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:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity.
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PMID:Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. 968 Mar 69

Zinc neurotoxicity has been demonstrated in ischemic, seizure, hypoglycemic, and trauma-induced neuronal death where Zn(2+) is thought to be synaptically released and taken up in neighbouring neurons, reaching toxic concentrations. We previously demonstrated that toxicity of extracellular Zn(2+) depended on entry, elevation in intracellular free Zn(2+) ([Zn(2+)](i)), a reduction in NAD(+) and ATP levels, and dysfunction of glycolysis and cellular metabolism. We suggested that PARP-1 activation alone can not explain this loss of neuronal NAD(+). NAD(+) was recently demonstrated to permeate neurons and glia, and we have now shown that exogenous NAD(+) can reduce Zn(2+) neurotoxicity, and 3-acetylpyridine, which generates inactive NAD(+), potentiated Zn(2+) neurotoxicity. Sirtinol and 2-hydroxynaphthaldehyde, inhibitors of the sirtuin pathway (SIRT proteins are NAD(+)-catabolic protein deacetylases), attenuated both acute and chronic Zn(2+) neurotoxicity. Resveratrol and fisetin (sirtuin activators) potentiated NAD(+) loss and Zn(2+) neurotoxicities. Furthermore, neuronal cultures derived from the Wld(s) mouse, which overexpress the NAD(+) synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT-1), had reduced sensitivity to Zn(2+) neurotoxicity. Finally, nicotinamide was demonstrated to attenuate CA1 neuronal death after 10 min of global ischemia in rat even if administered 1 h after the insult. Together with previous data, these results further implicate NAD(+) levels in Zn(2+) neurotoxicity.
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PMID:Zinc neurotoxicity is dependent on intracellular NAD levels and the sirtuin pathway. 1704 94

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

Resveratrol (3,4',5-trans-trihydroxystilbene) is a natural compound found in grapes and several medicinal plants and has been shown to have anticancer effects on various human cancer cells. The aim of this study was to further investigate the molecular mechanism of this anticancer effect. Resveratrol effect on cell growth, morphology and gene expression was investigated in estrogen receptor-negative MDA-MB-231 human breast cancer cell line. We show here that resveratrol-induced growth inhibition in the estrogen receptor negative MDA-MB-231 breast cancer cells is due to the induction of apoptosis as demonstrated by morphological, nuclear staining and PARP cleavage analysis. Resveratrol-induced growth inhibition was associated with transient activation of p44/42 mitogen-activated protein kinase (MAPK) (Thr202/Tyr204). Most importantly, resveratrol inhibited both the phosphorylation at Ser240/244 and the expression of the pS6 ribosomal protein. This protein is known to play an important role in the translation of mRNAs that have oligopyrimidine tracts in their 5' untranslated regions. Interestingly, only MAPK inhibitor was able to block resveratrol-induced growth inhibition suggesting that effects of resveratrol on cell growth are dependent on MAPK signaling. The data demonstrated that resveratrol-induced apoptosis is associated with MAPK signaling and with the inhibition of proteins that are involved in protein translation. This is the first data linking resveratrol with downregulation of protein translation via p44/42 MAPK and S6 ribosomal protein. We propose to use these proteins as predictive biomarkers to evaluate the treatment efficacy of resveratrol in estrogen receptor-negative human breast cancer.
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PMID:Resveratrol-induced growth inhibition in MDA-MB-231 breast cancer cells is associated with mitogen-activated protein kinase signaling and protein translation. 1755 6

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 (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

Osteoarthritis is an inflammatory disease of load-bearing synovial joints that is currently treated with drugs that exhibit numerous side effects and are only temporarily effective on pain, the main symptom of the disease. Consequently, there is an acute need for novel, safe and more effective chemotherapeutic agents for the treatment of osteoarthritis and related arthritic diseases. Resveratrol is a phytoalexin stilbene produced naturally by plants including red grapes, peanuts and various berries. Recent research in various cell models has demonstrated that resveratrol is safe and has potent anti-inflammatory properties. However, its potential for treating arthritic conditions has not been explored. In this study we provide experimental evidence that resveratrol inhibits the expression of VEGF, MMP-3, MMP-9 and COX-2 in human articular chondrocytes stimulated with the pro-inflammatory cytokine IL-1beta. Since these gene products are regulated by the transcription factor NF-kappaB, we investigated the effects of resveratrol on IL-1beta-induced NF-kappaB signaling pathway. Resveratrol, like N-Ac-Leu-Leu-norleucinal (ALLN) suppressed IL-1beta-induced proteasome function and the degradation of IkappaBalpha (an inhibitor of NF-kappaB) without affecting IkappaBalpha kinase activation, IkappaBalpha-phosphorylation or IkappaBalpha-ubiquitination which suppressed nuclear translocation of the p65 subunit of NF-kappaB and its phosphorylation. Furthermore, we observed that resveratrol as well as ALLN inhibited IL-1beta-induced apoptosis, caspase-3 activation and PARP cleavage in human articular chondrocytes. In summary, our results suggest that resveratrol suppresses apoptosis and inflammatory signaling through its actions on the NF-kappaB pathway in human chondrocytes. We propose that resveratrol should be explored further for the prophylactic treatment of osteoarthritis in humans and companion animals.
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PMID:Resveratrol suppresses interleukin-1beta-induced inflammatory signaling and apoptosis in human articular chondrocytes: potential for use as a novel nutraceutical for the treatment of osteoarthritis. 1860 98

Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic phytoalexin present mainly in grapes, red wine and berries, is known to possess strong chemopreventive and anticancer properties. Here, we demonstrated the anti-proliferative and apoptosis-inducing activities of resveratrol in human epidermoid carcinoma A431 cells. Resveratrol has cytotoxic effects through inhibiting cellular proliferation of A431 cells, which leads to the induction of apoptosis, as evident by an increase in the fraction of cells in the sub-G(1) phase of the cell cycle and Annexin-V binding of externalized phosphatidylserine. Results revealed that inhibition of proliferation is associated with regulation of the JAK/STAT pathway, where resveratrol prevents phosphorylation of JAK, thereby inhibiting STAT1 phosphorylation. Furthermore, resveratrol treatment actively stimulated reactive oxygen species (ROS) and mitochondrial membrane depolarization. Consequently, an imbalance in the Bax/Bcl-2 ratio triggered the caspase cascade and subsequent cleavage of PARP, thereby shifting the balance in favor of apoptosis. These observations indicate that resveratrol treatment inhibits JAK/STAT-mediated gene transcription and induce the mitochondrial cell death pathway.
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PMID:Regulation of apoptosis by resveratrol through JAK/STAT and mitochondria mediated pathway in human epidermoid carcinoma A431 cells. 1899 91

While lung cancer accounts for approximately 20% of cancer diagnoses, it is the leading cause of tumor-related deaths. The apoptotic effects of 3,5,4'-trihydroxystilbene (resveratrol), dibenzoylmethane (DBM), and their analogues on human lung cancer cells are generally unclear. The aims of this study were to evaluate the apoptotic effects and molecular mechanisms of resveratrol, DBM, and their analogues on human lung cancer cells. The results of the MTT and lactate dehydrogenase (LDH) leakage assays indicated that resveratrol, 3,5,4'-trimethoxy-trans-stilbene (MR-3), and 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB) could inhibit cell population growth and induce cell injury in A549 and CH27 cell lines. Resveratrol and HMDB could induce apoptotic cell death in the A549 and CH27 cell lines. Moreover, cellular growth of the A549 and CH27 cell lines might be inhibited by MR-3 through induction of apoptosis and regulation of the cell cycle. The A549 and CH27 cell lines treated with resveratrol, MR-3, and HMDB showed a time-dependent reduction of mitochondrial membrane potential, and the Bax/Bcl-2 ratio increased gradually with a higher concentration of polyphenols. The resveratrol-, MR-3-, and HMDB-induced apoptosis in the A549 and CH27 cell lines were controlled through activation of caspase-9 and caspase-3 and subsequent cleavage of PARP. In conclusion, we have demonstrated that resveratrol, DBM, and their analogues could be effective candidates for chemoprevention of lung cancer and HMDB might have the strongest ability for inducing apoptosis.
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PMID:Mechanisms of apoptotic effects induced by resveratrol, dibenzoylmethane, and their analogues on human lung carcinoma cells. 1944 15

Resveratrol, a naturally occurring polyphenolic antioxidant, is a compound holding promise for cancer chemoprevention. Previous studies suggest that 2,3',4,5'-tetramethoxy-trans-stilbene (TMS) and 3,4,4',5,-tetramethoxy-trans-stilbene (MR-4), both of which are derivatives of resveratrol, are potent apoptosis-inducing agents with clinical potential. In this study, we chemically synthesized 2,3',4,4',5'-pentamethoxy-trans-stilbene (PMS), the hybrid molecule of TMS and MR-4, and determined its effects on colon cancer growth. When compared with its parent compounds, PMS displayed more potent in vitro anti-mitogenic effect on colon cancer cells (Caco-2, HT-29 and SW1116). Moreover, PMS inhibited tumor growth in vivo in a colon cancer xenograft model. In this connection, PMS strongly induced apoptosis in HT-29 cells as evidenced by increased PARP cleavage, DNA fragmentation, and accumulation of sub-G(1) population. Further mechanistic analysis revealed that PMS enhanced the polymerization of microtubules, which was followed by G(2)/M mitotic arrest and caspase-dependent apoptosis. The activation of caspases-3, -7, -8, and -9 was involved in PMS-induced apoptosis with concomitant down-regulation of the pro-survival PI3K/Akt signaling. Collectively, these data suggest that PMS is a potent inducer of apoptosis via targeting microtubules and may merit investigation as a potential chemoprophylactic and therapeutic agent for colon cancer.
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PMID:2,3',4,4',5'-Pentamethoxy-trans-stilbene, a resveratrol derivative, is a potent inducer of apoptosis in colon cancer cells via targeting microtubules. 1959 9


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