PMID- 34718095 OWN - NLM STAT- MEDLINE DCOM- 20211220 LR - 20211220 IS - 1879-3169 (Electronic) IS - 0378-4274 (Linking) VI - 354 DP - 2022 Jan 1 TI - Aurantio-obtusin induces hepatotoxicity through activation of NLRP3 inflammasome signaling. PG - 1-13 LID - S0378-4274(21)00864-X [pii] LID - 10.1016/j.toxlet.2021.10.011 [doi] AB - Aurantio-obtusin (AO) is a major anthraquinone (AQ) compound derived from Cassiae semen (CS). Although pharmacological studies have shown that the CS extracts can serve as effective agents in preclinical and clinical practice, AQ-induced hepatotoxicity in humans has attracted widespread attention. To explore whether AO induces hepatotoxicity and its underlying mechanisms, we exposed larval zebrafish and mice to AO. We found that AO delayed yolk sac absorption, and increased liver area and inflammation in the larval zebrafish. This inflammation was manifested as an increase in liver neutrophils and the up-regulated mRNA expression of interleukin-6 (Il-6) and tumor necrosis factor-alpha (Tnf-alpha) in the larval zebrafish. Furthermore, a pharmacokinetics study showed that AO was quickly absorbed into the blood and rapidly metabolized in the mice. Of note, AO induced hepatotoxicity in a gender-dependent manner, characterized by liver dysfunction, increased hepatocyte necrosis with inflammatory infiltration, and up-regulated mRNAs of Il-6, Tnf-alpha and monocyte chemotactic protein 1(Mcp1) in the female mice after 28-day oral administration. It also highlighted that AO triggered NOD-like receptor protein (NLRP) signaling in the female mice, as evidenced by the increased NLRP3, Caspase-1, pro-IL-1beta, IL-1beta and IL-18. Finally, we found that AO led to a significant increase in potassium calcium-activated channel, subfamily N, member 4 (KCNN4) and reactive oxygen species (ROS) levels, along with decreased nuclear factor kappa B p65 (NF-kappaB p65), in the female mouse livers. In conclusion, AO induced hepatotoxicity by activating NLRP3 inflammasome signaling, at least in part, through increased KCNN4 and ROS production, and NF-kappaB inhibition. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Hu, Manjiang AU - Hu M AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Lin, Li AU - Lin L AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Liu, Jun AU - Liu J AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Zhong, Yizhou AU - Zhong Y AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Liang, Boxuan AU - Liang B AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Huang, Yuji AU - Huang Y AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Li, Zhiming AU - Li Z AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Lin, Xi AU - Lin X AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Wang, Bo AU - Wang B AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Zhang, Bingli AU - Zhang B AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Meng, Hao AU - Meng H AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Ye, Rongyi AU - Ye R AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Du, Jiaxin AU - Du J AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Dai, Mingzhu AU - Dai M AD - Hunter Biotechnology, Inc., Hangzhou, 310051, China. FAU - Peng, Yi AU - Peng Y AD - Hunter Biotechnology, Inc., Hangzhou, 310051, China. FAU - Li, Hongqun AU - Li H AD - Hunter Biotechnology, Inc., Hangzhou, 310051, China. FAU - Wu, Qinghong AU - Wu Q AD - Laboratory Animal Management Center, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Gao, Hongbin AU - Gao H AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Yang, Xingfen AU - Yang X AD - Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, 510515, China. FAU - Huang, Zhenlie AU - Huang Z AD - NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China. Electronic address: huangzhenlie858252@smu.edu.cn. LA - eng PT - Journal Article DEP - 20211028 PL - Netherlands TA - Toxicol Lett JT - Toxicology letters JID - 7709027 RN - 0 (Anthraquinones) RN - 0 (Drugs, Chinese Herbal) RN - 0 (Inflammasomes) SB - IM MH - Animals MH - Anthraquinones/*toxicity MH - Cassia/chemistry MH - Chemical and Drug Induced Liver Injury/*etiology/*physiopathology MH - Disease Models, Animal MH - Drugs, Chinese Herbal/toxicity MH - Female MH - Humans MH - Inflammasomes/*metabolism MH - Inflammation/*chemically induced/*physiopathology MH - Larva/drug effects MH - Mice MH - Signal Transduction/drug effects MH - Zebrafish/*metabolism OTO - NOTNLM OT - Aurantio-obtusin OT - Hepatotoxicity OT - KCNN4 OT - NF-kappaB OT - NLRP3 inflammasome OT - Reactive oxygen species COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2021/11/01 06:00 MHDA- 2021/12/21 06:00 CRDT- 2021/10/31 20:48 PHST- 2021/09/20 00:00 [received] PHST- 2021/10/15 00:00 [revised] PHST- 2021/10/26 00:00 [accepted] PHST- 2021/11/01 06:00 [pubmed] PHST- 2021/12/21 06:00 [medline] PHST- 2021/10/31 20:48 [entrez] AID - S0378-4274(21)00864-X [pii] AID - 10.1016/j.toxlet.2021.10.011 [doi] PST - ppublish SO - Toxicol Lett. 2022 Jan 1;354:1-13. doi: 10.1016/j.toxlet.2021.10.011. Epub 2021 Oct 28.