Investigation of Calcium Channel Blockers as Antiprotozoal Agents and Their Interference in the Metabolism of Leishmania (L.) infantum

Leishmaniasis and Chagas disease are neglected parasitic diseases endemic in developing countries; efforts to find new therapies remain a priority. Calcium channel blockers (CCBs) are drugs in clinical use for hypertension and other heart pathologies. Based on previous reports about the antileishmanial activity of dihydropyridine-CCBs, this work aimed to investigate whether the in vitro anti-Leishmania infantum and anti-Trypanosoma cruzi activities of this therapeutic class would be shared by other non-dihydropyridine-CCBs. Except for amrinone, our results demonstrated antiprotozoal activity for fendiline, mibefradil, and lidoflazine, with IC50 values in a range between 2 and 16 μM and Selectivity Index between 4 and 10. Fendiline demonstrated depolarization of mitochondrial membrane potential, with increased reactive oxygen species production in amlodipine and fendiline treated Leishmania, but without plasma membrane disruption. Finally, in vitro combinations of amphotericin B, miltefosine, and pentamidine against L. infantum showed in isobolograms an additive interaction when these drugs were combined with fendiline, resulting in overall mean sum of fractional inhibitory concentrations between 0.99 and 1.10. These data demonstrated that non-dihydropyridine-CCBs present antiprotozoal activity and could be useful candidates for future in vivo efficacy studies against Leishmaniasis and Chagas’ disease

Bioactivity And Chemical Composition Of The Essential Oil From The Leaves Of Guatteria Australis A.st.-hil.

Essential oil from the leaves of Guatteria australis was obtained by hydrodistillation, analyzed by Gas Chromatography coupled to Mass Spectromery (GC-MS) and their antiproliferative, antileishmanial, antibacterial, antifungal and antioxidant activities were also evaluated. Twenty-three compounds were identified among which germacrene B (50.66%), germacrene D (22.22%) and (E)-caryophyllene (8.99%) were the main compounds. The highest antiproliferative activity was observed against NCI-ADR/RES (TGI = 31.08 μg/ml) and HT-29 (TGI = 32.81 μg/ml) cell lines. It also showed good antileishmanial activity against Leishmania infantum (IC50 = 30.71 μg/ml). On the other hand, the oil exhibited a small effect against Staphylococcus aureus ATCC 6538, S. aureus ATCC 14458 and Escherichia coli ATCC 10799 (MIC = 250 μg/ml), as well as small antioxidant activity (457 μmol TE/g) assessed through ORACFL assay. These results represent the first report regarding chemical composition and bioactivity of G. australis essential oil.1-

Efficacy of sertraline against Trypanosoma cruzi: an in vitro and in silico study

Abstract Background Drug repurposing has been an interesting and cost-effective approach, especially for neglected diseases, such as Chagas disease. Methods In this work, we studied the activity of the antidepressant drug sertraline against Trypanosoma cruzi trypomastigotes and intracellular amastigotes of the Y and Tulahuen strains, and investigated its action mode using cell biology and in silico approaches. Results Sertraline demonstrated in vitro efficacy against intracellular amastigotes of both T. cruzi strains inside different host cells, including cardiomyocytes, with IC50 values between 1 to 10 μM, and activity against bloodstream trypomastigotes, with IC50 of 14 μM. Considering the mammalian cytotoxicity, the drug resulted in a selectivity index of 17.8. Sertraline induced a change in the mitochondrial integrity of T. cruzi, resulting in a decrease in ATP levels, but not affecting reactive oxygen levels or plasma membrane permeability. In silico approaches using chemogenomic target fishing, homology modeling and molecular docking suggested the enzyme isocitrate dehydrogenase 2 of T. cruzi (TcIDH2) as a potential target for sertraline. Conclusions The present study demonstrated that sertraline had a lethal effect on different forms and strains of T. cruzi, by affecting the bioenergetic metabolism of the parasite. These findings provide a starting point for future experimental assays and may contribute to the development of new compounds

Diverse anthropogenic disturbances shift Amazon forests along a structural spectrum

Amazon forests are being degraded by myriad anthropogenic disturbances, altering ecosystem and climate function. We analyzed the effects of a range of land-use and climate-change disturbances on fine-scale canopy structure using a large database of profiling canopy lidar collected from disturbed and mature Amazon forest plots. At most of the disturbed sites, surveys were conducted 10–30 years after disturbance, with many exhibiting signs of recovery. Structural impacts differed in magnitude more than in character among disturbance types, producing a gradient of impacts. Structural changes were highly coordinated in a manner consistent across disturbance types, indicating commonalities in regeneration pathways. At the most severely affected site – burned igapó (seasonally flooded forest) – no signs of canopy regeneration were observed, indicating a sustained alteration of microclimates and consequently greater vulnerability to transitioning to a more open-canopy, savanna-like state. Notably, disturbances rarely shifted forests beyond the natural background of structural variation within mature plots, highlighting the similarities between anthropogenic and natural disturbance regimes, and indicating a degree of resilience among Amazon forests. Studying diverse disturbance types within an integrated analytical framework builds capacity to predict the risk of degradation-driven forest transitions.Fil: Smith, Marielle N.. Bangor University; Reino Unido. Michigan State University; Estados UnidosFil: Stark, Scott C.. Michigan State University; Estados UnidosFil: Taylor, Tyeen C.. University of Michigan; Estados UnidosFil: Schietti, Juliana. Universidade Federal Do Amazonas; Brasil. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: de Almeida, Danilo Roberti Alves. Universidade de Sao Paulo; BrasilFil: Aragón, Susan. Universidade Federal Do Oeste Do Pará; BrasilFil: Torralvo, Kelly. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: Lima, Albertina P.. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: de Oliveira, Gabriel. University Of South Alabama; Estados UnidosFil: de Assis, Rafael Leandro. University of Oslo; Noruega. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: Leitold, Veronika. University of Maryland; Estados UnidosFil: Pontes-Lopes, Aline. Instituto Nacional de Pesquisas Espaciais; BrasilFil: Scoles, Ricardo. Universidade Federal Do Oeste Do Pará; BrasilFil: de Sousa Vieira, Luciana Cristina. Instituto Nacional de Pesquisas Espaciais; BrasilFil: Resende, Angelica Faria. Universidade de Sao Paulo; BrasilFil: Coppola, Alysha I.. ETH Zurich. Geological Institute Biogeosciences; SuizaFil: Brandão, Diego Oliveira. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: de Athaydes Silva Junior, João. Universidade Federal do Pará; BrasilFil: Lobato, Laura F.. Universidade Federal Do Oeste Do Pará; BrasilFil: Freitas, Wagner. Universidade Federal Do Oeste Do Pará; BrasilFil: Almeida, Daniel. Universidade Federal Do Oeste Do Pará; BrasilFil: Souza, Mendell S.. Universidade Federal Do Oeste Do Pará; BrasilFil: Minor, David M.. University of Maryland; Estados UnidosFil: Villegas, Juan Camilo. Universidad de Antioquia; ColombiaFil: Law, Darin J.. University of Arizona; Estados UnidosFil: Gonçalves, Nathan. Michigan State University; Estados UnidosFil: da Rocha, Daniel Gomes. The Mamirauá Sustainable Development Institute; Brasil. University of California at Davis; Estados UnidosFil: Guedes, Marcelino Carneiro. Ministerio da Agricultura Pecuaria e Abastecimento de Brasil. Empresa Brasileira de Pesquisa Agropecuaria; BrasilFil: Tonini, Hélio. Embrapa Pecuária Sul; BrasilFil: da Silva, Kátia Emídio. Ministerio da Agricultura Pecuaria e Abastecimento de Brasil. Empresa Brasileira de Pesquisa Agropecuaria; BrasilFil: van Haren, Joost. University of Arizona; Estados UnidosFil: Rosa, Diogo Martins. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: do Valle, Dalton Freitas. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: Cordeiro, Carlos Leandro. Instituto Internacional Para Sustentabilidade; BrasilFil: de Lima, Nicolas Zaslavsky. Universidade Federal Do Oeste Do Pará; BrasilFil: Shao, Gang. Michigan State University; Estados Unidos. Purdue University Libraries And School Of Information Studies; Estados UnidosFil: Menor, Imma Oliveras. University of Oxford; Reino UnidoFil: Conti, Georgina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Florentino, Ana Paula. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: Montti, Lía. Universidad Nacional de Mar del Plata; ArgentinaFil: Aragão, Luiz. Instituto Nacional de Pesquisas Espaciais; BrasilFil: McMahon, Sean M.. Smithsonian Environmental Research Center; Estados UnidosFil: Parker, Geoffrey G.. Smithsonian Environmental Research Center; Estados UnidosFil: Breshears, David D.. University of Arizona; Estados UnidosFil: Da Costa, Antonio Carlos Lola. Universidade Federal do Pará; BrasilFil: Magnusson, William E.. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: Mesquita, Rita. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: Camargo, José Luís C.. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: de Oliveira, Raimundo C.. Embrapa Amazônia Oriental; BrasilFil: de Camargo, Plinio B.. Universidade de Sao Paulo; BrasilFil: Saleska, Scott R.. University of Arizona; Estados UnidosFil: Nelson, Bruce Walker. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; Brasi