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: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased oxidative stress has been regarded as an important underlying cause for neuronal damage induced by cerebral ischemia/reperfusion (I/R) injury. In recent years, there has been increasing interest in investigating polyphenols from botanical source for possible neuroprotective effects against neurodegenerative diseases. In this study, we investigated the mechanisms underlying the neuroprotective effects of curcumin, a potent polyphenol antioxidant enriched in tumeric. Global cerebral ischemia was induced in Mongolian gerbils by transient occlusion of the common carotid arteries. Histochemical analysis indicated extensive neuronal death together with increased reactive astrocytes and microglial cells in the hippocampal CA1 area at 4 days after I/R. These ischemic changes were preceded by a rapid increase in lipid peroxidation and followed by decrease in mitochondrial membrane potential, increased cytochrome c release, and subsequently caspase-3 activation and apoptosis. Administration of curcumin by i.p. injections (30 mg/kg body wt) or by supplementation to the AIN76 diet (2.0 g/kg diet) for 2 months significantly attenuated ischemia-induced neuronal death as well as glial activation. Curcumin administration also decreased lipid peroxidation, mitochondrial dysfunction, and the apoptotic indices. The biochemical changes resulting from curcumin also correlated well with its ability to ameliorate the changes in locomotor activity induced by I/R. Bioavailability study indicated a rapid increase in curcumin in plasma and brain within 1 hr after treatment. Together, these findings attribute the neuroprotective effect of curcumin against I/R-induced neuronal damage to its antioxidant capacity in reducing oxidative stress and the signaling cascade leading to apoptotic cell death.
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PMID:Neuroprotective mechanisms of curcumin against cerebral ischemia-induced neuronal apoptosis and behavioral deficits. 1607 66

NAPOR-3 is a central nervous system RNA binding protein that is associated with downstream mRNA targets and has been demonstrated to be selectively overexpressed during apoptotic cell death. In this study, we first examined the regional distribution of NAPOR-3 mRNA in the adult rat brain by in situ hybridization: the transcript was abundantly expressed in many brain regions, mostly in gray matter, including the CA1-CA4 regions and dentate gyrus of the hippocampus, the piriform cortex and the cerebellar granule cell layer. We then investigated the role of NAPOR-3 in neuronal cell death by monitoring its mRNA and protein expression levels using semiquantitative RT-PCR and Western blotting, respectively. NAPOR-3 was overexpressed in rat organotypic slices exposed to staurosporine and to oxygen-glucose deprivation (OGD), an in vitro model of apoptotic cerebral ischemia, but not when exposed to glutamate toxicity. Our results also demonstrate that NAPOR-3 gene overexpression is an early step in the chain of signaling events leading to apoptosis, taking place upstream of caspase-3 activation. Finally, antisense-mediated downregulation of NAPOR-3 gene expression protected hippocampal cultures against OGD-induced apoptosis and prevented caspase-3 activation. Our results demonstrate that NAPOR-3 gene overexpression is necessary for the execution of OGD-induced programmed cell death.
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PMID:NAPOR-3 RNA binding protein is required for apoptosis in hippocampus. 1609 52

In vivo studies showed that tissue-plasminogen activator (t-PA) may aggravate neuronal injury after focal cerebral ischemia. We hypothesized that t-PA impairs survival-promoting cell signaling in the ischemic brain, which may be reversed by a neuroprotectant, i.e. melatonin. We examined the effects of t-PA (10 mg/kg, i.v.), administered alone or in combination with melatonin (4 mg/kg, i.p.), on ischemic injury, inducible nitric oxide synthase (iNOS) expression as well as Akt, Bcl-X(L) and caspase-3 signaling following 90 min of intraluminal middle cerebral artery (MCA) occlusion in mice. t-PA, delivered immediately after reperfusion onset, increased infarct volume at 24 hr after MCA occlusion, in accordance with previous findings. Melatonin reduced infarct size when administered alone and reversed the t-PA-induced brain injury. Immunohistochemical studies showed that t-PA treatment was associated with an accumulation of iNOS positive cells in ischemic brain areas, which was abolished after co-delivery of melatonin. Western blots revealed that t-PA decreased phosphorylated Akt levels, but did not influence Bcl-X(L) expression and caspase-3 activity in ischemic brain lysates. Co-treatment with melatonin restored phosphorylated Akt levels, increased Bcl-X(L) expression and reduced caspase-3 activity. We provide evidence that t-PA-induced brain injury is accompanied by an activation of iNOS and inhibition of phosphatidylinositol-3 kinase/Akt. That melatonin reversed these signaling changes and the t-PA-induced brain injury makes this indole attractive as an add-on treatment with thrombolytics.
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PMID:Tissue-plasminogen activator-induced ischemic brain injury is reversed by melatonin: role of iNOS and Akt. 1609 92

Several evidences suggest that cell death after cerebral ischemia involves both necrosis and apoptosis. However, it is still unknown which is the relative contribution of both types of cell death. Exposing rat cortical cultures to oxygen-glucose deprivation (OGD), we show the simultaneous presence of necrotic and apoptotic cells. The relative contribution of necrosis and apoptosis was dependent on the duration of the OGD. OGD-mediated apoptotic cell death is caspase-dependent because the addition of a pan-caspase inhibitor specifically blocked the apoptotic component of the OGD-mediated cell death. Moreover, we observed the activation of caspase-3, -7, and -9 after OGD in neurons and microglial cells. No activation of these caspases was observed in GFAP positive cells. Our results also show that calpain is related to OGD-mediated proteolysis of caspase-3 and -9 but not of caspase-7. These data suggest that different pathways could be involved in OGD-mediated caspase activation.
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PMID:Contribution of caspase-mediated apoptosis to the cell death caused by oxygen-glucose deprivation in cortical cell cultures. 1613 64

The aim of this study was to investigate the role of apoptosis or necrosis in the development of delayed infarct, and the relationship between the level of XIAP gene, caspase-3 activation and ischemic cell death following transient focal cerebral ischemia. Adult male Sprague-Dawley rats underwent right middle cerebral artery occlusion (MCAo) for 50 min and reperfusion for 0.5, 4, 8, 24 h, 3, 7, 14 days. On TTC-stained coronal sections, delayed infarct was observed to develop in the whole MCA territory, especially in frontoparietal cortex after ischemia. Near total infarct was shown in striatum 24 h after MCAo, while delayed infarct was evident in the cortex. By day 3, the infarct had progressively expanded to the nearly whole area of the frontoparietal cortex. Flow cytometric analysis of Annexin-V (marks apoptosis) and PI (propidium iodide, marks necrosis) labeling cells showed that MCAo dominantly induced necrosis in ischemic core, striatum. Apoptosis contributed to delayed infarct and cell death in the border zone, dorsolateral cortex and hippocampus. The time-course of caspase-3 activation was consistent with the changes of apoptosis and infarct following MCAo. Further RT-PCR experiments indicated that there was a biphasic regulation of XIAP in time- and region-dependent manner after ischemia. In the infarct core (striatum), following a transient and slight increase during 0.5 h to 4 h post-MCAo, expression of XIAP mRNA markedly decreased. On the other hand, a longer and larger upregulation of XIAP was observed at early time points in border zone (0.5 to 8 h, in dorsolateral cortex; 0.5 to 24 h in hippocampus), then the level of XIAP reduced. A negative correlation was observed between apoptosis and regulation of XIAP gene in these regions. Our findings suggest a possible association between expression of XIAP gene, apoptosis and delayed infarct following ischemia.
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PMID:Development of cerebral infarction, apoptotic cell death and expression of X-chromosome-linked inhibitor of apoptosis protein following focal cerebral ischemia in rats. 1613 48

The inhibition of the caspase-3 enzyme is reported to increase neuronal cell survival following cerebral ischemia. The peptide Z-DEVD-FMK is a specific caspase inhibitor, which significantly reduces vulnerability to the neuronal cell death. However, this molecule is unable to cross the blood-brain barrier (BBB) and to diffuse into the brain tissue. Thus, the development of an effective delivery system is needed to provide sufficient drug concentration into the brain to prevent cell death. Using the avidin (SA)-biotin (BIO) technology, we describe here the design of chitosan (CS) nanospheres conjugated with poly(ethylene glycol) (PEG) bearing the OX26 monoclonal antibody whose affinity for the transferrin receptor (TfR) may trigger receptor-mediated transport across the BBB. These functionalized CS-PEG-BIO-SA/OX26 nanoparticles (NPs) were characterized for their particle size, zeta potential, drug loading capacity, and release properties. Fluorescently labeled CS-PEG-BIO-SA/OX26 nanoparticles were administered systemically to mice in order to evaluate their efficacy for brain translocation. The results showed that an important amount of nanoparticles were located in the brain, outside of the intravascular compartment. These findings, which were also confirmed by electron microscopic examination of the brain tissue indicate that this novel targeted nanoparticulate drug delivery system was able to translocate into the brain tissue after iv administration. Consequently, these novel nanoparticles are promising carriers for the transport of the anticaspase peptide Z-DEVD-FMK into the brain.
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PMID:Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26. 1628 48

Anti-apoptotic treatment is a promising strategy for neuroprotection against various brain injuries resulting from ischemia or neuron degeneration. X-linked inhibitor of apoptosis protein (XIAP) is regarded as the most effective apoptosis inhibitor, in which C-terminal structure BIR3-RING mainly inhibits caspase-9-dependent apoptosis. In the present study, we fused XIAP (BIR3-RING) to the protein transduction domain (PTD) of antennapedia homeodomain of Drosophila (Antp HD), and then used the oxygen glucose deprivation (OGD)-induced hippocampal slices injury in vitro, and the rat transient middle cerebral artery ischemia (tMCAO) models in vivo, to explore the anti-apoptotic effect of this recombinant protein. The results showed that the PTD could efficiently mediate the transduction of BIR3-RING into the hippocampal slices and rat brains. PTD-BIR3-RING could decrease OGD-induced cell death in brain slices (p < 0.05). Intraperitoneal injection of PTD-BIR3-RING could attenuate terminal deoynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) positive cells and decrease cleaved caspase-3 in the ischemic bounder zone compared with the control animals (p < 0.05). Further studies showed that ischemia-induced neurological outcomes were improved in rats with PTD-BIR3-RING treatment (p < 0.05). These results demonstrate that PTD-BIR3-RING could attenuate cell death in OGD hippocampal slices and decrease cell apoptosis in tMCAO brains through inhibiting of caspase-3 cleavage, suggesting that PTD-mediated protein transduction provides a novel and effective approach for the therapies of brain diseases such as cerebral ischemia.
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PMID:Apoptosis inhibition in ischemic brain by intraperitoneal PTD-BIR3-RING (XIAP). 1629 46

Granulocyte colony-stimulating factor (G-CSF) protects neurons against experimental focal cerebral ischemia. However, its neuroprotective effect on human brain is unknown. We sought to determine whether G-CSF can protect the human cerebral neurons in vitro. Human cerebral-neuroblastoma hybrid cell line (A1) was exposed to oxygen and glucose deprivation with or without G-CSF. G-CSF promoted cell survival and decreased cytotoxicity effectively at 25 ng/ml. G-CSF reduced early apoptotic (annexin V+/PI-), and late apoptotic or necrotic (annexin V+/PI+) cells, and decreased active caspase-3 immunoreactivity. G-CSF could protect human cerebral neurons following in vitro ischemia.
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PMID:G-CSF protects human cerebral hybrid neurons against in vitro ischemia. 1629 88

It is well documented that N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors play a pivotal role in ischaemic brain injury. Recent studies have shown that kainate (KA) receptors are involved in neuronal cell death induced by seizure, which is mediated by the GluR6*PSD-95*MLK3 signalling module and subsequent c-Jun N-terminal kinase (JNK) activation. Here we investigate whether GluR6 mediated JNK activation is correlated with ischaemic brain injury. Our results show that cerebral ischaemia followed by reperfusion can enhance the assembly of the GluR6*PSD-95*MLK3 signalling module and JNK activation. As a result, activated JNK can not only phosphorylate the transcription factor c-Jun and up-regulate Fas L expression but can also phosphorylate 14-3-3 and promote Bax translocation to mitochondria, increase the release of cytochrome c and increase caspase-3 activation. These results indicate that GluR6 mediated JNK activation induced by ischaemia/reperfusion ultimately results in neuronal cell death via nuclear and non-nuclear pathways. Furthermore, the peptides we constructed, Tat-GluR6-9c, show a protective role against neuronal death induced by cerebral ischaemia/reperfusion through inhibiting the GluR6 mediated signal pathway. In summary, our results indicate that the KA receptor subunit GluR6 mediated JNK activation is involved in ischaemic brain injury and provides a new approach for stroke therapy.
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PMID:Neuroprotection against ischaemic brain injury by a GluR6-9c peptide containing the TAT protein transduction sequence. 1633 May 2

Adrenomedullin (AM) is a peptide hormone widely distributed in the central nervous system. Our previous study showed that AM gene delivery immediately after middle cerebral artery occlusion (MCAO) protected against cerebral ischemia/reperfusion (I/R) injury by promoting glial cell survival and migration. In the present study, we investigated the effect of delayed AM peptide infusion on ischemic brain injury at 24 h after MCAO. AM infusion significantly reduced neurological deficit scores at days 2, 4, and 8 after cerebral I/R. AM reduced cerebral infarct size at 8 and 15 days after surgery as determined by quantitative analysis. Double staining showed that AM infusion reduced TUNEL-positive apoptotic cells in both neurons and glial cells, as well as reduced caspase-3 activity in the ischemic area of the brain. In addition, AM treatment increased capillary density in the ischemic region at 15 days after I/R injury. Parallel studies revealed that AM treatment enhanced the proliferation of cultured endothelial cells as measured by both (3)H-thymidine incorporation and in situ BrdU labeling. Both in vitro and in vivo AM effects were blocked by calcitonin gene-related peptide (8-37), an AM receptor antagonist. Moreover, AM's effects were associated with increased cerebral nitric oxide (NO) levels, as well as decreased NAD(P)H oxidase activities and superoxide anion production. These results indicate that a continuous supply of exogenous AM peptide protects against I/R injury by improving the survival of neuronal and glial cells, and promoting angiogenesis through elevated NO formation and suppression of oxidative stress.
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PMID:Postischemic infusion of adrenomedullin protects against ischemic stroke by inhibiting apoptosis and promoting angiogenesis. 1634 85


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