The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-κB/NLRP3 signaling  

作　　者：Fang-ming Yang Di Fan Xiao-qian Yang Feng-hua Zhu Mei-juan Shao Qian Li Yu-ting Liu Ze-min Lin Shi-qi Cao Wei Tang Shi-jun He Jian-ping Zuo 

机构地区：[1]Laboratory of Immunology and Virology,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China [2]Laboratory of Immunopharmacology,State Key [3]University of Chinese Academy of Sciences,Beijing 100049,China

出　　处：《Acta Pharmacologica Sinica》2021年第4期593-603,共11页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(NSFC)(Grant No.81871240);the National Science and Technology Major Project“New Drug Creation and Manufacturing Program,”China(Grant No.2018ZX09711002-014-001);the Personalized Medicines—Molecular Signature-based“Drug Discovery and Development,”Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDA12020107 and XDA12020369).

摘　　要：Dry eye disease(DED)is a multifactorial disorder of the tears and ocular surface characterized by manifestations of dryness and irritation.Although the pathogenesis is not fully illuminated,it is recognized that inflammation has a prominent role in the development and deterioration of DED.β-aminoarteether maleate(SM934)is a water-soluble artemisinin derivative with antiinflammatory and immunosuppressive activities.In this study,we established scopolamine hydrobromide(SCOP)-induced rodent model as well as benzalkonium chloride(BAC)-induced rat model to investigate the therapeutic potential of SM934 for DED.We showed that topical application of SM934(0.1%,0.5%)significantly increased tear secretion,maintained the number of conjunctival goblet cells,reduced corneal damage,and decreased the levels of inflammatory mediators(TNF-α,IL-6,IL-10,or IL-1β)in conjunctiva in SCOP-induced and BAC-induced DED models.Moreover,SM934 treatment reduced the accumulation of TLR4-expressing macrophages in conjunctiva,and suppressed the expression of inflammasome components,i.e.,myeloid differentiation factor88(MyD88),Nod-like receptor protein 3(NLRP3),apoptosis-associated speck-like protein containing CARD(ASC),and cleaved caspase 1.In LPS-treated RAW 264.7 cells,we demonstrated that pretreatment with SM934(10μM)impeded the upregulation of TLR4 and downstream NF-κB/NLRP3 signaling proteins.Collectively,artemisinin analog SM934 exerts therapeutic benefits on DED by simultaneously reserving the structural integrity of ocular surface and preventing the corneal and conjunctival inflammation,suggested a further application of SM934 in ophthalmic therapy,especially for DED.

关 键 词：dry eye disease artemisinin derivative β-aminoarteether maleate inflammation MACROPHAGES TLR4 INFLAMMASOME 

分 类 号：R285[医药卫生—中药学]