Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both necrotic and apoptotic neuronal death are observed in various neurological and neurodegenerative disorders. Calpain is activated in various necrotic and apoptotic conditions, while caspase 3 is only activated in neuronal apoptosis. Despite the difference in cleavage-site specificity, an increasing number of cellular proteins are found to be dually susceptible to these cysteine proteases. These include alpha- and beta-fodrin, calmodulin-dependent protein kinases, ADP-ribosyltransferase (ADPRT/PARP) and tau. Intriguingly, calpastatin is susceptible to caspase-mediated fragmentation. Neurotoxic challenges such as hypoxia-hypoglycemia, excitotoxin treatment or metabolic inhibition of cultured neurons result in activation of both proteases. Calpain inhibitors can protect against necrotic neuronal death and, to a lesser extent, apoptotic death. Caspase inhibitors strongly suppress apoptotic neuronal death. Thus, both protease families might contribute to structural derangement and functional loss in neurons under degenerative conditions.
 ...
PMID:Calpain and caspase: can you tell the difference? 1063 85

After birth, constriction of the full-term ductus arteriosus produces ischemic hypoxia, caspase activation, DNA fragmentation (>70% of cell nuclei are positive by the terminal deoxynucleotidyl transferase nick-end labeling [TUNEL] technique), and permanent ductus closure. In contrast, the preterm ductus frequently fails to develop these changes. We used the TUNEL technique to examine rings of fetal ductus arteriosus (incubated for 24 h at different oxygen and glucose concentrations) to determine the roles of 1) constriction and shortening, 2) hypoxia, and 3) hypoglycemia in producing cell death. Under controlled conditions, late-gestation ductus rings had a low rate of TUNEL-positive staining (0.6 +/- 0.9%) that did not change during muscle shortening. Although hypoxia (6.9 +/- 3.5%) and hypoglycemia (2.4 +/- 1.9%) increased the incidence of TUNEL-positive staining, only the combination of hypoxia-plus-hypoglycemia increased the incidence to the range found in vivo (83 +/- 9.5%). The combination of hypoxia-plus-hypoglycemia was associated with an oligonucleosomal pattern of DNA fragmentation. Under the same experimental conditions, the preterm ductus was capable of developing a similar degree of TUNEL-positive staining as found at term. Although caspase-3 and caspase-7 were activated in rings exposed to hypoxia-plus-hypoglycemia, a nonselective caspase inhibitor, Z-VAD.FMK (which inhibited caspase-3 and caspase-7 cleavage in the rings), did not diminish the degree of TUNEL-positive staining. We hypothesize that the preterm ductus is capable of developing an extensive degree of cell death, if it can develop the same degree of hypoxia and hypoglycemia found in the full-term newborn ductus. We also hypothesize that cell death in the ductus wall may involve pathways that are not dependent on caspase-3 or -7 activation.
 ...
PMID:Effects of hypoxia, hypoglycemia, and muscle shortening on cell death in the sheep ductus arteriosus. 1273 84

Blockade of mitochondrial permeability transition protects against hypoglycemic brain damage. To study the mechanisms downstream from mitochondria that may cause neuronal death, we investigated the effects of cyclosporin A on subcellular localization of apoptosis-inducing factor and cytochrome c, activation of the cysteine proteases calpain and caspase-3, as well as its effect on brain extracellular calcium concentrations. Redistribution of cytochrome c occurred at 30 min of iso-electricity, whereas translocation of apoptosis-inducing factor to nuclei occurred at 30 min of recovery following 30 min of iso-electricity. Active caspase-3 and calpain-induced fodrin breakdown products were barely detectable in the dentate gyrus and CA1 region of the hippocampus of rat brain exposed to 30 or 60 min of insulin-induced hypoglycemia. However, 30 min or 3 h after recovery of blood glucose levels, fodrin breakdown products and active caspase-3 markedly increased, concomitant with a twofold increase in caspase-3-like enzymatic activity. When rats were treated with neuroprotective doses of cyclosporin A, but not with FK 506, the redistribution of apoptosis-inducing factor and cytochrome c was reduced and fodrin breakdown products and active caspase-3 immuno-reactivity was diminished whereas the extracellular calcium concentration was unaffected. We conclude that hypoglycemia leads to mitochondrial permeability transition which, upon recovery of energy metabolism, mediates the activation of caspase-3 and calpains, promoting cell death.
 ...
PMID:Cyclosporin A prevents calpain activation despite increased intracellular calcium concentrations, as well as translocation of apoptosis-inducing factor, cytochrome c and caspase-3 activation in neurons exposed to transient hypoglycemia. 1278 63

The cellular mechanisms that lead to neuronal death following glucose deprivation are not known, although it is recognized that hypoglycemia can lead to perturbations in intracellular calcium ([Ca2+]i) levels. Recently, activation of A1 adenosine receptors (A1AR) has been shown to alter [Ca2+]i and promote neuronal death. Thus, we examined if A1AR activation contributes to hypoglycemia-induced neuronal injury using rat cortical neurons. First, we observed that hypoglycemia was associated with large increases in neuronal adenosine release. Next, decreased neuronal viability was seen with progressive reduction in glucose concentration (25, 6, 3, 0.75 and 0 mM). Using the calcium-sensitive dye, Fluo-3, we observed both acute and long-term changes in relative [Ca2+]i during hypoglycemic conditions. Demonstrating a role for adenosine in this process, both the loss in neuronal viability and the early changes in [Ca2+]i were reversed by treatment with A1AR antagonists (8-cyclopentyl, 1,3-dipropylxanthine; 9-chloro-2-(2-furyl)(1,2,4)-triazolo(1,5-c)quinazolin-5-amine; and N-cyclopentyl-9-methyladenine). We also found that hypoglycemia induced the expression of the pro-apoptotic enzyme, caspase-3, and that A1AR antagonism reversed hypoglycemia-induced caspase-3 activity. Collectively, these data show that hypoglycemia induces A1ARs activation leading to alterations in [Ca2+]i, which plays a prominent role in leading to hypoglycemia-induced neuronal death.
 ...
PMID:A1 adenosine receptors mediate hypoglycemia-induced neuronal injury. 1476 97

Overexpression of Bcl-xl, a member of the Bcl-2 protein family, is reported to protect from a variety of stresses involving delayed cell death. We tested the ability of Bcl-xl overexpression to protect primary cultures of embryonic rat septal neurons subjected to one of four different stresses: 6 h of combined oxygen-glucose deprivation, which produces rapid cell death, or a 24 h exposure to hypoglycemia, hyperglycemia, or 1mM 3-nitropropionic acid (an inhibitor of mitochondrial respiration), which results in a more slowly-developing death. Prior to the stress neurons were transiently transfected to overexpress either green fluorescent protein only or green fluorescent protein along with wild-type Bcl-xl. Immediately after oxygen-glucose deprivation, many neurons expressing green fluorescent protein only showed process blebbing and disintegration, with only 49% of the initial cells remaining intact with processes. Neurons expressing both green fluorescent protein and Bcl-xl showed less damage (68% intact post-stress, P<0.05). This result indicates that Bcl-xl's saving effects are not due solely to blocking delayed (apoptotic) death, because death following oxygen-glucose deprivation was rapid and was not accompanied by increased activation of caspase-3. Bcl-xl expression also significantly protected against the hypoglycemic stress (23% intact 24 h post-stress with green fluorescent protein only, compared with 70% with Bcl-xl and green fluorescent protein), but did not protect from hyperglycemia or 3-nitropropionic acid. Thus Bcl-xl does not protect against all forms of delayed death. Bcl-xl's protective effects may include blocking early damaging events, perhaps by increasing mitochondrial function in the face of low levels of energy substrates. Bcl-xl's protective effects may require an intact electron transport chain.
 ...
PMID:Overexpression of Bcl-xl protects septal neurons from prolonged hypoglycemia and from acute ischemia-like stress. 1611 22

Damage to central nervous system white matter is observed following hypoglycemia, raising the possibility that hypoglycemia influences oligodendrocytes and myelination. To examine effects of hypoglycemia on oligodendrocytes and myelin formation, we studied cultured oligodendrocyte precursor cells and cerebellar slice cultures. We observed that with decreasing concentrations of glucose, oligodendrocyte precursor cell proliferation, maturation, and migration decreased. We also observed that hypoglycemia induced apoptotic cell death and activation of caspase-3 in oligodendrocyte precursor cells. Slice culture studies showed that glucose is required for myelinated fiber formation, as with reduction in the glucose concentration, the density of myelinated fibers decreased. Collectively, these data show that hypoglycemia inhibits oligodendrocyte development and myelination and that hypoglycemia triggers apoptotic cell death in oligodendrocyte precursor cells.
 ...
PMID:Hypoglycemia influences oligodendrocyte development and myelin formation. 1636 50

Perinatal hypoxic-ischemic brain damage is a major cause of neuronal and behavior deficits, in which the onset of injury can be before, at or after birth, and the effects may be delayed. Pontosubicular neuron necrosis (PSN) is one of perinatal hypoxic-ischemic brain injury and its pathological peculiarity is neuronal apoptosis. In this study, we investigated whether apoptotic cascade of PSN used a caspase-pathway or not, and whether hypoglycemia activated apoptosis or not. Sections of the pons of PSN with and without hypoglycemia were stained using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) and immunohistochemistry for glial fibrillary acidic protein (GFAP), Bcl-2, Bcl-x and activated caspase 3. Additionally, we performed immunoblot analysis of Bcl-2, Bcl-x and activated caspase 3. TUNEL-positive cell was closely associated with the presence of karyorrhexis. Under combination of karyorrhectic and TUNEL-positive cells, number of apoptotic cells in premature brains was significantly more than in mature brains. Hypoxic-ischemic brain injury was considered to easily lead to apoptosis in premature infants. Moreover, as this pathophysiology, caspase-pathway activation contributed to neuronal death from caspase-immunoexpression analyses. PSN with hypoglycemia showed large number of apoptotic cells and higher expression of activated caspase 3. The result may be more severe with the background of hypoglycemia and prematurity complicated by hypoxia and/or ischemia.
 ...
PMID:A histopathological study of premature and mature infants with pontosubicular neuron necrosis: neuronal cell death in perinatal brain damage. 1671 12

Cellular injury can involve the aberrant stimulation of cell cycle proteins in part through activation of phosphodiesterases (PDEs) and downstream expression of cell-cycle components such as cyclin D1. In mature non-proliferating cells activation of the cell cycle can lead to the induction of programmed cell death. In the present study, we investigated the in vitro neuroprotective efficacy and mechanism of action of vinpocetine (PDE1 inhibitor), trequinsin (PDE3 inhibitor), and rolipram (PDE4 inhibitor) in four mechanistically-distinct models of injury to primary rat cortical neurons as related to cell cycle regulation and apoptosis. Cellular injury was induced by hypoxia/hypoglycemia, veratridine (10 microM), staurosporine (1 microM), or glutamate (100 microM), resulting in average neuronal cell death rates of 43-48% as determined by MTT assay. Treatment with each PDE inhibitor (PDEI) resulted in a similar concentration-dependent neuroprotection profile with maximal effective concentrations of 5-10 microM (55-77% neuroprotection) in all four neurotoxicity models. Direct cytotoxicity due to PDE inhibition alone was not observed at concentrations below 100 microM. Further studies indicated that PDEIs can suppress the excitotoxic upregulation of cyclin D1 similar to the effects of flavopiridol, a cyclin-dependent kinase inhibitor, including suppression of pro-apoptotic caspase-3 activity. Overall, these data indicate that PDEIs are broad-spectrum neuroprotective agents acting through modulation of cell cycle elements and may offer a novel mode of therapy against acute injury to the brain.
 ...
PMID:Broad spectrum neuroprotection profile of phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 activation. 1739 1

The effect of general anesthetics on the developing brain is receiving growing attention. Nonetheless, there remains a paucity of evidence regarding the effect of sevoflurane, a widely used anesthetic in pediatric anesthesia. This study was designed to investigate the effect of sevoflurane on nerve cell apoptosis in the developing brain. Techniques to detect cell apoptosis included immunohistochemistry of cleaved caspase-3 and single-strand DNA, as well as electron microscopy. Elevated cleaved caspase-3 was also validated semi-quantitatively by immunoblotting assay. Mouse pups (day 7 postnatal) were subjected to sevoflurane inhalation. Twelve hours later, dramatically increased cleaved caspase-3 and single-strand DNA immunoreactivity were detected in the pup brains. Immunoblotting assay of cleaved caspase-3 revealed a significant increase after anesthetic exposure. Electron microscopy disclosed typical apoptotic morphology of the degenerative nerve cells. Blood glucose levels in the anesthetized group were not different from those of the control group, indicating that the neuronal apoptosis observed in the anesthetized group was not the result of hypoglycemia. Our results indicate that subanesthetic concentration of sevoflurane can trigger neuronal apoptosis in the postnatal mouse brain.
 ...
PMID:Subclinical concentration of sevoflurane potentiates neuronal apoptosis in the developing C57BL/6 mouse brain. 1885 26

The deficiency of glucose-6-phosphatase (G6Pase) underlies glycogen storage disease type Ia (GSD-Ia, von Gierke disease; MIM 232200), an autosomal recessive disorder of metabolism associated with life-threatening hypoglycemia, growth retardation, renal failure, hepatic adenomas, and hepatocellular carcinoma. Liver involvement includes the massive accumulation of glycogen and lipids due to accumulated glucose-6-phosphate and glycolytic intermediates. Proteomic analysis revealed elevations in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and other enzymes involved in glycolysis. GAPDH was markedly increased in murine G6Pase-deficient hepatocytes. The moonlighting role of GAPDH includes increasing apoptosis, which was demonstrated by increased TUNEL assay positivity and caspase 3 activation in the murine GSD-Ia liver. These analyses of hepatic involvement in GSD-Ia mice have implicated the induction of apoptosis in the pathobiology of GSD-Ia.
 ...
PMID:Activation of glycolysis and apoptosis in glycogen storage disease type Ia. 1941 92


1 2 3 4 Next >>