Nilotinib is an oral potent tyrosine kinase inhibitor that has diverse biological activities. However, its effects on hypercholesterolemia and associated disorders have not been studied yet. The present study explored the effect of nilotinib on atherosclerosis progression, endothelial dysfunction, and hyperlipidemia-associated hepatic injury in high-cholesterol (HC)-fed rabbits. Rabbits were classified into four groups: control, nilotinib, HC, and HC + nilotinib groups. Rabbits were fed either a regular diet or an HC-enriched diet for 8 weeks. By the end of the eighth week, blood and tissue samples were obtained for biochemical, histological, immunohistochemical, and in vitro analyses. Results indicated that the HC diet induced a significant elevation in the serum lipid parameters (triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), lactate dehydrogenase, and nitric oxide content. Endothelial dysfunction was evident through the impairment of acetylcholine-induced relaxation of isolated aortas and the histopathological lesions of the aortic specimen. Moreover, HC significantly increased serum malondialdehyde. Liver damage was clear through increase in serum transaminases and alkaline phosphatase, and it was further supported by histopathological examination. HC increased the expression of platelet-derived growth factor receptor (PDGFR)-B in both aorta and liver tissues. Interestingly, nilotinib administration retarded atherosclerosis progression and attenuated all of the aforementioned parameters. These data suggest that nilotinib may counteract atherosclerosis development, vascular dysfunction, and hepatic damage in HC-fed rabbits through interfering with PDGF-B.
Several metals including barium (Ba) known as environmental pollutants provoke deleterious effects on human health. The present work pertains to the potential ability of selenium (Se) and/or vitamin C, used as nutritional supplements, to alleviate the toxic effects induced by barium chloride (BaCl2) in the heart of adult rats. Animals were randomly divided into seven groups of six each: group 1, serving as negative controls, received distilled water; group 2 received in their drinking water BaCl2 (67 ppm); group 3 received both Ba and Se (sodium selenite 0.5 mg kg–1 of diet); group 4 received both Ba and vitamin C (200 mg kg–1 bodyweight) via force feeding; group 5 received Ba, Se, and vitamin C; and groups 6 and 7, serving as positive controls, received either Se or vitamin C for 21 days. The exposure of rats to BaCl2 caused cardiotoxicity as monitored by an increase in malondialdehyde, hydrogen peroxide, and advanced oxidation protein product levels, a decrease in Na+-K+ adenosine triphosphatase (ATPase), Mg2+ ATPase, and acetylcholinesterase activities and in antioxidant defense system (catalase, glutathione peroxidase, superoxide dismutase, glutathione, and nonprotein thiols). Plasma lactate dehydrogenase and creatine kinase activities, total cholesterol, triglyceride, and low-density lipoprotein–cholesterol levels increased, while high-density lipoprotein–cholesterol level decreased. Coadministration of Se and/or vitamin C restored the parameters indicated above to near control values. The histopathological findings confirmed the biochemical results. Se and vitamin C may be a promising therapeutic strategy for Ba-induced heart injury.
In a previous study, we have found that organophosphate (OP) pesticides such as chlorpyrifos (CPF), methyl parathion (MPT), and malathion (MLT) significantly induced genotoxicity in peripheral blood lymphocytes of rats. To explore the mechanism of OP-induced genotoxicity, we measured the formation of DNA interstrand cross-links (DICs) and apoptosis in peripheral blood lymphocytes of rats. Peripheral blood lymphocytes of rats were treated with CPF, MPT, and MLT individually and in combination at concentrations of 0.1 and 0.25 LC50 for 2, 4, 8, and 12 h at 37°C. Lipid peroxidation (LPO) was measured as a biomarker of oxidative stress. Apoptosis induced by CPF, MPT, and MLT individually and in combination was determined by measuring the intracellular level of active caspase-3 and caspase-9 by spectrofluorimetry. We found significant dose- and time-dependent increases in LPO, DICs formation and increase of intracellular active caspase-3 and caspase-9 in exposed peripheral blood lymphocytes of rats. These findings suggest that the studied pesticides have potential to induce oxidative stress, cause DNA adduct formation, and cause failure of adduct repair, which leads to apoptosis that is partially mediated by activation of intracellular caspase-3 and caspase-9.
Wogonoside is the main flavonoid of the traditional Chinese medicinal herb Scutellaria baicalensis Georgi and has been found to induce growth suppression in myelogenous leukemia cells. However, its activity in T acute lymphoblastic leukemia (T-ALL) is still unclear. In this study, T-ALL cell lines MOLT-3 and Jurkat were exposed to different concentrations of wogonoside for 48 h, and cell viability, cell cycle distribution, and apoptosis were measured. The involvement of signal transducers and activators of transcription 3 (STAT3) signaling in the activity of wogonoside was checked. The in vivo effect of wogonoside on T-ALL growth was investigated in a xenograft mouse model. Wogonoside significantly inhibited the viability of MOLT-3 and Jurkat cells, with the IC50 (the half maximal concentration) of 68.5 ± 3.8 and 52.6 ± 4.3 μM, respectively. However, healthy T lymphocytes were unaffected. Wogonoside-treated Jurkat cells exhibited a G1-phase cell cycle arrest and significant apoptosis, which was coupled with inactivation of STAT3 signaling. Overexpression of constitutively active STAT3 reversed wogonoside-mediated growth suppression and apoptosis and restored the expression of cyclin D1, Mcl-1, and Bcl-xL. In vivo studies demonstrated that wogonoside retarded tumor growth and suppressed STAT3 phosphorylation in Jurkat xenografts. In conclusion, wogonoside suppresses the growth of T-ALL through the STAT3 pathway and may have therapeutic benefits in this disease.
Combustion of biomass produces solid carbon particles, whereas their generation is highly unlikely when a biomass is heated instead of being burnt. For instance, in the Tobacco Heating System (THS2.2), the tobacco is heated below 350°C and no combustion takes place. Consequently, at this relatively low temperature, released compounds should form an aerosol consisting of suspended liquid droplets via a homogeneous nucleation process. To verify this assumption, mainstream aerosol generated by the heat-not-burn product, THS2.2, was assessed in comparison with mainstream smoke produced from the 3R4F reference cigarette for which solid particles are likely present. For this purpose, a methodology was developed based on the use of a commercial Dekati thermodenuder operating at 300°C coupled with a two-stage impactor to trap solid particles. If any particles were collected, they were subsequently analyzed by a scanning electron microscope and an electron dispersive X-ray. The setup was first assessed using glycerine-based aerosol as a model system. The removal efficiency of glycerin was determined to be 86 ± 2% using a Trust Science Innovation (TSI) scanning mobility particle sizer, meaning that quantification of solid particles can be achieved as long as their fraction is larger than 14% in number. From experiments conducted using the 3R4F reference cigarette, the methodology showed that approximately 80% in number of the total particulate matter was neither evaporated nor removed by the thermodenuder. This 80% in number was attributed to the presence of solid particles and/or low volatile liquid droplets. The particles collected on the impactor were mainly carbon based. Oxygen, potassium, and chloride traces were also noted. In comparison, solid particles were not detected in the aerosol of THS2.2 after passing through the thermodenuder operated at 300°C. This result is consistent with the fact that no combustion process takes place in THS2.2 and no formation and subsequent transfer of solid carbon particles is expected to occur in the mainstream aerosol.
There are limited data regarding effect of trastuzumab on radiation-induced cardiovascular toxicity when used sequentially or concomitantly. This experimental study aims to investigate effect of trastuzumab on radiation-induced cardiovascular toxicity with respect to the treatment sequence. One hundred and eight female Wistar albino rats were divided into six groups (G): G1 was control, G2 was trastuzumab, and G3 was radiotherapy (RT); G4 and G6 were sequential RT and trastuzumab; and G5 was concomitant RT and trastuzumab groups, respectively. Rats were killed at 6th h, 21st and 70th days after RT; thoracic aorta and heart samples were obtained. Transthoracic echocardiography and functional studies evaluating relaxation of thoracic aorta were performed. Subendothelial edema scores of thoracic aorta samples at 21st and 70th days were higher in RT groups (G3, G4, G5, and G6) (p < 0.001). There was a deterioration of relaxation responses of thoracic aorta samples in RT groups (p < 0.001). Cardiac fibrosis (CF) scores revealed detrimental effect of RT beginning from 6th h and trastuzumab from 21st day. RT groups showed further deterioration of CF at 70th day. Ejection fraction, left ventricular mass, and fractional shortening were significantly decreased in G4, G5, and G6. Trastuzumab may increase pathological damage in cardiovascular structures when used with RT regardless of timing.
Acrylamide (ACR) is a chemical intermediate utilized in industry. ACR is also formed during heating of foods containing carbohydrates and amino acids. Therefore, humans are widely exposed to ACR, and ACR neurotoxicity in humans is a significant public health issue attracting wide attention. In this study, we investigated the potential neuroprotective effects of epigallocatechin-3-gallate (EGCG), the most abundant polyphenolic compound in green tea, in PC12 cells treated with ACR. ACR-treated PC12 cells pretreated with various concentrations of EGCG (2.5, 5 and 10 μM) for 24 h had increased viability and acetylcholinesterase activity and reduced apoptosis and necrosis compared to cells exposed to ACR alone. EGCG reduced the expression of bax mRNA, decreased cytochrome c release, reduced intracellular calcium levels, inactivated caspase 3 and increased mitochondrial membrane potential, suggesting that EGCG prevents ACR-induced apoptosis through a mitochondrial-mediated pathway. In addition, EGCG inhibited the formation of reactive oxygen species and lipid peroxidation while enhancing superoxide dismutase activity and glutathione levels, thereby reducing oxidative stress. Our results indicate that pretreatment of PC12 cells with EGCG attenuates ACR-induced apoptosis by reducing oxidative stress. Therefore, drinking green tea may reduce nerve injury induced by ACR.
There are no common recommendations regarding electrocardiographic monitoring in occupationally exposed workers. Therefore, the present study was designed to investigate whether exposure to lead results in an increase of selected electrocardiography (ECG) pathologies, such as QT interval prolongation and repolarization disorders, in occupationally exposed workers. The study group included 180 workers occupationally exposed to lead compounds. The exposed group was divided according to the median of the mean blood lead level (PbBmean) calculated based on a series of measurements performed during 5-year observation period (35 µg/dl) into two subgroups: low exposure (LE, PbBmean = 20.0–35.0 µg/dl) and high exposure (HE, PbBmean = 35.1–46.4 µg/dl). The control group consisted of 69 healthy workers without occupational exposure to lead. ECG evaluation included the analysis of heart rate (HR), QT interval and repolarization abnormalities. Mean QT interval was significantly greater in the exposed population than in the control group by 2%. In the HE group, mean QT interval was significantly greater than in the control group by 4% and significantly different from those noted in the LE group. Positive correlations between QT interval and lead exposure indices were also reported. Besides, there was a negative correlation between HR and blood lead level. Increased concentration of lead in the blood above 35 μg/dl is associated with the QT interval prolongation, which may trigger arrhythmias when combined with other abnormalities, such as long QT syndrome. Therefore, electrocardiographic evaluation should be a part of a routine monitoring of occupationally exposed populations.
A series of new thiazacridine agents were synthesized and evaluated as antitumor agents, in terms of not only their cytotoxicity but also their selectivity. The cytotoxicity assay confirmed that all compounds showed cytotoxic activity and selectivity. The new compound, 3-acridin-9-ylmethyl-5-(5-bromo-1H-indol-3-ylmethylene)-thiazolidine-2,4-dione (LPSF/AA29 – 7a), proved to be the most promising compound as it presents lower half-maximal inhibitory concentration (IC50) values (ranging from 0.25 to 68.03 µM) depending on cell lineage. In HepG2 cells, the lowest IC50 value was exhibited by 3-acridin-9-ylmethyl-5-(4-piperidin-1-yl-benzylidene)-thiazolidine-2,4-dione (LPSF/AA36 – 7b; 46.95 µM). None of the synthesized compounds showed cytotoxic activity against normal cells (IC50 > 100 µM). The mechanism of death induction and cell cycle effects was also evaluated. Flow cytometric analysis revealed that the compounds LPSF/AA29 – 7a and LPSF/AA36 – 7b significantly increased the percentage of apoptotic cells and induced G2/M arrest in the cell cycle progression. Therefore, these new thiazacridine derivatives constitute promising antitumor agents whose cytotoxicity and selectivity properties indicate they have potential to contribute to or serve as a basis for the development of new cancer drugs in the future.
Mineral trioxide aggregate (MTA) is a calcium silicate dental cement used for various applications in dentistry. This study was undertaken to test whether the presence of three commercial brands of calcium silicate dental cements in the dental extraction socket of rats would affect the brain aluminium (Al) levels and oxidative stress parameters. Right upper incisor was extracted and polyethylene tubes filled with MTA Angelus, MTA Fillapex or Theracal LC, or left empty for the control group, were inserted into the extraction socket. Rats were killed 7, 30 or 60 days after operation. Brain tissues were obtained before killing. Al levels were measured by atomic absorption spectrometry. Thiobarbituric acid reactive substances (TBARS) levels, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were determined using spectrophotometry. A transient peak was observed in brain Al level of MTA Angelus group on day 7, while MTA Fillapex and Theracal LC groups reached highest brain Al level on day 60. Brain TBARS level, CAT, SOD and GPx activities transiently increased on day 7 and then returned to almost normal levels. This in vivo study for the first time indicated that initial washout may have occurred in MTA Angelus, while element leaching after the setting is complete may have taken place for MTA Fillapex and Theracal LC. Moreover, oxidative stress was induced and antioxidant enzymes were transiently upregulated. Further studies to search for oxidative neuronal damage should be done to completely understand the possible toxic effects of calcium silicate cements on the brain.
Lipid rescue is used as treatment of various poisonings despite weak scientific evidence. Some experimental studies have indicated a positive effect, but others have not. Clinical studies are lacking, wherefore a systematic review of virtually all published human case reports is presented. The case reports were searched for in PubMed and Web of Science and examined by two experts according to an assessment form grading the probability for a causal connection between lipid rescue and improved symptoms. A total of 160 cases were finally included, of which 30 had no positive effect of lipid rescue. Among the 130 included cases with alleged positive effect, 94 were oral poisonings and 36 were cases with local anesthetic systemic toxicity (LAST). The experts’ assessment resulted in a "certain" causal connection in three cases with LAST but not in oral poisoning. Moreover, the mean assessment score among the oral poisonings was significantly worse than the corresponding score in the cases with LAST. The average log p-value of the main toxins among the oral poisonings was significantly lower than the corresponding p-value in the cases with LAST. Among the oral poisonings, 91% had received some other resuscitative treatment more or less simultaneously with lipid rescue. Considering the findings of this study and the increasingly reported adverse effects of lipid rescue, it’s reasonable to strictly limit its use in clinical practice. We would not recommend it in oral poisonings.
Arsenic (As) is commonly associated with natural and human processes such as volcanic emissions, mining and herbicides production, being an important pollutant. Several studies have associated As intake with male fertility reduction, thus the aim of the present study was to evaluate whether vitamin C and/or zinc would counteract As side effects within the testicles. Adult male Wistar rats were divided into six experimental groups: control, sodium arsenite (5 mg/kg/day), vitamin C (100 mg/kg/day), zinc chloride (ZnCl2; 20 mg/kg/day), sodium arsenite + vitamin C and sodium arsenite + ZnCl2. Testicles and epididymis were harvested and either frozen or routinely processed to be embedded in glycol methacrylate resin. As reduced the seminiferous epithelium and tubules diameter due to germ cell loss. In addition, both the round spermatids population and the daily sperm production were reduced. However, ZnCl2 and vitamin C showed to be effective against such side effects, mainly regarding to sperm morphology. Long-term As intake increased the proportions of abnormal sperm, whereas the concomitant intake of As with zinc or vitamin C enhanced the proportions of normal sperm, showing that such compounds could be used to protect this cell type against morphological defects.
The testis is sensitive to cadmium, but studies investigating cadmium-induced testicular injury have not yet clearly revealed the underlying mechanisms. This study aimed to investigate the injurious effects of cadmium on rat testes and the role that autophagy plays in this process. Wistar rats were randomly divided into four groups and intraperitoneally injected with 0.2 (low), 0.4 (middle), and 0.8 mg/kg·body weight (high) cadmium chloride for 5 weeks, while the control rats were injected with equal volume of saline. Rats exposed to cadmium appeared inactive and had reduced body weights and increased testicular organ coefficients at the end of treatment compared with control rats. Atomic absorption results showed that cadmium levels increased with increased cadmium exposure. Hematoxylin and eosin staining of testicular sections showed seminiferous tubular atrophy, decreased pipe diameter, spermatogonial stem cells falling off the inner lining, and reduced germ cell layers of disorderly arrangements in cadmium-treated rats. Immunohistochemical and western blot results both showed that levels of the autophagy-related proteins Beclin1 and microtubule-associated protein 1 light chain 3B (LC3B) increased with increased cadmium exposure. We also found that LC3B-II and calcium-sensing receptor (CSR) levels in cadmium-exposed rats significantly increased. By immunofluorescence, we found that the percentage of cells that expressed the CSR was significantly higher in LC3B-positive than LC3B-negative cells. Together, our results showed that cadmium accumulates in the testes causing testicular injury, which may be related to increased autophagy levels. Furthermore, calcium disorders associated with the CSR may reveal a potential way to activate autophagy.
It is reported that methanol is generally used as an industrial solvent, antifreeze, windshield washer fluid, cooking fuel and perfume. Methanol ingestion can lead to severe metabolic disturbances, blindness, or even death. So far, few studies about its negative effects on cardiovascular system have been reported. The purpose of this study was to determine the vasoactive effect of methanol and roles of ion channels and signal transduction pathways on isolated rat aorta. The results suggested that the mechanism of methanol-induced vasorelaxation at low concentrations (<500 mM) was mediated by ATP-sensitive K+ (KATP) and L-type Ca2+ channels, but the mechanism at high concentrations (>600 mM) was related to KATP, voltage-dependent K+, big-conductance Ca2+-activated K+, L-type Ca2+ channels as well as prostacyclin, protein kinase C, β-adrenoceptors pathways. In addition, methanol induced a dose-dependent inhibition of vasoconstrictions caused by calcium chloride, potassium chloride, or norepinephrine. Further work is needed to investigate the relative contribution of each channel and pathway in methanol-induced vasoactive effect.
Glutathione-S-transferase (GST) and cytochrome P450 family 1 subfamily A polypeptide 1 (CYP1A1) metabolize and detoxify carcinogens, drugs, environmental pollutants, and reactive oxygen species. Changes of GST expression in tissues and gene mutations have been reported in association with many neoplastic skin diseases and dermatoses. Widely used artificial food coloring additives (AFCAs) also reported to effect primarily behavioral and cognitive function and cause neoplastic diseases and several inflammatory skin diseases. We aimed to identify the changes in expression of GSTs, CYP1A1, and vascular endothelial growth factor (VEGF) in rat skin which were maternally exposed AFCAs. A rat model was designed to evaluate the effects of maternal exposure of AFCAs on skin in rats. "No observable adverse effect levels" of commonly used AFCAs as a mixture were given to female rats before and during gestation. Immunohistochemical expression of GSTs, CYP1A1, and VEGF was evaluated in their offspring. CYP1A1, glutathione S-transferase pi (GSTP), glutathione S-transferase alpha (GSTA), glutathione S-transferase mu (GSTM), glutathione S-transferase theta (GSTT), and VEGF were expressed by epidermal keratinocytes, dermal fibroblasts, sebaceous glands, hair follicle, and subcutaneous striated muscle in the normal skin. CYP1A1, GSTA, and GSTT were expressed at all microanatomical sites of skin in varying degrees. The expressions of CYP1A1, GSTA, GSTT, and VEGF were decreased significantly, while GSTM expression on sebaceous gland and hair follicle was increased. Maternal exposure of AFCAs apparently effects expression of the CYP1A1, GSTs, and VEGF in the skin. This prominent change of expressions might play role in neoplastic and nonneoplastic skin diseases.
We studied occupational exposure to phthalates from first-morning-void urine sample of hairdressing apprentices by HPLC-MS/MS analyses and association with health status. Metabolites of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono ethyl phthalate (MEP), mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP) were detected in all urine samples, followed by metabolites mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono(2-etylhexyl) phthalate (MEHP) occurring in 97.06% and 86.76% of samples, respectively. Positive associations for females were observed between MnBP and fat-free mass index (FFMI) and age; negative associations were found between MEHP, MEOHP, MEHHP, sum of MEHP, MEHHP, MEOHP and vital capacity and also between MEHP and forced vital capacity (FVC of predicted value (PV)). Lengths of exposure were associated to MnBP, MEHHP, and MEP. We also documented positive associations between anthropometry (body mass index, waist-to-height ratio (WHtR), FFMI, fat mass index) and pulmonary function FVC% of PV for females and negative associations between WHtR, waist-to-hip ratio, FFMI and ratio of forced expiratory volume in 1 s (FEV1) to FVC (FEV1/FVC). We assume that factors of occupational environment of hairdressing apprentices are affected by phthalates and resulted in negative outcomes in breathing mechanism and influence of body composition. Adipose tissue could play role as confounding factor in urine excretion of phthalates because of their lipid solubility and accumulation.
Glyphosate (N-phosphonomethylglycine) has been used as a broad-spectrum herbicide that has been widely used in the agricultural industry and also available for home use. The main aim of this study is to present a general overview of glyphosate intoxication-related publications from its introducing since the early 1970s using bibliometric technique.
On June 23, 2016, a literature search of the Scopus database was performed. We then extracted and analyzed the data using well-established qualitative and quantitative bibliometric indices: Publication year, affiliation, document type, country name, subject category, journal name, publishing language, and collaboration and citation patterns.
We recognized a total of 3735 publications on glyphosate published between 1973 and 2015. There were 875 publications related to glyphosate intoxication in the Scopus database published between 1978 and 2015. Articles (757) comprised 86.5% of the total publications, followed by reviews (41; 4.7%). Most publications were published in English (87.9%), followed by Portuguese (6.6%). The number of publications related to glyphosate intoxication increased from 44 in 1978–1987 up to 152 in 1996–2005 and then quadrupled in 2006–2015. The United States was the leading country with 180 documents representing 20.6%, followed by Brazil (120; 13.7%), Canada (78; 8.9%), Argentina (61; 7.0%), and France (57; 6.5%). The 85.6% of the publications was cited, and the average of citation per document was 17.13 with h-index of 55. Furthermore, the United States achieved the highest h-index of 33. Most of the global international collaborations are made with researchers from the United States, who collaborated with 23 countries/territories in 44 publications.
The trends in global glyphosate-related research between 1978 and 2015 were evaluated by a bibliometric technique. Results showed that English was the leading publishing language, and the major publication type was original article. Findings showed that number of research publications related to glyphosate intoxication increased significantly in the last decade. The United States and Brazil are the two most productive countries in research on glyphosate intoxication. This study will be beneficial to policy makers by identifying areas that need greater investment and research funding to target appropriate agriculture sectors so as to improve glyphosate safety in a global setting.
The aim of the study is to investigate protective effect of resveratrol (Res) on acute kidney injury (AKI) in sepsis.
Rats in sham group received sham operation; in sham + Res received sham operation and Res (3 mg/kg); in cecal ligation and puncture (CLP) established as sepsis; in CLP + Res (3 mg/kg) with sepsis and Res (3 mg/kg); and in CLP + Res (10 mg/kg) with sepsis and Res (10 mg/kg). Survival rate, serum indexes, inflammatory factors, NF-B-P65, and SIRT1 were detected. Lipopolysaccharide (LPS) mesangial cell was with Res and SIRT1 silencing.
(1) Res intervention improved survival rate of CLP rat. (2) Compared to sham, serum creatinine, blood urine nitrogen, serum cystatin C, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, tumor necrosis factor-α, interleukin-1β, IL-6, and renal injury index increased in CLP group, while decreased in CLP + Res (3 mg/kg) and CLP + Res (10 mg/kg), significantly, as dose-dependent (p < 0.05). (3) With Res, NF-B-P65 and de-acetylated SIRT1 decreased, while SIRT1 and de-acetylated Nuclear factor kB-p65 9 NF-B-P65) increased, significantly (p < 0.05). (4) SIRT1 and de-acetylated NF-B-P65 decreased in LPS cells, while SIRT1 increased after Res intervention, significantly (p < 0.05). After silencing SIRT1, de-acetylated NF-B-P65 increased, significantly (p < 0.05).
Res increases the survival rate of septic rats by inhibiting inflammatory factors to ease AKI and promotes NF-B-P65 de-acetylation by upregulating SIRT1.
Methylphenidate (MPH) derivative drugs are used because of psychostimulants effects on attention-deficit hyperactivity disorder in children and adults. As far as we know, toxic or anti-proliferative effects of MPH against cartilage tissue were not studied in the literature. The present study was carried out to investigate the possible effects of MPH on the proliferation, viability and differentiation of primary human chondrocytes, in vitro.
Monolayer primary chondrocyte cultures were prepared using osteochondral tissue obtained from patients who underwent a total knee prosthesis operation. Stock solution of MPH was prepared and aliquots having 1–1000 µM concentrations of the drug was composed. These solutions were applied to the wells containing cultured chondrocyte samples within the well plates. Control groups were composed of pure chondrocyte culture and no solution was added into them. All groups were evaluated at 24, 48 and 72 h in order to determine the possible negative effects of the drug on the chondrocytes. The data were evaluated by Tukey’s honestly significantly different test following analysis of variance.
In the group where MPH was applied, it was found that viability, proliferation and stage-specific embryonic antigen-1 protein expression were decreased in comparison to the control group.
It was emphasized that clinicians should not disregard the fact that this drug might suppress chondrocyte cell proliferation and chondrogenic differentiation.
Mercury (Hg) represents a ubiquitous environmental heavy metal that could lead to severe toxic effects in a variety of organs usually at a low level. The present study focused on the liver oxidative stress, one of the most important roles playing in Hg hepatotoxicity, by evaluation of different concentrations of mercuric chloride (HgCl2) administration. Moreover, the protective potential of curcumin against Hg hepatotoxic effects was also investigated. Eighty-four rats were randomly divided into six groups for a three-days experiment: control, dimethyl sulfoxide control, HgCl2 treatment (0.6, 1.2, and 2.4 mg kg–1 day–1), and curcumin pretreatment (100 mg kg–1 day–1) groups. Exposure of HgCl2 resulted in acute dose-dependent hepatotoxic effects. Administration of 2.4 mg kg–1 HgCl2 significantly elevated total Hg, nonprotein sulfhydryl, reactive oxygen species formation, malondialdehyde, apoptosis levels, serum lactate dehydrogenase, and alanine transaminase activities, with an impairment of superoxide dismutase and glutathione peroxidase in the liver. Moreover, HgCl2 treatment activated nuclear factor-E2-related factor 2-antioxidant response element (Nrf2-ARE) signaling pathway in further investigation, with a significant upregulation of Nrf2, heme oxygenase-1, and -glutamylcysteine synthetase heavy subunit expression, relative to control. Pretreatment with curcumin obviously prevented HgCl2-induced liver oxidative stress, which may be due to its free radical scavenging or Nrf2-ARE pathway-inducing properties. Taking together these data suggest that curcumin counteracts HgCl2 hepatotoxicity through antagonizing liver oxidative stress.
The present research task is aimed to evaluate the role of exogenous α-lipoic acid (ALA) (100 mg/kg body weight) as hepatoprotective and potent antioxidant in amelioration of copper nanoparticle (CNP)-induced hepatotoxicity. Forty male rats were randomly assigned into four equal groups: group I (control), group II received CNPs, group III received CNPs + ALA, and finally group IV received ALA for 2 months. At the end of the experimental period, the rats were decapitated, and blood and liver tissue samples were collected for measurement of liver function tests, antioxidant status, lipid peroxidation (LPO), copper content, expression of some apoptotic genes, and histopathological analysis. CNPs induced marked hepatic damages as evident by severe alteration in hepatic biomarkers. This was accompanied by a significant elevation in hepatic LPO and induced nitric oxide, copper content, and expression level of apoptotic genes (C-myc and C-jun). In contrast, marked depletion for antioxidant parameters was detected. These findings were confirmed with severe pathological alterations. Coadministration of ALA as a powerful antioxidant attenuates the hepatotoxic effects of CNPs through improvement of liver parameters, oxidative status, genetic changes, and preservation of liver integrity through histopathological analysis. These results suggest that consumed ALA could be used as an applicable hepatoprotective agent against oxidative damage mediated by nanoparticles intoxication.
The wide application of silver nanoparticles (AgNPs) has pointed out the need to evaluate their potential risk and toxic effects on human health. Herein, the cytotoxic effects of Argovit™ AgNPs were evaluated on eight cancer cell lines. Further cytotoxic studies were performed in gynecological cancer cell lines from cervical (HeLa) and breast (MDA-MB-231 and MCF7) cancer. In both cases, the half maximal inhibitory concentration (IC50) of AgNPs produced the formation of reactive oxygen species (ROS) after 24 h of incubation, but it was not statistically significant compared with untreated cells. However, HeLa, MDA-MB-231, and MCF7 cells treated with the maximal IC of AgNPs induced the formation of ROS either at 12 or 24 h of incubation. Genotoxicity achieved by comet assay in HeLa, MDA-MB-231, and MCF7 cells revealed that exposure to IC50 of AgNPs does not induced noticeable DNA damage in the cells. However, the IC of AgNPs provoked severe DNA damage after 12 and 24 h of exposure. We conclude that, Argovit (polyvinylpyrrolidone-coated AgNPs) induce a cytotoxic effect in a time and dose-dependent manner in all the eight cancer cell lines tested. Nevertheless, the genotoxic effect is mainly restricted by the concentration effect. The results contribute to explore new therapeutic applications of AgNPs for malignances in murine models and to study in deep the cytotoxic and genotoxic effects of AgNPs in healthy cells at the surrounding tissue of the neoplasia.
Acquired immunodeficiency syndrome (AIDS) is a worldwide disease characterized by impairments of immune function. AIDS can be associated with oxidative stress (OS) that can be linked to selenium (Se) deficiency. Se is fundamental for the synthesis of selenoproteins, such as glutathione peroxidase and thioredoxin reductase. These enzymes catalyze the decomposition of reactive oxygen species and contribute to maintain equilibrium in cell redox status. Literature data indicate that organoselenium compounds, such as ebselen and diphenyl diselenide, have antioxidant properties in vitro and in vivo models associated with OS. Nevertheless, selenocompounds can also react and oxidize thiols groups, inducing toxicity in mammals. Here, we tested the potential cytotoxic and genotoxic properties of six analogs of the prototypal anti-HIV drug azidothymidine (AZT) containing Se (5'-Se-(phenyl)zidovudine; 5'-Se-(1,3,5-trimethylphenyl)zidovudine; 5'-Se-(1-naphtyl)zidovudine; 5'-Se-(4-chlorophenyl)zidovudine) (C4); 5'-Se-(4-methylphenyl)zidovudine (C5); and 5'-(4-methylbenzoselenoate)zidovudine). C5 increased the rate of dithiothreitol oxidation (thiol oxidase activity) and C2-C4 and C6 (at 100 µM) increased DNA damage index (DI) in human leukocytes. Moreover, C5 (200 µM) decreased human leukocyte viability to about 50%. Taken together, these results indicated the low in vitro toxicity in human leukocytes of some Se-containing analogs of AZT.
Hepatosteatosis is a complex disorder, in which insulin resistance and associated dyslipidemic and inflammatory conditions are fundamental. Dietary habit, especially regular consumption of fat and sugar-rich diet, is an important risk factor. Coconut and mustard oils (CO and MO) are medium-chain saturated and monounsaturated fats that are common dietary ingredients among the Indian populations. Present study analyzed the effect of prolonged consumption of the fresh and thermally oxidized forms of these oils on glucose tolerance and hepatosteatosis in male Wistar rats. Thermally oxidized CO (TCO) and MO (TMO) possessed higher amount of lipid peroxidation products and elevated p-anisidine values than their fresh forms. Dietary administration of TCO and TMO along with fructose altered glucose tolerance and increased hyperglycemia in rats. Dyslipidemia was evident by elevated levels of triglycerides and reduced high density lipoprotein cholesterol (HDLc) levels in fructose and edible oil-fed group (p < 0.05). Additionally, hepatic antioxidant status was diminished and oxidative stress markers were elevated in TCO- and TMO-fed rats. Substantiating these, hike in liver function marker enzyme activities were also observed in these animals. Supporting this, histological analysis revealed higher incidence of microvesicles and hepatocellular ballooning. Results thus suggest that consumption of thermally oxidized fats may cause hepatic damage.
Buprenorphine drug cartridge was made for autoinjector device for use in emergency and critical situations to reduce the morbidity and mortality. Water-filled cartridges were prepared and buprenorphine was injected aseptically in the cartridge, to make 0.05 and 0.10 mg/mL. Rats were injected intraperitoneally, buprenorphine (0.3 and 0.6 mg/kg), repeatedly with the autoinjector and compared with manual injection (7 days and 14 days) using various haematological and biochemical parameters. No significant change was observed in the body weight, organ to body weight ratio and haematological variables in any of the experimental groups compared with the control group. Except serum urea and aspartate aminotransferase, no significant change was observed in glucose, cholesterol, triglycerides, bilirubin, protein, albumin, creatinine, uric acid, alanine aminotransferase, gamma glutamyltransferase and alkaline phosphatase. The autoinjectors deliver the drugs with spray effect and force for faster absorption. In the present study, the autoinjector meant for intramuscular injection was injected intraperitoneally in rats, and the drug was delivered with force on the vital organs. No significant difference was observed in the autoinjector group compared to the manual group showing tolerability and safety of the buphrenorphine autoinjector. This study shows that buprenorphine autoinjector can be considered for further research work.
We investigate the effects of bone morphogenetic protein-7 (BMP-7) on models with silica-induced and macrophage-mediated fibrosis and its possible mechanisms in vitro.
Rat alveolar II epithelial (RLE-6TN) cells were incubated with the supernatant of mouse macrophage-like cells (RAW264.7) and treated with 0, 25, 50, and 100 μg/mL silica. Using Western blotting, the epithelial markers (surfactant proteins-C and E-cadherin) and the mesenchymal markers (fibronectin (FN) and viminten (Vim)) were detected. After neutralizing the BMP-7, the progress of fibrosis was assessed by the content of hydroxyproline (Hyp) and collagen I, III protein levels as well as the Smad signaling pathway proteins, including phosphorylated Smad1/5(P-Smad1/5) and phosphorylated Smad2/3(P-Smad2/3). Collagen I was also identified by immunofluorescence and pretreated with SB-431542, LDN-193189, or anti-BMP-7-neutralizing antibody. In addition, the levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 were detected using Western blotting.
The model of RLE-6TN cells was established successfully, the expressions of Vim, FN, MMP-2, and MMP-9 were upregulated, while the concentration of silica is increased. Neutralizing BMP-7 stimulated the decrease of P-Smad1/5 and the increase of P-Smad2/3, as well as the collagen I, collagen III, FN, and Hyp via Smad signaling pathway. Furthermore, pretreated with LDN-193189 or anti-BMP-7-neutralizing antibody, the expression of collagen I was increased, yet it was decreased with SB-431542 intervention.
The activated BMP/Smad and suppressed transforming growth factor-β/Smad pathways could suppress silica-induced fibrosis via a MMP-dependent mechanism. BMP-7 is expected to be the optimized strategy of delaying the interstitial changes.
Attenuated cardioprotective effect of ischemic preconditioning (IPC) by reduced nitric oxide (NO) is a hallmark during diabetes mellitus (DM). Recently, we reported that the formation of caveolin–endothelial nitric oxide synthase (eNOS) complex decreases the release of NO, which is responsible for attenuation of IPC-induced cardioprotection in DM rat heart. Heme oxygenase-1 (HO-1) facilitates release of NO by disrupting caveolin–eNOS complex. The activity of HO-1 is decreased during DM. This study was designed to investigate the role of hemin (HO-1 inducer) in attenuated cardioprotective effect of IPC in isolated diabetic rat heart.
DM was induced in male Wistar rat by single dose of streptozotocin. Cardioprotective effect was assessed in terms of myocardial infarct size and release of lactate dehydrogenase and creatine kinase in coronary effluent. The release of NO was estimated indirectly by measuring the release of nitrite in coronary effluent. Perfusion of sodium nitrite, a precursor of NO, was used as a positive control.
IPC-induced cardioprotection and increased release of nitrite were significantly attenuated in a diabetic rat as compared to a normal rat. Pretreatment with hemin and daidzein, a caveolin inhibitor, alone or in combination significantly restored the attenuated cardioprotection and increased the release of nitrite in diabetic rat heart. Zinc protoporphyrin, a HO-1 inhibitor, significantly abolished the observed cardioprotection and decreased the release of nitrite in hemin pretreated DM rat heart.
Thus, it is suggested that hemin restores the attenuated cardioprotective effect in diabetic rat heart by increasing the activity of HO-1 and subsequently release of NO.
Pesticides exposure causes usually harmful effects to the environment and human health. The present study aimed to investigate the potential toxic effects of penconazole, a triazole fungicide, on the cerebrum and cerebellum of adult rats. Penconazole was administered intraperitoneally to male Wistar rats at a dose of 67 mg kg–1 body weight every 2 days during 9 days. Results showed that penconazole induced oxidative stress in rat cerebrum and cerebellum tissues. In fact, we have found a significant increase in malondialdehyde, hydrogen peroxide, and advanced oxidation protein product levels, as well as an alteration of the antioxidant status, enzymatic (superoxide dismutase and catalase) and nonenzymatic (glutathione), the cholinergic function, and membrane-bound ATPases (Na+/K+-ATPase and Mg2+-ATPase). Penconazole also provoked histological alterations marked by pyknotic and vacuolated neurons in the cerebrum and apoptosis and edema in the cerebellum Purkinje cells’ layer. Therefore, the use of this neurotoxicant fungicide must be regularly monitored in the environment.
Conventional chemotherapy is the most valid method to cope with cancer; however, it has serious drawbacks such as decrease in production of blood cells or inflammation of the lining of the digestive tract. These side effects occur since generally the drugs used in chemotherapy are distributed evenly within the body of the patient and cannot distinguish the cancer cells from the healthy ones. In this study, folic acid (FA)-conjugated, polyethylene-coated magnetic nanoparticles (FA-MNPs), and doxorubicin (Dox)-loaded formulation (Dox-FA-MNPs) were prepared. The cytotoxicity of these nanoparticles on HeLa and Dox-resistant HeLa cells was investigated. Magnetic nanoparticles (MNPs), polyethylene glycol (PEG)-coated MNPs (PEG-MNPs), and FA-MNPs were successfully synthesized and characterized by several methods. Dox loading of FA-MNPs and release profile of Dox from the nanoparticles were studied. Cytotoxic effects of FA-MNPs and Dox-FA-MNPs on HeLa cells were analyzed. MNPs, PEG-MNPs, and FA-MNPs all had small sizes and supermagnetic behavior. High amounts of Dox could be loded onto the nanoparticles (290 μgmL–1). In 24 h, 15.7% of Dox was released from the Dox-FA-MNPs. The release was increased in acidic conditions (pH 4.1). Internalization studies showed that FA-MNPs and Dox-FA-MNPs were taken up efficiently by HeLa cells. The investigation of cytotoxicity of the particles indicated that 38–500 μgmL–1 Dox-FA-MNPs significantly decreased the proliferation of HeLa cells compared to FA-MNPs. Due to their size, magnetic properties, internalization, drug release, and cytotoxicity characteristics, the MNPs prepared in this study may have potential application as a drug delivery system in cancer chemotherapy.
Carisoprodol is a widely prescribed muscle relaxant and is also a drug known to be a subject to abuse. Despite the fact that carisoprodol has been available for prescription since 1959, a number of gaps in our knowledge of the toxicokinetics of this common drug exist. For example, the volume of distribution (Vd) for carisoprodol in humans has not been reported. A two-compartment pharmacokinetic model describing carisoprodol metabolism and that of the primary metabolite, meprobamate, was developed to better understand the pharmacokinetics of this drug. The model accounts for first pass metabolism of carisoprodol and was able to replicate the data from several previously reported data sets. Based on an analysis of four different data sets, the Vd for carisoprodol ranged from 0.93 to 1.3 L/kg, while that for meprobamate ranged from 1.4 to 1.6 L/kg. The model was also used to estimate the probable dose of this drug in an individual where questions concerning the drug’s role in her death had been posed. The model may, therefore, have significant utility for estimating doses of carisoprodol in medicolegal cases.
Glyceryl trinitrate (GTN) has been used widely as a potent vasodilator to treat heart conditions, such as angina pectoris and chronic heart failure. This study aims to elucidate the effect of exogenous nitric oxide (NO) administration, using GTN, on carbon tetrachloride (CCl4)-induced oxidative stress and liver injury in rats. The results obtained demonstrated that NO generated by the administration of GTN affords protection against CCl4-induced oxidative stress and liver injury. Administration of CCl4 resulted in a significant (p < 0.001) increase in lipid peroxidation and tissue damage markers (aspartate and alanine transaminase and lactate dehydrogenase) release in serum. Parallel to these changes, CCl4 also caused downregulation of antioxidant enzymes including glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST), and several fold induction in -glutamyl transpeptidase (GGT) activity. Subsequent administration of GTN resulted in significant (p < 0.001) recovery of GSH-metabolizing enzymes in a dose-dependent manner. Further, administration of NO inhibitor, NG-nitro-
MicroRNA (miRNA) has been reported to play important roles in regulating drug-induced liver injury. Ethyl acetate extract isolated from rhizoma Dioscoreae bulbifera (EF) has been reported to induce hepatotoxicity in our previous studies. This study aims to observe the altered liver miRNA profile and its related signalling pathway involved in EF-induced hepatotoxicity. Serum alanine/aspartate aminotransferase assay showed that EF (450 mg/kg)-induced hepatotoxicity in mice. Results of miRNA chip analysis showed that the expression of eight miRNAs was up-regulated and of other nine miRNAs was down-regulated in livers from EF-treated mice. Further, the altered expression of miR-200a-3p, miR-5132-5p and miR-5130 was validated using real-time polymerase chain reaction (PCR) assay. There were total seven predicted target genes of miR-200a-3p, miR-5132-5p and miR-5130. Only one kyoto encyclopedia genes and genomes pathway was annotated using those target genes, which is protein processing in endoplasmic reticulum (ER). Furthermore, liver expression of DnaJ subfamily A member 1, a key gene involved in protein processing in ER based on the altered miRNAs, was increased in EF-treated mice. In conclusion, the results demonstrated that EF altered the expression of liver miRNA profile and its related signalling pathway, which may be involved in EF-induced hepatotoxicity.
Several mechanisms for the pathogenesis of diabetic complications have been proposed, one of which is abnormal zinc (Zn) homeostasis. Zn is necessary for proper liver function since it has important antioxidant, anti-inflammatory, and antiapoptotic properties. We aimed to investigate whether or not Zn has morphologically protective effect on diabetes-induced liver damage in rats. In addition, we have investigated the role of Zn supplementation on apoptosis, lipid peroxidation levels, and the distribution of metallothionein (MT) in diabetic liver tissue. Wistar albino rats were divided into four groups: control, Zn, diabetic, and Zn-diabetic group. Experimental diabetes was induced by a single-dose streptozotocin intraperitoneally and Zn was administrated via gastric gavage tube for 6 weeks. MT expressions were showed with immunohistochemical staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used for apoptosis. Also, Zn, MT, and malondialdehyde (MDA) levels were determined in liver of rats. MDA levels of the Zn-supplemented diabetic group was less than the diabetic group though MT levels were increased. The number of apoptotic cells per unit area was found to be significantly decreased in this group. In the Zn-supplemented diabetic group, fibrotic tissue density and the collagen tissue density were observed less than the diabetic group. MT immunoreactivity was observed less in Zn-supplemented diabetic group. In conculusion, the present study indicated that Zn has a potential in preventing or even repairing effect against diabetic damage of the liver cells by increasing expression of MT and by reducing the apoptotic cell death and the oxidative stress.
Postmenopausal patients with breast cancer have two options for adjuvant endocrine therapy, tamoxifen and aromatase inhibitors (AIs) as well as radiotherapy (RT) and chemotherapy. However, there is limited data regarding the optimal sequencing of RT and tamoxifen/AIs. Thus, we aimed to evaluate the effects of tamoxifen and AIs on radiation-induced cardiotoxicity. Eighty ovariectomized rats were divided into eight groups (G). G1 was defined as a control group; G2, G3, G4, and G5 were RT, tamoxifen, anastrozle, and letrozole groups, respectively; G6, G7, and G8 were RT plus tamoxifen, anastrozle, and letrozole groups, respectively. Drugs were started 1 week before RT and continued until the animals were killed 16 weeks after RT. The heart tissues were then dissected and examined with light microscopy to determine endocardial thickness and cardiac fibrosis. The endocardial thickness scores of both RT alone and the tamoxifen groups as well as the cardiac fibrosis score of RT alone were higher than that the control group (p < 0.05 for all). There was no difference in the endocardial thickness and cardiac fibrosis scores of the RT-only group and the RT plus hormonotherapy groups (p > 0.05 for all). Concurrent administration of RT and hormonal therapy with either tamoxifen or AIs did not further amplify radiation-induced cardiac toxicity. This issue warrants further study.
Nano nickel oxide (NiO), widely used in industry, has recently been discovered to have pulmonary toxicity. However, no subchronic exposure studies about nano NiO-induced pulmonary fibrosis have been reported. The objective of this study was to investigate pulmonary fibrosis induced by nano NiO and its potential mechanism in rats. Male Wistar rats (n = 40, 200–240 g) were randomized into control group, nano NiO groups (0.015, 0.06, and 0.24 mg/kg), and micro NiO group (0.024 mg/kg). All rats were killed to collect lung tissue after intratracheal instillation of NiO particles twice a week for 6 weeks. To identify pulmonary fibrosis, Masson trichrome staining, hydroxyproline content, and collagen protein expression were performed. The results showed widespread lung fibrotic injury in histological examination and increased content of hydroxyproline, collagen types I and III in rat lung tissue exposed to nano NiO. To explore the potential pulmonary fibrosis mechanism, transforming growth factor beta 1 (TGF-β1) content was measured by enzyme-linked immunosorbent assay, and the messenger RNA expression of key indicators was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The TGF-β1 content was increased in nano NiO exposure groups, as well as the upregulated gene expression of TGF-β1, Smad2, Smad4, matrix metalloproteinase, and tissue inhibitor of metalloproteinase. The findings indicated that nano NiO could induce pulmonary fibrosis, which may be related to TGF-β1 activation.
There are many discrepancies among the results of studies on the genotoxicity of lead. The aim of the study was to explore lead-induced DNA damage, including oxidative damage, in relation to oxidative stress intensity parameters and the antioxidant defense system in human leukocytes. The study population consisted of 100 male workers exposed to lead. According to the blood lead (PbB) levels, they were divided into the following three subgroups: a group with PbB of 20–35 μg/dL (low exposure to lead (LE) group), a group with a PbB of 35–50 µg/dL (medium exposure to lead (ME) group), and a group with a PbB of >50 μg/dL (high exposure to lead (HE) group). The control group consisted of 42 healthy males environmentally exposed to lead (PbB < 10 μg/dL). A comet assay was used to measure the DNA damage in leukocytes. We measured the activity of superoxide dismutase (SOD), catalase, glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), and glutathione-S-transferase (GST) as well as the concentration of malondialdehyde (MDA), and the value of the total antioxidant capacity. The level of PbB was significantly higher in the examined subgroups than in the control group. The percentage of DNA in the tail was significantly higher in the LE, ME, and HE subgroups than in the control group by 10% (p = 0.001), 15% (p < 0.001), and 20% (p < 0.001), respectively. The activity of GR was significantly lower in the LE and ME subgroups than in the control group by 25% (p = 0.007) and 17% (p = 0.028), respectively. The activity of G6PD was significantly lower in the ME subgroup by 25% (p = 0.022), whereas the activity of GST was significantly higher in the HE subgroup by 101% (p = 0.001) than in the control group. Similarly, the activity of SOD was significantly higher in the LE and ME subgroups by 48% (p = 0.026) and 34% (p = 0.002), respectively. The concentration of MDA was significantly higher in the LE, ME, and HE subgroups than in the control group by 43% (p = 0.016), 57% (p < 0.001), and 108% (p < 0.001), respectively. Occupational lead exposure induces DNA damage, including oxidative damage, in human leukocytes. The increase in DNA damage was accompanied by an elevated intensity of oxidative stress.
Arsenic (As) is widely distributed in the environment, and humans can be exposed to As from various sources such as air, water, soil, and food. This study was performed to evaluate the As exposure levels in Korean adults by measuring total As in urine and its relation with the consumption of seafood, a favorite food in Korea. A total of 2077 adults were the study subjects; they ranged in age from 19 to 83, and they were recruited by probability sampling stratified by area, sex, and age. None of the subjects had been exposed to As occupationally. We collected information about the demographic characteristics, lifestyles, and food consumption of study subjects using a questionnaire and followed urine sampling. Diet was assessed in individual interviews using the 24-h recall method. Total As in urine was analyzed using inductively coupled plasma mass spectrometry (PerkinElmer NEXION 300S; Concord, Ontario, Canada). The geometric mean concentration of total As in urine was observed to be 97.6 µg/L and was higher in males (103.9 µg/L) than in females (93.0 µg/L). Total As levels in urine were affected by sex, age, seafood intake, and geographic location. In this study, total As in urine was positively correlated with fish and shellfish consumption, and was mainly determined by As intake through fish and shellfish/grains/flavors. These findings suggest that seafood consumption might be a major contributor to urinary As levels in Korean adults.
Cyclosporine-A (CsA) is an immunosuppressive drug which has been used to prevent rejection after organ transplantation and to treat certain autoimmune diseases. However, its therapeutic use is limited by nephrotoxicity. In this study, the modulator effect of allicin on the oxidative nephrotoxicity of CsA in rats was investigated. Furthermore, the effect of allicin on CsA-induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was estimated. Rats were divided into three groups, control, CsA (15 mg/kg, subcutaneously), and CsA/allicin (50 mg/kg, orally). At the end of the study, all rats were killed and then blood, urine samples, and kidneys were taken. CsA administration caused a severe nephrotoxicity which was evidenced by elevated kidney/body weight ratio, serum creatinine (Cr), blood urea nitrogen, lactate dehydrogenase, and urinary protein with a concomitant reduction in serum albumin and Cr clearance as compared with control. A significant increase in renal contents of malondialdehyde, myeloperoxidase, and tumor necrosis factor-alpha with a significant decrease in renal reduced glutathione, superoxide dismutase activities, and nitric oxide (NOx) content was detected upon CsA administration. Exposure to CsA increased the sensitivity of isolated urinary bladder rings to ACh. Histological analysis revealed that CsA caused tubular necrosis and moderate diffuse tubular atrophy. Allicin protected kidney tissue against the oxidative damage and the nephrotoxic effect of CsA and significantly reduced the responses of isolated bladder rings to ACh. Our study indicates that allicin administration has the potential to protect against CsA-induced renal injury by reducing oxidative stress and inflammation and restoring NOx level.
Oxybuprocaine (OBPC) is a widely used topical anesthetic in eye clinic, and prolonged and repeated usage of OBPC might be cytotoxic to the cornea, especially to the outmost corneal epithelium. In this study, we characterized the cytotoxic effect of OBPC on human corneal epithelial (HCEP) cells and investigated its possible cellular and molecular mechanisms using an in vitro model of non-transfected HCEP cells. Our results showed that OBPC at concentrations ranging from 0.025% to 0.4% had a dose- and time-dependent cytotoxicity to HCEP cells. Moreover, OBPC arrested the cells at S phase and induced apoptosis of these cells by inducing plasma membrane permeability, phosphatidylserine externalization, DNA fragmentation, and apoptotic body formation. Furthermore, OBPC could trigger the activation of caspase-2, -3, and -9, downregulate the expression of Bcl-xL, upregulate the expression of Bax along with the cytoplasmic amount of mitochondria-released apoptosis-inducing factor, and disrupt mitochondrial transmembrane potential. Our results suggest that OBPC has a dose- and time-dependent cytotoxicity to HCEP cells by inducing cell cycle arrest and cell apoptosis via a death receptor-mediated mitochondria-dependent proapoptotic pathway, and this novel finding provides new insights into the acute cytotoxicity and its toxic mechanisms of OBPC on HCEP cells.
Pyridorin®, a naturally occurring metabolite of vitamin B6 that inhibits and scavenges reactive oxygen species, is being developed as a potential therapeutic for acute kidney injury. An investigational new drug application (IND) was opened for Pyridorin in support of its ongoing oral drug clinical development program. Currently, a Pyridorin intravenous (IV) formulation is being developed for use in surgical patients. To support the IND for Pyridorin, a full battery of nonclinical Good Laboratory Practice compliant studies was performed with no neurological or behavioral signs of toxicity seen following oral or IV administration of pyridoxine dihydrochloride (the active ingredient in Pyridorin). However, excessive ingestion of vitamin B6 has been reported to cause neurotoxic syndrome in humans. Therefore, under Food and Drug Administration recommendation, a 7-day IV study in rats was conducted to further evaluate the drug’s potential to cause neurotoxicity. Blood plasma samples indicated that exposure to pyridoxamine dihydrochloride and its metabolites, pyridoxal, pyridoxine, and 4-pyridoxic acid was linearly dose proportional and independent of gender. At doses of up to 200 mg/kg/day pyridoxine dihydrochloride, no treatment-related effects were seen in rats, providing further evidence for the absence of pyridoxine dihydrochloride-related changes in the nervous system. A no observed adverse effect level of 200 mg/kg/day was identified for this study.
Studies have revealed that impairment of the pregnant body weight reduces the fetal body weight and causes minor changes in skeletal development. The aim of the present study was to assess the effects of maternal feed restriction during pregnancy in offspring immune system development. Pregnant Wistar rats were distributed into 5 groups: 1 control in which dams received food ad libitum and 4 experimental groups in which dams were fed restricted amounts of rodent ration (16, 12, 9, or 6 g/rat/day) from the 6th to 17th gestation day. Teratogenicity was assessed using classical teratological evaluation and developmental immunotoxicology protocols. Maternal body weight gain, fetus weight, and placenta weight were reduced for feed-restricted females from the groups fed 12, 9, and 6 g/rat/day (p < 0.05). No pup mortality was observed immediately after cesarean sections among the groups, and no visceral or skeletal malformations were detected. An immunoteratological study revealed an increase in the relative weight of the thymus and an increase in the phorbol myristate-acetate solution-induced hydrogen peroxide release by inflammatory cells in 21-day-old pups. Alterations in the delayed-type hypersensitivity response and the humoral immune response against sheep red blood cells were observed in pups from feed-restricted mothers. Feed restriction in Wistar rats during organogenesis did not promote structural malformations but resulted in offspring with lower birth weights and promoted significant changes in the immune responses of the rat pups.
Previous histopathological studies have shown the hepatotoxicity of paclitaxel (TXL). However, there is little known about the molecular pathway(s) of TXL-induced hepatotoxicity. Therefore, this study aimed to uncover the role of two transcription factors in the TXL-induced hepatotoxicity. Moreover, the hepato-protective effect of royal jelly (RJ) on TXL-induced toxicity was investigated. Wistar rats were divided into control and test groups. The test groups along with TXL received various doses of RJ (0, 50, 100 and 150 mg/kg, body weight). Biochemical hepatic functional assays, histopathological studies and hepatic superoxide dismutase level were determined. Additionally, the expression of E2f1 and cellular-myelocytomatosis (c-Myc) at messenger RNA (mRNA) level in the liver was evaluated. The hepatic functional biomarkers showed a significant (p < 0.05) elevation in the TXL-received animals, while RJ administration for 28 days resulted in a remarkable reduction in TXL-elevated alkaline phosphatase, alanine transaminase and lactate dehydrogenase levels. The TXL-treated animals showed a significant (p < 0.05) up-regulation of E2f1 and down-regulation of c-Myc at mRNA level, respectively. RJ lowered the expression of E2f1 while enhanced the expression of c-Myc in a dose-dependent manner. Our data suggest the hepato-protective effects of RJ on TXL-induced toxicity, which may attribute to a clear crosstalk between E2f1 and c-Myc as two regulators of liver growth.
Endogenous alcohol has been applied for spontaneous ethanol production via different metabolic pathways of the human body. Auto-brewery syndrome describes the patients with alcohol intoxication after ingesting carbohydrate-rich meals. The main objective of this study is to investigate the effect of diabetes mellitus (DM), liver cirrhosis (LC) and presence of both (DM and LC) on blood alcohol concentration (BAC) especially after carbohydrate ingestion. BAC has been measured by headspace gas chromatography-mass spectrometry in three groups of humans namely control, DM, LC and both (DM and LC) groups. The results showed that BAC in control group was 0.01–.3 mg/dL with mean 0.3 ± 0.41 mg/dL. In patients with DM, BAC is significantly higher than that of control group 4.85 ± 3.96 mg/dL. In patients with LC, BAC was 3.45 ± 2.65 mg/dL. In patients with both DM and LC, BAC increases to reach 10.88 ± 5.36 mg/dL. Endogenous ethanol production appears to increase in DM and LC. Also, it increased much more in patients with both diseases, but it did not reach toxic levels. On comparing BAC and blood glucose level in each group, all groups show insignificant correlations (p > 0.05).
N-nitrosodimethylamine (NDMA) is a toxicant found in foods and drinking water. Several synthetic agents used in alleviation of NDMA toxicity have been associated with serious side effects. Therefore, a safe and less toxic agent is desirable. In this study, betulinic acid (BA), a triterpenoid antioxidant, is proposed as a better and alternative agent to modulate NDMA-induced toxicity. Twenty-four Wistar rats were assigned into four groups of six rats each and treated with normal saline (control), BA (25 mg/kg), NDMA (5 mg/kg) and (BA + NDMA). BA was given by oral gavage for 14 consecutive days, while NDMA was administered intraperitoneally on days 7 and 12. Results showed that administration of NDMA significantly (p < 0.05) elevated the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase and gamma-glutamyl transferase by 51%, 48% and 81%, respectively. Also, NDMA intoxication significantly (p < 0.05) increased the levels of serum urea and creatinine by 64% and 82%, respectively, and decreased urinary creatinine by 67%. In addition, administration of NDMA significantly (p < 0.05) increased the levels of hepatic and renal DNA fragmentation by 44% and 61%, respectively, relative to control. The number of micronucleated polychromatic erythrocytes (mnPCEs) in NDMA-treated rats (11.1 ± 2.6 mnPCE/1000PCE) was significantly higher than control (4.3 ± 1.1 mnPCE/1000 PCE). Immunohistochemistry revealed strong expressions of Bcl-2 and nuclear p53 in NDMA-intoxicated rats. Interestingly, pretreatment with BA significantly (p < 0.05) ameliorated NDMA-induced changes in serum biochemical indices, mnPCEs, DNA fragmentation and expressions of Bcl-2 and p53 proteins. These findings suggest that BA protects against NDMA-induced toxicity via anti-oxidative and anti-apoptotic activities.
Hypofibrinogenemia is an important clinical consequence following envenomation by Lachesis muta muta, usually attenuated or prevented by administration of antivenom. The venom of L. m. muta contains both a metalloproteinase fibrinogenase and a serine protease thrombin-like enzyme, and exposure of fibrinogen to iron (Fe) and carbon monoxide (CO) has been demonstrated to decrease its catalysis by such enzymes. Using thrombelastographic analytical techniques, it was determined that this venom displayed weak procoagulant effects combined with fibrinogenolytic effects, and pretreatment of plasma with Fe and CO markedly attenuated venom-mediated effects. Additional experiments involving heparin exposure and varying calcium concentrations demonstrated that modification of fibrinogen with Fe and CO in human plasma rendered fibrinogen not recognizable to the fibrinogenolytic metalloproteinase but did not prevent polymerization by the thrombin-like serine protease. Lastly, when venom was exposed to CO in isolation and then placed in plasma, the fibrinogenase was inhibited but the thrombin-like enzyme was not inhibited. In sum, utilizing relatively facile modifications, we demonstrated with thrombelastography that Fe and/or CO addition can protect human plasmatic coagulation from fibrinogenase activity but not the effects of the thrombin-like activity of L. m. muta venom.
Colorectal cancer is the fourth leading cause of death. Various natural compounds are known to have antitumor properties. Garcinol, a polyisoprenylated benzophenone, has antioxidant and anti-inflammatory properties. In the current study, we investigated the anticancer activity of garcinol on human colorectal adenocarcinoma cell line (HT-29) human colon cancer cells.
HT-29 cells were treated with various concentrations of garcinol for 24 h. The effect of garcinol on HT-29 cells proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; the mRNA expression of microsomal prostaglandin E synthase-1 (mPGES-1), hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), C-X-C chemokine receptor type 4 (CXCR4), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) were examined by quantitative real-time polymerase chain reaction; apoptosis was detected by proportion of sub-G1 cell; caspase 3 activity and prostaglandin E2 (PGE2) level were determined by enzyme-linked immunosorbent assay and HT-29 cells migration was assessed using scratch test.
Garcinol preconditioning markedly decreased the expression of mPGES-1, HIF-1α, VEGF, CXCR4, MMP-2, and MMP-9. The proportion of cells in sub-G1 phase and caspase 3 activity were increased by garcinol treatment whereas the cell proliferation, PGE2 level, and cell migration were decreased in these cells, compared to the control group.
Our findings suggest that garcinol plays a critical role in elevating apoptosis and inhibiting HT-29 cells proliferation, angiogenesis, and invasion by suppressing the mPGES-1/PGE2/HIF-1α signaling pathways.
Zearalenone (ZEA) is a nonsteroidal estrogenic mycotoxin produced by Fusarium species. The exposure risk to humans and animals is the consumption of contaminated food and animal feeds. The aim of this study was to investigate ZEA-induced effects and its tumorigenic mechanism in TM3 cells (mouse Leydig cells). Cell proliferation, apoptosis, and gap junction intercellular communication (GJIC) were assessed in this study. Results showed that low concentrations of ZEA could significantly promote the growth of TM3 cells. The percentage of cell distribution was decreased significantly in G1/G0 phase and was increased significantly in S phase with 10 and 20 μg/L of ZEA for 72 h (p < 0.05, p < 0.01). The expressions of cyclin D1 and Cdk4 were significantly increased in the exposure groups compared with the control group (p < 0.05, p < 0.01). Compared with the control group, the apoptosis was significantly decreased in 10 and 20 μg/L groups (p < 0.01), and the ratio of Bax/Bcl-2 protein level was significantly decreased in a dose-dependent manner. The protein levels of proto-oncogene c-Myc, c-Jun, and c-Fos were significantly elevated and the protein levels of anti-oncogene p53 and phosphatase and tensin homolog (PTEN) were decreased obviously compared with the control group (p < 0.05, p < 0.01). ZEA affected the expressions of connexins and inhibited the activity of GJIC. These results demonstrated that ZEA can disturb the dynamic balance between proliferation and apoptosis and causes abnormal regulation of oncogenes, GJIC, and connexins in TM3 cells, which may easily induce the translation of normal cells into tumor cells.
Di-(2-ethylhexyl) phthalate (DEHP) is the most common plasticizer used in polyvinyl chloride-based plastics. DEHP is not covalently bound to the plastics and is easily released to the environment, resulting in human exposure. In this study, the adult rats were exposed to DEHP and its effects on the uterus was evaluated. Healthy adult female rats were treated with DEHP orally (with dose level 0, 1, 10, and 100 mg/kg body weight/day) for 30 days. No significant changes in the body weight and wet uterine weight were observed. Ovarian hormones and their receptor levels in the uterus were increased. Histological studies exhibited the structural abnormalities such as decrease in diameter, thinning of the layers and disruption in the glandular epithelium.
A combination of pentobarbital and phenytoin is used as a veterinary euthanasia drug. Because of its lethal effect, this study described pentobarbital–phenytoin combination veterinary drug human exposures reported to Texas poison centers during 2000–2015. Of 66 exposures, 73% involved female and 27% male patients. The distribution by patient age was 3% 0–5 years, 5% 6–19 years, 91% 20+ years, and 2% unknown. The most common routes were ocular (41%), ingestion (32%), injection (23%), and dermal (18%). The exposure reasons were unintentional (77%) and intentional (23%). The exposure site was the workplace (52%), patient’s own residence (38%), health-care facility (2%), and other/unknown (9%). The management site was managed on site (48%), at/en route to health-care facility (45%), referred to health-care facility (5%), and other (2%). The medical outcomes were no effect (23%), minor effect (30%), moderate effect (8%), major effect (8%), not followed nontoxic (3%), not followed minimal effects (24%), unable to follow potentially toxic (2%), and unrelated (3%). The most common adverse effects were ocular irritation/pain (18%), drowsiness/lethargy (15%), and coma (9%). The most common treatments were dilution/irrigation (70%), intravenous fluids (21%), and oxygen (14%). This study found few pentobarbital–phenytoin combination veterinary drug exposures were reported to Texas poison centers during a 16-year period. Although meant to be administered intravenously, the most common exposure routes were ocular and ingestion. Many of the exposures appeared to be unintentional and occurred at the workplace.
In the present study, we aimed to assess the potential protective effect of ascorbic acid (AA) against emamectin benzoate (EMB)-induced hepatotoxicity. For this purpose, biochemical, histopathological and analytical investigations were performed. Male Wistar rats were distributed into three groups, that is, a control group, an EMB group given 10 mg EMB/kg body weight (BW) by gavage and an EMB + AA group given 10 mg EMB/kg BW and vitamin C intraperitoneally (200 mg/kg). The duration of the treatment was 28 days and the duration of the study was 42 days. There was a statistically significant increase of all hepatic biomarkers, that is, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase activities, and glycemia, in EMB-treated group when compared with the control group. Light microscopic observations revealed variable signs of hepatotoxicity in the EMB group, which were represented by alteration of normal hepatic architecture, inflammatory cell infiltration, hepatocellular steatosis and foci of necrosis at 28 and 42 days post-treatment. However, co-treatment with vitamin C reduced EMB-related liver toxicity and diminished the abnormal biochemical and architectural damage. Emamectin B1a and B1b residues were detectable in all plasma samples of treated rats at 14, 21 and 28 days of treatment. The drug liver tissue concentration was significantly lower in EMB + AA group compared with EMB group at 28 and 42 days. In conclusion, the findings of the present study clearly indicate a significant protective action of vitamin C against EMB hepatotoxicity.
Anthrax is a bacterial disease caused by the aerobic sporeforming bacterium Bacillus anthracis. It has been suggested that oxidative stress plays an important role in the pathogenesis of B. anthracis. The aim of this study was to investigate serum paraoxonase 1 (PON1) activity, catalase activity, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) levels in patients with cutaneous anthrax.
Fifteen patients with cutaneous anthrax and 15 healthy controls were enrolled in this study. The serum MDA levels, SOD levels, paraoxonase, arylesterase, and catalase activities were measured using a spectrophotometer.
The serum SOD levels, paraoxonase, arylesterase, and catalase activities were significantly lower in patients with cutaneous anthrax than in controls (for all, p < 0.001), whereas MDA levels were significantly higher (p < 0.001). No significant correlation was found between serum paraoxonase activity, arylesterase activity, SOD levels, and MDA levels (all, p > 0.05) in patients with cutaneous anthrax.
The current study was the first to show decreased antioxidant levels and increased oxidant levels in patients with cutaneous anthrax. Therefore, decreased PON1 activity may play a role in the pathogenesis of cutaneous anthrax.
Tuberculosis (TB) is an intractable chronic infection. Disease treatment with anti-TB drugs remains challenging due to drug-induced hepatotoxicity. The toxicity of the anti-TB drugs rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) either alone or in combination was investigated in HepG2 cells. Assays of intracellular adenosine triphosphate (ATP) levels at 4-, 24- and 48-h post-exposure to gradient concentrations of RIF, INH and PZA were conducted. Drug-induced effects on mitochondrial membrane potential (MMP), mitochondrial complex I and complex III activity, nicotinamide adenine dinucleotide (NAD+) levels and cellular lactate production were assessed. Decreased ATP levels were dose-dependent and correlated with drug exposure duration. Approximate 24-h IC50s were 0.5 mM, 70 mM and 84 mM for RIF, INH and PZA, respectively. Twenty-four hours post-drug treatment, reductions of MMP (p = 0.0005), mitochondrial complex I and III activities (p = 0.0001 and p = 0.0003, respectively), NAD+ levels (p = 0.0057) and increased lactate production (p < 0.0001) were observed. Drug combinations used to mimic cumulative drug treatments induced a synergistic inhibition of mitochondrial complex I activity. An assessment of cellular ultrastructure using transmission electron microscopy indicated drug-induced mitophagy. Collectively, our study suggests that hepatotoxicity of commonly employed anti-TB drugs is mediated by their curtailment of mitochondrial function.
Acute exposure to systemic poisons represents an important challenge in clinical toxicology. We aimed to analyze the potential role of cardiac biomarkers, routine laboratory tests, and clinical scores as morbidity and in-hospital mortality predictors in patients intoxicated with various systemic poisons. We conducted a prospective study on adults acutely exposed to systemic poisons. We determined the PSS, Glasgow Coma Scale (GCS), and we performed electrocardiogram, laboratory tests, lactate and cardiac biomarkers (which were reassessed 4 h, respectively 6 h later). Of 120 patients included, 45% developed complications, 19.2% had a poor outcome, and 5% died. Multivariate logistic regression sustained lactate (odds ratio (OR) 1.58; confidence interval (CI) 95%: 0.97–2.59; p 0.066), MB isoenzyme of creatine kinase (6h-CKMB; OR 1.08; CI 95%: 1.02–1.16; p 0.018) as predictors for a poor outcome. A GCS < 10 (OR 0.113; CI 95%: 0.019–0.658; p 0.015) and 4h-lactate (OR 4.87; CI 95%: 0.79–29.82; p 0.087) predicted mortality after systemic poisons exposure. Receiver operating characteristic analysis showed that brain natriuretic peptide (area under the curve (AUC), 0.96; CI 95%: 0.92–0.99; p < 0.001), lactate (AUC, 0.91; CI 95%: 0.85–0.97; p < 0.001), and 6h-CKMB have good discriminatory capacity for predicting a poor outcome. In conclusion, these biomarkers, lactate, and GCS can be used to predict morbidity and mortality after systemic poisons exposure.
To evaluate effects of halofuginone (H) on radiation-induced lung injury (RILI), 60 rats were divided into six groups: Group (G) 1 control, G2 radiotherapy (RT) only, G3 and G4 2. 5 and 5 μg H and G5 and G6 RT + 2.5 and 5 μg H groups, respectively. A single dose of 12 Gy RT was given to both lungs. H was applied intraperitoneally with daily doses, until animals were killed at 6 and 16 weeks after RT. At 6th and 16th weeks of RT, five rats from each group were killed. Lung tissues were dissected for light and electron microscopy. Chronic inflammation, fibrosis and transforming growth factor-beta (TGF)-β scores of all study groups were significantly different at 6th and 16th week (p < 0.001). Chronic inflammation, fibrosis and TGF-β scores of G2 were higher than G5 and G6 at 6th and 16th weeks of RT. At 16th week, fibrosis and TGF-β scores of G5 were higher than G6 (p = 0.040 and 0.028, respectively). Electron microscopical findings also supported these results. Therefore, H may ameliorate RILI. The effect of the H was more prominent at higher dose and after long-term follow-up. These findings should be clarified with further studies.
Low fertility in rice caused by Chilo suppressalis has led to the use of diazinon to control this pest. Residue of pesticide could penetrate products and also food which can affect public health. The aim of this research was to determine health risk assessment of organophosphorus (OP) pesticide in rice, a strategic crop in Iran. Ninety rice samples were collected from 30 points during harvesting seasons from Rasht Area, Guilan Province, Iran from which 30 samples were prepared. The concentration of diazinon, the most common pesticide used in the study area, was determined by high-performance liquid chromatography. The result indicated that the total average of diazinon in rice samples (31.91 mg/kg) is by far higher than the maximum residue limit recommended by the European Union. According to the results, EDAI was 0.051 mg/kg day, while health risk index in rice was 10.2. Results showed that there is a health risk associated with the lifetime consumption of rice polluted by OP pesticide in the study area.
Biliary lithiasis, or sludge, and nephrolithiasis have been reported as a possible complication of ceftriaxone therapy. However, no study related to cefotaxime-induced biliary pseudolithiasis or nephrolithiasis was observed in the literature. Therefore, we investigated the comparative formation of biliary pseudolithiasis and nephrolithiasis after cefotaxime and ceftriaxone therapies.
The patients treated with ceftriaxone or cefotaxime were enrolled during the study period. Ultrasound imaging of the biliary and urinary tract was performed in all patients before and after the treatment. The patients with a positive sonographic finding at the end of treatment were followed up with monthly ultrasonography for 3 months.
The present study showed that abnormal biliary sonographic findings were demonstrated in 18 children (20.9%) treated with ceftriaxone, 13 (15.1%) had biliary lithiasis, 5 (5.8%) had biliary sludge and 1 (1.2%) had nephrolithiasis. Abnormal biliary sonographic findings were demonstrated in only four (5.9%) children treated with cefotaxime who had biliary sludge and only one (1.5%) had nephrolithiasis. It was observed that older age was at significantly higher risk of developing biliary sludge or stone formation. Receiver operating characteristic analysis was performed to determine the residual risk and analysis found that 4.5 years was the cut-off value for age.
The present study is unique in the literature for reporting for the first time gall bladder sludge and nephrolithiasis associated with cefotaxime use. Therefore, patients treated with cefotaxime should be monitored for serious complications like patients treated with ceftriaxone. Nevertheless, if third-generation cephalosporin is used, cefotaxime is recommended to be used rather than ceftriaxone.
This study was designed to determine the levels of prolactin, leptin, osteopontin, and follistatin in workers chronically and subacutely exposed to lead compounds. The examined population consisted of three groups. The first group was composed of 56 male workers who were chronically exposed to lead for 13.38 ± 10.38 years. The second group served as a control group and consisted of 24 male administrative workers, while the third group included 32 male workers exposed to lead for 40 ± 3 days. The levels of leptin, osteopontin, and prolactin were significantly lower in the group of workers chronically exposed to lead than in the control group by 42%, 26%, and 41%, respectively. The levels of follistatin did not differ between those groups. The levels of all measured hormones did not change after a short-term exposure to lead compared to baseline. Chronic lead exposure is associated with significantly decreased level of prolactin, leptin, and osteopontin. Lead-induced changes in the levels of these hormones may disturb many functions of the human body, including the immune response, metabolism, reproduction, and bone turnover.
Silibinin is a bioactive flavonolignan extracted from milk thistle, known as Silybum marianum. Silibinin exerts strong antiproliferative, proapoptotic, and anti-inflammatory effects. Many studies have shown that silibinin inhibits experimentally induced malignancies of the liver, prostate, skin, and colon as well as promotes inhibition of the proliferation of cancer cell lines in vitro. This study aimed to investigate the effects of silibinin on the human breast carcinoma cell lines MDA-MB-231 and MCF-7 in monolayer and spheroid cultures.
The MDA-MB-231 and MCF-7 cell lines were cultured in both monolayer and spheroid cultures. Cells were treated with silibinin at 24, 48, and 72 h of incubation. The 5-bromo-2'-deoxyuridine labeling index was used to determine the cells of the synthesis phase. Poly-ADP-ribose-polimerase immunohistochemical staining and the terminal deoxynucleotidyl transferase dUTP nick and labeling assay were used to determine the death of cells in both the monolayer and spheroid cultures.
An half maximal inhibitory concentration dose of silibinin in MDA-MB-231 and MCF-7 cells was 100 µM/mL at 24, 48, and 72 h of incubation. Terminal deoxynucleotidyl transferase dUTP nick and labeling positive cells and active poly-ADP-ribose-polimerase were detected after treatment with silibinin in both the monolayer and spheroid cultures. The dead cell count was higher in the MDA-MB-231 and MCF-7 cell lines with silibinin applied than in the controls.
Our study demonstrated that silibinin applications enhanced terminal deoxynucleotidyl transferase dUTP nick and labeling positive cells and active poly-ADP-ribose-polimerase in comparison to the control in both the monolayer and spheroid cultures.
Many microbial and plant-derived metabolites contribute to the production of inflammatory mediators and the expression of pro-inflammatory molecules. Ophiobolin A (OPA) is a fungal secondary metabolite produced by Bipolaris species. The aim of our study was to examine the acute effects of this compound on inflammatory processes.
Male Wistar rats were treated with 5% ethanol, 0.01 mg/kg OPA, 0.1 mg/kg OPA and 1.0 mg/kg OPA per os. After 24 h of the administrations, inflammatory mediators such as interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and myeloperoxidase (MPO) enzyme as well as heme oxygenase (HO) activity were measured in both plasma and cardiac tissue, along with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). We found that OPA caused a significant elevation in the concentrations of IL-6 and TNF-α, increased MPO activity and decreased HO enzyme activity in the plasma. While OPA induces inflammation in the plasma, it did not change the level of inflammatory mediators in the cardiac tissue and the concentrations of serum ALT and AST. Our findings indicate that rapid release of inflammatory mediators by OPA promotes systemic inflammation. However, this acute OPA treatment does not show toxic effects on the cardiac tissue and the concentrations of liver enzymes.
This study was conducted to assess the ability of the sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) II scoring systems, as well as the simplified acute physiology score (SAPS) II method to predict group mortality in intensive care unit (ICU) patients who were poisoned with paraquat. This will assist physicians with risk stratification.
The medical records of 244 paraquat-poisoned patients admitted to the ICU from January 2010 to April 2015 were examined retrospectively. The SOFA, APACHE II, and SAPS II scores were calculated based on initial laboratory data in the emergency department and during the first 24 h of ICU admission. The probability of death was calculated for each patient based on the SOFA score, APACHE II score, and SAPS II. The ability of the SOFA score, APACHE II score, and SAPS II method to predict group mortality was assessed using a receiver operating characteristic (ROC) curve and calibration analyses.
A total of 219 patients (mean age, 63 years) were enrolled. Sensitivities, specificities, and accuracies were 58.5%, 86.1%, and 64.0% for the SOFA, respectively; 75.1%, 86.1%, and 77.6% for the APACHE II scoring systems, respectively; and 76.1%, 79.1%, and 76.7% for the SAPS II, respectively. The areas under the curve in the ROC curve analysis for the SOFA score, APACHE II scoring system, and SAPS II were 0.716, 0.850, and 0.835, respectively.
The SOFA, APACHE II, and SAPS II had different capabilities to discriminate and estimate early in-hospital mortality of paraquat-poisoned patients. Our results show that although the SOFA and SAPS II are easier and more quickly calculated than APACHE II, the APACHE II is superior for predicting mortality. We recommend use of the APACHE II for outcome predictions and risk stratification in paraquat-poisoned patients in the ICU.
Disruption of blood–brain barrier (BBB) and subsequent oedema are major causes of the pathogenesis in ischaemic stroke with which the current clinical therapy remains unsatisfied. In this study, we examined the therapeutic effect of tetramethylpyrazine-2'-O-sodium ferulate (TSF)-a novel analogue of tetramethylpyrazine in alleviating BBB breakdown and brain oedema after cerebral ischaemia/reperfusion (I/R). Then, we explored the potential mechanism of the protection on BBB disruption in cerebral I/R rat models. Male Sprague-Dawley rats (250–300 g) were subjected to 120 min middle cerebral artery occlusion (MCAO), followed by 48 h reperfusion. TSF (10.8, 18 and 30 mg kg–1) and ozagrel (18 mg kg–1) were administrated by intravenous injection immediately for the first time and then received the same dose every 24 h for 2 days. We found that TSF treatment significantly attenuated the cerebral water content, infarction volume and improved neurological outcomes in MCAO rats compared to I/R models. Moreover, we investigated the effect of TSF on the BBB for that cerebral oedema is closely related to the permeability of the BBB. We found that the permeability of BBB was improved significantly in TSF groups compared to I/R model group by Evans blue leakage testing. Furthermore, the expressions of tight junction (TJ) proteins junction adhesion molecule-1 and occludin significantly decreased, but the protein expression of matrix metalloproteinase-9 (MMP-9) and aquaporin 4 (AQP4) increased after cerebral I/R, all of which were alleviated by TSF treatment. In conclusion, TSF significantly reduced BBB permeability and brain oedema, which were correlated with regulating the expression of TJ proteins, MMP-9 and AQP4. These findings provide a novel approach to the treatment of ischaemic stroke.
Fipronil, an insecticide of the phenylpyrazole class has been classified as a carcinogen by United States Environmental Protection Agency, yet very limited information is available about its genotoxic effects. Adult male and female animals were gavaged with various doses of fipronil (2.5, 12.5, and 25 mg/kg body weight (bw)) to evaluate micronucleus test (mice), chromosome aberration (CA), and comet assay (rats), respectively. Cyclophosphamide (40 mg/kg bw; intraperitoneal) was used as positive control. Another group of animals were pretreated with vitamin E orally (400 mg/kg bw) for 5 days prior to administration of fipronil (12.5 mg/kg). Fipronil exposure in both male and female mice caused significant increase in the frequency of micronuclei (MN) in polychromatic erythrocytes. Similarly, structural CAs in bone marrow cells and DNA damage in the lymphocytes was found to be significantly higher in the male and female rats exposed to fipronil as compared to their respective controls. The average degree of protection (male and female animals combined together) shown by pretreatment of vitamin E against fipronil-induced genotoxicity was 63.28%: CAs; 47.91%: MN formation; and 74.70%: DNA damage. Findings of this study demonstrate genotoxic nature of fipronil regardless of gender effect and documents protective role of vitamin E.
The decision of intubation and mechanical ventilation in poisoned patients with impaired consciousness can be a difficult task. The present study aimed to evaluate the power of Glasgow Coma Scale (GCS), acute physiology and chronic health evaluation (APACHE II), rapid acute physiology score (RAPS) and rapid emergency medicine score (REMS) at admission in predicting the need of intubation and mechanical ventilation in drug overdose patients with disturbed consciousness level (DCL). This prospective observational study was conducted on 104 poisoned patients who were admitted to Tanta Toxicological Unit with a DCL. Four scoring systems (GCS, APACHE II, RAPS and REMS) were recorded for all patients on admission. Discrimination was evaluated using receiver operating characteristics curve and calculating the area under the curve (AUC). Twenty-four cases required mechanical ventilation. The mechanically ventilated patients had significantly lower value of GCS and higher values of APACHE II, REMS and RAPS than other group (p < 0.001). Although the APACHE II score has the best AUC value (0.796) in predicting mechanical ventilation, there was no statistically significant difference between the four scores. GCS > 8 had 100% negative predictive value, while REMS > 8 had 100% positive predictive value.
Ethambutol (EMB) is conventionally used to treat tuberculosis and atypical Mycobacterium infections in combination with other antimycobacterial drugs. Eventually, EMB testicular toxicity has not been explored extensively yet. The aim of the study is to evaluate testicular toxicity of EMB. We explored the impact of EMB on male rats’ fertility, testosterone level and germ cells state, testicular pro- and anti-oxidant status and DNA damage, as well as identified EMB effects on cytochrome P-450 2E1 (CYP2E1) both with computer simulation and in vivo. We demonstrated that EMB administration to male rats decreased in epididymal sperm count (19%) and fertility index (53%). These events were accompanied by reduction in serum testosterone content (1.6 times) and appearance of spermatogenic epithelium damages. It was also found in testes the intensification of lipid peroxidation, decrease in reduced glutathione content and changes in DNA fragmentation. Additionally, computer simulation showed direct interaction of EMB with CYP2E1 active site and heme. On the top of this, we demonstrated that level of testicular CYP2E1 messenger RNA in EMB-treated rats was increased 8.7 folds and p-nitrophenol hydroxylase activity in testes rose three folds. As this shows, EMB-caused CYP2E1 induction, oxidative stress, and apoptosis in the testes contribute to inhibition of steroidogenesis enzymes and spermatogenesis disruption.
Dexmedetomidine is a highly selective α2-adrenoceptor agonist with sedation, anesthetic sparing, analgesia, sympatholytic, and neuroprotective properties. This study evaluated neuroprotective effects of dexmedetomidine on dopamine neurons correlated to histone acetylation via extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) pathway. Animals were randomly assigned to four groups and treatments were given as onetime doses: dimethyl sulfoxide (DMSO; n = 6), dexmedetomidine 1 mg/kg (n = 6), 10 mg/kg (n = 6), and 100 mg/kg (n = 6). Acetylation histone protein levels and ERK protein levels in rats dopamine neuron from striatum were determined by Western blotting after various doses of dexmedetomidine (1, 10, and 100 mg/kg) treatments. The messenger RNA expression related to signal transduction coupled to 5-hydroxytryptamine receptor (5-HTR) in striatum was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Dexmedetomidine administration increased expression of ERK1/2 phosphorylation and histones H3 acetylation. PD098059, an inhibitor of pERK1/2, almost completely blocked dexmedetomidine-induced histones H3 acetylation. In addition, bioinformatics analysis in combination with qRT-PCR demonstrated that dexmedetomidine could regulate the genes that are related to signal transduction coupled to 5-HTR via α2-adrenoceptor. Our results define dexmedetomidine as a modulator of histones H3 acetylation via ERK1/2 signaling pathway in dopamine neuron from striatum, which may provide clues for the mechanism underlying the neuroprotective effects of dexmedetomidine.
Abnormal activation of the Wnt/β-catenin signaling pathway increases survivin expression that is involved in hepatocarcinogenesis. Therefore, downregulation of survivin may provide an attractive strategy for treatment of hepatocellular carcinoma. In this regard, little is known about the anticancer effects of prodigiosin isolated from cell wall of Serratia marcescens on the survivin expression and induction of apoptosis in hepatocellular carcinoma cells.
Human hepatocellular carcinoma (HepG2) cells were treated with 100-, 200-, 400-, and 600-nM prodigiosin after which morphology of cells, cell number, growth inhibition, survivin expression, caspase-3 activation, and apoptotic rate were evaluated by inverted microscope, hemocytometer, MTT assay, RT-PCR, fluorometric immunosorbent enzyme assay, and flow cytometric analysis, respectively.
Prodigiosin changed morphology of cells to apoptotic forms and disrupted cell connections. This compound significantly increased growth inhibition rate and decreased metabolic activity of HepG2 cells in a dose- and time-dependent manner. After 24-, 48-, and 72-h treatments with prodigiosin at concentrations ranging from 100 nM to 600 nM, growth inhibition rates were measured to be 1.5–10%, 24–47.5%, and 55.5–72.5%, respectively, compared to untreated cells. At the same conditions, metabolic activities were measured to be 91–83%, 74–53%, and 47–31% for indicated concentrations of prodigiosin, respectively, compared to untreated cells. We also found that treatment of HepG2 cells for 48 h decreased significantly cell number and survivin expression and increased caspase-3 activation in a dose-dependent manner. Specifically, treatment with 600-nM prodigiosin resulted in 77% decrease in cell number, 88.5% decrease in survivin messenger RNA level, and 330% increase in caspase-3 activation level compared to untreated cells. An increase in the number of apoptotic cells (late apoptosis) ranging from 36.9% to 97.4% was observed with increasing prodigiosin concentrations.
From our data, prodigiosin is an attractive compound that turns the profile of high-level survivin expression in hepatocellular carcinoma cells into that of normal cells and may provide a novel approach to the hepatocellular carcinoma-targeted therapy.
As Notch receptors have been shown to induce chemoresistance, we hypothesized that delta-like ligand-4 (DLL4), a central Notch signalling ligand, might also participate in chemoresistance in breast cancer. To investigate this issue, overexpression of DLL4 was induced by transfection with expression vectors for DLL4 in the human breast cancer cell line Michigan cancer foundation-7 (MCF-7). It was found that DLL4 could be adaptively upregulated by docetaxel (DOC) treatment in a dose-dependent manner, but Notch1 was unaffected. Overexpression of DLL4 could significantly attenuate the cytotoxic effects of DOC by increasing Bcl-2 expression, while decreasing Bax expression, apoptosis rate and DNA damage. The protective effects of DLL4 made cells acquire chemoresistance against DOC and resulted in cancer cell survival. DLL4 is normally regarded as a regulator of vascular development. Our results expanded the understanding of DLL4. Since DLL4 may play an important role in the process of acquiring chemoresistance, it may be a promising target in overcoming chemoresistance in breast cancer.
Long noncoding RNAs (lncRNAs) are the new class of transcripts and pervasively transcribed in the genome, which have been found to play important functional roles in many tissues and organs. LncRNAs can interact with target gene to exert their functions. However, the function and mechanism of lncRNA in cleft palate (CP) development remain elusive. Here, we investigated the role of lncRNA H19 and its target gene insulin-like growth factor 2 (IGF2) in CP of mice. All-trans retinoic acid (atRA) is a well-known teratogenic effecter of CP. After establishment of the CP mouse model using atRA in vivo, we found that the rate of CP in mice was 100%. The tail lengths of fetuses in atRA-treated mice were shorter than those of control mice from embryonic day (E)12 to E17. The expression of lncRNA H19 and IGF2 were embryo age-related differences between atRNA-treated and control mice. In addition, the the relationship between lncRNA H19 and IGF2 were negative correlation in the critical period of developmental palate. These findings suggest that lncRNA H19 mediate atRA-induced CP in mice.
The fungicide carbendazim (CBZ) and insecticide chlorpyrifos (CPF) are currently applied together by farmers for the control of pests. Here, we investigated the impacts of 7 days oral co-exposure to 10 mg/kg body weight of CPF and 50 mg/kg body weight of CBZ on selected oxidative stress and antioxidant biomarkers in the liver, kidney, and spleen of female rats. The results showed that while the body weight gain and relative organ weights were not significantly affected after separate exposure to CPF and CBZ, there was a significant decrease in the body weight gain with concomitant increases in the relative kidney and spleen weights of rats treated with the mixture. Also, CPF and CBZ co-exposure significantly increased the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine (p < 0.05) when compared with the groups treated with CBZ or CPF alone and the control. The significant decreases in both antioxidant enzymes activities and nonenzymatic antioxidant level following individual administration of CPF and CBZ to rats were intensified in the co-exposure group (p < 0.05). Additionally, the marked increases in the levels of oxidative stress indices in liver, kidney, and spleen of rats treated with CPF or CBZ alone were intensified in the co-exposure group (p < 0.05). Histopathologically, co-exposure to CPF and CBZ exacerbates their individual effects on the liver, kidney, and spleen. These findings showed that co-exposure to CPF and CBZ in rats elicited more severe oxidative damage on the liver, kidney, and spleen of the rats, indicative of an additive effect compared to CPF or CBZ alone and as such, may pose a greater environmental risk to humans.
The present study aims to investigate the protective effect of quercetin against the joint toxic action induced by the mixture of four organophosphate pesticides (mixture-OPs) (dimethoate, acephate, dichlorvos, and phorate) at their corresponding no observed adverse effect level (NOAEL) using metabonomics. Rats were randomly divided into control, quercetin-treated, mixture-OPs-treated, and quercetin plus mixture-OPs-treated groups. Mixture-OPs and quercetin were given to the rats daily through drinking water and intragastric administration, respectively, for 90 days. The metabonomic profiles of rat urine were analyzed using ultra-performance liquid chromatography–mass spectrometry (UPLC/MS). The 14 metabolites significantly changed in the treatment groups compared with the control group, including the biomarkers of OPs exposure (dimethylphosphate, dimethyldithiophosphate, diethylphosphate) and the metabolites of quercetin (quercetin and isorhamnetina). The intensities of gentisic acid, creatinine, suberic acid, hippuric acid, uric acid, and citric acid significantly decreased, whereas the intensities of 7-methylguanine, estrone sulfate, and cholic acid significantly increased, in the mixture-OPs-treated group compared with the control group (p < 0.01). The variation tendency of the aforementioned metabolites was significantly ameliorated in the high-dose quercetin (50 mg/(kg bw day)) plus mixture-OPs-treated group compared with the mixture-OPs-treated group (p < 0.05). However, the intensities of these metabolites in the high-dose quercetin plus mixture-OPs-treated group were still significantly different from those of the control group (p < 0.05). Results indicated that high dose of quercetin elicits a partial protective effect on the toxicity induced by mixture-OPs, including fatty acid and energy metabolism, antioxidant defense system, DNA damage, and liver and kidney function.
The present study was designed to evaluate the effect of nanoselenium (Nano-Se) on hematological and biochemical parameters of rats experimentally intoxicated with lead (Pb). Thirty male rats were randomly divided into six groups as follows: the control, selenite, Nano-Se, Pb group, Pb + selenite, and Pb + Nano-Se groups. After 35 days, blood was collected from rats and hematology and serum biochemical parameters of oxidative stress were measured. The thiobarbituric acid reactive substances (TBARS) level of Pb group was significantly higher than other groups. Also, TBARS level was significantly lower in the Pb + Nano-Se group than Pb + selenite group. The serum superoxide dismutase activities were significantly lower in Pb group than the control, Pb + selenite, and Pb + Nano-Se groups. The catalase activities in the Pb group showed no significant change when compared to other groups. In the Pb group, packed cell volume was lower than the control group. A significant difference was observed between the control group and the Pb, Pb + selenite, and Pb + Nano-Se groups. In the Pb group, the numbers of white blood cell (WBC) decreased in comparison with the control group. Also, there was significant increase in WBC counts in the Pb + Nano-Se and Pb + selenite groups in comparison with Pb group. The number of lymphocytes in the Pb group decreased in comparison with the control group. By comparing the means of the Pb + Nano-Se and Pb + selenite groups together, it was determined that there were significant differences in the lymphocytes and neutrophil counts. In conclusion, usage of selenium compounds particularly Nano-Se particles inhibits the adverse effects of Pb on antioxidant activity and immune system function in the Pb poisoning.
Exposure to diesel exhaust particles (DEP) has long been associated with increased cardiovascular morbidity and mortality. The development of DEP toxicity seems to be linked to inflammation in which macrophages play a critical role. Macrophages can be polarized into proinflammatory M1 or anti-inflammatory M2 macrophages. The aim of this study was to identify the role of inflammation in DEP-induced toxicity by assessing the effects of DEP on macrophage polarization.
Monocyte-derived macrophages (M) were stimulated with interferon and lipopolysaccharide or interleukin (IL)-4 to obtain M1 and M2 subtypes, respectively. To test the polarization capacity of DEP, M cells were exposed to DEP and compared to M, M1, and M2. We also studied the effects of DEP on already-polarized M1 or M2. The M1 markers assessed were tumor necrosis factor α (TNF-α) and IL-1β, while the M2 markers were the mannose receptor C type 1 (MRC-1) and transglutaminase 2 (TGM2).
Western blots revealed a 31 kDa band corresponding to pro-IL-1β, but only in M1-polarized macrophages. In M1, we also observed an upregulation of TNF-α messenger RNA (mRNA) expression. MRC-1 and TGM2 mRNA expression were only significantly enhanced in M2. DEP had no effect on any of the M1/M2 markers assessed. Moreover, DEP were not able to modify the phenotype of already-polarized M1 or M2.
M incubation with DEP did not have any effect on macrophage polarization, at least on the markers assessed in this study, namely, TNF-α/IL-1β for M1, and MRC-1/TGM2 for M2. Hence, these data argue against an important role of inflammation in DEP-induced vascular toxicity.
Local anesthetic toxicity is thought to be mediated partly by inhibition of cardiac mitochondrial function. Intravenous (i.v.) lipid emulsion may overcome this energy depletion, but doses larger than currently recommended may be needed for rescue effect. In this randomized study with anesthetized pigs, we compared the effect of a large dose, 4 mL/kg, of i.v. 20% Intralipid® (n = 7) with Ringer’s acetate (n = 6) on cardiovascular recovery after a cardiotoxic dose of bupivacaine. We also examined mitochondrial respiratory function in myocardial cell homogenates analyzed promptly after needle biopsies from the animals. Bupivacaine plasma concentrations were quantified from plasma samples. Arterial blood pressure recovered faster and systemic vascular resistance rose more rapidly after Intralipid than Ringer’s acetate administration (p < 0.0001), but Intralipid did not increase cardiac index or left ventricular ejection fraction. The lipid-based mitochondrial respiration was stimulated by approximately 30% after Intralipid (p < 0.05) but unaffected by Ringer’s acetate. The mean (standard deviation) area under the concentration–time curve (AUC) of total bupivacaine was greater after Intralipid (105.2 (13.6) mg·min/L) than after Ringer’s acetate (88.1 (7.1) mg·min/L) (p = 0.019). After Intralipid, the AUC of the lipid-un-entrapped bupivacaine portion (97.0 (14.5) mg·min/L) was 8% lower than that of total bupivacaine (p < 0.0001). To conclude, 4 mL/kg of Intralipid expedited cardiovascular recovery from bupivacaine cardiotoxicity mainly by increasing systemic vascular resistance. The increased myocardial mitochondrial respiration and bupivacaine entrapment after Intralipid did not improve cardiac function.
Metal-on-metal (MoM) hip prostheses are known to release chromium and cobalt (Co), which negatively affect the health status, leading to prosthesis explant. Albumin (ALB) is the main serum protein-binding divalent transition metals. Its binding capacity can be affected by gene mutations or modification of the protein N-terminal region, giving the ischaemia-modified albumin (IMA). This study evaluated ALB, at gene and protein level, as marker of individual susceptibility to Co in MoM patients, to understand whether it could be responsible for the different management of this ion. Co was measured in whole blood, serum and urine of 40 MoM patients. A mutational screening of ALB was performed to detect links between mutations and metal binding. Finally, serum concentration of total ALB and IMA were measured. Serum total ALB concentration was in the normal range for all patients. None of the subjects presented mutations in the investigated gene. Whole blood, serum and urine Co did not correlate with serum total ALB or IMA, although IMA was above the normal limit in most subjects. The individual susceptibility is very important for patients’ health status. Despite the limited results of this study, we provide indications on possible future investigations on the toxicological response to Co.
It is known that lichens are utilized for the treatment of many diseases including ulcer, diabetes, and cancer for many years. Secondary metabolites in the structure of the lichens provide various activity properties for them. In the present study, cytotoxic and oxidative effects of main constituents of Pseudevernia furfuracea (L.) Zopf (Parmeliaceae), olivetoric acid (OA), and physodic acid (PA) were investigated on cultured human amnion fibroblasts (HAFs). OA and PA were isolated from P. furfuracea using column chromatography and their structures were determined by proton nuclear magnetic resonance and carbon-13 nuclear magnetic resonance. HAFs were incubated during 48 h in the presence of OA and PA, at different concentrations from 6.25 mg/L to 200 mg/L. OA showed higher cytotoxicity than PA. In fact, median inhibitory concentration values of OA and PA were 571.27 and 3373.69 mg/L, respectively. The lower concentrations (<50 mg/L) of OA and PA did not cause oxidative stress and genotoxicity; furthermore, they supported anti-oxidative capacity of HAFs. Therefore, all these data suggested that both tested metabolites, especially PA might be developed as natural health medicine to protect human body against oxidative stress and genotoxicity. As far as we know, this is the first report on the cytotoxic and anti-oxidative activities of OA and PA on HAFs.
Naringenin is a naturally occurring flavanones and has been found to exhibit free radical scavenging, enzyme inhibition, antioxidants, anti-inflammatory, and anticancer activities. Present study was designed to evaluate the protective role of naringenin against benzo[a]pyrene (B[a]P)-induced oxidative stress and pulmonary toxicity. Rats were treated with naringenin at a dose of 100 mg/kg body weight (b. wt.), by oral gavage. B[a]P in a single dose of 50 mg/kg b. wt. was given intraperitoneally. Total protein, total cell counts, lactate dehydrogenase, lipid peroxidation, reduced glutathione, antioxidant enzymes activities, lung histology and expression of nuclear factor kappa B (NF-B), and cyclo-oxygenase-2 (COX-2) was assessed to evaluate protective effects of naringenin. Histopathological and immunohistochemical studies were also carried out to observe lung toxicity and inflammation. B[a]P administration enhanced the levels of lung injury markers and reduced antioxidant enzymes activities. Naringenin treatment attenuated the levels of oxidative stress by restoring antioxidant enzymes, further improved lung histological damage and significant decrease in inflammatory responses. Naringenin also effectively decreased the expression of NF-B, and COX-2 induced by B[a]P. These findings suggest that naringenin supplementation is beneficial in maintaining the integrity of alveoli and the epithelium that may be used as a protective agent in B[a]P-induced oxidative stress and lung damage. However, further studies are warranted to elucidate the potential mechanism of action of naringenin.
This study compared different cytotoxicity test models for evaluating resin-based composites (RBCs) and assessed the biocompatibility of standard and bulk-fill RBCs.
A standard (spectrum TPH) and a bulk-fill (smart dentin replacement (SDR)) RBC were selected. Disc-shaped specimens (7 mm diameter) of 2 and 4 mm thickness were polymerized for 20 s with a LED curing light of 700 mW/cm2 irradiance. The specimens (n = 5) were subjected to micro-hardness testing and three cytotoxicity test models (direct contact, indirect contact and extract tests) with the established L-929 cell line. Hardness ratios of top and bottom surfaces of specimens were computed to assess the effectiveness of cure. For the direct and indirect contact tests, the cells were stained and zones of inhibition were analyzed after material contact for 24 h. For the extract test, cells were exposed to extracts for 24 h, and cell viability was measured. Data was analyzed using analysis of variance/Scheffe’s post hoc test and Pearson’s correlation (p < 0.05).
The lowest mean hardness ratio and highest cytotoxicity were observed for TPH at 4 mm. At 4-mm thickness, SDR was found to be biocompatible with all three models. Correlations between hardness ratio and cell viability ranged from r = 0.89–0.96 for the various tests. A significant correlation (r = 0.97) was also observed between the three test models.
Our data indicated consistency between direct contact, indirect contact and extract test models for cytotoxicity testing of RBCs. Bulk placement and curing at 4 mm for the bulk-fill RBC evaluated did not result in undue cytotoxicity.
The use of anabolic androgenic steroids (AAS) has grown among practitioners of recreational bodybuilding, with significant contributions of designer steroids, aiming muscle hypertrophy in healthy subjects. The abusive use of AAS in general is associated with adverse effects; one of the most worrisome is cancer development. The aim of this study was to evaluate the effectiveness of the cytokinesis block micronucleus (CBMN) test in human lymphocytes in identifying risk groups for cancer development in users of AAS. Blood was collected from 15 AAS users bodybuilders (G1), 20 non-users bodybuilders (G2) and 20 non-users sedentary (G3). MN analysis was performed on a minimum of 1000 binucleated lymphocytes. The occurrence of MN was significantly higher (p < 0.05) in individuals of G1 compared to G2 and G3. The results indicate the sensitivity of CBMN in human lymphocytes in the identification of chromosomal damage in consequence of AAS.
The primary hepatocytes were extracted and purified from mice through improved Seglen two-step perfusion method. Ethanol-induced injury hepatocytes model in mice was used to investigate the importance of glutathione S-transferase A1 (GSTA1) in hepatocytes injury by comparison with other indicators, such as alanine aminotransferase, aspartate aminotransferase, malondialdehyde, glutathione and superoxide dismutase. The release of GSTA1 was demonstrated to be an earlier and more sensitive indicator of hepatocytes injury than other indicators. Significant increases in GSTA1 were detected at 2 h after ethanol exposure, while other indicators were undetected at this time. A markedly difference in other indicators were observed at 6 and 8 h. The release of GSTA1 was significantly increased at a concentration of 50 mmol/L ethanol, the lowest exposure concentration than that in other indicators. In contrast, other indicators release was not statistically significant until concentrations of 75 mmol/L and 100 mmol/L ethanol. These results suggest that GSTA1 can be detected at the early stage of low concentration ethanol exposure and that GSTA1 is more sensitive and reliable marker in ethanol-induced hepatic injury.
The effects of short-term use of oral glucocorticoid (GC) on the skeleton are not well defined. To address this gap, the influences of 7 days, 21 days of GC administration on femurs of intact rats were investigated. Forty 4-month-old female Sprague–Dawley rats were randomly divided into control group (Cont) and prednisone-treated group (Pre) and administered either distilled water or prednisone acetate at doses of 3.5 mg/kg/day for 0, 7 and 21 days, respectively. All the femurs were harvested for dual-energy X-ray absorptiometry scan, biomechanical testing and micro computed tomography scan. The whole body weight, femur bone mineral density (BMD), all three-point bending test parameters, microstructural parameters increased or improved significantly in Cont at day 21 when compared to day 0. The whole body weight, distal femur BMD, Young’s modulus, bending stiffness, density of tissue volume and trabecular thickness (Tb.Th) decreased, while structure model index and trabecular separation (Tb.Sp) increased significantly in Pre at day 21 when compared to age-matched control but had no significant differences between day 7 and day 21. Our data demonstrate that 7-day use of prednisone does not influence on rats’ femur, and 21-day use of prednisone slows in rate of whole body weight gain, decreases femur metaphysis BMD and bone stiffness which mainly due to the deteriorated bone microstructure.
Perfluorooctanesulfonic acid (PFOS), a ubiquitous contaminant, has been used in various industrial applications. Currently few studies have documented the effects of chronic PFOS exposure on lipid metabolism, especially in aquatic organisms. The present study defined the effects of chronic exposure to low level of PFOS on lipid metabolism in F0 adult zebrafish and F1 offspring. Our findings revealed a severe fatty degeneration in the liver of F0 males treated with 0.5 μM PFOS and significant ultrastructure changes associated with substance transport or metabolism in liver and intestines (abnormal mitochondria and endoplasmic reticulum, disordered arrangement of inner microvilli within intracellular canaliculus). To address the potential trans-generational effects of PFOS exposure, the early gene expression related to lipid metabolism was measured by real-time quantitative polymerase chain reaction in F1 derived from chronically exposed parental fish. The results indicated that lepa (leptin α), kiss1 (kisspeptins), xdh (xanthine dehydrogenases), and insr (insulin receptor) were significantly upregulated in F1 while dgat1b (diacylglycerol O-acyltransferase), hb9 (motor neuron/pancreas homeobox), and Apoa1 (apolipoprotein A-I) were downregulated. These findings provided evidence that PFOS chronic exposure adversely impacts lipid metabolism in both F0 and F1 and demonstrated the validity of using zebrafish as an alternative model for PFOS chronic toxicity screening.
In the present study, coumarin and some coumarin derivatives (esculetin, scoparone, and 4-methylumbelliferone) were investigated for their lipid-lowering effect in rats. Male Sprague–Dawley rats (150–200 g) were divided into six groups and each group comprised of five rats. Hepatic injury-dependent hyperlipidemia was induced by carbon tetrachloride (CCl4, 1.25 ml/kg). Coumarin and coumarin derivatives esculetin (35 mg/kg), scoparone (35 mg/kg), 4-methylumbelliferone (35 mg/kg), or coumarin (30 mg/kg) were administered to experimental groups at 12-h intervals. Animals received the derivatives esculetin, scoparone or 4-methylumbelliferone prior to the administration of a single toxic dose of CCl4. Serum total cholesterol (TC), triglyceride (TG), very low-density lipoprotein cholesterol (VLDL-C), and low-density lipoprotein cholesterol (LDL-C) levels significantly increased in CCl4-treated group (p < 0.05, p < 0.01, p < 0.01, and p < 0.05, respectively), while levels of serum high-density lipoprotein cholesterol (HDL-C) decreased (p < 0.01). 4-Methylumbelliferone had no recovery effects on serum TC levels, however, significantly prevented CCl4-induced hyperlipidemia by reducing TG and VLDL-C levels (p < 0.05 and p < 0.05, respectively). In addition, coumarin had no recovery effect on any of the serum lipid parameters against CCl4-induced hyperlipidemia. Among the coumarin derivatives only esculetin and scoparone significantly prevented serum HDL-C in CCl4-induced dyslipidemia. The results from this study indicate that the chemical structure of coumarins plays an important role on the regulation of serum lipid profiles.
Sulfamonomethoxine (SMM) is widely used in the veterinary field in China. Although some clinical surveys have revealed that sulfonamide antibiotics cause adverse nervous system symptoms, the related mechanisms of maternal SMM exposure on the neurobehavioral development of offspring remain unclear. Here, we investigated the effects of perinatal SMM exposure on the physiological and behavioral responses of pubertal offspring mice and the underlying mechanisms. We randomly allocated pregnant mice into the groups treated with SMM at different doses and the saline-treated groups. Maternal mice were orally administered SMM daily from gestational day 1 to postpartum day 21. On postnatal day (PND) 22, the parameters of growth, endocrine hormones, and brain amino acid composition were assessed, as well as the brain transcript levels of key genes involved in the mammalian target of rapamycin (mTOR) signaling pathway. From PND 50 to 55, a battery of behavioral tests relevant to anxiety and memory were then administered. Analysis of the results indicated that the pups, particularly the pubertal female offspring, showed anxiety-like behavior. Moreover, the pubertal offspring showed cognitive impairments and fat accumulation. Furthermore, the relative mRNA expression of genes involved in the mTOR signaling pathway in females on PND 22 was elevated, whereas the expression of N-methyl-
Modulation of myometrial spontaneity by cadmium (Cd) and its regulatory pathways was studied in rat uterus in the absence and presence of blockers of different signaling pathways. Isometric tension in myometrial strips, under a resting tension of 1 g, mounted in organ bath containing Ringer–Locke solution (RLS) continuously aerated with carbogen, was measured using data acquisition system-based physiograph and Lab Chart Pro V7.3.7 software. Mean integral tension was measured for 8 min. Cd (1 nM–0.1 mM) not only produced concentration-dependent inhibitory effect on rat myometrium but it (10 µM) also significantly (p < 0.05) inhibited calcium chloride and BAY K-8644-induced myometrial contraction. Glybenclamide (10 µM), 4-aminopyridine (1 mM), and propranolol (10 µM) failed to significantly attenuate Cd-induced inhibitory responses, while L-NAME (0.1 mM), 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 25 µM), and 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22536; 1 µM) significantly (p < 0.05) produced inhibitory effects on Cd-induced myometrial relaxation. Phenylephrine (1 nM–10 µM) and salbutamol (0.01 nM–0.1 µM)-induced relaxant effects on rat myometrium were significantly potentiated by 10 µM Cd. Thus based on the results of present functional study, it may be inferred that inhibitory effects of Cd on rat myometrium are mediated through blockade of L-type calcium channels and activation of NOS-NO-sGC and/or AC-cAMP pathways.
Pesticide exposure may affect semen quality and male fertility in humans. The aim of the present work was to elucidate the adverse effects of deltamethrin (Delta), a synthetic pyrethroid, on exposed male mice and their offspring. Adult male Albino/Swiss mice received deltamethrin (5 mg/kg) daily for 35 days and mated with untreated females to produce offspring. Classical measurements of ejaculate and sperm quality and testicular histopathological changes were assessed. Deltamethrin treatment affects sperm quality and quantity in the ejaculated semen of mice that had also markedly impaired libido as measured by indices of mating and fertility and number of pregnant females housed with male mice exposed to this pesticide. Exposure mice to deltamethrin significantly decreased their testosterone and inhibin B levels and affected reproductive performance. Testes of exposed mice showed marked histopathological alterations as compared to the control group. The mice exposed to 5 mg/kg body weight/day of deltamethrin showed severe alterations of the seminiferous tubules, sloughing of the germ cells, the vacuolization of germ cell cytoplasm, and the disruption of spermatogenic cells compared to the control group. Altered pregnancy outcomes were directly attributed to damage of sperm of male mice exposed to deltamethrin compared to the control group. We concluded that exposure to deltamethrin affected the reproductive system of male mice explored by altered total sperm density, motility, and morphology in mice spermatozoa.
The limited effectiveness of the conventional methods for cancer treatment makes the researchers to find novel safe and effective therapeutic strategies. One of these strategies is to use small interfering RNAs (siRNAs). A major challenge here is the siRNA delivery into the cells. The purpose of this study was to design and prepare a biocompatible, biodegradable, and safe nanosized particle for siRNA delivery into human breast cancer MCF-7 and leukemia K562 cells. Chemically synthesized magnetic nanoparticles containing polyethyleneglycol-lactate polymer (PEG-LAC), chitosan, and polyethyleneimine (PEI) were successfully prepared and used as a gene delivery vehicle. The nanoparticles were characterized by Fourier transform infrared spectroscopy and zeta potential. The Fe3O4-PEG-LAC-chitosan-PEI nanoparticle showed efficient and stable survivin siRNA loading in gel retardation assay. The cytotoxicity of the prepared nanoparticle was studied using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay and was compared with that of mitoxantrone (MTX) in combination with the prepared siRNA delivery system to evaluate the possible synergic effect of MTX and survivin siRNA. The nanoparticles with and without noncomplementary siRNA showed low toxicity against both cell lines; however, a twofold decrease was observed in cell survival percent after MTX addition to MCF-7 cells treated with either nanoparticle itself or complexed with noncomplementary siRNA. While survivin siRNA nanoplex caused threefold decrease in the cell survival percent, its combination with MTX did not result in a significant increase in the cytotoxic effect. Therefore, Fe3O4-PEG-LAC-chitosan-PEI nanoparticle should be considered as a potential carrier for enhanced survivin siRNA delivery into MCF-7 and K562 cells.
Carbon monoxide (CO) poisoning is a leading cause of toxicity-related mortality and morbidity worldwide. Recent studies focused on CO-induced cardiovascular toxicity. Oxidative stress plays an important role in the pathophysiology of CO toxicity. The aim of this study was to elucidate the relationship between cardiac damage biomarkers and oxidative stress biomarkers in patients with CO-induced cardiotoxicity. This study was carried out on 36 CO-poisoned patients admitted to Zagazig University Hospitals. Forty healthy individuals (age- and sex-matched) were selected as a control group. Clinical examination and electrocardiography (ECG) were performed for CO-poisoned patients. These patients have been investigated for carboxyhaemoglobin percent (COHB%) and cardiac damage biomarkers; cardiac troponin I (cTn-I), heart-type fatty acid-binding protein 3 (H-FABP3). Oxidative stress biomarkers comprising malondialdehyde (MDA), asymmetric dimethylarginine (ADMA), and total antioxidant capacity (TAC) have been also assessed. All biomarkers have been assessed on admission (0 h) and 6 h after treatment of CO-poisoned patients with high-flow oxygen and compared with those of the control groups. ECG findings were abnormal in 31 patients (86.11%), where sinus tachycardia was the commonest finding (58.33%). There was a statistically significant increase of COHB%, MDA, ADMA, and H-FABP3 levels, and a significant decrease of TAC level in CO-poisoned patients compared to controls with no significant changes in cTn-I. Six hours following treatment, all measured parameters were significantly improved except for cTn-I, which was significantly increased when compared with admission status (0 h). Furthermore, H-FABP3 showed a significant positive correlation with COHB%, MDA, ADMA, and a negative correlation with TAC, while cTn-I was significantly correlated with COHB% only. ADMA and MDA seem to be the strongest determinants for the prediction of H-FABP3 changes and hence cardiovascular toxicity. Thus, cardiac damage in patients with CO poisoning could be partially mediated by CO-induced oxidative stress, where H-FABP3 level was directly and strongly associated with MDA and ADMA levels.
The objective of this study was to determine if the association between exposure to ambient air pollutants such as sulfur dioxide, nitrogen dioxde (NO2), nitrous oxide (NO), and PM10, and variation in lung function measures was modified by genotype. A validated questionnaire was administered to 71 African children to evaluate prevalence of respiratory symptoms. Atopy was evaluated by skin-prick testing and bihourly measures of lung function (spirometry) were collected. Gaseous air pollutant concentrations were monitored continuously. CD14 polymorphism was genotyped and plasma CD14 levels were measured. There was no statistically significant association between the CD14 (159) CT+TT polymorphism with any asthma-related phenotype. There was a significant association between lung function (forced expiratory volume in 1 second intraday variability) and NO2 and NO among participants carrying the CD14 CT/TT genotype for lags 1, 2, and the 5-day average. Similarly, statistically significant gene–pollutant interactions (p < 0.05) were found with NO and CD14 CT/TT at lag 2 and for the 5-day average. While there was no association with any respiratory phenotype (as determined by symptoms), the CD14 CT/TT genotype appeared to be protective to increased exposure to NO2 and NO.
Acute intentional benzodiazepine poisoning is marked by a significant loss of consciousness, aspiration pneumonia, and increased rates of mortality and morbidity, especially in older patients with underlying heart or lung disease. These patients may need flumazenil to reverse the respiratory effects of benzodiazepines. The positive effects of aminophylline on respiration and neonatal apnea improvement have been shown previously. However, its possible effects on increasing the level of consciousness have never been evaluated.
In a placebo-controlled study, we assessed the effectiveness of aminophylline on increasing the level of consciousness.
Time to full awakening was significantly shorter in those who received aminophylline (72 min vs. 881 min, p = 0.001), compared to those who received a placebo.
When "flumazenil" is contraindicated or unavailable, intravenous aminophylline can be used as a second choice.
The aim of the study was to examine whether antioxidant properties of 3,4,4',5-tetramethoxystilbene (DMU-212) contribute to its anticarcinogenic activity and whether DMU-212 affects the expression of apoptosis-related genes. Two-stage model of hepatocarcinogenesis was used; male Wistar rats were challenged with N-nitrosodiethylamine (NDEA), 200 mg/kg body weight (b.w.), intraperitoneal, then phenobarbital (PB) in drinking water (0.05%) was administered. Simultaneously, DMU-212 was given per os at a dose 20 or 50 mg/kg b.w. two times a week for 16 weeks. DMU-212 caused a moderate decrease in hepatic thiobarbituric acid reactive substances and protein carbonyls concentration elevated in rats treated with NDEA/PB. The activity of antioxidant enzymes examined reduced by NDEA/PB treatment was not restored in rats coadministered with DMU-212. Effects of DMU-212 on messenger RNA (mRNA) expression of antioxidant enzymes in rats challenged with NDEA/PB were diversified; no changes in their protein expression were noted in any of the groups. The expression of 17,000 genes was analyzed by Affymetrix® Rat Gene 1.1 ST Array; 15 apoptosis-related genes were selected and validated by RT-q PCR. The combined treatment with NDEA/PB and DMU-212 increased the mRNA level of some genes driving mitochondria-mediated apoptosis, whereas the mRNA expression of some anti-apoptotic genes triggering receptor-mediated apoptosis was reduced. The expression of genes encoding caspases-4, -8, -9, and -12 was also increased in rats treated with DMU-212. Although antioxidant effect of DMU-212 in rats challenged with NDEA/PB was moderate, its potential anticarcinogenic properties were demonstrated as evidenced by modulation of apoptosis-related genes.
This study examined the effects of acute tobacco smoking on cerebral oxygenation and autonomic function in 28 male, habitual smokers of shorter young smokers (YSM) or longer middle-aged smokers (MSM) smoking history. Following baseline testing, participants undertook a smoking protocol involving the consumption of two cigarettes within 15 min. Measures of cerebral oxygenation and autonomic function were collected before, during, and 0 min, 30 min, 1 h, and 4 h post-smoking. Tissue saturation index (TSI) for MSM was greater than YSM during cigarette consumption (p < 0.05). Moreover, MSM observed significant within-group changes for TSI during and post-cigarette consumption (p < 0.05). Further, MSM observed an increase in low frequency (LF) band from 30 min to 1 h post-consumption, followed by a decline, whereas elevations above MSM were observed in YSM at 4 h (p < 0.05). Both MSM and YSM showed a decrease in high-frequency (HF) band post-cigarette, while increased LF/HF ratio post-consumption was observed in YSM. A decline in the standard deviation of RR intervals, post-cigarette consumption was evident in MSM (p < 0.05). Moreover, the root mean square of RR interval in both groups similarly decreased following cigarette consumption (p < 0.05). Acute smoking affects heart rate variability, suggestive of vagal withdrawal, and maybe indicate an effect of smoking history. Additionally, prolonged smoking history alters cerebral microcirculatory responses to acute tobacco exposure in MSM.
This study was designed to investigate the alteration of redox status by commonly used antimalarials in Nigeria. Drugs used were artemisinin, artesunate, chloroquine, coartem and quinine at the final concentrations of 0.5–8.0 mg/mL. Blood samples were collected from malarial patients and apparently healthy humans for comparison. Reduced glutathione, catalase, superoxide dismutase (SOD) activities, protein content and lipid peroxidation were determined. All drugs significantly (p < 0.05) increases the protein level relative to control in normal blood, whereas in the infected, a significant (p < 0.05) reduction was observed. In normal blood, the antimalarials dose dependently decreased (p < 0.05) SOD and catalase activities with significant (p < 0.05) increase in the infected. The level of glutathione in normal blood significantly (p < 0.05) increases as compared with control, whereas in the infected, similar observation was made except that the levels were less, relative to control sample. Malondialdehyde level significantly (p < 0.05) increases with increase in drugs concentration even though less than the level in the control with few exceptions. These effects were dose dependent and more pronounced in non-malarial conditions. Commonly used antimalarials might alter the redox status in both healthy and non-healthy subjects thereby inducing oxidative stress.
Sensorineural hearing loss, ataxia, pyramidal signs, and vestibular deficits characterize superficial siderosis of the central nervous system. This study investigated changes in vestibular function, free radical formation, and phosphorylated cJun expression in the vestibular end organs after middle ear treatment with a ferric chloride (FeCl3) solution. A single injection of 70% FeCl3 solution into the unilateral middle ear cavity caused static vestibular symptoms, such as spontaneous nystagmus and head tilt. Asymmetric expression of c-Fos protein was observed in the bilateral vestibular nuclei and prepositus hypoglossal nuclei within 6 h after injection. Histopathologic examinations revealed partial hair cell loss, degeneration of the supporting stroma, and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells in the neuroepithelial layer of the crista ampullaris in FeCl3-treated animals. 5-(And-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester and diaminofluorescein–2 diacetate fluorescence and immunoreactivity for nitrotyrosine increased markedly in the sensory neuroepithelial layer and nerve bundles of the crista ampullaris after 2 h. Strong immunoreactivity for phospho-cJun and cJun was observed in the type I hair cells of the crista ampullaris 120 h after injection. Thus, a single short-term treatment with a high concentration of FeCl3 in the unilateral middle ear cavity can induce activation of intracellular signals for cJun protein and oxidative stress through the formation of reactive oxygen species and nitric oxide in vestibular sensory receptors, resulting in vestibular dysfunction. These results suggest that activation of intracellular signals for cJun protein and oxidative stress may be a key component of the pathogenesis of vestibular deficits in patients with superficial siderosis.
Clinical application of gentamicin may cause nephrotoxicity and ototoxicity. Our study is the first study to investigate the protective effects of edaravone against the gentamicin-induced ototoxicity. We investigated the protective effect of intraperitoneal (i.p.) edaravone application against gentamicin-induced ototoxicity in guinea pigs.
Fourteen guinea pigs were divided into two equal groups consisting of a control group and a study group. One-hundred sixty milligrams per kilogram subcutaneous gentamicin and 0.3 mL i.p. saline were applied simultaneously once daily to seven guinea pigs in the control group (group 1). One-hundred sixty milligrams per kilogram gentamicin was applied subcutaneously and 3 mg/kg edaravone was applied intraperitoneally once daily for 7 days simultaneously to seven guinea pigs in the study group (group 2). Following the drug application, auditory brainstem response measurements were performed for the left ear on the 3rd and 7th days.
Hearing threshold values of the group 1 and group 2 measured in the 3rd day of the study were detected as 57.14 ± 4.88 and 82.86 ± 7.56, respectively. This difference was statistically significant (p < 0.05). Hearing threshold values of the group 1 and group 2 measured in the 7th day of the study were detected as 87.14 ± 4.88 and 62.86 ± 4.88, respectively. This difference was statistically significant (p < 0.05).
A statistically significant difference between the average threshold values of edaravone-administered group 2 and that of group 1 without edaravone was found. These differences show that systemic edaravone administration could diminish ototoxic effects of gentamicin and the severity of the hearing loss.
Triptolide (TPL) is a main active compound isolated from Tripterygium wilfordii Hook f. Despite its positive therapeutic effect, the female reproductive toxicity of TPL is still the bottleneck of clinical application. The study was designed to investigate the adverse effects on mice ovary and underlying mechanism of TPL. Adult female NIH mice were treated with two therapeutic doses of TPL (25 and 50 μg/kg/d) for 50 days, respectively. Mice estrous cycle was detected by vaginal cytology method. Half mice from each group were selected randomly to perform superovulation. Quality and quantity of ovulated eggs were evaluated. Other mice from each group were executed for morphological study. Ovarian histological sections were stained by H&E staining for ovarian pathologic detection and follicular counts. Apoptotic granulosa cell (GC) was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Endoplasmic reticulum (ER) stress-related proteins and antiapoptotic X-linked inhibitor of apoptosis protein (XIAP) were detected by immunohistochemical method. Two doses of TPL resulted in estrous cycle disorder and follicles in development reservoir impairment. Quality and quantity of mice ovulated eggs significantly decreased after TPL treatment. Ovarian pathologic examination revealed TPL-induced TUNEL-positive GCs increase and ER stress–related proteins (78-kDa glucose-regulated protein, p-protein kinase-like endoplasmic reticulum kinase, p-eukaryotic initiation factor 2α, and CCAAT/enhancer binding protein homologous protein) expression upregulation. Meanwhile, the expression of antiapoptosis protein XIAP in mice ovary was obviously inhibited by TPL. Our results may demonstrate that therapeutic doses of TPL can injure ovary function, but there is no difference between high-dose and low-dose groups. GCs apoptosis by ER stress pathway and antiapoptotic function impairment may partly mediate TPL-induced ovary toxicity.
Methamphetamine abuse is one of the most medical and social problems many countries face. In spite of the ban on the use of methamphetamine, it is widely available in Iran’s drug black market. There are many analytical methods for the detection of methamphetamine in biological specimen. Oral fluid has become a popular specimen to test for the presence of methamphetamine. The purpose of the present study was to develop a method for the extraction and detection of methamphetamine in oral fluid samples using liquid–liquid extraction (LLE) and gas chromatography/mass spectrometry (GC/MS) methods. An analytical study was designed in that blank and 50 authentic oral fluid samples were collected to be first extracted by LLE and subsequently analysed by GC/MS. The method was fully validated and showed an excellent intra- and inter-assay precision (reflex sympathetic dystrophy 10%) for external quality control samples. Recovery with LLE methods was 96%. Limit of detection and limit of quantitation were 5 and 15 ng/mL, respectively. The method showed high selectivity, no additional peak due to interfering substances in samples was observed. The introduced method was sensitive, accurate and precise enough for the extraction of methamphetamine from oral fluid samples in forensic toxicology laboratories.
Impaired diastolic flow is characterized by decreased left ventricular (LV) filling diastole, abnormal LV distensibility, or delayed relaxation. B-Type natriuretic peptide (BNP) is an indicator of various cardiovascular diseases and body volume status. The aim of this study was to determine whether the lowering of dialysate sodium (Na) levels is effective on LV systolic and diastolic parameters and BNP in the maintenance of hemodialysis patients.
The study included 49 chronic hemodialysis patients. Left atrium (LA) diameter and LV ejection fraction, LV systolic and diastolic diameter, deceleration time (DT), pulmonary artery pressure (PAP), inferior vena cava diameter (IVCD), early diastolic transmitral flow (E) and late diastolic transmitral flow (A) velocities, E/A ratio, isovolumic relaxation time, peak early diastolic velocity (E'), late diastolic velocity (A') of tissue Doppler mitral annulus, and flow propagation velocity of mitral inflow (V p) were measured before and 6 months after hemodialysis with low Na dialysate.
Six months after low Na hemodialysis, a decrease was observed in echocardiographic parameters such as PAP and IVCD (p < 0.05, p < 0.001, and p < 0.001, respectively). However, a significant difference was not observed in LA diameter. In LV diastolic measurement of E and A waves, E/A ratio, DT, V p, septal E' and A', and lateral E' and A' exhibited significant improvement by low Na HD. BNP level was significantly reduced (p < 0.001).
Lowered dialysate Na concentration improves PAP, IVCD, and LV diastolic properties assessed by mitral inflow filling, tissue Doppler velocity, and mitral inflow velocity propagation.
Tobacco smoking is a serious threat to life and health of society. Among the most vulnerable to the toxic effects of tobacco smoke are foetuses and newborns. The objective of the research was to assess the impact of tobacco smoke exposure on oxytocin levels and biochemical oxidative stress parameters during pregnancy and after birth in an experimental model.
In the experiment, exposure to tobacco smoke of gravid and non-gravid rats was monitored. A reliable biomarker of exposure – cotinine – was used in the process and it was determined by means of high-performance liquid chromatography with diode array detection, which ensured high analytical accuracy and precision. Determination of oxytocin was performed by means of enzyme-linked immunosorbent assay. The levels of selected oxidative stress parameters: total protein concentration, uric acid, trolox equivalent antioxidant capacity, protein S-nitrosylation and lipid peroxidation (thiobarbituric acid reactive substances) were measured by spectrophotometric methods.
The effect of prenatal and postnatal exposure to tobacco smoke was a lower medium body mass of rat foetuses and pups. Oxidative stress during pregnancy, additionally intensified by tobacco smoke exposure, led to adaptive changes in properties of plasmatic antioxidant barriers. Moreover, the disturbance of oxidoreductive balance by tobacco smoke affects oxytocin fluctuations, what was observed in this study during lactation period. Therefore, women who smoke may breastfeed their children less frequently and for a shorter period.
Hepatic fibrosis is a leading cause of morbidity and mortality worldwide. Attenuation of fibrogenic process can significantly lower the mortality rate. However, pharmaceutical intervention at fibrogenesis stage remains a major task in medicine. So there is a need for a natural compound to treat hepatic fibrosis. This study was outlined to investigate the anti-fibrotic effect of β-amyrin in dimethylnitrosamine (DMN)-induced hepatic fibrosis male rats. Serum liver function markers (aspartate transaminase, alanine transaminase, alkaline phosphatase and lactate dehydrogenase), oxidative stress markers (malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, glutathione reduced content and vitamin C), tissue inflammatory marker (tumor necrosis factor α (TNF-α)), apoptosis marker (caspase 3) and fibrolytic marker (tissue inhibitor of metalloproteinase 1 (TIMP-1)) were evaluated before and after β-amyrin treatment in DMN-induced rat. β-Amyrin treatment attenuated the altered levels of the serum enzyme markers produced by DMN and caused a subsequent recovery toward normalization. Oxidative stress markers and TNF-α levels were reduced significantly (p < 0.001) as well as proteins’ (caspase-3 and TIMP-1) expression was reduced in β-amyrin–treated DMN rats. By virtue of β-amyrin properties of inhibiting oxidative stress, apoptosis, inflammation, and fibrogenesis, it might act as an ideal anti-inflammatory and anti-fibrogenic agent to halt the progression of liver fibrosis to chronicity.
Chronic use of nucleoside reverse transcriptase inhibitors (NRTIs) in managing human immunodeficiency virus (HIV) infection has been associated with several complications. Available management options for these complications have yielded controversial results, thus the need to urgently find newer alternatives. Naringin, a plant-derived flavonoid, has been shown to possess antioxidant and antiapoptotic properties which can be exploited in managing NRTI-induced complications. This study therefore investigated the effects of naringin on some NRTI-induced complications. Forty-nine rats (200–250 g) were divided into seven groups and were orally treated with stavudine (d4T)-only, d4T + naringin, d4T + vitamin E, zidovudine (AZT)-only, AZT + naringin, AZT + vitamin E, and distilled water, respectively. Drugs were administered once daily for 56 days, and oral glucose tolerance tests conducted on day 54 of the experiments and rats were thereafter sacrificed on day 56 by halothane overdose. Plasma samples and the left gastrocnemius muscles were stored at –80°C for further analysis. There was significant glucose intolerance, insulin resistance, oxidative stress, and apoptosis in the skeletal muscles of AZT- or d4T-only–treated rats. Naringin, however, significantly reduced fasting blood glucose and fasting plasma insulin concentrations, mitigated glucose intolerance, and insulin resistance in addition to reducing malondialdehyde and carbonyl protein concentrations when coadministered with either NRTIs. Furthermore, naringin improved antioxidant enzyme activities, reduced skeletal muscle BCL-2-associated X protein expression, and improved B-cell lymphoma-2 protein expression compared to AZT- or d4T-only–treated rats. Naringin ameliorated AZT- and d4T-induced complications and therefore should be further investigated as a possible nutritional supplement in managing HIV infection.
This experimental study was conducted to elucidate the possible protective/therapeutic effects of quercetin against methotrexate (Mtx)-induced kidney toxicity with biochemical and histopathological studies.
Twenty-four adult male rats were randomly divided into four groups, as follows: control group (saline intraperitoneally (i.p.), 9 days), Mtx group (20 mg/kg i.p., single dose), Mtx + quercetin group (50 mg/kg quercetin was orally administered 2 days before and 6 days after Mtx administration) and only quercetin group (50 mg/kg oral, 9 days). Structural changes were evaluated by hematoxylin–eosin and periodic acid–Schiff stainings. Apoptotic changes were investigated by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and caspase-3 antibody. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured in tissue and plasma samples.
Mtx compared with the control group, there was significant increase in nephrotoxic tissue damage findings, in addition to apoptotic index (APOI) and caspase-3 expression (p < 0.05). Mtx + quercetin group revealed significantly lower histopathological damage and APOI and caspase-3 expression decreased when compared to Mtx group. MDA levels were increased in Mtx group compared to others, and by the use of quercetin, this increase was significantly reduced. SOD levels were higher in Mtx group than others. This increase was evaluated as a relative increase arising from oxidative damage caused by Mtx.
As a result, Mtx administration may involve oxidative stress by causing structural and functional damage in kidney tissue in rats. Quercetin reduced the Mtx-induced oxidative stress through its antioxidant properties and so quercetin may be promising to alleviate Mtx-induced renal toxicity.
This study was designed to evaluate the hepato and neuroprotective activity of Daflon and low-dose radiation on thioacetamide (TAA)-induced liver damage and hepatic encephalopathy (HE) in rats. Effect of daily Daflon treatment (100 mg/kg body weight, Per OS (p.o.) for consecutive 3 days) and/or fractionated low-dose -radiation (LDR; 0.25 Gy, twice the total dose of 0.5 Gy at the 1st and 3rd day, respectively) was evaluated against TAA (300 mg/kg, intraperitoneal x 3) induced liver damage and HE in rats. Serum aspartate transaminase, alanine transaminase, -glutamyltransferase, total bilirubin, ammonia, and manganese were estimated to evaluate liver function. In addition, malondialdehyde (MDA) as well as reduced glutathione (GSH), glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) were determined to assess antioxidant capacity in liver tissue. Moreover, hepatic apoptotic markers (cysteine-dependent aspartate-directed proteases 3, 8 (caspase-3, 8) and cytochrome C) were estimated to indicate hepatic apoptosis. HE was evaluated through the determination of whole brain ammonia, manganese, MDA, GSH, GPX, SOD, CAT, and caspase-3. The cognitive and locomotor deficits were assessed via step through passive avoidance test, activity cage (actophotometer), -aminobutyric acid, and N-methyl-
The effect of 21 days of repeated oral administration of levofloxacin and enrofloxacin both alone and in combination with meloxicam, on the oxidative balance in blood was evaluated in rabbits. Rabbits were randomly allocated to six groups of four animals each. Control group was gavaged 5% dextrose and 2% benzyl alcohol. Three groups were exclusively gavaged meloxicam (0.2 mg/kg body weight o.d.), levofloxacin hemihydrate (10 mg/kg body weight b.i.d 12 h), and enrofloxacin (20 mg/kg body weight o.d.), respectively. Two other groups were co-gavaged meloxicam with levofloxacin hemihydrate and enrofloxacin, respectively. A reduction (p < 0.05) of reduced glutathione levels was observed in groups treated with meloxicam both alone and in combination with levofloxacin, whereas an increase (p < 0.01) in the levels of this antioxidant was observed in the groups treated with enrofloxacin. The activities of enzymes, glutathione peroxidase and superoxide dismutase, were induced (p < 0.05) in levofloxacin-alone treated group. Superoxide dismutase was also induced (p < 0.05) in meloxicam-alone treated group and inhibited (p < 0.05) in enrofloxacin-meloxicam co-treated group. The activity of catalase was non-significantly different between various groups. Enrofloxacin-treated groups had higher (p < 0.01) lipid peroxidation than control and levofloxacin-alone treated groups. Elevated lipid peroxidation was also observed in the groups treated with meloxicam both alone and in combination with levofloxacin (p < 0.05). In conclusion, these drugs have potential to induce oxidative imbalance, however, compared to levofloxacin, more oxidative damage is produced by enrofloxacin and meloxicam.
In vivo antidotal efficacy of new bis- quaternary 2-(hydroxyimino)-N-(pyridin-3yl) acetamide derivatives (HNK series), to counter multiples of lethal doses of nerve agent sarin (GB) and reactivation of acetylcholinesterase (AChE), was evaluated in Swiss albino mice. [Protection index PI; median lethal dose (LD50) of sarin with treatment/LD50 of sarin] was estimated, using 0.05, 0.10, and 0.20 LD50 as treatment doses of all the oximes with atropine against sarin poisoning. Dose-dependent time course study was conducted at 0.2, 0.4 and 0.8 LD50 dose of sarin for estimating maximum AChE inhibition. At optimized time (15 min), in vivo enzyme half inhibition concentration (IC50) was calculated. AChE reactivation efficacy of HNK series and pralidoxime (2-PAM) were determined by plotting shift of log IC50 doses. HNK-102 with atropine showed three fold higher PI compared to 2-PAM. In vivo IC50 of sarin for brain and serum AChE was found to be 0.87 LD50 (139.2 µg/kg) and 0.48 LD50 (77.23 µg/kg), respectively. Treatment with HNK-102 and HNK-111 (equal to their 0.20LD50) significantly reactivated sarin-intoxicated AChE (p < 0.05) at 2x IC50 dose of sarin, compared to 2-PAM. The study revealed that HNK-102 oxime was three times more potent as antidote, for acute sarin poisoning compared to 2-PAM in vivo.
Ketamine is a dissociative anesthetic agent with sympathomimetic effects used commonly for procedural sedation in emergency department. The present study aimed to reveal the effect of ketamine on myocardium by measuring ejection fraction (EF).
Patients less than 9 years old undergoing procedural sedation with ketamine secondary to minor trauma composed the study population by convenience sampling. Study patients received ketamine at a dose of 1.5 mg/kg. A cardiologist performed the measurements of cardiac contractility pre-ketamine and 10 min after the ketamine administration.
A total of 22 patients were enrolled into the study. Patient recruitment has been ceased after the 22nd patient because of the thought that more patients would not provide additional information. The study subjects had a mean age of 3.5 ± 2.2 years and 14 (64%) of them were male. EF reduced in 14 (63.6%) patients (mean: 5.6 ± 3.1; median: 5; interquartile range (IQR): 3.75–7; minimum–maximum (min–max): 1–14). Systolic blood pressures reduced in 10 of 14 patients with decreased EF and increased in 8 of 10 patients without decreased EF. The changes in systolic blood pressure in patients with decreased EF (n = 14) were as follows: –7.6 ± 10.9; median: –7.5; IQR: –16.5 to 1.75; and min–max: –30 to 9. There were two patients with elevated high-sensitive troponin.
Ketamine may reduce EF and systolic blood pressure in children less than 9 years old undergoing procedural sedation.
Pentavalent antimonial (Sb5+) drugs such as meglumine antimoniate (MA) are the mainstay treatment of leishmaniases in developing countries. The effects of these compounds on drug-metabolizing enzymes have not been characterized and their potential pharmacokinetic interactions with other drugs are therefore unknown. The present study investigated whether treatment with MA (300 mg Sb5+/kg body weight/day, subcutaneously) for 24 days affected the activities of cytochrome P450 (CYP)1A (ethoxyresorufin-O-deethylase), CYP2A5 (coumarin 7-hydroxylase), CYP2E1 (p-nitrophenol-hydroxylase), CYP2B9/10 (benzyloxy-resorufin-O-debenzylase), or CYP3A11 (erythromycin-N-demethylase) in the livers of Swiss Webster (SW) and DBA-2 male and female mice. The results showed that CYP2A5-, CYP2E1-, and CYP3A11-catalyzed reactions were unaffected by MA treatment. A decrease in CYP2B9/10 activity was noted in DBA-2 females (but not males) and was not observed in SW males or females. However, repeated MA administration reduced mouse liver CYP1A activity. CYP1A2 messenger RNA (mRNA) levels were not affected by MA and in vitro exposure of mouse liver microsomes to Sb3+ and Sb5+ did not reduce CYP1A activity. These findings suggested that in vivo treatment with Sb5+ drugs depressed CYP1A activity, without downregulating CYP1A2 mRNA expression. Since in vitro treatment of liver microsomes failed to inhibit CYP1A activity, this effect may require intact cells.
Adverse complications associated with antineoplastic drug-based cancer therapy are the major clinical drawbacks. Oxidative stress and inflammation play a major role in the damage due to cancer therapy. In the current study, we investigated the modulatory effect of vitamin C (Vit. C) on liver toxicity induced by 5-fluorouracil (5-FU) in rats. Animals were divided into four groups. Animals in group I received vehicle. Oral gavage of Vit. C (500 mg kg–1 body weight (b.wt.)) was given to the animals in group III and group IV. 5-FU (150 mg kg–1 b.wt.) was injected intraperitoneally to the animals in group II and group III. Findings of the present study revealed that oral administration of Vit. C significantly ameliorated the level of lipid peroxidation and the activity of myeloperoxidase. Vit. C administration markedly reduced the activation of nuclear factor B and expression of cyclooxygenase 2, whereas nuclear translocation of nuclear factor erythroid 2–related factor 2 was increased. Hepatic histopathological analyses further supported the protective effect of Vit. C. Findings of the current study demonstrate that the toxic free radicals and inflammatory mediators generated due to chemotherapy play a critical role in 5-FU–induced hepatic damage. Attenuating action of Vit. C may be due to the modulation of redox-sensitive transcription factors and associated target molecules.
A liberal amount of acrylamide (AA) is produced as a result of frying or baking foods in high temperatures, and individuals take certain amounts of AA everyday by consuming these food items. Pregnant women are also exposed to AA originating from food during pregnancy and their fetus are probably affected. The rats were divided into five different groups: control (C), corn oil (CO), vitamin E (Vit E), AA, and Vit E + AA, with eight pregnant rats in each group. On the 20th day of pregnancy, fetuses were removed and brain tissues of fetuses were examined for biochemical and histological changes. AA caused degeneration in neuron structures in fetal brain tissue and caused hemorrhagic damages; dramatically decreased brain-derived neurotrophic factor levels; increased malondialdehyde, total oxidant capacity levels; and decreased reduced glutathione and total antioxidant capacity levels (p < 0.05). On the other hand, it was determined that the Vit E, a neuroprotectant and a powerful antioxidant, suppressed the effects of AA on fetal development and fetal brain tissue damage for the above-mentioned parameters (p < 0.05). It is recommended to consume food containing Vit E as a protection to minimize the toxic effects of food-oriented AA on fetus development due to the widespread nature of fast-food culture in today’s life and the impossibility of protection from AA toxicity.
Ochratoxin A (OTA) induced DNA damage, cytotoxicity, and apoptosis in mammalian cell lines. Micro RNAs (miRNAs) are involved in physiological and developmental processes and contribute to cancer development and progression. In our study, high-throughput miRNA profiling and Kyoto Encyclopedia of Genes and Genomes analysis were applied to comparatively study the toxicity of OTA in HEK293 cells and HepG2 cells treated with 25 μM OTA for 24 h. In these two cells, the same changing miRNAs were mostly related to signal transduction pathways, whereas the different changing miRNAs were mostly related to human cancer pathways. DGCR8, Dicer1, and Drosha were significantly suppressed in HEK293 cells, indicating an impairment of miRNA biogenesis. The damage seemed more extensive in HEK293 cells. Cell models and in vivo models were also compared. Many miRNAs in vitro were markedly different from those in vivo; however, OTA toxicity was observed both in vitro and in vivo. The classification of deregulated pathways is similar. The biogenesis of miRNA was impaired in both lines. In conclusion, deregulated miRNAs in vitro are mostly related to human cancer and signal transduction pathways. The deregulated pathways in vivo are similar to those in vitro.
Paraquat (PQ) exposure could cause pulmonary fibrosis. The aim of this study was to investigate the protective effect of pyrrolidine dithiocarbamate (PDTC) in an acute PQ poison model. One hundred and forty-four Sprague Dawley rats were equally divided into three experimental groups: control group, PQ group, and PQ + PDTC group. At days 1, 3, 7, 14, 28, and 56 of treatment, the serum levels of transforming growth factor β1 (TGF-β1), the levels of hydroxyproline, the protein expression of nuclear factor B (NF-B) pathway, and histopathological change in lung tissue were assessed. The survival rate of rats treated with PQ + PDTC was increased compared with that of rats treated only with PQ (p < 0.05), and the occurrence of pathological changes was dramatically attenuated in the PQ + PDTC group. The serum levels of TGF-β1 and the hydroxyproline levels in the PQ group were significantly increased in a time-dependent manner compared with those in the control and PQ + PDTC groups on days 7, 14, 28, and 56 (p < 0.05). Additionally, the protein levels of NF-B proteins p65, inhibitor of B (IB) kinase (IKKβ, and IB-α were significantly downregulated in the PQ + PDTC group as determined by array analysis. The present findings suggest that overexpression of TGF-β1 may play an important role in PQ-induced lung injury and that PDTC, a strong NF-B inhibitor, can rescue PQ-induced pulmonary fibrosis by influencing the protein expression of NF-B pathway.
Poisoning is considered a significant health problem among elderly people in Poland. This report refers to patients treated for poisonings at the Toxicology Unit, Lodz, Poland, during the period 2008–2012. The data to be analyzed were obtained from medical records of elderly people. A group of 1167 patients aged 60+ was selected. The number of intentional poisonings in the group of patients was 417, which accounted for 35.7% of all poisonings among the elderly people. Patients attempting intentional poisonings included 301 (72.2%) women and 116 (27.8%) men. The most common cause of intentional poisonings were drugs—96.6% (n = 403). Benzodiazepines (46.9%) dominated among the intentional poisoning by drugs. During the analyzed 5 years, 80.3% (n = 335) were suicidal poisonings and 19.7% (n = 82) were demonstrative poisonings. Cardiovascular disease, which was diagnosed among 53.5% of the patients, was the most common physical illness. In conclusion, drugs are the most frequent type of the toxic agent responsible for poisoning cases among the elderly people. In this situation, the role of family doctors is very important: they should prescribe medicines in amounts not greater than absolutely necessary and maybe more often recommend psychiatric care for the elderly patients.
Bixin is a natural red pigment extracted from annatto. Although it is widely used as a coloring agent in food, there are few studies about the effect of this carotenoid on DNA. This study aimed to investigate the effects of bixin on cytotoxicity and genotoxicity induced by doxorubicin in HL60 cells. At concentrations above 0.3 μg/mL, bixin demonstrated cytotoxic effects in HL60 cells. Furthermore, this carotenoid was neither mutagenic nor genotoxic to HL60 cells and reduced the DNA damage induced by doxorubicin. Bixin and doxorubicin showed no apoptotic effect in HL60 cells, but the simultaneous combined treatments showed an increase in the percentage of apoptotic cells. In conclusion, our results showed that bixin modulates the cytotoxicity of doxorubicin via induction of apoptosis. The results of this study provide more knowledge about the toxic effects of anticancer treatments and how the natural compounds can be useful on these therapeutic approaches.
The research evaluating adipokines are very few in patients with acne vulgaris. The hypothesis that hyperinsulinemic and high glycemic index diet plays a role in the pathogenesis of acne is still controversial. In this study, we aimed to evaluate adipokines such as leptin (L), adiponectin (A), ghrelin and A levels, and A/L rates that indicate insulin resistance in nonobese patients with severe acne vulgaris.
Thirty patients who are nonobese with moderate acne vulgaris, aged 18 to 25 years, and 15 age–sex compatible controls were included in our study. The acne lesions were assessed using the Global Acne Grading Scale (GAGS). All participants were evaluated for the parameters that may affect the metabolism of serum L, A, and ghrelin levels in blood, and their body mass index were calculated. The significance level was determined as p ≤ 0.05.
Of the 30 patients, 17 were women and 13 were men. The mean age was 20.60 years and the mean duration of the disease were 2.8 years. All of patients had moderate acne vulgaris (GAGS 19–30). Of the 15 controls, 11 were women and 4 were men. The mean age was 21.20 years. There were not a statistically significant difference in L, ghrelin, A levels, and A/L ratio between the two groups.
Adipokines may have a role in the pathogenesis of acne vulgaris. L, A, ghrelin, and insulin resistance may not participate in the responsible mechanisms in nonobese patients with moderate acne vulgaris.
The purpose of this study was to characterize the zinc oxide nanoparticles (ZnO-NPs) and their bulk counterpart in suspensions and to access the impact of their acute oral toxicity at doses of 300 and 2000 mg/kg in healthy female Wistar rats. The hematological, biochemical, and urine parameters were accessed at 24 and 48 h and 14 days posttreatment. The histopathological evaluations of tissues were also performed. The distribution of zinc content in liver, kidney, spleen, plasma, and excretory materials (feces and urine) at 24 and 48 h and 14 days posttreatment were accessed after a single exposure at dose of 2000 mg/kg body weight. The elevated level of alanine amino transferase, alkaline phosphatase, lactate dehydrogenase, and creatinine were observed in ZnO-NPs at a dose of 2000 mg/kg at all time points. There was a decrease in iron levels in all the treated groups at 24 h posttreatment as compared to control groups but returned to their normal level at 14 days posttreatment. The hematological parameters red blood cells, hemoglobin, hematocrit, platelets, and haptoglobin were reduced at 48 h posttreatment at a dose of 2000 mg/kg ZnO-NPs and showed hemolytic condition. All the treated groups were comparable to control group at the end of 14 days posttreatment. The zinc concentration in the kidney, liver, plasma, feces, and urine showed a significant increase in both groups as compared to control. This study explained that ZnO-NPs produced more toxicological effect as compared to their bulk particles as evidenced through alteration in some hemato-biochemical parameters and with few histopathological lesions in liver and kidney tissues.
Tetrabromobisphenol A (TBBPA) is used to protect a wide range of electrical and electronic equipment, consumer electronics and office and communication equipment from catching fire. TBBPA reacts covalently with other monomers becoming an integral part of the cross-linked molecular structure. This study was conducted to evaluate the subchronic toxicity of TBBPA administered by gavage daily for 13 weeks at 0, 100, 300, and 1000 mg/kg/day in male and female CD® rats. A 6-week post-treatment control and 1000 mg/kg/day recovery groups were included. TBBPA exerted no marked effect on the rate of mortality, clinical signs, body or organ weights, feed consumption, histopathology, urinalysis, ophthalmology, and neurological outcomes in a functional observation battery, motor activity, serum thyroid stimulating hormone, serum triiodothyronine, or other serum chemistries. Although differences were observed for bilirubin and alkaline phosphatase, the observed alterations were within the normal range and thus were neither biologically or toxicologically meaningful. The single thyroid-related parameter affected by TBBPA was a reduction in serum thyroxine levels, but the decrease was not of sufficient magnitude to induce other more sensitive indicators of thyroid perturbation. The No Observed Adverse Effect Level was at least 1000 mg/kg/day, the highest dose tested. Based on an upper bound aggregate exposure for adults estimated by the European Union, the margin of exposure is approximately 5000, suggesting that, for the endpoints examined in this study, exposure to TBBPA presents a reasonable certainty of no harm.
T-2 toxin, a naturally produced Type A trichothecene mycotoxin, has been shown to damage the reproductive and developmental functions in livestocks. However, whether T-2 toxin can disturb the pubertal onset and development following prepubertal exposure remains unclear. To clarify this point, infantile female Sprague–Dawley rats were given a daily intragastric administration of vehicle or T-2 toxin at a dose of 375 μg/kg body weight for 5 consecutive days from postnatal day (PND) 15–19 (PND15–PND19). The days of vaginal opening, first diestrus, and first estrus in regular estrous cycle were advanced following T-2 toxin treatment, indicating prepubertal exposure to T-2 toxin induced the advancement of puberty onset. The relative weights of uterus and ovaries and the incidence of corpora lutea were all increased in T-2 toxin-treated rats; serum hormone levels of luteinizing hormone and estradiol and the messenger RNA expressions of gonadotropin-releasing hormone (GnRH) and GnRH receptor also displayed marked increases following exposure to T-2 toxin, all of which were well consistent with the manifestations of the advanced puberty onset. In conclusion, the present study reveals that prepubertal exposure to a high level of T-2 toxin promotes puberty onset in infantile female rats by advancing the initiation of hypothalamic–pituitary–gonadal axis function in female rats.
The present study was undertaken to evaluate the effect of diallylsulphide (DAS) against mercuric chloride (HgCl2)-induced oxidative stress in rat livers. Rats were randomly divided into four groups of six rats each and exposed to HgCl2 (50 mg/kg/body weight (b.w.)) intraperitoneally and/or DAS (200 mg/kg/b.w.) by gavage. HgCl2 administration enhanced alanine aminotransferase (AST) and aspartate aminotransferase (ALT) levels (p < 0.05) with reduction in the levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). However, treatment with DAS markedly attenuated HgCl2-induced biochemical alterations in liver and serum transaminases (AST and ALT; p < 0.05). Further, biochemical results were confirmed by histopathological changes as compared to HgCl2-intoxicated rats. Histopathology of liver also showed that administration of DAS significantly reduced the damage generated by HgCl2. The present study suggests that DAS shows antioxidant activity and plays a protective role against mercury-induced oxidative damage in the rat livers.
Hepatorenal toxicities are an important side effect of anthracycline antibiotics. The objective of this study was to determine whether sesamin (Ses) protects against acute doxorubicin (DOX)-induced hepatorenal toxicities. Rats received daily treatment with either 0.5% carboxymethylcellulose (10 mL/kg) or Ses (10, 20 and 40 mg/kg) orally for 10 days, followed by an intravenous injection at day 8 of either saline (10 mL/kg) or DOX (20 mg/kg). Hepatorenal toxicity was assessed by measuring the levels of serum creatinine (Cre), blood urea nitrogen (BUN), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP). The protein expression of 4-hydroxynonenal (4-HNE) in hepatorenal tissues was evaluated using immunohistochemistry. The malondialdehyde (MDA) content and antioxidant activity in the kidney and liver tissues were also measured. The results suggest that pretreatment with Ses ameliorated DOX-induced liver and kidney injury by lowering the serum ALT, AST, ALP, Cre and BUN levels (p < 0.05 or p < 0.01), and the histological damage to the liver and kidney tissues induced by DOX compared to control were also significantly attenuated by Ses. Furthermore, Ses significantly decreased the DOX-induced increase of MDA and 4-HNE and increased the activity of CAT, SOD and GPX compared to the DOX-treated rats (p < 0.05 or p < 0.01), whereas the change of DOX + Ses (10 mg/kg) group is not significant compared to the DOX-treated group (p > 0.05). These findings indicate that Ses elicits a typical protective effect against DOX-induced acute hepatorenal toxicity via the suppression of oxidative stress.
The use of doxorubicin (DOX) as an antitumor therapeutic agent is limited due to its cardiotoxic effects. Metformin (Met) and sitagliptin (Sitg) are suggested to improve cardiac function. The present study aimed to determine the potential protective effects of Met and Sitg on DOX-induced cardiotoxicity. Rats were divided into six groups: groups I, II, and III received normal saline, Met, and Sitg, respectively. Groups IV, V, and VI received DOX only, Met + DOX, and Sitg + DOX, respectively. Heart tissue was used for biochemical assays which measured cardiac reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS), and tumor necrosis factor α (TNF-α). Serum creatinine kinase (CK) and lactate dehydrogenase (LDH) were also measured. The heart apex was prepared for histological (hematoxylin and eosin) and immunohistochemical examination. Intoxication of DOX was associated with a significant elevation in serum CK-MB and LDH, reduction in cardiac GSH, and increased TBARS and TNF-α compared to the controls. Administration of Met or Sitg to DOX-intoxicated rats suppressed serum CK-MB and LDH. Moreover, cardiac GSH was elevated with decreased TBARS and TNF-α. These results were confirmed by histological study. Met and Sitg caused inhibition of caspase 3 and upregulation of B-cell lymphoma 2 (Bcl-2) expression in DOX-intoxicated animals. Sitg was found to exert a significantly better protective effect compared to that of Met. It was concluded that Sitg might be more effective than Met in reducing myocardial injury in DOX-induced cardiotoxicity in rats.
Industrial apple pomace, a biowaste generated during apple processing, is rich in cell wall polysaccharides and phenolics. These biologically active compounds are reported to be highly beneficial from the nutritional and health point of view. In the present study, the total phenolic content in the apple pomace aqueous extract (APE) was estimated and evaluated for its possible antioxidant and hepatoprotective efficacy in carbon tetrachloride (CCl4)-induced liver injury mice model. The aqueous extract exhibited 2,2-diphenyl-2-picrylhydrazyl free radical scavenging activity in vitro. Under in vivo study, mice were treated with APE (200 mg and 400 mg/kg body weight) for 2 weeks prior to the administration of CCl4 (30% v/v). The serum liver injury markers alanine transaminase, aspartate transaminase, and alkaline phosphatase were significantly lowered by APE in a dose-dependent manner. The levels of antioxidant parameters superoxide dismutase (SOD), reduced glutathione (redGSH), and lipid peroxidation were also improved by APE in liver homogenate. Histopathological studies revealed that APE treatment significantly lowered the CCl4-induced necrotic changes in the liver. Furthermore, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling assay showed that CCl4-induced apoptosis in the liver was significantly inhibited by APE in a dose-dependent manner. Immunohistochemistry results showed higher expression of nuclear erythroid 2-related factor 2 (Nrf2) in the liver of the APE-treated mice, a key regulator of antioxidative response. In conclusion, the results of the present study revealed the hepatoprotective efficacy of APE by inhibiting CCl4-induced apoptosis, which is due to its antioxidant activity and the ability to induce Nrf2 protein expression.
In the current study, we evaluated the endocrine disruption effect and oxidative stress implication of therapeutic dose of artemether–lumefantrine combination therapy on the ovary and uterus of rats. In this respect, female rats were divided into four groups: animals were per orally treated with tween 80 (control), artemether (4 mg kg–1 body weight), lumefantrine (24 mg kg–1 body weight) and artemether–lumefantrine (artemether, 4 mg kg–1 body weight and lumefantrine, 24 mg kg–1 body weight). We found that therapeutic doses of the drugs did not change the levels of ovarian hydrogen peroxide (H2O2) and malondialdehyde (MDA), but increased uterine levels of H2O2 and MDA and reduced ovarian and uterine levels of reduced glutathione. In addition, whilst ovarian glutathione peroxidase (GPx) activity reduced in the lumefantrine monotherapy group, uterine GPx increased in the artemether monotherapy as well as the artemether–lumefantrine groups. Furthermore, the drugs reduced ovarian and uterine glutathione-S-transferase and uterine superoxide dismutase activities. The drugs reduced oestrogen level, whereas follicle-stimulating hormone was reduced by lumefantrine and artemether–lumefantrine therapies. Additionally, artemether and lumefantrine monotherapies significantly increased prolactin and progesterone levels compared with the control (p < 0.05). The results suggest that in the absence of malarial parasite infection, the drugs induced oxidative stress in the ovary and uterus and disrupt hormonal balance in the rats.
Acetaminophen (APAP) overdose could induce liver damage and lead to acute liver failure. The treatment of APAP overdoses could be improved by new therapeutic strategies. Thymus spp., which has many beneficial effects and has been used in folk medicine, is one such potential strategy. In the present study, the hepatoprotective activity of the main constituents of Thymus spp., carvacrol and thymol, were evaluated in light of APAP-induced hepatotoxicity. We hoped to understand the hepatoprotective mechanism of these agents on the antioxidant system and pro-inflammatory cytokines in vitro. Dose-dependent effects of thymol and carvacrol (25, 50, and 100 µM) were tested on cultured HepG2 cells. N-Acetylcysteine (NAC) was tested as positive control. We showed that APAP inhibited HepG2 cell growth by inducing inflammation and oxidative stress. Incubating APAP-exposed HepG2 cells with carvacrol and thymol for 24 h ameliorated this inflammation and oxidative stress. We also evaluated alanine transaminase and lactate dehydrogenase levels of HepG2 cells. We found that thymol and carvacrol protected against APAP-induced toxicity in HepG2 cells by increasing antioxidant activity and reducing pro-inflammatory cytokines, such as tumor necrosis factor α and interleukin 1β. Taking together high-dose thymol and carvacrol treatment has an effect close to NAC treatment in APAP toxicity, but thymol has better treatment effect than carvacrol.
Intestinal mucositis is a serious toxic side effect of 5-fluorouracil (5-FU) treatment. Bu-Zhong-Yi-Qi decoction (BZYQD), a water extract of Chinese traditional herbal medicine, is widely used in chemotherapy in Asia as an alternative treatment to reduce the side effects of chemotherapy. However, the mechanism is unknown. To evaluate its mechanism, we investigated the effect of BZYQD on 5-FU-induced intestinal mucositis in mice, especially with regard to apoptosis in the intestinal mucosal epithelia. In the present study, mice were divided into three groups: control, 5-FU, and 5-FU + BZYQD. Mice in the 5-FU and 5-FU + BZYQD groups were administered 5-FU (100 mg/kg/day, intraperitoneally) for 6 days, and the mice in the latter group were given BZYQD (8 g/kg/day, intragastrically) beginning 4 days before 5-FU and continuing until the termination of the experiment. Loss in body weight and diarrhea during the 5-FU treatment were significantly attenuated by administration of BZYQD. The morphological signs of intestinal damage, including shortened villi height, crypt destruction, apoptosis, and necrosis, in intestinal mucosal epithelia were also reversed, accompanied by reduced neutrophil infiltration, nitrite levels, and inflammatory factors (tumor necrosis factor α and interleukin 1β) and increased levels of reduced glutathione. These results suggest that BZYQD inhibits 5-FU-induced intestinal mucositis, and this effect may be due to the reduction in apoptosis and necrosis in intestinal mucosal epithelia via the suppression of inflammatory cytokine upregulation. In conclusion, inhibiting cytokine-mediated apoptosis or necrosis can be the molecular mechanism by which BZYQD reduces the gastrointestinal side effects of cancer chemotherapy.
Contrast-induced nephropathy (CIN) is an iatrogenic medical event in stable cardiology patients that may lead to acute renal failure. There is no current successful therapy to manage CIN. Increasing evidence in experimental models and humans has suggested that this disease is associated with renal tubular and vascular injury triggered by oxidative stress. Considering the importance of reactive oxygen species (ROS) generation in the pathogenesis of CIN, the goal of the present study was to evaluate the effects of sildenafil on CIN development. Male Wistar rats were divided into control, CIN, and CIN pretreated with sildenafil (50 mg/kg/day). CIN was induced by water deprivation, N G-nitro-L-arginine methyl ester + indomethacin injections (10 mg/kg, intraperitoneally) and intravenous iohexol administration (3 g/kg). Renal function was evaluated through glomerular filtration rate (GFR), renal blood flow (RBF), plasma creatinine, uremia, and proteinuria. Oxidative stress was assessed by flow cytometry for intracellular ROS. Treatment with sildenafil attenuated the marked reduction of GFR and RBF in the CIN group. Moreover, sildenafil treatment in CIN rats reduced plasma creatinine, uremia, and proteinuria. Flow cytometry demonstrated that sildenafil attenuated the ROS production in the CIN group. These data suggest that sildenafil may be a new therapeutic agent to prevent CIN through its ability to preserve renal function and attenuate oxidative stress.
Nicotinamide riboside (NR) is a naturally occurring form of vitamin B3 present in trace amounts in some foods. Like niacin, it has been shown to be a precursor in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). The safety of Niagen™, a synthetic form of NR, was determined using a bacterial reverse mutagenesis assay (Ames), an in vitro chromosome aberration assay, an in vivo micronucleus assay, and acute, 14-day and 90-day rat toxicology studies. NR was not genotoxic. There was no mortality at an oral dose of 5000 mg/kg. Based on the results of a 14-day study, a 90-day study was performed comparing NR at 300, 1000, and 3000 mg/kg/day to an equimolar dose of nicotinamide at 1260 mg/kg/day as a positive control. Results from the study show that NR had a similar toxicity profile to nicotinamide at the highest dose tested. Target organs of toxicity were liver, kidney, ovaries, and testes. The lowest observed adverse effect level for NR was 1000 mg/kg/day, and the no observed adverse effect level was 300 mg/kg/day.
An oligodeoxynucleotide with CCT repeats (CCT ODN) has been found in our previous study to selectively downregulate Toll-like receptor 7/9 (TLR7/9)-mediated immune responses both in vitro and in vivo. In this study, we unexpectedly found that CCT ODN induced severe patchy hair loss around the mouth in male F1 mice (female Balb/c x male C57BL/6) with lupus-like nephritis induced by injecting allogenic lymphocytes and also in male Balb/c mice, but not in female F1 mice and Balb/c mice and either gender of C57BL/6 mice. Increased infiltration of natural killer group 2, member D (NKG2D+) cells in hair loss skin and upregulated interferon-gamma (IFN-) messenger RNA expression in cultured splenocytes were observed in male Balb/c mice. The CCT ODN-conditioned supernatants of cultured mouse splenocytes caused catagen-like changes to hair follicles (HFs). We hypothesized that the CCT ODN could induce patchy hair loss in the male mice with certain genetic traits by mobilizing NKG2D+ cells to HFs and by inducing the production of IFN- from immune cells. Taken together these data indicated that a gender and genetic preference of immune-regulatory oligonucleotides is causing unexpected clinical situations such as hair loss.
Tri-ortho–cresyl phosphate (TOCP) has been widely used as plasticizers, plastic softeners, and flame retardants in industry and reported to have delayed neurotoxicity and reproductive toxicology in animals. However, it remains to be elusive whether TOCP induces liver injury. In this study, male mice were orally administered different concentrations of TOCP (100, 200, or 400 mg/kg/day) for 28 days. Histological examination showed that TOCP led to serious hepatocellular injury. In addition, administration of TOCP induced a marked elevation in the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice. The content of malondialdehyde (MDA) was increased significantly in the liver after the mice were treated with TOCP; while there was a dramatic decrease in the content of glutathione (GSH) and the activities of antioxidative enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX). TOCP inhibited viability of mouse liver cancer Hepa 1-6 cells in a dose-dependent manner. Meanwhile, TOCP significantly increased MDA content and inhibited GSH content and the activities of SOD and GSH-PX in the cells, respectively. Oxidative stress dramatically inhibited viability of Hepa 1-6 cells; while inhibition of oxidative stress by N-acetyl-
To develop a mouse cell biosensor system for the high-throughput genotoxicity detection of chemicals, such as environmental pollutants.
We developed a novel reporter vector pGL4-GFP, wherein the firefly luciferase reporter gene in the pGL4.82 vector was replaced by the green fluorescent protein (GFP) gene from the pAcGFP1-N1 vector. To construct the reporter pGL4-p53-GFP (p53 promoter linked to GFP), a fragment containing the p53 gene promoter was generated by amplifying a region from –481 to +180 of mouse genomic DNA isolated from mouse tail tissue. We developed a mouse cell biosensor system for the high-throughput genotoxicity detection of new drugs by stably integrating the reporter plasmid of pGL4-p53-GFP into the mouse embryonic fibroblast cells. Various genotoxic agents were used to treat this biosensor system. The resulting fluorescence was directly observed under a fluorescence microscope, and the GFP protein level was measured through Western blot analysis.
The biosensor system was treated with genotoxic agents, such as doxorubicin, cyclophosphamide, and benzo(a)pyrene. The GFP protein expression was significantly increased in cells exposed to genotoxic agents but negatively responded to the non-genotoxic agent dimethyl sulfoxide, thereby proving the specificity and sensitivity of the biosensor system.
This novel in vitro biosensor system can be especially useful in genotoxicity detection.
Aim: Diazinon (DZN) is one of the most important organophosphorus compounds used to control pests in agriculture in many countries. Several studies have shown that exposure to DZN may alter protein expression in the liver. In order to further investigate the mechanism of DZN toxicity, differentially expressed ATP-interacting proteins, following subacute exposure to toxin, were separated and identified in rat liver. Main methods: Male rats were equally divided into four groups: control (corn oil) and DZN (15 mg/kg) by gavage once a day for 4 weeks. After homogenization of liver tissue, lysates were incubated ATP-sepharose beads. After several washes, ATP-interacting proteins were eluted and separated on 2-D polyacrylamide gels. Deferentially expressed proteins were cut and identified using matrix-assisted laser desorption/ionization/time-of-flight and Mascot database. Identified proteins were classified according to their biological process using protein analysis through evolutionary relationships (PANTHER) Web site. Key finding: In this work, we showed that several key proteins involved in biological processes such as antioxidant system, oxidative stress, apoptosis, and metabolism were differentially expressed after subacute exposure to DZN.
Prussian blue nanoparticle (PBNP), a new type of theranostic nanomaterial, had been used for cancer magnetic resonance imaging and photothermal therapy. However, their long-term toxicity after short exposure in vivo was still unclear. In this study, we investigated the dynamic changes of the biochemical and immunity indicators of mice after PBNPs injection through tail vein. Histological results showed that the PBNPs were mainly accumulated in liver and spleen. In the spleen, we found the frequency of T cells was starting to decrease after 1 day of PBNPs injection, but then slowly recovered to normal level after 60 days of injection. Meanwhile, the frequency of T cells in the blood was firstly decreased after the PBNPs injection, and then the T cell frequency kept increasing and recovered back to normal levels after 7 days of injection. The serum indexes of liver functions (alanine transaminase, aspartate transaminase, total bilirubin, and alkaline phosphatase) increased rapidly to a relatively high level only after 1 h of injection, which meant certain acute liver damage, but these indexes were gradually decreased to normal levels after 60 days of injection. These results indicate that PBNPs have acute toxicity in vivo, however, their long-term toxicity after short-time exposure is low, which might provide guidance for further applications of PBNPs in future.
To provide support for future pharmacology and preclinical studies, we have established a stable nonhuman primate animal model to demonstrate the histopathological changes in the gastrointestinal tract following gamma ray irradiation. In this study, 12 healthy rhesus monkeys were divided into 2 groups (control and radiation groups). Animals in the radiation group were exposed to gamma rays (cobalt 60 source) at a dose level of 6.5 Gy total body irradiation bilaterally (i.e. 3.25 Gy on each side). Control animals were sham exposed using identical procedures. After a 5-day in-life observation period, gastrointestinal tract tissues (esophagus, stomach, duodenum, jejunum, ileum, colon, and rectum) were collected and fixed in 10% neutral-buffered formalin for subsequent hematoxylin and eosin and 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry processing. The results showed that the esophagus was undergoing degeneration without obvious inflammatory changes, while the stomach and duodenum exhibited both degeneration and inflammation. From the jejunum to the rectum, late-stage inflammation with glandular regeneration, as well as a high-level BrdU labeling index, was present.
ALC67 is an N-acylated thiazolidine compound with promising anticancer activity that led to the recent discovery of a series of 3-propionyl thiazolidine-4-carboxylic acid ethyl esters as a family of novel antiproliferative agents. Since the mutagenic and genotoxic properties of marketed anticancer molecules constitute a main issue to be addressed, this study focused on the analysis of the mutagenicity, antimutagenecity, and genotoxicity of this molecule. The mutagenicity and antimutagenicity of ALC67 were evaluated by Ames test performed on Salmonella TA98 and TA100 strains. The genotoxicity of this molecule was investigated in the chromosomal aberration assay on human lymphocytes. All results revealed that the analyzed structure is not mutagenic in the two Salmonella strains tested and was not genotoxic in human lymphocytes in vitro. On the other hand, it showed a weak antimutagenic effect in these two bacterial strains. The above results indicate that after performing some more mutagenicity assays using the other recommended strains, this compound can be safely used for the development of new structures exhibiting anticancer activities.
Thousands suffer poisonous snake bite, often from defibrinogenating species annually. Three rattlesnake species in particular, the timber rattlesnake, Eastern diamondback rattlesnake, and Southern Pacific rattlesnake, cause clinically relevant hypofibrinogenemia via thrombin-like activity in their venom. It has been demonstrated that iron (Fe) and carbon monoxide (CO) change the ultrastructure of plasma thrombi and improve coagulation kinetics. Thus, the present investigation sought to determine if pretreatment of plasma with Fe and CO could attenuate venom-mediated catalysis of fibrinogen via thrombin-like activity. Human plasma was pretreated with ferric chloride (0–10 μM) and CO-releasing molecule-2 (0–100 μM) prior to exposure to 2.5–10 μg/ml of venom obtained from the aforementioned three species of rattlesnake. Coagulation kinetics were determined with thrombelastography. All three snake venoms degraded plasmatic coagulation kinetics to a significant extent, especially diminishing the speed of clot growth and strength. Pretreatment of plasma with Fe and CO completely abrogated the effects of all three venoms on coagulation kinetics. Further in vitro investigation of other pit viper venoms that possess thrombin-like activity is indicated to see if there is significant conservation of venom enzymatic target recognition of specific amino acid sequences such that Fe and CO can reliably attenuate venom-mediated catalysis of fibrinogen. These data also serve as a rationale for future preclinical investigation.
Hydroxyapatite nanoparticles (HAP NPs) are widely used for preparations of biomedical and biotechnological fields such as drug delivery, gene therapy, and molecular imaging. However, the current toxicological knowledge about HAP NPs is relatively limited. The present study was designed to investigate the toxicity potentials of various concentrations (0–1000 µg cm–2) of HAP NPs in cultured primary rat hepatocytes. Cell viability was detected by 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) release, while total antioxidant capacity (TAC) and total oxidative stress (TOS) levels were determined to evaluate the oxidative injury. The DNA damage was also analyzed via scoring liver micronuclei rates and determining 8-oxo-2-deoxyguanosine (8-OH-dG) levels. The results of MTT and LDH assays showed that the higher concentrations of dispersed HAP NPs (300, 500, and 1000 µg cm–2) decreased cell viability. Also, HAP NPs increased TOS (500 and 1000 µg cm–2) levels and decreased TAC (300, 500, and 1000 µg cm–2) levels in cultured hepatocytes. On the basis of increasing doses, the NPs as depending on dose caused significant increases of the number of micronucleated hepatocytes and 8-OH-dG levels as compared to control culture. Furthermore, the highest concentration of HAP NPs (1000 µg cm–2) exhibited cytotoxic activity. Based on these results, HAP NPs have a dose-dependent toxic effect in rat hepatocytes. Further extensive research in this field is promising and reasonable.
Colorectal cancer (CRC) is a serious health problem throughout the world. 5-Flurouracil, the first-line chemotherapy of colorectal cancer often produces more toxicity to neighboring cells; however, it is still used for CRC treatment. To overcome this, umbelliferone (UMB), a less toxic bioflavonoid has been used to test its anticancer effects on animal model. The objective of the present study is to evaluate the anticancer activity of UMB on 1,2-dimethylhydrazine (DMH)-induced rat colon tumorigenesis to determine the development of aberrant crypt foci (ACF), agyrophylic nucleolar organizer regions (AgNORs), mast cell recruitment, pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and also study the expressions of inducible nitric oxide synthase, cyclooxygenase (COX)-2, and apoptotic markers. DMH-induced rats showed increased ACF number (incidence), multiplicity and its distribution, counts of AgNORs, mast cells, inflammatory markers and apoptotic proteins. Interestingly, UMB supplementation to DMH-induced rats (group 4) significantly (p < 0.05) suppressed ACF development, AgNORs, mast cells, and inflammatory markers and increased the apoptotic markers as compared to DMH-induced rats (group 2). We concluded that UMB is a potential anticancer agent that can be used for the prevention and treatment of CRC.
Disability weights (DWs) are used in disease burden studies, with the calculation of the weight of the disability as years lived with disability versus years of lost life accounting for mortalities. Currently, there is a single DW score available for poisoning, which is considered to be a single health state. This makes it difficult to evaluate the differing burdens of poisonings involving various substances/conditions in comparison with other health states in countries with different patterns of substance abuse. The aim of this study is therefore to estimate the DWs of 18 common poisonings based on the expert elicitation method.
A panel of 10 medical clinicians who were familiar with the clinical aspects of different poisonings estimated the DWs of 50 health states by interpolating them on a calibrated Visual Analogue Scale. The DWs of some poisonings, such as alcohol, cannabis and heroin, had been estimated in previous studies and so were used to determine the external consistency of our panel. As a matter of routine, the DWs could vary on a scale between 0 (best health state) and 1 (worst health state).
Statistical analysis showed that both the internal (Cronbach’s α = 0.912) and external consistency of the panel were acceptable. The DWs for the different poisonings were estimated along a range from 0.830 for severe aluminium phosphide to 0.022 for mild benzodiazepine.
Different poisonings should be weighted differently since they vary widely. Unfortunately, they are currently all weighted the same.
Chronic arsenic exposure has been linked to many health problems including diabetes and cancer. In the present study, we assessed the protective effect of ellagic acid (EA) against toxicity induced by arsenic in isolated rat liver mitochondria. Reactive oxygen species (ROS) and mitochondrial membrane potential decline were assayed using dichlorofluorescein diacetate and rhodamine 123, respectively, and dehydrogenase activity obtained by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide conversion assay. Arsenic increased ROS levels and mitochondrial dysfunction, which led to a reduction in mitochondrial total dehydrogenase activity. Mitochondria pretreated with EA exposed to arsenic at various concentrations led to a reversal of ROS production and mitochondrial damage. Our results showed that mitochondria were significantly affected when exposed to arsenic, which resulted in excessive ROS production and mitochondrial membrane disruption. Pretreatment with EA, reduced ROS amounts, mitochondrial damage, and restored total dehydrogenase activity specifically associated with mitochondrial complex II. EA protective characteristics may be accomplished particularly throughout the mitochondrial maintenance either directly by its antioxidant property or indirectly through its maintaining of complex II. These findings also suggest a potential role for EA in treating or preventing mitochondria associated disorders.
Oxcarbazepine (OXC) is a 10-keto analogue of carbamazepine used in patients with partial and secondary generalized seizures. We evaluated ingestions of OXC reported to US poison centers for adverse effects from supratherapeutic doses and/or overdose.
Retrospective analysis of data reported to National Poison Data System from single-substance OXC ingestions between January 2000 and December 2012.
There were 18,867cases with a mean of 1451 exposures/year. The patients were predominantly adults with 5464 exposures in children <6 years (29%). The most commonly reported clinical effects were drowsiness (n = 4703, 25%), vomiting (n = 1559, 8%), tachycardia (n = 590, 3%), agitated (n = 342, 1.8%), hypotension (n = 178, 0.9%), electrolyte disturbance (n = 153, 0.8%), coma (n = 156, 0.8%), and seizures (n = 121, 0.6%). There were 176 patients with a major effect of which 31 involved were children and 1728 (9%) patients with moderate effects of which 300 involved were children. Five deaths were reported in adults. Intentional exposure (e.g. suicide) was the reason for exposure in 68% of patients with major effects and in all fatalities. Fifty-three percent of adults and 38% of children were managed in a health-care facility (HCF). HCF utilization levels remained consistent.
Severe outcomes appear to be infrequent (<1%). Unlike other anticonvulsants OXC does not appear to be proconvulsant in overdose.
Serious outcomes for OXC overdoses are unlikely in the pediatric patient. With only mild symptoms likely, observation at home may be appropriate for the majority of cases. In the adult population there appears to be few neurologic and cardiovascular complications even in the intentional exposure.
Secondhand smoke (SHS) is an important health issue worldwide. Inhaling SHS during pregnancy could cause abnormalities in the internal tissues of newborns, which may then impair fetal development and even cause severe intrauterine damage and perinatal death. However, the understanding of cytopathic mechanisms of SHS by maternal passive smoking on fetus liver during pregnancy is still limited. This study analyzed the effects of high-dose SHS (SHSH) on fetus liver using a maternal passive smoking animal model. Experiments showed that hepatic matrix metalloproteinase-9 activity and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling-positive cells were significantly increased in livers from fetuses of hamsters treated with SHSH. Similarly, expressions of both extrinsic and intrinsic apoptotic molecules were significantly higher in livers from fetuses of hamsters exposed to SHSH. Additionally, significantly increased inflammatory proteins, including transforming growth factor β, inducible nitric oxide synthase, and interleukin 1β, and fibrotic signaling molecules, including phosphorylated Smad2/3, SP1, and α-smooth muscle actin, were observed in the fetus livers from hamsters treated with SHSH. This study revealed that SHSH not only increased apoptosis through intrinsic and extrinsic pathways in the livers of fetuses from hamsters exposed to SHSH but also augmented hepatic fibrosis via Smad2/3 signaling.
To analyze the toxic effects of aristolochic acid (AA) on developed kidneys in zebrafish larvae, zebrafish at 3 days postfertilization were treated with various concentrations of AA for 24 h before the status of kidney injury was investigated from several points of view. It was found that 21% of the larvae treated with 10 µmoL/L AA exhibited evident periocular edema. When the concentrations of AA were increased to 20 and 40 µmoL/L, defect in the cardiovascular system characterized by slow heart beat and blood flow was seen coupled with periocular edema. Creatinine in the whole larval tissue determined by liquid chromatography–mass spectrometry/mass spectrometry exhibited dramatic increase in the treated groups in a dose-dependent manner within a certain range of doses. Several evident protein bands were detected by sodium dodecyl sulfate–polyacrylamide gel electrophoresis in supernatant of the treated larvae, indicating leakage of glomerular filtration barrier. Results of quantitative polymerase chain reaction show that the messenger RNA expression of nephrin in the 20 and 40 µmoL/L AA-treated groups decreased to 0.58 ± 0.062 and 0.37 ± 0.075-folds of the control, respectively. Kidney damage was further confirmed by the histological changes in paraffin sections of treated larvae, for example, cystic glomeruli and disorganized epithelia cells of pronephric tubules. Our results revealed that AA exerted toxic effects on developed kidney of zebrafish larvae in a dose-dependent manner and podocyte dysfunction may be involved in the kidney injury and proteinuria.
Periodontitis is a common infectious disease associated with destruction of periodontal ligaments and alveolar bones. CD4+ T cell-mediated immune response is involved in the progression of periodontitis. Tobacco consumption increases the risk of periodontal disease. However, the impact of nicotine on the interaction between human periodontal ligament (PDL) cells and CD4+ T cells remains unrevealed. Our study aims to investigate the effect of nicotine on PDL cells and the cocultured CD4+ T cells. The PDL cell cultures were established by explants from healthy individuals, exposed to nicotine or α-bungarotoxin (α-BTX), and incubated solely or in combination with CD4+ T cells. Afterwards, cell viability, secreted cytokines, and matrix metalloproteinases (MMPs) were evaluated. In monoculture of PDL cells, nicotine dramatically repressed cell viability and increased apoptosis. Meanwhile, α-BTX largely reversed the nicotine-induced apoptosis and increased viability of PDL cells. Compared with the monoculture, MMP-1, MMP-3, interleukin (IL)-1β, IL-6, IL-17, and IL-21 in supernatant of cocultures were markedly elevated after treatment with nicotine. Moreover, α-BTX significantly attenuated nicotine-triggered production of these components either in mono- or co-cultures. In addition, PDL cell-derived CXCL12 following nicotine treatment recruited CD4+ T cells. Above all, nicotine deteriorated periodontitis partially by promoting PDL cell–CD4+ T cell-mediated inflammatory response and matrix degradation.
Orellanine is a nephrotoxic toxin produced by some mushroom species of the Cortinarius genus, typically found in Europe and North America. The nephrotoxicity of Cortinarius orellanus is well known and was first recognized in the 1950s when this mushroom was identified as the cause of a mass poisoning in Poland. Typically, onset of symptoms is delayed for 1–2 weeks after ingestion. Some patients suffer mild gastrointestinal discomfort in the latency period before developing signs of renal impairment due to severe interstitial nephritis, acute focal tubular damage, and interstitial fibrosis. There is no specific antidote to orellanine poisoning. The mainstay of treatment is the prevention of secondary complications of kidney failure, adequate dialysis and, in the case of incomplete recovery, management of chronic renal insufficiency.
In this work, we aim to review about Cortinarius species, including epidemiological studies, chemical structure, toxicokinetics, toxic doses, mechanisms of toxicity, diagnosis, prognosis, and treatment options.
This study investigated the main target sites of chlorpyrifos (CPF), its effect on biochemical indices, and the pathological changes observed in rat liver and kidney function using gas chromatography/mass spectrometry. Adult female Wistar rats (n = 12) were randomly assigned into two groups (one control and one test group; n = 6 each). The test group received CPF via oral gavage for 21 days at 5 mg/kg daily. The distribution of CPF was determined in various organs (liver, brain, heart, lung, kidney, ovary, adipose tissue, and skeletal muscle), urine and stool samples using GCMS. Approximately 6.18% of CPF was distributed in the body tissues, and the highest CPF concentration (3.80%) was found in adipose tissue. CPF also accumulated in the liver (0.29%), brain (0.22%), kidney (0.10%), and ovary (0.03%). Approximately 83.60% of CPF was detected in the urine. CPF exposure resulted in a significant increase in plasma transaminases, alkaline phosphatase, and total bilirubin levels, a significant reduction in total protein levels and an altered lipid profile. Oxidative stress due to CPF administration was also evidenced by a significant increase in liver malondialdehyde levels. The detrimental effects of CPF on kidney function consisted of a significant increase in plasma urea and creatinine levels. Liver and kidney histology confirmed the observed biochemical changes. In conclusion, CPF bioaccumulates over time and exerts toxic effects on animals.
This study was performed to determine the effect of low-level exposure to a mixture of bisphenol A (BPA) and isobutylparaben (IBP) on male reproduction. Corn oil, BPA (0.05 mg/kg/day), IBP (2.5 mg/kg/day), and a BPA/IBP mixture (BPA 0.05 mg/kg/day and IBP 2.5 mg/kg/day) were administered once daily by oral gavage to female rats for 5 weeks from gestation day 6 to lactation day 21. Male pups were killed at postnatal day 70 and examined for developmental characteristics, body weight, testis and epididymis weight, steroid hormones, epididymal sperm count and motility, and histological changes in testis and epididymis. The BPA/IBP mixture produced a significant downregulation of epididymal sperm count and motility. BPA or IBP alone also reduced epididymal sperm count and motility compared to control. These results indicate that exposure to low-level BPA/IBP mixture, which showed no notable physiological response in early life stages, can decrease semen quality in adulthood.
Chlorpyrifos (CP) is an organophosphorus pesticide that induces oxidative stress through the production of free radicals and depletes intracellular antioxidant reserves. In this study, the efficacy of three antioxidants (melatonin, coenzyme Q10 (CoQ10), and vinpocetine) on alleviation of toxic effects of CP was evaluated.
Cytotoxicity of CP, in the presence or absence of effective doses of melatonin, CoQ10, and vinpocetine, was determined in human peripheral blood lymphocytes after 72-h exposure. The levels of acetylcholinesterase (AChE) activity along with tumor necrosis factor α (TNF-α), as inflammatory index, were measured. Further, the viability and oxidative stress markers including cellular mitochondrial activity, cell death modes (apoptosis vs. necrosis), total antioxidant power (TAP), total thiol molecules (TTM), lipid peroxidation (LPO), and myeloperoxidase (MPO) activity were measured.
CoQ10 and also the combination of the three antioxidants were the most notable in opposing toxicity of CP and led to increasing TAP and TTM; improvement of AChE activity; and lowering LPO, MPO, TNF-α, and apoptosis compared to CP alone.
CP toxicity overwhelms the intracellular antioxidant defense mechanisms. Exogenous supplementation with antioxidants, such as the ones we have investigated, seems to be effective in the prevention of cytotoxicity of CP.
Vigabatrin (VGB) is an antiepileptic drug thatincreases brain -aminobutyric acid (GABA) levels through irreversible inhibition of GABA transaminase. The aim of this study was to evaluate neurotoxicological effects of VGB measuring motor activity and genotoxic and mutagenic effects after a single and repeated administration. Male Wistar rats received saline, VGB 50, 100, or 250 mg/kg by gavage for acute and subchronic (14 days) treatments and evaluated in the rotarod task. Genotoxicity was evaluated using the alkaline version of the comet assay in samples of blood, liver, hippocampus, and brain cortex after both treatments. Mutagenicity was evaluated using the micronucleus test in bone marrow of the same animals that received subchronic treatment. The groups treated with VGB showed similar performance in rotarod compared with the saline group. Regarding the acute treatment, it was observed that only higher VGB doses induced DNA damage in blood and hippocampus. After the subchronic treatment, VGB did not show genotoxic or mutagenic effects. In brief, VGB did not impair motor activities in rats after acute and subchronic treatments. It showed a repairable genotoxic potential in the central nervous system since genotoxicity was observed in the acute treatment group.
Nitric oxide produced by inducible nitric oxide synthase (iNOS) regulates sepsis-induced hypotension. During septic shock, interleukin (IL)-1β is synthesized in endothelial cells and smooth muscle cells by endotoxin. Ethanol (EtOH) suppresses endotoxin-induced hypotension. The present study aimed to elucidate the effect of EtOH on gradual relaxation and iNOS expression induced by IL-1β in isolated rat superior mesenteric arteries (SMAs). Exposure to IL-1β–induced contraction in SMA rings, followed by a gradual relaxation of phenylephrine precontracted tone. Contraction was abolished by indomethacin (IM), cycloheximide (Chx), and endothelium denudation. In contrast, the gradual relaxation was abolished by NOS inhibitors, Chx, endothelium denudation, and inhibited by EtOH (50 and 100 mM). However, IM had no effect on relaxation. Western blot analysis demonstrated that iNOS expression was induced by IL-1β and was inhibited by EtOH and endothelium denudation. Furthermore, messenger RNA expression of iNOS, but not endothelial NOS, was inhibited by EtOH. These data suggest that IL-1β–induced contraction is mediated by thromboxane A2, whereas IL-1β–induced relaxation occurs via NO derived from iNOS. The endothelium plays an important role in vasorelaxation. Taken together, EtOH inhibits IL-1β–mediated vasorelaxation by suppressing endothelium iNOS expression. This study provides the first evidence of EtOH -induced inhibition of IL-1β–mediated vasorelaxation.
Biomedical application of silver nanoparticles (AgNPs) has been rapidly increasing. Owing to their strong antimicrobial activity, AgNPs are used in dermatology in the treatment of wounds and burns. However, recent evidence for their cytotoxicity gives rise to safety concerns. This study was undertaken as a part of an ongoing programme in our laboratory to develop a topical agent for wound healing. Here, we investigated the potential toxicity of AgNPs using normal human dermal fibroblasts (NHDF) and normal human epidermal keratinocytes (NHEK) with the aim of comparing the effects of AgNPs and ionic silver (Ag-I). Besides the effect of AgNPs and Ag-I on cell viability, the inflammatory response and DNA damage in AgNPs and Ag-I–treated cells were examined. The results showed that Ag-I were significantly more toxic than AgNPs both on NHDF and NHEK. Non-cytotoxic concentrations of AgNPs and Ag-I did not induce DNA strand breaks and did not affect inflammatory markers, except for a transient increase in interleukin 6 levels in Ag-I–treated NHDF. The results showed that AgNPs are more suitable for the intended application as a topical agent for wound healing up to the concentration 25 µg/mL.
ADAM33 represents an important gene of susceptibility for lung function impairment. This work aimed to evaluate the association between genetic polymorphism of ADAM33 at four single nucleotide polymorphisms (T1, T2, S1, and Q1) and arginase activity with respiratory functions impairment in wood workers. The study was done to compare ventilatory functions and arginase activity of 82 wood workers and 81 controls. Genotyping was determined by using the polymerase chain restriction fragment length polymorphism method. Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and peak expiratory flow rate (PEF) of the workers were significantly reduced compared with the controls. T1 single nucleotide polymorphism (SNP) was associated with obvious decline in the FEV1, FVC, and PEF in wood workers, while T2 SNP was associated with decline in FEV1 and PEF. A significant increase in arginase activity was found in T2 and S1 SNPs of the exposed workers. Increase in duration of exposure was correlated with the decline in ventilatory functions. This inverse correlation was significant for pulmonary function indices in AA and GG genotypes of T1 and T2, respectively. Moreover, significance was detected for FVC and FEV1 in AA and GA genotypes of S1 and Q1. A positive correlation between arginase activity and duration of exposure was found to be significant in GG genotype of S1 SNP. An association between ADAM33 gene polymorphism and impaired lung functions was detected in wood dust-exposed workers. Arginase activity may play an associated important role in increasing this impairment in wood workers.
Lead-contaminated opium is one of the new sources of lead exposure in our region. As far as the literature review is concerned, there are limited comparative studies about comparison of blood lead level (BLL) in addict patients with healthy controls.
We aimed to compare BLL and urine lead level (ULL) between opium addicts with the healthy control group.
Forty opium addict subjects (mean age: 43 ± 10 years) as the patient group and 40 healthy subjects (mean age: 41 ± 9 years) as the control group participated. Three milliliter of whole blood and urine was obtained from both groups and lead level was assessed using atomic absorption spectrophotometry.
The mean value of BLL in patient group was 7.14 ± 1.41 mcg/dL and that in the healthy control group was 5.42 ± 1.46 mcg/dL. The mean value of ULL was 2.62 ± 0.83 mcg/dL in the patient group and 2.50 ± 0.76 mcg/dL in the healthy control group.
BLL was different in the two groups (p < 0.001), but ULL was not (p = 0.5). There was a significant correlation between BLL with duration of opium addiction in the patient group (r = –0.403, p = 0.01). BLL and ULL were significantly correlated in controls (r = 0.436, p = 0.005) and not in patients.
It was observed that the BLL in opium addicts was significantly higher than that in the healthy control group. This can be due to use of adulterated opium with lead. Therefore, screening of blood lead concentration is helpful for opium-addict patients especially with nonspecific symptoms.
The aims of the study are to detect whether there are any possible effects of chronic carbon monoxide (CO) exposure on the argyrophilic nucleolar-organizing region (AgNOR)–associated protein synthesis and evaluate any possible relationship between the amount of AgNOR protein and the level of myocardial injury also and between AgNOR and histopathological evaluation methods. Adult male albino Wistar rats (n = 18) were randomly divided into three groups (groups A, B, and C). Group A served as control, while groups B and C were rats exposed to CO gas chronically (1000 and 3000 ppm CO concentration with a flow rate of 4 L/min for 30 min/day for 7 days, respectively). Total AgNOR area/nuclear area (TAA/NA) and the mean AgNOR numbers for each myocyte nucleus were determined. There were significant differences among all groups for TAA/NA ratio. These differences were not significant for mean AgNOR numbers. According to the histopathological evaluation scores, there were significant differences between the groups. The differences were significant among the groups for loss of sarcomere pattern. A strong positive correlation between histopathological injury scores and TAA/NA ratio was found (R sq = 0.48; p = 0.002), however, the correlation was not significant for mean AgNOR numbers (R sq = 0.08; p = 0.25). In conclusion, TAA/NA ratio can be used as an indicator for obtaining information about the level of myocardial damage instead of histopathological evaluation scores.
The goal of this in vitro study was to investigate the effect of lipid emulsion on apoptosis induced by a toxic dose of bupivacaine (BPV) in H9c2 rat cardiomyoblast cell lines. The effect of lipid emulsion on the decreased cell viability and count induced by BPV or mepivacaine (MPV) in the H9c2 cells was assessed using an 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay or a cell count assay. The effect of BPV or lipid emulsion combined with BPV on cleaved caspase 3, caspase 8, and Bax in H9c2 cells was investigated using Western blotting. A terminal deoxynucleotidyl transferase dUTP2'-deoxyuridine 5'-triphosphate nick end-labeling (TUNEL) assay was performed to detect apoptosis of H9c2 cells treated with BPV alone or lipid emulsion combined with BPV. The magnitude of lipid emulsion-mediated attenuation of decreased cell viability induced by BPV was higher than that of lipid emulsion-mediated attenuation of decreased cell viability induced by MPV. Lipid emulsion attenuated the increases in cleaved caspase 3, caspase 8 and Bax induced by BPV. Lipid emulsion attenuated the increases in TUNEL-positive cells induced by BPV. These results suggest that lipid emulsion attenuates a toxic dose of BPV-induced apoptosis via inhibition of the extrinsic and intrinsic apoptotic pathways. The protective effect of lipid emulsion may be partially associated with the relatively high lipid solubility of BPV.
Probiotics are live microorganisms ingested for the purpose of conferring a health benefit on the host. Development of new probiotics includes the need for safety evaluations that should consider factors such as pathogenicity, infectivity, virulence factors, toxicity, and metabolic activity. Clostridium butyricum MIYAIRI 588® (CBM 588®), an anaerobic spore-forming bacterium, has been developed as a probiotic for use by humans and food animals. Safety studies of this probiotic strain have been conducted and include assessment of antimicrobial sensitivity, documentation of the lack of Clostridium toxin genes, and evaluation of CBM 588® on reproductive and developmental toxicity in a rodent model. With the exception of aminoglycosides, to which anaerobes are intrinsically resistant, CBM 588® showed sensitivity to all antibiotic classes important in human and animal therapeutics. In addition, analysis of the CBM 588® genome established the absence of genes for encoding for α, β, or toxins and botulin neurotoxins types A, B, E, or F. There were no deleterious reproductive and developmental effects observed in mice associated with the administration of CBM 588®. These data provide further support for the safety of CBM 588® for use as a probiotic in animals and humans.
In this study, we aimed to investigate disulfide/thiol homeostasis in trichloroethylene (TCE) exposure. The study was carried out in 30 nonsmoker TCE-exposed workers with a variety of occupations. Additionally, 30 healthy nonsmoker volunteers were recruited as the control group. TCE exposure was determined by measuring urinary trichloroacetic acid (TCA) concentration. Median urinary TCA levels of exposed workers (20.5 mg/L) were significantly higher than control subjects (5 mg/L). Thiol and disulfide concentrations were determined using a novel automated method. Disulfide/thiol ratio was significantly higher in the exposed group (p < 0.001). Thiol/disulfide homeostasis was found to be disturbed in TCE-exposed workers. We predict that in TCE-exposed workers this disturbance can be a therapeutic target, and the efficiency of the treatment can easily be monitored by the novel method we used.
Dealing with pain is one of the most important issues of medicine. All of the studies aim to find a drug or combination of drugs in order to have more effective analgesia and less side effects. In this study, we aimed to investigate the antinociceptive effects of combination of paracetamol or ketamine with meperidine.
In this study, we evaluated the systemic antinociceptive effects of meperidine, paracetamol, and ketamine one by one with their combinations. We used 50 mice (weighing 25–30 g), which were divided into 5 groups with each group consisting of 10 mice. Meperidine was applied to animals with increasing doses and their tail flick latencies (TFL) were noted at 20, 40, 60, 90, 120, 180, and 240 min. The same protocol was repeated after the combination of meperidine with paracetamol or ketamine.
There was no analgesic effect on low doses of ketamine and paracetamol at TFL measurements. But the combination of low doses of these drugs with meperidine significantly increased TFL (p < 0.05).
It was observed that meperidine + ketamine and meperidine + paracetamol combinations have potent analgesic effect.
In the present study, thirty six male Sprague Dawley rats were randomly divided into six groups and were injected with varying doses of alloxan (Ax) and nicotinamide (NA). The serum levels of glucose, insulin, and adiponectin were measured weekly up to 4 weeks.
Elevated levels of glucose were observed in all groups on days 7, 14, 21, and 28, except in groups a and f (control). The serum insulin levels were significantly elevated in groups b and c on day 7, when compared with that in group f, whereas a decrease in the serum insulin levels was observed in groups d and e on days 21 and 28. The adiponectin levels showed inconsistencies on days 7 and 14. However, significant decrease in the adiponectin levels was observed on days 21 and 28. Histological section of the pancreas showed mild (group a), moderate (group b) to severe (groups c, d, and e) degenerative changes. Concomitant fatty changes in the liver and inflammatory infiltration of the kidney were markedly observed in all the treated groups, when compared to control.
These results suggested that the use of selective combination of Ax120 + NA50 injection demonstrated type II diabetes mellitus in rats.
The aim of this study was to evaluate the cytotoxic effects of three different light-cured orthodontic composites.
Light Bond (Reliance orthodontic products), Grengloo (Ormco corporation), and Kurasper F (Kuraray Europe GmbH) were selected for the experiment. Specimens were prepared according to the manufacturers’ instructions, measuring 5 mm in diameter and 2 mm in thickness. Fibroblast cells were obtained from healthy gingival connective tissues. The composite cylinders were incubated in Dulbecco’s modified Eagle’s culture medium for 72 h according to ISO 10993-5 standards. The xCELLigence method was used to evaluate fibroblast cell vitality. After seeding 200 mL of the cell suspensions into the wells (20,000 cells/well) of the E-plate 96, gingival fibroblasts were treated with bioactive components released by the orthodontic composite materials and monitored every 15 min for 121 h.
There were no significant differences between the human gingival fibroblast (HGF) cell indexes of the control and all testing groups (p > 0.05) at 24 and 48 h. Light Bond demonstrated statistically significant decrease in HGF index (p < 0.05) at 72 h, but there was no significant difference among the Kurasper F, Grengloo, and untreated control groups (p > 0.05). Light Bond (p < 0.001) and Grengloo (p < 0.05) groups had lower HGF cell index values when compared to untreated control group, but Kurasper F demonstrated no significant differences between the control groups at 96 h (p > 0.05).
Orthodontic composite materials include biologically active components and may change oral tissue. So, biocompatible orthodontic bonding composites should be used.
In this study, we investigated the alterations of matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinases (TIMPs), acute inflammation, and oxidative damage in the circulatory system and the intestine in response to mesenteric ischemia/reperfusion (I/R).
Twenty-one rats were divided randomly into the following three groups (n = 7 in each group): a sham group (CG), an ischemic group (IG), and an I/R group (I/RG). MMP-9, TIMP-1, and myeloperoxidase (MPO) were measured using the enzyme-linked immunosorbent assay method, and lipid peroxidation (quantified as thiobarbituric acid reactive substances (TBARS) content), ischemia-modified albumin, the prooxidant–antioxidant balance (PAB), and ferric-reducing antioxidant power (FRAP) were measured spectrophotometrically. The degree of intestinal injury was evaluated according to the Chiu scoring system.
A significant difference between the mean serum TIMP-1 and MMP-9 levels and the alanine transaminase activity was found among the groups. Compared with the I/RG group a significant difference in the mean tissue MMP-9, MPO, and TBARS levels in addition to the PAB and FRAP was found between the CG and IG groups. The level of MMP-9 also demonstrated a strong, positive, and valid correlation with the TBA-RS levels. A significant morphological change was observed in both the IG and the I/RG groups. The degree of intestinal injury was more severe in the I/R group and was characterized by either villous denudation or villous loss.
These results suggest that MMP-9, TIMP-1, MPO, and oxidative stress may be important in the intestinal injury development that is induced by acute mesenteric I/R in a rat model. MMP-9 overexpression may increase the extent of intestinal villous loss, particularly when MMP-9 is upregulated by the TBARS present in the intestinal injury.
Reactive oxygen species are believed to be involved in the development of sepsis. Plant-derived phenolic compounds are thought to be possible therapeutic agents against sepsis because of their antioxidant properties. Rosmarinic acid (RA) is a phenolic compound commonly found in various plants, which has many biological activities including antioxidant activity. The aim of this study was to investigate the effects of RA on sepsis-induced DNA damage in the lymphocytes and liver and kidney cells of Wistar albino rats by alkaline comet assay with and without formamidopyrimidine DNA glycosylase protein. The oxidative stress parameters such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and total glutathione (GSH) and malondialdehyde (MDA) levels in the liver and kidney tissues and an inflammatory cytokine, tumor necrosis factor α (TNF-α) level in plasma were also evaluated. It is found that DNA damage in the lymphocytes, livers, and kidneys of the RA-treated rats was significantly lower than that in the sepsis-induced rats. RA treatment also decreased the MDA levels and increased the GSH levels and SOD and GSH-Px activities in the livers and kidneys of the sepsis-induced rats. Plasma TNF-α level was found to be decreased in the RA-treated rats. It seems that RA might have a role in the attenuation of sepsis-induced oxidative damage not only by decreasing the DNA damage but also by increasing the antioxidant status and DNA repair capacity of the animals.
Amoxicillin (AMX) is one of the most commonly prescribed antibiotics for children, and childhood is the period to have the highest risk for toxicity cases including drug-induced adverse reactions. Some neurological adverse effects (anxiety, hyperactivity, confusion, convulsions, and behavioral changes) have been reported related to AMX treatment. In the present study, we aimed to determine the neurotoxic effects of AMX administration at clinically relevant doses in female juvenile rats. AMX was administered in single oral daily doses of 25 and 50 mg/kg for 14 days. According to our results, while AMX administration caused a significant increase in the immobility time of animals, swimming time of these animals significantly decreased. AMX administration significantly reduced the onset of pentylenetetrazole-induced convulsions. The serotonin levels of brain tissues in the AMX-administered groups were decreased significantly, which is thought to be related to depression. The glutamate levels in brain tissues increased significantly in AMX-administered groups, which is thought to be related to convulsion. Otherwise, superoxide dismutase and catalase activities were significantly decreased in brain tissues of AMX-administered groups. In conclusion, AMX administration triggered depression and shortened the time of the appearance of first seizure in juvenile rats. Also, altered brain neurotransmitter levels and increased oxidative stress observed in our study were thought to be the possible underlying mechanisms of AMX-induced neurotoxicity.
Grape skin and seeds contain large amounts of phytochemicals such as polyphenols, resveratrol, and proanthocyanidins, which possess antioxidant activities. Cisplatin is widely used in the treatment of cancer. High doses of cisplatin have also been known to produce acute adverse effects. The aim of this study was to investigate the protective effects of antioxidant properties of whole grape juice (with skin and seeds) on cisplatin-induced acute gastrointestinal tract disorders and nephrotoxicity in Wistar rats. Gastric emptying is significantly increased in whole grape juice-pretreated rats when compared to cisplatin treatment alone. The expression of ghrelin mRNA of stomach is increased in rats with whole grape juice. However, pretreatment with whole grape juice did not reduce renal function markers in acute renal toxicity. No significant changes were recorded in the oxidative stress/antioxidant status parameters of any study group. In contrast, pretreatment with whole grape juice slightly improved tubular cell vacuolization, tubular dilatation, and cast formation in renal tubules. These results show that consumption of whole grape juice induces somewhat beneficial effects in preventing cisplatin-mediated dyspepsia but does not offer protection against cisplatin-induced acute renal toxicity.
This article is devoted to the inquiry of three diseases of the liver: alcoholic liver disease (ALD), primary biliary cirrhosis (PBC), and autoimmune hepatitis (AIH). The aim of the study was to assess the changes in populations of circulating lymphocytes expressing antiapoptotic bcl-2 molecule and proapoptotic Fas (cluster of differentiation 95(CD95)) receptor in patients with ALD, AIH, and PBC.
The study population consisted of 110 patients with ALD (n = 50), PBC (n = 30), and AIH (n = 30) and age-matched healthy volunteers (n = 25). Peripheral blood lymphocytes were isolated, stained with monoclonal antibodies against CD4, CD8, and CD19 antigen; intracellular bcl-2; and surface Fas receptor (CD95) antigens, and estimated using the flow cytometric method.
Bcl-2 expression was the highest in CD4+ and CD19+ T lymphocytes in ALD; however, only the differences in median/mean fluorescence intensity values of CD4+bcl-2+ lymphocytes between ALD and PBC group and CD19+bcl-2+ between ALD and PBC groups were statistically significant, indicating the different role of B cells in pathology of ALD and PBC. In contrast to that, statistically significant higher percentage of CD4+, CD8+, and CD19+ bearing Fas receptor in all groups of patients with liver diseases in comparison with the control subjects were estimated. The highest expression of Fas in CD4+ lymphocytes in ALD and in CD8+ cells of PBC and AIH groups were detected.
Low expression of bcl-2 molecule and high expression of Fas in peripheral blood lymphocytes indicate significant dysregulation of apoptotic mechanisms not only in the liver but also in peripheral blood lymphocytes in all examined groups, especially in ALD group.
Artemisinin is an antimalarial drug previously reported to induce neurotoxicity and embryotoxicity in animal models. This study investigated the erythrocytes and reproductive toxicity potentials of artemisinin in female rats. Animals were randomly divided into four study groups of eight rats each. The control group (group I) received corn oil, the vehicle, while groups II–IV were orally exposed to 7, 35 and 70 mg kg–1 day–1 of artemisinin, respectively, by gastric intubation for 7 consecutive days. Subsequently, we evaluated the impact of artemisinin on the endocrine environment and selected markers of oxidative damage and antioxidant status of the erythrocytes, ovary and uterus. Artemisinin significantly increased hydrogen peroxide (H2O2) and malondialdehyde (MDA) levels and decreased catalase, glutathione peroxidase and superoxide dismutase activities in erythrocytes and uterus of rats compared with control group (p < 0.05). However, artemisinin did not alter ovarian MDA, H2O2, glutathione levels and catalase activity, while ovarian and uterine histological assessment revealed absence of visible lesions. Moreover, artemisinin significantly decreased follicle-stimulating hormone and increased progesterone levels compared with control (p < 0.05). Thus, these data suggest that in the absence of malarial parasite infection, artemisinin induced hormonal imbalance and oxidative damage in the erythrocytes and uterus but spared the ovary of rats.
The aim of this study was to evaluate the cytotoxicity of four low-shrink composites with new monomer technology on the bovine dental pulp-derived cells (bDPCs).
Ten samples were prepared for each group composites, and the samples were immersed in 7 mL of culture medium for 72 h at 37°C to extract residual monomer or cytotoxic substances. The culture medium containing the material extracts was sterile filtered for use on the cell cultures. Materials were incubated in medium with serum for 72 h. bDPCs were maintained in a medium with serum. A real-time cell analyzer was used to evaluate cell survival. After seeding 200 mL of the cell suspensions into the wells (10,000 cells/well) of the E-plate 96, bDPCs were treated with bioactive components released by the composite materials (1:1 and 1:2 dilutions) and monitored every 15 min for 50 h.
According to analysis of variance, there were significant differences between the cell indexes of the control and GC kalore (p < 0.05) and Bisco Reflexions (p < 0.001) groups for the 1:1 dilutions at 25 h. When evaluated at 50 h, 1:1 dilutions of GC Kalore (p < 0.01) and Bisco Reflexions (p < 0.001) reduced cell survival significantly.
Although composites resins are being advanced, their cytotoxic effects have been proceeding till this time. However, two of the four materials tested significantly reduced cell viability when compared with control.
Research should focus on the cytotoxicity of composites in addition to their mechanical properties.
The influence, on arsenic (As) urinary metabolic profile, of the level of As exposure was evaluated on chronic-exposed inhabitants of several locations of the Chaco-Pampean Plains in Argentina. Urinary As (UAs) was quantified as a measure of the level of exposure. The metabolic profile of UAs (inorganic As, monomethylarsonic acid, and dimethylarsinic acid) was also evaluated. The presence of T860C polymorphism on the arsenite methyltransferase encoding gene was investigated by desquamation of buccal cells. UAs showed a wide range of levels (from 18 µg/g to 4103 µg/g) of creatinine. A clear influence of age, gender, level of As exposure, and the presence of T860C polymorphism was observed on As metabolic profile. The influence of the level of exposure showed to be different between individuals carrying the wild type (WT) and the heterozygous (H) genotypes. Metabolic profile of individuals carrying the WT genotype seemed to be influenced by the level of exposure, while individuals with the H genotype did not. It is concluded that the level of As exposure seemed to have a significant influence on urinary metabolic profile of individuals carrying the WT genotype. In contrast, individuals carrying the H genotype seemed not to be affected the same way by increasing the As exposure level.
Palladium nanoparticles (Pd-NPs) and nickel oxide nanoparticles (NiO-NPs) were synthesized and loaded on activated carbon (AC). This novel material successfully used for the removal of methylene blue (MB) dye from aqueous medium. Full characterization of both material using X-ray diffraction, transmission electron microscopy, scanning electron microscopy and Brunauer–Emmet–Teller analyses for Pd-NP show their high surface area (>1340 m2/g) and low pore size (<20 Å) and average particle size lower than 45 Å and for NiO-NP show their high surface area (>1316.1554 m2/g) and low pore size (<20 Å) and average particle size lower than 46 Å in addition to high reactive atom and presence of various functional groups. These unique properties make them possible for efficient removal of MB. In batch experimental set-up, optimum conditions for maximum removal of MB by both adsorbents were attained following searching effect of variables such as central composite design. The Langmuir isotherm was found to be highly recommended for fitting the experimental equilibrium data. The kinetic of adsorption of MB on both adsorbents strongly can be fitted by a combination of pseudo-second order and intraparticle diffusion pathway. The experimental result achieved in this article shows the superiority of Pd-NP-AC for MB removal than NiO-NP-AC, so the maximum adsorption capacities of Pd-NP-AC and NiO-NP-AC were 555.5 mg/g and 588.2 mg/g, respectively.
To detect the blood genomic DNA methylation in coke oven workers and find a possible early screening index for occupational lung cancer, 74 coke oven workers as the exposed group and 47 water pump workers as the controls were surveyed, and urine samples and peripheral blood mononuclear cells (PBMCs) were collected. Airborne benzo[a]pyrene (B[a]P) levels in workplace and urinary 1-hydroxypyrene (1-OH-Py) levels were determined by high-performance liquid chromatography. DNA damage of PBMCs and the p14(ARK), p15(INK4b) and p16(INK4a) gene CpG island methylation in the promoter region were detected by comet assay and methylation-specific polymerase chain reaction techniques, respectively. Results show that compared with the controls, concentration of airborne B[a]Ps was elevated in the coke plant, and urinary 1-OH-Py’s level and DNA olive tail moment in comet assay were significantly increased in the coke oven workers, and p14(ARK), p15(INK4b) and p16(INK4a) gene methylation rates were also significantly increased. With the working years and urinary 1-OH-Py’s level, the rates of p14(ARK) and p16(INK4a) gene methylation were significantly increased while that of p15(INK4b) gene methylation displayed no statistical change. We conclude that PBMCs’ p14(ARK) and p16(INK4a) gene methylation may be used for screening and warning lung cancer in coke oven workers.
Benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) is a highly reactive DNA damage agent and can induce cell death through both p53-independent and -dependent pathways. However, little is known about the molecular mechanisms of p53-independent pathways in BPDE-induced cell death. To understand the p53-independent mechanisms, we have now examined BPDE-induced cytotoxicity in p53-deficient baby mouse kidney (BMK) cells. The results showed that BPDE could induce Bax and Bak activation, cytochrome c release, caspases activation, and necrotic cell death in the BMK cells. Bax and Bak, two key molecules of mitochondrial permeability transition pore, were interdependently activated by BPDE, with Bax and Bak translocation to and Bax/Bak homo-oligomerization in mitochondria, release of cytochrome c was induced. Importantly, cytochrome c release and necrotic cell death were diminished in BMK cells (Bax–/–), BMK cells (Bak–/–), and BMK cells (Bax–/–/Bak–/–). Furthermore, overexpression of Bcl-2 could ameliorate BPDE-induced cytochrome c release and necrosis. Together the findings suggested that BPDE-induced necrosis was modulated by the p53-independent pathway, which was related to the translocation of Bax and Bak to mitochondria, release of cytochrome c, and activation of caspases.
Paraquat (PQ) is a well-known quaternary nitrogen herbicide. The major target organ in PQ poisoning is the lung. Reactive oxygen species (ROS) and inflammation play a crucial role in the development of PQ-induced pulmonary injury. Neopterin is synthesized in macrophage by interferon and other cytokines. We aimed to evaluate the utility of neopterin as a diagnostic marker in PQ-induced lung toxicity. Sprague Dawley rats were randomly divided into two groups (sham and PQ), administered intraperitoneally 1 mL saline and PQ (15 mg/kg/mL) respectively. Blood samples and lungs were collected for analyses. Lung injury and fibrosis were seen in the PQ group. Serum total antioxidant capacity, lactate dehydrogenase (LDH), and lung transforming growth factor-1β (TGF-1β) levels were significantly higher than the sham group (in all, p < 0.001). In addition, in the PQ group, serum neopterin and lung malondialdehyde (MDA) levels were also significantly higher than the sham group (in all, p = 0.001). Serum neopterin levels were correlated with LDH activities, lung MDA, lung TGF-1β levels, and the degree of lung injury. These findings demonstrated that oxidative stress, reduction of antioxidant capacity, and inflammation play a crucial role in the PQ-induced lung injury. Elevated serum neopterin levels may be a prognostic parameter to determine extends of PQ-induced lung toxicity. Further studies may be performed to clarify the role of neopterin by different doses of PQ.
Lethal cardiac complications leading to death and various arrhythmias have been reported after organophosphate and/or carbamate poisonings. The present study focuses on the long-term effects of repeated low-level exposure to diazinon, propoxur, and chlorpyrifos (CPF) on cardiac function in rabbits. The yearly based experimental scheme of exposure consisted of two oral administration periods, lasting 3 months and 1 month each, interrupted by an 8-month washout period (total duration 12 months). At the end of the experimental scheme, the rabbits underwent an echocardiographic evaluation under sedation, after which they were killed and the tissue and serum samples were collected. A mild localized cardiotoxic effect was established by echocardiography for the three pesticides tested. Severe histological alterations were identified, especially in the diazinon-treated animals in agreement with increased persistence of this pesticide established in the cardiac tissue. In addition, all pesticides tested increased the oxidative stress and oxidative modifications in the genomic DNA content of the cardiac tissues, each one following a distinct mechanism.
Long-acting injectable formulations of antipsychotics have been an important treatment option to increase the compliance of the patient with schizophrenia by monitoring drug administration and identifying medication noncompliance and to improve the long-term management of schizophrenia. Risperidone, a serotoninergic 5-HT2 and dopaminergic D2 receptor antagonist, was developed to be a long-acting sustained-release formulation for the treatment of schizophrenia. In this study, 12-week subchronic toxicity study of risperidone-loaded microspheres (RMs) in rats by intramuscular injection with an 8-week recovery phase was carried out to investigate the potential subchronic toxicity of a novel long-acting sustained-release formulation. The results indicated that the dosage of 10–90 mg/kg of RM for 2 weeks did not cause treatment-related mortality. The main drug-related findings were contributed to the dopamine D2 receptor and α1-adrenoceptor antagonism of risperidone such as elevation of serum and pituitary prolactin levels and ptosis and changes in reproductive system (uterus, ovary, vagina, mammary gland, testis, seminal vesicle, epididymis, and prostate). In addition, foreign body granuloma in muscle at injection sites caused by poly-lactide-co-glycolide was observed. At the end of the recovery phase, these changes mostly returned to normal. The results indicated that RM had a good safety profile in rats.
In carbon monoxide (CO) poisoning, CO affects the oxygen-carrying capacity of the hemoglobin molecule. Nucleolar-organizing regions (NORs) are genetic loci on chromosomes that are composed of ribosomal DNA and proteins. NORs can be stained with silver. A total of 18 rats were exposed to CO in three different concentrations (1000, 3000, and 5000 ppm) with 6 rats as controls. The animals were euthanized 7 days after CO intoxication. Lung tissues were taken, embedded in paraffin blocks, and sectioned at 5 μm thickness. Argyrophilic nucleolar-organizing region (AgNOR) staining was carried out. One hundred nuclei per individual were evaluated, and total AgNOR number per total nuclear number and total AgNOR area per nuclear area (TAA/NA) for each nucleus were analyzed. The CO exposure groups had significantly higher TAA/NA values and AgNOR numbers than the control group (p < 0.05). Although the differences between 1000 ppm and the other two CO-exposed groups were meaningful (p < 0.05) in the TAA/NA values, there were no differences among the CO exposure groups for the AgNOR number (p > 0.05). The increase in TAA/NA value depends on the increase in the CO exposure. Significant correlations between both the AgNOR values and histopathological scoring methods were found. Therefore, AgNOR staining method may be used as an indirect indicator for evaluating the degree of cell damage rate.
Valproic acid (VPA) has been reported as inhibitor of histone deacetylases (HDACs). Several reports indicated that HDACs play a crucial role in the pathogenesis of fibrosis and hepatic stellate cell (HSC) activation. The present study was aimed to evaluate the anti-fibrotic effect of VPA against thioacetamide (TAA)-induced hepatic fibrosis and activation of the HSC in rat. VPA and TAA were administrated intraperitoneally at the dose of 400 and 200 mg/kg each at 2 days interval, respectively for a period of 6 weeks. Administration of TAA significantly increased the absolute and relative liver weight, aspartate aminotransferase and alanine aminotransferase levels, which were significantly decreased by VPA treatment as compared to TAA control. VPA treatment prevents the TAA-induced activation of HSC and decreases collagen deposition and infiltration of inflammatory cells as revealed by Sirius red and H&E staining. Interestingly, VPA co-treatment led to significantly increase the DNA damage and apoptosis in the activated HSC as compared to TAA control. Further, TAA decreased the expression of matrix metalloproteinase-2 (MMP-2), while VPA co-treatment significantly increased the expression of MMP-2 as compared to respective control. The present study clearly demonstrated that VPA treatment significantly alleviates TAA-induced activation of HSC and subsequent hepatic fibrosis.
The role of oxygen radicals are known for the pathogenesis of kidney damage. The aim of the present study was to investigate the antioxidative effects of melatonin, quercetin, and resveratrol on streptozotocin (STZ)-induced diabetic nephropathy in rats. A total of 35 male Wistar rats were divided into 5 groups as follows: control, diabetes mellitus (DM), DM + melatonin, DM + quercetin, and DM + resveratrol. All the injections started on the same day of single-dose STZ injection and continued for 30 days. At the end of this period, kidneys were removed and processed for routine histological procedures. Biochemical parameters and morphological changes were examined. In DM group, blood glucose levels were significantly increased, whereas body weights were decreased compared with the control group. Significant increases in blood urea nitrogen and tissue malondialdehyde (MDA) levels and decreases in superoxide dismutase and catalase activities were detected in DM group. Administration of melatonin, quercetin, and resveratrol significantly reduced these values. Melatonin was more efficient in reducing MDA levels than other antioxidants (p < 0.05). STZ-induced histopathological alterations including epithelial desquamation, swelling, intracytoplasmic vacuolization, brush border loss and peritubular infiltration. Additionally, basement membrane thickening and sclerotic changes were observed in glomerulus. Transforming growth factor-β1 positive cells were also increased. Melatonin, quercetin, and resveratrol significantly reduced these histopathological changes. Our results indicate that melatonin, quercetin, and resveratrol might be helpful in reducing diabetes-induced renal damage
Gastric cancer (GC) is one of the most common and life-threatening types of malignancies. Identification of the differentially expressed genes in GC is one of the best approaches for establishing new diagnostic and therapeutic targets. Furthermore, these investigations could advance our knowledge about molecular biology and the carcinogenesis of this cancer. To screen for the overexpressed genes in gastric adenocarcinoma, we performed suppression subtractive hybridization (SSH) on gastric adenocarcinoma tissue and the corresponding normal gastric tissue, and eight genes were found to be overexpressed in the tumor compared with those of the normal tissue. The genes were ribosomal protein L18A, RNase H2 subunit B, SEC13, eukaryotic translation initiation factor 4A1, tetraspanin 8, cytochrome c oxidase subunit 2, NADH dehydrogenase subunit 4, and mitochondrially encoded ATP synthase 6. The common functions among the identified genes include involvement in protein synthesis, involvement in genomic stability maintenance, metastasis, metabolic improvement, cell signaling pathways, and chemoresistance. Our results provide new insights into the molecular biology of GC and drug discovery: each of the identified genes could be further investigated as targets for prognosis evaluation, diagnosis, treatment, evaluation of the response to new anticancer drugs, and determination of the molecular pathogenesis of GC.
To investigate the effects of overexpression of nuclear factor E2-related factor-2 (NRF2) on lung injury in rats exposed to paraquat (PQ) poisoning.
A mifepristone (RU486)-inducible recombinant adenoviral vector carrying the human NRF2 gene (Ad-RUNRF2) was constructed and transfected via airway into the rats 7 days before the administration of RU486. Rats were orally challenged with PQ at 20 mg/kg 24 h after the injection of RU486. On days 0.5, 3 and 21 after PQ poisoning, the expressions of NRF2 and cytokines related to inflammation and oxidation in lung tissue were examined.
RU486 remarkably enhanced NRF2 mRNA and NRF2 protein levels in Ad-RUNRF2-transfected rats in a dose-dependent manner (p < 0.01). PQ stimulated compensatory overexpression of NRF2, heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO-1) in lungs on days 0.5 and 3 after exposure (p < 0.05), but depleted the expression of catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH), with an increased malondialdehyde (MDA) (p < 0.05). However, pretreatment with Ad-RUNRF2 and RU486 strongly enhanced the expression levels of NRF2, HO-1, NQO-1, CAT and GSH-Px in the lungs of PQ intoxicated rats, with increased GSH and decreased MDA (p < 0.05). Pretreatment with Ad-RUNRF2 and RU486 also strongly suppressed the PQ-induced activation of nuclear factor B (NF-B) and decreased the levels of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). In addition, Ad-RUNRF2 and RU486 induction significantly reduced PQ-induced pathological changes in lungs and attenuated lung oedema and protein leakage caused by PQ (p < 0.05).
RU486-induced overexpression of NRF2 in lungs transfected with Ad-RUNRF2 can ameliorate PQ-induced lung injury by the activation of the NRF2-antioxidant response element (ARE) pathway.
A case of organophosphate (OP) poisoning was admitted to the emergency room. The patient accepted treatment with pralidoxime (PAM), atropine, and supporting therapy. It was observed that even after 22 h after treatment, 960 mg of atropine was not enough for the patient to be atropinized. However, a 160-mg follow-up treatment of anisodamine was quite enough for atropinization after 4 h. As a case report, more studies are required before any definite conclusion can be reached regarding the use of anisodamine as a potential substitute for high-dose atropine in cases of OP poisoning.
There is a lack of data concerning the evaluation of scientific research productivity in paracetamol poisoning from the world. The purposes of this study were to analyse the worldwide research output related to paracetamol poisoning and to examine the authorship pattern and the citations retrieved from the Scopus database for over a decade.
Data were searched for documents with specific words regarding paracetamol poisoning as ‘keywords’ in the title or/and abstract. Scientific output was evaluated based on a methodology developed and used in other bibliometric studies. Research productivity was adjusted to the national population and nominal gross domestic product (GDP) per capita.
There were 1721 publications that met the criteria during study period from the world. All retrieved documents were published from 72 countries. The largest number of articles related to paracetamol poisoning was from the United States (US; 30.39%), followed by India (10.75%) and the United Kingdom (UK; 9.36%). The total number of citations at the time of data analysis was 21,109, with an average of 12.3 citations per each documents and median (interquartile range) of 4 (1–14). The h-index of the retrieved documents was 57. After adjusting for economy and population power, India (124.2), Nigeria (18.6) and the US (10.5) had the highest research productivity. Countries with large economies, such as the UK, Australia, Japan, China and France, tended to rank relatively low after adjustment for GDP over the entire study period.
Our study demonstrates evidence that research productivity related to paracetamol poisoning has increased rapidly during the recent years. The US obviously dominated in research productivity. However, certain smaller country such as Nigeria has high scientific output relative to their population size and GDP. A highly noticeable increase in the contributions of Asia-Pacific and Middle East regions to scientific literature related to paracetamol poisoning was also observed.
To authenticate the colon cancer preventive potential of silibinin, the efficacy of silibinin needs to be tested by evaluating an organ-specific biomarker. The aim of this study was to evaluate the impact of silibinin on the colonic expression of the caudal-type homeobox transcription factor (CDX2) an intestine specific tumor suppressor gene and its downstream targets in the colon of rats challenged with 1,2 dimethyl hydrazine (DMH). Rats of groups 1 and 2 were treated as control and silibinin control. Rats under groups 3 and 4 were given DMH (20 mg/kg body weight (b.w.) subcutaneously) once a week for 15 consecutive weeks from the 4th week of the experimental period. In addition, group 4 rats alone were treated with silibinin (50 mg/kg b.w. per os) everyday throughout the study period of 32 weeks. Histological investigation and messenger RNA and protein expression studies were performed in the colonic tissues of experimental rats. Findings of the study revealed that DMH administration significantly decreased the expression of CDX2 and Guanylyl cyclase C (GCC) in the colon of experimental rats. Further the decreased levels of CDX2 protein, colonic mucin content, and increased number of mast cells in the colon of DMH alone-administered rats reflects the onset of carcinogenesis. The pathological changes caused due to CDX2 suppression were attenuated by silibinin supplementation.
Titanium dioxide (TiO2) nanoparticles (NPs) are commonly used materials present in many consumables for which most people are exposed to. The biological hazards of the NPs on human health have been demonstrated previously. In this study, we aimed to assess the cytotoxicity potency of TiO2 NPs on the primary human amniotic fluid cells. The cells derived from amniotic fluid were treated with different dosages of TiO2 NPs for some periods. Cell adhesion status was assessed using a light microscopic observation. Cell proliferation and cell death rates were determined using trypan blue staining and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Also, mitotic index was determined using fluorescence in situ hybridization with chromosome 8 centromer-specific DNA probe. Disrupted cell adhesion, decreased proliferation, and increased mortality rates were detected in the cells that were treated with TiO2 NPs depending on the dosage (p < 0.001). Also, reduced mitotic index was determined in the cells depending on the time and TiO2 dosage when compared with the controls (p < 0.0001). These results showed that TiO2 NPs have high cytotoxicity for amniotic fluid-derived cells. Therefore, different products containing TiO2 NPs should be used with care, especially for pregnant women.
The aim of the present research was to examine the toxic influence of different doses of zearalenone (ZEN) on the liver, especially oxidative stress induced by ZEN on the liver. A total of 48 pregnant Sprague-Dawley rats were randomly assigned into 4 treatments groups with 12 animals in each. The rats were fed with a normal diet treated with 0 mg/kg (control), 50 mg/kg (treatment 1), 100 mg/kg (treatment 2), or 150 mg/kg (treatment 3) ZEN in feed on gestation days (GDs) 0–7 and then all the rats were fed with a normal diet on GDs 8–20. The experimental period lasted 21 days. The results showed that exposure to ZEN induced increase in aspartate amino transferase, alanine aminotransferase, and alkaline phosphatase activities and decrease in total protein and albumin content in a dose-dependent manner and also induce decrease in superoxide dismutase and glutathione peroxidase activities and increase in malondialdehyde content in a dose-dependent manner in the serum and the liver. The increased transcription of cytochrome P450 2E1 (CYP2E1) was detected in the liver after exposure to ZEN. These results suggested that ZEN not only caused damage in the liver of pregnant rats in a dose-dependent manner but also induced the messenger RNA expression of CYP2E1 in the liver.
Pityriasis rosea (PR) is a common, acute, and self-limited inflammatory skin disease. The typical clinical presentation includes the appearance of a primary "herald" patch followed within days to weeks by the onset of secondary scaly skin eruptions distributed along the skin tension line in most cases. Although PR is a well-known and relatively common disease, its cause is still not completely understood. However, viral agents, autoimmunity, psychogenic status, and numerous drugs have been proposed as possible factors to PR. Bupropion is known to cause hypersensitivity reactions. We present a clinical case of PR eruption caused by the use of bupropion. To the best of our knowledge, this is the first published case of PR associated with bupropion use.
The aim of this study was to investigate genotoxic and cytotoxic effects of doxorubicin, silymarin, or in combination on HepG2 cells for 24 and 48 h. Both doxorubicin and silymarin caused dose-dependent inhibition of cell proliferation. After 48 h of treatment, doxorubicin application caused dramatically increased ratio of apoptotic cells. Both 24 and 48 h of silymarin and doxorubicin–silymarin combination caused significant increases in the rate of apoptotic cells. Applications of doxorubicin and silymarin separately for 24 h led to deoxyribonucleic acid (DNA) damages. After 48 h of incubation, doxorubicin-induced genotoxic damage was 2-fold higher than the silymarin-induced damage. After 24 and 48 h, DNA damage in response to combined applications of doxorubicin and silymarin was indifferent from silymarin- and doxorubicin-induced damage respectively. There was not any difference in genotoxicity levels between incubation periods in combined applications of doxorubicin and silymarin. Lipid peroxidation levels increased in all applications. Biopharmacotherapy with chemotherapeutic agents are of interest in the issue of adjuvant therapy. Here, we demonstrate in vitro potential genotoxic and cytotoxic antitumor effect of silymarin on HepG2 cells at achievable plasma level concentrations.
Fasting has been recently discovered to improve overall health, but its beneficial effects in the presence of hepatic insufficiency have not been proven.
The influence of fasting on the metabolism, immunological aspects, and oxidative stress of 40 male carbon tetrachloride (CCl4)-intoxicated Wistar rats was investigated in the present study.
The rats were divided into four groups, including a placebo group, CCl4-intoxicated rats, which were injected subcutaneously with 1.0 ml/kg of CCl4 solution, a fasting group, which was fasted 12 h/day for 30 days, and a fourth group, which was injected with CCl4 and fasted.
The metabolism, immunity, and oxidative stress improved in CCl4-intoxicated rats fasted for 12 h/day for 30 days, as evidenced in significant increase (p < 0.05) in total protein, globulin, immunoglobulin M (IgM) and IgG levels, and total antioxidant capacity. In contrast, significant decrease (p < 0.05) in blood glucose, total cholesterol, low-density lipoprotein-cholesterol, alanine aminotransferase, C-reactive protein, and malondialdehyde levels were observed. Compared with CCl4-intoxicated rats, significant differences in the albumin, triacylglycerol, high-density lipoprotein-cholesterol, very low-density lipoprotein-cholesterol, cardiovascular risk factor, calcium and magnesium levels were not detected.
The results of the present study showed that fasting improved metabolism, immunity, and oxidative stress in CCl4-intoxicated rats. Thus, fasting during Ramadan is safe for patients with hepatic disorders, as the prophet Mohammed (S) said "Keep the fast, keep your health".
Effects on postnatal development of Swiss albino mice exposed to nickel (Ni2+) ions as nickel chloride haxahydrate (NiCl2·6H2O) during the gestation periods were evaluated in this study. Administration of Ni to pregnant females by gavage (46.125, 92.25, and 184.5 mg Ni/kg body weight (b.w.)) at doses below median lethal dose during 0–5 (preimplantation period), 6–13 (organogenetic period), and 14–18 days (fetal period) postconception. The dams were allowed to deliver and raise their pups. Significant (p < 0.05) decrease in litter size was observed after 184.5 mg Ni/kg b.w. during the three gestation periods particularly from preimplantation period as compared to organogenetic and fetal periods in comparison with the control group. Exposure to 184.5 mg Ni/kg b.w. during fetal period revealed higher mortality as compared to organogenetic period. Exposure to 184.5 mg Ni/kg b.w. increased the eye, limb, and tail anomalies during organogenetic period. Gestation index from preimplantation period was low at all the doses. Live birth index decreased during preimplantation and organogenetic periods after 184.5 mg Ni/kg b.w. The viability and weanling of pups decreased during all periods after 92.25 and 184.5 mg Ni/kg b.w. doses. A dose-dependent highly significant (p < 0.01) decrease in the body weight of offspring from day 0 to 6 weeks of age at all the doses during different gestation periods were observed. Maximum body weight decrease was observed in offspring from organogenetic period. This study concludes that young ones are vulnerable during different gestational and lactation period which indicates that Ni ingested by mothers constitutes a great threat to the progeny.
Doxorubicin (DOX) is used in the treatment of cancer. However, cardiotoxicity is its major dose-limiting factor. Mechanism of DOX–cardiac toxicity is not completely elucidated. The aim of the current study was to explore whether the addition of subeffective dose of curcumin (100 mg/kg) to nebivolol would produce a better impact in treating DOX-induced cardiac toxicity in comparison with monotherapy.
Male rats were used and subdivided into seven groups. Cardiac toxicity was induced in 6 groups by intraperitoneal injection of DOX over 23 days; of the six groups, five groups were treated with curcumin (100 and 200 mg/kg), nebivolol (1 and 2 mg/kg), and their combination; the sixth group was the control group used for comparison.
Oral administration of curcumin and/or nebivolol attenuated DOX cardiotoxicity as manifested by increasing survival rate, improvement in body weight, heart index, and ECG parameters, increase in ventricular isoprenaline responses, and improvement in cardiac enzymes, oxidative stress, apoptosis, and histopathological picture. The addition of the current low subeffective dose of curcumin to nebivolol ameliorated DOX cardiac toxicity to a much greater extent than monotherapy showing better antioxidant and antiapoptotic effects versus the per se effect of nebivolol. Therefore, the current study encourages adding low dose of curcumin to potentiate the effect of nebivolol in the clinical management of cardiac toxicity improving the patients’ quality of life if proper clinical safety data are available.
Ferric nitrilotriacetate (Fe-NTA) induces tissue necrosis as a result of lipid peroxidation (LPO) and oxidative damage that leads to high incidence of renal carcinomas. The present study was undertaken to evaluate the effect of diallyl sulphide (DAS) against Fe-NTA-induced nephrotoxicity. A total of 30 healthy male rats were randomly divided into 5 groups of 6 rats each: (1) control, (2) DAS (200 mg kg–1), (3) Fe-NTA (9 g Fe kg–1), (4) DAS (100 mg kg–1) + Fe-NTA (9 mg Fe kg–1) and (5) DAS (200 mg kg–1) + Fe-NTA (9 mg Fe kg–1). Fe-NTA + DAS-treated groups were given DAS for a period of 1 week before Fe-NTA administration. The intraperitoneal administration of Fe-NTA enhanced blood urea nitrogen and creatinine levels with reduction in levels of antioxidant enzymes. However, significant restoration of depleted renal glutathione and its dependent enzymes (glutathione reductase and glutathione-S-transferase) was observed in DAS pretreated groups. DAS also attenuated Fe-NTA-induced increase in LPO, hydrogen peroxide generation and protein carbonyl formation (p < 0.05). The results indicate that DAS may be beneficial in ameliorating the Fe-NTA-induced renal oxidative damage in rats.
Parkinson’s disease (PD) is a common neurodegenerative disorder in middle-aged and elderly people. This study aimed to elucidate the role of mesenchymal stem cells (MSCs) in management of PD in ovariectomized rat model. MSCs were excised from adipose tissue of both the omentum and the inguinal fat pad of male rats, grown, and propagated in culture; then characterized morphologically; and by the detection of surface markers gene expression. In this study, 40 ovariectomized animals were classified into 5 groups; group 1 was ovariectomized control, groups 2 to 5 were subcutaneously administered with rotenone for 14 days after 1 month of ovariectomy for induction of PD. Group 2 was left untreated; groups 3, 4, and 5 were treated with Sinemet®, Cerebrolysin®, and a single dose of adipose tissue-derived MSCs (ADMSCs), respectively. Y-chromosome gene (sry) was assessed by polymerase chain reaction (PCR) in brain tissue of the female rats. Serum transforming growth factor β (TGF-β), monocyte chemoattractant protein 1 (MCP-1), and brain-derived neurotrophic factor (BDNF) levels were assayed using enzyme-linked immunosorbent assay technique. Brain dopamine level was assayed fluorometrically, while brain tyrosine hydroxylase (TH) gene expression was detected by semiquantitative real-time PCR. The PD group showed significant increase in serum TGF-β and MCP-1 levels associated with significant decrease in serum BDNF, brain dopamine, and brain TH gene expression levels. In contrast, all treatments produce significant decrease in serum TGF-β and MCP-1 levels in concomitant with significant increase in serum BDNF, brain dopamine, and brain TH gene expression levels. In conclusion, the observed improvements in the studied biomarkers due to ADMSCs infusion might be attributed to their immunomodulatory, anti-inflammatory, and neurotrophic effects.
Polybrominated diphenyl ether (PBDE) levels in children and teenagers were higher than those of the adults and the highest levels were found in infants and toddlers. 2,2',3,3',4,4',5,5',6,6'-Decabrominated diphenyl ether (BDE-209) readily crosses the placental barrier and produces toxicity in the developing fetus, particularly to the developing brain.
This present study aims to investigate the potential effects of prenatal BDE-209 exposure on regulation of neurogenesis and learning function in an experimental rat model.
Pregnant rats received BDE-209 (10, 30, or 50 mg kg–1 day–1) or vehicle (arachis oil) through gastric gavage from gestation day 1 to 14 (n = 10 per group). The embryonic hippocampal neural stem cells (NSCs) from five pregnant rats in each group were collected on day 14 and cultured in vitro to determine the cell viability, apoptosis, and differentiation of NSCs using cell counting kit 8 assay, flow cytometry, and immunofluorescence staining, respectively. In total, 20 male offspring on postnatal day 25 from each group were chosen to evaluate learning ability using a Morris water navigation task assay.
The data showed that prenatal exposure to BDE-209 decreased cell viability and differentiation of NSCs but promoted apoptosis in a dose-dependent manner. Prenatal BDE-209 exposure also impaired rat-learning acquisition in a dose-dependent manner.
Prenatal BDE-209 exposure impairs rat-learning acquisition, possibly by affecting neurogenesis in the hippocampus during embryonic development.
This in vitro study was designed to investigate the molecular mechanisms of paraquat-induced damage using cultured human fetal lung fibroblasts (MRC-5 cells), in order to promote the development of improved therapies for paraquat poisoning. Paraquat’s effects on proliferation were examined by flow cytometry, on viscoelasticity by the micropipette aspiration technique, and on connective tissue growth factor (CTGF) expression by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Paraquat was found to significantly reduce the proliferation index of MRC-5 cells in a concentration-dependent manner (p < 0.05) and to significantly impair the viscoelastic properties in a time-independent manner (p < 0.05). Exposure to paraquat led to a significant and time-dependent increase in CTGF expression (p < 0.05) and induced changes in the morphology and biomechanical characteristics of the MRC-5 cells. These findings not only provide novel insights into the mechanisms of paraquat-induced lung fibrosis but may represent useful targets of improved molecular-based therapies for paraquat poisoning.
The aim of this prospective study was to establish the cord blood interleukin 1β (IL-1β) levels and asphyxia enzymes in term newborns and their relationship between delivery modes. We investigated whether cord blood level of IL-1β could be used as a reliable marker for detecting hypoxic stress and to determine the optimal cut-off level for IL-1β.
The study was designed prospectively. Cord blood samples were obtained at the time of delivery from 75 noninfected full-term neonates for the purpose of measuring cord blood levels of IL-1β. Women were classified into three groups according to the mode of delivery (20 vaginal delivery, 29 urgent caesarean section (with foetal distress) and 26 elective caesarean section). All cases were followed-up by hospitalization. Umbilical cord sampling was carried out for IL-1β, umbilical artery gas parameters and other asphyxia enzymes at the time of delivery. Cord blood IL-1β was measured by enzyme-linked immunosorbent assay. The perinatal outcomes of the cases were recorded after birth. Demographic characteristics, neonatal outcomes and laboratory findings were compared in all the three groups.
IL-1β levels showed statistically significant difference between groups (p < 0.01). The relationship was found between IL-1β cord blood levels and the mode of delivery. IL-1β levels of urgent caesarean section group were significantly higher than elective caesarean section and normal delivery group (p:0.001 and p:0.001, respectively). Normal delivery levels were significantly higher than the elective caesarean group (p:0.001).
Urgent section (foetal distress) and vaginal delivery (labour) were each associated with elevated IL-1β cord blood levels in noninfected full-term neonates, while only elective caesarean section was associated with decreased IL-1β levels. For the evaluation of newborns at high risk for perinatal hypoxic stress, cord blood IL-1β levels may lead the way. On the other hand, the mode of delivery may be associated with the effects on the immune system. Further investigations with larger patient groups are required to confirm our results.
Sinapic acid (SA) is a naturally occurring phenolic acid found in various herbal plants which is attributed with numerous pharmacological properties. This study was aimed to investigate the chemopreventive effect of SA on 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Rats were treated with DMH injections (20 mg kg–1 bodyweight (b.w.) subcutaneously once a week for the first 4 consecutive weeks and SA (20, 40 and 80 mg kg–1 b.w.) post orally for 16 weeks. At the end of the 16-week experimental period, all the rats were killed, and the tissues were evaluated biochemically. Our results reveal that DMH alone treatment decreased the levels/activities of lipid peroxidation by-products such as thiobarbituric acid reactive substances, conjugated dienes and antioxidants such as superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and reduced glutathione in the intestine and colonic tissues which were reversed on supplementation with SA. Moreover, the activities of drug-metabolizing enzymes of phase I (cytochrome P450 and P4502E1) were enhanced and those of phase II (glutathione-S-transferase, DT-diaphorase and uridine diphosphate glucuronosyl transferase) were diminished in the liver and colonic mucosa of DMH alone-treated rats and were reversed on supplementation with SA. All the above changes were supported by the histopathological observations of the rat liver and colon. These findings suggest that SA at the dose of 40 mg kg–1 b.w. was the most effective dose against DMH-induced colon carcinogenesis, and thus, SA could be used as a potential chemopreventive agent.
The present investigation deals with the antimetastatic role of luteolin (LUT) by inhibiting matrix metalloproteinase (MMP)-9 and -2 in azoxymethane (AOM)-induced colon carcinogenesis in Balb/C mice. Animals received AOM at a dosage of 15 mg/kg body weight intraperitoneally once a week for 3 weeks. AOM-induced mice was treated with LUT (1.2 mg of LUT/kg body weight/day orally). After the experimental period, the tumor markers such as -glutamyl transferase (GGT), 5' nucleotidase (5'ND), cathepsin-D (Cat-D), and carcinoembroyonic antigen (CEA) were elevated upon induction with AOM. Subsequent treatment with LUT results in the reduction of the tumor markers was recorded. The expressions of MMP-9 and MMP-2 were analyzed by reverse transcription–polymerase chain reaction (RT-PCR) and immunofluorescence methods. The expressions of MMP-9 and MMP-2 were increased during AOM induction and upon treatment with LUT reduced the expressions. RT-PCR analysis of tissue inhibitor of matrix metalloproteinase (TIMP)-2 was limited during AOM-induced colorectal cancer (CRC). Supplementation of LUT increased the expression of TIMP-2. To conclude, LUT acts as an antimetastatic agent by suppressing MMP-9 and MMP-2 productions and upregulating TIMP-2 expression, thereby suggesting that LUT can be a chemotherapeutic agent against CRC.
The toxic effects of x-ray radiation on eye development was measured using zebrafish as a model organism. Zebrafish embryos at 8 h post-fertilization (hpf) were irradiated using X-rays at doses of 1, 2, 4, and 8 Gy. At 24 and 48 hpf, x-ray radiation induced a significant increase in reactive oxygen species (ROS) content and cell apoptotic signals. Both of these increases were dose dependent and there were significant positive relationships between them at 24 hpf. At 48 and 72 hpf, the increase of ROS concentration can be eliminated by increasing activities of superoxide dismutase and catalase. Although the ROS generated by x-ray radiation caused a significant increase in cell apoptosis at 24 and 48 hpf, the cellular layers of the retina and lens formation in the irradiated groups were not significantly disrupted at 144 hpf compared with the control group, with the exception of a heterogeneous distribution of the cells in inner nuclear cell layer and a significant decrease in the diameters of whole eyes after 8 Gy irradiation. X-Ray radiation at later stages of gastrulation may not cause distinct optic complications; however, there is still a risk of microophthalmia at high doses of irradiation.
The mitochondrial oxidative phosphorylation system was studied in liver and heart homogenates after treatment of rats with benznidazole. The drug was given by oral gavage to adult female Wistar rats for 9 consecutive days (100 mg benznidazole/kg body weight as a daily dose). The mitochondrial state 4 and state 3 respiration rates, respiratory control, efficiency of oxidative phosphorylation (ADP/O), and ATPsynthase activity were assayed. The results showed that according to all these parameters, the mitochondria in cardiac homogenates were not affected in the rats treated with benznidazole. By contrast, mitochondria in the liver homogenates of drug-treated rats were altered, showing decreased respiratory control and a lower coefficient of ADP/O as a result of an increase in the state 4 respiration rate. These data indicate the possibility of production of an uncoupling factor leading to increased proton leakage through the inner mitochondrial membrane as a result of a 9-day treatment of rats with benzonidazole. The obtained experimental data might at least partly explain the nature of benznidazole toxicity in the liver treated with benznidazole.
The main purpose of this study was to assess the role of S100B protein, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP) in the evaluation of hypoxic brain injury in acute carbon monoxide (CO)-poisoned patients. This cross-sectional study was conducted among the patients with acute CO poisoning who referred to the emergency department in a 1-year period. Serum levels of S100B protein, NSE, and GFAP were determined on admission. A total of 55 CO-poisoned patients (mean age ± standard deviation, 45 ± 20.3 years; 60% women) were included in the study. The control group consisted of 25 healthy adults. The patients were divided into two groups according to whether they were conscious or unconscious. The serum levels of S100B, NSE, and GFAP were higher in patients than that in the control group. There was no significant difference between unconscious and conscious patients with respect to these markers. There was a statistically significant difference between the conscious and unconscious patients and the control group in terms of S100B and NSE levels. There was also a statistically significant difference between the unconscious patients and the control group in terms of GFAP levels. Increased serum S100B, NSE, and GFAP levels are associated with acute CO poisoning. These biomarkers can be useful in assessing the clinical status of patients with CO poisoning.
Puerarin, a potent free radicals scavenger, has been demonstrated to have protective efficacy in oxidative damage induced by nephrotoxins. In the present study, the attenuating effect of puerarin (PU) on lead (Pb)-induced apoptosis and oxidative stress was investigated in cultured primary rat proximal tubular (rPT) cells. Results showed that exposure to 0.5 µM Pb induced a decrease in cell viability accompanied with obvious cellular morphological alterations and caused an increase in apoptotic rate and apoptotic morphological changes. Simultaneously, depletion of mitochondrial membrane potential () and intracellular glutathione (GSH); elevation of caspase-3 activity, intracellular reactive oxygen species, and malondialdehyde levels; and inhibition of GSH peroxidase (GSH-Px) activity were revealed in the cells exposed to Pb alone. However, simultaneous supplementation with PU (50 and 100 µM) protected rPT cells from Pb-induced cytotoxicity through inhibiting apoptosis, attenuating lipid peroxidation, renewing mitochondrial function, and elevating the intracellular antioxidants (nonenzymatic and enzymic) levels. In conclusion, these findings suggested that PU, as a widely distributed dietary antioxidant, contributes potentially to inhibition of Pb-induced cytotoxicity in rPT cells.
Zebrafish are commonly used as experimental animals in otolaryngology studies. However, the behavioral characteristics of these fish are not well known, especially those related to the vestibular system. The goal of this study was to evaluate behavioral changes in zebrafish due to toxicity in the balance system.
Zebrafish were exposed to 1000 μM cisplatin for 6 h. We, then, periodically monitored swimming depth, total swimming distance, peak swimming velocity, and mean swimming velocity of the fish for approximately 21 days.
Total swimming distance (p < 0.0001), peak swimming velocity (p = 0.0063), and mean swimming velocity (p < 0.0001) in the cisplatin-administered group were significantly decreased when compared with control fish.
Our findings demonstrate that cisplatin can alter the locomotion behavior of zebrafish.
The purpose of this study was to evaluate the patients with acute amitriptyline poisoning and investigate predictive factors for the development of life-threatening complications.
Demographics, clinical, laboratory, and electrocardiographic (ECG) findings of 250 patients were evaluated retrospectively. Predictive parameters for the development of serious complications were studied.
Median age of patients was 14.6 years, of which, 70% of patients were female and 66% were in pediatric age group. The most common pathological clinical finding and laboratory abnormality were alteration of consciousness and hyponatremia. The rate of convulsive seizure, arrhythmia, and respiratory depression were 17 (6.8%), 16 (6.4%), and 11 (4.4%), respectively. These complications were more seen in pediatric patients than adults (15.8% and 1.2%). The incidence of hyponatremia was more in pediatric patients and severe poisoning groups (38.8 and 53.4%, respectively). The levels of amitriptyline and nortriptyline were significantly higher in the group with complications than the group without complications (p < 0.05). All adult patients were discharged with good prognosis. In pediatric age group, one patient was discharged with severe neurological sequelae and one patient died. QRS duration >100 ms, long corrected QT duration interval, and low Glasgow Coma Score (GCS) at admission were identified as independent risk factors for the development of life-threatening complications (odds ratio: 69.4, 1.9, and 1383, respectively; p < 0.05).
Amitriptyline poisoning may be associated with life-threatening complications, especially in pediatric age group and in patients with hyponatremia. Low GCS, presence of hyponatremia, high serum drug levels, and pathological ECG findings on admission may be helpful in predicting the development of complications and poor prognosis.
When lidocaine is locally delivered into the inner ear, it rapidly paralyzes the peripheral vestibular afferent neurons and induces unilateral vestibular loss. The goals of this study were to explore the possibility of developing intratympanic injection (IT) of lidocaine as a modality for treating acute vertigo. To evaluate the minimum concentration required, latent time, action duration, and possibility of lidocaine IT readministration to the vestibular system, we compared the development of horizontal nystagmus after IT of 2, 4, 6, 8, and 10% lidocaine solutions in rats. To identify the induction of vestibular compensation, c-Fos-like protein expression was observed in the vestibular nucleus. Results of our investigation showed that lidocaine IT concentrations greater than 4% induced vestibular hyporeflexia in the injected ear. In order to induce hyporeflexia 4 and 6% lidocaine solutions could also be repeatedly injected. Regardless of concentration, effects of the lidocaine IT dissipated gradually over time. Our findings could be used to develop novel methods for symptom control in vestibular disorder patients.
Toxicology in Malaysia has experienced rapid development and made great progress in education and research in conjunction with economic development in Malaysia over the past two decades.
The main objectives of this study were to analyse the research originating from Malaysia and published in toxicology journals and to examine the authorship pattern and the citations retrieved from the Scopus database.
Data from 1 January 2003 till 31 December 2012 were searched for documents with specific words in the toxicology field as a ‘source title’ and Malaysia as an affiliation country. Research productivity was evaluated based on a methodology we developed and used in other bibliometric studies by analysing: (a) total and trends of contributions in toxicology fields between 2003 and 2012; (b) Malaysian authorship pattern and productivity; (c) collaboration patterns; (d) journals in which Malaysian researchers publish; (e) the classification of journals to Institute for Scientific Information (ISI) or non-ISI; (f) impact factors (IFs) of all publications; and (g) citations received by the publications.
In total, 290 documents were retrieved from 55 international peer-reviewed toxicology journals. The quantity of publication increased by around 10-fold from 2003 to 2012. The h-index of the retrieved documents was 20. Of the 55 journal titles, 42 (76.4%) have their IF listed in the journal citation reports 2012. Forty-two documents (14.5%) were published in journals that had no official IF. The total number of citations, at the time of manuscript writing (5 August 2013), was 1707, with a median (interquartile range) of 3 (0–7). Malaysia collaborated mostly with countries in the Asia-Pacific regions (18.3%), especially India and Japan, followed by the Middle East and Africa (10.0%), especially Palestine and Yemen.
The present data show a promising rise and a good start for toxicology research activity in Malaysia. The sharing of relevant research questions by developed and developing countries can lead to research opportunities in the field of toxicology.
Drug-related skin disorders may occur in many different ways. Despite pigmentary changes being less important for morbidity, these changes precipitate depressed mood and reduce self-confidence. Testosterone is a steroid hormone from the androgen group and primarily used for the treatment of hypogonadism in males. Testosterone replacement can cause skin problems like acne, hair loss, redness, pain, or infection at the injection site.
The study was conducted on a 49-year-old man with adult onset idiopathic hypogonadotropic hypogonadism, which is an acquired form of isolated gonadotropin-releasing hormone deficiency. He was presented with lack of energy and decreased sexual function 10 years ago and was given an oil-based injectable blend of four esterized testosterone compounds as hormone replacement treatment in a urology polyclinic. He was referred to our polyclinic by endocrinologist because of progressive hyperpigmentation marked on his face and oral mucosa. In the present study, we report the first testosterone therapy-related facial and oral mucosal hyperpigmentation and acanthosis nigricans in the same patient.
Although advanced diagnostic and treatment methods are available, congenital heart disease (CHD) holds an important place among the causes of death within the first year of age. Therefore, several prognostic factors are needed for diagnosis and monitoring of these patients. In this study, which includes 66 CHD patients and 38 healthy control children, serum cardiac troponin-I (cTnI), high-sensitivity C-reactive protein (Hs-CRP), and N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) levels were analyzed for their prognostics values. The patient groups were categorized and then evaluated as cyanotic (n = 16), acyanotic (n = 50), symptomatic (n = 23), asymptomatic (n = 43), and isolated ventricular septal defect (VSD)-isolated atrial septal defect (ASD) groups. Cyanotic group was statistically compared with acyanotic group, symptomatic group with asymptomatic group, and VSD group with ASD group. Between the cyanotic, acyanotic, and control groups; between symptomatic and asymptomatic groups; and between the VSD and ASD groups, significant difference was not showed for age (p > 0.05). NT-proBNP was found to be significantly higher in the cyanotic group than acyanotic and control group, in the symptomatic group than asymptomatic group; and in the patient group than healthy control group (p < 0.05). Between the groups of VSD and ASD, significant difference was not showed (p > 0.05). The same comparison results for TnI and Hs-CRP were not significant (p > 0.05). TnI and Hs-CRP were only found significantly higher in the patient group than healthy control group (p < 0.05). Eventually, we think that NT-proBNP, Hs-CRP, and TnI might be used for clinical management and estimation of outcome of these disorders in the future and these also might be able to modify existing strategies, but much more studies are needed.
The aim of this study was to assess the potential subacute toxicity of zinc oxide (ZnO) nanoparticles (NPs) in Wistar rats in comparison with reference toxicant, zinc chloride (ZnCl2), of a non-nanoparticulate form. We therefore studied the relationships between zinc (Zn) accumulation, liver and kidney trace element levels, and plasmatic biochemical parameters. Rats in all groups were treated by intraperitoneal injection of ZnO NPs and/or ZnCl2 solution (25 mg/kg) every other day for 10 days. The contents of trace element in the liver and kidney were slightly modulated after ZnO NPs and/or ZnCl2 solution exposure. The same treatment increased the aspartate aminotransferase activity and uric acid concentration. However, ZnO NPs or ZnCl2 solution decreased the creatinine levels, whereas the combined intake of ZnO NPs and ZnCl2 decreased the glucose concentration. Interestingly, the analysis of the lyophilized powder of liver using the x-ray diffractometer showed the degradation of ZnO NPs in ZnO-treated group, instead there is a lack of NPs ZnO biosynthesis from the ZnCl2 solution injected in rats. These investigations suggest that combined injection of ZnO NPs and ZnCl2 solution has a possible toxic effect in rats. This effect could be related to Zn2+ ion release and accumulation of this element in organs. Our findings provide crucial information that ZnO appeared to be absorbed in the organs in an ionic form rather than in a particulate form.
Acetaminophen is at present one of the most commonly used analgesics and antipyretics. Recent evidence has suggested that oxidative stress is involved in the mechanism of acetaminophen intoxication. Paraoxonase-1 (PON1) plays an important role as an endogenous free-radical scavenging molecule. The aim of this study was to evaluate the influence of serum PON1 activity and oxidative stress in patients with acetaminophen intoxication.
A total of 20 patients with acetaminophen intoxication and 25 healthy controls were enrolled. Serum total antioxidant capacity (TAC), lipid hydroperoxide (LOOH) levels, and paraoxonase and arylesterase activities were measured spectrophotometrically.
The serum TAC levels and the paraoxonase and arylesterase activities were significantly lower in patients with acetaminophen intoxication compared with controls (all, p < 0.001), while the serum LOOH levels were significantly higher (p < 0.001).
Our results suggest that decreased PON1 activity seems to be associated with increased oxidative stress in patients with acetaminophen intoxication. Measuring serum PON1 activity may be useful in assessing the development of toxicity risk in acetaminophen toxicity. It would be useful to recommend vitamins with antioxidant effects such as vitamins C and E along with medical treatments.
Formaldehyde (FA) is one of the most widely used chemical compounds in industrial field. It is described as toxic, particularly to the nervous system, the urogenital system, and the respiratory tracts. In this study, we determined the effects of acute oral exposure to FA in rabbit brain tissue. A total of 16 rabbits were selected and divided into 2 groups: formaldehyde group (group F) and control group (group C). FA was administered to group F at a rate of 40 mg/kg/day via a nasogastric tube for 5 days. Saline was similarly administered to the eight controls. All the animals were euthanized after 5 days of exposure, and brain tissue samples were collected in 10% neutral formalin and embedded in paraffin. To investigate the effects of FA on the apoptotic process, we examined active caspase-3, Bax, and Bcl-2 immunohistochemical expression and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate –biotin nick-end labeling (TUNEL) reactivity in the rabbit brains. In addition, glial fibrillary acidic protein (GFAP) was biochemically assessed in brain tissue samples for neurotoxicity. We found that FA treatment caused a significant decrease in Bcl-2 expression and an increase in active caspase-3 and Bax expressions as well as an increase in the number of TUNEL-positive apoptotic cells. The GFAP level was found to be significantly higher in group F. In conclusion, acute oral exposure to FA caused DNA damage, apoptosis, and neuronal injury in the rabbit brains.
Over the past decade, emerging drugs of abuse and synthetic derivatives of more traditional agents have flooded the market. While Europe was the first to experience a surge in the use of drugs such as synthetic cathinones and cannabinoids, poison centers throughout the United States have seen a dramatic rise in calls related to these new designer drugs of abuse. In the majority of cases, care is largely supportive but significant medical and traumatic complications may occur. Providers must be aware of the ever-changing trends in abuse, so that they may optimally care for poisoned patients.
In this study, the removal of methylene green (MG) from aqueous solution based on two new adsorbents including silver nanoparticles and zinc oxide nanorods loaded on activated carbon (Ag-NP-AC and ZnO-NR-AC, respectively) has been carried out. The dependency of removal process to variables such as contact time, pH, amount of adsorbents, and initial MG concentration were examined and optimized. It was found that the maximum MG removal percentage was achieved at pH=7.0 following stirring at 400rmin–1 for 7 and 6min for Ag-NP-AC and ZnO-NR-AC, respectively. Equilibrium data were well fitted with the Langmuir model having maximum adsorption capacity of 166.7 and 200mgg–1 for Ag-NP-AC and ZnO-NR-AC, respectively. Thermodynamic parameters of MG adsorption on Ag-NP-AC such as enthalpy and entropy changes, activation energy, sticking probability, and Gibbs free energy changes show the spontaneous and endothermic nature of the removal process. Among different conventional kinetic models, the pseudo second-order kinetics in addition to particle diffusion mechanism is the best and efficient model for the prediction and explanation of experimental data of MG adsorption onto both adsorbents.
Endothelin-1 has been shown to increase neuronal activity and glutaminergic synaptic transmission by endothelin-A receptors (ETAR) in the nucleus tractus solitarius neurons that play an important role in epileptic seizures. Therefore, BQ-123 as an ETAR antagonist might attenuate neuronal excitability and glutaminergic synaptic transmission. The main purpose of the present study is to investigate the protective effect of acute BQ-123 treatment against pentylenetetrazole (PTZ)-induced tonic–clonic seizures. Wistar albino rats were divided into three groups: control, PTZ, and PTZ + BQ-123 groups. BQ-123 (3 mg/kg, intravenously) was administered for 15 min before injecting with PTZ (50 mg/kg, intraperitoneally). We determined a delay resulting from BQ-123 in "duration of the seizure onset." "Number of rats with major seizure" also decreased according to scoring with video camera in PTZ + BQ-123 group. In BQ-123-treated group, there were eight rats without a major seizure, but only one rat had a delayed major seizure. The brain tissue glutathione peroxidase activity was significantly decreased in the PTZ and PTZ + BQ-123 groups. According to the results of the control group, there was a significant increase in the protein carbonyl levels of the PTZ group and a significant increase in the nitric oxide levels of the PTZ + BQ-123 group. Histological examination showed an increase in the number of neuronal hyperchromatic nucleus especially in hippocampal gyrus dentatus region of BQ-123-treated group. We concluded that BQ-123 impeded the formation and spread of seizure to a great degree. The beneficial effects of BQ-123 were comparatively supported with biochemical parameters and histological examinations.
The aim of this study was to evaluate, the cytotoxicity of orthodontic composites in vitro as a function of degree of conversion (DC) and the light curing units (LCU) employed on mouse fibroblast (L929).
Cured samples of the composites Light bond (Reliance Orthodontic Products, Itasca, Illinois, USA), Ortho bracket paste (Bisco, Schaumburg, Illinois, USA), Opal bond MV (OPAL, South Jordan, Utah, USA), and Transbond XT (3M, Monrovia, California, USA) were prepared. Polymerization was performed with two LCUs: VALO Ortho (Ultradent, South Jordan, Utah, USA) is a third-generation LCU and Elipar S10 (3M, USA) is a second-generation LCU. Four samples were immersed in cell culture medium to obtain composite extracts. After incubation of L929 cell cultures with the extracts obtained, cytotoxicity was determined using the methyl tetrazolium test. Fourier transform infrared spectroscopy (FTIR) was used to evaluate DC for five samples. A multivariate analysis of variance (ANOVA), two-way ANOVA, and Tukey’s honestly significant difference test were utilized for statistical analyses.
Cytotoxicity and DC of all tested composites (p < 0.001) and the interaction between composites and LCUs (p < 0.01) were significantly different. LCUs had no significant influence on the cytotoxicity and DC of composite materials (p > 0.05). The correlations between cell viability and DC were positive for three composites but statistically insignificant.
Composites and LCUs must be matched with one another to result in satisfactory maximal biocompatibility and DC. Opal Bond plasma light-emitting diode combination was a better choice for cell viability. Three composites showed a positive correlation between cytotoxicity and DC. Therefore high-intensity LCUs can be said to efficiently affect polymerization, and so, higher DC rates may achieve higher cell viability rates.
The efficacy of methotrexate (MTX), a widely used chemotherapeutic drug, is limited by its gastrointestinal toxicity and the mechanism of which is not clear. The present study investigates the possible role of mitochondrial damage in MTX-induced enteritis. Small intestinal injury was induced in Wistar rats by the administration of 7 mg kg–1 body wt. MTX intraperitoneally for 3 consecutive days. MTX administration resulted in severe small intestinal injury and extensive damage to enterocyte mitochondria. Respiratory control ratio, the single most useful and reliable test of mitochondrial function, and 3-(4,5-dimethylthiazol-2-yll)-2,5-diphenyltetrazolium bromide reduction, a measure of cell viability were significantly reduced in all the fractions of MTX-treated rat enterocytes. A massive decrease (nearly 70%) in the activities of complexes II and IV was also observed. The results of the present study suggest that MTX-induced damage to enterocyte mitochondria may play a critical role in enteritis. MTX-induced alteration in mitochondrial structure may cause its dysfunction and decreases the activities of the electron chain complexes. MTX-induced mitochondrial damage can result in reduced adenosine triphosphate synthesis, thereby interfering with nutrient absorption and enterocyte renewal. This derangement may contribute to malabsorption of nutrients, diarrhea, and weight loss seen in patients on MTX chemotherapy.
The aim of this study was to investigate the protective effect of
Mercury, a heavy metal, is widespread and persistent in the environment and has been elucidated as a possible risk factor in cardiovascular diseases. Mercury has been reported to selectively impair the nitric oxide (NO) pathway in the vascular endothelium as a consequence of oxidative stress. Conversely, mercury per se causes endothelium-dependent vasorelaxation at lower concentration via the NO pathway. Little is known about the effects of mercury per se on other endothelial mediators. To elucidate possible mechanisms involved in this action, isometric tension was measured in aortic rings precontracted with phenylephrine (10 µM) from Wistar rats. Responses to increasing concentrations of inorganic mercuric chloride (10–12–10–5 M) were obtained in the presence and absence of endothelium. Inorganic mercury produced a biphasic response in endothelium-intact aortic rings and produced only vasoconstriction in endothelium-denuded aortic rings. To study the possible underlying mechanisms for the biphasic response of mercury, increasing concentrations of mercuric chloride (10–12–10–5 M) were used before and after NG-nitro-
Importance of the correct diagnosis in the correct early management of a scorpion stung patient by using antivenom is not emphasized, particularly when there are little evidences. A 65-year-old female was brought to our emergency department with the chief compliant of being stung by an unknown object 3 h earlier while traveling in an intercity bus. She became agitated and simultaneously experienced tachycardia, very severe generalized sweating, cold and wet extremities, bilateral diffuse crackle in the base of lungs, tachypnea, and lethargy. With the primitive diagnosis of myocardial infarction, scorpion sting was documented as the cause of this combined cholinergic and adrenergic syndrome after the scorpion was found in the patient’s bed clothes. She dramatically responded to the administration of low dose of scorpion antivenom. This case dramatically responded to the antivenom administration, especially the cholinergic and sympathetic signs, pulmonary edema, and electrocardiographic changes were fully and almost immediately recovered. Scorpion antivenom may reverse life-threatening manifestations of scorpion envenomation if used early and in appropriate patients.
This review comprehensively summarizes the effects of more than 15 mostly used pesticides on male reproductive physiology, as recent experimental and epidemiological research have indicated their alarming impact on overall human health. Mechanisms have described that pesticide exposure damages spermatozoa, alter Sertoli or Leydig cell function, both in vitro and in vivo and thus affects semen quality. But, the literature suggests a need for more intricate research in those pesticides that are defined as mutagens or carcinogens and directly affect the hypothalamic–pituitary–gonadal axis. This literature review also proposes specific solutions to overcome these health effects.
There is increasing evidence that herpes zoster (HZ) incidence rates among children and adults (aged <60 years) with a history of natural varicella are influenced primarily by the frequency of exogenous exposures, while asymptomatic endogenous reactivations help to cap the rate at approximately 550 cases/100,000 person-years when exogenous boosting becomes rare. The Antelope Valley Varicella Active Surveillance Project was funded by the Centers for Disease Control and Prevention in 1995 to monitor the effects of varicella vaccination in one of the three representative regions of the United States. The stability in the data collection and number of reporting sites under varicella surveillance from 1995–2002 and HZ surveillance during 2000–2001 and 2006–2007 contributed to the robustness of the discerned trends.
Varicella vaccination may be useful for leukemic children; however, the target population in the United States is all children. Since the varicella vaccine inoculates its recipients with live, attenuated varicella–zoster virus (VZV), clinical varicella cases have dramatically declined. Declining exogenous exposures (boosts) from children shedding natural VZV have caused waning cell-mediated immunity. Thus, the protection provided by varicella vaccination is neither lifelong nor complete. Moreover, dramatic increases in the incidence of adult shingles cases have been observed since HZ was added to the surveillance in 2000. In 2013, this topic is still debated and remains controversial in the United States.
When the costs of the booster dose for varicella and the increased shingles recurrences are included, the universal varicella vaccination program is neither effective nor cost-effective.
Adverse drug reactions (ADRs) can involve all tissues and organs, but liver injuries are considered among the most serious. A number of prospective, multicenter studies have confirmed a higher risk of ADRs in general among female subjects compared to a male cohort. Although drug-induced liver injury (DILI) is infrequently encountered, the preponderance of evidence suggests that women appear to be more susceptible than men to fulminate hepatic/acute liver failure especially in response to some anti-infective drugs and to autoimmune-like hepatitis following exposure to certain other therapeutic drugs. A number of hypotheses have been proposed to explain this sex difference in susceptibility to DILI. Collectively, these hypotheses suggest three basic sex-dependent mechanisms that include differences in various aspects of drug pharmacokinetics (PK) or pharmacodynamics following the administration of certain drugs; specific hormonal effects or interactions with immunomodulating agents or signaling molecules; and differences in the adverse response of the immune system to some drugs, reactive drug metabolites, or drug-protein adducts. At the preclinical drug safety stage, there is a need for more research on hormonal effects on drug PK and for additional research on gender differences in aberrant immune responses that may lead to idiosyncratic DILI in some female patients. Because the detection of rare but serious hepatic ADRs requires the exposure of very large patient populations, pharmacovigilance networks will continue to play a key role in the postmarketing surveillance for their detection and reporting.
During gestation and lactation, the experimental mice dams received one of the following treatments: (a) diet free of pesticide; (b) diet enriched with endosulfan (END); 30.0 µg kg–1; (c) diet free of pesticide + oral vitamin E (α-tocopherol; 200 mg kg–1 per mouse); and (d) diet enriched with END (30.0 µg kg–1) + oral vitamin E (200 mg kg–1 per mouse). At weaning, pups and dams were killed, and selected organs as well as blood samples were collected for analyses. Compared with the control results, END induced alteration in a number of biochemical and histopathological parameters either in the dams or their offspring. The ameliorative effect of vitamin E to superoxide dismutase based on the "ameliorative index (AI)" for mothers and pups was 0.84 and 0.72, respectively. The AI for malondialdehyde reached a maximum value of nearly equal to 1.0 for dams or pups. For butyryl cholinesterase, the AI was 0.90 and 0.94 for dams and pups, respectively. In conclusion, a dietary exposure during gestation and lactation to low dose of END caused significant changes in the mother but also in the weaned animals that had not been directly exposed to this pesticide. These biological and histological alterations could be reversed to a great extent by oral supplementation of vitamin E.
A sandwich enzyme-linked immunosorbent assay (ELISA) was developed to detect the venom of Indian cobra (Naja naja naja) in various tissues (brain, heart, lungs, liver, spleen, blood, kidneys, and tissue at the site of injection) of mice after cobra venom injected at different time intervals (0, 2, 4, 6, 8, and 12 h intervals up to 24 h). Whole venom antiserum or individual venom protein antiserum (14, 29, 65, 72, and 99 kDa) could recognize N. n. naja venom by Western blotting and ELISA, and antibody titer was also assayed by ELISA. Antiserum raised against cobra venom in rabbit significantly neutralized the toxicity of venom-injected mice at different time intervals after treatment. The assay could detect N. n. naja venom levels up to 2.5 ng/ml of tissue homogenate, and the venom was detected up to 24 h after venom injection. Venom was detected in brain, heart, lungs, liver, spleen, kidneys, tissue at the bite area, and blood. As observed in mice, tissue at the site of bite area showed the highest concentration of venom and the brain showed the least. Moderate amounts of venoms were found in liver, spleen, kidneys, heart, and lungs. Development of a simple, rapid, and species-specific diagnostic kit based on this ELISA technique useful to clinicians is discussed.
The present study investigated the effect of rutin, a natural flavonoid, on the expression of caspase activation recruitment domain (CARD) and pyrin domain (PYD) of apoptosis-associated speck-like protein (ASC), a mediator of inflammation, in the pancreas of rats administered with ethanol (EtOH) and high-fat diet (HFD). Pancreatitis was induced in male albino Wistar rats by administering EtOH (8–12 g/kg/day) and HFD (22% fat) for 90 days. In addition, rats also received 100 mg rutin/kg body weight orally from 31st day till the experimental period. Serum levels of cytokines, interleukin 18 (IL-18) and IL-6; activity levels of caspase-1 and myeloperoxidase (MPO); messenger RNA (mRNA) expression of tumor necrosis factor α (TNF-α), caspase-1, CARD and PYD of ASC; and histological changes in pancreas were assessed. We observed a significant elevation in serum IL-18, IL-6, caspase-1 and MPO activities, mRNA expression of PYD, TNF-α and caspase-1 in the pancreas of rats administered with EtOH and HFD. Rutin administration along with EtOH and HFD significantly upregulated the mRNA expression of CARD and downregulated PYD, caspase-1, and TNF-α expressions. Rutin supplementation was also found to reduce IL-18 and IL-6 levels; and inflammatory changes in tissue architecture were evidenced by histological observations. The anti-inflammatory activity of rutin might be due to its effect on modulating the expression of ASC complex that mediates inflammation.
In the present study, we evaluated the induced genome damage in peripheral blood lymphocytes from a sample of nurses occupationally exposed to low doses of different chemicals. A comprehensive multi-biomarker approach using cytogenetic endpoints was employed for analyzing chromosomal aberrations (CAs) and sister chromatid exchange (SCE) assay. The study included 20 nurses and 20 control subjects matched in age, gender and smoking habits. Nurses were exposed to different chemicals, such as cytostatic drugs, anaesthetics, formaldehyde and other sterilizing gases. Significant differences were found between exposure group and control group in terms of SCEs frequency (p < 0.001) but not in terms of replication index value (p = 0.845) and CAs (p = 0.236). Regression analyses indicated that the age and the exposure years did not influence the amount of the chromosomal damage among nurses. Vice versa, among controls, a positive correlation was found between the number of SCEs and age. In conclusion, our results suggest that a continuous long-term exposure to low doses of chemicals could result in increased levels of SCEs among nurses. This data emphasize the importance of biomonitoring nurses and other hospital workers handling drugs.
The mechanism of doxorubicin (DOX)-induced cardiotoxicity remains controversial. Wistar rats (n = 66) received DOX injections intraperitoneally and were randomly assigned to 2 experimental protocols: (1) rats were killed before (–24 h, n = 8) and 24 h after (+24 h, n = 8) a single dose of DOX (4 mg/kg body weight) to determine the DOX acute effect and (2) rats (n = 58) received 4 injections of DOX (4 mg/kg body weight/week) and were killed before the first injection (M0) and 1 week after each injection (M1, M2, M3, and M4) to determine the chronological effects. Animals used at M0 (n = 8) were also used at moment –24 h of acute study. Cardiac total antioxidant performance (TAP), DNA damage, and morphology analyses were carried out at each time point. Single dose of DOX was associated with increased cardiac disarrangement, necrosis, and DNA damage (strand breaks (SBs) and oxidized pyrimidines) and decreased TAP. The chronological study showed an effect of a cumulative dose on body weight (R = –0.99, p = 0.011), necrosis (R = 1.00, p = 0.004), TAP (R = 0.95, p = 0.049), and DNA SBs (R = –0.95, p = 0.049). DNA SBs damage was negatively associated with TAP (R = –0.98, p = 0.018), and necrosis (R = –0.97, p = 0.027). Our results suggest that oxidative damage is associated with acute cardiotoxicity induced by a single dose of DOX only. Increased resistance to the oxidative stress is plausible for the multiple dose of DOX. Thus, different mechanisms may be involved in acute toxicity versus chronic toxicity.
Cisplatin (CDDP) is one of the most frequently used antitumor agents, but its application is significantly limited by its hepatotoxicity. In the present study, we investigated the effects of crocin against CDDP-induced oxidative stress and apoptosis in the liver of Kunming mice. Crocin was administered to the mice once daily for 7 consecutive days at the doses of 6.25 and 12.5 mg/kg body weight orally. On day 1, a single intraperitoneal injection of CDDP was given at the dose of 10 mg/kg body weight. Crocin treatment significantly improved CDDP-induced hepatic damage as indicated by serum aspartate aminotransferase and alanine aminotransferase levels. Crocin relieved CDDP-induced oxidative stress by reducing malondialdehyde level and recovering the levels of glutathione and antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. In addition, liver histopathology indicated that crocin alleviated CDDP-induced focal necrosis. Immunohistochemical staining and Western blot analysis showed that crocin significantly decreased the levels of phospho-p38 mitogen-activated protein kinase (MAPK), tumor protein 53 (p53), and cleaved caspase-3. Taken together, our data suggest that crocin provides protective effects against CDDP-induced hepatoxicity by attenuating oxidative stress and inhibiting the activation of p38 MAPK, p53, and caspase-3.
The effect of dentin contacting materials on three-dimensional cultures of pulp-derived cells was evaluated in a dentin barrier test device using erbium-doped yttrium, aluminum, and garnet (Er:YAG) laser-treated dentin.
The test materials (iBond®, G-Bond™, and Vitrebond™) were applied on laser-treated or untreated dentin discs. After 24 h of exposure with perfusion of the test chamber, cell survival was evaluated by enzyme activity and related to a nontoxic control material. The mean values of control tissues were set to represent 100% viability. Data were analyzed using Kruskal–Wallis and Mann–Whitney U test.
Vitrebond was the most toxic material for both laser-treated and untreated dentin. On untreated dentin, G-bond was cytotoxic to the pulp-derived cells (p < 0.05), and iBond was similar to the negative control group (p > 0.05). However, G-Bond and iBond were not cytotoxic when they were applied to Er:YAG laser-treated dentin (p > 0.05).
Er:YAG laser treatment of dentin may protect the pulp cells from toxic substances of dentin contacting restorative materials; however, this effect is material related. Taking into consideration the limitations of this in vitro study, the Er:YAG laser treatment of dentin before restoration might be an option for decreasing the cytotoxic effects of the dental materials. Further research is required for clinical applications.
Aminophenol isomers (2-, 3-, and 4-aminophenols) are typically classified as industrial pollutants with genotoxic and mutagenic effects due to their easy penetration through the skin and membranes of human, animals, and plants. In the present study, a simple and efficient ultrasound-assisted emulsification microextraction procedure coupled with high-performance liquid chromatography with ultraviolet detector was developed for preconcentration and determination of these compounds in human fluid and environmental water samples. Effective parameters (such as type and volume of extraction solvent, pH and ionic strength of sample, and ultrasonication and centrifuging time) were investigated and optimized. Under optimum conditions (including sample volume: 5 mL; extraction solvent: chloroform, 80 µL; pH: 6.5; without salt addition; ultrasonication: 3.5 min; and centrifuging time: 3 min, 5000 rpm min–1), the enrichment factors and limits of detection were ranged from 42 to 51 and 0.028 to 0.112 µg mL–1, respectively. Once optimized, analytical performance of the method was studied in terms of linearity (0.085–157 µg mL–1, r 2 > 0.998), accuracy (recovery = 88.6– 101.7%), and precision (repeatability: intraday precision < 3.98%, and interday precision < 5.12%). Finally, applicability of the method was evaluated by the extraction and determination of these compounds in human urine, hair dye, and real water samples.
Galacto-oligosaccharide (GOS) is a naturally occurring prebiotic that beneficially affects the host by selectively stimulating growth and/or activity of one or a limited number of colon bacteria to improve host health. A novel GOS was administered by gavage to male and female Sprague Dawley rats at 0, 500, 1000, and 2000 mg/kg/day for 10 weeks. In males, administration of GOS was initiated prior to mating and continued for 91 days. Females received GOS beginning 2 weeks prior to mating through day 20 of lactation. Parents were observed daily, and body weight (BW) and feed consumption were measured. Vaginal smears, mating behavior, and observation of delivery/lactation were evaluated in parents. Effects on the reproductive function of parents including gonad function, estrous cycle, mating performance, fertility, delivery and lactation, and effects on the growth and development of pups were examined. No deaths occurred, and no general toxicological effects or abnormal reproductive functions were observed in any dose group. Pups were observed at birth and the following measurements were undertaken: BW, external differentiations, sensory functions, and reflex reactions during lactation and just prior to necropsy. No external malformations or differences in the number of pups, in the sex ratio, or BW at birth occurred in any dose group. Growth and development of pups were normal. The No Observed Effect Level for reproductive function of male and female parent animals and for the growth and development of their offspring was at least 2000 mg/kg/day.
HeLa cells were exposed to formaldehyde and its metabolic derivatives, methanol, formic acid, and acetaldehyde, to investigate that the toxicity of formaldehyde is not caused by the chemical group. After 1 h of treatment with formaldehyde, mitochondrial assays showed that low concentrations (e.g. 10 μmol/L) of formaldehyde promoted growth of the HeLa cells, while higher concentrations (e.g. ≥62.5 μmol/L) inhibited cell growth; while all four chemicals at a concentration of 125 μmol/L affected cell growth, formaldehyde affected the largest. Reactive oxygen species concentration increased with the concentration of the exposure chemical. The endogenous formaldehyde content increased the most in the formaldehyde group, but in other three groups, it did not increase as the exposure concentration increased. Expression of dehydrogenase (formaldehyde dehydrogenase (FDH)) in the formaldehyde (10.40) and methanol (10.60) groups increased significantly compared with the control (1), while it was similar to the control in formic acid (0.90) and acetaldehyde (1.10) groups. Our results suggest that formaldehyde could affect cell activity and even enter cells. Exposure to formaldehyde changes the endogenous formaldehyde concentration in cells within 24 h, and this induces expression of FDH for formaldehyde degradation to maintain the formaldehyde balance. The toxicity of formaldehyde is not caused by the carbon atoms in the aldehyde, hydroxyl, or carboxyl groups. Formaldehyde is hypothesized to be an important signaling molecule in the regulation of cell growth and maintenance of the endogenous formaldehyde level.
Excessive ingestion of caffeine-containing beverages is a rare cause of rhabdomyolysis. Here, we describe the case of a 44-year-old woman presented with nausea, vomiting, palpitations, and tea-colored urine 6 h after drinking a liter of black coffee containing approximately 565 mg of caffeine for mental alertness. Laboratory studies were notable for myoglobinuria and markedly elevated plasma creatine kinase (CK) level of 7315 U/L. With volume expansion and alkalization, her plasma CK level returned to normal within 5 days. Rhabdomyolysis should be considered a potential health hazard from excessive consumption of caffeine-containing products.
Serum Dickkopf-1(DKK-1) is elevated in many malignancies and is an important indicator of malignant potential. However, its significance in esophageal squamous cell cancer (ESCC) has not yet been clarified. We hypothesized a role for DKK-1 in patients with ESCC. The study consisted of 90 ESCC patients and 85 healthy controls. After diagnosis, the level of DKK-1 was measured in the serum samples by enzyme-linked immunosorbent assay and the levels of DKK-1 were much higher in the ESCC patients than in the healthy control group (p < 0.0001). For serum DKK-1, the sensitivity and specificity of the assay were 70 and 80%, respectively. The preoperative serum DKK-1 level was elevated in the ESCC patients. Although serum DKK-1 is not a specific biomarker for ESCC, it might be a useful marker for the diagnosis and treatment of ESCC.
The ameliorative effect of calcium channel blockers (CCBs) and a phfospholipase-A2 inhibitor in drug-/chemical-induced nephrotoxicity was investigated. Rats were divided into 7 groups of 5 rats in each group. In the gentamicin model, group I rats were pretreated with normal saline (10 ml kg–1), while groups II–VII rats were pretreated with normal saline (10 ml kg–1), ascorbic acid (10 mg kg–1), nifedipine (0.86 mg kg–1), verapamil (4.3 mg kg–1), diltiazem (3.43 mg kg–1), and prednisolone (0.57 mg kg–1), respectively, perorally 1 h before intraperitoneal (i.p.) injection of gentamicin (40 mg kg–1) for 14 days. In the carbon tetrachloride (CCl4) model, rats were pretreated with CCBs and prednisolone for 7 days before inducing nephrotoxicity with 20% CCl4 (1.5 ml kg–1). Rats were thereafter killed and blood and tissue samples were collected for assessments. I.p. injections of gentamicin and CCl4 caused significant hypernatremia, hypokalemia, hypocalcemia, hypophosphatemia, and hyperchloremic alkalosis and reduced renal tissue levels of antioxidants. Also, significant reductions in the hemoglobin, packed cell volume, red blood cells, and platelet indices were observed. Pretreatments with nifedipine (0.86 mg kg–1), verapamil (4.3 mg kg–1), diltiazem (3.43 mg kg–1), and prednisolone (0.57 mg kg–1) significantly ameliorated the deleterious effects of gentamicin and CCl4 possibly via antioxidant and anti-lipoperoxidation mechanisms. The results obtained in this study suggest potential clinical usefulness of tested CCBs and prednisolone in drug-/chemical-induced nephrotoxicity.
In this case report, successful use of omalizumab in the treatment of chronic urticarial and angioedema in a 24-year-old female patient with an allergic reaction history to almost every drug including steroids and antihistamines was presented. She also had allergy against a large number of foods, which were confirmed by oral provocation, specific Immunoglobulin E and allergy skin test.
Traumatic brain injury (TBI) consists of a primary and a secondary insult characterized by a biochemical cascade that plays a crucial role in cell death in the brain. Despite the major improvements in the acute care of head injury victims, no effective strategies exist for preventing the secondary injury cascade. This lack of success might be due to that most treatments are aimed at targeting neuronal population, even if studies show that astrocytes play a key role after a brain damage. In this work, we propose a new model of in vitro traumatic brain-like injury and use paracrine factors released by human mesenchymal stem cells (hMSCs) as a neuroprotective strategy. Our results demonstrate that hMSC-conditioned medium increased wound closure and proliferation at 12 h and reduced superoxide production to control conditions. This was accompanied by changes in cell morphology and polarity index, as both parameters reflect the ability of cells to migrate toward the wound. These findings indicate that hMSC is an important regulator of oxidative stress production, enhances cells migration, and shall be considered as a useful neuroprotective approach for brain recovery following injury.
The safety of dental amalgam as the primary material in dental restoration treatments has been debated since its introduction. It is widely accepted that amalgam restorations continuously release elemental mercury (Hg) vapor, which is inhaled and absorbed by the body and distributed to tissues, including the brain. The aim of the present study was to investigate whether the presence of amalgam fillings is correlated with brain Hg level. The Hg levels in the parietal lobes of the brains of 32 cadavers were analyzed with an atomic absorption spectrometer with the mercury hydride system. A total of 32 brain samples were tested; of these, 10 were from cadavers with amalgam fillings, while 22 of them were amalgam free. Hg was detected in 60.0% (6 of 10) of the samples in the amalgam group and in 36.3% (8 of 22) in the amalgam-free group. The average Hg level of the amalgam group was 0.97 ± 0.83 µg/g (minimum: 0.3 µg/g and maximum: 2.34 µg/g), and in the amalgam-free group, it was 1.06 ± 0.57 µg/g (minimum: 0.17 µg/g and maximum: 1.76 µg/g). The results of the present study showed no correlation between the presence of amalgam fillings and brain Hg level.
The study was aimed at evaluating, in vitro, cytotoxicity of four resin-based orthodontic cements (RBOC) as a function of degree of conversion (DC) and the light curing unit (LCU) employed on mouse fibroblast (L929).
Nine samples were manufactured for each group of cements using plasma-emulating light-emitting diode (LED) and conventional LED. Toxicity was assessed by immersing four specimens to culture medium (24 h/37°C) for extracting residual monomer or cytotoxic substance. Cell mitochondrial activity of L929 cell was evaluated using methyl tetrazolium (MTT) test. DC was evaluated by Fourier transform infrared spectroscopy for five samples.
Cements, LCUs, and interaction between cements and LCUs were found to play a statistically significant role in cytotoxicity (p < 0.0001). Opal band cement (OPAL) plasma LED was found noncytotoxic (90–100% cell viability). The other RBOC–LCU combinations were slightly cytotoxic (60–90% cell viability). Cements (p < 0.01) and LCUs (p < 0.05) had a statistically significant effect on DC. Conversely, interaction between cement and LCU had no statistically significant role on DC (p > 0.05). OPAL plasma LED displayed the highest levels of DC. The correlations between cell viability and DC were positive for three RBOCs.
Therefore, high-intensity LCUs can be said to efficiently affect polymerization, so higher DC rates may achieve higher cell viability rates.
Cements and LCUs must be matched to each another to result in higher DC and maximal biocompatibility. Dual cure systems presented relatively high cell survival and higher DC, thus expressing superior to single-cure systems with plasma LED.
Inhalation is an important route of aldehyde exposure, and lung is one of the main targets of aldehyde toxicity. Octanal is distributed ubiquitously in the environment and is a component of indoor air pollutants. We investigated whether octanal exposure enhances the inflammatory response in the human respiratory system by increasing the expression and release of cytokines and chemokines. The effect of octanal in transcriptomic modulation was assessed in the human alveolar epithelial cell line A549 using oligonucleotide arrays. We identified a set of genes differentially expressed upon octanal exposure that may be useful for monitoring octanal pulmonary toxicity. These genes were classified according to the Gene Ontology functional category and Kyoto Encyclopedia of Genes and Genomes analysis to explore the biological processes related to octanal-induced pulmonary toxicity. The results show that octanal affects the expression of several chemokines and inflammatory cytokines and increases the levels of interleukin 6 (IL-6) and IL-8 released. In conclusion, octanal exposure modulates the expression of cytokines and chemokines important in the development of lung injury and disease. This suggests that inflammation contributes to octanal-induced lung damage and that the inflammatory genes expressed should be studied in detail, thereby laying the groundwork for future biomonitoring studies.
Insulin resistance, oxidative stress, and proinflammatory cytokines play a key role in pathogenesis of nonalcoholic fatty liver disease (NAFLD). The aim of our study was to investigate the dynamics of oxidative/nitrosative stress in methionine–choline-deficient (MCD) diet -induced NAFLD in mice. Male C57BL/6 mice were divided into following groups: group 1: control group on standard diet; group 2: MCD diet for 2, 4, and 6 weeks (MCD2, MCD4, and MCD6, respectively). After treatment, liver and blood samples were taken for histopathology, alanine- and aspartate aminotransferase, acute phase reactants, and oxidative/nitrosative stress parameters. Liver malondialdehyde level was higher in all MCD-fed groups versus control group (p < 0.01), while nitrites + nitrates level showed a progressive increase. The activity of total superoxide dismutase and its isoenzymes was significantly lower in all MCD-fed groups (p < 0.01). Although catalase activity was significantly lower in MCD-fed animals at all intervals (p < 0.01), the lowest activity of this enzyme was evident in MCD4 group. Liver content of glutathione was lower in MCD4 (p < 0.05) and MCD6 group (p < 0.01) versus control. Ferritin and C-reactive protein serum concentration were significantly higher only in MCD6 group. Our study suggests that MCD diet induces a progressive rise in nitrosative stress in the liver. Additionally, the most prominent decrease in liver antioxidative capacity is in the fourth week, which implies that application of antioxidants would be most suitable in this period, in order to prevent nonalcoholic steatohepatitis but not the initial NAFLD phase.
Di(2-ethyl hexyl)-phthalate (DEHP) is an endocrine disrupter and is the most abundantly used phthalate derivative, which is suspected to be an inevitable environmental exposure contributing to the increasing incidence of type-2 diabetes in humans. Therefore, the present study was designed to address the dose-dependent effects of DEHP on insulin signaling molecules in L6 myotubes. L6 myotubes were exposed to different concentrations (25, 50, and 100 μM) of DEHP for 24 h. At the end of exposure, cells were utilized for assessing various parameters. Insulin receptor and glucose transporter4 (GLUT4) gene expression, insulin receptor protein concentration, glucose uptake and oxidation, and enzymatic and nonenzymatic antioxidants were significantly reduced, but glutamine fructose-6-phosphate amidotransferase, nitric oxide, lipid peroxidation, and reactive oxygen species levels were elevated in a dose-dependent manner in L6 myotubes exposed to DEHP. The present study in turn shows the direct adverse effect of DEHP on the expression of insulin receptor and GLUT4 gene, glucose uptake, and oxidation in L6 myotubes suggesting that DEHP exposure may have a negative influence on insulin signaling.
The neurotoxin paraquat (PQ) causes apoptosis of dopaminergic neurons in mammalian cell culture and animal models, mimicking an important pathological feature of Parkinson’s disease (PD). The phosphoinositide 3-kinase (PI3K)/Akt pathway is critical for several major survival signals in central nervous system neurons. Phosphatidylinositol 3-kinase 55 kDa gamma (p55PIK) is a regulatory subunit of PI3Ks with important roles in cell proliferation, antiapoptosis, and cell cycle progression. However, p55PIK involvement in mechanisms regarding progression and maintenance of neurodegenerative diseases is largely undetermined. We used PQ-induced apoptosis in human dopaminergic SH-SY5Y cells to investigate the association between p55PIK expression levels, subcellular location, and apoptosis. p55PIK expression was reduced in SH-SY5Y cells and p55PIK messenger RNA and protein expression levels were decreased after PQ treatment. Apoptosis induced by PQ was associated with caspase activation and decreased p55PIK expression. Restoration of p55PIK expression was observed after coincubation with a caspase inhibitor. Overexpressed full-length p55PIK in SH-SY5Y and human embryonic kidney 293 cells showed specific distribution in the nucleus and was cleaved in vitro by recombinant caspase 6 (C6), but not C3 and C7. A p55PIK construct lacking 24 N-terminal amino acids (N24) was tested for the presence of a potential C6-recognizable sequence and was found to express its proteins outside the nucleus. The results suggest that p55PIK may be involved in PQ-induced apoptosis signal transduction and that N24 is crucial for p55PIK subcellular localization. Thus, p55PIK could be a substrate of activated C6 during apoptosis, leading to loss of original biological functions and redistribution to disturb cell cycle progression.
Arsenic trioxide (As2O3) is a known environmental toxicant and potent chemotherapeutic agent. Significant correlation has been reported between arsenic exposure (including consumption of arsenic-contaminated water and clinical use of As2O3) and dysfunction in the nervous system. In this study, we aimed to elucidate the effect of resveratrol with neuroprotective activities on As2O3-induced oxidative damage and cerebral cortex injury. Twenty-four healthy Chinese Dragon Li cats of either sex were randomly divided into four groups: control (1 ml/kg physiological saline), As2O3 (1 mg/kg), resveratrol (3 mg/kg) and As2O3 (1 mg/kg) + resveratrol (3 mg/kg). As2O3+resveratrol-treated group were given resveratrol (3 mg/kg) 1 h before As2O3 (1 mg/kg) administration. Pretreatment with resveratrol upregulated the activities of antioxidant enzymes and attenuated As2O3-induced increases in reactive oxygen species and malondialdehyde production. In addition, resveratrol attenuated the As2O3-induced reduction in the level of reduced glutathione and the ratio of reduced glutathione to oxidised glutathione, and accumulation of arsenic in the cerebral cortex. These findings support neuroprotective effect of resveratrol on As2O3 toxicity in feline brain and provide a better understanding of the mechanism that resveratrol modulates As2O3-induced oxidative damage and a stronger rational for clinical use of resveratrol to protect brain against the toxicity of arsenic.
Dioscorea bulbifera L., a commonly used medicinal plant in China, is reported to induce hepatotoxicity. The present study is undertaken to investigate the hepatotoxicity induced by diosbulbin B (DB), a diterpene lactone isolated from D. bulbifera L., and to further explore its underlying mechanism. DB was administered to mice at the doses of 0, 16, 32, and 64 mg/kg once daily for 12 consecutive days. Liver injury induced by DB was evidenced by the increased activity of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). Liver histological evaluation showed that the mice treated with DB exhibited liver damage with the swelling of hepatocytes. Further results showed that the amount of malondialdehyde (MDA) in the liver was increased in mice treated with DB, while the glutathione amount and the enzymatic activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), copper/zinc–superoxide dismutase (CuZn-SOD), manganese-SOD (Mn-SOD), and catalase (CAT) were all decreased. DB also decreased the gene expression of CuZn-SOD and CAT. Taken together, our results indicate that oral administration of DB for 12 consecutive days can lead to the oxidative stress liver injury in mice.
A novel galacto-oligosaccharide (GOS) was administered by gavage to groups (10 males and 10 females) of Sprague-Dawley specific pathogen-free rats for 6 weeks from day 4 after birth at doses of 0, 500, 1000, or 2000 mg/kg/day. Each pup was subjected to a variety of observations to examine for development effects/changes after birth: general condition, clinical signs, functional examinations, grip strength and spontaneous movement, body weight and feed consumption, external differentiation, ophthalmological examination, urinalysis (including water consumption), hematology, blood chemistry, necropsy, organ weight, and histopathology. During the study period, no deaths occurred in any group and there were no observed effects from administration of GOS. Therefore, it was concluded that GOS had no effects on the development of animals 4 days after birth. Since, there were no abnormalities due to administration of GOS in the macroscopic examination, organ weight or histopathology of the reproductive organs or differentiation (incisor eruption and eyelid opening) of males or females, it was concluded that repeated oral administration of GOS at 2000 mg/kg/day for 6 weeks from day 4 after birth had no effects on postnatal development. The no observed effect level of GOS by repeated oral administration for 6 weeks from day 4 after birth was 2000 mg/kg/day for both males and females under the conditions of this study.
The effect of exposure to inhaled lead acetate in guinea pigs was evaluated. The present study comprised of five groups of guinea pigs including control (C), sensitized to ovalbumin (OA; S) and three groups exposed to 0.1, 0.2, and 0.4 M inhaled lead (Pb; n = 6 for each group). Tracheal responsiveness to methacholine and OA, total and differential white blood cells (WBCs) count in lung lavage, serum levels of cytokines (interferon (IFN-) and interleukin 4 (IL-4)), histamines, and immunoglobulin E (IgE), and Pb concentration in lung were measured. Tracheal responsiveness to methacholine, OA, total and differential WBC types as well as IL-4, IFN-, histamine, and IgE were significantly increased but IFN-/IL-4 were significantly decreased in sensitized animals as well as those exposed to high Pb concentrations when compared with the control group (from p < 0.05 to p < 0.001). In addition, there was not a significant difference in most measured values between animals exposed to high Pb concentration and group S. The Pb concentration in lung tissues of animals exposed to all three Pb concentrations was significantly higher than that of group C (p < 0.001 for all cases).These results showed that inhaled lead acetate exposure can induce lung inflammatory changes similar to sensitized animals. Therefore, exposure to environmental Pb pollution may cause asthma-like changes.
Chemoprevention opens new window in the prevention of all types of cancers including colon cancer. Aloin, an anthracycline in plant pigment, can be utilized as a protective agent in cancer induction. In the present study, we have evaluated the chemopreventive efficacy of aloin against 1,2-dimethylhydrazine (DMH)-induced preneoplastic lesions in the colon of Wistar rats. DMH-induced aberrant crypt foci (ACF) and mucin-depleted foci (MDF) have been used as biomarkers of colon cancer. Efficacy of aloin against the colon toxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, lipid peroxidation, ACF, MDF, histopathological changes, and expression levels of molecular markers of inflammation and tumor promotion. Aloin pretreatment ameliorates the damaging effects induced by DMH through a protective mechanism that involved reduction in increased oxidative stress enzymes (p < 0.001), ACF, MDF, cyclooxygenase-2, inducible nitric oxide synthase, interleukin-6, proliferating cell nuclear antigen protein expression, and tumor necrosis factor-α (p < 0.001) release. From the results, it could be concluded that aloin clearly protects against chemically induced colon toxicity and acts reasonably by inducing antioxidant level, anti-inflammatory and antiproliferative markers.
Accumulating evidence has shown that ethanol-induced iron overload plays a crucial role in the development and progression of alcoholic liver disease. We designed the present study to investigate the potential protective effect of quercetin, a naturally occurring iron-chelating antioxidant on alcoholic iron overload and oxidative stress. Ethanol-incubated (100 mmol/L) rat primary hepatocytes were co-treated by quercetin (100 µmol/L) and different dose of ferric nitrilotriacetate (Fe-NTA) for 24 h. When the hepatic enzyme releases in the culture medium, redox status of hepatocytes and the intercellular labile iron pool (LIP) level were assayed. Our data showed that Fe-NTA dose dependently induced cellular leakage of aspartate transaminase and lactate dehydrogenase, glutathione depletion, superoxide dismutase inactivation, and overproduction of malondialdehyde) and reactive oxygen species (ROS) of intact and especially ethanol-incubated hepatocytes. The oxidative damage resulted from ethanol, Fe-NTA, and especially their combined treatment was substantially alleviated by quercetin, accompanying the corresponding normalization of intercellular LIP level. Iron in excess, thus, may aggravate ethanol hepatotoxicity through Fenton-active LIP, and quercetin attenuated ethanol-induced iron and oxidative stress. To maintain intercellular LIP contributes to the hepatoprotective effect of quercetin besides its direct ROS-quenching activity.
In this randomized parallel study, we examined whether an acute ozone (O3) exposure leads to increased DNA strand breaks in human lymphocytes. The groups were exposed to 0.21 ppm O3 filtered air for two hours 30min and 4.5 h after exposure, DNA damage was determined in isolated lymphocytes using the Fast Micromethod. There was no detectable effect after O3 exposure. We conclude that an acute O3 exposure at the tested concentration does not lead to persistent DNA damage.
An overdose of acetaminophen (APAP) produces centrilobular hepatocellular necrosis. We aimed to investigate the hepatoprotective effects of N-acetylcysteine (NAC) only and hyperbaric oxygen (O2) treatment (HBOT) combined with NAC, and their anti-inflammatory properties in liver tissue. In the current study, a total of 32 male Sprague Dawley rats were divided into 4 groups: sham, APAP, NAC, and NAC + HBOT. In the APAP, NAC, and NAC + HBOT groups, liver injury was induced by oral administration of 1 g/kg APAP. The NAC group received 100 mg/kg NAC per day. NAC + HBOT group received intraperitoneal injection of 100 mg/kg/day NAC and were given HBOT at 2.8 ATA pressure with 100% O2 inhalation for 90 min every 12 h for 5 days. Rats in the sham group received distilled water only by gastric tube. All animals were killed on day 6 after APAP or distilled water administration. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, hepatic neopterin, tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) levels were measured. There was a significant increase in serum AST and ALT activities in the APAP group compared with the sham group (in both p = 0.001). NAC and NAC + HBOT groups had significant decreases in hepatic neopterin, TNF-α, and IL-6 levels compared with the APAP group. APAP administration caused extensive hepatic necrosis. NAC and NAC + HBO treatments significantly reduced APAP-induced liver injury. Our results showed that the liver damage in APAP toxicity was attenuated by NAC and NAC + HBO treatments. NAC + HBOT exhibit hepatoprotective activity against APAP-induced liver injury in rats.
Long-acting formulations of antipsychotics are important treatment options to increase the compliance of schizophrenic patients. Risperidone, a 5-HT2 and dopaminergic D2 receptor antagonist, was developed as long-acting sustained-release microspheres with poly(lactide-co-glycolide) (PLGA) as a drug carrier for the treatment of schizophrenia. In the present study, the main objective is to determine the nonclinical safety profile of risperidone-loaded microspheres (RM) in Beagle dogs after intramuscular administration for 3 months, once in 2 weeks, followed by 8-week recovery phase. No animal death was found and no special toxicological findings were observed. The findings, such as hypoactivity, ptosis, increased heart rate, and elevated serum and pituitary prolactin levels, were observed and related to the pharmacological effects of risperidone. The changes in the reproductive system (uterus, ovary, vagina, cervix, and mammary gland) were considered secondary to the prolactin elevation, and the congestion of spleen was related to risperidone. The foreign body granulomas at injection sites might be caused by PLGA. At the end of recovery phase, the above changes mostly recovered to normal, and on administering 3 mg/kg dose level once in 2 weeks on Beagle dogs showed no observed adverse effect. Taken together, RM had exhibited the acceptable safety.
The present study was designed to investigate the protective effects of carvacrol against thioacetamide (TAA)-induced oxidative stress, inflammation and apoptosis in liver of Wistar rats. In this study, rats were subjected to concomitant prophylactic oral pretreatment of carvacrol (25 and 50 mg kg–1 body weight (b.w.)) against the hepatotoxicity induced by intraperitoneal administration of TAA (300 mg kg–1 b.w.). Efficacy of carvacrol against the hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes, and expressions of inflammation and apoptosis. Carvacrol pretreatment prevented deteriorative effects induced by TAA through a protective mechanism in a dose-dependent manner that involved reduction of oxidative stress, inflammation and apoptosis. We found that the protective effect of carvacrol pretreatment is mediated by its inhibitory effect on nuclear factor kappa B activation, Bax and Bcl-2 expression, as well as by restoration of histopathological changes against TAA administration. We may suggest that carvacrol efficiently ameliorates liver injury caused by TAA.
Cigarette smoking is one of the most important risk factors for kidney cancer, but the molecular mechanism is poorly understood. To examine the expression change of histone H3 on lysine 27 trimethylase (H3K27me3) demethylases ubiquitously transcribed TPR gene on the X chromosome (UTX) in kidney cancer cell line 786-O after nicotine treatment, quantitative real-time-polymerase chain reaction and western blotting analysis were carried out. These results showed that nicotine can increase UTX messenger RNA and protein levels and also decrease the content of H3K27me3. The decreased content of H3K27me3 may activate specific gene expression and lead to kidney cancer. Future investigation on nicotine induced UTX expression and its epigenetic effect would deepen our understanding on nicotine toxicity and carcinogenicity.
Hyperthermia enhanced the clastogenicity of alkylating agents. We investigated whether quercetin (QU; 3,3',4',5,7-pentahydroxy flavone) or naringenin (NAR) can sensitize Ehrlich ascites tumour (EAT) to cisplatin (CP) hyperthermal intraperitoneal chemotherapy treatment and whether these flavonoids in combination with CP can ameliorate CP-induced micronuclei (MNs) in peripheral blood reticulocytes of mice.
Chromium picolinate (CrPic), which is used as a nutritional supplement and to treat type 2 diabetes, has gained much attention because of its cytotoxicity. This study evaluated the effects of CrPic on the viability of the chick embryo fibroblast (CEF) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, morphological detection, and flow cytometry. The results show that lower concentrations of CrPic (8 and 16 μM) did not damage CEF viability (p > 0.05). However, higher CrPic concentrations (400 and 600 μM) indicated a highly significant effect on the production of intracellular reactive oxygen species, alteration of mitochondrial membrane potential, intracellular calcium ion concentration, and the apoptosis rate (p < 0.01), contrary to lower CrPic concentrations (8 and 16 μM) and control group. Moreover, apoptotic morphological changes induced by these processes in CEF were confirmed using Hoechst 33258 staining. Cell death induced by higher concentrations of CrPic was caused by an apoptotic and a necrotic mechanism, whereas the main mechanism of oxidative stress-induced mitochondrial dysfunction was apoptotic death.
Statins induce antiproliferative effects and apoptotic response in various cancer cell types. Moreover, they also sensitize tumor cell lines from different origins to many agents. We aimed to investigate possible effects of Mevastatin (Mev) alone and sequential treatment of 5'-aza-2-deoxycitidine (DAC) and Mev on HL-60 cell line using XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) assay, lactate dehydrogenase release assay, flourescence microscopy, DNA fragmentation analysis, determination of DNA synthesis rate, and active caspase-3 assay. Messenger RNA (mRNA) expression of apoptotic and antiapoptotic genes were also evaluated by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) for BAX, BCL2, and XIAP genes and quantitative Real-time PCR for CASP3, CASP8, and CASP9 genes. We showed that treatment with Mev alone and DAC followed by Mev resulted in apoptotic response in a time- and dose-dependent manner. We also found that pretreatment with DAC sensitized HL-60 cells to Mev and caused more apoptotic cell death than Mev-alone treatment via caspase-3 activation and DNA fragmentation. Moreover, sequential addition of Mev after DAC diminished DNA synthesis rate more effectively than Mev-alone treatment. Furthermore, DAC pretreatment significantly increased CASP3 and CASP9 mRNA expression even with lower doses of Mev. BAX, BCL2, and XIAP gene mRNA levels were also found to be changed in the presence of DAC and Mev. Determination of the exact molecular effects of statins and DAC would allow us to identify new molecular targets to develop more effective treatment regimens for cancer.
This study aimed to evaluate the antidotal effect of a newly developed supramolecular complex, ferric porphyrins and a cyclodextrin dimer (FeIIIPIm3CD), that possess a higher binding constant and quicker binding rate to cyanide ions than those of hydroxocobalamin (OHCbl) in the presence of serum protein.
First, in vitro cytochrome activity and cell viability were evaluated in murine fibroblast cells cultured with various doses of FeIIIPIm3CD and potassium cyanide (KCN). Next, BALB/c mice were pretreated with intravenous OHCbl (0.23 mmol/kg), FeIIIPIm3CD (0.23 mmol/kg), or saline and then received KCN (lethal dose 100% (LD100): 0.23 mmol/kg) through a stomach tube. Finally, as a resuscitation model, KCN-induced apnea was treated with a bolus injection of an equimolar dose of antidotes followed by a slow infusion of the same reagent.
FeIIIPIm3CD showed dose-dependent antidotal effects in vitro. Pretreatment with FeIII PIm3CD prevented KCN-induced apnea significantly better than OHCbl. Resuscitation with FeIIIPIm3CD resulted in an earlier resumption of respiration than that seen with OHCbl. However, 24-h survival was similar among the treatments (FeIIIPIm3CD, nine of nine mice; OHCbl, eight of nine mice).
FeIIIPIm3CD exerted significant antidotal effects on cyanide toxicity in vitro and in vivo, with a potency equal in the mortality of cyanide-poisoned mice or superior in the respiratory status during an acute phase to those of OHCbl.
Atherosclerosis is morphologically an inflammatory disease, where endothelial dysfunction plays a key role in all the stages. The nitric oxide (NO) synthase 3 (NOS3) gene is responsible for the synthesis of endothelial NO synthase (eNOS) in humans and some genetic polymorphisms are considered "polymorphisms associated with risk" for the development of coronary artery diseases, such as acute coronary syndrome. Thus, the present study aimed to evaluate the influence of the -786T>C polymorphism of the eNOS gene on inflammatory and oxidative process. A prospective cohort study of 125 consecutive patients with clinical diagnosis of non-ST-elevation acute coronary syndromes was conducted. Patients were assessed using a standardized questionnaire. Blood samples were drawn to measure serum levels of high-sensitivity C-reactive protein, soluble CD40 ligand, interleukin-6 (IL-6), N-terminal prohormone of brain natriuretic peptide, immunoglobulin G antibodies against oxidized low-density lipoprotein. The genotypes for the -786T>C polymorphism in the 5'-flanking region of eNOS gene were determined. The -786C allele was found in 92 of 250 alleles (38.8%). No statistical association was observed between demographic and clinical characteristics and distribution of eNOS-786T>C polymorphism. We found that -786CC was associated with lower levels of IL-6. No significant differences were observed between the distribution of -786T>C polymorphism and other investigated markers.
Several methods are used to evaluate the inflammatory changes. Measurement of edema is the most commonly used method for evaluating artificially induced inflammation in rat model. In this context, we present a method for the measurement of volume of rat paw, in which two glass columns containing fluid are connected by a glass tube. Paw is immersed in one column and the other column is placed on weighing balance. Upon immersion of paw, equal volume of fluid displaced applies a force F, which shows specific and proportional increment in the level of fluid in both the columns, which could then be detected by weighing balance, as ‘Force = Weight’ of displaced fluid, using the specific gravity of the fluid and the volume of paw, and thus the change in the volume of paw can be calculated. The rat paw immersed in column without touching the wall of the column facilitates the accurate measurement of volume of paw when measured several times. Present method is validated for its accuracy and reproducibility when internal radii of both the columns were same or different. Presented method is also cost-effective and hence can be used for the academic and the commercial animal research purpose, without compromising the precision of the evaluation.
Uranium (U) accumulates and produces its toxic effects preferentially in the kidneys, especially in the proximal tubular structure. U disturbs the balance of pro-/antioxidants in the renal cortex after acute exposure. Other nephrotoxic agents, such as medications, also cause oxidative stress, but the effects of coexposure are not known. The aim of this study was to analyze the effect of chronic exposure to U and acute gentamicin treatment on the pro- and antioxidant status of the renal cortex of rats. Animals were chronically exposed (9 months) to a nonnephrotoxic level of U (40 mg/L) and then treated with daily injections of gentamicin at a range of doses (0, 5, 25, 100, and 150 mg/kg) during the last week of contamination. We studied changes in the gene expression, protein expression, and enzyme activity of key factors involved in the pro-/antioxidant balance in the renal cortex. At and above a dose of 100 mg/kg, gentamicin decreased the messenger RNA (mRNA) levels of catalase (CAT), copper/zinc superoxide dismutase (SOD) and increased the mRNA levels of heme oxygenase-1 in contaminated rats. This treatment decreased CAT activity, but did not significantly change the SOD protein level. Chronic exposure to U did not worsen these effects in our experimental conditions. In conclusion, gentamicin treatment disturbed the oxidative balance in our model’s renal cortex, but the chronic exposure to U at this nonnephrotoxic level did not appear to reinforce these effects.
To determine whether or not wave/interval dispersions in electrocardiography (ECG) are increased, and to define whether wave and interval dispersions are correlated with carboxyhemoglobin (COHb) levels.
ECG, complete blood count, and biochemical parameters were taken from 87 patients with carbon monoxide (CO) poisoning as well as 90 control patients with similar age, gender, and body mass index distribution. COHb levels were recorded in CO-poisoning patients. The COHb levels and the relationships with ECG parameters were studied.
Pmax, Pmin, Pd, PRmax, PRmin, PRd, QTmax, QTmin, QTd, cQTmax, cQTmin, cQTd, Tmax, Tmin, and Td in ECG were higher in intoxicated patients than the control group (p < 0.05 for all). Pearson’s correlation analyses showed moderately significant positive correlations between COHb level and Pmax (r = 0.224; p = 0.037) and Pd (r = 0.222; p = 0.039). The receiver–operator characteristic (ROC) curve showed that a Pd value of 38 ms determined by ECG separates patients with a COHb ≥ 20% with area under the ROC curve of 0.78 (95%CI = 0.71–0.83), a sensitivity of 67.9% (95%CI = 59.4–75.6), a specificity of 95% (95%CI = 83.0–99.2], a positive predictive value of 97.9% (95%CI = 92.5–99.7), and a negative predictive value of 46.3% (95%CI = 35.3–57.7.)
A significant increase in wave/interval dispersions in the ECG of CO-poisoning patients compared with controls may show that not only a part is affected but both atrium and the ventricles as a whole are affected by hypoxic ischemia. When COHb levels of the patients are unavailable, P dispersion on ECG may show CO poisoning level of the patient.
Gypenosides (Gyp), found in Gynostemma pentaphyllum Makino, has attracted more attention owing to its wide bioactivities. However, the effects of Gyp on esophageal cancer cells and colon cancer cells are still unknown. The present study was to investigate the possible anti-proliferative and anti-migration activity of Gyp on human colon cancer cells SW620 and esophageal cancer cells Eca-109. Cell viability was evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell membrane integrity was evaluated using flow cytometry following propidium iodide staining. Apoptotic cell death was determined by nuclear 4'-6-diamidino-2-phenylindole staining. Generation of intracellular reactive oxygen species (ROS) and changes in mitochondrial membrane potential ( m) was analyzed by flow cytometry using 2',7'-dichlorofluorescein–diacetate and rhodamine 123 staining, respectively. Wound healing assay was carried out to investigate Gyp-inhibited migration of SW620 and Eca-109 cells. The results indicated that Gyp inhibited cell proliferation and migration in SW620 and Eca-109 cells in dose- and time-dependent manner. Gyp elevated intracellular ROS level, decreased the m, and induced apoptotic morphology such as cell shrinkage and chromatin condensation, suggesting oxidative stress and mitochondria-dependent cell apoptosis that might be involved in Gyp-induced cell viability loss in SW620 and Eca-109 cells. The findings indicate Gyp may have valuable application in clinical colon cancer and esophageal cancer treatments.
Biochanin-A (BCA), a potent phytoconstituent, has been previously used as an antitumour, a dopaminergic neuron protective agent, an antioxidant, an anticholinergic and on other pharmacological activities including neuroprotection. The present study was aimed to evaluate the behavioural and neurochemical evidence of BCA in cognitive-deficit mice in scopolamine challenged and natural aged-induced amnesia models in young and aged mice, respectively. BCA has exhibited decrease in the transfer latency and increase in step through latency significantly (p < 0.001) in scopolamine-treated and natural aged mice of exteroceptive behavioural models such as elevated plus maze and passive shock avoidance paradigm, respectively. A decrease in acetylcholinesterase activity of whole brain was seen in scopolamine and aged mice with standard piracetam (Pira; p < 0.001) and BCA in dose-dependent manner. The antioxidant property of BCA was proven by increase in GSH (p < 0.01) and decrease in thiobarbituric acid reactive substances level significantly in a scopolamine-challenged and aged mice. The scopolamine-treated mice exhibited significant (p < 0.01) increase in the content of noradrenalin and dopamine, which is a sign of dementia, and these excess increased neurotransmitters were reversed by BCA 40 mg kg–1 (p < 0.05), BCA 20 mg kg–1 (p > 0.05), BCA 10 mg kg–1 (p < 0.05) and standard Pira (p < 0.05) when compared with scopolamine group. Furthermore, in histopathology of hippocampus, the Pira and BCA-treated mice were protected from the formation of pyknotic neurons, increases in the viable cells count and decreases in the number of degenerative cells compared with the scopolamine group. Hence, BCA could be potential enough for the betterment of Alzheimer’s disease.
Thallium poisoning is a rare condition that is often misdiagnosed, delaying appropriate treatment. Left untreated, thallium toxicity can permanently damage the nervous and digestive systems or, in severe cases, lead to paralysis and death. It is most often treated by an oral administration of Prussian blue. Thallium has a long physiological half-life, and Prussian blue cannot sequester thallium outside the digestive tract. Therefore, the first priority in treating severe thallium poisoning is to lower blood levels as soon as possible. We report the case of a patient with supralethal blood levels of thallium treated successfully using combined hemoperfusion (HP) and continuous veno-venous hemofiltration (CVVH). Three rounds of HP alone decreased blood thallium levels by 20.2%, 34.8%, and 32.2%, while each of the five subsequent rounds of CVVH reduced thallium blood levels by 63.5%, 64.2%, 42.1%, 18.6%, and 22.6%. The reversal of symptoms and prevention of lasting neurological damage indicates that HP, CVVH, 2,3-dimercaptopropane-1-sulfonate, neuroprotective agents along with supportive therapy were used successfully to treat a case of severe thallium poisoning.
Hydrofluoric acid (HF) is a dangerous chemical that can cause severe cutaneous burns as well as possible systemic toxicity.
We retrospectively analyzed all human HF exposure cases reported to the National Poison Control Center of Taiwan between 1991 and 2010.
In this 20-year survey, 324 calls were identified, with a majority of dermal exposure (84%). Occupational exposure accounted for 80% of all cases, with workers in semiconductor industry (61%), cleaning industry (15%), chemical or metal industry (13%), and other industries (11%). Electrolyte imbalances were uncommon, hypocalcemia, hypomagnesemia, and hypokalemia were recorded in 8.6%, 1.2%, and 1.5% of all cases, respectively. Most cases (64%) of dermal exposure received antidotal treatment. Treatment modalities of dermal exposure included calcium gluconate soaking, 49.8%; intravenous calcium, 20.6%; and topical use of calcium gluconate gel, 13.9%. Twenty patients (7%) received surgery. Following HF exposure, the majority of patients presented with mild (56.5%) or moderate (36.7%) toxic effects. However, four patients were severely intoxicated; two patients died of HF-related dysrhythmia and shock.
Significant symptomology may occur following HF exposure, and most of the HF exposure required hospitals evaluation. Calcium gluconate soaks appear to be effective in reducing local pain and tissue damage. Hyperkalemia should not be overemphasized as a common finding in HF exposure, hypokalemia tends to occur in cases of severe HF poisoning.
The isolated and identified triterpenoid, 1-hydroxytetratriacontane-4-one (C34H68O2), obtained from the methanolic leaf extract of Leucas aspera Linn. was explored for the first time for antisnake venom activity. The plant (L. aspera Linn.) extract significantly antagonized the spectacled cobra (Naja naja naja) venom induced lethal activity in a mouse model. It was compared with commercial antiserum obtained from King Institute of Preventive Medicine (Chennai, Tamil Nadu, India). N. naja naja venom induced a significant decrease in antioxidant superoxide dismutase, glutathione (GSH) peroxidase, catalase, reduced GSH and glutathione-S-transferase activities and increased lipid peroxidase (LPO) activity in different organs such as heart, liver, kidney and lungs. The histological changes following the antivenom treatment were also evaluated in all these organs. There were significant alterations in the histology. Triterpenoid from methanol extract of L. aspera Linn. at a dose level of 75 mg per mouse significantly attenuated (neutralized) the venom-induced antioxidant status and also the LPO activity in different organs.
Despite extensive use of organochlorinated pesticides (OCPs) such as dichlorodiphenyltrichloroethane (DDT) in Italy in the 1940s to 1970s, especially for public health control of malaria mosquitoes, information on their exposure levels among the general population is limited. These OCPs can be a source of health risk to human. A total of 137 blood samples were collected from residents of the general population of three Italian towns, Novafeltria, Pavia and Milan, to determine the levels of eight OCPs in blood serum. The concentrations of beta-hexachlorocyclohexane, hexachlorobenzene (HCB), 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethylene, 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE), 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane, 1,1-dichloro-2,2-bis (4-chlorophenyl)ethane, 1,1,1-trichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)-ethane and 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane were measured by gas chromatography–mass spectrometry. Variations in serum concentrations of OCPs with respect to place of residence, gender, age and body mass index (BMI) were evaluated by non-parametric tests. p,p'-DDE and HCB were the most abundant and major contributors of total OCP concentration. Their levels differed significantly between the three towns with a trend Milan > Novafeltria > Pavia ( p < 0.0001). Females had significantly higher concentrations of HCB and p,p'-DDE than males in the overall population sample. HCB concentrations were significantly higher in females than in males of Milan (p = 0.029). We observed positive correlations of p,p'-DDE and HCB with age in Novafeltria subjects (r = 0.468, p = 0.004). Total OCP concentrations differed significantly across BMI categories (p = 0.018) in overall population. We have demonstrated a clear pattern of the main OCPs in a fairly large population. Generally, our study provides information on OCPs exposure among the Italian general population and provides indications for further investigations.
Concentrations of 36 polychlorinated biphenyl (PCB) congeners were measured in serum of 372 Italian residents of general population living in Novafeltria, Pavia, and Milan. Total PCB level differed significantly between these sites (p < 0.0001) with median concentrations of 836.50, 1354.57, and 2062.08 pmol/g lipid, respectively. However, there is no evidence for the difference in distribution of total PCB levels by genders. Total dioxin-like PCBs differed significantly (p < 0.0001) between the sites (median 109.78, 50.88, and 166.99 pmol/g lipid, respectively) and genders of Novafeltria and Pavia (p = 0.011 and 0.009, respectively). PCB 138, 153, 170, and 180 differed significantly between the places of residence (p < 0.0001) with higher values in Milan population. In the overall population, total PCB and PCB 138, 153, 156, 170, and 180 correlated positively with age (correlations range between 0.320 and 0.569, p < 0.0001). In Novafeltria, the correlations ranged between 0.545 and 0.670, and in Pavia, the correlations ranged between 0.516 and 0.666. In Milan, correlations with age range between 0.327 and 0.417 for total PCB and congeners 138, 153, and 180. With an exception of PCB 170, there was no evidence of significant difference in the distribution of most abundant PCB congeners and total PCB across the body mass index categories.
Benzo[a]pyrene (B[a]P), a well-known carcinogen, is widespread in the environment. Although the neurotoxic effect of B[a]P has not drawn much attention, toxic effects of B[a]P on learning and memory have been reported. Since it is well known that neuronal apoptosis plays a major role in impairment of learning and memory triggered by many stimuli, an effort has been made to examine whether the B[a]P-induced neurotoxicity occurs through mitochondria-mediated apoptosis. Cultured newborn rat cerebral neurons were used to clarify the apoptosis induced by B[a]P in the study. After incubating with different doses of B[a]P in presence of S9 for 40 h, the apoptotic rates of B[a]P-treated neurons increased in a dose-dependent manner. Further analysis showed that B[a]P-induced apoptosis was accompanied by loss of mitochondrial membrane potential, release of cytochrome c from mitochondria to the cytosol, downregulation of antiapoptotic protein B-cell lymphoma-2 (Bcl-2) levels with concurrent upregulation in proapoptotic Bcl-2-associated X protein (Bax) levels, and increase in the levels and activities of caspases-9 and -3. However, there was no difference in the activity of caspase-8 between B[a]P-exposed neurons and controls. Collectively, these results showed that B[a]P upregulates Bax and downregulates Bcl-2 expression in cultured cerebral neurons, which leads to mitochondrial release of cytochrome c, caspase-3 activation and neuronal apoptotic death.
Although aeveral theories have been proposed including developmental/neurodegenerative processes, neurotransmitter abnormalities, viral infection, and immune dysfunction, the exact causative factor of schizophrenia is unclear. A relationship between inflammation and schizophrenia has been supported by abnormal cytokine production and altered antioxidant status. This study was aimed to examine the alterations in serum oxidative–antioxidative status and cytokine levels of schizophrenic patients.
A total of 91 schizophrenic patients from Saudi Arabia and 50 age- and sex-matched healthy controls were enrolled in the present study. Fresh blood samples were collected to measure the levels of cytokines and markers of oxidative stress by spectrophotometric assays simultaneously.
We observed that there was a significant increase in the levels of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 and a decrease in the levels of interferon-. Lipid peroxides are elevated in serum, while total-sulfhydryl levels were decreased. Also, the activities of superoxide dismutase and glutathione peroxidase were decreased, while the activities of catalase, glutathione reductase, and myeloperoxidase were found to be elevated in serum.
We conclude that inflammation resulting from dysregulation of cytokines and altered antioxidant systems may play a critical role in the etiology of schizophrenia.
Phthalates are diester derivatives of phthalic acid widely used in many commercial applications. The aim of this study is therefore to evaluate possible genotoxicity of di-n-hexyl phthalate (DHP) and dicyclohexyl phthalate (DCHP) at different concentrations using single-cell gel electrophoresis (comet) and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling (TUNEL) assays in testes samples of male rat pups. DCHP and DHP in corn oil were administered to the pregnant rats by gavage at the doses of 0 (vehicle), 20, 100, and 500 mg kg–1 day–1 from gestational day 6 (GD6) to GD19. After delivery, male rats were allowed to grow until prepubertal, pubertal, and adulthood. At necropsy, the blood samples were collected from heart and were excised immediately. The apoptotic cells of prepubertal, pubertal, and adult testis were detected using TUNEL assay. The comet assay was performed on blood lymphocytes and testes samples of adult male rats. The comet assay results showed that tail length, tail intensity, olive tail moment (OTM), and percentage of DNA present in tail were higher when DHP content was increased. Judging from the values of OTM and percentage of DNA, DHP could significantly induce DNA breakage at doses of 100 and 500 mg kg–1 day–1 compared with the control group. An increase in TUNEL-positive cells of prepubertal, pubertal, and adult testicular cells was observed in the treated groups. In conclusion, prenatal exposure to DHP and DCHP may possess genotoxic risk to testicular cells of rats at all stages of development, even at adulthood.
Over the past decade, complementary and alternative medicine (CAM) has become increasingly popular around the world.
In this study, we aim to investigate how frequently CAM is used and the types of CAM methods used for dermatological disease in Eastern Turkey.
We recruited 1610 patients from our clinic for this study. The sociodemographic features and the CAM methods were investigated with a survey.
The most common dermatological disorders included contact dermatitis (21.4%), acne vulgaris (17.5%), fungal infections (10.9%), eczema (6.3%), and warts (5.7%). The ratio of patients using at least one CAM method was 43.7% and that of those using two or more CAM methods was 20.8%. The most commonly used CAM methods were those using henna, cologne, moisturizing cream, prayer, and herbal therapy. Some patients were found to use some interesting and unusual CAM methods, such as putting out a cigarette over the skin on the back for anthrax, applying raw meat for furuncle, using fuel oil and nitric acid for contact dermatitis.
CAM methods are commonly used in our population. CAM methods often cause adverse reactions that may alter diagnostic skin findings and interfere with the efficacy of other medical therapies. Therefore, physicians should ask their patients about the use of CAM methods while collecting patient history. Physicians have a critical role in preventing improper use of CAM. In addition, further investigations into the efficacy, benefits, and risks of CAM methods should be carried out for better insight into those CAM methods.
The aim of the present study was to investigate whether cognitive behavioral impairment, induced by nicotine in offspring rats, was associated with the alteration of hippocampal short-term potentiation (STP) and long-term potentiation (LTP) and to discuss the potential underlying mechanism. Young adult offspring rats were randomly divided into three groups. The groups include: control group (CC), nicotine group 1 (NC), in which their mothers received nicotine from gestational day 3 (GD3) to GD18, and nicotine group 2 (CN), in which young adult offspring rats received nicotine from postnatal day 42 (PD42) to PD56. Morris water maze (MWM) test was performed and then field excitatory postsynaptic potentials elicited by the stimulation of perforant pathway were recorded in the hippocampal dentate gyrus region. The results of the MWM test showed that learning and memory were impaired by either prenatal or postnatal nicotine exposure. In addition, it was found that there was no statistical difference of the MWM data between both nicotine treatments. In the electrophysiological test, LTP and STP were significantly inhibited in both NC and CN groups in comparison with the CC group. Notably, STP in CN group was also lower than that in the NC group. These findings suggested that both prenatal and postnatal exposure to nicotine induced learning and memory deficits, while the potential mechanism might be different from each other due to their dissimilar impairments of synaptic plasticity.
Philodryas baroni—an attractively colored snake—has become readily available through the exotic pet trade. Most people consider this species harmless; however, it has already caused human envenomation. As little is known about the venom from this South American opisthoglyphous "colubrid" snake, herein, we studied its protein composition by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE), as well as its effects on the hemostatic system. Both reducing and nonreducing SDS-PAGE analysis demonstrated that the venom exhibits greatest complexity in the range of 50–80 kDa. The venom displayed proteolytic activity toward azocollagen, with a specific activity of 75.5 U mg–1, and rapidly hydrolyzed the Aα-chain of fibrinogen, exhibiting lower activity toward the Bβ- and -chains. The venom from P. baroni showed no platelet proaggregating activity per se, but it inhibited collagen- and thrombin-induced platelet aggregation. Prominent hemorrhage developed in mouse skin after intradermal injection of the crude venom, and its minimum hemorrhagic dose was 13.9 μg. When injected intramuscularly into the gastrocnemius of mice, the venom induced local effects such as hemorrhage, myonecrosis, edema, and leucocyte infiltration. Due to its venom toxicity shown herein, P. baroni should be considered dangerous to humans and any medically significant bite should be promptly reviewed by a qualified health professional.
This article provides an historical assessment of the role of radiotherapy in the treatment of inner ear infections.
The research utilized a literature-based evaluation of the use of x-rays during the first half of the 20th century on the treatment of otitis media (OM), mastoiditis, and cervical adenitis and their impact on the occurrence of deafness.
X-Rays were consistently found to be effective as a treatment modality at relatively low doses, in the range of 10–20% of the skin erythema dose, rapidly reducing inflammation, and accelerating the healing process. The mechanistic basis of the clinical successes, while addressed by contemporary researchers, is evaluated in the present article in light of current molecular biology advances, which indicate that clinically effective low doses of ionizing radiation act via the creation of an anti-inflammatory phenotype in highly inflamed tissue.
X-Ray treatment of OM, mastoiditis, and cervical adenitis was widely accepted in the first half of the 20th century by clinicians as an effective treatment when administered within an appropriate dosage range.
Methyl bromide (MeBr) is a chemically reactive compound that has found use as a fire retardant and fumigant used for wood, soil, fruits and grains. Its use is banned in many countries because of its ozone-depleting properties. Despite this ban, the use of MeBr persists in some parts of the world (e.g. New Zealand) due to its important role in maintaining strict biosecurity of exported and imported products. Its high chemical reactivity leads to a broad toxicological profile ranging from acute respiratory toxicity following inhalation exposure, through carcinogenicity to neurotoxicty. In this article, we discuss the chemistry of MeBr in the context of its mechanisms of toxicity. The chemical reactivity of MeBr clearly underlies its toxicity. Bromine (Br) is electronegative and a good leaving group; the + carbon thus facilitates electrophilic methylation of biological molecules including glutathione (GSH) via its – sulphur atom, leading to downstream effects due to GSH depletion. DNA alkylation, either directly by MeBr or indirectly due to reduction in GSH-mediated detoxification of reactive alkylating chemical species, might explain the carcinogenicity of MeBr. The neurotoxicity of MeBr is much more difficult to understand, but we speculate that methyl phosphates formed in cells might contribute to its neurone-specific toxicity via cholinesterase inhibition. Finally, evidence reviewed shows that it is unlikely for Br– liberated by the metabolism of MeBr to have any toxicological effect because the Br– dose is very low.
Muscle dysfunction in acute organophosphorus (OP) poisoning is a cause of death in human. The present study was conducted to identify the mechanism of action of OP in terms of muscle mitochondrial dysfunction. Electromyography (EMG) was conducted on rats exposed to the acute oral dose of malathion (400 mg/kg) that could inhibit acetylcholinesterase activity up to 70%. The function of mitochondrial respiratory chain and the rate of production of reactive oxygen species (ROS) from intact mitochondria were measured. The bioenergetic pathways were studied by measurement of adenosine triphosphate (ATP), lactate, and glycogen. To identify mitochondrial-dependent apoptotic pathways, the messenger RNA (mRNA) expression of bax and bcl-2, protein expression of caspase-9, mitochondrial cytochrome c release, and DNA damage were measured. The EMG confirmed muscle weakness. The reduction in activity of mitochondrial complexes and muscular glycogen with an elevation of lactate was in association with impairment of cellular respiration. The reduction in mitochondrial proapoptotic stimuli is indicative of autophagic process inducing cytoprotective effects in the early stage of stress. Downregulation of apoptotic signaling may be due to reduction in ATP and ROS, and genotoxic potential of malathion. The maintenance of mitochondrial integrity by means of artificial electron donors and increasing exogenous ATP might prevent toxicity of OPs.
We have reported previously that phenethyl isothiocyanate (PEITC) induces apoptosis in human osteosarcoma U-2 OS cells. Cytotoxic activity of PEITC towards other cancer cells such as human malignant melanoma and skin cancer cells has not been reported. In this study, the anticancer activity of PEITC towards human malignant melanoma cancer A375.S2 cells was investigated. To determine the mechanisms of PEITC inhibition of cell growth, the following end points were determined in A375.S2 cells: cell morphological changes, cell cycle arrest, DNA damage and fragmentation assays and morphological assessment of nuclear change, reactive oxygen species (ROS) and Ca2+ generations, mitochondrial membrane potential disruption, and nitric oxide and 10-N-nonyl acridine orange productions, expression and activation of caspase-3 and -9, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, poly (adenosine diphosphate-ribose) polymerase, and cytochrome c release, apoptosis-inducing factor and endonuclease G. PEITC induced morphological changes in time- and dose-dependent manner. PEITC induced G2/M phase arrest and induced apoptosis via endoplasmic reticulum stress-mediated mitochondria-dependent pathway. Western blot analysis showed that PEITC promoted Bax expression and inhibited Bcl-2 expression associated with the disintegration of the outer mitochondrial membrane causing cytochrome c release, and activation of caspase-9 and -3 cascade leading to apoptosis. We conclude that PEITC-triggered apoptotic death in A375.S2 cells occurs through ROS-mediated mitochondria-dependent pathways.
The aim of this study was to evaluate the effect of lead (Pb)-contaminated drinking water on magnetic resonance imaging (MRI)-estimated cardiac function, vascular reactivity, and serum lipids in rats. For 3 months, male Wistar rats, aged 4–6 weeks, were given drinking water with the addition of lead acetate at a concentration of 100 ppm Pb (10 rats) or water free from Pb (8 control rats). The cardiac MRI was performed at rest and under β-adrenergic stimulation on a 4.7 T scanner using electrocardiogram-triggered gradient echo (FLASH) cine sequence. After 1–2 weeks of the MRI test, experiments were performed ex vivo. After stabilization of perfusion pressure (PP), norepinephrine at doses from 0.01 to 5.0 μg was dissolved in Krebs solution, injected in a volume of 100 μl, and next infused at a concentration of 0.5 μg/ml into the isolated mesenteric artery. In this manner, preconstricted mesenteric bed was used to determine PP changes induced by acetylcholine, given at doses from 0.05 to 5.0 μg, before and during the infusion of nitric oxide synthase inhibitor (1.0 μg/ml). At the end, dobutamine (5 mg), followed by potassium chloride (10.5 mg), was injected. Lipid levels were determined enzymatically, blood Pb level was measured by the atomic absorption spectrophotometer. This study showed that Pb impairs the left ventricular systolic and diastolic function. Pb-induced changes in response to resistance of vessels to vasoactive agents may be secondary to the reduced left ventricular ejection fraction. The high-density lipoprotein subfraction 2 (HDL2) is involved in the cardiovascular effect of Pb.
Homocysteine and its metabolites (homocysteine thiolactone (HT)) induce seizures via different but still not well-known mechanisms. The role of nitric oxide (NO) in epileptogenesis is highly contradictory and depends on, among other factors, the source of NO production. The aim of the present study was to examine the effects of aminoguanidine, selective inhibitor of inducible NO synthase (iNOS), on HT-induced seizures. Aminoguanidine (50, 75, and 100 mg/kg, intraperitoneally (i.p.)) was injected to rats 30 min prior to inducing HT (5.5 mmol/kg, i.p.). Seizure behavior was assessed by seizure incidence, latency time to first seizure onset, number of seizure episodes, and their severity during observational period of 90 min. Number and duration of spike and wave discharges (SWDs) were determined in electroencephalogram (EEG). Seizure latency time was significantly shortened, while seizure incidence, number, and duration of HT-induced SWD in EEG significantly increased in rats receiving aminoguanidine 100 mg/kg before subconvulsive dose of HT. Aminoguanidine in a dose-dependent manner also significantly increased the number of seizure episodes induced by HT and their severity. It could be concluded that iNOS inhibitor (aminoguanidine) markedly aggravates behavioral and EEG manifestations of HT-induced seizures in rats, showing functional involvement of iNOS in homocysteine convulsive mechanisms.
(R)-Goniothalamin (R-GNT) is a secondary metabolite isolated from the plants of the genus Goniothalamus. This molecule has attracted the attention of researchers because of its selective cytotoxicity against tumor cells and its ability to induce apoptosis. (S)-Goniothalamin (S-GNT) is a synthetic enantiomer of R-GNT, and its mechanism of action is largely unknown. In this study, we investigated the activity of S-GNT in a human non-small cell lung cancer NCI-H460 cells. We observed that the cells exposed to this compound exhibited cytotoxicity in a concentration-dependent manner. Based on the data obtained through the assessment of apoptosis induction in situ and the comet assay, we suggest that this cytotoxicity occurs due to the potential ability of this molecule to induce DNA damage with the consequent induction of cell death via apoptosis. A significant reduction in the messenger RNA levels of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) gene that encodes the survivin protein was found. This novel finding may explain the inhibition of cell proliferation and induction of apoptosis in tumor cells caused by this compound.
The presence of benzene in motor gasoline has been a health concern for potential increased risk of acute myelogenous leukemia and perhaps other lymphatic/hematopoietic cancers for approximately 40 years. Because of the widespread and increasing use of gasoline by consumers and the high exposure potential of occupational cohorts, a thorough understanding of this issue is important. The current study utilizes an evidence-based approach to examine whether or not the available epidemiologic studies demonstrate a strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers. Among 67 epidemiologic studies initially identified, 54 were ranked according to specific criteria relating to the relevance and robustness of each study for answering the research question. The 30 highest-ranked studies were sorted into three tiers of evidence and were analyzed for strength, specificity, consistency, temporality, dose-response trends and coherence. Meta statistics were also calculated for each general and specific lymphatic/hematopoietic cancer category with adequate data. The evidence-based analysis did not confirm any strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers based on the epidemiologic studies available to date. These epidemiologic findings, combined with the evidence showing relatively low occupational benzene vapor exposures associated with gasoline formulations during the last three decades, suggest that current motor gasoline formulations are not associated with increased lymphatic/hematopoietic cancer risks related to benzene.
Carbon disulfide (CS2) has reproductive toxicity but the mechanism remains unclear. The aim of the present study was to investigate the effect of oxidative stress and DNA damage on embryo implantation of mice exposed to CS2 at peri-implantation. CS2 exposure was on gestational day 3 (GD3), GD4, GD5 and GD6, separately, and the number of embryonic day 9 (E9) mouse embryos was obtained. DNA damage of endometrial cells, oxidative stress and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) level in uterus tissues were tested with time series at different end points after exposure. The number of E9 mouse embryos significantly decreased in all CS2 exposure groups, especially on GD4 exposure. The rates of embryo implantation decreased by 43.05%, 63.74%, 60.45% and 47.26% for CS2 exposure on GD3, GD4, GD5 and GD6, respectively. Oxidative stress significantly increased within 24 h and reached the top level at 18 h after exposure. The same time-dependent trend was observed no matter when the exposure happened at peri-implantation. 8-OH-dG significantly increased at 18 h and 24 h after exposure by 893.8% and 647.4%, respectively, when compared with the control. The indexes of DNA damage significantly increased at 6 h after exposure, which appeared earlier than the changes of oxidative stress and 8-OH-dG. Besides, both oxidative stress and DNA damage showed a strong negative correlation with the number of E9 mouse embryos. The present study illustrated that CS2 directly induced DNA damage in endometrial cells and enhanced the action through oxidative stress, both of which were responsible for CS2-induced embryo loss.
The present study evaluated the efficacy of melatonin in cyclophosphamide (CP)-induced testicular injury, lipid peroxidative damage, and antioxidant enzymes status of the mice testis on the basis of biochemical and histological studies. Mice were pretreated with four different doses of melatonin (2.5, 5, 10, and, 20 mg/kg by body weight (b.w.)) via intraperitoneal injection for five consecutive days followed by injection with CP (200 mg/kg b.w.) 1 h after the last injection of melatonin on the 5th day. After 24 h, mice were euthanized, testes were immediately removed, and biochemical and histological studies were conducted. Treatment with melatonin significantly mitigates lipid peroxidation, superoxide dismutase, and catalase activity and the level of reduced glutathione content abnormality induced by CP in mice testis. Histological examination clearly demonstrates that pretreatment of melatonin prevented CP-induced spermatogenesis toxicity and spermatogenic cells reduction in mice testis. The protective effect of melatonin is likely due to the antioxidative properties of the indolamine existed in the chemical structure. Because melatonin is a safe, natural compound, it could be used concomitantly as a supplement to protect people undergoing chemotherapy against reproductive toxicity.
Knowledge of the ability of the female reproductive system to metabolize environmental chemicals is critical not only from the standpoint of toxicity but also from infertility risk assessment. Benzo(a)pyrene (BaP) is a toxicant that is released into the environment from automobile exhausts, cigarette smoke, burning of refuse, industrial emissions, and hazardous waste sites. In exposed animals, BaP becomes activated to reactive metabolites that interfere with target organ function and as a consequence cause toxicity. Studies on animal models conducted in our laboratories and those of others have shown that BaP possess endocrine disrupting properties. Thus, this chemical has the potential to cause infertility and cancers in the female genital tract. An understanding of BaP metabolism in the female reproductive system will be of importance in the diagnosis and management of female fertility as well as cancers in the reproductive tissues. Therefore, the objective of our study was to examine the metabolism of BaP by human ovarian subcellular fractions. Human ovary samples (eight individuals) were obtained from postoperative tissue removed from subjects with uterine tumors. Subcellular fractions (nuclear, cytosolic, mitochondrial, and microsomal) were prepared by differential centrifugation. BaP (1 μM and 3 μM) was individually incubated with individual subcellular fractions for 15 min and the products were analyzed by high-performance liquid chromatography. Among the different fractions tested, microsomal BaP metabolism was higher than the rest of the fractions. The BaP metabolites identified were as follows: BaP-9,10-diol, BaP-4,5-diol, BaP-7,8-diol, 9(OH) BaP, 3(OH) BaP, BaP-1,6-dione, BaP-3,6-dione, and BaP-6,12-dione. Of interest was the presence of DNA-reactive metabolites such as BaP-3,6-dione, BaP-6,12-dione, and BaP 7,8-diol, which have been implicated in the causation of infertility and cancer. Our results indicate that women who are exposed to BaP via cigarette smoke, occupational settings, and diet are more likely at a larger risk of this toxicant-induced infertility and cancer than others.
Liver radiofrequency ablation (RFA) has been shown to disrupt the mechanical component of the gut barrier. The aim of the present study was to investigate the consequences of liver RFA on the biological gut barrier in terms of the effects of bile production rate and bowel inflammatory state on intestinal microflora balance.
A total of 25 New Zealand rabbits were assigned to five groups (n = 5 per group): group CBD: subjected to common bile duct (CBD) extracorporeal bypass; group CBD-RFA: subjected to CBD bypass plus one session of open liver RFA; group RFA: subjected to liver RFA; group sham: subjected to sham operation; and group TBD: subjected to total bile deviation (TBD). In groups CBD and CBD-RFA, bile production rate was assessed for 48 h. In groups sham and RFA, measurement of biliary glycine conjugates of cholic and deoxycholic acid levels, histopathologic examination of the non-ablated liver tissue, morphometric analysis, and histopathologic examination of the terminal ileum and microbiological analysis of fecal and tissue samples collected from the jejunum and the cecum (and in group TBD) were performed at 48 h post-operation.
One session of liver RFA resulted in ablation of 18.7 ± 2.7% of liver weight. Following liver RFA, bile production rate was reduced, while the levels of biliary bile salts were not affected. There was mild injury of the non-ablated liver parenchyma, mild intestinal wall inflammation, intestinal mucosa atrophy, and intestinal microbial population overgrowth.
Reduced in bile production and mild bowel inflammation secondary to liver RFA impaired the biological gut barrier as manifested by intestinal microflora imbalance.
Fixed drug eruption (FDE) is an unusual drug-related side effect that results in recurrent lesions whenever the causative drugs are used. FDEs usually occur as a single, sharply demarcated, round erythematous patch or plaque, occasionally with localized bullae. The most common offending agents include antimicrobials, nonsteroidal anti-inflammatory drugs, and antiepileptics. There are some reports where contact dermatitis and cutaneous vasculitis have been associated with the use of flurbiprofen. We present the case of a 50-year-old man with flurbiprofen-induced generalized bullous FDE. To the best of our knowledge, the most serious form of FDE, the generalized bullous FDE, to be caused by flurbiprofen has not been reported previously.
This article presents a systematic review of the recent literature on the scientific support of electromyography (EMG) and nerve conduction velocity (NCV) in diagnosing the exposure and toxicity of organophosphorus pesticides (OP). Specifically, this review focused on changes in EMG, NCV, occurrence of intermediate syndrome (IMS), and OP-induced delayed polyneuropathy (OPIDN) in human. All relevant bibliographic databases were searched for human studies using the key words "OP poisoning", "electromyography", "nerve conduction study," and "muscles disorders". IMS usually occurs after an acute cholinergic crisis, while OPIDN occurs after both acute and chronic exposures. Collection of these studies supports that IMS is a neuromuscular junction disorder and can be recorded upon the onset of respiratory failure. Due to heterogeneity of reports on outcomes of interest such as motor NCV and EMG amplitude in acute cases and inability to achieve precise estimation of effect in chronic cases meta-analysis was not helpful to this review. The OPIDN after both acute and low-level prolonged exposures develops peripheral neuropathy without preceding cholinergic toxicity and the progress of changes in EMG and NCV is parallel with the development of IMS and OPIDN. Persistent inhibition of acetylcholinesterase (AChE) is responsible for muscle weakness, but this is not the only factor involved in the incidence of this weakness in IMS or OPIDN suggestive of AChE assay not useful as an index of nerve and muscle impairment. Although several mechanisms for induction of this neurodegenerative disorder have been proposed as were reviewed for this article, among them oxidative stress and resulting apoptosis can be emphasized. Nevertheless, there is little synchronized evidence on subclinical electrophysiological findings that limit us to reach a strong conclusion on the diagnostic or prognostic use of EMG and NCV for acute and occupational exposures to OPs.
Waste management workers (WMWs) around the world are at risk of work-related health disorders. The influence of employment duration on individuals occupationally exposed to solid waste was investigated in this study. The study comprised (n = 280) 180 WMWs and 100 controls. Employment duration was obtained from questionnaire survey and categorized into three groups: group I (0.5–2 years), group II (>2–4 years) and group III (>4–6 years). Blood sample (10 ml) was collected from the antecubital vein of subjects for analysis. WMWs exhibited significantly (p < 0.001) elevated inflammatory markers (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and ceruloplasmin (Cp)) relative to control. While Cp increased, ESR and CRP decreased with increasing WMWs’ employment duration. Alteration in oxidant/antioxidant markers was characterized by significant (p < 0.001) decrease in ferric-reducing ability of plasma (FRAP) and catalase activity together with marked (p < 0.01) elevation of thiobarbituric acid reactive substances (TBARS) and uric acid (UA). TBARS, UA and FRAP increased while catalase decreased with WMWs’ employment duration. In addition, WMWs exhibited significantly (p < 0.01) elevated immunoglobulin A (IgA) and IgG, which also increased and decreased, respectively, with job duration. The significantly (p < 0.01) decreased haemoglobin and haematocrit levels as well as the significantly (p < 0.001) elevated total leukocytes in WMWs increased with employment duration. Alanine aminotransferase increased and albumin decreased significantly (p < 0.05) in WMWs, and these changes also increased and decreased, respectively, with job duration. Data suggest that levels of alteration of important systemic markers of health/disease are related to WMWs’ employment or exposure duration.
Benzo(a)pyrene (BaP), a typical environmental carcinogen, can induce cell death both by protein 53 or tumor protein 53 (p53)-independent and -dependent pathways. However, little is known about the molecular mechanisms of p53-independent pathways in BaP-induced cell death. In this study, cells with different genetic background (including p53-proficient human fetal lung fibroblast cell lines (MRC-5), p53-deficient human non-small-cell lung carcinoma cell lines (H1299), and p53-knockdown cell lines (MRC-5p53–/–)) were used to establish models of BaP-induced cell death. The results showed that BaP (8, 16, 32, and 64 μM) induced necroptotic cell death in the cell lines. The necroptotic cell death and DNA damage were concurrently observed. In the three cell lines, at 24 h after treatment, BaP (8–64 μM) upregulated expressions of BAX, BCL-2, and cleaved caspase-3 proteins, but not their messenger RNA levels. The findings suggested that BaP-induced necroptosis was modulated by the p53-independent pathway, which was related to the induction of BAX, decreased expression of BCL-2, and activation of caspase-3.
Nifurtimox (Nfx) and benznidazole (Bz) have serious toxic side effects. Manufacturers warn about significant adverse effects when simultaneous alcohol consumption is being made, but its mechanism is not known. The levels and toxicity of these drugs are linked to their liver microsomal nitroreduction to reactive metabolites. In this study, we analyzed whether alcohol drinking enhanced those nitroreductive processes. Male and female Sprague-Dawley rats, 5–6 weeks old (125–150 g body weight) were used. They were fed ad libitum for 28 days with Lieber and De Carli control or alcohol regular liquid diets. The rats were separated into two dietary groups: ethanol and control group. Both were pair fed with the respective diet. Their liver microsomes were isolated and the nicotinamide adenine dinucleotide phosphate-dependent nitroreduction of Nfx and Bz were determined. Alcohol drinking significantly induced microsomal nitroreduction of these drugs in male rats (11% for Nfx and 41% for Bz) but not in females. The activity observed in the alcohol-induced male rats was 100% inhibited by diphenyleneiodonium and attributable to P450 reductase. Inductive effects of alcohol drinking on nitroreductive activation of both drugs might be only partially involved in the harmful interactions described.
The detrimental effect of nuclear accidents due to localized or whole body radiation exposure results in severe cellular damage. The current study was carried out to evaluate radiation-mediated variability in blood components of metal scrap workers exposed accidently to cobalt-60 source. Blood samples collected initially from five hospitalized patients, coded P1–P5, were processed for total leukocyte counts (TLC), platelet (PLT) counts, haemoglobin, estimation of DNA double strand breaks by measuring phosphorylated form of H2AX (-H2AX) and chromosomal aberrations (dicentrics). Blood cells count (TLC), in all the patients except P2, was found decreased. Dicentrics increased in all the five patients. -H2AX was found significantly elevated in patients P2 and P4. After 3 days, 21 subjects working in close vicinity of accident site were evaluated for the above-mentioned markers to confirm their possibility of radiation exposure; however, all the parameters in these subjects were found within normal limits. Blood from patients P1–P5 was collected again after 11 days. Studies revealed exorbitant increase in -H2AX in lymphocytes and monocytes of patients P1, P4 and P5. TLC and PLT count in these patients had fallen further. Dicentrics declined with time in all the five patients. Based on the studied blood biomarkers, we conclude that the five subjects showed signs of radiation exposure. Measurement on radiation dose could not be performed in the current study; however, the generated data particularly on dicentrics provide ample evidence of radiation exposure.
Naltrexone is a competitive opioid receptor antagonist acting at the µ- and k-opioid receptors that blocks the euphoric effects of exogenous administered opioids. When used in opioid-dependent patients, naltrexone can cause acute and severe withdrawal symptoms.
This was a cross-sectional study conducted from December 2007 to March 2008 and consisted of patients who had used naltrexone accidentally or deliberately and were referred to Loghman-Hakim Poison Hospital, Tehran, Iran. All symptoms and signs were assessed and the relationship between the dose of naltrexone, opioid dependence, and outcome was evaluated.
In 132 patients referred to our hospital, the most frequently reported symptoms and signs occurring in more than 10% of patients were agitation (96.2%), altered level of consciousness (38.6%), nausea (28%), vomiting (27.3%), abdominal pain (24.2%), diarrhea (16.7%), bone and muscle pain (15.9%), tachycardia (12.9%), and dilated pupils (11.4%). Being the most prominent symptom, the agitation was the most difficult aspect of withdrawal to manage. Except for agitation, no relationship was found between the presence of these symptoms and the dose of naltrexone used. Outcome of the patients (classified as complete recovery, partial recovery, death, and no follow-up) was related to the substance of addiction (p < 0.05) but not to the naltrexone dose.
Emergency physicians should be aware of the potential for severe agitation from naltrexone-precipitated hyperacute withdrawal and its appropriate management. Opioid-dependent patients who wish to continue withdrawal and abstinence must be encouraged to visit trained physicians and be warned about misuse of naltrexone.
The aim of this study was to document the effect of hesperidin on the key enzyme activities of carbohydrate metabolism, lipid profile, and membrane-bound adenosine triphosphatases (ATPases) during 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinogenesis. Hesperidin has been reported to have multiple biological properties. Breast cancer was induced by single dose of DMBA (20 mg/kg body weight (bw)). The results revealed that there was a significant increase in the activities of hexokinase, phosphoglucoisomerase, and aldolase and a concomitant decrease in the activities of glucose-6-phosphatase and fructose-1,6-diphosphatase in cancer-induced animals. The activities of ATPases were found to be decreased both in erythrocyte membrane and in the liver of mammary cancer-bearing animals. The lipid profiles such as total cholesterol, free cholesterol, phospholipids, triglycerides, and free fatty acids significantly increased and in contrast the ester cholesterol in plasma was found to be decreased, whereas it was found to be elevated in the liver of cancer-bearing groups. The altered levels of the above-mentioned biochemical parameters in cancer-bearing animals were significantly ameliorated by the administration of hesperidin at the dosage of 30 mg/kg bw for 45 days. The histopathological analysis of breast and liver tissues were well supported the modulatory property of hesperidin, and this might be associated with normalizing the gluconeogenesis process, stabilization of cell membranes, and modulation of lipid biosynthesis.
The Globally Harmonized System for Classification and Labelling of Chemicals (GHS) considers metallic alloys, such as nickel (Ni)-containing stainless steel (SS), as mixtures of substances, without considering that alloys behave differently compared to their constituent metals. This study presents an approach using metal release, explained by surface compositional data, for the prediction of inhalation toxicity of SS AISI 316L. The release of Ni into synthetic biological fluids is >1000-fold lower from the SS powder than from Ni metal, due to the chromium(III)-rich surface oxide of SS. Thus, it was hypothesized that the inhalation toxicity of SS is significantly lower than what could be predicted based on Ni metal content. A 28-day inhalation study with rats exposed to SS 316L powder (<4 µm, mass median aerodynamic diameter 2.5–3.0 µm) at concentrations up to 1.0 mg/L showed accumulation of metal particles in the lung lobes, but no signs of inflammation, although Ni metal caused lung toxicity in a similar published study at significantly lower concentrations. It was concluded that the bioaccessible (released) fraction, rather than the elemental nominal composition, predicts the toxicity of SS powder. The study provides a basis for an approach for future validation, standardization and risk assessment of metal alloys.
CV247 (CV), an aqueous mixture of copper (Cu) and manganese (Mn) gluconates, vitamin C and sodium salicylate increased the antitumour effects of cisplatin (CDPP; cis-diamminedichloroplatinum) in vitro. We hypothesized that the antioxidant and cyclooxygenase-2 (COX-2; prostaglandin-endoperoxide synthase 2) inhibitory components of CV can protect the kidneys from CDPP nephrotoxicity in rats. CDPP (6.5 mg/kg, intraperitoneally) slightly elevated serum creatinine (Crea) and blood urea nitrogen (BUN) 12 days after treatment. Kidney histology demonstrated extensive tubular epithelial damage and COX-2 immunoreactivity increased 14 days after treatment. A large amount of platinum (Pt) accumulated in the kidney of CDPP-treated rats. Furthermore, CDPP decreased renal iron (Fe), molybdenum (Mo), zinc (Zn), Cu and Mn concentrations and increased plasma Fe and Cu concentrations. CDPP elevated plasma free radical concentration. Treatment with CV alone for 14 days (twice 3 ml/kg/day orally) did not influence these parameters. Chronic CV administration after CDPP reduced renal histological damage and slightly decreased COX-2 immunoreactivity, while failed to prevent the increase in Crea and BUN levels. Blood free radical concentration was reduced, that is, CV improved redox homeostasis. CV restored plasma Fe and renal Fe, Mo and Zn, while decreased Pt and elevated Cu and Mn concentrations in the kidney. Besides the known synergistic antitumour effects with CDPP, CV partially protected the kidneys from CDPP nephrotoxicity probably through its antioxidant effect.
The use of silver nanoparticles (Ag-NPs) is rapidly increasing, but there are limited data on their effects on the aquatic environment. The present study aimed to determine the acute toxicity and evaluate the effect of subacute concentrations of Ag-NPs (Nanocid®: average particle size of 61 nm) on hematological and plasma biochemical indices of silver carp, Hypophthalmichthys molitrix, after 3, 7 and 14 days. The 24-, 48-, 72- and 96-h median lethal concentration (LC50) values of Nanocid for silver carp were estimated at 0.810, 0.648, 0.383 and 0.202 mg/L, respectively; 20% and 10% of the 96-h LC50 values (0.04 and 0.02 mg/L) were selected for subacute study. Red blood cell (RBC) count, hemoglobin (Hb) count and hematocrit (Hct) level were significantly reduced at both concentrations tested (p < 0.05). White blood cell (WBC), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), cortisol and glucose levels in Nanocid-treated groups were significantly higher than the controlled group at experimental periods (p < 0.05). In conclusion, Ag-NPs intoxication resulted in erythrocyte reduction, hematological disturbances, leucocytosis and stress response in silver carp and offered a simple tool to evaluate toxicity-derived alterations.
This study investigated the effects of thiamine pyrophosphate (TPP) at dosages of 10 and 20 mg/kg on oxidative stress induced in rat brain tissue with cisplatin and compared this with thiamine. Cisplatin neurotoxicity represents one of the main restrictions on the drug being given in effective doses. Oxidative stress is considered responsible for cisplatin toxicity. Our results showed that cisplatin increased the levels of oxidant parameters such as lipid peroxidation (thio barbituric acid reactive substance (TBARS)) and myeloperoxidase (MPO) in brain tissue and suppressed the effects of antioxidants such as total glutathione (GSH) and superoxide dismutase (SOD). TPP, especially at a dosage of 20 mg/kg, significantly reduced TBARS and MPO levels that increase with cisplatin administration compared with the thiamine group, while TPP significantly increases GSH and SOD levels. In addition, the level of 8-Gua (guanine), a product of DNA damage, was 1.7 ± 0.12 8-hydroxyl guanine (8-OH Gua)/105 Gua in brain tissue in the control group receiving cisplatin, compared with 0.97 ± 0.03 8-OH Gua/105 Gua in the thiamine pyrophosphate (20 mg/kg) group and 1.55 ± 0.11 8-OH Gua/105 Gua in the thiamine (20 mg/kg) group. These results show that thiamine pyrophosphate significantly prevents oxidative damage induced by cisplatin in brain tissue, while the protective effect of thiamine is insignificant.
The organochlorine pesticide, dichlorodiphenyltrichloroethane (DDT), is still used to combat the spread of malaria in several developing countries despite its accumulation and known hepatotoxic effects that have been demonstrated both in vitro and in vivo. N-Acetylcysteine (NAC) is a recognized hepatoprotective agent that has been reported to reduce hepatotoxicity initiated by many different compounds. The aim of this study was to determine whether NAC could counter in vitro hepatocyte injury induced by DDT or its two major metabolites, dichlorodiphenyldichloroethylene and dichlorodiphenyldichloroethane. HepG2 cell cultures were used to assess the following parameters of toxicity: cellular viability, intracellular levels of reactive oxygen species (ROS), mitochondrial membrane potential and initiation of apoptosis. None of the three test compounds induced ROS generation, yet exposure to any of the three compounds produced mitochondrial hyperpolarization, which was countered by NAC pretreatment. All three test compounds also induced apoptotic cell death, which was inhibited by NAC. Despite NAC counteracting some adverse intracellular changes due to organochlorine exposure, it appeared to aggravate the cytotoxic effects of the organochlorine compounds at low test concentrations. As the same outcome may also occur in vivo, results from the present study raise concern about the use of NAC as treatment for DDT-induced hepatotoxicity.
The present study investigated the genotoxic effects of flumorph in various organs (brain, liver, spleen, kidney and sperm) of mice. The DNA damage, measured as comet tail length (µm), was determined using the alkaline comet assay. The comet assay is a sensitive assay for the detection of genotoxicity caused by flumorph using mice as a model. Statistically significant increases in comet assay for both dose-dependent and duration-dependent DNA damage were observed in all the organs assessed. The organs exhibited the maximum DNA damage in 96 h at 54 mg/kg body weight. Brain showed maximum DNA damage followed by spleen > kidney > liver > sperm. Our data demonstrated that flumorph had induced systemic genotoxicity in mammals as it caused DNA damage in all tested vital organs, especially in brain and spleen.
Methanol, acetaldehyde, acetone, and ethanol, which are commonly used as biomarkers of several diseases, in acute intoxications, and forensic settings, can be detected and quantified in biological fluids. Gas chromatography (GC)–mass spectrometry techniques are complex, require highly trained personnel and expensive materials. Gas chromatographic determinations of ethanol, methanol, and acetone have been reported in one study with suboptimal accuracy. Our objective was to improve the assessment of these compounds in human blood using GC with flame ionization detection.
An amount of 50 µl of blood was diluted with 300 µl of sterile water, 40 µl of 10% sodium tungstate, and 20 µl of 1% sulphuric acid. After centrifugation, 1 µl of the supernatant was inje-cted into the gas chromatograph. We used a dimethylpolysiloxane capillary column of 30 m 0.25 mm 0.25 µm.
We observed linear correlations from 7.5 to 240 mg/l for methanol, acetaldehyde, and acetone and from 75 to 2400 mg/l for ethanol. Precision at concentrations 15, 60, and 120 mg/l for methanol, acetaldehyde, and acetone and 150, 600, and 1200 mg/ml for ethanol were 0.8–6.9%. Ranges of accuracy were 94.7–98.9% for methanol, 91.2–97.4% for acetaldehyde, 96.1–98.7% for acetone, and 105.5–111.6% for ethanol. Limits of detection were 0.80 mg/l for methanol, 0.61 mg/l for acetaldehyde, 0.58 mg/l for acetone, and 0.53 mg/l for ethanol.
This method is suitable for routine clinical and forensic practices.
The aim of this experimental study was to investigate the effects of mad honey (grayanotoxin, GTX), used in complementary medicine for a variety of purposes besides being food, on pain thresholds in normal mice as model for acute pain and diabetic mouse as model for neuropathic pain.
Hind paw withdrawal pain threshold to thermal stimulus was measured with a plantar analgesia meter in a mice model using healthy intact animals for acute pain and streptozotocin-induced diabetic animals for chronic neuropathic pain. Time and dose-dependent effects of intraperitoneally (i.p.) administered GTX were investigated in both acute and neuropathic pain.
In the acute pain model, administration of GTX caused a dose- and time-dependent marked increase in the pain latency values. In diabetic mice, which had markedly increased threshold to pain, GTX (0.1 mg/kg, i.p.) restored the mean pain latencies by decreasing from the pre-GTX treatment values of 3.2 ± 0.6 to 3.0 ± 0.9s at 10 min, 3.2 ± 0.6s at 20 min, 3.4 ± 0.6s at 30 min, 2.6 ± 0.5s at 60 min and 2.4 ± 0.6s (p < 0.05) at 100 min.
The results from this experimental study indicate that GTX exhibits significant analgesic activity and has potential benefits against painful diabetic neuropathy. This is compatible with the widespread use of GTX containing mad honey for alleviating pain. Further studies involving long-term applications are needed for a more decisive conclusion regarding the usefulness of GTX as an analgesic, especially in the treatment of painful neuropathy.
Mitogen-activated protein kinases (MAPKs) are involved in neuronal death caused by many cytotoxins. Conventional MAPKs consist of three family members: extracellular signal-regulated kinase-1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38. It has been originally shown that ERK1/2 is important for cell survival, whereas JNK and p38 are deemed stress responsive and thus involved in apoptosis. However, information describing the role of MAPKs in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced neurotoxicity is insufficient. The aim of this study was to identify the role of MAPK cascades in TCDD-induced neurotoxicity using differentiated pheochromocytoma (PC12) cells as a model for neuronal cells. Cell viability assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and flow cytometry analysis showed that TCDD attenuated cell viability with a dose- and time-dependent manner and significantly induced apoptosis in primary cortical neurons and PC12 cells. Western blot analysis indicated that TCDD markedly activated the expression of ERK1/2, JNK and p38 in TCDD-treated PC12 cells. Furthermore, PD98059 (ERK1/2 inhibitor), SP600125 (JNK inhibitor) and SB202190 (p38 inhibitor) notably blocked the effect of TCDD on cell apoptosis. Based on the findings above, it is concluded that the activation of MAPK signaling pathways may be associated with TCDD-mediated neuronal apoptosis.
Aim: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage the pain and inflammation. NSAIDs can cause serious side effects, including vision problems. However, the underlying mechanisms are still unclear. Therefore, we aimed to investigate the effect of meclofenamic acid (MFA) on retinal pigment epithelium (RPE). Materials and methods: In our study, we applied image analysis and whole-cell patch clamp recording to directly measure the effect of MFA on the gap junctional coupling between RPE cells. Results: Analysis of Lucifer yellow (LY) transfer revealed that the gap junction communication existed between RPE cells. Functional experiments using the whole-cell configuration of the patch clamp technique showed that a gap junction conductance also existed between this kind of cells. Importantly, MFA largely inhibited the gap junction conductance and induced the uncoupling of RPE cells.
Other NSAIDs, like aspirin and flufenamic acid (FFA), had the same effect. Conclusion: The gap junction functionally existed in RPE cells, which can be blocked by MFA. These findings may explain, at least partially, the vision problems with certain clinically used NSAIDs.
Dimerized translationally controlled tumor protein (dTCTP) plays a role in allergic diseases. A 7-mer peptide, dimerized translationally binding protein 2 (dTBP2), binds to dTCTP and inhibits dTCTP, suggesting that the 7-mer peptide may have therapeutic potential. We assessed the safety of dTBP2 by examining its cytotoxicity to both human bronchial epithelial cells and mice. dTBP2 did not cause cytotoxicity to the epithelial cells in concentrations up to 100 μg/ml. Also, dTBP2 caused no adverse effects upon repeated administration of 50 mg/kg over 24 h to mice. Hence, we conclude that dTBP2 is a safe candidate drug for use in the therapy of allergic diseases.
The aim of this study was to examine the antitumour activity of resveratrol in human colorectal cancer cell lines (HCT116 and Caco2) and to explore its mechanism of action assuming that it is by calorie-restriction effect. Resveratrol inhibited the proliferation of colon cancer cells with half maximal inhibitory concentration (IC50) equal to 50 and 130 μM for HCT116 and Caco2, respectively. Caco2 cells appeared with significant time-dependent increase in the glycolytic pathway, a behaviour that was absent in HCT116 cells. Resveratrol (100 μM) significantly decreased the glycolytic enzymes (pyruvate kinase and lactate dehydrogenase) in Caco2 cells, while an increase in citrate synthase activity and a decrease in glucose consumption were observed in both cell lines. Moreover, resveratrol downregulated the expressions of leptin and c-Myc, and decreased the content of vascular endothelial growth factor. The apoptotic markers, caspases 3 and 8, were activated and the Bax/BCl2 ratio was increased. The study suggested a promising anticancer activity of resveratrol, calorie-restriction pathway may be one of the driving forces for this activity.
The present study aimed to compare the effect of gender difference on hemodynamic consequences in the development of monocrotaline (MCT)-induced pulmonary hypertension in rat. The effect of antioxidant enzyme systems on the development of pulmonary hypertension mediated by the phytotoxin MCT and the effect of gender on these antioxidant systems were also investigated. For this purpose, the right ventricular pressures (RVPs) and right ventricular/heart weight (HW) ratios were compared between groups and the glutathione (GSH) level and superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) activities were determined in lung and liver tissue samples of rats. RVP and right ventricular/HW ratios significantly increased in the MCT group compared to the control group. In the MCT group, RVP was significantly higher in males than females. MCT-induced pulmonary hypertension resulted in decreased GSH level, decreased GST and SOD activities and increased CAT activity in lung and liver tissues of both male and female rats. In addition, the lung and liver GSH level and GST and SOD levels were higher in female control rats compared to male control rats. The results of the present study, that antioxidant enzyme activities were different between the groups, highlight the possible role of oxidative stress in the pathogenesis of MCT-induced pulmonary hypertension in rats. Moreover, the lower antioxidant defense capacity of male rats than female rats may be considered as a cause of more aggressive course of MCT-induced pulmonary hypertension in males compared to females.
It has been hypothesized that oils containing high levels of omega-3 polyunsaturated fatty acids, such as canola and fish oil, could counteract some of the adverse effects induced by phthalates. In the present study, the influence of different oily vehicles on di-butyl phthalate (DBP)-induced testicular toxicity and lipid profile was investigated. Pregnant Wistar rats were treated by oral gavage from gestation days 13 to 20 with DBP (500 mg/kg/day) diluted in three different vehicles: corn, canola or fish oil. Male fetuses were analyzed on gestation day 20. DBP exposure lowered intratesticular testosterone levels and anogenital distance, regardless of the vehicle used. The percentage of seminiferous cords containing multinucleated gonocytes and cord diameter was increased in DBP-exposed groups, compared with vehicle controls, with no difference between the three DBP-exposed groups. Clustering of Leydig cells was seen in all DBP groups. Lipid profile indicated that administration of canola and fish oil can increase the content of omega-3 fatty acids in rat testis. However, content of omega-3 was diminished in DBP-treated groups. Overall, our results indicate that different oily vehicles did not alter fetal rat testicular toxicity induced by a high DBP dose.
In the present study, we have evaluated the chemopreventive effects of perillyl alcohol (POH) against diethylnitrosamine-initiated and 2-AAF (2-acetylaminofluorine)-promoted hepatocarcinogenesis in Wistar rats. Efficacy of POH against 2-AAF-induced hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes and expression levels of proliferative markers. 2-AAF is a potent hepatotoxicant and a hepatic carcinogen that induces its effect by causing oxidative stress. Pre-treatment of POH prevented oxidative stress and tumour incidences. POH suppressed 2-AAF-induced early tumour markers, namely ornithine decarboxylase activity, thymidine phosphorylase and proliferating cell nuclear antigen (PCNA) protein and also suppressed the expression of pro-apoptotic protein P53. Histopathological findings revealed that POH-pretreated groups showed marked recovery. From our results, it could be concluded that POH markedly protects against chemically induced liver cancer and acts possibly by virtue of its antioxidant and antiproliferative activities.
This study aimed to investigate the implication of some apoptotic and lipid peroxidation markers in preeclampsia (PE). A total of 25 women with PE and 25 age- and parity-matched normal pregnant women were enrolled in this study. The malondialdehyde (MDA) level, caspase-9 activity and the percentage of DNA fragmentation were significantly higher in placental tissue of PE than in control women. The serum level of MDA was significantly elevated in women with PE having delivery by cesarean section (CS) than in women with PE having vaginal delivery. In vitro study demonstrated that the addition of 0.5 mM Fe2+ and 0.1 mM ascorbate caused increase in the production of MDA level in placental tissue with PE than normal placentas, and vitamin E (100 µM) caused lower inhibition of in vitro lipid peroxidation in placental tissue with PE when compared with normal tissue. The activity of caspase-9 and percentage of DNA fragmentation were associated with the severity of the PE and both could differentiate between PE and control women with 88% and 100% sensitivity and 96% and 100% specificity, respectively. The activities of caspase-8 and/or -9 were positively correlated with the maternal age but only caspase-8 was negatively correlated with neonatal birth weight and placental weight. In conclusion, the elevations of MDA, caspase-9 activity and the percentage of DNA fragmentation in the placentas of women with PE implicate the involvement of lipid peroxidation and apoptosis in PE. The placenta represents a considerable source of the elevated circulating MDA in PE.
We aimed to find the relationship between serum transforming growth factor beta 1(TGF-β1) and urinary monocyte chemoattractant protein-1 (MCP-1) throughout the course of diabetic nephropathy (DN) and to assess the relationship between both levels and other parameters of renal injury such as albumin/creatinine ratio and estimated glomerular filtration rate (eGFR). Serum TGF-β1, urinary MCP-1, eGFR, and glycosylated hemoglobin (HbA1c) were measured in 60 patients with type II diabetes mellitus with different degrees of nephropathy (20 patients with normoalbuminuria, 20 patients with microalbuminuria, and 20 patients with macroalbuminuria) and compared with 20 matched healthy control subjects. Both the levels of serum TGF-β1 and urinary MCP-1 were significantly higher in patients with micro- and macroalbuminuria (137.8 ± 69.5 and 329.25 ± 41.46 ng/dl, respectively, for TGF-β1 and 167.41 ± 50.23 and 630.87 ± 318.10 ng/g creatinine, respectively, for MCP-1) compared with normoalbuminuric patients and healthy controls (33.25 ± 17.5 and 29.64 ± 10.57 ng/dl, respectively, for TGF-β1 and 63.85 ± 21.15 and 61.50 ± 24.81 ng/g creatinine, respectively, for MCP-1; p < 0.001). There was a positive significant correlation between the levels of serum TGF-β1 and those of urinary MCP-1 (r = 0.73, p < 0.001). Also, serum TGF-β1 and urinary MCP-1 correlated positively with HbA1c (r = 0.49 and 0.55, respectively, p < 0.05 for both) and inversely with eGFR (r = –0.69 and –0.60, respectively, p < 0.001 for both). We can conclude that serum TGF-β1 and urinary MCP-1 can be used as the markers for detection of progression of DN. Antagonizing TGF-β1 and MCP-1 might be helpful in attenuating the progression of nephropathy in diabetic patients.
Hair dyes are widely used and very popular xenobiotics. Most of these products contain paraphenylenediamine (PPD) that can cause methemoglobinemia. We here report a case of severe methemoglobinemia that we treated using large amounts of methylene blue.
A 30-year-old man visited a regional hospital with cyanosis. He was congenitally blind and had autism. For several weeks, he had mistaken hair dye for toothpaste. When he arrived at a regional hospital, he was drowsy with cyanosis and his initial serum methemoglobin (MetHb) level was 59.5%. After being treated with 2 mg/kg methylene blue (1 mg/kg 2 administrations), he was transferred to a tertiary university hospital. Upon presentation at the Emergency Department in the tertiary hospital, his MetHb level was found to be 49.4% and his oxygen saturation was 80%. He was then admitted to the intensive care unit. After treatment with 4 mg/kg methylene blue (1 mg/kg 4 administrations), he successfully recovered.
Because PPD can result in serious methemoglobinemia, clinicians should test it in cyanotic patients who have been exposed to hair dye for an extended period.
The aim of the present study was to investigate the effect of vanadyl sulfate supplementation on the skin tissues of diabetic and control rats. In this study, 6–6.5 months old male Swiss albino rats were used. The animals were randomly divided into the following four groups: group I, control (nondiabetic intact animals); group II, vanadyl sulfate control; group III, streptozotocin (STZ)-diabetic animals and group IV, STZ-diabetic animals given vanadyl sulfate. The animals were made diabetic by intraperitoneal injection of a single dose of 65 mg/kg STZ in 0.01 M citrate buffer (pH = 4.5). From day 1 to day 60, 100 mg/kg vanadyl sulfate was given daily by gavage technique to one of the control and diabetic groups. Body weights and blood glucose levels were estimated on experimental days 0, 1 and 60. On the 60th day, skin tissue samples were taken, glutathione (GSH), lipid peroxidation (LPO), nonenzymatic glycosylation (NEG) and protein levels, catalase (CAT), superoxide dismutase (SOD) and glutathione-S-transferase (GST) activities were determined. Blood glucose, skin LPO and NEG levels increased, but skin GSH levels and CAT, SOD and GST activities decreased in the STZ group. Treatment with vanadyl sulfate reversed these effects. The present study showed that vanadyl sulfate exerted antioxidant properties and may prevent skin damage caused by diabetes.
Caffeine and 1,3-dimethylamylamine (DMAA) are widely used alone and in combination with dietary supplements. No investigation has determined the safety profile of chronic intake of caffeine or DMAA, alone or in combination, within the same study design. A total of 50 young and healthy men completed 12 weeks of daily supplementation with either a placebo (n = 11), caffeine at 250 mg day–1 (n = 14), DMAA at 50 mg day–1 (n = 13), or caffeine at 250 mg day–1 + DMAA at 50 mg day–1 (n = 12). Before and after 6 and 12 weeks of supplementation, the following variables were measured: body mass/composition, resting respiratory rate, blood pressure, 12-lead electrocardiogram, urinalysis, complete blood count, metabolic panel, lipid panel, and oxidative stress, inflammatory, and cardiac biomarkers. No interaction effects were noted for any variable (p > 0.05), with little change occurring across time for subjects in any of the four conditions. With the exception of urinary pH (p = 0.05; Pre (6.5 ± 0.1) higher than week 6 (6.1 ± 0.1)) and blood CO2 (p = 0.02; week 12 (25.9 ± 0.3 mmol L–1) higher than week 6 (24.8 ± 0.3 mmol L–1)), no time effect was noted for any other variable (p > 0.05). These data indicate that 12 weeks of daily supplementation with caffeine and DMAA, alone or in combination, does not result in a statistically significant change in any of the measured outcome variables.
The aim of the present study was to evaluate the protective effect of aqueous extract from Platycodon grandiflorum (BC703) on bile duct ligation (BDL)-induced hepatic fibrosis in rats. BDL rats were divided into three groups, which orally received distilled water or BC703 (10 or 50 mg/kg/day) for consecutive 28 days. Antifibrotic effects of BC703 on BDL-induced hepatic fibrosis in rats were estimated by assessing serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), blood urea nitrogen (BUN), transforming growth factor-beta 1 (TGF-β1) and hepatic levels of malondialdehyde (MDA), glutathione (GSH), total superoxide dismutase (SOD) and nitric oxide (NO). The biochemical observations were supplemented by histopathological examination of liver samples stained with hematoxylin and eosin and Masson’s trichrome stain. ALT, AST, TBIL and BUN were elevated in the group treated with BDL alone than in the sham-operated group. These elevations were significantly decreased by BC703 treatment. Hepatic GSH and SOD levels, depressed by BDL, were also increased in the BC703 group. In addition, increases in hepatic MDA and NO levels in the BDL-induced cholestasis were attenuated by BC703 treatment. Furthermore, BC703 treatment significantly reduced the serum level of fibrogenic cytokine, TGF-β1. Histopathological studies further substantiated the protective effect of BC703 on BDL-induced hepatic fibrosis in rat. BC703 may have beneficial effects not only on hepatic fibrosis by cholestasis but also on hepatic fibrosis development in patients with chronic hepatic disease.
The aim of this study was to investigate the role of serum cholinesterase (SChE) activity and S100B protein in the evaluation of patients with acute organophosphate (OP) poisoning. Patients with acute OP poisoning admitted to the emergency department were included in this cross-sectional study. Twenty healthy volunteers served as controls. The SChE activity and serum S100B were determined on admission. Patients were divided into two groups (low severity and high severity). Thirty-six patients diagnosed with acute OP poisoning were enrolled. Serum S100B concentrations were higher in patients than in the control group (p < 0.05). In the high-severity group, the SChE levels were lower and the S100Bs levels were higher than in the low-severity group. The SChE level was not different between survivors and nonsurvivors. S100B levels were higher in nonsurvivors than in survivors. According to receiver–operating characteristic curve analysis, the optimal cutoff value of serum S100B level to predict mortality was 236.5 pg/mL, with 71.4% sensitivity and 89.7% specificity. Our data suggest that initial SChE level is related to the clinical severity but not with mortality. S100B may be a useful marker in the assessment of clinical severity and prediction of mortality in acute OP poisoning.
Pesticides are used in agriculture to protect crops from insects–pests. Most of the field workers of North Indian population are exposed to commonly used insecticides. In the present study, pesticides induced oxidative stress as well as alterations in the level of acetylcholinesterase (AChE) in a total of 70 male healthy agricultural sprayers, exposed to pesticides for about 5 years, were studied and the results were compared with 70 controls. The levels of antioxidant enzymes (superoxide dismutase, CAT, glutathione-S-transferase and glutathione peroxidase), AChE, lipid peroxidation and glutathione (GSH) contents were determined in their blood erythrocytes (red blood cells (RBCs)). The results indicated significant increase in the levels of malondialdehyde as well as the activities of antioxidant enzymes in pesticide-exposed individuals. The levels of GSH, RBC-AChE activity and plasma antioxidant potential were sharply decreased when compared with control subjects. The ferric-reducing ability of plasma (FRAP) assay was carried out to evaluate the antioxidant potential of pesticide in exposed as well as healthy controls. A significant positive correlation was observed between plasma FRAP value and the activity of AChE from RBCs in pesticides sprayers. Furthermore, these results were supported by enhanced messenger RNA expressions of cytochrome P450 isoform 2E1 (CYP2E1) and gutathione-S-transferase isoform pi (GST-pi) in the white blood cells of the randomly selected pesticide-exposed individuals. The decreased GSH level in human red blood cells accompanied by increase in the levels of the activities of antioxidative enzymes and over expressions of CYP2E1 and GST-pi is an indicative of oxidative stress in pesticides-exposed individuals. The reduced activity of AChE indicates possible occurrence of perturbations in blood as well as neurotoxicity in pesticide sprayers.
Acute carbon monoxide poisoning (ACMP) leads to significant toxicity of the central nervous system and heart, and even death, following it, some patients suffered delayed encephalopathy. Until now, no theory had explained it exactly. It was reported that neovascularization was found in acute ischemic brains and also that angiopoietins (Ang) play important roles in the process of angiogenesis, for example, the members of Ang family, Ang-1 and Ang-2 may promote angiogenesis by combining with endothelial-specific cell surface tyrosine kinase receptor Tie-2. Interestingly, some studies suggested that small vascular injury may play an important role in the pathogenesis of delayed encephalopathy after carbon monoxide poisoning. Does neovascularization also occur in the brains after ACMP? Do Ang also take part in the pathologic processes in the brains that suffered ACMP? People know little about it. In the present study, we showed that neovascularization also occurred in the brains that suffered ACMP, and there are two expression peaks of Ang-1, Ang-2 and Tie-2, respectively, in the mice brains on the 3rd day and the 7th day following ACMP, and draw a conclusion that the Ang/Tie-2 system takes part in the pathologic processes in the brains that suffered ACMP by participating in neovascularization.
Channels responsible for slowly activating delayed-rectifier potassium current (IKs) are composed of KCNQ1 and KCNE1 subunits, and these channels play a role in the repolarization of cardiac action potentials. Recently, we showed that the antihyperlipidemic drug probucol, which induces QT prolongation, decreases the IKs after 24-h treatment. In the present study, we investigated the effects of three cholesterol-lowering agents (probucol, an enhancer of cholesterol efflux; simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; and triparanol, a 3β-hydroxysterol-24-reductase inhibitor) on cholesterol synthesis, the KCNQ1 current (IKCNQ1), and the IKs to clarify the differences in the modes of action of these agents on the IKs. Probucol did not inhibit cholesterol synthesis and had no effect on IKCNQ1, while IKs decreased after 24-h treatment. Simvastatin inhibited cholesterol synthesis and decreased IKCNQ1 and IKs. Additionally, the activation kinetics of IKs became faster, compared with that of control IKs. Triparanol inhibited cholesterol synthesis but did not reduce IKCNQ1 and IKs. However, the activation kinetics of IKs became faster. Our data indicated that the mechanism by which probucol inhibits IKs was not mediated by the inhibition of cholesterol synthesis but depended on an interaction with the KCNQ1/KCNE1 complex. Meanwhile, the reduction in cholesterol induced by simvastatin and triparanol is one of the mechanisms that affects the kinetics of Iks.
The aim of the present study was to investigate the long-term and high-dose application of ketamine on the liver by employing histologic and biochemical methods. A total of 30 male rats were randomly assigned to control and four treatment groups (n: 6). Saline for control group and different doses of ketamine for four treatment groups (40, 60, 80 and 100 mg kg–1) were administered intraperitoneal twice a day for 2 weeks. Immunohistological staining, light and electron microscopy were used to study tissue specimens. Histopathological changes were more severe and diverse in groups 80 and 100 mg kg–1 day–1, and the least significant change was observed in groups 40 and 60 mg kg–1 day–1. The most important ultrastructural changes were seen in mitochondria and in the rough endoplasmic reticulum. The immunoreactivity of calcineurin was determined as different. Prolonged use of ketamine caused hepatocellualar toxicity and histological changes in hepatocytes in a dose-dependent manner in all experimental groups.
Carbon monoxide (CO) is one of the leading causes of poisoning; it inhibits oxygen delivery, subsequently causing ischemic changes and ultimately death by multiorgan failure. Furthermore, thromboembolic episodes due to CO poisoning have been reported. However, intracardiac thrombus formation following exposure to CO has been very rarely described. Here, a case of right atrial large thrombus formation after CO poisoning is presented.
A previously healthy 24-year-old woman was referred for CO poisoning. She has attempted suicide, and her initial mental status was drowsy with focal memory loss. Her initial CO fraction was 16%, and initial laboratory data showed creatinine kinase-myocardial bound of 90.6 ng/mL (upper limit 5 ng/mL) and troponin I of 1.899 ng/mL (upper limit 1.5 ng/mL). A transthoracic echocardiography was performed 24 h after the accident, revealing a 30 15 mm nodular echogenic mass in the right atrium. Anticoagulation with low-molecular-weight heparin was started along with hyperbaric oxygen therapy. After 7 days of heparinization, the large thrombus in right atrium had resolved.
This report describes an intracardiac thrombus formation induced by CO poisoning. Because intracardiac thrombus can result in pulmonary embolism and cerebral embolic infarction, its consideration following CO poisoning is important.
Effects of flavonoids quercetin and chrysin on lipid peroxidation and histopathological changes in liver of diabetic mice were studied and compared with the antioxidant and reducing ability of quercetin and chrysin and their ability to chelate Fe2+ ions in vitro. Diabetes was induced in Swiss albino mice with a single intravenous injection of alloxan (75 mg kg–1). Two days after alloxan injection, flavonoid preparations (50 mg kg–1 per day) were given intraperitoneally for 7 days in diabetic mice. The lipid peroxidation was evaluated by measuring the malondialdehyde production using the 2-thiobarbituric acid test. Administration of quercetin and chrysin to diabetic mice resulted in a significant decrease in lipid peroxidation level in liver tissue. Treatment of diabetic mice with flavonoids solutions results in decreased number of vacuolated cells and degree of vacuolization of the liver tissue. The protective role of flavonoids against the reactive oxygen species–induced damages in diabetic mice gives a hope that they may exert similar protective action in humans.
Acute inhalation exposure to high levels of manganese (Mn) is associated with pulmonary edema and impaired function. The immune-mediated lung epithelium injury of Mn in vivo and in vitro experiments has been well characterized, whereas its apoptotic effect is not well defined. Our results show that human bronchial epithelial (16HBE) cells undergo caspase-9-mediated cell death in response to Mn. Loss of mitochondrial membrane potential (m), the formation of reactive oxygen species and release of cytochrome c were regulated during this process. In addition, decreasing c-Myc level and increasing of phosphorylated p53 (Ser 15) and WAF1/p21 were also taken part in Mn-mediated lung toxicity. Proteasome inhibitor MG132 could increase c-Myc protein in abundance. Taking together, our results demonstrate that caspase-9-dependent intrinsic pathway, the downregulation of c-Myc and the upregulation of p53 and phosphorylated p53 might be responsible for Mn-mediated apoptosis in 16HBE cells. Moreover, c-Myc decrease might be due to increased degradation through the ubiquitin–proteasome pathway.
Viscum album agglutinin-I (VAA-I) is a plant lectin, which possesses anti-inflammatory properties, including the ability to induce neutrophil apoptosis by a mechanism that is not completely understood. Among the three actin-binding membrane-anchoring proteins ezrin/radixin/moesin (ERM), neutrophils are known to express ezrin and moesin. The behavior of these proteins in apoptotic neutrophils is not well established. In the present study, the expression and localization of ezrin and moesin by Western blot and immunofluorescence revealed a clear degradation and relocalization of both the proteins during VAA-I-induced apoptosis. Also, flow cytometry analysis revealed that VAA-I markedly and significantly induced the cell surface expression of ezrin and moesin and this was reversed when cells were pretreated with the Syk inhibitor piceatannol. The expression of ezrin and moesin on the cell surface of apoptotic neutrophils may represent a mechanism responsible for the appearance of autoantibodies directed against ERM proteins, which have been found in the serum of patients suffering from autoimmune diseases. Therefore, the ability of VAA-I to increase cell surface expression of cytoskeletal proteins in apoptotic neutrophils provides important insight into a possible toxic mechanism of this plant lectin and this has to be considered for its potential utilization for in vivo treatment.
Sepsis, often initiated by an infection, is a state of disrupted inflammatory homeostasis. There is increasing evidence that oxidative stress has an important role in the development of sepsis-induced multiorgan failure. Resveratrol (RV) is a polyphenolic compound found in the skin of red fruits, such as mulberries and red grapes, and in peanuts. RV has been reported to have an antioxidant, antiproliferative, and anti-inflammatory properties in various models. It has also been found to inhibit the proliferation of a variety of human cancer cell lines, including breast, prostate, colon, pancreatic, and thyroid. This study has been undertaken to assess the role of RV on the sepsis-induced oxidative DNA damage in the lymphocytes of Wistar albino rats by the standard and formamidopyrimidine DNA glycosylase (Fpg)-modified comet assays. The parameters of tail length, tail intensity, and tail moment were evaluated for the determination of DNA damage. According to the study, the DNA damage was found to be significantly higher in the sepsis-induced rats when compared with the control rats (p < 0.05). The parameters were significantly decreased in the RV-treated sepsis-induced group when compared with the sepsis-induced group. The parameters in the sepsis-induced rats were found to be significantly higher in the Fpg-modified comet assay when compared with the standard comet assay (p < 0.05), and RV treatment decreases the DNA damage in the sepsis-induced rats, suggesting that the oxidative stress is likely to be responsible for DNA damage and RV might have a role in the prevention of sepsis-induced oxidative DNA damage.
Ipomoea carneaJacq. ssp. fistulosa (Mart. Ex Choisy; Convolvulaceae; I. carnea<) possesses a toxic component: an indolizidine alkaloid swainsonine (SW) that has immunomodulatory effects due to its inhibition of glycoprotein metabolism. It is also known that SW is excreted into both the amniotic fluid and milk of female rats exposed to I. carnea. Thus, the aim of this study was to determine whether SW exposure, either in utero or from the milk of dams treated with I. carnea, modulates offspring immune function into adulthood. In addition, adult (70 days old) and juvenile rats (21 days old) were exposed to I. carnea in order to evaluate several other immune parameters: lymphoid organs relative weight and cellularity, humoral and cellular immune responses. Offspring exposed to I. carnea during lactation developed rheumatoid arthritis (RA) in adulthood after an immunogenic challenge. In addition, both adult and juvenile rats exposed to I. carnea showed discrepancies in several immune parameters, but did not exhibit any decrease in humoral immune response, which was enhanced at both ages. These findings indicate that SW modulates immune function in adult rats exposed to SW during lactation and in juvenile and adult rats exposed to SW as juveniles and adults, respectively.
A number of studies have focused attention on various biochemical abnormalities evoked due to exposure to organochlorine pesticides (OCPs). The aim of the present study was to analyze the OCP residues in maternal and cord blood of women and assess the levels of different non-enzymatic oxidative stress markers as well as to establish correlation with OCP levels, if any. Thirty women in each group of full-term delivery (FTD; ≥37 weeks of gestation) and preterm delivery (PTD; <37 weeks of gestation) were enrolled in this study. Levels of OCPs like Hexachlorocyclohexane (HCH), endosulfan, p,p' Dichlorodiphenyldichloroethylene (DDE) and p,p’ Dichlorodiphenyltrichloroethane (DDT) were analyzed by gas chromatography. Non-enzymatic oxidative stress was measured by the quantification of malondialhyde (MDA), protein carbonyl, reduced glutathione (GSH) and ferric-reducing ability of plasma (FRAP). MDA and protein carbonyl levels were increased significantly, while the levels of GSH and FRAP were decreased in PTD in comparison to FTD cases. We have observed higher levels of β-HCH and α-endosulfan and increased oxidative stress in PTD than FTD cases. In PTD cases, a significant positive correlation was observed between maternal blood levels of β-HCH and MDA (r = .78), β-HCH and GSH (r = –.65), -HCH and MDA (r = .89), -HCH and GSH (r = –.74) and α-endosulfan and MDA (r = .54) in PTD cases. We also found significant correlations between cord blood levels of β-HCH and MDA (r = .59), β-HCH and GSH (r = –.69), -HCH and MDA (r = .62) and α-endosulfan and MDA (r = .54) in PTD cases. In conclusion, our results suggest that higher levels of some of the OCP residues may be associated with PTD and increased oxidative stress.