Elucidation of the mechanism on the effect of methylquercetin inhibiting cancer metastasis.

• Project/Area Number: 21K14888
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 40020:Wood science-related
• Research Institution: Gifu University
• Principal Investigator: Yamauchi Kosei 岐阜大学, 応用生物科学部, 准教授 (10805427)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: フラボノイド / 癌転移 / quercetin / MMP-1 / 抽出成分 / 遊走阻害

Outline of Research at the Start

クェルセチンは樹木や薬用植物，食品に広く含まれている代表的なフラボノイドの一種であり，多くの生物活性が報告されている。これまでにクェルセチンのメチル化体(MQ)が，クェルセチンよりも癌細胞の転移に関与する遊走を強力に阻害することが明らかとなっている。その作用機序の解明のため，MQの標的タンパク質の単離に用いるMQプローブの合成に成功している。本研究では本合成プローブを用いてMQの標的タンパク質を単離同定し，MQの作用メカニズムを分子レベルで明らかにする。

Outline of Final Research Achievements

Pull-down assays using the synthesized flavonoid probes suggested that MMP-1 was one of the target proteins of the quercetin derivative. Surface Plasmon Resonance (SPR) analysis confirmed that the interaction between the quercetin derivative and the recombinant MMP-1 catalytic domain was concentration-dependent.1H-15N HSQC NMR analysis showed that the quercetin derivative interacts with the metal ion vicinity of MMP-1. These results suggested that quercetin derivatives inhibited the activity of MMP-1 and suppressed the migration of cancer cells by binding near metal ions.

Academic Significance and Societal Importance of the Research Achievements

フラボノイドの生理機能は多岐に渡り、その有用性を示す報告は近年加速度的に増加している。そのため作用機序の解明や合成法、代謝過程などフラボノイドの動物細胞における影響について研究が行われ、年間1万報を超える関連論文が投稿されている。しかし、機能性成分として報告され続けているフラボノイド類の、直接的な作用機構は殆ど明らかにされておらず、その標的タンパク質の探索は世界的な競争になっている。本研究で、代表的なフラボノイドのひとつであるquercetin及びその誘導体の標的タンパク質及び、作用様式をNMR法を用いて初めて明らかにし、フラボノイドの活性メカニズムの一端を明らかにする事に成功した。

Research Products

• [Journal Article] Antioxidant components of the three different varieties of Indonesian ginger essential oil: In vitro and computational studies (2024)
  • Author(s): Badrunanto、Wahyuni Wulan Tri、Farid Muhammad、Batubara Irmanida、Yamauchi Kosei
  • Journal Title: Food Chemistry Advances Volume: 4 Pages: 100558-100558
  • DOI: 10.1016/j.focha.2023.100558
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ginsenoside Rg5 as an anticancer drug: a comprehensive review on mechanisms, structure?activity relationship, and prospects for clinical advancement (2024)
  • Author(s): Elsaman Tilal、Muddathir Ali Mahmoud、Mohieldin Ebtihal A. M.、Batubara Irmanida、Rahminiwati Min、Yamauchi Kosei、Mohamed Magdi Awadalla、Asoka Shadila Fira、B?sselberg Dietrich、Habtemariam Solomon、Sharifi-Rad Javad
  • Journal Title: Pharmacological Reports Volume: 76 Issue: 2 Pages: 287-306
  • DOI: 10.1007/s43440-024-00586-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] New flavan trimer from Daemonorops draco as osteoclastogenesis inhibitor (2024)
  • Author(s): Tsuchiya Ayaka、Suzuki Maki、Ito Ryotaro、Batubara Irmanida、Yamauchi Kosei、Mitsunaga Tohru
  • Journal Title: Fitoterapia Volume: 172 Pages: 105757-105757
  • DOI: 10.1016/j.fitote.2023.105757
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Garcidepsidone B from Garcinia parvifolia: antimicrobial activities of the medicinal plants from East and North Kalimantan against dental caries and periodontal disease pathogen (2023)
  • Author(s): Egra Saat、Kuspradini Harlinda、Kusuma Irawan Wijaya、Batubara Irmanida、Yamauchi Kosei、Mitsunaga Tohru
  • Journal Title: Medicinal Chemistry Research Volume: 32 Issue: 8 Pages: 1658-1665
  • DOI: 10.1007/s00044-023-03071-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chemical Constituent of Acacia auriculiformis Wood Extractives and Their Antioxidant Activity (2023)
  • Author(s): Prayogo Yanico Hadi、Batubara Irmanida、Sari Rita Kartika、Egra Saat、Yamauchi Kosei、Mitsunaga Tohru、Syafii Wasrin
  • Journal Title: Jurnal Sylva Lestari Volume: 11 Issue: 3 Pages: 370-381
  • DOI: 10.23960/jsl.v11i3.753
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The potential of five wild growing aromatic plants from Hemaq Beniung Customary Forest on antidiabetic activity (2023)
  • Author(s): Kuspradini Harlinda、Putri Agmi Sinta、Kiswanto Kiswanto、Sa’adah Hayatus、Fajriansyah、Rizqullah, Muhammad Akmal、Larasati, Anisa Gifta、Zulfa, Najmia Afifah、Egra, Saat、Yamauchi, Kosei、Mitsunaga, Tohru
  • Journal Title: Biodiversitas Journal of Biological Diversity Volume: 24 Issue: 4 Pages: 2156-2162
  • DOI: 10.13057/biodiv/d240427
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protein aggregation model to explain the bioactivity of condensed tannins (2023)
  • Author(s): Yamauchi Kosei、Soyano Mayu、Kobayashi Miho、Kamatari Yuji O.、Mitsunaga Tohru
  • Journal Title: Food Chemistry Volume: 416 Pages: 135870-135870
  • DOI: 10.1016/j.foodchem.2023.135870
  • Peer Reviewed
• [Journal Article] Potential of prospective medicinal plants of Rhizophoraceae from North Kalimantan, Indonesia (2023)
  • Author(s): Egra Saat、Kuspradini Harlinda、Kusuma Irawan Wijaya、Batubara Irmanida、Imra、Nurjannah Nurjannah、Wahyuni Etty、Yamauchi Kosei、Mitsunaga Tohru
  • Journal Title: Biodiversitas Journal of Biological Diversity Volume: 24 Issue: 3 Pages: 1346-1355
  • DOI: 10.13057/biodiv/d240303
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of flavonoid probes and the binding mode of the target protein and quercetin derivatives (2022)
  • Author(s): Tsuchiya Ayaka、Kobayashi Miho、Kamatari Yuji O.、Mitsunaga Tohru、Yamauchi Kosei
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 68 Pages: 116854-116854
  • DOI: 10.1016/j.bmc.2022.116854
  • Peer Reviewed / Open Access
• [Journal Article] Arnica montana L. extract containing 6‐O‐methacryloylhelenalin and 6‐O‐isobutyrylhelenalin accelerates growth and differentiation of human subcutaneous preadipocytes and leads volumizing of skin (2022)
  • Author(s): Sakamoto Kotaro、Watanabe Chiharu、Masutani Teruaki、Hirasawa Asuka、Wakamatsu Kanae、Iddamalgoda Arunasiri、Kakumu Yuya、Yamauchi Kosei、Mitsunaga Tohru
  • Journal Title: International Journal of Cosmetic Science Volume: 45 Issue: 1 Pages: 1-13
  • DOI: 10.1111/ics.12815
  • Peer Reviewed / Open Access
• [Journal Article] Ellagitannins from Rosa roxburghii suppress poly(I:C)-induced IL-8 production in human keratinocytes (2021)
  • Author(s): Takayama Satoru、Kawanishi Miho、Yamauchi Kosei、Tokumitsu Daiki、Kojima Hiroyuki、Masutani Teruaki、Iddamalgoda Arunasiri、Mitsunaga Tohru、Tanaka Hiroyuki
  • Journal Title: Journal of Natural Medicines Volume: in press Issue: 3 Pages: 623-632
  • DOI: 10.1007/s11418-021-01509-x
  • NAID: 40022589326
  • Peer Reviewed
• [Journal Article] New benzoic acid and caffeoyl derivatives with anti-inflammatory activities isolated from leaves of <i>Ilex kaushue</i> (2021)
  • Author(s): Kakumu Yuya、Nguyen Thi Minh Tu、Yamauchi Kosei、Mitsunaga Tohru
  • Journal Title: Natural Product Research Volume: 12 Issue: 12 Pages: 1-9
  • DOI: 10.1080/14786419.2021.1939334
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Molecular networking assisted in the rapid discovery of bioactive compounds from Excoecaria cochinchinensis leaves (2024)
  • Author(s): Yen Thi Hoang Kieu, Kosei Yamauchi, Tohru Mitsunaga
  • Organizer: 第74回日本木材学会
• [Presentation] Garcidepsidon B from Garcinia parvifolia: Antimicrobial Activities of The Medicinal Plants from North Kalimantan against Dental Caries and Periodontal Disease Pathogens (2024)
  • Author(s): Saat Egra, Kosei Yamauchi, Tohru Mitsunaga, Harlinda Kuspradini, Irawan Wijaya Kusuma, Irmanida Batubara
  • Organizer: 第74回日本木材学会
• [Presentation] Daemonorops draco果実由来竜血成分の骨粗鬆症抑制効果と作用機序の一考察 (2024)
  • Author(s): 土屋 綾香、中嶋 和紀、山内 恒生、光永 徹
  • Organizer: 第74回日本木材学会
• [Presentation] マウスのストレス性脳障害改善に及ぼすスギ材精油香気成分Ⅲ (2024)
  • Author(s): 竹山 大暁、山内 恒生、光永 徹
  • Organizer: 第74回日本木材学会
• [Presentation] Utilization of bioactive compound from plants. (2024)
  • Author(s): Kosei Yamauchi
  • Organizer: International Conference on Climate Change, Agriculture, Biodiversity, and Environment Study
• [Presentation] 竜血抽出物の成分探索と破骨細胞分化に及ぼす効果 (2023)
  • Author(s): 土屋綾香、山内恒生、光永徹
  • Organizer: 第６回樹木抽出成分研究交流会
• [Presentation] Daemonorops draco 果実抽出物の成分探索と破骨細胞ならびに骨粗鬆症モデルマウ スに及ぼす影響 (2023)
  • Author(s): 土屋綾香、山内恒生、光永 徹
  • Organizer: 東海地区創薬デザイン研究会
• [Presentation] 縮合型タンニンの生理作用機序を示すタンパク質凝集モデル (2023)
  • Author(s): 山内恒生、征矢野真由、小林美穂、鎌足雄司、光永 徹
  • Organizer: 東海地区創薬デザイン研究会
• [Presentation] キリンケツヤシ(Daemonorops draco)果実由来竜血の成分探索と破骨細胞分化ならびに骨粗鬆症モデルマウス骨量に及ぼす効果 (2023)
  • Author(s): 土屋綾香、山内恒生、光永 徹
  • Organizer: 第73回日本木材学会大会
• [Presentation] マウスのストレス性脳障害改善に及ぼす杉材精油香気成分 (2023)
  • Author(s): 竹山大暁、山内恒生、光永 徹
  • Organizer: 第73回日本木材学会大会
• [Presentation] 苦丁茶は成分の破骨細胞分化に及ぼす効果 (2022)
  • Author(s): 鈴木真希、各務裕也、山内恒生、光永 徹、Mihn Tu Thi Nguyen
  • Organizer: 日本生薬学会 第68回年会
• [Presentation] 有色木材心材の色調変化メカニズムの解明 (2022)
  • Author(s): 多賀勇亮、光永徹、山内恒生
  • Organizer: 日本ポリフェノール学会第15回学術集会
• [Presentation] 縮合型タンニンのタンパク質凝集モデル (2022)
  • Author(s): 山内恒生、征矢野真由、小林美穂、鎌足雄司、光永 徹
  • Organizer: 日本ポリフェノール学会第15回学術集会
• [Presentation] 破骨細胞分化抑制活性を有するDaemonorops draco抽出物の成分探索 (2022)
  • Author(s): 土屋綾香、山内恒生、光永 徹
  • Organizer: 日本ポリフェノール学会第15回学術集会
• [Presentation] NMRを用いたタンニンのタンパク質凝集メカニズムの解明 (2022)
  • Author(s): 山内恒生、菅原由喜、征矢野真由、小林美穂、鎌足雄司、光永 徹
  • Organizer: 日本木材学会中部支部大会
• [Presentation] 破骨細胞分化抑制活性を有するDaemonorops draco抽出物の成分探索とそのメカニズム (2022)
  • Author(s): 土屋綾香、イルマニダバツバラ、山内恒生、光永 徹
  • Organizer: 日本木材学会中部支部大会
• [Presentation] Neurite outgrowth effect on PC12 cells from Piper longum fruit extracts (2021)
  • Author(s): Runa Fujimoto, Masahiro Kassai, Kosei Yamauchi, Tohru Mitsunaga
  • Organizer: The 11th JCK Joint Symposium on Pharmacognosy
  • Int'l Joint Research
• [Presentation] Structural analysis of saponins from the leaves of Ilex kaushue (Kudingcha) (2021)
  • Author(s): Maki Suzuki, Minh Tu Thi Nguyen, Kosei Yamauchi, Tohru Mitsunaga
  • Organizer: The 11th JCK Joint Symposium on Pharmacognosy
  • Int'l Joint Research
• [Presentation] Bioactivity and mechanism of components in medicinal plant (2021)
  • Author(s): Kosei Yamauchi
  • Organizer: International Guest Lectures on Role Secondary Metabolite in Medicinal Plants
  • Int'l Joint Research / Invited
• [Presentation] Identification of NK cell activator from Citrus hystrix leaf extracts (2021)
  • Author(s): Takafumi Hara, Masahiro Kassai, Kosei Yamauchi, Tohru Mitsunaga
  • Organizer: The 11th JCK Joint Symposium on Pharmacognosy
  • Int'l Joint Research
• [Presentation] Strategy on elucidation of bioactivity mechanism of flavonoids (2021)
  • Author(s): Kosei Yamauchi
  • Organizer: Kalimantan Plant Biodiversity For The Development Of Medicines Seminar Series
  • Int'l Joint Research / Invited
• [Presentation] Investigation of Bioactivity Mechanism of Flavonoids in Cancer Cells (2021)
  • Author(s): Kosei Yamauchi, Ayaka Tsuchiya, Tohru Mitsunaga
  • Organizer: Annual Meeting of the Korean Society of Wood Science and Technology
  • Int'l Joint Research / Invited
• [Presentation] サイプレス材精油香気雰囲気下飼育によるマウスの肥満抑制 メカニズムの解明 (2021)
  • Author(s): 林 貴之, 山内 恒生, 光永 徹
  • Organizer: 第71回日本木材学会大会
• [Presentation] Garcinia kola 種子抽出成分の探索と口腔疾患原因菌に対する抗菌活性 (2021)
  • Author(s): 日置 裕介, Siaw ONWONA-AGYEMAN, 山内 恒生, 光永 徹
  • Organizer: 第71回日本木材学会大会
• [Presentation] 紫夏藤 (Millettia reticulata) 由来縮合型タンニンの構造解析とGTase阻害活性 (2021)
  • Author(s): 征矢野 真由、山内恒生、光永 徹
  • Organizer: 日本木材学会中部支部大会
• [Presentation] サイプレス材精油雰囲気下におけるマウスの肥満抑制作用とその作用機作 (2021)
  • Author(s): 林 貴之、山内恒生、光永徹
  • Organizer: 第65回 香料・テルペン及び精油化学に関する討論会
• [Presentation] がん遊走を阻害するquercetin誘導体の標的タンパク質の探索と作用機序の解明 (2021)
  • Author(s): 山内恒生，土屋綾香，小林美穂， 鎌足雄司, 光永 徹
  • Organizer: 日本ポリフェノール学会第14回学術集会
• [Presentation] 破骨細胞分化抑制活性を有する Daemonorops draco抽出物の成分探索 (2021)
  • Author(s): 土屋綾香，山内恒生，光永 徹
  • Organizer: 日本ポリフェノール学会第14回学術集会
• [Presentation] パープルハート(Peltogyne spp.) 芯材色素成分の構造と色調発現に関する研究 (2021)
  • Author(s): 多賀 勇亮，山内 恒生 ，光永 徹
  • Organizer: 日本ポリフェノール学会第14回学術集会