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陈思源,彭馥芝,刘建军,朱健芳,余望贻,刘旺华.基于TLR4/NF-κB信号通路探讨乙肝宁颗粒对肝纤维化模型大鼠的作用机制[J].湖南中医药大学学报英文版,2023,43(10):1771-1778.[Click to copy
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| 基于TLR4/NF-κB信号通路探讨乙肝宁颗粒对肝纤维化模型大鼠的作用机制 |
| 陈思源,彭馥芝,刘建军,朱健芳,余望贻,刘旺华 |
| (湖南中医药大学科技创新中心, 湖南 长沙 410208;湖南中医药大学医学院, 湖南 长沙 410208;湖南中医药大学中医学院, 湖南 长沙 410208) |
| 摘要: |
| 目的 从Toll样受体-4（Toll-like receptor 4, TLR4）/核因子κB（nuclear factor-κB, NF-κB）信号通路观察乙肝宁颗粒对肝纤维化（hepatic fibrosis, HF）模型大鼠的治疗作用及相关的作用机制。方法 将64只SD随机分为空白组（12只）和造模组（52只），造模组采用四氯化碳皮下注射联合慢性夹尾应激的方法建立HF模型，造模成功的48只大鼠随机分为模型组（12只）、联苯双酯组（50 mg/kg，12只）、乙肝宁颗粒高剂量组（9.18 g/kg，12只，以下简称高剂量组）、乙肝宁颗粒低剂量组(4.59 g/kg，12只，以下简称低剂量组）。治疗组连续灌胃给药治疗4周。治疗结束后，比较各组大鼠肝功能指标谷丙转氨酶（alanine aminotransferase, ALT）、谷草转氨酶（aspartate aminotransferase, AST）、总蛋白（total protein, TPO, TP）、白蛋白（albumin, ALB）的水平；HE和Masson染色观察大鼠肝组织纤维化情况，免疫组织化学法和Western blot实验检测肝组织TLR4、NF-κB蛋白表达情况。结果 （1）与空白组比较，模型组ALB、TP含量降低（P＜0.05），肝组织存在细胞排列紊乱、变性肿胀坏死、脂肪空泡形成、炎性浸润等病理现象；高剂量组肝组织损伤程度均有明显改善，脂肪空泡明显减少，胶原纤维沉积程度减轻；低剂量组改善情况低于高剂量组；联苯双酯组与高剂量组之间无明显差异（P＞0.05）。（2）与空白组相比，模型组大鼠肝脏指数、AST、ALT含量明显升高（P＜0.05），与模型组比较，高剂量组肝脏指数、AST、ALT含量降低（P＜0.05），低剂量组上述指标情况高于高剂量组（P＜0.05），联苯双酯组与高剂量组之间无明显差异（P＞0.05）。（3）与空白组相比，模型组大鼠肝脏组织中TLR4、NF-κB、TGF-β、Smad3蛋白表达增加（P＜0.05）；与模型组相比，高剂量组大鼠肝脏组织中TLR4、NF-κB、TGF-β、Smad3蛋白表达水平降低（P＜0.05），高剂量组降低的程度高于低剂量组（P＜0.01）；与联苯双酯组相比，高剂量组上述蛋白的表达水平无明显差异（P＞0.05）。结论 乙肝宁颗粒可改善HF模型大鼠肝脏指数、肝脏病理表现，其作用机制可能与抑制TLR4/NF-κB信号通路中TLR4、NF-κB、TGF-β、Smad3的表达有关，且高剂量组疗效优于低剂量组。 |
| 关键词: 乙肝宁颗粒 肝郁 肝纤维化 Toll样受体-4 核因子κB |
| DOI：10.3969/j.issn.1674-070X.2023.10.004 |
| Received:April 24, 2023 |
| 基金项目:湖南省自然科学基金项目(2020JJ4460)；湖南省教育厅重点项目（18A288）；湖南省中医药科研计划项目（D2022098）。 |
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| Mechanism of action of Yiganning Granules on hepatic fibrosis model rats through TLR4/NF-κB signaling pathway |
| CHEN Siyuan,PENG Fuzhi,LIU Jianjun,ZHU Jianfang,YU Wangyi,LIU Wanghua |
| (Science and Technology Innovation Center, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;School of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;School of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China) |
| Abstract: |
| Objective To observe the therapeutic effects of Yiganning Granules on hepatic fibrosis (HF) model rats and its related mechanism of action through Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway. Methods Sixty-four SD rats were randomly divided into blank group (n=12) and model preparation group (n=52). In model group, the HF model was established by subcutaneous injection of carbon tetrachloride combined with chronic tail-clamping stress. The 48 successfully modeled rats were randomly divided into model group (n=12), bifendate group (50 mg/kg, hereinafter referred to as western medicine group) (n=12), Yiganning Granules high-dose group (9.18 g/kg) (n=12, hereinafter referred to as high-dose group), and Yiganning Granules low-dose group (4.59 g/kg) (n=12, hereinafter referred to as low-dose group). The treatment group was treated by gavage continuously for 4 weeks. After treatment, the levels of liver function indices were compared among each group, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TPO, TP), and albumin (ALB). HE and Masson staining were used to observe the fibrosis of liver tissue in rats, and the protein expressions of TLR4 and NF-κB in liver tissue were measured by immunohistochemistry and Western blot. Results (1) Compared with blank group, the content of ALB and TP decreased (P＜0.05). There were pathological phenomena such as cell arrangement disorder, degeneration, swelling, and necrosis, fat vacuoles formation, and inflammatory infiltration in liver tissue. High-dose group showed obvious improvement in the degree of liver tissue damage, with a notable reduction in fat vacuoles and a decrease in the deposition degree of collagen fibers. The improvement of low-dose group was lower than that of high-dose group, and there was no significant difference between western medicine group and high-dose group (P＞0.05). (2) Compared with blank group, the liver index and the content of AST and ALT in model group increased significantly (P＜0.05), while the liver index and the content of AST and ALT in high-dose group decreased (P＜0.05) compared with model group. The above indices in low-dose group were higher than those in high-dose group (P＜0.05), and there was no significant difference between western medicine group and high-dose group (P＞0.05). (3) Compared with blank group, the protein expressions of TLR4, NF-κB, TGF-β, and Smad3 in the liver tissue of rats in model group increased (P＜0.05). Compared with model group, the protein expressions of TLR4, NF-κB, TGF-β, and Smad3 in the liver tissue of rats in high-dose group decreased (P＜0.05), with the decrease degree in high-dose group higher than that in low-dose group (P＜0.01). Compared with western medicine group, there was no significant difference in the expressions of the above proteins in high-dose group (P＞0.05). Conclusion Yiganning Granules can improve the liver indices and liver pathological manifestations of HF model rats, and its mechanism of action may be related to the inhibition of the expressions of TLR4, NF-κB, TGF-β, and Smad3 in TLR4/NF-κB signaling pathway, and the curative effects of high-dose group were better than those of low-dose group. |
| Key words: Yiganning Granules liver qi stagnation hepatic fibrosis Toll-like receptor-4 nuclear factor kappa B |
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