Dual-function natural products:Farnesoid X receptor agonist/inflammation inhibitor for metabolic dysfunction-associated steatotic liver disease therapy  

作　　者：WANG Kang ZHANG Pengfei SUN Huiyong CUI Shuang AO Lanjia CUI Ming XU Xiaowei WANG Lin XU Yuanyuan WANG Guangji WANG Hong HAO Haiping 

机构地区：[1]State Key Laboratory of Natural Medicines,Key Laboratory of Drug Metabolism&Pharmacokinetics,China Pharmaceutical University,Nanjing 210009,China [2]Basic Science Research Center Base(Pharmaceutical Science),Shandong province,Yantai University,Yantai 264005,China [3]Jiangsu Tasly Diyi Pharmaceutical Co.,Ltd,Huaian 223002,China

出　　处：《Chinese Journal of Natural Medicines》2024年第11期965-976,共12页中国天然药物（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.81930109,82321005,82073926,82373946 and 82073928);the Major State Basic Research DevelopmentProgramofChina(Nos.2021YFA1301300and 2022YFA1303800);Overseas Expertise Introduction Project for Discipline Innovation(No.G20582017001);the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University(Nos.SKLNMZZ202202 and SKLNMZZ202402);the Fundamental Research Funds for the Central Universities(No.2632023TD10);the Project Program of Basic Science Research Center Base(Pharmaceutical Science)of Yantai University(No.Y202204).

摘　　要：Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's complex pathophysiology,ther-apies that simultaneously target multiple pathways are highly desirable.One promising approach is dual-modulation of the famesoid X receptor(FXR),which regulates lipid and bile acid metabolism.However,FXR agonists alone are insufficient due to their limited anti-inflammatory effects.This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD.Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger(2018)for molecular docking.Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance(SPR)binding assay,reporter gene ana-lysis,and reverse transcription-polymerase chain reaction(RT-PCR).The anti-inflammatory properties of these compounds were eval-uated in AML12 cells treated with tumor necrosis factor-alpha(TNF-α).Dual-function compounds with FXR agonism and inflamma-tion inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α.The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid.Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists,with 15 exhibiting a strong affinity for FXR recombinant protein.Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb.Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones.Three compounds(2,6,and 8)were identifi

关 键 词：FXR agonist INFLAMMATION Dual modulator Natural products MASLD 

分 类 号：R965[医药卫生—药理学]