Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the present study was to investigate the potential cardioprotective effects of an original approach based on the properties of the X chromosome-linked Inhibitor of Apoptosis (XIAP), the most effective endogenous inhibitor of apoptosis. For this purpose, the C-terminal part of XIAP (BIR3 and RING domains) was fused to the protein transduction domain (PTD) of the HIV1 transactivator of transcription, which confers to fused protein the ability to cross cell membranes. This protein, so-called PTD-BIR3/RING, was administered intravenously in C57BL/6J mice subjected to 30 min coronary artery occlusion and 24 h of reperfusion. Administration of PTD-BIR3/RING at 5 min before and 30 min after the onset of reperfusion reduced infarct size vs control (23+/-2% vs 41+/-4% and 27+/-4% vs 41+/-3%, respectively, p<0.05). Similar reduction in infarct size was observed when PTD-BIR3/RING was administered prior to ischemia (28+/-1% vs 44+/-3%). In addition to inhibition of caspase-3 and -9 activities, PTD-BIR3/RING induced an inhibition of caspase-8 and several other actors of the apoptotic pathways. In conclusion, this study demonstrates that the administration of PTD-BIR3/RING reduces myocardial infarct size even when injected during reperfusion through interruption of caspase activation by pharmacologically mimicking endogenous XIAP.
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PMID:Cardioprotection against myocardial infarction with PTD-BIR3/RING, a XIAP mimicking protein. 1923 93

The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) and its receptors are widely expressed in the nervous system and various other tissues. PACAP exerts strong anti-apoptotic effects in neuronal cell lines and, according to recent data, also in non-neuronal cells. The peptide is present in the cardiovascular system and has various distinct effects. We have demonstrated earlier that PACAP has protective effects against in vitro ischemia/reperfusion-induced apoptosis in cardiomyocytes. Preconditioning with brief intermittent periods of ischemia is known to provide protection against ischemic injury. The aim of the present study was to investigate whether PACAP could enhance the protective effect of preconditioning against in vitro ischemic injury. Cultured cardiomyocytes were exposed to brief preconditioning ischemia followed by 2 h ischemia and 4 h reperfusion. Both PACAP treatment and preconditioning alone significantly increased cell viability and decreased the ratio of cell death. Pretreatment with PACAP was found to further reduce the level of cleaved caspase-8 but it did not lead to additional survival rate when compared to cells treated with PACAP or preconditioning alone. These results show that although both PACAP and preconditioning have a protective effect against ischemia/reperfusion-induced cardiomyocyte apoptosis, their effects are not additive.
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PMID:Effects of PACAP and preconditioning against ischemia/reperfusion-induced cardiomyocyte apoptosis in vitro. 1945 2

The aim of this study was to investigate the therapeutic efficacy and neuroprotective mechanisms of UCF-101, a novel Omi/HtrA2 inhibitor, following ischemia/reperfusion brain injury. Male Wistar rats were subjected to 2 hr of middle cerebral artery occlusion followed by reperfusion. Animals were divided into 3 groups: sham, vehicle-treated ischemia/reperfusion, and UCF-101 treatment. In the UCF-101 treatment group, rats were intraperitoneally administered UCF-101 (1.5 micromol/kg) 10 min prior to reperfusion. The rats were evaluated for neurological deficits, and brain infarct volume was assessed by 2,3,5-triphenyl tetrazolium chloride. TUNEL staining was utilized to evaluate the amount of apoptosis. In addition, expressions of protein caspase-8, caspase-3, FasL, and FLIP were examined by Western blot analysis. Results demonstrated that UCF-101 treatment significantly decreased cerebral infarct size by about 16.27% (P < 0.05) and also improved neurological behavior. TUNEL staining revealed that UCF-101 treatment significantly reduced TUNEL-positive cells in the cerebral cortex. Furthermore, the upregulation in the expression of FasL and the cleavage products of active caspase-8 and caspase-3 induced by ischemia was attenuated in mice treated with UCF-101, whereas upregulation of FLIP levels was increased. The present results demonstrated that UCF-101 protects against cerebral ischemia/reperfusion injury in mice. UCF-101 provided neuroprotection in vivo, and this was correlated with regulation of Fas-mediated apoptotic proteins. Taken together, the use of UCF-101 is a potent, neuroprotective factor for the treatment of focal cerebral ischemia.
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PMID:UCF-101, a novel Omi/HtrA2 inhibitor, protects against cerebral ischemia/reperfusion injury in rats. 1946 55

TNF-alpha has been reported to be relevant in stroke-induced neuronal death. However the precise function of TNF-alpha in brain ischemia remains controversial since there are data supporting either a detrimental or a protective effect. Here we show that TNF-alpha is released after oxygen-glucose deprivation (OGD) of cortical cultures and is a major contributor to the apoptotic death observed without affecting the OGD-mediated necrotic cell death. In this paradigm, apoptosis depends on TNF-alpha-induced activation of caspase-8 and -3 without affecting the activation of caspase-9. By using knock-out mice for TNF-alpha receptor 1, we show that the activation of both caspase-3 and -8 by TNF-alpha is mediated by TNF-alpha receptor 1. The pro-apoptotic role of TNF-alpha in OGD is restricted to neurons and microglia, since astrocytes do not express either TNF-alpha or TNF-alpha receptor 1. Altogether, these results show that apoptosis of cortical neurons after OGD is mediated by TNF-alpha/TNF-alpha receptor 1.
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PMID:Activation of caspase-8 by tumour necrosis factor receptor 1 is necessary for caspase-3 activation and apoptosis in oxygen-glucose deprived cultured cortical cells. 1955 59

Hypothermia is the most effective means of protecting the brain, heart and other organs during ischemia/reperfusion (I/R) injury. However, the precise mechanisms for hypothermia to inhibit I/R-induced endothelial cell apoptosis are not fully understood. In the present study, human umbilical endothelial cells (HUVECs) were exposed to ischemia followed by reperfusion under normothermia (37 degrees C) or hypothermia (33 degrees C). Our results showed that hypothermia markedly reduced I/R-induced endothelial cell apoptosis, the expression of cleaved caspase-3 and PARP. Moreover, hypothermia markedly reversed I/R-induced activation of Fas/caspase-8, the increase of Bax and decrease of Bcl-2. Furthermore, hypothermia inhibited JNK1/2 activation via MKP-1 induction. Together, these data demonstrate that hypothermia represses I/R-induced endothelial cell apoptosis by inhibiting both extrinsic- and intrinsic-dependent apoptotic pathways and activation of JNK1/2.
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PMID:Hypothermia attenuates ischemia/reperfusion-induced endothelial cell apoptosis via alterations in apoptotic pathways and JNK signaling. 1959 1

Activation of phospholipase A(2), degradation of membrane phospholipids resulting in tissue accumulation of arachidonic acid, and the activation of cyclooxygenase that leads to the formation of prostaglandin and free radicals may occur after hypoxic-ischemic damage. The aim of this study was to investigate the effects of indomethacin, a nonselective cyclooxygenase inhibitor, on caspase activity, glutathione levels and lipid peroxidation in newborn rats with hypoxic-ischemic encephalopathy. The effects of indomethacin were evaluated by measuring caspase-3 and caspase-8 activities and glutathione levels. Lipid peroxidation was evaluated by measuring concentrations of malondialdehyde in rat brains. Seven-day-old rat pups with the Levine-Rice model of hypoxic-ischemic cerebral injury were randomly divided into three study groups. In the indomethacin-treated group, rats were administered three doses of indomethacin, at a dose of 2 mg/kg every 12 h. Sham and the hypoxic-ischemic group of rats were given physiologic saline. The sham group underwent all surgical procedures except for arterial ligation. After 72 hours, the rats were decapitated and brain tissues were evaluated. Caspase-3 and caspase-8 activities and glutathione and malondialdehyde levels were evaluated in all groups. There was an obvious decrease in caspase-3 and caspase-8 activities and depleted glutathione levels were reversed in the indomethacin-treated group compared to the hypoxic-ischemia group (p<0.001). As indomethacin was unable to prevent lipid peroxidation, malondialdehyde concentrations increased to ischemia-induced levels. In conclusion, indomethacin administration after hypoxic-ischemic encephalopathy injury has a neuroprotective effect since it inhibits caspase activity and reverses the depletion of glutathione. However, it also aggravates lipid peroxidation-induced ischemia.
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PMID:The effects of indomethacin on caspases, glutathione level and lipid peroxidation in the newborn rats with hypoxic-ischemic cerebral injury. 1961 46

Pressure ulcer is a complex and significant health problem. Although the factors including pressure, shear, and ischemia have been identified in the etiology of pressure ulcer, the cellular and molecular mechanisms that contribute to the development of pressure ulcer are unclear. This study tested the hypothesis that the early-onset molecular regulation of pressure ulcer involves apoptosis in muscle tissue. Adult Sprague-Dawley rats were subjected to an in vivo protocol to mimic pressure-induced deep tissue injury. Static pressure was applied to the tibialis region of the right limb of the rats for 6 h each day on two consecutive days. The compression force was continuously monitored by a three-axial force transducer equipped in the compression indentor. The contralateral uncompressed limb served as intra-animal control. Tissues underneath the compressed region were collected for histological analysis, terminal dUTP nick-end labeling (TUNEL), cell death ELISA, immunocytochemical staining, and real-time RT-PCR gene expression analysis. The compressed muscle tissue generally demonstrated degenerative characteristics. TUNEL/dystrophin labeling showed a significant increase in the apoptotic muscle-related nuclei, and cell death ELISA demonstrated a threefold elevation of apoptotic DNA fragmentation in the compressed muscle tissue relative to control. Positive immunoreactivities of cleaved caspase-3, Bax, and Bcl-2 were evident in compressed muscle. The mRNA contents of Bax, caspase-3, caspase-8, and caspase-9 were found to be higher in the compressed muscle tissue than control. These results demonstrated that apoptosis is activated in muscle tissue following prolonged moderate compression. The data are consistent with the hypothesis that muscle apoptosis is involved in the underlying mechanism of pressure-induced deep tissue injury.
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PMID:Muscle apoptosis is induced in pressure-induced deep tissue injury. 1964 27

MicroRNAs (miRs) participate in most cellular functions by posttranscriptional regulation of gene expression albeit with little information regarding their role in ischemic preconditioning (IP) of stem cells. We report that IP of bone marrow-derived mesenchymal stem cells (MSCs) with two cycles of 30-min ischemia/reoxygenation (I/R) supported their survival under subsequent longer exposure to anoxia and following engraftment in the infarcted heart. IP significantly reduced apoptosis in MSCs through activation of Akt (Ser(473)) and ERK1/2 (Thr(202)/Tyr(204)) and nuclear translocation of hypoxia-inducible factor-1alpha (HIF-1alpha). We observed concomitant induction of miR-210 in the preconditioned MSCs ((PC)MSCs). Inhibition of HIF-1alpha or of miR-210 abrogated the cytoprotective effects of preconditioning. Extrapolation of these data to in vivo studies in a rat model of acute myocardial infarction predominantly improved stem cell survival after engraftment with a role for miR-210. Notably, multiple I/R cycles more effectively regulated the miR-210 and hence promoted MSC survival compared with single-cycle hypoxia of an equal duration. Real time PCR array for rat apoptotic genes, computational target gene analyses, and luciferase reporter assay identified FLICE-associated huge protein (FLASH)/caspase-8-associated protein-2 (Casp8ap2) in (PC)MSCs as the target gene of miR-210. Induction of FLASH/CASP8AP2 in miR-210 knocked-down (PC)MSCs resulted in increased cell apoptosis. Taken together, these data demonstrated that cytoprotection afforded by IP was regulated by miR-210 induction via FLASH/Casp8ap2 suppression. These results highlighted that IP by multiple short episodes of I/R is a novel strategy to promote stem cell survival.
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PMID:Ischemic preconditioning augments survival of stem cells via miR-210 expression by targeting caspase-8-associated protein 2. 1972 Nov 36

The release of cytochrome c from the mitochondria to the cytosol is a critical step for downstream caspase-mediated apoptotic signal transduction in ischemia-reperfusion (I/R)-induced myocardial tissue injury. 10-N-nonyl acridine orange (NAO), a cardiolipin-specific dye, has been shown to inhibit Bid-mediated cytochrome c release from isolated mitochondria in vitro; however, the possible protective effects of NAO and the mechanisms underlying the protection from myocardial I/R-induced tissue injury in a rat model are unknown. Male Sprague-Dawley rats were subjected to a 30-min coronary arterial occlusion followed by reperfusion. All rats received either vehicle or NAO (100 microg/kg iv) 10 min before the occlusion. The infarct size in the heart at 24 h after reperfusion was significantly reduced in NAO-treated rats compared with vehicle-treated rats. NAO treatment significantly reduced the cytosolic cytochrome c contents and caspase-9 activity in the ischemic region but did not affect caspase-8 activity. Furthermore, NAO treatment markedly suppressed the translocation of truncated Bid, a proapoptotic Bcl-2 family member, to the mitochondrial fraction. NAO also suppressed the mitochondrial swelling and oxygen uptake stimulated by calcium overload. The results suggest that NAO possesses protective effects against myocardial I/R injury, which may be due to the suppression of cytochrome c release through blockade of truncated Bid translocation to mitochondria and inhibition of the opening of mitochondrial permeability transition pores.
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PMID:Inhibition of cytochrome c release by 10-N-nonyl acridine orange, a cardiolipin-specific dye, during myocardial ischemia-reperfusion in the rat. 1994 77

Small-for-size liver grafts are a serious obstacle for partial orthotopic liver transplantation. Activated protein C (APC), a potent anticoagulant serine protease, is known to have cell-protective properties due to its anti-inflammatory and antiapoptotic activities. This study was designed to examine the cytoprotective effects of a preservation solution containing APC on small-for-size liver grafts, with special attention paid to ischemia-reperfusion injury and shear stress in rats. APC exerted cytoprotective effects, as evidenced by (1) increased 7-day graft survival; (2) decreased initial portal pressure and improved hepatic microcirculation; (3) decreased levels of aminotransferase and improved histological features of hepatic ischemia-reperfusion injury; (4) suppressed infiltration of neutrophils and monocytes/macrophages; (5) reduced hepatic expression of tumor necrosis factor alpha and interleukin 6; (6) decreased serum levels of hyaluronic acid, which indicated attenuation of sinusoidal endothelial cell injury; (7) increased hepatic levels of nitric oxide via up-regulated hepatic endothelial nitric oxide synthesis expression together with down-regulated hepatic inducible nitric oxide synthase expression; (8) decreased hepatic levels of endothelin 1; and (9) reduced hepatocellular apoptosis by down-regulated caspase-8 and caspase-3 activities. These results suggest that a preservation solution containing APC is a potential novel and safe product for small-for-size liver transplantation, alleviating graft injury via anti-inflammatory and antiapoptotic effects and vasorelaxing conditions.
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PMID:The cytoprotective effects of addition of activated protein C into preservation solution on small-for-size grafts in rats. 2003 25


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