2024/06/20 更新

写真a

イトウ ミカコ
伊藤 美佳子
ITO, Mikako
所属
大学院医学系研究科 附属神経疾患・腫瘍分子医学研究センター 神経疾患病態統御部門 講師
大学院担当
大学院医学系研究科
学部担当
医学部 医学科
職名
講師
外部リンク

学位 1

  1. 博士(工学) ( 2001年3月   大阪大学 ) 

研究キーワード 1

  1. 神経筋接合部 先天性筋無力症候群 分子状水素 微弱磁場

研究分野 5

  1. その他 / その他  / 分子生物学

  2. ライフサイエンス / 遺伝学

  3. ライフサイエンス / 神経科学一般

  4. ライフサイエンス / 応用分子細胞生物学

  5. ライフサイエンス / 分子生物学

現在の研究課題とSDGs 4

  1. 終板アセチルコリンエステラーゼ欠損症、及び、他の細胞外マトリックス分子欠損症におけるタンパク標的療法の開発研究

  2. 筋ジストロフィーにおける細胞外分子補充療法の開発

  3. パーキンソン病における腸内細菌叢の変化

  4. 超低周波微弱磁場の生体の反応解明と治療への応用

経歴 3

  1. 名古屋大学   大学院医学系研究科 附属神経疾患・腫瘍分子医学研究センター 神経疾患病態統御部門   講師

    2022年3月 - 現在

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    国名:日本国

  2. 名古屋大学   大学院医学系研究科 附属神経疾患・腫瘍分子医学研究センター 神経疾患病態統御部門   特任講師

    2017年4月 - 2022年3月

  3. 名古屋大学   大学院医学系研究科 附属神経疾患・腫瘍分子医学研究センター 神経疾患病態統御部門   助教

    2013年4月 - 2017年3月

学歴 3

  1. 大阪大学   工学系研究科   応用生物工学専攻

    - 2001年3月

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    国名: 日本国

  2. 大阪大学   工学研究科   生物工学

    - 2001年

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    国名: 日本国

  3. 大阪大学

    - 2001年

所属学協会 6

  1. 日本分子生物学会

  2. 日本生化学会

    2021年9月 - 現在

  3. 日本筋学会

    2015年4月 - 現在

  4. 日本筋学会

  5. 日本生化学会

  6. 分子生物学会

▼全件表示

 

論文 100

  1. Calcitriol ameliorates motor deficits and prolongs survival of Chrne-deficient mouse, a model for congenital myasthenic syndrome, by inducing Rspo2. 査読有り 国際誌

    Ohkawara B, Tomita H, Inoue T, Zhang S, Kanbara S, Koshimizu H, Miyasaka Y, Takeda JI, Nishiwaki H, Nakashima H, Ito M, Masuda A, Ishiguro N, Ogi T, Ohno T, Imagama S, Ohno K

    Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics   21 巻 ( 2 ) 頁: e00318   2024年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.neurot.2024.e00318

    PubMed

  2. Splicing regulation of GFPT1 muscle-specific isoform and its roles in glucose metabolisms and neuromuscular junction. 査読有り

    Farshadyeganeh P, Nazim M, Zhang R, Ohkawara B, Nakajima K, Rahman MA, Nasrin F, Ito M, Takeda JI, Ohe K, Miyasaka Y, Ohno T, Masuda A, Ohno K

    iScience   26 巻 ( 10 ) 頁: 107746   2023年10月

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    記述言語:英語   出版者・発行元:iScience  

    Glutamine:fructose-6-phosphate transaminase 1 (GFPT1) is the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP). A 54-bp exon 9 of GFPT1 is specifically included in skeletal and cardiac muscles to generate a long isoform of GFPT1 (GFPT1-L). We showed that SRSF1 and Rbfox1/2 cooperatively enhance, and hnRNP H/F suppresses, the inclusion of human GFPT1 exon 9 by modulating recruitment of U1 snRNP. Knockout (KO) of GFPT1-L in skeletal muscle markedly increased the amounts of GFPT1 and UDP-HexNAc, which subsequently suppressed the glycolytic pathway. Aged KO mice showed impaired insulin-mediated glucose uptake, as well as muscle weakness and fatigue likely due to abnormal formation and maintenance of the neuromuscular junction. Taken together, GFPT1-L is likely to be acquired in evolution in mammalian striated muscles to attenuate the HBP for efficient glycolytic energy production, insulin-mediated glucose uptake, and the formation and maintenance of the neuromuscular junction.

    DOI: 10.1016/j.isci.2023.107746

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  3. Extremely low-frequency electromagnetic field induces acetylation of heat shock proteins and enhances protein folding 査読有り

    Huang, ZZ; Ito, M; Zhang, SC; Toda, T; Takeda, JI; Ogi, T; Ohno, K

    ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY   264 巻   頁: 115482   2023年10月

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    記述言語:英語   出版者・発行元:Ecotoxicology and Environmental Safety  

    The pervasive weak electromagnetic fields (EMF) inundate the industrialized society, but the biological effects of EMF as weak as 10 µT have been scarcely analyzed. Heat shock proteins (HSPs) are molecular chaperones that mediate a sequential stress response. HSP70 and HSP90 provide cells under undesirable situations with either assisting covalent folding of proteins or degrading improperly folded proteins in an ATP-dependent manner. Here we examined the effect of extremely low-frequency (ELF)-EMF on AML12 and HEK293 cells. Although the protein expression levels of HSP70 and HSP90 were reduced after an exposure to ELF-EMF for 3 h, acetylations of HSP70 and HSP90 were increased, which was followed by an enhanced binding affinities of HSP70 and HSP90 for HSP70/HSP90-organizing protein (HOP/STIP1). After 3 h exposure to ELF-EMF, the amount of mitochondria was reduced but the ATP level and the maximal mitochondrial oxygen consumption were increased, which was followed by the reduced protein aggregates and the increased cell viability. Thus, ELF-EMF exposure for 3 h activated acetylation of HSPs to enhance protein folding, which was returned to the basal level at 12 h. The proteostatic effects of ELF-EMF will be able to be applied to treat pathological states in humans.

    DOI: 10.1016/j.ecoenv.2023.115482

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  4. <i>Fusobacterium</i> infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts 査読有り 国際誌

    Muraoka, A; Suzuki, M; Hamaguchi, T; Watanabe, S; Iijima, K; Murofushi, Y; Shinjo, K; Osuka, S; Hariyama, Y; Ito, M; Ohno, K; Kiyono, T; Kyo, S; Iwase, A; Kikkawa, F; Kajiyama, H; Kondo, Y

    SCIENCE TRANSLATIONAL MEDICINE   15 巻 ( 700 ) 頁: eadd1531   2023年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Science Translational Medicine  

    Retrograde menstruation is a widely accepted cause of endometriosis. However, not all women who experience retrograde menstruation develop endometriosis, and the mechanisms underlying these observations are not yet understood. Here, we demonstrated a pathogenic role of Fusobacterium in the formation of ovarian endometriosis. In a cohort of women, 64% of patients with endometriosis but <10% of controls were found to have Fusobacterium infiltration in the endometrium. Immunohistochemical and biochemical analyses revealed that activated transforming growth factor–β (TGF-β) signaling resulting from Fusobacterium infection of endometrial cells led to the transition from quiescent fibroblasts to transgelin (TAGLN)–positive myofibroblasts, which gained the ability to proliferate, adhere, and migrate in vitro. Fusobacterium inoculation in a syngeneic mouse model of endometriosis resulted in a marked increase in TAGLN-positive myofibroblasts and increased number and weight of endometriotic lesions. Furthermore, antibiotic treatment largely prevented establishment of endometriosis and reduced the number and weight of established endometriotic lesions in the mouse model. Our data support a mechanism for the pathogenesis of endometriosis via Fusobacterium infection and suggest that eradication of this bacterium could be an approach to treat endometriosis.

    DOI: 10.1126/scitranslmed.add1531

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  5. A mutation in DOK7 in congenital myasthenic syndrome forms aggresome in cultured cells, and reduces DOK7 expression and MuSK phosphorylation in patient-derived iPS cells 査読有り

    Zhang, SC; Ohkawara, B; Ito, M; Huang, ZZ; Zhao, F; Nakata, T; Takeuchi, T; Sakurai, H; Komaki, H; Kamon, M; Araki, T; Ohno, K

    HUMAN MOLECULAR GENETICS   32 巻 ( 9 ) 頁: 1511 - 1523   2023年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Human Molecular Genetics  

    At the neuromuscular junction, the downstream of tyrosine kinase 7 (DOK7) enhances the phosphorylation of muscle-specific kinase (MuSK) and induces clustering of acetylcholine receptors (AChRs). We identified a patient with congenital myasthenic syndrome (CMS) with two heteroallelic mutations in DOK7, c.653-1G>C in intron 5 and c.190G>A predicting p.G64R in the pleckstrin homology domain. iPS cells established from the patient (CMS-iPSCs) showed that c.653-1G>C caused in-frame skipping of exon 6 (120 bp) and frame-shifting activation of a cryptic splice site deleting seven nucleotides in exon 6. p.G64R reduced the expression of DOK7 to 10% of wild-type DOK7, and markedly compromised AChR clustering in transfected C2C12 myotubes. p.G64R-DOK7 made insoluble aggresomes at the juxtanuclear region in transfected C2C12 myoblasts and COS7 cells, which were co-localized with molecules in the autophagosome system. A protease inhibitor MG132 reduced the soluble fraction of p.G64R-DOK7 and enhanced the aggresome formation of p.G64RDOK7. To match the differentiation levels between patient-derived and control induced pluripotent stem cells (iPSCs), we corrected c.190G>A (p.G64R) by CRISPR/Cas9 to make isogenic iPSCs while retaining c.653-1G>C (CMS-iPSCsCas9). Myogenically differentiated CMS-iPSCs showed juxtanuclear aggregates of DOK7, reduced expression of endogenous DOK7 and reduced phosphorylation of endogenous MuSK. Another mutation, p.T77M, also made aggresome to a less extent compared with p.G64R in transfected COS7 cells. These results suggest that p.G64R-DOK7 makes aggresomes in cultured cells and is likely to compromise MuSK phosphorylation for AChR clustering.

    DOI: 10.1093/hmg/ddac306

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  6. Neural Isoforms of Agrin Are Generated by Reduced PTBP1-RNA Interaction Network Spanning the Neuron-Specific Splicing Regions in <i>AGRN</i> 査読有り 国際誌

    Bushra, S; Lin, YN; Joudaki, A; Ito, M; Ohkawara, B; Ohno, K; Masuda, A

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   24 巻 ( 8 )   2023年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Molecular Sciences  

    Agrin is a heparan sulfate proteoglycan essential for the clustering of acetylcholine receptors at the neuromuscular junction. Neuron−specific isoforms of agrin are generated by alternative inclusion of three exons, called Y, Z8, and Z11 exons, although their processing mechanisms remain elusive. We found, by inspection of splicing cis−elements into the human AGRN gene, that binding sites for polypyrimidine tract binding protein 1 (PTBP1) were extensively enriched around Y and Z exons. PTBP1−silencing enhanced the coordinated inclusion of Y and Z exons in human SH−SY5Y neuronal cells, even though three constitutive exons are flanked by these alternative exons. Deletion analysis using minigenes identified five PTBP1−binding sites with remarkable splicing repression activities around Y and Z exons. Furthermore, artificial tethering experiments indicated that binding of a single PTBP1 molecule to any of these sites represses nearby Y or Z exons as well as the other distal exons. The RRM4 domain of PTBP1, which is required for looping out a target RNA segment, was likely to play a crucial role in the repression. Neuronal differentiation downregulates PTBP1 expression and promotes the coordinated inclusion of Y and Z exons. We propose that the reduction in the PTPB1−RNA network spanning these alternative exons is essential for the generation of the neuron−specific agrin isoforms.

    DOI: 10.3390/ijms24087420

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  7. Effects of Pesticide Intake on Gut Microbiota and Metabolites in Healthy Adults 査読有り 国際誌

    Ueyama, J; Hayashi, M; Hirayama, M; Nishiwaki, H; Ito, M; Saito, I; Tsuboi, Y; Isobe, T; Ohno, K

    INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH   20 巻 ( 1 )   2023年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Environmental Research and Public Health  

    Animal experiments have indicated that pesticides may affect gut microbiota, which is responsible for the production of short-chain fatty acids (SCFAs) and polyamines. Here, we present a preliminary observation of the relationship between pesticide exposure and fecal SCFAs and polyamines in Japanese adults. In total, 38 healthy adults aged 69 ± 10 years (mean ± SD) were recruited and subjected to stool and spot urine tests. Urinary dialkylphosphates (DAP), 3-phenoxybenzoic acid, and glyphosate were assayed as pesticide exposure markers of organophosphorus insecticide (OP), a pyrethroid insecticide, and glyphosate, respectively. Significant negative correlations (p < 0.05, Spearman’s rank correlation coefficient) were found between urinary DAP, fecal acetate (r = −0.345), and lactate (r = −0.391). Multiple regression analyses revealed that urinary DAP was a significant explanatory variable of fecal acetate concentration (p < 0.001, β = −24.0, SE = 4.9, t = −4.9) with some vegetable intake (adjusted R-square = 0.751). These findings suggest that OP exposure is independently associated with lower fecal acetate levels, which may contribute to human health in middle-aged and older adult groups. Given that the human gut environment has long-term effects on the host, studies on wide-range age groups, including children, are necessary.

    DOI: 10.3390/ijerph20010213

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  8. Gut microbiota in dementia with Lewy bodies 査読有り 国際誌

    Nishiwaki, H; Ueyama, J; Kashihara, K; Ito, M; Hamaguchi, T; Maeda, T; Tsuboi, Y; Katsuno, M; Hirayama, M; Ohno, K

    NPJ PARKINSONS DISEASE   8 巻 ( 1 ) 頁: 169 - 169   2022年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:npj Parkinson's Disease  

    Gut microbiota and fecal bile acids were analyzed in 278 patients with α-synucleinopathies, which were comprised of 28 patients with dementia with Lewy bodies (DLB), 224 patients with Parkinson’s disease (PD), and 26 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). Similarly to PD, short-chain fatty acids-producing genera were decreased in DLB. Additionally, Ruminococcus torques and Collinsella were increased in DLB, which were not changed in PD. Random forest models to differentiate DLB and PD showed that high Ruminococcus torques and high Collinsella, which presumably increase intestinal permeability, as well as low Bifidobacterium, which are also observed in Alzheimer’s disease, were predictive of DLB. As Ruminococcus torques and Collinsella are also major secondary bile acids-producing bacteria, we quantified fecal bile acids and found that the production of ursodeoxycholic acid (UDCA) was high in DLB. Increased UDCA in DLB may mitigate neuroinflammation at the substantia nigra, whereas neuroinflammation may not be critical at the neocortex. Theraeutic intervention to increase Bifidobacteirum and its metabolites may retard the development and progression of DLB.

    DOI: 10.1038/s41531-022-00428-2

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  9. Examination of Abnormal Alpha-synuclein Aggregates in the Enteric Neural Plexus in Patients with Ulcerative Colitis 査読有り 国際誌

    Gibo, N; Hamaguchi, T; Miki, Y; Yamamura, T; Nakaguro, M; Ito, M; Nakamura, M; Kawashima, H; Hirayama, M; Hirooka, Y; Wakabayashi, K; Ohno, K

    JOURNAL OF GASTROINTESTINAL AND LIVER DISEASES   31 巻 ( 3 ) 頁: 290 - 300   2022年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Gastrointestinal and Liver Diseases  

    Background & Aims: Parkinson’s disease (PD) is the second most neurodegenerative disease after Alzheimer’s disease. Accumulating knowledge points to the notion that abnormal aggregation of alpha-synuclein (αSyn) starts in the gut and ascends to the substantia nigra via the vagus nerve in about a half of PD patients. Epidemiological studies revealed that ulcerative colitis (UC) increased the a risk for PD 1.3 to 1.8-folds. However, it remains unknown whether αSyn is abnormally aggregated in the enteric neurons in UC patients. Methods: We first inspected and optimized the immunostaining protocols with an anti-phosphorylated αSyn antibody, pSyn#64, using the brain and the gut of eight autopsied cases (five with PD and three without PD). Then, we examined abnormal αSyn aggregation in the enteric neurons in 23 and 18 colectomized patients with and without UC, respectively. Five or more sections were stained for αSyn in each of 87 and 25 paraffin-embedded blocks in patients with and without UC, respectively. Results: Ten different protocols of epitope exposure appropriately stained aggregated αSyn in the brain, but only a complete lack of epitope exposure stained aggregated αSyn in the colon with low background. Abnormal αSyn aggregates, which was confirmed by co-localization of p62, in the enteric neurons were detected in a single patient with UC but in no patient without UC. Conclusions: Omission of epitope exposure enabled us to immunostain aggregated αSyn in the colon by pSyn#64 with low nonspecific staining, but the number of 23 UC patients was not high enough to discern whether abnormal αSyn aggregation in the colonic neural plexus was increased in UC or not.

    DOI: 10.15403/jgld-4313

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  10. Short chain fatty acids-producing and mucin-degrading intestinal bacteria predict the progression of early Parkinson's disease 査読有り 国際誌

    Nishiwaki, H; Ito, M; Hamaguchi, T; Maeda, T; Kashihara, K; Tsuboi, Y; Ueyama, J; Yoshida, T; Hanada, H; Takeuchi, I; Katsuno, M; Hirayama, M; Ohno, K

    NPJ PARKINSONS DISEASE   8 巻 ( 1 ) 頁: 65 - 65   2022年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:npj Parkinson's Disease  

    To elucidate the relevance of gut dysbiosis in Parkinson’s disease (PD) in disease progression, we made random forest models to predict the progression of PD in two years by gut microbiota in 165 PD patients. The area under the receiver operating characteristic curves (AUROCs) of gut microbiota-based models for Hoehn & Yahr (HY) stages 1 and 2 were 0.799 and 0.705, respectively. Similarly, gut microbiota predicted the progression of Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) III scores in an early stage of PD with AUROC = 0.728. Decreases of short-chain fatty acid-producing genera, Fusicatenibacter, Faecalibacterium, and Blautia, as well as an increase of mucin-degrading genus Akkermansia, predicted accelerated disease progression. The four genera remained unchanged in two years in PD, indicating that the taxonomic changes were not the consequences of disease progression. PD patients with marked gut dysbiosis may thus be destined to progress faster than those without gut dysbiosis.

    DOI: 10.1038/s41531-022-00328-5

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  11. Extremely low-frequency pulses of faint magnetic field induce mitophagy to rejuvenate mitochondria 査読有り 国際誌

    Toda, T; Ito, M; Takeda, J; Masuda, A; Mino, H; Hattori, N; Mohri, K; Ohno, K

    COMMUNICATIONS BIOLOGY   5 巻 ( 1 ) 頁: 453 - 453   2022年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Communications Biology  

    Humans are frequently exposed to time-varying and static weak magnetic fields (WMF). However, the effects of faint magnetic fields, weaker than the geomagnetic field, have been scarcely reported. Here we show that extremely low-frequency (ELF)-WMF, comprised of serial pulses of 10 µT intensity at 1–8 Hz, which is three or more times weaker than the geomagnetic field, reduces mitochondrial mass to 70% and the mitochondrial electron transport chain (ETC) complex II activity to 88%. Chemical inhibition of electron flux through the mitochondrial ETC complex II nullifies the effect of ELF-WMF. Suppression of ETC complex II subsequently induces mitophagy by translocating parkin and PINK1 to the mitochondria and by recruiting LC3-II. Thereafter, mitophagy induces PGC-1α-mediated mitochondrial biogenesis to rejuvenate mitochondria. The lack of PINK1 negates the effect of ELF-WMF. Thus, ELF-WMF may be applicable for the treatment of human diseases that exhibit compromised mitochondrial homeostasis, such as Parkinson’s disease.

    DOI: 10.1038/s42003-022-03389-7

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  12. Extremely low-frequency pulses of faint magnetic field induce mitophagy to rejuvenate mitochondria 査読有り

    Takuro Toda; Mikako Ito; Jun-ichi Takeda; Akio Masuda; Hiroyuki Mino; Nobutaka Hattori; Kaneo Mohri; Kinji Ohno

    Communications Biology   5 巻   頁: 453   2022年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: https://doi.org/10.1038/s42003-022-03389-7

  13. Molecular Hydrogen Enhances Proliferation of Cancer Cells That Exhibit Potent Mitochondrial Unfolded Protein Response 査読有り 国際誌

    Hasegawa, T; Ito, M; Hasegawa, S; Teranishi, M; Takeda, K; Negishi, S; Nishiwaki, H; Takeda, JI; LeBaron, TW; Ohno, K

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   23 巻 ( 5 )   2022年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Molecular Sciences  

    Molecular hydrogen ameliorates pathological states in a variety of human diseases, animal models, and cell models, but the effects of hydrogen on cancer have been rarely reported. In addition, the molecular mechanisms underlying the effects of hydrogen remain mostly unelucidated. We found that hydrogen enhances proliferation of four out of seven human cancer cell lines (the responders). The proliferation-promoting effects were not correlated with basal levels of cellular reactive oxygen species. Expression profiling of the seven cells showed that the responders have higher gene expression of mitochondrial electron transport chain (ETC) molecules than the non-responders. In addition, the responders have higher mitochondrial mass, higher mitochondrial superoxide, higher mitochondrial membrane potential, and higher mitochondrial spare respiratory capacity than the non-responders. In the responders, hydrogen provoked mitochondrial unfolded protein response (mtUPR). Suppression of cell proliferation by rotenone, an inhibitor of mitochondrial ETC complex I, was rescued by hydrogen in the responders. Hydrogen triggers mtUPR and induces cell proliferation in cancer cells that have high basal and spare mitochondrial ETC activities.

    DOI: 10.3390/ijms23052888

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  14. Meclozine ameliorates skeletal muscle pathology and increases muscle forces in<i> mdx</i> mice 査読有り 国際誌

    Kawamura, Y; Hida, T; Ohkawara, B; Matsushita, M; Kobayashi, T; Ishizuka, S; Hiraiwa, H; Tanaka, S; Tsushima, M; Nakashima, H; Ito, K; Imagama, S; Ito, M; Masuda, A; Ishiguro, N; Ohno, K

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   592 巻   頁: 87 - 92   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochemical and Biophysical Research Communications  

    We screened pre-approved drugs for the survival of the Hu5/KD3 human myogenic progenitors. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, promoted the proliferation and survival of Hu5/KD3 cells. Meclozine increased expression of MyoD, but reduced expression of myosin heavy chain and suppressed myotube formation. Withdrawal of meclozine, however, resumed the ability of Hu5/KD3 cells to differentiate into myotubes. We examined the effects of meclozine on mdx mouse carrying a nonsense mutation in the dystrophin gene and modeling for Duchenne muscular dystrophy. Intragastric administration of meclozine in mdx mouse increased the body weight, the muscle mass in the lower limbs, the cross-sectional area of the paravertebral muscle, and improved exercise performances. Previous reports show that inhibition of phosphorylation of ERK1/2 improves muscle functions in mouse models for Emery-Dreifuss muscular dystrophy and cancer cachexia, as well as in mdx mice. We and others previously showed that meclozine blocks the phosphorylation of ERK1/2 in cultured cells. We currently showed that meclozine decreased phosphorylation of ERK1/2 in muscles in mdx mice but not in wild-type mice. This was likely to be one of the underlying mechanisms of the effects of meclozine on mdx mice.

    DOI: 10.1016/j.bbrc.2022.01.003

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  15. Altered gut microbiota in Parkinson's disease patients with motor complications 査読有り 国際誌

    Takahashi, K; Nishiwaki, H; Ito, M; Iwaoka, K; Takahashi, K; Suzuki, Y; Taguchi, K; Yamahara, K; Tsuboi, Y; Kashihara, K; Hirayama, M; Ohno, K; Maeda, T

    PARKINSONISM & RELATED DISORDERS   95 巻   頁: 11 - 17   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Parkinsonism and Related Disorders  

    Introduction: Parkinson's disease (PD) is associated with gut dysbiosis. However, whether gut dysbiosis can cause motor complications is unclear. Methods: Subjects were enrolled from four independent movement disorder centers in Japan. We performed 16S ribosomal RNA gene sequence analysis of gut microbiota. Relative abundance of gut microbiota and relationships between them and clinical characteristics were statistically analyzed. Analysis of co-variance (ANCOVA) was used to assess altered gut microbiota associated with wearing-off or dyskinesia. Results: We enrolled 223 patients with PD. Wearing-off was noted in 47.5% of patients and dyskinesia in 21.9%. We detected 98 genera of bacteria. Some changes in the gut microbiota were observed in patients with PD and motor complications. After Bonferroni correction, patients with wearing-off showed decreased relative abundance of Lachnospiraceae Blautia (p < 0.0001) and increased relative abundance of Lactobacillaceae Lactobacillus (p < 0.0001), but patients with dyskinesia no longer showed significant changes in the gut microbiota. Adjustment with two models of confounding factors followed by ANCOVA revealed that age (p < 0.0001), disease duration (p = 0.01), and wearing-off (p = 0.0004) were independent risks for the decreased relative abundance of Lachnospiraceae Blautia, and wearing-off (p = 0.009) was the only independent risk factor for the increased relative abundance of Lachnospiraceae Lactobacillus. Conclusion: Relative abundance of Lachnospiraceae Blautia and Lactobacillaceae Lactobacillus was significantly decreased and increased, respectively, in the gut microbiota of PD patients with motor complications. This indicates that an altered gut microbiota is associated with the development of motor complications in patients with advanced PD.

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  16. Enhancement of ethanol production and cell growth in budding yeast by direct irradiation of low-temperature plasma 査読有り

    Tanaka, H; Matsumura, S; Ishikawa, K; Hashizume, H; Ito, M; Nakamura, K; Kajiyama, H; Kikkawa, F; Ito, M; Ohno, K; Okazaki, Y; Toyokuni, S; Mizuno, M; Hori, M

    JAPANESE JOURNAL OF APPLIED PHYSICS   61 巻 ( SA )   2022年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Journal of Applied Physics  

    Ethanol production by budding yeast was compared between direct and indirect plasma irradiation. We observed enhancement of ethanol production and cell growth not by indirect plasma irradiation but by direct plasma irradiation. Glucose consumption was increased in budding yeast by direct plasma irradiation. Extracellular flux analysis revealed that glycolytic activity in the budding yeast was elevated by direct plasma irradiation. These results suggest that direct plasma irradiation enhances ethanol production in budding yeast by elevating the glycolytic activity.

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  17. Intestinal <i>Collinsella</i> may mitigate infection and exacerbation of COVID-19 by producing ursodeoxycholate 査読有り 国際誌

    Hirayama, M; Nishiwaki, H; Hamaguchi, T; Ito, M; Ueyama, J; Maeda, T; Kashihara, K; Tsuboi, Y; Ohno, K

    PLOS ONE   16 巻 ( 11 ) 頁: e0260451   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    The mortality rates of COVID-19 vary widely across countries, but the underlying mechanisms remain unelucidated. We aimed at the elucidation of relationship between gut microbiota and the mortality rates of COVID-19 across countries. Raw sequencing data of 16S rRNA V3-V5 regions of gut microbiota in 953 healthy subjects in ten countries were obtained from the public database. We made a generalized linear model (GLM) to predict the COVID- 19 mortality rates using gut microbiota. GLM revealed that low genus Collinsella predicted high COVID-19 mortality rates with a markedly low p-value. Unsupervised clustering of gut microbiota in 953 subjects yielded five enterotypes. The mortality rates were increased from enterotypes 1 to 5, whereas the abundances of Collinsella were decreased from enterotypes 1 to 5 except for enterotype 2. Collinsella produces ursodeoxycholate. Ursodeoxycholate was previously reported to inhibit binding of SARS-CoV-2 to angiotensin-converting enzyme 2; suppress pro-inflammatory cytokines like TNF-α, IL-1β, IL-2, IL-4, and IL-6; have antioxidant and anti-apoptotic effects; and increase alveolar fluid clearance in acute respiratory distress syndrome. Ursodeoxycholate produced by Collinsella may prevent COVID-19 infection and ameliorate acute respiratory distress syndrome in COVID-19 by suppressing cytokine storm syndrome.

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  18. Regulated splicing of large exons is linked to phase-separation of vertebrate transcription factors 査読有り 国際誌

    Kawachi, T; Masuda, A; Yamashita, Y; Takeda, J; Ohkawara, B; Ito, M; Ohno, K

    EMBO JOURNAL   40 巻 ( 22 ) 頁: e107485   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:EMBO Journal  

    Although large exons cannot be readily recognized by the spliceosome, many are evolutionarily conserved and constitutively spliced for inclusion in the processed transcript. Furthermore, whether large exons may be enriched in a certain subset of proteins, or mediate specific functions, has remained unclear. Here, we identify a set of nearly 3,000 SRSF3-dependent large constitutive exons (S3-LCEs) in human and mouse cells. These exons are enriched for cytidine-rich sequence motifs, which bind and recruit the splicing factors hnRNP K and SRSF3. We find that hnRNP K suppresses S3-LCE splicing, an effect that is mitigated by SRSF3 to thus achieve constitutive splicing of S3-LCEs. S3-LCEs are enriched in genes for components of transcription machineries, including mediator and BAF complexes, and frequently contain intrinsically disordered regions (IDRs). In a subset of analyzed S3-LCE-containing transcription factors, SRSF3 depletion leads to deletion of the IDRs due to S3-LCE exon skipping, thereby disrupting phase-separated assemblies of these factors. Cytidine enrichment in large exons introduces proline/serine codon bias in intrinsically disordered regions and appears to have been evolutionarily acquired in vertebrates. We propose that layered splicing regulation by hnRNP K and SRSF3 ensures proper phase-separation of these S3-LCE-containing transcription factors in vertebrates.

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  19. Plasma-activated Ringer's lactate solution inhibits the cellular respiratory system in HeLa cells 査読有り

    Tanaka, H; Maeda, S; Nakamura, K; Hashizume, H; Ishikawa, K; Ito, M; Ohno, K; Mizuno, M; Motooka, Y; Okazaki, Y; Toyokuni, S; Kajiyama, H; Kikkawa, F; Hori, M

    PLASMA PROCESSES AND POLYMERS   18 巻 ( 10 )   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Plasma Processes and Polymers  

    Nonequilibrium atmospheric pressure plasma has enabled a variety of new applications in medicine, agriculture, and other industries. It is particularly noteworthy that plasma itself and/or plasma-activated culture medium have been shown to preferentially kill various cancer cells. We have previously developed a plasma-activated Ringer's lactate solution (PAL) for use as a new cancer treatment. In this study, behaviors of extracellular and intracellular reactive oxygen and nitrogen species in the cellular respiratory system of PAL-treated HeLa cells were investigated using an extracellular flux analyzer and a probe to measure mitochondrial membrane potential. In PAL-treated HeLa cells, extracellular hydrogen peroxide in PAL was found to be responsible for the induction of intracellular hydrogen peroxide and apoptosis, while other components in PAL are responsible for the induction of non-H2O2 intracellular ROS and non-apoptotic cell death, which should be clarified by further experiments. We believe that these are long-lived species derived from plasma-activated lactates. Furthermore, we found that the plasma-activated lactates inhibited glycolysis and the tricarboxylic acid (TCA) cycle, but not the electron transport chain in HeLa cells. These results suggest that PAL induces multiple modes of cell death, including apoptosis through hydrogen peroxide, and non-apoptotic cell death associated with the impairment of mitochondrial functions (glycolysis and TCA cycle). These findings shed light on the novel mechanism underlying plasma-activated lactate-induced cell death.

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  20. Zonisamide upregulates neuregulin-1 expression and enhances acetylcholine receptor clustering at the in vitro neuromuscular junction 査読有り 国際誌

    Inoue, T; Ohkawara, B; Bushra, S; Kanbara, S; Nakashima, H; Koshimizu, H; Tomita, H; Ito, M; Masuda, A; Ishiguro, N; Imagama, S; Ohno, K

    NEUROPHARMACOLOGY   195 巻   頁: 108637 - 108637   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Neuropharmacology  

    Decreased acetylcholine receptor (AChR) clustering compromises signal transmission at the neuromuscular junction (NMJ) in myasthenia gravis, congenital myasthenic syndromes, and motor neuron diseases. Although the enhancement of AChR clustering at the NMJ is a promising therapeutic strategy for these maladies, no drug is currently available for this enhancement. We previously reported that zonisamide (ZNS), an anti-epileptic and anti-Parkinson's disease drug, enhances neurite elongation of the primary spinal motor neurons (SMNs). As nerve sprouting occurs to compensate for the loss of AChR clusters in human diseases, we examined the effects of ZNS on AChR clustering at the NMJ. To this end, we established a simple and quick co-culture system to reproducibly make in vitro NMJs using C2C12 myotubes and NSC34 motor neurons. ZNS at 1–20 μM enhanced the formation of AChR clusters dose-dependently in co-cultured C2C12 myotubes but not in agrin-treated single cultured C2C12 myotubes. We observed that molecules that conferred responsiveness to ZNS were not secreted into the co-culture medium. We found that 10 μM ZNS upregulated the expression of neuregulin-1 (Nrg1) in co-cultured cells but not in single cultured C2C12 myotubes or single cultured NSC34 motor neurons. In accordance with this observation, inhibition of the Nrg1/ErbB signaling pathways nullified the effect of 10 μM ZNS on the enhancement of AChR clustering in in vitro NMJs. Although agrin was not induced by 10 μM ZNS in co-cultured cells, anti-agrin antibody attenuated ZNS-mediated enhancement of AChR clustering. We conclude that ZNS enhances agrin-dependent AChR-clustering by upregulating the Nrg1/ErbB signaling pathways in the presence of NMJs.

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  21. Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology 査読有り 国際誌

    Ohkawara, B; Ito, M; Ohno, K

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   22 巻 ( 5 ) 頁: 1 - 16   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Molecular Sciences  

    Signal transduction at the neuromuscular junction (NMJ) is affected in many human dis-eases, including congenital myasthenic syndromes (CMS), myasthenia gravis, Lambert–Eaton my-asthenic syndrome, Isaacs’ syndrome, Schwartz–Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. The NMJ is a prototypic cholinergic synapse between the motor neuron and the skeletal muscle. Synaptogenesis of the NMJ has been extensively studied, which has also been extrapolated to further understand synapse formation in the central nervous system. Studies of genetically engineered mice have disclosed crucial roles of secreted molecules in the development and maintenance of the NMJ. In this review, we focus on the secreted signaling molecules which regulate the clustering of acetylcholine receptors (AChRs) at the NMJ. We first discuss the signaling pathway comprised of neural agrin and its receptors, low-den-sity lipoprotein receptor-related protein 4 (Lrp4) and muscle-specific receptor tyrosine kinase (MuSK). This pathway drives the clustering of acetylcholine receptors (AChRs) to ensure efficient signal transduction at the NMJ. We also discuss three secreted molecules (Rspo2, Fgf18, and con-nective tissue growth factor (Ctgf)) that we recently identified in the Wnt/β-catenin and fibroblast growth factors (FGF) signaling pathways. The three secreted molecules facilitate the clustering of AChRs by enhancing the agrin-Lrp4-MuSK signaling pathway.

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  22. Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model 査読有り

    Koshimizu, H; Ohkawara, B; Nakashima, H; Ota, K; Kanbara, S; Inoue, T; Tomita, H; Sayo, A; Kiryu-Seo, S; Konishi, H; Ito, M; Masuda, A; Ishiguro, N; Imagama, S; Kiyama, H; Ohno, K

    LIFE SCIENCES   263 巻   頁: 118577 - 118577   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Life Sciences  

    Neuropathic pain is caused by a lesion or a functional impairment of the sensory nervous system and allodynia is one of the frequently observed symptoms in neuropathic pain. Allodynia represents abnormal pain due to a non-noxious stimulus that does not normally provoke pain. Cellular mechanisms underlying neuropathic pain remain mostly elusive, and partial pain relief can be achieved in a limited number of patients by antidepressants, anticonvulsants topical anesthetics, and others. Zonisamide (ZNS) is widely used as an anti-epileptic and anti-Parkinson's disease drug. A recent report shows that ZNS suppresses neuropathic pain associated with diabetes mellitus in a mouse model. We made a mouse model of neuropathic pain in the hindlimb by cutting the nerve at the intervertebral canal at lumbar level 4 (L4). At 28 days after nerve injury, ZNS ameliorated allodynic pain, and reduced the expression of inflammatory cytokines and the nerve injury-induced increase of Iba1-positive microglia in the spinal dorsal horn at L4. In BV2 microglial cells, ZNS reduced the number of lipopolysaccharide-induced amoeboid-shaped cells, representing activated microglia. These results suggest that ZNS is a potential therapeutic agent for neuropathic pain partly by suppressing microglia-mediated neuroinflammation.

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  23. A set of random forest models for each amino acid substitution to predict pathogenicity of missense variants in the human genome

    Takeda J., Nanatsue K., Yamagishi R., Ito M., Ohno K.

    EUROPEAN JOURNAL OF HUMAN GENETICS   28 巻 ( SUPPL 1 ) 頁: 1003 - 1003   2020年12月

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    記述言語:日本語  

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  24. A set of random forest models for each amino acid substitution to predict pathogenicity of missense variants in the human genome 査読有り

    Takeda J, Nanatsue K, Yamagishi R, Ito M, Ohno K

    EUROPEAN JOURNAL OF HUMAN GENETICS   28 巻 ( SUPPL 1 ) 頁: 1003 - 1003   2020年12月

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    記述言語:日本語  

  25. Short-Chain Fatty Acid-Producing Gut Microbiota Is Decreased in Parkinson's Disease but Not in Rapid-Eye-Movement Sleep Behavior Disorder 査読有り 国際誌

    Nishiwaki, H; Hamaguchi, T; Ito, M; Ishida, T; Maeda, T; Kashihara, K; Tsuboi, Y; Ueyama, J; Shimamura, T; Mori, H; Kurokawa, K; Katsuno, M; Hirayama, M; Ohnoa, K

    MSYSTEMS   5 巻 ( 6 ) 頁: e00797-20   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:mSystems  

    Gut dysbiosis has been repeatedly reported in Parkinson's disease (PD) but only once in idiopathic rapid-eye-movement sleep behavior disorder (iRBD) from Germany. Abnormal aggregation of a-synuclein fibrils causing PD possibly starts from the intestine, although this is still currently under debate. iRBD patients frequently develop PD. Early-stage gut dysbiosis that is causally associated with PD is thus expected to be observed in iRBD. We analyzed gut microbiota in 26 iRBD patients and 137 controls by 16S rRNA sequencing (16S rRNA-seq). Our iRBD data set was meta-analyzed with the German iRBD data set and was compared with gut microbiota in 223 PD patients. Unsupervised clustering of gut microbiota by LIGER, a topic model-based tool for single-cell RNA sequencing (RNA-seq) analysis, revealed four enterotypes in controls, iRBD, and PD. Short-chain fatty acid (SCFA)-producing bacteria were conserved in an enterotype observed in controls and iRBD, whereas they were less conserved in enterotypes observed in PD. Genus Akkermansia and family Akkermansiaceae were consistently increased in both iRBD in two countries and PD in five countries. Short-chain fatty acid (SCFA)-producing bacteria were not significantly decreased in iRBD in two countries. In contrast, we previously reported that recognized or putative SCFA-producing genera Faecalibacterium, Roseburia, and Lachnospiraceae ND3007 group were consistently decreased in PD in five countries. In a-synucleinopathy, increase of mucin-layer-degrading genus Akkermansia is observed at the stage of iRBD, whereas decrease of SCFA-producing genera becomes obvious with development of PD. IMPORTANCE Twenty studies on gut microbiota in PD have been reported, whereas only one study has been reported on iRBD from Germany. iRBD has the highest likelihood ratio to develop PD. Our meta-analysis of iRBD in Japan and Germany revealed increased mucin-layer-degrading genus Akkermansia in iRBD. Genus Akkermansia may increase the intestinal permeability, as we previously observed in PD patients, and may make the intestinal neural plexus exposed to oxidative stress, which can lead to abnormal aggregation of prion-like a-synuclein fibrils in the intestine. In contrast to PD, SCFA-producing bacteria were not decreased in iRBD. As SCFA induces regulatory T (Treg) cells, a decrease of SCFA-producing bacteria may be a prerequisite for the development of PD. We propose that prebiotic and/or probiotic therapeutic strategies to increase the intestinal mucin layer and to increase intestinal SCFA potentially retard the development of iRBD and PD.

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  26. Identification of Qk as a Glial Precursor Cell Marker that Governs the Fate Specification of Neural Stem Cells to a Glial Cell Lineage 国際誌

    Takeuchi, A; Takahashi, Y; Iida, K; Hosokawa, M; Irie, K; Ito, M; Brown, JB; Ohno, K; Nakashima, K; Hagiwara, M

    STEM CELL REPORTS   15 巻 ( 4 ) 頁: 883 - 897   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Stem Cell Reports  

    During brain development, neural stem cells (NSCs) initially produce neurons and change their fate to generate glias. While the regulation of neurogenesis is well characterized, specific markers for glial precursor cells (GPCs) and the master regulators for gliogenesis remain unidentified. Accumulating evidence suggests that RNA-binding proteins (RBPs) have significant roles in neuronal development and function, as they comprehensively regulate the expression of target genes in a cell-type-specific manner. We systematically investigated the expression profiles of 1,436 murine RBPs in the developing mouse brain and identified quaking (Qk) as a marker of the putative GPC population. Functional analysis of the NSC-specific Qk-null mutant mouse revealed the key role of Qk in astrocyte and oligodendrocyte generation and differentiation from NSCs. Mechanistically, Qk upregulates gliogenic genes via quaking response elements in their 3′ untranslated regions. These results provide crucial directions for identifying GPCs and deciphering the regulatory mechanisms of gliogenesis from NSCs.

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  27. Gene Expression Profile at the Motor Endplate of the Neuromuscular Junction of Fast-Twitch Muscle 国際誌

    Huang, K; Li, J; Ito, M; Takeda, JI; Ohkawara, B; Ogi, T; Masuda, A; Ohno, K

    FRONTIERS IN MOLECULAR NEUROSCIENCE   13 巻   頁: 154 - 154   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers in Molecular Neuroscience  

    The neuromuscular junction (NMJ) is a prototypic chemical synapse between the spinal motor neuron and the motor endplate. Gene expression profiles of the motor endplate are not fully elucidated. Collagen Q (ColQ) is a collagenic tail subunit of asymmetric forms of acetylcholinesterase and is driven by two distinct promoters. pColQ1 is active throughout the slow-twitch muscle, whereas pColQ1a is active at the motor endplate of fast-twitch muscle. We made a transgenic mouse line that expresses nuclear localization signal (NLS)-attached Cre recombinase under the control of pColQ1a (pColQ1a-Cre mouse). RiboTag mouse expresses an HA-tagged ribosomal subunit, RPL22, in cells expressing Cre recombinase. We generated pColQ1a-Cre:RiboTag mouse, and confirmed that HA-tagged RPL22 was enriched at the NMJ of tibialis anterior (TA) muscle. Next, we confirmed that Chrne and Musk that are specifically expressed at the NMJ were indeed enriched in HA-immunoprecipitated (IP) RNA, whereas Sox10 and S100b, markers for Schwann cells, and Icam1, a marker for vascular endothelial cells, and Pax3, a marker for muscle satellite cells, were scarcely detected. Gene set enrichment analysis (GSEA) of RNA-seq data showed that “phosphatidylinositol signaling system” and “extracellular matrix receptor interaction” were enriched at the motor endplate. Subsequent analysis revealed that genes encoding diacylglycerol kinases, phosphatidylinositol kinases, phospholipases, integrins, and laminins were enriched at the motor endplate. We first characterized the gene expression profile under translation at the motor endplate of TA muscle using the RiboTag technique. We expect that our gene expression profiling will help elucidate molecular mechanisms of the development, maintenance, and pathology of the NMJ.

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  28. Meta-Analysisof Gut Dysbiosis in Parkinson's Disease 国際誌

    Nishiwaki, H; Ito, M; Ishida, T; Hamaguchi, T; Maeda, T; Kashihara, K; Tsuboi, Y; Ueyama, J; Shimamura, T; Mori, H; Kurokawa, K; Katsuno, M; Hirayama, M; Ohno, K

    MOVEMENT DISORDERS   35 巻 ( 9 ) 頁: 1626 - 1635   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Movement Disorders  

    Background: PD may begin with the intestinal accumulation of α-synuclein fibrils, which can be causally associated with gut dysbiosis. The variability of gut microbiota across countries prevented us from identifying shared gut dysbiosis in PD. Objectives: To identify gut dysbiosis in PD across countries. Methods: We performed 16S ribosomal RNA gene sequencing analysis of gut microbiota in 223 patients with PD and 137 controls, and meta-analyzed gut dysbiosis by combining our dataset with four previously reported data sets from the United States, Finland, Russia, and Germany. We excluded uncommon taxa from our analyses. For pathway analysis, we developed the Kyoto Encyclopedia of Genes and Genomes orthology set enrichment analysis method. Results: After adjusting for confounding factors (body mass index, constipation, sex, age, and catechol-O-methyl transferase inhibitor), genera Akkermansia and Catabacter, as well as families Akkermansiaceae, were increased, whereas genera Roseburia, Faecalibacterium, and Lachnospiraceae ND3007 group were decreased in PD. Catechol-O-methyl transferase inhibitor intake markedly increased family Lactobacillaceae. Inspection of these bacteria in 12 datasets that were not included in the meta-analysis revealed that increased genus Akkermansia and decreased genera Roseburia and Faecalibacterium were frequently observed across countries. Kyoto Encyclopedia of Genes and Genomes orthology set enrichment analysis revealed changes in short-chain fatty acid metabolisms in our dataset. Conclusions: We report that intestinal mucin layer-degrading Akkermansia is increased and that short-chain fatty acid–producing Roseburia and Faecalibacterium are decreased in PD across countries. © 2020 International Parkinson and Movement Disorder Society.

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  29. CTGF/CCN2 facilitates LRP4-mediated formation of the embryonic neuromuscular junction 査読有り 国際誌

    Ohkawara, B; Kobayakawa, A; Kanbara, S; Hattori, T; Kubota, S; Ito, M; Masuda, A; Takigawa, M; Lyons, KM; Ishiguro, N; Ohno, K

    EMBO REPORTS   21 巻 ( 8 ) 頁: e48462   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:EMBO Reports  

    At the neuromuscular junction (NMJ), lipoprotein-related receptor 4 (LRP4) mediates agrin-induced MuSK phosphorylation that leads to clustering of acetylcholine receptors (AChRs) in the postsynaptic region of the skeletal muscle. Additionally, the ectodomain of LRP4 is necessary for differentiation of the presynaptic nerve terminal. However, the molecules regulating LRP4 have not been fully elucidated yet. Here, we show that the CT domain of connective tissue growth factor (CTGF/CCN2) directly binds to the third beta-propeller domain of LRP4. CTGF/CCN2 enhances the binding of LRP4 to MuSK and facilitates the localization of LRP4 on the plasma membrane. CTGF/CCN2 enhances agrin-induced MuSK phosphorylation and AChR clustering in cultured myotubes. Ctgf-deficient mouse embryos (Ctgf−/−) have small AChR clusters and abnormal dispersion of synaptic vesicles along the motor axon. Ultrastructurally, the presynaptic nerve terminals have reduced numbers of active zones and mitochondria. Functionally, Ctgf−/− embryos exhibit impaired NMJ signal transmission. These results indicate that CTGF/CCN2 interacts with LRP4 to facilitate clustering of AChRs at the motor endplate and the maturation of the nerve terminal.

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  30. Zonisamide ameliorates progression of cervical spondylotic myelopathy in a rat model 国際誌

    Kanbara, S; Ohkawara, B; Nakashima, H; Ohta, K; Koshimizu, H; Inoue, T; Tomita, H; Ito, M; Masuda, A; Ishiguro, N; Imagama, S; Ohno, K

    SCIENTIFIC REPORTS   10 巻 ( 1 ) 頁: 13138 - 13138   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    Cervical spondylotic myelopathy (CSM) is caused by chronic compression of the spinal cord and is the most common cause of myelopathy in adults. No drug is currently available to mitigate CSM. Herein, we made a rat model of CSM by epidurally implanting an expanding water-absorbent polymer underneath the laminae compress the spinal cord. The CSM rats exhibited progressive motor impairments recapitulating human CSM. CSM rats had loss of spinal motor neurons, and increased lipid peroxidation in the spinal cord. Zonisamide (ZNS) is clinically used for epilepsy and Parkinson's disease. We previously reported that ZNS protected primary spinal motor neurons against oxidative stress. We thus examined the effects of ZNS on our rat CSM model. CSM rats with daily intragastric administration of 0.5% methylcellulose (n = 11) and ZNS (30 mg/kg/day) in 0.5% methylcellulose (n = 11). Oral administration of ZNS ameliorated the progression of motor impairments, spared the number of spinal motor neurons, and preserved myelination of the pyramidal tracts. In addition, ZNS increased gene expressions of cystine/glutamate exchange transporter (xCT) and metallothionein 2A in the spinal cord in CSM rats, and also in the primary astrocytes. ZNS increased the glutathione (GSH) level in the spinal motor neurons of CSM rats. ZNS potentially ameliorates loss of the spinal motor neurons and demyelination of the pyramidal tracts in patients with CSM.

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  31. InMeRF: prediction of pathogenicity of missense variants by individual modeling for each amino acid substitution 査読有り

    Takeda, J; Nanatsue, K; Yamagishi, R; Ito, M; Haga, N; Hirata, H; Ogi, T; Ohno, K

    NAR GENOMICS AND BIOINFORMATICS   2 巻 ( 2 ) 頁: lqaa038   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NAR Genomics and Bioinformatics  

    In predicting the pathogenicity of a nonsynonymous single-nucleotide variant (nsSNV), a radical change in amino acid properties is prone to be classified as being pathogenic. However, not all such nsSNVs are associated with human diseases. We generated random forest (RF) models individually for each amino acid substitution to differentiate pathogenic nsSNVs in the Human Gene Mutation Database and common nsSNVs in dbSNP. We named a set of our models ‘Individual Meta RF’ (InMeRF). Ten-fold cross-validation of InMeRF showed that the areas under the curves (AUCs) of receiver operating characteristic (ROC) and precision–recall curves were on average 0.941 and 0.957, respectively. To compare InMeRF with seven other tools, the eight tools were generated using the same training dataset, and were compared using the same three testing datasets. ROC-AUCs of InMeRF were ranked first in the eight tools. We applied InMeRF to 155 pathogenic and 125 common nsSNVs in seven major genes causing congenital myasthenic syndromes, as well as in VANGL1 causing spina bifida, and found that the sensitivity and specificity of InMeRF were 0.942 and 0.848, respectively. We made the InMeRF web service, and also made genome-wide InMeRF scores available online (https://www.med.nagoya-u.ac.jp/neurogenetics/InMeRF/).

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  32. tRIP-seq reveals repression of premature polyadenylation by co-transcriptional FUS-U1 snRNP assembly 査読有り 国際誌

    Masuda, A; Kawachi, T; Takeda, J; Ohkawara, B; Ito, M; Ohno, K

    EMBO REPORTS   21 巻 ( 5 ) 頁: e49890   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:EMBO Reports  

    RNA processing occurs co-transcriptionally through the dynamic recruitment of RNA processing factors to RNA polymerase II (RNAPII). However, transcriptome-wide identification of protein–RNA interactions specifically assembled on transcribing RNAPII is challenging. Here, we develop the targeted RNA immunoprecipitation sequencing (tRIP-seq) method that detects protein–RNA interaction sites in thousands of cells. The high sensitivity of tRIP-seq enables identification of protein–RNA interactions at functional subcellular levels. Application of tRIP-seq to the FUS-RNA complex in the RNAPII machinery reveals that FUS binds upstream of alternative polyadenylation (APA) sites of nascent RNA bound to RNAPII, which retards RNAPII and suppresses the recognition of the polyadenylation signal by CPSF. Further tRIP-seq analyses demonstrate that the repression of APA is achieved by a complex composed of FUS and U1 snRNP on RNAPII, but not by either one alone. Moreover, our analysis reveals that FUS mutations in familial amyotrophic lateral sclerosis (ALS) that impair the FUS-U1 snRNP interaction aberrantly activate the APA sites. tRIP-seq provides new insights into the regulatory mechanism of co-transcriptional RNA processing by RNA processing factors.

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  33. tRIP-seq reveals repression of premature polyadenylation by co-transcriptional FUS-U1 snRNP assembly

    Masuda Akio, Kawachi Toshihiko, Takeda Jun-ichi, Ohkawara Bisei, Ito Mikako, Ohno Kinji

    EMBO REPORTS   21 巻 ( 5 ) 頁: .   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  34. Fluctuating Weak Magnetic Fields Induce Marked Mitophagy

    Toda, T; Ito, M; Mori, K; Ohno, K

    FASEB JOURNAL   34 巻   2020年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1096/fasebj.2020.34.s1.03782

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  35. Molecular Hydrogen Manages Mitochondrial Proteostatic Stress and Induces Cellular Response

    Hasegawa, T; Ito, M; Hasegawa, S; Takeda, K; Nishiwaki, H; Negishi, S; Ohno, K

    FASEB JOURNAL   34 巻   2020年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1096/fasebj.2020.34.s1.09226

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  36. SRSF3 and hnRNP K Antagonistically Regulate Splicing of Large Exons

    Kawachi, T; Masuda, A; Takeda, J; Ito, M; Hamaguchi, T; Ohno, K

    FASEB JOURNAL   34 巻   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  37. Mianserin suppresses R-spondin 2-induced activation of Wnt/β-catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis (vol 12, 4512, 2019) 査読有り 国際誌

    Okura, T; Ohkawara, B; Takegami, Y; Ito, M; Masuda, A; Seki, T; Ishiguro, N; Ohno, K

    SCIENTIFIC REPORTS   10 巻 ( 1 ) 頁: 2995 - 2995   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    This Article contains errors in the Reference list. Reference 21 is incorrectly listed as: Masahiro N. et al. A genome-wide association study identifies susceptibility loci for ossification of the posterior longitudinal ligament of the spine. Nature Genetics 46(9), 1012–1016 (2014). The correct reference is listed below as ref. 1. Additionally, Reference 23 is incorrectly listed as: Rita D. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Research & Therapy 12(5), 216 (2010). The correct reference is listed below as ref. 2. Furthermore, Reference 25 is incorrectly listed as: Marlies, B. et al. The Reason for Discontinuation of the First Tumor Necrosis Factor (TNF) Blocking Agent Does Not Influence the Effect of a Second TNF Blocking Agent in Patients with Rheumatoid Arthritis. The Journal of Rheumatology 36(10), 2171–2177 (2009). The correct reference is listed below as ref. 3. In addition, there is an error in the legend of Figure 4, where: “The number of β-catenin-positive cells is divided by the number of DAPI signals to calculate the ratio of nuclear β-catenin-positive cells. The number of β-catenin-positive cells is divided by the number of DAPI signals to calculate the ratio of nuclear β-catenin-positive cells. *P < 0.05 by one-way ANOVA followed by Tukey’s post-hoc test. Scale = bar 200 μm (A), 100 μm (C), and 25 μm (D). (G) Model of Rspo2-mediated OA development, and the effect of mianserin.” should read:“The number of β-catenin-positive cells is divided by the number of DAPI signals to calculate the ratio of nuclear β-catenin-positive cells. *P < 0.05 by one-way ANOVA followed by Tukey’s post-hoc test. Scale bar = 200 μm (A), 100 μm (C), and 25 μm (D). (G) Model of Rspo2-mediated OA development, and the effect of mianserin.”.

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  38. Inhibition of cyclooxygenase-1 by nonsteroidal anti-inflammatory drugs demethylates MeR2 enhancer and promotes <i>Mbnl1</i> transcription in myogenic cells 査読有り 国際誌

    Huang, K; Masuda, A; Chen, GY; Bushra, S; Kamon, M; Araki, T; Kinoshita, M; Ohkawara, B; Ito, M; Ohno, K

    SCIENTIFIC REPORTS   10 巻 ( 1 ) 頁: 2558 - 2558   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    Muscleblind-like 1 (MBNL1) is a ubiquitously expressed RNA-binding protein, which is highly expressed in skeletal muscle. Abnormally expanded CUG-repeats in the DMPK gene cause myotonic dystrophy type 1 (DM1) by sequestration of MBNL1 to nuclear RNA foci and by upregulation of another RNA-binding protein, CUG-binding protein 1 (CUGBP1). We previously reported that a nonsteroidal anti-inflammatory drug (NSAID), phenylbutazone, upregulates MBNL1 expression in DM1 mouse model by demethylation of MeR2, an enhancer element in Mbnl1 intron 1. NSAIDs inhibit cyclooxygenase (COX), which is comprised of COX-1 and COX-2 isoforms. In this study, we screened 29 NSAIDs in C2C12 myoblasts, and found that 13 NSAIDs enhanced Mbnl1 expression, where COX-1-selective NSAIDs upregulated Mbnl1 more than COX-2-selective NSAIDs. Consistently, knockdown of COX-1, but not of COX-2, upregulated MBNL1 expression in C2C12 myoblasts and myotubes, as well as in myotubes differentiated from DM1 patient-derived induced pluripotent stem cells (iPSCs). Luciferase assay showed that COX-1-knockdown augmented the MeR2 enhancer activity. Furthermore, bisulfite sequencing analysis demonstrated that COX-1-knockdown suppressed methylation of MeR2. These results suggest that COX-1 inhibition upregulates Mbnl1 transcription through demethylation of the MeR2 enhancer. Taken together, our study provides new insights into the transcriptional regulation of Mbnl1 by the COX-1-mediated pathway.

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  39. Hydrogen water alleviates obliterative airway disease in mice 査読有り

    Ozeki, N; Yamawaki-Ogata, A; Narita, Y; Mii, S; Ushida, K; Ito, M; Hirano, S; Kurokawa, R; Ohno, K; Usui, A

    GENERAL THORACIC AND CARDIOVASCULAR SURGERY   68 巻 ( 2 ) 頁: 158 - 163   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:General Thoracic and Cardiovascular Surgery  

    Objective: Bronchiolitis obliterans syndrome arising from chronic airway inflammation is a leading cause of death following lung transplantation. Several studies have suggested that inhaled hydrogen can protect lung grafts from ischemia–reperfusion injury via anti-inflammatory and -oxidative mechanisms. We investigated whether molecular hydrogen-saturated water can preserve lung allograft function in a heterotopic tracheal allograft mouse model of obliterative airway disease Methods: Obliterative airway disease was induced by heterotopically transplanting tracheal allografts from BALB/c donor mice into C57BL/6 recipient mice, which were subsequently administered hydrogen water (10 ppm) or tap water (control group) (n = 6 each) daily without any immunosuppressive treatment. Histological and immunohistochemical analyses were performed on days 7, 14, and 21. Results: Hydrogen water decreased airway occlusion on day 14. No significant histological differences were observed on days 7 or 21. The cluster of differentiation 4/cluster of differentiation 3 ratio in tracheal allografts on day 14 was higher in the hydrogen water group than in control mice. Enzyme-linked immunosorbent assay performed on day 7 revealed that hydrogen water reduced the level of the pro-inflammatory cytokine interleukin-6 and increased that of forkhead box P3 transcription factor, suggesting an enhancement of regulatory T cell activity. Conclusions: Hydrogen water suppressed the development of mid-term obliterative airway disease in a mouse tracheal allograft model via anti-oxidant and -inflammatory mechanisms and through the activation of Tregs. Thus, hydrogen water is a potential treatment strategy for BOS that can improve the outcome of lung transplant patients.

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  40. Freeze-drying enables homogeneous and stable sample preparation for determination of fecal short-chain fatty acids 査読有り 国際誌

    Ueyama, J; Oda, M; Hirayama, M; Sugitate, K; Sakui, N; Hamada, R; Ito, M; Saito, I; Ohno, K

    ANALYTICAL BIOCHEMISTRY   589 巻   頁: 113508 - 113508   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Analytical Biochemistry  

    Background: The analysis methods for fecal short-chain fatty acids (SCFAs) have evolved considerably. Recently, the role of SCFAs in gastrointestinal physiology and their association with intestinal microbiota and disease were reported. However, the intra-fecal variability and storage stability of SCFAs have not been extensively investigated. The aim of this study was to understand the limitations of the measurement of SCFAs in crude feces and develop a useful pre-examination procedure using the freeze-drying technique. Methods: SCFAs in crude feces, obtained from healthy volunteers, and freeze-dried feces were determined by derivatization with isobutyl chloroformate, followed by liquid–liquid extraction with hexane, and separation and analysis using gas chromatography–mass spectrometry. Results: Among the SCFAS, the maximum intra-fecal variability was observed for iso-butyrate (coefficient of variation of 37.7%), but the freeze-drying procedure reduced this variability (coefficient of variation of 7.9%). Similar improvements were also observed for other SCFAs. Furthermore, significant decreases in the SCFA amounts were observed with storage at 4 °C for 24 h. Conclusions: The freeze-drying procedure affords fecal SCFA stability, even with storage at room temperature for 3 d. The freeze-drying procedure allows reliable SCFA measurements without labour-intensive processes. Therefore, the freeze-drying procedure can be applied in basic, clinical, and epidemiological studies.

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  41. Lewy小体病患者のメタメタ解析を用いた腸内細菌叢の関与の解明 査読有り

    平山 正昭, 石田 智大, 九鬼 桃茄, 浜口 知成, 伊藤 美佳子, 上山 純, 島村 徹平, 阿部 興, 勝野 雅央, 大野 欽司

    臨床神経学   59 巻 ( Suppl. ) 頁: S301 - S301   2019年11月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

  42. 神経変性疾患における短鎖脂肪酸の役割 査読有り

    九鬼 桃茄, 石田 智大, 浜口 知成, 伊藤 美佳子, 木村 郁夫, 長谷 耕二, 橋本 款, 大野 欽司, 平山 正昭

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   13回 巻   頁: 102 - 102   2019年7月

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    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

  43. パーキンソン病(PD)における腸内細菌 査読有り

    石田 智大, 九鬼 桃茄, 浜口 知成, 上山 純, 伊藤 美佳子, 柏原 健一, 前田 哲也, 坪井 義夫, 阿部 興, 島村 徹平, 森 宙史, 黒川 顕, 勝野 雅央, 大野 欽司, 平山 正昭

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集   13回 巻   頁: 102 - 102   2019年7月

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    記述言語:日本語   出版者・発行元:Movement Disorder Society of Japan (MDSJ)  

  44. Mianserin suppresses R-spondin 2-induced activation of Wnt/β-catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis 査読有り 国際誌

    Okura, T; Ohkawara, B; Takegami, Y; Ito, M; Masuda, A; Seki, T; Ishiguro, N; Ohno, K

    SCIENTIFIC REPORTS   9 巻 ( 1 ) 頁: 2808 - 2808   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    Aberrant activation of the Wnt/β-catenin signaling pathway promotes the progression of osteoarthritis (OA). We previously reported that R-spondin 2 (Rspo2), an activator of the Wnt/β-catenin signaling, facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/β-catenin signaling in endochondral ossification. However, the role of Rspo2 in OA remains elusive. Here, we showed that the amounts of Rspo2 protein in synovial fluid were increased in OA patients. We searched for a preapproved drug that suppresses Rspo2-induced Wnt/β-catenin signaling in chondrogenic cells and reduces joint pathology in a rat model of OA. In Rspo2-treated ATDC5 cells, mianserin, a tetracyclic antidepressant, inhibited Wnt/β-catenin signaling, increased proteoglycan production, and upregulated chondrogenic marker genes. Mianserin suppressed Rspo2-induced accumulation of β-catenin and phosphorylation of Lrp6. We identified that mianserin blocked binding of Rspo2 to its receptor Lgr5. We also observed that intraarticular administration of mianserin suppressed β-catenin accumulation and prevented OA progression in a rat model of OA. We conclude that mianserin suppresses abnormally activated Wnt/β-catenin signaling in OA by inhibiting binding of Rspo2 to Lgr5.

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  45. Quantification of hydrogen production by intestinal bacteria that are specifically dysregulated in Parkinson's disease 査読有り 国際誌

    Suzuki, A; Ito, M; Hamaguchi, T; Mori, H; Takeda, Y; Baba, R; Watanabe, T; Kurokawa, K; Asakawa, S; Hirayama, M; Ohno, K

    PLOS ONE   13 巻 ( 12 ) 頁: e0208313   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    Oral administration of hydrogen water ameliorates Parkinson’s disease (PD) in rats, mice, and humans. We previously reported that the number of putative hydrogen-producing bacteria in intestinal microbiota is low in PD compared to controls. We also reported that the amount of hydrogen produced by ingestion of lactulose is low in PD patients. The decreased hydrogen production by intestinal microbiota may be associated with the development and progression of PD. We measured the amount of hydrogen production using gas chromatography by seven bacterial strains, which represented seven major intestinal bacterial groups/ genera/species. Blautia coccoides and Clostridium leptum produced the largest amount of hydrogen. Escherichia coli and Bacteroides fragilis constituted the second group that produced hydrogen 34- to 93-fold lower than B. coccoides. Bifidobacterium pseudocatenulatum and Atopobium parvulum constituted the third group that produced hydrogen 559- to 2164-fold lower than B. coccoides. Lactobacillus casei produced no detectable hydrogen. Assuming that taxonomically neighboring strains have similar hydrogen production, we simulated hydrogen production using intestinal microbiota that we previously reported, and found that PD patients produce a 2.2-fold lower amount of intestinal hydrogen compared to controls. The lower amount of intestinal hydrogen production in PD was also simulated in cohorts of two other countries. The number of hydrogen-producing intestinal bacteria may be associated with the development and progression of PD. Further studies are required to prove its beneficial effect.

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  46. Inhalation of hydrogen gas elevates urinary 8-hydroxy-2'-deoxyguanine in Parkinson's disease. 査読有り 国際誌

    Hirayama M, Ito M, Minato T, Yoritaka A, LeBaron TW, Ohno K

    Medical gas research   8 巻 ( 4 ) 頁: 144 - 149   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Medical Gas Research  

    Hyposmia is one of the earliest and the most common symptoms in Parkinson's disease (PD). The benefits of hydrogen water on motor deficits have been reported in animal PD models and PD patients, but the effects of hydrogen gas on PD patients have not been studied. We evaluated the effect of inhalation of hydrogen gas on olfactory function, non-motor symptoms, activities of daily living, and urinary 8-hydroxy-2′-deoxyguanine (8-OHdG) levels by a randomized, double-blinded, placebo-controlled, crossover trial with an 8-week washout period in 20 patients with PD. Patients inhaled either 1.2-1.4% hydrogen-air mixture or placebo for 10 minutes twice a day for 4 weeks. Inhalation of low dose hydrogen did not significantly influence the PD clinical parameters, but it did increase urinary 8-OHdG levels by 16%. This increase in 8-OHdG is markedly less than the over 300% increase in diabetes, and is more comparable to the increase after a bout of strenuous exercise. Although increased reactive oxygen species is often associated with toxicity and disease, they also play essential roles in mediating cytoprotective cellular adaptations in a process known as hormesis. Increases of oxidative stress by hydrogen have been previously reported, along with its ability to activate the Nrf2, NF-κB pathways, and heat shock responses. Although we did not observe any beneficial effect of hydrogen in our short trial, we propose that the increased 8-OHdG and other reported stress responses from hydrogen may indicate that its beneficial effects are partly or largely mediated by hormetic mechanisms. The study was approved by the ethics review committee of Nagoya University Graduate School of Medicine (approval number 2015-0295). The clinical trial was registered at the University Hospital Medical Information Network (identifier UMIN000019082).

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  47. Differential effects of spinal motor neuron-derived and skeletal muscle-derived Rspo2 on acetylcholine receptor clustering at the neuromuscular junction 査読有り

    Li, J; Ito, M; Ohkawara, B; Masuda, A; Ohno, K

    SCIENTIFIC REPORTS   8 巻 ( 1 ) 頁: 13577 - -   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    We recently reported that R-spondin 2 (Rspo2), a secreted activator of Wnt/β-catenin signaling, promotes acetylcholine receptor (AChR) clustering and neuromuscular junction (NMJ) formation via its receptor, Lgr5. Rspo2 is expressed highly in spinal motor neurons (SMNs) and marginally in the skeletal muscle, but the origin of Rspo2 at the NMJ remains elusive. We rescued Rspo2-deficient (Rspo2−/−) mice by specifically expressing Rspo2 in the skeletal muscle and SMNs. SMN-specific Rspo2 mitigated or over-corrected abnormal features of the NMJs and AChR clusters observed in Rspo2−/− mice including (i) abnormal broadening of enlarged AChR clusters, (ii) three of six abnormal ultrastructural features, and (iii) abnormal expression of nine genes in SMNs and the diaphragm. In contrast, muscle-specific Rspo2 normalized all six abnormal ultrastructural features, but it had no effect on AChR clustering and NMJ formation at the light microscopy level or on abnormal gene expression in SMNs and the diaphragm. These results suggest that SMN-derived Rspo2 plays a major role in AChR clustering and NMJ formation in the postsynaptic region, and muscle-derived Rspo2 also plays a substantial role in juxtaposition of the active zones and synaptic folds.

    DOI: 10.1038/s41598-018-31949-7

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  48. Randomized, Double-Blind, Multicenter Trial of Hydrogen Water for Parkinson's Disease 査読有り 国際誌

    Yoritaka, A; Ohtsuka, C; Maeda, T; Hirayama, M; Abe, T; Watanabe, H; Saiki, H; Oyama, G; Fukae, J; Shimo, Y; Hatano, T; Kawajiri, S; Okuma, Y; Machida, Y; Miwa, H; Suzuki, C; Kazama, A; Tomiyama, M; Kihara, T; Hirasawa, M; Shimura, H; Oda, E; Ito, M; Ohno, K; Hattori, N

    MOVEMENT DISORDERS   33 巻 ( 9 ) 頁: 1505 - 1507   2018年9月

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    記述言語:英語   出版者・発行元:Movement Disorders  

    DOI: 10.1002/mds.27472

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  49. Protein-anchoring therapy to target extracellular matrix proteins to their physiological destinations 査読有り 国際誌

    Ito, M; Ohno, K

    MATRIX BIOLOGY   68-69 巻 ( - ) 頁: 628 - 636   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Matrix Biology  

    Endplate acetylcholinesterase (AChE) deficiency is a form of congenital myasthenic syndrome (CMS) caused by mutations in COLQ, which encodes collagen Q (ColQ). ColQ is an extracellular matrix (ECM) protein that anchors AChE to the synaptic basal lamina. Biglycan, encoded by BGN, is another ECM protein that binds to the dystrophin-associated protein complex (DAPC) on skeletal muscle, which links the actin cytoskeleton and ECM proteins to stabilize the sarcolemma during repeated muscle contractions. Upregulation of biglycan stabilizes the DPAC. Gene therapy can potentially ameliorate any disease that can be recapitulated in cultured cells. However, the difficulty of tissue-specific and developmental stage-specific regulated expression of transgenes, as well as the difficulty of introducing a transgene into all cells in a specific tissue, prevents us from successfully applying gene therapy to many human diseases. In contrast to intracellular proteins, an ECM protein is anchored to the target tissue via its specific binding affinity for protein(s) expressed on the cell surface within the target tissue. Exploiting this unique feature of ECM proteins, we developed protein-anchoring therapy in which a transgene product expressed even in remote tissues can be delivered and anchored to a target tissue using specific binding signals. We demonstrate the application of protein-anchoring therapy to two disease models. First, intravenous administration of adeno-associated virus (AAV) serotype 8-COLQ to Colq-deficient mice, resulting in specific anchoring of ectopically expressed ColQ-AChE at the NMJ, markedly improved motor functions, synaptic transmission, and the ultrastructure of the neuromuscular junction (NMJ). In the second example, Mdx mice, a model for Duchenne muscular dystrophy, were intravenously injected with AAV8-BGN. The treatment ameliorated motor deficits, mitigated muscle histopathologies, decreased plasma creatine kinase activities, and upregulated expression of utrophin and DAPC component proteins. We propose that protein-anchoring therapy could be applied to hereditary/acquired defects in ECM and secreted proteins, as well as therapeutic overexpression of such factors.

    DOI: 10.1016/j.matbio.2018.02.014

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  50. Loss of Sfpq Causes Long-Gene Transcriptopathy in the Brain

    Takeuchi Akihide, Iida Kei, Tsubota Toshiaki, Hosokawa Motoyasu, Denawa Masatsugu, Brown J. B., Ninomiya Kensuke, Ito Mikako, Kimura Hiroshi, Abe Takaya, Kiyonari Hiroshi, Ohno Kinji, Hagiwara Masatoshi

    CELL REPORTS   23 巻 ( 5 ) 頁: 1326-1341   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.celrep.2018.03.141

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  51. Molecular hydrogen upregulates heat shock response and collagen biosynthesis, and downregulates cell cycles: meta-analyses of gene expression profiles 国際誌

    Nishiwaki, H; Ito, M; Negishi, S; Sobue, S; Ichihara, M; Ohno, K

    FREE RADICAL RESEARCH   52 巻 ( 4 ) 頁: 434 - 445   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    Molecular hydrogen exerts its effect on multiple pathologies, including oxidative stress, inflammation, and apoptosis. However, its molecular mechanisms have not been fully elucidated. In order to explore the effects of molecular hydrogen, we meta-analysed gene expression profiles modulated by molecular hydrogen. We performed microarray analysis of the mouse liver with or without drinking hydrogen water. We also integrated two previously reported microarray datasets of the rat liver into meta-analyses. We used two categories of meta-analysis methods: the cross-platform method and the conventional meta-analysis method (Fisher’s method). For each method, hydrogen-modulated pathways were analysed by (i) the hypergeometric test (HGT) in the class of over-representation analysis (ORA), (ii) the gene set enrichment analysis (GSEA) in the class of functional class scoring (FCS), and (iii) the signalling pathway impact analysis (SPIA), pathway regulation score (PRS), and others in the class of pathway topology-based approach (PTA). Pathways in the collagen biosynthesis and the heat-shock response were up-regulated according to (a) HGT with the cross-platform method, (b) GSEA with the cross-platform method, and (c) PRS with the cross-platform method. Pathways in cell cycles were down-regulated according to (a) HGT with the cross-platform method, (b) GSEA with the cross-platform method, and (d) GSEA with the conventional meta-analysis method. Because the heat-shock response leads to up-regulation of collagen biosynthesis and a transient arrest of cell cycles, induction of the heat-shock response is likely to be a primary event induced by molecular hydrogen in the liver of wild-type rodents.

    DOI: 10.1080/10715762.2018.1439166

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  52. Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling 査読有り

    Miyamoto, K; Ohkawara, B; Ito, M; Masuda, A; Hirakawa, A; Sakai, T; Hiraiwa, H; Hamada, T; Ishiguro, N; Ohno, K

    PLOS ONE   12 巻 ( 9 ) 頁: e0184388 - -   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    Abnormal activation of the Wnt/β-catenin signaling is implicated in the osteoarthritis (OA) pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/β-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/β-catenin activity in the presence of 10 μM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), down-regulated Wnt/β-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator), and decreased expressions of Axin2 (a marker for Wnt/β-catenin signaling) and Mmp13 (matrix metalloproteinase 13). Fluoxetine suppressed a LiCl-induced increase of total β-catenin and a LiCl-induced decrease of phosphorylated β-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of β-catenin with Axin1, which is a scaffold protein forming the degradation complex for β-catenin. Fluoxetine suppressed LiCl-induced β-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed β-catenin accumulation.

    DOI: 10.1371/journal.pone.0184388

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  53. SRSF1 suppresses selection of intron-distal 5′ splice site of <i>DOK7</i> intron 4 to generate functional full-length Dok-7 protein 査読有り

    Bin Ahsan, K; Masuda, A; Rahman, MA; Takeda, J; Nazim, M; Ohkawara, B; Ito, M; Ohno, K

    SCIENTIFIC REPORTS   7 巻 ( 1 ) 頁: 10446 - -   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    Dok-7 is a non-catalytic adaptor protein that facilitates agrin-induced clustering of acetylcholine receptors (AChR) at the neuromuscular junction. Alternative selection of 5′ splice sites (SSs) of DOK7 intron 4 generates canonical and frame-shifted transcripts. We found that the canonical full-length Dok-7 enhanced AChR clustering, whereas the truncated Dok-7 did not. We identified a splicing cis-element close to the 3′ end of exon 4 by block-scanning mutagenesis. RNA affinity purification and mass spectrometry revealed that SRSF1 binds to the cis-element. Knocking down of SRSF1 enhanced selection of the intron-distal 5′ SS of DOK7 intron 4, whereas MS2-mediated artificial tethering of SRSF1 to the identified cis-element suppressed it. Isolation of an early spliceosomal complex revealed that SRSF1 inhibited association of U1 snRNP to the intron-distal 5′ SS, and rather enhanced association of U1 snRNP to the intron-proximal 5′ SS, which led to upregulation of the canonical DOK7 transcript. Integrated global analysis of CLIP-seq and RNA-seq also indicated that binding of SRSF1 immediately upstream to two competing 5′ SSs suppresses selection of the intron-distal 5′ SS in hundreds of human genes. We demonstrate that SRSF1 critically regulates alternative selection of adjacently placed 5′ SSs by modulating binding of U1 snRNP.

    DOI: 10.1038/s41598-017-11036-z

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  54. Wnt/β-catenin signaling suppresses expressions of <i>Scx, Mkx,</i> and <i>Tnmd</i> in tendon-derived cells 査読有り

    Kishimoto, Y; Ohkawara, B; Sakai, T; Ito, M; Masuda, A; Ishiguro, N; Shukunami, C; Docheva, D; Ohno, K

    PLOS ONE   12 巻 ( 7 ) 頁: e0182051   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    After tendon injuries, biomechanical properties of the injured tendon are not fully recovered in most cases. Modulation of signaling pathways, which are involved in tendon development and tendon repair, is one of attractive modalities to facilitate proper regeneration of the injured tendon. The roles of TGF-β signaling in tendon homeostasis and tendon development have been elucidated. In contrast, the roles of Wnt/β-catenin signaling in tendon remain mostly elusive. We found that the number of β-catenin-positive cells was increased at the injured site, suggesting involvement of Wnt/β-catenin signaling in tendon healing. Activation of Wnt/β-catenin signaling suppressed expressions of tenogenic genes of Scx, Mkx, and Tnmd in rat tendon-derived cells (TDCs) isolated from the Achilles tendons of 6-week old rats. Additionally, activation of Wnt/β-catenin reduced the amounts of Smad2 and Smad3, which are intracellular mediators for TGF-β signaling, and antagonized upregulation of Scx induced by TGF-β signaling in TDCs. We found that Wnt/β-catenin decreased Mkx and Tnmd expressions without suppressing Scx expression in Scx-programmed tendon progenitors. Our studies suggest that Wnt/β-catenin signaling is a repressor for tenogenic gene expressions.

    DOI: 10.1371/journal.pone.0182051

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  55. Protein-Anchoring Therapy of Biglycan for <i>Mdx</i> Mouse Model of Duchenne Muscular Dystrophy 査読有り

    Ito, M; Ehara, Y; Li, J; Inada, K; Ohno, K

    HUMAN GENE THERAPY   28 巻 ( 5 ) 頁: 428 - 436   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Human Gene Therapy  

    Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by loss-of-function mutations in DMD encoding dystrophin. No rational therapy is currently available. Utrophin is a paralog of dystrophin and is highly expressed at the neuromuscular junction. In mdx mice, utrophin is naturally upregulated throughout the muscle fibers, which mitigates muscular dystrophy. Protein-anchoring therapy was previously reported, in which a recombinant extracellular matrix (ECM) protein is delivered to and anchored to a specific target using its proprietary binding domains. Being prompted by a report that intramuscular and intraperitoneal injection of an ECM protein, biglycan, upregulates expression of utrophin and ameliorates muscle pathology in mdx mice, protein-anchoring therapy was applied to mdx mice. Recombinant adeno-associated virus serotype 8 (rAAV8) carrying hBGN encoding human biglycan was intravenously injected into 5-week-old mdx mice. The rAAV8-hBGN treatment improved motor deficits and decreased plasma creatine kinase activities. In muscle sections of treated mice, the number of central myonuclei and the distribution of myofiber sizes were improved. The treated mice increased gene expressions of utrophin and β1-syntrophin, as well as protein expressions of biglycan, utrophin, γ-sarcoglycan, dystrobrevin, and α1-syntrophin. The expression of hBGN in the skeletal muscle of the treated mice was 1.34-fold higher than that of the native mouse Bgn (mBgn). The low transduction efficiency and improved motor functions suggest that biglycan expressed in a small number of muscle fibers was likely to have been secreted and anchored to the cell surface throughout the whole muscular fibers. It is proposed that the protein-anchoring strategy can be applied not only to deficiency of an ECM protein as previously reported, but also to augmentation of a naturally induced ECM protein.

    DOI: 10.1089/hum.2015.088

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  56. Competitive regulation of alternative splicing and alternative polyadenylation by hnRNP H and CstF64 determines acetylcholinesterase isoforms 査読有り

    Nazim, M; Masuda, A; Rahman, MA; Nasrin, F; Takeda, JI; Ohe, K; Ohkawara, B; Ito, M; Ohno, K

    NUCLEIC ACIDS RESEARCH   45 巻 ( 3 ) 頁: 1455 - 1468   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nucleic acids research  

    Acetylcholinesterase (AChE), encoded by the ACHE gene, hydrolyzes the neurotransmitter acetylcholine to terminate synaptic transmission. Alternative splicing close to the 3΄ end generates three distinct isoforms of AChET, AChEH and AChER. We found that hnRNP H binds to two specific G-runs in exon 5a of human ACHE and activates the distal alternative 3΄ splice site (ss) between exons 5a and 5b to generate AChET. Specific effect of hnRNP H was corroborated by siRNA-mediated knockdown and artificial tethering of hnRNP H. Furthermore, hnRNP H competes for binding of CstF64 to the overlapping binding sites in exon 5a, and suppresses the selection of a cryptic polyadenylation site (PAS), which additionally ensures transcription of the distal 3΄ ss required for the generation of AChET. Expression levels of hnRNP H were positively correlated with the proportions of the AChET isoform in three different cell lines. HnRNP H thus critically generates AChET by enhancing the distal 3΄ ss and by suppressing the cryptic PAS. Global analysis of CLIP-seq and RNA-seq also revealed that hnRNP H competitively regulates alternative 3΄ ss and alternative PAS in other genes. We propose that hnRNP H is an essential factor that competitively regulates alternative splicing and alternative polyadenylation.

    DOI: 10.1093/nar/gkw823

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  57. Agrin-LRP4-MuSK signaling as a therapeutic target for myasthenia gravis and other neuromuscular disorders 査読有り

    Ohno, K; Ohkawara, B; Ito, M

    EXPERT OPINION ON THERAPEUTIC TARGETS   21 巻 ( 10 ) 頁: 949 - 958   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Expert Opinion on Therapeutic Targets  

    Introduction: Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including myasthenia gravis, Lambert-Eaton myasthenic syndrome, Isaacs’ syndrome, congenital myasthenic syndromes, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. Except for sarcopenia, all are orphan diseases. In addition, the NMJ signal transduction is impaired by tetanus, botulinum, curare, α-bungarotoxin, conotoxins, organophosphate, sarin, VX, and soman to name a few. Areas covered: This review covers the agrin-LRP4-MuSK signaling pathway, which drives clustering of acetylcholine receptors (AChRs) and ensures efficient signal transduction at the NMJ. We also address diseases caused by autoantibodies against the NMJ molecules and by germline mutations in genes encoding the NMJ molecules. Expert opinion: Representative small compounds to treat the defective NMJ signal transduction are cholinesterase inhibitors, which exert their effects by increasing the amount of acetylcholine at the synaptic space. Another possible therapeutic strategy to enhance the NMJ signal transduction is to increase the number of AChRs, but no currently available drug has this functionality.

    DOI: 10.1080/14728222.2017.1369960

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  58. Molecular hydrogen alleviates motor deficits and muscle degeneration in <i>mdx</i> mice 査読有り

    Hasegawa, S; Ito, M; Fukami, M; Hashimoto, M; Hirayama, M; Ohno, K

    REDOX REPORT   22 巻 ( 1 ) 頁: 26 - 34   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Redox Report  

    Objective: Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by a mutation in DMD encoding dystrophin. Oxidative stress accounts for dystrophic muscle pathologies in DMD. We examined the effects of molecular hydrogen in mdx mice, a model animal for DMD. Methods: The pregnant mother started to take supersaturated hydrogen water (>5 ppm) ad libitum from E15.5 up to weaning of the offspring. The mdx mice took supersaturated hydrogen water from weaning until age 10 or 24 weeks when they were sacrificed. Results: Hydrogen water prevented abnormal body mass gain that is commonly observed in mdx mice. Hydrogen improved the spontaneous running distance that was estimated by a counter-equipped running-wheel, and extended the duration on the rota-rod. Plasma creatine kinase activities were decreased by hydrogen at ages 10 and 24 weeks. Hydrogen also decreased the number of central nuclei of muscle fibers at ages 10 and 24 weeks, and immunostaining for nitrotyrosine in gastrocnemius muscle at age 24 weeks. Additionally, hydrogen tended to increase protein expressions of antioxidant glutathione peroxidase 1, as well as anti-apoptotic Bcl-2, in skeletal muscle at age 10 weeks. Discussion: Although molecular mechanisms of the diverse effects of hydrogen remain to be elucidated, hydrogen potentially improves muscular dystrophy in DMD patients.

    DOI: 10.1080/13510002.2015.1135580

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  59. Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling. 査読有り

    Kenji Otsuka, Mikako Ito, Bisei Ohkawara, Akio Masuda, Yu Kawakami, Ko Sahashi, Hiroshi Nishida, Naoki Mabuchi, Akemi Takano, Andrew G. Engel, Kinji Ohno

    Scientific Reports   5 巻 ( 13928 )   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/srep13928.

  60. Hydrogen ameliorates pulmonary hypertension in rats by anti-inflammatory and antioxidant effects. 査読有り

    Kishimoto Y, Kato T, Ito M, Azuma Y, Fukasawa Y , Ohno K, Kojima S

    J Thorac Cardiovasc Surg.   150 巻 ( 3 ) 頁: 645-54   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  61. A missense mutation in domain III in HSPG2 in Schwartz-Jampel syndrome compromises secretion of perlecan into the extracellular space. 査読有り

    Iwata S, Ito M, Nakata T, Noguchi Y, Okuno T, Ohkawara B, Masuda A, Goto T, Adachi M, Osaka H, Nonaka R, Arikawa-Hirasawa E, Ohno K.

    Neuromuscul Disord.   25 巻 ( 8 ) 頁: 667-71   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.nmd.2015.05.002

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  62. Dopaminergic neuron-like stem cells from human deciduous teeth promote neurological recovery in Parkinsonian rats by cell replacement and paracrine neuroregenerative mechanisms 査読有り

    Hiromi Fujii, Kohki Matsubara, Kiyoshi Sakai, Mikako Ito, Kinji Ohno, Minoru Ueda, Akihito Yamamoto

    Brain Research   10 巻 ( 1613 ) 頁: 59-72   2015年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  63. Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents. 査読有り

    Sobue S, Yamai K, Ito M, Ohno K, Ito M, Iwamoto T, Qiao S, Ohkuwa T, Ichihara M.

    Mol Cell Biochem.   403 巻 ( 1-2 ) 頁: 231-41   2015年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s11010-015-2353-y

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  64. Position-specific binding of FUS to nascent RNA regulates mRNA length. 査読有り

    Masuda A., Takeda J., Okuno T., Okamoto T., Ohkawara B., Ito M., Ishigaki S., Sobue G., Ohno K.

    Genes Dev.   29 巻 ( 10 ) 頁: 1045-57   2015年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1101/gad.255737.114.

  65. Congenital myasthenic syndrome in Japan: ethnically unique mutations in muscle nicotinic acetylcholine receptor subunits. 査読有り

    Azuma Y, Nakata T, Tanaka M, Shen XM, Ito M, Iwata S, Okuno T, Nomura Y, Ando N, Ishigaki K, Ohkawara B, Masuda A, Natsume J, Kojima S, Sokabe M, Ohno K.

    Neuromuscul Disord.   25 巻 ( 1 ) 頁: 60-9   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.nmd.2014.09.002.

  66. Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage by in utero ischemia-reperfusion 査読有り

    Mano, Y. and Kotani, T. and Ito, M. and Nagai, T. and Ichinohashi, Y. and Yamada, K. and Ohno, K. and Kikkawa, F. and Toyokuni, S.

    Free Radic Biol Med     頁: in press   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  67. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia 査読有り

    Matsushita, M. and Kitoh, H. and Ohkawara, B. and Mishima, K. and Kaneko, H. and Ito, M. and Masuda, A. and Ishiguro, N. and Ohno, K.

    PLoS ONE   8 巻 ( 12 ) 頁: e81569   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  68. LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated musk signaling in a position-specific manner 査読有り

    Ohkawara, B. and Cabrera-Serrano, M. and Nakata, T. and Milone, M. and Asai, N. and Ito, K. and Ito, M. and Masuda, A. and Ito, Y. and Engel, A. G. and Ohno, K.

    Hum Mol Genet     頁: in press   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  69. Verapamil protects against cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling 査読有り

    Takamatsu, A. and Ohkawara, B. and Ito, M. and Masuda, A. and Sakai, T. and Ishiguro, N. and Ohno, K.

    PLOS ONE     頁: in press   2014年

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  70. Mutations in the C-Terminal Domain of ColQ in Endplate Acetylcholinesterase Deficiency Compromise ColQ-MuSK Interaction 査読有り

    Nakata, T. and Ito, M. and Azuma, Y. and Otsuka, K. and Noguchi, Y. and Komaki, H. and Okumura, A. and Shiraishi, K. and Masuda, A. and Natsume, J. and Kojima, S. and Ohno, K.

    Hum Mutat   34 巻 ( 7 ) 頁: 997-1004   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  71. Collagen Q is a key player for developing rational therapy for congenital myasthenia andfor dissecting the mechanisms of anti-MuSK myasthenia gravis 査読有り

    Ohno, K. and Ito, M. and Kawakami, Y.

    J Mol Neurosci     頁: 3 pages   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  72. Specific binding of collagen Q to the neuromuscular junction is exploited to cure congenital myasthenia and to explore bases of myasthenia gravis 査読有り

    Ohno, K. and Ito, M. and Kawakami, Y. and Krejci, E. and Engel, A. G.

    Chem Biol Interact   203 巻 ( 1 ) 頁: 335-340   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  73. HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA 査読有り

    Rahman, M. A. and Masuda, A. and Ohe, K. and Ito, M. and Hutchinson, D. O. and Mayeda, A. and Engel, A. G. and Ohno, K.

    Sci Rep   3 巻   頁: 2931   2013年

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  74. Clinically applicable antianginal agents suppress osteoblastic transformation of myogenic cells and heterotopic ossifications in mice 査読有り

    Yamamoto, R. and Matsushita, M. and Kitoh, H. and Masuda, A. and Ito, M. and Katagiri, T. and Kawai, T. and Ishiguro, N. and Ohno, K.

    J Bone Miner Metab   31 巻 ( 1 ) 頁: 26-33   2013年

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  75. Molecular hydrogen attenuates fatty acid uptake and lipid accumulation through downregulating CD36 expression in HepG2 cells 査読有り

    Iio, A. and Ito, M. and Itoh, T. and Terazawa, R. and Fujita, Y. and Nozawa, Y. and Ohsawa, I. and Ohno, K. and Ito, M.

    Med Gas Res   3 巻 ( 1 ) 頁: 6   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  76. Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy 査読有り

    Yamashita, Y. and Matsuura, T. and Shinmi, J. and Amakusa, Y. and Masuda, A. and Ito, M. and Kinoshita, M. and Furuya, H. and Abe, K. and Ibi, T. and Sahashi, K. and Ohno, K.

    J Hum Genet   57 巻 ( 6 ) 頁: 368-74   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  77. Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson's disease in rats 査読有り

    Ito, M. and Hirayama, M. and Yamai, K. and Goto, S. and Ito, M. and Ichihara, M. and Ohno, K.

    Med Gas Res   2 巻 ( 1 ) 頁: 15   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  78. Protein-anchoring Strategy for Delivering Acetylcholinesterase to the Neuromuscular Junction 査読有り

    Ito, M. and Suzuki, Y. and Okada, T. and Fukudome, T. and Yoshimura, T. and Masuda, A. and Takeda, S. and Krejci, E. and Ohno, K.

    Mol Ther   20 巻 ( 7 ) 頁: 1384-92   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  79. CUGBP1 and MBNL1 preferentially bind to 3' UTRs and facilitate mRNA decay 査読有り

    Masuda, A. and Andersen, H. S. and Doktor, T. K. and Okamoto, T. and Ito, M. and Andresen, B. S. and Ohno, K.

    Sci Rep   2 巻   頁: 209   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  80. Molecular Hydrogen as an Emerging Therapeutic Medical Gas for Neurodegenerative and Other Diseases 査読有り

    Ohno, K. and Ito, M. and Ichihara, M. and Ito, M.

    Oxidative Medicine and Cellular Longevity   2012(2012) 巻   頁: Article ID 353152, 11 pages   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  81. Anti-MuSK autoantibodies block binding of collagen Q to MuSK 査読有り

    Kawakami, Y. and Ito, M. and Hirayama, M. and Sahashi, K. and Ohkawara, B. and Masuda, A. and Nishida, H. and Mabuchi, N. and Engel, A. G. and Ohno, K.

    Neurology   77 巻 ( 20 ) 頁: 1819-26   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  82. Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies 査読有り

    Ito, M. and Ibi, T. and Sahashi, K. and Ichihara, M. and Ito, M. and Ohno, K.

    Medical Gas Research   1 巻   頁: 24   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  83. Molecular hydrogen inhibits lipopolysaccharide/interferon gamma-induced nitric oxide production through modulation of signal transduction in macrophages 査読有り

    Itoh, T. and Hamada, N. and Terazawa, R. and Ito, M. and Ohno, K. and Ichihara, M. and Nozawa, Y. and Ito, M.

    Biochem Biophys Res Commun   411 巻 ( 1 ) 頁: 143-9   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  84. Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8 査読有り

    Kaneko, H. and Kitoh, H. and Matsuura, T. and Masuda, A. and Ito, M. and Mottes, M. and Rauch, F. and Ishiguro, N. and Ohno, K.

    Hum Genet   130 巻 ( 5 ) 頁: 671-83   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  85. Urinary 8-hydroxydeoxyguanosine correlate with hallucinations rather than motor symptoms in Parkinson's disease 査読有り

    Hirayama, M. and Nakamura, T. and Watanabe, H. and Uchida, K. and Hama, T. and Hara, T. and Niimi, Y. and Ito, M. and Ohno, K. and Sobue, G.

    Parkinsonism Relat Disord   17 巻 ( 1 ) 頁: 46-9   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  86. AG-dependent 3'-splice sites are predisposed to aberrant splicing due to a mutation at the first nucleotide of an exon 査読有り

    Fu, Y. and Masuda, A. and Ito, M. and Shinmi, J. and Ohno, K.

    Nucleic Acids Research   39 巻 ( 10 ) 頁: 4396-404   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  87. Molecular hydrogen suppresses Fc epsilon RI-mediated signal transduction and prevents degranulation of mast cells 査読有り

    Itoh, T. and Fujita, Y. and Ito, M. and Masuda, A. and Ohno, K. and Ichihara, M. and Kojima, T. and Nozawa, Y. and Ito, M.

    Biochemical and Biophysical Research Communications   389 巻 ( 4 ) 頁: 651-656   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  88. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson’s disease 査読有り

    Fu, Y. and Ito, M. and Fujita, Y. and Ito, M. and Ichihara, M. and Masuda, A. and Suzuki, Y. and Maesawa, S. and Kajita, Y. and Hirayama, M. and Ohsawa, I. and Ohta, S. and Ohno, K.

    Neuroscience Letters   453 巻   頁: 81–85   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  89. Tannic acid facilitates expression of the polypyrimidine tract binding protein and alleviates deleterious inclusion of CHRNA1 exon P3A due to an hnRNP H-disrupting mutation in congenital myasthenic syndrome 査読有り

    Bian, Y. and Masuda, A. and Matsuura, T. and Ito, M. and Okushin, K. and Engel, A. G. and Ohno, K.

    Hum Mol Genet   18 巻 ( 7 ) 頁: 1229-1237   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  90. hnRNP H enhances skipping of a nonfunctional exon P3A in CHRNA1 and a mutation disrupting its binding causes congenital myasthenic syndrome 査読有り

    Masuda, A. and Shen, X. M. and Ito, M. and Matsuura, T. and Engel, A. G. and Ohno, K.

    Hum Mol Genet   17 巻 ( 24 ) 頁: 4022-4035   2008年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  91. Viral vector-medicated expression of human collagen Q in cultured cells 査読有り

    Ito, M. and Masuda, A. and Jinno, S. and Katagiri, T. and Krejci, E. and Ohno, K.

    Chem Biol Interact   175 巻 ( 1-3 ) 頁: 346-348   2008年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  92. An upper limit of the ratio of DNA volume to nuclear volume exists in plants 査読有り

    Fujimoto, S. and Ito, M. and Matsunaga, S. and Fukui, K.

    Genes Genet Syst   80 巻 ( 5 ) 頁: 345-350   2005年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  93. Identification and characterization of methylated DNA binding protein in Arabidopsis 査読有り

    Ito, M. and Koike, A. and Yamaguchi, Y. and Koizumi, N. and Sano, H.

    Plant Physiology   133 巻   頁: 1747-1754   2003年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  94. Methylated DNA-binding proteins from Arabidopsis 査読有り

    Ito, M. and Koike, A. and Koizumi, N. and Sano, H.

    Plant Physiol   133 巻 ( 4 ) 頁: 1747-1754   2003年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  95. Periodic DNA methylation in maize nucleosomes and demethylation by environmental stress 査読有り

    Steward, N. and Ito, M. and Yamaguchi, Y. and Koizumi, N. and Sano, H.

    J Biol Chem   277 巻 ( 40 ) 頁: 37741-37746   2002年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  96. A chloroplast-resident DNA methyltransferase is responsible for hypermethylation of chloroplast genes in Chlamydomonas maternal gametes 査読有り

    Nishiyama, R. and Ito, M. and Yamaguchi, Y. and Koizumi, N. and Sano, H.

    Proc Natl Acad Sci U S A   99 巻 ( 9 ) 頁: 5925-5930   2002年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  97. Transition between two forms of heterochromatin at plant subtelomeres 査読有り

    Sykorova, E. and Fajkus, J. and Ito, M. and Fukui, K.

    Chromosome Res   9 巻 ( 4 ) 頁: 309-323   2001年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  98. Genome and Chromosome Dimensions of Lotus japonicus 査読有り

    Ito, M. and Miyamoto, J. and Mori, Y. and Fujimoto, S. and Uchiumi, T. and Abe, M. and Suzuki, A. and Tabata, S. and Fukui, K.

    J Plant Res   113 巻   頁: 435-442   2001年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  99. Characterization of Spinach (Spinacia oleracea L.) Chromosomes by Condensation Patterns and Physical Mapping of 5S and 45S rDNA by FISH 査読有り

    Ito, M. and Ohmido, N. and Akiyama, Y. and Fukui, K. and Koba, T.

    J. Ame. Soci. Hort. Sci.   125 巻   頁: 59-62   2000年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  100. Quantitative chromosome map of Arabidopsis thaliana L. by imaging methods 査読有り

    Ito, M. and Ohmido, N. and Akiyama, Y. and Fukui, K.

    Cytologia   65 巻   頁: 325-331   2000年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

▼全件表示

書籍等出版物 4

  1. 生物の科学遺伝 63ー5 タンパク質係留治療

    大野欽司,伊藤美佳子( 担当: 単著)

    エヌ・ティー・エス  2009年9月  ( ISBN:4860432819

     詳細を見る

    記述言語:日本語 著書種別:学術書

  2. 「クロモソーム植物染色体研究の方法」福井希一、向井康比己、谷口研至編著 アラビドプシスにおける染色体観察方法

    伊藤美佳子( 担当: 共著)

    養賢堂  2006年 

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    記述言語:日本語

  3. 植物細胞工学シリーズ13「植物細胞の分裂」町田康則、福田泰穂監修 シロイヌナズナ染色体の識別・同定

    伊藤美佳子 福井希一( 担当: 共著)

    秀潤社  2000年 

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    記述言語:日本語

  4. クロモソーム植物染色体研究の方法「アラビドプシスにおける染色体観察方法」

    2006 

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    養賢堂

MISC 2

  1. パーキンソン病患者の腸内細菌叢異常のメタ分析と予後因子

    西脇 寛, 伊藤 美佳子, 石田 智大, 浜口 知成, 前田 哲也, 柏原 健一, 坪井 義夫, 上山 純, 島村 鉄平, 森 宙史, 黒川 顕, 平山 正明, 大野 欽司  

    腸内細菌学雑誌34 巻 ( 2 ) 頁: 113 - 113   2020年4月

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    記述言語:日本語   出版者・発行元:(公財)腸内細菌学会  

  2. 低酸素条件下における選択的スプライシング機構の解明

    片岡直行, 伊藤美佳子, 増田章男, 大野欽司, 江口加代子, 伯野史彦, 高橋伸一郎, 中山恒  

    日本RNA学会年会要旨集21st 巻   2019年

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講演・口頭発表等 7

  1. Protein-anchoring therapy for delivering acetylcholinesterase to the neuromuscular junction 国際会議

    Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K

    11th International Meeting on Cholinesterases (Poster), Kazan, Russia 

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    開催年月日: 2012年6月

    記述言語:英語   会議種別:ポスター発表  

    国名:ロシア連邦  

  2. Protein-anchoring therapy For delivering acetylcholinesterase to the neuromuscular junction 国際会議

    Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K

    17th Annual Meeting of the Japan Society of Gene Therapy (Poster), Fukuoka, Japan 

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    開催年月日: 2011年7月

    記述言語:英語   会議種別:ポスター発表  

    国名:日本国  

  3. 分子状水素はパーキンソン病モデルラットの発症を抑制し、ヒト筋疾患の各種マーカーを改善する

    伊藤 美佳子、付 源、衣斐 達、大野 欽司

    日本分子生物学会 神戸 ワークショップ 

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    開催年月日: 2010年12月

    記述言語:日本語   会議種別:ポスター発表  

    国名:日本国  

  4. rAAV8-Mediated Protein-Anchoring Therapy for Targeting Collagen Q-Tailed Acetylcholinesterase to the Neuromuscular Junction 国際会議

    Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K

    American Society of Gene & Cell Therapy 13th Annual Meeting (Platform), Washington DC, USA 

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    開催年月日: 2010年5月

    記述言語:英語   会議種別:口頭発表(一般)  

    国名:アメリカ合衆国  

  5. rAAV8-mediated protein anchoring of asymmetric acetylcholinesterase (AChE) to the synaptic basal lamina at the neuromuscular junction (NMJ) 国際会議

    Ito M, Suzuki Y, Okada T, Fukudome T, Masuda A, Yoshimura T, Takeda S, Krejci E, Ohno K

    48th Annual Meeting of the American Society for Cell Biology (Poster), San Francisco, San Diego, California, USA 

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    開催年月日: 2008年12月

    記述言語:英語   会議種別:ポスター発表  

    国名:アメリカ合衆国  

  6. Adeno-associated virus serotype 8-mediated targeting of asymmetric acetylcholinesterase to the synaptic basal lamina at the neuromuscular junction 国際会議

    Ito M, Suzuki Y, Okada T, Fukudome T, Masuda A, Yoshimura T, Takeda S, Krejci E, Ohno K

    38th Annual Meeting, Society for Neuroscience (Poster), Washington DC, USA 

     詳細を見る

    開催年月日: 2008年11月

    記述言語:英語   会議種別:ポスター発表  

    国名:アメリカ合衆国  

  7. Gene Therapy for Collagen Q defects in congenital myasthenic syndromes 国際会議

    Ito M, Masuda A, Jinno S, Katagiri T, Krejci E, Ohno K

    The IXth International Meeting on Cholinesterases, Shuzou, China 

     詳細を見る

    開催年月日: 2007年5月

    記述言語:英語   会議種別:ポスター発表  

    国名:中華人民共和国  

▼全件表示

共同研究・競争的資金等の研究課題 8

  1. 先天性筋無力症候群における分子病態の解明と新規治療法の開発

    2019年4月 - 2020年3月

    学内共同研究 

  2. iPS 細胞を用いた先天性筋無力症候群の病態解析および新規治療法の開発

    2019年4月 - 2020年3月

    学内共同研究 

  3. 腸内細菌叢の変動によるパーキンソン病発症機序の解明と発症抑制・病態進行抑制法の開発

    2018年4月 - 2019年3月

    学内共同研究 

  4. パーキンソン病患者の腸内細菌層(マイクロバイオーム)解析による病態解明

    2016年4月 - 2017年4月

    学内共同研究 

  5. パーキンソン病の発症と病態進行に関わる腸内細菌叢の解明

    2015年10月 - 2016年9月

    学内共同研究 

  6. 筋ジストロフィーにおける細胞外分子biglycan補充療法の開発

    2012年 - 2013年

    学内共同研究 

  7. 分子状水素による血液製剤保存法の開発及び輸血関連性肺障害の予防効果の検討

    2010年8月 - 2011年3月

  8. 神経筋疾患におけるスプライシング異常

    2009年9月 - 2013年3月

▼全件表示

科研費 17

  1. 超低周波変動磁場によるミトコンドリア活性化機構の解明と低侵襲治療法の開発

    研究課題/研究課題番号:23K06412  2023年4月 - 2026年3月

    科学研究費助成事業  基盤研究(C)

    伊藤 美佳子

      詳細を見る

    担当区分:研究代表者 

    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    現代社会では人は日常的に地磁気や電化製品などによる超低周波磁場にさらされているが、微弱な磁場が生体に影響を与える報告はほとんどない。我々は1-8 Hzで8秒間に変動する10 μTの超低周波微弱パルス磁場がマイトファジーを誘導後ミトコンドリア新生を促進し、ホルミシス効果によりミトコンドリアを活性化することを見出した。本研究ではパーキンソン病の神経精神疾患とミトコンドリア病に対する超低周波微弱パルス磁場の効果を、モデルマウス、患者由来Cybrid細胞、患者由来iPS細胞を用いて検証する。さらに、生物に対する作用機構が知られていない超微弱磁場の量子力学的作用機構を明らかにする。

  2. 肢帯型先天性筋無力症の病態解析および新規治療法の開発

    研究課題/研究課題番号:20K06925  2020年4月 - 2024年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    伊藤 美佳子, 大河原 美静

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    先天的な神経筋接合部の分子欠損による先天性筋無力症候群 (congenital myasthenic syndromes, CMS)の原因として30種類の分子が報告されており、筋力低下や易疲労性を呈し、軽度から重度の呼吸困難、嚥下困難、四肢筋力低下が認められる。本研究では、CMS患者と同じ変異を持つマウスを作製し、神経筋接合部での病態機構解析を行う。またCMS患者由来iPS細胞を用いたGFPT1, DOK7の遺伝子変異の機能解析を行い、既認可薬からスクリーニングによる新規治療法の開発に取り組む。
    先天性筋無力症候群 (CMS: congenital myasthenic syndromes)は筋力低下や易疲労性を呈し、軽度から重度の呼吸困難、嚥下困難、四肢筋力低下が認められるが、その分子病態は十分解明されていない。CMSの中で、タンパク質や脂質の糖化酵素であるGFPT1(Glutamine:Fructose-6-Phosphate Transaminase 1)の変異が原因分子の一つであり、肢帯型の筋力低下が特徴である。GFPT1は、UDP-N-アセチルグルコサミンを合成するヘキソサミン生合成経路の律速酵素であり、UDP-GlcNAc)は、タンパク質および脂質のN結合型およびO結合型のグリコシル化の基質である。 GFPT1は多くの組織で至る所で発現している。骨格筋では、選択的スプライシングにより4ヌクレオチドのexon 9が含まれているGFPT1-L isoformが高発現しており、それは酵素活性が低く、この長いGFPT1-L isoformの役割は不明である。本研究ではhuman myoblast KD3/Hu5細胞を用いてこのisoformの生成には、スプライシングcis因子の破壊、RNA結合タンパクのartificial tethering、初期スプライセオソーム複合体の分離により、SRSF1 と Rbfox1/2 が協調的に増強し、hnRNP H/F がヒト GFPT1 exon 9 のリクルートメントを調節することにより、その包含を抑制することが明らかにした。また、骨格筋におけるGFPT1-Lバリアントの役割を調査するために、exon 9スキッピングマウスを作製し、その表現型を解析した。Gfpt1-L-/-マウスは若年では形態に変化が見られないが、高齢になるにつれて筋力低下が起きることが明らかになった。
    Gfpt1-L-/-マウスは、Gfpt1のexon 9を削除することにより、CRISPR / Casシステムを使用して、当施設の動物施設で作製した。骨格筋および心臓におけるexon 9のスキッピングは、RT-PCRによってホモ接合マウスで確認した。運動能を調べるために、加速ローターロッドテストでは、Gfpt1-L-/-マウスは、野生型マウスと比較して、12か月齢から筋持久力が20から30%低下することが明らかになった。 Gfpt1-L-/-マウスは、12か月齢で野生型マウスよりも体重増加を示した。骨格筋に GFPT1-L が存在しないため、GFPT1 と UDP-HexNAc の量がそれぞれ約 4.5 倍と約 2.8 倍に増加した。骨格筋のメタボロミクス分析により、Gfpt1-L-/-マウスのヘキソサミン生合成経路へ代謝物の増加が解糖経路を抑制し、ミトコンドリアの電子伝達系を強化する可能性が高いことを示された。高齢のGfpt1-L-/-マウスは、インスリンに応答してグルコース取り込み障害を示した。高齢のGfpt1-L-/-マウスは、筋力低下と疲労、小さく断片化されたアセチルコリン受容体クラスター、単純化されたシナプス後接合部ヒダを示した。これらは、GFPT1 変異による先天性筋無力症候群で観察されるものと同様であるがシビアではなかった。 一方、上腕三頭筋のRNA-seqデータでは、予想に反してGfpt1-L-/-マウスと野生型マウスの間に違いはなかった。
    現在までに得られたデータから、GFPT1-Lが骨格筋で欠損することで、神経筋接合部の構造異常を起こすことが判明し、シグナル伝達の障害が筋力低下の原因と考えられる。また、解糖系の代謝産物が減少しており、エネルギー産生の異常が推測される。
    現在は患者変異と同じ、c.722^723insG変異のモデルとしてexon9をスキップさせた、exon10にstop codonを出現させたshort GFPT1を有するマウスを作製しており、このマウスの表現型解析を行っている。c.716^717insGマウスの骨格筋神経筋接合部は、AChRのクラスタリングの断片化が見られたため、電子顕微鏡を用いて、骨格筋の細部の観察を行う。また、c.716^717insGマウスは野生型より体重が重く、皮下脂肪が多いことから、CTスキャンによる内臓脂肪組織の測定を予定している。
    マウスはヒトと異なり、筋組織でGFPT2の発現が高く、GFPT1の機能を補助する役割がある。GFPT1 c.722^723insGノックインマウスの表現系が顕著に出なかったのは、GFPT2がGFPT1の機能を補っているためと考えられる。そこで、GFPT2ノックアウトマウスにおいても作製しており、表現型解析を進めている。どちらも高齢になると表現型がみられるため、一定期間飼育後、運動試験及び糖鎖タンパク量の測定を行う。また、神経筋接合部特異的に発現している分子の変化を検出し、患者変異GFPT1において、異常を起こした分子メカニズムを詳細に解析する。

  3. iPS 細胞を用いた先天性筋無力症候群の病態解析および新規治療法の開発

    2019年4月 - 2020年3月

    学内共同研究 

      詳細を見る

    資金種別:競争的資金

  4. 先天性筋無力症候群における分子病態の解明と新規治療法の開発

    2019年4月 - 2020年3月

    学内共同研究 

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    資金種別:競争的資金

  5. 腸内細菌叢の変動によるパーキンソン病発症機序の解明と発症抑制・病態進行抑制法の開発

    2018年4月 - 2019年3月

    学内共同研究 

    伊藤 美佳子

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:1000000円

  6. iPS細胞を用いたGFPT1先天性筋無力症の病態解析および治療研究

    研究課題/研究課題番号:17K07094  2017年4月 - 2021年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    伊藤 美佳子, 大河原 美静

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    担当区分:研究代表者 

    配分額:5070000円 ( 直接経費:3900000円 、 間接経費:1170000円 )

    先天性筋無力症候群(CMS) の原因分子の一つに、タンパクや脂質の糖化酵素であるGFPT1の変異があり、肢帯型の筋力低下が特徴である。骨格筋ではGFPT1-L isoformが形成され、酵素活性が減少する。本研究ではGFPT1-L の骨格筋での役割を明らかにするため、モデルマウスGfpt1-L-/-を作製し、表現型解析を行った。
    また、CMS患者においてGFPT1 c.722^723insG変異を同定し、同変異のモデルマウスを作製したところ、運動機能の低下、グリコシル化タンパク質の量の減少、AChRクラスターの断片化、筋萎縮、筋線維間腔の増加など、患者と似た表現型を示した。
    先天性筋無力症候群は指定難病の対象となっており、全身の筋力低下, 易疲労性を呈し,生後 1 年以内に発症することが多い稀な疾患である。神経筋接合部を構成する遺伝子検査を実施し、変異が発見された場合は、CMSの原因となりうる変異かどうかを精査する必要がある。本研究では先天性筋無力症候群患者において、GFPT1内に複合ヘテロ変異を同定した。GFPT1の神経筋接合部での機能は不明な点が多く、GFPT1の骨格筋でのisoformについて調査した。また、患者変異を保有するマウスを作成し、病態の詳細な解析を行った。今後、治療薬のスクリーニング、治療法の開発へ応用できると期待している。

  7. iPS細胞を用いたGFPT1先天性筋無力症の病態解析および治療研究

    2017年4月 - 2020年3月

    科学研究費補助金  基盤研究(C)

      詳細を見る

    担当区分:研究代表者 

  8. パーキンソン病患者の腸内細菌層(マイクロバイオーム)解析による病態解明

    2016年4月 - 2017年4月

    学内共同研究 

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    資金種別:競争的資金

  9. 筋ジストロフィーにおける細胞外分子補充療法の開発

    2013年4月 - 2017年3月

    科学研究費補助金  基盤研究(C)

    伊藤美佳子

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    担当区分:研究代表者 

  10. 筋ジストロフィーにおける細胞外分子補充療法の開発

    2013年4月 - 2017年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    伊藤美佳子

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    資金種別:競争的資金

  11. 神経筋接合部の正常構築と分子病態研究(大野欽司)

    2012年4月 - 2015年3月

    科学研究費補助金  基盤研究(B)

    大野欽司

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    担当区分:研究分担者 

  12. 重症筋無力症における抗MuSK抗体の認識分子同定

    2011年4月 - 2013年3月

    科学研究費補助金  若手研究(B)

    伊藤美佳子

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    担当区分:研究代表者 

  13. 骨格筋細胞外分子欠損症における、組織標的シグナルを利用した汎用治療法の開発研究

    2009年4月 - 2011年3月

    科学研究費補助金  若手研究(B)

    伊藤美佳子

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    担当区分:研究代表者 

  14. 神経筋接合部信号伝達障害に対するタンパク標的治療法の開発研究

    2007年4月 - 2009年3月

    科学研究費補助金  若手研究(B)

    伊藤 美佳子

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    担当区分:研究代表者 

  15. 神経筋接合部の先天的分子欠損症に対するタンパク標的治療法の開発

    2006年

    厚生労働科学研究費補助金 

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    資金種別:競争的資金

  16. アラビドプシスにおけるメチル化DNA結合タンパク質の解析

    未来開拓学術研究推進事業 

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    資金種別:競争的資金

  17. Analysis of methylated DNA binding protein in Arabidopsis

      詳細を見る

    資金種別:競争的資金

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担当経験のある科目 (本学) 9

  1. 基礎医学セミナー

    2023

  2. 基盤医科学実習

    2023

  3. 生物学基礎1

    2023

  4. 基盤医科学実習

    2022

  5. 生物学基礎1

    2022

  6. 生物学基礎II

    2021

  7. 生物学基礎II

    2020

  8. 自然環境と人間

    2015

  9. 自然環境と人間

    2011

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担当経験のある科目 (本学以外) 1

  1. 生物学基礎II

    名古屋大学)