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)

We have used several complementary approaches to investigate the minimal contiguous sequence required for the in vitro self cleavage reaction performed by Neurospora VS RNA. Deletion analysis and site-directed mutagenesis revealed that only a single nucleotide is required upstream of the self-cleavage site, and that the identity of this nucleotide is not critical. This distinguishes VS RNA from all currently known ribozymes except hepatitis delta virus RNA. The shortest contiguous sequence capable of cleavage contains 153 nt downstream of the cleavage site. Linker insertion mutagenesis suggests that much of this downstream sequence is important for self-cleavage. Comparative sequence analysis of the VS plasmid from six natural isolates supports the importance in vivo of the minimal region determined by in vitro methods. Also, phylogenetic analysis raises the possibility of a recent horizontal transfer of the VS plasmid from Neurospora intermedia to Neurospora sitophila.
J Mol Biol 1993 Jul 20
PMID:Nucleotide sequence requirements for self-cleavage of Neurospora VS RNA. 834 16

Woodchucks infected with woodchuck hepatitis virus (WHV) and ground squirrels infected with ground squirrel hepatitis virus (GSHV) both develop hepatocellular carcinoma (HCC), but WHV-associated tumors arise more frequently and much earlier in life. These differences are preserved when the oncogenic potentials of the two viruses are examined in the same host (woodchucks). We examined RNA and genomic DNA from tumors arising from WHV- and GSHV-infected woodchucks to determine whether these viruses use the same oncogenic pathway. N-myc RNA was not expressed in normal liver but was expressed in 10 of 13 WHV-associated HCCs examined. Southern blot analysis showed that 7 of 17 WHV-induced tumors (41%) contained rearrangements at N-myc loci due to viral genomic integration. Six of these seven inserts affected N-myc2, and most of these were at the 5' end of the gene. In contrast, only two of seven GSHV-induced woodchuck HCCs expressed N-myc RNA, and only 1 of the 16 tumors (6%) contained a rearranged N-myc allele. The GSHV-associated HCCs all contained numerous viral insertions, so the low frequency of integration into N-myc loci by GSHV was not due to a general block to integration. Four of sixteen GSHV-induced tumors harbored amplified c-myc alleles, and five of seven GSHV tumors tested contained elevated c-myc RNA levels. By contrast, enhanced c-myc RNA levels were observed in only 2 of 13 WHV-induced HCC. We conclude that N-myc overexpression is a regular feature of WHV- but not GSHV-associated hepatocarcinogenesis in a common host. In contrast, c-myc transcriptional deregulation is rarely encountered in WHV-induced HCC but is frequent in GSHV-induced HCC.
Mol Cell Biol 1993 Jan
PMID:Differential activation of myc gene family members in hepatic carcinogenesis by closely related hepatitis B viruses. 838 Feb 30

The first membrane-spanning domain (m1) of the model cis Golgi protein M (formerly called E1) from the avian coronavirus infectious bronchitis virus is required for targeting to the Golgi complex. When inserted in place of the membrane-spanning domain of a plasma membrane protein (vesicular stomatitis virus G protein), the chimeric protein ("Gm1") is retained in the Golgi complex of transfected cells. To determine the precise features of the m1 domain responsible for Golgi targeting, we produced single amino acid substitutions in m1 and analyzed their effects on localization of Gm1. Expression at the plasma membrane was used as the criterion for loss of Golgi retention. Rates of oligosaccharide processing were used as a measure of rate and efficiency of transport through the Golgi complex. We identified four uncharged polar residues that are critical for Golgi retention of Gm1 (Asn465, Thr469, Thr476, and Gln480). These residues line one face of a predicted alpha-helix. Interestingly, when the m1 domain of the homologous M protein from mouse hepatitis virus is inserted into the G protein reporter, the chimeric protein is not efficiently retained in the Golgi complex, but transported to the cell surface. Although it possesses three of the four residues we identified as important in the avian m1 sequence, other residues in the membrane-spanning domain from the mouse protein must prevent efficient recognition of the polar face within the lipid bilayer of the cis Golgi.
Mol Biol Cell 1993 Jul
PMID:Retention of a cis Golgi protein requires polar residues on one face of a predicted alpha-helix in the transmembrane domain. 840 Apr 55

Substitution rates were estimated for the coding and noncoding regions of the hepatitis delta virus (HDV). The estimated rates of synonymous substitution in HDV were lower than the rates of substitution at non-synonymous sites and in the noncoding region. HDV has lower synonymous substitution rates than the hepatitis C virus, though both are RNA viruses. The relatively low rate of synonymous substitution in HDV may be due to a strong preference of G and C nucleotides at third codon positions. Variation in substitution rate among HDV lineages may be correlated with the clinical development of the HDV-induced hepatitis. The phylogenetic tree inferred for 24 HDV strains reveals similarities between lineages isolated from the same geographic region.
J Mol Evol 1995 Dec
PMID:Substitution rates in hepatitis delta virus. 858 17

Human hepatitis delta virus (HDV) poses a health threat in populations where chronic hepatitis B is endemic. It is a single-stranded RNA virus of 1700 nucleotides and both genomic and antigenomic sequences contain ribozymes which are important for viral replication. Using ribozyme constructs we show that several classes of antibiotics inhibit the self-cleavage reaction of the HDV ribozyme. Antibiotics of the aminoglycoside, peptide and tetracycline classes all inhibit HDV cleavage in vitro at micromolar concentrations. Neomycin (an aminoglycoside) inhibits HDV self-cleavage with a Ki value of 28 (+/- 10) microM. Neomycin inhibition can be reversed by increasing magnesium ion concentration in a competitive manner. Lead acetate cleaves positions G76, A42 and G28, which surround the ribozyme cleavage site. Both Mg2+ and neomycin prevent lead cleavage. Footprinting experiments using base-specific chemical probes revealed enhanced modifications of a set of bases by neomycin, overlapping with the above mentioned lead cleavages. These observations may indicate that neomycin directly displaces divalent metal ions essential for catalysis.
J Mol Biol 1996 Jun 28
PMID:Inhibition of the self-cleavage reaction of the human hepatitis delta virus ribozyme by antibiotics. 868 94

Tienilic acid-induced hepatitis is characterized by the presence of anti-liver and -kidney microsomal (anti-LKM2) autoantibodies in patient sera. Cytochrome P4502C9(CYP2C9), involved in the metabolism of tienilic acid, was shown to be a target for tienilic acid-reactive metabolites and for autoantibodies. To further investigate the relationship between drug metabolism and the pathogenesis of this drug-induced autoimmune disease, the specificity of anti-LKM2 autoantibodies toward CYP2C9 was first determined, and the antigenic sites on CYP2C9 were localized. By constructing several deletion mutants derived from CYP2C9 cDNA and by probing the corresponding proteins with different anti-LKM2 sera, we defined three regions (amino acids 314-322, 345-356, and 439-455); they interacted to form a major conformational autoantibody binding site. This binding site was immunoreactive with 100% of sera and allowed removal of the entire reactivity of the sera tested by immunoblotting. Epitope mapping studies have been performed for CYP2D6, CYP17, CYP21A2, and, recently, CYP3A. Those data were compared with the results obtained in the current study with CYP2C9 in an attempt to elucidate one of the mechanisms by which CYP becomes immunogenic.
Mol Pharmacol 1996 Aug
PMID:Tienilic acid-induced autoimmune hepatitis: anti-liver and-kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. 870 Jan 40

Although recurrence of hepatitis C virus (HCV) in orthotopic liver transplant (OLT) patients is frequent, the relationship between HCV recurrence and graft pathology, particularly in patients who also have a history of hepatitis B virus (HBV), is unclear. The recurrence of HCV after OLT was determined by reverse transcriptase-nested polymerase chain reaction (RT-PCR) in the sera and livers of 41 patients with OLT, 32 of whom underwent transplants for HCV or HBV-related disease. Results were compared with liver function tests, liver histology (including HBV immunohistochemistry), and antibody status. HCV PCR was more frequently positive in OLT patients with a history of HCV only (59%) than in those with a history of both HCV and HBV (41%) or no history of viral infection (2%). Recurrent HCV (60% overall) was associated with mild elevation of liver function tests and mild to moderate hepatitis. In patients who underwent transplants for both HCV and HBV disease, hepatitis on biopsy was more frequently associated with recurrent HBV than with recurrent HCV. We conclude that graft reinfection with HCV, which is frequent in OLT patients with or without HBV recurrence, is usually associated with only mild to moderate hepatitic changes compatible with graft survival.
Diagn Mol Pathol 1996 Jun
PMID:Hepatitis C virus reinfection in orthotopic liver transplant patients with or without concomitant hepatitis B infection. 872 94

An experimental acute liver injury model can be produced by the injection of bacterial lipopolysaccharide (LPS) into Propionibacterium acnes (P. acnes) pretreated rats. The massive liver cell necrosis is estimated by elevation of serum transaminase activities. In this study, we produced this necrosis in an in vitro model by using primary co-cultured rat liver cells. A novel method for the preparation of spheroids consisting of P. acnes pretreated parenchymal and nonparenchymal liver cells has been successfully developed quickly by the rotary culture system within 24 hr although it takes 7 days to form the spheroid using a collagen-conjugated thermo-responsive polymer such as a cell substratum. Clear elevations of transaminase activities, TNF-alpha and CINC-1/gro/KC leaked from these spheroids into the medium caused by the exposure of 10 microgram/ml LPS for 48 hr were observed. These results suggest that this rotary co-culture system of rat liver cells is a useful model as an alternative to animal tests for fulminant hepatitis.
Res Commun Mol Pathol Pharmacol 1995 Dec
PMID:Rapid formation of multicellular spheroids composed of Propionibacterium acnes pretreated adult rat liver cells by rotary culture and their immunological properties. 874 84

The LEC rat is a mutant strain displaying hereditary hepatitis, and shows abnormal accumulation of copper (Cu) similar to that occurring in Wilson's disease. We prepared a multicellular spheroid composed of LEC rat liver cells to investigate the mechanism for abnormal accumulation of Cu. These multicellular spheroids were prepared by detaching the monolayer on the collagen-conjugated thermo-responsive polymer coated culture dish at a temperature below the critical solution temperature and culturing on the non-adhesive substratum. Long-term cultured spheroids of LEC rat liver cells as well as SD rat liver cells were attempted. Non-parenchymal cells obtained by collagenase perfusion from the LEC liver were fewer than those from the SD liver. Cells from the LEC rat, over 11 weeks of age, did not form a cell sheet; however, a mixture of parenchymal cells from LEC rats over aged 11 weeks and non-parenchymal cells from SD rats of any age yielded intact spheroids. We examined the toxicity, the accumulation and distribution of Cu in spheroids. The accumulation of Cu in LEC spheroids was higher than that in SD spheroids. Results suggest that spheroids consisting of LEC liver cells are useful as an alternative model to in vivo tests to investigate the mechanism for abnormal accumulation of Cu in liver.
Res Commun Mol Pathol Pharmacol 1995 Nov
PMID:Abnormal hepatic copper accumulation of spheroid composed of liver cells from LEC rats in vitro. 874 89

Recent studies have shown that cytochrome P450 2E1 (CYP2E1) is a major catalyst of formation of trifluoroacetylated proteins, which have been implicated as target antigens in the mechanism of halothane hepatitis. In the present investigation, trifluoroacetylated CYP2E1 was detected immunochemically in livers of rats treated with halothane. Furthermore, high levels of autoantibodies that recognized purified rat CYP2E1 but not purified rat CYP3A were detected by enzyme-linked immunosorbent assay in 14 of 20 (70%) sera from patients with halothane hepatitis. Only very low levels of such antibodies were detected in sera from healthy controls, from patients anesthetized with halothane without developing hepatitis, or from patients with other liver diseases. The intracellular distribution of CF3CO-adducts was studied in highly differentiated FGC4 rat hepatoma cell cultures. High levels of adducts were found after 22-hr culture in the presence of halothane, and their generation was dependent on the expression of CYP2E1. Adducts were predominantly located in the endoplasmic reticulum but also, to a minor extent, on the cell surface, as detected by immunofluorescence. A very similar distribution was found for CYP2E1 in FGC4 cells, and immunoprecipitation experiments performed in cultures of FGC4-related Fao hepatoma cells suggest that surface immunoreactivity originates from a small fraction of intact CYP2E1 apoprotein. Human CYP2E1, expressed in V79 cells after cDNA transfection, was also detected to a minor extent in the plasma membrane, whereas no immunofluorescence was evident in parental V79 cells. It is suggested that immune responses to cell surface CYP2E1 could be involved in the pathogenesis of halothane hepatitis.
Mol Pharmacol 1996 Sep
PMID:Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis. 879 96


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