■铁凋亡在脑缺血再灌注(I/R)损伤的发生和发展中起着至关重要的作用,并受丝裂原活化蛋白激酶1/2(ERK1/2)的调控。在中国,脑得生丸(NDSP)用于预防和治疗脑硬化和中风。然而,NDSP对脑I/R诱导的铁凋亡的保护作用和作用机制尚不清楚。我们研究了NDSP是否通过调节铁凋亡来发挥其对I/R损伤的保护作用,并旨在阐明其潜在机制。
■使用大脑中动脉闭塞的Sprague-Dawley大鼠模型和体外氧-葡萄糖剥夺/复氧(OGD/R)模型评估NDSP的功效。使用氯化2,3,5-三苯基四唑(TTC)评估脑损伤,苏木精和伊红染色,尼氏染色,和神经评分。进行蛋白质印迹以确定谷胱甘肽过氧化物酶4(GPX4)的表达水平,二价金属离子转运蛋白-1(DMT1),溶质载体家族7成员11(SLC7A11),和转铁蛋白受体1(TFR1)。铁水平,氧化应激,和线粒体形态也进行了评估。网络药理学用于评估相关机制。
■NDSP(1.08g/kg)显著改善脑梗死面积,脑含水量,神经学评分,和脑组织损伤。此外,NDSP抑制I/R和OGD/R诱导的铁凋亡,GPX4和SLC7A11的蛋白质表达增加,TFR1和DMT1的抑制以及氧化应激和Fe2水平的整体降低证明了这一点。GPX4抑制剂RSL3消除了NDSP的体外保护作用。网络药理学分析显示,ERK1/2是核心靶基因,NDSP减少了磷酸化ERK1/2的数量。
■NDSP通过抑制脑I/R诱导的铁中毒发挥其对I/R的保护作用,这种机制与通过ERK1/2信号通路调节铁凋亡有关。
UNASSIGNED: Ferroptosis plays a crucial role in the occurrence and development of cerebral ischemia-reperfusion (I/R) injury and is regulated by mitogen-activated protein kinase 1/2 (ERK1/2). In China, Naodesheng Pills (NDSP) are prescribed to prevent and treat cerebrosclerosis and stroke. However, the protective effects and mechanism of action of NDSP against cerebral I/R-induced ferroptosis remain unclear. We investigated whether NDSP exerts its protective effects against I/R injury by regulating ferroptosis and aimed to elucidate the underlying mechanisms.
UNASSIGNED: The efficacy of NDSP was evaluated using a Sprague-Dawley rat model of middle cerebral artery occlusion and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model. Brain injury was assessed using 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin staining, Nissl staining, and neurological scoring. Western blotting was performed to determine the expression levels of glutathione peroxidase 4 (GPX4), divalent metal-ion transporter-1 (DMT1), solute carrier family 7 member 11 (SLC7A11), and transferrin receptor 1 (TFR1). Iron levels, oxidative stress, and mitochondrial morphology were also evaluated. Network pharmacology was used to assess the associated mechanisms.
UNASSIGNED: NDSP (1.08 g/kg) significantly improved cerebral infarct area, cerebral water content, neurological scores, and cerebral tissue damage. Furthermore, NDSP inhibited I/R- and OGD/R-induced ferroptosis, as evidenced by the increased protein expression of GPX4 and SLC7A11, suppression of TFR1 and DMT1, and an overall reduction in oxidative stress and Fe2+ levels. The protective effects of NDSP in vitro were abolished by the GPX4 inhibitor RSL3. Network pharmacology analysis revealed that ERK1/2 was the core target gene and that NDSP reduced the amount of phosphorylated ERK1/2.
UNASSIGNED: NDSP exerts its protective effects against I/R by inhibiting cerebral I/R-induced ferroptosis, and this mechanism is associated with the regulation of ferroptosis via the ERK1/2 signaling pathway.