{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T05:38:27Z","timestamp":1771306707163,"version":"3.50.1"},"reference-count":22,"publisher":"Portland Press Ltd.","issue":"1","license":[{"start":{"date-parts":[[2020,12,21]],"date-time":"2020-12-21T00:00:00Z","timestamp":1608508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,1,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cobalt nanoparticles (CoNPs) released from hip joint implants are known to have a toxic effect on several organs probably through increasing reactive oxygen species (ROS). Ferrous ion (Fe2+) is well-known to enhance oxidative stress by catalysing the production of ROS. However, in our pilot study, we found that Fe2+ conversely inhibited the ROS production induced by CoNPs. To elucidate the underlying mechanism, the present study treated vascular endothelial HUVEC and HMEC-1 cells with CoNPs alone or in combination with ferrous lactate [Fe(CH3CHOHCOO)2], ferrous succinate [Fe(CH2COO)2], and ferrous chloride (FeCl2). CoNP toxicity was evaluated by measuring cell viability, rate of apoptosis and lactose dehydrogenase (LDH) release, and intracellular ROS levels. Treatment with CoNPs decreased cell viability, LDH release, and ROS production and increased apoptosis. CoNPs increased hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) protein level and mRNA levels of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT1) downstream of HIF-1\u03b1 signalling. Silencing HIF-1\u03b1 attenuated CoNP toxicity, as seen by recovery of cell viability, LDH release, and ROS levels and reduced apoptosis. CoNPs caused a pronounced reduction of Fe2+ in cells, but supplementation with Fe(CH3CHOHCOO)2, Fe(CH2COO)2, and FeCl2 restored Fe2+ levels and inhibited HIF-1\u03b1 activation. Moreover, all three Fe2+-containing agents conferred protection from CoNPs; Fe(CH3CHOHCOO)2 and Fe(CH2COO)2 more effectively than FeCl2. In summary, the present study revealed that CoNPs exert their toxicity on human vascular endothelial cells by depleting intracellular Fe2+ level, which causes activation of HIF-1\u03b1 signalling. Supplements of Fe2+, especially in the form of Fe(CH3CHOHCOO)2 and Fe(CH2COO)2, mitigated CoNP toxicity.<\/jats:p>","DOI":"10.1042\/bsr20203456","type":"journal-article","created":{"date-parts":[[2020,12,21]],"date-time":"2020-12-21T09:42:38Z","timestamp":1608543758000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A paradox: Fe2+-containing agents decreased ROS and apoptosis induced by CoNPs in vascular endothelial cells by inhibiting HIF-1\u03b1"],"prefix":"10.1042","volume":"41","author":[{"given":"Wenfeng","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China"},{"name":"Department of Orthopaedics, The Sixth Affiliated Hospital of Nantong University, Yancheng, Jiangsu Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yake","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Orthopaedic Laboratory, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zihua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China"},{"name":"Orthopaedic Laboratory, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin-hua","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, Jiangsu Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zexu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China"},{"name":"Orthopaedic Laboratory, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huanjian","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The Sixth Affiliated Hospital of Nantong University, Yancheng, Jiangsu Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8885-171X","authenticated-orcid":false,"given":"Fan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2021,1,8]]},"reference":[{"key":"2021111620363649000_B1","doi-asserted-by":"publisher","first-page":"4413","DOI":"10.3892\/mmr.2017.7309","article-title":"Melatonin counteracts cobalt nanoparticle-induced cytotoxicity and genotoxicity by deactivating reactive oxygen species-dependent mechanisms in the NRK cell line","volume":"16","author":"Liu","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"2021111620363649000_B2","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1302\/2046-3758.510.BJR-2016-0016.R1","article-title":"Cytotoxicity and genotoxicity in liver cells induced by cobalt nanoparticles and ions","volume":"5","author":"Liu","year":"2016","journal-title":"Bone Joint Res."},{"key":"2021111620363649000_B3","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1007\/s12012-018-9498-3","article-title":"Cobalt administration causes reduced contractility with parallel increases in TRPC6 and TRPM7 transporter protein expression in adult rat hearts","volume":"19","author":"Laovitthayanggoon","year":"2019","journal-title":"Cardiovasc. Toxicol."},{"key":"2021111620363649000_B4","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.taap.2019.03.003","article-title":"Comparison of the neurotoxicity associated with cobalt nanoparticles and cobalt chloride in Wistar rats","volume":"369","author":"Zheng","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"2021111620363649000_B5","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1093\/mutage\/gen024","article-title":"Comparative genotoxicity of cobalt nanoparticles and ions on human peripheral leukocytes in vitro","volume":"23","author":"Colognato","year":"2008","journal-title":"Mutagenesis"},{"key":"2021111620363649000_B6","doi-asserted-by":"publisher","first-page":"455","DOI":"10.3109\/17435390.2013.796538","article-title":"Cytotoxicity and morphological transforming potential of cobalt nanoparticles, microparticles and ions in Balb\/3T3 mouse fibroblasts: an in vitro model","volume":"8","author":"Sabbioni","year":"2014","journal-title":"Nanotoxicology"},{"key":"2021111620363649000_B7","doi-asserted-by":"publisher","first-page":"905","DOI":"10.3109\/17435390.2014.991430","article-title":"Importance of the HIF pathway in cobalt nanoparticle-induced cytotoxicity and inflammation in human macrophages","volume":"9","author":"Nyga","year":"2015","journal-title":"Nanotoxicology"},{"key":"2021111620363649000_B8","doi-asserted-by":"publisher","first-page":"9504","DOI":"10.1074\/jbc.M310658200","article-title":"Role of iron (II)-2-oxoglutarate-dependent dioxygenases in the generation of hypoxia-induced phosphatidic acid through HIF-1\/2 and von Hippel-Lindau-independent mechanisms","volume":"279","author":"Mart\u00edn-Puig","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021111620363649000_B9","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.taap.2005.11.006","article-title":"Effects of 12 metal ions on iron regulatory protein 1 (IRP-1) and hypoxia-inducible factor-1 alpha (HIF-1alpha) and HIF-regulated genes","volume":"213","author":"Li","year":"2006","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"2021111620363649000_B10","doi-asserted-by":"publisher","first-page":"109249","DOI":"10.1016\/j.mehy.2019.109249","article-title":"Hypoxia inducible factors as mediators of reactive oxygen\/nitrogen species homeostasis in physiological normoxia","volume":"129","author":"Stuart","year":"2019","journal-title":"Med. Hypotheses"},{"key":"2021111620363649000_B11","doi-asserted-by":"crossref","first-page":"e746","DOI":"10.1111\/aos.13096","article-title":"Inhibition of HIF-1\u03b1 decreases expression of pro-inflammatory IL-6 and TNF-\u03b1 in diabetic retinopathy","volume":"95","author":"Gao","year":"2017","journal-title":"Acta Ophthalmol."},{"key":"2021111620363649000_B12","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.biopha.2017.04.103","article-title":"The pivotal role of HIF-1\u03b1 in lung inflammatory injury induced by septic mesenteric lymph","volume":"91","author":"Sun","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"2021111620363649000_B13","doi-asserted-by":"crossref","first-page":"8722","DOI":"10.12659\/MSM.913384","article-title":"Hypoxia-inducible factor 1-\u03b1 (HIF-1\u03b1) induces apoptosis of human uterosacral ligament fibroblasts through the death receptor and mitochondrial pathways","volume":"24","author":"Zhao","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"2021111620363649000_B14","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1038\/s41467-019-09482-6","article-title":"The lncRNA Neat1 promotes activation of inflammasomes in macrophages","volume":"10","author":"Zhang","year":"2019","journal-title":"Nat. Commun."},{"key":"2021111620363649000_B15","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1111\/odi.13058","article-title":"Autophagy-related gene expression regulated by HIF-1\u03b1 in salivary adenoid cystic carcinoma","volume":"25","author":"Liu","year":"2019","journal-title":"Oral Dis."},{"key":"2021111620363649000_B16","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.bpobgyn.2016.09.007","article-title":"Iron deficiency and iron deficiency anaemia in women","volume":"40","author":"Percy","year":"2017","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"2021111620363649000_B17","doi-asserted-by":"publisher","DOI":"10.1111\/1755-5922.12301","article-title":"Iron deficiency in heart failure: Efficacy and safety of intravenous iron therapy","volume":"35","author":"Kang","year":"2017","journal-title":"Cardiovasc. Ther."},{"key":"2021111620363649000_B18","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1007\/s12011-016-0789-x","article-title":"L-Ascorbic acid protected against extrinsic and intrinsic apoptosis induced by cobalt nanoparticles through ROS attenuation","volume":"175","author":"Liu","year":"2017","journal-title":"Biol. Trace Elem. Res."},{"key":"2021111620363649000_B19","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1080\/08923973.2018.1424901","article-title":"\u03b1-Tocopherol protected against cobalt nanoparticles and cocl2 induced cytotoxicity and inflammation in Balb\/3T3 cells","volume":"40","author":"Yan","year":"2018","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"2021111620363649000_B20","doi-asserted-by":"publisher","first-page":"98482","DOI":"10.18632\/oncotarget.21445","article-title":"Role of HIF-1a in regulating autophagic cell survival during cerebral ischemia reperfusion in rats","volume":"8","author":"Guo","year":"2017","journal-title":"Oncotarget"},{"key":"2021111620363649000_B21","first-page":"4824035","article-title":"Propofol alleviates apoptosis induced by chronic high glucose exposure via regulation of HIF-1\u03b1 in H9c2 cells","volume":"2019","author":"Pu","year":"2019","journal-title":"Oxid. Med. Cell*. Longev."},{"key":"2021111620363649000_B22","doi-asserted-by":"publisher","first-page":"30485","DOI":"10.1074\/jbc.M112.364208","article-title":"Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1","volume":"287","author":"Illing","year":"2012","journal-title":"J. Biol. Chem."}],"container-title":["Bioscience Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20203456\/901581\/bsr-2020-3456.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20203456\/901581\/bsr-2020-3456.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T21:01:25Z","timestamp":1637096485000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/bioscirep\/article\/41\/1\/BSR20203456\/227394\/A-paradox-Fe2-containing-agents-decreased-ROS-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1]]},"references-count":22,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1,29]]}},"URL":"https:\/\/doi.org\/10.1042\/bsr20203456","relation":{},"ISSN":["0144-8463","1573-4935"],"issn-type":[{"value":"0144-8463","type":"print"},{"value":"1573-4935","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,1]]},"published":{"date-parts":[[2021,1]]},"article-number":"BSR20203456"}}