2. Academic Validation
  3. Discovery of bakuchiol as an AIM2 inflammasome activator and cause of hepatotoxicity

Discovery of bakuchiol as an AIM2 inflammasome activator and cause of hepatotoxicity

  • J Ethnopharmacol. 2022 Nov 15;298:115593. doi: 10.1016/j.jep.2022.115593.
Tingting Liu 1,  Guang Xu 2,  Yurong Li 3,  Wei Shi 4,  Lutong Ren 4,  Zhie Fang 4,  Longxin Liang 4,  Yan Wang 4,  Yuan Gao 5,  Xiaoyan Zhan 4,  Qiang Li 4,  Wenqing Mou 4,  Li Lin 4,  Ziying Wei 4,  Zhiyong Li 4,  Wenzhang Dai 4,  Jia Zhao 4,  Hui Li 4,  Jiabo Wang 5,  Yanling Zhao 6,  Xiaohe Xiao 7,  Zhaofang Bai 8
Affiliations

Affiliations

  • 1 College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China; Military Institute of Chinese Materia, the Fifth Medical Center of PLA General Hospital, Beijing, China; School of Traditional Chinese Medicine, Capital Medical University, Beijing, China; The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, China.
  • 2 School of Traditional Chinese Medicine, Capital Medical University, Beijing, China. Electronic address: guang_xu@ccmu.edu.cn.
  • 3 Department of Military Patient Management, the Fifth Medical Center of PLA General Hospital, Beijing, China.
  • 4 Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China.
  • 5 School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
  • 6 Department of Pharmacy, the Fifth Medical Center of PLA General Hospital, Beijing, China. Electronic address: zhaoyl2855@126.com.
  • 7 Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China; Military Institute of Chinese Materia, the Fifth Medical Center of PLA General Hospital, Beijing, China. Electronic address: pharmacy302xxh@126.com.
  • 8 Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China; Military Institute of Chinese Materia, the Fifth Medical Center of PLA General Hospital, Beijing, China. Electronic address: baizf2008@hotmail.com.
PMID: 35973629 DOI: 10.1016/j.jep.2022.115593
Abstract

Ethnopharmacological relevance: Psoralea corylifolia (P. corylifolia Linn.) is a traditional Chinese medicinal plant that exhibits significant aphrodisiac, diuretic, and anti-rheumatic effects. However, it has been reported to cause hepatic injury, but the precise mechanisms remain unclear.

Aim of the study: To evaluate the safety and risk of P. corylifolia and to elucidate the underlying mechanisms of drug-induced liver injury.

Materials and methods: Western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, quantitative polymerase chain reaction (Q-PCR), and flow cytometry were used to explore the effect of bakuchiol (Bak), one of the most abundant and biologically active components of P. corylifolia, on the AIM2 inflammasome activation and the underlying mechanism. Furthermore, we used the lipopolysaccharides (LPS)-induced drug-induced liver injury (DILI) susceptible mice model to study the Bak-mediated hepatotoxicity.

Results: Bak induced the maturation of Caspase-1 P20, and significantly increased the expression of IL-1β and TNF-α (P < 0.0001) compared with the control group. Moreover, compared to the Bak group, knockdown of AIM2 inhibited Bak-induced Caspase-1 maturation and significantly decreased the production of IL-1β and TNF-α, but knockout of NLRP3 had no effect. Mechanistically, Bak-induced AIM2 inflammasome activation is involved in mitochondrial damage, mitochondrial DNA (mtDNA) release, and subsequent recognition of cytosolic mtDNA. Our in vivo data showed that co-exposure to LPS and non-hepatotoxic doses of Bak significantly increased the levels of ALT, AST, IL-1β, TNF-α, and IL-18, indicating that Bak can induce severe liver inflammation (P < 0.005).

Conclusions: The result shows that Bak activates the AIM2 inflammasome by inducing mitochondrial damage to release mtDNA, and subsequently binds to the AIM2 receptor, indicating that Bak may be a risk factor for P. corylifolia-induced hepatic injury.

Keywords

AIM2 inflammasome; Agonist; Bakuchiol; Drug-induced liver injury; Psoralea corylifolia..

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