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Elucidation of molecular mechanisms and therapeutic strategies for diabetic angiopathic complications

阐明糖尿病血管病变并发症的分子机制和治疗策略

基本信息

批准号：
17591074
负责人：
TSUKAHARA Hirokazu
金额：
$ 2.37万
依托单位：
University of Fukui
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Angiopathy is a major chronic complication of diabetic mellitus and an important cause of increased morbidity and mortality among the patients with diabetes. Possible mechanisms of untoward effects of hyperglycemia include high oxidative stress status. Loads of reactive oxygen species (ROS) that overburden antioxidant systems induce oxidative stress in the body. Major cellular targets of ROS are membrane lipids, proteins, nucleic acids, and carbohydrates. Other investigators and I have introduced specific biomarkers for oxidative damages and antioxidant defenses into the field of pediatric medicine. Specifically, I have presented age-related reference normal ranges of oxidative stress biomarkers, including urinary acrolein-lysine, 8-hydroxy-2'-deoxyguanosine, nitrite/nitrate, and pentosidine, and the changes of the parameters in diabetes mellitus. I have also presented the data indicating that expression of both adhesion molecules and chemokines in human microvascular endothelial cells induced by inflammatory cytokine TNF-α is inhibited significantly by pretreatment with antioxidants or NO donors, possibly in part through blocking the activation of NF-κB. These experimental results suggest a potential therapeutic approach using antioxidants or NO donors in the treatment of oxidative stress related inflammatory diseases. These informations will be helpful to understand the pathogenesis and management of diabetic angiopathy, including atherosclerosis, retinopathy and nephropathy.

血管病变是糖尿病的主要慢性并发症，是糖尿病患者发病率和死亡率增高的重要原因。高血糖不良反应的可能机制包括高氧化应激状态。大量的活性氧（ROS）使抗氧化系统过载，从而诱导体内的氧化应激。ROS的主要细胞靶标是膜脂质、蛋白质、核酸和碳水化合物。我和其他研究人员已经将氧化损伤和抗氧化防御的特定生物标志物引入儿科医学领域。具体而言，我已经提出了与年龄相关的氧化应激生物标志物的参考正常范围，包括尿丙烯醛-赖氨酸，8-羟基-2 '-脱氧鸟苷，亚硝酸盐/硝酸盐，和戊糖苷，以及糖尿病参数的变化。我还提供的数据表明，抗氧化剂或NO供体预处理可显著抑制炎性细胞因子TNF-α诱导的人微血管内皮细胞中粘附分子和趋化因子的表达，这可能部分通过阻断NF-κB的活化实现。这些实验结果表明，在治疗氧化应激相关的炎症性疾病中使用抗氧化剂或NO供体的潜在治疗方法。这些信息将有助于了解糖尿病血管病变，包括动脉粥样硬化，视网膜病变和肾病的发病机制和管理。