Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 75
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Toxicol In Vitro ; 68: 104946, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679257

RESUMO

No carcinogenesis or mutagenesis studies have been carried out with etomidate. The current study showed that etomidate has weak cytotoxic potential after 48 h exposure in human lymphocytes and has no hemolytic activity. The weak cytotoxicity seems to be related with redox imbalance of etomidate (40.9 and 81.9 µM) treated lymphocytes. At both etomidate concentrations, a slight decrease of the levels of GSH intracellular content and a significant increase in the amount of carbonylated proteins were observed after 48 h. The contribution of oxidative stress to genetic toxicity was only perceived when the enzyme Fpg was applied in the comet assay. Etomidate (40.9 and 81.9 µM) is a weak generator of oxidative DNA damage in lymphocytes. These damages to DNA probably were repaired, since no DNA strand breaks were detected in the standard alkaline comet assay (in the presence or absence of hepatic S9 microsomal fraction) without Fpg. Also, no micronucleated lymphocytes or carrying chromosomal aberrations were observed. Finally, etomidate (2046.8 and 4093.5 µM) was not mutagenic in the Salmonella/microsome mutagenicity assay, which used four Salmonella typhimurium strains (TA97a, TA98, TA100, and TA102) to detect frameshift and base-substitution mutations. In summary, etomidate is a weak oxidative DNA damaging anesthetic and is devoid of mutagenic properties in eukaryotic and prokaryotic models.

2.
Colloids Surf B Biointerfaces ; 193: 111148, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32512371

RESUMO

Nowadays, infections caused by fungi and protists constitute a serious problem for public health services. The limited number of treatment options coupled with the increasing number of resistant microorganisms makes necessary the development of new non-toxic antifungal and antiprotozoal agents. Cationic amino acid-based rhamnolipids have been recently prepared by our group and exhibited good antibacterial activity. In this work, the antifungal, antibiofilm and antiprotozoal activity of these new rhamnolipids was investigated against a collection of fluconazole-resistant strains of different Candida species and Acanthamoeba castellanii, respectively. The arginine-RLs exhibited good antifungal activity against all fluconazole-resistant Candida spp. strains tested at MICs ranging from 6.5 to 20.7 mg/L. Their mechanism of action involves alterations in the permeability of the cell membranes that provoke death by apoptosis. The Arginine based-RLs also disperse Candida biofilms at low concentrations, similar to the MICs. All RLs tested (anionic and cationic) showed antiprotozoal activity, the arginine derivatives had the best activity killing the Acanthamoeba castellanii at concentrations of 4 mg/L. Interestingly, these surfactants have a wide range of action against yeast and A. castellanii in which they do not show toxicity against keratinocytes and fibroblasts. These results indicate that these new rhamnolipids have a sufficiently wide safety margin to be considered good candidates for several pharmaceutical applications such as combating fungal resistance and microbial biofilms and the formulation of antiprotozoal drugs.

3.
Future Microbiol ; 15: 177-188, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32077323

RESUMO

The emergence of Candida spp. with resistance to antifungal molecules, mainly the azole class, is an increasing complication in hospitals around the globe. Aim: In the present research, we evaluated the synergistic effects of ketamine with two azole derivatives, itraconazole and fluconazole, on strains of Candida spp. to fluconazole. Materials & methods: The drug synergy was evaluated by quantifying the fractional inhibitory concentration index and by fluorescence microscopy and flow cytometry techniques. Results: Our achievements showed a synergistic effect between ketamine in addition to the two antifungal agents (fluconazole and itraconazole) against planktonic cells and biofilms of Candida spp. Conclusion: This combination promoted alteration of membrane integrity, generation of reactive oxygen species, damage to and DNA and externalization of phosphatidylserine.

4.
Toxicol In Vitro ; 62: 104718, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31706955

RESUMO

Ketamine is a potent uncompetitive NMDA receptor antagonist that provides amnesia, analgesia, environmental dissociation and immobility, where it has its cytotoxic effect well described in the literature. However, the work on its genotoxic/mutagenic potentials are scarce and insufficient and does not allow a reasonable evaluation of its role. Thus, in the present work, we decided to evaluate the genotoxic and mutagenic effects of ketamine on human peripheral blood leukocytes (PBLs) and Salmonella typhimurium (TA98, TA97a, TA100, and TA102) through several well-established experimental protocols based on different parameters in the presence or not of exogenous metabolizing S9 fraction. Our data revealed that ketamine induces a weak cytotoxic effect on human PBLs after 24 h and is devoided of hemolytic effects. A small amount of DNA strand breaks levels were detected in the modified comet assay (employment of FPG enzyme) only at highest concentrations (500 and 700 µg/mL) of ketamine, highlighting our pro-oxidant data regarding ketamine. However, the oxidative DNA lesions were almost completely repaired which reflects in the lack of mutagenesis (micronuclei and chromosomal aberrations) on human PBLs and no increases in revertants numbers on S. typhimurium/microsome test (500 to 5000 µg/plate). In summary, ketamine is a weak oxidative DNA damaging agent and is devoid of mutagenic properties on eukaryotic and prokaryotic models.


Assuntos
Anestésicos Dissociativos/toxicidade , Ketamina/toxicidade , Leucócitos/efeitos dos fármacos , Mutagênicos/toxicidade , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Aberrações Cromossômicas/induzido quimicamente , Ensaio Cometa , Quebras de DNA , Dano ao DNA , Hemólise/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Testes de Mutagenicidade , Estresse Oxidativo
5.
Obes Surg ; 29(3): 917-927, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30415354

RESUMO

BACKGROUND: Bariatric surgery leads to several anatomo-physiological modifications that may affect pharmacokinetic parameters and consequently alter the therapeutic effect of drugs, such as antibiotics. The pharmacokinetics of oral amoxicillin after Roux-en-Y gastric bypass (RYGB) surgery is unknown. OBJECTIVES: The objective of this study was to evaluate the impact of bariatric surgery on the pharmacokinetics of amoxicillin. METHODS: This study was performed as a randomized, open-label, single-dose clinical trial, with two periods of treatment, in which obese subjects (n = 8) received an amoxicillin 500 mg capsule orally before and 2 months after the RYGB surgery. The amoxicillin plasma concentration was determined by liquid chromatography coupled to mass spectrometry (LC-MS/MS). RESULTS: After the surgery, the mean weight loss was 17.03 ± 5.51 kg, and mean body mass index (BMI) decreased from 46.21 ± 2.82 to 38.82 ± 3.32 kg/m2. The mean amoxicillin area under the plasma concentration versus time curve from time zero to the time of the last quantifiable concentration (AUC0-tlast) increased significantly (3.5-fold); the maximum plasma concentration (Cmax) increased 2.8-fold after the bariatric surgery. No correlation was found between amoxicillin absorption, BMI, and weight loss percentage. CONCLUSION: The alterations observed in the amoxicillin pharmacokinetics suggest that obese subjects included in this trial had a substantially increase in amoxicillin systemic exposure after RYGB surgery. However, despite this increase, its exposure was lower than the values reported for non-obese volunteers. TRIAL REGISTRATION: Identifiers: NCT03588273.


Assuntos
Amoxicilina/farmacocinética , Antibacterianos/farmacocinética , Derivação Gástrica , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Perda de Peso/fisiologia , Administração Oral , Adulto , Amoxicilina/administração & dosagem , Amoxicilina/sangue , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Índice de Massa Corporal , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/sangue , Espectrometria de Massas em Tandem
6.
Cell Tissue Bank ; 19(3): 373-382, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29380095

RESUMO

Tissue bioengineering development is a global concern and different materials are studied and created to be safe, effective and with low cost. Nile Tilapia skin had shown its biological potential as covers for the burn wound. This study evaluates the tilapia skin histological, collagen properties and tensiometric resistance, after treatment by different sterilization methods. Tilapia skin samples were submitted to two sterilization processes: (1) chemical, which consisted in two 2% chlorhexidin baths, followed by sequential baths in increasing glycerol concentrations; and (2) radiation, when glycerolized skin samples were submitted to gamma radiation at 25, 30 and 50 kGy. Microscopic analyzes were performed through Haematoxylin-eosin and Picrosirius Red under polarized light. For tensiometric analysis, traction tests were performed. Glycerol treated skin presented a discrete collagen fibers disorganization within the deep dermis, while irradiated skin did not show any additional change. Throughout the steps of chemical sterilization, there was a higher proportion of collagen with red/yellow birefringence (type I) in the skin samples up to the first bath in chlorhexidin, when compared to samples after the first two glycerol baths (P < 0.005). However, there was no difference in relation to total collagen between groups. In irradiated skin, there was a larger total collagen preservation when using until 30 kGy (P < 0.005). Tensiometric evaluation did not show significant differences in relation to maximum load in the groups studied. We concluded that chemical and radiation (25 and 30 kGy) are efficient methods to sterilize Nile Tilapia skin without altering its microscopic or tensiometric characteristics.


Assuntos
Ciclídeos/microbiologia , Colágeno/análise , Pele/microbiologia , Pele/ultraestrutura , Esterilização/métodos , Animais , Queimaduras/terapia , Raios gama , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Engenharia Tecidual
7.
Microb Pathog ; 117: 32-42, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29229505

RESUMO

The increased incidence of candidemia in terciary hospitals worldwide and the cross-resistance frequency require the new therapeutic strategies development. Recently, our research group demonstrated three semi-synthetic naphthofuranquinones (NFQs) with a significant antifungal activity in a fluconazole-resistant (FLC) C. tropicalis strain. The current study aimed to investigate the action's preliminary mechanisms of NFQs by several standardized methods such as proteomic and flow cytometry analyzes, comet assay, immunohistochemistry and confocal microscopy evaluation. Our data showed C. tropicalis 24 h treated with all NFQs induced an expression's increase of proteins involved in the metabolic response to stress, energy metabolism, glycolysis, nucleosome assembly and translation process. Some aspects of proteomic analysis are in consonance with our flow cytometry analysis which indicated an augmentation of intracellular ROS, mitochondrial dysfunction and DNA strand breaks (neutral comet assay and γ-H2AX detection). In conclusion, our data highlights the great contribution of ROS as a key event, probably not the one, associated to anti-candida properties of studied NFQs.


Assuntos
Antifúngicos/farmacologia , Candida tropicalis/efeitos dos fármacos , Candida tropicalis/metabolismo , Farmacorresistência Fúngica/efeitos dos fármacos , Farmacorresistência Fúngica/fisiologia , Naftoquinonas/farmacologia , Proteômica , Espécies Reativas de Oxigênio/metabolismo , Antifúngicos/síntese química , Antifúngicos/química , Candida tropicalis/genética , Candidemia/microbiologia , Ciclo Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , DNA Fúngico/genética , Metabolismo Energético/efeitos dos fármacos , Fluconazol/farmacologia , Glicólise/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mitocôndrias/efeitos dos fármacos , Naftoquinonas/síntese química , Naftoquinonas/química , Estresse Psicológico
8.
Int Braz J Urol ; 44(1): 172-179, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29064652

RESUMO

PURPOSE: To assess the impact of sperm retrieval on the gonadal function of rats with impaired spermatogenesis by comparing testicular sperm extraction (TESE) to aspiration (TESA). The efficacy of these procedures to sperm obtainment was also compared. MATERIALS AND METHODS: A pilot study showed impaired spermatogenesis, but normal testosterone (T) production after a bilateral orchidopexy applied to 26 rats, which were randomly assigned into four groups: TESE (n=7), TESA (n=7), SHAM (n=6) and Control (n=6). The T levels were measured through comparative analysis after the orchidopexy. RESULTS: There was no statistical difference in the animal's baseline T levels after orchidopexy in comparison to the controls: the TESE and TESA groups, 6.66±4.67ng/mL; the SHAM group (orchidopexy only), 4.99±1.96ng/mL; and the Control, 4.75±1.45ng/ mL, p=0.27. Accordingly, no difference was found in the postoperative T levels: TESE, 5.35±4.65ng/mL; TESA, 3.96±0.80ng/mL; SHAM, 3.70±1.27ng/mL; p=0.4. The number of sperm cells found through TESE (41.0±7.0) was significantly larger than that found through TESA (21.3±8.1, p=0.001). Moreover, higher tissue weight was found through TESE (0.09±0.02g versus 0.04±0.04g, p=0.04). CONCLUSIONS: The testicular sperm capture performed in rats through extraction or aspiration, after orchidopexy, did not significantly decrease the T levels. The amount of sperm found through testicular sperm extraction was higher than that through testicular sperm aspiration.


Assuntos
Motilidade Espermática/fisiologia , Recuperação Espermática , Espermatogênese/fisiologia , Espermatozoides/fisiologia , Testículo/fisiologia , Animais , Masculino , Modelos Animais , Orquidopexia/métodos , Projetos Piloto , Distribuição Aleatória , Ratos , Ratos Wistar , Recuperação Espermática/efeitos adversos , Testículo/cirurgia , Testosterona/biossíntese
9.
Environ Sci Pollut Res Int ; 24(18): 15454-15461, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28510803

RESUMO

Pesticides are a complex mixture of chemicals used to protect crops from a number of pests and diseases. They have been considered as potential mutagenic agents. This study aims at evaluation of the mutagenic effect of pesticide exposure to agricultural workers through chromosomal aberrations (CA) and micronucleus (MN) assay in peripheral blood lymphocytes and oral mucosal cells, respectively. The exposed group was consisted with 97 farmers, while the control (un-exposed) group consisted of 55. The results showed a significant (p < 0.05) increase in frequency of CA and MN in the exposed group. Both CA and MN profiles were linked to a significant (p < 0.05) co-relation with the confounding factors such as smoking habits, alcohol, vegetables, tea/coffee, vitamins, and sweetener consumptions. More cytogenetic events were denoted in smoking and alcohol consumption as well as non-personal protective equipment (non-PPE) and low/no vegetables user farmers. In conclusion, a deficiency of dietary and medicaments-derived antioxidants, while consumption of alcohol and tobacco, as well as effects of radiation, heavy metal poisoning (especially from sweeteners), and non-PPE using habits, may contribute cytogenetic damage to the workers.


Assuntos
Aberrações Cromossômicas , Mutagênicos/toxicidade , Exposição Ocupacional , Praguicidas/toxicidade , Adolescente , Adulto , Idoso , Consumo de Bebidas Alcoólicas , Brasil , Dano ao DNA , Dieta , Fazendeiros , Humanos , Estilo de Vida , Linfócitos , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Fumar , Adulto Jovem
10.
Microb Pathog ; 107: 341-348, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28411060

RESUMO

Recent research has shown broad antifungal activity of the classic antidepressants selective serotonin reuptake inhibitors (SSRIs). This fact, combined with the increased cross-resistance frequency of the genre Candida regarding the main treatment today, fluconazole, requires the development of novel therapeutic strategies. In that context, this study aimed to assess the antifungal potential of fluoxetine, sertraline, and paroxetine against fluconazole-resistant Candida spp. planktonic cells, as well as to assess the mechanism of action and the viability of biofilms treated with fluoxetine. After 24 h, the fluconazole-resistant Candida spp. strains showed minimum inhibitory concentration (MIC) in the ranges of 20-160 µg/mL for fluoxetine, 10-20 µg/mL for sertraline, and 10-100.8 µg/mL for paroxetine by the broth microdilution method (M27-A3). According to our data by flow cytometry, each of the SSRIs cause fungal death after damaging the plasma and mitochondrial membrane, which activates apoptotic signaling pathways and leads to dose-dependant cell viability loss. Regarding biofilm-forming isolates, the fluoxetine reduce mature biofilm of all the species tested. Therefore, it is concluded that SSRIs are capable of inhibit the growth in vitro of Candida spp., both in planktonic form, as biofilm, inducing cellular death by apoptosis.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Candida/citologia , Candida/genética , Candida/crescimento & desenvolvimento , Contagem de Células , Morte Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , DNA Fúngico/efeitos dos fármacos , Fibroblastos/microbiologia , Citometria de Fluxo , Técnicas In Vitro , Potenciais da Membrana , Camundongos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Paroxetina/farmacologia , Plasma/efeitos dos fármacos , Inibidores de Captação de Serotonina/administração & dosagem , Sertralina/farmacologia
11.
J Ethnopharmacol ; 198: 460-467, 2017 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-28077331

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Casearia sylvestris is a medicinal plant traditionally used to treat snakebites, wounds, inflammation and gastric ulcers and scientific supports for have demonstrated its antitumor, antihyperlipidemic and antiparasitic properties. AIM OF THE STUDY: To assess the effects of a fraction with casearins (FC) on adult mice using classical experimental models of animal behavior and theoretical calculations to verify the interaction of Casearin X (Cas X) with neuron receptors. MATERIALS AND METHODS: Animals divided in 6 groups (n=9/group) were intraperitoneally treated with vehicle (DMSO 4%), FC (2.5, 5, 10 and 25mg/kg/day) and diazepam (2mg/kg) for 7 days. Thirty minutes after the last dose of treatment, acute toxicity and behavioral experiments were performed. RESULTS: The highest dose of FC (25mg/kg/day) caused diarrhea, weight loss and death of one animal. Elevated plus maze test showed that lower doses [2.5mg/kg/day (36.4±5.1s) and 5mg/kg/day (43.9±6.2s)] increased the time spent in open arms (TSOA). Open field test revealed reduction in the number of crossings (54.9%, 51.1%, 48% and 67.7% for 2.5, 5, 10 and 25mg/kg/day, respectively) in all doses of FC studied and decrease of rearings at 25mg/kg/day (p<0.05). Computational calculations showed that the inhibition constant (Ki) for the Cas X-D1 complex is up to 1000-fold more favourable than the Cas X-GABAA complex. All ∆G° values obtained for Cas X-D1 complexes were more negative than those seen with Cas X-GABAA complexes. CONCLUSIONS: Findings indicate a probable anxiolytic action of the FC since it reduces the number of crossings and rearings and prolonged the time spent in open arms, without sedative and myorelaxant effects, probably due to the interaction of Cas X with dopaminergic system.


Assuntos
Comportamento Animal/efeitos dos fármacos , Casearia/química , Diterpenos/farmacologia , Extratos Vegetais/farmacologia , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/isolamento & purificação , Ansiolíticos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Simulação por Computador , Diazepam/farmacologia , Diterpenos/administração & dosagem , Diterpenos/isolamento & purificação , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/toxicidade
12.
Chem Biodivers ; 13(6): 727-36, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27128202

RESUMO

Endophytic actinobacteria from the Brazilian medicinal plant Lychnophora ericoides were isolated for the first time, and the biological potential of their secondary metabolites was evaluated. A phylogenic analysis of isolated actinobacteria was accomplished with 16S rRNA gene sequencing, and the predominance of the genus Streptomyces was observed. All strains were cultured on solid rice medium, and ethanol extracts were evaluated with antimicrobial and cytotoxic assays against cancer cell lines. As a result, 92% of the extracts showed a high or moderate activity against at least one pathogenic microbial strain or cancer cell line. Based on the biological and chemical analyses of crude extracts, three endophytic strains were selected for further investigation of their chemical profiles. Sixteen compounds were isolated, and 3-hydroxy-4-methoxybenzamide (9) and 2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone (15) are reported as natural products for the first time in this study. The biological activity of the pure compounds was also assessed. Compound 15 displayed potent cytotoxic activity against all four tested cancer cell lines. Nocardamine (2) was only moderately active against two cancer cell lines but showed strong activity against Trypanosoma cruzi. Our results show that endophytic actinobacteria from L. ericoides are a promising source of bioactive compounds.


Assuntos
Actinobacteria/isolamento & purificação , Actinobacteria/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Antiprotozoários/farmacologia , Asteraceae/microbiologia , Produtos Biológicos/farmacologia , Metabolismo Secundário , Actinobacteria/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Brasil , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plantas Medicinais/microbiologia , Relação Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacos
13.
Antimicrob Agents Chemother ; 60(6): 3551-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27021328

RESUMO

The incidence of fungal infections and, in particular, the incidence of fungal antibiotic resistance, which is associated with biofilm formation, have significantly increased, contributing to morbidity and mortality. Thus, new therapeutic strategies need to be developed. In this context, natural products have emerged as a major source of possible antifungal agents. Berberine is a protoberberine-type isoquinoline alkaloid isolated from the roots, rhizomes, and stem bark of natural herbs, such as Berberis aquifolium, Berberis vulgaris, Berberis aristata, and Hydrastis canadensis, and of Phellodendron amurense Berberine has been proven to have broad antibacterial and antifungal activity. In the present study, the potential antifungal effect of berberine against fluconazole-resistant Candida and Cryptococcus neoformans strains, as well as against the biofilm form of Candida spp., was assessed. The antifungal effect of berberine was determined by a broth microdilution method (the M27-A3 method of the Clinical and Laboratory Standards Institute) and flow cytometry techniques, in which the probable mechanism of action of the compound was also assessed. For biofilm assessment, a colorimetric 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to determine the susceptibility of sessile cells. The isolates used in the study belonged to the Laboratory of Bioprospection and Experiments in Yeast (LABEL) of the Federal University of Ceará. After 24 and 72 h, fluconazole-resistant Candida and Cryptococcus neoformans strains showed berberine MICs equal to 8 µg/ml and 16 µg/ml, respectively. Cytometric analysis showed that treatment with berberine caused alterations to the integrity of the plasma and mitochondrial membranes and DNA damage, which led to cell death, probably by apoptosis. Assessment of biofilm-forming isolates after treatment showed statistically significant reductions in biofilm cell activity (P < 0.001).


Assuntos
Antifúngicos/farmacologia , Berberina/farmacologia , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Criptococose/tratamento farmacológico , Cryptococcus neoformans/efeitos dos fármacos , Fluconazol/farmacologia , Animais , Berberina/efeitos adversos , Biofilmes/crescimento & desenvolvimento , Candida/classificação , Candida/genética , Candidíase/microbiologia , Linhagem Celular , Proliferação de Células , Criptococose/microbiologia , Cryptococcus neoformans/classificação , Cryptococcus neoformans/genética , DNA Fúngico/genética , Farmacorresistência Fúngica , Fluconazol/efeitos adversos , Humanos , Células L , Camundongos , Testes de Sensibilidade Microbiana , Membranas Mitocondriais/efeitos dos fármacos , Tipagem Molecular , Técnicas de Tipagem Micológica
14.
Chem Biol Interact ; 239: 174-83, 2015 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-26134001

RESUMO

The strategy of antiangiogenic drugs is based on inhibiting formation of new blood vessels as alternative to limit cancer progression. In this work, we investigated the antitumor and antiangiogenic potential of eight thalidomide derivatives. Most of the molecules was not cytotoxic but 2a, 2d and 3d revealed weak antiproliferative activity on HL-60, Sarcoma 180 (S180) and normal peripheral blood mononuclear cells. Thalidomide, 2a and 2b were able to inhibit tumor growth (53.5%, 67.9% and 67.4%, respectively) in S180-bearing mice and presented moderate and reversible toxicity on liver, kidneys and spleens. Both analogs (2a and 2b) inhibited cell migration of endothelial (HUVEC) and melanoma cells (MDA/MB-435) at 50µg/mL. Immunohistochemistry labeling assays with CD-31 (PECAM-1) antibody showed microvascular density (MVD) was significantly reduced in thalidomide, 2a and 2b groups (30±4.9, 64.6±1.8 and 46.5±19.5%, respectively) (p<0.05). Neovascularization evaluated by Chorioallantoic Membrane Assay (CAM) with compounds 2a and 2b showed reduction of vessels' number (12. 9±2.3 and 14.8±3.3%), neovascularization area (13.1±1.7 and 14.3±1.7%) and total length of vessels (9.2±1.5 and 9.9±1.9%). On the other hand, thalidomide did not alter vascularization parameters. Consequently, addition of thiosemicarbazone pharmacophore group into the phthalimidic ring improved the in vivo antitumor and antiangiogenic potential of the analogs 2a and 2b.


Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Talidomida/química , Animais , Linhagem Celular Tumoral/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Feminino , Humanos , Camundongos , Neovascularização Patológica/tratamento farmacológico , Relação Estrutura-Atividade , Talidomida/análogos & derivados , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Biochimie ; 104: 147-55, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24952350

RESUMO

Pterocarpans, a family of isoflavonoids found in the diverse Fabaceae, display potent cytotoxic activity over a panel of tumor cell lines, and among those tested, 2,3,9- trimethoxypterocarpan displays the most potent activity. This study evaluates the effects of 2,3,9-trimethoxypterocarpan and its related derivatives on cell cycle progression and microtubule function in select breast cancer cell lines (MCF7, T47d and HS578T). The pterocarpans, with the exception of 3,4-dihydroxy-9-methoxipterocarpan, induced increased frequencies of mitotic cells by inducing arrest in prometaphase. While microtubule organization in interphase cells was not modified during treatment, mitotic cells exhibited high frequencies of monastral spindles surrounded by condensed chromosomes. Immunofluorescence staining with an anti-γ-tubulin antibody showed double-dot labeling in the spindle polar region, suggesting that pterocarpan treatment blocked centrosome segregation. We found that this mitotic arrest was reversible when the cells were treated for up to 24 h followed by recovery in drug-free medium, but not after 48-h treatment followed by incubation in drug-free medium. In that case, treated cells typically underwent cell multinucleation and apoptosis.


Assuntos
Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Prometáfase/efeitos dos fármacos , Pterocarpanos/farmacologia , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Prófase/efeitos dos fármacos , Pterocarpanos/química , Fatores de Tempo
16.
Antimicrob Agents Chemother ; 58(3): 1468-78, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24366745

RESUMO

Flavonoids are a class of phenolic compounds commonly found in fruits, vegetables, grains, flowers, tea, and wine. They differ in their chemical structures and characteristics. Such compounds show various biological functions and have antioxidant, antimicrobial, anti-inflammatory, and antiapoptotic properties. The aim of this study was to evaluate the in vitro interactions of flavonoids with fluconazole against Candida tropicalis strains resistant to fluconazole, investigating the mechanism of synergism. Three combinations formed by the flavonoids (+)-catechin hydrated, hydrated quercetin, and (-)-epigallocatechin gallate at a fixed concentration with fluconazole were tested. Flavonoids alone had no antifungal activity within the concentration range tested, but when they were used as a cotreatment with fluconazole, there was significant synergistic activity. From this result, we set out to evaluate the possible mechanisms of cell death involved in this synergism. Isolated flavonoids did not induce morphological changes or changes in membrane integrity in the strains tested, but when they were used as a cotreatment with fluconazole, these changes were quite significant. When evaluating mitochondrial damage and the production of reactive oxygen species (ROS) only in the cotreatment, changes were observed. Flavonoids combined with fluconazole were shown to cause a significant increase in the rate of damage and the frequency of DNA damage in the tested strains. The cotreatment also induced an increase in the externalization of phosphatidylserine, an important marker of early apoptosis. It is concluded that flavonoids, when combined with fluconazole, show activity against strains of C. tropicalis resistant to fluconazole, promoting apoptosis by exposure of phosphatidylserine in the plasma membrane and morphological changes, mitochondrial depolarization, intracellular accumulation of ROS, condensation, and DNA fragmentation.


Assuntos
Antifúngicos/farmacologia , Apoptose/efeitos dos fármacos , Candida tropicalis/efeitos dos fármacos , Catequina/análogos & derivados , Catequina/farmacologia , Fluconazol/farmacologia , Quercetina/farmacologia , Antifúngicos/administração & dosagem , Interações Medicamentosas , Farmacorresistência Fúngica/efeitos dos fármacos , Sinergismo Farmacológico , Fluconazol/administração & dosagem , Testes de Sensibilidade Microbiana , Espécies Reativas de Oxigênio/metabolismo
17.
Chem Biodivers ; 10(11): 1999-2006, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24243608

RESUMO

A series of chalcone derivatives, 1-15, were prepared by Claisen-Schmidt condensation and evaluated for their cytotoxicities on tumor cell lines and also against proteolytic enzymes such as cathepsins B and K. Of the compounds synthesized, (E)-3-(3,4-dimethoxyphenyl)-1-phenylprop-2-en-1-one (12), (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (13), (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (14), and (E)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one (15) showed significant cytotoxicities. The most effective compound was 15, which showed high cytotoxic activity with an IC50 value lower than 1 µg/ml, and no selectivity on the tumor cells evaluated. Substituents at C(4) of ring B were found to be essential for cytotoxicity. In addition, it was also demonstrated that some of these chalcones are moderate inhibitors of cathepsin K and have no activity against cathepsin B.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Catepsina B/antagonistas & inibidores , Catepsina K/antagonistas & inibidores , Chalcona/análogos & derivados , Chalcona/farmacologia , Catepsina B/metabolismo , Catepsina K/metabolismo , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia
18.
Toxicol In Vitro ; 27(7): 2076-83, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23912027

RESUMO

The down-regulation or loss of epithelial markers is often accompanied by the up-regulation of mesenchymal markers. E-cadherin generally suppresses invasiveness, whereas N-cadherin promotes invasion and metastasis in vitro. The aim of this work is to investigate the role of biflorin, a naphthoquinone with proven anticancer properties, on the expression of N-cadherin and AKT proteins in MDA-MB-435 invasive melanoma cancer cells after 12h of exposure to 1, 2.5 and 5 µM biflorin. Biflorin inhibited MDA-MB-435 invasion in a dose-dependent manner (p<0.01). Likewise, biflorin down-regulated N-cadherin and AKT-1 expression in a dose-dependent manner. Biflorin did not inhibit the adhesion of MDA-MB-435 cells to any tested substrates. Additionally, biflorin blocked the invasiveness of cells by down-regulating N-cadherin, most likely via AKT-1 signaling. As such, biflorin may be a novel anticancer agent and a new prototype for drug design.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Caderinas/antagonistas & inibidores , Regulação para Baixo/efeitos dos fármacos , Melanoma/tratamento farmacológico , Naftoquinonas/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Caderinas/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanócitos/citologia , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Naftoquinonas/efeitos adversos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo
19.
Life Sci ; 93(5-6): 201-7, 2013 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-23743169

RESUMO

AIM: The aim of this study was to determine the antimetastatic potential of biflorin using in vivo and in vitro approaches. MAIN METHODS: Biflorin was isolated from Capraria biflora collected in Fortaleza, Ceará, Brazil. Adhesion, migration and invasion assays were performed to avail of the antimetastatic potential of this quinone. Experimental metastasis was performed to avail of the antimetastatic potential of bilflorin using in vivo assay. KEY FINDINGS: Treatment with biflorin (25 and 50mg/kg/day) was shown to be effective in reducing B16-F10 melanoma metastasis in C57BL/6 mice. The administration of biflorin at 25mg/kg/day intraperitoneally inhibited the formation of metastases by about 57% compared to untreated control animals. When the animals were treated with 50mg/kg/day intraperitoneally, there was a 71% decrease in the number of lung metastases. Morphological assays showed the presence of hemosiderin and erythrocytes in the lung parenchyma, indicating the occurrence of hemorrhage, probably a side effect of biflorin. Biflorin at non-toxic concentrations (0.5, 1.0 and 1.5g/mL) was tested directly on B16-F10 cells in vitro, and it inhibited cell adhesion to type I collagen and cell motility using the wound-healing assay. SIGNIFICANCE: These data suggest that biflorin has a promising antimetastatic potential, as shown by its anti-adhesion, anti-migration and anti-invasion properties against a metastatic melanoma cell line. However, further studies are essential to elucidate its mechanism of action.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Melanoma Experimental/tratamento farmacológico , Naftoquinonas/uso terapêutico , Scrophulariaceae , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Feminino , Neoplasias Pulmonares/patologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Naftoquinonas/isolamento & purificação , Invasividade Neoplásica/patologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Distribuição Aleatória
20.
Vascul Pharmacol ; 58(5-6): 337-45, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23603277

RESUMO

Alpinia zerumbet is used in folk medicine in Brazil to treat hypertension. However, several pathways involved in the mechanism of vasorelaxation are still unclear. This study was designed to verify the antihypertensive effect of the methanolic fraction of the essential oil of A. zerumbet (MFEOAz) and to characterize its mechanism of action. The thoracic aortic rings from the Wistar rats were perfused in the organ chambers filled with Kreb's solution, where the tension of each ring was measured. The antihypertensive effect of MFEOAz was assessed in rats submitted to chronic hypertension by inhibition of nitric oxide synthesis by indirect measurement of blood pressure with indirect tail cuff method. MFEOAz relaxed phenylephrine and KCl-induced contraction of either endothelium-intact or endothelium-denuded rat aortic rings in a concentration-dependent manner. Pre-incubation with MFEOAz (100 and 300 µg/mL) in Ca(2+)-free Krebs solution attenuated phenylephrine- or caffeine-induced contraction. Pre-incubation with L-NAME, ODQ, wortmannin, atropine, indomethacin, catalase, SOD, TEA, 4-aminopyridine, glibenclamide, apamin, charybdotoxin, or iberiotoxin did not affect MFEOAz-induced relaxation. The intragastric administration of MFEOAz induced an antihypertensive effect. MFEOAz it seems inhibited the calcium influx via voltage-operated calcium channels and receptor-operated calcium channels, as well as inhibition of calcium mobilization from intracellular stores.


Assuntos
Alpinia/química , Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Óleos Voláteis/farmacologia , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/isolamento & purificação , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Brasil , Cálcio/metabolismo , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipertensão/fisiopatologia , Masculino , Medicina Tradicional , Óxido Nítrico/biossíntese , Óleos Voláteis/administração & dosagem , Óleos Voláteis/isolamento & purificação , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA