Bjørklund Geir, Gurgas Leonard, Hangan Tony
Council for Nutritional and Environmental Medicine (CONEM), Mo i Rana, Norway.
Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania.
Curr Med Chem. 2025 Apr 25. doi: 10.2174/0109298673374335250410074811.
AGEs are molecules formed by nonenzymatic glycation of proteins, lipids, and nucleic acids, a process accelerated under hyperglycemic conditions such as DM1. These molecules interact with specific receptors, particularly the Receptor for AGEs (RAGE), triggering intracellular signaling cascades that promote oxidative stress through the generation of Reactive Oxygen Species (ROS) and activation of inflammatory pathways. A critical pathological mechanism involves the formation of neoantigens, modified self-proteins that elicit immune responses. Structural alterations caused by AGEs expose new epitopes or modify existing ones, making them targets for autoreactive T cells and autoantibodies. This mechanism is implicated in autoimmune skin diseases such as vitiligo and bullous pemphigoid. Oxidative stress plays a central role in these diseases, exacerbated by AGEs through the generation of ROS and depletion of antioxidants, leading to melanocyte destruction in vitiligo and tissue damage in bullous pemphigoid. In addition, hypoxia enhances ROS production, mitochondria, and other cellular systems contributing to oxidative stress. Emerging evidence suggests that hypoxia can be mitigated by oxygen nanobubbles. Targeting AGE formation and oxidative stress presents a promising approach for the management of autoimmune skin disorders in DM1. Therapeutic strategies targeting AGE formation, oxidative stress, and immune dysregulation show promise for managing autoimmune skin disorders in Type 1 Diabetes Mellitus (T1DM). AGE inhibitors, such as aminoguanidine and pyridoxamine, reduce non-enzymatic protein glycation, limiting AGE accumulation and inflammatory signaling. Antioxidants, including polyphenols, vitamins C and E, N-acetylcysteine, selenium, and hydrogen-rich water, help neutralize Reactive Oxygen Species (ROS), restoring oxidative balance. Combining AGE inhibitors and antioxidants may provide synergistic benefits by reducing oxidative stress and protein immunogenicity. Additionally, immune modulation therapies, such as Treg therapy and cytokine inhibitors, aim to restore immune tolerance and prevent autoimmune activation. Anti-TNF-α and IL-6 inhibitors offer targeted inflammation suppression, while RAGE antagonists mitigate AGE-induced immune dysregulation. This study aims to explore the role of Advanced Glycation End products (AGEs) in the pathogenesis of autoimmune skin disorders associated with type 1 Diabetes Mellitus (DM1) and to evaluate potential therapeutic strategies targeting AGE formation and oxidative stress.
晚期糖基化终末产物（AGEs）是蛋白质、脂质和核酸非酶糖基化形成的分子，在糖尿病（DM1）等高血糖条件下，这一过程会加速。这些分子与特定受体相互作用，特别是晚期糖基化终末产物受体（RAGE），触发细胞内信号级联反应，通过产生活性氧（ROS）和激活炎症途径来促进氧化应激。一个关键的病理机制涉及新抗原的形成，即引发免疫反应的修饰自身蛋白。AGEs引起的结构改变会暴露新的表位或修饰现有的表位，使其成为自身反应性T细胞和自身抗体的靶点。这种机制与白癜风和大疱性类天疱疮等自身免疫性皮肤病有关。氧化应激在这些疾病中起核心作用，AGEs通过产生活性氧和消耗抗氧化剂使其加剧，导致白癜风中的黑素细胞破坏和大疱性类天疱疮中的组织损伤。此外，缺氧会增强活性氧的产生、线粒体和其他导致氧化应激的细胞系统。新出现的证据表明，氧纳米气泡可以缓解缺氧。针对AGE形成和氧化应激是治疗DM1相关自身免疫性皮肤病的一种有前景的方法。针对AGE形成、氧化应激和免疫失调的治疗策略有望用于管理1型糖尿病（T1DM）中的自身免疫性皮肤病。AGE抑制剂，如氨基胍和吡哆胺，可减少非酶蛋白糖基化，限制AGE积累和炎症信号传导。抗氧化剂，包括多酚、维生素C和E、N-乙酰半胱氨酸、硒和富氢水，有助于中和活性氧，恢复氧化平衡。联合使用AGE抑制剂和抗氧化剂可能通过降低氧化应激和蛋白质免疫原性提供协同益处。此外，免疫调节疗法，如调节性T细胞疗法和细胞因子抑制剂，旨在恢复免疫耐受并防止自身免疫激活。抗TNF-α和IL-6抑制剂可提供靶向性炎症抑制，而RAGE拮抗剂可减轻AGE诱导的免疫失调。本研究旨在探讨晚期糖基化终末产物（AGEs）在1型糖尿病（DM1）相关自身免疫性皮肤病发病机制中的作用，并评估针对AGE形成和氧化应激的潜在治疗策略。
