{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T19:43:40Z","timestamp":1774640620246,"version":"3.50.1"},"reference-count":46,"publisher":"Proceedings of the National Academy of Sciences","issue":"31","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,8,5]]},"abstract":"<jats:p>\n            Erythropoietin (EPO), a member of the type 1 cytokine superfamily, plays a critical hormonal role regulating erythrocyte production as well as a paracrine\/autocrine role in which locally produced EPO protects a wide variety of tissues from diverse injuries. Significantly, these functions are mediated by distinct receptors: hematopoiesis via the EPO receptor homodimer and tissue protection via a heterocomplex composed of the EPO receptor and CD131, the \u03b2 common receptor. In the present work, we have delimited tissue-protective domains within EPO to short peptide sequences. We demonstrate that helix B (amino acid residues 58\u201382) of EPO, which faces the aqueous medium when EPO is bound to the receptor homodimer, is both neuroprotective\n            <jats:italic>in vitro<\/jats:italic>\n            and tissue protective\n            <jats:italic>in vivo<\/jats:italic>\n            in a variety of models, including ischemic stroke, diabetes-induced retinal edema, and peripheral nerve trauma. Remarkably, an 11-aa peptide composed of adjacent amino acids forming the aqueous face of helix B is also tissue protective, as confirmed by its therapeutic benefit in models of ischemic stroke and renal ischemia\u2013reperfusion. Further, this peptide simulating the aqueous surface of helix B also exhibits EPO's trophic effects by accelerating wound healing and augmenting cognitive function in rodents. As anticipated, neither helix B nor the 11-aa peptide is erythropoietic\n            <jats:italic>in vitro<\/jats:italic>\n            or\n            <jats:italic>in vivo<\/jats:italic>\n            . Thus, the tissue-protective activities of EPO are mimicked by small, nonerythropoietic peptides that simulate a portion of EPO's three-dimensional structure.\n          <\/jats:p>","DOI":"10.1073\/pnas.0805594105","type":"journal-article","created":{"date-parts":[[2008,8,2]],"date-time":"2008-08-02T00:46:29Z","timestamp":1217637989000},"page":"10925-10930","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":270,"title":["Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin"],"prefix":"10.1073","volume":"105","author":[{"given":"Michael","family":"Brines","sequence":"first","affiliation":[{"name":"*Warren Pharmaceuticals, Ossining, NY 10562;"},{"name":"The Kenneth S. Warren Institute, Ossining, NY 10562;"}]},{"given":"Nimesh S. A.","family":"Patel","sequence":"additional","affiliation":[{"name":"Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and London School of Medicine and Dentistry, Queen Mary, University of London, London EC1M 6BQ, England;"}]},{"given":"Pia","family":"Villa","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, 20-20156 Milan, Italy;"},{"name":"National Research Council, Institute of Neuroscience, 20129 Milan, Italy"}]},{"given":"Courtenay","family":"Brines","sequence":"additional","affiliation":[{"name":"*Warren Pharmaceuticals, Ossining, NY 10562;"}]},{"given":"Tiziana","family":"Mennini","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, 20-20156 Milan, Italy;"}]},{"given":"Massimiliano","family":"De Paola","sequence":"additional","affiliation":[{"name":"Mario Negri Institute for Pharmacological Research, 20-20156 Milan, Italy;"}]},{"given":"Zubeyde","family":"Erbayraktar","sequence":"additional","affiliation":[{"name":"**Dokuz Eyl\u00fcl University, Izmir 35340, Turkey;"}]},{"given":"Serhat","family":"Erbayraktar","sequence":"additional","affiliation":[{"name":"**Dokuz Eyl\u00fcl University, Izmir 35340, Turkey;"}]},{"given":"Bruno","family":"Sepodes","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Lisbon, 1600 Lisbon, Portugal; and"}]},{"given":"Christoph","family":"Thiemermann","sequence":"additional","affiliation":[{"name":"Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and London School of Medicine and Dentistry, Queen Mary, University of London, London EC1M 6BQ, England;"}]},{"given":"Pietro","family":"Ghezzi","sequence":"additional","affiliation":[{"name":"The Kenneth S. Warren Institute, Ossining, NY 10562;"},{"name":"Mario Negri Institute for Pharmacological Research, 20-20156 Milan, Italy;"}]},{"given":"Michael","family":"Yamin","sequence":"additional","affiliation":[{"name":"*Warren Pharmaceuticals, Ossining, NY 10562;"}]},{"given":"Carla C.","family":"Hand","sequence":"additional","affiliation":[{"name":"The Kenneth S. Warren Institute, Ossining, NY 10562;"}]},{"given":"Qiao-wen","family":"Xie","sequence":"additional","affiliation":[{"name":"*Warren Pharmaceuticals, Ossining, NY 10562;"},{"name":"The Kenneth S. Warren Institute, Ossining, NY 10562;"}]},{"given":"Thomas","family":"Coleman","sequence":"additional","affiliation":[{"name":"*Warren Pharmaceuticals, Ossining, NY 10562;"},{"name":"The Kenneth S. Warren Institute, Ossining, NY 10562;"}]},{"given":"Anthony","family":"Cerami","sequence":"additional","affiliation":[{"name":"*Warren Pharmaceuticals, Ossining, NY 10562;"},{"name":"The Kenneth S. Warren Institute, Ossining, NY 10562;"}]}],"member":"341","published-online":{"date-parts":[[2008,8,5]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1177\/153537020322800101"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5001546"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0095-5108(05)70037-3"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5013-06.2007"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001907"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)82348-1"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/2302"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.2.493"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)31721-0"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1098313"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)82112-3"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0406491101"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0083-6729(06)74001-8"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/26773"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.2119\/2006-00045.Mennini"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.19.10526"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1031753100"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.20875"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.surneu.2007.07.061"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600443"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcts.2006.02.036"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.07-0721"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.64.s87.9.x"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0505047102"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308342101"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj1870661"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2006.09.064"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.17.8282"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.10.4103"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo-93-6-1349"},{"key":"e_1_3_3_31_2","first-page":"235","article-title":"Identification of a neurotrophic sequence in erythropoietin","volume":"1","author":"Campana WM","year":"1998","unstructured":"WM Campana, R Misasi, JS O'Brien, Identification of a neurotrophic sequence in erythropoietin. Int J Mol Med 1, 235\u2013241 (1998).","journal-title":"Int J Mol Med"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2006.05.008"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00847.x"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2008.07014.x"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1080\/000155502762064520"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(93)90850-M"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1159\/000105473"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2005.22.1011"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000132196.49028.a4"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.04684.x"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00221-007-1102-1"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-007-0907-8"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1159\/000123834"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600370"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1006\/brbi.1997.0512"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-4328(88)90157-X"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0805594105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T22:12:51Z","timestamp":1649801571000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0805594105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,8,5]]},"references-count":46,"journal-issue":{"issue":"31","published-print":{"date-parts":[[2008,8,5]]}},"alternative-id":["10.1073\/pnas.0805594105"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0805594105","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,8,5]]},"assertion":[{"value":"2008-05-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-08-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}