Are metabolites of flavonoids responsible for the health benefits of fruit and vegetable consumption?

寻找在老龄化期间保持人口健康的战略是一项重大挑战。香料是在水果、蔬菜、浆果、葡萄酒、巧克力、茶等中发现的植物化合物，科学报告揭示了摄入量与以最佳健康状态活到老年的可能性增加之间的联系。此外，新闻，互联网和食品和健康杂志包含无数的报道，描述富含类黄酮的食物对健康的影响。然而，富含类黄酮的食物没有与之相关的官方健康声明，政府也不支持增加其摄入量以提供人群健康益处。为什么富含类黄酮的食物可能有助于延缓与年龄有关的疾病和紊乱的发作？奇怪的是，这是因为我们实际上对黄酮类化合物的工作原理知之甚少，尽管它们被广泛研究。事实上，我们现在才对它们的新陈代谢有了基本的了解（即，身体如何分解和处理它们），以及这对它们的活动产生的影响。不幸的是，目前我们甚至没有基本的工具来研究类黄酮代谢的产物（即，市售代谢物），因此不能确定代谢影响其生物活性的程度。在本研究中，我们希望通过使用有机合成技术生产黄酮代谢产物来解决这个问题。然后，这些代谢物可以用作研究类黄酮代谢物的生理丰度、它们与饮食消耗的相关性（即，摄入量的标志物）、代谢对其活性的影响及其作用的分子机制。考虑到最近提出类黄酮代谢物的重要性的报道（Rodriguez-Mateos等人，2014年），这个项目是特别及时的，我们的团队是领导这项研究的有利条件，因为我们是全球少数几个正在探索类黄酮代谢物活性的团队之一。在鉴定了相对于其未代谢的对应物高40倍丰度的类黄酮代谢物后（Czank等人，2012; De Ferrars等人，2013 & 2014），我们最近一直在研究血管和炎症细胞培养模型中选定数量的这些代谢物的活性（di Gesso et al.，2015; Amin等人，2015）。我们已经观察到相对于在食物中发现的未代谢形式，它们的生物活性通常更大且差异更大。很明显，解锁类黄酮功能活性的关键在于它们的代谢产物。然而，类黄酮被代谢成大量的代谢物，并且单独研究每一种将是一项猛犸的事业;特别是因为已经鉴定了超过4000种独特的类黄酮结构，并且一种单独的类黄酮可以代谢形成超过20-30种不同的代谢副产物。一种被称为结构活性关系（SAR）分析的技术，通常用于药物发现，可以加速这一过程沿着。SAR建立了预测代谢对生物活性的影响所需的数据，而无需单独测试所有代谢物。这将提供推动类黄酮未来临床验证所需的有价值的信息，这对于确定这些化合物如何有助于健康至关重要。在这个项目中，我们将：使用合成化学开发类黄酮代谢物并鉴定代谢物活性（目标1，合成和活性筛选）;进一步合成修饰代谢物以确定改变其结构对其功能的影响（目标2，SAR分析）;通过确定活性化合物的影响，确定代谢对生物作用机制的影响（在目标1和2中确定）对与炎症和血管功能相关的生物学途径的影响。

Finding strategies to maintain population health during ageing represents a major challenge. Flavonoids are plant compounds found in fruits, vegetables, berries, wine, chocolate, tea, etc., and scientific reports reveal associations between intake and increased likelihood of surviving to old age in optimal health. In addition, the news, internet and food and health magazines contain countless reports describing the health effects of flavonoid-rich foods. However, flavonoid-rich foods do not have official health claims associated with them and the government does not endorse their increased intake for providing population health benefit. Why is this the case, when flavonoid-rich foods may be able to help delay the onset of age-related diseases and disorders? Oddly enough it's because we actually know very little about how flavonoids work, despite their extensive study. In fact, we are just now forming a basic understanding of their metabolism (i.e., how the body breaks them down and processes them), and the impact this has on their activity. Unfortunately, presently we don't even have the basic tools to study the products of flavonoid metabolism (i.e., commercially available metabolites) and therefore, are unable to establish the extent to which metabolism impacts their biological activity. In the present study, we hope to remedy this by producing flavonoid metabolites using organic synthesis techniques. These metabolites can then be used as a tool for investigating the physiological abundance of flavonoid metabolites, their correlation with dietary consumption (i.e., markers of intake), the impact of metabolism on their activity and their molecular mechanisms of action.Considering recent reports proposing the importance of flavonoid metabolites (Rodriguez-Mateos et al., 2014), this project is particularly timely, and our group is well-situated to lead this research, as we are one of a few groups globally who are exploring the activity of flavonoid metabolites. After identifying a 40-fold higher abundance of flavonoid metabolites relative to their unmetabolised counterparts (Czank et al., 2012; De Ferrars et al., 2013 & 2014), we have recently been investigating the activity of a select number of these metabolites in vascular and inflammatory cell culture models (di Gesso et al., 2015; Amin et al., 2015). We have observed often greater and differential bioactivity relative to their unmetabolised forms found in food. It's clear that the key to unlocking the functional activity of flavonoids lies with their metabolites. However, flavonoids are metabolised to an extensive array of metabolites, and studying each individually would be a mammoth undertaking; particularly as over 4000 unique flavonoid structures have been identified and one individual flavonoid could be metabolised to form greater than 20-30 distinct metabolic by-products. A technique called structure activity relationship (SAR) analysis, which is commonly used for drug discovery can speed this process along. SAR establishes the data necessary to predict the effect of metabolism on bioactivity without having to test all the metabolites individually. This will provide valuable information required to drive future clinical validation of flavonoids, which is paramount to establishing how these compounds contribute to health. In this project we will: develop flavonoid metabolites using synthetic chemistry and identify metabolite activity (Objective 1, synthesis and activity screening); further synthetically modify the metabolites to establish the effect of altering their structure on their function (Objective 2, SAR analysis); establish the effects of metabolism on biological mechanism of action by identifying the impact of the active compounds (identified in Objective 1 & 2) on biological pathways associated with inflammation and vascular function.