Formononetin Administration Ameliorates Dextran Sulfate Sodium-Induced Acute Colitis by Inhibiting NLRP3 Inflammasome Signaling Pathway

Abstract

Formononetin is a kind of isoflavone compound and has been reported to possess anti-inflammatory properties. In this present study, we aimed to explore the protective effects of formononetin on dextran sulfate sodium- (DSS-) induced acute colitis. By intraperitoneal injection of formononetin in mice, the disease severity of colitis was attenuated in a dose-dependent manner, mainly manifesting as relieved clinical symptoms of colitis, mitigated colonic epithelial cell injury, and upregulations of colonic tight junction proteins levels (ZO-1, claudin-1, and occludin). Meanwhile, our study found that formononetin significantly prevented acute injury of colonic cells induced by TNF-α in vitro, specifically manifesting as the increased expressions of colonic tight junction proteins (ZO-1, claudin-1, and occludin). In addition, the result showed that formononetin could reduce the NLRP3 pathway protein levels (NLRP3, ASC, IL-1β) in vivo and vitro, and MCC950, the NLRP3 specific inhibitor, could alleviate the DSS-induced mice acute colitis. Furthermore, in the foundation of administrating MCC950 to inhibit activation of NLRP3 inflammasome, we failed to observe the protective effects of formononetin on acute colitis in mice. Collectively, our study for the first time confirmed the protective effects of formononetin on DSS-induced acute colitis via inhibiting the NLRP3 inflammasome pathway activation.

Carnosol inhibits inflammasome activation by directly targeting HSP90 to treat inflammasome-mediated diseases

“…carnosol is i.p. injection and lots of other molecules, such as MCC950 and Formononetin, are also used in this application route 22,[70][71][72][73] .Intraperitoneal administration of carnosol with 200 mg/kg daily for 5 days has no effect on liver weight 73 . Furthermore, we confirmed that carnosol is well tolerated in mice when administered intraperitoneally at 120 mg/kg daily for 2 weeks.…”

NLRP3 inflammasome: A likely target for the treatment of allergic diseases

“…Several specific inhibitors, such as MCC950, CY‐09, arglabin, and glyburide, have been recently developed or identified to target NLRP3 inflammasome inhibition . The application of these specific NLRP3 inflammasome inhibitors has demonstrated therapeutic effects in various inflammatory disease mouse models, including models of myocardial infarction, fulminant hepatitis, steatohepatitis, lupus nephritis, atherosclerosis, Alzheimer's disease, brain injury, inflammatory bowel diseases, acute colitis, and carcinoma In allergic diseases, the application of MCC950 reduces skin and airway inflammation in mouse models of allergic dermatitis and asthma . More recently, 2 studies have shown that the targeted inhibition of NLRP3 inflammasomes with a specific inhibitor decreased IL‐1β and TH2 cytokines and inhibited HDM‐induced AHR and steroid‐resistant asthma in a mouse model .…”

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases

“…As we discussed above, the NLRP3 inflammasome is mainly produced in innate immunity cells, thus triggering the cascade immune and inflammatory reaction through the secretion of two pro-inflammatory cytokines including IL-1β and IL-18. As a result, the NLRP3 inflammasome is highly involved in the onset and development of various kinds of diseases, including cardiovascular diseases (myocardial ischemia/infarction, atherosclerosis, and hypertension), metabolic disorders (obesity, diabetes, and metabolic syndrome), digestive diseases (inflammatory bowel disease), renal diseases and CNS diseases ( Chen et al, 2017 ; Kammoun et al, 2018 ; Martinez et al, 2018 ; Nasoohi et al, 2018 ; Sharma et al, 2018 ; Wu et al, 2018b ; Yuan et al, 2018 ). In addition, it has been demonstrated that the polymorphism of the NLRP3 genes may lead to the occurrence of some congenital disorders in patients and animal models ( Lewis et al, 2011 ; Kuemmerle-Deschner et al, 2017 ; Landmann and Walker, 2017 ).…”