imagine (Institute of molecular genetics and genetic engineering)
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Exploring inflammatory and apoptotic signatures in distinct Crohn's disease phenotypes: Way towards molecular stratification of patients and targeted therapy
No full textBackground: Crohn's disease (CD) is chronic inflammatory bowel disease with different phenotypic characteristics influencing disease prognosis and therapeutic strategies. The aim of this pilot study was to analyze selected inflammatory and apoptotic markers in non-inflamed and inflamed samples of ileal mucosa of non-stricturing/non-penetrating (NS/NP) and stricturing (S) CD mucosal phenotypes in order to characterize their distinct profiles. Methods: From twenty CD patients (9 NS/NP, 11 S) paired non-inflamed and inflamed ileal biopsies were collected and used for analysis of cytokine (TNF and IL6) and apoptotic (Bcl2, Box, Fas and FasL) genes' expression levels by real-time PCR, while NF kappa B transcriptional potency was assessed by electromobility gel shift assay. Results: Our results demonstrated significant upregulation of TNF and IL6 in inflamed area of both NS/NP (p = 0.03, p = 0.01) and S phenotypes (p = 0.04, p = 0.04), respectively. However, TNF increase was more prominent in NS/NP compared to S inflamed mucosa (p = 0.02). Also, level of proapoptotic Box was significantly higher in NS/NP compared to S inflamed mucosa (p = 0.01). Opposing transcription potency of NF kappa B has been detected between two phenotypes: being decreased in NS/NP (p = 0.07) and increased in S (p = 0.1) inflamed compared to non-inflamed mucosa, demonstrating trend towards statistical significance. Conclusions: We found that two distinct CD phenotypes have specific molecular signatures. Obtained results could direct improvement of current and development of new therapeutic strategies based on more specific molecular stratification of CD patients
Clinical significance of TP53 aberrations and IGHV mutational status in chronic lymphocytic leukemia
Get PDFHronična limfocitna leukemija (HLL) izuzetno je heterogena bolest varijabilnog kliničkog toka. S jedne strane imamo, pacijente sa agresivnom i rezistentnom bolešću od koje umiru svega par meseci nakon dijagnoze, dok s druge strane spektra postoje pacijenti sa indolentnom, sporo progredirajućom bolešću koja ne zahteva lečenje decenijama. Razlozi su samo delimično poznati i već su decenijama unazad tema mnogobrojnih naučnih istraživanja. Tako je razvijen koncept prognostičkih i prediktivnih faktora u HLL-u, koji imaju za cilj da predvide klinički tok, odnosno terapijski ishod HLL-a. Liste prognostičkih i prediktivnih faktora su, sa boljim poznavanjem patofiziologije ove bolesti, svakom godinom sve duže, ali se i međusobno preklapaju. U ovom revijalnom radu izabrali smo aberacije TP53 gena i mutacioni status rearanžiranih IGHV (engl. immunoglobulin heavy variable) gena kao dva najznačajnija i najproučavanija faktora koji imaju i prognostički i prediktivni značaj.Chronic lymphocytic leukemia (CLL) is a very heterogeneous disease with a variable clinical course. On the one side of the spectrum, there are patients with aggressive and resistant disease, of which they die only a few months after diagnosis while, on the other side, there are patients with an indolent, slowly progressive disease that does not require treatment for decades. The reasons for this are only partially known, but they have been the subject of numerous scientific studies during the last several decades. Consequently, the concept of prognostic and predictive factors in CLL have emerged, which aims to predict the clinical course and its therapeutic outcome. With the improvement of understanding the pathophysiology of this disease, the lists of prognostic and predictive factors are getting longer every year, but they also overlap. In this review, we singled out the aberrations of the TP53 gene and the IGHV (immunoglobulin heavy variable) gene mutational status as the two most important and most studied factors that have both prognostic and predictive significance
Design, synthesis and in vivo evaluation of 3-arylcoumarin derivatives of rhenium(I) tricarbonyl complexes as potent antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA)
Get PDFWe have prepared a series of ten 3-arylcoumarin molecules, their respective fac-[Re(CO)(3)(bpy)L](+) and fac-[Re(CO)(3)(L(sic)L)Br] complexes and tested all compounds for their antimicrobial efficacy. Whereas the 3-arylcoumarin ligands are virtually inactive against the human-associated pathogens with minimum inhibitory concentrations (MICs) gt 150 mu M, when coordinated to the fac-[Re(CO)(3)](+) core, most of the resulting complexes showed remarkable antibacterial potency. Several rhenium complexes exhibit activity in nanomolar concentrations against Gram-positive pathogens such as Staphylococcus aureus strains, including methicillin-resistant S. aureus (MRSA) and Enterococcus faecium. The molecules do not affect bacterial cell membrane potential, but some of the most potent complexes strongly interact with DNA, indicating it as a possible target for their mode of action. In vivo studies in the zebrafish model showed that the complexes with anti-staphylococcal/MRSA activity were non-toxic to the organism even at much higher doses of the corresponding MICs. In the zebrafish-MRSA infection model, the complexes increased the survival rate of infected fish up to 100% and markedly reduced bacterial burden. Moreover, all rescued fish developed normally following the treatments with the metallic compounds
Towards the dynamic conservation of Serbian spruce (Picea omorika) western populations
Get PDFKey message High levels of genetic diversity, pronounced genetic structure and limitations to gene flow in Serbian spruce, a rare and endangered tree species from the refugial Balkan region, point towards a "one population-one unit" strategy for assembling a network of Genetic Conservation Units (GCUs) for its dynamic conservation. On the other hand, genetic information also permits to prioritize populations for conservation based on their contribution to genetic diversity and differentiation. Context Serbian spruce, Picea omorika (Panc.) Purk., is a rare, IUCN red-listed European conifer endemic to the Balkan region. Its current rigid conservation (without any intervention allowed in similar to 30 remnant populations) and the extant network of Genetic Conservation Units (four natural populations and three planted stands from the western part of the species range, in the Republic of Srpska, Bosnia and Herzegovina, RS-BH) might be ineffective in preserving the species' genetic diversity. Aims To facilitate implementation of dynamic conservation of Serbian spruce by re-assessing the number and size of remnant populations in RS-BH and updating genetic knowledge on these understudied western Serbian spruce populations. Methods Comprehensive field survey in RS-BH, genotyping 689 individuals from 14 western populations with ten highly informative nuclear EST-SSRs and analytical methods for prioritizing populations for conservation based on their contribution to the geographical structuring of genetic diversity. Results The genetic diversity of western Serbian spruce populations (Ae = 2.524, H-E = 0.451) is comparable with what was found for eastern ones; they are highly genetically differentiated (Hedrick's G'(ST) = 0.186; Jost's D = 0.097) and comprise ten distinct gene pools. Effective population size is often gt = 15. As much as 14% of alleles is not preserved in the extant GCUs established in natural populations. Eight populations positively contribute to within-population genetic diversity, four to genetic differentiation, and two are globally important in terms of diversity and differentiation. Although wildfires may contribute to admixture of different gene pools, re-establishment from seeds from extirpated populations has likely prevailed in studied populations. Conclusions A larger network of GCUs is required for the dynamic conservation of western Serbian spruce populations. A "one population-one unit" strategy, with 14 GCUs, would represent the safest approach to conserve species extant genetic variation in this part of the species range. Nonetheless, a strategy to prioritize populations for conservation based on their contribution to allelic diversity has been put forward. Given the rapid global warming and peculiarities of Serbian spruce distribution, habitat and life history traits, conservation measures based on a rigorously designed GCU network are urgent for its rescue and survival
New polynuclear 1,5-naphthyridine-silver(I) complexes as potential antimicrobial agents: The key role of the nature of donor coordinated to the metal center
No full textNew polynuclear silver(I) complexes with 1,5-naphthyridine (1,5-naph), [Ag(NO3)(1,5-naph)](n) (Ag1), [Ag (CF3COO)(1,5-naph)]n (Ag2) and [Ag(CF3SO3)(1,5-naph)](n) (Ag3) were synthesized by the reaction of the corresponding silver(I) salt and 1,5-naph in ethanol at room temperature. These complexes were characterized by NMR, IR and UV Vis spectroscopy, while their crystal structures were determined by single-crystal X-ray diffraction analysis. In all these complexes, 1,5-naph acts as a bridging ligand between two Ag(I) ions, while the remaining coordination sites are occupied by oxygen atom(s) of the corresponding anion. The antimicrobial efficiency of these silver(I) complexes was evaluated against the broad panel of Gram-positive and Gram-negative bacteria and fungi. The complexes showed good to moderate antibacterial activity with the minimal inhibitory concentration (MIC) values being in the range 2.5-100 mu g/mL (6.5-333.3 mu M), while their antifungal activity against the investigated Candida spp. was significantly higher (MIC = 0.78-6.25 mu g/mL; 2.6-20.8 mu M). Moreover, complexes Ag1 and Ag2 effectively inhibited C. albicans biofilms formation, while Ag1 was also shown to inhibit the formation of mixed C. albicans/Pseudomonas aeruginosa biofilms. Toxicological evaluations on zebrafish (Dario rerio) embryos revealed that all silver(I) complexes could be applied as antifungal agents, whereas Ag3 had the best therapeutic potential showing both the lowest MIC values against the tested Candida strains and the non-toxic in vivo response in the zebrafish embryos at these doses
Characterization of pH resistance and the proteolytic activity of GABA producing Lactobacillus brevis BGZLS10-17 in preparation of fermented milk beverage and the effects on the symptoms of the experimental autoimmune encephalomyelitis
Get PDFMultiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. The aim of this work was to study the probiotic effect of gamma-aminobutyric acid (GABA)-producer Lactobacillus brevis BGZLS10-17 on experimental autoimmune encephalomyelitis (EAE), an experimental animal MS model. Clinical EAE symptoms were monitored in Dark Agouti (DA) rats treated with L. brevis BGZLS10-17 strain, or supernatant obtained from 48 h culture of L. brevis BGZLS10-17 cultivated in growth medium with or without GABA precursor monosodium glutamate (MSG). The results revealed that oral administration of L. brevis BGZLS10-17 alleviates the symptoms of EAE in DA rats. Namely, treatment with BGZLS10-17 and the supernatant of the strain cultivated in medium with MSG delayed the onset, shortened the duration, and reduced the intensity of the disease in the period when the EAE symptoms in controls were most pronounced. The probiotic treated animals were completely recovered after forty days, unlike the control animals. The results indicate that supplementation with live strain or with supernatant containing GABA produced by L. brevis BGZLS10-17 could alleviate the EAE symptoms. However, the use of L. brevis BGZLS10-17 in functional food as probiotic for autoimmune diseases should be tested in clinical trials
Characterization of Microvesicles of Strain Lactobacillus Plantarum BGAN8 and Internalization by HT29 Cells
No full textThe down-regulation of Notch 1 signaling contributes to the severity of bone loss in aggressive periodontitis
No full textBackground The exact mechanisms of bone resorption in periodontitis have not been fully elucidated. The aims of this study were to analyze the expression of Notch signaling molecules, bone remodeling mediators, and pro-inflammatory cytokines in periodontitis patients and to determine their potential correlations. Methods The study included 130 individuals: 40 with aggressive periodontitis (AP group), 40 with chronic periodontitis (CP group), and 50 periodontally healthy controls. Total RNA was extracted from gingival crevicular fluid samples and relative gene expression of investigated molecules (Notch 1, Notch 2, Jagged 1, Hes 1, Hey 1, TNF-alpha, IL-17, RANKL, and OPG) was determined by reverse transcriptase - real-time polymerase chain reaction (RT-qPCR). Results In AP group, a significant increase of Notch 2, TNF-alpha, IL-17 and RANKL and a significant decrease of Notch 1 and Jagged 1 expression were observed compared to control group (P = 0.023, P = 0.005, P = 0.030, and P = 0.001 P = 0.031 and P = 0.029, respectively). Notch 2 and RANKL were also overexpressed in CP group compared to controls (P = 0.001 and P = 0.011). Significant correlations were observed in AP group between expression levels of the analyzed genes. Conclusion The present findings implicate Notch 2 overexpression in the ethiopathogenesis of bone resorption in aggressive and chronic periodontitis. The down-regulation of Notch 1 and Jagged 1 and loss of their osteoprotective function might cause a more excessive osteoclast formation and contribute to greater osteolysis in aggressive periodontitis
Structural, biological and in-silico study of quinoline-based chalcogensemicarbazones
No full textIn this work pharmaceutical application of focused library of six quinoline-based chalcogensemicarbazones (QBCs) was tested through determination of their antimicrobial activity against twenty-eight Gram-negative and Gram-positive strains from different origin. Pharmacokinetic properties have been assessed by the analysis of frequently employed drug likeness parameters. Computational study has been complemented with calculation of their global and local reactive properties, within the framework of density functional theory (DFT). Among other information, DFT calculations helped us to locate the most reactive sites of investigated QBCs and to identify their sensitivity towards the oxidation
Antimicrobial activity and DNA/BSA binding study of new silver(I) complexes with 1,8-naphthyridine
Get PDFSilver(I) compounds are well known for their pharmacological applications as antibiotics and have been also evaluated as potential anticancer agents. The use of simple silver(I) salts, such as AgNO3, as an antimicrobial agent, has been limited due to the formation of AgCl precipitate under the physiological conditions, preventing a major part of Ag(I) ions to reach the infected site. On the other hand, a slow and maintainable release of Ag(I) ion into the infected cell or tissue could be achieved by its administration in the form of complexes. Among different classes of ligands used for the synthesis of biologically active silver(I) complexes, a special attention was devoted to the aromatic nitrogen-containing heterocycles. Considering this, in the present study, we have synthesized two new silver(I) complexes with 1,8-naphthyridine (1,8-naph), polynuclear [Ag(CF3SO3)(1,8-naph)]n (Ag1) and dinuclear [Ag(1,8-naph)(H2O)]2(PF6)2 (Ag2), and evaluated their antimicrobial activity against Gram-positive and Gram-negative bacteria, as well as Candida spp. The obtained results revealed that these silver(I) complexes showed significant activity toward the Gram-positive Staphylococcus aureus and Candida spp. The values of binding constants of Ag1 and Ag2 to BSA are high enough to indicate their interaction to this biomolecule, but not so strong to prevent their release upon arrival to the target site. The partition coefficient (logP) values for Ag1 and Ag2 are -0.14 and 0.37, respectively, what is in accordance with those for pharmacophores in the Comprehensive Medicinal Chemistry database. Тhe investigated silver(I) complexes inside the cell could interact with DNA through the non-intercalative (electrostatic) mode.6th International Electronic Conference on Medicinal Chemistry session General: Presentation