{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:04:29Z","timestamp":1789524269739,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T00:00:00Z","timestamp":1706140800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K14971"],"award-info":[{"award-number":["21K14971"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["S6"],"award-info":[{"award-number":["S6"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016982","name":"Yamagata University","doi-asserted-by":"publisher","award":["21K14971"],"award-info":[{"award-number":["21K14971"]}],"id":[{"id":"10.13039\/100016982","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016982","name":"Yamagata University","doi-asserted-by":"publisher","award":["S6"],"award-info":[{"award-number":["S6"]}],"id":[{"id":"10.13039\/100016982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Bone marrow cells are the most sensitive to exposure to X-rays in the body and are selectively damaged even by doses that are generally considered permissive in other organs. Ascorbic acid (Asc) is a potent antioxidant that is reported to alleviate damages caused by X-ray exposure. However, rodents can synthesize Asc, which creates difficulties in rigorously assessing its effects in such laboratory animals. To address this issue, we employed mice with defects in their ability to synthesize Asc due to a genetic ablation of aldehyde reductase (Akr1a-KO). In this study, concentrations of white blood cells (WBCs) were decreased 3 days after exposure to X-rays at 2 Gy and then gradually recovered. At approximately one month, the recovery rate of WBCs was delayed in the Akr1a-KO mouse group, which was reversed via supplementation with Asc. Following exposure to X-rays, Asc levels decreased in plasma, bone marrow cells, and the liver during an early period, and then started to increase. X-ray exposure stimulated the pituitary gland to release adrenocorticotropic hormone (ACTH), which stimulated corticosterone secretion. Asc released from the liver, which was also stimulated by ACTH, appeared to be recruited to the bone marrow. Since corticosterone in high doses is injurious, these collective results imply that Asc protects bone marrow via its antioxidant capacity against ROS produced via exposure to X-rays and the cytotoxic action of transiently elevated corticosterone.<\/jats:p>","DOI":"10.3390\/antiox13020152","type":"journal-article","created":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T06:54:12Z","timestamp":1706165652000},"page":"152","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ascorbic Acid Protects Bone Marrow from Oxidative Stress and Transient Elevation of Corticosterone Caused by X-ray Exposure in Akr1a-Knockout Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Tomoki","family":"Bo","sequence":"first","affiliation":[{"name":"Laboratory Animal Center, Institute for Promotion of Medical Science Research, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidekazu","family":"Nohara","sequence":"additional","affiliation":[{"name":"Laboratory Animal Center, Institute for Promotion of Medical Science Research, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken-ichi","family":"Yamada","sequence":"additional","affiliation":[{"name":"Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Miyata","sequence":"additional","affiliation":[{"name":"Miyata Diabetes and Metabolism Clinic, 5-17-21 Fukushima, Fukushima-ku, Osaka 553-0003, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2267-7357","authenticated-orcid":false,"given":"Junichi","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"031002","DOI":"10.1088\/1361-6498\/ac7d18","article-title":"Medical management of acute radiation syndrome","volume":"42","author":"Dainiak","year":"2022","journal-title":"J. Radiol. Prot."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s40778-022-00214-z","article-title":"Impact of Age, Sex, and Genetic Diversity in Murine Models of the Hematopoietic Acute Radiation Syndrome (H-ARS) and the Delayed Effects of Acute Radiation Exposure (DEARE)","volume":"8","author":"Orschell","year":"2022","journal-title":"Curr. Stem Cell Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/path.5389","article-title":"Radiation-induced tissue damage and response","volume":"250","author":"McBride","year":"2020","journal-title":"J. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"Av3","DOI":"10.1667\/RRAV01.1","article-title":"A direct measurement of the radiation sensitivity of normal mouse bone marrow cells","volume":"178","author":"Till","year":"2012","journal-title":"Radiat. Res."},{"key":"ref_5","first-page":"270","article-title":"Glucocorticoids and irradiation-induced apoptosis in normal murine bone marrow B-lineage lymphocytes as determined by flow cytometry","volume":"79","author":"Garvy","year":"1993","journal-title":"Immunology"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ogawa, Y. (2016). Paradigm Shift in Radiation Biology\/Radiation Oncology-Exploitation of the \u201cH2O2 Effect\u201d for Radiotherapy Using Low-LET (Linear Energy Transfer) Radiation such as X-rays and High-Energy Electrons. Cancers, 8.","DOI":"10.3390\/cancers8030028"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.freeradbiomed.2020.07.013","article-title":"Ascorbic acid: The chemistry underlying its antioxidant properties","volume":"159","author":"Njus","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Fujii, J., Osaki, T., and Bo, T. (2022). Ascorbate Is a Primary Antioxidant in Mammals. Molecules, 27.","DOI":"10.3390\/molecules27196187"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0165-7992(93)90037-V","article-title":"Radioprotective effect of vitamins C and E","volume":"301","author":"Mattar","year":"1993","journal-title":"Mutat. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0027-5107(98)00153-5","article-title":"Radiation-induced long-lived radicals which cause mutation and transformation","volume":"421","author":"Koyama","year":"1998","journal-title":"Mutat. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19618","DOI":"10.3390\/ijms141019618","article-title":"A combination of pre- and post-exposure ascorbic acid rescues mice from radiation-induced lethal gastrointestinal damage","volume":"14","author":"Ito","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sato, T., Kinoshita, M., Yamamoto, T., Ito, M., Nishida, T., Takeuchi, M., Saitoh, D., Seki, S., and Mukai, Y. (2015). Treatment of irradiated mice with high-dose ascorbic acid reduced lethality. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117020"},{"key":"ref_13","first-page":"271","article-title":"Antioxidant effects of vitamin C in mice following X-irradiation","volume":"94","author":"Harapanhalli","year":"1996","journal-title":"Res. Commun. Mol. Pathol. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1742-4658.2006.05607.x","article-title":"Vitamin C. Biosynthesis, recycling and degradation in mammals","volume":"274","author":"Linster","year":"2007","journal-title":"FEBS J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1111\/j.1476-5381.2009.00282.x","article-title":"Vitamin C: Update on physiology and pharmacology","volume":"157","author":"Mandl","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13685","DOI":"10.1016\/S0021-9258(17)36884-9","article-title":"Cloning and chromosomal mapping of the human nonfunctional gene for L-gulono-gamma-lactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man","volume":"269","author":"Nishikimi","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19510","DOI":"10.1074\/jbc.M110.110247","article-title":"Ascorbate synthesis pathway: Dual role of ascorbate in bone homeostasis","volume":"285","author":"Gabbay","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1016\/j.bbagen.2012.07.003","article-title":"In vivo role of aldehyde reductase","volume":"1820","author":"Takahashi","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Fujii, J., Homma, T., Miyata, S., and Takahashi, M. (2021). Pleiotropic Actions of Aldehyde Reductase (AKR1A). Metabolites, 11.","DOI":"10.3390\/metabo11060343"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.bbr.2016.11.038","article-title":"Heightened aggressive behavior in mice deficient in aldo-keto reductase 1a (Akr1a)","volume":"319","author":"Homma","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ishii, N., Homma, T., Takeda, Y., Aung, N.Y., Yamada, K.I., Miyata, S., Asao, H., Yamakawa, M., and Fujii, J. (2021). Developmental retardation in neonates of aldehyde reductase (AKR1A)-deficient mice is associated with low ascorbic acid and high corticosterone levels. J. Nutr. Biochem., 91.","DOI":"10.1016\/j.jnutbio.2021.108604"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1042\/bj0221387","article-title":"Observations on the function of peroxidase systems and the chemistry of the adrenal cortex: Description of a new carbohydrate derivative","volume":"22","year":"1928","journal-title":"Biochem. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.bbrc.2005.08.156","article-title":"Ascorbate stimulates monooxygenase-dependent steroidogenesis in adrenal zona glomerulosa","volume":"338","author":"Mitani","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1210\/en.2007-0262","article-title":"Ascorbic acid transported by sodium-dependent vitamin C transporter 2 stimulates steroidogenesis in human choriocarcinoma cells","volume":"149","author":"Wu","year":"2008","journal-title":"Endocrinology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1152\/ajplegacy.1955.183.1.71","article-title":"Adrenal ascorbic acid and histological changes in male and female rats after half-body x-ray irradiation","volume":"183","author":"Wexler","year":"1955","journal-title":"Am. J. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s00726-007-0555-7","article-title":"SVCT1 and SVCT2: Key proteins for vitamin C uptake","volume":"34","author":"Savini","year":"2008","journal-title":"Amino Acids"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1081\/ERC-200044126","article-title":"Vitamin C is an important cofactor for both adrenal cortex and adrenal medulla","volume":"30","author":"Patak","year":"2004","journal-title":"Endocr. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"470","DOI":"10.2307\/3570343","article-title":"The effects of localized cathode-ray particle irradiation of the hypophysis and whole-body x-irradiation on gonadotrophin, thyrotrophin, and adrenocorticotrophin of the rat pituitary","volume":"1","author":"Mateyko","year":"1954","journal-title":"Radiat. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"620","DOI":"10.2307\/3571755","article-title":"Plasma and adrenal gland corticosterone levels after X-ray exposure in rats","volume":"23","author":"Hameed","year":"1964","journal-title":"Radiat. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1093\/ajcn\/86.1.145","article-title":"Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone","volume":"86","author":"Padayatty","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/0891-5849(95)00033-T","article-title":"Whole body X-ray irradiation to mice decreases ascorbic acid concentration in bone marrow: Comparison between ascorbic acid and vitamin E","volume":"19","author":"Umegaki","year":"1995","journal-title":"Free Radic. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1016\/j.freeradbiomed.2012.09.032","article-title":"Rapid and convenient detection of ascorbic acid using a fluorescent nitroxide switch","volume":"53","author":"Matsuoka","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/0378-1119(93)90728-L","article-title":"Identity of a major 3-deoxyglucosone-reducing enzyme with aldehyde reductase in rat liver established by amino acid sequencing and cDNA expression","volume":"127","author":"Takahashi","year":"1993","journal-title":"Gene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.4049\/jimmunol.157.4.1638","article-title":"Stress-induced changes in blood leukocyte distribution. Role of adrenal steroid hormones","volume":"157","author":"Dhabhar","year":"1996","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Galano, M., Venugopal, S., and Papadopoulos, V. (2022). Role of STAR and SCP2\/SCPx in the Transport of Cholesterol and Other Lipids. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012115"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s10565-008-9069-7","article-title":"Steroidogenic acute regulatory (StAR) protein and cholesterol side-chain cleavage (P450scc)-regulated steroidogenesis as an organ-specific molecular and cellular target for endocrine disrupting chemicals in fish","volume":"24","author":"Arukwe","year":"2008","journal-title":"Cell Biol. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Toor, A., Simmons, G., Sabo, R., Aziz, M., Martin, E., Bernard, R., Sriparna, M., McIntire, C., Kreiger, E., and Brophy, D. (2023). Intravenous Vitamin C Supplementation in Allogeneic Hematopoietic Cell Transplant Recipients: Salutary Impact on Clinical Outcomes. Res. Sq., preprint.","DOI":"10.21203\/rs.3.rs-3538792\/v1"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1182\/blood-2008-07-170936","article-title":"Intravenous administration of mesenchymal stem cells genetically modified with extracellular superoxide dismutase improves survival in irradiated mice","volume":"113","author":"Senagore","year":"2009","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1096\/fj.02-1167fje","article-title":"Impaired adrenal catecholamine system function in mice with deficiency of the ascorbic acid transporter (SVCT2)","volume":"17","author":"Bornstein","year":"2003","journal-title":"FASEB J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1093\/jn\/115.12.1630","article-title":"Requirement for ascorbic acid in a rat mutant unable to synthesize ascorbic acid","volume":"115","author":"Horio","year":"1985","journal-title":"J. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/0003-9969(95)00030-S","article-title":"Effect of marginal ascorbic acid deficiency on saliva level of cortisol in the guinea pig","volume":"40","author":"Enwonwu","year":"1995","journal-title":"Arch. Oral Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"139","DOI":"10.3109\/02841869409098397","article-title":"On radiation damage to normal tissues and its treatment. II. Anti-inflammatory drugs","volume":"33","author":"Michalowski","year":"1994","journal-title":"Acta Oncol."},{"key":"ref_43","first-page":"393","article-title":"Hormonal regulation of ascorbic acid in the adrenal of the rat","volume":"109","author":"Overbeek","year":"1985","journal-title":"Acta Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Gerber, A.N., Newton, R., and Sasse, S.K. (2021). Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era. J. Biol. Chem., 296.","DOI":"10.1016\/j.jbc.2021.100687"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1002\/jemt.10414","article-title":"Apoptosis in primary lymphoid organs with aging","volume":"62","author":"Sainz","year":"2003","journal-title":"Microsc. Res. Tech."},{"key":"ref_46","first-page":"174","article-title":"Adverse effect of cortisone on marrow regeneration following irradiation","volume":"40","author":"Thiersch","year":"1952","journal-title":"J. Lab. Clin. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1146\/annurev.immunol.18.1.309","article-title":"Glucocorticoids in T cell development and function*","volume":"18","author":"Ashwell","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kratschmar, D.V., Calabrese, D., Walsh, J., Lister, A., Birk, J., Appenzeller-Herzog, C., Moulin, P., Goldring, C.E., and Odermatt, A. (2012). Suppression of the Nrf2-dependent antioxidant response by glucocorticoids and 11\u03b2-HSD1-mediated glucocorticoid activation in hepatic cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0036774"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7519","DOI":"10.1074\/jbc.M116.773960","article-title":"Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2","volume":"292","author":"Alam","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s00213-001-0929-6","article-title":"A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress","volume":"159","author":"Brody","year":"2002","journal-title":"Psychopharmacology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.freeradbiomed.2021.03.017","article-title":"The role of vitamin C in epigenetic cancer therapy","volume":"170","author":"Mikkelsen","year":"2021","journal-title":"Free Radic. Biol. Med."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/2\/152\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:49:10Z","timestamp":1760104150000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/2\/152"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,25]]},"references-count":51,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["antiox13020152"],"URL":"https:\/\/doi.org\/10.3390\/antiox13020152","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,25]]}}}