TY - JOUR AU - Ababneh, Haneen AU - Balogh, Enikő AU - Csiki, Dávid Máté AU - Lente, Gréta AU - Fenyvesi, Ferenc AU - Tóth, Andrea AU - Jeney, Viktória TI - High glucose promotes osteogenic differentiation of human lens epithelial cells through hypoxia-inducible factor (HIF) activation JF - JOURNAL OF CELLULAR PHYSIOLOGY J2 - J CELL PHYSIOL PY - 2024 PG - 12 SN - 0021-9541 DO - 10.1002/jcp.31211 UR - https://m2.mtmt.hu/api/publication/34618976 ID - 34618976 AB - Cataract, a leading cause of blindness, is characterised by lens opacification. Type 2 diabetes is associated with a two- to fivefold higher prevalence of cataracts. The risk of cataract formation increases with the duration of diabetes and the severity of hyperglycaemia. Hydroxyapatite deposition is present in cataractous lenses that could be the consequence of osteogenic differentiation and calcification of lens epithelial cells (LECs). We hypothesised that hyperglycaemia might promote the osteogenic differentiation of human LECs (HuLECs). Osteogenic medium (OM) containing excess phosphate and calcium with normal (1 g/L) or high (4.5 g/L) glucose was used to induce HuLEC calcification. High glucose accelerated and intensified OM-induced calcification of HuLECs, which was accompanied by hyperglycaemia-induced upregulation of the osteogenic markers Runx2, Sox9, alkaline phosphatase and osteocalcin, as well as nuclear translocation of Runx2. High glucose-induced calcification was abolished in Runx2-deficient HuLECs. Additionally, high glucose stabilised the regulatory alpha subunits of hypoxia-inducible factor 1 (HIF-1), triggered nuclear translocation of HIF-1 alpha and increased the expression of HIF-1 target genes. Gene silencing of HIF-1 alpha or HIF-2 alpha attenuated hyperglycaemia-induced calcification of HuLECs, while hypoxia mimetics (desferrioxamine, CoCl2) enhanced calcification of HuLECs under normal glucose conditions. Overall, this study suggests that high glucose promotes HuLEC calcification via Runx2 and the activation of the HIF-1 signalling pathway. These findings may provide new insights into the pathogenesis of diabetic cataracts, shedding light on potential factors for intervention to treat this sight-threatening condition. LA - English DB - MTMT ER - TY - JOUR AU - Herczeg, Mihály AU - Demeter, Fruzsina AU - Nagy, Tibor AU - Rusznyák, Ágnes AU - Hodek, Jan AU - Sipos, Éva AU - Lekli, István AU - Fenyvesi, Ferenc AU - Weber, Jan AU - Kéki, Sándor AU - Borbás, Anikó TI - Block Synthesis and Step-Growth Polymerization of C-6-Sulfonatomethyl-Containing Sulfated Malto-Oligosaccharides and Their Biological Profiling JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 1 SN - 1661-6596 DO - 10.3390/ijms25010677 UR - https://m2.mtmt.hu/api/publication/34502650 ID - 34502650 AB - Highly sulfated malto-oligomers, similar to heparin and heparan-sulfate, have good antiviral, antimetastatic, anti-inflammatory and cell growth inhibitory effects. Due to their broad biological activities and simple structure, sulfated malto-oligomer derivatives have a great therapeutic potential, therefore, the development of efficient synthesis methods for their production is of utmost importance. In this work, preparation of α-(1→4)-linked oligoglucosides containing a sulfonatomethyl moiety at position C-6 of each glucose unit was studied by different approaches. Malto-oligomeric sulfonic acid derivatives up to dodecasaccharides were prepared by polymerization using different protecting groups, and the composition of the product mixtures was analyzed by MALDI-MS methods and size-exclusion chromatography. Synthesis of lower oligomers was also accomplished by stepwise and block synthetic methods, and then the oligosaccharide products were persulfated. The antiviral, anti-inflammatory and cell growth inhibitory activity of the fully sulfated malto-oligosaccharide sulfonic acids were determined by in vitro tests. Four tested di- and trisaccharide sulfonic acids effectively inhibited the activation of the TNF-α-mediated inflammatory pathway without showing cytotoxicity. LA - English DB - MTMT ER - TY - JOUR AU - Hermenean, Anca AU - Dossi, Eleftheria AU - Hamilton, Alex AU - Trotta, Maria Consiglia AU - Russo, Marina AU - Lepre, Caterina Claudia AU - Sajtos, Csilla AU - Rusznyák, Ágnes AU - Váradi, Judit AU - Bácskay, Ildikó AU - Budai, István AU - D’Amico, Michele AU - Fenyvesi, Ferenc TI - Chrysin Directing an Enhanced Solubility through the Formation of a Supramolecular Cyclodextrin–Calixarene Drug Delivery System: A Potential Strategy in Antifibrotic Diabetes Therapeutics JF - PHARMACEUTICALS J2 - PHARMACEUTICALS-BASE VL - 17 PY - 2024 IS - 1 SP - 1 EP - 20 PG - 20 SN - 1424-8247 DO - 10.3390/ph17010107 UR - https://m2.mtmt.hu/api/publication/34500966 ID - 34500966 AB - Calixarene 0118 (OTX008) and chrysin (CHR) are promising molecules for the treatment of fibrosis and diabetes complications but require an effective delivery system to overcome their low solubility and bioavailability. Sulfobutylated β-cyclodextrin (SBECD) was evaluated for its ability to increase the solubility of CHR by forming a ternary complex with OTX008. The resulting increase in solubility and the mechanisms of complex formation were identified through phase-solubility studies, while dynamic light-scattering assessed the molecular associations within the CHR-OTX008-SBECD system. Nuclear magnetic resonance, differential scanning calorimetry, and computational studies elucidated the interactions at the molecular level, and cellular assays confirmed the system’s biocompatibility. Combining SBECD with OTX008 enhances CHR solubility more than using SBECD alone by forming water-soluble molecular associates in a ternary complex. This aids in the solubilization and delivery of CHR and OTX008. Structural investigations revealed non-covalent interactions essential to complex formation, which showed no cytotoxicity in hyperglycemic in vitro conditions. A new ternary complex has been formulated to deliver promising antifibrotic agents for diabetic complications, featuring OTX008 as a key structural and pharmacological component. LA - English DB - MTMT ER - TY - JOUR AU - Rusznyák, Ágnes AU - Szászné Réti-Nagy, Katalin AU - Váradi, Judit AU - Bácskay, Ildikó AU - Vecsernyés, Miklós AU - Fenyvesi, Ferenc TI - Hidroxi-propil-béta-ciklodextrin celluláris internalizációjának és lizoszómákra gyakorolt hatásának vizsgálata JF - EGÉSZSÉGÜGYI INNOVÁCIÓS SZEMLE J2 - EÜ INNOV SZLE VL - 2 PY - 2023 IS - 2 SP - 57 EP - 64 PG - 8 SN - 2939-6026 DO - 10.56626/egis.v2i2.12924 UR - https://m2.mtmt.hu/api/publication/34688027 ID - 34688027 AB - A ciklodextrinek széles körben alkalmazott segédanyagok a lipofil gyógyszerek vízoldhatóságának és biológiai hasznosíthatóságának növelésére. Kutatócsoportunk korábban kimutatta, hogy a ciklodextrinek endocitózissal képesek bejutni a Caco-2 intesztinális epitél sejtekbe, azonban a különböző sejtek esetén történő celluláris internalizációt és az intracelluláris hatásait eddig még nem vizsgálták. Mindemellett a 2-hidroxi-propil-béta-ciklodextrin (HPBCD) koleszterin komplexáló tulajdonságának köszönhetően a C típusú Niemann Pick szindróma kezelésére alkalmazott molekula. Munkánk célja a HPBCD celluláris internalizációjának és a sejtekben található lizoszómákra gyakorolt hatásának vizsgálata és összehasonlítása Caco-2 intesztinális epitél, HeLa méhnyak epitél és hCMEC/D3 agyi endotél sejteken. LA - Hungarian DB - MTMT ER - TY - JOUR AU - Trotta, Maria Consiglia AU - Herman, Hildegard AU - Ciceu, Alina AU - Mladin, Bianca AU - Rosu, Marcel AU - Lepre, Caterina Claudia AU - Russo, Marina AU - Bácskay, Ildikó AU - Fenyvesi, Ferenc AU - Marfella, Raffaele AU - Hermenean, Anca AU - Balta, Cornel AU - D’Amico, Michele TI - Chrysin-based supramolecular cyclodextrin-calixarene drug delivery system: a novel approach for attenuating cardiac fibrosis in chronic diabetes JF - FRONTIERS IN PHARMACOLOGY J2 - FRONT PHARMACOL VL - 14 PY - 2023 SP - 1 EP - 17 PG - 17 SN - 1663-9812 DO - 10.3389/fphar.2023.1332212 UR - https://m2.mtmt.hu/api/publication/34502756 ID - 34502756 AB - Introduction: Cardiac fibrosis is strongly induced by diabetic conditions. Both chrysin (CHR) and calixarene OTX008, a specific inhibitor of galectin 1 (Gal-1), seem able to reduce transforming growth factor beta (TGF-β)/SMAD pro-fibrotic pathways, but their use is limited to their low solubility. Therefore, we formulated a dual-action supramolecular system, combining CHR with sulfobutylated β-cyclodextrin (SBECD) and OTX008 (SBECD + OTX + CHR). Here we aimed to test the anti-fibrotic effects of SBECD + OTX + CHR in hyperglycemic H9c2 cardiomyocytes and in a mouse model of chronic diabetes. LA - English DB - MTMT ER - TY - JOUR AU - Klusóczki, Ágnes AU - Oláh, Boglárka AU - Hosszú, Dominik AU - Fenyvesi, Ferenc AU - Gálné Remenyik, Judit AU - Homoki, Judit Rita AU - Gyöngyösi, Alexandra AU - Bácskay, Ildikó AU - Váradi, Judit TI - Effectiveness of Anthocyanin-Rich Sour Cherry Extract on Gliadin-Induced Caco-2 Barrier Damage JF - NUTRIENTS J2 - NUTRIENTS VL - 15 PY - 2023 IS - 18 SN - 2072-6643 DO - 10.3390/nu15184022 UR - https://m2.mtmt.hu/api/publication/34160368 ID - 34160368 AB - Several types of gluten-related disorders are known, in which the common starting point is gluten-induced zonulin release. Zonulin results in varying degrees of increased permeability in certain gluten-related disorders but is largely responsible for the development of further pathogenic processes and symptoms. Therefore, it is important to know the barrier-modulating role of individual nutritional components and to what extent the antioxidant substance supports the protection of gliadin-induced membrane damage with its radical scavenging capacity. We investigated the pH dependence of the gliadin-anthocyanin interaction using UV photometry, during which a concentration-dependent interaction was observed at pH 6.8. The barrier modulatory effect of the anthocyanin-rich sour cherry extract (AC) was analyzed on Caco-2 cell culture with pepsin-trypsin-resistant gliadin (PT-gliadin) exposure by TEER measurement, zonula occludens-1 (ZO-1), and Occludin immunohistochemistry. In addition to the TEER-reducing and TJ-rearranging effects of PT-gliadin, NF-κB activation, an increase in cytokine (TNF-α, IFN-γ, and IL-8) release, and mitochondrial ROS levels were observed. We confirmed the anti-inflammatory, stabilizing, and restoring roles of AC extract during gliadin treatment on the Caco-2 monolayer. The extract was able to significantly reduce cytokine and ROS levels despite the known interaction of the main components of the extract with PT-gliadin. LA - English DB - MTMT ER - TY - JOUR AU - Gutayné Tóth, Zsuzsanna AU - Gellén, Gabriella AU - Doan, Minh AU - Eliason, James F. AU - Vincze, János AU - Szente, Lajos AU - Fenyvesi, Ferenc AU - Kormosné, Goda Katalin AU - Vecsernyés, Miklós AU - Szabó, Gábor AU - Bacsó, Zsolt TI - Cholesterol-Depletion-Induced Membrane Repair Carries a Raft Conformer of P-Glycoprotein to the Cell Surface, Indicating Enhanced Cholesterol Trafficking in MDR Cells, Which Makes Them Resistant to Cholesterol Modifications JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 15 PG - 23 SN - 1661-6596 DO - 10.3390/ijms241512335 UR - https://m2.mtmt.hu/api/publication/34086081 ID - 34086081 N1 - Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, 4032, Hungary MTA-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Department of Analytical Chemistry, Institute of Chemistry, ELTE Eötvös Loránd University, Budapest, 1053, Hungary Great Lakes Stem Cell Innovation Center, Detroit, MI 48202, United States Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary CycloLab Cyclodextrin Research & Development Laboratory, Ltd, Budapest, 1097, Hungary Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Debrecen, 4032, Hungary Export Date: 15 September 2023 Correspondence Address: Bacso, Z.; Department of Biophysics and Cell Biology, Hungary; email: bacso@med.unideb.hu AB - The human P-glycoprotein (P-gp), a transporter responsible for multidrug resistance, is present in the plasma membrane’s raft and non-raft domains. One specific conformation of P-gp that binds to the monoclonal antibody UIC2 is primarily associated with raft domains and displays heightened internalization in cells overexpressing P-gp, such as in NIH-3T3 MDR1 cells. Our primary objective was to investigate whether the trafficking of this particular P-gp conformer is dependent on cholesterol levels. Surprisingly, depleting cholesterol using cyclodextrin resulted in an unexpected increase in the proportion of raft-associated P-gp within the cell membrane, as determined by UIC2-reactive P-gp. This increase appears to be a compensatory response to cholesterol loss from the plasma membrane, whereby cholesterol-rich raft micro-domains are delivered to the cell surface through an augmented exocytosis process. Furthermore, this exocytotic event is found to be part of a complex trafficking mechanism involving lysosomal exocytosis, which contributes to membrane repair after cholesterol reduction induced by cyclodextrin treatment. Notably, cells overexpressing P-gp demonstrated higher total cellular cholesterol levels, an increased abundance of stable lysosomes, and more effective membrane repair following cholesterol modifications. These modifications encompassed exocytotic events that involved the transport of P-gp-carrying rafts. Importantly, the enhanced membrane repair capability resulted in a durable phenotype for MDR1 expressing cells, as evidenced by significantly improved viabilities of multidrug-resistant Pgp-overexpressing immortal NIH-3T3 MDR1 and MDCK-MDR1 cells compared to their parents when subjected to cholesterol alterations. LA - English DB - MTMT ER - TY - JOUR AU - Képes, Zita AU - Hajdu, István AU - Fenyvesi, Ferenc AU - Trencsényi, György TI - Insights into recent preclinical studies on labelled cyclodextrin-based imaging probes: towards a novel oncological era JF - INTERNATIONAL JOURNAL OF PHARMACEUTICS J2 - INT J PHARM VL - 640 PY - 2023 SN - 0378-5173 DO - 10.1016/j.ijpharm.2023.122978 UR - https://m2.mtmt.hu/api/publication/33789335 ID - 33789335 AB - As malignancies remain one of the major health concerns worldwide, increasing focus has been centered around the application of cyclodextrins (CDs) in cancer imaging and therapy due to their outstanding inclusion forming capability. Albeit the physicochemical properties of CDs were intensively elucidated, the spread of their clinical application is limited by the relative paucity of knowledge about their pharmacokinetic profile, especially biodistribution. Studies applying fluorescently- CDs, or CD-based MRI contrast agents revealed much about pharmacokinetics and diagnostic applications; however, derivatives labelled with positron emitters seem superior molecular probes in the investigation of the route of CDs in biological niche. In vivo imaging based on preclinical tumor-bearing model systems are well-suited to evaluate the whole-body distribution of the two most frequently assessed CDs: randomly methylated ?-cyclodextrin (RAMEB), and hydroxypropyl-?-cyclodextrin (HPBCD). Exploiting the firm signaling interaction between cancer-related cyclooxygenase-2, prostaglandin E2 (PGE2) and RAS oncoprotein, radioconjugated, PGE2-affine CDs project the establishment of novel imaging probes and therapeutic agents. Currently, we provide an overview of the preclinical studies on CD pharmacokinetics highlighting the significance of the integration of translational discoveries into human patient care. LA - English DB - MTMT ER - TY - JOUR AU - Gyöngyösi, Alexandra AU - Csáki, Nikolett AU - Pető, Ágota AU - Szőke, Kitti AU - Fenyvesi, Ferenc AU - Bácskay, Ildikó AU - Lekli, István TI - BGP-15 Protects against Doxorubicin-Induced Cell Toxicity via Enhanced Mitochondrial Function JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 6 PG - 13 SN - 1661-6596 DO - 10.3390/ijms24065269 UR - https://m2.mtmt.hu/api/publication/33691053 ID - 33691053 AB - Doxorubicin (DOX) is an efficacious and commonly used chemotherapeutic agent. However, its clinical use is limited due to dose-dependent cardiotoxicity. Several mechanisms have been proposed to play a role in DOX-induced cardiotoxicity, such as free radical generation, oxidative stress, mitochondrial dysfunction, altered apoptosis, and autophagy dysregulation. BGP-15 has a wide range of cytoprotective effects, including mitochondrial protection, but up to now, there is no information about any of its beneficial effects on DOX-induced cardiotoxicity. In this study, we investigated whether the protective effects of BGP-15 pretreatment are predominantly via preserving mitochondrial function, reducing mitochondrial ROS production, and if it has an influence on autophagy processes. H9c2 cardiomyocytes were pretreated with 50 mu M of BGP-15 prior to different concentrations (0.1; 1; 3 mu M) of DOX exposure. We found that BGP-15 pretreatment significantly improved the cell viability after 12 and 24 h DOX exposure. BGP-15 ameliorated lactate dehydrogenase (LDH) release and cell apoptosis induced by DOX. Additionally, BGP-15 pretreatment attenuated the level of mitochondrial oxidative stress and the loss of mitochondrial membrane potential. Moreover, BGP-15 further slightly modulated the autophagic flux, which was measurably decreased by DOX treatment. Hence, our findings clearly revealed that BGP-15 might be a promising agent for alleviating the cardiotoxicity of DOX. This critical mechanism appears to be given by the protective effect of BGP-15 on mitochondria. LA - English DB - MTMT ER - TY - JOUR AU - Demeter, Fruzsina AU - Török, Patrik AU - Kiss, Alexandra AU - Kovásznai-Oláh, Richárd AU - Máthéné Szigeti, Zsuzsa AU - Baksa, Viktória AU - Kovács, Fruzsina AU - Balla , Noémi AU - Fenyvesi, Ferenc AU - Váradi, Judit AU - Borbás, Anikó AU - Herczeg, Mihály TI - First Synthesis of DBU-Conjugated Cationic Carbohydrate Derivatives and Investigation of Their Antibacterial and Antifungal Activity JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 4 PG - 20 SN - 1661-6596 DO - 10.3390/ijms24043550 UR - https://m2.mtmt.hu/api/publication/33635459 ID - 33635459 AB - The emergence of drug-resistant bacteria and fungi represents a serious health problem worldwide. It has long been known that cationic compounds can inhibit the growth of bacteria and fungi by disrupting the cell membrane. The advantage of using such cationic compounds is that the microorganisms would not become resistant to cationic agents, since this type of adaptation would mean significantly altering the structure of their cell walls. We designed novel, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)-derived amidinium salts of carbohydrates, which may be suitable for disturbing the cell walls of bacteria and fungi due to their quaternary ammonium moiety. A series of saccharide-DBU conjugates were prepared from 6-iodo derivatives of d-glucose, d-mannose, d-altrose and d-allose by nucleophilic substitution reactions. We optimized the synthesis of a d-glucose derivative, and studied the protecting group free synthesis of the glucose-DBU conjugates. The effect of the obtained quaternary amidinium salts against Escherichia coli and Staphylococcus aureus bacterial strains and Candida albicans yeast was investigated, and the impact of the used protecting groups and the sugar configuration on the antimicrobial activity was analyzed. Some of the novel sugar quaternary ammonium compounds with lipophilic aromatic groups (benzyl and 2-napthylmethyl) showed particularly good antifungal and antibacterial activity. LA - English DB - MTMT ER -