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医学科・大学院医歯学総合研究科(医学系)

教授
客員教授
助教
所在地
MAIL
分野HP

概要

 国民の健康維持、増進を図り、社会全体の公益に寄与することを目的として、当講座は2020年4月にジョイントリサーチ講座として開設されました。

概要

 加齢や外傷、疾病などによって失われた臓器を再生する技術は、近年急速に進歩しています。私たちは、次世代再生医療の担い手として、エム・テックス株式会社/株式会社ASPiA(旧株式会社笹原商事)が共同開発した、マジックファイバーに注目しています。マジックファイバーは、直径数ナノメートルという極めて細い繊維で構成された綿状の素材ですが、油を吸着するが水を吸収しないという優れた特徴を持ちます。2019年8月に発生した九州北部大雨に伴う佐賀鉄工所大町工場からの油流出事故、および2020年8月に発生したモーリシャス諸島での貨物船座礁事故に伴う油流出事故において、マジックファイバーは油処理作業に大活躍しました。

https://www.youtube.com/watch?v=aNxykdKS0X4&t=4s

 マジックファイバー油吸着材を使用した取り組みは「令和元年度 災害対応支援環境大臣表彰」を受賞しました。

https://www.env.go.jp/press/109377.html

 また、国民医療費が40兆円を超える現在において、健康寿命を延ばすという目標のもと、予防医学の重要度がますます高くなっています。予防医学の新たな担い手として、私たちは株式会社ASPiAの援助を得て、酸素ナノバブル、銀イオン水の機能に期待し、研究を進めています。
 加齢は骨粗鬆症/サルコペニア/変形性関節症などの運動器疾患、生活習慣病、循環器障害、発癌などの危険因子です。近年、生体の加齢変化は単なる物理的な劣化ではなく、分子シグナルによって積極的に制御された、生理活動であることが明らかとされました。この事実は、分子を意図的に操作することによって、加齢変化を予防することが可能であることを示唆します。私たちはこれまで、老化と疾患発症、代謝障害のメカニズムを解明することを目標として、サーチュイン遺伝子やPAI-1などの老化制御因子、腸内細菌叢、HIF(Hypoxia Inducible Factor; 低酸素誘導因子)などに注目し、これらの機能評価を行ってきました。細胞の低酸素環境に反応して活性化する転写因子HIF-1を発見し、その機能をつきとめた米ジョンズ・ホプキンズ大学のGregg L. Semenza教授,英オックスフォード大学のSir Peter J. Ratcliffe教授,米ハーバード大学のWilliam G. Kaelin教授が、2019年度のノーベル生理学・医学賞を受賞したことは記憶に新しいところです。HIF-1は、骨粗鬆症をはじめとして老化に伴う組織の退行性変化を制御しますが、酸素ナノバブル水により、HIF-1の異常な活性化が阻止されることが明らかとなってきています。

Outline

研究内容

  • ① 改良マジックファイバーを担体として活用した再生医療

    マジックファイバーは、素材、3次構造、繊維の太さなどに高い自由度を持ちます。細胞や成長因子などの担体として最適化した、改良マジックファイバーを開発し、再生医療を推進します。

  • ② 低酸素血症に対する酸素ナノバブル投与効果の検証

    私たちは、岐阜大学との共同研究により、ビーグル犬を用いて、酸素ナノバブル水の飲水が、全身麻酔下での呼吸抑制による低酸素血症を防ぐことを明らかにしました(日本宇宙航空環境医学会、および日本航空医療学会にて報告)。この成果は、酸素ナノカプセル水が、低酸素環境下での労働能力を向上させる可能性を示唆します。HIF-1活性化は、様々な退行性変化や癌の悪性化の原因であると報告されていますが、私たちは、酸素ナノバブル水投与による、治療/予防効果の検証を行います。

  • ③ 銀イオン水の抗ウイルス効果/感染性疾患に対する効果の検証

    従来から抗菌効果が広く知られている銀イオン水の、抗ウイルス効果やその持続性、濃度依存性などを検証し、新型コロナウイルス対策を目的とした開発を行います。

  • ④ 老化と疾患発症、代謝障害のメカニズム解明

    近年、長寿遺伝子サーチュインを活性化し、若返りが期待されるとして、NMN(ニコチンアミドモノヌクレオチド)が健康食品として注目されています。私たちは長年、サーチュイン遺伝子のひとつであるSIRT6に着目し、骨軟骨組織の加齢メカニズムを研究し、加齢にともなうSIRT6の活性低下は、骨粗鬆症、変形性膝関節症の原因となることを突き止めました。私たちは、骨や軟骨を中心にした生体の老化現象に対して、NMNの効果を検証します。PAI-1(Plasminogen Activator Inhibitor-1)は、細胞老化のマーカーかつそれ自身で細胞老化を惹起しますが、私たちは骨格系組織の代謝におけるPAI-1の機能を研究しています。私たちは、PAI-1阻害により、閉経後骨粗鬆症を予防すること、加齢に伴う筋力低下を予防することを見出しました。

  • ⑤ 腸内細菌による加齢制御機構の解明

    腸内には数10兆個という莫大な数の腸内細菌が生息しています。近年、腸内細菌の機能が注目され、腸内細菌と臓器間において多様なネットワークが構成されていることが明らかとなってきました。私たちは腸内細菌による骨格系組織の制御機構に注目し、研究を進めています。ポリフェノールの一つであるプロアントシアニジンは抗酸化作用が注目されていますが、分子量が大きく、消化管からはほとんど吸収されません。私たちは東北大学との共同研究により、アントシアニジンの経口摂取が、腸内細菌叢を変化させ、マウス卵巣摘出モデルの骨量低下、肥満を予防することを見出しました。この成果の一部は、プレスリリースされました。

論文業績

原著

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  3. Proanthocyanidin-rich grape seed extract improves bone loss, bone healing, and implant osseointegration in ovariectomized animals. Tenkumo T, Aobulikasimu A, Asou Y, Shirato M, Shishido S, Kanno T, Niwano Y, Sasaki K, Nakamura K. Scientific Reports 2020 Jun 1;10(1):8812.  IF 4.120

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  5. Osteoclast-Like Cells in Aneurysmal Disease Exhibit an Enhanced Proteolytic Phenotype. Kelly MJ, Igari K, Yamanouchi D. Int J Mol Sci. 2019 Sep 21;20(19). IF 4.183

  6. Digoxin Attenuates Receptor Activation of NF-κB Ligand-Induced Osteoclastogenesis in Macrophages. Igari K, Kelly MJ, Yamanouchi D. J Vasc Res. 2019;56(2):55-64. IF 1.855

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  13. A small-molecule PAI-1 inhibitor prevents bone loss by stimulating bone formation in a murine estrogen deficiency-induced osteoporosis model. Jin G, Aobulikasimu A, Piao J, Aibibula Z, Koga D, Sato S, Ochi H, Tsuji K, Nakabayashi T, Miyata T, Okawa A, Asou Y. FEBS Open Bio. 2018 Feb 16;8(4):523-532. doi: 10.1002/2211-5463.12390.  IF 1.782

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  16. Hyperglycemia attenuates receptor activator of NF-κB ligand-induced macrophage activation by suppressing insulin signaling. Kurihara C, Tanaka T, Yamanouchi D. J Surg Res. 2017 Jun 15;214:168-175. IF 2.051

  17. Hyperglycemia Suppresses RANKL-Induced Osteoclast Differentiation through LXRβ Expression in RAW264.7 Cells. Tanaka T, Takei Y, Zaima N, Moriyama T, Yamanouchi D.J Nutr Sci Vitaminol (Tokyo). 2017;63(1):28-34. IF 0.952

  18. Intraoperative evaluation of the effects of femoral component offset and head size on joint stability in total hip arthroplasty. Jinno T, Koga D, Asou Y, Morita S, Okawa A, Muneta T. J Orthop Surg (Hong Kong). 2017 Jan 1;25(1):2309499016684298. IF 0.994

  19. Pleiotropic Functions of High Fat Diet in the Etiology of Osteoarthritis. Asou Y, Iwata M, Ochi H, Ailixiding M, Aibibula Z, Piao J, Jin G, Hara Y, Okawa A. PLoS One. 2016 Sep 9;11(9):e0162794. IF 2.806

  20. Osteoclastogenic Differentiation of Macrophages in the Development of Abdominal Aortic Aneurysms. Takei Y, Tanaka T, Kent KC, Yamanouchi D. Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1962-71. IF 6.607

  21. Puerarin Suppresses Macrophage Activation via Antioxidant Mechanisms in a CaPO4-Induced Mouse Model of Aneurysm. Tanaka T, Moriyama T, Kawamura Y, Yamanouchi D. J Nutr Sci Vitaminol (Tokyo). 2016;62(6):425-431. IF 0.952

  22. Inter-rater agreement and checklist validation for postoperative wound assessment using smartphone images in vascular surgery. Wiseman JT, Fernandes-Taylor S, Gunter R, Barnes ML, Saunders RS, Rathouz PJ, Yamanouchi D, Kent KC.  J Vasc Surg Venous Lymphat Disord. 2016 Jul;4(3):320-328. IF 1.143

  23. Hyperglycemia Suppresses Calcium Phosphate-Induced Aneurysm Formation Through Inhibition of Macrophage Activation. Tanaka T, Takei Y, Yamanouchi D. J Am Heart Assoc. 2016 Mar 28;5(3) IF 4.425

  24. Xanthine oxidoreductase activation is implicated in the onset of metabolic arthritis. Aibibula Z, Ailixiding M, Iwata M, Piao J, Hara Y, Okawa A, Asou Y. Biochem Biophys Res Commun. 2016 Mar 25;472(1):26-32. IF 2.466

  25. Limited significance of screening computed tomography after cementless total hip arthroplasty with highly cross-linked polyethylene at 7-10 years of follow-up. Takada R, Jinno T, Koga D, Yamauchi Y, Asou Y, Muneta T, Okawa A. Mod Rheumatol. 2016 Feb 16:1-4.

  26. Case Report of Percutaneous Retrograde Transcollateral Recanalization of the Superior Mesenteric Artery via the Celiac Artery for Acute Mesenteric Ischemia. Gupta PK, Smith BK, Yamanouchi D. Medicine (Baltimore). 2015 Dec;94(50):e2036. IF 2.133

  27. MicroRNA-145 regulates osteoblastic differentiation by targeting the transcription factor Cbfb. Fukuda T, Ochi H, Sunamura S, Haiden A, Bando W, Inose H, Okawa A, Asou Y, Takeda S. FEBS Lett. 2015 Oct 24;589(21):3302-8.  IF 3.169

  28. Pivotal role of Sirt6 in the crosstalk among ageing, metabolic syndrome and osteoarthritis. Ailixiding M, Aibibula Z, Iwata M, Piao J, Hara Y, Koga D, Okawa A, Morita S, Asou Y. Biochem Biophys Res Commun. 2015 Oct 23;466(3):319-26. doi: 10.1016/j.bbrc.2015.09.019. IF 2.297

  29. Mitochondrial superoxide in osteocytes perturbs canalicular networks in the setting of age-related osteoporosis. Kobayashi K, Nojiri H, Saita Y, Morikawa D, Ozawa Y, Watanabe K, Koike M, Asou Y, Shirasawa T, Yokote K, Kaneko K, Shimizu T. Scientific Reports. 2015 Mar 16;5:9148. IF 5.578

  30. Enhancement of Runx2 expression is potentially linked to β-catenin accumulation in canine intervertebral disc degeneration. Iwata M, Aikawa T, Hakozaki T, Arai K, Ochi H, Haro H, Tagawa M, Asou Y, Hara Y. J Cell Physiol. 2014 Jun 11. IF 3.874

  31. Tumor necrosis factor-α enhances RANKL expression in gingival epithelial cells via protein kinase A signaling. Fujihara R, Usui M, Yamamoto G, Nishii K, Tsukamoto Y, Okamatsu Y, Sato T, Asou Y, Nakashima K, Yamamoto M. J Periodontal Res. 2014 Aug;49(4):508-17 IF 2.215

  32. Sirt6 regulates postnatal growth plate differentiation and proliferation via Ihh signaling. Piao J, Tsuji K, Ochi H, Iwata M, Koga D, Okawa A, Morita S, Takeda S, Asou Y. Scientific Reports. 2013 Oct 23;3:3022 IF 5.578

  33. Current status of medical treatment for abdominal aortic aneurysm. Kurosawa K, Matsumura JS, Yamanouchi D. Circ J. 2013;77(12):2860-6. Review. IF 3.685

  34. Aneurysmal disease: the abdominal aorta. Takayama T, Yamanouchi DSurg Clin North Am. 2013 Aug;93(4):877-91. Review. IF 1.932

  35. Cytoplasmic reactive oxygen species and SOD1 regulate bone mass during mechanical unloading. Morikawa D, Nojiri H, Saita Y, Kobayashi K, Watanabe K, Ozawa Y, Koike M, Asou Y, Takaku T, Kaneko K, Shimizu T. J Bone Miner Res. 2013 Nov;28(11):2368-80. IF 6.128

  36. Variations in gene and protein expression in canine chondrodystrophic nucleus pulposus cells following long-term three-dimensional culture. Iwata M, Ochi H, Asou Y, Haro H, Aikawa T, Harada Y, Nezu Y, Yogo T, Tagawa M, Hara Y. PLoS One. 2013 May 2;8(5):e63120. IF 3.73

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  38. Sema3A regulates bone-mass accrual through sensory innervations. Fukuda T, Takeda S, Xu R, Ochi H, Sunamura S, Sato T, Shibata S, Yoshida Y, Gu Z, Kimura A, Ma C, Xu C, Bando W, Fujita K, Shinomiya K, Hirai T, Asou Y, Enomoto M, Okano H, Okawa A, Itoh H. Nature. 2013 May 23;497(7450):490-3.  IF 38.597

  39. Initial responses of articular tissues in a murine high-fat diet-induced osteoarthritis model: pivotal role of the IPFP as a cytokine fountain. Iwata M, Ochi H, Hara Y, Tagawa M, Koga D, Okawa A, Asou Y. PLoS One. 2013 Apr 12;8(4) IF 3.73

  40. Evaluation of the association between runt-related transcription factor 2 expression and intervertebral disk aging in dogs. Itoh H, Hara Y, Tagawa M, Kato T, Ochi H, Koga D, Okawa A, Asou Y. Am J Vet Res. 2012 Oct;73(10):1553-9.  IF 1.269

  41. Balanced mineralization in the arterial system: possible role of osteoclastogenesis/osteoblastogenesis in abdominal aortic aneurysm and stenotic disease. Yamanouchi D, Takei Y, Komori K.  Circ J. 2012;76(12):2732-7. Review. IF 3.578

  42. Accelerated aneurysmal dilation associated with apoptosis and inflammation in a newly developed calcium phosphate rodent abdominal aortic aneurysm model. Yamanouchi D, Morgan S, Stair C, Seedial S, Lengfeld J, Kent KC, Liu B. J Vasc Surg. 2012 Aug;56(2):455-61. IF 2.879

  43. Suwanabol PA, Seedial SM, Shi X, Zhang F, Yamanouchi D, Roenneburg D, Liu B, Kent KC. Transforming growth factor-β increases vascular smooth muscle cell proliferation through the Smad3 and extracellular signal-regulated kinase mitogen-activated protein kinases pathways. J Vasc Surg. 2012 Aug;56(2):446-54. IF 2.879

  44. Comparison of different distal designs of femoral components and their effects on bone remodeling in 1-stage bilateral total hip arthroplasty. Yamauchi Y, Jinno T, Koga D, Asou Y, Morita S, Okawa A. J Arthroplasty. 2012 Sep;27(8):  IF 2.384

  45. Runx2 haploinsufficiency ameliorates the development of ossification of the posterior longitudinal ligament.Iwasaki M, Piao J, Kimura A, Sato S, Inose H, Ochi H, Asou Y, Shinomiya K, Okawa A, Takeda S. PLoS ONE. 2012;7(8):  IF 4.092

  46. Procyanidin B3 prevents articular cartilage degeneration and heterotopic cartilage formation in a mouse surgical osteoarthritis model. Aini H, Ochi H, Iwata M, Okawa A, Koga D, Okazaki M, Sano A, Asou Y. PLoS ONE. 2012;7(5):  IF 4.092

  47. Osteoarthritis: Procyanidin B3 prevents OA in vivo. Ray K. Nature Revews Rheumatology. 2012 Jun 29;8(7):369.  IF 8.388

  48. Results of carotid artery stenting with distal embolic protection with improved systems: Protected Carotid Artery Stenting in Patients at High Risk for Carotid Endarterectomy (PROTECT) trial. Matsumura JS, Gray W, Chaturvedi S, Yamanouchi D, Peng L, Verta P. J Vasc Surg. 2012 Apr;55(4):968-976. IF 2.879

  49. Delivery of plasmid DNA to vascular tissue in vivo using catheter balloons coated with polyelectrolyte multilayers. Saurer EM, Yamanouchi D (Equal First Author), Liu B, Lynn DM. Biomaterials. 2011 Jan;32(2):610-8. IF 7.404

  50. Zhang F, Banker G, Liu X, Suwanabol PA, Lengfeld J, Yamanouchi D, Kent KC, Liu B. The novel function of advanced glycation end products in regulation of MMP-9 production. J Surg Res. 2011 Dec;171(2):871-6. IF 2.247

  51. Osteopontin deficiency impairs wear debris-induced osteolysis via regulation of cytokine secretion from murine macrophages. Shimizu S, Okuda N, Kato N, Rittling SR, Okawa A, Shinomiya K, Muneta T, Denhardt DT, Noda M, Tsuji K, Asou Y. Arthritis Rheum. 2010 May;62(5):1329-37. IF 8.435

  52. The roles of TNFR1 in lipopolysaccharide-induced bone loss: dual effects of TNFR1 on bone metabolism via osteoclastogenesis and osteoblast survival.  Ochi, H ;Hara, Y ;Tagawa, M ;Shinomiya, K ;Asou, Y    J Orthop Res. 2010 May;28(5):657-63.査読あり IF 2.976

  53. Effects of caspase inhibitor on angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice. Yamanouchi D, Morgan S, Kato K, Lengfeld J, Zhang F, Liu B. Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):702-7. IF 7.215

  54. Protein kinase C delta mediates arterial injury responses through regulation of vascular smooth muscle cell apoptosis. Yamanouchi D, Kato K, Ryer EJ, Zhang F, Liu B. Cardiovasc Res. 2010 Feb 1;85(3):434-43. IF 6.051

  55. Caspase-mediated protein kinase C-delta cleavage is necessary for apoptosis of vascular smooth muscle cells. Kato K, Yamanouchi D, Esbona K, Kamiya K, Zhang F, Kent KC, Liu B. Am J Physiol Heart Circ Physiol. 2009 Dec;297(6):H2253-61. IF 3.712

  56. Anti-receptor for advanced glycation end products therapies as novel treatment for abdominal aortic aneurysm. Zhang F, Kent KC, Yamanouchi D, Zhang Y, Kato K, Tsai S, Nowygrod R, Schmidt AM, Liu B. Ann Surg. 2009 Sep;250(3):416-23. IF 7.900

  57. Arterial gene transfer of the TGF-beta signalling protein Smad3 induces adaptive remodelling following angioplasty: a role for CTGF. Kundi R, Hollenbeck ST, Yamanouchi D, Herman BC, Edlin R, Ryer EJ, Wang C, Tsai S, Liu B, Kent KC. Cardiovasc Res. 2009 Nov 1;84(2):326-35. IF 5.801

  58. TGF-beta through Smad3 signaling stimulates vascular smooth muscle cell proliferation and neointimal formation. Tsai S, Hollenbeck ST, Ryer EJ, Edlin R, Yamanouchi D, Kundi R, Wang C, Liu B, Kent KC. Am J Physiol Heart Circ Physiol. 2009 Aug;297(2):H540-9. IF 3.712

  59. Therapeutic approach against intimal hyperplasia of vein grafts through endothelial nitric oxide synthase/nitric oxide (eNOS/NO) and the Rho/Rho-kinase pathway. Sugimoto M, Yamanouchi D, Komori K. Surg Today. 2009;39(6):459-65. Review. IF 1.050

  60. Transforming growth factor-beta promotes recruitment of bone marrow cells and bone marrow-derived mesenchymal stem cells through stimulation of MCP-1 production in vascular smooth muscle cells. Zhang F, Tsai S, Kato K, Yamanouchi D, Wang C, Rafii S, Liu B, Kent KC. J Biol Chem. 2009 Jun 26;284(26):17564-74. IF 5.328

  61. Characterization of primary and restenotic atherosclerotic plaque from the superficial femoral artery: Potential role of Smad3 in regulation of SMC proliferation. Edlin RS, Tsai S, Yamanouchi D, Wang C, Liu B, Kent KC. J Vasc Surg. 2009 May;49(5):1289-95. IF 3.517

  62. Sarpogrelate hydrochloride reduced intimal hyperplasia in experimental rabbit vein graft. Kodama A, Komori K, Hattori K, Yamanouchi D, Kajikuri J, Itoh T. J Vasc Surg. 2009 May;49(5):1272-81. IF 3.517

  63. TNF-alpha-induced NF-kappaB signaling reverses age-related declines in VEGF induction and angiogenic activity in intervertebral disc tissues. Ohba T, Haro H, Ando T, Wako M, Suenaga F, Asou Y, Koyama K, Hamada Y, Nakao A. J Orthop Res. 2009 Feb;27(2):229-35.  IF 3.112

  64. Effects of compressive loading on biomechanical properties of disc and peripheral tissue in a rat tail model. Nakamura T, Iribe T, Asou Y, Miyairi H, Ikegami K, Takakuda K. Eur Spine J. 2009 Jun 26.  IF 1.956

  65. Biodegradable arginine-based poly(ester-amide) s as non-viral gene delivery reagents. Yamanouchi D, Wu J, Lazar AN, Kent KC, Chu CC, Liu B. Biomaterials. 2008 Aug;29(22):3269-77. IF 6.646

  66. Pitavastatin inhibits intimal hyperplasia in rabbit vein graft. Fujita H, Banno H, Yamanouchi D, Kobayashi M, Yamamoto K, Komori K. J Surg Res. 2008 Aug;148(2):238-43. IF 1.875

  67. The distinct role of the Runx proteins in chondrocyte differentiation and intervertebral disc degeneration: findings in murine models and in human disease. Sato S, Kimura A, Ozdemir J, Asou Y, Takeda S.他 Arthritis Rheum. 2008 Sep;58(9):2764-75.  IF 6.787

  68. Effects of pore size and implant volume of porous hydroxyapatite/collagen (HAp/Col) on bone formation in a rabbit bone defect model. Tsuchiya A, Sotome S, Asou Y, Kikuchi M, Koyama Y, Ogawa T, Tanaka J, Shinomiya K. J Med Dent Sci. 2008 Mar;55(1):91-9.

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