DNA Glycation from 3-Deoxyglucosone Leads to the Formation of AGEs: Potential Role in Cancer Auto-antibodies
DNA Glycation from 3-Deoxyglucosone Leads to the Formation of AGEs: Potential Role in Cancer Auto-antibodies
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DOI：
10.1007/s12013-015-0713-6
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发表时间：
2016-03-01
影响因子：
2.6
通讯作者：
Ahmad, Saheem
中科院分区：
文献类型：
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作者：
Ashraf, Jalaluddin M.;Shahab, Uzma;Ahmad, Saheem
非酶糖基化反应导致自由基的产生，自由基在衰老、糖尿病和癌症的病理生理中起着重要作用。3-脱氧葡萄糖（3-DG）是一种二羰基物质，可导致晚期糖基化终产物（AGEs）的形成。3-DG还与核酸的游离氨基发生反应，形成DNA-AGEs。虽然之前已经发现了核苷AGEs的建立，但没有广泛的研究来探讨3-DG在产生免疫原性和诱导癌症自身抗体中的作用。在本研究中，我们报道了3-DG-Arg-Fe3+系统形成的AGEs的免疫原性。光谱分析和熔融温度研究表明，DNA的结构扰动是修饰的结果。研究了天然DNA和3-DG-Arg-Fe3+ DNA在母兔体内的免疫原性。经过修饰的DNA具有高度的免疫原性，可引发高滴度的免疫原特异性抗体，而未经修饰的DNA几乎没有免疫原性。我们还报道了在不同类型癌症患者的血清中存在针对3-DG-Arg-Fe3+修饰DNA的自身抗体。从选定的癌症患者分离的淋巴细胞DNA中也检测到糖氧化病变。结果显示，3-DG-Arg-Fe3+-DNA的结构扰动产生新的表位，使分子具有免疫原性。
The non-enzymatic glycation reaction results in the generation of free radicals which play an important role in the pathophysiology of aging, diabetes, and cancer. 3-Deoxyglucosone (3-DG) is a dicarbonyl species which may lead to the formation of advanced glycation end products (AGEs). 3-DG also reacts with free amino group of nucleic acids resulting in the formation of DNA-AGEs. While the establishment of nucleoside AGEs has been revealed before, no extensive studies have been done to probe the role of 3-DG in the generation of immunogenicity and induction of cancer auto-antibodies. In this study, we report the immunogenicity of AGEs formed by 3-DG-Arg-Fe3+ system. Spectroscopic analysis and melting temperature studies suggest structural perturbations in the DNA as a result of modification. Immunogenicity of native and 3-DG-Arg-Fe3+ DNA was probed in female rabbits. The modified DNA was highly immunogenic eliciting high-titer immunogen-specific antibodies, while the unmodified form was almost non-immunogenic. We also report the presence of auto-antibodies against 3-DG-Arg-Fe3+-modified DNA in the sera of patients with different types of cancers. The glycoxidative lesions were also detected in the lymphocyte DNA isolated from selected cancer patients. The results show structural perturbations in 3-DG-Arg-Fe3+-DNA generating new epitopes that render the molecule immunogenic.