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Platelet protective efficacy of 3,4,5 trisubstituted isoxazole analogue by inhibiting ROS-mediated apoptosis and platelet aggregation

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Abstract

Thrombocytopenia is a major hematological concern in oxidative stress-associated pathologies and chronic clinical disorders, where premature platelet destruction severely affects the normal functioning of thrombosis and hemostasis. In addition, frequent exposure of platelets to chemical entities and therapeutic drugs immensely contributes in the development of thrombocytopenia leading to huge platelet loss, which might be fatal sometimes. Till date, there are only few platelet protective molecules known to combat thrombocytopenia. Hence, small molecule therapeutics are extremely in need to relieve the burden on limited treatment strategies of thrombocytopenia. In this study, we have synthesized a series of novel 3,4,5 trisubstituted isoxazole derivatives, among which compound 4a [4-methoxy-N’-(5-methyl-3-phenylisoxazole-4-carbonyl) benzenesulfonohydrazide] was found to significantly ameliorate the oxidative stress-induced platelet apoptosis by restoring various apoptotic markers such as ROS content, cytosolic Ca2+ levels, eIF2-α phosphorylation, mitochondrial membrane depolarization, cytochrome c release, caspase activation, PS externalization, and cytotoxicity markers. Additionally, compound 4a dose dependently inhibits collagen-induced platelet aggregation. Hence, compound 4a can be considered as a prospective molecule in the treatment regime of platelet activation and apoptosis and other clinical conditions of thrombocytopenia. Further studies might ensure the use of compound 4a as a supplementary therapeutic agent to treat, thrombosis and CVD-associated complications. Over all, the study reveals a platelet protective efficacy of novel isoxazole derivative 4a with a potential to combat oxidative stress-induced platelet apoptosis.

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Acknowledgments

Jagadish S, Naveen Kumar SK, and Paul M thanks UGC-BSR, and Rajeev N thanks UGC-RGNF for the research fellowship. Authors thank Dr. Hemshekhar M, University of Manitoba, Canada, Mr. Shanmuga M Sundaram, Mr. Vinayaka AC, Mr. Swethakumar B and Ms. Vishalakshi GJ, University of Mysore, Mysuru, for their kind help during the study. Authors also thank Vashishta from the IISc FACS facility, Bengaluru, and Central instrumentation facility, Institute of excellence (IOE), University of Mysore, Mysuru.

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Authors and Affiliations

  1. Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, 570006, India

    Swamy Jagadish, Narasimhamurthy Rajeev, Kothanahally S. Sharath Kumar, Mahesh Hegde, Marilinganadoddi P. Sadashiva & Kanchugarakoppal S. Rangappa

  2. Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, 570 006, India

    Swamy Jagadish, Somanathapura K. NaveenKumar, Manoj Paul & Kesturu S. Girish

  3. Department of Chemistry Regional Institute of Education, Manasagangotri, Mysuru, 570 006, India

    Kothanahally S. Sharath Kumar

  4. Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bengaluru, 560 056, India

    Basappa

  5. Department of Studies and Research in Biochemistry, Tumkur University, Tumkur, Karnataka, 572 103, India

    Kesturu S. Girish

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  1. Swamy Jagadish
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  2. Narasimhamurthy Rajeev
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  6. Mahesh Hegde
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  9. Kesturu S. Girish
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Correspondence to Kesturu S. Girish or Kanchugarakoppal S. Rangappa.

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Jagadish, S., Rajeev, N., NaveenKumar, S.K. et al. Platelet protective efficacy of 3,4,5 trisubstituted isoxazole analogue by inhibiting ROS-mediated apoptosis and platelet aggregation. Mol Cell Biochem 414, 137–151 (2016). https://doi.org/10.1007/s11010-016-2667-4

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