{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T12:19:54Z","timestamp":1763986794428,"version":"3.45.0"},"reference-count":43,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T00:00:00Z","timestamp":1763856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004586","name":"Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro\/FAPERJ","doi-asserted-by":"publisher","award":["E-26\/210.336\/2024","E-26\/150.042\/2023","E-26\/210.147\/2024"],"award-info":[{"award-number":["E-26\/210.336\/2024","E-26\/150.042\/2023","E-26\/210.147\/2024"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Brazilian Agencies of Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["304763\/2021-7"],"award-info":[{"award-number":["304763\/2021-7"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["0012017"],"award-info":[{"award-number":["0012017"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Membranes"],"abstract":"<jats:p>The subfamily ENA of the P-ATPases family transports Na+ and H+ in opposite directions and, for this reason, they are called Na+-ATPases. They are physiologically important at high pH and high salt conditions in which other Na+ transporters cannot operate. This is the case, for example, of Aspergilus and Arabidopsis, respectively. Since, during their lifecycle, the parasitic protozoa face alkaline and\/or high-saline environments, we postulated that the ENA subfamily could be a target for the treatment of serious and common illnesses driven by parasitic protozoa, as in the case of Chagas disease. The subgroup ATP4 ATPases, which is found in Plasmodium falciparum and Toxoplasma gondii, can be compared \u2014through phylogenetic analysis\u2014with the classic IID P-type ENA subfamily. Thus, some drugs that target PfATP4 ATPase and affect Na+ homeostasis are undergoing clinical trial, including spiroindolones. ENA-type ATPases (P-type ATPase IID) and ATP-type ATPase do not have structural homologs in mammals, appearing only in plants, fungi, and protozoan parasites, such as Trypanosoma cruzi, Leishmania sp., T. gondii, and P. falciparum. Therefore, this exclusivity points to Na+-ATPases as promising targets for medical projects aiming at new treatments contributing to the academic community.<\/jats:p>","DOI":"10.3390\/membranes15120349","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T11:47:22Z","timestamp":1763984842000},"page":"349","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impacts of Cipargamin on Na+-ATPase and Osmoregulation of Trypanosoma cruzi"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2251-6409","authenticated-orcid":false,"given":"Claudia Fernanda","family":"Dick","sequence":"first","affiliation":[{"name":"Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21590-902, Brazil"},{"name":"Graduate Program in Translational Biomedicine\/BIOTRANS, Grande Rio University\/UNIGRANRIO, Duque de Caxias 25071-202, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Angelica Celso de Lima Barreto da","family":"Silva","sequence":"additional","affiliation":[{"name":"Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21590-902, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriano","family":"de-Souza-Silva","sequence":"additional","affiliation":[{"name":"Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21590-902, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna","family":"Frechiani","sequence":"additional","affiliation":[{"name":"Graduate Program in Translational Biomedicine\/BIOTRANS, Grande Rio University\/UNIGRANRIO, Duque de Caxias 25071-202, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana","family":"Barbosa-de-Barros","sequence":"additional","affiliation":[{"name":"Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21590-902, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8009-7273","authenticated-orcid":false,"given":"Adalberto","family":"Vieyra","sequence":"additional","affiliation":[{"name":"Graduate Program in Translational Biomedicine\/BIOTRANS, Grande Rio University\/UNIGRANRIO, Duque de Caxias 25071-202, Brazil"},{"name":"Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil"},{"name":"National Center for Structural Biology and Bioimaging\/CENABIO, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Roberto","family":"Meyer-Fernandes","sequence":"additional","affiliation":[{"name":"Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21590-902, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1590\/S0074-02761909000200008","article-title":"Nova tripanozomiaze humana","volume":"1","author":"Chagas","year":"1909","journal-title":"Mem\u00f3rias Inst. Oswaldo Cruz"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1016\/S0140-6736(10)60061-X","article-title":"Chagas disease","volume":"375","author":"Rassi","year":"2010","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S1471-4922(01)02200-0","article-title":"Emerging Chagas disease in Amazonian Brazil","volume":"18","author":"Coura","year":"2002","journal-title":"Trends Parasitol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"441","DOI":"10.4315\/0362-028X-72.2.441","article-title":"Chagas\u2019 disease as a foodborne illness","volume":"72","author":"Pereira","year":"2009","journal-title":"J. Food Prot."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"F811","DOI":"10.1152\/ajprenal.00351.2003","article-title":"Kidneys sans glomeruli","volume":"286","author":"Beyenbach","year":"2004","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_6","first-page":"41","article-title":"Sodium\/Potassium Homeostasis in the Cell","volume":"12","author":"Jakob","year":"2013","journal-title":"Met. Ions Life Sci."},{"key":"ref_7","first-page":"193","article-title":"A physicomathematical model of sodium balance","volume":"26","author":"Landahl","year":"1964","journal-title":"Bull. Math. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/0006-3002(57)90343-8","article-title":"The influence of some cations on an adenosine triphosphatase from peripheral nerves","volume":"23","author":"Skou","year":"1957","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0005-2736(75)90265-5","article-title":"Ouabain-insensitive Na+ stimulation of an Mg2+-dependent ATPase in kidney tissue","volume":"394","author":"Proverbio","year":"1975","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF00587893","article-title":"Two modes of Na extrusion in cells from guinea pig kidney cortex slices","volume":"316","author":"Whittembury","year":"1970","journal-title":"Pfl\u00fcgers Arch. Eur. J. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dick, C.F., Meyer-Fernandes, J.R., and Vieyra, A. (2020). The Functioning of Na+-ATPases from Protozoan Parasites: Are These Pumps Targets for Antiparasitic Drugs?. Cells, 9.","DOI":"10.3390\/cells9102225"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/0005-2736(82)90502-8","article-title":"Partial characterization of the ouabain-insensitive, Na+-stimulated atpase activity of kidney basal-lateral plasma membranes","volume":"692","author":"Proverbio","year":"1982","journal-title":"Biochim. Biophys. Acta (BBA)-Biomembr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.bbamem.2006.04.025","article-title":"Molecular cloning and characterization of ouabain-insensitive Na+-ATPase in the parasitic protist, Trypanosoma cruzi","volume":"1758","author":"Iizumi","year":"2006","journal-title":"Biochim. Biophys. Acta (BBA)-Biomembr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5720","DOI":"10.1074\/jbc.RA118.006706","article-title":"Characterization of the ATP4 ion pump in Toxoplasma gondii","volume":"294","author":"Lehane","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4265","DOI":"10.1016\/j.bbagen.2013.04.034","article-title":"Inorganic phosphate uptake in Trypanosoma cruzi is coupled to K+ cycling and to active Na+ extrusion","volume":"1830","author":"Dick","year":"2013","journal-title":"Biochim. Biophys. Acta (BBA)-Gen. Subj."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.chom.2012.12.006","article-title":"Na+ regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials","volume":"13","author":"Spillman","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1016\/j.bbamem.2010.07.009","article-title":"Sodium or potassium efflux ATPase. A fungal, bryophyte, and protozoal ATPase","volume":"1798","author":"Benito","year":"2010","journal-title":"Biochim. Biophys. Acta (BBA)-Biomembr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1126\/science.1193225","article-title":"Spiroindolones, a potent compound class for the treatment of malaria","volume":"329","author":"Rottmann","year":"2010","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"101765","DOI":"10.1016\/j.tmaid.2020.101765","article-title":"The early preclinical and clinical development of cipargamin (KAE609), a novel antimalarial compound","volume":"36","author":"Bouwman","year":"2020","journal-title":"Travel Med. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.ijpddr.2015.07.001","article-title":"The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs","volume":"5","author":"Spillman","year":"2015","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1056\/NEJMoa1315860","article-title":"Spiroindolone KAE609 for Falciparum and Vivax Malaria","volume":"371","author":"White","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_22","first-page":"E5455","article-title":"(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium","volume":"111","author":"Ebert","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1093\/infdis\/jiv358","article-title":"A basis for rapid clearance of circulating ring-stage malaria parasites by the spiroindolone KAE609","volume":"213","author":"Zhang","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"34205","DOI":"10.1074\/jbc.M113.518993","article-title":"Trypanosoma brucei vacuolar transporter chaperone 4 (TbVtc4) is an acidocalcisome polyphosphate kinase required for in vivo infection","volume":"288","author":"Lander","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chiurillo, M.A., Carlson, J., Bertolini, M.S., Raja, A., and Lander, N. (2023). Dual localization of receptor-type adenylate cyclases and cAMP response protein 3 unveils the presence of two putative signaling microdomains in Trypanosoma cruzi. mBio, 14.","DOI":"10.1128\/mbio.01064-23"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1042\/bj3040227","article-title":"Ca2+\/H+ exchange in acidic vacuoles of Trypanosoma brucei","volume":"304","author":"Vercesi","year":"1994","journal-title":"Biochem. J."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Huang, G., and Docampo, R. (2024). Acidocalcisome localization of membrane transporters and enzymes in Trypanosoma brucei. Microbiol. Spectr., 12.","DOI":"10.1128\/spectrum.01128-24"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"37369","DOI":"10.1074\/jbc.M204744200","article-title":"A vacuolar-type H+-pyrophosphatase governs maintenance of functional acidocalcisomes and growth of the insect and mammalian forms of Trypanosoma brucei","volume":"277","author":"Lemercier","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Docampo, R. (2024). Advances in the cellular biology, biochemistry, and molecular biology of acidocalcisomes. Microbiol. Mol. Biol. Rev., 88.","DOI":"10.1128\/mmbr.00042-23"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/B978-0-12-407695-2.00002-0","article-title":"New insights into roles of acidocalcisomes and contractile vacuole complex in osmoregulation in protists","volume":"305","author":"Docampo","year":"2013","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Asady, B., Dick, C.F., Ehrenman, K., Sahu, T., Romano, J.D., and Coppens, I. (2020). A single Na+-Pi cotransporter in Toxoplasma plays key roles in phosphate import and control of parasite osmoregulation. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1009067"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13327","DOI":"10.1074\/jbc.RA118.003640","article-title":"Biochemical characterization and chemical inhibition of PfATP4-associated Na-ATPase activity in Plasmodium falciparum membranes","volume":"293","author":"Rosling","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1111\/mmi.14621","article-title":"Signaling pathways involved in environmental sensing in Trypanosoma cruzi","volume":"115","author":"Lander","year":"2021","journal-title":"Mol. Microbiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.mib.2021.07.017","article-title":"Metabolic flexibility in Trypanosoma cruzi amastigotes: Implications for persistence and drug sensitivity","volume":"63","author":"Dumoulin","year":"2021","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/S0022-1910(00)00170-0","article-title":"Ionic composition of the rectal contents and excreta of the reduviid bug Triatoma infestans","volume":"47","author":"Kollien","year":"2001","journal-title":"J. Insect Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"613S","DOI":"10.1080\/07315724.2007.10719667","article-title":"Mechanisms and Significance of Cell Volume Regulation","volume":"26","author":"Lang","year":"2007","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_38","first-page":"132","article-title":"Regulation of cell volume in health and disease","volume":"26","author":"McManus","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"43959","DOI":"10.1074\/jbc.M111.311530","article-title":"Hyperosmotic stress induces aquaporin-dependent cell shrinkage, polyphosphate synthesis, amino acid accumulation, and global gene expression changes in Trypanosoma cruzi","volume":"286","author":"Li","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1042\/BJ20070612","article-title":"Ablation of a small transmembrane protein of Trypanosoma brucei (TbVTC1) involved in the synthesis of polyphosphate alters acidocalcisome biogenesis and function, and leads to a cytokinesis defect","volume":"407","author":"Fang","year":"2007","journal-title":"Biochem. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"26114","DOI":"10.1074\/jbc.M102402200","article-title":"Rapid changes in polyphosphate content within acidocalcisomes in response to cell growth, differentiation, and environmental stress in Trypanosoma cruzi","volume":"276","author":"Ruiz","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.2174\/1381612826999201203213527","article-title":"Basic Biology of Trypanosoma cruzi","volume":"27","author":"Zuma","year":"2020","journal-title":"Curr. Pharm. Des."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.abb.2012.07.014","article-title":"Stress response to high osmolarity in Trypanosoma cruzi epimastigotes","volume":"527","author":"Bonansea","year":"2012","journal-title":"Arch. Biochem. Biophys."}],"container-title":["Membranes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0375\/15\/12\/349\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T12:17:08Z","timestamp":1763986628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0375\/15\/12\/349"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,23]]},"references-count":43,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["membranes15120349"],"URL":"https:\/\/doi.org\/10.3390\/membranes15120349","relation":{},"ISSN":["2077-0375"],"issn-type":[{"value":"2077-0375","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,23]]}}}