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Title: [Role of c-Jun N-terminal kinase-mediated FOXO3a nuclear translocation in neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage].
Author: Li DY, Wu JL, Luo LL, Qiao LN, Liu ZQ, Lu GY, Wang Y.
Journal: Zhongguo Dang Dai Er Ke Za Zhi; 2017 Apr; 19(4):458-462. PubMed ID: 28407836.
Abstract:
OBJECTIVE: To explore the mechanisms of neuroprotective effects of c-Jun N-terminal kinase (JNK)/FOXO3a transcription factor signaling pathway inhibition on hypoxic-ischemic neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage (HIBD). METHODS: Sixty-four 7-day-old Sprague-Dawley rats were divided into four groups: hypoxia-ischemia (HI), sham-operated, JNK specific inhibitor AS601245-treated, and DMSO vehicle. Rats' cerebral cortexes were collected at 24 hours after HI. Western blot was used to detect the protein expression of JNK, p-JNK, FOXO3a, nuclear and cytoplasmic FOXO3a, Bim, and CC3. TUNEL staining was used to detect the apoptotic cells. RESULTS: Compared with the sham-operated group, p-JNK protein increased (P<0.01), nuclear protein of FOXO3a increased (P<0.01), cytoplasmic protein decreased (P<0.01), and pro-apoptotic proteins Bim and CC3 increased 24 hours after HI (P<0.01). Compared with the HI and DMSO vehicle groups, p-JNK protein was reduced (P<0.01), nuclear protein of FOXO3a was also reduced (P<0.01), cytoplasmic protein increased (P<0.01), and Bim and CC3 proteins decreased (P<0.01) in the AS601245-treated group 24 hours after HI. TUNEL positive cells were reduced in the AS601245-treated rats compared with the HI and DMSO vehicle groups 24 hours after HI (P<0.01). CONCLUSIONS: JNK activity increases in the neonatal rat brain with HI damage. JNK activity inhibition can inhibit FOXO3a translocation from cytoplasm to nucleus and downregulate the levels of pro-apoptotic proteins Bim and CC3, leading to the reduction of neuronal apoptosis. 目的: 探讨抑制c-Jun氨基末端激酶（JNK）/核转录因子FOXO3a信号通路对缺氧缺血性脑损伤（HIBD）新生大鼠神经元凋亡的保护作用机制。方法: 将64只7日龄Sprague-Dawley大鼠随机分为假手术组、缺氧缺血（HI）组、二甲基亚砜（DMSO）溶剂组和JNK特异性抑制剂AS601245干预组（JNK抑制剂组）。各组分别在建模后24 h处死动物取大脑皮层，应用Western blot法定量检测JNK、p-JNK、FOXO3a、胞核FOXO3a、胞浆FOXO3a，以及促凋亡蛋白Bim及CC3的表达水平；应用TUNEL染色法检测神经细胞凋亡情况。结果: 与假手术组相比，HI后24 h，p-JNK蛋白水平增高（P < 0.01）；胞核FOXO3a蛋白水平增高，胞浆FOXO3a蛋白水平降低（P < 0.01）；Bim及CC3表达水平增高（P < 0.01）。与HI组及DMSO溶剂组相比，JNK抑制剂组p-JNK蛋白水平降低（P < 0.01）；胞核FOXO3a蛋白水平降低，胞浆FOXO3a蛋白水平增高（P < 0.01）；Bim及CC3表达水平降低（P < 0.01）。JNK抑制剂组的TUNEL染色阳性细胞表达较HI组及DMSO溶剂组减少（P < 0.01）。结论: 新生大鼠HIBD时，JNK发生磷酸化，活性增高；抑制JNK活性可抑制FOXO3a核转位，下调促凋亡蛋白Bim及CC3表达，减少神经细胞凋亡。

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