Sahakian, L and Filippone, RT and Stavely, R and Robinson, AM and Yan, XS and Abalo, R and Eri, R and Bornstein, JC and Kelley, MR and Nurgali, K, Inhibition of APE1/Ref-1 redox signaling alleviates intestinal dysfunction and damage to myenteric neurons in a mouse model of spontaneous chronic colitis, Inflammatory Bowel Diseases, 27, (3) pp. 388-406. ISSN 1078-0998 (2020) [Refereed Article]
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© 2020 Crohnís & Colitis Foundation.
Background:Inflammatory bowel disease (IBD) associates with damage to the enteric nervous system (ENS), leading to gastrointestinal (GI) dysfunction. Oxidative stress is important for the pathophysiology of inflammation-induced enteric neuropathy and GI dysfunction. Apurinic/ apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a dual functioning protein that is an essential regulator of the cellular response to oxidative stress. In this study, we aimed to determine whether an APE1/Ref-1 redox domain inhibitor, APX3330, alleviates inflammation-induced oxidative stress that leads to enteric neuropathy in the Winnie murine model of spontaneous chronic colitis.
Methods: Winnie mice received APX3330 or vehicle via intraperitoneal injections over 2 weeks and were compared with C57BL/6 controls. In vivo disease activity and GI transit were evaluated. Ex vivo experiments were performed to assess functional parameters of colonic motility, immune cell infiltration, and changes to the ENS.
Results: Targeting APE1/Ref-1 redox activity with APX3330 improved disease severity, reduced immune cell infiltration, restored GI function ,and provided neuroprotective effects to the enteric nervous system. Inhibition of APE1/Ref-1 redox signaling leading to reduced mitochondrial superoxide production, oxidative DNA damage, and translocation of high mobility group box 1 protein (HMGB1) was involved in neuroprotective effects of APX3330 in enteric neurons.
Conclusions: This study is the first to investigate inhibition of APE1/Ref-1ís redox activity via APX3330 in an animal model of chronic intestinal inflammation. Inhibition of the redox function of APE1/Ref-1 is a novel strategy that might lead to a possible application of APX3330 for the treatment of IBD.
|Item Type:||Refereed Article|
|Keywords:||APE1/Ref-1, APX3330, enteric nervous system, chronic intestinal inflammation, IBD, oxidative stress, DNA damage|
|Research Division:||Biological Sciences|
|Research Field:||Animal physiology - biophysics|
|Objective Group:||Clinical health|
|Objective Field:||Clinical health not elsewhere classified|
|UTAS Author:||Eri, R (Associate Professor Raj Eri)|
|Web of Science® Times Cited:||72|
|Deposited By:||Health Sciences|
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