Nobiletin and 5-Hydroxy-6,7,8,3',4'-pentamethoxyflavone Ameliorate 12- O-Tetradecanoylphorbol-13-acetate-Induced Psoriasis-Like Mouse Skin Lesions by Regulating the Expression of Ki-67 and Proliferating Cell Nuclear Antigen and the Differentiation of CD4+ T Cells through Mitogen-Activated Protein Kinase Signaling Pathways.

Psoriasis is a chronic and benign proliferative skin disease. Flavonoids in chenpi (aged tangerine peel) from tangerine ( Citrus reticulate Blanco), such as nobiletin (Nob), tangeretin, and 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone (5-HPMF), possess anti-inflammation and regulation of immune activity among others. In this study, psoriasis-like skin lesions were induced by 12- O-tetradecanoylphorbol-13-acetate (TPA), and the preventive effect of Nob and 5-HPMF on psoriasis-like skin lesions was evaluated. Results showed that skin lesions were dramatically reduced by Nob and 5-HPMF. Levels of cytokines, including interleukin (IL)-1β, IL-17, IL-4, IL-6, tumor necrosis factor-α, and interferon-γ, were also reduced after Nob and 5-HPMF treatment. The expression levels of p-ERK1/2 and p-p38 mitogen-activated protein kinase (MAPK) in the TPA group were 5.3, 4.8, and 5.7 but downregulated to 2.7, 2.9, and 2.3 in the Nob group and 2.4, 2.7, and 1.2 in the 5-HPMF group, respectively ( p ≤ 0.05). The expression of transcription factors Ki-67 and proliferating cell nuclear antigen (PCNA) and the differentiation of CD4+ T cells were reduced by downregulating the expression of the MAPK signaling pathways. The expression levels in TPA, Nob, and 5-HPMF groups were 0.649 ± 0.094, 0.218 ± 0.034, and 0.193 ± 0.042 for Ki-67 and 0.753 ± 0.114, 0.315 ± 0.094, and 0.294 ± 0.035 for PCNA, respectively. Moreover, 5-HPMF showed stronger reduction activity in the prevention of psoriasis than Nob, indicating that the 5-hydroxyl group facilitated the suppression of psoriasis.