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)

A complete DNA copy of the genome of a Jeryl Lynn strain of mumps virus (15,384 nucleotides) was assembled from cDNA fragments such that an exact antigenome RNA could be generated following transcription by T7 RNA polymerase and cleavage by hepatitis delta virus ribozyme. The plasmid containing the genome sequence, together with support plasmids which express mumps virus NP, P, and L proteins under control of the T7 RNA polymerase promoter, were transfected into A549 cells previously infected with recombinant vaccinia virus (MVA-T7) that expressed T7 RNA polymerase. Rescue of infectious virus from the genome cDNA was demonstrated by amplification of mumps virus from transfected-cell cultures and by subsequent consensus sequencing of reverse transcription-PCR products generated from infected-cell RNA to verify the presence of specific nucleotide tags introduced into the genome cDNA clone. The only coding change (position 8502, A to G) in the cDNA clone relative to the consensus sequence of the Jeryl Lynn plaque isolate from which it was derived, resulting in a lysine-to-arginine substitution at amino acid 22 of the L protein, did not prevent rescue of mumps virus, even though an amino acid alignment for the L proteins of paramyxoviruses indicates that lysine is highly conserved at that position. This system may provide the basis of a safe and effective virus vector for the in vivo expression of immunologically and biologically active proteins, peptides, and RNAs.
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PMID:Rescue of mumps virus from cDNA. 1077 22

Genetic susceptibility to type 1 autoimmune hepatitis in white northern Europeans is related to female sex, HLA alleles encoding the six amino acid sequence LLEQKR at positions 67-72 of the DRB1 polypeptide, and CTLA-4 gene polymorphism. The principal HLA alleles associated with type 1 autoimmune hepatitis in Britain and North America are DRB1*0301 and DRB1*0401. In this model of susceptibility, lysine at position 71 of the expressed DR molecule is the critical amino acid. In Japan, Argentina and Mexico, susceptibility is linked to DRB1*0405 and DRB1*0404. These two alleles encode arginine at position 71 rather than lysine, but they share the motif LLEQ-R with DRB1*0401 and DRB1*0301. Thus, K or R at position 71 in the context of LLEQ-R may be critical for susceptibility. This "shared motif" or "epitope" may optimize T-cell recognition of autoantigen, and other alleles that encode lysine at DRbeta71 may also affect susceptibility and outcome, possibly by increasing the density of lysine or arginine 71 molecules on the surface of antigen-presenting cells. Since the DRB1*0301 allele is part of the extended ancestral 8.1 haplotype, it carries with it additional risk factors for autoimmunity, including TNFA*2 and C4A*Q0. Type 1 autoimmune hepatitis is a polygenic disorder and other yet undefined polymorphic genes may be non-specific immunoregulators. These additional MHC encoded genes and other non-MHC encoded genes may be important determinants of disease susceptibility and severity in type 1 autoimmune hepatitis.
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PMID:Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. 1080 21

Five patients of cholestatic jaundice and multiple hyperaminoacidemias were uncovered during neonatal mass screening for homocystinuria. All five patients had increased plasma levels of methionine, citrulline, tyrosine, threonine, phenylalanine, lysine and arginine. Compared with those of age-matched cholestatic disease controls, idiopathic neonatal hepatitis (n=9) and biliary atresia (n=14), plasma levels of three amino acids, citrulline, methionine, and threonine, were significantly greater, respectively (P<0.01). Liver biopsies examined in four patients uniformly showed diffuse hepatic fatty liver with micro- and macrovesicular droplets without giant cell transformation. Administration of fat-soluble vitamins and formula milk containing middle-chain triglyceride resulted in normalization of amino acid profiles by 6 weeks after the treatment. All liver function tests normalized by 17 months of age.
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PMID:An undescribed subset of neonatal intrahepatic cholestasis associated with multiple hyperaminoacidemia. 1147 Jun 24

The asialoglycoprotein receptor (ASGP-R) on mammalian hepatocytes provides a unique means for the development of liver-specific carriers, such as liposomes, recombinant lipoproteins, and polymers for drug or gene delivery to the liver, especially to hepatocytes. The abundant receptors on the cells specifically recognize ligands with terminal galactose or N-acetylgalactosamine residues, and endocytose the ligands for an intracellular degradation process. The use of its natural ligand, i.e. asialofetuin, or synthetic ligands with galactosylated or lactosylated residues, such as galactosylated cholesterol, glycolipids, or galactosylated polymers has achieved significant targeting efficacy to the liver. There are several examples of successful targeted therapy for acute liver injury with asialofetuin-labeled and vitamin E-associated liposomes or with a caspase inhibitor loaded in sugar-carrying polymer particles, as well as for the delivery of a new antiviral agent, 9-(2-phosphonylmethoxyethyl)adenine. Liposome-mediated gene delivery to the liver is more difficult than to other organs, such as to lungs. It is still in its infancy due to difficulties in solving general issues, such as the circulatory stability of liposome-DNA complexes, and lysosomal or endosomal degradation of plasmid DNA. In spite of these existing concerns, several new approaches offer some reason for optimism, for example; intravenous injection of asialofetuin- or galactosylated cholesterol-labeled cationic liposomes has led to high transgene expression in the liver. In addition, specific antisense oligonucleotides against woodchuck hepatitis viruses incorporated into sialoorosomucoid-poly-L-lysine significantly inhibited viral replication in the liver. Finally, galactosylated polymers are promising for gene delivery, but require further studies to verify their potential applications.
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PMID:Targeting hepatocytes for drug and gene delivery: emerging novel approaches and applications. 1186 Dec 24

Our goal was to review the hypotheses in evolution that promise to elucidate the genetic bases of autoimmune hepatitis. DRB1*0301 and DRB1*0401 are the principal risk factors in Britain and the United States. Other susceptibility alleles in different ethnic groups commonly share the same or a similar motif at the critical DRbeta71 position of the HLA class II molecule. Disease severity may be determined by the number of alleles encoding lysine at the DRbeta1 position, the density of dimers presenting antigen, and the avidity of T-cell receptors for the displayed antigen. Concurrence on the same or different chromosomes of other nonspecific autoimmune promoters may also contribute. A negatively charged residue at the P4 position of antigenic peptides is preferred for binding to the disease-susceptibility alleles, and this complex may be recognized by promiscuous T cells. We conclude that autoimmune hepatitis is a model by which to study the genetic bases of autoimmunity.
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PMID:Genetic bases of autoimmune hepatitis. 1239 84

Current hypotheses suggest that autoimmune hepatitis (AIH) is triggered by an environmental factor in a genetically susceptible host. Multiple genes may interact to produce a "permissive gene pool" that determines both disease risk and phenotype. Studies of type 1 AIH have focused on the major histocompatibility complex (MHC), mapping susceptibility to the DRB1 region. Three different molecular models have been proposed based on histidine at DRbeta13, lysine at DRbeta71, and valine at DRbeta86. Although the lysine-71 model has been adapted to explain data from several other studies, the DRbeta13 and DRbeta86 models are exclusive to their founder populations. It is possible that all three models apply and that the different associations reflect the "molecular footprint" of the common environmental triggers in the different study populations. Studies outside the MHC have identified the CTLA4 A+49G, G allele as a possible second risk allele. There are many neutral polymorphisms in the genome, and further studies are currently needed to identify other disease alleles in type 1 AIH.
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PMID:Genetics in autoimmune hepatitis. 1244 7

The hepatotropic viruses, measles, and herpesviruses as well as different drugs were repeatedly shown to act presumably as a trigger in patients with autoimmune hepatitis (AI-H). On the other hand, it is known that viral infections stimulate interferon production, which inactivates the cytochrome P-450 enzymes involved in the metabolism of several endogenous substances and exogenous environmental agents. Moreover, it was reported that several cytokines, including interferons, as well as transforming growth factor beta1 and human hepatocyte growth factor, which are abundantly produced and released in the body during infections, also downregulated expression of major cytochrome P-450 and/or other biotransformation enzymes. It seems that all these factors, in addition to individual immune response and the nature and amount of the neoantigen(s) produced, impair the equilibrium of bioactivation and detoxication pathways, thus leading to the development of AI-H in a genetically predisposed person continually exposed to harmful environmental factor(s). Possible increased/decreased density of lysine residues at position D-related human leukocyte antigen locus (DR)beta71 of the antigen-binding groove may affect the eventual steroid-sparing effect of this critical amino acid at the cellular level. In addition, some food additives, such as monosodium glutamate (MSG) and/or aspartame regularly consumed in excessive amounts, may eventually disturb the delicate balance between a positively charged amino acid residue at position DRbeta71 (lysine or arginine) and a negatively charged amino acid residue at position P4 on the antigenic peptide (glutamic acid or aspartic acid). This may favor formation of a salt bridge between these amino acid residues within the hypervariable region 3 on the alpha-helix of the DRbeta polypeptide and facilitate autoantigen presentation and CD4 T-helper cell activation. MSG and aspartate may also depress serum concentrations of growth hormone, which downregulate the activity of several cytochrome P-450 hepatic and other drug-metabolizing enzymes, thus increasing sensitivity to some environmental agents and possibly influencing efficacy of treatment regimens and final outcome of patients with type 1 AI-H.
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PMID:Possible pathomechanism of autoimmune hepatitis. 1252 21

Utilization of proton transfer in catalysis, which is well known in the mechanisms of protein enzymes, has been described only relatively recently for RNA enzymes. In this article, we present a current understanding of proton transfer by nucleic acids. Rate enhancement and specificity conferred by general acid-base catalysis are discussed. We also present possibilities for electrostatic catalysis from general acids and bases as well as cationic base pairs. The microenvironments of a large RNA provide the possibility of histidine-like pK(a)s for proton transfer, as well as lysine- and arginine-like pK(a)s for electrostatic catalysis. Discussion on proton transfer focuses on the hepatitis delta virus (HDV) and hairpin ribozymes, with select examples drawn from the protein literature. Discussion on electrostatic catalysis also draws on these two ribozymes, and a postulate for electrostatic catalysis by a cationic base pair in the mechanism of peptidyl transfer in the ribosome is presented. We also provide a perspective on possibilities for phosphoryl transfer mechanisms involving phosphorane intermediates and unusual tautomeric forms of the bases. Lastly, a distinction is made between ground state and "transition state" pK(a)s. We favor a model in which changes in pH lead to changes in the distribution of reactive and nonreactive ionizations of the ribozyme molecules in the ground state, and therefore suggest that "pK(a) changes in the transition state" do not provide an acceptable explanation for observed pH-rate profiles.
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PMID:Catalytic roles for proton transfer and protonation in ribozymes. 1469 43

Procarboxypeptidase R (proCPR), also known as thrombin-activatable fibrinolysis inhibitor (TAFI), is present in plasma and can be activated to carboxypeptidase R (CPR) by trypsin-like enzymes such as thrombin and plasmin. CPR has the carboxypeptidase B-like activity that can inactivate the inflammatory peptides such as C5a by removing the C-terminal arginine and can interfere with fibrinolysis by removing C-terminal lysine residue of fibrin. In the present study, we conducted to produce monoclonal antibodies (mAbs) by using spleen cells from proCPR-deficient mice immunized by partially purified mouse proCPR. The mAbs obtained were IgM isotype and reacted with proCPR and interfered with activation of proCPR to CPR by thrombin-thrombomodulin complex. Some BALB/c mice implanted with the hybridoma died in 7 days, and intravenous injection of the mAb to BALB/c mice induced transient elevation of GOT and GPT in plasma although injection to the deficient mice did not. Furthermore, the histological features showed the focally lesions in liver tissue of BALB/c mice injected with the mAb. Since liver is the major site of proCPR synthesis, IgM mAb to proCPR should have induced local inflammation at the side resulting in induction of hepatitis.
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PMID:Hepatitis induced by an IgM monoclonal antibody against procarboxypeptidase R. 1584 Sep 63

Liver-kidney microsomal antibodies type 1 (LKM-1) are a diagnostic marker for autoimmune hepatitis type II (AIH-II). However, LKM autoantibodies are also detected in a small percentage of patients with chronic hepatitis C. The autoantigen to anti-LKM-1 has been identified to be CYP2D6. To identify the specific antigenic site of CYP2D6 for LKM-1 serum, we established an ELISA with peptides spanning the entire sequence of CYP2D6. Human CYP2D6 containing histidine tag was expressed in Escherichia coli. Purified CYP2D6 was digested by lysyl endopeptidase. The linker including the histidine tag has a lysine residue in its C-terminal and can be removed by digestion. Digested peptides were separated by reversed-phase HPLC and coated on ELISA plates chemically with glutaraldehyde. The immunoreactivity of two LKM-1-positive sera (HCV-negative) and five HCV-positive sera from Japanese patients was investigated with the plates. These sera recognized peptides 1-146, 181-214, 246-281, 284-391, and 412-429. The peptide 1-146 was recognized by LKM-1-positive sera but not HCV-positive sera and is a new epitope found in this study. Seven short peptides spanning peptide 1-146 were synthesized and ELISAs were conducted with these peptides. However, two sera recognized none of these peptides, suggesting that two LKM-1-positive sera recognize the conformational immunogenic site of peptide 1-146.
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PMID:A new epitope of CYP2D6 recognized by liver kidney microsomal autoantibody from japanese patients with autoimmune hepatitis. 1632 57


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