Manai Federico, Amadio Marialaura
Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy.
Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy.
Antioxidants (Basel). 2022 Sep 28;11(10):1924. doi: 10.3390/antiox11101924.
Dimethyl fumarate (DMF) is a well-known activator of Nrf2 (NF-E2-related factor 2), used in the treatment of psoriasis and multiple sclerosis. The mechanism of action consists in the modification of the cysteine residues on the Nrf2-inhibitor Keap1, thus leading to the dissociation of these two proteins and the consequent activation of Nrf2. Considering the paucity of evidence of DMF effects in the context of retinal endothelium, this study investigated the role of DMF in human retinal endothelial cells (HREC). Here, we show for the first time in HREC that DMF activates the Nrf2 pathway, thus leading to an increase in HO-1 protein levels and a decrease in intracellular ROS levels. Furthermore, this molecule also shows beneficial properties in a model of hyperglucose stress, exerting cytoprotective prosurvival effects. The overall collected results suggest that DMF-mediated activation of the Nrf2 pathway may also be a promising strategy in ocular diseases characterized by oxidative stress. This study opens a new perspective on DMF and suggests its potential repositioning in a broader therapeutical context.
富马酸二甲酯（DMF）是一种著名的Nrf2（NF-E2相关因子2）激活剂，用于治疗银屑病和多发性硬化症。其作用机制在于修饰Nrf2抑制剂Keap1上的半胱氨酸残基，从而导致这两种蛋白质解离，进而激活Nrf2。鉴于在视网膜内皮细胞环境中关于DMF作用的证据匮乏，本研究调查了DMF在人视网膜内皮细胞（HREC）中的作用。在此，我们首次在HREC中表明，DMF激活Nrf2途径，从而导致HO-1蛋白水平升高和细胞内ROS水平降低。此外，该分子在高糖应激模型中也显示出有益特性，发挥细胞保护的促生存作用。总体收集的结果表明，DMF介导的Nrf2途径激活在以氧化应激为特征的眼部疾病中也可能是一种有前景的策略。本研究为DMF开辟了新的视角，并表明其在更广泛治疗背景下潜在的重新定位。
