Case report of a patient with Erdheim-Chester disease presenting with neuro-endocrine symptoms and negative for BRAF mutation.

RATIONALE: Erdheim-Chester disease (ECD) is a rare progressive disease affecting multiple systems. It has recently been recognized as a neoplastic disease following the discovery of activating mutations in the MAPK pathway. There are several striking signs of ECD, such as the long bone involvement, as well as the hairy kidney appearance on computed tomography scan. It is rare for ECD to manifest neurological symptoms. Central nervous system involvement is a strong prognostic factor and independent predictor of death. ECD is characterized by the overproduction and accumulation of foamy histiocytes and Touton's giant cells in various tissues and organs. ECD is a multisystem disorder in which any organ may be affected. PATIENT CONCERNS: This case report describes a 57-year-old woman with headaches and ataxia as the first clinical manifestation, without characteristic bone pain, but with delayed enuresis. In addition to the renal involvement, this patient had rarer splenic involvement. DIAGNOSES: The imaging presentation of this patient was similar to that of a "multiple meningiomas". A combination of clinical, imaging and pathology for the diagnosis of ECD. INTERVENTIONS: Patients were given INF-α therapy. OUTCOMES: Fortunately, the patient responded well to INF-α treatment. LESSONS: ECD patient with neuro-endocrine symptoms.

Pyrvinium pamoate regulates MGMT expression through suppressing the Wnt/ß-catenin signaling pathway to enhance the glioblastoma sensitivity to temozolomide.

Temozolomide (TMZ) is the mainstream chemotherapeutic drug for treating glioblastoma multiforme (GBM), but the intrinsic or acquired chemoresistance to TMZ has become the leading clinical concern, which is related to the repair of DNA alkylation sites by O6-methylguanine-DNA methyltransferase (MGMT). Pyrvinium pamoate (PP), the FDA-approved anthelminthic drug, has been reported to inhibit the Wnt/ß-catenin pathway within numerous cancer types, and Wnt/ß-catenin signaling pathway can modulate the expression of MGMT gene. However, whether PP affects the expression of MGMT and enhances TMZ sensitivity in GBM cells remains unclear. In the present study, we found that PP and TMZ had synergistic effect on inhibiting the viability of GBM cells, and PP induced inhibition of MGMT and enhanced the TMZ chemosensitivity of GBM cells through down-regulating Wnt/ß-catenin pathway. Moreover, the overexpression of MGMT or ß-catenin weakened the synergy between PP and TMZ. The mechanism of PP in inhibiting the Wnt pathway was indicated that PP resulted in the degradation of ß-catenin via the AKT/GSK3ß/ß-catenin signaling axis. Moreover, Ser552 phosphorylation in ß-catenin, which promotes its nuclear accumulation and transcriptional activity, is blocked by PP that also inhibits the Wnt pathway to some extent. The intracranial GBM mouse model also demonstrated that the synergy between PP and TMZ could be achieved through down-regulating ß-catenin and MGMT, which prolonged the survival time of tumor-bearing mice. Taken together, our data suggest that PP may serve as the prospect medicine to improve the chemotherapeutic effect on GBM, especially for chemoresistant to TMZ induced by MGMT overexpression.

Involvement of Astrocytes and microRNA Dysregulation in Neurodegenerative Diseases: From Pathogenesis to Therapeutic Potential.

Astrocytes are the most widely distributed and abundant glial cells in the central nervous system (CNS). Neurodegenerative diseases (NDDs) are a class of diseases with a slow onset, progressive progression, and poor prognosis. Common clinical NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Although these diseases have different etiologies, they are all associated with neuronal loss and pathological dysfunction. Accumulating evidence indicates that neurotransmitters, neurotrophic factors, and toxic metabolites that are produced and released by activated astrocytes affect and regulate the function of neurons at the receptor, ion channel, antigen transfer, and gene transcription levels in the pathogenesis of NDDs. MicroRNAs (miRNAs) are a group of small non-coding RNAs that play a wide range of biological roles by regulating the transcription and post-transcriptional translation of target mRNAs to induce target gene expression and silencing. Recent studies have shown that miRNAs participate in the pathogenesis of NDDs by regulating astrocyte function through different mechanisms and may be potential targets for the treatment of NDDs. Here, we review studies of the role of astrocytes in the pathogenesis of NDDs and discuss possible mechanisms of miRNAs in the regulation of astrocyte function, suggesting that miRNAs may be targeted as a novel approach for the treatment of NDDs.

Epidemiology and survival of patients with spinal meningiomas: A SEER analysis.

BACKGROUND: The objective of this study is to determine the population-based estimates of the epidemiology, incidence, and outcomes of spinal meningiomas. METHODS: The data of patients with spinal meningiomas diagnosed between 2004 and 2016 were extracted from the SEER database. Descriptive analyses were conducted to evaluate the distribution and tumor-related characteristics of patients with spinal meningiomas. Multivariate logistic regression analysis was performed to predict which patients were inclined to be diagnosed with borderline or malignant spinal meningiomas. Possible prognostic indicators were analyzed by Kaplan-Meier curves and the Cox proportional hazards model. RESULTS: The age-adjusted incidence rate was 0.37 cases per 1,000,000 person-years between 2004 and 2016. Spinal meningiomas represented 4.25% of all meningiomas. A total of 4204 patients with spinal meningiomas were included in our study. Most of the patients were white and diagnosed at 60-69 years of age, and the female:male ratio was 4:1. Most of the tumors were benign and less than 3 cm in size. The most common pathological type was psammomatous meningioma. Surgery was the first choice of treatment for patients with spinal meningiomas. Male and pediatric patients were more vulnerable to borderline or malignant spinal meningiomas. Survival analysis showed that married, female, and younger patients with benign meningiomas had better overall survival than their counterparts. CONCLUSION: Spinal meningiomas are relatively rare lesions with a favorable prognosis. Psammomatous meningioma is the most common subtype. Male and pediatric patients are more frequently diagnosed with borderline or malignant spinal meningiomas. Surgery is the primary choice of treatment.

Dual functional nanoparticles efficiently across the blood-brain barrier to combat glioblastoma via simultaneously inhibit the PI3K pathway and NKG2A axis.

The blood-brain barrier (BBB) and complex tumour immunosuppressive micro-environment posed austere challenges for combatting brain tumours such as the glioblastoma. In this study, we have developed a novel dual functional dendrimer drug delivery system (DDS) by the PAMAM and loaded with siLSINCT5 (NP- siRNA) for efficiently across the BBB to inhibit glioblastoma. To achieve the goal of BBB crossing, on the surface of NP-siRNA was decorated with the cell penetrating peptides tLyp-1 (tLypNP-siRNA). Moreover, to overcome the immunosuppressive microenvironment within the glioblastoma (GBM) tissues, a checkpoint inhibitor named as anti-NKG2A monoclonal antibody (aNKG2A), which was able of promoting anti-tumour immunity by unleashing both T and NK Cells, was further conjugated on the surface of siLSINCT5-loaded nanoparticles via the pH-sensitive linkage. Therefore, the developed dual functional and siLSINCT5-loaded dendrimer nanoparticles (tLyp/aNKNP-siRNA) was supposed to have the ability to efficiently cross the BBB and inhibit GBM by simultaneously inhibit the LSINCT5-activated signalling pathways and activate the anti-tumour immunity. The hypothesis was thoroughly confirmed by in vitro cellular and in vivo animal experiments, and provided a novel strategy for combating glioblastoma.

Cerebral pleomorphic xanthoastrocytoma mimicking inflammatory granuloma: Two case reports.

RATIONALE: Pleomorphic xanthoastrocytoma (PXA) is a rare low-grade glial neoplasm of the central nervous system, which is difficult to distinguish from other neoplastic and non-neoplastic entities. Herein, we report 2 cases of PXA that had been misdiagnosed as an inflammatory granuloma. PATIENT CONCERNS: The first case was a 22-year-old man who originally presented with a generalized seizure 7 years previously. Magnetic resonance imaging (MRI) revealed a lesion in the right parietal lobe, leading to a diagnosis of inflammatory granuloma. The second case was a 43-year-old man who presented with repeated generalized seizures. MRI revealed a nodular lesion in the left temporal lobe. The magnetic resonance spectrum showed elevated Cho and NAA peaks and a decreased Cr peak. An inflammatory granuloma was suspected. DIAGNOSIS: After surgical treatment, histopathological examination revealed PXA. INTERVENTIONS: In the first case, after 10 months of anti-inflammatory treatment, the lesion was significantly reduced in size. During the following 7 years, the patient experienced generalized seizures 3 to 4 times annually. To control intractable epilepsy, the lesion was resected. In the second case, conservative treatment provided no benefit, and then the lesion was resected. OUTCOMES: In the first case, during a follow-up period of 14 months, the patient was seizure-free with no tumor recurrence. In the second case, after a 6 months of follow-up, the patient remained seizure-free with no tumor recurrence. LESSONS: The preoperative differential diagnosis of PXA is challenging due to the nonspecific symptoms and imaging manifestations. Considering the potential risk of malignant transformation of PXA, early surgery should be highlighted, and gross total resection is associated with a favorable prognosis.

Computational study on new natural compound inhibitors of indoleamine 2,3-dioxygenase 1.

Indoleamine 2,3-Dioxygenase (IDO), is a speed limiting enzyme that catalyzes the decomposition and metabolism of Tryptophan along Tryptophan-IDO-Kynurenine pathway [1]. Tryptophan is a necessary amino acid for activating cell growth and metabolism. Additionally, the insufficiency of Tryptophan can lead to immune system dysfunction. Raising the level of Indoleamine 2,3-Dioxygenase protein can promote stagnation and apoptosis of effector T cells [2].In contrast, the decline in the number of effect T cells naturally protects cancer cells from attack. Therefore, Indoleamine 2,3-Dioxygenase is a potential target for tumour immunotherapy, such as melanoma, ovarian cancer, lung cancer, leukaemia, and so on, especially in solid tumours [3]. In the study, we have done sets of virtual screening aided by computer techniques in order to find potentially effective inhibitors of Indoleamine 2,3-Dioxygenase. Firstly, screening based on structure was carried out by Libdock. Then, ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction were also analyzed. Molecular docking and 3D-QSAR pharmacophore generation were used to study the mechanism of these compounds and Indoleamine 2,3-Dioxygenase's binding. A molecular dynamic analysis was carried out to assess if these potential compound's binding is stable enough. According to the results of the analysis above, two potential compounds (ZINC000012495022 and ZINC000003791817) from the ZINC database were discovered to interact with Indoleamine 2,3-Dioxygenase with appropriate energy and proved to be none toxic. The study offered valuable information of Indoleamine 2,3-Dioxygenase inhibitor-based drug discovery in cancer therapy by increasing the activity of T cells and releasing immunity suppression [4, 5].

Long Non-Coding RNA PART1 Exerts Tumor Suppressive Functions in Glioma via Sponging miR-190a-3p and Inactivation of PTEN/AKT Pathway.

BACKGROUND: Glioma is the most commonly diagnosed primary brain tumor. Dysregulation of long non-coding RNA (lncRNA) is associated with initiation and development of various cancer types including glioma. METHODS: The relative expression of lncRNA was analyzed by real time-quantitative polymerase chain reaction (RT-qPCR). Cell counting kit (CCK-8) and flow cytometry analysis were applied to explore the role of prostate androgen-regulated transcript 1 (PART1) in glioma cell lines. Luciferase reporter assay, Western blotting and RT-qPCR were used to investigate the association between PART1, miR-190a-3p and phosphatase and tensin homolog deleted on chromosome ten (PTEN) in glioma cell lines. RESULTS: In the present study, we elucidated a pivotal role and molecular mechanism of lncRNA PART1 in glioma cell lines. It was found that PART1 was significantly downregulated in glioma tissues compared to normal tissues according to TCGA data and our RT-qPCR results. The cell-based assays showed that PART1 suppressed cell proliferation and triggered cell apoptosis in glioma cell lines. PART1 inactivated PI3K/AKT cascade in glioma cell lines. Transfection of constitutively activated AKT (Myr-AKT) reversed PART1 induced cell apoptosis and cell growth arrest. The bioinformatic analysis suggested that miR-190a-3p might bind to PART1. In the dual luciferase reporter assay, we validated that PART1 directly bound to miR-190a-3p in glioma cell lines. Furthermore, there was a reciprocal repression between PART1 and miR-190-3p. In addition, PART1 upregulated PTEN and inactivated PI3K/AKT pathway in glioma cell lines. Moreover, silencing of PTEN reversed PART1 overexpression induced cell growth arrest and apoptosis. In glioma tissues, the Pearson Correlation analysis showed that there was a strong-positive correlation between PART1 level and PTEN mRNA level. CONCLUSION: Taken together, the current study revealed a PART1/miR-190a-3p/PTEN/PI3K/AKT axis in glioma and provided novel insights for understanding the complex lncRNA-miRNA network in glioma.

Identification of driver genes and key pathways of prolactinoma predicts the therapeutic effect of genipin.

The purpose of the present study was to identify the potential targets and markers for diagnosis, therapy and prognosis in patients with prolactinoma at the molecular level and to determine the therapeutic effects of genipin in prolactinoma. The gene expression profiles of GSE2175, GSE26966 and GSE36314 were obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified after comparing between gene expression profiles of the prolactinoma tissues and normal tissues. Then, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and protein­protein interaction (PPI) network analysis were conducted. In addition, in vitro, scratch assay, colony­forming assay, Cell Counting Kit 8 (CCK8) assay and flow cytometry were performed to verify the functional effects of genipin. An aggregate of 12,695, 3,847 and 5,310 DEGs were identified from GSE2175, GSE26966 and GSE36314, respectively. The results of GO and KEGG analysis showed that the DEGs significant and important for prolactinoma were mostly involved with 'spindle pole' and 'oocyte meiosis'. A total of 20 genes were selected as hub genes with high degrees after PPI network analysis, including mitogen­activated protein kinase 1 (MAPK1), MYC, early growth response 1 (EGR1), Bcl2 and calmodulin 1 (CALM1). CCK8 assay, colony­forming assay and scratch assay were performed to verify the anti­prolactinoma effect of genipin. The results of flow cytometry showed that apoptosis was increased by genipin. MAPK1, MYC, EGR1, Bcl2 and CALM1 were screened as main hub genes. Genipin upregulated the expression level of EGR1 and p21 (downstream mediator of EGR1) and EGR1, inhibited the proliferation and migration of prolactinoma cells. Genipin is a promising drug for treatment of patients with prolactinoma.

Computational study on new natural compound agonists of stimulator of interferon genes (STING).

OBJECTIVE: This study aimed to screen lead compounds and medication candidates from drug library (ZINC database) which has potential agonist effect targeting STING protein. METHODS AND MATERIALS: A series of computer-aided virtual screening techniques were utilized to identify potential agonists of STING. Structure-based screening using Libdock was carried out followed by ADME (absorption, distribution, metabolism, excretion) and toxicity prediction. Molecular docking was performed to demonstrate the binding affinity and mechanism between ligands and STING dimers. Molecular dynamic simulation was utilized to evaluate the stability of ligand-receptor complex. Finally, animal experiment was conducted to validate the effectiveness of selected compounds. RESULTS: Three novel natural compounds 1,2,3 (ZINC000015149223, ZINC000011616633 and ZINC000001577210, respectively) from the ZINC15 database were found binding to STING with more favorable interaction energy. Also, they were predicted with less ames mutagenicity, rodent carcinogenicity, non-developmental toxic potential and tolerant with cytochrome P450 2D6 (CYP2D6). The ligand chemical structure analysis showed the three compounds were inborn axisymmetric, such chemical structures account for combining and activating process of STING protein dimers. The dynamic simulation analysis demonstrated that ZINC000015149223-, ZINC000011616633- and ZINC000001577210-STING dimer complex had more favorable potential energy compared with amidobenzimidazole (ABZI) and they can exist in natural environments stably. Animal experiments also demonstrated that these three compounds could suppress tumor growth. CONCLUSION: This study demonstrates that ZINC000015149223, ZINC000011616633 and ZINC000001577210 are potential agonists targeting STING protein. These compounds are safe drug candidates and have a great significance in STING agonists development.

Ginsenoside Rg1 attenuates protein aggregation and inflammatory response following cerebral ischemia and reperfusion injury.

Ginsenoside Rg1 (GS Rg1) is a glycosylated triterpenoid saponin extracted from Panax ginseng. We aim to investigate the impact of GS Rg1 on protein aggregation and inflammatory response in a cerebral ischemia/reperfusion (I/R) injury model. Rats were administered different doses of GS Rg1 (10, 20, or 40 mg/kg/day) or nimodipine (1 mg/kg/day) for 5 consecutive days. Cerebral I/R injury was induced by middle cerebral artery occlusion for 2 h followed by a 22 h reperfusion period. Next, we examined the differences in infarct volume and neurological deficit via TTC staining and Longa's scoring, respectively. Furthermore, the differences in protein aggregates, proteasome, IκBα and NF-κB in the cerebral cortices were investigated through western blotting. The distribution of ubiquitin, proteasome and NF-κB in the neocortex were examined through immunohistochemistry. Pro-inflammatory cytokines were measured using ELISA and proteasome activity was determined by fluorometric peptidaseassay. Treatment with GS Rg1 40 mg/kg resulted in a significantly lower infarct volume and improved the neurological deficit score as well as the histological appearance compared to the control I/R group (P < 0.05). GS Rg1 treatment resulted in significantly lower proinflammatory cytokine expressions and suppression of the nuclear translocation of NF-κB as well as the phosphorylation of IκBα (P < 0.01). Finally, GS Rg1 treatment decreased the proteasomal activity and protein aggregate accumulation in brain tissues (P < 0.01). Our results confirm the neuroprotective function of GS Rg1 at 40 mg/kg. This effect may be attributed to a decrease in ubiquitinated aggregates and a suppression of the inflammatory response after I/R insult.

Selection of the best point and angle of lateral ventricle puncture according to DTI reconstruction of peripheral nerve fibers.

This study aims to find accurate angles and depths of lateral ventricle puncture using diffusion tensor imaging (DTI) reconstruction, as well as to provide an optimized and alternative puncturing strategy.A total of 90 computed tomography (CT) images and 30 CT images with DTI were analyzed. The measurements were performed on coronal, sagittal, and horizontal planes. Some distances and angles were measured to determine the best angle and penetration depth during the puncture process. Important landmarks of the lateral ventricle were also measured, and a comparison of the differences between 2 hemispheres was also assessed.It showed that the vertical distance from the superior margin to inferior margin of the lateral ventricle was 22.2 ±â€Š0.5 mm and the length was 124.1 ±â€Š2.1 mm. In the frontal horn puncture approach, the penetration depth should be limited between 105.2 and 109.4 mm, the angle should be 71.6 ±â€Š2.7°. During the occipital horn puncture approach, puncturing depth was from 90.7 to 111.4 mm, and angle was 15.3 ±â€Š1.8°. Through the parietal lobe puncture approach, which was firstly brought out in this study, the puncturing length should be 124.4 to 130.2 mm and angle was 56.6 ±â€Š2.0°.The traditional recommended protocol of lateral ventricle puncture is not accurate, the refined lateral ventricle puncture protocol established in this study will reduce injury and remain function. A DTI imaging examination combining with nerve fibers reconstruction were strongly recommended before lateral ventricle puncture, which will help neurosurgeons to determine the best puncturing angles and depth.

Extraventricular Neurocytoma in the Left Frontal Lobe: A Case Report and Literature Review.

BACKGROUND: Neurocytoma is a rare brain neoplasm of neuroepithelial origin that occurs predominantly in the ventricular system adjacent to the interventricular foramen and septum pellucidum. However, extraventricular neurocytoma is an extremely rare entity, with poor clinical, radiologic, and histopathological characterization. Here we report a case of an extraventricular parafalcine neurocytoma in the left frontal lobe. We also examine previously reported cases of extraventricular neurocytoma in an attempt to provide an up-to-date summary of the condition. METHODS: A literature search was performed using PubMed with specific key terms, inclusion criteria, and exclusion criteria. Selected case studies and case series were then compared, and statistical analyses were performed where appropriate. We report a 59-year-old woman presenting with weakness in her right leg and urinary incontinence. Physical examination revealed muscle strength of grade 3/5 in the right lower extremity. Brain magnetic resonance imaging showed a parafalcine mass in the left frontal lobe, with perilesional edema; the cerebral falx and lateral ventricle were shifted due to the compression. Gross total resection was performed. RESULTS: Histopathological examination revealed a neurocytoma. Immunohistochemical staining showed diffuse positivity for synaptophysin. MIB-1 staining for Ki-67 antibody showed a labeling index of 20%. No adjuvant radiation or chemotherapy was administered. Brain computed tomography performed at a 3-month follow-up showed no signs of recurrence. CONCLUSION: Extraventricular neurocytoma occurring in the brain parenchyma is a very rare central nervous system tumor. Its clinical and radiologic manifestations are nonspecific. The diagnosis depends on histopathological and immunohistochemical examination. Surgical resection should be the first-choice treatment.

Alveolar soft part sarcoma with multiple brain and lung metastases in pregnancy: A case report and literature review.

RATIONAL: Alveolar soft part sarcomas (ASPSs) with multiple brain metastases in pregnancy is a rare entity. PATIENT CONCERNS: We report our experience with a 19-year-old pregnant woman who presented with intermittent headaches and vomiting at 38 weeks gestation. DIAGNOSES: The patient was initially diagnosed as brain metastasis according to computed tomography and magnetic resonance imaging (MRI) imaging. INTERVENTIONS: Cesarean section and craniotomy (complete resection of both brain metastatic lesions) was performed sequentially. OUTCOMES: A healthy baby girl was delivered safely and no neonatal malformations were found. Histological analysis confirmed the diagnosis of ASPS. Follow-up MRI performed 10 months after surgery revealed no residual tumor or signs of recurrence. LESSONS: We report a case of ASPS with multiple brain and lung metastases in a pregnant woman. We recommend timely MRI examination for diagnosis and have discussed the approach to the treatment of pregnant women with brain metastasis.

Serum expression level of miR-504 can differentiate between glioblastoma multiforme and solitary brain metastasis of non-small cell lung carcinoma.

PURPOSE: Gliomas are the most common primary intracranial tumors of the central nervous system (CNS), accounting for about one third of all brain tumors. Glioblastoma multiforme (GBM) is the aggressive grade IV glioma with survival as low as 2-5% in the second year post-diagnosis, hence necessitating efficient diagnostic markers. More than 50% of the non-small cell lung cancer (NSCLC) brain metastases are solitary lesions, often difficult to differentiate from gliomas by conventional imaging diagnostics. Here, we explored the utility of measuring serum expression levels of Micro-RNAs (miRs) 221, 608 and 504 as biomarkers for differentiating primary GBMs from solitary metastatic lesions of NSCLC. METHODS: Serum expression level of miRs 221, 608 and 504 were determined in 49 GBM, 27 NSCLC brain metastasis patients, and 30 cancer-free normal controls by real time PCR using commercially available miR specific primers. Mann-Whitney U test was used to compare the expression of each miR between each group. Receiver operating characteristics (ROC) curve analysis was also carried out to determine the feasibility of using miR expression as differential diagnosis test. RESULTS: Our results indicated that serum expression of mir-221 was upregulated in GBM as well as in metastatic NSCLC patients. Although both miR-608 and 504 were specifically downregulated only in the GBM patient group, ROC curve analysis showed that only miR-504 serum expression can be utilized as reliable differential diagnosis marker (sensitivity and specificity; 100 and 88.89% respectively). CONCLUSIONS: Serum expression level of miR-504 is a reliable biomarker to be used for differentiating primary GBM from solitary brain metastasis of NSCLC.

Erratum: Effect of granatin B on the glioma cancer by inducing apoptosis.

[This corrects the article on p. 3970 in vol. 8, PMID: 27725877.].

Effect of granatin B on the glioma cancer by inducing apoptosis.

Glioblastoma is a highly malignant cancer of glioma cells. Present study investigates the anti proliferative activity of granatin B on glioma cell by inducing apoptosis. In this study Glioma cell (U87) was used on which anti proliferative activity of granatin B (0, 20, 40 & 80 µM) assessed by 3-(4, 5-dimethylthylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Thereafter Apoptosis of glioma cell was assessed by apoptosis detection kit suing flow cytometer, DAPI staining and by estimating the activity of caspase 3 & 9 using caspase 3 & 9 kit. Expression of MMP9 protein was determined through gelatin zymography. Possible mechanism of apoptosis induction was proved by estimating the effect of granatin B with MMP9 agonist on cell proliferation, caspase 3 activity & MMP9 expression on glioblastoma cell. Result of the study suggested that granatin B significantly decreases the cell proliferation of glioma cell compared to 0 µM treated group. It was also observed that treatment with granatin B significantly induces apoptosis and increases the activity of caspase 3 & 9 protein compared to 0 µM treated group. Expression of MMP9 protein was also decreases with granatin B treatment of glima cell. MMP9 agonist significantly reverses the effect of granatin B on cell proliferation, caspase 3 and expression of MMP9 protein in glima cell. Present study concludes the anticancer activity of granatin B on glioblastoma cell by inducing apoptosis.

Combination therapy using Notch and Akt inhibitors is effective for suppressing invasion but not proliferation in glioma cells.

Molecular targeted therapy can potentially provide more effective treatment for patients with high-grade gliomas. Notch and Akt are notable target molecules as they play important roles in a variety of cellular processes, such as regeneration, differentiation, proliferation, migration, and invasion. Here, we assessed the therapeutic possibility of inhibiting Notch and Akt in gliomas using the clinically available, selective small molecule inhibitors MRK003 and MK-2206. We evaluated their efficacy individually and as a combination therapy in U251 and U87 glioma cell lines. We confirmed that MK-2206 effectively inhibits Akt phosphorylation in a dose-dependent manner, whereas MRK003 inhibits Notch signaling and Akt phosphorylation. Both MRK003 and MK-2206 significantly inhibited cell growth, migration, and invasion in a dose-dependent manner. Akt dephosphorylation was enhanced by combination therapy with MRK003 and MK-2206. However, the effect of combination treatment did not exceed that of MK-2206 monotherapy in proliferation assay. Inhibition of invasion, further enhanced by combination therapy, correlated with increased Akt inactivation. In summary, combination therapy with MRK003 and MK-2206 may be effective for inhibiting invasion but not proliferation.