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

D-galactosamine (D-GalN) toxicity is a useful experimental model of liver failure in human. It has been previously observed that PGE1 treatment reduced necrosis and apoptosis induced by D-GalN in rats. Primary cultured rat hepatocytes were used to evaluate if intracellular oxidative stress was involved during the induction of apoptosis and necrosis by D-GalN (0-40mM). Also, the present study investigated if PGE1 (1 microM) was equally potent reducing both types of cell death. The presence of hypodiploid cells, DNA fragmentation and caspase-3 activation were used as a marker of hepatocyte apoptosis. Necrosis was measured by lactate dehydrogenase (LDH) release. Oxidative stress was evaluated by the intracellular production of hydrogen peroxide (H2O2), the disturbances on the mitochondrial transmembrane potential (MTP), thiobarbituric-reacting substances (TBARS) release and the GSH/GSSG ratio. Data showed that intermediate range of D-GalN concentrations (2.5-10mM) induced apoptosis in association with a moderate oxidative stress. High D-GalN concentration (40 mM) induced a reduction of all parameters associated with apoptosis and enhanced all those related to necrosis and intracellular oxidative stress, including a reduction of GSH/GSSG ratio and MTP in comparison with D-GalN (2.5-10 mM)-treated cells. Although PGE1 reduced apoptosis induced by D-GalN, it was not able to reduce the oxidative stress and cell necrosis induced by the hepatotoxin in spite to its ability to abolish the GSH depletion.
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PMID:PGE1 protection against apoptosis induced by D-galactosamine is not related to the modulation of intracellular free radical production in primary culture of rat hepatocytes. 1207 54

Preeclampsia is a severe disorder of human pregnancy characterized by generalized activation of maternal endothelial cells. Oxidative stress of the placenta is considered a key intermediary step, precipitating deportation of apoptotic fragments into the maternal circulation, but the cause remains unknown. We hypothesize that intermittent placental perfusion, secondary to deficient trophoblast invasion of the endometrial arteries, leads to an ischemia-reperfusion-type insult. We therefore tested whether hypoxia-reoxygenation (H/R) in vitro stimulates apoptosis in human placental tissues compared with controls kept hypoxic or normoxic throughout. After H/R, release of cytochrome c from mitochondria was significantly increased and was associated with intense immunolabeling for active caspase 3 in the syncytiotrophoblast and fetal endothelial cells. There was also increased labeling of syncytiotrophoblastic nuclei for cleaved poly (ADP-ribose) polymerase (PARP), and higher cytosolic concentrations of cleaved PARP fragment were detected by Western blot. Syncytiotrophoblastic nuclei displayed increased chromatin condensation, and a significantly greater percentage was TUNEL positive. These changes were accompanied by increased lactate dehydrogenase release into the medium. Preadministration of the free radical scavenger, desferrioxamine, reduced cytochrome c release and the TUNEL-positive index, suggesting generation of hydroxyl radicals mediates these processes. By contrast, hypoxia alone caused a smaller increase in the TUNEL-positive index, and the majority of syncytiotrophoblastic nuclei displayed karyolysis, whereas normoxic controls remained euchromatic. We conclude that H/R stimulates apoptotic changes within the syncytiotrophoblast, whereas hypoxia principally induces necrosis. The quality of placental perfusion may therefore be a more important factor in the pathophysiology of preeclampsia than the absolute quantity.
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PMID:Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. 1208 65

Consumption of cycad seed products (Cycas circinalis) is one of the strongest epidemiological links to the Guamian neurological disorder amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), however, the putative toxin which causes neurodegeneration has never been identified definitively. To reexamine this issue, 6-7-mo-old, male CD-1 mice were assessed for motor and cognitive behaviours during and following feeding with pellets made from washed cycad flour. Cycad-fed animals showed early evidence of progressive motor and cognitive dysfunctions. Neurodegeneration measured using TUNEL and caspase-3 labeling was found in neocortex, various hippocampal fields, substantia nigra, olfactory bulb, and spinal cord. In vitro studies using rat neocortex have identified toxic compounds in washed cycad flour that induce depolarizing field potentials and lead to release of lactate dehydrogenase (LDH), both blocked by AP5. High-performance liquid chromatography (HPLC)/mass spectrometry of cycad flour samples failed to show appreciable amounts of other known cycad toxins, cycasin, MAM, or BMAA; only trace amounts of BOAA were present. Isolation procedures employing these techniques identified the most toxic component as beta-sitosterol beta-D-glucoside (BSSG). The present data suggest that a neurotoxin, or a toxic metabolite, not previously identified in cycad, is able to gain access to central nervous system (CNS) resulting in neurodegeneration of specific neural populations and in motor and cognitive dysfunctions. These data are consistent with a number of major features of ALS-PDC in humans.
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PMID:Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. 1209 62

The factors responsible for ALS-parkinsonism dementia complex (ALS-PDC), the unique neurological disorder of Guam, remain unresolved, but identification of causal factors could lead to clues for related neurodegenerative disorders elsewhere. Earlier studies focused on the consumption and toxicity of the seed of Cycas circinalis, a traditional staple of the indigenous diet, but found no convincing evidence for toxin-linked neurodegeneration. We have reassessed the issue in a series of in vitro bioassays designed to isolate non-water soluble compounds from washed cycad flour and have identified three sterol beta-d-glucosides as potential neurotoxins. These compounds give depolarizing field potentials in cortical slices, induce alterations in the activity of specific protein kinases, and cause release of glutamate. They are also highly toxic, leading to release of lactate dehydrogenase (LDH). Theaglycone form, however, is non-toxic. NMDA receptor antagonists block the actions of the sterol glucosides, but do not compete for binding to the NMDA receptor. The most probable mechanism leading to cell death may involve glutamate neuro/excitotoxicity. Mice fed cycad seed flour containing the isolated sterol glucosides show behavioral and neuropathological outcomes, including increased TdT-mediated biotin-dUTP nick-end labelling (TUNEL) positivity in various CNS regions. Astrocytes in culture showed increased caspase-3 labeling after exposure to sterol glucosides. The present results support the hypothesis that cycad consumption may be an important factor in the etiology of ALS-PDC and further suggest that some sterol glucosides may be involved in other neurodegenerative disorders.
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PMID:Isolation of various forms of sterol beta-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for ALS-parkinsonism dementia complex. 1215 76

A missense mutation (N1411) in Presenilin-2 (PS-2) gene is associated with early-onset familial Alzheimer's disease. In this study, SK-N-SH human neuroblastoma cells were transfected with wild-type and mutant PS-2 gene to examine presenilin-2 effects on apoptosis. Serum deprivation resulted in enhanced apoptosis in mutant PS-2 comparing with wild-type PS-2. Similarly, mutant PS-2 induced lactate dehydrogenase release to greater extent than wild-type PS-2. Time course experiment demonstrated that the increase in caspase-3-like activity was more pronounced and accelerated in mutant PS-2, compared to wild-type PS-2. While a significant decrease in bcl-2, an anti-apoptotic molecule, occurred in the cells overexpressing mutant PS-2, no significant change was observed in bax, a pro-apoptotic molecule, as compared with the cells overexpressing wild-type PS-2. Our study demonstrated that mutant PS-2 induces apoptosis accompanied by increased caspase-3-like activity and decreased bcl-2 expression in neuronal cells after serum-deprivation.
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PMID:N141I mutant presenilin-2 gene enhances neuronal cell death and decreases bcl-2 expression. 1217 18

We previously reported that adrenomedullin produced by cardiac myocytes acts as a local modulator in some cardiac disorders. However, the role of adrenomedullin (AM) in cardiomyocyte apoptosis remains to be clarified. The present study investigated the effect of AM on doxorubicin-induced cardiac myocyte apoptosis. Doxorubicin increased the number of cells with pyknotic nuclei and lactate dehydrogenase release, and AM dose-dependently (10(-10)-10(-8)6 M) inhibited these increases produced by doxorubicin. Treatment with AM also suppressed doxorubicin-induced DNA fragmentation and caspase-3 activation. 8-Bromo-cAMP, a cAMP analog, mimicked these antiapoptotic effects of AM. An AM/calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) and a protein kinase A inhibitor H89 attenuated the antiapoptotic effect of AM. CGRP-(8-37) and H89 had no apoptotic effect alone, but accelerated doxorubicin-induced apoptosis. Under serum-free conditions, AM secretion into the culture medium and expression of AM mRNA were significantly increased after treatment with doxorubicin. Hydrogen peroxide scavenger catalase and antioxidant N-acetyl-L-cysteine inhibited the doxorubicin-mediated increase in AM secretion and its gene expression. These results indicate that AM inhibits doxorubicin-induced cardiac myocyte apoptosis through a cAMP-dependent mechanism and suggest that augmented production of AM by doxorubicin has an endogenous antiapoptotic effect. AM, as an autocrine factor, may play a protective role against cardiomyocyte injury by doxorubicin.
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PMID:Adrenomedullin inhibits doxorubicin-induced cultured rat cardiac myocyte apoptosis via a cAMP-dependent mechanism. 1219 65

Although prior heat stress (HS) inhibits apoptosis in adenosine phosphate (ATP)-depleted renal epithelial cells (REC), the specific stress protein(s) responsible for cytoprotection have not been identified. The present study evaluated the hypothesis that Hsp72, the major inducible member of the Hsp70 family, protects REC against ATP depletion injury. In the presence of isopropyl-beta-D-thiogalactoside (IPTG), a stable line of transfected opossum kidney cells was induced to overexpress human Hsp72 tagged with the flag epitope. Transfected cells from 2 clones that expressed Hsp72 at a level comparable with wild-type cells were subjected to transient heat stress (43 degrees C for 1 hour). To assess the cytoprotective effect of Hsp72, transfected cells were subjected to transient ATP depletion followed by recovery in the presence vs the absence of IPTG. ATP depletion resulted in nuclear chromatin condensation without cell membrane injury (ie, minimal leak of lactate dehydrogenase) and activation of caspase-3, confirming that apoptosis is the major cause of cell death. In both clones cell survival 1-3 days after ATP depletion was significantly improved in the presence of IPTG. Selective overexpression of Hsp72 reproduced nearly 60% of the protective effect on the survival afforded by prior heat stress. In transfected cells subjected to ATP depletion, Hsp72 overexpression significantly inhibited caspase activation. In native renal cells brief ATP depletion markedly induced the expression of native Hsp72, a finding identical to that observed after renal ischemia in vivo. These studies are the first to directly show that Hsp72 per se mediates acquired resistance to ischemic injury in REC.
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PMID:Hsp72 expression enhances survival in adenosine triphosphate-depleted renal epithelial cells. 1238 Jun 81

Increased cell volume, accumulation of lipid droplets in the cytoplasm, and nuclear degeneration are phenomena indicating terminal differentiation of human sebocytes followed by holocrine secretion and cell death. The molecular pathways of natural and induced sebocyte elimination are still unknown, however. In this study, SZ95 sebocytes were found to exhibit DNA fragmentation after a 6 h culture followed by increased lactate dehydrogenase release after 24 h, indicating cell damage. With the help of morphologic studies and using Oil Red detection of cellular lipids, cell enlargement, accumulation of lipid droplets in the cytoplasm, and nuclear fragmentation could be observed under treatment with arachidonic acid. Staurosporine, a potent inhibitor of phospholipid Ca2+-dependent protein kinase, increased externalized phosphatidylserine levels on SZ95 sebocytes, detected by annexin V/propidium iodide flow cytometry, as early as after 1 h, whereas dose-dependent reduction of bcl-2 mRNA and protein expression, enhanced DNA fragmentation, and increased caspase 3 levels, detected by caspase 3 inhibitor/propidium iodide flow cytometry, were found after 6 h of treatment. SZ95 sebocyte death was detected as early as after 6 h of SZ95 sebocyte treatment with high staurosporine concentrations (10(-6)-10(-5) M). 5Alpha-dihydrotestosterone (10(-8)-10(-5) M) did not affect externalized phosphatidylserine levels and DNA fragmentation in SZ95 sebocytes but slightly decreased lactate dehydrogenase cell release. Neither acitretin nor 13-cis retinoic acid (10(-8)-10(-5) M) affected externalized phosphatidylserine levels, DNA fragmentation, and lactate dehydrogenase cell release, despite the increased caspase 3 levels under treatment with 13-cis retinoic acid. The combined staurosporine and 13-cis retinoic acid treatment enhanced DNA fragmentation in SZ95 sebocytes to the same magnitude as in cells only treated with staurosporine. In conclusion, SZ95 sebocytes in vitro undergo apoptosis, which can be enhanced by the terminal differentiation inductor arachidonic acid or by staurosporine and leads to cell death. 5Alpha-dihydrotestosterone inhibits SZ95 sebocyte death without involving apoptotic pathways, and retinoids did not affect the programmed death of human sebocytes. The latter result fits well with the currently reported inability of normal skin cells to undergo apoptosis after treatment with retinoids, in contrast to their malignant counterparts.
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PMID:Differentiation and apoptosis in human immortalized sebocytes. 1254 19

In this study we assessed the effect of acteoside that significantly improved cell viability and inhibited lactate dehydrogenase (LDH) release. Furthermore acteoside prevented a neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+)-induced apoptosis in CGNs. Accordingly, our flow cytometric analysis of CGNs after acteoside treatment revealed a decrease in the number of the MPP+-induced apoptotic cells (P < 0.001). Western blot analysis demonstrated that acteoside inhibits the active caspase-3 fragment (17 kDa) (P < 0.001) and the proteolytic poly (ADP-ribose) polymerase (PARP) fragment (85 kDa) expression (P < 0.001) following MPP + treatment in CGNs. We conclude that acteoside prevents the MPP+-induced apoptosis and inhibits the apoptosis-related pathway.
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PMID:Acteoside from Cistanche salsa inhibits apoptosis by 1-methyl-4-phenylpyridinium ion in cerebellar granule neurons. 1256 82

(1) Cadmium is an extremely toxic metal commonly found in industrial workplaces, a food contaminant and a major component of cigarette smoke. Cadmium can severely damage several organs, including the brain. In this work, we have studied both the cadmium toxicity on rat cortical neurons in culture and the possible protective effect of serum. (2) Our results indicate that: (1) cadmium is taken up by the neurons in a dose and serum dependent way; (2) cadmium, at concentrations from 1 micro M or 10 micro M (depending on the absence or the presence of serum) up to 100 micro M, decreases the metabolic capacity, which was evaluated by the XTT (tetrazolium salt) test; (3) cadmium induces apoptosis and LDH (lactate dehydrogenase) release in a dose dependent way; (4) in a serum-free medium, the cadmium-induced apoptosis is accompanied by caspase-3 activation; (5) both the caspase-3 activation and the cadmium-induced apoptosis are reversed by N-acethyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO), a selective caspase-3 inhibitor, indicating that the caspase-3 pathway is involved in cadmium-induced apoptosis in cortical neurons; and (6) the cadmium concentrations which produce caspase-3 activation do not modify the intracellular ATP levels; however, higher cadmium concentrations lead to both intracellular ATP depletion and ATP release, but do not increase the caspase-3 activity, indicating that cadmium also produces cellular death by necrosis. (3) These results suggest that cadmium induces either apoptosis or necrosis in rat cortical neurons, depending on the cadmium concentration.
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PMID:Apoptosis and necrosis: two distinct events induced by cadmium in cortical neurons in culture. 1264 92


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