Atopic dermatitis (AD) is a common chronic inflammatory skin disease, characterized by a T helper (Th)-2 cell-dominant inflammatory infiltrate and a defective epidermal permeability barrier. 1,2 Itch (or pruritus) is the major symptom of AD and causes a negative impact on quality of life. Intense itching is an unpleasant sensation, which evokes a strong desire to scratch. Moreover, itch-induced scratching aggravates skin lesions, and a vicious itch-scratch circle and consequent skin barrier destruction are easily established. 3,4 Previous studies exhibited that reducing physical stimulus to the skin, such as nail clipping, inhibits the development of AD in patients and AD-like phenotypes in a spontaneous mouse model. 5,6 However, the underlying mechanism through which scratching exacerbates dermatitis remains to be investigated.Transient receptor potential vanilloid type 1 (TRPV1), a nonselective cation channel with high permeability to calcium widely expressed in the epidermal keratinocytes, can be activated by heat, capsaicin, mechanical stimulus and endogenous inflammatory mediators. Stimulation of TRPV1 is reported to trigger neurogenic inflammatory mediator and neuropeptide releases, which ultimately contributes to the development of pruritus and diverse dermatoses. 7,8 Given the involvement of the TRPV1 receptor in the itching associated with pruritic inflammatory skin disease, we hypothesized

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Purpose To undercover the underlying mechanisms of luteolin against atopic dermatitis (AD), clinically characterized by recurrent eczematous lesions and intense itching, based on network pharmacology, molecular docking and in vivo experimental validation. Methods TCMSP, STITCH and SwissTargetPrediction databases were utilized to screen the corresponding targets of luteolin. Targets related to AD were collected from DisGeNET, GeneCards and TTD databases. PPI network of intersection targets was constructed through STRING 11.0 database and Cytoscape 3.9.0 software. GO and KEGG enrichment analysis were performed to investigate the critical pathways of luteolin against AD. Further, the therapeutic effects and candidate targets/signaling pathways predicted from network pharmacology analysis were experimentally validated in a mouse model of AD induced by 2, 4-dinitrofluorobenzene (DNFB). Results A total of 31 intersection targets were obtained by matching 151 targets of luteolin with 553 targets of AD. Among all, 20 core targets were identified by PPI network topology analysis, including IL-6, TNF, IL-10, VEGFA, IL-4, etc., and molecular docking indicated that luteolin binds strongly to these core targets. KEGG pathway enrichment analysis suggested that the intersected targets were significantly enriched in IL-17 signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation, JAK/STAT signaling pathway, etc. The in vivo experiment validated that luteolin could alleviate AD-like skin symptoms, as evidenced by the lower SCORAD score, the reduced infiltration of mast cells and the recovery of skin barrier function. Furthermore, luteolin restored immune balance by regulating the production of Th1/Th2/Th17-mediated cytokines, which were both the predicted core targets. Moreover, luteolin inhibited the phosphorylation of JAK2 and STAT3 in the lesional skin. Conclusion Together, the present study systematically clarifies the ameliorative effects and possible molecular mechanisms of luteolin against AD through the combination of network pharmacology and experimental validation, shedding light on the future development and clinical application of luteolin.

Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disorder. Obesity is associated with increased prevalence and severity of AD for reasons that remain poorly understood. Myricetin, a dietary flavonoid found in fruits and vegetables, is known to have anti-inflammatory effects, but its role in AD is unclear. Thus, we investigated the effects of obesity on exacerbation AD lesions, and evaluated the effects of myricetin on obese AD. Mice were fed normal diet (ND) or high-fat diet (HFD), and then 2,4-dinitrofluorobenzene (DNFB) was used to induce AD-like lesions. We found that obesity exacerbated AD lesions, and myricetin topical administration ameliorated symptoms and skin lesions of obsess AD mice such as dermatitis scores, scratching behavior, epidermal thickness and mast cell infiltration. In addition, myricetin reduced the levels of IgE and histamine, inhibited the infiltration of CD4+T cells and modulated the expression of Th1, Th2, Th17 and Th22 cytokines and pro-inflammatory factors (CCL17, CCL22, IL-1β, TGF-β). Moreover, myricetin restored impaired barrier function by reducing trans-epidermal water loss (TEWL), increasing lamellar body secretion, as well as up-regulating the mRNA and protein expression of filaggrin. Western blot results showed that significantly increased levels of phosphorylated IκB and NF-κB p65 was observed in the obese AD mice compared to the AD mice fed ND, while the myricetin could downregulated the phosphorylation of them, and inhibited mRNA expression of iNOS and COX2. Taken together, these results suggest that myricetin treatment exhibits potentially protective effects against the obese AD by inhibiting inflammatory response and restoring skin barrier function.

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