Targeting Non-Coding RNA for CNS Injuries: Regulation of Blood-Brain Barrier Functions.

Central nervous system (CNS) injuries are the most common cause of death and disability around the world. The blood-brain barrier (BBB) is located at the interface between the CNS and the surrounding environment, which protects the CNS from exogenous molecules, harmful agents or microorganisms in the blood. The disruption of BBB is a common feature of CNS injuries and participates in the pathological processes of secondary brain damage. Recently, a growing number of studies have indicated that non-coding RNAs (ncRNAs) play an important role in brain development and are involved in CNS injuries. In this review, we summarize the mechanisms of BBB breakdown after CNS injuries. We also discuss the effects of ncRNAs including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs) on BBB damage in CNS injuries such as ischemic stroke, traumatic brain injury (TBI), intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). In addition, we clarify the pharmacotherapies that could regulate BBB function via ncRNAs in CNS injuries, as well as the challenges and perspectives of ncRNAs on modulation of BBB function. Hence, on the basis of these effects, ncRNAs may be developed as therapeutic agents to protect the BBB for CNS injury patients.

FTY720 Reduces Endothelial Cell Apoptosis and Remodels Neurovascular Unit after Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. A sequence of pathological processes occurred when there is TBI. Previous studies showed that sphingosine-1-phosphate receptor 1 (S1PR1) played a critical role in inflammatory response in the brain after TBI. Thus, the present study was designed to evaluate the effects of the S1PR1 modulator FTY720 on neurovascular unit (NVU) after experimental TBI in mice. The weight-drop TBI method was used to induce TBI. Western blot (WB) was performed to determine the levels of SIPR1, claudin-5 and occludin at different time points. FTY720 was intraperitoneally administered to mice after TBI was induced. The terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL) assay was used to assess endothelial cell apoptosis. Immunofluorescence and WB were performed to measure the expression of tight junction proteins: claudin-5 and occludin. Evans blue (EB) permeability assay and brain water content were applied to evaluate the blood-brain barrier (BBB) permeability and brain edema. Immunohistochemistry was performed to assess the activation of astrocytes and microglia. The results showed that FTY720 administration reduced endothelial cell apoptosis and improved BBB permeability. FTY720 also attenuated astrocytes and microglia activation. Furthermore, treatment with FTY720 not only improved neurological function, but also increased the survival rate of mice significantly. These findings suggest that FTY720 administration restored the structure of the NVU after experimental TBI by decreasing endothelial cell apoptosis and attenuating the activation of astrocytes. Moreover, FTY720 might reduce inflammation in the brain by reducing the activation of microglia in TBI mice.

Human umbilical cord mesenchymal stem cell-derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin-mediated mitophagy.

AIMS: Recently, human umbilical cord mesenchymal stem cell (HucMSC)-derived exosome is a new focus of research in neurological diseases. The present study was aimed to investigate the protective effects of HucMSC-derived exosome in both in vivo and in vitro TBI models. METHODS: We established both mouse and neuron TBI models in our study. After treatment with HucMSC-derived exosome, the neuroprotection of exosome was investigated by the neurologic severity score (NSS), grip test score, neurological score, brain water content, and cortical lesion volume. Moreover, we determined the biochemical and morphological changes associated with apoptosis, pyroptosis, and ferroptosis after TBI. RESULTS: We revealed that treatment of exosome could improve neurological function, decrease cerebral edema, and attenuate brain lesion after TBI. Furthermore, administration of exosome suppressed TBI-induced cell death, apoptosis, pyroptosis, and ferroptosis. In addition, exosome-activated phosphatase and tensin homolog-induced putative kinase protein 1/Parkinson protein 2 E3 ubiquitin-protein ligase (PINK1/Parkin) pathway-mediated mitophagy after TBI. However, the neuroprotection of exosome was attenuated when mitophagy was inhibited, and PINK1 was knockdown. Importantly, exosome treatment also decreased neuron cell death, suppressed apoptosis, pyroptosis, and ferroptosis and activated the PINK1/Parkin pathway-mediated mitophagy after TBI in vitro. CONCLUSION: Our results provided the first evidence that exosome treatment played a key role in neuroprotection after TBI through the PINK1/Parkin pathway-mediated mitophagy.

Modified Skin Incision and Location of Burr-Hole Surgery via a Retrosigmoid Approach: An Anatomical Study.

Objective This study aims to reduce the tissue damage during craniotomy with retrosigmoid approach. A modified sickle-shaped skin incision was developed, and a new burr-hole positioning method was proposed. Methods Five adult cadaveric heads (10 sides) were used in this study. The sickle-shaped skin incision was performed during craniotomy. The nerves, blood vessels, and muscles were observed and measured under a microscope. Additionally, 62 dry adult skull specimens (left sided, n = 35; right sided, n = 27) were used to measure the distance between the most commonly used locating point (asterion [Ast] point) and the posteroinferior point of the transverse sigmoid sinus junction (PSTS) (Ast-PSTS), as well as the distance between the new locating O point and the PSTS (O-PSTS). Then, the reliability of the new locating O point was validated on the same five adult cadaveric heads (10 sides) used for the sickle-shaped skin incision. Results The sickle-shaped skin incision reduced the damage to the occipital nerves, blood vessels, and muscles during the surgery via a retrosigmoid approach. The dispersion and variability of O-PSTS were smaller than those of Ast-PSTS. Conclusion The sickle-shaped skin incision of the retrosigmoid approach can reduce the tissue damage and can completely expose the structures in the cerebellopontine angle. The modified O point is a more reliable locating point for a burr-hole surgery than the Ast point.

Expression and potential role of FOSB in glioma.

Background: FOSB is reported to be an oncogene in a variety of tumors. However, the expression and role of FOSB in glioma remain obscure. In this study, we aimed to explore the expression of FOSB in glioma and its biological role in glioblastoma multiforme (GBM). Methods: Western blot, immunohistochemical staining, and quantitative real-time polymerase chain reaction (RT-qPCR) were used to detect the expression of FOSB in clinical samples. FOSB was knocked down in cells to determine the effects of FOSB on the phenotypic changes of tumors by plate cloning, CCK-8 assay, and Transwell assay. Finally, subcutaneous tumorigenesis in nude mice was used to observe the tumorigenesis of glioma cell lines after the knockdown of the FOSB gene. Results: FOSB expression was higher in glioma compared with normal brain tissue. After the downregulation of FOSB, the expression of cleaved caspase-3 increased. Plate cloning and CCK-8 experiments showed that the proliferation of glioma cell lines decreased. The Transwell assay demonstrated that the glioblastoma cell lines had lower migration ability after the knockdown of FOSB. Finally, the tumor volume of U87 glioma cells in group sh-FOSB was smaller than that in the control group. The TUNEL staining in vitro showed that the apoptosis of sh-FOSB glioma cells increased. Conclusion: FOSB was highly expressed in glioma tissues. The viability of glioma cells decreased, and the ability of glioma cells to proliferate and migrate was reduced when FOSB was downregulated. Hence, FOSB may promote the development and migration of gliomas.

Transmastoid Trautman's Triangle Combined Low Retrosigmoid Approach for Foramen Magnum Meningiomas: Surgical Anatomy and Technical Note.

Objective This study was aimed to assess the potential of utilizing a transmastoid Trautman's triangle combined low retrosigmoid approach for ventral and ventrolateral foramen magnum meningiomas (FMMs) surgical treatment. Methods We simulated this transmastoid Trautman's triangle combined low retrosigmoid approach using five adult cadaveric heads to explore the associated anatomy in a step-by-step fashion, taking pictures of key positions as appropriate. We then employed this approach in a single overweight patient with a short neck who was suffering from large ventral FMMs and cerebellar tonsillar herniation. Results Through cadaver studies, we were able to confirm that this transmastoid Trautman's triangle combined with low retrosigmoid approach achieves satisfactory cranial nerve and vasculature visualization while also offering a wide view of the whole of the ventrolateral medulla oblongata. We, additionally, have successfully employed this approach to treat a single patient suffering from large ventral FMMs with cerebellar tonsillar herniation. Conclusion This transmastoid Trautman's triangle combined low retrosigmoid approach may represent a complement to treatment strategies for ventral and ventrolateral FMMs, particularly in patients with the potential for limited surgical positioning due to their being overweight, having a short neck and suffering from cerebellar tonsillar herniation.

Prediction of Risk Factors for the Evolution of Traumatic Subdural Effusion into Chronic Subdural Hematoma.

PURPOSE: To explore the risk factors of the evolution of traumatic subdural effusion (TSE) into chronic subdural hematoma (CSDH). MATERIALS AND METHODS: The 70 patients' gender, age, location of effusion, unilateral and bilateral, Glasgow coma score (GCS) at admission, presence or absence of brain contusion, the time of effusion appeared, daily amount of mannitol, mannitol number of days used, with or without atorvastatin calcium tablets, with or without antiplatelet aggregation drugs, with or without anticoagulant drugs, with or without abnormalities in blood coagulation routines, computed tomography (CT) layer height, the thickness, and CT value of the first effusion were analyzed by single factor. Logistic multivariate regression analysis was performed on the statistically significant indicators. Power of the regression model was evaluated using receiver operating characteristic (ROC) curve. RESULTS: Univariate analysis showed that the presence or absence of brain contusion, the time of effusion appeared, atorvastatin calcium tablets use or not, the CT value of the effusion, and TSE into CSDH evolution varied significantly compared to the non-evolved group (P<0.05). Logistic multivariate regression analysis showed that combined brain contusion (odds ratio (OR)=16.247, 95% confidence interval (CI), 1.831-144.157, P = 0.012), early onset of effusion (OR = 0.573, 95% CI: 0.349-0.941, P = 0.028), atorvastatin calcium tablets not used after effusion (OR = 60.028, 95% CI: 6.103-590.399, P = 0.0001), and high CT value (OR = 1.285, 95% CI: 1.067-1.547, P = 0.008) were risk factors for the evolution of TSE into CSDH. The ROC model suggested that the prediction of these risk factors had high diagnostic accuracy. CONCLUSION: TSE patients with brain contusion, early onset of effusion, without the usage of atorvastatin calcium tablets after effusion, and high CT value of the first effusion are at a risk of evolving into CSDH.

FOXO4 expression associates with glioblastoma development and FOXO4 expression inhibits cell malignant phenotypes in vitro and in vivo.

BACKGROUND AND AIM: Forkhead box protein O4 (FOXO4) is a transcription factor, and aberrant FOXO4 expression is associated with development of various human cancers. This study explored the role of FOXO4 in glioma in vitro and in vivo. METHODS: FOXO4 expression was first assessed in normal brain tissues, low-grade glioma, glioblastoma multiforme (GBM), normal human astrocytes (HA), and GBM cell lines, while manipulation of FOXO4 expression in glioma cell lines was assessed using qRT-PCR, Western blot, and cell viability CCK-8, Transwell, and a nude mouse subcutaneous xenograft assays. KEY FINDINGS: The data showed downregulated FOXO4 expression in GBM tissues and cell lines. FOXO4 overexpression induced by transfection with FOXO4 cDNA significantly inhibited GBM cell proliferation, migration, and invasion, but increased tumor cells to undergo apoptosis in vitro, while suppressed growth of GBM cell subcutaneous xenografts in nude mice. In conclusion, FOXO4 possesses an anti-cancer glioma activity, which could be a novel target for future control of GBM.

S100A8 Promotes Inflammation via Toll-Like Receptor 4 After Experimental Traumatic Brain Injury.

INTRODUCTION: S100 calcium-binding protein A8 (S100A8) is also known as macrophage-related protein 8, which is involved in various pathological processes in the central nervous system post-traumatic brain injury (TBI), and plays a critical role in inducing inflammatory cytokines. Accumulating evidences have indicated that toll-like receptor 4 (TLR4) is considered to be involved in inflammatory responses post TBI. The present study was designed to analyze the hypothesis that S100A8 is the key molecule that induces inflammation via TLR4 in TBI. METHODS: The weight-drop TBI model was used and randomly implemented on mice that were categorized into six groups: Sham, NS, S100A8, S100A8+TAK-242, TBI, and TBI+TAK-242 groups. In the S100A8+TAK-242 and TBI+TAK-242 groups, at half an hour prior to the intracerebroventricular administration of S100A8 or TBI, mice were intraperitoneally treated with TAK-242 that acts as a selective antagonist and inhibitor of TLR4. Furthermore, the protein recombinant of S100A8 was injected into the lateral ventricle of the brain of mice in the S100A8 and S100A8+TAK-242 groups. Sterile normal saline was injected into the lateral ventricle in the NS group. To evaluate the association between S100A8 and TLR4, Western blot, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and Nissl staining were employed. Simultaneously, the neurological score and brain water content were assessed. In the in vitro analysis, BV-2 microglial cells were stimulated with lipopolysaccharide LPS or S100A8 recombinant protein, with or without TAK-242. The expression of the related proteins was subsequently detected by Western blot or enzyme-linked immunosorbent assay. RESULTS: The levels of S100A8 protein and pro-inflammatory cytokines were significantly elevated after TBI. There was a reduction in the neurological scores of non-TBI animals with remarkable severe brain edema after the intracerebroventricular administration of S100A8. Furthermore, the TLR4, p-p65, and myeloid differentiation factor 88 (MyD88) levels were elevated after the administration of S100A8 or TBI, which could be restored by TAK-242. Meanwhile, in the in vitro analysis, due to the stimulation of S100A8 or LPS, there was an upregulation of p-p65 and MyD88, which could also be suppressed by TAK-242. CONCLUSION: The present study demonstrated that the TLR4-MyD88 pathway was activated by S100A8, which is essential for the development of inflammation in the brain after TBI.