Resveratrol ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice |
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| Institution: | 1. Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China;2. Department of Radiation Oncology, Tianjin Union Medical Center, Tianjin, China;3. Department of Pharmaceutical Sciences and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;4. Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China;5. Institute of Aging Research, College of Medicine Hangzhou Normal University, Zhejiang, China;1. Ryazan State Medical University named after academician IP Pavlov, Visokovoltnaya St. 9, Ryazan 390026, Russia;2. RUDN University, Miklukho–Maklai St. 6, Moscow 117198, Russia;3. Laboratory of Physicochemical and Ecological Pathophysiology, Institute of General Pathology and Pathophysiology, Baltiyskaya St. 8, Moscow 125315, Russia;4. Department of Biochemistry, Orenburg State Medical University, Sovetskaya St. 6, Orenburg 460000, Russia;5. Department of Biochemistry, South Ural State Medical University, Vorovskogo St. 64, Chelyabinsk, 454048, Russia;6. Laboratory of Biotechnology and Applied Bioelementology, Yaroslavl State University, Sovetskaya St. 14, Yaroslavl, 150000, Russia;7. All-Russian Research Institute of Medicinal and Aromatic Plants (VILAR), Grina St. 7, Moscow, 117216, Russia;8. Institute of Bioelementology (Russian Satellite Centre of Trace Element—Institute for UNESCO), Orenburg State University, Pobedy Ave. 13, Orenburg 460352, Russia;1. Department of Radiation Protection and Health, Federal Office for Radiation Protection, Ingolstaedter Landstr.1, 85764 Oberschleissheim,Germany;2. Institute of Epidemiology, Helmholtz Center Munich, 85764 Neuherberg, Germany;3. Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany;4. Department of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians—University Munich, 80539 Munich, Germany;1. Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, Lincoln''s Inn Fields Laboratory, London, United Kingdom;2. Haematopoietic Signalling Group, European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom;3. Mammalian Genetics Laboratory, The Francis Crick Institute, Lincoln''s Inn Fields Laboratory, London, United Kingdom;4. Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria;5. Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, University College London, London, United Kingdom;6. Flow Cytometry Laboratory, The Francis Crick Institute, Lincoln''s Inn Fields Laboratory, London, United Kingdom;7. Diabetes & Nutritional Sciences Division, Faculty of Life Sciences & Medicine, King''s College London, London, United Kingdom;1. Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland;2. Radiation Biology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland;1. College of Materials Science and Technology, Nanjing University of Aeronautics and Astronautics, Nanjing, 211106, China;2. Key Laboratory of Nuclear Technology Application and Radiation Protection in Astronautics (Nanjing University of Aeronautics and Astronautics), Ministry of Industry and Information Technology, Nanjing, 211106, China;1. Dipartimento di Scienze, Università “Roma TRE”, Roma, Italy;2. Istituto di Biologia Molecolare e Patologia, CNR, Roma, Italy;3. Sezione di Tossicologia e Scienze Biomediche, ENEA, Casaccia Roma, Italy |
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| 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. |
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