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复方茵丹汤对急性肝内胆汁淤积大鼠肝组织法尼醇受体及多耐药相关蛋白3表达的影响
Effect of Compound Yindan Decoction on the expression of farnesoid X receptor and multidrug resistance-associated protein 3 in rats with acute intrahepatic cholestasis
文章发布日期:2018年08月06日  来源:  作者:隋京利,孙凤霞,李晓玲,等  点击次数:262次  下载次数:14次

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【摘要】:目的研究复方茵丹汤对α-萘异硫氰酸酯(ANIT)诱导的大鼠急性肝内胆汁淤积的作用机制。方法将108只雄性SD大鼠随机分为正常对照组,模型组,中药复方茵丹汤高、中、低剂量组和阳性药对照组,每组18只,依据取材时间不同又将各组随机分为24、48、72 h 3个亚组,每组6只。模型组、中药组、阳性药对照组大鼠一次性给予2%ANIT按100 mg·kg-1·d-1灌胃造模,正常对照组予等容积色拉油灌胃。造模2 h后,中药高、中、低剂量组分别给予生药含量为24.48 g·kg-1·d-1、12.24 g·kg-1·d-1和6.12 g·kg-1·d-1的复方茵丹汤中药煎剂l ml/100 g体质量灌胃,模型组和正常对照组给予等容积生理盐水灌胃,阳性药对照组给予67.5 mg·kg-1·d-1熊去氧胆酸(UDCA)水溶液l ml/100 g体质量灌胃,均1次/d。造模后分别于24、48、72 h处死相应时相大鼠,采用RT-q-PCR、Western Blot和免疫组化技术检测法尼醇受体(FXR)及多耐药相关蛋白3(MRP3)在大鼠肝组织的表达水平。计量资料多组间比较采用单因素方差分析,进一步两两比较采用LSD-t检验。结果RT-q-PCR结果显示,与同时相正常组比较,模型组 FXR mRNA表达均明显降低(P值均<0.05);与同时相模型组比较,中药各剂量组及UDCA组FXR mRNA表达明显升高(P值均<0.05);中药高剂量组各时相FXR mRNA表达明显高于中、低剂量组(P值均<0.05)。与同时相正常组比较,模型组MRP3 mRNA表达均显著升高(P值均<0.05);与同时相模型组比较,除低剂量组24 h外,中药各剂量组及UDCA组MRP3 mRNA表达均明显升高(P值均<0.05);中药高剂量组48 h、72 h的MRP3 mRNA表达均明显高于中、低剂量组(P值均<0.05)。免疫组化结果显示,与同时相正常组比较,模型组FXR蛋白表达均显著降低(P值均<0.05);与模型组比较,24 h中药各剂量组及各时相UDCA组FXR蛋白表达均显著升高(P值均<0.05);中药高剂量组FXR蛋白表达明显高于同时相中、低剂量组和模型组(P值均<0.05)。与同时相正常组比较,模型组MRP3蛋白表达显著升高(P值均<0.05);与同时相模型组比较,除低剂量24 h外,中药各剂量组及UDCA组MRP3蛋白表达明显升高(P值均<0.05);中药高剂量组MRP3蛋白表达显著高于同时相低剂量组及72 h中剂量组(P值均<0.05)。Western Blot结果显示,与同时相正常组比较,模型组FXR蛋白表达均显著降低(P值均<0.05);与同时相模型组比较,中药各剂量组及UDCA组FXR蛋白表达均显著升高(P值均<0.05);中药高剂量组FXR蛋白表达均显著高于同时相中、低剂量组(P值均<0.05)。与同时相正常组比较,模型组MRP3蛋白表达均显著升高(P值均<0.05);与模型组比较,48 h及72 h中药中、高剂量组及UDCA组MRP3蛋白表达均明显升高(P值均<005);中药高剂量组48 h和72 h的MRP3蛋白表达均高于相应的中、低剂量组(P值均<0.05)。结论复方茵丹汤对ANIT灌胃诱导AIC大鼠的治疗作用可能与其上调FXR和MRP3基因、蛋白表达有关。
【Abstract】:ObjectiveTo investigate the mechanism of action of Compound Yindan Decoction on acute intrahepatic cholestasis induced by α-naphthyl isothiocyanate (ANIT) in rats. MethodsA total of 108 male Sprague-Dawley rats were randomly divided into normal control group, model group, high-, middle-, and low-dose traditional Chinese medicine (TCM) groups, and positive control group, with 18 rats in each group. According to the time of sampling, each group was divided into 24-hour, 48-hour, and 72-hour subgroups, with 6 rats in each subgroup. The model group, the TCM groups, and the positive control group were given a single dose of 2% ANIT (100 mg/kg/d) by gavage to establish the model, and the normal control group was given an equal volume of salad oil by gavage. At 2 hours after modeling, the high-, middle-, and low-dose TCM groups were given Compound Yindan Decoction 1 ml/100 g body weight once a day by gavage at a dose of 24.48 g·kg-1·d-1, 12.24 g·kg-1·d-1, and 6.12 g·kg-1·d-1; the model group and the normal control group were given an equal volume of normal saline once a day by gavage; the positive control group was given ursodeoxycholic acid (UDCA) solution 1 ml/100 g body weight once a day by gavage at a dose of 67.5 mg·kg-1·d-1. The rats were sacrificed at 24, 48, or 72 hours after modeling, and RT-q-PCR, Western blot, and immunohistochemistry were used to measure the expression of farnesoid X receptor (FXR) and multidrug resistance-associated protein 3 (MRP3) in liver tissue. A one-way analysis of variance was used for comparison between multiple groups, and LSD-t test was used for further comparison between two groups. ResultsAccording to the results of RT-q-PCR, compared with the normal control group at each time phase, the model group had a significant reduction in the mRNA expression of FXR (all P<005); compared with the model group at each time phase, all the TCM groups and the UDCA group had a significant increase in the mRNA expression of FXR (all P<0.05); the high-dose TCM group had significantly higher mRNA expression of FXR than the middle- and low-dose TCM groups at each time phase (all P<0.05). Compared with the normal control group at each time phase, the model group had a significant increase in the mRNA expression of MRP3 (all P<0.05); compared with the model group at each time phase, the UDCA group and all the TCM groups except the 24-hour low-dose TCM subgroup had a significant increase in the mRNA expression of MRP3 (all P<0.05); the 48- and 72-hour high-dose TCM subgroups had significantly higher mRNA expression of MRP3 than the middle- and low-dose TCM groups (all P<0.05). According to the results of immunohistochemistry, compared with the normal control group at each time phase, the model group had a significant reduction in the protein expression of FXR (all P<0.05); compared with the model group, the 24-hour high-, middle-, and low-dose TCM subgroups and the UDCA group at each time phase had a significant increase in the protein expression of FXR (all P<0.05); the high-dose TCM group had significantly higher protein expression of FXR than the middle- and low-dose TCM groups at each time phase (all P<0.05). Compared with the normal control group at each time phase, the model group had a significant increase in the protein expression of MRP3 (all P<0.05); compared with the model group at each time phase, the UDCA group and all the TCM groups except the 24-hour low-dose TCM subgroup had a significant increase in the protein expression of MRP3 (all P<0.05); the high-dose TCM group had significantly higher protein expression of MRP3 than the low-dose TCM group at each time phase and the 72-hour middle-dose TCM subgroup (all P<0.05). According to the results of Western blot, compared with the normal control group at each time phase, the model group had a significant reduction in the protein expression of FXR (all P<005); compared with the model group at each time phase, the high-, middle-, and low-dose TCM groups and the UDCA group had a significant increase in the protein expression of FXR (all P<0.05); the high-dose TCM group had significantly higher protein expression of FXR than the middle- and low-dose TCM groups at each time phase (all P<0.05). Compared with the normal control group at each time phase, the model group had a significant increase in the protein expression of MRP3 (all P<0.05); compared with the model group, the 48- and 72-hour middle- and high-dose TCM subgroups and the UDCA group had a significant increase in the protein expression of MRP3 (all P<0.05); at 48 and 72 hours, the high-dose TCM group had significantly higher protein expression of MRP3 than the middle- and low-dose TCM groups (all P<0.05). ConclusionCompound Yindan Decoction has a therapeutic effect on rats with acute intrahepatic cholestasis induced by ANIT through gavage, possibly by upregulating the mRNA and protein expression of FXR and MRP3.
【关键字】:胆汁淤积, 肝内; 法尼醇; 多耐药相关蛋白3; 大鼠, Sprague-Dawley
【Key words】:cholestasis, intrahepatic; farnesol; multidrug resistance-associated protein 3; rats, Sprague-Dawley
【引证本文】:SUI JL,SUN FX,LI XL,et al. Effect of Compound Yindan Decoction on the expression of farnesoid X receptor and multidrug resistance-associated protein 3 in rats with acute intrahepatic cholestasis[J]. J Clin Hepatol, 2018, 34(9): 1960-1966. (in Chinese)
隋京利, 孙凤霞, 李晓玲, 等. 复方茵丹汤对急性肝内胆汁淤积大鼠肝组织法尼醇受体及多耐药相关蛋3表达的影响[J]. 临床肝胆病杂志, 2018, 34(9): 1960-1966.

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