A derivative of tanshinone IIA and salviadione,15a,inhibits inflammation and alleviates DSS-induced colitis in mice by direct binding and inhibition of RIPK2  

作　　者：Cheng-hong Hu Yue Chen Tian-yang Jin Zhe Wang Bo Jin Jing Liao Chun-yong Ding Ao Zhang Wei-yang Tang Ling-xi Zhang Lei-yu Xu Fang-min Ning Guang Liang Xiao-hong Wei Yi Wang 

机构地区：[1]School of Pharmacy,Hangzhou Normal University,Hangzhou,311121,China [2]Chemical Biology Research Center,Wenzhou Medical University,School of Pharmaceutical Sciences,Wenzhou,325035,China [3]Pharm-X Center,College of Pharmaceutical Sciences,Shanghai Jiao Tong University,Shanghai,200240,China [4]School of Pharmaceutical Sciences,Hangzhou Medical College,Hangzhou,310051,China

出　　处：《Acta Pharmacologica Sinica》2025年第3期672-686,共15页中国药理学报(英文版)

基　　金：supported by the Key Scientific Research Project of Wenzhou City(ZY2021021 to YW);the National Natural Science Foundation of China(82361138563 to YW).

摘　　要：Inflammatory bowel diseases(IBDs)are chronic inflammatory conditions primarily affecting the gastrointestinal tract.Previous studies established the role of the NF-κB signaling pathway in the development of IBDs,suggesting that anti-inflammatory therapies might offer a viable treatment strategy.Tanshinone IIA and salviadione,both derived from Salviae Miltiorrhizae Radix et Rhizoma,possess anti-inflammatory and anti-oxidative activities.A series of new compounds were synthesized by hybridizing salviadione with tanshinone.Among these compounds,15a showed beneficial effects in LPS-induced acute lung injury and diabetes-induced renal injury mouse models.The current study explored the therapeutic efficacy of 15a using both acute and chronic colitis models and elucidated the underlying mechanisms.DSS-induced colitis models were established in mice,where acute colitis was treated with compound 15a(5 or 10 mg·kg−1·d−1)for 8 days,while chronic colitis mice received compound 15a(5 or 10 mg·kg−1·d−1,i.g.)during 2.5%DSS administration.The 15a treatment significantly alleviated DSS-induced pathological and inflammatory damages in both acute and chronic colitis mouse models.In mouse intestinal epithelial cell line MODE-K,pretreatment with compound 15a(5 or 10μM)significantly suppressed LPS+L18-MDP-induced inflammatory responses.The receptor-interacting serine/threonine kinase 2(RIPK2)was identified as a direct binding target of compound 15a using microarrays and recombinant human proteins.Moreover,15a could directly bind to and inhibit the phosphorylation of RIPK2,leading to the suppression of the NF-κB and MAPK signaling pathways.Furthermore,LEU153 and VAL32 were identified within the KD domain of RIPK2 as critical amino residues for the binding of 15a.Briefly,the current findings demonstrate that compound 15a holds promise as a therapeutic agent for managing acute and chronic colitis.

关 键 词：inflammatory bowel diseases COLITIS tanshinone lIA and salviadione derivatives molecular target RIPK2 

分 类 号：R285.5[医药卫生—中药学] R285[医药卫生—中医学]