台湾“三金四壳”汤剂治疗肝纤维化研究
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摘要
目的：
为了科学评价台湾“三金四壳”汤剂在治疗肝纤维化中的疗效,通过基础实验体外评价”三金四壳”汤剂对大鼠肝星状细胞HSC-T6活化的影响和对HepG2.215细胞中乙型肝炎病毒分泌两抗和病毒DNA合成的影响,初步探讨“三金四壳”汤剂治疗肝纤维化的作用机制。同时在开展基础实验评价时,结合“三金四壳”汤剂在治疗肝纤维中临床疗效观察,系统、客观地评价“三金四壳”汤剂对肝纤维化的治疗作用,为中华传统中药在肝纤维治疗和运用提供理论数据和临床经验。
方法：
“三金四壳”汤剂的疗效评价通过体外基础实验和临床疗效观察两部分组成。
在体外基础实验中选取了大鼠肝星状细胞HSC-T6和人肝癌细胞HepG2.215两种细胞模型。其中以大鼠肝星状细胞HSC-T6细胞模型观察“三金四壳”汤剂的抗肝纤维化作用,以人肝癌细胞HepG2.215细胞观察“三金四壳”汤剂体外抗乙型肝炎病毒作用。首先利用CCK-8检测试剂盒动态绘制HSC-T6细胞和HepG2.215细胞的的生长曲线,求出最佳实验周期和检测时间。通过CCK-8试剂盒检测“三金四壳”汤剂在HSC-T6细胞和HepG2.215细胞上的半数毒性浓度TC50,求出后续实验的最佳药物实验浓度。在HSC-T6细胞模型上,以肝纤维化经典信号通路TGF-β/Smad作为研究对象,通过荧光相对定量PCR检测法检测“三金四壳”汤剂对HSC-T6细胞中TGF-β mRNA转录水平的影响；其次再利用流式细胞计数检测“三金四壳”汤剂对HSC-T6细胞上TGF-p受体表达的影响；最后再通过Western blot蛋白免疫技术检测“三金四壳”汤剂对HSC-T6细胞中SMAD蛋白的表达水平的影响。由于临床上乙型肝炎患者通常也伴随肝纤维化的发生,因此在体外抗肝纤维化的基础研究中,加选了人肝癌细胞HepG2.215细胞模型,以观察“三金四壳”汤剂对乙型肝炎病毒的影响。先通过动态测定HepG2.215细胞病毒HBsAg和HBeAg两种病毒抗原的分泌规律,以及HBV DNA合成规律,选取最佳实验周期和检测时间。在“三金四壳”的半数毒性浓度TC50下,以ELISA酶联免疫法检测“三金四壳”汤剂对HepG2.215细胞上病毒表面抗原HBsAg和e抗原HBeAg分泌的抑制作用,利用荧光定量PCR法检测“三金四壳”汤剂对HepG2.215细胞内病毒HBV DNA合成的影响。
在临床研究方面,根据2008年7月至2012年12月从台湾林源泉中医诊所、保安堂中医诊所和健安堂中医诊所收治的28例肝纤维患者中,通过中医病征评分标准对患者进行治疗前各肝纤维临床病征评分,并根据中医临床诊断标准对患者进行中医分型。以“三金四壳”作为基础方,根据对证治疗、根据患者病征特性及疾病发展进程、中医分型等给予患者为期4-18个疗程的“三金四壳”汤剂作为治疗手段。“三金四壳”汤剂临床疗效的评价选取了中医疗效评价标准和西医疗效评价标准两个方面。在中医疗效方面,通过综合对各病征积分评分标准治疗前与治疗后的积分改变,以尼莫地平法计算出“三金四壳”汤剂对患者肝纤维病征改善程度,结果分别以显效、有效、无效表示“三金四壳”汤剂的总体疗效。其次通过观察“三金四壳”汤剂对肝病中各种病征程度的改善程度,观察“三金四壳”汤剂对肝病中各种病征的影响,尤其是对腹水患者腹水程度改善的影响。在评价“三金四壳”汤剂的西医疗效方面,通过检测患者血清中AST、ALT、TBil和ALP评估患者肝功能；检测患者血清中HA、 LN和PCⅢ水平,通过治疗前与治疗后各检测项目数值变化,最终结果以尼莫地平法分别按显效、有效和无效表示。
结果：
通过基础实验研究和临床疗效观察的初步结果显示,“三金四壳”汤剂对肝纤维具有良好的抑制作用。
HSC-T6细胞为雄性SD大鼠肝星状细胞,是经SV40转染了T抗原的永生细胞株,体外培养中能规律性分泌多种细胞因子和表达多种受体,是体外抗肝纤维化药物研究的重要细胞模型。在本研究中,根据HSC-T6细胞的生长规律和TGF-β分泌规律选择适宜的实验周期(4天),通过对HSC-T6细胞的TGF-β转录水平、HSC-T6细胞TGF-p受体表达和SMAD蛋白的表达来评价“三金四壳”汤剂抗肝纤维的疗效。通过初步实验结果得出：①与脂多糖模型组相比,“三金四壳”汤剂在100mg/ml和25mg/ml浓度下对TGF-β1的转录水平有较好的抑制作用,其中25mg/ml浓度效果最佳(P<0.01)；②在流式结果中显示,“三金四壳”汤剂对HSC-T6细胞上的TGF-β1受体无明显影响,结果显示在实验中各剂量组对HSC-T6细胞的TGF-β1受体均无统计学差异(P>0.05)；③在观察“三金四壳”汤剂对SMAD蛋白表达的影响中,选取了正性调节蛋白SMAD3和负性调节蛋白SMAD7作为研究靶点。根据Western blot初步结果显示,“三金四壳”汤剂主要针对SMAD7蛋白的表达,而对SMAD3蛋白的表达影响不大(P<0.05)。提示“三金四壳”汤剂主要是通过下调SMAD7蛋白,间接调节SMAD7/SMAD3比例来发挥临床抗肝纤维化作用。
抗乙型肝炎病毒研究方面,选用携带HBV全基因序列并能完整、稳定分泌乙型肝炎病毒表面抗原HBsAg和e抗原HBeAg的人肝癌细胞HepG2.215作为“三金四壳”汤剂体外抗乙型肝炎病毒药效评价模型。利用酶链免疫ELISA法观察“三金四壳”汤剂对HepG2.215细胞的HBsAg和HBeAg分泌的影响、荧光定量PCR法观察“三金四壳”汤剂对HBV DNA表达的影响。根据初步实验结果可见,“三金四壳”汤剂在HepG2.215细胞上对HBsAg和HBeAg抗原的半数抑制浓度分别为133.67mg/ml和129.99mg/ml,对应的治疗指数TI分别为1.57、1.62,显示“三金四壳”汤剂对HepG2.215细胞两抗的分泌有一定的抑制作用,但这些抑制作用基于“三金四壳”汤剂对细胞的毒性作用。在对病毒DNA合成的影响中发现,“三金四壳”汤剂在仅在200mg/ml浓度下(接近TC50)对病毒DNA合成有一定的抑制作用,其抑制率为43.27%(<50%),间接提示“三金四壳”汤剂对病毒DNA合成作用影响较弱。综上所述,“三金四壳”的生物疗效主要在于抗肝纤维化,对乙型肝炎仅存在有限的抑制作用。其中,“三金四壳”汤剂在体外主要对肝星状细胞中TGF-β/Smad信号通路发挥其抗纤维化作用,而对乙型肝炎病毒的复制仅在毒性浓度下对病毒DNA的合成有一定的抑制作用。
在“三金四壳”汤剂临床疗效观察中,收治中医诊所肝纤维化病人共28例。其中男性20例,女性8例,男女比例为5:2。最大年龄为84岁,最小年龄为33岁,平均年龄为58岁。其中肝硬化腹水患者12例,肝癌患者5例,酒精性肝炎2例,病毒性肝炎8例,急性肝炎1例。在接诊的28例的肝纤维患者中,接受疗程从4个疗程到18个疗程不等。除1例肝病代偿期患者在接受4个疗程后离世外,其余患者均生存在世。根据“三金四壳”临床疗效评价的初步结果显示,“三金四壳”汤剂无论是从中医诊断标准还是从西医诊断标准上对肝纤维的治疗均存在良好的治疗效果。
从中医评价标准来说,“三金四壳”总疗效为96.43%,在28例中显效5例,占17.86%,有效为22例,占78.57%。从“三金四壳”汤剂对肝纤患者各中医病征的疗效结果看来,“三金四壳”汤剂对纳差、口苦等两种病征效果较佳,二者的有效率均为100%。其后从疗效的强弱来看,依次为肋痛>腰酸>肝脾肿大>乏力>肢寒>腹胀>溏便>水肿>面色>发热>肝掌,对蜘蛛痣和消化道出血病征的疗效最差,两者均为60%。另外在针对肝纤腹水患者的治疗中发现,在接受“三金四壳”汤剂治疗6个疗程以上者,其腹水程度与治疗前明显减轻,腹围差增大,其疗效与接受治疗的疗程长短有关。综合利用尼莫地平法计算得出“三金四壳”汤剂在治疗腹水证中,对体重比和腹诊的疗效最佳,均为83.33%；其次为腹围比(有效率为75%),最差为腹水程度58.33%。从西医评价标准来看,根据“三金四壳”汤剂对肝纤指标和肝功指标的总体综合评价结果所显示,在28例肝纤维化患者“三金四壳”汤剂的总有效率为85.71%。其中显效2例(7.14%),有效22例(78.57%),无效4例(14.29%)。在肝功能疗效评价结果中显示,“三金四壳”汤剂对ALT的治疗作用最好,与治疗前对比,患者ALT数值下降61.16%,其次为AST(下降48.57%)、TBiL(下降42.33%)、ALP(下降35.14%)。对患者血清肝纤指标中,能有效降低HA、LN和PCⅢ均值。与治疗前相比,经“三金四壳”汤剂治疗后HA下降52.17%、LN下降42.86%、PCⅢ下降44.51%,显示“三金四壳”汤剂在治疗肝纤维化中具有保护肝脏、改善肝功、延缓肝纤维发展等作用。
结论:
“三金四壳”汤剂对肝纤维具有良好的抑制作用,能显著显著降低患者HA、LN和PCIII水平；同时能调节患者血清中ALT、AST、TBiL及ALP分泌水平,具有良好的保肝、护肝、延缓肝纤维发展作用；但对病毒性肝炎无明显的抑制病毒作用,推断“三金四壳”汤剂能改善病毒性肝炎患者的肝纤维症状可能是通过调节患者机体免疫水平而发挥其抗肝纤维作用的。
Objective:
To study the anti-hepatic fibrosis mechanism of "San Jin Si Ke" Chinese herb soup (SJSK for short) and the clinical curative effect, we observed the anti-hepatic fibrosis effect of SJSK soup through the study in vitro and in clinical.
Methods:
The evaluation of curative effect on anti-hepatic fibrosis of SJSK soup consisted of two parts:in vitro on basic study and evaluation in clinical.
In vitro on basic study, we investigated the anti-hepatic fibrosis mechanism of SJSK soup by the model of HSC-T6cell line, and the anti-virus effect on hepatic B virus by the HepG2.215cell line. The cellular signal pathway of TGF-β/SMAD was a classical pathway in hepatic fibrosis, so we evaluated the anti-hepatic fibrosis effect through three parts:the SJSK soup effect on the TGF-β gene transcription level, the effect on the expression level of TGF-β receptor and the effect on expression of SMAD protein. We detected the mRNA transcription level by Real-time PCR, and detected the expression level of TGF-β receptor by flow cytometry and the expression of SMAD protein by Western blot in the study. On the model of HepG2.215cell line, we detected the secretion level of HBsAg and HBeAg by ELISA, and the hepatic B virus DNA synthesize level by Real-time PCR method.
In clinical, we observed the28cases of patients with hepatic fibrosis. Those patients were collected from Linyuanquan clinic, Bao'antang clinic and Jian'antang clinic between2008to2012. We observed the development of the symptoms changed in the treatment with SJSK soup for more than4months, and compared the results between the pre-treatment and after-treatment with SJSK soup by the Nimodipine method. We took the SJSK soup as a basic prescription, adjusted others Chinese herbs according to the symptoms differed from TCM type. On the other hand,we also observed the clinical effect of the hepatic function and the degreed of hepatic fibrosis by testing the patients'serum, including HA,LN,PCⅢ, AST,ALT and so on.
Result:
According to the primary study of the SJSK soup in the treatment with hepatic fibrosis, we found that the SJSK soup had a good effect on anti-hepatic fibrosis both in vitro basic study and in clinical observation.
In the vitro basic study of the SJSK soup on HSC-T6model, we found that the SJSK soup impacted the TGF-β/Smad pathway by decreasing the transcription level of TGF-β and adjustment the SMAD protein level, but not impacted the TGF-β receptor. The TC50of SJSK soup on HSC-T6was114.51mg/ml, at the concentration of100mg/ml and25mg/ml, the SJSK soup would reduce the TGF-β transcription level and the expression level of SMAD7. On the HepG2.215cell line, the TC50of the SJSK soup was210.21mg/ml, the IC50of HBsAg and HBeAg was133.67mg/ml,129.99mg/ml respectively. The treatment index (TI) was1.57and1.62respectively which showed that the SJSK soup had some effect on anti-hepatic virus by decreasing the secretion of HBsAg and HBeAg. But on the study of the synthesis of viral, the result showed that the SJSK had little effect on limitation of viral DNA duplication.
On the observation of the curative effect of SJSK soup, we found that the SJSK soup would develop the hepatic function and improved the hepatic fibrosis level. In the improvement of the hepatic symptoms, the sequence from best to worst was as below:rib pain>backache>hepatosplenomegaly>fatigue>cold body>bloating>loose stools> edma>development of complexion>fever>hepatic palms. The total efficiency rate of clinical effect was96.55%. And with the treatment of SJSK soup for more than4months, the patients with ascites mitigated the degree of ascites. Compare with the results of pre-treatment, the ALT, AST, TBil and ALP all decrease to61.16%,48.57%,42.33%and35.14%respectively. The level of HA, LN, and PCIII decrease to52.17%,42.86%and44.51%.
Conclusion:
The SJSK soup had a good effect on anti-hepatic fibrosis by decrease the HA,LN, PCIII,ALT, AST and so on in the patients'serum, which indicated that the SJSK soup would protect the liver from damage and improve the hepatic function, prolonged the hepatic fibrosis development.
为了科学评价台湾“三金四壳”汤剂在治疗肝纤维化中的疗效,通过基础实验体外评价”三金四壳”汤剂对大鼠肝星状细胞HSC-T6活化的影响和对HepG2.215细胞中乙型肝炎病毒分泌两抗和病毒DNA合成的影响,初步探讨“三金四壳”汤剂治疗肝纤维化的作用机制。同时在开展基础实验评价时,结合“三金四壳”汤剂在治疗肝纤维中临床疗效观察,系统、客观地评价“三金四壳”汤剂对肝纤维化的治疗作用,为中华传统中药在肝纤维治疗和运用提供理论数据和临床经验。
方法：
“三金四壳”汤剂的疗效评价通过体外基础实验和临床疗效观察两部分组成。
在体外基础实验中选取了大鼠肝星状细胞HSC-T6和人肝癌细胞HepG2.215两种细胞模型。其中以大鼠肝星状细胞HSC-T6细胞模型观察“三金四壳”汤剂的抗肝纤维化作用,以人肝癌细胞HepG2.215细胞观察“三金四壳”汤剂体外抗乙型肝炎病毒作用。首先利用CCK-8检测试剂盒动态绘制HSC-T6细胞和HepG2.215细胞的的生长曲线,求出最佳实验周期和检测时间。通过CCK-8试剂盒检测“三金四壳”汤剂在HSC-T6细胞和HepG2.215细胞上的半数毒性浓度TC50,求出后续实验的最佳药物实验浓度。在HSC-T6细胞模型上,以肝纤维化经典信号通路TGF-β/Smad作为研究对象,通过荧光相对定量PCR检测法检测“三金四壳”汤剂对HSC-T6细胞中TGF-β mRNA转录水平的影响；其次再利用流式细胞计数检测“三金四壳”汤剂对HSC-T6细胞上TGF-p受体表达的影响；最后再通过Western blot蛋白免疫技术检测“三金四壳”汤剂对HSC-T6细胞中SMAD蛋白的表达水平的影响。由于临床上乙型肝炎患者通常也伴随肝纤维化的发生,因此在体外抗肝纤维化的基础研究中,加选了人肝癌细胞HepG2.215细胞模型,以观察“三金四壳”汤剂对乙型肝炎病毒的影响。先通过动态测定HepG2.215细胞病毒HBsAg和HBeAg两种病毒抗原的分泌规律,以及HBV DNA合成规律,选取最佳实验周期和检测时间。在“三金四壳”的半数毒性浓度TC50下,以ELISA酶联免疫法检测“三金四壳”汤剂对HepG2.215细胞上病毒表面抗原HBsAg和e抗原HBeAg分泌的抑制作用,利用荧光定量PCR法检测“三金四壳”汤剂对HepG2.215细胞内病毒HBV DNA合成的影响。
在临床研究方面,根据2008年7月至2012年12月从台湾林源泉中医诊所、保安堂中医诊所和健安堂中医诊所收治的28例肝纤维患者中,通过中医病征评分标准对患者进行治疗前各肝纤维临床病征评分,并根据中医临床诊断标准对患者进行中医分型。以“三金四壳”作为基础方,根据对证治疗、根据患者病征特性及疾病发展进程、中医分型等给予患者为期4-18个疗程的“三金四壳”汤剂作为治疗手段。“三金四壳”汤剂临床疗效的评价选取了中医疗效评价标准和西医疗效评价标准两个方面。在中医疗效方面,通过综合对各病征积分评分标准治疗前与治疗后的积分改变,以尼莫地平法计算出“三金四壳”汤剂对患者肝纤维病征改善程度,结果分别以显效、有效、无效表示“三金四壳”汤剂的总体疗效。其次通过观察“三金四壳”汤剂对肝病中各种病征程度的改善程度,观察“三金四壳”汤剂对肝病中各种病征的影响,尤其是对腹水患者腹水程度改善的影响。在评价“三金四壳”汤剂的西医疗效方面,通过检测患者血清中AST、ALT、TBil和ALP评估患者肝功能；检测患者血清中HA、 LN和PCⅢ水平,通过治疗前与治疗后各检测项目数值变化,最终结果以尼莫地平法分别按显效、有效和无效表示。
结果：
通过基础实验研究和临床疗效观察的初步结果显示,“三金四壳”汤剂对肝纤维具有良好的抑制作用。
HSC-T6细胞为雄性SD大鼠肝星状细胞,是经SV40转染了T抗原的永生细胞株,体外培养中能规律性分泌多种细胞因子和表达多种受体,是体外抗肝纤维化药物研究的重要细胞模型。在本研究中,根据HSC-T6细胞的生长规律和TGF-β分泌规律选择适宜的实验周期(4天),通过对HSC-T6细胞的TGF-β转录水平、HSC-T6细胞TGF-p受体表达和SMAD蛋白的表达来评价“三金四壳”汤剂抗肝纤维的疗效。通过初步实验结果得出：①与脂多糖模型组相比,“三金四壳”汤剂在100mg/ml和25mg/ml浓度下对TGF-β1的转录水平有较好的抑制作用,其中25mg/ml浓度效果最佳(P<0.01)；②在流式结果中显示,“三金四壳”汤剂对HSC-T6细胞上的TGF-β1受体无明显影响,结果显示在实验中各剂量组对HSC-T6细胞的TGF-β1受体均无统计学差异(P>0.05)；③在观察“三金四壳”汤剂对SMAD蛋白表达的影响中,选取了正性调节蛋白SMAD3和负性调节蛋白SMAD7作为研究靶点。根据Western blot初步结果显示,“三金四壳”汤剂主要针对SMAD7蛋白的表达,而对SMAD3蛋白的表达影响不大(P<0.05)。提示“三金四壳”汤剂主要是通过下调SMAD7蛋白,间接调节SMAD7/SMAD3比例来发挥临床抗肝纤维化作用。
抗乙型肝炎病毒研究方面,选用携带HBV全基因序列并能完整、稳定分泌乙型肝炎病毒表面抗原HBsAg和e抗原HBeAg的人肝癌细胞HepG2.215作为“三金四壳”汤剂体外抗乙型肝炎病毒药效评价模型。利用酶链免疫ELISA法观察“三金四壳”汤剂对HepG2.215细胞的HBsAg和HBeAg分泌的影响、荧光定量PCR法观察“三金四壳”汤剂对HBV DNA表达的影响。根据初步实验结果可见,“三金四壳”汤剂在HepG2.215细胞上对HBsAg和HBeAg抗原的半数抑制浓度分别为133.67mg/ml和129.99mg/ml,对应的治疗指数TI分别为1.57、1.62,显示“三金四壳”汤剂对HepG2.215细胞两抗的分泌有一定的抑制作用,但这些抑制作用基于“三金四壳”汤剂对细胞的毒性作用。在对病毒DNA合成的影响中发现,“三金四壳”汤剂在仅在200mg/ml浓度下(接近TC50)对病毒DNA合成有一定的抑制作用,其抑制率为43.27%(<50%),间接提示“三金四壳”汤剂对病毒DNA合成作用影响较弱。综上所述,“三金四壳”的生物疗效主要在于抗肝纤维化,对乙型肝炎仅存在有限的抑制作用。其中,“三金四壳”汤剂在体外主要对肝星状细胞中TGF-β/Smad信号通路发挥其抗纤维化作用,而对乙型肝炎病毒的复制仅在毒性浓度下对病毒DNA的合成有一定的抑制作用。
在“三金四壳”汤剂临床疗效观察中,收治中医诊所肝纤维化病人共28例。其中男性20例,女性8例,男女比例为5:2。最大年龄为84岁,最小年龄为33岁,平均年龄为58岁。其中肝硬化腹水患者12例,肝癌患者5例,酒精性肝炎2例,病毒性肝炎8例,急性肝炎1例。在接诊的28例的肝纤维患者中,接受疗程从4个疗程到18个疗程不等。除1例肝病代偿期患者在接受4个疗程后离世外,其余患者均生存在世。根据“三金四壳”临床疗效评价的初步结果显示,“三金四壳”汤剂无论是从中医诊断标准还是从西医诊断标准上对肝纤维的治疗均存在良好的治疗效果。
从中医评价标准来说,“三金四壳”总疗效为96.43%,在28例中显效5例,占17.86%,有效为22例,占78.57%。从“三金四壳”汤剂对肝纤患者各中医病征的疗效结果看来,“三金四壳”汤剂对纳差、口苦等两种病征效果较佳,二者的有效率均为100%。其后从疗效的强弱来看,依次为肋痛>腰酸>肝脾肿大>乏力>肢寒>腹胀>溏便>水肿>面色>发热>肝掌,对蜘蛛痣和消化道出血病征的疗效最差,两者均为60%。另外在针对肝纤腹水患者的治疗中发现,在接受“三金四壳”汤剂治疗6个疗程以上者,其腹水程度与治疗前明显减轻,腹围差增大,其疗效与接受治疗的疗程长短有关。综合利用尼莫地平法计算得出“三金四壳”汤剂在治疗腹水证中,对体重比和腹诊的疗效最佳,均为83.33%；其次为腹围比(有效率为75%),最差为腹水程度58.33%。从西医评价标准来看,根据“三金四壳”汤剂对肝纤指标和肝功指标的总体综合评价结果所显示,在28例肝纤维化患者“三金四壳”汤剂的总有效率为85.71%。其中显效2例(7.14%),有效22例(78.57%),无效4例(14.29%)。在肝功能疗效评价结果中显示,“三金四壳”汤剂对ALT的治疗作用最好,与治疗前对比,患者ALT数值下降61.16%,其次为AST(下降48.57%)、TBiL(下降42.33%)、ALP(下降35.14%)。对患者血清肝纤指标中,能有效降低HA、LN和PCⅢ均值。与治疗前相比,经“三金四壳”汤剂治疗后HA下降52.17%、LN下降42.86%、PCⅢ下降44.51%,显示“三金四壳”汤剂在治疗肝纤维化中具有保护肝脏、改善肝功、延缓肝纤维发展等作用。
结论:
“三金四壳”汤剂对肝纤维具有良好的抑制作用,能显著显著降低患者HA、LN和PCIII水平；同时能调节患者血清中ALT、AST、TBiL及ALP分泌水平,具有良好的保肝、护肝、延缓肝纤维发展作用；但对病毒性肝炎无明显的抑制病毒作用,推断“三金四壳”汤剂能改善病毒性肝炎患者的肝纤维症状可能是通过调节患者机体免疫水平而发挥其抗肝纤维作用的。
Objective:
To study the anti-hepatic fibrosis mechanism of "San Jin Si Ke" Chinese herb soup (SJSK for short) and the clinical curative effect, we observed the anti-hepatic fibrosis effect of SJSK soup through the study in vitro and in clinical.
Methods:
The evaluation of curative effect on anti-hepatic fibrosis of SJSK soup consisted of two parts:in vitro on basic study and evaluation in clinical.
In vitro on basic study, we investigated the anti-hepatic fibrosis mechanism of SJSK soup by the model of HSC-T6cell line, and the anti-virus effect on hepatic B virus by the HepG2.215cell line. The cellular signal pathway of TGF-β/SMAD was a classical pathway in hepatic fibrosis, so we evaluated the anti-hepatic fibrosis effect through three parts:the SJSK soup effect on the TGF-β gene transcription level, the effect on the expression level of TGF-β receptor and the effect on expression of SMAD protein. We detected the mRNA transcription level by Real-time PCR, and detected the expression level of TGF-β receptor by flow cytometry and the expression of SMAD protein by Western blot in the study. On the model of HepG2.215cell line, we detected the secretion level of HBsAg and HBeAg by ELISA, and the hepatic B virus DNA synthesize level by Real-time PCR method.
In clinical, we observed the28cases of patients with hepatic fibrosis. Those patients were collected from Linyuanquan clinic, Bao'antang clinic and Jian'antang clinic between2008to2012. We observed the development of the symptoms changed in the treatment with SJSK soup for more than4months, and compared the results between the pre-treatment and after-treatment with SJSK soup by the Nimodipine method. We took the SJSK soup as a basic prescription, adjusted others Chinese herbs according to the symptoms differed from TCM type. On the other hand,we also observed the clinical effect of the hepatic function and the degreed of hepatic fibrosis by testing the patients'serum, including HA,LN,PCⅢ, AST,ALT and so on.
Result:
According to the primary study of the SJSK soup in the treatment with hepatic fibrosis, we found that the SJSK soup had a good effect on anti-hepatic fibrosis both in vitro basic study and in clinical observation.
In the vitro basic study of the SJSK soup on HSC-T6model, we found that the SJSK soup impacted the TGF-β/Smad pathway by decreasing the transcription level of TGF-β and adjustment the SMAD protein level, but not impacted the TGF-β receptor. The TC50of SJSK soup on HSC-T6was114.51mg/ml, at the concentration of100mg/ml and25mg/ml, the SJSK soup would reduce the TGF-β transcription level and the expression level of SMAD7. On the HepG2.215cell line, the TC50of the SJSK soup was210.21mg/ml, the IC50of HBsAg and HBeAg was133.67mg/ml,129.99mg/ml respectively. The treatment index (TI) was1.57and1.62respectively which showed that the SJSK soup had some effect on anti-hepatic virus by decreasing the secretion of HBsAg and HBeAg. But on the study of the synthesis of viral, the result showed that the SJSK had little effect on limitation of viral DNA duplication.
On the observation of the curative effect of SJSK soup, we found that the SJSK soup would develop the hepatic function and improved the hepatic fibrosis level. In the improvement of the hepatic symptoms, the sequence from best to worst was as below:rib pain>backache>hepatosplenomegaly>fatigue>cold body>bloating>loose stools> edma>development of complexion>fever>hepatic palms. The total efficiency rate of clinical effect was96.55%. And with the treatment of SJSK soup for more than4months, the patients with ascites mitigated the degree of ascites. Compare with the results of pre-treatment, the ALT, AST, TBil and ALP all decrease to61.16%,48.57%,42.33%and35.14%respectively. The level of HA, LN, and PCIII decrease to52.17%,42.86%and44.51%.
Conclusion:
The SJSK soup had a good effect on anti-hepatic fibrosis by decrease the HA,LN, PCIII,ALT, AST and so on in the patients'serum, which indicated that the SJSK soup would protect the liver from damage and improve the hepatic function, prolonged the hepatic fibrosis development.
引文
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