Publications by authors named "Qianfa Long"

21 Publications

  • Page 1 of 1

Retinoblastoma tumor suppressor gene 1 enhances 5-Fluorouracil chemosensitivity through SDF-1/CXCR4 axis by regulating autophagy in gastric cancer.

Pathol Res Pract 2021 Jun 21;224:153532. Epub 2021 Jun 21.

Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China. Electronic address:

Due to lack of effective biomarkers for early diagnosis, most patients are diagnosed with advanced gastric cancer and have lower survival rates. 5-Fluorouracil (5-FU) is one of commonly used drugs for chemotherapy of gastric cancer, but drug resistance limits the wide application of agents. Retinoblastoma tumor suppressor gene 1 (RB1) is a key regulator in the progression of various human cancers, including gastric cancer. However, the effects of RB1 on chemosensitivity and the underlying mechanisms in gastric cancer (GC) are not clear. In this study, expressions of RB1 in GC cell lines were evaluated by RT-qPCR and western blot assay. CCK-8 was applied to examine the effect of 5-FU on cell viability. Meanwhile, IC50 values were calculated. The drug-resistance protein MDR1 and autophagy-related proteins were detected by western blot assay. Flow cytometry was used to detect cell cycle. The results showed that RB1 expressions were downregulated in GC cell lines and had significant differences between 5-FU resistance cell lines (SNU-620/5-FU and NUGC-3/5-FU) and non-resistance cell lines (SNU-620 and NUGC-3). Overexpression of RB1 enhanced 5-FU sensitivity of GC cells and caused cell cycle arrest in the S phase. Meanwhile, autophagy-related proteins were downregulated. Mechanistically, SDF-1/CXCR4 participated in the regulation of RB1 on cell autophagy. Autophagy activator, SDF-1 treatment and CXCR4 activation reversed the promoted effects of RB1 on 5-FU sensitivity in GC cells. In conclusion, our data revealed that RB1 was downregulated in GC cell lines. RB1 overexpression enhanced 5-FU chemosensitivity in GC cells by regulating cell autophagy via SDF-1/CXCR4 pathway. RB1 might serve as a promising therapeutic target of GC.
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http://dx.doi.org/10.1016/j.prp.2021.153532DOI Listing
June 2021

Antioxidant activity of mesenchymal stem cell-derived extracellular vesicles restores hippocampal neurons following seizure damage.

Theranostics 2021 3;11(12):5986-6005. Epub 2021 Apr 3.

Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University. No. 161, West 5th Road, Xincheng District, Xi'an, 710003, P. R. China.

Oxidative stress is a critical event in neuronal damage following seizures. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been shown to be promising nanotherapeutic agents in neurological disorders. However, the mechanism underlying MSC-EVs therapeutic efficacy for oxidative stress-induced neuronal damage remains poorly understood. We investigated the antioxidant and restoration activities of MSC-EVs on hippocampal neurons in response to HO stimulation and seizures . We also explored the potential underlying mechanism by injecting adeno-associated virus (AAV)-nuclear factor erythroid-derived 2, like 2 (Nrf2), a key antioxidant mediator, in animal models. MSC-EVs were enriched in antioxidant miRNAs and exhibited remarkable antioxidant activity evident by increased ferric ion-reducing antioxidant ability, catalase, superoxide dismutase, and glutathione peroxidase activities and decreased reactive oxygen species (ROS) generation, DNA/lipid/protein oxidation, and stress-associated molecular patterns in cultured cells and mouse models. Notably, EV administration exerted restorative effects on the hippocampal neuronal structure and associated functional impairments, including dendritic spine alterations, electrophysiological disturbances, calcium transients, mitochondrial changes, and cognitive decline after oxidative stress or . Mechanistically, we found that the Nrf2 signaling pathway was involved in the restorative effect of EV therapy against oxidative neuronal damage, while AAV-Nrf2 injection attenuated the antioxidant activity of MSC-EVs on the seizure-induced hippocampal injury. We have shown that MSC-EVs facilitate the reconstruction of hippocampal neurons associated with the Nrf2 defense system in response to oxidative insults. Our study highlights the clinical value of EV-therapy in neurological disorders such as seizures.
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http://dx.doi.org/10.7150/thno.58632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058724PMC
July 2021

Potential Applications of Nanomaterials and Technology for Diabetic Wound Healing.

Int J Nanomedicine 2020 3;15:9717-9743. Epub 2020 Dec 3.

School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, People's Republic of China.

Diabetic wound shows delayed and incomplete healing processes, which in turn exposes patients to an environment with a high risk of infection. This article has summarized current developments of nanoparticles/hydrogels and nanotechnology used for promoting the wound healing process in either diabetic animal models or patients with diabetes mellitus. These nanoparticles/hydrogels promote diabetic wound healing by loading bioactive molecules (such as growth factors, genes, proteins/peptides, stem cells/exosomes, etc.) and non-bioactive substances (metal ions, oxygen, nitric oxide, etc.). Among them, smart hydrogels (a very promising method for loading many types of bioactive components) are currently favored by researchers. In addition, nanoparticles/hydrogels can be combined with some technology (including PTT, LBL self-assembly technique and 3D-printing technology) to treat diabetic wound repair. By reviewing the recent literatures, we also proposed new strategies for improving multifunctional treatment of diabetic wounds in the future.
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http://dx.doi.org/10.2147/IJN.S276001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721306PMC
December 2020

MSC-derived exosomes protect against oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system.

Biomaterials 2020 10 28;257:120264. Epub 2020 Jul 28.

Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, No. 161, West 5th Road, Xincheng District, Xi'an, 710003, PR China. Electronic address:

Oxidative stress is a major cause of skin injury induced by damaging stimuli such as UV radiation. Currently, owing to their immunomodulatory properties, mesenchymal stem cell-derived exosomes (MSC-Exo), as a nanotherapeutic agent, have attracted considerable attention. Here, we investigated the therapeutic effects of MSC-Exo on oxidative injury in HO-stimulated epidermal keratinocytes and UV-irradiated wild type and nuclear factor-erythroid 2-related factor-2 (Nrf2) knocked down cell and animal models. Our findings showed that MSC-Exo treatment reduced reactive oxygen species generation, DNA damage, aberrant calcium signaling, and mitochondrial changes in HO-stimulated keratinocytes or UV-irradiated mice skin. Exosome therapy also improved antioxidant capacities shown by increased ferric ion reducing antioxidant power and glutathione peroxidase or superoxide dismutase activities in oxidative stress-induced cell and skin injury. In addition, it alleviated cellular and histological responses to inflammation and oxidation in cell or animal models. Furthermore, the NRF2 signaling pathway was involved in the antioxidation activity of MSC-Exo, while Nrf2 knockdown attenuated the antioxidant capacities of MSC-Exo in vitro and in vivo, suggesting that these effects are partially mediated by the NRF2 signaling pathway. These results indicate that MSC-Exo can repair oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system. Thus, MSC-Exo may be used as a potential dermatological nanotherapeutic agent for treating oxidative stress-induced skin diseases or disorders.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120264DOI Listing
October 2020

miR-665 promotes the progression of gastric adenocarcinoma via elevating FAK activation through targeting SOCS3 and is negatively regulated by lncRNA MEG3.

J Cell Physiol 2020 05 24;235(5):4709-4719. Epub 2019 Oct 24.

Division of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Studies have found that miR-665 acted as a tumor suppressor or an oncogene in different malignancies. miR-665 expression was elevated in gastric adenocarcinoma tissues; however, its role and mechanism in this disease are not fully clarified. The expression of miR-665 and its target gene was detected in human gastric adenocarcinoma tissues and cells. Moreover, we analyzed the effects of miR-665 on the proliferation, migration, and epithelial-mesenchymal transition (EMT) of gastric adenocarcinoma cells as well as tumor growth in vivo. The mechanisms of miR-665 in gastric adenocarcinoma were investigated by using molecular biology techniques. We found miR-665 was upregulated and suppressor of cytokine signaling 3 (SOCS3) was downregulated in gastric adenocarcinoma tissues and cells. Elevated miR-665 was positively correlated with tumor size, lymph node metastasis, invasion depth, TNM stage, and poor differentiation in gastric adenocarcinoma patients. Overexpression of miR-665 promoted, whereas knockdown of miR-665 suppressed the proliferation, migration, and EMT of gastric adenocarcinoma cells. Furthermore, we demonstrated that miR-665 functioned through targeting SOCS3, followed by activation of the FAK/Src signaling pathway in gastric adenocarcinoma cells. miR-665 antagomir inhibited tumor growth as well as the activation of the FAK/Src pathway but increased SOCS3 expression in nude mice. In addition, miR-665 expression was negatively regulated by long noncoding RNA maternally expressed gene 3 (MEG3). In conclusion, miR-665 acted as an oncogene in gastric adenocarcinoma by inhibiting SOCS3 followed by activation of the FAK/Src pathway and it was negatively modulated by MEG3. miR-665 may be a promising therapeutic target for the treatment of gastric adenocarcinoma.
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http://dx.doi.org/10.1002/jcp.29349DOI Listing
May 2020

Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice.

Theranostics 2019 14;9(20):5956-5975. Epub 2019 Aug 14.

Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, No. 161, West 5th Road, Xincheng District, Xi'an, 710003, P.R. China.

Mesenchymal stem cell-derived exosomes (MSC-Exo) have robust anti-inflammatory effects in the treatment of neurological diseases such as epilepsy, stroke, or traumatic brain injury. While astrocytes are thought to be mediators of these effects, their precise role remains poorly understood. To address this issue, we investigated the putative therapeutic effects and mechanism of MSC-Exo on inflammation-induced alterations in astrocytes. : Lipopolysaccharide (LPS)-stimulated hippocampal astrocytes in primary culture were treated with MSC-Exo, which were also administered in pilocarpine-induced status epilepticus (SE) mice. Exosomal integration, reactive astrogliosis, inflammatory responses, calcium signaling, and mitochondrial membrane potentials (MMP) were monitored. To experimentally probe the molecular mechanism of MSC-Exo actions on the inflammation-induced astrocytic activation, we inhibited the nuclear factor erythroid-derived 2, like 2 (Nrf2, a key mediator in neuroinflammation and oxidative stress) by sgRNA (in vitro) or ML385 (Nrf2 inhibitor) in vivo. : MSC-Exo were incorporated into hippocampal astrocytes as well as attenuated reactive astrogliosis and inflammatory responses in vitro and in vivo. Also, MSC-Exo ameliorated LPS-induced aberrant calcium signaling and mitochondrial dysfunction in culture, and SE-induced learning and memory impairments in mice. Furthermore, the putative therapeutic effects of MSC-Exo on inflammation-induced astrocytic activation (e.g., reduced reactive astrogliosis, NF-κB deactivation) were weakened by Nrf2 inhibition. : Our results show that MSC-Exo ameliorate inflammation-induced astrocyte alterations and that the Nrf2-NF-κB signaling pathway is involved in regulating astrocyte activation in mice. These data suggest the promising potential of MSC-Exo as a nanotherapeutic agent for the treatment of neurological diseases with hippocampal astrocyte alterations.
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http://dx.doi.org/10.7150/thno.33872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735367PMC
August 2020

High mobility group box-1 (HMGB1) antagonist BoxA suppresses status epilepticus-induced neuroinflammatory responses associated with Toll-like receptor 2/4 down-regulation in rats.

Brain Res 2019 08 12;1717:44-51. Epub 2019 Apr 12.

Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, West 5th Road, Xincheng District, Xi'an 710003, PR China. Electronic address:

It has been generally accepted that inflammatory responses induced by status epilepticus (SE) in the brain are associated with microglial activation. One important regulator of microglial activation is high mobility group box-1 (HMGB1) protein. HMGB1 exerts its influence on microglia via various pathways including Toll-like receptor (TLR) subtypes 2 and 4. To explore the HMGB1 role in the SE-induced microglial activation and the involvement of TLRs we conducted in vivo and ex vivo experiments using the HMGB1 antagonist BoxA. Blood-brain barrier (BBB) permeability, brain water content, hippocampal neuroinflammation and neuronal apoptosis were measured 24 h after the pilocarpine induction of status epilepticus (SE) in Sprague-Dawley rats treated with BoxA. In ex vivo experiments, post-SE microglia cells were isolated from the hippocampal CA1 area and subjected to lipopolysaccharide (LPS) stimulation followed by inflammatory cytokine IL-1β and IL-6 by qPCR and HMGB1, TLR2, TLR3 by Western blotting. A significant down-regulation of IL-1β, IL-6 and TNF-α but not HMGB1 was found in BoxA-treated compared to untreated animals. These changes were associated with decreased BBB permeability, reduced hippocampal neuronal apoptosis and reduction in hippocampal microglial activation. We conclude that BoxA-induced suppression of HMGB1-mediated neuroinflammatory responses is associated with TLR-2 and 4 down-regulation and should be explored as a potential therapeutic target.
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http://dx.doi.org/10.1016/j.brainres.2019.04.007DOI Listing
August 2019

Neuregulin1 attenuates cognitive deficits and hippocampal CA1 neuronal apoptosis partly via ErbB4 receptor in a rat model of chronic cerebral hypoperfusion.

Behav Brain Res 2019 06 28;365:141-149. Epub 2019 Feb 28.

Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.17 Changle West Road, Xi'an, 710032, PR China. Electronic address:

Neuregulin1 (NRG1) is an effective neuroprotectant. Previously we demonstrated that the expression of hippocampal NRG1/ErbB4 gradually decreased and correlates with neuronal apoptosis during chronic cerebral hypoperfusion (CCH). Here we aimed to further investigate the protective role of NRG1 in CCH. AG1478, an ErbB4 inhibitor, was used to explore the involvement of ErbB4 receptors in NRG1's action. Permanent bilateral common carotid artery occlusion (2VO) or sham operation was performed in Sprague-Dawley rats. NRG1 (100 μM) and AG1478 (50 mM) was administered intraventricularly. Eight weeks post-surgery, cognitive impairment was analyzed using Morris water maze (MWM) and radial arm water maze (RAWM) tests, followed by histological assessment of the survival and apoptosis of hippocampal CA1 neurons using NeuN and TUNEL immunostaining respectively. Expression of apoptosis-related proteins and ErbB4 activation (pErbB4/ErbB4) was evaluated by Western blotting. The results showed that NRG1 significantly improved the performances in MWM (spatial learning and memory) and RAWM (spatial working and reference memory), attenuated hippocampal CA1 neuronal loss and apoptosis, upregulated the expression of pErbB4/ErbB4 and the anti-apoptotic protein Bcl-2, and downregulated the expression of pro-apoptotic proteins of Cleaved (Cl)-caspase3 and Bax. In addition, the protective effects of NRG1 could be partly abolished by AG1478. Taken together, our study suggested that NRG1 ameliorates cognitive impairment and neuronal apoptosis partly via ErbB4 receptors in rats with CCH.
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http://dx.doi.org/10.1016/j.bbr.2019.02.046DOI Listing
June 2019

Letter: Thalamic Glioblastoma: Clinical Presentation, Management Strategies, and Outcomes.

Neurosurgery 2019 05;84(5):E288

Department of Pediatric Xi'an Jiaotong University Affiliated Children's Hospital, Xi'an Shaanxi, China.

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http://dx.doi.org/10.1093/neuros/nyz009DOI Listing
May 2019

The Expression of Hippocampal NRG1/ErbB4 Correlates With Neuronal Apoptosis, but Not With Glial Activation During Chronic Cerebral Hypoperfusion.

Front Aging Neurosci 2018 23;10:149. Epub 2018 May 23.

Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Permanent bilateral common carotid occlusion (2VO) is well-established to investigate the chronic cerebral hypoperfusion (CCH)-induced cognitive deficits. Besides, previous studies suggested that disturbance of Neuregulin1 (NRG1)/ErbB4 signaling is associated with cognitive impairments, as well as neuronal apoptosis and neuroinflammation in CNS. However, the expression pattern of hippocampal NRG1/ErbB4 has not been systematically investigated during CCH. Here, we aim to investigate the temporal changes of hippocampal NRG1/ErbB4 during CCH and their possible relationship with neuronal apoptosis and glial activation. Morris water maze (MWM) and Radial arm water maze (RAWM) tests were used to analyze cognitive impairment in 2VO rats at 28 days post-surgery, and Enzyme-Linked Immunosorbent Assay (ELISA), western blotting and immunostaining were performed at different time points (24 h, 7 days, 14 days, 28 days) to detect the expression pattern of NRG1/ErbB4 and the distribution of ErbB4. Neuronal nuclei (NeuN), NeuN/TUNEL, Iba1 and GFAP immunostaining and caspase activity in hippocampal CA1 subarea were assessed during CCH as well. We found that the expression of NRG1 and phosphorylated ErbB4 (pErbB4)/ErbB4 changed in a time-dependent manner (up-regulated in the acute phase and then decreased in the chronic phase of CCH). Besides, ErbB4-expressed neurons and selective types of GABAergic cells decreased after CCH, but the distribution pattern of ErbB4 remained unchanged. In addition, the expression of hippocampal NRG1/ErbB4 positively correlated with the level of neuronal apoptosis (both NeuN/TUNEL immunostaining and caspase-3 activity), but not with glial activation according to Pearson's correlation. These findings indicated that hippocampal NRG1/ErbB4 may be involved in the pathogenesis of CCH, especially neuronal apoptosis during CCH.
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http://dx.doi.org/10.3389/fnagi.2018.00149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974051PMC
May 2018

HMGB1 Neutralization Attenuates Hippocampal Neuronal Death and Cognitive Impairment in Rats with Chronic Cerebral Hypoperfusion via Suppressing Inflammatory Responses and Oxidative Stress.

Neuroscience 2018 07 17;383:150-159. Epub 2018 May 17.

Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No. 17 Changle West Road, Xi'an 710032, PR China. Electronic address:

High-mobility group box-1 (HMGB1) acts as a proinflammatory molecule once released into the extracellular space and inhibition of HMGB1 signaling has been reported be neuroprotective in neurodegenerative diseases. Besides, chronic cerebral hypoperfusion (CCH) causes cognitive impairment in neurodegenerative diseases. Here we tested the protective role of HMGB1 inhibition using anti-HMGB1 neutralizing antibody (Ab) against CCH in rats after bilateral common carotid artery occlusion (2VO). 169 male Sprague-Dawley rats underwent 2VO or sham operation. PBS, anti-HMGB1 Ab (1 mg/kg), or control IgG Ab (1 mg/kg) was intravenously administered post-operation. HMGB1 translocation, blood-brain barrier (BBB) permeability and glial activation were evaluated at 3 d, as well as the levels of inflammatory cytokines and oxidative stress. NeuN immunostaining and Morris Water Maze (MWM) were performed at 3 d, 4 w and 12 w. We found that anti-HMGB1 neutralizing Ab inhibited HMGB1 translocation in hippocampal CA1 subarea and improved hippocampal HMGB1 level. Besides, anti-HMGB1 Ab preserved BBB integrity and reduced glial activation, in association with the related changes in oxidative stress (increased activities of superoxide dismutase (SOD) and catalase (CAT), and decreased malondialdehyde (MDA) production) and inflammatory cytokines (increased gene expression of IL-1β, IL-6 and TNF) at 3 d. Additionally, anti-HMGB1 neutralizing Ab improved hippocampal CA1 neuronal survival and behavioral outcomes in the chronic phase (4 w and 12 w). Taken together, these findings suggest that HMGB1 neutralization suppresses hippocampal inflammatory responses and oxidative stress in the acute phase, and these changes exert long-lasting beneficial effects in the chronic phase of CCH.
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http://dx.doi.org/10.1016/j.neuroscience.2018.05.010DOI Listing
July 2018

3D-printed scaffolds with calcified layer for osteochondral tissue engineering.

J Biosci Bioeng 2018 Sep 16;126(3):389-396. Epub 2018 May 16.

Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, No. 127 Changle West Road, Xi'an 710032, PR China. Electronic address:

Treating full-layer injury of bone and cartilage is currently a significant challenge in orthopedic trauma repair. Joint damage typically includes chondral defects, and the underlying subchondral defect sites are difficult to repair. Tissue engineering technology could potentially be used to treat such injuries; however, results to date been unsatisfactory. The aim of this study was to design a multilayer composite scaffold containing cartilage, bone, and calcified layers to simulate physiological full-thickness bone-cartilage structure. The cartilage layer was created using an improved temperature-gradient thermally induced crystallization technology. The bone and calcified layers were synthesized using 3D printing technology. We examined the scaffold by using scanning electron microscope (SEM), X-ray diffraction (XRD), fluorescence staining, and micro computed tomography (Micro-CT), and observed clearly oriented structures in the cartilage layer, overlapping structures in the bone scaffold, and a compressed calcified layer. Biomechanical performance testing showed that the scaffolds were significantly stronger than scaffolds without a calcified layer (traditional scaffolds) in maximum tensile strength and maximum shear strength (P < 0.05). After inoculating cells onto the scaffolds, we observed similar cell adherence and proliferation to that observed in traditional scaffolds, likely because of the high porosity of the whole scaffold. Our scaffolds could be used in bone and cartilage full-thickness injury repair methods, as well as applications in the field of tissue engineering.
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http://dx.doi.org/10.1016/j.jbiosc.2018.03.014DOI Listing
September 2018

Mash1-dependent Notch Signaling Pathway Regulates GABAergic Neuron-Like Differentiation from Bone Marrow-Derived Mesenchymal Stem Cells.

Aging Dis 2017 May 2;8(3):301-313. Epub 2017 May 2.

2Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White, Temple and College Station, Texas, 76502, USA.

GABAergic neuronal cell grafting has promise for treating a multitude of neurological disorders including epilepsy, age-related memory dysfunction, Alzheimer's disease and schizophrenia. However, identification of an unlimited source of GABAergic cells is critical for advancing such therapies. Our previous study implied that reprogramming of bone marrow-derived mesenchymal stem cells (BMSCs) through overexpression of the Achaete-scute homolog 1 (Ascl1, also called Mash1) could generate GABAergic neuron-like cells. Here, we investigated mechanisms underlying the conversion of BMSCs into GABAergic cells. We inhibited γ-secretase (an enzyme that activates Notch signaling) with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) or manipulated the expression of Notch signaling components such as the (RBPJ), (Hes1) or Mash1. We demonstrate that inhibition of γ-secretase through DAPT down-regulates RBPJ and Hes1, up-regulates Mash1 and results in an enhanced differentiation of BMSCs into GABAergic cells. On the other hand, RBPJ knockdown in BMSCs has no effect on Mash1 gene expression whereas Hes1 knockdown increases the expression of Mash1. Transduction of Mash1 in BMSCs also increases the expression of Hes1 but not RBPJ. Moreover, increased GABAergic differentiation in BMSCs occurs with concurrent Mash1 overexpression and Hes1-silencing. Thus, the Mash1-dependent Notch signaling pathway regulates GABAergic neuron-like differentiation of BMSCs. These results also suggest that genetic engineering of BMSCs is a useful avenue for obtaining GABAergic neuron-like donor cells for the treatment of neurological disorders.
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http://dx.doi.org/10.14336/AD.2016.1018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440110PMC
May 2017

Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus.

Proc Natl Acad Sci U S A 2017 04 10;114(17):E3536-E3545. Epub 2017 Apr 10.

Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX 76502;

Status epilepticus (SE), a medical emergency that is typically terminated through antiepileptic drug treatment, leads to hippocampus dysfunction typified by neurodegeneration, inflammation, altered neurogenesis, as well as cognitive and memory deficits. Here, we examined the effects of intranasal (IN) administration of extracellular vesicles (EVs) secreted from human bone marrow-derived mesenchymal stem cells (MSCs) on SE-induced adverse changes. The EVs used in this study are referred to as A1-exosomes because of their robust antiinflammatory properties. We subjected young mice to pilocarpine-induced SE for 2 h and then administered A1-exosomes or vehicle IN twice over 24 h. The A1-exosomes reached the hippocampus within 6 h of administration, and animals receiving them exhibited diminished loss of glutamatergic and GABAergic neurons and greatly reduced inflammation in the hippocampus. Moreover, the neuroprotective and antiinflammatory effects of A1-exosomes were coupled with long-term preservation of normal hippocampal neurogenesis and cognitive and memory function, in contrast to waned and abnormal neurogenesis, persistent inflammation, and functional deficits in animals receiving vehicle. These results provide evidence that IN administration of A1-exosomes is efficient for minimizing the adverse effects of SE in the hippocampus and preventing SE-induced cognitive and memory impairments.
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http://dx.doi.org/10.1073/pnas.1703920114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410779PMC
April 2017

Downregulation of KDM4A Suppresses the Survival of Glioma Cells by Promoting Autophagy.

J Mol Neurosci 2016 Oct 11;60(2):137-44. Epub 2016 Aug 11.

Department of Neurosurgery, Xi'an Central Hospital, Xi'an, 710003, China.

Glioma is the most common type of primary intracranial tumor and has a poor prognosis. It has been reported that lysine-specific demethylase 4A (KDM4A) can promote tumor progression; however, its role in human glioma remains unclear. Western blot and qRT-PCR analyses showed that KDM4A was highly expressed in U87MG and T98G cells. 48 h after transfection with siKDM4A, the protein level of KDM4A was significantly downregulated. The silenced expression of KDM4A in T98G or U87MG cells inhibited cell viability and invasion, and aggravated cell apoptosis. We found that the siKDM4A led to a significant increase in acidic vesicular organelles (AVOs) and upregulated the expression of autophagy-related proteins, including LC3B-phosphatidylethanolamine conjugate, a cytosolic form of LC3B (LC3B-II/LC3B-I) and Beclin 1 in T98G and U87MG cells. Further studies demonstrated that after pretreatment with 3-MA (3 mmol/L) for 48 h, siKDM4A-transfected cells showed a prominent decrease in LC3B-II/LC3B-I and Beclin 1, accompanied by increased viability and invasion and decreased apoptosis. Our results suggest that the inhibition of KDM4A expression might efficiently suppress glioma cell survival by promoting autophagy, providing a promising agent for treating malignant gliomas.
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http://dx.doi.org/10.1007/s12031-016-0796-6DOI Listing
October 2016

MRI tracking of bone marrow mesenchymal stem cells labeled with ultra-small superparamagnetic iron oxide nanoparticles in a rat model of temporal lobe epilepsy.

Neurosci Lett 2015 Oct 25;606:30-5. Epub 2015 Aug 25.

Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.17 Changle West Road, Xi'an 710032, PR China. Electronic address:

Transplantation of bone marrow mesenchymal stem cells (BMSCs) is a promising approach for treatment of epilepsy. To our knowledge, there is little research on magnetic resonance imaging (MRI) tracking of BMSCs labeled with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles in a rat model of temporal lobe epilepsy (TLE). In this study, BMSCs were pre-labeled with USPIO nanoparticles, and then the cell apoptosis, proliferation, surface antigens, and multipotency were investigated. Lithium chloride-pilocarpine induced TLE models were administered by USPIO-labeled BMSCs (U-BMSCs), BMSCs, and saline through lateral ventricle injection as the experimental group, control I group and control II group, respectively, followed by MRI examination, electroencephalography (EEG) and Prussian blue staining. The cell experimental results showed that the labeled USPIO did not affect the biological characteristics and multiple potential of BMSCs. The U-BMSCs can be detected using MRI in vitro and in vivo, and observed in the hippocampus and adjacent parahippocampal cortical areas of the epileptic model. Moreover, electroencephalographic results showed that transplanted U-BMSCs, as well as BMSCs, were capable of reducing the number of epileptiform waves significantly (P<0.01) compared with control II group. All of these findings suggest that it is feasible to track transplanted BMSCs using MRI in a rat model of TLE, and support that USPIO labeling is a valuable tool for cell tracking in the study of seizure disorders.
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http://dx.doi.org/10.1016/j.neulet.2015.08.040DOI Listing
October 2015

Efficacy of radio frequency thermocoagulation in surgery for giant supratentorial meningiomas: a historical control study.

Clin Neurol Neurosurg 2015 Mar 27;130:26-32. Epub 2014 Dec 27.

Department of Ultrasonography, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Background: Surgery for giant meningiomas carries a high risk of bleeding and is time-consuming. This historical control study tests the hypothesis that the use of radio frequency thermocoagulation (RFT) during surgery improves outcome.

Methods: From November 2010 to October 2011, 20 giant vascularized meningiomas were surgically resected with intraoperative use of ultrasound-guided RFT prior to resection. The historical control group consisted of 25 patients in whom tumors were removed without RFT by the same surgical team. Blood loss during resection, changes in tumor consistency, time taken for the operation, and the extent of resection were compared between the two groups.

Results: There was less blood lost during resection and the duration of the operation was shorter in RFT-assisted surgery than in the historical control group (P<0.05). Apart from the effect of devascularization, the tumor consistency became soft after RFT, which could also be beneficial.

Conclusions: Satisfactory devascularization and tumor softening were achieved after RFT without incremental complications. RFT-assisted surgery for giant vascularized supratentorial meningiomas is easier and safer than non-RFT surgery.
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http://dx.doi.org/10.1016/j.clineuro.2014.12.008DOI Listing
March 2015

Hypoxia inducible factor-1α expression is associated with hippocampal apoptosis during epileptogenesis.

Brain Res 2014 Nov 19;1590:20-30. Epub 2014 Sep 19.

Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, No.17 Changle West Road, Xi׳an 710032, China. Electronic address:

Cell apoptosis can cause hippocampal neuronal loss after epileptic seizures. Hypoxia inducible factor (HIF)-1α is an important factor mediating apoptosis after brain injuries, such as cerebral ischemia and traumatic brain injures, but little research has been done on its role in the lithium chloride-pilocarpine induced epileptic model. Here, we used a rat model of pilocarpine-induced status epilepticus (SE) to investigate HIF-1α expression and apoptosis in the hippocampus, and to explore their relationship during epileptogenesis. 120 male Sprague Dawley (SD) rats were treated with lithium chloride-pilocarpine injections and divided into an experimental group (administered by MK-801) and a positive control group (administered by saline). Then the HIF-1α expression and hippocampal apoptosis were investigated by histological confirmation and western blotting at 24h, 3d, 7d and 14d, respectively. The results showed that the administration of MK-801 significantly reduced (P<0.05) HIF-1α expression and hippocampal apoptosis during epileptogenesis in comparison with the positive control. Moreover, the expression of HIF-1α and hippocampal apoptosis presented significant time-dependent changes (P<0.01) within 2 weeks, and their positive correlation (P<0.05) analyzed by Pearson׳s correlation analysis. Meanwhile, the HIF-1α immunostained cells were distributed in accord with TUNEL immunostained cells and Caspase-3 immunopositive cells in the hippocampus. These results indicate that the HIF-1α expression is associated with hippocampal apoptosis, and suggest that HIF-1α is an important factor during epileptogenesis.
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http://dx.doi.org/10.1016/j.brainres.2014.09.028DOI Listing
November 2014

Over-expression of Mash1 improves the GABAergic differentiation of bone marrow mesenchymal stem cells in vitro.

Brain Res Bull 2013 Oct 19;99:84-94. Epub 2013 Oct 19.

Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Fourth Military Medical University, No.17 Chang-le West Road, Xi'an 710032, China; Department of Neurosurgery, Qingdao 401 Hospital of PLA, No. 22 Minjiang Road, Qingdao 266071, China.

Bone marrow mesenchymal stem cells (BMSCs) have been shown to be a promising cell type for the study of neuronal differentiation; however, few attempts had been made to differentiate these cells into inhibitory gamma-aminobutyric acid (GABA)ergic neurons. In this study, we over-expressed mammalian achaete-scute homologue-1 (Mash1), a basic helix-loop-helix (bHLH) transcription factor, in Sprague-Dawley rat BMSCs via lentiviral vectors, and then induced neuronal differentiation of these cells using conditioned medium. Our Western blot results show that, under conditions of differentiation, Mash1-overexpressing BMSCs exhibit an increased expression of neuronal markers and a greater degree of neuronal morphology compared to control, non-Mash1-overexpressing cells. Using immunocytochemistry, we observed increased expression of glutamic acid decarboxylase 67 (GAD67), as well as neuron-specific nuclear protein (NeuN) and β3-tubulin, in Mash1-overexpressing BMSCs compared to control cells. Moreover, we also found the differentiated cells showed representative traces of action potentials in electrophysiological characterization. In conclusion, our study demonstrated that over-expression of Mash1 can improve GABAergic differentiation of BMSCs in vitro.
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http://dx.doi.org/10.1016/j.brainresbull.2013.10.005DOI Listing
October 2013

Genetically engineered bone marrow mesenchymal stem cells improve functional outcome in a rat model of epilepsy.

Brain Res 2013 Sep 6;1532:1-13. Epub 2013 Aug 6.

Department of Neurosurgery, The Central Hospital of Xi'an, Affiliated Hospital of Medical College of Xi'an Jiao Tong University, No. 185 Houzai Gate of North Street, Xi'an 710003, China; Xijing Institute of Clinical Neuroscience, Fourth Military Medical University, No. 17 Chang-le West Road, Xi'an 710032, China.

Bone marrow mesenchymal stem cells (BMSCs) hold a great promising approach for the treatment of epilepsy owing to their distinctive characteristics and multi-potency. However, there is little research focusing on the multi-potency of BMSCs in the treatment of epilepsy, the present study was designed to examine the influence of genetically engineered BMSCs (GE-BMSCs) on the functional outcome in a rat model of epilepsy. First, Hes1 gene of BMSCs was genetically engineered by RNA interference (RNAi), and then the GABAergic differentiation of GE-BMSCs was tested in vitro. Second, the lithium chloride-pilocarpine induced epileptic rats were administrated with the GE-BMSCs, the behavioral observation and electroencephalography (EEG) monitoring was employed to analyze the functional outcome on the epileptic model at different time points (day 7, day 14, day 21 and day 28), followed by histological verification. In vitro test showed that Hes1 silencing could promote BMSCs to differentiate into GABAergic neuron-like cells. In vivo test showed that GE-BMSCs graft could further improve the functional recovery of the epileptic rats, and the GABAergic differentiation of grafted GE-BMSCs was correlated with the functional recovery. Taken together, these data suggest that GE-BMSCs can improve the functional outcome in a rat model of epilepsy.
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http://dx.doi.org/10.1016/j.brainres.2013.07.020DOI Listing
September 2013

The tropism of neurally differentiated bone marrow stromal cells towards C6 glioma.

Neurosci Lett 2011 Oct 17;504(2):135-140. Epub 2011 Sep 17.

Xijing Institute of Clinical Neuroscience, Fourth Military Medical University, 17 Chang-le West Road, Xi'an 710032, China.

Recent studies have indicated that bone marrow stromal cells (BMSCs) have significant tropism towards glioma which makes them play an important role in carrying genes/drugs to inhibit the growth of glioma as cell vehicles. But BMSCs may differentiate into neural cells under entocranial environment and few researches support the idea that neurally differentiated bone marrow stromal cells (N-D-BMSCs) still hold the capacity of migrating to the tumor sites. The aim of our study was to investigate the tropism of N-D-BMSCs towards C6 glioma. In vitro migration assay was employed by transwell co-culture system and Student's t-test analysis indicated that N-D-BMSCs had the significant tropism towards C6 glioma-conditioned medium (GCM) (P<0.01). Furthermore, the vascular endothelial growth factor (VEGF) bioactivity of the C6 GCM was neutralized by the anti-rat VEGF antibody and our data suggested that the VEGF from C6 GCM hold chemoattraction for N-D-BMSCs and some other cytokines from the C6 GCM may be responsible for the chemoattraction for N-D-BMSCs. In vivo migration assay was carried out with cells transplantation and one way ANOVA analysis indicated that the tropism of N-D-BMSCs towards C6 glioma sites presented time variation (P-value=2.9E-20). Moreover, multiple comparisons for the time variables with the Student's t-test and the results suggested that the migration capacity of N-D-BMSCs towards C6 glioma sites reach the peak on the 7th day after transplantation. These results demonstrate that N-D-BMSCs as well as BMSCs have significant tropism towards C6 glioma.
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http://dx.doi.org/10.1016/j.neulet.2011.09.018DOI Listing
October 2011
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