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

Zheng-nan Ren1,2, Jun Yang3, Meng-ya Zhang1,2, Yi-wen Huang1,2, Dong-xiao Song1,2, Xun Sun4, Li-long Pan1, Jia Sun1,2
1 Wuxi Medical School and School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
2 State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
3 Department of General Surgery, Affiliated Hospital of Jiangnan University, Wuxi 214122, China
4 Department of Natural Products Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
Correspondence to: Xun Sun:, Li-long Pan:, Jia Sun:,
DOI: 10.1038/s41401-021-00744-y
Received: 5 March 2021
Accepted: 12 July 2021
Advance online: 6 August 2021


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.
Keywords: acute pancreatitis; resveratrol analog; sirtuin 1; signal transducer and activator of transcription 3; anti-inflammation

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