Development of transport system of NO and H2S based on Human serum albumin

• Project/Area Number: 15K08076
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: The University of Tokushima (2016-2017); Kumamoto University (2015)
• Principal Investigator: ISHIMA Yu 徳島大学, 大学院医歯薬学研究部(薬学系), 准教授 (00457590)
• Co-Investigator(Renkei-kenkyūsha): MARUYAMA Toru 熊本大学, 薬学部, 教授 (90423657)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ヒト血清アルブミン / 活性イオウ / 一酸化窒素 / 酸化ストレス疾 / 美白作用 / 酸化ストレス疾患 / 活性イオウ種 / Polysulfur / 抗酸化作用 / タンパク凝集

Outline of Final Research Achievements

This research is based on "the complete elucidation of the endogenous transport system of physiologically active gases by HSA and its clinical application", and the generation mechanism of modifications with NO or H2S have been clarified. As a result, it was inferred that crosstalk between NO and H2S. Also, in the measurement of Cysteine persulfide, it was confirmed that an oxidized form of polysulfide was abundantly present in HSA by the newly developed measurement method, and this oxidized form of polysulfide reacts sensitively to oxidative stress It was also possible to clarify that it changes from the early stage of the disease state.

Research Products

• [Journal Article] Thioredoxin-albumin fusion protein prevents copper enhanced zinc-induced neurotoxicity via its antioxidative activity. (2018)
  • Author(s): Tanaka KI, Shimoda M, Chuang VTG, Nishida K, Kawahara M, Ishida T, Otagiri M, Maruyama T, Ishima Y.
  • Journal Title: Int J Pharm. Volume: 535 Issue: 1-2 Pages: 140-147
  • DOI: 10.1016/j.ijpharm.2017.11.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dual therapeutic effects of an albumin-based nitric oxide donor on two experimental models of chronic kidney disease (2018)
  • Author(s): Oshiro S, Ishima Y, Maeda H, Honda N, Bi J, Kinoshita R, Ikeda M, Iwao Y, Imafuku T, Nishida K, Miyamura S, Watanabe H, Otagiri M, Maruyama T
  • Journal Title: J Pharm Sci Volume: 107 Issue: 3 Pages: 848-855
  • DOI: 10.1016/j.xphs.2017.10.023
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel S-sulfhydrated human serum albumin preparation suppresses melanin synthesis, (2018)
  • Author(s): Ikeda M, Ishima Y, Kinoshita R, Chuang VTG, Tasaka N, Matsuo N, Watanabe H, Shimizu T, Ishida T, Otagiri M, Maruyama T,
  • Journal Title: Redox Biology Volume: 14 Pages: 354-360
  • DOI: 10.1016/j.redox.2017.10.007
  • NAID: 120007029979
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Improved anticancer effects of albumin-bound paclitaxel nanoparticle via augmentation of EPR effect and albumin-protein interactions using S-Nitrosated Human Serum Albumin Dimer. (2017)
  • Author(s): Kinoshita R, Ishima Y, Chuang VTG, Nakamura H, Fang J, Watanabe H, Shimizu T, Okuhira K, Ishida T, Maeda H, Otagiri M, Maruyama T.
  • Journal Title: Biomaterials. Volume: 140 Pages: 162-169
  • DOI: 10.1016/j.biomaterials.2017.06.021
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Apoptosis induction of Poly-S-nitrosated human serum albumin in resistant solid tumor under hypoxia can be restored by phosphodiesterase 5 inhibition (2017)
  • Author(s): Ikeda M, Ishima Y, Chuang VTG, Ikeda T, Kinoshita R, Watanabe H, Ishida T, Otagiri M, Maruyama T
  • Journal Title: Nitric Oxide Volume: S1089-8603 Pages: 30269-5
  • DOI: 10.1016/j.niox.2017.04.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Quantitative determination of polysulfide in albumins, plasma proteins and biological fluid samples using a novel combined assays approach (2017)
  • Author(s): keda, M. Ishima, Y. Shibata, A. Chuang, V. T. G. Sawa, T. Ihara, H. Watanabe, H. Xian, M. Ouchi, Y. Shimizu, T. Ando, H. Ukawa, M. Ishida, T. Akaike, T. Otagiri, M. Maruyama, T.
  • Journal Title: Analytica Chimica Acta Volume: 969 Pages: 18-25
  • DOI: 10.1016/j.aca.2017.03.027
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Albumin-Based Nitric Oxide Traffic System for the Treatment of Intractable Cancers (2017)
  • Author(s): Ishima Y.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 40 Issue: 2 Pages: 128-134
  • DOI: 10.1248/bpb.b16-00867
  • NAID: 130005308413
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Human Serum Albumin as Carrier in Drug Delivery Systems (2016)
  • Author(s): 10.Ishima Y, Maruyama T
  • Journal Title: YAKUGAKU ZASSHI Volume: 136 Issue: 1 Pages: 39-47
  • DOI: 10.1248/yakushi.15-00227-1
  • NAID: 130005115184
  • ISSN: 0031-6903, 1347-5231
  • Year and Date: 2016-01-01
  • Peer Reviewed / Open Access
• [Journal Article] Mutants and molecular dockings reveal that the primary L-thyroxine binding site in human serum albumin is not the one which can cause familial dysalbuminemic hyperthyroxinemia. (2016)
  • Author(s): Kragh-Hansen U, Minchiotti L, Coletta A, Bienk K, Galliano M, Schiott B, Iwao Y, Ishima Y, Otagiri M
  • Journal Title: Biochim Biophys Acta. Volume: 1860 Issue: 4 Pages: 648-660
  • DOI: 10.1016/j.bbagen.2016.01.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human serum albumin hydropersulfide is a potent reactive oxygen species scavenger in oxidative stress conditions such as chronic kidney disease (2016)
  • Author(s): Shibata A, Ishima Y, Ikeda M, Sato H, Imafuku T, Chuang VT, Ouchi Y, Abe T, Watanabe H, Ishida T, Otagiri M, Maruyama T
  • Journal Title: Biochem Biophys Res Commun Volume: 479 Issue: 3 Pages: 578-583
  • DOI: 10.1016/j.bbrc.2016.09.113
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] S-Nitrosated human serum albumin dimer as novel nano-EPR enhancer applied to macromolecular anti-tumor drugs such as micelles and liposomes. (2015)
  • Author(s): Kinoshita R, Ishima Y, Ikeda M, Kragh-Hansen U, Fang J, Nakamura H, Chuang VT, Tanaka R, Maeda H, Kodama A, Watanabe H, Maeda H, Otagiri M, Maruyama T.
  • Journal Title: J Control Release. Volume: 217 Pages: 1-9
  • DOI: 10.1016/j.jconrel.2015.08.036
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nitration of indoxyl sulfate facilitates its cytotoxicity in human renal proximal tubular cells via expression of heme oxygenase-1. (2015)
  • Author(s): Ishima Y, Narisoko T, Kragh-Hansen U, Kotani S, Nakajima M, Otagiri M, Maruyama T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 465 Issue: 3 Pages: 481-7
  • DOI: 10.1016/j.bbrc.2015.08.043
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pleiotropic Effects of Levofloxacin, Fluoroquinolone Antibiotics, against Influenza Virus-Induced Lung Injury. (2015)
  • Author(s): Enoki Y, Ishima Y, Tanaka R, Sato K, Kimachi K, Shirai T, Watanabe H, Chuang VT, Fujiwara Y, Takeya M, Otagiri M, Maruyama T.
  • Journal Title: PLoS One. Volume: 10 Issue: 6 Pages: e0130248-e0130248
  • DOI: 10.1371/journal.pone.0130248
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Poly-S-nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide. (2015)
  • Author(s): Ishima Y, Inoue A, Fang J, Kinoshita R, Ikeda M, Watanabe H, Maeda H, Otagiri M, Maruyama T.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 2 Pages: 194-200
  • DOI: 10.1111/cas.12577
  • Peer Reviewed / Open Access
• [Journal Article] Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+/CD206+ Kupffer cell-targeted nano-antioxidant for the treatment of two acute hepatitis models. (2015)
  • Author(s): Maeda H, Hirata K, Watanabe H, Ishima Y, Chuang VT, Taguchi K, Inatsu A, Kinoshita M, Tanaka M, Sasaki Y, Otagiri M, Maruyama T.
  • Journal Title: J Pharmacol Exp Ther Volume: 352 Issue: 2 Pages: 244-257
  • DOI: 10.1124/jpet.114.219493
  • Peer Reviewed / Open Access
• [Presentation] 自然抗体としてのanti-PEG IgMがDoxilの血中濃度に与える影響 (2018)
  • Author(s): 久保幸代、清水太郎、鵜川真実、藤本麻葉、松本陽子、異島優、石田竜弘
  • Organizer: 日本薬学会第138年会
• [Presentation] 毛髪ケラチンに存在する活性イオウの発見と酸化ストレス応答 (2018)
  • Author(s): 田坂菜々美、池田真由美、清水太郎、異島優、石田竜弘
  • Organizer: 日本薬学会第138年会
• [Presentation] ポリスルフィド運搬体としてのヒト血清アルブミン (2018)
  • Author(s): 池田真由美、異島優、清水太郎、居原秀、赤池孝章、丸山徹、石田竜弘
  • Organizer: 日本薬学会第138年会
• [Presentation] 毛髪中に存在する活性イオウの発見とその生理的意義 (2017)
  • Author(s): 田坂菜々美、池田真由美、清水太郎、異島優、石田竜弘
  • Organizer: 第56回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
• [Presentation] 新規抗がん剤としての活性イオウ付加アルブミンの設計 (2017)
  • Author(s): 松尾菜々、池田真由美、清水太郎、異島優、石田竜弘
  • Organizer: 第56回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
• [Presentation] 酸化ストレスに応答するポリスルフィド化血清タンパク質の同定 (2017)
  • Author(s): 池田真由美、異島優、渡邊博志、小田切優樹、丸山徹、石田竜弘
  • Organizer: 第70回日本酸化ストレス学会学術集会
• [Presentation] ヒト血清アルブミンにおける活性イオウの検出と機能解明 (2017)
  • Author(s): 池田真由美、異島優、田坂菜々美、清水太郎、渡邊博志、小田切優樹、丸山徹、石田竜弘
  • Organizer: 第17回日本NO学会学術集会
• [Presentation] 毛髪中における活性イオウの検出とその生物活性評価 (2017)
  • Author(s): 田坂菜々美、池田真由美、清水太郎、異島優、石田竜弘
  • Organizer: 日本薬剤学会第32年会
• [Presentation] 活性イオウトラフィックタンパク質としてのヒト血清アルブミンの役割 (2017)
  • Author(s): 池田真由美、異島優、田坂菜々美、清水太郎、渡邊博志、小田切優樹、丸山徹、石田竜弘
  • Organizer: 日本薬剤学会第32年会
• [Presentation] 酸化ストレス早期発見に向けた血清パースルフィド定量の有用性評価 (2016)
  • Author(s): 池田 真由美、異島 優、渡邉 博志、石田 竜弘、小田切 優樹、丸山 徹
  • Organizer: 第33回日本薬学会九州支部大会
  • Place of Presentation: 鹿児島大学 群元キャンパス「鹿児島県・鹿児島市」
  • Year and Date: 2016-12-03
• [Presentation] 肝クッパー細胞指向性インターフェロンα2bの設計と肝保護効果 (2016)
  • Author(s): 皆吉 勇紀、前田 仁志、渡邊 博志、異島 優、小田切 優樹、丸山 徹
  • Organizer: 第33回日本薬学会九州支部大会
  • Place of Presentation: 鹿児島大学 群元キャンパス「鹿児島県・鹿児島市」
  • Year and Date: 2016-12-03
• [Presentation] S-ニトロソ化α1-酸性糖タンパク質によるガン治療への応用 (2016)
  • Author(s): 松坂 幸太朗、異島 優、木下 遼、渡邉 博志、小田切 優樹、丸山 徹
  • Organizer: 第33回日本薬学会九州支部大会
  • Place of Presentation: 鹿児島大学 群元キャンパス「鹿児島県・鹿児島市」
  • Year and Date: 2016-12-03
• [Presentation] NASH病態におけるDDS戦略の限界と一酸化窒素による治療抵抗性の克服 (2016)
  • Author(s): 前田 仁志、異島 優、皆吉 勇紀、一水 翔太、柳澤 洋輝、 渡邊 博志、小田切 優樹、丸山 徹
  • Organizer: 第38回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 名古屋市立大学大学院薬学研究科・薬学部「愛知県・名古屋市」
  • Year and Date: 2016-11-17
• [Presentation] S-Nitrosated human serum albumin dimer as a novel nano EPR enhancer applied to nanotechnology based anticancer drugs (2016)
  • Author(s): Ryo Kinoshita, Yu Ishima, Mayumi Ikeda, Jun Fang, Hiroshi Maeda,Masaki Otagiri, Toru Maruyama
  • Organizer: 2016Controlled Release Society Annual Meeting & Exposition
  • Place of Presentation: Seattle (USA)
  • Year and Date: 2016-07-17
  • Int'l Joint Research
• [Presentation] UW SOLUTION IMPROVED WITH HIGH ANTI-APOPTOTIC ACTIVITY BY S-NITROSATED HUMAN SERUM ALBUMIN (2016)
  • Author(s): Yu Ishima, Takuya Shinagawa, Shinji Yoneshige, Masaki Otagiri, Toru Maruyama
  • Organizer: The 16th Annual Scientific Meeting of the Nitric Oxide Society of Japan
  • Place of Presentation: 仙台国際センター「宮城県・仙台市」
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] S-Nitrosated human serum albumin dimer as a novel nano EPR enhancer applied to nanotechnology-based anticancer drug (2016)
  • Author(s): Ryo kinoshita, Yu Ishima, Mayumi Ikeda, Jun Fang, Hiroshi Maeda, Masaki Otagiri, Toru Maruyama
  • Organizer: Ryo kinoshita(D2), Yu Ishima, Mayumi Ikeda, Jun Fang, Hiroshi Maeda, Masaki Otagiri, Toru Maruyama
  • Place of Presentation: 仙台国際センター「宮城県・仙台市」
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Anti-tumor effect of Poly-S-nitrosated Human Serum Albumin is enhanced by phosphodiesterase 5 inhibitors. (2016)
  • Author(s): Mayumi Ikeda, Yu Ishima, Ryo Kinoshita, Hiroshi Watanabe, Tsuyoshi Ikeda, Masaki Otagiri, Toru Maruyama
  • Organizer: Ryo kinoshita(D2), Yu Ishima, Mayumi Ikeda, Jun Fang, Hiroshi Maeda, Masaki Otagiri, Toru Maruyama
  • Place of Presentation: 仙台国際センター「宮城県・仙台市」
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Sulfide Anti-Oxidant Buffer Enables Polysulfur to Be Detected by Methylene Blue Assay (2016)
  • Author(s): Mayumi Ikeda, Yu Ishima, Motonori Shibata, Hiroshi Watanabe, Ming Xian, Yuya Ouchi, Takaaki Akaike, Toru Maruyama
  • Organizer: Ryo kinoshita(D2), Yu Ishima, Mayumi Ikeda, Jun Fang, Hiroshi Maeda, Masaki Otagiri, Toru Maruyama
  • Place of Presentation: 仙台国際センター「宮城県・仙台市」
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Therapeutic potential of S-nitrosated α1-acid glycoprotein as a novel antibacterial agent (2016)
  • Author(s): Kotaro Matsusaka, Yu Ishima, Kaori Watanabe, Hiroshi Watanabe, Masaki Otagiri, Toru Maruyama
  • Organizer: Ryo kinoshita(D2), Yu Ishima, Mayumi Ikeda, Jun Fang, Hiroshi Maeda, Masaki Otagiri, Toru Maruyama
  • Place of Presentation: 仙台国際センター「宮城県・仙台市」
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] S-ニトロソ化 α1-酸性糖タンパク質による癌治療への応用 (2016)
  • Author(s): 松坂幸太朗、異島 優、木下 遼、渡邊博志、小田切優樹、丸山 徹
  • Organizer: 日本薬剤学会 第31回年会
  • Place of Presentation: 長良川国際会議場「岐阜県・岐阜市」
  • Year and Date: 2016-05-19
• [Presentation] PEGリポソームへのアルブミン修飾は、抗PEG抗体の産生を抑制する (2016)
  • Author(s): 山﨑 仁王、異島 優、清水 太郎、石田 竜弘
  • Organizer: 中国四国支部学術大会
  • Place of Presentation: 就実大学「岡山県・岡山市」
• [Presentation] S-Nitrosated human serum albumin dimer as novel nano EPR enhancer applied to nano-anticancer drugs (2015)
  • Author(s): Ryo Kinoshita, Yu Ishima, Mayumi Ikeda, Jun Fang, Hiroshi Maeda, Masaki Otagiri, Toru Maruyama
  • Organizer: Asian Federation for Pharmaceutical Sciences 2015
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2015-11-25
  • Int'l Joint Research
• [Presentation] Anti-tumor effect of Poly-S-nitrosated Human Serum Albumin is enhanced by phosphodiesterase 5 inhibitors. (2015)
  • Author(s): Mayumi Ikeda, Yu Ishima, Ryo Kinoshita, Hiroshi Watanabe, Tsuyoshi Ikeda, Masaki Otagiri, Toru Maruyama
  • Organizer: Asian Federation for Pharmaceutical Sciences 2015
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2015-11-25
  • Int'l Joint Research
• [Presentation] タンパク製剤を利用した酸化ストレス関連疾患への応用 (2015)
  • Author(s): 異島 優
  • Organizer: 第29回 日本キチン・キトサン学会大会
  • Place of Presentation: 東海大学熊本校舎、熊本
  • Year and Date: 2015-08-20
  • Invited
• [Presentation] Poly-S-二トロソ化ヒト血清アルブミンのHIF-1alpha抑制効果 (2015)
  • Author(s): 異島 優、井上 亜希、小田切 優樹、渡邊 博志、丸山 徹
  • Organizer: 第31回 日本DDS学会学術集会
  • Place of Presentation: 京王プラザホテル、東京
  • Year and Date: 2015-07-02
• [Presentation] 高分子抗癌剤治療における新規ナノEPR増強剤としての一酸化窒素付加アルブミン二量体の有用性評価 (2015)
  • Author(s): 異島 優、木下 遼、池田 真由美、渡邊 博志、小田切 優樹、丸山 徹
  • Organizer: 第15回 日本NO学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター、大阪
  • Year and Date: 2015-06-27
• [Book] Albumin in Medicine (2016)
  • Author(s): Masaki Otagiri, Victor Tuan Giam Chuang, Yu IShima
  • Total Pages: 277
  • Publisher: Springer
• [Remarks] 徳島大学大学院医歯薬学研究部 薬物動態制御学分野
  • URL: http://www.tokushima-u.ac.jp/ph/faculty/labo/ykz/
• [Remarks] 徳島大学薬学部薬物動態制御学
  • URL: http://www.tokushima-u.ac.jp/ph/faculty/labo/ykz/
• [Remarks] 熊本大学薬剤学分野
  • URL: http://www.pharm.kumamoto-u.ac.jp/Labs/Yakuzai/index.html
• [Patent(Industrial Property Rights)] 美白化粧料、及びそれに含まれるアルブミン系化合物の製造方法 (2017)
  • Inventor(s): 丸山徹、池田真由美、異島優、水田夕稀
  • Industrial Property Rights Holder: 丸山徹、池田真由美、異島優、水田夕稀
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-019852
  • Filing Date: 2017