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)

Oxidative stress is defined as a disturbance in the prooxidant-antioxidant balance in favor of the former and has been suggested to be a relevant factor in aging as well as in different pathological conditions, such as heart attack, diabetes, and cancer. Ubiquinol is very sensitive against oxygen radicals and gives ubiquinone as an oxidation product. Therefore, the ratio of ubiquinol to ubiquinone should be a good marker of oxidative stress because of its definition. A method for the simultaneous detection of ubiquinol-10 and ubiquinone-10 in human plasma is described. Heparinized human plasma was mixed with 5 volumes of methanol and 10 volumes of hexane. After vigorous shaking and centrifugation, the hexane phase (5 microliters) was injected immediately and directly on to reverse-phase HPLC equipped with an on-line reduction column and an electrochemical detector in order to avoid the oxidation of ubiquinol to ubiquinone. It was found that the ratio of ubiquinol-10 to ubiquinone-10 was about 95/5 in human plasma from healthy donors. A significant increase in the oxidized form (ubiquinone-10) content was observed in plasmas of patients with hepatitis, cirrhosis, and hepatoma when compared with normal subjects, suggesting increased oxidative stress in these patients.
Mol Aspects Med 1997
PMID:Plasma ratio of ubiquinol and ubiquinone as a marker of oxidative stress. 926 9

The effect of thioacetamide-induced liver cirrhosis on plasma and tissue manganese levels and the protective role of selenium, zinc and allopurinol supplements was investigated in rats. Control plasma and liver manganese (Mn) levels were found to be (mean +/- SD): 8.4 +/- 2.4 mg/L and 5.7 +/- 1.5 mg/g wet weight respectively. Plasma manganese levels were significantly increased (p < 0.001) whereas liver manganese levels were significantly reduced (p < 0.05) in the cirrhotic rats. Treatment with selenium, zinc and allopurinol reversed this trend and restored the manganese levels close to the normal values. Lung, spleen, and kidney manganese levels under control conditions were considerably lower than that of the liver tissue. However, these levels registered a significant increase (p < 0.05) in cirrhotic rats and this change was normalized after selenium, zinc and allopurinol treatment. There were no significant differences in the comparative efficacy of each of these protective agents. Zinc supplement considerably increased the plasma zinc levels and plasma Zn/Mn ratio had a good correlation with plasma zinc concentration. This ratio was significantly reduced in cirrhotic rats, but returned to the control level after zinc, selenium and allopurinol treatment. The results of this study indicate that the trace element, manganese, plays an important role in stabilizing cell structure and that this effect is mediated possibly by preserving the antioxidant activity of the tissues.
Mol Cell Biochem 1997 Aug
PMID:Effect of dietary selenium, zinc and allopurinol supplements on plasma and tissue manganese levels in rats with thioacetamide [correction of thiocetamide]-induced liver cirrhosis. 927 62

Mutations in three different genes of phosphorylase kinase (Phk) subunits, PHKA2, PHKB and PHKG2, can give rise to glycogen storage disease of the liver. The autosomal-recessive, liver-specific variant of Phk deficiency is caused by mutations in the gene encoding the testis/liver isoform of the catalytic gamma subunit, PHKG2. To facilitate mutation detection and to improve our understanding of the molecular evolution of Phk subunit isoforms, we have determined the structure of the human PHKG2 gene. The gene extends over 9.5 kilonucleotides and is divided into 10 exons; positions of introns are highly conserved between PHKG2 and the gene of the muscle isoform of the gamma subunit, PHKG1. The beginning of intron 2 harbors a highly informative GGT/GT microsatellite repeat, the first polymorphic marker in the PHKG2 gene at human chromosome 16p11.2-p12.1. Employing the gene sequence, we have identified homozygous translation-terminating mutations, 277delC and Arg44ter, in the two published cases of liver Phk deficiency who developed cirrhosis in childhood. As liver Phk deficiency is generally a benign condition and progression to cirrhosis is very rare, this finding suggests that PHKG2 mutations are associated with an increased cirrhosis risk.
Hum Mol Genet 1998 Jan
PMID:Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure and mutations associated with cirrhosis. 938 16

Hepatitis C virus (HCV), a major etiologic agent of transfusion associated hepatitis, is a positive, single-stranded RNA virus and is also known to be implicated in liver cirrhosis and hepatocellular carcinoma. Nonstructural protein 5A (NS5A) of HCV contains acidic and proline-rich amino acids in its carboxy-terminal half. These structural features resemble eukaryotic transcription activators. In this report, we show that NS5A functions as a potent transcriptional activator when fused to the yeast (Saccharomyces cerevisiae) GAL4 DNA-binding domain (1-147). The potential transcriptional activator maps to the C-terminal half of NS5A in the yeast cell. Therefore, our data provides the first evidence that NS5A may modulate host cell function at the transcriptional level.
Mol Cells 1997 Oct 31
PMID:Hepatitis C virus nonstructural protein 5A contains potential transcriptional activator domains. 938 55

Plasma collagen-binding vitronectin was assayed in 62 patients with chronic liver disease and 14 healthy control subjects. It was measured by an enzyme immunoassay using type I collagen and monoclonal antibody to vitronectin before and after treatment with heparin or dextran sulfate in vitro. The pretreatment level of plasma collagen-binding vitronectin (mean +/- S.E.M.) was 5.5 +/- 0.5 micrograms/ml in the controls, 8.2 +/- 0.3 micrograms/ml in chronic persistent hepatitis, 8.3 +/- 0.7 micrograms/ml in chronic active hepatitis, 7.9 +/- 0.7 micrograms/ml in liver cirrhosis, and 8.2 +/- 0.5 micrograms/ml in hepatocellular carcinoma with cirrhosis. After treatment with heparin, the percent collagen-binding vitronectin to total vitronectin was 20.6 +/- 2.0% in the controls, 24.7 +/- 4.1% in chronic persistent hepatitis, 28.6 +/- 2.5% in chronic active hepatitis, 42.6 +/- 4.5% in liver cirrhosis, and 31.8 +/- 2.3% in hepatocellular carcinoma. All percents were significantly increased compared to the pretreatment percent. The same pattern was also found after dextran sulfate treatment. Compared to that in the pretreatment state, the collagen-binding vitronectin after these treatments was more closely correlated with the serum levels of 7S collagen and hyaluronic acid. These results suggest that the collagen-binding activity of vitronectin may play an important role in the progression of liver disease and/or fibrosis through its activation with some glycosaminoglycans.
Res Commun Mol Pathol Pharmacol 1997 Sep
PMID:Plasma collagen-binding vitronectin activated by heparin and dextran sulfate in chronic liver disease. 938 91

alpha 1-Antitrypsin is the archetypal member of the serine proteinase inhibitor or serpin superfamily. Members of the family show structural homology based on a dominant A beta-sheet and a mobile reactive centre loop. Our recent crystal structure of alpha 1-antitrypsin stabilized with a point mutation showed the loop to be in a canonical inhibitory conformation in the absence of significant insertion into the A beta-sheet. It could be argued that the stabilizing mutation may induce the reactive centre loop to adopt an artificial, and unrepresentative, conformation and the finding seems to be at variance with studies assessing rates of peptide insertion into the A beta-sheet and limited proteolysis of the reactive loop. Here we present a 2.9 A structure of recombinant wild-type alpha 1-antitrypsin with no stabilizing mutations. Again, the reactive loop is in a canonical conformation in the absence of significant insertion into the A beta-sheet. A stabilizing salt bridge between P5 glutamate and arginine residues 196, 223 and 281, already identified in the mutant, provides strong evidence that this conformation is not an artefact of crystallization but represents the conformation of the circulating inhibitor in vivo. Comparison with the structure of alpha 1-antitrypsin stabilized with the Phe51Leu mutation indicates that the increased thermal stability of the mutant results from enhanced packing of aromatic residues in the hydrophobic core of the molecule. The structure of wild-type alpha 1-antitrypsin reveals a hydrophobic pocket between s2A and helices D and E that is filled on reactive loop insertion and the formation of biologically relevant loop-sheet polymers. This pocket may provide a target for rational drug design to prevent the formation of polymers and the associated plasma deficiency, liver cirrhosis and emphysema.
J Mol Biol 1998 Jan 23
PMID:Wild-type alpha 1-antitrypsin is in the canonical inhibitory conformation. 946 20

Although the liver was long known to play a major role in the uptake, synthesis, and disposition of glutamine, metabolite balance studies across the whole liver yielded apparently contradictory findings suggesting that little or no net turnover of glutamine occurred in this organ. Efforts to understand the unique regulatory properties of hepatic glutaminase culminated in the conceptual reformulation of the pathway for glutamine synthesis and turnover, especially as regards the role of sub-acinar distribution of glutamine synthetase and glutaminase. This chapter describes these processes as well as the role of glutamine in hepatocellular hydration, a process that is the consequence of cumulative, osmotically active uptake of glutamine into cells. This topic is also examined in terms of the effects of cell swelling on the selective stimulation or inhibition of other far-ranging cellular processes. The pathophysiology of the intercellular glutamine cycle in cirrhosis is also considered.
Adv Enzymol Relat Areas Mol Biol 1998
PMID:Hepatic glutamine transport and metabolism. 955 51

Patients with alpha1-antitrypsin (alpha1-AT) deficiency are at risk of developing early-onset panlobular basal emphysema, which has been attributed to uncontrolled proteolytic activity within the lung. Severe genetic deficiency of alpha1-AT is most commonly due to the Z mutation (342Glu--> Lys), which results in a block in alpha1-AT processing within the endoplasmic reticulum of hepatocytes. The retained alpha1-AT forms inclusions, which are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Our recent studies have shown that the accumulation of alpha1-AT is due to the Z mutation perturbing the structure of alpha1-AT to allow polymer formation, with a unique linkage between the reactive center loop of one alpha1-AT molecule and the A beta-pleated sheet of a second. The detection of loop-sheet polymers and other conformations of alpha1-AT in the lungs of patients with emphysema has been technically difficult. We show here that transverse urea-gradient-gel (TUG) electrophoresis and Western blot analysis may be used to characterize conformations of alpha1-AT in dilute samples of bronchoalveolar lavage fluid (BALF). This technique was used to demonstrate loop-sheet polymers in the lungs of patients with Z alpha1-AT-deficiency-related emphysema. Polymers were the predominant conformational form of alpha1-AT in BALF from the lungs of two of five Z homozygotes with emphysema, but were not detectable in any of 13 MM, MS, or MZ alpha1-AT controls. Because alpha1-AT loop-sheet polymers are inactive as proteinase inhibitors, this novel conformational transition will further reduce the levels of functional proteinase inhibitor in the lungs of the Z alpha1-AT homozygote, and so exacerbate tissue damage.
Am J Respir Cell Mol Biol 1998 May
PMID:Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema. 956 37

Hereditary tyrosinemia type I (HTI, McKusick 276700) is an autosomal recessive disease caused by deficient fumarylacetoacetate hydrolase (FAH, EC 3.7.1.2) activity. HTI is characterized by progressive liver dysfunction with nodular cirrhosis often leading to hepatocellular carcinoma. Two extremes of the clinical phenotype have been described: the "acute" (severe, early onset and death) and "chronic" (delayed onset and slow course) phenotype. Allelic heterogeneity and/or mutation reversion in hepatic cells have been proposed earlier to explain the clinical heterogeneity. Two probands (one "acute," one "chronic") from the French-Canadian isolate where HTI is prevalent were studied. Both were homozygous (germ line) for the severe splice mutation IVS12 + 5g --> a; both showed liver mosaicism for FAH immunoreactivity with evidence for mutation reversion to heterozygosity (IVS12 + 5g --> a/+) in FAH-stained nodules as shown by amplification of DNA extracted from microdissected nodules. Western blot analysis of proteins from a reverted FAH-expressing nodule showed 29 +/- 3% FAH immunoreactive material as compared to an average normal liver. This was consistent with the measured FAA hydrolytic activity (25%) in this large regenerating nodule. These findings show that genotypic heterogeneity is not a sufficient explanation for clinical heterogeneity and implicate epigenetic and other factors modifying the phenotype in HTI.
Mol Genet Metab 1998 Jun
PMID:Different clinical forms of hereditary tyrosinemia (type I) in patients with identical genotypes. 970 36

Effects of selenium deficiency, induced by thioacetamide, were investigated in rats. Thioacetamide (0.3 g/L) given in drinking water, as expected, caused a significant loss of selenium from the liver. It was accompanied by liver cirrhosis and a significant increase in the liver weight as well as liver to body weight ratio. A significant loss of selenium from spleen was also accompanied by an increase in its weight. Weights of lungs, testis and kidney, however, were not affected by thioacetamide and there was no change in their selenium content. Plasma levels of selenium were significantly reduced in the thioacetamide treated group. All these changes were confirmed to be due to selenium deficiency caused by thioacetamide, as supplementation with selenium reversed these changes. The mode of action of selenium is unknown but may involve anti-oxidant defense mechanisms.
Mol Cell Biochem 1998 Aug
PMID:Selenium and liver cirrhosis. 974 5


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