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10.1016/j.redox.2017.05.019

http://scihub22266oqcxt.onion/10.1016/j.redox.2017.05.019
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suck abstract from ncbi


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pmid28600983
      Redox+Biol 2017 ; 13 (ä): 266-277
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  • HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases #MMPMID28600983
  • Kung PH ; Hsieh PW ; Lin YT ; Lee JH ; Chen IH ; Wu CC
  • Redox Biol 2017[Oct]; 13 (ä): 266-277 PMID28600983 show ga
  • Protein disulfide isomerase (PDI) present at platelet surfaces has been considered to play an important role in the conformational change and activation of the integrin glycoprotein IIb/IIIa (GPIIb/IIIa) and thus enhances platelet aggregation. Growing evidences indicated that platelet surface PDI may serve as a potential target for developing of a new class of antithrombotic agents. In the present study, we investigated the effects of HPW-RX40, a chemical derivative of ?-nitrostyrene, on platelet activation and PDI activity. HPW-RX40 inhibited platelet aggregation, GPIIb/IIIa activation, and P-selectin expression in human platelets. Moreover, HPW-RX40 reduced thrombus formation in human whole blood under flow conditions, and protects mice from FeCl(3)-induced carotid artery occlusion. HPW-RX40 inhibited the activity of recombinant PDI family proteins (PDI, ERp57, and ERp5) as well as suppressed cell surface PDI activity of platelets in a reversible manner. Exogenous addition of PDI attenuated the inhibitory effect of HPW-RX40 on GPIIb/IIIa activation. Structure-based molecular docking simulations indicated that HPW-RX40 binds to the active site of PDI by forming hydrogen bonds. In addition, HPW-RX40 neither affected the cell viability nor induced endoplasmic reticulum stress in human cancer A549 and MDA-MB-231 cells. Taken together, our results suggest that HPW-RX40 is a reversible and non-cytotoxic PDI inhibitor with antiplatelet effects, and it may have a potential for development of novel antithrombotic agents.
  • |*Platelet Activation [MESH]
  • |Animals [MESH]
  • |Binding Sites [MESH]
  • |Blood Platelets/*drug effects/immunology [MESH]
  • |Cell Line, Tumor [MESH]
  • |Chlorobenzoates/*pharmacology [MESH]
  • |Enzyme Inhibitors/*pharmacology [MESH]
  • |Humans [MESH]
  • |Male [MESH]
  • |Mice [MESH]
  • |Mice, Inbred C57BL [MESH]
  • |Molecular Docking Simulation [MESH]
  • |Protein Binding [MESH]
  • |Protein Disulfide-Isomerases/antagonists & inhibitors/chemistry/*metabolism [MESH]


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