TY - CONF AU - Madácsy, Tamara AU - Varga, Árpád AU - Csákány-Papp, Noémi AU - Tél, Bálint AU - Pallagi, Petra AU - Szabó, Viktória AU - Kiss, Aletta Kata AU - Fanczal, Júlia AU - Rakonczay, Zoltán AU - Tiszlavicz, László AU - Rázga, Zsolt AU - Hohweiler, Meike AU - Kleger, Alexander AU - Gray, Mike AU - Hegyi, Péter AU - Maléth, József TI - Defective CFTR expression promotes epithelial cell damage in alcoholic pancreatitis and hepatitis by the impaired regulation of PMCA activity T2 - European Cystic Fibrosis Society 17th ECFS Basic Science Conference C1 - Albufeira PY - 2022 SP - 135 UR - https://m2.mtmt.hu/api/publication/34657419 ID - 34657419 LA - English DB - MTMT ER - TY - JOUR AU - Madácsy, Tamara AU - Varga, Árpád AU - Csákány-Papp, Noémi AU - Tél, Bálint AU - Pallagi, Petra AU - Szabó, Viktória AU - Kiss, Aletta Kata AU - Fanczal, Júlia AU - Rakonczay, Zoltán AU - Tiszlavicz, László AU - Rázga, Zsolt AU - Hohwieler, Meike AU - Kleger, Alexander AU - Gray, Mike AU - Hegyi, Péter AU - Maléth, József TI - Impaired regulation of PMCA activity by defective CFTR expression promotes epithelial cell damage in alcoholic pancreatitis and hepatitis. JF - CELLULAR AND MOLECULAR LIFE SCIENCES J2 - CELL MOL LIFE SCI VL - 79 PY - 2022 IS - 5 PG - 18 SN - 1420-682X DO - 10.1007/s00018-022-04287-1 UR - https://m2.mtmt.hu/api/publication/32800045 ID - 32800045 N1 - Department of Medicine, University of Szeged, Szeged, 6720, Hungary HAS-USZ Momentum Epithelial Cell Signaling and Secretion Research Group, University of Szeged, Szeged, 6720, Hungary First Department of Pediatrics, Semmelweis University, Budapest, Hungary Department of Pathophysiology, University of Szeged, Szeged, 6720, Hungary Department of Pathology, University of Szeged, Szeged, Hungary Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom Institute for Translational Medicine, University of Pécs, Pécs, Hungary Centre for Translational Medicine and Division for Pancreatic Disorders, Semmelweis University, Budapest, Hungary HCEMM-USZ Molecular Gastroenterology Research Group, University of Szeged, Szeged, 6720, Hungary Cited By :4 Export Date: 26 January 2024 CODEN: CMLSF Correspondence Address: Maléth, J.; Department of Medicine, Hungary; email: jozsefmaleth1@gmail.com AB - Alcoholic pancreatitis and hepatitis are frequent, potentially lethal diseases with limited treatment options. Our previous study reported that the expression of CFTR Cl- channel is impaired by ethanol in pancreatic ductal cells leading to more severe alcohol-induced pancreatitis. In addition to determining epithelial ion secretion, CFTR has multiple interactions with other proteins, which may influence intracellular Ca2+ signaling. Thus, we aimed to investigate the impact of ethanol-mediated CFTR damage on intracellular Ca2+ homeostasis in pancreatic ductal epithelial cells and cholangiocytes. Human and mouse pancreas and liver samples and organoids were used to study ion secretion, intracellular signaling, protein expression and interaction. The effect of PMCA4 inhibition was analyzed in a mouse model of alcohol-induced pancreatitis. The decreased CFTR expression impaired PMCA function and resulted in sustained intracellular Ca2+ elevation in ethanol-treated and mouse and human pancreatic organoids. Liver samples derived from alcoholic hepatitis patients and ethanol-treated mouse liver organoids showed decreased CFTR expression and function, and impaired PMCA4 activity. PMCA4 co-localizes and physically interacts with CFTR on the apical membrane of polarized epithelial cells, where CFTR-dependent calmodulin recruitment determines PMCA4 activity. The sustained intracellular Ca2+ elevation in the absence of CFTR inhibited mitochondrial function and was accompanied with increased apoptosis in pancreatic epithelial cells and PMCA4 inhibition increased the severity of alcohol-induced AP in mice. Our results suggest that improving Ca2+ extrusion in epithelial cells may be a potential novel therapeutic approach to protect the exocrine pancreatic function in alcoholic pancreatitis and prevent the development of cholestasis in alcoholic hepatitis. LA - English DB - MTMT ER - TY - GEN AU - Madácsy, Tamara AU - Varga, Árpád AU - Csákány-Papp, Noémi AU - Deák, Barnabás AU - Tél, Bálint AU - Pallagi, Petra AU - Szabó, Viktória AU - Fanczal, Júlia AU - Rakonczay, Zoltán AU - Rázga, Zsolt AU - Hohwieler, Meike AU - Kleger, Alexander AU - Gray, Mike AU - Hegyi, Péter AU - Maléth, József TI - Decreased calmodulin recruitment triggers PMCA4 dysfunction and pancreatic injury in cystic fibrosis PY - 2020 UR - https://m2.mtmt.hu/api/publication/32096788 ID - 32096788 AB - Exocrine pancreatic damage is a common complication of cystic fibrosis (CF), which can significantly debilitate the quality of life and life expectancy of CF patients. The cystic fibrosis transmembrane conductance regulator (CFTR) has a major role in pancreatic ductal ion secretion, however, it presumably has an influence on intracellular signaling as well. Here we describe in multiple model systems, including iPSC-derived human pancreatic organoids from CF patients, that the activity of PMCA4 is impaired by the decreased expression of CFTR in ductal cells. The regulation of PMCA4, which colocalizes and physically interacts with CFTR on the apical membrane of the ductal cells, is dependent on the calmodulin binding ability of CFTR. Moreover, CFTR seems to be involved in the process of the apical recruitment of calmodulin, which enhances its role in calcium signaling and homeostasis. Sustained intracellular Ca2+ elevation in CFTR KO cells undermined the mitochondrial function and increased apoptosis. Based on these, the prevention of sustained intracellular Ca2+ overload may improve the exocrine pancreatic function and may have a potential therapeutic aspect in CF. LA - English DB - MTMT ER - TY - THES AU - Fanczal, Júlia TI - The role of intracellular Ca 2+ signaling in the exocrine pancreatic damage during acute pancreatitis [Az intracelluláris Ca2+ szignalizáció szerepe az exokrin hasnyálmirigy sejtek károsodásának kialakulásában heveny hasnyálmirigy gyulladás során] PB - Szegedi Tudományegyetem (SZTE) PY - 2020 SP - 49 DO - 10.14232/phd.10488 UR - https://m2.mtmt.hu/api/publication/31933101 ID - 31933101 LA - English DB - MTMT ER - TY - CHAP AU - Molnár, Réka AU - Fanczal, Júlia AU - Madácsy, Tamara AU - Hegyi, Péter AU - Maléth, József ED - Rakonczay, Zoltán ED - Kiss, Lóránd TI - Investigation of the pancreatic ductal ion secretion in pancreatic ductal organoid cultures T2 - Proceedings of the EFOP-3.6.2-16-2017-00006 (LIVE LONGER) project PB - University of Szeged CY - Szeged SN - 9789633067642 PY - 2020 SP - 18 EP - 18 PG - 1 UR - https://m2.mtmt.hu/api/publication/31683899 ID - 31683899 LA - English DB - MTMT ER - TY - JOUR AU - Fanczal, Júlia AU - Pallagi, Petra AU - Görög, Marietta AU - Diszházi, Gyula AU - Almássy, János AU - Madácsy, Tamara AU - Varga, Árpád AU - Csernay-Biró, Péter AU - Katona, Xénia AU - Tóth, Emese AU - Molnár, Réka AU - Rakonczay, Zoltán AU - Hegyi, Péter AU - Maléth, József TI - TRPM2-mediated extracellular Ca2+ entry promotes acinar cell necrosis in biliary acute pancreatitis JF - JOURNAL OF PHYSIOLOGY-LONDON J2 - J PHYSIOL-LONDON VL - 598 PY - 2020 IS - 6 SP - 1253 EP - 1270 PG - 18 SN - 0022-3751 DO - 10.1113/JP279047 UR - https://m2.mtmt.hu/api/publication/31097108 ID - 31097108 N1 - * Megosztott szerzőség AB - Acute biliary pancreatitis is a significant clinical challenge as currently no specific pharmaceutical treatment exists. Intracellular Ca2+ overload, increased reactive oxygen species (ROS) production, mitochondrial damage and intra-acinar digestive enzyme activation caused by bile acids are hallmarks of acute biliary pancreatitis. Transient Receptor Potential Melastatin 2 (TRPM2) is a non-selective cation channel that has recently emerged as an important contributor to oxidative-stress-induced cellular Ca2+ overload across different diseases. We demonstrated that TRPM2 is expressed in the plasma membrane of mouse pancreatic acinar and ductal cells, which can be activated by increased oxidative stress induced by H2 O2 treatment and contributed to bile acid-induced extracellular Ca2+ influx in acinar cells, which promoted acinar cell necrosis in vitro and in vivo. These results suggest that the inhibition of TRPM2 may be a potential treatment option for biliary pancreatitis.Acute biliary pancreatitis poses a significant clinical challenge as currently no specific pharmaceutical treatment exists. Disturbed intracellular Ca2+ signalling caused by bile acids is a hallmark of the disease, which induces increased reactive oxygen species (ROS) production, mitochondrial damage, intra-acinar digestive enzyme activation and cell death. Because of this mechanism of action, prevention of toxic cellular Ca2+ overload is a promising therapeutic target. Transient Receptor Potential Melastatin 2 (TRPM2) is a non-selective cation channel that has recently emerged as an important contributor to oxidative-stress-induced cellular Ca2+ overload across different diseases. However, the expression and possible functions of TRPM2 in the exocrine pancreas remain unknown. Here we found that TRPM2 is expressed in the plasma membrane of mouse pancreatic acinar and ductal cells, which can be activated by increased oxidative stress induced by H2 O2 treatment. TRPM2 activity was found to contribute to bile acid-induced extracellular Ca2+ influx in acinar cells, but did not have the same effect in ductal cells. The generation of intracellular ROS in response to bile acids was remarkably higher in pancreatic acinar cells compared to isolated ducts, which can explain the difference between acinar and ductal cells. This activity promoted acinar cell necrosis in vitro independently from mitochondrial damage or mitochondrial fragmentation. In addition, bile-acid-induced experimental pancreatitis was less severe in TRPM2 knockout mice, whereas the lack of TRPM2 had no protective effect in cerulein induced acute pancreatitis. Our results suggest that the inhibition of TRPM2 may be a potential treatment option for biliary pancreatitis. This article is protected by copyright. All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Molnár, Réka AU - Madácsy, Tamara AU - Varga, Árpád AU - Németh, Margit AU - Katona, Xénia AU - Görög, Marietta AU - Molnár, Brigitta AU - Fanczal, Júlia AU - Rakonczay, Zoltán AU - Hegyi, Péter AU - Pallagi, Petra AU - Maléth, József TI - Mouse pancreatic ductal organoid culture as a relevant model to study exocrine pancreatic ion secretion JF - LABORATORY INVESTIGATION J2 - LAB INVEST VL - 100 PY - 2020 IS - 1 SP - 84 EP - 97 PG - 14 SN - 0023-6837 DO - 10.1038/s41374-019-0300-3 UR - https://m2.mtmt.hu/api/publication/30766190 ID - 30766190 N1 - First Department of Medicine, University of Szeged, Szeged, Hungary HAS-USZ Momentum Epithelial Cell Signaling and Secretion Research Group, University of Szeged, Szeged, Hungary Department of Pathophysiology, University of Szeged, Szeged, Hungary HAS-USZ Momentum Translational Gastroenterology Research Group, University of Szeged, Szeged, Hungary Institute for Translational Medicine and First Department Medicine, Medical School, University of Pécs, Pécs, Hungary Department of Public Health, University of Szeged, Szeged, Hungary Cited By :22 Export Date: 26 January 2024 CODEN: LAINA Correspondence Address: Maléth, J.; First Department of Medicine, Hungary; email: maleth.jozsef@med.u-szeged-hu AB - Pancreatic exocrine secretory processes are challenging to investigate on primary epithelial cells. Pancreatic organoid cultures may help to overcome shortcomings of the current models, however the ion secretory processes in pancreatic organoids-and therefore their physiological relevance or their utility in disease modeling-are not known. To answer these questions, we provide side-by-side comparison of gene expression, morphology, and function of epithelial cells in primary isolated pancreatic ducts and organoids. We used mouse pancreatic ductal fragments for experiments or were grown in Matrigel to obtain organoid cultures. Using PCR analysis we showed that gene expression of ion channels and transporters remarkably overlap in primary ductal cells and organoids. Morphological analysis with scanning electron microscopy revealed that pancreatic organoids form polarized monolayers with brush border on the apical membrane. Whereas the expression and localization of key proteins involved in ductal secretion (cystic fibrosis transmembrane conductance regulator, Na+/H+ exchanger 1 and electrogenic Na+/HCO3- cotransporter 1) are equivalent to the primary ductal fragments. Measurements of intracellular pH and Cl- levels revealed no significant difference in the activities of the apical Cl-/HCO3- exchange, or in the basolateral Na+ dependent HCO3- uptake. In summary we found that ion transport activities in the mouse pancreatic organoids are remarkably similar to those observed in freshly isolated primary ductal fragments. These results suggest that organoids can be suitable and robust model to study pancreatic ductal epithelial ion transport in health and diseases and facilitate drug development for secretory pancreatic disorders like cystic fibrosis, or chronic pancreatitis. LA - English DB - MTMT ER - TY - JOUR AU - Fanczal, Júlia AU - Pallagi, Petra AU - Görög, Marietta AU - Péter Bíró, Csaba AU - Madácsy, Tamara AU - Varga, Árpád AU - Rakonczay, Zoltán AU - Hegyi, Péter AU - Maléth, József TI - Characterization of the function of transient receptor potentialmelastatin 2 in mouse pancreas JF - PANCREATOLOGY J2 - PANCREATOLOGY VL - 19 PY - 2019 IS - Suppl 1 SP - S94 EP - S94 SN - 1424-3903 DO - 10.1016/j.pan.2019.05.249 UR - https://m2.mtmt.hu/api/publication/31399002 ID - 31399002 LA - English DB - MTMT ER - TY - JOUR AU - Molnár, Réka AU - Görög, Marietta AU - Fanczal, Júlia AU - Madácsy, Tamara AU - Németh, Margit AU - Varga, Árpád AU - Katona, Xénia AU - Rakonczay, Zoltán AU - Hegyi, Péter AU - Pallagi, Petra AU - Maléth, József TI - Pancreatic ductal organoid cultures are a suitable model to studypancreatic ductal ion secretion JF - PANCREATOLOGY J2 - PANCREATOLOGY VL - 19 PY - 2019 IS - Suppl 1 SP - S18 EP - S18 PG - 1 SN - 1424-3903 DO - 10.1016/j.pan.2019.05.039 UR - https://m2.mtmt.hu/api/publication/31398797 ID - 31398797 LA - English DB - MTMT ER - TY - JOUR AU - Madácsy, Tamara AU - Varga, Árpád AU - Schmidt, Anna AU - Fanczal, Júlia AU - Pallagi, Petra AU - Rakonczay, Zoltán AU - Hegyi, Péter AU - Rázga, Zsolt AU - Kleger, Alexander AU - Gray, Mike AU - Németh, István AU - Maléth, József TI - PMCA pump dysfunction promotes Ca2+ overload and pancreaticductal epithelial cell damage in cysticfibrosis JF - PANCREATOLOGY J2 - PANCREATOLOGY VL - 19 PY - 2019 IS - Suppl 1 SP - S17 EP - S18 PG - 2 SN - 1424-3903 DO - 10.1016/j.pan.2019.05.037 UR - https://m2.mtmt.hu/api/publication/31398652 ID - 31398652 LA - English DB - MTMT ER -