The markers and risk stratification model of intracranial aneurysm instability in a large Chinese cohort.

Intracranial aneurysm is the leading cause of nontraumatic subarachnoid hemorrhage. Evaluating the unstable (rupture and growth) risk of aneurysms is helpful to guild decision-making for unruptured intracranial aneurysms (UIA). This study aimed to develop a model for risk stratification of UIA instability. The UIA patients from two prospective, longitudinal multicenter Chinese cohorts recruited from January 2017 to January 2022 were set as the derivation cohort and validation cohort. The primary endpoint was UIA instability, comprising aneurysm rupture, growth, or morphology change, during a 2-year follow-up. Intracranial aneurysm samples and corresponding serums from 20 patients were also collected. Metabolomics and cytokine profiling analysis were performed on the derivation cohort (758 single-UIA patients harboring 676 stable UIAs and 82 unstable UIAs). Oleic acid (OA), arachidonic acid (AA), interleukin 1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were significantly dysregulated between stable and unstable UIAs. OA and AA exhibited the same dysregulated trends in serums and aneurysm tissues. The feature selection process demonstrated size ratio, irregular shape, OA, AA, IL-1ß, and TNF-α as features of UIA instability. A machine-learning stratification model (instability classifier) was constructed based on radiological features and biomarkers, with high accuracy to evaluate UIA instability risk (area under curve (AUC), 0.94). Within the validation cohort (492 single-UIA patients harboring 414 stable UIAs and 78 unstable UIAs), the instability classifier performed well to evaluate the risk of UIA instability (AUC, 0.89). Supplementation of OA and pharmacological inhibition of IL-1ß and TNF-α could prevent intracranial aneurysms from rupturing in rat models. This study revealed the markers of UIA instability and provided a risk stratification model, which may guide treatment decision-making for UIAs.

Endoscopic transcranial transdiaphragmatic approach in a single-stage surgery for giant pituitary adenomas.

Background: The treatment for giant pituitary adenomas (GPAs, maximal diameter >4 cm) remains challenging, with remarkable mortality and morbidity, and there is no consensus on the optimal surgical approach. Gross total resection (GTR) for GPAs is difficult to achieve through a single transsphenoidal or transcranial approach. Any residual tumor is at risk for postoperative apoplexy. In this study, we propose a new surgical technique for resecting the GPAs in a sing-stage transcranial surgery. Methods: A retrospective review of 4 patients with complicated GPAs, who had been treated via an endoscopic transcranial transdiaphragmatic approach in a single-stage surgery after routine transcranial resection, was performed. The following data was analyzed: clinical characteristics, preoperative imaging studies, resection rate, perioperative morbidity and mortality, as well as postoperative outcomes. Results: All patients had nonfunctioning GPAs and preoperative visual disturbances. In three patients, GTR was achieved, and in one patient, near-total resection (90%-100% of the tumor) was achieved. Three patients attained improved postoperative visual function, while one patient's vision remained unchanged. One patient suffered a deficiency in adrenocorticotropic hormone along with thyroid-stimulating hormone, and one patient developed diabetes insipidus. Notably, none of the patients suffered cerebrospinal fluid leakage. However, one patient developed an epidural hematoma and underwent decompressive craniectomy. Conclusions: The endoscopic transcranial transdiaphragmatic approach in a single-stage surgery can be efficiently and safely performed for maximal excision of GPAs with extensive suprasellar extension. Furthermore, relative to the conventional combined or staged approaches, this innovative surgical strategy provides neurosurgeons with a clear operative field with reduced invasiveness.

A Meaningful Strategy for Glioma Diagnosis via Independent Determination of hsa_circ_0004214.

Glioma is one of the most common primary tumors in the central nervous system. Circular RNAs (circRNAs) may serve as novel biomarkers of various cancers. The purpose of this study is to reveal the diagnostic value of hsa_circ_0004214 for glioma and to predict its molecular interaction network. The expression of hsa_circ_0004214 was evaluated by RT-qPCR. The vector and siRNAs changed the expression of hsa_circ_0004214 to judge its influence on the migration degree of glioma cells. hsa_circ_0004214 can be stably expressed at a high level in high-grade glioma tissue (WHO III/IV). The area under the ROC curve of hsa_circ_0000745 in glioma tissue was 0.88, suggesting good diagnostic value. While used to distinguish high-grade glioma, AUC value can be increased to 0.931. The multi-factor correlation analysis found that the expression of hsa_circ_0004214 was correlated with GFAP (+) and Ki67 (+) in immunohistochemistry. In addition, the migration capacity of U87 was enhanced by overexpression of hsa_circ_0004214. Through miRNA microarray analysis and database screening, we finally identified 4 miRNAs and 9 RBPs that were most likely to interact with hsa_circ_0004214 and regulate the biological functions of glioma. Hsa_circ_0004 214 plays an important role in glioma, its expression level is a promising diagnostic marker for this malignancy.

Transient receptor potential ion channels and cerebral stroke.

METHODS: The databases Pubmed, and the National Library of Medicine were searched for literature. All papers on celebral stroke and transient receptor potential ion channels were considered. RESULTS: Stroke is the second leading cause of death and disability, with an increasing incidence in developing countries. About 75 per cent of strokes are caused by occlusion of cerebral arteries, and substantial advances have been made in elucidating mechanisms how stroke affects the brain. Transient receptor potential (TRP) ion channels are calcium-permeable channels highly expressed in brain that drives Ca2+ entry into multiple cellular compartments. TRPC1/3/4/6, TRPV1/2/4, and TRPM2/4/7 channels have been implicated in stroke pathophysiology. CONCLUSIONS: Although the precise mechanism of transient receptor potential ion channels in cerebral stroke is still unclear, it has the potential to be a therapeutic target for patients with stroke if developed appropriately. Hence, more research is needed to prove its efficacy in this context.

Brain structural alterations detected by an automatic quantified tool as an indicator for MCI diagnosing in type 2 diabetes mellitus patients: A magnetic resonance imaging study.

Background and objectives: Type 2 diabetes mellitus (T2DM) is an important risk factors for mild cognitive impairment (MCI). Structural magnetic resonance imaging (sMRI) is an effective and widely used method to investigate brain pathomorphological injury in neural diseases. In present study, we aimed to determine the brain regional alterations that correlated to the incidence of MCI in T2DM patients. Materials and methods: Eighteen T2DM patients with and without MCI (DMCI/T2DM) respectively, and eighteen age/gender-matched healthy controls (HC) were recruited. Brain MRI imagines of all the individuals were subjected to automatic quantified brain sub-structure volume segmentation and measurement by Dr. brain ™ software. The relative volume of total gray matter (TGM), total white matter (TWM), and 68 pairs (left and right) of brain sub-structures were compared between the three groups. Cognitive function correlation analysis and receiver operating characteristic (ROC) curve analysis were conducted in the MCI-related brain regions in T2DM patients, and we utilized a machine learning method to classify the three group of subjects. Results: 10 and 27 brain sub-structures with significant relative volumetric alterations were observed in T2DM patients without MCI and T2DM patients with MCI, respectively (p < 0.05). Compared with T2DM patients without MCI, eight critical regions include right anterior orbital gyrus, right calcarine and cerebrum, left cuneus, left entorhinal area, left frontal operculum, right medial orbital gyrus, right occipital pole, left temporal pole had significant lower volumetric ratio in T2DM patients with MCI (p < 0.05). Among them, the decrease of volumetric ratio in several regions had a positive correlation with Montreal Cognitive Assessment (MoCA) scores and Mini-Mental State Examination (MMSE) scores. The classification results conducted based on these regions as features by random forest algorithm yielded good accuracies of T2DM/HC 69.4%, DMCI/HC 72.2% and T2DM/DMCI 69.4%. Conclusions: Certain brain regional structural lesions occurred in patients with T2DM, and this condition was more serious in T2DM patients combined with MCI. A systematic way of segmenting and measuring the whole brain has a potential clinical value for predicting the presence of MCI for T2DM patients.

Human Cerebral Organoid Implantation Alleviated the Neurological Deficits of Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) causes a high rate of mortality and disability, and its treatment is still limited. Loss of neurons in damaged area is hardly rescued by relative molecular therapies. Based on its disease characteristics, we transplanted human embryonic stem cell- (hESC-) derived cerebral organoids in the brain lesions of controlled cortical impact- (CCI-) modeled severe combined immunodeficient (SCID) mice. Grafted organoids survived and differentiated in CCI-induced lesion pools in mouse cortical tissue. Implanted cerebral organoids differentiated into various types of neuronal cells, extended long projections, and showed spontaneous action, as indicated by electromyographic activity in the grafts. Induced vascularization and reduced glial scar were also found after organoid implantation, suggesting grafting could improve local situation and promote neural repair. More importantly, the CCI mice's spatial learning and memory improved after organoid grafting. These findings suggest that cerebral organoid implanted in lesion sites differentiates into cortical neurons, forms long projections, and reverses deficits in spatial learning and memory, a potential therapeutic avenue for TBI.

TRPC5 mediates TMZ resistance in TMZ-resistant glioblastoma cells via NFATc3-P-gp pathway.

P-glycoprotein (P-gp) acts as a pump to transport cytotoxic drugs out of cells and is upregulated in cancer cells. Suppressing the expression of P-gp is an effective strategy to overcome multidrug resistance in cancer chemotherapy. Temozolomide (TMZ) is the recommended drug for the standard treatment of patients with glioblastoma, but its clinical application is restricted due to drug resistance. Transient receptor potential channel-5 (TRPC5), a Ca2+-permeable channel, has been attributed to a different drug resistance mechanism except DNA repair system; therefore, we aimed to elucidate the mechanism regarding the role of TRPC5 in TMZ resistance. TRPC5 and P-glycoprotein (P-gp) are upregulated in TMZ-resistant glioblastoma cell lines. The downregulation of TRPC5 inhibited P-gp expression and led to a significant reversal of TMZ resistance in TMZ-resistant cell lines. TRPC5-siRNA restricted the growth of tumour xenografts in an athymic nude mouse model of TMZ-resistant cells. In specimens from patients with recurrent glioblastoma, TRPC5 was found to be highly expressed, accompanied by the upregulation of P-gp expression. The nuclear factor of activated T cell isoform c3 (NFATc3), which acts as a transcriptional factor, bridges TRPC5 activity to P-gp induction. In conclusion, these results demonstrate the functional role of the TRPC5-NFATc3-P-gp signalling pathway in TMZ resistance in glioblastoma cells.

CircFOXO3 promotes glioblastoma progression by acting as a competing endogenous RNA for NFAT5.

BACKGROUND: Circular RNAs (circRNAs), a newly discovered type of endogenous noncoding RNA, have been proposed to mediate the progression of diverse types of tumors. Systematic studies of circRNAs have just begun, and the physiological roles of circRNAs remain largely unknown. Here, we focused on elucidating the potential role and molecular mechanism of circular forkhead box O3 (circFOXO3) in glioblastoma (GBM) progression. METHODS: First, we analyzed circFOXO3 alterations in GBM and noncancerous tissues through real-time quantitative reverse transcription PCR (qRT-PCR). Next, we used loss- and gain-of-function approaches to evaluate the effect of circFOXO3 on GBM cell proliferation and invasion. Mechanistically, fluorescent in situ hybridization, RNA pull-down, dual luciferase reporter, and RNA immunoprecipitation assays were performed to confirm the interaction between circFOXO3 and miR-138-5p/miR-432-5p in GBM. An animal model was used to verify the in vitro experimental findings. RESULTS: CircFOXO3 expression was significantly higher in GBM tissues than in noncancerous tissues. GBM cell proliferation and invasion were reduced by circFOXO3 knockdown and enhanced by circFOXO3 overexpression. Further biochemical analysis showed that circFOXO3 exerted its pro-tumorigenic activity by acting as a competing endogenous RNA (ceRNA) to increase expression of nuclear factor of activated T cells 5 (NFAT5) via sponging both miR-138-5p and miR-432-5p. Notably, tumor inhibition by circFOXO3 downregulation could be reversed by miR-138-5p/miR-432-5p inhibitors in GBM cells. Moreover, GBM cells with lower circFOXO3 expression developed less aggressive tumors in vivo. CONCLUSIONS: Our data demonstrate that circFOXO3 can exert regulatory functions in GBM and that ceRNA-mediated microRNA sequestration might be a potential strategy for GBM therapy.

TRPC5­induced autophagy promotes the TMZ­resistance of glioma cells via the CAMMKß/AMPKα/mTOR pathway.

Temozolomide (TMZ) is the first choice chemotherapy agent against glioblastoma, but the TMZ chemotherapy resistance has restricted the clinical application. Although autophagy is considered an adaptive response for cell survival under the pressure of chemotherapy and associated with chemotherapy resistance, its initiator and the precise molecular mechanism remains unknown. In the present study, it was determined that TMZ increases the transient receptor potential cation channel subfamily C member 5 (TRPC5) protein expression and the basal autophagy level, and the upregulation of autophagy is mediated by TRPC5 in glioma cells. Additionally, knockdown of TRPC5 upregulated the chemotherapy sensitivity in vitro and in vivo. Furthermore, TRPC5­small interfering RNA and pharmacological inhibition indicated that the Ca2+/calmodulin dependent protein kinase ß (CaMKKß)/AMP­activated protein kinase α (AMPKα)/mechanistic target of rapamycin kinase (mTOR) pathway mediates cell survival autophagy during TMZ treatment. In addition, TMZ­resistant U87/TMZ cells retained a high basal autophagy level, while silence of TRPC5 expression or inhibition of autophagy reversed TMZ resistance. Thus, the present study revealed that TRPC5, an initiator of autophagy, upregulated TMZ resistance via the CaMKKß/AMPKα/mTOR pathway and this indicated a novel therapeutic site for drug resistance in glioma chemotherapy.

Suppression of the Smurf1 Expression Inhibits Tumor Progression in Gliomas.

Glioblastoma, one of the common malignant brain tumors, results in the highly death, but its underlying molecular mechanisms remain unclear. Smurf1, a member of Nedd4 family of HECT-type ligases, has been reported to contribute to tumorigenicity through several important biological pathways. Recently, it was also found to participate in modulate cellular processes, including morphogenesis, autophagy, growth, and cell migration. In this research, we reported the clinical guiding significance of the expression of Smurf1 in human glioma tissues and cell lines. Western blotting analysis discovered that the expression of Smurf1 was increased with WHO grade. Immunohistochemistry levels discovered that high expression of Smurf1 is closely consistent with poor prognosis of glioma. In addition, suppression of Smurf1 can reduce cell invasion and increase the E-cadherin expression, which is a marker of invasion. Our study firstly demonstrated that Smurf1 may promote glioma cell invasion and suppression of the Smurf1 may provide a novel treatment strategy for glioma.

MicroRNA-320 inhibits cell proliferation in glioma by targeting E2F1.

MicroRNAs (miRs) are a class of small non-coding RNAs that are involved in the regulation of gene expression, and in cancer development and progression. In the present study, miR-320 expression was found to be significantly reduced in glioma tissue in comparison with that in adjacent healthy tissues. In the present study, in vitro analyses demonstrated that overexpression of miR-320 inhibited cell proliferation and metastasis, while antisense miR-320 oligonucleotides enhanced cell proliferation and migration in U251 and SHG-44 glioma cell lines, compared with that in negative control cells. Protein expression of E2F1, a cell-cycle regulator, was negatively regulated by miR-320. Therefore, the present study provides novel insights into the association between miR-320 and glioma development.

MicroRNA-210 overexpression predicts poorer prognosis in glioma patients.

MicroRNA-210 (miR-210) levels are elevated in many tumor types, are frequently associated with hypoxia induction, and are correlated with poor prognosis in many solid tumors. miR-210 regulates cell growth, angiogenesis, invasion, and apoptosis of many human tumors. In this study, we investigated the clinical significance of miR-210 expression in common brain tumors, or human gliomas. Glioma samples and normal brain tissues were analyzed using real-time quantitative reverse transcriptase polymerase chain reaction to characterize the expression patterns of miR-210. The association of miR-210 expression with clinicopathological parameters and prognosis of glioma patients was statistically analyzed. Gliomas were further divided by grade: pilocytic astrocytoma (World Health Organization [WHO] grade I), diffuse astrocytomas (WHO grade II), anaplastic astrocytomas (WHO grade III), and glioblastoma (WHO grade IV). There was a significantly higher expression level of miR-210 amongst the glioma tissues as compared with normal brain tissues (p<0.001). Increased expression of miR-210 in glioma tissues was significantly associated with advanced pathological grade (p<0.001) and low Karnofsky Performance Score (p=0.014). In addition, increased miR-210 levels were also associated with poor progression-free survival (PFS) and overall survival (OS) rates when compared to the normal control (both p<0.001), as calculated by Kaplan-Meier survival and Cox regression analyses. Furthermore, subgroup analyses showed that miR-210 expression was significantly associated with poor PFS and OS of glioma patients with high pathological grades (III-IV: both p<0.001). miR-210 is highly expressed in human gliomas and confers a poor prognosis in glioma patients. These findings may bring the development of novel, tailored pharmacological therapies for glioma patients.

Overexpression of the Notch3 receptor in non-functioning pituitary tumours.

Human non-functioning pituitary adenomas cause hypopituitarism or the compression of adjacent structures. At present, there is no available medical treatment for these tumours. The Notch3 pathway has an important role in the progression of non-functioning pituitary adenomas. We found, using reverse transcriptase-polymerase chain reaction, that Notch3 mRNA was significantly upregulated in clinically non-functioning pituitary adenomas, and, using Western blotting, that Notch3 protein was expressed at a higher level in non-functioning pituitary adenomas than in normal human pituitary tissue. In addition, using immunohistochemistry, we observed that Notch3 is highly expressed in the cytoplasm of adenoma cells compared to normal pituitary cells. These results suggest that the overexpression of Notch3 mRNA and protein by non-functioning pituitary adenomas may facilitate the growth of these tumours. Our results provide the first comprehensive analysis of Notch3 mRNA and protein overexpression in non-functioning pituitary tumours. This study provides new insights into the pathogenesis of human non-functioning pituitary adenomas and implicates the Notch3 pathway as a molecular therapeutic target for their treatment.

Protection by pyruvate against glutamate neurotoxicity is mediated by astrocytes through a glutathione-dependent mechanism.

Pyruvate, an endogenous metabolite of glycolysis, is an anti-toxicity agent. Recent studies have suggested possible roles for pyruvate in protecting CNS neurons from excitotoxic and metabolic insults. Utilizing cultures derived from embryonic rat cortex, the studies presented in this paper indicate that an astroglia-mediated mechanism is involved in the neuroprotective effects of pyruvate against glutamate toxicity. Glutamate-induced toxicity could be reversed by pyruvate in a mixed culture of cortex cells. Importantly, in pure neuronal cultures from the same tissue, pyruvate failed to protect against glutamate toxicity. Addition of astroglia to the pure neuronal cultures restores the ability of pyruvate to protect neurons from glutamate-induced toxicity. Our results further suggest that pyruvate can induce glia to up-regulate the synthesis of glutathione (GSH), an antioxidant that protects cells from toxins such as free radicals. Taken together, our data suggest that astroglia in mixed cultures are essential for mediating the effects of pyruvate, revealing a novel mechanism by which pyruvate, an important intermediate of tricarboxylic acid cycle in the body, may act to protect neurons from damage during insults such as brain ischemia.