EBC metabolomics for asthma severity.

Asthma is a heterogeneous disease with diverse severity and represents a considerable socio-economic burden. Exhaled Breath Condensate (EBC) is a biofluid directly obtained from the airway lining fluid non-invasively. We attempted to discriminate severe from mild-to-moderate asthma using EBC metabolomics based on both NMR and UHPLC-MS techniques. 36 patients were included in this study (15 patients with severe and 21 with mild-to-moderate asthma). EBC was collected and analyzed using both NMR and UHPLC-MS techniques for possible metabolites. Using PLS and oPLS analysis for the UHPLC-MS data, no metabolite was found to be sufficient for the discrimination of asthma severity. However, when another PLS-regression model was applied five metabolites were found to discriminate severe from mild-to-moderate asthma. Amino-acid lysine was the only metabolite that discriminated the two study groups using NMR data (p= 0.04, t-test with Welch's correction, AUC 0.66). EBC is an easily available biofluid which directly represents the lower airways but difficult-to-use for metabolomic analysis. Our study presents some encouraging findings for the discrimination of asthma severity subgroups using EBC metabolomics but more well-designed studies with a higher number of patients need to be conducted.

Losartan's molecular basis of interaction with membranes and AT1 receptor.

Physicochemical methods were used to study the thermal and dynamic changes caused by losartan in the membrane bilayers. In addition, molecular modeling was implemented to explore its topography both in membranes and AT(1) receptor. Its incorporation resulted in the modification of thermal profile of dipalmitoyl phosphatidylcholine (DPPC) bilayers in a concentration dependent way up to 20mol% as it is depicted from the combination of differential scanning calorimetry (DSC) and MAS data. In particular, the presence of losartan caused lowering of the phase transition temperature and abolishment of the pretransition. T(1) experiments revealed the location of the drug into the membrane bilayers. The use of a combination of biophysical methods along with docking experiments brought out a possible two-step mechanism which involves incorporation of losartan at the interface of membrane bilayers and diffusion in the upper parts of AT(1) receptor helices IV-VII.

Synthesis, cytotoxic activity, NMR study and stereochemical effects of some new pyrano[3,2-b]thioxanthen-6-ones and pyrano[2,3-c]thioxanthen-7-ones.

Some new substituted pyrano[3,2-b]thioxanthen-6-ones and pyrano[2,3-c]thioxanthen-7-ones were prepared and their cytotoxic activity was evaluated using acronycine as the reference compound. The conformation of the molecules was also investigated in an effort to correlate this parameter with the biological activity.

Megistosarcimine and megistosarconine, two alkaloids from Sarcomelicope megistophylla.

Two new alkaloids, megistosarcimine and megistosarconine, were isolated from the aerial parts of Sarcomelicope megistophylla. Their structures have been elucidated on the basis of their spectral data and molecular modeling.

How do antibodies and lectins recognize histo-blood group antigens? A 3D-QSAR study by comparative molecular field analysis (CoMFA).

The cross-reaction patterns of nine antibodies and three lectins against 12 H type 2 related oligosaccharides have been analysed by means of 3D-QSAR study. Three-dimensional descriptors of the molecular properties have been used in comparative molecular field analysis (CoMFA). Three different alignments were considered for the oligosaccharides. One, based on the superimposition of the oligosaccharide core, could be correlated to most of the antibody activities. A second alignment, based on a superimposition of the fucose residue, had to be taken into account for explaining the binding properties of Ulex europaeus isolectin I. Analysis of the QSAR data gives indications on the carbohydrate epitopes essential for antibody recognition and yields some insights about the nature of the molecular recognition. This study complements previous biochemical estimates of the H type 2 related oligosaccharide binding areas (Mollicone, R.; Cailleau, A.; Imberty, A.; Gane, P.; Pérez, S.; Oriol, R. Glycoconj. J. 1996, 13, 263-271).

Computer simulation of histo-blood group oligosaccharides: energy maps of all constituting disaccharides and potential energy surfaces of 14 ABH and Lewis carbohydrate antigens.

The three-dimensional structures of fourteen histo-blood groups carbohydrate antigens have been established through a combination of molecular mechanics and conformational searching methods. The conformational space available for each disaccharide, constituents of these determinants, has been throroughly characterized. The results have been organized in a data bank fashion. Larger relatives, i.e. 14 tri- and tetrasaccharides of histo-blood group antigens, have been modelled using a different method for exploring the complex potential energy surface. This approach is aimed at establishing all the possible families of conformations, along with the conformational pathways. Different conformational behaviours are exhibited by these oligosaccharides. Some of them, i.e. Le(x) and Le(y) tri and tetrasaccharides, are very rigid; 99% of their populations belong to the same conformational family. Others, like H type 1, H type 2 or H type 6 oligosaccharides, are essentially rigid, but a secondary conformational family, corresponding to 3-4% of the total population, can arise. Finally, the H types 3 and 4 trisaccharides, and the A type 1 and A type 2 tetrasaccharides are predicted to behave rather flexibly. The information gathered in the present investigation has been used to analyse the body of experimental evidence, either physical or biological, available for this series of carbohydrate antigens. Of special interest are the several different alignments that can be proposed for these molecules. They yield a realistic definition of the three-dimensional features of the epitopes thereby providing essential information about how carbohydrate antigens are recognized by proteins.

Structural studies of metalloporphyrins. Part XIa: Complexes of water-soluble zinc(II) porphyrins with amino acids: influence of ligand-ligand interactions on the stability of the complexes.

The stability constants of a series of complexes of the cationic water-soluble porphyrin ZnTMPyP with various amino acids have been determined by 1H NMR spectroscopy at pH 10.5. The following stability order has been observed: Tyr greater than Phe, Glu greater than Asp greater than Ile greater than Val greater than Gly. These results can be best rationalized by invoking complex stabilization due to ligand-ligand (e.g., stacking or electrostatic) interactions. Evidence for stacking interactions between the porphyrin ring and the aromatic ring of phenylalanine, tyrosine, and tryptophan was further provided by study of the complexation of these amino acids with the free-base porphyrin TMPyPH2. In this case, complexation constants increased in the order: Phe less than Tyr less than Trp. Attempts to form complexes of the amino acids with the anionic porphyrin ZnTCPP proved unsuccessful, indicating that electrostatic interactions play a major role in the stability of the zinc porphyrin-amino acids complexes.