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)

Neuronal apoptosis is involved in neurodegenerative diseases such as Alzheimer's disease and Parkinson.s disease. An efficient means of preventing it remains to be found. Some n-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA, 22 : 6n-3) and eicosapentaenoic acid (EPA, 20 : 5n-3) have been reported to be protective against the neuronal apoptosis and neuronal degeneration seen after spinal cord injury (SCI) [1]. However, it is unclear which kinds of PUFAs have the most potent ability to inhibit neuronal apoptosis and whether the simultaneous treatment of PUFAs inhibits the apoptosis. In the present study, we compared the abilities of various n-3- and n-6- PUFAs to inhibit the apoptosis induced after the administration of different apoptotic inducers, etoposide, okadaic acid, and AraC, in mouse neuroblastoma cells (Neuro2a). Preincubation with DHA (22 : 6n-3), eicosapentaenoic acid (EPA, 20 : 5n-3), alpha-linolenic acid (alpha-LNA, 18 : 3n-3), linoleic acid (LA, 18 : 2n-6), arachidonic acid (AA, 20 : 4n-3), and gamma-linolenic acid (gamma-LNA, 18 : 3n-6) significantly inhibited caspase-3 activity and LDH leakage but simultaneous treatment with the PUFAs had no effect on the apoptosis of Neuro2a cells. There were no significant differences of the anti-apoptotic eff ect among the PUFAs. These results suggest that PUFAs may not be effective for inhibiting neuronal cell death after acute and chronic neurodegenerative disorders. However, dietary supplementation with PUFAs may be beneficial as a potential means to delay the onset of the diseases and/or their rate of progression.
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PMID:Inhibitory effect of polyunsaturated fatty acids on apoptosis induced by etoposide, okadaic acid and AraC in Neuro2a cells. 1759 50

To test the hypothesis that an apoptotic process plays a role in the pathogenesis of cerebral lesions in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we examined samples from frontal, temporal, insular, and occipital regions, basal ganglia, and cerebellum from 4 patients with CADASIL, 2 with Binswanger disease, and 3 controls. Apoptotic cells were identified using in situ end labeling and activated caspase 3 immunostaining. Immunolabeling for Notch3, the beta-amyloid protein precursor, and phosphorylated neurofilament protein was performed on successive sections. Apoptosis of vascular cells was markedly increased in status cribrosus in CADASIL, both in basal ganglia and subcortical white matter, suggesting that concomitantly with Notch3 deposition it may play a causative role in the dilatation of Virchow-Robin spaces. Neuronal apoptosis was found in CADASIL, mostly in cortical layers 3 and 5. Its severity correlated semiquantitatively with the extent of ischemic lesions and axonal damage in the underlying white matter. It was more severe in demented patients. Only occasional apoptotic neurons were found in the Binswanger cases and none in the controls. This supports the view that neuronal apoptosis may contribute to cortical atrophy and cognitive impairment in patients with CADASIL and that it may, at least partly, result from axonal damage in the underlying white matter.
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PMID:Apoptosis in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. 1762 Sep 85

Neuronal death is one of the most prominent consequences of alcohol exposure during development. Ethanol-induced neuronal death appears to involve apoptosis. The objective of the present study was to characterize the effect of ethanol on neuronal cell viability and to determine the mechanism by which ethanol enhances apoptosis in neural cells. For these studies the rat pheochromocytoma (PC12) cells were used. PC12 cells were incubated for 24 h in the presence or absence of 100 mM ethanol. Apoptosis was induced by serum withdrawal. Ethanol in the presence of serum-containing media did not alter cell viability, while incubation of PC12 cells in serum-free media resulted in a significant increase in cell death that was further significantly increased by 35% in cells exposed to ethanol. The temporal response of the PC12 cells to serum withdrawal was studied over a period of 22 h. At least 18 h of ethanol exposure was necessary to observe a significant increase in death for cells incubated in serum-free media. An increase in the caspase-3 activity in PC12 cells deprived of serum was observed that was further increased by ethanol exposure. This increase of caspase-3 activity was correlated with an enhancement of caspase-9 activity. Ethanol exposure increased the amount of cytosolic cytochrome c in PC12 cells incubated in serum-free media but did not alter the level of cytochrome c in cells incubated in serum. Finally, a 26% increase was observed in the number of cells with depolarized mitochondria due to ethanol treatment. The present study implicates an increase in the mitochondrial outer membrane permeability as a potential mechanism of enhancement of apoptosis in serum-deprived PC12 cells by ethanol.
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PMID:Mechanism of ethanol enhancement of apoptosis and caspase activation in serum-deprived PC12 cells. 1770 24

Neuronal apoptosis plays a critical role in the pathogenesis of neurodegenerative disorders, and neuroprotective agents targeting apoptotic signaling could have therapeutic use. Here we report that cesium chloride, an alternative medicine in treating radiological poison and cancer, has neuroprotective actions. Serum and potassium deprivation induced cerebellar granule neurons to undergo apoptosis, which correlated with the activation of caspase-3. Cesium prevented both the activation of caspase-3 and neuronal apoptosis in a dose-dependent manner. Cesium at 8 mM increased the survival of neurons from 45 +/- 3% to 91 +/- 5% of control. Cesium's neuroprotection was not mediated by PI3/Akt or MAPK signaling pathways, since it was unable to activate either Akt or MAPK by phosphorylation. In addition, specific inhibitors of PI3 kinase and MAP kinase did not block cesium's neuroprotective effects. On the other hand, cesium inactivated GSK3beta by phosphorylation of serine-9 and GSK3beta-specific inhibitor SB415286 prevented neuronal apoptosis. These data indicate that cesium's neuroprotection is likely via inactivating GSK3beta. Furthermore, cesium also prevented H(2)O(2)-induced neuronal death (increased the survival of neurons from 72 +/- 4% to 89 +/- 3% of control). Given its relative safety and good penetration of the brain blood barrier, our findings support the potential therapeutic use of cesium in neurodegenerative diseases.
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PMID:Cesium chloride protects cerebellar granule neurons from apoptosis induced by low potassium. 1780 90

Organotypic cultures of rat cortex were used to test the hypotheses that nerve growth factor (NGF) is neuroprotective for immature cortical neurons and that ethanol abolishes this neuroprotection in a developmental stage-dependent manner. Samples were obtained on gestational day (G) 16 or postnatal day (P) 3 and cultured with ethanol (0 or 400 mg/dl) and NGF (0 or 30 ng/ml) for 72 h. Dying neurons were identified as exhibiting terminal nick-end labeling, immunoreactivity for activated caspase 3, or condensed nuclear chromatin. Two cortical compartments were examined in fetal tissue: a superficial, cell-sparse marginal zone (MZ) and a cell-dense cortical plate (CP). At P3, the CP was subdivided into a cell-dense upper cortical plate (UCP) and a less densely packed lower cortical plate (LCP). Neuronal death in the MZ was affected by neither NGF nor ethanol at both ages. In the fetal CP, NGF did not affect the incidence of cell death, but ethanol increased it. Treatment with NGF caused an upregulation of the expression of Neg, a gene known to be affected by NGF and ethanol. NGF did not ameliorate the ethanol-induced death. In pups, ethanol increased the amount of death in the LCP. NGF did protect against this death. Neither ethanol nor NGF altered the incidence of cell death in the UCP. The laminar-dependent neuroprotection did not correlate with expression of NGF receptors or Neg. Thus, NGF can be protective against the neurotoxic effect of ethanol in the neonatal brain. This effect is site selective and time dependent and it targets postmigratory, differentiating neurons.
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PMID:Nerve growth factor neuroprotection of ethanol-induced neuronal death in rat cerebral cortex is age dependent. 1786 43

The bioactive lipid mediator platelet activating factor (PAF) is recognized as a key effecter of neuronal apoptosis, yet it is not clear whether its G-protein coupled receptor (PAFR) initiates or prevents PAF neurotoxicity. Using PAFR-/- and congenic wild-type mice, we show that PAF triggers caspase-3/7 activity and neuronal death in PAFR-/- but not PAFR+/+ cerebellar granule neurons. Restoring receptor expression by recombinant adenoviral infection protected cells from PAF challenge. Neuronal death was not mediated by nitric oxide or N-methyl-d-aspartate receptor signaling given that N-nitro-l-arginine methyl ester and MK-801 did not inhibit PAF-induced neuronal loss in PAFR-/- neurons. To intervene in PAFR-independent neurotoxicity, the anti-apoptotic actions of three structurally distinct PAF antagonists were compared to a panel of plant and fungal benzoic acid derivatives. We found that the PAF antagonist BN 52021 but not FR 49175 or CV 3988 inhibited PAFR-independent neurotoxicity. Orsellinic acid, a fungal-derived benzoic acid, blocked PAF-mediated neuronal apoptosis without affecting PAFR-mediated neuroprotection. These findings demonstrate that PAF can transduce apoptotic death in primary neurons independently of its G-protein coupled receptor, that PAFR activation is neuroprotective, and that orsellinic acid effectively attenuates PAFR-independent neuronal apoptosis.
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PMID:Platelet activating factor-induced neuronal apoptosis is initiated independently of its G-protein coupled PAF receptor and is inhibited by the benzoate orsellinic acid. 1787 34

Recent studies confirmed that the new cell survival signal pathway of Insulin-PI3K-Akt exerted cyto-protective actions involving anti-apoptosis. This study was undertaken to investigate the potential neuroprotective effects of insulin in the pathogenesis of spinal cord injury (SCI) and evaluate its therapeutic effects in adult rats. SCI was produced by extradural compression using modified Allen's stall with damage energy of 40 g-cm force. One group of rats was subjected to SCI in combination with the administration of recombinant human insulin dissolved in 50% glucose solution at the dose of 1 IU/kg day, for 7 days. At the same time, another group of rats was subjected to SCI in combination with the administration of an equal volume of sterile saline solution. Functional recovery was evaluated using open-field walking, inclined plane tests, and motor evoked potentials (MEPs) during the first 14 days post-trauma. Levels of protein for B-cell lymphoma/leukemia-2 gene (Bcl-2), Caspase-3, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were quantified in the injured spinal cord by Western blot analysis. Neuronal apoptosis was detected by TUNEL, and spinal cord blood flow (SCBF) was measured by laser-Doppler flowmetry (LDF). Ultimately, the data established the effectiveness of insulin treatment in improving neurologic recovery, increasing the expression of anti-apoptotic bcl-2 proteins, inhibiting caspase-3 expression decreasing neuronal apoptosis, reducing the expression of proinflammatory cytokines iNOS and COX-2, and ameliorating microcirculation of injured spinal cord after moderate contusive SCI in rats. In sum, this study reported the beneficial effects of insulin in the treatment of SCI, with the suggestion that insulin should be considered as a potential therapeutic agent.
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PMID:Anti-apoptotic effect of insulin in the control of cell death and neurologic deficit after acute spinal cord injury in rats. 1789 11

Autophagy is a highly regulated cellular mechanism for the bulk degradation of cytoplasmic contents which seems to be implicated in a variety of physiological and pathological conditions relevant to neurological diseases. We were prompted to examine whether autophagy is involved in mechanisms of cell death after focal cerebral ischemia. To do so, we examined the protein level and distribution of Beclin 1 (Bcl2 interacting protein) and microtubule-associated protein 1 light chain 3 (LC3) which were previously found to promote autophagy. We found a dramatic elevation in Beclin 1 levels in the penumbra of rats challenged by cerebral ischemia. Beclin 1 elevations start at early stages postischemia (6 h) and it lasts for at least 48 h. A subpopulation of Beclin 1-upregulating cells is also expressing the active form of caspase-3. In addition, not all Beclin 1-upregulating cells display dense staining of LC3. Neuronal cells that overexpress Beclin 1 may exhibit damaged DNA but without changes in nuclear morphology, which indicates that not all the Beclin 1-upregulating cells are predestined to die. The upregulation of Beclin 1 and related changes of LC3 in the ischemic penumbra may represent enhanced autophagy either as a mechanism to recycle injured cells and reduce damage or a process leading to cell demise.
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PMID:Focal cerebral ischemia induces upregulation of Beclin 1 and autophagy-like cell death. 1793 1

In ischemic stroke, cytosolic death pathways are activated in injured neurons destined to die. Neuronal injury is modulated by cell surface receptors, among which the tumor necrosis factor receptor family obtained particular interest. Cytokine response modifier A (CrmA) is a cowpox virus-derived caspase inhibitor, which interferes with the so-called death-inducing signaling complex, thereby blocking receptor-mediated apoptosis. To elucidate CrmA's therapeutic potential in ischemic stroke, we characterized a transgenic mouse line expressing CrmA under a Thy1 promoter, which we subjected to intraluminal middle cerebral artery (MCA) occlusion. Using in situ hybridization histochemistry and Western blots, we show that the crmA gene integrated into chromosome 8 of the mouse genome, CrmA being expressed in the cerebral cortex and striatum. Although robustly expressed, transgenic CrmA did not influence ischemic injury, both when relatively long-lasting (90 min) and mild (30 min) MCA occlusions were imposed. As such, neither infarct volume, brain swelling or neurological deficits following 90-min ischemia, nor disseminated neuronal injury or caspase-3 activation following 30-min ischemia were influenced by CrmA. Our data argue against a therapeutic effect of CrmA in ischemic stroke.
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PMID:Poxvirus-derived cytokine response modifier A (CrmA) does not protect against focal cerebral ischemia in mice. 1802 83

Here we discuss the probable role of autophagy in cerebral ischemia based on our own recent data and the literature. We examined the protein level of Beclin 1 (Bcl-2 interacting protein) and microtubule-associated protein 1 light chain 3 (LC3) which were previously found to promote autophagy. We found a dramatic elevation in Beclin 1 levels and LC3 in the penumbra of rats challenged by cerebral ischemia. We found also that a subpopulation of Beclin 1-upregulating cells is also expressing the active form of caspase-3, and that all Beclin 1 upregulating cells display dense staining of LC3. Neuronal cells that overexpress Beclin 1 may exhibit damaged DNA but without changes in nuclear morphology, which indicates that not all the Beclin 1-upregulating cells are predestined to die. We conclude that the cell death in the penumbra bears a resemblance not only to necrosis, apoptosis, or a compromise between the two, but exhibits also biochemical and morphological characteristics of autophagic cell death. The question that constantly arises, however, is whether autophagic activity in damaged cells is the cause of death or is actually an attempt to prevent it as a part of an endogenous neuroprotective response.
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PMID:Upregulation of Beclin 1 in the ischemic penumbra. 1807 95


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