Abstract:Leishmaniases belong to the inglorious group of neglected tropical diseases, presenting different degrees of manifestations severity. It is caused by the transmission of more than 20 species of parasites of the Leishmania genus. Nevertheless, the disease remains on the priority list for developing new treatments, since it affects millions in a vast geographical area, especially low-income people. Molecular biology studies are pioneers in parasitic research with the aim of discovering potential targets for drug… Show more
“…In the presence of genomic perturbations, cells activate checkpoints to ensure that the integrity of their genome is uncompromised. In addition, cell cycle checkpoints guarantee that the next generation of cells has the necessary cellular supplies to survive, grow, and reproduce [20,48,67]. Our data indicate that Lm TERT-/-and Lm N420 are challenging in synthesizing DNA.…”
Section: Discussionmentioning
confidence: 93%
“…Considering the importance of the surveillance system in cell growth [20,47–49], it was necessary to see how much of an influence the ablation of Lm TERT has on the cell-cycle progression of the parasites, which may also explain the observed growth and replication impairments. We processed promastigote forms with propidium iodide.…”
The lack of efficient human vaccines and effective nontoxic drugs for leishmaniasis necessitates a search for new therapeutic targets. The telomere environment could provide potential targets against leishmaniasis. TERT, the telomerase reverse transcriptase component, has been on the radar for new therapeutic options against several diseases for more than two decades. In this study, we constructed a full deletion (LmTERT-/-) and an ORF disruption (LmN420) of the gene encoding the TERT component ofLeishmania major.LmTERT-/- andLmN420 parasites showed replicative and proliferative defects, growth impairment, cell cycle alterations, increased DNA damage, and progressive telomere shortening. Blockage of parasite altruism and the presence of autophagosomes characteristic of a senescent-like phenotype were also detected.LmTERT-/- andLmN420 parasites caused either micro lesion development or no visible lesions in mouse footpads and reduced infectivity in macrophages. While our checks to see if telomere erosion had reached theSCGgenes involved in lipophosphoglycan modification showed no changes, our proteomic assessment revealed a downregulation of a metacyclic-associated protein. Complementation of the knockout lineages using the WTLmTERT restored some of the lost phenotypes. Therefore, we speculate that the pleiotropic effects of the loss ofLmTERT advance the case for using it as a drug target against the parasite.
“…In the presence of genomic perturbations, cells activate checkpoints to ensure that the integrity of their genome is uncompromised. In addition, cell cycle checkpoints guarantee that the next generation of cells has the necessary cellular supplies to survive, grow, and reproduce [20,48,67]. Our data indicate that Lm TERT-/-and Lm N420 are challenging in synthesizing DNA.…”
Section: Discussionmentioning
confidence: 93%
“…Considering the importance of the surveillance system in cell growth [20,47–49], it was necessary to see how much of an influence the ablation of Lm TERT has on the cell-cycle progression of the parasites, which may also explain the observed growth and replication impairments. We processed promastigote forms with propidium iodide.…”
The lack of efficient human vaccines and effective nontoxic drugs for leishmaniasis necessitates a search for new therapeutic targets. The telomere environment could provide potential targets against leishmaniasis. TERT, the telomerase reverse transcriptase component, has been on the radar for new therapeutic options against several diseases for more than two decades. In this study, we constructed a full deletion (LmTERT-/-) and an ORF disruption (LmN420) of the gene encoding the TERT component ofLeishmania major.LmTERT-/- andLmN420 parasites showed replicative and proliferative defects, growth impairment, cell cycle alterations, increased DNA damage, and progressive telomere shortening. Blockage of parasite altruism and the presence of autophagosomes characteristic of a senescent-like phenotype were also detected.LmTERT-/- andLmN420 parasites caused either micro lesion development or no visible lesions in mouse footpads and reduced infectivity in macrophages. While our checks to see if telomere erosion had reached theSCGgenes involved in lipophosphoglycan modification showed no changes, our proteomic assessment revealed a downregulation of a metacyclic-associated protein. Complementation of the knockout lineages using the WTLmTERT restored some of the lost phenotypes. Therefore, we speculate that the pleiotropic effects of the loss ofLmTERT advance the case for using it as a drug target against the parasite.
“…These results were similar to, or higher than, those obtained for miltefosine, an apoptosis-inducing drug, which induced apoptosis in 79% of the promastigote population ( Paris et al, 2004 ). Additionally, it is important to identify novel targets that can disrupt the parasite’s cell cycle, for its consequent elimination ( Assis et al, 2021 ). Accordingly, NanoFKA inhibited the cell cycle of L .…”
Leishmaniasis encompasses a cluster of neglected tropical diseases triggered by kinetoplastid phatogens belonging to the genus Leishmania. Current therapeutic approaches are toxic, expensive, and require long-term treatment. Nanoparticles are emerging as a new alternative for the treatment of neglected tropical diseases. Silk Fibroin is a biocompatible and amphiphilic protein that can be used for formulating nanoemulsions, while kojic acid is a secondary metabolite with antileishmanial actions. Thus, this study evaluated the efficacy of a nanoemulsion, formulated with silk fibroin as the surfactant and containing kojic acid (NanoFKA), against promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. The NanoFKA had an average particle size of 176 nm, Polydispersity Index (PDI) of 0.370, and a Zeta Potential of −32.3 mV. It presented inhibitory concentration (IC50) values of >56 μg/mL and >7 μg/mL for the promastigote and amastigote forms, respectively. Ultrastructural analysis, cell cycle distribution and phosphatidylserine exposure showed that NanoFKA treatment induces apoptosis-like cell death and cell cycle arrest in L. (L.) amazonensis. In addition, NanoFKA exhibited no cytotoxicity against macrophages. Given these results, NanoFKA present leishmanicidal activity against L. (L.) amazonensis.
“…This Special Issue also published six comprehensive high quality review articles. These reviews covered a broad range of topics: the impact of 5-Bromo-2′-deoxyuridine (BrdU) on the proliferative behavior of cerebellar neuroblasts [ 6 ], the regulation of the cell cycle by telomerase [ 7 ], growth factors [ 8 ], heat shock transcription factors [ 9 ], Cyclin-Dependent Kinases and CTD Phosphatases [ 10 ], and the effects of low-dose radiation on the cell cycle [ 11 ].These reviews focused on various model organisms, including mammalian cells, plant cells, yeast, and parasites of the Leishmania genus .…”
mentioning
confidence: 99%
“…Among these studies, trypanosomatid telomere biology has generated great interest in the scientific community, as telomeres are essential for genome stability and cell cycle progression. In this comprehensive review, Dr. Cano and her colleagues aim to shed light on what we know about the phenomena behind telomere maintenance and how it impacts the parasites’ cell cycle and survival [ 7 ]. Their review covers the knowledge available so far on the Leishmania spp.…”
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