Abstract：
UNASSIGNED: The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPRmt may be a potential therapeutic target for ischemic stroke.
UNASSIGNED: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPRmt. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro.
UNASSIGNED: Inducing UPRmt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPRmt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPRmt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPRmt in vivo, which reduced infarction and improved neurological outcomes.
UNASSIGNED: These findings suggest that the UPRmt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPRmt mechanism may provide a new therapeutic avenue for ischemic stroke.
UNASSIGNED: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPRmt. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro.
UNASSIGNED: Inducing UPRmt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPRmt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPRmt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPRmt in vivo, which reduced infarction and improved neurological outcomes.
UNASSIGNED: These findings suggest that the UPRmt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPRmt mechanism may provide a new therapeutic avenue for ischemic stroke.
摘要：
■线粒体未折叠蛋白质反应（UPRmt）是一种进化上保守的线粒体反应，对于在组织损伤和疾病后在细胞应激下维持线粒体和能量稳态至关重要。这里,我们询问UPRmt是否可能是缺血性卒中的潜在治疗靶点.
■我们进行了大脑中动脉闭塞和氧-葡萄糖剥夺模型，以模拟体内和体外的缺血性中风，分别。使用寡霉素和meclizine触发UPRmt。我们用氯化2,3,5-三苯基四唑染色,行为测试,和Nissl染色以评估体内脑损伤。进行细胞计数试剂盒-8测定和钙黄绿素AM测定试剂盒以在体外测试脑损伤。
■用寡霉素诱导UPRmt保护神经元培养物免受氧-葡萄糖剥夺。UPRmt也可以用meclizine触发，这种食品和药物管理局批准的药物也可以保护神经元免受氧糖剥夺。用针对激活转录因子5的siRNA阻断UPRmt消除了meclizine的神经保护作用。在小鼠局灶性脑缺血模型中,用meclizine预处理能够在体内诱导UPRmt，减少梗塞并改善神经系统预后。
■这些发现表明，UPRmt在维持面临缺血/缺氧应激的神经元的存活方面很重要。UPRmt机制可能为缺血性卒中提供新的治疗途径。
■我们进行了大脑中动脉闭塞和氧-葡萄糖剥夺模型，以模拟体内和体外的缺血性中风，分别。使用寡霉素和meclizine触发UPRmt。我们用氯化2,3,5-三苯基四唑染色,行为测试,和Nissl染色以评估体内脑损伤。进行细胞计数试剂盒-8测定和钙黄绿素AM测定试剂盒以在体外测试脑损伤。
■用寡霉素诱导UPRmt保护神经元培养物免受氧-葡萄糖剥夺。UPRmt也可以用meclizine触发，这种食品和药物管理局批准的药物也可以保护神经元免受氧糖剥夺。用针对激活转录因子5的siRNA阻断UPRmt消除了meclizine的神经保护作用。在小鼠局灶性脑缺血模型中,用meclizine预处理能够在体内诱导UPRmt，减少梗塞并改善神经系统预后。
■这些发现表明，UPRmt在维持面临缺血/缺氧应激的神经元的存活方面很重要。UPRmt机制可能为缺血性卒中提供新的治疗途径。
