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

引用

Acta Pharmaceutica Sinica B 2024年第8期14卷 3561-3575页

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 Department of Surgery the Affiliated Hospital of Guizhou Medical UniversityGuiyang 550001China The Key Laboratory of Optimal Utilization of Natural Medicine Resources School of Pharmaceutical SciencesGuizhou Medical UniversityGuian New DistrictGuizhou 561113China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao SAR 999078China Guizhou Institute of Precision Medicine Affiliated Hospital of Guizhou Medical UniversityGuiyang 550001China

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 *** 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 *** transcriptome sequencing suggested thatα-M-γ-B regulated the immune system ***,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 ***,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-κ*** 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 *** conclusion,α-M-γ-B significantly attenuated the CIA phenotype by directly targeting NF-κB p65 and inhibiting its DNA binding *** results suggest thatα-M-γ-B has the potential to serve as an alternative candidate for treating *** 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

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