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Combined Mitigation of the Gastrointestinal and Hematopoietic Acute Radiation Syndromes by an LPA(2) Receptor-Specific Nonlipid Agonist

Patil, R. and Szabó, Erzsébet and Fells, James I. and Balogh, Andrea and Lim, K. G. and Tigyi, Gábor (2015) Combined Mitigation of the Gastrointestinal and Hematopoietic Acute Radiation Syndromes by an LPA(2) Receptor-Specific Nonlipid Agonist. Chemistry and Biology, 22 (2). pp. 206-216. ISSN 1074-5521

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Abstract

Pharmacological mitigation of injuries caused by high-dose ionizing radiation is an unsolved medical problem. A specific nonlipid agonist of the type 2 G protein coupled receptor for lysophosphatidic acid (LPA(2)) 2-[4-(1,3-dioxo-1H, 3H-benzoisoquinolin-2-yl) butylsulfamoyl] benzoic acid (DBIBB) when administered with a postirradiation delay of up to 72 hr reduced mortality of C57BL/6 mice but not LPA2 knockout mice. DBIBB mitigated the gastrointestinal radiation syndrome, increased intestinal crypt survival and enterocyte proliferation, and reduced apoptosis. DBIBB enhanced DNA repair by augmenting the resolution of gamma-H2AX foci, increased clonogenic survival of irradiated IEC-6 cells, attenuated the radiation-induced death of human CD34(+) hematopoietic progenitors and enhanced the survival of the granulocyte/macrophage lineage. DBIBB also increased the survival of mice suffering from the hematopoietic acute radiation syndrome after total-body irradiation. DBIBB represents a drug candidate capable of mitigating acute radiation syndrome caused by high-dose gamma-radiation to the hematopoietic and gastrointestinal system.

Item Type: Article
Uncontrolled Keywords: EXPRESSION; SELECTIVITY; MOUSE; INJURY; IDENTIFICATION; STEM-CELLS; DNA-DAMAGE; PARP inhibition; EPITHELIAL-CELLS; Lysophosphatidic acid; Sulfonamides/chemistry/*pharmacology/therapeutic use; Receptors, Lysophosphatidic Acid/*agonists/genetics/metabolism; Protein Structure, Tertiary; Naphthalimides/chemistry/*pharmacology/therapeutic use; Molecular Docking Simulation; Mice, Knockout; Mice, Inbred C57BL; MICE; Lysophospholipids/chemistry/*pharmacology/therapeutic use; Humans; Histones/metabolism; Gamma Rays; DNA Fragmentation/drug effects/radiation effects; Cell Line; Caspase 8/metabolism; BINDING SITES; Apoptosis/*drug effects/radiation effects; Animals; Acute Radiation Syndrome/metabolism/pathology/prevention & control
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 05 Oct 2017 13:49
Last Modified: 05 Oct 2017 13:49
URI: http://real.mtak.hu/id/eprint/65096

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