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)

In the present study, we investigated whether melatonin would prevent nitric oxide (NO)-induced apoptotic death of PGT-beta immortalized pineal cells. To examine the protective effect of melatonin, cytotoxicity assay, DNA fragmentation analysis, caspase-3 activity assay, and Western blotting for caspase-3 and poly(ADP-ribose) polymerase (PARP) were performed. Treatment of cells with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, was shown to induce apoptotic cell death in a dose-dependent manner, and pretreatment with melatonin (0.1 mm) attenuated the occurrence of NO-induced apoptotic cell death. DNA fragmentation in response to NO was also arrested by melatonin. Caspase-3 activity induced by NO was decreased with melatonin treatment. Furthermore, the active fragments of caspase-3 and PARP were almost completely absent following exposure to melatonin. To elucidate the protective mechanisms of action of melatonin, Western blot analyses for Bcl-2 expression and cytochrome c release were carried out. Pretreatment with melatonin (0.1 mm) induced the expression of Bcl-2 and suppressed the release of cytochrome c into the cytosol, thereby arresting NO-induced apoptotic cell death. These results suggest that the antiapoptotic effect of melatonin is associated with induction of Bcl-2 expression in PGT-beta cells, which in turn blocks caspase-3 activation and inhibits cytochrome c release into the cytosol.
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PMID:Melatonin suppresses NO-induced apoptosis via induction of Bcl-2 expression in PGT-beta immortalized pineal cells. 1222 Mar 28

We examined the linkage of nitric oxide (NO)-induced apoptosis to acceleration of brain aging of senescence-accelerated mouse prone 10 (SAMP10). The expression of neuronal nitric oxide synthase (nNOS) increased in the cerebral cortex of the brain of SAMP10 in an age-dependent manner and significantly higher levels of neuronal nitric oxide synthase (nNOS) were observed in both young and old SAMP10 as compared to age-matched controls. Moreover, a lower level of anti-apoptotic protein Bcl-2 and a higher level of pro-apoptotic protein cytochrome c in cytosol were observed in SAMP10 compared to the control. However, there was no significant difference in the expression of pro-apoptotic protein p53 between SAMP10 and the control. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive apoptotic cells were more abundant in the cerebral cortex of aged SAMP10 than in the control. The present results suggest that an age-dependent increase of NO by up-regulation of nNOS promotes the Bcl-2-linked apoptosis in the cerebral cortex of SAMP10 and this may cause the acceleration of brain aging of SAMP10.
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PMID:Bcl-2-linked apoptosis due to increase in NO synthase in brain of SAMP10. 1227 Jan 25

Nitric oxide (NO) is a small, diffusible, highly reactive molecule with a dichotomous regulatory role in the brain: an intra- and intercellular messenger under physiological conditions and a neurodegenerative agent under pathological conditions. We have recently demonstrated that long-lasting exposure to an neuronal nitric oxide synthase (nNOS) inhibitor down-regulated serine/threonine kinase (Akt) survival pathway and caused apoptosis in cerebellar granule cell cultures. The present study further substantiates the role of NO in neuronal survival by demonstrating that blocking its production down-regulates the activity of cAMP-responsive element binding protein (CREB), a transcription factor involved in cell survival and synaptic plasticity. Pharmacological dissection of the pathway linking NO to CREB shows that cGMP and its kinase are intermediate effectors. We also identify Bcl-2 as one of the anti-apoptotic genes down-regulated by NO shortage and decreased CREB phosphorylation. These results not only confirm the role of CREB in neuronal survival but also provide circumstantial evidence for a novel link among NO, CREB activation and survival.
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PMID:Nitric oxide regulates cGMP-dependent cAMP-responsive element binding protein phosphorylation and Bcl-2 expression in cerebellar neurons: implication for a survival role of nitric oxide. 1235 75

This study examined the role of nitric oxide (NO) in cytokine-induced apoptosis in adult cardiac fibroblasts (CFbs). In cultured adult rat CFbs, IL-1beta (5 ng/ml), but not interferon-gamma (10 ng/ml) or tumor necrosis factor-alpha (10 ng/ml), induced inducible NO synthase (iNOS) expression and NO production that was associated with an increase in caspase-3 activity and apoptotic cell death. Apoptotic frequency was reduced by the iNOS inhibitor S-methylisothiourea (3 x 10(-5) M). Apoptosis in response to IL-1beta was attenuated by the caspase-3 inhibitor [Z-Asp-Glu-Val-Asp-fluoromethyl ketone (Z-DVED-FMK)] but not by inhibition of guanylyl cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). IL-1beta-induced CFb apoptosis was associated with an increase in p53 and Bax protein expression with no changes in Bcl-2 or Bcl-x(L). Nuclear condensation and fragmentation occurred when isolated nuclei were exposed to an NO donor [Z-1[N-(2-aminoethyl)-N-(2-ammonoethyl)amino]diazen-1-ium-1,2-dioate (DETA-NONOate) 10(-5) M], an effect that was not blocked by the peroxynitrite scavenger Mn(III)tetrakis(4-benzoic acid) porphyrin chloride. Moreover, Mn(III)tetrakis(4-benzoic acid) porphyrin chloride attenuated but did not eliminate IL-1beta-induced CFb apoptosis, indicating that the proapoptotic effect of NO can occur independently of its conversion to peroxynitrite. Our results demonstrate that IL-1beta-induced iNOS expression can trigger NO-dependent apoptosis in adult CFbs, which appears to result from DNA damage and may be mediated by a p53-dependent apoptotic pathway.
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PMID:Mechanisms of cytokine induced NO-mediated cardiac fibroblast apoptosis. 1238 74

Vaccinia virus (VV) infects a broad range of host cells, and while it usually causes their lysis (i.e. necrosis), the nature of the cell-death phenomenon is not well understood. In this study, we show that VV induces apoptosis of cells of the murine macrophage line J774.G8, as revealed by morphological signs, DNA ladder formation, changes of mitochondrial membrane potential and annexin-V positivity. Apoptosis occurred in both untreated and IFN-gamma-pretreated macrophages, and could not be inhibited by aminoguanidine, a relatively specific inhibitor of inducible nitric oxide synthase. Inhibition of VV DNA synthesis and late gene expression by cytosine arabinoside also did not prevent apoptosis, while heat- or psoralen/UV-inactivated VV did not cause any apoptosis. Thus, VV early gene expression seems to be required for induction of apoptosis. At the cellular level, infection with VV induced a decrease in the levels of Bcl-x(L), an anti-apoptotic member of the Bcl-2 family. The importance of loss of Bcl-x(L) was demonstrated by prevention of VV-mediated apoptosis on expression of Bcl-2, a functional homologue of Bcl-x(L). Our findings provide evidence that induction of apoptosis by VV in macrophages requires virus early gene expression, does not involve nitric oxide, induces a decrease in mitochondrial membrane potential and is associated with altered levels of Bcl-x(L).
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PMID:Vaccinia virus induces apoptosis of infected macrophages. 1238 19

Glutamate, one of the excitatory neurotransmitters, contributes to the neuronal death associated with neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, and with ischemia. In Alzheimer's disease brains, there is a decreased number of dopamine D2 receptors, which might cause neuronal dysfunction or death. In the present study, bromocriptine exerted a protective effect against glutamate-induced cytotoxicity in rat cortical neurons. This neuroprotective effect was mediated via D2 receptors, because it was attenuated by domperidone, a D2 dopaminergic receptor antagonist. Another dopamine D2 agonist, quinpirole, also protected cells against glutamate toxicity. D2 agonists protected cells from calcium influx, nitric oxide, and peroxynitrite toxicity, which are thought to be the mediators of glutamate toxicity. The phosphatidylinositol 3 kinase (PI3K) inhibitor (LY294002) inhibited this neuroprotective effect of bromocriptine, in contrast to the mitogen-activated protein kinase kinase (MAPKK) inhibitor (PD98059), which did not counter the protective effect. Furthermore, Akt protein kinase, which is an effector of PI3K, was activated by bromocriptine, and the antiapoptotic protein Bcl-2 was up-regulated by bromocriptine treatment. These results suggest that D2 dopaminergic receptor activation plays an important role in neuroprotection against glutamate cytotoxicity and that the up-regulation of Bcl-2 expression via the PI3K cascade is, at least partially, involved in this effect.
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PMID:Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade. 1239 86

The present study tests the hypothesis that nitric oxide mediates the hypoxia-induced increase in expression of Bax and in DNA fragmentation in the cerebral cortex of newborn piglets, and that administration of N-nitro-L-arginine (NNLA), a nitric oxide synthase inhibitor, will prevent a change in hypoxia-induced expression of apoptotic genes and DNA damage. Piglets were assigned to normoxic, hypoxic, or NNLA-pretreated hypoxic groups. Cerebral tissue hypoxia was documented biochemically by measuring ATP and phosphocreatine (PCr) levels. Cerebral cortical neuronal nuclei were isolated and nuclear proteins were separated electrophoretically and probed with specific antibodies against Bcl-2 or Bax proteins. Neuronal nuclear DNA from normoxic, hypoxic, and NNLA-pretreated hypoxic animals was isolated, separated by electrophoresis on 1% agarose gel and stained with ethidium bromide. Cerebral hypoxia resulted in an increase in nuclear membrane Bax protein levels from 121.33+/-47.7 optical density (OD)xmm(2) in normoxic to 273.67+/-67.3 ODxmm(2) in hypoxic group (P<0.05 vs. normoxic), but levels in NNLA-pretreated hypoxic group were 155.78+/-48.3 ODxmm(2) (P<0.05 vs. hypoxic, P=NS vs. normoxic). Similarly, cerebral hypoxia resulted in the density of DNA fragments increasing from 1530.3+/-309.8 OD/mm(2) in the normoxic group to 5383.3+/-775 OD/mm(2) in the hypoxic group (P<0.05), while levels in NNLA-pretreated hypoxic group were 3574.0+/-952 OD/mm(2) (P<0.05 compared to hypoxic and normoxic groups). The data show that NNLA-pretreatment prevents the hypoxia-induced increase in Bax expression and DNA fragmentation demonstrating that the hypoxia-induced Bax gene expression and the DNA fragmentation are NO-mediated.
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PMID:Nitric oxide-mediated expression of Bax protein and DNA fragmentation during hypoxia in neuronal nuclei from newborn piglets. 1239 33

Photodynamic therapy (PDT) of cancer is a very promising technique based on the formation of singlet oxygen induced by a sensitizer after irradiation with visible light. The stimulation of tumor growth by nitric oxide (NO) was reported recently, and NO was shown to have a protective effect against PDT-induced tumor death. We investigated a putative direct effect of NO on tumor cell death induced by PDT, using the human lymphoblastoid CCRF-CEM cells and bisulfonated aluminum phthalocyanine (AlPcS2) as a sensitizer. Cells were incubated with AlPcS2 in the presence or absence of NO donors ((Z)-1-[(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, hydroxylamine and S-nitroso-N-acetylpenicillamine) or L-arginine. Under these conditions, in the absence of NO donors or L-arginine the cells died rapidly by apoptosis upon photosensitization. In the presence of NO donors or L-arginine, apoptotic cell death after photosensitization was significantly decreased. Modulation of cell death by NO was not due to S-nitrosylation of caspases and occurred at the level or upstream of caspase-9 processing. The protective effect of NO was reversed by incubating the cells with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of guanylyl cyclase, or with KT5823, an inhibitor of protein kinase G (PKG). Incubation with 8-bromo-cyclic guanosine monophosphate, a membrane permeable cyclic guanosine monophosphate analog, also decreased cell death induced by PDT. Although the protective effect of NO against apoptotic cell death in several models has been attributed to an increase in the expression of heme oxygenase-1, heat shock protein 70 or Bcl-2, this was not the case under our experimental conditions. These results show that NO decreases the extent of apoptotic cell death after PDT treatment through a PKG-dependent mechanism, upstream or at the level of caspase activation.
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PMID:Nitric oxide modulates tumor cell death induced by photodynamic therapy through a cGMP-dependent mechanism. 1240 51

Apoptosis and necrosis represent two distinct types of cell death. Apoptosis possesses unique morphologic and biochemical features which distinguish this mechanism of programmed cell death from necrosis. Extrinsic apoptotic cell death is receptor-linked and initiates apoptosis by activating caspase 8. Intrinsic apoptotic cell death is mediated by the release of cytochrome c from mitochondrial and initiates apoptosis by activating caspase 3. Cancer chemotherapy utilizes apoptosis to eliminate tumor cells. Agents which bind to the minor groove of DNA, like camptothecin and Hoechst 33342, inhibit topoisomerase I, RNA polymerase II, DNA polymerase and initiate intrinsic apoptotic cell death. Hoechst 33342-induced apoptosis is associated with disruption of TATA box binding protein/TATA box complexes, replication protein A/single-stranded DNA complexes, topoisomerase I/DNA cleavable complexes and with an increased intracellular concentration of E2F-1 transcription factor and nitric oxide concentration. Nitric oxide and transcription factor activation or respression also regulate the two apoptotic pathways. Some human diseases are associated with excess or deficient rates of apoptosis, and therapeutic strategies to regulate the rate of apoptosis include inhibition or activation of caspases, mRNA antisense to reduce anti-apoptotic factors like Bcl-2 and survivin and recombinant TRAIL to activate pro-apoptotic receptors, DR4 and DR5.
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PMID:Apoptosis: biochemical aspects and clinical implications. 1241 95

Two phenotypes of rat carotid arterial smooth muscle cells (SMC) have been isolated in our laboratory, and their proteolytic and anti-proteolytic activities have been investigated in the presence or absence of various stimulating agents. We report here a comparative study of the cytotoxic effects of nitric oxide (NO) donors, sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP), towards the swirling-type and the epithelioid-type SMCs. The concentration- and time-dependence of NO donors' capacity to induce cell deaths was measured by an intracellular acid phosphatase activity assay and cell counting. The typical morphological features of apoptosis, such as cell blebbing and cytoplasm condensation, were observed by phase contrast microscopy and with a fluorescent DNA-binding dye. Apoptotic cell deaths were confirmed using DNA fragmentation and terminal deoxyribonucelotidyl transferase-mediated dUTP nick end labelling (TUNEL) methods. Western blots were used to investigate the protein expression of several known mediators of apoptosis. It was found that both NO donors induced cell deaths in the SMC phenotypes. Compared to the swirling SMCs, the epithelioid SMCs were much more sensitive to these agents. A time- and dose-dependent decrease of cell viability was observed at NO donor concentrations higher than 0.2 mmol/l. Microscopic methods revealed cell morphology of apoptotic cell deaths. The 180-bp DNA multimers typical of apoptosis were shown by DNA fragmentation. TUNEL technique confirmed that apoptosis occurred most readily in the epithelioid SMCs than the swirling SMCs. When epithelioid SMCs were treated with SNP, changes in p53, p21(WAF1), Bcl-2, caspase 3 and PARP protein expression were found. These protein levels were unchanged when swirling SMCs were similarly treated.
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PMID:Cytotoxicity of nitric oxide donors in smooth muscle cells is dependent on phenotype, and mainly due to apoptosis. 1253 34


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