Supplemental deinoxanthin protects mice from irradiation-mediated systemic impairments by recovering hematopoietic and degenerative complications

Total body irradiation (TBI) is used as curative therapy for cancer patients and in bone marrow (BM) transplantation. However, TBI impairs organs and BM and dysregulates the fates of BM-residing hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Studies have suggested that TBI-mediated systemic injuries might be improved by preventing the overproduction of reactive oxygen species (ROS) and inflammatory mediators. In this work, we investigated whether Deinococcus radiodurans-derived deinoxanthin (DEIX) protects mice from sub-lethal TBI (5 Gy)-mediated complications and elucidated the associated mechanisms. Long-term oral supplementation with DEIX (25 mg/kg body weight, once per day for 42 consecutive days) protected mice against TBI-mediated decreases in organ and body weights, lifespan, and bone mass accrual. Supplemental DEIX inhibited TBI-mediated structural damage in the liver, kidney, and spleen and restored endogenous antioxidant defense systems in the liver and BM of TBI-exposed mice. Supplemental DEIX also suppressed BM impairment and the induction of senescence in BM-conserved HSCs and MSCs in TBI-exposed mice. That suppression involved the DEIX-induced restoration of TBI-stimulated disorder in osteogenic, osteoclastogenic, and adipogenic activation in BM. Additionally, supplemental DEIX recovered TBI-mediated defects in hematopoietic development and the multipotent functions of BM-derived cells. Moreover, the direct addition of DEIX in vitro diminished ROS accumulation and osteoclast formation and stimulated the proliferation and mineralization of BM-derived cells. Collectively, this study introduces the protective role of DEIX in TBI-mediated systemic defects and supports its clinical usefulness for patients who require TBI. Overall design: RNA seq profiling of whole BM cells that were isolated 14 days post-total body irradiation (TBI) from four groups: 1) non-TBI mice (control group; 1-I, 1-II, 1-III), 2) TBI-exposed mice who received oral gavage of 100 µL of olive oil (vehicle) (TBI group; 2-I, 2-II, 2-III ), 3) TBI-exposed mice who were orally treated with DEIX (TBI+DEIX group; 3-I, 3-II, 3-III), and 4) the mice received DEIX only (DEIX group; 4-I, 4-II, 4-III). Here, the mice received DEIX (25 mg/kg body weight) once per day for 14 consecutive days after 5 Gy TBI with ?-rays by regulating the dosage time (0.66 Gy/min) using the radioactive half-life of ?-rays on a rotating platform (Model IR-221, MDS Nordion, Ottawa, Canada).