Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Doxorubicin (DOX) is one of the most potent anticancer drugs and induces acute cardiac arrhythmias and chronic cumulative cardiomyopathy. Though DOX-induced cardiotoxicity is known to be caused mainly by ROS generation, a disturbance of Ca2+ homeostasis is also implicated one of the cardiotoxic mechanisms. In this study, a molecular basis of DOX-induced modulation of intracellular Ca2+ concentration ([Ca2+]i) was investigated. Treatment of adult rat cardiomyocytes with DOX increased [Ca2+]i irrespectively of extracellular Ca2+, indicating DOX-mediated Ca2+ release from intracellular Ca2+ stores. The DOX-induced Ca2+ increase was slowly processed and sustained. The Ca2+ increase was inhibited by pretreatment with a sarcoplasmic reticulum (SR) Ca2+ channel blocker, ryanodine or dantrolene, and an antioxidant, alpha-lipoic acid or alpha-tocopherol. DOX-induced ROS generation was observed immediately after DOX treatment and increased in a time-dependent manner. The ROS production was significantly reduced by the pretreatment of the SR Ca2+ channel blockers and the antioxidants. Moreover, DOX-mediated activation of caspase-3 was significantly inhibited by the Ca2+ channel blockers and a-lipoic acid but not a-tocopherol. In addition, cotreatment of ryanodine with alpha-lipoic acid resulted in further inhibition of the casapse-3 activity. These results demonstrate that DOX-mediated ROS opens ryanodine receptor, resulting in an increase in [Ca2+]i and that the increased [Ca2+]i induces ROS production. These observations also suggest that DOX/ROS-induced increase of [Ca2+]i plays a critical role in damage of cardiomyocytes.
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PMID:Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+ increase are reciprocally modulated in rat cardiomyocytes. 1707 70

Glutamate excitotoxicity is mediated by intracellular Ca(2+) overload, caspase-3 activation, and ROS generation. Here, we show that curcumin, tannic acid (TA) and (+)-catechin hydrate (CA) all inhibited glutamate-induced excitotoxicity. Curcumin inhibited PKC activity, and subsequent phosphorylation of NR1 of the NMDA receptor. As a result, glutamate-mediated Ca(2+) influx was reduced. TA attenuated glutamate-mediated Ca(2+) influx only when simultaneously administered, directly interfering with Ca(2+). Both curcumin and TA inhibited glutamate-induced caspase-3 activation. Although Ca(2+) influx was not attenuated by CA, caspase-3 was reduced by direct inhibition of the enzyme. All polyphenols reduced glutamate-induced generation of ROS.
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PMID:Distinct mechanisms underlie distinct polyphenol-induced neuroprotection. 1711 59

Pathologies of senescence, in particular those of neurosensory organs represent an important health problem. The improvement of the life expectation entails the fast increase of the frequency of the age-related hearing loss (ARHL) in the population. There are numerous factors that contribute to this process, which include altered vascular characteristics, hypoxia/ischemia, genetic mutations and production of reactive oxygen species. We were interested in understanding the mechanisms involved in the cochlear degeneration in a mouse model of ARHL, the cd/1 mice. Since in human, hypoxia/ischemia is an important pathogenetic factor for inner ear disease, the regulation of HIF-1 activity in the cochlea, the presence of radical oxygen species in the cochlea and its subsequent disturbances of cellular signaling cascades were investigated. In this study, we explored auditory function of cd/1 mice at the age of 4, 12 and 24 weeks and correlated it with the presence of oxidative damage in the cochlea, and cochlear HIF-1 responsive target genes regulation, involved in pathways promoting inflammation such as tumor necrosis factor (TNF-alpha), or cell death with the p53 protein, Bax protein and surviving factors with insulin-like growth factor-1 (IGF-1). After implantation of electrodes for auditory nerve acoustic thresholds measurements, we analyzed every cochlea. First, we confirmed that the cd/1 mice presented a characteristic profile of ARHL starting at 12 weeks of age. Then, according to our previous report [Riva, C., Longuet, M., Lucciano, M., Magnan, J., Lavieille, J.P., 2005. Implication of mitochondrial apoptosis in neural degeneration in a murin model for presbyacusis. Rev. Laryngol. Otol. Rhinol. 126 (2), 67-74], we noticed many alterations in the cochlea. Histologically, at 4 weeks, intensive HIF-1alpha expression was detected in the cochlea followed by ROS formation at 12 weeks, which may lead to cochlear degeneration and induction the onset of ARHL in the cd/1 mice model. In the cochlea, while the inner and the outer hair cells remained intact at 4 and 12 weeks, the spiral ganglion was more altered. Moreover, the Schwann cells of the spiral ganglion seemed to be more vulnerable to free radical damage than the neurons and degenerated more rapidly. The mechanisms of degeneration in the spiral ganglion involved a caspase-3 and Bax mediated-apoptosis via p53 protein accumulation. Since oxygen radicals are required for the post-translational stabilization of HIF-1alpha during hypoxia, the tandem " HIF-ROS " induced multiple reactions within the cochlea, like a strong inflammatory response with increased expression of TNF-alpha, and inhibition of neuronal protection mechanisms with repression of IGF-1.
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PMID:Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea. 1714 99

AMP-activated protein kinase influences cellular metabolism, glucose-regulated gene expression, and insulin secretion of pancreatic beta cells. Its sustained activation by culture at low glucose concentrations or in the presence of 5-aminoimidazole-4-carboxamide riboside (AICAR) was shown to trigger apoptosis in beta cells. This study shows that both low glucose- and AICAR-induced apoptosis are associated with increased formation of mitochondrial superoxide-derived radicals and decreased mitochondrial activity. Mitochondrial dysfunction was reflected by an increased oxidized state of the mitochondrial flavins (FMN/FAD) but not of NAD(P)H. It was accompanied by suppression of glucose oxidation and glucose-induced insulin secretion, while palmitate oxidation appeared unaffected. When the cellular accumulation of superoxide-derived radicals was quenched by the ROS scavengers vitamin E, N-acetylcysteine, or the SOD-mimetic compound MnTBAP, apoptosis was significantly inhibited. Both low glucose and AICAR also elevated the expression of BH3-domain-only Bcl-2 antagonists, and induced caspase-3 activation, causing caspase-dependent truncation of Bcl-2. Overexpression of recombinant human Bcl-2 prevented caspase-3 activation, endogenous Bcl-2 processing, and apoptosis, but did not attenuate oxygen radical formation, AMPK activation, or JNK phosphorylation. We conclude that apoptosis by prolonged AMPK activation in beta cells results from enhanced production of mitochondria-derived oxygen radicals and onset of the intrinsic mitochondrial apoptosis pathway, followed by caspase activation and Bcl-2 cleavage which may amplify the death signal.
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PMID:Increased oxygen radical formation and mitochondrial dysfunction mediate beta cell apoptosis under conditions of AMP-activated protein kinase stimulation. 1715 94

Epigallocatechin-3-gallate (EGCG) is a major constituent of green tea polyphenols. This study was aimed to investigate the possible mechanisms of EGCG-mediated inhibition against apoptosis in rat pheochromocytoma PC12 cells by exposure to CoCl(2). Exposure to CoCl(2) caused the generation of ROS and induced cell death with appearance of apoptotic morphology and DNA fragmentation. However, EGCG rescued the loss of viability in the cells exposed to CoCl(2) and led the reduction of DNA fragmentation and sub-G(1) fraction of cell cycle. Also, EGCG attenuated the CoCl(2)-induced disruption of mitochondrial membrane potential (DeltaPsim), release of cytochrome c from the mitochondria to cytosol and abolished the CoCl(2)-stimulated activities of the caspase cascades, caspase-9 and caspase-3. In addition, EGCG ameliorated the increase in the Bax to Bcl-2 ratio, a marker of apoptosis proceeding, induced by CoCl(2) treatment. Taken together, the present results suggest that EGCG inhibit the CoCl(2)-induced apoptosis of PC12 cells through the mitochondria-mediated apoptosis pathway involved in modulating the Bcl-2 family.
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PMID:Inhibition by epigallocatechin gallate of CoCl2-induced apoptosis in rat PC12 cells. 1724 Apr 4

4-Hydroxynonenal (HNE) is one of the most abundant aldehyde components of ox-LDL and it exerts various effects on intracellular and extracellular signaling cascades. In this mini-review, a brief synopsis of HNE-modulated signaling pathways will be presented mainly focused on cell death, including recent studies from our laboratory. The results of a number of studies demonstrate the ability of HNE to induce apoptosis and ROS formation in a dose-dependent manner. Several signaling pathways have been shown to be modulated by HNE, including MAP kinases, PKC isoforms, cell-cycle regulators, receptor tyrosine kinases and caspases. In order to get insight into the mechanisms of apoptotic response by HNE, MAP kinase and caspase activation pathways have been studied in 3T3 fibroblasts; HNE induced early activation of JNK and p38 proteins but down-regulated the basal activity of ERK-1/2. We have shown that HNE-induced release of cytochrome c from mitochondria, caspase-9 and caspase-3 activation. Activation of AP-1 along with increased c-Jun and phospho-c-Jun levels could be inhibited by pretreatment of cells with certain molecules such as resveratrol. Additionally, overexpression of dominant negative c-Jun and JNK1 in 3T3 fibroblasts prevented HNE-induced apoptosis, which indicated a role for JNK-c-Jun/AP-1 pathway. JNK-dependent induction of c-Jun/AP-1 activation data in the literature indicates a critical potential role for JNK in the cellular response against toxic products of lipid peroxidation.
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PMID:Apoptosis signalling by 4-hydroxynonenal: a role for JNK-c-Jun/AP-1 pathway. 1726 5

Cadmium immunotoxicity in rodents is primarily characterized by marked thymic damage and splenomegaly. To understand the toxicity of Cd on lymphoid cells in vivo, a single dose of Cd as CdCl2 (1.8 mg/kg, i.p.) was administered to male BALB/c mice and cytotoxicity (MTT assay), oxidative stress indicators (glutathione, reactive oxygen species) and apoptotic markers (mitochondrial membrane potential, caspase-3 activity, phosphatidylserine externalization, apoptotic DNA, intranucleosomal DNA fragmentation) were assessed in thymic and splenic single cell suspensions, at various time intervals. Lowering of body weight gain and cellularity and a loss in cell viability was seen in the Cd treated mice. The earliest significant increase in ROS at 18 h, followed by mitochondrial membrane depolarization, caspase-3 activation and GSH depletion at 24h in spleen and later at 48 h in thymus, strongly implicate the possible involvement of ROS. A pronounced inhibition of cell proliferative response at 48 h and 72 h may also be linked to Cd induced apoptosis. The morphological alterations including thymic cortical cell depletion and an increase in red pulp with diminished white pulp in spleen were observed at 48 h and beyond. The splenic cells appeared more susceptible than thymus cells to the adverse effects of Cd. The present study, therefore, demonstrates potentiation of oxidative stress followed by mitochondrial-caspase dependent apoptotic pathway. This may, in part, be responsible for causing suppression of cell proliferative response, thymic atrophy and splenomegaly.
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PMID:Role of oxidative stress and apoptosis in cadmium induced thymic atrophy and splenomegaly in mice. 1726 44

Chemoprevention by the use of naturally occurring substances is becoming a promising strategy to prevent cancer. In this study, the effects of isoobtusilactone A, a novel constituent isolated from the leaves of Cinnamomum kotoense, on the proliferation of human hepatoma Hep G2 cells were studied. Under our experimental conditions, isoobtusilactone A was found to elicit a concentration-dependent growth impediment (IC(50)=37.5 microM). The demise of these cells induced by isoobtusilactone A was apoptotic in nature, exhibiting a concentration-dependent increase in sub-G(1) fraction and DNA fragmentation. Subcellular fractionation analysis further revealed that Bax translocation to mitochondria resulted in a rapid release of cytochrome c, followed by activation of caspase 3 and PARP cleavage, and finally cell death. Isoobtusilactone A-treated cells also displayed transient increase of ROS during the earlier stage of the experiment, followed by the disruption of mitochondrial transmembrane potential (DeltaPsi(m)). The presence of a ROS scavenger (N-acetyl-L-cysteine) and an inhibitor of NADPH oxidase (diphenyleneiodonium chloride) blocked ROS production and the subsequent apoptotic cell death. In addition, in order to investigate the acute toxicity of isoobtusilactone A, groups of 5-6-week old Sprague-Dawley rats were subjected to oral administration of 350, or 700 mg/kg bw isoobtusilactone A four times each week for two weeks. There was no significant difference between control animals and treated animals with respect to the body weight gain, the body weight ratio of liver, spleen and kidney, haematological and clinical chemistry parameters. Taken together, our data suggest that ROS generated through the activation of NADPH oxidase plays an essential role in apoptosis induced by isoobtusilactone A, and the dosages of isoobtusilactone A tested in this study did not cause animal toxicity.
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PMID:Isoobtusilactone A-induced apoptosis in human hepatoma Hep G2 cells is mediated via increased NADPH oxidase-derived reactive oxygen species (ROS) production and the mitochondria-associated apoptotic mechanisms. 1732 Oct 26

This study investigates the mechanism of cell death induced by cadmium (Cd) in Chinese hamster ovary (CHO) cells. Cells exposed to 4 microM Cd for 24 h did not show signs of apoptosis, such as DNA fragmentation and caspase-3 activation. The pro-apoptotic (Bax) or anti-apoptotic (Bcl-2 and Bcl-xL) protein levels in the Bcl-2 family were not altered. However, an increase in propidium iodide uptake and depletion of ATP, characteristics of necrotic cell death, were observed. Cd treatment increased the intracellular calcium (Ca2+) level. Removal of the Ca2+ by a chelator, BAPTA-AM, efficiently inhibited Cd-induced necrosis. The increased Ca2+ subsequently mediated calpain activation and intracellular ROS production. Calpains then triggered mitochondrial depolarization resulting in cell necrosis. Cyclosporin A, an inhibitor of mitochondrial permeability transition, recovered the membrane potential and reduced the necrotic effect. The generated ROS reduced basal NF-kappaB activity and led cells to necrosis. An increase of NF-kappaB activity by its activator, PMA, attenuated Cd-induced necrosis. Calpains and ROS act cooperatively in this process. The calpain inhibitor and the ROS scavenger synergistically inhibited Cd-induced necrosis. Results in this study suggest that Cd stimulates Ca2+-dependent necrosis in CHO cells through two separate pathways. It reduces mitochondrial membrane potential by activating calpain and inhibits NF-kappaB activity by increasing the ROS level.
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PMID:Cadmium induces Ca2+-dependent necrotic cell death through calpain-triggered mitochondrial depolarization and reactive oxygen species-mediated inhibition of nuclear factor-kappaB activity. 1732 76

The mycotoxin CTN (citrinin), a natural contaminant in foodstuffs and animal feeds, has cytotoxic and genotoxic effects on various mammalian cells. CTN is known to cause cell injury, including apoptosis, but the precise regulatory mechanisms of CTN action, particularly in stem cells and embryos, are currently unclear. In the present paper, I report that CTN has cytotoxic effects on mouse embryonic stem cells and blastocysts, and is associated with defects in their subsequent development, both in vitro and in vivo. Experiments in embryonic stem cells (ESC-B5) showed that CTN induces apoptosis via ROS (reactive oxygen species) generation, increased Bax/Bcl-2 ratio, loss of MMP (mitochondrial membrane potential), induction of cytochrome c release, and activation of caspase 3. In this model, CTN triggers cell death via inactivation of the HSP90 [a 90 kDa isoform of the HSP (heat-shock protein) family proteins]/multichaperone complex and subsequent degradation of Ras and Raf-1, further inhibiting anti-apoptotic processes, such as the Ras-->ERK (extracellular-signal-regulated kinase) signal transduction pathway. In addition, CTN causes early developmental injury in mouse ESCs and blastocysts in vitro. Lastly, using an in vivo mouse model, I show that consumption of drinking water containing 10 muM CTN results in blastocyst apoptosis and early embryonic developmental injury. Collectively, these findings show for the first time that CTN induces ROS and mitochondria-dependent apoptotic processes, inhibits Ras-->ERK survival signalling via inactivation of the HSP90/multichaperone complex, and causes developmental injury in vivo.
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PMID:Citrinin induces apoptosis via a mitochondria-dependent pathway and inhibition of survival signals in embryonic stem cells, and causes developmental injury in blastocysts. 1733 Oct 71


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