Anti-inflammatory constituents in noni (Morinda citrifolia) fruits, sweet orange (Citrus sinensis) peel, and biotransformation pathway of nobiletin

Anti-inflammatory constituents from food sources are receiving increasing attention recent years due to the correlation between inflammation and cancer. A myriad of flavonoids, terpenoids, curcuminoids have been isolated from natural sources as potential anti-inflammatory agents. They often act by modulation of pro-inflammatory mediators such as prostaglandins, interleukins etc.; In this research we attempted to characterize the anti-inflammatory principals from noni (Morinda citrifolia) fruits and sweet orange ( Citrus sinensis) peels, along with evaluation of their activity in vivo. Solvent extraction and column chromatography were major techniques used for isolation of compounds, while structures were elucidated by integration of data from UV, IR, MS and NMR analysis. Anti-inflammatory activity was assessed by mouse ear edema model. Subsequent ELISA analysis was used for evaluation of their effects on anti-inflammatory mediators such as IL-1beta, IL-6 and PGE2.; Morinda citrifolia (Noni) is a tropical plant whose leaves, barks, roots and fruits have been used as traditional remedy for various diseases. Scopoletin, quercetin, ursolic acid were identified as major anti-inflammatory constituents in Noni fruit. Since ursolic acid was known to have anti-inflammatory activity, we characterized the mode of action of scopoletin and quercetin in mouse ear inflammation model. The most potent inhibition occurred at 0.5 mumol level for both quercetin (62.3%) and scopoletin (50.4%). Scopoletin mainly inhibited production PGE2 while quercetin had significant suppressing effect on IL-6 production. Both compounds showed moderate inhibition on IL-1beta production.; A total of 7 polymethoxy1flavones were identified from sweet orange peel. Nobiletin, a major component, and orange peel extract PMF fraction were tested for their anti-inflammatory activity. Nobiletin was found to suppress ear inflammation, and also the release of both IL-1beta and IL-6. More importantly, a synergistic effect was observed among PMFs for their anti-inflammatory activity and suppression effects on cytokines.; Another factor that came into our consideration is the metabolic fate of PMFs after ingestion. Nobiletin may undergo metabolic biotransformation in vivo, be demethylated by hepatic P450 enzymes, giving rise to more redox-active hydroxylated metabolites. We established a method by comparing the LC-MS profile of metabolites with a synthetic standard, which is one of our proposed metabolite, and then identify the structure of synthetic standard by NMR study. By using this method, we demonstrated that 3'-demethylation is a minor metabolism pathway in mouse. Further investigation in major biotransformation pathway is still in progress.