title: Mefloquine induces ROS mediated programmed cell death in malaria parasite: Plasmodium.
abstract: Recent studies pioneer the existence of a novel programmed cell death pathway in malaria parasite plasmodium and suggest that it could be helpful in developing new targeted anti-malarial therapies. Considering this fact, we evaluated the underlying action mechanism of this pathway in mefloquine (MQ) treated parasite. Since cysteine proteases play a key role in apoptosis hence we performed preliminary computational simulations to determine binding affinity of MQ with metacaspase protein model. Binding pocket identified using computational studies, was docked with MQ to identify it's potential to bind with the predicted protein model. We further determined apoptotic markers such as mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in MQ treated/untreated parasites by cell based assay. Our results showed low mitochondrial membrane potential, enhanced activity of cysteine protease and increased number of fragmented DNA in treated parasites compared to untreated ones. We next tested the involvement of oxidative stress in MQ mediated cell death and found significant increase in reactive oxygen species generation after 24 h of treatment. Therefore we conclude that apart from hemozoin inhibition, MQ is competent to induce apoptosis in plasmodium by activating metacaspase and ROS production.
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India.|Division of Parasitology, Central Drug Research Institute, CSIR-CDRI, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
authors.forename: Sarika
authors.initials: S
authors.lastname: Gunjan
authors.affiliation: Division of Parasitology, Central Drug Research Institute, CSIR-CDRI, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India.|Division of Molecular and Structural Biology, CSIR-CDRI, Lucknow, India.
authors.forename: Tanuj
authors.initials: T
authors.lastname: Sharma
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India.|Division of Parasitology, Central Drug Research Institute, CSIR-CDRI, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
authors.forename: Hemlata
authors.initials: H
authors.lastname: Dwivedi
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India.|Division of Parasitology, Central Drug Research Institute, CSIR-CDRI, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
authors.forename: Bhavana Singh
authors.initials: BS
authors.lastname: Chauhan
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India.|Division of Molecular and Structural Biology, CSIR-CDRI, Lucknow, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Imran Siddiqi
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India. renu1113@rediffmail.com.|Division of Parasitology, Central Drug Research Institute, CSIR-CDRI, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India. renu1113@rediffmail.com.
authors.forename: Renu
authors.initials: R
authors.lastname: Tripathi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D006801:Humans; D008288:Malaria / Q000469:parasitology*; D015767:Mefloquine / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010961:Plasmodium / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D015767:Mefloquine
keywords: Apoptosis; Mefloquine; Oxidative stress; Plasmodium