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Bavachin enhances NLRP3 inflammasome activation induced by ATP or nigericin and causes idiosyncratic hepatotoxicity |
Nan Qin1,2, Guang Xu1, Yan Wang1,3, Xiaoyan Zhan1, Yuan Gao4, Zhilei Wang1, Shubin Fu1, Wei Shi1, Xiaorong Hou1, Chunyu Wang1, Ruisheng Li5, Yan Liu5, Jiabo Wang1, Haiping Zhao6(), Xiaohe Xiao1,7(), Zhaofang Bai1() |
1. China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China 2. Department of Pharmacy, Nantong Hospital of Traditional Chinese Medicine, Nantong 226300, China 3. School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China 4. School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China 5. Research Center for Clinical and Translational Medicine, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China 6. School of Traditional Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China 7. Integrative Medical Centre, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China |
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Abstract Psoraleae Fructus (PF) is a well-known traditional herbal medicine in China, and it is widely used for osteoporosis, vitiligo, and other diseases in clinical settings. However, liver injury caused by PF and its preparations has been frequently reported in recent years. Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury (IDILI), but the mechanism underlying its hepatotoxicity remains unclear. This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity. Bavachin boosts the secretion of IL-1β and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C), monosodium urate crystal, or intracellular lipopolysaccharide. Bavachin does not affect AIM2 or NLRC4 inflammasome activation. Mechanistically, bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome. Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-1β via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI. These results suggest that bavachin specifically enhances the ATP- or nigericin-induced activation of the NLRP3 inflammasome. Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity. Moreover, bavachin and PF should be evaded among patients with diseases linked to the ATP- or nigericin-mediated activation of the NLRP3 inflammasome, which may be a dangerous factor for liver injury.
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Keywords
Psoraleae Fructus
bavachin
idiosyncratic drug-induced liver injury
caspase-1
IL-1β
NLRP3 inflammasome
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Corresponding Author(s):
Haiping Zhao,Xiaohe Xiao,Zhaofang Bai
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Just Accepted Date: 03 December 2020
Online First Date: 27 April 2021
Issue Date: 23 September 2021
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