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)

Doxorubicin (DOX) is a potent available antitumor agent; however, its clinical use is limited because of its cardiotoxicity. Cell death is a key component in DOX-induced cardiotoxicity, but its mechanisms are elusive. Here, we explore the role of superoxide, nitric oxide (NO), and peroxynitrite in DOX-induced cell death using both in vivo and in vitro models of cardiotoxicity. Western blot analysis, real-time PCR, immunohistochemistry, flow cytometry, fluorescent microscopy, and biochemical assays were used to determine the markers of apoptosis/necrosis and sources of NO and superoxide and their production. Left ventricular function was measured by a pressure-volume system. We demonstrated increases in myocardial apoptosis (caspase-3 cleavage/activity, cytochrome c release, and TUNEL), inducible NO synthase (iNOS) expression, mitochondrial superoxide generation, 3-nitrotyrosine (NT) formation, matrix metalloproteinase (MMP)-2/MMP-9 gene expression, poly(ADP-ribose) polymerase activation [without major changes in NAD(P)H oxidase isoform 1, NAD(P)H oxidase isoform 2, p22(phox), p40(phox), p47(phox), p67(phox), xanthine oxidase, endothelial NOS, and neuronal NOS expression] and decreases in myocardial contractility, catalase, and glutathione peroxidase activities 5 days after DOX treatment to mice. All these effects of DOX were markedly attenuated by peroxynitrite scavengers. Doxorubicin dose dependently increased mitochondrial superoxide and NT generation and apoptosis/necrosis in cardiac-derived H9c2 cells. DOX- or peroxynitrite-induced apoptosis/necrosis positively correlated with intracellular NT formation and could be abolished by peroxynitrite scavengers. DOX-induced cell death and NT formation were also attenuated by selective iNOS inhibitors or in iNOS knockout mice. Various NO donors when coadministered with DOX but not alone dramatically enhanced DOX-induced cell death with concomitant increased NT formation. DOX-induced cell death was also attenuated by cell-permeable SOD but not by cell-permeable catalase, the xanthine oxidase inhibitor allopurinol, or the NADPH oxidase inhibitors apocynine or diphenylene iodonium. Thus, peroxynitrite is a major trigger of DOX-induced cell death both in vivo and in vivo, and the modulation of the pathways leading to its generation or its effective neutralization can be of significant therapeutic benefit.
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PMID:Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. 1928 53

Although it has been well documented that drugs of abuse such as cocaine cause enhanced progression of human immunodeficiency virus (HIV)-associated neuropathological disorders, the underlying mechanisms mediating these effects remain poorly understood. The present study demonstrated that exposure of rat primary neurons to both cocaine and gp120 resulted in increased cell toxicity compared to cells treated with either factor alone. The combinatorial toxicity of cocaine and gp120 was accompanied by an increase in both caspase-3 activity and expression of the proapoptotic protein Bax. Furthermore, increased neurotoxicity in the presence of both the agents was associated with a concomitant increase in the production of intracellular reactive oxygen species and loss of mitochondrial membrane potential. Increased neurotoxicity mediated by cocaine and gp120 was ameliorated by NADPH oxidase inhibitor apocynin, thus underscoring the role of oxidative stress in this cooperation. Signaling pathways including c-jun N-teminal kinase (JNK), p38, extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK), and nuclear factor (NF)-kappaB were also identified to be critical in the neurotoxicity induced by cocaine and gp120. These findings thus underscore the role of oxidative stress, mitochondrial and MAPK signal pathways in cocaine and HIV gp120-mediated neurotoxicity.
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PMID:Cocaine and human immunodeficiency virus type 1 gp120 mediate neurotoxicity through overlapping signaling pathways. 1931 45

Neuronal apoptotic death involves the participation of reactive oxygen species (ROS), but their sources have not been completely elucidated. Previous studies have demonstrated that the ROS-producing enzyme NADPH oxidase is present in neuronal cells and that this enzyme could participate in the apoptotic neuronal death. Cerebellar granule neurons (CGN) undergo apoptosis when cells are transferred from a medium with 25 mM KCl (K25) to a 5 mM KCl (K5) medium or when they are treated with staurosporine (ST). Under these conditions, apoptotic death of CGN is dependent on ROS production. In this study, we evaluated the role of NOX2, an NADPH oxidase homolog, in the apoptotic death of CGN induced by two different conditions. In CGN from NOX2-deficient (ko) mice, a significantly lower rate of apoptotic death occurs compared with wild-type (wt) CGN. Also, caspase-3 activation, NADPH oxidase activity, and superoxide anion production induced by ST were markedly lower in ko neurons than in wt CGN. In contrast to the case with ST, when CGN were treated with K5, no differences were observed between ko and wt cells in any of the parameters measured. However, all NADPH oxidase inhibitors tested noticeably reduced cell death and apoptotic parameters induced by K5 in both wt and ko CGN. These results suggest that NOX2 could be necessary for apoptotic death induced by ST, but not by K5, which could require other member of the NOX family in the apoptotic process.
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PMID:NOX2 mediates apoptotic death induced by staurosporine but not by potassium deprivation in cerebellar granule neurons. 1936 Sep 6

This study was to investigate the role of calpain in the apoptosis of pulmonary microvascular endothelial cells (PMEC) during septic plasma stimulation. Septic plasma was collected from endotoxemic mice. In cultured PMEC, incubation with septic plasma stimulated calpain activation, increased caspase-3 activity and induced apoptotic cell death. These effects of septic plasma were abrogated by knockdown of calpain-1 but not calpain-2 using specific siRNA. Consistently, treatment with calpain inhibitor-III, or over-expression of calpastatin, an endogenous calpain inhibitor significantly decreased apoptosis induced by septic plasma. Septic plasma also induced NADPH oxidase activation and reactive oxygen species (ROS) production. Inhibiting NADPH oxidase or scavenging ROS attenuated calpain activity and decreased apoptosis in PMEC during septic plasma stimulation. In summary, our study demonstrates that ROS produced from NADPH oxidase stimulates calpain-1 activation, which induces apoptosis under septic conditions. Thus, targeting calpain-1/calpastatin may represent a potential strategy to protect against endothelial injury in sepsis.
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PMID:Calpain-1 induces apoptosis in pulmonary microvascular endothelial cells under septic conditions. 1937 62

Because neutrophil apoptosis plays a key role in resolving inflammation, identification of proteins regulating neutrophil survival should provide new strategies to modulate inflammation. Using a proteomic approach, coronin-1 was identified as a cytosolic protein cleaved during neutrophil apoptosis. Coronin-1 is an actin-binding protein that can associate with phagosomes and NADPH oxidase, but its involvement in apoptosis was currently unknown. In coronin-1-transfected PLB985 cells, coronin-1 overexpression did not modify the kinetics of granulocyte differentiation as assessed by CD11b labeling. Concerning apoptosis, increased coronin-1 expression in dimethylformamide-differentiated PLB985 significantly decreased gliotoxin-induced mitochondrial depolarization as compared with controls. Likewise, coronin-1 significantly decreased TRAIL-induced apoptosis with less mitochondrial depolarization, caspase-3 and caspase-9 activities, but not caspase-8 or Bid truncation suggesting that coronin-1 interfered with mitochondria-related events. To validate the prosurvival role of coronin-1 in a pathophysiological condition involving neutrophil-dominated inflammation, neutrophils from cystic fibrosis (CF) patients were studied. Circulating neutrophils from CF patients had more coronin-1 expression assessed by immunoblotting or proteomic analysis of cytosolic proteins. This was associated with a lower apoptosis rate than those from controls evidenced by delayed phosphatidylserine externalization and mitochondria depolarization. In addition, inflammatory neutrophils from CF patients lungs showed an intense coronin-1 immunolabeling. We concluded that coronin-1 could constitute a potential target in resolving inflammation.
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PMID:Coronin-1 is associated with neutrophil survival and is cleaved during apoptosis: potential implication in neutrophils from cystic fibrosis patients. 1945 22

The p38 mitogen-activated protein kinase (MAPK) is activated during heart diseases that might be associated with myocardial damage and cardiac remodeling process. Diabetic cardiomyopathy is associated with increased oxidative stress and inflammation. The purpose of this study was to investigate the role of p38alpha MAPK after experimental diabetes by using transgenic (TG) mice with cardiac-specific expression of a dominant-negative mutant form of p38alpha MAPK. The elevation of blood glucose was comparable between the nontransgenic (NTG) and TG mice. The expression of phospho-p38 MAPK and phospho-MAPK-activated protein kinase 2 levels were significantly suppressed in TG mice heart than in NTG mice after diabetes induction. Left ventricular (LV) dimension in systole was smaller, and the percent fractional shortening was higher in diabetic TG mice compared with diabetic NTG mice. In addition, diabetic TG mice had reduced cardiac myocyte diameter, content of cardiac fibrosis, LV tissue expressions of atrial natriuretic peptide, transforming growth factor beta1, and collagen III compared with diabetic NTG mice. Moreover, LV expression of NADPH oxidase subunits, p22(phox), p67(phox), gp91(phox), and Nox4, reactive oxygen species and lipid peroxidation levels were significantly increased in diabetic NTG mice, but not in diabetic TG mice. Furthermore, myocardial apoptosis, the number of caspase-3-positive cells, and the downregulation of antiapoptotic protein Bcl-X(L) were less in diabetic TG mice compared with diabetic NTG mice. In conclusion, our data establish that p38alpha MAPK activity is required for cardiac remodeling after diabetes induction and suggest that p38alpha MAPK may promote cardiomyocyte apoptosis by downregulation of Bcl-X(L).
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PMID:Dominant-negative p38alpha mitogen-activated protein kinase prevents cardiac apoptosis and remodeling after streptozotocin-induced diabetes mellitus. 1961 8

Phagocytosis and oxidative burst are critical host defense mechanisms in which neutrophils clear invading pathogens. Clearing phagocytic neutrophils by triggering apoptosis is an essential process for controlling inflammation. This study elucidates how various exercise bouts with/without hypoxia affected neutrophil bactericidal activity and subsequent apoptosis in humans. Fifteen sedentary males performed six distinct experimental tests in an air-conditioned normobaric hypoxia chamber: two normoxic exercises [strenuous exercise (SE; up to maximal O2 consumption) and moderate exercise (ME; 50% maximal O2 consumption for 30 min) while exposed to 21% O2], two hypoxic exercises (ME for 30 min while exposed to 12% and 15% O2), and two hypoxic exposures (resting for 30 min while exposed to 12% and 15% O2). The results showed that 1) plasma complement-C3a desArg/C4a desArg/C5a concentrations were increased, 2) expressions of L-selectin/lymphocyte functin-associated antigen-1/Mac-1/C5aR on neutrophils were enhanced, 3) phagocytosis of neutrophils to Esherichia coli and release of neutrophil oxidant products by E. coli were elevated, and 4) E. coli-induced phosphotidylserine exposure or caspase-3 activation of neutrophils were promoted immediately and 2 h after both 12% O2 exposure at rest and with ME as well as normoxic SE. Although neither normoxic ME nor breathing 15% O2 at rest influenced these complement- and neutrophil-related immune responses, ME at both 12% and 15% O2 resulted in enhanced complement activation in the blood, expressions of opsonic/complement receptors on neutrophils, or the bactericidal activity and apoptosis of neutrophils. Moreover, the increased neutrophil oxidant production and apoptosis by normoxic SE and hypoxic ME were ameliorated by treating neutrophils with diphenylene iodonium (a NADPH oxidase inhibitor). Therefore, we conclude that ME at 12-15% O2 enhances bactericidal capacity and facilitates the subsequent apoptosis of neutrophils.
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PMID:Systemic hypoxia enhances exercise-mediated bactericidal and subsequent apoptotic responses in human neutrophils. 1964 31

Cumulative doses of doxorubicin, a potent anticancer drug, lead to serious myocardial dysfunction. Numerous mechanisms including apoptosis have been proposed to account for its cardiotoxicity. Cardiac apoptosis induced by doxorubicin has been related to excessive reactive oxygen species production by the mitochondrial NADH dehydrogenase. Here, we explored whether doxorubicin treatment activates other superoxide anion generating systems such as the NADPH oxidases, membrane-embedded flavin-containing enzymes, and whether the subsequent oxidative stress contributes to apoptosis. We showed that doxorubicin treatment of rat cardiomyoblasts H9c2 triggers increases in caspase-3 like activity and hypoploid cells, both common features of apoptosis. Doxorubicin exposure also leads to a rapid superoxide production through NADPH oxidase activation. Inhibition of these enzymes using diphenyliodonium and apocynin reduces doxorubicin-induced reactive oxygen species production, caspase-3 like activity and sub-G1 cell population. In conclusion, NADPH oxidases participate to doxorubicin-induced cardiac apoptosis.
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PMID:NADPH oxidases participate to doxorubicin-induced cardiac myocyte apoptosis. 1969 79

Three new butanolides, tenuifolide A (1), isotenuifolide A (2), and tenuifolide B (3), a new secobutanolide, secotenuifolide A (4), and one new sesquiterpenoid, tenuifolin (5), along with 16 known compounds were isolated from the stems of Cinnamomum tenuifolium. Their structures were determined by spectroscopic analyses. Compound 4 was found to induce apoptotic-related DNA damage, increase sub-G1 cells, and inhibit the growth of human prostate cancer cells, DU145. In addition, treatment with 4 significantly increased intracellular H2O2 and/or peroxide. The results show that 4 induced (a) noticeable reduction of mitochondrial transmembrane potential (DeltaPsim); (b) significant increase in the ratio of cytochrome c concentration (cytosol/mitochondria); and (c) subsequent activation of caspase-9/caspase-3. Antiproliferation caused by 4 was found to markedly decrease when pretreated with caspase-9/caspase-3 inhibitor. In ROS scavenging, antioxidant, NADPH oxidase, and NO inhibitor studies, pretreatment of DU145 cells with either DPI, dexamethasone, L-NAME, or mannitol decreased 4-induced intracellular DCF fluorescence of ROS. These results suggest that an increase of H2O2 and/or peroxide by 4 is the initial apoptotic event and 4 has anticancer effects on DU145 cells.
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PMID:Cytotoxic compounds from the stems of Cinnamomum tenuifolium. 1975 30

We had earlier demonstrated that chronic exposure (30 days) to micro-molar concentration (0.50 microM) of arsenic induced head kidney macrophage (HKM) death in Clarias batrachus. The purpose of the present study is to characterize the nature of HKM death induced by arsenic and elucidate the signal transduction pathways involved in the process. Arsenic-induced HKM death was apoptotic in nature as evident from DNA gel, Annexin V-propidium iodide, Hoechst 33342 staining and TdT-mediated dUTP nick end labeling (TUNEL) assays. Inhibitor studies and immunoblot analyses further demonstrated that arsenic-induced HKM apoptosis involved activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase, a well-characterized caspase-3 substrate. Preincubation with antioxidants N-acetyl-cysteine or dimethyl sulfoxide significantly lowered reactive oxygen species (ROS) levels in arsenic-treated HKM and prevented caspase activation, malondialdehyde formation and HKM apoptosis. Arsenic induced membrane translocation of the NADPH oxidase subunit p47(phox). Preincubation with apocynin and diphenyleneiodonium chloride, both selective inhibitors of NADPH oxidases, prevented p47(phox) translocation, ROS production and HKM death. Exposure of HKM to arsenic induced the activation of mitogen-activated protein kinase family (MAPK) proteins including c-Jun NH(2)-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38). Preincubation of HKM with p38 inhibitor SB203580 and JNK inhibitor SP600125 protected the HKM against arsenic-induced apoptosis. We conclude that exposure to micro-molar concentration of arsenic induces ROS generation through the activation of NADPH oxidases, which in turn causes caspase-3 mediated HKM apoptosis. In addition, the study also indicates a role of p38-JNK pathway in arsenic-induced HKM apoptosis in C. batrachus.
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PMID:Low concentration of arsenic could induce caspase-3 mediated head kidney macrophage apoptosis with JNK-p38 activation in Clarias batrachus. 1978 97


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