Abstract
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.
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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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Acknowledgements
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).
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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.
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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
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DOI: https://doi.org/10.1038/s41401-021-00744-y
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