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)

Thapsigargin addition to thymocytes increased cytosolic Ca2+ by a factor of 8.5 with a time for half maximal effect (t1/2) of 2.5 min. Calcium signaling increased mitocondrial and endoplasmic reticulum nitric oxide synthase (NOS) activities by five and six times, with t1/2 of 16 and 48 min, respectively, followed by increases of 140% in intracellular [H2O2], 73% in hydroperoxide content, and 250% in thiobarbituric reactive substance content, with t1/2 of 13, 27, and 30 min, respectively. Mitochondrial dysfunction followed, and was characterized by decreased respiratory control, membrane depolarization, and decrease cytochrome c content release, processes with t1/2 of 101, 129, and 133 min, respectively. Increased UDP-GT gene expression, observed by mRNA synthesis, and the enzymatic activity of this protein had t1/2 of 52 and 187 min, respectively. These events were followed by caspase-3 activation (t1/2 = 210 min) and DNA laddering (t1/2 = 260 min) at the completion of the cell death program. Preincubation of thymocytes with NOS inhibitors (NG-methyl-L-arginine and L-Nomega-nitro-L-arginine methylester) halted the whole process through inhibition of mitochondrial and endoplasmic reticulum NOS activities and of DNA laddering.
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PMID:Kinetic analysis of thapsigargin-induced thymocyte apoptosis. 1545 89

We attempted to ascertain the neuroprotective effects and mechanisms of minocycline in inflammatory-mediated neurotoxicity using primary neuron/glia co-cultures treated with lipopolysaccharide (LPS). Neuronal cell death was induced by treatment with LPS for 48 h, and the cell damage was assessed using lactate dehydrogenase (LDH) assays and by counting microtubule-associated protein-2 (MAP-2) positive cells. Through terminal transferase deoxyuridine triphosphate-biotin nick end labeling (TUNEL)-staining and by measuring caspase-3 activity, we found that LPS-induced neuronal cell death was mediated by apoptosis. We determined that pre-treatment with minocycline significantly inhibited LPS-induced neuronal cell death. In addition, LPS induced inducible nitric oxide synthase (iNOS) expression significantly, resulting in nitric oxide (NO) production within glial cells, but not in neurons. Both nitric oxide synthase (NOS) inhibitors (N(G)-monomethyl-L-arginine monoacetate (L-NMMA) and S-methylisothiourea sulfate (SMT)) and minocycline inhibited iNOS expression and NO release, and increased neuronal survival in neuron/glia co-cultures. Pre-treatment with minocycline significantly inhibited the rapid and extensive production of tumor necrosis factor-alpha (TNF-alpha) mediated by LPS in glial cells. We also determined that the signaling cascade of LPS-mediated iNOS induction and NO production was mediated by TNF-alpha by using neutralizing antibodies to TNF-alpha. Consequently, our results show that the neuroprotective effect of minocycline is associated with inhibition of iNOS induction and NO production in glial cells, which is mediated by the LPS-induced production of TNF-alpha.
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PMID:Minocycline inhibits apoptotic cell death via attenuation of TNF-alpha expression following iNOS/NO induction by lipopolysaccharide in neuron/glia co-cultures. 1548 88

Recent studies have shown the involvement of Fas/Fas ligand (FasL) system and nitric oxide (NO) in ovarian follicle atresia. Here we asked whether Fas/Fas ligand system interacts with NO using rat granulosa cell culture. Soluble recombinant Fas ligand (rFasL), at 100 ng/ml, significantly decreased cell viability, as measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay, in the presence of 200 U/ml interferon-gamma, whereas the concurrent addition of a caspase inhibitor, Z-VAD-FMK, at 20 microm, significantly inhibited rFasL-induced cytotoxicity. Hoechst 33342 staining and flow cytometric analysis confirmed the induction of apoptosis in granulosa cells by 100 ng/ml rFasL in the presence of interferon-gamma, which was blocked by the concomitant addition of an NO donor, S-nitroso-N-acetylpenicillamine. Western blot analysis demonstrated that rFasL significantly up-regulated caspase-3, -8, and -9 activities in granulosa cells, which were attenuated by concurrent treatment with S-nitroso-N-acetylpenicillamine. Real-time quantitative RT-PCR revealed a significant decrease in inducible NO synthase mRNA levels in rFasL-induced apoptotic granulosa cells. In conclusion, we demonstrated the involvement of Fas/FasL system in inducing apoptosis through activation of a caspase-mediated cascade in rat granulosa cells, which is coupled with a decrease in inducible NO synthase expression. We further showed that NO inhibited Fas/FasL system-induced apoptosis by suppressing activation of the caspases, pointing to a cross-talk between Fas/FasL system-induced apoptosis pathway and NO-mediated antiapoptotic pathway in ovarian follicle atresia.
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PMID:Cross-Talk between Fas/Fas ligand system and nitric oxide in the pathway subserving granulosa cell apoptosis: a possible regulatory mechanism for ovarian follicle atresia. 1552 99

Hyperhomocysteinemia is believed to induce endothelial dysfunction and promote atherosclerosis; however, the pathogenic mechanism has not been clearly elucidated. In this study, we examined the molecular mechanism by which homocysteine (HCy) causes endothelial cell apoptosis and by which nitric oxide (NO) affects HCy-induced apoptosis. Our data demonstrated that HCy caused caspase-dependent apoptosis in cultured human umbilical vein endothelial cells, as determined by cell viability, nuclear condensation, and caspase-3 activation and activity. These apoptotic characteristics were correlated with reactive oxygen species (ROS) production, lipid peroxidation, p53 and Noxa expression, and mitochondrial cytochrome c release following HCy treatment. HCy also induced p53 and Noxa expression and apoptosis in endothelial cells from wild type mice but not in the p53-deficient cells. The NO donor S-nitroso-N-acetylpenicillamine, adenoviral transfer of inducible NO synthase gene, and antioxidants (alpha-tocopherol and superoxide dismutase plus catalase) but not oxidized SNAP, 8-Br-cGMP, nitrite, and nitrate, suppressed ROS production, p53-dependent Noxa expression, and apoptosis induced by HCy. The cytotoxic effect of HCy was decreased by small interfering RNA-mediated suppression of Noxa expression, indicating that Noxa up-regulation plays an important role in HCy-induced endothelial cell apoptosis. Overexpression of inducible NO synthase increased the formation of S-nitroso-HCy, which was inhibited by the NO synthase inhibitor N-monomethyl-l-arginine. Moreover, S-nitroso-HCy did not increase ROS generation, p53-dependent Noxa expression, and apoptosis. These results suggest that up-regulation of p53-dependent Noxa expression may play an important role in the pathogenesis of atherosclerosis induced by HCy and that an increase in vascular NO production may prevent HCy-induced endothelial dysfunction by S-nitrosylation.
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PMID:Nitric oxide inhibition of homocysteine-induced human endothelial cell apoptosis by down-regulation of p53-dependent Noxa expression through the formation of S-nitrosohomocysteine. 1556 2

Indices of oxidative stress, nitric oxide (NO) metabolism as well as the activity of caspase-3, an important enzyme of apoptotic cell death, were measured during the morphine withdrawal syndrome in liver and thymus of rats. Male Wistar rats were administered with morphine hydrochloride (i.p., at increasing doses from 10 to 100 mg/kg, twice a day, for 6 days). Thirty-six hours after the last administration the withdrawal syndrome was monitored using the specific autonomic and locomotor indices. During this period, weights of body and thymus significantly decreased. Oxidative stress in liver was accompanied by an increase in aspartate aminotransferase and gamma-glutamyl transferase in blood serum. No signs of oxidative stress could be demonstrated in thymus. The activity of the Ca(2+)-dependent isoform of nitric oxide synthase (NOS) in liver increased, while, the activity of the Ca(2+)-independent NOS diminished, the total activity of NOS in liver and thymus remained unchanged. The concentration of nitrates/nitrites in blood was decreased, in thymus increased, and in liver unchanged. Caspase-3 activity changed neither in liver, nor in thymus. The results are discussed from the perspective of possible antioxidant and antiapoptotic role of NO during morphine withdrawal syndrome.
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PMID:[Effects of morphine withdrawal on the indices of free radical homeostasis and nitric oxide system in rat liver and thymus]. 1562 95

Preservation of endothelial functions with low-dose nitric oxide (NO) and inhibition of excessive production of NO from inducible NO synthase (iNOS) is a potential therapeutic approach for acute stroke. Based on this hypothesis, an NO modulator, S-nitrosoglutathione (GSNO) was used, which provided neuroprotection in a rat model of focal cerebral ischemia. Administration of GSNO after the onset of ischemia reduced infarction and improved cerebral blood flow. To understand the mechanism of protection, the involvement of inflammation in ischemic brain injury was examined. Treatment with GSNO reduced the expression of tumor necrosis factor-alpha, interleukin-1beta, and iNOS; inhibited the activation of microglia/macrophage (ED1, CD11-b); and downregulated the expression of leukocyte function-associated antigen-1 and intercellular adhesion molecule-1 in the ischemic brain. The number of apoptotic cells (including neurons) and the activity of caspase-3 were also decreased after GSNO treatment. Further, the antiinflammatory effect of GSNO on expression of iNOS and activation of NF-kappaB machinery in rat primary astrocytes and in the murine microglial cell line BV2 was tested. Cytokine-mediated expression of iNOS and activation of NF-kappaB were inhibited by GSNO treatment. That GSNO protects the brain against ischemia/reperfusion injury by modulating NO systems, resulting in a reduction in inflammation and neuronal cell death was documented by the results.
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PMID:S-Nitrosoglutathione reduces inflammation and protects brain against focal cerebral ischemia in a rat model of experimental stroke. 1564 46

It has been shown that deletion of the gene encoding the inducible form of nitric oxide synthase (iNOS) results in a reduction of ischemia-induced apoptotic cell death, suggesting the detrimental role of iNOS. The signaling pathways by which iNOS mediates apoptotic cell death under ischemic conditions remain unclear. Understanding the molecular mechanisms of iNOS-mediated apoptotic cell death in ischemia may offer opportunities for potential therapeutic intervention. In the current study, undifferentiated rat pheochromocytoma PC12 cells, exposed to oxygen and glucose deprivation (OGD) followed by reperfusion (adding back oxygen and glucose, OGD-R), were used as an in vitro model of ischemia. The iNOS expression and activity were increased during OGD-R. OGD-R-induced apoptosis was demonstrated by the increase of LDH release, cytosolic release of cytochrome C and caspase-3 activity. Inhibition of iNOS activity by selective iNOS inhibitors, aminoguanidine and 1400W, reduces OGD-R-induced apoptotic cell death, as demonstrated by the decrease of LDH release, cytochrome C release, and caspase-3 activity. These results suggest the critical role of iNOS in mediating apoptosis under ischemic conditions, likely through the induction of caspase-3 activity.
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PMID:Inhibitors of iNOS protects PC12 cells against the apoptosis induced by oxygen and glucose deprivation. 1566 23

Farnesyltransferase inhibitors (FTIs) are currently under investigation for leukemia treatment. We evaluated the FTI manumycin A (manumycin) in two myeloid leukemia cell lines (U937 and HL-60). Manumycin induced nitric oxide production and apoptosis of the leukemia cells. Nitric oxide or other reactive oxygen species may induce oxidative DNA damage, and the number of apurinic sites increased after manumycin treatment, which was reversed by concurrent treatment with N-acetyl-L-cysteine. Since repair of DNA damage is important to cell survival, we hypothesized that methoxyamine, an inhibitor of base-excision repair, would enhance the antineoplastic effect of manumycin. The combination of manumycin and methoxyamine resulted in enhanced apoptosis by six criteria increased annexin V binding, release of mitochondrial cytochrome c into the cytosol, activation of caspase-9, activation of caspase-3, specific cleavage of poly-adenosyl ribose polymerase, and increase in the sub-G1 cell cycle fraction. The drug combination enhanced inhibition on the soft agar clonogenic assay and on the formazan dye cell viability assay. The effects of manumycin or manumycin plus methoxyamine on apoptosis were blocked by N-acetyl-L-cysteine, and partially by nitric oxide synthase inhibitors or scavenger of peroxide. We conclude that methoxyamine enhances manumycin-induced apoptosis in myeloid leukemia cells.
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PMID:Enhancement of manumycin A-induced apoptosis by methoxyamine in myeloid leukemia cells. 1574 47

An enhanced linkage-specific 9-O-acetylated sialic acid (9-O-AcSA) on peripheral blood mononuclear cells (PBMC) of children with acute lymphoblastic leukaemia, ALL (PBMC(ALL), 9-O-AcSA+ cells) was demonstrated by using a lectin, Achatinin-H, whose lectinogenic epitope was 9-O-AcSAalpha2-6GalNAc. Our aim was to evaluate the in vitro contributory role of this glycotope (9-O-AcSAalpha2-6GalNAc) towards the survival of these 9-O-AcSA+ cells in ALL patients. For direct comparison, 9-O-AcSA- cells were generated by removing O-acetyl group of 9-O-AcSA present on PBMC(ALL) using O-acetyl esterase. An elevated level of serum interferon gamma (IFN-gamma) in affected children led us to think that PBMC(ALL) are continuously exposed specifically to this cytokine. Accordingly, 9-O-AcSA+ and 9-O-AcSA- cells were exposed in vitro to IFN-gamma. A twofold increased NO release along with inducible NO synthase (iNOS) mRNA expression by the 9-O-AcSA+ cells was observed as compared to the 9-O-AcSA- cells. The decreased viability of IFN-gamma exposed 9-O-AcSA- cells as compared to 9-O-AcSA+ cells were reflected from a 5.0-fold increased caspase-3-like activity and a 10.0-fold increased apoptosis in the 9-O-AcSA- cells when production of NO was lowered by adding competitive inhibitor of iNOS in reaction mixture. Therefore, it may be envisaged that a link exists between induction of this glycotope and their role in regulating viability of PBMC(ALL). Taken together, it is reasonable to hypothesise that O-acetylation of sialic acids on PBMC(ALL) may be an additional mechanism that promotes the survival of lymphoblasts by avoiding apoptosis via IFN-gamma-induced NO production.
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PMID:Interferon gamma promotes survival of lymphoblasts overexpressing 9-O-acetylated sialoglycoconjugates in childhood acute lymphoblastic leukaemia (ALL). 1577 Jun 63

The effect of regucalcin, a regulatory protein in intracellular signaling system, on cell death and apoptosis was investigated. Sulforaphane, a naturally occurring isothiocyanate, is known to induce cell cycle arrest and apoptosis in cancer cells, although its effect has not been clarified in the cloned rat hepatoma H4-II-E cells. Hepatoma H4-II-E cells (wild-type) and stable regucalcin/pCXN2-transfected cells were cultured for 72 h in a medium containing 10% fetal bovine serum (FBS). Cells with subconfluency were changed to a medium containing either vehicle or sulforaphane (10(-7) or 10(-6) M) in the absence of FBS. After medium change, cells were cultured for 24, 48, or 72 h. The number of wild-type cells was significantly decreased in the presence of sulforaphane (10(-7) or 10(-6) M). Agarose gel electrophoresis showed the presence of low-molecular-weight deoxyribonucleic acid (DNA) fragments of adherent wild-type cells cultured with sulforaphane (10(-7) or 10(-6) M) for 24 h. Sulforaphane (10(-7) or 10(-6) M)-induced cell number and DNA fragmentation was significantly suppressed in transfectants. The effect of sulforaphane (10(-6) M) in decreasing the number of wild-type cells was significantly prevented in the presence of caspase-3 inhibitor (10(-9) M), while the presence of Nomega-nitro-L-arginine methylester (NAME), an inhibitor of nitric oxide synthase, did not prevent sulforaphane-induced death of wild-type cells. Sulforaphane (10(-6) M) did not have a significant effect on cell number of transfectants in the presence of caspase-3 inhibitor or NAME. This study demonstrates that sulforaphane induces cell death and apoptosis in the cloned rat hepatoma H4-II-E cells, and that overexpression of regucalcin suppresses sulforaphane-induced apoptotic cell death which is partly mediated through caspase-3..
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PMID:Overexpression of regucalcin suppresses apoptotic cell death in the cloned rat hepatoma H4-II-E cells induced by a naturally occurring isothiocyanate sulforaphane. 1580 9


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