title: Delta-tocotrienol suppresses radiation-induced microRNA-30 and protects mice and human CD34+ cells from radiation injury.
abstract: We reported that microRNA-30c (miR-30c) plays a key role in radiation-induced human cell damage through an apoptotic pathway. Herein we further evaluated radiation-induced miR-30 expression and mechanisms of delta-tocotrienol (DT3), a radiation countermeasure candidate, for regulating miR-30 in a mouse model and human hematopoietic CD34+ cells. CD2F1 mice were exposed to 0 (control) or 7-12.5 Gy total-body gamma-radiation, and CD34+ cells were irradiated with 0, 2 or 4 Gy of radiation. Single doses of DT3 (75 mg/kg, subcutaneous injection for mice or 2 μM for CD34+ cell culture) were administrated 24 h before irradiation and animal survival was monitored for 30 days. Mouse bone marrow (BM), jejunum, kidney, liver and serum as well as CD34+ cells were collected at 1, 4, 8, 24, 48 or 72 h after irradiation to determine apoptotic markers, pro-inflammatory cytokines interleukin (IL)-1β and IL-6, miR-30, and stress response protein expression. Our results showed that radiation-induced IL-1β release and cell damage are pathological states that lead to an early expression and secretion of miR-30b and miR-30c in mouse tissues and serum and in human CD34+ cells. DT3 suppressed IL-1β and miR-30 expression, protected against radiation-induced apoptosis in mouse and human cells, and increased survival of irradiated mice. Furthermore, an anti-IL-1β antibody downregulated radiation-induced NFκBp65 phosphorylation, inhibited miR-30 expression and protected CD34+ cells from radiation exposure. Knockdown of NFκBp65 by small interfering RNA (siRNA) significantly suppressed radiation-induced miR-30 expression in CD34+ cells. Our data suggest that DT3 protects human and mouse cells from radiation damage may through suppression of IL-1β-induced NFκB/miR-30 signaling.
authors: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, United States of America.
authors: Xiang Hong
authors: XH
authors: Li
authors: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, United States of America.
authors: Cam T
authors: CT
authors: Ha
authors: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, United States of America.
authors: Dadin
authors: D
authors: Fu
authors: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, United States of America.
authors: Michael R
authors: MR
authors: Landauer
authors: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, United States of America.
authors: Sanchita P
authors: SP
authors: Ghosh
authors: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, United States of America.
authors: Mang
authors: M
authors: Xiao
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005720:Gamma Rays; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000528:radiation effects; D011832:Radiation Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D011837:Radiation-Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014815:Vitamins / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018952:Antigens, CD34; D016207:Cytokines; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D011837:Radiation-Protective Agents; D051996:Transcription Factor RelA; D014815:Vitamins; D014810:Vitamin E; C082097:tocotrienol, delta