imagine (Institute of molecular genetics and genetic engineering)
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Contemporary molecular-biological investigations of papillary thyroid carcinoma prognostic factors and their potential for application in clinical practice
Get PDFPapilarni tiroidni karcinom (PTK) je najčešći oblik endokrinog maligniteta koji se javlja sa različitim stepenom
agresivnosti. Identifikacija pacijenata koji će imati teži klinički tok je jedan od najvećih problema tiroidne
onkologije. U ovom radu su predstavljeni savremeni tokovi bazičnih molekularno-bioloških istraživanja sa
ciljem selekcije molekularnih markera poboljšanih prognostičkih performansi. Savremeni markeri su
podeljeni na: molekularni “background” pacijenta (genski polimorfizmi); preoperativni cirkulišući markeri
(tumorska DNK i RNK, tumorske ćelije i ekstraćelijske vezikule); intraoperativni markeri; postoperativni
markeri (promene na nivou gena i proteina detektovane iz hirurški odstranjenog materijala) koji bi pomogli
u proceni opsega hirurškog zahvata i personalizaciji terapijskog toka. Takođe je dat osvrt na prednosti i
nedostatke svakog markera kao i mogućnost njihove primene u kliničkoj praksi.Papillary thyroid carcinoma (PTC), the most common form of endocrine malignancy displays various extents
of aggressiveness. Identification of patients who are at risk of developing more severe forms of the disease
is of great importance in thyroid oncology. In this review we summarized contemporary basic molecularbiological
research aimed to select molecular markers with improved prognostic accuracy. These markers are
divided as: patients’ molecular background (genetic polymorphisms); preoperative circulating markers
(tumor DNA and RNA, tumor cells and extracellular vesicles); intraoperative markers; postoperative markers
(changes on genetic and protein levels detected from surgically removed tissue) that could aid the
assessment of surgical extent and personalization of therapy. We also elaborated on benefits and
disadvantages of each marker and their applicability in clinical practice
Polyphenol rich extracts of Geranium L. species as potential natural antioxidant and antimicrobial agents
Get PDFOBJECTIVE: Plants and plant extracts are of great scientific interest due to the
chemical diversity and pharmacological properties of present bioactive molecules. The Geranium L. species are widely used in ethnomedicine. In the current study, the total phenolic and
tannin content, antioxidant and antimicrobial
activity of methanol extracts of eight Geranium
species were investigated.
MATERIALS AND METHODS: The total phenolic and tannin content were determined by the
FC method. Antioxidant capacity was evaluated
in FRAP, DPPH, and biochemical assays, while
antimicrobial activity was examined using the
broth microdilution method.
RESULTS: The high total phenolic (170.64-
636.32 mg GAE/g dry extract) and tannin content (37.80-414.02 mg GAE/g DE), along with significant total antioxidant (FRAP values 1.13-8.80
mmol Fe2+/g) and DPPH radical scavenging activity (SC50 values 4.24-34.52 µg/mL) were observed. The prominent antioxidant capacity was
confirmed in biochemical assays (OS values -1.47
– -13.02). The extracts exhibited significant antimicrobial activity against ATTC strains (MICs
dominantly in the range of 12.5-200 µg/mL) as
well as against clinical isolates of E. coli (MICs
mostly 50 and 100 µg/mL). The pronounced antioxidant and antimicrobial activity can be due to
the high phenolic content, particularly due to the
presence of hydrolyzable tannins.
CONCLUSIONS: Based on the high content of
polyphenols, pronounced antioxidant and antimicrobial activities, the examined extracts are
promising natural antioxidant and antimicrobial
agents with the potential medicinal purpose and
use as a functional food
Trendovi u molekularnoj biologiji/Trends in Molecular Biology
No full textMolekularna biologija doživljava svoj procvat u XXI veku. Od naučne discipline koja je početkom 1930-ih bila u povojima, i koja je nastojala da objedini genetiku, biohemiju i biofiziku kako bi rasvetlila tajne života, izrasla je u nauku čija su postignuća doprinela velikom napretku u medicini, veterini, poljoprivredi i farmaciji. Uz informaciono komunikacione tehnologije, molekularna biologija je najperspektivnija oblast istraživanja, od koje se očekuje da značajno doprinese boljitku života ljudi u budućnosti. U Srbiji je molekularna biologija prepoznata relativno rano, pre nego na mnogim drugim meridijanima. Već u školskoj 1972/73. se na Biološkom fakultetu u Beogradu (tada Prirodno-matematički fakultet) osniva smer- molekularna biologija i fiziologija. U našoj zemlji se tako edukuju generacije molekularnih biologa već pola veka. I veliki naučni instituti u Srbiji osnivaju laboratorije u kojima istraživanja prate, a ponekad i predvode, svetske trendove u molekularnoj biologiji. Jedna od tih naučnih institucija je Institut za molekularnu genetiku i genetičko inženjerstvo (IMGGI), osnovan 1986. godine u Beogradu. Već 35 godina naučnici iz IMGGI stavljaju najmodernije teme iz molekularne biologije u fokus svojih istraživanja. Ovaj Tematski zbornik ima za cilj da prikaže aktuelne teme i postignuća iz oblasti molekularne biologije u prethodnoj, 2020. godini i da svedoči o tome kako su naučnici u Srbiji učestvovali u tim svetskim trendovima. Poglavlja su rezultat doktorskih teza mladih molekularnih biologa ali i prikaz aktuelnih istraživanja u kojima je istaknut doprinos naših naučnika. Od godine 2020. se očekivao veliki napredak u mnogim disciplinama zahvaljujući novim saznanjima iz molekularne biologije. Početak godine je doneo pandemiju KOVID-19 bolesti, koja je imala sve karakteristike epidemija iz ranijih vekova. Bili smo na pragu velikog razočaranja. A onda je molekularna biologija upotrebila sve svoje kapacitete, tako što je omogućila karakterizaciju virusa, uzročnika bolesti, za izuzetno kratko vreme. Iz tog razloga metode za detekciju virusa su bile razvijene u rekordnom roku, te je brza i efikasna dijagnostika postala dostupna lekarima. A potom su se pojavile vakcine, rezultat modernih metoda genetičkog inženjerstva. I tako je 2020. godina ipak bila jedinstvena u istoriji, jer je odgovor na epidemiju bio brz i efikasan, zahvaljujući, u velikoj meri, molekularnoj biologiji. Iste godine, Nobelova nagrada za hemiju je dodeljena metodi koja efikasno i tačno edituje humani genom. Vrata medicine budućnosti su se širom otvorila. Ova sveska bi trebalo da bude prva u nizu godišnjih tematskih zbornika posvećenih aktuelnim temama iz molekularne biologije. Svesni smo kako će ovi rezultati izgledati za deceniju ili dve. Ali, ovo su „znakovi pored puta“ koje je naše vreme ostavilo, osvetljavajući put kojim se ide napred. Mi smo zadivljeni napretkom naše nauke, kad pogledamo u prošlost, ali smo i svesni koji su njeni dometi u odnosu na ono čemu nauka stremi. Radujemo se budućim sveskama i verujemo da će one otvarati nove perspektive i trasirati put napretka. Nadamo se da će ovaj Tematski zbornik naći put do mladih ljudi, da će ih inspirisati da se opredele za naučni rad, posebno za molekularnu biologiju. Verujemo da će buduće generacije uvideti da naučni rad i u ovoj zemlji može dati doprinos svetskoj nauci a pri tome i dovesti do poboljšanja života ljudi u našoj zemlji. Od svih koji su učestvovali u stvaranju ovog svedočenja o našem vremenu, poruka za vas koji dolazite je: „Hoćemo li na molekularnu?!“Kovid-19; Nobelova nagrada za hemIju: CRISPR/Cas9 tehnologija za editovanje genoma; Biomedicina: Retke bolesti; Biomedicina: Kompleksne bolesti; Molekularna biologija prokariota; Molekularna biologija biljak
Ectopic Expression of Ankrd2 Affects Proliferation, Motility and Clonogenic Potential of Human Osteosarcoma Cells
Get PDFSimple Summary Osteosarcoma is a rare malignancy of bone, primarily affecting children and young adults. The main objective of this study was to identify novel therapeutic targets to fight the progression of this insidious disease. To this aim, the role of Ankrd2, a stress- and mechano- sensor protein known for being mostly expressed in muscle fibers, was analyzed in the modulation of osteosarcoma progression. By subjecting human osteosarcoma cell lines expressing or silencing Ankrd2 to several functional assays, our results demonstrated that Ankrd2 is involved in the pathogenesis of this cancer. Nonetheless, due to observations obtained by other studies in other model systems, our findings also suggest that Ankrd2 might behave as a "double-faced" cancer driver gene. Ankrd2 is a protein known for being mainly expressed in muscle fibers, where it participates in the mechanical stress response. Since both myocytes and osteoblasts are mesenchymal-derived cells, we were interested in examining the role of Ankrd2 in the progression of osteosarcoma which features a mechano-stress component. Although having been identified in many tumor-derived cell lines and -tissues, no study has yet described nor hypothesized any involvement for this protein in osteosarcoma tumorigenesis. In this paper, we report that Ankrd2 is expressed in cell lines obtained from human osteosarcoma and demonstrate a contribution by this protein in the pathogenesis of this insidious disease. Ankrd2 involvement in osteosarcoma development was evaluated in clones of Saos2, U2OS, HOS and MG63 cells stably expressing Ankrd2, through the investigation of hallmark processes of cancer cells. Interestingly, we found that exogenous expression of Ankrd2 influenced cellular growth, migration and clonogenicity in a cell line-dependent manner, whereas it was able to improve the formation of 3D spheroids in three out of four cellular models and enhanced matrix metalloproteinase (MMP) activity in all tested cell lines. Conversely, downregulation of Ankrd2 expression remarkably reduced proliferation and clonogenic potential of parental cells. As a whole, our data present Ankrd2 as a novel player in osteosarcoma development, opening up new therapeutic perspectives
Self-Generated Hypoxia Leads to Oxidative Stress and Massive Death in Ustilago maydis Populations under Extreme Starvation and Oxygen-Limited Conditions
Get PDFUstilago maydis and Saccharomyces cerevisiae differ considerably in their response to water-transfer treatments. When stationary phase cells were transferred to pure water and incubated under limited supply of oxygen, the U. maydis cells suffered a catastrophic loss of viability while the S. cerevisiae population was virtually unaffected by the treatment. The major factor underlying the death of the U. maydis cells under those conditions was an oxygen-consuming cellular activity that generated a hypoxic environment, thereby inducing oxidative stress and accumulation of reactive oxygen species, which resulted in lethality. Importantly, a small residue of U. maydis cells that did survive was able to resume growth and repopulate up to the initial culture density when sufficient aeration was restored. The regrowth was dependent on the cellular factors (Adr1, Did4, Kel1, and Tbp1), previously identified as required for repopulation, after killing with hydrogen peroxide. Surprisingly, the survivors were also able to resume growth under apparently hypoxic conditions, indicating that these remnant cells likely switched to a fermentative mode of growth. We discuss the findings in terms of their possible relevance to the eco-evolutionary adaptation of U. maydis to risky environments
Improvement of the anti-Candida activity of itraconazole in the zebrafish infection model by its coordination to silver(I)
No full textIn order to develop a novel antifungal agent, we synthesized and completely structurally characterized the silver(I) complex with the known antimycotic itraconazole (itraco), [Ag(itraco-N)(2)]NO3 center dot H2O (Agitraco). The spectroscopic and crystallographic results revealed that, in this complex, two itraco ligands are monodentately coordinated to the Ag(I) ion via the triazole nitrogen atom forming a cationic [Ag(itraco-N)(2)]+ part, which is neutralized by the nitrate anion. The antifungal effect of silver(I) complex and itraconazole was evaluated against four different Candida species (C. albicans, C. glabrata, C. parapsilosis and C. krusei) by means of minimal inhibitory concentrations (MICs). Agitraco complex shows enhanced antifungal activity than itraco, being 2.3- and 4.5-fold more active against C. albicans and C. glabrata, respectively. The complex was also more efficient in inhibiting yeast to hyphae transition process in C. albicans, which is an important step in its pathogenesis. Part of the improved activity of Agitraco could be attributed to the greater induction of reactive oxygen species in Candida spp. with respect to itraco. The toxicity evaluation in the zebrafish model (Danio rerio) suggests that the Agitraco complex has better therapeutic profile and improved antifungal efficacy with respect to the parent drug, which were also proven in vivo using the zebrafish model of lethal disseminated candidiasis. Interaction of Agitraco with bovine serum albumin (BSA) was investigated with the aim to assess its binding affinity toward this biomolecule
The stress responsive gene ankrd1a is dynamically regulated during skeletal muscle development and upregulated following cardiac injury in border zone cardiomyocytes in adult zebrafish
No full textAnkyrin repeat domain 1 (ANKRD1) is a functionally pleiotropic protein found in the nuclei and sarcomeres of cardiac and skeletal muscles, with a proposed role in linking myofibrilar stress and transcriptional regulation. Rapid upregulation of its expression in response to both physiological and pathological stress supports the involvement of ANKRD1 in muscle tissue adaptation and remodeling. However, the exact role of ANKRD1 remains poorly understood. To begin to investigate its function at higher resolution, we have generated and characterized a TgBAC(ankrd1a:EGFP) zebrafish line. This reporter line displays transgene expression in slow skeletal muscle fibers during development and exercise responsiveness in adult cardiac muscle. To better understand the role of Ankrd1a in pathological conditions in adult zebrafish, we assessed ankrd1a expression after cardiac ventricle cryoinjury and observed localized upregulation in cardiomyocytes in the border zone. We show that this expression in injured hearts is recapitulated by the TgBAC(ankrd1a:EGFP) reporter. Our results identify novel expression domains of ankrd1a and suggest an important role for Ankrd1a in the early stress response and regeneration of cardiac tissue. This new reporter line will help decipher the role of Ankrd1a in striated muscle stress response, including after cardiac injury
C-protein alpha-antigen modulates the lantibiotic thusin resistance in Streptococcus agalactiae
No full textScreening for producers of potent antimicrobial peptides, resulted in the isolation of Bacillus cereus BGNM1 with strong antimicrobial activity against Listeria monocytogenes. Genome sequence analysis revealed that BGNM1 contains the gene cluster associated with the production of the lantibiotic, thusin, previously identified in B. thuringiensis. Purification of the antimicrobial activity confirmed that strain BGMN1 produces thusin. Both thusin sensitive and resistant strains were detected among clinical isolates of Streptococcus agalactiae. Random mutagenesis of a thusin sensitive strain, S. agalactiae B782, was performed in an attempt to identify the receptor protein for thusin. Three independent thusin resistant mutants were selected and their complete genomes sequenced. Comparative sequence analysis of these mutants with the WT strain revealed that duplication of a region encoding a 79 amino acids repeat in a C-protein alpha-antigen was a common difference, suggesting it to be responsible for increased resistance to thusin. Since induced thusin resistant mutants showed higher level of resistance than the naturally resistant B761 strain, complete genome sequencing of strain B761 was performed to check the integrity of the C-protein alpha-antigen-encoding gene. This analysis revealed that this gene is deleted in B761, providing further evidence that this protein promotes interaction of the thusin with receptor
Comparative analysis of International Prognostic Index for chronic lymphocytic leukemia, progression-risk score, and MD Anderson Cancer Center 2011 score: A single center experience
Get PDFUvod/Cilj Prognoza hronične limfocitne leukemije (HLL) značajno je unapređena u poslednje vreme. Među nekoliko prognostičkih modela čiji je cilj predviđanje vremena do prve terapije (eng. TTFT) izdvajaju se skor rizika od progresije (eng. PRS) i skor Centra za rak MD Anderson iz 2011. God. (eng. MDACC 2011), dok se internacionalni prognostički indeks za HLL (eng. CLL-IPI), iako primarno ustanovljen za predikciju ukupnog preživljavanja (eng. OS), dobro pokazao i u predikciji TTFT. Cilj ovog rada je da se ispita značaj pomenutih prognostičkih modela u pogledu predviđanja TTFT i OS. Metode Analizirana kohorta je obuhvatila 57 neselektovanih bolesnika sa HLL Univerzitetskog kliničkog centra Srbije sa prosečno agresivnijim profilom bolesti u odnosu na opštu populaciju de novo bolesnika sa HLL. Bolesnici su ocenjivani prema navedenim skorovima uz analizu TTFT i OS. Rezultati Bolesnici sa višim vrednostima CLL-IPI, PRS i MDACC 2011 primili su prvu terapiju značajno ranije u poređenju sa bolesnicima sa nižim vrednostima ovih skorova (p = 0,002, p = 0,019 i p lt 0,001, redom). U multivarijantnoj analizi, MDACC 2011 i CLL-IPI su zadržali prognostički značaj u predikciji TTFT (p = 0,001, odnosno p = 0,018), dok je PRS ovaj značaj izgubio. CLL-IPI je bio jedini značajan prediktor OS u univarijantnoj (p = 0,005) i u multivarijantnoj analizi (p = 0,013). Zaključak CLL-IPI, PRS i naročito MDACC 2011 su dobri prediktori TTFT čak i u kohortama bolesnika sa agresivnijom bolešću, dok je za predikciju OS od ova tri prognostička modela CLL-IPI jedini primenljiv. Ovi rezultati pokazuju da bi prognostičke modele trebalo ispitati na bolesnicima sa HLL u različitim fazama bolesti, kakvi se sreću u realnoj kliničkoj praksi.Introduction/Objective Prognostication of chronic lymphocytic leukemia (CLL) has been substantially improved in recent times. Among several prognostic models (PMs) focused on the prediction of time to first treatment (TTFT), progression-risk score (PRS), and MD Anderson Cancer Center score 2011 (MDACC 2011) are the most relevant, while CLL-International Prognostic Index (CLL-IPI), although originally developed to predict overall survival (OS), is also being used to estimate TTFT. The aim of this study was to investigate CLL-IPI, PRS, and MDACC 2011 prognostic values regarding TTFT and OS. Methods The analyzed cohort included 57 unselected Serbian CLL patients from a single institution, with the basic characteristics reflecting more aggressive disease than in the general de novo CLL population. The eligible patients were assigned investigated PMs, and TTFT and OS analyses were performed. Results Patients with higher risk scores according to CLL-IPI, PRS, and MDACC 2011 underwent treatment significantly earlier than patients with lower risk scores (p = 0.002, p = 0.019, and p lt 0.001, respectively). In multivariate analysis, MDACC 2011 and CLL-IPI retained their significance regarding TTFT (p = 0.001 and p = 0.018, respectively), while PRS did not. CLL-IPI was the only significant predictor of OS both at the univariate (p = 0.005) and multivariate (p = 0.013) levels. Conclusion CLL-IPI, PRS, and particularly MDACC 2011 are able to predict TTFT even in cohorts with more advanced-disease patients, while for prediction of OS, CLL-IPI is the only applicable among the three PMs. These results imply that PMs should be investigated in more diverse CLL populations, as it is in real-life setting
Efficient Direct Nitrosylation of alpha-Diimine Rhenium Tricarbonyl Complexes to Structurally Nearly Identical Higher Charge Congeners Activable towards Photo-CO Release
Get PDFThe reaction of rhenium alpha-diimine (N-N) tricarbonyl complexes with nitrosonium tetrafluoroborate yields the corresponding dicarbonyl-nitrosyl [Re(CO)(2)(NO)(N-N)X](+) species (where X = halide). The complexes, accessible in a single step in good yield, are structurally nearly identical higher charge congeners of the tricarbonyl molecules. Substitution chemistry aimed at the realization of equivalent dicationic species (intended for applications as potential antimicrobial agents), revealed that the reactivity of metal ion in [Re(CO)(2)(NO)(N-N)X](+) is that of a hard Re acid, probably due to the stronger pi-acceptor properties of NO+ as compared to those of CO. The metal ion thus shows great affinity for pi-basic ligands, which are consequently difficult to replace by, e.g., sigma-donor or weak pi-acids like pyridine. Attempts of direct nitrosylation of alpha-diimine fac-[Re(CO)(3)](+) complexes bearing pi-basic OR-type ligands gave the [Re(CO)(2)(NO)(N-N)(BF4)][BF4] salt as the only product in good yield, featuring a stable Re-FBF3 bond. The solid state crystal structure of nearly all molecules presented could be elucidated. A fundamental consequence of the chemistry of [Re(CO)(2)(NO)(N-N)X](+) complexes, it that the same can be photo-activated towards CO release and represent an entirely new class of photoCORMs