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)

Tetrazolium violet (TV), a potent anticancer agent, has been shown to induce cell growth-inhibition in tumor cells. However, the related mechanism has not been revealed yet. In this report we assessed the influence of TV on cell growth and cell cycle in brain tumor cells. Treatment of C6 tumor cells with TV (5-15 microM for 24-72 h) resulted in a growth inhibition in a dose and time-dependent manner and G0/G1 phase arrest, determined by flow cytometry analysis. These effects were accompanied by apoptosis other than necrosis, evidenced by nuclear condensation, terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay and trypan blue exclusion assay plus lactate dehydrogenase (LDH) release assay. Treatment of cells with TV at 15 microM for 24 h resulted in an increase in the activity of caspase-3, evidenced by colorimetric assay, and a dramatic up-regulation of p53, accompanied with a significant increase of Bax/Bcl-2 ratio, as evidenced by immunofluorescence assay. These results suggest that TV induces growth inhibition of C6 cells through p53-midiated apoptotic pathway and G0/G1 checkpoint mechanism. Although detailed mechanisms remain to be explored, selective blockage of tumor cells in G0/G1 phase accompanied by p53-associated apoptosis makes tetrazolium violet a promising anticancer agent, meriting further investigations.
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PMID:Tetrazolium violet induces G0/G1 arrest and apoptosis in brain tumor cells. 1631 59

We previously showed that C-phycocyanin (PC), an antioxidant biliprotein pigment of Spirulina platensis (a blue-green alga), effectively inhibited doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes. Here we investigated the cardioprotective effect of PC against ischemia-reperfusion (I/R)-induced myocardial injury in an isolated perfused Langendorff heart model. Rat hearts were subjected to 30 min of global ischemia at 37 degrees C followed by 45 min of reperfusion. Hearts were perfused with PC (10 microM) or Spirulina preparation (SP, 50 mg/l) for 15 min before the onset of ischemia and throughout reperfusion. After 45 min of reperfusion, untreated (control) hearts showed a significant decrease in recovery of coronary flow (44%), left ventricular developed pressure (21%), and rate-pressure product (24%), an increase in release of lactate dehydrogenase and creatine kinase in coronary effluent, significant myocardial infarction (44% of risk area), and TdT-mediated dUTP nick end label-positive apoptotic cells compared with the preischemic state. PC or SP significantly enhanced recovery of heart function and decreased infarct size, attenuated lactate dehydrogenase and creatine kinase release, and suppressed I/R-induced free radical generation. PC reversed I/R-induced activation of p38 MAPK, Bax, and caspase-3, suppression of Bcl-2, and increase in TdT-mediated dUTP nick end label-positive apoptotic cells. However, I/R also induced activation of ERK1/2, which was enhanced by PC treatment. Overall, these results for the first time showed that PC attenuated I/R-induced cardiac dysfunction through its antioxidant and antiapoptotic actions and modulation of p38 MAPK and ERK1/2.
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PMID:C-phycocyanin protects against ischemia-reperfusion injury of heart through involvement of p38 MAPK and ERK signaling. 1637 83

We investigated the mechanism of the pan-caspase inhibitor z-VAD-fmk's augmentation of TNFalpha-induced L929 cell death and found this mechanism differs from that of TNFalpha-induced L929 cell death. In the presence of 20 ng/ml TNFalpha, z-VAD-fmk initiated apoptosis and necrosis in the majority of L929 cells as measured by an agarose gel electrophoresis and lactate dehydrogenase(LDH)activity based assay. Mitochondrial permeability transition (MPT) inhibitor (cyclosporine A) effectively inhibited z-VAD-fmk-augmented cell death. In addition, z-VAD-fmk plus TNFalpha increased Bax expression without affecting Bcl-2 and cytochrome expression. Western-blot analysis showed that z-VAD-fmk plus TNFalpha caused persistent JNK activation and ERK inactivation. Poly(ADP-ribose) polymerase (PARP) inhibitor (DPQ) effectively reversed the cell death which was augmented by z-VAD-fmk, and z-VAD-fmk plus TNFalpha also caused PARP cleavage to an 85 KDa fragment. These results indicate that in the presence of TNFalpha, z-VAD-fmk further augments cell death which requires the mitochondrial permeability transition and the JNK activation. However, we did not detect the changes in cytochrome c expression and the participation of caspase-9 in this process, suggesting that there might exist an unknown signal pathway(s) from the mitochondria to the downstream protein PARP, which is cleaved in a caspase-independent manner.
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PMID:The augmentation of TNFalpha-induced cell death in murine L929 fibrosarcoma by the pan-caspase inhibitor Z-VAD-fmk through pre-mitochondrial and MAPK-dependent pathways. 1641 68

Gastrointestinal neuroendocrine tumours (NET) represent a heterogeneous tumour entity. The anti-neoplastic therapy of advanced NET disease is still unsatisfactory and innovative therapeutic approaches are needed. As NET frequently express insulin-like growth factors (IGFs) and their receptors (IGFR), known to promote survival, oncogenic transformation, tumour growth and spreading, the inhibition of the IGF/IGF-receptor system may offer possibilities for novel targeted treatment strategies of NET. Here, we studied the anti-neoplastic effects of an inhibition of the IGF-I receptor (IGF-1R) signalling in NET cells by the novel IGF-1R tyrosine kinase (TK) inhibitor NVP-AEW541, whose anti-neoplastic potency has not yet been tested in NET disease. Using two human NET cell lines with different growth characteristics, we demonstrated that NVP-AEW541 dose-dependently inhibited the proliferation of NET cells by inducing apoptosis and cell cycle arrest. Anti-neoplastic effects of NVP-AEW541 were also detected in primary cultures of human neuroendocrine gastrointestinal tumours. Apoptosis was characterized by activation of the apoptotic key enzyme, caspase-3, as well as by detection of changes in the expression of the pro- and anti-apoptotic proteins, BAX and Bcl-2, after NVP-AEW541 treatment. Cell cycle was arrested at the G1/S checkpoint. The anti-neoplastic effects of NVP-AEW541 involved the inactivation of ERK1/2. Induction of immediate cytotoxicity did not account for the anti-neoplastic effects of NVP-AEW541, as shown by measurement of lactate dehydrogenase release. Moreover, additive anti-neoplastic effects were observed when NVP-AEW541 was combined with cytostatics such as doxorubicin or the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin. This is the first report on the induction of apoptosis and cell cycle arrest by the IGF-1R-TK inhibitor, NVP-AEW541, in NET cells. The inhibition of the IGF/IGFR system appears to be a promising novel approach for future treatment strategies of NET disease.
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PMID:The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours. 1660 Dec 84

Exposure to sublethal stress can trigger endogenous protection against subsequent, higher levels of stress. We tested for this preconditioning phenomenon in a model of Parkinson's disease by applying 6-hydroxydopamine to the dopaminergic MN9D cell line. Exposure to sublethal concentrations of 6-hydroxydopamine (5-10 microM) protected against the toxic effects of a subsequent exposure to a higher concentration (50 microM), as measured by the Hoechst assay for nuclear viability. This was accompanied by little or no protection against 6-hydroxydopamine-induced lactate dehydrogenase release, decline in ATP, or reduction in (3)H-dopamine uptake. The antioxidant, N-acetyl cysteine (20 mM), when applied during preconditioning, abolished protection, as did the protein synthesis inhibitor, cycloheximide (0.2 microM). Preconditioning did not affect superoxide dismutase or glutathione peroxidase enzymes, or levels of heat shock protein-72. However, Bcl-2 protein levels rose with preconditioning. Preconditioning rapidly increased phosphorylation of kinases ERK1/2, Akt and JNK, and was abolished by pharmacological inhibitors of their activity. Finally, sublethal 6-hydroxydopamine preconditioned against the toxicity of proteasome inhibitor, MG-132 (1 microM). Thus, exposure of a dopaminergic cell line to sublethal oxidative stress can protect against additional oxidative stress due to translational and post-translational modifications, as well as confer 'cross-tolerance' against a different insult, proteasome inhibition.
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PMID:Effect of sublethal 6-hydroxydopamine on the response to subsequent oxidative stress in dopaminergic cells: evidence for preconditioning. 1695 75

Cyclic GMP-dependent protein kinases protein kinase G (PKG) Ialpha and PKGIbeta are major mediators of cGMP signaling in the cardiovascular system. PKGIalpha is present in the heart, although its role in protection against ischemia/reperfusion injury is not known. We investigated the direct effect of PKGIalpha against necrosis and apoptosis following simulated ischemia (SI) and reoxygenation (RO) in cardiomyocytes. Adult rat cardiomyocytes were infected with adenoviral vectors containing hPKGIalpha or catalytically inactive mutant hPKGIalphaK390A. After 24 h, the cells were subjected to 90 min of SI and 2 h RO for necrosis (trypan blue exclusion and lactate dehydrogenase release) or 18 h RO for apoptosis studies. To evaluate the role of K(ATP) channels, subgroups of cells were treated with 5-hydroxydecanoate (100 microm), HMR1098 (30 microm), or glibenclamide (50 microm), the respective blockers of mitochondrial, sarcolemmal, or both types of K(ATP) channels prior to SI. The necrosis observed in 33.7 +/- 1.6% of total myocytes in the SI-RO control group was reduced to 18.6 +/- 0.8% by PKGIalpha (mean +/- S.E., n = 7, p < 0.001). The apoptosis observed in 17.9 +/- 1.3% of total myocytes in the SI-RO control group was reduced to 6.0 +/- 0.6% by PKGIalpha (mean +/- S.E., n = 7, p < 0.001). In addition, PKGIalpha inhibited the activation of caspase-3 after SI-RO in myocytes. Myocytes infected with the inactive PKGIalphaK390A mutant showed no protection. PKGIalpha enhanced phosphorylation of Akt, ERK1/2, and JNK, increased Bcl-2, inducible nitric-oxide synthase, endothelial nitric-oxide synthase, and decreased Bax expression. 5-Hydroxydecanoate and glibenclamide abolished PKGIalpha-mediated protection against necrosis and apoptosis. However, HMR1098, had no effect. A scavenger of reactive oxygen species, as well as inhibitors of phosphatidylinositol 3-kinase, ERK, JNK1, and NOS, also blocked PKGIalpha-mediated protection against necrosis and apoptosis. These results show that opening of mitochondrial K(ATP) channels and generation of reactive oxygen species, in association with phosphorylation of Akt, ERK, and JNK, and increased expression of NOS and Bcl-2, play an essential role in the protective effect of PKGIalpha.
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PMID:Cyclic GMP-dependent protein kinase Ialpha attenuates necrosis and apoptosis following ischemia/reoxygenation in adult cardiomyocyte. 1703 26

Bee venom (BV) has been known to inhibit proliferation and induce apoptosis in cancer cells. However, the molecular mechanisms involved in BV-induced apoptosis are still uncharacterized in human leukemic cells. In the present study, we report that BV induces apoptosis in leukemic U937 cells through downregulation of ERK and Akt signal pathway. Furthermore, BV-induced apoptosis was accompanied by downregulation of Bcl-2, activation of caspase-3 and a subsequent poly(ADP-ribose)polymerase (PARP) cleavages. The induction of apoptosis also was accompanied by the downregulation of the inhibitor of apoptosis protein (IAP) family proteins. Caspase-3 inhibitor, z-DEVD-fmk, was significantly capable of restoring cell viability and BV-induced apoptosis through caspase-3 activation was significantly attenuated in Bcl-2-overexpressing cells. These results indicate that downregulation of Bcl-2 plays a major role in the initiation as an activator of a caspase-3 involved with BV-induced apoptosis. BV also triggered the activation of p38 MAPK and JNK, and downregulation of ERK and Akt. PD98059 (an inhibitor of ERK) or LY294002 (an inhibitor of Akt), but not an inhibitor of p38 MAPK and JNK, significantly decreased cell viability and increased lactate dehydrogenase (LDH) release. The results indicated that key regulators in BV-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of the ERK and Akt signal pathway.
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PMID:Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. 1705 70

Terminally differentiated adult injured cardiac myocytes have been used for various animal models of heart failure. It has recently been shown that isoproterenol induces injury in rat neonatal cardiac myocytes via a beta-adrenergic pathway, suggesting that it might be one of the factors involved in myocardial cell injury in heart failure in vivo. In the study, silibinin, a plant flavanoid from milk thistle was first evaluated for its protective effect against beta-adrenergic agonist isoproterenol-induced injury in cultured rat neonatal cardiac myocytes. The viability, activation of lactate dehydrogenase (LDH), and content of maleic dialdehyde (MDA) were chosen for measuring the degree of cardiac myocytes injury. As a result, silibinin protected isoproterenol-treated rat cardiac myocytes from death and significantly decreased LDH release and MDA production. Silibinin increased superoxide dismutase activity, decreased [Ca(2+)](i), and increased mitochondrial membrane potential (DeltaPsi). Furthermore, the release of pro-apoptotic cytochrome c from mitochondria was reduced by silibinin. Silibinin increased the expression of anti-apoptotic Bcl-2 family protein Bcl-2, and up-regulation of SIRT1 inhibited the translocation of Bax from cytoplasm to mitochondria, which caused mitochondrial dysfunction and cell injury. These results demonstrate that silibinin protects against isoproterenol-induced cardiac myocytes injury through resuming mitochondrial function and regulating the expression of SIRT1 and Bcl-2 family members.
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PMID:Silibinin protects against isoproterenol-induced rat cardiac myocyte injury through mitochondrial pathway after up-regulation of SIRT1. 1717 May 12

Statins are most commonly prescribed to reduce hypercholesterolemia; however, recent studies have shown that statins have additional benefits, including neuroprotection. Until now, the mechanism underlying statin-induced neuroprotection has been poorly understood. Recent in vivo studies from our lab reported the novel finding that simvastatin increased expression levels of a gene encoding for a major cell survival protein, bcl-2 [Johnson-Anuna et al., J. Pharmacol. Exp. Ther.312 (2005) 786]. The purpose of the present experiments was to determine if simvastatin could protect neurons from excitotoxicity by altering Bcl-2 levels. Neurons were pre-treated with simvastatin and challenged with a compound known to reduce Bcl-2 levels and induce cell death. Simvastatin pre-treatment resulted in a significant reduction in cytotoxicity (lactate dehydrogenase release and caspase 3 activation) following challenge compared with unchallenged neurons. In addition, chronic simvastatin treatment significantly increased Bcl-2 mRNA and protein levels while challenge resulted in a significant reduction in Bcl-2 protein abundance. G3139, an antisense oligonucleotide directed against Bcl-2, abolished the protective effects of simvastatin and eliminated simvastatin-induced up-regulation of Bcl-2 protein. These findings suggest that neuroprotection by simvastatin is dependent on the drug's previously unexplored and important effect of up-regulating Bcl-2.
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PMID:Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein. 1724 Nov 14

Beta-amyloid protein (Abeta) is the hallmark of pathogenic neurotoxins which contribute greatly to Alzheimer's disease (AD)-associated cascade including severe neuronal loss. In present study, icaritin, an active natural ingredient from a Chinese plant, Epimedium sagittatum maxim, was investigated to assess its neuroprotective effect against the toxicity induced with Abeta(25-35) in primary cultured rat cortical neuronal cells as well as the underlying mechanisms. Abeta(25-35) induced neuronal toxicity, characterized by decreased cell viability, lactate dehydrogenase (LDH) release, and neuronal DNA condensation, which is associated with both the loss of membrane potential and the alteration of the expression of Bcl-2 family proteins. The phenotype alternation induced by Abeta(25-35) could be reversed by icaritin. Furthermore, the neuroprotective effects of icaritin mentioned above were estrogen receptor dependent due to the blocking action induced by estrogen receptor antagonist ICI 182,780 and well matched binding affinity with estrogen receptor by a receptor-ligand docking experiment. mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD98059 weakened the protective effects, which implied mitogen-activated protein kinase/extracellular signal-regulated kinase pathway may also be involved in and partly contributed to the neuroprotective effects of icaritin.
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PMID:Neuroprotective effects of icaritin against beta amyloid-induced neurotoxicity in primary cultured rat neuronal cells via estrogen-dependent pathway. 1732 91


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