槲皮素对四氯化碳致大鼠肝纤维化的缓解作用及其机制研究

doi:10.5246/jcps.2022.11.071

中国药学(英文版) ›› 2022, Vol. 31 ›› Issue (11): 840-852.DOI: 10.5246/jcps.2022.11.071

槲皮素对四氯化碳致大鼠肝纤维化的缓解作用及其机制研究

张明康¹^,², 陈宇玥², 周燕², 武新安¹^,²^,³^,^*()

1. 兰州大学第一医院药剂科, 甘肃兰州 730000
2. 兰州大学药学院, 甘肃兰州 730000
3. 甘肃省临床用药风险防控工程研究中心, 甘肃兰州 730000

收稿日期:2022-04-30 修回日期:2022-05-18 接受日期:2022-06-26 出版日期:2022-11-30 发布日期:2022-11-30
通讯作者: 武新安
作者简介:
+ Tel.: +86-931-8356511, E-mail: wuxa@lzu.edu.cn
基金资助:
Natural Science Foundations of China (Grant No. 81960680), Lanzhou Chengguan District Science and Technology Project (Grant No. 2019RCCX0039), and Intra-hospital Fund of the First Hospital of Lanzhou University (Grant No. ldyyyn2018-10), China.

The alleviating effect of quercetin on carbon tetrachloride-induced liver fibrosis in rats and its underlying mechanism

Mingkang Zhang¹^,², Yuyue Chen², Yan Zhou², Xin'an Wu¹^,²^,³^,^*()

1 Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China
2 School of Pharmacy, Lanzhou University, Lanzhou 730000, China
3 Engineering Research Centre of Prevention and Control for Clinical Medication Risk of Gansu Province, Lanzhou 730000, China

Received:2022-04-30 Revised:2022-05-18 Accepted:2022-06-26 Online:2022-11-30 Published:2022-11-30
Contact: Xin'an Wu

摘要/Abstract

摘要：

槲皮素是一种广泛存在于蔬菜和水果中的酚类植物化学物质, 具有抗氧化、抗炎、抗病毒和免疫调节活性, 已成功应用于急慢性疾病的治疗。本研究目的是探讨槲皮素对大鼠肝纤维化的缓解作用并探讨其作用机制。将健康雄性SD大鼠随机分为正常组、模型组和槲皮素组, 每组6只。通过腹腔注射1 mL/kg四氯化碳(50% v/v, 溶于橄榄油), 每周2次, 持续6周诱导肝脏纤维化, 并于第7周灌胃给予槲皮素(100 mg/kg/d)持续至第12周结束。末次给药1 h后, 收集血液和肝脏样品。利用全自动生化仪检测血清肝功能参数(AST、ALT、ALP、GGT和TBA); HE、Masson和天狼星红染色观察肝组织病理形态; Western blotting评价肝纤维化因子(TGF-β1、α-SMA、MMP2和MMP9)和胆汁酸相关调节蛋白(FXR、CYP7A1、CYP8B1和CYP27A1)的表达; 采用试剂盒检测肝组织氧化应激标志物(GSH、GSH-Px、GR、SOD和MDA)的含量; 运用LC-MS/MS测定肝组织中胆汁酸含量。结果发现与模型组相比, 给予槲皮素治疗后可显著降低血清AST、ALT和TBA含量(P < 0.05); 肝纤维化损伤明显改善且纤维化因子TGF-β1、α-SMA、MMP2和MMP9的表达量均显著降低(P < 0.05); 肝GSH、GSH-Px、GR和SOD水平显著升高(P < 0.05), MDA水平显著降低(P < 0.05); 肝胆汁酸含量明显降低(P < 0.05), 且FXR表达量显著升高(P < 0.05), CYP7A1和CYP8B1表达量显著降低(P < 0.05)。研究表明, 槲皮素可有效缓解四氯化碳引起的肝纤维化损伤, 其作用机制与提高肝脏抗氧化应激能力, 减少纤维化因子表达和胆汁酸合成有关。

关键词: 槲皮素, 肝纤维化, 四氯化碳, 氧化应激, 纤维化细胞因子, 胆汁酸

Abstract:

Quercetin, a phenolic phytochemical widely present in vegetables and fruits, has antioxidant, anti-inflammatory, antiviral, and immunomodulatory activities, and it has been successfully used in the treatment of acute and chronic diseases. In the present study, we aimed to investigate the alleviation effect of quercetin on rat liver fibrosis and explore its mechanism of action. Healthy male SD rats were randomly divided into the normal group, model group, and quercetin group, with six rats in each group. Liver fibrosis was induced by intraperitoneal injection of 1 mL/kg carbon tetrachloride (50% v/v in olive oil) twice a week for 6 weeks, and quercetin (100 mg/kg/d) was administered orally in the 7th week until the end of the 12th week. Blood and liver samples were collected at 1 h after the last administration. Serum liver function parameters (AST, ALT, ALP, GGT, and TBA) were detected by an automatic biochemical analyzer. H&E, Masson, and Sirius red staining were used to observe the pathological morphology of liver tissue. Western blotting analysis was used to evaluate the expressions of liver fibrotic factors (TGF-β1, α-SMA, MMP2, and MMP9) and bile acid-related regulatory proteins (FXR, CYP7A1, CYP8B1, and CYP27A1). The oxidative stress markers (GSH, GSH-Px, GR, SOD, and MDA) in the liver tissue were detected using corresponding kits. The contents of bile acids in the liver tissue were determined by LC-MS/MS. The results showed that compared with the model group, quercetin treatment could significantly reduce serum AST, ALT, and TBA levels (P < 0.05). The fibrotic liver injury was significantly improved, and the expressions of fibrotic factors TGF-β1, α-SMA, MMP2, and MMP9 were significantly decreased (P < 0.05). Liver GSH, GSH-Px, GR, and SOD levels were significantly increased (P < 0.05), and the MDA level was significantly decreased (P < 0.05). The contents of hepatic bile acids were significantly decreased (P < 0.05), the expression of FXR was significantly increased (P < 0.05), and the expressions of CYP7A1 and CYP8B1 were significantly decreased (P < 0.05). This study suggested that quercetin could effectively alleviate carbon tetrachloride-induced liver fibrosis injury, and its mechanism of action was related to improving the liver’s ability to resist oxidative stress and reducing the expressions of fibrotic factors and bile acid synthesis.

Key words: Quercetin, Liver fibrosis, Carbon tetrachloride, Oxidative stress, Fibrosis cytokines, Bile acids

Supporting:

张明康, 陈宇玥, 周燕, 武新安. 槲皮素对四氯化碳致大鼠肝纤维化的缓解作用及其机制研究[J]. 中国药学(英文版), 2022, 31(11): 840-852.

Mingkang Zhang, Yuyue Chen, Yan Zhou, Xin'an Wu. The alleviating effect of quercetin on carbon tetrachloride-induced liver fibrosis in rats and its underlying mechanism[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(11): 840-852.

图/表 7

Table 1. LC-MS/MS analysis methods of bile acids.

Table 2. The effect of quercetin on serum biochemical parameters.

Figure 1. The effect of quercetin on liver histopathology. H&E staining. Magnification, ×200; Masson’s trichrome staining. Magnification, ×100; Sirus Red staining. Magnification, ×100.

Figure 2. The effect of quercetin on liver fibrosis-related regulatory proteins. Values are represented as mean ± SD for three rats in each group. *P < 0.05, **P < 0.01, compared with the control group; #P < 0.05, ##P < 0.01, compared with the model group. One-way ANOVA followed by Newman-Keuls multiple comparison test. TGF-β1: Transforming growth factor-β1; α-SMA: α-smooth muscle actin; MMP2: Matrix metalloproteinase 2; MMP9: Matrix metalloproteinase 9.

Figure 3. The effects of quercetin on liver oxidative stress. Values are represented as mean ± SD for six rats in each group. *P < 0.05, **P < 0.01, compared with the control group; #P < 0.05, ##P < 0.01, compared with the model group. One-way ANOVA followed by Newman-Keuls multiple comparison test. SD: Standard deviation; GSH: Glutathione; GSH-Px: Glutathione peroxidase; GR: Glutathion reductases; MDA: Malondialdehyde; SOD: Superoxide dismutase.

Figure 4. The effect of quercetin on liver bile acid. A: The concentration of liver unconjugated bile acid (ng/g). B: The concentration of liver TLCA (ng/g). C: The concentration of liver glycine-conjugated bile acids (ng/g). Values are represented as mean ± SD for six rats in each group. *P < 0.05, **P < 0.01, compared with the control group; # P< 0.05, ##P < 0.01, compared with the model group. One-way ANOVA followed by Newman-Keuls multiple comparison test.

Figure 5. The effect of quercetin on liver bile acid-related metabolic enzymes. Values are represented as mean ± SD for three rats in each group. *P < 0.05, **P < 0.01, compared with the control group; #P < 0.05, ##P < 0.01, compared with the model group. One-way ANOVA followed by Newman-Keuls multiple comparison test. FXR: Farnesol X receptor; CYP7A1: Cholesterol-7α-hydroxylase; CYP8B1: Cholesterol-12α-hydroxylase; CYP27A1: Cholesterol-27α-hydroxylase.

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槲皮素对四氯化碳致大鼠肝纤维化的缓解作用及其机制研究

The alleviating effect of quercetin on carbon tetrachloride-induced liver fibrosis in rats and its underlying mechanism

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