Inhibitory Effects of 4′-Demethylnobiletin, a Metabolite of Nobiletin, on 12-O-Tetradecanoylphorbol-13-acetate (TPA)-Induced Inflammation in Mouse Ears
Inhibitory Effects of 4′-Demethylnobiletin, a Metabolite of Nobiletin, on 12-O-Tetradecanoylphorbol-13-acetate (TPA)-Induced Inflammation in Mouse Ears
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DOI：
10.1021/acs.jafc.5b05156
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发表时间：
2015-12-30
影响因子：
6.1
通讯作者：
Xiao, Hang
中科院分区：
文献类型：
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作者：
Wu, Xian;Song, Mingyue;Xiao, Hang
诺比莱汀(Nobiletin，NOB)是柑橘类主要的黄酮类化合物，具有多种促进健康的功效。我们先前报道，NOB的主要代谢产物4‘-去甲基诺比林(4DN)能显著抑制脂多糖刺激的RAW 264.7巨噬细胞的炎症反应。在本研究中，我们进一步研究了4DN在TPA诱导的小鼠皮肤炎症中的抗炎作用。我们证明，局部应用4DN可减少TPA引起的小鼠耳肿胀，其作用强度为>；88+/-4.77%。这种抑制作用与抑制TPA诱导的促炎细胞因子IL-1β、IL-6和TNF-α的上调有关。免疫印迹结果显示，4DN对多种与炎症和癌变相关的蛋白质产生了深刻的影响。4丹参能显著降低TPA组小鼠iNOS、COX-2和MMP9的表达水平，抑制PI3K/Akt和ERK的磷酸化，升高HO-1和NQO1的水平。总体而言，实验结果表明，4DN在体内具有较强的抗炎作用，为利用NOB抑制炎症相关疾病提供了科学依据。
Nobiletin (NOB) is major citrus flavonoid with many health-promoting benefits. We reported previously that 4'-demethylnobiletin (4DN), a major metabolite of NOB, significantly inhibited lipopolysaccharide (LPS)-stimulated inflammation in RAW 264.7 macrophages. In this study, we further studied the anti-inflammatory effects of 4DN in TPA-induced skin inflammation in mice. We demonstrated that topical application of 4DN decreased TPA-induced ear edema by >88 +/- 4.77% in mice. This inhibitory effect was associated with inhibition on TPA-induced up-regulation of pro-inflammatory cytokines IL-1 beta, IL-6, and TNF-alpha. Immunoblotting results showed that 4DN resulted in profound effects on multiple proteins related with inflammation and carcinogenesis. 4DN significantly decreased the expression levels of iNOS, COX-2, and MMP-9, suppressed phosphorylation of PI3K/Akt and ERK, and increased the levels of HO-1 and NQO1 in TPA-treated mice. Overall, the results demonstrated that 4DN had strong anti-inflammatory effects in vivo, which provided a scientific basis for using NOB to inhibit inflammation-driven diseases.