The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure‐Based Virtual Screening to In Vivo Biological Activity

A mismatch between β‐oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3‐(2,2,2‐ trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington’s disease (HD). Here, new THP‐derived carnitine‐lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster

Origanum majorana L. polyphenols: in vivo antiepileptic effect, in silico evaluation of their bioavailability, and interaction with the NMDA receptor

Introduction: Epilepsy is a chronic brain disease characterized by repeated seizures and caused by excessive glutamate receptor activation. Many plants are traditionally used in the treatment of this disease. This study aimed to evaluate the bioavailability of a polyphenolic extract obtained from Origanum majorana L. (OMP) leaves, as well as its antiepileptic activity and its potential mechanism of action.Methods: We have developed and validated a simple, rapid, and accurate stability-indicating reversed-phase liquid chromatographic method for the simultaneous determination of caffeine and quercetin in rat plasma. The OMP antiepileptic effect was evaluated with pilocarpine-induced seizures, and a docking method was used to determine the possible interaction between caffeic acid and quercetin with the N-methyl-D-aspartate (NMDA) receptor.Results and Discussion: Both compounds tested showed low bioavailability in unchanged form. However, the tested extract showed an anticonvulsant effect due to the considerably delayed onset of seizures in the pilocarpine model at a dose of 100 mg/kg. The molecular docking proved a high-affinity interaction between the caffeic acid and quercetin with the NMDA receptor. Taken together, OLP polyphenols demonstrated good antiepileptic activity, probably due to the interaction of quercetin, caffeic acid, or their metabolites with the NMDA receptor

Design, synthesis, biological studies of new mitochondrial modulators improving neurological deficits in experimental models of Huntington's disease

2014 - 2015XIV n.s

Development of roll-waves in power-law fluids with non-uniform initial conditions

This paper investigates the spatial evolution of a disturbance in an open-channel flow of a power-law fluid at non-uniform accelerated and decelerated initial profiles, up to the occurrence of roll-waves in mild and steep slope channels. Both theoretical and numerical analyses are applied to the depth-averaged continuity and momentum conservation equations, deduced from the von K\ue1rm\ue1n's integral method. For the theoretical investigation, the nonlinear near-front expansion technique was applied. Then, the full nonlinear problem in its conservative formulation was numerically solved. Independently of the rheology of the flowing medium, non-uniform initial conditions strongly influence the perturbation celerity, the disturbance evolution and the roll-wave development. For mild slope channels, an initially decelerated profile of shear-thinning fluids has a stabilizing effect, while the opposite is found for accelerated profiles. For shear-thickening fluids, only the stabilizing effect caused by a decelerated profile is observed. In steep slope channels, independently of the fluid rheology, decelerated initial conditions promote roll-wave occurrence, while accelerated conditions inhibit the perturbation growth. Although experimental verifications are needed, the present results have to be properly accounted for in defining roll-wave prediction methods and in assigning appropriate boundary conditions to enhance or to reduce their formation

Inlet effects on roll-wave development in shallow turbulent open-channel flows

The present work investigates the effect of the flow profile induced by an inlet condition on the roll-wave evolution in turbulent clear-water flows. The study employs theoretical and numerical analyses. Firstly, the influence of the inlet condition on the spatial evolution of a single perturbation in a hypercritical flow is examined through the expansion near a wavefront analysis. The results show that an accelerated unperturbed profile reduces the disturbance spatial growth. A decelerated profile causes an increase. The effect of the flow profile on the spatial evolution of roll-wave trains is then numerically investigated solving the Saint Venant equations with a second-order Runge-Kutta Total Variation Diminishing (TVD) Finite Volume scheme. The numerical simulations comply with the analytical results for the initial and transition phases of the roll-wave development. The unperturbed profile influences even the roll-waves statistical characteristics in the final stage, with a more evident effect in case of accelerated profiles. The influence of the flow profile should be therefore accounted for in the formulation of predictive criteria for roll-waves appearance based on the estimation of the disturbance spatial growth rate

Inlet effects on roll-wave development in shallow turbulent open-channel flows

The present work investigates the effect of the flow profile induced by an inlet condition on the roll-wave evolution in turbulent clear-water flows. The study employs theoretical and numerical analyses. Firstly, the influence of the inlet condition on the spatial evolution of a single perturbation in a hypercritical flow is examined through the expansion near a wavefront analysis. The results show that an accelerated unperturbed profile reduces the disturbance spatial growth. A decelerated profile causes an increase. The effect of the flow profile on the spatial evolution of roll- wave trains is then numerically investigated solving the Saint Venant equations with a second-order Runge-Kutta Total Variation Diminishing (TVD) Finite Volume scheme. The numerical simulations comply with the analytical results for the initial and transition phases of the roll-wave development. The unperturbed profile influences even the roll-waves statistical characteristics in the final stage, with a more evident effect in case of accelerated profiles. The influence of the flow profile should be therefore accounted for in the formulation of predictive criteria for roll-waves appearance based on the estimation of the disturbance spatial growth rate

Food-Derived Bioactive Molecules from Mediterranean Diet: Nanotechnological Approaches and Waste Valorization as Strategies to Improve Human Wellness

The beneficial effects of the Mediterranean diet (MedDiet), the most widely followed healthy diet in the world, are principally due to the presence in the foods of secondary metabolites, mainly polyphenols, whose healthy characteristics are widely recognized. However, one of the biggest problems associated with the consumption of polyphenols as nutraceutical adjuvant concerns their bioavailability. During the last decades, different nanotechnological approaches have been developed to enhance polyphenol bioavailability, avoiding the metabolic modifications that lead to low absorption, and improving their retention time inside the organisms. This review focuses on the most recent findings regarding the encapsulation and delivery of the bioactive molecules present in the foods daily consumed in the MedDiet such as olive oil, wine, nuts, spice, and herbs. In addition, the possibility of recovering the polyphenols from food waste was also explored, taking into account the increased market demand of functional foods and the necessity to obtain valuable biomolecules at low cost and in high quantity. This circular economy strategy, therefore, represents an excellent approach to respond to both the growing demand of consumers for the maintenance of human wellness and the economic and ecological exigencies of our society