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) is the major etiological agent of posttransfusion and community-acquired non-A, non-B hepatitis. It is an enveloped virus, grouped as a separate genus in the Flaviviridae family. The plus-stranded RNA genome encodes a polyprotein of about 3000 amino acids with the structural proteins core, E1 and E2 residing in the amino terminal quarter of the polyprotein and the nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B in the remainder. Maturation of the structural proteins is mediated by host cell signalases located in the lumen of the endoplasmic reticulum and cleaving behind stretches of hydrophobic amino acids. At least two virally encoded proteinases are responsible for processing of the NS proteins: a zinc-dependent metallo-proteinase encompassing the NS2 domain and the amino terminal portion of NS3, which is essential for cleavage at the NS2/3 junction; a serine-type proteinase located in the amino terminal domain of NS3 is required for cleavage at all sites downstream of the NS3 carboxy terminus. However, although the NS3 domain contains proteolytic activity, with the exception of the NS5A/5B junction cleavage only occurs in the presence of NS4A. This 54 amino acid long peptide can modulate the proteolytic activity of the enzyme in cis and in trans, probably by the formation of a stable NS3/NS4A complex. Modulation of the proteinase activity may be a way to regulate the expression and replication of the HCV genome.
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PMID:Processing pathways of the hepatitis C virus proteins. 883 84

Two temperature-sensitive (ts) mutants of mouse hepatitis virus strain A59, ts43 and ts379, have been described previously to be ts in infectivity but unaffected in RNA synthesis (M. J. M. Koolen, A. D. M. E. Osterhaus, G. van Steenis, M. C. Horzinek, and B. A. M. van der Zeijst, Virology 125:393-402, 1983). We present a detailed analysis of the protein synthesis of the mutant viruses at the permissive (31 degrees C) and nonpermissive (39.5 degrees C) temperatures. It was found that synthesis of the nucleocapsid protein N and the membrane protein M of both viruses was insensitive to temperature. However, the surface protein S of both viruses was retained in the endoplasmic reticulum at the nonpermissive temperature. This was shown first by analysis of endoglycosidase H-treated and immunoprecipitated labeled S proteins. The mature Golgi form of S was not present at the nonpermissive temperature for the ts viruses, in contrast to wild-type (wt) virus. Second, gradient purification of immunoprecipitated S after pulse-chase labeling showed that only wt virus S was oligomerized. We conclude that the lack of oligomerization causes the retention of the ts S proteins in the endoplasmic reticulum. As a result, ts virus particles that were devoid of S were produced at the nonpermissive temperature. This result could be confirmed by biochemical analysis of purified virus particles and by electron microscopy.
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PMID:Characterization of two temperature-sensitive mutants of coronavirus mouse hepatitis virus strain A59 with maturation defects in the spike protein. 899 12

Halothane causes an idiosyncratic hepatitis that is thought to result, in part, from immune reactions against one or more lumenal endoplasmic reticulum (ER) proteins that have been covalently modified by the trifluoroacetyl chloride metabolite of halothane. In this study, we have identified a 170 kDa protein target of halothane in the liver of rats. The 170 kDa protein was first detected when proteins in lysates of hepatocytes from halothane-treated rats were immunoprecipitated with antisera against several resident ER proteins. This 170 kDa protein was found to be associated with other protein targets of halothane, including protein disulfide isomerase, a protein disulfide isomerase isoform, a 59 kDa carboxylesterase, and 78 kDa glucose-regulated protein. Immunoblotting with antiserum directed against the trifluoroacetylated hapten indicated that the 170 kDa protein was trifluoroacetylated. Based upon its subcellular localization, molecular mass, N-terminal amino acid sequence, and antigenicity, the trifluoroacetylated 170 kDa protein was identified as UDP-glucose:glycoprotein glucosyltransferase (UGGT), a lumenal ER protein that is thought to have a role in the folding of N-linked glycoproteins. Moreover, treatment of rats with halothane caused a 44% decrease in the activity of liver microsomal UGGT, and at least 36% of the change in the activity of the enzyme could be due to a decrease in the level of the protein. The results suggest that the function of UGGT in folding of N-linked glycoproteins may be affected by other resident ER proteins or xenobiotics such as halothane.
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PMID:UDP-glucose:glycoprotein glucosyltransferase associates with endoplasmic reticulum chaperones and its activity is decreased in vivo by the inhalation anesthetic halothane. 907 3

Using transmission electron microscopy and biochemical analysis, the effect of cuban red propolis against hepatitis induced by 1,000 mg kg-1 of galactosamine in rats was studied. An ethanolic extract of propolis was prepared and it was given to rats at doses of 10, 50 and 100 mg kg-1, 30 min before the hepatotoxin. Propolis extract prevented hepatocytes alterations induced by galactosamine. It was mainly seen in rough endoplasmic reticulum, Golgi complex, nucleus and plasma membrane of hepatocytes. Propolis extract induced reversion of the increased activity of alanine aminotransferase and malondialdehyde concentration in the serum of rats treated with galactosamine. The probable role of antioxidant activity of propolis in the prevention of hepatitis is discussed in this paper.
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PMID:Effects of Cuban red propolis on galactosamine-induced hepatitis in rats. 914 8

Envelopment of the hepatitis B virus (HBV) nucleocapsid depends on the large envelope protein L, which is expressed as a transmembrane polypeptide at the endoplasmic reticulum membrane. Previous studies demonstrated that the cytosolic exposure of the N-terminal pre-S domain (174 amino acids) of L was required for virion formation. N-terminal truncations of L up to Arg 103 were tolerated. To map sites in the remaining C-terminal part of pre-S important for virion morphogenesis, a series of 11 L mutants with linker substitutions between Asn 98 and Pro 171 was generated. The mutants formed stable proteins and were secreted in transfected cell cultures, probably as components of subviral hepatitis B surface antigen particles. All four constructs with mutations between Asn 98 and Thr 125 were unable to complement in trans the block in virion formation of an L-negative HBV genome in cotransfected HuH7 cells. These mutants had a transdominant negative effect on virus yield in cotransfections with the wild-type HBV genome. In contrast, all seven mutants with substitutions downstream of Ser 124 were able to envelop the nucleocapsid and to secrete HBV. The sequence between Arg 103 and Ser 124 is highly conserved among different HBV isolates and also between HBV and the woodchuck hepatitis virus. Point mutations in this region introducing alanine residues at conserved positions blocked virion formation, in contrast to mutations at nonconserved residues. These results demonstrate that the pre-S sequence between Arg 103 and Ser 124 has an important function in HBV morphogenesis.
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PMID:A short linear sequence in the pre-S domain of the large hepatitis B virus envelope protein required for virion formation. 937 94

Patients with alpha1-antitrypsin (alpha1-AT) deficiency are at risk of developing early-onset panlobular basal emphysema, which has been attributed to uncontrolled proteolytic activity within the lung. Severe genetic deficiency of alpha1-AT is most commonly due to the Z mutation (342Glu--> Lys), which results in a block in alpha1-AT processing within the endoplasmic reticulum of hepatocytes. The retained alpha1-AT forms inclusions, which are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Our recent studies have shown that the accumulation of alpha1-AT is due to the Z mutation perturbing the structure of alpha1-AT to allow polymer formation, with a unique linkage between the reactive center loop of one alpha1-AT molecule and the A beta-pleated sheet of a second. The detection of loop-sheet polymers and other conformations of alpha1-AT in the lungs of patients with emphysema has been technically difficult. We show here that transverse urea-gradient-gel (TUG) electrophoresis and Western blot analysis may be used to characterize conformations of alpha1-AT in dilute samples of bronchoalveolar lavage fluid (BALF). This technique was used to demonstrate loop-sheet polymers in the lungs of patients with Z alpha1-AT-deficiency-related emphysema. Polymers were the predominant conformational form of alpha1-AT in BALF from the lungs of two of five Z homozygotes with emphysema, but were not detectable in any of 13 MM, MS, or MZ alpha1-AT controls. Because alpha1-AT loop-sheet polymers are inactive as proteinase inhibitors, this novel conformational transition will further reduce the levels of functional proteinase inhibitor in the lungs of the Z alpha1-AT homozygote, and so exacerbate tissue damage.
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PMID:Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema. 956 37

The genetic diversity of hepatitis G virus (HGV) was investigated. By using a RT-PCR procedure, 14% of either HBV (hepatitis B virus)- or HCV (hepatitis C virus)-positive Korean hepatitis patients were proved to be HGV positives. Nucleotide sequences in the E1 region of the eight isolates from Korean patients and the six previously reported isolates were compared. Nucleotide substitutions spread uniformly throughout the E1 region. Sequence homology among the Korean isolates was 84-99% and 88-99% at the nucleotide and amino acid sequences, respectively, whereas those from different geographic areas was slightly lower at both levels. At least two genotypes might exist among the Korean HGV isolates. Compared to the corresponding region of HCV, the E1 sequence from HGV is moderately conserved. In addition, as frameshift mutations were observed in most of the Korean isolates compared to the prototype HGV sequence, the Korean isolates might not use the translational initiation site of the prototype HGV for polyprotein translation. Because a putative signal sequence of E1 for entry into endoplasmic reticulum starts from the N-terminus of the polyprotein, and capsid-like peptides composed of basic amino acids could not be detected from the upstream region of E1, the core protein of HGV is absent, or at least not present, at the region next to 5'-UTR. Therefore, HGV could be clearly distinguished from other genera of Flaviviridae.
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PMID:Analysis of the envelope region of hepatitis G virus isolated from Korean patients. 957 42

A novel strategy for anti-viral intervention of hepatitis B virus (HBV) through the disruption of the proper folding and transport of the hepadnavirus glycoproteins is described. Laboratory reared woodchucks chronically infected with woodchuck hepatitis virus (WHV) were treated with N-nonyl-deoxynojirimycin (N-nonyl-DNJ), an inhibitor of the endoplasmic reticulum (ER) alpha-glucosidases. The woodchucks experienced significant dose dependent decreases in enveloped WHV, resulting in undetectable amounts in some cases. The reduction in viremia correlated with the levels of hyperglucosylated glycan in the serum of treated animals. This correlation supports the mechanism of action associated with the drug and highlights the extreme sensitivity of the virus to this type of glycan inhibitor. At N-nonyl-DNJ concentrations that prevented WHV secretion, the glycosylation of most serum glycoproteins appeared unaffected, suggesting great selectivity for this class of therapeutics. Indeed, this may account for the low toxicity of the compound over the treatment period. We provide the first evidence that glucosidase inhibitors can be used in vivo to alter specific steps in the N-linked glycosylation pathway and that this inhibition has anti-viral effects.
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PMID:Treatment of chronic hepadnavirus infection in a woodchuck animal model with an inhibitor of protein folding and trafficking. 958 37

A 33 year-old Thai woman was diagnosed with scrub typhus infection according to clinical symptoms, eschar lesions compatible with the disease, and specific antibody to Rickettsia tsutsugamushi detected by indirect immunoperoxidase. Percutaneous transhepatic needle biopsies were taken before and 7 days after treatment with tetracycline to study the pathology of the liver. The liver tissue was evaluated by light microscopy, using H & E and Pinkerton's stains, and by transmission electron microscopy (TEM). Before treatment it showed reactive hepatitis. Rickettsia organisms within the hepatocytes and sinusoids detected by Pinkerton's stain appeared as tiny bright-red organisms. By TEM, the rod-shaped double-membrane Rickettsiae appeared intact in the cytoplasm of Kupffer's cells and hepatocytes. After tetracycline treatment, moderate levels of acidophilic and ballooning liver cells were observed. The degree of cytoplasmic organelle damage varied, including fatty metamorphosis, depletion of glycogen granules, loss of the mitochondrial cristae, dilatation of endoplasmic reticulum and cytoplasmic vacuolation. Rickettsia organisms cannot be visualized by Pinkerton's stain but were detected by TEM, in markedly vacuolated hepatocytes, in congested sinusoids and in Kupffer's cells. Intranuclear Rickettsia were discovered in the endothelial nucleus, showing various degrees of injury. Some were mildly degenerated, while others exhibited clumping of nucleoprotein at the cytoplasm periphery and large vacuolation centrally. Many indented organisms were found, and binary fission during Rickettsiae multiplication was always affected. Electron-microscopic examination of hepatic injury associated with scrub typhus is rare. This is the first ultrastructural localization of Rickettsiae in the infected human liver.
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PMID:Electron-microscopic examination of Rickettsia tsutsugamushi-infected human liver. 959 64

The mouse hepatitis virus (MHV) membrane (M) protein contains only O-linked oligosaccharides. We have used this protein as a model to study the structural requirements for O-glycosylation. We show that MHV M is modified by the addition of a single oligosaccharide side chain at the cluster of 4 hydroxylamino acids present at its extreme amino terminus and identified Thr at position 5 as the functional acceptor site. The hydroxylamino acid cluster, which is quite conserved among O-glycosylated coronavirus M proteins, is not in itself sufficient for O-glycosylation. Downstream amino acids are required to introduce a functional O-glycosylation site into a foreign protein. In a mutagenic analysis O-glycosylation was found to be sensitive to some particular changes but no unique sequence motif for O-glycosylation could be identified. Expression of mutant M proteins in cells revealed that substitution of any 1 residue was tolerated, conceivably due to the occurrence of multiple UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferases (GalNAc transferases). Indeed, MHV M served as a substrate for GalNac-T1, -T2, and -T3, as was demonstrated using an in situ glycosylation assay based on the co-expression of endoplasmic reticulum-retained forms of the GalNAc transferases with endoplasmic reticulum-resident MHV M mutants. The GalNAc transferases were found to have largely overlapping, but distinct substrate specificities. The requirement for a threonine as acceptor rather than a serine residue and the requirement for a proline residue three positions downstream of the acceptor site were found to be distinctive features.
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PMID:Structural requirements for O-glycosylation of the mouse hepatitis virus membrane protein. 979 8


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