{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T04:16:32Z","timestamp":1780805792456,"version":"3.54.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Malaria, a life-threatening mosquito-borne disease caused by\n                      <jats:italic>Plasmodium falciparum<\/jats:italic>\n                      , poses a substantial health burden on tropical and subtropical regions. Artemisinin, a sesquiterpene lactone isolated from\n                      <jats:italic>Artemisia annua<\/jats:italic>\n                      L., and its derivatives were initially used as monotherapies for malaria treatment. However, limitations such as short pharmacokinetic half-life and emerging drug resistance have driven the widespread adoption of artemisinin-based combination therapies (ACTs) as first-line interventions.\n                      <jats:italic>A. annua<\/jats:italic>\n                      contains other bioactive compounds such as arteannuin B, artemisinic acid, and scopoletin that exhibit distinct pharmacological properties. In this study, we aimed to devise a new strategy for treatment of malaria to overcome artemisinin resistance in\n                      <jats:italic>Plasmodium<\/jats:italic>\n                      species.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We systematically screened antimalarial compound ratios using murine malaria models and optimized a formula comprising arteannuin B, artemisinic acid, and scopoletin. Through integrated proteomic profiling and western blot validation, we elucidated the immunomodulatory mechanisms underlying the antimalarial efficacy of this combination.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Specifically, the formula strengthened host defense by modulating phagocytic activity in splenic macrophages, dendritic cells, and natural killer cells via Fc\u03b3 receptor-mediated pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These findings provide mechanistic insights into artemisinin-associated immune potentiation. Moreover, we have proposed a novel ACT strategy targeting host-parasite interactions, offering a promising approach to circumvent emerging artemisinin resistance in\n                      <jats:italic>Plasmodium<\/jats:italic>\n                      species.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1716096","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T06:25:28Z","timestamp":1764915928000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Proteomics-driven screening of artemisinin-based combination ratios and mechanistic insights into Plasmodium berghei infection in mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Liyu","family":"Hao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianliang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongyuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyue","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanhui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guimin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenru","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairu","family":"Huo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qili","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luqi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"B1","volume-title":"World malaria report","year":"2023"},{"key":"B2","first-page":"579","volume-title":"Advances in malaria research","author":"Gaur","year":"2017"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpddr.2018.05.003","article-title":"Longitudinal surveillance of drug resistance in Plasmodium falciparum isolates from the China-Myanmar border reveals persistent circulation of multidrug resistant parasites","volume":"8","author":"Bai","year":"2018","journal-title":"Int J Parasitol Drugs Drug Resist"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14127","article-title":"Combating multidrug-resistant Plasmodium falciparum malaria","volume":"284","author":"Thu","year":"2017","journal-title":"FEBS J"},{"key":"B5","doi-asserted-by":"publisher","first-page":"101815","DOI":"10.1016\/j.tmaid.2020.101815","article-title":"Rising temperature and its impact on receptivity to malaria transmission in Europe: A systematic review","volume":"36","author":"Fischer","year":"2020","journal-title":"Travel Med Infect Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01639-20","article-title":"Multidrug-resistant plasmodium falciparum parasites in the central highlands of Vietnam jeopardize malaria control and elimination strategies","volume":"65","author":"Quang","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0000000000000766","article-title":"Artemisinin and multidrug-resistant Plasmodium falciparum - a threat for malaria control and elimination","volume":"34","author":"Dhorda","year":"2021","journal-title":"Curr Opin Infect Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/tropicalmed8040195","article-title":"Feasibility and acceptability of a strategy deploying multiple first-line artemisinin-based combination therapies for uncomplicated malaria in the health district of kaya, Burkina Faso","volume":"8","author":"Kabore","year":"2023","journal-title":"Trop Med Infect Dis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"102193","DOI":"10.1016\/j.mib.2022.102193","article-title":"Plasmodium falciparum resistance to artemisinin-based combination therapies","volume":"69","author":"Ward","year":"2022","journal-title":"Curr Opin Microbiol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.6077","article-title":"Combination of artemisinin-based natural compounds from Artemisia annua L. for the treatment of malaria: Pharmacodynamic and pharmacokinetic studies","volume":"32","author":"Li","year":"2018","journal-title":"Phytother Res"},{"key":"B11","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1021\/cbe.3c00005","article-title":"Enhanced antimalarial activity of extracts of artemisia annua L. Achieved with aqueous solutions of salicylate salts and ionic liquids","volume":"1","author":"Ferreira","year":"2024","journal-title":"Chem Bio Eng"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.19540\/j.cnki.cjcmm.2023105.101","article-title":"Simultaneous determination of seven artemisinin-related compounds in Artemisia annua by UPLC-QQQ-MS\/MS","volume":"49","author":"Wang","year":"2024","journal-title":"Zhongguo Zhong Yao Za Zhi"},{"key":"B13","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s12906-020-2820-1","article-title":"Effects of lemon decoction on malaria parasite clearance and selected hematological parameters in Plasmodium berghei ANKA infected mice","volume":"20","author":"Shija","year":"2020","journal-title":"BMC Complement Med Ther"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2005.02.017","article-title":"The in vitro and in vivo antimalarial activity of Cardiospermum halicacabum L. and Momordica foetida Schumch. Et Thonn","volume":"99","author":"Waako","year":"2005","journal-title":"J Ethnopharmacol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1021\/np50092a005","article-title":"Crystal structure of artemisinic acid: a possible biogenetic precursor of antimalarial artemisinin from Artemisia annua","volume":"56","author":"Misra","year":"1993","journal-title":"J Nat Prod"},{"key":"B16","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/0014-4894(65)90014-7","article-title":"Drug resistance in Plasmodium berghei Vincke and Lips, 1948. 3. Multiple drug resistance","volume":"17","author":"Peters","year":"1965","journal-title":"Exp Parasitol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.3465","article-title":"Affordable and rapid HPTLC method for the simultaneous analysis of artemisinin and its metabolite artemisinic acid in Artemisia annua L","volume":"29","author":"Khan","year":"2015","journal-title":"BioMed Chromatogr"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.19540\/j.cnki.cjcmm.2017.0169","article-title":"Detection and analysis of effect of geographical environmental factors on spatial distribution of artemisinic acid in Artemisia annua","volume":"42","author":"Shi","year":"2017","journal-title":"Zhongguo Zhong Yao Za Zhi"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.apjtm.2016.05.004","article-title":"Effects of arteannuin B, arteannuic acid and scopoletin on pharmacokinetics of artemisinin in mice","volume":"9","author":"Zhang","year":"2016","journal-title":"Asian Pac J Trop Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0183047","article-title":"Differences in chemical constituents of Artemisia annua L from different geographical regions in China","volume":"12","author":"Zhang","year":"2017","journal-title":"PloS One"},{"key":"B21","article-title":"Review on study of Dao-di herbs Artemisiae Annuae Herba","volume":"41","author":"Zhang","year":"2016","journal-title":"Zhongguo Zhong Yao Za Zhi"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.4RI1020-713R","article-title":"The spleen: \u201cepicenter\u201d in malaria infection and immunity","volume":"110","author":"Ghosh","year":"2021","journal-title":"J Leukoc Biol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/s41597-020-00592-1","article-title":"Transcriptome analysis of blood and spleen in virulent and avirulent mouse malaria infection","volume":"7","author":"Zhao","year":"2020","journal-title":"Sci Data"},{"key":"B24","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1007\/s11033-025-10318-4","article-title":"Plasmodium yoelii as a model for malaria: insights into pathogenesis, drug resistance, and vaccine development","volume":"52","author":"Otun","year":"2025","journal-title":"Mol Biol Rep"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aau6085","article-title":"Structure and function of the immune system in the spleen","volume":"4","author":"Lewis","year":"2019","journal-title":"Sci Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2016.00131","article-title":"Spleen-dependent immune protection elicited by cpG adjuvanted reticulocyte-derived exosomes from malaria infection is associated with changes in T cell subsets\u2019 Distribution","volume":"4","author":"Martin-Jaular","year":"2016","journal-title":"Front Cell Dev Biol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14592","article-title":"Turf wars: exploring splenomegaly in sickle cell disease in malaria-endemic regions","volume":"177","author":"Tubman","year":"2017","journal-title":"Br J Haematol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017015008","article-title":"Red pulp macrophages in the human spleen are a distinct cell population with a unique expression of Fc-gamma receptors","volume":"2","author":"Nagelkerke","year":"2018","journal-title":"Blood Adv"},{"key":"B29","doi-asserted-by":"publisher","first-page":"8989","DOI":"10.1038\/s41598-025-93946-x","article-title":"Coal dust particles can upregulate the expression of NLRP3 inflammasome components in rat alveolar macrophages through phagocytosis","volume":"15","author":"Zhang","year":"2025","journal-title":"Sci Rep"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2314905120","article-title":"Antibodies elicited in humans upon chimeric hemagglutinin-based influenza virus vaccination confer FcgammaR-dependent protection in vivo","volume":"120","author":"Edgar","year":"2023","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1280986","article-title":"Nonfucosylation of an anti-TIGIT antibody enhances FcgammaR engagement, driving innate immune activation and antitumor activity","volume":"14","author":"Smith","year":"2023","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci15010053","article-title":"Spinal involvement of TRPV1 and PI3K\/AKT\/mTOR pathway during chronic postoperative pain in mice","volume":"15","author":"Santos","year":"2025","journal-title":"Brain Sci"},{"key":"B33","doi-asserted-by":"publisher","first-page":"114323","DOI":"10.1016\/j.intimp.2025.114323","article-title":"Notopterol mitigates osteoarthritis progression and relieves pain in mice by inhibiting PI3K\/Akt\/GPX4-mediated ferroptosis","volume":"151","author":"Zhou","year":"2025","journal-title":"Int Immunopharmacol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-09-3889","article-title":"FcgammaR-induced production of superoxide and inflammatory cytokines is differentially regulated by SHIP through its influence on PI3K and\/or Ras\/Erk pathways","volume":"108","author":"Ganesan","year":"2006","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E14-10-1457","article-title":"Rab31 and APPL2 enhance FcgammaR-mediated phagocytosis through PI3K\/Akt signaling in macrophages","volume":"26","author":"Yeo","year":"2015","journal-title":"Mol Biol Cell"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.03.002","article-title":"Rewiring phagocytic signal transduction","volume":"24","author":"Lowell","year":"2006","journal-title":"Immunity"},{"key":"B37","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s41588-021-00998-6","article-title":"Author Correction: Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice","volume":"54","author":"Wang","year":"2022","journal-title":"Nat Genet"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2003.11.007","article-title":"Phosphatidylinositol 3-kinase, phosphoinositide-specific phospholipase-Cgamma and protein kinase-C signal myelin phagocytosis mediated by complement receptor-3 alone and combined with scavenger receptor-AI\/II in macrophages","volume":"15","author":"Makranz","year":"2004","journal-title":"Neurobiol Dis"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.2010.05454.x","article-title":"Artemisinin inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-9 expression via a protein kinase Cdelta\/p38\/extracellular signal-regulated kinase pathway in phorbol myristate acetate-induced THP-1 macrophages","volume":"38","author":"Wang","year":"2011","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-012-1113-8","article-title":"Enhanced IL-12p40 production in LPS-stimulated macrophages by inhibiting JNK activation by artemisinin","volume":"35","author":"Cho","year":"2012","journal-title":"Arch Pharm Res"},{"key":"B41","doi-asserted-by":"publisher","first-page":"107284","DOI":"10.1016\/j.intimp.2020.107284","article-title":"Artemisinin ameliorates intestinal inflammation by skewing macrophages to the M2 phenotype and inhibiting epithelial-mesenchymal transition","volume":"91","author":"Huai","year":"2021","journal-title":"Int Immunopharmacol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1716096\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T06:25:30Z","timestamp":1764915930000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1716096\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,5]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2025.1716096"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1716096","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,5]]},"article-number":"1716096"}}