Key Laboratory of Hebei Neurology

Shijiazhuang, China

Key Laboratory of Hebei Neurology

Shijiazhuang, China
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Chen L.P.,Hebei Medical University | Chen L.P.,Key Laboratory of Hebei Neurology | Li Z.F.,Hebei Medical University | Ping M.,Hebei Medical University | And 7 more authors.
Neuroscience | Year: 2012

The mammalian subventricular zone (SVZ) is the largest germinative zone of the adult brain. Progenitor cells generated from the SVZ play important roles during the remyelination process. To determine the functional role of Olig2 in regulating astroglial differentiation in the mouse SVZ, we used the cuprizone mouse model to investigate demyelination. We found that cuprizone administration significantly enhanced the expression of Olig2 and increased astroglial differentiation in the SVZ, as compared with control. Moreover, cytoplasmic translocation of Olig2 occurred after demyelination. In vitro studies further revealed that supplementation of culture media with growth factors enhanced the oligodendroglial differentiation of oligodendrocyte progenitor cells (OPCs), whereas serum alone promoted astroglial differentiation and cytoplasmic translocation of Olig2. Additionally, the expression levels of bone morphogenetic proteins 2 and 4 (BMP2 and BMP4) and inhibitor of DNA binding 2 and 4 (Id2 and Id4) were greatly elevated during astroglial differentiation. BMP inhibition by noggin suppressed the astroglial differentiation of OPCs. Our results indicate that Olig2 may serve as a key regulator during the directional differentiation of progenitor cells after demyelination. The BMP signaling pathway may contribute to the cytoplasmic translocation and altered expression of Olig2 during the remyelination process. These findings provide a better understanding of the mechanisms involved in remyelination. © 2012 IBRO.

Feng X.,Hebei Medical University | Hou H.,Hebei Medical University | Zou Y.,Hebei Medical University | Guo L.,Hebei Medical University | Guo L.,Key Laboratory of Hebei Neurology
Bosnian Journal of Basic Medical Sciences | Year: 2017

Neurodegeneration, along with inflammatory demyelination, is an important component of multiple sclerosis (MS) pathogenesis. Autophagy is known to play a pivotal role in neuronal homeostasis and is implicated in several neurodegenerative disorders. However, whether autophagy is involved in the mechanisms of neuronal damage during MS remains to be investigated. Experimental autoimmune encephalomyelitis (EAE), an in vivo model of MS, was induced in female C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein p35-55. After that, autophagic flux in the spinal cord of mice was evaluated by detection of LC3-II and Beclin1 protein expressions. EAE mice were then administered with rapamycin and 3-methyladenine (3-MA) for 10 days. Afterward, the changes in LC3-II, Beclin1, and p62 expression, number of infiltrated inflammatory cells, demyelinated lesion area, and neuronal damage, as well as clinical scores, were assessed. Further, apoptotic cell rate and apoptosis-related protein expressions were monitored. We observed an impaired autophagic flux and increased neuronal damage in the spinal cords of EAE mice. We also found that rapamycin, an autophagy inducer, mitigated EAE-induced autophagy decrease, inflammation, demyelination and neuronal injury, as well as the abnormal clinical score. In addition, rapamycin suppressed cell apoptosis, and decreased Bax/Bcl-2 ratio and cleaved caspase-3 expression. Conversely, the effect of autophagy inhibitor 3-MA on EAE mice resulted in completely opposite results. These results indicated that autophagy deficiency, at least in part, contributed to EAE-induced neuronal injury and that pharmacological modulation of autophagy might be a therapeutic strategy for MS. © 2017 ABMSFBIH.

Li B.,Hebei Medical University | Li B.,Key Laboratory of Hebei Neurology | Cui W.,Hebei Medical University | Liu J.,Hebei Medical University | And 13 more authors.
Experimental Neurology | Year: 2013

Sulforaphane (SFN) is an organosulfur compound present in vegetables and has potent anti-oxidant and anti-inflammatory activities. This study was aimed at investigating the effect of treatment with SFN on inflammation and oxidative stress, and the potential mechanisms underlying the action of SFN in experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. Treatment with SFN significantly inhibited the development and severity of EAE in mice, accompanied by mitigating inflammatory infiltration and demyelination in the spinal cord of mice. The protective effect of SFN was associated with significantly improved distribution of claudin-5 and occludin, and decreased levels of MMP-9 expression, preserving the blood-brain barrier. Furthermore, the protection of SFN was also related to decreased levels of oxidative stress in the brains of mice by enhanced activation of the Nrf2/ARE pathway and increased levels of anti-oxidant HO-1 and NQO1 expression. In addition, treatment with SFN inhibited antigen-specific Th17 responses and enhanced IL-10 responses. Our data indicated that treatment with SFN inhibited EAE development and severity in mice by its anti-oxidant activity and antagonizing autoimmune inflammation. Our findings suggest that SFN and its analogues may be promising reagents for intervention of multiple sclerosis and other autoimmune diseases. © 2013 Elsevier Inc.

Li Y.,Hebei Medical University | Li Y.,Key Laboratory of Hebei Neurology | Li Y.,Hebei Institute of Cardiocerebrovascular Disease | Guo Y.,Hebei Medical University | And 17 more authors.
Neuroscience | Year: 2015

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder for which there is currently no effective treatment. Studies indicate that enhancing autophagy in mouse models of neurodegenerative disease can ameliorate the behavioral symptoms and pathological damage associated with the accumulation of pathological mutant proteins such as mutant superoxide dismutase (SOD1). This study investigated the effects of trehalose treatment on both early and end-stage disease in a transgenic mouse model of ALS via short-term (30. days after administration) and long-term (from 60. days after administration to death) trehalose treatment experiments. Sixty-day-old female SOD1-G93A transgenic mice were treated daily with 2% (w/v) trehalose in their drinking water for 30. days and monitored until they reached a neurological score of four, whereupon they were euthanized by cervical dislocation. Neurological, rotarod performance test and hanging wire test scores were recorded and body weight monitored. After death, the spinal cord was removed to assess the number of motor neurons and to measure the expression of mutant SOD1, LC3-II and p62. Trehalose significantly reduced the levels of mutant SOD1 and p62 and increased LC3-II in the spinal cords of 90-day-old SOD1-G93A transgenic mice. Furthermore, trehalose treatment significantly postponed disease onset, lengthened the time it took to reach a neurological score of 2 and preserved motor function; however, trehalose became less effective at delaying further disease progression as the disease progressed beyond a neurological score of 2 and it failed to extend the survival of SOD1-G93A transgenic mice. Additionally, independent of autophagy, trehalose consistently inhibited microgliosis and astrogliosis throughout the entire duration of the study. In conclusion, trehalose may be a useful add-on therapy in conjunction with other ALS treatment options to alleviate symptoms in early-stage ALS. © 2015 IBRO.

Wang L.,Hebei Medical University | Wang L.,Key Laboratory of Hebei Neurology | Li B.,Hebei Medical University | Li B.,Key Laboratory of Hebei Neurology | And 11 more authors.
Oncotarget | Year: 2017

Background: Multiple sclerosis (MS), a complex disease associated with multifocal demyelination of the central nervous system and poorly understood etiology. It has been previously indicated that many factors, including oxidative stress and p38MAPKSGK1 pathway, contribute to the pathogenesis of MS. Methods: This study, using an experimental autoimmune encephalomyelitis (EAE) model system, was aimed at investigating the molecular mechanisms determining interaction p38MAPK-SGK1 pathway and oxidative stress in MS pathogenesis. C57BL/6 mice was immunized with MOG35-55 peptide for EAE induction, which was followed by determination of the effect of treatment with classic p38 inhibitor SB203580 and antioxidant tempol on the development and progression of EAE. Results: Our experiments showed a dynamic change of immune inflammation, oxidative stress and p38MAPK-SGK1 pathway involvement in EAE demonstrating that p38MAPK-SGK1 pathway and oxidative stress contribute to the demyelination in central nerve system caused by Th17 inflammatory responses in a synergistic way. The administration of SB203580 and Tempol both markedly suppressed the progression of EAE. Furthermore, tempol showed a strong inhibiting effect to the p38MAPK-SGK1 pathway similar to SB203580 suggesting that oxidative stress exacerbates EAE via the activation of p38MAPK-SGK1 pathway. Conclusion: Cumulatively, our results show that oxidative stress p38MAPK-SGK1 signaling pathway may be a central player in EAE and even in MS. © Wang et al.

An T.,Hebei Medical University | An T.,Beijing Shunyi Hospital of China Medical University | Shi P.,Hebei Medical University | Duan W.,Hebei Medical University | And 15 more authors.
Molecular Neurobiology | Year: 2014

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease involving both upper and lower motor neurons. The mechanism of motor neuron degeneration is still unknown. Although many studies have been performed on spinal motor neurons, few have been reported on brainstem and its motor nuclei. The aim of this study was to investigate oxidative stress and autophagic changes in the brainstem and representative motor nuclei of superoxide dismutase 1 (SOD1)-G93A mouse model of ALS. The expression levels of cluster of differentiation molecule 11b (CD11b), glial fibrillary acidic protein, glutamate-cysteine ligase catalytic subunit, heme oxygenase-1, NAD(P)H: quinone oxidoreductase 1, voltage-dependent anion-selective channel protein 1, Sequestosome 1/p62 (p62), microtubule-associated protein 1 light chain 3B (LC3), and SOD1 proteins in brainstem were examined by Western blot analysis. Immunohistochemistry and immunofluorescence were performed to identify the cellular localization of SOD1, p62, and LC3B, respectively. The results showed that there were progressive asctrocytic proliferation and microglial activation, induction of antioxidant proteins, and increased p62 and LC3II expression in brainstem of SOD1-G93A mice. Additionally, SOD1 and p62 accumulated in hypoglossal, facial, and red nuclei, but not in oculomotor nucleus. Furthermore, electron microscope showed increased autophagic vacuoles in affected brainstem motor nuclei. Our results indicate that brainstem share similar gliosis, oxidative stress, and autophagic changes as the spinal cord in SOD1-G93A mice. Thus, SOD1 accumulation in astrocytes and neurons, oxidative stress, and altered autophagy are involved in motor neuron degeneration in the brainstem, similar to the motor neurons in spinal cord. Therefore, therapeutic trials in the SOD1G93A mice need to target the brainstem in addition to the spinal cord. © 2014 Springer Science+Business Media.

Zhang K.,Hebei Medical University | Shi P.,Hebei Medical University | An T.,Hebei Medical University | Wang Q.,Hebei Medical University | And 12 more authors.
Brain Research | Year: 2013

Autophagy dysregulation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The expression of LC3II and sequestosome 1 (P62) was progressively increased in the lumbar spinal cord of ALS mice. However, whether autophagy is activated or inhibited is still unclear. By treating mice with food restriction, a well-recognized way to induce autophagy, we found that 48 h of food restriction significantly reduced p62 and mutated SOD1 expressions at onset stage but not at pre-end stage in the spinal cord of SOD1-G93A mice. These data indicate that activating autophagy at a certain disease stage may have potential protective effects on ALS. © 2013 Elsevier B.V.

Guo Y.,Hebei Medical University | Guo Y.,Key Laboratory of Hebei Neurology | Guo Y.,Hebei Institute of Cardiocerebrovascular Disease | Zhang Y.,Roswell Park Cancer Institute | And 14 more authors.
Laboratory Investigation | Year: 2013

Oxidative stress is associated with the pathogenesis of amyotrophic lateral sclerosis (ALS). Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is one of the major cellular defense mechanisms against oxidative stress. However, the role of Nrf2-mediated neuroprotection (antioxidant defense) in the disease development of ALS remains unclear. To further investigate the role of Nrf2 in ALS, we genetically eliminate the Nrf2 gene from SOD1-G93A mice, a commonly used ALS mouse model, by generating a double mutant (Nrf2-/-SOD1-G93A mice). We found that it only had a modest impact on the course of disease by knocking out Nrf2 gene in these mice. Further studies demonstrated that, among previously known Nrf2-regulated phase II enzymes, only NAD(P)H: quinone oxidoreductase 1 induction was significantly affected by the elimination of Nrf2 gene in SOD1-G93A mice. Taken together, our data suggested that Nrf2 is not the sole mediator for the induction of antioxidant genes in SOD1-G93A mice, and Nrf2-mediated neuroprotection is not the key protective mechanism against neurodegeneration in those mice. © 2013 USCAP, Inc. All rights reserved.

Guo Y.,Hebei Medical University | Guo Y.,Key Laboratory of Hebei Neurology | Guo Y.,Institute of Cardiocerebrovascular Disease | Wang Q.,Hebei Medical University | And 11 more authors.
Brain Research | Year: 2012

TAR DNA-binding protein 43 (TDP-43) has been found to be related to the pathogenesis of amyotrophic lateral sclerosis (ALS). TDP-43 A315T transgenic mice develop degeneration of specific motor neurons, and accumulation of ubiquitinated proteins has been observed in the pyramidal cells of motor cortex of these mice. In this study, we found stress-responsive HO-1 induction and no autophagic alteration in motor cortex of TDP-43 A315T transgenic mice. Glial activation, especially astrocytic proliferation, occurred in cortical layer 5 and sub-meningeal region. Interestingly, we noticed that progressively thinned colon, swollen small intestine and reduced food intake, rather than severe muscle weakness, contributed to the death of TDP-43 A315T transgenic mice. Increased TDP-43 accumulation in the myenteric nerve plexus and increased thickness of muscular layer of colon were related to the intestinal dysfunction. © 2012 Elsevier B.V. All rights reserved.

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