Ziyuglycoside I attenuates collagen-induced arthritis through restoring the balance of Th17/Treg cells

Abstract

Objective: To investigate the therapeutic effect and primary pharmacological mechanism of Ziyuglycoside I (Ziyu I) on collagen-induced arthritis (CIA) mice. Methods: CIA mice were treated by 5, 10, or 20 mg/kg of Ziyu I or 2 mg/kg of methotrexate (MTX), and clinical manifestations as well as pathological changes were observed. T cell subsets were determined by flow cytometry. T cell viability was measured by CCK-8. The expressions of transforming growth factor beta (TGF-β) and IL-17 in serum were detected by Elisa. The mRNA expressions of RORγt and Foxp3 in mice spleen lymphocytes were detected by RT-qPCR. Molecular docking was used to detect whether there was a molecular interaction between Ziyu I and Akt. The activation of mTOR in T cells was verified by Western blotting or immunofluorescence. Results: Ziyu I treatment group could effectively alleviate the arthritis symptoms of CIA mice, including body weight, global score, arthritis index, number of swollen joints, etc. The pathological changes of joints and spleen in arthritic mice were improved effectively. The thymic index, T cell activity and RORγt production of Ziyu I treatment group were significantly reduced. Notably, through molecular docking, western blotting, and immunofluorescence analysis data, we found that Ziyu I could interact directly with Akt to reduce downstream mTOR activation and inhibit Th17 differentiation, thereby regulating Th17/Treg balance and improving arthritis symptoms. Conclusion: Our data showed that Ziyu I effectively improved arthritic symptoms of CIA in mice by inhibiting mTOR activation, thereby affecting Th17 differentiation and regulating Th17/Treg balance.

Efficacy and safety of Duhuo-Jisheng decoction in rheumatoid arthritis: A systematic review and meta-analysis of 42 randomized controlled trials

“…[116,119,120] It was found that columbianadin can inhibit the differentiation of CD4 T lymphocytes towards th17 cells and promote their differentiation towards treg cells in CIA mice and the spleen lymphocytes of balb/c mice. [91] Our meta-analysis indicated that DJD treatment could better improve the level of CD4 + , CD8 + , and CD4 + / CD8 + than rDMARDs. However, further research is necessary to confirm the efficacy of these aspects, as limited data (including 140 patients in the treatment and control groups) may lead to false positive results.…”

“…[90] Similarly, it was found that columbianadin can inhibit the secretion of the inflammatory cytokine IL-17A, promote its differentiation towards treg cells, and promote the secretion of anti-inflammatory cytokines. [91] Several studies have revealed that osthole, an active ingredients of Radix Angelicae Pubescentis (Du Huo), can inhibit the proliferation, migration, and invasion of RA fibroblast like synovial cells by weakening NF-κB signaling, [92] and activate AMPK to inhibit NLRP3 inflammasome activation. [93] Additionally, many inflammatory factors, including IL-1β, IL-6, TNF-α, etc., were found to be decreased by active ingredients or extracts in DJD in both in vivo and in vitro experiments of RA, such as senkyunolide I, [94] 18β-Glycyrrhetinic acid, [95] liquiritin, [96] polysaccharide from Radix Angelicae sinensis (Dang Gui), [97] paeoniflorin, [98][99][100][101][102] paeoniflorin-6'-O-benzene sulfonate, [103] curcumin, [104] the total saponins of Radix Achyranthis bidentatae (Niu Xi), [105] supercritical carbon dioxide extraction of Radix Achyranthis bidentatae (Niu Xi), [106] polysaccharide from Radix Saposhnikoviae divaricatae (Fang Feng), [107,108] and Radix Saposhnikoviae divaricatae (Fang Feng).…”