Anti-atherogenic effects of soy-isoflavones

描述(由申请人提供) 健康饮食与预防慢性炎症的关系 疾病早已被人们认识到。一个重要的例子是大豆-- 异黄酮类，其消费与 动脉粥样硬化的发生率。这些好处的核心是 化合物是它们与活性氧(ROS)和氮的相互作用 物种(RN)既是内生的，也是通过环境产生的 曝光。然而，人们对这些产品的生物学效应知之甚少。 这些反应中。本文提出了异黄酮衍生物， 与炎性氧化剂反应后得到的，具有很强的抗氧化性 致动脉粥样硬化的作用。低密度脂蛋白的氧化修饰 以及随后对血管细胞功能的影响是 动脉粥样硬化的形成。低密度脂蛋白氧化的抑制和细胞信号的调节 通路已被认为是抗动脉粥样硬化的关键机制。 异黄酮类。在这个提议中，这些概念被扩展，并且潜在的 新型异黄酮衍生物的抗动脉粥样硬化作用 探索了炎症(即氯化和硝化异黄酮类)。这是 重要的是因为其天然形式的异黄酮对低密度脂蛋白的抑制作用很差 体外氧化，然而它们的消耗与 脂质过氧化。此外，异黄酮类化合物对KEY的影响 参与动脉粥样硬化形成的炎性信号通路尚未明确。 在某些情况下，还表现出促炎作用。具体来说， 天然异黄酮已被证明能刺激单核细胞-内皮细胞 相互作用，病变形成的早期事件。基于这些概念 上面讨论的和这里提供的初步数据，调查人员 假设大豆异黄酮的抗动脉粥样硬化作用是介导的 与ROS和RNS反应产生的副产物。这一假设 将通过测试来追求特定的目标，以确定本地人的效果 和修饰异黄酮对：(1)氧化低密度脂蛋白，(2)氧化低密度脂蛋白和ROS/RNS诱导的作用 血管内皮细胞的细胞死亡；(3)oxLDL依赖的单核细胞 牢固地黏附于内皮细胞。这些研究将产生新的见解 进入异黄酮类和ROS/RNS之间的相互作用，从而直接影响 抗氧化性能，对炎症细胞有更微妙的影响 信号通路。此外，预计机械论的洞察力将获得 将提供关于异黄酮类和异黄酮类的可能的药效开发的信息 其他多酚类物质。

DESCRIPTION (provided by applicant) The association of a healthy diet and prevention of chronic inflammatory diseases has long been recognized. An important example are the soy- isoflavones, consumption of which is associated with a decrease in the incidence of atherosclerosis. Central to the beneficial effects of these compounds are their interactions with reactive oxygen (ROS) and nitrogen species (RNS) that are generated both endogenously and via environmental exposure. Little is known, however, on the biological effects of the products of these reactions. It is proposed herein that derivatives of isoflavones, obtained after reaction with inflammatory oxidants, have potent anti- atherogenic effects. Oxidative modification of low-density lipoprotein (LDL) and subsequent effects on vascular cell function are key elements of atherogenesis. Inhibition of LDL oxidation and modulation of cell signaling pathways have been proposed as key anti-atherogenic mechanisms for the isoflavones. In this proposal, these concepts are extended and the potential anti-atherogenic roles of novel derivatives of isoflavones formed at sites of inflammation (namely chlorinated and nitrated isoflavones) explored. This is important since isoflavones in their native form are poor inhibitors of LDL oxidation in vitro, yet their consumption is associated with a decrease in lipid peroxidation. Furthermore, the effects of isoflavones on key inflammatory signaling pathways involved in atherogenesis are poorly defined and in some instances pro-inflammatory effects demonstrated. Specifically, native isoflavones have been shown to stimulate monocyte-endothelial cell interactions, an early event in lesion formation. Based on the concepts discussed above and preliminary data presented herein, the investigators hypothesize that the anti-atherogenic effects of soy-isoflavones are mediated by products derived from their reactions with ROS and RNS. This hypothesis will be pursued by testing the specific aims to determine the effect of native and modified isoflavones on: (1) LDL oxidation, (2) oxLDL and ROS/RNS-induced cell death in vascular endothelial cells, and (3) oxLDL-dependent monocyte firm adhesion to endothelial cells. These studies will yield novel insights into the interplay between isoflavones and ROS/RNS that impact on both direct anti-oxidant properties, and more subtle effects on inflammatory cell signaling pathways. Also, it is anticipated that mechanistic insights gained will provide information on possible herapeutic development of isoflavones and other polyphenols.