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Matsuo T.,Hyogo Prefectural Awaji Hospital | Motohashi S.,Yamanashi University | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Walenga J.M.,Loyola University
Clinical and Applied Thrombosis/Hemostasis | Year: 2015

To study the production of anti-platelet factor 4 (anti-PF4)/heparin complex antibodies of Ig (immunoglobulin) G/IgA/IgM using enzyme-linked immunosorbent assay (ELISA; heparin-induced thrombocytopenia [HIT] antibodies) in 79 patients undergoing cardiovascular surgery, we employed Δoptical density (OD) as a marker of HIT-antibody production. The ΔODs were calculated from the differences in the ODs using ELISA. Patient were classified into 3 ΔOD ranges: ΔOD ≥ 1.0, ΔOD ≥ 0.4 to <1.0, and ΔOD < 0.4. The underlying disease, time course of the postoperative platelet count, d-dimer level, postoperative brain magnetic resonance imaging (MRI), use of cardiopulmonary bypass and postoperative thrombocytosis were not considered for the 3 ΔOD classifications. None of the 6 patients with ΔOD ≥1.0 and a positive functional assay was diagnosed with HIT due to the absence of HIT-derived thrombocytopenia. In conclusion, HIT-antibody production increased until day 7 after heparin cessation and reached a trace level on day 14. It was demonstrated that HIT-antibody production is in remission unless there is any evidence of a further increase during the second week postsurgery. © The Author(s) 2013 Source


Gohda K.,Computer aided Molecular Modeling Research Center | Fujimori K.,Osaka University of Pharmaceutical Sciences | Teno N.,Hiroshima International University | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Tsuda Y.,Kobe Gakuin University
Chemical Biology and Drug Design | Year: 2014

We here strove to overcome the limitations of expression analyses such as PCR and IHC, based on molecular recognition between target and probe molecules, by designing synthetic substrates specific to the target molecules to directly estimate the enzymatic functionality in situ. The specific substrate contains a probing unit, which is an organic fragment for specific enzyme binding, and a reactive unit, which is a natural peptide subject to catalysis. In this study, the activation of plasminogen to plasmin was examined in MDA-MB231 breast cancer cells using the plasmin-specific synthetic substrates designed from their inhibitors. The localization and function of the activated plasmin were successfully visualized by fluorophore combined with the specific substrate concurrently. This would be the first time for activated plasmin at work in situ by direct observation. Our concept to directly monitor the functionality of target enzymes can be used straightforwardly for other proteases such as cathepsins or caspases. Also, this substrate concept as a 'tailor-made substrate' would be utilized as a novel functional molecular probe in vivo with appropriate detectable probes. We designed synthetic substrates specific to target molecules to directly estimate enzymatic functionality in situ. It contains a probing unit, an organic fragment specific for enzyme-binding; and a reactive unit, a natural peptide subject to catalysis. In this study, activation of plasminogen to plasmin was examined in MDA-MB231 breast cancer cells, and the localization and function of plasmin were successfully visualized by fluorophore in the substrate. This would be the first time for activated plasmin at work in situ by direct observation. © 2013 John Wiley & Sons A/S. Source


Teno N.,Hiroshima International University | Gohda K.,Computer aided Molecular Modeling Research Center | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Tsuda Y.,Kobe Gakuin University | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

In the development of plasmin inhibitors, a novel chemotype, pyrrolopyrimidine scaffold possessing two motifs, a hydantoin-containing P4 moiety and a warhead-containing P1 moiety, is uncovered. A unique feature of the new line of the plasmin inhibitors is that the interaction between the plasmin inhibitors and key subsites in plasmin can be controlled by a spacer like hydantoin. The application of the novel chemotype is demonstrated by 1n and provides further evidence on the importance of hydantoin as the spacer. © 2014 Elsevier Ltd. All rights reserved. Source


Teno N.,Hiroshima International University | Gohda K.,Computer aided Molecular Modeling Research Center | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Sueda T.,Hiroshima International University | Tsuda Y.,Kobe Gakuin University
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Lysine-nitrile derivatives having a trisubstituted benzene, which belongs to a new chemical class, were prepared and tested for inhibitory activities against plasmin and the highly homologous plasma kallikrein and urokinase. The use of the novel chemotype in the development of plasmin inhibitors has been demonstrated by derivatives of compound 9. © 2011 Elsevier Ltd. All rights reserved. Source


Teno N.,Hiroshima International University | Gohda K.,Computer aided Molecular Modeling Research Center | Yamashita Y.,Hiroshima International University | Otsubo T.,Hiroshima International University | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2016

In this letter we report the design and synthesis of a series of plasmin inhibitors, which share the amino acid-based linker with limited free rotation between the hydantoin moiety and the benzimidazole scaffold. Our studies led to potent plasmin inhibitors and yielded important new insights into their structure-activity relationship for binding to the active site of plasmin. © 2016. Source

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