Tianjin Key Laboratory of Injuries

Tianjin, China

Tianjin Key Laboratory of Injuries

Tianjin, China

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Yang X.,China National Academy of Nanotechnology and Engineering | Liu X.,China National Academy of Nanotechnology and Engineering | Zhang X.,China National Academy of Nanotechnology and Engineering | Lu H.,China National Academy of Nanotechnology and Engineering | And 4 more authors.
Ultramicroscopy | Year: 2011

PC12 cells derived from rat pheochromocytoma can differentiate into sympathetic-neuron-like cells in response to nerve growth factor (NGF). These cells have been proved to be a useful cell model to study neuronal differentiation. NGF induces rapid changes in membrane morphology, neurite outgrowth, and electrical excitability. However, the relationship between the 3D morphological changes of NGF-differentiated PC12 cells and their electrophysiological functions remains poorly understood.In this study, we combined a recently developed Hopping Probe Ion Conductance Microscopy (HPICM) with patch-clamp technique to investigate the high-resolution morphological changes and functional ion-channel development during the NGF-induced neuronal differentiation of PC12 cells. NGF enlarged TTX-sensitive sodium currents of PC12 cells, which associated with cell volume, membrane surface area, surface roughness of the membrane, and neurite outgrowth. These results demonstrate that the combination of HPICM and patch-clamp technique can provide detailed information of membrane microstructures and ion-channel functions during the differentiation of PC12 cells, and has the potential to become a powerful tool for neuronal research. © 2011 Elsevier B.V.

Ning X.,Tianjin Medical University | Shi Z.,Tianjin Medical University | Shi Z.,Tianjin Neurological Institute | Shi Z.,Key Laboratory of Post trauma Neuro repair and Regeneration in Central Nervous System | And 17 more authors.
Cancer Letters | Year: 2015

Aberrant expression of the microRNA-200 (miR-200) family has been linked to the occurrence and development of various types of malignant tumors, including hepatocellular carcinoma (HCC), colon cancer and breast cancer. However, little is known about the precise mechanism by which miR-200 expression is downregulated. The intricate relationship between DNA methylation and histone modifications has become a subject of increasing interest. The expression of miR-200 family members is modified by similar or complementary epigenetic mechanisms in MGC-803 and BGC-823 gastric cancer cells and U87 MG glioma cells. Chromatin immunoprecipitation assays revealed that DNA methyltransferase 1 (DNMT1) bound to miR-200b/a/429 promoter regions, indicating an interaction between DNMT1 and the miR-200b/a/429 promoter. Furthermore, Co-Immunoprecipitation (Co-IP) detection showed that DNMT1, together with the PcG protein Enhancer of Zeste homolog 2 (EZH2), a histone methyltransferase, contributed to the transcriptional repression of microRNA-200 family members. Knockdown of EZH2 not only impacted H3K27 trimethylation but also reduced DNMT1 presence on the miR-200b/a/429 promoter. EZH2 appeared to be essential for DNMT1 recruitment to the promoter region. Silencing EZH2 and DNMT1 using drugs or RNA interference dramatically reduced the levels of miR-200b/a/429 expression. Collectively, these results indicated that EZH2 and DNMT1-mediated epigenetic silencing contributed to the progression of gastric cancer and glioblastoma, and therefore represents a novel therapeutic target for malignant tumors. © 2015 Elsevier Ireland Ltd.

Zheng Q.,Harbin Medical University | Zheng Q.,Heilongjiang Provincial Key Laboratory for Infection and Immunity | Han L.,Tianjin Medical University | Han L.,Tianjin Neurological Institute | And 27 more authors.
Neuro-Oncology | Year: 2014

Background. As a commonly mutated form of the epidermal growth factor receptor, EGFRvIII strongly promotes glioblastoma (GBM) tumor invasion and progression, but the mechanisms underlying this promotion are not fully understood. Methods. Through gene manipulation, we established EGFRvIII-, wild-type EGFR-, and vector-expressing GBM cells. We used cDNA microarrays, bioinformatics analysis, target-blocking migration and invasion assays, Western blotting, and an orthotopic U87MG GBM model to examine the phenotypic shifts and treatment effects of EGFRvIII expression in vitro and in vivo. Confocal imaging, co-immunoprecipitation, and siRNA assays detected the focal adhesion-associated complex and their relationships to the EGFRvIII/JAK2/STAT3 axis in GBM cells. Results. The activation of JAK2/STAT3 signaling is vital for promoting migration and invasion in EGFRvIII-GBM cells. AG490 or WP1066, the JAK2/STAT3 inhibitors, specifically destroyed EGFRvIII/JAK2/STAT3-related focal adhesions and depleted the activation of EGFR/Akt/FAK and JAK2/STAT3 signaling, thereby abolishing the ability of EGFRvIII-expressing GBM cells to migrate and invade. Furthermore, the RNAi silencing of JAK2 in EGFRvIII-expressing GBM cells significantly attenuated their ability to migrate and invade; however, as a result of a potential EGFRvIII-JAK2-STAT3 activation loop, neither EGFR nor STAT3 knockdown yielded the same effects. Moreover, AG490 or JAK2 gene knockdown greatly suppressed tumor invasion and progression in the U87MG-EGFRvIII orthotopic models. Conclusion. Taken together, our data demonstrate that JAK2/STAT3 signaling is essential for EGFRvIII-driven migration and invasion by promoting focal adhesion and stabilizing the EGFRvIII/JAK2/STAT3 axis. Targeting JAK2/STAT3 therapy, such as AG490, may have potential clinical implications for the tailored treatment of GBM patients bearing EGFRvIII-positive tumors. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

Wang Y.,Capital Medical University | Chen L.,Harbin Medical University | Bao Z.,Capital Medical University | Li S.,Capital Medical University | And 11 more authors.
Oncology Reports | Year: 2011

Activation of signal transducer and activator of trans- cription 3 (STAT3) is associated with poor clinical outcome of glioblastoma (GBM). However, the role of STAT3 in resistance to alkylator-based chemotherapy remains unknown. Here, we retrospectively analyzed the phosphorylated STAT3 (p-STAT3) profile of 68 GBM patients receiving alkylator therapy, identifying p-STAT3 as an independent unfavorable prognostic factor for progression-free and overall survival. Additionally, elevated p-STAT3 expression correlated with resistance to alkylator therapy. In vitro analysis revealed that U251 and U87 human glioma cells were refractory to treatment with the common alkylating agent temozolomide (TMZ), with only a modest impact on AKT and β-catenin activation in the context of high p-STAT3. Inhibition of STAT3 in these cells significantly enhanced the effect of TMZ. Inhibition of STAT3 dramatically decreased the IC50 of TMZ, increasing TMZ-induced apoptosis while up-regulating expression of Bcl-2 and down-regulating expression of Bax. Furthermore, inhibition of STAT3 increased TMZ-induced G0-G1 arrest and decreased Cyclin D1 expression compared to TMZ alone. Together, these results indicate that inhibition of STAT3 sensitizes glioma cells to TMZ, at least in part, by blocking the p-AKT and β-catenin pathways. These findings strongly support the hypothesis that STAT3 inhibition significantly improves the clinical efficacy of alkylating agents.

Sun L.,Tianjin Medical University | Sun L.,Tianjin Key Laboratory of Injuries | Yang L.,Tianjin Medical University | Yang L.,Tianjin Key Laboratory of Injuries | And 10 more authors.
Nitric Oxide - Biology and Chemistry | Year: 2013

Peroxynitrite-mediated protein tyrosine nitration represents a crucial pathogenic mechanism of stroke. Hydroxysafflor yellow A (HSYA) is the most important active component of the safflower plant. Here we assess the neuroprotective efficacy of HSYA and investigate the mechanism through anti-nitrative pathway. Rats were subjected to 60-min ischemia followed by reperfusion. HSYA (2.5-10 mg/kg) was injected at 1 h after ischemia onset. Other groups received HSYA (10 mg/kg) treatment at 3-9 h after onset. Infarct volume, brain edema, and neurological score were evaluated at 24 h after ischemia. Nitrotyrosine and inducible NO synthase (iNOS) expression, as well as NO level (nitrate/nitrite) in ischemic cortex was examined within 24 h after ischemia. The ability of HSYA to scavenge peroxynitrite was evaluated in vitro. Infarct volume was significantly decreased by HSYA (P < 0.05), with a therapeutic window of 3 h after ischemia at dose of 10 mg/kg. HSYA treatment also reduced brain edema and improved neurological score (P < 0.05). Nitrotyrosine formation was dose- and time-dependently inhibited by HSYA. The time window of HSYA in decreasing protein tyrosine nitration paralleled its action in infarct volume. HSYA also greatly reduced iNOS expression and NO content at 24 h after ischemia, suggesting prevention of peroxynitrite generation from iNOS. In vitro, HSYA blocked authentic peroxynitrite-induced tyrosine nitration in bovine serum albumin and primary cortical neurons. Collectively, our results indicated that post-ischemic HSYA treatment attenuates brain ischemic injury which is at least partially due to reducing nitrotyrosine formation, possibly by the combined mechanism of its peroxynitrite scavenging ability and its reduction in iNOS production. © 2013 Elsevier Inc. All rights reserved.

Gong D.,Royal Melbourne Hospital | Gong D.,Tianjin Medical University | Gong D.,Tianjin Neurological Institute | Gong D.,Key Laboratory of Post trauma Neuro repair and Regeneration in Central Nervous System | And 4 more authors.
Journal of Stroke and Cerebrovascular Diseases | Year: 2014

We describe a case of successful management of a growing basilar artery dissecting aneurysm by the Pipeline flow diversion embolization device (PED). A 48-year-old woman presented with severe headache, neck pain, and altered consciousness. Computed tomography showed subarachnoid hemorrhage located in basal cisterns, with a pontine infarct shown on magnetic resonance imaging. Digital subtraction angiography showed dissecting aneurysm of the trunk of the basilar artery, with growth over time on repeated imaging. Repeated imaging demonstrated growth in size of the aneurysm. The aneurysm was treated with PED with complete obliteration of the basilar artery aneurysm. Subsequent follow-up demonstrated good clinical recovery. © 2014 by National Stroke Association.

Liu Z.,Fifth Central Hospital of Tianjin | Jiang Z.,Fifth Central Hospital of Tianjin | Huang J.,Duke University | Huang S.,Duke University | And 7 more authors.
International Journal of Oncology | Year: 2014

Epidermal growth factor receptor (EGFR) signaling regulates glioblastoma cell proliferation, survival, migration and invasion and plays a key role in tumor progression. We show that microRNA-7 (miR-7) is a common regulator of the phosphoinositide-3-kinase (PI3K)/ATK and Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways, both of which are launched by EGFR through its two direct targets, the transcription factors PI3K and Raf-1, respectively. Enforced expression of miR-7 markedly decreased expression of PI3K, phosphorylated Akt, Raf-1, phosphorylated MEK 1/2, and cyclin D1, as well as slightly reduced expression of EGFR. Forced expression of PI3K or Raf-1 transcripts lacking the 3′-untranslated region (3′-UTR) partially reversed the effects of miR-7 on cell growth inhibition and cell cycle arrest in glioma cells. Additionally, transient expression of miR-7 in glioblastoma cells strongly inhibited in vivo glioblastoma xenograft growth. We conclude that miR-7 is a potential tumor suppressor in glioblastoma that acts by targeting multiple oncogenes related to the downstream pathway of EGFR and may serve as a novel therapeutic target for malignant gliomas.

Liu Z.,Fifth Central Hospital of Tianjin | Jiang Z.,Fifth Central Hospital of Tianjin | Huang J.,Duke University | Huang S.,Duke University | And 7 more authors.
International Journal of Oncology | Year: 2014

Intrinsic resistance of glioma cells to radiation and chemotherapy is currently hypothesized to be partially attributed to the existence of cancer stem cells. Emerging studies suggest that mesenchymal stem cells may serve as a potential carrier for delivery of therapeutic genes to disseminated glioma cells. However, the tropism character of mesenchymal stem cells for cancer stem cell-like glioma cells has rarely been described. In this study, we obtained homologous bone marrow-derived (BM-) and adipose tissue-derived (AT-) mesenchymal stem cells (MSCs), fibroblast, and cancer stem cell-like glioma cells (CSGCs) from tumor-bearing mice, and compared the tropism character of BM- and AT-MSCs for CSGCs with various form of existence. To characterize the cell proliferation and differentiation, the spheroids of CSGCs were cultured on the surface of the substrate with different stiffness, combined with or withdrew basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) in medium. Our results showed that the CSGCs during the process of cell proliferation, but not in resting and differentiated status, display strong tropism characteristics on both BM- and AT-MSCs, as well as the expression of their cell chemokine factors which mediate cell migration. If the conclusion is further confirmed, it may expose a fatal flaw of MSCs as tumor-targeted delivery of therapeutic agents in the treatment of the CSGCs, even other cancer stem cells, because there always exist a part of cancer stem cells that are in resting status. Overall, our findings provide novel insight into the complex issue of the MSCs as drug delivery in the treatment of brain tumors, especially in tumor stem cells.

Liu L.,Tianjin Medical University | Liu L.,Key Laboratory of Post Trauma Neuro Repair and Regeneration in Central Nervous System | Liu L.,Tianjin Key Laboratory of Injuries | Wei H.,Tianjin Medical University | And 12 more authors.
Critical Care Medicine | Year: 2011

Objective: Endothelial progenitor cells play an active role in vascular repair and revascularization of tissue damaged by traumatic, inflammatory, and ischemic injures. We correlate the changes in circulating endothelial progenitor cells with the severity of traumatic brain injury. The study is designed to investigate the endothelial progenitor cell mobilization after injury and a potential use of circulating endothelial progenitor cells as a prognostic marker for evaluating trauma severity and clinical outcomes. Design: A prospective cohort study conducted in two neurosurgical intensive care units of Tianjin Medical University General Hospital and Tianjin Huanhu Hospital (Tianjin, China). Patients: Patients with traumatic brain injury and age- and gender-matched healthy controls. Interventions: None. Measurements and Main Results: Changes in the levels of circulating endothelial progenitor cells were monitored for up to 21 days in 84 patients with traumatic brain injury. Results were correlated with the clinical assessment of injury severity as determined by the Glasgow Coma Scale. The level of circulating endothelial progenitor cells was found to be suppressed 24-48 hrs after injury but rapidly increased, reaching the highest at days 5-7 post-trauma. Circulating endothelial progenitor cells in patients with improved Glasgow Coma Scale scores were significantly higher than those with deteriorated conditions and remained persistently low in patients who died of trauma. Conclusions: The results suggest that the level of circulating endothelial progenitor cells correlates with the clinical severity and outcome of traumatic brain injury and may offer potential as a prognostic marker for traumatic brain injury. A long-term follow-up of these patients is ongoing. Copyright © 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Zhang K.,Tianjin Medical University | Zhang K.,Tianjin Neurological Institute | Zhang K.,Key Laboratory of Post trauma Neuro repair and Regeneration in Central Nervous System | Zhang K.,Tianjin Key Laboratory of Injuries | And 16 more authors.
Journal of Neuroimmune Pharmacology | Year: 2012

Extensive data have shown that Wnt/beta-catenin signaling is associated with various disease pathologies, including an important role in tumorigenesis. Here, we review the regulation of Wnt/beta-catenin signaling in glioma, with particular focus on the expression signatures of the main components in Wnt/beta-catenin signaling, the role of key factors in Wnt/beta-catenin signaling, and crosstalk with other signaling pathways. Finally, we discuss the involvement of microRNAs in Wnt/beta-catenin signaling in glioma. This review reveals new insights into the role of Wnt/beta-catenin signaling in gliomagenesis, and highlights new therapeutic approaches for glioma, based on the modulation of the Wnt/beta-catenin pathway. © 2012 Springer Science+Business Media, LLC.

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