{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T07:29:44Z","timestamp":1785914984834,"version":"3.56.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001332","name":"CSIR","doi-asserted-by":"publisher","award":["MLP0106"],"award-info":[{"award-number":["MLP0106"]}],"id":[{"id":"10.13039\/501100001332","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001332","name":"CSIR","doi-asserted-by":"publisher","award":["MLP2031"],"award-info":[{"award-number":["MLP2031"]}],"id":[{"id":"10.13039\/501100001332","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Our aim was to evaluate the antileishmanial potential of Shikonin (SKN), a natural topoisomerase inhibitor derived from Lithospermum erythrorhizon, against Leishmania donovani and to elucidate its mechanism of action through physiological, ultrastructural, and in silico studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>SKN inhibits the in vitro proliferation of both parasite forms, with IC50 values of 3\u00a0\u03bcM for promastigotes and 0.75\u00a0\u03bcM for intracellular amastigotes. Using a combination of biophysical and biochemical methods, we found that SKN exerts its cytotoxic effect by generating oxidative stress, mitochondrial dysfunction, and nuclear damage, leading to apoptotic cell death in the parasites. Ultrastructural analysis revealed morphological alterations and apoptotic features in treated parasites, which included mitochondrial swelling and organelle damage, nuclear pyknosis, and pronounced nuclear membrane swelling in the parasites. Since the unique bi-subunit topoisomerase of these parasites has structural differences from the human counterpart and is considered a potential drug target, we performed in-silico molecular docking studies to determine the binding affinity of SKN with topoisomerase 1B (TOP1B). SKN exhibits a stronger binding affinity with L. donovani 1B than the standard topoisomerase inhibitor, camptothecin, forming favorable interactions at the catalytic site. It also shows a lesser binding affinity with human TOP1B than camptothecin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Targeting the Leishmania parasite Topoisomerase with the natural naphthoquinone SKN inhibits parasite proliferation. SKN generates oxidative stress, leading to mitochondrial dysfunction, elevation of cytosolic calcium, and nuclear damage resulting in apoptotic cell death.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jambio\/lxaf260","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T11:26:17Z","timestamp":1761045977000},"source":"Crossref","is-referenced-by-count":2,"title":["Evaluation of the antileishmanial effects and the mode of action of the natural topoisomerase inhibitor shikonin in\n                    <i>Leishmania donovani<\/i>"],"prefix":"10.1093","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6482-0353","authenticated-orcid":false,"given":"Swetapadma","family":"Majhi","sequence":"first","affiliation":[{"name":"Electron Microscopy Unit, Sophisticated Analytical Instrument Facility & Research, CSIR \u2013 Central Drug Research Institute , Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031 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