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研究生:鍾澤裕
研究生(外文):Tse-Yu Chung
論文名稱:中草藥中的關鍵成份經由抑制鈉鉀幫浦活性達到活血機制之探討:從似固醇成份到非固醇成份
論文名稱(外文):Key ingredients in Chinese medicine for promoting blood circulation via their inhibition of Na+/K+-ATPase from steroid-like compounds to non-steroid ones
指導教授:曾志正曾志正引用關係
口試委員:李豐穎郭賓崇靳子蓉江佩倫
口試日期:2013-06-26
學位類別:博士
校院名稱:國立中興大學
系所名稱:生物科技學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:英文
論文頁數:73
中文關鍵詞:牛樟芝樟芝酸丹參丹參酚酸B鈉鉀幫浦
外文關鍵詞:Antrodia camphorateAntcinSaliva miltiorrhizaMagnesium lithospermate B:Na+/K+-ATPase
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許多中草藥具有活血化瘀的藥效,而這些中草藥被用於治療心血管疾病已有數千年之久。在這些中草藥中,似固醇分子通常為其化學組成中的主要成份。根據似固醇分子及強心配醣體的結構相似度來看,這些似固醇分子,像是從人參或三七分離出來的人參皂苷,透過對鈉鉀幫浦的活性抑制來達到其活血化瘀的作用。而在牛樟芝中其中一種主要的似固醇成份,Antcin A,是為同是具有兩種功效的活性成份,它不只能使醣皮質激素移動至細胞核內透過調控基因表現達到抑制發炎之功效,而且能抑制鈉鉀幫浦活性造成鈣離子增加,使得心肌收縮力增強,在這兩種機制的調控之下,進而達到抗發炎及活血之功效。
另一方面,我們想在活血中藥的成份中能找到不具有似固醇結構,但同樣具有抑制鈉鉀幫浦達到活血功效之成份。這邊選擇丹參的丹參酚酸鎂鹽B,其為一種從丹參找到的咖啡酸四聚體成份,雖然在結構上不具有固醇骨架,但能藉由兩個羧基跟鎂離子形成的鹽橋而形成相對堅硬的結構,其結構相似於強心配醣體。研究指出,丹參酚酸鎂鹽B具有跟強心配醣體中的哇巴因一樣抑制對鈉鉀幫浦的活性。總而言之,似固醇分子在這些具有活血功效的中藥成份中,扮演著在其治療功效上極為重要的活性成份;而能有效抑制鈉鉀幫浦活性的丹參酚酸鎂鹽B則具有淺力發展成為不具有固醇骨架的強心藥物。


Many Chinese medicines exhibit the bioactivity for promoting blood circulation and removing blood stasis, and they have contributed to the treatment of a lot of cardiovascular diseases for several thousand years. Steroid-like compounds are major ingredients of the chemical constituents of these Chinese medicines. In the view of the structural similarity between steroid-like compounds and cardiac glycosides, these steroid-like compounds, such as ginsenosides isolated from ginseng and sanqi, contributes to blood circulation via their significant inhibition of Na+/K+-ATPase. Antcin A, one of the major steroid-like compounds isolated from Niuchungchih, is the bi-functional compound possesses anti-inflammatory effects and enhances blood circulation via two different molecular mechanisms: regulating gene expression via the glucocorticoid receptor migration and increasing the inotropism through Na+/K+-ATPase inhibition
In another way, we want to find if the non-steroid compound from Chinese medicines can possess the bioactivity of promoting blood circulation via its inhibition on Na+/K+-ATPase. Magnesium lithospermate B (MLB), a caffeic acid tetramer of Danshen, instead of possessing the steroidal skeleton, but a relatively rigid structure similar to the steroid backbone can be formed due to salt bridges between Mg2+ and two caroboxyl groups. In our previous study, MLB also possessed the inhibitory potency on Na+/K+-ATPase in a dose-dependent manner as one of cardiac glycosides, ouabain. All in all, steroid-like compounds of Chinese medicines used in the treatment of cardiovascular diseases play as active ingredients. MLB has the potential to develop as a new cardioionic drug lacking of steroidal skeleton with its effective inhibition on Na+/K+-ATPase


LIST OF TABLES AND FIGURES

Research background
Figure 1. Niuchangchih fruiting bodies....................17
Figure 2. HPLC profile and structures of five major antcins (A, B ,C ,H, and K) of Niuchangchih.......................18
Figure 3. Proposed molecular mechanism responsible for the anti-inflammatory effect of antcin A in Niuchangchih Dried roots of Salvia miltiorrhiza..............................19
Figure 4. Dried roots of Salvia miltiorrhiza..............20
Figure 5. Structures of the major tanshinones and caffeic acid derivates in Danshen.................................21
Figure 6. Ca2+ and Na+ transport in ventricular myocytes..22
Figure 7. Crystal structure of Na+/K+-ATPase complexed with ouabain and K+............................................23
Figure 8. Structural characteristics of cardiac glycosides and istaroxime............................................24

Chapter 1
Figure 1. Chemical structures of ouabain, ginsenoside Rh2, five major antcins (A, B, C, H, and K) of Niuchangchih, cortisone, and ganoderic acid A...........................41
Figure 2. Inhibition of porcine Na+/K+-ATPase by 0.2 mM of the 9 steroid-like compounds shown in Figure 1............42
Figure 3. Inhibitory potency of antcin A, ginsenoside Rh2 and ouabain on porcine Na+/K+-ATPase......................43
Figure 4. Modeling of antcin A docking to the binding pocket of Na+/K+-ATPase a subunit................................44
Figure 5. Detailed molecular interaction between the binding pocket of Na+/K+-ATPase and ginsenoside Rh2, antcin A, antcin B, cortisone, or ganderic acid A...................45


Chapter 2
Figure 1. The 13C NMR spectra of LSB, MLB and Co-LSB......66
Figure 2. (A) The visible spectra of LSB in complex with various concentrations of Co2+. (B) The absorbance intensity of LSB titrated against Co2+ at 420 nm..........67
Figure 3. (Upper panels) Chemical structures of ouabain and MLB. (Middle panels) Modeling of ouabain and MLB binding to the binding pocket of Na+/K+-ATPase. (Lower panels) The amino acid residues of Na+/K+-ATPase close to ouabain or MLB ..........................................................68
Figure 4. Proposed molecular mechanism responsible for the therapeutic effects of ouabain, a cardiac glycoside, and MLB in cardiac cells..........................................70
Scheme 1. Plausible biosynthetic pathway of MLB...........71

TABLE OF CONTENTS
CHINESE ABSTRACT...........................................i
ENGLISH ABSTRACT..........................................ii
RESEARCH BACKGROUND........................................1
REFERENCES.................................................8
FIGURES...................................................17

CHAPTER 1
Inhibition of Na+/K+-ATPase by Antcins, Unique Steroid-Like Compounds in Antrodia camphorate
ABSTRACT..................................................25
INTRODUCTION..............................................26
MATERIALS AND METHODS.....................................28
RESULTS...................................................31
DISSCUSSION...............................................34
REFERENCES................................................36
FIGURES...................................................41

CHAPTER 2
Magnesium Lithospermate B Extracted from Salvia miltiorrhiza, A Potential Substitute for Cardiac Glycosides
ABSTRACT..................................................47
INTRODUCTION..............................................48
MATERIALS AND METHODS.....................................50
RESULTS...................................................53
DISSCUSSION...............................................60
REFERENCES................................................61
FIGURES...................................................66

CONCLUSION................................................72


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