Explore the vast range of titles available.

In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms.

Antioxidant activity of a pharmaceutical substance hypocard was compared with activity of nitromalic acid and well-known agents nicorandil and Mexidol. The ability of these substances to inhibit spontaneous and oxidant-induced LPO process in rat brain homogenate was analyzed. The mechanisms of these effects were studied. The antioxidant properties of hypocard manifested in the inhibition of Fe(II)-induced LPO were significantly more pronounced in comparison with Mexidol and nicorandil.

Iron-chelating activity of synthesized spirocyclic hydroxamic acids, their toxicity, and effects on mitochondrial function were studied using primary culture of cerebral cortical neurons from newborn rats. All tested compounds effectively chelated Fe(II) ions. Activity of spirocyclic hydroxamic acids more strictly depended on the structure their piperidine, but not imidazolidine fragment. All compounds were non-toxic for normal neuronal culture.

We performed screening of potential antioxidants among natural lactone and alkaloid derivatives and characterized their antioxidant effects. The substances exhibiting antioxidant and metal-chelating potential, in particular, tryptamine derivatives, are promising neuroprotector agents.

Analysis of antioxidant activity of synthesized selenourea derivatives showed that N,N’-substituted selenoureas inhibited Fe(III)-induced LPO in rat brain homogenate. On the other hand, oxygen- and sulfur-containing analogs exhibited no antioxidant activity or even slight prooxidant activity. Intramolecular alkylation of selenium atom also led to loss of antioxidant activity. Thus, antioxidant activity of the compounds was due to the presence of a nonalkylated selenium atom in N,N’-substituted selenourea analogs.

New 4-hydroxycoumarins and coumestans with tert -butyl and isobornyl substituents were synthesized. The cytotoxic profile and the antioxidant status of the synthesized compounds were assessed using in vitro models. The promise of the coumestans studied as potential antitumor agents is demonstrated. A possible mechanism of the action of the title compounds is associated with the antioxidant activity expressed in the ability to inhibit the process of lipid peroxidation and with the direct antiradical activity in the ORAC and DPPH assays.

A simple method for modifying sesquiterpene lactones with 3,5-bis(arylidene)piperi-din-4-ones using the phase-transfer catalytic aza-Michael addition in the MeCN—K 2 CO 3 system was developed. Molecular docking revealed that the synthesized conjugates of isoalantolactone, alantolactone, and dehydrocostus lactone with various bis(arylidene)-piperidones directly interact with the DNA binding site of the p50 subunit of nuclear factor κB, which may be indicative of their ability to induce apoptotic death of the tumor cells due to activation of the death receptor expression and, thereby, to exhibit an antitumor effect.

Human pluripotent stem cells (hPSCs) have the potential to differentiate into all cell types, a property known as pluripotency. A deeper understanding of how pluripotency is regulated is required to assist in controlling pluripotency and differentiation trajectories experimentally. Mathematical modelling provides a non-invasive tool through which to explore, characterise and replicate the regulation of pluripotency and the consequences on cell fate. Here we use experimental data of the expression of the pluripotency transcription factor OCT4 in a growing hPSC colony to develop and evaluate mathematical models for temporal pluripotency regulation. We consider fractional Brownian motion and the stochastic logistic equation and explore the effects of both additive and multiplicative noise. We illustrate the use of time-dependent carrying capacities and the introduction of Allee effects to the stochastic logistic equation to describe cell differentiation. We conclude both methods adequately capture the decline in OCT4 upon differentiation, but the Allee effect model has the advantage of allowing differentiation to occur stochastically in a sub-set of cells. This mathematical framework for describing intra-cellular OCT4 regulation can be extended to other transcription factors and developed into predictive models.

Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) have promising clinical applications which often rely on clonally-homogeneous cell populations. To achieve this, it is important to ensure that each colony originates from a single founding cell and to avoid subsequent merging of colonies during their growth. Clonal homogeneity can be obtained with low seeding densities; however, this leads to low yield and viability. It is therefore important to quantitatively assess how seeding density affects clonality loss so that experimental protocols can be optimised to meet the required standards. Here we develop a quantitative framework for modelling the growth of hESC colonies from a given seeding density based on stochastic exponential growth. This allows us to identify the timescales for colony merges and over which colony size no longer predicts the number of founding cells. We demonstrate the success of our model by applying it to our own experiments of hESC colony growth; while this is based on a particular experimental set-up, the model can be applied more generally to other cell lines and experimental conditions to predict these important timescales.

Osteoporosis is a multifactorial disease, the pathogenesis of which is caused by a complex interaction of genetic, hormonal, and metabolic factors. The challenges of early diagnosis highlight the need to identify genetic predictors to prevent bone mineral density (BMD) loss. Given the critical role of G-protein-coupled receptors (GPCRs) in bone development and remodeling, we investigated osteoporosis-associated single-nucleotide polymorphisms (SNPs) within GPCR genes using next-generation sequencing of patient cohorts. Subsequent screening via Sanger sequencing identified three SNPs for further analysis: rs1991517 in the thyroid-stimulating hormone receptor gene (TSHR), rs6166 in the follicle-stimulating hormone receptor gene (FSHR), and rs1042713 in the β2-adrenergic receptor gene (ADRB2). Our results reveal a significant association between osteoporosis and a specific homozygous genotype combination (TSHR rs1991517 CC, FSHR rs6166 AA, and ADRB2 rs1042713 AA). The functional impairment in osteodifferentiation was further validated in patient-derived cell lines harboring this triple-SNP combination. Thus, this study is the first to identify a specific combination of GPCR gene polymorphisms that may serve as a predictive biomarker for osteoporosis in early genetic screening.