Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.152
Filtrar
1.
Chem Commun (Camb) ; 56(3): 360-363, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31825399

RESUMO

A crystalline biohybrid with a 4 : 1 protein : cucurbituril mass ratio is presented. This result was achieved by engineering additional cucurbit[7]uril (Q7) binding sites into a ß-propeller protein. In contrast to the parent protein, Q7-controlled assembly of the engineered variant occurred in solution, as evidenced by NMR and SAXS measurements.


Assuntos
Proteínas de Bactérias/química , Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Sequência de Aminoácidos , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Imidazóis/metabolismo , Lectinas/química , Lectinas/genética , Lectinas/metabolismo , Ressonância Magnética Nuclear Biomolecular , Ralstonia solanacearum/metabolismo , Espalhamento a Baixo Ângulo , Difração de Raios X
2.
J Chem Theory Comput ; 15(11): 5829-5844, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31593627

RESUMO

A powerful computational strategy to determine the equilibrium association constant of two macromolecules with explicit-solvent molecular dynamics (MD) simulations is the "geometric route", which considers the reversible physical separation of the bound complex in solution. Nonetheless, multiple challenges remain to render this type of methodology reliable and computationally efficient in practice. In particular, in one, formulation of the geometric route relies on the potential of mean force (PMF) for physically separating the two binding partners restrained along a straight axis, which must be selected prior to the calculation. However, practical applications indicate that the calculation of the separation PMF along the predefined rectilinear pathway may be suboptimal and slowly convergent. Recognizing that a rectilinear straight separation pathway is generally not representative of how the protein complex physically separates in solution, we put forth a novel theoretical framework for binding free-energy calculations, leaning on the optimal curvilinear minimum free-energy path (MFEP) determined from the string method. The proposed formalism is validated by comparing the results obtained using both rectilinear and curvilinear pathways for a prototypical host-guest complex formed by cucurbit[7]uril (CB[7]) binding benzene, and for the barnase-barstar protein complex. On the basis of multi-microsecond MD calculations, we find that the calculations following the traditional rectilinear pathway and the string-based curvilinear pathway agree quantitatively, but convergence is faster with the latter.


Assuntos
Simulação de Dinâmica Molecular , Proteínas/química , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Benzeno/química , Benzeno/metabolismo , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Imidazóis/química , Imidazóis/metabolismo , Ligação Proteica , Proteínas/metabolismo , Ribonucleases/química , Ribonucleases/metabolismo , Termodinâmica
3.
Infez Med ; 27(3): 239-250, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31545767

RESUMO

After a long period of interferon-and ribavirin-based therapy (IFN/RBV), a very fast evolution in the development of directly acting antivirals (DAAs) has now established a totally new paradigm for the treatment chronic HCV infection. An efficacy rate within the 95-100% interval, safer and more tolerable drugs, much shorter treatment duration and a quicker establishment of the sustained virological response (SVR) are among the most relevant properties of new DAAs as compared to former IFN/RBV therapies. The last wave of DAAs is also characterized by a lesser tendency to generate or being victim of drug-drug interactions. Nevertheless, since the circumstances in which patients are also recipients of other medications are rather frequent, individualization of treatment is advised in order to minimize the risk of drug-drug interactions of clinical relevance. Three two-drug regimens are available in Italy for the treatment of chronic HCV infection: sofosbuvir/velpatasvir (SOF/VEL), glecaprevir/pibrentasvir (GLE/PIB) and grazoprevir/elbasvir (GZP/RLB). Based on the officially released summary of product characteristics (SmPC) of these three co-formulated dual regimens, we performed a comparative analysis concerning the drug-drug interactions possibly affecting the DAA regimens. According to specific individual conditions, including co-morbidities, the choice of the most appropriate regimen must carefully take into account, among the different variables, the metabolic profile of both DAAs and concurrent medications. The differences among the three regimens offer the possibility to avoid the occurrence of clinically relevant drug-drug interactions in most circumstance.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Benzofuranos/farmacologia , Carbamatos/farmacologia , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Imidazóis/farmacologia , Pirrolidinas/farmacologia , Quinoxalinas/farmacologia , Sofosbuvir/farmacologia , Sulfonamidas/farmacologia , Antivirais/metabolismo , Antivirais/uso terapêutico , Benzimidazóis/metabolismo , Benzofuranos/metabolismo , Carbamatos/metabolismo , Combinação de Medicamentos , Interações de Medicamentos , Hepatite C Crônica/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Imidazóis/metabolismo , Interferon-alfa/uso terapêutico , Itália , Polimedicação , Pirrolidinas/metabolismo , Quinoxalinas/metabolismo , Sofosbuvir/metabolismo , Sulfonamidas/metabolismo
4.
Med Mycol J ; 60(3): 71-74, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474693

RESUMO

Tinea pedis and tinea unguium are the most common dermatophytoses seen in the daily practice of dermatology. According to a report in Japan Foot Week 2006, it is estimated that about 1 in 5 Japanese have tinea pedis and that about 1 in 10 have tinea unguium. Thus far, use of oral antifungal agents has been the first-line therapy for onychomycosis. Many patients with onychomycosis, however, are elderly and have concomitant diseases as well as liver function disorder. Moreover, oral medications are reportedly associated with risks of impaired liver function and interactions. Due to such risks, therefore, treatment with topical agents is the only applicable therapy for most patients with onychomycosis. Recently, two topical agents (efinaconazole in 2014 and luliconazole in 2016) have been approved for the treatment of onychomycosis in Japan. Efinaconazole 10% solution is a triazole antifungal drug developed in Japan. Due to its low keratin affinity, efinaconazole shows high transungual penetration into nails and retains a high antifungal activity in the nail plate and the nail bed. Luliconazole 5% solution is an imidazole antifungal agent that has high keratin affinity. Luliconazole has also been shown in vitro to permeate from the superficial to the deep layers of the nail and to achieve concentrations above the MIC in all layers of the nail. Both efinaconazole 10% solution and luliconazole 5% solution have high antifungal activities for Trichophyton species. These two topical agents, therefore, have certainly increased treatment options for onychomycosis in the daily practice of dermatology.


Assuntos
Antifúngicos/administração & dosagem , Imidazóis/administração & dosagem , Onicomicose/tratamento farmacológico , Triazóis/administração & dosagem , Administração Tópica , Farmacorresistência Fúngica , Humanos , Imidazóis/metabolismo , Queratinas/metabolismo , Unhas/metabolismo , Onicomicose/microbiologia , Soluções , Triazóis/metabolismo , Trichophyton/efeitos dos fármacos
5.
J Steroid Biochem Mol Biol ; 194: 105447, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31415823

RESUMO

Dendrogenin A (DDA) is a newly-discovered steroidal alkaloid, which remains to date the first ever found in mammals. DDA is a cholesterol metabolites that induces cancer cell differentiation and death in vitro and in vivo, and thus behave like a tumor suppressor metabolite. Preliminary studies performed on 10 patients with estrogen receptor positive breast cancers (ER(+)BC) showed a strong decrease in DDA levels between normal matched tissue and tumors. This suggests that a deregulation on DDA metabolism is associated with breast carcinogenesis. To further investigate DDA metabolism on large cohorts of patients we have developed an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS) procedure for the quantification of DDA in liquid and in solid tissues. This method enabled the identification of DDA analogues such as its geometric isomer C17 and dendrogenin B (C26) in human samples showing that other 5,6α-epoxycholesterol conjugation products with biogenic amines exist as endogenous metabolites . We report here the first complete method of quantification of DDA in liquid and solid tissues using hydrophilic interaction liquid chromatography (HILIC). Two different methods of extraction using either a Bligh and Dyer organic extraction or protein precipitation were successfully applied to quantify DDA in solid and liquid tissues. The protein precipitation method was the fastest. The fact that this method is automatable opens up possibilities to study DDA metabolism in large cohorts of patients.


Assuntos
Colestanóis/análise , Imidazóis/análise , Mama/metabolismo , Neoplasias da Mama/metabolismo , Colestanóis/metabolismo , Cromatografia Líquida/métodos , Feminino , Humanos , Imidazóis/metabolismo
6.
Chemistry ; 25(57): 13088-13093, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31441544

RESUMO

A convenient supramolecular strategy for constructing a ratiometric fluorescent chemosensing ensemble, consisting of a macrocyclic host (cucurbit[8]uril CB[8]), and a pyrene-tagged amphiphilic peptide beacon (AP 1), is reported. AP 1 unfolds upon encapsulation of the pyrene termini into the hydrophobic CB[8] cavity. This changes pyrene excimer to monomer emission. Substrates with higher affinity for the CB[8] cavity can displace AP 1 from the ensemble. The released AP 1 folds again to form a pyrene excimer, which allows for the ratiometric fluorescence monitoring of the substrate. In this report, the ensemble capacity for ratiometric fluorescence monitoring of biological substrates, such as amino acid derivatives, specific peptides, and proteins, in aqueous media is demonstrated.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Substâncias Macromoleculares/química , Oligopeptídeos/química , Peptídeos/análise , Pirenos/química , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Fluorescência , Imidazóis/metabolismo , Oligopeptídeos/metabolismo , Peptídeos/química , Água/química
7.
Org Biomol Chem ; 17(34): 7863-7869, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31407758

RESUMO

Enzyme transition-state mimics can act as powerful inhibitors and allow structural studies that report on the conformation of the transition-state. Here, mannoimidazole, a mimic of the transition state of mannosidase catalyzed hydrolysis of mannosides, is shown to bind in a B2,5 conformation on the Clostridium perfringens GH125 α-1,6-mannosidase, providing additional evidence of a OS2-B2,5-1S5 conformational itinerary for enzymes of this family.


Assuntos
Clostridium perfringens/enzimologia , Inibidores Enzimáticos/metabolismo , Imidazóis/metabolismo , Manose/metabolismo , alfa-Manosidase/metabolismo , Biocatálise , Domínio Catalítico , Inibidores Enzimáticos/química , Imidazóis/química , Manose/análogos & derivados , Conformação Molecular , Mutação , Ligação Proteica , alfa-Manosidase/química , alfa-Manosidase/genética
8.
Molecules ; 24(15)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366105

RESUMO

The biological process, 3-O-galactosylation, is important in plant cells. To understand the mechanism of the reduction of flavonol antioxidative activity by 3-O-galactosylation, myricetin-3-O-galactoside (M3OGa) and myricetin aglycone were each incubated with 2 mol α,α-diphenyl-ß-picrylhydrazyl radical (DPPH•) and subsequently comparatively analyzed for radical adduct formation (RAF) products using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-Q-TOF-MS) technology. The analyses revealed that M3OGa afforded an M3OGa-DPPH adduct (m/z 873.1573) and an M3OGa-M3OGa dimer (m/z 958.1620). Similarly, myricetin yielded a myricetin-DPPH adduct (m/z 711.1039) and a myricetin-myricetin dimer (m/z 634.0544). Subsequently, M3OGa and myricetin were compared using three redox-dependent antioxidant analyses, including DPPH•-trapping analysis, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide radical (PTIO•)-trapping analysis, and •O2 inhibition analysis. In the three analyses, M3OGa always possessed higher IC50 values than those of myricetin. Conclusively, M3OGa and its myricetin aglycone could trap the free radical via a chain reaction comprising of a propagation step and a termination step. At the propagation step, both M3OGa and myricetin could trap radicals through redox-dependent antioxidant pathways. The 3-O-galactosylation process, however, could limit these pathways; thus, M3OGa is an inferior antioxidant compared to its myricetin aglycone. Nevertheless, 3-O-galactosylation has a negligible effect on the termination step. This 3-O-galactosylation effect has provided novel evidence that the difference in the antioxidative activities of phytophenols exists at the propagation step rather than the termination step.


Assuntos
Flavonoides/química , Depuradores de Radicais Livres/química , Galactosídeos/química , Superóxidos/química , Compostos de Bifenilo/antagonistas & inibidores , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/metabolismo , Dimerização , Flavonoides/metabolismo , Depuradores de Radicais Livres/metabolismo , Radicais Livres , Galactosídeos/metabolismo , Glicosilação , Imidazóis/química , Imidazóis/metabolismo , Cinética , Oxirredução , Picratos/antagonistas & inibidores , Células Vegetais/química , Células Vegetais/metabolismo , Superóxidos/antagonistas & inibidores , Superóxidos/metabolismo
9.
Chemosphere ; 235: 842-848, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31284132

RESUMO

Ionic liquids (ILs) have attracted attention in recent years due to their "greener" properties compared to conventional organic solvents. However, they may still pose a risk to the environment as their toxicity is not fully understood. Bioremediation of such ILs can be an economically and environmentally friendly approach. Therefore, this study aims to examine the interaction of three ILs (1-dodecylpyridnium chloride [DPy]+Cl, 1-Butyl-3-methylimidazolium chloride [BMIm]+Cl, and 1-Carbamoylmethyl pyridinium chloride [CMPy]+Cl) at different concentrations with an enriched ammonia oxidising bacteria (AOB) culture, and investigate their effects on the ammonia oxidation rate (AOR) as well as their removal and transformation. The results indicated that the longer chain IL [DPy]+Cl had a negative effect on the AOR while [BMIm]+Cl and [CMPy]+Cl enhanced the AOR. However, the IL removal rates displayed the opposite results as [DPy]+Cl was observed with the highest removal. It was found that biosorption played a major role in [DPy]+Cl removal. Biotransformation products for each IL were identified and their pathways were proposed. This study demonstrated that although longer chain ILs have a greater degree of removal, and they are also more toxic to AOB at higher concentration.


Assuntos
Bactérias/metabolismo , Imidazóis/metabolismo , Líquidos Iônicos/metabolismo , Compostos de Piridínio/metabolismo , Amônia/metabolismo , Biodegradação Ambiental , Biotransformação , Oxirredução , Solventes/metabolismo
10.
J Agric Food Chem ; 67(31): 8641-8648, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31322878

RESUMO

Prochloraz is a widely used imidazole fungicide that has to be analyzed together with its metabolites or transformation products for food safety monitoring purposes in the European Union. Although the focus in food of plant origin has been set on metabolites BTS 44595 and BTS 44596, we consider relevant the study of BTS 40348 metabolite, too, because it has been detected in both raw and processed foods based on citrus fruits in the EU. Metabolite BTS 40348 should be monitored in surface water due to its ecotoxicological effects. In this work, the synthesis and structural characterization of BTS 40348 metabolite of fungicide prochloraz is presented, because the structure is closely related to the chemistry and biological activity of the substance. Characterization using 13C and 1H NMR, infrared (IR), and Raman spectroscopy is detailed, together with confirmation by electrospray mass spectrometry analysis.


Assuntos
Fungicidas Industriais/química , Fungicidas Industriais/metabolismo , Imidazóis/química , Imidazóis/metabolismo , União Europeia , Fast Foods/análise , Contaminação de Alimentos/análise , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Resíduos de Praguicidas/química , Resíduos de Praguicidas/metabolismo , Análise Espectral Raman , Poluentes da Água/química
11.
J Pharm Biomed Anal ; 175: 112780, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31351249

RESUMO

Trace levels of microRNA-205, known as a biomarker of lung cancer, in human serum was quantified for the first-time using G-quadruplex DNAzyme linked to detection complementary probe and 1,1'-oxalyldiimidazole chemiluminescence (ODI-CL). First, capture complementary probes immobilized on the surface of paramagnetic bead selectively bound with microRNA-205 existing in human serum. Then, with the addition of detection complementary probe linked to hemin aptamer, a complex linked to hemin aptamer was formed with the completion of hybridization between microRNA-205 and two complementary probes. With the addition of hemin in the solution, finally, a complex linked to G-quadruplex DNAzyme was formed from the interaction of hemin aptamer and hemin. Resorufin, luminescent dye, was formed from the reaction of Amplex Red and H2O2 in the presence of the complex linked to DNAzyme acting as a horseradish peroxidase (HRP)-mimicking enzyme. The concentration of resorufin formed from the reaction was dependent on the concentration of microRNA-205 in human serum. Thus, the brightness of resorufin emitted in ODI-CL reaction was enhanced with the increase of microRNA-205. The limit of detection (LOD) of the biosensor with ODI-CL detection, capable of sensing microRNA-205 (dynamic range: 0.4-62.5 nM), was as low as 0.13 nM. It was confirmed that the biosensor can quantify trace levels of microRNA-205 with statistically acceptable accuracy, precision, and recovery.


Assuntos
Biomarcadores/metabolismo , DNA Catalítico/metabolismo , Imidazóis/metabolismo , MicroRNAs/metabolismo , Aptâmeros de Nucleotídeos/metabolismo , Técnicas Biossensoriais/métodos , Quadruplex G , Hemina/metabolismo , Peroxidase do Rábano Silvestre/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Limite de Detecção , Luminescência , Oxazinas/metabolismo
12.
J Colloid Interface Sci ; 554: 722-730, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31362264

RESUMO

The preparation of hydrophilic carbon dots (HCDs) with imidazolium dicyanamide ionic liquids (ILs) as precursor revealed a unique structure-activity relationship for the IL-HCDs. Their hydrophilicity, fluorescence nature and cytotoxicity are closely correlated to the alkyl side chain length of the imidazolium cationic moiety. (1) The hydrophilicity of the precursor ILs decreases with the alkyl chain length of their imidazolium cations (from ethyl, butyl, hexyl, octyl to decyl). On the contrary, that of the IL-HCDs increases with the alkyl chain length due to the emergence of COC, NH2 moiety. (2) The passivation effect of alkyl chain plays a dominative role in the enhancement of quantum yield (QY, from 4.6% to 48.0%) of IL-HCDs. The doping of nitrogen-containing moieties contributes marginally. (3) The increase of alkyl chain length leads to the weakening of IL-HCDs/bovine serum albumin (BSA) affinity with a decrease on the quenching constants from 12.59 × 104 to 1.779 × 104 L mol-1. (4) The cytotoxicity of IL-HCDs increases with the length of alkyl chain in the imidazolium cation, though the hydrophilicity of IL-HCDs is increased. In addition, the cytotoxicity of IL-HCDs/BSA is lower than that of IL-HCDs. The protective effect of BSA in the IL-HCDs/BSA 'protein corona' could be utilized to improve the biocompatibility of IL-HCDs.


Assuntos
Carbono/química , Imidazóis/química , Líquidos Iônicos/química , Nanopartículas/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/toxicidade , Carbono/metabolismo , Carbono/toxicidade , Bovinos , Sobrevivência Celular , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/metabolismo , Imidazóis/toxicidade , Líquidos Iônicos/metabolismo , Líquidos Iônicos/toxicidade , Células MCF-7 , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Nanopartículas/ultraestrutura , Soroalbumina Bovina/metabolismo , Relação Estrutura-Atividade
13.
Biomolecules ; 9(6)2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31242711

RESUMO

Alkyl-imidazolium chloride ionic liquids (ILs) have been broadly studied for biochemical and biomedical technologies. They can permeabilize lipid bilayer membranes and have cytotoxic effects, which makes them targets for drug delivery biomaterials. We assessed the lipid-membrane permeabilities of ILs with increasing alkyl chain lengths from ethyl to octyl groups on large unilamellar vesicles using a trapped-fluorophore fluorescence lifetime-based leakage experiment. Only the most hydrophobic IL, with the octyl chain, permeabilizes vesicles, and the concentration required for permeabilization corresponds to its critical micelle concentration. To correlate the model vesicle studies with biological cells, we quantified the IL permeabilities and cytotoxicities on different cell lines including bacterial, yeast, and ovine blood cells. The IL permeabilities on vesicles strongly correlate with permeabilities and minimum inhibitory concentrations on biological cells. Despite exhibiting a broad range of lipid compositions, the ILs appear to have similar effects on the vesicles and cell membranes.


Assuntos
Anti-Infecciosos/farmacologia , Anti-Infecciosos/toxicidade , Imidazóis/farmacologia , Imidazóis/toxicidade , Líquidos Iônicos/farmacologia , Líquidos Iônicos/toxicidade , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Permeabilidade da Membrana Celular , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/química , Imidazóis/metabolismo , Líquidos Iônicos/química , Líquidos Iônicos/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Ovinos
14.
Artigo em Inglês | MEDLINE | ID: mdl-31226007

RESUMO

In several studies focused on the residues of cyazofamid and its main metabolite 4-chloro-5-p-tolylimidazole-2-carbonitrile (CCIM) on tomato where it is widely used, CCIM has been shown to have higher acute toxicity than cyazofamid, and this is crucial to evaluate the potential food risk of cyazofamid and CCIM. In this study, the dissipation of cyazofamid and CCIM during tomato growth and tomato paste making process were assessed. The targeted compounds cyazofamid and CCIM were determined by LC-MS/MS. The results indicated that the half-life of cyazofamid was 4.6 days after applying in the field, and the maximum value of CCIM was 0.08 mg/kg at 3 days after the last application of cyazofamid, then gradually decreased. In addition, the concentrations of cyazofamid and CCIM were affected by different processing steps including washing, peeling, homogenisation, simmering, and sterilisation. Results showed that the mean losses of cyazofamid and CCIM were 92.3% and 75.2% after washing and peeling. The Processing Factor (PF) values were all less than 1. Especially for peeling, the PFs of cyazofamid and CCIM were 0.12 and 0.04, respectively.


Assuntos
Análise de Alimentos , Contaminação de Alimentos/análise , Manipulação de Alimentos , Imidazóis/análise , Imidazóis/metabolismo , Lycopersicon esculentum/química , Lycopersicon esculentum/crescimento & desenvolvimento , Nitrilos/análise , Sulfonamidas/análise , Sulfonamidas/metabolismo , Cromatografia Líquida , Lycopersicon esculentum/metabolismo , Nitrilos/metabolismo , Espectrometria de Massas em Tandem
15.
J Sci Food Agric ; 99(14): 6167-6172, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31226227

RESUMO

BACKGROUND: Grape is an important fruit consumed either fresh or processed, therefore, fungicide misuse of grape has become an issue of global food safety and human health. Pyraclostrobin, and cyazofamid have been applied to grape frequently. RESULTS: Here a simple QuEChERS (quick, easy, cheap, effective, rugged, and safe) liquid chromatography mass spectrometry technique has been developed and validated for the determination of pyraclostrobin, cyazofamid and its metabolite CCIM in open field grape samples. The recoveries of these three in the range of 0.01 to 5 mg kg-1 (n = 5) ranged from 73.1% to 97.9%. The relative standard deviations (RSDs) were below 12% for all cases. The limits of quantitation of each analyte was 0.005 mg kg-1 , which was lower than maximum residue limits of not only pyraclostrobin but also cyazofamid. Not only dissipation kinetics but also residue determination was obtained in grape for those three pesticides. Furthermore, their half-lives in grapes were 10.7-30.1 days, recommending the pre-harvest intervals for these three of 14 days. The calculated hazard quotient and acute hazard index lower than 100% illustrated the safety of intake of grape for the Chinese population for not only long-term but also short-term dietary risk assessment. CONSLUSIONS: The less than 30 day half-life illustrated that pyraclostrobin and cyazofamid could degrade relatively easily in the environment. The long-term and short-term dietary risk assessment also illustrated the intake safety of these three. Thus, a 14 day pre-harvest interval was safe and recommended. The results of this study contributed to environmental protection, food safety and human health. © 2019 Society of Chemical Industry.


Assuntos
Resíduos de Drogas/química , Fungicidas Industriais/química , Imidazóis/química , Estrobilurinas/química , Sulfonamidas/química , Vitis/química , China , Qualidade de Produtos para o Consumidor , Resíduos de Drogas/metabolismo , Contaminação de Alimentos/análise , Frutas/química , Fungicidas Industriais/metabolismo , Meia-Vida , Humanos , Imidazóis/metabolismo , Cinética , Medição de Risco , Estrobilurinas/metabolismo , Sulfonamidas/metabolismo , Espectrometria de Massas em Tandem , Vitis/metabolismo
16.
Org Biomol Chem ; 17(25): 6215-6220, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31179469

RESUMO

Here we report the endocytosis and excretion pathways of two different dye-conjugated cucurbit[7]urils, (cyanine 3-conjugated CB[7] and rhodamine X-conjugated CB[7]), which have great potential as molecular probes for live cell imaging. The dye-CB[7]s are translocated into live cells (human breast carcinoma cells, MCF-7) via multiple pathways, predominantly by clathrin-mediated endocytosis, and excreted from cells via lysosome-associated exocytosis. Interestingly, the CB[7] moiety has a substantial influence on the uptake and excretion pathways. These findings may widen the applications of the dyes conjugated to CB[7] and assist in the design of new molecular probes for live cell imaging.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/metabolismo , Carbocianinas/metabolismo , Endocitose/fisiologia , Exocitose/fisiologia , Corantes Fluorescentes/metabolismo , Imidazóis/metabolismo , Rodaminas/metabolismo , Hidrocarbonetos Aromáticos com Pontes/química , Carbocianinas/química , Fluorescência , Corantes Fluorescentes/química , Humanos , Imidazóis/química , Lisossomos/fisiologia , Células MCF-7 , Rodaminas/química
17.
Cells ; 8(6)2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174324

RESUMO

Methylglyoxal (MG) is a potent inducer of advanced glycation end products (AGEs). MG, long considered a highly cytotoxic molecule with potential anticancer value, is now being re-evaluated to a protumorigenic agent in some malignancies. Anaplastic thyroid cancer (ATC) is an extremely aggressive and highly lethal cancer for which conventional therapies have proved ineffective. Successful therapeutic intervention in ATC is undermined by our poor understanding of its molecular etiology. In the attempt to understand the role of MG in ATC aggressiveness, we used immunohistochemistry to examine the level of MG protein adducts in ATC and slow-growing papillary thyroid cancer (PTC). We detected a high level of MG adducts in ATC compared to PTC ones, suggesting a protumor role for MG-mediated dicarbonyl stress in ATC. Accordingly, MG adduct accumulation in ATC cells in vitro was associated with a marked mesenchymal phenotype and increased migration/invasion, which were both reversed by aminoguanidine (AG)-a scavenger of MG-and resveratrol-an activator of Glyoxalase 1 (Glo1), the key metabolizing enzyme of MG. Our study represents the first demonstration that MG, via AGEs, acts as a tumor-promoting factor in ATC and suggests that MG scavengers and/or Glo1 activators merit investigations as potential therapeutic strategies for this malignancy.


Assuntos
Aldeído Pirúvico/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/química , Imidazóis/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Lactoilglutationa Liase/genética , Lactoilglutationa Liase/metabolismo , Masculino , Pessoa de Meia-Idade , Ornitina/análogos & derivados , Ornitina/química , Ornitina/metabolismo , Aldeído Pirúvico/química , Aldeído Pirúvico/toxicidade , Transdução de Sinais/efeitos dos fármacos , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
18.
Nat Commun ; 10(1): 2303, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127106

RESUMO

The spin state transition from low spin to high spin upon substrate addition is one of the key steps in cytochrome P450 catalysis. External perturbations such as pH and hydrogen bonding can also trigger the spin state transition of hemes through deprotonated histidine (e.g. Cytochrome c). In this work, we report the isolated 2-methylimidazole Cobalt(II) [Co(TPP)(2-MeHIm)] and [Co(TTP)(2-MeHIm)], and the corresponding 2-methylimidazolate derivatives where the N-H proton of axial 2-MeHIm is removed. Interestingly, various spectroscopies including EPR and XAFS determine a high-spin state (S = 3/2) for the imidazolate derivatives, in contrast to the low-spin state (S = 1/2) of all known imidazole analogs. DFT assisted stereoelectronic investigations are applied to understand the metal-ligand interactions, which suggest that the dramatically displaced metal center allowing a promotion eg(dπ) → b1g([Formula: see text]) is crucial for the occurrence of the spin state transition.


Assuntos
Cobalto/química , Heme/química , Prótons , Biocatálise , Cobalto/metabolismo , Cristalografia por Raios X , Sistema Enzimático do Citocromo P-450/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Heme/análogos & derivados , Heme/metabolismo , Histidina/química , Concentração de Íons de Hidrogênio , Imidazóis/metabolismo , Ferro/química , Ligantes , Oxirredução
19.
Eur J Med Chem ; 176: 476-491, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31128449

RESUMO

Tumor suppressor protein p53 is important to the regulation of many cellular processes and the prevention of cancer development. In some cancer cells, the function of p53 is inhibited by murine double minute 2 protein (MDM2). To restore the function of p53, the inhibition or depletion of MDM2 has become a potential therapeutic treatment. We have successfully developed a series of small molecule MDM2 degraders that can promote the proteolysis of MDM2 oncoprotein, thus reactivating tumor suppressor p53. The superior degrader features a nutlin-based MDM2 ligand and a lenalidomide-based cereblon E3 ubiquitin ligase ligand with a short linker between the two ligands. At low nanomolar concentrations in RS4; 11 leukemia cells, this degrader promotes efficient degradation of MDM2. It also inhibits the proliferation of leukemia cells with an IC50 value of 3.2 nM and induces apoptosis effectively. All of these data indicate that MDM2 degraders are promising therapeutics for the treatment of cancers, such as leukemia.


Assuntos
Imidazóis/farmacologia , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/metabolismo , Ligação Proteica , Estereoisomerismo , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
20.
Int J Biol Macromol ; 135: 725-733, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31129210

RESUMO

Staphylopine is a newly identified broad-spectrum metallophore for metal acquisition, and it plays important roles in the survival and virulence of Staphylococcus aureus and other pathogens in the metal-scarce environment in hosts. CntK catalyzes the first step of staphylopine synthesis by converting L-histidine to D-histidine to provide an essential building block of staphylopine. Herein, the crystal structures of S. aureus CntK (SaCntK) and its C72S variant are determined at 1.82 and 1.58 Šresolution, respectively. SaCntK forms a homodimer and each subunit contains a two-domain α/ß structure. Its overall structure resembles diaminopimelate epimerase, although their sequence identities are lower than 22%. SaCntK is specific for histidine, whereas other proteinogenic amino acids, with the exception of arginine, do not show any binding with SaCntK. Structural modeling suggested that residues Asn16, Glu46, Gln47 and Glu208 are responsible for specific substrate binding, and their substitutions significantly reduced the binding of histidine to SaCntK. Structural modeling suggested SaCntK uses a two-base catalytic mechanism, which has been observed in many cofactor-independent racemases. Our study provides critical insights into the structure and functions of CntK in staphylopine synthesis, which makes it helpful for developing potential antibiotics targeting the staphylopine-mediated metal acquisition process in bacteria.


Assuntos
Histidina/metabolismo , Imidazóis/metabolismo , Metais/metabolismo , Racemases e Epimerases/química , Racemases e Epimerases/metabolismo , Staphylococcus aureus/enzimologia , Domínio Catalítico , Coenzimas/metabolismo , Cristalografia por Raios X , Evolução Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Multimerização Proteica , Estrutura Quaternária de Proteína , Staphylococcus aureus/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA