Modulation of the expression and activity of cathepsin S in reconstructed human skin by neohesperidin dihydrochalcone

化学 组织蛋白酶 基质金属蛋白酶 细胞生物学 生物化学 组织蛋白酶G 组织蛋白酶K 药理学 体外 生物 蛋白酵素 破骨细胞
作者
Juliette Sage,Justine Renault,Roxane Domain,Krzysztof K. Bojarski,Thibault Chazeirat,Ahlame Saidi,Éric Leblanc,Carine Nizard,Sergey A. Samsonov,Robin Kurfürst,Gilles Lalmanach,Fabien Lecaille
出处
期刊:Matrix Biology [Elsevier]
卷期号:107: 97-112 被引量:4
标识
DOI:10.1016/j.matbio.2022.02.003
摘要

Dysregulation of cathepsin S (Cat S), a cysteine protease involved in extracellular-matrix and basement membrane (BM) degradation, is a concomitant feature of several inflammatory skin diseases. Therefore, Cat S has been suggested as a potential therapeutic target. Flavonoids, which were identified as regulatory molecules of various proteolytic enzymes, exert beneficial effects on skin epidermis. Herein, thirteen flavonoid compounds were screened in vitro and in silico and neohesperidin dihydrochalcone (NHDC) was identified as a potent, competitive, and selective inhibitor (Ki=8±1 µM) of Cat S. Furthermore, Cat S-dependent hydrolysis of nidogen-1, a keystone protein of BM architecture, as well elastin, collagens I and IV was impaired by NHDC, while both expression and activity of Cat S were significantly reduced in NHDC-treated human keratinocytes. Moreover, a reconstructed human skin model showed a significant decrease of both mRNA and protein levels of Cat S after NHDC treatment. Conversely, the expression of nidogen-1 was significantly increased. NHDC raised IL-10 expression, an anti-inflammatory cytokine, and mediated STAT3 signaling pathway, which in turn dampened Cat S expression. Our findings support that NHDC may represent a valuable scaffold for structural improvement and development of Cat S inhibitors to preserve the matrix integrity and favor skin homeostasis during inflammatory events.
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