Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 826
Filtrar
1.
PLoS Negl Trop Dis ; 14(1): e0007481, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961864

RESUMO

BACKGROUND: Crystal violet (CV) was used for several years in blood banks to eliminate the parasite Trypanosoma cruzi in endemic areas in order to prevent transfusion-transmitted Chagas disease. One mechanism of action described for CV involves inhibition of proline uptake. In T. cruzi, proline is essential for host cell infection and intracellular differentiation among other processes, and can be obtained through the proline permease TcAAAP069. METHODOLOGY/PRINCIPAL FINDINGS: CV inhibited proline transporter TcAAAP069 and parasites overexpressing this permease were 47-fold more sensitive to this compound than control parasites. Using CV as reference molecule, loratadine, cyproheptadine, olanzapine and clofazimine were identified as structurally related compounds to CV (structural analogues) by in silico drug repurposing through a similarity-based virtual screening protocol. All these already-approved drugs for clinical use inhibited TcAAAP069 activity with different efficacies and also presented trypanocidal action in epimastigotes, trypomastigotes and amastigotes of the Y, CL Brener and Dm28c T. cruzi strains. Finally, a synergistic effect between benznidazole and the CV chemical analogues was evidenced by combination and dose-reduction indexes values in epimastigotes and trypomastigotes of the Y strain. CONCLUSIONS/SIGNIFICANCE: Loratadine, cyproheptadine and clofazimine inhibit TcAAAP069 proline transporter and also present trypanocidal effect against all T. cruzi life stages in strains from three different DTUs. These CV structural analogues could be a starting point to design therapeutic alternatives to treat Chagas disease by finding new indications for old drugs. This approach, called drug repurposing is a recommended strategy by the World Health Organization to treat neglected diseases, like Chagas disease, and combination therapy may improve the possibility of success of repositioned drugs.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inibidores , Violeta Genciana/química , Violeta Genciana/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Doença de Chagas/parasitologia , Clofazimina/farmacologia , Simulação por Computador , Reposicionamento de Medicamentos , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Loratadina/farmacologia , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Tripanossomicidas/química , Trypanosoma cruzi/genética , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/metabolismo
2.
Vet Parasitol ; 277: 108989, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794909

RESUMO

The aim of this study was to investigate whether the combination of thymol with eugenol has a synergistic effect on the immature life stages of Rhipicephalus sanguineus sensu lato (s.l.), to evaluate the cost-benefit ratio of using these compounds in combination, and to develop a formulation combining thymol with eugenol with activity on immature stages of R. sanguineus s.l. To evaluate synergism, thymol and eugenol, combined (ratio 1:1) or not, were tested at concentrations of 2.5, 5.0, 10.0, 15.0 and 20.0 mg/mL on unfed larvae and nymphs using a larval packet test, and 0.625, 1.25, 2.5, 5.0 and 10 mg/mL on engorged larvae and nymphs using an immersion test. A cost estimate was calculated to produce 1 L of a solution containing a concentration of thymol and eugenol, combined or not, that could cause a tick mortality rate greater than 95 %. Finally, a formulation was developed, consisting of a micellar dispersion containing polymers (MDP), with thymol + eugenol (1:1), at concentrations of 2.5, 5.0, 10.0, 15.0 and 20.0 mg/mL, and the activity was evaluated on unfed and engorged larvae and nymphs. For unfed larvae and nymphs, concentrations of 2.5 and 5.0 mg/mL and 2.5, 5.0 and 10.0 mg/mL, respectively, presented synergistic effects. In tests with engorged larvae and nymphs, respective concentrations of 0.625, 1.25 and 2.5 mg/mL and 2.5 and 5.0 mg/mL had synergistic effects. The estimated costs for producing a solution of 1 L with efficacy greater than 95 % was $5.97 using only thymol (15 mg/mL), $ 5.93 using only eugenol (15 mg/mL), and $ 3.97 using thymol + eugenol (1:1 - 5,0 mg/mL). In tests with MDP, the combination of thymol + eugenol resulted in a mortality rate higher than 95 % at concentration of 10 mg/mL for unfed and engorged larvae and nymphs. Thus, the combination of thymol + eugenol, depending on the concentration, has synergistic effects and this combination lowers the cost for the active ingredients thymol and eugenol. The combination of thymol + eugenol in MDP had acaricidal activity against immature life stages of R. sanguineus s.l.


Assuntos
Eugenol/farmacologia , Rhipicephalus sanguineus/efeitos dos fármacos , Timol/farmacologia , Acaricidas/economia , Acaricidas/farmacologia , Animais , Sinergismo Farmacológico , Eugenol/economia , Estágios do Ciclo de Vida/efeitos dos fármacos , Timol/economia
3.
Aquat Toxicol ; 218: 105337, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31739108

RESUMO

To understand effects of two widely used antidepressant on the antioxidant defense mechanism in the marine rotifer Brachionus koreanus, we assessed acute toxicity and measured population growth, reactive oxygen species (ROS) levels, glutathione (GSH) levels, and antioxidant enzymatic activities (GST, GR, and SOD) in response to fluoxetine hydrochloride (FLX) and sertraline hydrochloride (SER). The no observed effect concentration-24 h of fluoxetine and sertraline were 1000 µg/L and 450 µg/L, respectively, whereas the median lethal concentration (LC50)-24 h of fluoxetine and sertraline were 1560 µg/L and 507 µg/L, respectively. Both fluoxetine and sertraline caused significant reduction (P < 0.05) in the population growth rate indicating that both antidepressants have a potential adverse effect on life cycle parameters of B. koreanus. The intracellular ROS level and GSH level were significantly modulated (P < 0.05) in response to fluoxetine and sertraline. In addition, antioxidant enzymatic activities have shown significant modulation (P < 0.05) in response to FLX and SER in B. koreanus. Furthermore, transcriptional profiles of antioxidant genes (GSTs, SODs, and GR) have shown modulation in response to FLX compared to SER-exposed B. koreanus. Our results indicate that fluoxetine and sertraline induce oxidative stress, leading to reduction in the population density and modulation of antioxidant defense mechanism in the marine rotifer B. koreanus.


Assuntos
Antidepressivos/toxicidade , Fluoxetina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Rotíferos/efeitos dos fármacos , Sertralina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Antioxidantes/metabolismo , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Estágios do Ciclo de Vida/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Rotíferos/crescimento & desenvolvimento , Rotíferos/metabolismo
4.
Chemosphere ; 242: 125209, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31677519

RESUMO

The fungicide myclobutanil (MYC) is a common contaminant found in surface water. The aim of this study was to determine the acute toxicity, developmental effects, bioconcentration factor (BCF) and potential bio-molecular mechanisms of MYC toxicity in zebrafish. Susceptibility to MYC toxicity was life-stage dependent with adult fish being the most sensitive (96 h-LC50, 6.34 mg/L) followed by 72 h post-hatch (hph) larvae (8.90 mg/L), 12 hph larvae (20.53 mg/L) and embryos (42.54 mg/L). Zebrafish embryos and larvae (12 hph) responded with decreased hatching, heartbeat and growth, as well as abnormal spontaneous movement and development. BCFs were calculated by quantifying MYC concentrations from different tissues of adult zebrafish exposed to MYC for up to 11 days. Highest BCFs were obtained from gills (18.25 ±â€¯0.07), followed by viscera (16.78 ±â€¯0.04), head (13.13 ±â€¯0.08) and muscle (8.96 ±â€¯0.10). MYC (0.5 mg/L) inhibited gene expression related to cholesterol synthesis pathway, including 24-dehydrocholesterol reductase (DHCR24), 7-dehydrocholesterol reductase (DHCR7), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCRa), HMGCRb, farnesyl-diphosphate farnesyltransferase 1(FDFT1), squa-lene epoxidase (SQLE), isopentenyl-diphosphate delta isomerase 1 (IDI1) and CYP51, while no cholesterol changes were observed in the MYC treated group. These results will contribute to the literature assessing the environmental risk of MYC in aquatic environment.


Assuntos
Colesterol/biossíntese , Nitrilos/toxicidade , Triazóis/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , 32418 , Colesterol/genética , Embrião não Mamífero/efeitos dos fármacos , Feminino , Fungicidas Industriais/toxicidade , Larva/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Fatores Sexuais , Peixe-Zebra/metabolismo
5.
Vet Parasitol ; 277: 109011, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31841946

RESUMO

In the present study, the tick isolates were collected from Assam state, of northeastern region (NER) and characterized using in vitro bioassay, biochemical and molecular assays. Comparing LC50 value of susceptible IVRI-I and larvae of field isolates, revealed that RF against deltamethrin was highest for Morigaon (MGN = 21.8) and lowest for Sonitpur (SNP = 3.3) isolate. The RF against cypermethrin was highest for Nagaon (NGO = 5.0) and lowest for Barpeta (BPT = 1.2) isolate. Against coumaphos, the highest RF of 4.5 was calculated for BPT (4.5) and lowest for NGO (1.3) isolate. While using adults based assay, highest RF of 24.68 against deltamethrin and lowest RF of 4.96 was determined for MGN and SNP isolate, respectively. In contrast to the results obtained using larvae, against cypermethrin, highest RF was recorded for Kamrup Metropolitan (KMP) while it was NGO isolate using larvae. In case of coumaphos, both larvae and adults of BPT isolate were also highly resistant and lowest RF was detected in SNP (2.30) isolate. All the isolates were susceptible to ivermectin. A significant correlation (p < 0.01) between deltamethrin resistance and higher expression of glutathioneS-transferase was observed while no correlation with esterase and monooxygenase enzymes activity was noted. For the development of possible ecofriendly control measure, different accessions of Argemone mexicana and Datura metel plant species were collected, extracted and screened against adult ticks. Two accessions, NEA-03 and NED-06 collected from Amlighat and Diphu (East Karbi Anglong) were more than 90 % effective. Further dose response study of these accessions determined the LC50 values of 4.86 and 3.96 %, respectively.The resistance status of the collected tick isolates was compared with the data generated from other regions having higher livestock population and possibility of exploitation of identified plant species for the development of natural antitick product is discussed.


Assuntos
Acaricidas/farmacologia , Resistência a Inseticidas , Extratos Vegetais/farmacologia , Rhipicephalus/efeitos dos fármacos , Animais , Bovinos , Índia , Resistência a Inseticidas/efeitos dos fármacos , Dose Letal Mediana , Estágios do Ciclo de Vida/efeitos dos fármacos
6.
Chemosphere ; 239: 124802, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31521933

RESUMO

Pesticides are usually present as mixtures in water environments. Evaluating the toxic effects of individual pesticide may not be enough for protecting ecological environment due to interactions among substances. In this study, we aimed to examine the lethal doses and gene expression changes in zebrafish (Danio rerio) upon exposure to individual and mixture pesticides [malathion (MAL), chlorpyrifos (CHL) and lambda-cyhalothrin (LCY)]. Individual pesticide toxicity evaluation manifested that the toxicity of the three pesticides to D. rerio at various developmental stages (embryonic, larval, juvenile and adult stages) followed the order of LCY > CHL > MAL. On the contrary, the least toxicity to the animals was discovered from MAL. Most of the tested pesticides displayed lower toxicities to the embryonic stage compared with other life stages of zebrafish. Synergistic effects were monitored from two binary mixtures of LCY in combination with MAL or CHL and ternary mixture of MAL + CHL + LCY. The expressions of 16 genes involved in oxidative stress, immunity system, cell apoptosis and endocrine disruption at the mRNA level revealed that embryonic zebrafish were influenced by the individual or mixture pesticides. The expressions of Tnf, P53, TRα, Crh and Cyp19a exerted greater variations upon exposure to pesticide mixtures compared with their individual compounds. Collectively, the transcriptional responses of these genes might afford early warning biomarkers for identifying pollutant exposure, and the data acquired from this study provided valuable insights into the comprehensive toxicity of pesticide mixtures to zebrafish.


Assuntos
Misturas Complexas/toxicidade , Larva/efeitos dos fármacos , Praguicidas/toxicidade , Animais , Clorpirifos/toxicidade , Interações Medicamentosas , Disruptores Endócrinos/toxicidade , Estágios do Ciclo de Vida/efeitos dos fármacos , Malation/toxicidade , Nitrilos/toxicidade , Piretrinas/toxicidade , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo
7.
Parasit Vectors ; 12(1): 601, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870406

RESUMO

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


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Apoptose/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Fenalenos/química , Fenalenos/farmacologia , Humanos , Leishmania/citologia , Leishmania/crescimento & desenvolvimento , Leishmaniose/parasitologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Estrutura Molecular
8.
Int J Nanomedicine ; 14: 6073-6101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686803

RESUMO

Background: Amphotericin B (AmB) as a liposomal formulation of AmBisome is the first line of treatment for the disease, visceral leishmaniasis, caused by the parasite Leishmania donovani. However, nephrotoxicity is very common due to poor water solubility and aggregation of AmB. This study aimed to develop a water-soluble covalent conjugate of gold nanoparticle (GNP) with AmB for improved antileishmanial efficacy and reduced cytotoxicity. Methods: Citrate-reduced GNPs (~39 nm) were functionalized with lipoic acid (LA), and the product GNP-LA (GL ~46 nm) was covalently conjugated with AmB using carboxyl-to-amine coupling chemistry to produce GNP-LA-AmB (GL-AmB ~48 nm). The nanoparticles were characterized by dynamic light scattering, transmission electron microscopy (TEM), and spectroscopic (ultraviolet-visible and infrared) methods. Experiments on AmB uptake of macrophages, ergosterol depletion of drug-treated parasites, cytokine ELISA, fluorescence anisotropy, flow cytometry, and gene expression studies established efficacy of GL-AmB over standard AmB. Results: Infrared spectroscopy confirmed the presence of a covalent amide bond in the conjugate. TEM images showed uniform size with smooth surfaces of GL-AmB nanoparticles. Efficiency of AmB conjugation was ~78%. Incubation in serum for 72 h showed <7% AmB release, indicating high stability of conjugate GL-AmB. GL-AmB with AmB equivalents showed ~5-fold enhanced antileishmanial activity compared with AmB against parasite-infected macrophages ex vivo. Macrophages treated with GL-AmB showed increased immunostimulatory Th1 (IL-12 and interferon-γ) response compared with standard AmB. In parallel, AmB uptake was ~5.5 and ~3.7-fold higher for GL-AmB-treated (P<0.001) macrophages within 1 and 2 h of treatment, respectively. The ergosterol content in GL-AmB-treated parasites was ~2-fold reduced compared with AmB-treated parasites. Moreover, GL-AmB was significantly less cytotoxic and hemolytic than AmB (P<0.01). Conclusion: GNP-based delivery of AmB can be a better, cheaper, and safer alternative than available AmB formulations.


Assuntos
Anfotericina B/síntese química , Antiprotozoários/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Anfotericina B/química , Anfotericina B/farmacologia , Animais , Antiprotozoários/química , Candida albicans/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Difusão Dinâmica da Luz , Ergosterol/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/crescimento & desenvolvimento , Estágios do Ciclo de Vida/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Nanopartículas Metálicas/ultraestrutura , Camundongos , Carbonilação Proteica/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Ácido Tióctico/química , Resultado do Tratamento
9.
Aquat Toxicol ; 216: 105294, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31585273

RESUMO

Many ecologically important fishes, including mahi-mahi (Coryphaena hippurus), and their offspring were directly exposed to crude oil following the Deepwater Horizon (DWH) oil spill. Early life stage fish are especially vulnerable to the toxicity of crude oil-derived polycyclic aromatic hydrocarbons (PAHs). In teleosts, yolk sac proteins are the main energy source during development and are usually catabolized into ammonia or urea among other byproducts. Although excretion of these waste products is sensitive to oil exposure, we know little about the underlying mechanisms of this process. In this study, we examined the effects of crude oil on ammonia and urea handling in the early life stages of mahi. Mahi embryos exposed to 30-32 µg L-1 ∑PAH exhibited increased urea excretion rates and greater accumulation of urea in the tissues before hatch suggesting that ammonia, which is highly toxic, was converted into less-toxic urea. Oil-exposed embryos (6.3-32 µg L-1 ∑PAH) displayed significantly increased tissue ammonia levels at 42 hpf and upregulated mRNA levels of ammonia transporters (Rhag, Rhbg and Rhcg1) from 30 to 54 hpf. However, despite increased accumulation and higher expression of ammonia transporters, the larvae exposed to higher ∑PAH (30 µg L-1 ∑PAH) showed reduced ammonia excretion rates after hatch. Together, the increased production of nitrogenous waste reinforces previous work that increased energy demand in oil-exposed embryos is fueled, at least in part, by protein metabolism and that urea synthesis plays a role in ammonia detoxification in oil-exposed mahi embryos. To our knowledge, this study is the first to combine physiological and molecular approaches to assess the impact of crude-oil on both nitrogenous waste excretion and accumulation in the early life stages of any teleosts.


Assuntos
Amônia/metabolismo , Estágios do Ciclo de Vida/efeitos dos fármacos , Perciformes/crescimento & desenvolvimento , Perciformes/metabolismo , Poluição por Petróleo/análise , Petróleo/toxicidade , Ureia/metabolismo , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Larva/efeitos dos fármacos , Perciformes/genética , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Poluentes Químicos da Água/toxicidade
10.
Aquat Toxicol ; 216: 105299, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31593906

RESUMO

Selenium (Se) is an essential trace element of concern that is known to contaminate aquatic ecosystems as a consequence of releases from anthropogenic activities. Selenium is of particular toxicological concern for egg-laying vertebrates as they bioaccumulate Se through the diet and deposit excess Se to embryo-offspring via maternal transfer, a process which has been shown to result in significant teratogenic effects. The purpose of the present study was to determine and compare the in ovo effects of Se exposure on early development of a laboratory model fish species native to North American freshwater systems, the fathead minnow (Pimephales promelas), through two different exposure routes, maternal transfer and microinjection. For maternal transfer studies, fathead minnow breeding groups (3 females: 2 males) were exposed to diets containing Se-background levels (1.21 µg Se/g food, dry mass [dm]) or environmentally relevant concentrations of selenomethionine (SeMet; 3.88, 8.75 and 26.5 µg Se/g food dm) and bred for 28 days. Embryos were collected at different time points throughout the study to measure Se concentrations and to assess teratogenicity in embryos. While exposure to dietary Se did not negatively affect fecundity among treatment groups, the lowest treatment group (3.88 µg Se/g food dm) produced on average the most embryos per day, per female. The maternal transfer of excess Se occurred rapidly upon onset of exposure, reaching steady-state after approximately 14 days, and embryo Se concentrations increased in a dose-dependent manner. The greatest concentrations of maternally transferred Se significantly increased the total proportion of deformed embryo-larval fathead minnows but did not impact hatchability or survival. In a second study, fathead minnow embryos were injected with SeMet at concentrations of 0.00 (vehicle control), 9.73, 13.5 and 18.9 µg Se/g embryo dm. Microinjection of SeMet did not affect hatchability but significantly increased the proportion of deformed embryo-larval fish in a dose-dependent manner. There was a greater proportion of deformed fathead minnows at embryo Se concentrations of 18.9 µg Se/g embryo dm when exposed via microinjection versus maternal transfer at concentrations of 28.4 µg Se/g embryo dm. However, the findings suggest that both exposure routes induced analogous developmental toxicities in early life stage fish at Se concentrations between 9.73 and 13.5 µg Se/g embryo dm. Overall, this study demonstrated that microinjection has utility for studying the effects of Se in embryo-larval fish and is a promising method for the study of early life stage Se exposure in egg-laying vertebrates.


Assuntos
Cyprinidae/embriologia , Embrião não Mamífero/efeitos dos fármacos , Exposição Materna , Microinjeções , Selenometionina/administração & dosagem , Selenometionina/toxicidade , Animais , Antioxidantes/farmacologia , Dieta , Ecossistema , Feminino , Água Doce , Larva/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos , Modelos Lineares , Masculino , Reprodução/efeitos dos fármacos , Selênio/análise , Poluentes Químicos da Água/toxicidade
11.
Top Antivir Med ; 27(3): 123-127, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31634859

RESUMO

Antiretroviral therapy (ART) should be started as soon as possible after HIV diagnosis. Recommended starting ART regimens in patients with any baseline viral load include ictegravir plus tenofovir alafenamide (TAF)/emtricitabine (FTC), dolutegravir (DTG) plus abacavir/lamivudine, DTG plus TAF (or TDF)/FTC, or DTG plus 3TC. Initial laboratory evaluation includes CD4+ cell count, plasma HIV-1 RNA, and testing for HIV reverse transcriptase and protease resistance mutations. ART regimens do not need to be altered for virologic blips due to release of virus from chronically latently infected cells in patients otherwise exhibiting viral suppression. Patients with continuously undetectable viral load on ART pose virtually no risk of transmitting infection through sexual contact. This article is based on a case-based presentation by Michael S. Saag, MD, at the 2018 Clinical Conference at the National Ryan White Conference on HIV Care & Treatment in December 2018 and intended for clinicians who are new to HIV disease management.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Emtricitabina/uso terapêutico , Feminino , Infecções por HIV/transmissão , Transcriptase Reversa do HIV/efeitos dos fármacos , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Inibidores de Integrase/uso terapêutico , Lamivudina/uso terapêutico , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mutação , RNA Viral/sangue , Tenofovir/uso terapêutico , Carga Viral
12.
Int J Parasitol Drugs Drug Resist ; 10: 125-132, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31493763

RESUMO

Visceral leishmaniasis (VL) is associated with treatment complications due to the continued growth of resistant parasites toward currently available pathogen-directed therapeutics. To limit the emergence and combat resistant parasites there is a need to develop new anti-leishmanial drugs and alternative treatment approaches, such as host-directed therapeutics (HDTs). Discovery of new anti-leishmanial drugs including HDTs requires suitable in vitro assay systems. Herein, we modified and evaluated a series of resazurin assays against different life-stages of the VL causing parasite, Leishmania donovani to identify novel HDTs. We further analyzed the synergy of combinatorial interactions between traditionally used pathogen-directed drugs and HDTs for clearance of intracellular L. donovani. The inhibitory concentration at 50% (IC50) of the five evaluated therapies [amphotericin B (AMB), miltefosine, paromomycin, DNER-4, and AR-12 (OSU-03012)] was determined against promastigotes, extracellular amastigotes, and intracellular amastigotes of L. donovani via a resazurin-based assay and compared to image-based microscopy. Using the resazurin-based assay, all evaluated therapies showed reproducible anti-leishmanial activity against the parasite's different life-stages. These results were consistent to the traditional image-based technique. The gold standard of therapy, AMB, showed the highest potency against intracellular L. donovani, and was further evaluated for combinatorial effects with the HDTs. Among the combinations analyzed, pathogen-directed AMB and host-directed AR-12 showed a synergistic reduction of intracellular L. donovani compared to individual treatments. The modified resazurin assay used in this study demonstrated a useful technique to measure new anti-leishmanial drugs against both intracellular and extracellular parasites. The synergistic interactions between pathogen-directed AMB and host-directed AR-12 showed a great promise to combat VL, with the potential to reduce the emergence of drug-resistant strains.


Assuntos
Antiprotozoários/administração & dosagem , Quimioterapia Combinada/métodos , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Anfotericina B/administração & dosagem , Animais , Sinergismo Farmacológico , Interações Hospedeiro-Parasita/efeitos dos fármacos , Humanos , Leishmania donovani/crescimento & desenvolvimento , Leishmaniose Visceral/diagnóstico por imagem , Leishmaniose Visceral/parasitologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Fosforilcolina/administração & dosagem , Fosforilcolina/análogos & derivados , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem
13.
J Trace Elem Med Biol ; 56: 162-168, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473559

RESUMO

BACKGROUND: The pentavalent antimonial compounds are the first drug of choice for leishmania infection, but have several side effects that cause some restriction for use. Extension of nanoparticle use in biological research and proven effectiveness of manganese nanoparticles on fungi and bacteria, along with the lack of information about its antileishmanial effects, have motivated this study. Manganese can induce cell apoptosis by increasing FOXO3a-Bim/PUMA mRNA activation and activating of caspase-3 pathway. METHODS: This study was aimed to examine the efficacy of manganese oxide nanoparticles againstLeishmania major (MRHO/IR/75/ER) in vitro and in vivo. To evaluate the antileishmanial activity of NPs, light microscopic observation was used to determine the number of remaining parasites in each well. The MTT test was used to determine the cytotoxicity effects of Mn2O3 NPs against L. major promastigotes and macrophage cells. The effect of nanoparticles on cultured amastigotes under in vitro conditions was also investigated. The possible apoptosis of L. major by Mn2O3 NPs was evaluated with flow cytometry assay. Additionally, the preventive and therapeutic effects of Mn2O3 NPs in BALB/c mice following cutaneous L. major infection was tested. The effect of Mn2O3 NPs on promastigotes and amastigotes were proven by MTT assay and amastigote assay, respectively. RESULTS: The IC50 value of Mn2O3 NPs against L. major promastigotes and macrophages was 15 and 40 µg ml-1 respectively. The results of flow cytometry showed about 57% of the promastigotes were induced to apoptosis with Mn2O3 NPs. In in vivo studies, the size of the ulcers were significantly reduced, and the survival rate of the mice, in comparison with the control group, was increased. CONCLUSION: Mn2O3 NPs has a beneficial effect on L. major promastigotes in vitro and in vivo and could be considered as a candidate for the treatment of this infection.


Assuntos
Antiprotozoários/farmacologia , Leishmania major/efeitos dos fármacos , Compostos de Manganês/farmacologia , Nanopartículas/química , Óxidos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Leishmania major/crescimento & desenvolvimento , Leishmaniose Cutânea/parasitologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura
14.
Aquat Toxicol ; 216: 105291, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31525644

RESUMO

Most pesticides used in agriculture end up in the aquatic environment through runoff and leaching of treated crops. One of the most commonly used herbicides is glyphosate. This compound or its metabolites are frequently detected in surface water in Europe. In the present study, in vivo and in vitro studies were carried out using the early life stages of rainbow trout (Oncorhynchus mykiss) and the cell line RTL-W1 (a liver cell line from rainbow trout) to characterize the toxic effects of glyphosate at environmentally-realistic concentrations. Both studies were performed using the commercial formulation Roundup® GT Max, and technical-grade glyphosate for the in vitro study. Eyed-stage embryos were exposed for 3 weeks to sub-lethal concentrations (0.1 and 1 mg/L) of glyphosate using Roundup. Numerous toxicity endpoints were recorded such as survival, hatching success, larval biometry, developmental abnormalities, swimming activity, genotoxicity (formamidopyrimidine DNA-glycosylase Fpg-modified comet assay), lipid peroxidation (TBARS), protein carbonyls and target gene transcription. Concentrations neither affected embryonic or larval survival nor increased developmental abnormalities. However, a significant decrease was observed in the head size of larvae exposed to 1 mg/L of glyphosate. In addition, a significant increase in mobility was observed for larvae exposed to glyphosate at 0.1 mg/L. TBARS levels were significantly decreased on larvae exposed to 1 mg/L (a.i.), and cat and cox1 genes were differently transcribed from controls. DNA damage was detected by the Fpg-modified comet assay in RTL-W1 cell line exposed to the technical-grade glyphosate and Roundup formulation. The results suggest that chronic exposure to glyphosate, at environmental concentrations, could represent a potential risk for early life stages of fish.


Assuntos
Glicina/análogos & derivados , Herbicidas/toxicidade , Estágios do Ciclo de Vida/efeitos dos fármacos , Fígado/citologia , Oncorhynchus mykiss/crescimento & desenvolvimento , Animais , Células Sanguíneas/metabolismo , Gatos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Ensaio Cometa , Dano ao DNA , Embrião não Mamífero/efeitos dos fármacos , Exposição Ambiental , Regulação da Expressão Gênica/efeitos dos fármacos , Glicina/toxicidade , Larva/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Mutagênicos/toxicidade , Oncorhynchus mykiss/sangue , Oncorhynchus mykiss/embriologia , Carbonilação Proteica/efeitos dos fármacos , Natação , Poluentes Químicos da Água/toxicidade
15.
Aquat Toxicol ; 215: 105288, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31526926

RESUMO

Pharmaceuticals are used in medical treatment on a large scale and as a waste contaminate freshwater ecosystems. Growing amount of so-called civilization diseases, such as different type of cancer, significantly contribute to this form of pollution. The aim of the present study was to determine how the exposure to chemotherapeutics: cyclophosphamide (CP) and cisplatin (CDDP), at detected in environment concentrations, influence proteome profile, life history and population parameters of naturally setting surface waters Daphnia pulex and Daphnia pulicaria. The parameters important for crustaceans, survivorship and population growth rate, were importantly decreased by CDDP treatment but not influenced by CP. On the contrary, the individual growth rate was affected only by CP and exclusively in the case of D. pulicaria. In both clones treated with CP or CDDP, decreased number of eggs was observed. Interestingly, Daphnia males were less sensitive to tested chemotherapeutic than females. Proteome profile revealed that tested anticancer pharmaceuticals modified expression of some proteins involved in Daphnia metabolism. Moreover, males exposed to CDDP showed increased level of enzymes participating in DNA repair. Summing up, the contaminating environment chemotherapeutics reduced fitness of naturally occurring Daphnia species. In consequence this may affect functioning of the aquatic food webs.


Assuntos
Antineoplásicos/toxicidade , Daphnia/genética , Poluentes Químicos da Água/toxicidade , Análise de Variância , Animais , Cisplatino/toxicidade , Ciclofosfamida/toxicidade , Daphnia/efeitos dos fármacos , Daphnia/crescimento & desenvolvimento , Feminino , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Proteínas/metabolismo , Proteoma/metabolismo
16.
Int J Oncol ; 55(3): 570-584, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31364734

RESUMO

Human papillomavirus (HPV) is the most common sexually transmitted infection, exhibiting a tropism for the epidermis and mucosae. The link between persistent HPV infection and malignancies involving the anogenital tract as well as the head and neck has been well­established, and it is estimated that HPV­related cancers involving various anatomical sites account for 4.5% of all human cancers. Current prophylactic vaccines against HPV have enabled the prevention of associated malignancies. However, the sizeable population base of current infection in whom prophylactic vaccines are not applicable, certain high­risk HPV types not included in vaccines, and the vast susceptible population in developing countries who do not have access to the costly prophylactic vaccines, put forward an imperative need for effective therapies targeting persistent infection. In this article, the life cycle of HPV, the mechanisms facilitating HPV evasion of recognition and clearance by the host immune system, and the promising therapeutic strategies currently under investigation, particularly antiviral drugs and therapeutic vaccines, are reviewed.


Assuntos
Neoplasias/prevenção & controle , Papillomaviridae/efeitos dos fármacos , Infecções por Papillomavirus/tratamento farmacológico , Vacinas contra Papillomavirus/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos , Neoplasias/virologia , Papillomaviridae/crescimento & desenvolvimento , Papillomaviridae/imunologia , Infecções por Papillomavirus/complicações , Vacinas contra Papillomavirus/farmacologia
17.
Acta Parasitol ; 64(3): 612-616, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31286354

RESUMO

PURPOSE: Toxoplasma gondii is a protozoan from phylum Apicomplexa, which causes the toxoplasmosis infection; this one exhibits an apicoplast organelle which assists in the metabolism of isoprenoids and other pivotal mediators for the parasite survival. Statins are drugs that inhibit cholesterol synthesis, blocking the conversion of the substrate HMG-CoA to mevalonate, thus preventing the initial processes of the biosynthesis of these precursors, both in humans and parasite. Our goal was to verify whether the Toxoplasma gondii (RH strain) tachyzoites form pretreated with pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations could affect the infection processes, suggesting direct action on protozoa intracellular proliferation through the inhibition of isoprenoids in the parasite's apicoplast. METHODS: To have the adhesion, infection, and parasite proliferation during experimental infection investigated, HeLa cells (105) were subjected to a 24-hour infection by T. gondii tachyzoites forms of RH strain (5 × 105) pretreated for 30 min with pravastatin and/or simvastatin combined or not with pyrimethamine and sulfadiazine. RESULTS: Combined with conventional drugs at low concentrations pravastatin and simvastatin inhibit the adhesion, invasion, and intracellular proliferation of T. gondii in HeLa cells which are similar to the positive control. CONCLUSION: Pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations can be regarded as a promising, effective alternative to toxoplasmosis treatment with reduced side effects.


Assuntos
Antiprotozoários/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Pravastatina/farmacologia , Pirimetamina/farmacologia , Sinvastatina/farmacologia , Sulfadiazina/farmacologia , Toxoplasma/efeitos dos fármacos , Toxoplasmose/parasitologia , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Células HeLa , Humanos , Toxoplasma/crescimento & desenvolvimento , Toxoplasma/fisiologia , Toxoplasmose/tratamento farmacológico
18.
BMC Genomics ; 20(1): 482, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185901

RESUMO

BACKGROUND: Global biodiversity is decreasing at an alarming rate and amphibians are at the forefront of this crisis. Understanding the factors that negatively impact amphibian populations and effectively monitoring their health are fundamental to addressing this epidemic. Plasma glucocorticoids are often used to assess stress in amphibians and other vertebrates, but these hormones can be extremely dynamic and impractical to quantify in small organisms. Transcriptomic responses to stress hormones in amphibians have been largely limited to laboratory models, and there have been few studies on vertebrates that have evaluated the impact of multiple stressors on patterns of gene expression. Here we examined the gene expression patterns in tail tissues of stream-dwelling salamanders (Eurycea tynerensis) chronically exposed to the stress hormone corticosterone under different temperature regimes. RESULTS: We found unique transcriptional signatures for chronic corticosterone exposure that were independent of temperature variation. Several of the corticosterone responsive genes are known to be involved in immune system response (LY-6E), oxidative stress (GSTM2 and TRX), and tissue repair (A2M and FX). We also found many genes to be influenced by temperature (CIRBP, HSC71, HSP40, HSP90, HSP70, ZNF593). Furthermore, the expression patterns of some genes (GSTM2, LY-6E, UMOD, ZNF593, CIRBP, HSP90) show interactive effects of temperature and corticosterone exposure, compared to each treatment alone. Through a series of experiments we also showed that stressor induced patterns of expression were largely consistent across ages, life cycle modes, and tissue regeneration. CONCLUSIONS: Outside of thermal stressors, the application of transcriptomes to monitor the health of non-human vertebrate systems has been vastly underinvestigated. Our study suggests that transcriptomic patterns harbor stressor specific signatures that can be highly informative for monitoring the diverse stressors of amphibian populations.


Assuntos
Perfilação da Expressão Gênica , Estresse Fisiológico/genética , Urodelos/genética , Urodelos/fisiologia , Animais , Corticosterona/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Estágios do Ciclo de Vida/genética , Temperatura , Transcrição Genética/efeitos dos fármacos , Urodelos/crescimento & desenvolvimento
19.
Aquat Toxicol ; 213: 105222, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31212248

RESUMO

Pharmaceutically active compounds are major contaminants of aquatic environments that show direct and indirect effects on aquatic organisms even at low concentrations. The aim of this study was to assess the effects of the illicit drug methamphetamine and the antidepressant sertraline on clonal marbled crayfish Procambarus virginalis. Crayfish exposed to the environmentally relevant concentrations of methamphetamine of ∼1 µg L-1 did not exhibit significant differences from unexposed controls in distance moved, velocity, and activity level with or without available shelter. Sertraline-exposed (∼1 µg L-1) crayfish were significantly more active, regardless of available shelter, and moved greater distances when shelter was available, compared to control crayfish. Crayfish exposed to methamphetamine and sertraline spent significantly more time outside the shelters compared to controls. Sertraline-exposed crayfish spawned more frequently and showed higher mortality than controls. The results suggest that the low environmental concentrations of the tested compounds could alter the behavior and life history traits of crayfish, resulting in higher reproductive effort and mortality.


Assuntos
Organismos Aquáticos/efeitos dos fármacos , Organismos Aquáticos/crescimento & desenvolvimento , Astacoidea/efeitos dos fármacos , Astacoidea/crescimento & desenvolvimento , Comportamento Animal/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos , Metanfetamina/toxicidade , Sertralina/toxicidade , Animais , Invertebrados , Poluentes Químicos da Água/toxicidade
20.
Methods Mol Biol ; 1965: 173-186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31069675

RESUMO

The reproductive cycle encompasses processes such as sex organ differentiation and development in the early life stages and maturation of the gametes in the adult organism. During the early life stages, critical developmental programming of the endocrine and reproductive systems occurs, and exposure to chemicals during these critical developmental windows can result in impaired reproductive function later in life. It is therefore important to evaluate long-term consequences of early life stage exposure to endocrine-disrupting chemicals. The African clawed frog Xenopus tropicalis has several characteristics that facilitate studies of developmental and reproductive toxicity. Here I present a X. tropicalis life cycle test protocol including study design, exposure regimes, and endpoints for chemical disruption of sex differentiation, gonadal and Müllerian duct development, the thyroxin-regulated metamorphosis, estrogen synthesis (activity of the CYP19 aromatase enzyme), spermatogenesis, oogenesis, puberty and fertility.


Assuntos
Gametogênese/efeitos dos fármacos , Ductos Paramesonéfricos/crescimento & desenvolvimento , Xenopus/crescimento & desenvolvimento , Animais , Embrião não Mamífero/efeitos dos fármacos , Feminino , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Metamorfose Biológica/efeitos dos fármacos , Modelos Animais , Ductos Paramesonéfricos/efeitos dos fármacos , Diferenciação Sexual , Tiroxina/metabolismo , Xenopus/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA