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Published on: March 24, 2023
Oral Chinese patent medicine alleviates atopic dermatitis by regulating ALOX15-derived oxylipins disorder
Nan Ru1, Ming-Zhen Guo2, Hui Xu3
1State Key Laboratory of Bioactive Molecules and Druggability Assessment/Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs/Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility/The First Affiliated Hospital/The Sixth Affiliated Hospital/Guangdong Second Provincial General Hospital/Guangdong Engineering Research Center of Traditional Chinese Medicine & Health Products/International Cooperative Laboratory of TCM Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/College of Pharmacy/School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China; Shijie Hospital of Dongguan City, Dongguan, 523000, China.
Background:
Atopic dermatitis (AD) is a chronic inflammatory skin disease often exacerbated by psychological stress, yet the underlying mechanisms remain unclear. Wushe Zhiyang Pills (WZP), an oral Chinese patent medicine, is clinically used for dermatological conditions, but its efficacy and mechanisms in stress-aggravated AD have not been defined.
Purpose:
This study aims to evaluate the protective effects of WZP against AD under stress conditions, elucidate its molecular mechanisms, and identify its bioactive compounds.
Methods:
A murine AD model was established using repeated DNCB application, with or without chronic restraint stress to simulate psychological stress exposure. AD-like phenotypic severity, immune dysfunction, and inflammatory responses were comprehensively assessed. Targeted oxylipin lipidomics was performed to profile lipid mediator alterations, while molecular docking, molecular dynamics simulations, and cellular thermal shift assays (CETSA) were employed to identify and validate the direct target and active components of WZP.
Results:
WZP treatment significantly ameliorated AD-like symptoms, restored the Th1/Th2 immune balance, reduced mast cell infiltration and cutaneous inflammatory cytokine expression, and lowered serum IgE levels. Notably, psychological stress exacerbated AD by upregulating ALOX15 expression and disrupting the cutaneous oxylipin profile, with marked elevations in pro-inflammatory mediators such as 15-HETE. WZP effectively reversed these stress-induced oxylipin derangements. Mechanistically, cimifugin, a bioactive component of WZP, was identified as a direct inhibitor of ALOX15, binding stably to the enzyme and suppressing its activity, thereby restoring oxylipin homeostasis.
Conclusion:
WZP alleviates stress-aggravated AD by inhibiting ALOX15-mediated oxylipin disruption, with cimifugin as a key active component. This reveals a novel "Stress-ALOX15-oxylipin-inflammation" axis and supports WZP as a promising therapy for stress-associated AD.
