Anti‐inflammatory Effects of 4′‐Hydroxy Nobiletin, the Major Metabolite of Nobiletin

Abstract

Nobiletin, a citrus flavonoid has been associated with various biological activities including anti‐inflammation. We have found that 4′‐hydroxy nobiletin (4′HN) was a major colonic metabolite in mice fed with nobiletin, and the colonic levels of 4′HN were much higher than those of nobiletin. Herein, we studied anti‐in&# 64258;ammatory effects of 4′HN in lipopolysaccharide (LPS)‐treated RAW264.7 macrophages. Treatments of 4′HN at non‐cytotoxic concentrations dose‐dependently inhibited LPS‐induced nitric oxide production in macrophages. These inhibitory effects were much stronger than those produced by nobiletin. Western blot analysis showed that 4′HN drastically decreased protein expression levels of iNOS and COX‐2. Furthermore, 4′HN also inhibited LPS‐induced activation of Iκβ‐α, Akt and SAPK/JNK. Real‐time qRT‐PCR showed that 4′HN decreased mRNA levels of iNOS and COX‐2. Heme oxygenase‐1 (HO‐1, an antioxidant enzyme) has been reported to suppress inflammatory responses. Our results demonstrated that 4′HN significantly increased the both protein and mRNA levels of HO‐1, which may contribute to its anti‐inflammatory effects. Overall our results demonstrated that 4′HN is a potent anti‐inflammatory colonic metabolite of nobiletin, which provide a scientific basis for using nobiletin as a nutraceutical ingredient to inhibit inflammation‐related diseases such as colitis and colon cancer.Grant Funding Source : NIH: CA139174, AICR: 10A044