Hai-Feng Shu

Increased Expression of TRPV1 in the Cortex and Hippocampus from Patients with Mesial Temporal Lobe Epilepsy

Transient receptor potential vanilloid type-1 (TRPV1) is a ligand-gated nonselective cation channel that has been well characterized in peripheral pain pathway. Recent evidence from animal models of temporal lobe epilepsy (TLE) has supported the important role of TRPV1 in epileptogenesis. In this study, we investigated the expression and cellular distribution of TRPV1 in the temporal cortex (CTX) and hippocampus (HPC) from 26 patients with mesial TLE (MTLE) compared with 12 histologically normal samples. Reverse transcription-PCR and Western blotting revealed up-regulated mRNA and protein levels of TRPV1 in the MTLE group versus the control group. Immunohistochemistry data demonstrated that TRPV1 was mainly distributed in the cell bodies and dendrites of neurons. Double-labeled immunofluorescence further revealed that TRPV1 was localized on NeuN-positive neurons and GFAP-positive astrocytes, but not on HLA-positive microglia. In addition, its co-localization with glutamate and gamma-aminobutyric acid (GABA) indicated that TRPV1 was distributed on both glutamatergic and GABAergic neurons. Moreover, nerve growth factor, a sensitizing factor for TRPV1, was showed a higher expression pattern in MTLE patients. Taken together, our findings suggest that the overexpression and distribution patterns of TRPV1 might be involved in the pathogenesis and epileptogenesis of human MTLE.

Aerobic exercise for Parkinson's disease: a systematic review and meta-analysis of randomized controlled trials.

Background Although some trials assessed the effectiveness of aerobic exercise for Parkinsons disease (PD), the role of aerobic exercise in the management of PD remained controversial. Objective The purpose of this systematic review is to evaluate the evidence about whether aerobic exercise is effective for PD. Methods Seven electronic databases, up to December 2013, were searched to identify relevant studies. Two reviewers independently extracted data and assessed methodological quality based on PEDro scale. Standardised mean difference (SMD) and 95% confidence intervals (CI) of random-effects model were calculated. And heterogeneity was assessed based on the I2 statistic. Results 18 randomized controlled trials (RCTs) with 901 patients were eligible. The aggregated results suggested that aerobic exercise should show superior effects in improving motor actions (SMD, −0.57; 95% CI −0.94 to −0.19; p = 0.003), balance (SMD, 2.02; 95% CI 0.45 to 3.59; p = 0.01), and gait (SMD, 0.33; 95% CI 0.17 to 0.49; p<0.0001) in patients with PD, but not in quality of life (SMD, 0.11; 95% CI −0.23 to 0.46; p = 0.52). And there was no valid evidence on follow-up effects of aerobic exercise for PD. Conclusion Aerobic exercise showed immediate beneficial effects in improving motor action, balance, and gait in patients with PD. However, given no evidence on follow-up effects, large-scale RCTs with long follow-up are warrant to confirm the current findings.

Expression of the interleukin 6 system in cortical lesions from patients with tuberous sclerosis complex and focal cortical dysplasia type IIb.

Tuberous sclerosis complex (TSC) and focal cortical dysplasia type IIb (FCDIIb) are characterized by epilepsy-associated cerebral cortical malformations. To understand the potential role of the inflammatory cytokine interleukin 6 (IL-6) in the pathogenesis of these lesions, we analyzed the IL-6 system in TSC and FCDIIb cortical lesions and in control cortex (CTX). Greater messenger RNA and protein levels of IL-6 and of its receptors (i.e. IL-6 receptor [IL-6R] and glycoprotein 130 [gp130]) were observed in TSC and FCDIIb lesions versus CTX. Immunohistochemical analyses indicated that IL-6 and IL-6R were strongly expressed in misshapen cells, namely, dysmorphic neurons, giant neurons, and balloon cells. Glycoprotein 130 was diffusely expressed in nearly all cell types. Most IL-6/IL-6R+ misshapen cells colabeled with neuronal rather than astrocytic markers, suggesting a neuronal lineage; most IL-6/IL-6R+ balloon cells in FCDIIb expressed glial fibrillary acidic protein. Protein levels of Janus kinase 2 and phosphorylated signal transducer andactivatorof transcription 3 were greater than in CTX, suggesting involvement of the gp130-Janus kinase 2-signal transducer and activator of transcription 3 pathway in IL-6 signal transduction. Soluble IL-6R, but not soluble gp130, was greater in TSC and FCDIIb lesions than in CTX, indicating activation of this trans-signaling pathway. These results suggest that overexpression in the IL-6 system and activation of IL-6 signal transduction pathways may contribute to the pathogenesis of cortical lesions in TSC and FCDIIb.

The interleukin 17 system in cortical lesions in focal cortical dysplasias.

Focal cortical dysplasias (FCDs) are increasingly recognized as important causes of medically intractable epilepsy. To understand the potential role of the interleukin 17 (IL-17) system in the epileptogenesis of FCDs, we studied the expression patterns of the IL-17 system in 15 FCD type Ia (FCDIa), 12 FCD type IIa (FCDIIa), and 12 FCD type IIb (FCDIIb) cortical lesions and compared the results with those in cerebral cortex from 10 control patients. Protein levels of IL-17, IL-17 receptor (IL-17R), and downstream factors of the IL-17 pathway (nuclear factor-κB activator 1 [NFκB; ACT1] and NFκB-p65) were markedly elevated in FCDIa, FCDIIa, and FCDIIb. Moreover, protein levels of IL-17 and IL-17R positively correlated with the frequency of seizures in FCD patients. Immunostaining indicated that IL-17 and IL-17R are highly expressed in neuronal microcolumns, dysmorphic neurons, balloon cells, astrocytes, and vascular endothelial cells. Nuclear factor-κB activator 1 and NFκB-p65 were diffusely expressed in FCDs. In addition, we detected a few IL-17-positive, CD4-positive T lymphocytes in FCDIIa and FCDIIb but not in FCDIa. Taken together, these findings suggest that the overexpression of the IL-17 system and the activation of the IL-17 signal transduction pathway may be involved in the epileptogenicity of cortical lesions in FCDs, thus representing a novel potential target for antiepileptic therapy.

Increased expression of matrix metalloproteinase 9 in cortical lesions from patients with focal cortical dysplasia type IIb and tuberous sclerosis complex.

The malformative cortical lesions in the cerebral cortex that are characteristic of focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) are well-recognized causes of chronic intractable epilepsy in children. Increasing evidence suggests that extracellular matrix molecules play important roles in epileptogenesis. Matrix metalloproteinase 9 (MMP9), a typical extracellular matrix proteolytic protease, has been shown to participate in the occurrence of seizures in experimental models. In the present study, we used immunoblotting to analyze the levels of MMP9 protein in FCDIIb lesions, TSC tubers and control samples, which included epileptic neocortices from temporal lobe epilepsy and non-epileptic normal cortices (CTX). The cellular distribution of MMP9 was further investigated by immunohistochemical methods. Our findings demonstrated the elevated levels of the inactive and active forms of MMP9 protein in FCDIIb and TSC lesions compared with CTX. Furthermore, the immunohistochemical results showed that MMP9 was characteristically expressed in the following misshapen cells: hypertrophic neurons, dysmorphic neurons, balloon cells and giant cells. Additionally, double immunofluorescent staining revealed that the reactive astrocytes, but not the microglia, expressed high levels of MMP9. Taken together, our findings suggest that the overexpression and spatial distribution patterns of MMP9 may be linked with the intractable epilepsy caused by FCDIIb and TSC.

MicroRNA‑23a promotes neuroblastoma cell metastasis by targeting CDH1

CDH1 inactivation is important in tumor metastasis. In the present study, it was suggested that the mRNA and protein levels of CDH1 decreased in metastatic neuroblastoma (NB) tissues compared with those in primary NB tissues. The aim of the study was to explore the regulatory mechanisms of CDH1 downregulation in metastatic NB. MicroRNAs are small non-coding RNAs (~22 nt in length) that negatively regulate target mRNAs and are involved in various cancer-related processes, including metastasis. In the current study, miR-23a was shown to be upregulated in human metastatic NB tissues compared with primary NB tissues. Inhibition of miR-23a may significantly suppress NB cell migration and invasion. In vitro reporter assay suggested that CDH1 is a direct target gene of miR-23a. Furthermore, blocking the expression of miR-23a partly restored the expression of CDH1 in NB cells. These findings provide evidence that miR-23a is key in promoting NB cell migration and invasion through targeting CDH1, and suggest that exogenous miR-23a may have therapeutic value in treating NB metastasis.

Overexpression of MACC1 protein and its clinical implications in patients with glioma

Metastasis associated in colon cancer 1 (MACC1) has been regarded as a novel potential therapeutic target for multiple cancers. However, the impact of MACC1 in glioma remains unclear. The aim of this study was to analyze the correlation of MACC1 expression with the clinicopathological features of glioma. MACC1 mRNA and protein expression levels in human glioma tissues were detected by quantitative real-time polymerase chain reaction and immunohistochemistry assays, respectively. MACC1 mRNA and protein expression were both significantly higher in glioma tissues than in corresponding noncancerous brain tissues (both P < 0.001). In addition, statistical analysis suggested that high MACC1 expression was significantly correlated with advanced pathological grade (P = 0.004) and that patients with high expression of MACC1 protein exhibited a poorer prognosis than those with low MACC1 expression. Furthermore, Cox multivariate analysis showed that MACC1 overexpression was an independent prognostic factor for predicting the overall survival of glioma patients. In conclusion, expression of MACC1 in glioma could be adopted as a candidate biomarker for the diagnosis of clinical stage and for assessing prognosis, indicating for the first time that MACC1 may play an important role in the tumor development and progression in glioma. MACC1 might be considered as a novel therapeutic target against this cancer.

Expression of TRPV1 in cortical lesions from patients with tuberous sclerosis complex and focal cortical dysplasia type IIb

Tuberous sclerosis complex (TSC) and focal cortical dysplasia type IIb (FCDIIb) are recognized as causes of intractable epilepsy. Transient receptor potential vanilloid receptor 1 (TRPV1), a member of the transient receptor potential family, is the capsaicin receptor and is known to be involved in peripheral nociception. Recent evidence suggested that TRPV1 may be a contributing factor in epileptogenicity. Here, we evaluated the expression of TRPV1 in the cortical lesions of TSC and FCDIIb relative to normal control cortex. TRPV1 was studied in epilepsy surgery cases with TSC (cortical tubers; n=12) and FCDIIb (n=12) using immunocytochemistry, confocal analysis, and Western blotting (WB). Immunohistochemical location of the TRPV1 was predominately detected in the abnormal cell types, such as dysmorphic neurons, balloon cells (BCs) and giant cells. Co-localization assays further revealed that cells expressing TRPV1 mainly had a neuronal lineage, apart from some BCs in FCDIIb, which obviously were of astrocytic lineage. The increased TRPV1 expression within the dysplastic cortex of TSC and FCDIIb was confirmed by WB. Interestingly, both immunohistochemical and WB data indicated that TRPV1 might have both cytoplasm and nuclear distribution, suggesting a potential nuclear role of TRPV1. The over-expression of TRPV1 in cortical lesions of TSC and FCDIIb suggested the possible involvement of TRPV1 in the intrinsic and increased epileptogenicity of malformations of cortical development associated epilepsy diseases and may represent a potential antiepileptogenic target. However, the current data are merely descriptive, and further electrophysiological investigation is needed in the future.

The modulatory effects of bHLH transcription factors with the Wnt/β-catenin pathway on differentiation of neural progenitor cells derived from neonatal mouse anterior subventricular zone

The subventricular zone (SVZ) located adjacent to the lateral ventricles is the major site where neural progenitor cells (NPCs) are concentrated in the adult brain. NPCs in the anterior subventricular zone (SVZa) generate neuronal precursors and migrate along a highly localized pathway--the rostral migratory stream (RMS) to the olfactory bulb (OB), where they differentiate into interneurons. To investigate the modulatory effects of basic helix-loop-helix (bHLH) transcription factors on differentiation from SVZa NPCs, we firstly examined the distribution of bHLH family members (Mash1, Id2, and Hes1) in cultured mouse SVZa NPCs and evaluated their regulatory effects on differentiation by transfection with Mash1, Id2, or Hes1 eukaryotic expression plasmid. Furthermore, we assessed the effects of bHLH transcription factors on the expression of downstream molecules of the Wnt/beta-catenin pathway, beta-catenin and (Glycogen synthase kinase-3beta). Our results demonstrated that Mash1, Id2, Hes1 were all widely expressed in in vitro progenies from mouse SVZa NPCs. Analyses of SVZa NPCs transfected with eukaryotic expression plasmids showed that Mash1 promoted neuronal differentiation from SVZa NPCs, while Id2 and Hes1 repressed neuronal differentiation. In addition, we found that Id2 and Hes1 simulated expression of beta-catenin and GSK-3beta, while Mash1 inhibited their expression. Our results suggest that the classic bHLH transcription factors, Mash1, Id2 and Hes1, play important roles in the regulation of differentiation from SVZa NPCs. This modulation is possibly mediated by a coordination of bHLH and Wnt/beta-catenin signaling.

Comparison of the safety and efficacy of propofol with midazolam for sedation of patients with severe traumatic brain injury: a meta-analysis.

OBJECTIVE To perform a meta-analysis to compare the safety and efficacy of propofol with midazolam for sedation of patients with severe traumatic brain injury. MATERIALS AND METHODS Studies were included in the meta-analysis if they met the following criteria: randomized controlled trial of sedative-hypnotic agents including propofol and midazolam; patients had severe traumatic brain injury; the primary outcome was the Glasgow Outcome Scale score; secondary outcomes included mortality, therapeutic failure, intracranial pressure, and cerebral perfusion pressure. The data were analyzed using software for meta-analysis. RESULTS Seven relevant studies were identified. Three of these studies were excluded: one was a single-arm study, one compared morphine and propofol, and for one the full text article could not be obtained. The remaining 4 studies were included in the meta-analysis. The results of the meta-analysis showed that propofol and midazolam have similar effects on the Glasgow Outcome Scale score, mortality, intracranial pressure, and cerebral perfusion pressure. CONCLUSION Our meta-analysis of 4 studies showed that there are no important differences between propofol and midazolam when administered to provide sedation for patients with severe traumatic brain injury. Further randomized, controlled trials comparing propofol with midazolam for sedation of such patients are needed.