Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,3-Dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619), a potent activator of the large conductance Ca2+ activated potassium (BK(Ca)) channel, has been demonstrated to induce preconditioning (PC) in the heart. The aim of our study was to test the delayed PC effect of NS1619 in rat cortical neuronal cultures against oxygen-glucose deprivation, H2O2, or glutamate excitotoxicity. We also investigated its actions on reactive oxygen species (ROS) generation, and on mitochondrial and plasma membrane potentials. Furthermore, we tested the activation of the phosphoinositide 3-kinase (PI3K) signaling pathway, and the effect of NS1619 on caspase-3/7. NS1619 dose-dependently protected the cells against the toxic insults, and the protection was completely blocked by a superoxide dismutase mimetic and a PI3K antagonist, but not by BK(Ca) channel inhibitors. Application of NS1619 increased ROS generation, depolarized isolated mitochondria, hyperpolarized the neuronal cell membrane, and activated the PI3K signaling cascade. However, only the effect on the cell membrane potential was antagonized by BK(Ca) channel blockers. NS1619 inhibited the activation of capase-3/7. In summary, NS1619 is a potent inducer of delayed neuronal PC. However, the neuroprotective effect seems to be independent of cell membrane and mitochondrial BK(Ca) channels. Rather it is the consequence of ROS generation, activation of the PI3K pathway, and inhibition of caspase activation.
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PMID:Delayed neuronal preconditioning by NS1619 is independent of calcium activated potassium channels. 1818 41

Disruption of leptin signaling has been associated with both obesity and heart failure. We recently demonstrated that leptin deficiency in ob/ob mice and leptin insensitivity in db/db mice leads to increased myocyte apoptosis and left ventricular (LV) hypertrophy. We showed that LV mass, while similar among young ob/ob, db/db, and wild type (WT) mice, is significantly higher in old ob/ob and db/db versus WT. Ob/ob and db/db mice developed markedly increased rates of myocyte apoptosis by TUNEL and activated caspase-3 levels. An intriguing candidate for the study of obesity-associated cardiac hypertrophy and apoptosis is PI3K, which functions to not only regulate cell size but also maintain cell integrity through protection from apoptosis. Here we further show that ob/ob mice have decreased catalytic activity of phosphoinositide 3-kinase (PI3K) (p110alpha) which is reversed with leptin treatment. Leptin repletion in ob/ob mice also reduced both myocyte apoptosis and LV hypertrophy to WT levels. We have therefore concluded that normal leptin signaling is necessary to prevent age-related myocyte apoptosis and LV hypertrophy and that PI3K is a critical component of the leptin signaling axis. The decrease in p110alpha catalytic activity could explain the development of increased myocyte apoptosis and cardiac hypertrophy in these obese mouse models.
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PMID:Decreased p110alpha catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficient ob/ob mice. 1823 69

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

Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. The phytoestrogen puerarin, the main isoflavone glycoside found in the root of Pueraria lobata, has been used for various medicinal purposes in traditional Chinese medicines for thousands of years. Recent studies have indicated that the estrogen receptor (ER), through interaction with p85, regulates phosphoinositide 3-kinase (PI3K) activity, revealing a physiologic, non-nuclear function of ER that may be relevant in cytoprotection. In this study, we demonstrate that the phytoestrogen puerarin inhibits tert-butyl hydroperoxide (t-BHP)-induced oxidative injury via an ER-dependent Gbeta1/PI3K/Akt and heme oxygenase-1 (HO-1) pathway. Pretreatment of Hepa1c1c7 and HepG2 cells with puerarin significantly reduced t-BHP-induced caspase-3 activation and subsequent cell death. Also, puerarin up-regulated HO-1 expression and this expression conferred cytoprotection against oxidative injury induced by t-BHP. Moreover, puerarin induced Nrf2 nuclear translocation, which is upstream of puerarin-induced HO-1 expression, and PI3K activation, a pathway that is involved in induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection. Puerarin-induced up-regulation of HO-1 and cytoprotection against t-BHP were abolished by silencing Nrf2 expression with specific siRNA. Also, puerarin-mediated increases in PI3K activation and HO-1 induction were reversed by co-treatment with ICI 182,780 and pertussis toxin. Taken together, these results suggest that puerarin augments cellular antioxidant defense capacity through ER-dependent HO-1 induction via the Gbeta1/PI3K/Akt-Nrf2 signaling pathway, thereby protecting cells from oxidative stress.
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PMID:Mechanism of phytoestrogen puerarin-mediated cytoprotection following oxidative injury: estrogen receptor-dependent up-regulation of PI3K/Akt and HO-1. 1884 76

Diets high in soy are neuroprotective in experimental stroke. This protective effect is hypothesized to be mediated by phytoestrogens contained in soy, because some of these compounds have neuroprotective effects in in vitro models of cell death. We tested the ability of the soy phytoestrogens genistein, daidzein, and the daidzein metabolite equol to protect embryonic rat primary cortical neurons from ischemic-like injury in vitro at doses typical of circulating concentrations in human populations (0.1-1 microM). All three phytoestrogens inhibited lactate dehydrogenase (LDH) release from cells exposed to glutamate toxicity or the calcium-ATPase inhibitor, thapsigargin. In cells exposed to hypoxia or oxygen-glucose deprivation (OGD), pretreatment with the phytoestrogens inhibited cell death in an estrogen receptor (ER) dependent manner. Although OGD results in multiple modes of cell death, examination of alpha-spectrin cleavage and caspase-3 activation revealed that the phytoestrogens were able to inhibit apoptotic cell death in this model. In addition, blockade of phosphoinositide 3-kinase prevented the protective effects of genistein and daidzein, and blockade of mitogen-activated protein kinase prevented genistein-dependent neuroprotection. These results suggest that pretreatment with dietary levels of soy phytoestrogens can mimic neuroprotective effects observed with estrogen and appear to use the same ER-kinase pathways to inhibit apoptotic cell death.
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PMID:Soy phytoestrogens are neuroprotective against stroke-like injury in vitro. 1897 94

The aim of this study was to investigate the effect of capsaicin on hypoxia-reoxygenation (H/R)-induced apoptosis in primary rat hippocampal neurons. Three hours of hypoxia (1% O2) and subsequent reoxygenation for 24 h significantly increased the apoptotic death of hippocampal neurons, as evidenced by increases in both TUNEL-positive cell number and caspase-3 activity. Pretreatment with capsaicin (3-30 micromol/L) or the caspase-3-specific inhibitor acetyl-DEVD-CHO (100 micromol/L) markedly attenuated H/R-induced apoptosis in hippocampal neurons. Capsaicin also markedly induced the phosphorylation of Akt. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (10 micromol/L) prevented any capsaicin-induced survival effect in hippocampal neurons. Intracellular levels of reactive oxygen species (ROS), which were greatly increased after H/R, were significantly inhibited by capsaicin, pyrrolidine dithiocarbamate (PDTC) (50 micromol/L), and LY294002. Taken together, these data suggest that capsaicin protects against H/R-induced apoptosis of hippocampal neurons via the PI3K/Akt-mediated signaling pathway, which is related to the inhibition of oxidative stress and caspase-3 activation.
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PMID:Protection of capsaicin against hypoxia-reoxygenation-induced apoptosis of rat hippocampal neurons. 1901 74

Signaling by the B cell antigen receptor (BCR) is essential for B lymphocyte homeostasis and immune function. In immature B cells, ligation of the BCR promotes growth arrest and apoptosis, and BCR-driven balancing between pro-apoptotic extracellular signal-regulated kinase 1 and 2 (ERK1/2) and anti-apoptotic phosphoinositide 3-kinase-dependent Akt seems to define the final cellular apoptotic response. Dysfunction of these late BCR signaling events can lead to the development of immunological diseases. Here we report on novel cyclic AMP-dependent mechanisms of BCR-induced growth arrest and apoptosis in the immature B lymphoma cell line WEHI-231. BCR signaling to ERK1/2 and Akt requires cyclic AMP-regulated Epac, the latter acting as a guanine nucleotide exchange factor for Rap1 and H-Ras independent of protein kinase A. Importantly, activation of endogenously expressed Epac by a specific cyclic AMP analog enhanced the induction of growth arrest (reduced DNA synthesis) and apoptosis (nuclear condensation, annexin V binding, caspase-3 cleavage and poly-ADP-ribose polymerase processing) by the BCR. Our data indicate that cyclic AMP-dependent Epac signals to ERK1/2 and Akt upon activation of Rap1 and H-Ras, and is involved in BCR-induced growth arrest and apoptosis in WEHI-231 cells.
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PMID:B cell receptor-induced growth arrest and apoptosis in WEHI-231 immature B lymphoma cells involve cyclic AMP and Epac proteins. 1916 86

Nicastrin (NCT) is a component of the presenilin (PS)-dependent gamma-secretase complexes that liberate amyloid beta-peptides from the beta-Amyloid Precursor Protein. Several lines of evidence indicate that the members of these complexes could also contribute to the control of cell death. Here we show that over-expression of NCT increases the viability of human embryonic kidney (HEK293) cells and decreases staurosporine (STS)- and thapsigargin (TPS)-induced caspase-3 activation in various cell lines from human and neuronal origins by Akt-dependent pathway. NCT lowers p53 expression, transcriptional activity and promoter transactivation and reduces p53 phosphorylation. NCT-associated protection against STS-stimulated cell death was completely abolished by p53 deficiency. Conversely, the depletion of NCT drastically enhances STS-induced caspase-3 activation and p53 pathway and favored p53 nuclear translocation. We examined whether NCT protective function depends on PS-dependent gamma-secretase activity. First, a 29-amino acid deletion known to reduce NCT-dependent amyloid beta-peptide production did not affect NCT-associated protective phenotype. Second, NCT still reduces STS-induced caspase-3 activation in fibroblasts lacking PS1 and PS2. Third, the gamma-secretase inhibitor DFK167 did not affect NCT-mediated reduction of p53 activity. Altogether, our study indicates that NCT controls cell death via phosphoinositide 3-kinase/Akt and p53-dependent pathways and that this function remains independent of the activity and molecular integrity of the gamma-secretase complexes.
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PMID:p53-dependent control of cell death by nicastrin: lack of requirement for presenilin-dependent gamma-secretase complex. 1918 41

Thioredoxin (Trx) is a 12-kDa protein ubiquitously expressed in all living cells that fulfills a variety of biological functions related to cell proliferation and apoptosis. It is characterized by the highly conserved reduction/oxidation (redox)-active site sequence Trp-Cys-Gly-Pro-Cys-Lys. Trx acts as a powerful antioxidant and plays an important role in maintaining critical protein thiols in the reduced state. Moreover, it has been shown to scavenge reactive oxygen species (ROS) and to protect against oxidative stress. We have reported that Trx-1 protects against neuronal damage during focal ischemia. However, the mechanisms underlying this protective effect and the effect of Trx-1 on neuronal apoptosis during ischemia have not been fully clarified. In this study, we analyzed the effect of Trx-1 overexpression against neuronal degeneration after a short duration of transient brain ischemia. Mild focal ischemia was reported to induce neuronal death through apoptosis. We employed Fluorojade-B staining to detect neuronal degeneration. In Trx transgenic mice, a smaller number of Fluorojade-B-positive neurons were detected after ischemia-reperfusion than in wild-type mice. In addition, we detected cleaved caspase-3- and TUNEL-positive cells, which indicated caspase-dependent apoptosis. Fewer caspase-3- and TUNEL-positive neurons were detected after ischemia-reperfusion in Trx transgenic mice than in wild-type mice. Furthermore, Akt signaling was reported to play a role in neuronal survival in Trx-1 overexpressing mice. After ischemia-reperfusion, Western blot and immunohistochemical analysis indicated that phosphorylation of Akt was enhanced in Trx transgenic mice after ischemia-reperfusion. Intraventricular injection of LY294002,which is a phosphoinositide 3-kinase (PI3K), vanished the neuroprotective effect in Trx-1 transgenic mice. These results indicate that Trx-1 overexpression protects neurons from apoptosis after ischemia-reperfusion.
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PMID:Attenuation of neuronal degeneration in thioredoxin-1 overexpressing mice after mild focal ischemia. 1932 86

Epoxyeicosatrienoic acid(s) (EETs) have been shown to protect cardiovascular tissue against apoptosis dependent on activation of targets such as ATP-sensitive K+ (KATP) channels (sarcolemmal and mitochondrial), calcium-activated K+ channels, extracellular signal-regulated kinase or phosphoinositide 3-kinase (PI3K). We tested if EETs protect human atrial tissue ex vivo from hypoxia/reoxygenation (H/R) injury, and compared our results with myocardium from two rodent species, rats and mice. EETs reduced myocardial caspase 3 activity in all three species and protected against loss of mitochondrial membrane potential in primary cultures of neonatal rat ventricular myocytes submitted to H/R. In addition, EETs protected mouse pulmonary arteries ex vivo exposed to H/R. Myocardium and pulmonary arteries from genetically engineered mice having elevated plasma levels of EETs (Ephx2-/-) exhibited protection from H/R-induced injury over that of wild type controls, suggesting that endogenously produced EETs may have pro-survival effects. Electrophysiological studies in myocytes demonstrated that EETs can stimulate KATP currents even when PI3K is inhibited. Similarly, activation of PI3K/Akt occurred in the presence of the KATP channel blocker glibenclamide. Based upon loss of protection with EETs in the presence of either wortmannin (a PI3K inhibitor) or glibenclamide, simultaneous activation of at least 2 pathways, PI3K and KATP channels respectively, appears to be required for protection. In conclusion, we demonstrate that exogenous and endogenous EETs have powerful pro-survival effects in cardiovascular tissues including diseased human myocardium, mediated by activation of not only one but at least two pathways, PI3K and KATP channels.
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PMID:Protective actions of epoxyeicosatrienoic acid: dual targeting of cardiovascular PI3K and KATP channels. 1933 74


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