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1.
Immunity ; 41(2): 296-310, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25065623

RESUMO

Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed that microbial-specific indoles regulated intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is a ligand for PXR in vivo, and IPA downregulated enterocyte TNF-α while it upregulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2(-/-)) mice showed a distinctly "leaky" gut physiology coupled with upregulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier were corrected in Nr1i2(-/-)Tlr4(-/-) mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway that involves luminal sensing and signaling by TLR4.


Assuntos
Intestinos/imunologia , Receptores de Esteroides/imunologia , Junções Íntimas/imunologia , Receptor 4 Toll-Like/imunologia , Junções Aderentes/genética , Junções Aderentes/imunologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anticorpos/imunologia , Complexo CD3/imunologia , Células CACO-2 , Linhagem Celular , Feminino , Células HEK293 , Humanos , Indóis , Indometacina/farmacologia , Inflamação/imunologia , Intestinos/microbiologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/imunologia , Receptor de Pregnano X , Interferência de RNA , RNA Mensageiro , RNA Interferente Pequeno , Receptores de Esteroides/genética , Traumatismo por Reperfusão/imunologia , Transdução de Sinais/imunologia , Junções Íntimas/genética , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/biossíntese
2.
J Neurochem ; 139(4): 624-639, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27569447

RESUMO

In the pathogenesis of tauopathies, genetic and environmental factors have been identified. While familial clustering led to the identification of mutations in MAPT encoding the microtubule-associated protein tau, the high incidence of a sporadic tauopathy endemic in Guadeloupe was linked to the plant-derived mitochondrial complex I inhibitor annonacin. The interaction of both factors was studied in the present work in a realistic paradigm over a period of 12 months. Mice over-expressing either human wild-type tau or R406W mutant tau as well as non-transgenic mice received either regular drinking water or commercially available tropical fruit juice made of soursop (Annona muricata L.) as dietary source of neurotoxins. HPLC-MS analysis of this juice identified several Annonaceous acetogenins, mainly annonacin (16.2 mg/L), and 41 isoquinoline alkaloids (18.0 mg/L, mainly asimilobine and reticuline). After 12 month of juice consumption, several brain regions showed an increased number of neurons with phosphorylated tau in the somatodendritic compartment of R406W mice and, to a much lesser extent, of non-transgenic mice and mice over-expressing human wild-type tau. Moreover, juice drinking was associated with a reduction in synaptophysin immunoreactivity, as well as an increase in 3-nitrotyrosine (3NT) reactivity in all three genotypes. The increase in 3NT suggests that Annona muricata juice promotes the generation of reactive nitrogen species. This study provides first experimental evidence that long-lasting oral ingestion of a widely consumed environmental factor can induce somatodendritic accumulation of hyperphosphorylated tau in mice expressing rodent or human wild-type tau, and can accelerate tau pathology in R406W-MAPT transgenic mice.


Assuntos
Annona , Encéfalo/metabolismo , Sucos de Frutas e Vegetais , Extratos Vegetais/administração & dosagem , Proteínas tau/biossíntese , Animais , Annona/efeitos adversos , Encéfalo/efeitos dos fármacos , Linhagem Celular , Sucos de Frutas e Vegetais/efeitos adversos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Extratos Vegetais/efeitos adversos , Distribuição Aleatória , Proteínas tau/genética
3.
Artigo em Inglês | MEDLINE | ID: mdl-38160527

RESUMO

Cloxacillin and oxacillin are group M penicillins. The therapeutic monitoring of plasma concentrations of these antibiotics and those of their hydroxymethylated metabolites is of great clinical interest, especially in the choice of an adequate dosage allowing an effective treatment while limiting the occurrence of undesirable effects and the development of bacterial resistance. In this context, we conducted this work aiming at developing and validating a method allowing the determination of cloxacillin and oxacillin as well as the identification of their active metabolites in different biological matrices (CSF and plasma) using turbulent flow liquid chromatography coupled to high-resolution mass spectrometry. To do this, we carried out several optimisation tests. Subsequently, we validated our method according to the latest bioanalytical validation recommendations of the European Medicines Agency. The validation results showed that our method is specific and sensitive. We obtained good linearity in the range 0.5 to 100 µg/mL with correlation coefficients above 0.995. The lower limit of quantification was 0.5 µg/mL for each analyte. The method was found to be accurate with repeatability and reproducibility coefficients of variation below 15 %. Our method is also accurate with bias values below 15 %. Recovery values ranged from 87 % to 95 %. Finally, we were able to apply our method to the therapeutic monitoring of the analysed molecules and to identify their active metabolites. Our results suggest that LC-MS shows superiority in the therapeutic monitoring of these antibiotics due to the superiority of specificity shown by this method. This assay method can be routinely used for the daily plasma assays of patients treated with these antibiotics in the context of therapeutic monitoring.


Assuntos
Cloxacilina , Oxacilina , Humanos , Cloxacilina/análise , Monitoramento de Medicamentos/métodos , Reprodutibilidade dos Testes , Antibacterianos , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos
4.
Molecules ; 18(3): 3018-27, 2013 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-23467012

RESUMO

In an effort to find potent inhibitors of the protein kinases DYRK1A and CDK1/Cyclin B, a systematic in vitro evaluation of 2,500 plant extracts from New Caledonia and French Guyana was performed. Some extracts were found to strongly inhibit the activity of these kinases. Four aristolactams and one lignan were purified from the ethyl acetate extracts of Oxandra asbeckii and Goniothalamus dumontetii, and eleven aporphine alkaloids were isolated from the alkaloid extracts of Siparuna pachyantha, S. decipiens, S. guianensis and S. poeppigii. Among these compounds, velutinam, aristolactam AIIIA and medioresinol showed submicromolar IC50 values on DYRK1A.


Assuntos
Aporfinas/farmacologia , Proteína Quinase CDC2/antagonistas & inibidores , Ciclina B/antagonistas & inibidores , Alcaloides Indólicos/farmacologia , Lactamas/farmacologia , Extratos Vegetais/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Aporfinas/química , Alcaloides Indólicos/química , Lactamas/química , Ressonância Magnética Nuclear Biomolecular , Extratos Vegetais/química , Quinases Dyrk
5.
Int J Artif Organs ; 46(2): 113-119, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36583520

RESUMO

Continuous renal replacement therapy (CCRT) efficiently eliminates cefotaxime. To our knowledge, there are no previous in vitro studies dealing with the disposition of cefotaxime. We studied the elimination of cefotaxime by two filters in a model mimicking a session of CRRT using the NeckEpur® technology. The ST150®-polyacrylonitrile filter with the Prismaflex, Baxter-Gambro, and the AV1000®-polysulfone filter with the Multifiltrate Pro, Fresenius, were studied. Continuous filtration used a flowrate of 1 L/h in post-dilution only. Simulated blood flowrate was set at 200 mL/min. Routes of elimination were assessed using the NeckEpur® technology. Cefotaxime concentrations were measured using ultra high-performance liquid chromatography, and tandem mass spectrometry. Two sessions were performed using the ST® filter and three using the AV® filter. Stability of cefotaxime during 6 h was assessed in triplicate with a mean variation of concentrations of 2.4 ± 1.5% at the end of the study. The mean measured initial concentration in the central compartment (CC) for the five sessions was 52.4 mg/L. The mean amount eliminated from the CC at the end of the sessions using the ST150®-polyacrylonitrile and the AV1000®-polysulfone filters were 72% and 73%, respectively. The clearances of cefotaxime from the central compartment (CC) were 1.1 and 1.2 L/h, respectively. The mean sieving coefficient were 0.99 and 0.99, respectively. The mean percentages of the amount eliminated from the CC by filtration/adsorption were 87/13% and 92/8%, respectively. Both adsorption percentages were below 15%. We conclude neither the ST150®-polyacrylonitrile nor the AV1000®-polysulfone filters result in clinically significant adsorption of cefotaxime.


Assuntos
Cefotaxima , Polímeros , Polímeros/química , Resinas Acrílicas/química
6.
Rapid Commun Mass Spectrom ; 24(24): 3602-8, 2010 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-21080512

RESUMO

Collision-induced dissociation experiments of seven annonaceous acetogenins were carried out under high and low collision energy conditions. Each compound was studied as protonated or deprotonated and lithium- or sodium- cationized molecules, using ElectroSpray Ionisation (ESI) with a hybrid linear trap/orbitrap mass spectrometer (LTQ-Orbitrap®). The same ion species were studied with a Matrix-Assisted Laser Desorption Ionisation (MALDI) tandem mass spectrometer in a high collision energy regime (1 or 2 keV). Although each of the techniques showed some limitations in the detection of functional groups, unambiguous structural identification of the acetogenins was obtained. MALDI ToF-ToF has the advantage over ESI-based methods to provide mass spectra rich in informative fragments which allows the confirmation of some functional groups position. By contrast, ESI-LTQ-Orbitrap® analysis has the advantage over MALDI that the mass spectra are relatively simple with only fragments close to the functional groups. However, this technique needs to carry out experiments both in negative and positive ionization modes. Copyri


Assuntos
Acetogeninas/química , Espectrometria de Massas em Tandem/métodos , Íons/química , Lítio/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
7.
J Agric Food Chem ; 62(34): 8696-704, 2014 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-25088119

RESUMO

Epidemiological and toxicological studies have suggested Annonaceaeous acetogenins to be environmental neurotoxins responsible for sporadic atypical parkinsonism/dementia in tropical areas. These compounds are present in the tropical genus Annona (Annonaceae), known for its fruit-yielding cultivated species such as Annona cherimolia. This species is widely cultivated in South America, Spain, and Portugal and yields acetogenins in its seeds, stems, and roots. The presence of these compounds in the pulp of its fruit and in derived food products is unclear. An innovative and sensitive methodology by HPLC-ESI-LTQ-Orbitrap with postcolumn infusion of lithium iodide was used to identify the presence of low levels of acetogenins in an A. cherimolia Mill. fruit-based commercial alcoholic beverage. More than 80 representatives were detected, and the 31 most intense acetogenins were identified. All together these findings indicate that this species should be considered as a risk factor within the framework of a worldwide problem of food toxicity.


Assuntos
Acetogeninas/química , Bebidas Alcoólicas/análise , Annona/química , Cromatografia Líquida de Alta Pressão/métodos , Contaminação de Alimentos/análise , Neurotoxinas/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/instrumentação
8.
J Mass Spectrom ; 47(11): 1500-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23147829

RESUMO

Annonaceous acetogenins (AAGs) are a homogenous class of polyketides proposed as environmental neurotoxins. Previous dereplication studies of AAGs were limited by the use of low-resolution mass spectrometers. Only poor information in terms of structures was provided due to the limited fragmentation of protonated or sodium cationized species. An innovative approach, using reversed-phase high-performance liquid chromatography coupled to a hybrid linear ion trap/orbitrap mass spectrometer (LTQ-Orbitrap®), was therefore performed. Sensitivity was enhanced by post-column infusion of lithium, since AAGs have a high affinity for this cation. High level of structural information was obtained from low-energy-collision-induced dissociation fragmentation experiments of lithium-cationized AAGs ([M + Li](+) ions) as demonstrated with purified standards. The method was then applied to a total ethyl-acetate extract prepared from commercial soursop nectar (Annona muricata L.). The sensitivity, mass accuracy and specific fragmentation patterns proved to be particularly useful for characterization of the AAGs. Typical structural identification procedure and unexpected observations for specific structural types are illustrated, with major and minor compounds.


Assuntos
Acetogeninas/análise , Acetogeninas/química , Cromatografia Líquida de Alta Pressão/métodos , Lítio/química , Extratos Vegetais/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Acetatos/química , Annona/química , Cátions/química , Cromatografia de Fase Reversa/métodos , Modelos Moleculares , Sensibilidade e Especificidade
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