@{MTMT:34722657, title = {A plazmamembrán}, url = {https://m2.mtmt.hu/api/publication/34722657}, author = {Sarkadi, Balázs}, booktitle = {Orvosi patobiokémia}, unique-id = {34722657}, year = {2023}, pages = {298-314}, orcid-numbers = {Sarkadi, Balázs/0000-0003-0592-4539} } @article{MTMT:34471833, title = {Application of a Receptor-Binding-Domain-Based Simple Immunoassay for Assessing Humoral Immunity against Emerging SARS-CoV-2 Virus Variants}, url = {https://m2.mtmt.hu/api/publication/34471833}, author = {Mózner, Orsolya and Moldvay, Judit and Szabó, K.S. and Vaskó, Dorottya and Domján, Júlia and Ács, D. and Ligeti, Z. and Fehér, Csaba and Hirsch, Edit and Puskás, L. and Stahl, C. and Frey, M. and Sarkadi, Balázs}, doi = {10.3390/biomedicines11123193}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {11}, unique-id = {34471833}, year = {2023}, eissn = {2227-9059}, orcid-numbers = {Mózner, Orsolya/0000-0001-5784-7702; Vaskó, Dorottya/0000-0002-2502-0644; Sarkadi, Balázs/0000-0003-0592-4539} } @article{MTMT:34280401, title = {Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency}, url = {https://m2.mtmt.hu/api/publication/34280401}, author = {Broca-Brisson, Léa and Harati, Rania and Disdier, Clémence and Mózner, Orsolya and Gaston-Breton, Romane and Maïza, Auriane and Costa, Narciso and Guyot, Anne-Cécile and Sarkadi, Balázs and Apáti, Ágota and Skelton, Matthew R and Madrange, Lucie and Yates, Frank and Armengaud, Jean and Hamoudi, Rifat and Mabondzo, Aloïse}, doi = {10.7554/eLife.88459}, journal-iso = {ELIFE}, journal = {ELIFE}, volume = {12}, unique-id = {34280401}, issn = {2050-084X}, abstract = {Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared with those from healthy donors. The expression of neural progenitor cell markers SOX2 and PAX6 was reduced in CTD-derived organoids, while GSK3β, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in the abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression of a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3β, and other key proteins associated with clinical features of CTD patients. Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology and supports the concept that reinstating creatine levels in patients with CTD could result in therapeutic efficacy.}, year = {2023}, eissn = {2050-084X}, orcid-numbers = {Mózner, Orsolya/0000-0001-5784-7702; Sarkadi, Balázs/0000-0003-0592-4539; Armengaud, Jean/0000-0003-1589-445X; Mabondzo, Aloïse/0000-0002-0627-8949} } @article{MTMT:34175360, title = {Expression, Function and Trafficking of the Human ABCG2 Multidrug Transporter Containing Mutations in an Unstructured Cytoplasmic Loop}, url = {https://m2.mtmt.hu/api/publication/34175360}, author = {Mózner, Orsolya and Zámbó, Boglárka and Bartos, Zsuzsa and Gergely, Anna and Szabó, Kata Sára and Jezsó, Bálint and Telbisz, Ágnes Mária and Várady, György and Homolya, László and Hegedűs, Tamás and Sarkadi, Balázs}, doi = {10.3390/membranes13100822}, journal-iso = {MEMBRANES-BASEL}, journal = {MEMBRANES (BASEL)}, volume = {13}, unique-id = {34175360}, abstract = {The human ABCG2 multidrug transporter plays a crucial role in the absorption and excretion of xeno- and endobiotics, contributes to cancer drug resistance and the development of gout. In this work, we have analyzed the effects of selected variants, residing in a structurally unresolved cytoplasmic region (a.a. 354–367) of ABCG2 on the function and trafficking of this protein. A cluster of four lysines (K357–360) and the phosphorylation of a threonine (T362) residue in this region have been previously suggested to significantly affect the cellular fate of ABCG2. Here, we report that the naturally occurring K360del variant in human cells increased ABCG2 plasma membrane expression and accelerated cellular trafficking. The variable alanine replacements of the neighboring lysines had no significant effect on transport function, and the apical localization of ABCG2 in polarized cells has not been altered by any of these mutations. Moreover, in contrast to previous reports, we found that the phosphorylation-incompetent T362A, or the phosphorylation-mimicking T362E variants in this loop had no measurable effects on the function or expression of ABCG2. Molecular dynamics simulations indicated an increased mobility of the mutant variants with no major effects on the core structure of the protein. These results may help to decipher the potential role of this unstructured region within this transporter.}, year = {2023}, eissn = {2077-0375}, orcid-numbers = {Mózner, Orsolya/0000-0001-5784-7702; Bartos, Zsuzsa/0000-0001-9695-1422; Jezsó, Bálint/0000-0002-1306-4797; Telbisz, Ágnes Mária/0000-0003-0972-4606; Várady, György/0000-0003-2012-9680; Homolya, László/0000-0003-1639-8140; Hegedűs, Tamás/0000-0002-0331-9629; Sarkadi, Balázs/0000-0003-0592-4539} } @article{MTMT:34095016, title = {Interactions of the Anti-SARS-CoV-2 Agents Molnupiravir and Nirmatrelvir/Paxlovid with Human Drug Transporters}, url = {https://m2.mtmt.hu/api/publication/34095016}, author = {Bakos, Éva and Temesszentandrási-Ambrus, Csilla and Laczka, Csilla and Gáborik, Z. and Sarkadi, Balázs and Telbisz, Ágnes Mária}, doi = {10.3390/ijms241411237}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {34095016}, issn = {1661-6596}, abstract = {Orally administered small molecules may have important therapeutic potential in treating COVID-19 disease. The recently developed antiviral agents, Molnupiravir and Nirmatrelvir, have been reported to be efficient treatments, with only moderate side effects, especially when applied in the early phases of this disease. However, drug–drug and drug–transporter interactions have already been noted by the drug development companies and in the application notes. In the present work, we have studied some of the key human transporters interacting with these agents. The nucleoside analog Molnupiravir (EIDD-2801) and its main metabolite (EIDD-1931) were found to inhibit CNT1,2 in addition to the ENT1,2 nucleoside transporters; however, it did not significantly influence the relevant OATP transporters or the ABCC4 nucleoside efflux transporter. The active component of Paxlovid (PF-07321332, Nirmatrelvir) inhibited the function of several OATPs and of ABCB1 but did not affect ABCG2. However, significant inhibition was observed only at high concentrations of Nirmatrelvir and probably did not occur in vivo. Paxlovid, as used in the clinic, is a combination of Nirmatrelvir (viral protease inhibitor) and Ritonavir (a “booster” inhibitor of Nirmatrelvir metabolism). Ritonavir is known to inhibit several drug transporters; therefore, we have examined these compounds together, in relevant concentrations and ratios. No additional inhibitory effect of Nirmatrelvir was observed compared to the strong transporter inhibition caused by Ritonavir. Our current in vitro results should help to estimate the potential drug–drug interactions of these newly developed agents during COVID-19 treatment. © 2023 by the authors.}, keywords = {ABC transporter; OATP; CNT; ENT; COVID-19; molnupiravir; Nirmatrelvir; Paxlovid}, year = {2023}, eissn = {1422-0067}, orcid-numbers = {Temesszentandrási-Ambrus, Csilla/0000-0002-1348-8725; Sarkadi, Balázs/0000-0003-0592-4539; Telbisz, Ágnes Mária/0000-0003-0972-4606} } @article{MTMT:34083454, title = {Cancer stem cells in drug resistance: an introduction to the e-book covering the special issue on the “Cancer Stem Cells and Drug Resistance”}, url = {https://m2.mtmt.hu/api/publication/34083454}, author = {Sarkadi, Balázs}, doi = {10.20517/cdr.2023.23}, journal-iso = {CANCER DRUG RESIST}, journal = {CANCER DRUG RESISTANCE}, volume = {6}, unique-id = {34083454}, keywords = {APOPTOSIS; human; editorial; antineoplastic agent; immune response; multidrug resistance; lung cancer; cancer recurrence; cell population; cancer growth; cancer resistance; cancer immunotherapy; cell surface marker; immunosurveillance; cancer stem cell; Tumor microenvironment; epithelial mesenchymal transition; stem cell self-renewal}, year = {2023}, eissn = {2578-532X}, pages = {239-241}, orcid-numbers = {Sarkadi, Balázs/0000-0003-0592-4539} } @article{MTMT:33061607, title = {Genetic polymorphisms and decreased protein expression of ABCG2 urate transporters are associated with susceptibility to gout, disease severity and renal-overload hyperuricemia}, url = {https://m2.mtmt.hu/api/publication/33061607}, author = {Pálinkás, Márton and Szabó, Edit Zsuzsanna and Kulin, Anna and Mózner, Orsolya and Rásonyi, R. and Juhász, P. and Nagy, K. and Várady, György and Vörös, D. and Zámbó, Boglárka and Sarkadi, Balázs and Poór, Gyula}, doi = {10.1007/s10238-022-00848-7}, journal-iso = {CLIN EXP MED}, journal = {CLINICAL AND EXPERIMENTAL MEDICINE}, volume = {23}, unique-id = {33061607}, issn = {1591-8890}, year = {2023}, eissn = {1591-9528}, pages = {1277-1284}, orcid-numbers = {Kulin, Anna/0000-0002-2877-5831; Mózner, Orsolya/0000-0001-5784-7702; Várady, György/0000-0003-2012-9680; Sarkadi, Balázs/0000-0003-0592-4539; Poór, Gyula/0000-0001-9235-3900} } @article{MTMT:33264041, title = {Genetic Modulation of the GLUT1 Transporter Expression—Potential Relevance in Complex Diseases}, url = {https://m2.mtmt.hu/api/publication/33264041}, author = {Kulin, Anna and Kucsma, Nóra and Bohár, Balázs and Literáti-Nagy, Botond and Korányi, László and Cserepes, Judit and Somogyi, Anikó and Sarkadi, Balázs and Szabó, Edit Zsuzsanna and Várady, György}, doi = {10.3390/biology11111669}, journal-iso = {BIOLOGY-BASEL}, journal = {BIOLOGY-BASEL}, volume = {11}, unique-id = {33264041}, abstract = {The human GLUT1 (SLC2A1) membrane protein is the key glucose transporter in numerous cell types, including red cells, kidney, and blood-brain barrier cells. The expression level of this protein has a role in several diseases, including cancer and Alzheimer’s disease. In this work, to investigate a potential genetic modulation of the GLUT1 expression level, the protein level was measured in red cell membranes by flow cytometry, and the genetic background was analyzed by qPCR and luciferase assays. We found significant associations between red cell GLUT1 levels and four single nucleotide polymorphisms (SNP) in the coding SLC2A1 gene, that in individuals with the minor alleles of rs841848, rs1385129, and rs11537641 had increased, while those having the variant rs841847 had decreased erythrocyte GLUT1 levels. In the luciferase reporter studies performed in HEK-293T and HepG2 cells, a similar SNP-dependent modulation was observed, and lower glucose, serum, and hypoxic condition had variable, cell- and SNP-specific effects on luciferase expression. These results should contribute to a more detailed understanding of the genetic background of membrane GLUT1 expression and its potential role in associated diseases.}, year = {2022}, eissn = {2079-7737}, orcid-numbers = {Kulin, Anna/0000-0002-2877-5831; Literáti-Nagy, Botond/0000-0002-1319-6474; Somogyi, Anikó/0000-0003-0807-260X; Sarkadi, Balázs/0000-0003-0592-4539; Várady, György/0000-0003-2012-9680} } @article{MTMT:33092478, title = {Selective Fluorescent Probes for High-Throughput Functional Diagnostics of the Human Multidrug Transporter P-Glycoprotein (ABCB1)}, url = {https://m2.mtmt.hu/api/publication/33092478}, author = {Szabó, Edit Zsuzsanna and Kulin, Anna and Jezsó, Bálint and Kucsma, Nóra and Sarkadi, Balázs and Várady, György}, doi = {10.3390/ijms231810599}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {23}, unique-id = {33092478}, issn = {1661-6596}, abstract = {The multidrug transporter ABCB1 (MDR1, Pgp) plays an important role in the absorption, distribution, metabolism, and elimination of a wide range of pharmaceutical compounds. Functional investigation of the ABCB1 expression is also essential in many diseases, including drug-resistant cancer, inflammatory conditions, or Alzheimer disease. In this study, we examined the potential interaction of the ABCB1 multidrug transporter with a group of commercially available viability dyes that are generally considered not to penetrate into intact cells. Here, we demonstrate that the slow cellular accumulation of TO-PRO™-1 (TP1) or TO-PRO™-3 (TP3) was strongly inhibited by ABCB1-dependent dye extrusion. TP1/3 dye accumulation was not affected by the presence of ABCC1 or ABCG2, while this uptake was increased to the level in the ABCB1-negative cells by a specific P-glycoprotein inhibitor, Tariquidar. We suggest that TP compounds can be used as highly sensitive, selective, non-toxic, and stable dyes to examine the functional expression and properties of the ABCB1 multidrug transporter, especially in microplate-based high-throughput flow cytometry assays. In addition, we demonstrate the applicability of the TP dyes to efficiently select and separate even a very low number of Pgp-expressing intact cells.}, year = {2022}, eissn = {1422-0067}, orcid-numbers = {Kulin, Anna/0000-0002-2877-5831; Jezsó, Bálint/0000-0002-1306-4797; Sarkadi, Balázs/0000-0003-0592-4539; Várady, György/0000-0003-2012-9680} } @article{MTMT:32880405, title = {Interaction of crown ethers with the ABCG2 transporter and their implication for multidrug resistance reversal}, url = {https://m2.mtmt.hu/api/publication/32880405}, author = {Mioc, Marija and Telbisz, Ágnes Mária and Radman, Katarina and Bertosa, Branimir and Sumanovac, Tatjana and Sarkadi, Balázs and Kralj, Marijeta}, doi = {10.1007/s00418-022-02106-z}, journal-iso = {HISTOCHEM CELL BIOL}, journal = {HISTOCHEMISTRY AND CELL BIOLOGY}, volume = {158}, unique-id = {32880405}, issn = {0948-6143}, abstract = {Overexpression of ABC transporters, such as ABCB1 and ABCG2, plays an important role in mediating multidrug resistance (MDR) in cancer. This feature is also attributed to a subpopulation of cancer stem cells (CSCs), having enhanced tumourigenic potential. ABCG2 is specifically associated with the CSC phenotype, making it a valuable target for eliminating aggressive and resistant cells. Several natural and synthetic ionophores have been discovered as CSC-selective drugs that may also have MDR-reversing ability, whereas their interaction with ABCG2 has not yet been explored. We previously reported the biological activities, including ABCB1 inhibition, of a group of adamantane-substituted diaza-18-crown-6 (DAC) compounds that possess ionophore capabilities. In this study, we investigated the mechanism of ABCG2-inhibitory activity of DAC compounds and the natural ionophores salinomycin, monensin and nigericin. We used a series of functional assays, including real-time microscopic analysis of ABCG2-mediated fluorescent substrate transport in cells, and docking studies to provide comparative aspects for the transporter-compound interactions and their role in restoring chemosensitivity. We found that natural ionophores did not inhibit ABCG2, suggesting that their CSC selectivity is likely mediated by other mechanisms. In contrast, DACs with amide linkage in the side arms demonstrated noteworthy ABCG2-inhibitory activity, with DAC-3Amide proving to be the most potent. This compound induced conformational changes of the transporter and likely binds to both Cavity 1 and the NBD-TMD interface. DAC-3Amide reversed ABCG2-mediated MDR in model cells, without affecting ABCG2 expression or localization. These results pave the way for the development of new crown ether compounds with improved ABCG2-inhibitory properties.}, keywords = {ABCG2; multidrug resistance; Ionophores; CROWN ETHERS; ATP-binding cassette (ABC) transporters; In vitro functional studies}, year = {2022}, eissn = {1432-119X}, pages = {261-277}, orcid-numbers = {Mioc, Marija/0000-0001-5290-6945; Telbisz, Ágnes Mária/0000-0003-0972-4606; Sarkadi, Balázs/0000-0003-0592-4539} }