A novel resveratrol analog upregulates sirtuin 1 and inhibits inflammatory cell infiltration in acute pancreatitis

Acute pancreatitis (AP), an inflammatory disorder of the pancreas, is a complicated disease without specific drug therapy. (R)-4,6-dimethoxy-3-(4-methoxy phenyl)-2,3-dihydro-1H-indanone [(R)-TML104] is a synthesized analog of the natural product resveratrol sesquiterpenes (±) -isopaucifloral F. This study aimed to investigate the effect and underlying mechanism of (R)-TML104 on AP. The experimental AP model was induced by caerulein hyperstimulation in BALB/c mice. (R)-TML104 markedly attenuated caerulein-induced AP, as evidenced by decreased pancreatic edema, serum amylase levels, serum lipase levels, and pancreatic myeloperoxidase activity. In addition, (R)-TML104 significantly inhibited the expression of pancreatic chemokines C–C motif chemokine ligand 2 and macrophage inflammatory protein-2 and the infiltration of neutrophils and macrophages. Mechanistically, (R)-TML104 activated AMP-activated protein kinase and induced sirtuin 1 (SIRT1) expression. (R)-TML104 treatment markedly induced the SIRT1-signal transducer and activator of transcription 3 (STAT3) interaction and reduced acetylation of STAT3, thus inhibiting the inflammatory response mediated by the interleukin 6-STAT3 pathway. The effect of (R)-TML104 on SIRT1-STAT3 interaction was reversed by treatment with a SIRT1 inhibitor selisistat (EX527). Together, our findings indicate that (R)-TML104 alleviates experimental pancreatitis by reducing the infiltration of inflammatory cells through modulating SIRT1. Similar content being viewed by others Log in or create a free account to read this content Gain free access to this article, as well as selected content from this journal and more on nature.com or Data availability The authors declare that the main data supporting the findings of this study are available within the article. Extra data are available from the corresponding author upon request.

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The work was supported by funds from the National Natural Science Foundation of China (Grant nos: 80270666, 81870439, 81973322, 91642114, 31570915, and National Youth 1000 Talents Plan), the Natural Science Foundation for Distinguished Young Scholars of Jiangsu Province (Grant no: BK20200026), Jiangsu Province Recruitment Plan for High-level, Innovative and Entrepreneurial Talents (Innovative Research Team), Wuxi Social Development Funds for International Science & Technology Cooperation (Grant no: WX0303B010518180007PB), Jiangsu Province “Six Summit Talents” program (Grant no: YY-038), Jiangsu Province Qing Lan Project, National First-class Discipline Program of Food Science and Technology (Grant no: JUFSTR20180103), the Fundamental Research Funds for the Central Universities (Grant nos: JUSRP221037, JUSRP22007), Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant no: KYCX20_1876), Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province and Wuxi Taihu Talent Project. Shanghai Municipal Committee of Science and Technology (Grant no: 17JC1400200). Youth Project of Public Health Research Center of Jiangnan University (Grant no: JUPH201825); Translational Medicine Project of Wuxi Municipal Commission of Health and Family Planning (Grant no: ZM007); Wuxi City’s first “double hundred” young and middle-aged medical and health talents (Grant no: BJ2020045); Wuxi Social Development Science and Technology Demonstration Project (Grant no: N20201003). Author information Authors and Affiliations Contributions ZNR, MYZ, YH, and DXS performed experiments and analyzed data. XS synthesized and provided novel resveratrol analog (R)-TML104. JS and LLP designed and interpreted experiments. JY contributed to the data acquisition and critically reviewed the manuscript. ZNR, LLP, and JS wrote the paper. Corresponding authors Ethics declarations Competing interests The authors disclose no competing interests. Supplementary information Rights and permissions About this article Cite this article Ren, Zn., Yang, J., Zhang, My. et al. A novel resveratrol analog upregulates sirtuin 1 and inhibits inflammatory cell infiltration in acute pancreatitis. Acta Pharmacol Sin 43, 1264–1273 (2022). https://doi.org/10.1038/s41401-021-00744-y Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1038/s41401-021-00744-y