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)

We studied the effect of over-expression of Bcl-xl on cell death of the monocytic cell line U937. Over-expression of Bcl-xl inhibits apoptotic changes induced by Etoposide including cytochrome-c release, caspase-3 activation and DNA fragmentation. However, Etoposide treatment resulted in cell death in U937 cells over-expressing Bcl-xl, which had a necrotic-like phenotype with no evidence of caspase-3 activation. On the other hand, Bcl-xl over-expression did not prevent U937 cell apoptotic cell death in response to the specific proteasome inhibitor Lactacystin. There was no significant change in the level of Bcl-xl or evidence of its cleavage. These results suggest that Bcl-xl over-expression does not confer protection against cell death in U937 cells and that Lactacystin utilizes an apoptotic pathway not susceptible to Bcl-xl inhibition.
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PMID:Differential effect of Bcl-xl over-expression on cell death of the monocytic leukemia cell line U937. 1255 12

There is substantial evidence that cytokines induce apoptosis of vascular smooth muscle cells (VSMCs) in atherosclerosis. Its regulation, however, is not completely defined. The aim of this study is to investigate whether proteasome activity is related with apoptosis in VSMCs by tumor necrosis factor-alpha (TNF-alpha). Rat aorta smooth muscle cells were treated with TNF-alpha and proteasome inhibitor MG132 and then cell death was determined by morphology, viability, and DNA fragmentation. MG132 or TNF-alpha alone did not induce cell death. In contrast, co-treatment of TNF-alpha and proteasome inhibitor induced death and DNA degradation in VSMCs, suggesting proteasome inhibitor enhanced death activity of TNF-alpha. The death was not blocked by ascorbic acid but by nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine. Both caspase-3 and -8 were activated during the death by the proteasome inhibitor and TNF-alpha. The death was effectively blocked by the caspase-3 inhibitor z-DEVD-fmk, suggesting a role of caspase-3 in the death. Nonetheless, there were no significant alterations in the level of Bcl-2, Bcl-X(L), Bax and Bak by the proteasome inhibitor, nor any evidence of cytochrome (cyt) c release into cytosol from dying cells, suggesting that cyt c is not involved. These results suggest that proteasome inhibition potentiates TNF-mediated death in VSMCs in a cyt c-independent pathway. The present study proposes a new mechanism by which VSMCs undergo death by cytokines.
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PMID:Enhancement of TNF-alpha-mediated cell death in vascular smooth muscle cells through cytochrome c-independent pathway by the proteasome inhibitor. 1256 Jan 2

Clinical reports suggest that acute ethanol intoxication is often associated with lymphopenia. Previously, ethanol was reported to invoke thymocyte apoptosis. We studied the effect of ethanol on T cell apoptosis. In addition, we evaluated the molecular mechanism of ethanol-induced T cell apoptosis. Human T cells harvested from healthy subjects after an alcohol drinking binge showed enhanced T cell apoptosis (before, 0.4 +/- 0.2% versus after, 19.6 +/- 2.5% apoptotic lymphocytes/field; P < 0.001). In in vitro studies, ethanol in a concentration of 50 mm and higher enhanced the apoptosis of Jurkat cells. DNA isolated from ethanol-treated Jurkat cells displayed integer multiples of 180 base pairs. Ethanol decreased Jurkat cell expression of Bcl-2, whereas ethanol increased Jurkat cell expression of Bax. Jurkat cells treated with ethanol also showed translocation of cytochrome C into cytosol. Moreover, a caspase-9 inhibitor partially inhibited ethanol-induced Jurkat cell apoptosis. In in vivo studies, after binge drinking, T cell expression of Bcl-2 also decreased. In addition, binge drinking induced the cleavage of caspase-3, suggesting activation of caspase-3 in T cells. These results suggest that ethanol promotes T cell apoptosis through the activation of intrinsic or mitochondrial pathway.
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PMID:Ethanol promotes T cell apoptosis through the mitochondrial pathway. 1260 97

The cellular and molecular mechanisms of cold storage-ATN are not well characterized. In our earlier studies, cold storage caused necrosis of human proximal tubular epithelial (RPTE) cells, whereas apoptosis was prominent during rewarming. An intriguing finding was the pronounced swelling of the mitochondria in the cold, which promoted us to further characterize its role in rewarming-associated apoptosis. Human proximal tubular epithelial cells were cold stored in University of Wisconsin (UW) solution for 48 h followed by 24 h of rewarming in regular cell culture medium. During the cold storage, there was no significant change in the Bcl-2 to Bax protein ratio, mitochondrial location of cytochrome C or caspse-3 activity. However, during rewarming, the Bcl-2 to Bax ratio increased, cytochrome C was translocated to cytosol, and caspase-3 was activated: events and timing were consistent with the occurrence of apoptosis during rewarming. In a time-course experiment, mitochondrial swelling was discernable by electron microscopy as early as at 2 h. Cold storage of isolated-mitochondria for 2 h was attended by an increase in the opening of the permeability transition pores (PTP), suggesting PTP opening as an early mechanism for mitochondrial swelling. Addition of antioxidants (deferoxamine or 2-methyaminochroman) to the storage solution suppressed mitochondrial pore opening and swelling, Bcl-2 to Bax ratio increase, cytochrome C translocation, caspase-3 activation as well as rewarming-induced apoptosis. Our data demonstrate for the first time that apoptosis following cold storage and rewarming of human renal tubular cells is accompanied by specific mitochondrial events, and that these events and apoptosis can be suppressed by adding antioxidants to the cold storage solution.
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PMID:Involvement of the mitochondrial pathway in cold storage and rewarming-associated apoptosis of human renal proximal tubular cells. 1261 81

A neuropathological study of Holstein-Friesian calves with spinal muscular atrophy (SMA) demonstrated decreased numbers of motor neurons in the brachial and lumbo-sacral regions of the spinal cord, together with swelling and accumulation of phosphorylated neurofilaments, and neuronophagia in most of the remaining motor neurons. The pyramidal tracts, motor cortex and thalamus were not affected. Synaptophysin immunohistochemistry revealed a marked reduction of punctate terminals but only around swollen neurones, suggesting loss of terminal afferents on motor neurons at advanced stages of the degenerative process. An immunohistochemical study of proteins linked with cell death and cell survival demonstrated reduced expression of Fas, Fas-L, Bcl-2 and Bax in swollen motor neurons. Punctate cytochrome C immunoreactivity, consistent with mitochondrial localization, was detected in the soma of normal motor neurons, but not in swollen motor neurons. Finally, no labelling of motor neurons with antibodies to cleaved (active) caspase-3 (17kD) was detected, suggesting a lack of involvement of the apoptotic pathways in motor neuron death. Taken together, the present findings point to necrosis as a major cause of motor neuron death in the advanced stages of SMA in Holstein-Friesian calves.
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PMID:Cell death and decreased synaptic protein expression in the ventral horn of Holstein-Friesian calves with spinal muscular atrophy. 1263 90

The antitumor activity of a synthetic chenodeoxycholic acid derivative, HS-1200, on the p815 mastocytoma cell line was investigated. We present several lines of evidence indicating that HS-1200 at 35 microM induced apoptosis of p815 cells. Reduction of mitochondrial membrane potential, the release of cytochrome to cytosol, activation of caspase-3, nuclear condensation, production of poly(ADP-ribose) polymerase cleavage, generation of DNA fragmentation and nuclear condensation were demonstrated. Importantly, HS-1200 inhibited proteasome activity. Next, the combination treatment of HS-1200 or a proteasome inhibitor lactacystin was undertaken. Although the single treatment of 20 microM HS-1200 or 1 microM lactacystin induced apoptosis slightly, the combination treatment of them augmented prominently the extent of apoptosis. The combination therapy of HS-1200 and lactacystin could be potentially a therapeutic strategy reducing the extent and severity of treatment-related toxicity.
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PMID:Synthetic chenodeoxycholic acid derivative HS-1200-induced apoptosis of p815 mastocytoma cells is augmented by co-treatment with lactacystin. 1263 16

Emphysema is characterized by enlargement of the distal airspaces in the lungs due to destruction of alveolar walls. Alveolar endothelial and epithelial cell apoptosis induced by cigarette smoke is thought to be a possible mechanism for this cell loss. In contrast, our studies show that cigarette smoke condensate (CSC) induces necrosis in alveolar epithelial cells and human umbilical vein endothelial cells. Furthermore, study of the cell death pathway in a model system using Jurkat cells revealed that in addition to inducing necrosis, CSC inhibited apoptosis induced by staurosporine or Fas ligation, with both effects prevented by the antioxidants glutathione and dithiothreitol. Time course experiments revealed that CSC inhibited an early step in the caspase cascade, whereby caspase-3 was not activated. Moreover, cell-free reconstitution of the apoptosome in cytoplasmic extracts from CSC-treated cells, by addition of cytochrome-c and dATP, did not result in activation of caspases-3 or -9. Thus, smoke treatment may alter the levels of pro- and antiapoptogenic factors downstream of the mitochondria to inhibit active apoptosome formation. Therefore, unlike previous studies, cell death in response to cigarette smoke by necrosis and not apoptosis may be responsible for the loss of alveolar walls and inflammation observed in emphysema.
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PMID:Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. 1274 58

Cerebellar granule cells (CGC) cultured under 5mM KCl (K5) undergo apoptosis after 5 days in vitro (DIV). CGC death is reduced by chronic treatment with 25 mM KCl (K25) or NMDA. Also, when CGC cultured for 6-8 DIV in K25 are transferred to a K5 medium, cells die apoptotically. Moreover, Bcl-2 and Bcl-xL protect neurons from apoptosis, while Bax and Bcl-xS may act as proapototic proteins. It is suggested that these members of the Bcl-2 family may be involved in the cytochrome-c (cyt-c) release to the cytosol. Cytochrome-c is able to form a complex with other proteins to activate a cascade of proteases. In this work, we found that Bcl-2 levels in K5 cells did not show any change during 2-7 days in vitro (DIV); but cells grown with NMDA and K25 displayed an increase (55% approximately) of Bcl-2 from 4 DIV, as compared to control. Under these conditions, Bax levels showed a tendency to decrease with age under control cells and NMDA/K25 induced a reduction of approximately 10% in Bax levels from 4 DIV. On the other hand, in cells maintained in K25 during 7 DIV and then switched to a K5 medium, the levels of Bax showed a consistent decrease (30% after 8h). Under these conditions, the Bcl-2 levels did not show any significant change after 24h. Cytochrome-c levels were unaffected under K5, NMDA and K25 and only a marginal increase of cytochrome-c in the cytosol was detected at 6h after switching. We also found that caspase-9 was only activated under K25-deprivation meanwhile caspase-3 was involved in both protocols. These results suggest that the Bcl-2 family members, caspases activation and cytochrome-c release are involved in CGC death induced by K5 and their participation in this process could be different depending on neuronal maturation in culture.
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PMID:Mechanisms of cell death by deprivation of depolarizing conditions during cerebellar granule neurons maturation. 1282 Sep 87

We previously reported that dieldrin, one of the potential environmental risk factors for development of Parkinson's disease, induces apoptosis in dopaminergic cells by generating oxidative stress. Here, we demonstrate that the caspase-3-dependent proteolytic activation of protein kinase Cdelta (PKCdelta) mediates as well as regulates the dieldrin-induced apoptotic cascade in dopaminergic cells. Exposure of PC12 cells to dieldrin (100-300 microM) results in the rapid release of cytochrome C, followed by the activation of caspase-9 and caspase-3 in a time- and dose-dependent manner. The superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride significantly attenuates dieldrin-induced cytochrome C release, indicating that reactive oxygen species may contribute to the activation of pro-apoptotic factors. Interestingly, dieldrin proteolytically cleaves native PKCdelta into a 41 kDa catalytic subunit and a 38 kDa regulatory subunit to activate the kinase. The dieldrin-induced proteolytic cleavage of PKCdelta and induction of kinase activity are completely inhibited by pretreatment with 50-100 microM concentrations of the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK), indicating that the proteolytic activation of PKCdelta is caspase-3-dependent. Additionally, Z-VAD-FMK, Z-DEVD-FMK or the PKCdelta specific inhibitor rottlerin almost completely block dieldrin-induced DNA fragmentation. Because dieldrin dramatically increases (40-80-fold) caspase-3 activity, we examined whether proteolytically activated PKCdelta amplifies caspase-3 via positive feedback activation. The PKCdelta inhibitor rottlerin (3-20 microM) dose-dependently attenuates dieldrin-induced caspase-3 activity, suggesting positive feedback activation of caspase-3 by PKCdelta. Indeed, delivery of catalytically active recombinant PKCdelta via a protein delivery system significantly activates caspase-3 in PC12 cells. Finally, overexpression of the kinase-inactive PKCdelta(K376R) mutant in rat mesencephalic dopaminergic neuronal cells attenuates dieldrin-induced caspase-3 activity and DNA fragmentation, further confirming the pro-apoptotic function of PKCdelta in dopaminergic cells. Together, we conclude that caspase-3-dependent proteolytic activation of PKCdelta is a critical event in dieldrin-induced apoptotic cell death in dopaminergic cells.
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PMID:Dieldrin induces apoptosis by promoting caspase-3-dependent proteolytic cleavage of protein kinase Cdelta in dopaminergic cells: relevance to oxidative stress and dopaminergic degeneration. 1283 55

In recent years there has been an increasing interest in compounds present in foods that may prevent or slow the progression of chronic illnesses, such as cardiovascular disease, osteoporosis and cancer. Saponins have been reported to have important time-dependent anti-cancer properties. We have used a highly purified and characterized saponin fraction containing the soyasapogenol B glycosides (the 'B group' saponins) from soybeans (Glycine max L.) to demonstrate a reduction in SNB 19 human glioblastoma cell invasion (45% decrease compared to untreated cells) in vitro in a Matrigel invasion assay. We have also demonstrated that triterpenoid saponin induces apopotosis and affects mictochondiral function. Dose-dependent loss of mitochondrial trans-membrane potential in SNB 19 cells occurred with treatment, along with release of cytochrome c, processing of caspase-9, and -3 and specific cleavage of poly ADP-ribose polymerase (PARP), a substrate of caspase-3. The results suggest that the saponin fraction induces apoptosis in SNB19 human glioblastoma cells by stimulating cytochrome-c release and subsequent activation of a caspase cascade. Our observations clearly demonstrate the pro-apoptotic and anti-invasive activities of the soyasapogenol B glycosides from soybeans.
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PMID:Triterpenoids from Glycine max decrease invasiveness and induce caspase-mediated cell death in human SNB19 glioma cells. 1285 25


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