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鄭 且均ジョン チャギュン

所属部署医学研究科病態生化学分野
職名准教授
メールアドレス
ホームページURLhttp://kaken.nii.ac.jp/ja/r/00464579
生年月日
Last Updated :2020/06/03

研究者基本情報

学位

  • 博士(医学)

経歴

  •   2010年, 独立行政法人国立長寿医療研究センター, その他

研究活動情報

研究分野

  • ライフサイエンス, 神経科学一般
  • ライフサイエンス, 神経科学一般

研究キーワード

    包括脳ネットワーク, 神経細胞死, APP代謝, アミロイドβ蛋白(Aβ), アルツハイマー病, amyloid β, ATBF1ノックアウトマウス

論文

  • Establishment of Method for the Determination of Aggregated α-Synuclein in DLB Patient Using RT-QuIC Assay., Seok-Joo Park, Yun-Jung Lee, Jeong-Ho Park, Hyoung-Tae Jin, Myoung-Ju Choi, Cha-Gyun Jung, Hiroyasu Akatsu, Eun-Kyoung Choi, Yong-Sun Kim, Protein and peptide letters,   2020年04月19日, 査読有り, BACKGROUND: The accumulation of aggregated α-synuclein (αSyn) is known as one of the critical reasons to exhibit their variable molecular pathologies and phenotypes in synucleinopathies. Recent studies suggested that the real-time quaking-induced conversion (RT-QuIC) assay is one of the potential methods to detect these αSyn aggregates and could detect the aggregated αSyn in the brain tissue and cerebrospinal fluid (CSF) using the propensity of the prion-like oligomerization. OBJECTIVE: We tried to optimize the αSyn RT-QuIC assay based on the aggregation of αSyn in brain samples of synucleinopathies by comparing the conditions of the recently reported αSyn RT-QuIC assays. METHODS: This study applied a highly sensitive RT-QuIC assay using recombinant αSyn (rαSyn) to detect aggregated αSyn in the brain tissue from dementia with Lewy bodies (DLB). RESULTS: This study compared αSyn RT-QuIC assays under conditions such as beads, rαSyn as substrate, reaction buffers, and fluorescence detectors. We observed that the addition of beads and the use of 6x His-tagged rαSyn as substrate help to obtain higher positive responses from αSyn RTQuIC assay seeding with brain homogenate (BH) of DLB and phosphate buffer-based reaction showed higher positive responses than HEPES buffer-based reaction on both fluorescent microplate readers. We also observed that the DLB BHs gave positive responses within ~15-25 h, which is faster high positive responses than recently reported assays. CONCLUSION: This established αSyn RT-QuIC assay will be able to apply to the early clinical diagnosis of αSyn aggregates related disease in various biofluids such as CSF.
  • Dietary Lactoferrin supplementation prevents memory impairment and reduces Aβ generation., Abdelhamid M, Jung CG, Zhou CY, Abdullah M, Nakano M, Wakabayashi H, Abe F, Michikawa M, Corresponding author, J Alzheimer’s Dis, 74, (1) 245 - 259,   2020年03月, 査読有り
  • Beta-amyloid increases the expression levels of Tid1 responsible for neuronal cell death and amyloid beta production., Zhou CY, Taslima F, Abdelhamid M Mona, Kim SW, Akatsu H, Michikawa M, Jung CG, Corresponding author, Molecular Neurobiology, 57, (2) 1099 - 1114,   2020年02月, 査読有り
  • Alterations of both dendrite morphology and weaker electrical responsiveness in the cortex of hip area occur before rearrangement of the motor map in neonatal white matter injury model, Ueda Y, Bando Y, Misumi S, Ogawa S, Ishida A, Jung CG, Shimizu T, Hda H, Front. Neurol, 9, (443) ,   2018年06月, 査読有り
  • Disorganization of Oligodendrocyte Development in the Layer II/III of the Sensorimotor Cortex Causes Motor Coordination Dysfunction in a Model of White Matter Injury in Neonatal Rats., Ueda Y, Misumi S, Suzuki M, Ogawa S, Nishigaki R, Ishida A, Jung CG, Hida H, Neurochemical research, 43, (1) 127 - 137,   2018年01月, 査読有り
  • A novel biosensor with high signal-to-noise ratio for real-time measurement of dopamine levels in vivo., Ishida A, Imamura A, Ueda Y, Shimizu T, Marumoto R, Jung CG, Hida H, Journal of neuroscience research,   2017年11月, 査読有り
  • A diagnostic marker for superficial urothelial bladder carcinoma: lack of nuclear ATBF1 (ZFHX3) by immunohistochemistry suggests malignant progression., Makoto Kawaguchi, Noboru Hara, Vladimir Bilim, Hiroshi Koike, Mituko Suzuki, Tae-Sun Kim, Nan Gao, Yu Dong, Sheng Zhang, Yuji Fujinawa, Osamu Yamamoto, Hiromi Ito, Yoshihiko Tomita, Yuchi Naruse, Akira Sakamaki, Yoko Ishii, Koichi Tsuneyama, Masaaki Inoue, Johbu Itoh, Masanori Yasuda, Nobuo Sakata, Cha-Gyun Jung, Satoshi Kanazawa, Hiroyasu Akatsu, Hiroshi Minato, Takayuki Nojima, Kiyofumi Asai, Yutaka Miura, BMC cancer, 16, (1) 805 - 805,   2016年10月18日, 査読有り, BACKGROUND: Pathological stage and grade have limited ability to predict the outcomes of superficial urothelial bladder carcinoma at initial transurethral resection (TUR). AT-motif binding factor 1 (ATBF1) is a tumor suppressive transcription factor that is normally localized to the nucleus but has been detected in the cytoplasm in several cancers. Here, we examined the diagnostic value of the intracellular localization of ATBF1 as a marker for the identification of high risk urothelial bladder carcinoma. METHODS: Seven anti-ATBF1 antibodies were generated to cover the entire ATBF1 sequence. Four human influenza hemagglutinin-derived amino acid sequence-tagged expression vectors with truncated ATBF1 cDNA were constructed to map the functional domains of nuclear localization signals (NLSs) with the consensus sequence KR[X10-12]K. A total of 117 samples from initial TUR of human bladder carcinomas were analyzed. None of the patients had received chemotherapy or radiotherapy before pathological evaluation. RESULTS: ATBF1 nuclear localization was regulated synergistically by three NLSs on ATBF1. The cytoplasmic fragments of ATBF1 lacked NLSs. Patients were divided into two groups according to positive nuclear staining of ATBF1, and significant differences in overall survival (P = 0.021) and intravesical recurrence-free survival (P = 0.013) were detected between ATBF1+ (n = 110) and ATBF1- (n = 7) cases. Multivariate analysis revealed that ATBF1 staining was an independent prognostic factor for intravesical recurrence-free survival after adjusting for cellular grading and pathological staging (P = 0.008). CONCLUSIONS: Cleavage of ATBF1 leads to the cytoplasmic localization of ATBF1 fragments and downregulates nuclear ATBF1. Alterations in the subcellular localization of ATBF1 due to fragmentation of the protein are related to the malignant character of urothelial carcinoma. Pathological evaluation using anti-ATBF1 antibodies enabled the identification of highly malignant cases that had been overlooked at initial TUR. Nuclear localization of ATBF1 indicates better prognosis of urothelial carcinoma.
  • Tooth loss might not alter molecular pathogenesis in an aged transgenic Alzheimer's disease model mouse, Hiroshi Oue, Yasunari Miyamoto, Katsunori Koretake, Shinsuke Okada, Kazuya Doi, Cha-Gyun Jung, Makoto Michikawa, Yasumasa Akagawa, GERODONTOLOGY, 33, (3) 308 - 314,   2016年09月, 査読有り, Background and objectivePrevious studies have reported that tooth loss is a risk factor of Alzheimer's disease (AD). However, the association between tooth loss and cognition and the impact of tooth loss on the molecular pathogenesis of AD remain elusive. In this study, we tested the effect of tooth loss on learning and memory and on the molecular pathogenesis of AD in an aged AD model mice. Materials and methodsWe divided 14-month-old amyloid precursor protein (APP) transgenic mice, an AD model mouse line, into upper molar extracted group (experimental) and molar intact group (control). At 18months old, we analysed not only the changes of amyloid-beta (A), pyramidal cells in the brain but also the learning and memory ability with step-through passive avoidance test. ResultsThe amount of A and the number of pyramidal cells in the hippocampus were not significantly different between the experimental and control group. Similarly, the difference of learning and memory ability could not be distinguished between the groups. ConclusionNeither molecular pathogenesis of AD nor associated learning and memory were aggravated by tooth loss in these mice. The limited results of this study which used the aged mice may help the dental profession to plan and explain treatments to patients with AD, which must be designed while taking into account the severity of the AD symptoms.
  • Effects of overexpression of lipoprotein lipase (LPL) on Aβ burden and memory function in LPL and APP-double-transgenic mice, Nunome M, Enomoto H, Abdullah M, Ishida K, Gong JS, Jung CG, Kamijima M, Michikawa M, J Syst Integr Neurosci, 2, (4) 213 - 218,   2016年, 査読有り
  • Dysfunction in Motor Coordination in Neonatal White Matter Injury Model Without Apparent Neuron Loss, Sachiyo Misumi, Yoshitomo Ueda, Ruriko Nishigaki, Mina Suzuki, Akimasa Ishida, Cha-Gyun Jung, Hideki Hida, CELL TRANSPLANTATION, 25, (7) 1381 - 1393,   2016年, 査読有り, We made a white matter injury (WMI) model with mild hindlimb dysfunction by right common carotid artery occlusion followed by 6% oxygen for 60 min at postnatal day 3 (P3), in which actively proliferating oligodendrocyte (OL) progenitors are mainly damaged. To know whether this model is appropriate for cell therapy using OL progenitors, the pathological response to mild hypoxia-ischemia (H-I) in neurons and OL lineage cells and myelination failure were investigated along with gene expression analysis. In WMI model rats, coordinated motor function, as assessed by the accelerating rotarod test, was impaired. The dysfunction was accompanied by myelination failure in layers I-IV of the sensorimotor cortex. Although several oligo2-positive OLs stained positive for active caspase 3 in the cortex and white matter at 24 h after H-I, few NeuN-positive neurons were apoptotic. Argyrophil-III staining for damaged neurons revealed no increase in the number of degenerating cells in the model. Moreover, the total number of NeuN-positive neurons in the cortex was comparable to that of controls 7 days later. Retrograde labeling of the corticospinal tract with Fluoro-Gold revealed no significant loss of layer V neurons. In addition, no decrease in the numbers of cortical projecting neurons and layers V-VI neurons in both motor and sensory areas was observed. Interestingly, the numbers of inhibitory GABAergic cells immunoreactive for parvalbumin, calretinin, or somatostatin were preserved in the P26 cortex. Gene expression analysis at P5 revealed 98 upregulated and 65 downregulated genes that may relate to cell survival, myelin loss, and differentiation of OLs. These data suggest that impaired motor coordination was not induced by neuron loss but, rather, myelination failure in layers I-IV. As OL lineage cells are mainly damaged, this WMI model might be useful for cell-based therapy by replacing OL progenitors.
  • Arachidonic acid diet attenuates brain Aβ deposition in Tg2576 mice., Hosono T, Nishitsuji K, Nakamura T, Jung CG, Kontani M, Tokuda H, Kawashima H, Kiso Y, Suzuki T, Michikawa M, Brain research, 1613, 92 - 99,   2015年07月, 査読有り
  • Early constraint-induced movement therapy promotes functional recovery and neuronal plasticity in a subcortical hemorrhage model rat., Ishida A, Misumi S, Ueda Y, Shimizu Y, Cha-Gyun J, Tamakoshi K, Ishida K, Hida H, Behavioural brain research, 284, 158 - 166,   2015年05月, 査読有り
  • ATBF1 is a novel amyloid-β protein precursor (AβPP) binding protein that affects AβPP expression., Uhm KO, Kim MJ, Kawaguchi M, Akatsu H, Miura Y, Misumi S, Hida H, Choi EK, Kim YS, Michikawa M, Jung CG, Journal of Alzheimer's disease : JAD, 43, (1) 243 - 257,   2015年, 査読有り
  • Auraptene increases the production of amyloid-β via c-Jun N-terminal kinase-dependent activation of γ-secretase., Jung CG, Uhm KO, Horike H, Kim MJ, Misumi S, Ishida A, Ueda Y, Choi EK, Kim YS, Michikawa M, Hida H, Journal of Alzheimer's disease : JAD, 43, (4) 1215 - 1228,   2015年, 査読有り
  • Phosphatidylinositol-glycan-phospholipase D is involved in neurodegeneration in prion disease., Jin JK, Jang B, Jin HT, Choi EK, Jung CG, Akatsu H, Kim JI, Carp RI, Kim YS, PloS one, 10, (4) ,   2015年, 査読有り
  • Arachidonic or Docosahexaenoic Acid Diet Prevents Memory Impairment in Tg2576 Mice, Takashi Hosono, Akihiro Mouri, Kazuchika Nishitsuji, Cha-Gyun Jung, Masanori Kontani, Hisanori Tokuda, Hiroshi Kawashima, Hiroshi Shibata, Toshiharu Suzuki, Toshitaka Nabehsima, Makoto Michikawa, JOURNAL OF ALZHEIMERS DISEASE, 48, (1) 149 - 162,   2015年, 査読有り, It is believed that the amyloid beta-protein (A beta) plays a causative role in the development of Alzheimer's disease (AD). The amyloid-beta protein precursor (A beta PP), a substrate of A beta, and beta-secretase and beta-secretase complex proteins, which process A beta PP to generate A beta, are all membrane proteins. Thus, it is reasonable to assume that alterations in brain lipid metabolism modulate A beta PP and/or A beta metabolism. However, the role of cellular polyunsaturated fatty acids in A beta PP processing has not been completely understood yet. We report here that 4 months of treatment of Tg2576 mice with an arachidonic acid (ARA)-or a docosahexaenoic acid (DHA)-containing (ARA+ or DHA+) diet prevented memory impairment at 13 months of age. Although, A beta PP processing to generate soluble A beta PP and induce A beta synthesis was enhanced, A beta(1-42)/A beta(1-40) ratio decreased in 14-month-old Tg2576 mice fed with the ARA+ or DHA+ diet. The ARA+ or DHA+ diet did not alter the A beta PP levels and the expression levels of A beta-degrading enzymes. In cortical primary neuron cultures, ARA or DHA treatment also increased soluble A beta PP and A beta(1-40) levels, and decreased A beta(1-42)/A beta(1-40) ratio, which are similar to what were observed in Tg2576 mice fed with ARA+ or DHA+ diet. These findings suggest that not only the DHA+ diet, but also the ARA+ diet could prevent cognitive dysfunction in Tg2576 mice through the alteration of A beta PP processing.
  • Enhanced Electrical Responsiveness in the Cerebral Cortex With Oral Melatonin Administration After a Small Hemorrhage Near the Internal Capsule in Rats, Yoshitomo Ueda, Tadashi Masuda, Akimasa Ishida, Sachiyo Misumi, Yuko Shimizu, Cha-Gyun Jung, Hideki Hida, JOURNAL OF NEUROSCIENCE RESEARCH, 92, (11) 1499 - 1508,   2014年11月, 査読有り, Intracerebral hemorrhage (ICH) can cause direct brain injury at the insult site and indirect damage in remote brain areas. Although a protective effect of melatonin (ML) has been reported for ICH, its detailed mechanisms and effects on remote brain injury remain unclear. To clarify the mechanism of indirect neuroprotection after ICH, we first investigated whether ML improved motor function after ICH and then examined the underlying mechanisms. The ICH model rat was made by collagenase injection into the left globus pallidus, adjacent to the internal capsule. ML oral administration (15 mg/kg) for 7 days after ICH resulted in significant recovery of motor function. Retrograde labeling of the corticospinal tract by Fluoro-Gold revealed a significant increase in numbers of positive neurons in the cerebral cortex. Immunohistological analysis showed that ML treatment induced no difference in OX41-positive activated microglia/macrophage at day 1 (D1) but a significant reduction in 8-hydroxydeoxyguanosin-positive cells at D7. Neutral red assay revealed that ML significantly prevented H2O2-induced cell death in cultured oligodendrocytes and astrocytes but not in neurons. Electrophysiological response in the cerebral cortex area where the number of Fluoro-Gold-positive cells was increased was significantly improved in ML-treated rats. These data suggest that ML improves motor abilities after ICH by protecting oligodendrocytes and astrocytes in the vicinity of the lesion in the corticospinal tract from oxidative stress and causes enhanced electrical responsiveness in the cerebral cortex remote to the ICH pathology. (C) 2014 Wiley Periodicals, Inc.
  • Tooth loss induces memory impairment and neuronal cell loss in APP transgenic mice, Hiroshi Oue, Yasunari Miyamoto, Shinsuke Okada, Katsunori Koretake, Cha-Gyun Jung, Makoto Michikawa, Yasumasa Akagawa, BEHAVIOURAL BRAIN RESEARCH, 252, 318 - 325,   2013年09月, 査読有り, Tooth loss is a known risk factor of Alzheimer's disease (AD). However, the association of tooth loss with the molecular pathogenesis of AD is still unknown. The hypothesis that the molecular pathogenesis of AD is enhanced by molar tooth loss was tested. Seventeen female transgenic mice (J20) were divided into the experimental (EX, n=10) and control (C, n = 7) groups. In the EX group, maxillary bilateral molar teeth were extracted at the age of 6 months. In the C group, however, these teeth remained intact. Passive avoidance test was performed to evaluate learning and memory abilities right after tooth extraction (6 months old) and 4 months later (10 months old). After the test at 10 months, amyloid beta (A beta) deposition and changes of neuronal cell number and area in the hippocampus were investigated using half of the brains. The other half was homogenized and used to determine A beta 40 and A beta 42 levels by ELISA. At the 10 months of age, learning and memory abilities were significantly impaired in the EX group compared to the C group (P < 0.05). The neuronal cell number in the CA1 and CA3 regions was significantly lower in the EX group than in the C group (P < 0.05). Total A beta, A beta 40, and A beta 42 levels showed no significant intergroup difference. Molar tooth loss may cause neuronal cell loss in the hippocampus, leading to memory impairment; this process may be independent of the amyloid cascade. (C) 2013 Elsevier B.V. All rights reserved.
  • Differentiation of oligodendrocytes from mouse induced pluripotent stem cells without serum., Misumi S, Nishigaki R, Ueda Y, Watanabe Y, Shimizu Y, Ishida A, Jung CG, Hida H, Transl Stroke Res., 4, (2) 149 - 152,   2013年, 査読有り
  • [Tg2576 mouse model]., Jung CG, Michikawa M, Nihon rinsho. Japanese journal of clinical medicine, 69 Suppl 8, 252 - 255,   2011年10月, 査読有り
  • Beta-amyloid increases the expression level of ATBF1 responsible for death in cultured cortical neurons, Cha-Gyun Jung, Kyung-Ok Uhm, Yutaka Miura, Takashi Hosono, Hirofumi Horike, Kum Kum Khanna, Mi-Jeong Kim, Makoto Michikawa, MOLECULAR NEURODEGENERATION, 6,   2011年07月, 査読有り, Background: Recently, several lines of evidence have shown the aberrant expression of cell-cycle-related proteins and tumor suppressor proteins in vulnerable neurons of the Alzheimer's disease (AD) brain and transgenic mouse models of AD; these proteins are associated with various paradigms of neuronal death. It has been reported that ATBF1 induces cell cycle arrest associated with neuronal differentiation in the developing rat brain, and that gene is one of the candidate tumor suppressor genes for prostate and breast cancers in whose cells overexpressed ATBF1 induces cell cycle arrest. However, the involvement of ATBF1 in AD pathogenesis is as yet unknown. Results: We found that ATBF1 was up-regulated in the brains of 17-month-old Tg2576 mice compared with those of age-matched wild-type mice. Moreover, our in vitro studies showed that A beta 1-42 and DNA-damaging drugs, namely, etoposide and homocysteine, increased the expression ATBF1 level in primary rat cortical neurons, whereas the knockdown of ATBF1 in these neurons protected against neuronal death induced by A beta 1-42, etoposide, and homocysteine, indicating that ATBF1 mediates neuronal death in response to these substances. In addition, we found that ATBF1-mediated neuronal death is dependent on ataxia-telangiectasia mutated (ATM) because the blockage of ATM activity by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 function in neuronal death. Furthermore, A beta 1-42 phosphorylates ATM, and ATBF1 interacts with phosphorylated ATM. Conclusions: To the best of our knowledge, this is the first report that A beta 1-42 and DNA-damaging drugs increased the ATBF1 expression level in primary rat cortical neurons; this increase, in turn, may activate ATM signaling responsible for neuronal death through the binding of ATBF1 to phosphorylated ATM. ATBF1 may therefore be a suitable target for therapeutic intervention of AD.
  • Homocysteine, Another Risk Factor for Alzheimer Disease, Impairs Apolipoprotein E3 Function, Hirohisa Minagawa, Atsushi Watanabe, Hiroyasu Akatsu, Kayo Adachi, Chigumi Ohtsuka, Yasuo Terayama, Takashi Hosono, Satoshi Takahashi, Hideaki Wakita, Cha-Gyun Jung, Hiroto Komano, Makoto Michikawa, JOURNAL OF BIOLOGICAL CHEMISTRY, 285, (49) 38382 - 38388,   2010年12月, 査読有り, Apolipoprotein E (apoE) epsilon 4 and hyperhomocysteinemia are risk factors for Alzheimer disease (AD). The dimerization of apoE3 by disulfide bonds between cysteine residues enhances apoE3 function to generate HDL. Because homocysteine (Hcy) harbors a thiol group, we examined whether Hcy interferes with the dimerization of apoE3 and thereby impairs apoE3 function. We found that Hcy inhibits the dimerization of apoE3 and reduces apoE3-mediated HDL generation to a level similar to that by apoE4, whereas Hcy does not affect apoE4 function. Western blot analysis of cerebrospinal fluid showed that the ratio of apoE3 dimers was significantly lower in the samples from the patients with hyperhomocysteinemia than in those that from control subjects. Hyperhomocysteinemia induced by subcutaneous injection of Hcy to apoE3 knock-in mice decreased the level of the apoE3 dimer in the brain homogenate. Because apoE-HDL plays a role in amyloid beta-protein clearance, these results suggest that two different risk factors, apoE4 and hyperhomocysteinemia, may share a common mechanism that accelerates the pathogenesis of AD in terms of reduced HDL generation.
  • The ZFHX3 (ATBF1) transcription factor induces PDGFRB, which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress, Tae-Sun Kim, Makoto Kawaguchi, Mitsuko Suzuki, Cha-Gyun Jung, Kiyofumi Asai, Yuta Shibamoto, Martin F. Lavin, Kum Kum Khanna, Yutaka Miura, DISEASE MODELS & MECHANISMS, 3, (11-12) 752 - 762,   2010年11月, 査読有り, Ataxia telangiectasia (A-T) is a neurodegenerative disease caused by mutations in the large serine-threonine kinase ATM. A-T patients suffer from degeneration of the cerebellum and show abnormal elevation of serum alpha-fetoprotein. Here, we report a novel signaling pathway that links ATM via cAMP-responsive-element-binding protein (CREB) to the transcription factor ZFHX3 (also known as ATBF1), which in turn promotes survival of neurons by inducing expression of platelet-derived growth factor receptor beta (PDGFRB). Notably, AG1433, an inhibitor of PDGFRB, suppressed the activation of ATM under oxidative stress, whereas AG1433 did not inhibit the response of ATM to genotoxic stress by X-ray irradiation. Thus, the activity of a membrane-bound tyrosine kinase is required to trigger the activation of ATM in oxidative stress, independent of the response to genotoxic stress. Kainic acid stimulation induced activation of ATM in the cerebral cortex, hippocampus and deep cerebellar nuclei (DCN), predominately in the cytoplasm in the absence of induction of gamma-H2AX (a marker of DNA double-strand breaks). The activation of ATM in the cytoplasm might play a role in autophagy in protection of neurons against oxidative stress. It is important to consider DCN of the cerebellum in the etiology of A-T, because these neurons are directly innervated by Purkinje cells, which are progressively lost in A-T.
  • Treadmill running improves motor function and alters dendritic morphology in the striatum after collagenase-induced intracerebral hemorrhage in rats, Yasuyuki Takamatsu, Akimasa Ishida, Michiru Hamakawa, Keigo Tamakoshi, Cha-Gyun Jung, Kazuto Ishida, BRAIN RESEARCH, 1355, 165 - 173,   2010年10月, 査読有り, It is well known that early rehabilitation is effective for functional recovery after intracerebral hemorrhage (ICH); however, the mechanisms have not been well described. The purpose of this study was to elucidate the effects of early rehabilitative therapy (treadmill running) on recovery of motor function and alteration of brain histology after ICH. Male Wistar rats, under deep anesthesia, were placed in a stereotaxic apparatus and injected with collagenase into the left striatum to induce ICH. Sham operated animals were treated with saline. All animals were randomly assigned to treadmill exercise (for 30 min/day, 9 m/min, between 4 and 14 days after surgery) and control and were designated to one of four groups: sham +control (SC), sham+ treadmill (ST), ICH+control (IC), ICH+treadmill (IT). Motor deficit score (MDS) was assessed daily after surgery. volume of tissue lost, dendritic morphology and PSD-95 protein level in the striatum were analyzed at 15 days after surgery. The MDS of IT was significantly improved compared with IC over time. There were no differences between IT and IC in the volume of tissue lost (IT: 63.8%, IC: 61.8%), spine density or PSD-95 protein level in the striatum. However, dendritic length was increased and arborization was more complex in the contralateral striatum of the IT than the IC group (IT: 1226 mu m, IC: 937 mu m). These data suggest that treadmill running improves motor function after ICH and that improvement may be related to alteration of dendritic morphology in the striatum. (C) 2010 Elsevier B.V. All rights reserved.
  • Honokiol Increases ABCA1 Expression Level by Activating Retinoid X Receptor Beta, Cha-Gyun Jung, Hirofumi Horike, Byung-Yoon Cha, Kyung-Ok Uhm, Rena Yamauchi, Takamasa Yamaguchi, Takashi Hosono, Kagami Iida, Je-Tae Woo, Makoto Michikawa, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 33, (7) 1105 - 1111,   2010年07月, 査読有り, ABCA1, a member of the ATP-binding cassette transporter family, regulates high-density lipoprotein (HDL) metabolism and reverses cholesterol transport. Its expression is upregulated mainly by the activation of the liver X receptor (LXR), retinoid X receptor (RXR), and peroxisome proliferator-activated receptors (PPARs). To identify natural compounds that can upregulate ABCA1 expression, we developed a reporter assay using U251-MG (human glioma cell line) cells that stably express a human ABCA1 promoter-luciferase and performed a cell-based high-throughput screening of 118 natural compounds. Using this system, we identified honokiol, a compound extracted from Magnolia officinalis, as an activator of the ABCA1 promoter. We found that honokiol also increased ABCA1 mRNA and protein expression levels in a dose-dependent manner in U251-MG cells without significant cell death and also increased ABCA1, ABCG1 and apolipoprotein E (apoE) expression levels in THP-1 macrophages. PPAR antagonists did not diminish the induction of ABCA1 expression by honokiol in U251-MG cells. Cotreatment of the cells with honokiol and T0901317 (synthetic LXR ligand) further increased the ABCA1 expression level, whereas cotreatment with 9-cis retinoic acid had no additive effect compared with treatment with honokiol alone. We also found that honokiol has binding affinity to RXR beta. In this study, we identified for the first time honokiol as an upregulator of ABCA1 expression, which is mediated by the binding of honokiol to RXR beta as a ligand.
  • Fingolimod and related compounds in a spontaneous autoimmune polyneuropathy, Hye-Jung Kim, Cha-Gyun Jung, Danuta Dukala, Hyun Bae, Rafael Kakazu, Robert Wollmann, Betty Soliven, JOURNAL OF NEUROIMMUNOLOGY, 214, (1-2) 93 - 100,   2009年09月, 査読有り, We investigated potential therapeutic effects of sphingosine-1-phosphate (S1P) receptor modulators FTY720 (fingolimod) and selective S1P1 agonist SEW2871 on a spontaneous autoimmune polyneuropathy (SAP) when given orally at 7 mo (anticipated disease onset) for 4 weeks. Clinical severity, electrophysiologic and histological findings were ameliorated in mice treated with 1 mg/kg of FTY720. Subsequent studies showed that SEW2871 was also effective in halting the progression of SAP, which was accompanied by decreased proliferative and cytokine responses to myelin protein zero (P0), and an increase in regulatory T cells. We conclude that SIP receptor modulators may play a therapeutic role in autoimmune neuropathies. (c) 2009 Elsevier B.V. All rights reserved.
  • Mechanism underlying apolipoprotein E (ApoE) isoform-dependent lipid efflux from neural cells in culture., Minagawa H, Gong JS, Jung CG, Watanabe A, Lund-Katz S, Phillips MC, Saito H, Michikawa M, Journal of neuroscience research, 87, (11) 2498 - 2508,   2009年08月, 査読有り
  • Targeting of myelin protein zero in a spontaneous autoimmune polyneuropathy. contributed equally, Kim HJ, Jung CG, Jensen MA, Dukala D, Soliven B, Journal of immunology (Baltimore, Md. : 1950), 181, (12) 8753 - 8760,   2008年12月, 査読有り
  • Enhanced neurogenesis from neural progenitor cells with G1/S-phase cell cycle arrest is mediated by transforming growth factor beta1., Misumi S, Kim TS, Jung CG, Masuda T, Urakawa S, Isobe Y, Furuyama F, Nishino H, Hida H, The European journal of neuroscience, 28, (6) 1049 - 1059,   2008年09月, 査読有り
  • Increase in dopaminergic neurons from mouse embryonic stem cell-derived neural progenitor/stem cells is mediated by hypoxia inducible factor-1alpha., Kim TS, Misumi S, Jung CG, Masuda T, Isobe Y, Furuyama F, Nishino H, Hida H, Journal of neuroscience research, 86, (11) 2353 - 2362,   2008年08月, 査読有り
  • FTY720 modulates human oligodendrocyte progenitor process extension and survival., Miron VE, Jung CG, Kim HJ, Kennedy TE, Soliven B, Antel JP, Annals of neurology, 63, (1) 61 - 71,   2008年01月, 査読有り
  • A deletion mutation of the protein tyrosine phosphatase kappa (Ptprk) gene is responsible for T-helper immunodeficiency (thid) in the LEC rat, Atsushi Asano, Kouta Tsubomatsu, Cha-Gyun Jung, Nobuya Sasaki, Takashi Agui, MAMMALIAN GENOME, 18, (11) 779 - 786,   2007年11月, 査読有り, Bone marrow (BM)-derived T-cell progenitors differentiate into CD4 or CD8 single-positive (SP) cells in the thymus. We have previously reported that a single autosomal mutation, thid, causes a defect in the maturation of CD4 SP thymocytes and an abnormality of peripheral helper T cells in the LEC rat. In this study we attempted to identify a gene responsible for the thid mutation. We first performed genetic linkage analysis and mapped the thid locus between Myb and D1Rat392 on Chr 1. In this region we found an approximately 380-kb deletion from intron 3 of the Ptprk gene, which encodes a receptor-like protein tyrosine phosphatase type kappa (RPTP kappa) to intron 1 of the RGD1560849 predicted gene in the LEC rat genome. Reconstitution with syngenic BM cells transduced Ptprk but not the RGD1560849 predicted gene rescued development of CD4 SP cells in the LEC rat thymus. It is confirmed by this result that the Ptprk gene is responsible for the thid mutation in the LEC rat. Our results further suggest that RPTP kappa plays a critical role in the development of CD4 SP cells in the thymus.
  • Functional consequences of S1P1 receptor modulation in rat oligodendroglial lineage cells., Jung CG, Kim HJ, Miron VE, Cook S, Kennedy TE, Foster CA, Antel JP, Soliven B, Glia, 55, (16) 1656 - 1667,   2007年, 査読有り
  • Treatment with deferoxamine increases neurons from neural stem/progenitor cells, Hye-Jung Kim, Hideki Hida, Cha-Gyun Jung, Yutaka Miura, Hitoo Nishino, BRAIN RESEARCH, 1092, (1) 1 - 15,   2006年05月, 査読有り, Neural transplantation is a promising approach for treating neurodegenerative disease. Neural stem/progenitor cells (NPCs) are self-renewing and multipotent and thus are good candidates for donor cells when they have been clearly defined to differentiate into neurons. As neuronal differentiation follows cell cycle exit, we investigated whether neuron production from NPCs is increased by treatment with cell cycle blockers. NPCs from E12.5 rat ventral mesencephalon were cultured as neurospheres in DMEM/F12 medium containing N2 supplements and bFGF. Treatment of NPCs with deferoxamine, a G1/S phase blocker, increased the number of beta-tubulin III-positive cells after differentiation, concomitant with increases of MAP2 mRNA and protein, and a decrease of GFAP protein. Further, an increase in beta-tubulin III/BrdU double-positive cells and a decrease in GFAP/BrdU double-positive cells were confirmed. In real-time PCR, the expressions of p21(cip1), p27(kip1) and p57(kip2) mRNAs remained unaltered for 8 h after treatment with deferoxamine but were significantly elevated after I day. Deferoxamine specifically enhanced the elevation of p27(kip1) mRNA at 1-2 days and the accumulation of p27(kip1) protein at 3 days, along with the activation of neuroD promoter and the elevation of neuroD mRNA. Transfection of p27(kip1) into NPCs induced activation of neuroD promoter and increase of number of beta-tubulin III-positive cells. These data suggest that pretreatment with deferoxamine increases the number of neurons from NPCs related to prolonged p27(kip1) elevation and activation of the neuroD signaling pathway. In this way, regulation of the cell cycle should be a useful first step in engineering NPCs for neural transplantation. (c) 2006 Elsevier B.V. All rights reserved.
  • Homeotic factor ATBF1 induces the cell cycle arrest associated with neuronal differentiation, CG Jung, HJ Kim, M Kawaguchi, KK Khanna, H Hida, K Asai, H Nishino, Y Miura, DEVELOPMENT, 132, (23) 5137 - 5145,   2005年12月, 査読有り, The present study aimed to elucidate the function of AT motif-binding factor 1 (ATBF1) during neurogenesis in the developing brain and in primary cultures of neuroepithelial cells and cell lines (Neuro 2A and P19 cells). Here, we show that ATBF1 is expressed in the differentiating field in association with the neuronal differentiation markers beta-tubulin and MAP2 in the day E14.5 embryo rat brain, suggesting that it promotes neuronal differentiation. In support of this, we show that ATBF1 suppresses nestin expression, a neural stem cell marker, and activates the promoter of Neurod1 gene, a marker for neuronal differentiation. Furthermore, we show that in Neuro 2A cells, overexpressed ATBF1 localizes predominantly in the nucleus and causes cell cycle arrest. In P19 cells, which formed embryonic bodies in the floating condition, ATBF1 is mainly cytoplasmic and has no effect on the cell cycle. However, the cell cycle was arrested when ATBF1 became nuclear after transfer of P19 cells onto adhesive surfaces or in isolated single cells. The nuclear localization of ATBF1 was suppressed by treatment with caffeine, an inhibitor of PI(3)K-related kinase activity of ataxa-telangiectasia mutated (ATM) gene product. The cytoplasmic localization of ATBF1 in floating/nonadherent cells is due to CRM1-dependent nuclear export of ATBF1. Moreover, in the embryonic brain ATBF1 was expressed in the cytoplasm of proliferating stem cells on the ventricular zone, where cells are present at high density and interact through cell-to-cell contact. Conversely, in the differentiating field, where cell density is low and extracellular matrix is dense, the cell-to-matrix interaction triggered nuclear localization of ATBF1, resulting in the cell cycle arrest. We propose that ATBF1 plays an important role in the nucleus by organizing the neuronal differentiation associated with the cell cycle arrest.
  • Glial cell line-derived neurotrophic factor-induced signaling in Schwann cells, T Iwase, CG Jung, H Bae, M Zhang, B Soliven, JOURNAL OF NEUROCHEMISTRY, 94, (6) 1488 - 1499,   2005年09月, 査読有り, Glial cell line-derived neurotrophic factor (GDNF), a known survival factor for neurons, has recently been shown to stimulate the migration of Schwann cells (SCs) and to enhance myelination. GDNF exerts its biological effects by activating the Ret tyrosine kinase in the presence of glycosylphosphatidylinositol-linked receptor, GDNF family receptor (GFR) alpha 1. In Ret-negative cells, the alternative transmembrane coreceptor is the 140-kDa isoform of neural cell adhesion molecule (NCAM) associated with a non-receptor tyrosine kinase Fyn. We confirmed that GDNF, GFR alpha 1 and NCAM are expressed in neonatal rat SCs. We found that GDNF induces an increase in the partitioning of NCAM and heparan sulfate proteoglycan agrin into lipid rafts and that heparinase inhibits GDNF-signaling in SCs. In addition to activation of extracellular signal-regulated kinases, and phosphorylation of cAMP response element binding protein, we found that cAMP-dependent protein kinase A and protein kinase C are involved in GDNF-mediated signaling in SCs. Although GDNF did not promote the differentiation of purified SCs into the myelinating phenotype, it enhanced myelination in neuron-SC cocultures. We conclude that GDNF utilizes NCAM signaling pathways to regulate SC function prior to myelination and at early stages of myelin formation.
  • Pleiotrophin mRNA is highly expressed in neural stem (progenitor) cells of mouse ventral mesencephalon and the product promotes production of dopaminergic neurons from embryonic stem cell-derived nestin-positive cells., Jung CG, Hida H, Nakahira K, Ikenaka K, Kim HJ, Nishino H, FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 18, (11) 1237 - 1239,   2004年08月, 査読有り
  • High titer retroviral gene transduction to neural progenitor cells for establishment of donor cells for neural transplantation to parkinsonian model rats., Kodama Y, Hida H, Jung CG, Baba H, Isono M, Kobayashi H, Nishino H, Neurologia medico-chirurgica, 44, (7) 344 - 51; discussion 352,   2004年07月, 査読有り
  • Pleiotrophin exhibits a trophic effect on survival of dopaminergic neurons in vitro, H Hida, CG Jung, CZ Wu, HJ Kim, Y Kodama, T Masuda, H Nishino, EUROPEAN JOURNAL OF NEUROSCIENCE, 17, (10) 2127 - 2134,   2003年05月, 査読有り, To understand what kind of trophic factors are up-regulated in dopamine (DA)-depleted striatum, we first analysed the up-regulation of mRNAs using a DNA microarray in DA-depleted striatum where DAergic inputs were denervated by 6-OHDA. We then investigated whether or not such trophic factors had an effect on cultured dopaminergic neurons. The microarray analysis revealed that pleiotrophin (PTN), glial-derived neurotopic factor (GDNF) and others were up-regulated in DA-depleted striatum. As PTN has been reported to have a wide range of trophic effects on neurons, we focused on the functional role of PTN in the present study The increase in PTN mRNA was confirmed by Northern blotting at 1-3 weeks after the lesion, reaching a peak at 1 week. In embryonic day 15 mesencephalic neuron culture, PTN increased the number of tyrosine hydroxylase (TN) -positive neurons in a dose-dependent manner (125.2 +/- 2.0% of the control at 50 ng/mL), while a family protein, midkine (10 ng/mL) did not show any trophic effect (99.3 +/- 0.7%). In addition, the PTN effect on DAergic neurons was additive to the GDNF effect. As PTN did not increase the number of microtubule-associated protein-2 (MAP 2)-positive neurons or promote the proliferation of dopaminergic progenitors in a bromodeoxyuridine (BrdU) labelling study, the effect appeared to enhance the specific survival of dopaminergic neurons. Expression of PTN receptors (syndecan-3, PTP-zeta) was detected on the cultured mesencephalic neurons, and also up-regulated in DA-depleted striatum. The data indicate that PTN is up-regulated in DA-depleted striatum and exhibits a trophic effect specifically on the survival of cultured dopaminergic neurons.
  • Estrogen blocks 3-nitropropionic acid-induced [Ca2+](i) increase and cell damage in cultured rat cerebral endothelial cells, M Mogami, H Hida, Y Hayashi, K Kohri, Y Kodama, CG Jung, H Nishino, BRAIN RESEARCH, 956, (1) 116 - 125,   2002年11月, 査読有り, Systemic administration of 3-nitropropionic acid (3-NPA, a mycotoxin) induces brain damage accompanied by disturbance in the blood-brain barrier (BBB). Since the endothelial cells are important components of the BBB and the first target of a systemic intoxication, in the present study, the effect of 3-NPA on primary cultured rat brain endothelial cells (rBECs) was examined by studying intracellular Ca2+ ([Ca2+](i)) response using imaging techniques with fura-2. rBECs were prepared using a method of Kis et al. [Eur. J. Pharmacol. 368 (1999) 35-42] and Szabo et al. [Neurobiology 5 (1997) 1-16]. Almost all cells were immunoreactive to antibody against the factor VIII-related antigen (von-Willebrand factor). They showed a typical dose-dependent increase of [Ca2+](i) in response to ATP or bradykinin. Low concentrations of 3-NPA (1.7 mM, 3.4 mM) caused no changes, and a medium concentration (6.8 mM) increased the [Ca2+](i) gradually and progressively, and the increase was reversed incompletely back to the resting level after washing. A high concentration (13.6 mM) increased the [Ca2+](i) irreversibly. These elevations of [Ca2+]i were absent in a Ca2+-free medium. In endothelial cells treated with 17beta-estradiol (above 10(-5) M) or with a selective estrogen receptor modulator, tamoxifen (5 X 10(-7) M), no elevation of [Ca2+](i) was observed with 3-NPA treatment. The response to ATP was impaired after application of 3-NPA, but it was preserved by cotreatment with 17beta-estradiol or tamoxifen. An estrogen receptor antagonist ICI 182,780 inhibited these effects by 17beta-estradiol or tamoxifen. Lysosomal neutral red uptake and TUNEL experiments revealed the necrotic but not apoptotic cell death at least in this acute stage. Data indicate that a medium to high concentration of 3-NPA induces damage on rBECs as revealed by an accumulation of [Ca2+](i), but the damage was protected by cotreatment with 17beta-estradiol or tamoxifen, suggesting that estrogen may be protective for the brain vascular damage via estrogen receptor. (C) 2002 Elsevier Science B.V. All rights reserved.
  • Genetic association between low expression phenotype of CD62L (L-selectin) in peripheral CD4+ T cells and the thid (T-helper immunodeficiency) phenotype in the LEC rat., Jung CG, Miyamoto T, Tsumagari T, Agui T, Exp. Anim., 50, (4) 337 - 340,   2001年, 査読有り
  • Linkage mapping of the rat 8-oxoguanine DNA glycosylase gene to chromosome 4., Masuda K, Miyamoto T, Jung CG, Ding M, Cheng JM, Tsumagari T, Manabe T, Agui T, Exp. Anim., 50, (4) 353 - 354,   2001年, 査読有り
  • Genetic linkage analysis of X-ray hypersensitivity in the LEC mutant rat, T Agui, T Miyamoto, CG Jung, T Tsumagari, K Masuda, T Manabe, MAMMALIAN GENOME, 11, (10) 862 - 865,   2000年10月, 査読有り, The LEC rat has been reported to exhibit X-ray hyper sensitivity and deficiency in DNA double-strand break (DSB) repair. The present study was performed to map the locus responsible for this phenotype, the xhs (X-ray hypersensitivity), as the first step in identifying the responsible gene. Analysis of the progeny of (BN x LEC)F-1 x LEC backcrosses indicated that the X-ray hypersensitive phenotype was controlled by multiple genetic loci in contrast to the results reported previously. Quantitative trait loci (QTL) linkage analysis revealed two responsible loci located on Chromosomes (Chr) 4 and 1. QTL on Chr 4 exhibited very strong linkage to the X-ray hypersensitive phenotype, while QTL on Chr 1 showed weak linkage. The Rad52 locus, mutation of which results in hypersensitivity to ionizing radiation and impairment of DNA DSB repair in yeast, was reported to be located on the synteneic regions of mouse Chr 6 and human Chr 12. However, mapping of the rat Rad52 locus indicated that it was located 23 cM distal to the QTL on Chr 4. Furthermore, none of the radiosensitivity-related loci mapped previously in the rat chromosome were identical to the QTL on Chrs 4 and 1 in the LEC rat. Thus, it seems that X-ray hypersensitivity in the LEC rat is caused by mutation(s) in as-yet-undefined genes.
  • A missense mutation G2320R in the thyroglobulin gene causes non-goitrous congenital primary hypothyroidism in the WIC-rdw rat., Kim PS, Ding M, Menona S, Jung CG, Cheng JM, Miyamoto T, Lia B, Furudate S, Agui T, Molecular Endocrinology,, 14, (12) 862 - 865,   2000年, 査読有り
  • Elevated apoptosis of peripheral T lymphocytes in diabetic BB rats, CC Jung, T Kamiyama, T Agui, IMMUNOLOGY, 98, (4) 590 - 594,   1999年12月, 査読有り, Thymocytes and peripheral lymphocytes of BioBreeding (BB) diabetes-prone (BBDP) and diabetes-resistant (BBDR) rat were analysed by fluorescence-activated cell sorter (FACS). The number of CD4(-) CD8(-), CD4(+) CD8(-), CD4(-) CD8(+) and CD4(+) CD8(+) subsets was not different between BBDP and BBDR rat thymocytes, whereas spleen and lymph nodes in BBDP rats undergo severe T-cell lymphopenia. Notably, mature CD4(-) CD8(+) [T-cell receptor (TCR)-alpha beta(+) and CD5(+)] cells are certainly present in the BBDP rat thymus, unlike some previous reports, suggesting that the differentiation of CD4(-) CD8(+) from CD4(+) CD8(-) cells occurs normally in the BBDP rat thymus. As a cause of peripheral T-cell lymphopenia we suspected apoptosis of recent thymic emigrants. By FAGS analysis with fluorescein isothiocyanate-labelled annexin V, elevated apoptosis was evident in BBDP rat peripheral lymphocytes. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) staining in BBDP rat splenic sections revealed that a number of TUNEL-positive cells were observed in the T-lymphocyte-rich area. From these results, we postulate that an abnormally elevated apoptosis of peripheral T lymphocytes, but not impaired thymocyte differentiation, is a cause of the peripheral T-cell lymphopenia in BBDP rats.

MISC

  • ATBF1はAPP濃度に影響を及ぼす新規APP結合タンパク質である(ATBF1 is a novel APP binding protein that affects APP level), 鄭 且均, 川口 誠, 赤津 裕康, 道川 誠, Dementia Japan, 31, (4) 561 - 561,   2017年10月
  • 多価不飽和脂肪酸餌はLPSで誘導される脳内炎症を抑制する, 細野崇, 細野崇, 山内玲奈, 紺谷昌仙, 西辻和親, 鄭且均, 河島洋, 木曽良信, 道川誠, Dement Jpn, 24,   2010年09月15日
  • APP代謝及びAβ産生におけるATBF1(AT-motif binding factor 1)の機能解析, 厳 景玉, 赤津 裕康, 三浦 裕, 道川 誠, 鄭 且均, Dementia Japan, 24, (3) 370 - 370,   2010年09月
  • APP代謝及びAβ産生機構におけるホメオティック因子ATBF1の機能解析(The role of ATBF1 in APP processing and β generation), 鄭 且均, 厳 景玉, 三浦 裕, 赤津 裕康, 道川 誠, 神経化学, 49, (2-3) 666 - 666,   2010年08月
  • AβはATBF1の発現を上昇させ神経細胞死を誘導する(Aβ enhance the ATBF1 expression responsible for the neuronal cell death), 鄭 且均, 川口 誠, 三浦 裕, 赤津 裕康, 金 康善, 道川 誠, 神経化学, 47, (2-3) 258 - 258,   2008年08月

書籍等出版物

  • 基礎からわかる軽度認知症(MCI), 鄭且均, 共著, バイオマーカとMCI。, 医学書院,   2015年04月
  • .認証医学(上)その解明と治療の最新知見。, 鄭且均, 道川 誠, 共著, Tg2576マウス, 日本臨床社,   2011年10月
  • 神経栄養因子 ―その新しい展開, 飛田秀樹, 鄭 且均, 西野仁雄, 共著, 線条体の幹細胞分化因子, 中外医学社,   2004年01月
  • 神経疾患と再生医療。, 飛田秀樹, 鄭 且均, 西野仁雄, 共著, Parkinson病モデル動物への細胞治療, 最新医学社,   2002年07月
  • 神経幹細胞, 飛田秀樹, 鄭 且均, 西野仁雄, 共著, 中脳神経幹細胞のParkinson病モデル動物への応用, 中外医学社,   2002年01月

受賞

  •   2018年10月, 日本ラクトフェリン学会, 日本ラクトフェリン学会津田賞


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