Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell death-regulatory genes like caspases and bcl-2 family genes are involved in delayed cell death in the CA1 sector of hippocampus after global cerebral ischemia, but little is known about the mechanisms that trigger their expression. The authors found that expression of Fas and Fas-ligand messenger ribonucleic acid and protein was induced in vulnerable CA1 neurons at 24 and 72 hours after global ischemia. Fas-associating protein with a novel death domain (FADD) also was upregulated and immunoprecipitated and co-localized with Fas. Caspase-10 was activated and interacted with FADD protein to an increasing extent as the duration of ischemia increased. Moreover, caspase-10 co-localized with both FADD and caspase-3. These findings suggest that Fas-mediated death signaling may play an important role in signaling hippocampal neuronal death in CA1 after global cerebral ischemia.
 ...
PMID:Fas (CD95) may mediate delayed cell death in hippocampal CA1 sector after global cerebral ischemia. 1174 Feb 2

The exact molecular mechanism of ischemic neuronal death still remains unclear from rodents to primates. A number of studies using lower species animals have suggested implication of apoptosis cascade, while using monkeys the authors recently claimed necrosis cascade by calpain-induced leakage of lysosomal cathepsins (calpain-cathepsin hypothesis). This paper is to study implications of apoptotic versus necrotic cascades for the development of hippocampal CA1 neuronal death in the primate brain undergoing complete global ischemia. Here, we focused on two terminal cell death effectors; caspase-activated DNase (CAD) and lysosomal enzyme DNase II, in the monkey CA1 sector undergoing 18 min ischemia. The expressions of their mRNA and proteins, and the subcellular localizations as well as ultrastructure and specific DNA gel electrophoresis were examined. Expression of CAD was much less in the normal brain, compared with the lymph node or heart tissues. On day 1 after ischemia, however, CAD mRNA and protein were significantly increased in the CA1 sector, and then CAD protein immunohistochemically showed a translocation from the perikarya into the nucleus. Activated DNase II protein was significantly increased on days 2 and 3 after ischemia, and also showed a similar translocation indicating lysosomal leakage. Although the post-ischemic CA1 neurons showed positive terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining on days 3-5, they showed eosinophilic coagulation necrosis on light microscopy, and frank membrane disruption and mild chromatin condensation on electron microscopy. Furthermore, DNA smear pattern typical for necrosis was observed instead of DNA laddering. These data altogether suggest that the post-ischemic CA1 neuronal death of the monkey occurs not by apoptosis but by necrosis with participations of lysosomal enzymes DNase II and cathepsins as well as CAD. The interactions between apoptotic (caspase-3 and CAD) and necrotic (calpain, cathepsin and DNase II) cascades should be studied further.
 ...
PMID:Implications of CAD and DNase II in ischemic neuronal necrosis specific for the primate hippocampus. 1175 60

Hypoxic-ischemic encephalopathy (HIE) in neonates is a disorder of excessive neuronal excitation that includes seizures, abnormal EEG activity, and delayed failure of oxidative metabolism with elevated levels of lactic acid in the brain. Evidence from experimental models and clinical investigation indicates that HIE is triggered by a profound disruption in the function of glutamate synapses so that re-uptake of glutamate from the synapse is impaired and post-synaptic membranes containing glutamate receptors are depolarized. Severe hypoxemia preferentially depolarizes neuronal membranes, while ischemia probably has greater impact on the activity of glial glutamate re-uptake. Together, severe hypoxia and ischemia trigger a delayed cascade of events that may result in cell death by necrosis and/or apoptosis. Apoptosis is far more prominent in the neonate than in the adult and activation of cysteine proteases such as caspase-3 is a very important pathway in excitotoxic neonatal injury. Understanding the complex molecular networks triggered by an excitotoxic insult in the neonate provides insight into patterns of selective neuronal vulnerability and potential therapeutic strategies.
 ...
PMID:Excitotoxicity in neonatal hypoxia. 1175 16

Mitochondria are known to be involved in the early stage of apoptosis by releasing cytochrome c, caspase-9, and the second mitochondria-derived activator of caspases (Smac). We have reported that overexpression of copper/zinc superoxide dismutase (SOD1) reduced superoxide production and ameliorated neuronal injury in the hippocampal CA1 subregion after global ischemia. However, the role of oxygen free radicals produced after ischemia/reperfusion in the mitochondrial signaling pathway has not been clarified. Five minutes of global ischemia was induced in male SOD1-transgenic (Tg) and wild-type (Wt) littermate rats. Cytosolic expression of cytochrome c and Smac and activation of caspases were evaluated by immunohistochemistry, Western blot, and caspase activity assay. Apoptotic cell death was characterized by DNA nick end and single-stranded DNA labeling. In the Wt animals, early superoxide production, mitochondrial release of cytochrome c, Smac, and cleaved caspase-9 were observed after ischemia. Active caspase-3 was subsequently increased, and 85% of the hippocampal CA1 neurons showed apoptotic DNA damage 3 d after ischemia. Tg animals showed less superoxide production and cytochrome c and Smac release. Subsequent active caspase-3 expression was not evident, and only 45% of the neurons showed apoptotic DNA damage. A caspase-3 inhibitor (N-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone) reduced cell death only in Wt animals. These results suggest that overexpression of SOD1 reduced oxidative stress, thereby attenuating the mitochondrial release of cytochrome c and Smac, resulting in less caspase activation and apoptotic cell death. Oxygen free radicals may play a pivotal role in the mitochondrial signaling pathway of apoptotic cell death in hippocampal CA1 neurons after global ischemia.
 ...
PMID:Overexpression of copper/zinc superoxide dismutase in transgenic rats protects vulnerable neurons against ischemic damage by blocking the mitochondrial pathway of caspase activation. 1175 4

Male Wistar rats were subjected to intraperitoneal (i.p.) streptozotocin (STZ) administration (85 mg/kg) to evoke diabetes. Cerebral ischaemia was produced by injection of 0.03 ml of air into the left carotid followed by bilateral common carotid ligation. We studied the effect of application of two antioxidants--coenzyme Q10 (CoQ10, 10 mg/kg b.w., i.p. for seven days) and lipoic acid (LA, 100 mg/kg b.w., i.p. for seven days) on neurones and on the apoptosis-related enzyme--caspase-3 activity in the hippocampus and dentate gyrus. Ischaemia and diabetes lead to a decrease of nuclear and perikaryon diameters as well as neuronal density in the CA1, CA2, CA3 and dentate gyrus. Application of CoQ10 or LA for seven days improved the mean nucleus area and perikaryon area in almost all investigated structures. Both antioxidants diminished neuronal loss in the diabetes complicated with ischaemia but not in the animals with diabetes only. Activity of one of the key enzymes in apoptotic cell death, caspase-3 (CPP32), increased in hippocampus in the diabetic rats, in the animals with cerebral ischaemia and in the rats with both diabetes and ischaemia by about 80%, 33% and 53%, respectively. Either the CoQ10 or the LA treatment led to a significant decrease of the CPP32 activity in all experimental groups. Our results confirm the presence of neuronal damage and death in the hippocampus and dentate gyrus in the experimental STZ-diabetes and its aggravation by the additional cerebral ischaemia. The effects of the antioxidative treatment support the hypothesis of an important role of oxidative stress and free radicals in neuronal pathology in diabetes and ischaemia. The above results of CPP32 activity suggest an important role of apoptosis as a mechanism of cell death and demonstrate the positive effect of the CoQ10 and the LA treatment.
 ...
PMID:Neuronal death in the rat hippocampus in experimental diabetes and cerebral ischaemia treated with antioxidants. 1177 Jan 25

We conducted this study to determine whether high physiological levels of estradiol (proestrus) could protect the hippocampal CA1 neurons following transient global ischemia. Ovariectomized or ovary-intact female rats were subjected to 20 min of ischemia and allowed to survive for 96 h. Estradiol was administered subcutaneously in a group of ovariectomized rats 24 h before ischemia induction. Ending serum estrogen levels were correlated to cerebral blood flow (CBF), histologic assessment and immunofluorescent caspase-3 active peptide (C-3AP) positive cell count. Estradiol administration significantly improved CBF in the hippocampus (compared with intact or ovariectomized rats) but not in the parietal cortex. No significant differences in CBF between intact or ovariectomized rats were noted. Estradiol administration maintained serum levels of the steroid in estradiol-treated rats-about 10 times that of intact animals and more than 20 times that of ovariectomized animals. Morphologically, live cell counts in estradiol-treated rats were significantly higher than in intact or ovariectomized rats. Live cell counts were also significantly higher in intact than ovariectomized rats. C-3AP positive cell counts were much higher in ovariectomized rats than in intact and estradiol-treated rats. In conclusion, proestrus levels of 17beta-estradiol protect hippocampal CA1 neurons against transient global ischemia, through mechanisms that appear to involve improvement of perfusion and inhibition of caspase-3 activity.
 ...
PMID:Proestrus levels of estradiol during transient global cerebral ischemia improves the histological outcome of the hippocampal CA1 region: perfusion-dependent and-independent mechanisms. 1179 Mar 87

In retinitis pigmentosa, retinal detachment, age-related macular degeneration, and glaucoma, retinal neuronal cells are damaged by a common mechanism, apoptosis. Because apoptosis is an active process that requires de novo expression of a "death message", this process can be controlled by inhibiting the expression of the "death message". We first studied whether a retinal ischemia-reperfusion model can be used as a model for retinal neuronal apoptosis. In the retinal ischemia-reperfusion injuries, typical features of apoptosis, including TUNEL-positive cells, DNA ladder formation, and ultrastructural features of apoptosis were found. Using the model, systematic research to identify the "death message" was done by DNA microarray analysis. About 200 messages were found to be up- or down-regulated during the process of retinal ischemia-reperfusion. These genes were divided into four groups: (1) transcription factor genes, (2) cell cycle-related genes, (3) reactive oxygen scavenger genes and (4) molecular chaperon genes. The possible roles of such genes in neuronal apoptosis following retinal ischemia-reperfusion injury were studied. In the model, reactive oxygen species produced by reperfusion was found to generate lipid peroxides and induced up-regulation of a transcription factor, c-Jun, that further induced aberrant expression of cell cycle-related genes such as cyclin D1 in amacrine cells. However, because no controlled expression of cell cycle-related genes takes place in retinal neurons, amacrine cells died by a G1 arrest mechanism. On the other hand, horizontal cells never expressed cyclin D1 and the cells were found to die by necrosis. The study revealed a possible mechanism of retinal neuronal apoptosis and it also became apparent that different types of neurons use different "death messages". Furthermore, the possibility that inhibition of a "death message" sometimes induces necrosis rather than apoptosis was shown. This means that we need to try inhibition of the death mechanism upstream rather than downstream. Administration of thioredoxin, an endogenous reactive oxygen species that blocks generation of lipid peroxides and thus inhibits the death process upstream, was found to be neuroprotective against retinal ischemia-reperfusion injury. Aberrant expression of c-Jun and cyclin D1 was down-regulated by the treatment. Possible roles of caspases were also studied by using the ischemia-reperfusion injury, RCS rat, and excessive light exposure damage in wild type and caspase-1 deficient mice. Also, application of adeno-associated virus that carries Bcl-xL was tested to find possible neuroprotective effects on RCS rats. Our studies showed that caspase-1 played a more important role in the retinal photoreceptors and caspase-3 was important in neurons in the inner nuclear layer. Caspase-2 was found to be a major caspase in the retinal ganglion cell layer. In agreement with the findings, caspase-1 deficient mice showed less prominent light damage than wild type mice. Gene therapy by Bcl-xL was effective to protect retinal photoreceptor damage in RCS rats.
 ...
PMID:[Retinal neuronal cell death: molecular mechanism and neuroprotection]. 1180 59

Deoxyribonucleic acid fragmentation at nucleosomal junctions is a hallmark of neuronal apoptosis in ischemic brain injury, for which the mechanism is not fully understood. Using the in vitro cell-free apoptosis assay, the authors found that caspase-3-dependent deoxyribonuclease activity caused internucleosomal DNA fragmentation in brain-cell extracts in a rat model of transient focal ischemia. This in vitro deoxyribonuclease activity was completely inhibited by purified inhibitor of caspase-activated deoxyribonuclease protein, the specific endogenous inhibitor of caspase-activated deoxyribonuclease, or by caspase-activated deoxyribonuclease immunodepletion. The induction of the deoxyribonuclease activity was correlated with caspase-3 activation and caspase-3-mediated degradation of inhibitor of caspase-activated deoxyribonuclease. Furthermore, inhibiting caspase-3-like protease activity prevented the endogenous induction of internucleosomal DNA fragmentation in the ischemic brain. These results suggest that caspase-3-dependent caspase-activated deoxyribonuclease activity plays an important role in mediating DNA fragmentation after focal ischemia.
 ...
PMID:Induction of caspase-activated deoxyribonuclease activity after focal cerebral ischemia and reperfusion. 1180 89

In an attempt to establish more sensitive long-term neurofunctional measurements for neonatal hypoxic-ischemic brain injury, we examined skilled motor task and brainstem functions in adult rats after neonatal cerebral hypoxia-ischemia (H-I), using a staircase test and auditory brainstem response (ABR), respectively. Seven-day-old rats underwent a combination of left common carotid artery ligation and exposure to 8% O(2) for 1 h (n=16). The control animals only received sham operation (n=16). At 3 months of age, the staircase test and ABR were performed. In the staircase test, H-I animals showed marked impairment of skilled forelimb use in the side contralateral to the occluded artery, and the degree of brain damage correlated significantly to skilled forelimb use. In the ABR, H-I animals showed brainstem dysfunction assessed by measuring interpeak latencies for waves III-V and I-V. We also examined the brainstem with antibodies specific for activated caspase-3, a protein involved in initiation of apoptosis, and observed that caspase-3 was activated in the ipsilateral inferior colliculus at 24 h after H-I. The present study shows that both the staircase test and ABR are sensitive and objective long-term neurofunctional measurements that can be used in future studies to assess therapeutic intervention in this neonatal cerebral H-I model.
 ...
PMID:Effects of neonatal hypoxic-ischemic brain injury on skilled motor tasks and brainstem function in adult rats. 1181 12

Protein synthesis inhibition occurs in neurons immediately on reperfusion after ischemia and involves at least alterations in eukaryotic initiation factors 2 (eIF2) and 4 (eIF4). Phosphorylation of the alpha subunit of eIF2 [eIF2(alphaP)] by the endoplasmic reticulum transmembrane eIF2alpha kinase PERK occurs immediately on reperfusion and inhibits translation initiation. PERK activation, along with depletion of endoplasmic reticulum Ca2+ and inhibition of the endoplasmic reticulum Ca2+ -ATPase, SERCA2b, indicate that an endoplasmic reticulum unfolded protein response occurs as a consequence of brain ischemia and reperfusion. In mammals, the upstream unfolded protein response components PERK, IRE1, and ATF6 activate prosurvivial mechanisms (e.g., transcription of GRP78, PDI, SERCA2b ) and proapoptotic mechanisms (i.e., activation of Jun N-terminal kinases, caspase-12, and CHOP transcription). Sustained eIF2(alphaP) is proapoptotic by inducing the synthesis of ATF4, the CHOP transcription factor, through "bypass scanning" of 5' upstream open-reading frames in ATF4 messenger RNA; these upstream open-reading frames normally inhibit access to the ATF4 coding sequence. Brain ischemia and reperfusion also induce mu-calpain-mediated or caspase-3-mediated proteolysis of eIF4G, which shifts message selection to m 7 G-cap-independent translation initiation of messenger RNAs containing internal ribosome entry sites. This internal ribosome entry site-mediated translation initiation (i.e., for apoptosis-activating factor-1 and death-associated protein-5) can also promote apoptosis. Thus, alterations in eIF2 and eIF4 have major implications for which messenger RNAs are translated by residual protein synthesis in neurons during brain reperfusion, in turn constraining protein expression of changes in gene transcription induced by ischemia and reperfusion. Therefore, our current understanding shifts the focus from protein synthesis inhibition to the molecular pathways that underlie this inhibition, and the role that these pathways play in prosurvival and proapoptotic processes that may be differentially expressed in vulnerable and resistant regions of the reperfused brain.
 ...
PMID:Molecular pathways of protein synthesis inhibition during brain reperfusion: implications for neuronal survival or death. 1182 11


<< Previous 1 2 3 4 5 6 7 8 9 10