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A mismatch between &beta, 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&rsquo, 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.

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.

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.

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.

The field of controlled drug delivery continues to be one of the key areas of research in pharmaceutics and medicine. In these studies, hydrogel nanocomposite systems (NC-HYGs) have been extensively investigated because of their unique and tailorable properties. In fact, NC-HYGs mimic the native tissue microenvironment through their porous and hydrated molecular structure. Moreover, new reinforced polymeric hydrogels incorporating nanoparticles within the hydrogel network are being produced with the aim to improve the mechanical properties of the hydrogel and provide superior functionality, such as controlled release. This chapter covers the most recent developments in the field of nanocomposite hydrogels with emphasis on biomedical and pharmaceutical applications. In particular, we will discuss definitions, synthesis, characterization, and applications of hydrogel nanocomposites as drug-delivery systems. Moreover, future directions in designing more advanced nanocomposite hydrogels for biomedical and biotechnological applications will be provided.

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.

Background Mitochondrial dysfunction, characterized by abnormalities of mitochondrial biogenesis, dynamics, trafficking, and alterations in the synthesis of high-energy molecules, seems to play a fundamental role in the pathogenesis of neurodegeneration in Huntington’s disease (HD). Meldonium is a small molecule that inhibits endogenous carnitine synthesis and carnitine cell uptake. The decrease of carnitine availability inside the cell induces a significant reprogramming of cell metabolic pathways that apparently counters the mitochondrial dysfunction, at least in the case of heart or brain ischemia. Aims To evaluate neuroprotective actions of meldonium in both in vitro and in vivo HD models. Methods We used STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein (mHtt), and a transgenic Drosophila model of HD in which the expression of Htt, with a 128Q expansion (Q128HD-FL) in the nervous system, led to progressive motor performance deficits. Results We found that meldonium could prevent cytotoxicity induced by serum deprivation in STHdhQ111/Q111 cells. Meldonium could also reduce the accumulation of mHtt aggregates inside the cell. In addition, meldonium was able to upregulate the expression of PGC-1α, which is a master co-regulator of mitochondrial biogenesis, energy homeostasis, and antioxidant defense, as well as a potential HD target. As expected, the increase of PGC-1α was accompanied by the increment of mitochondrial mass and by the rebalancing of mitochondrial dynamics with a promotion of the mitochondrial fusion. Interestingly, when given per os, meldonium significantly alleviated motor dysfunction and prolonged the survival of transgenic Drosophila model of HD. Conclusions Our study strongly suggests, after considering these factors together, that meldonium (itself or as a lead structure for the synthesis of novel drugs) is a potential treatment for the management of HD.

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.

Microbial infections still remain one of the main issues for human health. The rapid development of resistance towards the most common antimicrobial drugs in bacteria represents today a challenge in the infections management. In the present work we have investigated the antibacterial activity of a group of compounds, namely silver N-heterocyclic carbene complexes, against a broad spectrum of bacteria. For the most promising compound, a biopolymeric nanocarrier has been developed, in order to potentiate the metal complex activity against both Gram +ve and Gram -ve. The polymeric nanovehicle is based on dextran, modified with oleic acid residues, that confer amphiphilic properties to the polysaccharide. We have characterized the obtained biomaterial and studied its ability to self-assemble into nanoparticles in aqueous environment. Next, the transdermal diffusion analyses have been carried out to evaluate the ability of the polymeric particles to penetrate tissues. Thanks to the strategy adopted, we have fabricated an antibacterial system to which K. pneumoniae and E. coli are the most sensitive.

Natural polyphenols are valuable compounds present in plants, fruits, legumes, chocolate, tea, wine and marine organisms possessing scavenging properties towards radical oxygen species. These abilities make polyphenols interesting either for the treatment of various diseases like inflammation and cancer or for anti-ageing purposes in cosmetic formulations. Unfortunately, such compounds lack in long-term stability, are very sensitive to light, and often present a low water solubility and poor bioavailability. To overcome these limitations and enhance polyphenols therapeutic applications, nanotechnology-based delivery systems have been developed, and among all, nanoencapsulation represented a promising strategy. This review described a recent overview of physicochemical nanoencapsulated polyphenols focusing on the most representative molecules such as resveratrol, quercetin, epigallocatechin-3-gallate, and curcumin.

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. 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, whereas the hydroethanolic extract and mucilages were ineffective. Saponins were also effective against MCF-7 cells with IC50 values of 4.195 ± 0.025 μg/ml. Conclusion. The present results suggest that C. europaea may have considerable potential for the development of effective natural anticancer agents.