title: Gamma-Tocotrienol Modulates Radiation-Induced MicroRNA Expression in Mouse Spleen.
abstract: Ionizing radiation causes depletion of hematopoietic cells and enhances the risk of developing secondary hematopoietic malignancies. Vitamin E analog gamma-tocotrienol (GT3), which has anticancer properties, promotes postirradiation hematopoietic cell recovery by enhancing spleen colony-forming capacity, and provides protection against radiation-induced lethality in mice. However, the underlying molecular mechanism involved in GT3-mediated postirradiation survival is not clearly understood. Recent studies have shown that natural dietary products including vitamin E provide a benefit to biological systems by modulating microRNA (miR) expression. In this study, we show that GT3 differentially modulates the miR footprint in the spleen of irradiated mice compared to controls at early times (day 1), as well as later times (day 4 and 15) after total-body irradiation. We observed that miR expression was altered in a dose- and time-dependent manner in GT3-pretreated spleen tissues from total-body irradiated mice. GT3 appeared to affect the expression of a number of radiation-modulated miRs known to be involved in hematopoiesis and lymphogenesis. Moreover, GT3 pretreatment also suppressed the upregulation of radiation-induced p53, suggesting the function of GT3 in the prevention of radiation-induced damage to the spleen. In addition, we have shown that GT3 significantly reduced serum levels of Flt3L, a biomarker of radiation-induced bone marrow aplasia. Further in silico analyses of the effect of GT3 implied the association of p38 MAPK, ERK and insulin signaling pathways. Our study provides initial insight into the mechanism by which GT3 mediates protection of spleen after total-body irradiation.
authors.affiliation: a   Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences Scientific Research Department, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland;
authors.forename: Sanchita P
authors.initials: SP
authors.lastname: Ghosh
authors.affiliation: b   Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
authors.forename: Rupak
authors.initials: R
authors.lastname: Pathak
authors.affiliation: c   Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and.
authors.forename: Parameet
authors.initials: P
authors.lastname: Kumar
authors.affiliation: a   Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences Scientific Research Department, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland;
authors.forename: Shukla
authors.initials: S
authors.lastname: Biswas
authors.affiliation: d   Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226024, India.
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: a   Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences Scientific Research Department, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland;
authors.forename: Vidya P
authors.initials: VP
authors.lastname: Kumar
authors.affiliation: b   Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
authors.affiliation: c   Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and.
authors.forename: Roopa
authors.initials: R
authors.lastname: Biswas
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000528:radiation effects*; D007328:Insulin / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D013997:Time Factors; D024508:Tocotrienols / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects
chemical_list: D007328:Insulin; D008565:Membrane Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D011837:Radiation-Protective Agents; D024508:Tocotrienols; D016159:Tumor Suppressor Protein p53; C084881:flt3 ligand protein; D048049:Extracellular Signal-Regulated MAP Kinases