Biopharmaceutical Characterization and Stability of Nabumetone-Cyclodextrins Complexes Prepared by Grinding.

Nabumetone (NAB) is a poorly soluble nonsteroidal anti-inflammatory prodrug (BCS class II drug) whose solubility is significantly improved by complexation with cyclodextrins (CDs). : The solid complexes, in a 1:1 molar ratio, were prepared by mechanochemical activation by grinding, using β-cyclodextrin (β-CD) and its derivatives, hydroxypropyl- and sulfobutylether-β-cyclodextrin (HP-β-CD and SBE-β-CD). The complexation was confirmed by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and attenuated total reflectance Fourier-transformed infrared spectroscopy (ATR-FTIR).

Comparison of Orthogonal Determination Methods of Acid/Base Constants with Meta-Analysis.

The accurate determination of acid/base constants (proton dissociation constants-p, or equivalently protonation constants-log) is essential for the physicochemical characterization of new molecules, especially in drug design and development, as these parameters thoroughly influence the pharmacokinetics and pharmacodynamics of drug action. While pH/potentiometric titration remains the gold standard method for determining acid/base constants, spectroscopic techniques-particularly nuclear magnetic resonance spectroscopy (as NMR/pH titrations)-have emerged as powerful alternatives for specific challenges in analytical chemistry, providing also information on the structure and site of protonation. In this study, we performed a comprehensive meta-analysis of protonation constants reported in the literature, measured using both potentiometry and NMR titrations.

Detailed Studies on the Methoxylation and Subsequent Dealkylation of -Diethylbenzenesulfonamide Using a Tailor-Made Electrosynthetic Reactor.

Benzenesulfonamides are an outstandingly important family of compounds in organic and medicinal chemistry. Herein, we report detailed studies on the electrochemical mono- and dideethylation of model compound -diethylbenzenesulfonamide. In this context, all parameters of the electrosynthesis were systematically investigated, with a special emphasis on solvent screening and the effect of water on the outcome of the reaction.

TREMSUCS-TCGA - an integrated workflow for the identification of biomarkers for treatment success.

Many publicly available databases provide disease related data, that makes it possible to link genomic data to medical and meta-data. The cancer genome atlas (TCGA), for example, compiles tens of thousand of datasets covering a wide array of cancer types. Here we introduce an interactive and highly automatized TCGA-based workflow that links and analyses epigenomic and transcriptomic data with treatment and survival data in order to identify possible biomarkers that indicate treatment success.

Development of Innovative Electrospun Nepafenac-Loaded Nanofibers-based Ophthalmic Inserts.

Electrospun nanofibers can be utilized to develop patient-centric ophthalmic formulations with reasonable bioavailability at the targeted site. The current study aimed to develop 0.1% w/w of nepafenac-loaded electrospun nanofibrous webs as potential candidates for ocular delivery of nepafenac with improved solubility and stability.

Characterization of Opioid Agonist Morphine Derivatives with Emphasis on Medicinal Chemistry.

Relieving severe pains is an unmet medical need, in which opioids are of prime importance and in the focus of pharmaceutical companies. The objective of this study is to characterize the physicochemical properties, namely basicity, lipophilicity and permeability of thirty opioid ligands, which include eleven newly synthesized compounds. pH-potentiometry and the shake-flask method were used for the characterization of species-specific basicity and lipophilicity.

High-Throughput Drug Stability Assessment via Biomimetic Metalloporphyrin-Catalyzed Reactions Using Laser-Assisted Rapid Evaporative Ionization Mass Spectrometry (LA-REIMS).

Building extensive drug candidate libraries as early in the development pipeline as possible, with high-throughput in vitro absorption, distribution, metabolism, and excretion (ADME) profiling, is crucial for the selection of lead compounds to guide subsequent research and production phases. Traditionally, the analysis of metabolic stability assays heavily relies on high-throughput LC-MS/MS (liquid chromatography tandem mass spectrometry) techniques to meet with the lead profiling demands. Laser-assisted rapid evaporative ionization mass spectrometry (LA-REIMS) is a quick and efficient technique for characterizing complex biological samples without laborious sample preparation.

The effect of mucoadhesive polymers on ocular permeation of thermoresponsive in situ gel containing dexamethasone-cyclodextrin complex.

Dexamethasone (DXM) is a commonly used corticosteroid in the treatment of ocular inflammatory conditions that affect more and more people. The aim of this study was to evaluate the effect of the combination of hydroxypropyl-β-cyclodextrin (HPBCD), in situ gelling formulations, and other mucoadhesive polymers, i.e.

Mild Heat Stress Alters the Physical State and Structure of Membranes in Triacylglycerol-Deficient Fission Yeast, .

We investigated whether the elimination of two major enzymes responsible for triacylglycerol synthesis altered the structure and physical state of organelle membranes under mild heat shock conditions in the fission yeast, . Our study revealed that key intracellular membrane structures, lipid droplets, vacuoles, the mitochondrial network, and the cortical endoplasmic reticulum were all affected in mutant fission yeast cells under mild heat shock but not under normal growth conditions. We also obtained direct evidence that triacylglycerol-deficient cells were less capable than wild-type cells of adjusting their membrane physical properties during thermal stress.

Mild Hyperthermia-Induced Thermogenesis in the Endoplasmic Reticulum Defines Stress Response Mechanisms.

Previous studies reported that a mild, non-protein-denaturing, fever-like temperature increase induced the unfolded protein response (UPR) in mammalian cells. Our dSTORM super-resolution microscopy experiments revealed that the master regulator of the UPR, the IRE1 (inositol-requiring enzyme 1) protein, is clustered as a result of UPR activation in a human osteosarcoma cell line (U2OS) upon mild heat stress. Using ER thermo yellow, a temperature-sensitive fluorescent probe targeted to the endoplasmic reticulum (ER), we detected significant intracellular thermogenesis in mouse embryonic fibroblast (MEF) cells.

Molecular Mechanisms of the Impaired Heparin Pentasaccharide Interactions in 10 Antithrombin Heparin Binding Site Mutants Revealed by Enhanced Sampling Molecular Dynamics.

Antithrombin (AT) is a critical regulator of the coagulation cascade by inhibiting multiple coagulation factors including thrombin and FXa. Binding of heparinoids to this serpin enhances the inhibition considerably. Mutations located in the heparin binding site of AT result in thrombophilia in affected individuals.

Synthesis and medicinal chemical characterisation of antiproliferative ,-functionalised isopulegol derivatives.

Benzylation of isopulegol furnished -benzyl-protected isopulegol, which was transformed into aminodiols epoxidation followed by ring opening of the corresponding epoxides and subsequent hydrogenolysis. On the other hand, (-)-isopulegol was oxidised to a diol, which was then converted into dibenzyl-protected diol derivatives. The products were then transformed into aminotriols by using a similar method.

Mental health competencies are stronger determinants of well-being than mental disorder symptoms in both psychiatric and non-clinical samples.

The present study aimed to investigate whether the strength of mental health competencies and the severity of mental disorder symptoms, and their interaction, differ in the strength of their associations with several dimensions of well-being in Hungarian adult psychiatric and non-clinical samples. All respondent in the psychiatric sample (129 patients (44 male, 85 female)) and in the non-clinical community sample (253 adults (43 male, 210 female)) completed the Mental Health Test, six measures of well-being and mental health, and the Symptom Checklist-90-Revised. Including both mental health competencies and mental disorder symptoms in a regression model in both samples can predict patients' well-being even more accurately.

A Novel 2-Methoxyestradiol Derivative: Disrupting Mitosis Inhibiting Cell Motility and Inducing Apoptosis in HeLa Cells In Vitro.

The clinical application of 2-methoxyestradiol (2ME) in cancer therapy has been limited by its low solubility and rapid metabolism. Derivatives of 2ME have been synthesised to enhance bioavailability and decrease hepatic metabolism. Compound , an analog of 2ME, has demonstrated exceptional pharmacological activity, in addition to promising pharmacokinetic profile.

A journey to your self: The vague definition of immune self and its practical implications.

The identification of immunogenic peptides has become essential in an increasing number of fields in immunology, ranging from tumor immunotherapy to vaccine development. The nature of the adaptive immune response is shaped by the similarity between foreign and self-protein sequences, a concept extensively applied in numerous studies. Can we precisely define the degree of similarity to self? Furthermore, do we accurately define immune self? In the current work, we aim to unravel the conceptual and mechanistic vagueness hindering the assessment of self-similarity.

Immobilization of human tyrosine hydroxylase onto magnetic nanoparticles - A novel formulation of a therapeutic enzyme.

Human tyrosine hydroxylase (hTH) has key role in the production of catecholamine neurotransmitters. The structure, function and regulation of hTH has been extensively researched area and the possibility of enzyme replacement therapy (ERT) involving hTH through nanocarriers has been raised as well. However, our understanding on how hTH may interact with nanocarriers is still lacking.

Diterpenes Isolated from Three Different Species and Their Antiproliferative Activities against Gynecological and Glioblastoma Cancer Cells.

Fourteen diterpenes were isolated from methanol extracts of the aerial parts of, "Marginatus", and . The compounds belong to the abietane (-, -, and ), -clerodane (-), and -kaurane (, ) classes. Three new compounds were isolated from , including 3--acetylornatin G (), 3,12-di--acetylornatin G (), ornatin B methyl ester (), and ornatin F (), for which we proposed a revised structure.

Clinical and Molecular Characterization of Nine Novel Antithrombin Mutations.

Antithrombin (AT) is the major plasma inhibitor of thrombin (FIIa) and activated factor X (FXa), and antithrombin deficiency (ATD) is one of the most severe thrombophilic disorders. In this study, we identified nine novel AT mutations and investigated their genotype-phenotype correlations. Clinical and laboratory data from patients were collected, and the nine mutant AT proteins (p.

Preliminary validation of the Mental Health Test in a psychiatric sample.

To assist psychiatrists and clinical psychologists to assess their patients' psychological immune competence-based capacities and resources, depending on the mental health disorder diagnosis and the severity of the symptoms, the present study examined the psychometric properties of the Mental Health Test in a psychiatric sample. The research was carried out in four Hungarian healthcare facilities using a cross-sectional design. A total of 331 patients (140 male, 188 female, and 3 who preferred not to disclose their gender) completed the Mental Health Test, six well-being and mental health measures, and the Symptom Checklist-90.

A Comparative Pharmacokinetic Study for Cysteamine-Containing Eye Drops as an Orphan Topical Therapy in Cystinosis.

Cystinosis is a low-prevalence lysosomal storage disease. The pathomechanism involves abnormal functioning of the cystinosine lysosomal cystine transporter (CTNS), causing intraliposomal accumulation of the amino acid cysteine disulfide, which crystallizes and deposits in several parts of the body. The most common ophthalmic complication of cystinosis is the deposition of "gold dust" cystine crystals on the cornea, which already occurs in infancy and leads to severe photosensitivity and dry eyes as it gradually progresses with age.

Single-cell immunophenotyping revealed the association of CD4+ central and CD4+ effector memory T cells linking exacerbating chronic obstructive pulmonary disease and NSCLC.

Introduction: Tobacco smoking generates airway inflammation in chronic obstructive pulmonary disease (COPD), and its involvement in the development of lung cancer is still among the leading causes of early death. Therefore, we aimed to have a better understanding of the disbalance in immunoregulation in chronic inflammatory conditions in smoker subjects with stable COPD (stCOPD), exacerbating COPD (exCOPD), or non-small cell lung cancer (NSCLC).

Methods: Smoker controls without chronic illness were recruited as controls.

Lipid-Based Nanocarriers for Delivery of Neuroprotective Kynurenic Acid: Preparation, Characterization, and BBB Transport.

Encapsulation possibilities of an extensively investigated neuroprotective drug (kynurenic acid, KYNA) are studied via lipid-based nanocarriers to increase the blood-brain barrier (BBB) specific permeability. The outcomes of various preparation conditions such as stirring and sonication time, concentration of the lipid carriers and the drug, and the drug-to-lipid ratio are examined. Considering the experimentally determined encapsulation efficiency, hydrodynamic diameter, and ζ-potential values, the initial lipid and drug concentration as well as the stirring and sonication time of the preparation were optimized.

DIY Virtual Chemical Libraries - Novel Starting Points for Drug Discovery.

The advancement of technologies such as library enumeration and synthetic feasibility prediction has made drug discovery pipelines rely more and more on virtual libraries, which provide a significantly larger pool of compounds than in-stock supplier catalogs. Virtual libraries from external sources, however, may be associated with long delivery time and high cost. In this study, we present a Do-It-Yourself (DIY) combinatorial chemistry library containing over 14 million almost completely novel products built from 1000 low-cost building blocks based on robust reactions frequently applied at medicinal chemistry laboratories.

Medicinal-Chemistry-Driven Approach to 2-Substituted Benzoxazole-Estradiol Chimeras: Synthesis, Anticancer Activity, and Early ADME Profile.

The efficient synthesis of novel estradiol-based A-ring-fused oxazole derivatives, which can be considered as benzoxazole-steroid domain-integrated hybrids containing a common benzene structural motif, is described. The target compounds were prepared from steroidal 2-aminophenol precursors by heterocycle formation or functional group interconversion (FGI) strategies. According to 2D projection-based t-distributed stochastic neighbor embedding (t-SNE), the novel molecules were proved to represent a new chemical space among steroid drugs.