An unusual nicotinamide derivative, 4-pyridone-3-carboxamide ribonucleoside (4PYR), is a novel endothelial toxin and oncometabolite

Our recent studies identified a novel pathway of nicotinamide metabolism that involves 4-pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR) and demonstrated its endothelial cytotoxic effect. This study tested the effects of 4PYR and its metabolites in experimental models of breast cancer. Mice were divided into groups: 4T1 (injected with mammary 4T1 cancer cells), 4T1 + 4PYR (4PYR-treated 4T1 mice), and control, maintained for 2 or 21 days. Lung metastasis and endothelial function were analyzed together with blood nucleotides (including 4PYR), plasma amino acids, nicotinamide metabolites, and vascular ectoenzymes of nucleotide catabolism. 4PYR metabolism was also evaluated in cultured 4T1, MDA-MB-231, MCF-7, and T47D cells. An increase in blood 4PYR in 4T1 mice was observed at 2 days. 4PYR and its metabolites were noticed after 21 days in 4T1 only. Higher blood 4PYR was linked with more lung metastases in 4T1 + 4PYR vs. 4T1. Decreased L-arginine, higher asymmetric dimethyl-L-arginine, and higher vascular ecto-adenosine deaminase were observed in 4T1 + 4PYR vs. 4T1 and control. Vascular relaxation caused by flow-dependent endothelial activation in 4PYR-treated mice was significantly lower than in control. The permeability of 4PYR-treated endothelial cells was increased. Decreased nicotinamide but enhanced nicotinamide metabolites were noticed in 4T1 vs. control. Reduced N-methylnicotinamide and a further increase in Met2PY were observed in 4T1 + 4PYR vs. 4T1 and control. In cultured breast cancer cells, estrogen and progesterone receptor antagonists inhibited the production of 4PYR metabolites. 4PYR formation is accelerated in cancer and induces metabolic disturbances that may affect cancer progression and, especially, metastasis, probably through impaired endothelial homeostasis. 4PYR may be considered a new oncometabolite.Subject terms: Mechanisms of disease, Pathogenesis, Breast cancer     

Antiviral Activity of a Cyclic Pro-Pro-β3-HoPhe-Phe Tetrapeptide against HSV-1 and HAdV-5

The core of Cyclolinopeptide A (CLA, cyclo(LIILVPPFF)), responsible for its high immunosuppressive activity, contains a Pro-Pro-Phe-Phe sequence. A newly synthesized cyclic tetrapeptide, cyclo(Pro-Pro-β³-HoPhe-Phe) (denoted as 4B8M) bearing the active sequence of CLA, was recently shown to exhibit a wide array of anti-inflammatory properties in mouse models. In this investigation, we demonstrate that the peptide significantly inhibits the replication of human adenovirus C serotype 5 (HAdV-5) and Herpes simplex virus type-1 (HSV-1) in epithelial lung cell line A-549, applying Cidofovir and Acyclovir as reference drugs. Based on a previously established mechanism of its action, we propose that the peptide may inhibit virus replication by the induction of PGE2 acting via EP2/EP4 receptors in epithelial cells. In summary, we reveal a new, antiviral property of this anti-inflammatory peptide.     

Synthesis,Docking Studies and Pharmacological Evaluation of Serotoninergic Ligands Containing a 5-Norbornene-2-Carboxamide Nucleus

A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT_1A, 5-HT_2A, and 5-HT_2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenucleus, in order to identify selective ligands for the above-mentioned subtype receptors. Arylpiperazines represents one of the most important classes of 5-HT_1AR ligands, and recent research concerning new derivatives has been focused on the modification of one or more portions of such pharmacophore. The combination of structural elements (heterocyclic nucleus, propyl chain and 4-substituted piperazine), known to be critical to the affinity to 5-HT_1A receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that Norbo-4 and Norbo-18 were the most active and promising derivatives for the serotonin receptor considered in this study.     

New,Eco-Friendly Method for Synthesis of 3-Chlorophenyl and 1,1′-Biphenyl Piperazinylhexyl Trazodone Analogues with Dual 5-HT1A/5-HT7 Affinity and Its Antidepressant-like Activity

Serotonin 5-HT_1A and 5-HT₇ receptors play an important role in the pathogenesis and pharmacotherapy of depression. Previously identified N-hexyl trazodone derivatives, 2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride (7a·HCl), with high affinity for 5-HT_1AR and 2-(6-(4-([1,1′-biphenyl]-2-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride (7b·HCl), a dual-acting 5-HT_1A/5-HT₇ receptor ligand, were prepared with a new microwave-assisted method. The protocol for the synthesis of 7a and 7b involved reductive alkylation under a mild reducing agent. We produced the final compounds with yield of 56–63% using ethanol or 51–56% in solvent-free conditions in 4 min. We then determined the 5-HT₇R binding mode for compounds 7a and 7b using in silico methods and assessed the preliminary ADME and safety properties (hepatotoxicity and CYP3A4 inhibition) using in vitro methods for 7a·HCl and 7b·HCl. Furthermore, we evaluated antidepressant-like activity of the dual antagonist of 5-HT_1A/5-HT₇ receptors (7b·HCl) in the forced swim test (FST) in mice. The 5-HT_1AR ligand (7a·HCl) with a much lower affinity for 5-HT₇R compared to that of 7b·HCl was tested comparatively. Both compounds showed antidepressant activity, while 5-HT_1A/5-HT₇ double antagonist 7b·HCl showed a stronger and more specific response.     

Chemical Composition and Biological Activity of Argentinian Propolis of Four Species of Stingless Bees

The chemical composition of propolis of four species of stingless bees (SLBs) from Argentina was determined, and its antibacterial and anticancer activity was evaluated on selected types of microbes and cancer cell lines. Volatile secretions of all propolis samples are formed by 174 C₂–C₁₅ organic compounds, mainly mono- and sesquiterpenes and their derivatives. The chromatograms of ether extracts showed 287 peaks, of which 210 were identified. The most representative groups in the extracts of various propolis samples were diterpenoids (mainly resin acids), triterpenoids and phenolic compounds: long-chain alkenyl phenols, resorcinols and salicylates. The composition of both volatile and extractive compounds turned out to be species-specific; however, in both cases, the pairwise similarity of the propolis of Scaptotrigona postica and Tetragonisca fiebrigi versus that of Tetragona clavipes and Melipona quadrifasciata quadrifasciata was observed, which indicated the similarity of the preferences of the respective species when choosing plant sources of resin. The composition of the studied extracts completely lacked flavonoids and phenolcarboxylic acids, which are usually associated with the biological activity and medicinal properties of propolis. However, tests on selected microbial species and cancer cell lines showed such activity. All propolis samples tested against Paenibacillus larvae, two species of Bacillus and E. coli showed biofilm inhibition unrelated to the inhibition of bacterial growth, leading to a decrease in their pathogenicity. Testing the anticancer activity of ether extracts using five types of cell cultures showed that all four types of propolis studied inhibit the growth of cancer cells in a dose- and time-dependent manner. Propolis harvested by T. clavipes demonstrated the highest cytotoxicity on all tested cell lines.     

Development and Validation of the LC–MS/MS Method for Determination of 130 Natural and Synthetic Cannabinoids in Cannabis Oil

Dietary supplements are widely available products used by millions of people around the world. Unfortunately, the procedure of adding pharmaceutical and psychoactive substances has recently been observed, in order to increase the effectiveness of supplements in the form of hemp oils. For this reason, it is extremely important to develop analytical methods for the detection of substances prohibited in dietary supplements and food products. In the present study, using the LC–MS/MS technique, an innovative method for the detection and quantification of 117 synthetic cannabinoids and 13 natural cannabinoids in dietary supplements and food products in the form of oils during one 13-min chromatographic run was developed. Each method was fully validated by characterization of the following parameters: The limit of detection was set to 0.1 ng/mL (100 µg/g, 0.01%). The limit of quantification ranged from 0.05 ng/mL to 50 ng/mL. The criteria assumed for systematic error caused by methodological bias (±20%) resulting from the recovery of analytes after the extraction process, as well as the coefficient of variation (CV) (≤20%), were met for all 130 tested compounds. The positive results of the validation confirmed that the developed methods met the requirements related to the adequacy of their application in a given scope. Additionally, methods developed using the LC–MS/MS technique were verified via proficiency tests. The developed analytical procedure was successfully used in the analysis of hemp oils and capsules containing them in the studied dietary supplements.     

An attempt to simulate structure and realistic images of scratches on rough polymeric surfaces

Numerical simulation of scratching has been shown to exhibit many advantages in material development and surface design and can provide detailed information associated with the scratch structure. However, the visual appearance of simulated scratches in real-world scenarios has seldom been studied. This study simulates the structure and visual appearance of scratches on rough polymer surfaces by combining the finite element method (FEM) with computer imaging (CI) techniques. FEM modeling of scratching incorporates a wide range of microgeometries in rough surfaces to ensure that the resulting scratch surfaces contain all features, regardless of whether they are visible to the human eye. Computer graphics produce realistic images of numeric scratch surfaces in real-world lighting conditions. This method demonstrates the advantages of easily simulating scratches on rough surfaces and assessing both abrasion strength and visual scratch resistance. Scratch tests on commercial polymer surfaces at different scratch forces demonstrate that the method can satisfactorily predict the structures and scales of scratches. The simulated images correlate closely with camera-acquired photographs in terms of the visual appearance of scratch surfaces, effect of lighting conditions, and dependence of the visual width of scratches on the scratching force, material, pigment, and additive in the material.     

Effect of Cr(III) passivation layer on surface modifications of zinc-nickel coatings in chloride solutions

Surface chemical and morphological modifications of as-plated and Cr(III)-passivated monophasic zinc-nickel coatings induced by corrosion in chloride solutions are demonstrated. The passivated samples showed slower anodic dissolution, less significant de-alloying, smaller surface dezincification and lower coating cracking, as demonstrated by Scanning Electron Microscopy and Energy Dispersive X-ray Spectroscopy (SEM-EDX) of the surface and inductively coupled plasma atomic emission spectroscopy solution analysis. Surface characterization by X-ray photoelectron spectroscopy (XPS), Raman spectroscopy and SEM-EDS indicated simonkolleite as the main corrosion product for both, as-plated and Cr(III)-passivated coatings. In contrast, only for as-plated coating, which experienced higher cracking, new Ni containing phases (metallic Ni and NiO) were evidenced. The phase transition via selective dissolution of zinc is supposed to increase the concentration of the structural defects and could explain cracking in the non-passivated Zn-Ni coating.