TY - JOUR AU - Hajnády, Zoltán AU - Nagy-Pénzes, Máté AU - Demény, Máté Ágoston AU - Kovács, Katalin AU - El-Hamoly, Tarek AU - Maléth, József AU - Hegyi, Péter AU - Polgár, Zsuzsanna AU - Hegedűs, Csaba AU - Virág, László TI - OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis JF - BIOMEDICINES J2 - BIOMEDICINES VL - 10 PY - 2022 IS - 10 PG - 17 SN - 2227-9059 DO - 10.3390/biomedicines10102543 UR - https://m2.mtmt.hu/api/publication/33153168 ID - 33153168 N1 - * Megosztott szerzőség AB - Acute pancreatitis (AP) is a potentially life-threatening gastrointestinal disease with a complex pathology including oxidative stress. Oxidative stress triggers oxidative DNA lesions such as formation of 7,8-dihydro-8-oxo-2′-oxoguanine (8-oxoG) and also causes DNA strand breaks. DNA breaks can activate the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1) which contributes to AP pathology. 8-oxoG is recognized by 8-oxoG glycosylase 1 (OGG1) resulting in the removal of 8-oxoG from DNA as an initial step of base excision repair. Since OGG1 also possesses a DNA nicking activity, OGG1 activation may also trigger PARP1 activation. In the present study we investigated the role played by OGG1 in AP. We found that the OGG1 inhibitor compound TH5487 reduced edema formation, inflammatory cell migration and necrosis in a cerulein-induced AP model in mice. Moreover, TH5487 caused 8-oxoG accumulation and reduced tissue poly(ADP-ribose) levels. Consistent with the indirect PARP inhibitory effect, TH5487 shifted necrotic cell death (LDH release and Sytox green uptake) towards apoptosis (caspase activity) in isolated pancreatic acinar cells. In the in vivo AP model, TH5487 treatment suppressed the expression of various cytokine and chemokine mRNAs such as those of TNF, IL-1β, IL1ra, IL6, IL16, IL23, CSF, CCL2, CCL4, CCL12, IL10 and TREM as measured with a cytokine array and verified by RT-qPCR. As a potential mechanism underlying the transcriptional inhibitory effect of the OGG1 inhibitor we showed that while 8-oxoG accumulation in the DNA facilitates NF-κB binding to its consensus sequence, when OGG1 is inhibited, target site occupancy of NF-κB is impaired. In summary, OGG1 inhibition provides protection from tissue injury in AP and these effects are likely due to interference with the PARP1 and NF-κB activation pathways. LA - English DB - MTMT ER - TY - JOUR AU - Nagy-Pénzes, Máté AU - Hajnády, Zoltán AU - Regdon, Zsolt AU - Demény, Máté Ágoston AU - Kovács, Katalin AU - El-Hamoly, Tarek AU - Maléth, József AU - Hegyi, Péter AU - Hegedűs, Csaba AU - Virág, László TI - Tricetin Reduces Inflammation and Acinar Cell Injury in Cerulein-Induced Acute Pancreatitis: The Role of Oxidative Stress-Induced DNA Damage Signaling JF - BIOMEDICINES J2 - BIOMEDICINES VL - 10 PY - 2022 IS - 6 PG - 20 SN - 2227-9059 DO - 10.3390/biomedicines10061371 UR - https://m2.mtmt.hu/api/publication/32886684 ID - 32886684 N1 - * Megosztott szerzőség LA - English DB - MTMT ER - TY - JOUR AU - Nagy-Pénzes, Máté AU - Hajnády, Zoltán AU - Regdon, Zsolt AU - Virág, László TI - Beneficial effects of tricetin in cerulein induced acute pancreatitis JF - FEBS OPEN BIO J2 - FEBS OPEN BIO VL - 11 PY - 2021 SP - 493 EP - 494 PG - 2 SN - 2211-5463 UR - https://m2.mtmt.hu/api/publication/32499339 ID - 32499339 LA - English DB - MTMT ER - TY - JOUR AU - Hajnády, Zoltán AU - Nagy-Pénzes, Máté AU - Regdon, Zsolt AU - Virág, László TI - Role of OGG1 in cerulein induced acute pancreatitis JF - FEBS OPEN BIO J2 - FEBS OPEN BIO VL - 11 PY - 2021 SP - 492 EP - 493 PG - 2 SN - 2211-5463 UR - https://m2.mtmt.hu/api/publication/32499259 ID - 32499259 LA - English DB - MTMT ER - TY - JOUR AU - El-Hamoly, T AU - Hajnády, Zoltán AU - Nagy-Pénzes, Máté AU - Bakondi, Edina AU - Regdon, Zsolt AU - Demény, Máté Ágoston AU - Kovács, Katalin AU - Hegedűs, Csaba AU - Abd, El-Rahman SS AU - Szabó, Éva AU - Maléth, József AU - Hegyi, Péter AU - Virág, László TI - Poly(ADP-ribose) polymerase 1 promotes inflammation and fibrosis in a mouse model of chronic pancreatitis JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 7 PG - 15 SN - 1661-6596 DO - 10.3390/ijms22073593 UR - https://m2.mtmt.hu/api/publication/31938546 ID - 31938546 N1 - * Megosztott szerzőség LA - English DB - MTMT ER - TY - JOUR AU - Regdon, Zsolt AU - Demény, Máté Ágoston AU - Kovács, Katalin AU - Hajnády, Zoltán AU - Nagy-Pénzes, Máté AU - Bakondi, Edina AU - Kiss, Alexandra AU - Hegedűs, Csaba AU - Virág, László TI - High‐content screening identifies inhibitors of oxidative stress‐induced parthanatos: cytoprotective and anti‐inflammatory effects of ciclopirox JF - BRITISH JOURNAL OF PHARMACOLOGY J2 - BR J PHARMACOL VL - 178 PY - 2021 IS - 5 SP - 1095 EP - 1113 PG - 19 SN - 0007-1188 DO - 10.1111/bph.15344 UR - https://m2.mtmt.hu/api/publication/31831963 ID - 31831963 N1 - Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary MTA-DE Cell Biology and Signaling Research Group, Debrecen, Hungary Cited By :7 Export Date: 4 October 2023 CODEN: BJPCB Correspondence Address: Hegedűs, C.; Department of Medical Chemistry, Hungary; email: hcsaba@med.unideb.hu Correspondence Address: Virág, L.; Department of Medical Chemistry, Hungary; email: lvirag@med.unideb.hu Correspondence Address: Virág, L.; MTA-DE Cell Biology and Signaling Research GroupHungary; email: lvirag@med.unideb.hu AB - Background and Purpose Excessive oxidative stress can induce PARP1‐mediated programmed necrotic cell death, termed parthanatos. Inhibition of parthanatos may be therapeutically beneficial in a wide array of diseases associated with tissue injury and inflammation. Our goal was to identify novel molecules inhibiting parthanatos. Experimental Approach A small library of 774 pharmacologically active compounds was screened in a Sytox Green uptake assay, which identified 20 hits that reduced hydrogen‐peroxide‐induced parthanatos with an efficiency comparable to the benchmark PARP inhibitor, PJ34. Key Results Of these hits, two compounds, antifungal ciclopirox and dopamine receptor agonist apomorphine, inhibited PAR polymer synthesis. These two compounds prevented the binding of PARP1 to oxidatively damaged DNA but did not directly interfere with the interaction between DNA and PARP1. Both compounds inhibited mitochondrial superoxide and H2O2 production and suppressed DNA breakage. Since H2O2‐induced damage is dependent on Fe2+‐catalysed hydroxyl radical production (Fenton chemistry), we determined the iron chelation activity of the two test compounds and found that ciclopirox and, to a lesser extent, apomorphine act as iron chelators. We also show that the Fe2+ chelation and indirect PARP inhibitory effects of ciclopirox translate to anti‐inflammatory actions as demonstrated in a mouse dermatitis model, where ciclopirox reduced ear swelling, inflammatory cell recruitment and poly(ADP‐ribosyl)ation. Conclusion and Implications Our findings indicate that the antimycotic drug, ciclopirox, acts as an iron chelator and thus targets an early event in hydrogen‐peroxide‐induced parthanatos. Ciclopirox has the potential to be repurposed as a cytoprotective and anti‐inflammatory agent. LA - English DB - MTMT ER - TY - JOUR AU - Bakondi, Edina AU - Singh, Salam Bhopen AU - Hajnády, Zoltán AU - Nagy-Pénzes, Máté AU - Regdon, Zsolt AU - Kovács, Katalin AU - Hegedűs, Csaba AU - Madácsy, Tamara AU - Maléth, József AU - Hegyi, Péter AU - Demény, Máté Ágoston AU - Nagy, Tibor AU - Kéki, Sándor AU - Szabó, Éva AU - Virág, László TI - Spilanthol Inhibits Inflammatory Transcription Factors and iNOS Expression in Macrophages and Exerts Anti-inflammatory Effects in Dermatitis and Pancreatitis JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 20 PY - 2019 IS - 17 PG - 18 SN - 1661-6596 DO - 10.3390/ijms20174308 UR - https://m2.mtmt.hu/api/publication/30791594 ID - 30791594 N1 - * Megosztott szerzőség AB - Activated macrophages upregulate inducible nitric oxide synthase (iNOS) leading to the profuse production of nitric oxide (NO) and, eventually, tissue damage. Using macrophage NO production as a biochemical marker of inflammation, we tested different parts (flower, leaf, and stem) of the medicinal plant, Spilanthes acmella. We found that extracts prepared from all three parts, especially the flowers, suppressed NO production in RAW macrophages in response to interferon-γ and lipopolysaccharide. Follow up experiments with selected bioactive molecules from the plant (α-amyrin, β-caryophylline, scopoletin, vanillic acid, trans-ferulic acid, and spilanthol) indicated that the N-alkamide, spilanthol, is responsible for the NO-suppressive effects and provides protection from NO-dependent cell death. Spilanthol reduced the expression of iNOS mRNA and protein and, as a possible underlying mechanism, inhibited the activation of several transcription factors (NFκB, ATF4, FOXO1, IRF1, ETS, and AP1) and sensitized cells to downregulation of Smad (TF array experiments). The iNOS inhibitory effect translated into an anti-inflammatory effect, as demonstrated in a phorbol 12-myristate 13-acetate-induced dermatitis and, to a smaller extent, in cerulein-induced pancreatitis. In summary, we demonstrate that spilanthol inhibits iNOS expression, NO production and suppresses inflammatory TFs. These events likely contribute to the observed anti-inflammatory actions of spilanthol in dermatitis and pancreatitis. LA - English DB - MTMT ER - TY - JOUR AU - Fellows, Rachel AU - Denizot, Jeremy AU - Stellato, Claudia AU - Cuomo, Alessandro AU - Jain, Payal AU - Stoyanova, Elena AU - Balazsi, Szabina AU - Hajnády, Zoltán AU - Liebert, Anke AU - Kazakevych, Juri AU - Blackburn, Hector AU - Correa, Renan Oliveira AU - Fachi, Jose Luis AU - Sato, Fabio Takeo AU - Ribeiro, Willian R. AU - Ferreira, Caroline Marcantonio AU - Peree, Helene AU - Spagnuolo, Mariangela AU - Mattiuz, Raphael AU - Matolcsi, Csaba AU - Guedes, Joana AU - Clark, Jonathan AU - Veldhoen, Marc AU - Bonaldi, Tiziana AU - Ramirez Vinolo, Marco Aurelio AU - Varga-Weisz, Patrick TI - Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 9 PY - 2018 PG - 15 SN - 2041-1723 DO - 10.1038/s41467-017-02651-5 UR - https://m2.mtmt.hu/api/publication/33570198 ID - 33570198 AB - The recently discovered histone post-translational modification crotonylation connects cellular metabolism to gene regulation. Its regulation and tissue-specific functions are poorly understood. We characterize histone crotonylation in intestinal epithelia and find that histone H3 crotonylation at lysine 18 is a surprisingly abundant modification in the small intestine crypt and colon, and is linked to gene regulation. We show that this modification is highly dynamic and regulated during the cell cycle. We identify class I histone deacetylases, HDAC1, HDAC2, and HDAC3, as major executors of histone decrotonylation. We show that known HDAC inhibitors, including the gut microbiota-derived butyrate, affect histone decrotonylation. Consistent with this, we find that depletion of the gut microbiota leads to a global change in histone crotonylation in the colon. Our results suggest that histone crotonylation connects chromatin to the gut microbiota, at least in part, via short-chain fatty acids and HDACs. LA - English DB - MTMT ER -