{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T14:14:31Z","timestamp":1774275271877,"version":"3.50.1"},"reference-count":86,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T00:00:00Z","timestamp":1774051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","award":["UID\/04378\/2025"],"award-info":[{"award-number":["UID\/04378\/2025"]}]},{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","award":["UID\/PRR\/04378\/2025"],"award-info":[{"award-number":["UID\/PRR\/04378\/2025"]}]},{"name":"Research Unit on Applied Molecular Biosciences\u2014UCIBIO","award":["LA\/P\/0140\/2020"],"award-info":[{"award-number":["LA\/P\/0140\/2020"]}]},{"name":"FCT and by the European Commission\u2019s Recovery and Resilience Facility","award":["UID\/04423\/2025"],"award-info":[{"award-number":["UID\/04423\/2025"]}]},{"name":"FCT and by the European Commission\u2019s Recovery and Resilience Facility","award":["UID\/PRR\/04423\/2025"],"award-info":[{"award-number":["UID\/PRR\/04423\/2025"]}]},{"name":"FCT and by the European Commission\u2019s Recovery and Resilience Facility","award":["LA\/P\/0101\/2020"],"award-info":[{"award-number":["LA\/P\/0101\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoX"],"abstract":"<jats:p>P-glycoprotein (P-gp), an efflux transporter highly expressed in renal tubules, plays a crucial role in the detoxification and protection of barrier\/excretory tissues from harmful xenobiotics. Xanthones and thioxanthones (TXs) are known for their antimicrobial and antitumor activities and for their ability to modulate membrane transporters such as P-gp. Previous studies have reported that (thio)xanthonic derivatives enhance P-gp expression and\/or activity in intestinal cells, reducing the intracellular accumulation of toxic substrates; however, their capacity to modulate P-gp in renal cells remains poorly explored. This study aimed to predict, in silico, TXs\u2019 binding sites within P-gp and to evaluate, in vitro, in human kidney (HK)-2 cells, the effects of selected TXs (TX1\u20135) on P-gp activity and expression, and protection against cisplatin-induced cytotoxicity. Computational studies identified preferential TX1\u20135 binding to the drug-binding pocket, particularly the rhodamine 123 (R) or modulator (M) sites, and to nucleotide-binding domain 1. In vitro, rhodamine 123 accumulation assays revealed increased P-gp transport activity after 120 min or 24 h exposure to TX1\u20135, except TX4. TX2 elicited the strongest effect (141% increase, p &lt; 0.0001), upregulated P-gp expression (24 h, p &lt; 0.0001), and significantly protected HK-2 cells from cisplatin-induced cytotoxicity (increased IC50, p &lt; 0.0001). Altogether, these findings position thioxanthones as promising scaffolds for the development of P-gp-targeted strategies to mitigate drug-induced nephrotoxicity.<\/jats:p>","DOI":"10.3390\/jox16020055","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:07:06Z","timestamp":1774271226000},"page":"55","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thioxanthone-Mediated Cytoprotection Against Cisplatin Toxicity: Exploring the Potential Involvement of P-Glycoprotein Through Computational and Experimental Approaches"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5684-7214","authenticated-orcid":false,"given":"J\u00e9ssica","family":"Veiga-Matos","sequence":"first","affiliation":[{"name":"UCIBIO\u2014Unidade de Ci\u00eancias Biomoleculares Aplicadas, Laborat\u00f3rio de Toxicologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"Toxicology Unit, Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Universidad de Salamanca, 37007 Salamanca, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7798-8641","authenticated-orcid":false,"given":"Daniel J. V. A. dos","family":"Santos","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Centro de Investiga\u00e7\u00e3o em Bioci\u00eancias e Tecnologias da Sa\u00fade, Universidade Lus\u00f3fona, 1749-024 Lisboa, Portugal"}]},{"given":"Andreia","family":"Palmeira","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"CIIMAR\u2014Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Universidade do Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-4672","authenticated-orcid":false,"given":"Em\u00edlia","family":"Sousa","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"CIIMAR\u2014Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Universidade do Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6836-6138","authenticated-orcid":false,"given":"Ana I.","family":"Morales","sequence":"additional","affiliation":[{"name":"Toxicology Unit, Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Universidad de Salamanca, 37007 Salamanca, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2540-4461","authenticated-orcid":false,"given":"Marta","family":"Prieto","sequence":"additional","affiliation":[{"name":"Toxicology Unit, Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Universidad de Salamanca, 37007 Salamanca, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-5119","authenticated-orcid":false,"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[{"name":"UCIBIO\u2014Unidade de Ci\u00eancias Biomoleculares Aplicadas, Laborat\u00f3rio de Toxicologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9962-7548","authenticated-orcid":false,"given":"Renata","family":"Silva","sequence":"additional","affiliation":[{"name":"UCIBIO\u2014Unidade de Ci\u00eancias Biomoleculares Aplicadas, Laborat\u00f3rio de Toxicologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/0005-2736(76)90160-7","article-title":"A Surface Glycoprotein Modulating Drug Permeability in Chinese Hamster Ovary Cell Mutants","volume":"455","author":"Juliano","year":"1976","journal-title":"Biochim. 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