中药肝豆汤治疗Wilson病疗效机制的研究进展
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摘要
Wilson病(WD)是一种以铜代谢障碍为生化特征的可治性神经遗传病,目前以青霉胺(PCA)为代表的金属络合剂驱铜治疗等治疗方法存在一定的局限性,使其治疗范围和效果受到限制,基因治疗尚处于实验室研究阶段,走向临床尚需时日。笔者等在现代医学对WD认识的基础上,根据对WD中医病机、证候学、中药方剂治疗学等方面的研究结果,创用中药组方肝豆汤治疗WD患者,获得了良好的临床疗效。基于此,笔者等在多个国家自然科学基金项目的资助下,从铜代谢的分子通路,Wnt/β-catenin通路和丝裂原激活的蛋白激酶(MAPK)通路等调控肝损伤的细胞信号通路,细胞外信号调节激酶(ERK)通路和肝激酶B1(LKB1)/腺苷酸活化蛋白激酶(AMPK)通路等调控神经元损伤的细胞信号通路等角度对肝豆汤治疗WD的疗效机制进行了系列研究,结果发现中药组方肝豆汤能多层次、多靶点调控铜代谢障碍所致的WD肝细胞和神经元细胞的调亡、自噬等细胞程序性死亡过程,并通过TX小鼠等WD的动物模型验证了上述实验结果,从而证明了肝豆汤组方的合理性、配伍的必要性和用药的准确性,并为肝豆汤组分的进一步优化提供了依据。文章最后对肝豆汤治疗WD疗效机制的未来研究方向提出了一些设想和可行性建议。
Wilson disease( WD) is a treatable neurological inherited disorder characterized by copper metabolism impairment. Metal chelating drugs,such as penicillamine,have been used to treat WD for decades,is exposuring its limitations of effect and utilize sphere. Genetic therapy was considered as the most potential way of curing WD,is still can only be achieved in the laboratory,which have massive problems to solve before its clinical utilization. Based on this,we started to research the curative mechanism of traditional Chinese medicine( TCM)donated by national natural science fund project funding,found that TCM formula Gandou decoction regulate the metabolic disorders caused by liver cells and neurons apoptosis,autophagy,such as programmed cell death,from the molecular pathways of copper metabolism, Wnt/β-catenin pathway and mitogen-activated protein kmase( MAPK) pathways regulating liver damage such as cell signaling pathways,extracellular signal-regulated kinase( ERK) pathway and liver kinase B1( LKB1)/adenosine monophosphate activated protein kinase( AMPK)pathway and the cell signaling pathway of neuronal damage. The above experimental results were verified by TX mice,a reliable WD animal models. This paper aimed to systematically review the research of GDD therapeutic mechanisms from the sight of programmed cell death,including aptosis and autophagy,and provided theoretical for formula optimization. In addition,we elaborated some assumptions and feasible advice for the further research of GDD therapeutic mechanism.
Wilson disease( WD) is a treatable neurological inherited disorder characterized by copper metabolism impairment. Metal chelating drugs,such as penicillamine,have been used to treat WD for decades,is exposuring its limitations of effect and utilize sphere. Genetic therapy was considered as the most potential way of curing WD,is still can only be achieved in the laboratory,which have massive problems to solve before its clinical utilization. Based on this,we started to research the curative mechanism of traditional Chinese medicine( TCM)donated by national natural science fund project funding,found that TCM formula Gandou decoction regulate the metabolic disorders caused by liver cells and neurons apoptosis,autophagy,such as programmed cell death,from the molecular pathways of copper metabolism, Wnt/β-catenin pathway and mitogen-activated protein kmase( MAPK) pathways regulating liver damage such as cell signaling pathways,extracellular signal-regulated kinase( ERK) pathway and liver kinase B1( LKB1)/adenosine monophosphate activated protein kinase( AMPK)pathway and the cell signaling pathway of neuronal damage. The above experimental results were verified by TX mice,a reliable WD animal models. This paper aimed to systematically review the research of GDD therapeutic mechanisms from the sight of programmed cell death,including aptosis and autophagy,and provided theoretical for formula optimization. In addition,we elaborated some assumptions and feasible advice for the further research of GDD therapeutic mechanism.
引文
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[2] Bull P C,Thomas G R,Rommens J M,et al. The Wilson disease gene is a putative copper transporting Ptype ATPase similar to the Menkes gene[J]. Nat Genet,1993,5(4):327-337.
[3] Petrukhin K,Fischer S G,Pirastu M,et al. Mapping,cloning and genetic characterization of the region containing the Wilson disease gene[J]. Nat Genet,1993,5(4):338-343.
[4] Tanzi R E,Petrukhin K,Chernov I,et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene[J]. Nat Genet,1993,5(4):344-350.
[5]杨任民.肝豆状核变性[M].北京:人民卫生出版社,2015:3-49.
[6] Czonkowska A,Litwin T,Dusek P,et al. Wilson disease[J]. Nat Rev Dis Primers,2018,4(1):21.
[7] Scheinberg I,Sternlieb I. Wilson's disease[J]. Major Probl Intern Med,1984,23:1-24.
[8] CHENG N,WANG K,HU W,et al. Wilson disease in the South chinese han population[J]. Can J Neurol Sci,2014,41(3):363-367.
[9]程楠,韩咏竹.肝豆状核变性的分子诊断与治疗[J].分子诊断与治疗,2018,10(4):217-221,227.
[10]蒋雨平.要提高我国肝豆状核变性病的诊断水平[J].中华医学杂志,2001,81(11):641.
[11] Amberger J S,Bocchini C A,Schiettecatte F,et al.OMIM. org:online mendelian inheritance in man(OMIM),an online catalog of human genes and genetic disorders[J]. Nucleic Acids Res,2015,43:789-798.
[12] Roberts E A,Schilsky M L. Diagnosis and treatment of Wilson disease:an update[J]. Hepatology,2008,47(6):2089-2111.
[13] Ferenci P,Roberts E A. Defining Wilson disease phenotypes:from the patient to the bench and back again[J]. Gastroenterology,2012,142(4):692-696.
[14] Schilsky M L. Long-term outcome for Wilson disease:85%good[J]. Clin Gastroenterol Hepatol,2014,12(4):690-691.
[15] Roybal J L,Endo M,Radu A,et al. Early gestational gene transfer with targeted ATP7B expression in the liver improves phenotype in a murine model of Wilson's disease[J]. Gene Ther,2012,19(11):1085-1094.
[16] Murillo O,Luqui D M,Gazquez C,et al. Long-term metabolic correction of Wilson's disease in a murine model by gene therapy[J]. J Hepatol,2016,64(2):419-426.
[17]洪铭范,胡纪原,胡文彬,等.肝豆状核变性的中医辨证分型[J].安徽中医学院学报,1998,17(1):10-11.
[18]杨任民,韩咏竹,任明山,等.中药治疗肝豆状核变性107例疗效观察[J].中医杂志,1993,34(11):72-73.
[19]张静,陈怀珍,艾文龙,等.肝豆汤联合DMPS驱铜治疗对Wilson病湿热内蕴型认知功能障碍的影响[J].中国实验方剂学杂志,2018,24(15):210-215.
[20]张静,方媛,崔圣伟,等.肝豆汤联合二巯基丙磺酸钠对湿热内蕴型肝豆状核变性患者的影响[J].中国实验方剂学杂志,2017,23(17):190-194.
[21]胡文彬,杨任民.肝豆片I号对肝豆状核变性患者铜生化及肝肾功能的影响[J].中医杂志,1997,38(7):414-416.
[22]胡文彬,杨任民.肝豆片I号对肝豆状核变性患者胆汁微量元素的影响的前瞻性研究[J].中国中西医结合杂志,2001,21(7):507-509.
[23]胡文彬,杨任民.肝豆片I号对肝豆状核变性患者微量元素排泄的影响[J].中国临床康复杂志,2003,7(30):4165.
[24] Maryon E B,Molloy S A,Kaplan J H. Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1[J]. Am J Physiol Cell Physiol,2013,304(8):768-779.
[25] Harris Z L,Gitlin J D. Genetic and molecular basis for copper toxicity[J]. Am J Clin Nutr,1996,63(5):836-841.
[26] Hellman N E,Kono S,Mancini G M,et al. Mechanisms of copper incorporation into human ceruloplasmin[J]. J Biol Chem,2002,277(48):46632-46638.
[27] Lutsenko S,Le Shane E S,Shinde U. Biochemical basis of regulation of human copper-transporting ATPases[J].Arch Biochem Biophys,2007,463(2):134-148.
[28] Heaton D N,George G N,Garrison G,et al. The mitochondrial copper metallochaperone Cox17 exists as an oligomeric,polycopper complex[J]. Biochemistry,2001,40(3):743-751.
[29] Carroll M C,Girouard J B,Ulloa J L,et al. Mechanisms for activating Cu-and Zn-containing superoxide dismutase in the absence of the CCS Cu chaperone[J].Proc Natl Acad Sci USA,2004,101(16):5964-5969.
[30] Walker J M,Huster D,Ralle M,et al. The N-terminal metal-binding site 2 of the Wilson's disease protein plays a key role in the transfer of copper from Atox1[J]. J Biol Chem,2004,279(15):15376-15384.
[31] Larin D,Mekios C,Das K,et al. Characterization of the interaction between the Wilson and Menkes disease proteins and the cytoplasmic copper chaperone,HAH1p[J]. J Biol Chem,1999,274(40):28497-28504.
[32]董健健,韩咏竹,程楠.肝豆汤对Wilson病模型TX小鼠肝细胞内铜代谢通路的分子调控机制[J].中国实验方剂学杂志,2016,22(24):128-133.
[33]王超旻,韩咏竹.中药肝豆汤对Wilson病模型TX小鼠铜代谢通路的分子调控机制研究[D].合肥:安徽中医药大学,2013.
[34]艾文龙,韩咏竹.中药肝豆汤对Wilson病动物模型TX小鼠肝细胞铜稳态调控的研究[D].合肥:安徽中医药大学,2013.
[35] Schaeffer M,Hopkins R G,Failla M L,et al. Hepatocytespecific localization and copper-dependent trafficking of the Wilson's disease protein in the liver[J]. Am J Physiol,1999,276(3 Pt 1):639-646.
[36] Forbes J R,Cox D W. Copper-independet trafficking of Wilson disease mutant ATP7B proteins[J]. Hum Mol Genet,2000,9(13):1927-1935.
[37]吕达平,韩咏竹,王训,等.肝豆状核变性患者肝细胞中P型ATP7B酶水平及功能的研究[J].临床神经病学杂志,2005,18(3):173-175.
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