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

在加拿大，与饮食和环境有直接或间接联系的慢性病流行正面临重大挑战。世界癌症研究基金会发现，富含水果和蔬菜的饮食可以大大降低患多种癌症的风险。因此，通过饮食调整进行化学预防，即增加水果和蔬菜的消费以及使用来自水果和蔬菜的新型食品成分，对于管理当前和新出现的卫生保健挑战将非常重要。具有抗氧化和细胞信号传导调节特性的黄酮、三萜和类胡萝卜素现在被广泛认为是水果中的主要成分，其提供超出基本营养功能的特定健康益处。 我的研究计划的总体愿景是为开发基于黄酮类化合物的功能性食品和营养保健品做出贡献，以降低人类慢性疾病的风险。该研究计划的长期目标是发现抗氧化和化学预防水果黄酮类化合物，其代谢产物和衍生物，然后探索安全有效分子的细胞信号传导调节特性。未来五年的研究将旨在促进我们在分子水平上了解水果类黄酮如何有助于保护免受各种致癌因素引起的DNA损伤。 在这项新的研究中，将利用分离的益生菌将吸收不良的聚合类黄酮（如原花青素）生物转化为简单的生物活性分子。新形成的分子将被分离和纯化，用于使用核磁共振和质谱进行结构解析。为了研究类黄酮及其代谢产物保护DNA损伤的能力，将使用人类细胞培养物的实验诱导突变模型。将使用多个参数评估DNA损伤，包括磷酸化组蛋白γ-H2 A的最灵敏的免疫荧光测定。在这项拟议的研究中，先进的分子方法，如DNA微阵列和全基因组RNAi筛选将用于鉴定黄酮类化合物及其代谢物诱导的DNA损伤信号转导，DNA修复机制和致癌基因的调控。还将探索通过ω-3脂肪酸的酰化来增强类黄酮的吸收。 HQP将在植物食品中存在的生物活性化合物的营养代谢组学的跨学科新兴领域进行培训。通过这项研究独特的食品生物活性制造方法，预计将推出新的癌症预防功能食品和营养保健品，有助于减少加拿大新兴癌症发病率造成的社会和经济负担。

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.