Watanabe Yoshifumi

Body is always exposed to both endogenous and exogenous oxidative stress, and neutralizes them with antioxidant defense system. Imbalance between oxidant and antioxidant produces reactive oxygen and nitrogen species, causing oxidation of protein, lipid, and DNA damage that lead to aging and various types of diseases such as neurodegenerative, pulmonary, or cardiovascular disease. Therefore, antioxidative agents are important for prevention and treatment of these diseases. In this study, we screened Okinawan plant extract library of 80 species to find nuclear factor erythroid-derived two-like-2 (Nrf2)-dependent antioxidant activity by antioxidant response element (ARE)-lucifearase reporter assay. The three species extracts of Garcinia subelliptica, Ocimum gratissimum, and Plectranthus Ornatus dose-dependently induced mRNA and protein expression of HO1, a downstream antioxidant gene of Nrf2. Furthermore, these extracts induced nuclear translocation of Nrf2 and the reduction of reactive oxygen species (ROS). These results suggested that these plants are natural antioxidant sources of Nrf2 activators.

DNA methylation is an epigenetic modification that regulates gene transcription. DNA methyltransferase 1 (DNMT1) plays an important role in DNA methylation. However, the involvement of DNMT1 and DNA methylation in the pathogenesis of atopic dermatitis (AD) remains unclear. In this study, microarray analysis revealed that peripheral blood mononuclear cells of AD patients with low DNMT1 expression (DNMT1-low) highly expressed dendritic cell (DC) activation-related genes. Also, DNMT1-low AD patients exhibited a higher itch score compared to AD patients with high DNMT1 expression (DNMT1-high). By using an AD-like mouse model induced by the application of Dermatophagoides farinae body ointment, we found that Dnmt1 expression was decreased, while the expression of CeC chemokine receptor type 7 (Ccr7) was upregulated in mouse skin DCs. Furthermore, mice exposed to social defeat stress exhibited Dnmt1 downregulation and Ccr7 upregulation in skin DCs. Additionally, dermatitis and itch-related scratching behavior were exacerbated in AD mice exposed to stress. The relationship between low DNMT1 and itch induction was found in both human AD patients and AD mice. In mouse bone marrowderived DCs, Ccr7 expression was inhibited by 5-aza-2-deoxycytidine, a methylation inhibitor. Furthermore, in mouse skin DCs, methylation of CpG sites in Ccr7 was modified by either AD induction or social defeat stress. Collectively, these findings suggest that social defeat stress exacerbates AD pathology through Dnmt1 downregulation and Ccr7 upregulation in mouse skin DCs. The data also suggest a role of DNMT1 downregulation in the exacerbation of AD pathology.