UMLS:C0023890 - FACTA Search

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Query: UMLS:C0023890 (cirrhosis)
42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenetic mechanisms of hepatitis C virus (HCV) infection are poorly known. An understanding of HCV biology and the potential clinical impact of HCV genetic variability is essential to managing, treating, and preventing HCV infections. HCV is a member of the Flaviviridae viral family. Its genome is a positive, single-strand RNA molecule. The structure of the HCV particles is poorly known due to the lack of an efficient cell culture system as well as a striking heterogeneity in density. The core protein may have a regulatory role on both viral and cellular gene expression. The mechanisms of HCV-RNA replication may include synthesis of negative strand intermediates, which drive synthesis of new positive RNA genomes. New procedures have been developed to better identify and characterize the HCV-RNA genome. The mechanisms of HCV persistence are currently unknown, although it is known that HCV chronicity develops despite humoral and cellular responses to HCV proteins. HCV-RNA shows significant genetic variability with an estimated rate of nucleotide change of approximately 10(-3) substitutions/site/year. Currently, three major HCV genotypes and three to seven minor subtypes can be distinguished. The geographical distribution of these genotypes and subtypes varies significantly. It appears that poor clinical response to interferon (IFN) is more common with HCV genotype 1. In addition, some studies have shown an association between chronic infection, severe chronic hepatitis, and cirrhosis with subtype 1b. Further, there is evidence for a potential direct effect of HCV in liver carcinogenesis, with subtype 1b possibly being an independent risk factor for hepatic carcinoma development. HCV-RNA circulates as a population of RNA molecules, which creates a heterogeneity referred to as "quasispecies." It is possible that some HCV strains might have direct clinical implications. It may be that highly heterogeneous populations observed prior to treatment might correlate with a lower rate of response to IFN therapy.
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PMID:Hepatitis C virus: molecular biology and genetic variability. 901 78

Hepatitis B virus, a major human pathogen with an estimated 300 million carriers worldwide, can lead to cirrhosis and liver cancer in cases of chronic infection. The virus consists of an inner nucleocapsid or core, surrounded by a lipid envelope containing virally encoded surface proteins. The core protein, when expressed in bacteria, assembles into core shell particles, closely resembling the native core of the virus. Here we use electron cryomicroscopy to solve the structure of the core protein to 7.4 A resolution. Images of about 6,400 individual particles from 34 micrographs at different levels of defocus were combined, imposing icosahedral symmetry. The three-dimensional map reveals the complete fold of the polypeptide chain, which is quite unlike previously solved viral capsid proteins and is largely alpha-helical. The dimer clustering of subunits produces spikes on the surface of the shell, which consist of radial bundles of four long alpha-helices. Our model implies that the sequence corresponding to the immunodominant region of the core protein lies at the tip of the spike and also explains other properties of the core protein.
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PMID:Determination of the fold of the core protein of hepatitis B virus by electron cryomicroscopy. 905 76

We previously reported that interferon-gamma (IFN-gamma) production by PBMC in response to HCV core protein was increased in patients with type C chronic liver disease. To understand better the pathophysiology of this disease, we evaluated production of IL-10 and IL-12 by PBMC from 41 patients with chronic HCV infection, including asymptomatic HCV carriers with persistently normal serum ALT values. IL-10 is known to inhibit many effector functions of the immune system, suppressing Th1-type cell development, while IL-12 stimulates differentiation of Th1-type cells, facilitating cell-mediated immunity. IL-10 production was determined by culturing lymphocytes with concanavalin A (Con A), while IL-12 was produced by monocytes in the presence of Staphylococcus aureus Cowan 1 (SAC) with or without recombinant HCV core protein, respectively. The cytokine levels in culture supernatants were measured by ELISA. Spontaneous IL-10 production was greater in patients with chronic hepatitis (CH) (229 +/- 119 pg/ml, P < 0.01) and liver cirrhosis (LC) (185 +/- 88 pg/ml, P < 0.05) than in controls (119 +/- 27 pg/ml), while it was decreased during IFN treatment (70 +/- 25 pg/ml). Both HCV core protein and Con A enhanced IL-10 production by cells from HCV-infected patients. IL-12 was not detectable in medium alone cultures, and SAC-induced IL-12 production did not differ between various patient groups and controls. Simultaneous addition of HCV protein resulted in an increase of IL-12 production in chronic liver disease compared with SAC-alone cultures. Addition of IL-10 to the cultures equally suppressed IFN-gamma production for both controls and patient groups, but the enhancing effect of IL-12 on IFN-gamma production was significantly less in LC than in controls and other patient groups. The findings suggest that secretion of IL-10/IL-12 by cells from control individuals and various patient groups may be different, and that the cytokines might show different effects on IFN-gamma production by some cells.
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PMID:Production of interleukins 10 and 12 by peripheral blood mononuclear cells (PBMC) in chronic hepatitis C virus (HCV) infection. 909 22

Persistent infection with hepatitis C virus (HCV) is associated with the development of liver cirrhosis and hepatocellular carcinoma. To examine the oncogenic potential of the HCV core gene product, primary rat embryo fibroblasts (REFs) were transfected with the core gene in the presence or absence of the H-ras oncogene. In contrast to a previous report (R. B. Ray, L. M. Lagging, K. Meyer, and R. Ray, J. Virol. 70:4438-4443, 1996), HCV core proteins from two different genotypes (type 1a and type 1b) were not found to transform REFs to tumorigenic phenotype in cooperation with the H-ras oncogene, although the core protein was successfully expressed 20 days after transfection. In addition, REFs transfected with E1A- but not core-expressing plasmid showed the phenotype of immortalized cells when selected with G418. The biological activity was confirmed by observing the transcription activation from two viral promoters, Rous sarcoma virus long terminal repeat and simian virus 40 promoter, which are known to be activated by the core protein from HCV-1 isolate. In contrast to the result with primary cells, the Rat-1 cell line, stably expressing HCV core protein, exhibited focus formation, anchorage-independent growth, and tumor formation in nude mice. HCV core protein was able to induce the transformation of Rat-1 cells with various efficiencies depending on the expression level of the core protein. These results indicate that HCV core protein has an oncogenic potential to transform the Rat-1 cell line but is not sufficient to either immortalize primary REFs by itself or transform primary cells in conjunction with the H-ras oncogene.
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PMID:Hepatitis C virus core from two different genotypes has an oncogenic potential but is not sufficient for transforming primary rat embryo fibroblasts in cooperation with the H-ras oncogene. 952 29

To assess the possible involvement of canine adenovirus type 1 (CAV-1) in naturally occurring cases of canine chronic liver disease, a polymerase chain reaction (PCR)-based assay was developed to detect a conserved region of the major core protein gene (pVII) of CAV-1 in formalin-fixed, paraffin-embedded liver sections. Results were compared with a standard avidin-biotin immunoperoxidase complex technique that detected CAV-1 antigens using a commercial monoclonal anti-adenovirus antibody. Seventeen cases of cirrhosis and 28 cases of chronic hepatitis with piecemeal necrosis and progressive fibrosis were selected for the study. Formalin-fixed, paraffin-embedded liver sections of 2 cases of infectious canine hepatitis (ICH) and crude DNA extract from CAV-1 (ATCC VR 293 Utrecht strain) served as positive controls. A 411-base-pair viral region was amplified and sequenced as CAV-1 pVII in both cases of infectious canine hepatitis and in the CAV-1 crude DNA extract. The 2 ICH cases were positive for CAV-1 antigens by the immunoperoxidase method. CAV-1 DNA or antigens were not detected by either technique in any of the 45 cases of chronic liver disease selected for the study. These results indicate that both PCR and immunohistochemistry are reliable and rapid techniques for detecting CAV-1 in formalin-fixed, paraffin-embedded liver sections of dogs with ICH. Several possibilities may explain the negative results obtained with both techniques in this study, including the noninvolvement of CAV-1 in canine chronic hepatitis and cirrhosis and the possibility that the virus causes initial damage, provokes a self-perpetuating chronic liver disease, and disappears.
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PMID:Use of polymerase chain reaction and immunohistochemistry for detection of canine adenovirus type 1 in formalin-fixed, paraffin-embedded liver of dogs with chronic hepatitis or cirrhosis. 978 18

Hepatitis B virus causes liver cirrhosis and hepatocellular cancer and is a major cause of death, particularly in Asia and sub-Saharan Africa. The virus consists of an inner core or nucleocapsid, which encloses the viral nucleic acid, with an outer lipid envelope containing surface-antigen proteins. The core protein, when expressed in E. coli, assembles into spherical shells containing 180 or 240 subunits, arranged with T = 3 or T = 4 icosahedral symmetry. The C-terminal region of the protein is involved in nucleic acid binding, and deletion of this region does not prevent capsid formation. C-terminally deleted hepatitis B core shells containing 240 subunits have been crystallized and data has been collected to 3. 6 A resolution from frozen crystals, using butanediol as a cryoprotectant. The crystals have C2 symmetry, with unit-cell parameters a = 538.0, b = 353.0, c = 369.6 A, beta = 132.3 degrees.
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PMID:Crystallization of hepatitis B virus core protein shells: determination of cryoprotectant conditions and preliminary X-ray characterization. 1008 78

Hepatitis B virus is a major cause of human liver disease. In the case of chronic infection the virus can lead to liver cancer and cirrhosis. The virion consists of an outer envelope containing lipids of the endoplasmic reticulum and virally-encoded surface proteins. This lipoprotein shell encloses the nucleocapsid or core antigen (HBcAg), which contains the viral genome. The capsid consists of dimers of a 183-residue protein, which can be divided into an assembly (residues 1-149) and a protamin-like domain (residues 150-183), responsible for polymerization into particles and RNA packaging, respectively. Upon expression of the core gene in bacteria the products are assembled into capsids resembling those of wild type particles. A purification protocol was developed for unpolymerised (dimeric) and polymerized HBcAg by fusion of six histidine residues to a C-terminal deletion mutant of the core protein allowing the isolation of the respective antigens after denaturing Ni2+-chelate affinity chromatography and renaturing dialysis. The possible incorporation of E. coli proteins during the assembly process and the inclusion of nucleic acids can be avoided. The method might be an attractive alternative to common purification protocols of hybrid virus-like particles (VLPs) for vaccine use.
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PMID:Purification of E. coli-expressed HIS-tagged hepatitis B core antigen by Ni2+ -chelate affinity chromatography. 1009 42

Hepatitis C Virus (HCV) causes most cases of posttransfusion hepatitis. Chronic HCV infection is highly related to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Current therapies are only minimally effective and no vaccine has been developed. DNA-based immunization could be of prophylactic and therapeutic value for HCV infection. By intramuscular inoculation in BALB/c mice with an HCV recombinant plasmid pCI-HCV-C, we found significant levels of IgM antibody, but no significant IgG rise. After boost the immunized mice with recombinant HCV-core protein (cp1-10; 1-164aa), the anticore IgG, verified by Western-blotting, rose rapidly, which was two weeks earlier than that with control plasmid. Spleen cells from pCI-HCV-C immunized mice gave higher proliferation index (PI) than control (P < 0.05). The PI of cp1-10 boosted mice was even higher. Proliferation blocking assay with mAb proved the responding cell to be of CD4+ CD8- phenotype, supporting specific priming of T helper cells. A 51Cr-releasing CTL assay specific for HCV-core was developed, and a specific CTL response against HCV-core was demonstrated in both pCI-HCV-C immunized mice and mice boosted with cp1-10. Strong cytotoxic activity against peptide-pulsed p815 cells (H-2d), but not EL-4 cells (H-2b), suggested MHC class I restriction of the CTL activity. Blocking of CTL with mAb proved the effector cells to be of CD4- CD8+. Three CTL epitopes in HCV-core protein were demonstrated. We failed to detect CTL when immunized only with core protein. The results suggested that vaccination with HCV-core derived DNA sequences could be an effective method to induce humoral and cellular immune responses to HCV.
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PMID:Characterization of the humoral and cellular immune responses against hepatitis C virus core induced by DNA-based immunization. 1046 52

Hepatitis C virus (HCV) is the major etiological agent of blood-borne non-A non-B hepatitis and a leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. HCV core protein is a multifunctional protein with regulatory functions in cellular transcription and virus-induced transformation and pathogenesis. Here we report on the identification of a bZIP nuclear transcription protein as an HCV core cofactor for transformation. This bZIP factor, designated LZIP, activates CRE-dependent transcription and regulates cell proliferation. Loss of LZIP function in NIH 3T3 cells triggers morphological transformation and anchorage-independent growth. We show that HCV core protein aberrantly sequesters LZIP in the cytoplasm, inactivates LZIP function and potentiates cellular transformation. Our findings suggest that LZIP might serve a novel cellular tumor suppressor function that is targeted by the HCV core.
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PMID:Hepatitis C virus core protein-induced loss of LZIP function correlates with cellular transformation. 1067 42

Hepatocellular carcinoma (HCC) is increasing in many countries as a result of an increase in hepatitis C virus (HCV) infection since World War II. The epidemiology of HCC varies with the global region. There have been conflicting observations from different parts of the world concerning the frequency of HCC in patients who in the distant past had post-transfusion non-A, non-B hepatitis. The genetic basis of hepatocarcinogenesis is still poorly understood. In hepatitis B virus (HVB) associated HCC, codon 249 mutation in the p 53 gene seems more related to exposure to aflatoxin B1 than to hepatocarcinogenesis itself. HCC that occurs in children in high HBV endemic regions could be associated with germ-line mutations, but little information is available; not much is known about chemical hepatocarcinogens in the environment other than aflatoxins. The X gene of HBV seems to play an important role in HBV-associated hepatocarcinogenesis. There are preliminary observations on the molecular mechanism of HCV-associated HCC, such as HCV core protein inducing HCC in transgenic mice and the NS3 genome transforming NIH 3T3 cells. Pathological distinction between preneoplastic and very early transformed lesions still depends on classical morphology, and a more genetically oriented differential diagnosis is required. Clinical diagnosis based on modern imaging has improved greatly, but is still unsatisfactory in the differential diagnosis of preneoplastic and early transformed nodules, because the vasculature changes that occur within the nodule are not accurately discerned with the current imaging. Use of sensitive des-gamma-carboxy prothrombin (PIVKA II) assay, and lectin affinity chromatography separating HCC specific subspecies of AFP molecules with a more practical biochemical technique will further improve diagnosis. Early diagnosis and transplantation are the best treatment at the moment, but transplantation is not widely available because of the donor shortage. Despite successful resection, the remnant cirrhotic liver frequently develops new HCC lesions, seriously curtailing long-term survival. All-out efforts should be directed to the prevention of HCC, through prevention of viral hepatitis, prevention of acute hepatitis from becoming chronic, prevention of chronic hepatitis from progressing to cirrhosis, and prevention of the cirrhotic liver from developing HCC (chemoprevention). At the moment, very few such studies exist.
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PMID:Hepatocellular carcinoma. 1072 7

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