Neonatal <i>Ogg1</i>/<i>Mutyh</i> knockout mice have altered inflammatory gene response compared to wildtype mice in the brain and lung after hypoxia-reoxygenation

Rognlien, Anne Gro Wesenberg; Wollen, Embjørg J.; Atneosen-Åsegg, Monica; Suganthan, Rajikala; Bjørås, Magnar; Saugstad, Ola Didrik

doi:10.1515/jpm-2018-0172

Cited by 6 publications

(3 citation statements)

References 38 publications

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“…Previous studies demonstrating an inflammation promoting role of OGG1 may provide clues for how this protein functions in AP. Animal models in which OGG1 has been shown to promote inflammation include contact hypersensitivity (skin inflammation; [ 18 ]), endotoxin shock (generalized, “whole body” inflammation) [ 18 ], asthma [ 46 ], Pseudomonas infection [ 47 ], hypoxia-reoxygenation-induced neuroinflammation [ 48 ] and TNF-induced lung inflammation [ 23 ]. Given the central role of NF-κB signaling in AP we considered this pathway as the most likely target of the OGG1 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

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

Hajnády

Nagy-Pénzes

Demény³

et al. 2022

Biomedicines

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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.

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Section: Discussionmentioning

confidence: 99%

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

Hajnády

Nagy-Pénzes

Demény³

et al. 2022

Biomedicines

View full text Add to dashboard Cite

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“…In turn, this inflammation can enhance acute allograft rejection, impair transplant tolerance and accelerate the progression of chronic rejection ( 25 ). A number of reports in cellular and animal models have shown that the levels of inflammatory factors, including IL-6 and IL-1β, were significantly increased after lung injury, whereas those of immunosuppressive factors, including IL-10, were decreased ( 26 , 27 ). Therefore, it is necessary to reduce the occurrence of inflammation to mitigate the damage induced by LIRI.…”

Section: Discussionmentioning

confidence: 99%

Mangiferin inhibits hypoxia/reoxygenation‑induced alveolar epithelial cell injury via the SIRT1/AMPK signaling pathway

Chen

Huang

2021

Exp Ther Med

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Lung ischemia-reperfusion injury (LIRI) is one of the complications that can occur after lung transplantation and may lead to morbidity and mortality. Mangiferin (MAF) is a naturally occurring glucosyl xanthone that has been documented to possess anti-inflammatory, immunomodulatory and potent antioxidant effects. The purpose of the present study was to investigate the effect of MAF on LIRI using a hypoxia-reoxygenation (H/R) cell model. In the present study, the viability of lung alveolar epithelial cells (A549) and H/R-A549 were detected by MTT assay. ELISA was used to evaluate the expression levels of IL-6 and IL-1β. TUNEL assay and western blotting were used to evaluate the apoptosis. In addition, H/R-A549 cells were treated with sirtinol, which is known inhibitor of sirtuin 1 (SIRT1) activity, to determine the effects of MAF on proteins associated with the SIRT1/5'AMP-activate protein kinase (AMPK) signaling pathway using western blotting. The results showed that 20 µM MAF exerted a protective effect on A549 cells against H/R mediating no clear cytotoxic effects. In terms of inflammation, MAF reduced IL-6, IL-1β, cyclooxygenase-2 and inducible nitric oxide synthase expression, which was accompanied by activation of the SIRT1/AMPK signaling pathway. In addition, compared with those in the group treated with sirtinol, expression of SIRT1, Bcl-2 and AMPK activity were elevated in MAF-treated H/R-A549 cells, whereas the expression of Bax, cleaved caspase-3 and cleaved caspase-9 was suppressed. TUNEL analysis of H/R-A549 cells treated with MAF in combination with sirtinol revealed that treatment with sirtinol blocked the SIRT1/AMPK signaling pathway and increased the apoptosis rate compared with the MAF group. Taken together, results of the present study revealed that MAF could inhibit lung H/R cell injury through the SIRT1/AMPK signaling pathway.

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“…The transcriptome of neonatal OGG1 −/− / MUTYH −/− mice was recently investigated after brain hypoxia reoxygenation, where altered gene expression patterns of inflammatory markers in the hippocampus/striatum were detected [ 110 ]. These results raise the hypothesis that OGG1 / MUTYH -mediated transcriptional regulation is important for brain stroke outcomes.…”

Section: Impact Of Dna Glycosylases On Acute Tissue Damage and Regeneration During Brain Injurymentioning

confidence: 99%

Impact of Oxidative DNA Damage and the Role of DNA Glycosylases in Neurological Dysfunction

Sousa

Luna

et al. 2021

IJMS

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The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, are beneficial to the proper functioning of fundamental cellular processes. At supraphysiological levels, however, ROS and associated lesions cause detrimental effects in brain cells, commonly observed in several neurodegenerative disorders. In this review, we focus on the impact of oxidative DNA base lesions and the role of DNA glycosylase enzymes repairing these lesions on brain function and disease. Furthermore, we discuss the role of DNA base oxidation as an epigenetic mechanism involved in brain diseases, as well as potential roles of DNA glycosylases in different epigenetic contexts. We provide a detailed overview of the impact of DNA glycosylases on brain metabolism, cognition, inflammation, tissue loss and regeneration, and age-related neurodegenerative diseases based on evidence collected from animal and human models lacking these enzymes, as well as post-mortem studies on patients with neurological disorders.

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Neonatal Ogg1/Mutyh knockout mice have altered inflammatory gene response compared to wildtype mice in the brain and lung after hypoxia-reoxygenation

Abstract: For the first time, we report that Ogg1 and Mutyh in combination protect against late inflammatory gene activation in the hippocampus/striatum and lung after neonatal hypoxia-reoxygenation.

Cited by 6 publications

References 38 publications

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

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

Mangiferin inhibits hypoxia/reoxygenation‑induced alveolar epithelial cell injury via the SIRT1/AMPK signaling pathway

Impact of Oxidative DNA Damage and the Role of DNA Glycosylases in Neurological Dysfunction

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