Oxygen Species In Liver Research Articles

White meat proteins were more conducive to hepatic antioxidative status than soybean and red meat proteins.

Intake of protein-rich foods might induce oxidative stress in organs. This study investigated the impacts of protein sources including casein, soybean, fish, chicken, pork, and beef proteins on hepatic oxidation and antioxidation status in rats. It was shown that meat proteins produced higher reactive oxygen species in livers (from 64,868 to 87,153F/mgpro) than casein (54,045F/mgpro) and soybean protein (48,361F/mgpro, p<.05). Pork and soybean proteins induced higher hepatic oxidative stress than fish, chicken and beef proteins by increasing malondialdehyde production (>16%, p<.05). White meat (fish and chicken) proteins promoted hepatic superoxide dismutase activity and total antioxidant capacity compared to soybean and red meat (pork and beef) proteins (p<.05). Compared to red meat proteins, white meat proteins increased hepatic expressions of thioredoxin and glutaredoxin. Rats fed red meat proteins showed hepatic steatosis with small vacuoles. Therefore, white meat proteins were more conducive to hepatic antioxidative status than soybean and red meat proteins. PRACTICAL APPLICATIONS: Intake of protein-rich foods may induce oxidative stress response at both cell and organ levels. The objective of this study was to investigate the impacts of different protein sources including casein, soybean, fish, chicken, pork, and beef proteins on oxidation and antioxidation status in rat livers. It was shown that meat proteins induced higher production of reactive oxygen species than casein and soybean protein. However, white meat proteins showed higher antioxidant capacity than soybean and red meat proteins by increasing hepatic superoxide dismutase activity and total antioxidant capacity. Therefore, compared to soybean and red meat proteins, white meat proteins lowered hepatic oxidative stress by reducing malondialdehyde production. This study suggested that intake of moderate white meat proteins was more conducive to hepatic antioxidative status than intake of soybean and red meat proteins. This study would promote the understanding of healthy effects of different protein sources.

Efficacy of Polymethoxylated Flavonoids from Citrus depressa Extract on Alcohol-induced Liver Injury in Mice

Alcohol consumption causes the accumulation of reactive oxygen species in liver, which leads to alcoholic fatty liver and hepatocyte injury. In this study, we investigated the effects of an ethanolic Citrus depressa extract and those of its main components on alcohol-induced liver damage using a mouse model. Four polymethoxylated flavonoids, namely, nobiletin, tangeretin, 5-O-demethylnobiletin, and sinensetin, were isolated from C. depressa extract. Treatment of ethanol fed mice with C. depressa extract, nobiletin, tangeretin, or 5-O-demethylnobiletin at 300 mg/kg for 8 weeks by oral administration alleviated the accumulation of lipid droplets in liver and significantly decreased the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (markers of liver damage). Also, in mice treated with ethanol plus nobiletin, tangeretin, or 5-O-demethylnobiletin, liver level of glutathione (an antioxidant) increased whereas levels of tumor necrosis factor-alpha (TNF-α), hepatic malondialdehyde, and hepatic cytochrome P450 2E1 (CYP2E1) mRNA decreased as compared with ethanol fed controls. These findings suggest C. depressa extract and polymethoxylated flavonoids had a protective effect on alcohol-induced liver injury, and that the mechanism involved is related to the regulation of hepatic CYP2E1-mediated oxidative stress.

The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice.

Titanium dioxide nanoparticles (TiO2 NPs) are authorized food additives, and children have the highest exposure. Therefore, children are likely more susceptible to the adverse effects of TiO2 NPs than adults. Previous study showed that oral administration of 50 mg/kg body weight (bw) TiO2 NPs increase plasma glucose in mice. However, few studies have directly compared the adverse effects of exposure to TiO2 NPs on plasma glucose metabolism of different age groups. In this study, the developing (age 3 weeks) and adult mice (age 10 weeks) were orally administered with 50 mg/kg bw TiO2 NPs per day. The TiO2 NPs induced hyperglycemia earlier in the developing mice than in the adult mice. Then mechanisms were analyzed after mice were oral administration of TiO2 NPs for 8 weeks and 26 weeks, respectively. Results showed that the treatment with TiO2 NPs activated xenobiotic biodegradation in livers of both developing and adult mice at the early stage. However, only in the developing mice, TiO2 NPs induced endoplasmic reticulum (ER) stress in livers and increased reactive oxygen species in livers and sera in the early stage. The ER stress and ROS activated an inflammation response and mitogen-activated protein kinase pathways, thereby inducing insulin resistance in the livers of developing mice at the early stage. The response of the adult mice was delayed, and these changes were observed in the late stage of the study. The results of this study all suggest that children are more susceptible than adults to the toxicity of orally administered TiO2 NPs.

Deficiency of the Mitochondrial NAD Kinase Causes Stress-Induced Hepatic Steatosis in Mice

The mitochondrial nicotinamide adenine dinucleotide (NAD) kinase (NADK2, also called MNADK) catalyzes phosphorylation of NAD to yield NADP. Little is known about the functions of mitochondrial NADP and MNADK in liver physiology and pathology. We investigated the effects of reduced mitochondrial NADP by deleting MNADK in mice. We generated MNADK knockout (KO) mice on a C57BL/6NTac background; mice with a wild-type Mnadk gene were used as controls. Some mice were placed on an atherogenic high-fat diet (16% fat, 41% carbohydrate, and 1.25% cholesterol supplemented with 0.5% sodium cholate) or given methotrexate intraperitoneally. We measured rates of fatty acid oxidation in primary hepatocytes using radiolabeled palmitate and in mice using indirect calorimetry. We measured levels of reactive oxygen species in mouse livers and primary hepatocytes. Metabolomic analyses were used to quantify serum metabolites, such as amino acids and acylcarnitines. The KO mice had metabolic features of MNADK-deficient patients, such as increased serum concentrations of lysine and C10:2 carnitine. When placed on the atherogenic high-fat diet, the KO mice developed features of nonalcoholic fatty liver disease and had increased levels of reactive oxygen species in livers and primary hepatocytes, compared with control mice. During fasting, the KO mice had a defect in fatty acid oxidation. MNADK deficiency reduced the activation of cAMP-responsive element binding protein-hepatocyte specific and peroxisome proliferator-activated receptor alpha, which are transcriptional activators that mediate the fasting response. The activity of mitochondrial sirtuins was reduced in livers of the KO mice. Methotrexate inhibited the catalytic activity of MNADK in hepatocytes and in livers in mice with methotrexate injection. In mice given injections of methotrexate, supplementation of a diet with nicotinamide riboside, an NAD precursor, replenished hepatic NADP and protected the mice from hepatotoxicity, based on markers such as increased level ofserum alanine aminotransferase. MNADK facilitates fatty acid oxidation, counteracts oxidative damage, maintains mitochondrial sirtuin activity, and prevents metabolic stress-induced non-alcoholic fatty liver disease in mice.

Peroxisomal enzymes in the liver of rats with experimental diabetes mellitus type 2.

Diabetes mellitus is relatively frequently associated with fatty liver disease. Increased oxidative stress probably plays an important role in the development of this hepatopathy. One of possible sources of reactive oxygen species in liver is peroxisomal system. There are several reports about changes of peroxisomal enzymes in experimental diabetes, mainly enzymes of fatty acid oxidation. The aim of our study was to investigate the possible changes of activities of liver peroxisomal enzymes, other than enzymes of beta-oxidation, in experimental diabetes mellitus type 2. Biochemical changes in liver of experimental animals suggest the presence of liver steatosis. The changes of serum parameters in experimental group are similar to changes in serum of patients with non-alcoholic fatty liver disease. We have shown that diabetes mellitus influenced peroxisomal enzymes by the different way. Despite of well-known induction of peroxisomal beta-oxidation, the activities of catalase, aminoacid oxidase and NADH-cytochrome b(5) reductase were not significantly changed and the activities of glycolate oxidase and NADP-isocitrate dehydrogenase were significantly decreased. The effect of diabetes on liver peroxisomes is probably due to the increased supply of fatty acids to liver in diabetic state and also due to increased oxidative stress. The changes of metabolic activity of peroxisomal compartment may participate on the development of diabetic hepatopathy.

Nickel induces hyperglycemia and glycogenolysis and affects the antioxidant system in liver and white muscle of goldfish Carassius auratus L.

The toxicity of nickel to mammals is well studied, whereas information on nickel effects on fish is scant. Goldfish exposure to 10–50mgL−1 of waterborne Ni2+ for 96h showed reduced glycogen levels by 27–33% and 37–40% in liver and white muscle, respectively, accompanied by substantial increases in blood glucose levels (by 15–99%). However, indices of oxidative damage to proteins (carbonyl proteins) and lipids (lipid peroxides) were largely unaffected by nickel exposure. In liver, the activities of antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GPx), were not affected by Ni2+ treatment, while catalase activity was elevated by 26%. In white muscle, however, substantial increases in SOD (by 38–147%) and GPx (by 2.5–5.5-fold) activities appeared to compensate for decreased catalase activity (by 59–69%) in order to resist Ni-induced oxidative perturbations. Both hepatic and muscular glutathione reductase activities were suppressed by 10–30% and 12–21%, respectively, after goldfish exposure to all Ni2+ concentrations used. However, the activity of glucose-6-phosphate dehydrogenase was remarkably enhanced (by 1.6–5.4-fold) in white muscle of Ni-exposed fish, indicating a strong potential increase in NADPH production under Ni exposure. Thus, the exposure of goldfish to 10–50mgL−1 of Ni2+ for 96h induces glycogenolysis and hyperglycemia, showing some similarities with a hypoxia response, and leads to a substantial activation of defense systems against reactive oxygen species in liver and white muscle in tissue-specific and concentration-dependent manner.

Role of the Inducible Nitric Oxide Synthase in the Onset of Fructose-Induced Steatosis in Mice

To test the hypothesis that the inducible nitric oxide synthase (iNOS) is involved in mediating the toll-like receptor 4-dependent effects on the liver in the onset of fructose-induced steatosis, wild-type and iNOS knockout (iNOS(-/-)) mice were either fed tap water or 30% fructose solution for 8 weeks. Chronic consumption of 30% fructose solution led to a significant increase in hepatic steatosis and inflammation as well as plasma alanine-aminotransferase levels in wild-type mice. This effect of fructose feeding was markedly attenuated in iNOS(-/-) mice. Hepatic lipidperoxidation, concentration of phospho-IκB, nuclear factor κB activity, and tumor necrosis factor-α mRNA level were significantly increased in fructose-fed wild-type mice, whereas in livers of fructose-fed iNOS(-/-) mice, lipidperoxidation, phospho-IκB, nuclear factor κB activity, and tumor necrosis factor-α expression were almost at the level of controls. However, portal endotoxin levels and hepatic myeloid differentiation factor 88 expression were significantly higher in both fructose-fed groups compared to controls. Taken together, these data suggest that (i) the formation of reactive oxygen species in liver is a key factor in the onset of fatty liver and (ii) iNOS is involved in mediating the endotoxin/toll-like receptor 4-dependent effects in the development of fructose-induced fatty liver.

Monochloramine produces reactive oxygen species in liver by converting xanthine dehydrogenase into xanthine oxidase

In the present study, we assessed the influence of monochloramine (NH 2Cl) on the conversion of xanthine dehydrogenase (XD) into xanthine oxidase (XO) in rat liver in vitro. When incubated with the partially purified cytosolic fraction from rat liver, NH 2Cl (2.5–20 μM) dose-dependently enhanced XO activity concomitant with a decrease in XD activity, implying that NH 2Cl can convert XD into the reactive oxygen species (ROS) producing form XO. The NH 2Cl (5 μM)-induced XD/XO interconversion in the rat liver cytosol was completely inhibited when added in combination with an inhibitor of NH 2Cl methionine (25 μM). A sulfhydryl reducing agent, dithiothreitol at concentrations of 0.1, 1 and 5 mM also dose-dependently reversed the NH 2Cl (5 μM)-induced XD/XO interconversion. These imply that NH 2Cl itself acts on the XD/XO interconversion, and that this conversion occurs at the cysteine residues in XD. Furthermore, using the fluorescent probe 2′,7′-dichlorodihydrofluorescein diacetate, it was found that NH 2Cl could increase ROS generation in the cytoplasm of rat primary hepatocyte cultures, and that this increase might be reversed by an XO inhibitor, allopurinol. These results suggest that NH 2Cl has the potential to convert XD into XO in the liver, which in turn may induce the ROS generation in this region.

Amelioration of sepsis-induced hepatic and ileal injury in rats by the leukotriene receptor blocker montelukast

Background: Sepsis is a generalized inflammatory response, which involves organ systems remote from the locus of the initial infectious insult, involves the release of cytokines and the subsequent formation of reactive oxygen and nitrogen species. Objective: The aim of this study was to investigate the possible protective effect of montelukast, a leukotriene receptor blocker, against oxidative damage in the liver and ileum of septic rats. Methods: Sepsis was induced by cecal ligation and puncture method in female Wistar albino rats. Sepsis and sham operated (control) groups received either saline or montelukast (10 mg/kg, ip) immediately after the operation and at 12 h. Twenty-four hours after the surgery, rats were decapitated and malondialdehyde (MDA) content—an index of lipid peroxidation, glutathione (GSH) levels—a key antioxidant, myeloperoxidase (MPO) activity—an index of neutrophil infiltration, and collagen contents were determined in the liver and ileum. Formation of reactive oxygen species in liver and ileal tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes. Both tissues were also analyzed histologically. Serum lactate dehydrogenase (LDH) and tumor necrosis factor- α (TNF- α) level were assessed in trunk blood. Results: Sepsis resulted in decreased GSH levels, and increased MDA levels, MPO activity, CL levels and collagen contents in both the liver and the ileum ( P < 0.05 – P < 0.001 ) indicating the presence of the oxidative damage. Similarly, serum TNF- α and LDH were elevated in the sepsis group as compared to control group. On the other hand, montelukast treatment reversed all these biochemical indices, as well as histopathological alterations, which were induced by sepsis. Conclusion: Findings of the present study suggest that montelukast possesses an anti-inflammatory effect on sepsis-induced hepatic and intestinal damage and protects against oxidative injury by a neutrophil-dependent mechanism.

Imbalance in the enzymatic system of production and consumption of active oxygen species in liver of AKR mice with spontaneous leucosis.

Activities of protective antioxidant enzymes, the rate of superoxide formation (v) in microsomal membranes and submitochondrial particles (SMP), and the concentrations of reduced and oxidized glutathione in cytosol were studied in the liver of AKR mice during the development of spontaneous leucosis. It was found that in the latent period of leucosis (mice of 3-6 months of age) the glutathione reductase (GR) activity in cytosol and mitochondria decreased and v in SMP increased. The increase in v in SMP did not result in the induction of Mn-SOD. In this stage of leucosis, the activities of Cu,Zn-SOD, GSH-Px, and G-6-PDH in cytosol were unchanged; at the same time, the GR activity and the concentration of reduced glutathione smoothly decreased. In the stage of developed leucosis (mice of 7-9 months of age), non-synchronous changes in the antioxidant system resulting in the shift of metabolism towards the prooxidant state were found. Comparison of our findings and the literature data demonstrates that the observed decrease in the SOD/GSH-Px ratio, the decrease in GR activity, and the increase in the v/Mn-SOD activity ratio are typical for pre-neoplastic changes in cell metabolism.

Effect of ethanol treatment on indices of cumulative oxidative stress

The effect of ethanol exposure upon several parameters relating to oxidative stress has been examined in brain and liver. A single administration of either acetaldehyde or ethanol was able to enhance rates of generation of reactive oxygen species in liver but this effect was not apparent in the cerebral cortex. Glutamine synthetase is especially sensitive to inactivation by free radicals and evidence for cumulative oxidative damage to this enzyme was found in liver and to a lesser extent in cerebral cortex. This enzyme was depressed in liver after both a single injection of acetaldehyde or ethanol, or after more extended dosing. The liver was also more susceptible than cerebral cortex, to pro-oxidant effects as judged by depression of glutathione after acute dosing with either solvent. Enzyme inhibition representing temporally summated oxidative events may be a more sensitive procedure than direct measurement of rates of formation of active oxygen species and may find especial utility in the detection of prolonged low level pro-oxidant activity.

Active oxygen species in the liver of rats submitted to chronic hypobaric hypoxia.

The spontaneous in situ liver chemiluminescence of female rats submitted to 4,400 m (simulated altitude) for 2 mo and of their corresponding controls at sea level was determined as an approach to the measurement of the intracellular steady-state concentrations of singlet oxygen and oxygen free radicals. Spontaneous liver chemiluminescence was decreased by approximately 40% in hypoxic rats, whereas CCl4-induced chemiluminescence was unchanged. Liver mitochondria isolated from hypoxic rats showed a 53% decreased rate of H2O2 production and an increased content of cytochrome b (36%), with normal content of cytochromes c1, c, and a-a3. Superoxide dismutase showed a 26% decrease in activity, whereas catalase and glutathione peroxidase activities were not significantly decreased by this extent of hypoxia. Cytochrome P-450 and glutathione contents were unchanged. There were no significant differences in the hydroperoxide-initiated chemiluminescence (an estimation of tissue chain-breaker antioxidants) of homogenates, mitochondria, and microsomes. Results suggest that in chronic hypoxia there is a lower rate of generation of active oxygen species in liver, leading to a decreased steady-state concentration of singlet oxygen.