Advanced glycation end products (AGEs) are generated by nonenzymatic modifications of macromolecules (proteins, lipids, and nucleic acids) by saccharides (glucose, fructose, and pentose) via Maillard reaction. The formed AGE molecules can be catabolized and cleared by glyoxalase I and II in renal proximal tubular cells. AGE-related diseases include physiological aging, neurodegenerative/neuroinflammatory diseases, diabetes mellitus (DM) and its complications, autoimmune/rheumatic inflammatory diseases, bone-degenerative diseases, and chronic renal diseases. AGEs, by binding to receptors for AGE (RAGEs), alter innate and adaptive immune responses to induce inflammation and immunosuppression via the generation of proinflammatory cytokines, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI). These pathological molecules cause vascular endothelial/smooth muscular/connective tissue-cell and renal mesangial/endothelial/podocytic-cell damage in AGE-related diseases. In the present review, we first focus on the cellular and molecular bases of AGE–RAGE axis signaling pathways in AGE-related diseases. Then, we discuss in detail the modes of action of newly discovered novel biomolecules and phytochemical compounds, such as Maillard reaction and AGE–RAGE signaling inhibitors. These molecules are expected to become the new therapeutic strategies for patients with AGE-related diseases in addition to the traditional hypoglycemic and anti-hypertensive agents. We particularly emphasize the importance of “metabolic memory”, the “French paradox”, and the pharmacokinetics and therapeutic dosing of the effective natural compounds associated with pharmacogenetics in the treatment of AGE-related diseases. Lastly, we propose prospective investigations for solving the enigmas in AGE-mediated pathological effects.

中文翻译：

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美拉德反应和晚期糖基化终产物 (AGE) 受体 (RAGE) 信号抑制剂作为 AGE 相关疾病患者的新型治疗策略的发展

高级糖基化终产物 (AGEs) 是由糖类（葡萄糖、果糖和戊糖）通过美拉德反应对大分子（蛋白质、脂质和核酸）进行非酶促修饰而产生的。形成的AGE分子可以被肾近端肾小管细胞中的乙二醛酶I和II分解代谢和清除。AGE相关疾病包括生理性衰老、神经退行性/神经炎症性疾病、糖尿病（DM）及其并发症、自身免疫性/风湿性炎症性疾病、骨退行性疾病和慢性肾脏疾病。AGEs 通过与 AGE 受体 (RAGEs) 结合，改变先天性和适应性免疫反应，通过产生促炎细胞因子、活性氧 (ROS) 和活性氮中间体 (RNI) 来诱导炎症和免疫抑制。这些病理分子在 AGE 相关疾病中引起血管内皮/平滑肌/结缔组织细胞和肾系膜/内皮/足细胞损伤。在本综述中，我们首先关注 AGE-RAGE 轴信号通路在 AGE 相关疾病中的细胞和分子基础。然后，我们详细讨论了新发现的新型生物分子和植物化学化合物的作用模式，例如美拉德反应和 AGE-RAGE 信号抑制剂。除了传统的降糖和抗高血压药物外，这些分子有望成为AGE相关疾病患者的新治疗策略。我们特别强调“代谢记忆”的重要性，“法国悖论”，与药物遗传学相关的有效天然化合物在治疗 AGE 相关疾病中的药代动力学和治疗剂量。最后，我们提出了解决 AGE 介导的病理效应之谜的前瞻性研究。