泽泻醇B乙酸酯抗乙肝作用及机理研究
|
摘要
由乙型肝炎病毒引起的肝炎是一种严重危害人体健康的病毒性传染病。据世界卫生组织报道,全球有超过20亿人为乙型肝炎病毒携带者,其中约3亿人为慢性终身感染者。而我国的乙肝患者就约占了一半,直到2008年我国乙肝表面抗原携带者约有9300万人。于此同时每年仍约有200万新发肝炎病人,其中乙型肝炎占20%。与非乙肝病毒携带者相比,慢性肝炎感染患者面临较高的肝硬化或癌变的风险。目前在尚未找到能彻底根治乙肝的方法同时,由于近年HBV免疫疫苗、各种抗病毒药物的应用而导致HBV变异株的出现,使HBeAg阴性慢性乙型病毒性肝炎患者(CHBV)增多。而在最新的科学研究中,研究人员发现在感染病毒的肝细胞核内存在的病毒共价闭合环状DNA (covalently closed circular DNA, cccDNA),是病毒持续感染久治不愈的重要原因。因此科学研究者在研制不同类型的临床治疗药物的项目上着重研究药物对乙肝病毒cccDNA的影响,希望能够找到直接可以清除病毒cccDNA的药物,让乙肝病人痊愈成为现实。
HBV复制大约分别四个阶段：(1)乙肝病毒颗粒首先与细胞膜上的受体羧肽酶D结合,脱去外膜进入细胞内；(2)在经衣壳蛋白的磷酸化作用后脱去衣壳,乙肝病毒进入细胞内,并在细胞内转变成超螺旋DNA结构(cccDNA)。超螺旋DNA是HBV的转录模板,它可转录mRNA,也是造成乙肝病毒无法清除的重要原因之一；(3)在mRNA指导作用下病毒先合成前基因RNA,并在细胞核外被衣壳包裹,然后再以前基因RNA为模板,在细胞核外经逆转录合成乙肝病毒DNA负链,随后合成乙肝病毒正链；(4)衣壳中的乙肝病毒由膜包裹后分泌到细胞外以完整的病毒颗粒进入到其它细胞,也可重新脱去衣壳进入细胞核内,以维持细胞核内病毒超螺旋DNA(cccDNA)的数量。因此每个病毒复制的步骤都是研究抗乙肝病毒的关键,只要阻断病毒的复制过程就可以有效地抑制病毒的增殖。
经过大量的研究,乙肝病毒对肝细胞并无直接致病性。相反由乙肝病毒所引发的肝细胞损害的机制主要是由细胞免疫反应所引起的。在HBV感染过程中,先由单核巨噬细胞摄取病毒抗原并加工,然后提呈给Th细胞。然后在单核巨噬细胞释放的白细胞介素1(IL-1)协助下,促使Th细胞活化增殖而释放白细胞介素2(IL-2)。IL-2刺激已被HBV抗原致敏的Tc细胞发生克隆性增殖,形成大量效应性T细胞,攻击受HBV感染的肝细胞,最后导致肝细胞变性坏死。目前认为, Tc细胞攻击靶细胞需依赖所谓“双识别”,即只有表达靶抗原和Ⅰ类MHC抗原的肝细胞,才可能被Tc细胞识别、攻击和破坏。而肝细胞凋亡、HBV感染等多种因素所致的肝细胞损害,其最终表现也是肝细胞死亡。
本实验以乙肝病毒感染机制、慢性乙肝与cccDNA关系的研究为基础,研究实验药物泽泻醇B乙酸酯对乙肝病毒HBV的抑制作用及其作用机制。泽泻为泽泻科植物泽泻的块茎,性味甘、淡、寒,归肾、膀胱经,是利水渗湿用药,主要用于小便不利、水肿胀满、泄泻、尿少、痰饮、眩晕、热淋涩痛等症。泽泻的化学成分比较复杂,而泽泻醇B乙酸酯属于三萜化类合物。在有关泽泻醇B乙酸酯的研究中,学者们发现泽泻醇B乙酸酯具有多种生物活性：(1)诱导多种肿瘤细胞凋亡；(2)逆转P糖蛋白过表达癌细胞的多药耐药性,提高细胞对抗肿瘤药物的敏感性；(3)抑制抗体过敏性反应；(4)抑制细胞中氮氧化物(NO)的合成反应；(5)抑制乙肝病毒抗原活性,等等。因此泽泻醇B乙酸酯在抗病毒方面具有很大的潜力。
在本实验过程中,通过体外、体内实验平行检测泽泻醇B对病毒DNA的影响、对病毒cccDNA的影响从而探索泽泻醇B乙酸酯抗乙肝病毒的机制。在实验中,泽泻醇B乙酸酯在2.215细胞和鸭胚肝细胞上的对病毒的抑制作用并不一致。在2.215细胞上,泽泻醇B乙酸酯的TC50为23.71mmol/L,而在鸭胚肝细胞上的TC50为25.62mmol/L。泽泻醇B乙酸酯在HepG2.215细胞上对病毒两抗分泌的治疗指数分别为1.15、0.74,提示在HepG2.215上泽泻醇B乙酸酯对乙型肝炎病毒表面抗原分泌的抑制作用是在对细胞的毒性作用基础上发挥的,而对病毒的e抗原则无抑制作用。在先天DHBV感染鸭胚原代肝细胞上,泽泻醇B乙酸酯对病毒DNA的治疗指数可达到4.08,则显示出较好的抗病毒作用。在体内实验中,泽泻醇B乙酸酯对病毒的DNA和肝组织中的cccDNA也有一定的抑制作用。通过本实验的初步结果间接提示了泽泻醇B乙酸酯需要经过体内代谢的活化作用才能发挥药物的抗病毒作用。
Hepatitis is a kind of serious infectious virusis caused by Hepatitis B virus. According to the reports from WTO, over 2 billion people are HBV carriers, and more than 300 million are chronic infected. About half of the HBV infected people are in our country. The number of the HBsAg carriers is 9.3 million till 2008 in China and increase with 2 million every year. Compared with those non-HBV carriers, the HBV carries faced with much higher risk of liver cancer and cirrhosis. With the therapy of HBV vaccine and other anti-HBV medicines, which makes the HBV virus variating quickly, increases more and more chronic HBV infected patients. Scientists find out that the cccDNA of the HBV virus exits in the liver is the key to the chronic infection of HBV. So people put more energy in seeking for the medicine witch can erase viral cccDNA in liver, and make it possible to heal the HBV carriers completely.
The HBV replication includes four classes:first, the virus exuviates adventitia and enters into the infected hepatocytes with phosphorylase, the virus draws off the capsid protein and turn to the structure of cccDNA. cccDNA is the HBV replication template, and it also can transcript to mRNA. Then the virus integrates pre-RNA with the instruction of mRNA, and envelops with capsid in extranuclear. The virus reverses transcripts to negative DNA chain with the pre-RNA as template, and synthesizes to positive DNA chain. At last the complete virus which has infectious ability is secreted to extranculear to maintain the numbers of cccDNA. So blocking off the every step of viral replication is the key to heal hepatitis B disease.
In a great deal of researches, scientists find that the liver damage is caused by cell-mediated immunity but not the HBV virus itself. In the course of HBV infection, the monocyte-macrophage cells incepts and processes the viral antigen, then submits to the Th cell. With the IL-1 secreted from macrophage, the Th-cells are activated to multiplication and release IL-2. Then the sensitized Tc cells proliferate and turn into effect T cells. The effect T cells attack the hepatocytes affected by HBV virus, which lead to the liver damage. The scientists think the hepatocytes which can express target antigen and type 1 MHC antigen can be attacked by the Tc cells. And the apoptosis of cells and the viral infection are also the reasons of the damage-too.
My experiment is based on the mechanism of the HBV infection and the relationship between the chronic hepatitis B and cccDNA to describe the anti-HBV effect of Acetate alisol B. Acetate alison B is isolate from Radix Astragliz. In traditional Chinese medicine, Radix Astragliz attributes to sweet, light, cold, owned by the kidney and bladder, used in diuresis.And the compounds of Radix Astragliz is very complicated. The Acetate alisol B attributes to triterpenoid compounds of classes. It has many activated functions, such as inducing tumor apoptosis, enhancing the sensitive of the cells to the anti-tumor medicine, inhibiting hypersensitivity and the synthesis of NO, restraining HBV virus. So Acetate alisol B is very potential in anti-HBV medicine research.
We detect the viral DNA replication, and the presence of viral cccDNA in vivo and in vitro synchronously. In the assay, we found that different results showed in different cell models. On the HepG2.215 cell model, the TC50 of Acetate alisol B was 23.71mM, and the therapy index (TI) of HBsAg and HBeAg were 1.15,0.74 respectively, which showed that the Acetate Aliso B had not anti-HBV effect on HepG2.215 cells. But strangely, the data on primary duck hepatocyte cells showed that the Acetate Aliso B had a great anti-HBV effect on it. The TI of Acetate also B on restrain DHBV DNA was 4.08. The anti-HBV effect of Acetate alisol B is not apparent in HepG2.215 cells, but shows preliminary effect in vivo. So we surmise the Acetate alisol B has the effect to restrain HBV after metabolism in liver.
HBV复制大约分别四个阶段：(1)乙肝病毒颗粒首先与细胞膜上的受体羧肽酶D结合,脱去外膜进入细胞内；(2)在经衣壳蛋白的磷酸化作用后脱去衣壳,乙肝病毒进入细胞内,并在细胞内转变成超螺旋DNA结构(cccDNA)。超螺旋DNA是HBV的转录模板,它可转录mRNA,也是造成乙肝病毒无法清除的重要原因之一；(3)在mRNA指导作用下病毒先合成前基因RNA,并在细胞核外被衣壳包裹,然后再以前基因RNA为模板,在细胞核外经逆转录合成乙肝病毒DNA负链,随后合成乙肝病毒正链；(4)衣壳中的乙肝病毒由膜包裹后分泌到细胞外以完整的病毒颗粒进入到其它细胞,也可重新脱去衣壳进入细胞核内,以维持细胞核内病毒超螺旋DNA(cccDNA)的数量。因此每个病毒复制的步骤都是研究抗乙肝病毒的关键,只要阻断病毒的复制过程就可以有效地抑制病毒的增殖。
经过大量的研究,乙肝病毒对肝细胞并无直接致病性。相反由乙肝病毒所引发的肝细胞损害的机制主要是由细胞免疫反应所引起的。在HBV感染过程中,先由单核巨噬细胞摄取病毒抗原并加工,然后提呈给Th细胞。然后在单核巨噬细胞释放的白细胞介素1(IL-1)协助下,促使Th细胞活化增殖而释放白细胞介素2(IL-2)。IL-2刺激已被HBV抗原致敏的Tc细胞发生克隆性增殖,形成大量效应性T细胞,攻击受HBV感染的肝细胞,最后导致肝细胞变性坏死。目前认为, Tc细胞攻击靶细胞需依赖所谓“双识别”,即只有表达靶抗原和Ⅰ类MHC抗原的肝细胞,才可能被Tc细胞识别、攻击和破坏。而肝细胞凋亡、HBV感染等多种因素所致的肝细胞损害,其最终表现也是肝细胞死亡。
本实验以乙肝病毒感染机制、慢性乙肝与cccDNA关系的研究为基础,研究实验药物泽泻醇B乙酸酯对乙肝病毒HBV的抑制作用及其作用机制。泽泻为泽泻科植物泽泻的块茎,性味甘、淡、寒,归肾、膀胱经,是利水渗湿用药,主要用于小便不利、水肿胀满、泄泻、尿少、痰饮、眩晕、热淋涩痛等症。泽泻的化学成分比较复杂,而泽泻醇B乙酸酯属于三萜化类合物。在有关泽泻醇B乙酸酯的研究中,学者们发现泽泻醇B乙酸酯具有多种生物活性：(1)诱导多种肿瘤细胞凋亡；(2)逆转P糖蛋白过表达癌细胞的多药耐药性,提高细胞对抗肿瘤药物的敏感性；(3)抑制抗体过敏性反应；(4)抑制细胞中氮氧化物(NO)的合成反应；(5)抑制乙肝病毒抗原活性,等等。因此泽泻醇B乙酸酯在抗病毒方面具有很大的潜力。
在本实验过程中,通过体外、体内实验平行检测泽泻醇B对病毒DNA的影响、对病毒cccDNA的影响从而探索泽泻醇B乙酸酯抗乙肝病毒的机制。在实验中,泽泻醇B乙酸酯在2.215细胞和鸭胚肝细胞上的对病毒的抑制作用并不一致。在2.215细胞上,泽泻醇B乙酸酯的TC50为23.71mmol/L,而在鸭胚肝细胞上的TC50为25.62mmol/L。泽泻醇B乙酸酯在HepG2.215细胞上对病毒两抗分泌的治疗指数分别为1.15、0.74,提示在HepG2.215上泽泻醇B乙酸酯对乙型肝炎病毒表面抗原分泌的抑制作用是在对细胞的毒性作用基础上发挥的,而对病毒的e抗原则无抑制作用。在先天DHBV感染鸭胚原代肝细胞上,泽泻醇B乙酸酯对病毒DNA的治疗指数可达到4.08,则显示出较好的抗病毒作用。在体内实验中,泽泻醇B乙酸酯对病毒的DNA和肝组织中的cccDNA也有一定的抑制作用。通过本实验的初步结果间接提示了泽泻醇B乙酸酯需要经过体内代谢的活化作用才能发挥药物的抗病毒作用。
Hepatitis is a kind of serious infectious virusis caused by Hepatitis B virus. According to the reports from WTO, over 2 billion people are HBV carriers, and more than 300 million are chronic infected. About half of the HBV infected people are in our country. The number of the HBsAg carriers is 9.3 million till 2008 in China and increase with 2 million every year. Compared with those non-HBV carriers, the HBV carries faced with much higher risk of liver cancer and cirrhosis. With the therapy of HBV vaccine and other anti-HBV medicines, which makes the HBV virus variating quickly, increases more and more chronic HBV infected patients. Scientists find out that the cccDNA of the HBV virus exits in the liver is the key to the chronic infection of HBV. So people put more energy in seeking for the medicine witch can erase viral cccDNA in liver, and make it possible to heal the HBV carriers completely.
The HBV replication includes four classes:first, the virus exuviates adventitia and enters into the infected hepatocytes with phosphorylase, the virus draws off the capsid protein and turn to the structure of cccDNA. cccDNA is the HBV replication template, and it also can transcript to mRNA. Then the virus integrates pre-RNA with the instruction of mRNA, and envelops with capsid in extranuclear. The virus reverses transcripts to negative DNA chain with the pre-RNA as template, and synthesizes to positive DNA chain. At last the complete virus which has infectious ability is secreted to extranculear to maintain the numbers of cccDNA. So blocking off the every step of viral replication is the key to heal hepatitis B disease.
In a great deal of researches, scientists find that the liver damage is caused by cell-mediated immunity but not the HBV virus itself. In the course of HBV infection, the monocyte-macrophage cells incepts and processes the viral antigen, then submits to the Th cell. With the IL-1 secreted from macrophage, the Th-cells are activated to multiplication and release IL-2. Then the sensitized Tc cells proliferate and turn into effect T cells. The effect T cells attack the hepatocytes affected by HBV virus, which lead to the liver damage. The scientists think the hepatocytes which can express target antigen and type 1 MHC antigen can be attacked by the Tc cells. And the apoptosis of cells and the viral infection are also the reasons of the damage-too.
My experiment is based on the mechanism of the HBV infection and the relationship between the chronic hepatitis B and cccDNA to describe the anti-HBV effect of Acetate alisol B. Acetate alison B is isolate from Radix Astragliz. In traditional Chinese medicine, Radix Astragliz attributes to sweet, light, cold, owned by the kidney and bladder, used in diuresis.And the compounds of Radix Astragliz is very complicated. The Acetate alisol B attributes to triterpenoid compounds of classes. It has many activated functions, such as inducing tumor apoptosis, enhancing the sensitive of the cells to the anti-tumor medicine, inhibiting hypersensitivity and the synthesis of NO, restraining HBV virus. So Acetate alisol B is very potential in anti-HBV medicine research.
We detect the viral DNA replication, and the presence of viral cccDNA in vivo and in vitro synchronously. In the assay, we found that different results showed in different cell models. On the HepG2.215 cell model, the TC50 of Acetate alisol B was 23.71mM, and the therapy index (TI) of HBsAg and HBeAg were 1.15,0.74 respectively, which showed that the Acetate Aliso B had not anti-HBV effect on HepG2.215 cells. But strangely, the data on primary duck hepatocyte cells showed that the Acetate Aliso B had a great anti-HBV effect on it. The TI of Acetate also B on restrain DHBV DNA was 4.08. The anti-HBV effect of Acetate alisol B is not apparent in HepG2.215 cells, but shows preliminary effect in vivo. So we surmise the Acetate alisol B has the effect to restrain HBV after metabolism in liver.
引文
[1]贾文祥主编,医学微生物学,人民卫生出版社,2008,8,第一版本：352-359
[2]Akuta N, Kumada H. Influence of hepatitis B virus genotypes on the response to antiviral therapies [J] Antimicrob Chemother 2005;55(2): 139-142
[3]Nassal M. Hepatitis B virus:reverse transcription a different way Virus Res.2008 (134):235-249,
[4]BeckJ. and Nassal M. HepatitisBvirus. WorId J Gastroenterol 2007)13: 48-64
[5]Ganem D. and Schneider R. et a I, Hepadnavi r idae:the viruses and thei r replication. Virology,2001 (4):174-177
[6]苏建家,覃国忠,杨春等,IGR-Ⅱ和HBxAg及ras基因在实验性肝癌组织中的表达[J]广西科学学报19974(4)：309-311
[7]覃柳亮,苏建家,杨春等,实验性肝癌过程中GGT酶阳性肝细胞灶、IGF-Ⅱ及HBxAg异常表达,[J]广西医学1998 20(1)：4-7
[8]Wang GH. and Seeger C. The reverse transcriptase of hepatitis B virus acts as a protein primer for viral DNA synthesis. Cell,1992 (71) 663-670
[9]Beck J, and Nassal M, Formation of a functional hepatitis B virus replication initiation complex involves a major structural alteration in the RNA template, Cell. Biol.1998 (18):6265-6272
[10]Hu J, and Boyer M, Hepatitis reverse transcriptase and epsilon RNA sequence required for specific interaction in vitro. J Virol,2006 (80):2141-2150
[11]Jassim SAA, Naji MA. Novel antiviral agents:a medicinal plant perspective, [J]. Appl Microb,2003 (95):412-427
[12]Maddrey WC, Hepatitis B:an important public health issue. J Med Virol 2000 (61):362-366
[13]中国卫生部,2008,4,23消息
[14]Lee WM, Hepatitis B virus infection. N England J Med 1997 (337): 33-45
[15]Karayiannis P, Novick DM, Lok ASF, et al, Hepat it i s B vi rus DNA in saliva, urine and seminal fluid of carriers of hepatitis B e antigens. Br Med J 1985 (290):1853-1856
[16]Babchereau J, Steinman RM. Dendritic cells and the control of immol/Lol/Lunity [J]. Nature,1998(392):245-252
[17]Abbas AK, Murphy KM, Sher A, et a1. Functional diversity of helper T lympholytes [J]. Nature,1996:383(6603):787-782
[18]Del Prete G,Meggi E, Romagnani S, et a1. Human Thl and Th2 cells: functional properties, mechanisms of regulation and role in disesae[J]. Lab Inverst,1994,70(3):299-306, [19] Fukuda R, Ishimura N, Nguyen TX, et a1. The expression of IL-2, IL-4 and interferon-gammol/Lol/La mRNA/using liver biopsies at different phases of acute exacerbation of chronic hepatitis B, [J]. Clin Exp Immol/Lol/Lunol,1995,100(3):446-448
[20]Wiland SF, Guidotti LG Chisari FV. Intrahepatic induction of alpha /beta interferon eliminates viral RNA—containing caps ids in hepatitis B virus transgenic mice, [J] Virol,2000,74:4165-4173
[21]万谟彬.慢性乙型肝炎防治的现状与前景[J].中华传染病杂志,2002,20(1)：57-59
[22]斯崇文,乙型肝炎抗病毒治疗策略的探讨, [J].中华内科杂志,2003,42：363-364
[23]Geneva, EASL International Consensus Conference on Hepatitis B [J] Hepatol,2003,38:533-540
[24]SF, Ching-Lung L, Man-Fung Y, Overcoming the problem of chronic hepatitis B virus. Infectious diseases,2006,3(2):197-202
[25]巫善明,骆成榆,美国肝病研究学会最新推荐的慢性乙型肝炎诊治指南世界感染杂志,2005,5(1)：84.86
[26]曲建慧,张玲霞,成军等.乙型肝炎治疗的新靶点与新方法, [J]世界华人消化杂志,2004,12(7)：1663-1666
[27]Zoulim E, Mechanism of viral persistence and resistance to nucleoside and nucletide analogs in chronic hepatitis B virus infection [J]. Antiviral Res,2004,64 (1):12-15.
[28]Tuttleman J, Poureel C, Smnmers J. Formation of the pool of covalently closed circular DNA in hepadnavirus infected cells, [J]. Cell 1986: 47:451-460
[29]Newbold J, Xin H, Tencza M, et al. The covalently closed duplex form of the hepadnav i rus genome ex i sts i n s i tu as a heterogeneous popu I at ion of viral mini chromosomes, J Virol 1995:69:3350-3357.
[30]Bettina Werle, Lapostolle, Scott Bowden et al, Persistence of cccDNA
during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy, Gastroenterology,2004,126(7):1750-1758
[31]Moraleda G, Saputelli J, Aldrich CE, et a1. Lack effect of antiviraI therapy in nondividing hepatoeyte cultures on the closed circular DNA of woodchuck hepatitis virus, J Virol 1997; 71:9392-9399
[32]Fourel I, Cullen JM, Saputelli J, et a1. Evidence that hepatocyte tllrnovcr is required for rapid clearance of duck Hepatitis B Virus during antiviral therapy of chronically infected ducks,[J]J Virol 1994; 68:8321-8330.
[33]Guo. IT, Zhou H, Liu C, et al. Apoptosis and regeneration of hepatocytes during recovery from transient hepadnavirus infections[J]. J Virol 2000:74:1495-1505.
[34]Th immol/Lol/LeR, Wieland S, Ste i gerC, et a I. CD8 (＋) T cell smed i ateviral clearance and disease pathogenesis during acute hepatitis B virus infection[J]. J Virol 2003:77:68.76
[35]Guidotti LG, Rochford R, Chung J, et a1. viral clearance without destruction of infected cells during acute HBV infection[J]. Science 1999; 284:825-829
[36]黄爱龙, 张定凤, 乙型肝炎慢性化机理进展,[J]中华医学杂志1996,76(8)：632—634
[37]Sureau C, Romet-LemonnelL, Mull ins JI, et a1. Production & hepatitis B virus is by differentiated human hepatome cell line after transfection with cloned cellular HBV-DNA, [J], Cell,1986,47:3758-381
[38]Sells MA, Purcell RH, et a1. Hepatitis B virus produced by transfected HepG2 cells cause Hepatitis in champanzees[J]. Proc Natl Acad Sci USA,1987 84(4):4641-4645
[39]Sells MA, Chen ML, Acs q et a1. Production of HBV virus particles in HepG2 cells'transfected cloned hepatitis B virus DNA [J]. Proc Natl Acad Sci USA, 1987,84(4):1005-1009
[40]Bchini R, Capel F, Dauguet C, et al, In vitro infection of human hepatoma(HepG2) cells with hepatitis Bvirus [J], Virol,1990,64(6): 3025-3032
[41]成军,斯崇文,HBV DNA转然细胞系的建立及应用研究进展[J].国外医学.流行病与传染病分册,1994,21(2)：60.64
[42]唐红,唐红林勇 泰山等,四环素基因表达调控系统介导的HBV X基因体外
表达细胞株的建立,中华微生物学和免疫学杂志,2002,22(2)：194-197
[43]米抒、傅希贤、张国庆,用2.215细胞株筛选抗乙型肝炎病毒药物的研究[J],中华传染病杂志,1992,72(10)：612.615
[44]Mason WS, CuUen J, Moraleda G, et a I, Lam i vud i ne therapy of WHV-infected woodchucks[J]J, Virology,1998,245(1):18-19
[45]Huang RL, Chen CF, Feng HY et a1. Anti-hepatitis B virus of seven compounds isolated from piper kadsura(choisy)ohwi [J]. J Chin Med, 2001,12 (3):179-190
[46]Wu MJ, Weng CY Ding HY, et a1. Anti-inf lammol/Lol/Latory and antiviral effects of Glossogyne tenuifolia[J]. Life Sciences,2005,76:1135-1146
[47]Key kavous P, Leonard I, W, Edward EK. In vitro anti-hepatitis B virus activities of 5'-O-Myristoyl analogue derivatives of 3'-Fluoro-2',3'-dideoxythymidine(FLT) and 3'-Azido-2' 3'-dideoxythymidine(AZT) [J] 。 J Pharm Pharmaceut Sci,1998,1(3): 108-114
[48]Gu CQ, Li JW, Chao FH. Inhibition of hepatitis B virus by D. fraction from Grifolafrondosa:synergistic effect of combination with interferon—a in HepG22.2.15[J], Research,2006,72:162-165
[49]王克霞,湛孝东,李朝品等.江西巴蜗牛多糖对乙肝病毒复制的抑制作用研究[J].药理学通报,2006,22(3)：378—379
[50]Fabricant DS, Farnsworth NR. The value of plants used in traditional medicine for drug discovery [J]. Envi ron Health Perspect,2001,109: 69-75
[51]Jassim SAA, Naji MA. Novel antiviral agents:a medicinal plant perspective [J]. J Appl Microb,2003,95:412-427
[52]左国营,刘树玲,徐贵丽.近20年来药用植物成分体外抗HBV活性的研究进展[J].世界华人消化杂志,2006,14(13)：1241-1246
[53]纪徐淮, 秦一中, 汪伟业等,rhIFN-ab和苦味叶下珠提取物对人肝癌细胞株PLC/PRF/5产生HBsAg的影响, 新消化病学杂志,1995：3(3)：136-138
[54]纪徐淮, 秦一中, 汪伟业等,苦味叶下珠提取物对人肝癌细胞株PLC／PRF／5产生HBsAg的影响,中国中药杂志,1993,18(8)：496-498
[55]温莹浩, 殷正丰, 康晓燕等,腺病毒介导IL-24联合化疗药物增强对肝癌细胞PLC/PRF/5增殖的抑制,中国肿瘤生物治疗杂志,2007,4：102-106
[56]奚忠,江春平,丁义涛等,ABCG2在肝细胞性肝癌组织和肝癌细胞株中的表达及意义, 世界华人消化杂志,2009,3： 96-99
[57]赵健,吕岩,郭亚军,E1B55kDa缺陷型腺病毒对人肝癌细胞的杀伤研究中华肿瘤杂志,2001,23(5)：366-368
[58]郭秀婵,蓝祥英,周玲等,乙型肝炎病毒和黄曲霉素协同作用诱发人肝细胞癌细胞株的建立,病毒学报,2001,17(3)：205-209
[59]0bora A, Shiratori Y, Okuno M, et a I, Synergistic induction of apoptosis by acyclic retino id and interferon-beta in human hepatocellular carcinoma cells. Hepatology,2002,36 (5):1115-1124.
[60]Wang Z, Ruan YB, Guan Y, et al. Expression of IGF-II in early experimental hepatocellular carcinomas and its significance in early diagnosis. world J Gastroenterol,2003,9 (2):267-270
[61]Kuroki. K, Eng F, Ishikanwa T, et al. gp180, a Host Cell Glycoprotein that Binds Duck Hepatitis B Virus Particles Is encoded by a Member of the Carboxypeptidase Gene Family, J, Biol.Chem.1995,270:15022-15028
[62]turinF. Bore(?)C. Benchaib M. et al, Butyrate, a cell cycle blocker、 inhibits early amplification of duck hepatitis B virus covanlently closed circular DNA after in vitro infection of duck hepatocytes J Virol,1996; 70(5):2691
[63]Francis J, Eng, Elena G, et al.gp180, a Protein that Binds Duck Hepatitis B Virus Particles,Has Metalloxarboxypeptidase D-like Enzymatic Activity, J. Biol. Chem,1998;273:8382-8388
[64]Li J, Tong S, Glycine Decaboxylase Mediates a Postbinding Step in Duck Hepatitis B Virus Infection, J. Virol.2004,78:1873-1881
[65]Summol/Lol/Lers J, W. S Mason, Replication of the Genome of Hepatitis B-like Virus by Reverse Transcription of an RNA Intermediate, Cell. 1982,29:403-415
[66]Jens, Hagel Stein, PH-independent uptake of hepatitis B virus in primary human hepatocytes virology 1997,229:292-294
[67]Qiao M, Scougall CA, Duszynski A. Kinetics of ear I y molecular events in duck hepatitis B virus replication in primary duck hepatocytes [J] Gen Virol 1999 80(8):2127-2135
[68]JT Guo JC Pauh. Topology of the large envelope protein of duck hepatitis B virus suggest a mechanism for membrane translocation during particle morphogenesis, [J] virol 1997,71:1107-1114
[69]Klaus M, Breiner, Heinz Schaller, Cellular receptor traffic is essential for productive duck hepatitis B virus infection, [J] Virol 2000,74:2203-2209
[70]Guo JT, Pugh JC, Monoclona ant ibodies to a 55—kilodalton protein present in duck liver inhibit infection of primary duck hepatocytes with duck hepatitis B virus, [J] Virol,1997; 7(6):4829-4831
[71]TOng S, Li J, Waads JR, Carboxypeptidase D is an avian hepatitis B virus receptor J Virol.1999; 73(10):8696-8699
[72]刘汉平,何金洋,梁波,扶正利湿活血复方对鸭胚肝细胞中鸭乙型肝炎病毒的抑制作用,时珍国医国药,2009,20：1670-1672
[73]MICHAEL BRUNS, STEFAN MISKA, SYLVIE CHASSOT, et al, Enhancement of Hepatitis B Virus Infection by Noninfectious Subviral Particles: JOURNAL OF VIROLOGY,1998,72(2):1462-1468
[74]吴培福,张国中,韩博等,应用鸭胚肝细胞扩增鸭肝炎病毒,中国兽医杂志,2009,45(6)：33-35
[75]Ren S, Nassal M, Hepatitis B virus(HBV)vi r ion and covalently closed circular DNA formation in primary tupaia hepatocytes and human hepatoma cell lines upon HBV genome transduction with replication effective adenovirus vectors, [J] Virol,2001,75(3):1104-1116
[76]Tsur imoto T, Fuj iyama A, Matsubara K, Stable expression and replication of hepatitis B virus genome in an integrated state in a human hepatoma cell line transected with the cloned viral DNA. Proc Natl Acad Sci U S A,1987,84 (2):444-448
[77]0. Hantz, R. Parent, D. Durantel, Persistence of the hepatitis B virus covalently closed circular DNA in HepaRG human hepatocyte-like cells, Journal of General Virology 2009,90,127-135
[78]Zhou T, Guo H, Guo JT, Cuconati A, et al, Hepatitis B vi rus e antigen production is dependent upon covalently closed circular(ccc)DNA in HepAD38 cell cultures and may Serve as a cccDNA surrogate in antiviral screening assays。Antivi ral,2006,20:132-135。
[80]Yang EB. Cao J. Su JJ, Chow E 2005. The tree shrews:useful animal models for the viral hepatitis and hepatocellular carcinoma [J]. Hepatogastroenterology,52(62):613-616
[81]Glebe D. Urban S. Viral and cellular determinants involved in hepadnaviral entry[J], World Gastroenterol,2007,13(1):22-38.
[82]Mason WS, Seal G, Summol/Lol/Lers J. Virus of Peking ducks with structural and biological relatedness to human hepatitis B virus. J Virol,1980,36:829-836.
[83]Sprengel R, Kaleta EF, Will H. Isolation an d characterization of a hepatitis B virus endemic in herons. J Virol,1988,62:932-937
[84]Nie W, Fu B,O Brien PC, et al. Flying lemurs—the flying tree shrews, Molecular cytogenetic evidence for a Scandentia-Dermoptera sister clade [J]. BMC Biol,2008,6:18-20
[85]庞其方,万新邦,胥爱源等.HBV感染树鼩的实验研究[J].医学研究通讯[J].1981,(9)：30—38.
[86]Su JJ, Yan QR, Gan YQ, Zhou DN, Huang DR, Huang GH 1987. Study on the HBV infection ofadult Tupaia[J Jl Zhonghna Binglixue Zazhi, (16):103-105
[87]W alter E, Keist R, Niederost B, et all, Hepatitis B virus infection of tupaia hepatocytes in vitro and in vivo [J]. Hepatology,1996.24(1):1-5
[88]Kock J, Nassal M, MacNelly S, et all. Efficient infection of primary tupaia hepatocytes with purified human and woolly monkey hepatitis B virus,[J]Virol, 2001,75(11):5084.5089
[89]Glebe D, AIiakbari M, Krass P, et al, Pre-sl antigen-dependent infection of Tupaia hepatocyte cultures with human hepatitis B virus [J]. Jm,2003,77(17): 9511-9521
[90]严瑞琪 苏建家 陈志英等,人乙型肝炎病毒实验感染成年树鼩的初步研究[J],广西医学院学报,1984 1(1)：10-15
[91]苏建家 严瑞琪,甘有全,成年树鼩实验感染人乙型肝炎病毒的研究[J],中华病理学杂志,1987 16(2)：103-107
[92]Y Li, JJ Su, LL Qin, et al, Synergistic effect of hepatitis B virus and aflatoxin B1 in hepatocarcinogenesis in tree shrews, [J] Ann Acad Med Sigapore 1999,28:67-71
[93]苏建家,李瑗,班克臣等,动态研究HBV和AFB诱发树鼩肝细胞癌过程中一些基因的表达,广西中医药大学学报,2001,18(2)；151-154
[94]周凤娟,胡振林,戴建新等,乙肝DNA疫苗pVAX—PS对树鼩的免疫保护作用,第二军医大学学报,2003,24(10)：120-123
[95]岳惠芬,陈茂伟,曹骥等,乙肝病毒X基因转基因树鼩模型的建立和病理学研究,广西医科大学学报,2006,23(2)：185-187
[96]王风水,陈红松,王宇等,树鼩感染人乙肝病毒动物模型研究中的非特异性反应,北京医科大学学报,1996,28(5)：340-342
[97]王树声, 苏建家, 冯百芳等,树鼩、熊猴感染人乙型肝炎病毒肝细胞内感染指征的研究,中华实验和临床病毒学杂志,2003,17(3)：92—94
[98]Von, Weizsacker F, Kock J, et al, The tupaia m ode 1 for the study of hepatitis B virus:direct infection and HBV genome transduction of primary tupaia hepatocytes. Methods 2004,96:153-161
[99]Summolers J, Smolec JM, SnyderR。 virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woochucks. Proc Natl Acad Sci U S A,1978,75:4533-4537
[100]Roggendorf M, I, uM. Tomas TH, Woodchuck hepatitis virus, Viral Hepatitis. Oxford:Blaekwell,2005:210224
[101]Bannash P, Khosh Khou NI, Hacker HJ,et al. Synergistic hepatocarcinogenic effect of hepadnaviral infection and dietany aflatoxin B1 in woodchucks [J] CancerRes1995:55,3318-3330
[102]Mason WS, CuUen J, Moraleda G, et al, Lamivudine therapy of WHV-infected woodchucks[J], Virology,1998,245(1):18-19
[103]孟忠吉,李新宇,李磊等,土拨鼠肝炎病毒可复制性克隆的构建和鉴定,肝脏,2009,14(2)：128-131
[104]Ren S, Nassal M. Hepatitis B virus(HBV)virion and covalently dosed circular DNA formation in primary tupaia hepatocytes and human hepatoma cell lines upon HBV genome transduction with replication-defective adenovirus vectors [J]. J Virol。 2001,75(3):1104-1116
[105]Glebe D, Alikbari M,Kraes P 。et al. Pre-sl antigen—dependent infection of Tupaia hepatocyte cultures with human hepatitis B virus[J]. J Virol。2003,77(17): 9511-9521
[106]乙型肝炎病毒：复制机制与基因封闭策略胡康洪中外健康文摘2008,5(8)：5—8
[107]杨月,用于乙型肝炎研究的动物模型,国外医学(微生物学分).1986.13(6)：246-248
[108]Barker LF, Maymard JE. Purcell RH. et al Viral hepatitis, type B, in experimental animals. Am J Med Sciences,1975,270(1):189-192
[109]Will H, Reset W. Weimer T, et al. Replication Strategy of human hepatitis B virus. J Virol.1987,61(3):904-911
[110]Tiollais P. Pourcel C. Dejean A. The hepatitis B virus. Nature.1985,317(6037): 489-49
[111]Gattaneo R. Will H, Hernandez N, et al. Signals regulating hepatitis B surface antigen transcription. Nature,1983.305(5931):336-338
[112]Nowak MA, Bonhoeffer S, Hill AM, et al. Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci USA 1996; 93:4398-4402
[113]John M. Murray, Stefan F, et al,Dynamics of hepatitis B virus clearance in chimpanzees, Proc Natl Acad Sci U S A.2005; 102(49):17780-17785.
[114]Wieland SF, Spangenberg HC, Thimmol/Lol/Le R, et al. Expansion and contraction of the hepatitis B virus transcriptional template in infected
chimpanzees [J]. Proc Natl Acad Sci U S A.2004,101(7):2129-2134
[115]Stefan F. Wieland, Hans Christian Spangenberg,et al, Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees, Chisari Proc Natl Acad Sci U S A.2004,101(7): 2129-2134.
[116]能一力,刘光泽,贾彦征HBV转基因小鼠免疫耐受机制的实验研究,世界华人消化杂志,2002；10：642—645
[117]Zheng Y, Chen WL, Louie SG, et al,Hepatitis B virus promotes hepatocarcinogenesis in transgenic mice. Hepatology 200 45:16-21
[118]Shlomai A, Shaul Y. Inhibition of hepatitis B virus expression and replication by RNA interference. Hepatolox,2003; 37:764-770
[119]Shlomai A, Shaul Y. RNA interference—small RNAs effectively fight viral hepatitis. Liver Int 2004; 24:526-53
[120]Larkin T, Clayton M, Sun B, et al, Hepatitis B virus transgenic mouse model of chronic liver disease. Nat Med 1999; 5:907-912
[121]屠亚军,琦祖和,杨鹏等,人乙型肝炎病毒X基因转基因小鼠模型的建立,中国医学科学院学报,2000；22：263—265
[122]Wiland SF,Guidotti LG Chisari FV. Intrahepatic induction of alpha/beta interferon eliminates viral RNA—containing capsids in hepatitis B virus transgenic mice [J]. J Virol,2000,74:4165-4173
[123]Rauschhuber C, Xu H, Salazar FH, et al, Exploring gene—deleted adenoviral vectors for delivery of short hairpin RNAs and reduction of hepatitis B virus infection in mice. Gene Med 2008; 10:878-889
[124]Isogawa M Kakimi K, Kamamoto H, et al, Differential dynamics of the peripheral and intrahepatic cytotoxic T lymphocyte response to hepatitis B surface antigen. Virology 2005; 333:293-300
[125]Yang PL, Althage A, Chung J, Hydrodynamic injection of viral DNA:a mouse model of acute hepatitis B virus infection. Proc Natf Acad Sci U S A 2002:99: 13825-13830
[126]Ohashi K, Marion PL, Nakai H, et al, Sustained survival of human hepatocytes in mice:A model for in vivo infection with human hepatitis B and hepatitis delta viruses. Nat Med 2000; 6:327-331
[127]蒋黎,毛青,王宇明等,HBV感染的人鼠嵌合肝动物模型的建立,第三军医大学学报,2003,25(5)：12
[128]Schultz U, Grgacic E, Nassal M. Duck hepatitis B virus:an invaluable model system for HBV infection. Adv Virus Res,2004,63 (1):68-70.
[129]邓学龙,朱宇同,方宏勋等.广州地区3个鸭种1日龄雏鸭垂直感染鸭乙肝病毒调查, [J].广东中医药大学学报,1997,14：274-275
[130]莫小余,李向阳,潘宗奇,等.中药抗先天性华南绿头鸭乙肝病毒的实验研究,[[J].中华医学研究杂志,2003,3：696—697
[131]邹移海,张薇,张奉学,等.广东省绿头鸭场鸭乙肝病毒自然携带状况调查[J].中国实验动物学杂志,2001,11(1)：9—11
[132]Fukuda R Okinaga S, Akagi S, et al. Alteration of infection pattern of duck hepatitis B virus by immol/Lol/Lunomodulatory drugs, [J]. J Med Virol,1988, 26(4):387-396
[133]李虹,陈文,徐纬,等.核酶对鸭乙型肝炎病毒感染体内抗病毒作用效果的观察[J].中华实验和临床病毒学杂志,1998,12：118.121
[134]朱万孚,席与萍,曲平,等.鸭乙型肝炎动物模型的研究叨.北京医科大学学报,1987,19(4)：223·226
[135]K. Vickery,J. S. Freiman, M, D, R Kearney,et al, Immol/Lol/Lunity in Pekin duck experimentally and naturally infected with duck hepatitis B virus J Med Virol 1989.28(4):231-236
[136]Mason W-S, Halpel T, MS, England J, et al. Experimental transmission of duck hepatitis B virus [J], Virology,1983,131:375-384.
[137]Pugh J-C, Simmol/Lol/Lons H. Duck hepatitis B virus infection of Muscovy duck hepatocytes and nature of virus resistance in vivo [J]. J Virol,1994,68(4): 2487-2494.
[138]JI-SU LI, SHU-PING TONG, AND JACK R, Characterization of a 120-Kilodalton Pre-S-Binding Protein as a Candidate Duck Hepatitis B Virus Receptor, JOURNAL OF VIROLOGY,1996,70 (9):6029-6035
[139]Rahma Tohidi-Esfahani, Karen Vickery and Yvonne Cossart, The early host innate immol/Lol/Lune response to duck hepatitis B virus infection, Journal of General Virology (2010),91:509-520
[140]NEWBOLD JE, XIN H, TENCZA M, et all The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral mini—chromosome[J]. J Virol,1995,69:3350-3357.
[141]DELMAS J, SCHORR O, JAM ARD C, et al. Inhibitory effect of adefovir on viral DNA synthesis and covalently closed circular DNA formation in duck hepatitis B virus—infected hepatocytes in vivo and in vitro [J]. Antimicrob Agents Chemother,2002,46(2):425-433
[142]NETTER HJ, CHASSOT S, CHANG SF, et al. Sequence heterogeneity of heron hepatitis B virus genomes determined by full—length DNA amplification and direct sequencing reveals novel and unique features[J]. J Gen Virol,1997, 78:1707-1718
[143]CHANG SF, NETTER HJ, HILDT E, et al, Duck hepatitis B virus expresses a regulatory HBx ·-like protein from a hidden open reading frame[J]. J Virol, 2001,75:161-170
[144]BOCK CT. SCHW INN S, LOCARNINI S, et al. Structural organization of the HBV minichromosome[J]. J Mol Biol,2001,307:183-196
[145]0FFENSPERGER WB, OFFENSPERGER S, KEPPLER HAFKEMEYER A. et al. Antiviral activities of penciclov and famciclovir on duck hepatitis B virus in vitro and in vivo [J]. Antivir Thera,1996,1(3):141-146.
[146]LIN E, LUSCOMBE C, COLLEDGE D, et al. Long term therapy with the guanine nucleoside analog penciclovir controls chronic duck hepatitis B virus infection in vivo [J]. Antimicro Agents Chemnother,1998,42(8):2132-2137.
[147]蒋定锋,闫梁,责海静等,鸭乙型肝炎病毒核心抗原DNA疫苗的构建及其诱导的体液免疫应答,微生物与感染,2009,4(3)：140-146
[148]Claudia Maenz, Christine Loscher, Inhibition of duck hepatitis B virus infection of liver cells by combined treatment with viral e antigen and carbohydrates, Journal of General Virology (2008),89,3016-3026
[149][8]Hannon G J. RNA interference. Nature,2002,418(6894):244-251
[150]Perrrillo RP. Current treatment of chronic hepatitis B benefits and limitations [J]. Semin Liver Dis 2005,25 supll 1:20-28.
[151]Lim SG, Ng TM, Kung N, Krastev Z, Volfova M, Husa P, Lee SS, Chan S, Shiffman ML, Washington MK, Rigney A, Anderson J, Mondou E, snow A, Sorbel J, Guan R, Rousseau F. Adouble—blind Placebo—controlled Study of emtricitabine in chronic hepatitis B [J]. Arch Intren Med,2006,166:49-56
[152]汤雁波,李卓荣.核苷类抗病毒药物研究进展.中国生化药物杂志.2004,25(1),44-47.
[153]De Clercq E. Antiviral drugs in current clinical use. Journal of Clinical Virology.2004,30,115-133.
[154]Hache C, Villeneuve JP. Lamivudine treatment in patients with chronic hepatitis B and cirrhosis. Expert. Opin. Pharmacother.2006,7(13),1835-1843.
[155]Guo JT,Zhou H, Liu C, et al. Apoptosis and regeneration of hepatocytes during recovery from transent hepadanvirus infections [J]. J Virol,2000,74:1495-1505
[156]Kajino K, Jilbert AR,Saputelli J, et al. Woodchuck hepatitis virus infections: very rapid recovery after a prolonged viremia and infection of virtually every hepatocyte [J]. J Virol,1994,68:5792-5803
[157]Danta M, Dusheiko G. Adefovir dipivoxil:review of a novel acyclic nucleoside analogue. Int. J. Clin. Pract.,2004,58(9),877-886.
[158]Baker DE. Adefovir dipivoxil:focus on its use in the treatment of chronic hepatitis B. Rev. Gastroenterol. Disord.2005,5(2),89-100
[159]Yuen MF, Lai CL. Adefovir dipivoxil in chronic hepatitis B infection. Expert. Opin. Pharmacother.,2004,5(11),2361-2367.
[160]Qaqish RB, Mattes KA, Ritchie DJ. Adefovir dipivoxil:a new antiviral agent for the treatment of hepatitis B virus infection. Clin. Ther.,2003,25(12),3084-3099
[161]Hadziyannis SJ, Papatheodoridis GV, Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection. Expert. Rev. Anti. Infect. Ther.,2004,2(4), 475-483
[162][48] Delmas J, Schorr 0, Jameard C, et al. Inhibitory effect of adefovir on viral DNA synthesis and covalently closed circular DNA formation in duck hepatitis B virus—infected hepatocytes in vivo and in vitro[J]. Antimicrobial Agents and Chemotherapy,2002.46(2):425-433
[163]William E, Delaney IV, Angeline, et al, Evolving therapies for the treatment of chronic hepatitis B virus infection [J]. Investig. Drugs 2002,11 (2):169-187
[164]张永兴,陈忻,许利平等.神奇的抗病毒中草药[M].北京：中国中医药出版社,2004.6-8.
[165]Huang RL, Huang YL, Ou JC, et al. Screening of 25 compounds isolated from Phyllanthus species for anti-human hepatitis B virus in vitro[J]. Phytother Res,2003,17:449-453
[166]Shin MS, Kang EH, Lee YI, et al. A flavonoid from medicinal plants blocks hepatitis B virus-e antigen secretion in HBV-infected hepatocytes [J]. Antiviral Res,2005,67:163-1681
[167]Ding PL, Liao ZX, Huang H, et al. (＋)- 12alpha—hydroxysophocarpine, a new quinolizidine alkaloid and related anti-HBV alkaloids from Sophora flavescens [J]. Bioorg Med Chem Lett,2006,16:1231-1235
[168]Shen YC, Lin YC, Chiang MY et al. Kadsuphilactones A and B, two novel triterpene dilactones from Kadsura philippinensis [J]. Org Lett, 2005,7:5348
[169]刘厚佳,胡晋红,孙莲娜,等.表儿茶酸等化合物对HBV DNA转染人肝癌细胞株的作用[J].第二军医大学学报,2001,22(3)：661-663
[170]Chin Teng Chang, Shin Lian Dong, Iall Lih Tsai, et al. Coumarinsand anti-HBV constituents from Zanthoxylum chinifolium [J]. Phytochemistry,1997,45(7):1419-1422
[171]Chang CT,Doong SL,Tsai IL,et al.Coumarins and anti—HBV constituents from zanthoxylum schinifolium[J]. Phytochemistry,1997,45:1419 -1422
[172]郑民实等.中草药抗HBsAg的实验研究.中国医院药学杂志,1988.8(3)：121
[173]杨鉴英等.中药抗乙型肝炎病毒的实验研究.中西医结合杂志,1989.9(8)：494-496
[174]焦成松等.香菇多糖脂质体治疗鸭乙型肝炎的初步观察.中西医结合杂志,1991,1(3)：24
[175]秦守杰.苦参素治疗慢性乙型肝炎90例疗效观察[J].郑州大学学报(医学版),2003,38(5)：8293
[176]纪徐淮等.人重组干扰素和叶下珠提取物对人肝癌细胞株PLC／PER5产生HBsAg的影响.中西医结合杂志,1992,2(1)：13
[177]Niv z, et al, fleet of PHYU anthus. amoro6. Duck Hepatitis B virus replication in vivo J Med Virol 1990:32(4)
[178]温志坚,曹敏,彭龙玲等.小柴胡汤提取物体外抗HBV的活性研究.中西医经合肝病杂志,2000,10(4)：29-318
[179]刘中景等.小柴胡抗鸭乙肝病毒的实验研究.中国中西医结合杂志,2000,11：853—855
[180]Yun-Bao Ma, Shu-ying Yao, Quang Zhang, et al,Two New Alkaloids and Active Anti-Hepatitis B Virus Constituents from Hypserpa nitida. Bioorg. Med. Chem. Lett.2007,10(2):337-341
[181]江苏新医学院.中药大辞典[M].上册.上海：上海科学技术出版社,1986,1462
[182]陶晋舆,吕环,张秋菊,等.泽泻抗动脉粥样硬化作用系列研究(二)[J]北京中医学院学报,1991,14(6)：51
[183]王新华.泽泻研究进展[J].中草药,1999,30(7)：557.
[184]郑虎占,董泽宏,佘靖.中药现代研究与应用[M].第4册.北京：学苑出版社,1998,3022)
[185]尹春萍,吴继洲.泽泻及其活性成分免疫调节作用研究进展[J].中草药,2001,32(12)：1132—1134.
[186]尹春萍,刘继红,张长弓.不同离子强度及PH值时泽泻和夏枯草对草酸钙结晶形成的抑制作用观察[J],同济医科大学学报,1996,25(4)：321—334
[187]尹春萍,刘继红,章咏裳,等.泽泻水提取物预防草酸钙结石形成的体外及动物实验研究[J].同济医科大学学报,1997,26(2)：99—102
[188]曹正国,刘继红,吴继洲,等.泽泻不同溶剂提取物对大鼠尿草酸钙结石形成的影响[J].中草药,2003,34(1)：45—46.
[189]李继承,吕连志,石元和,等.中药对腹膜孔调控作用的实验研究[J].中国中医基础医学杂志,1998,4(8)：20—25
[190]支广教道(日).泽泻的抗肾炎活性研究[J].国外医学-中医中药分册,1997,19(5)：58—61.
[191]杨新波,黄正明,曹文彬,等.泽泻水提取物对正常小鼠及高血糖小鼠血糖的影响[J].中药药理与临床,1998,14(6)：29—33
[192]戴岳,杭秉茜.泽泻对谷氨酸钠肥胖大鼠的影响[J],中成药,1992,14(2)：28—31.
[193]马兵,项阳,李涛,等.泽泻对Lewis肺癌自发性转移的抑制作用及其机制研究[J],中草药,2003,34(8)：743—745
[194]江苏新医学院编.中药大辞典(上册).上海：上海科学技术出版社,1986：14(6)：21—24
[195]Chen H W, Hsu M J, Chien C T, et all. Effect of alisol B acetate, a plant triterpene, on apoptosis in vascular smooth muscle cells and lymphocytes [J]. Eur J Pharmacol,2001,419:127-138
[196]Huang Y T, Huang D M, Chueh S C, et all. Alisol B acetate, a triterpene from Alismatis rhizoma, induces Bax nuclear translocation and apoptosis in human hormone resistant prostate cancer PC-3 cells [J]. Cancer Lett,2006.231:270-278.
[197]Zhang J X, Shen X L, et all. Revemal of P-gly-coprotein-mediated muhidrug resistance by alisol B 23—acetate [J]. Biochem Pharmacol, 2004,68:843-855.
[198]Fong W F, WangC, Zhu G Y, et all. Reversal of multi—drug resistance in cancer cells by Rhizoma Alismatis extract [J]. Phytomedicine, 2007,14:160-165.
[199]Kubo M, Matsuda H, Tomohiro N, et all. Studies on A lismatis rhizoma. I. Anti-allergic effects of methanol ex-ract and six terpene components from Alismatis rhi。zoma [J]. Biol Pharm Bull,1997,20(5):511-517
[200]Matsuda H, Tomohiro N, Yoshikawa M. et all. Studies on Alismatis rhizoma. Ⅱ. Anti-complementary activities of methanol extract and terpene components from Alis-matis rhizoma [J]. Biol Pharm Bull, 1998,21(12),1317-132117
[201]Matsuda H, Kageura T, Toguchida I, et all. Effects of sesquiterpenes and triterpenes from the rhizome of Alisma orientale on nitric oxide production in lipopolysaccharide activated macrophages:absolute stereostructures of Alismaketones. B 23-acetate and C 23-acetate [J]. Bioorg Med Chem Lett,1999,9:3081-3086.
[202]Kim N. et all. In vitro inducible nitric oxide synthesis inhibitors from Alismatis Rhizoma [J]. Biol Pharm Bull.1999,22(10):1147
[203]Jiang Z Y, Zhang X M, Zhang F X, et al. A new triterpene and anti-hepatitis B virus active compounds from Alisma orientalis [J]. Planta Med,2006,72(10):951-954 211
[204]Yong-Yuan Zhang, Daniel P. Theele, and Jesse Summol/Lol/Lers, Age-Related Differences in Amplification of Covalently Closed Circular DNA at Early Times after Duck Hepatitis B Virus Infection of Ducks, JOURNAL OF VIROLOGY,2005,79 (15):9896-9903
[2]Akuta N, Kumada H. Influence of hepatitis B virus genotypes on the response to antiviral therapies [J] Antimicrob Chemother 2005;55(2): 139-142
[3]Nassal M. Hepatitis B virus:reverse transcription a different way Virus Res.2008 (134):235-249,
[4]BeckJ. and Nassal M. HepatitisBvirus. WorId J Gastroenterol 2007)13: 48-64
[5]Ganem D. and Schneider R. et a I, Hepadnavi r idae:the viruses and thei r replication. Virology,2001 (4):174-177
[6]苏建家,覃国忠,杨春等,IGR-Ⅱ和HBxAg及ras基因在实验性肝癌组织中的表达[J]广西科学学报19974(4)：309-311
[7]覃柳亮,苏建家,杨春等,实验性肝癌过程中GGT酶阳性肝细胞灶、IGF-Ⅱ及HBxAg异常表达,[J]广西医学1998 20(1)：4-7
[8]Wang GH. and Seeger C. The reverse transcriptase of hepatitis B virus acts as a protein primer for viral DNA synthesis. Cell,1992 (71) 663-670
[9]Beck J, and Nassal M, Formation of a functional hepatitis B virus replication initiation complex involves a major structural alteration in the RNA template, Cell. Biol.1998 (18):6265-6272
[10]Hu J, and Boyer M, Hepatitis reverse transcriptase and epsilon RNA sequence required for specific interaction in vitro. J Virol,2006 (80):2141-2150
[11]Jassim SAA, Naji MA. Novel antiviral agents:a medicinal plant perspective, [J]. Appl Microb,2003 (95):412-427
[12]Maddrey WC, Hepatitis B:an important public health issue. J Med Virol 2000 (61):362-366
[13]中国卫生部,2008,4,23消息
[14]Lee WM, Hepatitis B virus infection. N England J Med 1997 (337): 33-45
[15]Karayiannis P, Novick DM, Lok ASF, et al, Hepat it i s B vi rus DNA in saliva, urine and seminal fluid of carriers of hepatitis B e antigens. Br Med J 1985 (290):1853-1856
[16]Babchereau J, Steinman RM. Dendritic cells and the control of immol/Lol/Lunity [J]. Nature,1998(392):245-252
[17]Abbas AK, Murphy KM, Sher A, et a1. Functional diversity of helper T lympholytes [J]. Nature,1996:383(6603):787-782
[18]Del Prete G,Meggi E, Romagnani S, et a1. Human Thl and Th2 cells: functional properties, mechanisms of regulation and role in disesae[J]. Lab Inverst,1994,70(3):299-306, [19] Fukuda R, Ishimura N, Nguyen TX, et a1. The expression of IL-2, IL-4 and interferon-gammol/Lol/La mRNA/using liver biopsies at different phases of acute exacerbation of chronic hepatitis B, [J]. Clin Exp Immol/Lol/Lunol,1995,100(3):446-448
[20]Wiland SF, Guidotti LG Chisari FV. Intrahepatic induction of alpha /beta interferon eliminates viral RNA—containing caps ids in hepatitis B virus transgenic mice, [J] Virol,2000,74:4165-4173
[21]万谟彬.慢性乙型肝炎防治的现状与前景[J].中华传染病杂志,2002,20(1)：57-59
[22]斯崇文,乙型肝炎抗病毒治疗策略的探讨, [J].中华内科杂志,2003,42：363-364
[23]Geneva, EASL International Consensus Conference on Hepatitis B [J] Hepatol,2003,38:533-540
[24]SF, Ching-Lung L, Man-Fung Y, Overcoming the problem of chronic hepatitis B virus. Infectious diseases,2006,3(2):197-202
[25]巫善明,骆成榆,美国肝病研究学会最新推荐的慢性乙型肝炎诊治指南世界感染杂志,2005,5(1)：84.86
[26]曲建慧,张玲霞,成军等.乙型肝炎治疗的新靶点与新方法, [J]世界华人消化杂志,2004,12(7)：1663-1666
[27]Zoulim E, Mechanism of viral persistence and resistance to nucleoside and nucletide analogs in chronic hepatitis B virus infection [J]. Antiviral Res,2004,64 (1):12-15.
[28]Tuttleman J, Poureel C, Smnmers J. Formation of the pool of covalently closed circular DNA in hepadnavirus infected cells, [J]. Cell 1986: 47:451-460
[29]Newbold J, Xin H, Tencza M, et al. The covalently closed duplex form of the hepadnav i rus genome ex i sts i n s i tu as a heterogeneous popu I at ion of viral mini chromosomes, J Virol 1995:69:3350-3357.
[30]Bettina Werle, Lapostolle, Scott Bowden et al, Persistence of cccDNA
during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy, Gastroenterology,2004,126(7):1750-1758
[31]Moraleda G, Saputelli J, Aldrich CE, et a1. Lack effect of antiviraI therapy in nondividing hepatoeyte cultures on the closed circular DNA of woodchuck hepatitis virus, J Virol 1997; 71:9392-9399
[32]Fourel I, Cullen JM, Saputelli J, et a1. Evidence that hepatocyte tllrnovcr is required for rapid clearance of duck Hepatitis B Virus during antiviral therapy of chronically infected ducks,[J]J Virol 1994; 68:8321-8330.
[33]Guo. IT, Zhou H, Liu C, et al. Apoptosis and regeneration of hepatocytes during recovery from transient hepadnavirus infections[J]. J Virol 2000:74:1495-1505.
[34]Th immol/Lol/LeR, Wieland S, Ste i gerC, et a I. CD8 (＋) T cell smed i ateviral clearance and disease pathogenesis during acute hepatitis B virus infection[J]. J Virol 2003:77:68.76
[35]Guidotti LG, Rochford R, Chung J, et a1. viral clearance without destruction of infected cells during acute HBV infection[J]. Science 1999; 284:825-829
[36]黄爱龙, 张定凤, 乙型肝炎慢性化机理进展,[J]中华医学杂志1996,76(8)：632—634
[37]Sureau C, Romet-LemonnelL, Mull ins JI, et a1. Production & hepatitis B virus is by differentiated human hepatome cell line after transfection with cloned cellular HBV-DNA, [J], Cell,1986,47:3758-381
[38]Sells MA, Purcell RH, et a1. Hepatitis B virus produced by transfected HepG2 cells cause Hepatitis in champanzees[J]. Proc Natl Acad Sci USA,1987 84(4):4641-4645
[39]Sells MA, Chen ML, Acs q et a1. Production of HBV virus particles in HepG2 cells'transfected cloned hepatitis B virus DNA [J]. Proc Natl Acad Sci USA, 1987,84(4):1005-1009
[40]Bchini R, Capel F, Dauguet C, et al, In vitro infection of human hepatoma(HepG2) cells with hepatitis Bvirus [J], Virol,1990,64(6): 3025-3032
[41]成军,斯崇文,HBV DNA转然细胞系的建立及应用研究进展[J].国外医学.流行病与传染病分册,1994,21(2)：60.64
[42]唐红,唐红林勇 泰山等,四环素基因表达调控系统介导的HBV X基因体外
表达细胞株的建立,中华微生物学和免疫学杂志,2002,22(2)：194-197
[43]米抒、傅希贤、张国庆,用2.215细胞株筛选抗乙型肝炎病毒药物的研究[J],中华传染病杂志,1992,72(10)：612.615
[44]Mason WS, CuUen J, Moraleda G, et a I, Lam i vud i ne therapy of WHV-infected woodchucks[J]J, Virology,1998,245(1):18-19
[45]Huang RL, Chen CF, Feng HY et a1. Anti-hepatitis B virus of seven compounds isolated from piper kadsura(choisy)ohwi [J]. J Chin Med, 2001,12 (3):179-190
[46]Wu MJ, Weng CY Ding HY, et a1. Anti-inf lammol/Lol/Latory and antiviral effects of Glossogyne tenuifolia[J]. Life Sciences,2005,76:1135-1146
[47]Key kavous P, Leonard I, W, Edward EK. In vitro anti-hepatitis B virus activities of 5'-O-Myristoyl analogue derivatives of 3'-Fluoro-2',3'-dideoxythymidine(FLT) and 3'-Azido-2' 3'-dideoxythymidine(AZT) [J] 。 J Pharm Pharmaceut Sci,1998,1(3): 108-114
[48]Gu CQ, Li JW, Chao FH. Inhibition of hepatitis B virus by D. fraction from Grifolafrondosa:synergistic effect of combination with interferon—a in HepG22.2.15[J], Research,2006,72:162-165
[49]王克霞,湛孝东,李朝品等.江西巴蜗牛多糖对乙肝病毒复制的抑制作用研究[J].药理学通报,2006,22(3)：378—379
[50]Fabricant DS, Farnsworth NR. The value of plants used in traditional medicine for drug discovery [J]. Envi ron Health Perspect,2001,109: 69-75
[51]Jassim SAA, Naji MA. Novel antiviral agents:a medicinal plant perspective [J]. J Appl Microb,2003,95:412-427
[52]左国营,刘树玲,徐贵丽.近20年来药用植物成分体外抗HBV活性的研究进展[J].世界华人消化杂志,2006,14(13)：1241-1246
[53]纪徐淮, 秦一中, 汪伟业等,rhIFN-ab和苦味叶下珠提取物对人肝癌细胞株PLC/PRF/5产生HBsAg的影响, 新消化病学杂志,1995：3(3)：136-138
[54]纪徐淮, 秦一中, 汪伟业等,苦味叶下珠提取物对人肝癌细胞株PLC／PRF／5产生HBsAg的影响,中国中药杂志,1993,18(8)：496-498
[55]温莹浩, 殷正丰, 康晓燕等,腺病毒介导IL-24联合化疗药物增强对肝癌细胞PLC/PRF/5增殖的抑制,中国肿瘤生物治疗杂志,2007,4：102-106
[56]奚忠,江春平,丁义涛等,ABCG2在肝细胞性肝癌组织和肝癌细胞株中的表达及意义, 世界华人消化杂志,2009,3： 96-99
[57]赵健,吕岩,郭亚军,E1B55kDa缺陷型腺病毒对人肝癌细胞的杀伤研究中华肿瘤杂志,2001,23(5)：366-368
[58]郭秀婵,蓝祥英,周玲等,乙型肝炎病毒和黄曲霉素协同作用诱发人肝细胞癌细胞株的建立,病毒学报,2001,17(3)：205-209
[59]0bora A, Shiratori Y, Okuno M, et a I, Synergistic induction of apoptosis by acyclic retino id and interferon-beta in human hepatocellular carcinoma cells. Hepatology,2002,36 (5):1115-1124.
[60]Wang Z, Ruan YB, Guan Y, et al. Expression of IGF-II in early experimental hepatocellular carcinomas and its significance in early diagnosis. world J Gastroenterol,2003,9 (2):267-270
[61]Kuroki. K, Eng F, Ishikanwa T, et al. gp180, a Host Cell Glycoprotein that Binds Duck Hepatitis B Virus Particles Is encoded by a Member of the Carboxypeptidase Gene Family, J, Biol.Chem.1995,270:15022-15028
[62]turinF. Bore(?)C. Benchaib M. et al, Butyrate, a cell cycle blocker、 inhibits early amplification of duck hepatitis B virus covanlently closed circular DNA after in vitro infection of duck hepatocytes J Virol,1996; 70(5):2691
[63]Francis J, Eng, Elena G, et al.gp180, a Protein that Binds Duck Hepatitis B Virus Particles,Has Metalloxarboxypeptidase D-like Enzymatic Activity, J. Biol. Chem,1998;273:8382-8388
[64]Li J, Tong S, Glycine Decaboxylase Mediates a Postbinding Step in Duck Hepatitis B Virus Infection, J. Virol.2004,78:1873-1881
[65]Summol/Lol/Lers J, W. S Mason, Replication of the Genome of Hepatitis B-like Virus by Reverse Transcription of an RNA Intermediate, Cell. 1982,29:403-415
[66]Jens, Hagel Stein, PH-independent uptake of hepatitis B virus in primary human hepatocytes virology 1997,229:292-294
[67]Qiao M, Scougall CA, Duszynski A. Kinetics of ear I y molecular events in duck hepatitis B virus replication in primary duck hepatocytes [J] Gen Virol 1999 80(8):2127-2135
[68]JT Guo JC Pauh. Topology of the large envelope protein of duck hepatitis B virus suggest a mechanism for membrane translocation during particle morphogenesis, [J] virol 1997,71:1107-1114
[69]Klaus M, Breiner, Heinz Schaller, Cellular receptor traffic is essential for productive duck hepatitis B virus infection, [J] Virol 2000,74:2203-2209
[70]Guo JT, Pugh JC, Monoclona ant ibodies to a 55—kilodalton protein present in duck liver inhibit infection of primary duck hepatocytes with duck hepatitis B virus, [J] Virol,1997; 7(6):4829-4831
[71]TOng S, Li J, Waads JR, Carboxypeptidase D is an avian hepatitis B virus receptor J Virol.1999; 73(10):8696-8699
[72]刘汉平,何金洋,梁波,扶正利湿活血复方对鸭胚肝细胞中鸭乙型肝炎病毒的抑制作用,时珍国医国药,2009,20：1670-1672
[73]MICHAEL BRUNS, STEFAN MISKA, SYLVIE CHASSOT, et al, Enhancement of Hepatitis B Virus Infection by Noninfectious Subviral Particles: JOURNAL OF VIROLOGY,1998,72(2):1462-1468
[74]吴培福,张国中,韩博等,应用鸭胚肝细胞扩增鸭肝炎病毒,中国兽医杂志,2009,45(6)：33-35
[75]Ren S, Nassal M, Hepatitis B virus(HBV)vi r ion and covalently closed circular DNA formation in primary tupaia hepatocytes and human hepatoma cell lines upon HBV genome transduction with replication effective adenovirus vectors, [J] Virol,2001,75(3):1104-1116
[76]Tsur imoto T, Fuj iyama A, Matsubara K, Stable expression and replication of hepatitis B virus genome in an integrated state in a human hepatoma cell line transected with the cloned viral DNA. Proc Natl Acad Sci U S A,1987,84 (2):444-448
[77]0. Hantz, R. Parent, D. Durantel, Persistence of the hepatitis B virus covalently closed circular DNA in HepaRG human hepatocyte-like cells, Journal of General Virology 2009,90,127-135
[78]Zhou T, Guo H, Guo JT, Cuconati A, et al, Hepatitis B vi rus e antigen production is dependent upon covalently closed circular(ccc)DNA in HepAD38 cell cultures and may Serve as a cccDNA surrogate in antiviral screening assays。Antivi ral,2006,20:132-135。
[80]Yang EB. Cao J. Su JJ, Chow E 2005. The tree shrews:useful animal models for the viral hepatitis and hepatocellular carcinoma [J]. Hepatogastroenterology,52(62):613-616
[81]Glebe D. Urban S. Viral and cellular determinants involved in hepadnaviral entry[J], World Gastroenterol,2007,13(1):22-38.
[82]Mason WS, Seal G, Summol/Lol/Lers J. Virus of Peking ducks with structural and biological relatedness to human hepatitis B virus. J Virol,1980,36:829-836.
[83]Sprengel R, Kaleta EF, Will H. Isolation an d characterization of a hepatitis B virus endemic in herons. J Virol,1988,62:932-937
[84]Nie W, Fu B,O Brien PC, et al. Flying lemurs—the flying tree shrews, Molecular cytogenetic evidence for a Scandentia-Dermoptera sister clade [J]. BMC Biol,2008,6:18-20
[85]庞其方,万新邦,胥爱源等.HBV感染树鼩的实验研究[J].医学研究通讯[J].1981,(9)：30—38.
[86]Su JJ, Yan QR, Gan YQ, Zhou DN, Huang DR, Huang GH 1987. Study on the HBV infection ofadult Tupaia[J Jl Zhonghna Binglixue Zazhi, (16):103-105
[87]W alter E, Keist R, Niederost B, et all, Hepatitis B virus infection of tupaia hepatocytes in vitro and in vivo [J]. Hepatology,1996.24(1):1-5
[88]Kock J, Nassal M, MacNelly S, et all. Efficient infection of primary tupaia hepatocytes with purified human and woolly monkey hepatitis B virus,[J]Virol, 2001,75(11):5084.5089
[89]Glebe D, AIiakbari M, Krass P, et al, Pre-sl antigen-dependent infection of Tupaia hepatocyte cultures with human hepatitis B virus [J]. Jm,2003,77(17): 9511-9521
[90]严瑞琪 苏建家 陈志英等,人乙型肝炎病毒实验感染成年树鼩的初步研究[J],广西医学院学报,1984 1(1)：10-15
[91]苏建家 严瑞琪,甘有全,成年树鼩实验感染人乙型肝炎病毒的研究[J],中华病理学杂志,1987 16(2)：103-107
[92]Y Li, JJ Su, LL Qin, et al, Synergistic effect of hepatitis B virus and aflatoxin B1 in hepatocarcinogenesis in tree shrews, [J] Ann Acad Med Sigapore 1999,28:67-71
[93]苏建家,李瑗,班克臣等,动态研究HBV和AFB诱发树鼩肝细胞癌过程中一些基因的表达,广西中医药大学学报,2001,18(2)；151-154
[94]周凤娟,胡振林,戴建新等,乙肝DNA疫苗pVAX—PS对树鼩的免疫保护作用,第二军医大学学报,2003,24(10)：120-123
[95]岳惠芬,陈茂伟,曹骥等,乙肝病毒X基因转基因树鼩模型的建立和病理学研究,广西医科大学学报,2006,23(2)：185-187
[96]王风水,陈红松,王宇等,树鼩感染人乙肝病毒动物模型研究中的非特异性反应,北京医科大学学报,1996,28(5)：340-342
[97]王树声, 苏建家, 冯百芳等,树鼩、熊猴感染人乙型肝炎病毒肝细胞内感染指征的研究,中华实验和临床病毒学杂志,2003,17(3)：92—94
[98]Von, Weizsacker F, Kock J, et al, The tupaia m ode 1 for the study of hepatitis B virus:direct infection and HBV genome transduction of primary tupaia hepatocytes. Methods 2004,96:153-161
[99]Summolers J, Smolec JM, SnyderR。 virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woochucks. Proc Natl Acad Sci U S A,1978,75:4533-4537
[100]Roggendorf M, I, uM. Tomas TH, Woodchuck hepatitis virus, Viral Hepatitis. Oxford:Blaekwell,2005:210224
[101]Bannash P, Khosh Khou NI, Hacker HJ,et al. Synergistic hepatocarcinogenic effect of hepadnaviral infection and dietany aflatoxin B1 in woodchucks [J] CancerRes1995:55,3318-3330
[102]Mason WS, CuUen J, Moraleda G, et al, Lamivudine therapy of WHV-infected woodchucks[J], Virology,1998,245(1):18-19
[103]孟忠吉,李新宇,李磊等,土拨鼠肝炎病毒可复制性克隆的构建和鉴定,肝脏,2009,14(2)：128-131
[104]Ren S, Nassal M. Hepatitis B virus(HBV)virion and covalently dosed circular DNA formation in primary tupaia hepatocytes and human hepatoma cell lines upon HBV genome transduction with replication-defective adenovirus vectors [J]. J Virol。 2001,75(3):1104-1116
[105]Glebe D, Alikbari M,Kraes P 。et al. Pre-sl antigen—dependent infection of Tupaia hepatocyte cultures with human hepatitis B virus[J]. J Virol。2003,77(17): 9511-9521
[106]乙型肝炎病毒：复制机制与基因封闭策略胡康洪中外健康文摘2008,5(8)：5—8
[107]杨月,用于乙型肝炎研究的动物模型,国外医学(微生物学分).1986.13(6)：246-248
[108]Barker LF, Maymard JE. Purcell RH. et al Viral hepatitis, type B, in experimental animals. Am J Med Sciences,1975,270(1):189-192
[109]Will H, Reset W. Weimer T, et al. Replication Strategy of human hepatitis B virus. J Virol.1987,61(3):904-911
[110]Tiollais P. Pourcel C. Dejean A. The hepatitis B virus. Nature.1985,317(6037): 489-49
[111]Gattaneo R. Will H, Hernandez N, et al. Signals regulating hepatitis B surface antigen transcription. Nature,1983.305(5931):336-338
[112]Nowak MA, Bonhoeffer S, Hill AM, et al. Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci USA 1996; 93:4398-4402
[113]John M. Murray, Stefan F, et al,Dynamics of hepatitis B virus clearance in chimpanzees, Proc Natl Acad Sci U S A.2005; 102(49):17780-17785.
[114]Wieland SF, Spangenberg HC, Thimmol/Lol/Le R, et al. Expansion and contraction of the hepatitis B virus transcriptional template in infected
chimpanzees [J]. Proc Natl Acad Sci U S A.2004,101(7):2129-2134
[115]Stefan F. Wieland, Hans Christian Spangenberg,et al, Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees, Chisari Proc Natl Acad Sci U S A.2004,101(7): 2129-2134.
[116]能一力,刘光泽,贾彦征HBV转基因小鼠免疫耐受机制的实验研究,世界华人消化杂志,2002；10：642—645
[117]Zheng Y, Chen WL, Louie SG, et al,Hepatitis B virus promotes hepatocarcinogenesis in transgenic mice. Hepatology 200 45:16-21
[118]Shlomai A, Shaul Y. Inhibition of hepatitis B virus expression and replication by RNA interference. Hepatolox,2003; 37:764-770
[119]Shlomai A, Shaul Y. RNA interference—small RNAs effectively fight viral hepatitis. Liver Int 2004; 24:526-53
[120]Larkin T, Clayton M, Sun B, et al, Hepatitis B virus transgenic mouse model of chronic liver disease. Nat Med 1999; 5:907-912
[121]屠亚军,琦祖和,杨鹏等,人乙型肝炎病毒X基因转基因小鼠模型的建立,中国医学科学院学报,2000；22：263—265
[122]Wiland SF,Guidotti LG Chisari FV. Intrahepatic induction of alpha/beta interferon eliminates viral RNA—containing capsids in hepatitis B virus transgenic mice [J]. J Virol,2000,74:4165-4173
[123]Rauschhuber C, Xu H, Salazar FH, et al, Exploring gene—deleted adenoviral vectors for delivery of short hairpin RNAs and reduction of hepatitis B virus infection in mice. Gene Med 2008; 10:878-889
[124]Isogawa M Kakimi K, Kamamoto H, et al, Differential dynamics of the peripheral and intrahepatic cytotoxic T lymphocyte response to hepatitis B surface antigen. Virology 2005; 333:293-300
[125]Yang PL, Althage A, Chung J, Hydrodynamic injection of viral DNA:a mouse model of acute hepatitis B virus infection. Proc Natf Acad Sci U S A 2002:99: 13825-13830
[126]Ohashi K, Marion PL, Nakai H, et al, Sustained survival of human hepatocytes in mice:A model for in vivo infection with human hepatitis B and hepatitis delta viruses. Nat Med 2000; 6:327-331
[127]蒋黎,毛青,王宇明等,HBV感染的人鼠嵌合肝动物模型的建立,第三军医大学学报,2003,25(5)：12
[128]Schultz U, Grgacic E, Nassal M. Duck hepatitis B virus:an invaluable model system for HBV infection. Adv Virus Res,2004,63 (1):68-70.
[129]邓学龙,朱宇同,方宏勋等.广州地区3个鸭种1日龄雏鸭垂直感染鸭乙肝病毒调查, [J].广东中医药大学学报,1997,14：274-275
[130]莫小余,李向阳,潘宗奇,等.中药抗先天性华南绿头鸭乙肝病毒的实验研究,[[J].中华医学研究杂志,2003,3：696—697
[131]邹移海,张薇,张奉学,等.广东省绿头鸭场鸭乙肝病毒自然携带状况调查[J].中国实验动物学杂志,2001,11(1)：9—11
[132]Fukuda R Okinaga S, Akagi S, et al. Alteration of infection pattern of duck hepatitis B virus by immol/Lol/Lunomodulatory drugs, [J]. J Med Virol,1988, 26(4):387-396
[133]李虹,陈文,徐纬,等.核酶对鸭乙型肝炎病毒感染体内抗病毒作用效果的观察[J].中华实验和临床病毒学杂志,1998,12：118.121
[134]朱万孚,席与萍,曲平,等.鸭乙型肝炎动物模型的研究叨.北京医科大学学报,1987,19(4)：223·226
[135]K. Vickery,J. S. Freiman, M, D, R Kearney,et al, Immol/Lol/Lunity in Pekin duck experimentally and naturally infected with duck hepatitis B virus J Med Virol 1989.28(4):231-236
[136]Mason W-S, Halpel T, MS, England J, et al. Experimental transmission of duck hepatitis B virus [J], Virology,1983,131:375-384.
[137]Pugh J-C, Simmol/Lol/Lons H. Duck hepatitis B virus infection of Muscovy duck hepatocytes and nature of virus resistance in vivo [J]. J Virol,1994,68(4): 2487-2494.
[138]JI-SU LI, SHU-PING TONG, AND JACK R, Characterization of a 120-Kilodalton Pre-S-Binding Protein as a Candidate Duck Hepatitis B Virus Receptor, JOURNAL OF VIROLOGY,1996,70 (9):6029-6035
[139]Rahma Tohidi-Esfahani, Karen Vickery and Yvonne Cossart, The early host innate immol/Lol/Lune response to duck hepatitis B virus infection, Journal of General Virology (2010),91:509-520
[140]NEWBOLD JE, XIN H, TENCZA M, et all The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral mini—chromosome[J]. J Virol,1995,69:3350-3357.
[141]DELMAS J, SCHORR O, JAM ARD C, et al. Inhibitory effect of adefovir on viral DNA synthesis and covalently closed circular DNA formation in duck hepatitis B virus—infected hepatocytes in vivo and in vitro [J]. Antimicrob Agents Chemother,2002,46(2):425-433
[142]NETTER HJ, CHASSOT S, CHANG SF, et al. Sequence heterogeneity of heron hepatitis B virus genomes determined by full—length DNA amplification and direct sequencing reveals novel and unique features[J]. J Gen Virol,1997, 78:1707-1718
[143]CHANG SF, NETTER HJ, HILDT E, et al, Duck hepatitis B virus expresses a regulatory HBx ·-like protein from a hidden open reading frame[J]. J Virol, 2001,75:161-170
[144]BOCK CT. SCHW INN S, LOCARNINI S, et al. Structural organization of the HBV minichromosome[J]. J Mol Biol,2001,307:183-196
[145]0FFENSPERGER WB, OFFENSPERGER S, KEPPLER HAFKEMEYER A. et al. Antiviral activities of penciclov and famciclovir on duck hepatitis B virus in vitro and in vivo [J]. Antivir Thera,1996,1(3):141-146.
[146]LIN E, LUSCOMBE C, COLLEDGE D, et al. Long term therapy with the guanine nucleoside analog penciclovir controls chronic duck hepatitis B virus infection in vivo [J]. Antimicro Agents Chemnother,1998,42(8):2132-2137.
[147]蒋定锋,闫梁,责海静等,鸭乙型肝炎病毒核心抗原DNA疫苗的构建及其诱导的体液免疫应答,微生物与感染,2009,4(3)：140-146
[148]Claudia Maenz, Christine Loscher, Inhibition of duck hepatitis B virus infection of liver cells by combined treatment with viral e antigen and carbohydrates, Journal of General Virology (2008),89,3016-3026
[149][8]Hannon G J. RNA interference. Nature,2002,418(6894):244-251
[150]Perrrillo RP. Current treatment of chronic hepatitis B benefits and limitations [J]. Semin Liver Dis 2005,25 supll 1:20-28.
[151]Lim SG, Ng TM, Kung N, Krastev Z, Volfova M, Husa P, Lee SS, Chan S, Shiffman ML, Washington MK, Rigney A, Anderson J, Mondou E, snow A, Sorbel J, Guan R, Rousseau F. Adouble—blind Placebo—controlled Study of emtricitabine in chronic hepatitis B [J]. Arch Intren Med,2006,166:49-56
[152]汤雁波,李卓荣.核苷类抗病毒药物研究进展.中国生化药物杂志.2004,25(1),44-47.
[153]De Clercq E. Antiviral drugs in current clinical use. Journal of Clinical Virology.2004,30,115-133.
[154]Hache C, Villeneuve JP. Lamivudine treatment in patients with chronic hepatitis B and cirrhosis. Expert. Opin. Pharmacother.2006,7(13),1835-1843.
[155]Guo JT,Zhou H, Liu C, et al. Apoptosis and regeneration of hepatocytes during recovery from transent hepadanvirus infections [J]. J Virol,2000,74:1495-1505
[156]Kajino K, Jilbert AR,Saputelli J, et al. Woodchuck hepatitis virus infections: very rapid recovery after a prolonged viremia and infection of virtually every hepatocyte [J]. J Virol,1994,68:5792-5803
[157]Danta M, Dusheiko G. Adefovir dipivoxil:review of a novel acyclic nucleoside analogue. Int. J. Clin. Pract.,2004,58(9),877-886.
[158]Baker DE. Adefovir dipivoxil:focus on its use in the treatment of chronic hepatitis B. Rev. Gastroenterol. Disord.2005,5(2),89-100
[159]Yuen MF, Lai CL. Adefovir dipivoxil in chronic hepatitis B infection. Expert. Opin. Pharmacother.,2004,5(11),2361-2367.
[160]Qaqish RB, Mattes KA, Ritchie DJ. Adefovir dipivoxil:a new antiviral agent for the treatment of hepatitis B virus infection. Clin. Ther.,2003,25(12),3084-3099
[161]Hadziyannis SJ, Papatheodoridis GV, Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection. Expert. Rev. Anti. Infect. Ther.,2004,2(4), 475-483
[162][48] Delmas J, Schorr 0, Jameard C, et al. Inhibitory effect of adefovir on viral DNA synthesis and covalently closed circular DNA formation in duck hepatitis B virus—infected hepatocytes in vivo and in vitro[J]. Antimicrobial Agents and Chemotherapy,2002.46(2):425-433
[163]William E, Delaney IV, Angeline, et al, Evolving therapies for the treatment of chronic hepatitis B virus infection [J]. Investig. Drugs 2002,11 (2):169-187
[164]张永兴,陈忻,许利平等.神奇的抗病毒中草药[M].北京：中国中医药出版社,2004.6-8.
[165]Huang RL, Huang YL, Ou JC, et al. Screening of 25 compounds isolated from Phyllanthus species for anti-human hepatitis B virus in vitro[J]. Phytother Res,2003,17:449-453
[166]Shin MS, Kang EH, Lee YI, et al. A flavonoid from medicinal plants blocks hepatitis B virus-e antigen secretion in HBV-infected hepatocytes [J]. Antiviral Res,2005,67:163-1681
[167]Ding PL, Liao ZX, Huang H, et al. (＋)- 12alpha—hydroxysophocarpine, a new quinolizidine alkaloid and related anti-HBV alkaloids from Sophora flavescens [J]. Bioorg Med Chem Lett,2006,16:1231-1235
[168]Shen YC, Lin YC, Chiang MY et al. Kadsuphilactones A and B, two novel triterpene dilactones from Kadsura philippinensis [J]. Org Lett, 2005,7:5348
[169]刘厚佳,胡晋红,孙莲娜,等.表儿茶酸等化合物对HBV DNA转染人肝癌细胞株的作用[J].第二军医大学学报,2001,22(3)：661-663
[170]Chin Teng Chang, Shin Lian Dong, Iall Lih Tsai, et al. Coumarinsand anti-HBV constituents from Zanthoxylum chinifolium [J]. Phytochemistry,1997,45(7):1419-1422
[171]Chang CT,Doong SL,Tsai IL,et al.Coumarins and anti—HBV constituents from zanthoxylum schinifolium[J]. Phytochemistry,1997,45:1419 -1422
[172]郑民实等.中草药抗HBsAg的实验研究.中国医院药学杂志,1988.8(3)：121
[173]杨鉴英等.中药抗乙型肝炎病毒的实验研究.中西医结合杂志,1989.9(8)：494-496
[174]焦成松等.香菇多糖脂质体治疗鸭乙型肝炎的初步观察.中西医结合杂志,1991,1(3)：24
[175]秦守杰.苦参素治疗慢性乙型肝炎90例疗效观察[J].郑州大学学报(医学版),2003,38(5)：8293
[176]纪徐淮等.人重组干扰素和叶下珠提取物对人肝癌细胞株PLC／PER5产生HBsAg的影响.中西医结合杂志,1992,2(1)：13
[177]Niv z, et al, fleet of PHYU anthus. amoro6. Duck Hepatitis B virus replication in vivo J Med Virol 1990:32(4)
[178]温志坚,曹敏,彭龙玲等.小柴胡汤提取物体外抗HBV的活性研究.中西医经合肝病杂志,2000,10(4)：29-318
[179]刘中景等.小柴胡抗鸭乙肝病毒的实验研究.中国中西医结合杂志,2000,11：853—855
[180]Yun-Bao Ma, Shu-ying Yao, Quang Zhang, et al,Two New Alkaloids and Active Anti-Hepatitis B Virus Constituents from Hypserpa nitida. Bioorg. Med. Chem. Lett.2007,10(2):337-341
[181]江苏新医学院.中药大辞典[M].上册.上海：上海科学技术出版社,1986,1462
[182]陶晋舆,吕环,张秋菊,等.泽泻抗动脉粥样硬化作用系列研究(二)[J]北京中医学院学报,1991,14(6)：51
[183]王新华.泽泻研究进展[J].中草药,1999,30(7)：557.
[184]郑虎占,董泽宏,佘靖.中药现代研究与应用[M].第4册.北京：学苑出版社,1998,3022)
[185]尹春萍,吴继洲.泽泻及其活性成分免疫调节作用研究进展[J].中草药,2001,32(12)：1132—1134.
[186]尹春萍,刘继红,张长弓.不同离子强度及PH值时泽泻和夏枯草对草酸钙结晶形成的抑制作用观察[J],同济医科大学学报,1996,25(4)：321—334
[187]尹春萍,刘继红,章咏裳,等.泽泻水提取物预防草酸钙结石形成的体外及动物实验研究[J].同济医科大学学报,1997,26(2)：99—102
[188]曹正国,刘继红,吴继洲,等.泽泻不同溶剂提取物对大鼠尿草酸钙结石形成的影响[J].中草药,2003,34(1)：45—46.
[189]李继承,吕连志,石元和,等.中药对腹膜孔调控作用的实验研究[J].中国中医基础医学杂志,1998,4(8)：20—25
[190]支广教道(日).泽泻的抗肾炎活性研究[J].国外医学-中医中药分册,1997,19(5)：58—61.
[191]杨新波,黄正明,曹文彬,等.泽泻水提取物对正常小鼠及高血糖小鼠血糖的影响[J].中药药理与临床,1998,14(6)：29—33
[192]戴岳,杭秉茜.泽泻对谷氨酸钠肥胖大鼠的影响[J],中成药,1992,14(2)：28—31.
[193]马兵,项阳,李涛,等.泽泻对Lewis肺癌自发性转移的抑制作用及其机制研究[J],中草药,2003,34(8)：743—745
[194]江苏新医学院编.中药大辞典(上册).上海：上海科学技术出版社,1986：14(6)：21—24
[195]Chen H W, Hsu M J, Chien C T, et all. Effect of alisol B acetate, a plant triterpene, on apoptosis in vascular smooth muscle cells and lymphocytes [J]. Eur J Pharmacol,2001,419:127-138
[196]Huang Y T, Huang D M, Chueh S C, et all. Alisol B acetate, a triterpene from Alismatis rhizoma, induces Bax nuclear translocation and apoptosis in human hormone resistant prostate cancer PC-3 cells [J]. Cancer Lett,2006.231:270-278.
[197]Zhang J X, Shen X L, et all. Revemal of P-gly-coprotein-mediated muhidrug resistance by alisol B 23—acetate [J]. Biochem Pharmacol, 2004,68:843-855.
[198]Fong W F, WangC, Zhu G Y, et all. Reversal of multi—drug resistance in cancer cells by Rhizoma Alismatis extract [J]. Phytomedicine, 2007,14:160-165.
[199]Kubo M, Matsuda H, Tomohiro N, et all. Studies on A lismatis rhizoma. I. Anti-allergic effects of methanol ex-ract and six terpene components from Alismatis rhi。zoma [J]. Biol Pharm Bull,1997,20(5):511-517
[200]Matsuda H, Tomohiro N, Yoshikawa M. et all. Studies on Alismatis rhizoma. Ⅱ. Anti-complementary activities of methanol extract and terpene components from Alis-matis rhizoma [J]. Biol Pharm Bull, 1998,21(12),1317-132117
[201]Matsuda H, Kageura T, Toguchida I, et all. Effects of sesquiterpenes and triterpenes from the rhizome of Alisma orientale on nitric oxide production in lipopolysaccharide activated macrophages:absolute stereostructures of Alismaketones. B 23-acetate and C 23-acetate [J]. Bioorg Med Chem Lett,1999,9:3081-3086.
[202]Kim N. et all. In vitro inducible nitric oxide synthesis inhibitors from Alismatis Rhizoma [J]. Biol Pharm Bull.1999,22(10):1147
[203]Jiang Z Y, Zhang X M, Zhang F X, et al. A new triterpene and anti-hepatitis B virus active compounds from Alisma orientalis [J]. Planta Med,2006,72(10):951-954 211
[204]Yong-Yuan Zhang, Daniel P. Theele, and Jesse Summol/Lol/Lers, Age-Related Differences in Amplification of Covalently Closed Circular DNA at Early Times after Duck Hepatitis B Virus Infection of Ducks, JOURNAL OF VIROLOGY,2005,79 (15):9896-9903
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |