A tailored tetravalent peptide displays dual functions to inhibit amyloid β production and aggregation.
Sato W; Watanabe-Takahashi M; Murata T; Utsunomiya-Tate N; Motoyama J; Anzai M; Ishihara S; Nishioka N; Uchiyama H; Togashi J; Nishihara S; Kawasaki K; Saito T; Saido T. C; Funamoto S*; Nishikawa K*
Commun. Biol., 6(1)383(1) 383 - 383, Apr. 2023, Scientific journal
Novel multivalent S100A8 inhibitory peptides attenuate tumor progression and metastasis by inhibiting the TLR4-dependent pathway.
Atsuko Deguchi; Miho Watanabe-Takahashi; Taishi Mishima; Tsutomu Omori; Umeharu Ohto; Nobuto Arashiki; Fumio Nakamura; Kiyotaka Nishikawa; Yoshiro Maru
Cancer gene therapy, 30 973 - 984, 17 Mar. 2023, Scientific journal
Hepatitis B Virus Utilizes a Retrograde Trafficking Route via the Trans-Golgi Network to Avoid Lysosomal Degradation.
Ying-Yi Li; Kazuyuki Kuroki; Tetsuro Shimakami; Kazuhisa Murai; Kazunori Kawaguchi; Takayoshi Shirasaki; Kouki Nio; Saiho Sugimoto; Tomoki Nishikawa; Hikari Okada; Noriaki Orita; Hideo Takayama; Ying Wang; Phuong Doan Thi Bich; Astuya Ishida; Sadahiro Iwabuchi; Shinichi Hashimoto; Takeshi Shimaoka; Noriko Tabata; Miho Watanabe-Takahashi; Kiyotaka Nishikawa; Hiroshi Yanagawa; Motoharu Seiki; Kouji Matsushima; Taro Yamashita; Shuichi Kaneko; Masao Honda
Cellular and molecular gastroenterology and hepatology, 15(3) 533 - 558, 2023, Scientific journal
A tetravalent peptide that binds to the RANK-binding region of TRAF6 via a multivalent interaction efficiently inhibits osteoclast differentiation.
Anzai M; Watanabe-Takahashi M; Kawabata H; Mizuno S; Taguchi Y; Inoue J; Nishikawa K
Biochem. Biophys. Res. Commun., 636(Pt 1) 178 - 183, Nov. 2022, Scientific journal
Development of a novel tetravalent peptide that absorbs subtilase cytotoxin by targeting the receptor-binding B-subunit
Shinichiro Hama; Miki Nakahara; Miho Watanabe-Takahashi; Eiko Shimizu; Hiroyasu Tsutsuki; Kinnosuke Yahiro; Kiyotaka Nishikawa
Biochemical and Biophysical Research Communications, Elsevier BV, 629(12) 95 - 100, Sep. 2022, Scientific journal
A unique peptide-based pharmacophore identifies an inhibitory compound against the A-subunit of Shiga toxin
Watanabe-Takahashi M; Senda M; Yoshino R; Hibino M; Hama S; Terada T; Shimizu K; Senda T; Nishikawa K
Scientific Reports, Springer Science and Business Media LLC, 12:11443(1), Jul. 2022, Scientific journal
Identification of a peptide motif that potently inhibits two functionally distinct subunits of Shiga toxin
Miho Watanabe-Takahashi; Masakazu Tamada; Miki Senda; Masahiro Hibino; Eiko Shimizu; Akiko Okuta; Atsuo Miyazawa; Toshiya Senda; Kiyotaka Nishikawa
Communications Biology, Springer Science and Business Media LLC, 4(1), Dec. 2021, Scientific journal
A nontoxigenic form of Shiga toxin 2 suppresses the production of amyloid β by altering the intracellular transport of amyloid precursor protein through its receptor-binding B-subunit
Waka Sato; Miho Watanabe-Takahashi; Takashi Hamabata; Koichi Furukawa; Satoru Funamoto; Kiyotaka Nishikawa
Biochemical and Biophysical Research Communications, Elsevier BV, 557 247 - 253, Jun. 2021, Scientific journal
The Inducible Amphisome Isolates Viral Hemagglutinin and Defends Against Influenza A Virus Infection.
Omi J; Watanabe-Takahashi M; Igai K; Shimizu E; Ching-Yi Tseng; Miyasaka, T; Waku T; Hama S; Nakanishi R; Goto Y; Nishino Y; Miyazawa A; Natori Y; Yamashita M; Kiyotaka Nishikawa K
Nat. Commun., 11(1)162(1) doi; 10.1038/s41467-019-13974- - 162, Jan. 2020, Scientific journal
Synthetic construction of sugar-amino acid hybrid polymers involving globotriaose or lactose and evaluation of their biological activities against Shiga toxins produced by Escherichia coli O157:H7
Koji Matsuoka; Kiyotaka Nishikawa; Yusuke Goshu; Tetsuo Koyama; Ken Hatano; Takahiko Matsushita; Miho Watanabe-Takahashi; Yasuhiro Natori; Daiyo Terunuma
Bioorganic & Medicinal Chemistry, Elsevier BV, 26(22) 5792 - 5803, Dec. 2018, Scientific journal
Exosome-associated Shiga toxin 2 is released from cells and causes severe toxicity in mice.
Miho Watanabe-Takahashi; Shinji Yamasaki; Masayuki Murata; Fumi Kano; Jun Motoyama; Jyoji Yamate; Jumpei Omi; Waka Sato; Hirofumi Ukai; Kentaro Shimasaki; Masaya Ikegawa; Miwa Tamura-Nakano; Ryohei Yanoshita; Yuri Nishino; Atsuo Miyazawa; Yasuhiro Natori; Noriko Toyama-Sorimachi; Kiyotaka Nishikawa
Scientific reports, 8(1) 10776 - 10776, 17 Jul. 2018, Scientific journal
The pleckstrin homology domain of p210 BCR-ABL interacts with cardiolipin to regulate its mitochondrial translocation and subsequent mitophagy.
Shimasaki K; Watanabe-Takahashi M; Umeda M; Funamoto S; Saito Y; Noguchi N; Kumagai K; hanada K; Tsukahara F; Maru Y; Shibata N; Naito M; Nishikawa K
Genes to Cells, 23(1) 22 - 34, Jan. 2018
Acquired Resistance to Shiga toxin-induced apoptosis by loss of CD77 expression in Human myelogenous leukemia cell line, THP-1.
Takahashi M; Hattori T; Watanabe-Takahashi M; Nishikawa K; Nito M
Biological and Pharmaceutical Bulletin, 41;9 1475 - 1479, 2018
Affinity-Based Screening of Tetravalent Peptides Identifies SubtypeS-elective Neutralizers of Shiga Toxin 2d, a Highly Virulent Subtype, by Targeting a Unique Amino Acid Involved in Its Receptor Recognition
Takaaki Mitsui; Miho Watanabe-Takahashi; Eiko Shimizu; Baihao Zhang; Satoru Funamoto; Shinji Yamasaki; Kiyotaka Nishikawa
INFECTION AND IMMUNITY, AMER SOC MICROBIOLOGY, 84(9) 2653 - 2661, Sep. 2016, Scientific journal
M-COPA, a novel Golgi system disruptor, suppresses apoptosis induced by Shiga toxin
Takayuki Hattori; Miho Watanabe-Takahashi; Isamu Shiina; Yoshimi Ohashi; Shingo Dan; Kiyotaka Nishikawa; Takao Yamori; Mikihiko Naito
GENES TO CELLS, WILEY, 21(8) 901 - 906, Aug. 2016, Scientific journal
Development of a Novel Tetravalent Synthetic Peptide That Binds to Phosphatidic Acid
Rina Ogawa; Kohjiro Nagao; Kentaro Taniuchi; Masaki Tsuchiya; Utako Kato; Yuji Hara; Takehiko Inaba; Toshihide Kobayashi; Yoshihiro Sasaki; Kazunari Akiyoshi; Miho Watanabe-Takahashi; Kiyotaka Nishikawa; Masato Umeda
PLOS ONE, PUBLIC LIBRARY SCIENCE, 10(7), Jul. 2015, Scientific journal
Identification of a Wide Range of Motifs Inhibitory to Shiga Toxin by Affinity-Driven Screening of Customized Divalent Peptides Synthesized on a Membrane
Mihoko Kato; Miho Watanabe-Takahashi; Eiko Shimizu; Kiyotaka Nishikawa
APPLIED AND ENVIRONMENTAL MICROBIOLOGY, AMER SOC MICROBIOLOGY, 81(3) 1092 - 1100, Feb. 2015, Scientific journal
Proteasome inhibitors prevent cell death and prolong survival of mice challenged by Shiga toxin
Takayuki Hattori; Miho Watanabe-Takahashi; Nobumichi Ohoka; Takashi Hamabata; Koichi Furukawa; Kiyotaka Nishikawa; Mikihiko Naito
FEBS OPEN BIO, ELSEVIER SCIENCE LONDON, 5 605 - 614, 2015, Scientific journal
Identification of a Peptide-Based Neutralizer That Potently Inhibits Both Shiga Toxins 1 and 2 by Targeting Specific Receptor-Binding Regions
Kazue Tsutsuki; Miho Watanabe-Takahashi; Yasuaki Takenaka; Eiji Kita; Kiyotaka Nishikawa
INFECTION AND IMMUNITY, AMER SOC MICROBIOLOGY, 81(6) 2133 - 2138, Jun. 2013, Scientific journal
Substrate ectodomain is critical for substrate preference and inhibition of γ-secretase
Satoru Funamoto; Toru Sasaki; Seiko Ishihara; Mika Nobuhara; Masaki Nakano; Miho Watanabe-Takahashi; Takashi Saito; Nobuto Kakuda; Tomohiro Miyasaka; Kiyotaka Nishikawa; Takaomi C. Saido; Yasuo Ihara
Nature Communications, 4, 2013, Scientific journal
An Orally Applicable Shiga Toxin Neutralizer Functions in the Intestine To Inhibit the Intracellular Transport of the Toxin
Miho Watanabe-Takahashi; Toshio Sato; Taeko Dohi; Noriko Noguchi; Fumi Kano; Masayuki Murata; Takashi Hamabata; Yasuhiro Natori; Kiyotaka Nishikawa
INFECTION AND IMMUNITY, AMER SOC MICROBIOLOGY, 78(1) 177 - 183, Jan. 2010, Scientific journal
Yip1A regulates the COPI-independent retrograde transport from the Golgi complex to the ER
Fumi Kano; Shinobu Yamauchi; Yumi Yoshida; Miho Watanabe-Takahashi; Kiyotaka Nishikawa; Nobuhiro Nakamura; Masayuki Murata
JOURNAL OF CELL SCIENCE, COMPANY OF BIOLOGISTS LTD, 122(13) 2218 - 2227, Jul. 2009, Scientific journal
Regulation of hepatic cholesterol synthesis by a novel protein (SPF) that accelerates cholesterol biosynthesis
Norihito Shibata; Kou-ichi Jishage; Makoto Arita; Miho Watanabe; Yosuke Kawase; Kiyotaka Nishikawa; Yasuhiro Natori; Hiroyasu Inoue; Hitoshi Shimano; Nobuhiro Yamada; Masafumi Tsujimoto; Hiroyuki Arai
FASEB JOURNAL, FEDERATION AMER SOC EXP BIOL, 20(14) 2642 - +, Dec. 2006, Scientific journal
A multivalent peptide library approach identifies a novel Shiga toxin inhibitor that induces aberrant cellular transport of the toxin
Kiyotaka Nishikawa; Miho Watanabe; Eiji Kita; Katsura Igai; Kazumi Omata; Michael B. Yaffe; Yasuhiro Natori
FASEB JOURNAL, FEDERATION AMER SOC EXP BIOL, 20(14) 2597 - +, Dec. 2006, Scientific journal
Development of dialyzer with immobilized glycoconjugate polymers for removal of Shiga-toxin
A Miyagawa; M Watanabe; K Igai; MCZ Kasuya; Y Natori; K Nishikawa; K Hatanaka
BIOMATERIALS, ELSEVIER SCI LTD, 27(17) 3304 - 3311, Jun. 2006, Scientific journal
Structural analysis of the interaction between Shiga toxin B subunits and linear polymers bearing clustered globotriose residues
M Watanabe; K Igai; K Matsuoka; A Miyagawa; T Watanabe; R Yanoshita; Y Samejima; D Terunuma; Y Natori; K Nishikawa
INFECTION AND IMMUNITY, AMER SOC MICROBIOLOGY, 74(3) 1984 - 1988, Mar. 2006, Scientific journal
Identification of the optimal structure required for a Shiga toxin neutralizer with oriented carbohydrates to function in the circulation
K Nishikawa; K Matsuoka; M Watanabe; K Igai; K Hino; K Hatano; A Yamada; N Abe; D Terunuma; H Kuzuhara; Y Natori
JOURNAL OF INFECTIOUS DISEASES, UNIV CHICAGO PRESS, 191(12) 2097 - 2105, Jun. 2005, Scientific journal
Oral therapeutic agents with highly clustered globotriose for treatment of Shiga toxigenic Escherichia coli infections
M Watanabe; K Matsuoka; E Kita; K Igai; N Higashi; A Miyagawa; T Watanabe; R Yanoshita; Y Samejima; D Terunuma; Y Natori; K Nishikawa
JOURNAL OF INFECTIOUS DISEASES, UNIV CHICAGO PRESS, 189(3) 360 - 368, Feb. 2004, Scientific journal
P210 BCR-ABLのPHドメインを標的とした新規ペプチド性CML治療薬の開発
長田 雅也; 高橋 美帆; 島﨑 健太朗; 柴田 識人; 内藤 幹彦; 西川 喜代孝
第41回日本分子生物学会, 2018
受容体結合部位を標的とした新規ペプチド性Subtilase cytotoxin阻害薬の開発
中原美樹; 高橋美帆; 及川英子; 八尋錦之助; 西川喜代孝
第22回腸管出血性大腸菌感染症研究会, 2018
酵素活性部位を標的とした新規ペプチド性Stx阻害薬の開発
日比野雅大; 高橋美帆; 玉田真一; 千田美紀; 奥田明子; 宮澤淳夫; 千田俊哉; 西川喜代孝
第22回腸管出血性大腸菌感染症研究会, 2018
新規CaMK2阻害ペプチドによるA型インフルエンザウイルス感染制御法の確立
濱 信一郎; 近江 純平; 中村 友美; 西村 浩輝; 高橋 美帆; 西川 喜代孝
第91回日本生化学会, 2018
RANK-TRAF6 signalを標的とした破骨細胞分化制御ペプチドの開発
安西 聖敬; 高橋 美帆; 中村友美; 川端 宏; 田口祐; 井上純一郎; 西川喜代孝
第91回日本生化学会, 2018
Exosome-associated Shiga toxin 2 is released from cells and causes severe toxicity in mice.
Miho Watanabe-Takahashi; Shinji Yamasaki; Masayuki Murata; Fumi Kano; Jun Motoyama; Jyoji Yamate; Jumpei Omi; Waka Sato; Hirofumi Ukai; Kentaro Shimasaki; Masaya Ikegawa; Miwa Tamura-Nakano; Ryohei Yanoshita; Yuri Nishino; Atsuo Miyazawa; Yasuhiro Natori; Noriko Toyama-Sorimachi; Kiyotaka Nishikawa
VTEC2018, 2018
Structural analysis of the interaction between Shiga toxin B subunits and linear polymers bearing clustered globotriose residues
VTEC2006, 2006, Poster presentation
Carbohydorate-containing linear polymers that neutralize Shiga toxin
VTEC 2003, 2003, Poster presentation
Patent right
P210 PH結合ペプチドおよび慢性骨髄性白血病治療薬
西川喜代孝, 高橋美帆, 島崎健太朗, 長田雅也
特願2018-210822
Patent right
Stx1毒性阻害ペプチドおよびStx1に起因する疾患の治療薬
西川喜代孝, 高橋美帆, 津々木一恵
特願2010-019315, 特願2010-019315
Patent right
Stx2阻害4価ペプチドおよびこのStx2阻害4価ペプチドを含む治療薬
西川喜代孝, 高橋美帆, 三井貴瑛, 山崎伸二
特願2013-13746, 特願2013-13746
Patent right
LT阻害4価ペプチドおよびETEC感染症治療薬
西川喜代孝, 高橋美帆, 谷川哲也
特願2014-128632, 特願2014-128632
Patent right
CT阻害4価ペプチドおよびコレラ治療薬
西川喜代孝, 高橋美帆, 山本洋, 濱端崇
特願2013-51032, 特願2014-050828
Patent right
CaMKII阻害ペプチドおよびこれを含有するCaMKII阻害剤
西川喜代孝, 高橋美帆, 西村浩輝, 高柳広, 尾藤晴彦
特許第5754008号, 特許第5754008号
Patent right
ヘマグルチニン結合ペプチド、および、これを含むインフルエンザウイルス感染症の予防・治療薬
西川喜代孝, 高橋美帆, 近江純平
特願2016-164971, 特願2016-164971
Patent right
Stx毒性阻害ペプチドおよびStxに起因する疾患の治療薬
西川喜代孝, 高橋美帆, 津々木一恵
特許第5635779号, 特許第5635779号
Patent right
破骨細胞分化制御ペプチド、および、破骨細胞分化に関連する疾患の含有する治療薬
西川喜代孝, 高橋美帆, 安西聖敬, 川端宏, 水野沙緒利
特願2018-163521, 特願2018-163521
Patent right
抗インフルエンザウイルス活性ペプチドおよびインフルエンザウイルス感染症の予防・治療薬
西川喜代孝, 高橋美帆, 近江純平, 濱信一郎
特願2018-163326, 特願2018-163326
Potential of amino acid transporter as a marker for inflammation of intestinal mucosa
川島 麗; 鎌田 弥生; 高橋 美帆; 藤田 朋恵; 市川 尊文
消化管粘膜傷害の局所的背景には、炎症因子から栄養素取り込みまで様々な機構が関連する。本課題は昨年度に引き続き、5-FUによる粘膜傷害モデルにおける炎症惹起に伴う栄養素や薬物などのさまざまな物質を外部環境から頻繁に輸送するトランスポーターに焦点を当て、その発現を検証した。特に生体では合成できず食物から取り入れる必要がある必須アミノ酸輸送体LATのmRNA発現を検証した。5FUにて消化管粘膜傷害を誘導したマウスの小腸を8分割し、部位特異性を視野に入れ、発現を検討した。コントロール群では、小腸部位に関係なく、一定レベルのLAT1発現が見られた。LAT2の発現は小腸の中心部で徐々に増加し遠位で減少する傾向があった。傷害群では、LAT1の発現は約20倍上昇した。特に、回腸で有意に増加した。一方で、LAT2の発現は減少した。LATの補助サブユニットである4F2hcの発現は、コントロール群の小腸で明確な部位傾向性を示さなかったが、傷害後、小腸全体で減少した。
傷害により細胞のターンオーバーが減少することで、すべての栄養素トランスポーターが発現減少する可能性を排除するため、グルコーストランスポーターであるSGLT1発現を検証したところ、コンロール群において、部位発現特異性は見られたものの、傷害依存性の発現上昇または現象は見られなかった。
LATを介した必須アミノ酸を含む中性アミノ酸の取り込みは、主に小腸の中心で起こると考えらており、リンパ球の活性化とホルモンによる刺激によってLAT1高発現が誘導されるとの報告もある。したがって、LAT1は、細胞の要求を満たすために必要なアミノ酸を供給するように発現が調整されるトランスポーターである損傷組織におけるLAT1発現の上昇は注目するに値すると見込んでおり、本結果により、アミノ酸の変動が特に炎症性条件下で発生する現象であると考えられた。, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, 2019/04 -2023/03, Grant-in-Aid for Scientific Research (C), Kitasato University
Development of a new therapeutic agent that inhibits the production of exosome-associated Shiga toxin 2
Takahashi Miho
After being incorporated into target cells, Shiga toxin 2 (Stx2) was actively released from the cells, and part of released Stx2a was associated with exosomes (refer to as exo-Stx2). To determine the intracellular molecules that regulate the production of exo-Stx2, we examined the effect of knockdown of Rabs (Rab11a, Rab11b, Rab27a, Rab27b, and Rab35) on the release of Stx2 in the culture medium. The results showed that the release of Stx2 was inhibited by Rab11b knockdown but not by the other Rabs knockdown, indicating that exo-Stx2 is released by Rab11b dependent machinery. By using a kinase substrate peptide array, we analyzed the hundreds of protein kinases activations in Stx treated cells, and found that the types of activated protein kinases were different between the case with Stx1 and Stx2 in the intracellular transport of Stx., Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, 2018/04 -2021/03, Grant-in-Aid for Scientific Research (C), Doshisha University
Development of a novel Shiga toxin inhibitor that targeting of intracellular transport of the toxin
Takahashi Miho
We synthesized substrate peptides of various kinases on a slide glass and using this, we analyzed the activities of kinases stimulated by Stx1a in the presence or absence of Stx inhibitors (MMA-tet, FRA-tet).We established a new multivalent peptide library screening by using tetravalent peptides synthesized on a cellulose membrane., Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, 2015/04 -2018/03, Grant-in-Aid for Scientific Research (C), Doshisha University
Development peptide-based compounds which bind to the specific receptor-binding region of Shiga toxin B subunit
TAKAHASHI Miho
To identify the peptide probes that specifically bind to one of the receptor-binding site 2 of Shiga toxin1 (Stx1), we established a novel screening system using the multivalent SPOT peptide array. We synthesized total 361 SPOT peptides on the cellulose membrane, and screened the peptides based on the binding affinities against the Stx1B subunit or Stx1 site 2 mutant (G62A). Finally, we identified 11 peptides that specifically bound to the Stx1B subunit, but not to G62A mutant. Furthermore, we found the 4 peptides among them (PQA-tet, KGA-tet, VIA-tet, YTA-tet) effectively inhibited the cytotoxicity for Stx1 in Vero cells. Thus, the multivalent SPOT peptide array technique may provide a powerful tool to identify a series of effective peptide-based Stx neutralizers which target a specific receptor binding region., Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, 2010 -2012, Grant-in-Aid for Young Scientists (B), Doshisha University
An orally applicable Shiga toxin neutralizer functions in the intestine to inhibit the intracellular transport of the toxin.
TAKAHASHI Miho
We found that PPP-tet, a peptide-based Stx2 inhibitor, completely inhibited fluid accumulation in the rabbit ileum caused by the direct injection of Stx2. We also found that PPP-tet accumulated in the ileal epithelial cells only through its formation of a complex with Stx2. The complex in cultured epithelial cells blocked the intracellular transport of Stx2 from the Golgi apparatus to the endoplasmic reticulum, the process that is essential for Stx2 cytotoxicity. Our results reveal that PPP-tet functions as a potent Stx neutralizer in the intestine by altering the intracellular transport of Stx2 in epithelial cells., Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, 2008 -2009, Grant-in-Aid for Young Scientists (B), Doshisha University