UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of chromaffin cells with nitric oxide (NO) donors (SNP and SNAP) and peroxynitrite produces a time- and dose-dependent necrotic and apoptotic cell death. Necrotic cell death was characterized by both an increase in lactate dehydrogenase and ATP release and changes in nuclei and cell morphology (as seen with fluorescence microscopy analysis with propidium iodide and Hoechst 33342). Apoptotic cell death was characterized by nuclear fragmentation and presence of apoptotic cell bodies, by a decrease in DNA content, and by an increase in DNA fragmentation. Treatment of chromaffin cells with lipopolysaccharide (LPS) or cytokines (interferon-gamma, tumor necrosis factor-alpha) resulted only in apoptotic cell death. Apoptotic effects of NO-inducing compounds were specifically reversed, depending on the stimuli, by the NO scavenger carboxy-PTIO (CPTio) or by the NOS inhibitors L-NMA and thiocitrulline. NO-induced apoptotic death in chromaffin cells was concomitant to a cell cycle arrest in G0G1 phase and a decrease in the number of chromaffin cells in the G2M and S phases of cell cycle. All NO-producing compounds were able to induce activation of caspase 3 and cytochrome c release, and specific inhibitors of caspase 3 and 9, such as Ac-DEVD-CHO (CPP32) and Ac-Z-LEHD-FMK, respectively, prevented NO-induced apoptosis in chromaffin cells. These results suggest that chromaffin cells could be good models for investigating the molecular basis of degeneration in diseases showing death of catecholaminergic neurons, phenomenon in which NO plays an important role.
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PMID:Nitric oxide and peroxynitrite induce cellular death in bovine chromaffin cells: evidence for a mixed necrotic and apoptotic mechanism with caspases activation. 1662 60

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

Status epilepticus results in preferential neuronal cell loss in the hippocampus. We evaluated the hypothesis that the repertoire of intracellular events in the vulnerable hippocampal CA3 subfield after induction of experimental temporal lobe status epilepticus entails upregulation of nitric oxide synthase II (NOS II), followed by the release of mitochondrial cytochrome c that triggers the cytosolic caspase-3 cascade, leading to apoptotic cell death. In Sprague-Dawley rats, significant and temporally correlated upregulation of NOS II (3-24h), but not NOS I or II expression, enhanced cytosolic translocation of cytochrome c (days 1 and 3), augmented activated caspase-3 in cytosol (days 1, 3 and 7) and DNA fragmentation (days 1, 3 and 7) was detected bilaterally in the hippocampal CA3 subfield after elicitation of sustained seizure activity by microinjection of kainic acid into the unilateral CA3 subfield. Application bilaterally into the hippocampal CA3 subfield of a selective NOS II inhibitor, S-methylisothiourea, significantly blunted these apoptotic events; a selective NOS I inhibitor, N(omega)-propyl-l-arginine or a potent NOS III inhibitor, N(5)-(1-iminoethyl)-l-ornithine was ineffective. We conclude that upregulation of NOS II contributes to apoptotic cell death in the hippocampal CA3 subfield via a cytochrome c/caspase-3 signaling cascade following the induction of experimental temporal lobe status epilepticus.
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PMID:Upregulation of nitric oxide synthase II contributes to apoptotic cell death in the hippocampal CA3 subfield via a cytochrome c/caspase-3 signaling cascade following induction of experimental temporal lobe status epilepticus in the rat. 1733 42

Reportedly, beta-amyloid peptides (Abeta40 and Abeta42) induce the neurodegenerative changes of Alzheimer's disease (AD) both directly by interacting with components of the cell surface to trigger apoptogenic signaling and indirectly by activating astrocytes and microglia to produce excess amounts of inflammatory cytokines. A possible cell surface target for Abetas is the p75 neurotrophin receptor (p75(NTR)). By using SK-N-BE neuroblastoma cells without neurotrophin receptors or engineered to express the full-length p75(NTR) or various parts of it, we have proven that p75(NTR) does mediate the Abeta-induced cell killing via its intracellular death domain (DD). This signaling via the DD activates caspase-8, which then activates caspase-3 and apoptogenesis. We also found a strong cytocidal interaction of direct p75(NTR)-mediated and indirect pro-inflammatory cytokine-mediated neuronal damage induced by Abeta. In fact, pro-inflammatory cytokines such as TNF-alpha and IL-1beta from Abeta-activated microglia potentiated the neurotoxic action of Aalpha mediated by p75(NTR) signaling. The pro-inflammatory cytokines probably amplify neuronal damage and killing by causing astrocytes to flood their associated neurons with NO and its lethal oxidizing ONOO- derivative. Indeed, we have found that a combination of three major pro-inflammatory cytokines, IL-1beta+IFN-gamma+TNF-alpha, causes normal adult human astrocytes (NAHA) to express nitric oxide synthase-2 (NOS-2) and make dangerously large amounts of NO via mitogen-activated protein kinases (MAPKs). Soluble Abeta40, the major amyloid precursor protein cleavage product, by itself stimulates astrocytes to express NOS-2 and make NO, possibly by activating p75(NTR) receptors, which they share with neurons, and can considerably amplify NOS-2 expression by the pro-inflammatory cytokine trio. These observations have uncovered a deadly synergistic interaction of Abeta peptides with pro-inflammatory cytokines in the neuron-astrocyte functional units of the AD brain. Finally, we have found that p75(NTR) and its DD also mediate the killing of SK-N-BE human neuroblastoma cells by the prion protein fragment PrP106-126. Thus, neurons expressing p75(NTR) as well as pro-inflammatory cytokine receptors are likely the preferential targets of Abetas and prions and the neurodegenerative diseases they cause.
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PMID:The killing of neurons by beta-amyloid peptides, prions, and pro-inflammatory cytokines. 1738 78

Pyramidal relay neurons in limbic cortex are vulnerable to denervation lesions, i.e. pyramidal neurons in layer IIalpha of piriform cortex undergo transsynaptic apoptosis after lesions that interrupt their inputs from the olfactory bulb. We have previously established the role of inhibitory interneurons in elaborating signals that lead to the apoptosis of projection neurons in these lesion models, i.e. the upregulation of neuronal NOS and release of nitric oxide. Thus, we have proposed that cortical interneurons play an essential role in transducing injury to degenerative effects for nearby pyramidal neurons. In the present study, we extend the previous findings to a toxic model of degeneration of pyramidal neurons in the adult paralimbic cortex, i.e. after exposure to the NMDA channel blocker MK801. Our findings indicate that treatment of adult rats with MK801 in doses previously found to cause alterations in pyramidal neurons of the retrosplenial cortex (5mg/kg) results in an active caspase 3 (+), ultrastructurally apoptotic type of cell death involving the same projection neurons of layer IIalpha that are also vulnerable to bulbotomy lesions. Interneurons of layer I are induced by MK801 treatment to higher levels of nNOS expression and the selective nNOS inhibitor BRNI ameliorates pyramidal cell apoptosis caused by MK801. Our results indicate that certain pyramidal neurons in piriform cortex are very sensitive to NMDA blockade as they are to disconnection from modality-specific afferents and that inhibitory interneurons play significant roles in mediating various types of pro-apoptotic insults to cortical projection neurons via nNOS/NO signaling.
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PMID:NMDA inhibitors cause apoptosis of pyramidal neurons in mature piriform cortex: evidence for a nitric oxide-mediated effect involving inhibitory interneurons. 1744 67

Human immunodeficiency virus dementia (HIV-D) is a nonfocal central nervous system manifestation characterized by cognitive, behavioral, and motor abnormalities. The pathophysiology of neuronal damage in HIV-D includes a direct toxic effect of viral proteins on neuronal cells and an indirect effect caused by the release of inflammatory mediators and neurotoxins by activated macrophages/microglia and astrocytes, culminating into neuronal apoptosis. Previous studies have documented that the nucleoside adenosine mediates neuroprotection by activating adenosine A(1) receptor subtype (A(1)AR) linked to suppression of neuronal excitability. In this study, we show that A(1)AR activation protects against HIV-1 Tat-induced toxicity in primary cultures of rat cerebellar granule neurons and in rat pheochromocytoma (PC12) cell. In PC12 cells, HIV-1 Tat increased [Ca(2+)](i) levels, release of nitric oxide (NO), and expression of inducible nitric-oxide synthase (iNOS) and A(1)AR. Activation of A(1)AR suppressed Tat-mediated increases in [Ca(2+)](i) and NO. Furthermore, A(1)AR agonists inhibited iNOS expression in a nuclear factor-kappaB (NF-kappaB)-dependent manner. It is noteworthy that activation of the A(1)AR or inhibition of NOS protected against Tat-induced apoptosis in PC12 cells and cerebellar granule cells. Moreover, activation of the A(1)AR-inhibited Tat-induced increases in the levels of proapoptotic proteins Bax and caspase-3. Taken together, our results demonstrate that the A(1)AR protects against HIV-1 toxicity by inhibiting NF-kappaB, thereby reducing the expression of iNOS and NO radicals and neuronal apoptosis.
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PMID:Activation of the adenosine A1 receptor inhibits HIV-1 tat-induced apoptosis by reducing nuclear factor-kappaB activation and inducible nitric-oxide synthase. 1760 15

Statins are widely used cholesterol-lowering drugs that selectively inhibit the enzyme 3-hydroxy-3-methylglutaryl CoA reductase, leading to decreased cholesterol biosynthesis. Emerging data indicate that statins stimulate apoptotic cell death in several types of proliferating tumor cells, including breast cancer cells, which is independent of its cholesterol-lowering property. The objective here was to elucidate the molecular mechanism(s) by which statins induce breast cancer cell death. Fluvastatin and simvastatin (5-10 mumol/L) treatment enhanced the caspase-3-like activity and DNA fragmentation in MCF-7 cells, and significantly inhibited the proliferation of MCF-7 cells but not MCF-10 cells (noncancerous epithelial cells). Statin-induced cytotoxic effects were reversed by mevalonate, an immediate metabolic product of the acetyl CoA/3-hydroxy-3-methylglutaryl CoA reductase reaction. Both simvastatin and fluvastatin enhanced nitric oxide ((.)NO) levels which were inhibited by mevalonate. Statin-induced (.)NO and tumor cell cytotoxicity were inhibited by 1400W, a more specific inhibitor of inducible nitric oxide synthase (iNOS or NOS II). Both fluvastatin and simvastatin increased iNOS mRNA and protein expression. Stimulation of iNOS by statins via inhibition of geranylgeranylation by GGTI-298, but not via inhibition of farnesylation by FTI-277, enhanced the proapoptotic effects of statins in MCF-7 cells. Statin-mediated antiproliferative and proapoptotic effects were exacerbated by sepiapterin, a precursor of tetrahydrobiopterin, an essential cofactor of (.)NO biosynthesis by NOS. We conclude that iNOS-mediated (.)NO is responsible in part for the proapoptotic, tumoricidal, and antiproliferative effects of statins in MCF-7 cells.
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PMID:Statin-induced breast cancer cell death: role of inducible nitric oxide and arginase-dependent pathways. 1767 Dec 9

Basic research on estrogen-related changes in cardiomyocyte gene expression is needed to provide a greater understanding of the effects of estrogen, so that hormone replacement trials and treatment can be based on a true comprehension of estrogen's pleiotropic effects. Therefore, we compared gene expression in models of estrogen depletion and estrogen replacement. Using gene expression array analysis, we examined differences in expression in cardiac tissue from ovariectomized (OVX), ovariectomized with 17beta-estradiol replacement (OVX/E2), and intact rats undergoing sham procedures (Sham). We found that OVX results in at least twofold changes in expression of genes involved in inflammation, vascular tone, apoptosis, and proteolysis compared with OVX/E2. With confirmation via real-time PCR, we found an OVX-induced increase in genes mediating inflammation (inhibin betaa, IL-6, TNF-alpha, SOCS2, SOCS3), an OVX-related decrease in the myocardial mRNA expression of genes involved in regulating vasodilation (endothelial NOS, soluble guanyl cyclase), an OVX-associated increase in extracellular matrix genes (collagen12alpha1, connexin 43), and an OVX-related increase in proapoptotic genes (caspase 3, calpain). Because details of cardiac signaling by SOCS genes are virtually unknown, we examined the protein expression for these genes via Western analyses. Although we observed OVX-related increases in SOCS2 and SOCS3 mRNA, SOCS2 and SOCS3 protein did not differ among groups. In light of these findings, investigation into the net effect of OVX on inflammation is warranted. These experiments add to existing evidence that estrogen can protect against negative changes associated with estrogen removal.
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PMID:Effect of ovariectomy on cardiac gene expression: inflammation and changes in SOCS gene expression. 1798 23

Recent studies have demonstrated that stromal cell-derived factor-1alpha (SDF-1alpha)/CXCR4 interaction regulates multiple cell signal pathways and a variety of cellular functions such as cell migration, proliferation, survival and angiogenesis. In present study, we aimed to determine the effect of SDF-1alpha on endothelial progenitor cells (EPCs) apoptosis induced by serum deprivation and the implication of phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) signaling in this effect. EPCs were isolated and characterized. SDF-1alpha decreased EPCs apoptosis induced by serum deprivation in a dose-dependent manner and the inhibitory effect was CXCR4 dependent as confirmed by the total abolishment by AMD3100, a CXCR4-specific peptide antagonist. SDF-1alpha treatment also significant decreased caspase-3 expression and activity. The inhibitory effect of SDF-1alpha on EPCs apoptosis was nearly completely abolished by PI3K inhibitors (either Wortmannin or LY294002) and partially abolished by NOS inhibitor, N(G)-nitro-arginine methyl ester, whereas inhibitors of MAPKs had no significant effect on this inhibitory effect. The treatment of EPCs with SDF-1alpha resulted in time-dependent Akt, eNOS, extracellular-regulated kinase (ERK1/2), p38 MAPK and c-Jun N-terminal kinase (JNK) phosphorylations. These findings suggest that PI3K/Akt/eNOS activation, but not MAPKs activation, is required for the inhibitory effect of SDF-1alpha on EPCs apoptosis.
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PMID:SDF-1alpha/CXCR4 decreases endothelial progenitor cells apoptosis under serum deprivation by PI3K/Akt/eNOS pathway. 1838 92

Pinocembrin is one of the flavonoids at the highest concentration in propolis. In this study, we investigated the neuroprotective effect of pinocembrin on ischemia/reperfusion and ischemia/reperfusion-like insults. Protection by pinocembrin was studied at the in vivo level using a model of middle cerebral artery occlusion and reperfusion in rats. Pinocembrin was administrated at the start of reperfusion. Pinocembrin markedly increased rat viability, reduced infarct volumes and neurological deficit scores in all treatment groups. Primary cortical neuronal cultures were subjected to oxygen-glucose deprivation/reoxygenation, a model of ischemia/reperfusion-like injury, and treated with pinocembrin at the start of reoxygenation. Neuronal survival rates were increased, LDH release was decreased and both neurite length and apoptosis were alleviated when pinocembrin was present during reoxygenation, and this protection was associated with the reduction of reactive oxygen species, nitric oxide and neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS), and an increase of glutathione. Moreover, DNA laddering was decreased in treatment groups of pinocembrin. Caspase-3 protein was down-regulated and PARP degradation was alleviated after pinocembrin treatments. Our results suggest that pinocembrin may be a novel therapeutic strategy to reduce cerebral ischemia/reperfusion injury, and may act by the anti-oxidative and anti-apoptotic effects.
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PMID:Pinocembrin protects rat brain against oxidation and apoptosis induced by ischemia-reperfusion both in vivo and in vitro. 1849 93

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