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)

Drug-induced injury to the liver can mimic any form of acute or chronic liver disease. Acute injury to the liver frequently is due to the action of cytochrome P450, which breaks down drugs into electrophiles or free radicals; these reactive metabolites can covalently bind to protein and unsaturated fatty acids or induce lipid peroxidation, respectively. These events may impair vital functions of the cell, such as maintenance of calcium homeostasis, leading to death; or hypothetically they may elicit a hypersensitivity reaction directed mainly at the liver. Glutathione and tocopherol play critical roles in cellular defense. Cholestatic disease caused by drugs results from a selective disturbance in bile secretion. Agents such as estrogens, chlorpromazine, and monohydroxy bile acids alter the chemical and physical properties of membranes, leading to impaired activity of carriers and pumps for bile acids and electrolytes. Certain drugs produce chronic liver disease that is pathologically identical to chronic active hepatitis, biliary cirrhosis, or alcoholic liver disease.
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PMID:Drug-induced hepatotoxicity. 351 64

We measured glutathione and cysteine concentrations in erythrocytes of chronic alcohol misusers with (20 subjects) and without liver cirrhosis (20 subjects). Glutathione levels were decreased, whereas those of cysteine were increased in all patients. Parenteral treatment with S-adenosylmethionine (SAME); (2 g daily in 250 ml 0.15 M NaCl for 15 days) corrected the erythrocyte thiol alterations. We conclude that parenteral treatment with SAME affects the metabolism of SH compounds in erythrocytes of alcoholic patients.
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PMID:Effect of S-adenosyl-L-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease. 781 44

Glutathione and amino acid concentrations were measured in arterial and hepatic vein plasma in four healthy volunteers and two patients with cirrhosis. There was no significant splanchnic efflux of glutathione (95% confidence limits, -0.501 to 0.405 mumol/min). After infusion of N-acetylcysteine (NAC) in a high dose (150 mg/kg body weight primer plus 15 mg/(h x kg BW), corresponding to treatment of acetaminophen overdose, there was no change in the splanchnic glutathione efflux (95% confidence limits, -0.531 to 0.375 mumol/min). NAC increased hepatic plasma flow rate from 0.90 +/- 0.531 min-1 to 0.97 +/- 0.11 (mean +/- SEM; p < 0.05). The effects of NAC treatment on plasma amino acids corresponded to an increased load on hepatic metabolic N conversion and transamination among nonessential amino acids. Splanchnic uptake of serine, alanine, cystine, isoleucine, and phenylalanine increased after NAC compatible with stimulated hepatic glutathione synthesis. In contrast to the rat, plasma glutathione in man probably originates mainly from extrahepatic tissues.
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PMID:No net splanchnic release of glutathione in man during N-acetylcysteine infusion. 851 1

Redox processes have been implicated in various biologic processes, including signal transduction, gene expression, and cell proliferation, and several molecules have been identified as redox regulators in cell activation. Glutathione is the oldest and most investigated molecule among them. Although details of the mechanisms by which glutathione regulates various aspects of cell biology remains to be characterized, the relationship between immunodeficiency and cellular glutathione status is well established. Redox dysregulation contributes to the pathogenesis of acquired immunodeficiency syndrome (AIDS). Human immunodeficiency virus (HIV)-infected patients and simian immunodeficiency virus (SIV)-infected rhesus macaques have, on the average, significantly decreased plasma cysteine and intracellular glutathione levels. Liver contains abundant levels of reducing factors. However, glutathione levels in serum and peripheral blood mononuclear cells of cirrhosis patients are lower compared to values detected in healthy individuals. In the present article, the significance of glutathione in regulating the functions of lymphocytes, especially those of liver-associated lymphocytes, has been described. A novel strategy for immune therapy of liver neoplasms with the use of redox-modulating agents has been proposed.
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PMID:Liver immunity and glutathione. 1122 52

Alcoholic liver disease (ALD) develops as a consequence of priming and sensitizing mechanisms rendered by cross-interactions of primary mechanistic factors and secondary risk factors. This concept, albeit not novel, is becoming widely accepted by the field, and more research is directed toward identifying and characterizing the interfaces of the cross-interactions to help understand individual predisposition to the disease. Another pivotal development is the beginning of cell type-specific research to elucidate specific contributions not only of hepatocytes, but also of hepatic macrophages, liver-associated lymphocytes, sinusoidal endothelial cells, and hepatic stellate cells to sensitizing and priming mechanisms. In particular, the critical role of hepatic macrophages has been highlighted and the priming mechanisms concerning this paracrine effect have been proposed. Glutathione depletion in hepatocyte mitochondria is considered the most important sensitizing mechanism. One of the contributing factors is decreased methionine metabolism. Remaining key questions include how altered methionine metabolism contribute to the pathogenesis of ALD; how cross-talk among nonparenchymal liver cells or between nonparenchymal cells and hepatocytes leads to ALD; how dysfunctional mitochondria determine the type of cell death in ALD; and what secondary factors are critical for the development of advanced ALD such as alcoholic hepatitis and cirrhosis.
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PMID:Current concepts in the pathogenesis of alcoholic liver injury. 1138 31

In alcohol-related liver disease, free radicals play a part in the pathogenesis of liver damage and may influence cell turnover. The aims of this study were to correlate lipid peroxidation, antioxidant defence and iron metabolism with cell proliferation and apoptosis in alcoholic liver injury, and also in comparison with virus-related liver disease. In 45 patients [10 with chronic alcoholic liver damage (CALD), 24 with HCV-related (HCV) and 11 with HBV-related chronic hepatitis (HBV)], and 10 control subjects, we investigated serum ferritin, liver tissue iron, cysteine, reduced/oxidized glutathione, malondialdehyde, histology with hepatocyte proliferation and the apoptotic index. Ferritin, iron levels and malondialdehyde were significantly higher in HCV and CALD than in HBV, and malondialdehyde correlated with both iron and ferritin. Glutathione levels were significantly lower in CALD than in HCV, HBV and control subjects, whereas cysteine levels were significantly higher. The apoptotic index was slightly lower in CALD, with apoptosis occurring more frequently in the centrilobular area, while CALD had fewer proliferating hepatocytes, both overall and in the periportal and centrilobular areas. This study confirms that chronic alcohol intake: (1) induces more peroxidative damage, which correlates with iron loading; (2) reduces antioxidant defence, lowering reduced glutathione liver availability; (3) induces an accumulation of cysteine, a glutathione precursor/metabolite in the liver, probably due to gamma-glutamyltransferase induction; (4) correlates with a lesser extent and different distribution of hepatocyte proliferation and apoptosis than in viral liver damage. This last finding may explain the different types of liver cirrhosis deriving from alcoholic liver damage and the lower cancer risk.
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PMID:Hepatocyte proliferation and apoptosis in relation to oxidative damage in alcohol-related liver disease. 1182 56

There is a great deal of concern regarding the hazard potential of human exposure to toxic substances and carcinogens as well as infectious agents in the environment. For monitoring purposes fish are well established with regard to aquatic pollution. However, for the human environment, mammalian species might be considered more relevant. As the various types of rats are one of the most common animals sharing human habitants they are natural candidates. In the present study, numbers of such wild rats were trapped in the metropolis of Bangkok and country regions of Thailand for comparison of lesions in the liver and lung which might provide indicators of carcinogens or other hazardous agents in the environment. Glutathione S transferase P form positive foci could be detected in livers, comparable to the laboratory rat case, but without any significant link to site of capture. In contrast, fatty liver and inflammation/cirrhosis were significantly more frequent in animals from the metropolis. Parasite infection also tended to be more prevalent, along with leptospirosis. Inflammatory change was similarly found in the lungs but without any variation between the city and countryside groups. These results suggest that wild rats could be employed as monitors of environmental agents of toxicological significance.
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PMID:Use of Wild Rodents for Environmental Monitoring - Comparison of Rats in Bangkok and Rural Areas of Thailand. 1271 96

Glutathione Transferases (GSTs) are crucial enzymes in the cell detoxification process catalyzing the nucleophilic attack of glutathione (GSH) on toxic electrophilic substrates and producing a less dangerous compound. GSTs studies are of great importance since they have been implicated in the development of drug resistance in tumoral cells and are related to human diseases such as Parkinson's, Alzheimer's, atherosclerois, liver cirrhosis, aging and cataract formation. In this review we start by providing an evolutionary perspective of the mammalian cytosolic GSTs known to date. Later on we focus on the more abundant classes alpha, mu and pi and their structure, catalysis, metabolic associated functions, drug resistance relation and inhibition methods. Finally, we introduce the recent insights on the GST class zeta from a metabolic perspective.
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PMID:Mammalian cytosolic glutathione transferases. 1869 Nov 23

Cirrhosis is a very common disease and its treatment is limited due to lack of effective drugs. Some studies indicate that this disease is associated with oxidative stress. Therefore, we decided to study the effect of trolox, an effective antioxidant, on experimental cirrhosis. Cirrhosis was induced by CCl4 administration (0.4 g/kg, intraperitoneally, three times per week, for 8 weeks) to Wistar male rats. Trolox was administered daily (50 mg/kg, orally). Fibrosis was assessed histologically and by measuring liver hydroxyproline content. Glutathione, lipid peroxidation and glycogen were measured in liver; serum markers of liver damage were also quantified. Transforming growth factor-beta (TGF-beta) was determined by Western blot and quantified densitometrically. Alkaline phosphatase, gamma-glutamyl transpeptidase and alanine aminotransferase increased in the group receiving CCl4; trolox completely or partially prevented these alterations. Glycogen was almost depleted by CCl4 but was partially preserved by trolox. Lipid peroxidation increased while glutathione decreased by CCl4 administration; trolox corrected both effects. Histology showed thick bands of collagen, necrosis and distortion of the hepatic parenchyma in the CCl4 group, such effects were prevented by trolox. Hydroxyproline content increased 5-fold by CCl4, while the group receiving both CCl4 and trolox showed no significant difference compared to the control group. CCl4 increased 3-fold TGF-beta, while trolox completely prevented this increase. We found that trolox effectively prevented cirrhosis induced with CCl4 in the rat. Our results suggest that the beneficial effects of trolox may be associated to its antioxidant properties and to its ability to reduce the profibrogenic cytokine TGF-beta expression.
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PMID:Trolox down-regulates transforming growth factor-beta and prevents experimental cirrhosis. 1881 77

Non-alcoholic fatty liver disease comprises a broad spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis. As a result of increases in the prevalences of obesity, insulin resistance, and hyperlipidemia, the number of people with hepatic steatosis continues to increase. Differences in susceptibility to steatohepatitis and its progression to cirrhosis have been attributed to a complex interplay of genetic and external factors all addressing the intracellular network. Increase in sugar or refined carbohydrate consumption results in an increase of insulin and insulin resistance that can lead to the accumulation of fat in the liver. Here we demonstrate how a multidisciplinary approach encompassing cellular reprogramming, transcriptomics, proteomics, metabolomics, modeling, network reconstruction, and data management can be employed to unveil the mechanisms underlying the progression of steatosis. Proteomics revealed reduced AKT/mTOR signaling in fibroblasts derived from steatosis patients and further establishes that the insulin-resistant phenotype is present not only in insulin-metabolizing central organs, e.g., the liver, but is also manifested in skin fibroblasts. Transcriptome data enabled the generation of a regulatory network based on the transcription factor SREBF1, linked to a metabolic network of glycerolipid, and fatty acid biosynthesis including the downstream transcriptional targets of SREBF1 which include LIPIN1 (LPIN) and low density lipoprotein receptor. Glutathione metabolism was among the pathways enriched in steatosis patients in comparison to healthy controls. By using a model of the glutathione pathway we predict a significant increase in the flux through glutathione synthesis as both gamma-glutamylcysteine synthetase and glutathione synthetase have an increased flux. We anticipate that a larger cohort of patients and matched controls will confirm our preliminary findings presented here.
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PMID:A Systems Biology Approach to Deciphering the Etiology of Steatosis Employing Patient-Derived Dermal Fibroblasts and iPS Cells. 2296 28


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