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LB-100 Enhances Drugs Efficacy through Inhibition of P-glycoprotien Expression in Multidrug-Resistant Glioblastoma and Non-Small Cell Lung Carcinoma Cellular Models
No full textBackground/Objectives: This study explores the potential of LB-100 (a protein phosphatase 2A—PP2A inhibitor) combined with adavosertib (a WEE1 kinase inhibitor) and doxorubicin (DOX), to overcome multidrug resistance (MDR) in cancer cells and enhance treatment efficacy. Methods: We evaluated LB-100 combinations with adavosertib and DOX in patient-derived glioblastoma and non-small cell lung carcinoma cells (NSCLCs) using a real-time cell analyzer. Effectiveness was also assessed through immunofluorescence assay, and interactions were analyzed via SynergyFinder+. We also examined P-glycoprotein (P-gp) expression and drug resistance genes’ expression in MDR glioblastoma and NSCLCs after LB-100 treatment, as well as LB-100 sensitizing effect on DOX and DOX accumulation. Results: LB-100 significantly boosts the effectiveness of adavosertib and DOX after multiple applications. It also enhances these drugs’ cytotoxicity in a single application without acting synergistically. Additionally, LB-100 reduces P-gp expression in MDR glioblastoma and NSCLCs, sensitizing them to DOX and increasing its accumulation. Conclusions: LB-100 enhances the effectiveness of drugs against MDR cancer cells, presenting a promising strategy to overcome drug resistance in glioblastoma and NSCLCs through P-gp modulation
Origin and Genealogy of Rare mtDNA Haplotypes Detected in the Serbian Population
No full textBackground: The Balkan Peninsula has served as an important migration corridor between Asia Minor and Europe throughout humankind’s history and a refugium during the Last Glacial Maximum. Past migrations such as the Neolithic expansion, Bronze Age migrations, and the settlement of Slavic tribes in the Early Middle Ages, are well known for their impact on shaping the genetic pool of contemporary Balkan populations. They have contributed to the high genetic diversity of the region, especially in mitochondrial DNA (mtDNA) lineages. Serbia, located in the heart of the Balkans, reflects this complex history in a broad spectrum of mtDNA subhaplogroups. Methods: To explore genetic diversity in Serbia and the wider Balkan region, we analyzed rare mtDNA subclades—R0a, N1a, N1b, I5, W, and X2—using publicly available data. Our dataset included already published sequences from 3499 HVS-I/HVS-II and 1426 complete mitogenomes belonging to West Eurasian and African populations, containing both contemporary and archaeological samples. We assessed the parameters of genetic diversity found in different subclades across the studied regions and constructed detailed phylogeographic trees and haplotype networks to determine phylogenetic relationships. Results: Our analyses revealed the observable geographic structure and identified novel mtDNA subclades, some of which may have originated in the Balkan Peninsula (e.g., R0a1a5, I5a1, W1c2, W3b2, and X2n). Conclusions: The geographic distribution of rare subclades often reveals patterns of past population movements, routes, and gene flows. By tracing the origin and diversity of these subclades, our study provided new insights into the impact of historical migrations on the maternal gene pool of Serbia and the wider Balkan region, contributing to our understanding of the complex genetic history of this important European crossroads
Downsizing Plastics, Upsizing Impact: How Microplastic Particle Size Affects Chironomus riparius bioturbation activity
No full textMicroplastic contamination in freshwater systems poses serious ecological risks, yet the role of particle size in shaping these impacts remains underexplored. This study investigates the influence of microplastic size on bioturbation activities of Chironomus riparius larvae, a process essential for sediment dynamics and nutrient cycling. Employing luminophore sediment profile imaging (LSPI), we tracked the vertical distribution of polyethylene particles within sediment layers, focusing on two distinct size ranges: small (53–63 μm) and large (250–300 μm) spherical particles. Microplastics (MPs) were introduced at a 0.076% sediment ratio to reflect natural exposure scenarios. Initial findings reveal that both particle sizes undergo downward transport, though with different patterns. Notably, smaller particles demonstrated a more pronounced effect on larval behaviour, appearing frequently in digestive tracts and suggesting increased bioavailability. Temporal analysis showed distinct reworking dynamics for each particle size, with larger particles exhibiting a delayed reworking time compared to the smaller particles. This highlights the critical influence of particle size on the fate and behavior of MPs in freshwater systems, with smaller particles potentially posing a greater ecological risk due to their quicker and more active incorporation into sedimentary processes. This study provides critical insights into sizespecific interactions between MPs and freshwater organisms, enhancing our understanding of their impacts on ecosystem health and sedimentary processes
Endothelial-Protective Actions of Diethylether Extract from Gentiana kochiana and Xanthone Gentiacaulein Against Oxidized LDL-Induced Injury—In Vitro Evaluation
No full textEndothelial dysfunction is an early pathophysiological event in atherosclerosis. The endothelial-protective abilities of diethylether extract (EE) from the Gentiana kochiana (Gentianaceae) herb and its main component, xanthone aglycone gentiacaulein (GC), were evaluated in an oxidized low-density lipoprotein (oxLDL)-treated EA.hy926 endothelial cell line. The EE and GC actions were assessed using cell viability assays, flow cytometry, immunoblot, DPPH, NBT, TBARS, conjugated diene formation, and Griess tests. Both EE and GC prevented oxLDL-induced apoptosis by reducing intracellular reactive oxygen species levels, mitochondrial depolarization, and caspase activation in EA.hy926 cells. EE and GC dose-dependently diminished oxLDL-induced cellular lipid peroxidation. In cell-free conditions, EE moderately scavenged superoxide anions and had no affinity toward DPPH radicals, GC did not interact with either of investigated free radicals, while both EE and GC effectively delayed Cu²⁺-induced LDL oxidation. EE and GC upregulated oxLDL-suppressed protective Akt/CREB/eNOS and ERK signals and restored oxLDL-reduced nitric oxide levels. Therefore, EE and GC effectively counteract oxLDL-induced endothelial apoptosis by reducing oxidative stress, promoting mitochondrial recovery, and enhancing the prosurvival Akt/CREB/eNOS axis and ERK activity. Our study is the first to demonstrate that xanthone-rich EE from aerial parts of G. kochiana and xanthone GC alleviate oxLDL-induced endothelial cell injury, underscoring their potential for cardiovascular protection
Mixture Containing 5% Polysaccharide Extract of Cerioporus squamosus (Huds.) Quélet, 5% Dexpanthenol, and 0.2% Hyaluronic Acid Shows In Vitro and In Vivo Wound Healing Properties
No full textBackground: This study explores wound healing and the antimicrobial potential
of a natural formulation containing a polysaccharide extract from Cerioporus squamosus,
hyaluronic acid, and dexpanthenol. Methods: Wound healing effects were assessed using
HaCaT keratinocytes, while antimicrobial activity was evaluated against human skin
pathogens using a microdilution assay. In vitro cytotoxicity tests ensured formulation
safety, whereas in vivo wound healing was further investigated using an animal model.
Gene expression analysis was performed to assess the molecular mechanisms involved.
Results: The unique glucan composition of C. squamosus (15.38% α-glucans and 7.91%
β-glucans) deviated from typical mushroom polysaccharide profiles, warranting further
exploration of its bioactivity. In vitro mushroom polysaccharides promoted 25.35% wound
closure after 24 hours, while the three-component formulation achieved 35.81% closure. Antibacterial
activity showed a minimum inhibitory concentration (MIC) of 0.44–1.75 mg/mL
and minimum bactericidal concentration (MBCs) of 0.88–3.50 mg/mL, while antifungal
activity ranged from 0.22 to 0.44 mg/mL (MICs) and 0.44 to 0.88 mg/mL (minimum fungicidal
concentration—MFC). In vivo data showed that 60% of treated wounds fully closed
by day 11, despite no statistically significant difference from the control. However, gene expression
analysis highlighted VEGF and collagen upregulation, indicating an enhancement
of wound healing on a molecular level. Conclusions: The novel three-component formulation
demonstrated consistent wound healing and antimicrobial properties, supporting its
potential as a safe and effective treatment for chronic and acute wounds
Postharvest quality maintenance of traditional Serbian peppers: The impact of heat treatment and storage temperature
No full textTraditional Serbian pepper cultivars, prized for their nutritional value and flavor, lack
established postharvest practices. The impact of storage conditions and hot water dipping
(HWD) at 55 ◦C for 1 min on the physicochemical properties of ‘Kurtovska Ajvaruša’,
‘Grkinja Babura’, and ‘Duga Bela Ljuta’ (Capsicum annuum L. var. longum) was examined.
Peppers were stored at 4 ◦C (with and without HWD pretreatment) and at 10 ◦C (without
HWD) for 21 days, followed by 3 days of shelf life. The main quality parameters measured
included general appearance, weight loss, chilling injury, decay incidence, color, histological
characteristics of pericarp, and quinic and succinic acid contents. Storage temperature,
duration, and HWD significantly affected the examined parameters. ‘Grkinja Babura’
retained higher water content with lower weight loss (5.2%) at 4 ◦C, while ‘Duga Bela Ljuta’
showed significant loss (8.7%) at 10 ◦C after 21 + 3 days. In ‘Duga Bela Ljuta’, both quinic
and succinic acid contents increased during cold storage, HWD treatment, and shelf life. In
contrast, in ‘Grkinja Babura’ and ‘Kurtovska Ajvaruša’, this trend was observed only for
quinic acid, whereas succinic acid content had a decreasing trend. HWD shows potential
to stabilize weight loss, preserve general appearance in two cultivars, and reduce chilling
injury (to 4.8%), as well as decay incidence (to 3.1%), indicating its potential to maintain
quality and marketability of these traditional pepper cultivars. These findings suggest that
HDW could have a high potential for sustainable strategies to improve the postharvest
quality of traditional pepper cultivars in the region
Changes in lipid metabolism in the visceral rather than the subcutaneous adipose tissue depot attenuate metabolic disturbances in obesity-resistant mice fed a high-fat diet
No full textObesity is characterized by an enlargement of white adipose tissue caused by caloric excess. The depot-specific adaptation of white adipose tissue in individuals resistant to obesity despite a high-calorie diet is crucial for understanding the pathogenesis of obesity and related metabolic disorders. Our aim was to characterize the metabolic and morphological state of obesity resistance and to investigate depot-specific changes in signaling pathways in epididymal visceral (eVAT) and inguinal subcutaneous (iSAT) white adipose tissue of C57BL/6J male mice on a high-fat diet (60 kcal% fats). After 14 weeks, the mice were categorized as obese (at least 30% higher body mass compared to the control group) or obesity-resistant (weight gain below 30%). Biochemical and morphological parameters, as well as histology, and signaling pathways involved in lipid metabolism, inflammation, and insulin sensitivity were investigated in eVAT and iSAT. The results showed unaltered body, total VAT and iSAT mass in obesity-resistant mice despite increased caloric intake. Leptin levels and glucose homeostasis were improved in these animals compared to the obese mice. In both eVAT and iSAT of the obesity-resistant mice, adipocyte size and lipolytic capacity were retained at control levels, while compared to the obese mice, preserved capacity for adipogenesis, improved local insulin sensitivity and the absence of inflammation were observed only in the eVAT. In conclusion, metabolic adaptation of eVAT rather than iSAT may have a substantial impact on the maintenance of the obesity-resistant phenotype with fewer metabolic complications, which could contribute to the improvement of existing obesity therapies.This is accepted manuscript version of the article: Vratarić M, Teofilović A, Vojnović Milutinović D, Veličković N, Vučićević Lj, Đmura G, Djordjevic A. Changes in lipid metabolism in visceral rather than the subcutaneous adipose tissue depot
attenuate metabolic disturbances in obesity-resistant mice fed a high-fat diet, The Journal of
Nutritional Biochemistry, 2025, 109912.
[https://doi.org/10.1016/j.jnutbio.2025.109912
Environmental Factors Determining the Distribution Pattern of Chironomidae in Different Types of Freshwater Habitats
No full textChironomidae are characterised by cosmopolitan distribution, high abundance
and diversity in different aquatic environments, which makes them ideal for studying
changes in freshwater ecosystems. To understand the environmental factors influencing
chironomid communities, we analysed how altitude and waterbody type (hydromorphological
features) affect their composition at 75 study sites from 49 watercourses. A total
of 110 chironomid taxa from five subfamilies were identified, with Prodiamesa olivacea,
Rheocricotopus fuscipes and Cricotopus bicinctus being the most frequent species. The lowest
values of all alpha diversity components were recorded in communities collected from
watercourses at altitudes up to 500 m a.s.l., while the highest values were observed in
small mountainous rivers and streams. Beta diversity showed that taxa turnover was
the dominant component in all situations analysed. Communities in large rivers with
fine substrate were characterised by the lowest taxa turnover and the highest levels of
nestedness, indicating the existence of an ecological gradient that reduces the number of
taxa from one site to another. We identified indicator taxa for different altitudes, as well as
groups of taxa that are typical for different waterbody types. Furthermore, the combination
of four water parameters (oxygen saturation, conductivity, concentration of ammonium
and nitrates) had the strongest influence on the chironomid community composition in the
studied watercourses
Postnatal overfeeding induces gut microbiota disturbances and impairs liver lipid metabolism through GPR43/FIAF/LPL pathway in the rat model of PCOS
No full textBackground & Aims
In women with polycystic ovary syndrome (PCOS), the incidence of metabolic
dysfunction-associated steatotic liver disease (MASLD) is high. The development
of PCOS-associated MASLD is accelerated by prepubertal obesity, but the extent
to which early-life weight gain exacerbates the metabolic features of PCOS is still
under debate. To clarify this, we analyzed the impact of overfeeding in early
postnatal period on metabolic features, gut microbiota profile and hepatic lipid
metabolism in the rat model of PCOS.
Methods
Wistar rats were divided into 4 groups, in which treatment with 5adihydrotestosterone (5a-DHT) was used to mimic hyperandrogenemia, whereas
litter size reduction was used to induce early postnatal overfeeding and
prepubertal obesity. The composition of the intestinal bacterial community was
determined by 16S rDNA sequencing. The level of short chain fatty acids was
measured by mass spectrometry. Hematoxylin-eosin-stained sections, Western
blots, and qRT-PCR were used to analyze hepatic lipid metabolism.
Results
Only postnatally overfed DHT-treated rats developed prominent obesity and
glucose intolerance, which was not associated with altered Firmicutes/Bacteroidetes ratio. Postnatal overfeeding shifted the microbiota composition towards
obesity-associated genera, while hyperandrogenemia led to reduced b-diversity
and an increased abundance of androgen-regulated genera. Interaction of
treatments reduced both a- and b-diversity and decreased the abundance of
beneficial butyrate-producing genera Roseburia, Oscillospira, and Ruminococcus
and plasma level of butyric acid. This shift in microbiota composition was
accompanied by decreased expression of G-protein coupled receptor 43 (GPR43),
fasting-induced adipocyte factor (FIAF), and increased expression of lipoprotein
lipase (LPL). In accordance with the altered GPR43/FIAF/LPL pathway,
increased expression of lipogenic transcription factors was observed in SLDHT animals, but this did not result in hepatic lipid deposition.
Conclusions
Early postnatal overfeeding is important factor in the development of PCOSrelated metabolic features, and it is associated with reduced a- and b-diversity and
decreased abundance of beneficial butyrate-producing genera in the PCOS animal
model. These changes impaired hepatic lipid metabolism via the
GPR43/FIAF/LPL pathway. Although these changes are not associated with
hepatic steatosis, they may pave the way for fatty liver disease in the long term.Joint Congress of the European Society for Paediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE) 2025: Connecting Endocrinology Across the Life Course; 2025 May 10-13; Copenhagen, Denmark. Bristol: Bioscientifica; 2025. EP903. (Endocrine Abstracts; Vol. 110)
The Effects of Subanesthetic and Anesthetic Doses of Alfaxalone on Behavioral Deficits in APP Knock-In Mouse Model of Alzheimer's disease
No full textNeurosteroids have recently gained attention as promising therapeutics for Alzheimer’s
disease (AD). Alfaxalone (ALX) is a synthetic analog of naturally occurring neurosteroid
allopregnanolone, with improved bioavailability and a lack of tolerance development with
extended use.
The effects of ALX in subanesthetic (10mg/kg) and anesthetic dose (40mg/kg) were
evaluated in a state-of-the-art mouse model of AD-like amyloidosis, APPNL-G-F knock-in (APP
KI) mice, provided by the RIKEN BRC through the National Bio-Resource Project of the
MEXT, Japan. Nine-month-old male APP KI mice and their wild-type (WT) littermates were
treated with ALX for 4 weeks (s.c.; 1/week), and their basal motor response and spatial
habituation were assessed using the Open Field (OF) test paradigm.
Behavioral analyses showed clear differences between genotypes, with APP KI mice
exhibiting reduced locomotor and vertical activities, along with impaired spatial habituation
compared to WT controls. In KI animals treated with a subanesthetic dose of ALX, all measured
parameters, such as locomotor activity, vertical activity, and time spent in the central area, were
not significantly altered. In contrast, the subanesthetic dose resulted in a loss of spatial
habituation in WT animals. However, administering the anesthetic dose of ALX reversed the
behavioral deficits in APP KI mice, bringing these values back to the levels observed in treated
WT animals.
The results highlight the dose-dependent effects of ALX on behavioral deficits in APP KI
mice as an animal model of AD and support further investigation of ALX as a promising
therapeutic in AD.Dragić M, editor. Book of abstracts: 9th Congress of Serbian Neuroscience Society; 2025 Oct 6-8; Belgrade, Serbia. Belgrade: Serbian Neuroscience Society; 2025