An anti-inflammatory role for bioactive nutrient isothiocyanates

描述(申请人提供)：新鲜水果和蔬菜是健康饮食的基础。它们不仅提供对人类健康至关重要的维生素和矿物质，而且还含有生物活性营养物质，在动物模型中已显示出预防癌症的有效性。虽然这种癌症化学预防的现象得到了很好的认识，但这些生物活性营养物质带来这些效果的机制仍然不清楚。此外，这些生物活性营养素产生的其他更微妙的健康益处的可能性大多被忽视了。 一类化学预防化合物，生物活性营养异硫氰酸酯(ITCs)，在花椰菜等十字花科蔬菜中含量丰富，其化学结构表明它们可以与细胞中的蛋白质发生共价反应。为了进一步了解这些化学物质的作用机制，我们进行了一项筛选，以分离生物活性营养物质ITC修饰的蛋白质靶标。我们分离出了这类生物活性营养素的一个主要靶点，它是炎症性疾病过程的关键介质。营养ITCs的修饰抑制了该蛋白质的酶活性，这表明生物活性营养ITCs可能抑制了驱动炎症的蛋白质的下游功能。 我们认为，该蛋白的生物活性营养ITC修饰的程度可能是有效传递的一个有价值的替代生物标志物。这种蛋白质的修饰代表了一种生物利用度的衡量标准，不仅可以应用于生物体液，还可以应用于潜在的靶组织。我们提出的实验旨在开发这种生物标记物作为一种手段，以检查生物利用度和跟踪药代动力学和药效学的生物活性营养ITCs在完整的动物。 此外，我们认为，生物活性营养物质ITCs可能由于其修饰和抑制这一关键的炎症介质的能力而具有先前未被认识的抗炎益处。我们将使用经典的炎症模型结合缺乏这种蛋白质靶点的动物来研究这种可能性。这些研究将使我们既可以探索生物活性营养物质ITCs的潜在抗炎特性，也可以确定其有效性的潜在分子机制。

DESCRIPTION (provided by applicant): Fresh fruits and vegetables are the foundation of a healthy diet. They not only provide vitamins and minerals that are essential for human health, but they also contain bioactive nutrients that have demonstrated efficacy in preventing cancer in animal models. While this phenomenon of cancer chemoprevention is well appreciated, the mechanism by which these bioactive nutrients bring about these effects remains obscure. Moreover, the possibility of other, more subtle health benefits arising from these bioactive nutrients has been mostly ignored. One class of chemopreventive compounds, the bioactive nutrient isothiocyanates (ITCs), are abundant in cruciferous vegetables such as broccoli, and have a chemical structure that suggest that they could covalently react with proteins in the cell. In an effort to further understand the mechanism of action of these chemicals, we undertook a screen to isolate protein targets of bioactive nutrient ITC modification. We isolated a predominant target of this class of bioactive nutrients that is a critical mediator of inflammatory disease processes. Modification by nutritional ITCs inhibits the enzymatic activity of this protein, suggesting bioactive nutrient ITCs may inhibit the downstream functions of the protein that drive inflammation. We propose that the degree of bioactive nutrient ITC modification of this protein may represent a valuable surrogate biomarker of effective delivery. Modification of this protein represents a measure of bioavailability that can be applied not only to biological fluids, but also to potential target tissues. We present experiments designed to develop this biomarker as a means to examine the bioavailability and trace the pharmacokinetics and pharmacodynamics of bioactive nutrient ITCs in an intact animal. In addition, we propose that the bioactive nutrient ITCs may have previously unappreciated anti-inflammatory benefits as a result of their ability to modify and inhibit this critical mediator of inflammation. We will examine this possibility using a classical model of inflammation in combination with animals deficient in this protein target. These studies will allow us to both probe the potential anti-inflammatory properties of bioactive nutrient ITCs, as well as define a potential molecular mechanism for their effectiveness.