| 引用本文: |
张鑫, 陆世银, 侯玲, 思斯, 张琳华, 周桂梅, 许文婧, 徐晓琳, 韦梦萍, 文娟.壮药叶下珠醇提物通过调控NF-κB/TGF-β1/Smad信号通路改善四氯化碳诱导的大鼠肝纤维化[J].湖南中医药大学学报,2026,46(3):472-482[点击复制] |
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| 壮药叶下珠醇提物通过调控NF-κB/TGF-β1/Smad信号通路改善四氯化碳诱导的大鼠肝纤维化 |
| 张鑫,陆世银,侯玲,思斯,张琳华,周桂梅,许文婧,徐晓琳,韦梦萍,文娟 |
| (柳州市中医医院(柳州市壮医医院), 广西 柳州 545026;柳州市柳铁中心医院, 广西 柳州 545007) |
| 摘要: |
| 目的 探讨叶下珠醇提物对四氯化碳（CCl4）诱导的大鼠肝纤维化（HF）的治疗作用，并基于核因子κB（NF-κB）/转化生长因子-β1（TGF-β1）/Smad信号通路探讨其潜在机制。方法 采用腹腔注射CCl4橄榄油溶液建立SD大鼠HF模型。将造模成功大鼠随机分为模型组、秋水仙碱组（0.12 mg/kg）及叶下珠醇提物低、中、高剂量组（4、8、16 g/kg）；另设正常组，每组8只。从第9周起灌胃给药，每天1次，连续4周。实验结束，称量体质量；检测肝脾脏指数；比色法测定血清中丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、丙二醛（MDA）、超氧化物歧化酶（SOD）水平；ELISA检测血清透明质酸（HA）、层粘连蛋白（LN）、Ⅲ型前胶原（PCⅢ）、Ⅳ型胶原（Ⅳ-C）与肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β、IL-6及TGF-β1的水平；HE、Masson及天狼星红染色观察肝组织病理变化；免疫组织化学检测肝组织α-平滑肌肌动蛋白（α-SMA）和Ⅰ型胶原（CollagenⅠ）表达水平；RT-qPCR及Western blot检测肝组织NF-κB、TGF-β1、Smad3、Smad7的mRNA和蛋白表达水平。结果 与正常组比较，模型组大鼠体质量、血清SOD水平、Smad7 mRNA与蛋白表达水平均降低（P＜0.01）；肝脾脏指数、血清ALT、AST、MDA、HA、LN、PCⅢ、Ⅳ-C、TNF-α、TGF-β1、IL-1β、IL-6水平、肝组织α-SMA、CollagenⅠ水平、肝组织NF-κB、TGF-β1、Smad3 mRNA与蛋白水平均升高（P＜0.01）。与模型组比较，各给药组大鼠体质量、血清SOD水平、Smad7 mRNA与蛋白水平均升高（P＜0.05，P＜0.01）；肝脾脏指数、血清ALT、AST、MDA、HA、LN、PCⅢ、Ⅳ-C、TNF-α、TGF-β1、IL-1β、IL-6水平、肝组织α-SMA、CollagenⅠ水平、肝组织NF-κB、TGF-β1、Smad3 mRNA与蛋白水平均降低（P＜0.05，P＜0.01）。与秋水仙碱组比较，叶下珠醇提物低、中剂量组大鼠体质量、血清SOD水平均降低（P＜0.01），肝脾脏指数、血清ALT、AST、MDA、HA、LN、PCⅢ、Ⅳ-C、TNF-α、TGF-β1、IL-1β、IL-6水平以及肝组织α-SMA、CollagenⅠ水平均升高（P＜0.05，P＜0.01）；叶下珠醇提物低剂量组肝组织NF-κB、TGF-β1、Smad3 mRNA与蛋白水平均升高（P＜0.01），Smad7 mRNA与蛋白水平均降低（P＜0.01）；叶下珠醇提物高剂量组肝组织NF-κB、TGF-β1、Smad3 mRNA与蛋白水平均降低（P＜0.01），Smad7 mRNA与蛋白水平均升高（P＜0.01）。与叶下珠醇提物低剂量组比较，叶下珠醇提物中、高剂量组大鼠体质量、血清SOD水平、Smad7 mRNA与蛋白水平均升高（P＜0.01）；肝脾脏指数、血清ALT、AST、MDA、HA、LN、PCⅢ、Ⅳ-C、TNF-α、TGF-β1、IL-1β、IL-6水平、肝组织α-SMA、CollagenⅠ水平、肝组织NF-κB、TGF-β1、Smad3 mRNA与蛋白水平均降低（P＜0.05，P＜0.01）。与叶下珠醇提物中剂量组比较，叶下珠醇提物高剂量组大鼠体质量、血清SOD水平、Smad7 mRNA与蛋白水平均升高（P＜0.05，P＜0.01）；肝脾脏指数、血清ALT、AST、MDA、HA、LN、PCⅢ、Ⅳ-C、TNF-α、TGF-β1、IL-1β、IL-6水平、肝组织α-SMA、CollagenⅠ水平、肝组织NF-κB、TGF-β1、Smad3 mRNA与蛋白水平均降低（P＜0.05，P＜0.01）。结论 叶下珠醇提物通过调控NF-κB/TGF-β1/Smad信号通路，增强抗氧化能力、减轻炎症反应与肝损伤、抑制肝星状细胞活化及胶原沉积，从而有效改善CCl4诱导的大鼠HF。 |
| 关键词: 叶下珠 肝纤维化 抗氧化 炎症因子 NF-κB/TGF-β1/Smad信号通路 |
| DOI：10.3969/j.issn.1674-070X.2026.03.006 |
| 投稿时间：2025-09-28 |
| 基金项目:广西壮族自治区中医药管理局中医药项目（GXZYB20240642）；广西中医药大学自然科学基金面上项目（2025LZ020）；柳州市科技攻关与新产品试制（2020NBAA0802）。 |
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| Ethanol extract of Zhuang medicine Yexiazhu (Phyllanthus Urinaria) ameliorates CCl4-induced hepatic fibrosis in rats by regulating the NF-κB/TGF-β1/Smad signaling pathway |
| ZHANG Xin, LU Shiyin, HOU Ling, SI Si, ZHANG Linhua, ZHOU Guimei, XU Wenjing, XU Xiaolin, WEI Mengping, WEN Juan |
| (Liuzhou Traditional Chinese Medical Hospital (Liuzhou Hospital of Zhuang Medicine), Liuzhou, Guangxi 545026, China;Liuzhou Municipal Liutie Central Hospital, Liuzhou, Guangxi 545007, China) |
| Abstract: |
| Objective To investigate the therapeutic effects of the ethanol extract of Yexiazhu (Phyllanthus urinaria) (EEPU) on carbon tetrachloride (CCl4)-induced hepatic fibrosis (HF) in rats and to explore its potential mechanism based on the nuclear factor-κB (NF-κB)/transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. Methods A HF model was established in SD rats by intraperitoneal injection of CCl4 olive oil solution. The successfully modeled rats were randomly assigned into model, colchicine (0.12 mg/kg), and low-, medium-, and high-dose EEPU groups (4, 8, 16 g/kg), with eight rats in each group, along with another normal control group. From the 9th week onwards, the modeled rats were given the corresponding drug intervention by gavage once daily for four consecutive weeks. At the end of the experiment, body weight was measured; liver and spleen indices were calculated; serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), and superoxide dismutase (SOD) were determined by colorimetry; serum levels of hyaluronic acid (HA), laminin (LN), type Ⅲ procollagen (PCⅢ), type Ⅳ collagen (Ⅳ-C), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and transforming growth factor-β1 (TGF-β1) were determined by ELISA; pathological changes in liver tissue were observed using HE, Masson, and Sirius Red staining; the expression levels of α-smooth muscle actin (α-SMA) and CollagenⅠ in liver tissue were determined by immunohistochemistry; mRNA and protein expression levels of NF-κB, TGF-β1, Smad3, and Smad7 in liver tissue were examined by RT-qPCR and Western blot. Results Compared with the normal group, the model group exhibited decreases in body weight, serum level of SOD, and mRNA and protein expression levels of Smad7 (P<0.01), as well as increases in liver and spleen indices, serum levels of ALT, AST, MDA, HA, LN, PCⅢ, Ⅳ-C, TNF-α, TGF-β1, IL-1β, and IL-6, levels of α-SMA and CollagenⅠ in liver tissue, mRNA and protein expression levels of NF-κB, TGF-β1, and Smad3 in liver tissue (P<0.01). Compared with the model group, all drug groups showed increases in body weight, serum levels of SOD, and mRNA and protein expression levels of Smad7 (P<0.05, P<0.01), along with decreases in liver and spleen indices, serum levels of ALT, AST, MDA, HA, LN, PCⅢ, Ⅳ-C, TNF-α, TGF-β1, IL-1β, and IL-6, levels of α-SMA and CollagenⅠ in liver tissue, as well as mRNA and protein expression levels of NF-κB, TGF-β1, and Smad3 in liver tissue (P<0.05, P<0.01). Compared with the colchicine group, the low- and medium-dose EEPU groups exhibited decreases in body weight and serum level of SOD (P<0.01), along with increases in liver and spleen indices, serum levels of ALT, AST, MDA, HA, LN, PCⅢ, Ⅳ-C, TNF-α, TGF-β1, IL-1β, and IL-6, as well as expression levels of α-SMA and CollagenⅠ in liver tissue (P<0.05, P<0.01). Furthermore, the low-dose EEPU group showed increases in mRNA and protein expression levels of NF-κB, TGF-β1, and Smad3 (P<0.01), along with decreases in those of Smad7 (P<0.01), whereas the high-dose EEPU group showed decreases in mRNA and protein expression levels of NF-κB, TGF-β1, and Smad3 (P<0.01) and increases in those of Smad7 (P<0.01). Compared with the low-dose EEPU group, the medium- and high-dose EEPU groups demonstrated increases in body weight, serum level of SOD, and mRNA and protein expression levels of Smad7 (P<0.01), decreases in liver and spleen indices, serum levels of ALT, AST, MDA, HA, LN, PCⅢ, Ⅳ-C, TNF-α, TGF-β1, IL-1β, and IL-6, levels of α-SMA and CollagenⅠ in liver tissue, as well as mRNA and protein expression levels of NF-κB, TGF-β1, and Smad3 in liver tissue (P<0.05, P<0.01). Compared with the medium-dose EEPU group, the high-dose EEPU group showed increases in body weight, serum level of SOD, and mRNA and protein expression levels of Smad7 (P<0.05, P<0.01), along with decreases in liver and spleen indices, serum levels of ALT, AST, MDA, HA, LN, PCⅢ, Ⅳ-C, TNF-α, TGF-β1, IL-1β, and IL-6, levels of α-SMA and CollagenⅠ in liver tissue, mRNA and protein expression levels of NF-κB, TGF-β1, and Smad3 in liver tissue (P<0.05, P<0.01). Conclusion EEPU effectively ameliorates CCl4-induced HF in rats by modulating the NF-κB/TGF-β1/Smad signaling pathway, enhancing antioxidant capacity, alleviating inflammatory response and liver damage, and inhibiting hepatic stellate cells activation and collagen deposition. |
| Key words: Yexiazhu (Phyllanthus Urinaria) hepatic fibrosis antioxidant inflammatory cytokines NF-κB/TGF-β1/Smad signaling pathway |
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