Osthole relieves skin damage and inhibits chronic itch through modulation of Akt/ZO-3 pathway in atopic dermatitis

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease with a significant impact on quality of life (Schmitt et al., 2015; Simpson et al., 2017). Skin barrier disruption, irritation, and itching are all clinical signs of AD. Tight junction (TJ) is a reticular structure formed by the interaction of transmembrane proteins (claudins, occludin, junctional adhesion molecule (JAM), etc.), cytoplasmic proteins (zonula occludens [ZOs], cingulin, etc.), and cytoskeletal proteins (actin, myosin, etc.), is necessary for maintaining skin barrier homeostasis in multicellular organisms (Saitoh et al., 2015). Keratinocyte TJ makes up the majority of the skin barrier, which serves as the first line of protection against contact allergens and infections (Yokouchi and Kubo, 2018). Defects in TJ increase the risk of skin disorders like allergic contact dermatitis and AD (Yosipovitch, 2004). The Zona occludens family, ZO-1, ZO-2, and ZO-3, are peripheral proteins found in junction sites (Inoko et al., 2003) and play a crucial role in preserving the structural integrity of TJ. ZO-1 and ZO-2 bind directly to claudins (Cldns) (Beutel et al., 2019; Umeda et al., 2006); and if ZO-1 and ZO-2 are both absent, TJ transmembrane proteins scatter throughout the cytoplasm and impair TJ functions (Umeda et al., 2006). One previous study has shown that low molecular weight Aloe polysaccharides partially restored ZO-1 expression and ameliorated AD induced skin barrier dysfunction in an ovalbumin-induced AD model (Na et al., 2020). The function of ZO-3 in AD, however, is not known.

Although AD significantly impairs patients' quality of life, effective therapies remain extremely limited and there is an urgent need for new pharmacological candidates for AD treatment (Laughter et al., 2000; Shaw et al., 2011). Osthole is a key ingredient of the traditional Chinese medicine Cnidium monnieri [L.] Cusson and is commonly used for itch and allergy relief (Zhang et al., 2015). Previous research has revealed that osthole, a natural phytochemical, inhibits transient receptor potential vanilloid 3 (TRPV3) cation channels (Sun et al., 2018), and alleviates AD symptoms by directly decreasing thymic stromal lymphopoietin (TSLP) production (Fu and Hong, 2019). Furthermore, osthole demonstrated anti-histaminic effect comparable to fexofenadine, a third-generation antihistamine drug (Karolina Kordulewska et al., 2015). Despite its impressive anti-allergic and anti-pruritic properties, the protective effects of osthole on the skin barrier in AD remain unknown.

In the current study, we explored the function of ZO-3 in AD induced skin barrier damage, and tested the therapeutic effect of osthole in a mouse model of AD. Our findings demonstrate that osthole restores ZO-3 expression and skin barrier functions in AD skin, and thereby, osthole's therapeutic potential in AD.

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