{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T16:14:27Z","timestamp":1787933667280,"version":"build-2784847793"},"reference-count":85,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,6,16]],"date-time":"2017-06-16T00:00:00Z","timestamp":1497571200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,6,16]],"date-time":"2017-06-16T00:00:00Z","timestamp":1497571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Generation of multiple mRNAs by alternative splicing is well known in the group of cytokines and has recently been reported for the human erythropoietin (EPO) gene. Here, we focus on the alternatively spliced <jats:italic>EPO<\/jats:italic> transcript characterized by deletion of exon 3 (hEPO\u03943). We show co-regulation of <jats:italic>EPO<\/jats:italic> and hEPO\u03943 in human diseased tissue. The expression of hEPO\u03943 in various human samples was low under normal conditions, and distinctly increased in pathological states. Concomitant up-regulation of hEPO\u03943 and <jats:italic>EPO<\/jats:italic> in response to hypoxic conditions was also observed in HepG2 cell cultures. Using LC-ESI-MS\/MS, we provide first evidence for the existence of hEPO\u03943 derived protein EV-3 in human serum from healthy donors. Contrary to EPO, recombinant EV-3 did not promote early erythroid progenitors in cultures of human CD34+ haematopoietic stem cells. Repeated intraperitoneal administration of EV-3 in mice did not affect the haematocrit. Similar to EPO, EV-3 acted anti-apoptotic in rat hippocampal neurons exposed to oxygen-glucose deprivation. Employing the touch-screen paradigm of long-term visual discrimination learning, we obtained first <jats:italic>in vivo<\/jats:italic> evidence of beneficial effects of EV-3 on cognition. This is the first report on the presence of a naturally occurring EPO protein isoform in human serum sharing non-erythropoietic functions with EPO.<\/jats:p>","DOI":"10.1038\/s41598-017-03167-0","type":"journal-article","created":{"date-parts":[[2017,6,12]],"date-time":"2017-06-12T10:23:06Z","timestamp":1497262986000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["EV-3, an endogenous human erythropoietin isoform with distinct functional relevance"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5601-516X","authenticated-orcid":false,"given":"Christel","family":"Bonnas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liane","family":"W\u00fcstefeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Winkler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romy","family":"Kronstein-Wiedemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekrem","family":"Dere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Specht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Boxberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Tonn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannelore","family":"Ehrenreich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert","family":"Stadler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge","family":"Sillaber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,6,16]]},"reference":[{"key":"3167_CR1","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1111\/j.1600-0609.2007.00818.x","volume":"78","author":"W Jelkmann","year":"2007","unstructured":"Jelkmann, W. Erythropoietin after a century of research: younger than ever. Eur. J. Haematol. \n                           78, 183\u2013205, doi:10.1111\/j.1600-0609.2007.00818.x (2007).","journal-title":"Eur. J. Haematol."},{"key":"3167_CR2","doi-asserted-by":"publisher","first-page":"65","DOI":"10.2174\/1389201053167257","volume":"6","author":"W Jelkmann","year":"2005","unstructured":"Jelkmann, W. Effects of erythropoietin on brain function. Curr. Pharm. Biotechnol. \n                           6, 65\u201379, doi:10.2174\/1389201053167257 (2005).","journal-title":"Curr. Pharm. Biotechnol."},{"key":"3167_CR3","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1023\/B:MEBR.0000043969.96895.3c","volume":"19","author":"H Ehrenreich","year":"2004","unstructured":"Ehrenreich, H. et al. Erythropoietin: novel approaches to neuroprotection in human brain disease. Metab. Brain Dis. \n                           19, 195\u2013206, doi:10.1023\/B:MEBR.0000043969.96895.3c (2004).","journal-title":"Metab. Brain Dis."},{"key":"3167_CR4","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1097\/00008506-200604000-00007","volume":"18","author":"M Hasselblatt","year":"2006","unstructured":"Hasselblatt, M., Ehrenreich, H. & Sir\u00e9n, A.-L. The brain erythropoietin system and its potential for therapeutic exploitation in brain disease. J. Neurosurg. Anesthesiol. \n                           18, 132\u20138, doi:10.1097\/00008506-200604000-00007 (2006).","journal-title":"J. Neurosurg. Anesthesiol."},{"key":"3167_CR5","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/nrn1687","volume":"6","author":"M Brines","year":"2005","unstructured":"Brines, M. & Cerami, A. Emerging biological roles for erythropoietin in the nervous system. Nat. Rev. Neurosci. \n                           6, 484\u201394, doi:10.1038\/nrn1687 (2005).","journal-title":"Nat. Rev. Neurosci."},{"key":"3167_CR6","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1038\/35088074","volume":"412","author":"M Digicaylioglu","year":"2001","unstructured":"Digicaylioglu, M. & Lipton, S. A. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature \n                           412, 641\u20137, doi:10.1038\/35088074 (2001).","journal-title":"Nature"},{"key":"3167_CR7","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/S0304-3940(00)01361-6","volume":"290","author":"AD Sinor","year":"2000","unstructured":"Sinor, A. D. & Greenberg, D. A. Erythropoietin protects cultured cortical neurons, but not astroglia, from hypoxia and AMPA toxicity. Neurosci. Lett. \n                           290, 213\u20135, doi:10.1016\/S0304-3940(00)01361-6 (2000).","journal-title":"Neurosci. Lett."},{"key":"3167_CR8","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/S0306-4522(96)00306-5","volume":"76","author":"E Morishita","year":"1997","unstructured":"Morishita, E., Masuda, S., Nagao, M., Yasuda, Y. & Sasaki, R. Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience \n                           76, 105\u201316, doi:10.1016\/S0306-4522(96)00306-5 (1997).","journal-title":"Neuroscience"},{"key":"3167_CR9","doi-asserted-by":"publisher","first-page":"4044","DOI":"10.1073\/pnas.051606598","volume":"98","author":"AL Sir\u00e9n","year":"2001","unstructured":"Sir\u00e9n, A. L. et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc. Natl. Acad. Sci. USA \n                           98, 4044\u20139, doi:10.1073\/pnas.051606598 (2001).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"3167_CR10","doi-asserted-by":"publisher","first-page":"10526","DOI":"10.1073\/pnas.97.19.10526","volume":"97","author":"ML Brines","year":"2000","unstructured":"Brines, M. L. et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc. Natl. Acad. Sci. USA \n                           97, 10526\u201331, doi:10.1073\/pnas.97.19.10526 (2000).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"3167_CR11","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1097\/00004647-199906000-00007","volume":"19","author":"M Bernaudin","year":"1999","unstructured":"Bernaudin, M. et al. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J. Cereb. Blood Flow Metab. \n                           19, 643\u201351, doi:10.1097\/00004647-199906000-00007 (1999).","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"3167_CR12","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1177\/1756285608098422","volume":"1","author":"C Bartels","year":"2008","unstructured":"Bartels, C., Sp\u00e4te, K., Krampe, H. & Ehrenreich, H. Recombinant human erythropoietin: novel strategies for neuroprotective\/neuro-regenerative treatment of multiple sclerosis. Ther. Adv. Neurol. Disord. \n                           1, 193\u2013206, doi:10.1177\/1756285608098422 (2008).","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"3167_CR13","doi-asserted-by":"publisher","unstructured":"W\u00fcstenberg, T. et al. Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia. Mol. Psychiatry \n                           16, 26\u201336, 1, doi:10.1038\/mp.2010.51 (2011).","DOI":"10.1038\/mp.2010.51"},{"key":"3167_CR14","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1007\/s13760-014-0286-y","volume":"114","author":"F Najmi Varzaneh","year":"2014","unstructured":"Najmi Varzaneh, F., Najmi Varzaneh, F., Azimi, A. R., Rezaei, N. & Sahraian, M. A. Efficacy of combination therapy with erythropoietin and methylprednisolone in clinical recovery of severe relapse in multiple sclerosis. Acta Neurol. Belg. \n                           114, 273\u20138, doi:10.1007\/s13760-014-0286-y (2014).","journal-title":"Acta Neurol. Belg."},{"key":"3167_CR15","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1111\/jon.12050","volume":"24","author":"K Egger","year":"2014","unstructured":"Egger, K. et al. White matter changes in patients with friedreich ataxia after treatment with erythropoietin. J. Neuroimaging \n                           24, 504\u20138, doi:10.1111\/jon.12050 (2014).","journal-title":"J. Neuroimaging"},{"key":"3167_CR16","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.jns.2013.11.015","volume":"337","author":"W Jang","year":"2014","unstructured":"Jang, W. et al. Safety and efficacy of recombinant human erythropoietin treatment of non-motor symptoms in Parkinson\u2019s disease. J. Neurol. Sci. \n                           337, 47\u201354, doi:10.1016\/j.jns.2013.11.015 (2014).","journal-title":"J. Neurol. Sci."},{"key":"3167_CR17","doi-asserted-by":"crossref","first-page":"5558","DOI":"10.1016\/S0021-9258(19)63387-9","volume":"252","author":"T Miyake","year":"1977","unstructured":"Miyake, T., Kung, C. K. & Goldwasser, E. Purification of human erythropoietin. J. Biol. Chem. \n                           252, 5558\u201364 (1977).","journal-title":"J. Biol. Chem."},{"key":"3167_CR18","doi-asserted-by":"publisher","first-page":"7580","DOI":"10.1073\/pnas.82.22.7580","volume":"82","author":"FK Lin","year":"1985","unstructured":"Lin, F. K. et al. Cloning and expression of the human erythropoietin gene. Proc. Natl. Acad. Sci. \n                           82, 7580\u201384, doi:10.1073\/pnas.82.22.7580 (1985).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"3167_CR19","unstructured":"Meisel, A., Priller, J., Bonnas, C. & Dirnagl, U. ERYTHROPOIETIN VARIANTS. Charit\u00e9 Universit\u00e4tsmedizin - Berlin. WIPO WO\/2006\/120030 (US20110008363)."},{"key":"3167_CR20","doi-asserted-by":"publisher","first-page":"23055","DOI":"10.1074\/jbc.271.38.23055","volume":"271","author":"VN Tsytsikov","year":"1996","unstructured":"Tsytsikov, V. N., Yurovsky, V. V., Atamas, S. P., Alms, W. J. & White, B. Identification and characterization of two alternative splice variants of human interleukin-2. J. Biol. Chem. \n                           271, 23055\u201360, doi:10.1074\/jbc.271.38.23055 (1996).","journal-title":"J. Biol. Chem."},{"key":"3167_CR21","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1006\/cimm.1998.1431","volume":"191","author":"Y Arinobu","year":"1999","unstructured":"Arinobu, Y. et al. Antagonistic effects of an alternative splice variant of human IL-4, IL-4delta2, on IL-4 activities in human monocytes and B cells. Cell. Immunol. \n                           191, 161\u20137, doi:10.1006\/cimm.1998.1431 (1999).","journal-title":"Cell. Immunol."},{"key":"3167_CR22","doi-asserted-by":"publisher","first-page":"3038","DOI":"10.1200\/JCO.2005.00.885","volume":"23","author":"S Wu","year":"2005","unstructured":"Wu, S. et al. Expression of interleukin-10 splicing variants is a positive prognostic feature in relapsed childhood acute lymphoblastic leukemia. J. Clin. Oncol. \n                           23, 3038\u201342, doi:10.1200\/JCO.2005.00.885 (2005).","journal-title":"J. Clin. Oncol."},{"key":"3167_CR23","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1046\/j.1365-2370.2002.00337.x","volume":"29","author":"U Johansson","year":"2002","unstructured":"Johansson, U., Cooke, S. P. & Londei, M. Identification of a new isoform of human IL-12 p35 mRNA. Eur. J. Immunogenet. \n                           29, 439\u201344, doi:10.1046\/j.1365-2370.2002.00337.x (2002).","journal-title":"Eur. J. Immunogenet."},{"key":"3167_CR24","first-page":"882","volume":"19","author":"R Sorg","year":"1991","unstructured":"Sorg, R. et al. Rapid and sensitive mRNA phenotyping for interleukins (IL-1 to IL-6) and colony-stimulating factors (G-CSF, M-CSF, and GM-CSF) by reverse transcription and subsequent polymerase chain reaction. Exp. Hematol. \n                           19, 882\u20137 (1991).","journal-title":"Exp. Hematol."},{"key":"3167_CR25","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/S0006-291X(03)01303-2","volume":"307","author":"MO Arcasoy","year":"2003","unstructured":"Arcasoy, M. O., Jiang, X. & Haroon, Z. A. Expression of erythropoietin receptor splice variants in human cancer. Biochem. Biophys. Res. Commun. \n                           307, 999\u20131007, doi:10.1016\/S0006-291X(03)01303-2 (2003).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"3167_CR26","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1242\/jcs.114.5.853","volume":"114","author":"CJ Robinson","year":"2001","unstructured":"Robinson, C. J. & Stringer, S. E. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J. Cell Sci. \n                           114, 853\u201365 (2001).","journal-title":"J. Cell Sci."},{"key":"3167_CR27","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1007\/s100249900103","volume":"2","author":"SE Juul","year":"1999","unstructured":"Juul, S. E., Yachnis, A. T., Rojiani, A. M. & Christensen, R. D. Immunohistochemical localization of erythropoietin and its receptor in the developing human brain. Pediatr. Dev. Pathol. \n                           2, 148\u201358, doi:10.1007\/s100249900103 (1999).","journal-title":"Pediatr. Dev. Pathol."},{"key":"3167_CR28","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1182\/blood.V77.11.2497.2497","volume":"77","author":"ST Koury","year":"1991","unstructured":"Koury, S. T., Bondurant, M. C., Koury, M. J. & Semenza, G. L. Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood \n                           77, 2497\u2013503 (1991).","journal-title":"Blood"},{"key":"3167_CR29","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1182\/blood.V71.2.524.524","volume":"71","author":"ST Koury","year":"1988","unstructured":"Koury, S. T., Bondurant, M. C. & Koury, M. J. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood \n                           71, 524\u20137 (1988).","journal-title":"Blood"},{"key":"3167_CR30","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1172\/JCI113363","volume":"81","author":"C Lacombe","year":"1988","unstructured":"Lacombe, C. et al. Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney. J. Clin. Invest. \n                           81, 620\u20133, doi:10.1172\/JCI113363 (1988).","journal-title":"J. Clin. Invest."},{"key":"3167_CR31","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1080\/00365520310008340","volume":"39","author":"F Tacke","year":"2004","unstructured":"Tacke, F. et al. Analysis of factors contributing to higher erythropoietin levels in patients with chronic liver disease. Scand. J. Gastroenterol. \n                           39, 259\u201366, doi:10.1080\/00365520310008340 (2004).","journal-title":"Scand. J. Gastroenterol."},{"key":"3167_CR32","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.1046\/j.1440-1746.2003.03144.x","volume":"18","author":"Y-Y Yang","year":"2003","unstructured":"Yang, Y.-Y. et al. Plasma erythropoietin level in patients with cirrhosis and its relationship to the severity of cirrhosis and renal function. J. Gastroenterol. Hepatol. \n                           18, 1156\u201361, doi:10.1046\/j.1440-1746.2003.03144.x (2003).","journal-title":"J. Gastroenterol. Hepatol."},{"key":"3167_CR33","doi-asserted-by":"publisher","first-page":"2434","DOI":"10.1002\/ijc.22961","volume":"121","author":"MS Wiesener","year":"2007","unstructured":"Wiesener, M. S. et al. Erythropoietin gene expression in renal carcinoma is considerably more frequent than paraneoplastic polycythemia. Int. J. cancer \n                           121, 2434\u201342, doi:10.1002\/ijc.22961 (2007).","journal-title":"Int. J. cancer"},{"key":"3167_CR34","doi-asserted-by":"publisher","first-page":"13581","DOI":"10.1007\/s13277-016-5279-4","volume":"37","author":"TR Stoyanoff","year":"2016","unstructured":"Stoyanoff, T. R. et al. Tumor biology of non-metastatic stages of clear cell renal cell carcinoma; overexpression of stearoyl desaturase-1, EPO\/EPO-R system and hypoxia-related proteins. Tumor Biol. \n                           37, 13581\u201393, doi:10.1007\/s13277-016-5279-4 (2016).","journal-title":"Tumor Biol."},{"key":"3167_CR35","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/1471-2407-13-14","volume":"13","author":"C Morais","year":"2013","unstructured":"Morais, C., Johnson, D. W., Vesey, D. A. & Gobe, G. C. Functional significance of erythropoietin in renal cell carcinoma. BMC Cancer \n                           13, 14, doi:10.1186\/1471-2407-13-14 (2013).","journal-title":"BMC Cancer"},{"key":"3167_CR36","doi-asserted-by":"publisher","first-page":"a011619","DOI":"10.1101\/cshperspect.a011619","volume":"3","author":"HF Bunn","year":"2013","unstructured":"Bunn, H. F. Erythropoietin. Cold Spring Harb. Perspect. Med. \n                           3, a011619 (2013).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"3167_CR37","doi-asserted-by":"publisher","first-page":"7972","DOI":"10.1073\/pnas.84.22.7972","volume":"84","author":"MA Goldberg","year":"1987","unstructured":"Goldberg, M. A., Glass, G. A., Cunningham, J. M. & Bunn, H. F. The regulated expression of erythropoietin by two human hepatoma cell lines. Proc. Natl. Acad. Sci. \n                           84, 7972\u201376 (1987).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"3167_CR38","doi-asserted-by":"publisher","first-page":"e1001236","DOI":"10.1371\/journal.pgen.1001236","volume":"6","author":"JK Pickrell","year":"2010","unstructured":"Pickrell, J. K., Pai, A. A., Gilad, Y. & Pritchard, J. K. Noisy splicing drives mRNA isoform diversity in human cells. PLoS Genet. \n                           6, e1001236, doi:10.1371\/journal.pgen.1001236 (2010).","journal-title":"PLoS Genet."},{"key":"3167_CR39","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1113\/jphysiol.2010.195057","volume":"589","author":"W Jelkmann","year":"2011","unstructured":"Jelkmann, W. Regulation of erythropoietin production. J. Physiol \n                           589, 1251\u20138, doi:10.1113\/jphysiol.2010.195057 (2011).","journal-title":"J. Physiol"},{"key":"3167_CR40","doi-asserted-by":"publisher","first-page":"W252","DOI":"10.1093\/nar\/gku340","volume":"42","author":"M Biasini","year":"2014","unstructured":"Biasini, M. et al. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. \n                           42, W252\u20138, doi:10.1093\/nar\/gku340 (2014).","journal-title":"Nucleic Acids Res."},{"key":"3167_CR41","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1093\/bioinformatics\/bti770","volume":"22","author":"K Arnold","year":"2006","unstructured":"Arnold, K., Bordoli, L., Kopp, J. & Schwede, T. The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics \n                           22, 195\u2013201, doi:10.1093\/bioinformatics\/bti770 (2006).","journal-title":"Bioinformatics"},{"key":"3167_CR42","doi-asserted-by":"publisher","first-page":"D387","DOI":"10.1093\/nar\/gkn750","volume":"37","author":"F Kiefer","year":"2009","unstructured":"Kiefer, F., Arnold, K., K\u00fcnzli, M., Bordoli, L. & Schwede, T. The SWISS-MODEL Repository and associated resources. Nucleic Acids Res. \n                           37, D387\u201392, doi:10.1093\/nar\/gkn750 (2009).","journal-title":"Nucleic Acids Res."},{"issue":"Suppl 1","key":"3167_CR43","doi-asserted-by":"publisher","first-page":"S162","DOI":"10.1002\/elps.200900140","volume":"30","author":"N Guex","year":"2009","unstructured":"Guex, N., Peitsch, M. C. & Schwede, T. Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: a historical perspective. Electrophoresis \n                           30(Suppl 1), S162\u201373, doi:10.1002\/elps.200900140 (2009).","journal-title":"Electrophoresis"},{"key":"3167_CR44","doi-asserted-by":"publisher","first-page":"3485","DOI":"10.1097\/00001756-200011090-00017","volume":"11","author":"P Lewczuk","year":"2000","unstructured":"Lewczuk, P. et al. Survival of hippocampal neurons in culture upon hypoxia: effect of erythropoietin. Neuroreport \n                           11, 3485\u20138, doi:10.1097\/00001756-200011090-00017 (2000).","journal-title":"Neuroreport"},{"key":"3167_CR45","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1038\/mp.2015.212","volume":"21","author":"I Hassouna","year":"2016","unstructured":"Hassouna, I. et al. Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus. Mol. Psychiatry \n                           21, 1752\u201367, doi:10.1038\/mp.2015.212 (2016).","journal-title":"Mol. Psychiatry"},{"key":"3167_CR46","doi-asserted-by":"publisher","first-page":"2571","DOI":"10.1128\/MCB.6.7.2571","volume":"6","author":"N Beru","year":"1986","unstructured":"Beru, N., McDonald, J., Lacombe, C. & Goldwasser, E. Expression of the erythropoietin gene. Mol. Cell. Biol. \n                           6, 2571\u20135, doi:10.1128\/MCB.6.7.2571 (1986).","journal-title":"Mol. Cell. Biol."},{"key":"3167_CR47","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/ki.1991.181","volume":"40","author":"CC Tan","year":"1991","unstructured":"Tan, C. C., Eckardt, K. U. & Ratcliffe, P. J. Organ distribution of erythropoietin messenger RNA in normal and uremic rats. Kidney Int. \n                           40, 69\u201376, doi:10.1038\/ki.1991.181 (1991).","journal-title":"Kidney Int."},{"key":"3167_CR48","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1101\/gad.1048803","volume":"17","author":"NA Faustino","year":"2003","unstructured":"Faustino, N. A. & Cooper, T. A. Pre-mRNA splicing and human disease. Genes Dev. \n                           17, 419\u201337, doi:10.1101\/gad.1048803 (2003).","journal-title":"Genes Dev."},{"key":"3167_CR49","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1111\/j.1530-0277.2011.01627.x","volume":"36","author":"H Boujedidi","year":"2012","unstructured":"Boujedidi, H. et al. Housekeeping gene variability in the liver of alcoholic patients. Alcohol. Clin. Exp. Res. \n                           36, 258\u201366, doi:10.1111\/j.1530-0277.2011.01627.x (2012).","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"3167_CR50","doi-asserted-by":"crossref","unstructured":"Kim, S. & Kim, T. Selection of optimal internal controls for gene expression profiling of liver disease. Biotechniques \n                           35, 456\u20138, 460 (2003).","DOI":"10.2144\/03353bm03"},{"key":"3167_CR51","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1146\/annurev-pathol-011110-130321","volume":"6","author":"FS Lee","year":"2011","unstructured":"Lee, F. S. & Percy, M. J. The HIF Pathway and Erythrocytosis. Annu. Rev. Pathol. Mech. Dis. \n                           6, 165\u201392, doi:10.1146\/annurev-pathol-011110-130321 (2011).","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"3167_CR52","doi-asserted-by":"publisher","first-page":"e124","DOI":"10.1159\/000081556","volume":"98","author":"P Ben\u00f6hr","year":"2004","unstructured":"Ben\u00f6hr, P., Harsch, S., Proksch, B. & Gleiter, C. H. Does angiotensin II modulate erythropoietin production in HepG2 cells? Nephron. Exp. Nephrol. \n                           98, e124\u201331, doi:10.1159\/000081556 (2004).","journal-title":"Nephron. Exp. Nephrol."},{"key":"3167_CR53","doi-asserted-by":"publisher","first-page":"C342","DOI":"10.1152\/ajpcell.00153.2012","volume":"304","author":"C-K Chiang","year":"2013","unstructured":"Chiang, C.-K., Nangaku, M., Tanaka, T., Iwawaki, T. & Inagi, R. Endoplasmic reticulum stress signal impairs erythropoietin production: a role for ATF4. Am. J. Physiol. Cell Physiol. \n                           304, C342\u201353, doi:10.1152\/ajpcell.00153.2012 (2013).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"3167_CR54","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1152\/physiolgenomics.00104.2002","volume":"12","author":"LA Sonna","year":"2003","unstructured":"Sonna, L. A., Cullivan, M. L., Sheldon, H. K., Pratt, R. E. & Lilly, C. M. Effect of hypoxia on gene expression by human hepatocytes (HepG2). Physiol. Genomics \n                           12, 195\u2013207, doi:10.1152\/physiolgenomics.00104.2002 (2003).","journal-title":"Physiol. Genomics"},{"key":"3167_CR55","doi-asserted-by":"crossref","first-page":"3116","DOI":"10.1016\/S0021-9258(17)35756-3","volume":"261","author":"PH Lai","year":"1986","unstructured":"Lai, P. H., Everett, R., Wang, F. F., Arakawa, T. & Goldwasser, E. Structural characterization of human erythropoietin. J. Biol. Chem. \n                           261, 3116\u201321 (1986).","journal-title":"J. Biol. Chem."},{"key":"3167_CR56","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/0003-9861(88)90135-X","volume":"265","author":"VC Broudy","year":"1988","unstructured":"Broudy, V. C., Tait, J. F. & Powell, J. S. Recombinant human erythropoietin: purification and analysis of carbohydrate linkage. Arch. Biochem. Biophys. \n                           265, 329\u201336, doi:10.1016\/0003-9861(88)90135-X (1988).","journal-title":"Arch. Biochem. Biophys."},{"key":"3167_CR57","doi-asserted-by":"publisher","first-page":"2633","DOI":"10.1021\/bi00383a034","volume":"26","author":"JM Davis","year":"1987","unstructured":"Davis, J. M., Arakawa, T., Strickland, T. W. & Yphantis, D. A. Characterization of recombinant human erythropoietin produced in Chinese hamster ovary cells. Biochemistry \n                           26, 2633\u20138, doi:10.1021\/bi00383a034 (1987).","journal-title":"Biochemistry"},{"key":"3167_CR58","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1038\/2302","volume":"5","author":"JC Cheetham","year":"1998","unstructured":"Cheetham, J. C. et al. NMR structure of human erythropoietin and a comparison with its receptor bound conformation. Nat. Struct. Biol. \n                           5, 861\u20136, doi:10.1038\/2302 (1998).","journal-title":"Nat. Struct. Biol."},{"key":"3167_CR59","first-page":"367","volume":"80","author":"CC Stella","year":"1995","unstructured":"Stella, C. C. et al. CD34-positive cells: biology and clinical relevance. Haematologica \n                           80, 367\u201387 (1995).","journal-title":"Haematologica"},{"key":"3167_CR60","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1002\/stem.1661","volume":"32","author":"LE Sidney","year":"2014","unstructured":"Sidney, L. E., Branch, M. J., Dunphy, S. E., Dua, H. S. & Hopkinson, A. Concise review: evidence for CD34 as a common marker for diverse progenitors. Stem Cells \n                           32, 1380\u20139, doi:10.1002\/stem.1661 (2014).","journal-title":"Stem Cells"},{"key":"3167_CR61","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1182\/blood.V77.3.419.419","volume":"77","author":"SB Krantz","year":"1991","unstructured":"Krantz, S. B. Erythropoietin. Blood \n                           77, 419\u201334 (1991).","journal-title":"Blood"},{"key":"3167_CR62","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1046\/j.1365-2141.1997.d01-2071.x","volume":"96","author":"K Shinjo","year":"1997","unstructured":"Shinjo, K., Takeshita, A., Higuchi, M., Ohnishi, K. & Ohno, R. Erythropoietin receptor expression on human bone marrow erythroid precursor cells by a newly-devised quantitative flow-cytometric assay. Br. J. Haematol. \n                           96, 551\u20138, doi:10.1046\/j.1365-2141.1997.d01-2071.x (1997).","journal-title":"Br. J. Haematol."},{"key":"3167_CR63","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1016\/j.ejcb.2005.07.001","volume":"84","author":"L Danielyan","year":"2005","unstructured":"Danielyan, L. et al. Similar protective effects of BQ-123 and erythropoietin on survival of neural cells and generation of neurons upon hypoxic injury. Eur. J. Cell Biol. \n                           84, 907\u201313, doi:10.1016\/j.ejcb.2005.07.001 (2005).","journal-title":"Eur. J. Cell Biol."},{"key":"3167_CR64","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/1741-7007-6-37","volume":"6","author":"B Adamcio","year":"2008","unstructured":"Adamcio, B. et al. Erythropoietin enhances hippocampal long-term potentiation and memory. BMC Biol. \n                           6, 37, doi:10.1186\/1741-7007-6-37 (2008).","journal-title":"BMC Biol."},{"key":"3167_CR65","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/j.neuropharm.2010.09.025","volume":"60","author":"C Leconte","year":"2011","unstructured":"Leconte, C. et al. Comparison of the effects of erythropoietin and its carbamylated derivative on behaviour and hippocampal neurogenesis in mice. Neuropharmacology \n                           60, 354\u201364, doi:10.1016\/j.neuropharm.2010.09.025 (2011).","journal-title":"Neuropharmacology"},{"key":"3167_CR66","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/1741-7007-7-37","volume":"7","author":"A El-Kordi","year":"2009","unstructured":"El-Kordi, A., Radyushkin, K. & Ehrenreich, H. Erythropoietin improves operant conditioning and stability of cognitive performance in mice. BMC Biol. \n                           7, 37, doi:10.1186\/1741-7007-7-37 (2009).","journal-title":"BMC Biol."},{"key":"3167_CR67","doi-asserted-by":"publisher","first-page":"234","DOI":"10.3109\/00365513.2015.1137351","volume":"76","author":"LM Ris\u00f8r","year":"2016","unstructured":"Ris\u00f8r, L. M., Fenger, M., Olsen, N. V. & M\u00f8ller, S. Hepatic erythropoietin response in cirrhosis. Scand. J. Clin. Lab. Invest. \n                           76, 234\u20139, doi:10.3109\/00365513.2015.1137351 (2016).","journal-title":"Scand. J. Clin. Lab. Invest."},{"key":"3167_CR68","first-page":"978","volume":"13","author":"R Moreau","year":"1989","unstructured":"Moreau, R. et al. Tissue hypoxia and hepatocellular insufficiency in patients with cirrhosis. Gastroent\u00e9rologie Clin. Biol. \n                           13, 978\u201383 (1989).","journal-title":"Gastroent\u00e9rologie Clin. Biol."},{"key":"3167_CR69","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1038\/bjc.2012.42","volume":"106","author":"M Aapro","year":"2012","unstructured":"Aapro, M., Jelkmann, W., Constantinescu, S. N. & Leyland-Jones, B. Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer. Br. J. Cancer \n                           106, 1249\u201358, doi:10.1038\/bjc.2012.42 (2012).","journal-title":"Br. J. Cancer"},{"key":"3167_CR70","doi-asserted-by":"publisher","first-page":"R977","DOI":"10.1152\/ajpregu.00577.2003","volume":"286","author":"J Fandrey","year":"2004","unstructured":"Fandrey, J. Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. AJP Regul. Integr. Comp. Physiol. \n                           286, R977\u201388, doi:10.1152\/ajpregu.00577.2003 (2004).","journal-title":"AJP Regul. Integr. Comp. Physiol."},{"key":"3167_CR71","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1128\/MCB.10.3.930","volume":"10","author":"GL Semenza","year":"1990","unstructured":"Semenza, G. L., Dureza, R. C., Traystman, M. D., Gearhart, J. D. & Antonarakis, S. E. Human erythropoietin gene expression in transgenic mice: multiple transcription initiation sites and cis-acting regulatory elements. Mol. Cell. Biol. \n                           10, 930\u20138, doi:10.1128\/MCB.10.3.930 (1990).","journal-title":"Mol. Cell. Biol."},{"key":"3167_CR72","first-page":"294","volume":"8","author":"Y-H Luo","year":"2009","unstructured":"Luo, Y.-H., Li, Z.-D., Liu, L.-X. & Dong, G.-H. Pretreatment with erythropoietin reduces hepatic ischemia-reperfusion injury. Hepatobiliary Pancreat. Dis. Int \n                           8, 294\u20139 (2009).","journal-title":"Hepatobiliary Pancreat. Dis. Int"},{"key":"3167_CR73","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.transproceed.2014.10.045","volume":"47","author":"Q-S Liu","year":"2015","unstructured":"Liu, Q.-S. et al. Erythropoietin pretreatment exerts anti-inflammatory effects in hepatic ischemia\/reperfusion-injured rats via suppression of the TLR2\/NF-\u03baB pathway. Transplant. Proc. \n                           47, 283\u20139, doi:10.1016\/j.transproceed.2014.10.045 (2015).","journal-title":"Transplant. Proc."},{"key":"3167_CR74","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1093\/ndt\/gfg547","volume":"19","author":"DA Vesey","year":"2004","unstructured":"Vesey, D. A. et al. Erythropoietin protects against ischaemic acute renal injury. Nephrol. Dial. Transplant \n                           19, 348\u201355, doi:10.1093\/ndt\/gfg547 (2004).","journal-title":"Nephrol. Dial. Transplant"},{"key":"3167_CR75","doi-asserted-by":"publisher","first-page":"1806","DOI":"10.1038\/sj.ki.5000356","volume":"69","author":"DW Johnson","year":"2006","unstructured":"Johnson, D. W. et al. Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure. Kidney Int. \n                           69, 1806\u201313, doi:10.1038\/sj.ki.5000356 (2006).","journal-title":"Kidney Int."},{"key":"3167_CR76","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1159\/000223229","volume":"30","author":"YR Song","year":"2009","unstructured":"Song, Y. R. et al. Prevention of acute kidney injury by erythropoietin in patients undergoing coronary artery bypass grafting: a pilot study. Am. J. Nephrol. \n                           30, 253\u201360, doi:10.1159\/000223229 (2009).","journal-title":"Am. J. Nephrol."},{"key":"3167_CR77","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1038\/26773","volume":"395","author":"RS Syed","year":"1998","unstructured":"Syed, R. S. et al. Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature \n                           395, 511\u20136, doi:10.1038\/26773 (1998).","journal-title":"Nature"},{"key":"3167_CR78","doi-asserted-by":"publisher","first-page":"561","DOI":"10.2741\/4408","volume":"21","author":"K Maiese","year":"2016","unstructured":"Maiese, K. Regeneration in the nervous system with erythropoietin. Front. Biosci. (Landmark Ed.) \n                           21, 561\u201396 (2016).","journal-title":"Front. Biosci. (Landmark Ed.)"},{"key":"3167_CR79","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1038\/sj.mp.4001907","volume":"12","author":"H Ehrenreich","year":"2007","unstructured":"Ehrenreich, H. et al. Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol. Psychiatry \n                           12, 206\u201320, doi:10.1038\/sj.mp.4001907 (2007).","journal-title":"Mol. Psychiatry"},{"key":"3167_CR80","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1053\/j.jrn.2007.10.029","volume":"18","author":"H Ehrenreich","year":"2008","unstructured":"Ehrenreich, H., Bartels, C., Sargin, D., Stawicki, S. & Krampe, H. Recombinant human erythropoietin in the treatment of human brain disease: focus on cognition. J. Ren. Nutr. \n                           18, 146\u201353, doi:10.1053\/j.jrn.2007.10.029 (2008).","journal-title":"J. Ren. Nutr."},{"key":"3167_CR81","doi-asserted-by":"publisher","first-page":"e59672","DOI":"10.1371\/journal.pone.0059672","volume":"8","author":"PL Kristensen","year":"2013","unstructured":"Kristensen, P. L. et al. Influence of erythropoietin on cognitive performance during experimental hypoglycemia in patients with type 1 diabetes mellitus: a randomized cross-over trial. PLoS One \n                           8, e59672, doi:10.1371\/journal.pone.0059672 (2013).","journal-title":"PLoS One"},{"key":"3167_CR82","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1542\/peds.2013-4307","volume":"133","author":"RK Ohls","year":"2014","unstructured":"Ohls, R. K. et al. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo. Pediatrics \n                           133, 1023\u201330, doi:10.1542\/peds.2013-4307 (2014).","journal-title":"Pediatrics"},{"key":"3167_CR83","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1111\/acps.12597","volume":"134","author":"KW Miskowiak","year":"2016","unstructured":"Miskowiak, K. W. et al. Effects of erythropoietin on memory-relevant neurocircuitry activity and recall in mood disorders. Acta Psychiatr. Scand. \n                           134, 249\u201359, doi:10.1111\/acps.12597 (2016).","journal-title":"Acta Psychiatr. Scand."},{"key":"3167_CR84","doi-asserted-by":"crossref","first-page":"15983","DOI":"10.1016\/S0021-9258(18)82348-1","volume":"268","author":"JP Boissel","year":"1993","unstructured":"Boissel, J. P., Lee, W. R., Presnell, S. R., Cohen, F. E. & Bunn, H. F. Erythropoietin structure-function relationships. Mutant proteins that test a model of tertiary structure. J. Biol. Chem. \n                           268, 15983\u201393 (1993).","journal-title":"J. Biol. Chem."},{"key":"3167_CR85","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1111\/jnc.13967","volume":"141","author":"N Miljus","year":"2017","unstructured":"Miljus, N. et al. Neuroprotection and endocytosis: erythropoietin receptors in insect nervous systems. Journal of Neurochemistry, 141(1), 63\u201374 (2017).","journal-title":"Journal of Neurochemistry"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03167-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03167-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03167-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T05:35:32Z","timestamp":1671773732000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03167-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,16]]},"references-count":85,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["3167"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-03167-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,16]]},"assertion":[{"value":"24 November 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 April 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 June 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"C.B. is listed as co-inventor of EPO-variant patents and performed the experiments during her employment at Epomedics; L.W., D.W., E.D., K.S., M.B., R.K.-W. and T.T. report no potential competing interest; H.E. has submitted\/holds use patents for EPO in stroke, schizophrenia and Multiple Sclerosis; H.S. is CEO of and holds stocks in Epomedics GmbH, and IS is employee of Epomedics GmbH.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"3684"}}