@article{MTMT:35196297, title = {The PARP inhibitor rucaparib blocks SARS-CoV-2 virus binding to cells and the immune reaction in models of COVID-19}, url = {https://m2.mtmt.hu/api/publication/35196297}, author = {Papp, H. and Tóth, Emese and Bóvári-Biri, J. and Bánfai, K. and Juhász, P. and Mahdi, M. and Russo, L.C. and Bajusz, Dávid and Sipos, Adrienn and Petri, László and Szalai, Tibor Viktor and Kemény, Ágnes and Madai, M. and Kuczmog, A. and Batta, Gyula and Mózner, Orsolya and Vaskó, Dorottya and Hirsch, Edit and Bohus, P. and Méhes, G. and Tőzsér, J. and Curtin, N.J. and Helyes, Zsuzsanna and Tóth, A. and Hoch, N.C. and Jakab, F. and Keserű, György Miklós and Pongrácz, J.E. and Bay, Péter}, doi = {10.1111/bph.17305}, journal-iso = {BR J PHARMACOL}, journal = {BRITISH JOURNAL OF PHARMACOLOGY}, unique-id = {35196297}, issn = {0007-1188}, abstract = {Background and Purpose: To date, there are limited options for severe Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus. As ADP-ribosylation events are involved in regulating the life cycle of coronaviruses and the inflammatory reactions of the host; we have, here, assessed the repurposing of registered PARP inhibitors for the treatment of COVID-19. Experimental Approach: The effects of PARP inhibitors on virus uptake were assessed in cell-based experiments using multiple variants of SARS-CoV-2. The binding of rucaparib to spike protein was tested by molecular modelling and microcalorimetry. The anti-inflammatory properties of rucaparib were demonstrated in cell-based models upon challenging with recombinant spike protein or SARS-CoV-2 RNA vaccine. Key Results: We detected high levels of oxidative stress and strong PARylation in all cell types in the lungs of COVID-19 patients, both of which negatively correlated with lymphocytopaenia. Interestingly, rucaparib, unlike other tested PARP inhibitors, reduced the SARS-CoV-2 infection rate through binding to the conserved 493–498 amino acid region located in the spike-ACE2 interface in the spike protein and prevented viruses from binding to ACE2. In addition, the spike protein and viral RNA-induced overexpression of cytokines was down-regulated by the inhibition of PARP1 by rucaparib at pharmacologically relevant concentrations. Conclusion and Implications: These results point towards repurposing rucaparib for treating inflammatory responses in COVID-19. © 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.}, keywords = {NFκB; rucaparib; ACE2; COVID-19; SARS-CoV-2 spike protein; SARS-CoV-2 RNA; viral lung inflammation}, year = {2024}, eissn = {1476-5381}, orcid-numbers = {Bajusz, Dávid/0000-0003-4277-9481; Kemény, Ágnes/0000-0002-4523-3938; Batta, Gyula/0000-0002-0442-1828; Mózner, Orsolya/0000-0001-5784-7702; Vaskó, Dorottya/0000-0002-2502-0644} } @article{MTMT:35162210, title = {Pattern of Expression of Genes Involved in Systemic Inflammation and Glutathione Metabolism Reveals Exacerbation of COPD}, url = {https://m2.mtmt.hu/api/publication/35162210}, author = {Oit-Wiscombe, Ingrid and Virág, László and Kilk, Kalle and Soomets, Ursel and Altraja, Alan}, doi = {10.3390/antiox13080953}, journal-iso = {ANTIOXIDANTS-BASEL}, journal = {ANTIOXIDANTS}, volume = {13}, unique-id = {35162210}, abstract = {To test the hypothesis that they serve as systemic biomarkers of chronic obstructive pulmonary disease (COPD), we profiled the mRNA expression of enzymes connected to systemic inflammation and GSH metabolism in peripheral blood mononuclear cells (PBMCs). These were taken from patients displaying acute exacerbation of COPD (AE-COPD) and stable COPD, and also from non-obstructive smokers and non-smokers. The expression of poly(ADP-ribose) polymerase-1 was increased, but that of histone deacetylase 2 was decreased in association with AE-COPD. The expression of modulatory subunit of glutamyl–cysteine ligase was higher and that of its catalytic subunit, together with the expression of dipeptidyl peptidase 4, was lower in COPD patients compared with non-obstructive smokers and non-smokers. Leukotriene A4 hydrolase saw increased expression in patients with COPD according to disease severity compared to non-obstructive individuals, whereas the expression of GSH peroxidase increased in non-obstructive smokers and COPD patients with the growing number of pack-years smoked. The results corroborate COPD and its acute exacerbation as a complex systemic disorder demonstrating distinct associations with the expression of enzymes linked to inflammation and the regulation of GSH metabolism.}, year = {2024}, eissn = {2076-3921}, pages = {1-14}, orcid-numbers = {Kilk, Kalle/0000-0003-4551-9466; Altraja, Alan/0000-0001-7798-9871} } @article{MTMT:35161382, title = {The roles of phosphorylation of signaling proteins in the prognosis of acute myeloid leukemia}, url = {https://m2.mtmt.hu/api/publication/35161382}, author = {Márton, Adrienn and Veres, Katalin Beáta and Erdődi, Ferenc and Udvardy, Miklós and Illés, Árpád and Rejtő, László}, doi = {10.3389/pore.2024.1611747}, journal-iso = {PATHOL ONCOL RES}, journal = {PATHOLOGY AND ONCOLOGY RESEARCH}, volume = {30}, unique-id = {35161382}, issn = {1219-4956}, abstract = {Signaling pathways of Retinoblastoma (Rb) protein, Akt-kinase, and Erk-kinase (extracellular signal-regulated kinase) have an important role in the pathogenesis of acute myeloid leukemia. Constitutive activation of these proteins by phosphorylation contributes to cell survival by regulation of cell cycle, proliferation and proapoptotic signaling processes. According to previous data phosphorylated forms of these proteins represent a worse outcome for cancer patients. We investigated the presence of phosphorylated Rb (P-Rb), Akt (P-Akt) and Erk (P-Erk) proteins by Western blot technique using phospho-specific antibodies in bone marrow or peripheral blood samples of 69 AML patients, 36 patients with myelodysplastic syndrome (MDS) and 10 healthy volunteers. Expression level of PTEN (Phosphatase and tensin homolog) and PHLPP (PH domain and leucine-rich repeat Protein Phosphatase) phosphatases, the negative regulators of Akt kinase pathway were also examined. We tested the effect of these proteins on survival and on the correlation with known prognostic features in AML. We found 46.3% of AML patients had detectable P-Rb, 34.7% had P-Akt and 28.9% had P-Erk protein. 66.1% of patients expressing PTEN, 38.9% PHLPP, 37.2% both PTEN and PHLPP and 32.2% neither PTEN nor PHLPP phosphatases. Compared to nucleophosmin mutation (NPMc) negative samples P-Erk was significantly less in nucleophosmin mutated patients, P-Rb was significantly less in patients’ group with more than 30 G/L peripheral leukocyte count by diagnosis. PHLPP was significantly present in FAB type M5. The expression of P-Rb represented significant better overall survival (OS), while P-Akt represented significantly worse event-free survival (EFS) in unfavorable cytogenetics patients. The presence of both PHLPP and PTEN phosphatases contributes to better OS and EFS, although the differences were not statistically significant. We confirmed significant positive correlation between P-Akt and PHLPP. Assessing the phosphorylation of Rb, Akt and Erk may define a subgroup of AML patients who would benefit especially from new targeted treatment options complemented the standard chemotherapy, and it may contribute to monitoring remission, relapse or progression of AML.}, year = {2024}, eissn = {1532-2807} } @article{MTMT:35131666, title = {Treatments with Diquat Reveal the Relationship between Protein Phosphatases (PP2A) and Oxidative Stress during Mitosis in Arabidopsis thaliana Root Meristems}, url = {https://m2.mtmt.hu/api/publication/35131666}, author = {Kelemen, Adrienn and Garda, Tamás and Kónya, Zoltán and Erdődi, Ferenc and Ujlaky-Nagy, László and Gabriella, Petra Juhász and Freytag, Csongor and Mikóné Hamvas, Márta and Máthé, Csaba}, doi = {10.3390/plants13141896}, journal-iso = {PLANTS-BASEL}, journal = {PLANTS-BASEL}, volume = {13}, unique-id = {35131666}, year = {2024}, eissn = {2223-7747}, pages = {1-16}, orcid-numbers = {Freytag, Csongor/0000-0002-3356-4182} } @article{MTMT:35075451, title = {Cytostatic Bacterial Metabolites Interfere with 5-Fluorouracil, Doxorubicin and Paclitaxel Efficiency in 4T1 Breast Cancer Cells}, url = {https://m2.mtmt.hu/api/publication/35075451}, author = {Schwarcz, Szandra and Nyerges, Petra and Bíró, Tímea Ingrid and Janka, Eszter Anna and Bay, Péter and Mikó, Edit}, doi = {10.3390/molecules29133073}, journal-iso = {MOLECULES}, journal = {MOLECULES}, volume = {29}, unique-id = {35075451}, issn = {1420-3049}, abstract = {The microbiome is capable of modulating the bioavailability of chemotherapy drugs, mainly due to metabolizing these agents. Multiple cytostatic bacterial metabolites were recently identified that have cytostatic effects on cancer cells. In this study, we addressed the question of whether a set of cytostatic bacterial metabolites (cadaverine, indolepropionic acid and indoxylsulfate) can interfere with the cytostatic effects of the chemotherapy agents used in the management of breast cancer (doxorubicin, gemcitabine, irinotecan, methotrexate, rucaparib, 5-fluorouracil and paclitaxel). The chemotherapy drugs were applied in a wide concentration range to which a bacterial metabolite was added in a concentration within its serum reference range, and the effects on cell proliferation were assessed. There was no interference between gemcitabine, irinotecan, methotrexate or rucaparib and the bacterial metabolites. Nevertheless, cadaverine and indolepropionic acid modulated the Hill coefficient of the inhibitory curve of doxorubicin and 5-fluorouracil. Changes to the Hill coefficient implicate alterations to the kinetics of the binding of the chemotherapy agents to their targets. These effects have an unpredictable significance from the clinical or pharmacological perspective. Importantly, indolepropionic acid decreased the IC50 value of paclitaxel, which is a potentially advantageous combination.}, year = {2024}, eissn = {1420-3049}, orcid-numbers = {Janka, Eszter Anna/0000-0003-0724-5281} } @article{MTMT:35067588, title = {Role of protein phosphatases in tumor angiogenesis: assessing PP1, PP2A, PP2B and PTPs activity}, url = {https://m2.mtmt.hu/api/publication/35067588}, author = {Fonódi, Márton and Nagy, Lilla Nikoletta and Boratkó, Anita}, doi = {10.3390/ijms25136868}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {2024}, unique-id = {35067588}, issn = {1661-6596}, year = {2024}, eissn = {1422-0067}, pages = {1-43} } @article{MTMT:34994838, title = {Guideline for designing microbiome studies in neoplastic diseases}, url = {https://m2.mtmt.hu/api/publication/34994838}, author = {Mikó, Edit and Sipos, Adrienn and Tóth, Emese and Lehoczki, Andrea Marianna and Fekete, Mónika and Sebő, É and Kardos, G and Bay, Péter}, doi = {10.1007/s11357-024-01255-4}, journal-iso = {GEROSCIENCE}, journal = {GEROSCIENCE: OFFICIAL JOURNAL OF THE AMERICAN AGING ASSOCIATION (AGE)}, volume = {46}, unique-id = {34994838}, issn = {2509-2715}, year = {2024}, eissn = {2509-2723}, pages = {4037-4057}, orcid-numbers = {Fekete, Mónika/0000-0001-8632-2120} } @article{MTMT:34981997, title = {Smoothelin-like protein 1 promotes insulin sensitivity and modulates the contractile properties of endometrial epithelial cells with insulin resistance}, url = {https://m2.mtmt.hu/api/publication/34981997}, author = {Keller, Ilka and Ungvári , Ádám and Kinter, Richárd and Szalmás, Fanni and Kókai, Endre and Lontay, Beáta}, doi = {10.3389/fendo.2024.1375771}, journal-iso = {FRONT ENDOCRINOL}, journal = {FRONTIERS IN ENDOCRINOLOGY}, volume = {15}, unique-id = {34981997}, issn = {1664-2392}, year = {2024}, eissn = {1664-2392}, pages = {1-17} } @article{MTMT:34874198, title = {The bacterial metabolite, lithocholic acid, has antineoplastic effects in pancreatic adenocarcinoma}, url = {https://m2.mtmt.hu/api/publication/34874198}, author = {Schwarcz, Szandra and Kovács, Patrik Bence and Nyerges, Petra and Ujlaki, Gyula and Sipos, Adrienn and Uray (Davis), Karen L. and Bay, Péter and Mikó, Edit}, doi = {10.1038/s41420-024-02023-1}, journal-iso = {CELL DEATH DISCOV}, journal = {CELL DEATH DISCOVERY}, volume = {10}, unique-id = {34874198}, abstract = {Lithocholic acid (LCA) is a secondary bile acid. LCA enters the circulation after bacterial synthesis in the gastrointestinal tract, reaches distantly located cancer cells, and influences their behavior. LCA was considered carcinogenic, but recent studies demonstrated that LCA has antitumor effects. We assessed the possible role of LCA in pancreatic adenocarcinoma. At the serum reference concentration, LCA induced a multi-pronged antineoplastic program in pancreatic adenocarcinoma cells. LCA inhibited cancer cell proliferation and induced mesenchymal-to-epithelial (MET) transition that reduced cell invasion capacity. LCA induced oxidative/nitrosative stress by decreasing the expression of nuclear factor, erythroid 2-like 2 (NRF2) and inducing inducible nitric oxide synthase (iNOS). The oxidative/nitrosative stress increased protein nitration and lipid peroxidation. Suppression of oxidative stress by glutathione (GSH) or pegylated catalase (pegCAT) blunted LCA-induced MET. Antioxidant genes were overexpressed in pancreatic adenocarcinoma and decreased antioxidant levels correlated with better survival of pancreatic adenocarcinoma patients. Furthermore, LCA treatment decreased the proportions of cancer stem cells. Finally, LCA induced total and ATP-linked mitochondrial oxidation and fatty acid oxidation. LCA exerted effects through the farnesoid X receptor (FXR), vitamin D receptor (VDR), and constitutive androstane receptor (CAR). LCA did not interfere with cytostatic agents used in the chemotherapy of pancreatic adenocarcinoma. Taken together, LCA is a non-toxic compound and has antineoplastic effects in pancreatic adenocarcinoma.}, year = {2024}, eissn = {2058-7716} } @article{MTMT:34864586, title = {Serine 39 in the GTP ‐binding domain of Drp1 is involved in shaping mitochondrial morphology}, url = {https://m2.mtmt.hu/api/publication/34864586}, author = {Ghani, Marvi and Szabó, Bernadett and Alkhatibe, Mahmoud and Amsalu, Hailemariam and Zohar, Peleg and Janka, Eszter Anna and Mótyán, János András and Tar, Krisztina}, doi = {10.1002/2211-5463.13820}, journal-iso = {FEBS OPEN BIO}, journal = {FEBS OPEN BIO}, volume = {14}, unique-id = {34864586}, issn = {2211-5463}, abstract = {Continuous fusion and fission are critical for mitochondrial health. In this study, we further characterize the role played by dynamin‐related protein 1 (Drp1) in mitochondrial fission. We show that a single amino acid change in Drp1 at position 39 from serine to alanine (S39A) within the GTP‐binding (GTPase) domain results in a fused mitochondrial network in human SH‐SY5Y neuroblastoma cells. Interestingly, the phosphorylation of Ser‐616 and Ser‐637 of Drp1 remains unaffected by the S39A mutation, and mitochondrial bioenergetic profile and cell viability in the S39A mutant were comparable to those observed in the control. This leads us to propose that the serine 39 residue of Drp1 plays a crucial role in mitochondrial distribution through its involvement in the GTPase activity. Furthermore, this amino acid mutation leads to structural anomalies in the mitochondrial network. Taken together, our results contribute to a better understanding of the function of the Drp1 protein.}, year = {2024}, eissn = {2211-5463}, pages = {1147-1165}, orcid-numbers = {Amsalu, Hailemariam/0000-0001-5787-7872; Zohar, Peleg/0009-0004-8466-8602; Janka, Eszter Anna/0000-0003-0724-5281} }