摘要
目的 探讨沉默信号调节器1(SIRT1)/叉头转录因子(FOXO1)信号通路对小鼠脑缺血再灌注损伤的调控作用。方法 24只清洁级C57雄性小鼠随机分为假手术组、缺血/再灌注组(I/R组)、SIRT1FOXO1信号通路抑制组(实验组),每组8只小鼠。I/R组与实验组采用夹闭、开放双侧颈总动脉法建立脑缺血再灌注损伤小鼠模型,同时实验组给予EX527(SIRT1抑制剂)腹腔注射,I/R组和假手术组腹腔注射等剂量的生理盐水。比较三组的神经功能缺损评分、脑组织含水量、感觉功能和行走协调能力评分,血浆中白介素-6(IL-6)、白细胞介素1(IL-1β)、细胞间黏附分子-1(ICAM-1)和肿瘤坏死因子-α(TNF-α)水平,SIRT1、FOXO1、NF-E2相关因子2(Nrf2)和血红素加氧酶1(HO-1)蛋白表达量,B淋巴细胞瘤-2(Bcl-2)、半胱氨酸蛋白酶-3(Caspase-3)、BCL-2关联蛋白X(Bax)和半胱氨酸蛋白酶-9(Caspase-9) mRNA表达,超氧化物歧化酶(SOD)、一氧化氮(NO)、丙二醛(MDA)和谷胱甘肽(GSH)含量。结果与假手术组相比,I/R组经功能缺损评分、行走协调能力评分和感觉功能、脑组织含水量、炎症因子水平、FOXO1蛋白表达、BAX、Caspase-3和Caspase-9 mRNA表达以及氧化应激指标NO和MDA含量均显著增加(P <0. 05),Nrf2、SIRT1和HO-1蛋白表达、Bcl-2 mRNA表达以及SOD和GSH含量均显著降低(P <0. 05);与I/R组相比,实验组所有指标变化更显著。结论 抑制SIRT1/FOXO1信号通路后,脑缺血/灌注小鼠神经功能降低,脑损伤程度均加重,由此推测SIRT1/FOXO1信号通路的激活与抑制脑缺血/灌注后的炎症反应、减轻氧化应激作用以及减缓细胞凋亡进程相关。
Objective To investigate the regulation of sirtuin1(SIRT1)/Forkhead box O1(FOXO1)signaling pathway in mice with cerebral ischemia-reperfusion injury.Methods 24 C57 male mice were randomly divided into three groups:sham operation group,ischemia/reperfusion group(I/R group)and SIRT1/FOXO1 signaling pathway inhibition group(experimental group),with 8 mice in each group.The mice model of cerebral ischemia-reperfusion injury were established in both the I/R group and experimental group,and the experimental group were given intraperitoneal injection therapy of Nicotinamide(SIRT1 inhibitor).Neurological deficit score,brain water content,sensory function and walking coordination score,plasma levels of Interleukin-6(IL-6),Interleukin-1β(IL-1β),intercellular cell adhesion molecule-1(ICAM-1)and Tumor Necrosis Factor-α(TNF-α),SIRT1,FOXO1,NF-E2-related factor 2(Nrf2)and heme oxygenase-1(HO-1)protein expression,B-cell lymphoma-2(Bcl-2),Caspase-3,BCL2-Associated X(Bax)and Caspase-9 mRNA expression,Superoxide dismutase(SOD),Nitric Oxide(NO),Mobile Device Assistant(MDA)and glutathione(GSH)content were compared among the three groups.Results Compared with the sham operation group,the functional defect score,walking coordination ability score,sensory function,brain water content,inflammatory factor levels,FOXO1 protein expression,BAX,Caspase-3 and Caspase-9 mRNA expression and oxidative stress indicators NO and MDA content increased significantly(P<0.05),Nrf2,SIRT1 and HO-1 protein expression,Bcl-2 mRNA expression,and SOD and GSH contents were significantly reduced(P<0.05).Compared with the I/R group,all the above indicators of the experimental group were significantly changed.Conclusion After inhibiting the SIRT1/FOXO1 signal pathway,the neurological function of cerebral ischemia/perfusion rats is reduced,and the degree of brain damage is increased.It is speculated that the activation of SIRT1/FOXO1 signaling pathway is correlated with the inhibition of the inflammatory response after cerebral ischemia/perfusion,the reduction of oxidative stress and the reduction of apoptosis.
作者
田博
肖敏
王小娜
TIAN Bo;XIAO Min;WANG Xiao-na(Department of Neurology,Xi'an Daxing Hospital,Xi'an Shaanxi 710016,China;Department of Neurology,Xi'an Municipal Labor Union Hospital,Xi'an Shaanxi 710100,China;Department of Neurology,Xunyi County People's Hospital,Xianyang Shaanxi 711300,China)
出处
《临床和实验医学杂志》
2020年第8期785-789,共5页
Journal of Clinical and Experimental Medicine
基金
陕西省国际科技合作计划项目(编号:2019KW-037)。
