TUG1 exacerbates cerebral ischemia-reperfusion injury through miR-340-5p-mediated PTEN.

Long non-coding RNAs (LncRNAs) play a substantial role in the process of cerebral ischemia-reperfusion injury (CIRI). The present work aimed to determine the probable mechanism by which LncRNA TUG1 exacerbates CIRI via the miR-340-5p/phosphatase and tensin homolog (PTEN) pathway. After developing a middle cerebral artery occlusion/reperfusion (MCAO/R) model, pcDNA-TUG1 together with miR-340-5p agomir were administrated in vivo. Furthermore, the neurologic defects in rats were assessed by a modified neurological severity score. Moreover, 2,3,5-Triphenyl-2 H-tetrazolium chloride stain-step was performed to determine the brain's infarct size. In addition, western blotting, immunohistochemistry, and qRT-PCR experiments were utilized for gauging the proteomic/genomic expression-profiles. Luciferase reporter assay validated correlations across TUG1, miR-340-5p, together with PTEN. The results indicated relatively reduced miR-340-5p levels in MCAO/R models, while upregulated TUG1 levels. The pcDNA-TUG1-treated rats indicated increasing neurological dysfunction, whereas the miR-340-5p agomir-treated rats showed improvement. Furthermore, miR-340-5p was determined to be the expected and confirmed TUG1 target. All things considered, the findings suggested that PTEN can serve as the target of miR-340-5p. In addition, TUG1 served as a miR-340-5p ceRNA, which promotes PTEN modulation. Furthermore, TUG1 overexpression decreased miR-340-5p's capacity to fend against CIRI. Conclusively, this work proved that in CIRI, targeting the TUG1/miR-340-5p/PTEN regulatory axis is a viable approach for the treatment of ischemic stroke.

TUG1 aggravates intracerebral hemorrhage injury by inhibiting angiogenesis in an miR-26a-dependent manner.

Long non-coding RNA taurine-upregulated gene 1 (TUG1) plays pivotal roles in angiogenesis, an important mechanism of neural repair after intracerebral hemorrhage (ICH). However, the role of TUG1 in angiogenesis following ICH is not clear. Therefore, in this study, we investigated the role and the underlying mechanism of TUG1 in neurologic impairment and cerebral angiogenesis following ICH. The ICH rat model was established and then rats were injected with TUG1-expressing plasmid (pcDNA-TUG1) or miR-26a mimic, a critical regulator of VEGF-mediated angiogenesis. We confirmed the overexpression of TUG1 and miR-26a by qRT-PCR. The neurological deficits of ICH rats were evaluated by modified neurological severity scores. The expression of angiogenesis markers VEGF and CD31 were examined by immunohistochemistry and western blot. The interaction between TUG1 and miR-26a was determined by luciferase reporter assay. Our results showed that ICH caused a marked upregulation of TUG1 and a significant downregulation of miR-26a. TUG1 overexpression led to the deterioration of neurologic function and inhibited cerebral angiogenesis in ICH rats. In contrast, overexpression of miR-26a alleviated the neurologic damage and promoted cerebral angiogenesis in ICH rats, but these could be attenuated by TUG1 overexpression. Furthermore, TUG1 directly bound to miR-26a and inhibited its expression. Importantly, TUG1 overexpression inhibited the expression of VEGF by targeting miR-26a. In conclusion, our results indicated that TUG1 aggravated ICH-mediated injury by suppressing angiogenesis by downregulating miR-26a. This suggests a rationale for targeting TUG1/miR-26a in the therapy of ICH.

Taurine-Upregulated Gene 1 Attenuates Cerebral Angiogenesis following Ischemic Stroke in Rats.

Objective: Angiogenesis is one of the therapeutic targets of cerebral infarction. Long noncoding RNAs (lncRNAs) can regulate the pathological process of angiogenesis following ischemic stroke. Taurine-upregulated gene 1 (TUG1), an lncRNA, is correlated to ischemic stroke. We intended to determine the effect of TUG1 on angiogenesis following an ischemic stroke. Materials and Methods: Middle cerebral artery occlusion (MCAO) was adopted to build a focal ischemic model of the rat brain, and pcDNA-TUG1 and miR-26a mimics were injected into rats. Neurological function was estimated through modified neurological severity scores. The volume of focal brain infarction was calculated through 2,3,5-triphenyltetrazolium chloride staining. The level of TUG1 and miR-26a was measured by PCR. The expression of vascular endothelial growth factor (VEGF) and CD31 was checked using immunohistochemistry and western blot. The correlation between miR-26a and TUG1 was verified through a luciferase reporter assay. Results: TUG1 increased noticeably while miR-26a was markedly reduced in MCAO rats. Overexpression of miR-26a improved neurological function recovery and enhanced cerebral angiogenesis in MCAO rats. TUG1 overexpression aggravated neurological deficits and suppressed cerebral angiogenesis in MCAO rats. Bioinformatics analysis revealed that miR-26a was one of the predicted targets of TUG1. Furthermore, TUG1 combined with miR-26a to regulate angiogenesis. TUG1 overexpression antagonized the role of miR-26a in neurological recovery and angiogenesis in MCAO rats. Conclusions: TUG1/miR-26a, which may act as a regulatory axis in angiogenesis following ischemic stroke, can be considered a potential target for cerebral infarction therapy.

TMCO1 expression promotes cell proliferation and induces epithelial-mesenchymal transformation in human gliomas.

Transmembrane and coiled-coil domains 1 (TMCO1) is a recently discovered transmembrane protein of endoplasmic reticulum (ER), which plays a critical role in maintaining calcium homeostasis. TMCO1 dysfunction has been proved to be closely related to a variety of human diseases, including glaucoma, deformities, mental retardation and tumorigenesis. However, the role of TMCO1 in gliomas remains unclear. The purpose of this study was to detect the role of TMCO1 in the pathogenesis and progression of gliomas. This study demonstrated that TMCO1 was upregulated in gliomas and its overexpression predicted poor prognosis. We also revealed that the expression of TMCO1 was associated with the World Health Organization (WHO) grade of gliomas. Knockdown of TMCO1 inhibited the proliferation and induced apoptosis of U87 and U251 cells. In addition, TMCO1 induced GBM cell migration and invasion by promoting epithelial-mesenchymal transition (EMT). These date collectively proved the crucial role of TMCO1 as a novel prognostic factor and underlying therapeutic target for glioma patients.

Transcranial direct-current stimulation protects against cerebral ischemia-reperfusion injury through regulating Cezanne-dependent signaling.

Transcranial direct-current stimulation (tDCS) is proved safe and shows therapeutic effect in cerebral ischemic stroke in clinical trials. But the underlying molecular mechanisms remain unclear. Here we show that tDCS treatment reduces the infarct volume after rat cerebral ischemia-reperfusion (I/R) injury and results in functional improvement of stroke animals. At the cellular and molecular level, tDCS suppresses I/R-induced upregulation of Cezanne in the ischemic neurons. Cezanne inhibition confers neuroprotection after rat I/R and oxygen glucose deprivation (OGD) in the cortical neuronal cultures. Inhibiting Cezanne increases the level of SIRT6 that is downregulated in the ischemic neurons. Suppressing SIRT6 blocks Cezanne inhibition-induced neuroprotective effect and overexpressing SIRT6 attenuates OGD-induced neuronal death. We further show that downregulating Cezanne reduces DNA double-strand break (DSB) through upregulation of SIRT6 in OGD-insulted neurons. Together, this study suggests that Cezanne-dependent SIRT6-DNA DSB signaling pathway may mediate the neuroprotective effect of tDCS in ischemic neurons.

Risk Factors for Intraprocedural Rerupture during Embolization of Ruptured Intracranial Aneurysms.

BACKGROUND: Intraprocedural rupture (IPR) is a devastating complication in endovascular treatment of ruptured intracranial aneurysms, but its risk factors have not been fully assessed. This study was performed to explore the risk factors for IPR during embolization of ruptured cerebral aneurysms. METHODS: A total of 1,494 patients with ruptured intracranial aneurysms who underwent endovascular interventional embolization were enrolled. Clinical characteristics were collected for each patient. Univariate and multivariate logistic regression analysis was employed to identify the factors independently associated with IPR. A receiver operating characteristic (ROC) curve analysis was performed to determine the cutoff values of continuous variables predicting IPR. RESULTS: Forty-one patients suffered from IPR (2.7%). Multivariate logistic regression analysis indicated that aneurysm size (odds ratio [OR], 0.819; 95% confidence interval [CI], 0.732-0.916), aneurysms with irregular morphology (OR, 2.162; 95% CI, 1.143-4.091), time from symptom onset to intervention (OR, 1.615; 95% CI, 1.207-2.161), and vasospasm during embolization (OR, 2.021; 95% CI, 1.038-3.934) were the independent risk factors of IPR. ROC curve analysis showed that the area under the curve for aneurysm size and time from onset to intervention were 0.697 (cutoff value, 3.4 mm; sensitivity, 78.8%; and specificity, 53.7%) and 0.659 (cutoff value, 2 days; sensitivity, 78.0%; and specificity, 45.2%), respectively. CONCLUSION: Aneurysms with irregular morphology, aneurysms ≤ 3.4 mm in diameter, time from onset to intervention > 2 days and cerebral vasospasm during embolization are independent risk factors for IPR during coil embolization of ruptured aneurysms. More attention should be paid to the factors increasing the risk of IPR in patients with ruptured aneurysms so as to minimize this complication.

An early neuroprotective effect of atorvastatin against subarachnoid hemorrhage.

Atorvastatin has been shown to reduce early brain edema and neuronal death after subarachnoid hemorrhage, but its mechanism is not clear. In this study, rat models of subarachnoid hemorrhage were established by autologous blood injection in the cisterna magna. Rat models were intragastrically administered 20 mg/kg atorvastatin 24 hours before subarachnoid hemorrhage, 12 and 36 hours after subarachnoid hemorrhage. Compared with the controls, atorvastatin treatment demonstrated that at 72 hours after subarachnoid hemorrhage, neurological function had clearly improved; brain edema was remarkably relieved; cell apoptosis was markedly reduced in the cerebral cortex of rats; the number of autophagy-related protein Beclin-1-positive cells and the expression levels of Beclin-1 and LC3 were increased compared with subarachnoid hemorrhage only. The ultrastructural damage of neurons in the temporal lobe was also noticeably alleviated. The similarities between the effects of atorvastatin and rapamycin were seen in all the measured outcomes of subarachnoid hemorrhage. However, these were contrary to the results of 3-methyladenine injection, which inhibits the signaling pathway of autophagy. These findings indicate that atorvastatin plays an early neuroprotective role in subarachnoid hemorrhage by activating autophagy. The experimental protocol was approved by the Animal Ethics Committee of Anhui Medical University, China (904 Hospital of Joint Logistic Support Force of PLA; approval No. YXLL-2017-09) on February 22, 2017.

PI3K/mTORC1/2 inhibitor PQR309 inhibits proliferation and induces apoptosis in human glioblastoma cells.

Glioblastoma (GBM) is the most common type of primary central nervous system tumor in adults, which has high mortality and morbidity rates, and short survival time, namely <15 months after the diagnosis and application of standard therapy, which includes surgery, radiation therapy and chemotherapy; thus, novel therapeutic strategies are imperative. The activation of the PI3K/AKT signaling pathway plays an important role in GBM. In the present study, U87 and U251 GBM cells were treated with the PI3K/mTORC1/2 inhibitor PQR309, and its effect on glioma cells was investigated. Cell Counting Kit­8 assay, 5­ethynyl­2'­deoxyuridine and colony formation assays revealed dose­ and time­dependent cytotoxicity in glioma cells that were treated with PQR309. Flow cytometry and western blotting revealed that PQR309 can significantly induce tumor cell apoptosis and arrest the cell cycle in the G1 phase. Furthermore, the expression levels of AKT, phosphorylated (p)­AKT, Bcl­2, Bcl­xL, Bad, Bax, cyclin D1, cleaved caspase­3, MMP­9 and MMP­2 were altered. In addition, the migration and invasion of glioma cells, as detected by wound healing, migration and Transwell invasion assays, exhibited a marked suppression after treating the cells with PQR309. These results indicated that PQR309 exerts an antitumor effect by inhibiting proliferation, inducing apoptosis, inducing G1 cell cycle arrest, and inhibiting invasion and migration in human glioma cells. The present study provides evidence supportive of further development of PQR309 for adjuvant therapy of GBM.

l-lysine confers neuroprotection by suppressing inflammatory response via microRNA-575/PTEN signaling after mouse intracerebral hemorrhage injury.

l-lysine is a basic amino acid that has been shown to exert neuroprotective effect. However, the underlying mechanism remains to be elucidated. In this study, we investigate how l-lysine exerts its neuroprotective effect in hemin-insulted mouse cortical neurons in vitro and the mouse model of intracerebral hemorrhage (ICH) in vivo. We demonstrate that l-lysine treatment promotes M2 microglial polarization and reduces inflammatory response both in vitro and in vivo, suggesting that l-lysine may play a neuroprotective role in ICH injury. Indeed, we show that l-lysine treatment reduces cortical neuronal death after hemin insult in vitro and decrease the number of degenerating neurons after ICH in vivo. l-lysine also improves the functional recovery of ICH animals in neurobehavioral tests. Consistent with the role of PTEN in regulating inflammatory response, we find that PTEN inhibition promotes M2 microglial polarization and suppresses pro-inflammatory response in mouse ICH injury, which contribute to the neuroprotective effect of l-lysine. Moreover, our results reveal that microRNA-575 directly suppressed PTEN to promote M2 microglial polarization and mediate the neuroprotective effect of l-lysine in ICH injury. Together, our results suggest that l-lysine confers neuroprotection after ICH injury through enhancing M2 microglial polarization and reducing inflammatory response, which is mediated by microRNA-575 upregulation and subsequent PTEN downregulation.

Six Immune Associated Genes Construct Prognostic Model Evaluate Low-Grade Glioma.

Background: The immunotherapy of Glioma has always been a research hotspot. Although tumor associated microglia/macrophages (TAMs) proves to be important in glioma progression and drug resistance, our knowledge about how TAMs influence glioma remains unclear. The relationship between glioma and TAMs still needs further study. Methods: We collected the data of TAMs in glioma from NCBI Gene Expression Omnibus (GEO) that included 20 glioma samples and 15 control samples from four datasets. Six genes were screened from the Differential Expression Gene through Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) network and single-cell sequencing analysis. A risk score was then constructed based on the six genes and patients' overall survival rates of 669 patients from The Cancer Genome Atlas (TCGA). The efficacy of the risk score in prognosis and prediction was verified in Chinese Glioma Genome Atlas (CGGA). Results: Six genes, including CD163, FPR3, LPAR5, P2ry12, PLAUR, SIGLEC1, that participate in signal transduction and plasma membrane were selected. Half of them, like CD163, FPR3, SIGLEC1, were mainly expression in M2 macrophages. FPR3 and SIGLEC1 were high expression genes in glioma associated with grades and IDH status. The overall survival rates of the high risk score group was significantly lower than that of the low risk score group, especially in LGG. Conclusion: Joint usage of the 6 candidate genes may be an effective method to diagnose and evaluate the prognosis of glioma, especially in Low-grade glioma (LGG).

ACSL4 suppresses glioma cells proliferation via activating ferroptosis.

Acyl­CoA synthetase long­chain family member 4 (ACSL4) is a member of the long chain family of acyl­CoA synthetase proteins, which have recently been shown to serve an important role in ferroptosis. Previous studies have suggested that ferroptosis is involved in the occurrence of glioma; however, the role of ACSL4 in glioma remains unknown. In the present study, a reduction of ferroptosis in human glioma tissues and glioma cells was observed. Subsequently, it was demonstrated that the expression of ACSL4 was also downregulated in human glioma tissues and cells. A ferroptosis inhibitor and inducer were used to investigate the effects of ferroptosis on viability. The results showed that promoting ferroptosis inhibited the proliferation of glioma cells, and that the use of inducers had the reverse effect. Therefore, it was hypothesized that the reduction in ACSL4 expression may have been involved in ferroptosis and proliferation in glioma. Overexpression of ACSL4 decreased expression of glutathione peroxidase 4 and increased the levels of ferroptotic markers, including 5­hydroxyeicosatetraenoic (HETE), 12­HETE and 15­HETE. Additionally, ACSL4 overexpression resulted in an increase in lactate dehydrogenase release and a reduction in cell viability. The opposite results were observed when ACSL4 was silenced. These findings suggest that ACSL4 regulates ferroptosis and proliferation of glioma cells. To further investigate the mechanism underlying ACSL4­mediated regulation of proliferation in glioma cells, cells were treated with small interfering (si)­ACSL4 and sorafenib, a ferroptosis inducer. sorafenib attenuated the ability of siRNA­mediated silencing of ACSL4, thus improving cell viability. These results demonstrate that ACSL4 protects glioma cells and exerts anti­proliferative effects by activating a ferroptosis pathway and highlight the pivotal role of ferroptosis regulation by ACSL4 in its protective effects on glioma. Therefore, ACSL4 may serve as a novel therapeutic target for the treatment of glioma.

Endoscopic surgery for thalamic hemorrhage breaking into ventricles: Comparison of endoscopic surgery, minimally invasive hematoma puncture, and external ventricular drainage.

PURPOSE: Thalamic hemorrhage breaking into ventricles (THBIV) is a devastating disease with high morbidity and mortality rates. Endoscopic surgery (ES) may improve outcomes, although there is no consensus on its superiority. We investigated the efficacy and safety of ES and compared the outcomes of different management strategies by ES, hematoma puncture and drainage (HPD), and external ventricular drainage (EVD) in patients with THBIV. METHODS: We retrospectively analyzed patients with THBIV treated by ES, HPD, or EVD at our hospital from June 2015 to June 2018. Patients were categorized into anteromedial and posterolateral groups based on THBIV location, and then the two groups were further divided into ES, HPD, and EVD subgroups. Individualized surgical approach was adopted according to the location of the hematoma in the ES subgroups. Patient characteristics and surgical outcomes were investigated. RESULTS: We analyzed 211 consecutive patients. There were no significant differences in clinical characteristics or incidence of perioperative procedure-related complications (postoperative rebleeding and intracranial infection) in either anteromedial or posterolateral groups. Compared with other therapeutic methods, the ES subgroups had the highest hematoma evacuation rate, shortest drainage time, and lowest incidence of chronic ventricular dilatation (all p < 0.05). Among the three anteromedial subgroups, ES subgroup had the best clinical outcomes which was assessed by the modified Rankin Scale, followed by HPD and EVD subgroups (p < 0.01); while in the posterolateral subgroups, clinical outcomes in the ES and HPD subgroups were similar and better than that in the EVD subgroup (p = 0.037). CONCLUSION: Individualized surgical ES approach for removal of thalamic and ventricular hematomas is a minimally invasive, safe, and effective strategy for the treatment of THBIV with a thalamic hematoma volume of 10-30 mL.

Prevalence and risk factors of microalbuminuria in patients with lacunar infarction.

Objectives: To investigate the prevalence and risk factors for microalbuminuria in patients with lacunar infarction. Methods: 702 lacunar infarction patients and 234 controls were recruited in this study, the concentration of urinary albumin and clinical characteristics were collected for each participant. We analyzed the prevalence of microalbuminuria in lacunar infarction patients, as well as the risk factors of microalbuminuria in patients with lacunar infarction. Results: The prevalence of microalbuminuria in patients with lacunar infarction was 32.8%, which was significantly higher than that in controls (9.8%, P＜0.001). Multiple linear regression analysis indicated that age, alcohol abuse, fasting blood glucose, systolic blood pressure, and triglyceride were positively associated with albumin/creatinine ratio levels. Multiple logistic regression analysis indicated that age (odds ratio [OR] = 1.067, 95% confidence interval [CI] = 1.029 to 1.105), alcohol abuse (OR = 3.001, 95% CI = 1.668 to 5.398), fasting blood glucose (OR = 2.014, 95% CI = 1.794 to 2.260), and systolic blood pressure (OR = 1.033, 95% CI = 1.010 to 1.056) were the independent risk factors for microalbuminuria in acute lacunar infarction patients, with high sensitivity, specificity, positive predictive value, and negative predictive value. Receiver operating characteristic curve analysis showed that the area under the curve for age, systolic blood pressure, and fasting blood glucose were 0.618 (cutoff value, 63.5 years; sensitivity, 54.8%; and specificity, 62.9%), 0.736 (cutoff level, 149.5 mmHg; sensitivity, 78.3%; and specificity, 61.2%) and 0.893 (cutoff value, 7 mmol/L; sensitivity, 92.2%; and specificity, 86%), respectively. Conclusion: Lacunar infarction was associated with higher microalbuminuria prevalence. Age, alcohol abuse, fasting blood glucose, and systolic blood pressure were individually significant and correlated factors of microalbuminuria in patients with lacunar infarction. More attention should be provided to this group of patients.

Microalbuminuria in patients with acute ischemic stroke.

OBJECTIVE: Microalbuminuria could be detected in patients with acute stroke. However, the association between microalbuminuria and the severity of ischemic stroke has not been systematically investigated. This study aimed to systematically explore the prevalence of microalbuminuria in ischemic stroke patients, and the association of microalbuminuria with the severity of ischemic stroke, as well as the prognostic value of microalbuminuria in cerebral infarction patients. METHODS: 160 ischemic stroke patients and 54 controls were enrolled and clinical characteristics were recorded. Severity of stroke was assessed by NIHSS score at admission, and outcome was measured using mRS score. The concentration of urinary microalbumin was collected for each participant. Multiple linear regression analysis was performed to evaluate the relationship between microalbuminuria and the severity of ischemic stroke, and logistic regression analysis was employed to identify the prognostic value of microalbuminuria in ischemic stroke patients. RESULTS: The incidence of microalbuminuria in ischemic stroke patients was 36.88%. The concentration of urinary microalbumin increased with the increasing of cerebral infarction size, and was independently correlated with NIHSS score at admission and mRS score at 3 months after onset. In multivariate logistic regression analyses, microalbuminuria was one of the independent risk factors for poor prognosis of cerebral infarction patients. CONCLUSIONS: MAU was found in approximately one-third of patients with acute ischemic stroke. It was correlated with the severity of cerebral infarction at admission and clinical outcomes at 3 months after onset and could be used as a potential indicator of poor prognosis in ischemic stroke patients.

PI3Kß inhibitor AZD6482 exerts antiproliferative activity and induces apoptosis in human glioblastoma cells.

Glioblastoma is the most common type of primary brain tumour in adults, and its pathogenesis is particularly complicated. Among the many possible mechanisms underlying its pathogenesis, hyperactivation of the PI3K/Akt pathway is essential to the occurrence and development of glioma through the loss of PTEN or somatic activating mutations in PIK3CA. In the present study, we investigated the effect of the PI3Kß inhibitor AZD6482 on glioma cells. The CCK-8 assay showed dose-dependent cytotoxicity in glioma cell lines treated with AZD6482. Additionally, AZD6482 treatment was found to significantly induce apoptosis and cell cycle arrest as detected using flow cytometry. Moreover, as shown using western blot analysis, the levels of p-AKT, p-GSK-3ß, Bcl-2, and cyclin D1 were decreased after AZD6482 treatment. In addition, we found that AZD6482 inhibited the migration and invasion of glioma cells as detected by wound healing and Transwell invasion assays. Taken together, our findings indicate that AZD6482 exerts an antitumour effect by inhibiting proliferation and inducing apoptosis in human glioma cells. AZD6482 may be applied as an adjuvant therapy to improve the therapeutic efficacy of glioblastoma treatment.

Identification of Core Biomarkers Associated with Outcome in Glioma: Evidence from Bioinformatics Analysis.

Glioma is the most common neoplasm of the central nervous system (CNS); the progression and outcomes of which are affected by a complicated network of genes and pathways. We chose a gene expression profile of GSE66354 from GEO database to search core biomarkers during the occurrence and development of glioma. A total of 149 samples, involving 136 glioma and 13 normal brain tissues, were enrolled in this article. 1980 differentially expressed genes (DEGs) including 697 upregulated genes and 1283 downregulated genes between glioma patients and healthy individuals were selected using GeoDiver and GEO2R tool. Then, gene ontology (GO) analysis as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Moreover, Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING) and Molecular Complex Detection (MCODE) plug-in was employed to imagine protein-protein interaction (PPI) of these DEGs. The upregulated genes were enriched in cell cycle, ECM-receptor interaction, and p53 signaling pathway, while the downregulated genes were enriched in retrograde endocannabinoid signaling, glutamatergic synapse, morphine addiction, GABAergic synapse, and calcium signaling pathway. Subsequently, 4 typical modules were discovered by the PPI network utilizing MCODE software. Besides, 15 hub genes were chosen according to the degree of connectivity, including TP53, CDK1, CCNB1, and CCNB2, the Kaplan-Meier analysis of which was further identified. In conclusion, this bioinformatics analysis indicated that DEGs and core genes, such as TP53, might influence the development of glioma, especially in tumor proliferation, which were expected to be promising biomarkers for diagnosis and treatment of glioma.

RIP3 deficiency protects against traumatic brain injury (TBI) through suppressing oxidative stress, inflammation and apoptosis: Dependent on AMPK pathway.

Traumatic brain injury (TBI) is a leading cause of disability and mortality in young adults worldwide. The pathophysiology is not fully understood. Programmed necrosis (necroptosis) is a newly identified mechanism of cell death combining features of both apoptosis and necrosis. Receptor-interacting protein 3 (RIP3) plays an important role in programmed necrosis. However, the effect of RIP3-related pathway in TBI is little to be known. We attempted to explore the significance of RIP3 in regulating TBI in vivo. Significantly, TBI induced over-expression of RIP3 in the hippocampus of mice, as well as RIP1 and phosphorylated mixed lineage kinase domain-like protein (MLKL). Mice after TBI exhibited cognitive dysfunction and activation of glia cells, which were significantly attenuated by RIP3-knockout (KO). Moreover, inflammation and oxidative stress in hippocampus were markedly induced by TBI in wild type (WT) mice. Of note, the reduction of pro-inflammatory cytokines and oxidants was observed in RIP3-deficient mice, which was linked to the blockage of NLR pyrin domain containing 3 (NLRP3)/apoptosis-associated speck-like protein containing a CARD (ASC)/Caspase-1 and kelch-like ECH-associated protein 1 (Keap 1) pathways. Further, TBI induced hippocampus apoptosis, evidenced by the increase of cleaved Caspase-8/-3 and poly (ADP)-ribose polymerase (PARP) in WT mice, whereas being decreased by RIP3-knockout. In addition, RIP3 knockout led to phosphorylation of AMP-activated protein kinase α (AMPKα) in hippocampus of mice after TBI. And of note, the in vitro findings indicated that RIP3-ablation attenuated oxidative stress, inflammation and apoptosis in astrocytes, which was dependent on AMPKα activation. Together, suppressing RIP3 might be served as a therapeutic target against brain injury through inhibiting inflammation, oxidative stress and apoptosis.

N-Terminal Pro-Brain Natriuretic Peptide Concentrations After Hypertensive Intracerebral Hemorrhage: Relationship With Hematoma Size, Hyponatremia, and Intracranial Pressure.

INTRODUCTION:: The role of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with hypertensive intracerebral hemorrhage (HICH) is poorly understood. This study aimed to investigate the secretion pattern of NT-proBNP in patients with HICH and to assess its relationship with hematoma size, hyponatremia, and intracranial pressure (ICP). METHODS:: This prospective study enrolled 147 isolated patients with HICH. Blood samples were obtained from each patient, and values of serum NT-proBNP, hematoma size, blood sodium, and ICP were collected for each patient. RESULTS:: The peak-to-mean concentration of NT-proBNP was 666.8 ± 355.1 pg/mL observed on day 4. The NT-proBNP levels in patients with hematoma volume >30 mL were significantly higher than those in patients with hematoma volume <30 mL ( P < .05). In patients with severe HICH, the mean concentration of NT-proBNP was statistically higher than that in patients with mild-moderate HICH ( P < .05), and the mean level of NT-proBNP in hyponatremia group was significantly higher than that in normonatremic group ( P < .05). In addition, the linear regression analysis indicated that serum NT-proBNP concentrations were positively correlated with ICP ( r = .703, P < .05) but negatively with blood sodium levels only in patients with severe HICH ( r = -.704, P < .05). The serum NT-proBNP levels on day 4 after admission were positively correlated with hematoma size ( r = .702, P < .05). CONCLUSION:: The NT-proBNP concentrations were elevated progressively and markedly at least in the first 4 days after HICH and reached a peak level on the fourth day. The NT-proBNP levels on day 4 were positively correlated with hematoma size. There was a notable positive correlation between plasma NT-proBNP levels and ICP in patients with severe HICH. Furthermore, only in patients with severe HICH, the plasma NT-proBNP levels presented a significant correlation with hyponatremia, which did not occur in patients with mild-moderate HICH.

TGX-221 inhibits proliferation and induces apoptosis in human glioblastoma cells.

Glioblastoma is the most common type of primary brain tumor in adults, with high mortality and morbidity rates. More effective therapeutic strategies are imperative. Previous studies have shown that the known p110-ß-selective inhibitor TGX-221 blocks the activation of PKB/Akt in PTEN-deficient cells. We treated U87 and U251 glioblastoma cells with TGX-221 to determine the effect of TGX-221. We performed a Cell Counting Kit-8 (CCK-8) test, EDU staining and cell cycle distribution analysis and found that TGX-221 inhibited glioblastoma cell proliferation. Next, the effect of TGX-221 on cell apoptosis was investigated using flow cytometry. These results demonstrated that TGX-221 induced apoptosis in glioblastoma cells. Moreover, migration and invasion assays revealed that TGX-221 inhibited human glioblastoma cell migration and invasion. Collectively, our study revealed that TGX-221 could inhibit proliferation and induce apoptosis in glioblastoma cells.

The role of N-terminal pro-brain natriuretic peptide in evaluating the prognosis of patients with intracerebral hemorrhage.

A prognostic biomarker that can provide a good prediction of prognosis in patients with intracerebral hemorrhage (ICH) would be beneficial in guiding the initial management decisions in the setting of ICH. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a biomarker of prognosis in patients with cardiovascular disease and ischemic stroke. However, the prognostic role of NT-proBNP in patients with spontaneous ICH is still a controversial issue. This study aimed to determine the prognostic value of NT-proBNP in patients with spontaneous ICH. A total of 132 patients from 571 ICH cases in inpatient settings were enrolled in this study. Blood samples from each subject were obtained and analyzed for NT-proBNP on admission and on days 4 and 7. The first end point was functional outcome at discharge, which was dichotomized into favorable or unfavorable; the secondary end point was mortality within 6 months after ICH. Compared with the baseline levels on admission after ICH, the NT-proBNP levels increased markedly on day 4 (P < 0.05). Multivariate logistic regression analysis indicated that the NT-proBNP level on day 4, the ICH score, and the APACHE II score were independent prognostic factors of functional outcome and 6-month mortality in ICH patients. A cutoff NT-proBNP level of 999.85 pg/ml predicted an unfavorable functional outcome (with 66.1% sensitivity and 98.7% specificity) and 6-month mortality (with 93.8% sensitivity and 92.0% specificity) in ICH patients. Thus, the NT-proBNP level on day 4 was found to be a powerful prognostic predictor of functional outcome and 6-month mortality in ICH patients, which would be beneficial to guiding the initial management decisions in the setting of ICH.