GDU-952, a novel AhR agonist ameliorates skin barrier abnormalities and immune dysfunction in DNFB-induced atopic dermatitis in mice

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2023-09-29 DOI:10.1016/j.bcp.2023.115835

Ye-Hao Liang , Peng Shu , Yong-Liang Li , Menggeng Li , Zi-Heng Ye , Shanpeng Chu , Zhi-Yun Du , Chang-Zhi Dong , Bernard Meunier , Hui-Xiong Chen

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引用次数: 0

Abstract

The aryl hydrocarbon receptor (AhR) is widely expressed in the skin. It controls immune-mediated skin responses to various external environmental signals, promote terminal differentiation of epidermal keratinocytes and participates the maintenance of the skin barrier function. As a therapeutic target, AhR activation modulates many diseases progression driven by immune/inflammatory processes such as atopic dermatitis (AD) and psoriasis. In this study, we revealed that GDU-952 is a novel AhR agonist, which is able to decreases IgE serum levels, to inhibit pro-inflammatory cytokines such as IL-6 and TNF-α and to induce immunoregulatory effects through restoring Th1/Th2 immune balance and promoting CD4⁺FOXP3⁺regulatory T (Treg) populations in AD skin lesions. Furthermore, GDU-952 can strengthen the skin barrier function through upregulating epidermal differentiation-related and tight junction proteins. This may alleviate AD symptoms, such as dermatitis scores, epidermal hyperplasia and mast cell infiltration. These results offer a rationale for further preclinical/clinical studies to evaluate the possible use of GDU-952 in the management of AD.

Abstract Image

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GDU-952是一种新型AhR激动剂，可改善DNFB诱导的小鼠特应性皮炎的皮肤屏障异常和免疫功能障碍。

芳香烃受体（AhR）在皮肤中广泛表达。它控制免疫介导的皮肤对各种外部环境信号的反应，促进表皮角质形成细胞的末端分化，并参与皮肤屏障功能的维持。作为一种治疗靶点，AhR激活调节许多由免疫/炎症过程驱动的疾病进展，如特应性皮炎（AD）和银屑病。在本研究中，我们发现GDU-952是一种新型的AhR激动剂，它能够降低IgE血清水平，抑制IL-6和TNF-α等促炎细胞因子，并通过恢复Th1/Th2免疫平衡和促进AD皮肤病变中CD4+FOXP3+调节性T（Treg）群来诱导免疫调节作用。此外，GDU-952可以通过上调表皮分化相关和紧密连接蛋白来增强皮肤屏障功能。这可能会缓解AD症状，如皮炎评分、表皮增生和肥大细胞浸润。这些结果为进一步的临床前/临床研究提供了基础，以评估GDU-952在AD管理中的可能用途。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.