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)

In an experimental model of liver cirrhosis, marked increases in ER proteasome content in rat livers were observed 5 h after acute i.p. injection of the hepatotoxicant CCl4. To confirm the role of CYP2E1 in mediating protein misfolding/damage in the ER via its metabolism of CCl4, 293T cells stably transfected with human CYP2E1 were exposed to CCl4 and cell ER fractions assessed for ubiquitination. Increases in ER ubiquitin conjugates were noted in CYP2E1/293T cells treated with CCl4 and not in controls, suggesting these effects are CYP2E1 specific. Finally, the role of CYP2E1 in ER homeostasis was investigated by examining the unfolded protein response (UPR). When exposed to CCl4, CYP2E1/293T cells but not 293T or CYP1A2/293T cells showed rapid induction of the UPR-inducible ER chaperone BiP. Collectively, the data presented suggest that CYP2E1 is capable of inducing significant ER protein damage and stress via its catalytic activation of pro-oxidants.
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PMID:Role of CYP2E1 activity in endoplasmic reticulum ubiquitination, proteasome association, and the unfolded protein response. 1579 36

Hepatocellular carcinoma is often diagnosed at an advanced stage, when it is not amenable to curative therapies. There is no effective chemotherapy. Advances in cancer biology suggest that a limited number of pathways are responsible for initiating and maintaining dysregulated cell proliferation, which is the major cellular alteration responsible for the cancer phenotype. New treatments in development target several of these critical pathways, including agents targeting the receptor tyrosine kinase pathways, the Wnt/beta-catenin signaling pathway, the ubiquitin/proteasome degradation pathway, the epigenetic DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, and telomerase. Several of these approaches hold significant promise for improving the long-term outcome of patients with advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, these approaches must be coupled with new strategies for halting or reversing the progression of chronic liver disease.
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PMID:Hepatocellular carcinoma: molecular pathways and new therapeutic targets. 1591 49

Myostatin, a transforming growth factor-beta (TGF-beta) super-family member, has been well characterized as a negative regulator of muscle growth and development. Myostatin has been implicated in several forms of muscle wasting including the severe cachexia observed as a result of conditions such as AIDS and liver cirrhosis. Here we show that Myostatin induces cachexia by a mechanism independent of NF-kappaB. Myostatin treatment resulted in a reduction in both myotube number and size in vitro, as well as a loss in body mass in vivo. Furthermore, the expression of the myogenic genes myoD and pax3 was reduced, while NF-kappaB (the p65 subunit) localization and expression remained unchanged. In addition, promoter analysis has confirmed Myostatin inhibition of myoD and pax3. An increase in the expression of genes involved in ubiquitin-mediated proteolysis is observed during many forms of muscle wasting. Hence we analyzed the effect of Myostatin treatment on proteolytic gene expression. The ubiquitin associated genes atrogin-1, MuRF-1, and E214k were upregulated following Myostatin treatment. We analyzed how Myostatin may be signaling to induce cachexia. Myostatin signaling reversed the IGF-1/PI3K/AKT hypertrophy pathway by inhibiting AKT phosphorylation thereby increasing the levels of active FoxO1, allowing for increased expression of atrophy-related genes. Therefore, our results suggest that Myostatin induces cachexia through an NF-kappaB-independent mechanism. Furthermore, increased Myostatin levels appear to antagonize hypertrophy signaling through regulation of the AKT-FoxO1 pathway.
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PMID:Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-kappaB-independent, FoxO1-dependent mechanism. 1688 77

Hepatocellular carcinoma is often diagnosed at an advanced stage, when potentially curative surgical or local ablative therapies are not feasible. There is no effective chemotherapy for hepatocellular carcinoma. Recent advances in cancer biology suggest that a limited number of signalling pathways may be responsible for uncontrolled cell proliferation, the major cellular alteration responsible for the cancer phenotype. Novel anticancer agents target these critical pathways, including the receptor tyrosine kinase pathways, the Wnt/beta-catenin signalling pathway, the ubiquitin/proteasome degradation pathway, the DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, telomerase and the cell cycle. These agents hold promise for improving the outcome of patients with intermediate and advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, to achieve long-term survival of the majority of patients, targeted anticancer therapies will need to be coupled with strategies aimed at reversing the progression of chronic liver disease.
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PMID:Emerging drugs for hepatocellular carcinoma. 1693 86

Morphologic criteria of steatohepatitis are steatosis, ballooning of hepatocytes, often but not constantly associated with Mallory bodies, pericellular fibrosis and inflammation. Liver cirrhosis follows in about 20-50%. With respect to etiology an alcoholic and non-alcoholic type can be distinguished, the latter being a characteristic hepatic lesion associated with the metabolic syndrome (type II diabetes, insulin resistance, obesity, dyslipidemia). Ballooning of hepatocytes as well as Mallory body formation are associated with a disturbance of the keratin intermediate filament cytoskeleton. Mallory bodies are protein aggregates consisting of keratin (particularly keratin 8), p62, a stress-induced adapter protein involved in signal transduction pathways, heat shock proteins, and ubiquitin. Oxidative stress is involved in Mallory body formation. Major sources of oxidative stress in alcoholic and non-alcoholic steatohepatitis are the microsomal biotransformation system (cytochrome P-450) and the mitochondria, together with an impaired antioxidant defense system. Oxidative stress leads to misfolding/unfolding, abnormal phosphorylation of keratins and disturbance of keratin 8: keratin 18 ratio, and thus interferes with intermediate filament assembly. Moreover, impairment of cellular defense against abnormal proteins, i. e. chaperone action and proteasomal degradation, leads to the accumulation of abnormal aggregation--prone keratins (particularly keratin 8) which after ubiquitination associate with the stress-induced ubiquitin-binding protein p62 to form Mallory bodies. Thus, Mallory body formation resembles an "off-folding" protein response of the amyloid type. These pathogenetic principles of the human disease are supported by immunohistochemical and gene expression studies in experimental animals and by transfection experiments in tissue culture cells.
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PMID:[Alcoholic and non-alcoholic steatohepatitis]. 1803 83

Proliferating cell nuclear antigen (PCNA) is a 36 kDa protein involved in several cellular mechanisms, including DNA synthesis and repair, cell cycle regulation and apoptosis. An alteration in PCNA structure might contribute to DNA-damage accumulation in cancer cells. This study was aimed to evaluate the PCNA pattern of expression, in terms of aggregation status, isoforms and post-translational modifications, in human hepatocellular carcinoma (HCC) and cirrhosis as well as in HCC cell lines. Twelve HCCs and surrounding cirrhotic tissues were analysed, along with HepG2, Hep3B and SNU-398 cell lines. Normal liver specimens and cirrhosis without HCC were included as controls. Both DNA-bound and DNA-unbound PCNA fractions were analysed, and PCNA pattern of expression was displayed on two-dimensional gel electrophoresis followed by western blot. Results were confirmed by mass spectrometry. To compare HCCs vs surrounding tissues, immunolabelling and immunostaining were performed. In 6 of 12 HCCs and in cell lines, we found three major PCNA acidic forms, corresponding to monomers, probably dimers and trimers, and a basic isoform. In the six remaining HCCs, only a PCNA acidic form associated with multiple basic isoforms was detected. Importantly, the PCNA basic form was not found in cirrhotic tissues. To clarify the nature of the detected PCNA isoforms, ubiquitin-specific immunoblotting as well as phosphatase treatment were employed. A PCNA-ubiquitylated form in cell lines and PCNA-phosphorylated isoforms in 6 of 12 HCCs were detected. Finally, in the DNA-bound fraction we detected only an acidic PCNA monomeric form. We conclude that human hepatocellular carcinoma expresses specific PCNA isoforms compared to those found in cirrhosis, implicating a role for PCNA functional alterations in hepatocarcinogenesis.
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PMID:Human hepatocellular carcinoma expresses specific PCNA isoforms: an in vivo and in vitro evaluation. 1852 Oct 65

Cirrhosis is characterized by skeletal muscle wasting. In this study, the effects of nitric oxide production on skeletal muscle protein nitration and degradation in cirrhosis were investigated. Cirrhosis was induced by bile duct ligation (BDL) in Sprague-Dawley rats for 4 weeks. The BDL-induced cirrhotic rats and sham-operated rats were then injected daily with either saline or N(G)-l-nitro-arginine methyl ester (l-NAME) for 7 days from week 4 to week 5, after which nitrite/nitrate, glutathione reduction, as well as protein nitration, ubiquitination, and degradation were assessed in skeletal muscle. Elevated muscular nitrite/nitrate concentrations, protein nitration, total ubiquitin conjugates, and degradation fragments of myosin heavy chain as well as diminished glutathione reduction levels were observed in BDL-induced cirrhotic rats as compared with controls. Administration of l-NAME for 1 week led to reduction of nitrite/nitrate levels; protein nitration was also decreased in the skeletal muscle. In addition, ubiquitination of muscular proteins and degradation of myosin heavy chain were significantly diminished after treatment of l-NAME. In conclusion, nitrosative stress occurred in the skeletal muscle of BDL-induced cirrhotic rats and may lead to increased proteolysis of muscle-specific structural proteins.
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PMID:Protein nitration is associated with increased proteolysis in skeletal muscle of bile duct ligation-induced cirrhotic rats. 1984 67

A rare variant of hepatocellular carcinoma (HCC) is encountered that produces small cirrhosis-like nodules diffusely throughout the liver (CL-HCC), instead of a larger evident mass. This pattern remains undetected as carcinoma clinically and radiographically and is unexpectedly discovered after liver transplantation in the explanted native liver. We studied 10 such cases (9 males and 1 female, age 35 to 80 y) from 4 medical centers. The pretransplant clinical, laboratory, and radiographical studies were reviewed to determine the cause and stage of liver disease, alpha-fetoprotein (AFP) levels, and detectability of a mass on imaging. All 10 cases had underlying cirrhosis of varying etiology [3 hepatitis C virus (HCV), 3 alcoholic hepatitis, 1 hepatitis B virus, 1 autoimmune, and 2 mixed HCV/alcoholic hepatitis and hemochromatosis/HCV] and underwent orthotopic liver transplantation with no preoperative clinical suspicion of HCC. Ultrasound and/or dynamic imaging showed cirrhosis and no definite HCC. AFP levels were only mildly elevated in only 3 of 10 cases (144, 150, and 252 ng/mL). Grossly, there were innumerable (from about 20 to >1000) small CL-HCC nodules (0.2 to 0.6 cm) scattered among cirrhotic nodules. Histologically, these were well or moderately differentiated HCC, often with pseudoglandular pattern, perinodular sclerotic rims, cholestasis, frequent Mallory bodies, and small vessel invasion. In addition to the usual HCC immunophenotype, CL-HCC showed frequent ubiquitin and cytoplasmic and membranous CD10 positivity, relatively low Ki-67 proliferative index and absence of AFP immunohistochemically. CL-HCC warrants recognition as a unique HCC variant that evades pretransplant detection despite massive tumor burden, mimics cirrhotic nodules, and shows some uncommon pathologic and immunophenotypical characteristics.
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PMID:Diffuse cirrhosis-like hepatocellular carcinoma: a clinically and radiographically undetected variant mimicking cirrhosis. 2046 69

Mallory bodies (MBs) and hyaline globules (HGs) are recognized as hepatocellular cytoplasmic inclusions in liver diseases. We reviewed 123 intrahepatic cholangiocarcinomas (ICCs) and encountered 16 cases (13.0%) in which cancer cells had MB-type inclusions and/or HG-type inclusions, both of which are positive for p62 and ubiquitin. The HG type was present in all 16 cases, and 5 cases contained the MB type. Of 16 patients, 12 had chronic liver disease that was related to alcoholic abuse in 4, hepatitis B surface antigen-positive in 3, and hepatitis C virus antibody-positive in 8. Viral infection and liver cirrhosis were more common in ICCs with p62+ inclusions (P = .0004 and P = .0199, respectively). Of 16 ICCs, 15 with hyaline inclusions had a peripheral tumor location (P = .0052). On ultrastructural examination, the MB type had an electron-dense fibrillar appearance, while the HG type appeared as rounded masses of granular materials. Our results suggest that intracytoplasmic hyaline bodies occasionally can be found in cholangiocarcinoma with chronic liver disease related to viral hepatitis or alcoholic intake.
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PMID:p62+ Hyaline inclusions in intrahepatic cholangiocarcinoma associated with viral hepatitis or alcoholic liver disease. 2071 3

Recently it has been shown that the expression of the immunoproteasome increased in proportion to the degree of chronic inflammation in both the liver cell cytoplasm and nuclei in liver biopsies from patients who had chronic active hepatitis or cirrhosis. In the present study, biopsies from patients with steatohepatitis, with or without Mallory-Denk body (MDB) formation, were studied by immunofluorescent staining. Normal liver showed colocalization of FAT10, LMP2, LMP7, and MECL-1 at the mitochondria. Only LMP2 and LMP7 were found in the cell nuclei. Liver biopsies from patients with steatohepatitis and MDB formation, and a case of hepatocellular carcinoma forming MDBs in the tumor cells, showed colocalization of FAT10 and ubiquitin with LMP2, LMP7 and MECL-1 within the MDB. This indicates involvement of the immunoproteasome in MDB formation in steatohepatitis cases and in a case of HCC forming MDBs. Prior studies have shown that the immunoproteasome was involved in drug-induced MDB formation using the same immunofluorescent colocalization approach as was used on these human liver biopsies. The increase in the immunoproteasome subunit proteins was made at the expense of the 26S proteasome. This indicates that the shift from the 26S to the immunoproteasome had occurred in the MDB positive hepatocytes.
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PMID:The immunoproteasome in steatohepatitis: its role in Mallory-Denk body formation. 2125 43


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