Green Tea and Grape Seed Extract in Prevention of Iron Overload Disease

描述（由申请人提供）：遗传性血色素沉着症（HFE）是一种遗传性疾病，由于不适当的高肠道铁吸收，导致铁在体内过度积累。如果不及时治疗，这种铁超载疾病会导致肝硬化、肝癌、充血性心力衰竭、内分泌失调和过早死亡。HFE蛋白中的Cys 282 Tyr突变是人类已知的最常见的缺陷遗传特征，比囊性纤维化、苯丙酮尿症和肌肉萎缩症加起来还要普遍。在绿茶和葡萄籽中大量存在的精选生物活性膳食多酚，由于其对各种疾病的健康益处，正受到科学家和消费者越来越多的兴趣。据报道，某些膳食多酚化合物在体内和体外具有广泛的作用，包括金属螯合活性，因此，定期摄入某些膳食多酚化合物可能通过减少膳食铁的利用，在防止铁过载方面发挥重要作用。我们的目的是研究绿茶和葡萄籽提取物（GSE）对肠道铁吸收的影响，以及这些生物活性多酚如何影响铁代谢，为开发绿茶、葡萄籽提取物及其相关多酚产品作为治疗人类铁超载疾病的新方法提供必要的基础。根据我们的初步数据和已发表的文献信息，我们选择绿茶和GSE作为试验生物活性膳食多酚。更重要的是，它们含有低水平的促进铁吸收的因子（如抗坏血酸）。研究表明，绿茶及其主要的多酚类化合物EGCG和GSE会减少肠道铁的吸收。基于这些关键信息，本应用程序的主要目标是利用人类铁超载疾病的动物模型来研究它们的治疗潜力，并探索这些多酚影响铁状态的机制。为了解决这些问题，我们将进行以下具体目的：(1)在人铁过载病遗传性血色素沉着症小鼠模型中，验证经常饮用绿茶和GSE预防铁过载的假设，并评估它们对不同铁吸收信号的抑制作用。(2)探讨绿茶和GSE抑制人体铁过载病小鼠肠道铁吸收、降低铁状态的机制。由于这些选择的生物活性多酚可以直接抑制肠道铁的吸收，因此我们的研究的成功完成将有助于提出未来的人体研究，以确定绿茶，GSE及其相关多酚化合物对铁超载疾病的治疗作用。我们的初步数据和之前发表的文献资料显示了这个项目的可行性。更好地了解多酚对铁吸收的抑制作用机制将对设计针对铁超载疾病的治疗策略具有重要意义。

DESCRIPTION (provided by applicant): Hereditary hemochromatosis (HFE) is a genetic disorder that results in an excessive accumulation of iron in the body due to inappropriately high intestinal iron absorption. If it remains untreated, this iron overload disease results in cirrhosis of liver, hepatic carcinoma, congestive heart failure, endocrinopathies and premature death. The Cys 282 Tyr mutation in the HFE protein is the most common defective genetic trait known in humans, more prevalent than cystic fibrosis, phenylketonuria and muscular dystrophy combined. Selected bioactive dietary polyphenols, which are abundantly present in green tea and grape seed, are receiving increasing interest from the scientists and consumers due to their reported health benefits for a variety of disorders. Because selected dietary polyphenolic compounds reportedly have a wide range of effects in vivo and vitro, including metal chelating activity, the regular intake of selected dietary polyphenolic compounds may have important role in preventing iron overload by reducing the utilization of dietary iron. Our goals of this application are to examine effects of green tea and grape seed extract (GSE) on intestinal iron absorption and how these bioactive polyphenols affect iron metabolism to provide the groundwork necessary to develop green tea, GSE and their related polyphenolic products as a novel treatment for the human iron overload disorders. Green tea and GSE are chosen as test bioactive dietary polyphenols due to our preliminary data and published literature information. More importantly, they contain low levels of enhancing factors (e.g., ascorbic acid) of iron absorption. Studies showed that green tea and its major polyphenolic compounds EGCG and GSE decrease intestinal iron absorption. Based on this key information, the major goals of this application are to investigate their therapeutic potential using animal models of human iron overload disorders and explore the mechanism by which these polyphenols affect iron status. To address these issues, we will carry out the following Specific Aims: (1) To test the hypothesis that regular consumption of green tea and GSE prevents iron overload, and to evaluate their inhibitory action against different iron absorptive signals in mouse models of human iron overload disease hereditary hemochromatosis. (2) To explore the mechanism by which green tea and GSE inhibit intestinal iron absorption and decrease iron status in various mouse models of human iron overload disease. Since these selected bioactive polyphenols can directly inhibit intestinal iron absorption, successful completion of our studies will help propose future human studies to determine the therapeutic benefits of green tea, GSE and their related polyphenolic compounds in iron overload disorders. Our preliminary data and previously published literature information show the feasibility of this project. A better understanding of the mechanisms of polyphenols' inhibitory action on iron absorption will be important for designing therapeutic strategies that target iron overload disorders. PUBLIC HEALTH RELEVANCE: We are assessing the capacity of green tea and grape seed extract by evaluating their effects in animal models of iron overload disease and characterizing its mechanism. The purpose of this research is to create a valuable foundation to provide the groundwork necessary to develop green tea, grape seed extract and their related products as a novel treatment for the human iron overload disorder. Together, these studies should allow development of effective strategies for future clinical studies with green tea, grape seed extract and other bioactive polyphenols for early prevention of iron overload.