In Vitro Cytotoxic Protective Effect of Alginate-Encapsulated Capsaicin Might Improve Skin Side Effects Associated with the Topical Application of Capsaicin

Chronic neuropathic pain, particularly peripheral pain, is a cause of great concern for diabetic patients. Current treatments include numerous agents such as capsaicinoids, a known deterrent of neuropathic pain despite the inconvenience associated with local side effects. In this context, the current work aims to elucidate the potential mechanisms involved in cytotoxicity by capsaicin and proposes an efficient formulation of capsaicin in alginate microcapsules, which significantly reduces side effects from capsaicin topical administration. For this, human dermal fibroblast cells were treated with alginate-microencapsulated capsaicin extracts and screened for potential cytotoxic effects produced by the treatment. Cell viability and morphology were examined, as well as oxidative stress status and anti-inflammatory potential. Our results show that the alginate encapsulated formulation of capsaicin exerted lower cytotoxic effects on human dermal fibroblasts as measured by cell viability and reactive oxygen species (ROS) production. Furthermore, the expression profiles of inflammatory cytokines were significantly altered by the treatment as compared with the control culture.     

Binding free energies in the SAMPL5 octa-acid host–guest challenge calculated with DFT-D3 and CCSD(T)

We have tried to calculate the free energy for the binding of six small ligands to two variants of the octa-acid deep cavitand host in the SAMPL5 blind challenge. We employed structures minimised with dispersion-corrected density-functional theory with small basis sets and energies were calculated using large basis sets. Solvation energies were calculated with continuum methods and thermostatistical corrections were obtained from frequencies calculated at the HF-3c level. Care was taken to minimise the effects of the flexibility of the host by keeping the complexes as symmetric and similar as possible. In some calculations, the large net charge of the host was reduced by removing the propionate and benzoate groups. In addition, the effect of a restricted molecular dynamics sampling of structures was tested. Finally, we tried to improve the energies by using the DLPNO–CCSD(T) approach. Unfortunately, results of quite poor quality were obtained, with no correlation to the experimental data, systematically too positive affinities (by ~50 kJ/mol) and a mean absolute error (after removal of the systematic error) of 11–16 kJ/mol. DLPNO–CCSD(T) did not improve the results, so the accuracy is not limited by the energy function. Instead, four likely sources of errors were identified: first, the minimised structures were often incorrect, owing to the omission of explicit solvent. They could be partly improved by performing the minimisations in a continuum solvent with four water molecules around the charged groups of the ligands. Second, some ligands could bind in several different conformations, requiring sampling of reasonable structures. Third, there is an indication the continuum-solvation model has problems to accurately describe the binding of both the negatively and positively charged guest molecules. Fourth, different methods to calculate the thermostatistical corrections gave results that differed by up to 30 kJ/mol and there is an indication that HF-3c overestimates the entropy term. In conclusion, it is a challenge to calculate binding affinities for this octa-acid system with quantum–mechanical methods.     

Influence of moisture on transient oxidation and reduction of alumina-supported platinum

The transient surface behavior on oxidation and reduction of a partially oxidized alumina-supported platinum catalyst containing residual water have been observed by AC electrical conductance (G) measurements.     

Binding free energies in the SAMPL6 octa-acid host–guest challenge calculated with MM and QM methods

We have estimated free energies for the binding of eight carboxylate ligands to two variants of the octa-acid deep-cavity host in the SAMPL6 blind-test challenge (with or without endo methyl groups on the four upper-rim benzoate groups, OAM and OAH, respectively). We employed free-energy perturbation (FEP) for relative binding energies at the molecular mechanics (MM) and the combined quantum mechanical (QM) and MM (QM/MM) levels, the latter obtained with the reference-potential approach with QM/MM sampling for the MM → QM/MM FEP. The semiempirical QM method PM6-DH+ was employed for the ligand in the latter calculations. Moreover, binding free energies were also estimated from QM/MM optimised structures, combined with COSMO-RS estimates of the solvation energy and thermostatistical corrections from MM frequencies. They were performed at the PM6-DH+ level of theory with the full host and guest molecule in the QM system (and also four water molecules in the geometry optimisations) for 10–20 snapshots from molecular dynamics simulations of the complex. Finally, the structure with the lowest free energy was recalculated using the dispersion-corrected density-functional theory method TPSS-D3, for both the structure and the energy. The two FEP approaches gave similar results (PM6-DH+/MM slightly better for OAM), which were among the five submissions with the best performance in the challenge and gave the best results without any fit to data from the SAMPL5 challenge, with mean absolute deviations (MAD) of 2.4–5.2 kJ/mol and a correlation coefficient (R²) of 0.77–0.93. This is the first time QM/MM approaches give binding free energies that are competitive to those obtained with MM for the octa-acid host. The QM/MM-optimised structures gave somewhat worse performance (MAD?=?3–8 kJ/mol and R²?=?0.1–0.9), but the results were improved compared to previous studies of this system with similar methods.     

Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking,MM/GBSA,QM/MM,and free-energy simulations

We have estimated the binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition. We have employed four different methods, based on five different crystal structures: first, we docked the ligands to the proteins with induced-fit docking with the Glide software and calculated binding affinities with three energy functions. Second, the docked structures were minimised in a continuum solvent and binding affinities were calculated with the MM/GBSA method (molecular mechanics combined with generalised Born and solvent-accessible surface area solvation). Third, the docked structures were re-optimised by combined quantum mechanics and molecular mechanics (QM/MM) calculations. Then, interaction energies were calculated with quantum mechanical calculations employing 970–1160 atoms in a continuum solvent, combined with energy corrections for dispersion, zero-point energy and entropy, ligand distortion, ligand solvation, and an increase of the basis set to quadruple-zeta quality. Fourth, relative binding affinities were estimated by free-energy simulations, using the multi-state Bennett acceptance-ratio approach. Unfortunately, the results were varying and rather poor, with only one calculation giving a correlation to the experimental affinities larger than 0.7, and with no consistent difference in the quality of the predictions from the various methods. For one set of ligands, the results could be strongly improved (after experimental data were revealed) if it was recognised that one of the ligands displaced one or two water molecules. For the other two sets, the problem is probably that the ligands bind in different modes than in the crystal structures employed or that the conformation of the ligand-binding site or the whole protein changes.     

Rigidity and gluing for Morse and Novikov complexes

We obtain rigidity and gluing results for the Morse complex of a real-valued Morse function as well as for the Novikov complex of a circle-valued Morse function. A rigidity result is also proved for the Floer complex of a hamiltonian defined on a closed symplectic manifold (M,) with c₁|_2(M)=[]|_2(M)=0. The rigidity results for these complexes show that the complex of a fixed generic function/hamiltonian is a retract of the Morse (respectively Novikov or Floer) complex of any other sufficiently C⁰ close generic function/hamiltonian. The gluing result is a type of Mayer-Vietoris formula for the Morse complex. It is used to express algebraically the Novikov complex up to isomorphism in terms of the Morse complex of a fundamental domain. Morse cobordisms are used to compare various Morse-type complexes without the need of bifurcation theory.     

Structural aspects in self-assembled systems of polyoxyethylene surfactants, as studied by the spin probe technique

Typical examples of structural characterization of self-assembled systems by the spin probes technique, selected from our representative results accumulated in the last years of systematic studies, are presented. The choice of the examples has aimed at emphasizing the potentiality of this technique in the study of self-assembled systems, in general, and of those of PEO surfactants, in particular. By using specific ESR parameters (the nitrogen hyperfine splitting (hfs), a_N, the rotational correlation time, τ_c, the order parameter, S) of a variety of properly chosen nitroxides, problems such hydration degree and profile of the PEO chains, ordering and order profile along these chains, their penetrability by the oil solvent, role of the terminal OH in the micellization, as well as differences in these quantities vs. the nature of the aggregate (micelle, reverse micelle, lamellar phase, etc.), nature of the surfactants (conventional or triblock copolymer), solubilizates (water in reverse micelles or various alcohols in micelles) and temperature have been discussed.     

Solvent-induced textural changes of as-synthesized mesoporous alumina, as reported by spin probe electron spin resonance spectroscopy

The effect of solvent used during the synthesis and postsynthesis treatment on textural properties of organized mesoporous aluminas was investigated and related to the behavior of spin probes studied by electron spin resonance (ESR) spectroscopy. It was found that the structure of surfactant aggregates serving in the as-synthesized precipitates as templates could be easily modified by treatment with different solvents. This treatment induces corresponding variations in surface areas, mesopore volumes, and mesopore diameters of the final products. The ESR spectrum of 5-doxyl stearic acid spin probe properly reflects the changes in template structure based on changes of the solvent used and represents an early indicator of the corresponding textural modifications of the mesoporous alumina.