title: A SIRT3/AMPK/autophagy network orchestrates the protective effects of trans-resveratrol in stressed peritoneal macrophages and RAW 264.7 macrophages.
abstract: Resveratrol gains a great interest for its strong antioxidant properties, while the molecular mechanisms underlie the beneficial effects on psychosocial stress remain controversial. In this study, we demonstrated that resveratrol protected peritoneal macrophages and RAW 264.7 cells from stress-induced decrease in the total cell count, phagocytic capability, reactive oxygen species generation, monodansylcadaverine and mitochondrial membrane potential in stressed mice. Resveratrol promoted stress-induced autophagy in both models. Modulation of autophagy by rapamycin or 3-methyladenine regulated the protective effect of resveratrol, suggesting a role of autophagy in the protective mechanisms of resveratrol. The comparison studies revealed that distinct mechanisms were implicated in the protective effect of resveratrol and other antioxidants (vitamin C and edaravone). Resveratrol promoted autophagy via upregulating SIRT3 expression and phosphorylation of AMP-activated protein kinase (AMPK). Knockdown of SIRT3 resulted in decreased autophagy and abolished protective effect of resveratrol. SIRT1 was also involved in the protective mechanism of resveratrol, although its effect on autophagy was unnoticeable. Pharmacological manipulation of autophagy modulated the effects of resveratrol on SIRT3 and AMPK, revealing the engagement of a positive feedback loop. In sharp contrast, vitamin C and edaravone effectively protected macrophages from stress-induced cytotoxicity, accompanied by downregulated SIRT3 expression and AMPK phosphorylation, and decreased level of autophagy response. Taken together, we conclude that a SIRT3/AMPK/autophagy network orchestrates in the protective effect of resveratrol in macrophages.
authors.affiliation: Anti-stress and Health Research Center, Pharmacy College, Jinan University, Guangzhou 510632, China; Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Duan
authors.affiliation: Anti-stress and Health Research Center, Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Li
authors.affiliation: Anti-stress and Health Research Center, Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Fang-Lan
authors.initials: FL
authors.lastname: Liu
authors.affiliation: Anti-stress and Health Research Center, Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Deng
authors.affiliation: Anti-stress and Health Research Center, Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Wu
authors.affiliation: Anti-stress and Health Research Center, Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Yuan
authors.affiliation: Anti-stress and Health Research Center, Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Bun
authors.initials: B
authors.lastname: Tsoi
authors.affiliation: Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Anti-stress and Health Research Center, Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Shao-Hui
authors.initials: SH
authors.lastname: Cai
authors.affiliation: Anti-stress and Health Research Center, Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurihara
authors.affiliation: Anti-stress and Health Research Center, Pharmacy College, Jinan University, Guangzhou 510632, China. Electronic address: rongronghe@jnu.edu.cn.
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: He
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D000983:Antipyrine / Q000008:administration & dosage / Q000031:analogs & derivatives; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000008:administration & dosage; D001343:Autophagy / Q000187:drug effects; D000077553:Edaravone; D005786:Gene Expression Regulation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D011494:Protein Kinases / Q000235:genetics*; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D020123:Sirolimus / Q000008:administration & dosage; D056566:Sirtuin 3 / Q000235:genetics*; D013267:Stilbenes / Q000008:administration & dosage*; D013315:Stress, Psychological / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; C525046:Sirt3 protein, mouse; D013267:Stilbenes; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D056566:Sirtuin 3; D001205:Ascorbic Acid; D000077185:Resveratrol; D000077553:Edaravone; D000983:Antipyrine; D020123:Sirolimus
keywords: Autophagy; Macrophage; Mitochondria; Oxidative stress; Resveratrol; SIRT3