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| 1 | Brain-derived neurotrophic factor and its related enzymes and receptors play important roles after hypoxic-ischemic brain damage显示文摘Brain-derived neurotrophic factor(BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression and associated factors following hypoxia-ischemia induced neonatal brain damage, and the significance of these changes are not fully understood. In the present study, a rat model of hypoxic-ischemic brain damage was established through the occlusion of the right common carotid artery, followed by 2 hours in a hypoxic-ischemic environment. Rats with hypoxic-ischemic brain damage presented deficits in both sensory and motor functions, and obvious pathological changes could be detected in brain tissues. The m RNA expression levels of BDNF and its processing enzymes and receptors(Furin, matrix metallopeptidase 9, tissuetype plasminogen activator, tyrosine Kinase receptor B, plasminogen activator inhibitor-1, and Sortilin) were upregulated in the ipsilateral hippocampus and cerebral cortex 6 hours after injury;however, the expression levels of these m RNAs were found to be downregulated in the contralateral hippocampus and cerebral cortex. These findings suggest that BDNF and its processing enzymes and receptors may play important roles in the pathogenesis and recovery from neonatal hypoxic-ischemic brain damage. This study was approved by the Animal Ethics Committee of the University of South Australia(approval No. U12-18) on July 30, 2018. | Liu-Lin Xiong Jie Chen Ruo-Lan Du Jia Liu Yan-Jun Chen Mohammed Al Hawwas Xin-Fu Zhou Ting-Hua Wang Si-Jin Yang Xue Bai | 2021 | Neural Regeneration Research2021，16，8： | 12 |
| 2 | TP53-induced glycolysis and apoptosis regulator alleviates hypoxia/ischemia-induced microglial pyroptosis and ischemic brain damage显示文摘Our previous studies have demonstrated that TP53-induced glycolysis and apoptosis regulator(TIGAR)can protect neurons after cerebral ischemia/reperfusion.However,the role of TIGAR in neonatal hypoxic-ischemic brain damage(HIBD)remains unknown.In the present study,7-day-old Sprague-Dawley rat models of HIBD were established by permanent occlusion of the left common carotid artery followed by 2-hour hypoxia.At 6 days before induction of HIBD,a lentiviral vector containing short hairpin RNA of either TIGAR or gasdermin D(LV-sh_TIGAR or LV-sh_GSDMD)was injected into the left lateral ventricle and striatum.Highly aggressively proliferating immortalized(HAPI)microglial cell models of in vitro HIBD were established by 2-hour oxygen/glucose deprivation followed by 24-hour reoxygenation.Three days before in vitro HIBD induction,HAPI microglial cells were transfected with LV-sh_TIGAR or LV-sh_GSDMD.Our results showed that TIGAR expression was increased in the neonatal rat cortex after HIBD and in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Lentivirusmediated TIGAR knockdown in rats markedly worsened pyroptosis and brain damage after hypoxia/ischemia in vivo and in vitro.Application of exogenous nicotinamide adenine dinucleotide phosphate(NADPH)increased the NADPH level and the glutathione/oxidized glutathione ratio and decreased reactive oxygen species levels in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Additionally,exogenous NADPH blocked the effects of TIGAR knockdown in neonatal HIBD in vivo and in vitro.These findings show that TIGAR can inhibit microglial pyroptosis and play a protective role in neonatal HIBD.The study was approved by the Animal Ethics Committee of Soochow University of China(approval No.2017LW003)in 2017. | Lan-Lan Tan Xiao-Lu Jiang Li-Xiao Xu Gen Li Chen-Xi Feng Xin Ding Bin Sun Zheng-Hong Qin Zu-Bin Zhang Xing Feng Mei Li | 2021 | Neural Regeneration Research2021，16，6： | 9 |
| 3 | 人参皂苷Rg1对幼龄大鼠缺氧缺血性脑损伤和神经元凋亡的保护作用显示文摘目的探讨人参皂苷Rg1(ginsenoside Rg1)对缺氧缺血性脑损伤(hypoxic-ischemic brain damage,HIBD)幼龄大鼠脑组织细胞凋亡、氧化应激和炎症反应的影响。方法幼龄Wistar大鼠分为健康对照组、模型组和模型给药组。跳台试验检测各组大鼠犯错次数,脑组织干湿重法计算各组大鼠脑含水率及脑指数;苏木精-伊红(HE)染色观察脑组织损伤程度;末端标记法(TUNEL)染色观察脑组织细胞凋亡水平;尼氏染色检测神经元凋亡情况;Western blotting检测脑组织Bax/Bcl-2、caspase-3、caspase-9蛋白表达;试剂盒检测丙二醛(MDA)和超氧化物歧化酶(SOD)含量;酶联免疫吸附法(ELISA)检测外周血白介素-6(IL-6)、诱导型一氧化氮合酶(iNOS)、白介素-4(IL-4)含量。结果与模型组相比,20 mg/kg和40 mg/kg人参皂苷Rg1显著降低HIBD幼龄大鼠跳台试验犯错次数、脑指数脑含水率和神经元凋亡数(P<0.05),缓解脑组织病理损伤,下调Bax/Bcl-2、cleaved cas9/cas9和cleaved cas3/cas3蛋白表达(P<0.05),减少IL-6和iNOS蛋白含量,增加IL-4蛋白含量(P<0.05)。结论人参皂苷Rg1能够缓解HIBD幼龄大鼠脑组织损伤,抑制神经元凋亡。 | 张明晓 方峰 杨艳 范俊利 袁鹏 | 2021 | 西安交通大学学报(医学版)2021，42，5： | 5 |
| 4 | 香兰素通过抑制自噬及PINK1信号通路改善新生大鼠低氧缺血性脑损伤与炎症反应显示文摘目的探讨香兰素(vanillin,Van)对新生大鼠低氧缺血性脑损伤(hypoxic-ischemic brain damage,HIBD)的影响及作用机制。方法将7日龄SD大鼠根据改良的Rice-Vannucci法构建HIBD模型,将120只新生大鼠随机分为5组:假手术(Sham)组、HIBD组、HIBD+Van(20 mg·kg^(-1))组、HIBD+Van(40mg·kg^(-1))、HIBD+Van(80 mg·kg^(-1))组,每组30只,香兰素处理组大鼠分别按照对应剂量腹腔内注射香兰素,每12h注射一次,连续注射2d,假手术组和HIBD组大鼠同时注射等量无菌生理盐水。48h后将各组大鼠麻醉后断头处死,收集脑组织计算脑组织含水量,TTC染色检测梗死面积,苏木精-伊红染色观察脑组织病理学变化,酶联免疫吸附法(enzyme linked immune sorbent assay,ELISA)检测脑组织中白细胞介素-1β(interleukin-1β,IL-1β)、白细胞介素-6(interleukin-6,IL-6)、白细胞介素-10(interleukin-10,IL-10)及肿瘤坏死因子-a(tumor necrosis factor,TNF-α)含量,免疫荧光染色检测脑组织微管相关蛋白1轻链3(microtubule-associated protein 1 light chain3,LC3)表达,蛋白质印迹(Western blot)检测脑组织自噬相关蛋白表达,实时定量PCR和Western blot检测PTEN诱导假定激酶1(PTEN induced putative kinase1,PINK1)mRNA与蛋白表达。结果与Sham组比较,HIBD组大鼠脑组织含水量显著增加(P<0.05),脑梗死面积显著增加(P<0.05),炎症细胞因子TNF-α、IL-1β与IL-6含量显著增加而抗炎因子IL-10含量显著降低(P<0.05),LC3荧光表达强度增加,Beclin-1蛋白表达水平和LC3-II/LC3-I比值显著升高(P<0.05),P62蛋白表达水平显著下降(P<0.05),同时,脑组织中PINK1mRNA与蛋白的表达水平均显著升高(P<0.05)。与HIBD组比较,不同剂量香兰素(20 mg·kg^(-1)、40 mg·kg^(-1)、80 mg·kg^(-1))作用下,大鼠脑组织含水量显著下降(P<0.05),脑梗死面积显著减小(P<0.05),炎症细胞因子TNF-α、IL-1β与IL-6含量显著下降而抗炎因子IL-10含量显著升高(P<0.05),LC3荧光表达强度减弱,Beclin-1蛋白表达水平和LC3-Ⅱ/LC3-Ⅰ比值显著降低(P<0.05),P62蛋白表达水平显著升高(P<0.05),而PINK1mRNA与蛋白的表达水平均显著降低(P<0.05)。结论香兰素具有改善新生大鼠低氧缺血性脑损伤、减轻炎症反应的作用,其机制可能抑制自噬及PINK1信号途径激活相关。 | 符玉水 符元证 霍开明 杨辉 钟丽花 杨方正 | 2021 | 脑与神经疾病杂志2021，29，8： | 5 |
| 5 | The role of pineal microRNA-325 in regulating circadian rhythms after neonatal hypoxic-ischemic brain damage显示文摘Circadian rhythm disorder is a common,but often neglected,consequence of neonatal hypoxic-ischemic brain damage(HIBD).However,the underlying molecular mechanisms remain largely unknown.We previously showed that,in a rat model of HIBD,up-regulation of microRNA-325(miR-325)in the pineal gland is responsible for the suppression of Aanat,a key enzyme involved in melatonin synthesis and circadian rhythm regulation.To better understand the mechanism by which miR-325 affects circadian rhythms in neonates with HIBD,we compared clinical samples from neonates with HIBD and samples from healthy neonates recruited from the First Affiliated Hospital of Soochow University(Dushuhu Branch)in 2019.We found that circulating miR-325 levels correlated positively with the severity of sleep and circadian rhythm disorders in neonates with HIBD.Furthermore,a luciferase reporter gene assay revealed that LIM homeobox 3(LHX3)is a novel downstream target of miR-325.In addition,in miR-325 knock-down mice,the transcription factor LHX3 exhibited an miR-325-dependent circadian pattern of expression in the pineal gland.We established a neonatal mouse model of HIBD by performing doublelayer ligation of the left common carotid artery and exposing the pups to a low-oxygen environment for 2 hours.Lhx3 mRNA expression was significantly down-regulated in these mice and partially rescued in miR-325 knockout mice subjected to the same conditions.Finally,we showed that improvement in circadian rhythm-related behaviors in animals with HIBD was dependent on both miR-325 and LHX3.Taken together,our findings suggest that the miR-325-LHX3 axis is responsible for regulating circadian rhythms and provide novel insights into the identification of potential therapeutic targets for circadian rhythm disorders in patients with neonatal HIBD.The clinical trial was approved by Institutional Review Board of Children’s Hospital of Soochow University(approval No.2015028)on July 20,2015.Animal experiments were approved by Animal Care and Use Committee,School of Medicine,Soochow University,China(approval No.XD-2016-1)on January 15,2016. | Ning Sha Hua-Wei Wang Bin Sun Min Gong Po Miao Xiao-Lu Jiang Xiao-Feng Yang Mei Li Li-Xiao Xu Chen-Xi Feng Yuan-Yuan Yang Jie Zhang Wen-Jing Zhu Yuan-Yuan Gao Xing Feng Xin Ding | 2021 | Neural Regeneration Research2021，16，10： | 4 |
| 6 | Magnet-targeted delivery of bone marrow-derived mesenchymal stem cells improves therapeutic efficacy following hypoxic-ischemic brain injury显示文摘hypoxicischemic brain injury;however,the therapeutic efficacy of bone marrow-derived mesenchymal stem cells largely depends on the number of cells that are successfully transferred to the target.Magnet-targeted drug delivery systems can use a specific magnetic field to attract the drug to the target site,increasing the drug concentration.In this study,we found that the double-labeling using superparamagnetic iron oxide nanoparticle and poly-L-lysine(SPIO-PLL)of bone marrow-derived mesenchymal stem cells had no effect on cell survival but decreased cell proliferation 48 hours after labeling.Rat models of hypoxic-ischemic brain injury were established by ligating the left common carotid artery.One day after modeling,intraventricular and caudal vein injections of 1×105 SPIO-PLL-labeled bone marrow-derived mesenchymal stem cells were performed.Twenty-four hours after the intraventricular injection,magnets were fixed to the left side of the rats’heads for 2 hours.Intravoxel incoherent motion magnetic resonance imaging revealed that the perfusion fraction and the diffusion coefficient of rat brain tissue were significantly increased in rats treated with SPIO-PLL-labeled cells through intraventricular injection combined with magnetic guidance,compared with those treated with SPIO-PLL-labeled cells through intraventricular or tail vein injections without magnetic guidance.Hematoxylin-eosin and terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)staining revealed that in rats treated with SPIO-PLL-labeled cells through intraventricular injection under magnetic guidance,cerebral edema was alleviated,and apoptosis was decreased.These findings suggest that targeted magnetic guidance can be used to improve the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation for hypoxic-ischemic brain injury.This study was approved by the Animal Care and Use Committee of The Second Hospital of Dalian Medical University,China(approval No.2016-060)on March 2,2016. | Chuang Sun Ao-Dan Zhang Hong-Hai Chen Jie Bian Zheng-Juan Liu | 2021 | Neural Regeneration Research2021，16，11： | 4 |
| 7 | 基于心肌缺血状态的脑心通方对于心、脑组织Toll样受体相关通路蛋白的影响显示文摘目的:探讨心肌缺血状态下脑心通方对于心、脑组织中Toll样受体(TLR)相关通路蛋白的影响,以期揭示心肌缺血状态下脑心通方对心、脑作用的特点。方法:将雄性SD大鼠随机分为正常组、模型组、给药组和阳性药组。模型组、给药组和阳性药组分别采用结扎左冠状动脉主干支的方法复制心肌缺血模型,正常组只穿线不结扎。用多功能生理信号采集处理系统采集心电图;测定血液中的心肌酶谱数据;干湿重法检测脑水肿情况。Western blot检测大鼠心脏、大脑皮层的Toll样受体相关蛋白α干扰素(IFN-α)、干扰素调节因子(IRF)3、IRF7、TLR2、TLR4、TLR7、TLR9、肿瘤坏死因子α(TNF-α)的表达。结果:给药后大鼠紊乱的心电图趋于稳定;血液中心肌酶谱天门冬氨酸氨基转移酶、丙氨酸氨基转移酶、乳酸脱氢酶含量和大鼠的脑含水量显著降低(P<0.05);免疫印迹结果表明脑心通方对心脏和大脑皮层中的IFN-α、IRF3、TLR2、TLR7、TLR9和TNF-α的表达都有显著的抑制作用(P<0.05,P<0.01)。结论:心肌缺血对脑的相关功能有一定影响,脑心通方对心肌缺血状态下的心和脑具有一定的干预作用。 | 谢丽荣 李倩楠 姜婷月 崔一然 刘欣 | 2021 | 中华中医药杂志2021，36，4： | 3 |
| 8 | 右美托咪定通过激活PI3K/AKT信号通路对前列腺素诱导分娩窒息子鼠氧化应激和炎症水平的影响及脑保护机制显示文摘目的探讨右美托咪定通过激活PI3K/AKT信号通路对前列腺素诱导分娩窒息子鼠氧化应激和炎症水平的影响及脑保护机制。方法将孕鼠随机分为对照组、模型组、右美托咪定低剂量组、右美托咪定高剂量组、右美托咪定+LY294002组。对照组孕鼠自然分娩,模型组与给药组孕鼠构建分娩窒息模型,分组处理孕鼠后分娩,每组选出12只子鼠检测其学习记忆能力、海马神经元损伤凋亡、脑组织超氧化物歧化酶(SOD)、丙二醛(MDA)、环氧化酶-2(COX-2)及白细胞介素-6(IL-6)水平、脑组织自噬及PI3K/AKT通路相关蛋白表达。结果与对照组相比,模型组子鼠海马神经元发生严重损伤,神经元凋亡率、脑组织MDA、COX-2及IL-6水平、LC3-II/LC3-I及Beclin-1、P62表达明显升高(P<0.05),目标象限停留时间、穿越原平台位置次数、神经元数量、脑组织SOD水平及p-PI3K/PI3K、p-Akt/Akt明显降低(P<0.05);与模型组相比,右美托咪定给药组子鼠海马神经元发生损伤均减轻,神经元凋亡率、脑组织MDA、COX-2及IL-6水平、LC3-II/LC3-I及Beclin-1、P62表达均降低(P<0.05),目标象限停留时间、穿越原平台位置次数、神经元数量、脑组织SOD水平及p-PI3K/PI3K、p-Akt/Akt均升高(P<0.05),且高剂量的右美托咪定作用更强;与右美托咪定高剂量组相比,右美托咪定+LY294002组子鼠各指标变化趋势发生逆转。结论右美托咪定可通过激活PI3K/AKT信号降低前列腺素诱导的分娩窒息新生子鼠氧化应激及炎症水平,抑制自噬,减轻子鼠海马神经元损伤及凋亡,改善其学习记忆功能,发挥脑保护作用。 | 葛亮 冷玉芳 张鹏 杜丽芳 韩旭东 | 2023 | 实用医学杂志2023，39，6： | 1 |
| 9 | 岩藻多糖对氧糖剥夺诱导的新生大鼠海马脑神经元的影响显示文摘目的:探讨岩藻多糖对氧糖剥夺(OGD)诱导的新生大鼠海马神经元的影响。方法:分离新生大鼠原代海马神经元后,分4组处理。空白组不做任何处理;Fuc组用100μg/mL岩藻多糖培养7 d;OGD组按OGD方法培养;OGD+Fuc组首先进行OGD诱导,然后用100μg/mL岩藻多糖培养7 d。分组处理后,MTT法检测细胞活力,AnnexinⅤ-FITC/PI双染法检测细胞凋亡;实时荧光定量PCR法检测白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)和诱导型一氧化氮合酶(iNOS)mRNA的表达;使用试剂盒测定细胞中超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量;Western blot法检测微管相关蛋白1轻链3(LC3)、Beclin-1、P62,Cleaved Caspase-3和9,磷脂酰肌醇-3激酶(PI3K)、磷酸化PI3K(p-PI3K)、蛋白激酶B(Akt)和磷酸化Akt(p-Akt)的表达。结果:OGD可降低神经元活力,增加凋亡率和Cleaved Caspase-3、Cleaved Caspase-9蛋白表达水平(P<0.05);升高SOD活性,降低MDA含量(P<0.05);升高IL-1β、TNF-α和iNOS mRNA表达水平(P<0.05);升高LC3和Beclin-1表达水平(P<0.05);降低p-PI3K、p-Akt和P62表达(P<0.05)。岩藻多糖可拮抗上述作用(P<0.05)。结论:岩藻多糖可能通过激活PI3K/Akt信号通路,减轻OGD诱导的神经元炎症反应、自噬和氧化应激水平,发挥神经元保护作用。 | 时英才 雷瑞瑞 周栩平 张网 段佳佳 | 2023 | 郑州大学学报(医学版)2023，58，6： | 1 |
| 10 | 电针对缺氧缺血性脑损伤大鼠海马神经元自噬及IGF-1/PI3K/Akt通路的影响显示文摘目的探讨电针对缺氧缺血性脑损伤(HIBD)新生大鼠海马神经元自噬及胰岛素样生长因子1(IGF-1)/磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(Akt)通路的影响。方法将108只新生大鼠随机分为假手术组、模型组、IGF-1组(0.2 mg/kg)、电针组、电针联合LY294002组(电针+PI3K抑制剂0.3 mg/kg),每组18只。采用左颈总动脉结扎和低氧处理2 h的方法构建新生大鼠HIBD模型(造模成功率为80%)。各组大鼠在手术清醒后和电针治疗结束后进行神经功能缺陷评分;酶联免疫吸附测定(ELISA)检测脑组织IGF-1的含量;苏木精-伊红(HE)染色观察脑组织病理学变化;透射电镜观察细胞自噬情况;免疫荧光双标法检测自噬标志物与神经元特异性核蛋白(NeuN)的共定位表达;Western blot法检测海马组织PI3K/Akt通路、自噬相关蛋白的表达[PI3K、磷酸化PI3K(p-PI3K)、Akt、磷酸化p-Akt(p-Akt)、Beclin-1、微管相关蛋白轻链3Ⅱ(LC3-Ⅱ)、微管相关蛋白轻链3Ⅰ(LC3-Ⅰ)]。结果与假手术组相比,HIBD模型组大鼠海马中神经元损伤加重,神经功能缺损评分、海马组织Beclin-1和LC3-Ⅱ/LC3-Ⅰ表达增加,脑组织IGF-1的含量以及海马组织p-PI3K/PI3K、p-Akt/Akt的表达降低;与模型组相比,IGF-1组、电针组神经元损伤减轻,神经功能缺损评分、Beclin-1和LC3-Ⅱ/LC3-Ⅰ、自噬小体数量、LC3/NeuN共表达的神经元减少或降低,脑组织IGF-1的含量、p-PI3K/PI3K、p-Akt/Akt的表达升高;上述差异均有统计学意义(P<0.05)。LY294002能显著降低IGF-1的水平,减弱电针对海马组织IGF-1/PI3K/Akt通路的激活和海马神经元自噬的抑制作用。结论电针可能通过激活IGF-1/PI3K/Akt通路,抑制海马神经元过度自噬,减轻新生大鼠HIBD。 | 曹娟 王红怡 王丽欣 陈小宁 林秋 杨庆红 陈东追 符玉秀 | 2022 | 实用临床医药杂志2022，26，14： | 1 |
| 11 | 低氧预处理人牙髓干细胞对缺氧缺血性脑损伤新生大鼠脑神经元自噬及ATG7的影响显示文摘目的探讨低氧预处理人牙髓干细胞(hDPSCs)对缺氧缺血性脑损伤(HIBD)新生大鼠脑神经元自噬及ATG7的影响,为hDPSCs临床应用提供理论依据。方法2021年6月-2022年9月选取7日龄SD大鼠72只随机分为假手术组(Sham组)、HIBD组、常氧预处理hDPSCs组(N-hDPSCs组)及低氧预处理hDPSCs组(H-hDPSCs组)。采用Rice-Vannucci法制备新生大鼠HIBD模型,造模后24h侧脑室移植N-hDPSCs与H-hDPSCs。移植24h后,采用免疫荧光双标染色结合Western Blots检测H-hDPSCs对损伤侧大脑皮层神经元自噬的影响;移植4d,采用苏木素-伊红(hematoxylin and eosin stain,HE)染色法和尼氏染色法观察损伤侧大脑皮层组织病理学变化。结果免疫荧光染色结果示,H-hDPSCs组与N-hDPSCs组大脑皮层神经元LC3-Ⅱ、Beclin-1、ATG7阳性细胞数量显著低于HIBD组,且H-hDPSCs组显著低于N-hDPSCs组(F=326.87、205.87、229.59,P<0.05);H-hDPSCs组与N-hDPSCs组大脑皮层神经元P62阳性细胞数量显著高于HIBD组,且H-hDPSCs组显著高于N-hDPSCs组(F=124.07,P<0.05)。Western Blots结果示,H-hDPSCs组与N-hDPSCs组大脑皮层神经元LC3-Ⅱ、Beclin-1蛋白表达水平显著低于HIBD组,且H-hDPSCs组显著低于N-hDPSCs组(F=46.949、43.330,P<0.05)。HE染色结果示,HIBD组大脑皮层神经细胞形态不规则,排列不整齐;N-hDPSCs组和H-hDPSCs组大脑皮层神经细胞形态较规则,排列较整齐;尼氏染色结果示,N-hDPSCs组和H-hDPSCs组大脑皮层神经细胞数均较HIBD组增加,且H-hDPSCs组显著高于N-hDPSCs组(F=312.44,P<0.05)。结论hDPSCs移植可下调HIBD新生大鼠脑神经元自噬相关蛋白Beclin-1、LC3-Ⅱ、ATG7的表达,上调P62的表达,从而抑制自噬,减轻新生大鼠HIBD,促进脑损伤修复,其中,低氧预处理hDPSCs移植的疗效更优。 | 高淑君 张浩 武沐洋 张新月 肖培伦 王晓莉 王凡涛 | 2023 | 中国儿童保健杂志2023，31，8： | 0 |
| 12 | Nrf2/GPX4信号通路介导的铁死亡在咪达唑仑减轻新生大鼠HIBD中的作用显示文摘目的:评价核因子E2相关因子2/谷胱甘肽过氧化物酶4(Nrf2/GPX4)信号通路介导的铁死亡在咪达唑仑减轻新生大鼠缺血缺氧性脑损伤(HIBD)中的作用。方法:健康新生大鼠90只,7日龄,体质量16~20 g,采用随机数字表法分为6组(n=15):假手术组(Sham组)、HIBD组和咪达唑仑低剂量(10 mg/kg)组(L组)、咪达唑仑中剂量(20 mg/kg)组(M组)、咪达唑仑高剂量(40 mg/kg)组(H组)和Nrf2抑制剂ML385组(I组)。采用结扎左颈动脉并在缺氧环境中暴露2 h建立HIBD模型。造模后第2天开始,各咪达唑仑组腹腔注射相应剂量咪达唑仑,Sham组和HIBD组腹腔注射等容量生理盐水,I组腹腔注射咪达唑仑40 mg/kg和Nrf2抑制剂ML38530 mg/kg,均1次/d,连续给药8 d。给药结束后,称重并进行水迷宫实验。水迷宫实验结束后取腹主动脉血样,然后断头取脑。采用ELISA法测定血清铁、IL-6、TNF-α浓度。采用紫外分光光度法和微量法测定海马组织铁和GSH含量。脑组织经HE染色和Nissl染色后观察海马神经元病理学结果;采用免疫荧光染色法测定海马Nrf2/神经元核抗原(NeuN)和GPX4/NeuN的阳性细胞数;采用Western blot法测定海马组织Nrf2、GPX4、4-羟基壬烯酸(4-HNE)表达。结果:与Sham组相比,HIBD组首次到达平台时间延长,穿越原平台位置次数减少,目标象限停留时间缩短,海马组织铁含量升高,GSH含量、Nrf2/NeuN和GPX4/NeuN的阳性细胞数降低,Nrf2和GPX4表达下调,4-HNE表达上调,血清铁、IL-6和TNF-α浓度升高(P<0.05),海马神经元损伤明显;与HIBD组相比,H组、M组和L组首次到达平台时间缩短,穿越原平台位置次数增多,目标象限停留时间延长,海马组织铁含量降低,GSH含量、Nrf2/NeuN和GPX4/NeuN的阳性细胞数升高,Nrf2和GPX4表达上调,4-HNE表达下调,血清铁、IL-6和TNF-α浓度降低(P<0.05),海马神经元损伤减轻;与H组相比,I组首次到达平台时间延长,穿越原平台位置次数减少,目标象限停留时间缩短,海马组织铁含量升高,GSH含量、Nrf2/NeuN和GPX4/NeuN的阳性细胞数降低,Nrf2和GPX4表达下调,4-HNE表达上调,血清铁、IL-6和TNF-α浓度升高(P<0.05),海马神经元损伤加重。结论:咪达唑仑减轻新生大鼠HIBD的机制可能与激活Nrf2/GPX4信号通路,抑制海马神经元铁死亡有关。 | 张化 袁静静 吕慧敏 年春苗 | 2023 | 中华麻醉学杂志2023，43，5： | 0 |
| 13 | β淀粉样蛋白对缺氧缺血性脑损伤新生鼠神经元凋亡影响的实验研究显示文摘目的:通过建立新生大鼠缺氧缺血性脑损伤(HIBD)模型,以β淀粉样蛋白(Aβ)为切入点,研究其在模型的表达以及与神经元凋亡的关系,探讨Aβ在新生鼠缺氧缺血性脑损伤模型中对神经元的作用及机制。方法:建立10日龄新生大鼠缺血性脑损伤模型,模型后2、4、8、24 h心脏灌注,分别检测脑组织中Aβ、脑内淀粉样前体蛋白(APP)、β-分泌酶(BACE1)、Caspase-3、Cleaved caspase-3、B淋巴细胞瘤-2(Bcl-2)的蛋白表达,BACE1的mRNA表达。使用BACE1抑制剂干预,实验分为三组,缺氧缺血组、抑制剂组和溶剂组,抑制剂组在缺氧缺血后即给予BACE1抑制剂AZD3293处理24 h后再次检测以上指标。结果:APP、Aβ的蛋白表达、BACE1的蛋白表达和mRNA水平在建模后呈时间依赖的上升,24 h达到高峰。同时,促凋亡蛋白Cleaved caspase-3在建模后也呈时间依赖的上升,24 h达到高峰。而在缺氧缺血2 h后,凋亡抑制蛋白Bcl-2的蛋白水平显著升高(P<0.05)。之后逐渐降低,24 h最低。当使用BACE1抑制剂后,Aβ及BACE1在脑组织中的表达显著下降(均P<0.05),而BACE1mRNA的表达没有变化(P>0.05)。同时促凋亡蛋白Cleaved caspase-3的表达明显下降(P<0.05),同时,Bcl-2蛋白的表达也显著升高(P<0.05)。结论:在新生鼠HIBD时Aβ产生增多,应用BACE1抑制剂可降低Aβ的表达,增加Bcl-2的表达,减轻神经元凋亡。 | 刘伟 吴鸿波 杨红秀 刘春静 李丽华 | 2024 | 陕西医学杂志2024，53，4： | 0 |
| 14 | miR-410-3p通过介导HMGB1的表达调控NF-κB信号通路调控缺氧缺血性脑损伤显示文摘目的:探究miR-410-3p通过介导HMGB1的表达调控NF-κB信号通路调控缺氧缺血性脑损伤的机制。方法:进行PC12细胞培养并分组:Normal组(正常PC12细胞)、NC组(缺血性处理的PC12细胞,转染阴性对照质粒)、Model组(缺血性处理的PC12细胞)、miR-410-3p mimic组(缺血性处理的PC12细胞,转染miR-410-3p过表达质粒)、HMGB1 vector组(缺血性处理的PC12细胞,转染HMGB1过表达质粒)、miR-410-3p mimic+HMGB1 vector组(缺血性处理的PC12细胞,共染miR-410-3p过表达和HMGB1过表达质粒)。双荧光素酶报告实验验证miR-410-3p和HMGB1靶向关系。Western blot检测各组细胞中HMGB1、NF-κB p65的蛋白表达情况,qRT-PCR检测miR-410-3p表达情况。CCK8和流式细胞术分别检测各组细胞增殖和凋亡情况。ELISA检测各组细胞炎症因子IL-8、IL-6、TNF-α含量。结果:miR-410-3p与HMGB1存在靶向关系。与Normal组相比,其余组细胞中miR-410-3p表达显著降低,HMGB1表达显著升高(均P<0.05)。与Normal组对比,其余各组细胞的增殖率明显下降,细胞凋亡率,炎症因子IL-8、IL-6、TNF-α含量,HMGB1、NF-κB p65水平均明显升高(均P<0.05)。miR-410-3p可促进细胞增殖,降低细胞凋亡率、炎症因子IL-8、IL-6、TNF-α含量及NF-κB p65水平,且miR-410-3p可通过负向调控HMGB1的表达,从而影响HMGB1/NF-κB通路对缺血性神经元的调控。结论:miR-410-3p过表达后,可通过抑制HMGB1/NF-κB通路表达,从而影响脑缺血性神经元细胞增殖、凋亡以及炎症损伤。 | 张显英 仇华 陈青 | 2022 | 中国免疫学杂志2022，38，18： | 0 |
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