Optimization of Glutathione Levels and Alzheimer Disease Risk in African Americans

优化非裔美国人的谷胱甘肽水平和阿尔茨海默病风险

• 批准号: 10475166
• 负责人: Sushil K Jain
• 金额: $ 50.72万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475166
• 关键词: Adverse effects; African American population; Alzheimer' s disease risk; Analysis of Variance; Animals; Antioxidants; Biological; Biological Availability; Biological Markers; Blood; Chemistry; Cholecalciferol; Clinical; Clinical Trials; Controlled Clinical Trials; Coupled; Cysteine; Data; Development; Diabetes Mellitus; Disease; Dose; Double-Blind Method; Ensure; Fasting; Future; GC gene; GLUT 4 protein; Genes; Glutathione; Goals; Grant; Health; Health Hazards; Human; Hydroxylation; Impairment; Incidence; Inflammation; Inflammatory; Ingestion; Insulin Resistance; Kidney Function Tests; Life Style; Link; Liver; Measurable; Mediating; Mediator of activation protein; Medical; Metabolic; Metabolism; Mixed Function Oxygenases; Modeling; Muscle; Natural Products; Nutrient; Obesity; Oral; Outcome; Oxidative Stress; Pain; Pathway interactions; Physiological; Placebo Control; Placebo Effect; Placebos; Population; Prediabetes syndrome; Pregnancy Tests; Public Health; Randomized; Randomized Controlled Clinical Trials; Rattus; Recommendation; Regulation; Regulator Genes; Reporting; Research Subjects; Risk; SLC2A1 gene; Safety; Serum; Statistical Data Interpretation; Supplementation; TNF gene; Testing; Therapeutic; Therapeutic Effect; Tissues; Translations; United States National Center for Health Statistics; Up-Regulation; Validation; Visit; Vitamin A; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; Whole Blood; capsule; chronic pain; clinical pain; cost; design; dietary supplements; efficacy clinical trial; efficacy trial; epidemiology study; experience; glucose metabolism; health disparity; improved; liver function; liver metabolism; member; mouse model; novel; novel strategies; preclinical study; prevent; side effect; success

Optimization of 25(OH) vitamin D levels in African Americans Public Health Issue: Low circulating levels of 25(OH) vitamin D (VD) have been correlated with many adverse health conditions and health disparities in African Americans (AA). Supraphysiological high-dose VD supplementation is required to eliminate the differences observed in the levels of circulating 25(OH)VD in AA and white subjects. However, recent studies have questioned the therapeutic effects of high-dose VD supplementation. Rationale: Glutathione (GSH) is a major physiological antioxidant. Recent studies report that low levels of GSH are linked to 25(OH)VD deficiencies in both animal and human studies. Animal studies using ZDF rats and a mouse model of 25(OH)VD deficiency have shown that, compared to supplementation with VD-alone, co-supplementation with VD (cholecalciferol) + L-cysteine (LC, a GSH precursor) led to an improvement in GSH status that resulted in significant increases in circulating levels of 25(OH)VD and reduced oxidative stress, TNF-α, and insulin resistance (IR). Approach: AA have reduced levels of glutathione (GSH), as well as a high incidence of insulin resistance (IR) and inflammatory disorders. This R33 application presents our design for a randomized, double-blind, placebo- controlled clinical trial to test the hypothesis that supplementation with VD in combination with L-cysteine (a GSH precursor) is more successful at optimizing the statuses of 25(OH)VD and GSH [biological signatures] and simultaneously decreasing TNF-α and IR [functional or clinical outcomes], suggesting a better therapeutic approach compared with supplementation with VD alone in AA subjects. Impact on Public Health: The successful completion of this R33 clinical trial will have a significant impact on the design of future efficacy clinical trials examining co-supplementation using a GSH precursor coupled with lower VD doses to reduce 25(OH)VD deficiency/inadequacy, inflammation, and IR biomarkers. The development of a safe, low-cost dietary supplement that can improve 25-hydroxy vitamin D status and reduce insulin resistance and inflammation would provide significant benefits in the treatment of pre-diabetes and health disparities, including chronic pain, in the African American population. This application, which is highly responsive to PAR-18-828, will replicate previous human studies and examine the outcome of biological signatures by combining the natural product L-cysteine with VD to optimize its supplementation and efficacy.

非裔美国人25（OH）维生素D水平的优化 公共卫生问题：25（OH）维生素D（VD）的低循环水平与许多疾病有关。 非裔美国人（AA）的不良健康状况和健康差异。超生理高剂量VD 需要补充以消除AA中循环25（OH）VD水平的差异 和白色受试者。然而，最近的研究对大剂量VD的治疗效果提出了质疑 补充。 基本原理：谷胱甘肽（GSH）是一种主要的生理抗氧化剂。最近的研究表明，低水平的 在动物和人类研究中，GSH与25（OH）VD缺乏有关。使用ZDF大鼠的动物研究 和25（OH）VD缺乏的小鼠模型显示，与单独补充VD相比， 与VD（胆钙化醇）+L-半胱氨酸（LC，GSH前体）的共同补充导致了 GSH状态导致循环中25（OH）VD水平显著升高， 应激、TNF-α和胰岛素抵抗（IR）。 方法：AA具有降低的谷胱甘肽（GSH）水平，以及胰岛素抵抗（IR）的高发病率 和炎症性疾病。本R33应用程序介绍了我们的随机、双盲、安慰剂设计， 对照临床试验，以检验补充VD与L-半胱氨酸（a GSH前体）在优化25（OH）VD和GSH状态方面更成功[生物特征] 同时降低TNF-α和IR [功能或临床结局]，提示更好的治疗方法 方法与AA受试者中单独补充VD相比。 对公共卫生的影响：R33临床试验的成功完成将对 设计未来的功效临床试验，检查使用GSH前体与 降低VD剂量以减少25（OH）VD缺乏/不足、炎症和IR生物标志物。的 开发一种安全，低成本的膳食补充剂，可以改善25-羟基维生素D的状态， 胰岛素抵抗和炎症将在糖尿病前期的治疗中提供显著的益处， 非裔美国人的健康差异，包括慢性疼痛。 该应用程序对PAR-18-828具有高度响应性，将复制先前的人体研究并检查 通过将天然产物L-半胱氨酸与VD组合以优化其生物特征的结果， 补充和功效。