The SOCS1/JAK2/STAT3 axis is strongly associated with tumor growth and progression,and participates in cytokine secretion in many diseases.However,the effects of the SOCS1/JAK2/STAT3 axis in experimental subarachnoid ...The SOCS1/JAK2/STAT3 axis is strongly associated with tumor growth and progression,and participates in cytokine secretion in many diseases.However,the effects of the SOCS1/JAK2/STAT3 axis in experimental subarachnoid hemorrhage remain to be studied.A subarachnoid hemorrhage model was established in rats by infusing autologous blood into the optic chiasm pool.Some rats were first treated with JAK2/STAT3 small interfering RNA(Si-JAK2/Si-STAT3)or overexpression plasmids of JAK2/STAT3.In the brains of subarachnoid hemorrhage model rats,the expression levels of both JAK2 and STAT3 were upregulated and the expression of SOCS1 was downregulated,reaching a peak at 48 hours after injury.Simultaneously,the interactions between JAK2 and SOCS1 were reduced.In contrast,the interactions between JAK2 and STAT3 were markedly enhanced.Si-JAK2 and Si-STAT3 treatment alleviated cortical neuronal cell apoptosis and necrosis,destruction of the blood-brain barrier,brain edema,and cognitive functional impairment after subarachnoid hemorrhage.This was accompanied by decreased phosphorylation of JAK2 and STAT3 protein,decreased total levels of JAK2 and STAT3 protein,and increased SOCS1 protein expression.However,overexpression of JAK2 and STAT3 exerted opposite effects,aggravating subarachnoid hemorrhage-induced early brain injury.Si-JAK2 and Si-STAT3 inhibited M1-type microglial conversion and the release of pro-inflammatory factors(inducible nitric oxide synthase,interleukin-1β,and tumor necrosis factor-α)and increased the release of anti-inflammatory factors(arginase-1,interleukin-10,and interleukin-4).Furthermore,primary neurons stimulated with oxyhemoglobin were used to simulate subarachnoid hemorrhage in vitro,and the JAK2 inhibitor AG490 was used as an intervention.The in vitro results also suggested that neuronal protection is mediated by the inhibition of JAK2 and STAT3 expression.Together,our findings indicate that the SOCS1/JAK2/STAT3 axis contributes to early brain injury after subarachnoid hemorrhage both in vitro and in vivo by inducing inflammatory responses.This study was approved by the Animal Ethics Committee of Anhui Medical University and the First Affiliated Hospital of University of Science and Technology of China(approval No.LLSC-20180202)on March 1,2018.展开更多
中药单体治疗脊髓损伤具有多途径、多靶点、不良反应少等优势,主要是通过调控Janus激酶/信号转导和转录激活因子(Janus kinase/signal transducer and activator of transcription,JAK/STAT)、核因子-κB(nuclear factor-κB,NF-κB)、...中药单体治疗脊髓损伤具有多途径、多靶点、不良反应少等优势,主要是通过调控Janus激酶/信号转导和转录激活因子(Janus kinase/signal transducer and activator of transcription,JAK/STAT)、核因子-κB(nuclear factor-κB,NF-κB)、核因子E2相关因子2/血红素加氧酶-1(nuclear factor E2 related factor/heme oxygenase-1,Nrf2/HO-1)、丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)、磷脂酰肌醇3-激酶/蛋白激酶B(phoinositide 3-kinase/protein kinase B,PI3K/Akt)、Wnt/β-catenin等信号通路,发挥降低炎症因子表达、抑制氧化应激反应、促进轴突再生、减少细胞凋亡等作用,从而修复脊髓损伤。但现有研究仍存在一些不足,如中药单体对脊髓损伤的有效性缺乏临床试验数据佐证,基础实验中脊髓损伤模型病证单一,信号通路及靶点上下游通路蛋白间的相互作用机制尚未阐明等,今后可借助分子生物技术、多组学技术、网络药理学等进一步明确中药单体修复脊髓损伤的作用机制,同时挖掘中医药更多潜在的分子标志物,为新药研发提供靶点。展开更多
基金This study was supported by the National Natural Science Foundation of China,No.81500375(to XQK)the Fundamental Research Funds for the Central Universities,No.WK9110000112(to YW)+1 种基金the Anhui Provincial Natural Science Foundation of China,No.1508085QH184(to YW)Shandong Provincial Natural Science Foundation of China,No.ZR2015HQ001(to XQK).
文摘The SOCS1/JAK2/STAT3 axis is strongly associated with tumor growth and progression,and participates in cytokine secretion in many diseases.However,the effects of the SOCS1/JAK2/STAT3 axis in experimental subarachnoid hemorrhage remain to be studied.A subarachnoid hemorrhage model was established in rats by infusing autologous blood into the optic chiasm pool.Some rats were first treated with JAK2/STAT3 small interfering RNA(Si-JAK2/Si-STAT3)or overexpression plasmids of JAK2/STAT3.In the brains of subarachnoid hemorrhage model rats,the expression levels of both JAK2 and STAT3 were upregulated and the expression of SOCS1 was downregulated,reaching a peak at 48 hours after injury.Simultaneously,the interactions between JAK2 and SOCS1 were reduced.In contrast,the interactions between JAK2 and STAT3 were markedly enhanced.Si-JAK2 and Si-STAT3 treatment alleviated cortical neuronal cell apoptosis and necrosis,destruction of the blood-brain barrier,brain edema,and cognitive functional impairment after subarachnoid hemorrhage.This was accompanied by decreased phosphorylation of JAK2 and STAT3 protein,decreased total levels of JAK2 and STAT3 protein,and increased SOCS1 protein expression.However,overexpression of JAK2 and STAT3 exerted opposite effects,aggravating subarachnoid hemorrhage-induced early brain injury.Si-JAK2 and Si-STAT3 inhibited M1-type microglial conversion and the release of pro-inflammatory factors(inducible nitric oxide synthase,interleukin-1β,and tumor necrosis factor-α)and increased the release of anti-inflammatory factors(arginase-1,interleukin-10,and interleukin-4).Furthermore,primary neurons stimulated with oxyhemoglobin were used to simulate subarachnoid hemorrhage in vitro,and the JAK2 inhibitor AG490 was used as an intervention.The in vitro results also suggested that neuronal protection is mediated by the inhibition of JAK2 and STAT3 expression.Together,our findings indicate that the SOCS1/JAK2/STAT3 axis contributes to early brain injury after subarachnoid hemorrhage both in vitro and in vivo by inducing inflammatory responses.This study was approved by the Animal Ethics Committee of Anhui Medical University and the First Affiliated Hospital of University of Science and Technology of China(approval No.LLSC-20180202)on March 1,2018.
文摘中药单体治疗脊髓损伤具有多途径、多靶点、不良反应少等优势,主要是通过调控Janus激酶/信号转导和转录激活因子(Janus kinase/signal transducer and activator of transcription,JAK/STAT)、核因子-κB(nuclear factor-κB,NF-κB)、核因子E2相关因子2/血红素加氧酶-1(nuclear factor E2 related factor/heme oxygenase-1,Nrf2/HO-1)、丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)、磷脂酰肌醇3-激酶/蛋白激酶B(phoinositide 3-kinase/protein kinase B,PI3K/Akt)、Wnt/β-catenin等信号通路,发挥降低炎症因子表达、抑制氧化应激反应、促进轴突再生、减少细胞凋亡等作用,从而修复脊髓损伤。但现有研究仍存在一些不足,如中药单体对脊髓损伤的有效性缺乏临床试验数据佐证,基础实验中脊髓损伤模型病证单一,信号通路及靶点上下游通路蛋白间的相互作用机制尚未阐明等,今后可借助分子生物技术、多组学技术、网络药理学等进一步明确中药单体修复脊髓损伤的作用机制,同时挖掘中医药更多潜在的分子标志物,为新药研发提供靶点。
