3,4-Methylenedioxy-β-Nitrostyrene Alleviates Dextran Sulfate Sodium–Induced Mouse Colitis by Inhibiting the NLRP3 Inflammasome

Abstract

Inflammatory bowel disease (IBD) has been reported to be associated with NLRP3 inflammasome activation. Therefore inhibiting inflammasome activation could be a new approach to treat IBD. Inflammasome inhibitors NLRP3-IN-2, JC124, and 3,4-methylenedioxy-β-nitrostyrene (MNS) were previously reported to exert anti-inflammatory effects in various disease models but not in the dextran sulfate sodium (DSS)–induced colitis model. Here, we showed that MNS was more efficient in inhibiting the secretion of interleukin-1β (IL-1β) by blocking oligomerization of apoptosis-associated speck-like protein (ASC) than NLRP3-IN-2 and JC124. To investigate the protective effects of MNS on enteritis, we administered intragastric MNS to DSS-induced colitis mice. The results demonstrated that MNS attenuated DSS-induced body weight loss, colon length shortening, and pathological damage. In addition, MNS inhibited the infiltration of macrophages and inflammatory cells and reduced IL-1β and IL-12p40 pro-inflammatory cytokines but had no significant effect on tumor necrosis factor α (TNF-α) and IL-6. Furthermore, we also found that the differentiation of IL-17A+interferon-γ (IFN-γ)+CD4+ T cell was decreased in the colon after MNS treatment, which might be mediated by IL-1β, etc. cytokine release. Taken together, MNS alleviated DSS-induced intestinal inflammation by inhibiting NLRP3 inflammasome activation, which may function as an effective therapeutic for IBD.

Role of NLRP3 in Parkinson's disease: Specific activation especially in dopaminergic neurons

“… Phase II trial N/A [ 124 ] YQ 128 Selective inhibition of NLRP3 and brain BBB penetrating LPS induced activation of NLRP3 in peritoneal macrophages in mice Preclinical trial N/A [ 125 ] JC-124 blocking ASC aggregation, activation of caspase-1, and release of IL-1β in macrophages that constitutively express active NLRP3 Mouse model of AD, neuroinflammation in mouse TBI, and mouse AMI, IBD. Preclinical trial N/A [ 126 , 127 ] CY-09 Binds to Walker A site in NACHT domain, inhibits ATPase activity Stroke, T2DM, diabetic retinopathy, diabetic liver injury, NAFLD, peritonitis, epilepsy, etc. Preclinical trial N/A [ 128 ] Tranilast Binds to NACHT disrupting NLRP3–NLRP3 interactions and blocking oligomerization gouty arthritis, cryopyrin-associated autoinflammatory syndromes, T2DM, GDM, nanoparticle cerebral toxicity, etc.…”

Portrayal of NLRP3 Inflammasome in Atherosclerosis: Current Knowledge and Therapeutic Targets

“…By interfering with the synthesis of IL-1β, IL-18 and caspase-1 activation, the spleen tyrosine kinase (Syk) and Src tyrosine kinase inhibitor, 3,4-methylenedioxy-β-nitrostyrene (MNS) is likewise a reliable and selective inhibitor of the NLRP3 inflammasome [144]. Subsequent findings indicate MNS binds to the LRR and NACHT domains of the NLRP3 protein, inhibiting ATPase function but not the inflammasome AIM2 or NLRC4.…”

The Role of Inflammasome NLPR3 in the Development and Therapy of Periodontitis

“…Except for the inflammasome inhibitors described above, more inflammasome inhibitors have been developed, such as NLRP3-IN-2 137 , JC124 138 , Arglabin 139 , Isoandrographolide 140 , Carvedilol 141 , and JC-171 142 . Unfortunately, their roles in periodontitis have not been clarified.…”