In Vitro Evaluation of Pharmacokinetic Properties of Selected Dual COX-2 and 5-LOX Inhibitors.

Evaluation of pharmacokinetic properties is a significant step at the early stages of drug development. In this study, an in vitro evaluation of the pharmacokinetic properties of five newly synthesized compounds was performed. These compounds belong to N-hydroxyurea and hydroxamic acid derivatives and analogs of NSAIDs indomethacin, flurbiprofen, diclofenac, ibuprofen, and naproxen (compounds , , , and , respectively) with dual COX-2 and 5-LOX inhibitory activity.

Integration of 3D-QSAR, molecular docking, and machine learning techniques for rational design of nicotinamide-based SIRT2 inhibitors.

Selective inhibitors of sirtuin-2 (SIRT2) are increasingly recognized as potential therapeutics for cancer and neurodegenerative diseases. Derivatives of 5-((3-amidobenzyl)oxy)nicotinamides have been identified as some of the most potent and selective SIRT2 inhibitors reported to date (​Ai et al., 2016​; ​Ai et al.

Data-Driven Modelling of Substituted Pyrimidine and Uracil-Based Derivatives Validated with Newly Synthesized and Antiproliferative Evaluated Compounds.

The pyrimidine heterocycle plays an important role in anticancer research. In particular, the pyrimidine derivative families of uracil show promise as structural scaffolds relevant to cervical cancer. This group of chemicals lacks data-driven machine learning quantitative structure-activity relationships (QSARs) that allow for generalization and predictive capabilities in the search for new active compounds.

In silico attempt to reveal the link between cancer development and combined exposure to the maize herbicides: Glyphosate, nicosulfuron, S-metolachlor and terbuthylazine.

Pesticides are crucial for crop protection and have seen a 50 % increase in use in the last decade. Besides preventing significant crop losses their use has raised health concerns due to consumer exposure through residues in food and water. The toxicity data from individual components is often used to assess overall mixture toxicity, but uncertainty persists in understanding the behaviors of individual chemicals within these mixtures.

Dihydroquercetin and biochaga reduce H2O2-induced DNA damage in peripheral blood mononuclear cells of obese women in vitro-a pilot study.

Systemic oxidative stress stemming from increased free radical production and reduced antioxidant capacity are common characteristics of obese individuals. Using hydrogen peroxide (H2O2) to induce DNA damage in vitro, in peripheral blood mononuclear cells (PBMCs) from obese subjects and controls, the DNA protective ability of dihidroqercetin (DHQ) and biochaga (B) alone or in combination, were evaluated. The effects of DHQ and B were estimated under two experimental conditions: pre-treatment, where cells were pre-incubated with the substances prior to H2O2 exposure; and post-treatment when cells were first exposed to H2 H2O2, and further treated with the compounds.

Molecular mechanisms of environmental pollutant-induced cartilage damage: from developmental disorders to osteoarthritis.

The objective of the present study was to review the molecular mechanisms of the adverse effects of environmental pollutants on chondrocytes and extracellular matrix (ECM). Existing data demonstrate that both heavy metals, including cadmium (Cd), lead (Pb), and arsenic (As), as well as organic pollutants, including polychlorinated dioxins and furans (PCDD/Fs) and polychlorinated biphenyls (PCB), bisphenol A, phthalates, polycyclic aromatic hydrocarbons (PAH), pesticides, and certain other organic pollutants that target cartilage ontogeny and functioning. Overall, environmental pollutants reduce chondrocyte viability through the induction apoptosis, senescence, and inflammatory response, resulting in cell death and impaired ECM production.

Application of parallel artificial membrane permeability assay technique and chemometric modeling for blood-brain barrier permeability prediction of protein kinase inhibitors.

This study aims to investigate the passive diffusion of protein kinase inhibitors through the blood-brain barrier (BBB) and to develop a model for their permeability prediction. We used the parallel artificial membrane permeability assay to obtain logPe values of each of 34 compounds and calculated descriptors for these structures to perform quantitative structure-property relationship modeling, creating different regression models. The logPe values have been calculated for all 34 compounds.

Antioxidative and anti-inflammatory effects of taxifolin in HO-induced oxidative stress in HTR-8/SVneo trophoblast cell line.

Oxidative stress has been implicated in numerous pregnancy-related disorders. Biologically active plant secondary metabolites, which are present in everyday diet, could prove effective therapeutic agents in preventing these disorders. This study evaluated effects of taxifolin (dihydroquercetin) on ROS production, markers of oxidative damage to lipids and proteins, activity of antioxidant enzymes and production of pro-inflammatory cytokines in HO-induced oxidative stress in trophoblast HTR-8/SVneo cells.

New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4-benzo[]imidazo[1,5-][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy.

KRM-II-81 (1) is an imidazodiazepine GABA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst.

Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells.

The synthesis of 24 hybrid molecules, consisting of naturally occurring sclareol (SCL) and synthetic 1,2,4-triazolo[1,5-a]pyrimidines (TPs), is described. New compounds were designed with the aim of improving the cytotoxic properties, activity, and selectivity of the parent compounds. Six analogs (12a-f) contained 4-benzylpiperazine linkage, while 4-benzyldiamine linkage was present in eighteen derivatives (12g-r and 13a-f).

Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation.

To provide back-up compounds to support the development of the GABA receptor (GABAAR) potentiator KRM-II-81, three novel analogs were designed: replacing the pyridinyl with 2'-Cl-phenyl (FR-II-60), changing the positions of the N and O atoms in the oxazole ring with addition of an ethyl group (KPP-III-34 and KPP-III-51), or substituting a Br atom for the ethynyl of KRM-II-81 (KPP-III-34). The compounds bound to brain GABAARs. Intraperitoneal administration of FR-II-60 and KPP-III-34 produced anticonvulsant activity in mice [maximal electroshock (MES)-induced seizures or 6 Hz-induced seizures], whereas KPP-III-51 did not.

DES-Amyloidoses "Amyloidoses through the looking-glass": A knowledgebase developed for exploring and linking information related to human amyloid-related diseases.

More than 30 types of amyloids are linked to close to 50 diseases in humans, the most prominent being Alzheimer's disease (AD). AD is brain-related local amyloidosis, while another amyloidosis, such as AA amyloidosis, tends to be more systemic. Therefore, we need to know more about the biological entities' influencing these amyloidosis processes.

Coupling AFM, DSC and FT-IR towards Elucidation of Film-Forming Systems Transformation to Dermal Films: A Betamethasone Dipropionate Case Study.

Polymeric film-forming systems have emerged as an esthetically acceptable option for targeted, less frequent and controlled dermal drug delivery. However, their dynamic nature (rapid evaporation of solvents leading to the formation of thin films) presents a true characterization challenge. In this study, we tested a tiered characterization approach, leading to more efficient definition of the quality target product profiles of film-forming systems.

The correlation between genetic factors and freezing of gait in patients with Parkinson's disease.

Background: Clinical-related risk factors to freezing of gait (FOG) in Parkinson's disease (PD) have been identified. Still, the influence of genetic variations on the FOG occurrence has been poorly studied thus far.

Aim: We aimed to evaluate the association of six selected polymorphisms of DRD2, ANKK1, and COMT genes with the FOG occurrence and explore the influence of ANNK1/DRD2 haplotypes on the onset of FOG in the group of PD patients.

Association of the methionine sulfoxide reductase A rs10903323 gene polymorphism with functional activity and oxidative modification of alpha-1-antitrypsin in COPD patients.

Objective: Chronic obstructive pulmonary disease (COPD) is multi-factorial disorder which results from environmental influences and genetic factors. We aimed to investigate whether methionine sulfoxide reductase A (MSRA) rs10903323 gene polymorphism is associated with COPD development and severity in Serbian adult population.

Methods: The study included 155 patients with COPD and 134 healthy volunteers.

Population exposure-response model of I in patients with benign thyroid disease.

Purpose: The study aimed to explore the relationship of different exposure measures with I therapy response in patients with benign thyroid disease, estimate the variability in the response, investigate possible covariates, and discuss dosing implications of the results.

Methods: A population exposure-response analysis was performed using nonlinear mixed-effects modelling. Data from 95 adult patients with benign thyroid disease were analysed.

Environmental and health hazards of military metal pollution.

An increasing body of literature has demonstrated that armed conflicts and military activity may contribute to environmental pollution with metals, although the existing data are inconsistent. Therefore, in this paper, we discuss potential sources of military-related metal emissions, environmental metal contamination, as well as routes of metal exposure and their health hazards in relation to military activities. Emission of metals into the environment upon military activity occurs from weapon residues containing high levels of particles containing lead (Pb; leaded ammunition), copper (Cu; unleaded), and depleted uranium (DU).

Chemical Characterization, Antioxidant and Antimicrobial Properties of Goji Berries Cultivated in Serbia.

Since the fruits of L. species (, goji berries) are promoted as a "superfood" with plenty of health benefits, there is extensive research interest in their nutritional and phytochemical composition. In the present study, the nutritional value, minerals, fatty acid composition, and bioactive compounds of L.

Synthesis, characterization, antimicrobial and cytotoxic activity of novel half-sandwich Ru(II) arene complexes with benzoylthiourea derivatives.

Three new ruthenium(II)-arene complexes, [Ru(η-p-cymene)(L)Cl] (C1) where L is N-((4 methoxyphenyl)carbamothioyl)benzamide; [Ru(η-p-cymene)(L)Cl] (C2) where L is 4-(3-benzoylthioureido)benzoic acid and [Ru(η-p-cymene)(L)Cl] (C3) where L is methyl 4-(3- benzoylthioureido)benzoate have been synthetized, characterized and evaluated for their antimicrobial and anticancer activity. Characterization was performed using H and C NMR, IR spectroscopy, mass spectrometry, electrical conductivity measurements and X-Ray diffraction analysis. X-Ray diffraction analysis of C1 showed typical expected "piano-stool" geometry with ruthenium coordinated to ligand via nitrogen and sulfur atoms of benzoylthiourea derivatives.

Biopharmaceutical characterization of rebamipide: The role of mucus binding in regional-dependent intestinal permeability.

In this study, we aimed to elucidate biopharmaceutical characteristics of the anti-ulcer drug rebamipide, with special emphasis on the influence of gastrointestinal (GI) mucus on rebamipide segmental-dependent permeability and absorption. Experimental studies and physiologically-based pharmacokinetic (GastroPlus) simulations were used to elucidate segmental-dependent absorption and pharmacokinetic (PK) profile, accounting for various drug properties, including solubility/dissolution limitations, regional-dependent drug affinity to mucus and membrane permeability, as well as physiological factors such as regional-pH differences along the intestine, thickness and types of mucus, transit time and surface areas. Low permeability and extensive binding to GI mucus were the key modeling features, and accounting for these resulted in good fitting between the predicted and in-vivo PK profiles, validating the ability of the model to pinpoint the underlying mechanisms of rebamipide limited oral bioavailability.

Impact of antipsychotic polypharmacy on nonadherence of oral antipsychotic drugs - A study based on blood sample analyses from 24,239 patients.

Nonadherence to oral antipsychotic drugs is a major issue in clinical psychiatry giving rise to treatment failure. Further, polypharmacy is common in the treatment of psychotic disorders due to insufficient treatment effect during monotherapy. As a potential circuit problem, we hypothesized that antipsychotic polypharmacy is associated with increased risk of nonadherence.