Identification of phosphodiesterase-4 as the therapeutic target of arctigenin in alleviating psoriatic skin inflammation

doi:10.1016/j.jare.2021.02.006

	Identification of phosphodiesterase-4 as the therapeutic target of arctigenin in alleviating psoriatic skin inflammation
	Li, Heng 1,2; Zhang, Xianglei 2,3; Xiang, Caigui 1,2; Feng, Chunlan 1; Fan, Chen 1; Liu, Moting 1,2; Lu, Huimin 1,2; Su, Haixia 2,3; Zhou, Yu 1; Qi, Qing 1
刊名	JOURNAL OF ADVANCED RESEARCH
	2021-11-01
卷号	33 页码:241-251
关键词	PDE4 Arctigenin Psoriasis Inflammation
ISSN号	2090-1232
DOI	10.1016/j.jare.2021.02.006
通讯作者	Xu, Yechun(ycxu@simm.ac.cn) ; Tang, Wei(tangwei@simm.ac.cn)
英文摘要	Introduction: Arctigenin, derived from Arctium lappa L., has multiple pharmacological activities, including immunoregulatory, anti-diabetic, anti-tumor, and neuroprotective effects. Nevertheless, the potential therapeutic target of arctigenin in modulating inflammation remains undefined. Objectives: In the present study, we identified that arctigenin was a phosphodiesterase-4 (PDE4) selective inhibitor for the first time. Further investigations were performed to fully uncover the effects and mechanism of arctigenin on experimental murine psoriasis model. Methods: Crystal structure determination, PDEs enzyme assay, and isothermal titration calorimetry were included to illustrate the binding specialty, inhibitory effects, and selectivity of arctigenin on PDE4D. The anti-inflammatory effects were conducted in LPS-activated human peripheral blood mononuclear cells (PBMCs) and RAW264.7 cells. Imiquimod-induced murine psoriasis was performed to uncover the therapeutic effects and mechanism of arctigenin in vivo. Results: Arctigenin could bind to the catalytic domain of PDE4D via formation of hydrogen bonds as well as-stacking interactions between the dibenzyl butyrolactone of arctigenin and several residues of PDE4D. Accordingly, arctigenin showed prominent anti-inflammation in human PBMCs and murine RAW264.7 cells. PDE4 inhibition by arctigenin resulted in elevation of intracellular cyclic adenosine monophosphate (cAMP) and phosphorylation of cAMP-response element binding protein (CREB), which were largely blocked through intervention of protein kinase A (PKA) activity by H89 treatment or reduction of protein expression by siRNA transfection. Moreover, we first identified that a topical application of arctigenin ameliorated experimental psoriatic manifestations in imiquimod-induced murine psoriasis model by decreasing adhesion and chemotaxis of several inflammatory cells. Further proteomics analysis revealed that arctigenin could rectify the immune dysfunction and hyperactivation of keratinocytes in the inflamed skin microenvironments, which might be largely related to the expression of Keratins. Conclusion: The research provided credible clew that inhibition of PDE4 by arctigenin might function as the potential therapeutic approach for the treatment of psoriasis. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.
资助项目	National Key R&D Program of China[2016YFA0502301] ; CAS Key Laboratory of Receptor Research[SIMM1904YKF-01] ; Science and Technology Commission of Shanghai Municipality, China[18431907100] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-006-011] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020231]
WOS关键词	ARCTIUM-LAPPA L. ; OXIDATIVE STRESS ; LUNG INJURY ; TH17 CELLS ; IN-VITRO ; INHIBITION ; MECHANISMS ; PROTECTS ; PATHWAY
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	ELSEVIER
WOS记录号	WOS:000701927300008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297523]
专题	中国科学院上海药物研究所
通讯作者	Xu, Yechun; Tang, Wei
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Antiinflammat & Immunopharmacol, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Li, Heng,Zhang, Xianglei,Xiang, Caigui,et al. Identification of phosphodiesterase-4 as the therapeutic target of arctigenin in alleviating psoriatic skin inflammation[J]. JOURNAL OF ADVANCED RESEARCH,2021,33:241-251.
APA	Li, Heng.,Zhang, Xianglei.,Xiang, Caigui.,Feng, Chunlan.,Fan, Chen.,...&Tang, Wei.(2021).Identification of phosphodiesterase-4 as the therapeutic target of arctigenin in alleviating psoriatic skin inflammation.JOURNAL OF ADVANCED RESEARCH,33,241-251.
MLA	Li, Heng,et al."Identification of phosphodiesterase-4 as the therapeutic target of arctigenin in alleviating psoriatic skin inflammation".JOURNAL OF ADVANCED RESEARCH 33(2021):241-251.