Department of Anesthesiology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China; Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China; School of Pharmacy and Medical Sciences, Faculty of Health Sciences, University of South Australia, Adelaide, South Australia 5000, Australia.
Institute of Neurological Disease, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China.
Exp Neurol. 2021 Dec;346:113835. doi: 10.1016/j.expneurol.2021.113835. Epub 2021 Aug 11.
It has been reported that Neonatal hypoxic-ischemic encephalopathy (HIE) could induce apoptosis in neonates and result in cognitive and sensory impairments, which are associated with poor developmental outcomes. Despite the improvement in neonatology, there is still no clinically effective treatment for HIE presently. Long non-coding RNAs (lncRNAs) play important roles in cellular homeostasis. Nevertheless, their effects in developing rat brains with HI is little known. Here, we established HIE model in neonate rats and explored the expression and function of lncRNAs in HI, and found the expression of 19 lncRNAs was remarkably changed in the brains of HI rats, compared to the sham group. Among them, three lncRNAs (TCONS_00041002, TCONS_00070547, TCONS_00045572) were enriched in the apoptotic process via gene ontology (GO) and pathway analysis, which were selected for the further qRT-PCR verification. Through lentivirus-mediated overexpression of these three lncRNAs, we found that overexpression of TCONS_00041002 attenuated the cell apoptosis, and increased the vitality of neurons after oxygen-glucose deprivation (OGD), therefore reduced the brain infarction and further promoted the neuron survival as well as improved the neurological disorders in the rats subjected to HIE. What's more, ceRNA network prediction and co-expression verification showed that the expression of TCONS_00041002 was positively associated with Foxe1, Pawr and Nfkbiz. Altogether, this study has exhibited that lncRNA TCONS_00041002 participates in the cell apoptosis and neuronal survival of HIE and represents a potential new target for the treatment of HIE.
据报道，新生儿缺氧缺血性脑病（HIE）可诱导新生儿细胞凋亡，导致认知和感觉障碍，与发育不良结局相关。尽管新生儿学有所改善，但目前仍没有针对 HIE 的临床有效治疗方法。长链非编码 RNA（lncRNA）在细胞稳态中发挥重要作用。然而，它们在 HI 发育大鼠大脑中的作用知之甚少。在这里，我们建立了新生大鼠 HIE 模型，探讨了 lncRNA 在 HI 中的表达和功能，发现与假手术组相比，HI 大鼠大脑中 19 个 lncRNA 的表达明显改变。其中，通过基因本体（GO）和途径分析，三个 lncRNA（TCONS_00041002、TCONS_00070547、TCONS_00045572）在细胞凋亡过程中显著富集，这些 lncRNA 被选择进行进一步的 qRT-PCR 验证。通过慢病毒介导的这三个 lncRNA 的过表达，我们发现 TCONS_00041002 的过表达可减弱细胞凋亡，并增加氧葡萄糖剥夺（OGD）后神经元的活力，从而减少脑梗死，进一步促进 HIE 大鼠神经元存活和改善神经功能障碍。此外，ceRNA 网络预测和共表达验证表明，TCONS_00041002 的表达与 Foxe1、Pawr 和 Nfkbiz 呈正相关。总之，本研究表明 lncRNA TCONS_00041002 参与 HIE 的细胞凋亡和神经元存活，代表了治疗 HIE 的一个潜在新靶点。
