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, Swetapadma Majhi Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR—Central Drug Research Institute, Sector-10 , Jankipuram Extension, Lucknow, Uttar Pradesh 226031 , Academy of Scientific and Innovative Research (AcSIR) , Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh 201 002 , India Search for other works by this author on: Oxford Academic Bhanu Priya Awasthi Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR—Central Drug Research Institute, Sector-10 , Jankipuram Extension, Lucknow, Uttar Pradesh 226031 , India Academy of Scientific and Innovative Research (AcSIR) , Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh 201 002 , India Search for other works by this author on: Oxford Academic Rakesh Kumar Sharma Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR—Central Drug Research Institute, Sector-10 , Jankipuram Extension, Lucknow, Uttar Pradesh 226031 , India Academy of Scientific and Innovative Research (AcSIR) , Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh 201 002 , India Search for other works by this author on: Oxford Academic Kalyan Mitra Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR—Central Drug Research Institute, Sector-10 , Jankipuram Extension, Lucknow, Uttar Pradesh 226031 , India Academy of Scientific and Innovative Research (AcSIR) , Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh 201 002 , India Corresponding author: Kalyan Mitra, E-mail: k_mitra@cdri.res.in Search for other works by this author on: Oxford Academic
https://orcid.org/0000-0002-6482-0353 Microscopy and Microanalysis, ozae034, https://doi.org/10.1093/mam/ozae034
Published:
06 May 2024
Article history
Received:
04 October 2023
Revision received:
09 February 2024
Accepted:
31 March 2024
Published:
06 May 2024
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Swetapadma Majhi, Bhanu Priya Awasthi, Rakesh Kumar Sharma, Kalyan Mitra, Buparvaquone Induces Ultrastructural and Physiological Alterations Leading to Mitochondrial Dysfunction and Caspase-Independent Apoptotic Cell Death in Leishmania donovani, Microscopy and Microanalysis, 2024;, ozae034, https://doi.org/10.1093/mam/ozae034
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Abstract
Leishmaniasis is a neglected tropical disease (endemic in 99 countries) caused by parasitic protozoa of the genus Leishmania. As treatment options are limited, there is an unmet need for new drugs. The hydroxynaphthoquinone class of compounds demonstrates broad-spectrum activity against protozoan parasites. Buparvaquone (BPQ), a member of this class, is the only drug licensed for the treatment of theileriosis. BPQ has shown promising antileishmanial activity but its mode of action is largely unknown. The aim of this study was to evaluate the ultrastructural and physiological effects of BPQ for elucidating the mechanisms underlying the in vitro antiproliferative activity in Leishmania donovani. Transmission and scanning electron microscopy analyses of BPQ-treated parasites revealed ultrastructural effects characteristic of apoptosis-like cell death, which include alterations in the nucleus, mitochondrion, kinetoplast, flagella, and the flagellar pocket. Using flow cytometry, laser scanning confocal microscopy, and fluorometry, we found that BPQ induced caspase-independent apoptosis-like cell death by losing plasma membrane phospholipid asymmetry and cell cycle arrest at sub-G0/G1 phase. Depolarization of the mitochondrial membrane leads to the generation of oxidative stress and impaired ATP synthesis followed by disruption of intracellular calcium homeostasis. Collectively, these findings provide valuable mechanistic insights and demonstrate BPQ's potential for development as an antileishmanial agent.
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antileishmanial agents, apoptosis, confocal microscopy, electron microscopy, mitochondria, naphthoquinone
© The Author(s) 2024. Published by Oxford University Press on behalf of the Microscopy Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
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Buparvaquone Induces Ultrastructural and Physiological Alterations Leading to Mitochondrial Dysfunction and Caspase-Independent Apoptotic Cell Death in Leishmania donovani - 24 Hours access
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