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 hepatic stellate (Ito) cell lies within the space of Disse and has a variety of functions. Stellate cells store vitamin A in characteristic lipid droplets. In the normal human liver, the cells can be identified by the presence of these lipid droplets; in addition, many stellate cells in the normal liver express alpha-smooth muscle actin. In acute liver injury, there is an expansion of the stellate cell population with increased alpha-smooth muscle actin expression; stellate cells appear to play a role in extracellular matrix remodelling after recovery from injury. In chronic liver injury, the stellate cell differentiates into a myofibroblast-like cell with marked expression of alpha-smooth muscle actin and occasional expression of desmin. Myofibroblast-like cells have a high fibrogenic capacity in the chronically diseased liver and are also involved in matrix degradation. In vitamin A intoxication, hypertrophy and proliferation of the stellate and myofibroblast-like cells may lead to non-cirrhotic portal hypertension, fibrosis and cirrhosis. In liver tumours, myofibroblast-like cells are involved in the capsule formation around the tumour and in the production of extracellular matrix within it. The transition of stellate cells into myofibroblast-like cells is regulated by an intricate network of intercellular communication between stellate cells and activated Kupffer cells, damaged hepatocytes, platelets, endothelial and inflammatory cells, involving cytokines and nonpeptide mediators such as reactive oxygen species, eicosanoids and acetaldehyde. The findings suggest that the stellate cell plays an active role in a number of human liver diseases, with a particular reactivity pattern in fibrotic liver disorders.
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PMID:The hepatic stellate (Ito) cell: its role in human liver disease. 909 76

Recent human genetic studies suggest that a predisposition to alcohol abuse and/or to develop alcoholism may be inherited. Pedigree analysis, linkage, and association studies have helped to detect marker loci and candidate genes that may prove useful in identifying individuals at risk. In particular, molecular genetic research into the causes of alcoholism has drawn attention to the potentially important role of alcohol- and acetaldehyde-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Functional polymorphisms have been observed at various genes encoding these enzyme proteins, all of which act to alter the rate of synthesis of the toxic metabolite acetaldehyde, or decrease its further oxidation. The occurrence of functional polymorphisms in alcohol-metabolizing enzymes makes them favored candidate genes suitable for further molecular genetic research. A positive selection of such genetic polymorphisms in some populations might act as a protective factor against alcohol abuse and alcohol-related disease outcomes. For example, individuals who show initial sensitivity to alcohol by virtue of their genetically controlled abnormality of ALDH2*2 allele are discouraged from excessive alcohol consumption. On the other hand, persons with the heterozygous ALDH2*2 genotype (ALDH2*1/2*2) are at higher risk for developing alcohol abuse-related end-organ damage than those with a homozygous ALDH2*1/2*1 genotype. Moreover, the frequency of C2 allele of cytochrome P45 02E1 was found to be higher in patients with nonfibrotic alcoholic liver disease than in patients with severe hepatic fibrosis or liver cirrhosis. Identification of putative alcoholism vulnerability genes by direct analysis of candidate genes and genetic linkage may therefore help improve approaches to prevention and treatment.
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PMID:Molecular genetic aspects of alcohol metabolism and alcoholism. 921 68

An acetaldehyde (AcH) adduct was prepared using rabbit low-density lipoprotein as carrier proteins. An antibody against this adduct was raised in Watanabe heritable hyperlipidemic rabbits and cross-reacted with human low-density lipoprotein and bovine serum albumin adducts. Using this antibody, serum anti-AcH-adduct antibody levels were measured by a direct ELISA method in 56 Japanese adults (healthy adults and patients with nonalcoholic gastrointestinal diseases, alcoholic liver injury, or alcoholic pancreatitis). The antibody level (mean +/- SD) was 22 +/- 10 microg/ml in healthy adults, 22 +/- 11 microg/ml in nonalcoholic gastrointestinal diseases, and 16 +/- 13 microg/ml in alcoholic pancreatitis. These antibody levels tended to increase with the progression of alcoholic liver injury, starting from fatty liver via hepatitis to cirrhosis, 29 +/- 24 microg/ml in fatty liver, 35 +/- 29 microg/ml in alcoholic hepatitis, and 46 +/- 54 microg/ml in alcoholic cirrhosis. The antibody level in patients taking 100 g or more of ethanol per day tended to be higher, compared with those in people taking less ethanol. A follow-up observation revealed that alcohol abstinence after hospitalization raised serum anti-AcH-adduct antibody level in some patients and kept it constantly low in other patients. The immunohistochemical study using the anti-AcH-adduct antibody revealed the presence of adduct-like substance in hepatocytes of liver biopsy specimens obtained from patients with alcoholic liver disease. The results indicate that the anti-AcH-adduct antibody may be associated with the progress of alcoholic liver diseases.
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PMID:An enzyme immune assay for serum anti-acetaldehyde adduct antibody using low-density lipoprotein adduct and its significance in alcoholic liver injury. 962 94

A great number of epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper alimentary tract cancer, including cancer of the oropharynx, larynx, and the esophagus, and for the liver. In contrast to those organs, the risk by which alcohol consumption increases cancer in the large intestine and in the breast is much smaller. However, although the risk is lower, carcinogenesis can be enhanced with relatively low daily doses of ethanol. Considering the high prevalence of these tumors, even a small increase in cancer risk is of great importance, especially in those individuals who exhibit a higher risk for other reasons. The epidemiological data on alcohol and other organ cancers are controversial and there is at present not enough evidence for a significant association. Although the exact mechanisms by which chronic alcohol ingestion stimulates carcinogenesis are not known, experimental studies in animals support the concept that ethanol is not a carcinogen, but under certain experimental conditions is a cocarcinogen and/or (especially in the liver) a tumor promoter. The metabolism of ethanol leads to the generation of acetaldehyde and free radicals. These highly reactive compounds bind rapidly to cell constituents and possibly to DNA. Acetaldehyde decreases DNA repair mechanisms and the methylation of cytosine in DNA. It also traps glutathione, an important peptide in detoxification. Furthermore, it leads to chromosomal aberrations and seems to be associated with tissue damage and secondary compensatory hyperregeneration. More recently, the finding of considerable production of acetaldehyde by gastrointestinal bacteria was reported. Other mechanisms by which alcohol stimulates carcinogenesis include the induction of cytochrome P4502E1, associated with an enhanced activation of various procarcinogens present in alcoholic beverages, in association with tobacco smoke and in diets, a change in the metabolism and distribution of carcinogens, alterations in cell cycle behavior such as cell cycle duration leading to hyperregeneration, nutritional deficiencies such as methyl, vitamin A, folate, pyrridoxalphosphate, zinc and selenium deficiency, and alterations of the immune system, eventually resulting in an increased susceptibility to certain viral infections such as hepatitis B virus and hepatitis C virus. In addition, local mechanisms in the upper gastrointestinal tract and in the rectum may be of particular importance. Such mechanisms lead to tissue injury such as cirrhosis of the liver, a major prerequisite for hepatocellular carcinoma. Thus, all these mechanisms, functioning in concert, actively modulate carcinogenesis, leading to its stimulation.
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PMID:Alcohol and cancer. 975 43

Alcohol-induced liver cirrhosis is one of the major causes of death worldwide. Strong evidence has established that ethanol's first metabolite, acetaldehyde, is highly fibrogenic and enhances the deposition of many extracellular matrix components by hepatic stellate cells. This article reviews our current knowledge of the molecular mechanisms whereby acetaldehyde induces these activities, with particular emphasis on those related to the upregulation of type I collagen.
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PMID:Acetaldehyde-mediated collagen regulation in hepatic stellate cells. 1037 17

Ethanol is one of the few nutrients that is profoundly toxic. Alcohol causes both whole-body and tissue-specific changes in protein metabolism. Chronic ethanol missuse increases nitrogen excretion with concomitant loss of lean tissue mass. Even acute doses of alcohol elicit increased nitrogen excretion. The loss of skeletal muscle protein (i.e., chronic alcoholic myopathy) is one of several adverse reactions to alcohol and occurs in up to two-thirds of all ethanol misusers. There are a variety of other diseases and tissue abnormalities that are entirely due to ethanol-induced changes in the amounts of individual proteins or groups of tissue proteins; for example, increased hepatic collagen in cirrhosis, reduction in myosin in cardiomyopathy, and loss of skeletal collagen in osteoporosis. Ethanol induces changes in protein metabolism in probably all organ or tissue systems. Clinical studies in alcoholic patients without overt liver disease show reduced rates of skeletal muscle protein synthesis though whole-body protein turnover does not appear to be significantly affected. Protein turnover studies in alcohol misusers are, however, subject to artifactual misinterpretations due to non-abstinence, dual substance misuse (e.g., cocaine or tobacco), specific nutritional deficiencies, or the presence of overt organ dysfunction. As a consequence, the most reliable data examining the effects of alcohol on protein metabolism is derived from animal studies, where nutritional elements of the dosing regimen can be strictly controlled. These studies indicate that, both chronically and acutely, alcohol causes reductions in skeletal muscle protein synthesis, as well as of skin, bone, and the small intestine. Chronically, animal studies also show increased urinary nitrogen excretion and loss of skeletal muscle protein. With respect to skeletal muscle, the reductions in protein synthesis do not appear to be due to the generation of reactive oxygen species, are not prevented with nitric oxide synthase inhibitors, and may be indirectly mediated by the reactive metabolite acetaldehyde. Changes in skeletal muscle protein metabolism have profound implications for whole body physiology, while protein turnover changes in organs such as the heart (exemplified by complex alterations in protein profiles) have important implications for cardiovascular function and morbidity.
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PMID:Protein metabolism in alcoholism: effects on specific tissues and the whole body. 1042 97

Acetaldehyde and malonildialdehyde can form hybrid protein adducts, named MAA adducts that have strong immunogenic properties. The formation of MAA adducts in the liver of chronic alcohol-fed rats is associated with the development of circulating antibodies that specifically recognized these adducts. The aim of this study was to examine whether MAA adducts might participate in the immune response associated with human alcohol-induced liver disease. Circulating antibodies against MAA adducts were evaluated in 50 patients with alcohol-induced hepatitis or cirrhosis, in 40 patients with non-alcohol-induced liver disease, in 15 heavy drinkers without liver damage and in 40 healthy controls by enzyme-linked immunosorbent assays (ELISA). Immunoglobulin G (IgG) reacting with MAA-modified proteins were significantly increased in the patients with alcohol-induced cirrhosis or hepatitis. The individual levels of anti-MAA IgG in those patients were associated with the severity of liver damage. Anti-MAA antibodies were also positively correlated with the levels of IgG recognizing epitopes generated by acetaldehyde and malonildialdehyde. However, competitive inhibition experiments indicated that the anti-MAA antibodies were unrelated to those against acetaldehyde- or malonildialdehyde-derived antigens and mainly recognized a specific, cyclic MAA epitope. Some degree of immune reactivity towards MAA adducts was also observed in patients with non-alcohol-induced liver injury. However, competitive ELISA showed that the antigens recognized by these sera were not the cyclic MAA adducts. Altogether, these results showed the formation of MAA antigens during alcohol-induced liver disease and suggest their possible contribution to the development of immunologic reactions associated with alcohol-related liver damage.
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PMID:Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease. 1073 43

Alcohol-induced cirrhosis results partially from the excessive production of collagen matrix proteins, which, predominantly alphaI(I) collagen, are produced and secreted by activated hepatic stellate cells (HSC). The accumulation of alphaI(I) collagen in HSC during cirrhosis is largely due to an increase in alphaI(I) collagen gene expression. Acetaldehyde, the major active metabolite of alcohol, is known to stimulate alphaI(I) collagen production in HSC. However, the mechanisms responsible for it remain unknown. The aim of this study was to elucidate the mechanisms by which alphaI(I) collagen gene expression is induced by acetaldehyde in rat HSC. In the present study, the acetaldehyde response element was located in a distal GC box, previously described as the UV response element, in the promoter of the alphaI(I) collagen gene (-1484 to -1476). The GC box was predominantly bound by the DNA binding transcription factor BTEB (basic transcription element binding protein), expression of which was acetaldehyde and UV inducible. Blocking BTEB protein expression significantly reduced the steady-state levels of the acetaldehyde-induced alphaI(I) collagen mRNA, suggesting that BTEB is required for this gene expression. Further studies found that acetaldehyde activated Jun N-terminal kinase (JNK) 1 and 2 and activator protein 1 (AP-1) transactivating activity. Inhibition of JNK activation resulted in the reduction of the acetaldehyde-induced BTEB protein abundance and alphaI(I) collagen mRNA levels, indicating that the expression of both genes is JNK dependent in HSC. Taken together, these studies demonstrate that BTEB mediates acetaldehyde-induced, JNK-dependent alphaI(I) collagen gene expression in HSC.
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PMID:The DNA binding protein BTEB mediates acetaldehyde-induced, jun N-terminal kinase-dependent alphaI(I) collagen gene expression in rat hepatic stellate cells. 1073 85

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


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