School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province 226001, China.
Teaching and Research Section of Clinical Medicine, Jiangsu Vocational College of Medicine, Yancheng 224005, China.
Int Immunopharmacol. 2023 Oct;123:110768. doi: 10.1016/j.intimp.2023.110768. Epub 2023 Aug 12.
Previous studies have shown that Alisol B 23-acetate (23ABA) had potent liver-protection effects, however, its roles and potential mechanisms in carbon tetrachloride (CCl)-induced liver fibrosis remain to be determined. The present study aimed to investigate the effects of 23ABA on CCl-induced liver fibrosis and tried to elucidate the underlying mechanisms by focusing on regulating of farnesoid X receptor (FXR). In vivo study found that 23ABA alleviated the CCl-induced liver injury, and showed no obvious systemic toxicity on mice. 23ABA inhibited the collagen production, decreased sera levels of hyaluronic acid (HA) and procollagen type III (PC-III), lowered mRNA expression of α-smooth muscle actin (α-SMA), fibronectin, collagen I and collagen III in livers of mice. 23ABA inhibited the mRNA expressions and the sera levels of interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α), as well as decreased the expression of cyclooxygenase 2 (COX-2) in fibrotic livers of mice. Besides, 23ABA decreased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased glutathione (GSH) level, enhanced activities of superoxide dismutase (SOD) and glutathione reductase (GR) as well as increased mRNA expression of nuclear factor-E2-related factor 2 (Nrf2), glutamate-cysteine ligase, catalytic subunit (GCLC) and glutamate-cysteine ligase, modifier subunit (GCLM). Further study showed that the anti-liver injury and anti-fibrotic effects of 23ABA were abrogated by FXR antagonist guggulsterone (GS) in vivo. In addition, the inhibition effects of 23ABA on liver inflammation and oxidative stress were also weakened by treatment with GS in CCl-induced fibrotic mice livers. In conclusion, the protective effects of 23ABA against CCl-induced liver injury and fibrosis, due to FXR-mediated regulation of liver inflammation and oxidative stress.
先前的研究表明，泽泻醇 B-23-醋酸酯（23ABA）具有很强的肝脏保护作用，但它在四氯化碳（CCl）诱导的肝纤维化中的作用和潜在机制仍有待确定。本研究旨在探讨 23ABA 对 CCl 诱导的肝纤维化的影响，并通过关注法尼醇 X 受体（FXR）的调节来试图阐明其潜在机制。体内研究发现，23ABA 减轻了 CCl 引起的肝损伤，并且对小鼠没有明显的全身毒性。23ABA 抑制胶原生成，降低血清透明质酸（HA）和 III 型前胶原（PC-III）水平，降低小鼠肝脏中α-平滑肌肌动蛋白（α-SMA）、纤维连接蛋白、I 型和 III 型胶原的 mRNA 表达。23ABA 抑制了纤维化肝脏中白细胞介素-6（IL-6）、IL-1β和肿瘤坏死因子-α（TNF-α）的 mRNA 表达和血清水平，同时降低了环氧合酶 2（COX-2）的表达。此外，23ABA 降低了活性氧（ROS）和丙二醛（MDA）的水平，增加了谷胱甘肽（GSH）的水平，增强了超氧化物歧化酶（SOD）和谷胱甘肽还原酶（GR）的活性，并增加了核因子-E2 相关因子 2（Nrf2）、谷氨酰胺半胱氨酸连接酶，催化亚基（GCLC）和谷氨酰胺半胱氨酸连接酶，调节亚基（GCLM）的 mRNA 表达。进一步的研究表明，在体内，FXR 拮抗剂金合欢素（GS）阻断了 23ABA 的抗肝损伤和抗纤维化作用。此外，在 CCl 诱导的纤维化小鼠肝脏中，用 GS 处理也减弱了 23ABA 对肝炎症和氧化应激的抑制作用。综上所述，23ABA 通过 FXR 介导的调节肝炎症和氧化应激，对 CCl 诱导的肝损伤和纤维化具有保护作用。
