{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:23:39Z","timestamp":1787235819033,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,4,30]],"date-time":"2022-04-30T00:00:00Z","timestamp":1651276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Saitama Medical University Young Doctors Educational Grant","award":["29-F-1-06 (AM)"],"award-info":[{"award-number":["29-F-1-06 (AM)"]}]},{"name":"Saitama Medical University Young Doctors Educational Grant","award":["01-F-1-03 (JO)"],"award-info":[{"award-number":["01-F-1-03 (JO)"]}]},{"name":"Saitama Medical University Young Doctors Educational Grant","award":["18-B-1-11 (AM)"],"award-info":[{"award-number":["18-B-1-11 (AM)"]}]},{"name":"Saitama Medical University Young Doctors Educational Grant","award":["19K08259 (FN)"],"award-info":[{"award-number":["19K08259 (FN)"]}]},{"name":"Saitama Medical University Young Doctors Educational Grant","award":["2019 (EN)"],"award-info":[{"award-number":["2019 (EN)"]}]},{"name":"Saitama Medical University Internal Research Grant","award":["29-F-1-06 (AM)"],"award-info":[{"award-number":["29-F-1-06 (AM)"]}]},{"name":"Saitama Medical University Internal Research Grant","award":["01-F-1-03 (JO)"],"award-info":[{"award-number":["01-F-1-03 (JO)"]}]},{"name":"Saitama Medical University Internal Research Grant","award":["18-B-1-11 (AM)"],"award-info":[{"award-number":["18-B-1-11 (AM)"]}]},{"name":"Saitama Medical University Internal Research Grant","award":["19K08259 (FN)"],"award-info":[{"award-number":["19K08259 (FN)"]}]},{"name":"Saitama Medical University Internal Research Grant","award":["2019 (EN)"],"award-info":[{"award-number":["2019 (EN)"]}]},{"name":"Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science","award":["29-F-1-06 (AM)"],"award-info":[{"award-number":["29-F-1-06 (AM)"]}]},{"name":"Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science","award":["01-F-1-03 (JO)"],"award-info":[{"award-number":["01-F-1-03 (JO)"]}]},{"name":"Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science","award":["18-B-1-11 (AM)"],"award-info":[{"award-number":["18-B-1-11 (AM)"]}]},{"name":"Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science","award":["19K08259 (FN)"],"award-info":[{"award-number":["19K08259 (FN)"]}]},{"name":"Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science","award":["2019 (EN)"],"award-info":[{"award-number":["2019 (EN)"]}]},{"name":"Ochiai Memorial Award Research Grant","award":["29-F-1-06 (AM)"],"award-info":[{"award-number":["29-F-1-06 (AM)"]}]},{"name":"Ochiai Memorial Award Research Grant","award":["01-F-1-03 (JO)"],"award-info":[{"award-number":["01-F-1-03 (JO)"]}]},{"name":"Ochiai Memorial Award Research Grant","award":["18-B-1-11 (AM)"],"award-info":[{"award-number":["18-B-1-11 (AM)"]}]},{"name":"Ochiai Memorial Award Research Grant","award":["19K08259 (FN)"],"award-info":[{"award-number":["19K08259 (FN)"]}]},{"name":"Ochiai Memorial Award Research Grant","award":["2019 (EN)"],"award-info":[{"award-number":["2019 (EN)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Oxygen-induced retinopathy (OIR) is an animal model for retinopathy of prematurity, which is a leading cause of blindness in children. Thioredoxin-1 (TRX) is a small redox protein that has cytoprotective and anti-inflammatory properties in response to oxidative stress. The purpose of this study was to determine the effect of TRX on OIR in newborn mice. From postnatal day 7, C57BL\/6 wild type (WT) and TRX transgenic (TRX-Tg) mice were exposed to either 21% or 75% oxygen for 5 days. Avascular and neovascular regions of the retinas were investigated using fluorescence immunostaining. Fluorescein isothiocyanate-dextran and Hoechst staining were used to measure retinal vascular leakage. mRNA expression levels of proinflammatory and angiogenic factors were analyzed using quantitative polymerase chain reaction. Retinal histological changes were detected using immunohistochemistry. In room air, the WT mice developed well-organized retinas. In contrast, exposing WT newborn mice to hyperoxia hampered retinal development, increasing the retinal avascular and neovascular areas. After hyperoxia exposure, TRX-Tg mice had enhanced retinal avascularization compared with WT mice. TRX-Tg mice had lower retinal neovascularization and retinal permeability during recovery from hyperoxia compared with WT mice. In the early stages after hyperoxia exposure, VEGF-A and CXCL-2 expression levels decreased, while IL-6 expression levels increased in WT newborn mice. Conversely, no differences in gene expressions were observed in the TRX-Tg mouse retina. IGF-1 and Angpt1 levels did not decrease during recovery from hyperoxia in TRX-Tg newborn mice. As a result, overexpression of TRX improves OIR in newborn mice by modulating proinflammatory and angiogenic factors.<\/jats:p>","DOI":"10.3390\/antiox11050899","type":"journal-article","created":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T06:23:08Z","timestamp":1651386188000},"page":"899","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Thioredoxin-1 Ameliorates Oxygen-Induced Retinopathy in Newborn Mice through Modulation of Proinflammatory and Angiogenic Factors"],"prefix":"10.3390","volume":"11","author":[{"given":"Junichi","family":"Ozawa","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe 3508550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe 3508550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Arai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe 3508550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5603-0565","authenticated-orcid":false,"given":"Mitsuhiro","family":"Haga","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe 3508550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoyuki","family":"Miyahara","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe 3508550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe 3508550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe 3508550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6137-4477","authenticated-orcid":false,"given":"Fumihiko","family":"Namba","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe 3508550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1016\/S0140-6736(13)60178-6","article-title":"Retinopathy of prematurity","volume":"382","author":"Smith","year":"2013","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.ophtha.2014.07.050","article-title":"Pathophysiology and mechanisms of severe retinopathy of prematurity","volume":"122","author":"Hartnett","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_3","first-page":"124","article-title":"Retinopathy of prematurity","volume":"78","author":"Bashinsky","year":"2017","journal-title":"N. C. Med. J."},{"key":"ref_4","first-page":"CD003665","article-title":"Vitamin E supplementation for prevention of morbidity and mortality in preterm infants","volume":"2003","author":"Brion","year":"2003","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/S0022-3476(97)70031-3","article-title":"Vitamin E prophylaxis to reduce retinopathy of prematurity: A reappraisal of published trials","volume":"131","author":"Raju","year":"1997","journal-title":"J. Pediatrics"},{"key":"ref_6","first-page":"CD004869","article-title":"Cysteine, cystine or N-acetylcysteine supplementation in parenterally fed neonates","volume":"2006","author":"Soghier","year":"2006","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1167\/iovs.12-10685","article-title":"Lack of the antioxidant glutathione peroxidase-1 (GPx1) exacerbates retinopathy of prematurity in mice","volume":"54","author":"Tan","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1146\/annurev.bi.54.070185.001321","article-title":"Thioredoxin","volume":"54","author":"Holmgren","year":"1985","journal-title":"Annu. Rev. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13963","DOI":"10.1016\/S0021-9258(18)71625-6","article-title":"Thioredoxin and glutaredoxin systems","volume":"264","author":"Holmgren","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15143","DOI":"10.1073\/pnas.191498798","article-title":"Circulating thioredoxin suppresses lipopolysaccharide-induced neutrophil chemotaxis","volume":"98","author":"Nakamura","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0165-2478(02)00033-0","article-title":"Enhanced resistancy of thioredoxin-transgenic mice against influenza virus-induced pneumonia","volume":"82","author":"Nakamura","year":"2002","journal-title":"Immunol. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1016\/j.freeradbiomed.2005.07.016","article-title":"Thioredoxin-1 suppresses lung injury and apoptosis induced by diesel exhaust particles (DEP) by scavenging reactive oxygen species and by inhibiting DEP-induced downregulation of Akt","volume":"39","author":"Nakamura","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1164\/rccm.200209-982OC","article-title":"Redox-active protein thioredoxin prevents proinflammatory cytokine- or bleomycin-induced lung injury","volume":"168","author":"Hoshino","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1089\/ars.2006.8.1835","article-title":"Overexpression of redox-active protein thioredoxin-1 prevents development of chronic pancreatitis in mice","volume":"8","author":"Ohashi","year":"2006","journal-title":"Antioxid. Redox Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"G772","DOI":"10.1152\/ajpgi.00425.2005","article-title":"Protective roles of redox-active protein thioredoxin-1 for severe acute pancreatitis","volume":"290","author":"Ohashi","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1089\/152308603770380106","article-title":"Redox regulation by thioredoxin in cardiovascular diseases","volume":"5","author":"Shioji","year":"2003","journal-title":"Antioxid. Redox Signal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1124\/jpet.107.134007","article-title":"Thioredoxin-1 ameliorates cigarette smoke-induced lung inflammation and emphysema in mice","volume":"325","author":"Sato","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1080\/10715760701199618","article-title":"Thioredoxin-1 attenuates indomethacin-induced gastric mucosal injury in mice","volume":"41","author":"Tan","year":"2007","journal-title":"Free Radic. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/pr.2016.100","article-title":"Human thioredoxin-1 attenuates the rate of lipopolysaccharide-induced preterm delivery in mice in association with its anti-inflammatory effect","volume":"80","author":"Namba","year":"2016","journal-title":"Pediatric Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Nagano, N., Tanaka, K., Ozawa, J., Watanabe, T., Miyake, F., Matsumura, S., Osada, K., Matsuoka, K., Tamura, M., and Namba, F. (2020). Attenuation of hyperoxic lung injury in newborn Thioredoxin-1-Overexpressing mice through the suppression of proinflammatory cytokine mRNA expression. Biomedicines, 8.","DOI":"10.3390\/biomedicines8030066"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.2174\/1381612824666180820143853","article-title":"Thioredoxin as a therapeutic target in cerebral ischemia","volume":"24","author":"Zeng","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_22","first-page":"101","article-title":"Oxygen-induced retinopathy in the mouse","volume":"35","author":"Smith","year":"1994","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_23","first-page":"576","article-title":"Variable oxygen exposure causes preretinal neovascularization in the newborn rat","volume":"34","author":"Penn","year":"1993","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1203\/00006450-200207000-00010","article-title":"Oxidative stress in preterm neonates at birth and on the seventh day of life","volume":"52","author":"Buonocore","year":"2002","journal-title":"Pediatric Res."},{"key":"ref_25","first-page":"222","article-title":"Reduced severity of oxygen-induced retinopathy in eNOS-deficient mice","volume":"42","author":"Brooks","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4131","DOI":"10.1073\/pnas.96.7.4131","article-title":"Overexpression of thioredoxin in transgenic mice attenuates focal ischemic brain damage","volume":"96","author":"Takagi","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1038\/nprot.2009.187","article-title":"Quantification of oxygen-induced retinopathy in the mouse: A model of vessel loss, vessel regrowth and pathological angiogenesis","volume":"4","author":"Connor","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.jphs.2018.03.002","article-title":"Establishment of an abnormal vascular patterning model in the mouse retina","volume":"136","author":"Morita","year":"2018","journal-title":"J. Pharmacol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.exer.2006.11.007","article-title":"New quantitative analysis, using high-resolution images, of oxygen-induced retinal neovascularization in mice","volume":"84","author":"Chikaraishi","year":"2007","journal-title":"Exp. Eye Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Nakamura, S., Imai, S., Ogishima, H., Tsuruma, K., Shimazawa, M., and Hara, H. (2012). Morphological and functional changes in the retina after chronic oxygen-induced retinopathy. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032167"},{"key":"ref_31","first-page":"3442","article-title":"Vascular development in primate retina: Comparison of laminar plexus formation in monkey and human","volume":"35","author":"Gariano","year":"1994","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s10633-009-9201-x","article-title":"Understanding ischemic retinopathies: Emerging concepts from oxygen-induced retinopathy","volume":"120","author":"Sapieha","year":"2010","journal-title":"Doc. Ophthalmol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1038\/nm1095-1024","article-title":"Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity","volume":"1","author":"Alon","year":"1995","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5177","DOI":"10.1167\/iovs.08-2584","article-title":"Through the eyes of a child: Understanding retinopathy through ROP the Friedenwald lecture","volume":"49","author":"Smith","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_35","first-page":"5089","article-title":"The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis","volume":"62","author":"Welsh","year":"2002","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7482","DOI":"10.1074\/jbc.M608289200","article-title":"Thioredoxin 1 and thioredoxin 2 have opposed regulatory functions on hypoxia-inducible factor-1alpha","volume":"282","author":"Zhou","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"203ra127","DOI":"10.1126\/scitranslmed.3006666","article-title":"Angiopoietin-1 guides directional angiogenesis through integrin \u03b1v\u03b25 signaling for recovery of ischemic retinopathy","volume":"5","author":"Lee","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1136\/bjophthalmol-2014-305690","article-title":"Toll-like receptor 3 activation drives the inflammatory response in oxygen-induced retinopathy in rats","volume":"99","author":"Cai","year":"2015","journal-title":"Br. J. Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.1089\/ars.2009.2522","article-title":"Direct association of thioredoxin-1 (TRX) with macrophage migration inhibitory factor (MIF): Regulatory role of TRX on MIF internalization and signaling","volume":"11","author":"Son","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1111\/j.1471-4159.2010.06573.x","article-title":"Temporal requirement of RPE-derived VEGF in the development of choroidal vasculature","volume":"112","author":"Le","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1096\/fasebj.13.13.1800","article-title":"Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron","volume":"13","author":"Suttner","year":"1999","journal-title":"Faseb. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.ejphar.2014.05.033","article-title":"Tissue kallikrein (kallidinogenase) protects against retinal ischemic damage in mice","volume":"738","author":"Masuda","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7556","DOI":"10.1167\/iovs.11-7185","article-title":"Differential expression of claudins in retinas during normal development and the angiogenesis of oxygen-induced retinopathy","volume":"52","author":"Luo","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/5\/899\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:05:16Z","timestamp":1760137516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/5\/899"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,30]]},"references-count":43,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["antiox11050899"],"URL":"https:\/\/doi.org\/10.3390\/antiox11050899","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,30]]}}}