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.

Antimicrobial and Antibiofilm Activity of Curcumin-Loaded Electrospun Nanofibers for the Prevention of the Biofilm-Associated Infections.

Curcumin extracted from the rhizome of Curcuma Longa has been used in therapeutic preparations for centuries in different parts of the world. However, its bioactivity is limited by chemical instability, water insolubility, low bioavailability, and extensive metabolism. In this study, the coaxial electrospinning technique was used to produce both poly (ε-caprolactone) (PCL)-curcumin and core-shell nanofibers composed of PCL and curcumin in the core and poly (lactic acid) (PLA) in the shell. Morphology and physical properties, as well as the release of curcumin were studied and compared with neat PCL, showing the formation of randomly oriented, defect-free cylindrical fibers with a narrow distribution of the dimensions. The antibacterial and antibiofilm potential, including the capacity to interfere with the quorum-sensing mechanism, was evaluated on Pseudomonas aeruginosa PAO1, and Streptococcus mutans, two opportunistic pathogenic bacteria frequently associated with infections. The reported results demonstrated the ability of the Curcumin-loading membranes to inhibit both PAO1 and S. mutans biofilm growth and activity, thus representing a promising solution for the prevention of biofilm-associated infections. Moreover, the high biocompatibility and the ability to control the oxidative stress of damaged tissue, make the synthesized membranes useful as scaffolds in tissue engineering regeneration, helping to accelerate the healing process.

Cationic Polymer Nanoparticles-Mediated Delivery of miR-124 Impairs Tumorigenicity of Prostate Cancer Cells.

MicroRNAs (miRNAs) play a pivotal role in regulating the expression of genes involved in tumor development, invasion, and metastasis. In particular, microRNA-124 (miR-124) modulates the expression of carnitine palmitoyltransferase 1A (CPT1A) at the post-transcriptional level, impairing the ability of androgen-independent prostate cancer (PC3) cells to completely metabolize lipid substrates. However, the clinical translation of miRNAs requires the development of effective and safe delivery systems able to protect nucleic acids from degradation. Herein, biodegradable polyethyleneimine-functionalized polyhydroxybutyrate nanoparticles (PHB-PEI NPs) were prepared by aminolysis and used as cationic non-viral vectors to complex and deliver miR-124 in PC3 cells. Notably, the PHB-PEI NPs/miRNA complex effectively protected miR-124 from RNAse degradation, resulting in a 30% increase in delivery efficiency in PC3 cells compared to a commercial transfection agent (Lipofectamine RNAiMAX). Furthermore, the NPs-delivered miR-124 successfully impaired hallmarks of tumorigenicity, such as cell proliferation, motility, and colony formation, through CPT1A modulation. These results demonstrate that the use of PHB-PEI NPs represents a suitable and convenient strategy to develop novel nanomaterials with excellent biocompatibility and high transfection efficiency for cancer therapy.

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

A mismatch between ß-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.

Metabolic syndrome, Mediterranean diet, and polyphenols: Evidence and perspectives.

Metabolic syndrome (MetS) is defined as the co-occurrence of metabolic risk factors that includes insulin resistance, hyperinsulinemia, impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, and visceral obesity. The clinical significance of MetS consists of identifying a subgroup of patients sharing a common physiopathological state predisposing to chronic diseases. Clinical and scientific studies pinpoint lifestyle modification as an effective strategy aiming to reduce several features accountable for the risk of MetS onset. Among the healthy dietary patterns, the Mediterranean diet (MedDiet) emerges in terms of beneficial properties associated with longevity. Current evidence highlights the protective effect exerted by MedDiet on the different components of MetS. Interestingly, the effect exerted by polyphenols contained within the representative MedDiet components (i.e., olive oil, red wine, and nuts) seems to be accountable for the beneficial properties associated to this dietary pattern. In this review, we aim to summarize the principal evidence regarding the effectiveness of MedDiet-polyphenols in preventing or delaying the physiopathological components accountable for MetS onset. These findings may provide useful insights concerning the health properties of MedDiet-polyphenols as well as the novel targets destined to a tailored approach to MetS.

Meldonium improves Huntington's disease mitochondrial dysfunction by restoring peroxisome proliferator-activated receptor γ coactivator 1α expression.

Mitochondrial dysfunction seems to play a fundamental role in the pathogenesis of neurodegeneration in Huntington's disease (HD). We assessed possible neuroprotective actions of meldonium, a small molecule affecting mitochondrial fuel metabolism, in in vitro and in vivo HD models. We found that meldonium was able to prevent cytotoxicity induced by serum deprivation, to reduce the accumulation of mutated huntingtin (mHtt) aggregates, and to upregulate the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in mHTT-expressing cells. The PGC-1α increase was accompanied by the increment of mitochondrial mass and by the rebalancing of mitochondrial dynamics with a promotion of the mitochondrial fusion. Meldonium-induced PGC-1α significantly alleviated motor dysfunction and prolonged the survival of a transgenic HD Drosophila model in which mHtt expression in the nervous system led to progressive motor performance deficits. Our study strongly suggests that PGC-1α, as a master coregulator of mitochondrial biogenesis, energy homeostasis, and antioxidant defense, is a potential therapeutic target in HD.

In-Situ Thermoresponsive Hydrogel Containing Resveratrol-Loaded Nanoparticles as a Localized Drug Delivery Platform for Dry Eye Disease.

Dry eye disease (DED) is a dynamic and complex disease that can cause significant damage to the ocular surface and discomfort, compromising the patient's quality of life. Phytochemicals such as resveratrol have received increasing attention due to their ability to interfere with multiple pathways related to these diseases. However, the low bioavailability and the poor therapeutic response of resveratrol hinder its clinical applications. Cationic polymeric nanoparticles, in combination with in situ gelling polymers, could represent a promising strategy to prolong drug corneal residence time reducing the frequency of administration and increasing the therapeutic response. Eyedrop formulations, based on acetylated polyethyleneimine-modified polylactic-co-glicolyc acid- (PLGA-PEI) nanoparticles loaded with resveratrol (RSV-NPs) were dispersed into poloxamer 407 hydrogel and characterized in terms of pH, gelation time, rheological properties, in vitro drugs release, and biocompatibility. Moreover, the antioxidant and anti-inflammatory effects of RSV were assessed in vitro by mimicking a DED condition through the exposition of epithelial corneal cells to a hyperosmotic state. This formulation exhibited sustained release of RSV for up to 3 days, exerting potent antioxidant and anti-inflammatory effects on corneal epithelial cells. In addition, RSV reversed the mitochondrial dysfunction mediated by high osmotic pressure, leading to upregulated sirtuin-1 (SIRT1) expression, an essential regulator of mitochondrial function. These results suggest the potential of eyedrop formulation as a platform to overcome the rapid clearance of current solutions for treating various inflammation- and oxidative stress-related diseases such as DED.

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-1ß 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.

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.

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.

Thermo-Responsive Gel Containing Hydroxytyrosol-Chitosan Nanoparticles (Hyt@tgel) Counteracts the Increase of Osteoarthritis Biomarkers in Human Chondrocytes.

Although osteoarthritis (OA) is a chronic inflammatory degenerative disease affecting millions of people worldwide, the current therapies are limited to palliative care and do not eliminate the necessity of surgical intervention in the most severe cases. Several dietary and nutraceutical factors, such as hydroxytyrosol (Hyt), have demonstrated beneficial effects in the prevention or treatment of OA both in vitro and in animal models. However, the therapeutic application of Hyt is limited due to its poor bioavailability following oral administration. In the present study, a localized drug delivery platform containing a combination of Hyt-loading chitosan nanoparticles (Hyt-NPs) and in situ forming hydrogel have been developed to obtain the benefits of both hydrogels and nanoparticles. This thermosensitive formulation, based on Pluronic F-127 (F-127), hyaluronic acid (HA) and Hyt-NPs (called Hyt@tgel) presents the unique ability to be injected in a minimally invasive way into a target region as a freely flowing solution at room temperature forming a gel at body temperature. The Hyt@tgel system showed reduced oxidative and inflammatory effects in the chondrocyte cellular model as well as a reduction in senescent cells after induction with H2O2. In addition, Hyt@tgel influenced chondrocytes gene expression under pathological state maintaining their metabolic activity and limiting the expression of critical OA-related genes in human chondrocytes treated with stressors promoting OA-like features. Hence, it can be concluded that the formulated hydrogel injection could be proposed for the efficient and sustained Hyt delivery for OA treatment. The next step would be the extraction of "added-value" bioactive polyphenols from by-products of the olive industry, in order to develop a green delivery system able not only to enhance the human wellbeing but also to promote a sustainable environment.

Assessment of in vivo estrogenic and anti-inflammatory activities of the hydro-ethanolic extract and polyphenolic fraction of parsley (Petroselinum sativum Hoffm.).

ETHNOPHARMACOLOGICAL RELEVANCE: Since the dawn of time, medicinal and aromatic plants (AMPs) represent a precious heritage for humanity, especially in developing countries, who exploit their virtues in traditional pharmacopoeia to cope with health problems such as diabetes, kidney stones, ulcer, and digestive disorders. Petroselinum sativum Hoffm. belongs to Apiaceae family. It is traditionally used to treat arterial hypertension, diabetes, cardiac disease, renal disease, and recently reported as a plant endowed with a female anti-infertility effect. AIM OF THE STUDY: This study aims to evaluate the in vivo effect of hydro-ethanolic extract and polyphenols of Petroselinum sativum Hoffm. on cholesterol, protein and estrogen levels, and characterize the chemical composition of polyphenolic fraction. In addition, acute toxicity and anti-inflammatory activity of tested extract was also investigated. MATERIALS AND METHODS: Chemical composition of polyphenolic fraction was determined using High-Performance Liquid Chromatography with Diode-Array Detection (HPLC-DAD). First, toxicological investigations including sub-acute toxicity were performed by measuring animals' weights daily for four weeks. Afterwards, histopathological examination of livers and kidneys, and serum assay of ASAT and ALAT were also checked. Next, the acute in vivo anti-inflammatory study of the hydro-ethanolic extract and polyphenols of Petroselinum sativum Hoffm. versus Indomethacin was conducted. Furthermore, we evaluated the estrogenic effect of its hydro-ethanolic extract and the polyphenolic fraction following biochemical assays for the determination of proteins, cholesterol and estrogen levels. RESULTS: The results revealed the presence of some phenolic compounds mainly ferulic acid, gallic acid and quercetin. Petroselinum sativum Hoffm. extracts also showed no evidence of hepatotoxicity nor nephrotoxicity, with remarkable anti-inflammatory activity, as well as a significant estrogenic effect compared to negative control. CONCLUSION: This study provides a scope of the potential use of Petroselinum sativum Hoffm. extracts in counteracting female infertility issues.

pH-Responsive Resveratrol-Loaded Electrospun Membranes for the Prevention of Implant-Associated Infections.

To date, the implant-associated infections represent a worldwide challenge for the recently reported bacterial drug resistance that can lead to the inefficacy or low efficacy of conventional antibiotic therapies. Plant polyphenolic compounds, including resveratrol (RSV), are increasingly gaining consensus as valid and effective alternatives to antibiotics limiting antibiotic resistance. In this study, electrospun polylactic acid (PLA) membranes loaded with different concentrations of RSV are synthesized and characterized in their chemical, morphological, and release features. The obtained data show that the RSV release rate from the PLA-membranes is remarkably higher in acidic conditions than at neutral pH. In addition, a change in pH from neutral to slightly acidic triggers a significant increase in the RSV release. This behavior indicates that the PLA-RSV membranes can act as drug reservoir when the environmental pH is neutral, starting to release the bioactive molecules when the pH decreases, as in presence of oral bacterial infection. Indeed, our results demonstrate that PLA-RSV2 displays a significant antibacterial and antibiofilm activity against two bacterial strains, Pseudomonas aeruginosa PAO1, and Streptococcus mutans, responsible for both acute and chronic infections in humans, thus representing a promising solution for the prevention of the implant-associated infections.

Phytochemical Study on Antioxidant and Antiproliferative Activities of Moroccan Caralluma europaea Extract and Its Bioactive Compound Classes.

BACKGROUND: Caralluma europaea (C. europaea) is a medicinal plant used in Moroccan popular medicine. Objective of the Study. The present work was aimed at identifying the chemical composition and the antioxidant and antiproliferative activities of hydroethanolic and bioactive compound classes of C. europaea) is a medicinal plant used in Moroccan popular medicine. Materials and Methods. The chemical composition was analyzed using HPLC. The antioxidant power was determined using both DPPH and FRAP assays. The antiproliferative activity was effectuated against cancerous cells using WST-1. RESULTS: The chemical analysis showed the presence of bioactive constituents such as quercetin, myricetin, and hesperetin. The polyphenol and flavonoid contents were estimated at 51.42 mg GA/g and 20.06 mg EQ/g, respectively. The EC50 values of FRAP assay of hydroethanolic, flavonoid, saponin, and mucilage extracts were 5.196 mg/ml, 4.537 mg/ml, 3.05 mg/ml, and 6.02 mg/ml, respectively. The obtained IC50 values with the DPPH test were 1.628 mg/ml, 1.05 mg/ml, 1.94 mg/ml, and 9.674 mg/ml, respectively. Regarding MDA-MB-231, saponins were highly effective even with the lowest concentration (15.62 µg/ml). The flavonoids decreased the cell viability with IC50 values of 43.62 ± 0.06 µg/ml). The flavonoids decreased the cell viability with IC50 values of 43.62 ± 0.06 µg/ml). The flavonoids decreased the cell viability with IC50 values of 43.62 ± 0.06 . CONCLUSION: The present results suggest that C. europaea) is a medicinal plant used in Moroccan popular medicine.