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‐κB 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‐κB/miR‐29a‐3p/Keap1 and SIRT1/NF‐κB/miR‐23a‐3p/cul3 signaling pathway.

中文翻译：

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白藜芦醇通过激活SIRT1-Nrf2信号通路改善类风湿性关节炎。

本研究旨在探讨白藜芦醇（RES）在类风湿关节炎（RA）中的生物学作用及其潜在机制。佐剂诱导的关节炎大鼠在模型建立后的第12天接受RES，然后进行关节炎评估，氧化应激测量，组织学检查和免疫组织化学染色。分离大鼠原代成纤维细胞样滑膜细胞（FLS）并在体外进行RES处理，然后检查细胞增殖和凋亡测定。进行了染色质免疫沉淀测定，萤光素酶报告基因测定，细胞内活性氧（ROS）测定，蛋白质印迹和实时荧光定量聚合酶链反应（qRT-PCR），以研究其机制。RES给药可降低关节炎评分和抗氧化酶的血清水平，减轻爪子肿胀，滑膜增生，炎性细胞浸润和软骨降解，并抑制滑膜组织中滑膜细胞的增殖。进一步的研究表明，RES通过激活沉默信息调节因子1（SIRT1）/核因子红系2相关因子2（Nrf2）信号传导通路来抑制ROS的产生和FLS增殖。证实NF‐κB通过直接与其启动子结合而负调控miR‐29a‐3p和miR‐23a‐3p表达。机理分析进一步表明，具有Nrf2负调控因子的，具有CNC同源性（ECH）相关蛋白1（Keap1）的Kelch样红细胞衍生蛋白是miR‐29a‐3p的下游靶标，而miR‐23a‐3p是下游的靶标直接定位的cullin3（cul3），Nrf2泛素化和降解的主要调节剂。总之，本研究提供了证据，表明RES通过SIRT1 /NF-κB/ miR-29a-3p / Keap1和SIRT1 /NF-κB/ miR-23a-3p / cul3信号通路激活Nrf2-ARE信号通路改善了RA。