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1.
PLoS One ; 15(5): e0229630, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401759

RESUMO

Chromoblastomycosis (CBM) is a chronic subcutaneous mycosis caused by traumatic implantation of many species of black fungi. Due to the refractoriness of some cases and common recurrence of CBM, a more effective and less time-consuming treatment is mandatory. The aim of this study was to identify compounds with in vitro antifungal activity in the Pathogen Box® compound collection against different CBM agents. Synergism of these compounds with drugs currently used to treat CBM was also assessed. An initial screening of the drugs present in this collection at 1 µM was performed with a Fonsecaea pedrosoi clinical strain according to the EUCAST protocol. The compounds with activity against this fungus were also tested against other seven etiologic agents of CBM (Cladophialophora carrionii, Phialophora verrucosa, Exophiala jeanselmei, Exophiala dermatitidis, Fonsecaea monophora, Fonsecaea nubica, and Rhinocladiella similis) at concentrations ranging from 0.039 to 10 µM. The analysis of potential synergism of these compounds with itraconazole and terbinafine was performed by the checkerboard method. Eight compounds inhibited more than 60% of the F. pedrosoi growth: difenoconazole, bitertanol, iodoquinol, azoxystrobin, MMV688179, MMV021013, trifloxystrobin, and auranofin. Iodoquinol produced the lowest MIC values (1.25-2.5 µM) and MMV688179 showed MICs that were higher than all compounds tested (5 - >10 µM). When auranofin and itraconazole were tested in combination, a synergistic interaction (FICI = 0.37) was observed against the C. carrionii isolate. Toxicity analysis revealed that MMV021013 showed high selectivity indices (SI ≥ 10) against the fungi tested. In summary, auranofin, iodoquinol, and MMV021013 were identified as promising compounds to be tested in CBM models of infection.


Assuntos
Antifúngicos/farmacologia , Cromoblastomicose/tratamento farmacológico , Sinergismo Farmacológico , Fungos/patogenicidade , Acetatos/farmacologia , Ascomicetos/efeitos dos fármacos , Ascomicetos/patogenicidade , Auranofina/farmacologia , Compostos de Bifenilo/farmacologia , Cromoblastomicose/microbiologia , Cromoblastomicose/patologia , Dioxolanos/farmacologia , Exophiala/efeitos dos fármacos , Exophiala/patogenicidade , Fungos/efeitos dos fármacos , Humanos , Iminas/farmacologia , Iodoquinol/farmacologia , Pirimidinas/farmacologia , Estrobilurinas/farmacologia , Triazóis/farmacologia
2.
Plant Dis ; 104(6): 1621-1628, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32320371

RESUMO

Postbloom fruit drop (PFD) of citrus is caused by the Colletotrichum acutatum and C. gloeosporioides species complexes. The disease is important when frequent rainfall occurs during the flowering period of citrus trees. In Brazil, until 2012, PFD was mainly controlled by preventive applications of the methyl-benzimidazole carbamate (MBC) carbendazim and demethylation-inhibitor (DMI) fungicides such as difenoconazole. Since then, mixtures containing the DMI tebuconazole and the quinone-outside inhibitor (QoI) trifloxystrobin have been commonly used. Fungicides are often applied preventively, sometimes even when conditions are not conducive for PFD development. Excessive fungicide applications may favor the selection of resistant populations of Colletotrichum spp. In this study, we assessed the fungicide sensitivity of C. acutatum isolates collected during the two distinct periods of PFD management in Brazil: before and after the trifloxystrobin and tebuconazole mixture became widely employed. The sensitivity of 254 C. acutatum isolates to carbendazim and difenoconazole and of 164 isolates to tebuconazole and trifloxystrobin was assessed. Mycelial growth inhibition of these isolates was evaluated for all the fungicides using either serial dilution of fungicide rates or the spiral gradient dilution method. In addition, inhibition of conidial germination was also assessed for trifloxystrobin. Analysis of partial ß-tub, cytb, and cyp51b gene sequences did not reveal any mutations related to resistance to MBCs, QoIs, and DMIs, respectively. In mycelial growth assays, mean EC50 values were 0.14, 0.11, and 0.21 µg/ml for difenoconazole, tebuconazole, and trifloxystrobin, respectively. The conidial germination inhibition by trifloxystrobin was similar among the tested isolates, and the mean EC50 value was 0.002 µg/ml. All isolates had similar mean mycelial growth inhibition for carbendazim, regardless of the fungicide concentrations. Therefore, based on similar EC50 values and molecular analyses, no shift in the sensitivity of isolates has been observed to the fungicides commonly used in different citrus-producing areas in Brazil.


Assuntos
Citrus , Colletotrichum , Acetatos , Benzimidazóis , Brasil , Carbamatos , Dioxolanos , Iminas , Doenças das Plantas , Estrobilurinas , Triazóis
3.
Ecotoxicol Environ Saf ; 194: 110446, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32171122

RESUMO

Pesticides can affect all receiving compartments, especially soils, and their fate and effects may be enhanced by temperature, increasing their risk to ecological functions of soils. In Brazil, the most widely used pesticides are the insecticide Kraft 36 EC® (a.s. abamectin) and the fungicide Score 250 EC® (a.s. difenoconazole), which are commonly used in strawberry, often simultaneously as a mixture. The aim of this study was to evaluate the toxicity of realistic environmental applications, single and in mixtures, for both pesticides to the springtail Folsomia candida and the plant species Allium cepa (onion) and Lycopersicum esculentum (tomato). Mesocosms filled with Brazilian natural soil (lattosolo) were dosed with water (control), Kraft (10.8 g a.s/ha), Score (20 g.a.s/ha) and Kraft + Score (10.8 + 20 g a.s./ha). The applications were repeated every 7 days, during 18 days of experiment, and simulating rainfall twice a week. Collembola reproduction tests were conducted with soils from the first (day 1) and last day (day 18) of experiment for each treatment. Plant toxicity tests were carried out in the experimental units. The experiments were run at 23 °C and 33 °C. Kraft, alone and in the binary mixture, showed high toxicity to the springtails in soils from both days 1 and 18, especially at 23 °C where it caused 100% mortality. Score however, was not toxic to the springtails. Plant growth was reduced by Score, but responses varied depending on temperature. This study indicates a high environmental risk of the insecticide Kraft, particularly at lower temperatures (23 °C), and an influence of temperature on pesticide fate and effects.


Assuntos
Dioxolanos/toxicidade , Ivermectina/análogos & derivados , Poluentes do Solo/toxicidade , Triazóis/toxicidade , Animais , Artrópodes/fisiologia , Brasil , Exposição Ambiental , Fungicidas Industriais , Inseticidas/toxicidade , Ivermectina/toxicidade , Praguicidas/toxicidade , Solo , Temperatura , Testes de Toxicidade
4.
Environ Sci Pollut Res Int ; 27(13): 15365-15374, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32077026

RESUMO

The dissipation and terminal residues of difenoconazole in whole bananas and pulp were investigated under field conditions. The residual levels of difenoconazole in various parts of bananas grown in Guangdong, Hainan and Yunnan were determined by a GC-ECD detection method after simple, rapid pretreatment. The mean recovery was 80.66~107.40%, and the relative standard deviation was 3.36~9.84%. The results showed that the half-lives of difenoconazole in whole bananas and in the pulp were 12.16~13.33 days and 17.77~20.38 days, respectively. At harvest intervals of 28 and 35 days after the last application, the terminal residues of difenoconazole in whole bananas and pulp were 0.45~0.84 mg/kg and 0.19~0.37 mg/kg, respectively, which were lower than the maximum residue level established in China. The distribution of difenoconazole in banana pulp and peels was studied. The results showed that until harvesting, the residue in the peels was always 2.19~12.30 times larger than that in the pulp. Difenoconazole was mainly absorbed by the banana peels but did not easily penetrate into the pulp. Based on dietary risk assessment results, the residual levels of difenoconazole at the sampling interval of 28 days after the last application were within acceptable limits for chronic and acute dietary risks in different populations in China. This study can provide a reference for the safe and rational use of difenoconazole as a fungicide and for the future research and application of banana pulp and peels.


Assuntos
Fungicidas Industriais/análise , Musa , Resíduos de Praguicidas/análise , China , Dioxolanos , Meia-Vida , Medição de Risco , Triazóis
5.
Anal Chim Acta ; 1098: 37-46, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31948585

RESUMO

In this work, a selective silica-based molecular imprinted solid-phase microextraction (SPME) sorbent was prepared through the sol-gel process. Difenoconazole was used as a template to prepare imprinted materials on the surface of mesoporous silica. The SPME fiber followed by gas chromatography-electron capture detection was applied for the extraction and determination of difenoconazole. Fourier transform infrared spectrometry, field emission scanning electron microscopy, X-ray diffraction, and thermal gravimetry were used to characterize the imprinted SPME fiber. Two different procedures were presented to prepare MCM-41@SiO2-difenoconazole. Also, a non-MCM molecularly imprinted polymer was synthesized to investigate the effect of MCM-41 on the selectivity and extraction efficiency of the sorbent. The important parameters (i.e., desorption time and temperature, ionic strength, stirring rate, pH, extraction temperature and time) affecting the extraction performance of the method were optimized. Under optimum conditions, the limits of detection and quantification were found to be 0.002 and 0.005 ng mL-1, respectively. Linear dynamic range was in the range of 0.01-1 ng mL-1. The intra- and inter-day relative standard deviations and fiber-to-fiber reproducibility were in the range of 4.3-7.5, 3.3-8.2 and 7.4-9.7%, respectively. The fiber was successfully applied for the selective extraction of difenoconazole from wheat and fruit samples and satisfactory results with extraction recoveries >73% were obtained.


Assuntos
Dioxolanos/isolamento & purificação , Frutas/química , Impressão Molecular , Dióxido de Silício/química , Microextração em Fase Sólida , Triazóis/isolamento & purificação , Triticum/química , Dioxolanos/química , Estrutura Molecular , Triazóis/química
6.
J Anal Toxicol ; 44(1): 103-108, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31504590

RESUMO

High doses of nutmeg (seeds from Myristica fragrans Houtt.) can be abused as a psychoactive drug due to phenylpropene ingredients. During controlled abstinence, e.g., in forensic psychiatric clinics, nutmeg abuse has to be distinguished from an ingestion of other spices having phenylpropene ingredients (e.g., black pepper or garden lovage) or unintentional low-dose nutmeg intake. The aim of this study was to develop an evaluation model for the estimation of time point and amount of nutmeg abuse and differentiation from ingestion of other spices or low doses of nutmeg based on the gas chromatographic-mass spectrometric (GC-MS) analysis of urine samples. A total of 3 volunteers ingested 1.5 g of freshly ground nutmeg. No symptoms were reported. Urine samples were collected for up to 3 days. In addition, 18 blank samples from volunteers with regular diet and 2 authentic samples from forensic psychiatry patients with supposed nutmeg abuse were analyzed. All samples were analyzed by GC-MS in full scan mode. Metabolites of the nutmeg ingredients safrole, myristicin and elemicin were identified via a library search. For semi-quantitative estimations, the area ratios of the analytes to the internal standard (MDMA-d5) were normalized to the creatinine concentration. Up to 8 different metabolites were detected for at least 18 hours after intake of 1.5 g of nutmeg. In the two authentic samples, the normalized area ratios of those metabolites were 0.5-14 times the maximum reached in the intake study. Two additional metabolites could be detected in authentic samples. Probably due to ingestion of other spices, 5 of the 8 metabolites after intake of 1.5 g of nutmeg were detected in blank urine samples as well. The intake of high doses of nutmeg can be differentiated from the ingestion of other spices or low doses of nutmeg via standard GC-MS analysis of urine and application of the proposed evaluation model.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas , Myristica , Psicotrópicos/urina , Detecção do Abuso de Substâncias/métodos , Compostos de Benzil/análise , Dioxolanos/análise , Humanos , Psicotrópicos/análise , Pirogalol/análogos & derivados , Pirogalol/análise , Safrol/análise , Sementes
7.
Artigo em Inglês | MEDLINE | ID: mdl-31674258

RESUMO

Solketal is a promising oxygenate additive that can be chemically derived from bioglycerol. Emulsification by a microwave-irradiating method was used to prepare the micro- and nanoemulsions of solketal dispersed in continuous ultra-low sulfur diesel (ULSD) due to the immiscibility of solketal with ULSD. The emissions from a direct-injection, four-stroke and naturally aspirated diesel engine fueled with each of these emulsions, and with neat ULSD, were analyzed and compared. The experimental results show that the nanoemulsion and microemulsions were successfully produced. In addition, an increasing engine speed resulted in lower NOx, CO and O2 but higher CO2 emissions. The nanoemulsion was found to produce the lowest NOx emission while neat ULSD produced the highest NOx emission among these three test fuels. The lowest CO emission was formed by fueling the micro-emulsion of dispersed solketal-in-ULSD. Moreover, the burning of the nanoemulsion in the diesel engine formed the highest CO2 along with the lowest O2 emissions. Hence, the nanoemulsion had the highest burning efficiency among the three test fuels for the diesel engine.


Assuntos
Dioxolanos/química , Emulsões/química , Gasolina , Emissões de Veículos/análise , Biocombustíveis , Dióxido de Carbono/análise , Monóxido de Carbono/análise , Micro-Ondas , Óxidos de Nitrogênio/análise , Enxofre/química
8.
Pest Manag Sci ; 76(4): 1344-1352, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31605502

RESUMO

BACKGROUND: Stem-end rot caused by Lasiodiplodia theobromae is one of the most important diseases of papaya in northeastern Brazil. It can be controlled effectively by demethylation inhibitor (DMI) fungicides, but the occurrence of DMI resistance may decrease fungicide efficacy. RESULTS: Detached fruit studies revealed that isolates with EC50 values of 6.07 and 6.28 µg mL-1 were not controlled effectively, but reduced virulence and ability to grow at temperatures ranging from 12 to 32 °C suggesting fitness penalties were observed. Cross-resistance was observed only between difenoconazole and propiconazole. The entire cytochrome P450 sterol 14α-demethylase (LtCYP51) gene and its flanking regions were cloned. The gene was 1746 bp in length and contained three introns. The predicted protein contained 525 amino acids. Phylogenetic tree analysis showed that the LtCYP51 belongs to the CYP51B clade. No amino acid variation was found between sensitive and resistant isolates; however, the gene was constitutively more highly expressed in resistant isolates. CONCLUSION: Resistance to DMI fungicides in L. theobromae is based on LtCYP51 gene overexpression and fitness penalties may be present in difenoconazole-resistant isolates. © 2019 Society of Chemical Industry.


Assuntos
Ascomicetos , Carica , Brasil , Dioxolanos , Farmacorresistência Fúngica , Fungicidas Industriais , Filogenia , Triazóis
9.
Chem Biodivers ; 17(2): e1900570, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31778280

RESUMO

A series of sarisan analogs containing 1,3,4-oxadiazole moieties were synthesized by iodine-mediated oxidative cyclization and screened in vitro for their antifungal activities at 50 µg/mL against five phytopathogenic fungi such as Valsa mali, Curvularia lunata, Alternaria alternate, Fusarium solani and Fusarium graminearum. 1,3,4-Oxadiazole derivatives 7e, 7p, 7r, 7t and 7u exhibited potent and a broad spectrum of antifungal activities against at least three phytopathogenic fungi at the concentration of 50 µg/mL. Especially, compound 7r displayed more potent antifungal activities against five phytopathogenic fungi than the positive control hymexazol. The EC50 of 7r against V. mali, C. lunata and A. alternate were 12.6, 14.5 and 17.0 µg/mL, respectively. Additionally, some interesting results of structure-activity relationships (SARs) were also observed.


Assuntos
Antifúngicos/síntese química , Produtos Biológicos/síntese química , Dioxolanos/química , Desenho de Fármacos , Oxidiazóis/química , Alternaria/efeitos dos fármacos , Antifúngicos/farmacologia , Ascomicetos/efeitos dos fármacos , Produtos Biológicos/farmacologia , Dioxolanos/farmacologia , Fusarium/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
10.
Chemosphere ; 244: 125491, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31835051

RESUMO

Polyethylene (PE) agricultural soil films are easily embrittled and decomposed to microplastics (MPs) in environment. As widely used pesticides in vegetable farmland, carbendazim, dipterex, diflubenzuron, malathion, difenoconazole have potential environmental and human safety risks. They are often coexisting with MPs in the environment, and may cause consequential pollution to the ecosystem. Studying the adsorption behavior between pesticides and PE agricultural soil films MPs would be helpful for the risk assessment of co-exposure of pesticides and MPs. Herein, a systematic study on batch adsorption experiments was performed to determine the adsorption process of pesticides on MPs, the environmental factors on adsorption capacity were evaluated, and the adsorption mechanisms were discussed. Results suggested that all these five pesticides can adsorb on MPs, especially for diflubenzuron and difenoconazole. The adsorption kinetics and isotherm fitted to the Pseudo-second-order and Freundlich model, respectively, indicating that besides the adsorption onto surface sites, mass transfer and intraparticle diffusion were involved in the adsorption process, and the adsorption process was mostly controlled by physical and chemical interactions. The adsorption amounts of 5 pesticides on PE MPs follow the order of DIF > DIFE > MAL > CAR > DIP with KF correlated positively with octanol-water partition coefficients (LogKow). The thermodynamic study indicates the adsorption of all pesticides as spontaneous and exothermic processes. The results of this study illustrated that PE MPs can be a good carrier of pesticides in agricultural field.


Assuntos
Microplásticos/química , Praguicidas/química , Poluentes do Solo/química , Adsorção , Agricultura , Difusão , Dioxolanos , Ecossistema , Cinética , Plásticos , Polietileno/química , Solo , Triazóis
11.
Environ Sci Pollut Res Int ; 26(34): 35253-35265, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31701422

RESUMO

Difenoconazole is a fungicide extensively used in agriculture. The aim of this study was to evaluate the effects of difenoconazole fungicide on the sperm quality of rats. Wistar rats were divided into four groups: control and exposed to 5 (D5), 10 (D10), or 50 mg-1 kg bw-1day (D50) of difenoconazole for 30 days, by gavage. Classical sperm parameters and surface-enhanced Raman scattering (SERS) were performed. Progressive motility, acrosomal integrity, and percentage of morphologically normal spermatozoa were reduced in the D10 and D50 groups in comparison with the control group. Sperm viability was reduced only in the D50 group. Sperm number in the testis and caput/corpus epididymis and daily sperm production were reduced in the three exposed groups. SERS measurements showed changes in the spectra of spermatozoa from D50 group, suggesting DNA damage. In addition, machine learning (ML) methods were used to evaluate the performance of three classification algorithms (artificial neural network-ANN, K-nearest neighbors-K-NN, and support vector machine-SVM) in the identification task of the groups exposed to difenoconazole. The results obtained by ML algorithms were very promising with accuracy ≥ 90% and validated the hypothesis of the exposure to difenoconazole reduces sperm quality. In conclusion, exposure of rats to different doses of the fungicide difenoconazole may impair sperm quality, with a recognizable classification pattern of exposure groups.


Assuntos
Dioxolanos/toxicidade , Fungicidas Industriais/toxicidade , Aprendizado de Máquina , Espermatozoides/efeitos dos fármacos , Triazóis/toxicidade , Animais , Dano ao DNA , Epididimo/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Análise Espectral Raman , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Máquina de Vetores de Suporte , Testículo/efeitos dos fármacos , Testes de Toxicidade
12.
Mol Cells ; 42(12): 884-892, 2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31735020

RESUMO

Piperlongumine (PL), a natural alkaloid compound isolated from long pepper (Piper longum), can selectively kill cancer cells, but not normal cells, by accumulation of reactive oxygen species (ROS). The objective of this study was to investigate functional roles of expression of SETDB1 and FosB during PL treatment in MCF7 breast cancer cells. PL downregulates SETDB1 expression, and decreased SETDB1 expression enhanced caspase 9 dependent-PARP cleavage during PL-induced cell death. PL treatment generated ROS. ROS inhibitor NAC (N-acetyl cysteine) recovered SETDB1 expression decreased by PL. Decreased SETDB1 expression induced transcriptional activity of FosB during PL treatment. PARP cleavage and positive annexin V level were increased during PL treatment with FosB overexpression whereas PARP cleavage and positive annexin V level were decreased during PL treatment with siFosB transfection, implying that FosB might be a pro-apoptotic protein for induction of cell death in PL-treated MCF7 breast cancer cells. PL induced cell death in A549 lung cancer cells, but molecular changes involved in the induction of these cell deaths might be different. These results suggest that SETDB1 mediated FosB expression may induce cell death in PL-treated MCF7 breast cancer cells.


Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/genética , Dioxolanos/farmacologia , Proteínas Proto-Oncogênicas c-fos/genética , Espécies Reativas de Oxigênio/metabolismo , Células A549 , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/genética , Humanos , Células MCF-7 , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/antagonistas & inibidores
13.
Drugs ; 79(16): 1785-1796, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31617141

RESUMO

Stiripentol (Diacomit®) is an orally-active, structurally unique anti-epileptic drug (AED) with multiple potential mechanisms of action, including enhancement of central γ-aminobutyric acid transmission. In the EU, stiripentol is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with Dravet syndrome (DS; previously known as severe myoclonic epilepsy of infancy), whose seizures are not adequately controlled with clobazam and valproate. This approval (and similar DS indications in the USA, Canada and Japan), reflect the results of the STICLO studies, two small, randomized controlled trials in which stiripentol as adjunctive therapy was associated with a markedly superior response rate after 2 months compared with placebo in patients aged between 3 and ≈ 21 years with DS that was inadequately controlled with clobazam and valproate. These short-term results have subsequently been supported and extended by findings from longer-term, open-label, observational studies, including a retrospective longitudinal cohort study, which showed that the efficacy of combining stiripentol with clobazam and valproate when started at paediatric age was maintained in mid-adulthood with up to 24 years of exposure, and up to 40 years of age. Drowsiness, appetite loss, weight loss, ataxia and tremor are the most common adverse events associated with the addition of stiripentol to clobazam and valproate. Based on the available evidence, stiripentol, as an adjunct to clobazam and valproate, is a demonstrably beneficial and generally well-tolerated second-line treatment for patients with DS.


Assuntos
Anticonvulsivantes/uso terapêutico , Dioxolanos/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Dioxolanos/administração & dosagem , Dioxolanos/efeitos adversos , Humanos , Convulsões/tratamento farmacológico
14.
Vet Parasitol ; 275: 108932, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31600614

RESUMO

This study describes the in vitro anthelmintic activity of a hydroalcoholic extract from the fruit of Piper cubeba and its major isolated components against the eggs and larvae of gastrointestinal nematodes obtained from naturally-infected ovines. In vitro anthelmintic activity was evaluated using the egg hatch test (EHT), larval development test (LDT) and L3 migration inhibition test (LMT). The extract showed ovicidal and larvicidal activity, with an EC50 of 200 µg/mL and 83.00 µg/mL in the EHT and LDT, respectively. The extract inhibited 100% of larval migration at the lowest tested concentration (95 µg/mL). The crude extract was purified using successive silica gel chromatographic columns, which revealed the lignans hinokinin, cubebin and dihydrocubebin as the major compounds that were present, which were then used in in vitro tests. Cubebin, dihydrocubebin and hinokinin showed higher activity than the crude extract, with an EC50 for ovicidal activity of 150.00 µg/mL, 186.70 µg/mL and 68.38 µg/mL, respectively. In the LDT, cubebin presented an EC50 of 14.89 µg/mL and dihydrocubebin of 30.75 µg/mL. Hinokinin inhibited 100% the larval development at all concentrations evaluated. In the LMT, dihydrocubebin inhibited 100% the larval migration in all concentrations evaluated while cubebin and hinokinin showed EC50 values of 0.89 µg/mL and 0.34 µg/mL, respectively. P. cubeba extract is rich in several classes of active compounds, but here we demonstrate that the described anthelmintic activity may be related to the presence of these lignans, which are present in larger concentrations than other components of the extract. Our results demonstrate for first time the anthelmintic activity against gastrointestinal nematodes in sheep for this class of special metabolites that are present in P. cubeba fruit. However, future detailed studies are needed to evaluate the effectiveness of P. cubeba fruits extract and active lignans in in vivo tests.


Assuntos
Enteropatias Parasitárias/veterinária , Lignanas/farmacologia , Nematoides/efeitos dos fármacos , Infecções por Nematoides/veterinária , Piper/química , Extratos Vegetais/farmacologia , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Animais , Benzodioxóis/química , Benzodioxóis/isolamento & purificação , Benzodioxóis/farmacologia , Cromatografia em Gel/veterinária , Dioxolanos/química , Dioxolanos/isolamento & purificação , Dioxolanos/farmacologia , Fezes/parasitologia , Frutas/química , Enteropatias Parasitárias/tratamento farmacológico , Enteropatias Parasitárias/parasitologia , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Larva/fisiologia , Lignanas/química , Lignanas/isolamento & purificação , Microscopia Eletrônica de Varredura/veterinária , Nematoides/crescimento & desenvolvimento , Nematoides/fisiologia , Infecções por Nematoides/tratamento farmacológico , Infecções por Nematoides/parasitologia , Óvulo/efeitos dos fármacos , Óvulo/fisiologia , Extratos Vegetais/química , Ovinos , Doenças dos Ovinos/parasitologia
15.
Epilepsia ; 60(11): 2255-2262, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31630399

RESUMO

OBJECTIVE: To assess the long-term efficacy and tolerability of stiripentol (STP) as an adjunctive treatment in different forms of refractory epilepsies. METHODS: The medical records of all individuals consecutively treated with STP as add-on therapy for refractory epilepsies, irrespective of their being focal, generalized, or both, and followed at Meyer Children's Hospital between January 2007 and May 2018, were reviewed. The drug scheme administration consisted of a starting dose of STP of 10-15 mg/kg/d with increments every week, up to a maximum of 50 mg/kg/d, based on both age and weight. Etiology of epilepsy was codified as structural, genetic, infectious, immune, metabolic, and unknown. Responders were defined as patients who achieved a seizure frequency reduction of ≥50%. Retention rate was defined as the probability of continuing STP without additional therapy. Tolerability was assessed by reporting adverse events. RESULTS: A total of 132 individuals aged from 5 months to 43 years received add-on STP, including 30 patients with Dravet syndrome (DS). The median follow-up was 14.8 months (range = 4 months-18 years, interquartile range = 25.72). Twenty-nine individuals (22%) received more than two antiepileptic drugs. Benzodiazepines, mainly clobazam, were the most commonly used add-on drugs. Sixty-six patients (50%) were responders, and 13 of them (9.8%) were seizure-free. Responder rate was higher in the genetic etiology group (57%), especially in DS (18/30; 60%), and in patients with refractory focal onset epilepsy without bilateral tonic-clonic seizures (5/15; 33%). The median relapse-free survival was 27 months in the 66 responders. The median time to STP failure was 24.6 months in all 132 individuals. SIGNIFICANCE: This study confirms the long-term efficacy of add-on STP treatment in patients with different types of refractory epilepsies, including focal onset epilepsy without bilateral tonic-clonic seizures. Further confirmations based on prospectively designed studies are required to confirm STP efficacy in focal epilepsy.


Assuntos
Anticonvulsivantes/administração & dosagem , Dioxolanos/administração & dosagem , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
17.
Cell Oncol (Dordr) ; 42(6): 847-860, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31493144

RESUMO

PURPOSE: Oxaliplatin is one of the most commonly used chemotherapeutic agents in the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Therefore, there is a pressing need to develop novel therapies to potentiate the efficacy and reduce the toxicity of oxaliplatin. Piperlongumine (PL), an alkaloid isolated from Piper longum L., has recently been identified as a potent agent against cancer cells in vitro and in vivo. In the present study, we investigated whether PL can potentiate the antitumor effect of oxaliplatin in gastric cancer cells. METHODS: Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells or tumor tissues was determined using an endpoint insulin reduction assay. Western blotting was used to analyze the expression levels of the indicated proteins. Nude mice xenograft models were used to test the effects of PL and oxaliplatin combinations on gastric cancer cell growth in vivo. RESULTS: We found that PL significantly enhanced oxaliplatin-induced growth inhibition in both gastric and colon cancer cells. Moreover, we found that PL potentiated the antitumor effect of oxaliplatin by inhibiting TrxR1 activity. PL combined with oxaliplatin markedly suppressed the activity of TrxR1, resulting in the accumulation of ROS and, thereby, DNA damage induction and p38 and JNK signaling pathway activation. Pretreatment with antioxidant N-acetyl-L-cysteine (NAC) significantly abrogated the combined treatment-induced ROS generation, DNA damage and apoptosis. Importantly, we found that activation of the p38 and JNK signaling pathways prompted by PL and oxaliplatin was also reversed by NAC pretreatment. In vivo, we found that PL combined with oxaliplatin significantly suppressed tumor growth in a gastric cancer xenograft model, and effectively reduced the activity of TrxR1 in tumor tissues. Remarkably, we found that PL attenuated body weight loss evoked by oxaliplatin treatment. CONCLUSIONS: Our data support a synergistic effect of PL and oxaliplatin and suggest that application of its combination may be more effective for the treatment of gastric cancer than oxaliplatin alone.


Assuntos
Antineoplásicos/farmacologia , Dioxolanos/farmacologia , Oxaliplatina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Sinergismo Farmacológico , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Tiorredoxina Redutase 1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Eur J Med Chem ; 183: 111650, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539780

RESUMO

Inspired by the traditional Chinese herbal pair of Polygala tenuifolia-Acori Tatarinowii for treating epilepsy, 33 novel substituted cinnamic α-asaronol esters and analogues were designed by Combination of Traditional Chinese Medicine Molecular Chemistry (CTCMMC) strategy, synthesized and tested systematically not only for anticonvulsant activity in three mouse models but also for LDH inhibitory activity. Thereinto, 68-70 and 75 displayed excellent and broad spectra of anticonvulsant activities with modest ability in preventing neuropathic pain, as well as low neurotoxicity. The protective indices of these four compounds compared favorably with stiripentol, lacosamide, carbamazepine and valproic acid. 68-70 exhibited good LDH1 and LDH5 inhibitory activities with noncompetitive inhibition type, and were more potent than stiripentol. Notably, 70, as a representative agent, was also shown as a moderately positive allosteric modulator at human α1ß2γ2 GABAA receptors (EC50 46.3 ±â€¯7.3 µM). Thus, 68-70 were promising candidates for developing into anti-epileptic drugs, especially for treatment of refractory epilepsies such as Dravet syndrome.


Assuntos
Anisóis/química , Anticonvulsivantes/química , Cinamatos/química , Medicamentos de Ervas Chinesas/química , Ésteres/química , L-Lactato Desidrogenase/antagonistas & inibidores , Polygala/química , Regulação Alostérica , Animais , Anisóis/farmacologia , Anticonvulsivantes/farmacologia , Carbamazepina/química , Carbamazepina/farmacologia , Cinamatos/farmacologia , Dioxolanos/química , Dioxolanos/farmacologia , Desenho de Fármacos , Medicamentos de Ervas Chinesas/farmacologia , Ésteres/farmacologia , Humanos , Medicina Tradicional Chinesa , Camundongos , Estrutura Molecular , Neuralgia/prevenção & controle , Receptores de GABA-A/metabolismo , Relação Estrutura-Atividade , Ácido Valproico/química , Ácido Valproico/farmacologia
19.
Chem Biol Interact ; 313: 108820, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518571

RESUMO

Natural products with potent activity and less toxicity provide major sources for development of novel anti-cancer drugs. Herein, we evaluated the effects and the underlying mechanisms of a novel piperlongumine (PL) analogue L50377 on non-small-cell lung cancer (NSCLC) cells. The results revealed that L50377 displayed greater potentials of suppressing cell growth than PL. In addition, L50377 promoted cell apoptosis and pyroptosis via stimulating reactive oxygen species (ROS) generation in NSCLC cells. More interestingly, ROS mediated NF-κB suppression might be implicated in the mechanisms of L50377-induced pyroptosis in NSCLC cells. Taken together, our results suggested that L50377 served as a novel chemical agent might have great potentials for NSCLC treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dioxolanos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Dioxolanos/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo
20.
Behav Pharmacol ; 30(8): 722-729, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31503069

RESUMO

Piperlongumine, an alkaloid compound extracted from Peper longum L, has been reported to produce neuroprotective effects in the brain and exert various pharmacological activities such as antitumor, antiangiogenic, anti-inflammatory and analgesic properties. The aim of this study was to investigate the antidepressant-like effects and the possible mechanism of action of piperlongumine in a chronic unpredictable stress (CUS) model. We found that, with venlafaxine as a positive control, orally administered piperlongumine (12.5 and 25 mg/kg) for 7 days, not a single dose, significantly reduced immobility time in the forced swimming test, but did not alter locomotor activity in the open field test, indicating that piperlongumine has antidepressant-like effects without nonspecific motor changes. Then, using the CUS model of depression, piperlongumine was administrated orally for 4 weeks, followed by sucrose preference and forced swimming tests to evaluate the depressive-like behaviors. We found that piperlongumine reversed both the decreased sucrose preference and increased immobility time in rats exposed to CUS. In addition, piperlongumine also reversed the increase in proinflammatory cytokine levels in the hippocampus of rats in the CUS model. Altogether, the present study demonstrated that piperlongumine exhibits the antidepressant-like effects in rats, which may be mediated by the inhibition of the neuronal inflammation in the hippocampus.


Assuntos
Depressão/tratamento farmacológico , Dioxolanos/farmacologia , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Cloridrato de Venlafaxina/farmacologia
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