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杨茂辉, 冉恒泉, 王何斌, 刘德钦, 李劲.汉黄芩素调节Hippo/YAP信号通路对肝硬化大鼠肝纤维化的影响[J].湖南中医药大学学报,2024,44(7):1160-1166[点击复制] |
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| 汉黄芩素调节Hippo/YAP信号通路对肝硬化大鼠肝纤维化的影响 |
| 杨茂辉,冉恒泉,王何斌,刘德钦,李劲 |
| (攀枝花学院附属医院肝胆外科, 四川 攀枝花 617000;攀枝花市中心医院肝胆外科, 四川 攀枝花 617000) |
| 摘要: |
| 目的 初步探讨汉黄芩素（Wogonin, Wog）调节河马（Hippo）/Yes-相关蛋白（Yes associated protein, YAP）信号通路对肝硬化大鼠肝纤维化的影响。方法 将大鼠分为空白对照组（腹腔注射等量生理盐水+灌胃等量生理盐水）、模型组（腹腔注射等量生理盐水+灌胃等量生理盐水）、阳性对照组（0.8 g/kg复方鳖甲软肝片溶液灌胃）和Wog低、中、高剂量组（7、14、28 mg/kg Wog腹腔注射），每组12只。除空白对照组外，其余各组腹腔注射四氯化碳溶液构建肝硬化模型。所有大鼠造模后给药干预，连续4周。检测大鼠血清肝功能指标谷丙转氨酶（alanine aminotransferase, AST）、谷草转氨酶（aspartate aminotransferase, ALT）；ELISA法检测血清纤维化指标Ⅲ型前胶原（type Ⅲ procollagen, PCⅢ）、透明质酸（hyaluronic acid hyaluronan, HA）、层粘连蛋白（laminin, LN）；HE、Masson及免疫组织化学染色法观察肝硬化大鼠肝纤维化程度；Ishak评分判断肝组织纤维化程度，分析胶原体积分数（collagen volume fraction， CVF）及Ⅰ型胶原（collagen-Ⅰ，COL-Ⅰ）和Ⅲ型胶原（collagen-Ⅲ，COL-Ⅲ）阳性表达；Western blot检测肝组织中α-平滑肌肌动蛋白（α-smooth muscle actin，α-SMA）、转化生长因子-β1（transforming growth factor-β1, TGF-β1）及Hippo/YAP信号通路蛋白表达水平。结果 与空白对照组比较，模型组AST、ALT、PCⅢ、HA、LN、Ishak评分、CVF、COL-Ⅰ、COL-Ⅲ、α-SMA、TGF-β1表达升高（P<0.05），p-大肿瘤抑制因子1（large tumor suppressor gene 1，LATS1）/LATS1、p-YAP/YAP表达降低（P<0.05）；与模型组比较，Wog低、中、高剂量组及阳性对照组AST、ALT、PCⅢ、HA、LN、Ishak评分、CVF、COL-Ⅰ、COL-Ⅲ、α-SMA、TGF-β1表达降低（P<0.05），p-LATS1/LATS1、p-YAP/YAP表达升高（P<0.05）。Wog各剂量组AST、ALT、PCⅢ、HA、LN、Ishak评分、CVF、COL-Ⅰ、COL-Ⅲ、α-SMA、TGF-β1水平均随剂量升高而降低（P<0.05）；p-LATS1/LATS1、p-YAP/YAP水平随剂量升高而升高（P<0.05）。结论 Wog可能通过抑制Hippo/YAP信号通路的激活，改善肝硬化大鼠肝纤维化。 |
| 关键词: 肝硬化 肝纤维化 汉黄芩素 Hippo信号通路 Yes-相关蛋白 |
| DOI：10.3969/j.issn.1674-070X.2024.07.003 |
| 投稿时间：2024-01-04 |
| 基金项目:四川省卫生和计划生育委员会科研课题项目（18PJ507）。 |
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| Effects of Wogonin on liver fibrosis in cirrhotic rats by regulating the Hippo/YAP signaling pathway |
| YANG Maohui, RAN Hengquan, WANG Hebin, LIU Deqin, LI Jin |
| (Department of Hepatobiliary Surgery, The Hospital of Panzhihua University, Panzhihua, Sichuan 617000, China;Department of Hepatobiliary Surgery, The Central Hospital of Panzhihua, Panzhihua, Sichuan 617000, China) |
| Abstract: |
| Objective To investigate the effects of Wogonin (Wog) on liver fibrosis in cirrhotic rats by regulating the Hippo/Yes associated protein (YAP) signaling pathway. Methods The rats were divided into blank control (with intraperitoneal injection of equal volume of saline solution + intragastric administration of equal volume of saline solution), model (with intraperitoneal injection of equal volume of saline solution + intragastric administration of equal volume of saline solution), positive control (with intragastric administration of 0.8 g/kg Compound Biejia Ruangan Tablets solution), low-, medium-, and high-dose (with intraperitoneal injection of 7, 14, 28 mg/kg Wog) Wog groups, with 12 rats in each group. Except for blank control group, the other groups were injected intraperitoneally with carbon tetrachloride in aqueous solution to construct cirrhosis models. After modeling, all rats were treated with corresponding drugs, for consecutive 4 weeks. The serum liver function indicators of rats including alanine aminotransferase (AST) and aspartate aminotransferase (ALT) were measured; ELISA was used to test serum fibrosis indicators including type Ⅲ procollagen (PCⅢ), hyaluronic acid (HA), and laminin (LN); Hatmatoxylin-eosin (HE), Masson and immunohistochemical staining were performed to observe the degree of liver fibrosis in cirrhotic rats; Ishak score was used to determine the degree of liver tissue fibrosis, the collagen volume fraction (CVF), and the positive expressions of collagen-I (COL-Ⅰ) and collagen-Ⅲ (COL-Ⅲ); Western blot was used to determine the expression levels of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and Hippo/YAP signaling pathway in liver tissue. Results Compared with blank control group, the expressions of AST, ALT, PCⅢ, HA, LN, Ishak score, CVF, COL-I, COL-Ⅲ, α-SMA, and TGF-β1 in model group were higher (P<0.05), the expressions of phosphorylation (p)-large tumor suppressor gene 1 (LATS1)/LATS1 and p-YAP/YAP were lower (P<0.05); compared with model group, the expressions of AST, ALT, PCⅢ, HA, LN, Ishak score, CVF COL-I, COL-Ⅲ, α-SMA, and TGF-β1 in low-, medium-, and high-dose Wog groups and positive control group were lower (P<0.05), the expressions of p-LATS1/LATS1 and p-YAP/YAP were higher (P<0.05). The levels of AST, ALT, PCⅢ, HA, LN, Ishak score, CVF, COL-Ⅰ, COL-Ⅲ, α-SMA and TGF-β1 in all dose Wog groups decreased with the increase of dose (P<0.05). While the levels of p-LATS1/LATS1 and p-YAP/YAP increased with the dose increasing (P<0.05). Conclusion Wog may improve liver fibrosis in cirrhotic rats by inhibiting the activation of Hippo/YAP signaling pathway. |
| Key words: liver cirrhosis liver fibrosis Wogonin Hippo signaling pathway Yes-associated protein |
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