Artemisinin analogue SM934 ameliorates DSS-induced mouse ulcerative colitis via suppressing neutrophils and macrophages

Abstract

Ulcerative colitis (UC) is a chronic, nonspecific inflammatory bowel disease (IBD) characterized by complicated and relapsing inflammation in the gastrointestinal tract. SM934 is a water-soluble artemisinin analogue that shows anti-inflammatory and immuno-regulatory effects. In this study, we investigated the effects of SM934 on UC both in vivo and in vitro. A mouse model of colitis was established in mice by oral administration of 5% dextran sulfate sodium (DSS). SM934 (3, 10 mg/kg per day, ig) was administered to the mice for 10 days. After the mice were sacrificed, colons, spleens and mesenteric lymph nodes (MLNs) were collected for analyses. We showed that SM934 administration restored DSS-induced body weight loss, colon shortening, injury and inflammation scores. Furthermore, SM934 administration significantly decreased the disease activity index (DAI), histopathological scores, and myeloperoxidase (MPO) activities in colonic tissues. Moreover, SM934 administration dose-dependently decreased the mRNA and protein levels of DSS-induced pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), and the percentage of macrophages and neutrophils in colon tissues. The effects of SM934 on LPS-stimulated RAW 264.7 cells and THP-1-derived macrophages were examined in vitro. Treatment with SM934 (0.8, 8, 80 μmol/L) dose-dependently decreased the production of pro-inflammatory mediators in LPS-stimulated RAW264.7 cells and THP-1-derived macrophages via inhibiting activation of the NF-κB signaling. Our results reveal the protective effects of SM934 on DSS-induced colitis can be attributed to its suppressing effects on neutrophils and macrophages and its inhibitory role in the NF-κB signaling, suggests that SM934 might be a potential effective drug for ulcerative colitis.

Attenuation of NF-κB in Intestinal Epithelial Cells Is Sufficient to Mitigate the Bone Loss Comorbidity of Experimental Mouse Colitis

“…Because of its central role in inflammatory responses and cytokine secretion in various diseases including colitis, we examined expression and activation of NF‐κB in IECs. Using DSS‐induced gut inflammation in NF‐κB reporter mouse model, in which NF‐κB signaling leads to the expression of a GFP‐luciferase reporter, we show that overall NF‐κB activation is significantly enhanced in IECs from DSS‐treated reporter mice (Fig.…”

Targeting NF-κB pathway for treating ulcerative colitis: comprehensive regulatory characteristics of Chinese medicines

“…SM934 (3, 10 mg/kg) is a water-soluble artemisinin analogue that shows significant attenuation of DSSinduced colonic inflammatory responses by suppressing the effects of macrophages and neutrophils and inhibiting the NF-κB signaling pathway [61]. Additionally, artesunate (10 30, and 50 mg/kg), a semi-synthetic derivative of artemisinin, exerts anti-inflammatory effects via regulating the TLR4-NF-κB signaling pathway in DSS-induced UC of rats [62].…”

Integrating Pharmacology and Microbial Network Analysis with Experimental Validation to Reveal the Mechanism of Composite Sophora Colon-Soluble Capsule against Ulcerative Colitis

“…As an important UC-related inflammation pathway, the IL-17 signaling pathway was a major pathway predicted by the network pharmacology analysis of CSCC against UC [30][31][32]. Although IL-17 signaling confers protection against extracellular pathogens in the host, the IL-17 family of cytokines plays a crucial role in the inflammatory pathology of autoimmune diseases, with a close correlation with the subset of T helper 17 ( 17) cells and…”