Dataset Information

Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis.

ABSTRACT: Inflammatory bowel disease (IBD) represents a group of chronic relapsing intestinal disorders. Rutaecarpine (RUT), isolated from the Traditional Chinese Medicine (TCM) of Evodia rutaecarpa, was reported to suppress IBD. However, the mechanism by which RUT ameliorates dextran sulfate sodium (DSS)-induced IBD is largely unknown. By use of nuclear factor-erythroid 2-related factor 2 (NRF2) knockout mice, cell-based studies, surface plasmon resonance (SPR), western blotting analysis, and molecular docking studies, the mechanism by which RUT affects DSS-induced colitis was explored. In DSS-treated wild-type mice but not in Nrf2-null mice, RUT significantly improved colitis as revealed by rescued body weight loss, improved histology and inflammation, and induced expression of NRF2 target genes in colon and ileum. Cell-based studies showed that RUT significantly increased the LD50 for hydrogen peroxide (H2O2)-induced cell damage, activated NRF2 nuclear translocation, and suppressed the production of reactive oxygen species in H2O2-treated HCT116 cells, activated NRF2 luciferase reporter activities in HCT116 cells and HepG2 cells, and induced expression of NRF2 target genes in primary intestinal epithelial cells. Molecular docking in silico and SPR assays indicated that RUT interacted with kelch-like ECH-associated protein 1 (KEAP1), and extracellular incubation studies revealed that RUT bound to the KEAP1 kelch domain with a calculated equilibrium dissociation constant Kd of 19.6 ?M. In conclusion, these results demonstrate that RUT ameliorates DSS-induced colitis, dependent on NRF2, and could be a potential therapeutic option for IBD patients. Mechanistically, RUT potentiates NRF2 nuclear translocation to upregulate NRF2-mediated antioxidant response by directly inhibiting KEAP1-NRF2 interaction.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7376370 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis.

Zhang Youbo Y Yan Tingting T Sun Dongxue D Xie Cen C Wang Tianxia T Liu Xiaoyan X Wang Jing J Wang Qiong Q Luo Yuhong Y Wang Ping P Yagai Tomoki T Krausz Kristopher W KW Yang Xiuwei X Gonzalez Frank J FJ

Free radical biology & medicine 20191223

Inflammatory bowel disease (IBD) represents a group of chronic relapsing intestinal disorders. Rutaecarpine (RUT), isolated from the Traditional Chinese Medicine (TCM) of Evodia rutaecarpa, was reported to suppress IBD. However, the mechanism by which RUT ameliorates dextran sulfate sodium (DSS)-induced IBD is largely unknown. By use of nuclear factor-erythroid 2-related factor 2 (NRF2) knockout mice, cell-based studies, surface plasmon resonance (SPR), western blotting analysis, and molecular d ...[more]

PMID: 31874248

Similar Datasets

Project description:Bruguiera gymnorrhiza (BG), a medicinal mangrove, and its fruit (a food material) (BGF), have traditionally been used to treat diarrhea (also known as ulcerative colitis) in folk medicine. However, the mechanism of action against colitis remains ambiguous. This study aimed to investigate the potential efficacy and mechanism of BGF on experimental colitis. Colitis was induced by oral intake of dextran sulfate sodium (DSS) and treated with aqueous extract of BGF (25, 50 and 100 mg/kg) for a week. The Disease Activity Index (DAI), colon length, and histological changes of colon were analyzed. The inflammatory and oxidative stress status was explored. The protein expression of Nrf2 and Keap1 in the colon was detected by Western blotting. The mRNA expression of Nrf2 downstream genes (GCLC, GCLM, HO-1 and NQO1) was determined by RT-PCR. Furthermore, the effect on intestinal flora was analyzed. Results indicated that BGF was rich in pinitol, and showed strong antioxidative activity in vitro. Compared with the DSS model, BGF effectively reduced the body weight loss and DAI, restored the colon length, repaired colonic pathological variations, and decreased the histological scores, which was superior to salicylazosulfapyridine (SASP) with smaller dosage. Moreover, BGF not only abated the levels of MDA and inflammatory mediators (TNF-α, IL-6, IL-1β, and IFN-γ), increased the level of IL-10, but also prevented the depletion of SOD and GSH. BGF upregulated the protein level of nuclear Nrf2 and mRNA levels of GCLC, GCLM, HO-1 and NQO1, while significantly inhibited the protein expression of Keap1 and cytosolic Nrf2. Besides, BGF promoted the growth of probiotics (Bifidobacterium, Anaerotruncus, and Lactobacillus) in the gut, and inhibited the colonization of pathogenic bacteria (Bacteroides and Streptococcus), which contributed to the maintenance of intestinal homeostasis. BGF possessed protective effect against DSS-induced colitis. The potential mechanism of BGF may involve the amelioration of inflammatory and oxidative status, activation of Keap1/Nrf2 signaling pathway, and maintenance of micro-ecological balance of the host. This study provides experimental evidence for the traditional application of BGF in the treatment of diarrhea, and indicates that BGF may be a promising candidate against colitis.

Project description:Macrophages-involved inflammation is considered to induce the damage in various diseases. Herein, novel therapeutics inhibiting over-activation of macrophages could prove an effective strategy to prevent inflammation-related diseases. Gaudichaudione H (GH), which is a natural small molecular compound isolated from Garcinia oligantha Merr. (Clusiaceae) has previously been demonstrated its anti-cancer effects on several cancer cell lines. However, no report has been published about the anti-inflammatory effect of GH to date. This study aims to examine the anti-inflammatory effects and potential molecular mechanism of GH, and provide new insights toward the treatment of inflammation. GH inhibited nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, cytokine interleukin-6 (IL-6) and tumor necrosis factor-? (TNF-?) production, and messenger RNA (mRNA) expression to attenuate inflammatory responses in lipopolysaccharide (LPS)-induced RAW 264.7 cells or stimulated bone marrow-derived macrophages (BMDMs). GH inhibited nuclear factor-?B (NF-?B) and mitogen-activated protein kinase (MAPK) pathways, the nuclear translocation of transcription factors NF-?B and activator protein 1 (AP-1), as well as upstream signaling of the toll-like receptor 4 (TLR4)-myeloid differentiation primary response 88 (MyD88) pathway in stimulated macrophages. Furthermore, the result of the intracellular signaling array showed that the phosphorylation of adenosine 5'-monophosphate-activated protein kinase-? (AMPK?), proline-rich Akt substrate of 40 kDa (PRAS40), and p38 could be down regulated by GH in BMDMs, indicating that the mechanism by which GH inhibited inflammation may be also associated with the energy metabolism pathway, PRAS40-mediated NF-?B pathway, cell proliferation, apoptosis, and autophagy, etc. In addition, GH alleviated dextran sodium sulfate (DSS)-induced colitis in mice by ameliorating weight loss, stool consistency change, blood in the stool, and colon shortening. GH decreased the protein and mRNA levels of IL-6 and TNF-?, iNOS and COX-2 mRNA expression, the activation of NF-?B and MAPK pathways, the phosphorylation of AMPK? and PRAS40, histological damage, and infiltration of macrophages in the colons of mice with DSS-induced colitis. Taken together, our results support that GH exerts the anti-inflammatory effects in macrophages in vitro through regulation of NF-?B and MAPK pathways, and DSS-induced colitis mouse model in vivo. These findings suggest that GH may be a promising candidate in treating macrophage-related inflammatory disease.

Dataset Information

Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis.

Publications

Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets