研究者詳細 - 大橋　俊孝

論文 - 大橋　俊孝

分割表示 122 件中 41 - 60 件目／全件表示 >>

Modifications of perineuronal nets and remodelling of excitatory and inhibitory afferents during vestibular compensation in the adult mouse. 査読国際誌

Alessio Faralli, Federico Dagna, Andrea Albera, Yoko Bekku, Toshitaka Oohashi, Roberto Albera, Ferdinando Rossi, Daniela Carulli

Brain structure & function 221 ( 6 ) 3193 - 209 2016年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Perineuronal nets (PNNs) are aggregates of extracellular matrix molecules surrounding several types of neurons in the adult CNS, which contribute to stabilising neuronal connections. Interestingly, a reduction of PNN number and staining intensity has been observed in conditions associated with plasticity in the adult brain. However, it is not known whether spontaneous PNN changes are functional to plasticity and repair after injury. To address this issue, we investigated PNN expression in the vestibular nuclei of the adult mouse during vestibular compensation, namely the resolution of motor deficits resulting from a unilateral peripheral vestibular lesion. After unilateral labyrinthectomy, we found that PNN number and staining intensity were strongly attenuated in the lateral vestibular nucleus on both sides, in parallel with remodelling of excitatory and inhibitory afferents. Moreover, PNNs were completely restored when vestibular deficits of the mice were abated. Interestingly, in mice with genetically reduced PNNs, vestibular compensation was accelerated. Overall, these results strongly suggest that temporal tuning of PNN expression may be crucial for vestibular compensation.

DOI： 10.1007/s00429-015-1095-7

COL4A6 is dispensable for autosomal recessive Alport syndrome 査読

Tomohiro Murata, Kan Katayama, Toshitaka Oohashi, Timo Jahnukainen, Tomoko Yonezawa, Yoshikazu Sado, Eiji Ishikawa, Shinsuke Nomura, Karl Tryggvason, Masaaki Ito

SCIENTIFIC REPORTS 6 2016年7月

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

Alport syndrome is caused by mutations in the genes encoding alpha 3, alpha 4, or alpha 5 (IV) chains. Unlike X-linked Alport mice, alpha 5 and alpha 6 (IV) chains are detected in the glomerular basement membrane of autosomal recessive Alport mice, however, the significance of this finding remains to be investigated. We therefore generated mice lacking both alpha 3 and alpha 6 (IV) chains and compared their renal function and survival with Col4a3 knockout mice of 129 x 1/Sv background. No significant difference was observed in the renal function or survival of the two groups, or when the mice were backcrossed once to C57BL/6 background. However, the survival of backcrossed double knockout mice was significantly longer than that of the mice of 129 x 1/Sv background, which suggests that other modifier genes were involved in this phenomenon. In further studies we identified two Alport patients who had a homozygous mutation in intron 46 of COL4A4. The alpha 5 and alpha 6 (IV) chains were focally detected in the glomerular basement membrane of these patients. These findings indicate that although a5 and a6 (IV) chains are induced in the glomerular basement membrane in autosomal recessive Alport syndrome, their induction does not seem to play a major compensatory role.

DOI： 10.1038/srep29450

Human collagen XV is a prominent histopathological component of sinusoidal capillarization in hepatocellular carcinogenesis. 査読

Kouji Kimura, Masaru Nakayama, Ichiro Naito, Takaaki Komiyama, Kouichi Ichimura, Hiroaki Asano, Kazunori Tsukuda, Aiji Ohtsuka, Toshitaka Oohashi, Shinichiro Miyoshi, Yoshifumi Ninomiya

International journal of clinical oncology 21 ( 2 ) 302 - 309 2016年4月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Increased expression of collagen XV has been reported in hepatocellular carcinogenesis in mice. The aim of this study was to confirm the previous murine findings in human hepatocellular carcinoma (HCC) specimens, along with the histopathological distribution of collagen XV in tumoral tissues. METHODS: Sixty-three primary HCC specimens were examined. Immunostaining of collagen XV and quantitative reverse transcriptional PCR of COL15A1, which encodes collagen XV, were performed. RESULTS: Positive staining of collagen XV was observed in all tumoral regions, regardless of differentiation level or pathological type of HCC, along the sinusoid-like endothelium, whereas collagen XV was not expressed in any non-tumoral region. The intensity score of collagen XV immunostaining and the mRNA value of COL15A1 were significantly correlated. COL15A1 expression in tumors was 3.24-fold higher than in non-tumoral regions. Multivariate analysis showed that COL15A1 expression was significantly higher in the absence of hepatitis virus and moderately differentiated HCC. CONCLUSIONS: COL15A1 mRNA was up-regulated in HCC and collagen XV was expressed along the sinusoid-like endothelium of HCC but not in non-tumoral regions, which implies that collagen XV contributes to the capillarization of HCC.

DOI： 10.1007/s10147-015-0888-2

CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-β3 function. 査読国際誌

Yuya Yoshioka, Mitsuaki Ono, Azusa Maeda, Tina M Kilts, Emilio Satoshi Hara, Hany Khattab, Junji Ueda, Eriko Aoyama, Toshitaka Oohashi, Masaharu Takigawa, Marian F Young, Takuo Kuboki

Bone 83 162 - 170 2016年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

The CCN family of proteins plays important roles in development and homeostasis of bone and cartilage. To understand the role of CCN4 in chondrogenesis, human bone marrow stromal cells (hBMSCs) were transduced with CCN4 adenovirus (adCCN4) or siRNA to CCN4 (siCCN4) in the presence or absence of transforming growth factor-β3 (TGF-β3). Overexpression of CCN4 enhanced TGF-β3-induced SMAD2/3 phosphorylation and chondrogenesis of hBMSCs in an in vitro assay using a micromass culture model. On the other hand, knockdown of CCN4 inhibited the TGF-β3-induced SMAD2/3 phosphorylation and synthesis of cartilage matrix in micromass cultures of hBMSCs. Immunoprecipitation-western blot analysis revealed that CCN4 bound to TGF-β3 and regulated the ability of TGF-β3 to bind to hBMSCs. In vivo analysis confirmed there was a significant decrease in the gene expression levels of chondrocyte markers in cartilage samples from Ccn4-knock out (KO) mice, compared to those from wild type (WT) control. In order to investigate the regenerative properties of the articular cartilage in Ccn4-KO mice, articular cartilage defects were surgically performed in the knee joints of young mice, and the results showed that the cartilage was partially repaired in WT mice, but not in Ccn4-KO mice. In conclusion, these results show, for the first time, that CCN4 has a positive influence on chondrogenic differentiation by modulating the effects of TGF-β3.

DOI： 10.1016/j.bone.2015.11.007

The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity. 査読国際誌

Toshitaka Oohashi, Midori Edamatsu, Yoko Bekku, Daniela Carulli

Experimental neurology 274 ( Pt B ) 134 - 44 2015年12月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

The hyaluronan and proteoglycanbinding link protein (Hapln) is a key molecule in the formation and control of hyaluronan-based condensed perineuronal matrix in the adult brain. This review summarizes the recent advances in understanding the role of Haplns in the formation and control of two distinct types of perineuronal matrices, one for "classical" PNN and the other for the specialized extracellular matrix (ECM) at the node of Ranvier in the central nervous system (CNS). We introduce the structural components of each ECM organization including the basic concept of supramolecular structure named "HLT model". We furthermore summarize the developmental and physiological role of perineuronal ECMs from the studies of Haplns and related molecules. Finally, we also discuss the potential mechanism modulating PNNs in the adult CNS. This layer of organized matrices may exert a direct effect via core protein or sugar moiety from the structure or by acting as a binding site for biologically active molecules, which are important for neuronal plasticity and saltatory conduction.

DOI： 10.1016/j.expneurol.2015.09.010

[Formation and roles of perineuronal extracellular matrices in the adult brain]. 査読

Toshitaka Oohashi, Midori Edamatsu, Yoko Bekku

Seikagaku. The Journal of Japanese Biochemical Society 87 ( 3 ) 393 - 6 2015年6月

RXR Partial Agonist Produced by Side Chain Repositioning of Alkoxy RXR Full Agonist Retains Antitype 2 Diabetes Activity without the Adverse Effects 査読

Kohei Kawata, Ken-ichi Morishita, Mariko Nakayama, Shoya Yamada, Toshiki Kobayashi, Yuki Furusawa, Sakae Arimoto-Kobayashi, Toshitaka Oohashi, Makoto Makishima, Hirotaka Naitou, Erika Ishitsubo, Hiroaki Tokiwa, Akihiro Tai, Hiroki Kakuta

JOURNAL OF MEDICINAL CHEMISTRY 58 ( 2 ) 912 - 926 2015年1月

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

We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: <bold>5</bold>, EC50 = 143 nM, E-max = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: <bold>8b</bold>, EC50 = 169 nM, E-max = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: <bold>7b</bold>, EC50 = 19 nM). NEt-4IB (<bold>8b</bold>) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to <bold>5</bold>.

DOI： 10.1021/jm501863r

Eosinophil Cationic Protein Shows Survival Effect on H9c2 Cardiac Myoblast Cells with Enhanced Phosphorylation of ERK and Akt/GSK-3β under Oxidative Stress. 査読

Hiroko Ishii, Shigeshi Kamikawa, Satoshi Hirohata, Akifumi Mizutani, Koji Abe, Masaharu Seno, Toshitaka Oohashi, Yoshifumi Ninomiya

Acta medica Okayama 69 ( 3 ) 145 - 53 2015年

記述言語：英語掲載種別：研究論文（学術雑誌）

Eosinophil cationic protein (ECP) is well known as a cationic protein contained in the basic granules of activated eosinophils. Recent studies have reported that ECP exhibits novel activities on various types of cells, including rat neonatal cardiomyocytes. Here we evaluated the effects of ECP on rat cardiac myoblast H9c2 cells. Our results showed that ECP enhanced the survival of the cells, in part by promoting the ERK and Akt/GSK-3β signaling pathways. ECP attenuated the cytotoxic effects of H2O2 on H9c2 cells as well as the production of reactive oxygen species, the number of apoptotic cells and caspase 3/7 activity in the cells. In conclusion, ECP activated the ERK and Akt/GSK-3β pathways, resulting in anti-oxidative effects on H9c2 cells that attenuated apoptosis.

肝細胞癌組織におけるXV型コラーゲン発現とその意義

木村紘爾, 中山勝, 小宮山高明, 市村浩一, 内藤一郎, 浅野博昭, 佃和憲, 大塚愛二, 大橋俊孝, 二宮善文

日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集 46回・61回 84 - 84 2014年6月

Light and electron microscopic detection of inflammation-targeting liposomes encapsulating high-density colloidal gold in arthritic mice. 査読国際誌

Ami Maehara, Keiichiro Nishida, Masumi Furutani, Emi Matsumoto, Aiji Ohtsuka, Yoshifumi Ninomiya, Toshitaka Oohashi

Inflammation research : official journal of the European Histamine Research Society ... [et al.] 63 ( 2 ) 139 - 47 2014年2月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: We have previously demonstrated the efficient and time-dependent transvascular localization of Sialyl Lewis X (SLX)-liposomes to inflammatory sites, but the final target of the SLX-liposomes remained uncertain. The aim of this study was to identify the target cells of the liposomes within the inflamed joints of collagen antibody-induced arthritis (CAIA) model mice. METHODS: SLX-liposomes and unlabeled liposomes encapsulating high-density colloidal gold were administered intravenously into the caudal vein of CAIA mice on day 5 after induction of arthritis when the inflammatory score was maximal (n = 6 per group). Six hours or 24 h after liposome administration, animals were euthanized and hind limbs and ankles were excised without perfusion. After fixation, synovial tissues were examined by light microscopy after silver enhancement of colloidal gold or by transmission electron microscopy. RESULTS: Silver-enhanced signals were detected within the cells around E-selectin-positive blood vessels in the synovium of the SLX-liposome group. These cells were positive for the macrophage/monocyte marker F4/80 or neutrophil marker Ly-6G. Transmission electron microscopy detected the colloidal gold signals together with liposome-like structures within the phagosomes of synovial macrophages. Transmission electron microscopy and energy dispersive X-ray spectrometry could determine gold elements in the lysosomes of synovial macrophages. CONCLUSIONS: The results of the current study demonstrate that SLX-liposomes primarily targeting E-selectin in activated endothelial cells could potentially deliver their contents into inflammatory cells around synovial blood vessels in arthritic joints.

DOI： 10.1007/s00011-013-0682-4

Design, synthesis, and preliminary ex vivo and in vivo evaluation of cationic magnetic resonance contrast agent for rabbit articular cartilage imaging 査読

Takayoshi Irie, Kazuhiro Oda, Akihiko Shiino, Mitsuhiko Kubo, Shigehiro Morikawa, Noboru Urushiyama, Shuji Aonuma, Takahide Kimura, Toshiro Inubushi, Toshitaka Oohashi, Naoki Komatsu

MedChemComm 4 ( 11 ) 1508 - 1512 2013年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Since early-stage diagnosis of osteoarthritis (OA) is necessary to retard the progress of the disease, magnetic resonance (MR) and computed tomography (CT) imaging agents have been applied to evaluate the integrity of the extracellular matrix (ECM) in the articular cartilage (AC). Although several negatively charged contrast agents were employed, they provided indirect images of the AC based on the coulombic repulsion with anionic glycosaminoglycans (GAGs) in the ECM. To achieve direct imaging of the ECM, positively charged contrast agents have quite recently been designed for optical and CT imaging. In this paper, we report on a positively charged MR contrast agent, DOTA-Gd-G 2R8, which was applied preliminarily to ex vivo and in vivo imaging of rabbit AC. In the ex vivo imaging, the contrast agent was accumulated in the AC in high concentration due to the strong coulombic attraction between the negative charge of the GAGs and the positive charge of the octaarginine (R8). The thickness of the AC measured in the MR image was found to be comparable to that determined by the histological staining of the slice. The AC was also observed in vivo by MR imaging with the use of DOTA-Gd-G2R8. © 2013 The Royal Society of Chemistry.

DOI： 10.1039/c3md00229b

Ten-m2 is required for the generation of binocular visual circuits. 査読国際誌

Timothy R Young, Michael Bourke, Xiaohong Zhou, Toshitaka Oohashi, Atomu Sawatari, Reinhard Fässler, Catherine A Leamey

The Journal of neuroscience : the official journal of the Society for Neuroscience 33 ( 30 ) 12490 - 509 2013年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Functional binocular vision requires that inputs arising from the two retinae are integrated and precisely organized within central visual areas. Previous studies have demonstrated an important role for one member of the Ten-m/Odz/teneurin family, Ten-m3, in the mapping of ipsilateral retinal projections. Here, we have identified a distinct role for another closely related family member, Ten-m2, in the formation of the ipsilateral projection in the mouse visual system. Ten-m2 expression was observed in the retina, dorsal lateral geniculate nucleus (dLGN), superior colliculus (SC), and primary visual cortex (V1) of the developing mouse. Anterograde and retrograde tracing experiments in Ten-m2 knock-out (KO) mice revealed a specific decrease in ipsilateral retinal ganglion cells projecting to dLGN and SC. This reduction was most prominent in regions corresponding to ventral retina. No change in the topography of ipsilateral or contralateral projections was observed. While expression of a critical ipsilateral fate determinant, Zic2, appeared unaltered, a notable reduction in one of its downstream targets, EphB1, was observed in ventral retina, suggesting that Ten-m2 may interact with this molecular pathway. Immunohistochemistry for c-fos, a neural activity marker, revealed that the area of V1 driven by ipsilateral inputs was reduced in KOs, while the ratio of ipsilateral-to-contralateral responses contributing to binocular activation during visually evoked potential recordings was also diminished. Finally, a novel two-alternative swim task revealed specific deficits associated with dorsal visual field. These data demonstrate a requirement for Ten-m2 in the establishment of ipsilateral projections, and thus the generation of binocular circuits, critical for mammalian visual function.

DOI： 10.1523/JNEUROSCI.4708-12.2013

Three mechanisms assemble central nervous system nodes of Ranvier. 査読国際誌

Keiichiro Susuki, Kae-Jiun Chang, Daniel R Zollinger, Yanhong Liu, Yasuhiro Ogawa, Yael Eshed-Eisenbach, María T Dours-Zimmermann, Juan A Oses-Prieto, Alma L Burlingame, Constanze I Seidenbecher, Dieter R Zimmermann, Toshitaka Oohashi, Elior Peles, Matthew N Rasband

Neuron 78 ( 3 ) 469 - 82 2013年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Rapid action potential propagation in myelinated axons requires Na⁺ channel clustering at nodes of Ranvier. However, the mechanism of clustering at CNS nodes remains poorly understood. Here, we show that the assembly of nodes of Ranvier in the CNS involves three mechanisms: a glia-derived extracellular matrix (ECM) complex containing proteoglycans and adhesion molecules that cluster NF186, paranodal axoglial junctions that function as barriers to restrict the position of nodal proteins, and axonal cytoskeletal scaffolds (CSs) that stabilize nodal Na⁺ channels. We show that while mice with a single disrupted mechanism had mostly normal nodes, disruptions of the ECM and paranodal barrier, the ECM and CS, or the paranodal barrier and CS all lead to juvenile lethality, profound motor dysfunction, and significantly reduced Na⁺ channel clustering. Our results demonstrate that ECM, paranodal, and axonal cytoskeletal mechanisms ensure robust CNS nodal Na⁺ channel clustering.

DOI： 10.1016/j.neuron.2013.03.005

Bral2 is indispensable for the proper localization of brevican and the structural integrity of the perineuronal net in the brainstem and cerebellum. 査読国際誌

Yoko Bekku, Mai Saito, Markus Moser, Maki Fuchigami, Ami Maehara, Masaru Nakayama, Shozo Kusachi, Yoshifumi Ninomiya, Toshitaka Oohashi

The Journal of comparative neurology 520 ( 8 ) 1721 - 36 2012年6月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Perineuronal nets (PNNs) are pericellular coats of condensed matrix that enwrap the cell bodies and dendrites of many adult central nervous system (CNS) neurons. These extracellular matrices (ECMs) play a structural role as well as instructive roles in the control of CNS plasticity and the termination of critical periods. The cartilage link protein Crtl1/Hapln1 was reported to be a trigger for the formation of PNNs in the visual cortex. Bral2/Hapln4 is another link protein that is expressed in PNNs, mainly in the brainstem and cerebellum. To assess the role of Bral2 in PNN formation, we examined the expression of PNN components in targeted mouse mutants lacking Bral2. We show here that Bral2-deficient mice have attenuated PNNs, but the overall levels of chondroitin sulfate proteoglycans, lecticans, are unchanged with the exception of neurocan. Bral2 deficiency markedly affected the localization of brevican in all of the nuclei tested, and neurocan concomitant with Crtl1 in some of the nuclei, whereas no effect was seen on aggrecan even with the attenuation of Crtl1. Bral2 may have a role in the organization of the PNN, in association with brevican, that is independent of aggrecan binding. There was a heterogenous attenuation of PNN components, including glycosaminoglycans, indicating the elaborate molecular organization of the PNN components. Strikingly, a slight decrease in the number of synapses in deep cerebellar nuclei neurons was found. Taken together, these results imply that Bral2-brevican interaction may play a key role in synaptic stabilization and the structural integrity of the PNN.

DOI： 10.1002/cne.23009

RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists. 査読国際誌

Hiroki Kakuta, Nobumasa Yakushiji, Ryosuke Shinozaki, Fuminori Ohsawa, Shoya Yamada, Yui Ohta, Kohei Kawata, Mariko Nakayama, Manabu Hagaya, Chisa Fujiwara, Makoto Makishima, Shigeyuki Uno, Akihiro Tai, Ami Maehara, Masaru Nakayama, Toshitaka Oohashi, Hiroyuki Yasui, Yutaka Yoshikawa

ACS medicinal chemistry letters 3 ( 5 ) 427 - 32 2012年5月

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

Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates.

DOI： 10.1021/ml300055n

Mechanical stretch enhances COL2A1 expression on chromatin by inducing SOX9 nuclear translocalization in inner meniscus cells. 査読国際誌

Tomoko Kanazawa, Takayuki Furumatsu, Motomi Hachioji, Toshitaka Oohashi, Yoshifumi Ninomiya, Toshifumi Ozaki

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 30 ( 3 ) 468 - 74 2012年3月

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

The meniscus plays an important role in controlling the biomechanics of the knee. However, the mechanical stress-related response in meniscus cells remains unclear. We investigated mechanical stretch-regulated gene expression in human meniscus cells. Human inner and outer meniscus cells were prepared from the inner and outer halves of the lateral meniscus. The gene expressions of Sry-type HMG box (SOX) 9 and α1(II) collagen (COL2A1) were assessed by real-time PCR analyses after cyclic tensile strain (CTS) treatment (0.5 Hz, 5% stretch). The localization and phosphorylation of SOX9 were evaluated by immunohistochemical and Western blot (WB) analyses. Chromatin immunoprecipitation (IP) analysis was performed to assess the stretch-related protein-DNA complex formation between SOX9 and the COL2A1 enhancer on chromatin. Type II collagen deposition and SOX9 production were detected only in inner menisci. CTS treatments increased expression of the COL2A1 and SOX9 genes in inner meniscus cells, but not in outer meniscus cells. In addition, CTS treatments stimulated nuclear translocalization and phosphorylation of SOX9 in inner meniscus cells. Chromatin IP analyses revealed that CTS increased the association between SOX9 and its DNA-binding site, included in the COL2A1 enhancer, on chromatin. Our results indicate that inner and outer meniscus cells have different properties in mechanical stretch-induced COL2A1 expression. In inner meniscus cells, mechanical stretch may have an essential role in the epigenetic regulation of COL2A1 expression.

DOI： 10.1002/jor.21528

[Cutting edge on research of cartilage metabolism. Recent progress in bio-molecular imaging of articular cartilage]. 査読

Toshitaka Oohashi, Keiichiro Nishida

Clinical calcium 21 ( 6 ) 896 - 902 2011年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）

In the process of cartilage degeneration seen in osteoarthritis, loss of proteoglycan from articular cartilage has been widely accepted as a critical early event, followed by collagen degradation designated as a point of no return. Recent advance in the development of targeted molecular probes and new imaging modalities enabled the detection of qualitative and functional change of articular cartilage. In this paper, we describe the recent progress of bio-molecular imaging of articular cartilage including our fluorescent-labeled glycosaminoglycan-binding octaarginine.

Clonal overgrowth of esophageal smooth muscle cells in diffuse leiomyomatosis-Alport syndrome caused by partial deletion in COL4A5 and COL4A6 genes. 査読国際誌

Toshitaka Oohashi, Ichiro Naito, Yasuyoshi Ueki, Tomoki Yamatsuji, Rattiya Permpoon, Noriaki Tanaka, Yoshio Naomoto, Yoshifumi Ninomiya

Matrix biology : journal of the International Society for Matrix Biology 30 ( 1 ) 3 - 8 2011年1月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

This is a study of a patient who manifests all of the features of a diffuse leiomyomatosis-Alport syndrome (DL-ATS), and her two-year-old son who has already been diagnosed with Alport syndrome. Fourteen years ago, the patient underwent a partial esophageal resection followed by a replacement with jejunum. Recently, she underwent a surgical resection of the esophagus due to esophageal dysfunction. Genetic analyses of COL4A5 and COL4A6 on the X-chromosome were efficiently performed using the genomic DNA of her son. We have identified a novel deletion of 194-kb in length, encompassing COL4A5-COL4A6 promoters as well as nearly the entire large intron 1 of COL4A5 and intron 2 of COL4A6. To uncover the relationship of the esophagus-specific occurrence of the tumor and the expression of those genes, immunohistochemical analyses of type IV collagen α chains were conducted in the non-affected individuals. The esophageal smooth muscle-specific expression of α5(IV) and α6(IV) chains in the gastrointestinal tract was observed. Moreover, CAG repeat analysis of the androgen receptor gene and an immunohistochemical analysis in the leiomyoma revealed clonal overgrowth of the cells which received X-inactivation on the non-affected allele. These results may suggest that the dominant effect was caused by the partial deletion of the esophageal smooth muscle-specific genes, COL4A5 and COL4A6.

DOI： 10.1016/j.matbio.2010.09.003

Development of an active targeting liposome encapsulated with high-density colloidal gold for transmission electron microscopy. 査読

Hideki Minematsu, Takayuki Otani, Toshitaka Oohashi, Masahiko Hirai, Kazunori Oie, Koichi Igarashi, Aiji Ohtsuka

Journal of electron microscopy 60 ( 1 ) 95 - 9 2011年

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

Active targeting of the liposome is an attractive strategy for drug delivery and in vivo bio-imaging. We previously reported the specific accumulation of Sialyl Lewis X (SLX) liposome to inflamed tissue in arthritic model mice or tumor-bearing mice. SLX-liposome encapsulation with fluorescent substances allows for the visualization of these liposomes by the time-dependent transvascular accumulation of fluorescent signals in the histological sections. In the present study, we developed a new SLX-liposome encapsulated with colloidal gold for transmission electron microscopic observation. We herein describe the characterization of the colloidal gold-loaded SLX-liposomes and demonstrate its specific targeting to the endothelial cells of tumor blood vessels in tumor-bearing mice.

DOI： 10.1093/jmicro/dfq071

Bral1: its role in diffusion barrier formation and conduction velocity in the CNS. 査読国際誌

Yoko Bekku, Lýdia Vargová, Yoshinobu Goto, Ivan Vorísek, Lesia Dmytrenko, Masahiro Narasaki, Aiji Ohtsuka, Reinhard Fässler, Yoshifumi Ninomiya, Eva Syková, Toshitaka Oohashi

The Journal of neuroscience : the official journal of the Society for Neuroscience 30 ( 8 ) 3113 - 23 2010年2月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SOC NEUROSCIENCE

At the nodes of Ranvier, excitable axon membranes are exposed directly to the extracellular fluid. Cations are accumulated and depleted in the local extracellular nodal region during action potential propagation, but the impact of the extranodal micromilieu on signal propagation still remains unclear. Brain-specific hyaluronan-binding link protein, Bral1, colocalizes and forms complexes with negatively charged extracellular matrix (ECM) proteins, such as versican V2 and brevican, at the nodes of Ranvier in the myelinated white matter. The link protein family, including Bral1, appears to be the linchpin of these hyaluronan-bound ECM complexes. Here we report that the hyaluronan-associated ECM no longer shows a nodal pattern and that CNS nerve conduction is markedly decreased in Bral1-deficient mice even though there were no differences between wild-type and mutant mice in the clustering or transition of ion channels at the nodes or in the tissue morphology around the nodes of Ranvier. However, changes in the extracellular space diffusion parameters, measured by the real-time iontophoretic method and diffusion-weighted magnetic resonance imaging (MRI), suggest a reduction in the diffusion hindrances in the white matter of mutant mice. These findings provide a better understanding of the mechanisms underlying the accumulation of cations due to diffusion barriers around the nodes during saltatory conduction, which further implies the importance of the Bral1-based extramilieu for neuronal conductivity.

DOI： 10.1523/JNEUROSCI.5598-09.2010

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