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:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Continuous endoplasmic reticulum (ER) stress, such as the accumulation of unfolded proteins, results in cell death and relates to the pathogenesis of some neurodegenerative diseases. Treatment of brefeldin A, an inhibitor of transport between the ER and Golgi complex, induced cell death during 24 h, which accompanied activation of caspase-2, caspase-3 and caspase-9, starting at 12 h and increasing time-dependently up to 28 h. Caspase-2 was expressed and activated in not only mitochondria and cytosol, but also in the microsomal fraction containing ER and Golgi. Of note is that overexpression of Bcl-x(L) or Bcl-2 in PC12 cells markedly suppressed brefeldin A-induced activation of caspases and resulting cell death. Delivery of anti-Bcl-2 antibody into the Bcl-2-overexpressed cells again recovered apoptosis. While the brefeldin A-treatment induced the phosphorylation of both c-Jun N-terminal kinase (JNK) and p38 MAPK, overexpression of Bcl-x(L) or Bcl-2 reduced the prolonged phosphorylation of JNK, but not of p38 MAPK. Pretreatment with a JNK inhibitor, SP600125, suppressed the brefeldin A-induced caspase-2 activation and cell death significantly. Thus, our results suggest that protective effects of Bcl-x(L) and Bcl-2 against brefeldin A-induced cell death appear to be dependent on the regulation of JNK activation.
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PMID:Suppression of endoplasmic reticulum stress-induced caspase activation and cell death by the overexpression of Bcl-xL or Bcl-2. 1730 Oct 78

A novel small molecule inhibitor, 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB), competes with the Bak BH3 peptide to bind Bcl-2 protein with a binding affinity of IC(50) = 0.70 microM, as assessed by a fluorescence polarization based binding assay. HL-60 cells express the highest levels of Bcl-2 among the cell lines examined. Treated with 5 microM of MNB only for 6 h, 85% of HL-60 cells were detected to undergo apoptosis. Pan-caspase inhibitor, Z-VAD-FMK, blocks MNB-induced apoptosis in HL-60 cells. Caspase-2, caspase-3, caspase-7, caspase-8, caspase-9, and PARP activation were observed at as early as 4 to 6 h of MNB treatment. In addition, it has been confirmed that the caspase-3 specific inhibitor, Z-DEVD-FMK, blocks the activation of caspase-8 in MNB-treated HL-60 cells. MNB treatment does not change Bcl-2 or Bax expression level in HL-60 cells, but causes Bid cleavage. Further experiments have illustrated that MNB inhibits the heterodimerization of Bcl-2 with Bax or Bid, reduces the mitochondrial membrane potential (DeltaPsimt), and induces cytochrome c release from mitochondria in HL-60 cells. These results suggest that MNB induces apoptosis in HL-60 by inhibiting the heterodimerization of Bcl-2 with pro-apoptosis Bcl-2 members, resulting in a decrease in the mitochondrial membrane potential and cytochrome c release, activation of caspases and PARP; it is a caspase-dependent process in which the activation of caspase-8 is dependent on the mitochondrial apoptosis signal transduction pathway. MNB prolongs the life spans of HL-60 bearing mice, potently kills fresh AML and ALL cells, indicating that it has the potential to be developed to treat leukemia.
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PMID:A novel Bcl-2 small molecule inhibitor 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB)-induced apoptosis in leukemia cells. 1739 62

Follicular lymphoma (FL) remains a fatal disease of increasing worldwide incidence. Since patients with FL eventually develop resistance to conventional anticancer agents, and due to BCL-2 overexpression present with profoundly compromised execution of mitochondrial pathway of apoptosis, targeting alternative pathways of cell demise may appear therapeutically beneficial. Herein we report for the first time the effects of an ER-Golgi transport inhibitor, Brefeldin A (BFA), alone and in combination with a small molecule Bcl-2 inhibitor HA14-1 or agonistic anti-Fas mAb, in the recently established human FL cell lines. All cell lines tested were sensitive to BFA-induced cytotoxicity and apoptosis. Moreover BFA-induced cell death was associated with profound ER stress, mitochondrial breach and subsequent caspase cascade activation, including caspase 2 activation. Interestingly, BFA-induced ER stress did not result in appearance of autophagic morphology in FL cells. Of importance, small molecule Bcl-2 antagonist, HA14-1 and agonistic anti-Fas mAb significantly enhanced BFA-mediated cytotoxicity and apoptosis, revealing novel and previously unexplored means to enhance ER stress-mediated cell killing in follicular lymphoma cells.
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PMID:Brefeldin A triggers apoptosis associated with mitochondrial breach and enhances HA14-1- and anti-Fas-mediated cell killing in follicular lymphoma cells. 1742 36

Oxidized low-density lipoprotein contains many potentially proatherogenic molecules, including oxysterols, which have been shown to induce apoptosis in various cell lines. The aim of this study was to investigate the pathway of apoptosis induced by oxidized low-density lipoprotein and the oxysterols, 7beta-hydroxycholesterol and cholesterol-5beta,6beta-epoxide, in two human monocytic cell lines. The HL-60 cells appeared to be more sensitive to oxidized low-density lipoprotein than U937 cells, whereas the isolated oxysterols were more potent inducers of apoptosis in the U937 cells. Caspase-2 inhibition decreased the number of viable cells in oxidized low-density lipoprotein-treated samples; however, it protected against cholesterol-5beta,6beta-epoxide-induced cell death. Western blot analysis was utilized to examine the effect of caspase-2 inhibition on the expression of the antiapoptotic protein Bcl-2. Pretreatment with the inhibitor protected against the decrease in Bcl-2 expression in oxidized low-density lipoprotein- and 7beta-hydroxycholesterol-treated U937 cells. In HL-60 cells, Bcl-2 was overexpressed in oxidized low-density lipoprotein-treated cells, but in the presence of the inhibitor Bcl-2 expression was returned to control levels. Depleted ATP concentrations in the cells suggest that both apoptosis and necrosis may have occurred simultaneously. Our results highlight differences in the signaling pathways induced by oxidized low-density lipoprotein, 7beta-hydroxycholesterol, and cholesterol-5beta,6beta-epoxide in U937 and HL-60 cells.
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PMID:Death-signaling pathways in human myeloid cells by oxLDL and its cytotoxic components 7beta-hydroxycholesterol and cholesterol-5beta,6beta-epoxide. 1799 74

Aberrations in proteins that control apoptosis and cell survival are common in cancer. These aberrations often reside in signalling proteins that control the activation of the apoptotic machinery or in the Bcl-2 family of proteins that control caspase activation. Recent evidence suggests that caspase 2, one of the most evolutionarily conserved caspases, may have multiple roles in the DNA damage response, cell cycle regulation and tumour suppression. These findings are unexpected and have important implications for our understanding of tumorigenesis and the treatment of cancer.
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PMID:Caspase 2 in apoptosis, the DNA damage response and tumour suppression: enigma no more? 1989 Mar 34

Alveolar epithelial cells of neonates are directly exposed to aspirated meconium during meconium aspiration syndrome (MAS). This study was designed to investigate the influence of quantity and time of meconium exposure on the cell viability and caspase activity in type II human alveolar epithelial cells. Human alveolar epithelial cells were incubated with human meconium suspension at different concentrations and for different times. Cell viability and DNA fragmentation were investigated together with caspases activity and the amount of Bcl-2 protein present. We found that cell viability was significantly lower in cells exposed to a higher concentration of meconium. This was also true for cells exposed to meconium for longer. Significantly higher DNA fragmentation, an approximately two- to fivefold increase, was observed in cells that had been exposed to higher (5% and 10%) concentration of meconium compared to those treated with lower (0.1% and 1%) concentrations (P < 0.05). The activity of most apoptotic initiators (caspase 2, 8, 9, 10) and effectors (caspase 3, 6) were found to be significantly higher in cells subject to greater meconium exposure compared to cells with no or minor meconium exposure. The level of Bcl-2 was also found to be significantly decreased in meconium-exposed cells (P < 0.05). In conclusion, human meconium would seem to induce direct cell death as well as caspase-dependent apoptosis in alveolar epithelial cells; the amount and period of exposure to meconium are crucial factors in this process. Thus, removing aspirated meconium should alleviate lung cell damage in neonates and improve the outcome with MAS.
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PMID:Meconium exposure dependent cell death and apoptosis in human alveolar epithelial cells. 2062 81

Exposure of cells to hyperthermia is known to induce apoptosis, although the underlying mechanisms are only partially understood. Here, we examine the molecular requirements necessary for heat-induced apoptosis using genetically modified Jurkat T-lymphocytes. Cells stably overexpressing Bcl-2/Bcl-x(L) or stably depleted of Apaf-1 were completely resistant to heat-induced apoptosis, implicating the involvement of the mitochondria-mediated pathway. Pretreatment of wild-type cells with the cell-permeable biotinylated general caspase inhibitor b-VAD-fmk (biotin-Val-Ala-Asp(OMe)-CH(2)F) both inhibited heat-induced apoptosis and affinity-labeled activated initiator caspase-2, -8, and -9. Despite this finding, however, cells engineered to be deficient in caspase-8, caspase-2, or the caspase-2 adaptor protein RAIDD (receptor-interacting protein (RIP)-associated Ich-1/CED homologous protein with death domain) remained susceptible to heat-induced apoptosis. Additionally, b-VAD-fmk failed to label any activated initiator caspase in Apaf-1-deficient cells exposed to hyperthermia. Cells lacking Apaf-1 or the pro-apoptotic BH3-only protein Bid exhibited lower levels of heat-induced Bak activation, cytochrome c release, and loss of mitochondrial membrane potential, although cleavage of Bid to truncated Bid (tBid) occurred downstream of caspase-9 activation. Combined, the data suggest that caspase-9 is the critical initiator caspase activated during heat-induced apoptosis and that tBid may function to promote cytochrome c release during this process as part of a feed-forward amplification loop.
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PMID:Activation of caspase-9, but not caspase-2 or caspase-8, is essential for heat-induced apoptosis in Jurkat cells. 2097 29

To explore the effect and mechanism of quercetin on proliferation and apoptosis of leukemia cells, and provide a theoretical basis for its clinical application. HL-60 leukemia cell lines was treated with different dose quercetin, the proliferation activity of leukemia cells was assessed by MTT method; the morphological changes of apoptosis of HL-60 cells, including nuclear condensation and DNA fragmentation, were observed by Hoechst 33258 fluorescence staining, the apoptosis rate and caspase 2,3 activation were assessed by flow cytometry, and the cell signal pathway including phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (pAkt), Bcl-2, Bax were detected by western blotting. Quercetin could significantly decrease the proliferation activity of HL-60 cells through the blockade of G(0)/G(1) phase, and induce the apoptosis of HL-60 cells in a time- and dose-dependent manner. Quercetin caused leukemia cells apoptosis by decreasing the protein expression of PI3K and Bax, the inhibitory phosphorylation of Akt, the decreased levels of Bcl-2 protein and increased activations of caspase-2 and -3, and increased poly(ADP-ribose) polymerase cleavage. Our results indicate that the apoptotic processes caused by quercetin are mediated by the decrease of pAkt and Bcl-2 levels, the increase of Bax level, and the activation of caspase families in HL-60 cells.
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PMID:Quercetin-induced apoptosis of HL-60 cells by reducing PI3K/Akt. 2255 76

Stem cell transplantation has been used to improve neural function in intracerebral hemorrhage (ICH). However, reports on bone marrow-derived mesenchymal stem cell (MSC) transplantation in ICH are limited. We aimed to explore the therapeutic effect and related mechanisms by transplantation of MSCs in rats with ICH. An experimental rat ICH model was established by intrastriatal administration of collagenase. The rats were randomly divided to receive either rat MSCs or PBS solution intravenously. In addition, behavioral tests using the modified neurological severity score (mNSS) were performed following ICH. Immunohistochemistry was performed to detect the Brdu-labeled MSCs and the protein expression of caspase 2, NF200 and GFAP in neural tissues. Western blotting and ELISA were performed to measure the protein expression of Akt and bcl-2 or the protein content of G-CSF and BDNF. The MSC-transplanted group demonstrated better neural function on the mNSS test following ICH compared with the control group (P<0.05). The MSC-transplanted group also showed reduced hemorrhage volume at 24 and 72 h following ICH. In the perihematomal regions of rat brain with ICH, a substantial number of Brdu-labeled MSCs were observed, and a high protein expression of caspase 3, NF200 and GFAP was found in the MSC-transplanted group. The protein content of Akt, Bcl-2, G-CSF and BDNF were all elevated by MSC transplantation. Intravenously transplanted MSCs are capable of improving functional recovery and restoring neurological deficits in experimental ICH. The mechanisms are associated with enhanced survival and differentiation of neural cells, and increased expression of anti-apoptotic proteins and trophic factors.
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PMID:Therapeutic effect of mesenchymal stem cells in rats with intracerebral hemorrhage: reduced apoptosis and enhanced neuroprotection. 2282 63

It is known that ionising radiation (IR) induces a complex signalling apoptotic cascade post-exposure to low doses ultimately to remove damaged cells from a population, specifically via the intrinsic pathway. Therefore, it was hypothesised that bystander reporter cells may initiate a similar apoptotic response if exposed to low doses of IR (0.05Gy and 0.5Gy) and compared to directly irradiated cells. Key apoptotic genes were selected according to their role in the apoptotic cascade; tumour suppressor gene TP53, pro-apoptotic Bax and anti-apoptotic Bcl2, pro-apoptotic JNK and anti-apoptotic ERK, initiator caspase 2 and 9 and effector caspase 3, 6 and 7. The data generated consolidated the role of apoptosis following direct IR exposure for all doses and time points as pro-apoptotic genes such as Bax and JNK as well as initiator caspase 7 and effector caspase 3 and 9 were up-regulated. However, the gene expression profile for the bystander response was quite different and more complex in comparison to the direct response. The 0.05Gy dose point had a more significant apoptosis gene expression profile compared to the 0.5Gy dose point and genes were not always expressed within 1h but were sometimes expressed 24h later. The bystander data clearly demonstrates initiation of the apoptotic cascade by the up-regulation of TP53, Bax, Bcl-2, initiator caspase 2 and effector caspase 6. The effector caspases 3 and 7 of the bystander samples demonstrated down-regulation in their gene expression levels at 0.05Gy and 0.5Gy at both time points therefore not fully executing the apoptotic pathway. Extensive analysis of the mean-fold gene expression changes of bystander data demonstrated that the apoptosis is initiated in the up-regulation of pro-apoptotic and initiator genes but may not very well be executed to final stages of cell death due to down-regulation of effector genes.
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PMID:Apoptosis is signalled early by low doses of ionising radiation in a radiation-induced bystander effect. 2345 91


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