Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have been using glial cells derived from aged mouse cerebral hemispheres (MACH) at several passages to study the responsiveness of astrocytes to microenvironmental signals in culture. In the present study, we examined the effects of excitatory amino acids on the activity of glutamine synthetase, a marker for astrocytes. MACH glia cell passages 25 to 29 were used. Culture groups were Dulbecco's modified Eagle's medium +10% fetal bovine serum (control); glutamate 100 microM; gamma-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA) 50 microM; kainic acid 10 microM; N-methyl-D-aspartate (NMDA) 10 microM. In all treated groups glutamine synthetase activity was significantly higher than in controls. We speculate that this increase represents an enhanced differentiation of immature astrocytes. In a second series, we examined the effects of glutamate receptor antagonists on glutamine synthetase activity as follows. MACH cultures were treated with glutamate 100 microM in combinations with either L(+)-2-amino-3-phosphonopropionic acid (L-AP3; 50 microM); D(-)-2-amino-5-phosphonopentanoic acid (D-AP5; 50 microM) or 6,7-dinitroquinoxaline-2,3-dione (DNQX, 50 microM). The increase in GS activity produced by glutamate was inhibited by the non-selective NMDA receptor antagonist, DNQX, but not by the metabotropic receptor antagonist, L-AP3 or a selective NMDA receptor antagonist, D-AP5. We also found that in cultures treated with glutamate, a number of astrocytes resembled "reactive astrocytes" morphologically. These astrocytes were absent in cultures treated with glutamate+DNQX. The findings provide supportive evidence that astrocytes from aged mouse cerebral hemispheres respond to excitatory amino acids and that this response is mediated by non-NMDA receptor activation.
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PMID:Stimulation of glutamine synthetase activity by excitatory amino acids in astrocyte cultures derived from aged mouse cerebral hemispheres may be associated with non-N-methyl-D-aspartate receptor activation. 888 86

Zinc-chelating agents, including ethambutol and its metabolite 2,2'(ethylenediamino)-dibutyric acid (EDBA) are toxic to retinal ganglion cells through a glutamate dependent mechanism. We explored whether such cell death was mediated through the caspase family of cysteine proteases. Retinal cultures were treated with EDBA alone, or EDBA plus a variety of known caspase inhibitors, and ganglion cell viability was assayed. EDBA killed 20-30% of ganglion cells. A general caspase inhibitor, BAF, prevented EDBA induced ganglion cell death. Specific inhibitors of caspase-3 and caspase-6 showed a similar ability to BAF in preventing EDBA mediated ganglion cell loss, whereas inhibitors of caspase-8 and caspase-9 were not able to rescue EDBA treated ganglion cells. A caspase-1,4 inhibitor was less effective than BAF. These studies show that a caspase mediated mechanism of apoptosis accents for a portion of EDBA mediated retinal ganglion cell death. This toxicity was mediated by downstream effector caspases, 3 and 6. Caspase inhibitors may prevent ganglion cell death secondary to ethambutol treatment.
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PMID:Caspase inhibitors block zinc-chelator induced death of retinal ganglion cells. 1092 89

Previously we showed that apoptosis is involved in N -methyl- D -aspartate (NMDA) induced excitotoxicity in adult rat retinas. Since rabbits have a higher endogenous level of glutamate in the retina and very different retinal structures, it is not clear if apoptosis is similarly involved in adult rabbit retinas after intravitreal injection of NMDA. In this study, we used ultrastructural features, TdT-mediated biotin-dUTP nick end labeling (TUNEL) and two caspase inhibitors to examine whether apoptosis is involved in NMDA-induced excitotoxicity in adult rabbit retinas. At 18 hr after an intravitreal injection of 400 nmoles NMDA, typical apoptotic features in degenerative cells in the retinal ganglion cell layer (RGCL) and the inner nuclear layer (INL) were noted by electron microscopy. TUNEL positive nuclei were detected in these layers as early as 4 hr showing maximal numbers at 18 hr. At 7 days, significant loss of nuclei from the RGCL was noted at the visual streak, the superior and the inferior retinas. These losses were abolished by simultaneous administration of MK-801 and ameliorated by YVAD, a caspase-1 inhibitor, but not by IETD, a caspase-8 inhibitor. These results indicated that, similar to adult rat retinas, apoptosis is involved in NMDA receptor-mediated excitotoxicity in rabbit retinas and that specific caspases may play important roles.
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PMID:N -methyl- D -aspartate (NMDA) induced apoptosis in adult rabbit retinas. 1099 63

After a stroke many neurons in the ischemic brain tissue die by a process called apoptosis, a form of cell death that may be preventable. The specific molecular cascades that mediate ischemic neuronal death are not well understood. The authors recently identified prostate apoptosis response-4 (Par-4) as a protein that participates in the death of cultured hippocampal neurons induced by trophic factor withdrawal and exposure to glutamate. Here, the authors show that Par-4 levels increase in vulnerable populations of hippocampal and striatal neurons in rats after transient forebrain ischemia; Par-4 levels increased within 6 hours of reperfusion and remained elevated in neurons undergoing apoptosis 3 days later. After transient focal ischemia in mice, Par-4 levels were increased 6 to 12 hours after reperfusion in the infarcted cortex and the striatum, and activation of caspase-8 occurred with a similar time course. Par-4 immunoreactivity was localized predominantly in cortical neurons at the border of the infarct area. A Par-4 antisense oligonucleotide protected cultured hippocampal neurons against apoptosis induced by chemical hypoxia and significantly reduced focal ischemic damage in mice. The current data suggest that early up-regulation of Par-4 plays a pivotal role in ischemic neuronal death in animal models of stroke and cardiac arrest.
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PMID:Evidence for the involvement of Par-4 in ischemic neuron cell death. 1132 19

Glutamate and the NO donor, nitroprusside, synergistically induced the death of B50 cells from a rat CNS-derived neuroblastoma cell line. With low [nitroprusside] (10 microM) both nitroprusside and glutamate were required. Under these conditions, nuclei became pyknotic and caspases were activated. The activities of caspase-3 and caspase-6 (effector caspases) were higher than those of caspase-8 and caspase-9 (initiator caspases). The activation of all four caspases was inhibited by cyclosporin A, with the order of susceptibility caspase-8=caspase-9=caspase-6>caspase-3. To identify the possible locus of cyclosporin A action, we used an antisense oligodeoxynucleotide to suppress the level of cyclophilin-A to<5% of its control value. Cyclophilin-A suppression largely reproduced the inhibitory effects of cyclosporin A. These results provide the first indication that cyclophilin-A participates in the activation of the caspase cascade in neuronal cells, in particular in the form of cascade elicited by excitotoxic stimuli. It is concluded that neuroprotection by cyclosporin A against excitotoxin-induced apoptosis is, at least partly, due to inhibition of cyclophilin-A.
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PMID:Cyclophilin-A is involved in excitotoxin-induced caspase activation in rat neuronal B50 cells. 1190 43

Epithelial cell apoptosis is an important regulator of normal gut mucosal turnover; however, excessive apoptosis may inhibit mucosal restitution during pathophysiologic states. Apoptosis is induced by oxidative stress and cytokines, but regulation by specific nutrients has been infrequently studied under these conditions. Glutamine (Gln) is an important metabolic fuel for intestinal epithelial cells and a precursor to the antioxidant glutathione (GSH), which has antiapoptotic effects. In cultured intestinal epithelial cells, Gln depletion increases oxidant-induced apoptosis. This study examined whether Gln protects against apoptosis induced by the cytokine tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) in the human colon carcinoma cell line, HT-29. TRAIL-induced apoptosis in HT-29 cells was characterized by an increase in the percentage of cells in the sub-G1 fraction by flow cytometry, nuclear condensation and the activation of caspase-8 and caspase-3. TRAIL-induced apoptosis was completely prevented by Gln, but not inhibited by other amino acids, including the GSH constituents, glutamate, cysteine and glycine. Similar antiapoptotic effects of Gln occurred when apoptosis was induced by a combination of tumor necrosis factor-alpha and interferon-gamma. Cellular GSH was oxidized during TRAIL-induced apoptosis. This effect was completely blocked by Gln, however, inhibition of GSH synthesis with buthionine sulfoximine did not alter Gln antiapoptotic effects. Furthermore, glutamate prevented GSH oxidation in response to TRAIL but did not protect against TRAIL-induced apoptosis. These results show that Gln specifically protects intestinal epithelial cells against cytokine-induced apoptosis, and that this occurs by a mechanism that is distinct from the protection against oxidative stress mediated by cellular GSH.
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PMID:Glutamine prevents cytokine-induced apoptosis in human colonic epithelial cells. 1451 85

We reported previously the autoantibodies directed to caspase-8 among patients with silicosis, systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) , and in healthy individuals. In this study, we analyzed the correlation between anti-caspase-8 autoantibody responses and HLA class II alleles in silicosis patients. The frequencies of HLA-DRB1*0406 were significantly higher in antibody positive patients (16.67%) than in control individuals (3.03%, p=0.0006). The lysine (K) at position 71 as in DRB1*0406 has been reported to be associated with rheumatoid arthritis (RA) and insulin dependent diabetes mellitus (IDDM). The haplotype HLA-DR4; DQB1*0302 was detected in 4 of 12 antibody positive patients. RA, IDDM, or pemphygus vulgaris link to the haplotype. The frequencies of DQB1*0401 were significantly lower in antibody positive patients (0%) than that in controls (13.33%, p=0.0390). The aspartic acid at position 57 in the DQB1 molecule as in DQB1*0401 is reported to play a role in the resistance to IDDM. The frequency of DPB1*0601 in antibody positive patients (5.88%) was significantly higher than that in controls (0.56%, p=0.0003). DPB1*0601 is reported to be a risk factor among RA patients, and glutamate at position 69 of the DPB1 molecule may be involved. Repeated and continuous screening of autoantibodies seems to be necessary among workers in contact with Si-related substances for the detection of immunological disorders in the early stage.
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PMID:Anti-caspase-8 autoantibody response in silicosis patients is associated with HLA-DRB1, DQB1 and DPB1 alleles. 1570 53

The purpose of this study is to determine if calcium/calmodulin-dependent protein kinase-II (CaMKII) plays a role in neuronal cell death and if inhibition of this kinase affords some neuroprotection in the RGC-5 retinal ganglion cell line. The RGC-5 cells were treated with glutamate at various concentrations for increasing increments of time. Cytotoxicity was assayed by measuring the lactate dehydrogenase (LDH) leakage from non-viable cells and TUNEL assays. The involvement of caspase-3, Bcl-2 and caspase-8 in glutamate-induced cytotoxicity was determined by immunoblots and/or real time RT-PCR. In addition, the autocamtide-2-related inhibitory peptide (AIP), a specific inhibitor of CaMKII, was used to determine the involvement of CaMKII in glutamate-induced RGC-5 cell death. Application of increasing concentrations of glutamate to RGC-5 cells caused a dose-dependent increase in the level of cell death after 24 h. There was a glutamate-stimulated increase in the expression of caspase-8 and caspase-3 and a corresponding decrease in Bcl-2. The active fragment of caspase-3 increased in glutamate-treated cells. An early transient increase in the expression of CaMKIIalpha(B) gene and a corresponding CaMKIIalpha nuclear translocation was found in glutamate-treated cells. Treatment with AIP blocked the activation of caspase-3 and protected RGC from glutamate-mediated cell death but did not alter the glutamate-enhanced expression levels of caspase-8 or caspase-3. This report shows the likely involvement of a transcript of the CaMKIIalpha gene in the cytotoxicity response of RGC-5 cells similar to previous reports in the neural retina. AIP is shown to be a neuroprotectant for RGC-5 cells as was reported for the neural retina.
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PMID:Retinal ganglion cell death and neuroprotection: Involvement of the CaMKIIalpha gene. 1602 57

In vitro studies have demonstrated that N-methyl-D-aspartate (NMDA) receptor activation rescue cerebellar granule neurons (CGN) from apoptotic death. It has been suggested that this effect mimics the transient glutamate receptors activation by mossy fibers during cerebellar development. We reported previously that CGN from postnatal days 2-4 (P2-P4) rats increased cell survival in response to NMDA treatment. In this study, we evaluated the effect of dizocilpine (MK-801) administrated for three consecutive days on the apoptotic death of CGN during development. MK-801 treatment decreased the large number of CGN condensed nuclei found at P8, but this drug increased the proportion of condensed nuclei at P16. We also found a high activity of caspases during the first postnatal week that decreased during development. MK-801 treatment did not modify the activity of caspase-8 at any age, but decreased caspase-9 activity at P8 and increased the activity of caspase-1 (76%) at P8, caspase-3 (160%) at P16 and caspase-9 (50%) at P12. These results suggest that NMDA receptor stimulation regulates the activity of caspases in a differential way and plays an important role in the in vivo CGN death during postnatal development.
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PMID:Effect of N-methyl-D-aspartate receptor blockade on caspase activation and neuronal death in the developing rat cerebellum. 1678 Oct 62

We examined the involvement of tumor necrosis factor (TNF)-alpha on glutamate-induced cytotoxicity in a differentiated neuronal cell line. In this study, we used nerve growth factor (NGF)-differentiated PC12h cells. Glutamate cytotoxicity was assessed using the MTS and TUNEL assays. To detect TNF-alpha levels in culture supernatants after glutamate exposure, we used ELISA methods. The involvement of caspase-8, which is downstream from TNF receptor 1 (TNF-R1) in glutamate-induced cytotoxicity, was determined by Western blot analysis. The MTS assay showed that the addition of glutamate resulted in dose-dependent cell death, while the TUNEL assay showed that glutamate induced apoptosis in differentiated PC12h cells in a dose-dependent manner. TNF-alpha levels in the supernatant of glutamate-exposed cells were significantly increased compared with those in unexposed cells. In addition, glutamate caused increases in the levels of caspase-8 protein. The increases in caspase-8 levels were ameliorated by pretreatment with soluble TNF-R1. Moreover, soluble TNF-R1 significantly ameliorated the cell death induced by glutamate. These results suggest that TNF-alpha released from neuronal cells may be associated with glutamate-induced neuronal cell death.
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PMID:Involvement of TNF-alpha in glutamate-induced apoptosis in a differentiated neuronal cell line. 1704 30


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