Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Background/aims: The liver apoptotic response to chronic alcohol consumption remains poorly characterized. The purpose of this study was to determine in rats the effects of chronic alcohol consumption on the relative magnitude of apoptosis in two major targets of alcohol-induced liver injury: the hepatocyte (Hep) and sinusoidal endothelial cell (SEC). Methods: Rats were fed a liquid diet containing either alcohol or isocaloric amounts of maltose-dextrin for 14 weeks. Hep and SEC were isolated by liver perfusion with collagenase followed by centrifugal elutriation. The state of the liver was assessed on the basis of light microscopic appearance, plasma liver enzymes (alanine and aspartate:2-oxoglutarate amino transferases), and the content of malondialdehyde in Hep. Apoptosis was assessed on the basis of DNA fragmentation in the whole organ (TUNEL), and caspase-3 and -8 activity in isolated cells. A mechanistic approach was also undertaken by measuring mRNA expression and the amount of protein for Fas/CD95, Fas ligand, caspase-3, Bax, Bcl-X(L), and Bcl-2 in the isolated Hep and SEC. Results: The livers of alcohol-fed rats displayed prominent steatosis. Oxidative stress was also present as reflected by an increase in the malondialdehyde content of Hep. Alcohol consumption increased apoptosis in the whole liver assessed on the basis of TUNEL procedure and in Hep and SEC as reflected by significant increase in caspase-3 activity. Of the multiple pro- and anti-apoptotic factors determined in this study, significant changes as assessed by both mRNA expression and the amount of proteins, were observed only in the SEC compartment. Conclusions: The data presented in this study indicate that: (1) chronic alcohol consumption in rats leads to a moderate augmentation of apoptosis in the whole liver and in two liver cell types which are targets for injury in alcoholic liver disease: Hep and SEC; (2) the mechanisms recruited/activated by these two types of liver cells to initiate and execute apoptosis in response to alcohol vary with the cell type.
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PMID:Chronic alcohol exposure of rats exacerbates apoptosis in hepatocytes and sinusoidal endothelial cells. 1125 13

Elevation of serum interleukin-6 (IL-6) levels is always associated with alcoholic liver disease (ALD), but the significance of such elevation is not clear. Here we show that chronic ethanol consumption induces significant apoptosis in the liver of IL-6 (-/-) mice but not IL-6 (+/+) mice. IL-6 (-/-) hepatocytes are more susceptible to ethanol- and tumor necrosis factor alpha- (TNFalpha-) induced apoptotic killing, which can be corrected by IL-6. Expression of both anti-apoptotic (such as Bcl-2 and Bcl-x(L)) and proapoptotic (such as Bax) proteins is markedly elevated in the liver of human ALD and chronically ethanol-fed IL-6 (+/+) mice. On the contrary, induction of Bcl-2 and Bcl-x(L) is not observed in the liver of chronically ethanol-fed IL-6 (-/-) mice, whereas expression of Bax protein remains elevated. Injection of IL-6 markedly induces expression of Bcl-2 and Bcl-x(L) but not Bax in the liver. Finally, high concentrations of ethanol inhibit IL-6-activated anti-apoptotic signal, but increasing the concentrations of IL-6 is able to overcome such inhibitory effect. These findings suggest that elevated serum IL-6 levels in ALD may overcome the inhibitory effect of ethanol on IL-6-mediated anti-apoptotic signals and prevent alcohol-induced hepatic apoptosis by induction of Bcl-2 and Bcl-x(L).
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PMID:Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-x(L) proteins. 1179 Nov 74

Some viral infections are reported to influence the susceptibility of peripheral blood mononuclear cells (PBMC) to apoptosis, which is related to disease progression. The current study was designed to monitor apoptosis in separated PBMC subsets, CD4+ and CD8+ T lymphocytes, and CD14+ monocytes under apoptotic stimuli in patients with chronic hepatitis C. Apoptosis was induced by serum starvation and by incubation with anti-CD3 antibody and with phorbol 12-myristate 13-acetate. With the escalating severity of liver disease, susceptibility of all PBMC subsets to apoptosis increased under the apoptotic stimulus of serum starvation (P<0.05). Consequently, increased susceptibility to apoptosis was associated with diminished intracellular expression of the antiapoptotic protein Bcl-2 (P<0.05). The current observations demonstrate that the abnormality of PBMC subsets in undergoing apoptosis as a result of the down-regulation of Bcl-2 expression may contribute to viral persistence and progression of liver disease in chronic hepatitis C.
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PMID:Increased susceptibility to apoptosis and attenuated Bcl-2 expression in T lymphocytes and monocytes from patients with advanced chronic hepatitis C. 1210 Dec 62

Microarray analysis of RNA from hepatitis C virus (HCV)-infected cirrhotic livers was performed to identify a gene expression signature of liver disease. The expression levels of approximately 13600 genes were analyzed using surgical material and core biopsy specimens from HCV-infected cirrhotic liver explants in comparison with reference samples of normal nondiseased liver. In addition, normal liver samples were compared with each other to determine normal physiologic variation in gene expression. A set of genes, including some associated with stress, acute-phase immune response, and hepatic stellate cell activation, had variable expression levels in normal livers. These genes were subtracted from the sets of genes differentially expressed in cirrhotic livers. To exclude cancer-related genes from our marker sets, we subtracted genes that also were expressed differentially in hepatocellular carcinomas. The resultant HCV- and liver disease-associated gene set provided a molecular portrait of several processes occurring in the HCV-infected liver. It included (1). genes expressed in activated lymphocytes infiltrating the cirrhotic liver, and activated liver macrophages; (2). genes involved in remodeling of extracellular matrix-cell and cell-cell interactions associated with cytoskeleton rearrangements; (3). genes related to the anti-apoptotic pathway of Bcl-2 signaling; and (4). genes involved with the interferon response and virus-host interactions. In conclusion, our microarray analysis identified several potential gene markers of HCV-associated liver disease and contributed to our rapidly expanding database of experiments describing HCV pathogenesis.
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PMID:Hepatitis C virus and liver disease: global transcriptional profiling and identification of potential markers. 1464 57

Bcl-2 oncoprotein regulates programmed cell death by providing a survival advantage to rapidly proliferating cells, and bax protein promotes apoptosis by enchanting cell susceptibility to apoptotic stimuli. In this study, we assessed the expression of bcl-2 and bax in liver biopsies from patients with chronic hepatitis (CH) Type B (HBV) and C (HCV). The study comprised 65 liver biopsies from 65 patients with HBV (n = 37) and HCV (n = 28) and 10 normal liver biopsies as controls. The HAI score ranged from 3/18-13/18, and the fibrosis Stage, from 1-6 (7 HBV/10 HCV). Pathologic examination included the following: (1) immunohistochemical stains in paraffin sections for bcl-2 and bax protein expression, (2) Western blot analysis (bcl-2 and bax protein levels evaluation), (3) ISH (detection of bcl-2 and bax mRNA), and (4) ISH (TUNEL-ABI [apoptotic body index]). In CH cases, both bcl-2 and bax protein and mRNA were detected in portal and intralobular lymphocytes and in cholangiolar epithelial cells in interface areas and fibrous bands. Bax protein and mRNA was expressed within hepatocytes and epithelial cells of interlobular ducts in portal tracts. Bcl-2 mRNA was present in periportal hepatocytes only in cases with Stage 5-6 fibrosis. Western blot analysis showed a decreased bcl-2 and an increased bax expression toward advanced fibrotic stages. In CH cases, ABI was reverse correlated with the percentage of bcl-2 expression and was correlated directly with the percentage of bax expression (P <.001). The results of this study suggest that in cases of chronic HBV or HCV infection, bax may be involved in the hepatocyte cycle regulation during infection, whereas its expression in intraportal bile duct epithelium implies that this protein enhances susceptibility of these particular cells to apoptosis. The increased bax expression and ABI in fibrosis Stages 1-5, imply that they are responsible for hepatocytes depletion through apoptosis, during progress of liver fibrosis and fibrous tissue accumulation, until cirrhosis is established. Bcl-2 mRNA expression in periportal hepatocytes only in Stages 5 and 6 suggests that this oncogene is involved in the late stages of progressive liver fibrosis and failure and furthermore that periportal hepatocytes are resistant to apoptosis. Bcl-2 expression, in cholangioles of interface area, suggests that this oncoprotein may be involved in growth regulation of these epithelial cells. Further research is warranted to specify the exact role of apoptosis and apoptotic genes involved in liver fibrosis process in cases of chronic HBV and HCV infection. This may lead to new strategies in the management of human liver disease to prevent the progression to chronic liver failure.
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PMID:Potential role of bcl-2 and bax mRNA and protein expression in chronic hepatitis type B and C: a clinicopathologic study. 1468 29

The central role of T cell activation in hepatocellular injury has been well documented. In this article, we provide evidence suggesting that T cells may also play a protective role in liver disease by releasing interleukin-22 (IL-22), a recently identified T cell-derived cytokine whose biological significance is unclear. IL-22 messenger RNA and protein expression are significantly elevated in T cell-mediated hepatitis induced by concanavalin A (ConA) but are less extensively elevated in the carbon tetrachloride-induced liver injury model. Activated CD3(+) T cells are likely responsible for the production of IL-22 in the liver after injection of ConA. The IL-22 receptor is normally expressed at high levels by hepatocytes and further induced after ConA injection. IL-22 blockade with a neutralizing antibody reduces signal transducer and activator of transcription factor 3 (STAT3) activation and worsens liver injury in T cell-mediated hepatitis, whereas injection of recombinant IL-22 attenuates such injury. In vitro treatment with recombinant IL-22 or overexpression of IL-22 promotes cell growth and survival in human hepatocellular carcinoma HepG2 cells. Stable overexpression of IL-22 in HepG2 cells constitutively activates STAT3 and induces expression of a variety of antiapoptotic (e.g., Bcl-2, Bcl-xL, Mcl-1) and mitogenic (e.g., c-myc, cyclin D1, Rb2, CDK4) proteins. Blocking STAT3 activation abolishes the antiapoptotic and mitogenic actions of IL-22 in hepatic cells. In conclusion, the T cell-derived cytokine IL-22 is a survival factor for hepatocytes; this suggests that T cell activation may also prevent and repair liver injury by releasing hepatoprotective cytokine IL-22 in addition to its previously documented central role in hepatocellular injury.
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PMID:Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. 1512 62

Apoptosis mediated via extrinsic or intrinsic pathways is essential for maintaining cellular homeostasis in the liver. The extrinsic pathway is triggered from the cell surface by engagement of death receptors as CD95, TRAIL (TNF-related apoptosis inducing ligand) and TNF (tumour necrosis factor) or TGF-beta (transforming growth factor beta) receptors. The intrinsic pathway is initiated from the mitochondria and can be influenced by Bcl-2 family members. Both pathways are intertwined and play a physiological role in the liver. Dysregulation of apoptosis pathways contributes to diseases as hepatocellular carcinoma, viral hepatitis, autoimmune hepatitis, ischaemia-reperfusion injury, iron or copper deposition disorders, toxic liver damage and acute liver failure. The apoptosis defects are often central pathogenetic events; hence molecular mechanisms of apoptosis give not only insight into disease mechanisms but also provide potential corresponding therapeutic candidates in liver disease. The focus of this review is the identification of apoptotic signalling components in the liver as therapeutic targets.
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PMID:Modulation of apoptosis as a target for liver disease. 1575 84

Interleukin-22 (IL-22) is a recently identified T cell-derived cytokine whose biological significance remains obscure. Previously, we have shown that IL-22 plays a protective role in T cell-mediated hepatitis induced by Concanavalin A (Con A), acting as a survival factor for hepatocytes. In the present paper, we demonstrate that hydrodynamic gene delivery of IL-22 cDNA driven either by a liver-specific albumin promoter or a human cytomegalovirus (CMV) promoter results in IL-22 protein expression, STAT3 activation, and expression of several anti-apoptotic proteins, including Bcl-xL, Bcl-2, and Mcl-1 in the liver. Immunohistochemical analysis reveals that IL-22 protein expression is mainly detected in the cytoplasm of hepatocytes. Overexpression of IL-22 by hydrodynamic gene delivery significantly protects against liver injury, necrosis, and apoptosis induced by administration of Con A, carbon tetrachloride (CCl4), or the Fas agonist Jo-2 mAb. Western blot analyses show that overexpression of IL-22 significantly enhances activation of STAT3 and expression of Bcl-xL, Bcl-2, and Mcl-1 proteins in liver injury induced by Con A. In conclusion, hydrodynamic gene delivery of IL-22 protects against liver injury induced by a variety of toxins, suggesting the therapeutic potential of IL-22 in treating human liver disease.
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PMID:Hydrodynamic gene delivery of interleukin-22 protects the mouse liver from concanavalin A-, carbon tetrachloride-, and Fas ligand-induced injury via activation of STAT3. 1621 20

The expansionable human hepatoma cell lines have potential for use in a bio-artificial liver (BAL) system for liver disease due to the shortage of donation. However, at present, bioartificial livers are incomplete and the functions need to be improved or at least maintained for a longer period. In the present study, the authors aimed to establish a novel hepatoma cell line for a longer-term or permanent artificial liver. For this purpose, bcl-2, an anti-apoptosis gene, was introduced into hepatoma HepG2 cells. Over-expression of Bcl-2 significantly inhibited apoptosis. After 15 d of serum-deprived culture, the viability of HepG2-Bcl2 was 51% while that of mock transfectant (HepG2-mock) was decreased to 14%. In the presence of hygromycin B, HepG2-mock were dead by day 6, while the HepG2-Bcl2 viability at day 9 was 65%. Over-expression of Bcl-2 prolonged the period of the stationary phase in the growth curve and did not affect the growth rate during the exponential phase. To test the liver function, albumin production was measured. After 10 d of culture, the albumin concentration in the culture supernatant of HepG2-Bcl2 was 30 ng ml(-1), while that of HepG2-mock was 23 ng ml(-1). The cytochrome P-450 activity per culture of 3-methyl-cholanthrene-treated HepG2-Bcl2 was double that of treated HepG2-mock. Introduction of Bcl-2 was effective for the generation of a novel hepatoma cell line for artificial livers.
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PMID:Generation of a novel apoptosis-resistant hepatoma cell line. 1623 83

The liver is continuously exposed to a large antigenic load that includes pathogens, toxins, tumor cells and dietary antigens. Amongst the hepatitis viruses, only hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma. Of the different antiviral defense systems employed by the tissue, apoptosis significantly contributes to the prevention of viral replication, dissemination, and persistence. Loss of tolerance to the liver autoantigens may result in autoimmune hepatitis (AIH). This review outlines the recent findings that highlight the role and mechanisms of apoptotic processes in the course of liver diseases. Among factors that contribute to liver pathology, we discuss the role of tumor necrosis factor (TNF)-alpha, HBx, ds-PKR, TRAIL, FasL, and IL-1alpha. Since TNF and FasL-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, these items will be discussed in greater detail in this review. We also highlight some recent discoveries that pave the way for the development of new therapeutic strategies by protecting hepatocytes (for example by employing Bcl-2, Bcl-XL or A1/Bfl-1, IAPs, or synthetic caspase inhibitors), or by the induction of apoptosis in stellate cells. The assessment of the severity of liver disease, as well as monitoring of patients with chronic liver disease, remains a major challenge in clinical hepatology practice. Therefore, a separate chapter is devoted to a novel cytochrome c-based method useful for the diagnosis and monitoring of fulminant hepatitis.
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PMID:Apoptosis in liver diseases--detection and therapeutic applications. 1625 9


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