Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 99, Issue -, Pages 463-471Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2016.09.007
Keywords
3,3 '-diindolylmethane; Oxidative stress; Radioprotection; Hematopoietic stem/progenitor cells
Funding
- National Natural Science Foundation of China [81071906, 81172127, 81572969]
- Ministry of Science and Technology Research Institutes Development Project [2014EG150134]
- Technology and Development and Research Projects for Research Institutes, Ministry of Science and Technology [2014EG150134]
- Tianjin Science and Technology Support Plan Project [14ZCZDSY00001]
- Natural Science Foundation of Tianjin [15JCQNJC46000]
- PUMC Youth Fund & the Fundamental Research Funds for the Central Universities [3332013044]
- Fundamental Research Funds for CAMS PUMC [2016RC310016]
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences Research Fund [1340, 1521]
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We have reported that hematopoietic system injury induced by total body irradiation (TBI) leads to generation of intracellular reactive oxygen species (ROS) and DNA damage, which are ameliorated by antioxidant agents. In the present study, we reported that administration of DIM, a potent antioxidant agent, not only protected mice against TBI-induced lethality, also ameliorated TBI-induced hematopoietic injury. The latter effect was probably attributable to DIM's inhibition of TBI-induced increases in ROS production in hematopoietic stem cells (HSCs) and the phosphorylation of histone H2AX (y-H2AX). In particular, DIM led to significant improvements in bone marrow (BM) HSC frequency, hematopoietic progenitor cell (HPC) clonogenic function, and multilineage engraftment after transplantation. A downregulation of NADPH oxidase 4 (NOX4) and an upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression were observed following DIM treatment. Notably, the anti-apoptotic potential of DIM was correlated with increased expression of the anti-apoptotic protein Bcl-2 and decreased expression of the pro-apoptotic protein Bax. These findings suggest that DIM attenuates TBI-induced hematopoietic injury through the inhibition of both oxidative stress in HSCs and hematopoietic cell apoptosis. Furthermore, we demonstrated that DIM protected BM hematopoietic cells against ionizing radiation and led to increased clonogenicity in vitro. Therefore, DIM has the potential to be used as an effective radioprotectant to ameliorate TBI-induced hematopoietic injury. (C) 2016 Elsevier Inc. All rights reserved.
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