Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres.

Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of the tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using a telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using a cellular thermal shift assay. Our data showed that the compound induced aggregation of the catalytic subunit (hTERT) of human telomerase, and molecular studies confirmed the binding of the hit compound with the active site of the enzyme. The ability of new derivatives to activate DNA double-strand breaks (DSBs) was determined by high-resolution microscopy and flow cytometry in tumor cell lines differing in telomere elongation mechanism. The compounds triggered DSBs in TERT-positive A549 and H460 lung cancer cell lines, but not in TERT-negative NHBE normal human bronchial epithelial and ALT-positive U2OS osteosarcoma cell lines, which indicates that the induction of DSBs was dependent on telomerase inhibition. The observed DNA damage activated DNA damage response pathways involving ATM/Chk2 and ATR/Chk1 cascades. Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents.

Novel chalcone-derived pyrazoles as potential therapeutic agents for the treatment of non-small cell lung cancer.

Lung cancer is considered to account for approximately one-fifth of all malignant tumor-related deaths worldwide and is therefore one of the most lethal malignancies. Pyrazole scaffold possesses a wide range of biological and pharmacological activities, which play important roles in medicinal chemistry. The present study reports the synthesis and in vitro biological characterization of nine pyrazoles derived from chalcones as potential anticancer agents for non-small cell lung cancer A-549, H226, and H460 cell lines. Most of the compounds efficiently inhibited the growth of all the tested cancer cell lines at micromolar concentrations. One of the most active compounds (PCH-1) was further evaluated for its effect on cell cycle distribution, apoptosis, migration, epithelial-mesenchymal transition, and oxidative stress. Furthermore, studies on the mechanism of action revealed that PCH-1 disrupts microtubule assembly, leading to cancer cell death. Molecular modeling studies confirmed the potent interaction of PCH-1 with the vinblastine binding site on tubulin. Overall, this study provides novel opportunities to identify anticancer agents in the pyrazole series.

Molecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump EmrE.

The current surge in bacterial multi-drug resistance (MDR) is one of the largest challenges to public health, threatening to render ineffective many therapies we rely on for treatment of serious infections. Understanding different factors that contribute to MDR is hence crucial from the global "one health" perspective. In this contribution, we focus on the prototypical broad-selectivity proton-coupled antiporter EmrE, one of the smallest known ligand transporters that confers resistance to aromatic cations in a number of clinically relevant species. As an asymmetric homodimer undergoing an "alternating access" protomer-swap conformational change, it serves as a model for the mechanistic understanding of more complex drug transporters. Here, we present a free energy and solvent accessibility analysis that indicates the presence of two complementary ligand translocation pathways that remain operative in a broad range of conditions. Our simulations show a previously undescribed desolvated apo state and anticorrelated accessibility in the ligand-bound state, explaining on a structural level why EmrE does not disrupt the pH gradient through futile proton transfer. By comparing the behavior of a number of model charged and/or aromatic ligands, we also explain the origin of selectivity of EmrE towards a broad class of aromatic cations. Finally, we explore unbiased pathways of ligand entry and exit to identify correlated structural changes implicated in ligand binding and release, as well as characterize key intermediates of occupancy changes.

Quest for the Molecular Basis of Improved Selective Toxicity of All-Trans Isomers of Aromatic Heptaene Macrolide Antifungal Antibiotics.

Three aromatic heptaene macrolide antifungal antibiotics, Candicidin D, Partricin A (Gedamycin) and Partricin B (Vacidin) were subjected to controlled cis-trans→ all trans photochemical isomerization. The obtained all-trans isomers demonstrated substantially improved in vitro selective toxicity in the Candida albicans cells: human erythrocytes model. This effect was mainly due to the diminished hemotoxicity. The molecular modeling studies on interactions between original antibiotics and their photoisomers with ergosterol and cholesterol revealed some difference in free energy profiles of formation of binary antibiotic/sterol complexes in respective membrane environments. Moreover, different geometries of heptaene: sterol complexes and variations in polyene macrolide molecule alignment in cholesterol-and ergosterol-containing membranes were found. None of these effects are of the crucial importance for the observed improvement of selective toxicity of aromatic heptaene antifungals but each seems to provide a partial contribution.

The impact of long-term changes in air temperature on renewable energy in Poland.

PURPOSE: This paper analysed from the statistical point of view the trends in observed air temperature in major Polish cities and presented a qualitative analysis of their potential impact on the operation of the selected renewable energy sources. It also reviews the relation between the air temperature and observed electrical load as well as changing numbers of cooling and heating degree days. The method involved a statistical analysis of historical mean daily temperature observed in 19 major Polish cities over the 1968-2018 period. The air temperature change impact on renewable energy sector in Poland, by affecting the heating and cooling demand, the electrical load and the renewables working conditions both, on supply and demand side. The analysis reports that the mean daily temperature in all major polish cities is exhibiting a statistically significant increasing trend, up to 0.52 °C/decade. The observed increase in air temperature reduces the heating demand in Poland, beneficially for the environment and renewable supply. Increasing cooling needs in summer raises the energy consumption and indoor thermal stress. The climate warming affects the operation conditions, energy source, driving force, capacity and efficiency of renewable energy sources. The investigated changes were favourable and unfavourable depending on the renewable technology and operation mode, and were stronger on the demand side than on the supply side.

Spatial representation of temporal complementarity between three variable energy sources using correlation coefficients and compromise programming.

Renewable energy sources have shown remarkable growth in recent times in terms of their contribution to sustainable societies. However, integrating them into the national power grids is usually hindered because of their weather-dependent nature and variability. The combination of different sources to profit from their beneficial complementarity has often been proposed as a partial solution to overcome these issues. Thus, efficient planning for optimizing the exploitation of these energy resources requires different types of decision support tools. A mathematical index for assessing energetic complementarity between multiple energy sources constitutes an important tool for this purpose, allowing a comparison of complementarity between existing facilities at different planning stages and also allowing a dynamic assessment of complementarity between variable energy sources throughout the operation, assisting in the dispatch of power supplies. This article presents a method for quantifying and spatially representing the total temporal energetic complementarity between three different variable renewable sources, through an index created from correlation coefficients and compromise programming. The method is employed to study the complementarity of wind speed, solar radiation and surface runoff on a monthly scale using continental Colombia as a case study during the year of 2015.•This paper describes a method for quantifying and spatially representing energetic complementarity between three renewable energy sources.•The method quantifies energetic complementarity by combining known metrics: correlations and compromise programming.•The proposed index for energetic complementarity assessment is sensitive to the time scale adopted.