School of Pharmacy, Dali University, Dali, 671000, China; Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China; China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China.
Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China; China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
J Ethnopharmacol. 2022 Mar 1;285:114796. doi: 10.1016/j.jep.2021.114796. Epub 2021 Nov 3.
Sophora flavescens is a traditional Chinese medicine commonly used in clinical practice, which has the effects of clearing away heat and dampness. Unfortunately, it has been reported that Sophora flavescens and its preparation may cause liver damage to a certain extent, but the exact mechanism is not clear.
To assess the safety and risk of Sophora flavescens and to elucidate the relationship between Idiosyncratic drug-induced liver injury (IDILI) and the NOD-like receptor family protein 3 (NLRP3) inflammasome.
Western blot, Caspase-Glo® 1 Inflammasome Assay, ELISA kits, Flow cytometry and FLIPRT Tetra system were used to study the effect of isoxanthohumol (IXN) on the activation of NLRP3 inflammasome and its mechanism. Combined with the lipopolysaccharide-mediated susceptibility IDILI model in mice to evaluate the hepatotoxicity of IXN.
IXN facilitates the activation of caspase-1 and secretion of interleukin (IL)-1β triggered by adenosine triphosphate (ATP), nigericin but not those induced by silicon dioxide and poly (I:C). Furthermore, the activation of NLR-family CARD-containing protein 4 (NLRC4) and the absent in melanoma 2 (AIM2) was not affected by IXN. Mechanistically, IXN promotes NLRP3-dependent apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) oligomerization and the generation of mitochondrial reactive oxygen species (mtROS) triggered by ATP. The in vivo data showed that non-hepatotoxic doses of IXN resulted in increased levels of glutamate-pyruvate transaminase, glutamate-oxaloacetate transaminase, tumor necrosis factor and IL-1β in the serum and showed increased liver inflammation in the susceptible IDILI model mediated by lipopolysaccharide.
These results show that IXN enhances NLRP3 inflammasome activation by promoting the accumulation of ATP-induced mtROS and ASC oligomerization to cause IDILI, indicating that IXN may be a risk factor for liver injury caused by the clinical use of Sophora flavescens.
苦参是一种常用于临床实践的中药，具有清热利湿的功效。不幸的是，据报道苦参及其制剂在一定程度上可能会导致肝损伤，但确切的机制尚不清楚。
评估苦参的安全性和风险，并阐明特发性药物性肝损伤（IDILI）与核苷酸结合寡聚化结构域样受体家族蛋白 3（NLRP3）炎性体之间的关系。
采用 Western blot、Caspase-Glo® 1 炎性体测定试剂盒、ELISA 试剂盒、流式细胞术和 FLIPRT Tetra 系统研究异黄腐醇（IXN）对 NLRP3 炎性体激活的影响及其机制。结合脂多糖介导的易感 IDILI 小鼠模型评估 IXN 的肝毒性。
IXN 促进三磷酸腺苷（ATP）、虎杖苷诱导的 caspase-1 激活和白细胞介素（IL）-1β分泌，但不促进二氧化硅和聚（I:C）诱导的 caspase-1 激活。此外，IXN 不影响 NLR 家族含 C 端半胱氨酸天冬氨酸蛋白酶募集域蛋白 4（NLRC4）和黑色素瘤缺失 2（AIM2）的激活。机制上，IXN 促进 NLRP3 依赖性凋亡相关斑点样蛋白（ASC）寡聚化和线粒体活性氧（mtROS）的产生，由 ATP 触发。体内数据显示，非肝毒性剂量的 IXN导致易感 IDILI 模型中血清谷氨酸-丙酮酸转氨酶、谷氨酸-草酰乙酸转氨酶、肿瘤坏死因子和 IL-1β水平升高，并导致脂多糖介导的肝脏炎症增加。
这些结果表明，IXN 通过促进 ATP 诱导的 mtROS 和 ASC 寡聚化的积累增强 NLRP3 炎性体激活，导致 IDILI，表明 IXN 可能是苦参临床应用引起肝损伤的一个危险因素。
