TY - CHAP AU - Sarkadi, Balázs ED - Mandl, József ED - Csala, Miklós TI - A plazmamembrán T2 - Orvosi patobiokémia PB - Medicina Könyvkiadó CY - Budapest SN - 9789632267821 PY - 2023 SP - 298 EP - 314 PG - 17 UR - https://m2.mtmt.hu/api/publication/34722657 ID - 34722657 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Mózner, Orsolya AU - Moldvay, Judit AU - Szabó, K.S. AU - Vaskó, Dorottya AU - Domján, Júlia AU - Ács, D. AU - Ligeti, Z. AU - Fehér, Csaba AU - Hirsch, Edit AU - Puskás, L. AU - Stahl, C. AU - Frey, M. AU - Sarkadi, Balázs TI - Application of a Receptor-Binding-Domain-Based Simple Immunoassay for Assessing Humoral Immunity against Emerging SARS-CoV-2 Virus Variants JF - BIOMEDICINES J2 - BIOMEDICINES VL - 11 PY - 2023 IS - 12 PG - 10 SN - 2227-9059 DO - 10.3390/biomedicines11123193 UR - https://m2.mtmt.hu/api/publication/34471833 ID - 34471833 N1 - Funding Agency and Grant Number: Post-COVID Research Program of the Hungarian Academy of Sciences [PC2022-7/2022]; Ministry of Culture and Innovation of Hungary from the National Research, Developmentand Innovation Fund [KDP-1017403]; European Union [RRF-2.3.1-21-2022-00015]; Ministry of Culture and Innovation from the National Research, Development and Innovation Fund [K-143039, PD-142301] Funding text: B.S. was supported by the Post-COVID Research Program of the Hungarian Academy of Sciences (PC2022-7/2022.); Project no. KDP-1017403 has been implemented with the support provided by the Ministry of Culture and Innovation of Hungary from the National Research, Developmentand Innovation Fund, financed under the KDP-2020 funding scheme (O.M.); Project no. RRF-2.3.1-21-2022-00015 has been implemented with the support provided by the European Union; the research has been implemented with the support provided by the Ministry of Culture and Innovation from the National Research, Development and Innovation Fund, financed under the [K-143039 and PD-142301]funding scheme. LA - English DB - MTMT ER - TY - JOUR AU - Broca-Brisson, Léa AU - Harati, Rania AU - Disdier, Clémence AU - Mózner, Orsolya AU - Gaston-Breton, Romane AU - Maïza, Auriane AU - Costa, Narciso AU - Guyot, Anne-Cécile AU - Sarkadi, Balázs AU - Apáti, Ágota AU - Skelton, Matthew R AU - Madrange, Lucie AU - Yates, Frank AU - Armengaud, Jean AU - Hamoudi, Rifat AU - Mabondzo, Aloïse TI - Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency JF - ELIFE J2 - ELIFE VL - 12 PY - 2023 PG - 22 SN - 2050-084X DO - 10.7554/eLife.88459 UR - https://m2.mtmt.hu/api/publication/34280401 ID - 34280401 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Mózner, Orsolya AU - Zámbó, Boglárka AU - Bartos, Zsuzsa AU - Gergely, Anna AU - Szabó, Kata Sára AU - Jezsó, Bálint AU - Telbisz, Ágnes Mária AU - Várady, György AU - Homolya, László AU - Hegedűs, Tamás AU - Sarkadi, Balázs TI - Expression, Function and Trafficking of the Human ABCG2 Multidrug Transporter Containing Mutations in an Unstructured Cytoplasmic Loop JF - MEMBRANES (BASEL) J2 - MEMBRANES-BASEL VL - 13 PY - 2023 IS - 10 PG - 14 SN - 2077-0375 DO - 10.3390/membranes13100822 UR - https://m2.mtmt.hu/api/publication/34175360 ID - 34175360 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Bakos, Éva AU - Temesszentandrási-Ambrus, Csilla AU - Laczka, Csilla AU - Gáborik, Z. AU - Sarkadi, Balázs AU - Telbisz, Ágnes Mária TI - Interactions of the Anti-SARS-CoV-2 Agents Molnupiravir and Nirmatrelvir/Paxlovid with Human Drug Transporters JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 14 SN - 1661-6596 DO - 10.3390/ijms241411237 UR - https://m2.mtmt.hu/api/publication/34095016 ID - 34095016 N1 - Research Centre for Natural Sciences—RCNS, Magyar Tudósok krt 2, Budapest, 1117, Hungary Charles River Laboratories, Irinyi József u. 4-20, Budapest, 1117, Hungary Export Date: 14 August 2023 Correspondence Address: Telbisz, Á.; Research Centre for Natural Sciences—RCNS, Magyar Tudósok krt 2, Hungary; email: telbisz.agnes@ttk.hu Funding details: Hungarian Scientific Research Fund, OTKA, FK 128751, K 138518 Funding details: Magyar Tudományos Akadémia, MTA, PC2022-7/2022 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH Funding text 1: This work was supported by the National Research Development and Innovation Office (NKFIH, OTKA) Grant number: FK 128751 (C.Ö.-L.) and K 138518 (C.Ö.-L.) and by a grant from the Hungarian Academy of Sciences (B.S., PC2022-7/2022). AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Sarkadi, Balázs TI - Cancer stem cells in drug resistance: an introduction to the e-book covering the special issue on the “Cancer Stem Cells and Drug Resistance” JF - CANCER DRUG RESISTANCE J2 - CANCER DRUG RESIST VL - 6 PY - 2023 IS - 2 SP - 239 EP - 241 PG - 3 SN - 2578-532X DO - 10.20517/cdr.2023.23 UR - https://m2.mtmt.hu/api/publication/34083454 ID - 34083454 N1 - Export Date: 01 August 2023; Cited By: 0; Correspondence Address: B. Sarkadi; Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Magyar Tudósok krt. 2, 1117, Hungary; email: sarkadi@biomembrane.hu LA - English DB - MTMT ER - TY - JOUR AU - Pálinkás, Márton AU - Szabó, Edit Zsuzsanna AU - Kulin, Anna AU - Mózner, Orsolya AU - Rásonyi, R. AU - Juhász, P. AU - Nagy, K. AU - Várady, György AU - Vörös, D. AU - Zámbó, Boglárka AU - Sarkadi, Balázs AU - Poór, Gyula TI - Genetic polymorphisms and decreased protein expression of ABCG2 urate transporters are associated with susceptibility to gout, disease severity and renal-overload hyperuricemia JF - CLINICAL AND EXPERIMENTAL MEDICINE J2 - CLIN EXP MED VL - 23 PY - 2023 SP - 1277 EP - 1284 PG - 8 SN - 1591-8890 DO - 10.1007/s10238-022-00848-7 UR - https://m2.mtmt.hu/api/publication/33061607 ID - 33061607 N1 - National Institute of Locomotor Diseases and Disabilities, Frankel Leo str. 38-40, Budapest, 1023, Hungary Doctoral School of Molecular Medicine, Semmelweis University, Budapest, Hungary Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Section of Rheumatology and Physiotherapy, Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary Export Date: 9 February 2023 CODEN: CEMLB Correspondence Address: Pálinkás, M.; National Institute of Locomotor Diseases and Disabilities, Frankel Leo str. 38-40, Hungary; email: mrpalinkas@gmail.com Correspondence Address: Poór, G.; Section of Rheumatology and Physiotherapy, Hungary; email: poor.gyula@orfi.hu Funding details: Semmelweis Egyetem, EFOP-3.6.3, VEKOP-16–2017-00009 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, K-128011 Funding details: Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, NKFIA Funding details: Innovációs és Technológiai Minisztérium Funding text 1: Open access funding provided by Semmelweis University. This study has been supported by grants from Hungarian National Development and Innovation Office (NKFIH K-128011 to Gy.V.), FIEK_16-1-2016-0005 (B.S.), and VEKOP-2.1.1-15-2016-00117 (Gy.V.). O.M. was supported by the KDP doctoral scholarship from the Ministry for Innovation and Technology (National Research, Development and Innovation Fund). B.Z. was supported by the Predoctoral Fellowship Grant of Semmelweis University (EFOP-3.6.3.-VEKOP-16–2017-00009). LA - English DB - MTMT ER - TY - JOUR AU - Kulin, Anna AU - Kucsma, Nóra AU - Bohár, Balázs AU - Literáti-Nagy, Botond AU - Korányi, László AU - Cserepes, Judit AU - Somogyi, Anikó AU - Sarkadi, Balázs AU - Szabó, Edit Zsuzsanna AU - Várady, György TI - Genetic Modulation of the GLUT1 Transporter Expression—Potential Relevance in Complex Diseases JF - BIOLOGY-BASEL J2 - BIOLOGY-BASEL VL - 11 PY - 2022 IS - 11 PG - 15 SN - 2079-7737 DO - 10.3390/biology11111669 UR - https://m2.mtmt.hu/api/publication/33264041 ID - 33264041 N1 - Összes idézések száma a WoS-ban: 0 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Szabó, Edit Zsuzsanna AU - Kulin, Anna AU - Jezsó, Bálint AU - Kucsma, Nóra AU - Sarkadi, Balázs AU - Várady, György TI - Selective Fluorescent Probes for High-Throughput Functional Diagnostics of the Human Multidrug Transporter P-Glycoprotein (ABCB1) JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 18 PG - 12 SN - 1661-6596 DO - 10.3390/ijms231810599 UR - https://m2.mtmt.hu/api/publication/33092478 ID - 33092478 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary Doctoral School of Molecular Medicine, Semmelweis University, Budapest, 1085, Hungary Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, 1094, Hungary Export Date: 10 February 2024 Correspondence Address: Sarkadi, B.; Institute of Enzymology, Hungary; email: sarkadi.balazs@ttk.hu Chemicals/CAS: calcein, 1461-15-0; multidrug resistance associated protein 2, 256503-65-8; tariquidar, 206873-63-4; ABCB1 protein, human; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Fluorescent Dyes; Neoplasm Proteins; Pharmaceutical Preparations AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Mioc, Marija AU - Telbisz, Ágnes Mária AU - Radman, Katarina AU - Bertosa, Branimir AU - Sumanovac, Tatjana AU - Sarkadi, Balázs AU - Kralj, Marijeta TI - Interaction of crown ethers with the ABCG2 transporter and their implication for multidrug resistance reversal JF - HISTOCHEMISTRY AND CELL BIOLOGY J2 - HISTOCHEM CELL BIOL VL - 158 PY - 2022 SP - 261 EP - 277 PG - 17 SN - 0948-6143 DO - 10.1007/s00418-022-02106-z UR - https://m2.mtmt.hu/api/publication/32880405 ID - 32880405 N1 - Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, 10000, Croatia ELKH Research Centre for Natural Sciences, Magyar Tudósok krt. 2, Budapest, 1117, Hungary Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, Zagreb, 10000, Croatia Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, 10000, Croatia Export Date: 5 July 2022 CODEN: HCBIF Correspondence Address: Kralj, M.; Division of Molecular Medicine, Bijenička cesta 54, Croatia; email: marijeta.kralj@irb.hr Funding details: Hrvatska Zaklada za Znanost, HRZZ, 316289, FP7-REGPOT-2012-2013-1, IP-2013-5660 Funding details: Institut Ruđer Bošković, IRB Funding text 1: This work was financed by Croatian Science Foundation project number IP-2013-5660 (“MultiCaST”) to MK. The work was also supported by the FP7-REGPOT-2012-2013-1 project, grant agreement number 316289–InnoMol. MM received a financial support from the Ruđer Bošković Institute for a short-term secondment to the ELKH Research Centre for Natural Sciences, Budapest. We sincerely thank Lucija Horvat for wonderful assistance with confocal microscopy, Dr Marijana Popović Hadžija and Lucija Lulić for invaluable experimental help. TŠ is thankful to Prof. K. Majerski for her support and introduction to the field of crown ethers. AB - 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. LA - English DB - MTMT ER -