Cardamonin, a natural flavone, alleviates inflammatory bowel disease by the inhibition of NLRP3 inflammasome activation via an AhR/Nrf2/NQO1 pathway.

Abstract

The present study aimed to evaluate the anti-colitis effect and underlying mechanisms of cardamonin, a natural flavone isolated from Alpinia katsumadai Hayata. The results showed that oral cardamonin significantly inhibited dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice, evidenced by improvement of disease activity index scores, myeloperoxidase activity, length shortening and histopathological changes of colons. A rectal administration of cardamonin also exhibited marked anti-colitis effect, suggesting that oral cardamonin might function in a prototype form. Cardamonin down-regulated levels of IL-1β, TNF-α, IL-6, NLRP3, cleaved caspase-1, ASC, cleaved IL-1β in colons of colitis mice. In vitro, cardamonin inhibited NLRP3 inflammasome activation in THP-1 and bone marrow-derived macrophages. It acted as an AhR activator, enhanced dissociation of AhR/HSP90 complexes, association of AhR/ARNT complexes, AhR nuclear translocation, XRE reporter gene activity, and AhR/ARNT/XRE DNA binding activity in THP-1 cells. The AhR antagonist CH223191 obviously abolished NLRP3 inflammasome activation inhibited by cardamonin. Furthermore, cardamonin elevated levels of Nrf2 and its target genes NQO1, Trx1, SOD2, HO-1, and the effect on NQO1 was the most obvious. The relationship of cardamonin-adjusted AhR activation, expressions of Nrf2 and NQO1, and NLRP3 inflammasome activation was confirmed by using CH223191, siAhR, ML385 and siNQO1, respectively. Finally, CH223191 was shown to abolish amelioration of cardamonin on DSS- and TNBS-induced colitis, inhibition of NLRP3 inflammasome activation and up-regulation of Nrf2 and NQO1 levels in colons. Taken together, cardamonin ameliorated colitis in mice through the activation of AhR/Nrf2/NQO1 pathway and consequent inhibition of NLRP3 inflammasome activation.

• Authors: Kai Wang, Qi Lv, Yu-Meng Miao, Si-Miao Qiao, Yue Dai, Zhi-Feng Wei
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 155 Pg. 494-509 (09 2018) ISSN: 1873-2968 [Electronic] England
• PMID: 30071202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Chalcones
• Flavones
• NF-E2-Related Factor 2
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nfe2l2 protein, mouse
• Nlrp3 protein, mouse
• Receptors, Aryl Hydrocarbon
• NAD(P)H Dehydrogenase (Quinone)
• Nqo1 protein, mouse
• cardamonin

Topics

• Animals
• Cell Survival (drug effects, physiology)
• Chalcones (pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Flavones (pharmacology, therapeutic use)
• Inflammatory Bowel Diseases (drug therapy, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• NAD(P)H Dehydrogenase (Quinone) (metabolism)
• NF-E2-Related Factor 2 (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (antagonists & inhibitors, metabolism)
• Receptors, Aryl Hydrocarbon (metabolism)
• Signal Transduction (drug effects, physiology)