Abstract
Gamma-tocotrienol (GT3) confers protection against ionizing radiation (IR)-induced injury. However, the molecular targets that underlie the protective functions of GT3 are not yet known. We have reported that mice lacking CCAAT enhancer binding protein delta (Cebpd−/−) display increased mortality to IR due to injury to the hematopoietic and intestinal tissues and that Cebpd protects from IR-induced oxidative stress and cell death. The purpose of this study was to investigate whether Cebpd mediates the radio protective functions of GT3. We found that GT3-treated Cebpd−/− mice showed partial recovery of white blood cells compared to GT3-treated Cebpd+/+ mice at 2 weeks post-IR. GT3-treated Cebpd−/− mice showed an increased loss of intestinal crypt colonies, which correlated with increased expression of inflammatory cytokines and chemokines, increased levels of oxidized glutathione (GSSG), S-nitrosoglutathione (GSNO) and 3-nitrotyrosine (3-NT) after exposure to IR compared to GT3-treated Cebpd+/+ mice. Cebpd is induced by IR as well as a combination of IR and GT3 in the intestine. Studies have shown that granulocyte-colony stimulating factor (G-CSF), mediates the radioprotective functions of GT3. Interestingly, we found that IR alone as well as the combination of IR and GT3 caused robust augmentation of plasma G-CSF in both Cebpd+/+ and Cebpd−/− mice. These results identify a novel role for Cebpd in GT3-mediated protection against IR-induced injury, in part via modulation of IR-induced inflammation and oxidative/nitrosative stress, which is independent of G-CSF.
Highlights
The health benefits of Vitamin E are mediated through its inherent antioxidant, neuroprotective, anti-inflammatory and stress/damage response properties [1,2,3]
Analysis of peripheral blood cells at 2 weeks post sublethal irradiation (6 Gy) revealed that the vehicle-treated Cebpd−/− mice displayed significantly reduced numbers of white blood cells (WBCs) and platelets compared to vehicle-treated Cebpd+/+ mice (Figure 1A–C), similar to our previously published study [29]
GT3-treatment of Cebpd−/− mice resulted in a significant increase in WBCs compared to respective vehicle-treated mice, it was significantly lower than the GT3-treated Cebpd+/+
Summary
The health benefits of Vitamin E are mediated through its inherent antioxidant, neuroprotective, anti-inflammatory and stress/damage response properties [1,2,3]. The Vitamin E family comprises of a set of related tocopherols and tocotrienols, collectively called tocols. The naturally occurring tocols encompass α-, β-, γ- and δ-tocopherol and α-, β-, γ- and δ-tocotrienol. Tocols and their derivatives have been extensively investigated as radiation countermeasure agents [4,5,6,7]. A number of studies have shown that tocotrienols are superior antioxidants compared to tocopherols and protect mice against radiation injury and promote post-radiation survival [8,9,10,11,12].
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