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Metabolic reprogramming of proinflammatory macrophages by target delivered roburic acid effectively ameliorates rheumatoid arthritis symptoms

查看全文 作　　者：Na [1]Jia;Yunzhen [1]Gao;Min [1]Li;Yi [1]Liang;Yuwen [2]Li;Yunzhu [1]Lin;Shiqi [1]Huang;Qing [1]Lin;Xun [1]Sun;Qin [1]He;Yuqin [1]Yao;Ben [1]Zhang;Zhirong [1]Zhang;Ling [1]Zhang 高影响力作者 机构地区：[1]Key Laboratory of Drug Targeting and Drug Delivery Systems,Ministry of Education,West China School of Pharmacy,College of Polymer Science and Engineering,State key Laboratory of Polymer Materials Engineering,West China School of Public Health and West China Fourth Hospital,Sichuan University,Chengdu 610041,P.R.China;[2]Department of Pharmacy,West China Hospital,Sichuan University,Chengdu 610041,China高影响力机构 出　　处：《Signal Transduction and Targeted Therapy》索引2023年第8卷第8期,共15页高影响力期刊 基　　金：This work was supported by the National Science Fund for Excellent Young Scholars(No:82022070);the Regional Innovation and Development Joint Fund(No:U20A20411). 摘　　要：Rheumatoid arthritis(RA)is a common chronic inflammatory disorder that usually affects joints.It was found that roburic acid(RBA),an ingredient from anti-RA herb Gentiana macrophylla Pall.,displayed strong anti-inflammatory activity.However,its medical application is limited by its hydrophobicity,lack of targeting capability and unclear functional mechanism.Here,we constructed a pH responsive dual-target drug delivery system hitchhiking RBA(RBA-NPs)that targeted both CD44 and folate receptors,and investigated its pharmacological mechanism.In rat RA model,the nanocarriers effectively delivered RBA to inflammatory sites and significantly enhanced the therapeutic outcomes compared with free RBA,as well as strongly reducing inflammatory cytokine levels and promoting tissue repair.Following analysis revealed that M1 macrophages in the joints were reprogrammed to M2 phenotype by RBA.Since the balance of pro-and anti-inflammatory macrophages play important roles in maintaining immune homeostasis and preventing excessive inflammation in RA,this reprogramming is likely responsible for the anti-RA effect.Furthermore,we revealed that RBA-NPs drove M1-to-M2 phenotypic switch by down-regulating the glycolysis level via blocking ERK/HIF-1α/GLUT1 pathway.Thus,our work not only developed a targeting delivery system that remarkably improved the anti-RA efficiency of RBA,but also identified a potential molecular target to reversely reprogram macrophages though energy metabolism regulation. 关 键 词：inflammatory metabolism programming
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