Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE‐1 and GSK‐3β Inhibitors

Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer′s disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6‐amino‐4‐phenyl‐3,4‐dihydro‐1,3,5‐triazin‐2(1H)‐ones as the first class of molecules able to simultaneously modulate BACE‐1 and GSK‐3β. Notably, one triazinone showed well‐balanced in vitro potencies against the two enzymes (IC₅₀ of (18.03±0.01) μM and (14.67±0.78) μM for BACE‐1 and GSK‐3β, respectively). In cell‐based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD‐modifying potential.     

Plasma Processing of Scaffolds for Tissue Engineering and Regenerative Medicine

Plasma processes are largely employed in the biomedical field for different kind of materials. In particular, in tissue engineering, biomaterials need to be totally integrated with biological systems in order to be employed as substitutes of artificial prostheses. Since most materials do not allow a correct integration with the biological environment, plasma processes have been demonstrated to be very versatile in altering the material surface properties in order to improve the biocompatibility of materials. The challenge is to plasma modify 3D scaffolds in order to be used for in vivo regeneration of human tissues. The correct 3D biointegration inside living tissues is the crucial objective, towards which many aspects are directed, from the material engineering to its surface modification and affinity with the biological environment. In this paper, the advances in low pressure plasma processes, applied to both 2D rigid substrates and 3D porous structures, are discussed. Further an in vivo experiment in ovine animals using plasma processed 3D scaffolds is illustrated.     

Surface chemical composition and fibrinogen adsorption-retention of fluoropolymer films deposited from an RF glow discharge

Fluoropolymer films have been deposited in the glow and afterglow regions of radio frequency glow discharges fed with C₂F₆−H₂ mixtures. Structure, growth rate, composition, and wettability of the films have been investigated by means of atomic force microscopy, electron spectroscopy for chemical analysis, secondary ion mass spectrometry, and water contact angle measurements.¹²⁵I labeled baboon fibrinogen in baboon plasma has been used to study the adsorption of the protein onto the films. Protein retention, i.e., the binding affinity of the adsorbed protein, has been examined by elution with a sodium dodecyl sulfate solution. Adsorption and retention of fibrinogen were correlated using multivariate statistical methods with the wettability, the degree of film fluorination, and the CF _x (1≤x≤3) group distribution of the coatings. This correlation identified the influence of each variable on the adsorption and retention of fibrinogen onto these substrates. These variables or surface properties can be easily balanced by properly tuning the experimental conditions of the glow discharge deposition process.     

Selective grafting of amine groups on polyethylene by means of NH3−H2 RF glow discharges

Plasma treatments in Radio Frequency Glow Discharges fed with NH₃−H₂ mixtures have been performed for modifying polyethylene surfaces. Treatment kinetics and the role of species present in the glow have been investigated. Actinometric Optical Emission Spectroscopy has been utilized as a plasma diagnostic technique. Electron Spectroscopy for Chemical Analysis has been utilized for studying surface composition of treated substrates, which have been examined both astreated and after derivatization of amine-functionalities with 4-trifluoromethylbenzaldehyde vapors. It has been found that experimental plasma parameters and plasma density of active species can be controlled to achieve selective grafting of-NH₂ among all other nitrogen-containing groups.     

Surface characterization of plasma deposited nano-structured fluorocarbon coatings for promoting in vitro cell growth

Nano-structured “teflon-like” coatings characterized by highly-fluorinated, random, ribbon-shaped, micrometers-long structures were deposited on polyethylenetherephtalate (PET) substrates by plasma enhanced-chemical vapour deposition (PE-CVD) using modulated radiofrequency (RF, 13.56 MHz) glow discharges fed with C₂F₄ in modulated discharge (MD) and continuous wave (CW) regimes. Surfaces obtained in this way featured identical chemical composition and different roughness in the nanometric scale. Water contact angle (WCA) measurements, scanning electron microscopy (SEM) and atomic force microscopy (AFM) were utilized to characterize the surfaces. A positive relationship was shown to exist between the WCA value and the mean nano-structure height and the area root-mean-square (RMS) roughness of coatings. The possibility of obtaining coatings of varying nano-structure height, i.e., roughness, in a nanometric scale represents a promising result for further use of these surfaces as substrates for experiments on cell adhesion, proliferation and growth.     

XPS, ICP and DPASV analysis of medieval pottery — Statistical multivariate treatment of data

Medieval ceramic sherds have been studied by inductively coupled plasma (ICP) emission spectroscopy and X-ray photoelectron spectroscopy (XPS) in order to acquire knowledge about technological achievements in pottery production in Apulia during the Middle Ages. The XPS results allow to characterize the surface glazes, which are transparent owing to the presence of PbO or opaque-white in case of Sn addition. The study of coloured glossy surfaces, after an optimized chemical etching, has also shed light on the pigment nature of the painted decorations, whose red colour is to be attributed to the presence of Pb₃O₄ and not of Fe oxides. Quantitative determinations were performed by ICP measurements on samples of differently coloured glazes, clayey slips and ceramic bulks. Pb and Cu, present in one green glaze, were also determined by differential pulsed anodic stripping voltammetry (DPASV). The analytical results were treated by different statistical techniques of multivariate analysis.     

Plasma deposition of thin films from a fluorine-containing cyclosiloxane

Thin films have been deposited from radio-frequency glow discharges fed with vapors of a silicon- and fluorine-containing organic compound, namely 2,4,6-tris[(3,3,3-trifluoropropyl) (methyl)] cyclotrisiloxane, in mixture with argon. 2,4,6-tris[(3,3,3-trifluoropropyl)(methyl)]cyclotrisiloxane A triode reactor has been utilized to deposit films by independently changing substrate temperature and bias-induced ion-bombardment. Laser interferometry, electron spectroscopy for chemical analysis and Fourier-transform infrared spectroscopy have been used to monitor film growth rate and composition. Results unambiguously show an activating effect of the ion-bombardment, which confirm the validity of the ion-assisted deposition model utilized for the plasma deposition of both teflon- and silicone-like films. In our experiments, low substrate temperature and bias conditions results in films with a “monomer-like” stoichiometry, while drastic conditions give origin to materials with a completely different composition and a markedly increased hardness. © 1994 John Wiley & Sons, Inc.     

Editorial

Plasmas and Polymers -     

Cell adhesion on nanotextured slippery superhydrophobic substrates

In this work, the response of Saos2 cells to polymeric surfaces with different roughness/density of nanometric dots produced by a tailored plasma-etching process has been studied. Topographical features have been evaluated by atomic force microscopy, while wetting behavior, in terms of water-surface adhesion energy, has been evaluated by measurements of drop sliding angle. Saos2 cytocompatibility has been investigated by scanning electron microscopy, fluorescent microscopy, and optical microscopy. The similarity in outer chemical composition has allowed isolation of the impact of the topographical features on cellular behavior. The results indicate that Saos2 cells respond differently to surfaces with different nanoscale topographical features, clearly showing a certain inhibition in cell adhesion when the nanoscale is particularly small. This effect appears to be attenuated in surfaces with relatively bigger nanofeatures, though these express a more pronounced slippery/dry wetting character.     

SERAPhiC: a benchmark for in silico fragment-based drug design

Our main objective was to compile a data set of high-quality protein-fragment complexes and make it publicly available. Once assembled, the data set was challenged using docking procedures to address the following questions: (i) Can molecular docking correctly reproduce the experimentally solved structures? (ii) How thorough must the sampling be to replicate the experimental data? (iii) Can commonly used scoring functions discriminate between the native pose and other energy minima? The data set, named SERAPhiC (Selected Fragment Protein Complexes), is publicly available in a ready-to-dock format ( http://www.iit.it/en/drug-discovery-and-development/seraphic.html ). It offers computational medicinal chemists a reliable test set for both in silico protocol assessment and software development.