imagine (Institute of molecular genetics and genetic engineering)
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Interplay of SOX transcription factors and microRNAs in the brain under physiological and pathological conditions
Get PDFPrecise tuning of gene expression, accomplished by regulatory networks of transcription factors, epigenetic modifiers, and microRNAs, is crucial for the proper neural development and function of the brain cells. The SOX transcription factors are involved in regulating diverse cellular processes during embryonic and adult neurogenesis, such as maintaining the cell stemness, cell proliferation, cell fate decisions, and terminal differentiation into neurons and glial cells. MicroRNAs represent a class of small non-coding RNAs that play important roles in the regulation of gene expression. Together with other gene regulatory factors, microRNAs regulate different processes during neurogenesis and orchestrate the spatial and temporal expression important for neurodevelopment. The emerging data point to a complex regulatory network between SOX transcription factors and microRNAs that govern distinct cellular activities in the developing and adult brain. Deregulated SOX/microRNA interplay in signaling pathways that influence the homeostasis and plasticity in the brain has been revealed in various brain pathologies, including neurodegenerative disorders, traumatic brain injury, and cancer. Therapeutic strategies that target SOX/microRNA interplay have emerged in recent years as a promising tool to target neural tissue regeneration and enhance neurorestoration. Numerous studies have confirmed complex interactions between microRNAs and SOX-specific mRNAs regulating key features of glioblastoma. Keeping in mind the crucial roles of SOX genes and microRNAs in neural development, we focus this review on SOX/microRNAs interplay in the brain during development and adulthood in physiological and pathological conditions. Special focus was made on their interplay in brain pathologies to summarize current knowledge and highlight potential future development of molecular therapies
Synthesis, physicochemical, and antimicrobial characteristics of novel poly(urethane-siloxane) network/silver ferrite nanocomposites
No full textIn situ polymerization was used to produce novel AgFeO2"PEG/polyurethane network nanocomposites (NP-PUs) with 30-60 wt% of soft poly(dimethylsiloxane) segments in polyurethane (PU), containing 1 wt% of PEG-coated AgFeO2 nanoparticles, AgFeO2"PEG. Physicochemical properties and in vitro biological activity of the NP-PUs were systematically evaluated in terms of AgFeO2"PEG (NP) addition and soft segment content. High-angle annular dark-field transmission electron microscopy showed that the nanoparticles were generally uniformly distributed in the PU matrix. Increased soft segment content caused significantly increased intensity of the broad, amorphous X-ray diffraction peaks of crystalline AgFeO2, probably because the chemical composition of PU affected the distribution of nanoparticles. The Young modulus, hardness, and plasticity of the NP-PUs were higher than for pure PU and increased with decreasing soft segment content. Decreased soft segment content induced higher microphase separation, increased hydrophilicity and swelling ability, but decreased cross-linking density. Additionally, NP-PUs had higher glass transition temperatures, improved thermal stability, and enhanced nanomechanical performance over pure PU. The NP-PUs demonstrated good selective inhibition of Candida albicans and Candida parapsilosis (30-55%) and no pronounced cytotoxicity to MRC5 human lung fibroblasts. Among the investigated AgFeO2"PEG/PUs, the best antifungal activity was shown by composites with 30 and 40 wt% soft segments. Consequently, the novel AgFeO2"PEG/polyurethane network nanocomposites could be further optimized to be used as biocompatible surfaces that also prevent formation of fungal biofilms. [GRAPHICS]
Design, synthesis, and biological evaluation of thiazole bioisosteres of goniofufurone through in vitro antiproliferative activity and in vivo toxicity
No full textThe synthesis of several new goniofufurone bioisosteres was achieved in which the phenyl residue was replaced by a thiazole ring. The key steps of the synthesis included the initial condensation of cyanohydrin benzoates with cysteine ethyl ester hydrochloride, followed by the subsequent reaction of resulting C-4 ' epimeric thiazolines with DBU, to introduce 5-deoxy functionality and to elaborate the thiazole ring in one step. Synthesized compounds showed potent growth inhibitory effects against selected human tumour cell lines, especially bioisostere 4, which in the culture of MCF-7 cells displayed the highest activity (IC50 = 0.19 nM) of all compounds under evaluation. This molecule exhibited 64474-fold higher antiproliferative activity than lead 2 and was1053-fold more active than the commercial antitumour agent doxorubicin in the culture of MCF-7 cells. The structural features of the tested compounds responsible for their antiproliferative activity have been identified by preliminary SAR analysis. The toxicity of the most active compound 4 was assessed by an in vivo experiment in a zebrafish model (Danio rerio), whereupon it was found non-toxic at any of the tested concentrations up to 125 mu M
Nucleic acid-based markers of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer
No full textThe progress that has been made in the treatment of rectal cancer has mostly resulted from multimodality strategy approach that combines surgery, chemotherapy and radiotherapy. In locally advanced rectal cancer (LARC), surgery remains the primary treatment, while neoadjuvant chemoradiotherapy (nCRT) is used to downsize or downstage the tumor before surgical resection. Highly variable response to nCRT observed in LARC patients raises the need for biomarkers to enable prediction and evaluation of treatment response in a more efficient and timely manner than currently available tools. The search for predictive biomarkers continues beyond blood proteins, which have failed in subsequent validation studies. This review presents nucleic acids based markers and their predictive potential in LARC patients. Most of the candidate biomarkers come from relatively small single-institution studies. The only candidate biomarker that emerged as relevant in more than a single study was elevated levels of Fusobacterium nucleatum nucleic acids in tumor tissue. Considering that this marker is easily accessible through non-invasive analysis of faecal samples, its predictive potential is worth further validation. The other candidate nucleic acid-based biomarkers require more consistent studies on larger cohorts before they can be considered for use in clinical setting
Phlomis fruticosa l. Exerts in vitro antineurodegenerative and antioxidant activities and induces prooxidant effect in glioblastoma cell line
Get PDFDespite the significant advances in drug development we are witnessing the inability of health systems to combat both neurodegenerative diseases and cancers, especially glioblastoma. Hence, natural products are comprehen-sively studied in order to provide novel therapeutic options. This study aimed to explore anti-neurodegenerative and anti-glioblastoma potential of extract of Phlomis fruticosa L. using in vitro model systems. It was found that the methanol extract of P. fruticosa was able to efficiently reduce activities of enzymes linked to neurodegenera-tive disease including acetylcholinesterase, butyrylcholinesterase and tyrosinase. Furthermore, P. fruticosa ex-tract has shown excellent antioxidant potential, as evidenced by six different methods. Analysis of cytotoxic ef-fect of P. fruticosa extract on A172 glioblastoma cell line revealed that the concentration of the extract necessary for 50 % inhibition of A172 growth (IC50) was 710 mu g/mL. The extract did not induce changes in proliferation and morphology of A172 glioblastoma cells. On the other side, production of ROS was increased in A172 cells treated with the extract. Observed cytotoxic effect of P. fruticosa extract might be based on increase in ROS generation upon treatment. Quantitative chemical analysis revealed the presence of twelve different polyphenols with the cis 3-O-caffeoylquinic acid being the most abundant. This study provided scientific evidence for further exploration of P. fruticosa as a promising natural anti-neurodegenerative therapeutic option
Genomic Analysis of Multidrug-Resistant Salmonella enterica Serovar Kentucky Isolates from Humans, Turkey, and Food in the Republic of Serbia
No full textOwing to the emerging resistance to antimicrobials in Salmonella Kentucky isolates around the globe, the genomic comparison of all the registered multidrug-resistant Salmonella Kentucky isolates in Serbia (five from humans, one from turkey flock, and one from meat) was done. Most of the isolates were isolated from patients returning from Egypt or Tunisia or originated from imported turkey flock and turkey meat. The comparative analysis of resistance and virulence genes was done. All isolates belonged to sequence type-ST198 and were resistant to ciprofloxacin (Cip). The resistance to Cip was mediated by target mutations of the gyrA and parC genes, which encode topoisomerase I and II, respectively. Multidrug-resistant phenotype to aminoglycosides, beta-lactam antibiotics, sulfonamides, and tetracyclines was detected in five isolates. However, none of the isolates was pan-resistant to antimicrobials. The number of single nucleotide polymorphisms between isolates varied from 8 to 43 and phylogenomics revealed the genetic proximity of the human isolate 10475/11 and the turkey meat isolate 5264/14, indicating a possible meat-to-human transfer. All isolates belonged to the main Salmonella Kentucky MDR lineage, carrying the Salmonella genomic island 1 (SGI1-K) subtype. The SGI1-K of Serbian isolates showed mosaicism attributed to rapid intraclonal evolution. Many virulence factors were detected in all the isolates, including SPI-1, SPI-2, SPI-3, SPI-4, SPI-5, SPI-9, and C63PI. Although Salmonella Kentucky has rarely been isolated from humans, food, and animals in Serbia, further surveillance is needed to diminish the risk of the spreading of resistant clones and their meat-to-human transmission
Synthesis, Anticancer Potential and Comprehensive Toxicity Studies of Novel Brominated Derivatives of Bacterial Biopigment Prodigiosin from Serratia marcescens ATCC 27117
Get PDFProdigiosins (prodiginines) are a class of bacterial secondary metabolites with remarkable biological activities and color. In this study, optimized production, purification, and characterization of prodigiosin (PG) from easily accessible Serratia marcescens ATCC 27117 strain has been achieved to levels of 14 mg/L of culture within 24 h. Furthermore, environmentally friendly bromination of produced PG was used to afford both novel mono- and dibrominated derivatives of PG. PG and its Br derivatives showed anticancer potential with IC50 values range 0.62-17.00 mu g/mL for all tested cancer cell lines and induction of apoptosis but low selectivity against healthy cell lines. All compounds did not affect Caenorhabditis elegans at concentrations up to 50 mu g/mL. However, an improved toxicity profile of Br derivatives in comparison to parent PG was observed in vivo using zebrafish (Danio rerio) model system, when 10 mu g/mL applied at 6 h post fertilization caused death rate of 100%, 30% and 0% by PG, PG-Br, and PG-Br-2,Br- respectively, which is a significant finding for further structural optimizations of bacterial prodigiosins. The drug-likeness of PG and its Br derivatives was examined, and the novel Br derivatives obey the Lipinski's "rule of five", with an exemption of being more lipophilic than PG, which still makes them good targets for further structural optimization
Differential expression of TLR7 and miRNA-146a genes in peripheral blood and skin samples of patients with systemic sclerosis
No full textBackground/Objectives: Progressive fibrosis of the skin and internal organs is one of the hallmarks of systemic sclerosis (SSc). Accumulative evidence demonstrates that Toll-like receptors (TLRs) may represent the link between immune activation and tissue fibrosis. Releasing of endogenous TLR ligands and their binding to TLR receptors complexed to autoantibodies might be one of the mechanisms that initiate fibrotic events. It arose recently that ‘fine-tuning’ of the TLR/NF-kB signaling pathway is taken place through down-regulation of IRAK1 gene via miR-146a. Methods: The expression of TLR7 and miRNA-146a genes in PBMNC of 50 SSc patients and 13 healthy individuals using RTqPCR technique was performed. Comparative analysis of these genes in affected and unaffected skin areas of the five SSc patient was performed in addition. Results: In skin tissue samples the expression of TLR7 gene was 56% lower in affected (mRSS score>10) compared to unaffected tissue sample. When peripheral blood samples were examined, we found that patients with severe skin involvement (mRSS score>10) showed 26% lower TLR7 expression compared to patients with mild skin involvement (mRSS score≤10). In addition, 19% lower level of miR-146a expression was detected in affected compared to unaffected skin sample. In peripheral blood samples, 37% lower expression of miR-146a was detected in patients with severe skin involvement compared to patients with mild skin involvement. Conclusion: Synchronized expression TLR7 and miR-146a genes in skin tissue samples and blood samples suggest that both of these molecules should be further investigated as noninvasive biomarkers for skin involvement in SSc patients.Abstracts from the 55th European Society of Human Genetics Conferenc
KLINIČKO-PATOLOŠKE KARAKTERISTIKE I ISHOD CD5 POZITIVNOG DIFUZNOG B KRUPNOĆELIJSKOG LIMFOMA I ZNAČAJ NIVOA EKSPRESIJE CD5: DESETOGODIŠNJE ISKUSTVO KLINIKE ZA HEMATOLOGIJU UKCS
No full textIntroduction: CD5 positive (CD5+) diffuse large B cell lymphoma (DLBCL) is
characterized by worse prognosis in comparison with general DLBCL population.
Aim: To describe clinicopathological features of CD5+ DLBCL patients treated at Clinic of
Hematology UCCS during period of from 2012-2021.
Methods: We retrospectively analysed 537 patients with DLBCL for the presence of CD5
marker on the basis of patients’ pathological reports at diagnosis.
Results: Clinicopathological features of CD5+ DLBCL patients are shown in Table 1.
Median PFS after first treatment line in CD5 positive cohort was 25 months (m) (95%CI
13.76-36.24), while median OS was not reached. Age, B symptoms, and extranodal disease
(ED) did not influence survival. Patients with bulky disease, nonGCB, and double expressors
(DEL) experienced significantly shorter PFS (p=0.03, P=0.043, and p=0.025, respectively),
but not OS. On the other hand, b2m levels >3.38 mg/L, LDH >1xULN, and IPI >2 were
associated with shorter OS (p=0.014, p=0.01, and p=0.015, respectively), without impact on
PFS, though. ECOG PS >1 was associated with shorter both PFS and OS (p=0.005 and
p=0.002).
Patients described as CD5+ exhibited median PFS 20m vs. 52m for CD5+/- and CD5-/+
designated patients (p=0.021). This significance was not confirmed in terms of OS whose
median was not reached in neither of groups.
Conclusion: Bulky disease, nonGCB, and DEL were associated with shorter PFS, elevated
b2m, LDH, and IPI>2 with shorter OS, end ECOG PS>1 with both shorter PFS and OS. The
strength of CD5 expression was significantly associated with PFS. CD5 should be considered
mandatory marker within immunohistochemistry analysis for DLBCL.Uvod: CD5 pozitivni (CD5+) difuzni B krupnoćelijski limfom (DBKL) se karakteriše
lošijom prognozom u odnosu na opštu DBKL populaciju.
Cilj: Opis kliničko-patoloških karakteristika pacijenata sa CD5+ DBKL koji su lečeni na
Klinici za hematologiju UKCS u periodu 2012-2021.
Metode: Retrospektivna analiza 537 DBKL pacijenata na prisustvo CD5 markera na osnovu
patohistoloških (PH) izveštaja na dijagnozi.
Rezultati: Deskriptivna statistika je prikazana u tabeli 1. Medijana PFS nakon prve terapijske
linije za sve pacijente u ispitivanoj grupi bila je 25 meseci (m) (95%CI 13.76–35.24), dok
medijana OS nije dostignuta. Starost na dijagnozi, B simptomi i ekstranodalna bolest (EB)
nisu značajno uticali na preživljavanje. Pacijenti sa "bulky" bolešću, nonGCB i "double
expressor" (DEL) su imali značajno kraće PFS (p=0.03, P=0.043 i p=0.025, redom), ne i OS.
Sa druge strane, nivo b2m >3.38 mg/L, LDH >1x gornja granica normalnog i IPI >2 su
pokazali povezanost sa kraćim OS (p=0.014, p=0.01 i p=0.015, redom), s tim da nisu bili
značajni u pogledu PFS. ECOG PS >1 je bio povezan sa kraćim PFS i OS (p=0.005 i
p=0.002).
Pacijenti označeni kao CD5+ imali medijanu PFS 20m vs. 52m kod CD5+/- i CD5-/+
(p=0.021). Ova razlika nije registrovana u pogledu OS, čija medijana nije dostignuta ni u
jednoj ni u drugoj grupi.
Zaključak: "Bulky" bolest, nonGCB i DEL su bili povezani sa kraćim PFS, povišen b2m,
LDH i IPI >2 sa kraćim OS, a ECOG PS >1 sa kraćim PFS i OS. Nivo ekspresije CD5 je bio
značajno povezan sa PFS. Razmotriti da CD5 marker bude obavezan deo
imunohistohemijskog panela u dijagnostici DBKL
Експресиони образац дуге некодирајуће РНК GAS5 и микроРНК- 222 код млађих пацијената оболелих од АМЛ
Get PDFAkutna mijeloidna leukemija (AML) je heterogeno maligno oboljenje kako na
kliničkom tako i na genetičkom nivou. AML ima lošu prognozu, i zato postoji
konstantna potreba za novim prognostičkim markerima, kao i markerima koji
mogu biti mete za inovativne terapeutike. U skorije vreme potraga za novim
biomarkerima je naučnicima skrenula pažnju ka nekodirajućim RNK, naročito
dugim nekodirajućim RNK (dnkRNK) i mikroRNK (miRNK). U ovom radu ispitali
smo nivo ekspresije „growth arrest-specific transcript 5“ (GAS5) dnkRNK kod 94
mlađih osoba obolelih od AML, kao i nivo ekspresije miR-222 u grupi od 39
osoba obolelih od AML sa normalnim kariotipom (AML-NK), u cilju da
ispitamo njihov prognostički potencijal. Naši rezultati su pokazali da je nivo
ekspresije GAS5 kod obolelih od AML niži u poređenju sa zdravim kontrolama, i
češći je u grupi sa nepovoljnom prognozom. U AML-NK grupi pacijenti su imali
povišenu ekspresiju miR-222 u poređenju sa zdravim kontrolama. Sinergistički
efekat „GAS5low/miR-222 high“ nije utvrđen. Ovo je prva studija koja je ispitala
interakciju ekspresije GAS5 i miR-222 kod obolelih od AML. Naši rezultati
indikuju potrebu za daljim ispitivanjem ove dve nekodirajuće RNK i njihove
potencijalne uloge u leukemogenezi i prognostici AML pacijenata.Акутна мијелоидна леукемија (АМЛ) је хетерогено малигно обољење како на
клиничком тако и на генетичком нивоу. АМЛ има лошу прогнозу, и зато постоји
константна потреба за новим прогностичким маркерима, као и маркерима који
могу бити мете за иновативне терапеутике. У скорије време потрага за новим
биомаркерима је научницима скренула пажњу ка некодирајућим РНК, нарочито
дугим некодирајућим РНК (днкРНК) и микроРНК (миРНК). У овом раду испитали
смо ниво експресије „growth arrest-specific transcript 5“ (GAS5) днкРНК код 94
млађих особа оболелих од АМЛ, као и ниво експресије miR-222 у групи од 39
особа оболелих од АМЛ са нормалним кариотипом (АМЛ-НК), у циљу да
испитамо њихов прогностички потенцијал. Наши резултати су показали да је ниво
експресије GAS5 код оболелих од АМЛ нижи у поређењу са здравим контролама, и
чешћи је у групи са неповољном прогнозом. У АМЛ-НК групи пацијенти су имали
повишену експресију miR-222 у поређењу са здравим контролама. Синергистички
ефекат „GAS5low/miR-222 high“ није утврђен. Ово је прва студија која је испитала
интеракцију експресије GAS5 и miR-222 код оболелих од АМЛ. Наши резултати
индикују потребу за даљим испитивањем ове две некодирајуће РНК и њихове
потенцијалне улоге у леукемогенези и прогностици АМЛ пацијената.Knjiga sažetaka: Treći Kongres biologa Srbije, Zlatibor, Srbija 21 - 25. 9. 2022