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)

Apoptosis is thought to play an important regulatory role in placental development and inappropriate trophoblast apoptosis has been implicated in complications of pregnancy such as pre-eclampsia. Here we show that apoptosis of a human extravillous trophoblast-derived cell line (SGHPL-4) can be regulated by nitric oxide (NO). Nitric oxide produced exogenously by the addition of NO donors was able to delay or inhibit apoptosis induced by a combination of tumour necrosis factor alpha and actinomycin D and to suppress the activity of caspase 3. Treatment with hepatocyte growth factor (HGF) stimulated expression of the inducible isoform of NO synthase and was also able to protect SGHPL-4 cells from caspase 3 activation and apoptosis. The inhibition of basal NO production with NO synthase inhibitors was shown to sensitise cells to apoptotic stimuli and to reduce the level of endogenous caspase 3 nitrosylation. The anti-apoptotic effects of NO in these extravillous trophoblast cells appear to be mediated through the production of cyclic GMP as inhibitors of soluble guanylate cyclase inhibited the protective effect of both HGF and NO donors.
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PMID:Nitric oxide protects human extravillous trophoblast cells from apoptosis by a cyclic GMP-dependent mechanism and independently of caspase 3 nitrosylation. 1283 87

Methamphetamine (METH)-induced neurotoxicity is characterized by a long-lasting depletion of striatal dopamine (DA) and serotonin as well as damage to striatal dopaminergic and serotonergic nerve terminals. Several hypotheses regarding the mechanism underlying METH-induced neurotoxicity have been proposed. In particular, it is thought that endogenous DA in the striatum may play an important role in mediating METH-induced neuronal damage. This hypothesis is based on the observation of free radical formation and oxidative stress produced by auto-oxidation of DA consequent to its displacement from synaptic vesicles to cytoplasm. In addition, METH-induced neurotoxicity may be linked to the glutamate and nitric oxide systems within the striatum. Moreover, using knockout mice lacking the DA transporter, the vesicular monoamine transporter 2, c-fos, or nitric oxide synthetase, it was determined that these factors may be connected in some way to METH-induced neurotoxicity. Finally a role for apoptosis in METH-induced neurotoxicity has also been established including evidence of protection of bcl-2, expression of p53 protein, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), activity of caspase-3. The neuronal damage induced by METH may reflect neurological disorders such as autism and Parkinson's disease.
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PMID:Current research on methamphetamine-induced neurotoxicity: animal models of monoamine disruption. 1289 Aug 83

Alzheimer's disease is marked by progressive accumulation of amyloid beta-peptide (Abeta) which appears to trigger neurotoxic and inflammatory cascades. Substantial activation of microglia as part of a local innate immune response is prominent at sites of Abeta plaques in the CNS. However, the role of activated microglia as Abeta APCs and the induction of adaptive immune responses has not been investigated. We have used primary microglial cultures to characterize Abeta-Ag presentation and interaction with Abeta-specific T cells. We found that IFN-gamma-treated microglia serve as efficient Abeta APCs of both Abeta1-40 and Abeta1-42, mediating CD86-dependent proliferation of Abeta-reactive T cells. When cultured with Th1 and Th2 subsets of Abeta-reactive T cells, Th1, but not Th2, cells, underwent apoptosis after stimulation, which was accompanied by increased levels of IFN-gamma, NO, and caspase-3. T cell apoptosis was prevented in the presence of an inducible NO synthase type 2 inhibitor. Microglia-mediated proliferation of Abeta-reactive Th2 cells was associated with expression of the Th2 cytokines IL-4 and IL-10, which counterbalanced the toxic levels of NO induced by Abeta. Our results demonstrate NO-dependent apoptosis of T cells by Abeta-stimulated microglia which may enhance CNS innate immune responses and neurotoxicity in Alzheimer's disease. Secretion of NO by stimulated microglia may underlie a more general pathway of T cell death in the CNS seen in neurodegenerative diseases. Furthermore, Th2 type T cell responses may have a beneficial effect on this process by down-regulation of NO and the proinflammatory environment.
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PMID:Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid beta-peptide presentation to Th1 cells. 1292 65

Formation of blood vessels is a fundamental element in the control of tumour growth in which vascular endothelial growth factor (VEGF) and nitric oxide (NO) have been demonstrated to be involved. Our aim was to analyse whether changes in the expression of endothelial NO synthase (eNOS) and VEGF in colonic tissue could be detected early and even before the identification of colon tumour-associated morphological modifications in azoxymethane-treated rats. We studied further whether aspirin treatment changed these parameters. An increased expression of both eNOS and VEGF in colonic tissue from azoxymethane-treated rats compared with that from control rats was found. Aspirin treatment (10 mg/kg of body weight per day) reduced eNOS expression, but failed to modify the expression of VEGF in the colonic tissue of azoxymethane-treated rats. No evidence of aberrant crypt formation or changes in the number of blood vessels were observed in the colon of any of the animals studied. Expression of the VEGF receptor Flk-1, but not Flt-1, was increased in colonic tissue of azoxymethane-treated rats compared with control rats. The expression of Flk-1 was mainly localized in the epithelial cells, particularly in the lower part of the crypt. Aspirin treatment reduced Flk-1 expression in both control and azoxymethane-treated rats. Caspase-3 activity, which has been considered as an apoptotic index, was almost undetectable in azoxymethane-treated rats. Aspirin treatment stimulated caspase-3 activity. Overexpression of eNOS, VEGF and its receptor Flk-1 occurred early after azoxymethane administration in rat colonic tissue, even before morphological changes associated with tumour generation were observed, and aspirin prevented the overexpression of both eNOS and VEGF receptor Flk-1.
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PMID:Aspirin inhibits endothelial nitric oxide synthase (eNOS) and Flk-1 (vascular endothelial growth factor receptor-2) prior to rat colon tumour development. 1294 28

IL-1beta is recognized as an effector cytokine contributing to islet beta-cell destruction during diabetes. We have previously shown in vitro that IL-1beta induces nitric oxide (NO) and beta-cell damage. Here, we show that IL-1beta administration in vivo to Wistar rats transiently increases manganese superoxide dismutase activity, whereas inducible NO synthase is not detected, and the levels of nitrate+nitrate do not change. Moreover, a significant decrease of mitochondrial aconitase, leading to a rise of hydroperoxides, and islet beta-cell apoptosis, involving caspase-3 and -8, is observed. Analysis of adhesion molecules in beta-cells showed that intercellular adhesion molecule-1 is highly expressed 48 h after IL-1beta administration and that this is concomitant to the fall of manganese superoxide dismutase activity. Thus, IL-1beta exerts a proapoptotic effect in vivo through mitochondrial enzyme alteration, which is not related to the inducible NO synthase pathway, and dysregulates the immune system through the up-regulation of adhesion molecules.
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PMID:Islet beta-cell apoptosis triggered in vivo by interleukin-1beta is not related to the inducible nitric oxide synthase pathway: evidence for mitochondrial function impairment and lipoperoxidation. 1450 May 61

Flavopiridol, an inhibitor of cyclin-dependent kinases and other protein kinases, induces in vitro apoptosis of malignant cells from B-cell chronic lymphocytic leukemia (B-CLL). Previously, we reported that nitric oxide (NO), produced by an inducible NO synthase (iNOS), spontaneously expressed by the B-CLL cells, contributed to their deficiency in apoptosis. In the present work, we show that ex vivo treatment of leukemic cells from B-CLL patients with flavopiridol results in the inhibition of iNOS expression, as determined by immunofluorescence and Western blotting, and in a marked inhibition of NO production measured in situ with a specific fluorescent probe (DAF-2 DA). These effects are accompanied by membrane, mitochondrial and nuclear events of apoptosis. Flavopiridol exposure also results in the stimulation of caspase 3 activity and in caspase-dependent cleavage of p27(kip1), a negative regulator of the cell cycle, which is overexpressed in B-CLL. Thus, flavopiridol is capable of downregulating both iNOS and p27(kip1) expression in B-CLL cells. Furthermore, flavopiridol-promoted apoptosis is partly reverted by an NO donor, suggesting that inhibition of the NO pathway could participate in the apoptotic effects of flavopiridol on the leukemic cells.
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PMID:Flavopiridol downregulates the expression of both the inducible NO synthase and p27(kip1) in malignant cells from B-cell chronic lymphocytic leukemia. 1467 37

The in vitro effect of gamma interferon (IFN-gamma) on nitric oxide (NO) production in a mouse CD5+ B1-like cell line, TH2.52, was studied. The TH2.52 cell line is the hybridoma line between mouse B lymphoma line and mouse splenic B cells and expresses a series of B1 markers. IFN-gamma induced a marked NO production in TH2.52 cells through the expression of an inducible type of NO synthase (iNOS). IFN-gamma-induced NO production was triggered by the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathway since it was inhibited by AG490, a JAK2 inhibitor. The growth of TH2.52 cells significantly was inhibited in the presence of IFN-gamma. A significant number of cells underwent apoptotic cell death, accompanied by the DNA fragmentation, annexin V binding, and caspase 3 activation. N(G)-monomethyl-L-arginine, an iNOS inhibitor, prevented IFN-gamma-induced cell death. Therefore, IFN-gamma-induced NO production was possible in causing cell death in TH2.52 cells. Further, IFN-gamma-induced NO production and cell death significantly were prevented by interleukin-4, a representative Th2 cytokine. The immunological significance of IFN-gamma-induced NO production in a mouse B1-like cell line is discussed.
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PMID:Gamma interferon-induced nitric oxide production in mouse CD5+ B1-like cell line and its association with apoptotic cell death. 1458 14

The therapeutic mechanism of taxol is believed to reside primarily in its ability to stabilize microtubules and prevent cell progression through mitosis. Taxol also can activate macrophage-mediated antitumor mechanism through a nitric oxide (NO)-dependent pathway. To address whether any mechanisms account for superficial urinary bladder tumor cell killing, we evaluated the effects of taxol on the growth and viability of murine bladder tumor-2 (MBT-2) cells in vitro, both in the absence and presence of murine macrophages. In addition, we evaluated whether a soluble factor generated from MBT-2 cells could modulate the antitumor activity of the taxol-activated macrophages. Although taxol inhibited the growth of MBT-2 cells, it did not kill the tumor cells. However, preincubation of macrophages with taxol significantly decreased the viability of MBT-2 cells. Secretion of NO correlated with MBT-2 cell killing, and the activated macrophages failed to kill tumor cell targets in the presence of NG-monomethyl-L-arginine, a competitive inhibitor of NO synthase. By the co-culture of macrophages and MBT-2 cells, untreated macrophages also released modest amount of NO and this was synergistically augmented by the treatment with taxol, indicating that MBT-2 tumor cells released some unknown factor that activated the macrophages and enhanced NO production. We named this factor the tumor-derived macrophage activating factor (TMAF). The TMAF-mediated activation of macrophages to enhance the NO production was not blocked by treatment of macrophages with oxidized low-density lipoprotein (Ox-LDL), implying that the scavenger receptor of macrophages is not involved. Sodium nitroprusside (SNP), an NO donor given to the MBT-2 cells, increased the activities of c-Jun N-terminal kinase and caspase-3 in MBT-2 cells and associated with nucleosomal fragmentation or apoptosis, whereas taxol had no direct effect on these parameters. Collectively, our results strongly suggest that taxol kills the murine bladder tumor cells through indirect activation of macrophages via NO-dependent apoptosis, instead of its better-known role as the direct antimitotic action. Our results further demonstrate that TMAF acts in synergy with taxol to activate the macrophages to elicit enhanced tumor cell killing ability.
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PMID:Soluble factor from murine bladder tumor-2 cell elevates nitric oxide production in macrophages and enhances the taxol-mediated macrophage cytotoxicity on tumor cells. 1462 29

When granulomatous experimental autoimmune thyroiditis (G-EAT) was induced in CBA/J or DBA/1 mice, thyroid lesions resolved in less severe (3+) G-EAT in wild-type mice or severe (5+) G-EAT in IFN-gamma(-/-) mice, but progressed to fibrosis in 5+ G-EAT in wild-type mice. To define the mechanisms leading to these distinct outcomes, the expression of inflammatory and apoptotic molecules and infiltrating cells was evaluated using immunohistochemistry, RT-PCR, and confocal microscopy. The ratio of CD4(+)/CD8(+) T cells in thyroid infiltrates was one factor that predicted G-EAT outcome. CD4(+) T cells outnumbered CD8(+) T cells when lesions progressed to fibrosis, while CD8(+) T cells outnumbered CD4(+) T cells in thyroids that resolved. Fas, Fas ligand, FLIP, TNF-alpha, inducible NO synthase, TGF-beta, and IFN-gamma were highly expressed by infiltrating cells when G-EAT progressed to fibrosis. The expression of active caspase-3 was low, possibly contributing to the persistence of CD4(+) T cells in fibrosis. In contrast, FLIP was mainly expressed by thyrocytes in resolving G-EAT, the expression of active caspase-3 was high, and resolution correlated with apoptosis of infiltrating cells. There was also relatively less expression of TGF-beta, IFN-gamma, TNF-alpha, and inducible NO synthase and higher expression of IL-10 in resolving G-EAT than in G-EAT that progressed to fibrosis. These differences were particularly striking when comparing IFN-gamma(-/-) vs wild-type mice. These results suggest that several opposing biological mechanisms contribute to the outcome of an ongoing autoimmune response. These include differential expression of pro- and antiapoptotic molecules, cytokines, and the ratio of CD4(+) vs CD8(+) T cells.
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PMID:Mechanisms of spontaneous resolution versus fibrosis in granulomatous experimental autoimmune thyroiditis. 1463 40

The efficacy of antineoplastic compounds can depend heavily on the genetic background of the cells exposed to the drugs. This becomes evident by the fact that HT-29 human colon cancer cells but not primary murine nontransformed colonocytes are efficiently submitted to apoptosis by the flavonoid flavone. By determining caspase-3 activation, plasma membrane disintegration, and nuclear fragmentation, we show here that flavone also does not promote apoptosis in preneoplastic NCOL-1 colonocytes derived from a nontransformed human biopsy specimen. In clear contrast, the antitumor drug camptothecin potently induces apoptosis in NCOL-1 cells associated with a specific down-regulation of the antiapoptotic factor bcl-XL at the mRNA and protein levels and with the activation of the mitochondrial apoptosis pathway. Confocal microscopy revealed an increased production of superoxide anion radicals in the mitochondria of NCOL-1 cells that preceded the apoptotic events. However, in the case of flavone, the mitochondrial oxygen radicals were effectively scavenged by physiological concentrations of nitric oxide (NO), whereas in the case of camptothecin, the available nitric oxide was rapidly scavenged by the production of large quantities of cytosolic superoxide anions. Increasing the levels of nitric oxide inside NCOL-1 cells by sodium nitroprusside prevented the apoptosis induction by camptothecin. Reducing the levels of nitric oxide by using the NO synthase inhibitor, Nomega-nitro-l-arginine methyl ester in NCOL-1 cells or using HT-29 cells that intrinsically have low NO levels enabled flavone to trigger the apoptosis pathway. In conclusion, our studies demonstrate that the intracellular levels of nitric oxide significantly change the apoptotic response to antineoplastic agents in colonic cells.
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PMID:Nitric oxide levels in human preneoplastic colonocytes determine their susceptibility toward antineoplastic agents. 1464 80


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