Friday, November 22, 2024
11/22/2024
SUMMARY/ABSTRACT Flavonoids, the most common group of polyphenolic compounds, widely occur in foods of plant origin. The estimated daily intake of flavonoids can be up to 2 g. Higher flavonoid intake has been associated with a lower risk of type 2 diabetes (T2D) and cardiovascular diseases (CVD) in some but not all studies. This inconsistency may be because nutrition research relies heavily on self-reported measures of dietary intake that are often prone to measurement error. Furthermore, dietary instruments do not account for individual genetic and/or microbiome differences and differences in metabolic response to diet. While validated biological markers may represent an alternative approach for measuring diet, there are no we ll-established biomarkers of flavonoid intake. To better understand the effects of dietary flavonoids on health and risk of chronic diseases, biomarkers for their exposure and effects are needed. Recently, we and others have demonstrated that flavonoids can scavenge toxic reactive carbonyl species (RCS) and carbonyl stress can be a new mechanistic target of flavonoids for prevention of metabolic disorders. In our studies, we have demonstrated that flavonoids can scavenge RCS to form related RCS conjugates, and therefore, prevent the formation of advanced glycation end products (AGEs) in mice. In addition, we also identified several novel flavonoid metabolites related to oxidative stress. However, it is unknown whether these findings can be extrapolated to humans. This application is aimed to test the hypothesis that dietary flavonoids and their RCS conjugates and oxidized metabolites, can serve as biomarkers of flavonoid intake, reflect inter-individual differences, and be inversely associated with the risk of carbonyl stress and oxidative stress associated metabolic diseases. This hypothesis will be tested in three aims. Aim 1 is to demonstrate the formation and pharmacokinetics of RCS conjugates of the major dietary flavonoids and their metabolites in humans. In this aim, we will conduct four acute pharmacokinetic studies of the major dietary flavonoids by giving volunteers four different flavonoid-rich foods (green tea, soy milk, orange juice, and blueberries), respectively. Aim 2 is to determine the post-prandial effects of flavonoid intake on carbonyl stress and related AGEs in humans. The goals of Aim 3 are to determine 1) whether biomarkers of flavonoid intake identified can represent habitual intake from two well phenotyped observational studies – the Men’s Lifestyle Validation Study (MLVS) and the Women’s Lifestyle Validation Study (WLVS), which have detailed and repeated measurements of diet using multiple 7-day diet records (7DDRs); and 2) whether biomarkers of flavonoid intake are prospectively associated with risk of T2D in a cohort of female nurses and whether RCS, AGEs, and oxidative stress markers are mediators of this association. At the completion of these studies, our expectation is that we will have identified objective biomarkers of flavonoids that reflect their intake and biological functions.
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