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Dysfunction of the endocannabinoid system (ES) has been identified in nonalcoholic fatty liver disease (NAFLD) and associated metabolic disorders. Cannabinoid receptor type 1 (CB1) expression is largely dependent on nutritional status. Thus, individuals suffering from NAFLD and metabolic syndrome (MS) have a significant increase in ES activity. Furthermore, oxidative/ nitrosative stress and inflammatory process modulation in the liver are highly influenced by the ES. Numerous experimental studies indicate that oxidative and nitrosative stress in the liver is associated with steatosis and portal inflammation during NAFLD. On the other hand, inflammation itself may also contribute to reactive oxygen species (ROS) production due to Kupffer cell activation and increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The pathways by which endocannabinoids and their lipid-related mediators modulate oxidative stress and lipid peroxidation represent a significant area of research that could yield novel pharmaceutical strategies for the treatment of NAFLD. Cumulative evidence suggested that the ES, particularly CB1 receptors, may also play a role in inflammation and disease progression toward steatohepatitis. Pharmacological inactivation of CB1 receptors in NAFLD exerts multiple beneficial effects, particularly due to the attenuation of hepatic oxidative/nitrosative stress parameters and significant reduction of proinflammatory cytokine production. However, further investigations regarding precise mechanisms by which CB1 blockade influences the reduction of hepatic oxidative/nitrosative stress and inflammation are required before moving toward the clinical phase of the investigation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Finasteride (FIN) inhibits neurosteroid synthesis and potentially improves the course of hepatic encephalopathy (HE). This study aimed to investigate the effects of FIN on brain oxidative stress and acetylcholinesterase (AchE) activity in acute thioacetamide-induced HE in rats. Male Wistar rats were divided into groups: 1. control; 2. thioacetamide-treated group (TAA; 900 mg/kg); 3. finasteride-treated group (FIN; 150 mg/kg); 4. group treated with FIN and TAA (FIN+TAA). Daily doses of FIN (50 mg/kg) and TAA (300 mg/kg) were administered intraperitoneally during three days and in FIN+TAA group FIN was administered 2h before every dose of TAA. FIN pretreatment prevented TAA-induced rise in malondialdehyde level in the cortex due to restoration of catalase activity and increased expression of superoxide dismutase 1 (SOD1) and induced an increase in malondialdehyde level in the thalamus due to reduction of glutathione peroxidase (GPx) and glutathione reductase (GR) activity. Although FIN pretreatment did not affect malondialdehyde level in hippocampus and caudate nucleus, hippocampal SOD1 expression was higher (p<0.05) and GR activity lower in FIN+TAA vs. TAA group (p<0.05). GPx activity was lower in caudate nucleus in FIN+TAA vs. TAA group (p<0.01). FIN pretreatment prevented TAA-induced rise in AchE activity in the thalamus and caudate nucleus and AchE activity correlates inversely in the thalamus (p<0.05) and positively in caudate nucleus (p<0.01) with malondialdehyde level. FIN has regionally selective effects on oxidative stress and AchE activity in the brain in acute TAA-induced HE in rats. The prooxidant role of FIN in the thalamus may be causally linked with inhibition of AchE.

The present study deals with the effects of rimonabant on oxidative/nitrosative stress in high diet- (HFD-) induced experimental nonalcoholic fatty liver disease (NAFLD). Male mice C57BL/6 were divided into the following groups: control group fed with control diet for 20 weeks (C; n = 6); group fed with HFD for 20 weeks (HF; n = 6); group fed with standard diet and treated with rimonabant after 18 weeks (R; n = 9); group fed with HFD and treated with rimonabant after 18 weeks (HFR; n = 10). Daily dose of rimonabant (10 mg/kg) was administered to HFR and R group by oral gavage for two weeks. Treatment induced a decrease in hepatic malondialdehyde concentration in HFR group compared to HF group (P < 0.01). The concentration of nitrites + nitrates in liver was decreased in HFR group compared to HF group (P < 0.01). Liver content of reduced glutathione was higher in HFR group compared to HF group (P < 0.01). Total liver superoxide dismutase activity in HFR group was decreased in comparison with HF group (P < 0.01). It was found that rimonabant may influence hepatic iron, zinc, copper, and manganese status. Our study indicates potential usefulness of cannabinoid receptor type 1 blockade in the treatment of HFD-induced NAFLD.

The aim of our study was to examine the effect of calorie restriction (CR) on oxidative and nitrosative liver injury in rats, induced by acute ethanol intoxication. Male Wistar rats were divided into groups: (1) control; (2) calorie-restricted groups with intake of 60-70% (CR60-70) and 40-50% of daily energy needs (CR40-50); (3) ethanol-treated group (E); (4) calorie-restricted, ethanol-treated groups (E+CR60-70 and E+CR40-50). Ethanol was administered in 5 doses of 2g/kg every 12h, and duration of CR was 5 weeks before ethanol treatment. Malondialdehyde and nitrite and nitrate level were significantly lower in E+CR60-70 and higher in E+CR40-50 vs. E group. Liver reduced glutathione content and activity of both superoxide dismutase izoenzymes were significantly higher in E+CR60-70 and lower in E+CR40-50 vs. E group. Oxidative stress may be a potential mechanism of hormetic effects of CR on acute ethanol-induced liver injury., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The aim of our study was to evaluate the effects of cold stress on hepatic oxidative damage during binge drinking in rats. Male Wistar rats were divided into the following groups: group 1: control; group 2: ethanol-treated; group 3: stress-exposed; group 4: stress-exposed and ethanol-treated group. Oxidative and nitrosative stress parameters in the liver were determined spectrophotometrically, 12 h after treatment. Liver malondialdehyde concentration was significantly higher in group 4 when compared with groups 2 and 3. The highest increase in nitric oxide concentration was demonstrated in group 4 in comparison with groups 2 and 3. Superoxide dismutase (SOD) activity was significantly lower in group 4 when compared with groups 2 and 3. Ethanol administration induced a larger decrease in the activity of copper-/zinc-SOD in group 4 in comparison with group 2. Activity of manganese-SOD (Mn-SOD) was significantly higher in groups 3 and 4, when compared with control values, but the greatest increase in the activity of Mn-SOD was demonstrated in group 2. We also evaluated statistically significant decrease in the level of reduced gluthatione in the liver of group 4 in comparison with group 3. Based on our study, it can be concluded that cold-exposed stress and binge ethanol drinking have additive effects in imbalance between pro-oxidant and antioxidant defense system in liver.

Introduction: Oxidative stress plays an important role in pathogenesis of alcoholic liver injury. The main source of free oxygen species is cytochrome P450-dependent monooxygenase, which can be induced by ethanol. ROLE OF CYTOCHROME P4502E1 IN ETHANOL-INDUCED OXIDATIVE STRESS: Reactive oxygen species produced by this enzyme are more important in intracellular oxidative damage compared to species derived from activated phagocytes. Free radicals lead to lipid peroxidation, enzymatic inactivation and protein oxidation. ROLE OF MITOCHONDRIA IN ALCOHOL-INDUCED OXIDATIVE STRESS. Production of mitochondrial reactive oxygen species is increased, and glutathione content is decreased in chronically ethanol-fed animals. Oxidative stress in mitochondria leads to mitochondrial DNA damage and has a dual effect on apoptosis. ROLE OF KUPFFER CELLS IN ALCOHOL-INDUCED LIVER INJURY: Chronic ethanol consumption is associated with increased release of endotoxin from gut lumen into portal circulation. Endotoxin activates Kupffer cells, which then release proinflammatory cytokines and oxidants. ROLE OF NEUTROPHILS IN ALCOHOL-INDUCED LIVER INJURY: Alcoholic liver injury leads to the accumulation of neutrophils, which release reactive oxygen species and lysosomal enzymes and contribute to hepatocyte damage and necrosis. ROLE OF NITRIC OXIDE IN ALCOHOL-INDUCED OXIDATIVE STRESS: High amounts of nitric oxide contribute to the oxidative damage, mainly by generating peroxynitrites. ROLE OF ANTIOXIDANTS IN ETHANOL-INDUCED OXIDATIVE STRESS: Chronic ethanol consumption is associated with reduced liver glutathione and alpha-tocopherol level and with reduced superoxide dismutase, catalase and glutathione peroxidase activity., Conclusion: Oxidative stress in alcoholic liver disease is a consequence of increased production of oxidants and decreased antioxidant defense in the liver.

OXIDATIVE PULMONARY DAMAGE: The pathogenesis of pulmonary emphysema is incompletely understood. Nearly 90% of all patients with chronic obstructive pulmonary diseases are smokers. Cigarette smoke is a rich source of oxidants. Oxidative stress increases oxidant generation, which cannot be neutralized with antioxidant defense mechanisms. Lipids, proteins and deoxyribonucleic acid are components of the cell that are most sensitive to oxidative damage. Oxygen radicals can modify amino acid side chains, form protein aggregates, cleave peptide bonds, and make proteins more susceptible to proteolytic degradation. It has been shown that neutrophils have a principal effector role in pulmonary tissue damage. Neutrophil elastase can damage air spaces by degrading elastin, and a variety of extracellular membrane proteins, proteoglycans, and glycoproteins. Neutrophil elastase can also stimulate inflammation by increasing interleukin-8 synthesis. Additionally, neutrophil elastase can activate or inactivate inhibitors of neutrophil collagenase, and secretory leukoprotease proteinase inhibitor. Apart from neutrophils, oxidative stress causes activation of other phagocytes and severe inflammatory response ensues. LIPID PEROXILATION AND PULMONARY EMPHYSEMA: Except protein oxidation and lipid peroxidation, oxidants may disturb signal transmission in the cells, as well as normal cell membrane function and function of organelles. Modified structure of deoxyribonucleic acid may cause mutations, which in absence of repairation enzyme activity lead to cell injury. IRON AND OXIDATIVE STRESS: Iron metabolism is also important in the development of pulmonary emphysema due to its role in production of some oxidants.

The aim of our study was to investigate the effects of binge drinking on paracetamol induced oxidative stress in mice liver. Male Swiss mice were divided into groups: control; ethanol-treated group (E) in five subsequent doses of 2 g/kg by orogastric tube; paracetamol-treated group (P) in a dose of 300 mg/kg intraperitoneally; group that received paracetamol 12 hrs after the last dose of ethanol (PE). Blood and liver samples were collected for determination of oxidative stress parameters 6, 24 and 48 hrs after treatment. Prior binge drinking potentiated paracetamol-induced rise in liver malondialdehyde level 48 hours after treatment in comparison with P and E groups (17.14 ± 1.98 vs 13.14 ± 0.82 and 12.99 ± 1.18 μmol/L, p

Methionine is an essential sulphur-containing amino acid involved in protein synthesis, regulation of protein function and methylation reactions. Dietary methionine restriction (0.12–0.17% methionine in food) extends the life span of various animal species and delays the onset of aging-associated diseases and cancers. In the liver, methionine restriction attenuates steatosis and delays the development of non-alcoholic steatohepatitis due to antioxidative action and metabolic reprogramming. The limited intake of methionine stimulates the fatty acid oxidation in the liver and the export of lipoproteins as well as inhibits de novo lipogenesis. These effects are mediated by various signaling pathways and effector molecules, including sirtuins, growth hormone/insulin-like growth factor-1 axis, sterol regulatory element binding proteins, adenosine monophosphate-dependent kinase and general control nonderepressible 2 pathway. Additionally, methionine restriction stimulates the synthesis of fibroblast growth factor-21 in the liver, which increases the insulin sensitivity of peripheral tissues. In the brain, methionine restriction delays the onset of neurodegenerative diseases and increases the resistance to various forms of stress through antioxidative effects and alterations in lipid composition. This review aimed to summarize the morphological, functional and molecular changes in the liver and brain caused by the methionine restriction, with possible implications in the prolongation of maximal life span. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of binge drinking on the prooxidant/antioxidant system in rat liver in acute cadmium (Cd) intoxication. Male Wistar rats were used in the experiments. They were divided into the following groups: 1. control, 2. ethanol-treated group, in five subsequent doses of 2 g kg-1, administered by an orogastric tube, 3. Cd-treated group in a single dose of 2.5 mg kg-1, administered intraperitoneally, 4. group that received Cd 12 h after the last dose of ethanol. Blood and liver samples for determination of oxidative stress parameters, were collected 24 h after treatment. When administered in combination, ethanol and Cd induced a more pronounced increase in the serum and liver malondialdehyde levels than either of the substances alone (p<0.01). Liver manganese superoxide dismutase (MnSOD) activity was increased in both the ethanol- and Cd-treated groups (p<0.01), while liver copper/zinc superoxide dismutase (Cu/ZnSOD) activity was elevated in the Cd group only. However, when administered in combination, ethanol and Cd induced a more pronounced decrease in liver MnSOD and Cu/ZnSOD activity 24 h after treatment (p<0.01). Based on our study, it can be concluded that ethanol may act synergistically with Cd in inducing lipid peroxidation and reduction in liver SOD activity. [ABSTRACT FROM AUTHOR]

Introduction Oxidative stress plays an important role in pathogenesis of alcoholic liver injury. The main source of free oxygen species is cytochrome P450-dependent monooxygenase, which can be induced by ethanol. Role of cytochrome P4502E1 in ethanol-induced oxidative stress Reactive oxygen species produced by this enzyme are more important in intracellular oxidative damage compared to species derived from activated phagocytes. Free radicals lead to lip id peroxidation, enzymatic inactivation and protein oxidation. Role of mitochondria in alcohol-induced oxidative stress Production of mitochondria! reactive oxygen species is increased, and glutathione content is decreased in chronically ethanol-fed animals. Oxidative stress in mitochondria leads to mitochondria! DXA damage and has a dual effect on apoptosis. Role of Kupffer cells in alcohol-induced liver injury Chronic ethanol consumption is associated with increased release of endotoxin from gut lumen into portal circulation. Endotoxin activates Kupffer cells, which then release proinflammatoty cytokines and oxidants. Role of neutrophils in alcohol-induced liver injury Alcoholic liver injury leads to the accumulation of neutrophils, which release reactive oxygen species and lysosomal enzymes and contribute to hepatocyte damage and necrosis. Role of nitric oxide in alcohol-induced oxidative stress High amounts of nitric oxide contribute to the oxidative damage, mainly by generating peroxynitrites. Role of antioxidants in ethanol-induced oxidative stress Chronic ethanol consumption is associated with reduced liver glutathione and a-tocopherol level and with reduced superoxide dismutase, catalase and glutathione peroxidase activity. Conclusion Oxidative stress in alcoholic liver disease is a consequence of increased production of oxidants and decreased antioxidant defense in the liver. [ABSTRACT FROM AUTHOR]

Development of nonalcoholic fatty liver disease (NAFLD) occurs through initial steatosis and subsequent oxidative stress. The aim of this study was to examine the effects of α-lipoic acid (LA) on methionine-choline deficient (MCD) diet-induced NAFLD in mice. Male C57BL/6 mice ( n=21) were divided into three groups ( n=7 per group): (1) control fed with standard chow, (2) MCD2 group-fed with MCD diet for 2 weeks, and (3) MCD2+LA group-2 weeks on MCD receiving LA i.p. 100 mg/kg/day. After the treatment, liver samples were taken for pathohistology, oxidative stress parameters, antioxidative enzymes, and liver free fatty acid (FFA) composition. Mild microvesicular hepatic steatosis was found in MCD2 group, while it was reduced to single fat droplets evident in MCD2+LA group. Lipid peroxidation and nitrosative stress were increased by MCD diet, while LA administration induced a decrease in liver malondialdehyde and nitrates+nitrites level. Similary, LA improved liver antioxidative capacity by increasing total superoxide dismutase (tSOD), manganese SOD (MnSOD), and copper/zinc-SOD (Cu/ZnSOD) activity as well as glutathione (GSH) content. Liver FFA profile has shown a significant decrease in saturated acids, arachidonic, and docosahexaenoic acid (DHA), while LA treatment increased their proportions. It can be concluded that LA ameliorates lipid peroxidation and nitrosative stress in MCD diet-induced hepatic steatosis through an increase in SOD activity and GSH level. In addition, LA increases the proportion of palmitic, stearic, arachidonic, and DHA in the fatty liver. An increase in DHA may be a potential mechanism of anti-inflammatory and antioxidant effects of LA in MCD diet-induced NAFLD. [ABSTRACT FROM AUTHOR]