Abstract：
Thioredoxin-reductase 2 (Txnrd2) belongs to the thioredoxin-reductase family of selenoproteins and is a key antioxidant enzyme in mammalian cells to regulate redox homeostasis. Here, we reported that Txnrd2 exerted a major influence in brain damage caused by Intracerebral hemorrhage (ICH) by suppressing endoplasmic reticulum (ER) stress oxidative stress and via Trx2/Prx3 pathway. Furthermore, we demonstrated that pharmacological selenium (Se) rescued the brain damage after ICH by enhancing Txnrd2 expression. Primarily, expression and localization of Txnrd2, Trx2 and Prx3 were determined in collagenase IV-induced ICH model. Txnrd2 was then knocked down using siRNA interference in rats which were found to develop more severe encephaledema and neurological deficits. Mechanistically, we observed that loss of Txnrd2 leads to increased lipid peroxidation levels and ER stress protein expression in neurons and astrocytes. Additionally, it was revealed that Se effectively restored the expression of Txnrd2 in brain and inhibited both the activity of ER stress protein activity and the generation of reactive oxygen species (ROS) by promoting Trx2/Prx3 kilter when administrating sodium selenite in lateral ventricle. This study shed light on the effect of Txnrd2 in regulating oxidative stress and ER stress via Trx2/Prx3 pathway upon ICH and its promising potential as an ICH therapeutic target.
摘要：
硫氧还蛋白还原酶2（Txnrd2）属于硒蛋白的硫氧还蛋白还原酶家族，是哺乳动物细胞中调节氧化还原稳态的关键抗氧化酶。这里,我们报道,Txnrd2通过抑制内质网(ER)应激氧化应激并通过Trx2/Prx3途径对脑出血(ICH)引起的脑损伤产生重要影响.此外，我们证明，药理硒（Se）通过增强Txnrd2表达来挽救ICH后的脑损伤。首先,在胶原酶IV诱导的ICH模型中确定Txnrd2，Trx2和Prx3的表达和定位。然后在发现发展更严重的脑水肿和神经缺陷的大鼠中使用siRNA干扰击倒Txnrd2。机械上,我们观察到Txnrd2的缺失导致神经元和星形胶质细胞的脂质过氧化水平和ER应激蛋白表达增加。此外,结果表明，硒在侧脑室给药亚硒酸钠时，通过促进Trx2/Prx3kilter，有效恢复了脑中Txnrd2的表达，并抑制了ER应激蛋白活性和活性氧（ROS）的产生。这项研究揭示了Txnrd2通过Trx2/Prx3途径调节ICH氧化应激和ER应激的作用及其作为ICH治疗靶标的潜力。
