Multi-Omics Approach Points to the Importance of Oxylipins Metabolism in Early-Stage Breast Cancer.

The involvement of oxylipins, metabolites of polyunsaturated fatty acids, in cancer pathogenesis was known long ago, but only the development of the high-throughput methods get the opportunity to study oxylipins on a system level. The study aimed to elucidate alterations in oxylipin metabolism as characteristics of breast cancer patients. We compared the ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) oxylipin profile signatures in the blood plasma of 152 healthy volunteers (HC) and 169 patients with different stages of breast cancer (BC). To integrate lipidomics, transcriptomics, and genomics data, we analyzed a transcriptome of 10 open database datasets obtained from tissues and blood cells of BC patients and SNP data for 33 genes related to oxylipin metabolism. We identified 18 oxylipins, metabolites of omega-3 or omega-6 polyunsaturated fatty acids, that were differentially expressed between BCvsHC patients, including anandamide, prostaglandins and hydroxydocosahexaenoic acids. DEGs analysis of tissue and blood samples from BC patients revealed that 19 genes for oxylipin biosynthesis change their expression level, with CYP2C19, PTGS2, HPGD, and FAAH included in the list of DEGs in the analysis of transcriptomes and the list of SNPs associated with BC. Results allow us to suppose that oxylipin signatures reflect the organism's level of response to the disease. Our data regarding changes in oxylipins at the system level show that oxylipin profiles can be used to evaluate the early stages of breast cancer.

Patterned Drug-Eluting Coatings for Tracheal Stents Based on PLA, PLGA, and PCL for the Granulation Formation Reduction: In Vivo Studies.

Expandable metallic stent placement is often the only way to treat airway obstructions. Such treatment with an uncoated stent causes granulation proliferation and subsequent restenosis, resulting in the procedure's adverse complications. Systemic administration of steroids drugs in high dosages slows down granulation tissue overgrowth but leads to long-term side effects. Drug-eluting coatings have been used widely in cardiology for many years to suppress local granulation and reduce the organism's systemic load. Still, so far, there are no available analogs for the trachea. Here, we demonstrate that PLA-, PCL- and PLGA-based films with arrays of microchambers to accommodate therapeutic substances can be used as a drug-eluting coating through securely fixing on the surface of an expandable nitinol stent. PCL and PLA were most resistant to mechanical damage associated with packing in delivery devices and making it possible to keep high-molecular-weight cargo. Low-molecular-weight methylprednisolone sodium succinate is poorly retained in PCL- and PLGA-based microchambers after immersion in deionized water (only 9.5% and 15.7% are left, respectively). In comparison, PLA-based microchambers retain 96.3% after the same procedure. In vivo studies on rabbits have shown that effective granulation tissue suppression is achieved when PLA and PLGA are used for coatings. PLGA-based microchamber coating almost completely degrades in 10 days in the trachea, while PLA-based microchamber films partially preserve their structure. The PCL-based film coating is most stable over time, which probably causes blocking the outflow of fluid from the tracheal mucosa and the aggravation of the inflammatory process against the background of low drug concentration. Combination and variability of polymers in the fabrication of films with microchambers to retain therapeutic compounds are suggested as a novel type of drug-eluting coating.

Particle Forming Amorphous Solid Dispersions: A Mechanistic Randomized Pharmacokinetic Study in Humans.

Amorphous solid dispersions (ASDs) are a promising drug-delivery strategy to overcome poor solubility through formulation. Currently, the understanding of drug absorption mechanisms from ASDs in humans is incomplete. Aiming to gain insights in this matter, we conducted a randomized cross-over design open-label clinical study (NCT03886766) with 16 healthy male volunteers in an ambulatory setting, using micro-dosed efavirenz as a model drug. In three phases, subjects were administered (1) solid ASD of efavirenz 50 mg or (2) dissolved ASD of efavirenz 50 mg or (3) a molecular solution of efavirenz 3 mg (non-ASD) as a control in block-randomized order. Endpoints were the pharmacokinetic profiles (efavirenz plasma concentration vs. time curves) and derived pharmacokinetic parameters thereof (AUC0-t, Cmax, tmax, and ka). Results showed that the dissolved ASD (intervention 2) exhibited properties of a supersaturated solution (compared to aqueous solubility) with rapid and complete absorption of the drug from the drug-rich particles. All interventions showed similar AUC0-t and were well tolerated by subjects. The findings highlight the potential of particle forming ASDs as an advanced drug-delivery system for poorly soluble drugs and provide essential insights into underlying mechanisms of ASD functioning in humans, partially validating current conceptual models.

Water-soluble triazole chitin derivative and its based nanoparticles: Synthesis, characterization, catalytic and antibacterial properties.

In this work, we treated chitin with 2-(azidomethyl)oxirane and successfully involved the resultant azido chitin derivatives in the ultrasound-assisted Cu(I)-catalyzed azido-alkyne click (CuAAC) reaction with propargylic ester of N,N,N-trimethyl glycine. Thus, we obtained novel water-soluble triazole chitin derivatives. The triazole chitin derivatives and their nanoparticles are characterized by a high in vitro antibacterial activity, which is the same or even higher than that of commercial antibiotics ampicillin and gentamicin. The obtained derivatives are non-toxic. Moreover, the obtained water-soluble polymers are highly efficient green catalysts for the aldol reaction in green solvent water. The catalysts can be easily extracted from the reaction mixture by its precipitation with green solvent ethanol followed by centrifugation and they can be reused at least 10 times.

Development and validation of the quantitative determination procedure of iodine in the iodides form in the kelp thallus by the ionometry method.

INTRODUCTION: Iodine is an important compound in the kelp thallus; it should be determined to control the quality of crude herbal drugs of Laminaria sp. The ionometry method is perspective iodine (in the iodides form) determination method in the crude herbal drugs; it is characterized by the availability and relative cheapness of iodide-selective electrodes and equipment in general. This method provides an effective combination of the determination step with the fast, simple, and safe step of sample preparation. AIM: The current study aims to develop and validate a simple, effective procedure for the quantitative determination of iodine in the form of iodide by ionometry in the kelp thallus (Laminaria sp.). MATERIALS AND METHODS: The determination of iodides was carried out by using the "Ecotest-120" pH meter. "Ekom-I" was used as an ion-selective electrode. Silver chloride electrode "ESR 10101" was used as a reference electrode. RESULTS AND DISCUSSION: The developed procedure has a suitable level of linearity (correlation coefficient = 0.9995%), correctness (variation coefficient = 1.58%), repeatability (variation coefficient = 6.67%), and analytical area (0.03-209.4 µg/mL analyte in the test solution). The procedure allows us to determine iodine in the form of iodides with an accuracy comparable to the accuracy of neutron activation analysis and can be recommended as an alternative to titrimetric methods existing in the world-leading pharmacopoeias.

Studying and Modeling of the Extraction Properties of the Natural Deep Eutectic Solvent and Sorbitol-Based Solvents in Regard to Biologically Active Substances from Glycyrrhizae Roots.

The purpose of this work was the studying and modeling of the extraction properties of the sorbitol-based natural deep eutectic solvent (NADES) and sorbitol-based solvents in regard to biologically-active substances (BASs) from Glycyrrhizae roots using theoretical fundamentals based on the laws of statistical physics, thermodynamics, and physical chemistry previously developed by us. In our studies, we used Glycyrrhizae roots, simple maceration, plant raw material:solvent ratio 1:10 w/v, temperature 25 °Ð¡, extraction time 24 h; standards of licuroside and glycyram; RP HPLC, differential scanning calorimetry, integral dielectric, impedance and conductivity spectroscopy method of analysis; the following solvents: sorbitol-based NADES sorbitol:malic acid:water (1:1:3 in molar ratio), a modified solvent based on NADES sorbitol:malic acid:water:glycerin (1:1:1:1 in molar ratio) and sorbitol-based solvents sorbitol:ethanol:water at different ratios. It has been found that regression equations for sorbitol-based solvents in coordinates predicted by the theory have a high value of determination coefficient that equals to R²e = 0.993 for glycyram and R²e = 0.976 for licuroside. It has been found that the extraction properties of sorbitol-based NADES with a dielectric constant (ε) equal to 33 ± 2 units are equivalent to those of the sorbitol:ethanol:water solvent with ε = 34 units, and the extraction properties of modified solvent based on NADES with ε = 41 ± 2 units are inferior to those of the sorbitol-ethanol-water solvents with maximum value of BASs yield with the dielectric constant range 40÷50 units. The theoretical fundamentals suggested provide a possibility for an explanation of the mechanism, quantitative description of the extraction properties of the solvent, and target search of the optimal solvent by its dielectric constant.

Novel side reaction accompanying cyclization of Glu(R1)-Glu(R2) dipeptides via lactamization of the Glu(R1) residue.

A series of linear peptides with the general formula H-Glu(R1)-Glu(R2)-OH was subjected to cyclization under standard conditions. Formation of respective 2,5-diketopiperazines was accompanied by transformation of the N-terminal Glu(R1) to pyroglutamic acid residue. Even in the case R1 is an amino acid residue attached to the N-terminal γ-carboxyl group, lactamization leads to its elimination. The observed reaction has not been reported so far in the literature. Correspondingly, an alternative route to Glu(R1)-Glu(R2)-containing 2,5-diketopiperazines was applied to improve the overall yields.