Moisă Stoica Roberta, Rusu Călin Mircea, Deftu Antonia Teona, Bacalum Mihaela, Radu Mihai, Radu Beatrice Mihaela
Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania.
Department of Life and Environmental Physics, Horia Hulubei National Institute for Physics and Nuclear Engineering, 077125 Măgurele, Romania.
Int J Mol Sci. 2025 May 26;26(11):5104. doi: 10.3390/ijms26115104.
Methylglyoxal is a reactive dicarbonyl intermediate in the advanced glycation end-product (AGE) pathway, and alterations in its levels have been detected in the plasma, cerebrospinal fluid, and brain parenchyma in various pathologies, particularly in diabetes. In this study, we investigate the effects of methylglyoxal (MGO) on murine brain microvascular endothelial cells at both physiological and pathological concentrations. We evaluate molecular parameters, including reactive oxygen species (ROS) production, cytosolic calcium signaling, and ATP synthesis, as well as cellular responses such as cytoskeletal remodeling, cell migration, adhesion, and permeability, across a concentration range of 0-1000 μM. At low concentrations (below ~250 μM), MGO does not induce oxidative stress; instead, it leads to an increase in cytosolic calcium levels and ATP production. At higher concentrations, however, MGO induces significant oxidative stress, which is accompanied by a marked decrease in cell viability, particularly at concentrations exceeding 500 μM. The modulation of key functional processes, including purinergic calcium signaling, actin filament synthesis, cell migration, and adhesion, reveals a threshold concentration beyond which cellular function is impaired due to oxidative stress. Below this threshold, the observed effects appear to be mediated primarily by non-oxidative mechanisms, likely involving protein glycation. In conclusion, our results suggest a dual action of methylglyoxal on brain endothelial cells, with distinct molecular mechanisms underlying its effects at physiological versus pathological concentrations.
甲基乙二醛是晚期糖基化终产物（AGE）途径中的一种活性二羰基中间体，在各种病理状态下，尤其是糖尿病患者的血浆、脑脊液和脑实质中，已检测到其水平的变化。在本研究中，我们研究了生理和病理浓度下甲基乙二醛（MGO）对小鼠脑微血管内皮细胞的影响。我们评估了分子参数，包括活性氧（ROS）生成、胞质钙信号传导和ATP合成，以及细胞反应，如细胞骨架重塑、细胞迁移、黏附和通透性，浓度范围为0-1000μM。在低浓度（低于约250μM）时，MGO不会诱导氧化应激；相反，它会导致胞质钙水平和ATP生成增加。然而，在较高浓度下，MGO会诱导显著的氧化应激，同时细胞活力显著下降，尤其是在浓度超过500μM时。对关键功能过程的调节，包括嘌呤能钙信号传导、肌动蛋白丝合成、细胞迁移和黏附，揭示了一个阈值浓度，超过该浓度，细胞功能会因氧化应激而受损。低于该阈值时，观察到的效应似乎主要由非氧化机制介导，可能涉及蛋白质糖基化。总之，我们的结果表明甲基乙二醛对脑内皮细胞具有双重作用，其在生理浓度和病理浓度下的作用具有不同的分子机制。
