Frontiers in Pharmacology (Jul 2022)
Chalcone Derivatives From Abelmoschus manihot Seeds Restrain NLRP3 Inflammasome Assembly by Inhibiting ASC Oligomerization
Abstract
Three chalcone derivatives, abelmanihotols A−C (1–3), and nine known compounds were isolated from A. manihot seeds, and their structures were determined using HRESIMS and NMR spectroscopic analysis. Compound 1 exhibited the most potent inhibitory effect (IC50 = 4.79 ± 0.72 μM) against lipopolysaccharide (LPS)-induced NO release in THP-1 cells, and significantly inhibited interleukin 1β (IL-1β) secretion, which is stimulated by LPS plus nigericin (IC50 = 11.86 ± 1.20 μM), ATP or MSU, in THP-1 cells. A preliminary mechanism of action study indicated that compound 1 blocked the formation of nucleotide oligomerization domain-like receptor protein-3 (NLRP3) inflammasome formation by suppressing apoptosis-associated speck-like protein oligomerization, thereby attenuating caspase-1 activation and IL-1β release. These results reveal that compound 1 is not only a potent and efficacious NLRP3 inflammasome inhibitor but also a promising drug for the treatment of NLRP3-related diseases.
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