Neural stem cell-derived exosome as a nano-sized carrier for BDNF delivery to a rat model of ischemic stroke.

Our previous study demonstrated the potential therapeutic role of human neural stem cell-derived exosomes (hNSC-Exo) in ischemic stroke. Here, we loaded brain-derived neurotrophic factor (BDNF) into exosomes derived from NSCs to construct engineered exosomes (BDNF-hNSC-Exo) and compared their effects with those of hNSC-Exo on ischemic stroke both in vitro and in vivo. In a model of H2O2-induced oxidative stress in NSCs, BDNF-hNSC-Exo markedly enhanced cell survival. In a rat middle cerebral artery occlusion model, BDNF-hNSC-Exo not only inhibited the activation of microglia, but also promoted the differentiation of endogenous NSCs into neurons. These results suggest that BDNF can improve the function of NSC-derived exosomes in the treatment of ischemic stroke. Our research may support the clinical use of other neurotrophic factors for central nervous system diseases.

Effect of differential hypoxia-related gene expression on glioblastoma.

OBJECTIVE: Glioblastoma (GB) is a refractory malignancy with a high rate of recurrence and treatment resistance. Hypoxia-related genes are promising prognostic indicators for GB, so we herein developed a reliable hypoxia-related gene risk scoring model to predict the prognosis of patients with GB. METHOD: Gene expression profiles and corresponding clinicopathological features of patients with GB were obtained from the Cancer Genome Atlas (TCGA; n = 160) and Gene Expression Omnibus (GEO) GSE7696 (n = 80) databases. Univariate and multivariate Cox regression analyses of differentially expressed hypoxia-related genes were performed using R 3.5.1 software. RESULT: Fourteen prognosis-related genes were identified and used to construct a risk signature. Patients with high-risk scores had significantly lower overall survival (OS) than those with low-risk scores. The median risk score was used as a critical value and for OS prediction in an independent external verification GSE7696 cohort. Risk score was not significantly affected by clinical-related factors. We also developed a prediction nomogram based on the TCGA training set to predict survival rates, and included six independent prognostic parameters in the TCGA prediction model. CONCLUSION: We determined a reliable hypoxia-related gene risk scoring model for predicting the prognosis of patients with GB.

Cerebral dopamine neurotrophic factor promotes the proliferation and differentiation of neural stem cells in hypoxic environments.

Previous research found that cerebral dopamine neurotrophic factor (CDNF) has a protective effect on brain dopaminergic neurons, and CDNF is regarded as a promising therapeutic agent for neurodegenerative diseases. However, the effects of CDNF on the proliferation, differentiation, and apoptosis of neural stem cells (NSCs), which are very sensitive to hypoxic environments, remain unknown. In this study, NSCs were extracted from the hippocampi of fetal rats and cultured with different concentrations of CDNF. The results showed that 200 nM CDNF was the optimal concentration for significantly increasing the viability of NSCs under non-hypoxic environmental conditions. Then, the cells were cultured with 200 nM CDNF under the hypoxic conditions of 90% N2, 5% CO2, and 5% air for 6 hours. The results showed that CDNF significantly improved the viability of hypoxic NSCs and reduced apoptosis among hypoxic NSCs. The detection of markers showed that CDNF increased the differentiation of hypoxic NSCs into neurons and astrocytes. CDNF also reduced the expression level of Lin28 protein and increased the expression of Let-7 mRNA in NSCs, under hypoxic conditions. In conclusion, we determined that CDNF was able to reverse the adverse proliferation, differentiation, and apoptosis effects that normally affect NSCs in a hypoxic environment. Furthermore, the Lin28/Let-7 pathway may be involved in this regulated function of CDNF. The present study was approved by the Laboratory Animal Centre of Southeast University, China (approval No. 20180924006) on September 24, 2018.

The safety and efficacy of magnetic nano-iron hyperthermia therapy on rat brain glioma.

Gliomas are a group of heterogeneous primary central nervous system tumors arising from glial cells. These tumors are associated with high morbidity and mortality. New opportunities for the development of effective therapies for malignant gliomas are urgently needed. Magnetic nano-particles can heat up tumor tissues and induce the killing of cancer cells. However, the in vivo action of magnetic nano-iron hyperthermia on brain gliomas has not been widely investigated. The safety, efficacy, and suitable dose of hyperthermia therapy remain unknown. We successfully established a rat model of brain glioma by injecting C6 glioma cells into the right caudate nuclei of rats. Fixed doses (2.5, 5, or 10 mg) of magnetic nano-iron were then injected into the tumors of tumor-bearing rats. The survival time of tumor-bearing rats was subsequently observed, and imaging studies were conducted on the brain tumors. Of the 80 rats that underwent C6 glioma cell implantation, 70 exhibited decreased mobility and appetite, and wasting. Establishment of this brain glioma model was confirmed to be successful by magnetic resonance imaging. After injection of different doses of magnetic nano-iron, the survival times of the different dose groups of tumor-bearing rats were not significantly different. However, the tumor size exhibited a significant decrease with magnetic nano-iron hyperthermia therapy. Injection of various doses of magnetic nano-iron was safe in tumor-bearing rats. The effective doses were 2.5 and 5 mg. Magnetic nano-iron hyperthermia significantly shrank the brain gliomas in tumor-bearing rats.

[Repairing front skull base and saddle bottom of cerebrospinal fluid rhinorrhea under endoscopy].

OBJECTIVE: To explore the methods and techniques of repairing cerebrospinal fluid (CSF) rhinorrhea and reconstructing the defects of skull base under endoscopy. METHODS: The clinical data of 26 patients undergoing endoscopic repair of CSF rhinorrhea were analyzed retrospectively. There were 19 males and 7 females with an average age of 31.5 years old. Rhinorrhea was classified into 4 types: ethmoidal sinus type (n = 6), sphenoid sinus type (n = 14) and mixed type (n = 6) and frontal sinus type (n = 0). RESULTS: The causes of rhinorrhea were as follows: traumatic leakage (n = 17), post-operative breakage of saddle area (n = 6), damage after endonasal surgery (n = 2) rhinorrhea after gamma-knife for pituitary (n = 1). All cases were successfully repaired via an endoscopic endonasal approach. Among them, 22 patients were repaired only once while 4 patients with recurrent CSF rhinorrhea were repaired again. The follow-up period was from 6 months to 4 years. And satisfactory outcomes were achieved in all. CONCLUSION: Accurate localization of CSF leakage, reliable reconstruction of skull base, secure fixation of adhesive materials and continuous lumbar CSF drainage are keys surgical techniques. Endoscopic repair of front skull base and saddle bottom of CSF rhinorrhea is a reliable, effective and mini-invasive surgical approach worth further popularization.

Enhanced cancer therapy with the combination of EGFR and VEGFR-2 targeting in an orthotopic glioblastoma model.

Using an orthotopic glioblastoma model, we investigated the activity of the combination of monoclonal antibody DC101 against vascular endothelial growth factor receptor-2 (VEGFR-2) and monoclonal antibody C225 against epidermal growth factor receptor (EGFR). Nude mice bearing intracerebral glioblastoma xenografts were administered either DC101 or C225, or the combination via intraperitoneal (i.p.) injection. Histopathological analysis of solid tumor volume, microvessel density, tumor cell proliferation and apoptosis were performed. In the DC101-treated group, solid tumor volume and microvessel density were reduced by 59.7% and 64%, respectively. The tumor cell proliferation level was reduced by 53.2% and tumor cell apoptosis was increased by 66.7% but there was enhanced tumor cell invasiveness. C225 alone reduced the invasiveness of tumor tissue, but had no effect on solid tumor growth, microvessel density, tumor cell proliferation or apoptosis. The combination cancer therapy with C225 and DC101 enhanced tumor treatment with reduced tumor volume, microvessel density, tumor cell proliferation level, and increased cancer cell apoptosis, while decreasing tumor cell invasiveness.