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)

Prolonged, moderate cerebral hypothermia is consistently neuroprotective after experimental hypoxia-ischaemia; however, it has not been tested in the preterm brain. Preterm (0.7 gestation) fetal sheep received complete umbilical cord occlusion for 25 min followed by cerebral hypothermia (fetal extradural temperature reduced from 39.4 +/- 0.3 to 29.5 +/- 2.6 degrees C) from 90 min to 70 h after the end of occlusion or sham cooling. Occlusion led to severe acidosis and profound hypotension, which recovered rapidly after release of occlusion. After 3 days recovery the EEG spectral frequency, but not total intensity, was increased in the hypothermia-occlusion group compared with normothermia-occlusion. Hypothermia was associated with a significant overall reduction in loss of immature oligodendrocytes in the periventricular white matter (P < 0.001), and neuronal loss in the hippocampus and basal ganglia (P < 0.001), with suppression of activated caspase-3 and microglia (isolectin-B4 positive). Proliferation was significantly reduced in periventricular white matter after occlusion (P < 0.05), but not improved after hypothermia. In conclusion, delayed, prolonged head cooling after a profound hypoxic insult in the preterm fetus was associated with a significant reduction in loss of neurons and immature oligodendroglia, with evidence of EEG and haemodynamic improvement after 3 days recovery, but also with a persisting reduction in proliferation of cells in the periventricular region. Further studies are required to evaluate the long-term impact of cooling on brain growth and maturation.
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PMID:The effect of cerebral hypothermia on white and grey matter injury induced by severe hypoxia in preterm fetal sheep. 1709 65

Optimal timing of therapeutic hypothermia for cardiac ischemia is unknown. Our prior work suggests that ischemia with rapid reperfusion (I/R) in cardiomyocytes can be more damaging than prolonged ischemia alone. Also, these cardiomyocytes demonstrate protein kinase C (PKC) activation and nitric oxide (NO) signaling that confer protection against I/R injury. Thus we hypothesized that hypothermia will protect most using extended ischemia and early reperfusion cooling and is mediated via PKC and NO synthase (NOS). Chick cardiomyocytes were exposed to an established model of 1-h ischemia/3-h reperfusion, and the same field of initially contracting cells was monitored for viability and NO generation. Normothermic I/R resulted in 49.7 +/- 3.4% cell death. Hypothermia induction to 25 degrees C was most protective (14.3 +/- 0.6% death, P < 0.001 vs. I/R control) when instituted during extended ischemia and early reperfusion, compared with induction after reperfusion (22.4 +/- 2.9% death). Protection was completely lost if onset of cooling was delayed by 15 min of reperfusion (45.0 +/- 8.2% death). Extended ischemia/early reperfusion cooling was associated with increased and sustained NO generation at reperfusion and decreased caspase-3 activation. The NOS inhibitor N(omega)-nitro-L-arginine methyl ester (200 microM) reversed these changes and abrogated hypothermia protection. In addition, the PKCepsilon inhibitor myr-PKCepsilon v1-2 (5 microM) also reversed NO production and hypothermia protection. In conclusion, therapeutic hypothermia initiated during extended ischemia/early reperfusion optimally protects cardiomyocytes from I/R injury. Such protection appears to be mediated by increased NO generation via activation of protein kinase Cepsilon; nitric oxide synthase.
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PMID:Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling. 1717 66

Mild hypothermia is a robust neuroprotective treatment for stroke. Understanding the mechanisms underlying hypothermia's benefits will lead to more effective treatments to prevent stroke damage. Delta protein kinase C (deltaPKC) is a kinase that has been strongly implicated in executing ischemic damage. We investigated the effects of hypothermia on deltaPKC activation, as determined by its subcellular translocation, proteolytic cleavage, and phosphorylation in a focal cerebral ischemia model. The amount of constitutively activated C-terminal catalytic fragment of deltaPKC (CF-deltaPKC) increased after stroke. Both hypothermia (30 degrees C) and the caspase-3-specific inhibitor, Z-DQMD-FMK, blocked the accumulation of activated deltaPKC in the penumbra. Other hallmarks of deltaPKC activation, its translocation to the mitochondria, and nucleus were observed in the penumbra as early as 10 mins after reperfusion. These events were blocked by hypothermia. Hypothermia also blocked CF-deltaPKC increases in the mitochondria and nuclei. Conversely, a specific deltaPKC activator, psideltaRACK, decreased the neuroprotective effect of hypothermia. Finally, deltaPKC activity may lead to mitochondrial injury and cytochrome c release, as the timing of cytochrome c release corresponded to the time course of deltaPKC translocation. Both cytochrome c release and deltaPKC translocation were blocked by hypothermia. In conclusion, hypothermia protects against ischemic damage in part by suppressing deltaPKC activation after stroke.
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PMID:Suppression of deltaPKC activation after focal cerebral ischemia contributes to the protective effect of hypothermia. 1729 47

Kainate receptor containing GluR6 subunit (KAR) is involved in the neuronal cell death induced by cerebral ischemia/reperfusion (I/R). Hypothermia is an effective neuroprotectant in brain ischemia, whereas the neuroprotective mechanisms have not been clearly established. The present study was set out to examine whether hypothermia would cause the alternation of the assembly of the GluR6-PSD95-MLK3 signaling module and the activation of c-Jun N-terminal kinase (JNK) pathway through KAR. Hypothermia (32 degrees C) was induced 10 min before ischemia and was maintained for 3 h after ischemia. Our results indicated that hypothermia could inhibit the assembly of GluR6-PSD95-MLK3 signaling module and suppressed the activation of MLK3, MKK4/7, and JNK3. The inhibition of JNK3 activation by hypothermia diminished the phosphorylation of the transcription factor c-Jun and downregulated FasL expression in hippocampal CA1. Meanwhile, the inhibition of JNK3 activation by hypothermia attenuated bax translocation, the release of cytochrome c, and the activation of caspase-3 in CA1 subfields. Both GluR6 antagonist NS102 and GluR6 antisense oligodeoxynucleotides partly blocked the aforementioned effects of hypothermia, which was further confirmed by histology. Taken together, our results strongly suggest that hypothermia decreased the increased assembly of the GluR6-PSD95-MLK3 signaling module and the activation of JNK pathway induced by I/R through KAR, which gave a new insight into the ischemic therapy.
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PMID:Neuroprotection of hypothermia against neuronal death in rat hippocampus through inhibiting the increased assembly of GluR6-PSD95-MLK3 signaling module induced by cerebral ischemia/reperfusion. 1817 94

In this investigation, we evaluated the effect of post-traumatic mild hypothermia on cell death in the hippocampus after fluid percussion traumatic brain injury (TBI) in rats. Adult male Sprague-Dawley rats were randomly divided into three groups (n = 40/group): TBI with hypothermia treatment (32 degrees C), TBI with normothermia (37 degrees C), and sham injury. The TBI model was induced by a fluid percussion TBI device. Mild hypothermia (32 degrees C) was achieved by partial immersion in a water bath (0 degrees C) under general anesthesia for 4h. All rats were killed at 24 or 72h after TBI. The ipsilateral hippocampal CA1 in all rats were analyzed by hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL), and 4',6-diamidino-2-phenylindole (DAPI) staining for determining cell death. Caspase-3 expression was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. At 24h, based on TUNEL and DAPI results, the cell death index was 28.80 +/- 2.60% and 32.10 +/- 1.40% in the normothermia TBI group, while reaching only 14.30 +/- 2.70% and 18.40 +/- 2.10% in the hypothermic TBI group (p < 0.01). Based on RT-PCR and Western blotting results, the expression of caspase-3 was 210.20 +/- 5.30% and 170.30 +/- 4.80% in the normothermic TBI group, while reaching only 165.10 +/- 3.70% and 130.60 +/- 4.10% in the hypothermic TBI group (p < 0.05). At 72h, based on TUNEL and DAPI results, the cell death index was 20.80 +/- 2.50% and 25.50 +/- 1.80% in the normothermic TBI group, while reaching only 10.20 +/- 2.60% and 15.50 +/- 2.10% in the hypothermic TBI group (p < 0.01). Based on RT-PCR and Western blotting results, the expression of caspase-3 was 186.20 +/- 6.20% and 142.30 +/- 5.10% in the normothermic TBI group, versus only 152.10 +/- 3.60% and 120.60 +/- 3.90% in the hypothermic TBI group (p < 0.05). Based on our findings, we conclude that post-traumatic hypothermia significantly attenuates cell death within the hippocampus following fluid percussion injury. Taken together with other studies, these observations support the premise that post-traumatic mild hypothermia can provide cerebral protection for patients with TBI.
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PMID:Effect of post-traumatic mild hypothermia on hippocampal cell death after traumatic brain injury in rats. 1923 65

Hyperthermia is common following traumatic brain injury (TBI) and has been associated with poor neurologic outcome, and hypothermia has emerged as a potentially effective therapy for TBI, although its mechanism is still unclear. In this study we investigated the effects of temperature modulations on astrocyte survival following traumatic injury and the involved MAPK pathways. Trauma was produced by scratch injury of a monolayer of confluent astrocytes in culture, followed by incubation at hypothermia (308 degree C), normothermia (378 degree C), or hyperthermia (398 degree C). The activation of MAPK pathways including extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase ( JNK), and p38 MAPK were measured at 0, 15, 30, 60, and 120 min after traumatic injury followed by temperature modulation. Apoptosis of astrocytes was assessed by quantitation of cleaved caspase-3 expression 24 h after injury. Our findings showed that only JNK activation at 15 min after trauma was reduced by hypothermia, and this was associated with a marked reduction in apoptosis. Hyperthermia activated both ERK and JNK and increased apoptosis. The specific JNK inhibitor, SP60025, markedly reduced JNK-induced apoptosis at normothermia and hyperthermia, and showed a dose-dependent effect. In conclusion, the JNK pathway appears to mediate traumatic injury-induced apoptosis in astrocytes. Prolonged hyperthermia as a secondary insult worsens apoptosis by increasing JNK activation. Hypothermia protects against traumatic injury via early suppression on JNK activation and subsequent prevention of apoptosis. Manipulation of the JNK pathway in astrocytes may represent a therapeutic target for ameliorating the devastating progression of tissue injury and cell death after TBI.
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PMID:Traumatic injury activates MAP kinases in astrocytes: mechanisms of hypothermia and hyperthermia. 1933 17

Recent clinical trials have demonstrated the efficacy and safety of therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy (HIE). We previously reported that the levels of non-protein-bound iron and ascorbic acid (AA) are increased in the CSF of infants with HIE. In this study, we investigated the effect of hypothermia on the combined cytotoxicity of Fe and AA for differentiated PC12 cells. The optimal settings for hypothermic treatment were a temperature of 30-32 degrees C, rescue time window of less than 6 h, and minimum duration of at least 24 h. Hypothermia effectively prevented the loss of the mitochondrial transmembrane potential from 6 h to 72 h (end of the study period) and attenuated the release of apoptotic proteins (cytochrome c and apoptosis-inducing factor) at 6 h of exposure to Fe-AA. Activation of caspase-3 was also delayed until 24 h. Akt was transiently activated, although no influence of temperature was observed. Elevation of oxidative stress markers, including ortho-, meta-, and di-tyrosine (markers of protein oxidation) and 4-hydroxynonenal (lipid peroxidation) was significantly attenuated when the temperature was reduced by 5 degrees C. The half-cell reduction potential (Ehc) of GSSG/2GSH redox couple ranged from -220 to -180 mV in unstressed differentiated PC12 cells, and apoptosis was triggered when Ehc exceeded -180 mV. Hypothermia prevented Ehc from rising above -180 mV within 24 h of exposure to Fe-AA. In conclusion, hypothermia prevented cell death due to Fe-AA toxicity by inhibiting apoptotic pathways through maintenance of a reduced cellular environment, as well as by alleviating oxidative stress.
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PMID:Hypothermic inhibition of apoptotic pathways for combined neurotoxicity of iron and ascorbic acid in differentiated PC12 cells: reduction of oxidative stress and maintenance of the glutathione redox state. 1952 61

Fatty livers are particularly susceptible to mitochondrial alterations after cold preservation. We thus aimed to improve graft integrity by brief hypothermic oxygenation prior to warm reperfusion. Macrovesicular steatosis was induced in rat livers by fasting and subsequent feeding of a fat-free diet enriched with carbohydrates. Fatty livers were retrieved and stored ischemically at 4 degrees C for 20 hours in histidine-tryptophan-ketoglutarate solution. Hypothermic reconditioning (HR) was performed in some livers by insufflation of gaseous oxygen via the caval vein during the last 90 minutes of preservation. Viability was assessed upon isolated reperfusion. HR resulted in a significant (approximately 5-fold) reduction of parenchymal (alanine aminotransferase and lactate dehydrogenase) and mitochondrial (glutamate dehydrogenase) enzyme release. Functional recovery (bile production, oxygen consumption, and tissue levels of adenosine triphosphate) was significantly improved by HR. In untreated grafts, cellular autophagy (cleavage of LC3B and protein expression of beclin-1) was significantly impaired (<50% of baseline) after preservation/reperfusion but was restored to normal values by HR. HR also increased cleavage of caspase 9 (P < 0.5) and caspase 3 enzyme activity (by a factor of 1.5). In contrast, histological signs of tissue necrosis were abundant after reperfusion in untreated livers and largely abrogated in reconditioned livers. In conclusion, HR limits mitochondrial defects and restores basal rates of cellular autophagy. This may represent a rescue mechanism for maintaining cellular homeostasis and tissue survival.
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PMID:Impaired autophagic clearance after cold preservation of fatty livers correlates with tissue necrosis upon reperfusion and is reversed by hypothermic reconditioning. 1956 17

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

Inhibition of the initial events occurring immediately after ischemia-reperfusion seems to be beneficial for reducing the extent of subsequent chronic neuronal cell injury. We investigated the effects of moderate hypothermia (32 degrees C) commencing 30 min before ischemia on reactive hyperemia by measuring cerebral blood flow (CBF) with a laser-Doppler flowmeter at the initial ischemia-reperfusion stage (60 min) following 10 min of global cerebral ischemia in rats. In normothermia, CBF was increased to approximately 240% and decreased thereafter, although it remained at approximately 150% after 60 min of ischemia-reperfusion. In contrast, hypothermia increased CBF to more than 270% after ischemia-reperfusion, then recovered to the basal level within 30 min. The period of reactive hyperemia under normothermia tended to be shortened by pre-administration of an NMDA antagonist, in a manner similar to hypothermia. Furthermore, hypothermia inhibited the presence of cells with caspase-3-like immunoreactivity in the hippocampal CA1 sector after 8 h of ischemia-reperfusion. Our findings indicate that hypothermia tends to shorten the period of reactive hyperemia during the initial ischemia-reperfusion stage. This phenomenon may be partly associated with activation of NMDA receptors and a beneficial effect of hypothermia in resisting progression of the neurotoxic cascade in the first 8 h after ischemia-reperfusion.
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PMID:Measurement of cerebral reactive hyperemia at the initial post-ischemia reperfusion stage under normothermia and moderate hypothermia in rats. 2003 16


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