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

Qicen Yao,1,* Qingchao Wu,2,* Xiayu Xu,1 Yixi Xing,1 Jin Liang,1 Qianqi Lin,1 Meiqiong Huang,1 Yiling Chen,1 Bo Lin,3 Weifei Chen1 1Department of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China; 2Department of Rheumatology and Immunology, Minda Hospital of Hubei Minzu University, Enshi, Hubei Province, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weifei ChenDepartment of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, 368 Yehai Boulevard, Haikou City, Hainan Province, People’s Republic of ChinaEmail chenwf130@163.comBo LinDepartment of Pharmacy, The Second Affiliated Hospital of Hainan Medical University, 368 Yehai Boulevard, Haikou City, Hainan Province, People’s Republic of ChinaEmail linbo13518072160@163.comPurpose: 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