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1.
Biofouling ; 36(2): 200-209, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32253933

RESUMO

Biodegradable polymers are promising binders and carriers for natural antifoulants. In the present study, an antifouling (AF) coating was developed by adding a non-toxic AF compound (butenolide) to a bio-based and biodegradable poly(lactic acid)-based polyurethane. Mass loss measurement showed that the polymer degraded in seawater at a rate of 0.013 mg cm-2 day-1. Measurements showed that butenolide was released from the coatings into seawater over a period of at least three months. Both the concentration of butenolide in the coatings and the ambient temperature determined the release rate of butenolide. The results further demonstrate that incorporating rosin into the coatings increase the self-renewal rate of the polymer and facilitated the long-term release of butenolide from the coating. The results show that poly(lactic acid)-based polyurethane is a suitable polymer for butenolide-based AF coatings.


Assuntos
4-Butirolactona/análogos & derivados , Plásticos Biodegradáveis/química , Incrustação Biológica/prevenção & controle , Desinfetantes/química , Poliésteres/química , Poliuretanos/química , 4-Butirolactona/química , Desinfetantes/análise , Água do Mar/química , Propriedades de Superfície
2.
Int J Pharm ; 578: 119096, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32006626

RESUMO

In contrast to the plethora of antibacterial agents, only a handful of antifungals are currently available to treat Candida albicans biofilm-associated infections. Additional novel antibiofilm strategies to eliminate C. albicans biofilm infections are needed. This study aims to improve the efficacy of a widely used azole, fluconazole by co-delivering it with a Pseudomonas aeruginosa quorum sensing molecule (QSM), N-3-oxo-dodecanoyl-L-homoserine lactone (C12AHL) in a liposomal formulation. C12AHL is known to inhibit C. albicans' morphological transition and biofilm formation. Four different formulations of liposomes with fluconazole (L-F), with C12AHL (L-H), with fluconazole and C12AHL (L-HF), and a drug-free control (L-C) were prepared using a thin-film hydration followed by extrusion method, and characterised. The effect of liposomes on colonising (90 min-24 h) and preformed (24 h) C. albicans biofilms were assessed using a standard biofilm assay. Biofilm viability (XTT reduction assay), biomass (Safranin-O staining) and architecture (confocal laser scanning microscopy, CLSM) were determined. Similar efficiencies of fluconazole entrapment were noticed in L-HF and L-F (11.74% vs 10.2%), however, L-HF released greater quantities of fluconazole compared to L-F during 24 h (4.27% vs 0.97%, P < 0.05). The entrapment and release of C12AHL was similar for L-H and L-HF liposomes (33.3% vs 33% and 88.9% vs 92.3% respectively). L-HF treated colonising, and preformed biofilms exhibited >80%, and 60% reduction in their respective viabilities at a fluconazole concentration as low as 5.5 µg/mL compared to 12% and 36%, respective reductions observed in L-F treated biofilms (P < 0.05). CLSM confirmed biofilm disruption, lack of hyphae, and reduction in biomass when treated with L-HF compared to other liposomal preparations. Liposomal co-delivery of C12AHL and fluconazole appears to suppress C. albicans biofilms through efficacious disruption of the biofilm, killing of constituent yeasts, and diminishing their virulence at a significantly lower antifungal dose. Therefore, liposomal co-formulation of C12AHL and fluconazole appears to be a promising approach to improve the efficacy of this common triazole against biofilm-mediated candidal infections.


Assuntos
4-Butirolactona/análogos & derivados , Antifúngicos/administração & dosagem , Candida albicans/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Fluconazol/administração & dosagem , Homosserina/análogos & derivados , Pseudomonas aeruginosa/fisiologia , Percepção de Quorum , 4-Butirolactona/administração & dosagem , 4-Butirolactona/química , Antifúngicos/química , Biofilmes/efeitos dos fármacos , Candida albicans/fisiologia , Liberação Controlada de Fármacos , Fluconazol/química , Homosserina/administração & dosagem , Homosserina/química , Lipossomos
3.
PLoS One ; 15(2): e0227811, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32023266

RESUMO

Anopheles darlingi is the main vector of malaria in Brazil, characterized by a high level of anthropophilia and endophagy. Imidacloprid, thiacloprid, and acetamiprid are the most widespread insecticides of the neonicotinoid group. However, they produce adverse effects on the non-target insects. Flupyradifurone has been marketed as an alternative to non-fluorinated neonicotinoids. Neonicotinoids containing trifluoroacethyl substituent reveal increased insecticidal activity due to higher hydrophobicity and metabolic stability. We synthesized novel neonicotinoid insecticides containing fluorinated acceptor groups and their interactions were estimated with the nicotinic acetylcholine receptor (nAChR) binding site by molecular docking studies, to evaluate their larvicidal activity against A. darlingi, and to assess their outdoor photodegradation behavior. New neonicotinoid analogues were prepared and characterized by NMR and mass-spectrometry. The synthesized molecules were modelled by time-dependent density functional theory and analyzed, their interaction with nAChR was investigated by molecular docking. Their insecticide activity was tested on Anopheles larvae collected in suburban area of Manaus, Brazil. Four new fluorinated neonicotinoid analogs were prepared and tested against 3rd instars larvae of A. darlingi showing high larvicidal activity. Docking studies reveal binding modes of the synthesized compounds and suggest that their insecticidal potency is governed by specific interactions with the receptor binding site and enhanced lipophilicity. 2-Chloro-5-(2-trifluoromethyl-pyrrolidin-1-ylmethyl)pyridine 5 showed fast degradation in water maintaining high larvicidal activity. All obtained substances possessed high larvicidal activity in low concentrations in 48 hours of exposure, compared to commercial flupyradifurone. Such activity is connected to a unique binding pattern of the synthesized compounds to insect's nAChR and to their enhanced bioavailability owing to introduction of fluorinated amino-moieties. Therefore, the compounds in question have a high potential for application as control agents for insects transmitting tropical diseases, and they will be less persistent in the environment.


Assuntos
Anopheles/efeitos dos fármacos , Halogenação , Inseticidas/toxicidade , Simulação de Acoplamento Molecular , Neonicotinoides/toxicidade , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/toxicidade , Animais , Inseticidas/química , Larva/efeitos dos fármacos , Neonicotinoides/síntese química , Neonicotinoides/química , Piridinas/química , Piridinas/toxicidade , Espectrofotometria Ultravioleta , Eletricidade Estática
4.
Molecules ; 25(1)2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31906599

RESUMO

The purpose of this study was to establish an extraction method for the kinsenoside compound from the whole plant Anoectochilus roxburghii. Ultrasound assisted extraction (UAE) and Ultra-high performance liquid chromatography (UPLC) method were used to extract and determine the content of kinsenoside, while response surface method (RSM) was used to optimize the extraction process. The best possible range for methanol concentration (0-100%), the liquid-solid ratio (5:1-30:1 mL/g), ultrasonic power (240-540 W), duration of ultrasound (10-50 min), ultrasonic temperature (10-60 °C), and the number of extractions (1-4) were obtained according to the single factor experiments. Then, using the Box-Behnken design (BBD) of response surface analysis, the optimum extraction conditions were obtained with 16.33% methanol concentration, the liquid-solid ratio of 10.83:1 mL/g and 35.00 °C ultrasonic temperature. Under these conditions, kinsenoside extraction yield reached 32.24% dry weight. The best conditions were applied to determine the kinsenoside content in seven different cultivation ages in Anoectochilus roburghii.


Assuntos
4-Butirolactona/análogos & derivados , Monossacarídeos/química , Orchidaceae/química , Ultrassom , 4-Butirolactona/química , Cromatografia Líquida de Alta Pressão , Temperatura
5.
Microbiol Res ; 231: 126354, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31678651

RESUMO

Quorum sensing (QS) in rhizobia regulates diverse processes determining the success and efficiency of association with the legume host. Despite the notable importance of QS as well as the well-known underlying variability in the genomic and metabolic components thereof, its study in rhizobia is largely restricted to few laboratory strains. In this work, QS phenomenon in the rhizobia nodulating pigeon pea- one of the most important legume crops of the global-south, is characterized. Using 16S rRNA and recombinaseA sequencing analysis, the selected QS-positive and host-beneficial isolates were identified to be taxonomically affiliated to the genus Ensifer. Their QS components, including homologues of QS genes, and the repertoire of N-acyl homoserine lactone (AHL) autoinducers were identified. Sequences of the QS homologues showed significant variabilities ranging from 10 to >20% with the known Ensifer sequences. Autoinducer profiling using LC-MS/MS revealed the production of long and short chain AHLs variably by the isolates, including 3-oxo-C12-homoserine lactone (3-O-C12-HSL) and 3-OH-C16-HSL as their first report in Rhizobiaceae. Motility and attachment- two of the most crucial traits for effective establishment on host roots were discovered to be QS dependent in in vitro analysis and the same was confirmed using expression analysis of their regulatory genes using qRT-PCR; both revealing a QS mediated repression of motility and promotion of attachment. This study highlights that Ensifer nodulating pigeon pea, although with significant variance in the anatomy of their QS components, regulate symbiotically crucial cell-processes via QS in a scheme that is conserved in multiple genera.


Assuntos
4-Butirolactona/análogos & derivados , Cajanus/microbiologia , Nodulação , Percepção de Quorum , Sinorhizobium , 4-Butirolactona/química , 4-Butirolactona/genética , 4-Butirolactona/metabolismo , Proteínas de Bactérias/genética , Cajanus/crescimento & desenvolvimento , Regulação Bacteriana da Expressão Gênica , Filogenia , Percepção de Quorum/genética , Percepção de Quorum/fisiologia , RNA Ribossômico 16S , Rhizobiaceae/classificação , Rhizobiaceae/isolamento & purificação , Rhizobiaceae/metabolismo , Sinorhizobium/isolamento & purificação , Sinorhizobium/metabolismo , Simbiose
6.
Eur J Med Chem ; 187: 111969, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31865018

RESUMO

Compounds inducing adiponectin production have therapeutic potential for metabolic diseases. During screening, heme oxygenase-1-inducing marliolide derivatives were identified as adiponectin-inducing compounds. Although some marliolide derivatives were directly bound to peroxisome proliferator-activated receptor γ (PPARγ), the adiponectin-inducing activity did not correlate with the PPARγ binding affinity. The most potent adiponectin inducing compound, (E,4S,5S)-3-butylidene-dihydro-4-hydroxy-5-methylfuran-2(3H)-one (1a), exhibited the weakest PPARγ binding activity. A docking simulation suggested that two 1a molecules can be present in two different sites within the PPARγ-ligand-binding pocket (LBP). Based on the docking model, novel linked butanolide dimer compounds were synthesized. A linked butanolide dimer compound, (3E,3'E,4S,4'S,5S,5'S)-3,3'-(decane-1,10-diylidene)bis(4-hydroxy-5-methyldihydrofuran-2(3H)-one) (3a), promoted adiponectin production in human bone marrow mesenchymal stem cells (hBM-MSCs) as a novel PPARγ full agonist (EC50, 4.34 µM). This linked butanolide dimer study provides novel insight into PPARγ biology, suggesting that small molecules can form multiple ligand interactions within the PPARγ-LBP and thereby affect the functional outcomes of PPARγ activation.


Assuntos
4-Butirolactona/farmacologia , Adipogenia/efeitos dos fármacos , Adiponectina/biossíntese , Células-Tronco Mesenquimais/efeitos dos fármacos , PPAR gama/agonistas , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , Células Cultivadas , Dimerização , Relação Dose-Resposta a Droga , Humanos , Células-Tronco Mesenquimais/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , PPAR gama/metabolismo , Relação Estrutura-Atividade
8.
Microbes Environ ; 34(4): 429-435, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31666459

RESUMO

The plant pathogen Pectobacterium carotovorum subsp. carotovorum (Pcc) regulates the expression of virulence factors by N-acylhomoserine lactone (AHL)-mediated quorum sensing. The LuxI family protein, ExpI, catalyzes AHL biosynthesis in Pcc. The structure of the predominant AHL produced by ExpI differs among Pcc strains, which may be divided into two quorum-sensing classes (QS classes) based on the AHL produced. In the present study, AHL produced by 282 Pcc strains were extracted and identified by LC-MS/MS. Seventy Pcc strains produced N-(3-oxooctanoyl)-l-homoserine lactone (3-oxo-C8-HSL) as the predominant AHL and were categorized into QS class I. Two hundred Pcc strains produced N-(3-oxohexanoyl)-l-homoserine lactone (3-oxo-C6-HSL) as the predominant AHL, and were categorized into QS class II-1. Twelve Pcc strains produced only small amounts of 3-oxo-C6-HSL, and were categorized into QS class II-2. The phylogenetic analysis revealed that the amino acid sequences of ExpI may be divided into two major clades (I and II). The Pcc strains categorized into ExpI clades I and II entirely matched QS classes I and II, respectively. A multiple alignment analysis demonstrated that only 6 amino acid substitutions were observed among ExpI from QS classes II-1 and II-2. Furthermore, many amino acid substitutions between QS classes I and II were concentrated at the C-terminal region. These amino acid substitutions are assumed to cause significant reductions in 3-oxo-C6-HSL in QS class II-2 or affect the substrate specificity of ExpI between QS classes I and II.


Assuntos
Acil-Butirolactonas/metabolismo , Variação Genética , Pectobacterium carotovorum/genética , Pectobacterium carotovorum/metabolismo , Doenças das Plantas/microbiologia , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/metabolismo , Acil-Butirolactonas/química , Sequência de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Homosserina/análogos & derivados , Homosserina/química , Homosserina/metabolismo , Pectobacterium carotovorum/classificação , Filogenia , Percepção de Quorum
9.
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
10.
Chem Pharm Bull (Tokyo) ; 67(10): 1088-1098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582628

RESUMO

In this study, we synthesized four series of novel L-homoserine lactone analogs and evaluated their in vitro quorum sensing (QS) inhibitory activity against two biomonitor strains, Chromobacterium violaceum CV026 and Pseudomonas aeruginosa PAO1. Studies of the structure-activity relationships of the set of L-homoserine lactone analogs indicated that phenylurea-containing N-dithiocarbamated homoserine lactones are more potent than (Z)-4-bromo-5-(bromomethylene)-2(5H)-furanone (C30), a positive control for biofilm formation. In particular, compared with C30, QS inhibitor 11f significantly reduced the production of virulence factors (pyocyanin, elastase and rhamnolipid), swarming motility, the formation of biofilm and the mRNA level of QS-related genes regulated by the QS system of PAO1. These results reveal 11f as a potential lead compound for developing novel antibacterial quorum sensing inhibitors.


Assuntos
4-Butirolactona/análogos & derivados , Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , 4-Butirolactona/síntese química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pseudomonas aeruginosa/crescimento & desenvolvimento , Percepção de Quorum/genética , Relação Estrutura-Atividade
11.
Int J Mol Sci ; 20(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430981

RESUMO

A library of isopulegol-based bi-, tri- and tetrafunctional chiral ligands has been developed from commercially available (-)-isopulegol and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. Michael addition of primary amines towards α-methylene-γ-butyrolactone, followed by reduction, was accomplished to provide aminodiols in highly stereoselective transformations. Stereoselective epoxidation of (+)-neoisopulegol, derived from natural (-)-isopulegol, and subsequent oxirane ring opening with primary amines afforded aminodiols. The regioselective ring closure of N-substituted aminodiols with formaldehyde was also investigated. Hydroxylation of (+)-neoisopulegol resulted in diol, which was then transformed into aminotriols by aminolysis of its epoxides. Dihydroxylation of (+)-neoisopulegol or derivatives with OsO4/NMO gave neoisopulegol-based di-, tri- and tetraols in highly stereoselective reactions. The antimicrobial activity of aminodiol and aminotriol derivatives as well as di-, tri- and tetraols was also explored. In addition, structure-activity relationships were examined by assessing substituent effects on the aminodiol and aminotriol systems.


Assuntos
Monoterpenos Cicloexânicos/síntese química , 4-Butirolactona/síntese química , 4-Butirolactona/química , Aminação , Amino Álcoois/síntese química , Amino Álcoois/química , Benzaldeídos/síntese química , Benzaldeídos/química , Catálise , Técnicas de Química Sintética , Monoterpenos Cicloexânicos/química , Ligantes , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Estereoisomerismo
12.
Molecules ; 24(15)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344938

RESUMO

Many Gram-negative bacteria can regulate gene expression in a cell density-dependent manner via quorum-sensing systems using N-acyl-homoserine lactones (AHLs), which are typical quorum-sensing signaling molecules, and thus modulate physiological characteristics. N-acyl-homoserine lactones are small chemical molecules produced at low concentrations by bacteria and are, therefore, difficult to detect. Here, a biosensor system method and liquid chromatography-tandem mass spectrometry were combined to detect and assay AHL production. As demonstrated by liquid chromatography-tandem mass spectrometry, Gluconacetobacter xylinus CGMCC No. 2955, a Gram-negative acetic acid-producing bacterium and a typical bacterial cellulose (BC) biosynthesis strain, produces six different AHLs, including N-acetyl-homoserine lactone, N-butanoyl-homoserine lactone, N-hexanoyl-homoserine lactone, N-3-oxo-decanoyl-homoserine lactone, N-dodecanoyl-homoserine lactone, and N-tetradecanoyl-homoserine lactone. Gluconacetobacter sp. strain SX-1, another Gram-negative acetic acid-producing bacterium, which can synthesize BC, produces seven different AHLs including N-acetyl-homoserine lactone, N-butanoyl-homoserine lactone, N-hexanoyl-homoserine lactone, N-3-oxo-octanoyl-homoserine lactone, N-decanoyl-homoserine lactone, N-dodecanoyl-homoserine lactone, and N-tetradecanoyl-homoserine lactone. These results lay the foundation for investigating the relationship between BC biosynthesis and quorum-sensing systems.


Assuntos
4-Butirolactona/análogos & derivados , Cromatografia Líquida , Gluconacetobacter/química , Espectrometria de Massas em Tandem , 4-Butirolactona/análise , 4-Butirolactona/química , Proteínas de Bactérias/biossíntese , Técnicas Biossensoriais , Celulose/biossíntese , Cromatografia Líquida/métodos , Gluconacetobacter/fisiologia , Percepção de Quorum , Espectrometria de Massas em Tandem/métodos
13.
Molecules ; 24(14)2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31330867

RESUMO

Three new γ-hydroxyl butenolides (1-3), a pair of new enantiomeric spiro-butenolides (4a and 4b), a pair of enantiomeric cyclopentenones (5a new and 5b new natural), and six known compounds (6-11), were isolated from Aspergillus sclerotiorum. Their structures were established by spectroscopic data and electronic circular dichroism (ECD) spectra. Two pairs of enantiomers [(+)/(-)-6c and (+)/(-)-6d] obtained from the reaction of 6 with acetyl chloride (AcCl) confirmed that 6 was a mixture of two pairs of enantiomers. In addition, the X-ray data confirmed that 7 was also a racemate. The new metabolites (1-5) were evaluated for their inhibitory activity against cancer and non-cancer cell lines. As a result, compound 1 exhibited moderate cytotoxicity to HL60 and A549 with IC50 values of 6.5 and 8.9 µM, respectively, and weak potency to HL-7702 with IC50 values of 17.6 µM. Furthermore, compounds 1-9 were screened for their antimicrobial activity using the micro-broth dilution method. MIC values of 200 µg/mL were obtained for compounds 2 and 3 towards Staphylococcus aureus and Escherichia coli, while compound 8 exhibited a MIC of 50 µ/mL towards Candida albicans.


Assuntos
4-Butirolactona/análogos & derivados , Aspergillus/química , Ciclopentanos/química , Microbiologia do Solo , Solo/química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Análise Espectral , Relação Estrutura-Atividade
14.
Int J Mol Sci ; 20(12)2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31238568

RESUMO

An electrospinning process was optimized to produce fibers of micrometric size with different combinations of polymeric and surfactant materials to promote the dissolution rate of an insoluble drug: firocoxib. Scanning Electron Microscopy (SEM) showed that only some combinations of the proposed carrier systems allowed the production of suitable fibers and further fine optimization of the technique is also needed to load the drug. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) suggest that the drug is in an amorphous state in the final product. Drug amorphization, the fine dispersion of the active in the carriers, and the large surface area exposed to water interaction obtained through the electrospinning process can explain the remarkable improvement in the dissolution performance of firocoxib from the final product developed.


Assuntos
4-Butirolactona/análogos & derivados , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/química , Portadores de Fármacos , Nanofibras , Polímeros , Sulfonas/administração & dosagem , Sulfonas/química , Tensoativos , 4-Butirolactona/administração & dosagem , 4-Butirolactona/química , Portadores de Fármacos/química , Nanofibras/química , Nanofibras/ultraestrutura , Polímeros/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Tensoativos/química , Termodinâmica
15.
Biomed Chromatogr ; 33(10): e4625, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31222844

RESUMO

The herb couple has special clinical significance in reducing the toxicity and increasing the efficacy of drugs. The combination of Radix Angelicae Dahuricae (Baizhi, BZ) and Rhizoma Chuanxiong (ChuanXiong, CX) is a traditional herb couple. The combination performs better than the CX extract alone in the treatment of migraine and has been used for thousands of years. However, the specific compatibility mechanisms are still unclear. Ligustilide, dl-3-n-butylphthalide and senkyunolide A are the major active ingredients in CX and BZ-CX decoction. However, a comprehensive study of the pharmacokinetics of CX has not been carried out. A gas chromatography-mass spectroscopy (GC-MS) method with high selectivity, sensitivity and accuracy was developed. An SH-Rxi-5Sil (30 m × 0.25 mm i.d., and 0.25 µm film thickness) column was employed in the GC separation. Selectivity, linearity, precision, accuracy, recovery, matrix effect and stability were used to validate the current GC-MS method. Using the validated method, this is the first time to study on the comparative pharmacokinetics of ligustilide, dl-3-n-butylphthalide and senkyunolide A from CX alone and BZ-CX decoction in rat plasma. The pharmacokinetic parameters (Cmax , Tmax , T1/2 , AUC0-t , AUC0-∞ and CLz/F) of all of the detected ingredients showed significant differences between the two groups (P < 0.05). The results are helpful for further investigation of the compatibility mechanism of BZ-CX decoction.


Assuntos
4-Butirolactona/análogos & derivados , Benzofuranos/sangue , Medicamentos de Ervas Chinesas , Cromatografia Gasosa-Espectrometria de Massas/métodos , 4-Butirolactona/sangue , 4-Butirolactona/química , 4-Butirolactona/farmacocinética , Administração Oral , Animais , Benzofuranos/química , Benzofuranos/farmacocinética , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
16.
PLoS One ; 14(6): e0218629, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220150

RESUMO

Senescence Marker Protein (SMP30) is a metalloenzyme that shows lactonase activity in the ascorbic acid (AA) biosynthesis pathway in non-primate mammals such as a mouse. However, AA biosynthesis does not occur in the primates including humans. Several studies have shown the role of SMP30 in maintaining calcium homeostasis in mammals. In addition, it is also reported to have promiscuous enzyme activity with an organophosphate (OP) substrate. Hence, this study aims to recombinantly express and purify the SMP30 proteins from both mouse and human, and to study their structural alterations and functional deviations in the presence of different divalent metals. For this, mouse SMP30 (MoSMP30) as well as human SMP30 (HuSMP30) were cloned in the bacterial expression vector. Proteins were overexpressed and purified from soluble fractions as well as from inclusion bodies as these proteins were expressed largely in insoluble fractions. The purified proteins were used to study the folding conformations in the presence of different divalent cations (Ca2+, Co2+, Mg2+, and Zn2+) with the help of circular dichroism (CD) spectroscopy. It was observed that both MoSMP30 and HuSMP30 acquired native folding conformations. To study the metal-binding affinity, dissociation constant (Kd values) were calculated from UV-VIS titration curve, which showed the highest affinity of MoSMP30 with Zn2+. However, HuSMP30 showed the highest affinity with Ca2+, suggesting the importance of HuSMP30 in maintaining calcium homeostasis. Enzyme kinetics were performed with γ-Thiobutyrolactone and Demeton-S in the presence of different divalent cations. Interestingly, both the proteins showed lactonase activity in the presence of Ca2+. In addition, MoSMP30 and HuSMP30 also showed lactonase activity in the presence of Co2+ and Zn2+ respectively. Moreover, both the proteins showed OP hydrolase activities in the presence of Ca2+ as well as Zn2+, suggesting the metal-dependent promiscuous nature of SMP30.


Assuntos
Proteínas de Ligação ao Cálcio/química , Cátions Bivalentes/química , Peptídeos e Proteínas de Sinalização Intracelular/química , Simulação de Dinâmica Molecular , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/metabolismo , Animais , Sítios de Ligação , Proteínas de Ligação ao Cálcio/metabolismo , Cátions Bivalentes/metabolismo , Dissulfóton/química , Dissulfóton/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Ligação Proteica , Homologia de Sequência de Aminoácidos
17.
Biomed Pharmacother ; 117: 109074, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177061

RESUMO

Atherosclerosis is initiated by the local inflammation response to lipid deposition, and the most commonly administered antiatherogenic drugs are statins. Based on traditional Chinese medicine (TCM) evidence, we aimed to find effective therapeutic agents other than statins. A TCM, Suxiao Jiuxin Pill (SX), has been widely used in curing cardiovascular diseases for thirty years. In this paper, a combination of pharmacologic studies and RNA-Seq transcriptomics were employed to explore the pharmacodynamic advantages of SX over atorvastatin in the ApoE-/- mouse. 113 differentially expressed genes that were modulated by SX to a greater degree than atorvastatin were primarily involved in immunomodulation. The expression of BTK, AKT1, c-jun and CD137 was effectively regulated by SX with better effect than atorvastatin. Then a dual-luciferase reporter assay for NF-κB inhibition was applied to identify active components in SX. As a result, Senkyunolide A (Sen A) and Ligustilide (Lig), the key immunomodulatory ingredients in SX, were found to inhibit the expression of CD137 which is a diagnostic biomarker in atherosclerosis. It was further confirmed that Lig effectively suppressed the expression of AP-1 and NF-κB and the phosphorylation of AKT. Therefore, Lig achieved its CD137 inhibition through suppressing the expression of AP-1 and AKT/NF-κB signaling pathway, which partly explains the immunomodulation of SX in atherosclerosis. Above all, phthalides may be the primary components of SX improving immune and inflammation response in atherosclerosis.


Assuntos
4-Butirolactona/análogos & derivados , Aterosclerose/tratamento farmacológico , Benzofuranos/farmacologia , Fatores Imunológicos/farmacologia , NF-kappa B/metabolismo , Fator de Transcrição AP-1/metabolismo , 4-Butirolactona/química , 4-Butirolactona/farmacologia , 4-Butirolactona/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/sangue , Aterosclerose/diagnóstico por imagem , Benzofuranos/química , Benzofuranos/uso terapêutico , Células HEK293 , Humanos , Fatores Imunológicos/sangue , Fatores Imunológicos/uso terapêutico , Mediadores da Inflamação/sangue , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
18.
Mar Drugs ; 17(6)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163670

RESUMO

Three new butenolide derivatives, namely aspernolides N-P (1-3), together with six known analogues (4-9), were isolated from the ethyl acetate (EtOAc) extract of the deep sea-derived fungus Aspergillus terreus YPGA10. The structures of compounds 1-3 were determined on the basis of comprehensive analyses of the nuclear magnetic resonance (NMR) and mass spectroscopy (MS) data, and the absolute configurations of 1 and 2 were determined by comparisons of experimental electronic circular dichroism (ECD) with calculated ECD spectra. Compound 1 represents the rare example of Aspergillus-derived butenolide derivatives featured by a monosubstituted benzene ring. Compounds 6-9 exhibited remarkable inhibitory effects against α-glucosidase with IC50 values of 3.87, 1.37, 6.98, and 8.06 µM, respectively, being much more active than the positive control acarbose (190.2 µM).


Assuntos
4-Butirolactona/análogos & derivados , Organismos Aquáticos/química , Aspergillus/química , Inibidores de Glicosídeo Hidrolases/farmacologia , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Acetatos/química , Dicroísmo Circular , Ativação Enzimática/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Espectroscopia de Ressonância Magnética , Espectrometria de Massas
19.
Mol Med Rep ; 20(1): 198-204, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115578

RESUMO

The present study aimed to investigate the antibacterial activity of striatisporolide A (SA) against Escherichia coli (E. coli) and the underlying mechanism. Antibacterial activity was evaluated according to the inhibitory rate and zone of inhibition. The antibacterial mechanism was investigated by analyzing alkaline phosphatase (AKP) activity and ATP leakage, protein expression, cell morphology and intracellular alterations in E. coli. The results demonstrated that SA exerted bacteriostatic effects on E. coli in vitro. AKP activity and ATP leakage analysis revealed that SA damaged the cell wall and cell membrane of E. coli. SDS­PAGE analysis indicated that SA notably altered the level of 10 and 35 kDa proteins. Scanning electron microscopy and transmission electron microscopy analyses revealed marked alterations in the morphology and ultrastructure of E. coli following treatment with SA. The mechanism underlying the antimicrobial effects of SA against E. coli may be attributed to its actions of disrupting the cell membrane and cell wall and regulation of protein level. The findings of the present study provide novel insight into the antimicrobial activity of SA as a potential natural antibacterial agent.


Assuntos
4-Butirolactona/análogos & derivados , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Traqueófitas/química , 4-Butirolactona/química , 4-Butirolactona/metabolismo , 4-Butirolactona/farmacologia , Trifosfato de Adenosina/química , Fosfatase Alcalina/genética , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Escherichia coli/ultraestrutura , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Extratos Vegetais/química , Extratos Vegetais/farmacologia
20.
Cell Mol Life Sci ; 76(17): 3349-3361, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31073744

RESUMO

The actin-related protein complex 2/3 (Arp2/3) generates branched actin networks important for many cellular processes such as motility, vesicular trafficking, cytokinesis, and intercellular junction formation and stabilization. Activation of Arp2/3 requires interaction with actin nucleation-promoting factors (NPFs). Regulation of Arp2/3 activity is achieved by endogenous inhibitory proteins through direct binding to Arp2/3 and competition with NPFs or by binding to Arp2/3-induced actin filaments and disassembly of branched actin networks. Arp2/3 inhibition has recently garnered more attention as it has been associated with attenuation of cancer progression, neurotoxic effects during drug abuse, and pathogen invasion of host cells. In this review, we summarize current knowledge on expression, inhibitory mechanisms and function of endogenous proteins able to inhibit Arp2/3 such as coronins, GMFs, PICK1, gadkin, and arpin. Moreover, we discuss cellular consequences of pharmacological Arp2/3 inhibition.


Assuntos
Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/metabolismo , Citoesqueleto de Actina , Complexo 2-3 de Proteínas Relacionadas à Actina/antagonistas & inibidores , Ligação Competitiva , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Endossomos/metabolismo , Fator de Maturação da Glia/química , Fator de Maturação da Glia/metabolismo , Humanos , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Tiazolidinas/química , Tiazolidinas/metabolismo
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