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1.
Curr Res Microb Sci ; 3: 100110, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35199071

RESUMO

Chagas disease (CD), caused by Trypanosoma cruzi, occurs in several countries in Latin America and non-endemic countries. Heterogeneity among T. cruzi population has been the Achilles' heel to find a better treatment for CD. In this study, we characterized the biochemical parameters and mitochondrial bioenergetics of epimastigotes differentiated from eight T. cruzi isolates (I1-I8) obtained from Brazilian CD patients. Molecular analysis of parasites DTUs grouped all of them as TcII. The profile of the growth curves in axenic cultures was distinct among them, except for I1 and I3 and I2 and I4. Doubling times, growth rates, cell body length, and resistance to benznidazole were also significantly different among them. All the isolates were more glucose-dependent than other T. cruzi strains adapted to grow in axenic culture. Mitochondrial bioenergetics analysis showed that each isolate behaved differently regarding oxygen consumption rates in non-permeabilized and in digitonin-permeabilized cells in the presence of a complex II-linked substrate. When complex IV-linked respiratory chain substrate was used to provide electrons to the mitochondrial respiratory chain (MRC), similarity among the isolates was higher. Our findings show that TcII epimastigotes derived from patients' trypomastigotes displayed their own characteristics in vitro, highlighting the intra-TcII diversity, especially regarding the functionality of mitochondrial respiratory complexes II and IV. Understanding T. cruzi intraspecific biological features help us to move a step further on our comprehension regarding parasite's survival and adaptability offering clues to improve the development of new therapies for CD.

2.
Planta Med ; 2021 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-34839466

RESUMO

Two pimaranes ent-pimara-8(14),15-dien-19-oic acid (1: ) and ent-8(14),15-pimaradien-3ß-ol (2: ), isolated from Aldama arenaria, and six semi-synthetic derivatives methyl ester of the ent-pimara-8(14),15-dien-19-oic acid (3: ), ent-pimara-8(14),15-dien-19-ol (4: ), acetate of ent-pimara-8(14),15-dien-19-ol (5: ), ent-pimara-8(14),15-dien-19-ol succinic acid (6: ), acetate of ent-8(14),15-pimaradien-3ß-ol (7: ), ent-8(14),15-pimaradien-3ß-ol succinic acid (8: ) were evaluated in vitro for their cytotoxic activities to childhood leukemia cell lines and leishmanicidal activity against the parasite Leishmania amazonensis. Among these compounds, 1: to 6: presented moderate cytotoxic activity, with compound 4: being the most active (GI50 of 2.6 µM for the HL60 line) and the derivatives 7: and 8: being inactive. Against the parasite Leishmania amazonensis, the most promising derivative was the acetate of ent-pimara-8(14),15-dien-19-ol (5: ), with EC50 of 20.1 µM, selectivity index of 14.5, and significant reduction in the parasite load. Pimarane analogues 1: , ent-pimara-8(14),15-dien-19-oic acid, and 2: , ent-8(14),15-pimaradien-3ß-ol, presented different activities, corroborating the application of such molecules as prototypes for the design of other derivatives that have greater cytotoxic or leishmanicidal potential.

3.
Acta Trop ; 222: 106054, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34273309

RESUMO

This study aimed to identify the Trypanosoma cruzi genotypes and their relationship with parasitic load in distinct geographic and ecotypic populations of Triatoma brasiliensis in two sites, including one where a Chagas disease (ChD) outbreak occurred in Rio Grande do Norte state, Brazil. Triatomine captures were performed in peridomestic and sylvatic ecotopes in two municipalities: Marcelino Vieira - affected by the outbreak; and Currais Novos - where high pressure of peridomestic triatomine infestation after insecticide spraying have been reported. The kDNA-PCR was used to select 124 T. cruzi positive triatomine samples, of which 117 were successfully genotyped by fluorescent fragment length barcoding (FFLB). Moreover, the T. cruzi load quantification was performed using a multiplex TaqMan qPCR. Our findings showed a clear ecotypic segregation between TcI and TcII harboured by T. brasiliensis (p<0.001). Although no genotypes were ecotypically exclusive, TcI was predominant in peridomestic ecotopes (86%). In general, T. brasiliensis from Rio Grande do Norte had a higher T. cruzi load varying from 3.94 to 7.66 x 106T. cruzi per insect. Additionally, TcII (median value=299,504 T. cruzi/intestine unit equivalents) had more than twice (p=0.1) the parasite load of TcI (median value=149,077 T. cruzi/intestine unit equivalents), which can be attributed to a more ancient co-evolution with T. brasiliensis. The higher prevalence of TcII in the sylvatic T. brasiliensis (70%) could be associated with a more diversified source of bloodmeals for wild insect populations. Either TcI or TcII may have been responsible for the ChD outbreak that occurred in the city of Marcelino Vieira. On the other hand, a smaller portion of T. brasiliensis was infected by TcIII (3%) in the peridomicile, in addition to T. rangeli genotype A (1%), often found in mixed infections. Our results highlight the need of understanding the patterns of T. cruzi genotype´s development and circulation in insect vectors and reservoirs as a mode of tracking situations of epidemiologic importance, as the ChD outbreak recently recorded for Northeastern Brazil.


Assuntos
Doença de Chagas , Triatoma , Trypanosoma cruzi , Animais , Brasil/epidemiologia , Doença de Chagas/epidemiologia , Surtos de Doenças , Genótipo , Humanos , Carga Parasitária , Reação em Cadeia da Polimerase em Tempo Real , Triatoma/parasitologia , Trypanosoma cruzi/genética
4.
Planta Med ; 86(11): 782-789, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32512613

RESUMO

Ten lignans (1:  - 10: ) were isolated from the hexane-ethyl acetate extract of Phyllanthus amarus leaves. Three of them, cubebin dimethyl ether (3: ), urinatetralin (4: ), and lintetralin (7: ) are described for the first time in this species, while phyllanthin (1: ), niranthin (2: ), 5-demethoxyniranthin (5: ), isolintetralin (6: ), hypophyllanthin (8: ), nirtetralin (9: ), and phyltetralin (10: ) have been already reported from P. amarus. Among the lignans tested against Trypanosoma cruzi intracellular amastigotes, 2: was the most active with an EC50 of 35.28 µM. Lignans 2, 5, 7: , and 9: showed inhibitory effects against Leishmania amazonensis promastigotes with EC50 of 56.34, 51.86, 23.57, and 43.27 µM, respectively. During in vitro infection assays, 5: reduced amastigotes by 91% at 103.68 µM concentration, whereas 7: and 9: reduced amastigotes by approximately 84% at 47.5 and 86.04 µM, respectively. Lignans 5, 7: , and 9: were more potent in intracellular amastigotes with EC50 of 2.76, 8.30, and 15.83 µM, respectively, than in promastigotes. CC50 for all samples was > 100 µg/mL, thus revealing low cytotoxicity against macrophages, and selectivity against the parasite. L. amazonensis promastigotes treated with compounds 2: and 9: showed decreased respiratory control of 38% and 25%, respectively, suggesting a change in mitochondrial membrane potential and lower ATP production.


Assuntos
Antiprotozoários , Leishmania mexicana , Lignanas , Phyllanthus , Extratos Vegetais
5.
PLoS One ; 14(4): e0214574, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30934013

RESUMO

BACKGROUND: Phlebotomine sand flies are vectors for several pathogens, with Leishmania being the most important. In Brazil, the main aetiological agent of American cutaneous leishmaniasis (ACL) is Leishmania (Viannia) braziliensis, and Nyssomyia neivai is one of its main vectors in São Paulo state and other areas of South America. Similar to other haematophagous insects, sand flies use volatile compounds called kairomones to locate their hosts for blood meals. A possible increase in the attractiveness of hosts infected with Leishmania infantum to their vectors has been demonstrated. In the present study, we aimed to investigate whether L. braziliensis-infected hosts present higher attractiveness to Ny. neivai and to identify differences in the volatile compounds released by infected and uninfected mice. RESULTS: Behavioural experiments in which sand fly females directly fed on infected or uninfected mice showed no significant differences in the attractiveness of the mice or the blood volume ingested. Y-tube olfactometer bioassays also revealed no significant differences in the attractiveness of these hosts to Ny. neivai. No differences were observed in the profiles of the volatile compounds released by the two groups of mice. However, PCA and cluster analysis were able to classify the 31 identified compounds into three clusters according to their abundances. This classification showed a possible role for individual variation in the absence of differences in volatile profiles and attractiveness between infected and uninfected mice. CONCLUSION: In this first cross-sectional study with an aetiological agent of ACL, there were no statistically significant differences in the attractiveness of infected hosts to their vector.


Assuntos
Comportamento Alimentar , Mordeduras e Picadas de Insetos , Insetos Vetores/fisiologia , Leishmania braziliensis , Leishmaniose Cutânea/transmissão , Psychodidae/fisiologia , Animais , Comportamento Animal , Bioensaio , Brasil , Análise por Conglomerados , Estudos Transversais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Feromônios/química , Phlebotomus , Análise de Componente Principal , Olfato
6.
J Biol Chem ; 292(29): 12324-12338, 2017 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-28550086

RESUMO

Leishmaniasis is one of the leading globally neglected diseases, affecting millions of people worldwide. Leishmania infection depends on the ability of insect-transmitted metacyclic promastigotes to invade mammalian hosts, differentiate into amastigotes, and replicate inside macrophages. To counter the hostile oxidative environment inside macrophages, these protozoans contain anti-oxidant systems that include iron-dependent superoxide dismutases (SODs) in mitochondria and glycosomes. Increasing evidence suggests that in addition to this protective role, Leishmania mitochondrial SOD may also initiate H2O2-mediated redox signaling that regulates gene expression and metabolic changes associated with differentiation into virulent forms. To investigate this hypothesis, we examined the specific role of SODA, the mitochondrial SOD isoform in Leishmania amazonensis Our inability to generate L. amazonensis SODA null mutants and the lethal phenotype observed following RNAi-mediated silencing of the Trypanosoma brucei SODA ortholog suggests that SODA is essential for trypanosomatid survival. L. amazonensis metacyclic promastigotes lacking one SODA allele failed to replicate in macrophages and were severely attenuated in their ability to generate cutaneous lesions in mice. Reduced expression of SODA also resulted in mitochondrial oxidative damage and failure of SODA/ΔsodA promastigotes to differentiate into axenic amastigotes. SODA expression above a critical threshold was also required for the development of metacyclic promastigotes, as SODA/ΔsodA cultures were strongly depleted in this infective form and more susceptible to reactive oxygen species (ROS)-induced stress. Collectively, our data suggest that SODA promotes Leishmania virulence by protecting the parasites against mitochondrion-generated oxidative stress and by initiating ROS-mediated signaling mechanisms required for the differentiation of infective forms.


Assuntos
Ferro/metabolismo , Leishmania mexicana/enzimologia , Mitocôndrias/enzimologia , Proteínas de Protozoários/metabolismo , Superóxido Dismutase/metabolismo , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/parasitologia , Células da Medula Óssea/patologia , Linhagem Celular , Células Cultivadas , Células Clonais , Feminino , Técnicas de Inativação de Genes , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Leishmania mexicana/crescimento & desenvolvimento , Leishmania mexicana/patogenicidade , Leishmania mexicana/ultraestrutura , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Carga Parasitária , Transporte Proteico , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/genética , Interferência de RNA , Superóxido Dismutase/antagonistas & inibidores , Superóxido Dismutase/genética , Virulência
7.
J Parasitol Res ; 2017: 5056314, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28210503

RESUMO

Strongyloidiasis is a parasitic neglected disease caused by the nematode Strongyloides stercoralis affecting 30 to 100 million people worldwide. Complications, strongly associated with alcoholism, organ transplants, and HTLV-1 virus, often arise due to late diagnosis, frequently leading to patient death. Lack of preemptive diagnosis is not the only difficulty when dealing with this parasite, since there are no gold standard diagnostic techniques, and the ones used have problems associated with sensitivity, resulting in false negatives. Treatment is also an issue as ivermectin and benzimidazoles administration leads to inconsistent cure rates and several side effects. Researching new anti-Strongyloides drugs is a difficult task since S. stercoralis does not develop until the adult stages in Mus musculus (with the exception of SCID mice), the main experimental host model. Fortunately, alternative parasite models can be used, namely, Strongyloides ratti and S. venezuelensis. However, even with these models, there are other complications in finding new drugs, which are associated with specific in vitro assay protocol steps, such as larvae decontamination. In this review, we highlight the challenges associated with new drug search, the compounds tested, and a list of published in vitro assay methodologies. We also point out advances being made in strongyloidiasis diagnosis so far.

8.
J Biol Inorg Chem ; 17(1): 107-12, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21866394

RESUMO

Copper complexes with fluorinated ß-diketones were synthesized and characterized in terms of lipophilicity and peroxide-assisted oxidation of dihydrorhodamine as an indicator of redox activity. The biological activity of the complexes was tested against promastigotes of Leishmania amazonensis. Inhibition of trypanosomatid-specific trypanothione reductase was also tested. It was found that the highly lipophilic and redox-active bis(trifluoroacetylacetonate) derivative had increased toxicity towards promastigotes. These results indicate that it is possible to modulate the activity of metallodrugs based on redox-active metals through the appropriate choice of lipophilic chelators in order to design new antileishmanials. Further work will be necessary to improve selectivity of these compounds against the parasite.


Assuntos
Cobre/química , Inibidores Enzimáticos/farmacologia , Leishmania mexicana/efeitos dos fármacos , Lipídeos/química , NADH NADPH Oxirredutases/antagonistas & inibidores , Compostos Organometálicos/farmacologia , Oxidantes/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cetonas/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Oxidantes/síntese química , Oxidantes/química , Oxirredução/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
9.
Antimicrob Agents Chemother ; 55(5): 2026-31, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21357292

RESUMO

The increasing resistance of malarial parasites to almost all available drugs calls for the identification of new compounds and the detection of novel targets. Here, we establish the antimalarial activities of risedronate, one of the most potent bisphosphonates clinically used to treat bone resorption diseases, against blood stages of Plasmodium falciparum (50% inhibitory concentration [IC50] of 20.3±1.0 µM). We also suggest a mechanism of action for risedronate against the intraerythrocytic stage of P. falciparum and show that protein prenylation seems to be modulated directly by this drug. Risedronate inhibits the transfer of the farnesyl pyrophosphate group to parasite proteins, an effect not observed for the transfer of geranylgeranyl pyrophosphate. Our in vivo experiments further demonstrate that risedronate leads to an 88.9% inhibition of the rodent parasite Plasmodium berghei in mice on the seventh day of treatment; however, risedronate treatment did not result in a general increase of survival rates.


Assuntos
Antimaláricos/uso terapêutico , Ácido Etidrônico/análogos & derivados , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Animais , Cromatografia em Camada Delgada , Ácido Etidrônico/uso terapêutico , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium falciparum/patogenicidade , Prenilação de Proteína/efeitos dos fármacos , Ácido Risedrônico , Terpenos/metabolismo
10.
Mem Inst Oswaldo Cruz ; 105(7): 945-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21120371

RESUMO

The activity of the antineoplastic drug tamoxifen was evaluated against Trypanosoma cruzi. In vitro activity was determined against epimastigote, trypomastigote and amastigote forms of CL14, Y and Y benznidazole resistant T. cruzi strains. Regardless of the strain used, the drug was active against all life-cycle stages of the parasite with a half maximal effective concentration ranging from 0.7-17.9 µM. Two experimental models of acute Chagas disease were used to evaluate the in vivo efficacy of treatment with tamoxifen. No differences in parasitemia and mortality were observed between control mock-treated and tamoxifen-treated mice.


Assuntos
Doença de Chagas/tratamento farmacológico , Tamoxifeno/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Doença Aguda , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/tratamento farmacológico , Falha de Tratamento
11.
Mem. Inst. Oswaldo Cruz ; 105(7): 945-948, Nov. 2010. graf, tab
Artigo em Inglês | LILACS | ID: lil-566191

RESUMO

The activity of the antineoplastic drug tamoxifen was evaluated against Trypanosoma cruzi. In vitro activity was determined against epimastigote, trypomastigote and amastigote forms of CL14, Y and Y benznidazole resistant T. cruzi strains. Regardless of the strain used, the drug was active against all life-cycle stages of the parasite with a half maximal effective concentration ranging from 0.7-17.9 µM. Two experimental models of acute Chagas disease were used to evaluate the in vivo efficacy of treatment with tamoxifen. No differences in parasitemia and mortality were observed between control mock-treated and tamoxifen-treated mice.


Assuntos
Animais , Feminino , Masculino , Camundongos , Doença de Chagas , Tamoxifeno , Tripanossomicidas , Trypanosoma cruzi , Doença Aguda , Camundongos Endogâmicos BALB C , Parasitemia , Falha de Tratamento
12.
Biometals ; 22(6): 1095-101, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19680603

RESUMO

In this study, Cu(II) complexes with fluorinated ligands were produced aiming at the development of new, less toxic antileishmanial metallodrugs. Complexes of the general formula CuL2 (L = lactate, trifluorolactate, 2-hydroxyisobutyrate, trifluoro-2-hydroxyisobutyrate) were synthesized in methanolic medium, purified by crystallization and characterized by elemental analysis and electronic and infrared spectroscopies. In vitro experiments with Leishmania amazonensis promastigotes showed that the trifluorolactate derivative more active than its non-fluorinated counterpart. Our results indicate that fluorinated chelators may be interesting to increase metal toxicity and/or open new paths for metallodrug chemotherapy against leishmaniasis.


Assuntos
Antiprotozoários/análise , Antiprotozoários/síntese química , Cobre/química , Fluoretos/química , Leishmania/efeitos dos fármacos , Antiprotozoários/uso terapêutico , Técnicas de Cultura de Células , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância de Spin Eletrônica , Halogenação , Hidroxibutiratos/química , Concentração Inibidora 50 , Ácido Láctico/química , Leishmania/crescimento & desenvolvimento , Leishmaniose/tratamento farmacológico , Ligantes , Estrutura Molecular , Espectrofotometria Infravermelho
13.
Nitric Oxide ; 15(3): 209-16, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16527502

RESUMO

Nitric oxide (NO) is considered a key molecule in the defense against intracellular pathogens, particularly Leishmania. The expression of inducible nitric oxide synthase and consequent production of NO by infected macrophages has been shown to correlate with leishmaniasis resistance in the murine model as well as in human patients. Nitric oxide donors have been used successfully in the treatment of cutaneous leishmaniasis in humans, although their mechanisms of action are not fully understood. In the present work, the dose-dependent cytotoxic effects of the NO-donors S-nitroso-N-acetyl-l-cysteine (SNAC) and S-nitrosoglutathione (GSNO) against Leishmania were evaluated. GSNO inhibited the growth of Leishmania major and Leishmania amazonensis with in vitro 50% inhibitory concentrations (IC(50)) of 68.8+/-22.86 and 68.9+/-7.9 micromol L(-1), respectively. The IC(50) for SNAC against L. major and L. amazonensis were, respectively, 54.6+/-8.3 and 181.6+/-12.5 micromol L(-1). The leishmanicidal activity of GSNO, but not of SNAC, was reversed by ascorbic acid (AA) and dithiothreitol (DTT), suggesting that the mechanism of action of GSNO is related to the transnitrosation of parasite proteins. These results demonstrate that SNAC and GSNO have leishmanicidal activity, and are thus potential therapeutic agents against cutaneous leishmaniasis.


Assuntos
Acetilcisteína/análogos & derivados , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Doadores de Óxido Nítrico , S-Nitrosoglutationa , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Animais , Sobrevivência Celular/efeitos dos fármacos , Humanos , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , S-Nitrosoglutationa/farmacologia , S-Nitrosoglutationa/uso terapêutico
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