3-(1H-Benzo[d]imidazol-6-yl)-5-(4-fluorophenyl)-1,2,4-oxadiazole (DDO7232), a Novel Potent Nrf2/ARE Inducer, Ameliorates DSS-Induced Murine Colitis and Protects NCM460 Cells against Oxidative Stress via ERK1/2 Phosphorylation.

Yu-Feng Wu,Qi-Dong You,Zheng-Yu Jiang,Lei Wang,Cui-Cui Li,Tian Liu,Li Li,Li-Li Xu,Bin Di

doi:10.1155/2018/3271617

Yu-Feng Wu, Qi-Dong You + Show 7 more

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https://doi.org/10.1155/2018/3271617

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Abstract

Ulcerative colitis (UC) is a common inflammatory bowel disease that can destroy the integrity of the colon and increase the risk of colorectal cancer. Oxidative stress is one of the critical pathogenic factors for UC, further impairing the entire affected colon. The Nrf2-ARE signaling pathway plays an important role in counteracting oxidative and electrophilic stress. Activation of the Nrf2-ARE pathway provides an indispensable defense mechanism for the treatment of UC. In this study, we identified a novel effective Nrf2 activator, DDO7232, which showed protective effects on NCM460 cells and therapeutic effects on DSS-induced colitis in mice. Mechanistic studies indicated that the Nrf2-ARE-inducing activity of DDO7232 was based on the activation of the ERK1/2 phosphorylation. The phosphorylation of Nrf2 Ser40 by p-ERK triggered the transport of Nrf2 into the nucleus and drove the expression of Nrf2-dependent antioxidant proteins. These results not only revealed the antioxidant mechanisms of DDO7232 but also provided an effective therapeutic option for the treatment of UC.

Highlights

Ulcerative colitis (UC) is a chronic relapsing-remitting inflammatory disease that has received widespread attention and research [1]
The Nuclear factor erythroid 2 p45-related factor 2 (Nrf2)-antioxidant responsive elements (AREs) pathway regulates a battery of detoxification enzymes and antioxidant proteins including NAD(P)H/quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC) [10]
Activation of Nrf2 positively regulates the transcription of NQO1 and HO-1, which are essential for reducing the risk of gastrointestinal inflammation through endogenous defense mechanisms

Summary

Introduction

Ulcerative colitis (UC) is a chronic relapsing-remitting inflammatory disease that has received widespread attention and research [1]. UC increases the risk of colorectal cancer, one of the most common malignancies in human beings [4, 5]. Identifying the etiology of UC is important for improving the current therapeutic strategies and preventing colorectal cancer [8, 9]. Oxidative stress is one of the major factors in the transformation of chronic inflammation into cancer and other diseases. The deficiency of antioxidant/detoxification enzymes, along with increases in reactive oxygen species (ROS) and nitrogen fragments, is harmful to colonic homeostasis [10]. Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a cytoprotective transcription factor [11, 12], regulates the expression of the downstream antioxidant/detoxification enzymes [13, 14]. During the early phase of inflammation-mediated tissue injury, the activation of Nrf might inhibit the production

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