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Neuroprotective effects of miR-532-5p against ischemic stroke.

MiR-532-5p 对缺血性脑卒中的神经保护作用.

  • 影响因子:2.53
  • DOI:10.1007/s11011-020-00544-z
  • 作者列表:"Mu J","Cheng X","Zhong S","Chen X","Zhao C
  • 发表时间:2020-02-21
Abstract

:Stroke can cause death and disability and has a high incidence with many complications. So far, effective treatment options for stroke are still limited. MicroRNA-532-5p (miR-532-5p) is significantly downregulated in stroke. However, the role of miR-532-5p in ischemic stroke is still unclear. In this study, we established an in vivo middle cerebral artery occlusion (MCAO) model in mice. The expression level of miR-532-5p, neurological score, infarct area, neuronal apoptosis, and phosphoinositide 3-kinase (PI3K)/Akt signaling pathway-related molecules were examined. Low miR-532-5p levels and high phosphatase and tensin homolog deleted on chromosome 10 (PTEN) levels were detected in the mouse MCAO model. MiR-532-5p overexpression improved neurological dysfunction, reduced the infarct area, attenuated neuronal injury and apoptosis, and promoted the activation of the PI3K/Akt signaling pathway in MCAO mice. In vitro, we treated mouse neuroblastoma cells (N2a) with oxygen-glucose deprivation and reperfusion (OGD/R). The expression level of miR-532-5p, cell viability, cell apoptosis, and the PI3K/Akt signaling pathway-related molecules were detected. Consistent with the in vivo tests, the miR-532-5p level was decreased and the PTEN level was increased in OGD-treated N2a cells in vitro. The miR-532-5p mimic increased cell viability, decreased cell apoptosis, and activated the PI3K/Akt signaling pathway. Furthermore, PTEN was verified as a target gene of miR-532-5p by luciferase reporter assay. PTEN overexpression attenuated the protective effect of miR-532-5p in OGD-treated N2a cells. In summary, these findings reveal that miR-532-5p protects against ischemic stroke by inhibiting PTEN and activating the PI3K/Akt signaling pathway and may serve as a novel therapeutic target for ischemic stroke.

摘要

: 脑卒中可导致死亡和残疾,发病率高,并发症多。到目前为止,中风的有效治疗选择仍然有限。MicroRNA-532-5p (miR-532-5p) 在卒中中显著下调。然而,miR-532-5p 在缺血性卒中中的作用尚不清楚。本研究中,我们建立了小鼠在体大脑中动脉闭塞 (MCAO) 模型。检测 miR-532-5p 、神经评分、梗死面积、神经元凋亡和磷酸肌醇 3-激酶 (PI3K)/Akt 信号通路相关分子的表达水平。在小鼠 MCAO 模型中检测到低 miR-532-5p 水平和高第 10 号染色体缺失的磷酸酶和张力蛋白同源物 (PTEN) 水平。MiR-532-5p 过表达可改善 MCAO 小鼠的神经功能障碍,缩小梗死面积,减轻神经元损伤和凋亡,促进 PI3K/Akt 信号通路的激活。在体外,我们用氧糖剥夺和再灌注 (OGD/R) 处理小鼠神经母细胞瘤细胞 (N2a)。检测 miR-532-5p 表达水平、细胞活力、细胞凋亡及 PI3K/Akt 信号通路相关分子。与体内试验一致,OGD 处理的 N2a 细胞在体外 miR-532-5p 水平降低,PTEN 水平升高。MiR-532-5p 模拟增加细胞活力,减少细胞凋亡,并激活 PI3K/Akt 信号通路。此外,通过荧光素酶报告基因检测证实 PTEN 是 miR-532-5p 的靶基因。过表达 PTEN 可减弱 miR-532-5p 对 OGD 处理的 N2a 细胞的保护作用。总之,这些发现揭示了 miR-532-5p 通过抑制 PTEN 和激活 PI3K/Akt 信号通路保护缺血性卒中,可能作为缺血性卒中的一个新的治疗靶点。

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发表时间:2020-01-29
来源期刊:Physical therapy
DOI:10.1093/ptj/pzaa022
作者列表:["Thilarajah S","Bower KJ","Hao PY","Tan D","Williams G","Larik A","Wai BC","Koh G","Clark RA"]

METHODS:BACKGROUND:People with stroke are not meeting recommended levels of physical activity. The modifiable factors associated with post-stroke physical activity levels need to be identified to develop targeted interventions. OBJECTIVE:The objective of this study was to investigate the factors at discharge from inpatient rehabilitation that are associated with physical activity levels at 3 months following discharge. DESIGN:This was a prospective cohort study. METHODS:Sixty-four people with stroke completed baseline assessments at discharge from inpatient rehabilitation and 55 completed the follow-up 3 months later. The candidate factors (i.e. gait speed, balance, strength, cognition, mood and motivation) were measured at discharge. The primary outcome measure at follow-up was walking related activity (measured by wrist-worn accelerometer). Secondary outcome measures were physical activity participation (Activity Card Sort) and intensity of physical activity (International Physical Activity Questionnaire - Short 7 days). Adjusted separate multivariable linear regression models or proportional odds regression models were used to evaluate the associations between candidate factors and physical activity. RESULTS:Gait speed and balance were associated with all aspects of physical activity. Higher level of intrinsic motivation was also associated with higher physical activity participation. Anxiety demonstrated a significant non-linear relationship with physical activity participation. LIMITATIONS:Inclusion of fatigue and individual muscle strength could have provided further insights into associations with steps per day. CONCLUSION:The results demonstrated that better physical function at discharge from inpatient rehabilitation was associated with future increased levels of physical activity. Additionally, higher levels of motivation impacted on increased physical activity participation. The influence of anxiety on physical activity participation requires further exploration. Mixed-method study designs can be utilized to further understand the factors associated with post-stroke physical activity.

翻译标题与摘要 下载文献
影响因子:2.57
发表时间:2020-01-06
DOI:10.1007/s12031-019-01474-x
作者列表:["Cheng, Xiao","Yang, Ying-Lin","Li, Wei-Han","Liu, Man","Zhang, Shan-Shan","Wang, Yue-Hua","Du, Guan-Hua"]

METHODS:Cerebral ischemia-reperfusion (I/R) is characterized by initial transient cerebral ischemia followed by reperfusion. Various pathophysiological processes are involved in brain injury and functional recovery during cerebral I/R. There are few studies on dynamic metabolic process after cerebral I/R. The present study was to observe dynamic alteration of brain injury, functional recovery, and metabolites after cerebral I/R in rats and discover potential metabolic markers. The cerebral I/R model was established by middle cerebral artery occlusion (MCAO) for 90 min, following reperfusion in rats. The results of cerebral infarction area, cerebral edema, and behavior test showed that there were dynamic changes in brain injury and functional recovery at different periods after cerebral I/R. Further analysis showed that the brain injury was severe on the first day of cerebral I/R, and there was a significant functional recovery from the 7th day of cerebral I/R, followed by an aggravation trend of brain injury from the days 7 to 28. Furthermore, Matrix-assisted laser desorption ionization mass spectrometry imaging analysis showed that the expression of ATP, glucose, and citric acid on 7th day was the highest during cerebral I/R, which indicated that energy metabolism and oxidative phosphorylation played important roles during cerebral I/R. In addition, the untargeted metabolomic results showed that the level of isocitric acid, the ratio of oxyglutaric acid/glutamic acid, and the level of pyruvic acid associated with the TCA cycle were also the highest on the 7th day during cerebral I/R, which indicated that the transient spontaneous recovery of ischemic brain on the 7th day after ischemia-reperfusion might be related to oxidative phosphorylation and energy metabolism in the brain in this period. In conclusion, the results suggest that some small molecule metabolites participate in the brain injury and functional recovery during cerebral I/R, which is of great significance to the development of therapeutic drugs and diagnostic markers.

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翻译标题与摘要 下载文献
影响因子:2.75
发表时间:2020-01-01
DOI:10.1007/s00702-019-02124-7
作者列表:["Wang, Xiaodong","Shi, Cunxian","Pan, Hongxia","Meng, Xiaowen","Ji, Fuhai"]

METHODS:The aims of this study were to study the effects of miR-2 on cerebral ischemia–reperfusion rats and to explore its further mechanism. Rats were assigned into sham, model, miR-22 control and miR-22 groups. Observation of neurological behaviors at 24 h after operation found that neurological functions were severely damaged in the model and miR-22 control groups and these damages were improved by miR-22. RT-PCR indicated that miR-22 mRNA level in the brain tissue was significantly decreased in the model and miR-22 control groups, but increased in the miR-22 group. TTC staining showed increased percentage of cerebral infarction volume in the model and miR-22 control groups and this increase was reduced by miR-22. Immunohistochemistry showed increased densities of CD34^+ and VEGF^+ microvessels in the cortex in the model and miR-22 control groups, which were further increased in the miR-22 group. ELISA showed increased serum VEGF and Ang-1 levels in the model and miR-22 control groups, which were also further increased in the miR-22 group. Western blot analysis showed increased phosphorylation level of PI3K and Akt in brain tissue in the model and miR-22 control groups, which were further increased in the miR-22 group. Administration of LY294002, a specific PI3K pathway inhibitor, significantly reversed all the effects of miR-22 on rats in the model group. miR-22 exerts its neuroprotective and angiogenic functions via the PI3K/Akt signaling pathway, at least partly, in rats under cerebral ischemia–reperfusion.

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