Many dietary bioactive components have been shown to suppress inflammation in various experimental models. TPA is widely used to induce skin inflammation in mice. Herein, we determined the protective effects of nobiletin (a citrus flavonoid, NOB) and its major metabolite 4′-demethylnobiletin (4DN), and curcumin (a dietary polyphenol, CUR) and its analog 7,7’-bromo-curcumin (CUR-Br) against TPA-induced skin inflammation. Growing evidence suggests that biotransformation plays critical roles in the bioactivities of dietary compounds. We reported previously that 4DN was one of the most abundant metabolites of NOB found in mice after long-term dietary administration of NOB, and its level in many tissues was much higher than that of NOB. Additionally, 4DN strongly inhibited LPS-stimulated inflammation in RAW 264.7 macrophages. Furthermore, we previously synthesized a series of CUR analogs with different substitution groups replacing the methoxy group, and determined their anti-inflammatory effects in LPS-stimulated macrophages and a colitis mouse model. And CUR-Br showed greater anti-inflammatory potency than did CUR in both models. In this study, we found that topical application of TPA led to ear edema in mice, and NOB, 4DN, CUR and CUR-Br greatly attenuated TPA-induced skin edema in a dose-dependent fashion. Moreover, 4DN and CUR-Br exerted much stronger anti-inflammatory effects than their parent compounds NOB and CUR, respectively. The inhibitory effects were associated with suppression on TPA-induced up-regulation of pro-inflammatory cytokines, such as IL-1β and IL-6. Mechanistic investigation shows that 4DN resulted in profound effects on multiple key proteins related with inflammation and carcinogenesis. 4DN significantly downregulated the expression of iNOS, COX-2 and MMP-9, suppressed phosphorylation of PI3K/Akt and ERK, and upregulated the expression of phase II antioxidant enzymes in TPA-treated mice. Both CUR-Br and CUR greatly diminished TPA-stimulated NFκB, STAT3, COX-2 and PI3K/Akt signaling pathways in mice. More importantly, not only did CUR-Br exhibit higher chemical stability than CUR, it also produced much stronger suppressive effects on the aforementioned signaling proteins. Overall, our results demonstrated that 4DN and CUR-Br had potent protective effects against TPA-induced skin inflammation, which provide a scientific basis for using these compounds to prevent inflammation-driven diseases in humans.

Inhibitory effects of 4′-demethylnobiletin, a major metabolite of nobiletin and 7,7’-bromo-curcumin, a bioactive analog of curcumin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation

256th National Meeting (2018)

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