Han Goeun, Gu Bon-Hee, Park Sun Young, Park Da Som, Hwang Su Mi, Ji Woonhak, Kim Seon Beom, Kim Myunghoo
Laboratory of Animal Immunology, Department of Animal Science, College of Natural Resource & Life Science, Pusan National University, Miryang, Republic of Korea; Institute for Future Earth, JYS Institute for Basic Science, Pusan National University, Busan, Republic of Korea.
Life and Industry Convergence Research Institute, Pusan National University, Miryang, Republic of Korea.
Biomed Pharmacother. 2025 May;186:118004. doi: 10.1016/j.biopha.2025.118004. Epub 2025 Mar 28.
The prevalence of atopic dermatitis (AD), a chronic inflammatory skin condition, is increasing. Coumarin derivatives, plant secondary metabolites, possess anti-inflammatory properties, but their specific role in AD treatment remain unclear. This study investigated the therapeutic potential of 7-geranyloxycoumarin (C#6), a selective coumarin derivative, in alleviating AD-like symptoms through multifaceted mechanisms. Among various coumarin derivatives tested, C#6 demonstrated remarkable efficacy in both in vitro and in vivo models. Notably, C#6 significantly suppressed interleukin-8 and thymic stromal lymphopoietin production in stimulated HaCaT cells. Experiments on an MC903-induced mouse model of AD revealed that topical administration of C#6 for 10 days led to a significant reduction in ear and epidermal thickness. Flow cytometry analysis showed a significant decrease in CD45 + leukocytes, eosinophils, and Th2 cells in C#6-treated AD mice. Importantly, 16S rRNA sequencing indicated that C#6 restored the disrupted skin microbiome by increasing the abundance of beneficial Lactobacillus and reducing pathogenic bacteria such as Enterobacteriaceae, Corynebacteriaceae, and Corynebacterium, contributing to maintaining skin microbiome balance. Molecular docking studies revealed high binding affinities of C#6 to key regulators, including NOD1, TLR2, PAR2, and TLR3, suggesting a role in modulating critical inflammatory pathways. Additionally, co-culture experiments revealed that C#6 treatment of TNF-α and IFN-γ-stimulated HaCaT cells suppressed inflammatory cytokines expression by THP-1 cells. Collectively, these findings demonstrate that C#6 exerts its anti-atopic effects by suppressing Th2-driven inflammation, reducing eosinophilic infiltration, modulating immune-epidermal crosstalk, and maintaining skin microbiome homeostasis, highlighting its potential as a promising therapeutic agent for AD management.
特应性皮炎（AD）是一种慢性炎症性皮肤病，其患病率正在上升。香豆素衍生物作为植物次生代谢产物，具有抗炎特性，但其在AD治疗中的具体作用仍不清楚。本研究调查了一种选择性香豆素衍生物7-香叶氧基香豆素（C#6）通过多方面机制缓解类AD症状的治疗潜力。在测试的各种香豆素衍生物中，C#6在体外和体内模型中均显示出显著疗效。值得注意的是，C#6显著抑制了刺激后的HaCaT细胞中白细胞介素-8和胸腺基质淋巴细胞生成素的产生。对MC903诱导的AD小鼠模型进行的实验表明，局部应用C#6 10天可显著降低耳部和表皮厚度。流式细胞术分析显示，C#6治疗的AD小鼠中CD45 +白细胞、嗜酸性粒细胞和Th2细胞显著减少。重要的是，16S rRNA测序表明，C#6通过增加有益的乳酸杆菌丰度并减少肠杆菌科、棒状杆菌科和棒状杆菌等病原菌，恢复了被破坏的皮肤微生物群，有助于维持皮肤微生物群平衡。分子对接研究表明，C#6与关键调节因子（包括NOD1、TLR2、PAR2和TLR3）具有高结合亲和力，表明其在调节关键炎症途径中发挥作用。此外，共培养实验表明，C#6处理TNF-α和IFN-γ刺激的HaCaT细胞可抑制THP-1细胞的炎性细胞因子表达。总的来说，这些发现表明，C#6通过抑制Th2驱动的炎症、减少嗜酸性粒细胞浸润、调节免疫-表皮相互作用以及维持皮肤微生物群稳态发挥其抗特应性作用，突出了其作为AD治疗有前景的治疗剂的潜力。
