasing worldwide. To date, many of them have been primarily addressed to verify the safety of the procedures but some improvements have already been reported, fortunately. Although the exact mechanisms of MSC‐induced beneficial activities are not entirely defined, they include neurogenesis and angiogenesis stimulation, antiapoptotic, immunomodulatory, and anti‐inflammatory actions. Most effects would be exerted through their paracrine expression of neurotrophic factors and cytokines, mainly delivered at damaged regions, given the innate propensity of MSCs to home to injured sites. Hopefully, in the near future more efficacious cell‐replacement therapies will be developed to substantially restore disease‐disrupted brain circuitry. The review focuses on studies using Mesenchymal Stem Cells in therapeutic strategies for chronic neurological disorders such as Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Parkinson's Disease. The main findings obtained by in vitro and in vivo experiments, as well as in clinical trials are outlined. Possible stem cell mediated mechanisms of action are discussed.

  October 20, 2017   doi: 10.1002/jcp.26192   open full text
• Effects of microRNA‐206 and its target gene IGF‐1 on sevoflurane‐induced activation of hippocampal astrocytes in aged rats through the PI3K/AKT/CREB signaling pathway.
  Tie‐Jun Liu, Bin Wang, Qun‐Xi Li, Xiao‐ Liu Dong, Xiao‐Liang Han, Shu‐Bo Zhang.
  Journal of Cellular Physiology. October 20, 2017
  The study aims to explore the effects of microRNA‐206 (miR‐206) targeting IGF‐1 on the activation of hippocampal astrocytes in aged rats induced by sevoflurane through the PI3K/AKT/CREB signaling pathway. Wistar rats and astrocytes were divided into the normal/blank, sham/negative control (NC), sevoflurane (sevo), miR‐206 mimics + sevo, miR‐206 inhibitors + sevo, miR‐206 NC + sevo, IGF‐1 shRNA + sevo and miR‐206 inhibitors + IGF‐1 shRNA + sevo groups. The Morris water maze test was exhibited to assess the cognitive functions. Glial fibrillary acidic protein (GFAP) expression was detected by immunofluorescence assay. Western blotting and RT‐qPCR were used to detect the expression of miR‐206, IGF‐1, PI3K, AKT, CREB, pPI3K, pAKT, pCREB, cytochrome‐c (Cyt‐c) and caspase‐3. Cell viability and apoptosis were detected by MTT assay and Annexin V/PI double staining respectively. Mitochondrial transmembrane potential (MTP) were determined by flow cytometry. The IGF‐1 shRNA + sevo group showed reduced miR‐206 expression. Compared with the normal/blank group, the sevo and miR‐206 NC + sevo groups showed decreased miR‐206 and GFAP expressions, cell viability and MTP but increased expressions of IGF‐1, PI3K, AKT, CREB, pPI3K, pAKT, pCREB, Cyt‐c and caspase‐3, as well as cell apoptosis. Similar trends were observed in the miR‐206 inhibitors + sevo group when compared with the sevo group. The study provides evidence that miR‐206 alleviates the inhibition of activation of hippocampal astrocytes in aged rats induced by sevoflurane by targeting IGT‐1 through suppressing the PI3K/AKT/CREB signaling pathway. This article is protected by copyright. All rights reserved

  October 20, 2017   doi: 10.1002/jcp.26248   open full text
• Shear Stress Upregulates Regeneration‐Related Immediate Early Genes in Liver Progenitors in 3D ECM‐like Microenvironments.
  Kenichiro Nishii, Erik Brodin, Taylor Renshaw, Rachael Weesner, Emma Moran, Shay Soker, Jessica L. Sparks.
  Journal of Cellular Physiology. October 20, 2017
  The role of fluid stresses in activating the hepatic stem/progenitor cell regenerative response is not well understood. This study hypothesized that immediate early genes (IEGs) with known links to liver regeneration will be upregulated in liver progenitor cells (LPCs) exposed to in vitro shear stresses on the order of those produced from elevated interstitial flow after partial hepatectomy. The objectives were: (1) to develop a shear flow chamber for application of fluid stress to LPCs in 3D culture; and (2) to determine the effects of fluid stress on IEG expression in LPCs. Two hours of shear stress exposure at ∼4 dyn/cm2 was applied to LPCs embedded individually or as 3D spheroids within a hyaluronic acid/collagen I hydrogel. Results were compared against static controls. Quantitative reverse transcriptase polymerase chain reaction was used to evaluate the effect of experimental treatments on gene expression. Twenty‐nine genes were analyzed, including IEGs and other genes linked to liver regeneration. Four IEGs (CFOS, IP10, MKP1, ALB) and three other regeneration‐related genes (WNT, VEGF, EpCAM) were significantly upregulated in LPCs in response to fluid mechanical stress. LPCs maintained an early to intermediate stage of differentiation in spheroid culture in the absence of the hydrogel, and addition of the gel initiated cholangiocyte differentiation programs which were abrogated by the onset of flow. Collectively the flow‐upregulated genes fit the pattern of an LPC‐mediated proliferative/regenerative response. These results suggest that fluid stresses are potentially important regulators of the LPC‐mediated regeneration response in liver. This article is protected by copyright. All rights reserved

  October 20, 2017   doi: 10.1002/jcp.26246   open full text
• Curcumin, hemostasis, thrombosis and coagulation.
  Faeze Keihanian, Amin Saeidinia, Ramin Khameneh Bagheri, Thomas P. Johnston, Amirhossein Sahebkar.
  Journal of Cellular Physiology. October 20, 2017
  Atherothrombotic cardiovascular disease is a major cause of mortality throughout the world. Platelet activation and aggregation play a central role in hemostasis and thrombosis. Herbal medicines have been traditionally used in the management of cardiovascular disease and can help in modifying its progression, particularly in hemostasis and the coagulation process, as well as altering platelet function tests and some coagulation parameters. Curcumin is a polyphenol derived from the Curcuma longa plant and has been used extensively in complementary and alternative medicine, as it is nontoxic and safe with various therapeutic properties. Modern scientific research has demonstrated its anti‐inflammatory, antioxidant, anti‐carcinogenic, antithrombotic, and cardiovascular protective effects. The present study reviewed previous studies in the literature, which support the positive activity of curcumin in hemostasis, anticoagulation, and fibrinolysis. We also presented molecular mechanisms associated with the antiplatelet and anticoagulant activities of curcumin and potential implications for the treatment of cardiovascular disease. This article is protected by copyright. All rights reserved

  October 20, 2017   doi: 10.1002/jcp.26249   open full text
• CircFUT10 reduces proliferation and facilitates differentiation of myoblasts by sponging miR‐133a.
  Hui Li, Jiameng Yang, Xuefeng Wei, Chengchuang Song, Dong Dong, Yongzhen Huang, Xianyong Lan, Martin Plath, Chuzhao Lei, Yun Ma, Xinglei Qi, Yueyu Bai, Hong Chen.
  Journal of Cellular Physiology. October 18, 2017
  Circular RNAs (circRNAs) have been identified in various tissues and cell types from human, monkey, porcine and mouse. However, knowledge on circRNAs in bovine muscle development is limited. We downloaded and analyzed the circRNAs sequencing data of bovine skeletal muscle tissue, and further characterized the role of a candidate circRNA (circFUT10) in muscle development. Quantitative real‐time PCR (qPCR) and western blot assays were used to confirm the expression of genes involved in myoblasts differentiation and proliferation. Flow cytometry was performed to assess cell cycle distribution and cell apoptosis. EdU incorporation and CCK‐8 assay were performed to demonstrate cell proliferation. We demonstrated that circFUT10 was highly (but differentially) expressed in embryonic and adult skeletal muscle tissue. circFUT10 induced bovine primary myoblasts differentiation and increased the expression of MyoD, MyoG and MyhC in mRNA and protein levels. circFUT10 increased the number of myoblasts in the G0/G1 phase of the cell cycle, and decreased the proportion of cells in the S‐phase. circFUT10 inhibited the proliferation of myoblasts and promoted them apoptosis. Via a luciferase screening assay, circFUT10 is observed to sponge to miR‐133a with three potential binding sites. Specifically, we show that circFUT10 regulated myoblasts differentiation and cell survival by directly binding to miR‐133a and inhibiting miR‐133a activity. Modulation of circFUT10 expression in muscle tissue may emerge as a potential target in breeding strategies attempting to control muscle development in cattle. This article is protected by copyright. All rights reserved