Abstract
Oroxindin is a flavonoid isolated from the traditional Chinese medicine Huang-Qin, which has shown various pharmacological activities including anti-inflammatory, antitumor, antioxidant, etc. Thus far, the effect of oroxindin on colonic inflammation and the underlying mechanism remain unknown. In this study, we investigated the tissue distribution of oroxindin and its therapeutic effects on ulcerative colitis (UC) as well as the underlying mechanisms. UC model was established in mice by administrating dextran sulfate sodium (DSS) in drinking water for 7 d. We first showed that oroxindin was largely absorbed by the colon as an active ingredient after normal mice received Huang-Qin-Tang, a traditional Chinese medicine decoction. UC mice were then treated with oroxindin (12.5, 25, 50 mg ·kg−1 ·d−1, i.g.) for 10 d. We found that oroxindin treatment greatly suppressed massive macrophages infiltration and attenuated pathological changes in colonic tissue. Furthermore, oroxindin treatment significantly inhibited the generation of IL-1β and IL-18 in the colon via inhibiting the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome formation and activation. In cultured macrophages, LPS induced NLRP3 inflammasome formation and caspase-1 activation, which were suppressed by oroxindin (12.5–50 μM). In LPS-treated macrophages, oroxindin dose-dependently restored the expression of TXNIP protein, leading to suppressing TXNIP-dependent NF-κB activation. In conclusion, these results demonstrate that oroxindin could be absorbed by the colon and attenuate inflammatory responses via inhibiting NLRP3 inflammasome formation and activation, which is related to the inhibitory effect on TXNIP-dependent NF-κB-signaling pathway. Hence, oroxindin has the potential of becoming an effective drug for treating UC.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81603587, 81603668); the Guangdong Natural Science Funds for Distinguished Young Scholar (No. 2018B030306027); the Key projects of basic research in Guangdong Province (No. A1-AFD018191A100); the Science & Technology Award for Young-aged Talents of China Association of Traditional Chinese Medicine (No. CACM-2017-QNRC2-C12); the Project of Guangzhou University of Chinese Medicine (No. A3-040219415009, A1-AFD018191A41); and by the Key Research and Development Program of Guangdong Province (2018KZDXM023).
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QL and RZ contributed to the animal experiments, cell experiments, and data analysis. KW, QL and FFN contributed to the LC–MS experiments. YJF and XL contributed to the study analysis and data analysis. QL, ZFP, and XLD, SWH, YZ, and XXZ contributed to the revision of the manuscript. YC and LZ contributed to the conception and design of the project.
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Liu, Q., Zuo, R., Wang, K. et al. Oroxindin inhibits macrophage NLRP3 inflammasome activation in DSS-induced ulcerative colitis in mice via suppressing TXNIP-dependent NF-κB pathway. Acta Pharmacol Sin 41, 771–781 (2020). https://doi.org/10.1038/s41401-019-0335-4
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DOI: https://doi.org/10.1038/s41401-019-0335-4
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