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Purpose Patients with Yusho, a condition caused by exposure to dioxins and dioxin-like compounds, have diverse mental and physical complaints. However, the relationship between dioxins and sleep disorders has not yet been examined. This cross-sectional study was designed to investigate problems associated with sleep among patients with Yusho. Methods A total of 140 participants (52.9% men, average age: 67.1 ± 12.2 years) were examined using questionnaires and medical interviews by an expert on sleep medicine. Demographic and clinical characteristics, including blood concentrations of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), which is the major cause of Yusho, were obtained from the results of recent surveys conducted by the Yusho Study Group. Results Moderate to severe symptoms of insomnia were present in 51.8% of the patients. The median Pittsburgh Sleep Quality Index global score (PSQI GS) was 8 (interquartile range: 5–11). The prevalence of restless legs syndrome/Willis–Ekbom disease (RLS/WED) was 30.7%; 24.3% of patients had severe RLS/WED (distressing symptoms with a frequency ≥ 1day per week). A higher blood concentration of 2,3,4,7,8-PeCDF (≥72.27 pg/g lipid) and severe RLS/WED were associated with higher odds of a PSQI GS ≥8, after adjusting for covariates (odds ratio [95% confidence interval]: 4.84 [1.10–21.25] and 4.15 [1.53–11.28], respectively). Conclusions Symptoms of insomnia were frequent, and the prevalence of RLS/WED was high in patients with Yusho. In addition to the presence of RLS/WED, a higher blood concentration of 2,3,4,7,8-PeCDF was associated with lower subjective sleep quality.

OVOLs (OVO-like proteins) are ubiquitously conserved genes encoding a C2H2 zinc finger transcription factor in mammals. Functional studies on OVOL1 and OVOL2 using knockout mice have suggested that these genes play a pivotal role in the development of epithelial tissues arising from germ cells; however, the role of the OVOL1–OVOL2 axis in normal and diseased tissues remains unclear. This review highlights recent advances in understanding how the OVOL1–OVOL2 axis modulates cell differentiation and proliferation in human keratinocytes, hair follicles, and benign or malignant skin tumors including squamous cell carcinoma and malignant melanoma. Furthermore, OVOL1 has been shown to be involved in the expression of skin barrier proteins including filaggrin (FLG), and its mutation or dysfunction leads to the development of atopic dermatitis (AD). OVOL1 has also been identified as a susceptibility gene for AD by genome-wide association studies, in addition to FLG. Therefore, we discuss the relationship between OVOL1 and FLG in the development of AD.

Background Persistent ultraviolet (UV) radiation in the form of sunlight causes photo-aging of the skin by reducing the production of type I collagen, the major constituent of the extracellular matrix of the dermis. Transforming growth factor (TGF)-β transforms dermal fibroblasts into α2-smooth muscle actin (ACTA2)-expressing myofibroblasts. Myofibroblasts produce a precursor form of type I collagen, type I procollagen (collagen I), consisting of pro-alpha1 (produced by the COL1A1 gene) and pro-alpha2 chains (produced by the COL1A2 gene). Smad2/3 is a key downstream molecule of TGF-β signaling. The mechanisms through which UV inhibits collagen I synthesis are not fully understood. 6-Formylindolo[3,2- b ]carbazole (FICZ) is an endogenous tryptophan photo-metabolite generated by UV irradiation. FICZ is well known as a high-affinity ligand for aryl hydrocarbon receptor (AHR). However, the physiological roles of FICZ in photo-aging have yet to be addressed. Objective To evaluate the effects of FICZ on the TGF-β-mediated ACTA2 and collagen I expression in normal human dermal fibroblasts (NHDFs). Methods Quantitative real-time polymerase chain reaction and western blot analysis were performed to determine the expression of ACTA2, COL1A1, and COL1A2 in NHDFs with or without FICZ and TGF-β. The phosphorylated Smad2/3 (pSmad2/3) protein levels in cytoplasmic or nuclear portions were investigated by western blot analysis. Immunofluorescence staining was conducted to evaluate pSmad2/3 localization, and F-actin staining with phalloidin was performed to visualize actin polymerization in myofibroblasts. The actions of FICZ on the TGF-β-mediated collagen I expression and nuclear translocation of pSmad2/3 were analyzed in the presence of selective AHR antagonists or in AHR-knockdown NHDFs. Results We found that FICZ significantly inhibited the TGF-β-induced upregulation of mRNA and protein levels of ACTA2 and collagen I and actin polymerization in myofibroblasts. FICZ did not disturb the phosphorylation of Smad2/3. Notably, FICZ reduced the expression of pSmad2/3 in the nucleus, while it increased that in the cytoplasm, suggesting that it inhibits the nuclear translocation of pSmad2/3 induced by TGF-β. The inhibitory actions of FICZ on the TGF-β-mediated collagen I expression and nuclear translocation of pSmad2/3 were independent of AHR signaling. Another endogenous AHR agonist, kynurenine, also inhibited the TGF-β-mediated ACTA2 and collagen I upregulation in NHDFs in an AHR-independent manner; however, its effects were insignificant in comparison with those of FICZ. Conclusions These findings suggest that the endogenous photo-product FICZ may be a key chromophore that involves in photo-aging. Downregulation of FICZ signaling is thus a potential strategy to protect against photo-aging.

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.

Exposure to dioxin-related compounds results in many adverse health effects. Several studies have examined the effects of dioxin-related compounds on human bone metabolism with inconsistent results. In Japan in 1968, accidental human exposure to rice oil contaminated with dioxin-related compounds led to the development of Yusho oil disease. The aim of this study was to determine whether exposure to dioxin-related compounds was associated with bone mineral density in Yusho patients. In 2010, 262 women and 227 men underwent dual-energy X-ray absorptiometry bone scans as part of the nationwide Yusho health examination. Serum levels of polychlorinated dibenzo-p-dioxin, polychlorinated dibenzofurans, and non-ortho polychlorinated biphenyls were measured using high-resolution gas chromatography and high-resolution mass spectrometry. When adjusted for prefecture, 1,2,3,4,7,8-HxCDD and 2,3,7,8-TCDF were significantly positively associated with Z-scores in men. No congeners were positively associated with Z-scores in women. After adjustment for prefecture and body mass index, one congener, 1,2,3,4,6,7,8-HpCDD, was negatively associated with Z-scores in women. In contrast, no congeners remained significant in men after adjusting for body mass index. This may suggest that 1,2,3,4,6,7,8-HpCDD has a negative effect on bone mineral density in women; however, the findings should be interpreted carefully, because no increase in the serum level of this congener was observed in patients with Yusho disease.

Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that binds to structurally diverse chemicals including dioxins, coal tar, flavonoids and tryptophan photoproducts. Upon ligation, cytoplasmic AHR translocates to the nucleus, heterodimerizes with aryl hydrocarbon receptor nuclear translocator and mediates numerous biological effects by inducing the transcription of various AHR-responsive genes such as epidermal barrier proteins. The activation of AHR usually generates oxidative stress. However, AHR also mediates antioxidant signaling by a plethora of ligands via nuclear factor-erythroid 2-related factor-2. Both oxidative and antioxidant ligands upregulate the expression of the filaggrin gene. We review the role of AHR signaling in the gene regulation of epidermal barrier proteins.

Background Benzo(a)pyrene (BaP) is an environmental contaminant found in cigarette smoke. It is well known that cigarette smoking exacerbates interleukin-8 (IL-8)-related inflammatory skin diseases such as psoriasis, palmoplantar pustulosis and acne. Although BaP has been shown to exert its biological effects via the aryl hydrocarbon receptor (AhR) signaling pathway, the mechanism of its inflammatory effects on skin remains unanswered. Objective To elucidate whether or not BaP cause AhR activation and subsequent oxidative stress leading to IL-8 production in normal human epidermal keratinocytes (NHEKs). Methods NHEKs exposed to BaP were analyzed. Immunofluorescence, real-time PCR, Western blotting, ELISA, reactive oxygen species (ROS) detection using H2DCFDA and RNA interference using si (small interfering) RNA were employed. Results Immunofluorescence analysis clearly demonstrated that BaP induced nuclear translocation of AhR from cytoplasm. The AhR activation subsequently induced CYP1A1 mRNA and protein expression in a dose-dependent manner. In addition, ROS and IL-8 production were coordinately augmented by BaP, whereas this was not the case in IL-1α, IL-6, TNF-α or GM-CSF production. Knockdown of AhR expression using siRNA transfection inhibited BaP-induced-ROS and IL-8 production, suggesting that these responses are strongly dependent on the AhR signaling pathway. Furthermore, the addition of N-acetyl cystein or catalase cancelled the IL-8 production by BaP, indicating that ROS production is essential for IL-8 production. Results This data highlights AhR-ROS-dependent regulation of IL-8 in NHEKs by BaP, providing a plausible explanation, at least in part, for why cigarette smoking exacerbates IL-8-related skin diseases such as psoriasis, palmoplantar pustulosis and acne.