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- W2800232023 abstract "Topical application of coal tar is one of the oldest dermatological therapies. Despite its longstanding clinical use and efficacy, the molecular mechanism of coal tar therapy was unknown until our discovery that coal tar activates the aryl hydrocarbon receptor (AHR). We also reported on the physiological role for the AHR in maintaining epidermal homeostasis. Now we screened novel compounds and existing drugs for 1) AHR activity using a luciferase reporter system, CYP1A1 enzyme activity and protein expression, 2) potential therapeutic effects in a 3D skin model for atopic dermatitis, and 3) genotoxicity by the Ames test. We identified three different classes of AHR ligands as novel candidate drugs with therapeutic activity. Active compounds included carboxamide derivatives, benzimidazoisoquinolines, and indazole derivatives. All compounds reduced the Th2 cytokine-mediated hallmarks of atopic dermatitis as witnessed by reduced epidermal thickeness, spongiosis and apoptosis, and increased levels of epidermal differentiation genes and proteins like involucrin, filaggrin and loricrin. Epxression of chemoattractants CCL2 and CCL26 in keratinocytes was significantly reduced in AHR-ligand treated cultures. The low CYP1A1 enzyme activity induced by the investigated compounds may indicate a low risk of toxicity especially since the Ames test was also negative. These results clearly point towards a pivotal role for the AHR in dampening inflammatory events in keratinocytes induced by atopic dermatitis-associated cytokines. The development of much needed novel topical drugs for atopic dermatitis may therefore be directed towards targeting the AHR in the skin. Since we found structurally diverse ligands to have similar therapeutic activities, the proposed ligand promiscuity of the AHR may be less important as previously thought. Instead, the level and duration of receptor activation may be key for the development of novel therapeutic AHR ligands." @default.
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- W2800232023 date "2018-05-01" @default.
- W2800232023 modified "2023-10-18" @default.
- W2800232023 title "1075 From old king coal to novel therapeutics for inflammatory skin diseases: The aryl hydrocarbon Receptor as a therapeutic target" @default.
- W2800232023 doi "https://doi.org/10.1016/j.jid.2018.03.1088" @default.
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