PDF(Pubmed)
Abstract：
Preventing islet β-cells death is crucial for treating type 2 diabetes mellitus (T2DM). Currently, clinical drugs are being developed to improve the quality of T2DM care and self-care, but drugs focused on reducing islets β-cell death are lacking. Given that β-cell death in T2DM is dominated ultimately by excessive reactive oxygen species (ROS), eliminating excessive ROS in β-cells is a highly promising therapeutic strategy. Nevertheless, no antioxidants have been approved for T2DM therapy because most of them cannot meet the long-term and stable elimination of ROS in β-cells without eliciting toxic side-effects. Here, it is proposed to restore the endogenous antioxidant capacity of β-cells to efficiently prevent β-cell death using selenium nanodots (SENDs), a prodrug of the antioxidant enzyme glutathione peroxidase 1 (GPX1). SENDs not only scavenge ROS effectively, but also \"send\" selenium precisely to β-cells with ROS response to greatly enhance the antioxidant capacity of β-cells by increasing GPX1 expression. Therefore, SENDs greatly rescue β-cells by restoring mitophagy and alleviating endoplasmic reticulum stress (ERS), and demonstrate much stronger efficacy than the first-line drug metformin for T2DM treatment. Overall, this strategy highlights the great clinical application prospects of SENDs, offering a paradigm for an antioxidant enzyme prodrug for T2DM treatment.
摘要：
预防胰岛β细胞死亡对治疗2型糖尿病(T2DM)至关重要。目前,正在开发临床药物，以提高2型糖尿病的护理和自我护理的质量，但是缺乏专注于减少胰岛β细胞死亡的药物。鉴于T2DM的β细胞死亡最终由过量的活性氧（ROS）主导，消除β细胞中过量的ROS是一种非常有前途的治疗策略。然而，目前尚无抗氧化剂被批准用于T2DM治疗,因为它们中的大多数不能在不引起毒副作用的情况下长期稳定地消除β细胞中的ROS。这里,建议使用硒纳米点（SENDs）恢复β细胞的内源性抗氧化能力，以有效防止β细胞死亡。抗氧化酶谷胱甘肽过氧化物酶1(GPX1)的前药。发送不仅有效地清除ROS，而且还将硒精确地“发送”到具有ROS反应的β细胞，通过增加GPX1表达来大大增强β细胞的抗氧化能力。因此,SENDs通过恢复线粒体自噬和减轻内质网应激（ERS）来极大地拯救β细胞，并证明比一线药物二甲双胍治疗T2DM的疗效强得多。总的来说,这一策略凸显了SENDs的巨大临床应用前景，提供了用于治疗T2DM的抗氧化酶前药的范例。
