APE1/Ref-1 as a Therapeutic Target for Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the gastrointestinal tract. The prevalence of IBD is increasing with approximately 4.9 million cases reported worldwide. Current therapies are limited due to the severity of side effects and long-term toxicity, therefore, the development of novel IBD treatments is necessitated. Recent findings support apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1) as a target in many pathological conditions, including inflammatory diseases, where APE1/Ref-1 regulation of crucial transcription factors impacts significant pathways. Thus, a potential target for a novel IBD therapy is the redox activity of the multifunctional protein APE1/Ref-1. This review elaborates on the status of conventional IBD treatments, the role of an APE1/Ref-1 in intestinal inflammation, and the potential of a small molecule inhibitor of APE1/Ref-1 redox activity to modulate inflammation, oxidative stress response, and enteric neuronal damage in IBD.

New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types

“…Apart from its involvement in cancer, Ref-1 has also been implicated in the protection of Dorsal root ganglion (DRG) neurons after cisplatin oncotherapy and also enteric neurons in Inflammatory bowel disease model via increased repair of oxidative DNA damage [ 73 , 74 ]. Furthermore, Ref-1 is implicated in regulating inflammatory responses in diseases such as rheumatoid arthritis, inflammatory bowel disease, and sepsis, influencing the activity of NFκB and maintaining the balance between pro-inflammatory and anti-inflammatory signaling pathways [ 75 , 76 ].…”

Krill Oil and Its Bioactive Components as a Potential Therapy for Inflammatory Bowel Disease: Insights from In Vivo and In Vitro Studies

“…This allows luminal pathogen invasion and leukocyte infiltration, resulting in barrier disruption [90,91]. Subsequently, cumulative damage to the intestinal tissue results in mucosal necrosis and ulceration, characteristic of IBD [92,93]. Mucosal NADPH oxidases (NOX), such as the NOX2 complex, NOX1, and dual oxidase 2 (DUOX2), which participate in endogenous ROS generation by catalysing chemical reactions, are activated during inflammation to produce greater amounts of ROS, and thus have been reported as novel IBD risk factors [91].…”

Yerba Mate (Ilex paraguariensis) Reduces Colitis Severity by Promoting Anti-Inflammatory Macrophage Polarization

“…In fact, the regulation of the M1/M2 balance has recently been considered as a potential therapeutic strategy for IBD [ 21 , 22 ]. Currently, there are several treatments for ulcerative colitis such as pharmacological intervention, immunomodulators, gut microbiota modulation, and biological targeting [ 23 , 24 , 25 , 26 , 27 ]. However, these treatments are not effective in all patients; some are expensive and with diverse side effects [ 28 , 29 ].…”