Tu Can, He Qin, Li Chun-Yu, Niu Ming, Han Zi-Xin, Ge Fei-Lin, Zhou Yuan-Yuan, Zhang Le, Wang Xiao-Hui, Zhu Jing-Xiao, Li Rui-Sheng, Song Hai-Bo, Xiao Xiao-He, Wang Jia-Bo
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
China Military Institute of Chinese Medicine, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China.
Front Pharmacol. 2019 Apr 5;10:335. doi: 10.3389/fphar.2019.00335. eCollection 2019.
[PM, synonym (Thunb.) Moldenke.], a well-known and commonly used Traditional Chinese Medicine and herbal dietary supplement for nourishing the kidney and liver, etc., has aroused wide concern for its reported potential hepatotoxicity. Previous clinical cases and experimental studies have suggested that mild immune stress (MIS) may be one of the susceptibility-related factors of idiosyncratic drug-induced liver injury (IDILI) caused by PM. In this paper, we found that the same dose of PM caused abnormal liver biochemical indicators and liver tissue damage in MIS model rats, while it did not result in liver injury in normal rats, further confirming that MIS is a susceptibility factor for PM-IDILI. Plasma chemokine/cytokine profiling indicated that the MIS model group was significantly different from the other groups, showing a significant upregulation of plasma chemokines, while the MIS/PM group showed upregulated expression of chemokines or pro-inflammatory cytokines. Liver histopathological examination indicated a small amount of inflammatory cytokine infiltration in the MIS group, but no hepatocyte injury, consistent with the plasma profiles of increased chemokines and unchanged inflammatory cytokines. Notably, metabolomics characterization showed that MIS caused reprogramming of these metabolic pathways (such as phenylalanine and glutamate pathways), which was associated with acute phase reactions and inflammatory responses. These results suggested that MIS may promote an immune response to the initial cellular injury induced by PM in the liver, and MIS-induced upregulation of chemokines and metabolic reprogramming may an important mechanism that mediates the susceptibility to PM-IDILI. Furthermore, via receiver operating characteristic (ROC) curves analysis, we identified 12 plasma cytokines (e.g., IP-10, MCP-1 and MIP-1α) and nine metabolomics biomarkers (e.g., L-Phenylalanine, Creatinine, and L-glutamine) with differential capabilities (all ROC AUC > 0.9) of identifying susceptibility model animals from normal ones, which might be of referable value for the clinical recognition of PM-IDILI susceptible individuals.
[淫羊藿，同义词（Thunb.）莫尔登克]，一种著名且常用的用于滋补肝肾等的传统中药和草药膳食补充剂，因其报道的潜在肝毒性而引起了广泛关注。先前的临床病例和实验研究表明，轻度免疫应激（MIS）可能是淫羊藿引起的特异质性药物性肝损伤（IDILI）的易感性相关因素之一。在本文中，我们发现相同剂量的淫羊藿在MIS模型大鼠中导致肝脏生化指标异常和肝组织损伤，而在正常大鼠中未导致肝损伤，进一步证实MIS是淫羊藿-IDILI的易感性因素。血浆趋化因子/细胞因子谱分析表明，MIS模型组与其他组有显著差异，血浆趋化因子显著上调，而MIS/淫羊藿组趋化因子或促炎细胞因子表达上调。肝脏组织病理学检查表明，MIS组有少量炎性细胞因子浸润，但无肝细胞损伤，这与血浆趋化因子增加和炎性细胞因子不变的情况一致。值得注意的是，代谢组学特征表明，MIS导致这些代谢途径（如苯丙氨酸和谷氨酸途径）重编程，这与急性期反应和炎症反应相关。这些结果表明，MIS可能促进对淫羊藿在肝脏中诱导的初始细胞损伤的免疫反应，MIS诱导的趋化因子上调和代谢重编程可能是介导淫羊藿-IDILI易感性的重要机制。此外，通过受试者工作特征（ROC）曲线分析，我们鉴定出12种血浆细胞因子（如IP-10、MCP-1和MIP-1α）和9种代谢组学生物标志物（如L-苯丙氨酸、肌酐和L-谷氨酰胺），它们具有区分易感性模型动物和正常动物的能力（所有ROC曲线下面积>0.9），这可能对淫羊藿-IDILI易感个体的临床识别具有参考价值。
