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)-TML104on 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.

Zheng-nan Ren;Jun Yang;Meng-ya Zhang;Yi-wen Huang;Dong-xiao Song;Xun Sun;Li-long Pan;Jia Sun

Wuxi Medical School and School of Food Science and Technology,Jiangnan University,Wuxi 214122,China;State Key Laboratory of Food Science and Technology,Jiangnan University,Wuxi 214122,China;Department of General Surgery,Affiliated Hospital of Jiangnan University,Wuxi 214122,China;Department of Natural Products Chemistry,School of Pharmacy,Fudan University,Shanghai 201203,China

中国药理学报（英文版）

[1]Zheng-nan Ren;Jun Yang;Meng-ya Zhang;Yi-wen Huang;Dong-xiao Song;Xun Sun;Li-long Pan;Jia Sun-.A novel resveratrol analog upregulates sirtuin 1 and inhibits inflammatory cell infiltration in acute pancreatitis)[J].中国药理学报（英文版）,2022(05):1264-1273

TML104,isopaucifloral,TML104on,selisistat

novel,resveratrol,analog,upregulates,sirtuin,inhibits,inflammatory,infiltration,acute,pancreatitis,Acute,AP,disorder,pancreas,complicated,disease,without,specific,drug,therapy,dimethoxy,phenyl,dihydro,1H,indanone,synthesized,natural,product,sesquiterpenes,This,study,aimed,investigate,effect,underlying,mechanism,experimental,model,was,induced,by,caerulein,hyperstimulation,BALB,mice,markedly,attenuated,evidenced,decreased,pancreatic,edema,serum,amylase,levels,lipase,myeloperoxidase,activity,In,addition,significantly,inhibited,expression,chemokines,motif,ligand,protein,neutrophils,macrophages,Mechanistically,activated,AMP,kinase,SIRT1,treatment,signal,transducer,activator,transcription,STAT3,interaction,reduced,acetylation,thus,inhibiting,response,mediated,interleukin,pathway,reversed,inhibitor,EX527,Together,our,findings,indicate,that,alleviates,reducing,cells,through,modulating

0.563336