Brusatol ameliorates 2, 4, 6-trinitrobenzenesulfonic acid-induced experimental colitis in rats: Involvement of NF-κB pathway and NLRP3 inflammasome

• Published in: International immunopharmacology 2018-11, Vol.64, p.264-274
• Main Authors: Zhou, Jiangtao, Wang, Tongtong, Dou, Yaoxing, Huang, Yanfeng, Qu, Chang, Gao, Jiansheng, Huang, Zijian, Xie, Youliang, Huang, Ping, Lin, Zhixiu, Su, Ziren
• Format: Article
• Language: English
• Subjects: Acids; Animals; Anti-inflammatory; Bioavailability; Biological activity; Bleeding; Body weight; Brusatol; Cell Survival - drug effects; Chemical compounds; Chinese medicine; Colitis - drug therapy; Colitis - immunology; Colon - pathology; Cytokines - analysis; Diarrhea; Drug delivery; Drug delivery systems; Dysentery; Enzyme-linked immunosorbent assay; IL-1β; Immunohistochemistry; Inflammasomes; Inflammatory bowel disease; Inflammatory bowel diseases; Interleukin 18; Interleukin 4; Lipopolysaccharides; Macrophages; Male; Medicinal plants; Mice; NF-E2-Related Factor 2 - physiology; NF-kappa B - antagonists & inhibitors; NF-kappa B - physiology; NF-κB; NF-κB protein; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - physiology; NLRP3 inflammasome; Oxidative Stress; Pharmacology; Prostaglandin E2; Quassins - pharmacology; Quassins - therapeutic use; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Rodents; Signal transduction; Signal Transduction - drug effects; Trinitrobenzenesulfonic Acid - toxicity; Tumor necrosis factor-α; Ulcerative colitis; Waterborne diseases; Western blotting
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2018.09.008

Brusatol is a main bioactive component derived from the Chinese medicinal plant Brucea javanica, which is traditionally used for the treatment of dysentery (also known as ulcerative colitis, UC). Previously, we have designed a novel brusatol self-microemulsifying drug delivery system (BR-SMEDDS) to increase its solubility and bioavailability, and enhance its bioactivities. In the present study, we established 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat model in vivo and lipopolysaccharide (LPS)-induced RAW 264.7 macrophages in vitro, to investigate the potential anti-inflammatory effect and underlying mechanism of BR-SMEDDS. Disease activity index (DAI) including body weight, stool consistency and gross bleeding was measured. Macroscopic and histological evaluations of colons were conducted. Relevant molecular events were determined by ELISA, qRT-PCR, immunohistochemistry or Western blotting. The results showed that BR notably inhibited the productions of TNF-α, pro-IL-1β, PGE2 and NO, and suppressed the NF-κB signaling pathway in LPS-stimulated macrophages. In parallel with the vitro experimental results, BR significantly attenuated diarrhea, colonic shortening, macroscopic damage and histological injury. BR treatment also increased the levels of TGF-β and IL-4, decreased the contents of IL-1β and IL-18, and elevated the levels of CAT, GSH and SOD in the colons. Furthermore, BR also markedly activated the Nrf2 expression and suppressed the NLRP3 inflammasome activation. Taken together, the anti-UC effect of BR might be intimately associated with the suppression of NF-κB and NLRP3-mediated inflammatory responses, and regulation of Nrf2-mediated oxidative stress. BR might have the potential to be further developed into a promising therapeutic agent for colitis treatment. •BR significantly attenuated the inflammatory response and suppressed the NF-κB signaling pathway in vitro.•BR effectively decreased DAI scores of rats and ameliorated macroscopic and histological colon pathological deterioration.•BR favorably regulated inflammatory status and diminished oxidative stress in TNBS-induced colitis.•BR markedly activated the Nrf2 expression and suppressed the NLRP3 inflammasome activation in the colons.•BR might have the potential to be further developed into a promising therapeutic agent for colitis treatment.