Interaction between hepatocytes and stellate cells in NASH

• Project/Area Number: 19K07509
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Nagoya City University
• Principal Investigator: Naiki-Ito Aya 名古屋市立大学, 医薬学総合研究院(医学), 准教授 (20509236)
• Co-Investigator(Kenkyū-buntansha): 野尻 俊輔 名古屋市立大学, 医薬学総合研究院(医学), 教授 (50381843) ; 高橋 智 名古屋市立大学, 医薬学総合研究院(医学), 教授 (60254281) ; 加藤 寛之 名古屋市立大学, 医薬学総合研究院(医学), 講師 (80791293)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 細胞間コミュニケーション / 疾患モデル / 肝線維化 / NASH / 星細胞

Outline of Research at the Start

肝細胞GJICの機能低下による、肝細胞の酸化ストレス増大、星細胞活性化により、NASHや肝発癌が促進することを発見した。本研究では、自らの核酸情報を運ぶエクソソームに着目し、肝細胞由来エクソソームによる星細胞の活性化機構を解明する。さらに、活性化した星細胞から分泌される増殖因子と、私たちが同定したNASH肝発癌遺伝子Bex1の関連を追究し、新規NASH予防法へ直結する基盤を確立する。

Outline of Final Research Achievements

Transgenic rats with dominant negative mutant of connexin 32, a hepatocyte gap junction protein, and dysfunction of gap-junctional intercellular communication, were treated with a high fat diet and dimethylnitrosamine to establish a model for induction of NASH, fibrosis, as well as insulin resistance. TNFα, Tgfβ1, NF-κB and JNK signaling was involved in the activation of hepatic stellate cells and NASH progression. Intake of chemicals inhibiting those signaling was found to have an inhibitory effect on NASH and fibrosis.

Academic Significance and Societal Importance of the Research Achievements

本研究では、ヒトのNASHで頻繁に併発するメタボリックシンドロームや肝線維症を随伴するNASHモデルを樹立した。このモデルを用いて、NASHに対する効果とそのメカニズムの検証が可能であることが明らかとなり、NASHの化学予防研究に有用なツールとなりえる。

Research Products

• [Journal Article] Usefulness of advanced monoenergetic reconstruction technique in dual-energy computed tomography for detecting bladder cancer (2022)
  • Author(s): Nakagawa M, Naiki T, Naiki-Ito A, Ozawa Y, Shimohira M, Ohnishi M, Shibamoto Y
  • Journal Title: Japanese Journal of Radiology Volume: 40(2) Issue: 2 Pages: 177-183
  • DOI: 10.1007/s11604-021-01195-5
  • NAID: 210000187175
  • Peer Reviewed / Open Access
• [Journal Article] Lactoferrin Prevents Hepatic Injury and Fibrosis via the Inhibition of NF-κB Signaling in a Rat Non-Alcoholic Steatohepatitis Model (2021)
  • Author(s): Aoyama Yoshinaga、Naiki-Ito Aya、Xiaochen Kuang、Komura Masayuki、Kato Hiroyuki、Nagayasu Yuko、Inaguma Shingo、Tsuda Hiroyuki、Tomita Mamoru、Matsuo Yoichi、Takiguchi Shuji、Takahashi Satoru
  • Journal Title: Nutrients Volume: 14 Issue: 1 Pages: 42-42
  • DOI: 10.3390/nu14010042
  • Peer Reviewed / Open Access
• [Journal Article] Testicular seminoma arising from infertile testes 6 years after microdissection testicular sperm extraction (2021)
  • Author(s): Shimizu Nobuhiko、Naiki Taku、Kobayashi Daichi、Naiki‐Ito Aya、Kawai Tatsuya、Xiaochen Kuang、Etani Toshiki、Nozaki Satoshi、Tomiyama Nami、Aoki Maria、Matsuyama Nayuka、Iwatsuki Shoichiro、Umemoto Yukihiro、Yasui Takahiro
  • Journal Title: IJU Case Reports Volume: 5 Issue: 1 Pages: 53-56
  • DOI: 10.1002/iju5.12391
  • Peer Reviewed / Open Access
• [Journal Article] Chronological transition in outcome of second-line treatment in patients with metastatic urothelial cancer after pembrolizumab approval: a multicenter retrospective analysis (2021)
  • Author(s): Isobe Teruki、Naiki Taku、Sugiyama Yosuke、Naiki-Ito Aya、Nagai Takashi、Etani Toshiki、Nozaki Satoshi、Iida Keitaro、Noda Yusuke、Shimizu Nobuhiko、Tomiyama Nami、Banno Rika、Kubota Hiroki、Hamamoto Shuzo、Ando Ryosuke、Kawai Noriyasu、Yasui Takahiro
  • Journal Title: International Journal of Clinical Oncology Volume: 27 Issue: 1 Pages: 165-174
  • DOI: 10.1007/s10147-021-02046-z
  • Peer Reviewed
• [Journal Article] Suppressive Effect and Molecular Mechanism of Houttuynia cordata Thunb. Extract against Prostate Carcinogenesis and Castration-Resistant Prostate Cancer (2021)
  • Author(s): Subhawa Subhawat、Naiki-Ito Aya、Kato Hiroyuki、Naiki Taku、Komura Masayuki、Nagano-Matsuo Aya、Yeewa Ranchana、Inaguma Shingo、Chewonarin Teera、Banjerdpongchai Ratana、Takahashi Satoru
  • Journal Title: Cancers Volume: 13 Issue: 14 Pages: 3403-3403
  • DOI: 10.3390/cancers13143403
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-Allergic Drug Suppressed Pancreatic Carcinogenesis via Down-Regulation of Cellular Proliferation (2021)
  • Author(s): Kachi Kenta、Kato Hiroyuki、Naiki-Ito Aya、Komura Masayuki、Nagano-Matsuo Aya、Naitoh Itaru、Hayashi Kazuki、Kataoka Hiromi、Inaguma Shingo、Takahashi Satoru
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 14 Pages: 7444-7444
  • DOI: 10.3390/ijms22147444
  • Peer Reviewed / Open Access
• [Journal Article] The roles of gap junctional intercellular communication in non-alcoholic steatohepatitis (NASH) and liver fibrosis (2021)
  • Author(s): Naiki-Ito Aya
  • Journal Title: Folia Pharmacologica Japonica Volume: 156 Issue: 3 Pages: 152-156
  • DOI: 10.1254/fpj.20100
  • NAID: 130008032908
  • ISSN: 0015-5691, 1347-8397
• [Journal Article] Cancer-Specific Targeting of Taurine-Upregulated Gene 1 Enhances the Effects of Chemotherapy in Pancreatic Cancer (2021)
  • Author(s): Tasaki Y, Suzuki M, Katsushima K, Shinjo K, Iijima K, Murofushi Y, Naiki-Ito A, Hayashi K, Qiu C, Takahashi A, Tanaka Y, Kawaguchi T, Sugawara M, Kataoka T, Naito M, Miyata K, Kataoka K, Noda T, Gao W, Kataoka H, Takahashi S, Kimura K, Kondo Y.
  • Journal Title: Cancer Research Volume: - Issue: 7 Pages: 1654-1666
  • DOI: 10.1158/0008-5472.can-20-3021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DPYD, down-regulated by the potentially chemopreventive agent luteolin, interacts with STAT3 in pancreatic cancer (2021)
  • Author(s): Kato H, Naiki-Ito A, Suzuki S, Inaguma S, Komura M, Nakao K, Naiki T, Kachi K, Kato A, Matsuo Y, Takahashi S.
  • Journal Title: Carcinogenesis Volume: - Issue: 7 Pages: 940-950
  • DOI: 10.1093/carcin/bgab017
  • Peer Reviewed / Open Access
• [Journal Article] Cell proliferation of rat bladder urothelium induced by nicotine is suppressed by the NADPH oxidase inhibitor, apocynin (2021)
  • Author(s): Suzuki S, Cohen SM, Arnold LL, Pennington KL, Gi M, Kato H, Naiki T, Naiki-Ito A, Wanibuchi H, Takahashi S.
  • Journal Title: Toxicology Letters Volume: 336 Pages: 32-38
  • DOI: 10.1016/j.toxlet.2020.11.005
  • NAID: 120007181781
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of γ-H2AX as a biomarker for detection of bladder carcinogens in F344 rats (2020)
  • Author(s): Suzuki S, Gi M, Toyoda T, Kato H, Naiki-Ito A, Kakehashi A, Ogawa K, Takahashi S, Wanibuchi H.
  • Journal Title: Journal of Toxicologic Pathology Volume: 33 Issue: 4 Pages: 279-285
  • DOI: 10.1293/tox.2020-0038
  • NAID: 130007931389
  • ISSN: 0914-9198, 1881-915X
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparative carcinogenicity study of a thick, straight-type and a thin, tangled-type multi-walled carbon nanotube administered by intra-tracheal instillation in the rat (2020)
  • Author(s): Saleh DM, Alexander WT, Numano T, Ahmed OHM, Gunasekaran S, Alexander DB, Abdelgied M, El-Gazzar AM, Takase H, Xu J, Naiki-Ito A, Takahashi S, Hirose A, Ohnishi M, Kanno J, Tsuda H.
  • Journal Title: Particle and Fibre Toxicology Volume: 17 Issue: 1 Pages: 48-48
  • DOI: 10.1186/s12989-020-00382-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel model of non-alcoholic steatohepatitis with fibrosis and carcinogenesis in connexin 32 dominant-negative transgenic rats (2020)
  • Author(s): Naiki-Ito A, Kato H, Naiki T, Yeewa R, Aoyama Y, Nagayasu Y, Suzuki S, Inaguma S, Takahashi S.
  • Journal Title: Archives of Toxicology Volume: 94 Issue: 12 Pages: 4085-4097
  • DOI: 10.1007/s00204-020-02873-5
  • Peer Reviewed / Open Access
• [Journal Article] The standard form of CD44 as a marker for invasion of encapsulated papillary carcinoma of the breast (2020)
  • Author(s): Kato H, Naiki-Ito A, Yamada T, Suzuki S, Yamashita Y, Inaguma S, Kondo N, Wanifuchi-Endo Y, Toyama T, Takahashi S.
  • Journal Title: Pathology International Volume: 70 Issue: 11 Pages: 835-843
  • DOI: 10.1111/pin.13001
  • Peer Reviewed
• [Journal Article] Dehydrozingerone, a Curcumin Analog, as a Potential Anti-Prostate Cancer Inhibitor In Vitro and In Vivo (2020)
  • Author(s): Mapoung S, Suzuki S, Fuji S, Naiki-Ito A, Kato H, Yodkeeree S, Sakorn N, Ovatlarnporn C, Takahashi S, Limtrakul Dejkriengkraikul P.
  • Journal Title: Molecules Volume: 25 Issue: 12 Pages: 2737-2737
  • DOI: 10.3390/molecules25122737
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Selective lysine-specific demethylase 1 inhibitor, NCL1, could cause testicular toxicity via the regulation of apoptosis (2020)
  • Author(s): Nozaki S, Naiki T, Naiki-Ito A, Iwatsuki S, Takeda T, Etani T, Nagai T, Iida K, Kato H, Suzuki T, Takahashi S, Umemoto Y, Yasui T.
  • Journal Title: Andrology Volume: 8 Issue: 6 Pages: 1895-1906
  • DOI: 10.1111/andr.12846
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hexane insoluble fraction from purple rice extract retards carcinogenesis and castration-resistant cancer growth of prostate through suppression of androgen receptor mediated cell proliferation and metabolism. (2020)
  • Author(s): 5.Yeewa, R., Naiki-Ito, A., Naiki, T., Kato, H., Suzuki, S., Chewonarin, T., Takahashi, S.
  • Journal Title: Nutrients Volume: 12 Issue: 2 Pages: 558-558
  • DOI: 10.3390/nu12020558
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Luteolin suppresses bladder cancer growth via regulation of mechanistic target of rapamycin pathway (2020)
  • Author(s): Iida Keitaro、Naiki Taku、Naiki‐Ito Aya、Suzuki Shugo、Kato Hiroyuki、Nozaki Satoshi、Nagai Takashi、Etani Toshiki、Nagayasu Yuko、Ando Ryosuke、Kawai Noriyasu、Yasui Takahiro、Takahashi Satoru
  • Journal Title: Cancer Science Volume: 111 Issue: 4 Pages: 1165-1179
  • DOI: 10.1111/cas.14334
  • Peer Reviewed / Open Access
• [Journal Article] Cotinine, a major nicotine metabolite, induces cell proliferation on urothelium in vitro and in vivo (2020)
  • Author(s): Suzuki Shugo、Cohen Samuel M.、Arnold Lora L.、Pennington Karen L.、Kato Hiroyuki、Naiki Taku、Naiki-Ito Aya、Yamashita Yoriko、Takahashi Satoru
  • Journal Title: Toxicology Volume: 429 Pages: 152325-152325
  • DOI: 10.1016/j.tox.2019.152325
  • Peer Reviewed / Open Access
• [Journal Article] Recruitment of miR-8080 by luteolin inhibits androgen receptor splice variant 7 expression in castration-resistant prostate cancer. (2019)
  • Author(s): Naiki-Ito A, Naiki T, Kato H, Iida K, Etani T, Nagayasu Y, Suzuki S, Yamashita Y, Inaguma S, Onishi M, Tanaka Y, Yasui T, Takahashi S.
  • Journal Title: Carcinogenesis Volume: 193 Issue: 8 Pages: 00-00
  • DOI: 10.1093/carcin/bgz193
  • Peer Reviewed / Open Access
• [Journal Article] Carcinogenic effect of potassium octatitanate (POT) fibers in the lung and pleura of male Fischer 344 rats after intrapulmonary administration (2019)
  • Author(s): Abdelgied Mohamed、El-Gazzar Ahmed M.、Alexander William T.、Numano Takamasa、Iigou Masaaki、Naiki-Ito Aya、Takase Hiroshi、Hirose Akihiko、Taquahashi Yuhji、Kanno Jun、Abdelhamid Mona、Abdou Khaled Abbas、Takahashi Satoru、Alexander David B.、Tsuda Hiroyuki
  • Journal Title: Particle and Fibre Toxicology Volume: 16 Issue: 1 Pages: 34-34
  • DOI: 10.1186/s12989-019-0316-2
  • Peer Reviewed / Open Access
• [Journal Article] MWCNT‐7 administered to the lung by intratracheal instillation induces development of pleural mesothelioma in F344 rats (2019)
  • Author(s): Numano Takamasa、Higuchi Hitomi、Alexander David B.、Alexander William T.、Abdelgied Mohamed、El‐Gazzar Ahmed M.、Saleh Dina、Takase Hiroshi、Hirose Akihiko、Naiki‐Ito Aya、Suzuki Shugo、Takahashi Satoru、Tsuda Hiroyuki
  • Journal Title: Cancer Science Volume: 110 Issue: 8 Pages: 2485-2492
  • DOI: 10.1111/cas.14121
  • Peer Reviewed / Open Access
• [Presentation] Chemopreventive effect of purple rice extract on rat non-alcoholic steatohepatitis and hepatocarcinogenesis (2021)
  • Author(s): Aya Naiki-Ito, Ranchana Yeewa, Hiroyuki Kato, Teera Chewonarin, Satoru Takahashi
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] 非アルコール性脂肪肝炎および肝線維化に対する紫米抽出物の抑制効果、第110回日本病理学会 (2021)
  • Author(s): 内木綾、加藤寛之、小村理行、稲熊真悟、高橋智
  • Organizer: 第110回日本病理学会
• [Presentation] 非アルコール性脂肪肝炎に対する紫米抽出物の化学予防効果 (2021)
  • Author(s): 内木綾、加藤寛之、小村理行、高橋智
  • Organizer: 第38回日本毒性病理学会・1回アジア毒性病理学連盟学術集会
• [Presentation] 非アルコール性脂肪肝炎・肝線維症に対する細胞間コミュニケーションの役割と予防剤の探索 (2021)
  • Author(s): 内木綾
  • Organizer: 第99回日本生理学会大会シンポジウム
  • Invited
• [Presentation] LuteolinはmTORシグナルとp21発現の制御により膀胱発がんを抑制する (2021)
  • Author(s): 内木綾、加藤寛之、小村理行、髙橋智
  • Organizer: 第37回日本毒性病理学会
• [Presentation] MiR-8080はandrogen receptorスプライスバリアントの発現低下により去勢抵抗性前立腺癌を抑制する (2020)
  • Author(s): 内木綾、加藤寛之、稲熊真悟、山下依子、髙橋智
  • Organizer: 第109回日本病理学会
• [Presentation] Cancer chemoprevention by antioxidant luteolin (2020)
  • Author(s): Aya Naiki-Ito, Hiroyuki Kato, Taku Naiki, Satoru Takahashi
  • Organizer: 第79回日本癌学会学術総会
  • Invited
• [Presentation] 酸化ストレスから見た発癌機序の分子病理学的解析と臨床応用への試み (2020)
  • Author(s): 内木綾
  • Organizer: 第66回日本病理学会秋期特別総会
  • Invited
• [Presentation] 去勢抵抗性前立腺癌におけるandrogen receptor splice variantの役割とmicroRNAによる制御機構 (2020)
  • Author(s): 内木 綾、加藤 寛之、鈴木 周五、髙橋 智
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 非アルコール性脂肪肝炎・肝線維症に対する細胞間コミュニケーションの役割と予防剤の探索 (2020)
  • Author(s): 内木 綾
  • Organizer: 第93回日本薬理学会年会
  • Invited
• [Presentation] LuteolinはRNAサイレンシングによるAR-V7制御により去勢抵抗性前立腺癌を抑制する (2019)
  • Author(s): 内木 綾、加藤 寛之、鈴木 周五、髙橋 智
  • Organizer: 第26回日本がん予防学会総会
• [Presentation] MiR-8080はandrogen receptorスプライスバリアントの発現低下により去勢抵抗性前立腺癌を抑制する (2019)
  • Author(s): 内木 綾、加藤 寛之、山下 依子、髙橋 智
  • Organizer: 第108回日本病理学会総会
• [Presentation] Luteolinの去勢抵抗性前立腺癌に対する抑制効果とandrogen receptor splice variantの役割 (2019)
  • Author(s): 内木 綾、内木 拓、加藤 寛之、山下 依子、髙橋 智
  • Organizer: 第78回日本癌学会学術総会