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)

Intravenous administration to mice of trans-pterostilbene (t-PTER; 3,5-dimethoxy-4'-hydroxystilbene) and quercetin (QUER; 3,3',4',5,6-pentahydroxyflavone), two structurally related and naturally occurring small polyphenols, inhibits metastatic growth of highly malignant B16 melanoma F10 (B16M-F10) cells. t-PTER and QUER inhibit bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. However, the molecular mechanism(s) linking polyphenol signaling and bcl-2 expression are unknown. NO is a potential bioregulator of apoptosis with controversial effects on Bcl-2 regulation. Polyphenols may affect NO generation. Short-term exposure (60 min/day) to t-PTER (40 microM) and QUER (20 microM) (approximate mean values of the plasma concentrations measured within the first hour after intravenous administration of 20 mg of each polyphenol/kg) down-regulated inducible NO synthetase in B16M-F10 cells and up-regulated endothelial NO synthetase in the vascular endothelium and thereby facilitated endothelium-induced tumor cytotoxicity. Very low and high NO levels down-regulated bcl-2 expression in B16M-F10 cells. t-PTER and QUER induced a NO shortage-dependent decrease in cAMP-response element-binding protein phosphorylation, a positive regulator of bcl-2 expression, in B16M-F10 cells. On the other hand, during cancer and endothelial cell interaction, t-PTER- and QUER-induced NO release from the vascular endothelium up-regulated neutral sphingomyelinase activity and ceramide generation in B16M-F10 cells. Direct NO-induced cytotoxicity and ceramide-induced mitochondrial permeability transition and apoptosis activation can explain the increased endothelium-induced death of Bcl-2-depleted B16M-F10 cells.
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PMID:Nitric oxide mediates natural polyphenol-induced Bcl-2 down-regulation and activation of cell death in metastatic B16 melanoma. 1713 64

The importance of hormone therapy in affording protection against the sequelae of global ischemia in postmenopausal women remains controversial. Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous estradiol ameliorates global ischemia-induced neuronal death and cognitive impairment in male and female rodents. However, the molecular mechanisms by which estrogens intervene in global ischemia-induced apoptotic cell death are unclear. Here we show that estradiol acts via the classical estrogen receptors, the IGF-I receptor, and the ERK/MAPK signaling cascade to protect CA1 neurons in ovariectomized female rats and gerbils. We demonstrate that global ischemia promotes early dephosphorylation and inactivation of ERK1 and the transcription factor cAMP-response element binding protein (CREB), subsequent down-regulation of the antiapoptotic protein Bcl-2, a known gene target of estradiol and CREB, and activation of caspase-3. Estradiol treatment increases basal phosphorylation of both ERK1 and ERK2 in hippocampal CA1 and prevents ischemia-induced dephosphorylation and inactivation of ERK1 and CREB, down-regulation of Bcl-2 and activation of the caspase death cascade. Whereas ERK/MAPK signaling is critical to CREB activation and neuronal survival, the impact of estradiol on Bcl-2 levels is ERK independent. These findings support a model whereby estradiol acts via the classical estrogen receptors and IGF-I receptors, which converge on activation of ERK/MAPK signaling and CREB to promote neuronal survival in the face of global ischemia.
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PMID:MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia. 1713 46

Growing evidence suggests that multiple spatially, temporally, and functionally distinct pools of cyclic nucleotides exist and regulate cardiac performance, from acute myocardial contractility to chronic gene expression and cardiac structural remodeling. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP and cyclic GMP, regulate the amplitude, duration, and compartmentation of cyclic nucleotide-mediated signaling. In particular, PDE3 enzymes play a major role in regulating cAMP metabolism in the cardiovascular system. PDE3 inhibitors, by raising cAMP content, have acute inotropic and vasodilatory effects in treating congestive heart failure but have increased mortality in long-term therapy. PDE3A expression is downregulated in human and animal failing hearts. In vitro, inhibition of PDE3A function is associated with myocyte apoptosis through sustained induction of a transcriptional repressor ICER (inducible cAMP early repressor) and thereby inhibition of antiapoptotic molecule Bcl-2 expression. Sustained induction of ICER may also cause the change of other protein expression implicated in human and animal failing hearts. These data suggest that the downregulation of PDE3A observed in failing hearts may play a causative role in the progression of heart failure, in part, by inducing ICER and promoting cardiac myocyte dysfunction. Hence, strategies that maintain PDE3A function may represent an attractive approach to circumvent myocyte apoptosis and cardiac dysfunction.
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PMID:Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart. 1733 39

Although there is substantial evidence supporting the neuroprotective efficacy of basic fibroblast growth factor (bFGF) in the rodent retina there is no consensus to date as to the protective mechanism involved. We hypothesise that bFGF can assert its neuroprotective effects directly on mouse photoreceptors transduced via the activation of specific intracellular signalling pathways. In mouse photoreceptor-derived 661W cells, bFGF promoted a rapid inactivation of glycogen synthase kinase 3beta (GSK3beta) by phosphorylation at Ser9. The effects of bFGF on GSK3beta were dependent on protein kinase A (PKA) activation, as inhibition of this pathway blocked inactivation. Furthermore, bFGF protection against oxidative stress was dependent on PKA inactivation of GSK3beta as PKA inhibition attenuated bFGF-induced protection. Furthermore, transfection of cells with mutant dominant negative GSK3betaS9A that cannot be phosphorylated on Ser9 also abrogated neuroprotection. Activation of the transcription factor cAMP-response element binding protein (CREB) and subsequent up-regulation of Bcl-2 in response to bFGF was also dependent on PKA as inhibition with H-89 attenuated increased pCREB levels and Bcl-2 expression. These results indicate that the protective efficacy of bFGF in mouse photoreceptors involves PKA-dependent inactivation of GSK3beta and subsequent up-regulation of Bcl-2 via CREB activation.
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PMID:bFGF promotes photoreceptor cell survival in vitro by PKA-mediated inactivation of glycogen synthase kinase 3beta and CREB-dependent Bcl-2 up-regulation. 1771 51

The acute neuronal degeneration in the ischemic core upon stroke is followed by a second wave of cell demise in the ischemic penumbra and neuroanatomically connected sites. This temporally delayed deleterious event of programmed cell death ('secondary degeneration') often exceeds the initial damage of stroke and, thus, contributes pivotally to significant losses in neurological functions. In fact, it is the injured neurons in these regions around the ischemic core zone that neuropharmacological prevention is targeting to preserve. Clinical and pre-clinical studies have focussed on neuroprotective interventions with caspase inhibitors, but it remains ambiguous whether diminishing or even silencing these aspartate-specific cysteine proteases are in sum beneficial for the clinical outcome. It is often ignored that caspase inhibitors are able to antagonize calpain and cathepsins, thereby protecting the cytoskeleton from damage. Moreover, there is a point of no return, beyond which interfering with caspases cannot rescue the cell, but spoil the obligate and necessary suicide program such that the cellular environment suffers from by-products of necrosis and secondary inflammation. Here we discuss novel alternative strategies to abrogate the death cascade at the level of the genomic response (transcription factors, NF-kappaB, CREB, ICER, HIF), of mitochondrial effectors (cytochrome c, Bcl-2, Smac/DIABLO, HtrA2), and of inhibitor of apoptosis proteins (IAPs). IAPs are the only known endogenous proteins that inhibit specifically and with high affinity the activity of both initiator and effector caspases. Based on compelling biochemical evidence, we argue that patronizing the neuronal endogenous anti-apoptotic machinery could be superior to the pharmacological inhibition of caspases at various levels, with regard to specificity, side effects, and the 'therapeutic window of opportunity'.
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PMID:Exploiting endogenous anti-apoptotic proteins for novel therapeutic strategies in cerebral ischemia. 1851 Nov 72

N-butylidenephthalide (BP), isolated from the chloroform extract of Angelica sinensis, has been examined for its antitumor effects on glioblastoma multiforme brain tumors; however, little is known about its antitumor effects on hepatocellular carcinoma cells. Two hepatocellular carcinoma cell lines, HepG2 and J5, were treated with either N-butylidenephthalide or a vehicle, and cell viability and apoptosis were evaluated. Apoptosis-related mRNA and proteins expressed, including orphan receptor family Nurr1, NOR-1, and Nur77, were evaluated as well as the effect of N-butylidenephthalide in an in vivo xenograft model. N-butylidenephthalide caused growth inhibition of both the cell lines at 25 microg/ml. Furthermore, N-butylidenephthalide-induced apoptosis seems to be related to Nur77 translocation from nucleus to cytosol, which leads to cytochrome c release and caspase-3-dependent apoptosis. N-butylidenephthalide-related tumor apoptosis was associated with phosphatidylinositol 3-kinase/protein kinase B (AKT)/glycogen synthase kinase-3beta rather than the mitogen-activated protein kinase or protein kinase C pathway. Blockade of AKT activation enhanced proliferation inhibition and the induction of phosphor-Bcl-2 and Nur77 proteins. Besides, the increasing apoptosis by BP via transfection wild-type cAMP-response element-binding protein (CREB) into tumor cell was suppressed by dominant phosphorylation site mutation of CREB. This finding suggested CREB pathway was also partly involved in tumor apoptosis caused by BP. Administration of N-butylidenephthalide showed similar antitumoral effects in both HepG2 and J5 xenograft tumors. N-Butylidenephthalide induced apoptosis in hepatocellular carcinoma cells, both in vitro and in vivo, suggesting a potential clinical use of this compound for improving the prognosis of hepatocellular carcinoma cells.
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PMID:The induction of orphan nuclear receptor Nur77 expression by n-butylenephthalide as pharmaceuticals on hepatocellular carcinoma cell therapy. 1857 87

To investigate the changes of inducible cAMP early repressor (ICER) and phosphodiesterase 3A in rats after myocardial infarction and to evaluate the beneficial effects of valsartan on cardiac function and ventricular remodeling. Rats were split into four groups: sham-operation group, pre-myocardial infarction group (valsartan administration 2 weeks before myocardial infarction), post-myocardial infarction group (valsartan administration after myocardial infarction) and myocardial infarction group (vehicle after myocardial infarction). Echocardiograph and hemodynamic data were measured and cardiocyte apoptosis was estimated by TUNEL staining. ICER, cAMP response element binding protein (CREB), phosphodiesterase 3A and Bcl-2 mRNA expression levels were assayed by real-time reverse transcriptase polymerase chain reaction and protein expression was measured using immunoblot analysis. ICER and CREB mRNA expression in the myocardial infarction group were higher and phosphodiesterase 3A and Bcl-2 mRNA expression were lower than the sham-operation group (Ps<0.01). Following the improvement of cardiac function and ventricular remodeling, ICER and CREB mRNA in pre- and post- myocardial-infarction groups were down-regulated, and phosphodiesterase 3A and Bcl-2 mRNA were up-regulated (P<0.05). The changes brought on by valsartan pre-myocardial infarction were stronger than post-myocardial infarction (P<0.05). These data suggest that there is a phosphodiesterase 3A-ICER positive-feedback loop leading to myocyte apoptosis and ongoing development of heart failure after myocardial infarction. Maintaining the function of phosphodiesterase 3A or reducing ICER may be an effective way to prevent myocardium apoptosis and heart dysfunction. Valsartan can ameliorate ventricular remodeling and heart failure by inhibiting the expression of ICER and increasing the expression of phosphodiesterase 3A.
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PMID:Interventional effect of valsartan on expression of inducible cAMP early repressor and phosphodiesterase 3A in rats after myocardial infarction. 1902 36

Chromatin can exert a regulatory effect on gene transcription by modulating the access of transcription factors to target genes. In the present study, we examined whether nuclear actions of the incretin hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, involve modulation of beta-cell chromatin structure. Stimulation of INS-1(832/13) beta-cells or dispersed mouse islets with glucose-dependent insulinotropic polypeptide or glucagon-like peptide-1 resulted in the post-translational modification of core H3 histones, through acetylation and phosphorylation. Both increased histone H3 acetyltransferase and reduced histone deacetylase activities contributed. Subsequent studies demonstrated that incretin-mediated histone H3 modifications involved activation of protein kinase A, p42/44 mitogen-activated protein kinase (MAPK), and p38 MAPK signaling modules, resulting in the activation of mitogen- and stress-activated kinase-1. Additionally, modification of histone H3 increased its association with the transcription factor, phosphorylated cAMP-response element-binding protein (phospho-CREB) and with cAMP-responsive CREB coactivator 2. Incretin-activated CREB-related Bcl-2 transcription was greatly reduced by a histone acetyltransferase inhibitor, demonstrating the functional importance of histone H3 modification. This appears to be the first demonstration of beta-cell chromatin modification in response to the incretins and the studies indicate that their regulatory effects involve coordinated nuclear interactions between specific signaling modules, chromatin-modifying enzymes and transcription factors.
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PMID:Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 modulate beta-cell chromatin structure. 1927

Flavonoid-rich foods have been shown to be effective at reversing age-related deficits in learning and memory in both animals and humans. However, little investigation of the preventative effects of flavonoids on the naturally aged animals was reported. In our study, 14-month-old female C57BL/6 J mice were orally administered 0.025%, 0.05% and 0.1% green tea catechins (GTC, w/v) in drinking water for 6 months; we found that a supplementation with 0.05% or 0.1% GTC prevented age-related spatial learning and memory decline of mice in the Morris water maze. Better performance of GTC-treated mice was associated with increased levels of cAMP-response element binding protein (CREB) phosphorylation in the hippocampus. The expressions of brain-derived neurotrophic factor (BDNF) and Bcl-2, two target genes of CREB which can exhibit long-term regulatory roles in synaptic plasticity and synaptic structure, were also increased. We also found that long-term 0.05% or 0.1% GTC administration prevented age-related reductions of two representative post-synaptic density proteins PSD95 and Ca(2+)/calmodulin-dependent protein kinase II, suggesting that synaptic structural changes may be involved. These results demonstrated that long-term 0.05% or 0.1% green tea catechin administration may prevent age-related spatial learning and memory decline of female C57BL/6 J mice by regulating hippocampal CREB signaling cascade.
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PMID:Long-term administration of green tea catechins prevents age-related spatial learning and memory decline in C57BL/6 J mice by regulating hippocampal cyclic amp-response element binding protein signaling cascade. 1940 6

We examined our hypothesis that (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) inhibits apoptosis in myocardial ischemia and reperfusion (I/R) injury in vivo via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and by reducing inflammation during I/R. To do this, we induced a 30-min period of ischemia by occlusion of the left anterior descending coronary artery of the rat followed by a 2-h (for phosphorylation of Akt), 6-h (for biochemical analysis), or 24-h (for functional analysis) period of reperfusion to determine the effect of CKD712 treatment. Pretreatment with CKD712 significantly improved myocardial function as evidenced by an increase in the +/-dP/dt and a decrease in the infarct size, which were antagonized by a PI3K inhibitor, wortmannin (WT). Interestingly, CKD712 increased the phosphorylation of Akt and cAMP-response element-binding protein and increased the expression of the Bcl-2 gene, but it reduced the expression of the Bax gene. CKD712 decreased not only the expression but also the activity of the caspase-3 protein in the myocardium after reperfusion. Thus, all of the antiapoptotic effects of CKD712 were significantly inhibited by WT. Furthermore, the antiapoptotic effects of CKD712 and its inhibition by WT in myocardium after reperfusion were confirmed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining. Finally, CKD712 was found to reduce the serum levels of the high-mobility group box 1 protein, tumor necrosis factor-alpha, and the cardiac troponin I protein in addition to tissue levels of malondialdehyde and myeloperoxidase activity in I/R hearts. Taken together, both the activation of PI3K/Akt and its anti-inflammatory action prevent apoptosis in myocardial I/R injury by CKD712.
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PMID:(S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) reduces rat myocardial apoptosis against ischemia and reperfusion injury by activation of phosphatidylinositol 3-kinase/Akt signaling and anti-inflammatory action in vivo. 1945 86


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