Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to investigate whether there was a particular hepatitis B virus (HBV) X protein (HBx) mutant associated with Taiwanese patients with hepatocellular carcinoma (HCC). Initially, the entire coding region of HBx gene from the serum samples of 14 Taiwanese patients were sequenced. A novel mutant, HBx-A31, was preferentially found in patients with HCC. Sera from 67 patients with HCC and 100 patients with chronic hepatitis B were thus subjected for codon 31 analysis using a dual amplification created restriction site method. HBx-A31 was detected more frequently in patients with HCC (52% versus 12%; P<0.001) and in patients with liver cirrhosis (44% versus 6%; P<0.001). Site directed mutagenesis experiment revealed that HBx-A31 was less effective in transactivating HBV enhancer I-X promoter complex, less efficient in supporting HBV replication, and less potent in enhancing TNF-alpha induced increment of CPP32/caspase 3 activities in HepG2 cells. In conclusion, a prevalent HBx mutant was identified in Taiwanese patients with hepatocellular carcinoma. Development of this mutant might represent a strategy of the virus to escape immune surveillance and thus contribute to the process of multiple-step hepatocarcinogenesis.
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PMID:Identification and characterization of a prevalent hepatitis B virus X protein mutant in Taiwanese patients with hepatocellular carcinoma. 1107 37

We demonstrated the induction of cell death in a hepatoma cell line by IFN-gamma and its possible mechanism. Among the 2 hepatitis B virus (HBV)-associated hepatoma cell lines, SNU-354 and SNU-368, IFN-gamma induced cell death and increased caspase-3 activity in SNU-368 but not in SNU-354. IFN-gamma induced several changes in the mRNA expression level of apoptosis-regulating genes, e.g., increased expression of Fas, caspase-1 and TNF-related apoptosis-inducing ligand (TRAIL). In particular, IFN-gamma potently increased the mRNA expression of TRAIL in both cell lines. However, it did not change the mRNA expression level of death-mediating TRAIL receptors, e.g., DR4 and DR5, which were constitutively expressed in both cell lines. In contrast, the decoy receptor DcR1 was expressed in SNU-354 but not in SNU-368, and its expression level in SNU-354 was increased by IFN-gamma. Another decoy receptor, DcR2, was constitutively expressed in both cell lines; however, its expression level in SNU-368 was decreased by IFN-gamma. In addition, exogenous recombinant TRAIL reduced viability in SNU-368, but not in SNU-354, cells. From these findings, we speculated that TRAIL up-regulation and the subsequent TRAIL-mediated apoptosis serve as a mechanism of IFN-gamma-induced cell death in SNU-368. To confirm this hypothesis, we demonstrated that soluble DR4-Fc fusion protein, a TRAIL pathway inhibitor, inhibited IFN-gamma-induced cell death in SNU-368. Our results demonstrated that IFN-gamma acts as an inducer of cell death through TRAIL-mediated apoptosis.
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PMID:IFN-gamma induces cell death in human hepatoma cells through a TRAIL/death receptor-mediated apoptotic pathway. 1141 Aug 75

Alcohol drinking and viral hepatitis are both recognized as major causes of liver disease worldwide, and they frequently coexist and synergistically cause liver injury in patients with chronic liver disease. Several mechanisms have been implicated in exacerbation of liver injury in patients with alcohol drinking and viral hepatitis. These include impairment of host defense and liver regeneration by alcohol consumption. The findings obtained from my laboratory have demonstrated that alcohol potentiates cooperatively several signals activated by hepatitis B virus X protein (HBX) or hepatitis C virus core protein, and HBX sensitizes hepatocytes to tumor necrosis factor-alpha (TNF-alpha)- and ethanol-induced apoptosis by a caspase-3-dependent mechanism, which may also contribute to the synergistic effect of alcohol drinking and viral hepatitis on liver injury.
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PMID:Interaction of alcohol and hepatitis viral proteins: implication in synergistic effect of alcohol drinking and viral hepatitis on liver injury. 1206 40

Despite its implication in the progression of hepatitis B virus (HBV)-associated liver disease, the pro-apoptotic function of HBx protein remains poorly understood. We show that the expression of HBx leads to hyperactivation of caspase-8 and caspase-3 upon treatment with tumor necrosis factor-alpha (TNF-alpha) or anti-Fas antibody, and this activation is correlated with the sensitivity to apoptosis. We demonstrate cytoplasmic co-localization and direct interaction between HBx and the cellular FLICE inhibitory protein (c-FLIP), a key regulator of the death-inducing signaling complex (DISC). Deletion analysis shows that the death effector domain 1 (DED1) of c-FLIP is important for the observed interaction. Overexpression of c-FLIP rescued the cells from HBx-mediated apoptosis, with both the full-length HBV genome and HBx expression vectors. Moreover, c-FLIP and caspase-8 inhibitor considerably protected cells from HBx-mediated apoptosis. These data suggest that HBx abrogates the apoptosis-inhibitory function of c-FLIP and renders the cell hypersensitive towards the TNF-alpha apoptotic signal even below threshold concentration. This provides a novel mechanism for deregulation of hepatic cell growth in HBV patients and a new target for intervention in HBV-associated liver cancer and disease.
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PMID:Pro-apoptotic function of HBV X protein is mediated by interaction with c-FLIP and enhancement of death-inducing signal. 1272 77

The hepatitis B virus X protein (HBx) is a multifunctional protein, acting on different targets (e.g. transcription factors, cytoplasmic kinases, and mitochondrial proteins) and exerting cellular effects as diverse as stimulation of cell proliferation and apoptosis. In its biological effects, the modulation of cellular Ca2+ signals has been proposed to be involved, but the direct assessment of Ca2+ homeostasis in HBx-transfected cells has not been carried out yet. In this work, we have employed for this purpose aequorin-based recombinant probes specifically targeted to intracellular organelles and microdomains. Using these probes, we observed that overexpression of HBx enhanced agonist-evoked cytosolic Ca2+ signals in HepG2 and HeLa cells, without affecting either the steady state of endoplasmic reticulum Ca2+ concentration or the kinetics of Ca2+ release. Rather, caspase-3-dependent cleavage of the plasma membrane Ca2+ ATPase could be demonstrated, and larger rises were detected in the cytoplasmic rim beneath the plasma membrane. In mitochondria, major morphological (fragmentation and swelling) and functional (reduced Ca2+ uptake) alterations were detected in HBx-expressing cells. As to the cellular consequences, we observed that HBx-induced apoptosis was markedly reduced when the alterations in Ca2+ signaling (e.g. by loading a Ca2+ chelator or preventing PMCA cleavage) or the downstream effects (e.g. by inhibiting mitochondrial permeability transition) were prevented. Overall, these results indicate that HBx perturbs intracellular Ca2+ homeostasis, acting on the extrusion mechanisms, and that this effect plays an important role in the control of HBx-related apoptosis.
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PMID:Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein. 1279 72

Hepatitis B virus (HBV) core promoter mutations have been implicated in the pathogenesis of fulminant hepatitis B. Due to the limited availability of primary human hepatocytes, the functional characterization of HBV mutants has been performed predominantly in transformed cells, which may not represent ideal model systems for studying virus-cell interactions. We and others have shown that primary hepatocytes of the tree shrew Tupaia belangeri support HBV infection and replication. In this study, we used primary Tupaia hepatocytes to analyze the phenotype of two HBV core promoter mutations that have been associated with a clinical outbreak of fatal fulminant hepatitis. Similar to previous findings in human hepatoma cells, the HBV core promoter mutations resulted in enhanced viral replication and core expression. Surprisingly, however, the presence of the mutations had a marked effect on hepatocyte viability not previously observed in hepatoma cells. Reduced cell viability was found to be due to the induction of apoptosis, as evidenced by caspase-3 activation and nuclear fragmentation. In conclusion, HBV mutants exhibit a novel phenotype in primary hepatocytes distinctly different from previous findings in hepatoma cell lines. This phenotype may have important implications for the understanding of the fulminant clinical course associated with HBV mutations.
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PMID:Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primary Tupaia hepatocytes. 1566 Mar 84

Persistent expression of hepatitis B virus (HBV) proteins is thought to be involved in virus-related hepatocarcinogenesis. Here, we compared the gene expression profile of cells persistently expressing the full-length HBV with that of negative control cells to comprehensively investigate virus-mediated changes in the gene expression of the host cells. RNA samples from both virus-expressing and negative control cells were used for the DNA array assay. DNA array assay and subsequent corroboration assays revealed that expression of 14 of 1,176 genes (1.2%) was altered in response to virus expression. The upregulated genes included CD44, high mobility group protein-I, thymosin beta-10 and 27-kD heat shock protein, while the downregulated genes included NM23-H1, all of which are thought to be associated with the development or progression of carcinoma in the liver or other organs. Furthermore, virus expression resulted in the decrease of two apoptosis-inducing molecules, caspase-3 and BAX, which may also contribute to carcinogenesis through prolonged survival of the host cell. Thus, expression of the virus genome caused carcinogenesis-related changes in host cell gene expression. HBV expression may change the host cell to a malignant phenotype through alterations in the expression levels of a set of genes.
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PMID:Alteration in gene expression profile by full-length hepatitis B virus genome. 1581 78

It is well-documented that alcohol drinking together with hepatitis viral infection accelerates liver injury; however the underlying mechanisms remain unknown. In this paper, we demonstrated that primary hepatocytes from transgenic mice overexpressing hepatitis B virus X protein (HBX) were more susceptible to ethanol- and TNF-alpha-induced apoptotic killing. Compared to normal control mouse hepatocytes, ethanol and/or TNF-alpha treatment led to a significant increase in reactive oxygen species, mitochondrial permeability transition, cytochrome C release, caspase-3 activity, and poly (ADP-ribose) polymerase degradation in hepatocytes from HBX transgenic mice. Blocking caspase-3 activity antagonized ethanol- and TNF-alpha-induced apoptosis in primary hepatocytes from HBX transgenic mice. Taken together, our findings suggest that HBX sensitizes primary mouse hepatocytes to ethanol- and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism, which may partly explain the synergistic effects of alcohol consumption and hepatitis B virus infection on liver injury.
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PMID:Hepatitis B virus X protein sensitizes primary mouse hepatocytes to ethanol- and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism. 1621 10

The smallest protein of hepatitis B virus, HBX, has been implicated in the development of liver diseases by interfering with normal cellular processes. Its role in cell proliferation has been unclear as both pro-apoptotic and anti-apoptotic activities have been reported. We showed molecular evidence that HBX induced apoptosis in HepG2 cells. A Bcl-2 Homology Domain 3 was identified in HBX, which interacted with anti-apoptotic but not pro-apoptotic members of the Bcl-2 family of proteins. HBX induced apoptosis when transfected into HepG2 cells, as demonstrated by both flow cytometry and caspase-3 activity. However, HBX protein may not be stable in apoptotic cells triggered by its own expression as only its mRNA or the fusion protein with the glutathione-S-transferase was detected in transfected cells. Our results suggested that HBX behaved as a pro-apoptotic protein and was able to induce apoptosis.
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PMID:Human hepatitis B virus X protein induces apoptosis in HepG2 cells: role of BH3 domain. 1627 70

Schizandrae chinensis, a traditional Chinese medicine herb, has been used to treat hepatitis B disease in Chinese hospital clinic. We have isolated two bioactive compounds, deoxyschizandrin and gamma-schizandrin, from S. chinensis. In the present, we reported that deoxyschizandrin and gamma-schizandrin could induce apoptosis in human promyelocytic leukemia cells (HL-60), as characterized by DNA fragmentation and poly (ADP) ribose polymerase (PARP) cleavage. Further molecular analysis showed that deoxyschizandrin and gamma-schizandrin caused the loss of mitochondrial membrane potential (DeltaPsim), cytochrome c release from mitochondrion to cytosol, truncation of Bid protein, and activation of caspase-3 and -9. However, they did not increase the intracellular level of reactive oxygen species (ROS). Antioxidants such as N-acetyl cysteine (NAC) and catalase did not block the apoptosis induced by deoxyschizandrin or gamma-schizandrin. These findings suggest that deoxyschizandrin and gamma-schizandrin-induced apoptosis in HL-60 cells involved ROS-independent mitochondrial dysfunction pathway.
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PMID:Molecular mechanism of apoptosis induced by schizandrae-derived lignans in human leukemia HL-60 cells. 1795 May 15


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