Gene/Protein Disease Symptom Drug Enzyme Compound
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Liver cirrhosis, an end-result of a wide variety of the liver diseases, is a world wide health problem. Because of its unique organ system, i.e., portal blood supply, bile formation and enterohepatic circulation, drug metabolism system, and sinusoidal lining cells such as Kupffer, endothelial and stellate cells, the liver is a target of a variety of hepatotoxic insults. Current data suggest that hepatocyte apoptosis is an essential feature contributing to liver injury in a wide range of acute and chronic liver diseases. With an improved understanding of the pathophysiological role of apoptosis in liver diseases, we are now entering an era where regulation of liver cell apoptosis is becoming a therapeutic possibility. Inhibition of hepatocyte apoptosis using a variety of different strategies may be therapeutically beneficial in liver injuries, such as alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), viral hepatitis, and cholestatic liver diseases. Considering the link between hepatocyte apoptosis and liver fibrosis, inhibition of hepatocyte apoptosis may also be an anti-fibrotic therapeutic strategy. Moreover, selective induction of apoptosis of activated stellate cells would be a unique approach to induce the resolution the phase of liver fibrosis. These concepts merit further clinical and basic investigation.
Curr Mol Med 2003 Sep
PMID:Mechanisms of liver injury: an overview. 1452 80

The TNFalpha receptor super-family consists of several members sharing a sequence homology in a unique function domain, the death domain, which is located in the intracellular portion of the receptor. These so-called death receptors, including Fas, TNF-R1 and TRAIL-R1/TRAIL-R2, are expressed on hepatocytes. When stimulated by their ligands, FasL, TNFalpha or TRAIL, respectively, the death receptors can activate multiple death domain-initiated apoptosis programs, including both extrinsic and intrinsic pathways. A cascade of caspases is activated, which cleave proteins important for the cell structure and function. Activation of the intrinsic pathway also leads to mitochondrial release of several apoptotic proteins and mitochondrial dysfunction, which kill the cell through both caspase-dependent and caspase-independent mechanisms. Death receptor-induced hepatocyte apoptosis contributes to the development of a number of liver diseases, including viral hepatitis, inflammatory hepatitis, Wilson's disease, alcoholic liver disease, endotoxiemia-induced liver failure and ischemia/reperfusion-induced liver damage. This article comprehensively reviews the mechanisms of induction and regulation of death receptor-initiated apoptosis in hepatocytes, examines how these molecular events affect our understanding of the pathogenesis of these diseases and further discusses the potential therapeutic application of the knowledge. We hope we can provide a cohesive and integrated perspective on the many aspects of these complicated processes.
Curr Mol Med 2003 Sep
PMID:Death receptor activation-induced hepatocyte apoptosis and liver injury. 1452 81

Recently CC chemokine receptor 5 (CCR5) related immune mechanisms and a functional mutation of the CCR5 gene have been implicated in hepatitis C virus (HCV) infection in a cohort of predominantly hemophiliac patients. The present study investigated the frequency and clinical consequences of the CCR5 Delta32 mutation in two genetically homogeneous populations of HCV infected patients with a different risk profile for infection. Genomic DNA samples from 333 German patients with chronic HCV infection were screened by PCR for the presence of the CCR5 Delta32 polymorphism. In-hospital patients admitted for other diseases than viral hepatitis but with a comparable risk for HCV exposure were used as control population ( n=125). Allele frequencies of CCR5 Delta32 polymorphism did not differ significantly between the two groups (7.6% and 9.5%, respectively) and control subjects (10.4%), and did not deviate from Hardy-Weinberg equilibrium in any group. Furthermore, there were no major differences between patients with respect to HCV genotypes, viral loads, liver enzymes, or fibrosis scores in relation to the presence or absence of the heterozygous CCR5 Delta32 mutation. Differences in inflammatory scores in liver biopsy samples and response to antiviral therapy in CCR5 Delta32 heterozygotes in one cohort could neither be reproduced in the other group of patients nor when both cohorts were pooled. These results argue against a strong effect of the CCR5 Delta32 deletion regarding these phenotypes. In conclusion, we found no increased frequency of the CCR5 Delta32 polymorphism in two independent cohorts of patients with HCV infection but without hemophilia as the main risk factor for infection. As the major difference to investigations demonstrating an association between CCR5 Delta32 and HCV infection is the selection of cases and controls, our study emphasizes the importance of epidemiological criteria for association studies of HCV infection.
J Mol Med (Berl) 2004 Jan
PMID:CC chemokine receptor 5 delta32 polymorphism in two independent cohorts of hepatitis C virus infected patients without hemophilia. 1467 28

Hepatitis E virus (HEV) infection results in hepatitis E, an acute and self-limited disease. The virus is transmitted in a faecal-oral manner and is a major cause of viral hepatitis in much of the developing world, where it causes rampant sporadic infections and large epidemics. A curious feature of hepatitis E is the unusually high rates of mortality that are observed in pregnant women, in whom the disease is exacerbated by the development of fulminant liver disease. In the absence of viable in vitro propagation systems, several geographical isolates of HEV have been maintained in vivo in nonhuman primates and, subsequently,the viral genome has been cloned and sequenced. HEV has been classified provisionally into a separate family known as the HEV-like viruses, which has at least four recognised genotypes, but has only a single serotype. The viral genome is a positive-stranded (+)RNA of ~7.5 kb and encodes at least three proteins. Open reading frame 1 ( ORF1) encodes the viral nonstructural polyprotein, which has domains that are homologous to some of the replication and processing enzymes found in other +RNA viruses. The HEV protein itself remains poorly characterised. The protein encoded by open reading frame 2( ORF2) is the major HEV capsid protein, and the protein encoded by open reading frame 3 ( ORF3) appears to be involved in virus-host interactions. Several questions related to the biology, epidemiology and pathogenesis of HEV remain unanswered; the progress of a few of these is reviewed here.
Expert Rev Mol Med 1999 Dec 06
PMID:Molecular biology and pathogenesis of hepatitis E virus. 1498 55

Members of the ADAR (adenosine deaminases acting on RNA) gene family are involved in one type of RNA editing that converts adenosine residues to inosine. The A-to-I editing of serotonin receptor subtype 2C (5-HT(2C)R) mRNA leads to replacement of three amino acid residues located within the intracellular loop II domain, resulting in dramatic alterations in G-protein coupling functions of the receptor. It has been speculated that RNA editing may play a role in several pharmacological and behavioral processes where the serotonergic plasticity is mediated through 5-HT(2C)R. Interferon-alpha (IFN-alpha) often causes severe depression in patients treated for chronic viral hepatitis and certain malignancies. In this study, we examined the effects of IFN-alpha on RNA editing in human glioblastoma cell lines, which express 5-HT(2C)R mRNAs. ADAR1 expression and the pattern of the 5-HT(2C)R mRNA editing rapidly changed in response to IFN-alpha, leading to the dominant expression of the 5-HT(2C)R-VSI isoform predicted to have reduced G-protein coupling functions. Our results support the hypothesis that 5-HT(2C)R mRNA editing has causative relevance in the pathophysiology of depression associated with cytokine therapy.
Brain Res Mol Brain Res 2004 Apr 29
PMID:Altered RNA editing of serotonin 5-HT2C receptor induced by interferon: implications for depression associated with cytokine therapy. 1509 87

The human xenobiotic-metabolizing enzyme cytochrome P450, CYP2A6, catalyzes the bioactivation of a number of carcinogens and drugs and is overexpressed in cases of liver diseases, such as cirrhosis, viral hepatitis, and parasitic infestation, and in certain tumor cells. This suggests that CYP2A6 may be a major liver catalyst in pathological conditions. In the present study, we have addressed molecular mechanisms underlying the regulation of the CYP2A6 gene. We present evidence of several proteins present in human hepatocytes that interact specifically with the 3'-untranslated region (UTR) of CYP2A6 mRNA. Biochemical and immunological evidence show that the RNA-protein complex of highest intensity contains the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 or a closely related protein. Mapping of the hnRNP A1 binding site within CYP2A6 3'-UTR reveals that the smallest portion of RNA supporting significant binding consists of 111 central nucleotides of the 3'-UTR. Our studies also indicate that hnRNPA1 from HepG2 cancer cells exhibits modified binding characteristics to the CYP2A6 3'-UTR compared with primary hepatocytes. We found that the level of CYP2A6 mRNA remains high in conditions of impaired transcription in primary human hepatocytes, showing that CYP2A6 expression can be affected post-transcriptionally in conditions of cellular stress. Our results indicate that the post-transcriptional regulation involves interaction of the hnRNP A1 protein with CYP2A6 mRNA. The present data suggest that hnRNPA1 is a critical regulator of expression of the human CYP2A6 gene and support the notion that this P450 isoform may be of particular significance in stressed human liver cells.
Mol Pharmacol 2004 Jun
PMID:Interaction of heterogeneous nuclear ribonucleoprotein A1 with cytochrome P450 2A6 mRNA: implications for post-transcriptional regulation of the CYP2A6 gene. 1515 34

Hepatitis A virus (HAV) infection is the leading cause of viral hepatitis throughout the world. HAV infection is mainly propagated via the fecal-oral route, and waterborne and foodborne outbreaks of the disease have been reported.HAV, the prototype of the genus Hepatovirus, belongs to the family Picornaviridae. Its 7.5-kb single-stranded RNA genome bears different distinct regions: the 5' and 3' noncoding regions (NCR), the P1 region, which encodes the structural proteins VP1, VP2, VP3, and a putative VP4, and the P2 and P3 regions encoding nonstructural proteins associated with replication. A single HAV serotype has been described, although seven genotypes have been defined. Since environmental samples usually contain low numbers of viral particles, sensitive methods such as molecular techniques based on nucleic acid amplification are required for their detection. However, even with the adoption of these techniques, the choice of the most adequate target is of relevant importance. The target region should be highly conserved, to increase the chance of detection, and should have an appropriate structure and length to allow sensitivity high enough for these kind of samples. As a target region, we have chosen a fragment of the 5'NCR flanked by highly conserved sequences that have been used for the primer design (forward primer from position 68 to position 85; reverse primer from position 222 to position 240 in the HM175 strain of HAV; GenBank accession number M14707). The internal part of this region, however, may present a certain degree of variation mainly owing to insertions and/or deletions, causing a variable size of the amplimer obtained, i.e., the wild-type HM175 strain gives a size of 174 bp whereas the cell-adapted pHM175 strain gives a size of 186 bp. For this reason it is extremely important to include a confirmative method such as Southern blot hybridization with an internal probe from a region not affected by the insertions/deletions.
Methods Mol Biol 2004
PMID:Hepatitis a virus: molecular detection and typing. 1515 22

Dominant types of viral hepatitis are presently A, B, and C with prophylactic immunization available only for A and B. Hepatitis B and C and human immunodeficiency virus (HIV) infection constitute a worldwide scourge and treatment is far from satisfactory. Each produces severe oxidative stress (OS) and secondary cellular damage of varying severity and, as in toxic hepatitis, progression and regression are dependent on redox balance between oxidation and antioxidation. Experimental and clinical studies suggest that xenobiotics and co-infections exert cumulative, detrimental effects on their pathogeneses and further deplete antioxidants. It is proposed therefore that in the clinical management of these infections and especially in their early stages, considerable benefit should accrue from antioxidant repletion at dosages substantially above recommended daily allowances (RDAs) in conjunction with a nutritious high protein diet. Because plasma zinc and selenium concentrations are very low, their replenishment by high dosages is urgent and mandatory particularly in advanced HIV infections bordering on acrodermatitis enteropathica. Also recommended is their long-term continuance at high normal levels.
Exp Mol Pathol 2004 Oct
PMID:Oxidative stress in viral hepatitis and AIDS. 1535 Dec 35

Liver homeostasis is achieved by the removal of diseased and damaged hepatocytes and their coordinated replacement to maintain a constant liver cell mass. Cirrhosis, viral hepatitis, and toxic drug effects can all trigger apoptosis in the liver as a means of removing the unwanted cells, and the Fas "death receptor" pathway comprises a major physiological mechanism by which this occurs. The susceptibility to Fas-mediated apoptosis is, in part, a function of the hepatocyte's proteome. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known to influence apoptosis, conceivably by regulating the expression of genes involved in apoptotic signaling. In this article, we present evidence demonstrating that AhR expression and function promote apoptosis in liver cells in response to Fas stimulation. Reintroduction of the AhR into the AhR-negative BP8 hepatoma cells as well as into primary hepatocytes from AhR knockout mice increases the magnitude of cell death in response to Fas ligand. Enhanced apoptosis correlates with increased caspase activity and mitochondrial cytochrome c release but not with the expression of several Bcl-2 family proteins. In vivo studies showed that in contrast to wild-type mice, AhR knockout mice are protected from the lethal effects of the anti-Fas Jo2 antibody. Moreover, down-regulation of the aryl hydrocarbon receptor nuclear translocator protein in vivo by adenovirus-mediated RNA interference to suppress AhR activity provided wild-type mice partial protection from Jo2-induced lethality.
Mol Pharmacol 2005 Mar
PMID:The aryl hydrocarbon receptor predisposes hepatocytes to Fas-mediated apoptosis. 1555 Jun 80

Tumor necrosis factor (TNF)-alpha-induced hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure. TNF-alpha exerts a variety of effects that are mediated mainly by TNF-receptor 1 (TNF-R1) in cell death. The activation of TNF-R1 leads to the activation of multiple apoptotic pathways involving the activation of the pro-death Bcl-2 family proteins, reactive oxygen species, C-Jun NH2-terminal kinase, cathepsin B, acidic sphingomyelinase and neutral sphingomyelinase. These pathways are closely interlinked and mainly act on mitochondria, which release the apoptogenic factors and other events, resulting in apoptosis. This article reviews the recent progress in the molecular mechanisms of TNF-alpha-induced apoptosis in hepatocytes, and discusses how these molecular findings are shaping our understanding of the pathogenesis of liver diseases and our strategy to develop novel therapeutics.
J Cell Mol Med
PMID:Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. 1560 73


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