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Water pollution from dyes is harmful to the environment, plants, animals, and humans and is one of the most widespread problems afflicting people throughout the world. Adsorption is a widely used method to remove contaminants derived from the textile industry, food colorants, printing, and cosmetic manufacturing from water. Here, aiming to develop new low-cost and up-scalable adsorbent materials for anionic dye remediation and water decontamination by electrostatic interactions, two cationic resins (R1 and R2) were prepared. In particular, they were obtained by copolymerizing 4-ammonium methyl and ethyl styrene monomers (M1 and M2) with dimethylacrylamide (DMAA), using N-(2-acryloylamino-ethyl)-acrylamide (AAEA) as cross-linker. Once characterized by several analytical techniques, upon their dispersion in an excess of water, R1 and R2 provided the R1- and R2-based hydrogels (namely R1HG and R2HG) with equilibrium degrees of swelling (EDS) of 900% and 1000% and equilibrium water contents (EWC) of 90 and 91%, respectively. By applying Cross’ rheology equation to the data of R1HG and R2HG’s viscosity vs. shear rate, it was established that both hydrogels are shear thinning fluids with pseudoplastic/Bingham plastic behavior depending on share rate. The equivalents of -NH3+ groups, essential for the electrostatic-based absorbent activity, were estimated by the method of Gaur and Gupta on R1 and R2 and by potentiometric titrations on R1HG and R2HG. In absorption experiments in bulk, R1HG and R2HG showed high removal efficiency (97–100%) towards methyl orange (MO) azo dye, fluorescein (F), and their mixture (MOF). Using F or MO solutions (pH = 7.5, room temperature), the maximum absorption was 47.8 mg/g in 90′ (F) and 47.7 mg/g in 120′ (MO) for R1, while that of R2 was 49.0 mg/g in 20′ (F) and 48.5 mg/g in 30′ (MO). Additionally, R1HG and R2HG-based columns, mimicking decontamination systems by filtration, were capable of removing MO, F, and MOF from water with a 100% removal efficiency, in different conditions of use. R1HG and R2HG represent low-cost and up-scalable column packing materials that are promising for application in industrial wastewater treatment.

Ursolic acid (UA), a pentacyclic triterpenoid acid found in many medicinal plants and aromas, is known for its antibacterial effects against multi-drug-resistant (MDR) Gram-positive bacteria, which seriously threaten human health. Unfortunately, UA water-insolubility, low bioavailability, and systemic toxicity limit the possibilities of its application in vivo. Consequently, the beneficial activities of UA observed in vitro lose their potential clinical relevance unless water-soluble, not cytotoxic UA formulations are developed. With a nano-technologic approach, we have recently prepared water-soluble UA-loaded dendrimer nanoparticles (UA-G4K NPs) non-cytotoxic on HeLa cells, with promising physicochemical properties for their clinical applications. In this work, with the aim of developing a new antibacterial agent based on UA, UA-G4K has been tested on different strains of the Enterococcus genus, including marine isolates, toward which UA-G4K has shown minimum inhibitory concentrations (MICs) very low (0.5–4.3 µM), regardless of their resistance to antibiotics. Time-kill experiments, in addition to confirming the previously reported bactericidal activity of UA against E. faecium, also established it for UA-G4K. Furthermore, cytotoxicity experiments on human keratinocytes revealed that nanomanipulation of UA significantly reduced the cytotoxicity of UA, providing UA-G4K NPs with very high LD50 (96.4 µM) and selectivity indices, which were in the range 22.4–192.8, depending on the enterococcal strain tested. Due to its physicochemical and biological properties, UA-G4K could be seriously evaluated as a novel oral-administrable therapeutic option for tackling difficult-to-treat enterococcal infections.

To exploit the full potential of pomegranate marcs, this study explores different conditions of ‘green’ extraction of ellagitannins and other bio-active phenolic compounds from the ‘external by-product’ of pomegranate industrial processing. Significant recoveries of ellagitannins, free ellagic acid and radical scavenging compounds were obtained by coupling both the traditional (MH) or the hydro-diffusion gravity (MHG) microwave assisted drying to a direct ultrasound assisted extraction (UAE) using a food-grade solvent (EtOH/H2O). The amounts of the ellagitannins after microwave drying were always significantly higher than with the traditional oven drying. Moreover, microwaves reduced the drying times from several hours to few minutes reaching comparable residual moisture content. The microwave hydro-diffusion gravity system allowed the recovery of bio-active compounds in the condensed water too. The comparison of UAE with traditional maceration and decoction highlighted the higher efficiency of UAE in the quicker extraction of bio-active compounds, except for the total ellagitannins which were better recovered after the longer maceration.

Nowadays, new water disinfection materials attract a lot of attention for their cost-saving and ease of application. Nevertheless, the poor durability of the matrices and the loss of physically incorporated or chemically attached antibacterial agents that can occur during water purification processes considerably limit their prolonged use. In this study, a polystyrene-based cationic resin (R4) with intrinsic broad-spectrum antibacterial effects was produced without needing to be enriched with additional antibacterial agents that could detach during use. Particularly, R4 was achieved by copolymerizing 4-ammonium-butyl-styrene (4-ABSTY) with N,N-dimethylacrylamide (DMAA) and using N-(2-acryloylamino-ethyl)-acrylamide (AAEA) as a cross-linker. The R4 obtained showed a spherical morphology, micro-dimensioned particles, high hydrophilicity, high-level porosity, and excellent swelling capabilities. Additionally, the swollen R4 to its maximum swelling capability, when dried with gentle heating for 3 h, released water following the Higuchi’s kinetics, thus returning to the original structure. In time–kill experiments on the clinical isolates of multidrug-resistant (MDR) pathogens of fecal origin, such as enterococci, Group B Salmonella species, and Escherichia coli, R4 showed rapid bactericidal effects on enterococci and Salmonella, and reduced E. coli viable cells by 99.8% after 4 h. When aqueous samples artificially infected by a mixture of the same bacteria of fecal origin were exposed for different times to R4 in a column, simulating a water purification system, 4 h of contact was sufficient for R4 to show the best bacterial killing efficiency of 99%. Overall, thanks to its physicochemical properties, killing efficiency, low costs of production, and scalability, R4 could become a cost-effective material for building systems to effectively reduce bacterial, even polymicrobial, water contamination.

Ursolic acid (UA) is a pentacyclic triterpenoid found in many medicinal plants and aromas endowed with numerous in vitro pharmacological activities, including antibacterial effects. Unfortunately, UA is poorly administered in vivo, due to its water insolubility, low bioavailability, and residual systemic toxicity, thus making urgent the development of water-soluble UA formulations. Dendrimers are nonpareil macromolecules possessing highly controlled size, shape, and architecture. In dendrimers with cationic surface, the contemporary presence of inner cavities and of hydrophilic peripheral functions, allows to encapsulate hydrophobic non-water-soluble drugs as UA, to enhance their water-solubility and stability, and to promote their protracted release, thus decreasing their systemic toxicity. In this paper, aiming at developing a new UA-based antibacterial agent administrable in vivo, we reported the physical entrapment of UA in a biodegradable not cytotoxic cationic dendrimer (G4K). UA-loaded dendrimer nanoparticles (UA-G4K) were obtained, which showed a drug loading (DL%) much higher than those previously reported, a protracted release profile governed by diffusion mechanisms, and no cytotoxicity. Also, UA-G4K was characterized by principal components analysis (PCA)-processed FTIR spectroscopy, by NMR and elemental analyses, and by dynamic light scattering experiments (DLS). The water solubility of UA-G4K was found to be 1868-fold times higher than that of pristine UA, thus making its clinical application feasible.

Numerous foods, plants, and their bioactive constituents (BACs), named nutraceuticals and phytochemicals by experts, have shown many beneficial effects including antifungal, antiviral, anti-inflammatory, antibacterial, antiulcer, anti-cholesterol, hypoglycemic, immunomodulatory, and antioxidant activities. Producers, consumers, and the market of food- and plant-related compounds are increasingly attracted by health-promoting foods and plants, thus requiring a wider and more fruitful exploitation of the healthy properties of their BACs. The demand for new BACs and for the development of novel functional foods and BACs-based food additives is pressing from various sectors. Unfortunately, low stability, poor water solubility, opsonization, and fast metabolism in vivo hinder the effective exploitation of the potential of BACs. To overcome these issues, researchers have engineered nanomaterials, obtaining food-grade delivery systems, and edible food- and plant-related nanoparticles (NPs) acting as color, flavor, and preservative additives and natural therapeutics. Here, we have reviewed the nanotechnological transformations of several BACs implemented to increase their bioavailability, to mask any unpleasant taste and flavors, to be included as active ingredients in food or food packaging, to improve food appearance, quality, and resistance to deterioration due to storage. The pending issue regarding the possible toxic effect of NPs, whose knowledge is still limited, has also been discussed.

The genus Acinetobacter consists of Gram-negative obligate aerobic pathogens, including clinically relevant species, such as A. baumannii, which frequently cause hospital infections, affecting debilitated patients. The growing resistance to antimicrobial therapies shown by A. baumannii is reaching unacceptable levels in clinical practice, and there is growing concern that the serious conditions it causes may soon become incurable. New therapeutic possibilities are, therefore, urgently needed to circumvent this important problem. Synthetic cationic macromolecules, such as cationic antimicrobial peptides (AMPs), which act as membrane disrupters, could find application in these conditions. A lysine-modified cationic polyester-based dendrimer (G5-PDK), capable of electrostatically interacting with bacterial surfaces as AMPs do, has been synthesized and characterized here. Given its chemical structure, similar to that of a fifth-generation lysine containing dendrimer (G5K) with a different core, and previously found inactive against Gram-positive bacterial species and Enterobacteriaceae, the new G5-PDK was also ineffective on the species mentioned above. In contrast, it showed minimum inhibitory concentration values (MICs) lower than reported for several AMPs and other synthetic cationic compounds on Acinetobacter genus (3.2–12.7 µM). Time-kill experiments on A. baumannii, A. pittii, and A. ursingii ascertained the rapid bactericidal effects of G5-PDK, while subsequent bacterial regrowth supported its self-biodegradability.

Low-molecular-weight organic ammonium salts exert excellent antimicrobial effects by interacting lethally with bacterial membranes. Unfortunately, short-term functionality and high toxicity limit their clinical application. On the contrary, the equivalent macromolecular ammonium salts, derived from the polymerization of monomeric ammonium salts, have demonstrated improved antibacterial potency, a lower tendency to develop resistance, higher stability, long-term activity, and reduced toxicity. A water-soluble non-quaternary copolymeric ammonium salt (P7) was herein synthetized by copolymerizing 2-methoxy-6-(4-vinylbenzyloxy)-benzylammonium hydrochloride monomer with N, N-di-methyl-acrylamide. The antibacterial activity of P7 was assessed against several multidrug-resistant (MDR) clinical isolates of both Gram-positive and Gram-negative species. Except for colistin-resistant Pseudomonas aeruginosa, most isolates were susceptible to P7, also including some Gram-negative bacteria with a modified charge in the external membrane. P7 showed remarkable antibacterial activity against isolates of Enterococcus, Staphylococcus, Acinetobacter, and Pseudomonas, and on different strains of Escherichia coli and Stenotrophomonas maltophylia, regardless of their antibiotic resistance. The lowest minimal inhibitory concentrations (MICs) observed were 0.6–1.2 µM and the minimal bactericidal concentrations (MBC) were frequently overlapping with the MICs. In 24-h time–kill and turbidimetric studies, P7 displayed a rapid non-lytic bactericidal activity. P7 could therefore represent a novel and potent tool capable of counteracting infections sustained by several bacteria that are resistant to the presently available antibiotics.

The growing resistance of bacteria to current chemotherapy is a global concern that urgently requires new and effective antimicrobial agents, aimed at curing untreatable infection, reducing unacceptable healthcare costs and human mortality. Cationic polymers, that mimic antimicrobial cationic peptides, represent promising broad-spectrum agents, being less susceptible to develop resistance than low molecular weight antibiotics. We, thus, designed, and herein report, the synthesis and physicochemical characterization of a water-soluble cationic copolymer (P5), obtained by copolymerizing the laboratory-made monomer 4-ammoniumbuthylstyrene hydrochloride with di-methyl-acrylamide as uncharged diluent. The antibacterial activity of P5 was assessed against several multi-drug-resistant clinical isolates of both Gram-positive and Gram-negative species. Except for strains characterized by modifications of the membrane charge, most of the tested isolates were sensible to the new molecule. P5 showed remarkable antibacterial activity against several isolates of genera Enterococcus, Staphylococcus, Pseudomonas, Klebsiella, and against Escherichia coli, Acinetobacter baumannii and Stenotrophomonas maltophilia, displaying a minimum MIC value of 3.15 µM. In time-killing and turbidimetric studies, P5 displayed a rapid non-lytic bactericidal activity. Due to its water-solubility and wide bactericidal spectrum, P5 could represent a promising novel agent capable of overcoming severe infections sustained by bacteria resistant the presently available antibiotics.

Drug resistance is a multifactorial phenomenon that limits the action of antibiotics and chemotherapeutics. Therefore, it is essential to develop new therapeutic strategies capable of inducing cytotoxic effects circumventing chemoresistance. In this regard, the employment of natural and synthetic cationic peptides and polymers has given satisfactory results both in microbiology, as antibacterial agents, but also in the oncological field, resulting in effective treatment against several tumors, including neuroblastoma (NB). To this end, two polystyrene-based copolymers (P5, P7), containing primary ammonium groups, were herein synthetized and tested on etoposide-sensitive (HTLA-230) and etoposide-resistant (HTLA-ER) NB cells. Both copolymers were water-soluble and showed a positive surface charge due to nitrogen atoms, which resulted in protonation in the whole physiological pH range. Furthermore, P5 and P7 exhibited stability in solution, excellent buffer capacity, and nanosized particles, and they were able to reduce NB cell viability in a concentration-dependent way. Interestingly, a significant increase in reactive oxygen species (ROS) production was observed in both NB cell populations treated with P5 or P7, establishing for both copolymers an unequivocal correlation between cytotoxicity and ROS generation. Therefore, P5 and P7 could be promising template macromolecules for the development of new chemotherapeutic agents able to fight NB chemoresistance.

Usually, the administration of drugs by feeding tube in dysphagic patients involves handling of marketing licenses outside their term, due to the lack of suitable formulations. This circumstance has put health professionals in the dilemma of choosing the formulation whose manipulation possibly does not alter the effectiveness of the drug. In this regard, a practical guide providing indications on the prescription, handling, and administration of drugs through enteral feeding tube could be of paramount utility. For this purpose, we have considered the 1047 solid oral pharmaceutical forms included in the formulary of San Paolo Hospital (Savona, Italy). From our analysis, it emerges that 95% of medicinal products are worryingly used off-label and 40% have to be managed by the hospital pharmacists without having suitable indications by either the manufacturers or by literature studies. To fill this gap, we have compiled a detailed table containing missing indications derived from pharmacist expertise and evidence-based practices, with the aim that the sharing of our procedures will contribute to make uniform pharmacological therapies from one hospital to another. This study will allow doctors to have easy access to information on drugs that can be prescribed and nurses to become familiar only with the pharmaceutical forms that can be administered.

To counteract the growing bacterial resistance, we previously reported the remarkable antimicrobial activity of amino acid-conjugated cationic dendrimers (CDs) against several Gram-negative species, establishing that the cationic lysine was essential for their potency. In this paper, CDs conjugated with lysine and arginine and encapsulating ursolic and oleanolic acids (UOACDs) were assumed to be excellent candidates for developing new antibacterial agents, possibly active against Gram-positive species. Indeed, both the guanidine group of arginine and the two triterpenoid acids are items known for directing antibacterial effects, particularly against Gram-positive bacteria. The cationic dendrimers were obtained by peripheral conjugation with the selected amino acids and by entrapping a physical mixture of the commercial triterpenoid acids. The cationic compounds were characterized and successfully tested against 15 Gram-positive isolates. Interesting minimum inhibitory concentration (MIC) values were obtained for all the dendrimer-drug agents, establishing that the antibacterial activity observed for the UOACDs strongly depended on the density and on the type of the cationic groups of the cationic amino acid-conjugated dendrimers and not on the presence and the release of UOA. Particularly, lysine was critical for potency, while arginine was critical for redirecting activity against Gram-positive species. Especially, a high cationic character, associated with a balanced content of lysine/arginine, produced a remarkable antimicrobial effect (MIC = 0.5–8.7 µM).

Human neuroblastoma (NB) is a pediatric tumor, which, after an initial response to therapy, usually develops resistance [...]

Due to the rapid increase of antimicrobial resistance with ensuring therapeutic failures, the purpose of this study was to identify novel synthetic molecules as alternatives to conventional available, but presently ineffective antibiotics. Variously structured cationic dendrimers previously reported have provided promising outcomes. However, the problem of their cytotoxicity towards eukaryotic cells has not been completely overcome. We have now investigated the antibacterial activities of three not cytotoxic cationic dendrimers (G5Ds: G5H, G5K, and G5HK) against several multidrug-resistant (MDR) clinical strains. All G5Ds displayed remarkable activity against MDR non-fermenting Gram-negative species such as P. aeruginosa, S. maltophilia, and A. baumannii (MICs = 0.5&ndash, 33.2 &micro, M). In particular, very low MIC values (0.5&ndash, 2.1 &micro, M) were observed for G5K, which proved to be more active than the potent colistin (2.1 versus 3.19 &micro, M) against P. aeruginosa. Concerning its mechanism of action, in time-killing and turbidimetric studies, G5K displayed a rapid non-lytic bactericidal activity. Considering the absence of cytotoxicity of these new compounds and their potency, comparable or even higher than that provided by the dendrimers previously reported, G5Ds may be proposed as promising novel antibacterial agents capable of overcoming the alarming resistance rates of several nosocomial non-fermenting Gram-negative pathogens.

Antibiotic resistance has increased markedly in Gram-negative bacteria, causing severe infections intractable with traditional drugs and amplifying mortality and healthcare costs. Consequently, to find novel antimicrobial compounds, active on multidrug resistant bacteria, is mandatory. In this regard, cationic antimicrobial peptides (CAMPs)—able to kill pathogens on contact—could represent an appealing solution. However, low selectivity, hemolytic toxicity and cost of manufacturing, hamper their massive clinical application. In the recent years—starting from CAMPs as template molecules—less toxic and lower-cost synthetic mimics of CAMPs, including cationic peptides, polymers and dendrimers, have been developed. Although the pending issue of hemolytic toxicity and biodegradability is still left not completely solved, cationic antimicrobial polymers (CAPs), compared to small drug molecules, thanks to their high molecular weight, own appreciable selectivity, reduced toxicity toward eukaryotic cells, more long-term activity, stability and non-volatility. With this background, an updated overview concerning the main manufactured types of CAPs, active on Gram-negative bacteria, is herein reported, including synthetic procedure and action’s mechanism. Information about their structures, antibacterial activity, advantages and drawbacks, was reported in the form of tables, which allow faster consultation and quicker learning concerning current CAPs state of the art, in order not to retrace reviews already available.

Drugs delivered by proper carriers enter into the cells much more rapidly and carry out their action much more promptly than in the free forms. A high drug concentration can be sustained for longer periods of time at the target site in the cell. In in vivo conditions, this would translate into a reduction of systemic toxicity, dosage and frequency of dosing. Dendritic polymers significantly affect drug delivery in terms of reaching the target site, modifying the bio-distribution of the drug, and enhancing the efficacy of different drugs including anticancer compounds. 2-({[2-({[(2-tolyl)amino]carbonothioyl}oxy)ethyl]amino}carbo-nyl)benzoic acid 1 is a thiocarbamate derivative belonging to an already reported class of non-nucleoside HIV-1 reverse transcriptase inhibitors. In in vitro assay it showed no cytotoxic effects but was endowed with very low solubility and poor activity against wild-type HIV-1 (EC50 = 27 μM). With the aim at improving its water solubility, 1 has been successfully incorporated inside non-toxic amino acids-modified core-shell hetero dendrimers. IR, NMR, zeta potential, mean size of particles, buffer capacity and in vitro release profile of prepared materials were reported. All dendriplexes were evaluated in cell-based assays to assess their cytotoxic profile. The obtained complexes, which harmonize a peripheral polycationic character and a buffer capacity which presuppose efficient cells penetration and increased residence time with a not PAMAM structured biodegradable scaffold, were well water-soluble and could rationally appear as a promising set of prodrugs for safe in vivo administrations.

Dendrimers are macromolecules characterized by high controlled size, shape and architecture, presence of inner cavities able to accommodate small molecules and many peripheral functional groups to bind target entities. They are of eminent interest for biomedical applications, including gene transfection, tissue engineering, imaging, and drug delivery. The well-known pharmacological activities of ursolic and oleanolic acids are limited by their small water solubility, non-specific cell distribution, low bioavailability, poor pharmacokinetics, and their direct administration could result in the release of thrombi. To overcome such problems, in this paper we described their physical incorporation inside amino acids-modified polyester-based dendrimers which made them highly water-soluble. IR, NMR, zeta potential, mean size of particles, buffer capacity and drug release profiles of prepared materials were reported. The achieved water-soluble complexes harmonize a polycationic character and a buffer capacity which presuppose efficient cell penetration and increased residence time with a biodegradable cell respectful scaffold, thus appearing as a promising team of not toxic prodrugs for safe administration of ursolic and oleanolic acids.

Macromolecular systems with well-defined sizes, shapes and high controlled architecture like dendrimers are of eminent interest in nanomedical applications such as drug delivery, gene transfection, and imaging. In this paper versatile protocols for the synthesis of polyester-based, hydrolysable, polycationic dendrimers have been setup. Fourth and fifth generation dendrimers equipped with several peripheral hydroxyl groups were prepared from 2, 2-bis(hydroxymethyl)propanoic acid. They were successfully esterified with arginine alone or mixed with lysine or O-methyltyrosine and with dipeptide arginine-glycine and seven polycationic dendrimers were finally obtained as hydrochlorides. Their structures and composition were confirmed by NMR analysis and by experimental molecular weight computed by volumetric titration and their buffer capacity was higher than fourth generation polyamidoamine (G4- PAMAM) derivatives taken as reference. The synthesized dendrimers harmonize a polycationic character and a buffer capacity which presuppose a good transfection efficiency with a degradable scaffold thus appearing as a promising team of new non-toxic vectors for biomedical applications.

Dendrimers, the emerging man made, highly branched, star-shaped macromolecules with nanometer-scale dimensions are well known for their well defined and high controlled architecture, their versatility and high functionality and are of eminent interest in nanomedical applications such as drug delivery, gene transfection, and imaging. In this paper, versatile protocols for the synthesis of polyester-based, hydrolysable, polycationic dendrimers have been setup. A fourth generation dendrimer equipped with 48 peripheral hydroxyl groups was prepared from 2,2-bis(hydroxymethyl)propanoic acid and was used for grafting BOC-amino acids or as “hypercores” on which dendrons functionalized with BOC-amino acids were attached. A library of 15 polycationic homo- and hetero-dendrimers in the form of hydrochloride was obtained. Their structures and composition were confirmed by NMR analysis and by experimental molecular weight computed by volumetric titration. Their buffer capacity and results obtained from cytotoxicity assays and tests of binding with both pDNA and siRNA were very satisfactory.

Glutamate is the major excitatory neurotransmitter in the brain. 2-Chloro-4-[2,5-dimethyl-1-(4-trifluoromethoxyphenyl)-1H-imidazol-4-ylethynyl]pyridine (5) (CTEP) is the first reported negative allosteric modulator of the metabotropic glutamate receptor 5 (mGlu5NAM) with a biological half-life of 48 hours in rodents and therefore considered an ideal tool for chronic studies in rats and mice. In this work an optimized protocol for the synthesis and purification of CTEP is reported. Through the developed new work up scrupulously described in detail, CTEP was obtained in 63 % yield, with a significant improvement in comparison with the methods reported in literature (27%) and in a tripled overall yield (27% versus 9%). Furthermore, all the intermediates between which the unreported multifunctional and appealing compound 8 as well as the final compound 5 were isolated, purified and fully characterized by IR, NMR ( 1H NMR and 13C NMR), melting point, except for the oily 7, and Elemental analysis.

Pomegranate fruit is recognized as an important source of health compounds and its juicy arils represent the most commercially exploitable part of the fruit. Nevertheless, by-products coming from pomegranate juice processing represent both a challenging disposal problem and a promising source of health ingredients. In particular, the marcs obtained after juice squeezing are usually discarded or used for oil production in virtue of their lipophilic fraction, although the residues of pericarp and arils are proven to still be a good source of hydrophilic compounds such as polyphenols. Pulsed ultrasound-assisted extraction, using just water as solvent, and spray-drying microdispersion, using low methoxyl pectin as polymeric matrix, have been employed, respectively, to extract and formulate the water-soluble bioactive molecules from these by-products. From 100 g of pomegranate fresh marcs, almost the same quantity of phenolic compounds found in 100 mL of the corresponding juice can be extracted with similar antioxidant activity, but with higher content in vitamin C and practically without total soluble solids. The extracts have been sprayed obtaining powders with an encapsulation efficiency of about 50%. The extracts, both before and after the microparticles production, have been characterized and their capacity in inhibition of platelets aggregation induced by thrombin has been tested ex vivo on human platelets (% inhibition: about 60% and 30% before and after microencapsulation, respectively). Finally, fresh-cut apple wedges were enriched by vacuum impregnation with the formulated extracts, tentatively used as potential novel ingredients, obtaining “polyphenol-enriched” apples.

Foods-derived multifunctional compounds, such as carotenoids, vitamins, phytosterols, polyunsaturated lipids, curcuminoids, flavonoids and polyphenols, in addition to the basic nutritional value, own extra health benefits and are considered “pharmaceutical-grade nutrients” better known as “nutraceuticals”. Similarly, phytochemicals from plants, characterized by analogous chemical structures, can be considered “pharmaceutical-grade molecules”. They could provide both diseases preventive actions and remarkable therapeutic benefits but, the efforts for identifying their mode of action and for applying them into food industry with health-promoting purposes, are often unsuccessful. Solubility is essential for a good absorption in the gastrointestinal tract and to achieve the systemic concentration necessary for an effective therapeutic activity, but the majority of these compounds are water-insoluble. Consequently, when ingested, they encounter many difficulties in crossing the diverse barriers to reach the bloodstream and to distribute to cells and tissues. Their absorption at gastric or intestinal level is troubled and in addition, they suffer from early degradation or fast metabolism, so rarely they manage to reach the site of action in therapeutically effective concentration and their clinical applications result strongly limited. Toxic excipients and harmful solubilizing agents were and are extensively used for solubilizing and delivering non-soluble bioactive chemicals (BACs) despite the resulting unpleasant side effects complained of by patients. During last decades, several new techniques, often resorting to nanotechnology, aiming at enhancing BACs solubility, at solving their pharmacokinetics drawbacks, at avoiding their early inactivation or fast metabolism, have been developed. On this background, the following chapter provides an overview concerning nanotechnology contribute and its technological advancements in “manufacturing” nutraceuticals and phytochemicals in more bioavailable nanoparticles. In addition, it is reviewed the involvement of nanoscience in developing and enhancing food-grade solid nanosized materials to be used as BACs “containers” and “vehicles” either for their safe and effective oral administration, in the frame of medical treatments, or for achieving smart food ingredients to improve the quality and shelf life of nourishments.

Even though immunotherapy has radically changed the search for anticancer therapies, there are still many different pathways that are open to intervention with traditional small molecules. To expand our investigation in the anticancer field, we report here a new series of compounds in which our previous pyrazole and imidazopyrazole scaffolds are linked to a differently decorated phenyl ring through an acylhydrazone linker. Preliminary tests on the library were performed at the National Cancer Institute (USA) against the full NCI 60 cell panel. The best compounds among the imidazopyrazole series were then tested by immunofluorescence staining for their inhibition of cell proliferation, apoptosis induction, and their effect on the cell cycle and on microtubules. Two compounds, in particular 4-benzyloxy-3-methoxybenzyliden imidazopyrazole-7-carbohydrazide showed good growth inhibition, with IC50 values in the low-micromolar range, and induced apoptosis. Both compounds altered the cell-cycle phases with the appearance of polyploid cells. Immunofluorescence analysis evidenced microtubules alterations; tubulin polymerization assays and docking studies suggested the tubulin system to be the possible, although not exclusive, target of the new acylhydrazone series reported here.

Etoposide (ETO) is a cytotoxic drug that exerts its effect by increasing reactive oxygen species (ROS) production. Although ETO is widely used, fast metabolism, poor solubility, systemic toxicity, and multi-drug resistance induction all limit its administration dosage and its therapeutic efficiency. In order to address these issues, a biodegradable dendrimer was prepared for entrapping and protecting ETO and for enhancing its solubility and effectiveness. The achieved dendrimer complex with ETO (CPX 5) showed the typical properties of a well-functioning delivery system, i.e., nanospherical morphology (70 nm), optimal Z-potential (&minus, 45 mV), good drug loading (37%), very satisfying entrapment efficiency (53%), and a remarkably improved solubility in biocompatible solvents. In regards to its cytotoxic activity, CPX 5 was tested on neuroblastoma (NB) cells with very promising results. In fact, the dendrimer scaffold and ETO are able to exert per se a cytotoxic and pro-oxidant activity on human NB cells. When CPX 5 is combined with ETO, it shows a synergistic action, slowly releasing the drug over time and significantly improving and protracting bioactivity. On the basis of these findings, the prepared ETO reservoir represents a novel biodegradable and promising device for the delivery of ETO into NB cells.

Natural polyphenols such as Gallic Acid (GA) form an important class of bioactive chemical entities that, having innumerable biological properties, could represent a safer alternative to common drugs against several disorders, including platelet aggregation, radical oxygen species (ROS) hyperproduction, oxidative stress (OS) and bacterial infections. Unfortunately, their clinical uses are limited by pharmacokinetics drawbacks and high sensitivity to environmental factors. In order to overcome these problems and to exploit the GA curative potentials, it has been linked to a biodegradable nanospherical dendrimer matrix, capable of protecting it, thus obtaining a GA-enriched nanosized dendrimer (GAD) endowed with a strong antioxidant capacity. GAD activity as an inhibitor of platelet aggregation and ROS accumulation and its antibacterial efficiency are evaluated here and compared to those of free GA, obtaining outcomes never achieved. Regarding platelet aggregation induced by thrombin and collagen, the GAD proved to be stronger by 7.1 and 7.3 times, respectively. Furthermore, the GAD showed a ROS inhibitory activity higher than that of GA by 8.1 (thrombin) and 6.9 (collagen) times. Concerning the antibacterial activities, evaluated on eleven multi-resistant Gram-positive strains of clinical relevance, the GAD is far more potent than GA, by exerting a growth inhibitory activity at MIC (μM) concentrations lower by factors in the range 12–50.

Environmental factors, oxidation and microorganisms contamination, are the major causes for food spoilage, which leads to sensory features alteration, loss of quality, production of harmful chemicals and growth of foodborne pathogens capable to cause severe illness. Synthetic preservatives, traditional conserving methods and food packaging (FP), although effective in counteracting food spoilage, do not allow the real-time monitoring of food quality during storage and transportation and assent a relatively short shelf life. In addition, FP may protect food by the spoilage caused by external contaminations, but is ineffective against foodborne microorganisms. FP preservative functionalities could be improved adding edible natural antioxidants and antimicrobials, but such chemicals are easily degradable. Nowadays, thanks to nanotechnology techniques, it is possible to improve the FP performances, formulating and inserting more stable antioxidant/antimicrobial ingredients, improving mechanical properties and introducing intelligent functions. The state-of-the-art in the field of nanomaterial-based improved FP, the advantages that might derive from their extensive introduction on the market and the main concerns associated to the possible migration and toxicity of nanomaterials, frequently neglected in existing reviews, have been herein discussed.

The immune system and the central nervous system message each other to preserving central homeostasis. Both systems undergo changes during aging that determine central age-related defects. Ellagic acid (EA) is a natural product which is beneficial in both peripheral and central diseases, including aging. We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion (EAm), that largely increased the EA solubility, in young and old mice. Oral EAm did not modify animal weight and behavioral skills in young and old mice, but significantly recovered changes in &ldquo, ex-vivo, in vitro&rdquo, parameters in old animals. Cortical noradrenaline exocytosis decreased in aged mice. EAm administration did not modify noradrenaline overflow in young animals, but recovered it in old mice. Furthermore, GFAP staining was increased in the cortex of aged mice, while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones. EAm treatment significantly reduced CD45 signal in both young and old cortical lysates, it diminished GFAP immunopositivity in young mice, but failed to affect IBA-1 expression in both young and old animals. Finally, EAm treatment significantly reduced IL1beta expression in old mice. These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders.

Ellagic acid (EA) is a bioactive natural polyphenol with antioxidant and several other beneficial properties, but unfortunately it cannot be exploited for in vivo therapeutic applications because of its poor water solubility and accordingly low bioavailability. Aiming to increase EA solubility, an EA solid microdispersion was realized by employing only water and low methoxylated pectin as a food compatible excipient by applying spray drying technology. It showed a 22% (w/w) Drug Loading (DL), a 30 times improved water solubility and remarkable radical scavenging activity. Subsequently, adopting non-PAMAM hydrophilic and amphiphilic dendrimers as nanocontainers, two EA nanodispersions were achieved (60–70 nm) with 46 and 53% (w/w) DL, water solubility 300 to 1000 times higher than that of free EA and good antioxidant capability. In both cases, toxic agents such as castor oil, Tween 80 or the extensively used but not so safe PEG400 were avoided and no previously used carriers, including β-cyclodextrins, were adopted. The prepared micro- and nanodispersions showed water solubility never obtained before and represent non-toxic EA reservoirs suitable for food and biomedical applications.

It is well-known that the health properties attributed to several fruits, herbs, seeds and their processed foods/beverages are due to an important group of natural polyphenols classified as hydrolysable tannins (HT) named ellagitannins (ETs), that encompass both one or more gallic acid (GA) units and one or more hexahydroxydiphenoic acid (HHDP) units, ester-connected with a sugar residue. In vivo, ETs are rather not absorbed and in gastrointestinal tract (GIT), they are hydrolysed providing mainly ellagic acid (EA). Due to its trivial water-solubility, first pass effect, metabolism in GIT, or irreversible binding to cellular DNA and proteins, EA has a very low bioavailability. Some authors are studying methods to increase EA water-solubility and thus to improve its bioavailability. At the same, EA metabolism to urolithins (UROs), whose concentration and activity is inter-individual and intra-individual dependent, is still under study and not completely elucidate. Numerous in vitro and in vivo studies have been carried out to define the molecular and cellular events underlying the beneficial effects that this compound and its metabolites exert in pathological conditions. The anti-inflammatory and the antioxidant properties of EA attracted the interest of researchers for its potential health benefits in humans, including anti-cancer, anti-diabetes activities and cardio-protection. Nevertheless, lately the attention paid to EA is focusing on its potential protective action towards several neurodegenerative disorders. Thus, EA is investigated as a potential “lead compound” endowed with multi-target pharmacological properties on CNS. Since the identification of the pharmacophore(s) responsible for both health benefits and collateral effects of this compound is crucial in drug discovery, this review aims to provide an all-round updated analysis of the literature concerning EA involvement in several CNS disorders, hoping that such information will be useful to researchers involved in multi-target drug design for CNS.

Selected members of the large rolipram-related GEBR family of type 4 phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term potentiation and to improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, few if any structure-activity relationship studies have been performed to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone. Furthermore, we assessed the stability of the observed ligand conformations in the context of the intact enzyme using molecular dynamics simulations. The longer and more flexible ligands appear to be capable of forming contacts with the regulatory portion of the enzyme, thus possibly allowing some degree of selectivity between the different PDE4 isoforms.

An unprecedented, highly convergent, high-yielding, one-pot synthesis of (acyl)hydrazones and thiosemicarbazones was carried out by the in situ condensation of isolable iminium chlorides of imidazolidin-2-(thio)one, tetrahydropyrimidin-2-thione and indole derivatives with nitrogen nucleophiles in the presence of a base. The developed reaction procedure is largely advantageous. It is highly parallelizable, no intermediates need to be isolated and minimal sample handling is required during the purification steps. Some relevant reaction parameters including reaction temperature and p $$K_\mathrm{a}$$ of the base are discussed. NMR analysis was carried out to assess the stereochemistry of the obtained compounds. The stereochemical outcome of the reaction was found to be affected by the nature of the nitrogen-containing nucleophile being the majority of the derivatives isolated as single geometric isomers. The cytotoxicity and antiviral activities of the prepared compounds have been preliminary assessed. In cell-based screenings some of the derivatives proved to be cytotoxic at low micromolar concentrations and interesting anti-Reo-1 properties have been detected.

l-arginine is often covalently linked to vectors for gene or drug delivery as a means of increasing their transfection activity and reducing toxicity. This strategy relies on the protection of basic nitrogen atoms, for example, by employing the tert-butoxycarbonyl group. Our aim in the present work was to prepare the widely described α N, ω N, ω′ N-tris(tert-butyloxycarbonyl)-l-arginine as a single isomer in high yield and with high levels of purity for use in the esterification of dendrimers with several peripheral hydroxyl groups. Following three reported protocols which assured this goal, we observed the unexpected formation of four additional isomers. Using the first procedure, α N, ω N, ω′ N-tris(tert-butyloxycarbonyl)-l-arginine was never obtained. The second procedure delivered the desired compound as a mixture of geometric isomers (E/Z), while the third protocol led to a single isomer in high yield and purity, but with an unreported symmetrical structure. Since Boc protection is transient, this discovery would seem to be of little interest, but preliminary results from an ongoing investigation of the behavior of each of the isomers obtained in the esterification reactions of interest has shown that their reactivity depends on their structure. Although this research is ongoing, here we report a detailed description of these unexpected results, along with an NMR investigation focusing on the double-bond geometry and position which enabled confirmation of the structures.

The glycosylation of D-galactose glycopolymers to produce functionalized polymers expected to be bioactive as substrates or inhibitors of enzymes of the copper amine oxidase class (CAOs, EC 1.4.3.6), attained previously with an unpractical, but significant process requesting a large excess of glycosyl acceptor, has now been achieved with a method based on the use of peracetylated D-galactose moieties, in the presence of SnCl4 or BF3·Et2O as promoters, which employs glycosyl donors in nearly stoichiometric ratio with the desired glycosyl acceptor. After the synthesis of an appropriate model molecule acting as a guide, the new method was set up with extensive NMR investigations on the same model molecule and soluble polymeric reagents and products, performing a full rationalization of the chemical behavior of the various α and β pyranose and furanose forms of D-galactose residues. Glycosylated systems containing functionalities protected with trifluoroacetyl and acetyl groups were fully deprotected in one step through a reduction procedure with NaBH4.

The multistep preparation of the new 10-substituted 2-(1-piperazinyl)pyrimido[1,2- a ]benzimidazol-4(10 H )-ones 6a – o , and of the two isomers 10-ethyl-2-(diethylamino)pyrimido[1,2- a ]benzimidazol-4(10 H )-one 6p and 10-ethyl-4-(diethylamino)pyrimido[1,2- a ]benzimidazol-2(10 H )-one 13 , as well as the in vitro evaluation of their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen or the Ca 2+ ionophore A23187 were here described. Nine out of fifteen 2-(1-piperazinyl)derivatives ( 6g – o ) showed good inhibitory properties towards all the platelet aggregation agonists used. Moreover, a molecular modelling study has been performed on two of the best compounds of this series ( 6i and 6o ) to confirm in silico their interactions with the catalytic site of human platelet PDE3, using the X-ray data of the PDE3B isoform in complex with an inhibitor.

A surface extract of the aerial parts of Salvia chamaedryoides afforded 13 diterpenes (1-13), with seven compounds (1, 3, 4, 7-9, 12) described for the first time. The structures of the new compounds were established using 1D and 2D NMR spectroscopic methods, HRESIMS, and ECD data. The potential hypoglycemic effects of the crude extract, fractions, and pure compounds from S. chamaedryoides were investigated by inhibition of α-glucosidase and α-amylase enzymes. The extract and its fractions showed a moderate dose-dependent inhibition; the pure compounds exhibited differential inhibitory activity against these two enzymes. Molecular modeling studies were also performed to suggest the interaction mode of compound 3 in the α-glucosidase enzyme active site. The antimicrobial activity of the purified compounds was investigated against 26 clinical pathogens. No activity was detected for the Gram-negative species tested nor on Candida albicans and C. glabrata, while variable susceptibilities were observed using Gram-positive staphylococcal and enterococcal species.

As a part of a work aimed at the synthesis of properly functionalized nanostructured glycopolymers suitable for interaction studies with copper amine oxidases, D-galactose was transformed through a six step sequence into the monomer N-(4-vinylbenzoyl)-6-amino-6-deoxy-D-galactose (1) which was converted into nanostructured crosslinked polymers (R1) by radical precipitation polymerization and into linear polymers (P1) by solution polymerization. The linear polymers were useful models for setting up glycosylation reactions to introduce N-trifluoroacetyl-4-(4-hydroxybutoxy)benzylamine residues in the presence of camphor sulfonic acid as the catalyst and to extend them to the nanostructured systems. The advancement of the glycosylation reaction was performed through the synthesis and glycosylation of N-benzoyl-6-amino-6-deoxy-D-galactose (9) as the model molecule for accurate NMR investigations. The removal of the trifluoroacetyl protecting group, unexpectedly stable, in glycosylated P1 and R1 was achieved with sodium borohydride.

Saccharidic monomers and a macromonomer were synthesized and copolymerized in the presence of divinylbenzene (DVB) as crosslinker in conditions of separation of phases to give hydrophilic nanostructured sugar-based vinyl copolymers. Appropriate model molecules such as N -benzyl- d -gluconamide for the saccharidic copolymers and 4-(4-chlorobutoxy)benzaldehyde and ( E )-4-(4-chloro-2-butenyloxy)benzaldehyde for electrophilic reagents prefiguring possible copper amine oxidase inhibitors allowed identification of conditions for useful monofunctionalizations mainly at the position 2 of the saccharidic units. The examined samples of the nanostructured copolymers from one of the monomers proved to be stable enough to tolerate the functionalization reactions without loss of morphology.

Through the synthesis and study of model systems as proper dithiane derivatives, vinyl monomers and soluble copolymeric reagents containing 2-unsubstituted 1,3-dithiane rings, we attained the key synthon 1,3-dithiane-5-methanol. Through its reaction with commercial resins, new polymeric reagents useful for supported organic synthesis and combinatorial chemistry were developed. Exploiting the reactivity of position 2 in 1,3-dithiane rings, such polymeric reagents were employed in the production of aldehydes from alkyl halides through a process entirely free from unpleasant odors.

A new series of indole-based analogues were recently identified as potential anticancer agents. The Knoevenagel-type indoles herein presented were prepared via a one-pot condensation of iminium salts with active methylene reagents and were isolated as single geometric isomers. Biological evaluation in different cell-based assays revealed an antiproliferative activity for some analogues already in the nanomolar range against leukaemia, breast and renal cancer cell lines. To explain these effects, the most promising analogues of the series were engaged in further cell-based studies. Compounds 5e, l, p and 6a, b highlighted a pro-apoptotic potential being able to induce apoptosis in HL60, K562 and MCF-7 cell lines in a dose and time-dependent manner. The ability of these compounds to arrest cell cycle at the G2/M phase inspired the immunofluorescence studies which allowed us to identify tubulin as a potential target for compounds 5l and 6b.

A new group of 5-(alkylamino)-9-isopropyl[1,2,4]triazolo[4,3- a ][1,8]naphthyridine derivatives bearing a CONHR group at the 6-position ( 1c – g ), designed to obtain new effective analgesic and/or anti-inflammatory agents, were synthesized and tested along with three new 9-alkyl-5-(4-alkyl-1-piperazinyl)- N,N -diethyl [1,2,4]triazolo[4,3- a ][1,8]naphthyridine-6-carboxamides ( 2b – d ). Besides, a new class of analogues of compounds 1 and 2 , bearing a Mannich base moiety at the 9-position ( 12a – d ), as well as the novel N,N -diethyl-5-(isobutylamino)-8-methyl-10-oxo-10 H -pyrimido[1,2- a ][1,8]naphthyridine-6-carboxamide ( 15 ) were prepared and tested. Compounds 1c – g exhibited very interesting anti-inflammatory properties in rats, whereas compounds 2b – d and 15 proved to be endowed with prevalent analgesic activity frequently associated with sedative effects in mice. On the contrary, the Mannich bases 12a – d resulted inactive. The most effective (80% inhibition of oedema) and potent (threshold dose 1.6 mg kg −1 with 31% inhibition of oedema) anti-inflammatory compound 1d did not show gastrolesive effects following 100 mg kg −1 oral administration in rats.

Et3N-mediated condensation of preformed or in situ generated indole iminium salts with active methylene reagents provides stereoselectively Knoevenagel-type indoles in moderate to good yields.