Hiroshi Uchi1, Mao Yasumatsu2, Saori Morino-Koga3, Chikage Mitoma2, Masutaka Furue4. 1. Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: uchihir@dermatol.med.kyushu-u.ac.jp. 2. Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 3. Division of Statistics, Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 4. Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Abstract
BACKGROUND: Dioxins and other environmental pollutants are toxic and remain in biological tissues for a long time leading to various levels of oxidative stress. Although the toxicity of these agents has been linked to activation of the aryl hydrocarbon receptor (AHR), no effective treatment has been developed. OBJECTIVE: To explore novel phytochemicals that inhibit AHR activation in keratinocytes. METHODS: Keratinocytes were used in this study because the skin is one of the organs most affected by dioxin and other environmental pollutants. HaCaT cells, which are a human keratinocyte cell line, and normal human epidermal keratinocytes were stimulated with benzo[a]pyrene to induce AHR activation, and the effects of traditional Japanese Kampo herbal formulae were analyzed. Quantification of mRNA, western blotting, immunofluorescence localization of molecules, siRNA silencing, and visualization of oxidative stress were performed. RESULTS: Cinnamomum cassia extract and its major constituent cinnamaldehyde significantly inhibited the activation of AHR. Cinnamaldehyde also activated the NRF2/HO1 pathway and significantly alleviated the production of reactive oxygen species in keratinocytes. The inhibition of AHR signaling and the activation of antioxidant activity by cinnamaldehyde operated in a mutually independent manner as assessed by siRNA methods In addition, AHR signaling was effectively inhibited by traditional Kampo formulae containing C. cassia. CONCLUSION: Cinnamaldehyde has two independent biological activities; namely, an inhibitory action on AHR activation and an antioxidant effect mediated by NRF2/HO1 signaling. Through these dual functions, cinnamaldehyde may be beneficial for the treatment of disorders related to oxidative stress such as dioxin intoxication, acne, and vitiligo.
BACKGROUND:Dioxins and other environmental pollutants are toxic and remain in biological tissues for a long time leading to various levels of oxidative stress. Although the toxicity of these agents has been linked to activation of the aryl hydrocarbon receptor (AHR), no effective treatment has been developed. OBJECTIVE: To explore novel phytochemicals that inhibit AHR activation in keratinocytes. METHODS: Keratinocytes were used in this study because the skin is one of the organs most affected by dioxin and other environmental pollutants. HaCaT cells, which are a human keratinocyte cell line, and normal human epidermal keratinocytes were stimulated with benzo[a]pyrene to induce AHR activation, and the effects of traditional Japanese Kampo herbal formulae were analyzed. Quantification of mRNA, western blotting, immunofluorescence localization of molecules, siRNA silencing, and visualization of oxidative stress were performed. RESULTS:Cinnamomum cassia extract and its major constituent cinnamaldehyde significantly inhibited the activation of AHR. Cinnamaldehyde also activated the NRF2/HO1 pathway and significantly alleviated the production of reactive oxygen species in keratinocytes. The inhibition of AHR signaling and the activation of antioxidant activity by cinnamaldehyde operated in a mutually independent manner as assessed by siRNA methods In addition, AHR signaling was effectively inhibited by traditional Kampo formulae containing C. cassia. CONCLUSION:Cinnamaldehyde has two independent biological activities; namely, an inhibitory action on AHR activation and an antioxidant effect mediated by NRF2/HO1 signaling. Through these dual functions, cinnamaldehyde may be beneficial for the treatment of disorders related to oxidative stress such as dioxin intoxication, acne, and vitiligo.
Authors: Margaret Connolly; Andrea Axtell; Sean Hickey; Ann Whalen; Lucy McNamara; Dorothy Albright; Jonathan Friedstat; Jeremy Goverman Journal: Eplasty Date: 2017-06-01