Oxidative Stress Response In Liver Research Articles

Conserved glucokinase regulation in zebrafish confirms therapeutic utility for pharmacologic modulation in diabetes

Glucokinase (GCK) is an essential enzyme for blood glucose homeostasis. Because of its importance in glucose metabolism, GCK is considered an attractive target for the development of antidiabetic drugs. However, a viable therapeutic agent has still to emerge, prompting efforts to improve understanding of the complex regulation and biological effects of GCK. Using the vertebrate organism zebrafish, an attractive model to study metabolic diseases and pharmacological responses, we dissected the complexities of gck regulation and unraveled effects of Gck modulation. We found that while gck expression in zebrafish islet cells is constitutive, gck expression in the liver is regulated by nutritional status, confirming similarity to the mammalian system. A combination of transgenic gck reporter lines and our diabetes model, the pdx1 mutant, allowed monitoring of gck expression under pathological conditions, revealing reduced gck expression and activity in the liver, which was unresponsive to nutrient stimulation, and decreased expression in the islet due to the reduced number of β-cells. Gck activation substantially ameliorated hyperglycemia in pdx1 mutants, without inducing oxidative stress responses in liver or islet. In-depth characterization of Gck activity and regulation at the cellular level in a whole-organism diabetes model clarifies its applicability as a drug target for therapies.

Dehydration induced hypoxia and its role on mitochondrial respiratory enzymes and oxidative stress responses in liver of Asian stinging catfish Heteropneustes fossilis

In the present study, Water Deprived Condition (WPC, up to 18 h) induced hypoxia and altered oxidative stress (OS) physiology along with responses of respiratory chain enzyme in Heteropneustes fossilis are described . The body O2 saturation level in the fish was declined with respect to air exposure. Higher levels of lipid peroxidation and protein carbonylation were recorded in the tissue of fish exposed to 6 h of WPC stress. The regulation of the mitochondrial complex and antioxidant enzymes, small antioxidant molecules indicated that the fish can moderately survive up to 6 h of air exposure. Probably with the onset of metabolic depression, it can critically resist the dehydration stress up to 18 h. Although the activities of glutathione peroxidase and reductase were elevated, activities of antioxidant enzymes such as superoxide dismutase and catalase were insufficient to combat WPC induced ROS and OS generated under hypoxia. The small antioxidant molecules played a key role in elimination of ROS. The elevated complex II activity was probably responsible for resisting the complex I, II and IV mediated electron leakage events in mitochondria of the fish under WPC. The total H2O2 removing capacity was less under WPC while the total units of all calculated antioxidants were alleviated signifying an interesting mechanism of WPC induced OS in the fish.

Acute Abamectin Exposure Induces Oxidative Stress Responses in Liver of Male Albino Rats

Background: Acute oral and dermal toxicity tests are considered as a regulatory assessment in systemic toxicity of agrochemicals. Aim: this study achieved to study the effect of single oral and dermal sub-lethal exposure of abamectin on the oxidative stress biomarkers in the liver of male albino rats. Methods: forty rats were divided into three groups as control, oral and dermal. The tested dose was ½ of LD50 for oral and dermal experiments. Results: exposure to abamectin (ABM) at sub-lethal doses oral or dermal is connected with induction of oxidative stress in the liver of male albino rats. Oxidative stress is evidenced by the increase in lipid and protein oxidation (MDA and PC) biomarkers. As well, antioxidant enzymes such as CAT and GST were increased hepatocytes. On the other hand, glutathione and glutathione peroxidase (GPx) and SOD were markedly reduced. Acetylcholinesterase (AChE) activity in hepatocytes was markedly increased in both oral and dermal exposure. Conclusion: this study through light on the importance of responsible use of pesticides in reducing the hazard impact of agrochemicals.

Acute triflumuron exposure induces oxidative stress responses in liver and kidney of Balb/C mice.

Triflumuron (TFM) is one of the most widely used insecticides over the world. It is a benzoylphenyl urea that belongs to the class of insect growth regulators. This insecticide acts by inhibiting insect's chitin synthesis and by consequences, making insect more susceptible to pathogens and malformations. TFM effects have been reported in mammalians and crops. However, studies that reveal its toxicity mechanisms are limited. In this line, the current study aimed to determine the implication of oxidative stress in the toxicity induced by TFM and particularly in the perturbation of biochemical parameters in male Balb/C mice. Male Balb/C mice were divided into three groups receiving TFM at doses of 250, 350, and 500 mg/kg bw respectively. The occurrence of oxidative stress in both kidney and liver tissues was monitored by measuring of oxidative stress markers. TFM caused an increase as protein carbonyls generation, malondialdehyde induction (MDA) and catalase (CAT), superoxide dismutase (SOD), glutathion peroxidase (Gpx), as well as glutathion S transferase (GST) activities. In the same conditions, we have evaluated the effect of TFM treatment on biochemical parameters. In response to the three TFM doses, we showed significant dose dependent inductions in all tested oxidative stress markers. However, TFM caused an increase in the liver enzyme activities as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), g-glutamyltranspeptidase (GTT), and total bilirubin (BILT) in a dose-dependent manner. Equally, renal markers as urea, uric acid, albumin, and creatinine were increased in the same manner. We can conclude that oxidative damage seems to be a key determinant of TFM-induced toxicity in both liver and kidney of male Balb/C mice. Moreover, the oxidative stress is more pronounced in the liver than in the kidney. Thus, TFM may be considered as a hepatotoxic insecticide.

Studies on effects of static electric field exposure on liver in mice

With the development of ultra-high-voltage direct-current transmission, the intensity of static electric field (SEF) under transmission lines increased, which has aroused public attention on its potential health effects. In order to examine effects of SEF exposure on liver, institute of cancer research mice were exposed to SEF with intensities of 27.5 kV/m, 34.7 kV/m and 56.3 kV/m, respectively. In each intensity of SEF exposure, a corresponding sham exposure group was used. Several indices relating to liver function (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) and oxidative stress (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA)) were tested after exposure of 7, 14, 21 and 35 days. Results showed that exposure to SEF with intensities of 27.5 kV/m and 34.7 kV/m for 35 days did not significantly influence any detected indices above. Under SEF exposure with intensity of 56.3 kV/m, the SOD activity in liver was significantly increased after exposure of 7 and 14 days. However, no significant increase was found in MDA content as well as the activities of AST and ALT between exposure group and sham exposure group during SEF exposure of 56.3 kV/m. It suggested that from three SEF intensities, only exposure to SEF with intensity of 56.3 kV/m (7 and 14 days) caused a temporary oxidative stress response in liver expressed by the increase in activity of SOD, but it did not produce oxidative damage. This biological effect may be related to the increase of mitochondrial membrane potential of hepatocytes caused by SEF exposure. When the membrane potential exceeds a threshold, Q cycle in mitochondria will be affected, which will result in an increase of superoxide anion concentration and ultimately an oxidative stress.

Perturbations in ROS-related processes of the fish Gambusia holbrooki after acute and chronic exposures to the metals copper and cadmium.

Metallic contamination is a widespread phenomena, particularly in areas impacted by human activities, and has become a relevant environmental concern. However, the toxicity of metals on fish requires full characterization in terms of short- and long-term effects. Thus, the purpose of this study was to determine the acute and chronic oxidative stress response in liver and gills of Gambusia holbrooki exposed to copper and cadmium. To assess the effects of these two metals, we adopted a strategy of analyzing the pollution effects caused by salts of the two metallic elements, and we quantified the oxidative stress biomarkers catalase, glutathione reductase, glutathione-S-transferases, and lipid peroxidation after exposure (4 and 28 days) to ecologically relevant concentrations, thus simulating actual conditions of exposure in the wild. Our results showed that copper elicited strong effects in all tested biomarkers for both acute and chronic challenges. Cadmium caused a similar response and was shown to cause significant changes particularly in catalase and glutathione-S-transferases activities. These findings evidence that ecologically relevant concentrations of common anthropogenic contaminants are causative agents of serious imbalances (namely oxidative stress) that are likely to trigger life-threatening events.

Oxidative Stress Responses and Recovery Patterns in the Liver of Oreochromis niloticus Exposed to Chlorpyrifos-Ethyl

Chlorpyrifos is the most common insecticide in freshwater ecosystems, and detected in agricultural and fishery product. In this study, Oreochromis niloticus were exposed to 5, 10 and 15 ppb sublethal concentrations of chlorpyrifos in order to determine the oxidative stress response in liver. Acetylcholinesterase (AChE) activity was significantly inhibited. Superoxide dismutase activity (SOD) increased after 15 days of chlorpyrifos treatments at all concentrations (146.95%, 53.04%, 208.70%, respectively). Malondialdehyde levels were higher than that of the control level after 15 days of 5 ppb (95.65%), 10 ppb (69.56%) and 15 ppb (252.17%) chlorpyrifos treatments. Malondialdehyde levels were also increased ranging from 59.09%, 113.63% to 195.46% after 30 days of 5, 10 and 15 ppb chlorpyrifos exposures. Glutathione S-transferase activity decreased except for 15 days low concentration exposure. Catalase (CAT) activity decreased while there is no significant alteration in glutathione peroxidase activity. After recovery period, the low concentration group of chlorpyrifos provided a protection in AChE activity during recovery, but fish were observed to be unable to overcome the inhibition of AChE activity at high concentration groups. CAT activity remained reduced, SOD activity increased whereas the other biochemical parameters recovered to control levels. Results of this study suggest that chlorpyrifos induces oxidative stress in the liver of O. niloticus and this effect is not related with anti-acetylcholinesterase activity of pesticide.

Diethylhexyl Phthalate에 노출된 동자개, Pseudobagrus fulvidraco의 항산화 효소활성의 변동

The effects of diethylhexyl phthalate (DEHP) on various oxidative stress responses in liver, kidney and gill tissues of freshwater bagrid catfish Pseudobagrus fulvidraco were investigated under laboratory conditions. Bagrid catfish were intraperitoneally injected with sunflower seed oil containing nominal concentrations of 0, 300 or 900mg DEHP per kilogram of body weight for 3 days and the effects after last injection were assessed in liver, kidney and gill tissues of the exposed organisms. The oxidative stress responses of fish were evaluated by analyzing the level of glutathione (GSH), as well as the activities of antioxidant enzymes such as glutathione S-transferase (GST), glutathione peroxidase (GPx) and glutathione reductase (GR). After exposure to the DEHP, there were significant decrease in GR, GPx activity and GSH content in liver of fish exposed to 900 mg DEHP per kilogram of body weight compared to the control group. Compared with the control group, significant decreases in renal GPx and GR activity were observed in the DEHP treatment groups (900 mg <TEX>$kg^{-1}$</TEX> bw). However, no significant difference was observed in any oxidative stress responses in gills between the DEHP-treated and the untreated group of fish. The findings of the present investigation show that DEHP induce oxidative stress and the liver was the most affected organ followed by the kidney and gills. Furthermore, the changes of GPx and GR activities may be important indicators of oxidative stress responses but additional study is required to confirm the oxidative stress of DEHP.

Pharmacological rescue of the 14CoS/14CoS mouse: hepatocyte apoptosis is likely caused by endogenous oxidative stress.

Whereas ch/ch wild-type mice and ch/14CoS heterozygotes are viable, 14CoS/14CoS mice homozygous for a 3800 kb deletion on chromosome 7 die during the first day postpartum. Death is caused by disruption of the fumarylacetoacetate hydrolase (Fah) gene; absence of FAH, final enzyme in the tyrosine catabolism pathway, leads to accumulation of reactive electrophilic intermediates. In this study, we kept 14CoS/14CoS mice alive for 60 d with oral 2-(2-nitro-4-trifluoromethyl-benzyol)-1,3-cyclohexanedione (NTBC), an inhibitor of p-hydroxyphenylpyruvate dioxygenase, second enzyme in the tyrosine catabolic pathway. The 70% of NTBC-treated 14CoS/14CoS mice that survived 60 d showed poor growth and developed corneal opacities, compared with ch/14CoS littermates; NTBC-rescued Fah(-/-) knockout mice did not show growth retardation or ocular toxicity. NTBC-rescued 14CoS/14CoS mice also exhibited a striking oxidative stress response in liver and kidney, as measured by lower GSH levels and mRNA induction of four genes: glutamate cysteine ligase catalytic (Gclc) and modifier (Gclm) subunits, NAD(P)H:quinone oxidoreductase (Nqo1), and heme oxygenase-1 (Hmox1). Withdrawal of NTBC for 24-48 h from rescued adult 14CoS/14CoS mice resulted in severe apoptosis of the liver, detected histologically and by cytochrome c release from the mitochondria, increased caspase 3-like activity, and further decreases in GSH content. In kidney, proximal tubular epithelial cells were abnormal. Human hereditary tyrosinemia type I (HT1), caused by mutations in the FAH gene, is an autosomal recessive disorder in which the patient usually dies of liver fibrosis and cirrhosis during early childhood; NTBC treatment is known to prolong HT1 children's lives-although liver fibrosis, cirrhosis, hepatocarcinoma, and corneal opacities sometimes occur. The mouse data in the present study are consistent with the possibility that endogenous oxidative stress-induced apoptosis may be the underlying cause of liver pathology seen in NTBC-treated HT1 patients.

3,4-Dichloroaniline-induced oxidative stress in liver of crucian carp ( Carassius auratus)

3,4-Dichloroaniline (DCA) and its analogs are widely used as chemical intermediates in the synthesis of herbicides, azo dyes, and pharmaceuticals. They bring danger to growth, development, and propagation of aquatic organisms. The purpose of this study was to show DCA-induced oxidative stress response in liver of crucian carp ( Carassius auratus). Superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), and NO synthase (NOS) in liver were measured in crucian carp after exposure to DCA solution (0.2, 0.4, and 0.8 mg/L, respectively) for 15 days and compared with the control. DCA significantly induced SOD activity and enhanced MDA concentration in liver of crucian carp. Compared with the control, GSH and NO concentrations decreased and NOS activity was inhibited in crucian carp liver 15 days after DCA treatment. The data suggested that DCA-induced free radical generation and antioxidant depletion, and caused oxidative stress and lipid peroxidation in liver of crucian carp.

Dioxin Increases Reactive Oxygen Production in Mouse Liver Mitochondria

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) causes an oxidative stress response in liver and several extrahepatic tissues. The subcellular sources and underlying mechanisms of dioxin-induced reactive oxygen, however, are not well understood. In this study, we examined whether mitochondria, organelles that consume the majority of cellular oxygen, might be a source of dioxin-induced reactive oxygen. Female C57BL/6 mice were treated with dioxin (15 μg/kg body wt ip) on 3 consecutive days, and liver mitochondria were examined at 1, 4, and 8 weeks after the first treatment. Mitochondrial aconitase activity, an enzyme inactivated by superoxide, was decreased by 44% at 1 week, 22% at 4 weeks, and returned to control levels at 8 weeks. Dioxin elevated succinate-stimulated mitochondrial H2O2 production twofold at 1 and 4 weeks; H2O2 production remained significantly elevated at 8 weeks. The enhanced H2O2 production was due to neither increased Mn-superoxide dismutase activity nor decreased mitochondrial glutathione peroxidase activity. Dioxin treatment augmented mitochondrial glutathione, but not glutathione disulfide levels, a result that might be explained by increased mitochondrial glutathione reductase activity. Liver ATP levels were significantly lowered at 1 and 4 weeks, the peak times of mitochondrial reactive oxygen production. Increased dioxin-stimulated reactive oxygen at 1 and 4 weeks did not appear to be related to the observed decrease in cytochrome oxidase activity, since State 3 and State 4 respiration were not diminished. To our knowledge, this is the first report to show that dioxin increases mitochondrial respiration-dependent reactive oxygen production, which may play an important role in dioxin-induced toxicity and disease.