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PARK7 Diminishes Oxidative Stress-Induced Mucosal Damage in Celiac Disease.
Oxidative Medicine and Cellular Longevity ( IF 7.310 ) Pub Date : 2020-09-07 , DOI: 10.1155/2020/4787202
Apor Veres-Székely 1 , Mária Bernáth 1 , Domonkos Pap 2 , Réka Rokonay 1 , Beáta Szebeni 2 , István M Takács 1 , Rita Lippai 1 , Áron Cseh 1 , Attila J Szabó 1, 2 , Ádám Vannay 1, 2
Affiliation  

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.

中文翻译:

PARK7减少了乳糜泻中氧化应激诱导的粘膜损伤。

腹腔疾病(CD)是一种慢性的,免疫介导的小肠肠病,伴随着由麸质触发的十二指肠粘膜的氧化损伤。先前,我们的研究小组报道了CD儿童中抗氧化蛋白帕金森氏病7(PARK7)的粘膜水平升高。在本研究中,我们调查了PARK7水平升高对小肠上皮细胞和粘膜完整性的作用。使用免疫荧光染色研究了患有CD的儿童的十二指肠粘膜和FHs74Int十二指肠上皮细胞上PARK7的存在。为了研究氧化应激的作用,用H 2 O 2处理了FHs74Int细胞在不存在或存在Comp23(PARK7结合化合物)的情况下。通过基于DCFDA的测定法确定细胞内活性氧(ROS)的积累。通过MTT,LDH和膜联蛋白V凋亡测定法测量细胞活力。通过免疫荧光染色和实时RT PCR研究细胞骨架的破坏和细胞粘附。使用衍生自对照和Comp-23预处理小鼠的肠囊离体研究了PARK7对粘膜通透性的影响。Comp23处理减少了H 2 O 2诱导的ROS的细胞内积累,从而保留了细胞骨架的完整性以及FHs74Int细胞的生存能力。因此,Comp23处理可增加抗氧化剂(NRF2TRX1GCLCHMOX1NQO1),细胞周期调节剂(TP53CDKN1APCNABCL2BAX)和H 2 O 2的细胞粘附分子(ZO1CDH1VCLITGB5处理的细胞。Comp23预处理可大大降低小肠通透性。在这项研究中,我们证明,PARK7结合型Comp23通过增加NRF2和P53调控基因的表达来减少十二指肠上皮细胞的氧化损伤。我们的结果表明,PARK7在CD黏膜完整性的维持中起着重要作用。
更新日期:2020-09-08
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