Neuroprotective Effect of SGLT2 Inhibitors

Patients with diabetes are at higher risk of cardiovascular diseases and cognitive impairment. SGLT2 inhibitors (Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin, Sotagliflozin) are newer hypoglycemic agents with many pleiotropic effects. In this review, we discuss their neuroprotective potential. SGLT2 inhibitors (SGLT2i) are lipid-soluble and reach the brain/serum ratio from 0.3 to 0.5. SGLT receptors are present in the central nervous system (CNS). Flozins are not fully SGLT2-selective and have an affinity for the SGLT1 receptor, which is associated with protection against ischemia/reperfusion brain damage. SGLT2i show an anti-inflammatory and anti-atherosclerotic effect, including reduction of proinflammatory cytokines, M2 macrophage polarization, JAK2/STAT1 and NLRP3 inflammasome inhibition, as well as cIMT regression. They also mitigate oxidative stress. SGLT2i improve endothelial function, prevent remodeling and exert a protective effect on the neurovascular unit, blood-brain barrier, pericytes, astrocytes, microglia, and oligodendrocytes. Flozins are also able to inhibit AChE, which contributes to cognitive improvement. Empagliflozin significantly increases the level of cerebral BDNF, which modulates neurotransmission and ensures growth, survival, and plasticity of neurons. Moreover, they may be able to restore the circadian rhythm of mTOR activation, which is quite a novel finding in the field of research on metabolic diseases and cognitive impairment. SGLT2i have a great potential to protect against atherosclerosis and cognitive impairment in patients with type 2 diabetes mellitus.     

Synthesis of Epoxy Methacrylate Resin and Coatings Preparation by Cationic and Radical Photocrosslinking

This work involves the synthesis of hybrid oligomers based on the epoxy methacrylate resin. The EA resin was obtained by the modification of industrial-grade bisphenol A-based epoxy resin and methacrylic acid has been synthesized in order to develop multifunctional resins comprising both epoxide group and reactive, terminal unsaturation. Owing to the presence of both epoxy and double carbon–carbon pendant groups, the reaction product exhibits photocrosslinking via two distinct mechanisms: (i) cationic ring-opening polymerization and (ii) free radical polymerization. Monitoring of EA synthesis reactions over time using PAVs, MAAC and NV parameters, and the FT-IR method reveals that esterification reactions proceed faster at the start, exhibiting over 40% of conversion within the initial 60 min, which can be associated with a relatively high concentration of reactive sites and low viscosity of the reaction mixture at the initial reaction stage. With the further increase in the reaction time, the reaction rate tends to decrease. The control of the EA synthesis process can guide how to adjust reactions to obtain EAs with desired characteristics. Based on obtained values, one can state that the optimum synthesis time of about 4–5 h should be adopted to prepare EAs having both epoxy groups and unsaturated double bonds. The structure of the obtained EA was confirmed by FT-IR and NMR methods, as well as the determination of partial acid value and epoxy equivalent. Samples at various stages of synthesis were cured with UV radiation in order to study the kinetics of the process according to cationic and radical polymerization determined via photo-differential scanning calorimetry (photo-DSC) and real-time infrared spectroscopy (RT-IR) and then the properties of the cured coatings were tested. It turned out that the cationic polymerization was slower with a lower conversion of the photoreactive groups, as compared to the radical polymerization. All the obtained EA coatings were characterized by good properties of cured coatings and can be successfully used in the coating-forming sector.     

Isotretinoin and Thalidomide Down-Regulate c-MYC Gene Expression and Modify Proteins Associated with Cancer in Hepatic Cells

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. The number of cases is increasing and the trend for the next few years is not encouraging. HCC is usually detected in the advanced stages of the disease, and pharmacological therapies are not entirely effective. For this reason, it is necessary to search for new therapeutic options. The objective of this work was to evaluate the effect of the drugs isotretinoin and thalidomide on c-MYC expression and cancer-related proteins in an HCC cellular model. The expression of c-MYC was measured using RT-qPCR and western blot assays. In addition, luciferase activity assays were performed for the c-MYC promoters P1 and P2 using recombinant plasmids. Dose-response-time analyses were performed for isotretinoin or thalidomide in cells transfected with the c-MYC promoters. Finally, a proteome profile analysis of cells exposed to these two drugs was performed and the results were validated by western blot. We demonstrated that in HepG2 cells, isotretinoin and thalidomide reduced c-MYC mRNA expression levels, but this decrease in expression was linked to the regulation of P1 and P1-P2 c-MYC promoter activity in isotretinoin only. Thalidomide did not exert any effect on c-MYC promoters. Also, isotretinoin and thalidomide were capable of inducing and repressing proteins associated with cancer. In conclusion, isotretinoin and thalidomide down-regulate c-MYC mRNA expression and this is partially due to P1 or P2 promoter activity, suggesting that these drugs could be promising options for modulating the expression of oncogenes and tumor suppressor genes in HCC.     

Combining Molecular Dynamic Information and an Aspherical-Atom Data Bank in the Evaluation of the Electrostatic Interaction Energy in Multimeric Protein-Ligand Complex: A Case Study for HIV-1 Protease

Computational analysis of protein–ligand interactions is of crucial importance for drug discovery. Assessment of ligand binding energy allows us to have a glimpse of the potential of a small organic molecule to be a ligand to the binding site of a protein target. Available scoring functions, such as in docking programs, all rely on equations that sum each type of protein–ligand interactions in order to predict the binding affinity. Most of the scoring functions consider electrostatic interactions involving the protein and the ligand. Electrostatic interactions constitute one of the most important part of total interactions between macromolecules. Unlike dispersion forces, they are highly directional and therefore dominate the nature of molecular packing in crystals and in biological complexes and contribute significantly to differences in inhibition strength among related enzyme inhibitors. In this study, complexes of HIV-1 protease with inhibitor molecules (JE-2147 and darunavir) were analyzed by using charge densities from the transferable aspherical-atom University at Buffalo Databank (UBDB). Moreover, we analyzed the electrostatic interaction energy for an ensemble of structures, using molecular dynamic simulations to highlight the main features of electrostatic interactions important for binding affinity.     

Ion chromatography for the analysis of glyphosate and its selected metabolites. A review

Among all known compounds with herbicide activity glyphosate, has been the most commercially successful one. Currently, it is under evaluation because of its possible cancerogenic properties. However, the question is—if it is possible to completely withdraw it from use. Before it can happen, it is important to be sure of all its benefits and limitations, and this requires further detailed research. Due to the extent and prevalence of its use, glyphosate ends up in the environment and then in food and our bodies. There are several methods used for their determination. One of them is ion chromatography. Taking into account its advantages and disadvantages, as well as its rapid development, their importance in this field can be expected to increase in the near future. This paper summarizes the literature data from the past 22 years. The applications of ion chromatography in the determination of glyphosate in various types of environmental, food, and other samples are described. Moreover, the methods used so far are compared with the possibilities offered by ion chromatography, which main advantages and benefits are easy availability, low operating costs, green chemistry aspects, and suitable validation parameters.     

Expedient Synthesis of Oxaboracyclic Compounds Based on Naphthalene and Biphenyl Backbone and Phase-Dependent Luminescence of their Chelate Complexes

The approach to a series of six- and seven-membered oxaboraheterocycles based on naphthalene or biphenyl backbones was developed. The key synthetic step involved Br/Li exchange in respective potassium (bromoaryl)trifluoroborates followed by quenching with selected electrophiles (CO₂, DMF, Me₂Si(H)Cl) and hydrolytic workup. Two ring-expanded benzoxaborole congeners were obtained by an additional reduction step with LiAlH₄ or NaBH₄. The obtained boracyclic compounds were characterized in detail by NMR spectroscopy and single-crystal X-ray diffraction. Specifically, biphenyl-based systems show dynamic behaviour interpreted in terms of inversion of non-planar seven-membered boraheterocycles. The acidity of the obtained compounds varies very strongly (pK_a ranges from 3.1–9.6) depending on their structure. Due to the enhanced boron Lewis acidity, selected compounds were used as a basis for luminescent complexes with 8-hydroxyquinoline. A strong phase-dependent variation of emission-band maximum (480–527 nm) and photoluminescence quantum yield (10–95 %) was observed, which was rationalized in terms of specific aggregation effects.     

Behavior of peptides and computer-assisted optimization of peptides separations in a normal-phase thin-layer chromatography system with and without the addition of ionic liquid in the eluent

The addition of an ionic liquid into the mobile phase appeared to be useful in optimization of chromatographic separation of peptides. Different behavior of peptides in thin-layer chromatography (TLC) was observed after addition of 1-ethyl-3-methylimidazolium tetra fluoroborate to the eluent in comparison to the system without the ionic liquid. Nonlinear dependence of the retention coefficient, R(M), of peptides on the volume percentage of acetonitrile in the eluent was found in normal-phase TLC with and without immidazolium tetra fluoroborate in the mobile phase. In general, R(M) increased with increasing concentration of acetonitrile. In TLC systems without the ionic liquid, R(M) can be described well with a quadratic function. On the other hand, in a TLC system with an ionic liquid as the additive to the mobile phase, the retention behavior is better described with a third-degree polynomial function. The potential usefulness of ionic liquids for optimization of separation of peptides was demonstrated. Optimization of the separation conditions was supported by a commercially available computer program.     

How does the type of counterion influence the polymerization rate and thermal properties of tailored choline-based linear- and star-shaped poly(ionic liquid)s PILs?

The synthesis of tailored [2-(methacryloyloxy)ethyl]-trimethylammonium chloride (ChMA/Cl⁻) and bis(trifluoromethanesulfonate) imide (ChMA/NTf₂⁻)-based ionic homopolymers by sustainable activators generated by electron transfer atom transfer radical polymerization (ATRP) method has been demonstrated. Linear and four-arm star-shaped macromolecules were obtained with the use of two synthetic strategies: (a) direct polymerization of ionic monomers with counterions differing in hydrophilicity (prepolymerization) and (2) modification by ion exchange from Cl⁻ to NTf₂⁻ (postpolymerization) using both classical ATRP initiator and pentaerythritol-based initiator. The effect of counterions on the polymerization kinetics and the physicochemical and thermodynamical properties of resulted poly(ionic liquid)s (PILs) has been investigated. Results showed that polymerizations of ChMA/NTf₂⁻ proceeded with higher rate in comparison to ChMA/Cl⁻ one independently on the predetermined topologies (linear and four-arm star-shaped). From thermodynamical point of view, the glass transition temperature T_g increased with molecular weight M_n for linear- and star-shaped PILs for both types of counterion. In addition, star-shaped polymers of comparable M_n to linear ones were characterized by slightly higher T_g values. The resulting polyelectrolytes, after modification via exchange of Cl⁻ anions to NTf₂⁻ ones were characterized by much higher T_g in comparison to those produced by direct polymerization of ionic monomer, indicating the crucial role of postpolymerization modification on thermodynamical properties of PILs. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 2681–2691     

Permeability of the Perindopril Arginine under In Vitro Conditions across Caco-2 Monolayer and Biomimetic Phospholipid Membrane

Perindopril arginine (PA) as an angiotensin-converting enzyme (ACE) inhibitor is widely used in cardiovascular diseases, especially in systemic hypertension and heart failure. Although the pharmacokinetics of PA are well documented, there is no available detailed data on its permeation in in vitro conditions. The present study aimed to assess the transport of PA across both biological membranes and artificial biomimetic ones. For the determination of PA transport, the Caco-2 cell line was selected as a reliable in vitro model of gastrointestinal biological barriers. Additionally, a novel 96-well plate with phospholipid membrane PermeaPad was used to evaluate the transport of PA by passive diffusion. We confirmed that PA is relatively poorly permeable across the Caco-2 monolayer. The permeability results obtained from the non-cell-based model demonstrated higher transport of PA as compared to that of Caco-2. Thus, PA transport across the biological membranes might be suggested to be regulated by the membrane transporters.