UNIPROT:P10415 - FACTA Search

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)

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

We previously reported that a sub-necrogenic dose (20 mg/kg) of diethylnitrosamine (DENA) can induce the development of liver cancer when rats undergo a fasting-re-feeding regimen. The present study was undertaken to establish whether fasting followed by re-feeding builds up mechanisms able to trigger liver fibrosis, eventually leading to cirrhosis and cancer. Adult male rats, for fasted 4 days, were given 20 mg/kg of DENA after 1 day of re-feeding; in parallel, consistently fed animals receiving 20 mg/kg (sub-necrogenic) or 200 mg/kg (necrogenic dose) of DENA were used as negative and positive controls, respectively. All three groups were then subjected to the 2-acetylaminofluorene/carbon tetrachloride promoting regimen. Fasting induced moderate apoptosis in liver tissue, as evidenced by increased levels of transforming growth factor-beta1 (TGF-beta1) and Bax proteins and by a dramatic drop in the level of Bcl-2. Subsequent re-feeding caused all changes to revert except TGF-beta1 up-regulation. Histological findings of inflammation and fibrosis were consistently associated with increased production of TGF-beta1, the inflammatory cytokine with the most pronounced profibrogenic action. Thus, up-regulation of TGF-beta1 expression appears as a major mechanism by which the fasting-re-feeding regimen predisposes to initiation and promotion of liver carcinogenesis in rats. Avoiding fasting-re-feeding could be considered in the nutritional status of patients with liver fibrosis.
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PMID:Early induction of TGF-beta1 through a fasting-re-feeding regimen promotes liver carcinogenesis by a sub-initiating dose of diethylnitrosamine. 1654 46

Apoptosis is one of the events that are involved in liver fibrogenesis. Thus, factors that affect apoptosis may be used to modulate liver fibrosis. We have recently reported that Salvia miltiorrhiza plays a protective role in carbon tetrachloride (CCl4)-induced hepatic fibrosis. In this study, we aimed to evaluate whether S. miltiorrhiza modulated CCl4-induced hepatic apoptosis in rats. Male Wistar rats were given orally either vehicle or water-extract of S. miltiorrhiza (50 mg kg(-1) twice daily) for nine weeks beginning from the start of CCl4 administration. A group of normal rats was included for comparison. Hepatocyte DNA fragmentation and cytosolic caspase-3 and caspase-8 activity were determined in the experimental animals. Hepatic cytosolic Bax, Bcl-2, cytochrome c, and calpain-mu expressions were measured by Western blot analysis. Hepatic mitochondrial glutathione levels were assessed by colorimetric assay. Compared with normal rats, rats receiving CCl4 alone showed profound DNA fragmentation associated with an increased cytosolic fraction of cytochrome c and calpain-mu protein expressions and a decreased mitochondrial glutathione level. In contrast, a decreased laddering of DNA fragmentation was noted in rats receiving CCl4 plus S. miltiorrhiza extract. The mitochondrial glutathione level was significantly increased in rats receiving CCl4 plus S. miltiorrhiza extract compared with those receiving CCl4 alone. Additionally, cytosolic caspase-3 activity and cytosolic fractions of Bax, Bcl-2, cytochrome c, and calpain-mu protein expressions were decreased in rats receiving CCl4 plus S. miltiorrhiza extract compared with those receiving CCl4 alone. The cytosolic caspase-8 activity in rats receiving CCl4 alone was no different from those receiving CCl4 plus S. miltiorrhiza extract. These results indicated that chronic administration of S. miltiorrhiza ameliorated CCl4-mediatd hepatic apoptosis in rats. This effect may be related to the antioxidant properties of S. miltiorrhiza.
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PMID:Water-soluble extract of Salvia miltiorrhiza ameliorates carbon tetrachloride-mediated hepatic apoptosis in rats. 1664 Aug 35

Suppression of activation or proliferation, or induction of apoptosis in hepatic stellate cells (HSCs) have been proposed as therapeutic strategies against liver fibrosis. Salvia miltiorrhiza has been reported to exert antifibrotic effects in rats with hepatic fibrosis, but its mechanisms of action remain to be clarified. We have investigated the effects of salvianolic acid A (Sal A), an active principle from S. miltiorrhiza, on the proliferation-related biomarkers in a cell line of rat HSCs (HSC-T6) stimulated with platelet-derived growth factor-BB homodimer (PDGF-BB). DNA synthesis (bromodeoxyuridine (BrdU) incorporation), cell cycle related proteins and apoptosis markers were determined to evaluate the inhibitory effects of Sal A. The results showed that Sal A (1-10 microM) concentration-dependently attenuated PDGF-BB-stimulated proliferation (BrdU incorporation) in HSC-T6 cells. Sal A at 10 microM induced cell apoptosis in PDGF-BB-incubated HSCs, together with a reduction of Bcl-2 protein expression, induction of cell cycle inhibitory proteins p21 and p27, and down-regulation of cyclins D1 and E, suppression of Akt phosphorylation, reduction in PDGF receptor phosphorylation, and an increase in caspase-3 activity. Sal A exerted no direct cytotoxicity on primary hepatocytes and HSC-T6 cells under experimental concentrations. Our results suggested that Sal A inhibited PDGF-BB-activated HSC proliferation, partially through apoptosis induction.
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PMID:Antiproliferative effect of salvianolic acid A on rat hepatic stellate cells. 1680 53

In vitro and animal data suggest that hepatitis C virus (HCV) proteins might interfere with signal transducer and activator of transcription 3 (Stat3) signaling. It remains unknown whether Stat3 influences the apoptotic-proliferation balance and how this may relate to liver fibrosis progression in HCV-infected patients. We assessed Stat3 expression and DNA-binding as well as expression of its regulators protein inhibitor of activated Stat 3 (Pias3) and suppressor of cytokine signaling 3 (Socs3) in 65 HCV-infected livers at various stages of fibrosis progression. We then determined the level of expression of the proliferation markers cyclin D1 and proliferating cell nuclear antigen (PCNA) in conjunction with pro- and antiapoptotic markers Bax and Bcl-2 in the same liver samples. With the onset of fibrosis, Stat3 DNA-binding decreased and became almost undetectable in livers with bridging fibrosis or cirrhosis. Stat3 DNA-binding inversely correlated with Pias3 expression and Stat3-Pias3 interaction increased with the progression of fibrosis. Cyclin D1 and PCNA in hepatocytes decreased dramatically during fibrosis progression and levels highly correlated with Stat3 expression. In addition, an antiapoptotic profile due to upregulation of Bcl-2 principally in infiltrating inflammatory cells was observed with progressing fibrosis. In conclusion, fibrosis progression is characterized by a continuous decline in Stat3 DNA-binding activity related to overexpression and progressive interaction of Pias3-Stat3. The decrease in Stat3 activity correlated with reduced hepatocytes proliferation and a positive antiapoptotic balance in infiltrating inflammatory cells that are known mediators of cell damage in HCV.
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PMID:Role of signal transducer and activator of transcription 3 in liver fibrosis progression in chronic hepatitis C-infected patients. 1731 96

The accumulation of hydrophobic bile acids in the liver is considered to play a pivotal role in the induction of apoptosis of hepatocytes during cholestasis. Thus, factors that affect apoptosis may be used to modulate liver fibrosis. Yin-Chen-Hao-Tang (YCHT) decoctions have been recognised as a hepatoprotective agent for jaundice and various types of liver diseases. We used an experimental rat model of bile-duct ligation (BDL) to test whether YCHT plays a regulatory role in the pathogenesis of hepatic apoptosis. BDL-plus-YCHT groups received 250 or 500 mg kg (-1) YCHT by gavage once daily for 27 days. YCHT significantly ameliorated the portal hypertensive state and serum TNF-alpha compared with the vehicle-treated control group. In BDL-plus-YCHT-treated rats, hepatic glutathione contents were significantly higher than than in BDL-only rats. BDL caused a prominent liver apoptosis that was supported by an increase in Bax and cytochrome c protein and increased expression of Bax and Bcl-2 messenger RNA. The normalising effect of YCHT on expression of Bax and Bcl-2 mRNA was dependent on the dose of YCHT, 500 mg kg (-1) having the greater effect on both Bax and Bcl-2 of mRNA levels. Additionally, YCHT treatment down-regulated both hepatic caspase-3 and -8 activities of BDL rats. This study demonstrates the anti-apoptotic properties of YCHT and suggests a potential application of YCHT in the clinical management of hepatic disease resulting from biliary obstruction.
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PMID:Yin-Chen-Hao-Tang ameliorates obstruction-induced hepatic apoptosis in rats. 1743 Jun 43

Suppression of hepatic stellate cell (HSC) growth and activation, and induction of apoptosis, have been proposed as therapeutic strategies for the treatment and prevention of liver fibrosis. Our previous study showed that the Chinese herb Ligusticum chuanxiong (LC) inhibits platelet-derived growth factor (PDGF-BB)-induced HSC proliferation. The present study was designed to investigate the active principles and their action mechanisms. With a bioactivity-directed fractionation approach, DNA synthesis (bromodeoxyuridine (BrdU) incorporation), cell cycle related proteins and apoptosis markers were determined to evaluate the inhibitory effects of active principles of LC. Two phthalides, Z,Z'-6,8',7,3'-diligustilide (1) and levistolide A (2), from LC significantly abrogated PDGF-BB-induced proliferation in both rat and human HSC lines. These inhibitory effects of compounds 1 and 2 were associated with reduction of alpha-smooth muscle actin and collagen expressions. The cell cycle promoting proteins, cyclins D1, D2, E, A and B1, were downregulated while the inhibitory proteins p21 and 27 were up-regulated. JNK phosphorylation was up-regulated by compounds 1 and 2. In HSC-T6, the two compounds induced apoptosis through the activation of caspases 9 and 3, increase in cytosolic cytochrome c release, and downregulation of Bcl-2 and Akt phosphorylation. Moreover, neither phthalides caused direct cytotoxicity to either HSCs or rat primary hepatocytes under experimental concentrations. These results indicate that two phthalides from LC inhibited PDGF-BB-activated HSC proliferation possibly through cell cycle inhibition and apoptosis mechanisms. They might be potential anti-fibrotic drugs for the treatment and prevention of hepatic fibrosis.
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PMID:Studies on antiproliferative effects of phthalides from Ligusticum chuanxiong in hepatic stellate cells. 1752 May 22

A protective effect of Rho-kinase inhibitor on various organ injuries is gaining attention. Regarding liver injury, Rho-kinase inhibitor is reported to prevent carbon tetrachloride (CCl4)- or dimethylnitrosamine-induced liver fibrosis and hepatic ischemia-reperfusion injury in rats. Because Rho-kinase inhibitor not only improved liver fibrosis but also reduced serum alanine aminotransferase (ALT) level in CCl4-induced liver fibrosis, we wondered whether Rho-kinase inhibitor might exert a direct hepatocyte-protective effect. We examined this possibility in acute CCl4 intoxication in rats. Rho-kinase inhibitor, HA-1077, reduced serum alanine ALT level in rats with acute liver injury induced by CCl4 with the improvement of histological damage and the reduction of the number of apoptotic cells. In cultured rat hepatocytes in serum-free condition, HA-1077 reduced apoptosis evaluated by quantitative determination of cytoplasmic histone-associated DNA oligonucleosome fragments with the reduction of caspase-3 activity and the enhancement of Bcl-2 expression. HA-1077 stimulated phosphorylation of Akt, and wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway, abrogated the reduction of hepatocyte apoptosis by HA-1077 in vitro. Furthermore, wortmannin abrogated the reduction of serum ALT level by HA-1077 in rats with acute liver injury induced by CCl4, suggesting that the activation of PI3-kinase/Akt pathway may be involved in the hepatocyte-protective effect by Rho-kinase inhibitor in vivo. In conclusion, Rho-kinase inhibitor prevented hepatocyte damage in acute liver injury induced by CCl4 in rats and merits consideration as a hepatocyte-protective agent in liver injury, considering its direct antiapoptotic effect on hepatocytes in vitro.
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PMID:Rho-kinase inhibitor prevents hepatocyte damage in acute liver injury induced by carbon tetrachloride in rats. 1776 35

Hepatic stellate cells (HSCs) play an important role in hepatic fibrogenesis. In response to liver injury, HSCs undergo a process called activation, which involves 2 steps jonit nation from quiescent phenotype to myofibroblast-like phenotype, and perpetuation that maintains the activated phenotype of HSCs. The fate of the activated HSCs depends on the apoptotic and survival signals that they receive. The apoptosis of HSCs results from a series of complex and interrelated signaling events. Apoptotic signals for the activated HSCs include proteins from membrane receptors, such as death receptors, nerve growth factor receptor and peripheral-type benzodiazepine receptor, as well as proteins from cytoplasm such as Bcl-2 family members. The survival signals for the activated HSCs are induced by some kinases and cytokines including tissue inhibitors of metalloproteinase-1, Rho/Rho kinase, platelet-derived growth factor, transforming growth factor beta-1, and insulin-like growth factor-1. Approaches that specifically initiate HSC apoptosis are promising to be direct and effective strategies to treat liver fibrosis. Although it remains unclear whether the activated HSCs could be reversed back to the quiescent phenotype, the different expression and sensitivity of pro-apoptotic and survival molecules between quiescent and activated HSCs provide a prospect to develop therapeutic approaches that specifically targets apoptosis of the activated HSCs. These therapeutic strategies to induce HSC apoptosis are current research hotspot and the future for the patients with liver fibrosis and cirrhosis.
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PMID:Apoptotic and survival signals in hepatic stellate cells. 1800 61

Liver fibrosis due to hepatic stellate cell (HSC) activation represents a common response to chronic liver injury. PTK787/ZK222584 (PTK/ZK) is a pan-VEGFR tyrosine kinase inhibitor. The aim of this study was to examine the effect of PTK/ZK in liver fibrosis. In primary HSCs, PTK/ZK inhibited the expression of alpha-smooth muscle actin (alpha-SMA), collagen, tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as cell proliferation, migration and actin filament formation. PTK/ZK-induced apoptosis of HSCs, which was correlated with increased caspase-3 activation and suppressed Bcl-2 expression. PTK/ZK also induced cell cycle arrest, accompanied by increasing the expression of p27(Kip1) and downregulation of cyclin D1 and cyclin E. PTK/ZK significantly inhibited vascular endothelial growth factor (VEGF) expression, as well as VEGF-simulated cell proliferation and phosphorylation of Akt in activated HSCs. In a murine fibrotic liver, PTK/ZK attenuated collagen deposition and alpha-SMA expression in carbon tetrachloride-induced fibrosis in both a 'prevention' and 'treatment' dosing scheme. These beneficial effects were associated with reduced phosphorylation of Akt and suppressed mRNA expression of procollagen-(I), TIMP-1, matrix metalloproteinase-9 and CD31. These findings provide novel insights into the potential value of blocking VEGF signaling by a small molecule tyrosine kinase inhibitor in treating hepatic fibrosis.
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PMID:PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling. 1911 84

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