Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have progressive liver disease that frequently leads to cirrhosis and death. We previously showed that hepatocytes exposed to HCV and HIV envelope proteins undergo apoptosis via an innocent-bystander mechanism as a result of the cell surface binding of these proteins, independent of direct viral infection. Here, we have defined the mechanism of this hepatocytic apoptosis. We observed enhanced signal transducer and activator of transcription factor 1 (STAT1) activation and phosphorylation after costimulation with HCV-E2 and HIV-gp120. Moreover, inhibitor studies indicated that Lyn kinase, p38 mitogen-activated protein kinase, and protein kinase C delta might be involved in STAT1 phosphorylation. To elucidate the downstream STAT1-mediated signaling, we overexpressed wild-type STAT1 alpha and the C-terminal domain-deleted mutant STAT1 beta . STAT1 alpha overexpression increased cell apoptosis and Fas ligand expression, compared with STAT1 beta overexpression. STAT1 alpha also enhanced the release of cytochrome c from the mitochondria and caspase-3 activity. These studies indicate that the HCV/HIV envelope proteins cooperatively induce hepatocytic apoptosis by activating a novel downstream STAT1 signaling pathway.
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PMID:Signal transducer and activator of transcription factor 1 mediates apoptosis induced by hepatitis C virus and HIV envelope proteins in hepatocytes. 1719 63

IL-4 is overexpressed in liver grafts during severe recurrent hepatitis C and rejection. Hepatocyte apoptosis is involved in both these phenomena. We therefore examined the proapoptotic effect of IL-4 on HepG2 cells and human hepatocytes in vitro, together with the underlying mechanisms. We first measured IL-4 receptor expression, STAT6 activation by IL-4, and STAT6 inhibition by an anti-IL-4 antibody or by STAT6 siRNA transfection. We then focused on the pathways involved in IL-4-mediated apoptosis and the role of STAT6 activation in apoptosis initiation. The IL-4 receptor was expressed on both cell types, and STAT6 was activated by IL-4. Both anti-IL-4 and STAT-6 siRNA inhibited this activation. IL-4 induced apoptosis of both HepG2 cells (P=0.008 vs. untreated control) and human hepatocytes (P<0.001 vs. untreated control). IL-4 reduced the mitochondrial membrane potential, activated Bid and Bax, and augmented caspase 3, 8, and 9 activity. STAT6 blockade inhibited IL-4-induced apoptosis. Expression of Fas and Fas ligand was unaffected when HepG2 cells and hepatocytes were cultured with IL-4, and Fas/FasL pathway blockade failed to inhibit IL-4-induced apoptosis. These results show that IL-4 induces apoptosis of human hepatocytes through IL-4 receptor binding, STAT6 activation, decreased mitochondrial membrane potential, and increased caspase activation, independently of the Fas pathway. IL-4 might thus contribute to the progression of severe liver graft damage.
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PMID:Interleukin-4 induces human hepatocyte apoptosis through a Fas-independent pathway. 1728 23

Hepatocyte apoptosis is an important feature of liver injury in hepatitis C virus (HCV) infection. However, the mechanism of apoptosis and consequences on disease progression in vivo have not been investigated fully in part due to the lack of adequate small animal models. In this study, transgenic (tg) mice were produced that express conditionally HCV structural proteins (core, E1, E2 and p7) in the liver following Cre-mediated DNA recombination. Using a novel Cre-estrogen receptor fusion protein (Cre-ER) induction strategy, tamoxifen was injected intraperitoneally (i.p.), which induced Cre nuclear translocation, transgene recombination and HCV protein expression in the liver. Hepatic expression of HCV core and envelope proteins resulted in increased hepatocyte apoptosis, detected by the TUNEL assay, between 7 and 33 days after induction. These results were confirmed by the presence of increased levels of apoptosis-associated cytokeratin 18 (CK-18) in the sera of the same animals. The presence of cleaved caspase-3 and elevated levels of CHOP/GADD153 in the liver suggests an endoplasmic reticulum (ER) stress-associated apoptosis mechanism. This study suggests an in vivo correlation between HCV structural protein expression, ER stress and hepatocyte apoptosis, implicating a potentially important mechanism of HCV pathogenesis.
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PMID:Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice. 1762 8

Persistent infection of hepatitis C virus (HCV) can lead to a high risk for hepatocellular carcinoma (HCC). HCV core protein plays important roles in HCV-related hepatocarcinogenesis, because mice carrying the core protein exhibit multicentric HCCs without hepatic inflammation and fibrosis. However, the precise mechanism of hepatocarcinogenesis in these transgenic mice remains unclear. To evaluate whether the core protein modulates hepatocyte proliferation and apoptosis in vivo, we examined these parameters in 9- and 22-month-old transgenic mice. Although the numbers of apoptotic hepatocytes and hepatic caspase 3 activities were similar between transgenic and nontransgenic mice, the numbers of proliferating hepatocytes and the levels of numerous proteins such as cyclin D1, cyclin-dependent kinase 4 and c-Myc, were markedly increased in an age-dependent manner in the transgenic mice. This increase was correlated with the activation of peroxisome proliferator-activated receptor alpha (PPARalpha). In these transgenic mice, spontaneous and persistent PPARalpha activation occurred heterogeneously, which was different from that observed in mice treated with clofibrate, a potent peroxisome proliferator. We further demonstrated that stabilization of PPARalpha through a possible interaction with HCV core protein and an increase in nonesterified fatty acids, which may serve as endogenous PPARalpha ligands, in hepatocyte nuclei contributed to the core protein-specific PPARalpha activation. In conclusion, these results offer the first suggestion that HCV core protein induces spontaneous, persistent, age-dependent and heterogeneous activation of PPARalpha in transgenic mice, which may contribute to the age-dependent and multicentric hepatocarcinogenesis mediated by the core protein.
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PMID:Hepatitis C virus core protein induces spontaneous and persistent activation of peroxisome proliferator-activated receptor alpha in transgenic mice: implications for HCV-associated hepatocarcinogenesis. 1776 15

The virus-encoded viroporins are known to modify membrane permeability and play an essential role in virus budding. Here, a comparative analysis of the membrane permeabilization capacity of a number of viroporins was performed in baby hamster kidney cells. Synthesis of 6K protein from Sindbis virus, E from mouse hepatitis virus, M2 from influenza A virus, and 2B and 3A from poliovirus enhanced membrane permeability to different extents. We show that two proteins from hepatitis C virus, p7 and NS4A, also display viroporin activity to a level comparable to 6K protein. In addition to their capacity to disrupt ionic cellular homeostasis and promote bacterial cell lysis, the expressed viroporins were able to induce cell death. Degradation of internucleosomal DNA and generation of apoptotic bodies were observed upon viroporin expression. Consistently, cleavage of translation initiation factor 4GI and poly-(ADP-ribose) polymerase indicated activation of effector caspase-3. We found that poliovirus 2B localizes partially in mitochondria and induces an anomalous perinuclear distribution of these organelles. Mitochondria morphology was also altered after expression of other viroporins. Finally, detection of cytochrome c release from mitochondria suggests involvement of the mitochondrial pathway in viroporin-induced apoptosis. These findings suggest that viroporins induce caspase-dependent programmed cell death.
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PMID:Viroporins from RNA viruses induce caspase-dependent apoptosis. 1796 Nov 83

Silymarin, used by 30 to 40% of liver disease patients, is composed of six major flavonolignans, each of which may contribute to silymarin's hepatoprotective properties. Previous studies have only described the pharmacokinetics for two flavonolignans, silybin A and silybin B, in healthy volunteers. The aim of this study was to determine the pharmacokinetics of the major silymarin flavonolignans in liver disease patients. Healthy volunteers and three patient cohorts were administered a single, 600-mg p.o. dose of milk thistle extract, and 14 blood samples were obtained over 24 h. Silybin A and B accounted for 43% of the exposure to the sum of total silymarin flavonolignans in healthy volunteers and only 31 to 38% in liver disease cohorts as a result of accumulation of silychristin (20-36%). Area under the curve (AUC(0-24h)) for the sum of total silymarin flavonolignans was 2.4-, 3.3-, and 4.7-fold higher for hepatitis C virus (HCV) noncirrhosis, nonalcoholic fatty liver disease (p <or= 0.03), and HCV cirrhosis cohorts (p <or= 0.03), respectively, compared with healthy volunteers (AUC(0-24h) = 2021 ng . h/ml). Caspase-3/7 activity correlated with the AUC(0-24h) for the sum of all silymarin conjugates among all subjects (R(2) = 0.52) and was 5-fold higher in the HCV cirrhosis cohort (p <or= 0.005 versus healthy). No correlation was observed with other measures of disease activity, including plasma alanine aminotransferase, interleukin 6, and 8-isoprostane F(2alpha), a measure of oxidative stress. These findings suggest that the pharmacokinetics of silymarin is altered in patients with liver disease. Patients with cirrhosis had the highest plasma caspase-3/7 activity and also achieved the highest exposures for the major silymarin flavonolignans.
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PMID:The pharmacokinetics of silymarin is altered in patients with hepatitis C virus and nonalcoholic Fatty liver disease and correlates with plasma caspase-3/7 activity. 1856 43

We previously reported that cells harboring the hepatitis C virus (HCV) RNA replicon as well as those expressing HCV NS3/4A exhibited increased sensitivity to suboptimal doses of apoptotic stimuli to undergo mitochondrion-mediated apoptosis (Y. Nomura-Takigawa, et al., J. Gen. Virol. 87:1935-1945, 2006). Little is known, however, about whether or not HCV infection induces apoptosis of the virus-infected cells. In this study, by using the chimeric J6/JFH1 strain of HCV genotype 2a, we demonstrated that HCV infection induced cell death in Huh7.5 cells. The cell death was associated with activation of caspase 3, nuclear translocation of activated caspase 3, and cleavage of DNA repair enzyme poly(ADP-ribose) polymerase, which is known to be an important substrate for activated caspase 3. These results suggest that HCV-induced cell death is, in fact, apoptosis. Moreover, HCV infection activated Bax, a proapoptotic member of the Bcl-2 family, as revealed by its conformational change and its increased accumulation on mitochondrial membranes. Concomitantly, HCV infection induced disruption of mitochondrial transmembrane potential, followed by mitochondrial swelling and release of cytochrome c from mitochondria. HCV infection also caused oxidative stress via increased production of mitochondrial superoxide. On the other hand, HCV infection did not mediate increased expression of glucose-regulated protein 78 (GRP78) or GRP94, which are known as endoplasmic reticulum (ER) stress-induced proteins; this result suggests that ER stress is not primarily involved in HCV-induced apoptosis in our experimental system. Taken together, our present results suggest that HCV infection induces apoptosis of the host cell through a Bax-triggered, mitochondrion-mediated, caspase 3-dependent pathway(s).
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PMID:Hepatitis C virus infection induces apoptosis through a Bax-triggered, mitochondrion-mediated, caspase 3-dependent pathway. 1876 89

Hepatitis C virus (HCV) NS3/4A (non-structural 3 and 4 B) protease plays a key role in the processing of polyprotein precursor and it becomes an attractive target for antiviral drug discovery. We developed a cell-based assay for monitoring of the NS3/4A protease activity in mammalian cells that is an important step in screening of specific drugs against the protease. The recombinant caspase 3 (rCasp3) was used as the specific substrate for NS3/4A protease. The endogenous cleavage sites in the procaspase 3 molecule were substituted by decapeptides specific for NS3/4A protease. The activation of rCasp3 depended on its specific cleavage by NS3/4A protease and resulted in an apoptosis of stable cells expressing the protease. The difference in cell viability between the cells expressing NS3/4A protease transfected with rCasp3 and the counterparts pretreated with NS3/4A protease inhibitors could be estimated by a spectrophotometry based on 3-(4,5-dimethylthioazol- 2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) staining of cells in microplates. Thus, we developed a simple and cost-effective colorimetric assay for evaluating NS3/4A protease activity enabling the screening of candidate NS3/4A protease inhibitors.
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PMID:Development of a cell-based assay for monitoring hepatitis C virus ns3/4a protease activity. 1899 87

Hepatitis C virus (HCV) infection is a leading cause of liver-related morbidity and mortality throughout the world. There is no vaccine available and current therapy is only partially effective. Since HCV infects only a minority of hepatocytes, we hypothesized that induction of apoptosis might be a promising approach for the treatment of hepatitis C. In the present study, recombinant caspase-3 gene (re-caspase-3) was used because it has the ability to induce apoptosis that is independent of the initiator caspases. An HCV-specific promoter is required to regulate the cytotoxic caspase-3 expression in HCV-infected cells. It has been reported that HCV core protein can specifically activate the 2',5'-oligoadenylate synthetase (OAS) gene promoter in human hepatocytes. Therefore, we constructed an expression vector consisting of the re-caspase-3 under the OAS gene promoter (pGL3-OAS-re-caspase-3) and then investigated its effect on HCV core-positive liver cells. It was found that the pGL3-OAS-re-caspase-3 construct induced apoptosis in HCV core-positive liver cells, but not in normal liver cells. These results strongly suggested that the transfer of the re-caspase-3 gene under the OAS promoter was a novel targeting approach for the treatment of HCV infection.
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PMID:Treatment of hepatitis C virus core-positive hepatocytes with the transfer of recombinant caspase-3 using the 2',5'-oligoadenylate synthetase gene promoter. 1957 19

Bovine viral diarrhea virus (BVDV; genus Pestivirus) can exist as two biotypes, cytopathogenic (CP) and non-cytopathogenic (NCP). The CP form differs from NCP by the continual expression of free non-structural protein 3 (NS3). CP BVDV infection of cultured cells induces apoptosis, whereas NCP BVDV infection has been reported to block the induction of beta interferon (IFN-beta). To investigate the viral mechanisms underlying these effects, NS3 or NS2-3 proteins of NCP and CP BVDV biotypes, together with the cognate NS3 co-factor NS4A, were expressed in cells, and their effect on apoptosis and induction of IFN-beta was investigated. Expression of NS3/4A resulted in increased activity of caspase-9 and caspase-3, indicating induction of the intrinsic apoptosis pathway. Mutational analysis revealed that a protease-inactive NS3/4A was unable to induce apoptosis, suggesting that NS3 protease activity is required for initiation of apoptosis during CP BVDV infection. The ability of NS2-3 to modulate activation of the IFN-beta promoter was also investigated. These studies confirmed that, unlike the related hepatitis C virus and GB virus-B, BVDV proteases are unable to inhibit TLR3- and RIG-I-dependent activation of the IFN-beta promoter. These data suggest that BVDV NS3/4A is responsible for regulating the levels of cellular apoptosis and provide new insights regarding the viral elements associated with CP biotype pathogenesis.
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PMID:Expression of the NS3 protease of cytopathogenic bovine viral diarrhea virus results in the induction of apoptosis but does not block activation of the beta interferon promoter. 1979 4


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