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Targeting the AKT/mTOR/p70S6K Pathway for Oligodendrocyte Differentiation and Myelin Regeneration in Neurological Disorders.

The AKT/mTOR/p70S6K pathway has been shown to potentially promote spinal cord injury (SCI) repair in rats. However, its exact mechanism and beyond needs to be further explored. This study aims to explore the AKT/mTOR/p70S6K pathway in oligodendrocyte precursor cell (OPC) differentiation, microglial polarization differentiation, and the role of these in myelin regeneration in vitro. The isolation, induction and characterization of rat primary neuronal stem cells, OPCs and oligodendrocytes were investigated with immunofluorescence and RT-qPCR. Then, the role of AKT/mTOR/p70S6K signaling was explored using western blotting and immunofluorescence, the effect on myelination was examined with OPC-dorsal root ganglion (DRG) neurons co-culture, and the influence of M1/M2 polarization status of microglia on myelin formation was also observed by adding M1/M2 supernatants into OPC-DRG neurons co-culture. Activation of the AKT/mTOR/p70S6K pathway elevated the expression of oligodendrocyte differentiation markers, including MBP, PLP and MOG, which also promoted the colocalization of MBP and NFH in OPC-DRG neurons co-culture. More interestingly, stimulation of the AKT/mTOR/p70S6K pathway facilitated M2 polarization of rat microglia. M2 polarization of microglia enhanced OPC differentiation to oligodendrocytes and myelin formation. Our findings highlight the potential of targeting the AKT/mTOR/p70S6K pathway in promoting oligodendrocyte differentiation and myelin regeneration in neurological disorders such as SCI.

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Bone marrow mesenchymal stem cell exosomal miR-345-3p ameliorates cerebral ischemia-reperfusion injury by targeting TRAF6.

The purpose of this study was to investigate the effects of bone marrow mesenchymal stem cells (BMSCs) exosomal miR-345-3p and tumor necrosis factor receptor-associated factor 6 (TRAF6) on cerebral ischemia reperfusion (CIR) injury. Exosomes (Exos) derived from BMSCs were isolated and identified. PC12 (rat pheochromocytoma) cells were used to establish an oxygen and glucose deprivation/reoxygenation (OGD/R) model. Cell counting kit-8, TUNEL staining, lactate dehydrogenase staining, RT-qPCR, and western blotting were utilized for analyzing the functions of miR-345-3p about PC12 cells. Dual-luciferase reporter experiment was then to confirm the link between miR-345-3p and TRAF6. Finally, using male SD rats, the middle cerebral artery occlusion (MCAO) model was constructed. Regulation of I/R damage in MCAO rats of miR-345-3p and TRAF6 were further explored in the changes of modified neurological severity score, cerebral infarction pictures, relative infarct volume, and histopathological changes. After OGD/R treatment, neuronal apoptosis was dramatically increased. After treatment with exosomal miR-345-3p, OGD/R-induced neuroapoptosis was dramatically inhibited. Exosomal miR-345-3p inhibited OGD/R-induced neuroapoptosis by down-regulating the expression of TRAF6. However, the miR-345-3p inhibitor aggravated the changes caused by OGD/R. The corresponding regulations of miR-345-3p were reversed with TRAF6 overexpression. The animal experiments in vivo further verified that miR-345-3p ameliorated brain I/R injury in MCAO rats by targeting TRAF6. This study found that BMSCs-exosomal miR-345-3p protected against CIR injury by decreasing TRAF6.

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Electroacupuncture pretreatment alleviates cerebral ischemia-reperfusion injury by down-regulating miR-155-5p.

Increasing evidence shows that electroacupuncture pretreatment (EP) plays a crucial role in cerebral ischemia-reperfusion (I/R) injury, and cerebral I/R injury is the most serious complication of ischemic stroke treatment. The role of miR-155-5p in cerebral I/R injury has been studied, but the regulation of EP on miR-155-5p has not been reported. The middle cerebral artery occlusion (MCAO) rats were used to investigate the role of EP in cerebral I/R injury. Longa and modified neurological severity scores (mNSS) were used to evaluate neurological impairment. HE staining and TUNEL staining were used to evaluate brain injury. The expressions of miR-155-5p, Yin Yang 1 (YY1) and p53 were detected by qRT-PCR. The expressions of related proteins were detected by western blot. The binding of YY1 to miR-155-5p was verified by dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. Rat brain microvascular endothelial cells (BMECs) were isolated and cultured for in vitro experiments. Oxygen-glucose deprivation/reoxygenation (OGD/R) was used to verify the role of YY1, p53 and miR-155-5p in cerebral I/R injury in vitro. MCAO modeling induced brain injury, apoptosis, and increased levels of miR-155-5p, YY1, and p53. EP markedly alleviated brain injury and reduced levels of miR-155-5p, p53, and YY1. miR-155 agomir markedly increased the expression of miR-155-5p and p53. miR-155 antagomir decreased the levels of miR-155-5p and p53. Dual-luciferase reporter and ChIP assay verified that YY1 regulated miR-155-5p expression. YY1 shNRA greatly decreased miR-155-5p and p53. Inhibition of p53 decreased miR-155-5p expression. Both miR-155-5p inhibitor and YY1 shRNA promoted proliferation, inhibited apoptosis, and decreased levels of ICAM-1 and E-selectin of OGD/R-treated BMECs. Inhibition of p53 strengthened the effect of miR-155-5p inhibitor and YY1 shNRA on BMECs. Electroacupuncture pretreatment alleviates cerebral ischemia-reperfusion injury by regulating the YY1/p53/miR-155-5p axis.

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The Positional Relationship between Lacunae and White Matter Hyperintensity in Patients with Cerebral Small Vessel Disease.

Lacunae and white matter hyperintensity (WMH) are two crucial imaging biomarkers of cerebral small vessel disease (CSVD). Multiple studies have revealed a close relationship between WMH and lacunae and found that a double penumbra existed at the edge of WMH that affects lacunae formation. The study aimed to explore the spatial distribution characteristics and possible influencing factors of lacuna in relation to white matter hyperintensity in patients with CSVD. A total of 480 CSVD patients with WMH and with or without lacunae were included. Data about blood biochemical indicators, cerebrovascular CT angiography, 24-hour ambulatory blood pressure and ambulatory electrocardiogram, brain magnetic resonance imaging, and transcranial Doppler ultrasound were gathered from all subjects. They were categorised into four groups based on the spatial interaction between lacunae and WMH. Univariate analyses and multiple logistic regression analyses were used to compare the differences in traditional vascular risk factors, heart rate and blood pressure indicators, arterial pulsatility index (PI) values, and arterial stenosis among different groups. The average age of 480 patients was (58.63 ± 11.91) years, with 347 males (72.3%). Univariate analysis indicated that age, fasting blood glucose, triglycerides, total cholesterol, highdensity lipoprotein, 24-hour and daytime and night systolic and diastolic blood pressure, nocturnal heart rate, heart rate variability, PI values of ipsilateral and contralateral MCA (middle cerebral artery) and ICA (Internal carotid artery) of the lacunae, Fazekas score of PWMH (periventricular white matter hyperintensities), the proportion of MCA or ICA with stenosis rate over 50% on the ipsilateral side of the lacunae were significantly different between different groups (p < 0.05). High fasting blood glucose (OR=1.632, 95% CI= (1.128, 2.361), p =0.009), (OR=1.789, 95%CI= (1.270, 2.520), p = 0.001), (OR=1.806, 95% CI= (1.292, 2.524), p =0.001) was identified as a risk factor for lacunae formation by logistic regression analysis. High fasting blood glucose can be considered a risk factor for lacunae formation in patients with WMH. The more severe the PWMH and the higher the nocturnal heart rate, the more likely the lacunae, as well as PWMH, overlap completely. Ipsilateral arteriosclerosis and stenosis are independent risk factors for no contact between lacunae and PWMH.

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The Association of the Spatial Location of Contrast Extravasation with Symptomatic Intracranial Hemorrhage after Endovascular Therapy in Acute Ischemic Stroke Patients.

Contrast extravasation (CE) on brain non-contrast computed tomography (NCCT) after endovascular therapy (EVT) is commonly present in patients with acute ischemic stroke (AIS). Substantial uncertainties remain about the relationship between the spatial location of CE and symptomatic intracranial hemorrhage (sICH). Therefore, this study aimed to evaluate this association. We performed a retrospective screening on consecutive patients with AIS due to LVO (AIS-LVO) who had CE on NCCT immediately after EVT for anterior circulation large vessel occlusion (LVO). We used the Alberta stroke program early CT Score (ASPECTS) scoring system to estimate the spatial location of CE. Multivariable logistic regression was performed to achieve the risk factors of sICH. In this study, 115 of 153 (75.1%) anterior circulation AIS-LVO patients had CE on NCCT. After excluding 9 patients, 106 patients were enrolled in the final analysis. In multivariate regression analysis, atrial fibrillation (AF) (adjusted OR [aOR] 6.833, 95% confidence interval [CI] 1.331-35.081, P = 0.021) and CE-ASPECTS (aOR 0.602, 95% CI 0.411-0.882 P = 0.009) were associated with sICH. In subgroup analysis, CE at the internal capsule (IC) region was an independent risk factor for sICH (aOR 5.992, 95% CI 1.010-35.543 P < 0.05). These and conventional variables were incorporated as a predict model, with AUC of 0.899, demonstrating good discrimination and calibration for sICH in this study cohort. The spatial location of CE on NCCT immediately after EVT was an independent and strong risk factor for sICH in acute ischemic stroke patients.

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Modified Risk of Paradoxical Embolism More Effectively Evaluates the Risk of Stroke Associated with Patent Foramen Ovale.

Through an analysis of the risk factors associated with patent foramen ovale (PFO)-related stroke (PS), we aimed to modify the Risk of Paradoxical Embolism (RoPE) to assess the risk of PS. A retrospective collection of ischemic stroke (IS) patients with PFO admitted to the Department of Neurology at Beijing Chaoyang Hospital was conducted. The patients were classified into PS and non-PS groups. PS risk factors and RoPE scoring were analyzed based on clinical data, laboratory indicators, and imaging data. Independent risk factors were incorporated into the RoPE scoring system for enhancement. Significant differences were observed between the two groups regarding total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and uric acid levels. The transverse diameter of the left atrium was significantly larger in the non-PS group compared to the PS group. Multivariate logistic regression revealed that higher LDL-C levels and a smaller transverse diameter of the left atrium increased the risk of PS. The modified RoPE score was derived by assigning 1 point each for high LDL-C levels and the absence of transverse diameter enlargement in the left atrium. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves for the classical and modified RoPE score distinguishing PS were 0.661 and 0.798, respectively. LDL-C levels and transverse diameter of the left atrium were identified as independent risk factors for PS. The modified RoPE scoring system exhibited superior performance in assessing the risk of PS compared to the original RoPE score.

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