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Salidroside suppresses cell growth and inflammatory response of fibroblast-like synoviocytes via inhibition of phosphoinositol-3 kinase/threonine kinase signaling in rheumatoid arthritis

Unterdrückung von Zellwachstum und entzündlicher Reaktion fibroblastenartiger Synoviozyten durch Salidrosid via Inhibition des Phosphatidylinositol-3-Kinase-/Proteinkinase-Signalwegs bei rheumatoider Arthritis

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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.

Zusammenfassung

Hintergrund

Salidrosid (Sal) ist ein natürliches Produkt, das gewöhnlich aus Rhodiola rosea L. isoliert wird und bei dem zahlreiche pharmakologische Wirkungen (z. B. Verbesserung von Apoptose und Inflammation sowie Wirkung als Antioxidans) bei verschiedenen Krankheiten festgestellt wurden, aber seine konkrete Funktion bei rheumatoider Arthritis (RA) ist noch nicht dargelegt worden. In der vorliegenden Arbeit war es das Ziel, die spezifische Rolle und die zugrunde liegenden Mechanismen von Sal bei mit RA assoziierten fibroblastenartigen Synoviozyten (RA-FLS) zu untersuchen.

Methoden

Zur Prüfung der Lebensfähigkeit von normalen FLS und RA-FLS wurde das Zellzählungssystem CCK‑8 („cell counting kit 8“) eingesetzt. Zellapoptose bei RA-FLS wurde mittels Durchflusszytometrie gemessen. Mit Westernblots wurde der Gehalt an apoptose- und signalwegassoziierten Proteine bestimmt. Zur Untersuchung der RA-FLS-Migration und -Invasion wurden Wundheilungs- und Transwell-Assays durchgeführt. ELISA-Tests wurden zur Bestimmung der Wirkung von Sal auf durch Tumornekrosefaktor-alpha (TNF-α) induzierte Inflammation in RA-FLS verwendet. Ein RA-Tiermodell wurde mithilfe der Induktion durch CFA („complete Freund’s adjuvant“, komplettes Freund-Adjuvans) etabliert, und die histopathologischen Veränderungen im Synovialgewebe des Rattenmodells wurden anhand der Hämatoxylin-Eosin(HE)-Färbung analysiert.

Ergebnisse

RA-FLS wurden mit 200 μM Sal für 24 h behandelt, und die Zelllebensfähigkeit wurde so wesentlich unterdrückt. Sal förderte die RA-FLS-Apoptose. Die Migrations- und Invasionsfähigkeit von RA-FLS wurde durch Sal deutlich inhibiert. Durch Sal-Inkubation reduzierten sich die Werte der inflammatorischen Zytokine Interleukin‑8 (IL-8), IL-1β und IL‑6 in RA-FLS unter der Stimulation von TNF‑α. In der Folge wurde durch Sal die Expression von phosphorylierter Phosphatidylinositol-3-Kinase (p-PI3K) und Proteinkinase (p-AKT) in RA-FLS downreguliert. Nach Behandlung mit dem Signalwegaktivator 740Y‑P (20 μM) in RA-FLS kehrte sich der fördernde Effekt von Sal auf die Zellapoptose um, und seine inhibitorischen Effekte auf die Zelllebensfähigkeit, -migration, -invasion und entzündliche Reaktion wurden aufgehoben. Sal inhibierte also die RA-Entstehung im CFA-induzierten Rattenmodell.

Schlussfolgerung

Sal unterdrückte Zellwachstum und entzündliche Reaktionen in RA-FLS durch Inaktivierung des PI3K/AKT-Signalwegs.

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Acknowledgements

We appreciate all participants who contributed to the study

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Authors and Affiliations

  1. Department of Rheumatology and Immunology, Qinghai University Affiliated Hospital, 810000, Xining, China

    Yajing Qin & Juan Su

  2. Qinghai University Affiliated Hospital, No. 29 Tongren Road, Chengxi District, Xining, Qinghai, China

    Juan Su

Authors
  1. Yajing Qin
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  2. Juan Su
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Contributions

Y. Qin was the main designer of this study. Y. Qin and J. Su performed the experiments and analyzed the data. Y. Qin and J. Su drafted the manuscript. Y. Qin and J. Su read and approved the final manuscript.

Corresponding author

Correspondence to Juan Su.

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Conflict of interest

Y. Qin and J. Su declare that they have no competing interests.

All procedures performed in studies involving human participants or on human tissue were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. The Institutional Animal Care and Use Committee of Qinghai University Affiliated Hospital approved all the animal procedures.

Additional information

Redaktion

Ulf Müller, Ladner, Bad Nauheim

Uwe Lange, Bad Nauheim

Data Availability Statement

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Qin, Y., Su, J. Salidroside suppresses cell growth and inflammatory response of fibroblast-like synoviocytes via inhibition of phosphoinositol-3 kinase/threonine kinase signaling in rheumatoid arthritis. Z Rheumatol 83 (Suppl 1), 78–87 (2024). https://doi.org/10.1007/s00393-023-01431-5

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