(S)-(-)-blebbistatin O-benzoate has the potential to improve atopic dermatitis symptoms in NC/Nga mice by upregulating epidermal barrier function and inhibiting type 2 alarmin cytokine induction.

Autor: Sahara S; Research and Development Division, PIAS Corporation, Kobe, Hyogo, Japan., Ueno A; Research and Development Division, PIAS Corporation, Kobe, Hyogo, Japan., Wakita N; Research and Development Division, PIAS Corporation, Kobe, Hyogo, Japan., Iwai M; Research and Development Division, PIAS Corporation, Kobe, Hyogo, Japan., Uda J; Research and Development Division, PIAS Corporation, Kobe, Hyogo, Japan., Nakaoji K; Research and Development Division, PIAS Corporation, Kobe, Hyogo, Japan., Hamada K; Research and Development Division, PIAS Corporation, Kobe, Hyogo, Japan., Maeda A; Office of Management and Planning, Osaka University, Suita, Osaka, Japan., Kaneda Y; Vice President Office, Osaka University, Suita, Osaka, Japan., Fujimoto M; Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 May 07; Vol. 19 (5), pp. e0302781. Date of Electronic Publication: 2024 May 07 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0302781
Abstrakt: Atopic dermatitis is a multi-pathogenic disease characterized by chronic skin inflammation and barrier dysfunction. Therefore, improving the skin's ability to form an epidermal barrier and suppressing the production of cytokines that induce type 2 inflammatory responses are important for controlling atopic dermatitis symptoms. (-)-Blebbistatin, a non-muscle myosin II inhibitor, has been suggested to improve pulmonary endothelial barrier function and control inflammation by suppressing immune cell migration; however, its efficacy in atopic dermatitis is unknown. In this study, we investigated whether (S)-(-)-blebbistatin O-benzoate, a derivative of (-)-blebbistatin, improves dermatitis symptoms in a mite antigen-induced atopic dermatitis model using NC/Nga mice. The efficacy of the compound was confirmed using dermatitis scores, ear thickness measurements, serum IgE levels, histological analysis of lesions, and filaggrin expression analysis, which is important for barrier function. (S)-(-)-Blebbistatin O-benzoate treatment significantly reduced the dermatitis score and serum IgE levels compared to those in the vehicle group (p < 0.05). Furthermore, the histological analysis revealed enhanced filaggrin production and a decreased number of mast cells (p < 0.05), indicating that (S)-(-)-blebbistatin O-benzoate improved atopic dermatitis symptoms in a pathological model. In vitro analysis using cultured keratinocytes revealed increased expression of filaggrin, loricrin, involucrin, and ceramide production pathway-related genes, suggesting that (S)-(-)-blebbistatin O-benzoate promotes epidermal barrier formation. Furthermore, the effect of (S)-(-)-blebbistatin O-benzoate on type 2 alarmin cytokines, which are secreted from epidermal cells upon scratching or allergen stimulation and are involved in the pathogenesis of atopic dermatitis, was evaluated using antigens derived from mite feces. The results showed that (S)-(-)-blebbistatin O-benzoate inhibited the upregulation of these cytokines. Based on the above, (S)-(-)-blebbistatin O-benzoate has the potential to be developed as an atopic dermatitis treatment option that controls dermatitis symptoms by suppressing inflammation and improving barrier function by acting on multiple aspects of the pathogenesis of atopic dermatitis.
Competing Interests: A patent including part of this work has been filed by PIAS Corporation and Osaka University [PCT/JP2021/047502]. There are no more patents, products in development or marketed products to declare. This does not alter the authors’ adherence to the policies of PLOS ONE on sharing data and materials.
(Copyright: © 2024 Sahara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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