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

Abstract

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.

Bakuchiol Alleviates Hyperglycemia-Induced Diabetic Cardiomyopathy by Reducing Myocardial Oxidative Stress via Activating the SIRT1/Nrf2 Signaling Pathway

“…Many previous studies have already revealed the two redox-sensitive proteins closely implicated in the therapeutic effects on diabetic cardiomyopathy [ 21 , 46 , 57 , 58 ]. More importantly, SIRT1 is involved in the regulation and control of oxidative stress that are associated with diverse stimulus, which appears to be exerted by activating Nrf2, indicating that Nrf2 serves as an important downstream target of SIRT1 signaling [ 25 , 26 , 31 , 59 ]. Additionally, novel observations have suggested that BAK inhibits ROS generation in cardiomyocytes via SIRT1.…”

“…Moreover, nuclear factor-erythroid 2-related factor 2 (Nrf2), an important transcription factor that binds to antioxidant-responsive elements (AREs), shows an outstanding performance in attenuating oxidative damage to consolidate the cellular defense system against diabetic cardiomyopathy [ 23 , 24 ]. Numerous studies have also clearly indicated that SIRT1 could manifest its antioxidative effects via the activation of Nrf2 [ 25 , 26 ]. Therefore, it is of great interest to probe whether SIRT1/Nrf2 signaling plays a vital role in the amelioration actions of BAK against diabetic cardiomyopathy.…”

Natural products and phytochemical nanoformulations targeting mitochondria in oncotherapy: an updated review on resveratrol

“…Resveratrol exerts an inhibitory effect on the function of thyroxine so that resveratrol supplementation enhances the expression of BAD and inhibits PD-1 to suppress oral cancer cells [62]. By down-regulation of the snail signaling pathway, resveratrol reduces EMT to inhibit the invasion of colon cancer cells [63]. It is worth mentioning that resveratrol activates tumor suppressor Rad9 to induce premature senescence in lung and breast cancer cells [64].…”

“…However, the accumulating data have shown that the major mechanism for the antioxidant activity of resveratrol is related to its effect on the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Resveratrol, by activation of the Nrf2 signaling pathway, ameliorates oxidative stress [68] to improve colitis [69], arthritis [63], diabetes [70] and non-alcoholic fatty liver disease [71].…”

Dietary resveratrol attenuates oxidative stress in Pacific whiteleg shrimp, Litopenaeus vannamei, in response to ammonia stress

“…Resveratrol (trans-3,4,5-Trihydroxystilbene) is a natural polyphenol found in particularly high concentrations in red wine as well as numerous plants, such as grapes, peanuts, and other groundnuts. It has been attracted intense interest for its potentially beneficial effects and the mechanism of action (Robb, et al, 2008;Wang et al, 2019). It exhibits anti-oxidant, anti-inflammatory, anti-aging and anti-tumorigenic effects (Robb et al, 2008;Kim et al, 2018;Wang et al, 2019).…”