Classification, risk factors, and outcomes of patients with progressive hemorrhagic injury after traumatic brain injury.

BACKGROUND: According to the pathoanatomic classification system, progressive hemorrhagic injury (PHI) can be categorized into progressive intraparenchymal contusion or hematoma (pIPCH), epidural hematoma (pEDH), subdural hematoma (pSDH), and traumatic subarachnoid hemorrhage (ptSAH). The clinical features of each type differ greatly. The objective of this study was to determine the predictors, clinical management, and outcomes of PHI according to this classification. METHODS: Multivariate logistic regression analysis was used to identify independent risk factors for PHI and each subgroup. Patients with IPCH or EDH were selected for subgroup propensity score matching (PSM) to exclude confounding factors before evaluating the association of hematoma progression with the outcomes by classification. RESULTS: In the present cohort of 419 patients, 123 (29.4%) demonstrated PHI by serial CT scan. Of them, progressive ICPH (58.5%) was the most common type, followed by pEDH (28.5%), pSDH (9.8%), and ptSAH (3.2%). Old age (≥ 60 years), lower motor Glasgow Coma Scale score, larger primary lesion volume, and higher level of D-dimer were independent risk factors related to PHI. These factors were also independent predictors for pIPCH, but not for pEDH. The time to first CT scan and presence of skull linear fracture were robust risk factors for pEDH. After PSM, the 6-month mortality and unfavorable survival rates were significantly higher in the pIPCH group than the non-pIPCH group (24.2% vs. 1.8% and 12.1% vs. 7.3%, respectively, p < 0.001), but not significantly different between the pEDH group and the non-pEDH group. CONCLUSIONS: Understanding the specific patterns of PHI according to its classification can help early recognition and suggest targeted prevention or treatment strategies to improve patients' neurological outcomes.

ACT001 attenuates microglia-mediated neuroinflammation after traumatic brain injury via inhibiting AKT/NFκB/NLRP3 pathway.

BACKGROUND: Microglia-mediated neuroinflammatory response following traumatic brain injury (TBI) is considered as a vital secondary injury factor, which drives trauma-induced neurodegeneration and is lack of efficient treatment. ACT001, a sesquiterpene lactone derivative, is reportedly involved in alleviation of inflammatory response. However, little is known regarding its function in regulating innate immune response of central nervous system (CNS) after TBI. This study aimed to investigate the role and underlying mechanism of ACT001 in TBI. METHODS: Controlled cortical impact (CCI) models were used to establish model of TBI. Cresyl violet staining, evans blue extravasation, neurobehavioral function assessments, immunofluorescence and transmission electron microscopy were used to evaluate therapeutic effects of ACT001 in vivo. Microglial depletion was induced by administering mice with colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Cell-cell interaction models were established as co-culture system to simulate TBI conditions in vitro. Cytotoxic effect of ACT001 on cell viability was assessed by cell counting kit-8 and activation of microglia cells were induced by Lipopolysaccharides (LPS). Pro-inflammatory cytokines expression was determined by Real-time PCR and nitric oxide production. Apoptotic cells were detected by TUNEL and flow cytometry assays. Tube formation was performed to evaluate cellular angiogenic ability. ELISA and western blot experiments were used to determine proteins expression. Pull-down assay was used to analyze proteins that bound ACT001. RESULTS: ACT001 relieved the extent of blood-brain barrier integrity damage and alleviated motor function deficits after TBI via reducing trauma-induced activation of microglia cells. Delayed depletion of microglia with PLX5622 hindered therapeutic effect of ACT001. Furthermore, ACT001 alleviated LPS-induced activation in mouse and rat primary microglia cells. Besides, ACT001 was effective in suppressing LPS-induced pro-inflammatory cytokines production in BV2 cells, resulting in reduction of neuronal apoptosis in HT22 cells and improvement of tube formation in bEnd.3 cells. Mechanism by which ACT001 functioned was related to AKT/NFκB/NLRP3 pathway. ACT001 restrained NFκB nuclear translocation in microglia cells through inhibiting AKT phosphorylation, resulting in decrease of NLRP3 inflammasome activation, and finally down-regulated microglial neuroinflammatory response. CONCLUSIONS: Our study indicated that ACT001 played critical role in microglia-mediated neuroinflammatory response and might be a novel potential chemotherapeutic drug for TBI. Video Abstract.

MicroRNA-126-3p/-5p Overexpression Attenuates Blood-Brain Barrier Disruption in a Mouse Model of Middle Cerebral Artery Occlusion.

Background and Purpose- Blood-brain barrier (BBB) disruption is a critical pathological feature after stroke. MicroRNA-126 (miR-126) maintains BBB integrity by regulating endothelial cell function during development. However, the role of miR-126-3p and -5p in BBB integrity after stroke is unclear. Here, we investigated whether miR-126-3p and -5p overexpression regulates BBB integrity after cerebral ischemia. Methods- A lentivirus carrying genes encoding miR-126-3p or -5p was stereotactically injected into adult male Institute of Cancer Research mouse brains (n=36). Permanent middle cerebral artery occlusion was performed 2 weeks after virus injection. Brain infarct volume, edema volume, and modified neurological severity score were assessed at 1 and 3 days after ischemia. Immunostaining of ZO-1 (zonula occludens-1) and occludin was used to evaluate BBB integrity. IL-1ß (interleukin-1ß), TNF-α (tumor necrosis factor-α), VCAM-1 (vascular cell adhesion molecule-1), and E-selectin expression levels were determined by real-time polymerase chain reaction and Western blot analysis. Results- The expression of miR-126-3p and -5p decreased at 1 and 3 days after ischemia (P<0.05). Injection of lentiviral miR-126-3p or -5p reduced brain infarct volume and edema volume (P<0.05) and attenuated the decrease in ZO-1/occludin protein levels and IgG leakage at 3 days after stroke (P<0.05). Injection of lentiviral miR-126-5p improved behavioral outcomes at 3 days after stroke (P<0.05). miR-126-3p and -5p overexpression downregulated the expression of proinflammatory cytokines IL-1ß and TNF-α and adhesion molecules VCAM-1 and E-selectin, as well as decreased MPO+ (myeloperoxidase positive) cell numbers at 3 days after ischemia (P<0.05). Conclusions- miR-126-3p and -5p overexpression reduced the expression of proinflammatory cytokines and adhesion molecules, and attenuated BBB disruption after ischemic stroke, suggesting that miR-126-3p and -5p are new therapeutic targets in the acute stage of stroke.

Phosphatase Actin Regulator-1 (PHACTR-1) Knockdown Suppresses Cell Proliferation and Migration and Promotes Cell Apoptosis in the bEnd.3 Mouse Brain Capillary Endothelial Cell Line.

BACKGROUND The phosphatase actin regulator-1 (PHACTR-1) gene on chromosome 6 encodes an actin and protein phosphatase 1 (PP1) binding protein, Phactr-1, which is highly expressed in brain tissues. Phactr-1 expression is involved in physiological and pathological cerebral microvascular events. This study aimed to investigate the role of expression of Phactr-1 in a mouse brain capillary endothelial cell line, bEnd.3, by knockdown the PHACTR-1 gene. MATERIAL AND METHODS Three bEnd.3 cell groups were studied, CON (normal control cells), NC (control scramble transfected cells), and KD (cells with PHACTR-1 gene knockdown). The PHACTR-1 gene was knocked down using transfection with small hairpin RNA (shRNA). In the three cell groups cell proliferation, migration, and apoptosis were studied by MTT and colony formation assays, transwell and scratch assays, and flow cytometry. The related cell pathways of associated with Phactr-1 knockdown were studied by Western blot. RESULTS Phactr-1 knockdown suppressed bEnd.3 cell proliferation and migration, promoted cell apoptosis, and downregulated the expressions of migration-associated proteins, including matrix metalloproteinase (MMP)-2 and MMP-9 and upregulated apoptosis-associated proteins, including Bax, Bcl-2, cleaved caspase-3, and caspase-3. CONCLUSIONS Phactr-1 was shown to have a role in the inhibition of endothelial cell proliferation and migration, promoted cell apoptosis, and regulated matrix metalloproteinases and apoptosis-associated proteins. These findings indicate that the expression of the Phactr-1 should be studied further in the cerebral microvasculature, both in vitro and in vivo, regarding its potential as a diagnostic and therapeutic target for cerebral microvascular disease.

Sesamin protects SH-SY5Y cells against mechanical stretch injury and promoting cell survival.

BACKGROUND: Sesamin is a well-known antioxidant extracted from sesame seeds that exhibits various curative effects. The present study investigated whether sesamin would protect neuroblastoma SH-SY5Y cells against mechanical stretch injury-induced increases in reactive oxygen species (ROS) and apoptosis. Additionally, the mechanisms underlying these actives were investigated. Following exposure to mechanical stretch injury, cells were incubated for further investigations. Lactate dehydrogenase and Cell Counting Kit-8 assays were used to assess cell viability, and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay and flow cytometric analysis were performed to evaluate changes in mitochondrial membrane potential (ΔΨm). Furthermore, intracellular levels of ROS production were measured by 20, 70-dichlorofluorescein diacetate staining, the mRNA levels of matrix metallopeptidase 9 (MMP-9) were evaluated using real-time polymerase chain reaction analysis, and the determinations had also been made on related proteins by Western blot analysis. RESULTS: Exposure to mechanical stretch injury significantly decreased cell viability but this decrease was attenuated by pretreatment with sesamin (50 µM). Sesamin also significantly inhibited mechanical stretch injury-induced increases in intracellular ROS production, attenuated declines in ΔΨm, diminished the expressions of pro-apoptotic proteins, and decreased cell apoptosis. Stretch injury increased Bax and cleaved caspase 3 levels, enhanced the gene expression of MMP-9, increased the phosphorylation levels of Akt, p38, and JNK and decreased Bcl-2 levels in the cells. However, pretreatment with sesamin reduced the mechanical stretch injury-induced overexpression of MMP-9. CONCLUSIONS: Sesamin protected SH-SY5Y cells against stretch injury by attenuating increases in ROS levels and suppressing apoptosis. Accordingly, sesamin seems to be a potentially therapeutic agent in the treatment of traumatic brain injury.

Sesamin alleviates blood-brain barrier disruption in mice with experimental traumatic brain injury.

Sesamin, a major lignan of sesame oil, was reported to have neuroprotective effects in several brain injury models. However, its protective action in maintaining blood-brain barrier (BBB) integrity has not been studied. In this study we investigated the effects of sesamin on the BBB in a mouse model of traumatic brain injury (TBI) and explored the underlying mechanisms. Adult male C57BL/6 mice were subjected to a controlled cortical impact (CCI) injury and then received sesamin (30 mg·kg-1·d-1, ip). The mice were euthanized on the 1st and 3rd days after CCI injury and samples were collected for analysis. Sesamin treatment significantly attenuated CCI-induced brain edema on the 1st and 3rd days after the injury, evidenced by the decreases in water content, tissue hemoglobin levels, Evans blue extravasation and AQP4 expression levels in the ipsilateral cortical tissue compared with the vehicle-treated group. Furthermore, sesamin treatment significantly alleviated CCI-induced loss of the tight junction proteins ZO-1 and occludin in the brain tissues. The neuroprotective mechanisms of sesamin were further explored in cultured mouse brain microvascular bEnd.3 cells subjected to biaxial stretch injury (SI). Pretreatment with sesamin (50 µmol/L) significantly alleviated SI-induced loss of ZO-1 in bEnd.3 cells. Furthermore, we revealed that pretreatment with sesamin significantly attenuated SI-induced oxidative stress and early-stage apoptosis in bEnd.3 cells by decreasing the activation of ERK, p-38 and caspase-3. In conclusion, sesamin alleviates BBB disruption at least partly through its anti-oxidative and anti-apoptotic effects on endothelial cells in CCI injury. These findings suggest that sesamin may be a promising potential therapeutic intervention for preventing disruption of the BBB after TBI.

Effect of Electro-Acupuncture on Neuroplasticity of Spinal Cord-Transected Rats.

BACKGROUND This study aimed to evaluate the effects of electro-acupuncture (EA) on neuroplasticity associated with the expressions of neurotrophic factors (NTFs) and their receptors in rats subjected to spinal cord transection (SCT). MATERIAL AND METHODS A total of 144 rats were randomly divided into 3 groups (n=48 per group): sham-operated group, SCT group, and EA (electro-acupuncture) group. Rats in SCT and EA groups received spinal cord transection at T10-T11 vertebral levels. Then, EA group rats received EA treatment. Reverse transcription polymerase chain reaction was used to detect NTFs and receptors at the mRNA level. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to detect the expression of NTFs and their receptors. Basso, Beattie, Bresnahan (BBB) scores and cortical somato-sensory evoked potentials (CSEP) were evaluated to assess the recovery of motor and sensory functions. We also measured BDA (Biotinylated dextran amine) axonal tracing, CGRP (Calcitonin gene-related peptide), GAP-43 (Growth-associated protein), and synaptophysin immunohistochemistry (IHC). RESULTS EA treatment led to obvious improvement in hindlimb locomotor and sensory functions. CNTF, FGF-2, and TrkB mRNA were significantly upregulated, while NGF, PDGF, TGF-b1, IGF-1, TrkA, and TrkC mRNA were concomitantly downregulated in the caudal spinal segment (CSS) following EA. Immunohistochemistry demonstrated an increased number of CGRP fibers, GAP-43, and synaptophysin profiles in the CSS in the EA rats. CONCLUSIONS EA may promote the recovery of neuroplasticity in rats subjected to SCT. This could be attributed to the systematic regulation of NTFs and their receptors after EA.

Predicting posttraumatic hydrocephalus: derivation and validation of a risk scoring system based on clinical characteristics.

Posttraumatic hydrocephalus (PTH) is a disorder of disturbed cerebrospinal fluid (CSF) dynamics after traumatic brain injury (TBI). It can lead to brain metabolic impairment and dysfunction and has a high risk of clinical deterioration and worse outcomes. The incidence and risk factors for the development of PTH after decompressive craniectomy (DC) has been assessed in previous studies, but rare studies identify patients with higher risk for PTH among all TBI patients. This study aimed to develop and validate a risk scoring system to predict PTH after TBI. Demographics, injury severity, duration of coma, radiologic findings, and DC were evaluated to determine the independent predictors of PTH during hospitalization until 6 months following TBI through logistic regression analysis. A risk stratification system was created by assigning a number of points for each predictor and validated in an independent cohort. The model accuracy was assessed by the area under the receiver operating characteristic curve (AUC). Of 526 patients in the derivation cohort, 57 (10.84%) developed PTH during 6 months follow up. Age > 50 yrs (Odd ratio [OR] = 1.91, 95% confidence interval [CI] 1.09-3.75, 4 points), duration of coma ≥1 w (OR = 5.68, 95% CI 2.57-13.47, 9 points), Fisher grade III (OR = 2.19, 95% CI 1.24-4.36, 5 points) or IV (OR = 3.87, 95% CI 1.93-8.43, 7 points), bilateral DC (OR = 6.13, 95% CI 2.82-18.14, 9 points), and extra herniation after DC (OR = 2.36, 95% CI 1.46-4.92, 5 points) were independently associated with PTH. Rates of PTH for the low- (0-12 points), intermediate- (13-22 points) and high-risk (23-34 points) groups were 1.16%, 35.19% and 78.57% (p < 0.0001). The corresponding rates in the validation cohort, where 17/175 (9.71%) developed PTH, were 1.35%, 37.50% and 81.82% (p < 0.0001). The risk score model exhibited good-excellent discrimination in both cohorts, with AUC of 0.839 versus 0.894 (derivation versus validation) and good calibration (Hosmer-Lemshow p = 0.56 versus 0.68). This model will be useful to identify patients at high risk for PTH who may be candidates for preventive interventions, and to improve their outcomes.

SIRT2 inhibition exacerbates neuroinflammation and blood-brain barrier disruption in experimental traumatic brain injury by enhancing NF-κB p65 acetylation and activation.

Sirtuin 2 (SIRT2) is a member of the sirtuin family of NAD(+) -dependent protein deacetylases. In recent years, SIRT2 inhibition has emerged as a promising treatment for neurodegenerative diseases. However, to date, there is no evidence of a specific role for SIRT2 in traumatic brain injury (TBI). We investigated the effects of SIRT2 inhibition on experimental TBI using the controlled cortical impact (CCI) injury model. Adult male mice underwent CCI or sham surgery. A selective brain-permeable SIRT2 inhibitor, AK-7, was administrated 30 min before injury. The volume of the brain edema lesion and the water content of the brain were significantly increased in mice treated with AK-7 (20 mg/kg), compared with the vehicle group, following TBI (p < 0.05 at 1 day and p < 0.05 at 3 days, respectively). Concomitantly, AK-7 administration greatly worsened neurobehavioral deficits on days 3 and 7 after CCI. Furthermore, blood-brain barrier disruption and matrix metalloproteinases (MMP)-9 activity increased following SIRT2 inhibition. AK-7 treatment increased TBI-induced microglial activation both in vivo and in vitro, accompanied by a large increase in the expression and release of inflammatory cytokines. Mechanistically, SIRT2 inhibition increased both K310 acetylation and nuclear translocation of NF-κB p65, leading to enhanced NF-κB activation and up-regulation of its target genes, including aquaporin 4 (AQP4), MMP-9, and pro-inflammatory cytokines. Together, these data demonstrate that SIRT2 inhibition exacerbates TBI by increasing NF-κB p65 acetylation and activation. Our findings provide additional evidence of an anti-inflammatory effect of SIRT2. SIRT2 is a member of the sirtuin family of NAD+-dependent protein deacetylases. Our study suggests that the SIRT2 inhibitor AK-7 exacerbates traumatic brain injury (TBI) via a potential mechanism involving increased acetylation and nuclear translocation of NF-κB p65, resulting in up-regulation of NF-κB target genes, including aquaporin 4 (AQP4), matrix metalloproteinase 9 (MMP-9), and pro-inflammatory cytokines. Our findings provide additional evidence of an anti-inflammatory effect of SIRT2.

Depletion of thymopoietin inhibits proliferation and induces cell cycle arrest/apoptosis in glioblastoma cells.

BACKGROUND: Glioblastoma (GBM) is the most malignant nervous system tumor with an almost 100 % recurrence rate. Thymopoietin (TMPO) has been demonstrated to be upregulated in various tumors, including lung cancer, breast cancer, and so on, but its role in GBM has not been reported. This study was aimed to determine the role of TMPO in GBM. METHODS: Publicly available Oncomine dataset analysis was used to explore the expression level of TMPO in GBM specimens. Then the expression of TMPO was knocked down in GBM cells using lentiviral system, and the knockdown efficacy was further validated by real-time quantitative PCR and western blot analysis. Furthermore, the effects of TMPO silencing on GBM cell proliferation and apoptosis were examined by MTT, colony formation, and flow cytometry analysis. Meanwhile, the expression of apoptotic markers caspase-3 and poly(ADP-ribose) polymerase (PARP) were investigated by western blot analysis. RESULTS: This study observed that the expression of TMPO in GBM specimens was remarkably higher than that in normal brain specimens. Moreover, knockdown of TMPO could significantly inhibit cell proliferation and arrest cell cycle progression at the G2/M phase. It also found that TMPO knockdown promoted cell apoptosis by upregulation of the cleavage of caspase-3 and PARP protein levels which are the markers of apoptosis. CONCLUSIONS: The results suggested TMPO might be a novel therapeutic target for GBM.

Relationship between trauma-induced coagulopathy and progressive hemorrhagic injury in patients with traumatic brain injury.

Progressive hemorrhagic injury (PHI) can be divided into coagulopathy-related PHI and normal coagu- lation PHI. Coagulation disorders after traumatic brain injuries can be included in trauma-induced coagulopathy (TIC). Some studies showed that TIC is associated with PHI and increases the rates of disability and mortality. In this review, we discussed some mechanisms in TIC, which is of great importance in the development of PHI, including tissue factor (TF) hypothesis, protein C pathway and thrombocytopenia. The main mechanism in the relation of TIC to PHI is hypocoagulability. We also reviewed some coagulopathy parameters and proposed some possible risk factors, predictors and therapies.

Endogenous TGFß1 Plays a Crucial Role in Functional Recovery After Traumatic Brain Injury Associated with Smad3 Signal in Rats.

Transforming growth factor-ß 1 (TGFß1) has a diverse role in astrogliosis and neuronal survival, but the underlying mechanism remains to be elucidated, especially in traumatic brain injury (TBI). Here, we show that the expression of TGFß1 was increased in the pericontusional region, accompanied with astrogliosis and neuronal loss in TBI rats. Moreover, TGFß1 knockdown not only reduced the number of neurons and inhibited astrogliosis but also resulted in a significant neurological dysfunction in rats with TBI. Subsequently, Smad3, a key downstream signal of TGFß1, was involved in pericontusional region after TBI. These findings therefore indicate that TGFß1 is involved in neuroprotection and astrogliosis, via activation of down stream Smad3 signal in the brain after injury.

Neuroglobin and Nogo-a as biomarkers for the severity and prognosis of traumatic brain injury.

OBJECTIVE: To identify the early changes of serum neuroglobin and Nogo-A concentrations and the relations to traumatic brain injury (TBI) severity and prognosis. METHODS: Serum samples were obtained and analyzed from 34 patients with TBI within the first 96 h after injury. Comparative analysis combined with Glasgow Coma Scale (GCS) scores and the 6-month prognosis of these patients was performed. RESULTS: Significant correlations were found between peak serum neuroglobin and Nogo-A concentrations and a patient's GCS score on admission (p < 0.001). The mean peak serum neuroglobin and Nogo-A concentrations were both significantly higher in patients with an unfavorable outcome at 6 months after injury (p < 0.05). CONCLUSIONS: Serum neuroglobin and Nogo-A levels could be suggested as biomarkers for predicting TBI severity and prognosis.

Quantitative assessment of the association between XRCC3 C18607T polymorphism and glioma risk.

XRCC3 has an important function in the DNA double-strand break, and XRCC3 C18607T polymorphism is a common polymorphism at exon 7 of the XRCC3 gene. Published data on the association between XRCC3 C18607T polymorphism and glioma risk were inconclusive. Electronic databases of PubMed, and Embase were searched for studies assessing the association between XRCC3 C18607T polymorphism and glioma risk. Pooled odds ratio (OR) and 95 % confidence interval (95 % CI) were calculated to estimate the association. Ten studies with five studies from Caucasians and five studies from Asians were included, including 9,369 subjects. Meta-analysis of total included studies showed that XRCC3 C18607T polymorphism was associated with increased risk of glioma (T vs. C: OR = 1.14, 95 % CI 1.02-1.28, P = 0.02; TT vs. CC: OR = 1.37, 95 % CI 1.03-1.83, P = 0.03; TT vs. CC/CT: OR = 1.31, 95 % CI 1.00-1.71, P = 0.05; TT/CT vs. CC: OR = 1.12, 95 % CI 1.02-1.22, P = 0.02). Meta-analysis of the five studies from Asians showed that XRCC3 C18607T polymorphism was associated with increased risk of glioma (T vs. C: OR = 1.22, 95% CI 1.09-1.36, P < 0.01; TT vs. CC: OR = 1.89, 95 % CI 1.38-2.57, P < 0.01; TT vs. CC/CT: OR = 1.78, 95 % CI 1.31-2.40, P < 0.01; TT/CT vs. CC: OR = 1.19, 95 % CI 1.04-1.36, P = 0.01). Meta-analysis of the five studies from Caucasians didn't find the association. In conclusion, the finding from the meta-analysis provides strong evidence for the association between XRCC3 C18607T polymorphism and glioma risk.

Fatal deterioration of delayed acute subdural hematoma after mild traumatic brain injury: two cases with brief review.

Both delayed posttraumatic intracerebral hemorrhage and epidural hematoma have been well described in the neurosurgical literatures. However, delayed posttraumatic acute subdural hematoma which happens more than a week with a rapid progress after mild traumatic brain injury and causes death of patient is rarely reported. We show two such cases and briefly review the literature and discuss the probable pathogenesis of their rapid progress.

Transplantation of astrocyte-derived mitochondria into injured astrocytes has a protective effect following stretch injury.

Traumatic brain injury (TBI) is a global public-health problem. Astrocytes, and their mitochondria, are important factors in the pathogenesis of TBI-induced secondary injury. Mitochondria extracted from healthy tissues and then transplanted have shown promise in models of a variety of diseases. However, the effect on recipient astrocytes is unclear. Here, we isolated primary astrocytes from newborn C57BL/6 mice, one portion of which was used to isolate mitochondria, and another was subjected to stretch injury (SI) followed by transplantation of the isolated mitochondria. After incubation for 12 h, cell viability, mitochondrial dysfunction, calcium overload, redox stress, inflammatory response, and apoptosis were improved. Live-cell imaging showed that the transplanted mitochondria were incorporated into injured astrocytes and fused with their mitochondrial networks, which was in accordance with the changes in the expression levels of markers of mitochondrial dynamics. The astrocytic IKK/NF-κB pathway was decelerated whereas the AMPK/PGC-1α pathway was accelerated by transplantation. Together, these results indicate that exogenous mitochondria from untreated astrocytes can be incorporated into injured astrocytes and fuse with their mitochondrial networks, improving cell viability by ameliorating mitochondrial dysfunction, redox stress, calcium overload, and inflammation.

Dynamics of N6-methyladenosine modification during Alzheimer's disease development.

N6-methyladenosine (m6A) modification is a common RNA modification in the central nervous system and has been linked to various neurological disorders, including Alzheimer's disease (AD). However, the dynamic of mRNA m6A modification and m6A enzymes during the development of AD are not well understood. Therefore, this study examined the expression profiles of m6A and its enzymes in the development of AD. The results showed that changes in the expression levels of m6A regulatory factors occur in the early stages of AD, indicating a potential role for m6A modification in the onset of the disease. Additionally, the analysis of mRNA m6A expression profiles using m6A-seq revealed significant differences in m6A modification between AD and control brains. The genes with differential methylation were found to be enriched in GO and KEGG terms related to processes such as inflammation response, immune system processes. And the differently expressed genes (DEGs) are negatively lryassociated with genes involved in microglia hemostasis, but positively associated with genes related to "disease-associated microglia" (DAM) associated genes. These findings suggest that dysregulation of mRNA m6A modification may contribute to the development of AD by affecting the function and gene expression of microglia.

Hemorrhagic stroke-induced subtype of inflammatory reactive astrocytes disrupts blood-brain barrier.

Astrocytes undergo disease-specific transcriptomic changes upon brain injury. However, phenotypic changes of astrocytes and their functions remain unclear after hemorrhagic stroke. Here we reported hemorrhagic stroke induced a group of inflammatory reactive astrocytes with high expression of Gfap and Vimentin, as well as inflammation-related genes lipocalin-2 (Lcn2), Complement component 3 (C3), and Serpina3n. In addition, we demonstrated that depletion of microglia but not macrophages inhibited the expression of inflammation-related genes in inflammatory reactive astrocytes. RNA sequencing showed that blood-brain barrier (BBB) disruption-related gene matrix metalloproteinase-3 (MMP3) was highly upregulated in inflammatory reactive astrocytes. Pharmacological inhibition of MMP3 in astrocytes or specific deletion of astrocytic MMP3 reduced BBB disruption and improved neurological outcomes of hemorrhagic stroke mice. Our study demonstrated that hemorrhagic stroke induced a group of inflammatory reactive astrocytes that were actively involved in disrupting BBB through MMP3, highlighting a specific group of inflammatory reactive astrocytes as a critical driver for BBB disruption in neurological diseases.

Endorepellin downregulation promotes angiogenesis after experimental traumatic brain injury.

Endorepellin plays a key role in the regulation of angiogenesis, but its effects on angiogenesis after traumatic brain injury are unclear. This study explored the effects of endorepellin on angiogenesis and neurobehavioral outcomes after traumatic brain injury in mice. Mice were randomly divided into four groups: sham, controlled cortical impact only, adeno-associated virus (AAV)-green fluorescent protein, and AAV-shEndorepellin-green fluorescent protein groups. In the controlled cortical impact model, the transduction of AAV-shEndorepellin-green fluorescent protein downregulated endorepellin while increasing the number of CD31+/Ki-67+ proliferating endothelial cells and the functional microvessel density in mouse brain. These changes resulted in improved neurological function compared with controlled cortical impact mice. Western blotting revealed increased expression of vascular endothelial growth factor and angiopoietin-1 in mice treated with AAV-shEndorepellin-green fluorescent protein. Synchrotron radiation angiography showed that endorepellin downregulation promoted angiogenesis and increased cortical neovascularization, which may further improve neurobehavioral outcomes. Furthermore, an in vitro study showed that downregulation of endorepellin increased tube formation by human umbilical vein endothelial cells compared with a control. Mechanistic analysis found that endorepellin downregulation may mediate angiogenesis by activating vascular endothelial growth factor- and angiopoietin-1-related signaling pathways.

Association of the MTHFR C677T polymorphism with primary brain tumor risk.

Methylenetetrahydrofolate reductase (MTHFR) gene plays key roles not only in folate metabolism but also in carcinogenesis. The single nucleotide polymorphism MTHFR C677T has been indicated in the development of various tumors. The effect of the MTHFR C677T polymorphism on brain tumors remains poorly understood. We performed the present meta-analysis and aimed to provide a better understanding of the pathogenesis of brain tumors. A literature search of the PubMed, Embase, Web of Science, and Wanfang databases was carried out for potential relevant publications. We calculated the pooled odds ratio (OR) with corresponding 95% confidence interval (95% CI) to assess the association of MTHFR C677T with the susceptibility to brain tumors. We also performed stratified analysis and sensitivity analysis to further estimate the genetic association. All statistical analyses were conducted by the use of STATA 11.0 (STATA Corporation, College Station, TX, USA). Eight case-control studies involving a total of 3,059 cases and 3,324 controls were retrieved according to the inclusion criteria. The overall ORs suggested that the MTHFR C677T variant can exert a risk effect on brain tumor development under the following contrast models (OR(TC vs. CC) = 1.14, 95% CI 1.02-1.27, P OR = 0.018; OR(TT + TC vs. CC)= 1.23, 95% CI 1.01-1.51, P(OR) = 0.043). No significant correlation was identified among the Caucasians, but not among the Asians. In addition, the TC genotype carriers were more susceptible to meningioma when compared with the CC genotype carriers (OR(TC vs. CC) = 1.38, 95% CI 1.15-1.65, P(OR) < 0.001). The MTHFR C677T polymorphism seemed to exert no effect on glioma risk. The current meta-analysis firstly provides evidence that the MTHFR C677T polymorphism may modify the risk for brain tumors, particularly meningioma. The role of the MTHFR C677T variant in brain tumor pathogenesis across diverse ethnicities needs further elucidation by more future studies with large sample size.