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 疾病早已被认识。 一个重要的例子是大豆- 其消费量减少， 动脉粥样硬化的发病率。 这些有益效果的核心是 化合物是它们与活性氧（ROS）和氮的相互作用 物种（RNS）是由内源性和通过环境 exposure. 然而，人们对这些产品的生物效应知之甚少 这些反应。 在此提出，可以使用异黄酮的衍生物， 在与炎症氧化剂反应后获得，具有强效的抗 致动脉粥样硬化作用 低密度脂蛋白（LDL）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 抑制LDL氧化和调节细胞信号传导 已提出的途径作为关键的抗动脉粥样硬化机制， 你好 在本提案中，这些概念得到了扩展， 新的在动脉粥样硬化部位形成的甾酮衍生物的抗动脉粥样硬化作用 炎症（即氯化和硝化的丙酮）进行了研究。 这是 这一点很重要，因为它们的天然形式是LDL的不良抑制剂 氧化在体外，但他们的消费与减少， 脂质过氧化 此外，还研究了三萜酮对大鼠 参与动脉粥样硬化形成的炎症信号传导途径定义不清 并且在某些情况下表现出促炎作用。 具体地说， 天然异黄酮已被证明可以刺激单核细胞-内皮细胞 相互作用，病变形成的早期事件。 基于所述概念 上述讨论和本文提供的初步数据，研究人员 假设大豆异黄酮的抗动脉粥样硬化作用是通过 与ROS和RNS反应产生的副产物。 这一假设 将通过测试的具体目标，以确定本地的影响， 和修饰的藜芦酮对：（1）LDL氧化，（2）oxLDL和ROS/RNS诱导的 血管内皮细胞中的细胞死亡，和（3）oxLDL依赖性单核细胞 与内皮细胞牢固粘附。 这些研究将产生新的见解 研究了干扰素和ROS/RNS之间的相互作用， 抗氧化特性，以及对炎症细胞更微妙的影响 信号通路 此外，预计获得的机械见解 将提供关于可能的大麻酮开发的信息， 其他多酚

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.