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)

Disturbances of the methionine cycle may result in liver injury. Patients with alcohol-induced liver disease often exhibit hypermethioninemia and a delayed clearance (CL) of methionine, but the extent to which transsulfuration and remethylation pathways of the cyclic methionine metabolism are affected is unknown. Methionine turnover was determined in 7 healthy volunteers and 6 patients with alcohol-induced cirrhosis after oral administration of 2 mg/kg [(2)H(3)-methyl-1-(13)C]methionine, which permitted us to follow transsulfuration by its decarboxylation to (13)CO(2) and remethylation by replacement of the labeled methyl group by an unlabeled one. Basal plasma concentrations of endogenous methionine (50 +/- 5 vs. 25 +/- 2 micromol/L, mean +/- SEM, P <.001) were significantly higher in patients with cirrhosis and its CL was significantly decreased (774 +/- 103 vs. 2,050 +/- 141 mL/min, P <.001). Methionine turnover amounted to 42 +/- 4 vs. 27 +/- 3 micromol/kg/h (P <.05) in controls and patients with cirrhosis, respectively. The fraction of administered methionine undergoing remethylation was lower in patients with cirrhosis (7.6 +/- 1.5 vs. 14.1 +/- 1.1%, P <.005). However, because of the larger pool of circulating methionine, the total flux of methionine through the remethylation pathway was similar in both groups. A significantly lower fraction of the administered dose appeared in the form of (13)CO(2) in breath in patients with cirrhosis (2.2 +/- 0.4 vs. 11.0 +/- 0.8%, P <.001). In conclusion, the data indicate that the liver with cirrhosis compensates for a decreased activity of remethylating enzymes by operating at higher concentrations of methionine. In contrast, transsulfuration is impaired in patients with alcohol-induced cirrhosis such that an assessment of transsulfuration by a simple breath test may provide a clinically useful estimate of hepatic function.
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PMID:Remethylation and transsulfuration of methionine in cirrhosis: studies with L-[H3-methyl-1-C]methionine. 1239 29

Dietary cirrhosis of the liver was produced in 223 rats, and then therapy of the condition attempted. Administration of lipotropic factors (casein, methionine, choline) was followed not only by reduction of fat infiltration and by regeneration of hepatic parenchyma but, by a reduction of the degree of the fibrosis. In one group of rats, comparison of sections obtained by biopsy, before treatment, with findings at necropsy, after completed therapy, indicated apparent reduction of the fibrosis and of the amount of ceroid and considerable restoration of architecture. This improvement, however, was obtained neither with complete regularity nor in a short time. In very severe cirrhosis, as a rule, the effect of a lipotropic diet was disappointing, even after prolonged treatment up to 200 to 240 days. It is assumed that factors determining prevention are beneficial only to a limited extent in treatment. The therapy of very severe cirrhosis may require the interaction of further beneficial factors (nutritional and hormonal). Best therapeutic results were obtained by the combination of an adequate amount of casein with methionine or liver extract, and by the combination of methionine with liver extract. Methionine and thiouracil, both of which, singly, are effective in the prevention of dietary hepatic cirrhosis in rats, have proved to be less effective for the therapy of cirrhosis, when administered together, than methionine given alone for the same purpose. Under identical conditions, female rats have shown greater resistance to the production of dietary hepatic cirrhosis and a more favorable response to therapeutic dietary factors, than male rats.
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PMID:Treatment of experimental dietary cirrhosis of the liver in rats. 1815 40

1. Cysteic acid fed to albino rats as 12.5 to 15 per cent of the McCollum stock diet caused portal necrosis and cirrhosis of the liver within 2 weeks. Concentrations of cysteic acid of 6.25 per cent or less in the diet produced no liver lesions within 2 weeks. 2.dl-Methionine fed as 6.4 to 12.4 per cent of the McCollum stock diet or of a low protein, low fat diet, resulted in severe atrophy of the liver cells but no cirrhosis of the liver. 3. Taurine fed as 1 to 10 per cent of the McCollum stock diet produces no liver lesions. 4. For reasons discussed in the paper, it is concluded that the liver necrosis and cirrhosis produced by cystine and cysteic acid are not dependent upon the S-S linkage of the cystine, the oxidation of the sulfur, the formation and excretion of large amounts of urinary sulfate, or the presence of an amino group separated from a sulfur molecule by a 2 carbon chain.
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PMID:EFFECTS OF EXCESS DIETARY CYSTEIC ACID, dl-METHIONINE, AND TAURINE ON THE RAT LIVER. 1987 Dec 39

Six groups of rats on different diets were exposed to the inhalation of carbon tetrachloride (about 300 p. p. m.) for 150 days. Food intake and changes in weight were followed throughout the experiment. Animals fed a diet low in protein showed greater susceptibility than rats on a diet high in protein. Methionine was a good substitute for protein (casein) in the diet. Increase in fat intake with correspondingly lower carbohydrate intake exerted a harmful effect, especially evident in combination with a low protein diet. In this change of the fat: carbohydrate ratio, whether the increased fat or the lowered carbohydrate is the specific factor must remain unanswered at the present time. Necrotizing nephrosis was the presenting sign of the intoxication caused by carbon tetrachloride, in addition to hepatic changes, such as hydropic degeneration, necrosis, and cirrhosis. Dietary factors (methionine and methionine-containing protein, as well as low fat intake) more consistently prevented renal injury than cirrhosis of the liver. Under identical dietary conditions, especially with higher fat intake, male rats appeared to evince greater susceptibility to carbon tetrachloride than female rats. The significance of this observation and its wider applicability has been discussed.
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PMID:INFLUENCE OF DIETARY FACTORS AND SEX ON THE TOXICITY OF CARBON TETRACHLORIDE IN RATS. 1987 42

The 148 Isoleucine to Methionine protein variant (I148M) of patatin-like phospholipase domain-containing 3 (PNPLA3), a protein is expressed in the liver and is involved in lipid metabolism, has recently been identified as a major determinant of liver fat content. Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver: from simple steatosis to steatohepatitis and progressive fibrosis. Furthermore, the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis, and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis, and possibly chronic hepatitis B virus hepatitis, hereditary hemochromatosis and primary sclerosing cholangitis. All in all, studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases. Remarkably, the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation, suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes, directly promoting fibrogenesis. Therefore, PNPLA3 is a key player in liver disease progression. Assessment of the I148M polymorphism will possibly inform clinical practice in the future, whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.
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PMID:PNPLA3 I148M polymorphism and progressive liver disease. 2422 41

Non-alcoholic steatohepatitis (NASH) is the leading cause of cirrhosis worldwide and the most rapidly growing indication for liver transplantation. Macrophages are the important cellular component in the inflammatory milieu in NASH. Inflammatory and pro-fibrotic mediators produced by macrophages causes significant tissue injury in many inflammatory diseases. Therefore, inhibition of the inflammatory macrophages would be a promising approach to attenuate NASH. In this study, we studied the implication of SYK pathway in NASH, and investigated PLGA nanoparticles-based delivery of SYK pathway inhibitor as an effective and promising therapeutic approach for the treatment of NASH. We found positive correlation between SYK expression with the pathogenesis of NASH and alcoholic hepatitis in patients. Importantly, SYK expression was significantly induced in M1-differentiated inflammatory macrophages. To inhibit SYK pathway specifically, we used a small-molecule inhibitor R406 that blocks Fc-receptor signaling pathway and reduces immune complex-mediated inflammation. R406 dose-dependently inhibited nitric-oxide release and M1-specific markers in M1-differentiated macrophages. Thereafter, we synthesized PLGA nanoparticles to deliver R406 to increase the drug pharmacokinetics for the efficient treatment of NASH. We investigated the therapeutic efficacy of R406-PLGA in-vitro in differentiated macrophages, and in-vivo in Methionine-Choline-deficient (MCD)-diet induced NASH mouse model. R406-PLGA inhibited M1-specific differentiation markers in RAW and bone-marrow-derived macrophages. In-vivo, R406 and more strongly R406-PLGA ameliorated fibrosis, inflammation and steatosis in mice. R406 and more significantly R406-PLGA reduced ALT, AST, cholesterol and triglyceride plasma levels. These results suggest that delivery of SYK inhibitor using PLGA nanoparticles can be a potential therapeutic approach for the treatment of Non-alcoholic steatohepatitis.
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PMID:Therapeutic inhibition of spleen tyrosine kinase in inflammatory macrophages using PLGA nanoparticles for the treatment of non-alcoholic steatohepatitis. 3021 79

Patients with decompensated cirrhosis are highly susceptible to develop bacterial infections and these can trigger multiorgan failure associated with high in-hospital mortality. Neutrophils from patients with decompensated cirrhosis exhibit marked alterations that may explain the susceptibility of these patients to develop bacterial infections. These neutrophil alterations include marked defects in intracellular signaling pathways involving serine/threonine kinases such as protein kinase B (AKT), p38-mitogen-activated protein kinase (MAPK), and the MAP kinases1/2; activation of the NADPH oxidase complex; myeloperoxidase (MPO) release; and bactericidal activity of neutrophils stimulated by the bacterial peptide formyl-Methionine-Leucine-Phenylalanine (fMLF). Impaired activity of the NADPH oxidase 2 (NOX2) complex is also related to reduced levels of expression of its major components through post-transcriptional mechanisms. In addition, the catalytic NOX2 component gp91 phox is subject to degradation by elastase highly present in patients' plasma. A defect in the protein kinase B (AKT) and p38 MAPK-mediated signaling pathways may explain the decrease in phosphorylation of p47 phox (an important component of the NADPH oxidase complex) and MPO release, in response to neutrophil stimulation by fMLF. Most of these alterations are reversible ex vivo with TLR7/8 agonists (CL097, R848), raising the possibility that these agonists might be used in the future to restore neutrophil antibacterial functions in patients with cirrhosis.
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PMID:Review of Defective NADPH Oxidase Activity and Myeloperoxidase Release in Neutrophils From Patients With Cirrhosis. 3113 93


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