Antihypertensive Effect of Food-Origin Isothiocyanate Soluble Epoxide Hydrolase Inhibitors

食品源异硫氰酸酯可溶性环氧化物水解酶抑制剂的抗高血压作用

• 批准号: 10411131
• 负责人: Fawzy Elbarbry
• 金额: $ 12.16万
• 依托单位: PACIFIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10411131
• 关键词: Acetylcholinesterase; Acids; Address; Adult; Adverse effects; Affect; Affinity; American; American Heart Association; Angiotensin II; Animal Model; Antihypertensive Agents; Antiinflammatory Effect; Antioxidants; Arachidonic Acids; Binding; Biological Assay; Blood; Blood Pressure; Brassica; Broccoli - dietary; Cabbage - dietary; Cardiovascular Diseases; Cauliflower; Cause of Death; Cessation of life; Chemoprevention; Chronic; Clinical Sciences; Consumption; Coronary artery; Coronary heart disease; Cytochrome P450; Cytosol; Death Rate; Development; Diet; Docking; Doctor of Pharmacy; Dose; Drug Interactions; Drug Kinetics; Effectiveness; Endothelium; Enrollment; Enzymes; Epoxide hydrolase; Epoxy Compounds; Family; Fatty Acids; Female; Fluorescence; Food; Functional disorder; Goals; Healthcare; Horseradish; Human; Hypertension; Inbred SHR Rats; Incidence; Incubated; Individual; Inflammation; Isothiocyanates; Kale - dietary; Kidney; Kinetics; Laboratories; Lepidium sativum; Liver; Measures; Modeling; Molecular; Monophenol Monooxygenase; Morbidity - disease rate; Mustard; Natural Products; Nature; Oral; Oxidative Stress; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phenethyl Isothiocyanate; Plants; Play; Population; Property; Rattus; Readiness; Recombinants; Regulation; Research; Research Infrastructure; Research Training; Resources; Risk; Role; Sodium Chloride; Stroke; Students; Sulforaphane; Testing; Therapeutic; Tissues; Treatment Cost; Uncertainty; Uninsured; United States; Universities; Vegetables; Watercress; allyl isothiocyanate; analog; base; benzyl isothiocyanate; blood pressure reduction; cardiovascular risk factor; cost; cruciferous vegetable; dietary; graduate student; high risk; hypertensive; improved; in vivo; inhibitor; kidney vascular structure; male; minimal risk; mortality; novel; pharmacokinetic characteristic; prevent; side effect; skills; therapeutic target; training opportunity; undergraduate student

PROJECT SUMMARY/ABSTRACT It is estimated that hypertension affects nearly one third of adult Americans (approximately 75 million persons). Unfortunately, whether the hypertension is treated or not, only approximately 50% of adults with hypertension have their blood pressure controlled and therefore have higher risk of cardiovascular morbidity and mortality as well as increased use of health care resources. Hypertension was listed as the leading or contributing cause of death in more than 470,000 Americans in 2019 leading to a death rate of 19.9 per 100,000. In 2012, the calculated total cost of treating hypertension in the US was $51.2 billion and the American Heart Association (AHA) estimates that the total cost of treating hypertension in the US in 2025 will be $225 billion. In the last five years, our laboratory has been investigating newer and safer agents from nature that have the potential to treat and/or protect against hypertension. We have demonstrated that chronic administration of sulforaphane (SF), an isothiocyanate (ITC), to young spontaneously hypertensive rats (SHR) results in preventing the progressive rise in blood pressure in this animal model. The observed antihypertensive effect of the examined ITC was significantly correlated with inhibition of the renal soluble epoxide hydrolase (sEH), a key enzyme in metabolizing endogenously derived fatty acid epoxide and considered an important therapeutic target in a wide range of human cardiovascular diseases. Since ITCs are natural products and rich in the diet, they can provide a viable option for hypertensive patients and prehypertensive individuals who are unable or unwilling to use current antihypertensive agents because of their cost, adverse effects, or risk of drug-drug interactions. These individuals will not only benefit from the potential antihypertensive effect of ITCs, but also receive the documented chemoprevention, antioxidant, and anti-inflammatory effects associated with their use. The objective of this proposal is to study the sEH inhibition and blood pressure lowering effects of several naturally- occurring ITCs, and to identify the structural factors that modulate their effectiveness as sEH inhibitors. The positive impact of this research is to identify potent antihypertensive ITCs with favorable pharmacokinetic properties and affordable cost. Specific Aim 1 will evaluate the potency, selectivity, and mechanism of inhibition of human and rat sEH by ITCs. Specific Aim 2 will investigate the anti-hypertensive effect of the most active ITC compound in SHR. This application offers excellent research training opportunities for undergraduate and graduate students, furthers and strengthens Dr. Elbarbry and his team’s research skills and preparedness for other proposals, and will make significant contributions to the enhancement of the Pacific University’s research infrastructure.

项目概要/摘要 据估计，高血压影响着近三分之一的美国成年人（约 7500 万人）。 不幸的是，无论高血压是否得到治疗，只有大约 50% 的成年人患有高血压 血压得到控制，因此心血管疾病发病和死亡的风险较高 以及增加医疗保健资源的使用。高血压被列为导致以下疾病的主要原因 2019 年，超过 47 万美国人死亡，死亡率为每 10 万人中 19.9 人。 2012 年， 据计算，美国治疗高血压的总费用为 512 亿美元，美国心脏协会 美国心脏协会 (AHA) 估计，到 2025 年，美国治疗高血压的总费用将达到 2250 亿美元。在过去的五 多年来，我们的实验室一直在研究来自大自然的更新、更安全的药物，这些药物有可能治疗 和/或预防高血压。我们已经证明，长期服用萝卜硫素（SF）是一种 异硫氰酸盐（ITC）对年轻的自发性高血压大鼠（SHR）可防止其进行性升高 在该动物模型中的血压。所检查的 ITC 观察到的抗高血压作用是 与肾可溶性环氧化物水解酶（sEH）的抑制显着相关，sEH是代谢中的关键酶 内源性衍生的脂肪酸环氧化物，被认为是多种疾病的重要治疗靶点 人类心血管疾病。由于 ITC 是天然产品并且富含饮食，因此它们可以提供可行的 无法或不愿意使用当前药物的高血压患者和高血压前期人士的选择 由于其成本、不良反应或药物间相互作用的风险而选择抗高血压药物。这些 个人不仅会受益于 ITC 的潜在降压作用，而且还会获得 记录了与其使用相关的化学预防、抗氧化和抗炎作用。这 本提案的目的是研究几种天然物质的 sEH 抑制和降血压作用 发生的 ITC，并确定调节其作为 sEH 抑制剂有效性的结构因素。这 这项研究的积极影响是确定具有良好药代动力学的有效抗高血压 ITC 属性和负担得起的成本。具体目标 1 将评估抑制的效力、选择性和机制 ITC 对人类和大鼠 sEH 的影响。具体目标2将研究最活跃的ITC的抗高血压作用 SHR 中的化合物。该应用程序为本科生和学生提供了极好的研究培训机会 研究生，进一步加强了 Elbarbry 博士及其团队的研究技能和准备工作 其他提案，将为加强太平洋大学的研究做出重大贡献 基础设施。