药学学报

ID	Item	Number	P-Value
GO:0006120	Mitochondrial electron transport, NADH to ubiquinone	45	4.19e-067
GO:0008137	NADH dehydrogenase (ubiquinone) activity	44	1.34e-066
GO:0005747	Mitochondrial respiratory chain complex Ⅰ	43	4.40e-062
GO:0005739	Mitochondrion	147	6.42e-057
GO:0032981	Mitochondrial respiratory chain complex Ⅰ assembly	42	2.77e-052
GO:0055114	Oxidation-reduction process	98	1.86e-049
GO:0051287	NAD binding	31	7.05e-043
GO:0005759	Mitochondrial matrix	69	3.14e-042
GO:0005743	Mitochondrial inner membrane	76	3.82e-041
GO:0005829	Cytosol	197	1.03e-030
GO:0009055	Electron carrier activity	32	6.34e-028
GO:0006099	Tricarboxylic acid cycle	21	2.10e-027
GO:0070062	Extracellular exosome	166	1.05e-025
GO:0004029	Aldehyde dehydrogenase (NAD) activity	15	1.54e-021
GO:0043209	Myelin sheath	31	2.35e-019
GO:0006090	Pyruvate metabolic process	14	8.02e-019
GO:0006069	Ethanol oxidation	11	5.15e-017
GO:0004129	Cytochrome-c oxidase activity	15	7.55e-016
GO:0007584	Response to nutrient	21	1.84e-015
GO:0005524	ATP binding	94	1.86e-015

Item

Number

P-Value

GO:0006120

Mitochondrial electron transport, NADH to ubiquinone

4.19e-067

GO:0008137

NADH dehydrogenase (ubiquinone) activity

1.34e-066

GO:0005747

Mitochondrial respiratory chain complex Ⅰ

4.40e-062

GO:0005739

Mitochondrion

147

6.42e-057

GO:0032981

Mitochondrial respiratory chain complex Ⅰ assembly

2.77e-052

GO:0055114

Oxidation-reduction process

1.86e-049

GO:0051287

NAD binding

7.05e-043

GO:0005759

Mitochondrial matrix

3.14e-042

GO:0005743

Mitochondrial inner membrane

3.82e-041

GO:0005829

Cytosol

197

1.03e-030

GO:0009055

Electron carrier activity

6.34e-028

GO:0006099

Tricarboxylic acid cycle

2.10e-027

GO:0070062

Extracellular exosome

166

1.05e-025

GO:0004029

Aldehyde dehydrogenase (NAD) activity

1.54e-021

GO:0043209

Myelin sheath

2.35e-019

GO:0006090

Pyruvate metabolic process

8.02e-019

GO:0006069

Ethanol oxidation

5.15e-017

GO:0004129

Cytochrome-c oxidase activity

7.55e-016

GO:0007584

Response to nutrient

1.84e-015

GO:0005524

ATP binding

1.86e-015

ID	Item	Number	P-Value
GO:0006120	Mitochondrial electron transport, NADH to ubiquinone	45	4.19e-067
GO:0008137	NADH dehydrogenase (ubiquinone) activity	44	1.34e-066
GO:0005747	Mitochondrial respiratory chain complex Ⅰ	43	4.40e-062
GO:0005739	Mitochondrion	147	6.42e-057
GO:0032981	Mitochondrial respiratory chain complex Ⅰ assembly	42	2.77e-052
GO:0055114	Oxidation-reduction process	98	1.86e-049
GO:0051287	NAD binding	31	7.05e-043
GO:0005759	Mitochondrial matrix	69	3.14e-042
GO:0005743	Mitochondrial inner membrane	76	3.82e-041
GO:0005829	Cytosol	197	1.03e-030
GO:0009055	Electron carrier activity	32	6.34e-028
GO:0006099	Tricarboxylic acid cycle	21	2.10e-027
GO:0070062	Extracellular exosome	166	1.05e-025
GO:0004029	Aldehyde dehydrogenase (NAD) activity	15	1.54e-021
GO:0043209	Myelin sheath	31	2.35e-019
GO:0006090	Pyruvate metabolic process	14	8.02e-019
GO:0006069	Ethanol oxidation	11	5.15e-017
GO:0004129	Cytochrome-c oxidase activity	15	7.55e-016
GO:0007584	Response to nutrient	21	1.84e-015
GO:0005524	ATP binding	94	1.86e-015

Item

Number

P-Value

GO:0006120

Mitochondrial electron transport, NADH to ubiquinone

4.19e-067

GO:0008137

NADH dehydrogenase (ubiquinone) activity

1.34e-066

GO:0005747

Mitochondrial respiratory chain complex Ⅰ

4.40e-062

GO:0005739

Mitochondrion

147

6.42e-057

GO:0032981

Mitochondrial respiratory chain complex Ⅰ assembly

2.77e-052

GO:0055114

Oxidation-reduction process

1.86e-049

GO:0051287

NAD binding

7.05e-043

GO:0005759

Mitochondrial matrix

3.14e-042

GO:0005743

Mitochondrial inner membrane

3.82e-041

GO:0005829

Cytosol

197

1.03e-030

GO:0009055

Electron carrier activity

6.34e-028

GO:0006099

Tricarboxylic acid cycle

2.10e-027

GO:0070062

Extracellular exosome

166

1.05e-025

GO:0004029

Aldehyde dehydrogenase (NAD) activity

1.54e-021

GO:0043209

Myelin sheath

2.35e-019

GO:0006090

Pyruvate metabolic process

8.02e-019

GO:0006069

Ethanol oxidation

5.15e-017

GO:0004129

Cytochrome-c oxidase activity

7.55e-016

GO:0007584

Response to nutrient

1.84e-015

GO:0005524

ATP binding

1.86e-015

ID	Item	Number	P-Value
-	Carbohydrate metabolism	91	1.15e-038
hsa04932	Non-alcoholic fatty liver disease (NAFLD)	60	4.55e-035
hsa05012	Parkinson's disease	58	1.72e-034
hsa00190	Oxidative phosphorylation	56	2.35e-034
hsa05010	Alzheimer's disease	61	5.42e-033
-	Overview	60	2.54e-031
-	Energy metabolism	57	2.53e-030
hsa01200	Carbon metabolism	47	3.89e-030
hsa05016	Huntington's disease	60	1.31e-029
-	Endocrine and metabolic diseases	63	2.48e-025
hsa00010	Glycolysis/Gluconeogenesis	34	9.41e-025
hsa00640	Propanoate metabolism	24	1.72e-023
hsa00620	Pyruvate metabolism	27	1.98e-023
hsa00020	Citrate cycle (TCA cycle)	22	2.94e-021
-	Amino acid metabolism	62	6.57e-021
-	Neurodegenerative diseases	69	3.59e-020
hsa00280	Valine, leucine and isoleucine degradation	25	7.05e-020
-	Lipid metabolism	70	1.26e-018
hsa00071	Fatty acid degradation	21	7.63e-015
-	Metabolism of cofactors and vitamins	43	3.37e-014

Item

Number

P-Value

Carbohydrate metabolism

1.15e-038

hsa04932

Non-alcoholic fatty liver disease (NAFLD)

4.55e-035

hsa05012

Parkinson's disease

1.72e-034

hsa00190

Oxidative phosphorylation

2.35e-034

hsa05010

Alzheimer's disease

5.42e-033

Overview

2.54e-031

Energy metabolism

2.53e-030

hsa01200

Carbon metabolism

3.89e-030

hsa05016

Huntington's disease

1.31e-029

Endocrine and metabolic diseases

2.48e-025

hsa00010

Glycolysis/Gluconeogenesis

9.41e-025

hsa00640

Propanoate metabolism

1.72e-023

hsa00620

Pyruvate metabolism

1.98e-023

hsa00020

Citrate cycle (TCA cycle)

2.94e-021

Amino acid metabolism

6.57e-021

Neurodegenerative diseases

3.59e-020

hsa00280

Valine, leucine and isoleucine degradation

7.05e-020

Lipid metabolism

1.26e-018

hsa00071

Fatty acid degradation

7.63e-015

Metabolism of cofactors and vitamins

3.37e-014

ID	Item	Number	P-Value
-	Carbohydrate metabolism	91	1.15e-038
hsa04932	Non-alcoholic fatty liver disease (NAFLD)	60	4.55e-035
hsa05012	Parkinson's disease	58	1.72e-034
hsa00190	Oxidative phosphorylation	56	2.35e-034
hsa05010	Alzheimer's disease	61	5.42e-033
-	Overview	60	2.54e-031
-	Energy metabolism	57	2.53e-030
hsa01200	Carbon metabolism	47	3.89e-030
hsa05016	Huntington's disease	60	1.31e-029
-	Endocrine and metabolic diseases	63	2.48e-025
hsa00010	Glycolysis/Gluconeogenesis	34	9.41e-025
hsa00640	Propanoate metabolism	24	1.72e-023
hsa00620	Pyruvate metabolism	27	1.98e-023
hsa00020	Citrate cycle (TCA cycle)	22	2.94e-021
-	Amino acid metabolism	62	6.57e-021
-	Neurodegenerative diseases	69	3.59e-020
hsa00280	Valine, leucine and isoleucine degradation	25	7.05e-020
-	Lipid metabolism	70	1.26e-018
hsa00071	Fatty acid degradation	21	7.63e-015
-	Metabolism of cofactors and vitamins	43	3.37e-014

Item

Number

P-Value

Carbohydrate metabolism

1.15e-038

hsa04932

Non-alcoholic fatty liver disease (NAFLD)

4.55e-035

hsa05012

Parkinson's disease

1.72e-034

hsa00190

Oxidative phosphorylation

2.35e-034

hsa05010

Alzheimer's disease

5.42e-033

Overview

2.54e-031

Energy metabolism

2.53e-030

hsa01200

Carbon metabolism

3.89e-030

hsa05016

Huntington's disease

1.31e-029

Endocrine and metabolic diseases

2.48e-025

hsa00010

Glycolysis/Gluconeogenesis

9.41e-025

hsa00640

Propanoate metabolism

1.72e-023

hsa00620

Pyruvate metabolism

1.98e-023

hsa00020

Citrate cycle (TCA cycle)

2.94e-021

Amino acid metabolism

6.57e-021

Neurodegenerative diseases

3.59e-020

hsa00280

Valine, leucine and isoleucine degradation

7.05e-020

Lipid metabolism

1.26e-018

hsa00071

Fatty acid degradation

7.63e-015

Metabolism of cofactors and vitamins

3.37e-014

ID	Item	Number	P-Value
GO:0005829	Cytosol	216	1.55e-059
GO:0005739	Mitochondrion	120	1.29e-046
GO:0005759	Mitochondrial matrix	58	3.33e-036
GO:0005524	ATP binding	104	9.92e-028
GO:0005743	Mitochondrial inner membrane	55	3.83e-027
GO:0043209	Myelin sheath	34	1.99e-025
GO:0051287	NAD binding	20	7.92e-024
GO:0006099	Tricarboxylic acid cycle	17	1.54e-021
GO:0070062	Extracellular exosome	135	3.93e-021
GO:0006120	Mitochondrial electron transport, NADH to ubiquinone	19	1.69e-019
GO:0008137	NADH dehydrogenase (ubiquinone) activity	17	5.69e-017
GO:0018105	Peptidyl-serine phosphorylation	24	7.99e-017
GO:0005747	Mitochondrial respiratory chain complex Ⅰ	17	1.30e-016
GO:0042493	Response to drug	36	8.35e-016
GO:0042802	Identical protein binding	49	1.85e-015
GO:0030168	Platelet activation	22	2.84e-015
GO:0009055	Electron carrier activity	20	3.39e-015
GO:0006754	ATP biosynthetic process	13	9.68e-015
GO:0006090	Pyruvate metabolic process	11	2.84e-014
GO:0004672	Protein kinase activity	27	2.89e-014

Item

Number

P-Value

GO:0005829

Cytosol

216

1.55e-059

GO:0005739

Mitochondrion

120

1.29e-046

GO:0005759

Mitochondrial matrix

3.33e-036

GO:0005524

ATP binding

104

9.92e-028

GO:0005743

Mitochondrial inner membrane

3.83e-027

GO:0043209

Myelin sheath

1.99e-025

GO:0051287

NAD binding

7.92e-024

GO:0006099

Tricarboxylic acid cycle

1.54e-021

GO:0070062

Extracellular exosome

135

3.93e-021

GO:0006120

Mitochondrial electron transport, NADH to ubiquinone

1.69e-019

GO:0008137

NADH dehydrogenase (ubiquinone) activity

5.69e-017

GO:0018105

Peptidyl-serine phosphorylation

7.99e-017

GO:0005747

Mitochondrial respiratory chain complex Ⅰ

1.30e-016

GO:0042493

Response to drug

8.35e-016

GO:0042802

Identical protein binding

1.85e-015

GO:0030168

Platelet activation

2.84e-015

GO:0009055

Electron carrier activity

3.39e-015

GO:0006754

ATP biosynthetic process

9.68e-015

GO:0006090

Pyruvate metabolic process

2.84e-014

GO:0004672

Protein kinase activity

2.89e-014

ID	Item	Number	P-Value
GO:0005829	Cytosol	216	1.55e-059
GO:0005739	Mitochondrion	120	1.29e-046
GO:0005759	Mitochondrial matrix	58	3.33e-036
GO:0005524	ATP binding	104	9.92e-028
GO:0005743	Mitochondrial inner membrane	55	3.83e-027
GO:0043209	Myelin sheath	34	1.99e-025
GO:0051287	NAD binding	20	7.92e-024
GO:0006099	Tricarboxylic acid cycle	17	1.54e-021
GO:0070062	Extracellular exosome	135	3.93e-021
GO:0006120	Mitochondrial electron transport, NADH to ubiquinone	19	1.69e-019
GO:0008137	NADH dehydrogenase (ubiquinone) activity	17	5.69e-017
GO:0018105	Peptidyl-serine phosphorylation	24	7.99e-017
GO:0005747	Mitochondrial respiratory chain complex Ⅰ	17	1.30e-016
GO:0042493	Response to drug	36	8.35e-016
GO:0042802	Identical protein binding	49	1.85e-015
GO:0030168	Platelet activation	22	2.84e-015
GO:0009055	Electron carrier activity	20	3.39e-015
GO:0006754	ATP biosynthetic process	13	9.68e-015
GO:0006090	Pyruvate metabolic process	11	2.84e-014
GO:0004672	Protein kinase activity	27	2.89e-014

Item

Number

P-Value

GO:0005829

Cytosol

216

1.55e-059

GO:0005739

Mitochondrion

120

1.29e-046

GO:0005759

Mitochondrial matrix

3.33e-036

GO:0005524

ATP binding

104

9.92e-028

GO:0005743

Mitochondrial inner membrane

3.83e-027

GO:0043209

Myelin sheath

1.99e-025

GO:0051287

NAD binding

7.92e-024

GO:0006099

Tricarboxylic acid cycle

1.54e-021

GO:0070062

Extracellular exosome

135

3.93e-021

GO:0006120

Mitochondrial electron transport, NADH to ubiquinone

1.69e-019

GO:0008137

NADH dehydrogenase (ubiquinone) activity

5.69e-017

GO:0018105

Peptidyl-serine phosphorylation

7.99e-017

GO:0005747

Mitochondrial respiratory chain complex Ⅰ

1.30e-016

GO:0042493

Response to drug

8.35e-016

GO:0042802

Identical protein binding

1.85e-015

GO:0030168

Platelet activation

2.84e-015

GO:0009055

Electron carrier activity

3.39e-015

GO:0006754

ATP biosynthetic process

9.68e-015

GO:0006090

Pyruvate metabolic process

2.84e-014

GO:0004672

Protein kinase activity

2.89e-014

ID	Item	Number	P-Value
hsa00230	Purine metabolism	55	2.81e-028
-	Nucleotide metabolism	56	2.28e-025
hsa01200	Carbon metabolism	40	8.05e-024
-	Carbohydrate metabolism	68	1.12e-022
-	Overview	48	7.69e-022
hsa00620	Pyruvate metabolism	25	2.12e-021
hsa05012	Parkinson's disease	41	3.07e-019
hsa05016	Huntington's disease	44	2.40e-017
-	Neurodegenerative diseases	61	8.25e-017
hsa00071	Fatty acid degradation	22	9.38e-017
hsa00280	Valine, leucine and isoleucine degradation	22	9.38e-017

Item

Number

P-Value

hsa00230

Purine metabolism

2.81e-028

Nucleotide metabolism

2.28e-025

hsa01200

Carbon metabolism

8.05e-024

Carbohydrate metabolism

1.12e-022

Overview

7.69e-022

hsa00620

Pyruvate metabolism

2.12e-021

hsa05012

Parkinson's disease

3.07e-019

hsa05016

Huntington's disease

2.40e-017

Neurodegenerative diseases

8.25e-017

hsa00071

Fatty acid degradation

9.38e-017

hsa00280

Valine, leucine and isoleucine degradation

9.38e-017

ID	Item	Number	P-Value
hsa00230	Purine metabolism	55	2.81e-028
-	Nucleotide metabolism	56	2.28e-025
hsa01200	Carbon metabolism	40	8.05e-024
-	Carbohydrate metabolism	68	1.12e-022
-	Overview	48	7.69e-022
hsa00620	Pyruvate metabolism	25	2.12e-021
hsa05012	Parkinson's disease	41	3.07e-019
hsa05016	Huntington's disease	44	2.40e-017
-	Neurodegenerative diseases	61	8.25e-017
hsa00071	Fatty acid degradation	22	9.38e-017
hsa00280	Valine, leucine and isoleucine degradation	22	9.38e-017

Item

Number

P-Value

hsa00230

Purine metabolism

2.81e-028

Nucleotide metabolism

2.28e-025

hsa01200

Carbon metabolism

8.05e-024

Carbohydrate metabolism

1.12e-022

Overview

7.69e-022

hsa00620

Pyruvate metabolism

2.12e-021

hsa05012

Parkinson's disease

3.07e-019

hsa05016

Huntington's disease

2.40e-017

Neurodegenerative diseases

8.25e-017

hsa00071

Fatty acid degradation

9.38e-017

hsa00280

Valine, leucine and isoleucine degradation

9.38e-017

基于中药整合药理学平台的生脉饮治疗心律失常的分子机制

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吕冬梅 ¹ , 崔如意 ¹ , 周荣荣 ² , 许海玉 ¹^,^*

药学学报 | 研究论文·药理学 2018,53(5): 743-748

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药学学报 | 研究论文·药理学 2018, 53(5): 743-748

基于中药整合药理学平台的生脉饮治疗心律失常的分子机制

全屏

吕冬梅¹, 崔如意¹, 周荣荣², 许海玉¹^,^*

作者信息

1.中国中医科学院中药研究所, 北京 100700

2.山西中医药大学基础医学院, 山西晋中 030600

通讯作者:

* 许海玉, Tel:86-10-64014411, E-mail:hy_xu627@163.com

Molecular mechanism of Shengmaiyin for arrhythmia based on integrative pharmacology

Dong-mei LÜ¹, Ru-yi CUI¹, Rong-rong ZHOU², Hai-yu XU¹^,^*

Affiliations

1. Institute of Chinese Materia Medica, China Academy of Chinese Medicinal Sciences, Beijing 100700, China

2. School of Basic Medicine, Shanxi University of Chinese Medicine, Jinzhong 030600, China

出版时间: 2018-05-12 doi: 10.16438/j.0513-4870.2017-1123

文章导航

摘要

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生脉饮被广泛应用于心律失常并取得了很好的疗效，由于中药复方的复杂性，其治疗心律失常的药理学机制尚未得到阐释。本研究借助中药整合药理学平台，对生脉饮治疗心律失常分子机制进行研究。结果显示，生脉饮可能通过作用于碳代谢、嘌呤代谢、糖类代谢等能量代谢相关通路或通过调节ATP水平来达到对心律失常的治疗作用。本研究还得到生脉饮中发挥这一作用的主要药物成分可能是人参。

关键词

生脉饮 / 分子机制 / 整合药理学 / 心律失常 / 人参 / 能量代谢

Abstract

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Shengmaiyin is widely used in the treatment of arrhythmia and has achieved a good effect. Due to the complexity of traditional Chinese medical formula, the pharmacological mechanism of Shengmaiyin in the treatment of arrhythmia is unclear. In this study, we used the internet-based Computation Platform (www.tcmip.cn) to explore the molecular mechanism. Shengmaiyin was found to treat the arrhythmia by modulating the pathway related to energy metabolism such as carbon metabolism, purine metabolism, carbohydrate metabolism, or by regulating the level of ATP. In this study, we find that the main active drug component in Shengmaiyin may be ginseng.

Key words

Shengmaiyin / molecular mechanism / integrative pharmacology / arrhythmia / ginseng / energy metabolism

引用本文

吕冬梅, 崔如意, 周荣荣, 许海玉. 基于中药整合药理学平台的生脉饮治疗心律失常的分子机制. 药学学报, 2018 , 53 (5) : 743 -748 . DOI: 10.16438/j.0513-4870.2017-1123

Dong-mei LÜ, Ru-yi CUI, Rong-rong ZHOU, Hai-yu XU. Molecular mechanism of Shengmaiyin for arrhythmia based on integrative pharmacology[J]. Acta Pharmaceutica Sinica, 2018 , 53 (5) : 743 -748 . DOI: 10.16438/j.0513-4870.2017-1123

正文

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中药方剂是中医临床治疗的一种主要方式和手段, 而中药经典名方作为承载中医原创理论的代表性方剂, 成为了中医药研究的热点之一。整合药理学(integrative pharmacology, IP)是研究多成分药物与机体相互作用及其整合规律和作用原理的一门学科, 是药理学研究的新方向, 它融合了中药学、化学、药代动力学、药理学和计算科学等多学科, 是一门交叉学科。中药整合药理学是一门新兴学科, 以大数据和模型计算为基础, 以多学科交叉、多层次融合为手段, 探索中药方剂的作用物质实体与机体相互作用的规律, 被广泛应用到中药有效成分辨识、分子机制、配伍理论的分子机制等方面^{[1, 2]}。

中药整合药理学平台以大数据库为依托, 运用人工智能、网络计算和数据挖掘等方法与技术, 旨在突破中医药传承与发展面临的关键科学问题。其主要功能有:中药成分识别、ADME预测、靶标预测、网络构建与分析和“组-效”关系构建等。在整合药理学平台V1.0版本已实现了药物靶标预测、网络构建与分析、药物与疾病关键靶标分析及网络分析可视化等功能。中药整合药理学平台在中药药效物质基础研究、分子机制探讨和中药新药研发等方面将有较好的应用, 也有力地支撑了中医原创思维的科学价值揭示和名医传承经验总结, 可供中医药院校、科研院所等从业人员学习和研究使用^[2]。

生脉饮又名生脉散, 来源于《丹溪心法》, 由人参、麦冬和五味子三味中药组成, 具有益气生津、敛阴止汗的功效, 常用于治疗气阴两虚证, 是益气养阴名方。现代中成药制剂益心舒胶囊、安神健脑液等都是以生脉饮为基础方进行加减而来, 且疗效显著并获得了广泛的临床应用^[3]。目前对生脉饮的药理作用已经有了较为深入的研究, 有研究表明生脉饮能不同程度地影响心血管系统、各种原因引起的休克、免疫功能、生长发育和学习记忆能力等^[4]。生脉饮现代研究已初步探明其主要物质基础, 其主要有效成分为皂苷类、多糖类、黄酮类、木脂素类、氨基酸和微量元素等物质。人参中人参皂苷、人参多糖属于主要化学成分, 具有抗休克、强心、降低外周血管阻力和降压, 抗缺氧、保护心肌、调节胆固醇代谢、降血脂、降低血糖等作用; 麦冬多糖、甾体皂苷是麦冬的主要有效成分, 有保护心肌、抗心肌缺血、改善左室功能与抗休克、降低血糖等作用; 五味子含挥发油、有机酸、多糖等成分, 具有镇咳、抗肝损伤、降糖、提高免疫力等药理作用^[5]。有研究表明心肌缺血再灌注后的心律失常与氧自由基和心肌细胞凋亡有关^[6], 而生脉饮可以抗氧化并且通过抑制细胞凋亡、保护心肌从而发挥对心肌细胞的超微结构的调节以达到对心肌细胞的保护作用, 益心作用很好^[4]。血清药理学研究发现生脉饮对高糖环境下损伤的H9c2心肌细胞具有抗凋亡的作用, 此作用可能与阻断线粒体凋亡通路有关^[4], 且生脉饮水提物和单体的含药血清都能明显缓解细胞的凋亡, 且随着浓度的增加效果明显, 其中生脉饮水提物与单体的效果相当^[5]。

本研究借助中药整合药理学平台(http://www.tcmip.cn/), 浅析生脉饮治疗心律失常的药效物质基础及其分子机制, 为生脉饮有效成分辨识及其质量控制、分子机制与临床应用提供科学依据。

材料与方法

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化学成分来源 在整合药理学平台(http://www.tcmip.cn/)的药材数据库中, 对中药材“人参”、“麦冬”、“五味子”, 收集所有化学成分, 建立生脉饮的化学成分数据库。

候选靶标来源 在整合药理学平台疾病/证候靶标数据库中, 以“arrhythmia”作为疾病或症状关键词进行检索, 勾选检索出来的所有靶标, 作为候选的疾病靶标。在中药靶标预测界面对所建立的“人参-麦冬-五味子”化学成分库中的成分进行靶标预测, 选取相似性分数大于等于0.8的成分预测靶标作为候选。

靶标预测 整合药理学平台利用OpenBabel软件提取化学成分MACCS分子指纹, 通过生脉饮中化学成分二维结构(.mol)与DrugBank中认证药物(Approved)进行化学指纹特征比对, 以Tanimoto系数进行相似性打分, 打分系数大于0.8为相似性的药物, 相似性的药物作用的靶标为生脉饮作用的潜在靶标。

蛋白质-蛋白质相互作用(PPI)信息 生脉饮作用的潜在靶标与心律失常疾病靶标之间的PPI, 通过整合药理学平台的PPI数据库获得, 该平台镶嵌了HAPPI、Reactome、OPHID、InAct、HPRD、MINT、DIP和PDZBase等数据库中蛋白质-蛋白质相互作用数据。

网络构建与分析 通过整合药理学平台网络分析模块, 针对生脉饮作用的潜在靶标与心律失常疾病靶标之间的PPI信息计算网络特征值, 以“节点连接度(degree)”的2倍中位数为卡值, 选取中药靶标-疾病基因互作网络的核心节点(hubs); 在此基础上, 以“degree”、“节点紧密度(closeness)”和“节点介度(betweenness)”的中位数为卡值, 选取同时满足3个卡值的节点为中药方剂矫正疾病失衡网络的关键靶标网络。然后, 对关键靶标网络进行通路富集分析, 选取P-value前30的通路, 构建“中药方剂-中药材-化学成分-核心靶标-关键通路”的多层次关联网络。并对关键靶标网络和多层次关联网络进行可视化。

基因功能和通路富集分析 基因功能和通路富集分析在整合药理学评价进行, 相关信息来自于GO数据库(http://www.geneontology.org)和KEGG通路数据库(Kyoto Encyclopedia of Genes and Genomes, http://www.genome.jp/kegg/)。

结果

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1 生脉饮化学成分靶标预测及分析

人参共收集化学成分158个, 主要为人参皂苷类及有机酸和酯类等, 已有研究表明人参皂苷Rg1可明显减少大鼠缺血性/再灌注心律失常的发生率, 并减少心肌梗死面积, 其机制可能为通过调控内源性线粒体凋亡途径而发挥作用^[7]。麦冬共收集化学成分53个, 主要为黄酮类物质。五味子共收集化学成分98个, 主要为挥发性成分如β-甜没药烯(β-bisabolene)、α-松油烯(α-terpinene)等。人参的158个成分共预测出2 000个靶标, 麦冬的53个成分共预测出247个靶标, 五味子98个成分共预测出70个靶标, 这些靶标中人参与五味子共有靶标8个, 五味子与麦冬共有靶标1个, 人参与麦冬共有靶标174个。

对中药方剂候选靶标进行基因分析(表 1), 可见候选靶标基因功能分析涉及线粒体电子传递、线粒体、丙酮酸代谢、乙醇氧化和ATP结合等条目。对中药方剂候选靶标进行通路富集分析(表 2), 可见涉及通路有碳水化合物代谢、非酒精性脂肪肝病(NAFLD)、帕金森病和氧化磷酸化等通路。

2 生脉饮治疗心律失常的核心靶标网络、基因功能和通路富集分析

2.1 核心靶标网络

通过整合药理学分析的网络分析模块, 基于PPI相互作用数据库, 构建生脉饮药物组合潜在靶标与疾病靶标相互作用网络。根据条件筛选出关键靶标411个, 根据degree值(图 1)仅显示前100个靶点, 图中节点的大小与degree值成正比关系, 其中核心组合化学成分直接作用节点84个, 疾病与药物共有靶点1个为ATP1A1, 推测生脉饮对心律失常的治疗作用可能与能量代谢有关, 已有研究表明心律失常家兔其体内的Na⁺-K⁺-ATP酶活性低于正常家兔^[8]。

2.2 基因功能分析

通过GO和KEGG数据库的基因和功能分析, 生脉饮药物靶标与疾病靶标基因功能分析结果显示有细胞质基质、线粒体、线粒体基质、ATP结合、线粒体内膜、髓鞘、NAD结合、胞外外来体、三羧酸循环和线粒体电子传递等多个条目(表 3)。基因功能分析结果显示有ATP结合、线粒体和三羧酸循环等多个与能量代谢相关条目, 在通路富集中也发现核苷酸代谢、碳代谢和糖类代谢等多条与能量代谢相关通路。推测心律失常可能与人体能量代谢有较大关联。查阅文献可得, 致命室性快速型心律失常(LVTA)可导致能量代谢改变及氧化损伤, 可能与线粒体功能异常相关^[9]。二磷酸果糖镁盐对缺血再灌注心律失常的心肌细胞损伤有明显的保护作用, 其机制可能与改善能量代谢、拮抗氧自由基、减少钙离子内流有关^[10]。短期禁食具有抗大鼠心肌缺血/再灌注心律失常的作用, 其机制可能与改善心肌组织的能量代谢有关^[11]。

2.3 通路富集分析

通过整合药理学平台进行靶标通路富集分析, 关键通路根据P-value值图 2中仅显示前30条通路, 通路富集分析结果显示主要集中在嘌呤代谢、碳代谢、核苷酸代谢、碳水化合物代谢、丙酮酸代谢和帕金森病等信号通路。

通路富集分析结果涉及多个方面, 如碳代谢、嘌呤代谢、丙酮酸代谢、核苷酸代谢等多个代谢通路以及帕金森病、亨廷顿病等疾病相关通路(表 4), 进一步证明前面所述生脉饮对心律失常的干预作用可能与能量代谢相关。

3 生脉饮治疗心律失常的“中药-成分-靶标-通路”多维网络分析

从图 2可看出相关通路主要有糖类代谢(carbohydrate metabolism)、内分泌系统(endocrine system)、碳代谢(carbon metabolism)、氨基酸代谢(amino acid metabolism)、嘌呤代谢(purine metabolism)、氧化磷酸化(oxidative phosphorylation)等与能量代谢有关通路。这些通路相关的核心靶标共计151个, 与101个“人参-麦冬-五味子”化学成分相关联, 其中人参成分81个, 麦冬成分15个, 五味子成分8个, 人参跟麦冬共有成分2个, 人参跟五味子共有成分1个。从候选靶标网络图中可以看出药物潜在靶标与疾病靶标之间有一共同靶标ATP1A1, 推测生脉饮对心律失常的干预作用可能与ATP水平或能量代谢有关。再进一步分析“药物-成分-靶标-通路”网络图可以发现作用于ATP1A1的药物化学成分中, 人参中化学成分最多, 可推测生脉散中对心律失常起主要作用的药物成分为人参, 查阅文献可知已有研究表明人参单体皂苷具有明显的抗心律失常作用^[12]。而且人参的正性肌力作用可能与其对心肌Na⁺-K⁺-ATP酶的抑制有关^[13]。

讨论

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本研究借助中药整合药理学计算平台, 研究生脉饮对心律失常发挥治疗作用的物质基础及其分子机制, 发现其可能作用于碳代谢、糖类代谢和氧化磷酸化等能量代谢相关通路或调节ATP水平来达到治疗心律失常的作用。还发现人参中多种化学成分可以作用于药物潜在与疾病共同靶标ATP1A1, 推测生脉饮中对心律失常发挥主要治疗作用的药物可能是人参, 并且对生脉饮治疗心律失常分子机制的进一步研究提供了一些方向。

本文获得预测结果, 与生脉饮前期文献有较好一致性, 如Shen等^[7]认为人参皂苷Rg1可明显减少大鼠缺血性心律失常的发生率, 其机制可能通过调控内源性线粒体凋亡途径而发挥作用, 生脉饮药物靶标与疾病靶标基因功能分析也显示涉及线粒体与线粒体内膜等多个与线粒体相关条目, 证明生脉饮对心律失常的治疗作用可能与其对线粒体的调节作用有关, 并且可以推测生脉饮中参与调控线粒体的主要药物为人参。Zhen^[5]血清药理学研究发现生脉饮对高糖环境下损伤的H9c2心肌细胞具有抗凋亡的作用, 其作用可能与阻断线粒体凋亡通路有关, 而Feng^[6]认为心肌缺血再灌注后的心律失常与氧自由基和心肌细胞凋亡有关。生脉饮药物靶标与疾病靶标基因功能分析也显示多个与线粒体相关条目, 证明了前面的研究结果。

生脉饮治疗心律失常已经取得了很好的疗效, 对其分子机制及发挥作用的药效物质基础进行研究可以为生脉饮及其所含中药成分的进一步研究提供依据, 也为心律失常的临床治疗提供借鉴与参考。但本研究是基于整合药理学平台的预测, 具体机制及物质基础还需通过实验加以验证, 望本研究能够为生脉饮的进一步研究及心律失常的治疗提供一些参考。

基金

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国家“重大新药创制”科技重大专项(2014ZX09201021-009)
国家重点基础研究发展计划（973）项目(2015CB554406)
国家自然科学基金面上资助项目(81473414)

参考文献

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文献

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参考文献引证文献

排序方式：

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Xu HY, Yang HJ. Integrative pharmacology:new paradigm of modernization of Chinese medicine[J]. China J Chin Mater Med (中国中药杂志), 2014, 39:357-362.

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Xu HY, Liu ZM, Fu Y, et al. Exploiture and application of an internet-based computation platform for integrative pharmacology of traditional Chinese medicine[J]. China J Chin Mater Med (中国中药杂志), 2017, 42:3633-3638.

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Gen Y, Xu HY, Ma YX. Composition principles of formula containing Shengmaisan in dictionary of Chinese medicine prescription[J]. Chin J Exp Tradit Med Form (中国实验方剂学杂志), 2017, 23:200-205.

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Lin MS, Chen ZJ, Luo L, et al. Research on the present situation of Shengmaiyin and the development of Shengmai preparations[J]. Pharm Clin Chin Mat Med (中药与临床), 2017, 8:69-73.

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Zhen BL. Experimental Study of Mechanisms of Traditional Chinese Medical Shengmaisan against Myocardial Apoptosis Induced by High Glucose (生脉散抑制高糖环境下心肌细胞凋亡的分子机制研究)[D]. Beijing: China PLA General Hospital, 2014. http://cdmd.cnki.com.cn/Article/CDMD-90115-1015504337.htm

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Feng XG. The correlation of the oxyradical of myocardial ischemia reperfusion injury, cardiomyocyte apoptosis and ischemia reperfusion arrhythmia in rat[J]. Cardiovasc Dis J Integr Tradit Chin Western Med (中西医结合心血管病杂志), 2016, 4:73-76.

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Shen WY, Li YD, Yang SD. The effect of ginsenoside Rg1 on ischemic rats/reperfusion arrhythmia[J]. J Clin Cardiol (心血管病杂志), 2017, 33:465-469.

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Zhao YR. Study on the Effects of Recuperating-heart Granule on the Activities of Na⁺, K⁺-ATPase of Heart Tissue on CHD Celerity Arrhythmia Model (养心颗粒对冠心病快速型心律失常家兔模型心肌组织Na⁺-K⁺-ATP酶活性影响的研究)[D]. Heilongjiang: Heilongjiang University of Chinese Medicine, 2008. http://cdmd.cnki.com.cn/Article/CDMD-10228-2008179636.htm

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Zheng ZT, Chen WW, Weng JQ, et al. The alteration of energy metabolism and oxidative injury in the myocardia suffering from lethal ventricular tachyarrhythmia[J]. Chin J Forensic Med (中国法医学杂志), 2016, 31:543-546.

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Li XL. Beneficial Effects of Fructose Diphosphate Magnesium on Myocardial Arrhythmia Induced by Ischemia-reperfusion Injury and Their Mechanisms in Rats (二磷酸果糖镁盐抗心律失常作用及其机理研究)[D]. Chongqing: Chongqing Medical University, 2014. http://cdmd.cnki.com.cn/Article/CDMD-10631-2004080111.htm

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2018年第53卷第5期

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doi: 10.16438/j.0513-4870.2017-1123

接收时间：2017-11-14
首发时间：2026-01-15
出版时间：2018-05-12

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收稿日期：2017-11-14
修回日期：2018-01-22

基金

国家“重大新药创制”科技重大专项(2014ZX09201021-009)

国家重点基础研究发展计划（973）项目(2015CB554406)

国家自然科学基金面上资助项目(81473414)

作者信息

1.中国中医科学院中药研究所, 北京 100700

2.山西中医药大学基础医学院, 山西晋中 030600

通讯作者:

* 许海玉, Tel:86-10-64014411, E-mail:hy_xu627@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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ID	Item	Number	P-Value
GO:0006120	Mitochondrial electron transport, NADH to ubiquinone	45	4.19e-067
GO:0008137	NADH dehydrogenase (ubiquinone) activity	44	1.34e-066
GO:0005747	Mitochondrial respiratory chain complex Ⅰ	43	4.40e-062
GO:0005739	Mitochondrion	147	6.42e-057
GO:0032981	Mitochondrial respiratory chain complex Ⅰ assembly	42	2.77e-052
GO:0055114	Oxidation-reduction process	98	1.86e-049
GO:0051287	NAD binding	31	7.05e-043
GO:0005759	Mitochondrial matrix	69	3.14e-042
GO:0005743	Mitochondrial inner membrane	76	3.82e-041
GO:0005829	Cytosol	197	1.03e-030
GO:0009055	Electron carrier activity	32	6.34e-028
GO:0006099	Tricarboxylic acid cycle	21	2.10e-027
GO:0070062	Extracellular exosome	166	1.05e-025
GO:0004029	Aldehyde dehydrogenase (NAD) activity	15	1.54e-021
GO:0043209	Myelin sheath	31	2.35e-019
GO:0006090	Pyruvate metabolic process	14	8.02e-019
GO:0006069	Ethanol oxidation	11	5.15e-017
GO:0004129	Cytochrome-c oxidase activity	15	7.55e-016
GO:0007584	Response to nutrient	21	1.84e-015
GO:0005524	ATP binding	94	1.86e-015

Item

Number

P-Value

GO:0006120

Mitochondrial electron transport, NADH to ubiquinone

4.19e-067

GO:0008137

NADH dehydrogenase (ubiquinone) activity

1.34e-066

GO:0005747

Mitochondrial respiratory chain complex Ⅰ

4.40e-062

GO:0005739

Mitochondrion

147

6.42e-057

GO:0032981

Mitochondrial respiratory chain complex Ⅰ assembly

2.77e-052

GO:0055114

Oxidation-reduction process

1.86e-049

GO:0051287

NAD binding

7.05e-043

GO:0005759

Mitochondrial matrix

3.14e-042

GO:0005743

Mitochondrial inner membrane

3.82e-041

GO:0005829

Cytosol

197

1.03e-030

GO:0009055

Electron carrier activity

6.34e-028

GO:0006099

Tricarboxylic acid cycle

2.10e-027

GO:0070062

Extracellular exosome

166

1.05e-025

GO:0004029

Aldehyde dehydrogenase (NAD) activity

1.54e-021

GO:0043209

Myelin sheath

2.35e-019

GO:0006090

Pyruvate metabolic process

8.02e-019

GO:0006069

Ethanol oxidation

5.15e-017

GO:0004129

Cytochrome-c oxidase activity

7.55e-016

GO:0007584

Response to nutrient

1.84e-015

GO:0005524

ATP binding

1.86e-015

ID	Item	Number	P-Value
-	Carbohydrate metabolism	91	1.15e-038
hsa04932	Non-alcoholic fatty liver disease (NAFLD)	60	4.55e-035
hsa05012	Parkinson's disease	58	1.72e-034
hsa00190	Oxidative phosphorylation	56	2.35e-034
hsa05010	Alzheimer's disease	61	5.42e-033
-	Overview	60	2.54e-031
-	Energy metabolism	57	2.53e-030
hsa01200	Carbon metabolism	47	3.89e-030
hsa05016	Huntington's disease	60	1.31e-029
-	Endocrine and metabolic diseases	63	2.48e-025
hsa00010	Glycolysis/Gluconeogenesis	34	9.41e-025
hsa00640	Propanoate metabolism	24	1.72e-023
hsa00620	Pyruvate metabolism	27	1.98e-023
hsa00020	Citrate cycle (TCA cycle)	22	2.94e-021
-	Amino acid metabolism	62	6.57e-021
-	Neurodegenerative diseases	69	3.59e-020
hsa00280	Valine, leucine and isoleucine degradation	25	7.05e-020
-	Lipid metabolism	70	1.26e-018
hsa00071	Fatty acid degradation	21	7.63e-015
-	Metabolism of cofactors and vitamins	43	3.37e-014

Item

Number

P-Value

Carbohydrate metabolism

1.15e-038

hsa04932

Non-alcoholic fatty liver disease (NAFLD)

4.55e-035

hsa05012

Parkinson's disease

1.72e-034

hsa00190

Oxidative phosphorylation

2.35e-034

hsa05010

Alzheimer's disease

5.42e-033

Overview

2.54e-031

Energy metabolism

2.53e-030

hsa01200

Carbon metabolism

3.89e-030

hsa05016

Huntington's disease

1.31e-029

Endocrine and metabolic diseases

2.48e-025

hsa00010

Glycolysis/Gluconeogenesis

9.41e-025

hsa00640

Propanoate metabolism

1.72e-023

hsa00620

Pyruvate metabolism

1.98e-023

hsa00020

Citrate cycle (TCA cycle)

2.94e-021

Amino acid metabolism

6.57e-021

Neurodegenerative diseases

3.59e-020

hsa00280

Valine, leucine and isoleucine degradation

7.05e-020

Lipid metabolism

1.26e-018

hsa00071

Fatty acid degradation

7.63e-015

Metabolism of cofactors and vitamins

3.37e-014

ID	Item	Number	P-Value
GO:0005829	Cytosol	216	1.55e-059
GO:0005739	Mitochondrion	120	1.29e-046
GO:0005759	Mitochondrial matrix	58	3.33e-036
GO:0005524	ATP binding	104	9.92e-028
GO:0005743	Mitochondrial inner membrane	55	3.83e-027
GO:0043209	Myelin sheath	34	1.99e-025
GO:0051287	NAD binding	20	7.92e-024
GO:0006099	Tricarboxylic acid cycle	17	1.54e-021
GO:0070062	Extracellular exosome	135	3.93e-021
GO:0006120	Mitochondrial electron transport, NADH to ubiquinone	19	1.69e-019
GO:0008137	NADH dehydrogenase (ubiquinone) activity	17	5.69e-017
GO:0018105	Peptidyl-serine phosphorylation	24	7.99e-017
GO:0005747	Mitochondrial respiratory chain complex Ⅰ	17	1.30e-016
GO:0042493	Response to drug	36	8.35e-016
GO:0042802	Identical protein binding	49	1.85e-015
GO:0030168	Platelet activation	22	2.84e-015
GO:0009055	Electron carrier activity	20	3.39e-015
GO:0006754	ATP biosynthetic process	13	9.68e-015
GO:0006090	Pyruvate metabolic process	11	2.84e-014
GO:0004672	Protein kinase activity	27	2.89e-014

Item

Number

P-Value

GO:0005829

Cytosol

216

1.55e-059

GO:0005739

Mitochondrion

120

1.29e-046

GO:0005759

Mitochondrial matrix

3.33e-036

GO:0005524

ATP binding

104

9.92e-028

GO:0005743

Mitochondrial inner membrane

3.83e-027

GO:0043209

Myelin sheath

1.99e-025

GO:0051287

NAD binding

7.92e-024

GO:0006099

Tricarboxylic acid cycle

1.54e-021

GO:0070062

Extracellular exosome

135

3.93e-021

GO:0006120

Mitochondrial electron transport, NADH to ubiquinone

1.69e-019

GO:0008137

NADH dehydrogenase (ubiquinone) activity

5.69e-017

GO:0018105

Peptidyl-serine phosphorylation

7.99e-017

GO:0005747

Mitochondrial respiratory chain complex Ⅰ

1.30e-016

GO:0042493

Response to drug

8.35e-016

GO:0042802

Identical protein binding

1.85e-015

GO:0030168

Platelet activation

2.84e-015

GO:0009055

Electron carrier activity

3.39e-015

GO:0006754

ATP biosynthetic process

9.68e-015

GO:0006090

Pyruvate metabolic process

2.84e-014

GO:0004672

Protein kinase activity

2.89e-014

ID	Item	Number	P-Value
hsa00230	Purine metabolism	55	2.81e-028
-	Nucleotide metabolism	56	2.28e-025
hsa01200	Carbon metabolism	40	8.05e-024
-	Carbohydrate metabolism	68	1.12e-022
-	Overview	48	7.69e-022
hsa00620	Pyruvate metabolism	25	2.12e-021
hsa05012	Parkinson's disease	41	3.07e-019
hsa05016	Huntington's disease	44	2.40e-017
-	Neurodegenerative diseases	61	8.25e-017
hsa00071	Fatty acid degradation	22	9.38e-017
hsa00280	Valine, leucine and isoleucine degradation	22	9.38e-017

Item

Number

P-Value

hsa00230

Purine metabolism

2.81e-028

Nucleotide metabolism

2.28e-025

hsa01200

Carbon metabolism

8.05e-024

Carbohydrate metabolism

1.12e-022

Overview

7.69e-022

hsa00620

Pyruvate metabolism

2.12e-021

hsa05012

Parkinson's disease

3.07e-019

hsa05016

Huntington's disease

2.40e-017

Neurodegenerative diseases

8.25e-017

hsa00071

Fatty acid degradation

9.38e-017

hsa00280

Valine, leucine and isoleucine degradation

9.38e-017