Role of copper chelating agents: between old applications and new perspectives in neuroscience.

The role of copper element has been an increasingly relevant topic in recent years in the fields of human and animal health, for both the study of new drugs and innovative food and feed supplements. This metal plays an important role in the central nervous system, where it is associated with glutamatergic signaling, and it is widely involved in inflammatory processes. Thus, diseases involving copper (II) dyshomeostasis often have neurological symptoms, as exemplified by Alzheimer's and other diseases (such as Parkinson's and Wilson's diseases). Moreover, imbalanced copper ion concentrations have also been associated with diabetes and certain types of cancer, including glioma. In this paper, we propose a comprehensive overview of recent results that show the importance of these metal ions in several pathologies, mainly Alzheimer's disease, through the lens of the development and use of copper chelators as research compounds and potential therapeutics if included in multi-target hybrid drugs. Seeing how copper homeostasis is important for the well-being of animals as well as humans, we shortly describe the state of the art regarding the effects of copper and its chelators in agriculture, livestock rearing, and aquaculture, as ingredients for the formulation of feed supplements as well as to prevent the effects of pollution on animal productions.

A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties.

New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARα/γ partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes.

Green Methods to Recover Bioactive Compounds from Food Industry Waste: A Sustainable Practice from the Perspective of the Circular Economy.

The worrying and constant increase in the quantities of food and beverage industry by-products and wastes is one of the main factors contributing to global environmental pollution. Since this is a direct consequence of continuous population growth, it is imperative to reduce waste production and keep it under control. Re-purposing agro-industrial wastes, giving them new life and new directions of use, is a good first step in this direction, and, in global food production, vegetables and fruits account for a significant percentage. In this paper, brewery waste, cocoa bean shells, banana and citrus peels and pineapple wastes are examined. These are sources of bioactive molecules such as polyphenols, whose regular intake in the human diet is related to the prevention of various diseases linked to oxidative stress. In order to recover such bioactive compounds using more sustainable methods than conventional extraction, innovative solutions have been evaluated in the past decades. Of particular interest is the use of deep eutectic solvents (DESs) and compressed solvents, associated with green techniques such as microwave-assisted extraction (MAE), ultrasonic-assisted extraction (UAE), pressurized liquid extraction (PLE) and pulsed-electric-field-assisted extraction (PEF). These novel techniques are gaining importance because, in most cases, they allow for optimizing the extraction yield, quality, costs and time.

A New Antidiabetic Agent Showing Short- and Long-Term Effects Due to Peroxisome Proliferator-Activated Receptor Alpha/Gamma Dual Agonism and Mitochondrial Pyruvate Carrier Inhibition.

A new series of analogues or derivatives of the previously reported PPARα/γ dual agonist LT175 allowed the identification of ligand 10, which was able to potently activate both PPARα and -γ subtypes as full and partial agonists, respectively. Docking studies were performed to provide a molecular explanation for this different behavior on the two different targets. In vivo experiments showed that this compound induced a significant reduction in blood glucose and lipid levels in an STZ-induced diabetic mouse model displaying no toxic effects on bone, kidney, and liver. By examining in depth the antihyperglycemic activity of 10, we found out that it produced a slight but significant inhibition of the mitochondrial pyruvate carrier, acting also through insulin-independent mechanisms. This is the first example of a PPARα/γ dual agonist reported to show this inhibitory effect representing, therefore, the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.

Novel Phenothiazine/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex multi-factorial neurodegenerative disorder for which only few drugs (including donepezil, DPZ) are available as symptomatic treatments; thus, researchers are focusing on the development of innovative multi-target directed ligands (MTDLs), which could also alter the course of the disease. Among other pathological factors, oxidative stress has emerged as an important factor in AD that could affect several pathways involved in the onset and progression of the pathology. Herein, we propose a new series of hybrid molecules obtained by linking a phenothiazine moiety, known for its antioxidant properties, with N-benzylpiperidine or N-benzylpiperazine fragments, mimicking the core substructure of DPZ. The investigation of the resulting hybrids showed, in addition to their antioxidant properties, their activity against some AD-related targets, such as the inhibition of cholinesterases (both AChE and BChE) and in vitro Aß1-40 aggregation, as well as the inhibition of the innovative target fatty acid amide hydrolase (FAAH). Furthermore, the drug-likeness properties of these compounds were assessed using cheminformatic tools. Compounds 11d and 12d showed the most interesting multi-target profiles, with all the assayed activities in the low micromolar range. In silico docking calculations supported the obtained results. Compound 13, on the other hand, while inactive in the DPPH assay, showed the best results in the in vitro antioxidant cell assays conducted on both HepG2 and SHSY-5Y cell lines. These results, paired with the low or absent cytotoxicity of these compounds at tested concentrations, allow us to aim our future research at the study of novel and effective drugs and pro-drugs with similar structural characteristics.

Food Industry Byproducts as Starting Material for Innovative, Green Feed Formulation: A Sustainable Alternative for Poultry Feeding.

Rising global populations and enhanced standards of living in so-called developing countries have led to an increased demand of food, in particular meat, worldwide. While increasing the production of broiler meat could be a potential solution to this problem, broiler meat is plagued by health concerns, such as the development of antimicrobial resistance and lower meat quality. For this reason, the supplementation of poultry feed with vitamins and antioxidant compounds, such as polyphenols, has become an attractive prospect for research in this sector. Such supplements could be obtained by extraction of agricultural byproducts (in particular, grape pomaces and artichoke leaves and bracts), thus contributing to reductions in the total amount of waste biomass produced by the agricultural industry. In this review, the effects of poultry feed supplementation with bioactive extracts from grape pomace (skins and/or seeds), as well as extracts from artichoke leaves and bracts, were explored. Moreover, the various methods that have been employed to obtain extracts from these and other agricultural byproducts were listed and described, with a particular focus on novel, eco-friendly extraction methods (using, for example, innovative and biocompatible solvents like Deep Eutectic Solvents (DESs)) that could reduce the costs and energy consumption of these procedures, with similar or higher yields compared to standard methods.

Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease.

Alzheimer's disease (AD) is a widespread multifactorial aging-related pathology, which includes cholinergic deficit among its main causes. Following a multi-target design strategy, the structure of the approved drug donepezil was taken as the starting point for generating some new potential multi-functional compounds. Therefore, a series of twenty molecular hybrids were synthesized and assayed against three different enzymes, namely the well-established targets acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the innovative one fatty acid amide hydrolase (FAAH). In silico studies confirmed the interaction of benzylpiperidine and the benzylpiperazine isostere with the catalytic anionic site (CAS) of AChE, while the aryloxycarbonyl portion appeared to be important for the interaction with the peripheral site (PAS). A QSAR study was carried out on AChE inhibition data, which revealed that the inhibition potency seems to depend upon the length of the spacer and the number of polar atoms. The docking poses of selected compounds within BChE and FAAH were also calculated. Furthermore, pharmacokinetics and drug-likeness properties were assessed by chemoinformatic tools. Several piperidine derivatives (in particular compound 10) showed interesting profiles as multi-target directed agents, while the lead piperazine derivative 12 (SON38) was found to be a more potent and selective AChE inhibitor (IC50 = 0.8 nM) than donepezil, besides being able to bind bivalent copper cations (pCu = 7.9 at physiological pH). Finally, the selected lead compounds (10 and 12, SON38) did not show significant cytotoxicity on SH-SY5Y and HepG2 cells at the highest tested concentration (100 µM) in a MTT assay.

A chemoinformatics search for peroxisome proliferator-activated receptors ligands revealed a new pan-agonist able to reduce lipid accumulation and improve insulin sensitivity.

The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a chemoinformatics search approach for new ligands that let us identify a novel PPAR pan-agonist with a very attractive activity profile being able to reduce lipid accumulation and improve insulin sensitivity. This compound represents, therefore, the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.

A New Series of Aryloxyacetic Acids Endowed with Multi-Target Activity towards Peroxisome Proliferator-Activated Receptors (PPARs), Fatty Acid Amide Hydrolase (FAAH), and Acetylcholinesterase (AChE).

A new series of aryloxyacetic acids was prepared and tested as peroxisome proliferator-activated receptors (PPARs) agonists and fatty acid amide hydrolase (FAAH) inhibitors. Some compounds exhibited an interesting dual activity that has been recently proposed as a new potential therapeutic strategy for the treatment of Alzheimer's disease (AD). AD is a multifactorial pathology, hence multi-target agents are currently one of the main lines of research for the therapy and prevention of this disease. Given that cholinesterases represent one of the most common targets of recent research, we decided to also evaluate the effects of our compounds on the inhibition of these specific enzymes. Interestingly, two of these compounds, (S)-5 and 6, showed moderate activity against acetylcholinesterase (AChE) and even some activity, although at high concentration, against Aß peptide aggregation, thus demonstrating, in agreement with the preliminary dockings carried out on the different targets, the feasibility of a simultaneous multi-target activity towards PPARs, FAAH, and AChE. As far as we know, these are the first examples of molecules endowed with this pharmacological profile that might represent a promising line of research for the identification of novel candidates for the treatment of AD.

Natural Compounds for the Prevention and Treatment of Cardiovascular and Neurodegenerative Diseases.

Secondary metabolites from plants and fungi are stimulating growing interest in consumers and, consequently, in the food and supplement industries. The beneficial effects of these natural compounds are being thoroughly studied and there are frequent updates about the biological activities of old and new molecules isolated from plants and fungi. In this article, we present a review of the most recent literature regarding the recent discovery of secondary metabolites through isolation and structural elucidation, as well as the in vitro and/or in vivo evaluation of their biological effects. In particular, the possibility of using these bioactive molecules in the prevention and/or treatment of widely spread pathologies such as cardiovascular and neurodegenerative diseases is discussed.

A Review of Recent Patents (2016-2019) on Plant Food Supplements with Potential Application in the Treatment of Neurodegenerative and Metabolic Disorders.

In the near future, it is expected that the prevalence of illnesses related to the increasing life expectancies and quality of life, such as neurodegenerative diseases and cardiovascular diseases related to metabolic disorders, will soar to unprecedented levels, leading to high socioeconomic costs. To address this rising threat, natural products are emerging as a novel strategy for the prevention and therapy of these ages- and lifestyle-related diseases, thanks to their high marketability and few side effects. In this patent review, we summarize selected patents for food supplements, functional and fortified foods, filed from 2016 to 2019, categorizing them based on the biological activity of their components.