Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of neutrophils with tumor necrosis factor-alpha (TNF-alpha) in the presence of cycloheximide induced apoptosis within 3 h, as evaluated by the occurrence of morphological nuclear changes characteristic of apoptosis. Pretreatment of neutrophils with dibutyryl cyclic AMP (dbcAMP) suppressed the TNF-alpha/cycloheximide-induced apoptosis in neutrophils in a concentration-dependent manner, while dbcAMP by itself did not induce any morphological changes. Forskolin, or a phosphodiesterase inhibitor, also produced a concentration-dependent inhibition on apoptosis. This inhibition by dbcAMP was completely reversed by pretreatment with the protein kinase A inhibitor, N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline sulphonamide (H-89). DbcAMP also inhibited the TNF-alpha/cycloheximide-induced activation of caspase-3, but it had no effect on the activation of caspase-8 in human neutrophils. Furthermore, dbcAMP did not directly inhibit activated caspase-3 activity. Inhibitor of protein kinase C, phosphatidylcholine-specific phospholipase C, tyrosine kinase, nitric oxide synthase, or granulocyte colony-stimulating factor or granulocyte monocyte colony-stimulating factor did not affect apoptosis. These results indicate that the elevation of levels of endogenous intracellular cyclic AMP and subsequent activation of protein kinase A play a crucial role in the prevention of apoptosis triggered by TNF-alpha/cycloheximide in human neutrophils, and that the possible target of cyclic AMP is a product in the metabolic pathway between caspase-8 and caspase-3.
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PMID:Inhibition of tumor necrosis factor-alpha induced neutrophil apoptosis by cyclic AMP: involvement of caspase cascade. 1035 95

Apoptotic cell death has been implicated in Alzheimer's disease pathology and amyloid peptide induced neurotoxicity. We investigated the survival promoting effects of Propentofylline in two models of apoptotic cell death, nerve growth factor withdrawal and beta-amyloid mediated cell death in nerve growth factor differentiated rat pheochromocytoma cell lines. The increase in cell death as measured by lactate dehydrogenase release in response to nerve growth factor withdrawal was suppressed by nitric oxide donor S-nitroso-N-acetylpenicillamine (12.5 to 200 microM) and by 8-bromoguanosine-3',5'-cyclic monophosphate (1.25 to 10mM). Both agents decreased cell death mediated by 25 microM beta-amyloid, suggesting that the protective mechanism involves guanosine -3', 5'-cyclic monophosphate. In support of this hypothesis we can show that S-nitroso-N-acetylpenicillamine increases intracellular levels of guanosine -3',5'-cyclic monophosphate in pheochromocytoma cell lines 3 to 8 fold.Propentofylline, a phosphodiesterase inhibitor, has previously demonstrated neuroprotective activity in stroke models and is a potential candidate for therapeutic treatment in neurodegenerative diseases. The present findings support this claim by providing evidence that Propentofylline has protective effects in both nerve growth factor withdrawal and beta-amyloid mediated cell death. Lactate dehydrogenase release was significantly reduced and caspase-3-like activity was attenuated after cotreatment with Propentofylline. Furthermore Propentofylline dose responsively increases intracellular guanosine-3',5'-cyclic monophosphate levels over the same dose range that provided protection. We hypothesized that guanosine-3',5'-cyclic monophosphate is a key mediator of neuroprotection under these conditions.
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PMID:Guanosine 3',5'-cyclic monophosphate mediated inhibition of cell death induced by nerve growth factor withdrawal and beta-amyloid: protective effects of propentofylline. 1097 37

Exisulind and its analogues are inhibitors of cyclic GMP phosphodiesterases (PDEs) that have been shown to activate and induce protein kinase G, resulting in the induction of apoptosis in colon cancer cells. These drugs also reduce beta-catenin protein levels and decrease cyclin D1 mRNA levels in SW480 cells. Herein we report on studies pertaining to exisulind regulation of beta-catenin levels and activity in colon tumor cells. Exisulind and its higher-affinity PDE analogues, (Z)-5-fluoro-2-methyl-(4-pyridylidene)-3-(N-benzyl)-indenylacetamide hydrochloride (CP461) and (Z)-1H-indene-3-acetamide, 5-fluoro-2-methyl-N-(phenylmethyl)-1-[(3,4,5-trimethoxyphenyl)methylene] (CP248), reduced beta-catenin, including the nuclear beta-catenin in SW480 cells (EC(50) approximately 200 microM, 1 microM, and <1 microM, respectively). The 50% reduction of beta-catenin was seen in 8-14 hr. There was no change in beta-catenin mRNA. Exisulind-induced beta-catenin reduction was blocked by the proteasomal inhibitor MG132 (Z-leu-Leu-Leu-CHO), indicating that the effect of exisulind involved ubiquitin-proteasomal degradation. A consequence of reduced beta-catenin in SW480 cells was that exisulind, CP461, and CP248 caused a concentration- and time-dependent decrease in cyclin D1 levels (EC(50) approximately 300 microM, 1 microM, and <1 microM, respectively) in 4 hr. The effect was via decreased cyclin D1 mRNA levels. Exisulind-induced degradation of beta-catenin was not blocked by the inhibition of caspase-3 activity and/or apoptosis, and some SW480 cells showed a reduction in beta-catenin levels before the appearance of early apoptosis indicators. Expression of the N-terminal 170 amino acid fragment of beta-catenin reduced the effects of beta-catenin degradation, cyclin D1 reduction, and the apoptosis response to exisulind. These results indicate that exisulind-induced beta-catenin degradation precedes the induction of apoptosis and that the down-regulation of inappropriate beta-catenin-activated genes accounts in part for the pro-apoptotic effects of exisulind and CP461 in colon tumor cells.
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PMID:Pro-apoptotic actions of exisulind and CP461 in SW480 colon tumor cells involve beta-catenin and cyclin D1 down-regulation. 1239 15

Recent reports indicate that cAMP-elevating agents can protect against cell death induced by many stimuli, including tumour necrosis factor-alpha (TNF-alpha). We investigated the ability of cAMP-elevating agents to modulate TNF-alpha-mediated cytotoxicity in L929 cells. Using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) reduction assay and a DNA fragmentation assay as indicators of cell survival, we have shown that forskolin confers partial protection against TNF-alpha-mediated cytotoxicity and inhibits TNF-alpha-induced internucleosomal DNA fragmentation in L929 cells. The protection conferred by forskolin is cAMP-independent since 1,9-dideoxyforskolin (an adenylate cyclase-inactive analog) also protected against TNF-alpha, while both dibutyryl-cAMP and the cAMP-phosphodiesterase inhibitor theophylline were not protective. This is the first example (that we know of) of cAMP-independent cytoprotection by forskolin. We conclude that forskolin acts in a cAMP-independent manner, potentially at a site upstream of caspase-3 activation, to protect against TNF-alpha-mediated cytotoxicity in L929 cells, and that cAMP elevation, in general, does not confer protection against TNF-alpha-induced death in L929 cells. In addition, we observed that Cyclosporin A, a mitochondrial permeability transition (MPT) inhibitor, protected L929 cells against TNF-alpha, underlining the importance of mitochondria in the cytotoxic process induced by TNF-alpha in L929 cells.
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PMID:The adenylate cyclase activator forskolin partially protects L929 cells against tumour necrosis factor-alpha-mediated cytotoxicity via a cAMP-independent mechanism. 1239 72

Nitric oxide may play a role in phosphodiesterase (PDE) inhibitor-induced rat mesenteric vasculitis. The present study was conducted to identify cellular sources of iNOS, determine the distribution of nitrotyrosine (NT) residues as a footprint of peroxynitrite (ONOO-) production, and evaluate their association with vascular apoptosis. To dissociate primary events from secondary changes associated with the inflammatory response, rats were given the PDE IV inhibitor CI-1018 orally at 750 mg/kg alone or concurrently with dexamethasone (DEX) intraperitoneally at 1 mg/kg for 4-5 days. Neutrophil (PMN) involvement in apoptosis was investigated in CI-1018 treated rats dosed with rabbit anti-rat PMN serum (APS). iNOS expression, NT residues, and caspase-3 were detected by immuno-histochemistry. Apoptosis was evaluated by TUNEL assay. CI-1018 induced vascular lesions were associated with iNOS expression in endothelial cells and inflammatory infiltrates; NT was evident only in the latter. Caspase-3 and TUNEL-positive staining were prominent only in medial smooth muscle cells (SMC) from CI-1018-treated rats and only when associated with active inflammation. iNOS- and NT-positive inflammatory cells were present in close proximity to SMC with caspase-3 staining. Inflammatory infiltrates were absent in rats given DEX with minimal SMC necrosis and hemorrhage remained. DEX eliminated apoptosis and immunoreactivity associated with caspase-3, iNOS, and NT. APS depletion of PMNs decreased the incidence and severity of vasculitis but failed to abolish completely caspase-3 immunoreactivity. Expression patterns for caspase-3, iNOS, and NT demonstrated that nitrative stress is a prominent feature of PDE inhibitor-induced vasculitis, with a possible role in medial SMC apoptosis. Further, medial SMC apoptosis may not be a primary event, but instead may be secondary to the inflammatory response.
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PMID:Apoptosis and nitrative stress associated with phosphodiesterase inhibitor-induced mesenteric vasculitis in rats. 1458 32

The rd mouse, an accepted animal model for photoreceptor degeneration in retinitis pigmentosa, has a recessive mutation for the gene encoding the beta-subunit of the cGMP phosphodiesterase. This mutation results in high levels of cGMP, which leaves an increased number of the cGMP-gated channels in the open state, thus allowing intracellular calcium (Ca(2+)) to rise to toxic levels, and rapid photoreceptor degeneration follows. To delineate the events in rd photoreceptor degeneration, we demonstrated an increase in calpain and caspase-3 activity, hypothesizing that Ca(2+)-mediated apoptosis in photoreceptors is mediated by calpain, involving mitochondrial depolarization and caspase-3 activation. To examine this hypothesis further, a murine photoreceptor-derived cell line (661W) was treated with the Ca(2+) ionophore A23187, cGMP-gated channel agonist 8-bromo-cGMP, or phosphodiesterase inhibitor isobutylmethylxanthine to mimic the increased Ca(2+) influx seen in the rd photoreceptors. Ca(2+)-induced cell death in 661W cells was found to be mediated by calpain and caspase-3 and could be completely inhibited by the calpain inhibitor SJA6017, implicating both calpain and caspases in the apoptotic process. The apoptotic events correlated in an SJA6017-inhibitable manner with bid cleavage, mitochondrial depolarization, cytochrome c release, and caspase-3 and -9 activation. We concluded that Ca(2+) influx in the rd model of photoreceptor degeneration leads to the activation of the cysteine protease calpain, which executes apoptosis via modulation of caspase-3 activity.
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PMID:Calcium-induced calpain mediates apoptosis via caspase-3 in a mouse photoreceptor cell line. 2880 51

Autotaxin (ATX) was originally identified as a potent tumor cell motility-stimulating factor that displays multiple enzymatic activities including ATPase, Type I nucleotide pyrophosphatase/phosphodiesterase, and lysophospholipase D, depending on its substrates. We demonstrate herein that ATX is a key regulator of extracellular lysophosphatidic acid (LPA) that can act as survival factor, in addition to its mitogenic activity in mouse fibroblasts. Introduction of atx gene into NIH3T3 cells resulted in resistance to conditional apoptosis induced by serum-deprivation, and exogenous ATX protein prevented cells from death by starvation. Flow cytometric analysis showed that co-treatment of ATX with lysophosphatidylcholine as substrate rescued NIH3T3 cells from cellular apoptosis, and this survival activity of ATX was also demonstrated by caspase-3 degradation and PARP cleavage resulting from the enzymatic activity of extracellular ATX. Furthermore, the effect of ATX in preventing apoptosis appears to be mediated through the G-protein-coupled receptor pathway followed by the activation of phosphoinositide 3-kinase and Akt pathway leading to enhanced cell survival. These findings provide novel insights into understanding the functions of ATX as a key regulator of bioactive phospholipids and suggest interventions to correct dysfunction in conditions of tumor cell growth and metastasis.
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PMID:Autotaxin (lysoPLD/NPP2) protects fibroblasts from apoptosis through its enzymatic product, lysophosphatidic acid, utilizing albumin-bound substrate. 1621 96

In earlier studies from this laboratory, Xanthomonas campestris pv. glycines was found to exhibit a nutrition stress-related postexponential rapid cell death (RCD). The RCD was exhibited in protein-rich media but not in starch or other minimal media. This RCD in X. campestris pv. glycines was found to display features similar to those of the programmed cell death (PCD) of eukaryotes. Results of the present study showed that the observed RCD in this organism is both positively and negatively regulated by small molecules. The amino acids glycine and l-alanine as well as the D isomers of valine, methionine, and threonine were found to induce the synthesis of an active caspase-3-like protein that was associated with the onset of RCD. Addition of pyruvate and citrate to the culture medium induced both the synthesis of active caspase-3-like protein and RCD. Higher levels of intracellular accumulation of pyruvate and citrate were also observed under conditions favoring RCD. On the other hand, dextrin and maltose, the hydrolytic products of starch, inhibited the synthesis of the caspase-3-like protein. Addition of glucose and cyclic AMP (cAMP) to the RCD-favoring medium prevented RCD. Glucose, cAMP, caffeine (a known inhibitor of a phosphodiesterase that breaks down cAMP), and forskolin (from the herb Coleus forskholii, known to activate the enzyme adenylate cyclase that forms cAMP) inhibited the caspase enzyme activity in vivo and consequently the RCD process. The addition of glucose and other inhibitors of RCD enhanced intracellular cAMP accumulation. This is the first report demonstrating the involvement of small molecules in the regulation of nutrition stress-related stationary-phase rapid cell death in X. campestris pv. glycines, which is programmed.
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PMID:Molecules involved in the modulation of rapid cell death in Xanthomonas. 1685 30

We report the chromosomal localization, mutant gene identification, ophthalmic appearance, histology, and functional analysis of two new hereditary mouse models of retinal degeneration not having the Pde6brd1("r", "rd", or "rodless") mutation. One strain harbors an autosomal recessive mutation that maps to mouse chromosome 5. Sequence analysis showed that the retinal degeneration is caused by a missense point mutation in exon 13 of the beta-subunit of the rod cGMP phosphodiesterase (beta-PDE) gene (Pde6b). The gene symbol for this strain was set as Pde6brd10, abbreviated rd10 hereafter. Mice homozygous for the rd10 mutation showed histological changes at postnatal day 16 (P16) of age and sclerotic retinal vessels at four weeks of age, consistent with retinal degeneration. Retinal sections were highly positive for TUNEL and activated caspase-3 immunoreactivity, specifically in the outer nuclear layer (ONL). ERGs were never normal, but rod and cone ERG a- and b-waves were easily measured at P18 and steadily declined over 90% by two months of age. Protein extracts from rd10 retinas were positive for beta-PDE immunoreactivity starting at about the same time as wild-type (P10), though signal averaged less than 40% of wild-type. Interestingly, rearing rd10 mice in total darkness delayed degeneration for at least a week, after which morphological and functional loss progressed irregularly. With the second strain, a complementation test with rd1 mice revealed that the retinal degeneration phenotype observed represents a possible new allele of Pde6b. Sequencing demonstrated a missense point mutation in exon 16 of the beta-subunit of rod phosphodiesterase gene, different from the point mutations in rd1 and rd10. The gene symbol for this strain was set as Pde6bnmf137, abbreviated nmf137 hereafter. Mice homozygous for this mutation showed retinal degeneration with a mottled retina and white retinal vessels at three weeks of age. The exon 13 missense mutation (rd10) is the first known occurrence of a second mutant allele spontaneously arising in the Pde6b gene in mice and may provide a model for studying the pathogenesis of autosomal recessive retinitis pigmentosa (arRP) in humans. It may also provide a better model for experimental pharmaceutical-based therapy for RP because of its later onset and milder retinal degeneration than rd1 and nmf137.
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PMID:Two mouse retinal degenerations caused by missense mutations in the beta-subunit of rod cGMP phosphodiesterase gene. 1726 5

Cellular injury can involve the aberrant stimulation of cell cycle proteins in part through activation of phosphodiesterases (PDEs) and downstream expression of cell-cycle components such as cyclin D1. In mature non-proliferating cells activation of the cell cycle can lead to the induction of programmed cell death. In the present study, we investigated the in vitro neuroprotective efficacy and mechanism of action of vinpocetine (PDE1 inhibitor), trequinsin (PDE3 inhibitor), and rolipram (PDE4 inhibitor) in four mechanistically-distinct models of injury to primary rat cortical neurons as related to cell cycle regulation and apoptosis. Cellular injury was induced by hypoxia/hypoglycemia, veratridine (10 microM), staurosporine (1 microM), or glutamate (100 microM), resulting in average neuronal cell death rates of 43-48% as determined by MTT assay. Treatment with each PDE inhibitor (PDEI) resulted in a similar concentration-dependent neuroprotection profile with maximal effective concentrations of 5-10 microM (55-77% neuroprotection) in all four neurotoxicity models. Direct cytotoxicity due to PDE inhibition alone was not observed at concentrations below 100 microM. Further studies indicated that PDEIs can suppress the excitotoxic upregulation of cyclin D1 similar to the effects of flavopiridol, a cyclin-dependent kinase inhibitor, including suppression of pro-apoptotic caspase-3 activity. Overall, these data indicate that PDEIs are broad-spectrum neuroprotective agents acting through modulation of cell cycle elements and may offer a novel mode of therapy against acute injury to the brain.
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PMID:Broad spectrum neuroprotection profile of phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 activation. 1739 1


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