Cargando…

OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis

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 acti...

Descripción completa

Detalles Bibliográficos
Autores principales: Hajnády, Zoltán, Nagy-Pénzes, Máté, Demény, Máté A., Kovács, Katalin, El-Hamoly, Tarek, Maléth, József, Hegyi, Péter, Polgár, Zsuzsanna, Hegedűs, Csaba, Virág, László
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599718/
https://www.ncbi.nlm.nih.gov/pubmed/36289805
http://dx.doi.org/10.3390/biomedicines10102543
_version_ 1784816662543859712
author Hajnády, Zoltán
Nagy-Pénzes, Máté
Demény, Máté A.
Kovács, Katalin
El-Hamoly, Tarek
Maléth, József
Hegyi, Péter
Polgár, Zsuzsanna
Hegedűs, Csaba
Virág, László
author_facet Hajnády, Zoltán
Nagy-Pénzes, Máté
Demény, Máté A.
Kovács, Katalin
El-Hamoly, Tarek
Maléth, József
Hegyi, Péter
Polgár, Zsuzsanna
Hegedűs, Csaba
Virág, László
author_sort Hajnády, Zoltán
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9599718
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-95997182022-10-27 OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis Hajnády, Zoltán Nagy-Pénzes, Máté Demény, Máté A. Kovács, Katalin El-Hamoly, Tarek Maléth, József Hegyi, Péter Polgár, Zsuzsanna Hegedűs, Csaba Virág, László Biomedicines Article 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. MDPI 2022-10-12 /pmc/articles/PMC9599718/ /pubmed/36289805 http://dx.doi.org/10.3390/biomedicines10102543 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hajnády, Zoltán
Nagy-Pénzes, Máté
Demény, Máté A.
Kovács, Katalin
El-Hamoly, Tarek
Maléth, József
Hegyi, Péter
Polgár, Zsuzsanna
Hegedűs, Csaba
Virág, László
OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis
title OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis
title_full OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis
title_fullStr OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis
title_full_unstemmed OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis
title_short OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis
title_sort ogg1 inhibition reduces acinar cell injury in a mouse model of acute pancreatitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599718/
https://www.ncbi.nlm.nih.gov/pubmed/36289805
http://dx.doi.org/10.3390/biomedicines10102543
work_keys_str_mv AT hajnadyzoltan ogg1inhibitionreducesacinarcellinjuryinamousemodelofacutepancreatitis
AT nagypenzesmate ogg1inhibitionreducesacinarcellinjuryinamousemodelofacutepancreatitis
AT demenymatea ogg1inhibitionreducesacinarcellinjuryinamousemodelofacutepancreatitis
AT kovacskatalin ogg1inhibitionreducesacinarcellinjuryinamousemodelofacutepancreatitis
AT elhamolytarek ogg1inhibitionreducesacinarcellinjuryinamousemodelofacutepancreatitis
AT malethjozsef ogg1inhibitionreducesacinarcellinjuryinamousemodelofacutepancreatitis
AT hegyipeter ogg1inhibitionreducesacinarcellinjuryinamousemodelofacutepancreatitis
AT polgarzsuzsanna ogg1inhibitionreducesacinarcellinjuryinamousemodelofacutepancreatitis
AT hegeduscsaba ogg1inhibitionreducesacinarcellinjuryinamousemodelofacutepancreatitis
AT viraglaszlo ogg1inhibitionreducesacinarcellinjuryinamousemodelofacutepancreatitis