Bone marrow stromal cells-derived exosomes reduce neurological damage in traumatic brain injury through the miR-124-3p/p38 MAPK/GLT-1 axis.

BACKGROUND: Mounting evidence indicates that stem cell-derived exosomal miRNAs have therapeutic effects on traumatic brain injury (TBI). This research is focused on exploring the molecular processes of miR-124-3p obtained from bone marrow stromal cells-derived exosomes (BMSCs-Exos) in attenuating posttraumatic glutamate-mediated excitotoxicity. METHODS: We created a TBI rat model and analyzed the expression profile of miRNA through miRNA microarray. The miR-124-3p and p38 MAPK levels were analyzed utilizing RT-qPCR and western blotting. Dual-luciferase reporter (DLR) assay showed the targeting relationship between miR-124-3p and p38 MAPK. We subsequently conducted a TUNEL assay and flow cytometry to evaluate the neuronal apoptotic rate in an in vitro glutamate-mediated excitotoxicity model treated with BMSCs-Exos enriched with miR-124-3p (BMSCs-ExosmiR-124-3p). Moreover, the levels of p38 MAPK and glutamate transporter-1 (GLT-1) were measured by western blotting. Furthermore, BMSCs-ExosmiR-124-3p were administered to the TBI rats, and their neuroprotective effects were observed using western blotting, immunohistochemistry, histological staining, magnetic resonance imaging (MRI), and Morris water maze (MWM). RESULTS: The results revealed that the brains of TBI rats exhibited lowered miR-124-3p and enhanced p38 MAPK levels. DLR assay demonstrated miR-124-3p's role in targeting p38 MAPK and negatively regulating its expression. In vitro and in vivo studies confirmed that BMSCs-ExosmiR-124-3p attenuated glutamate-mediated excitotoxicity by downregulating p38 MAPK and upregulating GLT-1 expressions via transferring exosomal miR-124-3p. Moreover, histopathological evaluation and MRI results showed that BMSCs-ExosmiR-124-3p remarkably alleviated neuronal cell death and minimized the lesion volumes post-TBI. MWM outcomes illustrated that BMSCs-ExosmiR-124-3p treatment could substantially improve neurological function post-TBI. Furthermore, the effects of treatment with p38 MAPK inhibitor SB203580 were similar to BMSCs-ExosmiR-124-3p. CONCLUSION: Overall, the outcomes of the current report highlighted that BMSCs-ExosmiR-124-3p can lead to the upregulation of GLT-1 in TBI rat models by inhibiting the p38 MAPK signaling pathway, hence alleviating glutamate-mediated excitotoxicity and attenuating neurological damage post-TBI.

Exosomes derived from bone marrow mesenchymal stem cells attenuate neurological damage in traumatic brain injury by alleviating glutamate-mediated excitotoxicity.

BACKGROUND: Traumatic brain injury (TBI) is one of the major contributors to disability and death worldwide. Glutamate-mediated excitotoxicity, one of the secondary injuries occurring after TBI, leads to extreme neuronal apoptosis, and can be a potential target for intervention. Bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exos) have demonstrated neuroprotective effects on TBI. However, their precise role and the underlying mechanism by which they regulate glutamate-mediated excitotoxicity have not yet been determined. Therefore, this study aimed to determine whether BMSCs-Exos alleviate glutamate excitotoxicity post-TBI and their associated mechanism. METHODS: BMSCs-Exos were extracted from the BMSCs incubation medium and identified by transmission electron microscopy, nanoparticle trafficking analysis, and western blotting. The neuroprotective effects of BMSCs-Exos on glutamate excitotoxicity were investigated in the glutamate-mediated excitotoxicity neuronal cell model and the TBI rat model (TBI induced by controlled cortical impact) using western blotting and TUNEL assay. Cortical lesion samples were collected post-TBI on day-1 and day-14 to study histology. In addition, cortical lesion volume on days 1, 3 and 7 following TBI was determined using T2-weighted magnetic resonance imaging (MRI), and cognitive function was assessed at 4 weeks following TBI using the Morris water maze (MWM) test. RESULTS: BMSCs-Exos were observed to be spherical with a mean diameter of 109.9 nm, and expressed exosomal markers CD9, CD81 and TSG101. BMSCs-Exos were efficiently endocytosed by astrocytes after co-incubation for 24 h. In vitro studies revealed that 125 µM of glutamate significantly induced neuronal apoptosis, which was attenuated by BMSCs-Exos in astrocyte-neuron co-cultures. This attenuation was mediated by the upregulation of glutamate transporter-1 (GLT-1) level and the downregulation of p-p38 MAPK level in astrocytes. Similar results were obtained in vivo, wherein we verified that PKH67-labeled BMSCs-Exos administered intravenously could reach the perilesional cortex crossing the blood-brain barrier and significantly reduce glutamate levels in the perilesional cortex of the TBI rat, accompanied by increased GLT-1 level and downregulation in p-p38 MAPK level. Additionally, western blotting and TUNEL staining also revealed that BMSCs-Exos significantly downregulated the expression of pro-apoptosis markers, including cleaved caspase-3 and cleaved caspase-9, and attenuated neuronal apoptosis following TBI. Immunohistochemical analysis and Nissl staining showed that BMSCs-Exos significantly increased GLT-1-positive cells, and the number of apoptotic neurons decreased in the perilesional cortex. Moreover, MRI and MWM results revealed that BMSCs-Exos significantly minimized cortical lesion volume and ameliorated cognitive function after TBI. The underlying neuroprotective mechanism of BMSCs-Exos may be due to an increase in GLT-1 level in astrocytes by blocking the p38 MAPK signaling pathway. CONCLUSION: Taken together, our findings demonstrate that the implementation of BMSCs-Exos may be an effective prospective therapy for attenuating post-TBI neurological damage.

Using Local Anesthesia for Burr Hole Surgery of Chronic Subdural Hematoma Reduces Postoperative Complications, Length of Stay, and Hospitalization Cost: A Retrospective Cohort Study From a Single Center.

Purpose: The purpose of the current study was to compare the effects of local anesthesia (LA) and general anesthesia (GA) on the surgical process and postoperative recovery of patients with unilateral chronic subdural hematoma (CSDH). Patients and Methods: A retrospective cohort study was conducted on patients with unilateral CSDH who underwent burr hole surgery between the years 2013 and 2018. Patients who received local anesthesia were allocated to the LA group, and the patients who received general anesthesia were allocated to the GA group. The clinical data, postoperative complication, length of stay, and hospitalization cost of these two groups were compared and analyzed. Results: Data from 105 patients was collected for this study. Fifty one patients were assigned to the LA group and 54 to GA group. The duration of anesthesia and operation of the LA group was 37.71 (10.55) min; while for the GA group the duration was 56.04 (8.37) min (p < 0.001). The time from operation to discharge in GA group was greatly longer than that in LA group [(8.51 (1.49) days vs. 10.46 (2.34) days, respectively; p < 0.001]. Hospitalization cost for LA group was 2,721.54 (504.66) USD, which was significantly lesser than that for GA patients [3,314.82 (493.52) USD; p < 0.001]. The total number of complications in LA patients was less than that in GA patients [6 vs. 29 cases, respectively; p < 0.001]. The number of patients with residual hematoma in the LA group was

Combined Application of Quantitative Susceptibility Mapping and Diffusion Kurtosis Imaging Techniques to Investigate the Effect of Iron Deposition on Microstructural Changes in the Brain in Parkinson's Disease.

Objectives: Brain iron deposition and microstructural changes in brain tissue are associated with Parkinson's disease (PD). However, the correlation between these factors in Parkinson's disease has been little studied. This study aimed to use quantitative susceptibility mapping combined with diffusion kurtosis imaging to investigate the effects of iron deposition on microstructural tissue alterations in the brain. Methods: Quantitative susceptibility mapping and diffusion kurtosis imaging were performed on 24 patients with early PD, 13 patients with advanced PD, and 25 healthy controls. The mean values of magnetic susceptibility and diffusion kurtosis were calculated for the bilateral substantia nigra, red nucleus, putamen, globus pallidus, and caudate nucleus, and compared between the groups. Correlation analyses between the diffusion kurtosis of each nucleus and its magnetic susceptibility parameters in PD patients and healthy controls were performed. Results: The study found a significant increase in iron deposition in the substantia nigra, red nucleus, putamen and globus pallidus, bilaterally, in patients with PD. Mean kurtosis values were increased in the substantia nigra but decreased in the globus pallidus; axial kurtosis values were decreased in both the substantia nigra and red nucleus; radial kurtosis values were increased in the substantia nigra but showed an opposite trend in the globus pallidus and caudate nucleus. In the substantia nigra of patients with PD, magnetic susceptibility was positively correlated with mean and radial kurtosis values, and negatively correlated with axial kurtosis. None of these correlations were significantly different in the control group. In the putamen, magnetic susceptibility was positively correlated with mean, axial, and radial kurtosis only in patients with advanced-stage PD. Conclusion: Our study provides new evidence for brain iron content and microstructural alterations in patients with PD. Iron deposition may be a common mechanism for microstructural alterations in the substantia nigra and putamen of patients with PD. Tracking the dynamic changes in iron content and microstructure throughout the course of PD will help us to better understand the dynamics of iron metabolism and microstructural alterations in the pathogenesis of PD and to develop new approaches to monitor and treat PD.

pH-Responsive Multifunctional Theranostic Rapamycin-Loaded Nanoparticles for Imaging and Treatment of Acute Ischemic Stroke.

Stroke is the second leading cause of death globally and the most common cause of severe disability. Several barriers need to be addressed more effectively to treat stroke, including efficient delivery of therapeutic agents, rapid release at the infarct site, precise imaging of the infarct site, and drug distribution monitoring. The present study aimed to develop a bio-responsive theranostic nanoplatform with signal-amplifying capability to deliver rapamycin (RAPA) to ischemic brain tissues and visually monitor drug distribution. A pH-sensitive theranostic RAPA-loaded nanoparticle system was designed since ischemic tissues have a low-pH microenvironment compared with normal tissues. The nanoparticles demonstrated good stability and biocompatibility and could efficiently load rapamycin, followed by its rapid release in acidic environments, thereby improving therapeutic accuracy. The nano-drug-delivery system also exhibited acid-enhanced magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging signal properties, enabling accurate multimodal imaging with minimal background noise, thus improving drug tracing and diagnostic accuracy. Finally, in vivo experiments confirmed that the nanoparticles preferentially aggregated in the ischemic hemisphere and exerted a neuroprotective effect in rats with transient middle cerebral artery occlusion (tMCAO). These pH-sensitive multifunctional theranostic nanoparticles could serve as a potential nanoplatform for drug tracing as well as the treatment and even diagnosis of acute ischemic stroke. Moreover, they could be a universal solution to achieve accurate in vivo imaging and treatment of other diseases.

Imaging of glutamate in acute traumatic brain injury using chemical exchange saturation transfer.

BACKGROUND: Chemical exchange saturation transfer (CEST) is an important contrast mechanism in the field of magnetic resonance imaging. Herein, we used CEST for glutamate (GluCEST) imaging to evaluate the Glu alterations in acute mild to moderate traumatic brain injury (TBI) and correlated such alterations with the cognitive outcome at 1-month postinjury. METHODS: Thirty-two patients with well-documented mild-to-moderate TBI and 15 healthy controls (HC group) underwent 3.0-Tesla magnetic resonance imaging (MRI) with GluCEST, and magnetic resonance spectroscopy (MRS) scans. The Montreal Cognitive Assessment (MoCA) examination was administered to all study subjects at 1-month postinjury for cognitive outcome acquisition and divided TBI patients into patients with good cognitive outcome (GCO group) and with poor cognitive outcome (PCO group). RESULTS: The GluCEST% values for the occipital gray matter (OGM) and bilateral parietooccipital white matter (PWM) were higher in the PCO group compared with the HC and GCO groups (P<0.05), whereas the GluCEST% value showed no significant differences between the GCO and HC groups (P>0.05). In comparison with HCs, TBI patients had a significantly increased GluCEST% value for the OGM and bilateral PWM (P<0.05). GluCEST performed better than MRS in the prediction of cognitive outcome for TBI patients (P<0.05). CONCLUSIONS: Glu is significantly increased in acute TBI and strongly correlates with the cognitive outcome at 1month postinjury. GluCEST may supply new insight into TBI and help to improve the accuracy of short-term outcome prediction.

An Amyloid-ß Targeting Chemical Exchange Saturation Transfer Probe for In Vivo Detection of Alzheimer's Disease.

A reliable and reproducible detection of Aß deposits would be beneficial for the early diagnosis of Alzheimer's disease (AD). In the present study, the feasibility of applying chemical exchange saturation transfer (CEST) for Aß deposit detection using angiopep-2 as a probe was evaluated, and it was demonstrated that CEST could detect angiopep-2 and Aß-angiopep-2 aggregates in vitro. Furthermore, APP/PS1 mice injected with angiopep-2 exhibited a significantly higher in vivo CEST effect when compared with controls. The distribution of Aß deposits detected by CEST imaging was consistent with the histological staining results. The present study is the first to report a reliable exogenous CEST probe to noninvasively evaluate Aß deposits in APP/PS1 mice. Furthermore, these results demonstrate the potential for clinical AD diagnosis and Aß-targeted drug therapy assessment using CEST imaging with the angiopep-2 probe.

Nuclear Overhauser Enhancement-Mediated Magnetization Transfer Imaging in Glioma with Different Progression at 7 T.

Glioma is a malignant neoplasm affecting the central nervous system. The conventional approaches to diagnosis, such as T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and contrast-enhanced T1WI, give an oversimplified representation of anatomic structures. Nuclear Overhauser enhancement (NOE) imaging is a special form of magnetization transfer (MT) that provides a new way to detect small solute pools through indirect measurement of attenuated water signals, and makes it possible to probe semisolid macromolecular protons. In this study, we investigated the correlation between the effect of NOE-mediated imaging and progression of glioma in a rat tumor model. We found that the NOE signal decreased in tumor region, and signal of tumor center and peritumoral normal tissue markedly decreased with growth of the glioma. At the same time, NOE signal in contralateral normal tissue dropped relatively late (at about day 16-20 after implanting the glioma cells). NOE imaging is a new contrast method that may provide helpful insights into the pathophysiology of glioma with regard to mobile proteins, lipids, and other metabolites. Further, NOE images differentiate normal brain tissue from glioma tissue at a molecular level. Our study indicates that NOE-mediated imaging is a new and promising approach for estimation of tumor progression.

Hepatoma-derived growth factor-2 is highly expressed during development and in spinal cord injury.

Hepatoma­derived growth factor­2 (HDGF­2) is expressed in neurons, astrocytes and oligodendrocytes of the adult mouse brain. However, it has remained elusive whether HDGF­2 is expressed in the spinal cord and is involved in the its development and repair. In the present study, the expression of HDGF­2 was investigated in rat spinal cords at different developmental stages and following spinal cord injury (SCI). Protein levels of HDGF­2 were examined using western blot analysis, while the distribution pattern and cell populations of HDGF­2 protein expression were characterized using immunohistochemistry. Western blot analysis demonstrated that the levels of HDGF­2 protein expression were the greatest in the spinal cord on embryonic day 19, and were also highly expressed in rat spinal cords on post­natal day 7 (P7); however, they were low at P14 and not detectable at two months. HDGF­2 expression was significantly upregulated in the embryonic spinal cord and injured spinal cord. By contrast, the expression of HDGF­2 was low in uninjured adult spinal cords. HDGF­2 expression in the fetal rat spinal cord and injured spinal cord was significantly higher than that in uninjured adult spinal cord tissues (P<0.05). The number of cells positive for HDGF­2 was 141±62, 107±33 and 92±18 at days 1, 21 and 45 following SCI, respectively, as opposed to 50±9 in uninjured rats, and a significant difference was identified between the different time­points following SCI (P<0.01). In conclusion, the overexpression of HDGF­2 in the embryonic spinal cord and injured spinal cord may be involved in fetal spinal cord development and repair of SCI, respectively.

The expression of cytoglobin as a prognostic factor in gliomas: a retrospective analysis of 88 patients.

BACKGROUND: Evidence suggests that cytoglobin (Cygb) may function as a tumor suppressor gene. METHODS: We immunohistochemically evaluated the expression of Cygb, phosphatidylinositol-3 kinase (PI-3K), phosphorylated (p)-Akt, Interleukin-6 (IL-6), tumor necrosis factor-α (TNFα) and vascular endothelial growth factor (VEGF) in 88 patients with 41 high-grade gliomas and 47 low-grade gliomas. Intratumoral microvessel density (IMD) was also determined and associated with clinicopathological factors. RESULTS: Low expression of Cygb was significantly associated with the higher histological grading and tumor recurrence. A significant negative correlation emerged between Cygb expression and PI3K, p-Akt, IL-6, TNFα or VEGF expression. Cygb expression was negatively correlated with IMD. There was a positive correlation between PI3K, p-Akt, IL-6, TNFα and VEGF expression with IMD.High histologic grade, tumor recurrence, decreased Cygb expression, increased PI3K expression, increased p-Akt expression and increased VEGF expression correlated with patients' overall survival in univariate analysis. However, only histological grading and Cygb expression exhibited a relationship with survival of patients as independent prognostic factors of glioma by multivariate analysis. CONCLUSIONS: Cygb loss may contribute to tumor recurrence and a worse prognosis in gliomas. Cygb may serve as an independent predictive factor for prognosis of glioma patients.

Comparison of manually shaped and computer-shaped titanium mesh for repairing large frontotemporoparietal skull defects after traumatic brain injury.

OBJECT: The object of this study was to compare the effects and complications of manual and computer-aided shaping of titanium meshes for repairing large frontotemporoparietal skull defects following traumatic brain injury. METHODS: From March 2005 to June 2011, 161 patients with frontotemporoparietal skull defects were observed. Patients were divided into 2 groups according to the repair materials used for cranioplasty: 83 cases used computer-aided shaping for the titanium mesh, whereas the remaining 78 cases used a manually shaped titanium mesh. The advantages and disadvantages of the 2 methods were compared. RESULTS: No case of titanium mesh loosening occurred in either group. Subcutaneous fluid collection, titanium mesh tilt, and temporal muscle pain were the most common complications. In the manually shaped group, there were 14 cases of effusion, 10 cases of titanium mesh tilt, and 15 cases of temporal muscle pain. In the computer-aided group, there were 6 cases of effusion, 3 cases of titanium mesh tilt, and 6 cases of temporal muscle pain. The differences were significant between the 2 groups (p < 0.05). Other common complications were scalp infection, exposure of titanium mesh, epidural hematoma, and seizures. In the computer-aided group, the operative time decreased (p < 0.01), the number of screws used was reduced (p < 0.01), and the satisfaction of patients was significantly increased (p < 0.05). CONCLUSIONS: Computer-aided shaping of titanium mesh for repairing large frontotemporoparietal skull defects decreases postoperative complications and the operative duration, reduces the number of screws used, increases the satisfaction of patients, and restores the appearance of the patient's head, making it an ideal choice for cranioplasty.

Systematic comparison of cervical and extra-cervical surgical approaches for endoscopic thyroidectomy.

OBJECTIVE: To evaluate the clinical application of different surgical approaches for endoscopic thyroidectomy and provide more rational treatment criteria. METHODS: Collect all randomized controlled trials, multi-center studies, clinical controlled trials, clinical trials and other comparative studies of endoscopic thyroidectomy with a large sample size in different databases through an established search strategy, make a systematic analysis of all the included literature. RESULTS: This study selected 12 publications for analysis from more than 800 articles: these included six publications describing cervical thyroidectomy (A) and six publications describing extra-cervical thyroidectomy (B). Conversion to open surgery occurred in 29 patients in group A and only 4 in group B (p < 0.001). The patients in group A experienced shorter hospital stays than patients in group B (1.90 ± 0.80 vs. 4.03 ± 0.99 days, p < 0.001), and there was shorter operating time in group A (p < 0.001). Hemorrhage occurred in 3 cases in group A and 8 cases in group B (p = 0.04), Seroma occurred in 25 cases in group B but in no cases in group A (p < 0.001). Postoperative cosmetic results evaluated by verbal response scales (VRS) registered showed: group A (3.35 ± 0.60) and group B (3.74 ± 0.50; p < 0.001). Other complications such as recurrent laryngeal nerve injury and hypocalcemia showed no significant differences. CONCLUSIONS: Evaluation of the different surgical approaches for endoscopic thyroidectomy shows that the incidence of hemorrhage and seroma are higher in the extra-cervical group, but the rate of conversion to conventional open surgery is significantly higher in the cervical group. Furthermore, patients who undergo extra-cervical endoscopic thyroidectomy are associated with longer operating time and hospital stays; however, these studies suggest that the extra-cervical surgical approach for endoscopic thyroidectomy is preferable for dealing with more kinds of thyroid tumor and leaving no scars on neck.