N-Glycoside of Indolo[2,3-]pyrrolo[3,4-]carbazole LCS1269 Exerts Anti-Glioblastoma Effects by G2 Cell Cycle Arrest and CDK1 Activity Modulation: Molecular Docking Studies, Biological Investigations, and ADMET Prediction.

Indolo[2,3-]pyrrolo[3,4-]carbazole scaffold is successfully used as an efficient structural motif for the design and development of different antitumor agents. In this study, we investigated the anti-glioblastoma therapeutic potential of glycosylated indolocarbazole analog LCS1269 utilizing in vitro, in vivo, and in silico approaches. Cell viability was estimated by an MTT assay.

Effect of HS and cysteine homeostasis disturbance on ciprofloxacin sensitivity of Escherichia coli in cystine-free and cystine-fed minimal medium.

Endogenous HS has been proposed to be a universal defense mechanism against different antibiotics. Here, we studied the role of HS transiently generated during ciprofloxacin (CF) treatment in M9 minimal medium with sulfate or produced by E. coli when fed with cystine.

Antimicrobial and Antioxidant Activity of Some Nitrogen-Containing Heterocycles and Their Acyclic Analogues.

We investigated antimicrobial and antioxidant activity of nitrogen-containing heterocycles and their acyclic analogues, some of which can be considered as promising in terms of biological activity. Based on structure, 26 tested compounds were divided into 4 groups. In the test with 2,2-diphenyl-1-picrylhydrazyl (DPPH), the compounds of the group 2 had the highest radical-binding activity (RBA) (53-78%), while those of group 3 had the lowest values (1.

Regulation of Cysteine Homeostasis and Its Effect on Sensitivity to Ciprofloxacin in LB Medium.

Cysteine and its derivatives, including HS, can influence bacterial virulence and sensitivity to antibiotics. In minimal sulfate media, HS is generated under stress to prevent excess cysteine and, together with incorporation into glutathione and export into the medium, is a mechanism of cysteine homeostasis. Here, we studied the features of cysteine homeostasis in LB medium, where the main source of sulfur is cystine, whose import can create excess cysteine inside cells.

Phosphate starvation is accompanied by disturbance of intracellular cysteine homeostasis in Escherichia coli.

Metabolic rearrangements that occur during depletion of essential nutrients can lead to accumulation of potentially dangerous metabolites. Here we showed that depletion of phosphate (P), accompanied by a sharp inhibition of growth and respiration, caused a transient excess of intracellular cysteine due to a decrease in the rate of protein synthesis. High cysteine level can be dangerous due to its ability to produce ROS and reduce Fe to Fenton-reactive Fe.

Influence of Growth Medium Composition on Physiological Responses of to the Action of Chloramphenicol and Ciprofloxacin.

The ability of hydrogen sulfide (HS) to protect bacteria from bactericidal antibiotics has previously been described. The main source of HS is the desulfurization of cysteine, which is either synthesized by cells from sulfate or transported from the medium, depending on its composition. Applying electrochemical sensors and a complex of biochemical and microbiological methods, changes in growth, respiration, membrane potential, SOS response, HS production and bacterial survival under the action of bactericidal ciprofloxacin and bacteriostatic chloramphenicol in commonly used media were studied.

Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate.

Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells.

A novel glycosylated indolocarbazole derivative LCS1269 effectively inhibits growth of human cancer cells in vitro and in vivo through driving of both apoptosis and senescence by inducing of DNA damage and modulating of AKT/mTOR/S6K and ERK pathways.

In recent decades, indolocarbazole glycosides containing sugar moieties have attracted attention due to their diverse anti-tumor activities. In the present study, a series of new indolo [2,3-a]pyrrolo [3,4-c]carbazole derivatives were synthesized for the first time. First of all, we have shown that compound 6e (LCS1269) had the most pronounced effect on inhibiting tumor growth in the transferable solid and non-solid murine tumors as compared with other synthesized indolocarbazole derivatives.

Study of the early response of Escherichia coli lpcA and ompF mutants to ciprofloxacin.

In most previous studies the sensitivity of Escherichia coli outer membrane mutants to ciprofloxacin (CF) was studied by MIC method. In the present work, the early response of these mutants to CF was studied using physiological and biochemical methods and electrochemical sensors. The use of sensors made it possible to monitor dissolved oxygen, potassium and extracellular sulfide continuously directly in growing cultures in real time.

Study of the contribution of active defense mechanisms to ciprofloxacin tolerance in Escherichia coli growing at different rates.

Using rpoS, tolC, ompF, and recA knockouts, we investigated their effect on the physiological response and lethality of ciprofloxacin in E. coli growing at different rates on glucose, succinate or acetate. We have shown that, regardless of the strain, the degree of changes in respiration, membrane potential, NAD/NADH ratio, ATP and glutathione (GSH) strongly depends on the initial growth rate and the degree of its inhibition.

Study of antioxidant activity of fodder grasses using microbial test systems.

Aim: To measure the biological activities of extracts of fodder grasses Onobrýchis arenária, Galéga orientális and Rhaponticum carthamoides that are commonly planted in Europe, Middle East and eastern Africa.

Methods And Results: Microbial test-systems based on Escherichia coli BW25113 that allow measurement of gene expression, growth and survival, biofilm formation (BF) in combination with the standard chemical procedures were used. The extracts studied had radical scavenging and metal-chelating activities and induced expression of antioxidant genes via generation of hydrogen peroxide.

Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate.

Prostate cancer is the second most common type of cancer among men. Its main method of treatment is chemotherapy, which has a wide range of side effects. One of the solutions to this challenge is targeted delivery to prostate cancer cells.

PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation.

Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out the selection of ligands for the creation of conjugates based on the drug docetaxel and synthesized a series of three docetaxel conjugates.

Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them.

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is a suitable target for specific delivery of antitumor drugs and diagnostic agents due to its overexpression in prostate cancer cells. In the current work, we describe the design, synthesis, and biological evaluation of novel low-molecular PSMA ligands and conjugates with fluorescent dyes FAM-5, SulfoCy5, and SulfoCy7. evaluation of synthesized PSMA ligands on the activity of PSMA shows that the addition of aromatic amino acids into a linker structure leads to a significant increase in inhibition.

Pharmacophore hybridization approach to discover novel pyrazoline-based hydantoin analogs with anti-tumor efficacy.

In search for new and safer anti-cancer agents, a structurally guided pharmacophore hybridization strategy of two privileged scaffolds, namely diaryl pyrazolines and imidazolidine-2,4-dione (hydantoin), was adopted resulting in a newfangled series of compounds (H1-H22). Herein, a bio-isosteric replacement of "pyrrolidine-2,5-dione" moiety of our recently reported antitumor hybrid incorporating diaryl pyrazoline and pyrrolidine-2,5-dione scaffolds with "imidazoline-2,4-dione" moiety has been incorporated. Complete biological studies revealed the most potent analog among all i.

Effect of resveratrol and quercetin on the susceptibility of Escherichia coli to antibiotics.

Activities of plant polyphenols (PPs), resveratrol and quercetin, alone or in combination with four conventional antibiotics against Escherichia coli have been investigated. In medium without antibiotics, both polyphenols caused a dose-dependent growth inhibition. However, pretreatment with resveratrol (40 and 100 μg ml) and quercetin (40 μg ml) reduced the bacteriostatic effect of kanamycin, streptomycin, cefotaxime and partially of ciprofloxacin.

Study of the relationship between extracellular superoxide and glutathione production in batch cultures of Escherichia coli.

Aerobically growing Escherichia coli generates superoxide flux into the periplasm via the oxidation of dihydromenaquinone and simultaneously carries out continuous transmembrane cycling of glutathione (GSH). Here we have shown that, under the conditions of a gradual decrease in dissolved oxygen (dO), characteristic of batch culture, the global regulatory system ArcB/ArcA can play an important role in the coordinated control of extracellular superoxide and GSH fluxes and their interaction with intracellular antioxidant systems. The lowest superoxide production was observed in the menA and arcB mutants, while the atpA, atpC and atpE mutants generated superoxide 1.

Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine-2,5-dione Hybrids as Potential Antitumor Agents.

In search of novel and effective antitumor agents, pyrazoline-substituted pyrrolidine-2,5-dione hybrids were designed, synthesized and evaluated in silico, in vitro and in vivo for anticancer efficacy. All the compounds exhibited remarkable cytotoxic effects in MCF7 and HT29 cells. The excellent antiproliferative activity toward MCF7 (IC =0.

Tannic and gallic acids alter redox-parameters of the medium and modulate biofilm formation.

Tannic (TA) and gallic (GA) acids are known to have both anti- and prooxidant properties however recently they have been described as potential anti-biofilm agents although their mechanisms of action on bacterial cells remain obscure. The aim of our research was to elucidate the role of prooxidant actions of these plant phenolic compounds in bactericidal effects and biofilm formation. In our experiments, both compounds demonstrated strong oxidative properties that altered activity of stress regulons and contributed to decrease of CFU and ability of cells to maintain membrane potential.

Cysteine homeostasis under inhibition of protein synthesis in Escherichia coli cells.

Increased intracellular cysteine poses a potential danger to cells due to the high ability of cysteine to reduce free iron and promote the Fenton reaction. Here, we studied ways to maintain cysteine homeostasis in E. coli cells while inhibiting protein synthesis with valine or chloramphenicol.

The sharp phase of respiratory inhibition during amino acid starvation in Escherichia coli is RelA-dependent and associated with regulation of ATP synthase activity.

Amino acid starvation causes an RelA-dependent increase in the regulatory nucleotide (p)ppGpp that leads to pleiotropic changes in Escherichia coli metabolism, but the role of (p)ppGpp in regulation of respiration remains unclear. Here we demonstrate that amino acid starvation is accompanied by sharp RelA-dependent inhibition of respiration. The sharp phase of inhibition is absent in relA mutants, and can be prevented by translation inhibitors chloramphenicol and tetracycline, which abolish accumulation of (p)ppGpp.

The role of sulfides in stress-induced changes of Eh in Escherichia coli cultures.

Real-time monitoring of the state of bacterial cultures is important in both experiment and biotechnology. Using Eh and sulfide sensors, we demonstrated that the abrupt reversible reduction in Eh (Eh jump), occurring during transition of E. coli from exponential growth to starvation and antibiotic-induced stresses, is the result of sulfide excretion from the cells.

Relationship between Escherichia coli growth rate and bacterial susceptibility to ciprofloxacin.

The effect of Escherichia coli growth rate on its susceptibility to ciprofloxacin was investigated using bacteria grown on different carbon sources and harboring mutations in genes encoding tricarboxylic acid cycle enzymes. A 1-h treatment of the wild type (wt) grown on glucose, succinate, malate, α-ketoglutarate or acetate with 0.3 μg ml-1 ciprofloxacin decreased the number of surviving cells (CFU ml-1), 560, 110, 74, 62 and 5 times, respectively.