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)

Cadmium (Cd2+) is a highly toxic metal that affects the endocrine system. We have previously shown that Cd2+ induces caspase-3 activation and apoptosis of anterior pituitary cells and that endogenous nitric oxide (NO) protects these cells from Cd2+. Here we investigate the mechanisms by which NO exerts this protective role. Cd2+ (25 microM) reduced the mitochondrial membrane potential (MMP) as measured by flow cytometry. Cd2+-induced apoptosis was mitochondrial dependent since cyclosporin A protected the cells from this metal. Inhibition of NO synthesis with 0.5 mM L-NAME increased the effect of Cd2+ on MMP, whereas the NO donor DETANONOate (0.1 mM) reduced it. Cd2+ increased the production of reactive oxygen species (ROS) as measured by flow cytometry. This effect was electron-transfer-chain-dependent since it was inhibited by rotenone. In fact, rotenone reduced the cytotoxic effect of the metal. The action of Cd2+ on mitochondrial integrity was ROS dependent. Trolox, an antioxidant, inhibited the effect of the metal on the MMP. Cd2+-induced increase in ROS generation was reduced by DETANONOate. There are discrepancies concerning the role of NO in Cd2+ toxicity. Here we show that NO reduces Cd2+ toxicity by protecting the mitochondria from oxidative stress in a system where NO plays a regulatory role.
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PMID:Nitric oxide protects the mitochondria of anterior pituitary cells and prevents cadmium-induced cell death by reducing oxidative stress. 1645 99

This study was carried out to investigate the apoptotic effects of glycoprotein (SNL glycoprotein, 150-kDa) isolated from Solanum nigrum Linne, which has been used as an antipyretic and anticancer agent in folk medicine. We found that SNL glycoprotein consists of carbohydrate content (69.74%) and protein content (30.26%), which contains more than 50% hydrophobic amino acids such as glycine and proline. SNL glycoprotein showed remarkable cytotoxic and apoptotic effects at 40 microg/ml of SNL glycoprotein for 4 h in HCT-116 cells. In the activity of the apoptotic related proteins [caspase-3 and poly(ADP-ribose)polymerase (PARP)], the results showed that SNL glycoprotein (40 microg/ml) has a stimulatory effect on caspase-3 activation and PARP cleavage in HCT-116 cells. Moreover, SNL glycoprotein blocked nuclear factor-kappa B (NF-kappaB) activation and reduced inducible nitric oxide (iNO) production. Interestingly, pyrrolidine dithiocarbamate (PDTC, for NF-kappaB inhibitor) and N omega-Nitro-L-arginine methylester hydrochloride (L-NAME, for NO inhibitor) effectively stimulated the caspase-3 activation in HCT-116 cells. The results in this experiment indicated that SNL glycoprotein induces apoptosis through the NF-kappaB activation and inducible nitric oxide (iNO) production in HCT-116 cells. Here, we speculate that SNL glycoprotein is one of the chemotherapeutic agents and of the modulators for apoptotic signals in HCT-116 cells.
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PMID:150 kDa glycoprotein isolated from Solanum nigrum Linne stimulates caspase-3 activation and reduces inducible nitric oxide production in HCT-116 cells. 1652 44

Nitric oxide (NO) and the expression of endothelial (eNOS) and inducible (iNOS) isoforms of nitric oxide synthase (NOS) are recognized as important mediators of physiological and pathological processes of renal ischemia/reperfusion (I/R) injury, but little is known about their role in apoptosis. The ability of the eNOS/NO system to regulate the iNOS/NO system and thus promote apoptosis was assessed during experimental renal I/R. Renal caspase-3 activity and the number of TUNEL-positive cells increased with I/R, but decreased when NOS/NO systems were blocked with L-NIO (eNOS), 1400W (iNOS), and N-nitro-l-arginine methyl ester (L-NAME; a nonselective NOS inhibitor). I/R increased renal eNOS and iNOS expression as well as NO production. The NO increase was eNOS- and iNOS-dependent. Blockage of NOS/NO systems with L-NIO or L-NAME also resulted in a lower renal expression of iNOS and iNOS mRNA; in contrast, eNOS expression was not affected by iNOS-specific blockage. In conclusion, two pathways define the role of NOS/NO systems in the development of apoptosis during experimental renal I/R: a direct route, through eNOS overexpression and NO production, and an indirect route, through expression/activation of the iNOS/NO system, induced by eNOS.
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PMID:NO and NOS isoforms in the development of apoptosis in renal ischemia/reperfusion. 1654 Mar 95

p38 MAPK is activated during heart diseases that might associate with myocardial damage and deterioration of cardiac function. In a rat model of myocardial injury, we have investigated cardioprotective effects of the inhibition of p38 MAPK using a novel, orally available p38alpha MAPK inhibitor. Rats were treated with N(omega)-nitro-l-arginine methyl ester (l-NAME, 40 mg.kg(-1).day(-1)) in drinking water plus 1% salt for 14 days and ANG II (0.5 mg.kg(-1).day(-1)) for 3 days. A selective p38alpha MAPK inhibitor, SD-282 (60 mg/kg), was administrated orally, twice a day for 4 days, starting 1 day before ANG II administration. The cardioprotective effects of p38alpha MAPK inhibition were evaluated by improvement of cardiac function, reduction of inflammatory cell infiltration, and cardiomyocyte apoptosis. SD-282 significantly improved cardiac function indicated by increasing stroke volume, cardiac output, ejection fraction, and stroke work and significantly decreasing arterial elastance. SD-282 also significantly reduced macrophage infiltration as judged by reduction of a specific marker, ED-1-positive staining cells (P < 0.05) in the myocardium. Furthermore, cardiomyocyte apoptosis as indicated by caspase-3 immunohistochemical staining was abolished by SD-282, and this effect may contribute to the reduction of myocardial damage evaluated by imaging analysis (P < 0.05 in both cases). Data suggest that p38alpha MAPK may play a critical role in the pathogenesis of cardiac dysfunction. Inhibition of p38alpha MAPK may be used as a novel cardioprotective strategy in attenuation of inflammatory response and deterioration of cardiac function that occurs in acute cardiovascular disease such as myocardial infarction.
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PMID:Selective inhibition of p38alpha MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury. 1675 Dec 95

HMG-CoA reductase inhibitors improve endothelial function and exert antiproliferative effects on vascular smooth muscle cells of systemic vessels. This study was aimed to assess the protective effects of pravastatin (an HMG-CoA reductase inhibitor) against monocrotaline-induced pulmonary hypertension in rats. Pravastatin (PS, 10 mg/kg/day) or vehicle were given orally for 28 days to Wistar male rats injected or not with monocrotaline (MC, 60 mg/kg intraperitonealy) and treated or not by N(omega)-nitro-L-arginine methyl ester (L-NAME) 15 mg/kg/day. At 4 weeks, monocrotaline-injected rats developed severe pulmonary hypertension, with an increase in right ventricular pressure (RVP) and right ventricle/left ventricle+septum weight ratio (RV/LV+S), associated with a decrease in pulmonary artery dilation induced either by acetylcholine or sodium nitroprusside. Hypertensive pulmonary arteries exhibited an increase in medial thickness, medial wall area, endothelial cell apoptosis, and a decrease of endothelial nitric oxide synthase (eNOS) expression. Monocrotaline-rat lungs showed a significant decrease of eNOS expression (4080+/-27 vs 12189+/-761 arbitrary density units [ADU] for MC and control groups respectively, P<0.01) and a significant increase of cleaved caspase-3 expression by western blotting (Control=11628+/-2395 vs MC=2326+/-2243 ADU, P<0.05). A non-significant trend toward a reduced mortality was observed with pravastatin (relative risk of death = 0.33; 95% confidence interval [0.08-1.30], P= 0.12 for MC+PS vs MC groups). Pravastatine induced a protection against the development of the pulmonary hypertension (RVP in mmHg: 30+/-3 vs 45+/-4 and RV/LV+S: 0.46+/-0.04 vs 0.62+/-0.05 for MC+PS and MC groups respectively, P<0.05) and was associated with a significant reduction of MC-induced thickening (61+/-6 mum vs 81+/-3 mum for MC+PS and MC groups respectively, P= 0.01) of the medial wall of the small intrapulmonary arteries. Pravastatin partially restored acetylcholine-induced pulmonary artery vasodilation in MC rats (Emax=65+/-5% and 46+/-3% for MC+PS and MC group respectively, P<0.05) but had no effect on acetylcholine-induced pulmonary artery vasodilation in MC+L-NAME rats. It also prevented apoptosis and restored eNOS expression of pulmonary artery endothelial cells, as well as in the whole lung. Pravastatin reduces the development of monocrotaline-induced pulmonary hypertension and improves endothelium-dependent pulmonary artery relaxation, probably through a reduced apoptosis and a restored eNOS expression of endothelial cells.
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PMID:The HMG-CoA reductase inhibitor, pravastatin, prevents the development of monocrotaline-induced pulmonary hypertension in the rat through reduction of endothelial cell apoptosis and overexpression of eNOS. 1689 5

The aim of this study was to investigate the inhibitory effect of non-aglycone cyanidin on TNF-alpha-induced endothelial cell apoptosis and its mechanism through enhancing expression of thioredoxin in endothelial cells. We found that exposure of the serum-starved BAECs to TNF-alpha increased significantly the number of dead cells, the cleaved caspase-3 and cleaved poly(ADP-ribose)polymerase (RARP)assayed by Western blot, whereas supplementation with cyanidin considerably suppressed these events. Inhibitors of the Akt, ERK1/2, Src kinase and transfection with a dominant-negative Akt cDNA blocked the inhibitory effect of cyanidin on cleaved caspase-3. Cyanidin significantly elevated expression of endothelial nitric oxide synthase (eNOS) and thioredoxin (Trx). The increased Trx expression was blocked by siRNA transfection of cGMP-dependent protein kinase (PKG) and by using a PKG inhibitor, KT5823. Cyanidin also ameliorated TNF-alpha-induced decrease of Trx S-nitrosylation and intracellular glutathione and elevation of 4-hydroxynonenal (4-HNE), a major aldehydic product of lipid peroxidation. Furthermore, cyanidin also restored S-nitrosylation of caspase-3 and reduced the rise in expression and acetylation of tumor suppression gene p53. However, KT5823 or L-NAME, an inhibitor of eNOS, removed the preventive effects of cyanidin. Our data show that inhibitory effect of cyanidin on TNF-alpha-induced apoptosis involves multiple pathways, such as Akt activation, eNOS and thioredoxin expression in endothelial cells.
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PMID:Inhibitory effect of polyphenol cyanidin on TNF-alpha-induced apoptosis through multiple signaling pathways in endothelial cells. 1704 69

Nitrogen Dioxide (NO2) is a product of high-temperature combustion and an environmental oxidant of concern. We have recently reported that early changes in NO2-exposed human bronchial epithelial cells are causally linked to increased generation of proinflammatory mediators, such as nitric oxide/nitrite and cytokines like interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-8. The objective of the present in vitro study was to further delineate the cellular mechanisms of NO2-mediated toxicity, and to define the nature of cell death that ensues upon exposure of normal human bronchial epithelial (NHBE) cells to a brief high dose of NO2. Our results demonstrate that the NHBE cells undergo apoptotic cell death during the early post-NO2 period, but this is independent of any significant increase in caspase-3 activity. However, necrotic cell death was more prevalent at later time intervals. Interestingly, an increased expression of HO-1, a redox-sensitive stress protein, was observed in NO2-exposed NHBE cells at 24 h. Since neutrophils (PMNs) play an active role in acute lung inflammation and resultant oxidative injury, we also investigated changes in human PMN-NHBE cell interactions. As compared to normal cells, increased adhesion of PMNs to NO2-exposed cells was observed, which resulted in an increased NHBE cell death. The latter was also increased in the presence of IL-8 and TNF-alpha + interferon (IFN)-gamma, which correlated with upregulation of intercellular adhesion molecule-1 (ICAM-1). Our results confirmed an involvement of nitric oxide (NO) in NO2-induced cytotoxicity. By using NO synthase inhibitors such as L-NAME and 3-aminoguanidine (AG), a significant decrease in cell death, PMN adhesion, and ICAM-1 expression was observed. These findings indicate a role for the L-arginine/NO synthase pathway in the observed NO2-mediated toxicity in NHBE cells. Therapeutic strategies aimed at controlling excess generation of NO and/or inflammatory cytokines may be useful in alleviating NO2-mediated adverse effects on the bronchial epithelium.
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PMID:Effects of nitrogen dioxide on the expression of intercellular adhesion molecule-1, neutrophil adhesion, and cytotoxicity: studies in human bronchial epithelial cells. 1716 65

Aldose reductase (AR) is a ubiquitously expressed protein with pleiotrophic roles as an efficient catalyst for the reduction of toxic lipid aldehydes and mediator of hyperglycemia, cytokine, and growth factor-induced redox-sensitive signals that cause secondary diabetic complications. Although AR inhibition has been shown to be protective against oxidative stress signals, the role of AR in regulating nitric oxide (NO) synthesis and NO-mediated apoptosis has not been elucidated to date. We therefore investigated the role of AR in regulating lipopolysaccharide (LPS)-induced NO synthesis and apoptosis in RAW 264.7 macrophages. Inhibition or RNA interference ablation of AR suppressed LPS-stimulated production of NO and overexpression of iNOS mRNA. Inhibition or ablation of AR also prevented the LPS-induced apoptosis, cell cycle arrest, activation of caspase-3, p38-MAPK, JNK, NF-kappaB, and AP1. In addition, AR inhibition prevented the LPS-induced down-regulation of Bcl-xl and up-regulation of Bax and Bak in macrophages. L-Arginine increased and L-NAME decreased the severity of cell death caused by LPS and AR inhibitors prevented it. Furthermore, inhibition of AR prevents cell death caused by HNE and GS-HNE, but not GS-DHN. Our findings for the first time suggest that AR-catalyzed lipid aldehyde-glutathione conjugates regulate the LPS-induced production of inflammatory marker NO and cytotoxicity in RAW 264.7 cells. Inhibition or ablation of AR activity may be a potential therapeutic target in endotoximia and other inflammatory diseases.
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PMID:Aldose reductase mediates endotoxin-induced production of nitric oxide and cytotoxicity in murine macrophages. 1738 9

TP508 is a 23-amino acid peptide derived from human prothrombin that increases cartilage matrix production and reduces alkaline phosphatase activity without changing chondrocyte proliferation. This study tested the hypothesis that TP508 acts by blocking the onset of apoptosis associated with hypertrophy. Rat costochondral resting zone chondrocytes and human auricular chondrocytes were cultured in DMEM containing 50microM ascorbic acid and 10% FBS. Apoptosis was induced by treatment of confluent cultures with chelerythrine, tamoxifen, or inorganic phosphate (Pi) for 24h. One half of the cultures received TP508 (0, 0.7, or 7microg/ml). Apoptosis was assessed as a function of DNA fragmentation ([3H]-thymidine labeled DNA fragments), TUNEL staining, and cell viability using the MTT assay, as well as by assessing the Bcl-2/Bax mRNA and protein ratios and caspase-3 activity. The universal NO synthase inhibitor l-NMMA was used to assess the effect of NO production on chondrocyte apoptosis and specific NO synthase subspecies were identified using iNOS inhibitor 1400W and nNOS inhibitor vinyl-l-NIO, as well as l-NAME, which inhibits both iNOS and eNOS. Finally, we assessed if TP508 would block NO production induced by the apoptogens. Chelerythrine, tamoxifen and Pi-induced apoptosis and this was reversed by TP508. All apoptogens increased NO production and this was reduced by TP508. TP508 reduced NO levels to the same extent as 1400W but not to the same extent as l-NAME, suggesting that its effects are mediated primarily by iNOS. In addition, TP508 reduced the effect of chelerythrine to the same extent as 1400W and l-NAME, again indicating that it acts via inhibition of an iNOS pathway. TP508 also regulated Bcl-2/Bax mRNA in a time and dose-dependent manner. The Bcl-2/Bax mRNA ratio was 0.11 in the absence of TP508 at 1h and 4.95 at 7microg/ml TP508; by 3h the ratio was approximately 1 in both groups. The Bcl-2/Bax protein ratio also increased by 63% at 1h. TP508 did not affect caspase-3 activity. TP508 also caused a dose-dependent increase in protein kinase C (PKC) activity within 9min that was maximal at 270min. These results show that TP508 prevents apoptosis in growth plate chondrocytes via inhibition of iNOS-dependent NO and suggest a possible role for PKC in the mechanism.
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PMID:Thrombin peptide TP508 prevents nitric oxide mediated apoptosis in chondrocytes in the endochondral developmental pathway. 1802 91

Nitric oxide (NO) has emerged as an important endogenous inhibitor of apoptosis. In this study, we postulated that the mechanism of apoptosis inhibition by NO would include stimulation of heat shock protein 70 (Hsp70) expression. Rats were subjected to unilateral ureteral obstruction (UUO) or sham operation, and kidneys were harvested 5 and 14 days after obstruction. After 14 days of obstruction, decreased endogenous NO and lower inducible nitric oxide synthase (iNOS) expression at mRNA and protein levels associated with downregulation of Hsp70 protein expression were shown in apoptosis induction, regulated by mitochondrial signal pathway, through the increased pro-apoptotic ratio Bax/BcL(2) and consequently caspase 3 activity. Conversely, 5 days after kidney obstruction, increased Hsp70 expression linked to increase NO and iNOS expression at transcriptional and post-transcriptional levels with absence of apoptotic response, were demonstrated. In obstructed neonatal rats, in vivo administration of l-Arginine induced heat shock protein 70 (Hsp70) expression, which was associated with cytoprotection from apoptosis and transiently decreased nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase activity. Opposite effects were obtained after nitro L-Arginine methyl ester (L-NAME) treatment. The interaction between B-cell lymphoma 2 anti-apoptotic members (BcL(2)) and Hsp70 in the presence of L-Arginine and L-NAME, was determined by coimmunoprecipitation. Binding of BcL(2) and Hsp70 increased after L-Arginine administration. These findings suggest that NO can produce resistance to obstruction-induced cell death by mitochondrial apoptotic pathway, through the induction of Hsp70 expression, in neonatal unilateral ureteral obstruction.
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PMID:Cytoprotective role of nitric oxide associated with Hsp70 expression in neonatal obstructive nephropathy. 1828 Feb 60


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