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

doi:10.1038/s41401-020-0484-5

	The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-kappa B/NLRP3 signaling
	Yang, Fang-ming 1,2; Fan, Di 1,2; Yang, Xiao-qian 2; Zhu, Feng-hua 2; Shao, Mei-juan 1,2; Li, Qian 2; Liu, Yu-ting 2,3; Lin, Ze-min 2; Cao, Shi-qi 2,3; Tang, Wei 2,3
刊名	ACTA PHARMACOLOGICA SINICA
	2020-08-03
页码	11
关键词	dry eye disease artemisinin derivative beta-aminoarteether maleate inflammation macrophages TLR4 inflammasome
ISSN号	1671-4083
DOI	10.1038/s41401-020-0484-5
通讯作者	He, Shi-jun(heshijun@simm.ac.cn) ; Zuo, Jian-ping(jpzuo@simm.ac.cn)
英文摘要	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. beta-aminoarteether maleate (SM934) is a water-soluble artemisinin derivative with anti-inflammatory 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-alpha, IL-6, IL-10, or IL-1 beta) 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 (10 mu M) impeded the upregulation of TLR4 and downstream NF-kappa B/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.
资助项目	National Natural Science Foundation of China (NSFC)[81871240] ; National Science and Technology Major Project New Drug Creation and Manufacturing Program, China[2018ZX09711002-014-001] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020107] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020369]
WOS关键词	OCULAR-SURFACE ; BENZALKONIUM CHLORIDE ; IMMUNOSUPPRESSIVE ACTIVITY ; EXPRESSION ; ACIDS ; CLASSIFICATION ; INFLAMMATION ; CONTRIBUTES ; DERIVATIVES ; DEFINITION
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000555417900005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292246]
专题	中国科学院上海药物研究所
通讯作者	He, Shi-jun; Zuo, Jian-ping
作者单位	1.Shanghai Univ Tradit Chinese Med, Lab Immunol & Virol, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Yang, Fang-ming,Fan, Di,Yang, Xiao-qian,et al. The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-kappa B/NLRP3 signaling[J]. ACTA PHARMACOLOGICA SINICA,2020:11.
APA	Yang, Fang-ming.,Fan, Di.,Yang, Xiao-qian.,Zhu, Feng-hua.,Shao, Mei-juan.,...&Zuo, Jian-ping.(2020).The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-kappa B/NLRP3 signaling.ACTA PHARMACOLOGICA SINICA,11.
MLA	Yang, Fang-ming,et al."The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-kappa B/NLRP3 signaling".ACTA PHARMACOLOGICA SINICA (2020):11.