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Papers - KIKUCHI Shin

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Histone deacetylase inhibition prevents cell death induced by loss of tricellular tight junction proteins in temperature-sensitive mouse cochlear cells.

Kenichi Takano, Takuya Kakuki, Yakuto Kaneko, Takayuki Kohno, Shin Kikuchi, Tetsuo Himi, Takashi Kojima

PloS one ( PUBLIC LIBRARY SCIENCE ) 12 ( 8 ) e0182291 2017.08 [Refereed] [International journal]

Tricellular tight junctions (tTJs) are specialized structures that occur where the corners of three cells meet to seal adjacent intercellular space. The molecular components of tTJs include tricellulin (TRIC) and lipolysis-stimulated lipoprotein receptor (LSR) which recruits TRIC, are required for normal hearing. Although loss of TRIC causes hearing loss with degeneration of cochlear cells, the detailed mechanisms remains unclear. In the present study, by using temperature-sensitive mouse cochlear cells, US/VOT-E36 cell line, we investigated the changes of TRIC and LSR during cochlear cell differentiation and the effects of histone deacetylase (HDAC) inhibitors against cell degeneration induced by loss of TRIC and LSR. During cell differentiation induced by the temperature change, expression of TRIC and LSR were clearly induced. Treatment with metformin enhanced expression TRIC and LSR via AMPK during cell differentiation. Loss of TRIC and LSR by the siRNAs induced cell death in differentiated cells. Treatment with HDAC inhibitors trichostatin A and HDAC6 inhibitor prevented the cell death induced by loss of TRIC and LSR. Collectively, these findings suggest that both tTJ proteins TRIC and LSR have crucial roles for the differentiated cochlear cell survival, and that HDAC inhibitors may be potential therapeutic agents to prevent hearing loss.

DOI PubMed

The bicellular tensile force sorts the localization of LSRs in bicellular and tricellular junctions.

Takayuki Kohno, Shin Kikuchi, Takafumi Ninomiya, Takashi Kojima

Annals of the New York Academy of Sciences ( WILEY ) 1397 ( 1 ) 185 - 194 2017.06 [Refereed] [International journal]

Lipolysis-stimulated lipoprotein receptors (LSRs) localize to tricellular tight junctions. Recent studies have shown that changes in the localization and expression profiles of LSRs are associated with malignancy of endometrial carcinomas, although the precise mechanisms by which malignant progression induces changes in the localization of LSRs are still unknown. In this study, we found that changes in cell tension correlated with alterations in the junctional localization of LSRs in endometrial cancer Sawano cells. At high cell densities, myosin phosphatase target subunit 1 (MYPT1) localized to bicellular junctions, whereas activated myosin regulatory light chain 2 (MRLC2) was dislocated from these regions, suggesting that circumferential tensile forces decreased at high cell densities. Under these conditions, LSRs localized to tricellular junctions. In contrast, a phosphorylated form of MRLC2 localized to bicellular regions, while MYPT1 was excluded from these regions, suggesting that tensile forces formed along the circumferential edge at low cell densities. It is noteworthy that, when cells were cultured under these conditions, LSRs localized to bicellular regions. Upon treatment with a myosin inhibitor, LSR localization in bicellular junctions decreased at low cell densities. Overall, our results indicate that the modulation of cellular tension was involved in the translocation of LSRs from bicellular to tricellular tight junctions.

DOI PubMed

1．クラウド活用のために：「情報薬」の開発と応用

辰巳治之, 溝口照悟, 新見隆彦, 太田秀造, 竹中郁夫, 菊池真, 市川量一, 二宮孝文, 戸倉一, 山口徳蔵

日本皮膚科学会雑誌 ( 公益社団法人日本皮膚科学会 ) 127 ( 11 ) 2455 - 2461 2017

クラウドを流れる情報を，どの様に活用するかが重要である．そこで，原点に戻り，情報の定義を「人の心を動かすもの」とすると，分子生物学的に「細胞を動かすもの」といえ，医療に活用できるところから「情報薬」という発想に辿り着いた．例えば，医療情報の氾濫による弊害は一種の社会病であり，「情報薬」により予防できる．そこでクラウド活用のためのワイドスペクトラムな「情報薬」について説明し，その応用について述べる．

DOI CiNii

Staurosporine induces formation of two types of extra-long cell protrusions: actin-based filaments and microtubule-based shafts.

Takayuki Kohno, Takafumi Ninomiya, Shin Kikuchi, Takumi Konno, Takashi Kojima

Molecular pharmacology ( AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS ) 87 ( 5 ) 815 - 24 2015.05 [Refereed] [International journal]

Staurosporine (STS) has been known as a classic protein kinase C inhibitor and is a broad-spectrum inhibitor targeting over 250 protein kinases. In this study, we observed that STS treatment induced drastic morphologic changes, such as elongation of a very large number of nonbranched, actin-based long cell protrusions that reached up to 30 mu m in an hour without caspase activation or PARP cleavage in fibroblasts and epithelial cells. These cell protrusions were elongated not only from the free cell edge but also from the cell-cell junctions. The elongation of STS-dependent protrusions was required for ATP hydrolysis and was dependent on myosin-X and fascin but independent of Cdc42 and VASP. Interestingly, in the presence of an actin polymerization inhibitor, namely, cytochalasin D, latrunculin A, or jasplakinolide, STS treatment induced excess tubulin polymerization, which resulted in the formation of many extra-long microtubule (MT)-based protrusions toward the outside of the cell. The unique MT-based protrusions were thick and linear compared with the STS-induced filaments or stationary filopodia. These protrusions, which were composed of microtubules, have been scarcely observed in cultured non-neuronal cells. Taken together, our findings revealed that STS-sensitive kinases are essential for the maintenance of normal cell morphology, and a common unidentified molecular mechanism is involved in the formation of the following two different types of protrusions: actin-based filaments and MT-based shafts.

DOI PubMed

c-Jun N-terminal kinase inhibitor SP600125 enhances barrier function and elongation of human pancreatic cancer cell line HPAC in a Ca-switch model.

Takumi Konno, Takafumi Ninomiya, Takayuki Kohno, Shin Kikuchi, Norimasa Sawada, Takashi Kojima

Histochemistry and cell biology ( SPRINGER ) 143 ( 5 ) 471 - 9 2015.05 [Refereed] [International journal]

c-Jun N-terminal kinase (JNK), known as a stress-activated protein kinase, regulates normal epithelial biological processes, including assembly of adherens and tight junctions, and it is involved in the development of several cancers. The JNK inhibitor SP600125 enhances epithelial barrier function through modulation of tight junction molecules in normal human pancreatic epithelial cells. Furthermore, this JNK inhibitor suppresses the growth of human pancreatic cancer cells. However, the effects of SP600125 on the epithelial barrier in human pancreatic cancer cells remain unknown. In the present study, the JNK inhibitor SP600125 markedly enhanced the barrier function and cell elongation of well-differentiated human pancreatic cancer cell line HPAC in a Ca-switch model. The epithelial barrier function induced by SP600125 was regulated by phosphorylated beta-catenin without changes in the tight junction molecules. The cell elongation induced by SP600125 was closely related to the expression of the F-actin-binding protein DrebrinE. These findings suggest that JNK is involved in the regulation of the epithelial barrier function and cell shape during remodeling of pancreatic cancer cells. The JNK inhibitor SP600125 may have potential as a therapeutic drug for pancreatic cancer via induction of differentiation.

DOI PubMed

Mitochondrial fission augments capsaicin-induced axonal degeneration.

Hao Chiang, Nobuhiko Ohno, Yu-Lin Hsieh, Don J Mahad, Shin Kikuchi, Hitoshi Komuro, Sung-Tsang Hsieh, Bruce D Trapp

Acta neuropathologica ( SPRINGER ) 129 ( 1 ) 81 - 96 2015.01 [Refereed] [International journal]

Capsaicin, an agonist of transient receptor potential vanilloid receptor 1, induces axonal degeneration of peripheral sensory nerves and is commonly used to treat painful sensory neuropathies. In this study, we investigated the role of mitochondrial dynamics in capsaicin-induced axonal degeneration. In capsaicin-treated rodent sensory axons, axonal swellings, decreased mitochondrial stationary site length and reduced mitochondrial transport preceded axonal degeneration. Increased axoplasmic Ca2+ mediated the alterations in mitochondrial length and transport. While sustaining mitochondrial transport did not reduce axonal swellings in capsaicin-treated axons, preventing mitochondrial fission by overexpression of mutant dynamin-related protein 1 increased mitochondrial length, retained mitochondrial membrane potentials and reduced axonal loss upon capsaicin treatment. These results establish that mitochondrial stationary site size significantly affects axonal integrity and suggest that inhibition of Ca2+-dependent mitochondrial fission facilitates mitochondrial function and axonal survival following activation of axonal cationic channels.

DOI PubMed

髄鞘形成期における初代培養ラット後根神経節細胞への組み替えアデノウイルスを用いた変異MPZ cDNAの導入

菊池真, 小塚直樹, 二宮孝文, 山下利春, 武田秀勝, 舘延忠

札幌医科大学保健医療学紀要 13 21 - 27 2011 [Refereed]

Tricellulin is expressed in autotypic tight junctions of peripheral myelinating Schwann cells.

Shin Kikuchi, Takafumi Ninomiya, Haruyuki Tatsumi, Norimasa Sawada, Takashi Kojima

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society ( SAGE PUBLICATIONS LTD ) 58 ( 12 ) 1067 - 73 2010.12 [Refereed] [International journal]

Autotypic tight junctions are formed by tight junction-like structures in three regions of myelinating Schwann cells, the paranodal loops, Schmidt-Lanterman incisures, and outer/inner mesaxons, and various tight junction molecules, including claudin-19 and junctional adhesion molecule (JAM)-C. Our findings demonstrate the identification and subcellular distribution of a novel tricellular tight junction protein, tricellulin (TRIC), in the autotypic tight junctions of mouse myelinating Schwann cells, compared with the autotypic adherens junction protein E-cadherin and the autotypic tight junction protein JAM-C, which are expressed in the paranodal loops, Schmidt-Lanterman incisures, and mesaxons. In real-time RT-PCR, the expression level of TRIC mRNA was about 10-fold higher in the sciatic nerve than in the spinal cord or cerebrum. In immunostaining, TRIC signals were completely restricted to the peripheral nervous system (PNS) and strongly concentrated at the paranodal loops, Schmidt-Lanterman incisures, and mesaxons of myelinating Schwann cells. In addition, TRIC was expressed in the thin region of the paranode and there was a gap between TRIC and the Na(+) channel. Furthermore, TRIC was more distally located from the node than E-cadherin and was colocalized with JAM-C. It is possible that TRIC may be a component to maintain the integrity for PNS myelin function and morphology. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 58:1067-1073, 2010)

DOI PubMed

c-Jun N-terminal kinase is largely involved in the regulation of tricellular tight junctions via tricellulin in human pancreatic duct epithelial cells.

Takashi Kojima, Jun Fuchimoto, Hiroshi Yamaguchi, Tatsuya Ito, Akira Takasawa, Takafumi Ninomiya, Shin Kikuchi, Noriko Ogasawara, Tsuyoshi Ohkuni, Tomoyuki Masaki, Koichi Hirata, Tetsuo Himi, Norimasa Sawada

Journal of cellular physiology ( WILEY-LISS ) 225 ( 3 ) 720 - 33 2010.11 [Refereed] [International journal]

Tricellulin (TRIC) is a tight junction protein at tricellular contacts where three epithelial cells meet, and it is required for the maintenance of the epithelial barrier. To investigate whether TRIC is regulated via a c-Jun N-terminal kinase (JNK) pathway, human pancreatic HPAC cells, highly expressed at tricellular contacts, were exposed to various stimuli such as the JNK activators anisomycin and 12-O-tetradecanoylphorbol 13-acetate (TPA), and the proinflammatory cytokines IL-1 beta, TNF alpha, and IL-1 alpha. TRIC expression and the barrier function were moderated by treatment with the JNK activator anisomycin, and suppressed not only by inhibitors of JNK and PKC but also by siRNAs of TRIC. TRIC expression was induced by treatment with the PKC activator TPA and proinflammatory cytokines IL-1 beta, TNF alpha, and IL-1 alpha, whereas the changes were inhibited by a JNK inhibitor. Furthermore, in normal human pancreatic duct epithelial cells using hTERT-transfected primary cultured cells, the responses of TRIC expression to the various stimuli were similar to those in HPAC cells. TRIC expression in tricellular tight junctions is strongly regulated together with the barrier function via the JNK transduction pathway. These findings suggest that JNK may be involved in the regulation of tricellular tight junctions including TRIC expression and the barrier function during normal remodeling of epithelial cells, and prevent disruption of the epithelial barrier in inflammation and other disorders in pancreatic duct epithelial cells. J. Cell. Physiol. 225: 720-733, 2010. (C) 2010 Wiley-Liss, Inc.

DOI PubMed

The acid-sensing ion channel 2 (ASIC2) of ciliated cells in the developing rat nasal septum.

Shin Kikuchi, Takafumi Ninomiya, Tomoyuki Kawamata, Noriko Ogasawara, Takashi Kojima, Nobutada Tachi, Haruyuki Tatsumi

Archives of histology and cytology ( INT SOC HISTOLOGY & CYTOLOGY ) 73 ( 2 ) 81 - 9 2010 [Refereed] [Domestic journal]

The airway epithelium is exposed to an acidic environment in certain conditions. The acid-sensing ion channel 2 (ASIC2) belongs to the epithelial amiloride-sensitive sodium channel and degenerin (ENaC/DEG) family and is expressed on cilia of the respiratory epithelium. The aim of this study was to detect the expression of ASIC2 in the nasal septum in the embryonic stage of the rat. ASIC2 expression was not observed in the primary cilium but was found in some cilia on embryonic day 17 (E17). After E18, all cilia showed ASIC2 immunoreactivity. RT-PCR analysis revealed that ASIC2b, a subtype of ASIC2, was expressed in the nasal septum while ASIC2a was not. Quantitative Real-time RT-PCR studies indicated that the expression level of ASIC2 mRNA was highest on E21, just before birth. These results imply that ASIC2 plays little part in the development of the nasal septum epithelium. On the other hand, ASIC2, especially ASIC2b, may function for the survival and retention of ciliated cells of the nasal septum against dynamic changes in the pH environment at birth.

DOI PubMed

Expression and localization of tricellulin in human nasal epithelial cells in vivo and in vitro

Tsuyoshi Ohkuni, Takashi Kojima, Noriko Ogasawara, Tomoyuki Masaki, Takafumi Ninomiya, Shin Kikuchi, Mitsuru Go, Ken-ichi Takano, Tetsuo Himi, Norimasa Sawada

MEDICAL MOLECULAR MORPHOLOGY ( SPRINGER TOKYO ) 42 ( 4 ) 204 - 211 2009.12 [Refereed]

Tricellulin was identified as the first marker of the tricellular tight junction, which forms at the meeting points of three cells, and it is required for the maintenance of the transepithelial barrier. Although it is also considered to be important for the mucosal barrier of the upper respiratory tract, little is known about its expression and localization. In the present study, we examined the expression and localization of tricellulin in normal human nasal epithelial cells in vivo and in vitro, especially using primary cultures and telomerase reverse transcriptase (hTERT)-transfected cells. In human nasal epithelial cells in vivo and in vitro, mRNA and protein of tricellulin were detected. It was localized not only at tricellular contacts but also at bicellular borders, and in part colocalized with occludin. In human nasal epithelium, by immunoelectron microscopy analysis, tricellulin-associated gold particles were observed around the junction-like structure of the uppermost region. By treatment with 10% fetal bovine serum (FBS), expression of tricellulin mRNA was weakly increased, whereas that of bicellular tight junction molecules was strongly increased, in real-time PCR. These results suggest that tricellulin is stably expressed in human nasal epithelial cells and may play an important role for the sealing of the corner at tricellular contacts to prevent infiltration by various inhaled viruses and antigens.

DOI PubMed

Expression of ASIC2 in ciliated cells and stereociliated cells

Shin Kikuchi, Takafumi Ninomiya, Tomoyuki Kawamata, Haruyuki Tatsumi

CELL AND TISSUE RESEARCH ( SPRINGER ) 333 ( 2 ) 217 - 224 2008.08 [Refereed]

Acid-sensing ion channel 2 (ASIC2) plays a role as a mechanorecptor and acid receptor in the peripheral and central nervous systems. However, several recent studies have suggested that ASIC2 is expressed in several organs, in addition to the nervous system. We have examined the expression and distribution of ASIC2 in rat ciliated cells (trachea and oviduct) and stereociliated cells (epididymis, Corti organ, and ampullary crest) by immunohistochemistry and transmission electron microscopy (TEM). Imunohistochemistry revealed that ASIC2 was expressed in both ciliated cells and stereociliated cells, but the localization differed between these cell types. In ciliated cells, ASIC2 was coexpressed with a cilial marker (acetylated tubulin). In stereociliated cells stained with a stereocilial marker (phalloidin), ASIC2 was observed in the cell body. Observation by TEM suggested that ASIC2 expression was present at the apical side of the cilial membrane in ciliated cells and at the apical side of the cell body in stereociliated cells. This study thus indicates that the proton receptor ASIC2 is expressed in both ciliated and stereociliated cells.

DOI PubMed

Expression of tight junction proteins in epithelium including Ck20-positive M-like cells of human adenoids in vivo and in vitro

Ken-ichi Takano, Takashi Kojima, Noriko Ogasawara, Mitsuru Go, Shin Kikuchi, Takafumi Ninomiya, Makoto Kurose, Jun-ichi Koizumi, Ryuta Kamekura, Masaki Murata, Satoshi Tanaka, Hideki Chiba, Tetsuo Himi, Norimasa Sawada

JOURNAL OF MOLECULAR HISTOLOGY ( SPRINGER ) 39 ( 3 ) 265 - 273 2008.06 [Refereed]

The human adenoid epithelium forms a continuous barrier against a wide variety of exogenous antigens. In this study, to elucidate the structures of the epithelial barrier in the human adenoid, including M-cells, we identified M-cells using an anti-cytokeratin 20 (Ck20) antibody and investigated expression of tight junction proteins in human adenoid epithelium in vivo and in vitro. In human adenoid epithelium and primary cultures, mRNAs of occludin, junctional adhesion molecule-A, ZO-1, and claudin-1, -4, -7, and -8 were detected by reverse transcription-polymerase chain reaction, whereas claudin-2 and -9 were expressed in vitro. In the epithelium in vivo, some Ck20-positive cells were randomly observed and indicated pocket-like structures, whereas Ck7 was positive in almost cells. Transmission electron microscopy revealed that Ck20-associated gold particles could be identified in M-like cells which had short microvilli and harboured the lymphocyte in the pocket-like structure. In primary cultures in vitro, Ck20-positive cells were also detected and had a function to take up fluorescent microparticles. In Ck20-positive cells in vivo and in vitro, expression of occludin, ZO-1, claudin-1 and -7 were observed at cell borders. These results indicate that the epithelial barrier of the human adenoid is stably maintained by expression of tight junction proteins in the epithelium including Ck20-positive M-like cells.

DOI PubMed

The change of grip strength in a patient with congenital myotonic dystrophy over a 4-year period

Shin Kikuchi, Naoki Kozuka, Eiji Uchida, Takafumi Ninomiya, Haruyuki Tatsumi, Hidekatsu Takeda, Nobutada Tachi

Journal of the Japanese Physical Therapy Association ( 1 ) 11 ( 1 ) 23 - 27 2008 [Refereed]

Myotonic dystrophy (MyD) is a neuromuscular disease that is autosomal dominant and the most common form of muscular dystrophy affecting adults. The clinical features of MyD include a multisystemic disorder characterized by myotonia, progressive muscle weakness and wasting, cataracts, premature balding and mental retardation. The most severe type of MyD is classified as congenital MyD (CMyD). The muscle weakness in CMyD is very severe, but muscle development can be observed in the period of growth. However, no clinical case of this type has been reported yet. Therefore, we report on a girl with CMyD who had an increase in muscle strength over a four-year period. The girl with CMyD participated in this study from the age of 9 to the age of 12. The measurement of muscle strength was recorded as the maximum score of grip strength with the use of dynamometers. Grip strength was assessed once a year by the same two physical therapists. Grip strength of CMyD for each year was markedly weak when compared with the normal controls, but muscle strength changed within some specific growth areas. The muscle weakness in CMyD was remarkable, but the result showed that specific muscle strength of CMyD in childhood was actually increased.

DOI PubMed

Spinal muscular atrophy with respiratory distress type 1(SMARD1)の臨床

舘延忠, 菊池真, 仙石泰仁, 小塚直樹, 野上亜津彩

小児科診療 69 131 - 132 2006 [Refereed]

A new mutation of IGHMBP2 gene in spinal muscular atrophy with respiratory distress type 1

N Tachi, S Kikuchi, N Kozuka, A Nogami

PEDIATRIC NEUROLOGY ( ELSEVIER SCIENCE INC ) 32 ( 4 ) 288 - 290 2005.04 [Refereed]

This report presents a new mutation in the first Japanese female infant with spinal muscular atrophy with respiratory distress type 1. She manifested the characteristic clinical features, including early-onset respiratory failure due to diaphragmatic paralysis and severe distal muscle weakness. Muscle biopsy in the femoral muscle indicated massive neurogenic changes. Sural nerve biopsy disclosed a moderate reduction of myelinated fibers, predominantly reduced large fibers. She had a novel homozygous missense mutation 2685 C -> A, leading to a T879K substitution in the immunoglobulin mu-binding protein 2 gene. Both parents were heterozygous for this mutation. (c) 2005 by Elsevier Inc. All rights reserved.

DOI PubMed

急性の脳障害を呈した小児のリハビリテーション

谷口志穂, 小塚直樹, 横串算敏, 菊池真, 坪田貞子, 加藤正巳

北海道リハビリテーション学会雑誌 33 57 - 61 2005 [Refereed]

aprataxin遺伝子変異689ins T患者の小脳症状、末梢神経症状に関する報告

堀本佳誉, 小塚直樹, 菊池真, 舘延忠

北海道理学療法 22 58 - 62 2005 [Refereed]

先天性筋強直性ジストロフィー症における3年間の筋力変化

菊池真, 小塚直樹, 舘延忠, 堀本佳誉, 内田英二, 仙石泰仁, 武田秀勝

北海道理学療法 21 69 - 73 2004 [Refereed]

Non-radioactive PCR southern method for analysis of CTG repeat in myotonic dystrophy

Naoki Kozuka, Nobutada Tachi, Kazuhiro Ohya, Eiji Uchida, Shin Kikuchi, Yasuhito Sengoku

No To Hattatsu ( 5 ) 35 ( 5 ) 380 - 387 2003 [Refereed]

Myotonic dystrophy (MyD) is a hereditary neuromuscular disorder of an autosomal dominant trait. MyD is caused by an expansion of unstable CTG trinucleotide repeat in the 3′ untranslated region of mRNA coding myotonin protein kinase (MT-PK). We analyzed CTG repeat expansion in 10 patients with congenital MyD and their relatives using the non-radioactive PCR Southern method. The region containing the CTG repeat was amplified by PCR using specific primers. The PCR products were electrophoresed on a 1% agarose gel and transferred to a nylon membrane. The CTG repeat expansion was shown using a fluorescein-labelled (CTG) 10 probe. To estimate the number of CTG repeats, we compared the smears obtained on Southern blotting with a picture of PCR products and a DNA size marker (100 bp). We compared our results of radioactive Southern blotting for genomic DNA digested by Eco RI or Bgl I and for PCR products. In congenital MyD patients, heterogeneous smears (3.89-10.22kb: about 1252-3362 CTG repeat) were observed, whereas in the adult type MyD had heterogeneous smears (0.92-1.82kb: about 262-562 CTG repeat). In asymptomatic MyD patients, there were heterogeneous smears (0.35-1.16kb: about 72-342 CTG repeat). These results demonstrated anticipation. We conclude that the non-radioactive PCR Southern method is useful and convenient for the DNA diagnosis of MyD.

DOI PubMed

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Papers - KIKUCHI Shin