Ashraf J M, Abdullah S M S, Ahmad S, Fatma S, Baig M H, Iqbal J, Madkhali A M, Jerah A B A
Jazan University, Faculty of Applied Medical Sciences, Jazan, Saudi Arabia.
Biochemistry (Mosc). 2017 May;82(5):579-586. doi: 10.1134/S0006297917050066.
Advanced glycation end-products (AGEs) have been found to be critically involved in initiation or progression of diabetes secondary complications (nephropathy, retinopathy, neuropathy, and angiopathy). Various hyper-glycating carbonyl compounds such as 3-deoxyglucosone (3-DG) are produced in pathophysiological conditions that form AGEs in high quantity both in vivo and in vitro. In the first stage of this study, we glycated histone H2A protein by 3-DG, and the results showed the formation of various intermediates and AGEs as well as structural changes in the protein. In the second stage, we studied the immunogenicity of native and 3-DG-glycated H2A protein in female rabbits. The modified H2A was highly immunogenic, eliciting high titer immunogen-specific antibodies, while the unmodified form was almost nonimmunogenic. Antibodies against standard carboxymethyllysine (CML) and pentosidine were detected in the immunized female rabbits, which demonstrates the immunogenic nature of AGEs (CML and pentosidine) as well. The results show both structural perturbation and AGEs have the capacity of triggering the immune system due to the generation of neoepitopes that render the molecule immunogenic. This study shows the presence of autoantibodies against 3-DG-modified H2A, CML, and pentosidine in the sera of type 2 diabetes patients having secondary complications. Autoantibodies against damaged H2A and AGEs may be significant in the assessment of initiation/progression of secondary complications in type 2 diabetes mellitus patients or may be used as a marker for early detection of secondary complications in diabetes.
晚期糖基化终产物（AGEs）已被发现与糖尿病继发并发症（肾病、视网膜病变、神经病变和血管病变）的发生或发展密切相关。在病理生理条件下会产生各种高糖基化羰基化合物，如3-脱氧葡萄糖酮（3-DG），其在体内和体外均可大量形成AGEs。在本研究的第一阶段，我们用3-DG使组蛋白H2A糖基化，结果显示形成了各种中间体和AGEs以及蛋白质的结构变化。在第二阶段，我们研究了天然和3-DG糖基化的H2A蛋白在雌性兔子中的免疫原性。修饰后的H2A具有高度免疫原性，可引发高滴度的免疫原特异性抗体，而未修饰的形式几乎没有免疫原性。在免疫的雌性兔子中检测到了针对标准羧甲基赖氨酸（CML）和戊糖苷的抗体，这也证明了AGEs（CML和戊糖苷）的免疫原性。结果表明，由于新表位的产生使分子具有免疫原性，结构扰动和AGEs都有触发免疫系统的能力。本研究显示2型糖尿病继发并发症患者血清中存在针对3-DG修饰的H2A、CML和戊糖苷的自身抗体。针对受损H2A和AGEs的自身抗体可能在评估2型糖尿病患者继发并发症的发生/发展中具有重要意义，或可作为糖尿病继发并发症早期检测的标志物。
