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)

Collagen synthesis and degradation in normal and carbon-tetrachloride-injured male Wistar rats at early and late stages of liver fibrosis, and the potential beneficial effects of zinc supplementation on liver fibrogenesis and collagenolysis have been assessed by measuring hepatic collagen content and prolyl hydroxylase and collagenase activities. No significant changes in hepatic collagen and prolyl hydroxylase activities were observed between control rats (82 +/- 25 cpm/mg protein) and rats with induced cirrhosis (107 +/- 23 cpm/mg protein) after 4 weeks of carbon tetrachloride injury. By this time, hepatic collagenase activity was significantly lower in rats with induced cirrhosis (61 +/- 9 micro units/mg protein) than in control rats (133 +/- 31 micro units/mg protein) (p < 0.05). This result was prevented by zinc administration, since hepatic collagenase activity was similar in zinc-supplemented, carbon-tetrachloride-injured rats and normal rats (148 +/- 19 micromicrons/mg protein). After 16 weeks, all carbon-tetrachloride-injured rats had cirrhosis. Hepatic collagen content and prolyl hydroxylase activity were significantly higher in carbon-tetrachloride-injured rats than in controls. These effects were partially prevented by zinc administration, since only two of the seven zinc-supplemented, carbon-tetrachloride-injured rats had cirrhosis. Moreover, prolyl hydroxylase activity was significantly lower in zinc-supplemented injured rats (263 +/- 27 cpm/mg protein) than in the non-supplemented respective controls (389 +/- 52 cpm/mg protein) (p < 0.05). No significant changes in hepatic collagenase activity were observed at this stage of liver injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fibrogenic and collagenolytic activity in carbon-tetrachloride-injured rats: beneficial effects of zinc administration. 783 96

To examine whether serum collagenase activity reflects the amount of hepatic collagenase in the fibrotic liver, we measured serum collagenase activity in 67 patients with chronic liver disease and in 26 healthy controls. Collagenase activity in serum was measured after reactivation by denaturing and dissociating the inhibitors with 3 M KSCN and 1 mM aminophenylmercuric acetate. Serum collagenase activity was 35% lower than control in chronic persistent hepatitis, 48% lower in chronic active hepatitis, 56% lower in liver cirrhosis and 68% lower in hepatocellular carcinoma. To interpret this finding of low serum collagenase activity, we measured serum concentration of TIMP (Tissue Inhibitor of Metallo-Proteinases). Serum TIMP concentration was increased as liver disease developed, and it was inversely correlated with serum collagenase activity. These results suggest that in this assay condition serum collagenase activity is influenced by TIMP, and thus may not reflect the amount of hepatic collagenase in patients with chronic liver disease.
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PMID:Serum collagenase activity in chronic liver diseases. 789 42

Chronic iron overload can result in hepatic fibrosis and cirrhosis. Activated lipocytes, through increased production of collagen and extracellular matrix, play an important role in hepatic fibrogenesis in several types of experimental liver injury, but their contribution to hepatic injury after iron overload is unknown. This study examines the effect of iron overload on lipocyte activation, in vivo. Male Sprague-Dawley rats were fed a chow diet supplemented with 1% carbonyl iron for up to 20 mo. Controls were fed the chow diet alone. Lipocytes were prepared by sequential pronase and collagenase perfusion of the livers, followed by density-gradient centrifugation. Lipocyte activation was assessed by immunohistochemistry of liver sections and by Western blot analysis of alpha-smooth muscle actin expression in freshly isolated lipocytes. In addition, to measure the biosynthetic capability of these lipocytes, collagen and noncollagen protein production was determined after 3 days in culture, using [3H]proline incorporation. The hepatic iron concentration was increased by eightfold in the iron-loaded rats, and lipocytes from these animals expressed alpha-smooth muscle actin. Collagen production was increased by 2.5-fold, and noncollagen protein production was elevated by twofold in lipocytes isolated from iron-loaded rats. In the iron-loaded livers, autofluorescent material with the characteristics of lipofusion was present in periportal zones. Chronic iron overload expression results in the activation of lipocytes, as determined by increased expression of alpha-smooth muscle actin and by increased production of both collagen and noncollagen protein. This activation may contribute to iron-induced hepatic fibrogenesis.
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PMID:Chronic iron overload causes activation of rat lipocytes in vivo. 790 Aug 6

Alcoholic and, to a lesser extent, nonalcoholic patients with liver disease have serum antibodies to acetaldehyde-protein adducts produced in vitro. These antibodies presumably reflect the presence of adducts in the liver, but the protein that triggers this immune response has not been identified. To study this, we measured the reactivity of cytosolic proteins to rabbit IgG developed against a P-450 2E1-acetaldehyde adduct, isolated from alcohol-fed rats, that recognizes acetaldehyde-modified epitopes in proteins. Adducts were determined on Western blots by scanning densitometry of antibody-linked alkaline phosphatase activity in 4 normal livers and in needle biopsy specimens from subjects with liver disease, 17 alcoholic and 14 nonalcoholic. In all livers, except for a normal one, we found a reactive protein of at least 200 kD, similar to the collagen-acetaldehyde adduct we reported to be markedly increased in rats with experimentally induced cirrhosis. The immunostaining intensity in the alcoholic patients with liver disease was eightfold (p < 0.01) and that in nonalcoholic patients with liver disease was fourfold, greater (p < 0.02) than the weak staining in normal livers; it correlated with the degree of inflammation and serum AST or gamma-glutamyl transpeptidase activities. The adduct was reproduced on incubation of normal cytosolic proteins with 2.5 mmol/L acetaldehyde, whereas higher concentrations yielded many additional adducts; the adduct also reacted with IgG antibody to rat collagen type I and disappeared after digestion with collagenase, suggesting that the target protein is a form of collagen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Collagen-acetaldehyde adducts in alcoholic and nonalcoholic liver diseases. 791 86

Marked changes in the redox state of liver cells in carbon tetrachloride (CCl4)-induced cirrhosis after chronic treatment with the hepatotoxin (4-8 weeks) were observed. A shift of the redox state towards the reduced side is noticed in both compartments, cytosol and mitochondria. At 8 weeks of treatment an imbalance between these two compartments was evident. The alteration produced by the CCl4 treatment in the cell redox state might be related to the mitochondrial damage elicited by the hepatotoxin. Adenosine treatment to CCl4-poisoned rats was able to counteract the effect of the hepatotoxin on the redox equilibrium; hence, it could be linked to the beneficial action of the nucleoside in the maintenance of mitochondrial function. The changes in the hepatocyte redox state, induced by CCl4 and/or adenosine, seem to modify collagen and nitrogen metabolism, indicating a linear correlation between the redox state and the collagen synthesis rate, whereas an inverse relationship was observed with collagenase activity. The possible role of the changes in cell redox state as signals for communication between parenchymal and mesenchymal liver cells is discussed. The results suggest an important correlation among mitochondrial function, cellular redox state, and regulation of collagen metabolism that could be relevant for the physio-pathology of this model of experimental cirrhosis.
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PMID:Possible role of cell redox state on collagen metabolism in carbon tetrachloride-induced cirrhosis as evidenced by adenosine administration to rats. 803 47

In alcoholic liver disease, it is well-known that ethanol and its metabolites induce hepatic fibrosis. With progress in injury, the accumulation of extracellular matrix, which consists of type I, III, IV collagen and laminine, occurs in the area of hepatic central vein and perihepatocytes. In these fibrotic areas, the activated lipocytes (transitional cell and myofibroblast, etc), which may be transformed from Ito cell by fibrogenic cytokines, are increased and may play an important role in the progression of alcoholic hepatic fibrosis. Actually, a recent study indicates that chronic ethanol consumption sensitizes the response of lipocytes to TGF beta. It is observed that acetaldehyde and lactate stimulate collagen production and that acetaldehyde increases collagen mRNA expression and collagen gene transcription in cultured human fibroblast. The extracellular matrix is degraded by matrix metalloproteinases (MMPs). The collagenase activity is decreased in progression of liver cirrhosis and is regulated by fibrogenic cytokines. Acetaldehyde decreases by 50% of the collagenase mRNA expression in fibroblast. It is clear that hepatic fibrosis may progress under the balance of collagen production and degradation, which are associated with fibrogenic cytokines. Thus, in the search for mechanism of alcoholic hepatic fibrosis, it is important to elucidate how ethanol and its metabolites influence the activation of lipocytes through fibrogenic cytokines.
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PMID:[Alcoholic liver cirrhosis]. 811 91

One of the contributory factors to the development of cirrhosis is a decrease in collagenase activity, which may be related to levels of inhibitors such as serum tissue inhibitor of metalloproteinase. We therefore measured serum tissue inhibitor of metalloproteinase and serum procollagen III peptides (another proposed marker of fibrosis) in 16 healthy controls and 44 alcoholic patients with biopsy-proved liver disease, namely steatosis without fibrosis (n = 13), perivenular fibrosis (n = 10), septal fibrosis or cirrhosis or both (n = 15) and alcoholic hepatitis (n = 6). In alcoholic patients, serum tissue inhibitor of metalloproteinase values strongly correlated with fibrosis (rs = 0.70, p < 0.001). Compared with values in controls (177 +/- 12 ng/ml), serum tissue inhibitor of metalloproteinase was significantly elevated in perivenular fibrosis (330 +/- 22 ng/ml, p < 0.05), in septal fibrosis, cirrhosis or both (406 +/- 29 ng/ml, p < 0.001) and in alcoholic hepatitis (526 +/- 140 ng/ml, p < 0.001) but not in steatosis (204 +/- 17 ng/ml). In contrast, procollagen III peptides were significantly increased only in the septal fibrosis-cirrhosis group but not in the perivenular fibrosis group. With the threshold defined as the upper value of the steatosis group (resulting in a specificity of 100%), we found that serum tissue inhibitor of metalloproteinase was elevated in 50% of patients with perivenular fibrosis, in 87% of subjects with extensive fibrosis (septal fibrosis, cirrhosis or both) and in 67% of individuals with alcoholic hepatitis. The overall sensitivity of serum tissue inhibitor of metalloproteinase for detecting either perivenular fibrosis or more extensive fibrosis was 71%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tissue inhibitor of metalloproteinase is increased in the serum of precirrhotic and cirrhotic alcoholic patients and can serve as a marker of fibrosis. 818 71

To examine the clinical significance of serum collagenase activity in chronic liver disease, serum collagenase activity was determined in 50 patients with chronic liver disease and in 24 healthy controls. Collagenase activity was measured after reactivation by denaturing and dissociating the inhibitors with potassium thiocyanate and aminophenylmercuric acetate. In patients with chronic persistent hepatitis, serum collagenase activity was 37% lower than controls, 50% lower in those with chronic active hepatitis, 66% lower in those with cirrhosis and 68% lower in those with hepatocellular carcinoma. Serum collagenase activity was significantly and inversely correlated with serum levels of the aminoterminal propeptide of type III procollagen and type IV collagen 7S domain, indicating that serum collagenase activity decreased as liver active fibrogenesis and/or fibrosis occurred. In contrast, serum levels of the metalloproteinase inhibitor was 30% higher than controls in patients with chronic active hepatitis, 50% higher in those with cirrhosis and 80% higher in those with hepatocellular carcinoma and was inversely correlated with serum collagenase activity. These results suggest that in this assay condition serum collagenase activity is influenced by the metallo-proteinase tissue inhibitor and thus does not reflect the amount of collagenase in the fibrotic liver.
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PMID:Serum collagenase activity in patients with chronic liver disease. 822 26

The treatment of alcoholic liver disease at present consists of abstinence from alcohol, bed rest, and dietary intake or administration of adequate amounts of calories and protein. Besides corticosteroids, which have been shown to improve hospital survival in severely ill patients with alcoholic hepatitis and liver transplantation in advanced cirrhosis, no successful specific therapy is available for alcoholic liver disease. Potential new therapeutic approaches include: (1) Treatment with specific dietary supplements such as polyunsaturated lecithin, which in baboons prevented the progression of the early stages of pericentral and interstitial fibrosis to septal fibrosis and cirrhosis; (2) antagonists to cytokines or antibodies to cytokine receptors for cytokines that have been shown to enhance hepatocellular necrosis or fibrosis; (3) substances that block pathways of oxygen radical formation or increase their metabolism or binding to form nonharmful compounds; (4) inhibition of collagen synthesis by proline analogues that increase intracellular collagen degradation or increase in collagen degradation by stimulation of collagenase or by insertion of exogenous DNA encoding amino or carboxyterminal peptides of procollagen into hepatocytes; and (5) stimulation of hepatic regeneration and recovery from alcohol-inducer liver injury.
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PMID:Treatment of alcoholic liver disease. 833 5

The matrix metalloproteinases (MMPs) gene family includes MMP-1 (interstitial collagenase), MMP-2 (72 kD type IV collagenase/gelatinase), MMP-3 (stromelysin/transin), MMP-7 (putative MMP; pump-1), MMP-8 (granulocyte collagenase) and MMP-9 (92 kD type IV collagenase/gelatinase). This gene family has the common characteristics in the gene structure as follows: All of MMPs have the active site metal ion-binding domain. All six enzymes are activated with the concomitant removal of N-terminal segment of the latent enzyme. The removed segment contains an unpaired cystein residue within the conserved amino acid sequence PRCGVPDV, located immediately adjacent to the proenzyme cleavage site. The authors showed the gene expression of MMP-1 in the process of hepatic fibrosis. The remarkable expression was noted on fibroblasts and macrophages within the newly-formed fibrous bands with lots of infiltrated lymphocytes. Liver cirrhosis did not showed the positive dots of MMP-1 mRNA. On the other hands, the expression of TIMP reported by Takahara et al., revealed the high level of expression in the advanced fibrosis.
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PMID:[Gene expression of MMPs and TIMPs in the process of hepatic fibrosis]. 846 57


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