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)

Interferon therapy may decrease the risk of hepatocellular carcinoma in patients with hepatitis C virus (HCV)-related liver cirrhosis. Interaction of the cellular protein kinase PKR with the PKR-binding domain (PKR-bd) of HCV-NS5A protein may affect cellular growth control and viral resistance to interferon therapy. Mutations within the PKR-bd, which comprises the interferon sensitivity determining region (ISDR), have been associated with interferon sensitivity. To determine whether or not there is an association between HCV heterogeneity and the presence of hepatocellular carcinoma, HCV-1b genomic regions were amplified and directly sequenced from serum samples obtained from 82 patients with liver cirrhosis, 53 with, and 29 without hepatocellular carcinoma. None of them had received antiviral therapy. When compared with the deduced consensus sequence, the median number of amino acid changes in the PKR-bd was higher among samples from patients with (4.22) than from those without hepatocellular carcinoma (1.62; P <.001), and isolates with 3 or more amino acid changes were significantly more common among the former (60%) than among the later (6%, P <.001). No such differences were observed in other viral regions, including Core, E2-HVR-1, E2-PePHD, NS3, and the 5' and 3' PKR-bd flanking regions. In addition, amino acid variation in viral regions other than HVR-1 did not accumulate over time in the analyzed sequential serum samples obtained from patients with or without hepatocellular carcinoma. Therefore, a mutated HCV-PKR-bd phenotype is very common in cirrhotic patients with hepatocellular carcinoma.
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PMID:High amino acid variability within the NS5A of hepatitis C virus (HCV) is associated with hepatocellular carcinoma in patients with HCV-1b-related cirrhosis. 1143 47

Hepatitis C virus (HCV), discovered in 1989, is the major causative agent of parenteral non-A, non-B hepatitis worldwide. Following the development of a method of diagnosing HCV infection, it became apparent that HCV frequently causes chronic hepatitis. Persistent infection with HCV is implicated in liver cirrhosis and hepatocellular carcinoma. Current worldwide estimations suggest that more than 170 million people have been infected with HCV, an enveloped positive single-stranded RNA (9.6-kilobases) virus belonging to the Flaviviridae. The HCV genome shows remarkable sequence variation, especially in the hypervariable region 1 of the E2 protein-encoding region, and globally, HCV appears to be distributed with more than 30 genotypes. Complicated "quasispecies" and frequent mutations of viral genomes have also emerged. The HCV genome encodes a large polyprotein precursor of about 3,000 amino acid residues, and this precursor protein is cleaved by the host and viral proteinases to generate at least 10 proteins in the following order: NH2-core-envelope (E1)-E2-p7-nonstructural protein 2 (NS2)-NS3-NS4A-NS4B-NS5A-NS5B-COOH. These viral proteins not only function in viral replication but also affect a variety of cellular functions. Although several explanations have been proposed, the mechanisms of HCV infection and replication in targeted cells, the mechanism of persistent viral infection, and the pathogenesis of hepatic diseases (hepatitis or hepatocellular carcinoma) are all poorly understood. A major reason why these mechanisms remain unclear is the lack of a good experimental HCV replication system. Although several classical trials using cultured cells have been reported, several new, more promising experimental strategies (generations of infectious cDNA clone, replicon, animal models, etc.) are currently being designed and tested, in order to resolve these problems. In addition, new therapies for chronic hepatitis have also been developed. The enormous body of information collected thus far in the field of HCV research is summarized below, and an overview of the current status of HCV molecular virology of HCV is provided.
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PMID:Molecular virology of hepatitis C virus. 1143 27

AIM:To detect HCV infection in patients with HCC and other liver diseases by the immunohistochemical method.METHODS: The expression of HCV antigen was identified by means of LSAB (labelled streptavidin-biotin) method using anti-NS3 monoclonal antibody.RESULTS: The positive rates of HCV antigen in the three groups of HCC, liver cirrhosis and hepatitis were 13.5% (7/52), 12.5% (2/16), and 10% (4/40) respectively, while in the samples from patients with constitutional jaundice and normal liver samples, no HCV antigen was found. HCV antigen could be seen in the nuclei and/or cytoplasms of carcinoma cells and/or pericancerous hepatocytes. In HCC, HCV antigen was more often seen in nuclei than in cytoplasms. The positive rate of HCV antigen in pericancerous tissues was higher than that in cancerous tissues.CONCLUSION: HCV is associated with HCC,and HCV infection enhances the development of liver diseases. HCV affects the initiative period of HCC and induces the malignant phenotypic alteration of hepatocytes.
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PMID:Immunohistochemical detection of HCV infection in patients with hepatocellular carcinoma and other liver diseases. 1181 35

Hepatitis C virus (HCV) infects more than 180 million of the world's population and causes a persistent infection that over decades can result in cirrhosis and hepatocellular carcinoma. Treatment is only partially effective and control is likely only with the development of effective vaccines. Currently, only chimpanzees can be infected with HCV and alternative animal and tissue culture models are badly needed. We have used mice transgenic for HLA-DR and human CD4 to analyse the specificity of murine responses to the HCV NS3 antigen in an effort to determine whether the epitopes recognized correspond to those recognized by human T cells. Indeed, determinants mapped in transgenic mice overlap with those in a patient exposed to HCV through infection. This result provides hope that such an animal model may be a useful tool with which to analyse particular aspects of immune responses to HCV in vivo.
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PMID:Epitopes of the NS3 protein of hepatitis C virus: recognition in HLA-DR4 transgenic mice. 1186 68

Hepatitis C virus (HCV) infection is a major worldwide health problem, causing chronic hepatitis, liver cirrhosis and primary liver cancer (Hepatocellular carcinoma). HCV encodes a precursor polyprotein that is enzymatically cleaved to release the individual viral proteins. The viral non-structural proteins are cleaved by the HCV NS3 serine protease. NS3 is regarded currently as a potential target for anti-viral drugs thus specific inhibitors of its enzymatic activity should be of importance. A prime requisite for detailed biochemical studies of the protease and its potential inhibitors is the availability of a rapid reliable in vitro assay of enzyme activity. A novel assay for measurement of HCV NS3 serine protease activity was developed for screening of HCV NS3 serine protease potential inhibitors. Recombinant NS3 serine protease was isolated and purified, and a fluorometric assay for NS3 proteolytic activity was developed. As an NS3 substrate we engineered a recombinant fusion protein where a green fluorescent protein is linked to a cellulose-binding domain via the NS5A/B site that is cleavable by NS3. Cleavage of this substrate by NS3 results in emission of fluorescent light that is easily detected and quantitated by fluorometry. Using our system we identified NS3 serine protease inhibitors from extracts obtained from natural Indian Siddha medicinal plants. Our unique fluorometric assay is very sensitive and has a high throughput capacity making it suitable for screening of potential NS3 serine protease inhibitors.
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PMID:A novel high throughput screening assay for HCV NS3 serine protease inhibitors. 1250 40

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Studies of HCV replication and pathogenesis have so far been hampered by the lack of an efficient tissue culture system for propagating HCV in vitro. Although HCV is primarily a hepatotropic virus, an increasing body of evidence suggests that HCV also replicates in extrahepatic tissues in natural infection. In this study, we established a B-cell line (SB) from an HCV-infected non-Hodgkin's B-cell lymphoma. HCV RNA and proteins were detectable by RNase protection assay and immunoblotting. The cell line continuously produces infectious HCV virions in culture. The virus particles produced from the culture had a buoyant density of 1.13 to 1.15 g/ml in sucrose and could infect primary human hepatocytes, peripheral blood mononuclear cells (PBMCs), and an established B-cell line (Raji cells) in vitro. The virus from SB cells belongs to genotype 2b. Single-stranded conformational polymorphism and sequence analysis of the viral RNA quasispecies indicated that the virus present in SB cells most likely originated from the patient's spleen and had an HCV RNA quasispecies pattern distinct from that in the serum. The virus production from the infected primary hepatocytes showed cyclic variations. In addition, we have succeeded in establishing several Epstein-Barr virus-immortalized B-cell lines from PBMCs of HCV-positive patients. Two of these cell lines are positive for HCV RNA as detected by reverse transcriptase PCR and for the nonstructural protein NS3 by immunofluorescence staining. These observations unequivocally establish that HCV infects B cells in vivo and in vitro. HCV-infected cell lines show significantly enhanced apoptosis. These B-cell lines provide a reproducible cell culture system for studying the complete replication cycle and biology of HCV infections.
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PMID:Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virus in vivo and in vitro: the apoptotic effects of virus infection. 1252 48

Using 4 McAbs to HCV-C, E, NS3 and NS4 regions' antigens and PcAb to HBsAg, 59 cases of hepatocellular carcinoma(HCC) and 35 cases of liver cirrhosis(LC) were tested by immunohistochemistry technique. Positive reactions for hepatitis C virus were mainly present in the cytoplasm of hepatocytes and tumor cells with fine granules. The positive rates of HCV were 17.2% in HCC(29 cases) of Beijing, 26.7% in HCC(30 cases) of Shenyang and 14.3% in LC(35 cases) of Shenyang. C region's McAb had the highest positive rate of detection, which suggested that C region's protein had a high level expression. The positive rates of hepatitis B virus surface antigen were 63.0% in HCC(29 cases) of Beijing, 73.3% in HCC(30 cases) of Shenyang and 54.3% in LC(35 cases) of Shenyang, all of which were higher than their positive rate for HCV detected. In HCC and LC, HBV and HCV inclined to suppress the opposite side.
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PMID:[Detection of hepatitis C virus-C, E, NS3 and NS4 regions' antigens in hepatocellular carcinoma and liver cirrhosis]. 1252 45

Chronic hepatitis C virus (HCV) infection develops in 85% of exposed individuals and 20% develop cirrhosis. However, the pathogenesis of this process is not well-understood. The objective of this study was to determine whether HCV-reactive T cells play a role in the process of development of cirrhosis during chronic HCV infection. We analyzed 21 human leukocyte antigen (HLA)-A2 patients with chronic HCV infection (9 with histology of inflammation and 12 with histology of fibrosis/cirrhosis). The frequency of CD8(+) T cells reactive to 12 HCV-derived epitopes was determined by an interferon-gamma enzyme-linked immunospot (ELISPOT) assay. The frequency of CD4(+) Th1 and Th2 cells reactive to the HCV core antigen was determined by interferon-gamma and interleukin-5 ELISPOT assays, respectively. Patients with histology of inflammation showed a significantly higher CD8(+) T-cell response to five HCV-derived epitopes (YLLPRRGPRL [core], CINGVCWTV [NS3], LLCPAGHAV [NS3], ILAGYGAGV [NS4B], and GLQDCTMLV [NS5B]) as compared with patients with histology of fibrosis/cirrhosis. Also, patients with histology of inflammation showed a significantly higher CD4(+) Th1 response to the HCV core antigen as compared to patients with histology of fibrosis/cirrhosis. These results indicate that a lack of an optimal T-cell response to HCV is associated with the development of cirrhosis during chronic HCV infection.
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PMID:Lack of optimal T-cell reactivity against the hepatitis C virus is associated with the development of fibrosis/cirrhosis during chronic hepatitis. 1255 24

Current therapeutic options for hepatitis C are limited, especially for genotype 1. For genotypes 2 and 3, pegylated interferon in combination with ribavirin, can lead to a sustained virological response in up to 80% of patients. Unfortunately, adverse effects of IFN and ribavirin are a major problem and the list of contraindications for HCV therapy is long, including decompensated cirrhosis of the liver and psychiatric disorders. Therefore, alternative therapeutic approaches are needed. New delivery options for IFN and ribavirin are aimed at optimising efficiency and reducing adverse effects. Recent progress in the molecular virology of HCV has identified new targets for antiviral intervention. Inhibition of HCV gene expression and replication as well as immunotherapeutic concepts aimed at enhancing the cellular immune response against HCV are being explored. Solution of the crystal structures of HCV key enzymes led to the design of specific inhibitors including compounds active against the well characterised NS3 serine protease and RNA-dependent RNA polymerase which are currently in the early phase clinical investigation. New strategies for inhibiting HCV gene expression include the use of antisense oligodeoxynucleotides and ribozymes. Immunomodulation by agents such as inosine monophosphate dehydrogenase inhibitors, thymosin-alpha 1, histamine or amantadine are being studied in combination with IFN and/or ribavirin. Immunotherapeutic vaccination with recombinant HCV E1 protein improved host immunity against HCV and thus seems to be a promising new option.
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PMID:Current therapy and new molecular approaches to antiviral treatment and prevention of hepatitis C. 1462 84

Hepatitis C virus (HCV) is a positive-stranded RNA virus that causes severe liver diseases, such as cirrhosis and hepatocellular carcinoma. HCV uses an RNA-dependent RNA polymerase to replicate its genome and an internal ribosomal entry site to translate its proteins. HCV infection is characterized by an increase in the concentrations of reactive oxygen species (ROS), the effect of which on HCV replication has yet to be determined. In this report, we investigated the effect of ROS on HCV replication, using a bicistronic subgenomic RNA replicon and a genomic RNA that can replicate in human hepatoma cells. The treatment with peroxide at concentrations that did not deplete intracellular glutathione or induce cell death resulted in significant decreases in the HCV RNA level in the cells. This response could be partially reversed by the antioxidant N-acetylcysteine. Further studies indicated that such a suppressive response to ROS was not due to the suppression of HCV protein synthesis or the destabilization of HCV RNA. Rather, it occurred rapidly at the level of RNA replication. ROS appeared to disrupt active HCV replication complexes, as they reduced the amount of NS3 and NS5A in the subcellular fraction where active HCV RNA replication complexes were found. In conclusion, our results show that ROS can rapidly inhibit HCV RNA replication in human hepatoma cells. The increased ROS levels in hepatitis C patients may therefore play an important role in the suppression of HCV replication.
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PMID:Reactive oxygen species suppress hepatitis C virus RNA replication in human hepatoma cells. 1475 26


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