UNIPROT:P10415 - FACTA Search

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

Despite recent advances in understanding molecular mechanisms involved in glioblastoma progression, the prognosis of the most malignant brain tumor continues to be dismal. Because the flavonoid kaempferol is known to suppress growth of a number of human malignancies, we investigated the effect of kaempferol on human glioblastoma cells. Kaempferol induced apoptosis in glioma cells by elevating intracellular oxidative stress. Heightened oxidative stress was characterized by an increased generation of reactive oxygen species (ROS) accompanied by a decrease in oxidant-scavenging agents such as superoxide dismutase (SOD-1) and thioredoxin (TRX-1). Knockdown of SOD-1 and TRX-1 expression by small interfering RNA (siRNA) increased ROS generation and sensitivity of glioma cells to kaempferol-induced apoptosis. Signs of apoptosis included decreased expression of Bcl-2 and altered mitochondrial membrane potential with elevated active caspase-3 and cleaved poly(ADP-ribose) polymerase expression. Plasma membrane potential and membrane fluidity were altered in kaempferol-treated cells. Kaempferol suppressed the expression of proinflammatory cytokine interleukin-6 and chemokines interleukin-8, monocyte chemoattractant protein-1, and regulated on activation, normal T-cell expressed and secreted. Kaempferol inhibited glioma cell migration in a ROS-dependent manner. Importantly, kaempferol potentiated the toxic effect of chemotherapeutic agent doxorubicin by amplifying ROS toxicity and decreasing the efflux of doxorubicin. Because the toxic effect of both kaempferol and doxorubicin was amplified when used in combination, this study raises the possibility of combinatorial therapy whose basis constitutes enhancing redox perturbation as a strategy to kill glioma cells.
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PMID:Kaempferol induces apoptosis in glioblastoma cells through oxidative stress. 1787 51

This study examined if glutaredoxin-1 (Glrx1), a redox-regulator of thioredoxin superfamily, plays any role in the redox signaling of ischemic myocardium. The hearts were subjected to 30 min of coronary occlusion followed by 24 h of reperfusion. Another group of hearts was rendered tolerant to ischemia (preconditioned, PC) by four cyclic episodes of 5 min ischemia each followed by another 10 min of reperfusion, which was then subjected to 30 min ischemia and 24 h of coronary occlusion. While ischemia/reperfusion had no effect on Glrx1 expression, adaptation to ischemia resulted in the up-regulation of Glrx1 expression, which was inhibited by cadmium, a known inhibitor of Glrx1. CdCl(2) also abolished cardioprotection afforded by PC as evidenced by its ability to partially increase myocardial infarct size without affecting cardiomyocyte apoptosis. The amount of ROS was significantly decreased in the PC heart, which was abolished by CdCl(2). The cardioprotective role of Glrx1was further confirmed with Glrx1 transgenic and knockout mice. The mouse hearts overexpressing Glrx1 exhibited significantly improved post-ischemic ventricular recovery and reduced myocardial infarct size while hearts deficient in Glrx1 exhibited depressed functional recovery and increased infarct size as compared to the wild-type hearts. Furthermore, Glrx1-overexpressing hearts exhibited reduced and Glrx1-deficient hearts exhibited increased ROS production during ischemia and reperfusion. Adapted hearts showed increased Akt phosphorylation that was inhibited by CdCl(2). The amount of Bcl-2 protein expression was not affected by the inhibition of Glrx1. Taken together, the results of this study implicate a role of Glrx1 in cardioprotection and redox signaling of the ischemic myocardium.
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PMID:Role of glutaredoxin-1 in cardioprotection: an insight with Glrx1 transgenic and knockout animals. 2323 Jun 6

In this study, we determined the changes in the intracellular redox environment of the heart during ischemia and reperfusion and the effects of resveratrol on such changes. Because redox regulation by thioredoxin (Trx) plays a crucial role in signal transduction and cytoprotection against ROS, the effects of resveratrol on the changes in the amounts of thioredoxin were monitored in an attempt to determine the role of intracellular thioredoxin in resveratrol-mediated changes in intracellular redox environment and its role in resveratrol-mediated cardioprotection. Rats were randomly divided into four groups: group I, control (rats were gavaged with vehicle only); group II, rats were gavaged with 2.5 mg/kg body wt resveratrol per day for 10 days; group III, rats were given resveratrol for 10 days, but on the 7th day, they were treated with shRNA against Trx-1; group IV, rats were given resveratrol for 10 days, but were injected (iv) with cisplatin (1 mg/kg body wt) on days 1, 3, 5, 7, and 9. In concert, two groups of mice (Dn-Trx-1) and a corresponding wild-type group were also gavaged with 2.5 mg/kg body wt resveratrol for 10 days. After 10 days, isolated rat and mouse hearts perfused via working mode were made globally ischemic for 30 min followed by 2 h of reperfusion. Ischemia/reperfusion developed an infarct size of about 40% and resulted in about 25% apoptotic cardiomyocytes, which were reduced by resveratrol. Cisplatin, but not shRNA-Trx-1, abolished the cardioprotective abilities of resveratrol. In the experiments with mouse hearts, similar to rat hearts, resveratrol significantly reduced the ischemia/reperfusion-mediated increase in infarct size and apoptosis in both groups. MDA formation, a presumptive marker for lipid peroxidation, was increased in the I/R group and reduced in the resveratrol group, and resveratrol-mediated reduction in MDA formation was abolished with cisplatin, but not with shRNA-Trx-1. I/R-induced reduction in GSH/GSSH ratio was prevented by resveratrol, and resveratrol-mediated preservation of GSH/GSSG ratio was reduced by cisplatin, but not by sh-RNA-Trx-1. RT-PCR revealed an increase in both Trx-1 and Trx-2 transcripts; but only Trx-2 protein, not Trx-1 protein, was enhanced with resveratrol by Western blot analysis. Electron paramagnetic resonance spectroscopic study revealed that resveratrol treatment significantly increased the decay rates of nitroxide radicals compared to control hearts, suggesting that resveratrol can switch into the reduction state more compared to control heart. Finally, resveratrol generated a survival signal by phosphorylation of Akt and increase in induction of Bcl-2 expression, which was inhibited by cisplatin, but not by shRNA-Trx-1. Taken together, the results of this study indicate that resveratrol provides cardioprotection by maintaining intracellular redox environments, and Trx-2 is likely to play a role in switching I/R-induced death signal into survival signal.
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PMID:Redox regulation of resveratrol-mediated switching of death signal into survival signal. 2301 55

Docetaxel, a second-generation taxane, is one of the most powerful anticancer drugs for breast cancer. It has been widely used in the metastatic setting but also in the adjuvant or neoadjuvant setting for breast cancer patients. However, docetaxel is not effective for all breast cancers. The response rate is 40-60% even in first-line chemotherapy and it decreases to 20-30% in the second-or third-line chemotherapy. Therefore, it is very important to predict the sensitivity of docetaxel with high accuracy in order to avoid unnecessary treatment. Docetaxel binds to beta-tubulin and promotes polymerization, resulting in interference with mitosis. Unfortunately, the mechanism of sensitivity or resistance to docetaxel has not been fully understood. Recent studies in this area have demonstrated various mechanisms involved in the anti-tumor activity of docetaxel: (1) efflux (p-glycoprotein), (2) metabolism (CYP3A4), (3) beta-tubulin (isotype class I and III), (4) cell cycle (HER2, BRCA1), (5) apoptosis (p53, Bcl-2, thioredoxin), and (6) cell proliferation (MIB-1, nuclear grade). In addition, recently, gene expression profiling has been applied to the prediction of response to docetaxel in breast cancer. This work has reviewed recent studies, including ours, which have evaluated the association between these biological parameters and response to docetaxel in breast cancer.
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PMID:[Prediction of response to docetaxel in breast cancer]. 1828 55

Sildenafil citrate (SC), a drug for erectile dysfunction, is now emerging as a cardiopulmonary drug. Our study aimed to determine a novel role of sildenafil on cardioprotection through stimulating angiogenesis during ischaemia (I) reperfusion (R) at both capillary and arteriolar levels and to examine the role of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) in this mechanistic effect. Rats were divided into: control sham (CS), sildenafil sham (SS), control+IR (CIR) and sildenafil+IR (SIR). Rats were given 0.7 mg/kg, (i.v) of SC or saline 30 min. before occlusion of left anterior descending artery followed by reperfusion (R). Sildenafil treatment increased capillary and arteriolar density followed by increased blood flow (2-fold) compared to control. Treatment with sildenafil demonstrated increased VEGF and Ang-1 mRNA after early reperfusion. PCR data were validated by Western blot analysis. Significant reduction in infarct size, cardiomyocyte and endothelial apoptosis were observed in SC-treated rats. Increased phosphorylation of Akt, eNOS and expression of anti-apoptotic protein Bcl-2, and thioredoxin, hemeoxygenase-1 were observed in SC-treated rats. Echocardiography demonstrated increased fractional shortening and ejection fraction following 45 days of reperfusion in the treatment group. Stress testing with dobutamine infusion and echocardiogram revealed increased contractile reserve in the treatment group. Our study demonstrated for the first time a strong additional therapeutic potential of sildenafil by up-regulating VEGF and Ang-1 system, probably by stimulating a cascade of events leading to neovascularization and conferring myocardial protection in in vivo I/R rat model.
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PMID:Sildenafil-mediated neovascularization and protection against myocardial ischaemia reperfusion injury in rats: role of VEGF/angiopoietin-1. 1837 38

Hydrogen sulfide (H(2)S) is an endogenously produced gaseous signaling molecule with diverse physiological activity. The potential protective effects of H(2)S have not been evaluated in the liver. The purpose of the current study was to investigate if H(2)S could afford hepatoprotection in a murine model of hepatic ischemia-reperfusion (I/R) injury. Hepatic injury was achieved by subjecting mice to 60 min of ischemia followed by 5 h of reperfusion. H(2)S donor (IK1001) or vehicle were administered 5 min before reperfusion. H(2)S attenuated the elevation in serum alanine aminotransferase (ALT) by 68.6% and aspartate aminotransferase (AST) by 70.8% compared with vehicle group. H(2)S-mediated cytoprotection was associated with an improved balance between reduced glutathione (GSH) vs. oxidized glutathione (GSSG), an attenuated formation of lipid hydroperoxides, and an increased expression of thioredoxin-1 (Trx-1). Furthermore, H(2)S inhibited the progression of apoptosis after I/R injury by increasing the protein expression of heat shock protein (HSP-90) and Bcl-2. These results indicate that H(2)S protects the murine liver against I/R injury through an upregulation of intracellular antioxidant and antiapoptotic signaling pathways.
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PMID:Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling. 1856 6

Oxidative stress is implicated in menopause-associated hypertension and cardiovascular disease. The role of antioxidants in this process is unclear. We questioned whether the downregulation of thioredoxin (TRX) is associated with oxidative stress and the development of hypertension and target-organ damage (cardiac hypertrophy) in a menopause model. TRX is an endogenous antioxidant that also interacts with signaling molecules, such as apoptosis signal-regulated kinase 1 (ASK-1), independently of its antioxidant function. Aged female wild-type (WT) and follitropin receptor knockout (FORKO) mice (20-24 wk), with hormonal imbalances, were studied. Mice were infused with ANG II (400 ng x kg(-1) x min(-1); 14 days). Systolic blood pressure was increased by ANG II in WT (166+/-8 vs. 121+/-5 mmHg) and FORKO (176+/-7 vs. 115+/-5 mmHg; P<0.0001; n=9/group) mice. In ANG II-infused FORKO mice, cardiac mass was increased by 42% (P<0.001). This was associated with increased collagen content and augmented ERK1/2 phosphorylation (2-fold). Cardiac TRX expression and activity were decreased by ANG II in FORKO but not in WT (P<0.01) mice. ASK-1 expression, cleaved caspase III content, and Bax/Bcl-2 content were increased in ANG II-infused FORKO (P<0.05). ANG II had no effect on cardiac NAD(P)H oxidase activity or on O(2)(*-) levels in WT or FORKO. Cardiac ANG II type 1 receptor expression was similar in FORKO and WT. These findings indicate that in female FORKO, ANG II-induced cardiac hypertrophy and fibrosis are associated with the TRX downregulation and upregulation of ASK-1/caspase signaling. Our data suggest that in a model of menopause, protective actions of TRX may be blunted, which could contribute to cardiac remodeling independently of oxidative stress and hypertension.
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PMID:Cardiac hypertrophy is associated with altered thioredoxin and ASK-1 signaling in a mouse model of menopause. 1867 90

Bcl-2 is reported to augment the antioxidant capacity of cells and this is hypothesized to contribute to the anti-apoptotic activity of this oncoprotein. We generated a number of stable Jurkat cell lines expressing varying levels of Bcl-2, and showed a strong correlation between Bcl-2 levels and resistance to Fas-mediated apoptosis. While individual differences could be detected, there was no overall correlation between Bcl-2 and the expression and activity of superoxide dismutases, catalase, glutathione peroxidases, thioredoxin, thioredoxin reductases, and peroxiredoxins. Cells transfected with Bcl-2 averaged 70% more glutathione than parental cells, but there was no correlation between glutathione and resistance to apoptosis. This challenges the hypothesis that the anti-apoptotic properties of Bcl-2 are linked to a global increase in antioxidant status.
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PMID:Inhibition of receptor-mediated apoptosis upon Bcl-2 overexpression is not associated with increased antioxidant status. 1868 9

Bz-423 is a proapoptotic 1,4-benzodiazepine with potent therapeutic properties in murine models of lupus and psoriasis. Bz-423 modulates the F(1)F(0)-ATPase, inducing the formation of superoxide within the mitochondrial respiratory chain, which then functions as a second messenger initiating apoptosis. Herein, we report the signaling pathway activated by Bz-423 in mouse embryonic fibroblasts containing knockouts of key apoptotic proteins. Bz-423-induced superoxide activates cytosolic ASK1 and its release from thioredoxin. A mitogen-activated protein kinase cascade follows, leading to the specific phosphorylation of JNK. JNK signals activation of Bax and Bak which then induces mitochondrial outer membrane permeabilization to cause the release of cytochrome c and a commitment to apoptosis. The response of these cells to Bz-423 is critically dependent on both superoxide and JNK activation as antioxidants and the JNK inhibitor SP600125 prevents Bax translocation, cytochrome c release, and cell death. These results demonstrate that superoxide generated from the mitochondrial respiratory chain as a consequence of a respiratory transition can signal a sequential and specific apoptotic response. Collectively, these data suggest that the selectivity of Bz-423 observed in vivo results from cell-type specific differences in redox balance and signaling by ASK1 and Bcl-2 proteins.
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PMID:Bz-423 superoxide signals apoptosis via selective activation of JNK, Bak, and Bax. 1871 27

Recent studies have demonstrated the cardioprotective abilities of resveratrol, a polyphenolic antioxidant present in red wine. Resveratrol can also kill cancer cells at relatively higher doses by exerting a death signal. We reasoned that resveratrol might possess the ability to protect the cells at lower doses as observed during pharmacological preconditioning of the heart, while at higher doses cause cell death as found for cancer cells. To test this hypothesis, rats were randomly fed for 14 days by gavaging any of the four doses of resveratrol - 2.5, 5.0, 25 or 50 mg/kg - while vehicle-fed animals served as placebo control. After 14 days, isolated working hearts were prepared from both experimental and control animals, and the hearts were subjected to 30-min global ischemia followed by 2 h of reperfusion. The rats fed either 2.5 or 5 mg/kg dose of resveratrol for 14 days provided cardioprotection as evidenced by improved post-ischemic ventricular recovery and reduction of myocardial infarct size and cardiomyocyte apoptosis compared to control. In contrast, the hearts fed either 25 or 50 mg/kg dose of resveratrol depressed cardiac function and increased myocardial infarct size and number of apoptotic cells. The results for Western blots and RT-PCR demonstrated an increase of protein and RNA transcripts of redox proteins including thioredoxin (Trx)-1, Trx-2, glutaredoxin (Grx)-1, Grx-2, redox factor Ref-1 as well as redox-sensitive transcription factor NFkappaB, and survival factors such as phosphorylated-Akt (p-Akt), and Bcl-2 in the animals fed lower doses (2.5 and 5 mg/kg) of resveratrol, while the reverse was true for the animals fed higher doses (25 and 50 mg/kg) of resveratrol. The results thus indicate that at lower doses (2.5 or 5 mg/kg), resveratrol exerts survival signal by up-regulating anti-apoptotic and redox proteins Akt and Bcl-2, while at higher doses (>25 mg/kg), it potentiates a death signal by down-regulating redox proteins and up-regulating pro-apoptotic proteins.
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PMID:Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose. 2289 70

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