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)

The c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in ischemic brain injury. The d-retro-inverso form of c-Jun N-terminal kinase-inhibitor (D-JNKI1), a cell-permeable inhibitor of JNK, powerfully reduces neuronal death induced by permanent and transient ischemia, even when administered 6 h after the ischemic insult, offering a clinically relevant window. We investigated the JNK molecular cascade activation in rat cerebral ischemia and the effects of D-JNKI1 on this cascade. c-Jun activation starts after 3 h after ischemia and peaks at 6 h in the ischemic core and in the penumbra at 1 h and at 6 h respectively. The 6 h c-Jun activation peak correlates well with that of P-JNK. We also examined the activation of the two direct JNK activators, MAP kinase kinase 4 (MKK4) and MAP kinase kinase 7 (MKK7). MKK4 showed the same time course as JNK in both core and penumbra, reaching peak activation at 6 h. MKK7 did not show any significant increase of phosphorylation in either core or penumbra. D-JNKI1 markedly prevented the increase of P-c-Jun in both core and penumbra and powerfully inhibited caspase-3 activation in the core. These results confirm that targeting the JNK cascade using the TAT cell-penetrating peptide offers a promising therapeutic approach for ischemia, raising hopes for human neuroprotection, and elucidates the molecular pathways leading to and following JNK activation.
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PMID:Time-course of c-Jun N-terminal kinase activation after cerebral ischemia and effect of D-JNKI1 on c-Jun and caspase-3 activation. 1790 Aug 13

The purpose of this study was to enhance our understanding of the mechanisms of neuronal death after focal cerebral ischemia and the neuroprotective effects of tamoxifen (TMX). The phosphorylation state of 31 protein kinases/signaling proteins and superoxide anion (O(2)(-)) production in the contralateral and ipsilateral cortex was measured after permanent middle cerebral artery occlusion (pMCAO) in ovariectomized rats treated with placebo or TMX. The study revealed that pMCAO modulated the phosphorylation of a number of kinases/proteins in the penumbra at 2 h after pMCAO. Of significant interest, phospho-ERK1/2 (pERK1/2) was elevated significantly after pMCAO. TMX attenuated the elevation of pERK1/2, an effect correlated with reduced infarct size. In situ detection of O(2)(-) production showed a significant elevation at 1-2 h after pMCAO in the ischemic cortex with enhanced oxidative damage detected at 24 h. ERK activation may be downstream of free radicals, a suggestion supported by the findings that cells positive for O(2)(-) had high pERK activation and that a superoxide dismutase (SOD) mimetic, tempol, significantly attenuated pERK activation after MCAO. TMX treatment significantly reduced the MCAO-induced elevation of O(2)(-) production, oxidative damage, and proapoptotic caspase-3 activation. Additionally, pMCAO induced a significant reduction in the levels of manganese SOD (MnSOD), which scavenge O(2)(-), an effect largely prevented by TMX treatment, thus providing a potential mechanistic basis for the antioxidant effects of TMX. As a whole, these studies suggest that TMX neuroprotection may be achieved via an antioxidant mechanism that involves enhancement of primarily MnSOD levels, with a corresponding reduction of O(2)(-) production, and downstream kinase and caspase-3 activation.
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PMID:Tamoxifen neuroprotection in cerebral ischemia involves attenuation of kinase activation and superoxide production and potentiation of mitochondrial superoxide dismutase. 1790 Dec 29

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

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

After an ischemic stroke, neurons in the core are rapidly committed to die, whereas neuron death in the slowly developing penumbra is more amenable to therapeutic intervention. Microglia activation contributes to delayed inflammation, but because neurotoxic mechanisms in the penumbra are not well understood, we developed an in vitro model of microglia activation and propagated neuron killing. To recapitulate inflammatory triggers in the core, microglia were exposed to oxygen glucose-deprived neurons and astrocytes. To model the developing penumbra, the microglia were washed and allowed to interact with healthy naive neurons and astrocytes. We found that oxygen-glucose deprivation (OGD)-stressed neurons released glutamate, which activated microglia through their group II metabotropic glutamate receptors (mGluRs). Microglia activation involved nuclear factor kappaB (NF-kappaB), a transcription factor that promotes their proinflammatory functions. The activated microglia became neurotoxic, killing naive neurons through an apoptotic mechanism that was mediated by tumor necrosis factor-alpha (TNF-alpha), and involved activation of both caspase-8 and caspase-3. In contrast to some earlier models (e.g., microglia activation by lipopolysaccharide), neurotoxicity was not decreased by an inducible nitric oxide synthase (iNOS) inhibitor (S-methylisothiourea) or a peroxynitrite scavenger [5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphinato iron (III) chloride], and did not require p38 mitogen-activated protein kinase (MAPK) activation. The same microglia neurotoxic behavior was evoked without exposure to OGD-stressed neurons, by directly activating microglial group II mGluRs with (2S,2'R,3'R)-2-(2'3'-dicarboxycyclopropyl) glycine or glutamate, which stimulated production of TNF-alpha (not nitric oxide) and mediated TNF-alpha-dependent neurotoxicity through activation of NF-kappaB (not p38 MAPK). Together, these results support potential therapeutic strategies that target microglial group II mGluRs, TNFalpha overproduction, and NF-kappaB activation to reduce neuron death in the ischemic penumbra.
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PMID:Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. 1857 26

The low-density lipoprotein receptor-related protein (LRP), a member of the low-density lipoprotein receptor gene family, mediates cellular signal transduction pathways. In this study we investigated the role of LRP in cell death. We found that incubation of mouse embryonic fibroblasts in serum-free media induces caspase-3 activation, an effect that is attenuated in LRP-deficient (LRP(-/-)) mouse embryonic fibroblasts. Since we previously demonstrated that middle cerebral artery occlusion (MCAO) in mice induces shedding of the LRP ectodomain, we investigated here whether cerebral ischemia induces regulated intramembrane proteolysis of LRP and whether this process is related to cell death. We found that MCAO induces an increase in gamma-secretase activity in the ischemic hemisphere and that treatment with the gamma-secretase inhibitor L-685,458 improves the neurological outcome and results in a 50% decrease in the volume of the ischemic lesion. Furthermore, MCAO caused nuclear translocation of the intracellular domain of LRP in neurons within the area of ischemic penumbra, and this effect was attenuated in mice treated with L-685,458. Finally, inhibition of either LRP or gamma-secretase attenuated cerebral ischemia-induced caspase-3 cleavage and apoptotic cell death. In summary, our results indicate that gamma-secretase-mediated regulated intramembrane proteolysis of LRP results in cell death under ischemic conditions.
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PMID:Regulated intramembrane proteolysis of the low-density lipoprotein receptor-related protein mediates ischemic cell death. 1840 1

The transcription factor NF-kappaB is a key regulator of inflammation and cell survival. NF-kappaB activation increases following cerebral ischemia. We previously showed accelerated aging process in NF-kappaB p50 subunit knockout (p50 -/-) mice under physiological condition. The present investigation concerned the role of NF-kappaB p50 gene in ischemia-induced neuronal cell death. In an animal model of permanent middle cerebral artery occlusion (MCAO), infarct formation, apoptotic cell death and cell proliferation were examined in adult wild type (WT) and p50-/- mice. The ischemic infarct volume was significantly larger in p50-/- mice than that in WT mice. Consistently, the numbers of cells in the penumbra region positive to terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL) and caspase-3 staining were significantly more in p50-/- mice than that in WT mice. To identify proliferation after cerebral ischemia, bromodeoxyurindine (BrdU) was intraperitoneal injected daily after MCAO. Ischemia increased BrdU positive cells in the penumbra, subventricular zone, corpus callosum, and cerebral cortex, while cell proliferation was hampered in p50-/- mice. These results suggest that NF-kappaB signaling is a neuroprotective mechanism and may play a role in cell proliferation in the stroke model of permanent MCAO.
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PMID:Cell death and proliferation in NF-kappaB p50 knockout mouse after cerebral ischemia. 1865 23

X-linked inhibitor of apoptosis protein (XIAP) is a potent suppressor of neuronal death. The aim of this study was to investigate the expression of XIAP after ischemia in the human and rat developing brain. Autopsy specimens from 19 children with neuropathologic diagnosis of focal cerebral ischemic infarct were processed immunohistochemically for XIAP expression. XIAP positive cells were compared in pathologically classified acute (1-4 d), subacute (5-30 d), and chronic (months) strokes vs. age-matched controls with normal brain histology. For the animal studies, ischemia was induced in 1-wk-old rats by unilateral carotid artery occlusion and transient hypoxia. XIAP expression was quantified at four time points after ischemia in the infarct core and peri-infarct area. Neuronal XIAP expression was higher in the penumbra of subacute human infarcts compared with controls (p < 0.05). XIAP expression in the peri-infarct of rat pup was highest at 7 d postischemic injury (p < 0.05). The increase in XIAP expression was associated with a reduction in activated caspase-3 in ischemic neonatal rat brain. Our results demonstrate that XIAP expression postischemic injury is delayed in both species and may continue for several days. Therefore, potentiation of XIAP expression may be neuroprotective in the developing brain.
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PMID:X-linked inhibitor of apoptosis protein expression after ischemic injury in the human and rat developing brain. 1870 98

The p75 neurotrophin receptor (p75(NTR)) is involved in neuronal functions ranging from induction of apoptosis and growth inhibition to the promotion of survival. p75(NTR) expression is induced in the central nervous system (CNS) by a range of pathological conditions, where it seems to have a role in neuronal death and axonal growth inhibition. The cellular mechanisms driving p75(NTR) expression in cell lines and primary neurons is Sp1 dependent (Ramos et al. [2007] J. Neurosci. 27:1498). In this study, we analyzed the spatiotemporal profile of p75(NTR) expression after an ischemic lesion induced by cortical devascularization (CD). Our results show that p75(NTR) expression occurs in isolated neurons of the ischemic lesion site. The p75(NTR+) neurons presented morphological alterations and active caspase-3 staining. Some p75(NTR+) neurons were also positive for sortilin. The peak of p75(NTR) expression was localized 3 days postlesion (3DPL) in the penumbra. Sp1 transcription factor nuclear localization was observed in p75(NTR+) neurons. The overall level of Sp1 expression was increased until 14DPL on the ipsilateral hemisphere. With primary cortical neurons, we demonstrated that p75(NTR) expression is induced by excitotoxic stress and correlated with increased Sp1 abundance. We conclude that p75(NTR) expression is localized in selected neurons of the ischemic lesion and that these neurons are probably condemned to apoptotic cell death. In primary neuronal culture, it is clear that excitotoxicity and Sp1 are involved in induction of p75(NTR) expression, although, in vivo, some additional mechanisms are likely to be involved in the control of p75(NTR) expression in specific neurons in vivo.
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PMID:p75 NTR expression is induced in isolated neurons of the penumbra after ischemia by cortical devascularization. 1915 69

In vitro nitric oxide (NO) regulates calpain and caspase-3 activation, and in vivo neuronal nitric oxide synthase (nNOS), calpain and caspase-3 participate in the ischemic brain injury. Our objective was to investigate whether nNOS was involved in the ischemic brain injury through activating calpain and caspase-3 during experimental stroke. Rats received 1-h ischemia by intraluminant filament, and then reperfused for 23h (R 23h). nNOS inhibitor 7-nitroindozale (7-NI, 50mg/kg) was administrated intraperitoneally 5min before ischemia. Our data showed that treatment with 7-NI markedly reduced neurological deficits, the brain swelling, and the infarct volume at R 23h. Enzyme studies revealed significant suppression of the activities of m-calpain and caspase-3 in penumbra and core, and the activities of mu-calpain in penumbra, but not in core, in 7-NI-treated rats versus vehicle-treated rats. Western blot analysis demonstrated that 7-NI markedly increased the levels of MAP-2 and spectrin in penumbra and core compared with vehicle-treated rats. Histopathological studies displayed that 7-NI significantly reduced the necrotic cell death in penumbra and core, and apoptotic cell death in penumbra, but not in core. These data demonstrate the involvement of NO produced by nNOS in the ischemic neuronal injury through affecting the activation of calpain and caspase-3 in penumbra and core after experimental stroke, which provides a new perspective on possible mechanisms of action of nNOS inhibition in cerebral ischemia.
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PMID:Inhibition of nNOS reduces ischemic cell death through down-regulating calpain and caspase-3 after experimental stroke. 1916 6


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