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Comprehensive investigation of hepatotoxicity of the mixture containing phthalates and bisphenol A
No full textConnections between the mixture containing bis(2- ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and bisphenol A (BPA) and liver injury were explored through in silico investigation and 2 in vivo models. Comparative Toxicogenomics Database (CTD), ShinyGO, ToppCluster and Cytoscape were used for bioinformatic analysis. In vivo subacute study was performed on rats - five groups (n = 6): (1) Control: corn oil, (2) DEHP: 50 mg/kg b.w./day, (3) DBP: 50 mg/kg b.w./day, (4) BPA: 25 mg/kg b.w./day, (5) MIX: DEHP + DBP + BPA. Zebrafish embryos were exposed to the investigated substances in different doses, singularly and combined (binary and ternary mixtures). Liver injury was linked to 75 DEHP, DBP, and BPA genes, mostly connected to inflammation/oxidative stress. In rats, significant alterations in redox status/bioelements and pathohistology were most notable or exclusively present in MIX (probable additive effects). BPA decreased liver area (LA) index in dose-dependent manner. DEHP (< 2 µg/mL) and DBP (≤ 5 µg/mL) reduced LA values, while their higher doses increased LA index. The effect of DBP in binary mixtures led to a lethal outcome at the two highest concentrations, while the hepatotoxicity of DEHP/DBP/BPA mixture was dictated by BPA (confirmed by the benchmark dose analysis)
Supplementary information for the article: Kabic, J., Novovic, K., Kekic, D., Trudic, A., Opavski, N., Dimkic, I., Jovcic, B., & Gajic, I. (2023). Comparative genomics and molecular epidemiology of colistin-resistant Acinetobacter baumannii. Computational and Structural Biotechnology Journal, 21, 574–585. https://doi.org/10.1016/j.csbj.2022.12.045
Get PDFRelated to published version: [https://imagine.imgge.bg.ac.rs/handle/123456789/1784]Supplementary data associated with this article can be found in the online version at doi:[10.1016/j.csbj.2022.12.045.
Endorhizosphere of indigenous succulent halophytes: a valuable resource of plant growth promoting bacteria
Get PDFThe adaptability of halophytes to increased soil salinity is related to complex rhizosphere interactions. In this study, an integrative approach, combining culture-independent and culture-dependent techniques was used to analyze the bacterial communities in the endorizosphere of indigenous succulent halophytes Salicornia europaea, Suaeda maritima, and Camphorosma annua from the natural salt marshes of Slano Kopovo (Serbia). The 16 S rDNA analyses gave, for the first time, an insight into the composition of the endophytic bacterial communities of S. maritima and C. annua. We have found that the composition of endophyte microbiomes in the same habitat is to some extent influenced by plant species. A cultivable portion of the halophyte microbiota was tested at different NaCl concentrations for the set of plant growth promoting (PGP) traits. Through the mining of indigenous halotolerant endophytes, we obtained a collection representing a core endophyte microbiome conferring desirable PGP traits. The majority (65%) of the selected strains belonged to the common halotolerant/halophilic genera Halomonas, Kushneria, and Halobacillus, with representatives exhibiting multiple PGP traits, and retaining beneficial traits in conditions of the increased salinity. The results suggest that the root endosphere of halophytes is a valuable source of PGP bacteria supporting plant growth and fitness in salt-affected soils.The authors would like to express their gratitude to dr Jelica Novaković,
research associate (Faculty of Biology, University of Belgrade) for her assistance
in collection and determination of plants samples
Proteome Dynamics in Autism Spectrum Disorders (ASD)
No full textAutism spectrum disorder (ASD) is a complex, prevalent neurodevelopmental disorder with significant
genotype and phenotype heterogeneity. Recent studies suggest dysregulated protein synthesis as a
key mechanism in ASD. This study explores altered translation in ASD using induced pluripotent stem
cells (iPSCs), a promising tool for disease modelling. We introduced ASD-relevant mutations in FMR1,
PTEN, and TSC2 into iPSCs from healthy donors via CRISPR/Cas9. The iPSCs were then differentiated
into iNeurons and cortical organoids, and their proteomes were analysed using mass spectrometry.
TSC2 and PTEN mutants showed similar profiles in both models, while FMR1 showed differences only
in organoids, not in iNeurons. GO enrichment analysis revealed increased abundance of proteins
associated with mitochondrial processes, such as cellular respiration and protein synthesis, reflecting
mTORC1 hyperactivation due to PTEN and TSC2 mutations. Downregulated proteins were related to
transcriptional and epigenetic regulation. Notably, dysregulated proteins included genes linked to ASD
(SFARI gene list), emphasizing the proteomic data's relevance. These findings are expected to
elucidate ASD's molecular underpinnings, covering both specific mutations and shared alterations
among different ASD-related mutations.GBM Compact: Focus on Proteomics, 5th - 6th September 202
Presence of leukemic clone-specific immunoglobulin heavy chain rearrangements in neonatal blood spots of children with B-cell precursor acute lymphoblastic leukemia
No full textIntroduction
Childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be traced back to birth using leukemic clone-specific immunoglobulin heavy chain (IGH) rearrangements, implying prenatal origin of this disease.
Methods
We retrospectively analyzed neonatal blood spots (Guthrie cards) of 24 patients with childhood BCP-ALL aged 1–9.6 years (median 3.1 years) for the presence of clonotypic IGH rearrangements identified in diagnostic bone marrow samples. Based on the sequences of IGH rearrangements, 2 patient-specific primers were designed for each patient and used in semi-nested polymerase chain reaction for the detection of preleukemic clones at birth.
Results
Clonotypic IGH rearrangements were detected in neonatal blood spots of 54.2% of patients (13/24). In two cases with double IGH rearrangements detected at diagnosis, only one rearrangement was present at birth, while in the third case both leukemic rearrangements were detected in neonatal blood. Guthrie card-positive findings were significantly more frequent in children ≤5 years of age than in older children (p = 0.011). Regarding patients' characteristics at birth and at diagnosis, Guthrie card-positivity was not associated with sex, birth weight and mother's age, as well as with white blood cell count, percentage of bone marrow blasts, immunophenotype and the presence of ETV6/RUNX1 and TCF3/PBX1 fusion genes at diagnosis.
Conclusion
Our study confirms that a large proportion of childhood BCP-ALL originates in utero, regardless of the molecular subtype defined by chromosomal aberrations. The observed trend toward younger age at diagnosis in Guthrie card-positive versus Guthrie card-negative patients implies that the age at diagnosis depends on the presence of preleukemic clone at birth, as well as on the timing of postnatal transforming genetic events
Biotechnological production of bacterial pigment prodigiosin and bioactive properties of its metal complexes with Cu(II) and Zn(II)
Get PDFProdigiosin (PG, Fig. 1a) is a biologically active
pyrrolylpyrromethene alkaloid whose structure was
first confirmed in 1962 [1]. PG is commonly
produced by Gram-negative bacteria, such as
Serratia spp. and has an eco-physiological role [2].
Its biological activities were extensively researched,
and numerous pharmacological properties were
established, including anticancer and
immunosuppressive However, high cost of extraction and purification
still represent the bottleneck in the microbial
production of PG. Meat and fish processing wastes have high potential as raw materials for conversion
into useful products of higher value. In this study,
meat offcuts were assessed as the sole nutrient for
the fermentative production of PG from S.
marcescens. Using this substrate lowered the
cultivation medium cost and shortened the
fermentation time to 12 h, while allowing a
satisfying PG yield of 83.1 mg/L. The isolated PG
was used in one-step reactions with CuCl₂ or ZnCl₂
in terc-BuOH at 25 °C. The obtained [Cu(PG)Cl] (Fig.
1b) and [Zn(PG)₂] (Fig. 1c) complexes were
characterized by UV-Vis and IR spectroscopy and
their bioactivity potential was assessed.
Antimicrobial activity was assessed in a disc assay
against 4 human pathogens: Escherichia coli NCTC
9001, Pseudomonas aeruginosa ATCC 10332,
Staphylococcus aureus NCTC 6571, Candida
albicans ATCC 10231, but no effect was observed
for the tested concentrations of 200 μg per disc and
lower. However, the anticancer potential of the new
derivatives is promising and the bovine serum
albumin (BSA) binding study revealed that
complexes bind to BSA tightly and reversibly [4].10th International Conference of MIKROBIOKOSMOS, Larissa from 30 Novewmber to 2 December 2023
Uloga vazopresinskog sistema paraventrikularnog jedra u razvoju hipertenzije
Get PDFVazopresin ili antidiuretički hormon je peptidni molekul koji na vrlo složen način utiče na kardivovaskularnu
i osmotsku homeostazu. Glavni izvori vazopresina su supraoptičko i paraventrikularno jedro hipotalamusa.
Paraventrikularno jedro je ključna centralna stuktura u neuralnoj i endokrinoj regulaciji krvnog pritiska. Sastoji
se od dve funkcionalne celine – neuroendokrine (sekretorne) i autonomne, koje su integralno
povezane u modulaciji kardiovaskularnog odgovora na različite fiziološke zahteve. Neuroendokrini magnocelularni
neuroni sintetišu i oslobađaju vazopresin u cirkulaciju, gde vazopresin ispoljava svoje hormonsko
dejstvo. Jedan deo sintetisanog vazopresina oslobađa se i lokalno, unutar samog jedra, delujući kao
neurotrasmiter/neuromodulator i utičući na signalizaciju okolnih neurona. Manja grupacija parvocelularnih
neurona učestvuje u sekretornom odgovoru paraventrikularnog jedra na različite stresore, menjajujući
aktivnost hipotalamo-hipofizno-nadbubrežne osovine. Autonomni deo paraventrikularnog jedra
dire-ktno ili indirektno reguliše simpatičku aktivnost usmerenu ka kardiorenalnom sistemu. Brojne studije
na životinjama i ljudima ukazuju na važnu vezu između nivoa sinteze vazopresina i nastanka hipertenzije.
Različiti molekularno-biološki pristupi korišćeni su za procenu i izučavanje uticaja promene ekspresije i
strukture centralnih i perifernih vazopresinskih receptora na krvni pritisak. Budući da je hipertenzija oboljenje
sa izraženom incidencom u humanoj populaciji i da povećava rizik od razvoja kardiovaskularnih
komplikacija visokog mortaliteta, od presudnog je značaja pronaći uzrok njenog nastanka. Rasvetljivanje
mehanizama kojima vazopresinski sistem doprinosi genezi hipertenzije imalo bi veliki biomedicinski značaj
i omogućilo bi razvoj antihipertenzivnih lekova nove generacije veće efikasnosti.Vasopressin or antidiuretic hormone is a peptide molecule that regulates osmotic and cardiovascular
homeostasis in a complex manner. The main sources of vasopressin are the supraoptic and paraventricular
nucleus of the hypothalamus. Paraventricular nucleus is the pivotal central structure involved in neural
and endocrine regulation of blood pressure. It is composed of two functionally separate compartments
– neuroendocrine (secretory) and autonomic, which integratively modulate cardiovascular response according
to various physiological demands. Neuroendocrine magnocellular neurons are responsible for vasopressin
synthesis and its secretion into the bloodstream, where vasopressin exerts hormonal effects.
Some portion of synthesized vasopressin is released locally within the nucleus itself, acting as neurotransmitter/
neuromodulator and altering signalization of the surrounding neurons. Small amount of parvocellular
neurons is involved in secretory response of the paraventricular nucleus to various stressors,
changing the activity of hypothalamo-hypophyseal-adrenal axis. Autonomic part of the paraventricular nucleus
directly or indirectly regulates the sympathetic charge toward the cardiorenal system. Numerous
animal and human experimental studies indicate the important connection between vasopressin levels
and the development of hypertension. Various genetic approaches have been used to determine and
study the influence of expressional and structural changes in central and peripheral vasopressin receptors
on blood pressure. Since hypertension shows high incidence in the human population and increases a
risk for high mortality cardiovascular complications, it is essential to understand what causes it. Elucidating
the mechanism behind vasopressin contribution to generate hypertension would have a significant
biomedical impact and it would ensure the development of new generation antihypertensive drugs with
increased efficacy
Parkinson’s disease – state of the art
Get PDFParkinsonova bolest (PB) je kompleksno progresivno neurodegenerativno oboljenje sa nerazjašnjenom
etiopatogenezom. Odlikuje je, između ostalog, narušena struktura i funkcija komponenti dopaminskog sistema
u delu mozga u kome se nalaze centri za izvođenje voljnih pokreta, kogniciju i pamćenje, dok su na
ćelijskom nivo karakteristične neuroinflamacija, narušavanje strukture i funkcija mnogih organela uključujući
mitohondrije, lizozome ili transportne vezikule, poremećen redoks status, nepravilno savijanje proteina
koje uslovljava njihovo neadekvatno funkcionisanje, stvaranje unutarćelijskih depozita različitih
supstanci (molekula/jona). Obično se manifestuje kombinacijom niza motornih i nemotornih simptoma,
uključujući tremor pri mirovanju, usporenost i osiromašenost pokreta (bradikinezija), ukočenost mišića
(rigidnost) ruku, nogu i vrata, gubitak posturalnih refleksa, fleksibilan položaj tela, kao i konstipacija, urinarna
disfunkcija, impotencija, poremećaji faza sna, prekomerna dnevna pospanost, nemogućnost gutanja
pljuvačke, znojenje, mučnina, anksioznost, apatija, depresija, demencija. Dijagnostikovanje PB se vrši
posredno na osnovu prisustva minimum dva motorna simptoma i adekvatan odgovor na antiparkinson
terapiju, a sa sigurnošću se potvrđuje tek post-mortem analizama utvrđivanjem postojanja karakterističnih
patohistoloških promena u različitim regionima mozga. Kao potencijalni uzročnici njenog nastanka i
progresije izdvajaju se genski faktori, faktori spoljašnje sredine, kao i njihovo međusobno delovanje. Izazovi
PB su ne samo nemogućnost ranog uspostavljanja dijagnoze, poteškoće u procenjivanju toka bolesti,
identifikacija potencijalnih biomarkera i signalnih puteva koji su uključeni u patogenezu, njihova uloga
u kliničkoj prezentaciji bolesti, već i terapija. Iako se ovo hronično oboljenje leči različitim lekovima (farmakoterapija),
hirurškim zahvatima, i potpornim, komplementarnim i alternativnim terapijama, ni jedan
od navedenih vidova terapije ne omogućava potpuno ozdravljenje već kontrolu simptoma radi što dužeg
nezavisnog funkcionisanja obolelih.Parkinson’s disease (PD) is a complex progressive neurodegenerative disease with uncertain etiopathogenesis.
Among others, it is characterized by impaired structure and function of components of the dopamine
system in regions of the brain responsible for performing voluntary movements, cognition and
memory; neuroinflammation; disruption of structure and function of various organelles including mitochondria,
lysosomes or transport vesicles, disturbed redox status, misfolding of proteins, intracellular deposition
of various substances (molecules/ions). Usually PD is manifested by a combination of several
motor and non-motor symptoms, including resting tremor, slowness of movement and speed (bradykinesia),
stiffness of arms, legs and neck muscles (rigidity), loss of postural reflexes, flexible body position,
along with constipation, urinary dysfunction, impotence, sleep disorders, excessive daytime sleepiness,
inability to swallow saliva, sweating, nausea, anxiety, apathy, depression, dementia. Diagnosing is performed
indirectly based on the presence of at least two motor symptoms and an adequate response to antiparkinsonian
therapy, while it can be confirmed with certainty only by post-mortem analysis according
to the existence of characteristic pathohistological changes in different regions of the brain. In PD pathogenesis
the relative contribution of genes, environmental/lifestyle factors, as well as their specific interactions
has been recognized. The challenges of PD are not only the impossibility of early diagnosis,
difficulties in assessing the course of the disease, the identification of potential biomarkers and signaling
pathways involved in pathogenesis, their role in the clinical presentation of the disease, but also the therapy.
Although the PD patients are treated with various drugs (pharmacotherapy), surgical interventions,
and supportive, complementary and alternative therapies, none of the mentioned types of therapy provide
the healing but they enable the control of the symptoms for the longest possible independent functioning
of the patients
Genetic factors impacting the efficacy and toxicity of methotrexate therapy in rheumatoid arthritis patients
Get PDFReumatoidni artritis (RA) je hronično, inflamatorno, autoimunsko oboljenje koje se karakteriše bolom,
otokom i destrukcijom sinovijalnih zglobova, što može da dovede do invaliditeta i prerane smrti obolelih.
Terapija izbora na samom početku tretmana je monoterapija metotreksatom (MTX), koji je zbog
svoje efikasnosti i dobrog bezbednosnog profila kao i zbog smanjivanja učestalosti komorbiditeta i
mortaliteta obolelih osoba, i danas zlatni standard u terapiji RA. Međutim, studije su pokazale da odgovor
na terapiju metotreksatom pokazuje 33-65% pacijenata, dok se tretman prekida kod 16% obolelih
na monoterapiji zbog neželjenih efekata. Na ishod terapije, između ostalog, utiče i genetički
profil pacijenata ali ova veza nije dovoljno objašnjena. Genske varijacije u vidu polimorfizama pojedinačnih
nukleotida mogu da modifikuju odgovor osobe na različite faktore spoljašnje sredine, među
njima i na odgovor na farmakološku terapiju. Ovaj rad će pokušati da obuhvati pregled uticaja pojedinačnih
polimorfizama na efikasnost i toksičnost terapije metotreksatom kod obolelih od RA.Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease characterized by impairment of
synovial joints. Due to its efficacy, safety, and relatively low costs, MTX remains the cornerstone drug and
a key part of the initial treatment strategy for RA patients. However, studies have shown that only 33-65%
of patients respond to methotrexate therapy, and 16% of patients discontinue monotherapy due to side
effects. The therapy outcome is influenced by the genetic profile of the patients, but this association is not
yet fully understood. Gene variations in the form of single nucleotide polymorphisms can modify a person's
response to various environmental factors, including their response to pharmacological therapy. This paper
aims to provide an overview of the impact of individual polymorphisms on the efficacy and toxicity of
methotrexate therapy in RA patients
Spontaneously fermented ancient wheat sourdoughs in breadmaking: Impact of flour quality on sourdough and bread physico-chemical properties
Get PDFIn this study changes during fermentation of spontaneously fermented modern and ancient (spelt, emmer, and khorasan) wheat sourdoughs and their feasibility to act as leavening agents in breadmaking were evaluated. During 6 h of fermentation, sourdough was characterized for lactic acid bacteria and yeasts counts, pH, total titratable acidity (TTA), proteolytic activity, rheological and electrophoretic profiles. The effects of 25 and 50 g/100g sourdough addition on physico-chemical and sensory properties of refined wheat flour bread were also investigated. Although in all sourdoughs a pH drop, increase in proteolytic activity, gliadin and glutenin degradation with fermentation were recorded, due to different flour composition and microbial activity, tested sourdoughs significantly differed in rheological properties and breadmaking quality. Wheat sourdough being characterized by the highest acidification, increase in proteolytic activity, and the most extensive hydrolysis of gliadins, resulted in bread with the lowest specific volume and hardest crumb texture. Emmer sourdough, having the highest TTA, ash and wet gluten content, exhibited the highest extensibility, the least pronounced changes in proteolytic activity and the electrophoretic pattern which produced bread with the highest volume and softest texture. In general, ancient wheat varieties have shown great potential in sourdough breadmaking in comparison to modern wheat