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

Polylactic Acid/Poly(vinylpyrrolidone) Co-Electrospun Fibrous Membrane as a Tunable Quercetin Delivery Platform for Diabetic Wounds

Diabetic wound infections (DWI) represent one of the most costly and disruptive complications in diabetic mellitus. The hyperglycemic state induces a persistent inflammation with immunological and biochemical impairments that promotes delayed wound healing processes and wound infection that often results in extended hospitalization and limb amputations. Currently, the available therapeutic options for the management of DWI are excruciating and expensive. Hence, it is essential to develop and improve DWI-specific therapies able to intervene on multiple fronts. Quercetin (QUE) exhibits excellent anti-inflammatory, antioxidant, antimicrobial and wound healing properties, which makes it a promising molecule for the management of diabetic wounds. In the present study, Poly-lactic acid/poly(vinylpyrrolidone) (PP) co-electrospun fibers loaded with QUE were developed. The results demonstrated a bimodal diameter distribution with contact angle starting from 120°/127° and go to 0° in less than 5 s indicating the hydrophilic nature of fabricated samples. The release QUE kinetics, analyzed in simulated wound fluid (SWF), revealed a strong initial burst release, followed by a constant and continuous QUE release. Moreover, QUE-loaded membranes present excellent antibiofilm and anti-inflammatory capacity and significantly reduce the gene expression of M1 markers tumor necrosis factor (TNF)-α, and IL-1β in differentiated macrophages. In conclusion, the results suggested that the prepared mats loaded with QUE could be a hopeful drug-delivery system for the effective treatment of diabetic wound infections

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

2014 - 2015XIV n.s

PLA Nanofibers for Microenvironmental-Responsive Quercetin Release in Local Periodontal Treatment

The management of periodontitis remains a vital clinical challenge due to the interplay between the microorganisms of the dental biofilm and the host inflammatory response leading to a degenerative process in the surrounding tissues. Quercetin (QUE), a natural flavonol found in many foods, including apples, onions and tea, has exhibited prolonged and strong antibiofilm and anti-inflammatory effects both in vitro and in vivo. However, its clinical application is limited by its poor stability and water solubility, as well as its low bioavailability. Thus, in the present study, electrospun polylactic acid (PLA) nanofibers loaded with different amounts (5–10% w/w) of QUE were produced to rapidly respond to the acidic microenvironment typical of periodontal pockets during periodontal disease. This strategy demonstrated that PLA-QUE membranes can act as a drug reservoir releasing high QUE concentrations in the presence of oral bacterial infection (pH < 5.5), and thus limiting Pseudomonas aeruginosa PAO1 and Streptococcus mutans biofilm maturation. In addition, released QUE exerts antioxidant and anti-inflammatory effects on P. gingivalis Lipopolysaccharide (LPS)-stimulated human gingival fibroblast (HGFs). The reported results confirmed that PLA-QUE membranes could inhibit subgingival biofilm maturation while reducing interleukin release, thereby limiting host inflammatory response. Overall, this study provided an effective pH-sensitive drug delivery system as a promising strategy for treating periodontitis

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

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