Dietary activators of antioxidant response element-linked gene expression for good vascular health

对人类群体及其饮食习惯的研究表明，增加蔬菜和水果的消费与降低心脏病和中风的风险有关。这表明这些食物使主要血管保持良好的状态。水果，尤其是甘蓝类蔬菜(花椰菜、卷心菜、花椰菜和球芽甘蓝)是健康饮食的重要组成部分，因为它们含有高水平的化合物，与低心脏病风险有关。它们受益的关键可能是它们诱导和增强抵御血管损伤的内源性防御能力，以及对抗体内高胆固醇和高血脂的发展。良好的血管健康与大量产生蛋白质有关，这些蛋白质由一系列基因编码，这些基因与维持良好的血管结构和功能有关。保护性基因是通过与其DNA中被称为“抗氧化反应元件(ARE)”的一段AT相互作用来调节的。保护蛋白产量的增加是通过刺激一种名为Nrf2的蛋白质实现的，这种蛋白质通常残留在细胞内，但在细胞核外移动到细胞核中。在正常状态下，Nrf2主要保持在细胞核外；在刺激下，它进入细胞核，绑定保护性基因，使它们产生更多的编码蛋白。增加ARE相关基因蛋白的水平可增强对血管中自发损伤的保护，/通过与氧、活性氮和糖的反应来保护血管内蛋白质和脂类的结构和功能。Nrf2的另一个显着特性是它能够关闭某些ARE相关基因/特别是那些与过度产生胆固醇和脂质有关的基因。水果和蔬菜中的次要成分可以刺激NRF2做到这一点。我们认为最重要的成分是：从植物油(油菜籽)中发现的所谓‘omega-3脂肪酸’衍生的产品，传统上在胡萝卜和其他蔬菜中发现的胡萝卜素/化合物，在油菜和越来越受欢迎的‘火箭’沙拉中发现的硫代葡萄糖苷/化合物，在葡萄汁和洋葱中发现的多酚/化合物，以及在洋葱和大蒜中发现的烷基二硫化物/化合物。目前尚不清楚这些化合物中的哪一类及其成员在增强血管中ARE相关的保护反应方面最有效。该项目的目标是使用两种人类细胞系/细胞，一种是血管中发现的典型细胞，另一种是典型的肝细胞(制造胆固醇和脂质的地方)/，它们已经被转基因，以产生具有绿色荧光的Nrf2。我们可以在显微镜下研究Nrf2对来自水果和蔬菜的化合物的反应进入细胞核的运动，并制作一段延时视频。来自水果和蔬菜的化合物将被研究其产生强烈和持久的NRF2激活以及相关细胞保护免受损伤和脂质积累的能力。将对来自许多植物品种的化合物进行研究，以使植物变得更好，以增强细胞健康。Nrf2效应的数学模型将被改进，以预测水果和蔬菜消费对健康的好处。最后，我们将研究健康人类志愿者在饮食中依次添加植物油、番茄汁/酱、西兰花和火箭沙拉期间血管健康的情况。该项目的成功完成将揭示哪些常见水果和蔬菜可能对维持血管处于良好状态最有益，哪些水果和蔬菜具有降低坏胆固醇和血脂并提高好胆固醇的能力，如果包括在我们今世后代的饮食中，可能是有益的。

Studies of human populations and their eating habits have shown that increased consumption of vegetables and fruit is associated with decreased risk of heart disease and stroke. This suggests these foodstuffs keep major blood vessels in a good state. Fruit and particularly Brassica vegetables (broccoli, cabbage, cauliflower and Brussel sprouts) are important components of a healthy diet because they have high levels of compounds linked to low risk of heart disease. The key to their benefit is probably their ability to induce and increase endogenous defences against blood vessel damage and counter the development of high cholesterol and lipids in the body. Good health of blood vessels is associated with a high production of proteins encoded by a battery of genes associated with maintenance of good blood vessel structural and function. The protective genes are regulated through interactions with at a section of their DNA called an 'antioxidant response element (ARE)'. Increased production of protective proteins is achieved by stimulating a protein called 'nrf2' that normally residues in the cell but outside of the cell nucleus to move into the nucleus. In the normal state, nrf2 is held predominantly outside the nucleus; on stimulation, it moves into the nucleus, bunds protective genes and makes them produce more of their encoded protein. Increased levels of ARE-linked gene proteins provide for increased protection against spontaneous damage in the blood vessels / by reactions with oxygen, reactive nitrogen species and sugars - preserving the structure and functions of proteins and lipids within the blood vessels. A further remarkable property of nrf2 is its ability to switch off certain ARE-linked genes / particularly those associated with the excessive production of cholesterol and lipids. Minor components in fruit and vegetables can stimulate nrf2 to do this. We think the most important components are: products derived from so-called 'omega-3 fatty acids' found in vegetables oils ('Canola'), carotenoids / compounds traditionally found in carrots but also in other vegetables, glucosinolates / compounds found in Brassica vegetables and also in increasingly popular 'Rocket' salad, polyphenols / compounds found in grape juice and also in onions, and alkyl disulphides / compounds found in onions and garlic. It is not clear currently which of these groups of compounds and members thereof are most effective in enhancing the ARE-linked protective responses in blood vessels. The aim of this project is to use two human cell lines / cells originating from human tissue but now grow continuously in culture, a cell typical of those found in blood vessels and one typical of liver cells (where cholesterol and lipids are made) / that have been genetically modified to produce nrf2 with a green fluorescence. We can them study nrf2 movement into the nucleus in responsive to compounds from fruit and vegetable under the microscope and make a time-lapsed video. Compounds from fruit and vegetables will be studied for their ability to produce strong and prolonged activation of nrf2 and associated cell protection from damage and accumulation of lipids. Compounds from many plant varieties will be studied to fine the plants best for enhancing cell health. Mathematical models of the nrf2 effects will be refined to predict health benefits from fruit and vegetable consumption. Finally, we will study the health of blood vessels in healthy human volunteers during periods when we supplement their diet successively with vegetable oil, tomato juice/paste, broccoli and Rocket salad. Successful completion of this project will reveal the varieties of common fruit and vegetables that are likely most beneficial in maintaining blood vessels in a good state and also which fruit and vegetables have the ability to decrease bad cholesterol and lipids and raise good cholesterol, and likely beneficial if include in our diets for current and future generations.