Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Food Chem Toxicol. 2023 Aug;178:113914. doi: 10.1016/j.fct.2023.113914. Epub 2023 Jun 20.
Cholestatic liver injury is caused by toxic action or allergic reaction, resulting in abnormality of bile formation and excretion. Few effective therapies have become available for the treatment of cholestasis. Herein, we found that tectorigenin (TG), a natural isoflavone, showed definite protective effects on alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury, significantly reversing the abnormality of plasma alanine/aspartate aminotransferase, total/direct bilirubin and alkaline phosphatase, as well as hepatic reactive oxygen species, catalase and superoxide dismutase. Importantly, the targeted metabolomic determination found that BA homeostasis could be well maintained in TG-treated cholestatic mice, especially the levels of glycocholic acid, tauromuricholic acid, taurocholic acid, taurolithocholic acid, tauroursodeoxycholic acid and taurodeoxycholic acid. Overall, primary/secondary and amidated/unamidated bile acid (BA) levels were significantly altered upon ANIT stimulation but could be restored by TG intervention to certain extents. In addition, TG boosted the expression of farnesoid x receptor (FXR), which in turn upregulated multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP) to accelerate the excretion of BA. Meanwhile, TG enhanced the expression of Nrf2 and its upstream genes PI3K/Akt and downstream target genes HO-1, NQO1, GCLC and GCLM to strengthen the antioxidant capacity. Taken together, TG plays a vital role in maintaining BA homeostasis and ameliorating cholestatic liver injury through regulating FXR-mediated BA efflux and Nrf2-mediated antioxidative pathways.
胆汁淤积性肝损伤是由毒性作用或过敏反应引起的，导致胆汁形成和排泄异常。目前，针对胆汁淤积症的治疗方法非常有限。本研究发现，葛根素（TG），一种天然异黄酮，对α-萘基异硫氰酸酯（ANIT）诱导的胆汁淤积性肝损伤具有明确的保护作用，可显著逆转血浆丙氨酸/天冬氨酸转氨酶、总/直接胆红素和碱性磷酸酶的异常，并能改善肝脏活性氧、过氧化氢酶和超氧化物歧化酶的水平。重要的是，靶向代谢组学测定发现，TG 处理的胆汁淤积小鼠的 BA 平衡可以得到很好的维持，尤其是甘氨胆酸、牛磺熊去氧胆酸、牛磺胆酸、牛磺鹅去氧胆酸、牛磺熊去氧胆酸和牛磺脱氧胆酸的水平。总体而言，原发性/次级和酰胺化/非酰胺化胆汁酸（BA）水平在 ANIT 刺激下显著改变，但可通过 TG 干预在一定程度上恢复。此外，TG 增强了法尼醇 X 受体（FXR）的表达，进而上调多药耐药蛋白 2（MRP2）和胆汁盐输出泵（BSEP），以加速 BA 的排泄。同时，TG 增强了 Nrf2 及其上游基因 PI3K/Akt 和下游靶基因 HO-1、NQO1、GCLC 和 GCLM 的表达，以增强抗氧化能力。综上所述，TG 通过调节 FXR 介导的 BA 外排和 Nrf2 介导的抗氧化途径，在维持 BA 平衡和改善胆汁淤积性肝损伤方面发挥着重要作用。
