Dataset Information

Time-Dependent Measurement of Nrf2-Regulated Antioxidant Response to Ionizing Radiation Toward Identifying Potential Protein Biomarkers for Acute Radiation Injury.

ABSTRACT: PURPOSE:Potential acute exposure to ionizing radiation in nuclear or radiological accidents presents complex mass casualty scenarios that demand prompt triage and treatment decisions. Due to delayed symptoms and varied response of radiation victims, there is an urgent need to develop robust biomarkers to assess the extent of injuries in individuals. EXPERIMENTAL DESIGN:The transcription factor Nrf2 is the master of redox homeostasis and there is transcriptional evidence of Nrf2-dependent antioxidant response activation upon radiation. The biomarker potential of Nrf2-dependent downstream target enzymes is investigated by measuring their response in bone marrow extracted from C57Bl/6 and C3H mice of both genders for up to 4 days following 6 Gy total body irradiation using targeted MS. RESULTS:Overall, C57Bl/6 mice have a stronger proteomic response than C3H mice. In both strains, male mice have more occurrences of upregulation in antioxidant enzymes than female mice. For C57Bl/6 male mice, three proteins show elevated abundances after radiation exposure: catalase, superoxide dismutase 1, and heme oxygenase 1. Across both strains and genders, glutathione S-transferase Mu 1 is consistently decreased. CONCLUSIONS AND CLINICAL RELEVANCE:This study provides the basis for future development of organ-specific protein biomarkers used in diagnostic blood test for radiation injury.

SUBMITTER: Liu K

PROVIDER: S-EPMC7213060 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Time-Dependent Measurement of Nrf2-Regulated Antioxidant Response to Ionizing Radiation Toward Identifying Potential Protein Biomarkers for Acute Radiation Injury.

Liu Kate K Singer Elizabeth E Cohn Whitaker W Micewicz Ewa D ED McBride William H WH Whitelegge Julian P JP Loo Joseph A JA

Proteomics. Clinical applications 20190904 6

<h4>Purpose</h4>Potential acute exposure to ionizing radiation in nuclear or radiological accidents presents complex mass casualty scenarios that demand prompt triage and treatment decisions. Due to delayed symptoms and varied response of radiation victims, there is an urgent need to develop robust biomarkers to assess the extent of injuries in individuals.<h4>Experimental design</h4>The transcription factor Nrf2 is the master of redox homeostasis and there is transcriptional evidence of Nrf2-de ...[more]

PMID: 31419066

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Project description:Radiation therapy is an integral part of treatment for cancer patients; however, major side effects of this modality include aberrant bone remodeling and bone loss. Ionizing radiation (IR) is a major external factor that contributes to a significant increase in oxidative stress such as reactive oxygen species (ROS), has been implicated in osteoporotic phenotypes, and has been implicated in osteoporotic phenotypes, bone loss, and fracture risk. One of the major cellular defenses against heightened oxidative stress is mediated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master transcription factor that regulates induction of antioxidant gene expression and phase II antioxidant enzymes. Our objective was to test the hypothesis that loss of functional Nrf2 increases radiation-induced bone loss. We irradiated (single dose, 20Gy) the hindlegs of age- and sex-matched Nrf2(+/+) and Nrf2(-/-) mice. After 1 month, microCT analysis and histology revealed a drastic overall decrease in the bone volume after irradiation of mice lacking Nrf2. Although radiation exposure led to bone loss in mice with intact Nrf2, it was dramatically enhanced by loss of Nrf2. Furthermore, in the absence of Nrf2, a decrease in osteoblast mineralization was noted in calvarial osteoblasts compared with wild-type controls, and treatment with a common antioxidant, N-acetyl-l-cysteine (NAC), was able to rescue the mineralization. As expected, we observed a higher number of osteoclasts in Nrf2(-/-) mice compared to Nrf2(+/+) mice, and after irradiation, the trend remained the same. RT-PCR analysis of calvarial osteoblasts revealed that in the absence of Nrf2, the expression of RANKL was increased after irradiation. Interestingly, RANKL expression was suppressed when the calvarial osteoblasts were treated with NAC before IR exposure. Taken together, our data suggest that loss of Nrf2 leads to heightened oxidative stress and increased susceptibility to radiation-induced bone loss.

Dataset Information

Time-Dependent Measurement of Nrf2-Regulated Antioxidant Response to Ionizing Radiation Toward Identifying Potential Protein Biomarkers for Acute Radiation Injury.

Publications

Time-Dependent Measurement of Nrf2-Regulated Antioxidant Response to Ionizing Radiation Toward Identifying Potential Protein Biomarkers for Acute Radiation Injury.

Similar Datasets

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