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)

Euonymus alatus (Thunb.) Sieb (EA) is a traditional Korean herbal medicine, commonly used to treat tumors in Korea and China for centuries. Our earlier studies have indicated that EA exhibits antitumor properties, but its mechanism remains to be elucidated. In this study, we evaluated the molecular mechanism of EA in a human uterine leiomyomal smooth muscle cell (ULSMC) line. Water extracts of EA have been reported to not only function as antioxidants but also cause cytotoxic effect. We investigated the mechanism of EA-induced cytotoxicity in human ULSMC. When cells were cultured with 20-200 microg/mL EA for 6 h, caspase-3 was activated and then cells fell into apoptosis. Induction of apoptosis by EA was accompanied with increase of the cytosolic fractions of cytochrome c prior to the activation of caspase-3. The preculture with 5 mM of buthionine sulfoximine, an inhibitor of glutathione synthesis, facilitated EA-induced induction of apoptosis. The preculture with N-benzyloxycarbonyl-valyl-alanyl-aspartyl fluoromethylketone, a pan-caspase inhibitor, partially suppressed the induction of apoptosis. EA showed little toxic effect on peripheral blood mononuclear cells from healthy volunteers. These results indicate that EA acts as a prooxidant and induces caspase-3 activation and apoptosis via mitochondrial pathway.
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PMID:Euonymus alatus (Thunb.) Sieb induces apoptosis via mitochondrial pathway as prooxidant in human uterine leiomyomal smooth muscle cells. 1668 71

The pathobiology of traumatic brain injury (TBI) includes activation of multiple caspases followed by cell death with a spectrum of apoptotic phenotypes. There are initiator (e.g. caspase-2, -8, and -9) and effector (e.g. caspase-3 and -7) caspases. Recently, caspase-2 and -8 have been shown to regulate cell death via provoking cytochrome c release from the mitochondria upstream of caspase-9. Here, we show that an intracerebral injection of the pan-caspase inhibitor boc-Aspartyl(OMe)-fluoromethylketone (BAF; 1 micromol) 1 min after TBI in rats reduces caspase-3-like activity, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and tissue damage, and cytochrome c release in ipsilateral cortex at 24 h versus vehicle. To investigate whether either caspase-2 and/or caspase-8 activation may contribute to cytochrome release, the effect of BAF treatment on caspase-2 and caspase-8 proteolysis was also examined. boc-aspartyl(OMe)-fluoromethylketone treatment inhibited proteolysis of caspase-2 but not caspase-8 24 h after TBI in rats versus vehicle. However, BAF with or without nerve growth factor (12.5 ng/h x 14 days intracerebrally via osmotic pump) did not result in differences in motor function, Morris water maze performance, hippocampal neuron survival, nor contusion volume at 14 days. These data suggest that BAF treatment reduces acute cell death after TBI by inhibiting mitochondrial release of cytochrome c, possibly via a mechanism involving initiator caspases; however, BAF appears to delay cell death, rather than result in permanent protection.
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PMID:boc-Aspartyl(OMe)-fluoromethylketone attenuates mitochondrial release of cytochrome c and delays brain tissue loss after traumatic brain injury in rats. 1673 44

p38 MAPK is activated during heart diseases that might associate with myocardial damage and deterioration of cardiac function. In a rat model of myocardial injury, we have investigated cardioprotective effects of the inhibition of p38 MAPK using a novel, orally available p38alpha MAPK inhibitor. Rats were treated with N(omega)-nitro-l-arginine methyl ester (l-NAME, 40 mg.kg(-1).day(-1)) in drinking water plus 1% salt for 14 days and ANG II (0.5 mg.kg(-1).day(-1)) for 3 days. A selective p38alpha MAPK inhibitor, SD-282 (60 mg/kg), was administrated orally, twice a day for 4 days, starting 1 day before ANG II administration. The cardioprotective effects of p38alpha MAPK inhibition were evaluated by improvement of cardiac function, reduction of inflammatory cell infiltration, and cardiomyocyte apoptosis. SD-282 significantly improved cardiac function indicated by increasing stroke volume, cardiac output, ejection fraction, and stroke work and significantly decreasing arterial elastance. SD-282 also significantly reduced macrophage infiltration as judged by reduction of a specific marker, ED-1-positive staining cells (P < 0.05) in the myocardium. Furthermore, cardiomyocyte apoptosis as indicated by caspase-3 immunohistochemical staining was abolished by SD-282, and this effect may contribute to the reduction of myocardial damage evaluated by imaging analysis (P < 0.05 in both cases). Data suggest that p38alpha MAPK may play a critical role in the pathogenesis of cardiac dysfunction. Inhibition of p38alpha MAPK may be used as a novel cardioprotective strategy in attenuation of inflammatory response and deterioration of cardiac function that occurs in acute cardiovascular disease such as myocardial infarction.
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PMID:Selective inhibition of p38alpha MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury. 1675 Dec 95

Increasing evidence suggests that apoptosis is a contributing factor to neuronal cell death in traumatic brain injury (TBI). There is increased expression, cleavage and activation of caspases as well as other proteins known to regulate apoptosis in neurons after TBI. These proteins include the proto-oncogene Bcl-2 which belongs to a family of proteins with both pro- and anti-apoptotic properties. To investigate the role of apoptosis in TBI and the importance of Bcl-2 protein on the severity and outcome of injury, Bcl-2 overexpressing transgenic and wild-type control mice were subjected to the controlled cortical impact model of TBI. There was no significant difference in the cleavage of caspase-3 or caspase-9 detected by Western blotting of hippocampal samples from transgenic or wild-type mice after TBI. Bcl-2 transgenic mice had smaller contusion volumes and increased numbers of surviving neurons in CA2 but not other regions of hippocampus compared to wild-type controls. By contrast, there was no difference in motor function determined by the round beam balance and wire grip tests between transgenic and wild-type mice after TBI. Cognitive function assessed by the Morris water maze was also not different between groups. These results suggest that overexpression of Bcl-2 is only partially neuroprotective and other members of this protein family may prove to be more important in protecting neurons from cell death.
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PMID:Transgenic mice that overexpress the anti-apoptotic Bcl-2 protein have improved histological outcome but unchanged behavioral outcome after traumatic brain injury. 1678 76

Thyroid hormone insufficiency adversely affects cortical development; however, its effect on apoptosis modulation during cerebral cortex development is not understood. We investigated the effect of perinatal hypothyroidism on apoptosis and its mechanisms during rat cerebral cortex development. Primary hypothyroidism was induced by feeding methimazole (0.025% wt/vol) in the drinking water to pregnant and lactating rats and continued until the animals were killed (hypothyroid group). Cerebral cortices from pups were harvested at different postnatal ages (postnatal d 0, 8, 16, and 24 and adult), and apoptosis was quantitated by terminal deoxynucleotide transferase-mediated dUTP nick end labeling and cleaved caspase-3 immunoreactivity. Compared with the euthyroid, primary somatosensory cortex (S1) in the hypothyroid group exhibited enhanced apoptosis. In S1 of euthyroid rats, apoptotic cells were mostly found in cortical layers I-III and the proportion of apoptotic cells enhanced significantly in the hypothyroid group (P < 0.001). Most of the apoptotic cells were neurons, as assessed by double immunolabeling. A significantly increased activation of caspase-3 and -7, decreased levels of antiapoptotic proteins Bcl-2 and Bcl-x(L), and increased levels of proapoptotic protein Bax was observed in the developing cerebral cortex of hypothyroid rats, compared with the euthyroid (P < 0.001). In addition, hypothyroidism significantly elevated the levels of 53-kDa pro-nerve growth factor (P < 0.001) and p75 neurotrophin receptor (P < 0.001) and decreased TrkA expression. Taken together, we provide evidence for the possible contribution of pro-nerve growth factor/p75 neurotrophin receptor pathway in hypothyroidism-enhanced apoptosis during rat cortical development. Thus, the present study may help in explaining the mechanism of the deleterious effect of thyroid hormone deficiency on cerebral cortex development in children.
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PMID:Increased pro-nerve growth factor and p75 neurotrophin receptor levels in developing hypothyroid rat cerebral cortex are associated with enhanced apoptosis. 1679 16

Calpains and cathepsins are two families of proteases that play an important role in ischemic cell death. In this study, we investigated the effect of E64d, a mu-calpain and cathepsin B inhibitor, in the prevention of neuronal and endothelial apoptotic cell death after focal cerebral ischemia in rats. Rats underwent 2 hr of transient focal ischemia from middle cerebral artery occlusion (MCAO) and were sacrificed 24 hr later. E64d (5 mg/ kg intraperitoneally) was administered 30 min before MCAO. Assessment included neurological function, infarction volume, brain water content, blood-brain barrier permeability, histology, and immunohistochemistry. The E64d-treated rats had significant brain protection against ischemic damage. We observed a reduction of infarction volume, brain edema, and improved neurological scores in E64d-treated rats compared with the nontreated control. Furthermore, there was a remarkable reduction in both proteases and caspase-3 activation and apoptotic changes in both neurons and endothelial cells in E64d-treated rats. These results suggest that E64d protects the brain against ischemic/reperfusion injury by attenuating neuronal and endothelial apoptosis.
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PMID:Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats. 1680 20

Coptidis rhizoma (C. rhizoma) had been demonstrated as an antioxidant and anticancer agent, however, its antioral cancer mechanism still remains unclear. Using water extracts of C. rhizoma, growth and apoptosis-related experiments for the treatment of multi-stage of oral cancer were carried out on immortalized human oral keratinocytes (IHOK), primary oral cancer cells (HN4), metastatic oral cancer cells (HN12) and human skin keratinocytes (HaCaT) by MTT assay, three-dimensional (3-D) raft cultures, western blotting, cell cycle analysis, nuclear staining and cytochrome c expression related to the apoptosis signaling pathway. C. rhizoma inhibited the proliferation of immortalized and malignant oral keratinocytes in a dose- and time-dependent manner. In 3-D organotypic culture, C. rhizoma-treated cells showed less maturation than the control cells, displaying low surface keratinization and decreased epithelial thickness. The major mechanism of growth inhibition by C. rhizoma appears to be the induction of apoptosis, which is supported by the results of the cell cycle analysis, FITC-annexin V staining, DNA fragmentation assay and DAPI staining. The induction of apoptosis by C. rhizoma was more prominent in immortalized keratinocytes than in malignant oral keratinocytes. Cytochrome-c release from mitochondria, accompanied by the activation of caspase-3, was observed in C. rhizoma-treated IHOK and oral cancer cells. These results suggest that C. rhizoma has apoptotic effects in immortalized and malignant oral keratinocytes via the mitochondrial signaling pathway.
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PMID:Extract of Coptidis rhizoma induces cytochrome-c dependent apoptosis in immortalized and malignant human oral keratinocytes. 1680 85

Ethanol is able to cross the placenta, which may cause teratogenicity. Here we investigated whether ethanol consumption during pregnancy (ECDP), even at doses unable to cause malformation, might increase the susceptibility of fetal rat liver to oxidative insults. Since cholestasis is a common condition in alcoholic liver disease and pregnancy, exposure to glycochenodeoxycholic acid (GCDCA) has been used here as the oxidative insult. The mothers received drinking water without or with ethanol from 4 weeks before mating until term, when placenta, maternal liver, and fetal liver were used. Ethanol induced a decreased GSH/GSSG ratio in these organs, together with enhanced gamma-glutamylcysteine synthetase and glutathione reductase activities in both placenta and fetal liver. Lipid peroxidation in placenta and fetal liver was enhanced by ethanol, although it had no effect on caspase-3 activity. Although the basal production of reactive oxygen species (ROS) was higher by fetal (FHs) than by maternal (AHs) hepatocytes in short-term cultures, the production of ROS in response to the presence of varying GCDCA concentrations was higher in AHs and was further increased by ECDP, which was associated to a more marked impairment in mitochondrial function. Moreover, GCDCA-induced apoptosis was increased by ECDP, as revealed by enhanced Bax-alpha/Bcl-2 ratio (both in AHs and FHs) and the activity of caspase-8 (only in AHs) and caspase-3. In sum, our results indicate that although AHs are more prone than FHs to producing ROS, at doses unable to cause maternal liver damage ethanol consumption causes oxidative stress and apoptosis in fetal liver.
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PMID:Maternal ethanol consumption during pregnancy enhances bile acid-induced oxidative stress and apoptosis in fetal rat liver. 1682 60

Satratoxin G (SG) is a macrocyclic trichothecene mycotoxin produced by Stachybotrys chartarum, the "black mold" suggested to contribute etiologically to illnesses associated with water-damaged buildings. Using an intranasal instillation model in mice, we found that acute SG exposure specifically induced apoptosis of olfactory sensory neurons (OSNs) in the olfactory epithelium. Dose-response analysis revealed that the no-effect and lowest-effect levels at 24 hr postinstillation (PI) were 5 and 25 microg/kg body weight (bw) SG, respectively, with severity increasing with dose. Apoptosis of OSNs was identified using immunohistochemistry for caspase-3 expression, electron microscopy for ultrastructural cellular morphology, and real-time polymerase chain reaction for elevated expression of the proapoptotic genes Fas, FasL, p75NGFR, p53, Bax, caspase-3, and CAD. Time-course studies with a single instillation of SG (500 microg/kg bw) indicated that maximum atrophy of the olfactory epithelium occurred at 3 days PI. Exposure to lower doses (100 microg/kg bw) for 5 consecutive days resulted in similar atrophy and apoptosis, suggesting that in the short term, these effects are cumulative. SG also induced an acute, neutrophilic rhinitis as early as 24 hr PI. Elevated mRNA expression for the proinflammatory cytokines tumor necrosis factor-alpha, interleukin-6 (IL-6) , and IL-1 and the chemokine macrophage-inflammatory protein-2 (MIP-2) were detected at 24 hr PI in both the ethmoid turbinates of the nasal airways and the adjacent olfactory bulb of the brain. Marked atrophy of the olfactory nerve and glomerular layers of the olfactory bulb was also detectable by 7 days PI along with mild neutrophilic encephalitis. These findings suggest that neurotoxicity and inflammation within the nose and brain are potential adverse health effects of exposure to satratoxins and Stachybotrys in the indoor air of water-damaged buildings.
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PMID:Satratoxin G from the black mold Stachybotrys chartarum evokes olfactory sensory neuron loss and inflammation in the murine nose and brain. 1683 65

Even though reperfusion is the treatment of choice in patients admitted with acute myocardial infarction, reperfusion itself has been demonstrated to activate various pathological factors especially following procedures of cardiac revascularization. 5-hydroxytryptamine (5HT) is one such factor activated during reperfusion and is known to trigger the post ischemic contractile dysfunction and pathological apoptosis. Here we demonstrate the potential effects of the 5-HT(2)A antagonist sarpogrelate in protecting the myocardium against reperfusion injury of heart. Male Wistar rats weighing between 220 and 240 g were subjected to 30 min left coronary artery (LCA) occlusion and 120 min reperfusion. Sarpogrelate (4 mg/kg) was infused intravenously for 30 min either before LCA occlusion or at reperfusion. Following reperfusion the samples were collected for infarction area, immunohistochemistry, western blotting and myocardial metabolite analysis. Sarpogrelate infusion before ischemia resulted in (a) significant recovery of post ischemic cardiac functions (LVDP, EDP), (b) significant reduction in the infarct size among the risk area after triphenyl tetrazolium chloride staining (p<0.001), (c) decreased tissue water content (p<0.05), (d) well preserved myocardial ATP (p<0.05), (e) reduction in Bcl-2 downregulation and caspase 3 activation and (g) less prevalence of apoptotic cells (3.1+/-0.4% to 15.2+/-0.6%, drug versus control). Treating the rats with sarpogrelate during reperfusion also showed similar results. This study thus demonstrates the protective effects of sarpogrelate and supports the role for 5-HT2A inhibition in preventing the reperfusion injury of the heart.
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PMID:5-HT2 receptor blocker sarpogrelate prevents downregulation of antiapoptotic protein Bcl-2 and protects the heart against ischemia-reperfusion injury. 1687 2


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