Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:The effect of chondroitin sulfate against CCl4-induced hepatotoxicity. 1273 1

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.
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PMID:Pharmacological rescue of the 14CoS/14CoS mouse: hepatocyte apoptosis is likely caused by endogenous oxidative stress. 1289 38

Hepatic stellate cells (HSC) play an important role in the development of liver cirrhosis. They are a major source of extracellular matrix and during fibrogenesis undergo an activation process characterized by increased proliferation and collagen synthesis. In this study, we investigated the anti-fibrogenic effect of zinc supplementation on zinc deficiency induced HSC activation. Isolated HSC were incubated with or without zinc chelator, diethylenetriamine penta-acetic acid (DTPA). Type I collagen expression in HSC was detected by immunohistochemistry. The involvement of glutathione (GSH) homeostasis in the anti-fibrogenic action of zinc was also investigated, as GSH is implicated in many cellular events, such as regulation of cell proliferation, remodeling of extracellular matrix and oxidative stress. Intracellular GSH was measured by HPLC. Enhanced type I collagen expression, apoptosis and cell cycle arrest were found in HSC when DTPA was added, but they were inhibited with supplementation with zinc. Zinc deficiency caused a reduction in intracellular GSH 8 h after the addition of DTPA compared with control levels. The results of this study show that in HSC, the chelation of zinc triggers a progression of collagen synthesis and this involves the depletion of intracellular GSH levels after the addition of DTPA.
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PMID:Involvement of intracellular glutathione in zinc deficiency-induced activation of hepatic stellate cells. 1290 56

For many liver malignancies, major hepatectomy is the usual therapy. Although a normal liver has a tremendous capacity for regeneration, liver hepatectomy in humans is usually carried out on a diseased liver and, in such cases, liver regeneration takes place in a cirrhotic remnant. Mitochondrial function in cirrhotic livers shows a variety of changes compared to control livers. This study investigated how mitochondrial respiratory function and antioxidant capacity change following partial hepatectomy of cirrhotic livers, because liver regeneration requires greater energy demands and control of oxidative stress. Cirrhosis was induced in male Wistar-Furth rats by administration of thioacetamide. NADH-cytochrome c reductase activity, mitochondrial glutathione peroxidase activity and mitochondrial GSH levels were all significantly lowered in cirrhotic livers and in the cirrhotic remnants up to 72 h after 70% hepatectomy when compared to the corresponding controls. Lower respiratory control ratios with succinate as substrate were also observed from 6 to 48 h post-hepatectomy. At 24 h post-hepatectomy, higher levels of lipid peroxidation were observed. We conclude that, compared to the controls, cirrhotic livers have diminished oxidative phosphorylation capabilities due to changes in NADH and FADH(2)-linked respiration as well as impaired antioxidant defenses following partial hepatectomy. Both of these factors, if critical, could then impede liver regeneration.
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PMID:Mitochondrial respiratory function and antioxidant capacity in normal and cirrhotic livers following partial hepatectomy. 1474

Oxidation of ethanol via alcohol dehydrogenase (ADH) explains various metabolic effects of ethanol but does not account for the tolerance. This fact, as well as the discovery of the proliferation of the smooth endoplasmic reticulum (SER) after chronic alcohol consumption, suggested the existence of an additional pathway which was then described by Lieber and DeCarli, namely the microsomal ethanol oxidizing system (MEOS), involving cytochrome P450. The existence of this system was initially challenged but the effect of ethanol on liver microsomes was confirmed by Remmer and his group. After chronic ethanol consumption, the activity of the MEOS increases, with an associated rise in cytochrome P450, especially CYP2E1, most conclusively shown in alcohol dehydrogenase negative deer mice. There is also cross-induction of the metabolism of other drugs, resulting in drug tolerance. Furthermore, the conversion of hepatotoxic agents to toxic metabolites increases, which explains the enhanced susceptibility of alcoholics to the adverse effects of various xenobiotics, including industrial solvents. CYP2E1 also activates some commonly used drugs (such as acetaminophen) to their toxic metabolites, and promotes carcinogenesis. In addition, catabolism of retinol is accelerated resulting in its depletion. Contrasting with the stimulating effects of chronic consumption, acute ethanol intake inhibits the metabolism of other drugs. Moreover, metabolism by CYP2E1 results in a significant release of free radicals which, in turn, diminishes reduced glutathione (GSH) and other defense systems against oxidative stress which plays a major pathogenic role in alcoholic liver disease. CYP1A2 and CYP3A4, two other perivenular P450s, also sustain the metabolism of ethanol, thereby contributing to MEOS activity and possibly liver injury. CYP2E1 has also a physiologic role which comprises gluconeogenesis from ketones, oxidation of fatty acids, and detoxification of xenobiotics other than ethanol. Excess of these physiological substrates (such as seen in obesity and diabetes) also leads to CYP2E1 induction and nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), with pathological lesions similar to those observed in alcoholic steatohepatitis. Increases of CYP2E1 and its mRNA prevail in the perivenular zone, the area of maximal liver damage. CYP2E1 up-regulation was also demonstrated in obese patients as well as in rat models of obesity and NASH. Furthermore, NASH is increasingly recognized as a precursor to more severe liver disease, sometimes evolving into "cryptogenic" cirrhosis. The prevalence of NAFLD averages 20% and that of NASH 2% to 3% in the general population, making these conditions the most common liver diseases in the United States. Considering the pathogenic role that up-regulation of CYP2E1 also plays in alcoholic liver disease (vide supra), it is apparent that a major therapeutic challenge is now to find a way to control this toxic process. CYP2E1 inhibitors oppose alcohol-induced liver damage, but heretofore available compounds are too toxic for clinical use. Recently, however, polyenylphosphatidylcholine (PPC), an innocuous mixture of polyunsaturated phosphatidylcholines extracted from soybeans (and its active component dilinoleoylphosphatidylcholine), were discovered to decrease CYP2E1 activity. PPC also opposes hepatic oxidative stress and fibrosis. It is now being tested clinically.
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PMID:The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role. 1555 33

It has been suggested that oxidative stress participates in the pathogenesis of hepatitis C virus infection. It also has been made clear that redox status in T cell and macrophage relates to the activity of virus infectious disease such as HIV infection. With such background we evaluated the relationship between the intracellular redox status of T cell and macrophage and the activity of HCV positive chronic liver disease. Intracellular GSH and GSSG levels of T cell and macrophage were determined in twenty-five HCV positive asymptomatic carriers (C-ASC), sixty-three chronic hepatitis patients (C-CH), ten HCV positive liver cirrhosis patients (C-LC) and twenty-nine healthy controls. The intracellular GSH levels of T cell (T-GSH) significantly decreased in both C-CH and C-LC compared with healthy controls. No significant differences in the T-GSH levels were found between healthy controls and C-ASC. T-GSH levels of C-CH and C-LC were significantly lower compared with C-ASC. The intracellular GSH levels of macrophage (CD14-GSH) of C-LC were significantly decreased compared with healthy controls. The CD14-GSH levels of C-CH and C-LC were significantly lower compared with C-ASC. There was no correlation between intracellular GSH, GSSG levels and the serum levels of iron-related markers, fibrogenesis markers and other clinical parameters. These results suggest that the intracellular redox status of T cell and macrophage relates to the progression of HCV related chronic liver disease.
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PMID:[The relationship between the intracellular redox status of immune cells and progression of hepatitis C virus related chronic liver disease]. 1555 20

Patients with chronic cholestasis, particularly those with associated cirrhosis, are susceptible to infectious complications. A predictable consequence of cholestasis is malabsorption of fat-soluble vitamins and free radical scavengers. On the other hand, it has been postulated that cholestasis affects polymorphonuclear leukocytes function by impeding chemotaxis, phagocytosis and superoxide anion release in experimental animals. This work is aimed to evaluate the antioxidant status and phagocytic activity of neutrophils in chronic liver disease patients. 15 primary biliary cirrhosis (PBC) patients, 15 primary sclerosing cholangitis (PSC) patients, 15 chronic viral hepatitis C (HCV) patients, and 15 healthy individuals (control group) were included in this study. Levels of catalase (Cat), superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GPx) and malondialdehyde (MDA) were assessed in both serum and neutrophils homogenates. Neutrophils function was estimated by nitroblue tetrazolium (NBT) reduction assay. A marked decrease in the antioxidant status was observed in serum and neutrophils' homogenate of patients with chronic liver diseases compared to healthy subjects. Significant elevation of lipid peroxides was found in all groups of liver disease patients. The majority of patients had reduced value in NBT reduction assay, which suggested a lack of response to infection by neutrophils. In conclusion, deficient antioxidant defense mechanisms may lead to excess oxygen free radicals formation that promote the pathological process in the liver. The use of free radicals scavengers by chronic liver patients may potentiate the antioxidant defense system against oxidative stress.
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PMID:Study of antioxidant enzymes level and phagocytic activity in chronic liver disease patients. 1571 21

Homocysteine (Hcy), an intermediate in methionine metabolism, has been proposed to be involved in hepatic fibrogenesis. Impaired liver function can alter Hcy metabolism. The aim of the present study was to determine plasma Hcy alterations in acute obstructive cholestasis and the subsequent biliary cirrhosis. Cholestasis was induced by bile duct ligation and sham-operated and unoperated rats were used as controls. The animals were studied on the days 7th, 14th, 21st and 28th after the operation. Plasma Hcy, cysteine, methionine, nitric oxide (NO) and liver S-adenosyl-methionine (SAM), S-adenosyl-homocysteine (SAH), SAM to SAH ratio and glutathione were measured. Chronic L-NAME treatment was also included in the study. Plasma Hcy concentrations were transiently elevated by the day 14th after bile duct ligation (P < 0.01) and subsequently returned to control levels. Similar relative fluctuations in plasma Hcy were observed in BDL rats after intraperitoneal methionine overload. Plasma methionine, cysteine and nitrite and nitrate were significantly increased after bile duct ligation. SAM to SAH ratio was diminished by the 1st week of cholestasis and remained significantly decreased throughout the study. These events were accompanied by a decrease in GSH to GSSG ratio in the liver. Chronic L-NAME treatment improved SAM to SAH ratio and prevented the elevation of plasma Hcy and methionine (P < 0.05) while couldn't influence the other parameters. In conclusion, this study demonstrates alterations in plasma Hcy and liver SAM and SAH contents in precirrhotic stages and in secondary biliary cirrhosis, for the first time. In addition, we observed that plasma Hcy concentrations in BDL rats follow a distinct pattern of alteration from what has been previously reported in other models of cirrhosis. NO overproduction may contribute to plasma Hcy elevation and liver SAM depletion after cholestasis.
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PMID:Homocysteine alterations in experimental cholestasis and its subsequent cirrhosis. 1576 80

The aim of this study was to evaluate a possible relationship between lymphomonocyte expression of heat shock proteins (HSP) 60/27 and plasma levels of pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) and markers of antioxidant/oxidative status [glutathione (GSH), alpha glutathione-S-transferase activity (alpha GST), malonyldialdeyde (MDA), 4-hydroxinonenal (4-HNE), and S-nitrosothiols (S-NO)] in patients with chronic liver diseases. Entered into the study were 47 subjects: 10 healthy controls, 16 patients with HCV-related chronic hepatitis (CH), and 16 patients with HCV-related and 5 with alcohol-related liver cirrhosis (10 Child A and 11 Child B+C). HSP60 was clearly expressed only in 5% of patients and lowly in the control group. HSP27 was clearly expressed in 46.7% of CH and 71.4% of cirrhotic patients but was lowly present in healthy subjects. A significant difference was found between patients with a low expression of HSP27 (negative patients) and those with a high HSP27 expression (positive patients) of plasma levels both of antioxidants (GSH, p < 0.05), and of markers of enhanced production of free radicals and cytokines (alpha GST, TNF-alpha and IL-6, p < 0.05; MDA, 4-HNE and S-NO, p < 0.01) as well as for alcohol use and degree of liver impairment. The present data are the first showing that, particularly in conditions of enhanced oxidative stress, lymphomonocytes from liver disease patients present an increased expression of HSP27.
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PMID:Heat shock protein 27 expression in patients with chronic liver damage. 1596 49

We investigated glutathione level, activities of selenium independent GSH peroxidase, selenium dependent GSH peroxidase, GSH S-transferase, GSH reductase and the rate of lipid peroxidation expressed as the level of malondialdehyde in liver tissues obtained from patients diagnosed with cirrhosis or hepatocellular carcinoma. GSH level was found to be lower in malignant tissues compared to adjacent normal tissues and it was higher in cancer than in cirrhotic tissue. Non-Se-GSH-Px activity was lower in cancer tissue compared with adjacent normal liver or cirrhotic tissue, while Se-GSH-Px activity in cancer was found to be similar to its activity in cirrhotic tissue and lower compared to control tissue. An increase in GST activity was observed in cirrhotic tissue compared with cancer tissue, whereas the GST activity in cancer was lower than in adjacent normal tissue. The activity of GSH-R was similar in cirrhotic and cancer tissues, but higher in cancer tissue compared to control liver tissue. An increased level of MDA was found in cancer tissue in comparison with control tissue, besides its level was higher in cancer tissue than in cirrhotic tissue. Our results show that the antioxidant system of cirrhosis and hepatocellular carcinoma is severely impaired. This is associated with changes of glutathione level and activities of GSH-dependent enzymes in liver tissue. GSH and enzymes cooperating with it are important factors in the process of liver diseases development.
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PMID:Glutathione and GSH-dependent enzymes in patients with liver cirrhosis and hepatocellular carcinoma. 1640 76


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