• Title/Summary/Keyword: Neuroplasticity

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The role of Purkinje cell-derived VEGF in cerebellar astrogliosis in Niemann-Pick type C mice

  • Park, Min Hee;Lee, Ju Youn;Jeong, Min Seock;Jang, Hyung Sup;Endo, Shogo;Bae, Jae-sung;Jin, Hee Kyung
    • BMB Reports
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    • v.51 no.2
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    • pp.79-84
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    • 2018
  • Niemann-Pick type C disease (NP-C) is a fatal neurodegenerative disorder caused by a deficiency of NPC1 gene function, which leads to severe neuroinflammation such as astrogliosis. While reports demonstrating neuroinflammation are prevalent in NP-C, information about the onset and progression of cerebellar astrogliosis in this disorder is lacking. Using gene targeting, we generated vascular endothelial growth factor (VEGF) conditional null mutant mice. Deletion of VEGF in cerebellar Purkinje neurons (PNs) led to a significant increase of astrogliosis in the brain of NP-C mice in addition to the loss of PNs, suggesting PN-derived VEGF as an important factor in NP-C pathology. Moreover, replenishment of VEGF in neurons improved brain pathology in NP-C mice. Overall, our data provide a new pathological perspective on cerebellar astrogliosis in NP-C and suggest the importance of VEGF as a therapeutic target for this disease.

Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway

  • Kim, Namoh;Min, Woo-Kie;Park, Min Hee;Lee, Jong Kil;Jin, Hee Kyung;Bae, Jae-sung
    • BMB Reports
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    • v.49 no.5
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    • pp.288-292
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    • 2016
  • Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy-induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity.

AMD3100 improves ovariectomy-induced osteoporosis in mice by facilitating mobilization of hematopoietic stem/progenitor cells

  • Im, Jin Young;Min, Woo-Kie;Park, Min Hee;Kim, NamOh;Lee, Jong Kil;Jin, Hee Kyung;Choi, Je-Yong;Kim, Shin-Yoon;Bae, Jae-Sung
    • BMB Reports
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    • v.47 no.8
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    • pp.439-444
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    • 2014
  • Inhibition of an increase of osteoclasts has become the most important treatment for osteoporosis. The CXCR4 antagonist, AMD3100, plays an important role in the mobilization of osteoclast precursors within bone marrow (BM). However, the actual therapeutic impact of AMD3100 in osteoporosis has not yet been ascertained. Here we demonstrate the therapeutic effect of AMD3100 in the treatment of ovariectomy-induced osteoporosis in mice. We found that treatment with AMD3100 resulted in direct induction of release of SDF-1 from BM to blood and mobilization of hematopoietic stem/progenitor cells (HSPCs) in an osteoporosis model. AMD3100 prevented bone density loss after ovariectomy by mobilization of HSPCs, suggesting a therapeutic strategy to reduce the number of osteoclasts on bone surfaces. These findings support the hypothesis that treatment with AMD3100 can result in efficient mobilization of HSPCs into blood through direct blockade of the SDF-1/CXCR4 interaction in BM and can be considered as a potential new therapeutic intervention for osteoporosis.

Neuropeptide Y improves cisplatin-induced bone marrow dysfunction without blocking chemotherapeutic efficacy in a cancer mouse model

  • Park, Min Hee;Jung, In Kyung;Min, Woo-Kie;Choi, Jin Ho;Kim, Gyu Man;Jin, Hee Kyung;Bae, Jae-sung
    • BMB Reports
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    • v.50 no.8
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    • pp.417-422
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    • 2017
  • Cisplatin is the most effective and widely used chemotherapeutic agent for many types of cancer. Unfortunately, its clinical use is limited by its adverse effects, notably bone marrow suppression leading to abnormal hematopoiesis. We previously revealed that neuropeptide Y (NPY) is responsible for the maintenance of hematopoietic stem cell (HSC) function by protecting the sympathetic nervous system (SNS) fibers survival from chemotherapy-induced bone marrow impairment. Here, we show the NPY-mediated protective effect against bone marrow dysfunction due to cisplatin in an ovarian cancer mouse model. During chemotherapy, NPY mitigates reduction in HSC abundance and destruction of SNS fibers in the bone marrow without blocking the anticancer efficacy of cisplatin, and it results in the restoration of blood cells and amelioration of sensory neuropathy. Therefore, these results suggest that NPY can be used as a potentially effective agent to improve bone marrow dysfunction during cisplatin-based cancer therapy.

Neuropeptide Y-based recombinant peptides ameliorate bone loss in mice by regulating hematopoietic stem/progenitor cell mobilization

  • Park, Min Hee;Kim, Namoh;Jin, Hee Kyung;Bae, Jae-sung
    • BMB Reports
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    • v.50 no.3
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    • pp.138-143
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    • 2017
  • Ovariectomy-induced bone loss is related to an increased deposition of osteoclasts on bone surfaces. We reported that the 36-amino-acid-long neuropeptide Y (NPY) could mobilize hematopoietic stem/progenitor cells (HSPCs) from the bone marrow to the peripheral blood by regulating HSPC maintenance factors and that mobilization of HSPCs ameliorated low bone density in an ovariectomy-induced osteoporosis mouse model by reducing the number of osteoclasts. Here, we demonstrated that new NPY peptides, recombined from the cleavage of the full-length NPY, showed better functionality for HSPC mobilization than the full-length peptide. These recombinant peptides mediated HSPC mobilization with greater efficiency by decreasing HSPC maintenance factors. Furthermore, treatment with these peptides reduced the number of osteoclasts and relieved ovariectomy-induced bone loss in mice more effectively than treatment with full-length NPY. Therefore, these results suggest that peptides recombined from full-length NPY can be used to treat osteoporosis.

Inhibition of GM3 Synthase Attenuates Neuropathology of Niemann-Pick Disease Type C by Affecting Sphingolipid Metabolism

  • Lee, Hyun;Lee, Jong Kil;Bae, Yong Chul;Yang, Song Hyun;Okino, Nozomu;Schuchman, Edward H.;Yamashita, Tadashi;Bae, Jae-Sung;Jin, Hee Kyung
    • Molecules and Cells
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    • v.37 no.2
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    • pp.161-171
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    • 2014
  • In several lysosomal storage disorders, including Niemann-Pick disease Type C (NP-C), sphingolipids, including glycosphingolipids, particularly gangliosides, are the predominant storage materials in the brain, raising the possibility that accumulation of these lipids may be involved in the NP-C neurodegenerative process. However, correlation of these accumulations and NP-C neuropathology has not been fully characterized. Here we derived NP-C mice with complete and partial deletion of the Siat9 (encoding GM3 synthase) gene in order to investigate the role of ganglioside in NP-C pathogenesis. According to our results, NP-C mice with homozygotic deletion of GM3 synthase exhibited an enhanced neuropathological phenotype and died significantly earlier than NP-C mice. Notably, in contrast to complete depletion, NP-C mice with partial deletion of the GM3 synthase gene showed ameliorated NP-C neuropathology, including motor disability, demyelination, and abnormal accumulation of cholesterol and sphingolipids. These findings indicate the crucial role of GM3 synthesis in the NP-C phenotype and progression of CNS pathologic abnormality, suggesting that well-controlled inhibition of GM3 synthesis could be used as a therapeutic strategy.

Defective Self-Renewal and Differentiation of GBA-Deficient Neural Stem Cells Can Be Restored By Macrophage Colony-Stimulating Factor

  • Lee, Hyun;Bae, Jae-sung;Jin, Hee Kyung
    • Molecules and Cells
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    • v.38 no.9
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    • pp.806-813
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    • 2015
  • Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene (GBA), which encodes the lysosomal enzyme glucosylceramidase (GCase). Deficiency in GCase leads to characteristic visceral pathology and lethal neurological manifestations in some patients. Investigations into neurogenesis have suggested that neurodegenerative disorders, such as GD, could be overcome or at least ameliorated by the generation of new neurons. Bone marrowderived mesenchymal stem cells (BM-MSCs) are potential candidates for use in the treatment of neurodegenerative disorders because of their ability to promote neurogenesis. Our objective was to examine the mechanism of neurogenesis by BM-MSCs in GD. We found that neural stem cells (NSCs) derived from a neuronopathic GD model exhibited decreased ability for self-renewal and neuronal differentiation. Co-culture of GBA-deficient NSCs with BM-MSCs resulted in an enhanced capacity for self-renewal, and an increased ability for differentiation into neurons or oligodendrocytes. Enhanced proliferation and neuronal differentiation of GBA-deficient NSCs was associated with elevated release of macrophage colony-stimulating factor (M-CSF) from BM-MSCs. Our findings suggest that soluble M-CSF derived from BM-MSCs can modulate GBA-deficient NSCs, resulting in their improved proliferation and neuronal differentiation.

Role of neuropeptide Y in the bone marrow hematopoietic stem cell microenvironment

  • Park, Min Hee;Min, Woo-Kie;Jin, Hee Kyung;Bae, Jae-sung
    • BMB Reports
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    • v.48 no.12
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    • pp.645-646
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    • 2015
  • The sympathetic nervous system (SNS) or neurotransmitters in the bone marrow microenvironment has been known to regulate hematopoietic stem cell (HSC) functions such as self-renewal, proliferation and differentiation. However, the specific role of neuropeptide Y (NPY) in this process remains relatively unexplored. In this study, we demonstrated that NPY deficient mice have significantly reduced HSC numbers and impaired bone marrow regeneration due to apoptotic destruction of SNS fibers and/or endothelial cells. Moreover, NPY treatment prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while conditional knockout mice lacking the Y1 receptor in macrophages did not restore bone marrow dysfunction in spite of NPY injection. Transforming growth factor-beta (TGF-β) secreted by NPY-mediated Y1 receptor stimulation in macrophages plays a key role in neuroprotection and HSC survival in the bone marrow. Therefore, this study reveals a new role of NPY in bone marrow HSC microenvironment, and provides an insight into the therapeutic application of this neuropeptide.

Effects of Aquatic Exercise on Vestibulo-motor and Expression of GAP-43 in Diffuse brain Injury Rats (수중운동이 미만성 뇌손상 백서의 전정-운동 및 GAP-43 발현에 미치는 영향)

  • Yang, Seung-Hoon
    • The Journal of the Korea Contents Association
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    • v.9 no.12
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    • pp.656-664
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    • 2009
  • The purposes of this study were to examine whether aquatic exercise has influence on the neuroplasticity and vestibulo-motor function in diffuse brain injury rats. 80 Sprague-Dawley rats were assigned to four groups; Group I: control group (n=20), Group II: aquatic exercise (n=20), Group III: treadmill exercise with change of velocity and inclination (n=20), Group IV: simple treadmill exercise (n=20). And we applied exercise each groups for 3 weeks except Group I. Before the rats were sacrificed to identify immunohistochemistry study at each time of measurement day, Rota-Rod test was given to assess changes in vestibulomotor function. then, the immunohistochemistry study of GAP-43 in discrete regions of the rat brain was performed to measure changes in neuroplasticity. The results demonstrate that aquatic exercise group is more effective than other groups. expression of GAP-43 and vestibulo-motor function were increased most in aquatic exercise group. Therefore, this study suggest that aquatic exercise may effective therapeutic approach to increase neuroplasticity and vestibulo-motor function in traumatic brain injury.