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

描述(申请人提供)：遗传性血色沉着症(HFE)是一种遗传性疾病，由于肠道铁吸收过高而导致体内铁的过度积累。如果不进行治疗，这种铁超负荷疾病会导致肝硬变、肝癌、充血性心力衰竭、内分泌疾病和过早死亡。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、苯丙酮尿症和肌肉营养不良加在一起更常见。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大的兴趣。由于选定的膳食多酚化合物据报道在体内和体外具有广泛的作用，包括金属螯合活性，因此经常摄入选定的膳食多酚化合物可能通过减少膳食铁的利用而在防止铁超载方面发挥重要作用。我们的应用目标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、GSE及其相关多酚产品作为治疗人类铁过载疾病的新疗法提供必要的基础。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作为试验的生物活性膳食多酚。更重要的是，它们含有低水平的铁吸收促进因子(如抗坏血酸)。研究表明，绿茶及其主要多酚化合物EGCG和GSE降低了肠道铁的吸收。基于这一关键信息，该应用的主要目标是利用人类铁过载障碍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，我们将实现以下具体目标：(1)检验经常饮用绿茶和GSE可防止铁超载的假设，并在人类铁超负荷疾病遗传性血色素沉着症小鼠模型中评估它们对不同铁吸收信号的抑制作用。(2)探讨绿茶和GSE抑制人铁超载性疾病小鼠肠道铁吸收、降低铁状态的作用机制。由于这些选定的生物活性多酚可以直接抑制肠道铁的吸收，我们的研究的成功完成将有助于推动未来的人类研究，以确定绿茶、GSE及其相关多酚化合物在铁超载疾病中的治疗效果。我们的初步数据和之前发表的文献资料表明了这一项目的可行性。更好地了解多酚抑制铁吸收的机制对于设计针对铁超载障碍的治疗策略将是重要的。 与公共健康相关：我们正在通过评估绿茶和葡萄籽提取物在铁超负荷疾病动物模型中的作用并表征其机制来评估其能力。这项研究的目的是为开发绿茶、葡萄籽提取物及其相关产品作为治疗人类铁超载障碍的新药物奠定有价值的基础。总而言之，这些研究应该可以为未来的临床研究开发有效的策略，使用绿茶、葡萄籽提取物和其他生物活性多酚来早期预防铁负荷。

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.