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)

Resveratrol is a polyphenolic phytoalexin that is present in various fruits, in the skin of red grapes and peanuts. Recent studies have shown that resveratrol exhibits potent antioxidant properties and is able to exert anti-inflammatory and anti-catabolic properties in several cell types. The pro-inflammatory cytokine interleukin-1beta (IL-1beta) plays a pivotal role in the pathogenesis of osteoarthritis (OA) in humans and animals. In this article we investigated whether resveratrol is able to block the effects of IL-1beta, specifically the activation of caspase-3 and subsequent cleavage of poly (ADP-ribose) polymerase (PARP) in human articular chondrocytes. Cultures of human chondrocytes were prestimulated with 10 ng/mL IL-1beta for 1, 12, and 24 h before being co-treated with IL-1beta and 100 microM resveratrol or 50 microM of the caspase inhibitor Z-DEVD-FMK for 1, 12, and 24 h, respectively in vitro. Resveratrol significantly reduced the IL-1beta-induced inhibition of expression of cartilage-specific collagen type II and signal transduction receptor beta1-integrin in a time-dependent manner. Incubation of chondrocytes with IL-1beta resulted in the activation of caspase-3 and PARP cleavage. These effects were abolished through co-treatment with resveratrol. Furthermore, co-treatment of IL-1beta-stimulated cells with the caspase inhibitor Z-DEVD-FMK blocked activation of caspase-3 and PARP cleavage, suggesting that this process is a caspase-dependent pathway. In summary, our results confirm that resveratrol is an effective inhibitor of chondrocyte apoptosis in vitro. These findings suggest that this dietary polyphenolic compound may have future applications in the nutraceutical-based therapy of human and animal OA.
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PMID:Resveratrol inhibits IL-1 beta-induced stimulation of caspase-3 and cleavage of PARP in human articular chondrocytes in vitro. 1740 69

Dopamine (DA) is an oxidant that may contribute to the degeneration of dopaminergic neurons. The present study demonstrates that DA-induced cytotoxicity in human-derived neurotypic cells, SH-SY5Y, is prevented by resveratrol, one of the major antioxidative constituents found in the skin of grapes. SH-SY5Y cells, a neuroblastoma cell line, treated with DA at 300 and 500 microM for 24 h underwent apoptotic death as determined by characteristic morphological features, including nuclear condensation, and loss of mitochondrial membrane potential (MMP). Flow cytometric analysis using Annexin V showed that DA can induce significant and severe apoptosis. Exposure to resveratrol (5 microM) for 1 h prior to the DA treatment attenuated DA-induced cytotoxicity, and rescued the loss of MMP. To investigate the apoptotic signaling pathways relevant to the restoration of DA-induced apoptosis by resveratrol, we carried out quantitative analysis of Bcl-2, caspase-3, and cleaved poly ADP-ribose polymerase (PARP) by immunoblot analysis. Resveratrol pretreatment led to a decrease in cleavage of PARP, an increase in the Bcl-2 protein, and activation of caspase-3. These results suggest that DA may be a potential oxidant of neuronal cells at biologically relevant concentrations. Resveratrol may protect SH-SY5Y cells against this cytotoxicity, reducing intracellular oxidative stress through canonical signal pathways of apoptosis and may be of biological importance in the prevention of a dopaminergic neurodegenerative disorder such as Parkinson disease.
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PMID:Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine. 1760 92

Although resveratrol, an active ingredient derived from grapes and red wine, possesses chemopreventive properties against several cancers, the molecular mechanisms by which it inhibits cell growth and induces apoptosis have not been clearly understood. Here, we examined the molecular mechanisms of resveratrol and its interactive effects with TRAIL on apoptosis in prostate cancer PC-3 and DU-145 cells. Resveratrol inhibited cell viability and colony formation, and induced apoptosis in prostate cancer cells. Resveratrol downregulated the expression of Bcl-2, Bcl-X(L) and survivin and upregulated the expression of Bax, Bak, PUMA, Noxa, and Bim, and death receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Treatment of prostate cancer cells with resveratrol resulted in generation of reactive oxygen species (ROS), translocation of Bax to mitochondria and subsequent drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO, and AIF) to cytosol, activation of effector caspase-3 and caspase-9, and induction of apoptosis. Resveratrol-induced ROS production, caspase-3 activity and apoptosis were inhibited by N-acetylcysteine. Bax was a major proapoptotic gene mediating the effects of resveratrol as Bax siRNA inhibited resveratrol-induced apoptosis. Resveratrol enhanced the apoptosis-inducing potential of TRAIL, and these effects were inhibited by either dominant negative FADD or caspase-8 siRNA. The combination of resveratrol and TRAIL enhanced the mitochondrial dysfunctions during apoptosis. These properties of resveratrol strongly suggest that it could be used either alone or in combination with TRAIL for the prevention and/or treatment of prostate cancer.
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PMID:Molecular mechanisms of resveratrol (3,4,5-trihydroxy-trans-stilbene) and its interaction with TNF-related apoptosis inducing ligand (TRAIL) in androgen-insensitive prostate cancer cells. 1763 62

A previous study from our lab has shown that the polyphenol-rich pomegranate juice can protect the neonatal mouse brain against hypoxic-ischemic (H-I) injury when given to mothers in their drinking water. To test the hypothesis that this protection is due to the polyphenols in the juice, we studied the effects of the pomegranate polyphenol extract in the same neonatal H-I model. To further explore the role of a specific polyphenol in neonatal H-I we investigated the effects of resveratrol. The neuroprotective effects of resveratrol have been demonstrated in adult models of stroke, but had not previously been examined in neonates. We show that pomegranate polyphenols and resveratrol reduce caspase-3 activation following neonatal H-I. Resveratrol reduced caspase-3 activation when given before the injury but not when given 3 h after the injury. In addition to preventing caspase-3 activation, resveratrol also reduced calpain activation. Finally, we show that resveratrol can protect against tissue loss measured at 7 days after the injury. These and other recent findings suggest that polyphenols should be further investigated as a potential treatment to decrease brain injury due to neonatal H-I.
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PMID:Pomegranate polyphenols and resveratrol protect the neonatal brain against hypoxic-ischemic injury. 1776 4

Resveratrol (RES), a natural plant polyphenol, has gained interest as a nontoxic chemopreventive agent capable of inducing tumor cell death in a variety of cancer types. However, the early molecular mechanisms of RES-induced apoptosis are not well defined. Using the human breast cancer cell lines MDA-MB-231 and MCF-7, we demonstrate that RES is antiproliferative and induces apoptosis in a concentration- and time-dependent manner. Preceding apoptosis, RES instigates a rapid dissipation of mitochondrial membrane potential by directly targeting mitochondria. This is followed by release of cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) into the cytoplasm and substantial increase in the activities of caspases-9 and -3 in MDA-MB-231 cells. In addition, live cell microscopy demonstrates that RES causes an early biphasic increase in the concentration of free intracellular calcium ([Ca2+]i), probably resulting from depletion of the endoplasmic reticulum stores in breast cancer cells. In caspase-3-deficient MCF-7 cells, apoptosis is mediated by the Ca2+-activated protease, calpain, leading to the degradation of plasma membrane Ca2+-ATPase isoform 1 and fodrin; the degradation is attenuated by buffering [Ca2+]i and blocked by calpain inhibitors. Mitochondrial permeability transition pore antagonists also blocked calpain activation. In vivo mouse xenograft studies demonstrate that RES treatment inhibits breast cancer growth with no systemic toxicities. Together, these results suggest a critical role for mitochondria not only in the intrinsic apoptotic pathway but also in the Ca2+ and calpain-dependent cell death initiated by RES. Thus, RES may prove useful as a nontoxic alternative for breast cancer treatment.
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PMID:Mitochondria, calcium, and calpain are key mediators of resveratrol-induced apoptosis in breast cancer. 1784

Resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenolic compound found in plant products, including red grapes, exhibits anticancer, antioxidant, and anti-inflammatory properties. Using an animal model of multiple sclerosis (MS), we investigated the use of resveratrol for the treatment of autoimmune diseases. We observed that resveratrol treatment decreased the clinical symptoms and inflammatory responses in experimental allergic encephalomyelitis (EAE)-induced mice. Furthermore, we observed significant apoptosis in inflammatory cells in spinal cord of EAE-induced mice treated with resveratrol compared with the control mice. Resveratrol administration also led to significant down-regulation of certain cytokines and chemokines in EAE-induced mice including tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-2, IL-9, IL-12, IL-17, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), and Eotaxin. In vitro studies on the mechanism of action revealed that resveratrol triggered high levels of apoptosis in activated T cells and to a lesser extent in unactivated T cells. Moreover, resveratrol-induced apoptosis was mediated through activation of aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) and correlated with up-regulation of AhR, Fas, and FasL expression. In addition, resveratrol-induced apoptosis in primary T cells correlated with cleavage of caspase-8, caspase-9, caspase-3, poly(ADP-ribose) polymerase, and release of cytochrome c. Data from the present study demonstrate, for the first time, the ability of resveratrol to trigger apoptosis in activated T cells and its potential use in the treatment of inflammatory and autoimmune diseases including, MS.
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PMID:Resveratrol (trans-3,5,4'-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. 1787 69

The inflammatory process plays a pivotal role during the pathogenesis of osteoarthritis, dominated by catabolic processes initiated by pro-inflammatory cytokines such as IL-1beta. Resveratrol, a natural phytoalexin occurring in various fruits has previously been shown to exhibit anti-inflammatory properties in several cell types. We investigated, whether resveratrol may be a useful blocker of pro-inflammatory cytokine signalling pathways in arthritis. We first examined the effects of resveratrol on the proliferation and production of IL-1beta in primary human articular chondrocytes treated with IL-1betain vitro. Resveratrol reversed significantly IL-1beta-reduced cell proliferation and blocked IL-1beta-stimulated cell membrane bound- and mature IL-1beta synthesis in chondrocytes. Furthermore, resveratrol was able to inhibit the IL-1beta-induced degradation of mitochondria and apoptosis in chondrocytes in a time-dependent manner. Because caspase inhibitor Z-DEVD-FMK abolished the IL-1beta-induced apoptosis in chondrocytes, we examined the effect of resveratrol on the caspase pathway and found that resveratrol blocked the cysteine protease caspase-3 and subsequent cleavage of the DNA repair enzyme PARP. Additionally, resveratrol reversed the IL-1beta-induced up-regulation of reactive oxygen species (ROS) in chondrocytes. Finally, we show that resveratrol induced ubiquitin-independent degradation of tumor suppressor gene protein p53 and inhibited p53-induced apoptosis in chondrocytes in a dose-dependent manner. Our results indicate that resveratrol seems to be an effective in vitro anti-inflammatory agent and has a chondroprotective capacity through suppression of (1) IL-1beta- (2) ROS- and (3) tumor suppressor protein p53-production. Further studies should be undertaken to define a possible implication of resveratrol in osteoarthritis therapy and cartilage tissue engineering.
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PMID:Regulation of inflammation signalling by resveratrol in human chondrocytes in vitro. 1795 54

Resveratrol, a polyphenol present in grapes and red wine, exerts wide biological properties including antioxidant, chemoprevention and cardioprotective effects. It was recently reported that resveratrol attenuates the oxidative DNA damage in neuronal cells. However, whether resveratrol attenuates the UVB-induced cell death in skin still remains largely unknown. In this study, to confirm the photoprotection properties of resveratrol, we investigated the effect of the pretreatment of resveratrol on UVB-treated HaCaT cells and molecular mechanisms concerning apoptotic pathways. Our data showed that HaCaT cells markedly decreased cell proliferation rates after UVB irradiation. Notably, the pretreatment of resveratrol on UVB irradiation resulted in an increase in cell survival which concomitantly reduced the reactive oxygen species production. Furthermore, the activation of caspase-3 and -8 was partially decreased in resveratrol-pretreated HaCaT cells, implying that the attenuation of caspase-3 and -8 activation is involved in cell survival after UVB irradiation. Thus, our data indicate that resveratrol may be a promising photoprotection agent, used in sunscreen products, to reduce cell death in UV-damaged skin.
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PMID:Protective effects of resveratrol on UVB-irradiated HaCaT cells through attenuation of the caspase pathway. 1820 89

Resveratrol, a polyphenol found in grapes and other fruit and vegetables, is a powerful chemopreventive and chemotherapeutic molecule potentially of interest for the treatment of breast cancer. The human breast cancer cell line MCF-7, which is devoid of caspase-3 activity, is refractory to apoptotic cell death after incubation with resveratrol. Here we show that resveratrol arrests cell proliferation, triggers death and decreases the number of colonies of cells that are sensitive to caspase-3-dependent apoptosis (MCF-7 casp-3) and also those that are unresponsive to it (MCF-7vc). We demonstrate that resveratrol (i) acts via multiple pathways to trigger cell death, (ii) induces caspase-dependent and caspase-independent cell death in MCF-7 casp-3 cells, (iii) induces only caspase-independent cell death in MCF-7vc cells and (iv) stimulates macroautophagy. Using BECN1 and hVPS34 (human vacuolar protein sorting 34) small interfering RNAs, we demonstrate that resveratrol activates Beclin 1-independent autophagy in both cell lines, whereas cell death via this uncommon form of autophagy occurs only in MCF-7vc cells. We also show that this variant form of autophagic cell death is blocked by the expression of caspase-3, but not by its enzymatic activity. In conclusion, this study reveals that non-canonical autophagy induced by resveratrol can act as a caspase-independent cell death mechanism in breast cancer cells.
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PMID:Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells. 1842 1

Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. This results in the expression of the Bcr-Abl fusion protein, a constitutively active protein tyrosine kinase. Although there are a few treatment options with Bcr-Abl kinase inhibitors, drug resistance is often encountered. One of the major obstacles in overcoming drug resistance in CML is the high endogenous levels of heat shock protein 70 (Hsp70). Resveratrol is a phytoalexin produced by several plants. We studied the chemotherapeutic effects and mode of action of resveratrol on K562 (CML) cells. Resveratrol induced apoptosis in K562 cells in a time-dependent manner. This was established by increased annexin V binding, corroborated with an enhanced caspase-3 activity and a rise in the sub-G(0)/G(1) population. Resveratrol treatment also caused suppression of Hsp70 both in mRNA and protein levels. The downregulation of Hsp70 by resveratrol exposure was correlated with a diminished presence of heat shock factor 1 (HSF1) in the nucleus, and the downregulation of transcriptional activity of HSF1. High endogenous levels of Hsp70 have been found to be a deterrent for sensitivity to chemotherapy. We show here that resveratrol could considerably enhance the apoptosis induction in K562 cells by 17-allylamino-17-demethoxygeldanamycin, an anticancer agent that inhibits Hsp90 but augments Hsp70 levels. We conclude that resveratrol significantly downregulated Hsp70 levels through inhibition of HSF1 transcriptional activity and appreciably augmented the pro-apoptotic effects of 17-allylamino-17-demethoxygeldanamycin.
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PMID:Resveratrol induces apoptosis in K562 (chronic myelogenous leukemia) cells by targeting a key survival protein, heat shock protein 70. 1842 57

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