1. Toxicity assessment of three emerging bisphenols (BPA, BPAP and BPC) and their binary mixtures in an advanced in vitro 3D HepG2 cell modelMartina Štampar, Tim Ravnjak, Alja Štern, Bojana Žegura, 2026, izvirni znanstveni članek Povzetek: Bisphenols (BPs) are industrial chemicals extensively used in polycarbonate plastics and epoxy resins for everyday products, including food and beverage containers, toys, and thermal paper, representing major sources of human exposure. Bisphenol A (BPA) is the most prevalent; however, due to its endocrine-disrupting, reproductive, and genotoxic effects, it is classified as a substance of high concern by the European Chemicals Agency. Regulatory restrictions have prompted the use of structural analogues, including bisphenol AP (BPAP) and bisphenol C (BPC); however, emerging evidence suggests they may pose similar or greater health risks. Comprehensive data on their toxicity and human exposure, especially in mixtures, remain limited. This study assessed the cytotoxic and genotoxic effects of BPA, and less studied analogues BPAP, BPC, and their binary mixtures using a human-relevant 3D HepG2 spheroid model, representing an advanced in vitro system. Spheroids were exposed for 24 and 96 h, and effects were evaluated by ATP-based viability assays, comet assay, and targeted transcriptomics. None of the bisphenols induced significant cytotoxicity, although slight reductions in viability were observed for BPAP, BPC, and mixtures. DNA strand breaks were detected after exposure to BPA, BPC, and mixtures. Transcriptomic analysis revealed modest stress responses and strong upregulation of xenobiotic metabolism genes (CYP1A1, CYP1A2, CYP3A4, UGT1A1, NAT2), indicating cellular recognition of the tested bisphenols as bioactive xenobiotics. Antioxidant and DNA repair genes were largely unchanged, except for upregulation of oxidative stress markers HMOX1 and SRXN1 and a slight increase in OGG1, indicating oxidative DNA damage. Importantly, mixture effects were predominantly additive, with no evidence of synergistic interactions under the tested conditions. Overall, bisphenol exposure primarily triggered oxidative stress and metabolic responses rather than robust DNA damage signalling, suggesting that genotoxicity is largely mediated by reactive oxygen species. By integrating multiple endpoints in a 3D liver model, this study provides a more comprehensive assessment of bisphenol toxicity and highlights potential risks associated with BPA analogues and their mixtures, supporting the need for a comprehensive safety assessment to evaluate their suitability as replacements in consumer products.
Ključne besede: bisphenol, DNA damage, oxidative stress, complex mixtures, metabolism
Objavljeno v DiRROS: 10.07.2026; Ogledov: 169; Prenosov: 179
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2. Higher incidence of common polymorphisms in the genes of folate and methionine cycles in children with orofacial clefs and congenital heart defects compared to their unaffected siblingsNataša Karas Kuželički, Alenka Šmid, Maša Vidmar, Tina Kek, Andreja Eberlinc, Borut Geršak, Uroš Mazić, Irena Mlinarič-Raščan, Ksenija Geršak, 2024, izvirni znanstveni članek Povzetek: Background: Bioequivalence risk assessment as an extension of quality risk management lacks examples of quantitative approaches to risk assessment at an early stage of generic drug development. The aim of our study was to develop a model-based approach for bioequivalence risk assessment that uses pharmacokinetic and physicochemical characteristics of drugs as predictors and would standardize the first step of risk assessment. Methods: The Sandoz in-house bioequivalence database of 128 bioequivalence studies with poorly soluble drugs (23.5% non-bioequivalent) was used to train and validate the model. Four different modeling approaches, random forest, XGBoost, logistic regression and naïve Bayes, were compared. Results: Among the best performing machine learning models, random forest was selected and optimized for the number of features, resulting in an accuracy of 84% on the test data set. The most important features for prediction were those related to solubility (dose number, acid dissociation constant), absorption and elimination rate, effective permeability, variability of pharmacokinetic endpoints, and absolute bioavailability. All features had a conceivable influence on the model predictions. Conclusion: The model was used to develop a bioequivalence risk assessment approach to categorize drugs in early development into high, medium or low risk classes.
Ključne besede: congenital heart disease, folate metabolism, FPGS, genetics, orofacial clefts, polymorphisms, sibling pairs
Objavljeno v DiRROS: 04.06.2026; Ogledov: 218; Prenosov: 228
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3. Deregulation in adult IgA vasculitis skin as the basis for the discovery of novel serum biomarkersMatija Bajželj, Matjaž Hladnik, Rok Blagus, Vesna Jurčić, Ana Markež, Tanya Deniz Toluay, Snežna Sodin-Šemrl, Alojzija Hočevar, Katja Lakota, 2024, izvirni znanstveni članek Povzetek: Introduction: Immunoglobulin A vasculitis (IgAV) in adults has a variable disease course, with patients often developing gastrointestinal and renal involvement and thus contributing to higher mortality. Due to understudied molecular mechanisms in IgAV currently used biomarkers for IgAV visceral involvement are largely lacking. Our aim was to search for potential serum biomarkers based on the skin transcriptomic signature. Methods: RNA sequencing analysis was conducted on skin biopsies collected from 6 treatment-naïve patients (3 skin only and 3 renal involvement) and 3 healthy controls (HC) to get insight into deregulated processes at the transcriptomic level. 15 analytes were selected and measured based on the transcriptome analysis (adiponectin, lipopolysaccharide binding protein (LBP), matrix metalloproteinase-1 (MMP1), C-C motif chemokine ligand (CCL) 19, kallikrein-5, CCL3, leptin, C-X-C motif chemokine ligand (CXCL) 5, osteopontin, interleukin (IL)-15, CXCL10, angiopoietin-like 4 (ANGPTL4), SERPIN A12/vaspin, IL-18 and fatty acid-binding protein 4 (FABP4)) in sera of 59 IgAV and 22 HC. Machine learning was used to assess the ability of the analytes to predict IgAV and its organ involvement. Results: Based on the gene expression levels in the skin, we were able to differentiate between IgAV patients and HC using principal component analysis (PCA) and a sample-to-sample distance matrix. Differential expression analysis revealed 49 differentially expressed genes (DEGs) in all IgAV patient's vs. HC. Patients with renal involvement had more DEGs than patients with skin involvement only (507 vs. 46 DEGs) as compared to HC, suggesting different skin signatures. Major dysregulated processes in patients with renal involvement were lipid metabolism, acute inflammatory response, and extracellular matrix (ECM)-related processes. 11 of 15 analytes selected based on affected processes in IgAV skin (osteopontin, LBP, ANGPTL4, IL-15, FABP4, CCL19, kallikrein-5, CCL3, leptin, IL-18 and MMP1) were significantly higher (p-adj < 0.05) in IgAV serum as compared to HC. Prediction models utilizing measured analytes showed high potential for predicting adult IgAV. Conclusion: Skin transcriptomic data revealed deregulations in lipid metabolism and acute inflammatory response, reflected also in serum analyte measurements. LBP, among others, could serve as a potential biomarker of renal complications, while adiponectin and CXCL10 could indicate gastrointestinal involvement.
Ključne besede: acute inflammatory response, adults, IgA vasculitis, lipid metabolism, machine learning, RNA sequencing, serum biomarkers
Objavljeno v DiRROS: 04.06.2026; Ogledov: 245; Prenosov: 170
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4. Stefin B and cystatin C deficiency suppresses tumor growth and alters tumor microenvironment in a breast cancer modelPetra Matjan-Štefin, Janja Završnik, Miha Butinar, Georgy Mikhaylov, Boris Turk, Olga Vasiljeva, 2026, izvirni znanstveni članek Povzetek: Background/Objectives: Cysteine cathepsins and their endogenous inhibitors have been shown to possess context-dependent functions in cancer progression, including the regulation of tumor metabolic pathways. Stefin B and cystatin C, intracellular and extracellular protease inhibitors, respectively, can modulate tumor biology through protease-dependent and protease-independent mechanisms. This study investigated their combined functions and potential roles as tumor promoters in breast cancer in a spontaneous breast cancer mouse model (PyMT mice). Methods: We generated PyMT transgenic mice lacking both stefin B and cystatin C (double-knockout, DKO) and compared their tumor growth kinetics, proliferation, apoptosis, and metastatic burden with those of wild-type control mice. Immunohistochemistry was performed to characterize tumor macrophage infiltration and polarization. Results: DKO mice demonstrated delayed tumor onset, significantly slower tumor growth, reduced proliferation, increased apoptosis, and fewer lung metastases compared to wild-type controls. Immunohistochemistry revealed enhanced macrophage infiltration of the tumors, accompanied by a pronounced shift toward antitumorigenic M1 (CD86+) polarization, while M2 (CD206+) populations remained unchanged, indicating an immunological reprogramming of the tumor microenvironment toward a pro-inflammatory, tumor-suppressive state. Conclusions: Our results demonstrated a potential function of stefin B and cystatin C as tumor promoters in breast cancer through complementary mechanisms. Simultaneous depletion of both inhibitors revealed synergistic effects and remodeled the immune microenvironment to favor tumor suppression. These results suggest previously unknown roles for stefin B and cystatin C in tumor development and progression, which encourage further investigation of the cancer metabolic mechanisms underlying tumor behavior and their dynamic interplay with the microenvironment.
Ključne besede: cystatin C, stefin B, tumor microenvironment, cysteine cathepsins, cancer metabolism, protease inhibitors
Objavljeno v DiRROS: 12.05.2026; Ogledov: 365; Prenosov: 307
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5. Enrichment of rare variants in nuclear-encoded mitochondrial metabolism genes in patients with early-onset or familial parkinson’s diseaseGaber Bergant, Vesna M. Van Midden, Polina Tsygankova, Dorian Laslo, Valentino Rački, Dejan Georgiev, Eliša Papić, Marija Branković, Milena Janković, Marina Svetel, Nataša Teran, Natasa Dragasević Misković, Igor N. Petrović, Aleš Maver, Ivana Novaković, Zvezdan Pirtošek, Martin Rakuša, Vladimira Vuletić, Borut Peterlin, 2026, izvirni znanstveni članek Ključne besede: mitochondrial metabolism, mitochondrial variants, mutation burden analysis
Objavljeno v DiRROS: 05.05.2026; Ogledov: 279; Prenosov: 201
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6. Microbiome-derived short-chain fatty acids and tryptophan metabolites in children with autism spectrum disorder : a stool–urine multi-omics analysisJoško Osredkar, Teja Fabjan, Uroš Godnov, Maja Jekovec-Vrhovšek, Damjan Osredkar, Petra Finderle, Kristina Kumer, Maša Zorec, Lijana Fanedl, Gorazd Avguštin, 2026, izvirni znanstveni članek Povzetek: Autism spectrum disorder (ASD) has been associated with alterations in the gut microbiota and its metabolites, particularly short-chain fatty acids (SCFAs) and microbiota-derived tryptophan catabolites, which may influence neurodevelopment through immune and epigenetic mechanisms. We investigated whether stool SCFAs and tryptophan-pathway metabolites differ between children with ASD and typically developing controls, and whether these metabolites associate with ASD severity and systemic biochemical signatures. In this cross-sectional study, we analyzed stool samples from 229 children (160 with ASD, 69 controls) with complete SCFA and tryptophan-metabolite data, while urine metabolomics data were available for a subset and were used for exploratory stool–urine integration analyses. Children with ASD and controls were similar in age, but the ASD group had a higher proportion of males. Absolute concentrations of individual SCFAs, total SCFAs, and derived indices were broadly comparable between groups; nominal differences in propionate/acetate ratio and caproate did not remain significant after false discovery rate correction. Similarly, stool tryptophan-pathway metabolites reported as ng/a.u. based on the NanoDrop-derived proxy (tryptophan, kynurenine, indole-3-acetic, indole-3-lactic, indole-3-propionic, indole-3-aldehyde, N-acetyl-tryptophan, serotonin, melatonin, tryptamine) and functional ratios (kynurenine/tryptophan, indole-derived/tryptophan, serotonin/tryptophan) showed no robust ASD–control differences; N-acetyl-tryptophan was nominally higher in ASD but did not survive multiple-testing correction. In the ASD subgroup with available Childhood Autism Rating Scale (CARS) data (n = 34), SCFA and tryptophan indices showed only weak, non-significant correlations with global ASD severity. In contrast, correlation analyses revealed two coherent metabolic modules, i.e., an SCFA block with very strong internal correlations among individual SCFAs and total SCFAs and a tryptophan block with strong correlations between metabolites and their normalized ratios, while cross-module correlations were modest. These results indicate that stool SCFA and microbiota-derived tryptophan profiles do not robustly distinguish ASD from controls in this cohort, but they form stable metabolic modules compatible with microbiome–epigenome frameworks.
Ključne besede: autism spectrum disorder, gut microbiota, short-chain fatty acids, tryptophan metabolism, indole metabolites, kynurenine pathway, epigenetics, microbiome–epigenome interaction, metabolomics, pediatrics
Objavljeno v DiRROS: 05.05.2026; Ogledov: 314; Prenosov: 236
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7. Diverse inhibitors of de novo purine synthesis promote AICAR-induced AMPK activation and glucose uptake in L6 myotubesKlemen Dolinar, Katarina Miš, Katja Šopar, Mateja Šutar, Meta Božič, Matic Kolar, Tim Hropot, Pablo Miguel Garcia-Roves, Alexander V. Chibalin, Sergej Pirkmajer, 2025, izvirni znanstveni članek Povzetek: Methotrexate, an immunosuppressant and anticancer drug, promotes glucose uptake and lipid oxidation in skeletal muscle via activation of AMP-activated protein kinase (AMPK). Methotrexate promotes AMPK activation by inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide (ZMP) formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), which converts ZMP, an endogenous purine precursor and an active form of the pharmacological AMPK activator AICAR, to IMP during de novo purine synthesis. In addition to methotrexate, inhibition of purine synthesis underpins the therapeutic effects of a number of commonly used immunosuppressive, anticancer, and antimicrobial drugs, raising the question of whether activation of AMPK in skeletal muscle could be a recurrent feature of these drugs. Using L6 myotubes, we found that AICAR-induced AMPK activation and glucose uptake were enhanced by inhibitors of the conversion of IMP to GMP (mycophenolate mofetil) or of IMP to AMP (alanosine) as well as by indirect inhibitors of human (trimetrexate) and bacterial ATIC (sulfamethoxazole). 6-Mercaptopurine, which inhibits the conversion of IMP to GMP and AMP, activated AMPK, increased glucose uptake, and suppressed insulin signaling, but did not enhance the effect of AICAR. As determined by measuring oxygen consumption rate, none of these agents suppressed mitochondrial function. Overall, our results indicate that IMP metabolism is a gateway for the modulation of AMPK and its metabolic effects in skeletal muscle cells.
Ključne besede: AMP‐activated protein kinase (AMPK), folate metabolism, glucose uptake, insulin signaling, purine metabolism, skeletal muscle cells
Objavljeno v DiRROS: 09.04.2026; Ogledov: 293; Prenosov: 330
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8. Disrupted vitamin D metabolism in hepatocellular carcinoma : free and bioavailable 25(OH)D as novel biomarkers of hepatic reserve and clinical riskJoško Osredkar, Matej Rakuša, Aleš Jerin, Borut Štabuc, Martin Zaplotnik, Saša Štupar, Darko Siuka, 2026, izvirni znanstveni članek Povzetek: Background: Although total 25-hydroxyvitamin D (25(OH)D) measurements may not accurately reflect functional vitamin D status, vitamin D deficiency is common in hepatocellular carcinoma (HCC). The contribution of altered vitamin D-binding protein (VDBP) and albumin to impaired bioavailability is poorly characterized in liver cancer. Methods: We measured total, free, and bioavailable 25(OH)D, VDBP, and albumin in 46 HCC patients and 87 healthy controls during winter and summer. Correlations with Child–Pugh score, Barcelona Clinic Liver Cancer (BCLC) stage, and disease aetiology were evaluated. Results: HCC patients exhibited significantly lower VDBP (177.3 ± 237.0 vs. 239.9 ± 141.9 mg/L, p < 0.001) and albumin (35.9 ± 5.4 vs. 48.0 ± 3.9 g/L, p < 0.001) compared to winter controls. Total 25(OH)D was lower in HCC (39.3 ± 22.1 nmol/L) versus summer controls (75.0 ± 22.8 nmol/L, p < 0.001) but comparable to winter controls (p = 0.061). HCC patients lacked seasonal variation in vitamin D fractions, unlike the controls. VDBP negatively correlated with free (ρ = −0.606, p < 0.001) and bioavailable 25(OH)D (ρ = −0.541, p < 0.001). Child–Pugh score correlated positively with BCLC stage (ρ = 0.378, p = 0.012) and inversely with albumin (ρ = −0.565, p < 0.001). Conclusions: Free and bioavailable vitamin D are profoundly compromised in HCC, reflecting impaired hepatic synthetic function and systemic inflammation. These fractions may serve as novel metabolic biomarkers superior to total 25(OH)D for assessing vitamin D deficiency and guiding individualized supplementation strategies in patients with liver cancer.
Ključne besede: hepatocellular carcinoma, vitamin D metabolism, 25-hydroxyvitamin D, free vitamin D, bioavailable vitamin D, vitamin D-binding protein, albumin, Child-Pugh score, BCLC staging, biomarkers
Objavljeno v DiRROS: 08.04.2026; Ogledov: 284; Prenosov: 180
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9. MAGEA3/6 tumour antigens regulate glycolytic protein hexokinase to enhance pancreatic cancer cell survival under metabolic stressVesna Jurjevič, Jerneja Koren, Sima Tozandehjani, Sara Uhan, Lara Snoj, Barbara Breznik Vittori, Juan Solano, Klementina Fon Tacer, 2024, objavljeni povzetek znanstvenega prispevka na konferenci Ključne besede: pancreatic cancer, metabolism, MAGE, oncology
Objavljeno v DiRROS: 25.02.2026; Ogledov: 551; Prenosov: 146
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10. Data from: Single and combined toxicity of BPA, BPAP, and BPC in a 3D human hepatic modelMartina Štampar, Tim Ravnjak, Alja Štern, Bojana Žegura, 2026, zaključena znanstvena zbirka raziskovalnih podatkov Ključne besede: bisphenol, DNA damage, oxidative stress, complex mixtures, metabolism
Objavljeno v DiRROS: 03.02.2026; Ogledov: 264; Prenosov: 187
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