Biomarkers of Dietary Flavonoid Intake, Carbonyl Stress, and Metabolic Risk

膳食类黄酮摄入量、羰基应激和代谢风险的生物标志物

• 批准号: 10675105
• 负责人: Shilpa Nandana Bhupathiraju
• 金额: $ 66.7万
• 依托单位: NORTH CAROLINA AGRI & TECH ST UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675105
• 关键词: 4 hydroxynonenal; Acrolein; Acute; Advanced Glycosylation End Products; Aging; Algorithms; Apple; Biological Availability; Biological Markers; Biological Process; Blueberries; Cardiovascular Diseases; Carotenoids; Chemicals; Chronic Disease; DNA; Diabetes Mellitus; Diet; Diet Records; Dietary Assessment; Dietary Flavonoid; Dietary intake; Disease; Disease Management; Drug Kinetics; Edible Plants; Epidemiology; Exposure to; Female; Flavonoids; Folic Acid; Food; Genetic; Glyoxal; Goals; Green tea; Health; Health Professional; Human; Individual; Individual Differences; Ingestion; Intake; Juice; Kinetics; Knowledge; Life Style; Lipids; Malondialdehyde; Measurement; Measures; Mediating; Mediator; Metabolic; Metabolic Diseases; Metabolism; Methods; Molecular; Mus; Natural Products; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; Nurses; Nurses' Health Study; Nutritional Study; Observational Study; Oranges; Oxidative Stress; Participant; Patient Self-Report; Phase; Phenotype; Pilot Projects; Plasma; Prevention; Property; Proteins; Pyruvaldehyde; Reaction; Reactive Inhibition; Research; Risk; Sampling; Soy Milk; Stress; Structure; Testing; Time; Urine; Validation; Woman; cohort; diabetes risk; dietary; dosage; epidemiology study; expectation; follow-up; gut microbiota; host microbiota; instrument; men; metabolomics; microbiome; novel; prevent; prospective; response; social; validation studies; volunteer

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.

摘要/摘要 类黄酮是最常见的多酚化合物，广泛存在于植物源食品中。这 估计每天黄酮类化合物的摄入量可达2克。较高的类黄酮摄入量与 在一些但并非全部研究中，降低 2 型糖尿病 (T2D) 和心血管疾病 (CVD) 的风险。这 不一致可能是因为营养研究严重依赖于自我报告的饮食摄入量测量结果 往往容易出现测量误差。此外，饮食工具并没有考虑到个体遗传 和/或微生物组差异以及对饮食的代谢反应的差异。在经过验证的生物标记物的同时 可能代表了测量饮食的另一种方法，但目前还没有成熟的生物标志物 类黄酮摄入量。为了更好地了解膳食类黄酮对健康和慢性病风险的影响， 需要针对其暴露和影响的生物标志物。最近，我们和其他人已经证明 黄酮类化合物可以清除有毒的反应性羰基物质（RCS），并且羰基应激可以成为一种新的机制 类黄酮预防代谢紊乱的目标。在我们的研究中，我们已经证明类黄酮 可以清除RCS以形成相关的RCS结合物，从而防止高级细胞的形成 小鼠糖基化终末产物（AGE）。此外，我们还鉴定了几种新型黄酮代谢物 与氧化应激有关。然而，尚不清楚这些发现是否可以推断到人类。这 该应用旨在检验膳食类黄酮及其 RCS 缀合物和氧化的假设 代谢物，可以作为黄酮类摄入量的生物标志物，反映个体间差异，并呈反比 与羰基应激和氧化应激相关代谢疾病的风险有关。这个假设 将在三个目标上进行测试。目的 1 是证明 RCS 缀合物的形成和药代动力学 人类主要膳食类黄酮及其代谢物。为实现这一目标，我们将开展四项重点工作： 通过给志愿者提供四种不同的富含类黄酮的食物，对主要膳食类黄酮进行药代动力学研究 （绿茶、豆奶、橙汁和蓝莓）。目标2是确定餐后 类黄酮摄入量对人体羰基应激和相关 AGE 的影响。目标 3 的目标是 确定 1) 确定的类黄酮摄入量生物标志物是否可以代表两个孔的习惯摄入量 表型观察研究 – 男性生活方式验证研究 (MLVS) 和女性生活方式 验证研究 (WLVS)，使用多次 7 天饮食对饮食进行详细和重复的测量 记录（7DDR）； 2) 类黄酮摄入量的生物标志物是否与 T2D 风险前瞻性相关 在一组女护士中进行研究，以及 RCS、AGE 和氧化应激标志物是否是这一因素的调节因素 协会。完成这些研究后，我们期望我们能够确定目标 反映其摄入量和生物功能的类黄酮生物标志物。