Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 764
Filtrar
1.
Parasitol Res ; 119(8): 2587-2595, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32524267

RESUMO

Lycorine is an Amaryllidaceae alkaloid that presents anti-Trichomonas vaginalis activity. T. vaginalis causes trichomoniasis, the most common non-viral sexually transmitted infection. The modulation of T. vaginalis purinergic signaling through the ectonucleotidases, nucleoside triphosphate diphosphohydrolase (NTPDase), and ecto-5'-nucleotidase represents new targets for combating the parasite. With this knowledge, the aim of this study was to investigate whether NTPDase and ecto-5'-nucleotidase inhibition by lycorine could lead to extracellular ATP accumulation. Moreover, the lycorine effect on the reactive oxygen species (ROS) production by neutrophils and parasites was evaluated as well as the alkaloid toxicity. The metabolism of purines was assessed by HPLC. ROS production was measured by flow cytometry. Cytotoxicity against epithelial vaginal cells and fibroblasts was tested, as well as the hemolytic effect of lycorine and its in vivo toxicity in Galleria mellonella larvae. Our findings showed that lycorine caused ATP accumulation due to NTPDase inhibition. The alkaloid did not affect the ROS production by T. vaginalis; however, it increased ROS levels in neutrophils incubated with lycorine-treated trophozoites. Lycorine was cytotoxic against vaginal epithelial cells and fibroblasts; conversely, it was not hemolytic neither exhibited toxicity against the in vivo model of G. mellonella larvae. Overall, besides having anti-T. vaginalis activity, lycorine modulates ectonucleotidases and stimulates neutrophils to secrete ROS. This mechanism of action exerted by the alkaloid could enhance the susceptibility of T. vaginalis to host immune cell, contributing to protozoan clearance.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Amaryllidaceae/química , Antiprotozoários/farmacologia , Neutrófilos/metabolismo , Nucleosídeo-Trifosfatase/antagonistas & inibidores , Fenantridinas/farmacologia , Extratos Vegetais/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Tricomoníase/metabolismo , Trichomonas vaginalis/enzimologia , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/metabolismo , Humanos , Neutrófilos/efeitos dos fármacos , Nucleosídeo-Trifosfatase/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/crescimento & desenvolvimento , Trichomonas vaginalis/metabolismo , Trofozoítos/efeitos dos fármacos , Trofozoítos/enzimologia , Trofozoítos/crescimento & desenvolvimento , Trofozoítos/metabolismo
2.
Korean J Parasitol ; 58(2): 135-145, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32418382

RESUMO

Infections caused by Trichomonas vaginalis in humans are one of the main public health problems caused by sexually transmitted diseases. Objective of this study was to evaluate potential biological activity of the medicinal plant Argemone mexicana (Mexican poppy) on T. vaginalis. Methanolic extracts of the stems and leaves of A. mexicana, and different fractions were prepared with solvents of different polarities. The extracts and functional groups were detected containing sterols, triterpenes, quinones, flavonoids and, alkaloids. Extracts from both the stems and leaves of A. mexicana inhibited the growth of T. vaginalis with half-maximal inhibitory concentration value of 70.6 and 67.2 µg/ml, respectively. In the active fractions, the most abundant compounds were berberine and jatrorrhizine, with presumed antiparasitic activity.


Assuntos
Extratos Vegetais/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/crescimento & desenvolvimento , Protocolos de Quimioterapia Combinada Antineoplásica , Vacinas Bacterianas , Ciclofosfamida , Depressão Química , Relação Dose-Resposta a Droga , Doxorrubicina , Fluoruracila , Técnicas In Vitro , Leucovorina , Metanol , Extratos Vegetais/química , Folhas de Planta/química , Caules de Planta/química , Quinonas , Esteróis , Triterpenos
3.
Parasitol Int ; 76: 102086, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32112829

RESUMO

Trichomonas vaginalis is the protozoan parasite responsible for the most prevalent, non-viral, sexually transmitted disease, which affects millions of people around the world. The main treatment against this disease is metronidazole and some other nitroimidazole derivatives. However, between five and 20% of clinical cases of trichomoniasis are caused by parasites resistant to these drugs. Here we present three compounds that were selected using an innovative strategy, to propose them as possible drugs to combat trichomoniasis, using the glycolytic enzyme triose phosphate isomerase (TvTIM) as the drug target. In the genome of Trichomonas vaginalis there are two genes that encode for two isoforms of TvTIM, known as TvTIM1 and TvTIM2, varying by four out of 254 aminoacid residues. In this study, we used high-throughput virtual screening to search molecules that bind specifically to TvTIM isoforms, in which 34 compounds were selected from a library of nearly 450,000 compounds. The effects of the 34 compounds on the conformation and enzymatic activity of both TvTIM isoforms and their human homolog (HsTIM) were evaluated. We found three compounds that bind specifically, modify the conformation and inhibit TvTIM2 only; although the sequence of both isoforms of TvTIM is almost identical. The selectivity of these compounds towards TvTIM2 is explained by the lower conformational stability of this isoform and that these interactions can inhibit the activity of this enzyme and have an effect against this parasite. These compounds represent promising alternatives for the development of new therapeutic strategies against trichomoniasis.


Assuntos
Antiprotozoários/farmacologia , Tricomoníase/prevenção & controle , Trichomonas vaginalis/efeitos dos fármacos , Triose-Fosfato Isomerase/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Humanos
4.
Parasit Vectors ; 13(1): 59, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046788

RESUMO

BACKGROUND: Trichomonas vaginalis is the causative agent of trichomoniasis, which is one of the most common sexually transmitted diseases worldwide. Trichomoniasis has a high incidence and prevalence and is associated with serious complications such as HIV transmission and acquisition, pelvic inflammatory disease and preterm birth. Although trichomoniasis is treated with oral metronidazole (MTZ), the number of strains resistant to this drug is increasing (2.5-9.6%), leading to treatment failure. Therefore, there is an urgent need to find alternative drugs to combat this disease. METHODS: Herein, we report the in vitro and in silico analysis of 12 furanyl N-acylhydrazone derivatives (PFUR 4, a-k) against Trichomonas vaginalis. Trichomonas vaginalis ATCC 30236 isolate was treated with seven concentrations of these compounds to determine the minimum inhibitory concentration (MIC) and 50% inhibitory concentration (IC50). In addition, compounds that displayed anti-T. vaginalis activity were analyzed using thiobarbituric acid reactive substances (TBARS) assay and molecular docking. Cytotoxicity analysis was also performed in CHO-K1 cells. RESULTS: The compounds PFUR 4a and 4b, at 6.25 µM, induced complete parasite death after 24 h of exposure with IC50 of 1.69 µM and 1.98 µM, respectively. The results showed that lipid peroxidation is not involved in parasite death. Molecular docking studies predicted strong interactions of PFUR 4a and 4b with T. vaginalis enzymes, purine nucleoside phosphorylase, and lactate dehydrogenase, while only PFUR 4b interacted in silico with thioredoxin reductase and methionine gamma-lyase. PFUR 4a and 4b led to a growth inhibition (< 20%) in CHO-K1 cells that was comparable to the drug of choice, with a promising selectivity index (> 7.4). CONCLUSIONS: Our results showed that PFUR 4a and 4b are promising molecules that can be used for the development of new trichomonacidal agents for T. vaginalis.


Assuntos
Antiprotozoários , Hidrazonas , Trichomonas vaginalis/efeitos dos fármacos , Animais , Antiprotozoários/farmacologia , Antiprotozoários/toxicidade , Células CHO , Cricetulus , Humanos , Hidrazonas/farmacologia , Hidrazonas/toxicidade , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular/métodos , Tricomoníase/tratamento farmacológico
5.
Molecules ; 25(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059495

RESUMO

We prepared a series of 10 carbamates derivatives based on two common antiprotozoal drugs: metronidazole (1-5) and secnidazole (6-10). The compounds were tested in vitro against a set of two amitochondriate protozoa: Giardia duodenalis and Trichomonas vaginalis. Compounds 1-10 showed strong antiprotozoal activities, with potency values in the low micromolar-to-nanomolar range, being more active than their parent drugs. Metronidazole carbamate (1) was the most active of the series, with nanomolar activities against G. duodenalis (IC50 = 460 nM) and T. vaginalis (IC50 = 60 nM). The potency of compound 1 was 10 times greater than that of metronidazole against both parasites. None of compounds showed in vitro cytotoxicity against VERO cells tested at 100 µM. Molecular dynamics of compounds 1-10, secnidazole, and metronidazole onto the ligand binding site of pyruvate-ferredoxin oxidoreductase of T. vaginalis and the modeled -tubulin of G. duodenalis revealed putative molecular interactions with key residues in the binding site of both proteins implicated in the mode of action of the parent drugs.


Assuntos
Antiprotozoários/farmacologia , Carbamatos/química , Metronidazol/análogos & derivados , Metronidazol/química , Antiprotozoários/síntese química , Antiprotozoários/química , Carbamatos/síntese química , Carbamatos/farmacologia , Giardia lamblia/efeitos dos fármacos , Giardia lamblia/patogenicidade , Giardíase/tratamento farmacológico , Giardíase/parasitologia , Metronidazol/síntese química , Metronidazol/farmacologia , Tricomoníase/tratamento farmacológico , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/patogenicidade
6.
Parasitol Res ; 119(2): 725-736, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31853622

RESUMO

The treatment for trichomoniasis, based on 5'-nitroimidazol agents, has been presenting failures related to allergic reactions, side effects, and the emergence of resistant isolates. There are no alternative drugs approved for the treatment of these cases; thus, the search for new active molecules is necessary. In this scenario, chalcones have been extensively studied for their promising biological activities. Here, we presented the synthesis of three hydroxychalcones (3a, b, and c), in vitro and in silico analyses against Trichomonas vaginalis. The in vitro biological evaluation showed that hydroxychalcone 3c presented anti-T. vaginalis activity, with complete death in 12 h of incubation at minimum inhibitory concentration (MIC) of 100 µM. 3c showed a dose-dependent cytotoxicity against mammalian VERO cell line, but the association of 3c at 12.5 µM and metronidazole (MTZ) at 40 µM showed 95.31% activity against T. vaginalis trophozoites after 24 h of exposure and did not affect the VERO cell growth, appearing to be a good alternative. In silico analysis by molecular docking showed that 3c could inhibit the activity of TvMGL (methionine gamma-lyase), TvLDH (lactate dehydrogenase), and TvPNP (purine nucleoside phosphorylase) affecting the T. vaginalis survival and also suggesting a different mechanism of action from MTZ. Therefore, these results propose that hydroxychalcones are promising anti-T. vaginalis agents and must be considered for further investigations regarding trichomoniasis treatment.


Assuntos
Chalconas/farmacologia , Metronidazol/farmacologia , Tricomoníase/tratamento farmacológico , Trichomonas vaginalis/efeitos dos fármacos , Animais , Chlorocebus aethiops , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Células Vero
7.
Eur J Clin Microbiol Infect Dis ; 39(2): 345-351, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31705339

RESUMO

The purpose was to evaluate whether probiotics can increase the effectiveness of antimicrobial therapy. Ninety women with Trichomonas vaginalis (TV) in the presence BV were included in the study of regimens for therapy combination with metronidazole and vaginal probiotics. For 7 days, the probiotics group patients received metronidazole at 500 mg twice a day and 1 capsule of probiotic Gynophilus® vaginally twice a day; the placebo group patients in addition to metronidazole received a placebo instead of a probiotic. For the next 7 days, patients in both groups in order restore normal microflora were given the probiotics vaginally. Before the treatment, on the 4th, 8th, and 15th day of therapy complaints, pH and redox potential of the vaginal fluid were recorded, TV detection culturally, microflora of the vagina with the qPCR-RT and microscopically. Adding probiotics to traditional therapy of TV in the presence of BV increased the likelihood of cure from TV (88.6 and 42.9% in the probiotic and placebo groups, respectively) and from BV (63.6 and 11.9%, respectively). We have found that the addition of probiotics to antimicrobial therapy causes the decrease in the inflammatory response and significant changes in the vagina's physicochemical parameters (decreased of the pH values, increased of the redox potential) already on the fourth day of the therapy. The changes in the metronidazole's antimicrobial action implementation when a probiotic is added are the reason of increasing the TV therapy's effectiveness in the BV presence.


Assuntos
Antiprotozoários/uso terapêutico , Coinfecção , Metronidazol/uso terapêutico , Probióticos/administração & dosagem , Vaginite por Trichomonas/tratamento farmacológico , Vaginite por Trichomonas/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Vaginose Bacteriana/microbiologia , Administração Intravaginal , Adulto , Antiprotozoários/farmacologia , Terapia Combinada , Feminino , Humanos , Concentração de Íons de Hidrogênio , Metronidazol/farmacologia , Resultado do Tratamento , Vaginite por Trichomonas/diagnóstico , Trichomonas vaginalis/citologia , Vaginose Bacteriana/diagnóstico , Adulto Jovem
8.
Parasitol Res ; 118(12): 3565-3570, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31701295

RESUMO

The flagellated protozoon Trichomonas vaginalis, responsible for trichomoniasis, can establish a symbiotic relationship with the bacterium Mycoplasma hominis and can harbor double-stranded RNA Trichomonasvirus (TVV). In this study, we investigated by real-time PCR the prevalence of the four TVVs and of M. hominis among 48 T. vaginalis strains isolated in Italy, and we evaluated a possible association with metronidazole resistance. Fifty percent of the analyzed trichomonad strains tested positive for at least one TVV T. vaginalis, with TVV2 being the most prevalent, followed by TVV1 and TVV3. Two T. vaginalis strains were infected by TVV4, detected in Europe for the first time. Interestingly, we found more than one TVV species in 75% of positive trichomonad strains. M. hominis was present in 81.25% of T. vaginalis isolates tested, and no statistically significant association was observed with the infection by any TVV. Metronidazole sensitivity of T. vaginalis isolates was evaluated in vitro, and no correlation was observed between minimal lethal concentration and the presence of TVVs. This is the first report on TVV infection of T. vaginalis in Italy. Even if no association of TVV positive isolates with the presence of the symbiont M. hominis or with metronidazole resistance was observed, further studies are needed to shed light on the effective role of infecting microorganisms on the pathophysiology of T. vaginalis.


Assuntos
Mycoplasma hominis/isolamento & purificação , Vírus de RNA/isolamento & purificação , Trichomonas vaginalis/microbiologia , Trichomonas vaginalis/virologia , Antiprotozoários/farmacologia , Resistência a Medicamentos , Humanos , Itália , Metronidazol/farmacologia , Mycoplasma hominis/classificação , Mycoplasma hominis/genética , Mycoplasma hominis/fisiologia , Prevalência , Vírus de RNA/classificação , Vírus de RNA/genética , Vírus de RNA/fisiologia , RNA de Cadeia Dupla/genética , RNA Viral/genética , Simbiose , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/fisiologia
9.
Biometals ; 32(6): 887-899, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31586273

RESUMO

Metallothioneins (MTs) have been identified in a wide variety of organisms from bacteria to humans. The biological functions of these MTs have a key role in metalloregulatory metabolism and its expression is induced in response to different stimuli, particularly by divalent metal cations. Also, the action of MTs have been implicated in the survival of pathogens in presence of microbicidal concentration of divalent cations, which allows the establishment of the infection. Trichomonas vaginalis is a protozoan parasite that adapts to the microenvironment of the male urogenital tract, where cations such as zinc (Zn2+) and cadmium (Cd2+) are present. Nevertheless, the molecular mechanisms of metal tolerance and homeostasis is not yet dilucidated in this parasite. In this study, we have identified 4 potential MT-like sequences (tvmt´s) in T. vaginalis genome. Because tvmt-2, -3, and -4 corresponds to truncated partial genes, we characterized the trichomonad tvmt-1 gene. The bioinformatic analyses and the predicted protein (TvMT-1) show similar properties to the reported in other MTs. The expression patterns of tvmt-1 in the presence of several divalent cations (Fe2+, Mn2+, Zn2+ and Cd2+) were analyzed and we demonstrated that Cd2+ induce significantly their expression. By indirect immunofluorescence assays, we corroborated this positive regulation of TvMT-1 in the cytoplasm of parasites grown in the presence of Cd2+. The tvmt-1 promoter contains putative metal responsive elements, which are probably the responsible for the Cd2+-dependent expression of this gene. Our results suggest that tvmt-1 gene encode a metallothionein that may be responsible for the homeostatis and detoxification of Cd+2 in T. vaginalis.


Assuntos
Cádmio/farmacologia , Metalotioneína/genética , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/genética , Homeostase/efeitos dos fármacos , Metalotioneína/metabolismo , Trichomonas vaginalis/metabolismo
10.
Artigo em Inglês | MEDLINE | ID: mdl-31451503

RESUMO

Trichomoniasis is a sexually transmitted disease with hundreds of millions of annual cases worldwide. Approved treatment options are limited to two related nitro-heterocyclic compounds, yet resistance to these drugs is an increasing concern. New antimicrobials against the causative agent, Trichomonas vaginalis, are urgently needed. We show here that clinically approved anticancer drugs that inhibit the proteasome, a large protease complex with a critical role in degrading intracellular proteins in eukaryotes, have submicromolar activity against the parasite in vitro and on-target activity against the enriched T. vaginalis proteasome in cell-free assays. Proteomic analysis confirmed that the parasite has all seven α and seven ß subunits of the eukaryotic proteasome although they have only modest sequence identities, ranging from 28 to 52%, relative to the respective human proteasome subunits. A screen of proteasome inhibitors derived from a marine natural product, carmaphycin, revealed one derivative, carmaphycin-17, with greater activity against T. vaginalis than the reference drug metronidazole, the ability to overcome metronidazole resistance, and reduced human cytotoxicity compared to that of the anticancer proteasome inhibitors. The increased selectivity of carmaphycin-17 for T. vaginalis was related to its >5-fold greater potency against the ß1 and ß5 catalytic subunits of the T. vaginalis proteasome than against the human proteasome subunits. In a murine model of vaginal trichomonad infection, proteasome inhibitors eliminated or significantly reduced parasite burden upon topical treatment without any apparent adverse effects. Together, these findings validate the proteasome of T. vaginalis as a therapeutic target for development of a novel class of trichomonacidal agents.


Assuntos
Antitricômonas/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/genética , Vaginite por Trichomonas/tratamento farmacológico , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/genética , Sequência de Aminoácidos , Animais , Anti-Infecciosos/farmacologia , Citoplasma/parasitologia , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Parasitária/métodos , Proteômica/métodos , Doenças Sexualmente Transmissíveis/tratamento farmacológico , Doenças Sexualmente Transmissíveis/parasitologia , Tricomoníase/tratamento farmacológico , Tricomoníase/parasitologia , Vaginite por Trichomonas/parasitologia
11.
ACS Infect Dis ; 5(8): 1456-1470, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31265248

RESUMO

It is estimated that Trichomonas vaginalis affects an astonishing 3.9% of the world's population, and while many of those infected are asymptomatic, progression of the disease can lead to serious health problems. Currently, the nitroimidazoles constitute the only drug class approved to treat trichomoniasis in the United States, which makes the spread of drug resistance a realistic concern. We developed a new image-based, high-throughput, and high-content assay for testing natural products (purified compounds and extracts) for antitrichomonal activity. Applying this assay system to a library of fungal natural product extracts led to the identification of three general classes of natural product inhibitors that exhibited moderate to strong activities against T. vaginalis: anthraquinones, xanthone-anthraquinone heterodimers, and decalin-linked tetramic-acid-containing metabolites. The tetramate natural products emerged as the most promising candidate molecules with pyrrolocin A (51) exhibiting potent activity against the parasite (EC50 = 60 nM), yet this metabolite showed limited toxicity to mammalian cell lines (selectivity index values of 100 and 167 versus 3T3 fibroblast and Ect1 normal cervical cells, respectively). The imaging-based assay system is a powerful tool for the bioassay-guided purification of single-component antitrichomonal biomolecules from complex natural product mixtures.


Assuntos
Antiprotozoários/farmacologia , Produtos Biológicos/farmacologia , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Processamento de Imagem Assistida por Computador/métodos , Trichomonas vaginalis/efeitos dos fármacos , Antiprotozoários/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Linhagem Celular , Feminino , Fibroblastos/efeitos dos fármacos , Fungos/química , Humanos , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologia , Quinonas/isolamento & purificação , Quinonas/farmacologia , Sensibilidade e Especificidade , Vaginite por Trichomonas/tratamento farmacológico
12.
Int J Parasitol ; 49(9): 697-704, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31254529

RESUMO

Trichomonas vaginalis is a primary urogenital parasite that causes trichomoniasis, a common sexually transmitted disease. As the first line of host defense, vaginal epithelial cells play critical roles in orchestrating vaginal innate immunity and modulate intracellular Cl- homeostasis via the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel that plays positive roles in regulating nuclear factor-κB (NF-κB) signalling. However, the association between T. vaginalis infection and intracellular Cl- disequilibrium remains elusive. This study showed that after T. vaginalis infection, CFTR was markedly down-regulated by cysteine proteases in vaginal epithelial cells. The intracellular Cl- concentration ([Cl-]i) was consequently elevated, leading to NF-κB signalling activation via serum- and glucocorticoid-inducible kinase-1. Moreover, heightened [Cl-]i and activated NF-κB signalling could be sustained in a positive feedback regulatory manner resulting from decreased intracellular cAMP through NF-κB-mediated up-regulation of phosphodiesterase 4. The results conclusively revealed that the intracellular Cl- of the human vaginal epithelium could be dynamically modulated by T. vaginalis, which contributed to mediation of epithelial inflammation in the human vagina.


Assuntos
Cloretos/metabolismo , Vaginite por Trichomonas/prevenção & controle , Trichomonas vaginalis/efeitos dos fármacos , Vagina/patologia , Western Blotting , Linhagem Celular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Cisteína Proteases/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Epitélio/metabolismo , Epitélio/parasitologia , Epitélio/patologia , Feminino , Humanos , Proteínas Imediatamente Precoces/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Vaginite por Trichomonas/parasitologia , Vagina/metabolismo , Vagina/parasitologia
13.
J Infect Chemother ; 25(12): 955-964, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31189504

RESUMO

Trichomonas vaginalis (T. vaginalis) is a common sexually transmitted infection, affecting the urogenital tract. Trichomoniasis is customarily treated with metronidazole (MTZ). MTZ is known to cause undesirable side effects and there is several reports on MTZ resistant T. vaginalis. Thus, the present study aimed to in-vitro evaluate the activity of DNA minor groove binder drug ''Netropsin dihydrochloride'' against metronidazole-sensitive T. vaginalis isolates (G and U isolates) and resistant T. vaginalis isolate (ATCC50138) (R isolate). Netropsin was tested at concentrations ranging from 3.5 to 200 µg/ml. It showed effectiveness against all isolates with MLC of 12.5 µg/ml for G and U isolates and of 25 µg/ml for R isolate. Cytotoxicity assay of isolates exposed to the respective MLC of netropsin for 42 h showed a highly significant reduction in the death percentage of MCDK cell line as compared to the effect elicited by drug free controls. The hemolytic activity was evaluated by hemolytic assay and by monitoring the interaction of T. vaginalis isolates with human erythrocytes by inverted microscopy and scanning electron microscopy. The hemolytic assay showed (0%) hemolysis of RBCs incubated with T. vaginalis isolates treated with the corresponding MLC of netropsin for 24 h. Scanning electron microscopy revealed cytoskeletal deformities of netropsin treated isolates. Taken together, these observations suggest that netropsin is a promising therapy for T. vaginalis infection affecting its viability, virulence, cytopathogenic and hemolytic activity with a mechanism of action that might overcome T. vaginalis resistance to metronidazole.


Assuntos
Antibacterianos/farmacologia , Netropsina/farmacologia , Vaginite por Trichomonas/tratamento farmacológico , Trichomonas vaginalis/efeitos dos fármacos , Animais , Antibacterianos/uso terapêutico , Cães , Resistência a Medicamentos , Feminino , Hemólise/imunologia , Humanos , Células Madin Darby de Rim Canino , Metronidazol/farmacologia , Metronidazol/uso terapêutico , Netropsina/uso terapêutico , Testes de Sensibilidade Parasitária , Vaginite por Trichomonas/parasitologia , Trichomonas vaginalis/imunologia , Trichomonas vaginalis/isolamento & purificação , Trichomonas vaginalis/patogenicidade , Trofozoítos/efeitos dos fármacos , Trofozoítos/imunologia , Vagina/parasitologia
14.
Fitoterapia ; 136: 104179, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31121252

RESUMO

Essential oils, mixtures of volatile compounds, are targets of research for new antimicrobial drugs. In order to verify the potential from species of the Nectandra genus, the present study evaluated the essential oils from Nectandra amazonum, Nectandra cuspidata, Nectandra gardineri, Nectandra hihua and Nectandra megapotamica to prospect samples with high concentration of a component and its antibacterial, antibiofilm and anti-Trichomonas vaginalis activities. The essential oils from the leaves and barks were extracted by steam distillation and analyzed by gas chromatography coupled to mass spectrometry (GC-MS). The concentrations of 10 and 100 µg/mL of the essential oil were evaluated and the inhibition of bacterial growth and biofilm formation were measured, while for the evaluation of anti-T. vaginalis trophozoite viability, the concentrations from 7.8 to 1000 µg/mL were tested. Seventy-three compounds were identified from essential oils, highlighted bicyclogermacrene (up to 49.9%), elemicin (up to 42.4%), intermedeol (up to 58.2%), (E)-asarone (up to 45.9%) and (+)-α-bisabolol (up to 93.7%). The essential oil from N. megapotamica leaves presented 93.7% of (+)-α-bisabolol and demonstrated the high capacity of inhibition of the biofilm formation, in particular, against Staphylococcus aureus methicillin resistant (MRSA) and Pseudomonas aeruginosa. This sample also had significant activity against T. vaginalis (IC50 of 98.7 µg/mL) and demonstrated cytotoxic and hemolytic effects in Vero cells and human erythrocytes. In general, the Nectandra genus revealed high chemical variability and a N. megapotamica specimen accumulated a compound on high concentration with great potential for biotechnological exploration as a new antibiofilm and anti-T. vaginalis.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Lauraceae/química , Óleos Voláteis/farmacologia , Sesquiterpenos/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , Animais , Antiprotozoários/farmacologia , Brasil , Chlorocebus aethiops , Eritrócitos/efeitos dos fármacos , Humanos , Sesquiterpenos Monocíclicos , Compostos Fitoquímicos/farmacologia , Casca de Planta/química , Folhas de Planta/química , Células Vero
15.
Eur J Med Chem ; 175: 215-233, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082765

RESUMO

α-Santonin, a sesquiterpene lactone isolated from Artemisia Santonica, possesses diverse bioactivities including antioxidant, anti-inflammation, immunosuppressive, anti-roundworm, anti-malaria, etc. However, its bioactivities are not satisfactory and need to be further optimized. Thus, many α-santonin derivatives were synthesized on the basis of rings A, B and C for the discovery of new analogues with prominent bioactivities. Herein, we reviewed and discussed the related synthetic methodologies, diverse bioactivities and structure-activity relationships (SAR) of α-santonin derivatives.


Assuntos
Santonina/química , Santonina/farmacologia , Adjuvantes Imunológicos/farmacologia , Anti-Inflamatórios/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Herbicidas/farmacologia , Humanos , Inibidores de Lipoxigenase/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Plantas/efeitos dos fármacos , Santonina/síntese química , Relação Estrutura-Atividade , Trichomonas vaginalis/efeitos dos fármacos , Tripanossomicidas/farmacologia
16.
J Mol Graph Model ; 90: 180-191, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31100677

RESUMO

Trichomonas vaginalis is the causative agent of trichomoniasis, a highly prevalent sexually transmitted infection worldwide. Nitroimidazole drugs, such as metronidazole and tinidazole, are the only recommended treatment, but cases of resistance represent at least 5%. In case of resistance or therapeutic failure, posology with higher doses is used, culminating in the increase of the toxic effects of the treatment. In this context, the development of new drugs becomes an eminent necessity. Hologram quantitative structure-activity relationship (HQSAR) models using nitroimidazole derivatives were generated to discover the relationship between the different chemical structures and the activity against cells and the selectivity against susceptible and resistant strains. One model of each strain was chosen for interpretation, both showed good internal coefficient (q2LOO values: 0.607 for susceptible strain and 0.646 for resistant strain subsets) and great values in other internal and external validations metrics. From the contribution of fragments to HQSAR models, several differences between the most and least potent compounds were found: 5-nitroimidazole contributes positively while 4-nitroimidazole negatively. QSAR models employing random forest (RF-QSAR) machine learning technique were also built and a robust model was obtained from resistant strain activity prediction (q2LOO equals to 0.618). The constructed HQSAR and RF-QSAR models were employed to predict the activity of three newly planned nitroimidazole derivatives in the design of new drugs candidates against T. vaginalis strains.


Assuntos
Antiprotozoários/farmacologia , Nitroimidazóis/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , Resistência a Medicamentos/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade
17.
Parasitology ; 146(9): 1206-1216, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31046845

RESUMO

Trichomonas vaginalis is a protozoan parasite that causes trichomoniasis in humans, the most prevalent non-viral sexually transmitted disease (STD). Imidazole compounds are used for the treatment of trichomoniasis, and metronidazole is the most commonly prescribed. However, these compounds can lead to parasite resistance and unwanted side effects. Therefore, there is a need for an alternative treatment for this disease. Here, we explored the potential of clotrimazole (CTZ) and zinc compounds, as well as CTZ complexed with zinc salts ([1] acetate [Zn(CTZ)2(Ac)2] and [2] a chloride [Zn(CTZ)2Cl2] complexes) against T. vaginalis. We synthesized the zinc complexed CTZ compounds and determined their concentration values that inhibited parasite growth by 50% (IC50). We used scanning and transmission electron microscopy to visualize the ultrastructural alterations induced by CTZ and their zinc complexes. The incubation of the parasites with [Zn(CTZ)2(Ac)2] complex inhibited their growth, yielding an IC50 of 4.9 µm. Moreover, there were changes in the shape of treated parasites, including the formation of surface projections that subsequently detached from the cell, in addition to changes in the hydrogenosomes, endoplasmic reticulum and Golgi complex. We found [Zn(CTZ)2(Ac)2] to be a highly effective compound against T. vaginalis in vitro, suggesting its potential utility as an alternative chemotherapy for trichomoniasis.


Assuntos
Antiprotozoários/farmacologia , Clotrimazol/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , Zinco/farmacologia , Animais , Humanos , Concentração Inibidora 50 , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Ratos , Trichomonas vaginalis/crescimento & desenvolvimento , Trichomonas vaginalis/ultraestrutura
18.
Toxins (Basel) ; 11(4)2019 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013660

RESUMO

Cantharidin (CTD) is a toxic monoterpene produced by blister beetles (Fam. Meloidae) as a chemical defense against predators. Although CTD is highly poisonous to many predator species, some have evolved the ability to feed on poisonous Meloidae, or otherwise beneficially use blister beetles. Great Bustards, Otis tarda, eat CTD-containing Berberomeloe majalis blister beetles, and it has been hypothesized that beetle consumption by these birds reduces parasite load (a case of self-medication). We examined this hypothesis by testing diverse organisms against CTD and extracts of B. majalis hemolymph and bodies. Our results show that all three preparations (CTD and extracts of B. majalis) were toxic to a protozoan (Trichomonas vaginalis), a nematode (Meloidogyne javanica), two insects (Myzus persicae and Rhopalosiphum padi) and a tick (Hyalomma lusitanicum). This not only supports the anti-parasitic hypothesis for beetle consumption, but suggests potential new roles for CTD, under certain conditions.


Assuntos
Acaricidas/toxicidade , Antiparasitários/toxicidade , Cantaridina/toxicidade , Besouros , Inseticidas/toxicidade , Animais , Afídeos/efeitos dos fármacos , Feminino , Larva/efeitos dos fármacos , Masculino , Nematoides/efeitos dos fármacos , Carrapatos/efeitos dos fármacos , Trichomonas vaginalis/efeitos dos fármacos
19.
ACS Infect Dis ; 5(3): 345-352, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30701958

RESUMO

Trichomoniasis is caused by the parasitic protozoan Trichomonas vaginalis and is the most prevalent, nonviral sexually transmitted disease. The parasite has shown increasing resistance to the current 5-nitroimidazole therapies indicating the need for new therapies with different mechanisms. T. vaginalis is an obligate parasite that scavenges nucleosides from host cells and then uses salvage pathway enzymes to obtain the nucleobases. The adenosine/guanosine preferring nucleoside ribohydrolase was screened against a 2000-compound diversity fragment library using a 1H NMR-based activity assay. Three classes of inhibitors with more than five representatives were identified: bis-aryl phenols, amino bicyclic pyrimidines, and aryl acetamides. Among the active fragments were 10 compounds with ligand efficiency values greater than 0.5, including five with IC50 values <10 µM. Jump-dilution and detergent counter screens validated reversible, target-specific activity. The data reveals an emerging SAR that is guiding our medicinal chemistry efforts aimed at discovering compounds with nanomolar potency.


Assuntos
Antiprotozoários/química , Inibidores Enzimáticos/química , N-Glicosil Hidrolases/antagonistas & inibidores , Proteínas de Protozoários/antagonistas & inibidores , Trichomonas vaginalis/enzimologia , Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Ligantes , N-Glicosil Hidrolases/genética , N-Glicosil Hidrolases/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Vaginite por Trichomonas/parasitologia , Trichomonas vaginalis/química , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/genética
20.
Int J Antimicrob Agents ; 53(2): 116-127, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30612993

RESUMO

Trichomonas vaginalis is the causative agent of the most common non-viral sexually transmitted disease worldwide. The infection may be associated with severe complications, including infertility, preterm labour, cancer and an increased risk of human immunodeficiency virus (HIV) transmission. Treatment remains almost exclusively based on 5-nitroimidazoles, but resistance is on the rise. This article provides an overview of clinically evaluated systemic and topical treatment options for human trichomoniasis and summarises the current state of knowledge on various herbal, semisynthetic and synthetic compounds evaluated for their anti-Trichomonas efficacy in vitro.


Assuntos
Antiprotozoários/uso terapêutico , Resistência a Medicamentos/genética , Doenças Sexualmente Transmissíveis/tratamento farmacológico , Vaginite por Trichomonas/tratamento farmacológico , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/genética , Feminino , Humanos , Iridaceae/química , Lamiaceae/química , Metronidazol/uso terapêutico , Nifuratel/uso terapêutico , Extratos Vegetais/farmacologia , Doenças Sexualmente Transmissíveis/parasitologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA