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Braz. arch. biol. technol ; 64: e21190750, 2021. tab, graf
Article in English | LILACS | ID: biblio-1249207


Abstract In this paper, the antibacterial activity of triazole functionalized cyclodextrin (CD.Click) and cyclodextrin-triazole-titanium based nanocomposite (CD.COM) was evaluated. The results indicated that CD.Click and CD.COM perform a wide range of antibacterial activity against both gram positive (Staphylococcus aureus and Bacillus subtilis) and gram negative (Escherichia coli and Pseudomonas aeruginosa) bacteria. The cytotoxic effect of CD.COM was investigated in vitro on cancerous cell lines (cervical cancer, breast carcinoma and sarcoma osteogenic) and fibroblast cells by MTT assay. The cell viability evaluation confirmed that the growth of cancerous cells is inhibited in a dose and time dependent way without any significant effect on the normal fibroblast cells.

Triazoles/chemical synthesis , beta-Cyclodextrins/chemical synthesis , In Vitro Techniques/instrumentation , Antibiotics, Antineoplastic
Biomédica (Bogotá) ; 40(4): 749-763, oct.-dic. 2020. tab, graf
Article in Spanish | LILACS | ID: biblio-1142439


Resumen: Introducción. Trypanosoma cruzi, agente causal de la enfermedad de Chagas, exhibe una sustancial heterogeneidad fenotípica y genotípica que puede influir en las variaciones epidemiológicas y clínicas de la enfermedad, así como en la sensibilidad a los fármacos utilizados en el tratamiento. Objetivo. Evaluar la sensibilidad in vitro al benznidazol, el nifurtimox y el posaconazol de 40 cepas clonadas de T. cruzi de Paraguay, con distintos genotipos, huéspedes y localidades de origen. Materiales y métodos. En su estado epimastigote, los parásitos se incubaron en medio de cultivo LIT (Liver Infusion Tryptose) con diferentes concentraciones de cada fármaco en ensayos por triplicado. El grado de sensibilidad se estimó a partir de las concentraciones inhibitorias del 50 y el 90% (IC50 e IC90) y se obtuvieron los valores promedio y la desviación estándar de cada cepa y fármaco. La significación estadística entre grupos se determinó mediante análisis de varianzas con el test no paramétrico de Wilcoxon/Kruskal-Wallis y valores de p<0,05. Resultados. Se observó un amplio rango de respuesta a los fármacos. Se identificaron dos grupos de parásitos (A y B) con diferencias significativas en la sensibilidad al benznidazol (p<0,0001), y tres grupos (A, B, C) en cuanto a la sensibilidad al nifurtimox y el posaconazol (p<0,0001). Conclusiones. En general, las cepas fueron más sensibles al nifurtimox que al benznidazol y el posaconazol. Estas diferencias evidencian la heterogeneidad de las poblaciones de T. cruzi que circulan en Paraguay, lo que debe considerarse en el tratamiento y el seguimiento de las personas afectadas.

Abstract: Introduction: Trypanosoma cruzi, the causative agent of Chagas disease, shows substantial phenotypic and genotypic heterogeneity, which can influence the epidemiological and clinical variations of the disease and the sensitivity to the drugs used in the treatment. Objective: To assess the in vitro susceptibility to benznidazole, nifurtimox, and posaconazole of 40 cloned strains of T. cruzi isolated in Paraguay belonging to different genotypes, hosts, and localities. Materials and methods: We incubated the parasites in their epimastigote stage in LIT culture medium with different concentrations of each drug in triplicate assays. The degree of susceptibility was estimated by the inhibitory concentrations of 50 and 90% (IC50 and IC90) to obtain the average values and the standard deviation for each strain and drug. We determined the statistical significance between groups by analysis of variances with the Wilcoxon/Kruskal-Wallis non-parametric test and values of p<0.05. Results: A wide range of drug response was observed. Two groups of parasites (A and B) were identified as having significant differences in susceptibility to benznidazole (p<0.0001), and three groups (A, B, C) to nifurtimox and posaconazole (p<0.0001). Conclusions: Overall, the isolates were more susceptible to nifurtimox than benznidazole and posaconazole. Such differences highlight the heterogeneity of T. cruzi populations circulating in Paraguay, an aspect to consider in the treatment and follow up of patients.

Paraguay , Trypanosoma cruzi , Triazoles , Chagas Disease , Nifurtimox , Nitroimidazoles
Article in English | WPRIM | ID: wpr-878294


Objective@#This research was performed to evaluate the effect of tebuconazole (TBZ) on reproductive organs of male rats and to assess the protective role of combined essential trace elements in alleviating the detrimental effect of TBZ on male reproductive function.@*Methods@#For this purpose, 48 rats were exposed to 100 mg/kg TBZ, TBZ supplemented with zinc (Zn), selenium (Se), copper (Cu), and iron (Fe), TBZ + (Se + Zn); TBZ + Cu; or TBZ + Fe. The experiment was conducted for 30 consecutive days.@*Results@#TBZ caused a significant perturbation in mineral levels and reduction in reproductive organs weights, plasma testosterone level, and testicular antioxidant enzyme activities. The TBZ-treated group also showed a significant increase in sperm abnormalities (count, motility, and viability percent), plasma follicle-stimulating hormone and luteinizing hormone concentrations, lipid peroxidation, protein oxidation, and severe DNA degradation in comparison with the controls. Histopathologically, TBZ caused testis impairments. Conversely, treatment with trace elements, in combination or alone, improved the reproductive organ weights, sperm characteristics, TBZ-induced toxicity, and histopathological modifications in testis.@*Conclusion@#TBZ exerts significant harmful effects on male reproductive system. The concurrent administration of trace elements reduces testis dysfunction, fertility, and toxicity induced by TBZ.

Animal Feed/analysis , Animals , Antioxidants/metabolism , Diet , Dietary Supplements/analysis , Fungicides, Industrial/adverse effects , Male , Minerals/metabolism , Mutagenicity Tests , Rats , Rats, Wistar , Spermatozoa/physiology , Testis/physiology , Trace Elements/metabolism , Triazoles/adverse effects
Rev. Soc. Bras. Med. Trop ; 53: e20190477, 2020. tab, graf
Article in English | LILACS | ID: biblio-1057272


Abstract INTRODUCTION: Benznidazole (BZL) and Nifurtimox (NFX) are the pharmacological treatment for acute phase Chagas Disease (CD); however, therapy resistance and residual mortality development remain important unresolved issues. Posaconazole (POS) has shown a trypanocidal effect in vivo and in vitro. Thus, this study aimed at comparing the T. Cruzi parasitic load-reducing effect of the combination of BZL+POS against that of monotherapy with either, during acute phase CD, in an experimental murine model. METHODS Nineteen Wistar rats were randomly allocated to four groups and inoculated with the trypomastigotes of T. cruzi strain´s JChVcl1. The rats were administered anti-parasites from day 20-29 post-infection. The Pizzi and Brener method was used for parasitemia measurement. Longitudinal data analysis for the continuous outcome of repeated measures was performed using parasitemia as the outcome measured at days 20, 22, 24, 27, and 29 post-infection. RESULTS All four groups had similar parasitic loads (p=0.143) prior to therapy initiation. Among the three treatment groups, the BZL+POS (n=5) group showed the highest mean parasitic load reduction (p=0.000) compared with the control group. Likewise, the BZL+POS group rats showed an earlier therapeutic effect and were the only ones without parasites in their myocardial samples. CONCLUSIONS: Treatment of acute phase CD with BZL+POS was more efficacious at parasitemia and myocardial injury reduction, compared with monotherapy with either.

Animals , Rats , Triazoles/administration & dosage , Trypanocidal Agents/administration & dosage , Chagas Disease/drug therapy , Parasitemia/drug therapy , Nitroimidazoles/administration & dosage , Acute Disease , DNA, Protozoan , Rats, Wistar , Disease Progression , Disease Models, Animal , Drug Therapy, Combination , Parasite Load
Article in English | WPRIM | ID: wpr-773417


OBJECTIVE@#To evaluate the synergy of the Burkholderia signaling molecule cis-2-dodecenoic acid (BDSF) and fluconazole (FLU) or itraconazole (ITRA) against two azole-resistant C. albicans clinical isolates in vitro and in vivo.@*METHODS@#Minimum inhibitory concentrations (MICs) of antibiotics against two azole-resistant C. albicans were measured by the checkerboard technique, E-test, and time-kill assay. In vivo antifungal synergy testing was performed on mice. Analysis of the relative gene expression levels of the strains was conducted by quantitative reverse-transcription polymerase chain reaction (qRT-PCR).@*RESULTS@#BDSF showed highly synergistic effects in combination with FLU or ITRA with a fractional inhibitory concentration index of ⪕ 0.08. BDSF was not cytotoxic to normal human foreskin fibroblast cells at concentrations of up to 300 μg/mL. The qRT-PCR results showed that the combination of BDSF and FLU/ITRA significantly inhibits the expression of the efflux pump genes CDR1 and MDR1 via suppression of the transcription factors TAC1 and MRR1, respectively, when compared with FLU or ITRA alone. No dramatic difference in the mRNA expression levels of ERG1, ERG11, and UPC2 was found, which indicates that the drug combinations do not significantly interfere with UPC2-mediated ergosterol levels. In vivo experiments revealed that combination therapy can be an effective therapeutic approach to treat candidiasis.@*CONCLUSION@#The synergistic effects of BDSF and azoles may be useful as an alternative approach to control azole-resistant Candida infections.

Antifungal Agents , Pharmacology , Burkholderia cenocepacia , Chemistry , Candida albicans , Physiology , Candidiasis , Drug Therapy , Drug Resistance, Fungal , Fatty Acids, Monounsaturated , Fluconazole , Pharmacology , Humans , Microbial Sensitivity Tests , Triazoles , Metabolism
São Paulo; s.n; 2019. 126 p. ilus.
Thesis in Portuguese | LILACS, SES-SP, SESSP-CTDPROD, SES-SP, SESSP-TESESESSP, SES-SP | ID: biblio-1145917


A utilização de fungicidas azólicos pode estar ligada a resistência aos fármacos utilizados no tratamento da aspergilose invasiva. Em cepas de Aspergillus fumigatus, foram descritas mutações no gene cyp51A resultando em menor afinidade azol-alvo e resistência antifúngica. Mecanismos de resistência aos triazóis já foram descritos em isolados ambientais de áreas agrícolas e em pacientes sob tratamento. A similaridade dos compostos azólicos, clínicos e agrícolas, e o mesmo mecanismo de ação na célula fúngica podem contribuir para a seleção de cepas com resistência cruzada no hospedeiro e no meio ambiente. O gene cyp51A codifica a enzima-chave na produção de ergosterol da membrana celular-14-demetilase, alvo de todos os compostos azólicos. Mutações no gene cyp51A resultam na produção de enzima com alterações em sua conformação tridimensional levando à menor afinidade azol-alvo e resistência antifúngica. A indução de tais mutações foi atribuída à exposição extensiva das cepas ambientais a agrotóxicos fungicidas triazólicos. Estudos em diversos países sugerem que esses produtos exercem pressão seletiva em fenótipos resistentes de A. fumigatus O objetivo deste estudo foi avaliar a hipótese da origem ambiental de mecanismos de resistência a triazólicos, em 2 isolados clínicos e 2 ambientais de A. fumigatus, modulada pela exposição a um fungicida agrícola. Modelo de horta experimental, parte orgânica e parte exposta a agrotóxico triazólico, foi construída e inoculada com os 4 isolados, todos selvagens não mutantes de A. fumigatus. Ao longo de um ano, 11 pulverizações e recuperações mensais dos 4 isolados a partir de amostras de solo permitiram monitorar possível emergência de resistência aos triazólicos: difenoconazol, metconazol, tebuconazol, itraconazol, voriconazol e posaconazol. A busca da resistência foi feita pela determinação de MIC, tanto de fungicidas quanto de fármacos triazólicos e pesquisa de mutações gênicas no gene cyp51A e sua região promotora. O gene cyp51A sequenciado para um desses isolados não apresentou mutações. Conclui-se que a pulverização de difenoconazol não resultou em alteração de MIC de triazóis nas cepas expostas indicando que não houve seleção de fenótipos resistentes. Outra possibilidade é que, de fato, o tempo de exposição, ou volume/concentração de fungicida não foram suficientes para pressão seletiva.

Triazoles , Solid Waste Grinding , Agrochemicals
Article in Chinese | WPRIM | ID: wpr-773106


The aim of the study is to explore exogenous S3307 on alleviating low-temperature stress of coix seedlings. The coix cultivar, "No 5 Yiliao", was selected as the plant material, through nutrient solution cultivating in greenhouse, the effect of different S3307 concentrations(1, 3, 5, 7, 9 mg·L~(-1)) on coix seedlings traits and physiological indicators were explored under low-temperature stress. The results showed, under low-temperature 5 mg·L~(-1) S3307 could significantly increase coix seedlings stem diameter and biomass, which stem diameter and above-ground biomass, low-ground biomass separately were enhanced 11.90%, 13.59%, 10.99%. Leaf width and lateral root number separately were enhanced 7.63%, 37.52%. Meanwhile, addition of 5 mg·L~(-1) S3307 could significantly reduce relative conductivity and MDA, separately being reduced 23.33%, 17.42% compared to CKL. S3307 could also significantly increase soluble sugar and proline content, which leaf soluble sugar and proline content separately were enhanced 17.16%, 11.87%, which root soluble sugar and proline content separately were enhanced 20.00%, 33.42%. Additionally, S3307 could alleviate the cells destroy in ultra-structure level by improving cell membrane structure and chloroplast capsule layer structure. 5 mg·L~(-1) S3307 could enhance the low temperature tolerance of coix seedlings by regulating the growth and physiological indexes, and thus alleviate the damage caused by low-temperature to the coix seedlings.

Coix , Cold Temperature , Seedlings , Stress, Physiological , Triazoles , Pharmacology
Electron. j. biotechnol ; 34: 76-82, july. 2018. ilus, graf
Article in English | LILACS | ID: biblio-1047373


Background: Jatropha curcas L., as an important strategic biofuel resource with considerable economic potential, has attracted worldwide attention. However, J. curcas has yet to be domesticated. Plant height, an important agronomic trait of J. curcas, has not been sufficiently improved, and the genetic regulation of this trait in J. curcas is not fully understood. Zinc finger proteins (ZFPs), a class of transcription factors, have previously been shown to play critical roles in regulating multiple aspects of plant growth and development and may accordingly be implicated in the genetic regulation of plant height in J. curcas. Results: In this study, we cloned JcZFP8, a C2H2 ZFP gene in J. curcas. We found that the JcZFP8 protein was localized in the nucleus and contained a conserved QALGGH motif in its C2H2 structure. Furthermore, ectopic expression of JcZFP8 under the control of the 35S promoter in transgenic tobacco resulted in dwarf plants with malformed leaves. However, when JcZFP8 was knocked out, the transgenic tobacco did not show the dwarf phenotype. After treatment with the gibberellic acid (GA) biosynthesis inhibitor paclobutrazol (PAC), the dwarf phenotype was more severe than plants that did not receive the PAC treatment, whereas application of exogenous gibberellin3 (GA3) reduced the dwarf phenotype in transgenic plants. Conclusions: The results of this study indicate that JcZFP8 may play a role in J. curcas plant phenotype through GA-related pathways. Our findings may help us to understand the genetic regulation of plant development in J. curcas and to accelerate breeding progress through engineering of the GA metabolic pathway in this plant. How to cite: Shi X,Wu Y, Dai T, et al. JcZFP8, a C2H2 zinc-finger protein gene from Jatropha curcas, influences plant development in transgenic tobacco.

Tobacco/genetics , Jatropha , Plant Development , CYS2-HIS2 Zinc Fingers/genetics , Plant Growth Regulators/genetics , Transcription Factors , Triazoles , Plants, Genetically Modified/growth & development , Cloning, Molecular , Gene Expression Regulation, Plant , Real-Time Polymerase Chain Reaction , Gibberellins
Arch. argent. pediatr ; 116(3): 451-454, jun. 2018. tab
Article in Spanish | LILACS, BINACIS | ID: biblio-950025


La información sobre el uso de posaconazol en niños es escasa. Se realizó este estudio descriptivo retrospectivo entre agosto de 2010 y marzo de 2017 para evaluar las características clínicas, microbiológicas y la evolución de los pacientes tratados con posaconazol. Se incluyeron 16 niños. Mediana de edad: 161 meses (rango intercuartílico -RIC- 69-173 m). Todos tenían enfermedad subyacente y presentaban infección fúngica invasiva probada. Los aislamientos más frecuentes fueron Mucor spp. y Aspergillus spp. La dosis media de posaconazol fue 600 mg/día (400-800 mg/día) y la mediana de duración del tratamiento, 223 días (RIC 48-632). Diez pacientes presentaron efectos adversos, pero solo uno requirió suspensión del antifúngico debido a alteraciones hidroelectrolíticas.

There is limited information on the use of posaconazole in children. This retrospective and descriptive study was conducted to evaluate the clinical, microbiological characteristics and evolution of patients treated with posaconazole between August 2010 and March 2017. We included 16 children. Median age: 161 months (interquartile range -IQR-69-173m). All had underlying disease and a proven invasive fungal infection. The most frequent isolated were Mucor spp. and Aspergillus spp. The mean posaconazole dose was 600 mg /day (400-800 mg/day) and the median duration of treatment was 223 days (IQR 48-632). Ten patients had adverse effects, but only one required suspension of the antifungal treatment due to hydroelectrolytic disorders.

Humans , Child, Preschool , Child , Adolescent , Triazoles/therapeutic use , Invasive Fungal Infections/drug therapy , Antifungal Agents/therapeutic use , Time Factors , Triazoles/administration & dosage , Triazoles/adverse effects , Retrospective Studies , Dose-Response Relationship, Drug , Tertiary Care Centers , Invasive Fungal Infections/microbiology , Hospitals, Pediatric , Antifungal Agents/administration & dosage , Antifungal Agents/adverse effects
Biosci. j. (Online) ; 34(3): 603-614, mai/jun. 2018. tab
Article in English | LILACS | ID: biblio-966910


The application of fungicides in different operating conditions is a usual practice for maintaining the productive potential in sugarcane varieties considered susceptible to orange rust, however, the physiological effects provided by the different application methods are unknown. The objective of this study was to evaluate the photosynthetic responses (gas exchange and chlorophyll content) in the SP81-3250 sugarcane variety, in function of different operational conditions of the aerial and ground application of fungicide in the orange rust control. Two application of fungicides of the chemical groups Strobilurins and Triazoles were carried out in the experimental units in different treatments. In the aerial applications, two application rates (30 and 40 L ha-1) and three nozzle orientations (0º, 90º and 135º) and in the ground application was used 200 L ha-1 and flat fan spray nozzles with air induction (AI11004-VS). Gas exchange evaluations were performed with an IRGA and amount of chlorophyll a and b with a chlorophyll meter. Data were analyzed using Student's t-test for independent samples, at 0.05 significance. The aerial application provided better photosynthetic responses and chlorophyll a and b contents in leaf limb compared to ground application. Significant differences were detected in gas exchange and chlorophyll content between application rates and angulation of the spray nozzles in the boom. Fungicide applications provided increments of more than 19 t ha-1 compared to the control, depending on the spraying technique employed. Aerial application with 30 L ha-1 and 0° of deflection is a viable option to provide safer applications as a function of the larger droplet size.

A aplicação de fungicidas em diferentes condições operacionais é uma prática usual para manter o potencial genético em variedades de cana-de-açúcar consideradas susceptíveis à ferrugem laranja, porém os efeitos fisiológicos proporcionados pelos diferentes métodos de aplicação são desconhecidos. O objetivo deste estudo foi avaliar as respostas fotossintéticas (troca gasosa e teor de clorofila) na variedade de cana-de-açúcar SP81-3250, em função de diferentes condições operacionais de aplicação aérea e terrestre de fungicida no controle da ferrugem alaranjada. Duas aplicações de fungicidas dos grupos químicos Estrobilurinas e Triazóis foram realizadas nas unidades experimentais em diferentes tratamentos. Nas aplicações aéreas, foram utilizadas duas taxas de aplicação (30 e 40 L ha-1) e três orientações do ângulo dos bicos (0º, 90º e 135º) e na aplicação terrestre 200 L ha-1 e pontas de pulverização de jato plano com indução de ar (AI11004 -VS). As avaliações de trocas gasosas foram realizadas com analisador de gás IRGA e a quantidade de clorofila a e b com um medidor de clorofila. Os dados foram analisados utilizando o teste t de Student para amostras independentes, com um valor de 0,05 de significancia. A aplicação aérea proporcionou melhores respostas fotossintéticas e os teores de clorofila a e b no membro foliar em comparação com a aplicação terrestre. Foram detectadas diferenças significativas na troca gasosa e no teor de clorofila entre as taxas de aplicação e a angulação dos bicos de pulverização na barra. As aplicações de fungicidas proporcionaram incrementos de mais de 19 t ha-1 em relação ao tratamento controle, dependendo da técnica de pulverização empregada. A aplicação aérea com 30 L ha-1 e 0° de deflexão é uma opção viável para proporcionar aplicações mais seguras em função do maior tamanho das gotas.

Saccharum , Fungicides, Industrial , Triazoles , Strobilurins
Int. j. morphol ; 36(1): 345-357, Mar. 2018. tab, graf
Article in English | LILACS | ID: biblio-893233


SUMMARY: An alternative superovulator to replace clomiphene citrate is needed as clomiphene citrate is associated with low pregnancy rates. Anastrozole is an effective superovulator, but it has not been well researched. In order to determine the effectiveness of anastrozole as a superovulator and to compare it with clomiphene citrate in similar situations, this study ascertained the effects of these drugs on the expression of the focal adhesion proteins, vinculin and integrin β5, which are uterine receptivity markers, in the uterine epithelial cells of day 1 and day 6 pregnant Wistar rats. The results show that vinculin and integrin β5 are co-localized at the base of the uterine epithelium at day 1 of pregnancy whereas at day 6, they disassemble from the basal focal adhesions and co-localize and significantly increase their expression apically (p≤0.0001). Moreover, there is a significant difference in the protein expression levels of vinculin and integrin b5 in uterine luminal epithelial cells between untreated (control) and chlomiphene citrate treated rats (p≤0.0001), anastrozole and chlomiphene citrate treated rats at day 6 (p≤0.0001) suggesting the interpretation that anastrozole seems to enhance their expression in order to perhaps assist in the implantation process of the blastocyst. The immunofluorescence experiments agree with the vinculin and integrin β5 gene expression findings in which at day 6 of pregnancy, vinculin and integrin β5 gene expression are significantly upregulated in uterine luminal epithelial cells in the anastrozole treated group relative to the calibrator sample (p≤0.0001). These findings suggest that anastrozole is implantation friendly.

RESUMEN: Es necesario un superovulador alternativo para reemplazar el citrato de clomifeno, debido a que está asociado con bajas tasas de preñez. El anastrozol es un superovulador eficaz, sin embargo es poca su investigación. Con el fin de determinar la efectividad del anastrozol como superovulador y compararlo con citrato de clomifeno en situaciones similares, se determinaron los efectos de estos fármacos sobre la expresión de las proteínas de adhesión focal, vinculina e integrina β5, en marcadores de receptividad uterina en días 1 y 6, en las células epiteliales uterinas de ratas Wistar preñadas. Los resultados muestran que la vinculina y la integrina β5 se co-localizan en la base del epitelio uterino al día 1 de la gravidez mientras que al día 6 se desmontan de las adherencias focales basales, co-localizan y aumentan significativamente su expresión apicalmente (p≤0.0001). Además, existe una diferencia significativa en los niveles de expresión de proteína de vinculina e integrina β5 en células epiteliales luminales uterinas entre ratas no tratadas (control) y tratadas con citrato declomifeno (p≤0.0001), ratas tratadas con anastrozol y citrato declomifeno al día 6 (p≤0,0001) sugiriendo la interpretación de que el anastrozol parece mejorar su expresión con el fin de ayudar en el proceso de implantación del blastocisto. Los experimentos de inmunofluorescencia coinciden con los resultados de la expresión de los genes vinculina e integrina β5 en los cuales al día 6 de la preñez, la vinculina y la integrina β5 están significativamente reguladas en células epiteliales luminales uterinas en el grupo tratado con anastrozol con respecto a la muestra del calibrador (p<0,0001). Estos hallazgos sugieren que el anastrozol es favorable para la implantación.

Animals , Female , Pregnancy , Rats , Integrins/drug effects , Nitriles/pharmacology , Triazoles/pharmacology , Uterus/drug effects , Vinculin/drug effects , Epithelial Cells/drug effects , Focal Adhesions/drug effects , Integrins/genetics , Integrins/physiology , Microscopy, Confocal , Microscopy, Fluorescence , Rats, Wistar , Real-Time Polymerase Chain Reaction , Vinculin/genetics , Vinculin/physiology
Frontiers of Medicine ; (4): 726-734, 2018.
Article in English | WPRIM | ID: wpr-771271


Bromodomain-containing 4 (BRD4) has been considered as an important requirement for disease maintenance and an attractive therapeutic target for cancer therapy. This protein can be targeted by JQ1, a selective small-molecule inhibitor. However, few studies have investigated whether BRD4 influenced acute promyelocytic leukemia (APL), and whether BRD4 had interaction with promyelocytic leukemia-retinoic acid receptor α (PML/RARα) fusion protein to some extent. Results from cell viability assay, cell cycle analysis, and Annexin-V/PI analysis indicated that JQ1 inhibited the growth of NB4 cells, an APL-derived cell line, and induced NB4 cell cycle arrest at G1 and apoptosis. Then, we used co-immunoprecipitation (co-IP) assay and immunoblot to demonstrate the endogenous interaction of BRD4 and PML/RARα in NB4 cells. Moreover, downregulation of PML/RARα at the mRNA and protein levels was observed upon JQ1 treatment. Furthermore, results from the RT-qPCR, ChIP-qPCR, and re-ChIP-qPCR assays showed that BRD4 and PML/RARα co-existed on the same regulatory regions of their target genes. Hence, we showed a new discovery of the interaction of BRD4 and PML/RARα, as well as the decline of PML/RARα expression, under JQ1 treatment.

Apoptosis , Azepines , Pharmacology , Cell Differentiation , Down-Regulation , Gene Expression Regulation, Neoplastic , Humans , Leukemia, Promyelocytic, Acute , Drug Therapy , Genetics , Nuclear Proteins , Genetics , Promyelocytic Leukemia Protein , Genetics , RNA, Messenger , Genetics , Retinoic Acid Receptor alpha , Genetics , Transcription Factors , Genetics , Triazoles , Pharmacology , Tumor Cells, Cultured
Article in Chinese | WPRIM | ID: wpr-813207


To investigate the effect of bromodomain and extra-terminal (BET) protein inhibitor JQ1 on expression of autoimmune-related genes in CD4+T cells from patients with systemic lupus erythematosus (SLE).
 Methods: Peripheral CD4+T cells were isolated by positive selection with CD4 microbeads. The percentage of CD4+T cells were detected by flow cytometry. CD4+T cells were treated by JQ1 at 100 nm/L for 6, 24, 48 h. The expression of T cell-related genes was measured by quantitative real-time PCR (qPCR). The secretion levels of cytokines in culture supernatant were measured by ELISA at 48 h.
 Results: The percentage of CD4+T cells isolated by CD4 microbeads is 97.2%. Compared with the control group, the mRNA expression levels of IFNG, IL-17F, IL-21, CXCR5 and FOXP3 were down-regulated at 6, 24 and 48 h (P<0.05), and IL-17A mRNA level was decreased at 6 and 24 h (P<0.01); while IL-4 mRNA level was up-regulated at 24, 48 h (P<0.01), and TGF-β1 mRNA level was up-regulated at 6 and 48 h (P<0.05) in SLE CD4+T cells treated with JQ1. The secretion levels of IFN-γ and IL-21 in JQ1-treated group were decreased significantly (P<0.05), while the secretion levels of IL-4 and TGF-β were up-regulated compared with control group (P<0.05).
 Conclusion: JQ1 can reverse the immune dysregulation and improve the immunity homeostasis in CD4+T cells from patients with SLE.

Azepines , Pharmacology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes , Cell Biology , Metabolism , Cytokines , Metabolism , Flow Cytometry , Humans , Interferon-gamma , Metabolism , Lupus Erythematosus, Systemic , Allergy and Immunology , Metabolism , Proteins , RNA, Messenger , Metabolism , Time Factors , Transforming Growth Factor beta1 , Triazoles , Pharmacology
Rev. chil. infectol ; 35(1): 15-21, 2018. tab, graf
Article in Spanish | LILACS | ID: biblio-899772


Resumen Introducción En pediatría no existe consenso en la dosificación de posaconazol (PSC) para profilaxis y tratamiento de la infección fúngica invasora (IFI), usándose la medición de concentraciones plasmáticas (CPs) del fármaco. Objetivo Describir la experiencia de monitoreo de las CPs de PSC en niños inmunocomprometidos con IFI y determinar si las dosis recomendadas alcanzan CPs efectivas en profilaxis (≥ 0,7 µg/mL) y tratamiento (≥ 1,25 µg/mL). Método Análisis retrospectivo en niños que recibieron PSC suspensión como profilaxis o tratamiento entre enero de 2012 y octubre de 2016, en las unidades de Oncología y Trasplante de Médula Ósea del Hospital Calvo Mackenna. Resultados 78 CPs en seis pacientes (4 indicaciones de profilaxis y 4 tratamientos) fueron revisados. La mediana de dosis de PSC fue de 12,5 y 18,8 mg/kg/d para profilaxis y tratamiento, respectivamente, resultando CP mediana de 0,97 y 1,8 μg/mL, respectivamente. En profilaxis, se registraron 40/67 (60%) con CP ≥ 0,70 μg/mL recibiendo una mediana de dosis de 12,5 mg/kg/d. Mientras que para el tratamiento: 5/11 (46%), presentaron CP ≥ 1,25 μg/mL, recibiendo una mediana de dosis de 18 mg/kg/d. Conclusión Nuestros resultados se ajustan a lo recomendado para la dosificación de PSC, pero evidencian una necesidad de realizar una monitorización individualizada para mantener adecuadas CPs.

Background There is no consensus on the optimal dosage use of posaconazole (PSC) for invasive fungal infection (IFI) in pediatric patients and normally it is adjusted with drug levels (DLs) ≥ 0.7 μg/ml and ≥ 1.25 μg/ml for prophylaxis and treatment, respectively. Objective To describe the experience of monitoring DLs of PSC in immunocompromised pediatric patients with IFI and to determine if the recommended doses reach CP effective in prophylaxis (≥ 0.7 μg/mL) and treatment (≥ 1.25 μg/mL). Method A retrospective analysis in children who received PSC from January 2012 to October 2016, in the Oncology and Bone Marrow Transplant units at Hospital Calvo Mackenna was done Six patients with 78 DLs were reviewed (4 prophylaxis and 4 treatment). Median PSC dose was 12.5 and 18.8 mg/kg/d for prophylaxis and treatment, resulting in mean DLs of 0.97 and 1.8 μg/mL respectively. In prophylaxis 40/67 (60%) were recorded with DLs ≥ 0.70 μg/mL receiving a median dose of 12.5 mg/kg/d. While for treatment: 5/11 (46%) presented DLs ≥ 1.25 μg/mL, receiving a median dose of 18 mg/kg/d. Conclusion Our results are in line with the recommended for PSC dosage, but individualized monitoring is required to maintain adequate DLs.

Humans , Male , Female , Child, Preschool , Child , Adolescent , Triazoles/pharmacokinetics , Invasive Fungal Infections/prevention & control , Invasive Fungal Infections/drug therapy , Immunocompetence/drug effects , Antifungal Agents/pharmacokinetics , Triazoles/administration & dosage , Triazoles/blood , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Retrospective Studies , Treatment Outcome , Immunocompromised Host/drug effects , Drug Monitoring , Dose-Response Relationship, Drug , Drug Interactions , Hospitals, Pediatric , Antifungal Agents/administration & dosage , Antifungal Agents/blood
Rev. Soc. Bras. Med. Trop ; 50(5): 712-714, Sept.-Oct. 2017. tab, graf
Article in English | LILACS | ID: biblio-897020


Abstract Basidiobolomycosis is an unusual fungal skin infection that rarely involves the gastrointestinal tract. This study reported a 5-year-old boy with gastrointestinal basidiobolomycosis that had been misdiagnosed as gastrointestinal lymphoma. He was treated by surgical resection and a combination of posaconazole and amphotericin B deoxycholate with an acceptable response and no recurrence.

Humans , Male , Child, Preschool , Colonic Diseases/microbiology , Zygomycosis/pathology , Zygomycosis/drug therapy , Zygomycosis/diagnostic imaging , Gastrointestinal Neoplasms/diagnosis , Liver Diseases/microbiology , Lymphoma/diagnosis , Triazoles/therapeutic use , Tomography, X-Ray Computed , Amphotericin B/therapeutic use , Treatment Outcome , Colonic Diseases/pathology , Colonic Diseases/diagnostic imaging , Deoxycholic Acid/therapeutic use , Diagnosis, Differential , Drug Combinations , Gastrointestinal Neoplasms/pathology , Liver Diseases/pathology , Liver Diseases/diagnostic imaging , Lymphoma/pathology , Antifungal Agents/therapeutic use
Biosci. j. (Online) ; 33(5): 1188-1196, sept./oct. 2017. ilus, tab
Article in English | LILACS | ID: biblio-966286


The aim was to study the effect of early application of two fungicide mixtures on the control of Asian rust and powdery mildew, as well as on grain yield in five soybean cultivars at two sowing dates. The experiment was carried in the experimental area of FAMV/UPF. The cultivars A 4910 RG (super-early), BMX Apolo RR, A 6001 RR and Fundacep 55 RR (early) and Coodetec 214 RR (moderate), established at 13/11/2007 and 3/12/2007 were used. Trifolia of these cultivars were treated twice with the fungicides ciproconazol + azoxystrobin (Priori Xtra®, 0.3 L ha-1 plus Nimbus® adjuvant 0.6 L ha- 1) and epoxiconazol + pyraclostrobin (Opera®, 0.5 L ha-1), in three moments 1: pre-closure of the space between the lines and 21 days after; 2: pre-closure of space between rows and R5.1 stage (10% of beginning seed); and 3: R1 (beginning bloom) and R5.1 stages. The severity (% of affected leaf area) of powdery mildew and number of lesions cm2 of Asian rust were evaluated. After that plants were harvested, the thousand grain weight (g) and grain yield (kg ha-1) were quantified. The experimental design was a split-plot with four replicates, where the main plot were the five cultivars, and the subplots were the control treatment (untreated plants) and the six chemical control programs. Tukey and t-Student tests (p0.05) were used for separation of means of treatments and seasons, respectively. In general terms, foliar application of fungicides controlled both Asian rust and powdery mildew, as well as generated an increase on the thousand grain weight and grain yield. However, there seems to be an interaction among soybean genotypes and sowing date. Thus, our results allow us to infer that the chemical control of leaf diseases in the soybean crop depends of the cultivar and sowing date.

O objetivo foi estudar o efeito da aplicação antecipada de duas misturas de fungicidas no controle da ferrugem asiática e do oídio, bem como no rendimento de grãos em cinco cultivares de soja em duas épocas de semeadura. O experimento foi conduzido no campo experimental da FAMV/UPF. Utilizaram-se as cultivares A 4910 RG (super precoce), BMX Apolo RR, A 6001 RR e Fundacep 55 RR (precoces) e Coodetec 214 RR (moderado), estabelecidas em 13/11/2007 e 3/12/2007. Os fungicidas piraclostrobina + epoxiconazole e azoxistrobina + ciproconzole foram pulverizados duas vezes em 1: pré-fechamento do espaço entre as linhas e 21 dias após, 2: pré-fechamento do espaço entre as linhas e R5.1 (10% de granação), e 3: R1 (início da floração) e R5.1. Avaliaram-se a severidade (% da área foliar afetada) do oídio e o número de lesões cm2 da ferrugem asiática. Logo após as plantas foram colhidas, o peso de mil grãos (g) e rendimento de grãos (kg ha-1) foram quantificados. O delineamento experimental utilizado foi o de parcelas divididas com quatro repetições, onde a parcela principal foram as cinco cultivares, e as subparcelas foram o tratamento controle (plantas não tratadas) e os seis programas de controle químico. Para a separação das médias dos tratamentos e épocas, foram utilizados os testes de Tukey e t-Student (p0.05), respectivamente. De modo geral, a aplicação foliar de fungicidas controlou tanto a ferrugem asiática como o oídio, assim como também gerou um aumento do peso de mil grãos e rendimento de grãos. No entanto, parece existir uma interação entre os genótipos e data de semeadura. Assim, nossos resultados nos permitem inferir que o controle químico das doenças foliares na cultura da soja depende do cultivar e da data de semeadura.

Soybeans , Triazoles , Phakopsora pachyrhizi , Strobilurins , Fungicides, Industrial
Arch. endocrinol. metab. (Online) ; 61(4): 391-397, July-Aug. 2017. tab, graf
Article in English | LILACS | ID: biblio-887576


ABSTRACT Aromatase is a cytochrome P450 enzyme (CYP19A1 isoform) able to catalyze the conversion of androgens to estrogens. The aromatase gene mutations highlighted the action of estrogen as one of the main regulators of bone maturation and closure of bone plate. The use of aromatase inhibitors (AI) in boys with short stature has showed its capability to improve the predicted final height. Anastrozole (ANZ) and letrozole (LTZ) are nonsteroidal inhibitors able to bind reversibly to the heme group of cytochrome P450. In this review, we describe the pharmacokinetic profile of both drugs, discussing possible drug interactions between ANZ and LTZ with other drugs. AIs are triazolic compounds that can induce or suppress cytochrome P450 enzymes, interfering with metabolism of other compounds. Hydroxilation, N-dealkylation and glucoronidation are involved in the metabolism of AIs. Drug interactions can occur with azole antifungals, such as ketoconazole, by inhibiting CYP3A4 and by reducing the clearance of AIs. Antiepileptic drugs (lamotrigine, phenobarbital, and phenytoin) also inhibit aromatase. Concomitant use of phenobarbital or valproate has a synergistic effect on aromatase inhibition. Therefore, it is important to understand the pharmacokinetics of AIs, recognizing and avoiding possible drug interactions and offering a safer prescription profile of this class of aromatase inhibitors. Arch Endocrinol Metab. 2017;61(3):391-7.

Humans , Male , Female , Triazoles/pharmacokinetics , Body Height/drug effects , Aromatase Inhibitors/pharmacokinetics , Nitriles/pharmacokinetics , Cytochrome P-450 Enzyme System/metabolism , Aromatase Inhibitors/therapeutic use , Drug Interactions , Letrozole , Anastrozole
Mem. Inst. Oswaldo Cruz ; 112(5): 376-381, May 2017. tab, graf
Article in English | LILACS | ID: biblio-841795


BACKGROUND Sporothrix brasiliensis is the most virulent sporotrichosis agent. This species usually responds to antifungal drugs, but therapeutic failure can occur in some patients. Antifungal susceptibility tests have been performed on this species, but no clinical breakpoints (CBPs) are available. In this situation, minimal inhibitory concentration (MIC) distributions and epidemiological cutoff values (ECVs) support the detection of identification of resistant strains. OBJECTIVES To study the MIC distributions of five antifungal drugs against S. brasiliensis and to propose tentative ECVs. METHODS MICs of amphotericin B (AMB), itraconazole (ITR), ketoconazole (KET), posaconazole (POS), and terbinafine (TRB) against 335 S. brasiliensis strains were determined by the Clinical and Laboratory Standards Institute broth microdilution method. FINDINGS The proposed ECV, in µg/mL, for AMB, ITR, KET, POS, and TRB were 4.0, 2.0, 1.0, 2.0, and 0.25, respectively. Percentages of wild-type strains in our population for the above antifungal drugs were 98.48, 95.22, 95.33, 100, and 97.67%, respectively. MAIN CONCLUSIONS These ECVs will be useful to detect strains with resistance, to define CBPs, and to elaborate specific therapeutic guidelines for S. brasiliensis. Rational use of antifungals is strongly recommended to avoid the emergence of resistant strains and ensure the therapeutic effectiveness of sporotrichosis.

Humans , Animals , Cats , Sporothrix/drug effects , Triazoles/pharmacology , Amphotericin B/pharmacology , Itraconazole/pharmacology , Ketoconazole/pharmacology , Antifungal Agents/pharmacology , Naphthalenes/pharmacology , Drug Resistance , Cats , Anti-Infective Agents
Rev. Assoc. Med. Bras. (1992) ; 63(4): 371-378, Apr. 2017. graf
Article in English | LILACS | ID: biblio-842545


Summary Aromatase inhibitors have emerged as an alternative endocrine therapy for the treatment of hormone sensitive breast cancer in postmenopausal women. The use of third-generation inhibitors represented by exemestane, letrozol and anastrozole is currently indicated. Anastrozole is a nonsteroidal compound and a potent selective inhibitor of the aromatase enzyme. Although a few studies have shown that its pharmacodynamic and pharmacokinetic properties may be affected by interindividual variability, this drug has been recently used in all configurations of breast cancer treatment. In metastatic disease, it is currently considered the first-line treatment for postmenopausal women with estrogen receptor-positive breast tumors. Anastrozole has shown promising results in the adjuvant treatment of early-stage breast cancer in postmenopausal women. It has also achieved interesting results in the chemoprevention of the disease. Therefore, due to the importance of anastrozole both for endocrine treatment and chemoprevention of hormone-sensitive breast cancer in postmenopausal women, we proposed the current literature review in the SciELO and PubMed database of articles published in the last 10 years.

Resumo Os inibidores de aromatase têm emergido como uma endocrinoterapia alternativa para o tratamento de câncer de mama sensível a hormônios em mulheres pós-menopáusicas. A utilização de inibidores de terceira geração, representados por exemestano, letrozol e anastrozol, é atualmente indicada. Anastrozol é um composto não esteroide e um inibidor potente e seletivo da enzima aromatase. Embora alguns estudos tenham demonstrado que as suas propriedades farmacodinâmicas e farmacocinéticas podem ser afetadas pela variabilidade interindividual, esse fármaco tem sido recentemente utilizado em todas as configurações de tratamento do câncer de mama. Na doença metastática, é atualmente considerado o tratamento de primeira linha em mulheres pós-menopáusicas com tumores de mama e receptor de estrogênio positivo. O anastrozol tem mostrado resultados promissores no tratamento adjuvante do câncer de mama em estágio inicial em mulheres na pós-menopausa. Ele também conseguiu resultados interessantes na quimioprevenção da doença. Portanto, em virtude da importância do anastrozol tanto no tratamento endócrino quanto na quimioprevenção do câncer de mama hormoniossensível em mulheres na pós-menopausa, propusemos a atual revisão da literatura na base de dados SciELO e PubMed de artigos publicados nos últimos 10 anos.

Humans , Female , Triazoles/therapeutic use , Breast Neoplasms/prevention & control , Breast Neoplasms/drug therapy , Chemoprevention/methods , Aromatase Inhibitors/therapeutic use , Nitriles/therapeutic use , Tamoxifen/therapeutic use , Tamoxifen/pharmacokinetics , Triazoles/pharmacokinetics , Reproducibility of Results , Treatment Outcome , Chemotherapy, Adjuvant , Postmenopause , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Agents, Hormonal/pharmacokinetics , Aromatase Inhibitors/pharmacokinetics , Anastrozole , Nitriles/pharmacokinetics
Braz. j. infect. dis ; 21(1): 79-87, Jan.-Feb. 2017. tab, graf
Article in English | LILACS | ID: biblio-839188


Abstract The current increment of invasive fungal infections and the availability of new broad-spectrum antifungal agents has increased the use of these agents by non-expert practitioners, without an impact on mortality. To improve efficacy while minimizing prescription errors and to reduce the high monetary cost to the health systems, the principles of pharmacokinetics (PK) and pharmacodynamics (PD) are necessary. A systematic review of the PD of antifungals agents was performed aiming at the practicing physician without expertise in this field. The initial section of this review focuses on the general concepts of antimicrobial PD. In vitro studies, fungal susceptibility and antifungal serum concentrations are related with different doses and dosing schedules, determining the PD indices and the magnitude required to obtain a specific outcome. Herein the PD of the most used antifungal drug classes in Latin America (polyenes, azoles, and echinocandins) is discussed.

Humans , Antifungal Agents/pharmacokinetics , Polyenes/therapeutic use , Polyenes/pharmacokinetics , Aspergillosis/metabolism , Aspergillosis/drug therapy , Azoles/therapeutic use , Azoles/pharmacokinetics , Triazoles/therapeutic use , Triazoles/pharmacokinetics , Candidiasis/metabolism , Candidiasis/drug therapy , Microbial Sensitivity Tests , Area Under Curve , Dose-Response Relationship, Drug , Echinocandins/therapeutic use , Echinocandins/pharmacokinetics , Latin America , Antifungal Agents/therapeutic use