1′-Acetoxychavicol acetate inhibits NLRP3-dependent inflammasome activation via mitochondrial ROS suppression

Abstract

The nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing (NLRP) 3 inflammasome is a multiprotein complex that triggers Caspase-1-mediated IL-1β production and pyroptosis, and its dysregulation is associated with the pathogenesis of inflammatory diseases. The 1′-acetoxychavicol acetate (ACA) is a natural compound in the rhizome of tropical ginger Alpinia species with anti-microbial, -allergic, and -cancer properties. In this study, we found that ACA suppressed NLRP3 inflammasome activation in mouse bone marrow-derived macrophages and human THP-1 monocytes. ACA inhibited Caspase-1 activation and IL-1β production by NLRP3 agonists such as nigericin, monosodium urate (MSU) crystals, and ATP. Moreover, it suppressed oligomerization of the adapter molecule, apoptosis-associated speck-like protein containing a CARD (ASC) and Caspase-1-mediated cleavage of pyroptosis executor Gasdermin D. Mechanistically, ACA inhibited generation of mitochondrial reactive oxygen species (ROS) and prevented release of oxidized mitochondrial DNA, which trigger NLRP3 inflammasome activation. ACA also prevented NLRP3 inflammasome activation in vivo, as evidenced in the MSU crystal-induced peritonitis and dextran sodium sulfate (DSS)-induced colitis mouse models accompanied by decreased Caspase-1 activation. Thus, ACA is a potent inhibitor of the NLRP3 inflammasome for prevention of NLRP3-associated inflammatory diseases.

Knockdown of hsa_circ_0000729 Inhibits the Tumorigenesis of Non-Small Cell Lung Cancer Through Mediation of miR-1281/FOXO3 Axis

“…10,11 Meanwhile, pyroptosis is a programmed cell death which is majorly regulated by caspase 1. 12,13 In addition, caspase 1 is often upregulated when the growth of NSCLC cells is inhibited, suggesting that the promotion of pyroptosis might be associated with the progression of NSCLC. 14 Therefore, it is necessary to investigate the correlation between hsa_circ_0000729 and pyroptosis in NSCLC cells with the purpose of exploring new effective strategies against NSCLC.…”

Natural Products for Cancer Therapy: A Review of Their Mechanism of Actions and Toxicity in the Past Decade

“…e nonpolar extracts of the rhizomes reported many types of plant sterols such as stigmasterol, β-sitosterol and several closely related phenylpropanoids such as ACA and 1′-acetoxyeugenol acetate (AEA). ACA being the major phytoconstituent of the plant, has been widely investigated for its pharmacological activities which include antiallergy, anti-inflammatory, antiulcer, antiviral and antitumour [67][68][69].…”

Systemic inflammatory response syndrome is triggered by mitochondrial damage (Review)

“…Emerging evidence has suggested that mtDNA serves a key role in activating the NLRP3 inflammasome. Sok et al ( 50 ) revealed that inhibiting release of oxidative mtDNA decreased generation of mitochondrial ROS and inhibited activation of NLRP3 inflammasomes. Severe fever with thrombocytopenia syndrome caused by viral infection can also cause the release of oxidative mtDNA and activate the NLRP3 inflammasome, leading to intensive inflammation ( 51 ).…”