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)

The focus of this study is to examine the ability of FK506, an immunosuppressant that inhibits calcineurin activation, to limit caspase-3 activation in oligodendroglia following spinal cord injury (SCI). To better establish a role for calcineurin and caspase-3 activation in oligodendroglia following SCI, rats received a contusion injury to the spinal cord followed by treatment with FK506 or rapamycin (another immunosuppressant with no detectable inhibitory action on calcineurin activation). Animals were then sacrificed at 8 days postinjury and spinal cord tissue was processed using immunofluorescence histochemistry to examine cellular caspase-3 activation in ventral and dorsal white matter. In all treatment groups, numerous oligodendroglia were found to express the activated form of caspase-3 in regions proximal and distal to the injury epicenter. However, our findings suggest that treatment with FK506, but not rapamycin reduces the number of oligodendroglia expressing activated caspase-3 and increases the number of surviving oligodendroglia in dorsal white matter. These results provide initial evidence that agents that reduce the actions of calcineurin and subsequent caspase-3 activation may prove beneficial in the treatment of traumatic SCI.
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PMID:FK506 treatment inhibits caspase-3 activation and promotes oligodendroglial survival following traumatic spinal cord injury. 1242 26

Nanomolar concentrations of human amylin promote death of RINm5F cells in a time- and concentrationdependent manner. Morphological changes of chromatin integrity suggest that cells are predominantly undergoing apoptosis. Human amylin induces significant activation of caspase-3 and strong and sustained phosphorylation of stress-activated protein kinases, c-Jun N-terminal kinase (JNK) and p38, that precedes cell death. Extracellular signal-regulated kinase (ERK) activation was not concomitant with JNK and/or p38 activation. Activation of caspase-3 and mitogen-activated protein kinases (MAPKs) was detected by Western blot analysis. Addition of the MEK1 inhibitor PD 98059 had no effect on amylin-induced apoptosis, suggesting that ERK activation does not play a role in this apoptotic scenario. A correlative inhibition of JNK activation by the immunosuppressive drug FK506, as well as a selective inhibition of p38 MAPK activation by SB 203580, significantly suppressed procaspase-3 processing and the extent of amylin-induced cell death. Moreover, simultaneous pretreatment with both FK506 and SB 203580, or with the caspase-3 inhibitor Ac-DEVD-CHO alone, almost completely abolished procaspase-3 processing and cell death. Thus, our results suggest that amylin-induced apoptosis proceeds through sustained activation of JNK and p38 MAPK followed by caspase-3 activation.
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PMID:Amylin-induced cytotoxicity is associated with activation of caspase-3 and MAP kinases. 1253 May 40

It is usually accepted that prion and amyloid-beta (A beta) peptides induce apoptotic cell death. However, the mechanisms that trigger neuronal death, induced by these amyloidogenic peptides, remain to be clarified. In the present study we analysed the neurotoxic effects of the synthetic prion and A beta peptides, PrP106-126 and A beta 25-35, in primary cultures of rat brain cortical cells. PrP106-126 and A beta 25-35 incubated at a concentration of 25 micro m for 24 h, did not affect cell membrane integrity, but decreased the metabolic capacity of the cells. The intracellular free Ca2+ concentration and reactive oxygen species levels increased significantly after 24 h treatment with PrP106-126 and A beta 25-35. Furthermore, these peptides (after 24 h exposure) also induced cytochrome c release from mitochondria and increased caspase-3-like activity. FK506, an inhibitor of the Ca2+/calmodulin-dependent phosphatase, calcineurin, was able to prevent cytochrome c release, caspase-3 activation and cell death induced by A beta 25-35 or PrP106-126 peptides. Taken together these data suggest that calcineurin is involved in A beta 25-35 and PrP106-126 neurotoxicity.
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PMID:Involvement of calcineurin in the neurotoxic effects induced by amyloid-beta and prion peptides. 1267 Mar 7

Ischemia/reperfusion of heart causes contractile dysfunction, necrosis and/or apoptosis and is a major cause of human death, but the molecular mechanisms are unclear. We show that ischemia alone (without reperfusion) is sufficient to induce apoptosis and mitochondrial dysfunction, and we have investigated the mechanism responsible; 30 and 60 min stop-flow ischemia in Langendorff-perfused rat hearts induced progressive (a). release of cytochrome c from mitochondria to cytosol, (b). inhibition of the mitochondrial respiratory functions, (c). activation of caspase-3-like protease activity and (d). DNA strand breaks (however, only 2% of myocyte nuclei were TUNEL positive at 60 min). Fifteen minutes pre-perfusion of hearts with cyclosporin A, an inhibitor of mitochondrial-permeability transition (MPT), largely prevented all these ischemic changes. Pre-perfusion of hearts with FK506, an inhibitor of calcineurin, caused no protection. Pre-perfusion with DEVD-CHO, an inhibitor of caspase-3-like proteases, completely prevented ischemia-induced DNA strand breaks, but only partially blocked cytochrome c release and mitochondrial respiratory inhibition. Reperfusion of hearts after 30 min ischemia further stimulated caspase activity and nuclear apoptosis. We conclude that ischemia-induced MPT causes release of cytochrome c, which then activates the caspases that execute apoptosis and feedback to cause further cytochrome c release. The MPT-induced cytochrome c release is also largely responsible for the ischemic respiratory inhibition, which might contribute to contractile dysfunction or necrosis at reperfusion.
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PMID:Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia. 1268 12

We previously reported synergistic induction of apoptosis by IFN-gamma plus either cyclosporin A (CsA) or tacrolimus (FK506) in gastric carcinoma cells. In this study, we aimed to elucidate the mechanism for this synergistic induction of apoptosis. IFN-gamma plus CsA synergistically induced caspase-3 mediated apoptosis in gastric carcinoma cells. Although IFN-gamma induced activation of signal transducer and activator of transcription1 (STAT1) and expression of interferon regulatory factor-1 (IRF-1) mRNA, IFN-gamma alone was not able to induce caspase-3 activation and apoptosis. When gastric carcinoma cells were treated with cyclohexamide, a protein synthesis inhibitor, following IFN-gamma pretreatment, caspase-3 was activated, and apoptosis was markedly induced. These findings suggest the existence of IFN-gamma-induced anti-apoptotic pathway and we evaluated the effect of IFN-gamma and CsA on calcium-sensitive nuclear factor-kappa B (NF-kappa B) activation. IFN-gamma increased intracellular calcium ion concentration ([Ca(2+)](i)) consisting of a spike and a sustained phase, and the latter was completely abrogated by CsA. Activation of NF-kappa B occurred in response to IFN-gamma, and which was markedly inhibited by either CsA or FK506. NF-kappa B decoy also enhanced the cytotoxic effect of IFN-gamma. These results suggest that IFN-gamma may simultaneously induce the STAT1-mediated apoptotic pathway and the anti-apoptotic pathway through calcium-activated NF-kappa B and that inhibition of the latter by CsA may result in dominance of the apoptosis-inducing pathway.
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PMID:Inhibition of interferon-gamma-activated nuclear factor-kappa B by cyclosporin A: A possible mechanism for synergistic induction of apoptosis by interferon-gamma and cyclosporin A in gastric carcinoma cells. 1276

FK506, a calcineurin inhibitor, shows potent neuroprotective effects in animal models such as those of stroke and neurodegenerative diseases. However, the mechanism underlying these neuroprotective effects is unclear. In this study, an in vitro model, in which FK506 protected the cells against cell death, was established and analyzed in detail by pharmacological experiments. Thapsigargin (TG), an inhibitor of endoplasmic reticulum calcium-ATPase, induced SH-SY5Y cell death. FK506 concentration-dependently protected the cells from this type of death. In contrast, FK506 did not suppress SH-SY5Y cell death caused by the following molecules: tunicamycin (TM), an inhibitor of N-linked glycosylation; etoposide (Eto), a topoisomerase II inhibitor; and staurosporine (STS), a phospholipid/calcium-dependent protein kinase inhibitor. Additionally, FK506 did not inhibit TG-induced cell death in either SK-N-MC or HeLa cell lines. FK506 completely inhibited caspase-3 activation and apoptosis caused by TG in a concentration-dependent manner, but not that caused by TM, Eto, and STS. TG did not activate caspase-3 in SK-N-MC cells, although it slightly activated caspase-3 in HeLa cells. FK506 did not change caspase-3 activity in either SK-N-MC or HeLa cell lines. Cyclosporin A, another calcineurin inhibitor, showed the same results as FK506 in this study, whereas rapamycin, an immunosuppressant not associated with calcineurin activity, did not have any effect in this context. Thus, the suppressive effects of FK506 on cell death are specific to SH-SY5Y cells treated with TG and are caused by the inhibition of calcineurin and subsequent suppression of caspase-3 activation. Therefore, an in vitro system using SH-SY5Y cells treated with TG could provide a model reflective of certain aspects of the neuroprotective activity of FK506.
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PMID:Detailed in vitro pharmacological analysis of FK506-induced neuroprotection. 1287 56

Beta-amyloid (Abeta) peptide has been suggested to play important roles in the pathogenesis of Alzheimer's disease (AD). Abeta peptide neurotoxicity was shown to induce disturbance of cellular calcium homeostasis. However, whether modulation of calcium release from the endoplasmic reticulum (ER) can protect neurons from Abeta toxicity is not clearly defined. In the present study, Abeta peptide-triggered ER calcium release in primary cortical neurons in culture is modulated by Xestospongin C, 2-aminoethoxydiphenyl borate or FK506. Our results showed that reduction of ER calcium release can partially attenuate Abeta peptide neurotoxicity evaluated by LDH release, caspase-3 activity and quantification of apoptotic cells. While stress signals associated with perturbations of ER functions such as up-regulation of GRP78 was significantly attenuated, other signaling machinery such as activation of caspase-7 transmitting death signals from ER to other organelles could not be altered. We further provide evidence that molecular signaling in mitochondria play also a significant role in determining neuronal apoptosis because Abeta peptide-triggered activation of caspase-9 was not significantly reduced by attenuating ER calcium release. Our results suggest that neuroprotective strategies aiming at reducing Abeta toxicity should include molecular targets linked to ER perturbations associated with ER calcium release as well as mitochondrial stress.
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PMID:Reduction of calcium release from the endoplasmic reticulum could only provide partial neuroprotection against beta-amyloid peptide toxicity. 1471 97

We studied the intracellular events associated with pancreatic beta cell apoptosis by IFN-gamma/TNF-alpha synergism. IFN-gamma/TNF-alpha treatment of MIN6N8 insulinoma cells increased the amplitude of high voltage-activated Ca(2+) currents, while treatment with IFN-gamma or TNF-alpha alone did not. Cytosolic Ca(2+) concentration ([Ca(2+)](c)) was also increased by IFN-gamma/TNF-alpha treatment. Blockade of L-type Ca(2+) channel by nifedipine abrogated death of insulinoma cells by IFN-gamma/TNF-alpha. Diazoxide that attenuates voltage-activated Ca(2+) currents inhibited MIN6N8 cell death by IFN-gamma/TNF-alpha, while glibenclamide that accentuates voltage-activated Ca(2+) currents augmented insulinoma cell death. A protein kinase C inhibitor attenuated MIN6N8 cell death and the increase in [Ca(2+)](c) by IFN-gamma/TNF-alpha. Following the increase in [Ca(2+)](c), calpain was activated, and calpain inhibitors decreased insulinoma cell death by IFN-gamma/TNF-alpha. As a downstream of calpain, calcineurin was activated and the inhibition of calcineurin activation by FK506 diminished insulinoma cell death by IFN-gamma/TNF-alpha. BAD phosphorylation was decreased by IFN-gamma/TNF-alpha because of the increased calcineurin activity, which was reversed by FK506. IFN-gamma/TNF-alpha induced cytochrome c translocation from mitochondria to cytoplasm and activation of caspase-9. Effector caspases such as caspase-3 or -7 were also activated by IFN-gamma/TNF-alpha treatment. These results indicate that IFN-gamma/TNF-alpha synergism induces pancreatic beta cell apoptosis by Ca(2+) channel activation followed by downstream intracellular events such as mitochondrial events and caspase activation and also suggest the therapeutic potential of Ca(2+) modulation in type 1 diabetes.
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PMID:Role of calcium in pancreatic islet cell death by IFN-gamma/TNF-alpha. 1515 22

Studies were carried out to characterize the effects of cyclosporines and FK506 on the formation and survival of osteoclasts deriving from mouse bone marrow cultures. Cyclosporin A (CsA), cyclosporin B (CsB), cyclosporin H (CsH), and FK506 all inhibited receptor activator of NFkappaB ligand (RANKL)-stimulated tartrate-resistant acid phosphatase (TRAP) activity and generation of TRAP+ multinucleated cells in the cultures. CsA and CsG were approximately equipotent, CsH was approximately one order of magnitude less potent than the other cyclosporines, and FK506 was approximately two orders of magnitude more potent than CsA and CsG. All of the inhibitors demonstrated greater potency and efficacy on decreasing the number of TRAP+ multinucleated cells than on decreasing total TRAP activity. Further evidence that late stages were more sensitive to inhibition was obtained in experiments in which CsA was present for different segments of the RANKL-stimulated culture period. CsA was as efficacious when added for the final 2 days of a 4-day culture as when added for the entire culture period, whereas it was less effective if added for only the first 2 days of the culture. When CsA or FK506 were added for 1 day to cultures in which osteoclasts had already formed, the numbers of TRAP+ osteoclasts decreased. Treatment with CsA or FK506 produced nuclear fragmentation and disruption of the multinucleated osteoclasts and an increase in caspase-3 activity. The apoptosis inhibitor z-VAD partially prevented the inhibitory effects of CsA and FK506 on the survival of TRAP+ multinucleated cells in the cultures and also preserved the normal osteoclast morphology. The data indicate that an important component of the inhibitory effects of CsA and FK506 on marrow-derived osteoclasts is the induction of apoptosis.
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PMID:Cyclosporine A and FK506 induce osteoclast apoptosis in mouse bone marrow cell cultures. 1520 40

To clarify the molecular basis of the cytoprotective properties of immunophilin ligands (IPLs), the anti-apoptotic effects of IPLs were determined in human glioma U251 cells. GPI1046 and V10367, non-immunosuppressive IPLs (NI-IPLs), as well as FK506, an immunosuppressive IPL (I-IPL), had cytoprotective effects against hydrogen peroxide (H20O)-induced apoptotic cell death in U251 cells. H2O2 increased both the ratio of bax/bcl-2 and the p53 mRNA expression. However, pre-treatment with FK506 and V10367 significantly prevented any increase in this ratio or p53 mRNA expression. GPI1046 also reduced the ratio of bax/bcl-2 to the normal level. In addition, H2O2 significantly increased activities of all three caspases, caspase-3, caspase-8, and caspase-9, in comparison with non-H2O2 controls. However, FK506 prevented the increase of these caspase activities. On the other hand, it is well-known that glutathione (GSH) and neurotrophic factor (NTF) is related to the induction of apoptosis in neuronal cells. In U251 cells, FK506, GPI1046 and V10367 had GSH-activating and NTF-activating effects. Thus, the immunosuppressive effect is not essential for the cytoprotective properties of IPLs, and IPLs have multiple beneficial properties such as the anti-apoptotic effect, GSH-activating effect, and NTF-activating effect, although the anti-apoptotic effect of NI-IPLs is independent of the regulation of apoptotic activators such as caspase-3.
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PMID:Molecular basis of anti-apoptotic effect of immunophilin ligands on hydrogen peroxide-induced apoptosis in human glioma cells. 1526 Jan 30


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