Rivastigmine-Benzimidazole Hybrids as Promising Multitarget Metal-Modulating Compounds for Potential Treatment of Neurodegenerative Diseases.

With the goal of combating the multi-faceted Alzheimer's disease (AD), a series of Rivastigmine-Benzimidazole (RIV-BIM) hybrids was recently reported by us as multitarget-directed ligands, thanks to their capacity to tackle important hallmarks of AD. In particular, they exhibited antioxidant activity, acted as cholinesterase inhibitors, and inhibited amyloid-ß (Aß) aggregation. Herein, we moved forward in this project, studying their ability to chelate redox-active biometal ions, Cu(II) and Fe(III), with widely recognized roles in the generation of oxidative reactive species and in protein misfolding and aggregation in both AD and Parkinson's disease (PD). Although Cu(II) chelation showed higher efficiency for the positional isomers of series 5 than those of series 4 of the hybrids, the Aß-aggregation inhibition appears more dependent on their capacity for fibril intercalation than on copper chelation. Since monoamine oxidases (MAOs) are also important targets for the treatment of AD and PD, the capacity of these hybrids to inhibit MAO-A and MAO-B was evaluated, and they showed higher activity and selectivity for MAO-A. The rationalization of the experimental evaluations (metal chelation and MAO inhibition) was supported by computational molecular modeling studies. Finally, some compounds showed also neuroprotective effects in human neuroblastoma (SH-SY5Y cells) upon treatment with 1-methyl-4-phenylpyridinium (MPP+), a neurotoxic metabolite of a Parkinsonian-inducing agent.

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.

Microbial Resistance to Antibiotics and Biofilm Formation of Bacterial Isolates from Different Carp Species and Risk Assessment for Public Health.

The aim of this research was to investigate the effects of biofilm on antibiotic resistance of the bacterial isolates present in fish meat and to assess the risk of antibiotic residues for public health. Common carp, silver carp and grass carp fishes were purchased from retail stores for an in vitro biofilm investigation and a drug-resistant pattern determination. In all samples, up to 104 CFU/g of bacteria, such as Escherichia coli, Aeromonas hydrophila, Shewanella putrefaciens, Vibrio spp. and Staphylococcus spp., were observed. Isolates from the samples and their biofilms were subjected to an antibiogram assay using antibiotics such as amoxicillin, ampicillin, cefotaxime, ciprofloxacin, chloramphenicol, gentamicin, streptomycin, tetracycline and trimethoprim. Obtained results showed that some of the isolates were sensitive to antibiotics and some were resistant. Results of LC-MS/MS analysis showed that antibiotics residues were present in fish samples in the range between 4.9 and 199.4 µg/kg, with a total sum of 417.1 µg/kg. Estimated daily intake (EDI) was established to be 0.274 µg/kg of body weight/day for men and 0.332 µg/kg of body weight/day for women, with an acceptable daily intake (ADI) of 8.5 and 7.0 µg/kg of body weight/day for men and women, respectively. The results of the present study, therefore, highlight the safe consumption of fresh fish.

Dietary vitamin D: growth, physiological and health consequences in broiler production.

Vitamins are needed in trace amounts in dietary formulations for poultry; however, they are critical for the health, maintenance, and performance of important body organs. Broilers have a lot of leg issues because of their rapid development and lack of exercise. Because of commercial broilers have limited access to direct sunlight, vitamin D supplementation in the feed is critical to reducing the risk of bone deformation and maximizing development. Vitamin D deficiency causes skeletal abnormalities, which may lead also to financial problems. The latest scientific findings on the source, metabolism, mechanisms of action, and functions of vitamin D in broilers are the subject of this review paper.

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.

Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV-BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid ß-peptide (Aß) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aß42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9-1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1-58.7%) and Cu(II)-induced (40.3-60.8%) Aß aggregation and also to narrow (22.4-42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aß42 and oxidative stress. Therefore, RIV-BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.

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.

Occurrence and Characterization of Penicillium Species Isolated from Post-Harvest Apples in Lebanon.

The apple is one of the most important fruit tree crops in the Mediterranean region. Lebanon, in particular, is among the top apple producer countries in the Middle East; however, recently, several types of damage, particularly rot symptoms, have been detected on fruits in cold storage. This study aims to identify the causal agents of apple decay in Lebanese post-harvest facilities and characterize a set of 39 representative strains of the toxigenic fungus Penicillium. The results demonstrated that blue mould was the most frequent fungal disease associated with apples showing symptoms of decay after 3-4 months of storage at 0 °C, with an average frequency of 76.5% and 80.6% on cv. Red and cv. Golden Delicious apples, respectively. The morphological identification and phylogenetic analysis of benA gene showed that most Penicillium strains (87.2%) belong to P. expansum species whereas the remaining strains (12.8%) belong to P. solitum. Furthermore, 67.7% of P. expansum strains produced patulin when grown on apple puree for 14 days at 25 °C with values ranging from 10.7 mg kg-1 to 125.9 mg kg-1, whereas all P. solitum did not produce the mycotoxin. This study highlights the presence of Penicillium spp. and their related mycotoxin risk during apple storage and calls for the implementation of proper measures to decrease the risk of mycotoxin contamination of apple fruit products.

Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-ß (Aß) aggregation. Some of these hybrids also prevented Aß-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 µM); Aß aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.

(2-Aminobenzothiazole)-Methyl-1,1-Bisphosphonic Acids: Targeting Matrix Metalloproteinase 13 Inhibition to the Bone.

Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, certain MMPs, such as MMP-2, -9, and -13, can be overexpressed in pathological states, including cancer and metastasis. Consequently, the development of MMP inhibitors (MMPIs) has been explored for a long time as a strategy to prevent and hinder metastatic growth, but the important side effects linked to promiscuous inhibition of MMPs prevented the clinical use of MMPIs. Therefore, several strategies were proposed to improve the therapeutic profile of this pharmaceutical class, including improved selectivity toward specific MMP isoforms and targeting of specific organs and tissues. Combining both approaches, we conducted the synthesis and preliminary biological evaluation of a series of (2-aminobenzothiazole)-methyl-1,1-bisphosphonic acids active as selective inhibitors of MMP-13 via in vitro and in silico studies, which could prove useful for the treatment of bone metastases thanks to the bone-targeting capabilities granted by the bisphosphonic acid group.

Derivatives of Tenuazonic Acid as Potential New Multi-Target Anti-Alzheimer's Disease Agents.

Alzheimer's disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti-cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1-5), including tenuazonic-donepezil (TA-DNP) hybrids (4 and 5) due to the clinical importance of the anti-AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi-functional anti-neurodegenerative drugs, as exemplified by hybrid 5, a promising non-cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH-SY5Y human neuroblastoma cells.

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.

Beyond the Canonical Endocannabinoid System. A Screening of PPAR Ligands as FAAH Inhibitors.

In recent years, Peroxisome Proliferator-Activated Receptors (PPARs) have been connected to the endocannabinoid system. These nuclear receptors indeed mediate the effects of anandamide and similar substances such as oleoyl-ethanolamide and palmitoyl-ethanolamide. An increasing body of literature describing the interactions between the endocannabinoid system and PPARs has slowly but surely been accumulating over the past decade, and a multitarget approach involving these receptors and endocannabinoid degrading enzyme FAAH has been proposed for the treatment of inflammatory states, cancer, and Alzheimer's disease. The lack of knowledge about compounds endowed with such an activity profile therefore led us to investigate a library of readily available, well-characterized PPAR agonists that we had synthesized over the years in order to find a plausible lead compound for further development. Moreover, we propose a rationalization of our results via a docking study, which sheds some light on the binding mode of these PPAR agonists to FAAH and opens the way for further research in this field.

Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy.

Matrix metalloproteinases (MMPs) are a family of enzymes involved at different stages of cancer progression and metastasis. We previously identified a novel class of bisphosphonic inhibitors, selective for MMPs crucial for bone remodeling, such as MMP-2. Due to the increasing relevance of specific MMPs at various stages of tumor malignancy, we focused on improving potency towards certain isoforms. Here, we tackled MMP-9 because of its confirmed role in tumor invasion, metastasis, angiogenesis, and immuno-response, making it an ideal target for cancer therapy. Using a computational analysis, we designed and characterized potent MMP-2/MMP-9 inhibitors. This is a promising approach to develop and clinically translate inhibitors that could be used in combination with standard care therapy for the treatment of skeletal malignancies.

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.