Fruit flavonoids and their metabolites: mechanisms of action in biological systems

In Canada, significant challenges are being faced from chronic disease epidemics, which are directly or indirectly linked to diet and the environment. The World Cancer Research Fund has found that diets high in fruits and vegetables substantially reduce risks of several cancers. Therefore, chemoprevention through diet modification, i.e. increased consumption of fruits and vegetables as well as the use of novel food ingredients derived from fruits and vegetables, will be important in managing the current and emerging health care challenges. Flavonoids, triterpenes and carotenoids with antioxidant and cell signaling modulating properties are now widely recognized to be the principle components in fruits that provide specific health benefits beyond the basic nutritional functions. The overall vision of my research program is to contribute to the development of flavonoids-based functional foods and nutraceuticals to reduce the risk of chronic disorders of humans. The long-term objective of the research program is to discover antioxidant and chemopreventive fruit flavonoids, their metabolites and derivatives and then to explore the cell signaling modulating properties of safe and efficacious molecules. The next five years of research will aim to advance our understanding at the molecular level of how fruit flavonoids contribute to the protection against DNA damage caused by various carcinogenic factors. In this novel study, bio-conversion of poorly absorbed polymerized flavonoids such as proanthocyanidins into simple bioactive molecules will be achieved using isolated probiotic bacteria. The newly formed molecules will be isolated and purified for structure elucidation using nuclear magnetic resonance and mass spectroscopy. To investigate the ability of flavonoids and their metabolites to protect DNA damage, experimentally-induced mutagenesis models of human cell cultures will be used. DNA damage will be assessed using multiple parameters including the most sensitive immunofluorescence assay of phosphorylated histone protein, gamma-H2A.X. In this proposed research, advanced molecular approaches such as DNA microarrays and genome-wide RNAi screening will be used to identify flavonoids and their metabolites-induced regulation of genes involved in DNA damage signaling, DNA repair mechanisms and carcinogenesis. Enhancement of absorption of flavonoids through acylation of omega-3 fatty acids will also be explored. HQPs will be trained in interdisciplinary emerging areas of nutritional metabolomics of bioactive compounds present in plant foods. Through the unique food bioactive manufacturing approaches of this research, it is expected to introduce novel cancer preventive functional foods and nutraceuticals that could contribute to reduce the social and economic burdens due to the emerging cancer incidence in Canada.