Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China, 325000; Department of Cardiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China, 314000.
Department of Cardiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China, 314000.
Eur J Pharm Sci. 2022 May 1;172:106164. doi: 10.1016/j.ejps.2022.106164. Epub 2022 Mar 5.
Atherosclerosis is the common pathophysiological foundation of ischaemic stroke and myocardial ischaemia. Oxidative stress is intricately related to the progress of atherosclerosis. DL-3-n-butylphthalide (NBP) is a synthesized raceme of L-3-n-butylphthalide that is first isolated from celery. As a neuroprotective agent, NBP also exhibits potent antioxidative activity. Our research aimed to evaluate the effect of NBP on atherosclerosis and to explore the underlying antioxidative mechanisms and targets. Firstly, we detected the protective effect of NBP on ApoE model of atherosclerosis. NBP showed high efficiency as a therapeutic agent against the formation of atherosclerotic plaques and oxidative events in HFD-treated ApoE mice. We have also evaluated the effect of NBP on oxidized-LDL (oxLDL)-induced oxidative damage and Keap-1/ Nrf-2 interaction by utilizing rat aortic endothelial cells (ECs) and mouse primary peritoneal macrophages (MPMs). Furthermore, we investigated the possibility that NBP improves oxLDL-stimulated oxidative stress in a Keap-1- dependent way in ECs by siRNA technique. Using molecular dynamics (MD) simulation, we detected that Keap-1, a negative adaptor of Nrf-2, may be one of the target protein of NBP. Our studies show that amelioration of oxidative stress by NBP may provide a potential therapeutic strategy for atherosclerosis or cardio-cerebrovascular events from atherosclerosis.
动脉粥样硬化是缺血性卒中和心肌缺血的常见病理生理基础。氧化应激与动脉粥样硬化的进展密切相关。DL-3-正丁基苯酞（NBP）是芹菜中首次分离出的 L-3-正丁基苯酞的合成外消旋体。作为一种神经保护剂，NBP 还具有很强的抗氧化活性。我们的研究旨在评估 NBP 对动脉粥样硬化的作用，并探讨其潜在的抗氧化机制和靶点。首先，我们检测了 NBP 对 ApoE 模型动脉粥样硬化的保护作用。NBP 对 HFD 处理的 ApoE 小鼠动脉粥样硬化斑块形成和氧化事件具有高效的治疗作用。我们还评估了 NBP 对氧化型低密度脂蛋白（oxLDL）诱导的氧化损伤和 Keap-1/Nrf-2 相互作用的影响，方法是利用大鼠主动脉内皮细胞（ECs）和小鼠原代腹腔巨噬细胞（MPMs）。此外，我们通过 siRNA 技术研究了 NBP 是否可能以 Keap-1 依赖的方式改善 oxLDL 刺激的 ECs 中的氧化应激。通过分子动力学（MD）模拟，我们检测到 Keap-1，即 Nrf-2 的负调节因子，可能是 NBP 的靶蛋白之一。我们的研究表明，NBP 改善氧化应激可能为动脉粥样硬化或由动脉粥样硬化引起的心脑血管事件提供一种潜在的治疗策略。
