UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cell apoptosis contributes to atherosclerosis and may be exacerbated by oxidative stress. Results from clinical trials using antioxidant supplementation are equivocal and could be enhanced by antioxidants with additional non-antioxidant properties such as alpha -lipoic acid and alpha -tocopherol. The aim of this study was to investigate the effects of these antioxidants on cytoprotective pathways and endothelial apoptosis. Endothelial cells were incubated with alpha -lipoic acid and alpha -tocopherol, alone or in combination, prior to incubation with H(2)O(2) or staurosporine. alpha -lipoic acid pre-treatment alone increased caspase-3 activity in a dose-dependent manner. Both H(2)O(2) and staurosporine increased DNA fragmentation and caspase-3 activity and pre-treatment of cells with alpha -lipoic acid and/or alpha -tocopherol failed to prevent stress-induced apoptosis. Neither antioxidant treatments nor apoptotic inducers alone altered expressions of Bcl-2, Bax, HSP70 or pERK1/2 or pJNK. alpha -lipoic decreased pERK2 in staurosporine-treated cells in a dose-dependent manner. These findings indicate that pre-incubation with alpha -lipoic acid and alpha -tocopherol, alone or in combination, does not protect against oxidative- or non-oxidative-induced apoptosis in endothelial cells. Moreover, we have demonstrated a non-antioxidant, dose-dependent role of alpha -lipoic acid in caspase-3 and ERK2 activation. These data provide an insight and indicate caution in the use of high doses of alpha -lipoic acid as an antioxidant.
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PMID:Evidence for a non-antioxidant, dose-dependent role of alpha -lipoic acid in caspase-3 and ERK2 activation in endothelial cells. 1590 27

Andrographolide is the main labdane diterpene present in Andrographis paniculata. Two lines of evidence report immunostimulant and anti-inflammatory properties for andrographolide in different models. Using murine T-cells in vitro we demonstrated that andrographolide and to a lesser extent, 14-deoxyandrographolide (14-DAP), reduced significantly, in a dose-dependent manner, the IFN-gamma production induced by concanavaline A (CON-A), with an IC50 of 1.7 +/- 0.07 microM and 35.8 +/- 0.50 microM, respectively. Andrographolide, but not 14-DAP, inhibited partially the IL-2 production induced by CON-A. Andrographolide at doses of 5 and 10 microM reduced the extracellular-signal-regulated protein kinase (ERK1/2) phosphorylation induced by CON-A, whereas 14-DAP only reduced ERK1 and partially the ERK2 phosphorylation. The inhibition of ERK1/2 phosphorylation was associated to a decrease in the IFN-gamma production, due that UO126, a specific ERK1/2 inhibitor, also reduced the IFN-gamma production in murine T-cells induced by CON-A. Additionally, andrographolide and to a lesser extent 14-DAP, at doses of 50 microM and 100 microM, respectively, reduced the apoptosis induced by hydrocortisone and PMA in thymocytes, which was associated to a decrease in caspase-3 like activity. We conclude that both diterpenic labdanes isolated from A. paniculata can exert potent immunosuppressant effects without affecting the viability of the cells.
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PMID:Andrographolide inhibits IFN-gamma and IL-2 cytokine production and protects against cell apoptosis. 1593 81

Smoking is a major cause of human lung cancer. Past studies suggest that apoptosis might influence the malignant phenotype, but little is known about the association between apoptosis and cigarette smoke (CS)-induced lung pathogenesis. Using an in situ cell death detection kit (TA300), the association of CS with apoptosis was determined in a concentration-dependent manner. Furthermore, the expression of related proteins were investigated in the terminal bronchiole areas of the lung tissue from rats exposed to CS. Results showed that the expression of phosphotyrosine proteins was increased significantly in lung tissue of rats exposed to CS from 5 to 15 cigarettes. Using Western blotting and immunoprecipitation assay, Fas, a death receptor, was proved just be one of these phosphotyrosine proteins. CS triggered activation of MAP kinase (p38/JNK or ERK2) pathway, which led to Jun or p53 phosphorylation and FasL induction links Fas phosphorylation. Further, smoke treatment produced an increase in the level of proapoptotic proteins (Bax, t-Bid, cytochrome c and caspase-3), but a decline in Bcl-2, procaspase-8 and procaspase-9 proteins. Thus, CS-induced apoptosis may result from two main mechanisms, one is the activation of p38/JNK-Jun-FasL signaling, and the other is stimulated by the stabilization of p53, increase in the ratio of Bax/Bcl-2, release of cytochrome c; thus, leading to activation of caspase cascade.
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PMID:Induction of apoptosis in the lung tissue from rats exposed to cigarette smoke involves p38/JNK MAPK pathway. 1597 Feb 77

Nerve growth factor (NGF) differentiated pheochromocytoma PC12 cells exposed to 1-methyl-4-phenylpyridinium (MPP+) toxin were used as an in vitro pharmacological model of Parkinson's disease to examine the neuroprotective effects of 4-hydroxy-2,2,6,6-tetramethyl piperidine-n-oxyl (Tempol), a free radical scavenger and a superoxide dismutase-mimetic compound. MPP+-induced PC12 cell death was measured 72 h after exposure to 1.5 mM MPP+ by the release of lactate dehydrogenease, caspase-3 activation and stimulation of survival and stress mitogen-activated protein kinases. Exposure of PC12 cells to MPP+ activated ERK1 and ERK2 (forty-fold over control after 72 h), JNK1 and JNK2 (fourfold after 48 h) and p-38alpha (tenfold after 24 h). Pretreatment of PC12 cells with 500 microM Tempol, 1 h before induction of the MPP+ insult, reduced by 70% the release of LDH into the medium, inhibited caspase-3 activity by 30% and improved by 33% mitochondrial function, effects correlated with a 70% reduction in ERK1 and ERK2 phosphorylation activity. These findings support the neuroprotective effect of Tempol in the MPP+-induced PC12 cell death model and its use as a potential drug for treatment of Parkinson's disease.
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PMID:Neuroprotective effects of the stable nitroxide compound Tempol on 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in the Nerve Growth Factor-differentiated model of pheochromocytoma PC12 cells. 1698 7

The importance of hormone therapy in affording protection against the sequelae of global ischemia in postmenopausal women remains controversial. Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous estradiol ameliorates global ischemia-induced neuronal death and cognitive impairment in male and female rodents. However, the molecular mechanisms by which estrogens intervene in global ischemia-induced apoptotic cell death are unclear. Here we show that estradiol acts via the classical estrogen receptors, the IGF-I receptor, and the ERK/MAPK signaling cascade to protect CA1 neurons in ovariectomized female rats and gerbils. We demonstrate that global ischemia promotes early dephosphorylation and inactivation of ERK1 and the transcription factor cAMP-response element binding protein (CREB), subsequent down-regulation of the antiapoptotic protein Bcl-2, a known gene target of estradiol and CREB, and activation of caspase-3. Estradiol treatment increases basal phosphorylation of both ERK1 and ERK2 in hippocampal CA1 and prevents ischemia-induced dephosphorylation and inactivation of ERK1 and CREB, down-regulation of Bcl-2 and activation of the caspase death cascade. Whereas ERK/MAPK signaling is critical to CREB activation and neuronal survival, the impact of estradiol on Bcl-2 levels is ERK independent. These findings support a model whereby estradiol acts via the classical estrogen receptors and IGF-I receptors, which converge on activation of ERK/MAPK signaling and CREB to promote neuronal survival in the face of global ischemia.
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PMID:MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia. 1713 46

A new hydrophobic platinum(IV) complex, LA-12, a very efficient anticancer drug lacking cross-resistance with cisplatin (CDDP), is now being tested in clinical trials. Here we investigated the apoptogenic activity of LA-12 and its effect on gap-junctional intercellular communication (GJIC) in the rat liver epithelial cell line WB-F344. LA-12 induced apoptosis much more efficiently than did CDDP due to a combination of rapid penetration into the cell and attack on DNA, leading to fast activation of p53 and caspase-3. Exposure of WB-F344 cells to LA-12 led to rapid induction of the time- and dose-dependent decrease in GJIC. On the molecular level, loss of GJIC induced by LA-12 was mediated by activation of extracellular signal-regulated kinase (ERK)-1 and ERK-2, as demonstrated by the use of inhibitors of ERK activation. Inhibition of GJIC was linked to rapid hyperphosphorylation of connexin-43 and disappearance of connexon clusters from membranes, which was not observed in the case of CDDP.
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PMID:Apoptosis and inhibition of gap-junctional intercellular communication induced by LA-12, a novel hydrophobic platinum(IV) complex. 1746 56

Pretreatment with diazoxide, mitochondrial K(ATP) channel opener, was found to protect the rat heart against ischemia/reperfusion injury. Our aim was also to characterize the effects of diazoxide on the alterations of regulatory myocardial proteins, on mitochondrial ultrastructure, integrity and induction of apoptotic responses. Isolated rat hearts were Langendorff perfused and subjected to index ischemia (II) induced by 25 min global ischemia and 35 min reperfusion. In diazoxide- treated hearts, diazoxide (50 micromol/l) was applied 15 min before II. The levels and activation of specific proteins were determined using specific antibodies, activities of matrix metalloproteinases by zymography using gelatin as a substrate. The ultrastructure of mitochondria was investigated by electron microscopy of ultrathin sections of mitochondrial fractions embedded in Epon812. In rat hearts pretreated with diazoxide we found better recovery of contractile function after II. Electron microscopy studies revealed that application of diazoxide was connected with better preservation of mitochondrial integrity at basal conditions and after II in comparison to control hearts. Ischemia induced activation of caspase-3 as well as decrease of mitochondria-associated Bcl-2 levels but diazoxide treatment did not significantly influence these changes. On the other hand, diazoxide pretreatment reduced the cytosolic levels of pro-apoptotic Bax protein. Western blot analysis revealed that application of diazoxide increased activation of both ERK-1 and ERK-2 as compared with control hearts. ERK-2 activities were also higher in diazoxide-treated hearts after II when compared to control hearts. Moreover, application of diazoxide inhibited the activities of tissue matrix metalloproteinases (MMP-2). The results suggest that the cardioprotection mediated by diazoxide in rats is associated with preservation of mitochondrial integrity and function. The effect of diazoxide on ERK pathway points to the involvement of this signaling cascade in diazoxide-mediated adaptive responses of myocardium to ischemia.
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PMID:Changes in rat myocardium associated with modulation of ischemic tolerance by diazoxide. 1766 May 80

Fibronectin regulates many cellular processes, including migration, proliferation, differentiation, and survival. Previously, we showed that squamous cell carcinoma (SCC) cell aggregates escape suspension-induced, p53-mediated anoikis by engaging in fibronectin-mediated survival signals through focal adhesion kinase (FAK). Here we report that an altered matrix, consisting of a mutated, nonfunctional high-affinity heparin-binding domain and the V region of fibronectin (V+H-), induced anoikis in human SCC cells; this response was blocked by inhibitors of caspase-8 and caspase-3. Anoikis was mediated by downregulation of integrin alpha v in a panel of SCC cells and was shown to be proteasome-dependent. Overexpression of integrin alpha v or FAK inhibited the increase in caspase-3 activation and apoptosis, whereas suppression of alpha v or FAK triggered a further significant increase in apoptosis, indicating that the apoptosis was mediated by suppression of integrin alpha v levels and dephosphorylation of FAK. Treatment with V+H- decreased the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, and direct activation of ERK by constitutively active MEK1, an ERK kinase, increased ERK1 and ERK2 phosphorylation and inhibited the increase in apoptosis induced by V+H-. ERK acted downstream from alpha v and FAK signals, since alpha v and FAK overexpression inhibited both the decrease in ERK phosphorylation and the increase in anoikis triggered by V+H-. These findings provide evidence that mutations in the high-affinity heparin-binding domain in association with the V region of fibronectin, or altered fibronectin matrices, induce anoikis in human SCC cells by modulating integrin alpha v-mediated phosphorylation of FAK and ERK.
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PMID:An altered fibronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK. 1787 63

Resveratrol (RSVL), a phytoalexin found in abundance in grapes and other grape-related products, has been shown to be antiproliferative and protective against various types of cancers, including breast cancer. However, the precise underlying mechanisms are not well understood. In this study, we show that treatment with RSVL induces growth inhibition and apoptosis in a highly invasive and metastatic breast cancer cell line MDA-MB-231. Cleavage of caspase-3 and PARP and fragmentation of DNA were observed following exposure to RSVL. Co-treatment with pan-caspase inhibitor completely prevents cell death induced by RSVL. We found that RSVL-induced apoptosis correlates with sustained activation of ERK1/2 and suppression of Bcl-2 expression. Inhibition of ERK1/2 activation by its specific inhibitor or small interfering RNA reverses the effect of RSVL on Bcl-2 suppression and inhibits apoptosis, while overexpression of MEK1, which is directly upstream of both ERK1 and ERK2, enhances apoptosis induced by RSVL. Moreover, ERK1/2 was found to act upstream of caspase-3 to induce apoptosis, while it was not directly involved in caspase-3 cleavage. The other closely related MAPK members, p38 and JNK are not involved in apoptosis induced by RSVL in MDA-MB-231 cells. These results suggest that activation of ERK1/2 is required for RSVL-induced apoptosis in MDA-MB-231 cells.
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PMID:ERK1/2 activation is required for resveratrol-induced apoptosis in MDA-MB-231 cells. 1857 53

Some neurosteroids show neuroprotective action in in vitro and in vivo studies, but their interaction with apoptotic/necrotic processes has been only partially unraveled. The aim of the present study was to examine the effect of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), pregnenolone (PGL) and allopregnanolone (Allo) on staurosporine-, glutamate-, and NMDA-induced damage in primary cortical neuronal culture. DHEA, DHEAS and PGL (0.1 and 1 microM) inhibited the staurosporine-evoked LDH release and decreased the number of apoptotic cells as shown by Hoechst;s staining, whereas Allo was without effect. The neurosteroids affected neither the staurosporine-evoked changes in caspase-3 activity nor the decrease in mitochondrial membrane potential. It was also shown that protective effects of DHEA, DHEAS and PGL against staurosporine-induced LDH release were attenuated by extracellular signal-regulated kinase (ERK)--mitogen-activated protein kinase (MAPK) inhibitor--PD 98059 (5 microM) but not by phosphatidylinositol-3-kinase (PI3-K) inhibitors such as LY 294002 (1 microM) or wortmannin (10 nM). The involvement of ERK2-MAPK in protective effects of neurosteroids was confirmed by Western blot study. Further study demonstrated that glutamate-induced cell damage was attenuated by DHEA, DHEAS, and PGL, but not by Allo. None of the steroids influenced NMDA-induced LDH release. The results of the present in vitro studies suggest that excitatory neurosteroids DHEA, DHEAS and PGL at physiological concentrations participate in the inhibition of cortical neuronal degeneration elicited by staurosporine and glutamate, whereas the most potent positive modulator of GABA(A) receptor--Allo--has no effect. Moreover, neurosteroids appear to attenuate the staurosporine-induced cell damage in a caspase-3 independent way and their neuroprotective mechanism of action involves the increase in ERK-MAPK phosphorylation.
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PMID:Excitatory neurosteroids attenuate apoptotic and excitotoxic cell death in primary cortical neurons. 1895 90

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