Study on the pathological role of AGEs in renal diseases

糖基化终产物（AGEs）是通过非酶促糖基化和氧化（糖基氧化）反应形成的糖基化终产物，对蛋白质进行修饰. AGEs在人类病理学中的研究最初集中在持续高血糖的糖尿病。然而，最近的研究表明，在血糖正常的尿毒症和动脉粥样硬化中AGE的生成增加。他们的AGE积累不能归因于高血糖症。收集的证据表明，在氧化应激下，增加的羰基化合物，来自碳水化合物和脂质，修饰蛋白质，不仅通过糖氧化反应，而且还通过脂氧化反应，导致不仅AGEs，但也高级脂氧化终产物（ALE）的形成。因此，病理损伤可能处于羰基过载状态，具有潜在的破坏性蛋白质（“羰基应激”）。组织蛋白中AGEs/ALE的增加可能揭示了涉及碳水化合物和脂质的非酶生物化学的广泛紊乱。Immu ...更多信息 用AGEs /ALE的特异性抗体进行的非组织化学研究，在人类动脉粥样硬化、糖尿病肾病、尿毒症透析相关的淀粉样变性中确定了“羰基应激”。AGEs/ALE修饰的蛋白质对几种类型的细胞表现出不同的生物学效应。羰基化合物本身交联基质蛋白并改变其结构和功能。它们进一步与细胞表面蛋白相互作用，阻断细胞内信号传导，并诱导细胞反应。我们最近发现了一种抑制羰基应激和AGE/ALE形成的新化合物。该化合物抑制暴露于羰基化合物的培养细胞中的细胞内蛋白质酪氨酸磷酸化。在大鼠颈动脉球囊损伤模型中口服该化合物有效地抑制了新生内膜增殖。这些结果表明羰基化合物包埋在治疗疾病的有用性。少

Proteins are modified with advanced glycation end products (AGEs) formed by non - enzymatic glycation and oxidation (glycoxidation) reaction. Research on AGEs in human pathology initially focused on diabetes with sustained hyperglycemia. Recent studies, however, demonstrated the increased AGE genesis in normoglycemic uremia and atherosclerosis. Their AGE accumulation cannot be attributed to hyperglycemia. Gathered evidence has suggested that, under oxidative stress, the increased carbonyl compounds, derived from both carbohydrates and lipids, modify proteins by not only glycoxidation reaction but also lipoxidation reaction, leading to formation of not only AGEs but also advanced lipoxidation end products (ALEs). Thus, the pathological lesions might be in a state of carbonyl overload with potentially damaging proteins ("carbonyl stress"). The increased AGEs/ALEs in tissue proteins may betray abroad derangement in non - enzymatic biochemistry involving both carbohydrates and lipids. Immu … More nohistochemical studies with specific antibodies to AGEs /ALEs, identified "carbonyl stress" in human atherosclerosis, diabetic nephropathy, uremic dialysis related amyloidosis._Proteins modified with AGEs/ALEs exhibited various biological effects on several types of cells. The carbonyl compounds per se crosslink matrix proteins and alter their structure and function. They further interact with cell surface proteins, transduce the intracellular signaling, and induce cellular responses. These biological activities might account in part for the pathology.We recently found a novel compound that inhibits the carbonyl stress and AGE/ALE formation. This compound inhibits the intracellular protein - tyrosine phosphorylation in cultured cells exposed to carbonyl compounds. Oral administration of the compound in a rat carotid artery balloon injury model effectively inhibited the neointimal proliferation. These findings suggest the usefulness of carbonyl compound entrapping in the treatment of the diseases. Less