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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.
J Infect Dev Ctries ; 15(11): 1774-1781, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34898511

RESUMO

INTRODUCTION: Acute Chagas disease involving reactivation can occur after organ transplant, and follow-up by direct parasitological or molecular methods is essential for monitoring the parasitic load in such patients. In contrast, there is a little data on the parasitic load in long-term organ recipients. In this study, we examined the parasitic load in long-term kidney transplant patients and assessed the possibility of late Chagas disease reactivation. METHODOLOGY: Blood cultures and real-time PCR were used to assess the parasitic load in four immunosuppressed patients who underwent kidney transplants (between 1996 and 2014) and were also treated for parasites. RESULTS: There were no positive blood culture or real-time PCR results in Chagas disease patients who received kidney transplants. The real-time PCR presented detection limit of 0.1 parasite equivalent/mL. The time interval between the transplant and sample collection varied from one to 19 years. CONCLUSIONS: No parasites were detected in the evaluated patients. The use of benznidazole and immunosuppressive therapy may have contributed to control the T. cruzi infection. In transplanted patients with Chagas disease, the use of methods such real-time PCR and blood culture can monitor the parasitic load and prevent disease reactivation.


Assuntos
Doença de Chagas/diagnóstico , Carga Parasitária/métodos , Transplantados , Trypanosoma cruzi/isolamento & purificação , Adulto , Idoso , Brasil , Doença de Chagas/parasitologia , DNA de Protozoário/sangue , Feminino , Humanos , Transplante de Rim/efeitos adversos , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos
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.
Parasitol Res ; 120(2): 705-713, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33415404

RESUMO

Leishmaniasis is one of the most neglected parasitic infections of the world and current therapeutic options show several limitations. In the search for more effective drugs, plant compounds represent a powerful natural source. Artemisinin is a sesquiterpene lactone extracted from Artemisia annua L. leaves, from which dihydroartemisinin (DQHS) and artesunic acid (AA)/artesunate are examples of active derivatives. These lactones have been applied successfully on malaria therapy for decades. Herein, we investigated the sensitivity of Leishmania braziliensis, one of the most prevalent Leishmania species that cause cutaneous manifestations in the New World, to artemisinin, DQHS, and AA. L. braziliensis promastigotes and the stage that is targeted for therapy, intracelular amastigotes, were more sensitive to DQHS, showing EC50 of 62.3 ± 1.8 and 8.9 ± 0.9 µM, respectively. Cytotoxicity assays showed that 50% of bone marrow-derived macrophages cultures were inhibited with 292.8 ± 3.8 µM of artemisinin, 236.2 ± 4.0 µM of DQHS, and 396.8 ± 6.7 µM of AA. The control of intracellular infection may not be essentially attributed to the production of nitric oxide. However, direct effects on mitochondrial bioenergetics and H2O2 production appear to be associated with the leishmanicidal effect of DQHS. Our data provide support for further studies of artemisinin and derivatives repositioning for experimental leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Artemisininas/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Animais , Metabolismo Energético/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Leishmania braziliensis/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Mitocôndrias/metabolismo , Succinatos/farmacologia
5.
Acta Trop ; 215: 105803, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33373585

RESUMO

Chagas disease is a neglected tropical disease strongly associated with low socioeconomic status, affecting nearly 8 million people - mainly Latin Americans. The current infection risk is based on acute case reports, most of which are typically associated with oral transmissions. In the semi-arid region of Northeastern Brazil, serious outbreaks of this transmission type have surged in the last years. One of those occurred in 2016 in the state of Rio Grande do Norte. Rural residents of four municipalities surrounding Marcelino Vieira ingested sugar cane juice - which was probably ground with Trypanosoma cruzi-infected insects. Eighteen cases of Chagas disease were confirmed serologically, with two deaths reported. Socioeconomic information, schooling of residents and the structure of peridomestic and domestic environments in the rural area of Marcelino Vieira, along with entomological indicators, were investigated to understand better the factors related to the outbreaks in this region. We found triatomines (mainly Triatoma brasiliensis) in 35% (24/67) of domiciliary units and all rocky outcrops inspected (n = 7). Overall, 25% (91/357) of examined T. brasiliensis were infected by T. cruzi in artificial ecotopes, with almost the same prevalence in the sylvatic environment (22%; 35/154). Among all ecotopes investigated, wood/tile/brick piles were the ones linked to high insect infestations and triatomine T. cruzi infection prevalence. Ninety-five percent of people interviewed recognized the triatomines and knew the classic route of transmission of disease - triatomine bite-dependent. However, only 7.5% admitted knowledge that Chagas disease can also be acquired orally - which poses a risk this transmission route currently recognized. Here, we highlight the physical proximity between humans and triatomine populations with high T. cruzi infection prevalence as an additional risk factor to oral/vector contaminations. In sum, residents have low income, low level of education, and/or a willful disregard for the routes of Chagas disease transmission (specifically oral transmission), a combination of factors that may have favored the Chagas disease outbreak. We here provide recommendations to avoid further outbreaks.


Assuntos
Doença de Chagas/transmissão , Surtos de Doenças , Animais , Brasil/epidemiologia , Doença de Chagas/epidemiologia , Entomologia , Humanos , Insetos Vetores , Prevalência , Fatores de Risco , Fatores Socioeconômicos
6.
Exp Parasitol ; 219: 108016, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33035543

RESUMO

Different genotoxic agents can lead to DNA single- and double-strand breaks, base modification and oxidation. As most living organisms, Trypanosoma cruzi is subjected to oxidative stress during its life cycle; thus, DNA repair is essential for parasite survival and establishment of infection. The mitochondrion plays important roles beyond the production of ATP. For example, it is a source of signaling molecules, such as the superoxide anion and H2O2. Since T. cruzi has only one mitochondrion, the integrity of this organelle is pivotal for parasite viability. H2O2 and methyl methanesulfonate cause DNA lesions in T. cruzi that are repaired by different DNA repair pathways. Herein, we evaluate mitochondrial involvement during the repair of nuclear and mitochondrial DNA in T. cruzi epimastigotes incubated with these two genotoxic agents under conditions that induce repairable DNA damage. Overall, in both treatments, an increase in oxygen consumption rates and in mitochondrial H2O2 release was observed, as well as maintenance of ATP levels compared to control. Interestingly, these changes coincided with DNA repair kinetics, suggesting the importance of the mitochondrion for this energy-consuming process.


Assuntos
Reparo do DNA/fisiologia , DNA Mitocondrial/fisiologia , Mitocôndrias/fisiologia , Trypanosoma cruzi/fisiologia , Trifosfato de Adenosina/metabolismo , Núcleo Celular/genética , Núcleo Celular/fisiologia , Dano ao DNA , Reparo de Erro de Pareamento de DNA/fisiologia , Peróxido de Hidrogênio/metabolismo , Cinética , Metanossulfonato de Metila/farmacologia , Mutagênicos/farmacologia , Fosforilação Oxidativa , Estresse Oxidativo , Consumo de Oxigênio/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética
7.
Pathog Dis ; 78(6)2020 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-32926094

RESUMO

Screenings of natural products have significantly contributed to the discovery of novel leishmanicidal agents. In this study, three known cruzioseptins-antibacterial peptides from Cruziohyla calcarifer skin-were synthesized and evaluated against promastigotes and amastigotes stages of Leishmania (L.) amazonensis and L. (V.) braziliensis. EC50 ranged from 9.17 to 74.82 µM, being cruzioseptin-1 the most active and selective compound, with selectivity index > 10 for both promastigotes and amastigotes of L. (V.) braziliensis. In vitro infections incubated with cruzioseptins at 50 µM showed up to ∼86% reduction in the amastigote number. Cruzioseptins were able to destabilize the parasite's cell membrane, allowing the incorporation of a DNA-fluorescent dye. Our data also demonstrated that hydrophobicity and charge appear to be advantageous features for enhancing parasiticidal activity. Antimicrobial cruzioseptins are suitable candidates and alternative molecules that deserve further in vivo investigation focusing on the development of novel antileishmanial therapies.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Peptídeos/química , Peptídeos/farmacologia , Anfíbios/metabolismo , Animais , Humanos , Leishmaniose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Pele/metabolismo
8.
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
9.
J Nat Prod ; 83(1): 55-65, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31895573

RESUMO

A new method of screening was developed to generate 770 organic and water-soluble fractions from extracts of nine species of marine sponges, from the growth media of 18 species of marine-derived fungi, and from the growth media of 13 species of endophytic fungi. The screening results indicated that water-soluble fractions displayed significant bioactivity in cytotoxic, antibiotic, anti-Leishmania, anti-Trypanosoma cruzi, and inhibition of proteasome assays. Purification of water-soluble fractions from the growth medium of Penicillium solitum IS1-A provided the new glutamic acid derivatives solitumine A (1), solitumine B (2), and solitumidines A-D (3-6). The structures of compounds 1-6 have been established by analysis of spectroscopic data, chemical derivatizations, and vibrational circular dichroism calculations. Although no biological activity could be observed for compounds 1-6, the new structures reported for 1-6 indicate that the investigation of water-soluble natural products represents a relevant strategy in finding new secondary metabolites.


Assuntos
Glutamatos/química , Regiões Antárticas , Fungos/química , Estrutura Molecular , Penicillium/química , Água
10.
Artigo em Inglês | MEDLINE | ID: mdl-31454702

RESUMO

Phospholipase A2 toxins present in snake venoms interact with biological membranes and serve as structural models for the design of small peptides with anticancer, antibacterial and antiparasitic properties. Oligoarginine peptides are capable of increasing cell membrane permeability (cell penetrating peptides), and for this reason are interesting delivery systems for compounds of pharmacological interest. Inspired by these two families of bioactive molecules, we have synthesized two 13-mer peptides as potential antileishmanial leads gaining insights into structural features useful for the future design of more potent peptides. The peptides included p-Acl, reproducing a natural segment of a Lys49 PLA2 from Agkistrodon contortrix laticinctus snake venom, and its p-AclR7 analogue where all seven lysine residues were replaced by arginines. Both peptides were active against promastigote and amastigote forms of Leishmania (L.) amazonensis and L. (L.) infantum, while displaying low cytotoxicity for primary murine macrophages. Spectrofluorimetric studies suggest that permeabilization of the parasite's cell membrane is the probable mechanism of action of these biomolecules. Relevantly, the engineered peptide p-AclR7 was more active in both life stages of Leishmania and induced higher rates of ethidium bromide incorporation than its native template p-Acl. Taken together, the results suggest that short peptides based on phospholipase toxins are potential scaffolds for development of antileishmanial candidates. Moreover, specific amino acid substitutions, such those herein employed, may enhance the antiparasitic action of these cationic peptides, encouraging their future biomedical applications.


Assuntos
Venenos de Crotalídeos/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Peptídeos/farmacologia , Fosfolipases A2/farmacologia , Agkistrodon/metabolismo , Animais , Células Cultivadas , Venenos de Crotalídeos/síntese química , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/síntese química
11.
Oxid Med Cell Longev ; 2019: 5080798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30728886

RESUMO

Prostate cancer development has been associated with changes in mitochondrial activity and reactive oxygen species (ROS) production. Melatonin (MLT) and docosahexaenoic acid (DHA) have properties to modulate both, but their protective role, mainly at early stages of prostate cancer, remains unclear. In this study, the effects of MLT and DHA, combined or not, on PNT1A cells with regard to mitochondria bioenergetics, ROS production, and proliferation-related pathways were examined. Based on dose response and lipid accumulation assays, DHA at 100 µM and MLT at 1 µM for 48 h were chosen. DHA doubled and MLT reduced (40%) superoxide anion production, but coincubation (DM) did not normalize to control. Hydrogen peroxide production decreased after MLT incubation only (p < 0.01). These alterations affected the area and perimeter of mitochondria, since DHA increased whereas MLT decreased, but such hormone has no effect on coincubation. DHA isolated did not change the oxidative phosphorylation rate (OXPHOS), but decreased (p < 0.001) the mitochondrial bioenergetic reserve capacity (MBRC) which is closely related to cell responsiveness to stress conditions. MLT, regardless of DHA, ameliorated OXPHOS and recovered MBRC after coincubation. All incubations decreased AKT phosphorylation; however, only MLT alone inhibited p-mTOR. MLT increased p-ERK1/2 and, when combined to DHA, increased GSTP1 expression (p < 0.01). DHA did not change the testosterone levels in the medium, whereas MLT alone or coincubated decreased by about 20%; however, any incubation affected AR expression. Moreover, incubation with luzindole revealed that MLT effects were MTR1/2-independent. In conclusion, DHA increased ROS production and impaired mitochondrial function which was probably related to AKT inactivation; MLT improved OXPHOS and decreased ROS which was related to AKT/mTOR dephosphorylation, and when coincubated, the antiproliferative action was related to mitochondrial bioenergetic modulation associated to AKT and ERK1/2 regulation. Together, these findings point to the potential application of DHA and MLT towards the prevention of proliferative prostate diseases.


Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , Metabolismo Energético/fisiologia , Melatonina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Ácidos Docosa-Hexaenoicos/farmacologia , Humanos , Masculino , Melatonina/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Espécies Reativas de Oxigênio , Transdução de Sinais
12.
Rev Soc Bras Med Trop ; 51(6): 831-835, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30517539

RESUMO

INTRODUCTION: Chagas disease (CD) prevention and control rely on studies of its distribution, characteristics of individuals affected and mode of transmission. CD data in Brazil are scarce; a retrospective analysis of the clinical characteristics of 80 patients treated at the Clinical Hospital of UNICAMP, Campinas, Brazil, was performed. METHODS: Patient data records were analyzed. RESULTS: Thirty percent of the patients probably got infected through vector-borne transmission, 65% came from endemic areas, a predominance of cardiac and cardiodigestive forms was found among males, and the cardiac form prevailed (51%). CONCLUSIONS: The results update the view on the epidemiology of CD in Campinas, Brazil.


Assuntos
Doença de Chagas , Registros Hospitalares/estatística & dados numéricos , Brasil/epidemiologia , Doença de Chagas/diagnóstico , Doença de Chagas/tratamento farmacológico , Doença de Chagas/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos
13.
Rev. Soc. Bras. Med. Trop ; 51(6): 831-835, Nov.-Dec. 2018. graf
Artigo em Inglês | LILACS | ID: biblio-1041490

RESUMO

Abstract INTRODUCTION: Chagas disease (CD) prevention and control rely on studies of its distribution, characteristics of individuals affected and mode of transmission. CD data in Brazil are scarce; a retrospective analysis of the clinical characteristics of 80 patients treated at the Clinical Hospital of UNICAMP, Campinas, Brazil, was performed. METHODS: Patient data records were analyzed. RESULTS: Thirty percent of the patients probably got infected through vector-borne transmission, 65% came from endemic areas, a predominance of cardiac and cardiodigestive forms was found among males, and the cardiac form prevailed (51%). CONCLUSIONS: The results update the view on the epidemiology of CD in Campinas, Brazil.


Assuntos
Humanos , Masculino , Feminino , Registros Hospitalares/estatística & dados numéricos , Doença de Chagas/diagnóstico , Doença de Chagas/tratamento farmacológico , Doença de Chagas/epidemiologia , Brasil/epidemiologia , Prevalência , Estudos Retrospectivos , Pessoa de Meia-Idade
14.
Biomed Pharmacother ; 108: 1703-1711, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30372873

RESUMO

Chagas disease is a major health problem not only in Latin America but also in Europe and North America due to the spread of this disease into nonendemic areas. In terms of global burden, this major tropical infection is considered to be one of the most neglected diseases, and there are currently only two available chemotherapies: benznidazole and nifurtimox. Unfortunately, although these chemotherapies are beneficial in the acute phase of the disease, benznidazole and nifurtimox lead to significant side effects, including hepatitis and neurotoxicity. Therefore, the search for and development of more effective, safe and inexpensive anti-Trypanosoma cruzi drugs are required. In this work, a series of 10 nitroaromatic Schiff bases bearing different (nitro) aromatic rings-was synthesized. Subsequently, the in vitro and in vivo anti-T. cruzi activities of the Schiff bases were investigated, as well as the in vivo toxicity and the biological effects. The basic structure of the most promising in vivo Schiff base, 10 would be useful in the synthesis of new compounds for Chagas disease treatment.


Assuntos
Hidrocarbonetos Aromáticos/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Testes de Toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Administração Oral , Animais , Feminino , Hidrocarbonetos Aromáticos/síntese química , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Parasitemia/tratamento farmacológico , Bases de Schiff/química , Bases de Schiff/toxicidade , Tripanossomicidas/química , Tripanossomicidas/toxicidade
15.
Int J Parasitol Drugs Drug Resist ; 8(3): 430-439, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30293058

RESUMO

Tritryps diseases are devastating parasitic neglected infections caused by Leishmania spp., Trypanosoma cruzi and Trypanosoma brucei subspecies. Together, these parasites affect more than 30 million people worldwide and cause high mortality and morbidity. Leishmaniasis comprises a complex group of diseases with clinical manifestation ranging from cutaneous lesions to systemic visceral damage. Antimonials, the first-choice drugs used to treat leishmaniasis, lead to high toxicity and carry significant contraindications limiting its use. Drug-resistant parasite strains are also a matter for increasing concern, especially in areas with very limited resources. The current scenario calls for novel and/or improvement of existing therapeutics as key research priorities in the field. Although several studies have shown advances in drug discovery towards leishmaniasis in recent years, key knowledge gaps in drug discovery pipelines still need to be addressed. In this review we discuss not only scientific and non-scientific bottlenecks in drug development, but also the central role of public-private partnerships for a successful campaign for novel treatment options against this devastating disease.


Assuntos
Descoberta de Drogas/métodos , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/efeitos adversos , Antiprotozoários/uso terapêutico , Antiprotozoários/toxicidade , Doença de Chagas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/estatística & dados numéricos , Descoberta de Drogas/legislação & jurisprudência , Descoberta de Drogas/estatística & dados numéricos , Descoberta de Drogas/tendências , Humanos , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Parcerias Público-Privadas , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Trypanosomatina/efeitos dos fármacos
16.
J Nat Prod ; 81(1): 188-202, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29297684

RESUMO

The isolation and identification of a series of new pseudoceratidine (1) derivatives from the sponge Tedania brasiliensis enabled the evaluation of their antiparasitic activity against Plasmodium falciparum, Leishmania (Leishmania) amazonensis, Leishmania (Leishmania) infantum, and Trypanosoma cruzi, the causative agents of malaria, cutaneous leishmaniasis, visceral leishmaniasis, and Chagas disease, respectively. The new 3-debromopseudoceratidine (4), 20-debromopseudoceratidine (5), 4-bromopseudoceratidine (6), 19-bromopseudoceratidine (7), and 4,19-dibromopseudoceratidine (8) are reported. New tedamides A-D (9-12), with an unprecedented 4-bromo-4-methoxy-5-oxo-4,5-dihydro-1H-pyrrole-2-carboxamide moiety, are also described. Compounds 4 and 5, 6 and 7, 9 and 10, and 11 and 12 have been isolated as pairs of inseparable structural isomers differing in their sites of bromination or oxidation. Tedamides 9+10 and 11+12 were obtained as optically active pairs, indicating an enzymatic formation rather than an artifactual origin. N12-Acetylpseudoceratidine (2) and N12-formylpseudoceratidine (3) were obtained by derivatization of pseudoceratidine (1). The antiparasitic activity of pseudoceratidine (1) led us to synthesize 23 derivatives (16, 17, 20, 21, 23, 25, 27-29, 31, 33, 35, 38, 39, 42, 43, 46, 47, 50, and 51) with variations in the polyamine chain and aromatic moiety in sufficient amounts for biological evaluation in antiparasitic assays. The measured antimalarial activity of pseudoceratidine (1) and derivatives 4, 5, 16, 23, 25, 31, and 50 provided an initial SAR evaluation of these compounds as potential leads for antiparasitics against Leishmania amastigotes and against P. falciparum. The results obtained indicate that pseudoceratidine represents a promising scaffold for the development of new antimalarial drugs.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Antiparasitários/química , Antiparasitários/farmacologia , Poríferos/química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacos
17.
PLoS Negl Trop Dis ; 11(8): e0005852, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28832582

RESUMO

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, presents a variable clinical course, varying from asymptomatic to serious debilitating pathologies with cardiac, digestive or cardio-digestive impairment. Previous studies using two clonal T. cruzi populations, Col1.7G2 (T. cruzi I) and JG (T. cruzi II) demonstrated that there was a differential tissue distribution of these parasites during infection in BALB/c mice, with predominance of JG in the heart. To date little is known about the mechanisms that determine this tissue selection. Upon infection, host cells respond producing several factors, such as reactive oxygen species (ROS), cytokines, among others. Herein and in agreement with previous data from the literature we show that JG presents a higher intracellular multiplication rate when compared to Col1.7G2. We also showed that upon infection cardiomyocytes in culture may increase the production of oxidative species and its levels are higher in cultures infected with JG, which expresses lower levels of antioxidant enzymes. Interestingly, inhibition of oxidative stress severely interferes with the intracellular multiplication rate of JG. Additionally, upon H2O2-treatment increase in intracellular Ca2+ and oxidants were observed only in JG epimastigotes. Data presented herein suggests that JG and Col1.7G2 may sense extracellular oxidants in a distinct manner, which would then interfere differently with their intracellular development in cardiomyocytes.


Assuntos
Interações Hospedeiro-Parasita , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/parasitologia , Oxidantes/metabolismo , Trypanosoma cruzi/crescimento & desenvolvimento , Animais , Antioxidantes/farmacologia , Cálcio/metabolismo , Respiração Celular , Células Cultivadas , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Citocinas/biossíntese , Citocinas/imunologia , Humanos , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Miócitos Cardíacos/efeitos dos fármacos , Oxidantes/farmacologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Trypanosoma cruzi/classificação , Trypanosoma cruzi/fisiologia
18.
Parasitology ; 144(11): 1498-1510, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28653592

RESUMO

Trypanosoma cruzi is exposed to oxidative stresses during its life cycle, and amongst the strategies employed by this parasite to deal with these situations sits a peculiar trypanothione-dependent antioxidant system. Remarkably, T. cruzi's antioxidant repertoire does not include catalase. In an attempt to shed light on what are the reasons by which this parasite lacks this enzyme, a T. cruzi cell line stably expressing catalase showed an increased resistance to hydrogen peroxide (H2O2) when compared with wild-type cells. Interestingly, preconditioning carried out with low concentrations of H2O2 led untransfected parasites to be as much resistant to this oxidant as cells expressing catalase, but did not induce the same level of increased resistance in the latter ones. Also, presence of catalase decreased trypanothione reductase and increased superoxide dismutase levels in T. cruzi, resulting in higher levels of residual H2O2 after challenge with this oxidant. Although expression of catalase contributed to elevated proliferation rates of T. cruzi in Rhodnius prolixus, it failed to induce a significant increase of parasite virulence in mice. Altogether, these results indicate that the absence of a gene encoding catalase in T. cruzi has played an important role in allowing this parasite to develop a shrill capacity to sense and overcome oxidative stress.


Assuntos
Catalase/metabolismo , Estresse Oxidativo , Transdução de Sinais , Trypanosoma cruzi/metabolismo , Animais , Catalase/genética , Linhagem Celular , Doença de Chagas/parasitologia , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Camundongos , NADH NADPH Oxirredutases/metabolismo , Rhodnius/parasitologia , Superóxido Dismutase/metabolismo , Transfecção , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/patogenicidade
19.
Mem. Inst. Oswaldo Cruz ; 111(7): 460-468, tab, graf
Artigo em Inglês | LILACS | ID: lil-787557

RESUMO

The 70 kDa heat shock protein (HSP70) is a molecular chaperone that assists the parasite Leishmania in returning to homeostasis after being subjected to different types of stress during its life cycle. In the present study, we evaluated the effects of HSP70 transfection of L. amazonensis promastigotes (pTEX-HSP70) in terms of morphology, resistance, infectivity and mitochondrial bioenergetics. The pTEX-HSP70 promastigotes showed no ultrastructural morphological changes compared to control parasites. Interestingly, the pTEX-HSP70 promastigotes are resistant to heat shock, H2O2-induced oxidative stress and hyperbaric environments. Regarding the bioenergetics parameters, the pTEX-HSP70 parasites had higher respiratory rates and released less H2O2 than the control parasites. Nevertheless, the infectivity capacity of the parasites did not change, as verified by the infection of murine peritoneal macrophages and human macrophages, as well as the infection of BALB/c mice. Together, these results indicate that the overexpression of HSP70 protects L. amazonensis from stress, but does not interfere with its infective capacity.


Assuntos
Animais , Feminino , Proteínas de Choque Térmico HSP70/fisiologia , Leishmania mexicana/fisiologia , Leishmaniose Cutânea/parasitologia , Proteínas de Protozoários/fisiologia , Estresse Fisiológico , Proteínas de Choque Térmico HSP70/genética , Leishmania mexicana/genética , Leishmania mexicana/ultraestrutura , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/fisiologia , Estresse Oxidativo , Proteínas de Protozoários/genética , Transfecção/métodos
20.
Mem Inst Oswaldo Cruz ; 0: 0, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-27304024

RESUMO

The 70 kDa heat shock protein (HSP70) is a molecular chaperone that assists the parasite Leishmania in returning to homeostasis after being subjected to different types of stress during its life cycle. In the present study, we evaluated the effects of HSP70 transfection of L. amazonensis promastigotes (pTEX-HSP70) in terms of morphology, resistance, infectivity and mitochondrial bioenergetics. The pTEX-HSP70 promastigotes showed no ultrastructural morphological changes compared to control parasites. Interestingly, the pTEX-HSP70 promastigotes are resistant to heat shock, H2O2-induced oxidative stress and hyperbaric environments. Regarding the bioenergetics parameters, the pTEX-HSP70 parasites had higher respiratory rates and released less H2O2 than the control parasites. Nevertheless, the infectivity capacity of the parasites did not change, as verified by the infection of murine peritoneal macrophages and human macrophages, as well as the infection of BALB/c mice. Together, these results indicate that the overexpression of HSP70 protects L. amazonensis from stress, but does not interfere with its infective capacity.


Assuntos
Proteínas de Choque Térmico HSP70/fisiologia , Leishmania mexicana/fisiologia , Leishmaniose Cutânea/parasitologia , Proteínas de Protozoários/fisiologia , Estresse Fisiológico , Animais , Feminino , Proteínas de Choque Térmico HSP70/genética , Leishmania mexicana/genética , Leishmania mexicana/ultraestrutura , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/fisiologia , Estresse Oxidativo , Proteínas de Protozoários/genética , Transfecção/métodos
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