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Title: [Effects of Anluohuaxianwan on transforming growth factor-β1 and related signaling pathways in rats with carbon tetrachloride-induced liver fibrosis].
Author: Lu W, Gao YH, Wang ZZ, Cai YS, Yang YQ, Miao YQ, Pei F, Liu XE, Zhuang H.
Journal: Zhonghua Gan Zang Bing Za Zhi; 2017 Apr 20; 25(4):257-262. PubMed ID: 28494543.
Abstract:
Objective: The traditional Chinese medicine Anluohuaxianwan (ALHXW) has been used to treat liver fibrosis induced by chronic hepatitis B virus (HBV) infection. However, the anti-fibrosis mechanisms of ALHXW remain to be investigated. This study used a rat model of carbon tetrachloride (CCl(4))-induced liver fibrosis to explore the potential antifibrogenic mechanisms of ALHXW. Methods: Twenty-seven male Wistar rats were randomly assigned to control group, model group, and treatment group (n = 9 per group). Rats in the model and treatment group were injected intraperitoneally with 40% CCl(4)(2 ml/kg), and rats in the control group were administered saline twice a week for 6 weeks. Starting at week 4 following model construction, rats in the treatment group received daily gavages with ALHXW solution (concentration 0.15 g/ml) daily, while rats in the control and model groups were given saline for a total of 6 weeks. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured from blood samples collected at the end of weeks 3, 6 and 9. Histopathological examination of liver tissue was performed to evaluate liver fibrosis at week 9. At the same time, the mRNA expression of TGF-β1 and Smads in liver tissues was quantified by real-time reverse transcription polymerase chain reaction (RT-PCR), and TGF-β1 protein level in the liver was measured by Western blot. Inter-group comparison was performed using analysis of variance (ANOVA) when the continuous data were normally distributed and satisfied the homogeneity of variance; otherwise, nonparametric tests were used. Categorical data were compared between groups using nonparametric tests. Results: ALHXW markedly alleviated liver injury in the treatment group after 3 weeks of therapy as indicated by a significantly reduced level of ALT compared with the model group [(162.98 ± 73.14)U/L vs (322.52 ± 131.76)U/L, P = 0.047], and a 39.8% reduction in AST level compared with the model group[ (537.56 ± 306.06)U/L vs (892.98 ± 358.19)U/L, P = 0.053]. Moreover, at the end of the 6-week therapy, histopathological diagnosis showed that liver fibrosis was significantly reduced in the ALHXW-treated group compared with that in the model group (P = 0.002). The relative expression of TGF-β1 mRNA and protein in the liver were significantly lower in ALHXW-treated rats than that in model rats (1.34 ± 0.31 vs 1.78 ± 0.45, P = 0.025; 0.39 ± 0.02 vs 0.57 ± 0.04, P = 0.003). Conclusion: ALHXW treatment can reverse CCl(4)-induced liver fibrosis in rats. Its mechanisms of anti-fibrosis may occur through the inhibition of TGF-β1 synthesis and TGF-β1/Smads signaling pathway, which in turn suppress the activation of hepatic stellate cells and thereby reverses fibrosis. 目的： 中成药安络化纤丸已应用于临床治疗慢性乙型肝炎导致的肝纤维化，但其逆转肝纤维化的机制未明确。本研究利用四氯化碳（CCl(4)）诱导的大鼠肝纤维化模型，探索安络化纤丸抗纤维化的可能机制。 方法： 27只雄性wistar大鼠随机分为对照组、模型组和治疗组（n = 9），其中模型组和治疗组大鼠腹腔注射40% CCl(4) 2 ml/kg、对照组大鼠腹腔注射等渗盐水，每周2次、共6周。从建模第4周开始，治疗组大鼠每日灌胃安络化纤丸溶液（浓度为0.15 g/ml），其他两组大鼠灌胃等渗盐水，共6周。治疗3周和6周取血检测丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）。治疗6周结束后，取大鼠肝组织进行病理组织学评价，同时用荧光定量PCR法检测肝组织转化生长因子β1（TGFβ1）和Smads基因mRNA表达水平，用蛋白印迹法检测TGFβ1蛋白表达水平。计量资料是正态分布且满足方差齐性检验，多组间比较采用单因素方差分析；否则多组间比较采用非参数检验。等级资料多组间比较，采用非参数检验。 结果： 安络化纤丸治疗3周后，肝细胞损害减轻，治疗组大鼠ALT水平较模型组显著降低，（162.98±73.14）U/L对比（322.52±131.76）U/L，P = 0.047；AST水平较模型组下降39.8%，（537.56±306.06）U/L对比（892.98±358.19）U/L，P = 0.053。安络化纤丸治疗6周后，治疗组大鼠肝纤维化程度较模型组有显著改善（P = 0.002）。治疗组大鼠TGFβ1基因mRNA和蛋白相对表达水平显著低于模型组（1.34±0.31对比1.78±0.45，P = 0.025；0.39±0.02对比0.57±0.04，P = 0.003），差异均有统计学意义。 结论： 安络化纤丸能够逆转CCl(4)诱导的大鼠肝纤维化，其作用机制可能通过影响TGFβ1产生，从而抑制肝星状细胞激活而发挥抗肝纤维化作用。.

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