Dimethyl Fumarate-Loaded Transethosomes: A Formulative Study and Preliminary Ex Vivo and In Vivo Evaluation

In this study, transethosomes were investigated as potential delivery systems for dimethyl fumarate. A formulative study was performed investigating the effect of the composition of transethosomes on the morphology and size of vesicles, as well as drug entrapment capacity, using cryogenic transmission electron microscopy, photon correlation spectroscopy, and HPLC. The stability of vesicles was evaluated, both for size increase and capability to control the drug degradation. Drug release kinetics and permeability profiles were evaluated in vitro using Franz cells, associated with different synthetic membranes. The in vitro viability, as well as the capacity to improve wound healing, were evaluated in human keratinocytes. Transmission electron microscopy enabled the evaluation of transethosome uptake and intracellular fate. Based on the obtained results, a transethosome gel was further formulated for the cutaneous application of dimethyl fumarate, the safety of which was evaluated in vivo with a patch test. It was found that the phosphatidylcholine concentration affected vesicle size and lamellarity, influencing the capacity to control dimethyl fumarate’s chemical stability and release kinetics. Indeed, phosphatidylcholine 2.7% w/w led to multivesicular vesicles with 344 nm mean size, controlling the drug’s chemical stability for at least 90 days. Conversely, phosphatidylcholine 0.9% w/w resulted in 130 nm sized unilamellar vesicles, which maintained 55% of the drug over 3 months. These latest kinds of transethosomes were able to improve wound healing in vitro and were easily internalised by keratinocytes. The selected transethosome gel, loading 25 mg/mL dimethyl fumarate, was not irritant after cutaneous application under occlusion, suggesting its possible suitability in the treatment of wounds caused by diabetes mellitus or peripheral vascular diseases.     

Characterisation of virgin olive oils from European olive cultivars introduced in Tunisia

The behaviour of three European olive varieties, Ascolana Tenera, Koroneiki and Picholine, cultivated in the north of Tunisia, was compared to an autochthonous variety, Chétoui. Most of the quality indices and the fatty acid composition showed significant variations between the olive oils. Among the introduced varieties, the Picholine cultivar had the highest value of oleic acid (61%) whereas the Ascolana Tenera cultivar was noteworthy for its lowest content of phenolic compounds (175 mg/kg) and presented the highest level of palmitic acid. The Chétoui variety presented a high content of oleic and linoleic acids. But all samples, both the autochthonous Chétoui and the introduced cultivars, have similar levels of antioxidant compounds, with the exception of phenols. The aroma composition showed significant differences between the oils from the foreign cultivars. The major volatile component was the C‐6 aldehyde fraction whose content varied greatly between the different varieties studied: The E‐2‐hexenal content ranged from 1.6 mg/kg of oil in the Ascolana Tenera variety to >5 mg/kg for the Picholine and Koroneiki cultivars, whereas the Chétoui variety had the lowest levels of volatile compounds, with the exception of the hexanal level which was tenfold higher than in the foreign cultivars. Therefore, our results showed that two of the introduced varieties, Koroneiki and Picholine, showed good adaptation to the Tunisian cultivation conditions. So far, we claim the possibility to develop the successful cultivation of these latter imported varieties in the country.     

Mesenchymal Stromal Cells Preconditioning: A New Strategy to Improve Neuroprotective Properties

Neurological diseases represent one of the main causes of disability in human life. Consequently, investigating new strategies capable of improving the quality of life in neurological patients is necessary. For decades, researchers have been working to improve the efficacy and safety of mesenchymal stromal cells (MSCs) therapy based on MSCs’ regenerative and immunomodulatory properties and multilinear differentiation potential. Therefore, strategies such as MSCs preconditioning are useful to improve their application to restore damaged neuronal circuits following neurological insults. This review is focused on preconditioning MSCs therapy as a potential application to major neurological diseases. The aim of our work is to summarize both the in vitro and in vivo studies that demonstrate the efficacy of MSC preconditioning on neuronal regeneration and cell survival as a possible application to neurological damage.     

Inactivation of Polyphenoloxidase by Pulsed Light

The effect of pulsed light on the inactivation of polyphenoloxidase (PPO) in model solutions was investigated focusing on the effect of enzyme concentration and total energy dose of the treatment. PPO inactivation increased with the dose of the treatment. Complete enzyme inactivation was achieved by pulsed light doses higher than 8.75 J cm^?2. At low PPO concentrations (4 to 10 U), the enzyme resulted highly inactivated by pulsed light treatment. Further increase in enzyme units determined a progressive decrease in PPO inactivation. The latter was attributed to protein structural modifications including cleavage and unfolding/aggregation phenomena. PPO amounts higher than 10 U probably favoured enzyme conformations that were less prone to intermolecular rearrangements leading to inactivation.     

Non‐parametric smoothing and prediction for nonlinear circular time series

Not much research has been done in the field of circular time‐series analysis. We propose a non‐parametric theory for smoothing and prediction in the time domain for circular time‐series data. Our model is based on local constant and local linear fitting estimates of a minimizer of an angular risk function. Both asymptotic arguments and empirical examples are used to describe the accuracy of our methods.     

Spiro[chromane-2,4'-piperidine]-based histone deacetylase inhibitors with improved in vivo activity

A series of spiro[chromane-2,4'-piperidine] derivatives based on a previously published lead benzyl spirocycle 1 and bearing various N-aryl and N-alkylaryl substituents on the piperidine ring were prepared as novel histone deacetylase (HDAC) inhibitors. The compounds were evaluated for their abilities to inhibit nuclear HDACs, their in vitro antiproliferative activities, and in vitro ADME profiles. Based on these activities, 4-fluorobenzyl and 2-phenylethyl spirocycles were selected for further characterization. In vivo pharmacokinetic (PK) studies showed that both compounds exhibit an overall lower clearance rate, an increased half-life, and higher AUCs after intravenous and oral administration than spiropiperidine 1 under the conditions used. The improved PK behavior of these two compounds also correlated with superior in vivo antitumor activity in an HCT-116 xenograft model.