Novel Semisynthetic Derivatives of Bile Acids as Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibitors.

An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC50 up to 0.29 µM. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdp1 enzyme

Analysing Dynamical Behavior of Cellular Networks via Stochastic Bifurcations

The dynamical structure of genetic networks determines the occurrence of various biological mechanisms, such as cellular differentiation. However, the question of how cellular diversity evolves in relation to the inherent stochasticity and intercellular communication remains still to be understood. Here, we define a concept of stochastic bifurcations suitable to investigate the dynamical structure of genetic networks, and show that under stochastic influence, the expression of given proteins of interest is defined via the probability distribution of the phase variable, representing one of the genes constituting the system. Moreover, we show that under changing stochastic conditions, the probabilities of expressing certain concentration values are different, leading to different functionality of the cells, and thus to differentiation of the cells in the various types

Interaction of Copper-Based Nanoparticles to Soil, Terrestrial, and Aquatic Systems: Critical Review of the State of the Science and Future Perspectives

In the past two decades, increased production and usage of metallic nanoparticles (NPs) has inevitably increased their discharge into the different compartments of the environment, which ultimately paved the way for their uptake and accumulation in various trophic levels of the food chain. Due to these issues, several questions have been raised on the usage of NPs in everyday life and has become a matter of public health concern. Among the metallic NPs, Cu-based NPs have gained popularity due to their cost-effectiveness and multifarious promising uses. Several studies in the past represented the phytotoxicity of Cu-based NPs on plants. However, comprehensive knowledge is still lacking. Additionally, the impact of Cu-based NPs on soil organisms such as agriculturally important microbes, fungi, mycorrhiza, nematode, and earthworms are poorly studied. This review article critically analyses the literature data to achieve a more comprehensive knowledge on the toxicological profile of Cu-based NPs and increase our understanding of the effects of Cu-based NPs on aquatic and terrestrial plants as well as on soil microbial communities. The underlying mechanism of biotransformation of Cu-based NPs and the process of their penetration into plants has also been discussed herein. Overall, this review could provide valuable information to design rules and regulations for the safe disposal of Cu-based NPs into a sustainable environment

Recent origin of the methacrylate redox system in geobacter sulfurreducens AM-1 through horizontal gene transfer

The origin and evolution of novel biochemical functions remains one of the key questions in molecular evolution. We study recently emerged methacrylate reductase function that is thought to have emerged in the last century and reported in Geobacter sulfurreducens strain AM-1. We report the sequence and study the evolution of the operon coding for the flavin-containing methacrylate reductase (Mrd) and tetraheme cytochrome с (Mcc) in the genome of G. sulfurreducens AM-1. Different types of signal peptides in functionally interlinked proteins Mrd and Mcc suggest a possible complex mechanism of biogenesis for chromoproteids of the methacrylate redox system. The homologs of the Mrd and Mcc sequence found in δ-Proteobacteria and Deferribacteres are also organized into an operon and their phylogenetic distribution suggested that these two genes tend to be horizontally transferred together. Specifically, the mrd and mcc genes from G. sulfurreducens AM-1 are not monophyletic with any of the homologs found in other Geobacter genomes. The acquisition of methacrylate reductase function by G. sulfurreducens AM-1 appears linked to a horizontal gene transfer event. However, the new function of the products of mrd and mcc may have evolved either prior or subsequent to their acquisition by G. sulfurreducens AM-1.The work has been supported by a grant of the HHMI International Early Career Scientist Program (55007424), the Spanish Ministry of Economy and Competitiveness (EUI-EURYIP-2011-4320) as part of the EMBO YIP program, two grants from the Spanish Ministry of Economy and Competitiveness, "Centro de Excelencia Severo Ochoa 2013–2017 (Sev-2012-0208)" and (BFU2012-31329), the European Union and the European Research Council under grant agreement/n335980_EinME

Enhanced Incentive Motivation for Sucrose-Paired Cues in Adolescent Rats: Possible Roles for Dopamine and Opioid Systems

Vulnerability to the effects of drugs of abuse during adolescence may be related to altered incentive motivation, a process believed to be important in addiction. Incentive motivation can be seen when a neutral stimulus acquires motivational properties through repeated association with a primary reinforcer. We compared adolescent (postnatal day (PND) 24–50) and adult (>PND 70) rats on a measure of incentive motivation: responding for a conditioned reinforcer (CR). Rats learned to associate the delivery of 0.1 ml of 10% sucrose with a conditioned stimulus (CS; light and tone); 30 pairings per day were given over 14 days. Then, we measured responding on a lever delivering the CS (now a CR) after injections of amphetamine (0, 0.25 or 0.5 mg/kg). We also examined responding for CR when the CS and sucrose were paired or unpaired during conditioning, and responding for the primary reinforcer (10% sucrose) in control experiments. Finally, we examined the effects of D1 and D2 dopamine receptor antagonists (SCH 39166 and eticlopride, respectively) and an opioid receptor antagonist (naltrexone) on responding for a CR in adolescent rats. Adolescents but not adults acquired responding for a CR, but adolescents responded less than adults for the primary reinforcer. Responding for a CR depended upon the pairing of the CS and sucrose during conditioning. Both dopamine and opioid receptor antagonists reduced responding for the CR. Therefore, incentive motivation may be enhanced in adolescents compared with adults, and incentive motivation may be mediated in part by both dopamine and opioid systems