Xiao-Yuan Mao

Huperzine A Ameliorates Cognitive Deficits in Streptozotocin-Induced Diabetic Rats

The present study was designed to probe the effects of Huperzine A (HupA) on diabetes-associated cognitive decline (DACD) using a streptozotocin (STZ)-injected rat model. Diabetic rats were treated with HupA (0.05 and 0.1 mg/kg) for seven weeks. Memory functions were evaluated by the water maze test. Nissl staining was selected for detecting neuronal loss. Protein and mRNA levels of brain-derived neurotrophic factor (BDNF) were analyzed by ELISA and real-time PCR, respectively. The activities of choline acetylase (ChAT), Acetylcholinesterase (AChE), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), NF-κB p65 unit, TNF-α, IL-1β, IL-6 and caspase-3 were measured using corresponding kits. After seven weeks, diabetic rats exhibited remarkable reductions in: body weight, percentage of time spent in target quadrant, number of times crossing the platform, ChAT and BDNF levels, SOD, GSH-Px and CAT accompanied with increases in neuronal damage, plasma glucose levels, escape latency, mean path length, AChE, MDA level as well as CAT, NF-κB p65 unit, TNF-α, IL-1β, IL-6 and caspase-3 in cerebral cortex and hippocampus. Supplementation with HupA significantly and dose-dependently reversed the corresponding values in diabetes. It is concluded that HupA ameliorates DACD via modulating BDNF, oxidative stress, inflammation and apoptosis.

Topiramate protects against glutamate excitotoxicity via activating BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons

Topiramate (TPM) was previously found to have neuroprotection against neuronal injury in epileptic and ischemic models. However, whether TPM protects against glutamate-induced excitotoxicity in hippocampal neurons is elusive. Our present work aimed to evaluate the protective effect of TPM against glutamate toxicity in hippocampal neurons and further figure out the potential molecular mechanisms. The in vitro glutamate excitotoxic model was prepared with 125μM glutamate for 20min. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) analysis and Hoechst 33342 staining were conducted to detect neuronal survival. The protein expressions of brain-derived neurotrophic factor (BDNF), TrkB, mitogen-activated protein kinase (MAPK) cascade (including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK), cyclic AMP response element binding protein (CREB), Bcl-2, Bax and β-actin were detected via Western blot assay. Our results demonstrated that TPM protected hippocampal neurons from glutamate toxicity. Meanwhile, the pretreatment of TPM for 10min significantly prevented the down-regulation of BDNF and the phosphorylation of TrkB. Furthermore, the elevation of phosphorylated EKR expression was significantly inhibited after blockade of TrkB by TrkB IgG, while no alterations of phosphorylated JNK and p38 MAPK were found in the cultured hippocampal neurons. Besides, it was also found that the enhanced phosphorylation of CREB was evidently reversed under excitotoxic conditions after treating with U0126 (the selective inhibitor of ERK). The protein level of Bcl-2 was also observed to be remarkably increased after TPM treatment. In conclusion, these findings implicate that TPM exerts neuroprotective effects against glutamate excitotoxicity in hippocampal neurons and its protection may be modulated through BDNF/TrkB-dependent ERK pathway.

Gene-Wide Tagging Study of the Association Between KCNT1 Polymorphisms and the Susceptibility and Efficacy of Genetic Generalized Epilepsy in Chinese Population

The causes of genetic generalized epilepsies (GGEs) are still uncertain now. Some studies found that the human potassium channel, subfamily T, member 1 (KCNT1) is the candidate gene causing malignant migrating partial seizures of infancy and autosomal dominant nocturnal frontal lobe epilepsy which are all rare genetic generalized epilepsies. The aims of this study were going to evaluate the association between KCNT1 common variations and the susceptibility and drug resistance of genetic generalized epilepsies in Chinese population.

Gap junction as an intercellular glue: Emerging roles in cancer EMT and metastasis

Metastasis is a common phenomenon in the progression and dissemination of cancer. It is estimated that metastasis accounts for 90% cancer-related mortality. Although the formation of tumor metastasis is relatively well understood, the underlying molecular mechanisms responsible for the emergence of aggressive cancer phenotype are still elusive. Figuring out the mechanisms by which cancer cells evade from the tumor is beneficial for obtaining novel and effectively therapeutic approaches. Primary tumors are composed of various subpopulations of cells with heterogeneous metastatic characteristics and the occurrence of metastatic dissemination is mainly dependent upon the interactions between tumor and the surrounding microenvironment. Tumor microenvironment (TME) such as extracellular matrix, macrophages, fibroblasts, stem cells and endothelial cells can orchestrate events critical to tumor evolution toward metastasis. GJ serves as an important communication between tumor cells and stromal cells. Increased GJs coupling blocks metastatic potential in some cancer animal models such as breast cancer and melanoma. Besides, epithelial-to-mesenchymal transition (EMT) is also a crucial step in the metastatic process and there are signs that GJs contribute to cell adhesion and migration (the pathological feature of EMT) in breast cancer. Therefore, we propose that GJ serves as an intercellular glue to suppress EMT and cancer metastasis.

Comparison of the predictive abilities of pharmacogenetics-based warfarin dosing algorithms using seven mathematical models in Chinese patients

AIM This study is aimed to find the best predictive model for warfarin stable dosage. MATERIALS & METHODS Seven models, namely multiple linear regression (MLR), artificial neural network, regression tree, boosted regression tree, support vector regression, multivariate adaptive regression spines and random forest regression, as well as the genetic and clinical data of two Chinese samples were employed. RESULTS The average predicted achievement ratio and mean absolute error of the algorithms were ranging from 52.31 to 58.08% and 4.25 to 4.84 mg/week in validation samples, respectively. The algorithm based on MLR showed the highest predicted achievement ratio and the lowest mean absolute error. CONCLUSION At present, MLR may be still the best model for warfarin stable dosage prediction in Chinese population. Original submitted 10 November 2014; Revision submitted 18 February 2015.

Baicalein ameliorates cognitive deficits in epilepsy-like tremor rat.

Baicalein has been shown to possess various pharmacological actions. The current work was designed to assess the neuroprotection of baicalein against cognitive deficits in epilepsy-like tremor rat (TRM). Epileptic characteristics and memory functions were assessed by electroencephalograms recording and Morris water maze test, respectively. The changes of oxidative indicators including malondialdehyde (MDA), catalase (CAT), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), Mn-SOD, glutathione (GSH), glutathione peroxidase (GSH-PX) and 8-isoprostane were measured using corresponding commercial kits. Real-time RT-PCR and immunoassay were employed to detect activities of various inflammatory mediators such as NF-κB p65, TNF-α, IL-1β, IL-6 and IL-10. Western blot analysis was performed to determine heat shock protein (HSP) 70 and mitogen-activated protein kinases (MAPKs) (including ERK, JNK and p38) proteins. Our results illustrated that baicalein significantly ameliorated epileptiform activity and cognitive deficits in TRM. Besides, reduced oxidative stress and inflammatory responses were also found in TRM treated with baicalein. Furthermore, there were evident alterations of HSP70 and MAPK cascades at protein levels after 14-day pretreatment with baicalein. It was concluded that the neuroprotective effect of baicalein against cognitive dysfunction might be associated with suppressing oxidative stress, inhibiting inflammation and mediating HSP70 as well as MAPK cascades in absence-like TRM.

A critical overview of long non-coding RNA in glioma etiology 2016: an update

With the development of whole genome and transcriptome sequencing technologies, a growing body of long non-coding RNAs (lncRNAs) has been identified and is receiving increasing attention. LncRNAs are non-protein encoding transcripts whose functions are crucial for advancing our comprehensive understanding of biological processes in human health and diseases, specifically glioma. It has been established that lncRNAs are differently expressed in the central nervous system and may play a vital role in glioma. As of June 2016, 20 lncRNAs have been identified that may play a role in glioma pathogenesis. Investigation into the role of lncRNAs in glioma may help to identify potential biomarkers which can improve the diagnosis and treatment of glioma. In this paper, we review current understanding of the function of lncRNAs in glioma initiation and progression.

Effect of CYP2C9–VKORC1 interaction on warfarin stable dosage and its predictive algorithm

This study aimed to identify the effect of CYP2C9–VKORC1 interaction on warfarin dosage requirement and its predictive algorithm by investigating four populations. Generalized linear model was used to evaluate the relationship between the interaction and warfarin stable dosage (WSD), whereas multiple linear regression analysis was applied to construct the WSD predictive algorithm. To evaluate the effect of CYP2C9–VKORC1 interaction on the predictive algorithms, we compared the algorithms with and without the interaction. The interaction was significantly associated with WSD in the Chinese and White cohorts (P values < 0.05). In the algorithms that considered the interaction, the predictive success rates improved by only 0.12% in the Chinese patients and by a maximum of 0.02% in the White patients under four different CYP2C9 classifications. Thus, VKORC1–CYP2C9 interaction can affect WSD. However, the discrepancy between the predictive results obtained using the predictive algorithm with and without CYP2C9–VKORC1 interaction was negligible and can therefore be disregarded.

Silencing of Forkhead box D1 inhibits proliferation and migration in glioma cells

Despite the extensive role of Forkhead box transcription factors in the development and progression of various cancers, little is known about their role in glioma. We examined the expression and function of Forkhead box D1 (FOXD1) in glioma cell behavior and found that FOXD1 was upregulated and directly correlated with the glioma grade. Data analysis also revealed significant differences in FOXD1 expression for both gene expression profiles (GSE4290 and GSE7696) and the TCGA datasets. Additionally, decreased FOXD1 expression in U251 and U87 glioma cells caused a delay in cell growth and a disruption in colony formation. FOXD1 silencing also promoted generation of apoptotic bodies containing nuclear fragments. Cells with suppressed expression of FOXD1 markedly reduced glioma cell migration. Our results suggest that FOXD1 may serve as a novel regulator of glioblastoma cell behavior that may offer a novel target for gene targeted glioma therapies.

Prognostic and predictive values of CDK1 and MAD2L1 in lung adenocarcinoma

Lung cancer remains as the leading cause of cancer-related death worldwide, and lung adenocarcinoma (LUAD) is the most common histological subtype. This study aims to investigate biomarkers associated with cancer progression and prognosis of LUAD. We integrated expression profiles of 668 lung cancer patients in five datasets from the Gene Expression Omnibus (GEO) and identified a panel of differentially expressed genes (DEGs). Function enrichment analysis highlighted that these genes were closely associated with the carcinogenesis of LUAD, such as cell cycle, ECM-receptor interaction and p53 signaling pathway. Cyclin-dependent kinase 1 (CDK1) and MAD2 mitotic arrest deficient-like 1 (MAD2L1), two critical mitotic checkpoint genes, were selected for further study. Elevated expression of CDK1 and MAD2L1 was validated in an independent LUAD cohort. Kaplan-Meier analysis revealed that CDK1 and MAD2L1 expression was negatively correlated with both overall survival (OS) and relapse-free survival (RFS). In conclusion, CDK1 and MAD2L1 were adverse prognostic biomarkers for LUAD whose increased expression could render patients with LUAD a high risk of cancer recurrence and poor survival, suggesting that they might be applied as potential targets for LUAD treatment.