Potent Inhibitory Effect of BJ-3105, a 6-Alkoxypyridin-3-ol Derivative, on Murine Colitis Is Mediated by Activating AMPK and Inhibiting NOX

Abstract

Inflammatory bowel disease (IBD) is a chronic relapsing inflammation in the gastrointestinal tract. Biological therapeutics and orally available small molecules like tofacitinib (a JAK inhibitor) have been developed to treat IBD, but half of the patients treated with these drugs fail to achieve sustained remission. In the present study, we compared the therapeutic effects of BJ-3105 (a 6-alkoxypyridin-3-ol derivative) and tofacitinib in IBD. BJ-3105 induced activation of AMP-activated protein kinase (AMPK) in the kinase activity measurement and recovery from cytokine-induced AMPK deactivation in HT-29 human colonic epithelial cells. Similar to tofacitinib and D942 (an AMPK activator), BJ-3105 inhibited IL-6-induced JAK2/STAT3 phosphorylation and TNF-α-stimulated activation of IKK/NF-κB, and consequently, stimulus-induced upregulations of inflammatory cytokines and inflammasome components. In addition, unlike tofacitinib or D942, BJ-3105 inhibited NADPH oxidase (NOX) activation and consequent superoxide production induced by activators (mevalonate and geranylgeranyl pyrophosphate) of the NOX cytosolic component Rac. In mice, oral administration with BJ-3105 ameliorated dextran sulfate sodium (DSS)-induced colitis and azoxymethane/DSS-induced colitis-associated tumor formation (CAT) much more potently than that with tofacitinib. Moreover, BJ-3105 suppressed the more severe form of colitis and CAT formation in mice with AMPK knocked-out in macrophages (AMPKαfl/fl-Lyz2-Cre mice) with much greater efficacy than tofacitinib. Taken together, our findings suggest BJ-3105, which exerted a much better anti-colitis effect than tofacitinib through AMPK activation and NOX inhibition, is a promising candidate for the treatment of IBD.

Nicotinamide Mononucleotide Combined With Lactobacillus fermentum TKSN041 Reduces the Photoaging Damage in Murine Skin by Activating AMPK Signaling Pathway

“…It is mainly involved in regulating sugar, lipid, and energy metabolism, and studies have shown that activating AMPK inhibits inflammation and oxidative stress ( Salt and Hardie, 2017 ). In addition to maintaining cellular energy homeostasis, experiments have shown that inhibiting AMPK activity significantly increases the expression levels of the inflammatory factors TNF-α, IL-1β, and IL-6, thereby increasing inflammation damage ( Gurung et al, 2020 ). In addition, high AMPK expression levels in young cells promote the activities of factors, such as SIRT1, FOXO, and PGC-1α, thereby inhibiting NF-κB activity.…”

Alginate Oligosaccharides Ameliorate DSS-Induced Colitis through Modulation of AMPK/NF-κB Pathway and Intestinal Microbiota

“…Inflammation was known to reduce AMPK activity through multiple mechanisms [ 20 ]. Consistently, AMPK phosphorylation was shown to be significantly decreased in LPS-stimulated RAW 264.7 cells [ 39 , 40 , 41 ] and in the colonic tissues of DSS-induced colitis mice [ 42 ]. However, AMPK activation, which is initiated by phosphorylation, exerts anti-inflammatory activities in immune cells such as macrophages, neutrophils, T cells, and mast cells [ 26 , 43 , 44 ].…”

“…However, AMPK activation, which is initiated by phosphorylation, exerts anti-inflammatory activities in immune cells such as macrophages, neutrophils, T cells, and mast cells [ 26 , 43 , 44 ]. AMPK activator administration has been confirmed to attenuate DSS-induced colitis in mice [ 42 , 45 ]. Like previous studies [ 39 , 40 ], our results showed that AMPK phosphorylation was downregulated in macrophages in response to 1mh LPS treatment and p-AMPK level was decreased in the colonic tissues of DSS-induced mice, but AOS could induce AMPK activity in vivo and in vitro by increasing AMPK phosphorylation.…”

Investigation of the Active Ingredients and Mechanism of Hudi Enteric-Coated Capsules in DSS-Induced Ulcerative Colitis Mice Based on Network Pharmacology and Experimental Verification

“…The inhibition of these two proteins might alleviate multiple pathological features such as cell growth and apoptosis by mediating the expressions of various genes in response to cell stimuli, and decelerate the degeneration of colonic inflammation. 42,43 Furthermore, the mRNA level of IL-17 in colonic tissues was also remarkably arisen in UC mice while the HDC treatment restrained this enhancement. The above results suggested that HDC might inhibit the IL-17/ JAK2/STAT3 signaling pathway which precludes the secretion of proinflammatory cytokines in UC mice.…”