Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV), a member of the Flaviviridae family, has been recognised to be responsible for both parenterally transmitted and sporadic non-A and non-B hepatitis affecting 1-3% of the world population. HCV is a positive stranded RNA virus encoding a single polyprotein which contains at least ten unique structural and non-structural proteins. Amongst these the structural protein E2 has been of special interest for vaccine development and the serine protease NS3, which is responsible for cleavage of the polyprotein, for the development of small molecule inhibitors. We will focus on the contribution of computational techniques and the use of structural information for the design and discovery of novel therapeutic agents for these targets. Both drug discovery and vaccine design efforts will be discussed taking into account also the problem of emerging resistance.
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PMID:Hepatitis C virus proteins as targets for drug development: the role of bioinformatics and modelling. 1210

According to two highly conserved genome sequences within the helicase(NS3) region and 5'-uncoding(5' UTR) region, we designed two sets of primer pairs to detect HGV RNA by RT-nested PCR in order to study HGV infection in Chinese population. Three hundred and fifty-four serum specimens of various liver diseases were collected from Beijing, Qin Huangdao and Henan areas. Seventy-nine out of 354(22.3%) specimens were HGV RNA positive. Among 254 known clinical hepatitis/liver disease samples, 50(19.6%) were HGV RNA positive. Thirteen HGV RNA positive samples(30.2%) were derived from 43 cryptogenic or nonA-E hepatitis. In 57 commercial blood donors who were antibody positive to HCV 16(30.2%) were HGV RNA positive, suggesting HGV infection is common in various population. It may be an etiological factor which leads to nonA-E hepatitis and post-transfusion hepatitis.
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PMID:[Detection of hepatitis G virus infection among clinical patients with hepatitis/liver diseases in China by reverse transcription-nested polymerase chain reaction]. 1251 1

A correlation between the detection of proteins and an activity of the pathological process was analyzed in a study of the content of the C virus hepatitis (CVH) proteins in hepatic cells of patients with chronic C hepatitis (CCH). The expression of CVH proteins in frozen sections of biopsy samples of 69 CCH patients was evaluated by using the immune-histological method involving original monoclonal antibodies (MCA) to 5 CVH proteins. The results of the detection of proteins in patients were compared with an activity and stage of CCH (by using histological tests and a level of alanine aminotransferase--AAT). A set of the CVH proteins were found in the liver of 74% of patients, i.e. core proteins, NS3, NS4A, NS4B and NS5A--in 28, 43, 43, 55 and 58%, respectively. All studied proteins were detected in the cytoplasm of hepatocytes. Proteins were found in the liver more often as compared with the detection rate of CVH RNA in the blood serum (61%). This demonstrates a high sensitivity of the discussed test at detecting the CVH infection. The accumulation of the core protein was shown to correlate with the presence of the replicative form of CVH RNA in the liver and with a higher level of AAT. The quantity of NS5 A-expressing cells correlated directly with a CCH stage. The quantity of NSB- and NS3-positive hepatocytes correlated negatively with an activity of the inflammatory-and-necrotic processes in the liver. Hyper-fermentation was found more often among the antigen-positive patients. The CCH histological activity was proven to be reliably higher at a simultaneous detection of CCH proteins in the liver and of CVH RNA--in the serum.
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PMID:[Analysis of hepatitis C virus proteins in hepatic cells of patients with chronic hepatitis C]. 1260 53

Hepatitis C virus is one of the causative agents of non-A non-B hepatitis. Since one of viral proteins, NS3, has serine protease activity indispensable for virus maturation. NS3 serine protease is considered to be a suitable target for anti-HCV reagents. We report an assay of HCV NS3 protease in living cells. We designed peptide substrates bearing one of the sequences of HCV NS3 protease cleavage sites sandwiched with fluorescent proteins CFP and YFP. Substrates were expressed and cleaved efficiently in HeLa cells by cotransfection with HCV NS3 protease. The relationship between the progress of cleavage reaction and the change in fluorescence of the substrate emitted from living cells was confirmed. As a group of candidates for inhibitor of HCV NS3 protease, we chose RNA aptamers, nucleic acid ligands selected from a completely random RNA pool by in vitro selection. We found that 3 classes of aptamers, G9-I, II and III, bound NS3 protease specifically and inhibited cleavage in vitro. We studied the effect of RNA aptamers introduced into HeLa cells. The addition of G9-II RNA in the medium at a concentration of 2.5 micro g/ml reduced cleavage by one-third that of control.
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PMID:Inhibition of hepatitis C virus serine protease in living cells by RNA aptamers detected using fluorescent protein substrates. 1267 11

GBV-B virus is a close relative to hepatitis C virus (HCV) that causes hepatitis in tamarins, and thus, is an attractive surrogate model for HCV. In this study, we demonstrate that the host range of GBV-B extends to the common marmoset with an infection profile similar to that observed for tamarins. Marmoset hepatocytes were susceptible to in vitro infection with GBV-B. Virus was efficiently secreted into the medium, and approximately 25% of hepatocytes were positive for NS3 staining. In an attempt to induce persistent infections, tamarins were immunosuppressed with FK506 and inoculated with GBV-B. Although no chronic infections were induced, the duration of viremia was increased in most animals. In one animal, the duration of viremia was extended to 46 weeks, but viral clearance occurred 18 weeks after stopping FK506 therapy. The greater availability of marmosets in comparison to tamarins will greatly facilitate future research efforts with this model.
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PMID:Comparison of tamarins and marmosets as hosts for GBV-B infections and the effect of immunosuppression on duration of viremia. 1283 4

Hepatocellular carcinoma (HCC) is the most important primary hepatic cancer and is a common cancer type worldwide. Many aetiological factors have been related to HCC development, such as liver cirrhosis, hepatitis viruses and alcohol consumption. Inactivation of the p53 tumour suppressor gene is one of the most common abnormalities in many tumours, including HCC. p53 is of crucial importance for the regulation of the cell cycle and the maintenance of genomic integrity. In HCC, hepatitis B and C virus (HBV and HCV) effect carcinogenic pathways, independently leading to anomalies in p53 function. Several authors have reported that some HCV proteins, such as the core, NS5A and NS3 proteins, interact with p53 and prevent its correct function. The mechanisms of action of these HCV proteins in relation to p53 are not completely clear, but they might cause its cytoplasmic retention or accumulation in the perinuclear region where the protein is not functional. The identification of the interactions between p53 and HCV proteins is of great importance for therapeutic strategies aimed at reducing the chronicity and/or carcinogenicity of the virus.
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PMID:Hepatocellular carcinoma: molecular interactions between hepatitis C virus and p53 in hepatocarcinogenesis. 1498 3

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

A double polymerase chain reaction, involoving nested primers deduced from NS3-5 regions of the hepatitis G virus (GBV-c/HGV) genome, was developed for a sensitive and specific detection of GBV-C (HGV) RNA. With this method, 10 anti-HGV positive patients with non A-E hepatitis and 10 healthy subjects were tested. Among 10 patients, GBV-C RNA was detected in 9, 8, 4, 9 patients by the NS-3 (1) primers, the NS3(2) primers, the NS4 primers, the NS5(1) primers and the NS5(2) primers respectively. Control sera from 10 healthy subjects did not reveal GBV-C (HGV) RNA by any set of the primers. These data suggest that the detection rate of GBV-C (HGV) RNA is different in various set of primers, the NS3(1) and the NS5(2) primers are superior to other primers and are more suitable for RT-PCR of GBV-C (HGV) RNA.
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PMID:[Detection of hepatitis G virus RNA in sera in non A-E hepatitis patients using polymerase chain reaction with multiple set primers]. 1561 20

Hepatitis C virus (HCV) can cause liver disease of variable severity. Expansion of preexisting memory CD8 T cells by cross-reactivity with a new heterologous virus infection has been shown in mice to shape the repertoire of the primary response and to influence virus-related immunopathology. To determine whether this mechanism can influence the course of HCV infection, we analyzed the features of the HCV-specific CD8 T cell response in eight patients with acute HCV infection, two of whom had a particularly severe illness. Patients with severe hepatitis, but not those with mild disease, showed an extremely vigorous CD8 T cell response narrowly focused on a single epitope (NS3 1073-1081), which cross-reacted with an influenza neuraminidase sequence. Our results suggest that CD8 T cell cross-reactivity influences the severity of the HCV-associated liver pathology and depicts a model of disease induction that may apply to different viral infections.
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PMID:Heterologous T cell immunity in severe hepatitis C virus infection. 1575 2

Anti-liver-kidney microsome type 1 (LKM1) autoantibodies directed against the cytochrome P450 2D6 (CYP2D6) are considered specific markers of type 2 autoimmune hepatitis, but are also found in 5% of sera from patients chronically infected by hepatitis C virus (HCV). Molecular mimicry between HCV proteins and CYP2D6 has been proposed to explain the emergence of these autoantibodies. Anti-LKM1 autoantibodies from hepatitis C-infected patients were affinity-purified against immobilized CYP2D6 protein and used to screen a phage display library. CYP2D6 conformational epitopes were identified using phage display analysis and the identification of statistically significant pairs (SSPs). Cross-reactivity between CYP2D6 and HCV protein candidates was tested by immunoprecipitation. Nineteen different clones were isolated, and their sequencing resulted in the mapping of a conformational epitope to the region of amino acids 254-288 of CYP2D6. Candidate HCV proteins for molecular mimicry included: core, E2, NS3 and NS5a. Affinity-purified autoantibodies from HCV+/LKM1+ patients immunoprecipitated either NS3, NS5a, or both, and these reactivities were specifically inhibited by immobilized CYP2D6. In conclusion, HCV+/LKM1+ sera recognize a specific conformational epitope on CYP2D6 between amino acids 254 to 288, the region that contains the major linear epitope in type 2 autoimmune hepatitis patients. Cross-reactivity due to molecular mimicry at the B-cell level was shown between the CYP2D6 and the HCV NS3 and NS5a proteins and could explain the presence of anti-LKM1 in patients chronically infected with HCV. Further investigation of the role played by this molecular mimicry in HCV-infected patients may lead to more specific strategies for diagnosis and treatment.
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PMID:LKM1 autoantibodies in chronic hepatitis C infection: a case of molecular mimicry? 1603 45


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