title: Inhibition of aryl hydrocarbon receptor signaling and induction of NRF2-mediated antioxidant activity by cinnamaldehyde in human keratinocytes.
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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchi
authors.affiliation: Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Mao
authors.initials: M
authors.lastname: Yasumatsu
authors.affiliation: Division of Statistics, Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Morino-Koga
authors.affiliation: Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Chikage
authors.initials: C
authors.lastname: Mitoma
authors.affiliation: 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.
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives* / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000378:metabolism; D002460:Cell Line; D032904:Cinnamomum aromaticum / Q000737:chemistry*; D004147:Dioxins / Q000633:toxicity; D004785:Environmental Pollutants / Q000633:toxicity; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D020835:Medicine, Kampo; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000171:Acrolein; D000975:Antioxidants; D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D004147:Dioxins; D004785:Environmental Pollutants; D051547:Heme Oxygenase-1; D051267:NF-E2-Related Factor 2; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C495635:NFE2L2 protein, human; C496541:HMOX1 protein, human; C012843:cinnamaldehyde
keywords: Aryl hydrocarbon receptor; Cinnamaldehyde; Keishibukuryogan; Keratinocytes; Nrf2