Title

活血中草藥中似類固醇成分對鈉鉀幫浦的抑制作用.

Translated Titles

Steroid-like compounds in Chinese medicines of promoting blood circulation and their inhibitory potency on Na+/K+-ATPase.

DOI

10.6845/NCHU.2010.00928

Authors

陳榮佑

Key Words

強心配醣體 ; 鈉鉀幫浦 ; 似類固醇成分 ; 分子模擬 ; cardiac glycosides ; Na+/K+-ATPase ; steroid-like compounds ; molecular modeling

PublicationName

中興大學生物科技學研究所學位論文

Volume or Term/Year and Month of Publication

2010年

Academic Degree Category

博士

Advisor

曾志正

Content Language

英文

Chinese Abstract

強心配醣體藉由可逆性的抑制心肌細胞膜上鈉鉀幫浦而達到強心的作用。傳統上用於「活血」的中草藥中也大量地發現與強心配醣體結構相似的似類固醇成分。推論這些成分應該也能透過抑制鈉鉀幫浦而提供這些中草藥在心臟治療上的效果。確實在此次的研究中發現這些中草藥中的似類固醇成分具有抑制鈉鉀幫浦的能力。例如中藥蟾酥中的bufalin就具有很強的抑制能力。而大量存在於夏枯草中的五環三萜類成分,ursolic acid及oleanolic acid則具有和人參皂苷Rh2相似的中等抑制能力,而Rh2是本次試驗的人參皂苷中抑制能力最強的。經由分子模擬發現這些似類固醇成分在抑制鈉鉀幫浦能力上的明顯差異,主要是因為它們與鈉鉀幫浦形成氫鍵能力上的不同以及形成疏水性作用力強度上的差異。更深入研究發現,各種人參皂苷對鈉鉀幫浦的抑制能力也深受其結構上醣基的影響,也就是這些醣基可能造成空間障礙使得某些人參皂苷無法有效抑制鈉鉀幫浦。僅有與強心配醣體一樣只在結構C-3位置上具有醣基的人參皂苷,例如Rg3及Rh2,才具有較顯著的抑制能力。當在C-6及C-20位置上加上醣基將嚴重影響甚至喪失其抑制能力。透過此次研究我們發現到這些廣泛存在的似類固醇成分似乎能夠透過有效的抑制鈉鉀幫浦而達到強心活血的功效。

English Abstract

The positive inotropic effect of cardiac glycosides lies in their reversible inhibition on the membrane-bound Na+/K+-ATPase located in human myocardium. Several steroid-like compounds possessing a core structure similar to the steroid nucleus of cardiac glycosides have been found in many traditional Chinese medicines conventionally used for promoting blood circulation. These compounds putatively contribute to the partial therapeutic effect of their corresponding medicinal products through the same mechanism of inhibiting Na+/K+-ATPase. All steroid-like compounds examined in present study displayed more or less inhibitory potency on Na+/K+-ATPase. Bufalin from ChanSu exhibited much higher inhibitory potency than the others. Among the pentacyclic triterpenoids examined, ursolic acid and oleanolic acid existing in Prunella vulgaris were moderate inhibitors of Na+/K+-ATPase, and their inhibitory potency was comparable to that of ginsenoside Rh2, the strongest inhibitor among the ginsenosides examined in this study. The drastic difference observed in the inhibitory potency of bufalin, ginsenoside Rh2, and pentacyclic triterpenoids is ascribed mainly to the number of hydrogen bonds and partially to the strength of hydrophobic interaction between the compounds and residues around the deep cavity of Na+/K+-ATPase. Moreover, inhibitory potency of ginsenosides on Na+/K+-ATPase is significantly affected by sugar attachment that might cause steric hindrance of their binding to Na+/K+-ATPase. Ginsenosides, such as Rg3 and Rh2, with sugar moieties attached only to the C-3 position of the steroid-like structure, equivalent to the sugar position in cardiac glycosides, substantially inhibit Na+/K+-ATPase. However, their inhibitory potency is abolished when sugar moieties are linked to the C-6 or C-20 position of the steroid-like structure. In this study, we realized that steroid-like compounds seem to possess cardiac therapeutic effects via effective inhibition on Na+/K+-ATPase.

Topic Category 農業暨自然資源學院 > 生物科技學研究所
生物農學 > 生物科學
Reference
  1. RESEARCH BACKGROUND
    連結:
  2. 1 Li XC, Yu C, Sun WK, Liu GY, Jia JY, Wang YP. Pharmacokinetics of magnesium lithospermate B after intravenous administration in beagle dogs. Acta Pharmacol Sin 2004; 25: 1402-7.
    連結:
  3. 2 Lu YR, Foo LY. Polyphenolics of Salvia - a review. Phytochemistry 2002; 59: 117-40.
    連結:
  4. 3 Shigematsu T, Tajima S, Nishikawa T, Murad S, Pinnell SR, Nishioka I. Inhibition of collagen hydroxylation by lithospermic acid magnesium salt, a novel compound isolated from Salviae-Miltiorrhizae Radix. Bba-Gen Subjects 1994; 1200: 79-83.
    連結:
  5. 4 Karmin O, Lynn EG, Vazhappilly R, Au-Yeung KKW, Zhu DY, Siow YL. Magnesium tanshinoate B (MTB) inhibits low density lipoprotein oxidation. Life Sci 2001; 68: 903-12.
    連結:
  6. 5 Yokozawa T, Lee TW, Oura H, Nonaka G, Nishioka I. Effect of magnesium lithospermate B in rats with sodium-induced hypertension and renal failure. Nephron 1992; 60: 460-5.
    連結:
  7. 6 Fung KP, Wu J, Zeng LH, Wong HNC, Lee CM, Hon PM, et al. Lithospermic acid B as an antioxidant based protector of cultured ventricular myocytes and aortic endothelial cells of rabbits. Life Sci 1993; 53: 189-93.
    連結:
  8. 7 Yokozawa T, Chung HY, Dong E, Oura H. Confirmation that magnesium lithospermate B has a hydroxyl radical scavenging action. Exp Toxicol Pathol 1995; 47: 341-4.
    連結:
  9. 8 Kasimu R, Tanaka K, Tezuka Y, Gong ZN, Li JX, Basnet P, et al. Comparative study of seventeen Salvia plants: Aldose reductase inhibitory activity of water and MeOH extracts and liquid chromatography mass spectrometry (LC-MS) analysis of water extracts. Chem Pharm Bull 1998; 46: 500-4.
    連結:
  10. 9 Wu XJ, Wang YP, Wang W, Sun WK, Xu YM, Xuan LJ. Free radical scavenging and inhibition of lipid peroxidation by magnesium lithospermate B. Acta Pharmacologica Sinica 2000; 21: 855-8.
    連結:
  11. 10 Tzen JTC, Jinn TR, Chen YC, Li FY, Cheng FC, Shi LS, et al. Magnesium lithospermate B possesses inhibitory activity on Na+,K+-ATPase and neuroprotective effects against ischemic stroke. Acta Pharmacologica Sinica 2007; 28: 609-15.
    連結:
  12. 11 Li-Saw-Hee FL, Lip GY. Digoxin revisited. QJM 1998; 91: 259-64.
    連結:
  13. 12 Lin SC, Way EL. A high affinity Ca2+-ATPase in enriched nerve-ending plasma membranes. Brain Res 1982; 235: 387-92.
    連結:
  14. 13 Wang JKT, Portbury S, Thomas MB, Barney S, Ricca DJ, Morris DL, et al. Cardiac glycosides provide neuroprotection against ischemic stroke: Discovery by a brain slice-based compound screening platform. P Natl Acad Sci USA 2006; 103: 10461-6.
    連結:
  15. 16 Blaustein MP. Physiological effects of endogenous ouabain: control of intracellular Ca2+ stores and cell responsiveness. Am J Physiol 1993; 264: 1367-87.
    連結:
  16. 17 Sweadner KJ. Isozymes of the Na+/K+-ATPase. Biochim Biophys Acta 1989; 988: 185-220.
    連結:
  17. 19 Kaplan JH. Biochemistry of Na,K-ATPase. Annu Rev Biochem 2002; 71: 511-35.
    連結:
  18. 20 Malik N, Canfield VA, Beckers MC, Gros P, Levenson R. Identification of the mammalian Na,K-ATPase beta 3 subunit. Journal of Biological Chemistry 1996; 271: 22754-8..
    連結:
  19. 21 Zurzolo C, Rodriguez-Boulan E. Delivery of Na+,K+-ATPase in polarized epithelial cells. Science 1993; 260: 550-2.
    連結:
  20. 22 Gottardi CJ, Caplan MJ. Delivery of Na+,K+-ATPase in polarized epithelial cells. Science 1993; 260: 552-4.
    連結:
  21. 23 Fambrough DM, Lemas MV, Hamrick M, Emerick M, Renaud KJ, Inman EM, et al. Analysis of subunit assembly of the Na-K-ATPase. Am J Physiol 1994; 266: 579-89.
    連結:
  22. 24 Lutsenko S, Kaplan JH. An essential role for the extracellular domain of the Na,K-ATPase beta-subunit in cation occlusion. Biochemistry-Us 1993; 32: 6737-43.
    連結:
  23. 25 Beguin P, Wang XY, Firsov D, Puoti A, Claeys D, Horisberger JD, et al. The gamma subunit is a specific component of the Na,K-ATPase and modulates its transport function. Embo J 1997; 16: 4250-60.
    連結:
  24. 26 Scheinerbobis G, Farley RA. Subunit requirements for expression of functional sodium pumps in yeast-cells. Bba Biomembranes 1994; 1193: 226-34.
    連結:
  25. 27 Sweadner KJ, Arystarkhova E, Donnet C, Wetzel RK. FXYD proteins as regulators of the Na,K-ATPase in the kidney. Ann Ny Acad Sci 2003; 986: 382-7.
    連結:
  26. 28 Geering K, Beguin P, Garty H, Karlish S, Fuzesi M, Horisberger JD, et al. FXYD proteins: New tissue- and isoform-specific regulators of Na,K-ATPase. Ann Ny Acad Sci 2003; 986: 388-94.
    連結:
  27. 29 Therien AG, Karlish SJD, Blostein R. Expression and functional role of the gamma subunit of the Na,K-ATPase in mammalian cells. Journal of Biological Chemistry 1999; 274: 12252-6.
    連結:
  28. 30 Morth JP, Pedersen BP, Toustrup-Jensen MS, Sorensen TL, Petersen J, Andersen JP, et al. Crystal structure of the sodium-potassium pump. Nature 2007; 450: 1043-9.
    連結:
  29. 31 Shinoda T, Ogawa H, Cornelius F, Toyoshima C. Crystal structure of the sodium-potassium pump at 2.4 Å resolution. Nature 2009; 459: 446-50.
    連結:
  30. 32 Ogawa H, Shinoda T, Cornelius F, Toyoshima C. Crystal structure of the sodium-potassium pump (Na+,K+-ATPase) with bound potassium and ouabain. Proc Natl Acad Sci U S A 2009; 106: 13742-7.
    連結:
  31. 33 McGrail KM, Phillips JM, Sweadner KJ. Immunofluorescent localization of three Na,K-ATPase isozymes in the rat central nervous system: both neurons and glia can express more than one Na,K-ATPase. J Neurosci 1991; 11: 381-91.
    連結:
  32. 34 Herrera VL, Cova T, Sassoon D, Ruiz-Opazo N. Developmental cell-specific regulation of Na+-K+-ATPase alpha 1-, alpha 2-, and alpha 3-isoform gene expression. Am J Physiol 1994; 266: 1301-12.
    連結:
  33. 36 Watts AG, Sanchez-Watts G, Emanuel JR, Levenson R. Cell-specific expression of mRNAs encoding Na+,K+-ATPase alpha- and beta-subunit isoforms within the rat central nervous system. Proc Natl Acad Sci U S A 1991; 88: 7425-9.
    連結:
  34. 37 Blanco G, Mercer RW. Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function. Am J Physiol-Renal 1998; 44: 633-50.
    連結:
  35. 38 Glynn IM. Annual review prize lecture. 'All hands to the sodium pump'. J Physiol 1993; 462: 1-30.
    連結:
  36. 39 Fambrough DM. The sodium pump becomes a family. Trends Neurosci 1988; 11: 325-8.
    連結:
  37. 40 Levenson R. Isoforms of the Na,K-ATPase: family members in search of function. Rev Physiol Biochem Pharmacol 1994; 123: 1-45.
    連結:
  38. 41 Zahler R, Brines M, Kashgarian M, Benz EJ, Gilmorehebert M. The cardiac conduction system in the rat expresses the alpha-2 and alpha-3 isoforms of the Na+,K+-ATPase. P Natl Acad Sci USA 1992; 89: 99-103.
    連結:
  39. 42 Shamraj OI, Grupp IL, Grupp G, Melvin D, Gradoux N, Kremers W, et al. Characterisation of Na/K-ATPase, its isoforms, and the inotropic response to ouabain in isolated failing human hearts. Cardiovasc Res 1993; 27: 2229-37.
    連結:
  40. 43 Zhang J, Lee MY, Cavalli M, Chen L, Berra-Romani R, Balke CW, et al. Sodium pump alpha 2 subunits control myogenic tone and blood pressure in mice. J Physiol 2005; 569: 243-56.
    連結:
  41. 48 Hieber V, Siegel GJ, Fink DJ, Beaty MW, Mata M. Differential distribution of (Na, K)-ATPase alpha-isoforms in the central- nervous-system. Cell Mol Neurobiol 1991; 11: 253-62.
    連結:
  42. 49 Woo AL, James PF, Lingrel JB. Sperm motility is dependent on a unique isoform of the Na,K-ATPase. J Biol Chem 2000; 275: 20693-9.
    連結:
  43. 50 Sanchez G, Timmerberg B, Tash J, Blanco G. The Na,K-ATPase alpha 4 isoform from humans has distinct enzymatic properties and is important for sperm motility. J Androl 2006: 42-2.
    連結:
  44. 51 Muller-Ehmsen J, Juvvadi P, Thompson CB, Tumyan L, Croyle M, Lingrel JB, et al. Ouabain and substrate affinities of human Na+,K+-ATPase alpha(1)beta(1), alpha(2)beta(1), and alpha(3) beta(1) when expressed separately in yeast cells. Am J Physiol Cell Physiol 2001; 281: 1355-64.
    連結:
  45. 52 Blanco G, Koster JC, Sanchez G, Mercer RW. Kinetic properties of the alpha 2 beta 1 and alpha 2 beta 2 isozymes of the Na,K-ATPase. Biochemistry-Us 1995; 34: 319-25.
    連結:
  46. 53 Pierre SV, Sottejeau Y, Gourbeau JM, Sanchez G, Shidyak A, Blanco G. Isoform specificity of Na-K-ATPase-mediated ouabain signaling. Am J Physiol-Renal 2008; 294: 859-66.
    連結:
  47. 54 Blanco G, Mercer RW. Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function. Am J Physiol 1998; 275: 633-50.
    連結:
  48. 55 Lebovitz RM, Takeyasu K, Fambrough DM. Molecular characterization and expression of the (Na+/K+)-ATPase alpha- subunit in Drosophila Melanogaster. Embo J 1989; 8: 193-202.
    連結:
  49. 56 Morris JF, Ismail-Beigi F, Butler VP, Jr., Gati I, Lichtstein D. Ouabain-sensitive Na+,K+-ATPase activity in toad brain. Comp Biochem Physiol A Physiol 1997; 118: 599-606.
    連結:
  50. 57 Liu AY, Bentley PJ. A comparison of the toxicity of ouabain in vivo and in vitro in the frog, Rana pipiens, and the toad, Bufo marinus. Comp Gen Pharmacol 1971; 2: 476-8.
    連結:
  51. 58 Schwartz A, Lindenmayer GE, Allen JC. The sodium-potassium adenosine triphosphatase: pharmacological, physiological and biochemical aspects. Pharmacol Rev 1975; 27: 3-134.
    連結:
  52. 59 O'Brien WJ, Lingrel JB, Wallick ET. Ouabain binding kinetics of the rat alpha two and alpha three isoforms of the sodium-potassium adenosine triphosphate. Arch Biochem Biophys 1994; 310: 32-9.
    連結:
  53. 61 Abeywardena MY, McMurchie EJ, Russell GR, Charnock JS. Species variation in the ouabain sensitivity of cardiac Na+/K+-ATPase. A possible role for membrane lipids. Biochem Pharmacol 1984; 33: 3649-54.
    連結:
  54. 62 Wang J, Velotta JB, McDonough AA, Farley RA. All human Na+-K+-ATPase alpha-subunit isoforms have a similar affinity for cardiac glycosides. Am J Physiol Cell Physiol 2001; 281: 1336-43.
    連結:
  55. 63 Crambert G, Hasler U, Beggah AT, Yu C, Modyanov NN, Horisberger JD, et al. Transport and pharmacological properties of nine different human Na, K-ATPase isozymes. J Biol Chem 2000; 275: 1976-86.
    連結:
  56. 64 Holzinger F, Frick C, Wink M. Molecular basis for the insensitivity of the Monarch (Danaus-Plexippus) to cardiac glycosides. Febs Lett 1992; 314: 477-80.
    連結:
  57. 65 Labeyrie E, Dobler S. Molecular adaptation of Chrysochus leaf beetles to toxic compounds in their food plants. Mol Biol Evol 2004; 21: 218-21.
    連結:
  58. 66 Price EM, Lingrel JB. Structure-function relationships in the Na,K-ATPase alpha subunit: site-directed mutagenesis of glutamine-111 to arginine and asparagine-122 to aspartic acid generates a ouabain-resistant enzyme. Biochemistry-Us 1988; 27: 8400-8.
    連結:
  59. 67 Taylor R. A pig in a poke - xenotransplants and infectious-disease. Nat Med 1995; 1: 728-9.
    連結:
  60. 70 Schonfeld W, Weiland J, Lindig C, Masnyk M, Kabat MM, Kurek A, et al. The lead structure in cardiac glycosides is 5 beta, 14 beta-androstane-3 beta 14-diol. Naunyn Schmiedebergs Arch Pharmacol 1985; 329: 414-26.
    連結:
  61. 71 Melero CP, Medarde M, San Feliciano A. A short review on cardiotonic steroids and their aminoguanidine analogues. Molecules 2000; 5: 51-81.
    連結:
  62. 72 Sulakhe PV, Elimban V, Dhalla NS. Characterization of a partially purified Na+,K+-ATPase from dog heart. Adv Myocardiol 1985; 6: 249-57.
    連結:
  63. 73 Blaustein MP. The interrelationship between sodium and calcium fluxes across cell membranes. Rev Physiol Biochem Pharmacol 1974; 70: 33-82.
    連結:
  64. 74 Crambert G, Balzan S, Paci A, Decollogne S, Montali U, Ghione S, et al. Functional characterization of an endogenous digitalis-like factor in human newborn plasma. Effects on rat (Na+/K+)-ATPase isoforms and on binding to placenta. Ann N Y Acad Sci 1997; 834: 621-5.
    連結:
  65. 75 Hamlyn JM, Manunta P. Ouabain, digitalis-like factors and hypertension. J Hypertens Suppl 1992; 10: 99-111.
    連結:
  66. 76 Goto A, Yamada K, Yagi N, Yoshioka M, Sugimoto T. Physiology and pharmacology of endogenous digitalis-like factors. Pharmacol Rev 1992; 44: 377-99.
    連結:
  67. 77 Goto A, Yamada K. Ouabain-like factor. Curr Opin Nephrol Hypertens 1998; 7: 189-96.
    連結:
  68. 78 Tymiak AA, Norman JA, Bolgar M, DiDonato GC, Lee H, Parker WL, et al. Physicochemical characterization of a ouabain isomer isolated from bovine hypothalamus. Proc Natl Acad Sci U S A 1993; 90: 8189-93.
    連結:
  69. 79 Hamlyn JM, Blaustein MP, Bova S, DuCharme DW, Harris DW, Mandel F, et al. Identification and characterization of a ouabain-like compound from human plasma. Proc Natl Acad Sci U S A 1991; 88: 6259-63.
    連結:
  70. 80 Prassas I, Diamandis EP. Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov 2008; 7: 926-35.
    連結:
  71. 81 Bagrov AY, Shapiro JI, Fedorova OV. Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol Rev 2009; 61: 9-38.
    連結:
  72. 82 Prassas I, Diamandis EP. Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov 2008; 7: 926-35.
    連結:
  73. 83 Tzen JT, Chen RJ, Chung TY, Chen YC, Lin NH. Active compounds in Chinese herbs and medicinal animal products which promote blood circulation via inhibition of Na+, K+-ATPase. Chang Gung Med J 2010; 33: 126-36.
    連結:
  74. CHAPTER 1
    連結:
  75. 1 Gong X, Sucher NJ. Stroke therapy in traditional Chinese medicine (TCM): prospects for drug discovery and development. Trends Pharmacol Sci 1999; 20: 191-6.
    連結:
  76. 2 Kim H. Neuroprotective herbs for stroke therapy in traditional eastern medicine. Neurol Res 2005; 27: 287-301.
    連結:
  77. 3 Li-Saw-Hee FL, Lip GY. Digoxin revisited. QJM 1998; 91: 259-64.
    連結:
  78. 4 Schonfeld W, Menke KH, Schonfeld R, Repke KR. 5 Beta,14 beta-androstane-3 beta,14-diol binds to the digitalis receptor site on Na/K-ATPase. J Enzyme Inhib 1987; 2: 37-45.
    連結:
  79. 5 Zhou J. Bioactive glycosides from Chinese medicines. Mem Inst Oswaldo Cruz 1991; 86 Suppl 2: 231-4.
    連結:
  80. 7 Morth JP, Pedersen BP, Toustrup-Jensen MS, Sorensen TL, Petersen J, Andersen JP, et al. Crystal structure of the sodium-potassium pump. Nature 2007; 450: 1043-9.
    連結:
  81. 8 Ogawa H, Shinoda T, Cornelius F, Toyoshima C. Crystal structure of the sodium-potassium pump (Na+,K+-ATPase) with bound potassium and ouabain. Proc Natl Acad Sci U S A 2009; 106: 13742-7.
    連結:
  82. 9 Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M. Charmm - a program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem 1983; 4: 187-217.
    連結:
  83. 10 Qiu LY, Krieger E, Schaftenaar G, Swarts HGP, Willems PHGM, De Pont JJHHM, et al. Reconstruction of the complete ouabain-binding pocket of Na,K-ATPase in gastric H,K-ATPase by substitution of only seven amino acids. Journal of Biological Chemistry 2005; 280: 32349-55.
    連結:
  84. 11 Dixon SL, Merz KM. One-dimensional molecular representations and similarity calculations: Methodology and validation. J Med Chem 2001; 44: 3795-809.
    連結:
  85. 12 Rao SN, Head MS, Kulkarni A, LaLonde JM. Validation studies of the site-directed docking program LibDock. J Chem Inf Model 2007; 47: 2159-71.
    連結:
  86. 13 Yang Z, Luo H, Wang H, Hou H. Preparative isolation of bufalin and cinobufagin from Chinese traditional medicine ChanSu. J Chromatogr Sci 2008; 46: 81-5.
    連結:
  87. 14 Jia WWG, Bu XX, Philips D, Yan H, Liu GY, Chen XG, et al. Rh2, a compound extracted from ginseng, hypersensitizes multidrug-resistant tumor cells to chemotherapy. Can J Physiol Pharm 2004; 82: 431-7.
    連結:
  88. 15 Lee IK, Kim DH, Lee SY, Kim KR, Choi SU, Hong JK, et al. Triterpenoic acids of Prunella vulgaris var. lilacina and their cytotoxic activities In Vitro. Arch Pharm Res 2008; 31: 1578-83.
    連結:
  89. 16 Tan LL, Cai X, Hu ZH, Ni XL. Localization and dynamic change of saikosaponin in root of Bupleurum chinense. J Integr Plant Biol 2008; 50: 951-7.
    連結:
  90. 18 Wang FS, Xu LX, Zhao YJ, Liu AR, Jin LZ, Zhang XQ. Determination of bile acids in bear gall drainage by thin layer chromatographic scanning. Yao Xue Xue Bao 1989; 24: 397-400.
    連結:
  91. 19 Liu Y, Chen W, Qiao C, Zhao N. Determination of sarsasapogenin in Anemarrhena asphodeloides Bunge by GC. Zhongguo Zhong Yao Za Zhi 1999; 24: 554-5, 75.
    連結:
  92. 21 Zhang M, Zhang Y, Xie J. Simultaneous determination of jujuboside A, B and betulinic acid in semen Ziziphi spinosae by high performance liquid chromatography-evaporative light scattering detection. J Pharm Biomed Anal 2008; 48: 1467-70.
    連結:
  93. 23 Xu Q, Ma X, Liang X. Determination of astragalosides in the roots of Astragalus spp. using liquid chromatography tandem atmospheric pressure chemical ionization mass spectrometry. Phytochem Analysis 2007; 18: 419-27.
    連結:
  94. 24 Kowalski R. Studies of selected plant raw materials as alternative sources of triterpenes of oleanolic and ursolic acid types. J Agr Food Chem 2007; 55: 656-62.
    連結:
  95. 25 Liu H. Oleanolic acid and ursolic acid: Research perspectives. J Ethnopharmacol 2005; 100: 92-4.
    連結:
  96. 26 Liu J. Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol 1995; 49: 57-68.
    連結:
  97. 27 Zheng J, He JG, Ji BP, Li Y, Zhang XF. Antihyperglycemic activity of Prunella vulgaris L. in streptozotocin-induced diabetic mice. Asia Pac J Clin Nutr 2007; 16: 427-31.
    連結:
  98. 28 Kageyama S, Kurokawa M, Shiraki K. Extract of Prunella vulgaris spikes inhibits HIV replication at reverse transcription in vitro and can be absorbed from intestine in vivo. Antivir Chem Chemoth 2000; 11: 157-64.
    連結:
  99. 29 Psotova J, Kolar M, Sousek J, Svagera Z, Vicar J, Ulrichova J. Biological activities of Prunella vulgaris extract. Phytother Res 2003; 17: 1082-7.
    連結:
  100. 30 Psotova J, Chlopcikova S, Miketova P, Simanek V. Cytoprotectivity of Prunella vulgaris on doxorubicin-treated rat cardiomyocytes. Fitoterapia 2005; 76: 556-61.
    連結:
  101. 31 Kojima H, Ogura H. Constituents of the labiate plants. Triterpenoids from Prunella Vulgaris. Phytochemistry 1986; 25: 729-33.
    連結:
  102. 32 Kim DH, Jung EA, Sohng IS, Han JA, Kim TH, Han MJ. Intestinal bacterial metabolism of flavonoids and its relation to some biological activities. Arch Pharm Res 1998; 21: 17-23.
    連結:
  103. 33 Akao T, Hayashi T, Kobashi K, Kanaoka M, Kato H, Kobayashi M, et al. Intestinal bacterial hydrolysis is indispensable to absorption of 18-beta-glycyrrhetic acid after oral administration of glycyrrhizin in rats. J Pharm Pharmacol 1994; 46: 135-7.
    連結:
  104. 36 Prassas I, Diamandis EP. Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov 2008; 7: 926-35.
    連結:
  105. 37 Wang JKT, Portbury S, Thomas MB, Barney S, Ricca DJ, Morris DL, et al. Cardiac glycosides provide neuroprotection against ischemic stroke: Discovery by a brain slice-based compound screening platform. P Natl Acad Sci USA 2006; 103: 10461-6.
    連結:
  106. 38 Tzen JTC, Jinn TR, Chen YC, Li FY, Cheng FC, Shi LS, et al. Magnesium lithospermate B possesses inhibitory activity on Na+,K+-ATPase and neuroprotective effects against ischemic stroke. Acta Pharmacologica Sinica 2007; 28: 609-15.
    連結:
  107. 39 Cho SO, Ban JY, Kim JY, Ju HS, Lee IS, Song KS, et al. Anti-ischemic activities of Aralia cordata and its active component, oleanolic acid. Arch Pharm Res 2009; 32: 923-32.
    連結:
  108. 1 Sengupta S, Toh SA, Sellers LA, Skepper JN, Koolwijk P, Leung HW, et al. Modulating angiogenesis - The yin and the yang in ginseng. Circulation 2004; 110: 1219-25.
    連結:
  109. 2 Lei XL, Chiou GCY. Cardiovascular pharmacology of Panax notoginseng (Burk) Chen,F.H. and Salvia miltiorrhiza. Am J Chinese Med 1986; 14: 145-52.
    連結:
  110. 3 Chan P, Thomas GN, Tomlinson B. Protective effects of trilinolein extracted from panax notoginseng against cardiovascular disease. Acta Pharmacol Sin 2002; 23: 1157-62.
    連結:
  111. 4 Cicero AF, Vitale G, Savino G, Arletti R. Panax notoginseng (Burk) effects on fibrinogen and lipid plasma level in rats fed on a high-fat diet. Phytother Res 2003; 17: 174-8.
    連結:
  112. 5 Dong TT, Cui XM, Song ZH, Zhao KJ, Ji ZN, Lo CK, et al. Chemical assessment of roots of Panax notoginseng in China: regional and seasonal variations in its active constituents. J Agric Food Chem 2003; 51: 4617-23.
    連結:
  113. 6 Leung KS, Chan K, Bensoussan A, Munroe MJ. Application of atmospheric pressure chemical ionisation mass spectrometry in the identification and differentiation of Panax species. Phytochem Anal 2007; 18: 146-50.
    連結:
  114. 7 Hasegawa H. Proof of the mysterious efficacy of ginseng: basic and clinical trials: metabolic activation of ginsenoside: deglycosylation by intestinal bacteria and esterification with fatty acid. J Pharmacol Sci 2004; 95: 153-7.
    連結:
  115. 8 Nah SY, Kim DH, Rhim H. Ginsenosides: Are any of them candidates for drugs acting on the central nervous system? Cns Drug Rev 2007; 13: 381-404.
    連結:
  116. 9 Zhu S, Zou K, Cai S, Meselhy MR, Komatsu K. Simultaneous determination of triterpene saponins in ginseng drugs by high-performance liquid chromatography. Chem Pharm Bull (Tokyo) 2004; 52: 995-8.
    連結:
  117. 10 Dan M, Su MM, Gao XF, Zhao T, Zhao AH, Xie GX, et al. Metabolite profiling of Panax notoginseng using UPLC-ESI-MS. Phytochemistry 2008; 69: 2237-44.
    連結:
  118. 12 Li-Saw-Hee FL, Lip GY. Digoxin revisited. QJM 1998; 91: 259-64.
    連結:
  119. 13 Lin SC, Way EL. A high affinity Ca2+-ATPase in enriched nerve-ending plasma membranes. Brain Res 1982; 235: 387-92.
    連結:
  120. 15 Morth JP, Pedersen BP, Toustrup-Jensen MS, Sorensen TL, Petersen J, Andersen JP, et al. Crystal structure of the sodium-potassium pump. Nature 2007; 450: 1043-9.
    連結:
  121. 16 Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M. Charmm - a program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem 1983; 4: 187-217.
    連結:
  122. 17 Qiu LY, Krieger E, Schaftenaar G, Swarts HGP, Willems PHGM, De Pont JJHHM, et al. Reconstruction of the complete ouabain-binding pocket of Na,K-ATPase in gastric H,K-ATPase by substitution of only seven amino acids. Journal of Biological Chemistry 2005; 280: 32349-55.
    連結:
  123. 18 Qiu LY, Koenderink JB, Swarts HG, Willems PH, De Pont JJ. Phe783, Thr797, and Asp804 in transmembrane hairpin M5-M6 of Na+,K+-ATPase play a key role in ouabain binding. J Biol Chem 2003; 278: 47240-4.
    連結:
  124. 19 Dixon SL, Merz KM. One-dimensional molecular representations and similarity calculations: Methodology and validation. J Med Chem 2001; 44: 3795-809.
    連結:
  125. 20 Rao SN, Head MS, Kulkarni A, LaLonde JM. Validation studies of the site-directed docking program LibDock. J Chem Inf Model 2007; 47: 2159-71.
    連結:
  126. 21 Diller DJ, Merz KM. High throughput docking for library design and library prioritization. Proteins 2001; 43: 113-24.
    連結:
  127. 22 Willett P, Barnard JM, Downs GM. Chemical similarity searching. J Chem Inf Comp Sci 1998; 38: 983-96.
    連結:
  128. 24 Kim DH, Jung EA, Sohng IS, Han JA, Kim TH, Han MJ. Intestinal bacterial metabolism of flavonoids and its relation to some biological activities. Arch Pharm Res 1998; 21: 17-23.
    連結:
  129. 25 Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M. Degradation of ginsenosides in humans after oral administration. Drug Metab Dispos 2003; 31: 1065-71.
    連結:
  130. 26 Wang JKT, Portbury S, Thomas MB, Barney S, Ricca DJ, Morris DL, et al. Cardiac glycosides provide neuroprotection against ischemic stroke: Discovery by a brain slice-based compound screening platform. P Natl Acad Sci USA 2006; 103: 10461-66.
    連結:
  131. 27 Tzen JTC, Jinn TR, Chen YC, Li FY, Cheng FC, Shi LS, et al. Magnesium lithospermate B possesses inhibitory activity on Na+,K+-ATPase and neuroprotective effects against ischemic stroke. Acta Pharmacologica Sinica 2007; 28: 609-15.
    連結:
  132. 29 Tian J, Fu F, Geng M, Jiang Y, Yang J, Jiang W, et al. Neuroprotective effect of 20(S)-ginsenoside Rg3 on cerebral ischemia in rats. Neurosci Lett 2005; 374: 92-7.
    連結:
  133. 30 Zhou XM, Cao YL, Dou DQ. Protective effect of ginsenoside-Re against cerebral ischemia/reperfusion damage in rats. Biol Pharm Bull 2006; 29: 2502-5.
    連結:
  134. 31 Yuan QL, Yang CX, Xu P, Gao XQ, Deng L, Chen P, et al. Neuroprotective effects of ginsenoside Rb1 on transient cerebral ischemia in rats. Brain Res 2007; 1167: 1-12.
    連結:
  135. 32 Chen LM, Zhou XM, Cao YL, Hu WX. Neuroprotection of ginsenoside Re in cerebral ischemia-reperfusion injury in rats. J Asian Nat Prod Res 2008; 10: 439-45.
    連結:
  136. 14 Skou JC, Esmann M. The Na,K-ATPase. J Bioenerg Biomembr 1992; 24: 249-61.
  137. 15 Lingrel JB. Na,K-ATPase: isoform structure, function, and expression. J Bioenerg Biomembr 1992; 24: 263-70.
  138. 18 Lingrel JB, Kuntzweiler T. Na+,K+-ATPase. J Biol Chem 1994; 269: 19659-62..
  139. 35 Lu XP, Leffert HL. Induction of sodium pump beta 1-subunit mRNA expression during hepatocellular growth transitions in vitro and in vivo. J Biol Chem 1991; 266: 9276-84.
  140. 44 Hundal HS, Marette A, Mitsumoto Y, Ramlal T, Blostein R, Klip A. Insulin induces translocation of the alpha 2 and beta 1 subunits of the Na+/K+-ATPase from intracellular compartments to the plasma membrane in mammalian skeletal muscle. J Biol Chem 1992; 267: 5040-3.
  141. 45 Urayama O, Shutt H, Sweadner KJ. Identification of three isozyme proteins of the catalytic subunit of the Na,K-ATPase in rat brain. J Biol Chem 1989; 264: 8271-80.
  142. 46 Lytton J, Lin JC, Guidotti G. Identification of two molecular forms of Na+,K+-ATPase in rat adipocytes. Relation to insulin stimulation of the enzyme. J Biol Chem 1985; 260: 1177-84.
  143. 47 Mobasheri A, Avila J, Cozar-Castellano I, Brownleader MD, Trevan M, Francis MJ, et al. Na+, K+-ATPase isozyme diversity; comparative biochemistry and physiological implications of novel functional interactions. Biosci Rep 2000; 20: 51-91.
  144. 60 Akera T, Larsen FS, Brody TM. The effect of ouabain on sodium- and potassium-activated adenosine triphosphatase from the hearts of several mammalian species. J Pharmacol Exp Ther 1969; 170: 17-26.
  145. 68 Rose AM, Mellett BJ, Valdes R. Na,K-ATPase isoform(s) in pig heart explains reduced response to cardiac glycosides. Clinical Chemistry 1996; 42: 622-32.
  146. 69 Rose AM, Qazzaz HM, Zolotarjova N, Mellett BJ, Martin AW, Valdes R. Sodium pump isoforms in xenotransplantation: Importance of biochemical compatibility. Clinical Chemistry 2000; 46: 234-41.
  147. 6 Goldenberg H, Fernandez A. Simplified method for the estimation of inorganic phosphorus in body fluids. Clin Chem 1966; 12: 871-82.
  148. 17 Zhou QL, Zhang ZQ, Nagasawa T, Hiai S. The structure activity relationship of saikosaponins and glycyrrhizin derivatives for Na+, K+-ATPase inhibiting action. Yao Xue Xue Bao 1996; 31: 496-501.
  149. 20 Fu WW, Hou WB, Dou DQ, Hua HM, Gui MH, Fu R, et al. Saponins of polygalacic acid type from Platycodon grandiflorum. Yao Xue Xue Bao 2006; 41: 358-60.
  150. 22 Sun ZR, Zhai MP, Wang WQ, Li YR. Effects of density on seedling growth and glycyrrhizinic acid content in Glycyrrhiza uralensis. Zhongguo Zhong Yao Za Zhi 2007; 32: 2222-6, 81.
  151. 34 Attele AS, Wu JA, Yuan CS. Ginseng pharmacology - Multiple constituents and multiple actions. Biochem Pharmacol 1999; 58: 1685-93.
  152. 35 Rose AM, Qazzaz HM, Zolotarjova N, Mellett BJ, Martin AW, Valdes R. Sodium pump isoforms in xenotransplantation: Importance of biochemical compatibility. Clinical Chemistry 2000; 46: 234-41.
  153. 40 Annunziato L, editor. New strategies in stroke intervention. New York: Springer; 2009.
  154. CHAPTER 2
  155. 11 Jiang Y, Liu W, Wang XM, Zhong GG, Zhang WJ, Chen L, et al. Calcium channel blockade and anti-free-radical actions of panaxatriol saponins in cultured myocardiocytes. Zhongguo Yao Li Xue Bao 1996; 17: 138-41.
  156. 14 Goldenberg H, Fernandez A. Simplified method for the estimation of inorganic phosphorus in body fluids. Clin Chem 1966; 12: 871-82.
  157. 23 Schultheis PJ, Wallick ET, Lingrel JB. Kinetic analysis of ouabain binding to native and mutated forms of Na,K-ATPase and identification of a new region involved in cardiac glycoside interactions. J Biol Chem 1993; 268: 22686-94.
  158. 28 Zhang YG, Liu TP. Influences of ginsenosides Rb1 and Rg1 on reversible focal brain ischemia in rats. Zhongguo Yao Li Xue Bao 1996; 17: 44-8.