https://orcid.org/0000-0002-5095-5687
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Abstract
Purpose
The goal of the current study was to identify longitudinal changes in urinary metabolites following IR exposure and to determine potential alleviation of radiation toxicities by administration of recombinant APC formulations.
Materials and methods
Female adult WAG/RijCmcr rats were irradiated with 13.0 Gy leg-out partial body X-rays; longitudinally collected urine samples were subject to LC-MS based metabolomic profiling. Sub-cohorts of rats were treated with three variants of recombinant APC namely, rat wildtype (WT) APC, rat 3K3A mutant form of APC, and human WT APC as two bolus injections at 24 and 48 hours post IR.
Results
Radiation induced robust changes in the urinary profiles leading to oxidative stress, severe dyslipidemia, and altered biosynthesis of PUFAs, glycerophospholipids, sphingolipids, and steroids. Alterations were observed in multiple metabolic pathways related to energy metabolism, nucleotide biosynthesis and metabolism that were indicative of disrupted mitochondrial function and DNA damage. On the other hand, sub-cohorts of rats that were treated with rat wildtype-APC showed alleviation of radiation toxicities, in part, at the 90-day time point, while rat 3K3A-APC showed partial alleviation of radiation induced metabolic alterations 14 days after irradiation.
Conclusions
Taken together, these results show that augmenting the Protein C pathway and activity via administration of recombinant APC may be an effective approach for mitigation of radiation induced normal tissue toxicity.
Correction Statement
This article has been corrected with minor changes. These changes do not impact the academic content of the article.
Acknowledgements
The authors would like to acknowledge the Metabolomics Shared Resource at Georgetown University (Washington, DC, USA) partially supported by NIH/NCI/CCSG grant P30-CA051008.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
Notes on contributors
Shivani Bansal
Shivani Bansal received her PhD in natural product chemistry from National Institute of Pharmaceutical Education and Research, Mohali, India. She currently works as Staff Scientist in the Metabolomics Shared Resource at Georgetown University. She used metabolomics approaches for biomedical research with a focus in cancer, radiation metabolomics and neurodegenerative diseases.
Sunil Bansal
Sunil Bansal received his PhD in Medicinal Chemistry from National Institute of Pharmaceutical Education and Research, Mohali, India. He currently works as Staff Scientist in Metabolomics Shared Resource at Georgetown University. His current research is focused on method development for identification and characterization of biomarkers in radiation oncology by using mass spectrometry-based techniques.
Brian L. Fish
Brian L. Fish received his Bachelor of Arts from Binghamton University. He has been working as a Program Director at Medical College of Wisconsin for 44 years. He specializes in the use of rodent models for radiation injury.
Yaoxiang Li
Yaoxiang Li, MS, is a researcher in the lab of Professor Amrita K. Cheema at Georgetown University Medical Center. He has a background in computation and statistics and uses it to develop bioinformatic tools and statistical methods to solve complex "omics" problems. His research focuses on radiation effects, statistical and mathematical methods applied to biology, and biomarker discovery prediction models.
Xiao Xu
Xiao Xu is a researcher in Dr. Griffin’s laboratory at Scripps Institute and specializes in APC biology.
Jose A. Fernandez
Jose A. Fernandez conducts research at The Scripps Research Institute that is centered on proof of principle studies of protein C. Relevant experience includes: The production of recombinant mouse proteins of the protein C pathway and specific variants that alter the functionality of the molecule. The characterization of original methods to determine the levels of mouse-activated protein C and protein S in mouse plasma. The production of monoclonal antibodies directed against these proteins. These accomplishments in the protein C system were the consequence of more than three decades of research in the field, resulting in more than 200 publications, that helped to advance the knowledge on the protein C pathways in the human system.
John H. Griffin
John H. Griffin received his PhD in biophysics from the University of California, Davis, and received postdoctoral training at Harvard Medical School (E.R. Blout lab) and at the NIH (C.B. Anfinsen lab). Griffin has directed NIH-funded studies of blood coagulation and plasma proteins for four decades at the Scripps Research Institute.
Heather A. Himburg
Heather A. Himburg received her PhD in biomedical engineering from Duke University, Durham, NC and completed a postdoctoral fellowship at Duke University, Durham, NC. She currently serves as associate professor in the Department of Radiation Oncology, Medical College of Wisconsin. Her research program is aimed at the development of therapeutics to mitigate radiation damage to radiosensitive organs including the bone marrow, heart, lung, and kidneys.
Marjan Boerma
Marjan Boerma received her PhD in radiation biology from the University of Leiden, The Netherlands, and completed a postdoctoral fellowship at the University of Arkansas for Medical Sciences (UAMS). She currently directs the Division of Radiation Health at UAMS and serves as Associate Director of Basic Sciences at the Winthrop P. Rockefeller Cancer Institute. Her research program is aimed at identifying strategies to reduce normal tissue toxicities from exposure to ionizing radiation.
Meetha Medhora
Meetha Medhora received her PhD in Molecular Biology from Jawaharlal Nehru University, New Delhi, India, and completed a postdoctoral fellowship at Washington School of Medicine, St. Louis, Missouri. She currently serves as Professor Emeritus in Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin. Her research program is aimed at the mitigation of radiation injury to the lungs, biomarkers to predict lethal delayed effects of acute radiation exposure (DEARE) and cardiovascular injuries caused by radiation.
Amrita K. Cheema
Amrita K. Cheema, PhD, is a professor of Oncology and Biochemistry at Georgetown University Medical Center. She is the associate director of the Center for Metabolomic Studies and co-directs the Waters Center of Innovation in Metabolomics at Georgetown University Medical Center (GUMC). Her extramurally funded research program is focused on delineating small molecule biomarkers that are predictive of exposure to ionizing radiation as well for adverse outcomes of radiotherapy. Her laboratory has also developed several tools and workflows for furthering metabolomics-based molecular phenotyping for clinical and translational research. Amrita’s work has been documented in more than 70 peer-reviewed publications and 5 biomarker patents.