Small moleculeα-methylene-γ-butyrolactone,an evolutionarily conserved moiety in sesquiterpene lactones,ameliorates arthritic phenotype via interference DNA binding activity of NF-κB  

作　　者：Kegang Linghu Wenqing Cui Taiqin Li Yueting Tuo Dasong Wang Huiqi Pan Tian Zhang Ligen Lin Hua Yu Xiaoxia Hu Haiyang Li Xiangchun Shen 

机构地区：[1]Department of Surgery,the Affiliated Hospital of Guizhou Medical University,Guiyang 550001,China [2]The Key Laboratory of Optimal Utilization of Natural Medicine Resources,School of Pharmaceutical Sciences,Guizhou Medical University,Guian New District,Guizhou 561113,China [3]State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macao,Macao SAR 999078,China [4]Guizhou Institute of Precision Medicine,Affiliated Hospital of Guizhou Medical University,Guiyang 550001,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第8期3561-3575,共15页药学学报（英文版）

基　　金：support by the National Natural Science Foundation of China(82260801);China Postdoctoral Science Foundation(2023M730815,China);Excellent Young Talents Plan of Guizhou Medical University(2023110,China);the Guizhou Provincial Scientific and Technologic Innovation Base([2023]003,China);the High Level Innovation Talents(GCC[2023]048,China);Science and Technology Development Fund,Macao SAR(0159/2020/A3,China);Guizhou Provincial Science and Technology Project(ZK[2024]152,China);Guizhou Provincial Health Commission Science and Technology Foundation(gzwkj2023-153,China)are gratefully acknowledged.

摘　　要：Rheumatoid arthritis(RA)is an inflammatory disease accompanied by abnormal synovial microenvironment(SM).Sesquiterpene lactones(SLs)are the main anti-inflammatory ingredients of many traditional herbs utilized in RA treatment.α-Methylene-γ-butyrolactone(α-M-γ-B)is a core moiety that widely exists in natural SLs.This study was designed to investigate the anti-arthritic potential ofα-M-γ-B as an independent small molecule in vitro and in vivo.α-M-γ-B exhibited stronger electrophilicity and anti-inflammatory effects than the other six analogs.α-M-γ-B inhibited the production of pro-inflammatory mediators via repolarizing M1 macrophages into M2 macrophages.The transcriptome sequencing suggested thatα-M-γ-B regulated the immune system pathway.Consistently,α-M-γ-B attenuated collagen type II-induced arthritic(CIA)phenotype,restored the balance of Tregs-macrophages and remodeled SM via repolarizing the synovial-associated macrophages in CIA mice.Mechanistically,althoughα-M-γ-B did not prevent the trans-nucleus of NF-κB it interfered with the DNA binding activity of NF-κB via direct interaction with the sulfhydryl in cysteine residue of NF-κB p65,which blocked the activation of NF-κB.Inhibition of NF-κB reduced the M1 polarization of macrophage and suppressed the synovial hyperplasia and angiogenesis.α-M-γ-B failed to ameliorate CIA in the presence of N-acetylcysteine or when the mice were subjected to the macrophage-specific deficiency of Rela.In conclusion,α-M-γ-B significantly attenuated the CIA phenotype by directly targeting NF-κB p65 and inhibiting its DNA binding ability.These results suggest thatα-M-γ-B has the potential to serve as an alternative candidate for treating RA.The greater electrophilicity ofα-M-γ-B,the basis for triggering strong anti-inflammatory activity,accounts for the reason whyα-M-γ-B is evolutionarily conserved in the SLs by medical plants.

关 键 词：a-Methylene-gbutyrolactone Rheumatoid arthritis NF-κB p65 Synovial microenvironment Sesquiterpene lactones 

分 类 号：R96[医药卫生—药理学]