Isolation and Evaluation of Anticarcinogenic Glucosinolates

抗癌芥子油苷的分离与评价

• 批准号: 7523682
• 负责人: PAUL TALALAY
• 金额: $ 35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7523682
• 关键词: Abbreviations; Amino Acids; Angiogenesis Inhibition; Animals; Anthracenes; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Anticarcinogenic Agents; Antioxidants; Apoptosis; Benzo(a)pyrene; Biological; Biological Assay; Biological Availability; Brassica; Broccoli - dietary; Butane; Butanes; Butylated Hydroxyanisole; Cabbage - dietary; Carcinogens; Cauliflower; Cell Line; Cells; Characteristics; Chemical Agents; Chemicals; Chemopreventive Agent; Chemoprotection; Chemoprotective Agent; Chronic Disease; Class; Clinical; Clinical Research; Condition; Cultured Cells; DNA Damage; Development; Diet Modification; Drug Kinetics; Edible Plants; Enzyme Induction; Enzymes; Evaluation; Family; Food; Gastric Drugs; Glucosinolates; Glucuronosyltransferase; Glutathione S-Transferase; Goals; Grant; Growth and Development function; Health Benefit; Helicobacter pylori; Histone Deacetylase; Human; Hydrolysis; Individual; Inflammation; Intervention; Intestines; Isothiocyanates; Kilogram; Laboratories; Lead; Malignant Neoplasms; Mammalian Cell; Methods; Mus; Myrosinase; NAD(P)H Dehydrogenase (Quinone); NAD(P)H dehydrogenase (quinone) 1, human; NQO1 gene; Numbers; Oxidants; Phase; Phenotype; Phytochemical; Plant Components; Plants; Prevention; Preventive Intervention; Probiotics; Procedures; Prodrugs; Production; Property; Public Health; Quinone Reductases; Radiation; Reactive Oxygen Species; Recommendation; Reduced Glutathione; Response Elements; Risk Reduction; Skin; Skin Neoplasms; Sulforaphane; System; Technology; Testing; Thioglucosides; Toxic effect; Ultraviolet B Radiation; Vegetables; anthracene; cohort; countercurrent chromatography; dimethylbenzanthracene; disorder risk; gastrointestinal; glucoraphanin; heme oxygenase-1; improved; inhibitor/antagonist; malignant stomach neoplasm; method development; milligram; neoplastic; novel; partition chromatography; prebiotics; programs; reactive oxygen intermediate; therapy development; tumor

DESCRIPTION (provided by applicant): The overall goals are to develop plant-derived glucosinolates (GS) for long-term human use as dietary chemoprotectors against cancer and other chronic diseases. GS are a large family of thioglucoside N-hydroxysulfates synthesized by plants from several classes of amino acids. They are very abundant in crucifers (broccoli, cabbage, cauliflower) and are likely to provide the main phytochemical contribution to the chemoprotective properties of these plants. GS are the stable, biologically inactive storage forms of isothiocyanates which are potent inhibitors of tumor development and growth. Bioactivation (conversion) of GS to isothiocyanates is catalyzed by plant cell myrosinase and by the gastrointestinal microflora. Mechanistic understanding of the mode of action of these phytochemicals has advanced greatly. The principal obstacles to progress are now lack of adequate quantities of pure GS for evaluation in cells, animals, and humans, and to control and improve bioavailability. Aim 1 is concerned with developing more efficient methods for isolating and purifying new and already known GS on a progressively larger scale from milligrams to kilograms. With support of this grant, a major advance has been our development of highly efficient continuous, centrifugal, counter-current partition chromatography methods which are easily scalable, and have made possible the production of almost 1 kg of glucoraphanin (the precursor of sulforaphane) and its submission to the NCI RAPID program for clinical development. This aim seeks to expand this novel and highly efficient separation technology for isolation of additional new glucosinolates guided by their biological activities. Aim 2 will evaluate the biological activities of a small number of the most promising candidate GS. Activity testing will include evaluating phase 2 enzyme induction, antioxidant, and anti-inflammatory potencies in cell lines; prevention of mouse skin tumors; and protection of human skin against UV. Proposed studies will also assay the antibiotic activity of GS hydrolysates against Helicobacter pylori (a major causative agent of gastric cancer). Aim 3 will identify individuals with high and low GS to isothiocyanate conversion phenotypes and attempt to discern the factors contributing to these characteristics. Cohorts with stable low conversion phenotypes will be subjected to a variety of dietary modifications, including prebiotic and probiotic interventions, in order to increase conversions and improve the bioavailability of isothiocyanates from GS, and enhance their protective efficacy. This information will advance our development of GS as chemoprotectors and could lead to major health benefits. PUBLIC HEALTH RELEVANCE: The goals of this project are to identify plant components that block the development of cancer and other chronic diseases by boosting our cellular defenses against oxidants, DNA-damaging chemicals, inflammation and radiation. We will isolate these components in adequate quantities for evaluation in animals and humans, and formulate appropriate recommendations to achieve disease risk reduction in humans.

描述（由申请人提供）：总体目标是开发植物来源的葡萄糖醇（GS），用于长期人类用作针对癌症和其他慢性疾病的饮食化学保护剂。 GS是一个大型硫葡萄糖苷N-羟基硫酸盐，由几类氨基酸的植物合成。它们在十字花序（西兰花，卷心菜，花椰菜）中非常丰富，并且可能对这些植物的化学保护性能提供主要的植物化学贡献。 GS是异硫氰酸盐的稳定，生物学上不活跃的储存形式，它们是肿瘤发育和生长的有效抑制剂。 GS向异硫氰酸盐的生物活化（转化）由植物细胞霉菌酶和胃肠道菌群催化。对这些植物化学物质的作用方式的机械理解已大大提高。现在，进步的主要障碍是缺乏足够数量的纯GS来评估细胞，动物和人类，无法控制和改善生物利用度。 AIM 1关注的是开发更有效的方法来隔离和净化新的且已知的GS，从毫克到公斤逐渐更大。在支持这笔赠款的支持下，我们的一项重大进步是我们开发了高效的连续，离心，反电流色谱方法，这些方法易于扩展，并且使得生产了将近1 kg的葡萄糖磷酸素（Sulforaphane的前代）及其对NCI快速发展的临床开发计划的产生。该目标旨在扩大这种新颖且高效的分离技术，以隔离其生物学活性引导的其他新葡萄糖醇。 AIM 2将评估少数最有前途的候选GS的生物学活动。活性测试将包括评估2期酶诱导，抗氧化剂和细胞系中的抗炎效果；预防小鼠皮肤肿瘤；保护人皮肤对紫外线的保护。拟议的研究还将分析GS水解酸盐对幽门螺杆菌（胃癌的主要病因）的抗生素活性。 AIM 3将识别出高和低GS的个体来异硫氰酸酯转化表型，并试图辨别造成这些特征的因素。具有稳定的低转化型表型的队列将受到各种饮食修饰，包括益生元和益生菌干预措施，以增加转化率并改善GS的异硫氰酸酯的生物利用度，并提高其保护效率。这些信息将推动我们作为化学保护器的GS发展，并可能带来重大健康益处。公共卫生相关性：该项目的目标是通过促进我们针对氧化剂，减轻DNA的化学物质，炎症和放射的细胞防御措施来确定阻止癌症和其他慢性疾病发展的植物成分。我们将以足够的数量来分离这些组件，以评估动物和人类，并提出适当的建议，以减少人类疾病的风险。