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)

Hepatitis C virus (HCV) infects over 170 million people worldwide. Chronic infection occurs in 50-80% of cases and eventually leads to cirrhosis and hepatocellular carcinoma. The HCV lifecycle is only partly understood owing to the lack of a productive cell culture system. Several molecules have been implicated in the receptor complex at the surface of target cells, but the mode of HCV entry remains unknown. Persistent infection appears to be due to weak CD4+and CD8+ T-cell responses during acute infection, which fail to control viral replication. When chronic infection is established, HCV does not appear to be cytopathic. Liver lesions appear to result from locally driven immune responses, which are mainly non-specific. Local inflammation triggers fibrogenesis, in which hepatic stellate cells play a major role. Cirrhosis is facilitated by external factors, such as chronic alcohol consumption and viral co-infections. Patients with cirrhosis are at high risk of developing hepatocellular carcinoma. The role of HCV proteins in hepatocarcinogenesis is unknown. Further progress in our understanding of HCV infection and pathogenesis awaits the advent of new model systems and technologies.
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PMID:Pathophysiology of hepatitis C virus infection and related liver disease. 1503 26

Chronic infection by hepatitis C virus (HCV) can lead to severe hepatitis and cirrhosis and is closely associated with hepatocellular carcinoma. The replication cycle of HCV is poorly understood but is likely to involve interaction with host factors. In this report, we show that NS5B, the HCV RNA-dependent RNA polymerase (RdRp), interacts with a human RNA helicase, p68. Transient expression of NS5B alone, as well as the stable expression of all the nonstructural proteins in a HCV replicon-bearing cell line (V. Lohmann, F. Korner, J.-O. Koch, U. Herian, L. Theilmann, and R. Bartenschlager, Science 285:110-113), causes the redistribution of endogenous p68 from the nucleus to the cytoplasm. Deletion of the C-terminal two-thirds of NS5B (NS5BDeltaC) dramatically reduces its coimmunoprecipitation (co-IP) with endogenous p68, while the deletion of the N-terminal region (NS5BDeltaN1 and NS5BDeltaN2) does not affect its interaction with p68. In consistency with the co-IP results, NS5BDeltaC does not cause the relocalization of p68 whereas NS5BDeltaN1 does. With a replicon cell line, we were not able to detect a change in positive- and negative-strand synthesis when p68 levels were reduced using small interfering RNA (siRNA). In cells transiently transfected with a full-length HCV construct, however, the depletion (using specific p68 siRNA) of endogenous p68 correlated with a reduction in the transcription of negative-strand from positive-strand HCV RNA. Overexpression of NS5B and NS5BDeltaN1, but not that of NS5BDeltaC, causes a reduction in the negative-strand synthesis, indicating that overexpressed NS5B and NS5BDeltaN1 sequesters p68 from the replication complexes (thus reducing their replication activity levels). Identification of p68 as a cellular factor involved in HCV replication, at least for cells transiently transfected with a HCV expression construct, is a step towards understanding HCV replication.
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PMID:Cellular RNA helicase p68 relocalization and interaction with the hepatitis C virus (HCV) NS5B protein and the potential role of p68 in HCV RNA replication. 1511 10

Chronic infection by HCV is closely correlated with liver diseases such as cirrhosis, steatosis, and hepatocellular carcinoma. To understand how long-term interaction between HCV and the host leads to pathogenesis, we identified cellular proteins that interact with NS5A and NS5B using a biochemical approach. Stable cell lines that express flag-NS5A or flag-NS5B under tetracycline induction were generated. The induced flag-tagged proteins were immunoprecipitated (IP'd) and associated proteins separated on 2D gels. Protein spots that specifically co-IP'd with NS5A or NS5B were identified by mass spectrometry. HSP27 was identified as a protein that specifically co-IP'd with NS5A but not with NS5B. The N-terminal regions of NS5A (a.a. 1-181) and HSP27 (a.a. 1-122) were defined to be the domains that interact with each other. HSP27 is generally distributed in the cytoplasm. When heat shocked, HSP27 is concentrated in the ER where NS5A is co-localized.
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PMID:Proteomic approach identifies HSP27 as an interacting partner of the hepatitis C virus NS5A protein. 1512 Jun 31

Chronic infection with hepatitis B virus (HBV) is an important clinical problem due to its worldwide distribution and potential of adverse sequelae including hepatocellular carcinoma (HCC). Hepatitis B e antigen (HBeAg) is a biomarker of active viral proliferation in hepatocytes and infectivity. The prevalence of HBeAg among subjects chronically infected with HBV decreases with the increase in age. Case series studies have found a lowest seroprevalence of HBeAg in HCC patients compared with patients affected with chronic hepatitis B and liver cirrhosis. Case-control studies have shown a significantly higher seroprevalence of HBeAg in HCC cases than matched controls. A recent long-term follow-up study has shown a significantly elevated HCC risk for seropositives of both hepatitis B surface antigen (HBsAg) and HBeAg compared with seropositives of HBsAg only and seronegatives. The biological gradient remained in further stratification analyses by serum level of alanine transaminase and status of liver cirrhosis detected by ultrasonography. The cumulative HCC risk from age 30 to 70 years has been estimated to be 87% for those who were persistently seropositive on HBsAg and HBeAg, 12% for those with persistent seropositivity of HBsAg only, and 1% for those who were seronegative on HBsAg and HBeAg.
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PMID:Seropositivity of hepatitis B e antigen and hepatocellular carcinoma. 1518 77

Hepatocellular carcinoma (HCC) is the most important primary hepatic cancer, being a common cancer type worldwide. Many aetiological factors have been related with HCC development, such as cirrhosis, hepatitis viruses and alcohol. Chronic infection with hepatitis B (HBV) and C viruses (HCV) often results in cirrhosis and enhances the probability of developing HCC. The underlying mechanisms that lead to malignant transformation of infected cells, however, remain unclear. HBV is a DNA virus that integrates into the host genome, and this integration is believed, in part, to be carcinogenic. Besides, the virus encodes a 17 kDa protein, HBx, which is known to be a causative agent in the formation of HCC. On the contrary, HCV is a RNA virus that does not integrate into the host genome but likely induces HCC through host protein interactions or via the inflammatory response to the virus. Products encoded in the HCV genome interfere with and disturb intracellular signal transduction. Some HCV proteins, such as the core protein, NS3 and NS5A, have seen to have a regulatory effect on cellular promoters, to interact with a number of cellular proteins, and to be involved in programmed-cell death modulation under certain conditions. The identification of these proteins functions in HCC development and the subsequent development of strategies to inhibit protein-protein interactions may be the first step towards reducing the chronicity and/or of the carcinogenicity of these two viruses.
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PMID:Hepatocellular carcinoma: role of hepatitis B and hepatitis C viruses proteins in hepatocarcinogenesis. 1535 43

Chronic infection with hepatitis B virus (HBV) is endemic to sub-Saharan Africa and parts of Asia where persistence of the virus is commonly associated with complicating cirrhosis and hepatocellular carcinoma (HCC). Licensed therapies for HBV are partially effective in selected patients and development of novel treatments remains an important global medical objective. HBV has an unusually compact genome that restricts the ability of the virus to evade potentially therapeutic nucleic acid hybridization. Thus, exploiting the RNA interference (RNAi) pathway, which enables sequence-specific target RNA degradation using small interfering RNA (siRNA), is well suited to developing novel treatment for HBV infection. Several studies, both in vitro and in vivo, have demonstrated that HBV replication can be inhibited in transfected cells by synthetic siRNA duplexes and also Pol III-derived short hairpin RNA (shRNA) sequences. The effectiveness of anti-HBV sequences varies considerably, and is likely to result from differences in activation of the RNAi pathway by individual siRNA species. Exclusion of potentially toxic off-target effects and also development of efficient methods of hepatotropic nucleic acid delivery are important prerequisites before RNAi can be used successfully for anti-HBV treatment.
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PMID:Exploiting the RNA interference pathway to counter hepatitis B virus replication. 1569 93

Chronic infection with hepatitis B virus (HBV) is one of the most common causes of cirrhosis of the liver and hepatocellular carcinoma worldwide, frequently requiring liver transplantation. Other nonliver organ transplants get infected de novo or through reactivation from previous active or inactive infections. With significant improvements in the surgical techniques and immunosuppressive regimens over the last 20 years, organ transplantation has become the most effective and lifesaving therapy for patients with chronic renal failure, cirrhosis, hepatocarcinoma, and heart failure. Until recently chronic HBV infection was considered a formal contraindication for liver transplantation, since recurrence of infection without prophylaxis occurs in 75% to 90% of the patients, with significant morbidity and mortality and few therapeutic alternatives. However, the introduction of hepatitis B immunoglobulin (HBIG) a decade ago to reduce the risk of reinfection of liver grafts, and more recently the availability of nucleoside analogues with few side effects and easy administration, have led to a dramatic improvement in patient outcomes with a risk of long-term HBV reinfection of less than 10% with combined HBIG and lamivudine prophylaxis. Chronic HBV infection in kidney, heart, and other organs has become a serious long-term problem and one of the most frequent and important comorbidities affecting graft and patient survival. Fortunately the introduction of nucleoside analogues allows significant control of viral replication and prevents progression of liver disease and other organ damage. In the present article we discuss the current indications for HBV prophylaxis and treatment prior to and after organ transplantation, as well as the most cost-effective way to apply different regimens to reduce side effects and improve survival and quality of life after transplantation.
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PMID:Is hepatitis B immunoglobulin prophylaxis needed for liver transplantation in the era of new antivirals? 1596 78

At least five hepatitis viruses are known to date. Infection by enterically transmitted viruses (HAV and HEV) is generally benign compared with the disease caused by parenterally transmitted viruses (HBV, HCV, and HDV). Chronic infection by HBV is common and may evolve to cirrhosis and hepatocellular carcinoma (HCC). Eight HBV genotypes (A-H) have been described, with the South American genotype F being the most divergent. Seven clades of HDV have been described; among them, the South American genotype III is associated to a high frequency of fulminant hepatitis. HCV infection leads to a high rate of chronicity and HCC. From the six HCV genotypes, infection with genotype 1 might have the worst prognostic. Chronic infection by HCV and HBV is the major risk factor for HCC, which occurs, in the majority of the cases, as a consequence of cirrhosis. However, there is growing evidence that some HBV and HCV proteins might contribute to the generation of HCC. Some HBV and HCV variants and specific mutations within the viral genomes might be more frequently associated with the evolution to HCC. Although more studies are needed, emerging evidence indicates that it might be important to address the genetic variability of these viruses and their contribution to the development of HCC.
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PMID:Genotypic variability of hepatitis viruses associated with chronic infection and the development of hepatocellular carcinoma. 1600 Sep 30

Hepatitis C virus is an RNA virus that is associated with chronic infection in the majority of people infected. Chronic infection with hepatitis C virus is the cause of significant morbidity and mortality worldwide and is associated with a large spectrum of liver disease including cirrhosis and hepatocellular carcinoma. End-stage liver disease due to chronic hepatitis C virus infection is currently the leading indication for liver transplantation in the USA. Hepatitis C virus genotyping of viral isolates circulating in the blood during chronic infection has become an important part of hepatitis C virus monitoring in chronically infected patients, and is useful as a prognostic indicator and to direct duration of therapy. This review will summarize information on hepatitis C genotyping, describe the limitations of current commercially available methods, give information on more recently developed methods, and provide a look to the future in terms of where advances in hepatitis C virus genotyping assays need to be made.
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PMID:Molecular methods of hepatitis C genotyping. 1601 69

Chronic infection with hepatitis C virus (HCV) is known to be a risk factor for not only cirrhosis and steatosis but also hepatocellular carcinoma (HCC). A number of diagnostic and prognostic molecular markers are being identified by transcriptomic and proteomic analysis of HCC today. However, the analyses are performed on HCC in general, and the studied tissues are HCV infected, HBV infected, infected with both or neither, or the infection status may be unknown. The authors performed proteomic analysis of cancerous and noncancerous tissues from HCC patients with HCV infection, and determined that, in the cancerous tissues, HSP70 family proteins such as GRP78, HSC70, GRP75 and HSP70.1, glutaine synthetase isoforms, HSP60, alpha-enolase, phosphoglycerate mutase 1, ATP synthetase beta chain and triosephosphate isomerase were increased whereas albumin, ferritin light chain, smoothelin, tropomyosin beta chain, arginase 1, aldolase B and kietohexokinase were decreased. The aim of this study is to understand the pathogenesis of HCV-HCC using proteomic analysis of samples from HCV-HCC patients on which transcriptomics has already been performed.
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PMID:Current progress in proteomic study of hepatitis C virus-related human hepatocellular carcinoma. 1609 91


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