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Analysis of the urinary metabolic profiles in irradiated rats treated with Activated Protein C (APC), a potential mitigator of radiation toxicity. Int J Radiat Biol 2023;99(7):1109-1118

Date

02/25/2023

Pubmed ID

36827630

Pubmed Central ID

PMC10330346

DOI

10.1080/09553002.2023.2182001

Scopus ID

2-s2.0-85148957703 (requires institutional sign-in at Scopus site)

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.

Author List

Bansal S, Bansal S, Fish BL, Li Y, Xu X, Fernandez JA, Griffin JH, Himburg HA, Boerma M, Medhora M, Cheema AK

Author

Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Female
Humans
Metabolome
Metabolomics
Protein C
Radiation Injuries
Rats