Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases

The NLRP3 inflammasome's core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS's great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound.

Quantification of $\alpha$-Methylene-$\gamma$-butyrolactone Extracted from Different Parts of \it{Alstroemeria wilhelmina} and Evaluation of it's Antigenicity Using the Guinea-Pig Maximization Test

To detect the type of contact dermatitis caused due to the handling of Alstroemeria wilhelmina, 1% α-methylene-γ-butyrolactone (α-MBL) dissolved in physiological saline and a five-fold diluted saline solution of original extracts of flowers, leaves and stems of the flower were applied to guinea-pigs for induction treatment, and 0.1% α-MBL physiological saline and a ten-fold diluted solution of the original extracts were applied to the animals as the challenge treatment in compliance with the guinea-pig maximization test (GMT). As a consequence, not only primary irritant dermatitis was observed, but also delayed type allergic contact dermatitis due to Alstroemeria wilhelmina was observed. α-MBL determined in the extracts using high-performance liquid chromatography (HPLC) was found to be the biochemical material cause of the contact dermatitis. The flower region contained α-MBL in the highest concentrations compared with those of the leaves and stems. Therefore, the quantification of α-MBL in the extracts was concluded as being a useful evaluating method for contact dermatitis due to the handling of Alstroemeria.