Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic cirrhosis produced by repeated inhalation of carbon tetrachloride is associated with reduced levels of microsomal cytochrome P450. In this study the C19-steroids androstenedione and testosterone were used as specific probes of the functional activity of several forms of cytochrome P450 in microsomal fractions from control and cirrhotic rat liver. The principal finding, that androstenedione 16 alpha-hydroxylation and testosterone 2 alpha-, 16 alpha-, and 17 alpha-hydroxylation were reduced to 14%-38% of control activity, strongly suggests that levels of the male sexually differentiated cytochrome P450 (P(450)16 alpha) are decreased in hepatic cirrhosis. The activity of other cytochrome P450-mediated C19-steroid hydroxylases, with the exception of androstenedione 6 beta-hydroxylase, appeared essentially unaltered in microsomes from cirrhotic rats. Cirrhosis induced by carbon tetrachloride was also associated with greatly decreased activity of the microsomal cytochrome P450-independent 17 beta-oxidoreductase, an enzyme that catalyzes the conversion of androstenedione to testosterone. Consequently, and in view of the impaired activity of cytochrome P450-mediated testosterone 17 alpha-hydroxylation, the capacity of cirrhotic microsomes to catalyze the interconversion of androstenedione and testosterone was much lower than that of control microsomes. The present data confirm and extend earlier observations that selective impairment of drug oxidation pathways occurs in hepatic cirrhosis. These changes are unrelated to the acute toxicity produced by carbon tetrachloride exposure. The available evidence supports the assertion that specific forms of cytochrome P450 are subject to altered regulation in cirrhosis.
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PMID:Impaired androgen 16 alpha-hydroxylation in hepatic microsomes from carbon tetrachloride-cirrhotic male rats. 358 1

Defects of the respiratory chain are a typical feature of mitochondrial diseases and occur also during normal aging where they have been described in postmitotic tissues. The present study addresses the question of defect expression in the normal and cirrhotic liver. Randomly distributed defects of complex III (ubiquinone-cytochrome-c-oxidoreductase) and of complex IV (cytochrome-c-oxidase) of the respiratory chain have been detected with age-related increasing frequency both in normal and cirrhotic livers. No defects were present for complex II (succinate-dehydrogenase) and complex V (adenosine triphosphate-synthase) and in liver cell carcinomas. Sixty-one of 107 normal livers (57%) showed defects of the respiratory chain. The defects occurred in advanced age (over 50 years) in 87%. In contrast 50 of 64 cirrhotic livers (78%) had defects and approximately 60% occurred after age 50. The defects were caused by a loss of enzyme protein involving both nuclearly and mitochondrially coded subunits. Ninety-four percent of the defects (n = 275) involved complex IV selectively. In 4% selective defects of complex III were found and combined defects of both complexes occurred in only 2%. In situ hybridization and polymerase chain reaction (PCR) studies for the detection of the common deletion (4.977 bp) and of various point mutations of mitochondrial DNA (mtDNA) revealed no consistent molecular genetic abnormalities in microdissected respiratory chain defective liver cell areas. Single point mutations at nt 3243 and/or 5692 were found only in 7 of 18 microdissected probes from 6 patients. The results show that defects of the respiratory chain occur already in normal livers most probably during cell aging and at a higher rate in cirrhosis. The random defect pattern favors a stochastic process, e.g., free radical damage. However, the role of mutations of mtDNA remains to be established.
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PMID:Defects of the respiratory chain in the normal human liver and in cirrhosis during aging. 930 2

Alpha1-antitrypsin (AAT) deficiency is characterized by the accumulation of the misfolded mutant, Z form of alpha1-antitrypsin (PiZ) inside the lumen of the hepatic endoplasmic reticulum (ER). Both human patients and PiZ transgenic mice have similar symptoms of hepatic failure culminating in cirrhosis and hepatocellular carcinoma. The involvement of molecular chaperones, as well as the relevance of oxidative stress in this disease is not characterized well yet. Here, we show that, in the PiZ transgenic mice, the 58-kDa protein disulfide isomerase (PDI), the most important oxidoreductase and chaperone of the endoplasmic reticulum, is in a complex with PiZ, which is accompanied by a decrease of protein disulfide reductase activity of the ER. PiZ transgenic mice have a shift toward a more reduced ER environment and an elevation of cytoplasmic chaperones and antioxidant enzymes. Our data suggest that lower availability of PDI and a decreased protein disulfide reductase activity of the ER along with a cytoplasmic stress may contribute to the toxic effects of PiZ aggregation.
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PMID:Changes of endoplasmic reticulum chaperone complexes, redox state, and impaired protein disulfide reductase activity in misfolding alpha1-antitrypsin transgenic mice. 1657 74

Aldo-keto reductase family 1, member B10 (AKR1B10), a cancer-related oxidoreductase, is expressed in well-differentiated hepatocellular carcinomas (HCCs). However, AKR1B10 levels are minimal in normal liver tissues (NLs), similar to the 70-kilodalton heat shock protein (HSP70) and glypican-3. Moreover, the role of AKR1B10 in chronic hepatitis or cirrhosis, which are considered preneoplastic conditions for HCC, has not been fully elucidated. The aim of this study was to evaluate the expression of AKR1B10, HSP70, and glypican-3 in 61 HCC tissue samples compared to corresponding non-tumorous liver tissues (NTs), comprising 42 chronic hepatitis and 19 cirrhosis cases to clarify the significance of molecular changes at the preneoplastic stages of HCC. Immunohistochemical analysis demonstrated that the median expression levels of AKR1B10 were higher in HCCs than in NTs (p<0.001) and higher in NTs than NLs (p<0.001) with 54.8%, 2.1%, and 0.3% expression in HCCs, NTs, and NLs, respectively. HSP70 and glypican-3 were expressed in HCCs, but minimally in NTs and NLs with no significant difference between expression in NTs and NLs. Furthermore, a multivariate analysis identified an association between hepatic steatosis and AKR1B10 expression in NTs (p=0.020). Of the three protein expressed in well-differentiated HCCs, only AKR1B10 was upregulated in preneoplastic conditions, and a steatosis-related factor might influence its expression.
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PMID:Expression of aldo-keto reductase family 1 member b10 in the early stages of human hepatocarcinogenesis. 2474 92

To identify novel tumor-associated proteins, we analyzed the protein expression patterns from experimental hepatocellular carcinoma (HCC) that were induced using hepatocarcinogenesis models in rats. Rats were subjected to two previously described protocols of hepatocarcinogenesis using diethylnitrosamine as a carcinogen: the alternative Solt-Farber (aS&F) protocol, which induces HCC within 9 months, and Schiffer's model, which induces cirrhosis and multifocal HCC within 18 weeks. The patterns of protein expression from tumors and normal liver tissue were examined by SDS-PAGE and the bands identified at 33-34 kDa were analyzed by mass spectrometry. The prostaglandin reductase 1 (PTGR1) showed the highest number of peptides, with a confidence of level >99%. The increased expression of PTGR1 in tumors was confirmed in these two models by Western blotting and by increase in alkenal/one oxidoreductase activity (25-fold higher than normal liver). In addition, the gene expression level of Ptgr1, as measured by qRT-PCR, was increased during cancer development in a time-dependent manner (200-fold higher than normal liver). Furthermore, PTGR1 was detected in the cytoplasm of neoplastic cells in rat tumors and in 12 human HCC cases by immunohistochemistry. These analyses were performed by comparing the expression of PTGR1 to that of two well-known markers of hepatocarcinoma, Glutathione S-transferase pi 1 (GSTP1) in rats and glypican-3 in humans. The increased expression and activity of PTGR1 in liver carcinogenesis encourage further research aimed at understanding the metabolic role of PTGR1 in HCC and its potential application for human cancer diagnosis and treatment.
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PMID:Increased expression of prostaglandin reductase 1 in hepatocellular carcinomas from clinical cases and experimental tumors in rats. 2485 74

BACKGROUND Hepatocellular carcinoma (HCC) remains difficult to diagnose at an early stage. Aldo-keto reductase family 1 member B10 (AKR1B10) is an oxidoreductase that is upregulated in some chronic liver diseases. The aim of this study was to use immunohistochemistry to evaluate the expression of AKR1B10 in liver tissue from patients with HCC of different stages. MATERIAL AND METHODS Forty-four patients with a tissue diagnosis of HCC (35 males and 9 females) with 37 control samples of liver tissue containing liver cirrhosis were studied using immunohistochemistry for the expression of AKR1B10. Histological examination determined the grade of HCC; the stage of HCC was determined according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Serum alpha-fetoprotein (AFP) levels were measured and compared between the patients with HCC. RESULTS Immunohistochemistry showed increased expression of AKR1B10 in moderately-differentiated HCC compared with well-differentiated HCC, poorly-differentiated HCC, and liver cirrhosis (P<0.05). Sensitivity and specificity of AKR1B10 expression in HCC were high at a cutoff integral optical density (IOD) value of 89.5. A significant increase in AKR1B10 expression was found in early-stage HCC (P<0.05). Serum AFP levels were increased in patients with poorly-differentiated HCC, were increased in intermediate-stage HCC, and were significantly increased in advanced-stage HCC (P<0.05). CONCLUSIONS Immunohistochemistry showed that the expression of AKR1B10 was increased in tumor tissue from patients with early-stage HCC. Further studies are needed to determine the role of AKR1B10 in the early detection of HCC.
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PMID:Immunohistochemistry Detects Increased Expression of Aldo-Keto Reductase Family 1 Member B10 (AKR1B10) in Early-Stage Hepatocellular Carcinoma. 3032 12

Aim: Investigation of characteristics of different duodenal microbial colonization states in patients with liver cirrhosis (LC). Materials & methods: Deep-sequencing analyses of the 16S rRNA gene V1-V3 regions were performed. Results: Both bacterial compositions and richness were different between the three-clustered LC microbiotas, in other words, Cluster_1_LC, Cluster_2_LC and Cluster_3_LC. Cluster_1_LC were more likely at severe dysbiosis status due to its lowest modified cirrhosis dysbiosis ratio. OTU12_Prevotella and OTU10_Comamonas were most associated with Cluster_1_LC and Cluster_3_LC, respectively, while OTU38_Alloprevotella was vital in Cluster_2_LC. Pyruvate-ferredoxin/flavodoxin oxidoreductase, dihydroorotate dehydrogenase and branched-chain amino acid transport system substrate-binding protein were most associated with Cluster_1_LC, Cluster_2_LC and Cluster_3_LC, respectively. Conclusion: The three duodenal microbial colonization states had distinct representative characteristics, which might reflect the health status of cirrhotic patients.
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PMID:Characteristics of three microbial colonization states in the duodenum of the cirrhotic patients. 3266 59

Liver fibrosis is a reversible wound-healing response to acute or chronic liver injury that can progress to cirrhosis and liver cancer. Finding new strategies for prevention and management of liver fibrosis is urgently needed. It is known that hepatic stellate cell (HSC) is the primary source of extracellular matrix that drives liver fibrosis progression. Herein, we carried out a comprehensive secretome profiling to identify NMN-induced changes in secretory proteins and found that NMN suppressed the secretion of profibrotic protein and oxidoreductase in activated HSC (LX-2) cells, while real-time quantitative PCR analysis revealed that NMN downregulated profibrotic gene expression, resulting in HSC inactivation. Next, we demonstrated that nicotinamide mononucleotide (NMN) reduced the accumulation of liver extracellular matrix in thioacetamide (TAA) and carbon tetrachloride (CCl4) induced mouse models for liver fibrosis. Furthermore, we determined that NMN inhibited oxidation-mediated 15-PGDH degradation to promote prostaglandin E2 degradation and suppress HSC activation. In summary, our results propose that NMN supplementation is a new therapeutic approach for liver fibrosis prevention.
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PMID:Nicotinamide mononucleotide inhibits hepatic stellate cell activation to prevent liver fibrosis via promoting PGE2 degradation. 3322 Apr 24