Investigation of cytoprotective triggering mechanism of flavonoids targeting stress sensing mechanisms

• Project/Area Number: 20K11529
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Nagoya University
• Principal Investigator: Matsushima Miyoko 名古屋大学, 医学系研究科(保健), 講師 (10509665)
• Co-Investigator(Kenkyū-buntansha): 川部 勤 名古屋大学, 医学系研究科(保健), 教授 (20378219)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: フラボノイド / Nrf2 / オートファジー / HO-1 / p62 / heme oxygenase-1 / ストレスセンシング / 細胞膜

Outline of Research at the Start

フラボノイドは天然の機能性成分で、多彩な細胞保護効果を示す。本研究ではフラボノイドは共通した起点となる細胞膜でセンシングされ、普遍的な生体防御機構を誘導すると考え、細胞がフラボノイドを感知するストレスセンシング機構を探索・同定し、フラボノイドの多彩な細胞保護効果の発揮の出発点となる分子機構を解明する。

Outline of Final Research Achievements

Flavonoids exhibit beneficial effects, and one such flavonoid, quercetin, exerts cytoprotective effects via HO-1 induced by Nrf2 activation. In the present study, we showed that quercetin-induced HO-1 was involved in the regulation of autophagy. Quercetin induced the conversion of LC3-I to LC3-II while also inducing p62 expression and phosphorylation at serine residue 351. These results suggest that quercetin would induce selective autophagy, and quercetin-induced p62 might create a positive feedback loop in Keap1-Nrf2 system. Moreover, HO-1 deletion enhanced the expression levels of p62 induced by quercetin, suggesting that HO-1 might negatively regulate p62 expression. In summary, quercetin induced selective autophagy, and HO-1 induced by quercetin negatively regulated the expression of p62. These results suggested that selective autophagy induced by quercetin might exert cytoprotective effects under regulation of HO-1 activity.

Academic Significance and Societal Importance of the Research Achievements

ストレスは老化、炎症性疾患、アレルギー性疾患などさまざまな疾患の病態形成に関与し、ストレスによって誘導される生体防御機構がこれら疾患の制御の基盤となっている。フラボノイドは野菜等から摂取できるため、健康状態や疾患感受性に合わせたフラボノイドを含む食事指導を行うことで、より安全にかつ効果的にさまざまな疾患の発症を予防・軽減できる。本研究でフラボノイドがいかにストレスセンシング機構を作動させ、対応する生体防御機構を誘導するかを評価することにより、生体防御の強化やアンチエイジングに貢献し、これからの超高齢社会にも低コストで十分に対応できる対策を構築できる可能性があると考える。

Research Products

• [Journal Article] Analysis of Airstream Inside the Slip Joint of Tracheal Intubation Tube for Breathing Measurement (2023)
  • Author(s): Tsukada Tsuyoshi、Hasegawa Yoshihiro、Farisi Muhammad Salman Al、Matsushima Miyoko、Kawabe Tsutomu、Shikida Mitsuhiro
  • Journal Title: IEEJ Transactions on Sensors and Micromachines Volume: 143 Issue: 1 Pages: 6-12
  • DOI: 10.1541/ieejsmas.143.6
  • ISSN: 1341-8939, 1347-5525
  • Year and Date: 2023-01-01
  • Peer Reviewed
• [Journal Article] Decrease in cholesterol in the cell membrane is essential for Nrf2 activation by quercetin (2023)
  • Author(s): Matsushima Miyoko、Nose Haruka、Tsuzuki Hikaru、Takekoshi Masahiro、Kusatsugu Yuto、Taniguchi Hinata、Ohdachi Tomoko、Hashimoto Naozumi、Sato Mitsuo、Kawabe Tsutomu
  • Journal Title: The Journal of Nutritional Biochemistry Volume: 116 Pages: 109329-109329
  • DOI: 10.1016/j.jnutbio.2023.109329
  • Peer Reviewed
• [Journal Article] Correlation of theophylline levels in rat exhaled breath and lung tissue after its intravenous injection (2022)
  • Author(s): Matsushima Miyoko、Tanihata Souma、Kusakabe Junpei、Okahira Momoha、Ito Hiroshi、Yamamoto Atsushi、Yamamoto Masanori、Yamamoto Ryohei、Kawabe Tsutomu
  • Journal Title: Journal of Breath Research Volume: 16 Issue: 3 Pages: 036003-036003
  • DOI: 10.1088/1752-7163/ac6b4b
  • Peer Reviewed
• [Journal Article] Development of MEMS Flow and Pressure Sensor Device for Detection of Extravasation at an Early Stage (2022)
  • Author(s): Hasegawa Yoshihiro、Shimohira Chihiro、Matsushima Miyoko、Sugiyama Tomoshi、Kawabe Tsutomu、Shikida Mitsuhiro
  • Journal Title: IEEJ Transactions on Electrical and Electronic Engineering Volume: 18 Issue: 1 Pages: 139-146
  • DOI: 10.1002/tee.23706
  • Peer Reviewed
• [Journal Article] Resistance to mutant KRAS V12-induced senescence in an hTERT/Cdk4-immortalized normal human bronchial epithelial cell line (2022)
  • Author(s): Muraki N, Yamada M, Doki H, Nakai R, Komeda K, Goto D, Kawabe N, Matsuoka K, Matsushima M, Kawabe T, Tanaka I, Morise M, Shay JW, Minna JD, Sato M.
  • Journal Title: Exp Cell Res . Volume: 414 Issue: 1 Pages: 113053-113053
  • DOI: 10.1016/j.yexcr.2022.113053
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Miniaturization of Respiratory Measurement System in Artificial Ventilator for Small Animal Experiments to Reduce Dead Space and Its Application to Lung Elasticity Evaluation (2021)
  • Author(s): Yoshida Homare、Hasegawa Yoshihiro、Matsushima Miyoko、Sugiyama Tomoshi、Kawabe Tsutomu、Shikida Mitsuhiro
  • Journal Title: Sensors Volume: 21 Issue: 15 Pages: 5123-5123
  • DOI: 10.3390/s21155123
  • Peer Reviewed
• [Journal Article] Involvement of heme oxygenase-1 in suppression of T cell activation by quercetin (2020)
  • Author(s): Sugiyama Tomoshi、Matsushima Miyoko、Ohdachi Tomoko、Hashimoto Naozumi、Hasegawa Yoshinori、Yokoi Kohei、Kawabe Tsutomu
  • Journal Title: Immunopharmacology and Immunotoxicology Volume: 42 Issue: 4 Pages: 295-305
  • DOI: 10.1080/08923973.2020.1759623
  • Peer Reviewed
• [Presentation] Effects of localization changes of caveolin-1 on Nrf2-HO-1 activation induced by quercetin (2022)
  • Author(s): Fuzuki Hayashi, Miyoko Matsushima, Hikaru Tsuzuki, Moeko Ohara, Nodoka Shimasaki, Ayumi Tajima, Hinata Taniguchi, Hina Kawashima, Sayaka Takagi, Nanami Yoshida, Tsutomu Kawabe
  • Organizer: 第51回日本免疫学会
• [Presentation] Positive effects on selective autophagy by quercetin-induced heme oxygenase-1 (2022)
  • Author(s): Hinata Taniguchi, Miyoko Matsushima, Sayaka Takagi, Moeko Ohara, Hikaru Tsuzuki, Nodoka Shimasaki, Ayumi Tajima, Hina Kawashima, Fuzuki Hayashi, Nanami Yoshida, Tsutomu Kawabe
  • Organizer: 第51回日本免疫学会
• [Presentation] Synergistic effects of Toll-like receptor signaling on inflammation induced by silica nanoparticles (2022)
  • Author(s): Nanami Yoshida, Miyoko Matsushima, Moeko, Ohara, Hikaru Tsuzuki, Nodoka Shimasaki, Ayumi Tajima, Hinata Taniguchi, Hina Kawashima, Sayaka Takagi, Fuzuki Hayashi, Tsutomu Kawabe
  • Organizer: 第51回日本免疫学会
• [Presentation] Analysis of lymphocyte differentiation and proliferation in NC/Nga mice (2022)
  • Author(s): Hikaru Tsuzuki, Miyoko Matsushima, Ayumi Tajima, Moeko Ohara, Nodoka Shimasaki, Hinata Taniguchi, Hina Kawashima, Sayaka Takagi, Fuzuki Hayashi, Nanami Yoshida, Tsutomu Kawabe
  • Organizer: 第51回日本免疫学会
• [Presentation] Modulation of proinflammatory responses by diazinon in mast cells (2022)
  • Author(s): Moeko Ohara, Miyoko Matsushima, Hina Kawashima, Hikaru Tsuzuki, Nodoka Shimasaki, Ayumi Tajima, Hinata Taniguchi, Sayaka Takagi, Fuzuki Hayashi, Nanami Yoshida, Tsutomu Kawabe
  • Organizer: 第51回日本免疫学会
• [Presentation] 症状発現に関わるアレルゲンエピトープの探索 (2022)
  • Author(s): 小原萌恵子、松島充代子、佐藤光夫、伊藤浩明、川部 勤
  • Organizer: 第71回日本アレルギー学会学術大会
• [Presentation] 環境からのストレスに備えるケルセチンによる細胞保護作用の新規機序の検討 (2022)
  • Author(s): 都築 光、松島充代子、竹腰正広、谷口ひなた、小原萌恵子、島崎温香、田島歩実、佐藤光夫、川部 勤
  • Organizer: 第52回日本職業・環境アレルギー学会総会・学術大会
• [Presentation] Wireless MEMS Thermal Flow Sensor System Integrated on Medical Mask for Emergency Medical Treatment (2022)
  • Author(s): Tsuyoshi Tsukada, Yoshihiro Hasegawa, Farisi Muhammad Salman Al, Shin Hasegawa, Miyoko Matsushima, Tsutomu Kawabe, Mitsuhiro Shikida
  • Organizer: Asia-Pacific Conference of Transducers and Micro-Nano Technology 2022 (APCOT2022)
  • Int'l Joint Research
• [Presentation] Involvement of p62 on Activation of Heme Oxygenase-1 Induced by Quercetin (2021)
  • Author(s): Yuki Hayashi, Miyoko Matsushima, Goki Inoue, Ko Iwaki, Teppei Yamashita, Moeko Ohara, Hikaru Tsuzuki and Tsutomu Kawabe
  • Organizer: 第50回日本免疫学会
• [Presentation] Effects of localization changes of caveolin-1 on cellular function induced by quercetin (2021)
  • Author(s): Hikaru Tsuzuki, Miyoko Matsushima, Goki Inoue, Ko Iwaki, Yuki Hayashi, Teppei Yamashita, Moeko Ohara, Tsutomu Kawabe
  • Organizer: 第50回日本免疫学会
• [Presentation] Investigation of B-cell differentiation on atopic dermatitis model mice (2021)
  • Author(s): Moeko Ohara, Miyoko Matsushima, Hikaru Tsuzuki, Goki Inoue, Ko Iwaki, Yuki Hayashi, Teppei Yamashita, Tsutomu Kawabe
  • Organizer: 第50回日本免疫学会
• [Presentation] Attenuation of signal transduction induced by diazinon in RBL-2H3 cells (2021)
  • Author(s): Goki Inoue, Miyoko Matsushima, Ko Iwaki, Yuki Hayashi, Teppei Yamashita, Moeko Ohara, Hikaru Tsuzuki, Tsutomu Kawabe
  • Organizer: 第50回日本免疫学会
• [Presentation] Effects on function of macrophages by diazinon-modified metabolic status (2021)
  • Author(s): Ko Iwaki, Miyoko Matsushima, Goki Inoue, Yuki Hayashi, Teppei Yamashita, Moeko Ohara, Hikaru Tsuzuki and Tsutomu Kawabe
  • Organizer: 第50回日本免疫学会
• [Presentation] Analysis of efferocytosis on type 2-skewed immune responses in NC/Nga mice (2021)
  • Author(s): Teppei Yamashita, Miyoko Matsushima, Goki Inoue, Ko Iwaki, Yuki Hayashi, Moeko Ohara, Hikaru Tsuzuki and Tsutomu Kawabe
  • Organizer: 第50回日本免疫学会
• [Presentation] 呼吸の物理量情報をもとに評価する心肺機能 (2021)
  • Author(s): 川部 勤、松島充代子、長谷川 信、長谷川義大、式田光宏
  • Organizer: 第 58 回日本臨床生理学会総会
• [Presentation] Modulatory effects of diazinon on mast cell activation. (2020)
  • Author(s): Miyoko Matsushima, Kazuko Atsumi, Moeko Ohara, Masahiro Takekoshi, Yuka Tsubosaki, Goki Inoue, Ko Iwaki, Yuki Hayashi, Teppei Yamashita, Tsutomu Kawabe
  • Organizer: JSA/WAO XXVII World Allergy Congress (WAC 2020) conjoint with the APAPARI 2020 Congress
  • Int'l Joint Research
• [Presentation] 肥満細胞の即時型および遅発型反応に対するダイアジノンの免疫修飾作用 (2020)
  • Author(s): 岩城 巧、松島充代子、坪﨑由夏、小原萌恵子、竹腰正広、井上剛希、川部 勤
  • Organizer: 第51回日本職業・環境アレルギー学会総会・学術大会
• [Presentation] 呼気分析を応用した非侵襲的治療薬物モニタリングシステムの検討 (2020)
  • Author(s): 川部 勤、松島充代子、橋本直純、佐藤光夫、長谷川好規、山本良平、山本 敦
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Presentation] 呼吸に伴い変化する物理量の解析から得られる生体情報の意義についての検討 (2020)
  • Author(s): 川部 勤、松島充代子、橋本直純、佐藤光夫、長谷川好規、長谷川 信、長谷川義大、式田光宏
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Book] ポリイミドの高機能設計と応用技術 (2022)
  • Author(s): 執筆者 : 57名、技術情報協会
  • Total Pages: 566
  • Publisher: 技術情報協会
  • ISBN: 9784861048876