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.
School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
J Ethnopharmacol. 2022 Nov 15;298:115593. doi: 10.1016/j.jep.2022.115593. Epub 2022 Aug 13.
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.
To evaluate the safety and risk of P. corylifolia and to elucidate the underlying mechanisms of drug-induced liver injury.
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.
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).
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.
补骨脂（Psoralea corylifolia）是一种传统的中药，具有显著的壮阳、利尿和抗风湿作用。然而，据报道它会导致肝损伤，但确切的机制尚不清楚。
评估补骨脂的安全性和风险，并阐明药物性肝损伤的潜在机制。
使用 Western blot、酶联免疫吸附测定（ELISA）、免疫荧光、定量聚合酶链反应（Q-PCR）和流式细胞术来探讨补骨脂中最丰富和生物活性最强的成分之一补骨脂酚（Bak）对 AIM2 炎性体激活的影响及其潜在机制。此外，我们使用脂多糖（LPS）诱导的药物性肝损伤（DILI）易感小鼠模型来研究 Bak 介导的肝毒性。
Bak 诱导 caspase-1 P20 的成熟，并与对照组相比，显著增加了 IL-1β 和 TNF-α 的表达（P<0.0001）。此外，与 Bak 组相比，AIM2 的敲低抑制了 Bak 诱导的 caspase-1 成熟，并显著降低了 IL-1β 和 TNF-α 的产生，但 NLRP3 的敲除没有影响。机制上，Bak 诱导的 AIM2 炎性体激活涉及线粒体损伤、线粒体 DNA（mtDNA）释放以及随后对细胞质 mtDNA 的识别。我们的体内数据表明，LPS 和非肝毒性剂量的 Bak 共同暴露显著增加了 ALT、AST、IL-1β、TNF-α 和 IL-18 的水平，表明 Bak 可引起严重的肝炎症（P<0.005）。
结果表明，Bak 通过诱导线粒体损伤释放 mtDNA 来激活 AIM2 炎性体，随后与 AIM2 受体结合，表明 Bak 可能是补骨脂引起肝损伤的一个危险因素。
