Pharmacological inhibition of the ubiquitin-specific protease 8 effectively suppresses glioblastoma cell growth.

Glioblastoma (GBM) is a malignant brain tumor. The purpose of this study is to estimate the potential effects and underlying mechanisms of a ubiquitin-specific protease 8 (USP8) small-molecule inhibitor on the phenotypic characteristics of GBM cells. The growth, migration, invasion, and stemness of GBM LN229 and T98G cells were evaluated by conducting cell proliferation, colony formation, wound healing, transwell, Ki-67 staining, spheroid formation, and ionizing radiation assays, and the results collectively showed the suppressive effects of USP8 inhibition on GBM cells. Furthermore, transcriptomic profiling of GBM cells treated with the USP8 inhibitor deubiquitinase (DUB)-IN-1 revealed significantly altered mRNA expression induced by pharmacological USP8 inhibition, from which we confirmed downregulated Aurora kinase A (AURKA) protein levels using immunoblotting assays. Our findings indicated that the proliferation, invasion, and stemness of LN229 and T98G cells were markedly suppressed by USP8 inhibition. Pharmacological USP8 suppression elicits multiple tumor-inhibitory effects, likely through dysregulating various mRNA expression events, including that of the key cell cycle regulator and oncogenic protein AURKA. Therefore, our observations corroborate the GBM-supportive roles of USP8 and suggest pharmacological USP8 inhibition is a viable therapeutic approach to target GBM. The purpose of this study was to investigate the effect and mechanism of action of the USP8 inhibitor DUB-IN-1 on GBM.

SREBP2/Rab11s/GLUT1/6 network regulates proliferation and migration of glioblastoma.

Cholesterol serves a vital role in the occurrence and development of glioblastoma multiforme (GBM). Furthermore, cholesterol synthesis is regulated by sterol regulatory element-binding protein 2 (SREBP2), and certain glucose transporters (GLUTs) and Ras-related protein Rab11 (Rab11) small GTPase family members (Rab11s) may contribute to the process. The Cancer Genome Atlas was used to analyze the relationship between prognosis and GLUT gene expressions. To investigate the regulatory effect of Rab11s and SREBP2 on GLUTs during tumor progression, single cell RNA sequencing (scRNA-seq), western blotting and reverse transcription-quantitative PCR were performed on glioma tissues and the T98G GBM cell line. Cell viability and migration were assessed by performing MTT and wound healing assays, respectively. Moreover, the dual-luciferase reporter gene assay was conducted to predict the sterol regulatory elements in the promoter regions of the target genes. The results demonstrated that high SREBP2, GLUT1 and GLUT6 expression was associated with poor survival of patients with GBM. ScRNA-seq distinguished glioblastoma cells by EGFR and indicated the related lipid metabolism signaling pathways. Moreover, the results indicated that GLUT1 and GLUT6 were regulated by SREBP2 and Rab11s. Rab11s and SREBP2 also contributed to T98G cell viability and migration. Additionally, the results indicated that Rab11s, GLUT1 and GLUT6 were transcriptionally regulated by SREBP2. Therefore, the present study suggested that the SREBP2/Rab11/GLUT network promoted T98G cell growth, thus, identifying potential therapeutic targets for GBM.

Tanshinone IIA Microemulsion Protects against Cerebral Ischemia Reperfusion Injury via Regulating H3K18ac and H4K8ac In Vivo and In Vitro.

Tanshinone IIA (TanIIA) has neuroprotective effects against cerebral ischemia reperfusion injury (CIRI), but its clinical application is limited due to poor water solubility and robust first pass elimination property. In this study, we developed microemulsion loaded with TanIIA (TanIIA ME) to break through these limitations, and explored the neuroprotective effect of TanIIA ME against CIRI and the epigenetic regulation mechanism of this neuroprotection. In vivo, middle cerebral artery occlusion (MCAO) models were treated with TanIIA ME and TanIIA solution or sodium valproate as a control. The effect of TanIIA ME on HDAC activity was determined by ELISA assay. In addition, we used primary hippocampal neurons to establish oxygen-glucose deprivation and reoxygenation (OGD/R) models. Lactate dehydrogenase (LDH) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were performed to investigate the neuroprotective efficacy of TanIIA ME. Subsequently, the expression of H3K18ac, H4K8ac, NMDAR1, caspase-3, and MAP-2 were investigated in MCAO or OGD/R models treated with TanIIA ME, TanIIA solution or sodium valproate. In vivo experimental results indicated that TanIIA ME significantly reduced neurological scores, infarction volume, and HDAC activity compared with TanIIA solution and MCAO group, accompanied by upregulation of H3K18ac, H4K8ac, and MAP-2 expression and downregulation of NMDAR1 and caspase-3 expression. Additionally, in OGD/R models, the results demonstrated that TanIIA ME treatment had a better neuroprotective effect along with increased H3K18ac, H4K8ac, and MAP-2 expression and decreased NMDAR1 and caspase-3 expression, compared with the other treatments except sodium valproate. Overall, TanIIA ME treatment exhibited superior efficacy in protecting against CIRI through mechanisms that might involve the inhibition of NMDAR1 and caspase-3 expression and the enhancement of MAP-2 expression by regulating histone H3K18 and H4K8 acetylation. Thus, TanIIA ME could be potentially used to develop a promising drug for the treatment of ischemic stroke.

Synergistic Effect of Statins and Abiraterone Acetate on the Growth Inhibition of Neuroblastoma via Targeting Androgen Receptor.

Neuroblastoma is the most common extracranial neuroendocrine tumor in childhood. Although many studies have tried to find effective treatments, there are still numerous limitations in current clinical targeted therapy. So, it is important to find new therapeutic targets and strategies from a new perspective. Our previous study reported that the androgen receptor (AR) promotes the growth of neuroblastoma in vitro and in vivo. Based on documentary investigation, we postulated that the AR-SCAP-SREBPs-CYP17/HMGCR axis may regulate cholesterol and androgens synthesis and form a positive enhancement loop promoting NB progression. Clinical samples and Oncomine database analysis proved the activation of AR-SCAP-SREBPs-CYP17/HMGCR axis in neuroblastoma. The combination of inhibitors of HMGCR (statins) and CYP17A1 (abiraterone acetate) showed synergistic effect that significantly inhibited the proliferation and migration with decreased expression of related genes detected in vitro and in vivo suggesting the dual-targeted therapy had the potential to inhibit the progression of neuroblastoma in spite of its MYCN status. This study provides new ideas for clinical treatment of neuroblastoma with efficacy and reduced toxicity.

Long-Term Survival of Primary Intracranial Plasmablastic Lymphoma: Case Report and Review of the Literature.

BACKGROUND: Primary intracranial plasmablastic lymphoma (PIPBL) is a rare malignant tumor. CASE DESCRIPTION: We present a case of PIPBL in a 32-year-old man who complained of a progressive growing, painful mass on the right parieto-occipital part of head. Computed tomography and magnetic resonance imaging revealed a homogeneously enhanced mass with partial bone destruction. The patient underwent total resection and cranioplasty in one stage. Histopathologic examination showed large tumor cells with immunoblast-like nuclei. Immunohistochemical staining displayed CD38(+), CD138(+), Mum-1(+), CD20(-), and PAX-5(-). The patient received chemotherapy. The patient has survived more than 3.5 years after operation, with follow-up. We also review the clinical data, molecular pathologic traits, treatment, and prognosis of additional 6 cases with PIPBL in the literature. CONCLUSIONS: This study provides important clinical information for the diagnosis and treatment of PIPBL.

A new method for evaluation of motor injury after acute brain ischemic damage.

PURPOSE: Motor impairment is an important index for assessing the extent of brain injury. The present study uses a new method, the movement capture analysis (MOCA) system, for assessing motor damage after acute ischemia. MATERIALS AND METHODS: Forty rats were divided into four groups: standard ischemia, sham-operated, Dizocilpine (MK-801), and Ginkgo biloba extract (GBE) groups. Brain ischemia was induced using the temporary right middle cerebral artery occlusion model. Longa score and MOCA were used to assess motor injury one day after ischemia. Infarct volume was delineated with 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining. The correlation of infarct volume with Longa score and MOCA data was calculated. RESULTS: Compared with the sham-operated group (0.10 ± 0.31), Longa scores of MK-801 (2.33 ± 0.73), GBE (1.80 ± 0.58), and standard (2.88 ± 0.83) groups showed a statistical difference (p < 0.05); however, it was unable to discern the difference between MK-801 and standard groups. MOCA was able to clearly discern the differences in motor disparity among the four groups, standard (1.00 ± 0.19), sham-operated group (0.17 ± 0.02), MK-801 (0.79 ± 0.08), GBE (0.38 ± 0.05) (p < 0.05). Both MK-801 (18.03 ± 0.96%) and GBE (10.82 ± 1.93%) treatment reduced infarct size compared with the standard ischemia group (25.88 ± 1.16%) (p < 0.05). The MOCA data showed a more significant correlation with infarct size than Longa score (r = 0.85:0.53). CONCLUSIONS: MOCA system proved to be more sensitive than the Longa score. It may potentially be more accurate method for behavioral evaluation in clinical trials.

Serotonin transporter (5-HTT) gene polymorphisms and susceptibility to epilepsy: a meta-analysis and meta-regression.

AIMS: Serotonin transporter (5-HTT) plays a central role in the regulation of serotonin (5-hydroxytryptamine [5-HT]) synaptic function. Disturbances in 5-HT transmission are the most frequently reported neurobiological substrates of suicidal behavior. Emerging evidence has shown that the common polymorphisms in the 5-HTT gene may contribute to the risk of epilepsy, but individually published studies showed inconclusive results. This meta-analysis aimed to derive a more precise estimation of the associations between 5-HTT gene polymorphisms and susceptibility to epilepsy. METHODS: A literature search of PubMed, Embase, Web of Science, and China BioMedicine (CBM) databases was conducted on articles published before June 1st, 2013. Crude odds ratios with 95% confidence intervals were calculated. RESULTS: Seven studies were assessed with a total 1303 epilepsy patients and 1288 healthy controls. The meta-analysis results indicated that there was no significant relationship between 5-HTT gene polymorphisms and an increased risk of epilepsy. Further subgroup analysis based on ethnicity also found no significant association between 5-HTT gene polymorphisms and epilepsy risk among both Caucasian and Asian populations. In addition, there was also no significant association between 5-HTT gene polymorphisms and the risk of psychiatric comorbidity in patients with epilepsy. CONCLUSION: In conclusion, the current meta-analysis indicates that 5-HTT gene polymorphisms might not be the primary determinants of epilepsy susceptibility. 5-HTT genes might be expected to interact with other genes in different signaling pathways to initiate and promote the epileptogenic process.

Triple pathology in patients with temporal lobe epilepsy: A case report and review of the literature.

The coexistence of three intracranial lesions related to epileptic pathogenesis is known as 'triple pathology' and has rarely been reported. In this study we report a case of temporal lobe epilepsy (TLE) with the coexistence of hippocampal sclerosis (HS), focal cortical dysplasia (FCD) and ganglioglioma in the temporal lobe. A 29-year-old male who had experienced recurrent seizures for four years was admitted to hospital. Cerebral magnetic resonance imaging (MRI) was conducted and T2-weighted and fluid-attenuated inversion recovery sequence (FLAIR) images revealed a reduced hippocampal volume with an increased FLAIR signal on the right side and a slightly enlarged temporal horn, which are typical imaging findings for HS and FCD. The patient underwent resectioning of the right anterior temporal lobe, hippocampus and amygdala, in addition to the lesion located in the medial temporal lobe. Immunohistochemical analysis of the medial temporal lobe lesion confirmed a ganglioglioma (WHO grade I) in the medial temporal lobe. During the first eight months following surgery, the patient's seizures were controlled with zonisamide and phenytoin. Electroencephalogram (EEG) assessment post-surgery confirmed the absence of epileptic discharges. Based on a literature review and a detailed review of this case, we postulate two possible explanations for the pathogenesis of 'triple pathology': i) 'triple pathology' is a combination of pathological progression and occasionality; and ii) 'triple pathology' lesions have similar pathological origins.