典型文献
Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity
文献摘要：
Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases.Pregnane X receptor(PXR)is a key regulator in endo-and xeno-biotics metabolism,which has been considered as a promising therapeutic target for cholestasis.In this study we conducted human PXR(hPXR)agonistic screening using dual-luciferase reporter gene assays,which led to discovering a series of potent hPXR agonists from a small Euphorbiaceae diterpenoid library,containing 35 structurally diverse diterpenoids with eight different skeleton types.The most active compound 6,a lathyrane diterpenoid(5/11/3 ring system),dose-dependently activated hPXR with a high selectivity,and significantly upregulated the expression of hPXR downstream genes CYP3A4 and UGT1A1.In LCA-induced cholestasis mouse model,administration of compound 6(50 mg kg-1.d-1,ip)for 7 days significantly suppressed liver necrosis and decreased serum levels of AST,ALT,Tbili,ALP,and TBA,ameliorating LCA-induced cholestatic liver injury.We further revealed that compound 6 exerted its anti-cholestatic efficacy via activation of PXR pathway,accelerating the detoxification of toxic BAs and promoting liver regeneration.These results suggest that lathyrane diterpenoids may serve as a promising scaffold for future development of anti-cholestasis drugs.
文献关键词：
中图分类号：
作者姓名：
Dong Huang;Ying-yuan Zhao;Rui-min Wang;Wei Li;Fang-yu Yuan;Xue-long Yan;Xiao Yang;Gui-hua Tang;Sheng Yin;Hui-chang Bi
作者机构：
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China;NMPA Key Laboratory for Research and Evaluation of Drug Metabolism,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China
文献出处：
引用格式：
[1]Dong Huang;Ying-yuan Zhao;Rui-min Wang;Wei Li;Fang-yu Yuan;Xue-long Yan;Xiao Yang;Gui-hua Tang;Sheng Yin;Hui-chang Bi-.Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity)[J].中国药理学报（英文版）,2022(08):2139-2146
A类：
Cholestasis,Pregnane,hPXR,agonistic,lathyrane,Tbili
B类：
Natural,product,screening,discovery,novel,anti,cholestasis,activity,major,cause,series,bile,flow,malfunction,related,liver,diseases,receptor,key,regulator,endo,xeno,biotics,metabolism,which,has,been,considered,promising,therapeutic,target,In,this,study,we,conducted,human,using,dual,luciferase,reporter,assays,discovering,potent,agonists,from,small,Euphorbiaceae,library,containing,structurally,diverse,diterpenoids,eight,different,skeleton,types,most,active,compound,system,dose,dependently,activated,high,selectivity,significantly,upregulated,expression,downstream,genes,CYP3A4,UGT1A1,LCA,induced,mouse,model,administration,ip,days,suppressed,necrosis,decreased,serum,levels,AST,ALT,ALP,TBA,ameliorating,cholestatic,injury,We,further,revealed,that,exerted,its,efficacy,via,activation,pathway,accelerating,detoxification,toxic,BAs,promoting,regeneration,These,results,suggest,may,serve,scaffold,future,development,drugs
AB值：
0.614797
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机标中图分类号，由域田数据科技根据网络公开资料自动分析生成，仅供学习研究参考。
