Elucidation of molecular mechanisms and therapeutic strategies for diabetic angiopathic complications

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。高血糖不良影响的可能机制包括高氧化应激状态。活性氧（ROS）的负荷覆盖抗氧化系统诱导氧化应激在体内。活性氧的主要细胞靶点是膜脂、蛋白质、核酸和碳水化合物。我和其他研究者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。具体来说，我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/硝酸盐和戊苷，以及糖尿病患者参数的变化。我还提出了一些数据，表明炎症细胞因子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被抗氧化剂或NO供体预处理显著抑制，部分可能是通过阻断NF-κB的激活。这些实验结果提示了使用抗氧化剂或NO供体治疗氧化应激相关炎症性疾病的潜在治疗方法。这些信息将有助于了解糖尿病血管病变的发病机制和治疗，包括动脉粥样硬化、视网膜病变和肾病。

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.