{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T23:37:30Z","timestamp":1794353850710,"version":"4.9.0"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,2,18]],"date-time":"2019-02-18T00:00:00Z","timestamp":1550448000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,2,18]],"date-time":"2019-02-18T00:00:00Z","timestamp":1550448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The increasing potential for accidental radiation exposure from either nuclear accidents or terrorist activities has escalated the need for radiation countermeasure development. We previously showed that a 30-day course of high-dose captopril, an ACE inhibitor, initiated 1\u20134\u2009h after total body irradiation (TBI), improved Hematopoietic Acute Radiation Syndrome (H-ARS) and increased survival in mice. However, because of the time likely required for the deployment of a stockpiled radiation countermeasure to a radiation mass casualty site, there is a need for therapies that can be administered 24\u201348\u2009hours after initial exposure. Using C57BL\/6 mice exposed to an LD<jats:sub>50-80\/30<\/jats:sub> of <jats:sup>60<\/jats:sup>Co TBI (7.75\u20137.9\u2009Gy, 0.615\u2009Gy\/min), we show that low-dose captopril administration, initiated as late as 48\u2009h post-TBI and continued for 14 days, significantly enhanced overall survival similarly to high-dose, rapid administration. Captopril treatment did not affect radiation-induced cell cycle arrest genes or the immediate loss of hematopoietic precursors. Reduced mortality was associated with the recovery of bone marrow cellularity and mature blood cell recovery at 21\u201330 days post-irradiation. Captopril reduced radiation-induced cytokines EPO, G-CSF, and SAA in the plasma. Finally, delayed captopril administration mitigated brain micro-hemorrhage at 21 days post-irradiation. These data indicate that low dose captopril administered as late as 48\u2009h post-TBI for only two weeks improves survival that is associated with hematopoietic recovery and reduced inflammatory response. These data suggest that captopril may be an ideal countermeasure to mitigate H-ARS following accidental radiation exposure.<\/jats:p>","DOI":"10.1038\/s41598-019-38651-2","type":"journal-article","created":{"date-parts":[[2019,2,18]],"date-time":"2019-02-18T11:03:22Z","timestamp":1550487802000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Delayed Captopril Administration Mitigates Hematopoietic Injury in a Murine Model of Total Body Irradiation"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8368-2753","authenticated-orcid":false,"given":"Elizabeth A.","family":"McCart","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young H.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyoti","family":"Jha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ognoon","family":"Mungunsukh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Bradley","family":"Rittase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Thomas A.","family":"Summers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannie","family":"Muir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0822-8993","authenticated-orcid":false,"given":"Regina M.","family":"Day","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,2,18]]},"reference":[{"key":"38651_CR1","doi-asserted-by":"publisher","first-page":"613","DOI":"10.3109\/09553001003746059","volume":"86","author":"BN Pandey","year":"2010","unstructured":"Pandey, B. N., Kumar, A., Tiwari, P. & Mishra, K. P. Radiobiological basis in management of accidental radiation exposure. Int J Radiat Biol. 86, 613\u2013635 (2010).","journal-title":"Int J Radiat Biol."},{"key":"38651_CR2","doi-asserted-by":"publisher","first-page":"ii54","DOI":"10.1093\/jrr\/rry004","volume":"59","author":"N Dainiak","year":"2018","unstructured":"Dainiak, N. Medical management of acute radiation syndrome and associated infections in a high-casualty incident. J Radiat Res. 59, ii54\u2013ii64 (2018).","journal-title":"J Radiat Res."},{"key":"38651_CR3","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1080\/13543776.2016.1231805","volume":"26","author":"VK Singh","year":"2016","unstructured":"Singh, V. K., Romaine, P. L., Newman, V. L. & Seed, T. M. Medical countermeasures for unwanted CBRN exposures: part II radiological and nuclear threats with review of recent countermeasure patents. Expert Opin Ther Pat. 26, 1399\u20131408 (2016).","journal-title":"Expert Opin Ther Pat."},{"key":"38651_CR4","unstructured":"U.S. Food & Drug Administration. Radiological and nuclear emergency preparedness information from FDA, https:\/\/www.fda.gov\/EmergencyPreparedness\/Counterterrorism\/MedicalCountermeasures\/MCMIssues\/ucm602102.htm?utm_campaign=20180329%20MCMi&utm_medium=email&utm_source=Eloqua#mcms (2018)."},{"key":"38651_CR5","first-page":"9","volume":"28","author":"J Meder","year":"1980","unstructured":"Meder, J. & Michalowski, A. Changes in cellularity and\/or weight of mouse hemopoietic tissues as a measure of acute radiation effects. Arch Immunol Ther Exp (Warsz). 28, 9\u201318 (1980).","journal-title":"Arch Immunol Ther Exp (Warsz)."},{"key":"38651_CR6","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1089\/ars.2013.5635","volume":"20","author":"L Shao","year":"2014","unstructured":"Shao, L., Luo, Y. & Zhou, D. Hematopoietic stem cell injury induced by ionizing radiation. Antioxid Redox Signal. 20, 1447\u20131462 (2014).","journal-title":"Antioxid Redox Signal."},{"key":"38651_CR7","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1667\/RR14406.1","volume":"186","author":"AR Kennedy","year":"2016","unstructured":"Kennedy, A. R., Maity, A. & Sanzari, J. K. A review of radiation-induced coagulopathy and new findings to support potential prevention strategies and treatments. Radiat Res. 186, 121\u2013140 (2016).","journal-title":"Radiat Res."},{"issue":"Suppl 1","key":"38651_CR8","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1002\/stem.5530130731","volume":"13","author":"G Wagemaker","year":"1995","unstructured":"Wagemaker, G. Heterogeneity of radiation sensitivity of hemopoietic stem cell subsets. Stem Cells. 13(Suppl 1), 257\u2013260 (1995).","journal-title":"Stem Cells."},{"key":"38651_CR9","doi-asserted-by":"publisher","first-page":"906","DOI":"10.4161\/cbt.28883","volume":"15","author":"EY So","year":"2014","unstructured":"So, E. Y. & Ouchi, T. Decreased DNA repair activity in bone marrow due to low expression of DNA damage repair proteins. Cancer Biol & Ther. 15, 906\u2013910 (2014).","journal-title":"Cancer Biol & Ther."},{"key":"38651_CR10","first-page":"121","volume":"1846","author":"D Heylmann","year":"2014","unstructured":"Heylmann, D., Rodel, F., Kindler, T. & Kaina, B. Radiation sensitivity of human and murine peripheral blood lymphocytes, stem and progenitor cells. Biochim Biophys Acta. 1846, 121\u2013129 (2014).","journal-title":"Biochim Biophys Acta."},{"key":"38651_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1667\/RR0751.1","volume":"167","author":"P Tamulevicius","year":"2007","unstructured":"Tamulevicius, P., Wang, M. & Iliakis, G. Homology-directed repair is required for the development of radioresistance during S phase: interplay between double-strand break repair and checkpoint response. Radiat Res. 167, 1\u201311 (2007).","journal-title":"Radiat Res."},{"key":"38651_CR12","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.semradonc.2008.11.006","volume":"19","author":"JS Greenberger","year":"2009","unstructured":"Greenberger, J. S. & Epperly, M. Bone marrow-derived stem cells and radiation response. Semin Radiat Oncol. 19, 133\u2013139 (2009).","journal-title":"Semin Radiat Oncol."},{"key":"38651_CR13","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1080\/09553000802317778","volume":"84","author":"TA Davis","year":"2008","unstructured":"Davis, T. A., Mungunsukh, O., Zins, S., Day, R. M. & Landauer, M. R. Genistein induces radioprotection by hematopoietic stem cell quiescence. Int J Radiat Biol. 84, 713\u2013726 (2008).","journal-title":"Int J Radiat Biol."},{"key":"38651_CR14","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1016\/j.intimp.2012.12.029","volume":"15","author":"RM Day","year":"2013","unstructured":"Day, R. M. et al. Enhanced hematopoietic protection from radiation by the combination of genistein and captopril. Int Immunopharm. 15, 348\u2013356 (2013).","journal-title":"Int Immunopharm."},{"key":"38651_CR15","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1182\/blood-2003-11-3828","volume":"104","author":"S Charrier","year":"2004","unstructured":"Charrier, S. et al. Inhibition of angiotensin I-converting enzyme induces radioprotection by preserving murine hematopoietic short-term reconstituting cells. Blood. 104, 978\u2013985 (2004).","journal-title":"Blood."},{"key":"38651_CR16","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.exphem.2010.01.004","volume":"38","author":"TA Davis","year":"2010","unstructured":"Davis, T. A. et al. Timing of captopril administration determines radiation protection or radiation sensitization in a murine model of total body irradiation. Exp Hematol. 38, 270\u2013281 (2010).","journal-title":"Exp Hematol."},{"key":"38651_CR17","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.exphem.2010.12.002","volume":"39","author":"M Barshishat-Kupper","year":"2011","unstructured":"Barshishat-Kupper, M. et al. Captopril modulates hypoxia-inducible factors and erythropoietin responses in a murine model of total body irradiation. Exp Hematol. 39, 293\u2013304 (2011).","journal-title":"Exp Hematol."},{"key":"38651_CR18","doi-asserted-by":"crossref","unstructured":"Stroth, U. & Unger, T. The renin-angiotensin system and its receptors. J Cardiovasc Pharmacol. 33(Suppl 1), S21\u201328; discussion S41\u201323 (1999).","DOI":"10.1097\/00005344-199900001-00005"},{"key":"38651_CR19","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1161\/HYPERTENSIONAHA.115.06474","volume":"67","author":"S Kim","year":"2016","unstructured":"Kim, S. et al. Angiotensin II Regulation of Proliferation, Differentiation, and Engraftment of Hematopoietic Stem Cells. Hypertension. 67, 574\u2013584 (2016).","journal-title":"Hypertension."},{"key":"38651_CR20","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1634\/stemcells.18-4-287","volume":"18","author":"K Rodgers","year":"2000","unstructured":"Rodgers, K., Xiong, S., Steer, R. & DiZerega, G. Effect of angiotensin II on hematopoietic progenitor cell proliferation. Stem Cells. 18, 287\u2013294 (2000).","journal-title":"Stem Cells."},{"key":"38651_CR21","doi-asserted-by":"publisher","first-page":"3601","DOI":"10.1182\/blood-2008-03-144766","volume":"112","author":"ET Zambidis","year":"2008","unstructured":"Zambidis, E. T. et al. Expression of angiotensin-converting enzyme (CD143) identifies and regulates primitive hemangioblasts derived from human pluripotent stem cells. Blood. 112, 3601\u20133614 (2008).","journal-title":"Blood."},{"key":"38651_CR22","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1161\/01.HYP.0000159191.98140.89","volume":"45","author":"FH Bahlmann","year":"2005","unstructured":"Bahlmann, F. H. et al. Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension. 45, 526\u2013529 (2005).","journal-title":"Hypertension."},{"key":"38651_CR23","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1002\/stem.170339","volume":"17","author":"JE Chisi","year":"1999","unstructured":"Chisi, J. E., Wdzieczak-Bakala, J., Thierry, J., Briscoe, C. V. & Riches, A. C. Captopril inhibits the proliferation of hematopoietic stem and progenitor cells in murine long-term bone marrow cultures. Stem Cells. 17, 339\u2013344 (1999).","journal-title":"Stem Cells."},{"key":"38651_CR24","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1111\/j.1365-2125.1992.tb05644.x","volume":"34","author":"MC Pratt","year":"1992","unstructured":"Pratt, M. C. et al. Effect of angiotensin converting enzyme inhibitors on erythropoietin concentrations in healthy volunteers. Br J Clin Pharmacol. 34, 363\u2013365 (1992).","journal-title":"Br J Clin Pharmacol."},{"key":"38651_CR25","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/bs.vh.2017.02.001","volume":"105","author":"YC Kim","year":"2017","unstructured":"Kim, Y. C., Mungunsukh, O. & Day, R. M. Erythropoietin Regulation by Angiotensin II. Vitam Horm. 105, 57\u201377 (2017).","journal-title":"Vitam Horm."},{"key":"38651_CR26","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1124\/mol.113.091157","volume":"85","author":"YC Kim","year":"2014","unstructured":"Kim, Y. C. et al. Mechanism of erythropoietin regulation by angiotensin II. Mol Pharmacol. 85, 898\u2013908 (2014).","journal-title":"Mol Pharmacol."},{"key":"38651_CR27","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.4161\/cc.10.9.15444","volume":"10","author":"XZ Shen","year":"2011","unstructured":"Shen, X. Z. & Bernstein, K. E. The peptide network regulated by angiotensin converting enzyme (ACE) in hematopoiesis. Cell Cycle. 10, 1363\u20131369 (2011).","journal-title":"Cell Cycle."},{"key":"38651_CR28","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1097\/HP.0000000000000094","volume":"106","author":"NI Ossetrova","year":"2014","unstructured":"Ossetrova, N. I. et al. Early-response biomarkers for assessment of radiation exposure in a mouse total-body irradiation model. Health Phys. 106, 772\u2013786 (2014).","journal-title":"Health Phys."},{"key":"38651_CR29","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1093\/rpd\/ncu165","volume":"159","author":"NI Ossetrova","year":"2014","unstructured":"Ossetrova, N. I., Sandgren, D. J. & Blakely, W. F. Protein biomarkers for enhancement of radiation dose and injury assessment in nonhuman primate total-body irradiation model. Radiat Prot Dosimetry. 159, 61\u201376 (2014).","journal-title":"Radiat Prot Dosimetry."},{"key":"38651_CR30","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1093\/rpd\/ncw176","volume":"172","author":"NI Ossetrova","year":"2016","unstructured":"Ossetrova, N. I. et al. Non-human primate total-body irradiation model with limited and full medical supportive care including filgrastim for biodosimetry and injury assessment. Radiat Prot Dosimetry. 172, 174\u2013191 (2016).","journal-title":"Radiat Prot Dosimetry."},{"key":"38651_CR31","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.2174\/0929867323666160418114600","volume":"23","author":"M De Buck","year":"2016","unstructured":"De Buck, M. et al. Structure and expression of different serum amyloid A (SAA) variants and their concentration-dependent functions during host insults. Curr Med Chem. 23, 1725\u20131755 (2016).","journal-title":"Curr Med Chem."},{"key":"38651_CR32","doi-asserted-by":"crossref","unstructured":"De Buck, M., Gouwy, M., Struyf, S., Opdenakker, G. & Van Damme, J. The ectoenzyme-side of matrix metalloproteinases (MMPs) makes inflammation by serum amyloid A (SAA) and chemokines go round. Immunol Lett. (2018).","DOI":"10.1016\/j.imlet.2018.06.001"},{"key":"38651_CR33","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1089\/bsp.2010.0041","volume":"8","author":"N Hafer","year":"2010","unstructured":"Hafer, N., Maidment, B. W. & Hatchett, R. J. The NIAID radiation countermeasures program business model. Biosecur Bioterror. 8, 357\u2013363 (2010).","journal-title":"Biosecur Bioterror."},{"key":"38651_CR34","unstructured":"National Institute of Allergy and Infectious Diseases, National Institutes of Health. Radiation Countermeasure Focused Product Development, https:\/\/www.niaid.nih.gov\/research\/radiation-countermeasure-product-development (2017)."},{"key":"38651_CR35","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1016\/0360-3016(94)00430-S","volume":"31","author":"P Mauch","year":"1995","unstructured":"Mauch, P. et al. Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys. 31, 1319\u20131339 (1995).","journal-title":"Int J Radiat Oncol Biol Phys."},{"key":"38651_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-29013-5","volume":"8","author":"M Yamaguchi","year":"2018","unstructured":"Yamaguchi, M. et al. The thrombopoietin mimetic romiplostim leads to the complete rescue of mice exposed to lethal ionizing radiation. Sci Rep. 8, 10659 (2018).","journal-title":"Sci Rep."},{"key":"38651_CR37","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1097\/HP.0000000000000279","volume":"108","author":"VK Singh","year":"2015","unstructured":"Singh, V. K., Romaine, P. L. & Seed, T. M. Medical countermeasures for radiation exposure and related injuries: characterization of medicines, FDA-approval status and inclusion into the strategic national stockpile. Health Phys. 108, 607\u2013630 (2015).","journal-title":"Health Phys."},{"key":"38651_CR38","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s13578-015-0057-3","volume":"5","author":"C Li","year":"2015","unstructured":"Li, C. et al. Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation. Cell & Biosci. 5, 65 (2015).","journal-title":"Cell & Biosci."},{"key":"38651_CR39","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1080\/09553000601132642","volume":"83","author":"TA Davis","year":"2007","unstructured":"Davis, T. A., Clarke, T. K., Mog, S. R. & Landauer, M. R. Subcutaneous administration of genistein prior to lethal irradiation supports multilineage, hematopoietic progenitor cell recovery and survival. Int J Radiat Biol. 83, 141\u2013151 (2007).","journal-title":"Int J Radiat Biol."},{"key":"38651_CR40","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1007\/s00280-002-0434-6","volume":"49","author":"KE Rodgers","year":"2002","unstructured":"Rodgers, K. E., Xiong, S. & diZerega, G. S. Accelerated recovery from irradiation injury by angiotensin peptides. Cancer Chemother Pharmacol. 49, 403\u2013411 (2002).","journal-title":"Cancer Chemother Pharmacol."},{"key":"38651_CR41","first-page":"1074","volume":"26","author":"A Rousseau-Plasse","year":"1998","unstructured":"Rousseau-Plasse, A. et al. Lisinopril, an angiotensin I-converting enzyme inhibitor, prevents entry of murine hematopoietic stem cells into the cell cycle after irradiation in vivo. Exp Hematol. 26, 1074\u20131079 (1998).","journal-title":"Exp Hematol."},{"key":"38651_CR42","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.cyto.2008.03.002","volume":"42","author":"AD Panopoulos","year":"2008","unstructured":"Panopoulos, A. D. & Watowich, S. S. Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and \u2018emergency\u2019 hematopoiesis. Cytokine. 42, 277\u2013288 (2008).","journal-title":"Cytokine."},{"key":"38651_CR43","doi-asserted-by":"publisher","first-page":"2641","DOI":"10.1016\/j.ajpath.2015.06.016","volume":"185","author":"S Villapol","year":"2015","unstructured":"Villapol, S. et al. Hepatic expression of serum amyloid A1 is induced by traumatic brain injury and modulated by telmisartan. Am J Pathol. 185, 2641\u20132652 (2015).","journal-title":"Am J Pathol."},{"key":"38651_CR44","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1189\/jlb.3VMR0315-080R","volume":"98","author":"RD Ye","year":"2015","unstructured":"Ye, R. D. & Sun, L. Emerging functions of serum amyloid A in inflammation. J Leukoc Biol. 98, 923\u2013929 (2015).","journal-title":"J Leukoc Biol."},{"key":"38651_CR45","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1182\/blood-2008-03-139923","volume":"113","author":"RL He","year":"2009","unstructured":"He, R. L. et al. Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2. Blood. 113, 429\u2013437 (2009).","journal-title":"Blood."},{"key":"38651_CR46","doi-asserted-by":"publisher","first-page":"27","DOI":"10.4103\/0976-0105.177703","volume":"7","author":"AB Nair","year":"2016","unstructured":"Nair, A. B. & Jacob, S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharmacol. 7, 27\u201331 (2016).","journal-title":"J Basic Clin Pharmacol."},{"key":"38651_CR47","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/S0378-5173(99)00362-2","volume":"194","author":"AO Nur","year":"2000","unstructured":"Nur, A. O. & Zhang, J. S. Recent progress in sustained\/controlled oral delivery of captopril: an overview. International journal of pharmaceutics. 194, 139\u2013146 (2000).","journal-title":"International journal of pharmaceutics."},{"key":"38651_CR48","unstructured":"U.S. Food & Drug Administration. http:\/\/www.accessdata.fda.gov\/scripts\/cdrh\/cfdocs\/cfcfr\/CFRSearch.cfm?CFRPart=314&showFR=1&subpartNode=21:5.0.1.1.4.9, (2013)."},{"key":"38651_CR49","doi-asserted-by":"publisher","first-page":"507571","DOI":"10.1155\/2012\/507571","volume":"2012","author":"P Aebersold","year":"2012","unstructured":"Aebersold, P. FDA Experience with medical countermeasures under the Animal Rule. Advances in preventive medicine. 2012, 507571 (2012).","journal-title":"Advances in preventive medicine."},{"key":"38651_CR50","first-page":"737","volume":"13","author":"CW McPherson","year":"1963","unstructured":"McPherson, C. W. Reduction of Psuedomonas aeruginosa and coliform bacteria in mouse drinking water following treatment with hyrdochloric acid and chlorine. Lab Animal Care. 13, 737\u2013744 (1963).","journal-title":"Lab Animal Care."},{"key":"38651_CR51","unstructured":"Wooding, W. M. Planning Pharmaceutical Clinical Trials: Basic Statistical Principles. (John Wiley & Sons, Inc., 1994)."},{"key":"38651_CR52","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/S1130-6343(05)73633-3","volume":"29","author":"G Escribano","year":"2005","unstructured":"Escribano, G., Torrado, D. & Torrado, D. Stability study of an aqueous formulation of captopril at 1 mg\/ml (Spanish). Farm Hosp. 29, 30\u201336 (2005).","journal-title":"Farm Hosp."},{"key":"38651_CR53","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1093\/ajcp\/43.4.326","volume":"43","author":"RJ Hartsock","year":"1965","unstructured":"Hartsock, R. J., Smith, E. B. & Petty, C. S. Normal variations with aging of the amount of hematopoietic tissue in bone marrow from the anterior iliac crest. a study made from 177 cases of sudden death examined by necropsy. Am J Clin Pathol. 43, 326\u2013331 (1965).","journal-title":"Am J Clin Pathol."},{"key":"38651_CR54","doi-asserted-by":"crossref","unstructured":"Gorbunov, N. V. & Kiang, J. G. Ghrelin therapy decreases incidents of intracranial hemorrhage in mice after whole-body ionizing irradiation combined with burn trauma. Int J Mol Sci. 18 (2017).","DOI":"10.3390\/ijms18081693"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-38651-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-38651-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-38651-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T06:05:14Z","timestamp":1671257114000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-38651-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,18]]},"references-count":54,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["38651"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-38651-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,18]]},"assertion":[{"value":"27 September 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 December 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 February 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"2198"}}