草苁蓉环烯醚萜苷对大鼠肝脏癌前病变保护机制的实验研究
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摘要
目的：
了解草苁蓉环烯醚萜苷(IGBR)对肝癌前病变的防治作用及IGBR对肝组织中凋亡相关蛋白、肝细胞生长因子(HGF)、转化生长因子β(TGF-β/smad)信号通路的关键蛋白以及金属蛋白酶(MMP)和组织金属蛋白抑制剂(TIMP)的表达水平的影响,探讨IGBR阻断癌前病变的机理。
方法：
将50只Wistar雄性大鼠适应性饲养一周后随机分为5个组,每组为10只,分别为假处理组、模型组、IGBR低剂量组、IGBR中剂量组、IGBR高剂量组。在实验开始第1天按0.1ml/100g给假处理组大鼠一次性腹腔注射生理盐水,并饲喂正常饲料共56天。余4组大鼠一次性经腹腔注射DEN200mg/kg,从第15天开始在饲料中添加0.008%乙酰氨基芴(AAF),同时IGBR低、中、高剂量3个组分别按125、250、500mg/kg剂量灌胃IGBR至第56天。在实验第22天将所有组的大鼠肝脏行70%切除,第56天处死大鼠。实验期间观察大鼠一般状态,体重变化；测肝脏重量,计算肝脏再生度；用比色法测定肝匀浆及肝脏线粒体中天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)、γ-谷氨酰转肽酶(γ-GT)、过氧化氢酶(CAT)、超氧化物岐化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)、谷胱甘肽S-转移酶(GST)活性及丙二醛(MDA)含量；用苏木精-伊红(HE)染色法,观察肝脏组织病理形态变化；用western blot法测定肝组织中HGF、bax、bcl-2、caspase-3、 TGF-β1、转化生长因子β1受体Ⅰ和Ⅱ(TPRⅠ、T3RⅡ)、smad2/3、smad4、 smad7、α-平滑肌肌动蛋白(α-SMA)、MMP-13、MMP-2、TIMP-1、TIMP-2蛋白的表达变化。
结果：
1.IGBR促进大鼠食欲,能改善大鼠的精神状态、皮毛色泽。各组大鼠间无明显体重变化,但模型组肝脏重量明显高于其它组(P<0.05)。IGBR具有降低肝再生度及肝再生指数的趋势,但无统计学意义。
2.组织病理学结果显示,模型组大鼠肝脏表面凹凸不平,质地硬,可见直径不等的结节,结节数明显多于其它组；HE染色结果显示,肝细胞失去正常排列,肝小叶结构消失,汇管区有以卵圆细胞为主的小细胞增生,纤维隔内有大量胶原沉积,有较明显纤维组织增生；肝细胞胞浆疏松,发生广泛的变性水肿,水样变性甚至气球样变性甚至灶状坏死,肝小叶中见嗜碱性肝细胞和玻璃样的透明肝细胞灶混合排列拥挤形成的肝细胞增生结节；IGBR干预后各剂量组大鼠肝脏较模型组表面光滑,边缘钝,灰白色结节较模型组减少；HE染色显示IGBR各剂量组大鼠肝小叶结构基本存在,可见嗜酸性细胞变性,肝细胞水肿较轻。有不同程度坏死灶,肝细胞异型性明显减少,病理性核分裂相减少,病变较轻。
3.模型组大鼠肝组织匀浆和肝脏线粒体中AST、ALT、γ-GT活性升高,解毒酶GST活性和MDA含量显著高于假处理组,SOD、CAT、GSH-PX活性显著低于假处理组；IGBR干预后可降低大鼠肝组织匀浆和肝脏线粒体中ALT、AST、γ-GT、GST活性和MDA含量,升高SOD、CAT、GSH-PX活性。
4.蛋白印迹实验结果显示,癌前病变大鼠肝组织中HGF、bcl-2、TGF-β1、 smad2/3、smad4、α-SMA、TIMP-1、MMP-2、TIMP-2蛋白表达增加,明显高于假处理组,caspase-3、smad7、MMP-13蛋白表达减少,显著低于假处理组： IGBR干预后可减少大鼠肝组织中HGF、TGF-β1、smad2/3、smad4、α-SMA、TIMP-1、MMP-2、TIMP-2蛋白的表达,增加bax、caspase-3、MMP-13蛋白表达。
结论：
IGBR对肝脏癌前病变具有明显的保护作用,其可能机制如下：
1.IGBR可能增强肝脏抗氧化活性而抑制脂质过氧化作用。
2.IGBR可抑制肝再生,可能与降低HGF水平有关。
3.IGBR调节肝脏中bcl-2与bax的比值,诱导肝细胞凋亡。
4.IGBR影响smad蛋白表达而调控TGF-β信号通路。
5.IGBR降低肝脏α-SMA的表达,调节肝脏MMP和TIMP的比值,减少纤维化病变。
Objective
To investigate the inhibitory effects and mechanisms of irioid glucosides from Boschniakia rossicica (IGBR) on hepatic preneoplasia of rats through the determination of apoptosis-related proteins, hepatocyte growth factor (HGF), members of transforming growth factor β1(TGF-β1)/smads signaling pathway, as well as the metrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in liver tissues.
Methods
After1week adaptation,50wistar rats were randomly divided into5groups: sham operated group, model group, IGBR low-dose group (DEN-AAF+125mg/kg IGBR-PH), IGBR medium-dose group (DEN-AAF+250mg/kg IGBR-PH), IGBR high-dose group (DEN-AAF+500mg/kg IGBR-PH). The sham operated group were initiated with a single intraperitoneal injection of saline (0.1ml/100g) on the1st day and fed basal diets for56days. The other four groups were initiated with a single intraperitoneal injection of DEN (200mg/kg) on the1st day and fed diets containing0.008%acetylaminofluorene (AAF) from the15th day, for a piriod of42days. Low-dose, mediun-dose and high-dose IGBR groups were administered125,250,500mg/kg IGBR from the1st day, for a piriod of56days. The animals were subjected to two-thirds partial hepatectomy on the22nd day. During the experiment, the general state and body weights of the rats were recorded. At the end of experiment, the animals were killed and the liver extracted immediately. The whole liver and regenerating liver were weighed and the regenerating indexes of liver were callculated. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamy transpeptidase (γ-GT), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), glutathione-S'-transferase (GST), and malondialdehyde (MDA) were determined. The histological changes of livers were observed by Hematoxylin-eosin (HE) staining. HGF, bax, bcl-2, caspase-3, TGF-β1, TGF-Preceptor TβRⅠ, TβRⅡ, smad2/3, smad4, smad7, a-smooth muscle actin (a-SMA), MMP-13, MMP-2, TIMP-1and TIMP-2in liver were determined with western blot assays.
Conclusion
1. IGBR improved the general state, including mental state, color pattern and appetite. The body weight of rats in each groups had no differences in statistics. But liver weights of rats in model group were increased than the other groups. IGBR have the tendency to ruduce the weight and the indexes of regenerating liver, but the difference had no significance statistically.
2. The livers of model group were hard, coarse and tarnish, with some observable small nodules. The number of nodules in the model group was bigger than the other groups. HE staining showed that the loss of structure of hepatic lobules, oval cell proliferation in portal area, collagen deposition in fibrous septum, obvious fibroplastic proliferation, watery cytoplasm, ballooning degeneration or spotty necrosis. The eosinophilic degeneration and hyaline proliferation were observed in hepatic lobule, forming atypical focal nodilar hyperplasia. The Immunohischemistry study showed scattered GST-P+foci in the liver of the model group, indicating the successful establishment of the animal model with hepatic preneoplasia. Compared with the model group, the rat liver of IGBR groups were smooth and tender, with less grey nodules. HE staining showed that there were less destruction of liver, including decreased number of swelling liver cells, eosinophilic degeneration, necrotic foci, as well as less atypia proliferation and pathological karyokinesis in the livers of IGBR groups as compared with the model group.
3. The levels of AST, ALT, y-GT, GST and MDA in the liver of the model group were increased as compared with the sham operated group, while the SOD, CAT, GSH-PX activities were dereased. The administration with IGBR reduced the liver activities of y-GT, GST, ALT and AST, increased the liver SOD, CAT, GSH-PX and decreased the liver MDA level in rats with hepatic preneoplastic lesions.
4. The protein expression of HGF, bcl-2, TGF-β1, smad2/3, smad4, a-SMA, TIMP-1, MMP-2, TIMP-2in the liver of the model group were increased as compared with the sham operated group, while the protein expression of caspase-3, smad7, MMP-13expression were dereased. The administration with IGBR reduced the protein expression of HGF, TGF-β1, smad2/3, smad4, a-SMA, TIMP-1, MMP-2, TIMP-2, increased the liver protein expression of bax, caspase-3, MMP-13in rats with hepatic preneoplastic lesions.
Conclusion:
IGBR had the protective effect on hepatic preneoplasia and the possible mechanisms isare as follows:
1. IGBR enhanced the antioxidative function of liver and inhibited the lipid peroxidation.
2. IGBR inhibited liver regeneration, probably via the downregulation of HGF.
3. IGBR regulated the bcl-2/bax ratio and induced hepatocyte apoptosis.
4. IGBR regulated the TGF-β/smads signaling pathway by affecting the protein expression of smads.
5. IGBR down-regulated the protein expression of a-SMA, and regulated the ratios of MMPs/TIMPs in the liver, which may contribute to reduced liver fibrosis.
了解草苁蓉环烯醚萜苷(IGBR)对肝癌前病变的防治作用及IGBR对肝组织中凋亡相关蛋白、肝细胞生长因子(HGF)、转化生长因子β(TGF-β/smad)信号通路的关键蛋白以及金属蛋白酶(MMP)和组织金属蛋白抑制剂(TIMP)的表达水平的影响,探讨IGBR阻断癌前病变的机理。
方法：
将50只Wistar雄性大鼠适应性饲养一周后随机分为5个组,每组为10只,分别为假处理组、模型组、IGBR低剂量组、IGBR中剂量组、IGBR高剂量组。在实验开始第1天按0.1ml/100g给假处理组大鼠一次性腹腔注射生理盐水,并饲喂正常饲料共56天。余4组大鼠一次性经腹腔注射DEN200mg/kg,从第15天开始在饲料中添加0.008%乙酰氨基芴(AAF),同时IGBR低、中、高剂量3个组分别按125、250、500mg/kg剂量灌胃IGBR至第56天。在实验第22天将所有组的大鼠肝脏行70%切除,第56天处死大鼠。实验期间观察大鼠一般状态,体重变化；测肝脏重量,计算肝脏再生度；用比色法测定肝匀浆及肝脏线粒体中天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)、γ-谷氨酰转肽酶(γ-GT)、过氧化氢酶(CAT)、超氧化物岐化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)、谷胱甘肽S-转移酶(GST)活性及丙二醛(MDA)含量；用苏木精-伊红(HE)染色法,观察肝脏组织病理形态变化；用western blot法测定肝组织中HGF、bax、bcl-2、caspase-3、 TGF-β1、转化生长因子β1受体Ⅰ和Ⅱ(TPRⅠ、T3RⅡ)、smad2/3、smad4、 smad7、α-平滑肌肌动蛋白(α-SMA)、MMP-13、MMP-2、TIMP-1、TIMP-2蛋白的表达变化。
结果：
1.IGBR促进大鼠食欲,能改善大鼠的精神状态、皮毛色泽。各组大鼠间无明显体重变化,但模型组肝脏重量明显高于其它组(P<0.05)。IGBR具有降低肝再生度及肝再生指数的趋势,但无统计学意义。
2.组织病理学结果显示,模型组大鼠肝脏表面凹凸不平,质地硬,可见直径不等的结节,结节数明显多于其它组；HE染色结果显示,肝细胞失去正常排列,肝小叶结构消失,汇管区有以卵圆细胞为主的小细胞增生,纤维隔内有大量胶原沉积,有较明显纤维组织增生；肝细胞胞浆疏松,发生广泛的变性水肿,水样变性甚至气球样变性甚至灶状坏死,肝小叶中见嗜碱性肝细胞和玻璃样的透明肝细胞灶混合排列拥挤形成的肝细胞增生结节；IGBR干预后各剂量组大鼠肝脏较模型组表面光滑,边缘钝,灰白色结节较模型组减少；HE染色显示IGBR各剂量组大鼠肝小叶结构基本存在,可见嗜酸性细胞变性,肝细胞水肿较轻。有不同程度坏死灶,肝细胞异型性明显减少,病理性核分裂相减少,病变较轻。
3.模型组大鼠肝组织匀浆和肝脏线粒体中AST、ALT、γ-GT活性升高,解毒酶GST活性和MDA含量显著高于假处理组,SOD、CAT、GSH-PX活性显著低于假处理组；IGBR干预后可降低大鼠肝组织匀浆和肝脏线粒体中ALT、AST、γ-GT、GST活性和MDA含量,升高SOD、CAT、GSH-PX活性。
4.蛋白印迹实验结果显示,癌前病变大鼠肝组织中HGF、bcl-2、TGF-β1、 smad2/3、smad4、α-SMA、TIMP-1、MMP-2、TIMP-2蛋白表达增加,明显高于假处理组,caspase-3、smad7、MMP-13蛋白表达减少,显著低于假处理组： IGBR干预后可减少大鼠肝组织中HGF、TGF-β1、smad2/3、smad4、α-SMA、TIMP-1、MMP-2、TIMP-2蛋白的表达,增加bax、caspase-3、MMP-13蛋白表达。
结论：
IGBR对肝脏癌前病变具有明显的保护作用,其可能机制如下：
1.IGBR可能增强肝脏抗氧化活性而抑制脂质过氧化作用。
2.IGBR可抑制肝再生,可能与降低HGF水平有关。
3.IGBR调节肝脏中bcl-2与bax的比值,诱导肝细胞凋亡。
4.IGBR影响smad蛋白表达而调控TGF-β信号通路。
5.IGBR降低肝脏α-SMA的表达,调节肝脏MMP和TIMP的比值,减少纤维化病变。
Objective
To investigate the inhibitory effects and mechanisms of irioid glucosides from Boschniakia rossicica (IGBR) on hepatic preneoplasia of rats through the determination of apoptosis-related proteins, hepatocyte growth factor (HGF), members of transforming growth factor β1(TGF-β1)/smads signaling pathway, as well as the metrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in liver tissues.
Methods
After1week adaptation,50wistar rats were randomly divided into5groups: sham operated group, model group, IGBR low-dose group (DEN-AAF+125mg/kg IGBR-PH), IGBR medium-dose group (DEN-AAF+250mg/kg IGBR-PH), IGBR high-dose group (DEN-AAF+500mg/kg IGBR-PH). The sham operated group were initiated with a single intraperitoneal injection of saline (0.1ml/100g) on the1st day and fed basal diets for56days. The other four groups were initiated with a single intraperitoneal injection of DEN (200mg/kg) on the1st day and fed diets containing0.008%acetylaminofluorene (AAF) from the15th day, for a piriod of42days. Low-dose, mediun-dose and high-dose IGBR groups were administered125,250,500mg/kg IGBR from the1st day, for a piriod of56days. The animals were subjected to two-thirds partial hepatectomy on the22nd day. During the experiment, the general state and body weights of the rats were recorded. At the end of experiment, the animals were killed and the liver extracted immediately. The whole liver and regenerating liver were weighed and the regenerating indexes of liver were callculated. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamy transpeptidase (γ-GT), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), glutathione-S'-transferase (GST), and malondialdehyde (MDA) were determined. The histological changes of livers were observed by Hematoxylin-eosin (HE) staining. HGF, bax, bcl-2, caspase-3, TGF-β1, TGF-Preceptor TβRⅠ, TβRⅡ, smad2/3, smad4, smad7, a-smooth muscle actin (a-SMA), MMP-13, MMP-2, TIMP-1and TIMP-2in liver were determined with western blot assays.
Conclusion
1. IGBR improved the general state, including mental state, color pattern and appetite. The body weight of rats in each groups had no differences in statistics. But liver weights of rats in model group were increased than the other groups. IGBR have the tendency to ruduce the weight and the indexes of regenerating liver, but the difference had no significance statistically.
2. The livers of model group were hard, coarse and tarnish, with some observable small nodules. The number of nodules in the model group was bigger than the other groups. HE staining showed that the loss of structure of hepatic lobules, oval cell proliferation in portal area, collagen deposition in fibrous septum, obvious fibroplastic proliferation, watery cytoplasm, ballooning degeneration or spotty necrosis. The eosinophilic degeneration and hyaline proliferation were observed in hepatic lobule, forming atypical focal nodilar hyperplasia. The Immunohischemistry study showed scattered GST-P+foci in the liver of the model group, indicating the successful establishment of the animal model with hepatic preneoplasia. Compared with the model group, the rat liver of IGBR groups were smooth and tender, with less grey nodules. HE staining showed that there were less destruction of liver, including decreased number of swelling liver cells, eosinophilic degeneration, necrotic foci, as well as less atypia proliferation and pathological karyokinesis in the livers of IGBR groups as compared with the model group.
3. The levels of AST, ALT, y-GT, GST and MDA in the liver of the model group were increased as compared with the sham operated group, while the SOD, CAT, GSH-PX activities were dereased. The administration with IGBR reduced the liver activities of y-GT, GST, ALT and AST, increased the liver SOD, CAT, GSH-PX and decreased the liver MDA level in rats with hepatic preneoplastic lesions.
4. The protein expression of HGF, bcl-2, TGF-β1, smad2/3, smad4, a-SMA, TIMP-1, MMP-2, TIMP-2in the liver of the model group were increased as compared with the sham operated group, while the protein expression of caspase-3, smad7, MMP-13expression were dereased. The administration with IGBR reduced the protein expression of HGF, TGF-β1, smad2/3, smad4, a-SMA, TIMP-1, MMP-2, TIMP-2, increased the liver protein expression of bax, caspase-3, MMP-13in rats with hepatic preneoplastic lesions.
Conclusion:
IGBR had the protective effect on hepatic preneoplasia and the possible mechanisms isare as follows:
1. IGBR enhanced the antioxidative function of liver and inhibited the lipid peroxidation.
2. IGBR inhibited liver regeneration, probably via the downregulation of HGF.
3. IGBR regulated the bcl-2/bax ratio and induced hepatocyte apoptosis.
4. IGBR regulated the TGF-β/smads signaling pathway by affecting the protein expression of smads.
5. IGBR down-regulated the protein expression of a-SMA, and regulated the ratios of MMPs/TIMPs in the liver, which may contribute to reduced liver fibrosis.
引文
[1]中华人民共和国卫生部.全国第三次死因回顾抽样调查报告[M].北京：中国协和医科大学出版社,2008,10.
[2]Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture [J]. Eur J Cancer,2001,8:S4-S66.
[3]Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006 [J]. Annals of oncology,2007,18(3):581-592.
[4]张海波.诱发性大鼠肝癌模型的研究现状与评价[J].医学综述,2002,(6)320-322.
[5]Rabes HM, Scholze P, Jantsch B. Growth kinetics of diethylnitrosamine-induced, enzyme-deficient "preneoplastic" liver cell populations in vivo and in vitro [J]. Cancer Res,1972,32(11):2577-2586.
[6]腾红丽.原发性肝癌中医药临床研究进展[J].中国中医药信息杂志,2005,12(9)：103-105.
[7]李知玉,杨大国.中医药防治肝癌前病变的研究进展[J].中西医结合肝病杂志,2003,(4)：254-257.
[8]党双锁,张正国,袁利超,等.大黄素和黄芪多糖对大鼠实验性肝癌的抑制作用[J].西安交通大学学报,2006,27(3)：250-253.
[9]孙仓,常桂英,张桂荣.草苁蓉现代研究进展[J].特产研究,1997,(2)：37-39.
[10]杨树春,于海峰,王雪松,等.草苁蓉资源的开发与利用[J].特种经济动植物,1998,1(1)：18-20.
[11]王秀丽,宋志坚.草苁蓉研究进展[J].黑龙江科技信息,2009,20：122.
[12]郑红月,腾杰,王冰,等.草苁蓉的形态组织鉴定[J].中药材,2001,24(8)557-559.
[13]Chang WC, Li JS, Li SD, et al. Study on the biological properties of Boschniakia rossica [J]. China Med Mater,1988,11:9.
[14]尹宗柱,金荣镐,李晶俊.长白山草苁蓉中四个环烯醚萜化合物的分离和结构鉴定.中华医药理论与临床(康建亭等主编)第一卷,北京,北京科学技术出版社,1997.
[15]尹学哲,许惠仙,金爱花,等.草苁蓉环烯醚萜苷对肺癌细胞增殖和凋亡影响[J].中国公共卫生.2010,(7)：805-806
[16]朴龙,杨振凯,杨阳,等.草苁蓉环烯醚萜对内毒素诱导D-半乳糖胺致敏小鼠肝细胞凋亡的影响[J].前沿科学,2011,(2)：11-14.
[17]尹学哲,许惠仙,金爱花,等.草苁蓉环烯醚萜苷对移植鳞癌VX2荷瘤兔的抑瘤作用[J].中国实验方剂学杂志.2010(6)：134-136+140..
[18]汪霞,周微,李天,等.草苁蓉环烯醚萜对肝癌前病变大鼠血清标志酶及抗氧化活性的影响[J].食品科技.2010(7)：242-245.
[19]王环震,刘恒兴,韩金红,等.肝纤维化大鼠部分肝切除后肝星状细胞活化和肝细胞生长因子的表达[J].中国临床和解剖学杂志,2008；26(4)：400-402.
[20]黄艳,黄成,李俊.肝纤维化病程中Kupffer细胞分泌的细胞因子对肝星状细胞活化增殖、凋亡的调控[J].中国药理学通报,2010,26(1)：9-13.
[21]Kim BC, Mamura M, Choi KS, et al. Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatomacells [J]. MolCellBiol,2002,22(5):1369-1378.
[22]吴晓玲,曾维政,王丕龙.中药对TGFβ/Smad信号通路的干预作用[J].第四军医大学学报,2005,26(14)：1339-1341.
[23]Solt DB, Farber E. New principle for the analysis of chemical carcinogenesis [J]. Nature,1976,263(5580):701-703.
[24]史冀华,朱盛兴,张水军.大鼠肝部分切除术的应用解剖及实施[J].世界华人消化杂志,2008,(22)：2516-2520.
[25]刘景河,梁忠岩.草苁蓉化学成分与药理研究进展[J].特产究,2001,(4)：55-58.
[26]金艳峰.草苁蓉乙醇提取物对人肝癌SMMC-7721细胞株增殖及凋亡的干预作用[D].延吉：延边大学,2007.
[27]Quan J, Yin X, Xu H. Boschniakia rossica prevents the carbon tetrachloride-induced hepatotoxicity in rat [J]. Exp Toxic Pathol,2011,63:53-59.
[28]金明,李勇,朴春梅,等.草苁蓉提取物在大鼠肝脏化学致癌初期对血清一氧化氮含量和一氧化氮合酶活性的影响[J].延边大学医学学报,2001,24(4)：247-249.
[29]黄红国.草苁蓉乙醇提取物对大鼠肝维化的治疗作用[D].延边大学：延边大学,2002.
[30]迟立超.草苁蓉多糖的抗炎作用及毒性实验研究[D].吉林大学：吉林大学,2008.
[31]朴龙,张学武,金香子,等.草苁蓉提取物对衰老大鼠脑组织自由基的影响[J].中西医结合学报,2003,(2)：125-127.
[32]周丽莎,朱书秀,王小月,等.草苁蓉提取物对阿尔茨海默病模型大鼠海马神经干细胞巢蛋白及学习记忆的影响[J].时珍国医国药,2008,(11)：2671-2673.
[33]尹学哲,许惠仙,徐俊萍,等.草苁蓉提取物抑制肺癌细胞增殖分子机制的研究[J].食品科技,2011,(5)：191-193+198.
[34]邓敬桓,秦雪.原发性肝癌发生机制的研究进展[J].环境与健康杂志,2007,(11)：924-926.
[35]刘琳琳,任进.化学物质导致肝脏早期癌变的相关机制研究进展[J].中国药物与临床,2004,(5)：325-329.
[36]Lin CP, Liu JD, Chow JM, et al. Small-molecule c-Myc inhibitor,10058-F4, inhibits proliferation, downregulates human telomerase reverse transcriptase and enhances chemosensitivity in human hepatocellular carcinoma cell[J].Anticancer Drugs,2007,18(2):161-170.
[37]张海波.诱发性大鼠肝癌模型的研究现状与评价[J].医学综述,2002,(6)320-322..
[38]张新立,史景泉,卞修武.DEN诱发大鼠肝癌变的病理形态与细胞增殖活性的定量研究[J].第三军医大学学报,2001,(3)：304-307.
[39]Chakraborty T, Chatterjee A, Rana A, et al. Cell proliferation and hepatocarcinogenesis in rat initiated by diethylnitrosamine and promoted by phenobarbital:potential roles of early DNA damage and liver metallothionein expression [J]. Life Sci,2007,81(6):489-499.
[40]Rabes HM, Scholze P, Jantsch B. Growth kinetics of diethylnitrosamine-induced, enzyme-deficient"preneoplastic"liver cell populations in vivo and in vitro [J]. Cancer Res,1972,32(11):2577-2586.
[41]Sakairi T, Kobayashi K, Goto K, et al. Greater expression of transforming growth factor alpha and proLiferating cell nuclear antigen staining in mouse hepatoblastomas than hepatocellular carcinomas induced by a diethylnitrosamine-sodium phenobarbital regimen [J]. Toxicol Pathol,2001, 29(4):479-482.
[42]Barbisan LF, Scolastici C, Miyamoto M, at al.Effects of crude extracts of Agaricus blazei on DNA damage and on rat liver carcinogenesis induced by diethylnitrosamine [J].Genet Mol Res,2003,2(3):295-308.
[43]Fujise Y, Okano JI, Nagahara T, at al.Preventive effect of caffeine and curcumin on hepato-carcinogenesis in diethylnitrosamine-induced rats [J]. Int J Oncol, 2012,24:1343.
[44]钱妍,金岩,李媛等.肝复健冲剂抑制二乙基亚硝胺诱导大鼠肝癌形成的机制[J].浙江中医学院学报,2003,(2)：56-58.
[45]刘振国.柴胡皂甙(SSd)对二乙基亚硝胺致大鼠肝癌的抑制作用和免疫功能的影响[D].兰州：兰州大学,2008.
[46]叶健,徐锡坤,周建伟,等.复方半枝莲防治二乙基亚硝胺诱发大鼠肝癌的研究[J].中国中西医结合消化杂志,2002,10(2)：67-70.
[47]严瑞琪,王辉云,李俊丽,等.柑皮油对二乙基亚硝胺诱发大鼠肝癌前病变的抑制[J].癌症,1997,16(1)：22-25.
[48]Martins PN, Neuhaus P. Surgical anatomy of the liver, hepatic vasculature and bile ducts in the rat [J]. Liver Int,2007,27(3):384-392.
[49]Martins PN, Theruvath TP, Neuhaus P. Rodent models of partial hepatectomies [J]. Liver Int,2008,28(1):3-11.
[50]张红军.广泛肝切除术后门静脉高压所致肝损伤及其干预的实验研究[D].第二军医大学：第二军医大学,2007.
[51]李瀚,张六通,梅家俊,等.左旋谷氨酸单钠-肝再生-大鼠模型的建立[J].世 界华人消化杂志,2000,8(7)：824-826.
[52]Baier PK, Baumgartner U, Hempel S,at al. Kupffer cells infiltrate liver tissue early after ischemia-reperfusion and partial hepatectomy [J]. Eur Surg Res,2005, 37(5):290-297.
[53]金海玲,李天洙,全吉淑,等.草苁蓉提取物对大鼠肝脏致癌过程中GST-P表达的影响[J].中国中医药科技,2000,(6)：374.
[54]付松柏,周玉珠,周琳.AFP、AFU、Y-GT在肝癌诊断及鉴别中的临床价值[J].航空航天医药,2005,(2)：3-4.
[55]张锦生,应越英,徐元鼎.以γ-谷氨酰转肽酶为标记对实验性肝癌癌变过程的研究[J].上海第一医学院学报,1983,(4)：263-268+323-324.
[56]王刚,刘荣,蒋均远,等.腹腔镜和开腹肝切除对机体肝脏功能的影响[J].中国普通外科杂志,2007,(6)：552-555.
[57]Yamaguchi M, Tsurusaki Y, Misawa H, et al. Potential role of regucalcin as a specific biochemical marker of chronic liver injury with carbon tetrachloride administration in rats [J]. Mol Cell Biochem,2002,241(1-2):61-67.
[58]刘德传,吴仕九,丁辉,等.清香散对湿热型肝癌模型组大鼠ALT、AST、IL-8水平的影响[J].陕西中医,2004,25(5)：473-475.
[59]黄仙娥.AST/ALT比值在肝病中的变化及预后评估[J].中国实验诊断学,2009,(1)：117-118.
[60]孙步彤,盛传伦,关勇,等.线粒体型天门冬氨酸氨基转移酶同工酶测定及其应用价值[J].中国实验诊断学,2005,9(5)：770-772.
[61]仝君,童师雯,王丹,等.HBV感染者血清AST/ALT比值及HBV血清标志物联合检测的辅助诊断价值研究[J].标记免疫分析与临床,2011,(1)：7-11.
[62]李兴华,王丽英,李广生.LEC鼠自发性肝癌谷胱甘肽S-转移酶表达的意义[J].吉林大学学报,2005,31(1)：25-26.
[63]常福厚,扈廷茂.三种中药及绿茶对烟焦油引起的小鼠肝ANDM和GST活性变化的影响[J].动物医学进展,2006,(2)：79-83.
[64]Schroder P, Lyubenova L, Huber C. Do heavy metals and metalloids influence the detoxification of organic xenobiotics in plants [J]. Environ Sci Pollut Res Int. 2009,16(7):795-804.
[65]Niedzwiedz A, Nicpon J, Zawadzki M, at al. The influence of road trans-port on the activities of glutathione reductase, glutathione peroxidase, and glutathione-S-transferase in equineerythrocytes [J]. Vet Clin Pathol.2012,41(1): 123-126.
[66]宫芸芸,韩驰,陈君石.茶多酚、茶色素对肝癌癌前病变大鼠肝脏Ⅱ相解毒酶的诱导及其在化学预防中的作用[J].卫生研究,2000,(3)：159-161.
[67]彭海燕,章永红,杨早,等.豆楮方对DEN诱发大鼠肝癌的防治作用[J].南京中医药大学学报,2007,(1)：58-60.
[68]Zhang C, Zhang M, Sun Y, at al. Effect of dibutyl phthalate and di-(2-ethylhexyl) phthalate on urine SOD activity and MDA content in rats].Nan Fang Yi Ke Da Xue Xue Bao [J].2012,32(2):160-164.
[69]贺凤.运动性血色素下降发生过程中大鼠血清及肝脏MDA、SOD、GSH-PX变化的动态观察[D].北京：北京体育大学,2004.
[70]邓海平,俞诗源,陈玉琴,等.X射线辐射对仔鼠体重、皮毛生长及肝、肾脏组织SOD、CAT活力及MDA含量的影响[J].动物学报,2008,54(6)：1029-1037.
[71]田志杰,沈南,吕仕杰,等.高强度微波辐射对Wistar大鼠血清SOD、HSP70和肝脏MDA、Mit肿胀的影响[J].四川动物,2009,28(4)：528-531.
[72]卢峻,陈英松,阿古拉等.蒙医温针对大鼠疲劳型肝脏MDA、GSH含量及GSH-PX,SOD活性的影响[J].针刺研究.2007,32(3)：167-169.
[73]Montazerifar F, Hashemi M, Karajibani M, at al. Evaluation of lipid peroxidation and erythrocyte glutathione peroxidase and superoxide dismutase in hemodialysis patients.Saudi J Kidney Dis Transpl [J].2012,23(2):274-9.
[74]黄琳,陆付耳,杨小玉,等.黄连解毒汤对胰岛素抵抗大鼠肝脏线粒体氧化应激的影响[J].中国中西医结合杂志,2008,28(8)：725-728.
[75]朱平.临床分子遗传学[M].北京：北京医科大学出版社,2002.
[76]丰平,刘树红,李霞,等.槲芪散对肝癌前病变大鼠肝脏线粒体结构的影[J].中医药理与临床,2008,24(1)：56-57.
[77]毛德文,邱华,余晶,等.解毒化瘀Ⅱ方对实验性肝衰竭大鼠肝脏坏死面积 及肝线粒体超微结构的影响[J].广西中医药,2006,29(8)：46-49.
[78]Megli FM, Sabatini K. Mitochondrial phospholipid bilayer structure is ruined after liver oxidative injury in vivo [J]. FEBS Lett,2004,573:68-72.
[79]Frank V, Eva V, James FD. The role of active oxygen species in plant signal transduction[J]. Plant Science,2001,161:405-414.
[80]沈明花,全吉淑,柳明洙,等.草苁蓉提取物对大鼠肝癌前病变模型血清抗氧化酶活性及肿瘤坏死因子的影响[J].山东中医杂志,2004,23(2)：97-99.
[81]Barash H, R Gross E, Edrei Y, et al. Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation -induced double-strand DNA breaks [J]. Proc Natl Acad Sci U S A,2010,107(5):2207-2212.
[82]Kountouras J, Boura P, lyqidakis NJ. Liver regeneration after hepatectomy [J]. Hepatogastroenterology,2001,48:556-62.
[83]Court FG, Wemyss-Holden SA, Dennison AR, et al. The mystery of liver regeneration [J]. Br Surg,2002,89 (9):1089-1095.
[84]Matsuoka T, Maeda Y, Matsuo K, et al. Hepatocyte growth factor prevents peritoneal fibrosis in an animal model of encapsulating peritoneal sclerosis [J]. J Nephrol,2008,21(1):64-73.
[85]Ramadori G, Armbrust T. Cytokines in the liver [J]. Eur J Gastroenterol Hepatol, 2001,13(7):777-784.
[86]陈伟,张新华,钟翠平.肝再生的分子生物学研究进展[J].解剖科学进展,2003,(3)：253-257.
[87]Inagaki Y, Higashi K, Kushida M, et al. Hepatocyte growth factor suppresses profibrogenic signal transduction via nuclear export of Smad3 with galectin-7 [J]. Gastroenterology,2008,134(4):1180-1190.
[88]Pawlowski R, Jura J.ALR and liver regeneration [J]. Mol cell Biochem,2006, 288(1-2):159-169.
[89]杨怀滔,荣成,陈智芳,等.肝细胞生长因子(HGF)对肝再生的影响[J].科技信息,2009,(26)：407-408.
[90]Tomiya T, Omata M, Imamura H,at al. Impaired liver regeneration in acute liver failure:the significance of cross-communication of growth associated factors in liver regeneration [J]. Hepatol Res,2008, S29-S33.
[91]黄莹莹,孙剑勇.肝细胞生长因子与肝纤维化关系研究进展[J].医学综述,2011,(6)：825-827.
[92]Kanemura H, Iimuro Y, Takeuchi M, et al. Hepatocyte growth factor gene transfer with naked plasmid DN A ameliorates dimethylnitrosamine- induced liver fibrosis in rats [J]. Hepatol Res,2008,38(9):930-939.
[93]董海峰.肝细胞生长素治疗重型病毒性肝炎[J].中国现代药物应用,2009,3(12)：83-84.
[94]Nakamura T, Matsumoto K, Mizuno S, et al. Hepatocyte growth factor prevents tissue fibrosis, remodeling, and dysfunction in cardiomyo-pathic hamster hearts [J]. Am J Physiol Heart Circ Physiol,2005,288(5):2131-2139.
[95]俞维,焦娜.HGF/c-Met信号通路与肿瘤的研究进展[J].中国误诊学杂志,2010,(23)：5565-5566.
[96]Okubo H, Moriyama M, Tanaka N et al. Detection of serum and intrahepatic hepatocyte growth factor during DEN-induced carcinogenesis in the rat [J]. Hepatol Res,2002,24(4):385-394.
[97]Vetelainen R, van Vliet AK, van Gulik TM. Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy [J]. Ann Surg,2007,245(1):44-50.
[98]钱晓峰,张峰等.重组肝细胞生长因子促进大鼠移植肝细胞的再生[J].中华器官移植,2005,26(11)：679-681.
[99]Hamada T, Kamada H, Hayashi T, et al. Protein C inhibitor regulates hepatocyte growth factor activator-mediated liver regeneration in mice [J]. Gut,2008,57(3): 365-373.
[100]Hu Mingtai, Ha Xiaoqin, Gao Peng. The mechanism of Hepatocyte growth factor antagonist NK4 inhibiting the tumor [J]. Journal of Fourth Military Medical University,2008,29(1):86-88.
[101]Cramer T, Schuppan D, Bauer M, et al. Hepatocyte growth factor gene transfer with naked plasmid DNA amelioratesdimethylnitrosamine-induced liver fibrosis in rats [J]. Live Int,2004,24(4):335-344.
[102]Kim WH, Matsumoto K, Bessho K, et al. Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis [J]. Am J Pathol,2005,166(4):1017-1028.
[103]罗运权,吴孟超,陈汉.肝细胞生长因子及其受体基因在大鼠肝脏癌变过程中的表达[J].外科理论与实践,1998,(1)：33-35.
[104]Huh G, Factor M, Sanchez A, et al. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair [J]. Proc Natl Acad Sci USA,2004,101(13):4477-4482.
[105]吕璟.肝再生相关细胞因子的探究[J].解剖科学进展,2005,11(2)：174-179.
[106]Jaeschke H. Inflammation in response to hepatocellular apoptosis [J]. Hpatology, 2002,35(4):964-966.
[107]甘华山,陈友琴.细胞凋亡与病毒性肝炎[J].世界华人消化杂志,2001,9(5)：579-581.
[108]Elsharkawy AM, Oakley F, Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis [J]. Apoptosis,2005,10(5):927-939.
[109]Murphy FR, Issa R, Zhou X, eta. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition:implications for reversibility of liver fibrosis [J].J Biol Chem,2002,277(13):11069-11076.
[110]Canbay A, Taimr P, Torok N, et al. Apoptotic body engulfment by a human stellate cell line is profibrogenic [J]. Lab Invest,2003,83:655-663.
[111]Breckenridge DG, Stojanovic M,Marcellus RC, et al. Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol [J].J Cell Biol,2003,160 (7):1115-11127.
[112]杨琳,吴东瑛,辛彦.癌前病变Caspase-3表达下调与胃黏膜癌变的关联[J].中华肿瘤杂志,2006,(5)：357-360.
[113]高文信,刘洪静,王颖,等.Caspase-3在口腔粘膜癌前病变及鳞状细胞癌中的表达研究[J].现代口腔医学杂志,2003,(2)：109-111.
[114]宁巍巍,刘同慎,李笑岩,等.大鼠肝癌发生过程中Caspase-3的表达及意义[J].滨州医学院学报,2009,(5)：321-323.
[115]Park DY, Sol MY, Suh KS, at al.Expressions of transforming growth factor (TGF)-betal and TGF-beta type Ⅱ receptor and their relationship with apoptosis during chemical hepatocarcinogenesis in rats [J].Hepatol Res,2003,27(3): 205-213.
[116]谢晶日,梁国英,李明,等.益气活血化瘀法对大鼠肝癌过程中Caspase-3及组织学影响的研究[J].中医药信息,2009,(1)：68-69+100.
[117]Awasthi YC, Sharma R, Cheng JZ, et al. Role of 4-hydroxynonenal in stress-mediated apoptosis signaling [J]. Mol Aspects Med,2003,24(4-5): 219-230.
[118]解燕茹.凋亡调控蛋白Bcl-2、Bax与非酒精性脂肪性肝病的关系及药物干预研究[D].山西医科大学：山西医科大学,2010.
[119]罗新华,杨勤,程明亮,等.肝纤维化形成过程中大鼠肝组织Bcl-2、Bax表达的动态研究[J].贵州医药,2004,(7)：579-581.
[120]贾旭东,韩驰,陈君石.茶多酚、茶色素对大鼠肝癌癌前病变抑制作用及机理研究[J].卫生研究,2001,(3)：168-169.
[121]宗蕾,姚登福,吴玮,等.Bcl-2在肝细胞癌变过程中凋亡抑制作用的动态分析[J].世界华人消化杂志,2007,(21)：2279-2283.
[122]龙冬梅.细胞凋亡及凋亡相关基因在大鼠肝癌促癌过程中的作用研究[D].第三军医大学：第三军医大学,2001.
[123]杨早,章永红,彭海燕,等.番荔枝总提取物对二乙基亚硝胺诱发大鼠肝脏癌前病变的影响[J].上海中医药杂志,2006,(5)54-57：.
[124]张光谋,李虎,王兴平.大鼠肝脏癌前病变与bcl-2和bax表达关系[J].中国公共卫生,2011,(11)：1448-1450.
[125]刘洪付.Bcl-2和Bax在DEN诱发大鼠肝癌细胞上的表达[D].泰山医学院：泰山医学院,2011.
[126]何田田,熊二峰,陈清,等.大鼠肝脏癌前病变肝细胞凋亡及Fas/FasL的表达[J].新乡医学院学报,2010,(3)：239-243.
[127]Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis [J]. Gastroenterology,2003,125(2):437-443.
[128]Issa R, Williams E, Trim N, et al. Apoptosis of hepatic stellate cells: involvement in resolution of billary fibrosis and regulation by soluble growth factors [J]. Gut,2001,48 (4):548-557.
[129]Akazawa Y, Gores G J. Death recep tor-mediated liver injury [J]. Semin LiverDis,2007,27 (4):327-338.
[130]陶艳艳,刘成海.TGF-β1刺激肝星状细胞活化与肝纤维化的分子病理机制研究进展[J].中西医结合肝病杂志,2006,16(2)：125-127.
[131]Friedman S L. Hepatic stellate cells:protean, multifunctional, and enigmatic cells of the liver [J]. Physiol Rev,2008,88(1):125-172.
[132]周明玉,程明亮.TGFβ1刺激肝星状细胞的活化与肝纤维化的研究进展[J].贵州医药,2008,32(8)：751-753.
[133]Tsukada S, Parsons CJ, Rippe RA.Mechanisms of liver fibrosis [J]. Clin Chim Acta,2006,364(1-2):33-60.
[134]Ward DG, Cheng Y, N'Kontchou G, et al. Changes in the serum proteome associated with the development of hepatocellular carcinoma in hepatitis C-related cirrhosis [J]. Br J Cancer,2006,94(2):287-292.
[135]郭顺根,戴敏,张玮.肝纤维化发生发展与信号转导途径[J].中国组织化学与细胞化学杂志,200,312：106-111.
[136]Pardali K, Kowanetz M, Heldin CH, et al. Smad pathway-specific transcriptional regulation of the cell cycle inhibitor p21(WAF1/Cip1) [J]. J Cell Physiol,2005,204(1):260-272.
[137]Tsukada S, Westwick JK, Ikejima K, et al. SMAD and p38 MAPK signaling pathways independently regulate alphal(Ⅰ) collagen gene expression in unstimulated and transforming growth factor-beta- stimulated hepatic stellate cells [J]. J Biol Chem,2005,280(11):10055-10064.
[138]Novakova-Jiresova A, Van Gameren MM, Coppes RP, et al.Transforming growth factor-beta plasma dynamics and postirradiation lung injury in lung cancer patients [J]. Radiother Oncol,2004,71(2):183-189.
[139]施承松,王祥珍.转化生长因子β1在宫颈癌组织中的表达及其意义[J].广东医学院学报,2005,23(5)：515-516.
[140]王秀梅,刘成敏,张成仁.转化生长因子β1信号传导通路在口腔鳞癌中的功能意义[J].中华肿瘤杂志,2009,1(31)：28-32.
[141]Simeone DM, Zhang L, Graziano K,et al. Smad4 mediates activation of mitogenactivated Protein kinases by TGF-beta in Pancreatic acinar cells [J]. Am J Physiol Cell Physiol,2001,281(1):C311-C319.
[142]LIU X, HU H, YIN JQ. Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis [J]. Liver Int,2006,26 (1):8-22.
[143]Konrad L, Scheiber JA, Schwarz L,at al. TGF-betal and TGF-beta2 strongly enhance the secretion of plasminogen activator inhibitor-1 and matrix metalloproteinase-9 of the human prostate cancer cell line PC-3 [J].Regul Pept, 2009,155(1-3):28-32.
[144]Fukumura Y, Kumasaka T, Mitani K, et al. Expression of transforming growth faetor betal, beta2, and beta3 in chronic, cancer-associated, obstructive pancreatitis [J]. Arch Pathol Lab Med,2006,130(3):356-361.
[145]Jong HS, Lee HS, Kim TY, et al. Attenuation of transforming growth factor beta-induced growth inhibition in human hepatocellular carcinoma cell lines by cyclin Dloverexpression [J].Biochem Biophys Res Commun,2002,292(2): 383-389.
[146]Herrmann J, Haas U, Gressner A M, et al.TGF-beta up-regulates serum response factor in activated hepatic stellate cells [J]. Biochim Biophys Acta,2007, 1772(11-12):1250-1257.
[147]程朋,曾维政,张涛.TGF-p/Smads信号转导通路与肿瘤研究进展[J].中国肿瘤,2008,17(3)：202-207.
[148]熊振芳.蕲艾提取液对肝纤维化大鼠TGFβ-Smad信号转导通路的影响[D].湖北中医药大学：湖北中医药大学,2010.
[149]林文生,张农,张颂文,等.PAI-1在TGF-β1基因和反义TGF-β1基因转染人肝癌细胞株中的表达[J].临床与实验病理学杂志,2000,16(3)：221-223.
[150]过建春,陈群伟,包剑锋,等.转化生长因子β1在肝纤维化发病中的作用[J].国际消化病杂志,2009,29(2)：86-88.
[151]林国友,童夏生,陈春晓.肝硬化患者血浆表皮生长因子和转化生长因子p1的表达[J].浙江医学,2007,(6)：626-627.
[152]Abou-Shady M, Baer HU, Friess H, et al. Transforming growth factor betas and their signaling receptors in human hepatocellular carcinoma [J]. Am J Surg, 1999; 177:209-215.
[153]徐新保,冷希圣,杨晓.反义Smad4基因转染对抗昆明小鼠肝脏纤维化发展的效果观察[J].中国普通外科杂志,2004,19：50-52.
[154]Tsukada S, Parsons CJ, Rippe RA. Mechanisms of liver fibrosis [J]. Clin Chim Acta,2006,364(1-2):33-60.
[155]Mccafrey TA, Consigli S, Du B, et al. Decreased type II/type I TGF-beta receptor ratio in cells derived from human atherosclerotic lesions. Conversion from an antiproliferative to profibrotic response to TGF-betal [J]. J Clin Invest, 1995,96(6):2667-2675
[156]俞蕾敏,吕宾,李善高,等.大鼠肝硬化形成过程中肝组织TGF-β1, Smad3, Smad7水平动态的变化[J].世界华人消化杂志2007,15(30)：3163-3267.
[157]孔丽.肝癥口服液含药血清对肝癌细胞TGF-pi/Smads信号转导通路的调控作用[D].河北医科大学：河北医科大学,2005.
[158]王奕,季光,王育群,等.二甲基亚硝胺致大鼠肝癌前病变TGF-βRⅡ的表达及中药的调节[J].浙江中西医结合杂志,2001,11(1)：23-24.
[159]Park DY, Hwang SY, Suh KS. Expression of transforming growth factor (TGF)-betal and TGF-beta type Ⅱ receptor in preneoplastic lesions during chemical hepatocarcinogenesis of rats.Toxicol Pathol [J].2001,29:541-549.
[160]Ichimura R, Mizukami S, Takahashi M, at al. Disruption of Smad-dependent signaling for growth of GST-P-positive lesions from the early stage in a rat two-stage hepatocarcinogenesis model [J]. Toxicol Appl Pharmacol,2010,25.
[161]崔巍.外源性TGF-β1对WB鼠肝脏上皮细胞内磷酸化Smad2/Smda3和Smad7分布的影响[D].中国医科大学：中国医科大学,2005.
[162]LiJ H, Zhu HJ, Huang XR, et al. Smad7 inhibits fibortic effect of TGF-beta on rnal tubular epihthelia cells by blocking Smada2 activation [J]. J Am Soc Nephorl,2002,13:1464-1472.
[163]Barthelemy-Brichant N, David JL, Bosquee L, et al. Increased TGFbetal plasma level in patients with lung cancer:potential mechanisms [J]. Eur J Clin Invest,2002,32(3):193-198.
[164]Zhao L, Sheldon K, ChenM, et a.l The predictive role of plasma TGF-betal during radiation therapy for radiation-induced lung toxicity deserves further study in patients with non-small cell lung cancer [J]. Lung Cancer,2008,59(2): 232-239.
[165]Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signaling [J]. Nature,1997,389(6651):631-635.
[166]华赟鹏,李绍强,赖佳明,等.实验性大鼠肝脏癌变过程中转化生长因子-β1/Smads信号通路系列变化的研究[J].南方医科大学学报,2008,(10)：1848-1852.
[167]Park DY, Lee CH, SolMY, et al. Expression and localization of the transforming growth factor-beta type I receptor and Smads in preneoplastic lesions during chemical hepatocarcinogenesis in rats. J Korean Med Sci [J].2003,18(4): 510-519.
[168]Yan X, Lin Z, Chen Y. Regulation of TGF-beta signaling by Smad7 [J]. Acta Biochim Biophys Sin (Shanghai),2009,41(4):263-272.
[169]Agarwal C, Britton ZT, Alaseirlis DA, et al. Healing and normal fibroblasts exhibit differential proliferation, collagen production, alph -SMA expression, and contraction [J]. Ann Biomed Eng,2006,34(4):653-659.
[170]姜大朋,李昭铸,蒋志涛,等.肝细胞生长因子阻抑TGF-β1诱导大鼠韧带成纤维细胞a-SMA过表达及其机制[J].中国康复医学杂志,2009,(10)：906-909.
[171]刘恒兴,刘斌,王环震,等.大鼠肝部分切除后肝细胞再生及肝星状细胞α-平滑肌肌动蛋白表达变化与肝细胞生长因子的干预作用[J].中国组织工 程研究与临床康复,2008,12(18)：3511-3514.
[172]王宇,高毅,黄宇琦,等,实验性肝纤维化间质胶原酶表达的研究[J].中华消化杂志,2003,20(1)：67-69.
[173]郭来,王再谟.肝心宁胶囊对肝纤维化HA,LN,PCⅢ,C-Ⅳ的影响及机理研究[J].中华中医药学刊,2008,26(5)：1049-1051.
[174]朴熙绪,黄红果,朴东明.草苁蓉乙醇提取物对二甲基亚硝胺诱导大鼠肝纤维化的治疗作用[J].世界华人消化杂志,2005,(18)：2205-2209.
[175]Visser, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases:Structure, function and bio-chemistry [J]. Cir Res,2003, 827-839.
[176]熊敏莉,吴建新.基质金属蛋白酶及其抑制因子与肝纤维化[J].实用医学杂志,2008,(24)：4318-4321.
[177]Hirano S, Bless D, Heisey D, et al. Roles of hepatocyte growth factor and transforming growth factor betal in production of extracellular matrix by canine vocal fold fibroblasts [J]. Laryngoscope,2003,113(1):144-148.
[178]杨牧祥,张一听,于文涛,等.柔肝消癥饮对肝硬化大鼠肝脏TIMP-1和TGFp-1表达的影响[J].中国中西医结合消化杂志,2010,(6)：377-380.
[179]Weiss A, Goldman S, Shalev E. The matrix metalloproteinases (MMPS) in the decidua and fetal membranes [J]. Front Biosci.2007,12:649-659.
[180]Sakaida I, Hironaka K, Terai S, Okita K.Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrixmetalloproteinases (MMPs) of Kupffer cells [J]. Life Sci,2003,72(8): 943-959.
[181]赵志海,辛绍杰,赵景民,等.实验性肝纤维化逆转过程中基质金属蛋白酶表达的动态研究[J].临床肝胆病杂志,2007,(1)：21-23.
[182]Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases:structure function, and biochemistry [J]. Circ Res 2003, 92(8):827-839.
[183]Murphy FR, Issa R, Zhou X, Ratnarajah S, et al. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metailoproteinase-1 is mediated via effects on matrix metalloproteinase inhibition:implications for reversibility of liver fibrosis [J]. J Biol Chem,2002,277(13):11069-11076
[184]杨长青,王吉耀,郭津生,等,基质金属蛋白酶1表达质粒对实验性肝纤维化的影响[J].中华消化杂志,2004,20(5)：297-299.
[185]姜宪辉,叶华,孙雷.TNF-α、MMP-1及其抑制剂在肝纤维化组织中的表达及其相关性研究[J].中国现代医药杂志,2008,10(10)：36-38.
[186]赵志海,辛绍杰,赵景民,等.实验性肝纤维化形成和逆转过程中基质金属蛋白酶13蛋白及其mRNA表达[J].军医进修学院学报,2002,23(3)：214-216.
[187]Fortunato SJ, Menon R, Lombardi SJ. Amniochorion gelatinase- gelatinase inhibitor imbalance in vitro:a possible infectious pathway to rupture [J]. Obstet Gynecol,2000,95(2):240-244.
[188]El-Gindy I, El Rahnan AT, El- Alim MA, et al. Diagnostic potential of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as non-invasive markers of hepatic fibrosis in patients with HCV related chronic liver disease [J]. Egypt J Immuno,2003,10(1):127-135.
[189]蒋泽生,方石岗,高毅,等.二乙基亚硝胺诱发大鼠肝细胞癌发生过程中基质金属蛋白酶动态变化[J].世界华人消化杂志,2001,9：759-762.
[190]Sivaramakrishnan V, Niranjali Devaraj S.Morin regulates the expression of NF-kappaB-p65, COX-2 and matrix metalloproteinases in diethylnitrosamine induced rat hepatocellular carcinoma [J]. Chem Biol Interact,2009,180(3): 353-359.
[191]王宪波,刘平,唐志鹏,等.大鼠肝纤维化形成中基质金属蛋白酶2、9活性变化的病理意义[J].中华肝脏病杂志,2004,12(5)：267-270.
[192]Hemmann S, Graf J, Roderfeld M,et al. Expression of MMPs and TIMPs in liver fibrosis-a systematic review with special emphasis on anti-Fibrotic strategies [J]. J Hepatol,2007,46(5):955-975.
[193]Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs):an ancient family with structural and functional diversity [J]. Biochim Biophys Acta,2010,1803(1):55-71.
[194]Visse R, NagaseH. Matrix metalloproteinases and tissue inhibitors of Metalloproteinases:structure, function, and biochemistry [J]. Circ Res,2003, 92 (8):827-839.
[195]Roderfeld M, Hemmann S, Roeb E. Mechanisms of fibrinolysis in chronic liver injury (with special emphasis on MMPs and TIMPs) [J]. Z Gast roent-erol, 2007,45(1):25-33.
[1]Diaz-Gil JJ, Escartin P, Garcia-Canero R, et al. Purification of a liver DNA-synthesis promoter fromplasma of partially hepatectomized rats [J].BiochemJ,1986,235(1):49-55.
[2]Naldini L, Vigna E, Narsimhan RP, et al. Hepatocyte growth factor (HGF) stimulates the tyrosine kinaseactivity of the receptor encoded by the proto-oncogene c-MET [J]. Oncogene,1991,6(4):501-504.
[3]Stamos J, Lazarus R A, Yao X, et al. Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor [J]. EMBO J,2004,23(12): 2325-2335.
[4]Kirchhofer D, Lipari MT, Santell L, et al. Utilizing the activation mechanism of serine proteases to engineer hepatocyte growth factor into a Met antagonist [J]. Proc Natl Acad Sci USA,2007,104(13):5306-5311.
[5]Komada M, Kitamura N. The cell dissociation and motility triggered by scatter factor/hepatocyte growth factor are mediated through the cytoplasmic domain of the c-Met receptor [J]. Oncogene,1993,8(9):2381-2390.
[6]Comoglio PM. Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells [J]. EXS,1993,65(1):131-165.
[7]Tajima H, Matsumoto K, Nakamura T. Regulation of cell growth and motility by hepatocyte growth factor and receptor expression in various cell species [J]. Exp Cell Res,1992,202(2):423-431.
[8]Tajima H, Higuchi O, Mizuno K, et al. Tissue distribution of hepatocyte growth factor receptor and its exclusive down-regulation in a regenerating organ after injury [J]. J Biochem Tokyo,1992,111(3):401-406.
[9]Block GD, Locker J, Bowen WC, et al. Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes inducedby HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium [J]. J Cell Biol,1996,132(6):1133-1149.
[10]Kono S, Nagaike M, Matsumoto K, et al. Marked induction of hepatocyte growth factor mRNA in intact kidney and spleen in response to injury of distant organs [J]. Biochem Biophys Res Commun,1992,186(2):991-998.
[11]Ramadori G, Neubauer K, Odenthal M, et al. The gene of hepatocyte growth factor is expressed in fat-storing cells of rat liver and is downregulated during cell growth and by transforming growth factor-beta [J]. Biochem Biophys Res Commun,1992,183(2):739-742
[12]Taub R. Liver regeneration:from myth to mechanism [J]. Nat Rev Mol Cell Biol, 2004,5(10):836-847.
[13]Michalopoulos GK, Zarnegav R. Hepatocyte growth factor [J]. Hepatology 1992, 151(1):149-155.
[14]Lindroos PM, Zarnegar R, Michalopoulos GK. Hepatocyte growth factor (hepatopoietin A) rapidly increases in plasma before DNA synthesis and liver regeneration stimulated by partial hepatectomy and carbon tetrachloride administration [J]. Hepatology,1991,13(4):743-749.
[15]Michalopoulos GK, Defrances MC. Liver regeneration [J]. Science,1997, 276(5309):60-66.
[16]Shiota G, Kawasaki H. Hepatocyte growth factor in transgenic mice [J]. Int J Exp Pathol,1998,79(5):267-277.
[17]Kinoshita T, Hirao S, Matsumoto K, et al. Possible endocrine control by hepatocyte growth factor of liver regeneration after partial hepatectomy [J]. Biochem Biophys Res Commun 1991,177(1):330-335
[18]Tomiya T, Nagoshi S, Fujiwara K. Significance of serum human hepatocyte growth factor levels in patients with hepatic failure [J]. Hepatology,1992, 15(1):1-4.
[19]俞炯,姚一帆,吕建等.部分肝切除小鼠肝再生的研究[J].温州医学院学报,2008,(5)：415-417.
[20]朱洪,郭永章,李立等.促肝细胞生长素对慢性肝损伤鼠肝部分切除术后肝细胞的影响[J].中国普通外科杂志,2002,11(1)：29-32.
[21]朱洪,张炳彦,郭永章,等.肝细胞生长因子对慢性肝损伤时肝部分切除术后肝细胞影响的实验研究[J].肝胆外科杂志,2001,9(1)：59-61.
[22]Kaido T, Yoshikawa A, Seto S. Hepatocyte growth factor supply accelerates compensatory hypertrophy caused by portal branch ligation in normal and jaundiced rats [J]. J Surg Res,1999,85(1):115-119.
[23]Cramer T, Schuppan D, Bauer M, at al.Hepatocyte growth factor and c-Met expression in rat and human liver fibrosis.Liver Int [J].2004,24(4):335-44.
[24]Takemura M, Furuta N, Nakamura S, et al. Determination and clinical significance of human hepatocyte growth factor in serum [J]. Rinsho Byori,1992, 40(11):1168-1172.
[25]吴福生,郑树森,吴灵娇,等.肝细胞生长因子及其受体c-met在肝细胞癌中的表达与预后价值[J].中华外科杂,2006,(9)： 603-608.
[26]Vejchapipat P, Tangkijvanich P, Theamboonlers A, et al. Association between serum hepatocyte growth factor and survival in untreated hepatocellular carcinoma [J]. J Gastroenterol,2004,39(12):1182-1188.
[27]Shiota G, Rhoads DB, Wang TC, at al. Hepatocyte growth factor inhibits growth of hepatocellular carcinoma cells [J]. Proc Natl Acad Sci U.S.A 1999,89(1): 373-377.
[28]Shiota G, Kawasaki H. HePatoeyte growth factor in transgenie mice [J]. Int J EWP Pathol,1998,79(5):267-277.
[29]Taira K, Hiroyasu S,Shiraishi M, et al. Role of the Fas system in liver regeneration after a partial hepatectomy in rats [J]. Eur Surg Res,2001,33: 334-341.
[30]梁明,李峰,李静媛.外源性肝细胞生长因子抗肝细胞凋亡机制的研究[J].肝脏,2007,(6)：466-468.
[31]Kim WH, Matsumoto K, Bessho K, et al. Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis [J]. Am J Pathol,2005,166(4):1017-1028.
[32]时多.大鼠肝再生过程中细胞凋亡及机制研究[D].第二军医大学：第二军医大学,2008.
[33]Sato M, Kakubari M, Kawamura M, et al. The decrease in total collagen fibers in the liver by hepatocyte growth factor after formation of cirrhosis induced by thioacetamide [J]. Biochem Pharmacol,2000,59(6):681-690.
[34]Horiguchi K, Hirano T, Ueki T, et al. Treating liver cirrhosis indogs with hepatocyte growth factor gene therapy via the hepatic ar-tery [J]. J Hepatobiliary Pancreat Surg,2009,16(2):171-177.
[35]Shukla MN, Rose JL, Ray R, et al. Hepatocyte growth factor inhibits epithelial to myofibroblast transition in lung cells via smad7 [J]. Am J Respir Cell Mol Biol, 2009,40(6):643-653.
[36]Inagaki Y, Higashi K, Kushida M, et al. Hepatocyte growth factor suppresses profibrogenic signal transduction via nuclear export of Smad3 with galectin-7 [J]. Gastroenterology,2008,1180-1190.
[37]姜大朋,李昭铸,蒋志涛,等.肝细胞生长因子阻抑TGF-β1诱导大鼠韧带成纤维细胞α-SMA过表达及其机制[J].中国康复医学杂志,2009,(10)：906-909.
[38]Schievenbusch S, Strack I, Scheffler M,at al. Profiling of anti-fibrotic signaling by hepatocyte growth factor in renal fibroblasts [J]. Biochem Biophys Res Commun.2009,385(1):55-61.
[1]黄文林,朱孝峰.信号转导[M].北京：人民卫生出版社,2005.
[2]Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signaling [J]. Nature,1997,389(6651):631-635.
[3]Wang W, Huang XR, Canlas E, et al. Essential role of Smad3 in angiotensin II-induced vascular fibrosis [J]. Circ Res,2006,98(8):1032-9.
[4]Visse R,NagaseH.Matrix metalloproteinases and tissue inhibitors of Metalloproteinases:structure, function, and biochemistry [J]. Circ Res,2003, 92 (8):827-839.
[5]Hemmann S, Graf J, Roderfeld M,et al. Expression of MMPs and TIMPs in liver fibrosis-a systematic review with special emphasis on anti-Fibrotic strategies [J]. J Hepatol,2007,46(5):955-975.
[6]Patterson ML, Atkinson SJ, Knauper V, et al. Specific collagenolysis by gelatinase A,MMP-2, is determined by the hemopexin domain and not the fibronectin-like domain [J]. FEBS Lett,2001,503(2-3):158-162.
[7]Roderfeld M, Hemmann S, Roeb E.Mechanisms of fibrinolysis in chronic liver injury (with special emphasis on MMPs and TIMPs) [J]. Z Gastroenterol,2007, 45(1):25-33.
[8]Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs):an ancient family with structural and functional diversity [J]. Biochim Biophys Acta, 2010,1803(1):55-71.
[9]Tsukada S, Parsons CJ, Rippe RA. Mechanisms of liver fibrosis [J]. Clin Chim Acta,2006,364(1-2):33-60.
[10]Pan CH, Wen CH, Lin CS. Interplay of angiotensin Ⅱ and angiotensin(1-7) in the regulation of matrix metalloproteinases of human cardiocytes [J]. Exp Physiol, 2008,93(5):599-612.
[11]Hu H, Yin JQ. Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis [J]. Liver Int.2006,26(1):8-22.
[12]Bednarek N, Svedin P, Garnotel R, Favrais G, et al. Increased MMP-9 and TIMP-1 in mouse neonatal brain and plasma and in human neonatal plasma after hypoxia-ischemia:a potential marker of neonatal encephalopathy [J]. Pediatr Res, 2012,71(1):63-70.
[13]Murphy FR, Issa R, Zhou X, Ratnarajah S, et al. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metailoproteinase-1 is mediated via effects on matrix metalloproteinase inhibition:implications for reversibility of liver fibrosis [J]. J Biol Chem,2002,277(13):11069-11076.
[14]Yu WH, Yu S, Meng Q, et al. TIMP-3 binds to sulphated glycosaminog-lycans of the extracellular matrix [J]. J Biol Chem,2000,275(40):31226-31232.
[15]Kinoshita J, Kitamura K, Kabashima A, et al. Clinical significance of vascular endothelial growth factor-C (VEGF-C) in breast cancer [J]. Breast Cancer Res Treat,2001,66(2):159-164.
[16]Kopp JB, Factor VM, Mozes M, et al. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease [J]. Lab Invest,1996,74 (6):991-1003.
[17]李蕾.肝纤维化中肝星状细胞迁移及RhoA作用机制的研究[D].复旦大学,2006.
[18]Wells RG. Fibrogenesis.V.TGF-beta signaling pathways [J]. Am J physiol Gastrointest Liver Physiol,2000,279(5):G845-G850.
[19]邰伯军,姚登福,邹黎,等.肝细胞癌变过程中TGF-β1及TNF-α的动态表达与改变[J].胃肠病学和肝病学杂志,2006,(3)：277-280.
[20]蒋莹,赵金仙.肝硬化组织转化生长因子(β-1(TGFβ-1)的表达及临床意义[J].新疆医科大学学报,2008,(6)：739.
[21]李国强,王学浩,孙跃明,等.肝硬化肝癌大鼠TGF-β-1和受体的表达及其意义[J].中国肿瘤临床,2003,(2)：60-63.
[22]张一昕,杨牧祥,于文涛,等.柔肝消癥饮对肝硬化大鼠血清及肝脏转化生长因子β1的影响[J].中西医结合肝病杂志,2011,(1)：31-33.
[23]马蓉,黎音,付娟娟.TβRⅠ和Smad4在肝细胞癌中的表达及意义[J].新疆医科大学学报,2007,(6)：584-585+588.
[24]俞蕾敏,吕宾,李善高,等.大鼠肝硬化形成过程中肝组织TGF-β1,Smad3, Smad7水平动态的变化[J].世界华人消化志,2007,(30)：3163-3167.
[25]徐新保,何振平,梁志清,等.腺病毒介导反义Smad4基因大鼠体内转移对实验性肝纤维化的治疗作用[J].中华消化杂志,2004,(6)：53-54.
[26]翁红雷,Axel M.Gressner,Steven Dooley.肝星状细胞IFN-γ信号传导途径及对TGF-β的抑制[A].[C],2004：275.
[27]Ichimura R, Mizukami S, Takahashi M, at al. Disruption of Smad-dependent signaling for growth of GST-P-positive lesions from the early stage in a rat two-stage hepatocarcinogenesis model [J]. Toxicol Appl Pharmacol.2010,25.
[28]王奕,季光,王育群,等.二甲基亚硝胺致大鼠肝癌前病变TGF-βRⅡ的表达及中药的调节[J].浙江中西医结合杂志,2001,11(1)：23-24.
[29]华赞鹏,李绍强,赖佳明,等.实验性大鼠肝脏癌变过程中转化生长因子 -β1/Smads信号通路系列变化的研究[J].南方医科大学学报,2008,(10)：1848-1852.
[30]廖丹,罗光汉,吴继周,等.TGF-β1和smad4mRNA在慢性肝炎、肝硬化、肝癌癌旁组织的表达及意义[J].世界华人消化杂志,2004,(09)：81-84.
[31]Park DY, Sol MY, Suh KS, at al. Expressions of transforming growth factor (TGF)-betal and TGF-beta type Ⅱ receptor and their relationship with apoptosis during chemical hepatocarcinogenesis in rats.Hepatol Res [J].2003,27(3): 205-213.
[32]Park DY, Hwang SY, Suh KS. Expression of transforming growth factor (TGF)-betal and TGF-beta type Ⅱ receptor in preneoplastic lesions during chemical hepatocarcinogenesis of rats.Toxicol Pathol [J].2001,29(5):541-9.
[33]Park DY, Lee CH, SolMY, et al. Expression and localization of the transforming growth factor-beta type I receptor and Smads in preneoplastic lesions during chemical hepatocarcinogenesis in rats [J]. J Korean Med Sci.2003,18(4): 510-519.
[34]Koniaris LG,M cKillop IH, Schwartz SI, et al. Liver regeneration [J]. J Am CollSurg,2003,197(4):634-659.
[35]高春芳.转化生长因子p1与肝纤维化[J].中华医学杂志,2005,85(15)：1074-1077.
[36]SakamotoT,Liu Z, MuraseN,etal. Mitosis and apoptosis in the liver of interleukin-6-deficientmice after partialhepatectomy [J]. Hepatology,1999,29(2):403-411.
[37]王春雷,黄志强,周宁新,等.TGF-β1诱导肝硬化小鼠肝细胞凋亡信号转导机制的研究[J].中国普通外科杂志,2004,574-577.
[38]尹纪业.肝非实质细胞在肝再生中的作用研究[D].中国人民解放军军事医学科学院：中国人民解放军军事医学科学院,2007.
[39]Miwa Y, Harrison PM, Farzaneh F,et al. Plasma levels and hepatic mRNA expression of transforming growth factor-betal in patients with fulminanthepatic failure [J]. J Hepatol,1997,27(5):780-788.
[40]袁发焕,王海燕,李惊子.ECM,MMPs/TIMPs及其调节研究进展[J].国外医 学(生理、病理科学与临床分册),2000,(2)：93-96.
[41]Nagashio Y, Ueno H, Imamura M. Inhibition of transforming growth factor beta decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice [J]. Lab Invest,2004,84(12):1610-1618.
[42]Cai T, Lei QY, Wang LY, et al. TGF-beta 1 modulated the expression of alpha 5 beta 1 integrin and integrin-mediated signaling in human hepatocarcinoma cells [J]. Biochem BiophysRes Commun,2000,274 (2):519-525.
[43]RiederH, Armbrust T, Meyer zum Buschenfelde KH,et al. Contribution of sinusoidal endothelial liver cells to liver fibrosis:expression of transforming growth factor-beta 1 receptors and modulation of plasmin-generating enzymes by transforming growth factor-beta 1 [J]. Hepatology,1993,18(4):937-944.
[44]杨牧祥,张一昕,于文涛,等.柔肝消癥饮对肝硬化大鼠肝脏TIMP-1和TGFp-1表达的影响[J].中国中西医结合消化杂志,2010,(6)：377-380.
[45]Tsukada S, Parsons CJ, Rippe RA. Mechanisms of liver fibrosis [J]. Clin Chim Acta,2006,364(1-2):33-60.
[46]Gooch JL, Gorin Y, Zhang BX, et al. Involvement of calcineurin in transforming growth factor-βmediated regulation of extracellular-matrix accumulation [J]. J BiolChen,2006,279 (15):15561-15570
[47]袁发焕,王海燕,李惊子.ECM,MMPs/TIMPs及其调节研究进展[J].国外医学(生理、病理科学与临床分册),2000,(2)：93-96.
[48]熊敏莉,吴建新.基质金属蛋白酶及其抑制因子与肝纤维化[J].实用医学杂志,2008,(24)：4318-4321.
[49]陈妍,崔文丽,黎音.肝硬化组织中MMP-1和VEGF的表达及其意义[J].新疆医科大学学报,2008,(5)：551-553.
[50]赵志海,辛绍杰,赵景民,等.实验性肝纤维化逆转过程中基质金属蛋白酶表达的动态研究[J].临床肝胆病杂志,2007,(1)：21-23.
[51]陈江,章荣华,吴蕙岭,等.实验性肝纤维化形成和逆转过程中MMP-2及其抑制物TIMP-2表达的动态研究[J].中国卫生检验杂志,2010,(10)：2401-2403+2406.
[52]张平,李国富,刘娅,等.基质金属蛋白酶-2在肝硬化患者肝组织中的表达[J].宁夏医学院学报,2008,(4)：443-444+451+554.
[53]于晓红.Ⅳ型胶原酶门脉灌注对四氯化碳诱导兔肝硬化影响的实验研究[D].中国人民解放军军医进修学院：中国人民解放军军医进修学院,2011.
[54]Duka I, Bakris G. Influence of microalbuminuria in achieving blood pressure goals [J]. Curr Opin Nephrol Hypertense,2008,17(5):457-463.
[55]鲍利民,齐若梅,高欣,等.ELISA法检测尿微量白蛋白的临床应用与评价[J].中国卫生检验杂志,2006,16(2)：227-228.
[56]Kralliedde J, Viberti G. Microalbuminuria and cardiovascular risk [J]. Am J Hypertens,2004,17(10):986-993.
[57]蒋莹,赵文军.基质金属蛋白酶组织抑制因子-1在肝硬化组织中的表达及意义[J].新疆医科大学学报,2007,(10).
[58]杨牧祥,张一听,于文涛,等.柔肝消癥饮对肝硬化大鼠肝脏TIMP-1和TGFp-1表达的影响[J].中国中西医结合消化杂志,2010,(6)：1128-1129.
[59]朱跃科,段钟平,王宝恩,等.芪参益气滴丸对DMN大鼠肝纤维化及肝组织TIMP-1表达的影响[J].中国新药与临床杂志,2007,(1)：11-16.
[60]El-Gindy I, El Rahman A T, El-Alim M A, et al. Diagnostic potential of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as non-invasive markers of hepatic fibrosis in patients with HCV related chronic liver disease [J]. Egypt J Immunol,2003:10 (1):27-35.
[61]杨长青,胡国龄,谭德明,等.基质金属蛋白酶-1、反义金属蛋白酶组织抑制因子-1表达质粒对大鼠肝纤维化的影响[J].中华传染病杂志,2000,(1)：28-31.
[62]谢碧红,杨觉民,吴引伟.化纤复肝方对慢性肝炎患者MMP-1、TIMP-1及其抑制因子表达的影响[J].辽宁中医杂志,2011,(8)：1665-1666.
[63]张虹,周欢琴,翁秀妹,等.肝病患者血浆MMP-3、TIMP-1、u-PA和u-PAR水平的临床研究[J].中国卫生检验杂志,2010,(1)：107-109.
[64]刘江,施柏年,何建方,等.氧化苦参碱对慢性乙肝和肝硬化患者血清MMP-2和TIMP-2的影响[J].中国中西医结合杂志,2005,(11)989-992.
[65]朱虹,吴樱樱,徐明,等.肝灵对胆汁淤积性肝硬化大鼠肝组织MMP-13、TIMP-1和NF-κBp65表达的影响[J].安徽医科大学学报,2005,(6)：29-32.
[2]Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture [J]. Eur J Cancer,2001,8:S4-S66.
[3]Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006 [J]. Annals of oncology,2007,18(3):581-592.
[4]张海波.诱发性大鼠肝癌模型的研究现状与评价[J].医学综述,2002,(6)320-322.
[5]Rabes HM, Scholze P, Jantsch B. Growth kinetics of diethylnitrosamine-induced, enzyme-deficient "preneoplastic" liver cell populations in vivo and in vitro [J]. Cancer Res,1972,32(11):2577-2586.
[6]腾红丽.原发性肝癌中医药临床研究进展[J].中国中医药信息杂志,2005,12(9)：103-105.
[7]李知玉,杨大国.中医药防治肝癌前病变的研究进展[J].中西医结合肝病杂志,2003,(4)：254-257.
[8]党双锁,张正国,袁利超,等.大黄素和黄芪多糖对大鼠实验性肝癌的抑制作用[J].西安交通大学学报,2006,27(3)：250-253.
[9]孙仓,常桂英,张桂荣.草苁蓉现代研究进展[J].特产研究,1997,(2)：37-39.
[10]杨树春,于海峰,王雪松,等.草苁蓉资源的开发与利用[J].特种经济动植物,1998,1(1)：18-20.
[11]王秀丽,宋志坚.草苁蓉研究进展[J].黑龙江科技信息,2009,20：122.
[12]郑红月,腾杰,王冰,等.草苁蓉的形态组织鉴定[J].中药材,2001,24(8)557-559.
[13]Chang WC, Li JS, Li SD, et al. Study on the biological properties of Boschniakia rossica [J]. China Med Mater,1988,11:9.
[14]尹宗柱,金荣镐,李晶俊.长白山草苁蓉中四个环烯醚萜化合物的分离和结构鉴定.中华医药理论与临床(康建亭等主编)第一卷,北京,北京科学技术出版社,1997.
[15]尹学哲,许惠仙,金爱花,等.草苁蓉环烯醚萜苷对肺癌细胞增殖和凋亡影响[J].中国公共卫生.2010,(7)：805-806
[16]朴龙,杨振凯,杨阳,等.草苁蓉环烯醚萜对内毒素诱导D-半乳糖胺致敏小鼠肝细胞凋亡的影响[J].前沿科学,2011,(2)：11-14.
[17]尹学哲,许惠仙,金爱花,等.草苁蓉环烯醚萜苷对移植鳞癌VX2荷瘤兔的抑瘤作用[J].中国实验方剂学杂志.2010(6)：134-136+140..
[18]汪霞,周微,李天,等.草苁蓉环烯醚萜对肝癌前病变大鼠血清标志酶及抗氧化活性的影响[J].食品科技.2010(7)：242-245.
[19]王环震,刘恒兴,韩金红,等.肝纤维化大鼠部分肝切除后肝星状细胞活化和肝细胞生长因子的表达[J].中国临床和解剖学杂志,2008；26(4)：400-402.
[20]黄艳,黄成,李俊.肝纤维化病程中Kupffer细胞分泌的细胞因子对肝星状细胞活化增殖、凋亡的调控[J].中国药理学通报,2010,26(1)：9-13.
[21]Kim BC, Mamura M, Choi KS, et al. Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatomacells [J]. MolCellBiol,2002,22(5):1369-1378.
[22]吴晓玲,曾维政,王丕龙.中药对TGFβ/Smad信号通路的干预作用[J].第四军医大学学报,2005,26(14)：1339-1341.
[23]Solt DB, Farber E. New principle for the analysis of chemical carcinogenesis [J]. Nature,1976,263(5580):701-703.
[24]史冀华,朱盛兴,张水军.大鼠肝部分切除术的应用解剖及实施[J].世界华人消化杂志,2008,(22)：2516-2520.
[25]刘景河,梁忠岩.草苁蓉化学成分与药理研究进展[J].特产究,2001,(4)：55-58.
[26]金艳峰.草苁蓉乙醇提取物对人肝癌SMMC-7721细胞株增殖及凋亡的干预作用[D].延吉：延边大学,2007.
[27]Quan J, Yin X, Xu H. Boschniakia rossica prevents the carbon tetrachloride-induced hepatotoxicity in rat [J]. Exp Toxic Pathol,2011,63:53-59.
[28]金明,李勇,朴春梅,等.草苁蓉提取物在大鼠肝脏化学致癌初期对血清一氧化氮含量和一氧化氮合酶活性的影响[J].延边大学医学学报,2001,24(4)：247-249.
[29]黄红国.草苁蓉乙醇提取物对大鼠肝维化的治疗作用[D].延边大学：延边大学,2002.
[30]迟立超.草苁蓉多糖的抗炎作用及毒性实验研究[D].吉林大学：吉林大学,2008.
[31]朴龙,张学武,金香子,等.草苁蓉提取物对衰老大鼠脑组织自由基的影响[J].中西医结合学报,2003,(2)：125-127.
[32]周丽莎,朱书秀,王小月,等.草苁蓉提取物对阿尔茨海默病模型大鼠海马神经干细胞巢蛋白及学习记忆的影响[J].时珍国医国药,2008,(11)：2671-2673.
[33]尹学哲,许惠仙,徐俊萍,等.草苁蓉提取物抑制肺癌细胞增殖分子机制的研究[J].食品科技,2011,(5)：191-193+198.
[34]邓敬桓,秦雪.原发性肝癌发生机制的研究进展[J].环境与健康杂志,2007,(11)：924-926.
[35]刘琳琳,任进.化学物质导致肝脏早期癌变的相关机制研究进展[J].中国药物与临床,2004,(5)：325-329.
[36]Lin CP, Liu JD, Chow JM, et al. Small-molecule c-Myc inhibitor,10058-F4, inhibits proliferation, downregulates human telomerase reverse transcriptase and enhances chemosensitivity in human hepatocellular carcinoma cell[J].Anticancer Drugs,2007,18(2):161-170.
[37]张海波.诱发性大鼠肝癌模型的研究现状与评价[J].医学综述,2002,(6)320-322..
[38]张新立,史景泉,卞修武.DEN诱发大鼠肝癌变的病理形态与细胞增殖活性的定量研究[J].第三军医大学学报,2001,(3)：304-307.
[39]Chakraborty T, Chatterjee A, Rana A, et al. Cell proliferation and hepatocarcinogenesis in rat initiated by diethylnitrosamine and promoted by phenobarbital:potential roles of early DNA damage and liver metallothionein expression [J]. Life Sci,2007,81(6):489-499.
[40]Rabes HM, Scholze P, Jantsch B. Growth kinetics of diethylnitrosamine-induced, enzyme-deficient"preneoplastic"liver cell populations in vivo and in vitro [J]. Cancer Res,1972,32(11):2577-2586.
[41]Sakairi T, Kobayashi K, Goto K, et al. Greater expression of transforming growth factor alpha and proLiferating cell nuclear antigen staining in mouse hepatoblastomas than hepatocellular carcinomas induced by a diethylnitrosamine-sodium phenobarbital regimen [J]. Toxicol Pathol,2001, 29(4):479-482.
[42]Barbisan LF, Scolastici C, Miyamoto M, at al.Effects of crude extracts of Agaricus blazei on DNA damage and on rat liver carcinogenesis induced by diethylnitrosamine [J].Genet Mol Res,2003,2(3):295-308.
[43]Fujise Y, Okano JI, Nagahara T, at al.Preventive effect of caffeine and curcumin on hepato-carcinogenesis in diethylnitrosamine-induced rats [J]. Int J Oncol, 2012,24:1343.
[44]钱妍,金岩,李媛等.肝复健冲剂抑制二乙基亚硝胺诱导大鼠肝癌形成的机制[J].浙江中医学院学报,2003,(2)：56-58.
[45]刘振国.柴胡皂甙(SSd)对二乙基亚硝胺致大鼠肝癌的抑制作用和免疫功能的影响[D].兰州：兰州大学,2008.
[46]叶健,徐锡坤,周建伟,等.复方半枝莲防治二乙基亚硝胺诱发大鼠肝癌的研究[J].中国中西医结合消化杂志,2002,10(2)：67-70.
[47]严瑞琪,王辉云,李俊丽,等.柑皮油对二乙基亚硝胺诱发大鼠肝癌前病变的抑制[J].癌症,1997,16(1)：22-25.
[48]Martins PN, Neuhaus P. Surgical anatomy of the liver, hepatic vasculature and bile ducts in the rat [J]. Liver Int,2007,27(3):384-392.
[49]Martins PN, Theruvath TP, Neuhaus P. Rodent models of partial hepatectomies [J]. Liver Int,2008,28(1):3-11.
[50]张红军.广泛肝切除术后门静脉高压所致肝损伤及其干预的实验研究[D].第二军医大学：第二军医大学,2007.
[51]李瀚,张六通,梅家俊,等.左旋谷氨酸单钠-肝再生-大鼠模型的建立[J].世 界华人消化杂志,2000,8(7)：824-826.
[52]Baier PK, Baumgartner U, Hempel S,at al. Kupffer cells infiltrate liver tissue early after ischemia-reperfusion and partial hepatectomy [J]. Eur Surg Res,2005, 37(5):290-297.
[53]金海玲,李天洙,全吉淑,等.草苁蓉提取物对大鼠肝脏致癌过程中GST-P表达的影响[J].中国中医药科技,2000,(6)：374.
[54]付松柏,周玉珠,周琳.AFP、AFU、Y-GT在肝癌诊断及鉴别中的临床价值[J].航空航天医药,2005,(2)：3-4.
[55]张锦生,应越英,徐元鼎.以γ-谷氨酰转肽酶为标记对实验性肝癌癌变过程的研究[J].上海第一医学院学报,1983,(4)：263-268+323-324.
[56]王刚,刘荣,蒋均远,等.腹腔镜和开腹肝切除对机体肝脏功能的影响[J].中国普通外科杂志,2007,(6)：552-555.
[57]Yamaguchi M, Tsurusaki Y, Misawa H, et al. Potential role of regucalcin as a specific biochemical marker of chronic liver injury with carbon tetrachloride administration in rats [J]. Mol Cell Biochem,2002,241(1-2):61-67.
[58]刘德传,吴仕九,丁辉,等.清香散对湿热型肝癌模型组大鼠ALT、AST、IL-8水平的影响[J].陕西中医,2004,25(5)：473-475.
[59]黄仙娥.AST/ALT比值在肝病中的变化及预后评估[J].中国实验诊断学,2009,(1)：117-118.
[60]孙步彤,盛传伦,关勇,等.线粒体型天门冬氨酸氨基转移酶同工酶测定及其应用价值[J].中国实验诊断学,2005,9(5)：770-772.
[61]仝君,童师雯,王丹,等.HBV感染者血清AST/ALT比值及HBV血清标志物联合检测的辅助诊断价值研究[J].标记免疫分析与临床,2011,(1)：7-11.
[62]李兴华,王丽英,李广生.LEC鼠自发性肝癌谷胱甘肽S-转移酶表达的意义[J].吉林大学学报,2005,31(1)：25-26.
[63]常福厚,扈廷茂.三种中药及绿茶对烟焦油引起的小鼠肝ANDM和GST活性变化的影响[J].动物医学进展,2006,(2)：79-83.
[64]Schroder P, Lyubenova L, Huber C. Do heavy metals and metalloids influence the detoxification of organic xenobiotics in plants [J]. Environ Sci Pollut Res Int. 2009,16(7):795-804.
[65]Niedzwiedz A, Nicpon J, Zawadzki M, at al. The influence of road trans-port on the activities of glutathione reductase, glutathione peroxidase, and glutathione-S-transferase in equineerythrocytes [J]. Vet Clin Pathol.2012,41(1): 123-126.
[66]宫芸芸,韩驰,陈君石.茶多酚、茶色素对肝癌癌前病变大鼠肝脏Ⅱ相解毒酶的诱导及其在化学预防中的作用[J].卫生研究,2000,(3)：159-161.
[67]彭海燕,章永红,杨早,等.豆楮方对DEN诱发大鼠肝癌的防治作用[J].南京中医药大学学报,2007,(1)：58-60.
[68]Zhang C, Zhang M, Sun Y, at al. Effect of dibutyl phthalate and di-(2-ethylhexyl) phthalate on urine SOD activity and MDA content in rats].Nan Fang Yi Ke Da Xue Xue Bao [J].2012,32(2):160-164.
[69]贺凤.运动性血色素下降发生过程中大鼠血清及肝脏MDA、SOD、GSH-PX变化的动态观察[D].北京：北京体育大学,2004.
[70]邓海平,俞诗源,陈玉琴,等.X射线辐射对仔鼠体重、皮毛生长及肝、肾脏组织SOD、CAT活力及MDA含量的影响[J].动物学报,2008,54(6)：1029-1037.
[71]田志杰,沈南,吕仕杰,等.高强度微波辐射对Wistar大鼠血清SOD、HSP70和肝脏MDA、Mit肿胀的影响[J].四川动物,2009,28(4)：528-531.
[72]卢峻,陈英松,阿古拉等.蒙医温针对大鼠疲劳型肝脏MDA、GSH含量及GSH-PX,SOD活性的影响[J].针刺研究.2007,32(3)：167-169.
[73]Montazerifar F, Hashemi M, Karajibani M, at al. Evaluation of lipid peroxidation and erythrocyte glutathione peroxidase and superoxide dismutase in hemodialysis patients.Saudi J Kidney Dis Transpl [J].2012,23(2):274-9.
[74]黄琳,陆付耳,杨小玉,等.黄连解毒汤对胰岛素抵抗大鼠肝脏线粒体氧化应激的影响[J].中国中西医结合杂志,2008,28(8)：725-728.
[75]朱平.临床分子遗传学[M].北京：北京医科大学出版社,2002.
[76]丰平,刘树红,李霞,等.槲芪散对肝癌前病变大鼠肝脏线粒体结构的影[J].中医药理与临床,2008,24(1)：56-57.
[77]毛德文,邱华,余晶,等.解毒化瘀Ⅱ方对实验性肝衰竭大鼠肝脏坏死面积 及肝线粒体超微结构的影响[J].广西中医药,2006,29(8)：46-49.
[78]Megli FM, Sabatini K. Mitochondrial phospholipid bilayer structure is ruined after liver oxidative injury in vivo [J]. FEBS Lett,2004,573:68-72.
[79]Frank V, Eva V, James FD. The role of active oxygen species in plant signal transduction[J]. Plant Science,2001,161:405-414.
[80]沈明花,全吉淑,柳明洙,等.草苁蓉提取物对大鼠肝癌前病变模型血清抗氧化酶活性及肿瘤坏死因子的影响[J].山东中医杂志,2004,23(2)：97-99.
[81]Barash H, R Gross E, Edrei Y, et al. Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation -induced double-strand DNA breaks [J]. Proc Natl Acad Sci U S A,2010,107(5):2207-2212.
[82]Kountouras J, Boura P, lyqidakis NJ. Liver regeneration after hepatectomy [J]. Hepatogastroenterology,2001,48:556-62.
[83]Court FG, Wemyss-Holden SA, Dennison AR, et al. The mystery of liver regeneration [J]. Br Surg,2002,89 (9):1089-1095.
[84]Matsuoka T, Maeda Y, Matsuo K, et al. Hepatocyte growth factor prevents peritoneal fibrosis in an animal model of encapsulating peritoneal sclerosis [J]. J Nephrol,2008,21(1):64-73.
[85]Ramadori G, Armbrust T. Cytokines in the liver [J]. Eur J Gastroenterol Hepatol, 2001,13(7):777-784.
[86]陈伟,张新华,钟翠平.肝再生的分子生物学研究进展[J].解剖科学进展,2003,(3)：253-257.
[87]Inagaki Y, Higashi K, Kushida M, et al. Hepatocyte growth factor suppresses profibrogenic signal transduction via nuclear export of Smad3 with galectin-7 [J]. Gastroenterology,2008,134(4):1180-1190.
[88]Pawlowski R, Jura J.ALR and liver regeneration [J]. Mol cell Biochem,2006, 288(1-2):159-169.
[89]杨怀滔,荣成,陈智芳,等.肝细胞生长因子(HGF)对肝再生的影响[J].科技信息,2009,(26)：407-408.
[90]Tomiya T, Omata M, Imamura H,at al. Impaired liver regeneration in acute liver failure:the significance of cross-communication of growth associated factors in liver regeneration [J]. Hepatol Res,2008, S29-S33.
[91]黄莹莹,孙剑勇.肝细胞生长因子与肝纤维化关系研究进展[J].医学综述,2011,(6)：825-827.
[92]Kanemura H, Iimuro Y, Takeuchi M, et al. Hepatocyte growth factor gene transfer with naked plasmid DN A ameliorates dimethylnitrosamine- induced liver fibrosis in rats [J]. Hepatol Res,2008,38(9):930-939.
[93]董海峰.肝细胞生长素治疗重型病毒性肝炎[J].中国现代药物应用,2009,3(12)：83-84.
[94]Nakamura T, Matsumoto K, Mizuno S, et al. Hepatocyte growth factor prevents tissue fibrosis, remodeling, and dysfunction in cardiomyo-pathic hamster hearts [J]. Am J Physiol Heart Circ Physiol,2005,288(5):2131-2139.
[95]俞维,焦娜.HGF/c-Met信号通路与肿瘤的研究进展[J].中国误诊学杂志,2010,(23)：5565-5566.
[96]Okubo H, Moriyama M, Tanaka N et al. Detection of serum and intrahepatic hepatocyte growth factor during DEN-induced carcinogenesis in the rat [J]. Hepatol Res,2002,24(4):385-394.
[97]Vetelainen R, van Vliet AK, van Gulik TM. Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy [J]. Ann Surg,2007,245(1):44-50.
[98]钱晓峰,张峰等.重组肝细胞生长因子促进大鼠移植肝细胞的再生[J].中华器官移植,2005,26(11)：679-681.
[99]Hamada T, Kamada H, Hayashi T, et al. Protein C inhibitor regulates hepatocyte growth factor activator-mediated liver regeneration in mice [J]. Gut,2008,57(3): 365-373.
[100]Hu Mingtai, Ha Xiaoqin, Gao Peng. The mechanism of Hepatocyte growth factor antagonist NK4 inhibiting the tumor [J]. Journal of Fourth Military Medical University,2008,29(1):86-88.
[101]Cramer T, Schuppan D, Bauer M, et al. Hepatocyte growth factor gene transfer with naked plasmid DNA amelioratesdimethylnitrosamine-induced liver fibrosis in rats [J]. Live Int,2004,24(4):335-344.
[102]Kim WH, Matsumoto K, Bessho K, et al. Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis [J]. Am J Pathol,2005,166(4):1017-1028.
[103]罗运权,吴孟超,陈汉.肝细胞生长因子及其受体基因在大鼠肝脏癌变过程中的表达[J].外科理论与实践,1998,(1)：33-35.
[104]Huh G, Factor M, Sanchez A, et al. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair [J]. Proc Natl Acad Sci USA,2004,101(13):4477-4482.
[105]吕璟.肝再生相关细胞因子的探究[J].解剖科学进展,2005,11(2)：174-179.
[106]Jaeschke H. Inflammation in response to hepatocellular apoptosis [J]. Hpatology, 2002,35(4):964-966.
[107]甘华山,陈友琴.细胞凋亡与病毒性肝炎[J].世界华人消化杂志,2001,9(5)：579-581.
[108]Elsharkawy AM, Oakley F, Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis [J]. Apoptosis,2005,10(5):927-939.
[109]Murphy FR, Issa R, Zhou X, eta. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition:implications for reversibility of liver fibrosis [J].J Biol Chem,2002,277(13):11069-11076.
[110]Canbay A, Taimr P, Torok N, et al. Apoptotic body engulfment by a human stellate cell line is profibrogenic [J]. Lab Invest,2003,83:655-663.
[111]Breckenridge DG, Stojanovic M,Marcellus RC, et al. Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol [J].J Cell Biol,2003,160 (7):1115-11127.
[112]杨琳,吴东瑛,辛彦.癌前病变Caspase-3表达下调与胃黏膜癌变的关联[J].中华肿瘤杂志,2006,(5)：357-360.
[113]高文信,刘洪静,王颖,等.Caspase-3在口腔粘膜癌前病变及鳞状细胞癌中的表达研究[J].现代口腔医学杂志,2003,(2)：109-111.
[114]宁巍巍,刘同慎,李笑岩,等.大鼠肝癌发生过程中Caspase-3的表达及意义[J].滨州医学院学报,2009,(5)：321-323.
[115]Park DY, Sol MY, Suh KS, at al.Expressions of transforming growth factor (TGF)-betal and TGF-beta type Ⅱ receptor and their relationship with apoptosis during chemical hepatocarcinogenesis in rats [J].Hepatol Res,2003,27(3): 205-213.
[116]谢晶日,梁国英,李明,等.益气活血化瘀法对大鼠肝癌过程中Caspase-3及组织学影响的研究[J].中医药信息,2009,(1)：68-69+100.
[117]Awasthi YC, Sharma R, Cheng JZ, et al. Role of 4-hydroxynonenal in stress-mediated apoptosis signaling [J]. Mol Aspects Med,2003,24(4-5): 219-230.
[118]解燕茹.凋亡调控蛋白Bcl-2、Bax与非酒精性脂肪性肝病的关系及药物干预研究[D].山西医科大学：山西医科大学,2010.
[119]罗新华,杨勤,程明亮,等.肝纤维化形成过程中大鼠肝组织Bcl-2、Bax表达的动态研究[J].贵州医药,2004,(7)：579-581.
[120]贾旭东,韩驰,陈君石.茶多酚、茶色素对大鼠肝癌癌前病变抑制作用及机理研究[J].卫生研究,2001,(3)：168-169.
[121]宗蕾,姚登福,吴玮,等.Bcl-2在肝细胞癌变过程中凋亡抑制作用的动态分析[J].世界华人消化杂志,2007,(21)：2279-2283.
[122]龙冬梅.细胞凋亡及凋亡相关基因在大鼠肝癌促癌过程中的作用研究[D].第三军医大学：第三军医大学,2001.
[123]杨早,章永红,彭海燕,等.番荔枝总提取物对二乙基亚硝胺诱发大鼠肝脏癌前病变的影响[J].上海中医药杂志,2006,(5)54-57：.
[124]张光谋,李虎,王兴平.大鼠肝脏癌前病变与bcl-2和bax表达关系[J].中国公共卫生,2011,(11)：1448-1450.
[125]刘洪付.Bcl-2和Bax在DEN诱发大鼠肝癌细胞上的表达[D].泰山医学院：泰山医学院,2011.
[126]何田田,熊二峰,陈清,等.大鼠肝脏癌前病变肝细胞凋亡及Fas/FasL的表达[J].新乡医学院学报,2010,(3)：239-243.
[127]Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis [J]. Gastroenterology,2003,125(2):437-443.
[128]Issa R, Williams E, Trim N, et al. Apoptosis of hepatic stellate cells: involvement in resolution of billary fibrosis and regulation by soluble growth factors [J]. Gut,2001,48 (4):548-557.
[129]Akazawa Y, Gores G J. Death recep tor-mediated liver injury [J]. Semin LiverDis,2007,27 (4):327-338.
[130]陶艳艳,刘成海.TGF-β1刺激肝星状细胞活化与肝纤维化的分子病理机制研究进展[J].中西医结合肝病杂志,2006,16(2)：125-127.
[131]Friedman S L. Hepatic stellate cells:protean, multifunctional, and enigmatic cells of the liver [J]. Physiol Rev,2008,88(1):125-172.
[132]周明玉,程明亮.TGFβ1刺激肝星状细胞的活化与肝纤维化的研究进展[J].贵州医药,2008,32(8)：751-753.
[133]Tsukada S, Parsons CJ, Rippe RA.Mechanisms of liver fibrosis [J]. Clin Chim Acta,2006,364(1-2):33-60.
[134]Ward DG, Cheng Y, N'Kontchou G, et al. Changes in the serum proteome associated with the development of hepatocellular carcinoma in hepatitis C-related cirrhosis [J]. Br J Cancer,2006,94(2):287-292.
[135]郭顺根,戴敏,张玮.肝纤维化发生发展与信号转导途径[J].中国组织化学与细胞化学杂志,200,312：106-111.
[136]Pardali K, Kowanetz M, Heldin CH, et al. Smad pathway-specific transcriptional regulation of the cell cycle inhibitor p21(WAF1/Cip1) [J]. J Cell Physiol,2005,204(1):260-272.
[137]Tsukada S, Westwick JK, Ikejima K, et al. SMAD and p38 MAPK signaling pathways independently regulate alphal(Ⅰ) collagen gene expression in unstimulated and transforming growth factor-beta- stimulated hepatic stellate cells [J]. J Biol Chem,2005,280(11):10055-10064.
[138]Novakova-Jiresova A, Van Gameren MM, Coppes RP, et al.Transforming growth factor-beta plasma dynamics and postirradiation lung injury in lung cancer patients [J]. Radiother Oncol,2004,71(2):183-189.
[139]施承松,王祥珍.转化生长因子β1在宫颈癌组织中的表达及其意义[J].广东医学院学报,2005,23(5)：515-516.
[140]王秀梅,刘成敏,张成仁.转化生长因子β1信号传导通路在口腔鳞癌中的功能意义[J].中华肿瘤杂志,2009,1(31)：28-32.
[141]Simeone DM, Zhang L, Graziano K,et al. Smad4 mediates activation of mitogenactivated Protein kinases by TGF-beta in Pancreatic acinar cells [J]. Am J Physiol Cell Physiol,2001,281(1):C311-C319.
[142]LIU X, HU H, YIN JQ. Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis [J]. Liver Int,2006,26 (1):8-22.
[143]Konrad L, Scheiber JA, Schwarz L,at al. TGF-betal and TGF-beta2 strongly enhance the secretion of plasminogen activator inhibitor-1 and matrix metalloproteinase-9 of the human prostate cancer cell line PC-3 [J].Regul Pept, 2009,155(1-3):28-32.
[144]Fukumura Y, Kumasaka T, Mitani K, et al. Expression of transforming growth faetor betal, beta2, and beta3 in chronic, cancer-associated, obstructive pancreatitis [J]. Arch Pathol Lab Med,2006,130(3):356-361.
[145]Jong HS, Lee HS, Kim TY, et al. Attenuation of transforming growth factor beta-induced growth inhibition in human hepatocellular carcinoma cell lines by cyclin Dloverexpression [J].Biochem Biophys Res Commun,2002,292(2): 383-389.
[146]Herrmann J, Haas U, Gressner A M, et al.TGF-beta up-regulates serum response factor in activated hepatic stellate cells [J]. Biochim Biophys Acta,2007, 1772(11-12):1250-1257.
[147]程朋,曾维政,张涛.TGF-p/Smads信号转导通路与肿瘤研究进展[J].中国肿瘤,2008,17(3)：202-207.
[148]熊振芳.蕲艾提取液对肝纤维化大鼠TGFβ-Smad信号转导通路的影响[D].湖北中医药大学：湖北中医药大学,2010.
[149]林文生,张农,张颂文,等.PAI-1在TGF-β1基因和反义TGF-β1基因转染人肝癌细胞株中的表达[J].临床与实验病理学杂志,2000,16(3)：221-223.
[150]过建春,陈群伟,包剑锋,等.转化生长因子β1在肝纤维化发病中的作用[J].国际消化病杂志,2009,29(2)：86-88.
[151]林国友,童夏生,陈春晓.肝硬化患者血浆表皮生长因子和转化生长因子p1的表达[J].浙江医学,2007,(6)：626-627.
[152]Abou-Shady M, Baer HU, Friess H, et al. Transforming growth factor betas and their signaling receptors in human hepatocellular carcinoma [J]. Am J Surg, 1999; 177:209-215.
[153]徐新保,冷希圣,杨晓.反义Smad4基因转染对抗昆明小鼠肝脏纤维化发展的效果观察[J].中国普通外科杂志,2004,19：50-52.
[154]Tsukada S, Parsons CJ, Rippe RA. Mechanisms of liver fibrosis [J]. Clin Chim Acta,2006,364(1-2):33-60.
[155]Mccafrey TA, Consigli S, Du B, et al. Decreased type II/type I TGF-beta receptor ratio in cells derived from human atherosclerotic lesions. Conversion from an antiproliferative to profibrotic response to TGF-betal [J]. J Clin Invest, 1995,96(6):2667-2675
[156]俞蕾敏,吕宾,李善高,等.大鼠肝硬化形成过程中肝组织TGF-β1, Smad3, Smad7水平动态的变化[J].世界华人消化杂志2007,15(30)：3163-3267.
[157]孔丽.肝癥口服液含药血清对肝癌细胞TGF-pi/Smads信号转导通路的调控作用[D].河北医科大学：河北医科大学,2005.
[158]王奕,季光,王育群,等.二甲基亚硝胺致大鼠肝癌前病变TGF-βRⅡ的表达及中药的调节[J].浙江中西医结合杂志,2001,11(1)：23-24.
[159]Park DY, Hwang SY, Suh KS. Expression of transforming growth factor (TGF)-betal and TGF-beta type Ⅱ receptor in preneoplastic lesions during chemical hepatocarcinogenesis of rats.Toxicol Pathol [J].2001,29:541-549.
[160]Ichimura R, Mizukami S, Takahashi M, at al. Disruption of Smad-dependent signaling for growth of GST-P-positive lesions from the early stage in a rat two-stage hepatocarcinogenesis model [J]. Toxicol Appl Pharmacol,2010,25.
[161]崔巍.外源性TGF-β1对WB鼠肝脏上皮细胞内磷酸化Smad2/Smda3和Smad7分布的影响[D].中国医科大学：中国医科大学,2005.
[162]LiJ H, Zhu HJ, Huang XR, et al. Smad7 inhibits fibortic effect of TGF-beta on rnal tubular epihthelia cells by blocking Smada2 activation [J]. J Am Soc Nephorl,2002,13:1464-1472.
[163]Barthelemy-Brichant N, David JL, Bosquee L, et al. Increased TGFbetal plasma level in patients with lung cancer:potential mechanisms [J]. Eur J Clin Invest,2002,32(3):193-198.
[164]Zhao L, Sheldon K, ChenM, et a.l The predictive role of plasma TGF-betal during radiation therapy for radiation-induced lung toxicity deserves further study in patients with non-small cell lung cancer [J]. Lung Cancer,2008,59(2): 232-239.
[165]Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signaling [J]. Nature,1997,389(6651):631-635.
[166]华赟鹏,李绍强,赖佳明,等.实验性大鼠肝脏癌变过程中转化生长因子-β1/Smads信号通路系列变化的研究[J].南方医科大学学报,2008,(10)：1848-1852.
[167]Park DY, Lee CH, SolMY, et al. Expression and localization of the transforming growth factor-beta type I receptor and Smads in preneoplastic lesions during chemical hepatocarcinogenesis in rats. J Korean Med Sci [J].2003,18(4): 510-519.
[168]Yan X, Lin Z, Chen Y. Regulation of TGF-beta signaling by Smad7 [J]. Acta Biochim Biophys Sin (Shanghai),2009,41(4):263-272.
[169]Agarwal C, Britton ZT, Alaseirlis DA, et al. Healing and normal fibroblasts exhibit differential proliferation, collagen production, alph -SMA expression, and contraction [J]. Ann Biomed Eng,2006,34(4):653-659.
[170]姜大朋,李昭铸,蒋志涛,等.肝细胞生长因子阻抑TGF-β1诱导大鼠韧带成纤维细胞a-SMA过表达及其机制[J].中国康复医学杂志,2009,(10)：906-909.
[171]刘恒兴,刘斌,王环震,等.大鼠肝部分切除后肝细胞再生及肝星状细胞α-平滑肌肌动蛋白表达变化与肝细胞生长因子的干预作用[J].中国组织工 程研究与临床康复,2008,12(18)：3511-3514.
[172]王宇,高毅,黄宇琦,等,实验性肝纤维化间质胶原酶表达的研究[J].中华消化杂志,2003,20(1)：67-69.
[173]郭来,王再谟.肝心宁胶囊对肝纤维化HA,LN,PCⅢ,C-Ⅳ的影响及机理研究[J].中华中医药学刊,2008,26(5)：1049-1051.
[174]朴熙绪,黄红果,朴东明.草苁蓉乙醇提取物对二甲基亚硝胺诱导大鼠肝纤维化的治疗作用[J].世界华人消化杂志,2005,(18)：2205-2209.
[175]Visser, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases:Structure, function and bio-chemistry [J]. Cir Res,2003, 827-839.
[176]熊敏莉,吴建新.基质金属蛋白酶及其抑制因子与肝纤维化[J].实用医学杂志,2008,(24)：4318-4321.
[177]Hirano S, Bless D, Heisey D, et al. Roles of hepatocyte growth factor and transforming growth factor betal in production of extracellular matrix by canine vocal fold fibroblasts [J]. Laryngoscope,2003,113(1):144-148.
[178]杨牧祥,张一听,于文涛,等.柔肝消癥饮对肝硬化大鼠肝脏TIMP-1和TGFp-1表达的影响[J].中国中西医结合消化杂志,2010,(6)：377-380.
[179]Weiss A, Goldman S, Shalev E. The matrix metalloproteinases (MMPS) in the decidua and fetal membranes [J]. Front Biosci.2007,12:649-659.
[180]Sakaida I, Hironaka K, Terai S, Okita K.Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrixmetalloproteinases (MMPs) of Kupffer cells [J]. Life Sci,2003,72(8): 943-959.
[181]赵志海,辛绍杰,赵景民,等.实验性肝纤维化逆转过程中基质金属蛋白酶表达的动态研究[J].临床肝胆病杂志,2007,(1)：21-23.
[182]Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases:structure function, and biochemistry [J]. Circ Res 2003, 92(8):827-839.
[183]Murphy FR, Issa R, Zhou X, Ratnarajah S, et al. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metailoproteinase-1 is mediated via effects on matrix metalloproteinase inhibition:implications for reversibility of liver fibrosis [J]. J Biol Chem,2002,277(13):11069-11076
[184]杨长青,王吉耀,郭津生,等,基质金属蛋白酶1表达质粒对实验性肝纤维化的影响[J].中华消化杂志,2004,20(5)：297-299.
[185]姜宪辉,叶华,孙雷.TNF-α、MMP-1及其抑制剂在肝纤维化组织中的表达及其相关性研究[J].中国现代医药杂志,2008,10(10)：36-38.
[186]赵志海,辛绍杰,赵景民,等.实验性肝纤维化形成和逆转过程中基质金属蛋白酶13蛋白及其mRNA表达[J].军医进修学院学报,2002,23(3)：214-216.
[187]Fortunato SJ, Menon R, Lombardi SJ. Amniochorion gelatinase- gelatinase inhibitor imbalance in vitro:a possible infectious pathway to rupture [J]. Obstet Gynecol,2000,95(2):240-244.
[188]El-Gindy I, El Rahnan AT, El- Alim MA, et al. Diagnostic potential of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as non-invasive markers of hepatic fibrosis in patients with HCV related chronic liver disease [J]. Egypt J Immuno,2003,10(1):127-135.
[189]蒋泽生,方石岗,高毅,等.二乙基亚硝胺诱发大鼠肝细胞癌发生过程中基质金属蛋白酶动态变化[J].世界华人消化杂志,2001,9：759-762.
[190]Sivaramakrishnan V, Niranjali Devaraj S.Morin regulates the expression of NF-kappaB-p65, COX-2 and matrix metalloproteinases in diethylnitrosamine induced rat hepatocellular carcinoma [J]. Chem Biol Interact,2009,180(3): 353-359.
[191]王宪波,刘平,唐志鹏,等.大鼠肝纤维化形成中基质金属蛋白酶2、9活性变化的病理意义[J].中华肝脏病杂志,2004,12(5)：267-270.
[192]Hemmann S, Graf J, Roderfeld M,et al. Expression of MMPs and TIMPs in liver fibrosis-a systematic review with special emphasis on anti-Fibrotic strategies [J]. J Hepatol,2007,46(5):955-975.
[193]Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs):an ancient family with structural and functional diversity [J]. Biochim Biophys Acta,2010,1803(1):55-71.
[194]Visse R, NagaseH. Matrix metalloproteinases and tissue inhibitors of Metalloproteinases:structure, function, and biochemistry [J]. Circ Res,2003, 92 (8):827-839.
[195]Roderfeld M, Hemmann S, Roeb E. Mechanisms of fibrinolysis in chronic liver injury (with special emphasis on MMPs and TIMPs) [J]. Z Gast roent-erol, 2007,45(1):25-33.
[1]Diaz-Gil JJ, Escartin P, Garcia-Canero R, et al. Purification of a liver DNA-synthesis promoter fromplasma of partially hepatectomized rats [J].BiochemJ,1986,235(1):49-55.
[2]Naldini L, Vigna E, Narsimhan RP, et al. Hepatocyte growth factor (HGF) stimulates the tyrosine kinaseactivity of the receptor encoded by the proto-oncogene c-MET [J]. Oncogene,1991,6(4):501-504.
[3]Stamos J, Lazarus R A, Yao X, et al. Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor [J]. EMBO J,2004,23(12): 2325-2335.
[4]Kirchhofer D, Lipari MT, Santell L, et al. Utilizing the activation mechanism of serine proteases to engineer hepatocyte growth factor into a Met antagonist [J]. Proc Natl Acad Sci USA,2007,104(13):5306-5311.
[5]Komada M, Kitamura N. The cell dissociation and motility triggered by scatter factor/hepatocyte growth factor are mediated through the cytoplasmic domain of the c-Met receptor [J]. Oncogene,1993,8(9):2381-2390.
[6]Comoglio PM. Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells [J]. EXS,1993,65(1):131-165.
[7]Tajima H, Matsumoto K, Nakamura T. Regulation of cell growth and motility by hepatocyte growth factor and receptor expression in various cell species [J]. Exp Cell Res,1992,202(2):423-431.
[8]Tajima H, Higuchi O, Mizuno K, et al. Tissue distribution of hepatocyte growth factor receptor and its exclusive down-regulation in a regenerating organ after injury [J]. J Biochem Tokyo,1992,111(3):401-406.
[9]Block GD, Locker J, Bowen WC, et al. Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes inducedby HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium [J]. J Cell Biol,1996,132(6):1133-1149.
[10]Kono S, Nagaike M, Matsumoto K, et al. Marked induction of hepatocyte growth factor mRNA in intact kidney and spleen in response to injury of distant organs [J]. Biochem Biophys Res Commun,1992,186(2):991-998.
[11]Ramadori G, Neubauer K, Odenthal M, et al. The gene of hepatocyte growth factor is expressed in fat-storing cells of rat liver and is downregulated during cell growth and by transforming growth factor-beta [J]. Biochem Biophys Res Commun,1992,183(2):739-742
[12]Taub R. Liver regeneration:from myth to mechanism [J]. Nat Rev Mol Cell Biol, 2004,5(10):836-847.
[13]Michalopoulos GK, Zarnegav R. Hepatocyte growth factor [J]. Hepatology 1992, 151(1):149-155.
[14]Lindroos PM, Zarnegar R, Michalopoulos GK. Hepatocyte growth factor (hepatopoietin A) rapidly increases in plasma before DNA synthesis and liver regeneration stimulated by partial hepatectomy and carbon tetrachloride administration [J]. Hepatology,1991,13(4):743-749.
[15]Michalopoulos GK, Defrances MC. Liver regeneration [J]. Science,1997, 276(5309):60-66.
[16]Shiota G, Kawasaki H. Hepatocyte growth factor in transgenic mice [J]. Int J Exp Pathol,1998,79(5):267-277.
[17]Kinoshita T, Hirao S, Matsumoto K, et al. Possible endocrine control by hepatocyte growth factor of liver regeneration after partial hepatectomy [J]. Biochem Biophys Res Commun 1991,177(1):330-335
[18]Tomiya T, Nagoshi S, Fujiwara K. Significance of serum human hepatocyte growth factor levels in patients with hepatic failure [J]. Hepatology,1992, 15(1):1-4.
[19]俞炯,姚一帆,吕建等.部分肝切除小鼠肝再生的研究[J].温州医学院学报,2008,(5)：415-417.
[20]朱洪,郭永章,李立等.促肝细胞生长素对慢性肝损伤鼠肝部分切除术后肝细胞的影响[J].中国普通外科杂志,2002,11(1)：29-32.
[21]朱洪,张炳彦,郭永章,等.肝细胞生长因子对慢性肝损伤时肝部分切除术后肝细胞影响的实验研究[J].肝胆外科杂志,2001,9(1)：59-61.
[22]Kaido T, Yoshikawa A, Seto S. Hepatocyte growth factor supply accelerates compensatory hypertrophy caused by portal branch ligation in normal and jaundiced rats [J]. J Surg Res,1999,85(1):115-119.
[23]Cramer T, Schuppan D, Bauer M, at al.Hepatocyte growth factor and c-Met expression in rat and human liver fibrosis.Liver Int [J].2004,24(4):335-44.
[24]Takemura M, Furuta N, Nakamura S, et al. Determination and clinical significance of human hepatocyte growth factor in serum [J]. Rinsho Byori,1992, 40(11):1168-1172.
[25]吴福生,郑树森,吴灵娇,等.肝细胞生长因子及其受体c-met在肝细胞癌中的表达与预后价值[J].中华外科杂,2006,(9)： 603-608.
[26]Vejchapipat P, Tangkijvanich P, Theamboonlers A, et al. Association between serum hepatocyte growth factor and survival in untreated hepatocellular carcinoma [J]. J Gastroenterol,2004,39(12):1182-1188.
[27]Shiota G, Rhoads DB, Wang TC, at al. Hepatocyte growth factor inhibits growth of hepatocellular carcinoma cells [J]. Proc Natl Acad Sci U.S.A 1999,89(1): 373-377.
[28]Shiota G, Kawasaki H. HePatoeyte growth factor in transgenie mice [J]. Int J EWP Pathol,1998,79(5):267-277.
[29]Taira K, Hiroyasu S,Shiraishi M, et al. Role of the Fas system in liver regeneration after a partial hepatectomy in rats [J]. Eur Surg Res,2001,33: 334-341.
[30]梁明,李峰,李静媛.外源性肝细胞生长因子抗肝细胞凋亡机制的研究[J].肝脏,2007,(6)：466-468.
[31]Kim WH, Matsumoto K, Bessho K, et al. Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis [J]. Am J Pathol,2005,166(4):1017-1028.
[32]时多.大鼠肝再生过程中细胞凋亡及机制研究[D].第二军医大学：第二军医大学,2008.
[33]Sato M, Kakubari M, Kawamura M, et al. The decrease in total collagen fibers in the liver by hepatocyte growth factor after formation of cirrhosis induced by thioacetamide [J]. Biochem Pharmacol,2000,59(6):681-690.
[34]Horiguchi K, Hirano T, Ueki T, et al. Treating liver cirrhosis indogs with hepatocyte growth factor gene therapy via the hepatic ar-tery [J]. J Hepatobiliary Pancreat Surg,2009,16(2):171-177.
[35]Shukla MN, Rose JL, Ray R, et al. Hepatocyte growth factor inhibits epithelial to myofibroblast transition in lung cells via smad7 [J]. Am J Respir Cell Mol Biol, 2009,40(6):643-653.
[36]Inagaki Y, Higashi K, Kushida M, et al. Hepatocyte growth factor suppresses profibrogenic signal transduction via nuclear export of Smad3 with galectin-7 [J]. Gastroenterology,2008,1180-1190.
[37]姜大朋,李昭铸,蒋志涛,等.肝细胞生长因子阻抑TGF-β1诱导大鼠韧带成纤维细胞α-SMA过表达及其机制[J].中国康复医学杂志,2009,(10)：906-909.
[38]Schievenbusch S, Strack I, Scheffler M,at al. Profiling of anti-fibrotic signaling by hepatocyte growth factor in renal fibroblasts [J]. Biochem Biophys Res Commun.2009,385(1):55-61.
[1]黄文林,朱孝峰.信号转导[M].北京：人民卫生出版社,2005.
[2]Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signaling [J]. Nature,1997,389(6651):631-635.
[3]Wang W, Huang XR, Canlas E, et al. Essential role of Smad3 in angiotensin II-induced vascular fibrosis [J]. Circ Res,2006,98(8):1032-9.
[4]Visse R,NagaseH.Matrix metalloproteinases and tissue inhibitors of Metalloproteinases:structure, function, and biochemistry [J]. Circ Res,2003, 92 (8):827-839.
[5]Hemmann S, Graf J, Roderfeld M,et al. Expression of MMPs and TIMPs in liver fibrosis-a systematic review with special emphasis on anti-Fibrotic strategies [J]. J Hepatol,2007,46(5):955-975.
[6]Patterson ML, Atkinson SJ, Knauper V, et al. Specific collagenolysis by gelatinase A,MMP-2, is determined by the hemopexin domain and not the fibronectin-like domain [J]. FEBS Lett,2001,503(2-3):158-162.
[7]Roderfeld M, Hemmann S, Roeb E.Mechanisms of fibrinolysis in chronic liver injury (with special emphasis on MMPs and TIMPs) [J]. Z Gastroenterol,2007, 45(1):25-33.
[8]Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs):an ancient family with structural and functional diversity [J]. Biochim Biophys Acta, 2010,1803(1):55-71.
[9]Tsukada S, Parsons CJ, Rippe RA. Mechanisms of liver fibrosis [J]. Clin Chim Acta,2006,364(1-2):33-60.
[10]Pan CH, Wen CH, Lin CS. Interplay of angiotensin Ⅱ and angiotensin(1-7) in the regulation of matrix metalloproteinases of human cardiocytes [J]. Exp Physiol, 2008,93(5):599-612.
[11]Hu H, Yin JQ. Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis [J]. Liver Int.2006,26(1):8-22.
[12]Bednarek N, Svedin P, Garnotel R, Favrais G, et al. Increased MMP-9 and TIMP-1 in mouse neonatal brain and plasma and in human neonatal plasma after hypoxia-ischemia:a potential marker of neonatal encephalopathy [J]. Pediatr Res, 2012,71(1):63-70.
[13]Murphy FR, Issa R, Zhou X, Ratnarajah S, et al. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metailoproteinase-1 is mediated via effects on matrix metalloproteinase inhibition:implications for reversibility of liver fibrosis [J]. J Biol Chem,2002,277(13):11069-11076.
[14]Yu WH, Yu S, Meng Q, et al. TIMP-3 binds to sulphated glycosaminog-lycans of the extracellular matrix [J]. J Biol Chem,2000,275(40):31226-31232.
[15]Kinoshita J, Kitamura K, Kabashima A, et al. Clinical significance of vascular endothelial growth factor-C (VEGF-C) in breast cancer [J]. Breast Cancer Res Treat,2001,66(2):159-164.
[16]Kopp JB, Factor VM, Mozes M, et al. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease [J]. Lab Invest,1996,74 (6):991-1003.
[17]李蕾.肝纤维化中肝星状细胞迁移及RhoA作用机制的研究[D].复旦大学,2006.
[18]Wells RG. Fibrogenesis.V.TGF-beta signaling pathways [J]. Am J physiol Gastrointest Liver Physiol,2000,279(5):G845-G850.
[19]邰伯军,姚登福,邹黎,等.肝细胞癌变过程中TGF-β1及TNF-α的动态表达与改变[J].胃肠病学和肝病学杂志,2006,(3)：277-280.
[20]蒋莹,赵金仙.肝硬化组织转化生长因子(β-1(TGFβ-1)的表达及临床意义[J].新疆医科大学学报,2008,(6)：739.
[21]李国强,王学浩,孙跃明,等.肝硬化肝癌大鼠TGF-β-1和受体的表达及其意义[J].中国肿瘤临床,2003,(2)：60-63.
[22]张一昕,杨牧祥,于文涛,等.柔肝消癥饮对肝硬化大鼠血清及肝脏转化生长因子β1的影响[J].中西医结合肝病杂志,2011,(1)：31-33.
[23]马蓉,黎音,付娟娟.TβRⅠ和Smad4在肝细胞癌中的表达及意义[J].新疆医科大学学报,2007,(6)：584-585+588.
[24]俞蕾敏,吕宾,李善高,等.大鼠肝硬化形成过程中肝组织TGF-β1,Smad3, Smad7水平动态的变化[J].世界华人消化志,2007,(30)：3163-3167.
[25]徐新保,何振平,梁志清,等.腺病毒介导反义Smad4基因大鼠体内转移对实验性肝纤维化的治疗作用[J].中华消化杂志,2004,(6)：53-54.
[26]翁红雷,Axel M.Gressner,Steven Dooley.肝星状细胞IFN-γ信号传导途径及对TGF-β的抑制[A].[C],2004：275.
[27]Ichimura R, Mizukami S, Takahashi M, at al. Disruption of Smad-dependent signaling for growth of GST-P-positive lesions from the early stage in a rat two-stage hepatocarcinogenesis model [J]. Toxicol Appl Pharmacol.2010,25.
[28]王奕,季光,王育群,等.二甲基亚硝胺致大鼠肝癌前病变TGF-βRⅡ的表达及中药的调节[J].浙江中西医结合杂志,2001,11(1)：23-24.
[29]华赞鹏,李绍强,赖佳明,等.实验性大鼠肝脏癌变过程中转化生长因子 -β1/Smads信号通路系列变化的研究[J].南方医科大学学报,2008,(10)：1848-1852.
[30]廖丹,罗光汉,吴继周,等.TGF-β1和smad4mRNA在慢性肝炎、肝硬化、肝癌癌旁组织的表达及意义[J].世界华人消化杂志,2004,(09)：81-84.
[31]Park DY, Sol MY, Suh KS, at al. Expressions of transforming growth factor (TGF)-betal and TGF-beta type Ⅱ receptor and their relationship with apoptosis during chemical hepatocarcinogenesis in rats.Hepatol Res [J].2003,27(3): 205-213.
[32]Park DY, Hwang SY, Suh KS. Expression of transforming growth factor (TGF)-betal and TGF-beta type Ⅱ receptor in preneoplastic lesions during chemical hepatocarcinogenesis of rats.Toxicol Pathol [J].2001,29(5):541-9.
[33]Park DY, Lee CH, SolMY, et al. Expression and localization of the transforming growth factor-beta type I receptor and Smads in preneoplastic lesions during chemical hepatocarcinogenesis in rats [J]. J Korean Med Sci.2003,18(4): 510-519.
[34]Koniaris LG,M cKillop IH, Schwartz SI, et al. Liver regeneration [J]. J Am CollSurg,2003,197(4):634-659.
[35]高春芳.转化生长因子p1与肝纤维化[J].中华医学杂志,2005,85(15)：1074-1077.
[36]SakamotoT,Liu Z, MuraseN,etal. Mitosis and apoptosis in the liver of interleukin-6-deficientmice after partialhepatectomy [J]. Hepatology,1999,29(2):403-411.
[37]王春雷,黄志强,周宁新,等.TGF-β1诱导肝硬化小鼠肝细胞凋亡信号转导机制的研究[J].中国普通外科杂志,2004,574-577.
[38]尹纪业.肝非实质细胞在肝再生中的作用研究[D].中国人民解放军军事医学科学院：中国人民解放军军事医学科学院,2007.
[39]Miwa Y, Harrison PM, Farzaneh F,et al. Plasma levels and hepatic mRNA expression of transforming growth factor-betal in patients with fulminanthepatic failure [J]. J Hepatol,1997,27(5):780-788.
[40]袁发焕,王海燕,李惊子.ECM,MMPs/TIMPs及其调节研究进展[J].国外医 学(生理、病理科学与临床分册),2000,(2)：93-96.
[41]Nagashio Y, Ueno H, Imamura M. Inhibition of transforming growth factor beta decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice [J]. Lab Invest,2004,84(12):1610-1618.
[42]Cai T, Lei QY, Wang LY, et al. TGF-beta 1 modulated the expression of alpha 5 beta 1 integrin and integrin-mediated signaling in human hepatocarcinoma cells [J]. Biochem BiophysRes Commun,2000,274 (2):519-525.
[43]RiederH, Armbrust T, Meyer zum Buschenfelde KH,et al. Contribution of sinusoidal endothelial liver cells to liver fibrosis:expression of transforming growth factor-beta 1 receptors and modulation of plasmin-generating enzymes by transforming growth factor-beta 1 [J]. Hepatology,1993,18(4):937-944.
[44]杨牧祥,张一昕,于文涛,等.柔肝消癥饮对肝硬化大鼠肝脏TIMP-1和TGFp-1表达的影响[J].中国中西医结合消化杂志,2010,(6)：377-380.
[45]Tsukada S, Parsons CJ, Rippe RA. Mechanisms of liver fibrosis [J]. Clin Chim Acta,2006,364(1-2):33-60.
[46]Gooch JL, Gorin Y, Zhang BX, et al. Involvement of calcineurin in transforming growth factor-βmediated regulation of extracellular-matrix accumulation [J]. J BiolChen,2006,279 (15):15561-15570
[47]袁发焕,王海燕,李惊子.ECM,MMPs/TIMPs及其调节研究进展[J].国外医学(生理、病理科学与临床分册),2000,(2)：93-96.
[48]熊敏莉,吴建新.基质金属蛋白酶及其抑制因子与肝纤维化[J].实用医学杂志,2008,(24)：4318-4321.
[49]陈妍,崔文丽,黎音.肝硬化组织中MMP-1和VEGF的表达及其意义[J].新疆医科大学学报,2008,(5)：551-553.
[50]赵志海,辛绍杰,赵景民,等.实验性肝纤维化逆转过程中基质金属蛋白酶表达的动态研究[J].临床肝胆病杂志,2007,(1)：21-23.
[51]陈江,章荣华,吴蕙岭,等.实验性肝纤维化形成和逆转过程中MMP-2及其抑制物TIMP-2表达的动态研究[J].中国卫生检验杂志,2010,(10)：2401-2403+2406.
[52]张平,李国富,刘娅,等.基质金属蛋白酶-2在肝硬化患者肝组织中的表达[J].宁夏医学院学报,2008,(4)：443-444+451+554.
[53]于晓红.Ⅳ型胶原酶门脉灌注对四氯化碳诱导兔肝硬化影响的实验研究[D].中国人民解放军军医进修学院：中国人民解放军军医进修学院,2011.
[54]Duka I, Bakris G. Influence of microalbuminuria in achieving blood pressure goals [J]. Curr Opin Nephrol Hypertense,2008,17(5):457-463.
[55]鲍利民,齐若梅,高欣,等.ELISA法检测尿微量白蛋白的临床应用与评价[J].中国卫生检验杂志,2006,16(2)：227-228.
[56]Kralliedde J, Viberti G. Microalbuminuria and cardiovascular risk [J]. Am J Hypertens,2004,17(10):986-993.
[57]蒋莹,赵文军.基质金属蛋白酶组织抑制因子-1在肝硬化组织中的表达及意义[J].新疆医科大学学报,2007,(10).
[58]杨牧祥,张一听,于文涛,等.柔肝消癥饮对肝硬化大鼠肝脏TIMP-1和TGFp-1表达的影响[J].中国中西医结合消化杂志,2010,(6)：1128-1129.
[59]朱跃科,段钟平,王宝恩,等.芪参益气滴丸对DMN大鼠肝纤维化及肝组织TIMP-1表达的影响[J].中国新药与临床杂志,2007,(1)：11-16.
[60]El-Gindy I, El Rahman A T, El-Alim M A, et al. Diagnostic potential of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as non-invasive markers of hepatic fibrosis in patients with HCV related chronic liver disease [J]. Egypt J Immunol,2003:10 (1):27-35.
[61]杨长青,胡国龄,谭德明,等.基质金属蛋白酶-1、反义金属蛋白酶组织抑制因子-1表达质粒对大鼠肝纤维化的影响[J].中华传染病杂志,2000,(1)：28-31.
[62]谢碧红,杨觉民,吴引伟.化纤复肝方对慢性肝炎患者MMP-1、TIMP-1及其抑制因子表达的影响[J].辽宁中医杂志,2011,(8)：1665-1666.
[63]张虹,周欢琴,翁秀妹,等.肝病患者血浆MMP-3、TIMP-1、u-PA和u-PAR水平的临床研究[J].中国卫生检验杂志,2010,(1)：107-109.
[64]刘江,施柏年,何建方,等.氧化苦参碱对慢性乙肝和肝硬化患者血清MMP-2和TIMP-2的影响[J].中国中西医结合杂志,2005,(11)989-992.
[65]朱虹,吴樱樱,徐明,等.肝灵对胆汁淤积性肝硬化大鼠肝组织MMP-13、TIMP-1和NF-κBp65表达的影响[J].安徽医科大学学报,2005,(6)：29-32.