Cyclo‐glycylproline attenuates hydrogen peroxide‐induced cellular damage mediated by the MDM2‐p53 pathway in human neural stem cells
Cyclo‐glycylproline attenuates hydrogen peroxide‐induced cellular damage mediated by the MDM2‐p53 pathway in human neural stem cells
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DOI：
10.1002/jcp.30940
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发表时间：
2022-12
影响因子：
5.6
通讯作者：
K. Murotomi;Harumi Kagiwada;Kazumi Hirano;Shoko Yamamoto;Noriaki Numata;Yo Matsumoto;H. Kaneko;M. Na
中科院分区：
文献类型：
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作者：
K. Murotomi;Harumi Kagiwada;Kazumi Hirano;Shoko Yamamoto;Noriaki Numata;Yo Matsumoto;H. Kaneko;M. Na
环甘氨酰脯氨酸（cGP）是一种含有甘氨酸和脯氨酸之间缩合键的环状二肽，由胰岛素样生长因子-1的N-末端三肽环化产生。先前的研究表明，cGP给药在缺血性脑损伤大鼠中发挥神经保护作用并增强再生能力。cGP的疗效是通过调节胰岛素样生长因子-1（IGF-1）的生物利用度来实现的，然而，cGP对脑损伤的神经保护作用的分子机制仍有待阐明。在目前的研究中，我们研究了暴露于氧化应激的人胎儿神经干细胞（hfNSC）中cGP介导的分子机制，这是影响几种脑疾病发展的关键因素，包括创伤性脑损伤和帕金森病。我们发现cGP处理以剂量依赖性方式减弱了培养的hfNSC中氧化应激诱导的细胞死亡。转录组分析显示，在氧化应激条件下，p53介导的信号传导被激活，伴随着cGP处理的hfNSC中小鼠双微体2同源物（MDM 2）（一种p53特异性E3泛素连接酶）的上调。通过使用一个全面的蛋白磷酸化阵列，我们发现，cGP诱导Akt信号通路的激活，从而增强MDM 2的表达，在hfNSCs暴露于氧化应激。此外，MDM 2抑制剂nutlin-3抑制cGP对氧化应激诱导的细胞死亡和凋亡的保护作用。因此，cGP减弱了人NSC中IGF-1信号传导和MDM 2-p53通路之间相互作用介导的氧化应激诱导的细胞死亡。我们揭示了脑损伤模型中cGP诱导神经保护特性的分子机制。
Cyclo‐glycylproline (cGP), a cyclic dipeptide containing a condensation bond between glycine and proline, is produced by the cyclization of the N‐terminal tripeptide of insulin‐like growth factor‐1. Previous studies have shown that cGP administration exerts a neuroprotective effect and enhances the regenerative ability in rats with ischemic brain injury. The efficacy of cGP is medicated by regulating the bioavailability of insulin‐like growth factor‐1 (IGF‐1), however, the molecular mechanisms underlying the neuroprotective effects of cGP on brain damage remains to be elucidated. In the current study, we investigated the cGP‐mediated molecular mechanism in human fetal neural stem cells (hfNSCs) exposed to oxidative stress, which is a key factor affecting the development of several brain diseases, including traumatic brain injury and Parkinson's disease. We found that cGP treatment attenuated oxidative stress‐induced cell death in cultured hfNSCs in a dose‐dependent manner. Transcriptome analysis revealed that under oxidative stress conditions, p53‐mediated signaling was activated, accompanied by upregulation of mouse double minute 2 homolog (MDM2), a p53‐specific E3 ubiquitin ligase, in cGP‐treated hfNSCs. By using a comprehensive protein phosphorylation array, we found that cGP induced the activation of Akt signaling pathway, which enhanced the expression of MDM2, in hfNSCs exposed to oxidative stress. Moreover, the MDM2 inhibitor nutlin‐3 inhibited the protective effect of cGP on oxidative stress‐induced cell death and apoptosis. Therefore, cGP attenuates oxidative stress‐induced cell death mediated by the interplay between IGF‐1 signaling and the MDM2‐p53 pathway in human NSCs. We revealed the molecular mechanism underlying cGP‐induced neuroprotective properties in a model of brain damage.