PARK7 Diminishes Oxidative Stress-Induced Mucosal Damage in Celiac Disease

• Published in: Oxidative medicine and cellular longevity 2020, Vol.2020 (2020), p.1-13
• Main Authors: Vannay, Ádám, Szabó, Attila J., Lippai, Rita, Takács, István M., Szebeni, Beáta, Rokonay, Réka, Pap, Domonkos, Bernáth, Mária, Veres-Székely, Apor, Cseh, Áron
• Format: Article
• Language: English
• Subjects: Apoptosis; Benzamides - pharmacology; Biopsy; Celiac disease; Celiac Disease - enzymology; Celiac Disease - pathology; Cell Adhesion - drug effects; Cell culture; Cell Death - drug effects; Cell growth; Cell Line; Cytoskeleton - drug effects; Cytoskeleton - pathology; Cytotoxicity; Disease; Duodenum - drug effects; Duodenum - pathology; Epithelial Cells - drug effects; Epithelial Cells - enzymology; Epithelial Cells - pathology; Humans; Intestinal Mucosa - enzymology; Intestinal Mucosa - pathology; Intracellular Space - metabolism; Models, Biological; Oxidative Stress; Pediatrics; Permeability; Permeability - drug effects; Protein Deglycase DJ-1 - metabolism; Pyridines - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Transcription factors
• ISSN: 1942-0900; 1942-0994
• DOI: 10.1155/2020/4787202

Coeliac disease (CD) is a chronic, immune-mediated small intestinal enteropathy, accompanied with gluten-triggered oxidative damage of duodenal mucosa. Previously, our research group reported an increased mucosal level of the antioxidant protein Parkinson’s disease 7 (PARK7) in children with CD. In the present study, we investigated the role of increased PARK7 level on the epithelial cell and mucosal integrity of the small intestine. The presence of PARK7 was investigated using immunofluorescent staining on duodenal mucosa of children with CD and on FHs74Int duodenal epithelial cells. To investigate the role of oxidative stress, FHs74Int cells were treated with H2O2 in the absence or presence of Comp23, a PARK7-binding compound. Intracellular accumulation of reactive oxygen species (ROS) was determined by DCFDA-based assay. Cell viability was measured by MTT, LDH, and Annexin V apoptosis assays. Disruption of cytoskeleton and cell adhesion was investigated by immunofluorescence staining and by real-time RT PCR. Effect of PARK7 on mucosal permeability was investigated ex vivo using intestinal sacs derived from control and Comp-23-pretreated mice. Comp23 treatment reduced the H2O2-induced intracellular accumulation of ROS, thus preserving the integrity of the cytoskeleton and also the viability of the FHs74Int cells. Accordingly, Comp23 treatment increased the expression of antioxidants (NRF2, TRX1, GCLC, HMOX1, NQO1), cell-cycle regulators (TP53, CDKN1A, PCNA, BCL2, BAX), and cell adhesion molecules (ZO1, CDH1, VCL, ITGB5) of H2O2-treated cells. Pretreatment with Comp23 considerably decreased the small intestinal permeability. In this study, we demonstrate that PARK7-binding Comp23 reduces the oxidative damage of duodenal epithelial cells, via increased expression of NRF2- and P53-regulated genes. Our results suggest that PARK7 plays a significant role in the maintenance of mucosal integrity in CD.