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

抗氧化反应元件相关基因表达的膳食激活剂，促进良好的血管健康

• 批准号: BB/G005699/1
• 负责人: Paul Thornalley
• 金额: $ 83.37万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG005699%2F1
• 关键词: Dietary; activators; antioxidant; response; element

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.

对人口及其饮食习惯的研究表明，增加蔬菜和水果的摄入量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处于良好状态。水果，特别是芸苔类蔬菜（花椰菜、卷心菜、花椰菜和抱子甘蓝）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，可以降低患心脏病的风险。其益处的关键可能是它们能够诱导和增强内源性防御血管损伤的能力，并对抗体内高胆固醇和脂质的发展。良好的血管健康与大量蛋白质的产生有关，这些蛋白质是由一系列与维持良好血管结构和功能相关的基因编码的。保护性基因通过与DNA中称为“抗氧化反应元件（are）”的部分相互作用来调节。保护性蛋白的增加是通过刺激一种叫做“nrf2”的蛋白质来实现的，这种蛋白质通常留在细胞内，但在细胞核外移动到细胞核内。在正常状态下，nrf2主要位于细胞核外；在刺激下，它进入细胞核，结合保护基因，使它们产生更多的编码蛋白质。通过与氧、活性氮和糖的反应，增加了对血管自发损伤的保护，从而保护了血管内蛋白质和脂质的结构和功能。nrf2的另一个显著特性是它能够关闭某些与胆固醇和脂质过量产生相关的基因。水果和蔬菜中的少量成分可以刺激nrf2做到这一点。我们认为最重要的成分是：从植物油（菜籽油）中发现的所谓的“omega-3脂肪酸”衍生的产品，胡萝卜素/化合物传统上存在于胡萝卜中，但也存在于其他蔬菜中，芥子油苷/化合物存在于芸苔菜和越来越受欢迎的“火箭”沙拉中，多酚/化合物存在于葡萄汁和洋葱中，烷基二硫化物/化合物存在于洋葱和大蒜中。目前尚不清楚哪一组化合物及其成员在增强血管中与are相关的保护反应方面最有效。该项目的目的是使用两种人类细胞系/细胞起源于人体组织，但现在在培养中持续生长，一种是血管中发现的典型细胞，另一种是肝细胞（产生胆固醇和脂质）的典型细胞，这两种细胞经过基因改造，可以产生绿色荧光的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，并制作延时视频。来自水果和蔬菜的化合物将被研究，因为它们有能力产生强大和持久的nrf2激活，并相关的细胞保护免受损害和脂质积累。将研究来自许多植物品种的化合物，以确定最有利于增强细胞健康的植物。nrf2效应的数学模型将得到完善，以预测食用水果和蔬菜对健康的益处。最后，我们将研究健康人类志愿者在连续补充植物油、番茄汁/番茄酱、西兰花和火箭沙拉期间的血管健康状况。这个项目的成功完成将揭示常见水果和蔬菜的种类，这些水果和蔬菜可能对维持血管的良好状态最有益，而且哪些水果和蔬菜有能力降低坏胆固醇和脂质，提高好胆固醇，如果将它们纳入我们的饮食中，可能对我们的后代有益。

项目成果

Antioxidant response element cytoprotective response in aortic endothelial cells coordinated by transcription factor Nrf2 is regulated through frequency-modulated translocational oscillations

由转录因子 Nrf2 协调的主动脉内皮细胞中的抗氧化反应元件细胞保护反应通过调频易位振荡进行调节

• DOI: 10.1016/j.atherosclerosis.2015.04.024
• 发表时间: 2015
• 期刊: Atherosclerosis
• 影响因子: 5.3
• 作者: Xue M

Frequency Modulated Translocational Oscillations of Nrf2 Mediate the Antioxidant Response Element Cytoprotective Transcriptional Response.

• DOI: 10.1089/ars.2014.5962
• 发表时间: 2015-09-01
• 期刊: Antioxidants & redox signaling
• 影响因子: 6.6
• 作者: Xue M;Momiji H;Rabbani N;Barker G;Bretschneider T;Shmygol A;Rand DA;Thornalley PJ
• 通讯作者: Thornalley PJ

Frequency modulated translocational oscillations of Nrf2, a transcription factor functioning like a wireless sensor.

Nrf2 的调频易位振荡，Nrf2 是一种像无线传感器一样发挥作用的转录因子。

• DOI: 10.1042/bst20150060
• 发表时间: 2015
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Xue M

Measurement of glyoxalase gene expression.

乙二醛酶基因表达的测量。

• DOI: 10.1042/bst20140026
• 发表时间: 2014
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Xue M