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: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Magnesium-dependent neutral sphingomyelinase (N-SMase) present in plasma membranes is an enzyme that can be activated by stress in the form of inflammatory cytokines, serum deprivation, and hypoxia. The design of small molecule N-SMase inhibitors may offer new therapies for the treatment of inflammation, ischemic injury, and cerebral infarction. Recently, we synthesized a series of difluoromethylene analogues (SMAs) of sphingomyelin. We report here the effects of SMAs on the serum/glucose deprivation-induced death of neuronally differentiated pheochromocytoma (PC-12) cells and on cerebral infarction in mice. SMAs inhibited the enhanced N-SMase activity in the serum/glucose-deprived PC-12 cells, and thereby suppressed the apoptotic sequence: ceramide formation, c-Jun N-terminal kinase phosphorylation, caspase-3 activation, and DNA fragmentation in the nuclei. Administration of SMA-7 (10 mg/kg i.v.) with IC50= 3.3 microM to mice whose middle cerebral arteries were occluded reduced significantly the size of the cerebral infarcts, compared to the control mice. These results suggest that N-SMase is a key component of the signaling pathways in cytokine- and other stress-induced cellular responses, and that inhibiting or stopping N-SMase activity is an important strategy to prevent neuron death from ischemia.
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PMID:Inhibition of sphingomyelinase activity helps to prevent neuron death caused by ischemic stress. 1523 3

Recent studies have indicated that proteins in the transforming growth factor-beta superfamily alter damage induced by various neuronal injuries. Of these proteins, glial cell line-derived neurotrophic factor (GDNF) and bone morphogenetic protein-7 (BMP-7) have unique protective and regenerative effects in stroke animals. Delivery of GDNF or BMP-7 to brain tissue reduced cerebral infarction and improved motor functions in stroke animals. Pretreatment with these factors reduced caspase-3 activity and DNA fragmentation in the ischemic brain region, suggesting that antiapoptotic effects are involved. Beside the protective effects, BMP-7 given after stroke improves locomotor function. These regenerative effects of BMP-7 may involve the enhancement of dendritic growth and remodeling. In this review, we illustrate the neuroprotective and neuroregenerative properties of GDNF and BMP-7 and emphasize their therapeutic potential for stroke.
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PMID:Stroke and TGF-beta proteins: glial cell line-derived neurotrophic factor and bone morphogenetic protein. 1567 Jun 22

Free radicals are involved in neurodegenerative disorders, such as ischemia and aging. We have previously demonstrated that treatment with diets enriched with blueberry, spinach, or spirulina have been shown to reduce neurodegenerative changes in aged animals. The purpose of this study was to determine if these diets have neuroprotective effects in focal ischemic brain. Adult male Sprague-Dawley rats were fed with equal amounts of diets (blueberry, spinach, and spirulina) or with control diet. After 4 weeks of feeding, all animals were anesthetized with chloral hydrate. The right middle cerebral artery was ligated with a 10-O suture for 60 min. The ligature was later removed to allow reperfusional injury. Animals were sacrificed and brains were removed for caspase-3 enzymatic assays and triphenyltetrazolium chloride staining at 8 and 48 h after the onset of reperfusion. A subgroup of animals was used for locomotor behavior and biochemical assays. We found that animals which received blueberry, spinach, or spirulina enriched diets had a significant reduction in the volume of infarction in the cerebral cortex and an increase in post-stroke locomotor activity. There was no difference in blood biochemistry, blood CO2, and electrolyte levels among all groups, suggesting that the protection was not indirectly mediated through the changes in physiological functions. Animals treated with blueberry, spinach, or spirulina had significantly lower caspase-3 activity in the ischemic hemisphere. In conclusion, our data suggest that chronic treatment with blueberry, spinach, or spirulina reduces ischemia/reperfusion-induced apoptosis and cerebral infarction.
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PMID:Dietary supplementation with blueberries, spinach, or spirulina reduces ischemic brain damage. 1581 66

Stroke-induced neurological deficits and mortality are often associated with timing of treatment after the onset of stroke. We showed that local delivery of the human tissue kallikrein gene into rat brain immediately after middle cerebral artery occlusion (MCAO) exerts neuroprotection. In this study, we investigated the effect of systemic delivery of the kallikrein gene 8 hr after MCAO. Expression of recombinant human tissue kallikrein after gene transfer was identified in the ischemic brain region and blood vessels. Intravenous injection of adenovirus encoding the kallikrein gene significantly reduced neurological deficit scores 2 and 7 days after gene transfer. Kallikrein gene transfer also reduced ischemia-reperfusion (I/R)-induced cerebral infarction and promoted the survival and migration of glial cells from penumbra to the ischemic core from 3 to 14 days after gene delivery. Kallikrein reduced I/R-induced apoptosis of neuronal cells and inhibited inflammatory cell accumulation in the ischemic brain. These effects were blocked by the kinin B2 receptor antagonist icatibant. In addition, kallikrein enhanced angiogenesis and promoted neurogenesis after I/R and the stimulatory effect of kinin on neuronal cell proliferation was confirmed in primary cultured neuronal cells. The protective effects of kallikrein, through the kinin B2 receptor, were accompanied by increased cerebral nitric oxide and Bcl-2 levels, Akt phosphorylation, and reduced NAD(P)H oxidase activity, superoxide production, Bax levels, and caspase-3 activity. These results indicate that delayed systemic administration of the kallikrein gene after onset of stroke protects against ischemic brain injury by inhibiting apoptosis and inflammation and by promoting angiogenesis and neurogenesis.
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PMID:Kallikrein protects against ischemic stroke by inhibiting apoptosis and inflammation and promoting angiogenesis and neurogenesis. 1645 54

Kallikrein cleaves low molecular weight kininogen to generate vasoactive kinins, which bind to the kinin B2 receptor, triggering a host of biological effects. Kallikrein gene delivery has been shown previously to reduce ischemia/reperfusion-induced cerebral infarction. In this study, we tested the hypothesis that the kinin B2 receptor plays a protective role in ischemic brain injury using kinin B2 receptor gene knockout (B2R-KO) mice subjected to middle cerebral artery occlusion (MCAO). The mortality rate and neurological deficit scores of B2R-KO mice (n=48) after MCAO were significantly increased compared with wild-type (WT) mice (n=40) when examined over a 14-day period. In addition, the infarct volume in B2R-KO mice was significantly larger than in WT mice at days 1 and 3 after MCAO. Similarly, apoptotic cells, detected by TUNEL labeling counterstained with propidium iodide, and caspase-3 activity in the ischemic brain increased significantly in B2R-KO mice at days 1 and 3 after MCAO. Furthermore, the accumulation of neutrophils in the ischemic brain of B2R-KO mice after MCAO increased when compared with WT mice and was associated with elevated tumor necrosis factor alpha expression. These alterations in B2R-KO mice correlated with decreased NO levels, Akt, and glycogen synthase kinase-3beta phosphorylation and increased nicotinamide-adenine dinucleotide oxidase activity. These results indicate that the kinin B2 receptor promotes survival and protects against brain injury by suppression of apoptosis and inflammation induced by ischemic stroke.
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PMID:Postischemic brain injury is exacerbated in mice lacking the kinin B2 receptor. 1839 Oct 96

Excitatory amino acids (EAAs) play an important role during ischemic brain injury. In this study we examined the protective effect of histogranin (HN), an endogenous peptide that antagonizes excitatory amino acids-mediated activity noncompetitively, in an animal model of cerebral ischemia. Adult rats were anesthetized with chloral hydrate. Histogranin was given intracerebroventricularly before a 60-min middle cerebral artery occlusion (MCAo). Animals were examined for their locomotor activity 2 days after MCAo. Histogranin significantly increased locomotor activity in the stroke rats. Histogranin pretreatment reduced the volume of cerebral infarction and the caspase-3 immunoreactivity in the stroke animals. Taken together, our data suggest that histogranin is protective against ischemic brain injury. The protective effect may involve anti-apoptotic mechanisms.
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PMID:Histogranin reduced brain injury after transient focal ischemia in rats. 1690 27

Tacrolimus (FK506) has a neuroprotective action on cerebral infarction produced by cerebral ischemia, however, detailed mechanisms underlying this action have not been fully elucidated. We examined temporal profiles of survival-and death-related signals, Bad phosphorylation, release of cytochrome c (cyt.c), activation of caspase 3 and DNA fragmentation in the brain during and after middle cerebral artery occlusion (MCAo) in mice, and then examined the effect of tacrolimus on these signals. C57BL/6J mice were subjected to transient MCAo by intraluminal suture insertion for 60 min. Tacrolimus (1 mg/kg, i.p.) was administered immediately after MCAo. There were biphasic increases in the release of cyt.c in the ischemic core and penumbra; with the first increase toward the end of the occlusion period and the second increase 3-12 h after reperfusion. Tacrolimus significantly inhibited the increase of cytosolic cyt.c during ischemia and reperfusion. Phosphorylated Bad, Ser-136 (P-Bad(136)) and Ser-155 (P-Bad(155)) were detected 30 min after MCAo and after reperfusion in the ischemic cortex, respectively. Tacrolimus increased P-Bad(136) during ischemia and prolonged P-Bad(155) expression after reperfusion. Tacrolimus also decreased caspase-3 and terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling-positive cells, and reduced the size of infarct 24 h after reperfusion. Our study provided the first evidence that the neuroprotective action of tacrolimus involved inhibition of biphasic cyt.c release from mitochondria, possibly via up-regulation of Bad phosphorylation at different sites after focal cerebral ischemia and reperfusion.
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PMID:Tacrolimus (FK506) attenuates biphasic cytochrome c release and Bad phosphorylation following transient cerebral ischemia in mice. 1693 31

Studies have illustrated that fatty acids, especially polyunsaturated fatty acids (PUFA), have a role in regulating oxidative stress via the enhancement of antioxidative defense capacity or the augmentation of oxidative burden. Elevated oxidative stress has been implicated in the pathogenesis of brain injury associated with cerebral ischemia/reperfusion (I/R). The objective of this study was to assess whether treatment with fatty acids after focal cerebral I/R induced by occlusion of the common carotid arteries and the middle cerebral artery has effects on brain injury in a rat model. PUFA, including arachidonic acid (AA) and docosahexaenoic acid (DHA), and the saturated fatty acid, stearic acid (SA), were administrated 60 min after reperfusion via intraperitoneal injection. AA and DHA aggravated cerebral ischemic injury, which manifested as enlargement of areas of cerebral infarction and increased impairment of motor activity, in a concentration-dependent manner. However, there were no remarkable differences in post-ischemic alterations between the SA and saline groups. The post-ischemic augmentation of injury in AA and DHA treatment groups was accompanied by increases in the permeability of the blood-brain barrier (BBB), brain edema, metalloproteinase (MMP) activity, inflammatory cell infiltration, cyclooxygenase 2 (COX-2) expression, caspase 3 activity, and malondialdehyde (MDA) production, and by a decrease in the brain glutathione (GSH) content. Furthermore, we found that either AA or DHA alone had little effect on free radical generation in neuroglia, but they greatly increased the hydrogen peroxide-induced oxidative burden. Taken together, these findings demonstrate the detrimental effect of PUFA such as AA and DHA in post-ischemic progression and brain injury after cerebral I/R is associated with augmentation of cerebral I/R-induced alterations, including oxidative changes.
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PMID:Detrimental effects of post-treatment with fatty acids on brain injury in ischemic rats. 1785 1

Secretoneurin (SN), a neuropeptide derived from secretogranin II, promotes neurite outgrowth of immature cerebellar granule cells. SN also aids in the growth and repair of neuronal tissue, although the precise mechanisms underlying the promotion of brain tissue neuroprotection and plasticity by SN are not understood. Here, in a rat model of stroke and in ischemic human brain tissue, SN was markedly upregulated in both neurons and endothelial cells. SN-mediated neuroprotection rescued primary cortical cell cultures from oxygen/glucose deprivation. SN also induced expression of the antiapoptotic proteins Bcl-2 and Bcl-xL through the Jak2/Stat3 pathway and inhibited apoptosis by blocking caspase-3 activation. In addition, rats with occluded right middle cerebral arteries showed less cerebral infarction, improved motor performance, and increased brain metabolic activity following i.v. administration of SN. Furthermore, SN injection enhanced stem cell targeting to the injured brain in mice and promoted the formation of new blood vessels to increase local cortical blood flow in the ischemic hemisphere. Both in vitro and in vivo, SN not only promoted neuroprotection, but also enhanced neurogenesis and angiogenesis. Our results demonstrate that SN acts directly on neurons after hypoxia and ischemic insult to further their survival by activating the Jak2/Stat3 pathway.
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PMID:Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke. 1807 66

Fulminant hepatic failure is a serious disease that has a poor cure rate unless liver transplantation is performed. Edaravone, a free radical scavenger, has been approved for the treatment of acute cerebral infarction, and its mechanism of action involves scavenging free radicals generated in ischemic tissues. We assessed the ability of 3-methyl-1-phenyl-2-pyrazolim-5-one (edaravone) to prevent Fas-induced acute liver failure in mice and examined the mechanisms underlying the observed effects. BALB/c mice were administered 0.25 microg/g (i.v.) body weight of a purified hamster agonist anti-Fas monoclonal antibody (clone Jo2). The mice also received either edaravone or isotonic sodium chloride solution before or after Jo2 treatment. Edaravone improved the survival rate of the mice markedly. Histopathological findings and serum aspartate aminotransferase levels showed that edaravone reduced the degree of liver injury caused by Jo2. Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling staining showed that edaravone reduced the number of apoptotic hepatocytes. Edaravone also prevented cytochrome c release and caspase 3 activity, recognized as markers of apoptosis after mitochondrial disruption. Therefore, we considered that the antiapoptotic activity of edaravone involved blocking signals in the mitochondria-dependent pathway of Fas-induced apoptosis. Mitochondrial Bcl-xL and Bax, which form a channel in the mitochondrial membrane and, by their balance, regulate its permeability, are involved in mitochondrial disruption. Western blotting showed that the Bcl-xL-Bax ratio of the edaravone group was much higher than that of the control group. In conclusion, edaravone might protect hepatocytes from Fas-induced mitochondria-dependent apoptosis by regulating mitochondrial Bcl-xL and Bax.
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PMID:Edaravone prevents Fas-induced fulminant hepatic failure in mice by regulating mitochondrial Bcl-xL and Bax. 1818 Jun 97


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