GPA Peptide-Induced Nur77 Localization at Mitochondria Inhibits Inflammation and Oxidative Stress through Activating Autophagy in the Intestine

Abstract

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. Nur77, belongs to the NR4A subfamily of nuclear hormone receptors, plays a critical role in controlling the pathology of colitis. The aim of this study is to investigate the protection effect and mechanism of Gly-Pro-Ala (GPA) peptide, isolated from fish skin gelatin hydrolysate, in a mouse model of dextran sulfate sodium- (DSS-) induced colitis and intestinal epithelial cells (IECs) stimulated by lipopolysaccharide (LPS). In vivo, GPA treatment alleviates DSS-induced weight loss, disease activity index (DAI) increase, colon length shortening, and colonic pathological damage. Production of proinflammatory cytokines, ROS, and MDA is significantly decreased by GPA treatment. In vitro, GPA significantly inhibits proinflammatory cytokine production, cytotoxicity, ROS, and MDA in IECs. Furthermore, GPA induces autophagy to suppress inflammation and oxidative stress. GPA promotes Nur77 translocation from the nucleus to mitochondria where it facilitates Nur77 interaction with TRAF6 and p62, leading to the induction of autophagy. In addition, GPA contributed to the maintenance of tight junction architecture in vivo and in vitro. Taken together, GPA, as a Nur77 modulator, could exert anti-inflammatory and antioxidant effects by inducing autophagy in IECs, suggesting that GPA may be promising for the prevention of colitis.

The Functional Interplay between Gut Microbiota, Protein Hydrolysates/Bioactive Peptides, and Obesity: A Critical Review on the Study Advances

“…It has been reported that oxidative stress and inflammatory signals concurrently play roles that negatively impact adipose tissue and disrupt the regulation of vascular function in obesity [ 62 ]. Research has also revealed that body fluctuations resulting from metabolic disorders contribute to alterations in the gut microbial bacteria balance and disruption of the intestinal epithelial barrier which may trigger the release of pro-inflammatory cytokines and reactive oxygen species [ 63 ]. This process eventually leads to a cycle of uncontrolled oxidative stress and inflammation in the body [ 63 ].…”

“…Research has also revealed that body fluctuations resulting from metabolic disorders contribute to alterations in the gut microbial bacteria balance and disruption of the intestinal epithelial barrier which may trigger the release of pro-inflammatory cytokines and reactive oxygen species [ 63 ]. This process eventually leads to a cycle of uncontrolled oxidative stress and inflammation in the body [ 63 ]. Thus, activities that reduce chances of developing metabolic disorders, such as weight management can act as appropriate therapeutic approaches to prevent excessive oxidation and inflammatory signaling in the body.…”

METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice

“…The expression of METTL3 was determined in collected clinical IBD and normal control colon samples, as well as in the DSS-induced IBD mouse model. Mouse intestinal epithelial cells are widely used as in vitro models for IBD-related research [ 18 , 19 ]. lipopolysaccharides (LPS) were known to be increased in IBD mucosa [ 20 ] and also use to mimic the inflammatory response in IBD [ 18 , 21 ].…”

“…Mouse intestinal epithelial cells are widely used as in vitro models for IBD-related research [ 18 , 19 ]. lipopolysaccharides (LPS) were known to be increased in IBD mucosa [ 20 ] and also use to mimic the inflammatory response in IBD [ 18 , 21 ]. Herein, we transfected a mouse intestinal epithelial cell line MODE-K with lentivirus contained short hairpin RNA targeting METTL3 to achieve METTL3 knockdown, treated the cell line with LPS, and determined cell viability, apoptosis, apoptotic caspase3/9, inflammatory factor (IL-1β, TNF-α, IL-6, and IL-18) and inflammatory enzymes (COX-2 iNOS).…”

GPA peptide enhances Nur77 expression in intestinal epithelial cells to exert a protective effect against DSS‐induced colitis

“…After 14 days, the mice were humanely euthanized, and the colons were excised, measured, and sectioned for further analysis. [26][27][28] Subsequently, to further confirm the key role of Nur77 in the effect of GPA, GPA was intragastrically administered daily at 100 mg/kg. Wild-type (WT) or Nur77 −/− mice were randomly assigned to the control group, DSS group, and GPA (100 mg/kg) + DSS group.…”