{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:57:01Z","timestamp":1790607421337,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":270,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Parasitology Research"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Malaria remains a major global health problem, with uneven progress and the greatest disease burden clustered in sub\u2010Saharan Africa. Antimalarial drug resistance continues to undermine malaria control efforts, with widespread resistance reported in\n                    <jats:italic>Plasmodium falciparum,<\/jats:italic>\n                    including reduced susceptibility to artemisinin\u2010based combination therapies (ACTs). However, despite increasing concerns over the long\u2010term effectiveness of ACTs, the processes through which resistance to artemether\u2013lumefantrine (AL) partner drugs evolves and contributes to resistance against individual drug components remain poorly understood. Consequently, we investigated AL resistance in\n                    <jats:italic>Plasmodium berghei ANKA<\/jats:italic>\n                    towards understanding resistance development to full ACT regimens rather than individual drugs. Firstly, drug efficacy was evaluated using the standard 4\u2010day suppressive test (4\u2010DT), with baseline effective doses (ED\n                    <jats:sub>50<\/jats:sub>\n                    and ED\n                    <jats:sub>90<\/jats:sub>\n                    ) for the parental line determined as 1.45 and 2.80\u2009mg\/kg, respectively. Following 20 stepwise in vivo drug selection pressure passages, from the parental (0th) to the 20th passage in mice over 26 weeks, resistance increased by 2.85\u2010fold in ED\n                    <jats:sub>50<\/jats:sub>\n                    and 2.65\u2010fold increase in ED\n                    <jats:sub>90<\/jats:sub>\n                    , indicating reduced drug susceptibility and stepwise resistance selection. After five drug\u2010free passages and recovery following 45 days of cryopreservation at \u221280\u00b0C, the parasite retained slight resistance across all assays, indicating a stable resistance phenotype. In conclusion, continuous drug exposure successfully led to the development of\n                    <jats:italic>P. berghei<\/jats:italic>\n                    parasites with reduced sensitivity to AL, as evidenced by significantly lower chemo\u2010suppression in resistant lines compared with sensitive controls (\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 0.05). These findings demonstrate that AL resistance can be progressively selected over a period of time and stability maintained in\n                    <jats:italic>P. berghei<\/jats:italic>\n                    , providing insights into the durability and evolutionary vulnerability of ACTs under sustained drug pressure. Future studies should enhance the level of resistance, evaluate its stability, and investigate the molecular basis of AL resistance to identify reliable genetic markers for monitoring resistance to ACTs.\n                  <\/jats:p>","DOI":"10.1155\/japr\/1895485","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:10:37Z","timestamp":1790604637000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Experimental Evolution of Reduced Susceptibility to Artemether\u2013Lumefantrine in\n                    <i>Plasmodium berghei<\/i>\n                    Following Serial Drug Pressure"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6254-2747","authenticated-orcid":false,"given":"Stephen Mwangi","family":"Njoroge","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1564-5579","authenticated-orcid":false,"given":"Shadrack Kanyonji","family":"Kimani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6282-8207","authenticated-orcid":false,"given":"Teresia Wambui","family":"Ngonjo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9867-0478","authenticated-orcid":false,"given":"Maureen Stella","family":"Olunga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8075-6083","authenticated-orcid":false,"given":"Julius","family":"Seng\u2032ete Wambua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5186-8713","authenticated-orcid":false,"given":"Milka Wambui","family":"Waithera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamida Yahaya","family":"Wawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3918-2370","authenticated-orcid":false,"given":"James","family":"Ng\u2032ang\u2032a Waweru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S405668"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dcit.2026.100076"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fuab047"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-025-05339-0"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-024-04844-y"},{"key":"e_1_2_12_6_2","volume-title":"Assessment of Molecular Markers of Artemether-Lumefantrine Tolerance\/Resistance Among Patients With Acute Uncomplicated Plasmodium falciparum Malaria in Ilorin Metropolis, Ilorin Kwara State, Nigeria","author":"Abdulraheem J. O.","year":"2025"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13195680"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-024-01008-2"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-025-05393-8"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-62479-2"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.62946\/IJMPHS\/3.1.497-509"},{"key":"e_1_2_12_12_2","volume-title":"An in Vitro Chemogenomic Screening System to Identify the Molecular Targets of Antimalarial Drug Candidates","author":"Bower-Lepts C.","year":"2023"},{"key":"e_1_2_12_13_2","volume-title":"WHO Malaria Policy Advisory Group: Meeting Report, 8-10 April 2025","author":"World Health Organization","year":"2025"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-021-03585-6"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1602094"},{"key":"e_1_2_12_16_2","doi-asserted-by":"publisher","DOI":"10.37934\/arfmts.88.2.123132"},{"key":"e_1_2_12_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exppara.2009.03.010"},{"key":"e_1_2_12_18_2","volume-title":"Investigation of Pyronaridine Resistance In Plasmodium berghei Anka Isolates","author":"KimanI S. K.","year":"2016"},{"key":"e_1_2_12_19_2","doi-asserted-by":"publisher","DOI":"10.5897\/AJBR2020.1097"},{"key":"e_1_2_12_20_2","volume-title":"Plasmodium berghei ANKA: Selection of Pyronaridine Resistance in Mouse Model","author":"Kimani S.","year":"2014"},{"key":"e_1_2_12_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2023.107012"},{"key":"e_1_2_12_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41559-021-01397-0"},{"key":"e_1_2_12_23_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-026-05869-1"},{"key":"e_1_2_12_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30048-8"},{"key":"e_1_2_12_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4381"},{"key":"e_1_2_12_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.5.2817-2826.2004"},{"key":"e_1_2_12_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/vcp.12886"},{"key":"e_1_2_12_28_2","doi-asserted-by":"publisher","DOI":"10.1080\/00034983.1992.11812694"},{"key":"e_1_2_12_29_2","doi-asserted-by":"publisher","DOI":"10.4314\/ijs.v27i3.8"},{"key":"e_1_2_12_30_2","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/5721449"},{"key":"e_1_2_12_31_2","doi-asserted-by":"publisher","DOI":"10.1155\/sci5\/7344444"},{"key":"e_1_2_12_32_2","volume-title":"Studies On Comparative Insecticidal Resistance","author":"Bali R.","year":"2025"},{"key":"e_1_2_12_33_2","doi-asserted-by":"publisher","DOI":"10.1080\/00034983.1980.11687304"},{"key":"e_1_2_12_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-003-1029-9"},{"key":"e_1_2_12_35_2","doi-asserted-by":"publisher","DOI":"10.1111\/tmi.70072"},{"key":"e_1_2_12_36_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-015-0550-5"},{"key":"e_1_2_12_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00109-24"},{"key":"e_1_2_12_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)02706-5"},{"key":"e_1_2_12_39_2","volume-title":"Report on Antimalarial Drug Efficacy, Resistance and Response: 10 Years of Surveillance (2010-2019)","author":"World Health Organization","year":"2020"},{"key":"e_1_2_12_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14474"},{"key":"e_1_2_12_41_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens15020179"},{"key":"e_1_2_12_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-12-187"},{"key":"e_1_2_12_43_2","volume-title":"Combating Drug Resistance in Plasmodium falciparum: The Pharmacodynamic Impact of Artemisinin Ring-Stage Resistance and Transmission of Atovaquone Resistance","author":"Sayeed A. A.","year":"2024"},{"key":"e_1_2_12_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.03169-23"},{"key":"e_1_2_12_45_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes13101734"},{"key":"e_1_2_12_46_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-024-04855-9"}],"container-title":["Journal of Parasitology Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/japr\/1895485","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1155\/japr\/1895485","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/japr\/1895485","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:10:43Z","timestamp":1790604643000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/japr\/1895485"}},"subtitle":[],"editor":[{"given":"Satabdi","family":"Datta Choudhury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":46,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1155\/japr\/1895485"],"URL":"https:\/\/doi.org\/10.1155\/japr\/1895485","archive":["Portico"],"relation":{},"ISSN":["2090-0023","2090-0031"],"issn-type":[{"value":"2090-0023","type":"print"},{"value":"2090-0031","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2026-06-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"1895485"}}