Wuxi Clinical Science Research Institute

Wuxi, China

Wuxi Clinical Science Research Institute

Wuxi, China
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Yin Y.,Nanjing Medical University | Yin Y.,Wuxi Clinical Science Research Institute | Zhang X.,Nanjing Medical University | Zhang X.,Wuxi Clinical Science Research Institute | And 16 more authors.
Neurobiology of Disease | Year: 2013

Astrocytes react to central nervous system (CNS) injury and participate in gliotic responses, imparting negative, as well as positive effects on axonal regeneration. Despite the considerable biochemical and morphological changes astrocytes undergo following insult, and the known influence of steroids on glial activation, details surrounding glucocorticoid receptor expression and activity are lacking. Such mechanistic information is essential for advancing and enhancing therapies in the treatment of CNS injuries. Using an in vitro wound-healing assay, we found glucocorticoid receptor β (GRβ), not GRα, is upregulated and acts as a regulator of gliosis after injury. In addition, our results suggest that GRβ interacts with β-catenin and is a necessary component for proliferation and migration in both injured astrocytes and glioma cells. Further analysis indicated GRβ/β-catenin interaction as a key modulator of astrocyte reactivity through sustained Wnt/β-catenin/TCF signaling in its dominant-negative effect on GRα mediated trans-repression by a GSK-3β-independent manner. These findings expand our knowledge of the mechanism of GRβ action in promoting astrocyte proliferation and migration following injury and in glioma. This information furthers our understanding the function of glucocorticoid receptor in CNS injury and disease, as well as in the basic biochemical responses astrocytes undergo in response to injury and glioma pathogenesis. © 2013 Elsevier Inc.


Yin Y.,Nanjing Medical University | Yin Y.,Wuxi Clinical Science Research Institute | Sun W.,Nanjing Medical University | Xiang J.,Wuxi Clinical Science Research Institute | And 9 more authors.
Journal of Neuro-Oncology | Year: 2013

Our recent study demonstrated that glutamine synthetase (GS) may not only serve as a glutamate-converting enzyme in glial cells, but may also function as a regulator of astrocyte migration after injury. In this report, we showed that GS expression increased in cultured rat C6 glioma cells that underwent long-term serially propagation. The stable overexpression of GS in C6 glioma cells resulted in growth arrest and motility suppression; however the stable knockdown of GS resulted in motility enhancement. In correlation with cell aggregation, N-cadherin levels increased at sites of cell-cell contact in C6 cells overexpressing GS, and decreased in C6 cells with stable GS knockdown; total N-cadherin expression levels remained unchanged in these cells. In addition, levels of p21, a potent cyclin-dependent kinase inhibitor, increased, while cyclin D1 levels decreased in C6 cells overexpressing GS. Our additional studies showed that N-cadherin-mediated cell-cell contacts were implicated in GS-induced cell growth arrest and impairment of cell migration, as evidenced by the inhibition of GS on cell growth and motility by the neutralizing anti-N-cadherin monoclonal antibody (GC-4 mAb). Collectively, these observations suggest a novel mechanism of growth regulation by GS that involves N-cadherin mediated cell-cell contact. © 2013 Springer Science+Business Media New York.


Li Z.-W.,Nanjing Medical University | Li J.-J.,Shanghai JiaoTong University | Wang L.,The 9th Peoples Hospital of Wuxi | Zhang J.-P.,Nanjing Medical University | And 7 more authors.
Journal of Neuroinflammation | Year: 2014

Background: Astrogliosis is a common phenomenon after spinal cord injury (SCI). Although this process exerts positive effects on axonal regeneration, excessive astrogliosis imparts negative effects on neuronal repair and recovery. Epidermal growth factor receptor (EGFR) pathway is critical to the regulation of reactive astrogliosis, and therefore is a potential target of therapeutics to better control the response. In this report, we aim to investigate whether blocking EGFR signaling using an EGFR tyrosine kinase specific inhibitor can attenuate reactive astrogliosis and promote functional recovery after a traumatic SCI.Method: The astrocyte scratch injury model in vitro and the weight-drop SCI model in vivo were used as model systems. PD168393 was used to inhibit EGFR signaling activation. Astrocytic activation and phosphorylated EGFR (pEGFR) were observed after immunofluorescence staining and Western blot analysis. The rate of proliferation was determined by immunofluorescence detection of BrdU-incorporating cells located next to the wound. The levels of TNF-α, iNOS, COX-2 and IL-1β in the culture medium under different conditions were assayed by ELISA. Western blot was performed to semi-quantify the expression of EGFR/pEGFR, glial fibrillary acid protein (GFAP) and chondroitin sulfate proteoglycans (CSPGs). Myelin was stained by Luxol Fast Blue Staining. Cresyl violet eosin staining was performed to analyze the lesion cavity volume and neuronal survival following injury. Finally, functional scoring and residual urine recording were performed to show the rats' recovery.Results: EGFR phosphorylation was found to parallel astrocyte activation, and EGFR inhibitor PD168393 potently inhibited scratch-induced reactive astrogliosis and proinflammatory cytokine/mediator secretion of reactive astrocytes in vitro. Moreover, local administration of PD168393 in the injured area suppressed CSPGs production and glial scar formation, and resulted in reduced demyelination and neuronal loss, which correlated with remarkable hindlimb motor function and bladder improvement in SCI rats.Conclusions: The specific EGFR inhibitor PD168393 can ameliorate excessive reactive astrogliosis and facilitate a more favorable environment for axonal regeneration after SCI. As such, EGFR inhibitor may be a promising therapeutic intervention in CNS injury. © 2014 Li et al.; licensee BioMed Central Ltd.


Zou J.,Nanjing Medical University | Zou J.,Wuxi Clinical Science Research Institute | Wang Y.-X.,Shanghai JiaoTong University | Mu H.-J.,Nanjing Medical University | And 7 more authors.
Neurochemistry International | Year: 2011

Astrocytes undergo reactive transformation in response to physical injury (reactive gliosis) that may impede neural repair. Glutamine synthetase (GS) is highly expressed by astrocytes, and serves a neuroprotective function by converting cytotoxic glutamate and ammonia into glutamine. Glutamine synthetase was down-regulated in reactive astrocytes at the site of mechanical spinal cord injury (SCI) and in cultured astrocytes at the margins of a scratch wound, suggesting that GS may modulate reactive transformation and glial scar development. We evaluated this potential function of GS using siRNA-mediated GS knock-down. Suppression of astrocytic GS by GS siRNA increased cell migration into the scratch wound zone and decreased substrate adhesion as indicated by the number of focal adhesions expressing the adaptor protein paxillin. Migration was enhanced by glutamine and suppressed by glutamate, in contrast to the result expected if enhanced migration was due solely to changes in glutamine and glutamate concomitant with reduced GS activity. The membrane type 1-matrix metalloproteinase (MT1-MMP) was up-regulated in GS siRNA-treated astrocytes, while a broad-spectrum MMP antagonist inhibited migration in both wild type and GS knock-down astrocytes. In addition, GS siRNA inhibited expression of integrin β1, while antibody-mediated inhibition of integrin β1 impaired direction-specific protrusion and motility. Thus, GS may modulate motility and substrate adhesion through transmembrane integrin β1 signaling to the cytoskeleton and by MMT-mediated proteolysis of the extracellular matrix. © 2010 Elsevier Ltd. All rights reserved.


Yin Y.,Nanjing Medical University | Yin Y.,Wuxi Clinical Science Research Institute | Sun W.,Nanjing Medical University | Li Z.,Wuxi Clinical Science Research Institute | And 9 more authors.
Neurochemistry International | Year: 2013

Methylprednisolone (MP) has been widely used as a standard therapeutic agent for the treatment of spinal cord injury (SCI). Because of its controversial beneficial effects, the combination of MP and other pharmacological agents aimed at enhancing functional recovery is desirable. The phosphodiesterase 4 (PDE4) inhibitor rolipram has been implicated in promotion of regeneration due to elevating cAMP. In the present study, we sought to determine the effects of MP and rolipram, administered in combination, after spinal cord injury (SCI) in adult rats. Here we show that in vitro administration of rolipram and MP significantly increased neuron survival and promoted neurite outgrowth of neurons on the inhibitory substrate CSPGs by upregulation of MMP-2 expression; in vivo administration of rolipram and MP inhibited CSPG expression and increase CSPG digestion after rat SCI. Rolipram and MP combining treatment promoted significant neuroprotection through reduced motoneuron death, minimized lesion cavity, and increased regeneration of lesioned corticospinal tract (CST) axons beyond the lesion site after SCI. Enhanced functional recovery was also observed. Overall, our study strongly suggested that the combination treatment of MP and rolipram may represent a promising strategy for clinically applicable pharmacological therapy for rapid initiation of neuroprotection after SCI. © 2013 Elsevier Ltd.All rights reserved.


Liu C.,Huadong Sanitarium | Wu W.,Shanghai JiaoTong University | Zhang B.,Nanjing Medical University | Zhang B.,Wuxi Clinical Science Research Institute | And 3 more authors.
Molecular Medicine Reports | Year: 2013

Glutamine synthetase (GS) is an enzyme involved in an endogenous mechanism of protection against glutamate neurotoxicity and is important in the regulation of astrocyte migration. To date, limited information is available concerning the expression of GS in normal spinal cords and following injury. In the present study, GS expression was identified in astrocytes, oligodendrocytes and microglia in normal rat spinal cords. Following traumatic spinal cord injury (SCI), the glutamate concentration increased rapidly at 1 h and returned to baseline rapidly. However, the GS activity and protein levels were found to decrease at 4 h and then increase gradually from day 3 following SCI. The quantification of astrocytes, oligodendrocytes and activated microglia/macrophages, as well as immunohistochemistry staining of day 7 post-injured spinal cords, indicated that the astrocytes and microglia/macrophages contributed to the increase in GS. Collectively, the results provided evidence for the temporospatial expression and location of GS following SCI and suggested that the changes in GS levels may contribute to glutamate neurotoxicity and glial cell response following SCI.


Jiang M.,Jiangsu Institute of Nuclear Medicine | Jiang M.,Nanjing Medical University | Jiang M.,Wuxi Clinical Science Research Institute | Cai G.,Jiangsu Institute of Nuclear Medicine | And 3 more authors.
Asian Journal of Chemistry | Year: 2013

2-Bromo-2-methyl-propionic acid 4-benzothiazole-2-ylazo-phenyl ester (BPBE), 2-bromo-2-methyl-propionic acid 4-(6-methoxybenzothiazole-2-ylazo)phenyl ester (BPMBE) and 2-bromo-2-methyl-propionic acid 4-(6-nitro-benzothiazole-2- ylazo)phenyl ester (BPNBE) were synthesized and acted as initiators for the heterogeneous atom transfer radical polymerization of methyl methacrylate under copper(I) bromide/2,2′-bipyridine catalytic system, respectively. The azobenzothiazole-based end group of polymethyl methacrylate was characterized via UV-visible spectroscopy. All rates of polymerizations exhibited first-order kinetic with respect to the monomer and a linear increase in the number-average molecular weight with increasing monomer conversion was observed for all these initiation systems. The polydispersity indices of the polymethyl methacrylates were relatively low (1.08-1.37) up to high conversions at 60 °C. Moreover, the initiation systems exhibit a high activity that polymerizations could even be performed at ambient temperature (30 °C).

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