imagine (Institute of molecular genetics and genetic engineering)
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Benzimidazole-based dual dipeptidyl peptidase-4 and xanthine oxidase inhibitors
No full textMultiple-targeting compounds might reduce complex polypharmacy of multifactorial diseases, such as diabetes, and contribute to the greater therapeutic success. Targeting reactive oxygen species-producing enzymes, as xanthine oxidase (XO), might suppress progression of diabetes-associated vascular complications. In this study a small series of benzimidazole derivatives (1-9) was evaluated for inhibitory activity against dipeptidyl peptidase-4 (DPP-4) and XO. One 1,3-disubstituted-benzimidazole-2-imine (5) and 1,3-thiazolo [3,2-a] benzimidazolone derivative (8) were shown as effective dual DPP-4 and XO inhibitors, with IC50 values lower than 200 mu M, and predicted binding modes with both target enzymes. Both selected dual inhibitors (compounds 5 and 8) did not show cytotoxicity to a greater extent on Caco-2 cells even at concentration of 250 mu M. These structures represent new non-purine scaffolds bearing two therapeutic functionalities, being DPP-4 and XO inhibitors, more favorable in comparison to DPP-4 inhibitors with DPP-4 as a single target due to pleiotropic effects of XO inhibition.This is the peer-reviewed version of the article: Tomović, K.; Ilić, B. S.; Smelcerović, Z.; Miljković, M.; Yancheva, D.; Kojić, M.; Mavrova, A. T.; Kocić, G.; Smelcerović, A. Benzimidazole-Based Dual Dipeptidyl Peptidase-4 and Xanthine Oxidase Inhibitors. Chemico-Biological Interactions 2020, 315. [https://doi.org/10.1016/j.cbi.2019.108873].Published version: [https://imagine.imgge.bg.ac.rs/handle/123456789/1376
Dinuclear silver(I) complexes with a pyridine-based macrocyclic type of ligand as antimicrobial agents against clinically relevant species: the influence of the counteranion on the structure diversification of the complexes
No full textNew dinuclear silver(i) complexes withN,N ',N '',N '''-tetrakis(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane (tpmc), [Ag-2(NO3)(tpmc)]NO3 center dot 1.7H(2)O (1), [Ag-2(CF3SO3)(2)(tpmc)] (2), and [Ag-2(tpmc)](BF4)(2) (3) were synthesized and characterized by NMR (H-1 and(13)C), IR and UV- Vis spectroscopy, cyclic voltammetry and molar conductivity measurements. The molecular structures of the complexes were determined by single-crystal X-ray diffraction analysis. The spectroscopic and crystallographic data showed that the structure of the complexes strongly depends on the nature of the counteranion of silver(i) salt used for their synthesis. The antimicrobial activity of complexes1-3was examined against Gram-positive and Gram-negative bacteria and different species of unicellular fungus Candida spp. The ability of these complexes to inhibit the formation of Candida biofilms and to eradicate the already formed biofilms was tested in the standard microtiter plate-based assay. In addition, a bioelectrochemical testing of the antimicrobial activity of complex 1 against early biofilm was also performed. The obtained results indicated that complexes 1-3 showed increased activity toward Gram-negative bacteria and Candida spp. and could inhibit the formation of biofilms. In most cases, these complexes had positive selectivity indices and showed similar or even better activity with respect to the clinically used silver(i) sulfadiazine (AgSD). The values of the binding constants for complexes 1-3 to bovine serum albumin (BSA) were found to be high enough to indicate their binding to this biomolecule, but not so high as to prevent their release upon arrival at the target site. Moreover, the positive values of partition coefficients for these complexes indicated their ability to be transported through the cell membrane. Once inside the cell, complexes 1-3 could induce the formation of the reactive oxygen species (ROS) in C. albicanscells and/or interact with DNA. Taken together, silver(i) complexes with the tpmc ligand could be considered as novel antimicrobial compounds with favourable pharmacological properties, being safer than AgSD
In vitro assessment of pesticide residues bioaccessibility in conventionally grown blueberries as affected by complex food matrix
No full textThe aim of this study was to investigate the bioaccessibility of pesticide residues in blueberries (com-mercial and sample from controlled field trial) from Serbia, involving the presence of a complex food matrix and to assess the potential risk to human health. The presence of nine active substances (azox-ystrobin, boscalid, fludioxonil, cyprodinil, pyrimethanil, pyridaben, pyriproxyfen, acetamiprid and thia-metoxam) in initial blueberry samples was determined in concentration range from 5.15 mu g/kg for thiametoxam to 187 mu g/kg for azoxystrobin. Clothianidin, metabolite of thiametoxam, was not detected in any blueberry sample. However, after in vitro digestion, the content of initially detected pesticides residues was significantly decreased or it was below limit of quantification resulting in the total bio-accessibility of about 15%. Azoxystrobin, pyrimethanil and fludioxonil was quantified in digestive juice at concentrations which were about 81%, 37% and 10% less than the inital concentration, respectively. The presence of food matrix during digestion of blueberries even more severely reduced concentration of pesticide residues (total bioaccessibility was about 7%) compared to digestion without the food matrix. Only azoxystrobin was quantified after digestion with food matrix in concentration of 27 mu g/kg in sample from controlled field trial and detected in two commercial samples but below the limit of quantification. Furthermore, chronic risk assessment indicated that risk is acceptable for the health of different human subpopulation groups. The current study on pesticides residues, most commonly applied on blueberries, provides for the first time an insight into their bioaccessibility under conditions that mimic physiological environment of human digestive tract
Anti-Virulence Potential and In Vivo Toxicity of Persicaria maculosa and Bistorta officinalis Extracts
Get PDFMany traditional remedies represent potential candidates for integration with modern medical practice, but credible data on their activities are often scarce. For the first time, the anti-virulence potential and the safety for human use of the ethanol extracts of two medicinal plants, Persicaria maculosa (PEM) and Bistorta officinalis (BIO), have been addressed. Ethanol extracts of both plants exhibited anti-virulence activity against the medically important opportunistic pathogen Pseudomonas aeruginosa. At the subinhibitory concentration of 50 mu g/mL, the extracts demonstrated a maximal inhibitory effect (approx. 50%) against biofilm formation, the highest reduction of pyocyanin production (47% for PEM and 59% for BIO) and completely halted the swarming motility of P. aeruginosa. Both extracts demonstrated better anti-quorum sensing and antibiofilm activities, and a better ability to interfere with LasR receptor, than the tested dominant extracts' constituents. The bioactive concentrations of the extracts were not toxic in the zebrafish model system. This study represents an initial step towards the integration of P. maculosa and B. officinalis for use in the treatment of Pseudomonas infections
Complete mitogenome data for the Serbian population: the contribution to high-quality forensic databases
No full textMitochondrial genome (mtDNA) is a valuable resource in resolving various human forensic casework. The usage of variability of complete mtDNA genomes increases their discriminatory power to the maximum and enables ultimate resolution of distinct maternal lineages. However, their wider employment in forensic casework is nowadays limited by the lack of appropriate reference database. In order to fill in the gap in the reference data, which, considering Slavic-speaking populations, currently comprises only mitogenomes of East and West Slavs, we present mitogenome data for 226 Serbians, representatives of South Slavs from the Balkan Peninsula. We found 143 (sub)haplogroups among which West Eurasian ones were dominant. The percentage of unique haplotypes was 85%, and the random match probability was as low as 0.53%. We support previous findings on both high levels of genetic diversity in the Serbian population and patterns of genetic differentiation among this and ten studied European populations. However, our high-resolution data supported more pronounced genetic differentiation among Serbians and two Slavic populations (Russians and Poles) as well as expansion of the Serbian population after the Last Glacial Maximum and during the Migration period (fourth to ninth century A.D.), as inferred from the Bayesian skyline analysis. Phylogenetic analysis of haplotypes found in Serbians contributed towards the improvement of the worldwide mtDNA phylogeny, which is essential for the interpretation of the mtDNA casework
Proteomic profile of extracellular vesicles released by Lactiplantibacillus plantarum BGAN8 and their internalization by non-polarized HT29 cell line
Get PDFIn recent years the role of extracellular vesicles (EVs) of Gram-positive bacteria in host-microbe cross-talk has become increasingly appreciated, although the knowledge of their biogenesis, release and host-uptake is still limited. The aim of this study was to characterize the EVs released by the dairy isolate Lactiplantibacillus plantarum BGAN8 and to gain an insight into the putative mechanism of EVs uptake by intestinal epithelial cells. The cryo-TEM observation undoubtedly demonstrated the release of EVs (20 to 140 nm) from the surface of BGAN8, with exopolysaccharides seems to be part of EVs surface. The proteomic analysis revealed that the EVs are enriched in enzymes involved in central metabolic pathways, such as glycolysis, and in membrane components with the most abundant proteins belonging to amino acid/peptide ABC transporters. Putative internalization pathways were evaluated in time-course internalization experiments with non-polarized HT29 cells in the presence of inhibitors of endocytic pathways: chlorpromazine and dynasore (inhibitors of clathrin-mediated endocytosis-CME) and filipin III and nystatin (disrupting lipid rafts). For the first time, our results revealed that the internalization was specifically inhibited by dynasore and chlorpromazine but not by filipin III and nystatin implying that one of the entries of L. plantarum vesicles was through CME pathway
Quinolines and quinolones as antibacterial, antifungal, anti-virulence, antiviral and anti-parasitic agents
No full textInfective diseases have become health threat of a global proportion due to appearance and spread of microorganisms resistant to majority of therapeutics currently used for their treatment. Therefore, there is a constant need for development of new antimicrobial agents, as well as novel therapeutic strategies. Quinolines and quinolones, isolated from plants, animals, and microorganisms, have demonstrated numerous biological activities such as antimicrobial, insecticidal, anti-inflammatory, antiplatelet, and antitumor. For more than two centuries quinoline/quinolone moiety has been used as a scaffold for drug development and even today it represents an inexhaustible inspiration for design and development of novel semi-synthetic or synthetic agents exhibiting broad spectrum of bioactivities. The structural diversity of synthetized compounds provides high and selective activity attained through different mechanisms of action, as well as low toxicity on human cells. This review describes quinoline and quinolone derivatives with antibacterial, antifungal, anti-virulent, antiviral, and anti-parasitic activities with the focus on the last 10 years literature
Controlled Curcumin Release from Hydrogel Scaffold Platform Based on 2-Hydroxyethyl Methacrylate/Gelatin/Alginate/Iron(III) Oxide
No full textThe strategy of combining polymers of natural and synthetic origin with inorganic components to use their unique synergistic effect for the development of the novel, sophisticated, and efficient 3D polymeric biomaterials, whose structure and properties mimic the extracellular matrix and simultaneously represent the suitable hydrogel platform for controlled drug release, is presented. The novel versatile 2-hydroxyethyl methacrylate/gelatin/alginate/iron(III) oxide based hydrogels are prepared by a simple but effective method-modified porogenation. Chemical composition, morphology, swelling capacity, porosity, mechanical properties, effects on cell viability, and in vitro degradation are tested to correlate the material's composition with the corresponding properties. The hydrogels show an interconnected porous microstructure, satisfactory mechanical strength, pH-sensitivity, and favorable curcumin release performances. The materials show good compatibility with healthy human fibroblast in cell culture judged by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, suggesting newly synthesized hydrogels as potentially a new generation of 3D biomaterials with tunable properties for versatile biomedical and pharmaceutical applications
Efficient protein extraction for shotgun proteomics from hydrated and desiccated leaves of resurrection Ramonda serbica plants
No full textResurrection plantRamonda serbicais a suitable model to investigate vegetative desiccation tolerance. However, the detailed study of these mechanisms at the protein level is hampered by the severe tissue water loss, high amount of phenolics and polysaccharide, and possible protein modifications and aggregations during the extraction and purification steps. When applied toR.serbicaleaves, widely used protein extraction protocols containing polyvinylpolypyrrolidone and ascorbate, as well as the phenol/SDS/buffer-based protocol recommended for recalcitrant plant tissues failed to eliminate persistent contamination and ensure high protein quality. Here we compared three protein extraction approaches aiming to establish the optimal one for both hydrated and desiccatedR.serbicaleaves. To evaluate the efficacy of these protocols by shotgun proteomics, we also created the firstR.serbicaannotated transcriptome database, available at. The detergent-free phenol-based extraction combined with dodecyl-beta-D-maltoside-assisted extraction enabled high-yield and high-purity protein extracts. The phenol-based protocol improved the protein-band resolution, band number, and intensity upon electrophoresis, and increased the protein yield and the number of identified peptides and protein groups by LC-MS/MS. Additionally, dodecyl-beta-D-maltoside enabled solubilisation and identification of more membrane-associated proteins. The presented study paves the way for investigating the desiccation tolerance inR.serbica, and we recommend this protocol for similar recalcitrant plant material.Related to supp. material: [https://imagine.imgge.bg.ac.rs/handle/123456789/1837
Chemo- and biocatalytic esterification of marchantin A and cytotoxic activity of ester derivatives
No full textChemical and biocatalytic synthesis of seven previously undescribed marchantin A ester derivatives has been presented. Chemical synthesis afforded three peresterified bisbibenzyl products (TE1-TE3), while enzymatic method, using lipase, produced regioselective monoester derivatives (ME1-ME4). The antiproliferative activities of all prepared derivatives of marchantin A were tested on MRC-5 healthy human lung fibroblast, A549 human lung cancer, and MDA-MB-231 human breast cancer cell lines. All tested esters were less cytotoxic in comparison to marchantin A, but they also exhibited lower cytotoxicity against healthy cells. Monoesters displayed higher cytotoxic activities than the corresponding peresterified products, presumably due to the presence of free catechol group. Monohexanoyl ester ME3 displayed the same IC50 like marchantin A against MDA-MB-231 cells, but the selectivity was higher. In this way, regioselective enzymatic monoesterification enhanced selectivity of marchantin A. ME3 was also the most active among all derivatives against lung cancer cells A549 with the slightly lower activity and selectivity in comparison to marchantin A.Peer-reviewed manuscript: [https://imagine.imgge.bg.ac.rs/handle/123456789/1755