目的探讨Dickkopf-1(DKK-1)、LINGO-1、小窝蛋白1(caveolin-1)在脑出血中的表达水平变化及其与病情严重程度的关系。方法选取2017年5月-2019年5月在本院就诊的脑出血患者70例,少量出血25例,中量出血24例,大量出血21例;根据美国国立卫生...目的探讨Dickkopf-1(DKK-1)、LINGO-1、小窝蛋白1(caveolin-1)在脑出血中的表达水平变化及其与病情严重程度的关系。方法选取2017年5月-2019年5月在本院就诊的脑出血患者70例,少量出血25例,中量出血24例,大量出血21例;根据美国国立卫生研究院卒中量表(National institutes of health stroke scale,NIHSS)评分评估脑出血患者的病情严重程度其中轻型26例、中型24例、重型20例;采用多田氏公式计算患者出血量,其中少量25例、中量24例、大量21例;手术入路通道中临近血肿0.5cm脑组织作为脑出血组,将远隔血肿位置的脑组织作为对照组;采用免疫组化染色检测相关因子的表达水平。结果脑出血组DKK-1、LINGO-1、caveolin-1阳性表达率高于对照组(P<0.05);大量出血患者阳性表达率高于中量和少量出血患者(P<0.05);中量出血患者DKK-1、LINGO-1、caveolin-1阳性表达率高于少量出血患者(P<0.05)。重型脑出血患者DKK-1、LINGO-1、caveolin-1阳性表达率高于中型和轻型脑出血患者(P<0.05);中型脑出血患者DKK-1、LINGO-1、caveolin-1阳性表达率高于轻型脑出血患者(P<0.05)。结论 Dickkopf-1、LINGO-1、caveolin-1在脑出血患者脑组织中高表达,并随着患者病情严重程度的加重,Dickkopf-1、LINGO-1、caveolin-1表达水平越高。展开更多
The differentiation of and myelination by oligodendrocytes （OLs） are exquisitely regulated by a series of intrinsic and extrinsic mechanisms. As each OL can make differing numbers of myelin segments with variable le...The differentiation of and myelination by oligodendrocytes （OLs） are exquisitely regulated by a series of intrinsic and extrinsic mechanisms. As each OL can make differing numbers of myelin segments with variable lengths along similar axon tracts, myelination can be viewed as a graded process shaped by inhibitory/ inductive cues during development. Myelination by OLs is a prime example of an adaptive process determined by the microenvironment and architecture of the central nervous system （CNS）. In this review, we discuss how myelin formation by OLs may be controlled by the heterogeneous microenvironment of the CNS. Then we address recent findings demonstrating that neighboring OLs may compete for available axon space, and highlight our current understanding of myelin-based inhibitors of axonal regeneration that are potentially responsible for the reciprocal dialogue between OLs and determine the numbers and lengths of myelin internodes. Understanding the mechanisms that control the spatiotemporal regulation of myelinogenic potential during development may provide valuable insight into therapeutic strategies for promoting remyelination in an inhibitory microenvironment.展开更多
Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system.It is mainly expressed by oligodendrocytes.Although previous studies have found regulato...Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system.It is mainly expressed by oligodendrocytes.Although previous studies have found regulatory roles for Nogo-A in neurite outgrowth inhibition,neuronal homeostasis,precursor migration,plasticity,and neurodegeneration,its functions in the process of oxidative injury are largely uncharacterized.In this study,oligodendrocytes were extracted from the cerebral cortex of newborn Sprague-Dawley rats.We used hydrogen peroxide(H2O2)to induce an in vitro oligodendrocyte oxidative damage model and found that endogenously expressed Nogo-A is significantly upregulated in oligodendrocytes.After recombinant virus Ad-ZsGreen-rat Nogo-A infection of oligodendrocytes,Nogo-A expression was increased,and the infected oligodendrocytes were more susceptible to acute oxidative insults and exhibited a markedly elevated rate of cell death.Furthermore,knockdown of Nogo-A expression in oligodendrocytes by Ad-ZsGreen-shRNA-Nogo-A almost completely protected against oxidative stress induced by exogenous H2O2.Intervention with a Nogo-66 antibody,a LINGO1 blocker,or Y27632,an inhibitor in the Nogo-66-NgR/p75/LINGO-1-RhoA-ROCK pathway,did not affect the death of oligodendrocytes.Ad-ZsGreen-shRNA-Nogo-A also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and inhibited BCL2 expression in oligodendrocytes.In conclusion,Nogo-A aggravated reactive oxygen species damage in oligodendrocytes,and phosphorylated extracellular signal-regulated kinase 1/2 and BCL2 might be involved in this process.This study was approved by the Ethics Committee of Peking University People’s Hospital,China(approval No.2018PHC081)on December 18,2018.展开更多
The purpose of this study was to observe the expression of LINGO-1 after cerebral ischemia, investigate the effects of retinoic acid（RA） on the expression of LINGO-1 and GAP-43, and the number of synapses, and to em...The purpose of this study was to observe the expression of LINGO-1 after cerebral ischemia, investigate the effects of retinoic acid（RA） on the expression of LINGO-1 and GAP-43, and the number of synapses, and to emplore the repressive effect of LINGO-1 on neural regeneration after cerebral ischemia. The model of permanent focal cerebral ischemia was established by the modified suture method of middle cerebral artery occlusion（MCAO） in Sprague-Dawley（SD） rats. The expression of LINGO-1 was detected by Western blotting and that of GAP-43 by immunohistochemistry. The number of synapses was observed by transmission electron microscopy. The SD rats were divided into three groups： sham operation（sham） group, cerebral ischemia（CI） group and RA treatment（RA） group. The results showed that the expression level of LINGO-1 at 7th day after MCAO in sham, CI and RA groups was 0.266±0.019, 1.215±0.063 and 0.702±0.081, respectively（P〈0.01）. The number of Gap-43-positive nerve cells at 7th day after MCAO in sham, CI and RA group was 0, 59.08±1.76 and 76.20±3.12 per high power field, respectively（P〈0.05）. The number of synapses at 7th day after MCAO was 8.42±0.13, 1.74±0.37 and 5.39±0.26 per μm2, respectively（P〈0.05）. It is concluded that LINGO-1 expression is up-regulated after cerebral ischemia, and RA inhibits the expression of LINGO-1, promotes the expression of GAP-43 and increases the number of synapses. It suggests that LINGO-1 may be involved in the pathogenesis of cerebral ischemia, which may provide an experimenal basis for LINGO-1 antogonist, RA, for the treatment of cerebral ischemia.展开更多
文摘目的探讨Dickkopf-1(DKK-1)、LINGO-1、小窝蛋白1(caveolin-1)在脑出血中的表达水平变化及其与病情严重程度的关系。方法选取2017年5月-2019年5月在本院就诊的脑出血患者70例,少量出血25例,中量出血24例,大量出血21例;根据美国国立卫生研究院卒中量表(National institutes of health stroke scale,NIHSS)评分评估脑出血患者的病情严重程度其中轻型26例、中型24例、重型20例;采用多田氏公式计算患者出血量,其中少量25例、中量24例、大量21例;手术入路通道中临近血肿0.5cm脑组织作为脑出血组,将远隔血肿位置的脑组织作为对照组;采用免疫组化染色检测相关因子的表达水平。结果脑出血组DKK-1、LINGO-1、caveolin-1阳性表达率高于对照组(P<0.05);大量出血患者阳性表达率高于中量和少量出血患者(P<0.05);中量出血患者DKK-1、LINGO-1、caveolin-1阳性表达率高于少量出血患者(P<0.05)。重型脑出血患者DKK-1、LINGO-1、caveolin-1阳性表达率高于中型和轻型脑出血患者(P<0.05);中型脑出血患者DKK-1、LINGO-1、caveolin-1阳性表达率高于轻型脑出血患者(P<0.05)。结论 Dickkopf-1、LINGO-1、caveolin-1在脑出血患者脑组织中高表达,并随着患者病情严重程度的加重,Dickkopf-1、LINGO-1、caveolin-1表达水平越高。
基金supported by the US National Multiple Sclerosis Society Harry Weaver Neuroscience Scholar Award (JF 2142-A2/T)Research Grant (RG 4541A3)the US National institute of Health/National institute of Neurological Disorders and Stroke (NS062796-02)
文摘The differentiation of and myelination by oligodendrocytes （OLs） are exquisitely regulated by a series of intrinsic and extrinsic mechanisms. As each OL can make differing numbers of myelin segments with variable lengths along similar axon tracts, myelination can be viewed as a graded process shaped by inhibitory/ inductive cues during development. Myelination by OLs is a prime example of an adaptive process determined by the microenvironment and architecture of the central nervous system （CNS）. In this review, we discuss how myelin formation by OLs may be controlled by the heterogeneous microenvironment of the CNS. Then we address recent findings demonstrating that neighboring OLs may compete for available axon space, and highlight our current understanding of myelin-based inhibitors of axonal regeneration that are potentially responsible for the reciprocal dialogue between OLs and determine the numbers and lengths of myelin internodes. Understanding the mechanisms that control the spatiotemporal regulation of myelinogenic potential during development may provide valuable insight into therapeutic strategies for promoting remyelination in an inhibitory microenvironment.
基金This work was supported by the National Natural Science Foundation of China,No.81870996(to JZ).
文摘Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system.It is mainly expressed by oligodendrocytes.Although previous studies have found regulatory roles for Nogo-A in neurite outgrowth inhibition,neuronal homeostasis,precursor migration,plasticity,and neurodegeneration,its functions in the process of oxidative injury are largely uncharacterized.In this study,oligodendrocytes were extracted from the cerebral cortex of newborn Sprague-Dawley rats.We used hydrogen peroxide(H2O2)to induce an in vitro oligodendrocyte oxidative damage model and found that endogenously expressed Nogo-A is significantly upregulated in oligodendrocytes.After recombinant virus Ad-ZsGreen-rat Nogo-A infection of oligodendrocytes,Nogo-A expression was increased,and the infected oligodendrocytes were more susceptible to acute oxidative insults and exhibited a markedly elevated rate of cell death.Furthermore,knockdown of Nogo-A expression in oligodendrocytes by Ad-ZsGreen-shRNA-Nogo-A almost completely protected against oxidative stress induced by exogenous H2O2.Intervention with a Nogo-66 antibody,a LINGO1 blocker,or Y27632,an inhibitor in the Nogo-66-NgR/p75/LINGO-1-RhoA-ROCK pathway,did not affect the death of oligodendrocytes.Ad-ZsGreen-shRNA-Nogo-A also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and inhibited BCL2 expression in oligodendrocytes.In conclusion,Nogo-A aggravated reactive oxygen species damage in oligodendrocytes,and phosphorylated extracellular signal-regulated kinase 1/2 and BCL2 might be involved in this process.This study was approved by the Ethics Committee of Peking University People’s Hospital,China(approval No.2018PHC081)on December 18,2018.
基金supported by grants from the Key Programs for Science and Technology Development of Hubei Province,China(No.2007AA301B34-2)the Openning Fund for Key Laboratory of Molecular Imaging of Hubei Province,China(No.2008-74)
文摘The purpose of this study was to observe the expression of LINGO-1 after cerebral ischemia, investigate the effects of retinoic acid（RA） on the expression of LINGO-1 and GAP-43, and the number of synapses, and to emplore the repressive effect of LINGO-1 on neural regeneration after cerebral ischemia. The model of permanent focal cerebral ischemia was established by the modified suture method of middle cerebral artery occlusion（MCAO） in Sprague-Dawley（SD） rats. The expression of LINGO-1 was detected by Western blotting and that of GAP-43 by immunohistochemistry. The number of synapses was observed by transmission electron microscopy. The SD rats were divided into three groups： sham operation（sham） group, cerebral ischemia（CI） group and RA treatment（RA） group. The results showed that the expression level of LINGO-1 at 7th day after MCAO in sham, CI and RA groups was 0.266±0.019, 1.215±0.063 and 0.702±0.081, respectively（P〈0.01）. The number of Gap-43-positive nerve cells at 7th day after MCAO in sham, CI and RA group was 0, 59.08±1.76 and 76.20±3.12 per high power field, respectively（P〈0.05）. The number of synapses at 7th day after MCAO was 8.42±0.13, 1.74±0.37 and 5.39±0.26 per μm2, respectively（P〈0.05）. It is concluded that LINGO-1 expression is up-regulated after cerebral ischemia, and RA inhibits the expression of LINGO-1, promotes the expression of GAP-43 and increases the number of synapses. It suggests that LINGO-1 may be involved in the pathogenesis of cerebral ischemia, which may provide an experimenal basis for LINGO-1 antogonist, RA, for the treatment of cerebral ischemia.
