HSP70 of Leishmania amazonensis alters resistance to different stresses and mitochondrial bioenergetics

Codonho, Bárbara Santoni; Costa, Solange dos Santos; Peloso, Eduardo de Figueiredo; Joazeiro, Paulo Pinto; Gadelha, Fernanda Ramos; Giorgio, Selma

doi:10.1590/0074-02760160087

Cited by 11 publications

(6 citation statements)

References 43 publications

(65 reference statements)

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“…After that, cells were centrifuged at 1500× rpm for 10 min and resuspended in 50 µl of buffer’s kit. Parasites treated with H 2 O 2 at 600 μM for 30 min were used as a positive control [27]. A fluorescence microscope (Leica TCS; Leica Microsystems, Wetzlar, Germany) was used to observe the cells, using an excitation wavelength of 640 nm and emission wavelengths of 665 nm, the signal for Deep Red which should appear localized in the cytoplasm.…”

Section: Methodsmentioning

confidence: 99%

In vitro activity of 1H-phenalen-1-one derivatives against Leishmania spp. and evidence of programmed cell death

et al. 2019

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BackgroundThe in vitro activity against Leishmania spp. of a novel group of compounds, phenalenone derivatives, is described in this study. Previous studies have shown that some phenalenones present leishmanicidal activity, and induce a decrease in the mitochondrial membrane potential in L. amazonensis parasites, so in order to elucidate the evidence of programmed cell death occurring inside the promastigote stage, different assays were performed in two different species of Leishmania.MethodsWe focused on the determination of the programmed cell death evidence by detecting the characteristic features of the apoptosis-like process, such as phosphatidylserine exposure, mitochondrial membrane potential, and chromatin condensation among others.ResultsThe results showed that four molecules activated the apoptosis-like process in the parasite. All the signals observed were indicative of the death process that the parasites were undergoing.ConclusionsThe present results highlight the potential use of phenalenone derivatives against Leishmania species and further studies should be undertaken to establish them as novel leishmanicidal therapeutic agents.

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Section: Methodsmentioning

confidence: 99%

In vitro activity of 1H-phenalen-1-one derivatives against Leishmania spp. and evidence of programmed cell death

et al. 2019

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“…The orthologue of Hsp70 in several Leishmania spp. has also been linked to parasite's resistance to pentavalent antimonial treatment, as it induces Hsp70 expression which provides stress tolerance against the drug (Brochu et al 2004;Maharjan and Madhubala 2015;Codonho et al 2016). TbbHsp70 was detected in glycosomes with high confidence and the flagellum (Table 1) (Güther et al 2014;Subota et al 2014).…”

Section: Tablementioning

confidence: 99%

The Hsp70/J-protein machinery of the African trypanosome, Trypanosoma brucei

Bentley

Jamabo

Boshoff

2019

Cell Stress and Chaperones

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The etiological agent of the neglected tropical disease African trypanosomiasis, Trypanosoma brucei, possesses an expanded and diverse repertoire of heat shock proteins, which have been implicated in cytoprotection, differentiation, as well as progression and transmission of the disease. Hsp70 plays a crucial role in proteostasis, and inhibition of its interactions with co-chaperones is emerging as a potential therapeutic target for numerous diseases. In light of genome annotations and the release of the genome sequence of the human infective subspecies, an updated and current in silico overview of the Hsp70/J-protein machinery in both T. brucei brucei and T. brucei gambiense was conducted. Functional, structural, and evolutionary analyses of the T. brucei Hsp70 and J-protein families were performed. The Hsp70 and J-proteins from humans and selected kinetoplastid parasites were used to assist in identifying proteins from T. brucei, as well as the prediction of potential Hsp70-J-protein partnerships. The Hsp70 and Jproteins were mined from numerous genome-wide proteomics studies, which included different lifecycle stages and subcellular localisations. In this study, 12 putative Hsp70 proteins and 67 putative J-proteins were identified to be encoded on the genomes of both T. brucei subspecies. Interestingly there are 6 type III J-proteins that possess tetratricopeptide repeat-containing (TPR) motifs. Overall, it is envisioned that the results of this study will provide a future context for studying the biology of the African trypanosome and evaluating Hsp70 and J-protein interactions as potential drug targets.

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“…Following the manufacturer's protocol, parasites were incubated with the compounds at the IC 90 concentration for 24 h, then washed, and incubated with 5 µM of CellRox Reagent for 30 min at 26 • C. Then, parasites were centrifuged and resuspended in buffer. H 2 O 2 at 600 µM for 30 min was used as positive control [29]. A fluorescence microscope (EVOS FL) was used to observe the cells.…”

Section: Oxidative Stressmentioning

confidence: 99%

Withanolides from Withania aristata as Antikinetoplastid Agents through Induction of Programmed Cell Death

et al. 2019

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Leishmaniasis and American trypanosomiasis are parasitic diseases that cause significant clinical, social and economic impact on the population of tropical and subtropical countries. Their current treatment is limited and presents multiple drawbacks, including high toxicity, high cost, lengthy treatment plans, as well as the emergence of resistant species. Therefore, there is a need to find new lead compounds with high potency against parasites and low toxicity in patients. In the present work, the bioguided fractionation of an endemic plant from the Canary Islands, Withania aristata, led to the identification of withanolide-type metabolites (1–3) with leishmanicidal and trypanocidal activities. Compounds 1 and 3 showed a significant dose-dependent inhibition effect on the proliferation of L. amazonensis promastigotes and T. cruzi epimastigotes, higher than the reference drugs, miltefosine and benznidazole, respectively. Moreover, compounds 1–3 were more potent (IC50 0.055–0.663 µM) than the reference drug against the intracellular amastigote stage of L. amazonensis, with a high selectivity index on murine macrophage cells (SI 58.66–216.73). Studies on the mechanism of death showed that the compounds induced programmed cell death or that which was apoptosis-like. The present findings underline the potential of withanolides as novel therapeutic antikinetoplastid agents.

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HSP70 of Leishmania amazonensis alters resistance to different stresses and mitochondrial bioenergetics

Cited by 11 publications

References 43 publications

In vitro activity of 1H-phenalen-1-one derivatives against Leishmania spp. and evidence of programmed cell death

In vitro activity of 1H-phenalen-1-one derivatives against Leishmania spp. and evidence of programmed cell death

The Hsp70/J-protein machinery of the African trypanosome, Trypanosoma brucei

Withanolides from Withania aristata as Antikinetoplastid Agents through Induction of Programmed Cell Death

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