Modulation of the arachidonic acid cascade by food polyphenols - A comprehensive analysis of their effects on 5-Lipoxygenase, Cytochrome-P450 and autoxidation pathways

• Applicant: Professor Dr. Nils Helge Schebb
• Subject Area: Food Chemistry
• Term: since 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258197145

Eicosanoids and oxidative metabolites of other poly-unsaturated fatty acids (PUFAs) are involved in intracellular signaling as well as the regulation of pain, and represent one of the most potent classes of endogenous mediators of inflammation. Due to their crucial physiological role more than half of the world pharmaceuticals directly influence the formation of these oxylipins. Although several studies demonstrate that nutrition alters the endogenous oxylipin pattern, the influence of most food ingredients, such as polyphenols, on the formation of oxylipins has not been investigated yet. Moreover, the studies demonstrating a significant impact of polyphenols on the arachidonic acid (AA) cascade and inflammation focused on the analysis of expression levels of single enzymes or the levels of single eicosanoids. These approaches disregard that the regulation of biological processes relies on a multitude of oxylipins. Thus, monitoring of single individual oxylipins draws an incomplete picture.Therefore, in this project, we will mechanistically investigate the impact of polyphenols on the AA cascade. For this purpose we will employ liquid chromatography mass spectrometry (LC-MS) for the quantification of a comprehensive set of oxylipins of all branches of the AA cascade as targeted metabolomics approach. We will analyze the effect of polyphenols on the activity of cyclooxgenase, lipoxygenase, cytochrome P450 and epoxide hydrolase pathways of the AA cascade in different cell culture assays as well as in cell free approaches. Moreover, we will utilize the oxylipin pattern to monitor oxidative stress occurring during inflammation and its amelioration by food-born antioxidants. With these high-content screening tools, we will not only discover potentially active polyphenols, but also gain information on their mode of action, quantitative data on their potency and qualitative data on the breadth of their effects. Subsequently, the most potent compounds will be investigated in rodent models of lipopolysaccharid induced sepsis and dextran sulfate sodium induced acute and chronic colitis. Changes in the oxylipin pattern will be correlated to physiological, histopathological and molecular biological parameters of inflammation. Overall, this project will lead to a deeper understanding of the nutritionally induced alterations in oxylipin patterns and their impact on inflammation. We will identify those polyphenols that potently alter regulatory lipid levels, elucidate their mechanistic mode of action and evaluate their biological effects in vivo. The obtained data will help to understand the general influence of polyphenols on inflammation and to evaluate their potential therapeutic value in modulating acute and chronic inflammatory processes.

• DFG Programme: Research Grants