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Novel Ruthenacarborane–NSAID Conjugates
No full textThe significant side effects associated with platinum-based anticancer agents have driven the continuous pursuit of novel, non-platinum-based metal compounds. Ruthenium-based organometallic compounds have emerged as promising alternatives, owing to their distinctive and adaptable biochemical properties. The research efforts are focused on the development of ruthenacarborane-based anticancer drugs. The combination of ruthenium(II) complexes, recognized for their inherent anticancer potential, with carboranes, boron-rich clusters possessing unique chemical and physical characteristics, and NSAIDs, known to inhibit COX, an enzyme overexpressed in tumors, offers a novel approach for cancer therapy. Consequently, combining these three moieties into a single molecule represents a compelling strategy to develop drugs with a dual mode of action. Herein, we report the synthesis of a series of ruthenacarborane-(η6-p-cymene)–NSAID conjugates (4a, 4b, 5b, and 6b) by linking NSAIDs (flurbiprofen, fenoprofen, and ibuprofen) to ruthenacarborane complexes using methylene and ethylene spacers, while maintaining the integrity of the sensitive ester groups present in the system. The synthesized conjugates were thoroughly characterized using multinuclear (1H, 11B, and 13C) NMR spectroscopy. Notably, the conjugates demonstrated low COX inhibition and no cytotoxic potential against different cancer cell lines, probably due to oxidative deactivation confirmed by cyclic voltammetry (CV). This indicates that the conjugation of this type of ruthenacarborane with NSAIDs does not result in novel anticancer drugs
Proferroptotic response to nutrient deprivation and sorafenib treatment in hepatocellular carcinoma cells – a microscopic study
No full textNutrient deprivation (ND) is already recognised as a potential adjuvant therapy for cancer treatment. In
the recent study by Krstic et al [1], a positive correlation between ND-induced sensitisation of
hepatocellular carcinoma (HCC) cells to sorafenib (Sfb), a drug used to treat HCC, and p53 status was
demonstrated. This indicates the essential role of p53 in the priming HCC cells for regulated cell death
(RCD). Preliminary microscopic data indicated a possible involvement of ferroptosis, an iron-dependent
RCD characterised by the accumulation of lipid peroxides, in this process. Therefore, we wanted to find
out whether ferroptosis plays a role in the removal of HCC cells depending on p53 status.
To this end, p53 wild-type (p53 WT) and p53 knockout (p53 KO) HepG2 cells were grown in growth
medium (GM) or in starvation medium (SM) and treated with Sfb (10 μM) or with the ferroptosis inducer
RSL-3 (3 μM) for 6 hours. The morphological signs of ferroptosis and the immunopositivity of the main
regulator of ferroptosis-related signalling pathways, nuclear factor erythroid 2-related factor 2 (Nrf2)
and ferritin heavy chain 1 (FTH1), which is involved in the sequestration of iron, were analysed
microscopically. In addition, western blotting of the Nrf2 downstream antiferroptotic proteins -
glutathione peroxidase 4 (GPX4) and cystine glutamate antiporter (xCT) - and of FTH1 was performed.
The level of lipid peroxidation was determined by analysing the oxidation of Bodipy 581/591 C11 using
flow cytometry.
The results showed activation of the proferroptotic pathway by ND, as reduced nuclear translocation of
Nrf2 was detected, followed by lower levels of GPX4, xCT and FTH1 (Figure 2). Microscopically, this
was followed by increased accumulation of lipids and lipofuscin. However, the extent of lipid
peroxidation was not altered. The effects of RSL-3 were similar to those of ND, but in combination of
those two a significant increase in lipid peroxidation was observed. The proferroptotic effects of Sfb
were weak, as it only inhibited GPX4 protein expression and slightly increased lipid peroxidation.
However, in combination with ND, an accumulation of lipids/lipofuscin and a tendency to accumulate
lipid peroxides was observed, which was supported by the inhibition of the Nrf2/GPX4/xCT axis.
These results suggest an involvement of ferroptosis in the clearance of HCC cells during ND in
combination with Sfb. The proferroptotic effect of RSL-3, ND and Sfb is p53-dependent, as no reduction
of GPX4 and xCT was detected in the p53 KO HepG2 cells. This could at least partially explain the
resistance of p53 KO HCC to these treatments.Book of abstracts : 17th Multinational Congress on Microscopy : 17MCM; 2025 Sep 7-12; Portorož, Slovenia. Ljubljana : Slovene Society for Microscopy; 2025. p. 222-3
Phytochemical Composition and Antiradical Potential of Thymus pannonicus All. Extracts: EPR and Orbitrap-Based Evaluation
No full textThymus pannonicus All. is a perennial aromatic herb prevalent in Central and Eastern Europe, known for its chemotypic diversity, particularly thymol- and citral-rich types. The citral chemotype, found uniquely in the Vršac Mountains (Serbia), is being cultivated due to its aromatic and health-promoting properties. However, the free radical scavenging activity of this chemotype remains poorly characterized. This study aimed to evaluate the antiradical potential of T. pannonicus extracts using electron paramagnetic resonance (EPR) spectroscopy and to elucidate its phytochemical profile using Orbitrap high-resolution mass spectrometry. Aerial parts of T. pannonicus were extracted using four solvents: water, ethanol (EtOH), 50% ethanol, and methanol (MeOH), by maceration (1:5 w/v) at 40 °C for 4 h. Antiradical activity against DPPH and hydroxyl radicals (•OH) was assessed using EPR spectroscopy. The spin-trapping agent DEPMPO was used for the detection of short-lived radicals. The phytochemical composition of extracts was analyzed via Orbitrap LC-MS, and the relative abundance of compounds was determined based on peak areas. EPR spectroscopy revealed that the tested extracts exhibit notable antioxidant potential, with significant differences in radical scavenging efficiency depending on both solvent and radical type. The extract prepared in 50% ethanol displayed the highest DPPH radical scavenging activity (81.84%), suggesting a good balance of polarity to extract a broad range of antioxidant compounds. The methanolic extract also showed substantial activity (58.24%) against DPPH radicals. In contrast, hydroxyl radicals (•OH), which are highly reactive and damaging species, were most effectively neutralized by the methanol (95.37%) and aqueous (84.54%) extracts. Complementary Orbitrap-MS analysis provided insight into the phytochemical composition underlying these radical-scavenging properties. High levels of phenolic acids and flavonoids were detected across the samples, with methanol extract being especially rich in
these bioactive compounds. Rosmarinic acid was found in particularly high concentration in the methanolic extract, consistent with its known antioxidant capacity. Among salvianolic acids, salvianolic acid H stood out with notably high levels in the same extract, contributing further to the strong radicalscavenging ability observed. Additionally, the methanolic extract was rich in flavonoid aglycones such as luteolin and apigenin, as well as thymusin, all of which are associated with potent antioxidative mechanisms, including direct radical neutralization and metal chelation. All T. pannonicus extracts exhibited notable free radical scavenging activity, especially against hydroxyl radicals. The strong antiradical activity is likely attributed to a complex mixture of phenolic acids and flavonoids, as revealed by Orbitrap analysis. These findings support the therapeutic potential of T. pannonicus, particularly the citral chemotype, in oxidative stress-related applications. Further studies should explore its selectivity against other biologically relevant radical species.Tosti T, Dapčević A, Tešić Ž, editors. Book of abstrcats: 29th International Symposium on Separation Sciences: ISSS 2025; 2025 Sep 25-27; Belgrade, Serbia. Belgrade: Serbian Chemical Society; 2025. p. 51
A Study of Fish Community at the Obedska Bara Ramsar Site and Pathways to Sustainable Management
No full textThe study was conducted on the Obedska Bara Ramsar site at two localities,
Krstonoši´ca okno and canal Vok, to provide insight into fish community status by analysing
fish biomass, biodiversity, and changes after restoration measures. A total of 685 fish
samples were examined across four periods, from 2011 to 2023. Biodiversity index, relative
biomass, and non-native species were analysed to evaluate the restoration measures’
influence. All parameters showed a negative trend until the restoration works were implemented,
after which they increased. This study also provides recommendations to improve
the site considering the Mission Restore our Ocean and Waters by 2030
PARP inhibition increases sensitivity to cisplatin in non-small-cell lung carcinoma via the induction of TET-dependent hydroxymethylation
No full textIntroduction: Platinum-based chemopotentiation by poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) has been confirmed in some non-small-cell lung carcinoma (NSCLC) models, but the molecular mechanisms of PARPi synergy with chemotherapeutics remain poorly clarified. This study aimed to evaluate the efficacy of PARPi niraparib in mitigating resistance to cisplatin through increased ten-eleven translocation (TET) enzymatic activity and 5-hydroxymethylcytosine (5hmC) level in human NSCLC model.
Methods: The chemosensitivity of human NSCLC, sensitive and multidrug-resistant (NCI-H460 and NCI-H460/R, respectively), lung adenocarcinoma cell line (A549), and normal embryonic lung fibroblasts (MRC-5) to increasing concentrations of cisplatin was studied by the MTT assay. The MTT and the median effect analyses were used to evaluate the efficacy of niraparib combinatorial synergy with cisplatin, dimethyloxalylglycine (DMOG), and vitamin C. The inhibition of PARP activity was determined by the PARP activity assay. The global level of 5hmC was examined by confocal microscopy, slot-blot, and flow cytometry, which was used for monitoring cell death at different stages. The protein level of lamin B, PARP1, procaspase-3, and TETs was assessed by Western blotting. The expression of the TET enzyme was analyzed by real-time quantitative PCR.
Results: The chemosensitivity to cisplatin was found to be correlated with the level of 5hmC in NSCLC and MRC-5 cell lines. A549 was characterized with the lowest sensitivity to cisplatin and the 5hmC level and was selected for chemosensitization via PARPi-dependent restoration of the 5hmC level. Treatment of A549 cells with niraparib resulted in decreased PARP activity, increased 5hmC level, and synergism with cisplatin by promoting cisplatin-induced apoptosis. The treatment with niraparib and cisplatin resulted in synergistic effect in the hydroxylase activity of TET2 in terms of increased 5hmC production in A549 cells.
Conclusion: The improved response to cisplatin following PARPi-mediated sensitization of A549 cells, accompanied by the restoration of 5hmC levels, provides additional insights into the epigenetic mechanisms underlying the synergy between PARPi and cisplatin. The use of PARPi in clinical settings could increase the number of patients enriched in 5hmC, who might benefit from platinum-based therapy. Additionally, targeting epigenetic marks could provide a molecular basis for personalized cancer therapy directed to overcome tumor resistance
Multiple low dose streptozotocin-induced diabetes as a model for studying autoimmune diabetes in humans
No full textThe autoimmune response directed against pancreatic β cells is the most essential
pathogenic process in type 1 diabetes (T1D) in humans. Spontaneous animal models of T1D greatly contribute to our understanding of the disease pathogenesis and
therapeutic options. Amongst many disease models, a significant proportion of T1D
research is performed on multiple low dose streptozotocin induced diabetes in experimental animals, in parallel. Here, we discuss advantages of this model for contemporary T1D research. Additionally, challenges and perspectives for further improvement
of the model are presented
Hybrid Platinum(IV)-Naproxen Nanostructured Drugs Reprogram Melanoma Cells and Overpower Cisplatin
No full textThe concept of hybrid drugs that integrate cytotoxic and anti-inflammatory activity, enabling the simultaneous delivery of a chemotherapeutic agent and a non-steroidal anti-inflammatory drug (NSAID) into the tumor microenvironment (TME), was created with the aim of blocking the mitogenic signals that lead to tumor renewal. Here, we provide for the first time a detailed insight into the mechanism of action of a platinum(IV) complex based on the cisplatin (CP) scaffold bearing two deprotonated NSAID ligands (naproxenate (Npx)) in axial position ([CP(Npx)2]), free and immobilized in nanostructured silica SBA-15 (SBA-15|[CP(Npx)2]), in a melanoma model. The conjugate in free or loaded form diminished the viability of cancer cells more potently than CP, with an exceptional preference for the malignant phenotype. Type I and II programed cell death, senescence, and terminal differentiation of the surviving cell fraction were the basic mechanisms of action by which the new hybrid molecule achieved its effect in vitro. In the mouse melanoma model, the application of the therapeutic agents led to a reduction in tumor volume, extinguishing of intratumoral inflammation, and an overall better toxicity profile compared to CP. Overall, this approach improved the efficacy of chemotherapy by removing obstacles that cause chronic inflammation in the TME
On the tumor cell growth limiting potential of newly synthesized acridine-1,8-dione derivatives
No full textA series of acridine derivatives, namely 10-(4-substituted benzyl)-9-(4-hydroxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-tetrahydroacridine-1,8(2H,5H)-diones, was synthesized via the Hantzsch-type multicomponent reaction between dimedone, 4-hydroxybenzaldehyde and 4-substituted benzylamine. The cytotoxic potential of these compounds was evaluated against human ovarian (A2780), melanoma (A375), colon (HCT 116) and breast cancer (MCF-7) cell lines, as well as normal human lung fibroblasts (MRC-5) and keratinocytes (HaCaT). Tested cell lines displayed different but moderate sensitivity to the investigated compounds, with the exception of compounds with a methyl (2) and a bromo group on the benzyl ring (6). These two compounds were almost equally effective against all cancer cell lines tested, suggesting that their activity is more general and less dependent on cell-specific characteristics. Compound 2 showed satisfying solubility, thus appeared to be the most acceptable for further examination and the A375 cell line was selected as the platform for evaluating the compound as the most sensitive to the applied treatment. This compound was shown to induce cell cycle arrest in G2/M phase, accelerating aging manifested through development of differentiated as well as senescent-like phenotype and subsequent fragmentation of genetic material. All aforementioned effects were accompanied with strong increment in production of reactive oxygen/nitrogen species (ROS/RNS). Docking studies against topoisomerase IIβ, hypoxia-inducible factor (HIF) 2α and mitogen-activated extracellular signal-regulated kinase (MEK) 1 revealed that treatment with tested compound might interfere with key signaling pathways involved in cell proliferation, and metabolic features of crucial importance for tumor progression. The obtained results contribute to the expansion of biologically relevant chemical space, thus providing guidelines for the assessment of new candidates for anticancer drugs
A curated dataset on the distribution of West Palaearctic freshwater bivalves
No full textFreshwater bivalves (FWB) are attracting scientific and societal attention given their essential
ecosystem services, ecological functions, and poor conservation status. Current knowledge
of the spatial distribution of West Palearctic FWB is poor preventing the understanding
of biogeography and conservation planning. One of the priorities of the pan-European
networking project “CONFREMU - Conservation of freshwater mussels: a pan-European
approach” funded by the European Union, was to fill the knowledge gap on the distribution
of FWB in Europe and adjacent regions. Based on the efforts of this network of scientists, we
provide the most complete, taxonomically, and geographically accurate distribution of FWB
species for the entire West Palearctic. The dataset contains 270,287 geo-referenced records
of 93 native and 8 non-native FWB from 1674 to 2023. The dataset compiles information
from private records from 82 specialists and multiple sources (e.g., published articles, grey
literature, biodiversity databases, and scientific collections). This dataset, available online,
represents an important data source for future studies on the biodiversity, biogeography, and
conservation of these important organisms
Insights into bioactivity guided chemical profiling of Ziziphus jujuba Mill. fruits wild-growing in Montenegro
No full textJujube (Ziziphus jujuba Mill.) is a highly abundant wild-growing plant in Montenegro. It has been utilized since old times for various bioactive properties by the natives, however its detailed chemical characterization, antimicrobial, antioxidant and cytotoxic potential have not been extensively explored. Herein, we used crud methanol extract and three fractions (methylene chloride, n-butanol and aqueous) to asses bioactive features of fruits from this wild growing edible plant, after which we performed the targeted analysis of phenolic compounds of n-butanol fraction by (UHPLC-DAD-MS/MS). Our antioxidant assays showed the highest radical scavenging potential for n-butanol fraction using DPPH and ABTS methods. As for the antimicrobial activity of extract and three fractions, generally aqueous showed the least promising antibacterial and antifungal properties, whereas methylene chloride, methanol and n-butanol fractions showed quite promising antimicrobial potential. E. coli and S. aureus strains were the most susceptible to the compounds present in the methylene chloride and n-butanol fractions with MIC of 0.01–0.025 mg/mL, and MBC 0.025–0.05 mg/mL, along with MRSA strain, which was the most susceptible to the effects of methanol extract with MIC of 0.10 mg/mL and MBC 0.15 mg/mL. The results of antifungal activity showed lower potential to inhibit growth of pathogenic fungi than bacteria, whereas cytotoxicity assay showed extracts have no effects towards HaCaT skin cell line.The n-butanol fraction had the overall most promising activity, and therefore was subjected to more in depth chemical analysis