chondroitin-sulfates and Carbon-Tetrachloride-Poisoning

Reactive oxygen species (ROC) are the main causes of carbon tetrachloride (CCl4)-induced acute liver injury. Chondroitin-4-sulphate (C4S) is known to inhibit lipid peroxidation through antioxidant mechanisms. Activation of nuclear factor (NF)-kappaB and caspases may strongly intensify inflammation and cell damage, in addition to that directly exerted by ROS. We investigated whether treatment with C4S, besides exerting antioxidant activity, was able to modulate NF-kappaB and apoptosis activation in CCl4-induced liver injury in mice.. Acute hepatitis was induced in mice by an i.p. injection of CCl(4). Varying doses of C4S were administered i.p. 1 h before, 6 and 12 h after CCl4 injection. 24 h after CCl4 injection, the mice were killed for biochemical and histological analysis.. CCl4 injection produced: marked elevation of alanine aminotransferase and aspartate aminotransferase; hepatic membrane lipid peroxidation, assayed by 8-isoprostane levels; and depletion of reduced glutathione and superoxide dismutase. CCl4 also decreased NF-kappaB translocation and IkBalpha, and increased gene expression of mRNA and protein of metalloproteases (MMP)-2 and -9, and of pro- and cleaved forms of caspases-3 and -7. There was also increased liver polymorphonuclear infiltration, evaluated by elastase assay, and hepatic cell disruption.C4S treatment inhibited lipid peroxidation; blocked NF-kappaB activation and IkBalpha protein loss; decreased mRNA and proteins for MMPs and caspases; restored endogenous antioxidants; limited hepatic polymorphonuclear accumulation and tissue damage.. As antioxidants may inhibit NF-kappaB and caspase activation, we hypothesize that treatment with C4S was able to inhibit NF-kappaB and apoptosis activation in hepatic injury.

Topics: Acute Disease; Animals; Antioxidants; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Caspases; Chemical and Drug Induced Liver Injury; Chondroitin Sulfates; Enzyme Activation; Male; Mice; Mice, Inbred Strains; NF-kappa B; Random Allocation

Oxidative stress is involved in the pathogenesis of chemically mediated liver injury. Since glycosaminoglycans possess antioxidant activity, the aim of this work was to assess the protective effects of hyaluronic acid and chondroitin-4-sulphate treatment in a model of carbon tetrachloride-induced liver injury. Liver damage was induced in male rats by an intraperitoneal injection of carbon tetrachloride (1 ml/kg in vegetal oil). Serum alanine aminotransferase and aspartate aminotransferase, hepatic malondialdehyde, plasma TNF-alpha, hepatic reduced glutathione and catalase, and myeloperoxidase, an index of polymorphonuclear infiltration in the jeopardised hepatic tissue, were evaluated 24 h after carbon tetrachloride administration. Carbon tetrachloride produced a marked increase in serum alanine aminotransferase and aspartate aminotransferase activities, primed lipid peroxidation, enhanced plasma TNF-alpha levels, induced a severe depletion of reduced glutathione and catalase, and promoted neutrophil accumulation. Intraperitoneal treatment of rats with hyaluronic acid (25 mg/kg) or chondroitin-4-sulphate (25 mg/kg) failed to exert any effect in the considered parameter, while the combination treatment with both glycosaminoglycans (12,5 + 12,5 mg/kg) decreased the serum levels of alanine aminotransferase and aspartate aminotransferase, inhibited lipid peroxidation by reducing hepatic malondialdehyde, reduced plasma TNF-alpha, restored the endogenous antioxidants, and finally decreased myeloperoxidase activity. These results suggest that hyaluronic acid and chondroitin-4-sulphate possess a different antioxidant mechanism and consequently the combined administration of both glycosaminoglycans exerts a synergistic effect with respect to the single treatment.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride Poisoning; Catalase; Chemical and Drug Induced Liver Injury; Chondroitin Sulfates; Glutathione; Glycosaminoglycans; Hyaluronic Acid; Lipid Peroxidation; Liver; Male; Malondialdehyde; Neutrophil Infiltration; Oxidation-Reduction; Peroxidase; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Hepatic fibrosis involves the interplay of many factors including reactive oxygen species. Recent reports described antioxidant properties of glycosaminoglycans (GAGs). Since several findings have shown that hyaluronic acid (HYA) and chondroitin-4-sulphate (C4S) may act as antioxidant molecules, the aim of this research was to evaluate the antioxidant effects of HYA and C4S treatment in a rat model of liver fibrosis. The effect on tissue inhibitors of metalloproteinases (TIMPs) was also studied. Liver fibrosis was induced in rats by eight intraperitoneal injections of CCl4, twice a week for 6 weeks. HYA or C4S alone (25 mg/kg) or HYA and C4S in combination (12.5 + 12.5 mg/kg) were administered daily by the same route during the 6 weeks. At the end of the 6-week treatment period (24 h after the last dose of GAGs), the following parameters were evaluated: (1) serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, as index of hepatic cell disruption; (2) hepatic conjugated dienes (CD), as index of lipid peroxidation; (3) hepatic TIMPs activity and expression; (4) hepatic superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity, as index of endogenous defences; (5) hepatic hydroxyproline, as index of collagen deposition. CCl4-induced liver fibrosis enhanced lipid peroxidation and TIMPs activation, increased ALT and AST, depleted antioxidants SOD and GPx, and caused collagen deposition in liver tissue. Treatment with GAGs, especially when in combination, successfully reduced ALT and AST rise, lipid peroxidation by evaluating conjugated dienes, TIMPs activation and mRNA expression, partially restored SOD and GPx activities, and limited collagen deposition in the hepatic tissue. The data obtained showed that these molecules were able to limit hepatic injury induced by chronic CCl4 intoxication and especially limited liver fibrosis. They also confirm that HYA and C4S may exert antioxidant mechanism, while reduction of TIMPs expression suggests that GAGs may influence MMPs and TIMPs imbalance in liver fibrosis.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Chondroitin Sulfates; Collagen; Disease Models, Animal; Glycosaminoglycans; Hyaluronic Acid; Injections, Intraperitoneal; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; Rats; Rats, Sprague-Dawley

This study was conducted to develop a new biomaterial to be used for an antioxidative drug. In this study, the hepatoprotective effect of chondroitin sulfate (CS) (100 mg/kg and 200 mg/kg body weight) was investigated at the antioxidative enzyme levels of liver total homogenate and mitochondria fraction. And the carbone tetrachloride (CCl(4))-induced rats were used as hepatotoxic models. The CCl(4) induced rat has been widely used as a hepatotoxic model due to its practicality, convenience and cost effectiveness since the generation of free oxygen radicals by CCl(4) injection was proposed as an important causative agent of hepatotoxicity. Malondialdehyde (MDA) levels were determined as well as the activities of superoxide dismutase (SOD), catalase (CAT), reduced-glutathione (GSH), oxidized-glutathione (GSSG) and glutathione peroxidase (GPx) in the liver. In addition, histopathology of liver tissue was investigated. Liver antioxidative enzyme activity was elevated while MDA concentration was decreased in all CS treated animals. The results demonstrated that CS protected oxidative stress in a dose dependent manner. Moreover, inflammation and cirrhosis in liver tissue of CS treated group were significantly decreased. It gave us an impression that CS might be a radical scavenger.

Topics: Animals; Antioxidants; Carbon Tetrachloride Poisoning; Catalase; Chemical and Drug Induced Liver Injury; Chondroitin Sulfates; Disease Models, Animal; Female; Glutathione; Glutathione Disulfide; Glutathione Peroxidase; Lipid Peroxidation; Malondialdehyde; Mitochondria, Liver; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Derangements in iron metabolism following liver damage were studied with special reference to iron deposit in relation to reticuloendothelial functions. In clinical studies, the metabolic fate of chondroitin sulfuric 59Fe, given intravenously, was examined in patients with chronic hepatitis or liver cirrhosis, diagnosed by liver biopsy. In experimental studies, liver damage was induced in rats by carbon tetrachloride (CCl4) injection and the labeled iron was similarly administered. 1) In patients with chronic hepatitis or liver cirrhosis, a reduction in uptake and utilization rates of the labeled iron was observed. 2) In rats with CCl4-induced liver damage, these parameters of the reticuloendothelial function were more reduced in parallel with the extent of hepatic fibrosis. 3) Similar conclusion was obtained from the analysis of iron distribution among tissues and of iron incorporation into several fractions of the liver: that is the uptake into non-hemin iron was less as the fibrosis advanced. In addition, more iron was incorporated into hemosiderin fraction and less into ferritin fraction. The findings may suggest a derangement in apoferritin synthesis as well as in release mechanism of deposit iron. 4) It is suggested that derangements in iron metabolism following liver damage are mainly due to reduction of the reticuloendothelial functions, but are partly due to changes in hematopoiesis and protein metabolism.

Topics: Animals; Carbon Tetrachloride Poisoning; Chondroitin; Chondroitin Sulfates; Chronic Disease; Hepatitis; Humans; Iron; Liver Cirrhosis; Male; Mononuclear Phagocyte System; Rats