Natural Potent NAAA Inhibitor Atractylodin Counteracts LPS-Induced Microglial Activation

doi:10.3389/fphar.2020.577319

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	Natural Potent NAAA Inhibitor Atractylodin Counteracts LPS-Induced Microglial Activation
	Yang, Longhe 1; Ji, Chunyan 2; Li, Yitian 2; Hu, Fan 1; Zhang, Fang 1; Zhang, Haiping 3; Li, Long 4; Ren, Jie 2; Wang, Zhaokai 1; Qiu, Yan 2
刊名	FRONTIERS IN PHARMACOLOGY
	2020-10-02
卷号	11 页码:9
关键词	NAAA inhibitor atractylodin > anti-inflammation microglia traditional Chinese medicine
ISSN号	1663-9812
DOI	10.3389/fphar.2020.577319
英文摘要	N-acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme that inhibits the degradation of palmitoylethanolamide (PEA), an endogenous lipid that induces analgesic, anti-inflammation, and anti-multiple sclerosis through PPAR alpha activation. Only a few potent NAAA inhibitors have been reported to date, which is mainly due to the restricted substrate-binding site of NAAA. Here, we established a high-throughput fluorescence-based assay for NAAA inhibitor screening. Several new classes of NAAA inhibitors were discovered from a small library of natural products. One of these is atractylodin, a polyethylene alkyne compound from the root ofAtractylodes lancea(Thunb) DC., which significantly inhibits NAAA activity and has an IC(50)of 2.81 mu M. Kinetic analyses and dialysis assays suggested that atractylodin engages in competitive inhibitionviareversible reaction to the enzyme. Docking assays revealed that atractylodin occupies the catalytic cavity of NAAA, where the atractylodin furan head group has a hydrophobic-related interaction with the backbone of the Trp181 and Leu152 residues of human NAAA. Further investigation indicated that atractylodin significantly increases PEA and OEA levels and dose-dependently inhibits LPS-induced nitrate, TNF-alpha, IL-1 beta, and IL-6 pro-inflammatory cytokine release in BV-2 microglia. Our results show that atractylodin elevates cellular PEA levels and inhibits microglial activation by inhibiting NAAA activity, which in turn could contribute to NAAA functional research.
资助项目	Fujian Provincial Natural Science Foundation[2018J05142] ; Scientific Research Foundation of Third Institute of Oceanography, Ministry of Natural Resources[2016006] ; Scientific Research Foundation of Third Institute of Oceanography, Ministry of Natural Resources[2020010] ; National Natural Science Foundation of China[81901133]
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	FRONTIERS MEDIA SA
WOS记录号	WOS:000577709200001
内容类型	期刊论文
源URL	[http://119.78.100.204/handle/2XEOYT63/15669]
专题	中国科学院计算技术研究所期刊论文_英文
通讯作者	Wang, Zhaokai; Qiu, Yan
作者单位	1.Minist Nat Resources, Inst Oceanog 3, Tech Innovat Ctr Utilizat Marine Biol Resources, Xiamen, Peoples R China 2.Xiamen Univ, Sch Med, Inst Eye, Fujian Prov Key Lab Ophthalmol & Visual Sci, Xiamen, Peoples R China 3.Chinese Acad Sci, Shenzhen Inst Adv Technol, Joint Engn Res Ctr Hlth Big Data Intelligent Anal, Ctr High Performance Comp, Shenzhen, Peoples R China 4.Ningbo Univ, Inst Drug Discovery Technol, Ningbo, Peoples R China
推荐引用方式 GB/T 7714	Yang, Longhe,Ji, Chunyan,Li, Yitian,et al. Natural Potent NAAA Inhibitor Atractylodin Counteracts LPS-Induced Microglial Activation[J]. FRONTIERS IN PHARMACOLOGY,2020,11:9.
APA	Yang, Longhe.,Ji, Chunyan.,Li, Yitian.,Hu, Fan.,Zhang, Fang.,...&Qiu, Yan.(2020).Natural Potent NAAA Inhibitor Atractylodin Counteracts LPS-Induced Microglial Activation.FRONTIERS IN PHARMACOLOGY,11,9.
MLA	Yang, Longhe,et al."Natural Potent NAAA Inhibitor Atractylodin Counteracts LPS-Induced Microglial Activation".FRONTIERS IN PHARMACOLOGY 11(2020):9.