title: Resveratrol ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice.
abstract: Our recent studies showed that total body irradiation (TBI) induces long-term bone marrow (BM) suppression in part by induction of hematopoietic stem cell (HSC) senescence through NADPH oxidase 4 (NOX4)-derived reactive oxygen species (ROS). Therefore, in this study we examined whether resveratrol (3,5,4'-trihydroxy-trans-stilbene), a potent antioxidant and a putative activator of Sirtuin 1 (Sirt1), can ameliorate TBI-induced long-term BM injury by inhibiting radiation-induced chronic oxidative stress and senescence in HSCs. Our results showed that pretreatment with resveratrol not only protected mice from TBI-induced acute BM syndrome and lethality but also ameliorated TBI-induced long-term BM injury. The latter effect is probably attributable to resveratrol-mediated reduction of chronic oxidative stress in HSCs, because resveratrol treatment significantly inhibited TBI-induced increase in ROS production in HSCs and prevented mouse BM HSCs from TBI-induced senescence, leading to a significant improvement in HSC clonogenic function and long-term engraftment after transplantation. The inhibition of TBI-induced ROS production in HSCs is probably attributable to resveratrol-mediated downregulation of NOX4 expression and upregulation of Sirt1, superoxide dismutase 2 (SOD2), and glutathione peroxidase 1 expression. Furthermore, we showed that resveratrol increased Sirt1 deacetylase activity in BM hematopoietic cells; and Ex527, a potent Sirt1 inhibitor, can attenuate resveratrol-induced SOD2 expression and the radioprotective effect of resveratrol on HSCs. These findings demonstrate that resveratrol can protect HSCs from radiation at least in part via activation of Sirt1. Therefore, resveratrol has the potential to be used as an effective therapeutic agent to ameliorate TBI-induced long-term BM injury.
authors.affiliation: Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Zhai
authors.forename: Yueying
authors.initials: Y
authors.lastname: Wang
authors.forename: Junling
authors.initials: J
authors.lastname: Zhang
authors.forename: Hongying
authors.initials: H
authors.lastname: Wu
authors.forename: Yingying
authors.initials: Y
authors.lastname: Wang
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Li
authors.forename: Deguan
authors.initials: D
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Wang
authors.forename: Jianhui
authors.initials: J
authors.lastname: Chang
authors.forename: Qi
authors.initials: Q
authors.lastname: Hou
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.forename: Aimin
authors.initials: A
authors.lastname: Meng
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects*; D013267:Stilbenes / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D011837:Radiation-Protective Agents; D013267:Stilbenes; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol