H2S inhibits LiCl/pilocarpine-induced seizures and promotes neuroprotection by regulating TRPV2 expression via the AC3/cAMP/PKA pathway.

It is widely acknowledged that epilepsy is a neurological disorder characterized by recurrent and atypical neuronal discharges, resulting in transient dysfunction within the brain. The protective role of hydrogen sulfide (H2S) in epilepsy has been elucidated by recent studies, but the underlying mechanisms remain poorly understood. To investigate this, the concentration of H2S was measured by spectrophotometry and a fluorescent probe in LiCl/Pilocarpine (LiCl/Pilo)-induced seizures in rats. The localization of proteins was examined using immunofluorescence. Electroencephalogram and behavioral tests were employed to evaluate the occurrence of seizures. Neuropathological changes in the hippocampus were examined by hematoxylin-eosin staining, Nissl staining, and transmission electron microscopy. Through proteomics and bioinformatics analysis, we identified the differential proteins in the hippocampus of rats following H2S intervention. Protein changes were detected through western blotting. The results showed that H2S treatment significantly alleviated seizures and minimized post-seizures neurological damage in rats. Proteomics analysis revealed adenylate cyclase 3 (AC3) as a protein potentially targeted by H2S. Moreover, the AC3 activator forskolin reversed the downregulation effect of H2S on the AC3/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/transient receptor potential vanilloid 2 (TRPV2) signaling pathway. In conclusion, H2S targets and downregulates the expression of AC3, thereby modulating the AC3/cAMP/PKA signaling pathway to regulate the expression of TRPV2 in LiCl/Pilo-induced seizures, ultimately leading to seizure inhibition and neuroprotection.

Association Between HTRA1, GAS6 and IFNGR2 Gene Polymorphisms and Stroke Susceptibility in the Chinese Han Population.

Background: Stroke has a high disability rate, and 30% of stroke cases have an unknown cause. Accurate diagnosis and treatment of stroke requires consideration of several rare heritable and non-heritable factors. Objective: This study aimed to evaluate the impacts of three genetic polymorphisms (rs369149111 in HTRA1, rs1803628 in GAS6 and rs9808753 in IFNGR2) on stroke susceptibility among the Chinese Han population. Methods: Three single nucleotide polymorphisms (SNPs) from 623 stroke cases and 572 healthy controls were genotyped by the Agena MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis to evaluate the associations of three SNPs with stroke susceptibility. Additionally, SNP-SNP interactions were analyzed by multifactor dimensionality reduction (MDR). Results: As demonstrated by the overall analysis, rs9808753 in IFNGR2 (allele: OR = 1.25, 95% CI = 1.06-1.47, p = 0.007; homozygous: OR = 1.59, 95% CI = 1.14-2.23, p = 0.007; dominant: OR = 1.31, 95% CI = 1.02-1.67, p = 0.032; recessive: OR = 1.42, 95% CI = 1.05-1.91, p = 0.022; additive: OR = 1.26, 95% CI = 1.07-1.48, p = 0.007) was associated with an increased susceptibility to stroke. Besides, stratification analysis suggested that rs9808753 was associated with an increased risk of stroke in subgroup aged ≤ 64 years, males and drinkers (p < 0.05). And rs1803628 in GAS6 was significantly associated with an increased susceptibility to stroke in non-smokers (p < 0.05). Conclusion: A risk-increasing effect of IFNGR2 rs980875 on stroke was detected in this study, which further broadens the understanding of the relationship between genetic polymorphisms and stroke susceptibility.

Association of CASZ1 genetic variants with stroke risk in the Chinese population.

BACKGROUND: Stroke is a heterogeneous disease with multiple etiologies, placing a heavy burden on the world. Our purpose was to clarify the association between CASZ1 genetic variants and stroke risk in the Chinese population. METHODS: The Agena MassARRAY platform effectively genotyped three single nucleotide polymorphisms of CASZ1 in recruited 591 stroke patients and 553 healthy controls. Logistic regression genetic models were employed to evaluate the relationship between CASZ1 polymorphisms and stroke risk through odds ratios (ORs) and 95% confidence intervals (CIs). Then, the interaction between CASZ1 variants was detected by multifactor dimensionality reduction (MDR). Moreover, functional enrichment analyses of the CASZ1 gene were performed by Metascape. RESULTS: In this study, CASZ1 rs4845941 and rs778228 were significantly associated with an increased risk of stroke. In particular, the gender-stratified analysis also showed that rs778228 of CASZ1 had an association with higher stroke risk in females. The relationship between stroke susceptibility and the interaction models of rs4845941, rs778228, and rs17035539 forecasted by MDR were analyzed to improve the ability to predict stroke risk. Furthermore, we found CASZ1 and related genes might facilitate the occurrence of stroke. CONCLUSIONS: This study demonstrated that CASZ1 genetic variants (rs4845941 and rs778228) contribute to the occurrence of stroke in the Chinese population, and therefore has important implications for treating and preventing stroke.

CYP1B1 Genetic Variants (rs10916 and rs2855658) Are Associated with Increased Risk of Ischemic Stroke in Chinese Han Population.

INTRODUCTION: Ischemic stroke (IS) is an extremely complex disease caused by the combined action of multiple environmental and genetic factors. CYP1B1 is a member of the cytochrome P450 protein family, and it is an important human drug-metabolizing enzymes. We aimed to explore the association between CYP1B1 genetic variants and IS risk in Chinese Han population. METHODS: We recruited 1,150 participants to conduct a "case-control" study. The assessment of association between candidate CYP1B1 genetic variants (rs2855658, rs10916, rs162560, rs2567206) and IS risk was performed by SNPStats online software. In addition, false-positive report probability analysis was used to detect whether the positive findings were just chance or noteworthy observations. Finally, the interaction of candidate SNPs in IS risk was evaluated by multifactor dimensionality reduction. RESULTS: The results showed that CYP1B1-rs2855658 was a risk factor for IS among ≥60-year-old (dominant: p = 0.034; overdominant: p = 0.026), smoking (heterozygote: p = 0.009; dominant: p = 0.004; overdominant: p = 0.012; log-additive: p = 0.003), and drinking participants (homozygous: p = 0.036; dominant: p = 0.019; recessive: p = 0.012; log-additive: p = 0.006). CYP1B1-rs10916 also was a risk factor for IS patients among ≥60-year-old (heterozygote: p = 0.047; overdominant: p = 0.048), smoking (dominant: p = 0.050; overdominant: p = 0.049), and drinking participants (dominant: p = 0.019; overdominant: p = 0.038; log-additive: p = 0.013). CONCLUSION: CYP1B1-rs10916 and CYP1B1-rs2855658 can increase the IS risk in Chinese Han population who are ≥60 years old, smoking, or drinking alcohol.

Tumor-treating fields (TTFields)-based cocktail therapy: a novel blueprint for glioblastoma treatment.

Glioblastoma is one of the most common malignant tumors in the central nervous system. Due to the high plasticity, heterogeneity and complexity of the tumor microenvironment, these tumors are resistant to almost all therapeutic strategies when they reach an advanced stage. Along with being a unique and effective way to kill cancer cells, tumor-treating fields (TTFields) has emerged as a breakthrough among glioblastoma therapies since the advent of temozolomide (TMZ), and the combination of these treatments has gradually been promoted and applied in the clinic. The combination of TTFields with other therapies is particularly suitable for this type of "cold" tumors and has attracted a large amount of attention from clinicians and researchers in the era of cancer cocktail therapy. Here, we introduced the current treatment regimen for glioblastoma, highlighting the unique advantages of TTFields in the treatment of glioblastoma. Then, we summarized current glioblastoma clinical trials that combine TTFields and other therapies. In addition, the main and potential mechanisms of TTFields were introduced to further understand the rationale for each combination therapy. Finally, we focused on the most advanced technologies applied in glioblastoma research and treatment and the prospect of their combination with TTFields. This review provides a unique overview of glioblastoma treatment.

Radiological model based on the standard magnetic resonance sequences for detecting methylguanine methyltransferase methylation in glioma using texture analysis.

This study aims to build a radiological model based on standard MR sequences for detecting methylguanine methyltransferase (MGMT) methylation in gliomas using texture analysis. A retrospective cross-sectional study was undertaken in a cohort of 53 glioma patients who underwent standard preoperative magnetic resonance (MR) imaging. Conventional visual radiographic features and clinical factors were compared between MGMT promoter methylated and unmethylated groups. Texture analysis extracted the top five most powerful texture features of MR images in each sequence quantitatively for detecting the MGMT promoter methylation status. The radiomic signature (Radscore) was generated by a linear combination of the five features and estimates in each sequence. The combined model based on each Radscore was established using multivariate logistic regression analysis. A receiver operating characteristic (ROC) curve, nomogram, calibration, and decision curve analysis (DCA) were used to evaluate the performance of the model. No significant differences were observed in any of the visual radiographic features or clinical factors between different MGMT methylated statuses. The top five most powerful features were selected from a total of 396 texture features of T1, contrast-enhanced T1, T2, and T2 FLAIR. Each sequence's Radscore can distinguish MGMT methylated status. A combined model based on Radscores showed differentiation between methylated MGMT and unmethylated MGMT both in the glioblastoma (GBM) dataset as well as the dataset for all other gliomas. The area under the ROC curve values for the combined model was 0.818, with 90.5% sensitivity and 72.7% specificity, in the GBM dataset, and 0.833, with 70.2% sensitivity and 90.6% specificity, in the overall gliomas dataset. Nomogram, calibration, and DCA also validated the performance of the combined model. The combined model based on texture features could be considered as a noninvasive imaging marker for detecting MGMT methylation status in glioma.

A Novel Glucose Metabolism-Related Gene Signature for Overall Survival Prediction in Patients with Glioblastoma.

INTRODUCTION: Glioblastoma (GBM) is one of the most frequent primary intracranial malignancies, with limited treatment options and poor overall survival rates. Alternated glucose metabolism is a key metabolic feature of tumour cells, including GBM cells. However, due to high cellular heterogeneity, accurately predicting the prognosis of GBM patients using a single biomarker is difficult. Therefore, identifying a novel glucose metabolism-related biomarker signature is important and may contribute to accurate prognosis prediction for GBM patients. METHODS: In this research, we performed gene set enrichment analysis and profiled four glucose metabolism-related gene sets containing 327 genes related to biological processes. Univariate and multivariate Cox regression analyses were specifically completed to identify genes to build a specific risk signature, and we identified ten mRNAs (B4GALT7, CHST12, G6PC2, GALE, IL13RA1, LDHB, SPAG4, STC1, TGFBI, and TPBG) within the Cox proportional hazards regression model for GBM. RESULTS: Depending on this glucose metabolism-related gene signature, we divided patients into high-risk (with poor outcomes) and low-risk (with satisfactory outcomes) subgroups. The results of the multivariate Cox regression analysis demonstrated that the prognostic potential of this ten-gene signature is independent of clinical variables. Furthermore, we used two other GBM databases (Chinese Glioma Genome Atlas (CGGA) and REMBRANDT) to validate this model. In the functional analysis results, the risk signature was associated with almost every step of cancer progression, such as adhesion, proliferation, angiogenesis, drug resistance, and even an immune-suppressed microenvironment. Moreover, we found that IL31RA expression was significantly different between the high-risk and low-risk subgroups. CONCLUSION: The 10 glucose metabolism-related gene risk signatures could serve as an independent prognostic factor for GBM patients and might be valuable for the clinical management of GBM patients. The differential gene IL31RA may be a potential treatment target in GBM.

Comparison of Radiomics Analyses Based on Different Magnetic Resonance Imaging Sequences in Grading and Molecular Genomic Typing of Glioma.

OBJECTIVE: To investigate the value of radiomics analyses based on different magnetic resonance (MR) sequences in the noninvasive evaluation of glioma characteristics for the differentiation of low-grade glioma versus high-grade glioma, isocitrate dehydrogenase (IDH)1 mutation versus IDH1 wild-type, and mutation status and 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (+) versus MGMT promoter methylation (-) glioma. METHODS: Fifty-nine patients with untreated glioma who underwent a standard 3T-MR tumor protocol were included in the study. A total of 396 radiomics features were extracted from the MR images, with the manually delineated tumor as the volume of interest. Clinical imaging diagnostic features (tumor location, necrosis/cyst change, crossing midline, and the degree of enhancement or peritumoral edema) were analyzed by univariate logistic regression to select independent clinical factors. Radiomics and combined clinical-radiomics models were established for grading and molecular genomic typing of glioma by multiple logistic regression and cross-validation. The performance of the models based on different sequences was evaluated by using receiver operating characteristic curves, nomograms, and decision curves. RESULTS: The radiomics model based on T1-CE performed better than models based on other sequences in predicting the tumor grade and the IDH1 status of the glioma. The radiomics model based on T2 performed better than models based on other sequences in predicting the MGMT methylation status of glioma. Only the T1 combined clinical-radiomics model showed improved prediction performance in predicting tumor grade and the IDH1 status. CONCLUSIONS: The results demonstrate that state-of-the-art radiomics analysis methods based on multiparametric MR image data and radiomics features can significantly contribute to pretreatment glioma grading and molecular subtype classification.

Organoid models of glioblastoma: advances, applications and challenges.

The high mortality and poor clinical prognosis of glioblastoma multiforme (GBM) are concerns for many GBM patients as well as clinicians and researchers. The lack of a preclinical model that can easily be established and accurately recapitulate tumour biology and the tumour microenvironment further complicates GBM research and its clinical translation. GBM organoids (GBOs) are promising high-fidelity models that can be applied to model the disease, develop drugs, establish a living biobank, mimic therapeutic responses and explore personalized therapy. However, GBO models face some challenges, including deficient immune responses, absent vascular system and controversial reliability. In recent years, considerable progress has been achieved in the improvement of brain tumour organoid models and research based on such models. In addition to the traditional cultivation method, these models can be cultivated via genetic engineering and co-culture of cerebral organoids and GBM. In this review, we summarize the applications of GBM organoids and related advances and provide our opinions on associated limitations and challenges.

MDM2 promotes the proliferation and inhibits the apoptosis of pituitary adenoma cells by directly interacting with p53.

INTRODUCTION: Pituitary adenomas constitute one of the most common intracranial tumours. The mouse double minute 2 homologue (MDM2) is considered as an important oncogene in many tumours, but it has been little studied in pituitary adenomas and the mechanism is not well understood. The purpose of this study was to investigate the function of MDM2 and its primary mechanism of action in pituitary adenoma cells. MATERIAL AND METHODS: The expression of MDM2 in pituitary adenoma cell lines and normal cells was determined by real-time polymerase chain reaction (RT-PCR). The proliferation and apoptosis of pituitary adenoma cells after inhibition of MDM2 expression were detected by MTS and flow cytometry, respectively. The protein expressions of MDM2 and p53 were detected by western blot. Co-IP was used to detect the direct binding between MDM2 and p53. RESULTS: The results of RT-PCR showed that MDM2 was significantly up-regulated in pituitary adenoma cell lines. Inhibition of MDM2 suppressed the proliferation and promoted apoptosis of pituitary adenoma cells. However, inhibiting the expression of MDM2 can promotethe protein expression of p53. The results of co-IP showed that MDM2 interacted with p53 by direct combination. Then, we inhibited the expressions of p53 and MDM2 simultaneously in the pituitary adenoma cells by co-transfecting siRNAs, and the results showed that, compared with the group that inhibited MDM2 alone, cell proliferation of the co-transfected group increased and apoptosis of the cotransfected group decreased, which was similar to the NC group. CONCLUSIONS: Taken together, these results suggest that MDM2 promoted the proliferation and inhibited the apoptosis of pituitary adenoma cells by directly interacting with p53 in pituitary adenoma cells. Therefore, MDM2-p53 may serve as a novel marker and therapeutic target for pituitary adenomas.

Expressions of plasma cystatin C, D-dimer and hypersensitive C-reactive protein in patients with intracranial progressive hemorrhagic injury after craniocerebral injury, and their clinical significance.

OBJECTIVE: To investigate the expressions of plasma cystatin C (Cys-C), D-dimer (D-D) and hypersensitive C-reactive protein (hs-CRP) in patients with intracranial progressive hemorrhagic injury (IPHI) after craniocerebral injury, and their clinical significance. METHODS: Forty-two IPHI patients and 20 healthy participants (control) were enrolled. The severity and outcome of IPHI were determined according to the Glasgow Coma Scale and Glasgow Outcome Scale, and the plasma Cys-C, hs-CRP and D-D levels were measured. RESULTS: The plasma Cys-C, D-D and hs-CRP levels in the IPHI group were significantly higher than those in the control group (p < 0.01). There were significant differences of plasma Cys-C, D-D and hs-CRP levels among different IPHI patients according to the Glasgow Coma Scale and according to the Glasgow Outcome Scale (all p < 0.05). In the IPHI patients, the plasma Cys-C, D-D and hs-CRP levels were positively correlated with each other (p < 0.001). CONCLUSION: The increase of plasma Cys-C, D-D and hs-CRP levels may be involved in IPHI after craniocerebral injury. The early detection of these indexes may help to understand the severity and outcome of IPHI.

Potential Neuroprotective Effect of miR-451 Against Cerebral Ischemia/Reperfusion Injury in Stroke Patients and a Mouse Model.

OBJECTIVE: Recently, microRNAs (miRs) have been reported to be novel regulators in ischemic stroke. In this study, we investigated the pattern of miR-451 expression along with its clinical application in human ischemic stroke and in an in vivo mouse model. METHODS: The level of miR-451 was evaluated in patients and mice after ischemic stroke. National Institute of Health Stroke Scale scores and brain infarct volume were analyzed to the correlation of miR-451 expression and clinical information. In addition, blood samples and brain tissues were collected from an established middle cerebral artery occlusion model consisting of 12 adult male mice at 24 hours after the middle cerebral artery occlusion. RESULTS: The results showed that miR-451 levels in the circulating blood of ischemic stroke patients were greatly decreased compared with the control. Further correlation analysis revealed a negative association between miR-451 and National Institute of Health Stroke Scale scores (r = -0.6104, P < 0.001) and infarct volume (r = -0.5442, P < 0.001). Moreover, miR-451 was down-regulated in response to middle cerebral artery occlusion in vivo, along with a negative correlation between miR-451 in brain and blood (r = 0.9240, P < 0.01). In addition, forced expression of miR-451 weakened ischemic brain infarction and apoptosis levels in focal ischemia-stroked mice, while downregulation of miR-451 significantly augmented ischemic injury. CONCLUSIONS: In conclusion, miR-451 displays the neuroprotective effect in ischemic stroke and might serve as a novel therapeutic target of ischemic stroke.

Expressions of plasma cystatin C, D-dimer and hypersensitive C-reactive protein in patients with intracranial progressive hemorrhagic injury after craniocerebral injury, and their clinical significance / Expressões da cistatina C plasmática, dímero D e proteína C reativa hipersensível em pacientes com lesão hemorrágica progressiva intracraniana após trauma crânio-encefálico e seus significados clínicos

ABSTRACT Objective To investigate the expressions of plasma cystatin C (Cys-C), D-dimer (D-D) and hypersensitive C-reactive protein (hs-CRP) in patients with intracranial progressive hemorrhagic injury (IPHI) after craniocerebral injury, and their clinical significance. Methods Forty-two IPHI patients and 20 healthy participants (control) were enrolled. The severity and outcome of IPHI were determined according to the Glasgow Coma Scale and Glasgow Outcome Scale, and the plasma Cys-C, hs-CRP and D-D levels were measured. Results The plasma Cys-C, D-D and hs-CRP levels in the IPHI group were significantly higher than those in the control group (p < 0.01). There were significant differences of plasma Cys-C, D-D and hs-CRP levels among different IPHI patients according to the Glasgow Coma Scale and according to the Glasgow Outcome Scale (all p < 0.05). In the IPHI patients, the plasma Cys-C, D-D and hs-CRP levels were positively correlated with each other (p < 0.001). Conclusion The increase of plasma Cys-C, D-D and hs-CRP levels may be involved in IPHI after craniocerebral injury. The early detection of these indexes may help to understand the severity and outcome of IPHI.

RESUMO Objetivo Investigar as expressões da cistatina C plasmática (Cys-C), dímero-D (D-D) e proteína C-reativa hipersensível (hs-CRP) em pacientes com lesão hemorrágica progressiva intracraniana (IPHI) após lesão craniocerebral e seus significados clínicos. Métodos Quarenta e dois pacientes com IPHI e 20 indivíduos saudáveis (controle) foram incluídos. A gravidade e o resultado do IPHI foram determinados de acordo com a Escala de Coma de Glasgow (GCS) e Escala de Resultados de Glasgow (GOS), e os níveis plasmáticos Cys-C, hs-CRP e D-D foram detectados. Resultados Os níveis plasmáticos de Cys-C, D-D e hs-CRP no grupo IPHI foram significativamente maiores do que no grupo controle (P <0,01). Houve diferença significativa entre os níveis plasmáticos de Cys-C, D-D e hs-CRP entre os diferentes pacientes com IPHI de acordo com a GCS e entre os diferentes pacientes com IPHI de acordo com o GOS, respectivamente (todos P <0,05). Em pacientes com IPHI, os níveis plasmáticos de Cys-C, D-D e hs-CRP foram positivamente correlacionados entre si (P <0,001). Conclusão O aumento dos níveis plasmáticos de Cys-C, D-D e hs-CRP pode estar envolvido no IPHI após trauma crânio-encefálico. A detecção precoce desses índices pode ajudar a entender a gravidade e o resultado do IPHI.

Increased risk of post-stroke epilepsy in Chinese patients with a TRPM6 polymorphism.

OBJECTIVES: We attempted to determine whether a functional polymorphism of TRPM6 (rs2274924) is associated with susceptibility to epilepsy following ischemic stroke, and to further explore the effect of this polymorphism on serum levels of Mg2+ in post-stroke patients. METHODS: We carried out a case-control study on 378 post-stroke epilepsy patients and 420 controls (stroke patients without secondary epilepsy). We used DNA sequencing to determine the genotypes of the TRPM6 rs2274924 polymorphism, and used the ion selective electrode method to measure serum levels of Mg2+. RESULTS: The distribution of the CC genotype and the frequency of the C allele were significantly higher in the post-stroke epilepsy patients than in the controls (P < 0.01). With regard to the post-stroke epilepsy patients, the serum levels of Mg2+ decreased significantly in the TRPM6 rs2274924 C allele carriers compared to the rs2274924 T allele carriers. CONCLUSION: The TRPM6 rs2274924 polymorphism may be associated with susceptibility to epilepsy following stroke, and the C allele may be associated with increased risk of post-stroke epilepsy. The TRPM6 rs2274924 polymorphism may also influence serum levels of Mg2+ in post-stroke epilepsy patients.

N-Acetyl Serotonin Protects Neural Progenitor Cells Against Oxidative Stress-Induced Apoptosis and Improves Neurogenesis in Adult Mouse Hippocampus Following Traumatic Brain Injury.

In this study, with primary mouse neural progenitor cells (NPCs), we investigated the neuroprotective effect of a tropomyosin-related kinase receptor B (TrkB) agonist, N-acetyl serotonin (NAS), against hydrogen peroxide (H2O2)-induced toxicity. We found that pre-incubation with NAS not only ameliorates H2O2-induced cell viability loss, lactate dehydrogenase (LDH) release, and proliferative and migratory capacity impairments, but counteracts H2O2-triggered production of nitric oxide (NO), reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-deoxyguanosine (8-OHdG) in a dose-dependent manner. Additionally, pre-treatment with NAS was able to attenuate H2O2-induced apoptosis in NPCs, evidenced by the decreased percentage of apoptotic cells and altered expression of apoptosis-related factors. Furthermore, in differentiated NPCs, NAS improves H2O2-induced reduction in neurite growth. Mechanistic studies revealed that the protective effects of NAS in NPCs may be mediated by the TrkB/PI3K/Akt/ cAMP response element binding protein (CREB) signaling cascades. In a mouse traumatic brain injury (TBI) model, we found that systemic administration of 30 mg/kg NAS could improve hippocampal neurogenesis, manifested by the increased number of SOX-2-positive cells and increased expression of phosphorylated CREB in the dentate gyrus (DG) area. Treatment with NAS also ameliorates cognitive impairments caused by TBI, as assessed by Y-maze and contextual and cued fear conditioning tests. Taken together, these results provide valuable insights into the neuroprotective and neuroregenerative effects of NAS, suggesting it may have therapeutic potential for the treatment of TBI.

δ-Opioid Receptor Activation Attenuates the Oligomer Formation Induced by Hypoxia and/or α-Synuclein Overexpression/Mutation Through Dual Signaling Pathways.

We have recently demonstrated that δ-opioid receptor (DOR) activation attenuates α-synuclein expression/aggregation induced by MPP(+) and/or severe hypoxia. Since α-synuclein plays a critical role in the pathogenesis of Parkinson's disease, DOR activation may trigger an antiparkinson pathway(s) against α-synuclein-induced injury. However, the underlying mechanism is unknown yet. In HEK293T and PC12 cells, we investigated the effects of DOR activation on the oligomer formation induced by α-synuclein overexpression and mutation in normoxic and hypoxic conditions and explored the potential signaling pathways for DOR protection. We found that (1) increased expression of both wild-type and A53T-mutant α-synuclein led to the formation of α-synuclein oligomers and cytotoxic injury; (2) DOR activation largely attenuated the formation of toxic α-synuclein oligomers induced by α-synuclein overexpression/mutation and/or hypoxia; (3) DOR activation attenuated α-synuclein-induced cytotoxicity through TORC1/SIK1/CREB, but not the phospho-CREB pathway, while DOR activation reduced hypoxic cell injury through the phospho-CREB mechanism; and (4) the interaction of α-synuclein and the DJ-1 was involved in the mechanisms for DOR-mediated protection against α-synuclein oligomer formation. Our findings suggest that DOR attenuates the formation of toxic α-synuclein oligomers through the phos-CREB pathway under hypoxic conditions, and through TORC1/SIK1/CREB pathways in the conditions of α-synuclein overexpression and mutation. The DJ-1 gene was involved in the DOR protection against parkinsonian injury.

The delta-opioid receptor and Parkinson's disease.

Parkinson's disease (PD) is a common degenerative neurological disease leading to a series of familial, medical, and social problems. Although it is known that the major characteristics of PD pathophysiology are the dysfunction of basal ganglia due to injury/loss of dopaminergic neurons in the substantia nigra pars compacta dopaminergic and exhaustion of corpus striatum dopamine, therapeutic modalities for PD are limited in clinical settings up to date. It is of utmost importance to better understand PD pathophysiology and explore new solutions for this serious neurodegenerative disorder. Our recent work and those of others suggest that the delta-opioid receptor (DOR) is neuroprotective and serves an antiparkinsonism role in the brain. This review summarizes recent progress in this field and explores potential mechanisms for DOR-mediated antiparkinsonism.

Kissing aneurysms of the distal anterior cerebral artery: A case report and literature review.

Intracranial 'kissing' aneurysms are rare types of multiple aneurysms referring to two adjacent aneurysms arising from identical or different arteries with separate origins and partially adherent walls. The present study reported a 54-year-old female patient, who was identified with a 'kissing' aneurysm in the A3 segment of the bilateral anterior cerebral arteries, as demonstrated by head computed tomography and emergency cerebral digital subtraction angiography analysis. In total, 12 days following the clipping of the aneurysms, the patient was discharged with a Modified Rankin Scale=0 and recovered well with no neurological deficits. Based on previous literature, it was indicated that the majority of patients with 'kissing' aneurysm have a good prognosis and the cure rate is as high as 96.8%. However, the recovery rate may not be that high as the sample size is not large enough to thoroughly demonstrate the complete prognosis of 'kissing' aneurysms.

Blood-Brain Barrier Disruption, Sodium Fluorescein, And Fluorescence-Guided Surgery Of Gliomas.

PURPOSE: Sodium fluorescein (SF) is an ideal dye for intraoperative guided-resection of high-grade gliomas (HGGs). However, it is not well understood whether the SF-guided technique is suitable for different grades of gliomas, and the correlation between fluorescence and pathology is also not yet clear. MATERIALS AND METHODS: In this study, we investigated 28 patients, including 23 patients with HGG and 5 patients with low-grade glioma (LGG). All patients were treated using the SF-guided technique on a Pentero 900 microscope (Carl Zeiss, Oberkochen, Germany). Claudin-5 immunohistochemical (IHC) staining for the tumours and peritumour tissues was analyzed. RESULTS: Intraoperative yellow fluorescence was noted in all the HGGs but not in the LGGs. Claudin-5 expression in the blood brain barrier endothelial cells was downregulated and disconnected in the HGGs (p < 0.05), but had no difference or slightly decreased in the LGGs (p > 0.05). CONCLUSIONS: The SF-guided technique is suitable for HGG surgery but not for LGG surgery. Downregulation of claudin-5 expression may contribute to the presence of yellow fluorescence in the glioma in SF-guided surgery.

MiR-206 is down-regulated and suppresses cell proliferation by targeting FOXP1 in brain gliomas.

Aberrant expression of miR-206 has been repeatedly found and demonstrated to play crucial roles in cancers. However, the role of miR-206 in brain glioma remains unclear. To address this issue, we detected miR-206 expression of 60 gliomas and 18 normal peritumor tissues, and found that miR-206 is significantly down-regulated in gliomas. Further in silico analysis of 198 glioma samples from the Chinese Glioma Genome Atlas (CGGA) indicated that miR-206 is significantly down-regulated in high grade gliomas and that miR-206 predicts favorable patients' prognosis. Notably, we found that miR-206 expression is negatively correlated with Ki-67 staining, indicating a proliferative inhibition of miR-206 in gliomas. To explore the crucial role of miR-206 in gliomas, we constructed miR-206 stably overexpressed LN229 glioma cell lines and found that the proliferation is significantly inhibited. Through flow cytometry (FCM) analyses, we found that the apoptotic rate is increased and the cell cycle is arrested in LN229 cells after overexpression of miR-206. Bioinformatic analysis, qPCR, western blot and luciferase assay indicated that the Forkhead Box Protein 1 (FOXP1) is a direct target of miR-206 in gliomas. Overexpression of FOXP1 could partially rescue the proliferative inhibition in the miR-206 stably overexpressed LN229 cells. In summary, our results suggest that miR-206 might function as a tumor suppressor of gliomas by inhibition of proliferation and could serve as a promising candidate for therapeutic applications in glioma by targeting FOXP1.