Department of Anesthesiology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, P.R. China.
Eur Rev Med Pharmacol Sci. 2018 Sep;22(17):5678-5687. doi: 10.26355/eurrev_201809_15835.
Dishevelled-Axin (DIX) domain containing 1 (DIXDC1), a novel DIX domain-containing protein and a positive regulator of Wingless (Wnt) signaling, has previously been reported to play multiple roles in neurodevelopment and neurological disorders. However, whether DIXDC1 plays a role during cerebral ischemia/reperfusion injury remains unknown. In this study, we investigated the potential role of DIXDC1 in neuronal injury induced by oxygen-glucose deprivation and reoxygenation (OGD/R), an in vitro model of cerebral ischemia/reperfusion injury.
Neuronal injury was induced by OGD/R treatment. Relative mRNA expression of DIXDC1 was detected by real-time quantitative polymerase chain reaction (RT-qPCR). Protein expression of DIXDC1 and β-catenin was determined by Western blot. Cell viability was examined by the cell counting kit-8 assay. Cell cytotoxicity was detected by the lactate dehydrogenase assay. Cell apoptosis was detected by the caspase-3 activity assay. The activity of Wnt/β-catenin signaling was detected by the luciferase reporter assay.
TWe found that DIXDC1 expression was significantly upregulated in hippocampal neurons following OGD/R treatment. Small interfering RNA-mediated silencing of DIXDC1 significantly impaired viability and promoted cell injury and apoptosis in neurons with OGD/R treatment. In contrast, overexpression of DIXDC1 increased the viability and reduced cell injury and apoptosis in neurons with OGD/R treatment, showing protective effects against OGD/R injury. Furthermore, our results showed that DIXDC1 promoted the expression of β-catenin and activation of Wnt signaling. Notably, inhibition of Wnt signaling significantly abrogated DIXDC-mediated neuroprotective effects.
Our results demonstrate that DIXDC1 prevents OGD/R-induced neuronal injury by promoting Wnt/β-catenin signaling. Our study indicates that DIXDC1 may play an important role in cerebral ischemia and reperfusion serving as a potential target for the treatment of cerebral ischemia/reperfusion injury.
Dishevelled-Axin (DIX) 结构域包含 1 (DIXDC1) 是一种新型的 DIX 结构域蛋白，也是 Wingless (Wnt) 信号的正向调节剂，先前研究表明其在神经发育和神经疾病中发挥多种作用。然而，DIXDC1 是否在脑缺血再灌注损伤中发挥作用仍不清楚。本研究旨在探讨 DIXDC1 在氧葡萄糖剥夺再复氧（OGD/R）诱导的神经元损伤（体外脑缺血再灌注损伤模型）中的潜在作用。
通过 OGD/R 处理诱导神经元损伤。采用实时定量聚合酶链反应（RT-qPCR）检测 DIXDC1 的相对 mRNA 表达。采用 Western blot 检测 DIXDC1 和 β-连环蛋白的蛋白表达。通过细胞计数试剂盒-8 检测细胞活力。通过乳酸脱氢酶检测试剂盒检测细胞毒性。通过 caspase-3 活性检测试剂盒检测细胞凋亡。通过荧光素酶报告基因检测试剂盒检测 Wnt/β-连环蛋白信号通路的活性。
我们发现，OGD/R 处理后海马神经元中 DIXDC1 的表达明显上调。用小干扰 RNA 介导的 DIXDC1 沉默显著损害了 OGD/R 处理后的神经元活力，并促进了细胞损伤和凋亡。相反，过表达 DIXDC1 增加了 OGD/R 处理后的神经元活力，减少了细胞损伤和凋亡，对 OGD/R 损伤具有保护作用。此外，我们的结果表明，DIXDC1 促进了 β-连环蛋白的表达和 Wnt 信号通路的激活。值得注意的是，抑制 Wnt 信号通路显著削弱了 DIXDC 介导的神经保护作用。
我们的研究结果表明，DIXDC1 通过促进 Wnt/β-连环蛋白信号通路来防止 OGD/R 诱导的神经元损伤。我们的研究表明，DIXDC1 在脑缺血和再灌注中可能发挥重要作用，可作为治疗脑缺血/再灌注损伤的潜在靶点。
