A review on the role of different ephrins in glioma.

Gliomas, tumors of glial cells, are the most common malignant tumors of the brain. Ephrins are protein ligands that act through tyrosine kinases receptor family, Eph receptors. In glioma, an inverse relationship has been identified between ephrin A1 ligand and EphA2 receptors i.e. there has been a decrease in the expression of ephrin A1 and increase in the expression of EphA2. The forced expression of ephrin A1 decreases the proliferation of glioma by internalizing the EphA2 receptors. The ligand (ephrin A1)-independent effects of EphA2 receptors are oncogenic in nature, while the binding of EphA2 with ephrin A1 decreases the glioma proliferation. An increase in EphA4 may be important in enhancing cellular proliferation and migration of glioblastoma through FGFR-MAPK-Akt signaling pathway, while a decrease in the expression of EphA5 may be crucial in increasing the cellular proliferation and thus, ephrin A5 acts as a tumor suppressor in glioma by negatively regulating the expression of EGFR. The higher expression levels of EphB2 and its ligand, ephrin B1 may decrease the cell adhesion and increase the invasion capacity of glioma through HIF-2α-EphB2-paxillin signalling. There is also a key role of ephrin B2 and EphB2 in promoting migration, invasion and conferring resistance to glioma cell. Ephrin B2 contributes in the pathogenesis of glioma by promoting angiogenesis through VEGF-A. An increase in ephrin B3 may also be important in the increasing tumorigenicity of glioma. The present review describes the role of different ephrins in the pathogenesis of glioma.

Potential Drug Prediction of Glioblastoma Based on Drug Perturbation-Induced Gene Expression Signatures.

OBJECTIVES: Glioblastoma (GBM) is a malignant brain tumor which is the most common and aggressive type of central nervous system cancer, with high morbidity and mortality. Despite lots of systematic studies on the molecular mechanism of glioblastoma, the pathogenesis is still unclear, and effective therapies are relatively rare with surgical resection as the frequently therapeutic intervention. Identification of fundamental molecules and gene networks associated with initiation is critical in glioblastoma drug discovery. In this study, an approach for the prediction of potential drug was developed based on perturbation-induced gene expression signatures. METHODS: We first collected RNA-seq data of 12 pairs of glioblastoma samples and adjacent normal samples from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by DESeq2, and coexpression networks were analyzed with weighted gene correlation network analysis (WGCNA). Furthermore, key driver genes were detected based on the differentially expressed genes and potential chemotherapeutic drugs and targeted drugs were found by correlating the gene expression profiles with drug perturbation database. Finally, RNA-seq data of glioblastoma from The Cancer Genome Atlas (TCGA) dataset was collected as an independent validation dataset to verify our findings. RESULTS: We identified 1771 significantly DEGs with 446 upregulated genes and 1325 downregulated genes. A total of 24 key drivers were found in the upregulated gene set, and 81 key drivers were found in the downregulated gene set. We screened the Crowd Extracted Expression of Differential Signatures (CREEDS) database to identify drug perturbations that could reverse the key factors of glioblastoma, and a total of 354 drugs were obtained with p value < 10-10. Finally, 7 drugs that could turn down the expression of upregulated factors and 3 drugs that could reverse the expression of downregulated key factors were selected as potential glioblastoma drugs. In addition, similar results were obtained through the analysis of TCGA as independent dataset. CONCLUSIONS: In this study, we provided a framework of workflow for potential therapeutic drug discovery and predicted 10 potential drugs for glioblastoma therapy.

GABAergic System Dysfunction in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) refers to a series of neurodevelopmental diseases characterized by two hallmark symptoms, social communication deficits and repetitive behaviors. Gamma-aminobutyric acid (GABA) is one of the most important inhibitory neurotransmitters in the central nervous system (CNS). GABAergic inhibitory neurotransmission is critical for the regulation of brain rhythm and spontaneous neuronal activities during neurodevelopment. Genetic evidence has identified some variations of genes associated with the GABA system, indicating an abnormal excitatory/inhibitory (E/I) neurotransmission ratio implicated in the pathogenesis of ASD. However, the specific molecular mechanism by which GABA and GABAergic synaptic transmission affect ASD remains unclear. Transgenic technology enables translating genetic variations into rodent models to further investigate the structural and functional synaptic dysregulation related to ASD. In this review, we summarized evidence from human neuroimaging, postmortem, and genetic and pharmacological studies, and put emphasis on the GABAergic synaptic dysregulation and consequent E/I imbalance. We attempt to illuminate the pathophysiological role of structural and functional synaptic dysregulation in ASD and provide insights for future investigation.

The GTF2I rs117026326 polymorphism is associated with neuromyelitis optica spectrum disorder but not with multiple sclerosis in a Northern Han Chinese population.

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are common demyelinating disorders of the central nervous system. The etiology and pathogenesis of MS and NMOSD remain unclear. The pathogenesis of these two diseases involves a genetic predisposition as well as environmental factors. NMOSD sometimes co-exists with Sjögren's syndrome, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and these diseases are frequently associated with central nervous system disorder involvement, as manifest in MS- and NMOSD-like clinical features. Genetic variant rs117026326 upstream of the general transcription factor II-I (GTF2I) has been associated with primary Sjögren's syndrome, SLE and RA in East Asian populations. In this study, we genotyped single nucleotide rs117026326 polymorphisms of the GTF2I gene in 168 patients with MS, 144 patients with NMOSD, and 1403 healthy controls. We observed a significant genetic association between the variant rs117026326 and NMOSD (P = 1.09 × 10-11, OR = 2.535), however, the association with MS was not significant (P = .4289, OR = 1.129). Gene expression analyses showed that there was no significant association between the messenger RNA expression of GTF2I and genotypes at the variant. We conclude that the risk T allele of rs117026326 increases the risk of NMOSD, suggesting that NMOSD and MS may have different genetic risk factors.

Primary Sphenoidal Sinus Lymphoma with Initial Presentation as Unilateral Abducens Nerve Palsy Symptom.

A 48-year-old man presented with 3 days of mild horizontal diplopia in the left direction, followed by the onset of headache 17 days later. A physical examination revealed isolated left abducens nerve palsy. Head computed tomography (CT) and magnetic resonance imaging (MRI) scans revealed soft-tissue density neoplasms that occupied the sphenoidal sinus and further invaded to destroy the clivus. Immunohistochemical staining of neoplasms was performed from biopsies samples. The pathological diagnosis was extranodal natural killer (NK)/T-cell lymphoma (ENKL), nasal type, associated with Epstein-Barr virus (EBV). The patient subsequently exhibited secondary symptoms (fever, night sweats), enlarged lymph nodes, renal metastases, and hemophagocytic syndrome, with clinical diagnosis stage IV of ENKL. The patient has a poor prognosis. This report is unique in two aspects: the unilateral abducens nerve palsy as the initial and isolated symptom of ENKL, and the primary sphenoidal sinus ENKL.

Adult severe encephalitis/encephalopathy with a reversible splenial lesion of the corpus callosum: A case report.

RATIONALE: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion of the corpus callosum (MERS) is a recently identified clinically and radiologically distinct syndrome. Clinical symptoms and lesions on the magnetic resonance imaging (MRI) often disappear in 1 week or a few weeks. However, MERS manifesting as a severe clinical course with significant sequela has not yet been reported. PATIENT CONCERNS: A 42-year-old male presented with a 3-day history of headache, fever, and irrational speech. Physical examination showed a body temperature of 39.5°C, dysarthria, dyscalculia, recent memory disturbance, and otherwise normal vital signs. The patient developed status epilepticus and progressive consciousness disturbance. MRI showed abnormal patchy signals in the splenium of the corpus callosum. DIAGNOSIS: The clinical feature and the characteristic of MRI are mostly consistent with MERS. At the same time, we made a differential diagnosis by testing the NMDARAb, AMPA1Ab, AMPA2Ab, LG1Ab, CASPR2Ab, GABABRAb in CSF and serum. INTERVENTIONS: The subject was treated with ganciclovir, antiepileptic, and antipyretic therapy. OUTCOMES: The subject was living a virtually normal life with persistent mild memory disturbance. MRI showed that the abnormal signals in the splenium of the corpus callosum had disappeared, but hyperintensity on T2-weighted and FLAIR imaging was noted in the centrum semiovale. LESSONS: MERS is a rare clinicoradiological syndrome, which can manifest as severe symptoms as well. Early diagnosis and treatment should be emphasized, and the diagnostic value of MRI is highlighted. Clinicians should be alert to the potential sequela.

Therapeutic effects and safety of olcegepant and telcagepant for migraine: A meta-analysis.

OBJECTIVE: To evaluate the therapeutic effects and adverse reactions of olcegepant and telcagepant for the treatment of migraine. DATA RETRIEVAL: We identified studies using Medline (1966-01/2012-06), PubMed (1966-01/2012-06), Scopus (1980-01/2012-06), Cochrane Central Register of Controlled Trials (1980-01/2012-06) and China National Knowledge Infrastructure (1980-01/2012-06). SELECTION CRITERIA: The included studies were double-blind, randomized and placebo-controlled trials of olcegepant or telcagepant for the treatment of single acute migraine in patients with or without aura. Adverse reaction data were also included. Two independent investigators performed quality evaluation and data extraction using Jadad scoring. Meta-analyses were undertaken using RevMan 5.0.25 software. MAIN OUTCOME MEASURES: Pain relief rate, pain-free rate, and incidence of adverse reactions were measured in patients 2 and 24 hours after injection of olcegepant and oral telcagepant. RESULTS: Six randomized, controlled trials were included. Meta-analysis demonstrated that compared with placebo, the pain relief rate (odds ratio, OR = 5.21, 95% confidence interval, CI: 1.91-14.2, P < 0.01) and pain-free rate (OR = 31.11, 95% CI: 3.80-254.98, P < 0.01) significantly increased 2 hours after 2.5 mg/d olcegepant treatment. Pain relief rate and pain-free rate 2 and 24 hours after treatment with telcagepant 150 mg/d and 300 mg/d were superior to placebo (P < 0.01). Moreover, the remission rate of unrelenting headache was higher after 24 hours of 300 mg/d telcagepant treatment compared with 150 mg/d (OR = 0.78, 95% CI: 0.62-0.97, P < 0.05). The incidence of adverse reactions with olcegepant was not significantly greater than placebo (P = 0.28), but within 48 hours of administration of telcagepant 300 mg/d, the incidence of adverse reactions was higher than placebo (OR = 1.21, 95% CI: 1.04-1.42, P < 0.01). Few studies have compared the therapeutic effects of olcegepant and telcagepant. CONCLUSION: The calcitonin-gene-related peptide receptor antagonists olcegepant and telcagepant have shown good therapeutic effects in the treatment of migraine. Moreover, the incidence of adverse reactions compares favorably with placebo, although liver transaminases may become elevated after long-term use.

A new variant nummular headache: large diameter accompanied with bitrigeminal hyperalgesia and successful treatment with carbamazepine.

Nummular headache (NH) is defined as a focal head pain that is exclusively felt in a small area, which is typically 1-6 cm in diameter. Neurological examinations are normal in all patients, but this report describes a new variant. A patient was identified who presented with focal head pain that was approximately 8 cm in diameter and bitrigeminal hyperalgesia on neurological examination. Treatment with carbamazepine provided significant analgesic relief in terms of both the frequency and intensity of pain. The findings enlarge the clinical diversity of this headache disorder. The pathogenic mechanisms of NH may be similar to trigeminal neuralgia in particular patients.

Overexpression of apolipoprotein E4 increases kainic-acid-induced hippocampal neurodegeneration.

Apolipoprotein E (apoE) has an intricate biological function in modulating immune responses and apoE isoforms exhibit diverse effects on neurodegenerative and neuroinflammatory disorders. In the present study, we investigated the individual roles of apoE isoforms in the kainic acid (KA)-induced hippocampal neurodegeneration with focus on immune response and microglia functions. ApoE2, 3 and 4 transgenic mice as well as wild-type (WT) mice were treated with KA by intranasal route. ApoE4 overexpressing mice revealed several peculiarities as compared with other transgenic mice and WT mice, i.e. (1) they had more severe KA-induced seizures than apoE2 and 3 mice, (2) they exhibited neuron loss in hippocampus that was higher than in apoE2, 3 and WT mice, (3) KA administration resulted in higher counts of their head drops in the cross-area of elevated plus-maze, (4) they showed lower KA-induced rearing activity than apoE2 mice in the open-field test, (5) their KA-induced microglial expression of MHC-II and CD86 was elevated compared to apoE3 mice, (6) the KA-induced increase of microglial iNOS was higher than that in the other groups of mice, and (7) the TNF-α and IL-6 expression was decreased 7 days after KA application compared to untreated mice and mice treated 1 day with KA. However, the signaling pathway of NFκB or Akt seemed not to be involved in apoE-isoform dependent susceptibility to KA-induced neurotoxicity. In conclusion, over-expression of apoE4 deteriorated KA-induced hippocampal neurodegeneration in C57BL/6 mice, which might result from a higher up-regulation of microglia activation compared to apoE2 and 3 transgenic mice and WT mice.

APOE ε3 attenuates experimental autoimmune neuritis by modulating T cell, macrophage and Schwann cell functions.

Human apolipoprotein E (apoE) is a 34.2kDa glycosylated protein with three isoforms (apoE2, apoE3 and apoE4). Experimental autoimmune neuritis (EAN), an animal model for human Guillain-Barré syndrome, is an immune-mediated experimental disorder of the peripheral nervous system (PNS). Increased susceptibility to EAN in apoE deficient mice has been previously found. To elucidate the isoform-dependent effects of apoE on EAN, we used human apoE2, E3 and E4 transgenic mice (Tg) immunized with P0 peptide 180-199, as well as T cell proliferation test, macrophage and Schwann cell (SC) cultures to investigate the effects of apoE isoforms on the functions of T cells, macrophages and SCs both under naïve conditions and in EAN. Clinical signs of EAN were most severe in wild type (WT) C57BL/6 mice and apoE4 Tg mice, followed by apoE2 Tg mice and apoE3 Tg mice (WT≈E4>E2>E3, p<0.01). At the nadir of EAN, spleen weight and lymphocyte proliferation were in line with the clinical severity of the disease. Proliferation tests of purified T cells from naive mice stimulated with phytohemagglutinin or interleukin-12 showed isoform-specific differences (WT≈E4>E3≈E2, p<0.01). Macrophages from both naïve and EAN mice produced nitric oxide upon inflammatory stimulation with lipopolysaccharide, interferon-γ, polyinosinic:polycytidylic acid or combinations thereof, in an isoform-dependent manner (WT≈E4>E2>E3, p<0.01). Generalized intervention with 1400W, a specific inducible nitric oxide synthase inhibitor, significantly suppressed the clinical course of EAN in apoE2, E3 and E4 Tg mice and in WT mice. During the recovery stage of disease, the highest expression of CD178 (FasL) on SCs was found in apoE3 Tg mice. Our data support an isoform-dependent effect of apoE on EAN. This might be due to the isoform-specific effects of apoE on functions of T cells, macrophages and SCs, which contribute to the distinct clinical courses of EAN. ApoE3 might not only inhibit the onset and suppress the clinical severity of EAN, but also enhance the termination of immune responses in the PNS.

TNF-alpha receptor 1 deficiency reduces antigen-presenting capacity of Schwann cells and ameliorates experimental autoimmune neuritis in mice.

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic pro-inflammatory cytokine with potentially neurodestructive effects and plays a pivotal role in autoimmune demyelinating disease. To address the role of TNF-alpha in the pathogenesis of experimental autoimmune neuritis (EAN), the current study investigated the antigen-presenting capacity of Schwann cells (SCs) in EAN induced by P0 protein peptide 106-125 in TNF-alpha receptor 1 deficient (TNFR1(-/-)) mice. The antigen-presenting capacity of SCs was assessed by the expression of MHC class II (MHCII), CD40, CD80 and CD86 molecules on activated SCs as well as by induction of T cell proliferation in co-cultures of P0 protein peptide 106-125 specific T cells with activated SCs. In addition, the expression of inducible nitric oxide synthase (iNOS) was measured in activated SCs by flow cytometry. TNFR1(-/-) EAN mice developed significantly delayed and reduced clinical signs of EAN compared to wild type EAN mice. In parallel, the expression of MHCII, CD80 and iNOS on SCs were decreased in TNFR1(-/-) mice compared to wild type mice. Likewise, proliferation of P0 protein peptide 106-125 specific T cells simulated by activated SCs of TNFR1(-/-) EAN mice was lower than that of wild type EAN mice. Our data suggest that TNF-alpha may exert pro-inflammatory effects in EAN via TNFR1 by up-regulating the antigen-presenting function and iNOS production of SCs.