title: Resveratrol via sirtuin-1 downregulates RE1-silencing transcription factor (REST) expression preventing PCB-95-induced neuronal cell death.
abstract: Resveratrol (3,5,4'-trihydroxystilbene) (RSV), a polyphenol widely present in plants, exerts a neuroprotective function in several neurological conditions; it is an activator of class III histone deacetylase sirtuin1 (SIRT1), a crucial regulator in the pathophysiology of neurodegenerative diseases. By contrast, the RE1-silencing transcription factor (REST) is involved in the neurotoxic effects following exposure to polychlorinated biphenyl (PCB) mixture A1254. The present study investigated the effects of RSV-induced activation of SIRT1 on REST expression in SH-SY5Y cells. Further, we investigated the possible relationship between the non-dioxin-like (NDL) PCB-95 and REST through SIRT1 to regulate neuronal death in rat cortical neurons. Our results revealed that RSV significantly decreased REST gene and protein levels in a dose- and time-dependent manner. Interestingly, overexpression of SIRT1 reduced REST expression, whereas EX-527, an inhibitor of SIRT1, increased REST expression and blocked RSV-induced REST downregulation. These results suggest that RSV downregulates REST through SIRT1. In addition, RSV enhanced activator protein 1 (AP-1) transcription factor c-Jun expression and its binding to the REST promoter gene. Indeed, c-Jun knockdown reverted RSV-induced REST downregulation. Intriguingly, in SH-SY5Y cells and rat cortical neurons the NDL PCB-95 induced necrotic cell death in a concentration-dependent manner by increasing REST mRNA and protein expression. In addition, SIRT1 knockdown blocked RSV-induced neuroprotection in rat cortical neurons treated with PCB-95. Collectively, these results indicate that RSV via SIRT1 activates c-Jun, thereby reducing REST expression in SH-SY5Y cells under physiological conditions and blocks PCB-95-induced neuronal cell death by activating the same SIRT1/c-Jun/REST pathway.
authors: IRCSS SDN, Naples 80131, Italy.
authors: Natascia
authors: N
authors: Guida
authors: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Via Pansini, 5, 80131 Naples, Italy.
authors: Giusy
authors: G
authors: Laudati
authors: IRCSS SDN, Naples 80131, Italy.
authors: Serenella
authors: S
authors: Anzilotti
authors: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Via Pansini, 5, 80131 Naples, Italy.
authors: Agnese
authors: A
authors: Secondo
authors: Department of Public Health, 'Federico II' University of Naples, Naples, Italy.
authors: Paolo
authors: P
authors: Montuori
authors: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Via Pansini, 5, 80131 Naples, Italy.
authors: Gianfranco
authors: G
authors: Di Renzo
authors: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Via Pansini, 5, 80131 Naples, Italy; Division of Pharmacology, Department of Science and Technology, University of Sannio, Via Port'Arsa 11, 82100 Benevento, Italy.
authors: Lorella M T
authors: LM
authors: Canzoniero
authors: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Via Pansini, 5, 80131 Naples, Italy; Division of Pharmacology, Department of Science and Technology, University of Sannio, Via Port'Arsa 11, 82100 Benevento, Italy. Electronic address: cformisa@unisannio.it.
authors: Luigi
authors: L
authors: Formisano
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D020868:Gene Silencing; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002227:Carbazoles; D011078:Polychlorinated Biphenyls; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D000077185:Resveratrol; D056564:Sirtuin 1; D013267:Stilbenes; D000099229:RE1-Silencing Transcription Factor; C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; C032904:2,2',3,5',6-pentachlorobiphenyl; C447939:SIRT1 protein, human
keywords: PCB-95; REST; Resveratrol; SIRT1; c-Jun