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Dietary and microbial oxazoles induce intestinal inflammation by modulating aryl hydrocarbon receptor responses.

Shankar S. Iyer, Thomas Gensollen, Amit Gandhi, Sungwhan F. Oh, Joanna F. Neves, Frederic Collin, Richard Lavin, Carme Serra, Jonathan Glickman, Punyanganie S. A. de Silva, R. Balfour Sartor, Gurdyal Besra, Russell Hauser, , Anthony Maxwell, Amadeu Llebaria, Richard S. Blumberg

Cell (2018) 173(5) p1123–1134.e11

 Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium.


Synthesis, characterization, and self-assembly of a tetrathiafulvalene (TTF)-triglycyl derivative

Pérez-Rentero, S., Eritja, R., Häring, M., Saldías, C., Díaz, D.D.

Applied Sciences (Switzerland), 8 (5), art. no. 671, 2018

 In this work, we describe the synthesis, characterization, and self-assembly properties of a new tetrathiafulvalene (TTF)–triglycyl low-molecular-weight (LMW) gelator. Supramolecular organogels were obtained in various solvents via a heating–cooling cycle. Critical gelation concentrations (CGC) (range ˜ 5–50 g/L) and thermal gel-to-sol transition temperatures (Tgel) (range ˜ 36–51 °C) were determined for each gel. Fourier transform infrared (FT-IR) spectroscopy suggested that the gelator is also aggregated in its solid state via a similar hydrogen-bonding pattern. The fibrillar microstructure and viscoelastic properties of selected gels were demonstrated by means of field-emission electron microscopy (FE-SEM) and rheological measurements. As expected, exposure of a model xerogel to I2 vapor caused the oxidation of the TTF unit as confirmed by UV-vis-NIR analysis. However, FT-IR spectroscopy showed that the oxidation was accompanied with concurrent alteration of the hydrogen-bonded network.


The role of SeDeM for characterizing the active substance and polyvinyilpyrrolidone eliminating metastable forms in an oral lyophilizate—A preformulation study

Borges, P.F., García-Montoya, E., Pérez-Lozano, P., Jo, E., Miñarro, M., Manich, A., Suñé-Negre, J.M.

 PLoS ONE, 13 (4), art. no. e0196049, 2018

 A preformulation study of an oral lyophilisate with cetirizine dihydrochloride (CTZ) as active ingredient, mannitol and PVP K30 as bulking agents is presented. CTZ shown a humidity content of 0.150% and a spontaneous hygroscopicity of 0.200% (both determined by SeDeM diagram), demonstrating an adequate stability behavior in solid form. A design of experiments (DoE) performed with both mannitol and PVP K30, followed by a simple factorial design (32) has determined the optimum combination of excipients and CTZ, and showed that a higher proportion of PVP K30 was able to prevent metastable forms generated by mannitol.


New approach based on immunochemical techniques for monitoring of selective estrogen receptor modulators (SERMs) in human urine

Salvador, J.-P., Vila-Roca, E., Monfort, N., Ventura, R., Marco, M.-P.

Journal of Pharmaceutical and Biomedical AnalysisVolume 156, 15 July 2018, Pages 147-152

 Antiestrogenic compounds such as tamoxifen, toremifen and chlomifen are used illegally by athletes to minimize physical impacts such as gynecomastia resulting from the secondary effects of anabolic androgenic steroids, used to increase athletic efficiency unlawfully. The use of these compounds is banned by the World Anti-Doping Agency (WADA) and controls are made through analytical methodologies such as HPLC–MS/MS, which do not fulfil the sample throughput requirements. Moreover, compounds such as tamoxifen are also used to treat hormone receptor-positive breast cancer (ER?+?).Therapeutic drug monitoring (TDM) of tamoxifen may also be clinically useful for guiding treatment decisions. An accurate determination of these drugs requires a solid phase extraction of patient serum followed by HPLC–MS/MS. In the context of an unmet need of high-throughput screening (HTS) and quantitative methods for antiestrogenic substances we have approached the development of antibodies and an immunochemical assay for the determination of these antiestrogenic compounds. The strategy applied has taken into consideration that these drugs are metabolized and excreted in urine as the corresponding 4-hydroxylated compounds. A microplate-based ELISA procedure has been developed for the analysis of these metabolites in urine with a LOD of 0.15, 0.16 and 0.63?µg/L for 4OH-tamoxifen, 4OH-toremifen and 4OH-clomifen, respectively, much lower than the MRPL established by WADA (20?µg/L).


Enzyme-linked immunosorbent assays for therapeutic drug monitoring coumarin oral anticoagulants in plasma

Salvador, J.-P., Tassies, D., Reverter, J.-C., Marco, M.-P.

Analytica Chimica Acta,2018

 The development of high-throughput immunochemical assays to assist on precision medicine for patients treated with coumarin oral anticoagulants (OA) is reported. The assays are able to quantitate Warfarin (W) and/or Acenocoumarol (ACL) directly in plasma samples without any previous sample pretreatment. The detectabilities (W, 3.52?±?2.25?nM and ACL, 1.56?±?0.64?nM) and the working ranges achieved (W, 1.19?±?0.73 to 12.05?±?2.99?nM and ACL 0.63?±?0.20 to 10.19?±?6.69?nM) are within the therapeutic levels usually found in patients treated with these drugs. The assays are specific with only cross-recognition of 4'-NH2-ACL on the ACL ELISA, which is one of the main metabolites of this drug. Moreover, accuracy studies performed with blind spiked samples show very good correlation between the spiked and the measured concentrations. Finally, a small clinical pilot study has been performed analyzing 96 plasma samples from treated and untreated patients, showing that the assay is able to quantitate ACL. The results obtained allow envisaging the possibility to use these assays for pharmacokinetic studies, dosage assessment or therapeutic drug monitoring.


Vesicular nanostructures composed of oleic acid and phosphatidylcholine:Effect of pH and molar ratio

K. Talló, V. Moner, M. De Cabo, M. Cócera, O. López

Chemistry and Physics of Lipids 213 (2018) 96–101

Phospholipids and fatty acids are the main building blocks of biological membranes. Oleic acid is a monounsaturated omega-9 fatty acid commonly found in many natural sources. Its characteristic kinked structure grants this molecule with a great number of biological properties. To better understand the role that this kind of fatty acids play into phospholipid membranes, nanostructured systems formed with hydrogenated soy phosphatidylcholine and oleic acid were studied in this work by means of cryo-electron microscopy, dynamic light scattering and differential scanning calorimetry. Differences concerning size, morphology and phase behavior were found when those systems were prepared at different conditions of pH and molar ratio between both compounds. Broadly, it was seen how alkaline mediums and high proportions of oleic acid reduced the size of the structures and increased the fluidity of the membranes. The ease of preparation of these lipid systems, and the response to pH suggests a future use of these systems as model membranes or delivery systems.


Chromonic self-assemblies in a series of dialkyl-thiacarbocyanine dyes and generalization of a facile route for the synthesis of fluorescent nanostructured silica fibers

Magana, J.R., Solans, C., Salonen, L.M., Carbó-Argibay, E., Gallo, J., Tiddy, G.J.T., Rodríguez-Abreu, C.

 Journal of the Taiwan Institute of Chemical Engineers, 2018

 In the search for new chromonic liquid crystals, we have explored the self-assembly behavior in water of a series of high-purity dialkylthiacarbocyanine dyes with different alkyl chain lengths and acetate as counterion. The dimer model was used to fit the UV–vis spectra and estimate the dissociation energy between molecules, which increases with the alkyl chain length suggesting that not only aromatic p–p interactions but also entropic/steric effects contribute to the aggregation process. NMR spectra suggest the existence of aromatic stacking interactions within the aggregates. At high concentrations, the dyes form nematic and hexagonal chromonic liquid crystals (CLC) in water within a limited range of alkyl chain lengths (ethyl to butyl); for longer lengths (pentyl) no liquid crystals were observed because of insufficient dye solubility. From small angle X-ray scattering patterns, it can be inferred that dye aggregates have cylindrical morphology with a multimolecular cross-section. The dye aggregates template the formation of silica nanofibers synthetized via sol–gel method in alkaline media. After removing excess dye, the silica/dye nanofibers showed high fluorescence emission with superb photochemical stability. The present report demonstrates a generalized route for the wet synthesis of nanostructured silica nanofibers with tunable optical properties.


Analysis of the neurotoxic effects of neuropathic organophosphorus compounds in adult zebrafish

Melissa Faria, Inmaculada Fuertes, Eva Prats, Jose Luis Abad, Francesc Padrós, Cristian Gomez-Canela, Josefina Casas, Jorge Estevez, Eugenio Vilanova, Benjamin Piña & Demetrio Raldúa

Scientific Reports volume 8, Article number: 4844 (2018)

 Inhibition and aging of neuropathy target esterase (NTE) by exposure to neuropathic organophosphorus compounds (OPs) can result in OP-induced delayed neuropathy (OPIDN). In the present study we aimed to build a model of OPIDN in adult zebrafish. First, inhibition and aging of zebrafish NTE activity were characterized in the brain by using the prototypic neuropathic compounds cresyl saligenin phosphate (CBDP) and diisopropylphosphorofluoridate (DFP). Our results show that, as in other animal models, zebrafish NTE is inhibited and aged by both neuropathic OPs. Then, a neuropathic concentration inhibiting NTE activity by at least 70% for at least 24 h was selected for each compound to analyze changes in phosphatidylcholines (PCs), lysophosphatidylcholines (LPCs) and glycerolphosphocholine (GPC) profiles. In spite to the strong inhibition of the NTE activity found for both compounds, only a mild increase in the LPCs level was found after 48 h of the exposure to DFP, and no effect were observed by CBDP. Moreover, histopathological evaluation and motor function outcome analyses failed to find any neurological abnormalities in the exposed fish. Thus, our results strongly suggest that zebrafish is not a suitable species for the development of an experimental model of human OPIDN.


Fluorescent microarray for multiplexed quantification of environmental contaminants in seawater samples

Sanchis, A., Salvador, J.-P., Campbell, K., Elliott, C.T., Shelver, W.L., Li, Q.X., Marco, M.-P.

Talanta, 184, pp. 499-506. 2018

 The development of a fluorescent multiplexed microarray platform able to detect and quantify a wide variety of pollutants in seawater is reported. The microarray platform has been manufactured by spotting 6 different bioconjugate competitors and it uses a cocktail of 6 monoclonal or polyclonal antibodies raised against important families of chemical pollutants such as triazine biocide (i.e. Irgarol 1051®), sulfonamide and chloramphenicol antibiotics, polybrominated diphenyl ether flame-retardant (PBDE, i.e. BDE-47), hormone (17ß-estradiol), and algae toxin (domoic acid). These contaminants were selected as model analytes, however, the platform developed has the potential to detect a broader group of compounds based on the cross-reactivity of the immunoreagents used. The microarray chip is able to simultaneously determine these families of contaminants directly in seawater samples reaching limits of detection close to the levels found in contaminated areas (Irgarol 1051®, 0.19?±?0,06?µg?L-1; sulfapyridine, 0.17?±?0.07?µg?L-1; chloramphenicol, 0.11?±?0.03?µg?L-1; BDE-47, 2.71?±?1.13?µg?L-1; 17ß-estradiol, 0.94?±?0.30?µg?L-1 and domoic acid, 1.71?±?0.30?µg?L-1). Performance of the multiplexed microarray chip was assessed by measuring 38 blind spiked seawater samples containing either one of these contaminants or mixtures of them. The accuracy found was very good and the coefficient of variation was

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