School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China; School of Traditional Chinese Medicine, Capital Medical University, Beijing, China; Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China.
Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China; The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, China.
J Ethnopharmacol. 2024 Jan 30;319(Pt 1):117063. doi: 10.1016/j.jep.2023.117063. Epub 2023 Aug 18.
Dictamnus dasycarpus Turcz. (Dictamni Cortex, DC), a Chinese herbal medicine, is commonly used for treating chronic dermatosis and rheumatism, but can also cause herb-induced liver injury (HILI). Our study has demonstrated that DC can induce idiosyncratic HILI, but the mechanism remains unknown. The NLRP3 inflammasome has become a major target for addressing many diseases. The activation of NLRP3 inflammasome is responsible for many liver-related inflammatory diseases, including idiosyncratic HILI.
The objective of our study was to demonstrate the mechanism underlying the idiosyncratic HILI induced by DC and clarify the susceptible component in DC.
Bone marrow-derived macrophages (BMDMs) and THP1 cells were selected to assess the effect of isomaculosidine (IMD) on NLRP3 inflammasome activation in vitro. Western blot, ELISA and Caspase-Glo® 1 Inflammasome Assay, flow cytometry and Immunofluorescence were employed to detect the mechanism of IMD on NLRP3 inflammasome activation. To assess the efficacy of IMD in vivo, mice were intravenously administrated with LPS and then IMD were injected intraperitoneally for 6 h.
The results of our in vitro studies demonstrate that IMD, the major constituent of DC, specifically promoted ATP- and nigericin-induced activation of NLRP3 inflammasome, but not NLRC4 and AIM2 inflammasomes. Additionally, IMD promoted nigericin-induced ASC oligomerization. Notably, synergistic induction of mtROS played a key role on the activation of NLRP3 inflammasome. IMD increased the mtROS production in the activation of NLRP3 inflammasome induced by nigericin. In addition, the results of our in vivo study showed that the combination of nonhepatotoxic doses of LPS and IMD can increase the levels of ALT, AST, and DBIL, leading to liver injury.
IMD specifically facilitated the activation of NLRP3 inflammasome induced by nigericin and ATP, which is responsible for DC-induced idiosyncratic HILI.
白鲜皮（Dictamni Cortex，DC）是一种中国草药，常用于治疗慢性皮肤病和风湿病，但也可能导致草药性肝损伤（HILI）。我们的研究表明，DC 可诱导特发性 HILI，但机制尚不清楚。NLRP3 炎性体已成为治疗许多疾病的主要靶点。NLRP3 炎性体的激活与许多肝脏相关的炎症性疾病有关，包括特发性 HILI。
本研究旨在探讨 DC 诱导的特发性 HILI 的机制，并阐明 DC 中的易感成分。
选用骨髓来源的巨噬细胞（BMDMs）和 THP1 细胞，评估异毛蕊花苷（IMD）对体外 NLRP3 炎性体激活的影响。采用 Western blot、ELISA 和 Caspase-Glo® 1 炎性体测定法、流式细胞术和免疫荧光法检测 IMD 对 NLRP3 炎性体激活的机制。为评估 IMD 在体内的疗效，用 LPS 静脉注射小鼠，然后腹腔注射 IMD 6 h。
体外研究结果表明，IMD 是 DC 的主要成分，可特异性促进 ATP 和 Nigericin 诱导的 NLRP3 炎性体激活，但不促进 NLRC4 和 AIM2 炎性体激活。此外，IMD 促进 Nigericin 诱导的 ASC 寡聚化。值得注意的是，mtROS 的协同诱导在 NLRP3 炎性体的激活中起着关键作用。IMD 增加了 Nigericin 诱导的 NLRP3 炎性体激活中的 mtROS 产生。此外，体内研究结果表明，非肝毒性剂量的 LPS 和 IMD 联合使用可增加 ALT、AST 和 DBIL 水平，导致肝损伤。
IMD 特异性促进 Nigericin 和 ATP 诱导的 NLRP3 炎性体激活，这是 DC 诱导的特发性 HILI 的原因。
