Presenilin1 exerts antiproliferative effects by repressing the Wnt/ß-catenin pathway in glioblastoma.

BACKGROUND: Glioblastoma and Alzheimer's disease (AD) are the most common and devastating diseases in the central nervous system. The dysfunction of Presenilin1 is the main reason for AD pathogenesis. However, the molecular function of Presenilin1 and its relative mechanism in glioblastoma remain unclear. METHODS: Expression of presenilin1 in glioma was determined by IHC. CCK-8, colony formation, Flow cytometry, Edu staining were utilized to evaluate functions of presenilin1 on glioblastoma proliferation. The mechanism of above process was assessed by Western blotting and cell immunofluorescence. Mouse transplanting glioblastoma model and micro-MRI detection were used to verified presenilin1 function in vivo. RESULTS: In this study, we found that all grades of glioma maintained relatively low Presenilin1 expression and that the expression of Presenilin1 in high-grade glioma was significantly lower than that in low-grade glioma. Moreover, the Presenilin1 level had a positive correlation with glioma and glioblastoma patient prognosis. Next, we determined that Presenilin1 inhibited the growth and proliferation of glioblastoma cells by downregulating CDK6, C-myc and Cyclin D1 to arrest the cell cycle at the G1/S phase. Mechanistically, Presenilin1 promoted the direct phosphorylation of ß-catenin at the 45 site and indirect phosphorylation at the 33/37/41 site, then decreased the stabilized part of ß-catenin and hindered its translocation from the cytoplasm to the nucleus. Furthermore, we found that Presenilin1 downregulation clearly accelerated the growth of subcutaneous glioblastoma, and Presenilin1 overexpression significantly repressed the subcutaneous and intracranial transplantation of glioblastoma by hindering ß-catenin-dependent cell proliferation. CONCLUSION: Our data implicate the antiproliferative effect of Presenilin1 in glioblastoma by suppressing Wnt/ß-catenin signaling, which may provide a novel therapeutic agent for glioblastoma. Video Abstract.

Risk factors associated with the progression of extra-axial hematoma in the original frontotemporoparietal site after contralateral decompressive surgery in traumatic brain injury patients.

PURPOSE: To introduced our experience with progressive extra-axial hematoma (EAH) in the original frontotemporoparietal (FTP) site after contralateral decompressive surgery (CDS) in traumatic brain injury patients and discuss the risk factors associated with this dangerous situation. METHODS: This retrospective study was conducted on 941 patients with moderate or severe TBI treated in Daping Hospital, Army Medical University, Chongqing, China in a period over 5 years (2013-2017). Only patients with bilateral lesion, the contralateral side being the dominant lesion, and decompressive surgery on the contralateral side conducted firstly were included. Patients were exclude if (1) they underwent bilateral decompression or neurosurgery at the original location firstly; (2) although surgery was performed first on the contralateral side, surgery was done again at the contralateral side due to re-bleeding or complications; (3) patients younger than 18 years or older than 80 years; and (4) patients with other significant organ injury or severe disorder or those with abnormal coagulation profiles. Clinical and radiographic variables reviewed were demographic data, trauma mechanisms, neurological condition assessed by Glasgow coma scale (GCS) score at admission, pupil size and reactivity, use of mannitol, time interval from trauma to surgery, Rotterdam CT classification, type and volume of EAH, presence of a skull fracture overlying the EAH, status of basal cistern, size of midline shift, associated brain lesions and types, etc. Patients were followed-up for at least 6 months and the outcome was graded by Glasgow outcome scale (GOS) score as favorable (scores of 4-5) and unfavorable (scores of 1-3). Student's t-test was adopted for quantitative variables while Pearson Chi-squared test or Fisher's exact test for categorical variables. Multivariate logistic regression analysis was also applied to estimate the significance of risk factors. RESULTS: Initially 186 patients (19.8%) with original impact locations at the FTP site and underwent surgery were selected. Among them, 66 met the inclusion and exclusion criteria. But only 50 patients were included because the data of the other 16 patients were incomplete. Progressive EAH developed at the original FTP site in 11 patients after the treatment of, with an incidence of 22%. Therefore the other 39 patients were classified as the control group. Multivariate logistic regression analysis showed that both the volume of the original hematoma and the absence of an apparent midline shift were significant predictors of hematoma progression after decompressive surgery. Patients with fracture at the original impact site had a higher incidence of progressive EAH after CDS, however this factor was not an important predictor in the multivariate model. We also found that patients with progressive EAH had a similar favorable outcome with control group. CONCLUSION: Progressive EAH is correlated with several variables, such as hematoma volumes ≥10 mL at the original impact location and the absence of an apparent midline shift (<5 mm). Although progressive EAH is devastating, timely diagnosis with computed tomography scans and immediate evacuation of the progressive hematoma can yield a favorable result.

Apoptosis induction effect of Apocynum venetum polyphenol on human U87 glioma cells via NF-κB pathway.

Aim: Apocynum venetum polyphenol (AVP) was used in in vitro glioma cells culture to prove the growth inhibitory effect of AVP on human U87 glioma cells via NF-κB pathway. Materials & methods: The MTT assay, DAPI morphology, quantitative PCR and western blot experiments were used for determination in vitro. Results & conclusion: AVP can also induce U87 cancer cells apoptosis illustrated by DAPI morphology. AVP could enhance the mRNA and protein expression of IκB-α, TNF-α, TRAIL, caspase-3 and caspase-9 in U87 cancer cells and reduce those of NF-κBp65, cIAP-1, cIAP-2, TGF-ß2, CyclinD1, VEGF and IL-8. After ammonium pyrrolidine dithiocarbamate (PDTC) treatment, the NF-κBp65 expression was reduced in U87 cells, and AVP could raise these effects. The results of HPLC indicate that AVP mainly contains six constituents. The growth inhibitory effects of AVP on U87 glioma cells are predominantly from these natural active constituents.

Effects of hypothalamus destruction on the level of plasma corticosterone after blast injury and its relation to interleukin-6 in rats.

Hypothalamus-pituitary-adrenal (HPA) axis is involved in the modulation of the innate immune response. The purpose of this study was to evaluate the dynamic relationship between plasma corticosterone and interleukin-6 in the hypothalamus-destroyed rats after blast injury. A total of 105 Sprague-Dawley rats were divided randomly into normal control (normal), sham operated (sham), blast injury plus sham operated (blast injury) and blast injury plus hypothalamus destruction groups. Symmetric electrolytic bilateral destruction of the hypothalamus was performed for the deeply anesthetic rats under sterile conditions. Seven days after the destruction of the hypothalamus, the animals were succumbed to moderate blast injury using a BST-I bioimpact machine. Plasma corticosterone and IL-6 levels were determined by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. After blast injury, the corticosterone level in the hypothalamus-destroyed rats was significantly lower than that in the rats without destruction of hypothalamus at 3h (P<0.01) or from 5 to 8h (P<0.05). Reduction of corticosterone may be intrinsically correlated with the severe tissue injury and increased mortality (4/15 vs. 0/15, P<0.05). Circulating IL-6 level was markedly elevated in response to blast injury and hypothalamus destruction further increased IL-6 secretion (P<0.05). We concluded that elevation of pro-inflammatory IL-6 secretion might compensate the impaired HPA axis function after the trauma occurred in the hypothalamus-destroyed rats. These results also suggested that release of hypothalamus hormones is necessary to maintain certain magnitude of innate immunity after trauma.

Retrospective study on the endovascular embolization for traumatic carotid cavernous fistula.

OBJECTIVE: To retrospectively analyze 95 cases of traumatic carotid cavernous fistula treated by endovascular embolization. METHODS: From January 1994 to December 2008, 95 patients with traumatic carotid cavernous fistula were treated in our hospital. All patients received selective cerebral angiography through femoral artery catheterization. Accordingly, 89 cases were treated by detachable balloon embolization, 5 by platinum microcoils and 1 by covered-stent, respectively. RESULTS: In the study, 61 cases achieved successful balloon embolization at the first time. Fifty-six cases had multiple balloons due to the big fistula. Nine cases received balloon embolization twice. But among the 5 patients treated with platinum microcoils, one developed slight brainstem ischemia. After operation the patient had hemiparesis and swallow difficulty, but gradually recovered 3 months later. No neurological deficits were observed in other cases. All the cases recovered. Eighty-five cases were followed up for 1-15 years and no recurrence was found. CONCLUSIONS: The endovascular embolization for traumatic carotid cavernous fistula is minimally invasive, safe, effective and reliable. The detachable balloon embolization is the first choice in the treatment of TCCF.

[Effect of topiramate and carbamazepine on bone metabolism in children with epilepsy].

OBJECTIVE: To assess bone health in epileptic children who have been treated with topiramate (TPM) or carbamazepine (CBZ). METHODS: Sixty-three epileptic children who received TPM or CBZ treatment and 36 eileptic children who did not receive any drug treatment (control group) were enrolled. Bone mineral density (BMD) at lumbar vertebrae (L1-L4) and radius-ulna was evaluated by the dual-energy X-ray absorptiometry method. Biochemical indices of bone metabolism, including serum calcium, phosphorus and alkaline phosphatase contents were measured. RESULTS: The serum calcium content was higher in the TPM group (2.41+/-0.17 mmol/L), but it was lower in the CBZ group (2.15+/-0.26 mmol/L) than that (2.26+/-0.11 mmol/L) in the control group (p<0.05). The serum phosphorus content in both the TPM (1.55+/-0.17 mmol/L) and the CBZ groups (1.52+/-0.26 mmol/L) was significantly lower than that in the control group (1.70+/-0.30 mmol/L) (p<0.05). There were no significant differences in the serum content of alkaline phosphatase between three groups. BMD was significantly reduced in both the TPM and the CBZ groups when compared to the control group (p<0.05). CONCLUSIONS: TPM and CBZ may result in alterations in serum contents of calcium, phosphorus and alkaline phosphatase as well as BMD reduction.

LEF1-AS1 is implicated in the malignant development of glioblastoma via sponging miR-543 to upregulate EN2.

Glioblastoma (GBM) has been regarded as the most aggressive disease in the nervous system. Accumulating literatures have illustrated the crucial role of competing endogenous RNAs (ceRNAs) network in the pathogenesis and progression of various tumors. The promoting effect of LEF1-AS1 on GBM development has been previously identified. This study attempted to explore the underlying mechanism of LEF1-AS1 in GBM. Data of clinical GBM patients was downloaded from TCGA and GEO databases. The proliferative ability, clonogenic vitality, invasive, and migratory capabilities of GBM cells were measured using Cell counting kit-8 (CCK-8), colony formation and transwell assays. Luciferase reporter gene analysis was performed to verify the correlations between LEF1-AS1/EN2 and miR-543. qRT-PCR and western blotting were implemented to evaluate the mRNA and protein levels, respectively. Our results consolidated that LEF1-AS1 was highly expressed in GBM tissue specimens and its up-regulation induced unfavorable prognosis. The loss/gain-of-function analyses verified that LEF1-AS1 promoted the GBM cell malignant behaviors. Mechanically, LEF1-AS1 acted as a ceRNA for miR-543 and positively regulated engrailed homeobox 2 (EN2) expression. Down-regulation of miR-543 elevated GBM cell malignant behaviors, which was reversed by LEF1-AS1 knockdown. Meanwhile, the LEF1-AS1 inhibition could arrest the promoting effect of high-regulated EN2 on GBM cell aggressiveness and vice versa. In conclusion, our findings identified LEF1-AS1 as a ceRNA for miR-543 and showed that EN2 was positively regulated by LEF1-AS1. The LEF1-AS1/miR-543/EN2, as a novel ceRNA network, was implicated in the progression of GBM, which provided a novel insight for GBM treatment.

A persistent primitive hypoglossal artery-posterior inferior cerebellar artery convergence aneurysm treated by stent-assisted coil embolization: A case report.

RATIONALE: Persistent primitive hypoglossal artery (PPHA) is often associated with intracranial anomalies such as aneurysms. Surgical treatment of aneurysms on the PPHA is challenging due to that the posterior circulation depends solely on PPHA. PATIENT CONCERNS: A case of an 83-year-old woman with a large aneurysm on PPHA presented with vertigo was reported. DIAGNOSIS: Three-dimensional angiogram revealed a wide-neck aneurysm on the PPHA. INTERVENTIONS: The aneurysm was successfully treated using a novel low-profile visualized intraluminal support stent-assisted coiling technique. OUTCOMES: No complications occurred during the procedure. The final angiogram confirmed the patency of the posterior inferior cerebellar artery and the parent artery and its distal branches. LESSONS: Our case suggests that stent-assisted coil embolization is safe and effective for the treatment of aneurysms on the PPHA.

Sortilin promotes glioblastoma invasion and mesenchymal transition through GSK-3ß/ß-catenin/twist pathway.

High aggressiveness is a hallmark of glioblastoma and predicts poor prognosis of patients with glioblastoma. The expression level of sortilin has been preliminarily reported to be elevated in high-grade glioma; however, the potential significance of sortilin in glioblastoma progression has not been elucidated. In this study, we investigated the oncogenic effect of sortilin in glioblastoma. Increased levels of sortilin were noted in the mesenchymal subtype of glioblastoma and highly aggressive subtypes of glioblastoma tissues and cell lines. In addition, high levels of sortilin predicted poor prognoses in patients with glioblastoma. Sortilin knockdown or inhibition with AF38469 (an orally bioavailable inhibitor of sortilin) significantly suppressed migration and invasion by inhibiting EMT-like mesenchymal transition in glioblastoma cells. Furthermore, we proved that sortilin promoted cell invasion mainly via Glycogen synthase kinase 3 beta (GSK-3ß)/ß-catenin/Twist-induced EMT-like mesenchymal transition in glioblastoma. Taken together, our results demonstrate a critical role of sortilin in glioblastoma invasion and EMT-like mesenchymal transition, indicating that sortilin contributes to glioblastoma progression. These data also highlight the dramatic antitumor effects of AF38469 in glioblastoma, suggesting that AF38469 is a potentially powerful antitumor agent for sortilin-overexpressing human glioblastoma.

Prognostic value of apolipoprotein E epsilon4 allele in patients with traumatic brain injury: a meta-analysis and meta-regression.

AIMS: Current scientific evidence suggests that the apolipoprotein E epsilon4 (APOE4) allele may be associated with a good prognosis for patients with traumatic brain injury (TBI); however, many existing studies have yielded inconclusive results. This meta-analysis aims to obtain a more precise estimation of the association between APOE4 allele and prognosis of TBI patients. METHODS: A literature search of PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CNKI and CBM databases was conducted for articles published before July 1st, 2013. Crude odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: Thirteen cohort studies were included with a total of 662 TBI patients with APOE4 (+) and 1614 TBI patients with APOE4 (-). The meta-analysis results revealed that the APOE4 allele was associated with a poor prognosis in TBI patients (OR=0.68, 95% CI: 0.48-0.96, p=0.027). Subgroup analysis by ethnicity indicated that TBI patients with APOE4 (+) had a worse prognosis than those with APOE4 (-) in Asian populations (OR=0.46, 95% CI: 0.21-0.99, p=0.046), but not in Caucasian populations (OR=0.75, 95% CI: 0.53-1.08, p=0.120). A further subgroup analysis by TBI grade showed that the APOE4 allele was associated with poor prognosis in severe TBI patients (OR=0.43, 95% CI: 0.21-0.87, p=0.020). However, there was no evidence for any association between the APOE4 allele and poor prognosis in patients with other grades of TBI (all p>0.05). CONCLUSION: The current meta-analysis indicates that the APOE4 allele may be associated with a poor prognosis in severe TBI patients and in Asian populations. The APOE4 allele may be used as a biomarker in predicting the prognosis of TBI patients.

High-dose glucocorticoids induce decreases calcium in hypothalamus neurons via plasma membrane Ca(2+) pumps.

In our previous studies, we occasionally found that high-dose glucocorticoids (GC) induced decrease in [Ca(2+)](i) in hypothalamus neurons. In previous articles, modulation of Ca(2+) channels by GC has been shown to contribute to the elementary regulation of several neuronal functions. However, little is known about the regulation of the Ca efflux pathways that counterbalance the Ca(2+) influx in neurons caused by high-dose GC. In this study, we demonstrate that a high-dose of GC (10 M dexamethasone) caused a 20% decrease in [Ca(2+)](i) within 2 s in cultured hypothalamic neurons; furthermore, we show that an antagonist of the GC receptor blocks this action. To ascertain the temporal sequence of relevant calcium transport mechanisms we selectively blocked the main calcium transporters, including sodium/calcium exchanger (NCX), plasma membrane calcium pumps (PMCA), and P-type Ca(2+)-ATPases of the sarcoplasmic reticulum (SERCA). The GC-induced [Ca(2+)](i) decrease disappeared completely when PMCA was blocked, but not when NCX and SERCA were blocked. These results suggest that high-dose GC (10(-6) M) rapidly decreases [Ca(2+)](i) by activating PMCA but not NCX or SERCA.