{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T04:53:27Z","timestamp":1771822407303,"version":"3.50.1"},"reference-count":74,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,8,14]],"date-time":"2020-08-14T00:00:00Z","timestamp":1597363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007359","name":"Fondazione Banco di Sardegna","doi-asserted-by":"publisher","award":["Prot. U1056.2014\/AI.938MGB Prat. 2014.0040."],"award-info":[{"award-number":["Prot. U1056.2014\/AI.938MGB Prat. 2014.0040."]}],"id":[{"id":"10.13039\/100007359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Although artemisinin-based combination therapies (ACTs) treat Plasmodium falciparum malaria effectively throughout most of the world, the recent expansion of ACT-resistant strains in some countries of the Greater Mekong Subregion (GMS) further increased the interest in improving the effectiveness of treatment and counteracting resistance. Recognizing that (1) partially denatured hemoglobin containing reactive iron (hemichromes) is generated in parasitized red blood cells (pRBC) by oxidative stress, (2) redox-active hemichromes have the potential to enhance oxidative stress triggered by the parasite and the activation of artemisinin to its pharmaceutically active form, and (3) Syk kinase inhibitors block the release of membrane microparticles containing hemichromes, we hypothesized that increasing hemichrome content in parasitized erythrocytes through the inhibition of Syk kinase might trigger a virtuous cycle involving the activation of artemisinin, the enhancement of oxidative stress elicited by activated artemisinin, and a further increase in hemichrome production. We demonstrate here that artemisinin indeed augments oxidative stress within parasitized RBCs and that Syk kinase inhibitors further increase iron-dependent oxidative stress, synergizing with artemisinin in killing the parasite. We then demonstrate that Syk kinase inhibitors achieve this oxidative enhancement by preventing parasite-induced release of erythrocyte-derived microparticles containing redox-active hemichromes. We also observe that Syk kinase inhibitors do not promote oxidative toxicity to healthy RBCs as they do not produce appreciable amounts of hemichromes. Since some Syk kinase inhibitors can be taken daily with minimal side effects, we propose that Syk kinase inhibitors could evidently contribute to the potentiation of ACTs.<\/jats:p>","DOI":"10.3390\/antiox9080753","type":"journal-article","created":{"date-parts":[[2020,8,14]],"date-time":"2020-08-14T13:00:18Z","timestamp":1597410018000},"page":"753","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Syk Kinase Inhibitors Synergize with Artemisinins by Enhancing Oxidative Stress in Plasmodium falciparum-Parasitized Erythrocytes"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1439-3920","authenticated-orcid":false,"given":"Ioannis","family":"Tsamesidis","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"},{"name":"UMR 152 Pharma-Dev, Universit\u00e9 de Toulouse, IRD, UPS, 31000 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3887-5414","authenticated-orcid":false,"given":"Karine","family":"Reybier","sequence":"additional","affiliation":[{"name":"UMR 152 Pharma-Dev, Universit\u00e9 de Toulouse, IRD, UPS, 31000 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Carmina","family":"Pau","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrizia","family":"Virdis","sequence":"additional","affiliation":[{"name":"Department of Clinical, Surgical and Experimental Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Fozza","sequence":"additional","affiliation":[{"name":"Department of Clinical, Surgical and Experimental Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francoise","family":"Nepveu","sequence":"additional","affiliation":[{"name":"UMR 152 Pharma-Dev, Universit\u00e9 de Toulouse, IRD, UPS, 31000 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9042-5528","authenticated-orcid":false,"given":"Philip S.","family":"Low","sequence":"additional","affiliation":[{"name":"Purdue Institute for Drug Discovery and Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco Michelangelo","family":"Turrini","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Turin, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2954-7053","authenticated-orcid":false,"given":"Antonella","family":"Pantaleo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0166-6851(96)02763-6","article-title":"Hemoglobin catabolism and iron utilization by malaria parasites","volume":"83","author":"Rosenthal","year":"1996","journal-title":"Mol. 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