Resveratrol Ameliorates Systemic Sclerosis via Suppression of Fibrosis and Inflammation Through Activation of SIRT1/mTOR Signaling

Abstract

Purpose

Resveratrol (Res) is a natural polyphenolic compound found in several plants and reported as a promising biological molecule with effective anti-fibrosis and anti-inflammatory activities. However, the underlying mechanism of Res on systemic sclerosis (SSc) remains unclear. In the study, we identified the key cellular signaling pathways involved in the Res regulatory process on SSc.

Methods

Res-targeted genes interaction network was constructed using the STITCH database, and the shared Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in both SSc and Res-targeted genes were then identified. The top five enriched KEGG pathways were visualized by GOplot. KEGG pathways associated with Res-targeted genes were established by Pathway Builder Tool 2.0. Quantitative real-time PCR (qRT-PCR) was used to assess the expression of sirtuin 1 (SIRT1), mammalian targeted of rapamycin (mTOR), and cytokines.

Results

Enrichment analysis of Res-targeted genes showed 79 associated pathways, 27 of which were also involved in SSc. Particularly, SIRT1/mTOR signaling was found as one of the crucial regulatory pathways. In vitro results suggested that SIRT1-mediated mTOR degradation ameliorated bleomycin (BLM)-induced fibrosis and inflammation. Res was capable of elevating the SIRT1 level in fibroblasts and partially reversing mTOR-dependent induction of fibrosis and inflammation.

Conclusion

These results indicated that Res is a feasible and effective choice for SSc and therapeutic target of mTOR could be a potential alternative for treatment of SSc.

Keywords:

• resveratrol
• systemic sclerosis
• SIRT1
• mTOR
• signaling

Acknowledgments

This study was supported by the Research and Development fund of the Second Affiliated Hospital of Hainan Medical University (Hospital Fund Number: 2018–19).

Author Contributions

WC and BL designed the study. QY and QW collated the data, analyzed the data and produced the initial draft of the manuscript. QY, QW, XX, YX, JL, QL, MH, YC, BL and WC revised the figures and tables. QY, QW, BL and WC helped to draft the manuscript. All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

All authors declared no conflicts of interest.