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: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptotic death caused by diseases or toxic insults is preceded and determined by endoplasmic reticulum dysfunction and altered intraluminar calcium homeostasis in many different cell types. With the present study we have explored the possibility that the ER stress could be involved also in apoptotic death induced by serum deprivation in neuronal cells. We have chosen as a model of study the cell line HN9.10e, constituted by immortalized hippocampal neuroblasts. The Ca(++) concentration in the lumen of the ER has been evaluated by using the low affinity Ca(++) probe Mag-fluo-4. We show that serum deprivation lowers the ER Ca(++) concentration with a time course closely related to the increase of apoptosis incidence. Serum deprivation also enhances the expression of a well-known marker of ER stress, the glucose-regulated protein-78 (GRP-78), a member of the heat shock/stress response protein family. Moreover, in serum-deprived neuroblasts, following GRP-78 up-regulation, the ER-associated procaspase-12 is cleaved with a time course which parallels the ER calcium loss while activation of caspase-3 is a later event. Depletion of ER Ca(++) by thapsigargin, a specific inhibitor of the ER-associated Ca(++) ATPase, also produces caspase-12 processing and apoptotic cell death, whereas agents capable of reducing the ER calcium loss protect the cells from serum-deprivation-induced apoptosis. These findings indicate that, in hippocampal neuroblasts, Ca(++) mobilization from ER and caspase-12 activation are components of the molecular pathway that leads to apoptosis triggered by serum deprivation and may constitute an amplifying loop of the mitochondrial pathway.
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PMID:Serum-withdrawal-dependent apoptosis of hippocampal neuroblasts involves Ca++ release by endoplasmic reticulum and caspase-12 activation. 1739 92

Calcium ion is essential for cellular functions including signal transduction. Uncontrolled calcium stress has been linked causally to a variety of neurodegenerative diseases. Thapsigargin, which inhibits Ca(2+)-ATPase in the endoplasmic reticulum (ER) and blocks the sequestration of calcium by the ER, induced apoptotic cell death (chromatin condensation and nuclear fragmentation) accompanied by GRP78 protein expression and caspase-3 activation in rat fetal cortical neurons (days in vitro 9-10). Blockade of N-methyl-D-aspartate (NMDA) receptors with NMDA antagonists induced apoptosis without GRP78 protein expression. Apoptosis accompanied both caspase-9 and caspase-3 activation. We then examined whether GSK-3 is involved in thapsigargin-induced cell death by using GSK-3 inhibitors. We assayed the effects of selective GSK-3 inhibitors, SB216763, alsterpaullone and 1-azakenpaullone, on thapsigargin-induced apoptosis. These inhibitors completely protected cells from thapsigargin-induced apoptosis. In addition, GSK-3 inhibitors inhibited caspase-9 and caspase-3 activation accompanied by thapsigargin-induced apoptosis. These results suggest that thapsigargin induces caspase-dependent apoptosis mediated through GSK-3beta activation in rat cortical neurons.
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PMID:Caspase-dependent apoptosis induced by thapsigargin was prevented by glycogen synthase kinase-3 inhibitors in cultured rat cortical neurons. 1740 51

Maintenance of Ca2+ homeostasis is essential for normal cellular function and survival. Recent evidences suggest that Ca2+ is also an important player of apoptosis. We demonstrated that the plasma membrane Ca2+ ATPase (PMCA) isoform 4b, a key element of cellular Ca2+ homeostasis, was cleaved by caspase-3 during the course of apoptosis. This cleavage of PMCA removed the entire regulatory region from the C terminus, leaving behind a 120-kDa catalytic fragment. Since loss of PMCA activity could lead to intracellular Ca2+ overload and consequently necrotic cell death, an important question is whether the apoptotic fragment of PMCA retains full activity or it is inactivated. To address this question, we constructed a C-terminally truncated mutant that corresponded to the caspase-3 fragment of PMCA4b and showed that it was fully and constitutively active. This mutant was targeted properly to the plasma membrane when it was expressed stably or transiently in several different cell lines. We followed truncation of PMCA during apoptosis induced by mitochondrial or receptor-mediated pathways and found that a similar fragment of 120 kDa was formed and remained intact for several hours after treatment. We have also demonstrated that the caspase-3 cleavage site is an important structural element of PMCA and found that the accessibility of the caspase-3 site depended strongly on the conformational state of the protein.
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PMID:Cleavage of the plasma membrane Ca+ATPase during apoptosis. 1744 84

We previously reported that orthovanadate composed of vanadate (V(5+)) activates phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling through inhibition of protein tyrosine phosphatases, thereby eliciting neuroprotection in brain ischemia/reperfusion injury. However, therapeutic doses of orthovanadate are associated with diarrhea due to inhibition of ATPase. By contrast, vanadyl (V(4+)) organic compounds show low cytotoxicity. Since both vanadate and vanadyl inhibit protein tyrosine phosphatases, we tested whether bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) [VO(OPT)] in a vanadyl form elicits a neuroprotection in brain ischemia. In a mouse transient middle cerebral artery occlusion (MCAO) model, pre- and post-treatments with VO(OPT) significantly reduced infarct volume in a dose-dependent manner. Like orthovanadate, activation of the PI3K/Akt pathway mediated neuroprotective action. VO(OPT) treatment inhibited reduced Akt phosphorylation at Ser-473 following brain ischemia and restored decreased phosphorylation of forkhead box class O (FOXO) family members such as FKHR, FKHRL1, and AFX. Consistent with inhibition of FOXO dephosphorylation, VO(OPT) treatment blocked elevated expression of Fas-ligand, Bim and active caspase-3 24 h after ischemia/reperfusion. Taken together, a vanadyl compound, VO(OPT) elicits neuroprotective effects on brain ischemia/reperfusion injury without apparent side effects.
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PMID:Activation of phosphatidylinositol 3-kinase/protein kinase B pathway by a vanadyl compound mediates its neuroprotective effect in mouse brain ischemia. 1762 7

Apoptotic pathways represent the mechanisms of programmed cell death that counteract initiation and progression of cancer. New therapeutic targets are currently being explored on the basis of our detailed knowledge of the mechanisms and factors involved in apoptosis. In recent years, numerous proteins have been identified, which act as tumour suppressors or as oncoproteins in caspase-independent programmed cell death mechanisms, in which lysosomes are implicated for their lysosomal functions in cancer, mainly attributed to lysosomal proteinases, particularly the cathepsins. If cathepsins are released from the lysosomal lumen into the cytoplasm they initiate a number of processes that may cause either apoptotic or non-apoptotic (necrotic) cell death. The release of cathepsin D into the cytoplasm by vacuolar-type ATPase (V-ATPase) inhibitors produces the characteristic signs of apoptotic cell death, including caspase-3 activation and DNA laddering. For the destabilisation of the lysosomal membrane, two methods are available having therapeutic potential: the formation of reactive oxygen species (ROS) by irradiation or by enzymatic reactions and the lysosomal membrane permeabilisation by lysosomotropic compounds. Findings also suggest that the deregulation of polyamine metabolism or cytotoxic metabolites generated from the oxidative deamination of spermine by amine oxidases in association with lysosomotropic compounds may induce apoptosis. Cross-resistance of cells to cytotoxic actions of a wide variety of natural and synthetic anticancer drugs is the well-known phenomenon called multidrug resistance (MDR), due to glycoprotein P that functions as an ATP-dependent pump. The sensitisation of tumour cells to anticancer drugs by lysosomotropic compounds, and particularly the sensitisation of MDR-resistant cells recommend scrutinizing the potential of lysosomotropic drugs in cancer therapy.
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PMID:Lysosomotropic compounds and spermine enzymatic oxidation products in cancer therapy (review). 1767 72

It is clinicopathologically important to elucidate the cell kinetics for the maintenance of normal gastric epithelium. In a rat gastric mucosa isolated after stimulation, a number of cells were exfoliated into the gastric lumen of the pit region. The present study was undertaken to clarify the origin of exfoliated cells and their histochemical profiles by taking the advantages of cryotechniques. As results, most of the exfoliated cells were identified as pit-parietal cells labeled with both peanut-lectin and anti-H+/K+-ATPase antibody. Quantitative analysis verified a time-dependent increase in the number of exfoliated cells in the gastric mucosa isolated after stimulation. The exfoliated cells exhibited a diffuse intracellular staining for E-cadherin, suggesting a dissociation of the adhesion molecule prior to the cell exfoliation. It should be noted that most of the exfoliated cells were negative to the apoptotic markers (TUNEL staining and caspase-3). Ultrastructurally, autophagosome-like structures consisting of H+/K+-ATPase positive membranes were frequently seen in the exfoliated pit-parietal cells. In addition, the pit-parietal cell exfoliation was accompanied by sealing of their basal portion with the cytoplasmic processes of adjacent surface mucous cells. The present morphological findings provide a new insight into the cell kinetics in the gastric epithelium in vitro.
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PMID:Exfoliation of gastric pit-parietal cells into the gastric lumen associated with a stimulation of isolated rat gastric mucosa in vitro: a morphological study by the application of cryotechniques. 1829 80

Several research teams have proposed that shrinkage and swelling in cells undergoing apoptosis and oncosis are not only the earliest morphological markers of the two modes of cell death but are also obligatory steps in the development of the death machinery. We examined this hypothesis as well as the role of monovalent cations as major intracellular osmolytes using vascular smooth muscle cells (VSMC) from the rat aorta and C7-MDCK cells derived from the Madin-Darby canine kidney. 48-hr inhibition of the Na(+)-K+ pump with ouabain did not affect VSMC survival and delayed serum deprivation-induced apoptosis at a step upstream of caspase-3 via elevation of the [Na+]i/[K+]i ratio and the expression of Na+ i-sensitive antiapoptotic genes including mortalin. Transient and modest (15-20%) shrinkage observed in serum-deprived VSMC did not contribute to triggering of the apoptotic machinery. In contrast to VSMC, ouabain led to oncosis of C7-MDCK cells, indicated by swelling and resistance to the pan-caspase inhibitor z-VAD.fmk. In these cells, the death signal was mediated by interaction of ouabain with the Na(+)-K(+)-ATPase alpha-subunit but was independent of the inhibition of Na(+)-K+ pump-mediated ion fluxes and elevation of the [Na+]i/[K+]i ratio.
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PMID:Apoptosis vs. oncosis: role of cell volume and intracellular monovalent cations. 1872 43

Diets high in soy are neuroprotective in experimental stroke. This protective effect is hypothesized to be mediated by phytoestrogens contained in soy, because some of these compounds have neuroprotective effects in in vitro models of cell death. We tested the ability of the soy phytoestrogens genistein, daidzein, and the daidzein metabolite equol to protect embryonic rat primary cortical neurons from ischemic-like injury in vitro at doses typical of circulating concentrations in human populations (0.1-1 microM). All three phytoestrogens inhibited lactate dehydrogenase (LDH) release from cells exposed to glutamate toxicity or the calcium-ATPase inhibitor, thapsigargin. In cells exposed to hypoxia or oxygen-glucose deprivation (OGD), pretreatment with the phytoestrogens inhibited cell death in an estrogen receptor (ER) dependent manner. Although OGD results in multiple modes of cell death, examination of alpha-spectrin cleavage and caspase-3 activation revealed that the phytoestrogens were able to inhibit apoptotic cell death in this model. In addition, blockade of phosphoinositide 3-kinase prevented the protective effects of genistein and daidzein, and blockade of mitogen-activated protein kinase prevented genistein-dependent neuroprotection. These results suggest that pretreatment with dietary levels of soy phytoestrogens can mimic neuroprotective effects observed with estrogen and appear to use the same ER-kinase pathways to inhibit apoptotic cell death.
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PMID:Soy phytoestrogens are neuroprotective against stroke-like injury in vitro. 1897 94

Accumulating evidence suggests that endoplasmic reticulum (ER) stress by mechanisms that include ER Ca(2+) depletion via NO-dependent down-regulation of sarcoendoplasmic reticulum Ca(2+) ATPase 2b (SERCA2b) contributes to beta-cell death in type 1 diabetes. To clarify whether the molecular pathways elicited by NO and ER Ca(2+) depletion differ, we here compare the direct effects of NO, in the form of the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), with the effects of SERCA2 inhibitor thapsigargin (TG) on MAPK, nuclear factor kappaB (NFkappaB), Bcl-2 proteins, ER stress, and apoptosis. Exposure of INS-1E cells to TG or SNAP caused caspase-3 cleavage and apoptosis. Both TG and SNAP induced activation of the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP). However, other classical ER stress-induced markers such as up-regulation of ER chaperone Bip and alternative splicing of the transcription factor Xbp-1 were exclusively activated by TG. TG exposure caused NFkappaB activation, as assessed by IkappaB degradation and NFkappaB DNA binding. Inhibition of NFkappaB or the Bcl-2 family member Bax pathways protected beta-cells against TG- but not SNAP-induced beta-cell death. These data suggest that NO generation and direct SERCA2 inhibition cause two quantitative and qualitative different forms of ER stress. In contrast to NO, direct ER stress induced by SERCA inhibition causes activation of ER stress signaling pathways and elicit proapoptotic signaling via NFkappaB and Bax.
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PMID:Inhibition of nuclear factor-kappaB or Bax prevents endoplasmic reticulum stress- but not nitric oxide-mediated apoptosis in INS-1E cells. 1955 21

Apoptotic effects of protocatechuic acid (PCA) at 1, 2, 4, 8 micromol/L on human breast cancer MCF7 cell, lung cancer A549 cell, HepG2 cell, cervix HeLa cell, and prostate cancer LNCaP cell were examined. Results showed that PCA concentration-dependently decreased cell viability, increased lactate dehydrogenase leakage, enhanced DNA fragmentation, reduced mitochondrial membrane potential, and lowered Na(+)-K(+)-ATPase activity for these cancer cells (P < 0.05). PCA also concentration-dependently elevated caspase-3 activity in five cancer cells (P < 0.05), but this agent at 2-8 micromol/L significantly increased caspase-8 activity (P < 0.05). PCA concentration-dependently decreased intercellular adhesion molecule level in test cancer cells (P < 0.05) but significantly inhibited cell adhesion at 2-8 micromol/L (P < 0.05). PCA also concentration-dependently lowered the levels of interleukin (IL)-6 and IL-8 in five cancer cells (P < 0.05), but this agent at 2-8 micromol/L significantly suppressed vascular endothelial growth factor production (P < 0.05). These findings suggest that PCA is a potent anticancer agent to cause apoptosis or retard invasion and metastasis in these five cancer cells.
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PMID:Apoptotic effects of protocatechuic acid in human breast, lung, liver, cervix, and prostate cancer cells: potential mechanisms of action. 1960 77


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