Resveratrol ameliorates rheumatoid arthritis via activation of SIRT1-Nrf2 signaling pathway

被引:98
作者
Wang, Gaoyuan [1 ]
Xie, Xinxin [2 ]
Yuan, lingli [3 ]
Qiu, Jie [4 ]
Duan, Wenchao [4 ]
Xu, Bin [1 ]
Chen, Xiaoyu [5 ]
机构
[1] Anhui Med Univ, Affiliated Hosp 1, Dept Orthopaed, 218 Jixi Rd, Hefei 230022, Anhui, Peoples R China
[2] Anhui Med Univ, Affiliated Hosp 1, Dept Ultrasound, Hefei, Anhui, Peoples R China
[3] Bengbu Med Coll, Affiliated Hosp 2, Dept Orthopaed, Bengbu, Peoples R China
[4] Anhui Med Univ, Affiliated Hosp 1, Endoscopy Ctr, Hefei, Anhui, Peoples R China
[5] Anhui Med Univ, Dept Histol & Embryol, 81 Meishan Rd, Hefei 230032, Anhui, Peoples R China
关键词
fibroblast-like synoviocytes; oxidative stress; reactive oxygen species; resveratrol; rheumatoid arthritis; OXIDATIVE STRESS; MODULATION; NRF2;
D O I
10.1002/biof.1599
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The present study was designed to explore the biological role of resveratrol (RES) in rheumatoid arthritis (RA) and the underlying mechanism. The adjuvant-induced arthritic rats were administered RES on the 12th day after model establishment, and then arthritis assessment, oxidative stress measurement, histological examination, and immunohistochemical staining were performed. The primary rat fibroblast-like synoviocytes (FLS) were isolated and treated with RES in vitro and then cell proliferation and apoptosis assay were examined. Chromatin immunoprecipitation assay, luciferase reporter assay, intracellular reactive oxygen species (ROS) determination, western blot, and quantitative real time-polymerase chain reaction (qRT-PCR) were performed to investigate the mechanisms. RES administration decreased arthritis scores and serum levels of antioxidant enzymes, attenuated paw swelling, synovial hyperplasia, inflammatory cell infiltration, and cartilage degradation, as well as inhibited synoviocyte proliferation in synovial tissues. Further investigation indicated that RES inhibited ROS production and FLS proliferation through activating the silent information regulator 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. NF-kappa B was confirmed to negatively regulate miR-29a-3p and miR-23a-3p expression by directly binding to its promoter. Mechanistic analyses further revealed that Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1), a negative regulator of Nrf2, was a downstream target of miR-29a-3p, while miR-23a-3p directly targeted cullin3 (cul3), a master regulator of ubiquitination and degradation of Nrf2. Together, the present study provided evidence that RES ameliorated RA through activation of Nrf2-ARE signaling pathway via SIRT1/NF-kappa B/miR-29a-3p/Keap1 and SIRT1/NF-kappa B/miR-23a-3p/cul3 signaling pathway.
引用
收藏
页码:441 / 453
页数:13
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