Correction of glutathione deficiency for treatment of diabetic nephropathy

纠正谷胱甘肽缺乏症治疗糖尿病肾病

• 批准号: 8250827
• 负责人: PAOLO FANTI
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250827
• 关键词: Acetylcysteine; Adopted; Adverse effects; Affect; Albumins; Animal Model; Antioxidants; Blood; Cancer Patient; Cells; Characteristics; Chemicals; Chronic Kidney Failure; Clinical; Clinical Research; Clinical Trials; Complement; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Dialysis procedure; Dietary Intervention; Dose; Double-Blind Method; Effectiveness; Enzymes; Equilibrium; Excretory function; Flavonolignans; Foundations; Free Radicals; Future; Generations; Glutathione; Glycoproteins; High Prevalence; Hormones; Individual; Inflammation; Inflammatory; Injury; Intake; Intervention; Investigation; Kidney; Kidney Diseases; Kidney Transplantation; Metabolism; Milk Thistle; Milk thistle extract; Monitor; Non-Insulin-Dependent Diabetes Mellitus; Oral; Oral Administration; Outcome Measure; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Pathogenesis; Pathology; Patients; Peripheral; Peroxidases; Pilot Projects; Placebo Control; Placebos; Plants; Plasma; Process; Production; Property; Proteins; Proteinuria; Randomized; Reactive Oxygen Species; Reduced Glutathione; Relative (related person); Renal Tissue; Renal function; Reporting; Research; Safety; Severities; Silymarin; Superoxide Dismutase; Supplementation; Testing; Therapeutic; Therapeutic Effect; Transferase; Tubular formation; Urine; Validation; Veterans; Work; active method; alpha-1-microglobulin; arm; beta-Chemokines; bikunin; conventional therapy; cytokine; design; diabetic; dietary supplements; improved; insight; interest; monocyte; novel marker; peripheral blood; prevent; primary outcome; public health relevance; secondary outcome; small molecule; urinary

DESCRIPTION (provided by applicant): Oxidative stress and glutathione (GSH) imbalance are major contributors to the pathogenesis of diabetic nephropathy. Circulating monocytes participate to this process since these cells carry a high oxidative burden and are found in diabetic renal tissue. Current options for the treatment of oxidative stress in diabetic nephropathy are limited and only partially effective, thus interest in the development of new strategies is high. N-acetylcysteine (NAC) and the milk thistle (MTh) plant flavonolignans are nutritional supplements with complementary antioxidant properties. Both supplements are capable of neutralizing directly toxic free radicals but, more importantly, NAC is substrate for the intracellular generation of GSH and the MTh flavonolignans are inducers of many cellular enzymes participating in GSH metabolism, including GSH-reductase (GSH-R), GSH-peroxidase (GSH-Px), GSH-S-transferases (GST) and superoxide dismutase (SOD). We propose that combined oral supplementation of NAC and MTh flavonolignans will reduce proteinuria and urinary and systemic manifestations of oxidative stress and inflammation, which are characteristically observed in patients with T2DM and related nephropathy. We expect these effects to be achieved with minimal or no side effects, and with good patient tolerance. To test this hypothesis, we propose a double-blind randomized, placebo-controlled, five-arm pilot study which includes a dose ranging component in patients with T2DM and established nephropathy. Intervention will consist of the individual and combined oral administration of one level of NAC and two levels of MTh flavonolignans or placebo for three months. The primary outcome measure will be urinary excretion of albumin, a marker of glomerular injury. Secondary outcome measures will be alpha-1 microglobulin, a marker of tubular injury, and urinary excretion of inflammatory cytokines and C-C chemokines, i.e. markers of renal inflammation. In plasma and in peripheral blood monocytes from the same patients, we will analyze GSH content and activity of GSH metabolizing enzymes. In addition, we will analyze the plasma and urine glycoproteome, with focus on those glycoproteins serving as inflammatory cell messengers and hormones. These variables will be monitored in relation to both treatment allocation and prevalent blood and urine levels of the active treatment. Throughout the trial, we will monitor the safety and tolerability of this combination treatment. Validation of the proposed hypothesis will provide preliminary evidence of efficacy, safety and tolerability of combination treatment with NAC and MTh flavonolignans and it will be the necessary first step for the future design of more definitive clinical investigation and of mechanistic research in animal models of T2DM and diabetic nephropathy. PUBLIC HEALTH RELEVANCE: Oxidative stress (OS) consists of high production and low disposal of toxic pro-oxidant chemicals, and it is very common in patients with Type 2 Diabetes Mellitus (T2DM) and diabetic kidney disease. Veterans have high prevalence of T2DM, diabetic kidney disease, and associated OS. OS causes progression of diabetic kidney disease, with spilling of protein in the urine and, eventually, with the need for dialysis or kidney transplantation. In most cases, the available treatments cannot stop the progression of diabetic kidney disease and the spilling of protein in the urine. We suspect this is because no conventional treatments can completely correct OS in diabetic kidney disease. We propose to test if the combination of two potent antioxidant nutritional supplements, N-acetylcysteine and the milk thistle extract silymarin, is capable of correcting the OS and the spilling of protein in the urine in Veterans with T2DM and diabetic kidney disease.

描述（由申请人提供）： 氧化应激和谷胱甘肽（GSH）失衡是糖尿病肾病发病机制的主要因素。循环单核细胞参与这一过程，因为这些细胞携带高氧化负荷，并在糖尿病肾组织中发现。目前治疗糖尿病肾病氧化应激的选择是有限的，只有部分有效，因此在新的策略的发展兴趣很高。N-乙酰半胱氨酸（NAC）和奶蓟（MTh）植物黄酮木脂素是具有互补抗氧化特性的营养补充剂。这两种补充剂都能够直接中和有毒的自由基，但更重要的是，NAC是细胞内产生GSH的底物，MTh黄酮木脂素是参与GSH代谢的许多细胞酶的诱导剂，包括GSH还原酶（GSH-R），GSH过氧化物酶（GSH-Px），GSH-S-转移酶（GST）和超氧化物歧化酶（SOD）。我们建议联合口服补充NAC和MTh黄酮木脂素将减少蛋白尿和氧化应激和炎症的泌尿和全身表现，这是T2 DM和相关肾病患者的特征性观察。我们希望这些效果能够以最小或无副作用的方式实现，并且具有良好的患者耐受性。为了检验这一假设，我们提出了一项双盲、随机、安慰剂对照、五组初步研究，其中包括在患有T2 DM和已确诊肾病的患者中进行的剂量范围研究。干预将包括单独和联合口服一种水平的NAC和两种水平的MTh黄酮木脂素或安慰剂三个月。主要的结果指标是尿白蛋白排泄，这是肾小球损伤的标志物。次要结局指标将是α-1微球蛋白（肾小管损伤的标志物）和炎性细胞因子和C-C趋化因子（即肾脏炎症的标志物）的尿排泄。在同一患者的血浆和外周血单核细胞中，我们将分析GSH含量和GSH代谢酶的活性。此外，我们将分析血浆和尿液糖蛋白质组，重点是作为炎症细胞信使和激素的糖蛋白。将根据治疗分配以及活性治疗的普遍血液和尿液水平来监测这些变量。在整个试验过程中，我们将监测这种联合治疗的安全性和耐受性。验证所提出的假设将提供NAC和MTh黄酮木脂素联合治疗的疗效、安全性和耐受性的初步证据，这将是未来设计更明确的临床研究和T2 DM和糖尿病肾病动物模型机制研究的必要的第一步。 公共卫生相关性： 氧化应激（Oxidative stress，OS）是一种由大量产生和低排放的有毒促氧化化学物质组成的过程，在2型糖尿病（Type 2 Diabetes Mellitus，T2 DM）和糖尿病肾病（Diabetes肾病）患者中非常常见。退伍军人具有T2 DM、糖尿病肾病和相关OS的高患病率。OS导致糖尿病肾病的进展，伴随尿中蛋白质溢出，最终需要透析或肾移植。在大多数情况下，现有的治疗方法不能阻止糖尿病肾病的进展和尿中蛋白质的溢出。我们怀疑这是因为没有常规治疗可以完全纠正糖尿病肾病的OS。我们建议测试两种有效的抗氧化营养补充剂，N-乙酰半胱氨酸和水飞蓟提取物水飞蓟素的组合，是否能够纠正T2 DM和糖尿病肾病退伍军人的OS和尿中蛋白质溢出。