Abstract
The skin is an important physiological barrier against external stimuli, such as ultraviolet radiation (UV), xenobiotics, and bacteria. Dermal inflammatory reactions are associated with various skin disorders, including chemical-induced irritation and atopic dermatitis. Modulation of skin inflammatory response is a therapeutic strategy for skin diseases. Here, we synthesized chrysin-derivatives and identified the most potent derivative of Compound 6 (CPD 6). We evaluated its anti-inflammatory effects in vitro cells of macrophages and keratinocytes, and in vivo dermatitis mouse models. In murine macrophages stimulated by lipopolysaccharide (LPS), CPD 6 significantly attenuated the release of inflammatory mediators such as nitric oxide (NO) (IC50 for NO inhibition: 3.613 μM) and other cytokines. In cultured human keratinocytes, CPD 6 significantly attenuated the release of inflammatory cytokines induced by the combination of IFN-γ and TNF-α, UV irradiation, or chemical irritant stimulation. CPD 6 inhibited NFκB and JAK2/STAT1 signaling pathways, and activated Nrf2/HO-1 signaling. In vivo relevancy of anti-inflammatory effects of CPD 6 was observed in acute and chronic skin inflammation models in mice. CPD 6 showed significant anti-inflammatory properties both in vitro cells and in vivo dermatitis animal models, mediated by the inhibition of the NFκB and JAK2-STAT1 pathways and activation of Nrf2/HO-1 signaling. We propose that the novel chrysin-derivative CPD 6 may be a potential therapeutic agent for skin inflammation.
Highlights
Skin protects the body from external stimuli, such as xenobiotics, bacteria, and ultraviolet (UV) radiation, and prevents the loss of moisture from the body [1,2]
In order to identify a potent anti-inflammatory synthetic flavonoid, we initially evaluated the inhibitory effects of chrysin (CPD 1) and its derivatives (CPD 2 to 10; Figure 1A) on the release of nitric oxide (NO) in murine macrophage RAW 264.7 cells stimulated by lipopolysaccharide (LPS)
The anti-oxidant and chemo-preventive potential of chrysin has been reported suggesting this molecule as a promising drug candidate [31], and Choi et al have reported that chrysin attenuates atopic dermatitis in mouse models [23], providing an important clue of the therapeutic potential of chrysin against skin inflammation
Summary
Skin protects the body from external stimuli, such as xenobiotics, bacteria, and ultraviolet (UV) radiation, and prevents the loss of moisture from the body [1,2]. When the skin comes in contact with harmful stimuli, an inflammatory reaction occurs, and the barrier function is gradually lost. Inflammatory reactions, which can be acute or chronic, are characterized by pain, swelling, redness, and heat [3]. Excessive inflammatory reaction resulting from an impaired immune system can contribute to the development of various skin disorders such as allergic/irritant contact dermatitis, atopic dermatitis, and psoriasis [5,6]. These chronic recurring disorders are characterized by various clinical symptoms of edema and epidermal hyperproliferation [7,8]. Urgent needs exist to develop new anti-inflammatory agents with optimal efficacy and minimal side effects
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