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)

The intragastric alcohol infusion rat model (IAIRM) of alcoholic liver disease (ALD) has been utilized in various laboratories to study various aspects of ALD pathogenesis including oxidative stress, cytokine upregulation, hypoxic damage, apoptosis, ubiquitin-proteasome pathway and CYP2E1 induction. The basic value of the model is that it produces pathologic changes which resemble ALD including microvesicular and macrovesicular fat, megamitochondria, apoptosis, central lobular and pericellular fibrosis, portal fibrosis, bridging fibrosis, central necrosis, and mixed inflammatory infiltrate including PMNs and lymphocytes. The model is valuable because the diet and ethanol intake are totally under the control of the investigator. A steady state can be maintained with high or low blood alcohol levels for long periods. The cycling of the blood alcohol levels, when a constant infusion rate of alcohol is maintained, simulates binge drinking. Using this model the importance of dietary fat, especially the degree of saturation of the fatty acids on the induction of liver pathology, has been documented. The role of endotoxin, the Kupffer cell, TNFalpha, and NADPH oxidase have been demonstrated. The importance of 2E1 in oxidative stress induction has been shown using inhibitors of the isozyme. The importance of dietary iron in the pathogenesis of cirrhosis has been documented. Acetaldehyde has been shown to play a role in preventing liver pathology by preventing NFkappaB activation. Using the model, to maintain high blood alcohol levels is found to be necessary to demonstrate proteasomal peptidase inhibition. Ubiquitin synthesis is also inhibited at high blood alcohol levels in the IAIRM model. Oxidized proteins accumulate in the liver at high blood alcohol levels. Neoantigens derived from protein adducts formed with products of oxidation induce autoimmune mechanisms of liver injury. Thus, in many ways the model has revolutionized our understanding of the pathogenesis of ALD.
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PMID:Intragastric ethanol infusion model for cellular and molecular studies of alcoholic liver disease. 1117 72

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of treatment. Therapy must include correction of nutritional deficiencies, while taking into account changes of nutritional requirements. Methionine is normally activated to S-adenosylmethionine (SAMe). However, in liver disease, the corresponding enzyme is depressed. The resulting deficiencies can be attenuated by the administration of SAMe but not by methionine. Similarly, phosphatidylethanolamine methyltransferase activity is depressed, but the lacking phosphatidylcholine (PC) can be administrated as polyenylphosphatidylcholine (PPC). Chronic ethanol consumption increases CYP2E1, resulting in increased generation of toxic acetaldehyde and free radicals, tolerance to ethanol and other drugs, and multiple ethanol-drug interactions. Experimentally, PPC opposes CYP2E1 induction and fibrosis. Alcoholism and hepatitis C infection commonly co-exist, with acceleration of fibrosis, cirrhosis, and hepatocellular carcinoma. PPC is being tested clinically as a corresponding antifibrotic agent. Available antiviral agents are contraindicated in the alcoholic. Anti-inflammatory agents, such as steroids, may be selectively useful. Finally, anticraving agents, such as naltrexone or acamprosate, should be part of therapy.
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PMID:Liver diseases by alcohol and hepatitis C: early detection and new insights in pathogenesis lead to improved treatment. 1126 19

Hepatic stellate cells (HSCs) are responsible for type I collagen deposition in liver fibrosis that leads to cirrhosis. The purpose of this study was to examine potential molecular signals that lead to increased alpha(2)(I) collagen gene expression by acetaldehyde, the primary metabolite of alcohol and malondialdehyde (MDA), a lipid peroxidation product known to be associated with chronic liver injury. MDA and the combination of MDA and acetaldehyde were employed to determine the effect on alpha(2)(I) collagen gene expression as assessed by transient transfection analysis and reverse transcriptase polymerase chain reaction (RT-PCR). Immunoblot and subsequent immunoprecipitation analysis examined stress-activated protein kinase (SAPK) activity. Cotransfection with a dominant negative mutant for c-jun nuclear kinase (dnJNK1) was also employed with the alpha(2)(I) collagen promoter. MDA increased alpha(2)(I) collagen gene expression nearly 2.5- to 3-fold, however there was no synergistic effect of the combination of acetaldehyde and MDA on alpha(2)(I) collagen gene activation and expression. Acetaldehyde, MDA, or both significantly increased JNK activity when compared to untreated stellate cells. The dnJNK1 expression vector abrogated alpha(2)(I) collagen transgene activity. In conclusion, JNK activation appears to be critical in the signaling cascade of oxidative metabolites of chronic alcohol-related liver injury and collagen gene activation.
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PMID:Aldehydes potentiate alpha(2)(I) collagen gene activity by JNK in hepatic stellate cells. 1129 27

Alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) and cytochrome P-4502E1 (CYP2E1), and then to acetate by aldehyde dehydrogenase (ALDH). Polymorphisms of these ethanol-metabolizing enzymes may be associated with inter-individual difference in alcohol metabolism and susceptibility to alcoholic liver disease. We determined genotype and allele frequencies of ALDH2, CYP2E1, ADH2, and ADH3 in male Korean patients with alcoholic cirrhosis (n=56), alcoholics without evidence of liver disease (n=52), and nondrinkers (n=64) by using PCR or PCR-directed mutagenesis followed by restriction enzyme digestion. The prevalences of heterozygous ALDH2*1/*2 plus homozygous ALDH2*2/*2 in patients with alcoholic cirrhosis (7.1%) and alcoholics without evidence of liver disease (3.8%) were significantly lower than that in nondrinkers (45.3%). The c2 allele frequencies of the CYP2E1 in alcoholic cirrhosis, alcoholics without evidence of liver disease, and nondrinkers were 0.21, 0.20, and 0.20, respectively. Allele frequencies of ADH2*2 in the three groups were 0.78, 0.74, and 0.77 and those of ADH3*1 were 0.94, 0.98, and 0.95. Therefore, we confirmed the observation that the ALDH2*2 gene protects against the development of alcoholism. However, the development of cirrhosis in Korean alcoholic patients was not associated with polymorphisms of ethanol-metabolizing enzymes.
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PMID:Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population. 1174 56

Recent studies have demonstrated that circulating antibodies against malondialdehyde-acetaldehyde (MAA)-haptenated proteins are significantly increased in patients with alcohol-induced cirrhosis and hepatitis and correlate with the severity of liver damage. Additionally, when proteins are haptenated with MAA, they become highly immunogenic in vivo in the absence of adjuvants. However, the mechanism(s) of this immunogenicity are currently unknown. Initial in vitro studies on the effects of MAA-modified proteins on cells demonstrated an increase in cell death at concentrations that were cell type specific and time-dependent. Since immunogenicity due to cell death has been described, we investigated the mechanism(s) by which cell death was occurring. Assessment of cell death in splenocytes after 1 h found significant levels of apoptosis as compared to controls. After 5 h, a significant and dose-dependent necrosis occurred in which cells were exposed to >62.5 microg/ml (43.1 mM) MAA-haptenated protein. After 24 h, exposure to >31.3 microg/ml (21.6 mM) MAA-haptenated protein resulted in significant levels of necrosis, although DNA laddering studies found apoptosis was occurring as well. Morphological changes in the cells were observed by light microscopy that correlated with a "low" forward scatter population by flow cytometry. Since necrosis has been implicated in enhancing both primary and secondary immune responses, and necrosis was predominantly occurring in response to MAA-haptenated proteins, a possible mechanism by which the immunogenicity of MAA modification of proteins in vivo may occur is suggested. Specifically, MAA modification of self proteins may result in the death of various cell types, most likely those in the liver. These necrotic materials may induce anti-MAA antibodies and other auto antibodies, whose levels may then correlate with the severity of ALD.
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PMID:Malondialdehyde-acetaldehyde-haptenated protein induces cell death by induction of necrosis and apoptosis in immune cells. 1196 31

Apoptosis plays an important role in the progression of alcohol-induced liver disease to cirrhosis. Oxidative stress is an early event in the development of apoptosis. The major aim of this study was to study the conditions in which oxidative stress occurs in chronic alcoholism and its relationship with apoptosis of hepatocytes. We have found that oxidative stress is associated with chronic ethanol consumption in humans and in rats, in the former independently of the existence of alcohol-induced liver disease. Ethanol or acetaldehyde induces apoptosis in hepatocytes isolated from alcoholic rats, but not in those from control rats. Inhibition of aldehyde dehydrogenase, but not of cytochrome P450 2E1, prevents ethanol-induced cell death. Ethanol-induced apoptosis is caused by increased reactive oxygen species (ROS) driven by increased availability of the reduced form of nicotinamide-adenine dinucleotide (NADH) owing to mitochondrial acetaldehyde metabolism and it is prevented by blocking the opening of mitochondrial permeability transition (MPT) pores with cyclosporine A. Inhibition of nitric oxide (NO) synthase or addition of antioxidant vitamins C and E completely prevented ethanol-induced apoptosis. Mitochondrial oxidative stress, which occurs during chronic alcoholism, renders hepatocytes susceptible to apoptosis. On the other hand, the CD95 ligand expression was up-regulated by acetaldehyde. In conclusion, ethanol induces apoptosis via 2 different pathways: MPT and up-regulation of the expression of CD95-Fas ligand. The overproduction of ROS by mitochondria, driven by acetaldehyde metabolism, is a common trigger of both mechanisms.
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PMID:Mitochondrial oxidative stress and CD95 ligand: a dual mechanism for hepatocyte apoptosis in chronic alcoholism. 1198 71

An aldehyde-dehydrogenase (ALDH2) deficiency is a biological curb on excess alcohol-drinking. This enzyme deficiency is very common amongst Oriental people while it is relatively rare for most other populations. We observe that there is good geographical correlation between the prevalence of the mutant ALDH2*2 alleles and hepatitis B virus (HBV) infections. Populations that demonstrate a high ALDH2*2 prevalence are all located in HBV-endemic areas. Further, studies have shown that HBV and alcohol drinking exhibit a synergistic effect upon liver cirrhosis and cancer. A shorter life span for those with HBV infection and heavy alcohol consumption may result in a selection of the ALDH2*2 gene. We postulate that there may be patterns of evolutionary adaptation for ALDH2 deficiency in certain HBV-endemic areas and that these adaptations can produce differences in human alcohol-drinking capability.
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PMID:Why can't Chinese Han drink alcohol? Hepatitis B virus infection and the evolution of acetaldehyde dehydrogenase deficiency. 1220 10

At present, the relation between alcoholic consumption and the development of hepatic injury is clearly defined. However, the influence of genetic factors, the existence of associated pathologies, and the concomitant use of other hepatotoxic agents should also be considered.During chronic drunkenness, great quantities of oxygen free radicals are produced, redox balance is disturbed, and the defensive capacity of natural antioxidants is exceeded. All these factors originate an "oxidative stress," that totally distorts the hepatocellular function. Llkewise, an increase in the acetaldehyde intracellular concentration modifies several cellular proteins, deteriorating even more the hepatic activity. The importance of the "neo-antigens" between cellular components and acetaldehyde is still undefined, as well as their role in the formation of the Mallory Bodies.On the other hand, the complex network of intercellular and intracellular communications that includes cytokines, adherence molecules and membrane receptors are essential elements to be considered in the alcoholic liver disease genesis. The endotoxin, the TNF-a, the IL-8, as well as the ROIs production seem to be the most important factors.With reference to Alcoholic Hepatitis, the development of an exaggerated inflammatory response with the existence of neutrophiles may be the main mechanism of hepatocellular injury (82, 167, 168.)The final diagnosis of Alcoholic Hepatitis is histological. This also enables to measure the injury severity and to determine the presence of fibrosis and/or cirrhosis, in which case prognosis is more uncertain.Should a history of exaggerated alcoholic ingestion exist, diagnosis could be clinically determined. There is a great variability of clinical symptoms, and some patients present chronic liver disease complications frequently. Those who develop severe liver insufficiency will present leukocytosis, icterus and fever. In these cases, mortality can be as high as 80 per cent. There is no relationship between the alteration of liver function tests and the injury severity.The usefulness of antioxidants in cirrhosis has been demonstrated in animal modeis and in some studies made in human voluntarles. However, their role as therapy within the context of Alcoholic Hepatitis has not been yet defined.In conclusion, several therapeutic approaches have been investigated and from all of them, only steroids have proven to be effective on patients properly selected. The discriminative function (DF) benefit has been confirmed in certain studies. Should a patient have a DIF of more than 93, he/she may receive corticosterold treatment. Contral ndicati ons are a bsol ute when the patientpresents infection, renal insufficiency or gastrointestinal bleeding.Once the patient has been compensated, ABSTINENCE is essential. Likewise, an appropriate nutritional support is an important part of the treatment.Where the possibility of Liver Transplant exists, this should be planned if there is a deterioration of the patient's general condition or if he/she compiles with the necessary criteria, since the survival rate in these cases is similar to those who received a transpiant due to other causes.
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PMID:[ALCOHOLIC HEPATITIS] 1221 43

Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality worldwide. For example, the Veterans Administration Cooperative Studies reported that patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality of >60%. Interactions between acetaldehyde, reactive oxygen and nitrogen species, inflammatory mediators and genetic factors appear to play prominent roles in the development of ALD. The cornerstone of therapy for ALD is lifestyle modification, including drinking and smoking cessation and losing weight, if appropriate. Nutrition intervention has been shown to play a positive role on both an inpatient and outpatient basis. Corticosteroids are effective in selected patients with alcoholic hepatitis and pentoxifylline appears to be a promising anti-inflammatory therapy. Some complementary and alternative medicine agents, such as milk thistle and S-adenosylmethionine, may be effective in alcoholic cirrhosis. Treatment of the complications of ALD can improve quality of life and, in some cases, decrease short-term mortality.
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PMID:Advances in alcoholic liver disease. 1282 59

Ethanol toxicity on liver is a function of duration of alcoholism, amount of daily intake of alcohol and patient's nutrition. The threshold of alcohol toxicity on the liver is about 40 g of ethanol daily in men and 20-30 g in women, however liver cirrhosis develops in no more than 8-20% of patients exceeding this values. Ethanol is oxidized in the liver to acetaldehyde--a compound considerably more toxic than ethanol itself. Despite small amount of alcohol dehydrogenase (ADH) found in gastric mucosa, the metabolism of ethanol in this site may have an important hepatoprotective effect. The oxidation of ethanol is associated with a change of hepatocyte redox homeostasis, which leads to a number of metabolic disorders such as lactic acidosis, hyperlipidaemia and hyperuricaemia. Chronic ethanol consumption does not influence ADH activity, but has a profound stimulatory effect on microsomal enzymes, in particular cytochrome CYP2E1. This fact is responsible for development in alcoholic liver associated with rise of oxygen consumption, excessive production of free radicals and increased metabolism of ethanol, vitamin A and testosterone. Ethanol and acetaldehyde have a deleterious effect, both the direct and indirect, on hepatocytes e.g., generating radical oxygen species and damaging intestinal mucosal barrier. Cellular oxidative stress that is caused by both an excess of free radicals and the antioxidatives' deficiency (glutathion, vitamin E, phosphatidylcholine), may be the principal factor responsible for progression of alcoholic liver disease. Among other factors accelerating alcohol-related liver lesion there are certain drugs, high fat diet, infection with HCV and genetic factors (female sex, enzymatic polymorphic forms of ADH and ALDH, hemochromatosis). Great importance in pathogenesis of necrotic and inflammatory hepatic events is being attributed to portal endotoxaemia and cytokines induced within the liver, in particular TNF-alpha and interleukin 8. These cytokines play a key role in development of alcoholic hepatitis, which clinical severity ranges from subclinical to fatal forms. Apart from abstinence, the treatment of alcohol liver disease is based on hyperalimentation, since alcoholism is generally associated with protein malnutrition. In severe forms of alcohol hepatitis corticosteroids are recommended.
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PMID:[Alcoholic liver disease]. 1290 Dec 71


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