BACKGROUND:Neuroinflammation is a common therapeutic target for traumatic brain injury (TBI) due to its contribution to delayed secondary cell death and has the potential to occur for years after the initial insult. Previous studies demonstrate that miR-429 is up-regulated in the brain lesions of TBI mice, while its role in regulating neuroinflammation and brain injury remains largely unknown. METHOD:The expression of miR-429 in LPS-activated microglia and microglia in TBI model was detected by RT-PCR. The effects of miR-429 inhibitors on LPS-activated microglia in vitro as well as neurological recovery and post-traumatic neuroinflammatory response in TBI model mice were detected in vivo. RESULTS:LPS and TBI significantly induce the up-expression of miR-429, inflammatory cytokines, MAPK-p38 and phosphorylated NF-κB in microglia, which were all inhibited by miR-429 inhibitors. Meanwhile, miR-429 inhibitors also attenuated the neurological impairment in TBI mice. Bioinformatics analysis showed that miR-429 could target and inhibit the expression of dual specificity protein phosphatase 1 (DUSP1), thus inhibiting the expression of MAPK-p38 and phosphorylated NF-κB. CONCLUSION:miR-429 plays a pro-inflammatory role in activated microglia by targeting DUSP1 signaling pathway. Inhibiting miR-429 can attenuate the inflammatory response of microglia and TBI-mediated brain damage.

译文

背景:神经炎症是创伤性脑损伤(TBI)的常见治疗靶点,因为它可导致延迟的继发性细胞死亡,并且有可能在最初的伤害后数年内发生。先前的研究表明,miR-429在TBI小鼠的脑损伤中被上调,而其在调节神经炎症和脑损伤中的作用仍然未知。
方法:采用RT-PCR技术检测miR-429在LPS激活的小胶质细胞和TBI模型小胶质细胞中的表达。体内检测到miR-429抑制剂对LPS激活的小胶质细胞的作用以及TBI模型小鼠的神经功能恢复和创伤后神经炎症反应。
结果:LPS和TBI显着诱导小胶质细胞中miR-429,炎性细胞因子,MAPK-p38和磷酸化NF-κB的表达,均被miR-429抑制剂抑制。同时,miR-429抑制剂也减轻了TBI小鼠的神经功能损害。生物信息学分析表明,miR-429可以靶向并抑制双重特异性蛋白磷酸酶1(DUSP1)的表达,从而抑制MAPK-p38和磷酸化的NF-κB的表达。
结论:miR-429通过靶向DUSP1信号通路在活化的小胶质细胞中起促炎作用。抑制miR-429可以减弱小胶质细胞的炎症反应和TBI介导的脑损伤。

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