{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T14:33:23Z","timestamp":1762353203071,"version":"3.40.5"},"reference-count":55,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T00:00:00Z","timestamp":1654214400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000182","name":"US Army Medical Research and Materiel Command","doi-asserted-by":"publisher","award":["W81XWH\u201018\u20102\u20100029"],"award-info":[{"award-number":["W81XWH\u201018\u20102\u20100029"]}],"id":[{"id":"10.13039\/100000182","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Primaquine (PQ) and Tafenoquine (TQ) are clinically important 8\u2010aminoquinolines (8\u2010AQ) used for radical cure treatment of <jats:italic>P<\/jats:italic>.\u00a0<jats:italic>vivax<\/jats:italic> infection, known to target hepatic hypnozoites. 8\u2010AQs can trigger haemolytic anaemia in individuals with glucose\u20106\u2010phosphate dehydrogenase deficiency (G6PDd), yet the mechanisms of haemolytic toxicity remain unknown. To address this issue, we used a humanized mouse model known to predict haemolytic toxicity responses in G6PDd human red blood cells (huRBCs). To evaluate the markers of eryptosis, huRBCs were isolated from mice 24\u201348\u00a0h post\u2010treatment and analysed for effects on phosphatidylserine (PS), intracellular reactive oxygen species (ROS) and autofluorescence. Urinalysis was performed to evaluate the occurrence of intravascular and extravascular haemolysis. Spleen and liver tissue harvested at 24\u00a0h and 5\u20137\u00a0days post\u2010treatment were stained for the presence of CD169+ macrophages, F4\/80+ macrophages, Ter119+ mouse RBCs, glycophorin A+ huRBCs and murine reticulocytes (muRetics). G6PDd\u2010huRBCs from PQ\/TQ treated mice showed increased markers for eryptosis as early as 24\u00a0h post\u2010treatment. This coincided with an early rise in levels of muRetics. Urinalysis revealed concurrent intravascular and extravascular haemolysis in response to PQ\/TQ. Splenic CD169+ macrophages, present in all groups at day 1 post\u2010dosing were eliminated by days 5\u20137 in PQ\/TQ treated mice only, while liver F4\/80\u00a0macrophages and iron deposits increased. Collectively, our data suggest 8\u2010AQ treated G6PDd\u2010huRBCs have early physiological responses to treatment, including increased markers for eryptosis indicative of oxidative stress, resulting in extramedullary haematopoiesis and loss of splenic CD169+ macrophages, prompting the liver to act as the primary site of clearance.<\/jats:p>","DOI":"10.1111\/jcmm.17362","type":"journal-article","created":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T06:39:30Z","timestamp":1654324770000},"page":"3675-3686","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mechanisms of 8\u2010aminoquinoline induced haemolytic toxicity in a G6PDd humanized mouse model"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3784-4499","authenticated-orcid":false,"given":"Siobhan","family":"Flaherty","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology The University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pamela","family":"Strauch","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology The University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahdi","family":"Maktabi","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology The University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon S.","family":"Pybus","sequence":"additional","affiliation":[{"name":"Division of Experimental Therapeutics Walter Reed Army Institute of Research  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory","family":"Reichard","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery Experimental Therapeutics Branch Walter Reed Army Institute of Research  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larry A","family":"Walker","sequence":"additional","affiliation":[{"name":"National Center for Natural Products Research and Department of Biomolecular Sciences School of Pharmacy The University of Mississippi  University Mississippi USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosemary","family":"Rochford","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology The University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,6,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2015.11.006"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2008.12.005"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60073-2"},{"issue":"9","key":"e_1_2_9_5_1","first-page":"572","article-title":"Caring for glucose\u20106\u2010phosphate dehydrogenase (G6PD)\u2010deficient patients: implications for pharmacy","volume":"40","author":"Bubp J","year":"2015","journal-title":"P T"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001339"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0000000000000039"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep45963"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(15)00191-X"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40101-020-00251-9"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62684"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a025585"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00011-19"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1952.72930340027010c"},{"issue":"2","key":"e_1_2_9_15_1","first-page":"303","article-title":"The hemolytic effect of primaquine. 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