Abstract：
Psoraleae Fructus (PF, Psoralea corylifolia L.), a traditional medicine with a long history of application, is widely used clinically for the treatment of various diseases. However, the reports of PF-related adverse reactions, such as hepatotoxicity, phototoxic dermatitis, and allergy, are increasing year by year, with liver injury being the mostly common. Our previous studies have demonstrated that PF and its preparations can cause liver injury in lipopolysaccharide (LPS)-mediated susceptibility mouse model, but the mechanism of PF-related liver injury is unclear. In this study, we showed that PF and bavachinin, a major component of PF, can directly induce the expression of caspase-1 and interleukin-1β (IL-1β), indicating that PF and bavachinin can directly triggered the activation of inflammasome. Furthermore, pretreatment with NLR family pyrin domain-containing 3 (NLRP3), NLR family CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome inhibitors, containing MCC950, ODN TTAGGG (ODN) and carnosol, all significantly reversed bavachinin-induced inflammasome activation. Mechanistically, bavachinin dose-dependently promote Gasdermin D (GSDMD) post-shear activation and then induce mitochondrial reactive oxygen species (mtROS) production and this effect is markedly inhibited by pretreatment with N-Acetylcysteine amide (NAC). In addition, combination treatment of LPS and bavachinin significantly induced liver injury in mice, but not LPS or bavachinin alone, and transcriptome analysis further validated these results. Thus, PF and bavachinin can induce the activation of inflammasome by promoting GSDMD cleavage and cause hepatotoxicity in mice. Therefore, PF, bavachinin, and PF-related preparations should be avoided in patients with inflammasome activation-associated diseases.
摘要：
补骨脂（PF，补骨脂L.），一种有着悠久应用历史的传统药物，临床上广泛用于各种疾病的治疗。然而,PF相关不良反应的报告，如肝毒性，光毒性皮炎，和过敏,逐年增加，肝损伤是最常见的。我们之前的研究已经证明,在脂多糖(LPS)介导的易感性小鼠模型中,PF及其制剂可引起肝损伤,但PF相关性肝损伤的机制尚不清楚。在这项研究中,我们展示了PF和bavachinin，PF的主要组成部分，能直接诱导caspase-1和白细胞介素-1β(IL-1β)的表达,表明PF和bavachinin可以直接触发炎症小体的激活。此外，用含有NLR家族pyrin结构域的3（NLRP3）预处理，NLR家族CARD结构域包含4（NLRC4）或在黑色素瘤2（AIM2）炎性体抑制剂中缺失，含有MCC950，ODNTTAGGG（ODN）和鼠尾草，所有显著逆转bavachinin诱导的炎性小体激活。机械上,bavachinin剂量依赖性地促进剪切后的GasderminD（GSDMD）活化，然后诱导线粒体活性氧（mtROS）的产生，这种作用被N-乙酰半胱氨酸酰胺（NAC）预处理显着抑制。此外,LPS和bavachinin联合治疗显著诱导小鼠肝损伤，但不能单独使用LPS或bavachinin，和转录组分析进一步验证了这些结果。因此，PF和bavachinin可以通过促进GSDMD裂解来诱导炎症小体的激活并引起小鼠的肝毒性。因此,PF,bavachinin,炎症小体激活相关疾病患者应避免使用PF相关制剂。
