Salidroside Suppresses Cell Growth and Inflammatory Response of Fibroblast-like Synoviocytes Via Inhibition of Phosphoinositol-3 Kinase/threonine Kinase Signaling in Rheumatoid Arthritis

Overview

Journal Z Rheumatol

Publisher Springer

Specialty Rheumatology

Date 2023 Oct 18

PMID 37851166

Authors

Yajing Qin

Juan Su

Affiliations

Soon will be listed here.

Abstract

Background: Salidroside (Sal) is a natural product commonly isolated from Rhodiola rosea L., which has been found to have numerous pharmacological activities (e.g., ameliorating apoptosis and inflammation, and acting as an antioxidant) in various diseases, but its concrete function in rheumatoid arthritis (RA) has not been revealed yet. Here, we aimed to explore the specific role and underlying mechanisms of Sal in RA-fibroblast-like synoviocytes (RA-FLSs).

Methods: Cell counting kit 8 (CCK-8) was used to assess the viability of normal-FLSs and RA-FLSs. Cell apoptosis in RA-FLSs was evaluated by flow cytometry. Western blotting was prepared to examine the levels of apoptosis- and signaling-related proteins. Wound-healing and Transwell assays were conducted to examine RA-FLSs migration and invasion. Enzyme-linked immunosorbent assay (ELISA) was used to assess the effect of Sal on tumor necrosis factor-alpha (TNF-α)-induced inflammation in RA-FLSs. RA animal model was established through complete Freund's adjuvant (CFA) induction, and the histopathological changes in synovial tissues of the rat model were analyzed by H&E staining.

Results: RA-FLSs were treated with 200 μM Sal for 24 h, and cell viability was significantly suppressed. Sal promoted RA-FLSs apoptosis. The migratory and invasive abilities of RA-FLSs were markedly inhibited by Sal. Sal incubation reduced the levels of inflammatory cytokines interleukin‑8 (IL-8), IL-1β, and IL‑6 in RA-FLSs under the stimulation of TNF‑α. Subsequently, Sal downregulated phosphorylated phosphatidylinositol‑3 kinase (p-PI3K) and protein kinase (p-AKT) expression in RA-FLSs. After the treatment with pathway activator 740Y‑P (20 μM) in RA-FLSs, the promotive effect of Sal on cell apoptosis was reversed, and inhibitory effects of it on cell viability, migration, invasion, and inflammatory response were abolished. Sal inhibited RA development in the CFA-induced rat model.

Conclusion: Sal suppressed cell growth and inflammation in RA-FLSs by inactivating PI3K/AKT-signaling pathways.

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References

Sparks J . Rheumatoid Arthritis. Ann Intern Med. 2019; 170(1):ITC1-ITC16. DOI: 10.7326/AITC201901010. View

Bottini N, Firestein G . Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol. 2012; 9(1):24-33. PMC: 3970924. DOI: 10.1038/nrrheum.2012.190. View

Chen Z, Bozec A, Ramming A, Schett G . Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol. 2018; 15(1):9-17. DOI: 10.1038/s41584-018-0109-2. View

Bartok B, Firestein G . Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010; 233(1):233-55. PMC: 2913689. DOI: 10.1111/j.0105-2896.2009.00859.x. View

Korb-Pap A, Bertrand J, Sherwood J, Pap T . Stable activation of fibroblasts in rheumatic arthritis-causes and consequences. Rheumatology (Oxford). 2016; 55(suppl 2):ii64-ii67. DOI: 10.1093/rheumatology/kew347. View

Wang J, Xiao L, Zhu L, Hu M, Wang Q, Yan T . The effect of synthetic salidroside on cytokines and airway inflammation of asthma induced by diisocyanate (TDI) in mice by regulating GATA3/T-bet. Inflammation. 2014; 38(2):697-704. DOI: 10.1007/s10753-014-9979-x. View

Zhu L, Wei T, Gao J, Chang X, He H, Miao M . Salidroside attenuates lipopolysaccharide (LPS) induced serum cytokines and depressive-like behavior in mice. Neurosci Lett. 2015; 606:1-6. DOI: 10.1016/j.neulet.2015.08.025. View

Zhu L, Wei T, Chang X, He H, Gao J, Wen Z . Effects of Salidroside on Myocardial Injury In Vivo In Vitro via Regulation of Nox/NF-κB/AP1 Pathway. Inflammation. 2015; 38(4):1589-98. DOI: 10.1007/s10753-015-0134-0. View

Zhu L, Liu Z, Ren Y, Wu X, Liu Y, Wang T . Neuroprotective effects of salidroside on ageing hippocampal neurons and naturally ageing mice via the PI3K/Akt/TERT pathway. Phytother Res. 2021; 35(10):5767-5780. DOI: 10.1002/ptr.7235. View

10.

Gui D, Cui Z, Zhang L, Yu C, Yao D, Xu M . Salidroside attenuates hypoxia-induced pulmonary arterial smooth muscle cell proliferation and apoptosis resistance by upregulating autophagy through the AMPK-mTOR-ULK1 pathway. BMC Pulm Med. 2017; 17(1):191. PMC: 5726034. DOI: 10.1186/s12890-017-0477-4. View

11.

Gao H, Peng L, Li C, Ji Q, Li P . Salidroside Alleviates Cartilage Degeneration Through NF-κB Pathway in Osteoarthritis Rats. Drug Des Devel Ther. 2020; 14:1445-1454. PMC: 7166061. DOI: 10.2147/DDDT.S242862. View

12.

Wu M, Hu R, Wang J, An Y, Lu L, Long C . Salidroside Suppresses IL-1β-Induced Apoptosis in Chondrocytes via Phosphatidylinositol 3-Kinases (PI3K)/Akt Signaling Inhibition. Med Sci Monit. 2019; 25:5833-5840. PMC: 6691749. DOI: 10.12659/MSM.917851. View

13.

Zhu L, Chen T, Chang X, Zhou R, Luo F, Liu J . Salidroside ameliorates arthritis-induced brain cognition deficits by regulating Rho/ROCK/NF-κB pathway. Neuropharmacology. 2015; 103:134-42. DOI: 10.1016/j.neuropharm.2015.12.007. View

14.

Liu Y, Tang H, Liu X, Chen H, Feng N, Zhang J . Frontline Science: Reprogramming COX-2, 5-LOX, and CYP4A-mediated arachidonic acid metabolism in macrophages by salidroside alleviates gouty arthritis. J Leukoc Biol. 2018; 105(1):11-24. DOI: 10.1002/JLB.3HI0518-193R. View

15.

Li X, Wang Y . Cinnamaldehyde Attenuates the Progression of Rheumatoid Arthritis through Down-Regulation of PI3K/AKT Signaling Pathway. Inflammation. 2020; 43(5):1729-1741. DOI: 10.1007/s10753-020-01246-5. View

16.

Yu Z, Xu H, Wang H, Wang Y . Foxc1 promotes the proliferation of fibroblast-like synoviocytes in rheumatoid arthritis via PI3K/AKT signalling pathway. Tissue Cell. 2018; 53:15-22. DOI: 10.1016/j.tice.2018.05.011. View

17.

Yang B, Ge Y, Zhou Y, Wang J, Xie X, Li S . miR-124a inhibits the proliferation and inflammation in rheumatoid arthritis fibroblast-like synoviocytes via targeting PIK3/NF-κB pathway. Cell Biochem Funct. 2019; 37(4):208-215. DOI: 10.1002/cbf.3386. View

18.

Wei Y, Hong H, Zhang X, Lai W, Wang Y, Chu K . Salidroside Inhibits Inflammation Through PI3K/Akt/HIF Signaling After Focal Cerebral Ischemia in Rats. Inflammation. 2017; 40(4):1297-1309. DOI: 10.1007/s10753-017-0573-x. View

19.

Xu M, Shi H, Gao X, Wang H . Salidroside attenuates myocardial ischemia-reperfusion injury via PI3K/Akt signaling pathway. J Asian Nat Prod Res. 2013; 15(3):244-52. DOI: 10.1080/10286020.2012.762358. View

20.

Liu R, Tao E, Yu S, Liu B, Dai L, Yu L . The Suppressive Effects of the Petroleum Ether Fraction from Atractylodes lancea (Thunb.) DC. On a Collagen-Induced Arthritis Model. Phytother Res. 2016; 30(10):1672-1679. DOI: 10.1002/ptr.5671. View