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Investigation on vasopeptidase inhibition and its application to pulmonary hypertension

Research Project

Project/Area Number 23590123
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Biological pharmacy
Research InstitutionKobe Pharmaceutical University

Principal Investigator

EMOTO Noriaki  神戸薬科大学, 薬学部, 教授 (30294218)

Project Period (FY) 2011 – 2013
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2011: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywordsエンドセリン / エンドセリン変換酵素 / ブラジキニン / 肺高血圧症 / 肺線維症 / 遺伝子欠損マウス / ブラジキニンニン / ナトリウム利尿ペプチド
Research Abstract

We have investigated the possibilities that endothelin-converting enzyme (ECE) is involved in the pathogenesis of pulmonary hypertension and pulmonary fibrosis through other vasoactive peptides in addition to endothelin by using genetically modified mice. We have demonstrated that ECE heterozygous mice were resistant to develop hypoxia-induce pulmonary hypertension by upregulating bradykinin system. We also showed that ECE heterozygous mice were resistant to induce bleomycin-induced pulmonary fibrosis by potentiating CGRP pathway. These results suggest that ECE plays an important role to the pathogenesis of pulmonary hypertension and pulmonary fibrosis, and that ECE may be a plausible target for the therapeutic intervention to these disorders.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • 2011 Research-status Report
  • Research Products

    (50 results)

All 2014 2013 2012 2011 Other

All Journal Article (28 results) (of which Peer Reviewed: 20 results) Presentation (21 results) (of which Invited: 6 results) Remarks (1 results)

  • [Journal Article] Inhibition of vascular endothelial growth factor receptor under hypoxia causes severe, human-like pulmonary arterial hypertension in mice : Potential roles of interleukin-6 and endothelin2014

    • Author(s)
      Van Hung T, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Suzuki Y, Hirata KI
    • Journal Title

      Life Sci

      Volume: (in press)

    • Related Report
      2013 Final Research Report
  • [Journal Article] Vascular endothelium derived endothelin-1 is required for normal heart function after chronic pressure overload in mice2014

    • Author(s)
      Heiden S, Vignon-Zellweger N, Masuda S, Yagi K, Nakayama K, Yanagisawa M, Emoto N
    • Journal Title

      PLOS ONE

      Volume: (in press)

    • Related Report
      2013 Final Research Report
  • [Journal Article] Inhibition of vascular endothelial growth factor receptor under hypoxia causes severe, human-like pulmonary arterial hypertension in mice: Potential roles of interleukin-6 and endothelin.2014

    • Author(s)
      Van Hung T, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Suzuki Y, Hirata KI.
    • Journal Title

      Life Sci.

      Volume: 印刷中 Issue: 2 Pages: 313-328

    • DOI

      10.1016/j.lfs.2013.12.215

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Vascular endothelium derived endothelin-1 is required for normal heart function after chronic pressure overload in mice.2014

    • Author(s)
      Heiden S, Vignon-Zellweger N, Masuda S, Yagi K, Nakayama K, Yanagisawa M, Emoto N.
    • Journal Title

      PLoS One.

      Volume: 印刷中

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Non-invasive and Simple Assessment of Cardiac Output and Pulmonary Vascular Resistance with Whole-body Impedance Cardiography is Useful for Monitoring Patients with Pulmonary Hypertension2013

    • Author(s)
      Taniguchi Y, Emoto N, Miyagawa K, Nakayama K, Kinutani H, Tanaka H, Shinke T, Hirata, K
    • Journal Title

      Circ J

      Volume: (in press)

    • NAID

      10031191768

    • Related Report
      2013 Final Research Report
  • [Journal Article] Endothelin-converting enzyme-1 gene ablation attenuates pulmonary fibrosis via CGRP–cAMP/EPAC1 pathway2013

    • Author(s)
      Hartopo AB, Emoto N, Vignon-Zellweger N, Suzuki Y, Yagi K, Nakayama K, Hirata KI
    • Journal Title

      Am. J. Respir. Cell Mol. Biol

      Volume: 48 Pages: 465-476

    • Related Report
      2013 Final Research Report
  • [Journal Article] Michael addition-aromatization reaction of dienylimines bearing a leaving group and its application to the preparation of thiol-selective labeling reagents capable of forming strong carbon-sulfur bonds.2013

    • Author(s)
      Miyoshi M, Aoki Y, Uno Y, Araki M, Kamatani T, Fujii D, Fujita Y, Takeda N, Ueda M, Kitagawa H, Emoto N, Mukai T, Tanaka M, Miyata O.
    • Journal Title

      J Org Chem.

      Volume: 78 Issue: 22 Pages: 11433-11443

    • DOI

      10.1021/jo402002k

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Glycosaminoglycan Overproduction in the Aorta Increases Aortic Calcification in Murine Chronic Kidney Disease.2013

    • Author(s)
      Purnomo E, Emoto N, Nugrahaningsih DAA, Nakayama K, Yagi K, Heiden S, Nadanaka S, Kitagawa H, Hirata KI.
    • Journal Title

      JAHA

      Volume: 2 Issue: 5

    • DOI

      10.1161/jaha.113.000405

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chronic hyperaldosteronism in Cryptochrome null mice induces high-salt- and blood pressure-independent kidney damage in mice.2013

    • Author(s)
      Nugrahaningsih DAA, Emoto N, Vignon-Zellweger N, Purnomo E, Yagi K, Nakayama K, Doi M, Okamura H, Hirata KI.
    • Journal Title

      Hypertens Res.

      Volume: 37 Issue: 3 Pages: 202-209

    • DOI

      10.1038/hr.2013.143

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A New Class of Drug for Pulmonary Arterial Hypertension: Can a Rho-kinase Inhibitor Break the Stagnation in Treating It?2013

    • Author(s)
      Miyagawa K, Emoto N.
    • Journal Title

      Circ J.

      Volume: 77 Pages: 2477-2478

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activation of Wnt5a-Ror2 signaling associated with epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells during renal fibrosis.2013

    • Author(s)
      Li, X., Yamagata, K., Nishita, M., Endo, M., Arfian, N., Rikitake, Y., Emoto, N., Hirata, K., Tanaka, Y., Minami, Y.
    • Journal Title

      Genes Cells

      Volume: 18 Issue: 7 Pages: 608-619

    • DOI

      10.1111/gtc.12064

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Non-invasive and Simple Assessment of Cardiac Output and Pulmonary Vascular Resistance with Whole-body Impedance Cardiography is Useful for Monitoring Patients with Pulmonary Hypertension.2013

    • Author(s)
      Taniguchi Y, Emoto N, Miyagawa K, Nakayama K, Kinutani H, Tanaka H, Shinke T, Hirata, K.
    • Journal Title

      Circ J.

      Volume: 77 Pages: 2483-2489

    • NAID

      10031191768

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Subsequent Shunt Closure after Targeted Medical Therapy can be an Effective Strategy for Secundum Atrial Septal Defect with Severe Pulmonary Arterial Hypertension.2013

    • Author(s)
      Taniguchi Y, Emoto N, Miyagawa K, Nakayama K, Kinutani H, Tanaka H, Shinke T, Okada K, Okita Y, Hirata, K.
    • Journal Title

      Heart Vessels.

      Volume: 29 Issue: 2 Pages: 282-285

    • DOI

      10.1007/s00380-013-0351-0

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Endothelin-Converting Enzyme-1 Gene Ablation Attenuates Pulmonary Fibrosis via CGRP-cAMP/EPAC1 Pathway.2013

    • Author(s)
      Hartopo AB, Emoto N, Vignon-Zellweger N, Suzuki Y, Yagi K, Nakayama K, Hirata K.
    • Journal Title

      Am J Respir Cell Mol Biol.

      Volume: 48 Issue: 4 Pages: 465-476

    • DOI

      10.1165/rcmb.2012-0354oc

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Efficacy of right ventricular free-wall longitudinal speckle-tracking strain for predicting long-term outcome in patients with pulmonary hypertension.2013

    • Author(s)
      Motoji Y, Tanaka H, Fukuda Y, Ryo K, Emoto N, Kawai H, Hirata K.
    • Journal Title

      Circ J.

      Volume: 77 Pages: 756-763

    • NAID

      10031138968

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] ET-1 deletion from endothelial cells protects the kidney during the extension phase of ischemia/reperfusion injury2012

    • Author(s)
      Arfian N, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Hirata KI
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 425 Pages: 443-449

    • Related Report
      2013 Final Research Report
  • [Journal Article] Physiological relevance of hydrolysis of atrial natriuretic peptide by endothelin-converting enzyme-12012

    • Author(s)
      Nakayama K, Emoto E, Suzuki Y, Vignon-Zellweger N, Yagi K, Hirata KI
    • Journal Title

      Kobe J. Med. Sci

      Volume: 58

    • NAID

      110009591545

    • Related Report
      2013 Final Research Report
  • [Journal Article] Molecular Biology of Endothelin-1 in the Renal and Cardiovascular Systems2012

    • Author(s)
      Vignon-Zellweger N, Heiden S, Miyauchi T, Emoto N
    • Journal Title

      Life Sci

      Volume: 91 Pages: 490-500

    • Related Report
      2013 Final Research Report
  • [Journal Article] ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy2012

    • Author(s)
      Adiarto S, Heiden S, Vignon-Zellweger N, Nakayama K, Yagi K, Yanagisawa M, Emoto N
    • Journal Title

      Life Sci

      Volume: 91 Pages: 651-657

    • Related Report
      2013 Final Research Report
  • [Journal Article] Differences in hemodynamic parameters and exercise capacity between patients with pulmonary arterial hypertension and chronic heart failure.2012

    • Author(s)
      Nishio R, Tanaka H, Tsuboi Y, Kinutani H, Taniguchi Y, Shigeru M, Toh R, Miura Y, Sakai Y, Emoto N, Kawai H, Hirata K.
    • Journal Title

      J Cardiopulm Rehabil Prev.

      Volume: 32 Issue: 6 Pages: 379-385

    • DOI

      10.1097/hcr.0b013e318272bc0b

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Physiological relevance of hydrolysis of atrial natriuretic peptide by endothelin-converting enzyme-1.2012

    • Author(s)
      Nakayama K, Emoto N, Suzuki Y, Vignon-Zellweger N, Yagi K, Hirata K.
    • Journal Title

      Kobe J Med Sci.

      Volume: 58

    • NAID

      110009591545

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] ET-1 deletion from endothelial cells protects the kidney during the extension phase of ischemia/reperfusion injury.2012

    • Author(s)
      Arfian N, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Hirata K.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 425 Issue: 2 Pages: 443-449

    • DOI

      10.1016/j.bbrc.2012.07.121

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Comparison of medium-dose losartan/hydrochlorothiazide and maximal-dose angiotensin II receptor blockers in the treatment of Japanese patients with uncontrolled hypertension: the Kobe-CONNECT Study.2012

    • Author(s)
      Toh R, Ishida T, Nishimura K, Nonaka H, Inoue Y, Kitagawa Y, Suematsu M, Miki T, Emoto N, Hirata K.
    • Journal Title

      Hypertens Res.

      Volume: 35 Issue: 11 Pages: 1080-1086

    • DOI

      10.1038/hr.2012.110

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Endothelin and endothelin receptors in the renal and cardiovascular systems.2012

    • Author(s)
      Vignon-Zellweger N, Heiden S, Miyauchi T, Emoto N.
    • Journal Title

      Life Sci.

      Volume: in press

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy.2012

    • Author(s)
      Adiarto S, Heiden S, Vignon-Zellweger N, Nakayama K, Yagi K, Yanagisawa M, Emoto N.
    • Journal Title

      Life Sci.

      Volume: in press

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Renal function and blood pressure: molecular insights into the biology of endothelin-1.2011

    • Author(s)
      Vignon-Zellweger N, Heiden S, Emoto N.
    • Journal Title

      Contrib Nephrol.

      Volume: 172 Pages: 18-34

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Utility of right ventricular free wall speckle-tracking strain for evaluation of right ventricular performance in patients with pulmonary hypertension.2011

    • Author(s)
      Fukuda Y, Tanaka H, Sugiyama D, Ryo K, Onishi T, Fukuya H, Nogami M, Ohno Y, Emoto N, Kawai H, Hirata K.
    • Journal Title

      J Am Soc Echocardiogr.

      Volume: 24 Pages: 1101-1108

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Correlation of C4ST-1 and ChGn-2 expression with chondroitin sulfate chain elongation in atherosclerosis.2011

    • Author(s)
      Anggraeni VY, Emoto N, Yagi K, Mayasari DS, Nakayama K, Izumikawa T, Kitagawa H, Hirata K.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 406 Pages: 36-41

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] B radykinin Attenuated Hypoxia Induced Pulmonary Arterial Hypertension through Bradykinin 2 Receptor2014

    • Author(s)
      Suzuki Y, Raharjo SB, Nakayama K, Yagi K, Miyagawa K, Satwiko MG, Muliawan HS, Emoto N
    • Organizer
      The 7th Asian Pacific Congress of Heart Failure
    • Related Report
      2013 Final Research Report
  • [Presentation] Fulton's Index was Considerably Higher in Endothelin-1 Transgenic Mice Compared to Their Littermates in Hypoxic Induced Pulmonary Arterial Hypertension but not Significantly between Gender2014

    • Author(s)
      Satwiko MG, Nakayama K, Yagi K, Miyagawa K, Suzuki Y, Muliawan HS, Hirata KI, Emoto N
    • Organizer
      The 7th Asian Pacific Congress of Heart Failure
    • Related Report
      2013 Final Research Report
  • [Presentation] Endothelin Receptor Antagonist and Heart Failure2014

    • Author(s)
      Emoto N.
    • Organizer
      7th Asian Pacific Congress of Heart Failure and 23rd Annual Scientific Meeting of Indonesian Heart Association
    • Place of Presentation
      インドネシア
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Bradykinin Attenuated Hypoxia Induced Pulmonary Arterial Hypertension through Bradykinin 2 Receptor.2014

    • Author(s)
      Suzuki Y, Raharjo SB, Nakayama K, Yagi K, Miyagawa K, Satwiko MG, Muliawan HS, Emoto N
    • Organizer
      The 7th Asian Pacific Congress of Heart Failure.
    • Place of Presentation
      インドネシア
    • Related Report
      2013 Annual Research Report
  • [Presentation] Endothelin converting enzyme inhibition attenuates early albuminuria and late renal failure in streptozotocin induced diabetic mice2013

    • Author(s)
      Nakayama K, Vignon-Zellweger N, Heiden S, Suzuki Y, Okano T, Miyagawa K, Yagi K, Yanagisawa M, Emoto N
    • Organizer
      ET-13: The 13th International Conference on Endothelin
    • Related Report
      2013 Final Research Report
  • [Presentation] Role of Bradykinin and Endothelin-Converting Enzyme-1 in Pulmonary Hypertension2013

    • Author(s)
      Raharjo SB, Emoto N, Yuniadi Y, Nakayama K, Harimurti GM
    • Organizer
      ET-13: The 13th International Conference on Endothelin
    • Related Report
      2013 Final Research Report
  • [Presentation] 肺高血圧症の診断および治療戦略の再構築2013

    • Author(s)
      江本憲昭
    • Organizer
      第61回日本心臓病学会学術集会
    • Place of Presentation
      熊本
    • Related Report
      2013 Annual Research Report
  • [Presentation] 96. Analysis of ET-1 system in mild and severe pulmonary arterial hypertension in mice.2013

    • Author(s)
      Hung TV, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Suzuki Y, Hirata KI
    • Organizer
      ET-13: The 13th International Conference on Endothelin
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] Role of Bradykinin and Endothelin-Converting Enzyme-1 in Pulmonary Hypertension.2013

    • Author(s)
      Raharjo SB, Emoto N, Yuniadi Y, Nakayama K, Harimurti GM
    • Organizer
      ET-13: The 13th International Conference on Endothelin
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] Endothelial cell-derived Endothelin-1 Knock-out Preserves Cortex Architecture after Ischemic-reperfusion Episode in Mice2012

    • Author(s)
      Arfian N, Yagi K, Nakayama K, Ali H, Mayasari DS, Purnomo E, Emoto N
    • Organizer
      49th Congress of the European-Renal-Association/European -Dialysis-and-Transplant-Associatio n (ERA-EDTA)
    • Related Report
      2013 Final Research Report
  • [Presentation] Deletion of Endothelin-1 from Endothelial Cell In vivo and ETAR Blocking In vitro Attenuate Fibrosis and Myofibroblast Formation2012

    • Author(s)
      Arfian N, Emoto N, Yagi K, Nakayama K, Ali H, Hartopo AB, Nugrahaningsih DA, Yanagisawa M, Hirata KI
    • Organizer
      49th Congress of the European-Renal-Association/European -Dialysis-and-Transplant-Associatio n (ERA-EDTA)
    • Related Report
      2013 Final Research Report
  • [Presentation] Potentiating bradykinin pathway by genetic suppression of endothelin-converting enzyme-1 prevented hypoxic induced pulmonary hypertension and right ventricular hypertrophy2011

    • Author(s)
      Suzuki Y, Raharjo SB, Nakayama K, Vignon-Zellweger N, Heiden S, Arfian N, Hartopo AB, Yagi K, Emoto N
    • Organizer
      ET-12: The 12th International Conference on Endothelin
    • Related Report
      2013 Final Research Report
  • [Presentation] Endothelin converting enzyme-1 genetic inhibition prevents bleomycin-induced pulmonary fibrosis in mice2011

    • Author(s)
      Hartopo AB, Arfian N, Nugrahaningsih DAA, Vignon-Zellweger N, Heiden S, Nakayama N, Yagi Y, Hirata KI, Emoto N
    • Organizer
      ET-12: The 12th International Conference on Endothelin
    • Related Report
      2013 Final Research Report
  • [Presentation] Role of endothelin-converting enzyme-1 inhibition in pulmonary vein remodeling during development of secondary pulmonary hypertension2011

    • Author(s)
      Hartopo AB, Emoto N, Yagi K, Nakayama K, Anggraeni VY, Ali H, Arfian N, Mayasari DS, Nugrahaningsih DAA, Purnomo E, Hirata KI
    • Organizer
      18th Congress of Asia Pacific Society of Cardiology
    • Related Report
      2013 Final Research Report
  • [Presentation] ENDOTHELIN CONVERTING ENZYME-1 GENETIC INHIBITION PREVENTS BLEOMYCIN-INDUCED PULMONARY FIBROSIS IN MICE2011

    • Author(s)
      Anggoro B. Hartopo, Nur Arfian, Dwi A. A. Nugrahaningsih, Nicolas Vignon-Zellweger, Susi Heiden, Kazuhiko Nakayama, Keiko Yagi, Ken-ichi Hirata, Noriaki Emoto
    • Organizer
      The 12th International Conference on Endothelin
    • Place of Presentation
      Cambridge
    • Related Report
      2011 Research-status Report
  • [Presentation] Potentiating Bradykinin Pathway by Genetic Suppression of Endothelin-converting Enzyme-1 Prevented Hypoxic induced Pulmonary Hypertension and Right Ventricular Hypertrophy.2011

    • Author(s)
      Yoko Suzuki, Sunu Budhi Raharjo, Kazuhiko Nakayama, Nicolas Vignon, Susi Heiden, Nur Arfian, Anggoro Budi Hartopo, Keiko Yagi, Noriaki Emoto
    • Organizer
      The 12th International Conference on Endothelin
    • Place of Presentation
      Cambridge
    • Related Report
      2011 Research-status Report
  • [Presentation] 「肺高血圧」エンドセリンのトランスレーショナルリサーチ¬―心不全、肺高血圧から糖尿病性腎症まで―

    • Author(s)
      江本憲昭
    • Organizer
      日本循環器学会 第142回東海・第127回北陸合同地方会
    • Place of Presentation
      金沢
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 肺高血圧症におけるエンドセリン変換酵素ー病態への関与と治療標的としての展望ー

    • Author(s)
      江本憲昭
    • Organizer
      第17回日本病態プロテアーゼ学会学術集会
    • Place of Presentation
      浜松
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] エンドセリンのトランスレーショナルリサーチー分子遺伝学的研究から肺高血圧症の治療応用までー

    • Author(s)
      江本憲昭
    • Organizer
      第60回日本心臓病学会学術集会
    • Place of Presentation
      金沢
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] エンドセリンによる心血管リモデリングー体血管と肺血管の類似点と相違点ー

    • Author(s)
      江本憲昭
    • Organizer
      第35回日本高血圧学会総会
    • Place of Presentation
      金沢
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] Molecular Dissection of Pathophysiological Roles of the Endothelin System in Pulmonary Arterial Hypertension: Lessons from Genetically Mofdified Mice

    • Author(s)
      江本憲昭
    • Organizer
      第76回日本循環器学会総会
    • Place of Presentation
      横浜
    • Related Report
      2012 Research-status Report
    • Invited
  • [Remarks]

    • URL

      http://www.kobepharma-u.ac.jp/~clinical/publications/index.html

    • Related Report
      2013 Final Research Report

URL: 

Published: 2011-08-05   Modified: 2019-07-29  

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