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

The cardiac outflow tract (OFT) of birds and mammals undergoes complex remodeling in the transition to a dual circulation. We have previously suggested a role of myocardial hypoxia and hypoxia inducible factor (HIF)-1 in the apoptosis-dependent remodeling of the OFT. In the present study, we transduced recombinant adenovirus-mediated HIF-1alpha in embryonic chick OFT myocardium to test its role in OFT remodeling. HIF-1alpha reduced the prevalence of apoptosis in OFT cardiomyocytes at stages 25 and 30, as determined by lysosome accumulation and caspase-3 activity. Associated conotruncal defects included malrotation of the aorta and excessive infundibular myocardium. HIF-1 targets induced in these gain-of-function experiments included vascular endothelial growth factor (VEGF), inducible nitric oxide synthase, and stromal cell-derived factor-1. To test the role of VEGF in this context, an adenovirus expressing secreted Flk1 (VEGF receptor 2) that binds and blocks VEGF signaling was targeted to the OFT myocardium. This caused increased cell death in the OFT myocardium at stages 25 and 30. Associated conotruncal heart defects included malrotation of the aorta, defects in the subpulmonic infundibulum associated with a small right ventricle, and increased OFT mesenchyme with failure of semilunar valve formation. We conclude that hypoxia signaling through HIF-1 and VEGF provides an autocrine survival signal in the developing cardiac OFT and that perturbation in this pathway causes OFT defects that model congenital human conotruncal heart defects.
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PMID:Hypoxia-inducible transcription factor-1alpha triggers an autocrine survival pathway during embryonic cardiac outflow tract remodeling. 1846 28

Malignant melanoma is the most deadly form of skin cancer due to its highly metastatic nature. Untargeted therapies are ineffective for treating metastatic disease, leading to the development of agents specifically inhibiting proteins or pathways deregulated in melanoma. The deregulation of inducible nitric oxide synthase (iNOS) is one such event occurring in melanoma, and is correlated with poor survival. Current iNOS inhibitors, such as PBIT [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea], require high concentrations for clinical efficacy causing systemic toxicity. To develop more potent agents effective at significantly lower concentrations, a novel isosteric analogue of PBIT was synthesized, called PBISe [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea], in which sulfur was replaced with selenium. PBISe kills melanoma cells >10-fold more effectively than PBIT, and cultured cancer cells are 2- to 5-fold more sensitive than normal cells. Like PBIT, PBISe targets iNOS but also has new inhibitory properties acting as an Akt3 pathway inhibitor and mitogen-activated protein kinase (MAPK) cascade activator, which causes decreased cancer cell proliferation and increased apoptosis. Inhibition of cellular proliferation mediated by PBISe induced a G2-M phase cell cycle block linked to excessively high MAPK activity causing decreased cyclin D1 and increased p21 as well as p27 levels. PBISe promotes apoptosis by inhibiting Akt3 signaling, elevating cleaved caspase-3 and PARP levels. Compared with PBIT, PBISe reduced tumor development by 30% to 50% in mice inducing a 2-fold increase in apoptosis with negligible associated systemic toxicity. Collectively, these results suggest that PBISe is a potent chemotherapeutic agent with novel properties enabling the targeting of iNOS, Akt3, and MAPK signaling, thereby promoting melanoma cell apoptosis and inhibition of proliferation.
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PMID:PBISe, a novel selenium-containing drug for the treatment of malignant melanoma. 1848 17

Hemorrhagic shock (HS) is an oxidative stress that causes intestinal tissue injury. Heme oxygenase 1 (HO-1) is induced by oxidative stress and is thought to play an important role in the protection of tissues from oxidative injury. We previously reported the ileum to be the most susceptible to HS-induced tissue injury site in the intestine because HO-1 induction is the lowest at this site. We also previously demonstrated that glutamine (GLN) significantly induced HO-1 in the lower intestinal tract. In the present study, we investigated whether GLN pretreatment improves HS-induced intestinal tissue injury in the ileum by HO-1 induction. Treatment of rats with GLN (0.75 g/kg, i.v.) markedly induced functional HO-1 protein in mucosal epithelial cells in the ileum. Glutamine treatment before HS (MAP of 30 mmHg for 60 min) significantly ameliorated HS-induced mucosal inflammation and apoptotic cell death in the ileum, as judged by significant decreases in gene expression of TNF-alpha, iNOS, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1, myeloperoxidase activity, the number of infiltrated neutrophils, DNA fragmentation by in situ oligo ligation assay, and activated caspase-3 expression, and by increases in gene expression of IL-10 and Bcl-2. In contrast, treatment with tin mesoporphyrin, a specific inhibitor of HO activity, abolished the beneficial effect of GLN pretreatment. These findings indicate that GLN pretreatment significantly ameliorated tissue injury in the ileum after HS by inducing HO-1. Glutamine treatment may thus protect mucosal cells from HS-induced oxidative damage via the anti-inflammatory and antiapoptotic properties of HO-1.
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PMID:Prevention of hemorrhagic shock-induced intestinal tissue injury by glutamine via heme oxygenase-1 induction. 1849 9

Chronic exposure of pancreatic islets to elevated levels of palmitate leads to beta-cell dysfunction. We examined possible involvement of mitogenactivated protein kinases (MAPKs) and caspase-3 in palmitate-induced beta-cell dysfunction and tested the influence of the anti-diabetic drug rosiglitazone (ROZ). Palmitate amplified glucose-stimulated augmentation of intracellular free calcium ([Ca2+]i) and insulin secretion in incubated islets. ROZ suppressed this amplification, whereas it modestly augmented glucose-induced increase in these events. ROZ suppressed short-term palmitate-induced phosphorylation of pro-apoptotic MAPKs, i.e., SAPK/JNK and p38. Long-term islet culturing with palmitate induced inducible nitric oxide synthase (iNOS) and activated SAPK/JNK-p38. ROZ counteracted these effects. Both palmitate and cytokines activated caspase-3 in MIN6c4-cells and isolated islets. ROZ suppressed palmitate- but not cytokine-induced caspase-3 activation. Finally, after palmitate culturing, ROZ reversed the inhibitory effect on glucose-stimulated insulin release. We suggest that ROZ counteracts palmitateinduced deleterious effects on beta-cell function via suppression of iNOS, pro-apoptotic MAPKs and caspase-3 activities, as evidenced by restoration of glucose-stimulated insulin release.
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PMID:Rosiglitazone counteracts palmitate-induced beta-cell dysfunction by suppression of MAP kinase, inducible nitric oxide synthase and caspase 3 activities. 1856 Jul 59

Flavonoids are polyphenols frequently consumed in the diet which have been suggested to exert a number of beneficial actions on human health, including intestinal anti-inflammatory activity. Their properties have been studied in numerous cell types, but little is known about their effect on leukocyte biology. We have selected 9 flavonoids (extended to 14 flavonoids plus the related polyphenol resveratrol in some cases) with different structural features to characterize their effects on leukocyte viability, proliferation, and expression of cyclooxygenase 2 (EC 1.14.99.1), inducible nitric oxide synthase (iNOS, EC 1.14.13.39) and proinflammatory cytokines (TNF-alpha, IFN-gamma, IL-2), as well as to elucidate the structural requirements in each case. Quiescent and concanavalin A-stimulated rat splenocytes were used as a model. Flavonoids (50 microM) had a dramatic inhibitory effect on cytokine secretion. Inducible nitric oxide synthase expression was also blocked largely by some flavonoids, especially quercetin, luteolin and apigenin, while cyclooxygenase 2 was downregulated only by apigenin, diosmetin and quercetin. Apigenin, luteolin, genistein and quercetin had substantial cytotoxic/proapoptotic effects, while chrysin, daidzein, hesperetin and kaempferol did not reduce cell viability. In contrast, all flavonoids had powerful antiproliferative effects. However, none of the compounds activated caspase 3 (EC 3.4.22.56), but actually lowered caspase 3 activation and expression in concanavalin A-stimulated cells. The activity of the quercetin metabolite isorhamnetin was generally lower than that of the parent compound. We conclude that flavonoids have powerful effects on lymphocytes with distinct structural requirements that may contribute to their intestinal anti-inflammatory activity. The bioactivity of orally administered flavonoids may be dampened by biotransformation in vivo, particularly in extraintestinal sites.
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PMID:Effect of flavonoids on rat splenocytes, a structure-activity relationship study. 1859 Jul 7

Pancreatic islet microendothelium and beta cells exhibit an interdependent physical and functional relationship. In this study, we analyzed the effect of chronic hyperglycemia on human pancreatic islet microendothelial cells as well as the involvement of the phosphatidylinositol 3-kinase/Akt and nephrin pathways, interleukin-1beta, and nitric oxide production. In addition, whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can reverse the response to high-glucose conditions was investigated. Proliferation of purified islet microendothelial cells cultured under hyperglycemic conditions (28 mmol/L glucose) decreased compared to that of normoglycemic cells (from 12.7% after 2 days to 47.7% after 30 days, P < 0.05). In parallel, apoptosis progressively increased from 7% after 2 days to 79% after 30 days in high glucose (P < 0.05) concomitant with an early increase of caspase-3 activity. Intermittent hyperglycemia induced greater apoptosis than sustained hyperglycemia. Apoptosis was accompanied by a reduced p-Akt/Akt ratio and inhibition of nephrin tyrosine phosphorylation. Pravastatin (1 mumol/L) decreased apoptosis induced by high glucose or oxidized LDL and increased Akt phosphorylation. Hyperglycemia significantly increased the production of the proinflammatory cytokine interleukin-1beta and stimulated the expression of inducible nitric oxide synthase and the production of nitric oxide, possibly relevant to beta cell mass and function. Thus, chronic hyperglycemia reduces islet microendothelial cell survival by inhibiting the serine-threonine kinase Akt pathway, and the effect of pravastatin on this pathway represents a potential tool to improve islet vascularization and, indirectly, islet function.
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PMID:Hyperglycemia induces apoptosis of human pancreatic islet endothelial cells: effects of pravastatin on the Akt survival pathway. 1859 14

A series of 10 heterocyclic compounds purified from Allanblackia were tested on two B cell lines, ESKOL and EHEB, and on cells from B-CLL patients. Several molecules inhibited the proliferation of both cell lines and promoted apoptosis of B-CLL cells through different mechanisms, some of them elicited a dissipation of the mitochondrial transmembrane potential, other triggered caspase-3 activation and cleavage of the inducible nitric oxide synthase. Blood mononuclear cells and B-lymphocytes from healthy donors appeared less sensitive than B-CLL cells. These results indicate that these molecules may be of interest in the development of new therapies for B-CLL.
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PMID:Apoptotic effects on B-cell chronic lymphocytic leukemia (B-CLL) cells of heterocyclic compounds isolated from Guttiferaes. 1865 57

The generation of endogenous hydrogen sulfide may either limit or contribute to the degree of tissue injury caused by ischemia/reperfusion. A total of 74 male Wistar rats were used to investigate the effects of endogenous and exogenous hydrogen sulfide in renal ischemia/reperfusion. Administration of the irreversible cystathionine gamma-lyase (CSE) inhibitor, dL-propargylglycine, prevented the recovery of renal function after 45 min ischemia and 72 h reperfusion. The hydrogen sulfide donor sodium hydrosulfide attenuated the (renal, tubular, and glomerular) dysfunction and injury caused by 45 min ischemia and 6 h reperfusion. Western blot analysis of kidneys taken at 30 min reperfusion showed that sodium hydrosulfide significantly attenuated phosphorylation of mitogen-activated protein kinases (p-38, c-JUN N-terminal protein kinase 1/2, and extracellular signal-regulated kinase 1/2) and activation of nuclear factor-kappaB. At 6 h reperfusion, sodium hydrosulfide significantly attenuated the histological score for acute tubular necrosis, the activation of caspase-3 and Bid, the decline in the expression of anti-apoptotic Bcl-2, and the expression of nuclear factor-kappaB-dependent proteins (inducible nitric oxide synthase, cyclo-oxygenase-2, and intercellular adhesion molecule-1). These findings suggest that (1) the synthesis of endogenous hydrogen sulfide by CSE is essential to protect the kidney against ischemia/reperfusion injury and dysfunction and aids in the recovery of renal function following ischemia/reperfusion, (2) hydrogen sulfide generated by sodium hydrosulfide reduces ischemia/reperfusion injury and dysfunction, and morphological changes of the kidney, and (3) the observed protective effects of hydrogen sulfide are due to both anti-apoptotic and anti-inflammatory effects.
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PMID:Generation of endogenous hydrogen sulfide by cystathionine gamma-lyase limits renal ischemia/reperfusion injury and dysfunction. 1867 78

alpha-Synuclein is the fundamental component of Lewy bodies which occur in the brain of 60% of sporadic and familial Alzheimer's disease patients. Moreover, a proteolytic fragment of alpha-synuclein, the so-called non-amyloid component of Alzheimer's disease amyloid, was found to be an integral part of Alzheimer's dementia related plaques. However, the role of alpha-synuclein in pathomechanism of Alzheimer's disease remains elusive. In particular, the relationship between alpha-synuclein and amyloid beta is unknown. In the present study we showed the involvement of alpha-synuclein in amyloid beta secretion and in the mechanism of amyloid beta evoked mitochondria dysfunction and cell death. Rat pheochromocytoma PC12 cells transfected with amyloid beta precursor protein bearing Swedish double mutation (APPsw) and control PC12 cells transfected with empty vector were used in this study. alpha-Synuclein (10microM) was found to increase by twofold amyloid beta secretion from control and APPsw PC12 cells. Moreover, alpha-synuclein decreased the viability of PC12 cells by about 50% and potentiated amyloid beta toxicity leading to mitochondrial dysfunction and caspase-dependent programmed cell death. Inhibitor of caspase-3 (Z-DEVD-FMK, 100microM), and a mitochondrial permeability transition pore blocker, cyclosporine A (2microM) protected PC12 cells against alpha-synuclein or amyloid beta evoked cell death. In contrast Z-DEVD-FMK and cyclosporine A were ineffective in APPsw cells containing elevated amount of amyloid beta treated with alpha-synuclein. It was found that the inhibition of neuronal and inducible nitric oxide synthase reversed the toxic effect of alpha-synuclein in control but not in APPsw cells. Our results indicate that alpha-synuclein enhances the release and toxicity of amyloid beta leading to nitric oxide mediated irreversible mitochondria dysfunction and caspase-dependent programmed cell death.
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PMID:alpha-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells. 1880 2

Glucuronoxylomannan (GXM) is the major component of Cryptococcus capsular polysaccharide, which represents an essential virulence factor for this yeast. Cryptococcus neoformans infections in immunocompetent rats are associated with inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production by macrophages. This study demonstrates in vitro and in vivo that GXM promotes iNOS expression with NO production in rat macrophages. GXM also induced macrophage apoptosis after 48 h of culture, with this phenomenon being prevented by the iNOS inhibitor, aminoguanidine. The NO-induced macrophage apoptosis triggered by GXM was dependent on interactions with CD18, Fcgamma receptor II and protein kinase C activation, without participation of tyrosine kinases or mitogen-activated protein kinases. Furthermore, this study reveals that GXM down-regulates the macrophage caspase-3 activity, induces a caspase-independent cell death and promotes depolarization of mitochondria membrane potential with increased cytosolic expression of the apoptosis-inducing factor. Taken together, this study describes the pathways and mechanisms involved in the macrophage apoptosis promoted by GXM through NO generation. These findings indicate new mechanisms of immunomodulation for the main capsular polysaccharide of C. neoformans.
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PMID:Cryptococcus neoformans glucuronoxylomannan induces macrophage apoptosis mediated by nitric oxide in a caspase-independent pathway. 1892 17


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