Journal
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcimb.2021.774899
Keywords
liposome; stress; Leishmania donovani; HO-3867; apoptosis
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Funding
- Council of Scientific and Industrial Research (CSIR) grant [BSC0114]
- UK Research and Innovation grant A global Network for Neglected Tropical Diseases [MR/P027989/1]
- J.C. Bose National Fellowship
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The study demonstrates that the liposomal formulation of HO-3867 is effective in inducing apoptosis in Leishmania parasites while being safe for normal murine macrophages. The treatment effectively reduces intracellular L. donovani amastigote burden by inducing parasite killing through ROS and NO activity.
Lack of vaccine and increasing chemotherapeutic toxicities currently necessitate the development of effective and safe drugs against various forms of leishmaniases. We characterized the cellular stress induced by a novel curcumin analogue, HO-3867, encapsulated within the phosphatidylcholine-stearylamine (PC-SA) liposome for the first time against Leishmania. The liposomal formulation of HO-3867 (i.e., PC-SA/HO-3867) initiated oxidative stress-induced apoptosis in L. donovani, revealed by altered cell morphology, phosphatidylserine externalization, mitochondrial depolarization, intracellular lipid accumulation, and cell cycle arrest in promastigotes. Liposomal HO-3867 was observed to be a strong apoptosis inducer in L. donovani and L. major in a dose-dependent manner, yet completely safe for normal murine macrophages. Moreover, PC-SA/HO-3867 treatment induced L. donovani metacaspase and PARP1 activation along with downregulation of the Sir2 gene. PC-SA/HO-3867 arrested intracellular L. donovani amastigote burden in vitro, with reactive oxygen species (ROS) and nitric oxide (NO)-mediated parasite killing. These data suggest that liposomal HO-3867 represents a highly promising and non-toxic nanoparticle-based therapeutic platform against leishmaniasis inspiring further preclinical developments.
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