腎指向性を付与した一酸化炭素送達システムの創製と致死性横紋筋融解症治療への展開

2020 Fiscal Year Annual Research Report

• Project/Area Number: 18H02604
• Research Institution: Kumamoto University
• Principal Investigator: 丸山 徹 熊本大学, 大学院生命科学研究部(薬), 教授 (90423657)
• Co-Investigator(Kenkyū-buntansha): 渡邊 博志 熊本大学, 大学院生命科学研究部(薬), 准教授 (70398220) ; 前田 仁志 熊本大学, 大学院生命科学研究部(薬), 助教 (80791483)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: COデリバリーシステム / 横紋筋融解症 / 急性腎障害 / アルブミン創薬プラットフォーム / 災害医療 / アルブミン融合技術 / 一酸化炭素

Outline of Annual Research Achievements

前年度までに検討したクラッシュ症候群誘発AKIモデルに対する腎指向型COデリバリーシステムの治療効果(生存率、腎機能、腎障害、血液及び生化学パラメータ、尿所見)を再度検証した。ここでは、コントロール群としてsaline群と腎指向性ペプチドを付与していないCOデリバリーシステムを用いた。その結果、saline投与群では全てのラットが5時間以内に死亡したのに対して、腎指向性ペプチドを付与していないCOデリバリーシステムでは48時間後で40%の生存を認め、腎指向型COデリバリーシステム投与群では48時間後でも100%の生存が確認された。そこで、腎指向性ペプチドを付与していないCOデリバリーシステムが全例生存した24時間後における腎機能、腎障害、血液及び生化学パラメータ、尿所見を評価したところ、生存率の結果を反映し、いずれにおいても腎指向型COデリバリーシステム投与による改善効果を認めた。また、本モデルに対するCO供給能を、血中CO濃度推移ならびに腎臓と他の臓器内濃度により評価した。その結果、血中CO濃度は静脈内投与後すみやかに減少し、90分後でベースライン付近の値を示したことから、投与後90分以降では臓器への移行が完了したと判断した。投与後90分における腎臓中CO量は、肝臓と比較すると低値を示したものの、臓器重量で補正すると肝臓と同程度であり、肺や心臓と比較して高値であったことから、COデリバリーシステムの腎指向性を確認した。最後に、COによる腎保護効果のメカニズムをヒト近位尿細管細胞を用いて検討した。低分子CO供与体であるCORMの処理により、ATP合成を促進することで組織修復を司どるAMPK、生体内の抗酸化防御システムを担うNrf-2の活性化を認めたことから、腎指向型COデリバリーシステムによる腎障害の抑制メカニズムには、上記分子の関与が示唆された。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Cysteinylated albumin as a potential biomarker for the progression of kidney disease in patients with type 2 diabetes (2021)
  • Author(s): Imafuku T, Watanabe H, Oniki K, Yoshida A, Kato H, Nakano T, Tokumaru K, Fujita I, Arimura N, Maeda H, Sakamoto Y, Kondo N, Morita A, Saruwatari J, Tanaka M, Matsushita K, Wada T, Fukagawa M, Otagiri M, Fitzgerald ML, Jinnouchi H, Maruyama T.
  • Journal Title: Diabetes Care Volume: 26 Pages: dc203003.
  • DOI: 10.2337/dc20-3003.
  • Peer Reviewed / Open Access
• [Journal Article] An acute phase protein alfa1-acid glycoprotein mitigates AKI and its progression to CKD through its anti-inflammatory action (2021)
  • Author(s): Hiroshi Watanabe*,#, Rui Fujimura*, Yuto Hiramoto*, Ryota Murata, Kento Nishida, Jing Bi, Tadashi Imafuku, Hisakazu Komori, Hitoshi Maeda, Ayumi Mukunoki, Toru Takeo, Naomi Nakagata, Motoko Tanaka, Kazutaka Matsushita, Masafumi Fukagawa, Toru Maruyama# *equal contribution; #equal correspondence
  • Journal Title: Sci Rep. Volume: 12;11(1) Pages: 7953
  • DOI: 10.1038/s41598-021-87217-8.
  • Peer Reviewed / Open Access
• [Journal Article] Reduction-responsive and multi-drug deliverable albumin nanoparticles: an antitumor drug to Abraxane_ against human pancreatic tumor-bearing mice (2021)
  • Author(s): Naoki Hirakawa, Yu Ishima, Ryo Kinoshita, Ryuto Nakano, Victor Tuan Giam Chuang, Hidenori Ando, Taro Shimizu, Keiichiro Okuhira, Toru Maruyama, Masaki Otagiri, Tatsuhiro Ishida
  • Journal Title: ACS Applied Bio Materials Volume: 4,5 Pages: 4302-4309
  • DOI: 10.1016/j.lfs.2020.118991.
  • Peer Reviewed / Open Access
• [Journal Article] Sacran, a sulfated polysaccharide, suppresses the absorption of lipids and modulates the intestinal flora in non-alcoholic steatohepatitis model rats (2021)
  • Author(s): Miwa Goto, Kazuo Azuma, Hidetoshi Arima, Shinichiro Kaneko, Taishi Higashi, Keiichi Motoyama, Akihiro Michihara, Takae Shimizu, Daisuke Kadowaki, Toru Maruyama, Masaki Otagiri, Daisuke Iohara, Fumitoshi Hirayama, Makoto Anraku
  • Journal Title: Life Sci Volume: 1;268 Pages: 118991
  • DOI: 10.1111/1744-9987.13500.
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of a new measurement method of indoxyl sulfate in hemodialysis patients (2020)
  • Author(s): Takaya Abe, Mitsutaka Onoda, Tomohiko Matsuura, Jun Sugimura, Wataru Obara, Nariyuki Sasaki, Tetsuo Kato, Kenta Tatsumi, Toru Maruyama
  • Journal Title: Ther Apher Dial Volume: 25(1) Pages: 44-49.
  • DOI: 10.1248/bpb.b20-00472.
  • Peer Reviewed / Open Access
• [Journal Article] Effect of cinacalcet on the redox status of albumin in secondary hyperparathyroidism patients receiving hemodialysis (2020)
  • Author(s): Tadashi Imafuku, Motoko Tanaka, Koki Tokunaga, Shigeyuki Miyamura, Hiromasa Kato, Shoma Tanaka, Takehiro Nakano, Kenshiro Hirata, Daisuke Kadowaki, Hitoshi Maeda, Kazutaka Matsushita, Masaki Otagiri, Hirotaka Komaba, Masafumi Fukagawa, Hiroshi Watanabe, Toru Maruyama
  • Journal Title: Biol Pharm Bull Volume: 43(10) Pages: 1583-1590
  • DOI: 10.1248/bpb.b20-00929.
  • Peer Reviewed / Open Access
• [Journal Article] Effects of uremic toxins on the binding of aripiprazole to human serum albumin (2020)
  • Author(s): Koji Nishi, Keiki Sakurama, Hiroshi Watanabe, Toru Maruyama, Keishi Yamasaki, Masaki Otagiri
  • Journal Title: Biol Pharm Bull Volume: 44(3) Pages: 437-441
  • DOI: 10.1016/j.ijbiomac.2020.07.184.
  • Peer Reviewed / Open Access
• [Journal Article] Effects of surface-deacetylated chitin nanofibers on non-alcoholic steatohepatitis model rats and their gut microbiota (2020)
  • Author(s): Miwa Goto, Daisuke Iohara, Akihiro Michihara, Shinsuke Ifuku, Kazuo Azuma, Daisuke Kadowaki, Toru Maruyama, Masaki Otagiri, Fumitoshi Hirayama, Makoto Anraku
  • Journal Title: Int J Biol Macromol Volume: 1;164 Pages: 659-666
  • DOI: 10.1248/cpb.c20-00026.
  • Peer Reviewed / Open Access
• [Journal Article] Drug delivery system for refractory cancer therapy via an endogenous albumin transport system (2020)
  • Author(s): Yu Ishima, Toru Maruyama, Masaki Otagiri, Tatsuhiro Ishida
  • Journal Title: Chem Pharm Bull (Tokyo) Volume: 68(7) Pages: 583-588
  • DOI: 10.1038/s41598-020-75025-5.
  • Peer Reviewed / Open Access
• [Journal Article] Systemic and sustained thioredoxin analogue prevents acute kidney injury and its-associated distant organ damage in renal ischemia reperfusion injury mice (2020)
  • Author(s): Kento Nishida*, Hiroshi Watanabe*,#, Masako Miyahisa, Yuto Hiramoto, Hiroto Nosaki, Rui Fujimura, Hitoshi Maeda, Masaki Otagiri, Toru Maruyama# *equal contribution; #equal correspondence
  • Journal Title: Sci Rep Volume: 26;10(1) Pages: 20635
  • DOI: 10.3390/antiox9100965.
  • Peer Reviewed / Open Access
• [Journal Article] The late-stage protective effect of Mito-TEMPO against acetaminophen-induced hepatotoxicity in mouse and three-dimensional cell culture models (2020)
  • Author(s): Mohammad Abdullah-Al-Shoeb, Kenta Sasaki, Saori Kikutani, Nanami Namba, Keiichi Ueno, Yuki Kondo, Hitoshi Maeda, Toru Maruyama, Tetsumi Irie, Yoichi Ishitsuka
  • Journal Title: Antioxidants (Basel) Volume: 9;9(10) Pages: 965
  • DOI: 10.1016/j.xphs.2020.06.011.
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of the Interaction of Daptomycin With Site II on Human Serum Albumin (2020)
  • Author(s): Keishi Yamasaki, Keiki Sakurama, Koji Nishi, Hiroshi Watanabe, Toru Maruyama, Hakaru Seo, Masaki Otagiri, Kazuaki Taguchi
  • Journal Title: J Pharm Sci Volume: 109(9) Pages: 2919-2924
  • DOI: 10.3390/toxins12080502.
  • Peer Reviewed / Open Access
• [Journal Article] Indoxyl sulfate contributes to adipose tissue inflammation through the activation of NADPH oxidase (2020)
  • Author(s): Shoma Tanaka*, Hiroshi Watanabe*,#, Takehiro Nakano, Tadashi Imafuku, Hiromasa Kato, Kai Tokumaru, Nanaka Arimura, Yuki Enoki, Hitoshi Maeda, Motoko Tanaka, Kazutaka Matsushita, Masafumi Fukagawa, Toru Maruyama# *equal contribution; #equal correspondence
  • Journal Title: Toxins (Basel) Volume: 5;12(8) Pages: 502
  • DOI: 10.1016/j.jconrel.2020.05.036.
  • Peer Reviewed / Open Access
• [Journal Article] Development of a long acting FGF21 analogue-albumin fusion protein and its anti-diabetic effects (2020)
  • Author(s): Hiroshi Watanabe*,#, Masako Miyahisa*, Mayuko Chikamatsu*, Kento Nishida, Yuki Minayoshi, Mei Takano, Shota Ichimizu, Yoshihiro Kobashigawa, Hiroshi Morioka, Hitoshi Maeda, Toru Maruyama# *equal contribution; #equal correspondence
  • Journal Title: J Control Release Volume: 10;324: Pages: 522-531
  • DOI: 10.1038/s41598-020-68337-z.
  • Peer Reviewed / Open Access
• [Journal Article] A synthetic retinoic acid receptor agonist Am80 ameliorates renal fibrosis via inducing the production of alpha-1-acid glycoprotein (2020)
  • Author(s): Hiroshi Watanabe*,#, Jing Bi *, Ryota Murata *, Rui Fujimura , Kento Nishida, Tadashi Imafuku, Yuka Nakamura, Hitoshi Maeda, Ayumi Mukunoki, Toru Takeo, Naomi Nakagata , Yuki Kurauchi, Hiroshi Katsuki , Motoko Tanaka, Kazutaka Matsushita , Masafumi Fukagawa, Toru Maruyama# *equal contribution; #equal correspondence
  • Journal Title: Sci Rep Volume: 10;10(1) Pages: 11424
  • DOI: 10.34067/KID.0000772019
  • Peer Reviewed / Open Access
• [Journal Article] Advanced oxidation protein products contribute to renal tubulopathy via perturbation of renal fatty acids (2020)
  • Author(s): Imafuku T, Watanabe H, Satoh T, Matsuzaka T, Inazumi T, Kato H, Tanaka S, Nakamura Y, Nakano T, Tokumaru K, Maeda H, Mukunoki A, Takeo T, Nakagata N, Tanaka M, Matsushita K, Tsuchiya S, Sugimoto Y, Shimano H, Fukagawa M, Maruyama T.
  • Journal Title: Kidney360 Volume: 1;(8) Pages: 781-796
  • DOI: 10.1016/j.clinbiochem.2020.04.010.
  • Peer Reviewed / Open Access
• [Journal Article] Changes in redox state of albumin before and after kidney transplantation in patients with end-stage renal disease (2020)
  • Author(s): Ryota Tanaka, Tadashi Imafuku, Yosuke Suzuki, Kento Nishida, Kotaro Matsusaka, Toshitaka Shin, Yuhki Sato, Yu Ishima, Hiroshi Watanabe, Hiromitsu Mimata, Toru Maruyama, Hiroki Itoh
  • Journal Title: Clin Biochem Volume: 81 Pages: 20-26
  • DOI: 10.1371/journal.pone.0233925.
  • Peer Reviewed / Open Access
• [Journal Article] In vivo evaluation of drug dialyzability in a rat model of hemodialysis (2020)
  • Author(s): Masaki Fukunaga, Daisuke Kadowaki, Mika Mori, Satomi Hagiwara, Yuki Narita, Junji Saruwatari, Ryota Tanaka, Hiroshi Watanabe, Keishi Yamasaki, Kazuaki Taguchi, Hiroki Ito, Toru Maruyama, Masaki Otagiri, Sumio Hirata
  • Journal Title: PLoS One Volume: 12;15(6) Pages: e0233925
  • DOI: 10.3390/antiox9050387.
  • Peer Reviewed / Open Access
• [Journal Article] The DsbA-L gene is associated with respiratory function of the elderly via its adiponectin multimeric or antioxidant properties (2020)
  • Author(s): Kentaro Oniki, Hirofumi Nohara, Ryunosuke Nakashima, Yui Obata, Narumi Muto, Yuki Sakamoto, Keiko Ueno-Shuto, Tadashi Imafuku, Yu Ishima 5 , Hiroshi Watanabe, Toru Maruyama, Koji Otake, Yasuhiro Ogata, Mary Ann Suico, Hirofumi Kai, Tsuyoshi Shuto, Junji Saruwatari
  • Journal Title: Sci Rep Volume: 6;10(1) Pages: 5973
  • DOI: 10.34067/KID.0000782019
  • Peer Reviewed / Open Access
• [Journal Article] alfa1-acid glycoprotein attenuates adriamycin-induced nephropathy via CD163 expressing macrophages induction. (2020)
  • Author(s): Rui Fujimura*, Hiroshi Watanabe*,#, Kento Nishida, Yukio Fujiwara, Tomoaki Koga T, Jing Bi, Tadashi Imafuku, Kazuki Kobayashi, Hisakazu Komori, Masako Miyahisa, Hitoshi Maeda, Motoko Tanaka, Kazutaka Matsushita, Takashi Wada, Masafumi Fukagawa, Toru Maruyama T# *equal contribution and #equal corresponding author
  • Journal Title: Kidney360 Volume: 1;(5) Pages: 343-353
  • DOI: 10.34067/KID.0000782019
  • Peer Reviewed / Open Access