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Article(id=1218551237289624009, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218551229794403031, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2018-0394, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1524758400000, receivedDateStr=2018-04-27, revisedDate=1527955200000, revisedDateStr=2018-06-03, acceptedDate=null, acceptedDateStr=null, onlineDate=1768454854557, onlineDateStr=2026-01-15, pubDate=1536940800000, pubDateStr=2018-09-15, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768454854557, onlineIssueDateStr=2026-01-15, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768454854557, creator=13701087609, updateTime=1768454854557, updator=13701087609, issue=Issue{id=1218551229794403031, tenantId=1146029695717560320, journalId=1189982191388893191, year='2018', volume='53', issue='9', pageStart='1387', pageEnd='1582', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768454852770, creator=13701087609, updateTime=1768457118357, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1218560732426322043, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218551229794403031, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1218560732426322044, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218551229794403031, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1406, endPage=1413, ext={EN=ArticleExt(id=1218551237872632322, articleId=1218551237289624009, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Study of the anti-heart failure mechanisms of compatibility of Gualou with Xiebai in basis of network pharmacology, columnId=1218263312677130587, journalTitle=Acta Pharmaceutica Sinica, columnName=SPECIAL REPORTS, runingTitle=null, highlight=null, articleAbstract=

This study was designed to explore the anti heart failure mechanisms of the compatibility of Gualou with Xiebai based on network pharmacology in rat model of myocardial ischemia-reperfusion injury. Using the databases of Traditional Chinese Medicine Database@Taiwan (TCM Database@Taiwan), Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Drug Repositioning and Adverse Drug Reaction Chemical-Protein Interactome (DRAR-CPI) and Universal Protein Resource (Uniprot) to screen compounds and predict the target of active components, the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, we predicted the biological pathway and signal pathway in the compatibility of Gualou with Xiebai. The effects of Gualou Xiebai dropping pills on the apoptosis of myocardial cells and the expression of protein kinase B (Akt), p-Akt and cysteine aspartate-specific proteinase (caspase-3) protein were examined in the related signal pathway phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) of myocardial ischemia reperfusion injury in rats. Twenty two compounds, such as 10 α-cucurbita-5, 24-diene-3β-ol and macrostemonoside were found to protect rats from heart failure through multiple targets, multiple biological pathways and multiple pathways, involving biological pathways such as hormone stimulation reaction, phosphorylation, apoptosis regulation, and signaling pathways such as insulin, mitogen-activated protein kinase (MAPK), cell apoptosis and so on. After the intervention of Gualou Xiebai dropping pills, the PI3K-Akt signaling pathway was activated to promote the phosphorylation of Akt protein, reduce the expression of caspase-3 protein, inhibit apoptosis and protect the myocardium. The data verify the results of the network pharmacology, and explain the mechanisms of anti-heart failure activity of combination of Gualou with Xiebai.

, correspAuthors=Hai-yan YAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2018 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Chun-cai ZOU, Hai-yan YAN, Mei-ling WEI), CN=ArticleExt(id=1218551240456323872, articleId=1218551237289624009, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=基于网络药理学分析瓜蒌薤白配伍抗心力衰竭的作用机制研究, columnId=1218263312865874270, journalTitle=药学学报, columnName=专题报道, runingTitle=null, highlight=null, articleAbstract=

基于网络药理学预测及大鼠心肌缺血-再灌注损伤模型验证的方法，对瓜蒌薤白配伍抗心力衰竭的作用机制进行探讨。运用Traditional Chinese Medicine Database@Taiwan（TCM Database@Taiwan）、TraditionalChinese Medicine Systems Pharmacology Database and Analysis Platform（TCMSP）、Drug Repositioning and AdverseDrug Reaction Chemical-Protein Interactome（DRAR-CPI）、Universal Protein Resource（Uniprot）数据库进行化合物筛选及活性成分靶点预测，借助Database for Annotation，Visualization，and Integrated Discovery（DAVID）数据库进行生物途径和信号通路分析，预测瓜蒌薤白配伍的作用机制。考察瓜蒌薤白滴丸预处理对心肌缺血-再灌注损伤大鼠心肌细胞凋亡及相关信号通路磷脂酰肌醇3-激酶/丝氨酸苏氨酸激酶（phosphatidylinositol-3-kinase/proteinkinase B，PI3K/Akt）中Akt、磷酸化丝氨酸/苏氨酸激酶（phosphorylated protein kinase B，p-Akt）和半胱氨酸天冬氨酸蛋白酶-3（cysteine aspartate-specific proteinase，caspase-3）蛋白表达的影响。发现10α-cucurbita-5，24-diene-3β-ol和macrostemonoside等22个化合物通过多靶点、多生物途径及多通路方式协同抗心力衰竭，涉及激素刺激反应、磷酸化过程、细胞凋亡调控等生物学途径和胰岛素、丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）、细胞凋亡等信号通路。瓜蒌薤白滴丸预处理可通过激活PI3K-Akt信号通路，促进Akt蛋白磷酸化，降低caspase-3蛋白表达，发挥抑制细胞凋亡、保护心肌作用，验证了网络药理学结果，综合阐释了瓜蒌薤白配伍抗心力衰竭的作用机制。

, correspAuthors=鄢海燕, authorNote=null, correspAuthorsNote=
* 鄢海燕, Tel:86-533-3932185, E-mail:
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J Shanghai Univ Trandit Chin Med (上海中医药大学学报), 2018, 32: 82-85., articleTitle=null, refAbstract=null), Reference(id=1218970806437204356, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[12], rfOrder=11, authorNames=null, journalName=null, refType=null, unstructuredReference=Fan Y, Bergmann A. The cleaved-caspase-3 antibody is a marker of caspase-9-like DRONC activity in Drosophila [J]. Cell Death Differ, 2010, 17: 534-539., articleTitle=null, refAbstract=null), Reference(id=1218970806579810705, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[13], rfOrder=12, authorNames=null, journalName=null, refType=null, unstructuredReference=Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the reperfusion injury salvage kinase (RISK)-pathway[J]. Cardiovasc Res, 2004, 61: 448-460., articleTitle=null, refAbstract=null), Reference(id=1218970806701445532, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[14], rfOrder=13, authorNames=null, journalName=null, refType=null, unstructuredReference=McGuire VA, Gray A, Monk CE, et al. Cross talk between the Akt and p38α pathways in macrophages downstream of toll-like receptor signaling [J]. Mol Cell Biol, 2013, 33: 4152-4165., articleTitle=null, refAbstract=null), Reference(id=1218970806831468970, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[15], rfOrder=14, authorNames=null, journalName=null, refType=null, unstructuredReference=Sussman MA, Völkers M, Fischer K, et al. Myocardial Akt: the omnipresent nexus[J]. Physiol Rev, 2011, 91: 1023- 1070., articleTitle=null, refAbstract=null)], funds=[Fund(id=1218970804524601546, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, awardId=KJ2015ZD41, language=CN, fundingSource=安徽高校省级自然科学研究重大项目(KJ2015ZD41), fundOrder=null, country=null), Fund(id=1218970804650430683, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, awardId=KJ2016SD60, language=CN, fundingSource=安徽高校省级自然科学研究重大项目(KJ2016SD60), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1218970796282794572, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, xref=null, ext=[AuthorCompanyExt(id=1218970796303766095, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, companyId=1218970796282794572, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. 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Pharmacy Department of Anhui No.2 Provincial People's Hospital, Hefei 230041, China), AuthorCompanyExt(id=1218970796433789536, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, companyId=1218970796417012317, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.安徽省第二人民医院药学部, 安徽 合肥 230041)])], figs=[ArticleFig(id=1218970800833614780, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=EN, label=null, caption=null, figureFileSmall=RPyJ/nCH7cNWIuiyyDBgZg==, figureFileBig=MP42CP+J8+inY7xsMG0ZiQ==, tableContent=null), ArticleFig(id=1218970800951055303, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=CN, label=Figure 1, caption=

Compounds ()-target protein ()-pathways () network

, figureFileSmall=RPyJ/nCH7cNWIuiyyDBgZg==, figureFileBig=MP42CP+J8+inY7xsMG0ZiQ==, tableContent=null), ArticleFig(id=1218970801135604697, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=EN, label=null, caption=null, figureFileSmall=GGAKazi2PAjyIniCy2ai9A==, figureFileBig=uNIuNneD1xSdj8k49fY/JQ==, tableContent=null), ArticleFig(id=1218970801240462308, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=CN, label=Figure 2, caption= Stained sections of Gualou Xiebai dropping pills against myocardial apoptosis induced by ischemia and reperfusion injury in rats (×200).

A: Sham operation group; B: Model group; C: Gualou-Xiebai dropping pills group; D: Wortmannin group; E: Gualou-Xiebai dropping pills + wortmannin group; F: Compound Danshen dropping pills group; 1: Normal cells; 2: Apoptotic cells

, figureFileSmall=GGAKazi2PAjyIniCy2ai9A==, figureFileBig=uNIuNneD1xSdj8k49fY/JQ==, tableContent=null), ArticleFig(id=1218970801336931309, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=EN, label=null, caption=null, figureFileSmall=kubj8t1LTKJJ4Aq300giaA==, figureFileBig=IByleOwFfo0yZYxLbwynWg==, tableContent=null), ArticleFig(id=1218970801487926272, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=CN, label=Figure 3, caption= The protein expressions of caspase-3, p-Akt and Akt were determined by Western blot analysis (A).

The protein expression of caspase-3 (B), p-Akt (C) and Akt (D) relative to β-tubulin. 1: Sham operation group; 2: Gualou-Xiebai dropping pills group; 3: Compound Danshen dropping pills group; 4: Model group; 5: Wortmannin group; 6: Gualou-Xiebai dropping pills + wortmannin group. n = 6, $\overline{x}±s$. *P < 0.05, **P < 0.01 vs model group; ##P < 0.01 vs Gualou Xiebai dropping pills group

, figureFileSmall=kubj8t1LTKJJ4Aq300giaA==, figureFileBig=IByleOwFfo0yZYxLbwynWg==, tableContent=null), ArticleFig(id=1218970801580199949, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Mol ID Compound Molecular formula Source
MOL007165 10α-Cucurbita-5, 24-diene-3β-ol C30H50O Gualou
MOL007171 5-Dehydrokarounidiol C30H46O2 Gualou
MOL007172 7-oxo-Dihydrokaro-unidiol C30H48O3 Gualou
MOL002881 Diosmetin C16H12O6 Gualou
MOL005530 Hydroxygenkwanin C16H12O6 Gualou
MOL007179 Linolenic acid ethyl ester C20H34O2 Gualou
MOL001494 Mandenol C20H36O2 Gualou
MOL006756 Schottenol C29H50O Gualou
MOL004355 Spinasterol C29H48O Gualou
MOL007180 Vitamin-e C24H34N4O5S Gualou
MOL000098 Quercetin C15H10O7 Gualou
MOL006946 Adenosine C10H13N5O4 Gualou, Xiebai
MOL000358 Beta-sitosterol C29H50O Xiebai
MOL000631 Coumaroyltyramine C17H17NO3 Xiebai
MOL002341 Hesperetin C16H14O6 Xiebai
MOL007640 Macrostemonoside C27H44O3 Xiebai
MOL004328 Naringenin C15H12O5 Xiebai
MOL000332 n-Coumaroyltyramine C17H17NO3 Xiebai
MOL007650 PGA C20H32O4 Xiebai
MOL007651 Prostaglandin B1 C20H32O4 Xiebai
MOL001973 Sitosteryl acetate C31H52O2 Xiebai
MOL000483 (Z)-3-Acrylamide C19H18NO4 Xiebai
), ArticleFig(id=1218970801718611998, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=CN, label=Table 1, caption=

Information on main compounds in Gualou and Xiebai. (Z)-3-Acrylamide: (Z)-3-(4-Hydroxy-3-methoxy-phenyl)-N-[2-(4-hydroxyphenyl)ethyl]acrylamide

, figureFileSmall=null, figureFileBig=null, tableContent=
Mol ID Compound Molecular formula Source
MOL007165 10α-Cucurbita-5, 24-diene-3β-ol C30H50O Gualou
MOL007171 5-Dehydrokarounidiol C30H46O2 Gualou
MOL007172 7-oxo-Dihydrokaro-unidiol C30H48O3 Gualou
MOL002881 Diosmetin C16H12O6 Gualou
MOL005530 Hydroxygenkwanin C16H12O6 Gualou
MOL007179 Linolenic acid ethyl ester C20H34O2 Gualou
MOL001494 Mandenol C20H36O2 Gualou
MOL006756 Schottenol C29H50O Gualou
MOL004355 Spinasterol C29H48O Gualou
MOL007180 Vitamin-e C24H34N4O5S Gualou
MOL000098 Quercetin C15H10O7 Gualou
MOL006946 Adenosine C10H13N5O4 Gualou, Xiebai
MOL000358 Beta-sitosterol C29H50O Xiebai
MOL000631 Coumaroyltyramine C17H17NO3 Xiebai
MOL002341 Hesperetin C16H14O6 Xiebai
MOL007640 Macrostemonoside C27H44O3 Xiebai
MOL004328 Naringenin C15H12O5 Xiebai
MOL000332 n-Coumaroyltyramine C17H17NO3 Xiebai
MOL007650 PGA C20H32O4 Xiebai
MOL007651 Prostaglandin B1 C20H32O4 Xiebai
MOL001973 Sitosteryl acetate C31H52O2 Xiebai
MOL000483 (Z)-3-Acrylamide C19H18NO4 Xiebai
), ArticleFig(id=1218970801844441128, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No. PDBID Protein number Target name Protein class
1 2BIY O15530 PDPK1 Phosphoinositide-dependent protein kinase 1
2 1NSI P35228 NOS2 Nitric oxide synthase, inducible
3 1UKI P45983 MAPK8 Mitogen-activated protein kinase 8
4 1ZEO P37231 PPARG Peroxisome proliferator-activated receptor gamma
5 2GU8 P17612 PRKACA cAMP-dependent protein kinase catalytic subunit alpha
6 1A9U Q16539 MAPK14 Mitogen-activated protein kinase 14
7 1FT4 P19438 1FT4 Tumor necrosis factor receptor superfamily member 1A
8 1F3M Q13153 PAK1 Serine/threonine-protein kinase PAK 1
9 1TVO P28482 MAPK1 Mitogen-activated protein kinase 1
10 2AUH P06213 INSR Insulin receptor
11 2CYK P05112 IL4 Interleukin-4
12 1G0Y P14778 IL1R1 Interleukin-1 receptor type Ⅰ
13 1GMN P14210 HGF Hepatocyte growth factor
14 11GS P09211 GSTP1 Glutathione S-transferase P
15 1R0E P49841 GSK3B Glycogen synthase kinase-3 beta
16 1GFW P42574 CASP3 Caspase-3
17 1CTR P0DP23 CALM1 Calmodulin
18 3CQW P31749 AKT1 RAC-alpha serine/threonine-protein kinase
19 1OPL P00519 ABL1 Proto-oncogene tyrosine-protein kinase ABL1
20 2ILK P22301 IL10 Interleukin-10
21 2Z5X P21397 MAOA Amine oxidase [flavin-containing] A
22 3JDW P50440 GATM Glycine amidinotransferase, mitochondrial
3 1B2T P78423 CX3CL1 Fractalkine
24 1ICE P29466 CASP1 Caspase-1
25 1H0C P21549 AGXT Serine--pyruvate aminotransferase
26 2G1N P00797 REN Renin
27 1R4L Q9BYF1 ACE2 Angiotensin-converting enzyme 2
28 1CGH P08311 CTSG Cathepsin G
), ArticleFig(id=1218970802020601915, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=CN, label=Table 2, caption=

Main potential target information related to heart failure in Gualou and Xiebai

, figureFileSmall=null, figureFileBig=null, tableContent=
No. PDBID Protein number Target name Protein class
1 2BIY O15530 PDPK1 Phosphoinositide-dependent protein kinase 1
2 1NSI P35228 NOS2 Nitric oxide synthase, inducible
3 1UKI P45983 MAPK8 Mitogen-activated protein kinase 8
4 1ZEO P37231 PPARG Peroxisome proliferator-activated receptor gamma
5 2GU8 P17612 PRKACA cAMP-dependent protein kinase catalytic subunit alpha
6 1A9U Q16539 MAPK14 Mitogen-activated protein kinase 14
7 1FT4 P19438 1FT4 Tumor necrosis factor receptor superfamily member 1A
8 1F3M Q13153 PAK1 Serine/threonine-protein kinase PAK 1
9 1TVO P28482 MAPK1 Mitogen-activated protein kinase 1
10 2AUH P06213 INSR Insulin receptor
11 2CYK P05112 IL4 Interleukin-4
12 1G0Y P14778 IL1R1 Interleukin-1 receptor type Ⅰ
13 1GMN P14210 HGF Hepatocyte growth factor
14 11GS P09211 GSTP1 Glutathione S-transferase P
15 1R0E P49841 GSK3B Glycogen synthase kinase-3 beta
16 1GFW P42574 CASP3 Caspase-3
17 1CTR P0DP23 CALM1 Calmodulin
18 3CQW P31749 AKT1 RAC-alpha serine/threonine-protein kinase
19 1OPL P00519 ABL1 Proto-oncogene tyrosine-protein kinase ABL1
20 2ILK P22301 IL10 Interleukin-10
21 2Z5X P21397 MAOA Amine oxidase [flavin-containing] A
22 3JDW P50440 GATM Glycine amidinotransferase, mitochondrial
3 1B2T P78423 CX3CL1 Fractalkine
24 1ICE P29466 CASP1 Caspase-1
25 1H0C P21549 AGXT Serine--pyruvate aminotransferase
26 2G1N P00797 REN Renin
27 1R4L Q9BYF1 ACE2 Angiotensin-converting enzyme 2
28 1CGH P08311 CTSG Cathepsin G
), ArticleFig(id=1218970802133848134, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No. ID GO functional annotation Target number P-value
1 GO:0009725 Response to hormone stimulus 10 2.19e-8
2 GO:0007243 Protein kinase cascade 10 2.35e-8
3 GO:0009719 Response to endogenous stimulus 10 5.14e-8
4 GO:0007242 Intracellular signaling cascade 14 2.07e-7
5 GO:0006468 Protein amino acid phosphorylation 11 3.12e-7
6 GO:0044093 Positive regulation of molecular function 10 1.17e-6
7 GO:0016310 Phosphorylation 11 1.65e-6
8 GO:0042981 Regulation of apoptosis 11 1.73e-6
9 GO:0043067 Regulation of programmed cell death 11 1.90e-6
10 GO:0010941 Regulation of cell death 11 1.96e-6
11 GO:0070201 Regulation of establishment of protein localization 6 3.63e-6
12 GO:0043066 Negative regulation of apoptosis 8 4.47e-6
13 GO:0043069 Negative regulation of programmed cell death 8 4.90e-6
14 GO:0060548 Negative regulation of cell death 8 5.00e-6
15 GO:0051338 Regulation of transferase activity 8 6.20e-6
16 GO:0032880 Regulation of protein localization 6 6.92e-6
17 GO:0010627 Regulation of protein kinase cascade 7 7.83e-6
18 GO:0006796 Phosphate metabolic process 11 9.64e-6
19 GO:0043434 Response to peptide hormone stimulus 6 1.18e-5
20 GO:0050727 Regulation of inflammatory response 5 1.46e-5
), ArticleFig(id=1218970802310008923, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=CN, label=Table 3, caption=

GO biological process enrichment analysis of potential targets of active ingredients in Gualou and Xiebai

, figureFileSmall=null, figureFileBig=null, tableContent=
No. ID GO functional annotation Target number P-value
1 GO:0009725 Response to hormone stimulus 10 2.19e-8
2 GO:0007243 Protein kinase cascade 10 2.35e-8
3 GO:0009719 Response to endogenous stimulus 10 5.14e-8
4 GO:0007242 Intracellular signaling cascade 14 2.07e-7
5 GO:0006468 Protein amino acid phosphorylation 11 3.12e-7
6 GO:0044093 Positive regulation of molecular function 10 1.17e-6
7 GO:0016310 Phosphorylation 11 1.65e-6
8 GO:0042981 Regulation of apoptosis 11 1.73e-6
9 GO:0043067 Regulation of programmed cell death 11 1.90e-6
10 GO:0010941 Regulation of cell death 11 1.96e-6
11 GO:0070201 Regulation of establishment of protein localization 6 3.63e-6
12 GO:0043066 Negative regulation of apoptosis 8 4.47e-6
13 GO:0043069 Negative regulation of programmed cell death 8 4.90e-6
14 GO:0060548 Negative regulation of cell death 8 5.00e-6
15 GO:0051338 Regulation of transferase activity 8 6.20e-6
16 GO:0032880 Regulation of protein localization 6 6.92e-6
17 GO:0010627 Regulation of protein kinase cascade 7 7.83e-6
18 GO:0006796 Phosphate metabolic process 11 9.64e-6
19 GO:0043434 Response to peptide hormone stimulus 6 1.18e-5
20 GO:0050727 Regulation of inflammatory response 5 1.46e-5
), ArticleFig(id=1218970802490364018, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No. ID Pathway Target number P-value
1 hsa04910 Insulin signaling pathway 8 5.04e-5
2 hsa04660 T cell receptor signaling pathway 7 1.29e-4
3 hsa04722 Neurotrophin signaling pathway 7 2.71e-4
4 hsa04012 ErbB signaling pathway 6 4.20e-4
5 hsa05200 Pathways in cancer 10 5.31e-4
6 hsa04010 MAPK signaling pathway 9 6.41e-4
7 hsa04664 Fc epsilon RI signaling pathway 5 0.00254
8 hsa05210 Colorectal cancer 5 0.00333
9 hsa04510 Focal adhesion 7 0.00339
10 hsa04914 Apoptosis 5 0.00378
11 hsa05215 Prostate cancer 5 0.00411
12 hsa04912 GnRH signaling pathway 5 0.00579
13 hsa05213 Endometrial cancer 4 0.00661
14 hsa04614 Renin-angiotensin system 3 0.00689
15 hsa05014 Amyotrophic lateral sclerosis (ALS) 4 0.00697
16 hsa04621 NOD-like receptor signaling pathway 4 0.0107
17 hsa04062 Chemokine signaling pathway 6 0.0119
18 hsa05211 Renal cell carcinoma 4 0.0149
19 hsa00260 Glycine, serine and threonine metabolism 3 0.0221
20 hsa04960 Aldosterone-regulated sodium reabsorption 3 0.0371
21 hsa04620 Toll-like receptor signaling pathway 4 0.0388
22 hsa04930 Type Ⅱ diabetes mellitus 3 0.0476
), ArticleFig(id=1218970802712662160, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=CN, label=Table 4, caption=

KEGG signaling pathway enrichment analysis of potential anti-heart failure targets in Gualou and Xiebai

, figureFileSmall=null, figureFileBig=null, tableContent=
No. ID Pathway Target number P-value
1 hsa04910 Insulin signaling pathway 8 5.04e-5
2 hsa04660 T cell receptor signaling pathway 7 1.29e-4
3 hsa04722 Neurotrophin signaling pathway 7 2.71e-4
4 hsa04012 ErbB signaling pathway 6 4.20e-4
5 hsa05200 Pathways in cancer 10 5.31e-4
6 hsa04010 MAPK signaling pathway 9 6.41e-4
7 hsa04664 Fc epsilon RI signaling pathway 5 0.00254
8 hsa05210 Colorectal cancer 5 0.00333
9 hsa04510 Focal adhesion 7 0.00339
10 hsa04914 Apoptosis 5 0.00378
11 hsa05215 Prostate cancer 5 0.00411
12 hsa04912 GnRH signaling pathway 5 0.00579
13 hsa05213 Endometrial cancer 4 0.00661
14 hsa04614 Renin-angiotensin system 3 0.00689
15 hsa05014 Amyotrophic lateral sclerosis (ALS) 4 0.00697
16 hsa04621 NOD-like receptor signaling pathway 4 0.0107
17 hsa04062 Chemokine signaling pathway 6 0.0119
18 hsa05211 Renal cell carcinoma 4 0.0149
19 hsa00260 Glycine, serine and threonine metabolism 3 0.0221
20 hsa04960 Aldosterone-regulated sodium reabsorption 3 0.0371
21 hsa04620 Toll-like receptor signaling pathway 4 0.0388
22 hsa04930 Type Ⅱ diabetes mellitus 3 0.0476
), ArticleFig(id=1218970804063228065, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Group Apoptosis rate/%
Model group 35.74 ± 2.77
Gualou-Xiebai dropping pills group 22.71 ± 1.53*
Wortmannin group 36.81 ± 2.53#
Gualou-Xiebai dropping pills + wortmannin group 28.17 ± 2.35*#
Compound Danshen dropping pills group 18.87 ± 1.21*
), ArticleFig(id=1218970804235194541, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218551237289624009, language=CN, label=Table 5, caption=

Compare of each group myocardial apoptotic index. n = 6, $\overline{x}±s$. *P < 0.05 vs model group; #P < 0.05 vs Gualou Xiebai dropping pills group

, figureFileSmall=null, figureFileBig=null, tableContent=
Group Apoptosis rate/%
Model group 35.74 ± 2.77
Gualou-Xiebai dropping pills group 22.71 ± 1.53*
Wortmannin group 36.81 ± 2.53#
Gualou-Xiebai dropping pills + wortmannin group 28.17 ± 2.35*#
Compound Danshen dropping pills group 18.87 ± 1.21*
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基于网络药理学分析瓜蒌薤白配伍抗心力衰竭的作用机制研究
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邹纯才 1 , 鄢海燕 1, * , 魏美玲 2
药学学报 | 专题报道 2018,53(9): 1406-1413
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药学学报 | 专题报道 2018, 53(9): 1406-1413
基于网络药理学分析瓜蒌薤白配伍抗心力衰竭的作用机制研究
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邹纯才1, 鄢海燕1, * , 魏美玲2
作者信息
  • 1.皖南医学院药学院, 安徽 芜湖 241002
  • 2.安徽省第二人民医院药学部, 安徽 合肥 230041

通讯作者:

* 鄢海燕, Tel:86-533-3932185, E-mail:
Study of the anti-heart failure mechanisms of compatibility of Gualou with Xiebai in basis of network pharmacology
Chun-cai ZOU1, Hai-yan YAN1, * , Mei-ling WEI2
Affiliations
  • 1. Pharmacy School of Wannan Medical College, Wuhu 241002, China
  • 2. Pharmacy Department of Anhui No.2 Provincial People's Hospital, Hefei 230041, China
出版时间: 2018-09-15 doi: 10.16438/j.0513-4870.2018-0394
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摘要
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基于网络药理学预测及大鼠心肌缺血-再灌注损伤模型验证的方法，对瓜蒌薤白配伍抗心力衰竭的作用机制进行探讨。运用Traditional Chinese Medicine Database@Taiwan（TCM Database@Taiwan）、TraditionalChinese Medicine Systems Pharmacology Database and Analysis Platform（TCMSP）、Drug Repositioning and AdverseDrug Reaction Chemical-Protein Interactome（DRAR-CPI）、Universal Protein Resource（Uniprot）数据库进行化合物筛选及活性成分靶点预测，借助Database for Annotation，Visualization，and Integrated Discovery（DAVID）数据库进行生物途径和信号通路分析，预测瓜蒌薤白配伍的作用机制。考察瓜蒌薤白滴丸预处理对心肌缺血-再灌注损伤大鼠心肌细胞凋亡及相关信号通路磷脂酰肌醇3-激酶/丝氨酸苏氨酸激酶（phosphatidylinositol-3-kinase/proteinkinase B，PI3K/Akt）中Akt、磷酸化丝氨酸/苏氨酸激酶（phosphorylated protein kinase B，p-Akt）和半胱氨酸天冬氨酸蛋白酶-3（cysteine aspartate-specific proteinase，caspase-3）蛋白表达的影响。发现10α-cucurbita-5，24-diene-3β-ol和macrostemonoside等22个化合物通过多靶点、多生物途径及多通路方式协同抗心力衰竭，涉及激素刺激反应、磷酸化过程、细胞凋亡调控等生物学途径和胰岛素、丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）、细胞凋亡等信号通路。瓜蒌薤白滴丸预处理可通过激活PI3K-Akt信号通路，促进Akt蛋白磷酸化，降低caspase-3蛋白表达，发挥抑制细胞凋亡、保护心肌作用，验证了网络药理学结果，综合阐释了瓜蒌薤白配伍抗心力衰竭的作用机制。

瓜蒌薤白  /  配伍  /  心力衰竭  /  网络药理学  /  心肌缺血再灌注损伤

This study was designed to explore the anti heart failure mechanisms of the compatibility of Gualou with Xiebai based on network pharmacology in rat model of myocardial ischemia-reperfusion injury. Using the databases of Traditional Chinese Medicine Database@Taiwan (TCM Database@Taiwan), Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Drug Repositioning and Adverse Drug Reaction Chemical-Protein Interactome (DRAR-CPI) and Universal Protein Resource (Uniprot) to screen compounds and predict the target of active components, the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, we predicted the biological pathway and signal pathway in the compatibility of Gualou with Xiebai. The effects of Gualou Xiebai dropping pills on the apoptosis of myocardial cells and the expression of protein kinase B (Akt), p-Akt and cysteine aspartate-specific proteinase (caspase-3) protein were examined in the related signal pathway phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) of myocardial ischemia reperfusion injury in rats. Twenty two compounds, such as 10 α-cucurbita-5, 24-diene-3β-ol and macrostemonoside were found to protect rats from heart failure through multiple targets, multiple biological pathways and multiple pathways, involving biological pathways such as hormone stimulation reaction, phosphorylation, apoptosis regulation, and signaling pathways such as insulin, mitogen-activated protein kinase (MAPK), cell apoptosis and so on. After the intervention of Gualou Xiebai dropping pills, the PI3K-Akt signaling pathway was activated to promote the phosphorylation of Akt protein, reduce the expression of caspase-3 protein, inhibit apoptosis and protect the myocardium. The data verify the results of the network pharmacology, and explain the mechanisms of anti-heart failure activity of combination of Gualou with Xiebai.

Gualou-Xiebai  /  compatibility  /  heart failure  /  network pharmacology  /  myocardial ischemia reperfusion injury
邹纯才, 鄢海燕, 魏美玲. 基于网络药理学分析瓜蒌薤白配伍抗心力衰竭的作用机制研究. 药学学报, 2018 , 53 (9) : 1406 -1413 . DOI: 10.16438/j.0513-4870.2018-0394
Chun-cai ZOU, Hai-yan YAN, Mei-ling WEI. Study of the anti-heart failure mechanisms of compatibility of Gualou with Xiebai in basis of network pharmacology[J]. Acta Pharmaceutica Sinica, 2018 , 53 (9) : 1406 -1413 . DOI: 10.16438/j.0513-4870.2018-0394
正文
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瓜蒌为葫芦科植物栝楼(Trichosanthes kirilowii Maxim.)或双边栝楼(Trichosanthes rosthornii Harms.)的成熟果实[1], 主产于河南、河北、山东、安徽等地, 具宽胸散结之功效, 用于胸痹心痛等。薤白为百合科植物小根蒜(Allium macrostemon Bge.)或薤(Allium chinense G. Don)的干燥鳞茎[1], 具利水渗湿, 除痹之功效, 用于水肿、癌肿等。
瓜蒌薤白配伍使用源自于张仲景的《金匮要略·胸痹心痛短气病脉证治》篇, 用于胸痹心痛等。课题组前期对瓜蒌薤白配伍抗大鼠心肌缺血-再灌注损伤(myocardial ischemia reperfusion injury, MIRI)的药效学进行了研究, 发现瓜蒌薤白配伍可有效抑制MIRI大鼠心电图ST段的抬高, 降低大鼠肌酸激酶MB同工酶、肌红蛋白、心肌肌钙蛋白-T值(P < 0.05或P < 0.01), 改善心肌组织状况, 降低心肌梗死百分率(P < 0.01)[2]。研究表明心肌细胞凋亡对MIRI起主导作用, PI3K/Akt信号通路可能是调控细胞凋亡最重要的途径之一[3]。
因此, 本课题采用网络药理学方法[4, 5], 构建瓜蒌薤白配伍的化学成分-靶点蛋白-信号通路, 探讨瓜蒌薤白配伍的作用机制。在此基础上, 观察瓜蒌薤白滴丸预处理对急性心肌缺血-再灌注损伤大鼠心肌细胞凋亡及凋亡相关信号通路PI3K/Akt中蛋白表达的影响, 采用原位末端脱氧核苷酸转移酶标记(TdT-mediated dUTP nick-end labeling, TUNEL)法测定心肌细胞凋亡百分率, 蛋白质免疫印迹法测定Akt、p-Akt和caspase-3蛋白的表达。检测心肌缺血-再灌注损伤对大鼠心肌细胞凋亡及PI3K/Akt通路中蛋白表达的影响, 探讨PI3K信号通路特异性阻断剂渥曼青霉素(wortmannin)对瓜蒌薤白滴丸调控心肌细胞凋亡及蛋白表达的作用, 明确瓜蒌薤白配伍抗心力衰竭的作用机制。
材料与方法
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实验动物   SPF级Sprague Dawley (SD)大鼠, 雄性, 体重180~250 g, 由浙江省实验动物中心提供, 合格证号: SCXK (浙) 2008-0033。
药品与试剂   瓜蒌薤白滴丸(批号: 20140101, 皖南医学院药学院药物制剂及质量控制课题组提供); 凯基TUNEL细胞凋亡原位检测试剂盒(南京凯基生物科技发展有限公司, KGA7032);二喹啉甲酸 (bicinchoninic acid, BCA)蛋白测定试剂盒(武汉博士德生物工程有限公司, AR0146);超敏电化学发光(electro-chemiluminesence, ECL)试剂盒BeyoECL Plus (P0018)、caspase-3抗体(AC033)、phospho-Akt (Ser473)抗体(AA329-1)、Akt抗体(AA326)、tubulin抗体(AT819)、辣根过氧化物酶(horseradish peroxidase, HRP)标记山羊抗兔IgG (H+L) (A0208)、HRP标记山羊抗小鼠IgG (H+L) (A0216)、wortmannin (S1952) (碧云天生物技术研究所)。
仪器   HX-300小动物呼吸机、BL-420生物机能采集系统(成都泰盟软件有限公司); TE70X型半干转膜仪(美国Hoefer); Chemi Scope 3400化学发光成像系统(Clinx Science Instruments Co., Ltd); DYY-2C型电泳仪(北京六一仪器厂)。
数据库及分析软件   数据库主要包括TCM Database@Taiwan (http://tcm.cmu.edu.tw/)、TCMSP (http://lsp.nwsuaf.edu.cn/tcmsp.php)、DRAR-CPI (http://cpi.bio-x.cn/drar)、UniProt (http://www.uniprot.org/)、CooLGeN (http://ci.smu.edu.cn/CooLGeN/Home.php)、DAVID数据库(https://david.ncifcrf.gov/tools.jsp); 分析软件主要有ChemBioDrawUltta 14.0、Gephi0.9.2软件。
化学成分的筛选  通过检索TCM Database@ Taiwan、TCMSP数据库(检索日期为2018年3月18日), 筛选出符合口服生物利用度(oral bioavailability, OB)≥30%、类药性(drug like, DL)≥0. 18的化合物21个。腺苷(adenosine)的OB为15.98%, DL为0.18, 该化合物为已知瓜蒌薤白中的药效成分[6], 因此共获得22个化合物, 见表 1。所有化合物分子结构式采用ChemBioDrawUltta 14.0软件进行绘制, 结果保存为MDL SDfile (*.sdf)文件格式备用。
潜在靶点的预测  登陆DRAR-CPI数据库分别上传表 1中各成分sdf格式文件(数据上传日期为2018年3月18日, 完成日期为2018年4月2日), 选择Z'-score < -1筛选蛋白靶点并将PDB ID导入UniProt数据库, 获得瓜蒌薤白中各成分的基因靶点(检索日期为2018年4月3日)。
心力衰竭相关的靶标蛋白质的收集  通过CooLGeN数据库, 以“heart failure”为关键词, 捜索Medline及GeneRIF数据库, 收集与心力衰竭相关的靶点蛋白(检索日期为2018年4月5日)。
生物功能及靶点通路注释分析  将靶点蛋白复制至DAVID数据库的列表中, 选择标示符为official_gene_symbol, 物种注释为homo sapiens, 进行GOTERM_BP_DIRECT富集分析和Kyoto Ency_clopedia of Genes and Genomes (KEGG)_PATHWAY通路注释分析(检索日期为2018年4月6日)。
成分-蛋白靶点-信号通路网络分析和构建  根据预测结果, 使用Gephi软件将筛选出来的活性成分、靶点蛋白和作用通路构建成分-靶点蛋白-信号通路网络。
动物分组及给药  SPF级SD大鼠随机分为6组, 每组6只, 假手术组、模型组、wortmannin组分别给予生理盐水, 瓜蒌薤白滴丸组22.5 g·kg-1, 瓜蒌薤白滴丸22.5 g·kg-1和wortmannin合用组, 复方丹参滴丸组85.05 mg·kg-1, 每天1次, 灌胃, 灌胃体积3 mL·kg-1。造模前15 min, wortmannin组及wortmannin合用组腹腔注射wortmannin 15 μg·kg-1, 其余各组腹腔注射生理盐水, 注射体积5 mL·kg-1。
MIRI动物模型制备   将大鼠腹腔注射10%水合氯醛(3 mL·kg-1)麻醉, 气管插管, 监测心电图变化, 左冠状动脉结扎30 min后解结扎再灌注120 min。再灌注结束后, 于左心室取血并置于含乙二胺四乙酸二钠抗凝剂的取血管中, 制备血浆置于-80 ℃冰箱, 备用; 同时取心脏并于心尖处分两部分, 分别置于-80 ℃冷冻和用4%多聚甲醛溶液固定24~48 h, 备用。
心肌细胞凋亡测定   取出4%多聚甲醛固定心脏, 采用TUNEL法检测大鼠心肌细胞的凋亡指数。凋亡指数(apoptosis index, AI), 即心肌细胞凋亡率= (凋亡心肌细胞数/心肌细胞总数)×100%[7]。
心肌组织蛋白提取及Western blot法分析   取-80 ℃保存的心脏, 称重并匀浆。按心脏重量(g) :裂解液(mL)= 1:10加入RIPA裂解液, 混匀, 冰上孵育至完全裂解, 13 000 ×g离心5 min, 取上清液即为蛋白样品。用BCA蛋白定量试剂盒计算各样品蛋白浓度。用聚丙烯酰胺凝胶电泳分离蛋白样品, 半干式转膜法转膜, 将转好的PVDF膜用BSA封闭后进行抗体孵育, 一抗、二抗分别为小鼠抗兔单克隆抗体、HRP标记的羊抗兔IgG; ECL自显影; 凝胶成像系统拍照观察Akt、p-Akt、caspase-3蛋白的表达情况[5]。
统计学分析   应用SPSS 13.0软件进行统计分析, 各统计指标以均数±标准差($\overline{x}±s$)表示, 两组间比较用t检验。P < 0.05为差异有统计学意义, P < 0.01为差异有显著统计学意义。
结果
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1 靶点的预测
通过DRAR-CPI数据库共得到324个靶点蛋白, 其中与Medline及GeneRIF数据库中心力衰竭相匹配的靶点蛋白有56个, 将56个靶点蛋白复制至DAVID数据库的列表中, 获得KEGG_PATHWAY通路注释分析结果, 与P < 0.05的注释通路相对应的靶点蛋白有28个, 见表 2。
2 靶点生物功能分析
Gene ontology (GO)生物功能分析是指从生物功能上对基因产物进行标准化描述, 对基因产物进行注释, 通过GO富集分析可以了解差异基因富集的生物学功能。将28个靶点蛋白复制至DAVID数据库的列表中, 获得GOTERM_BP_DIRECT富集分析结果, 按P值大小排序, 前20个GO生物功能结果见表 3。生物学过程与激素刺激反应(response to hormone stimulus)、磷酸化(phosphorylation)和细胞凋亡调控(regulation of apoptosis)等相关性大。
3 靶点信号通路分析
为进一步明确28个靶点蛋白的生物学功能, 通过对信号通路进行富集分析, 可知与心力衰竭相关的通路, 包括胰岛素信号通路(insulin signaling pathway)、MAPK信号通路(MAPK signaling pathway)、细胞凋亡(apoptosis)等, P < 0.05的信号通路富集结果, 见表 4。
4 活性成分-靶点蛋白-信号通路网络分析和构建
使用Gephi软件将筛选出来的22个瓜蒌薤白中的活性成分、28个靶点蛋白和22条信号通路构建活性成分-靶点蛋白-信号通路网络(图 1)。瓜蒌薤白中的活性成分和靶点蛋白、作用通路间存在复杂的网络关系, 瓜蒌薤白中活性成分可作用于不同的靶点蛋白, 借助不同的信号通路发挥作用。
在各信号途径中, PI3K/Akt信号通路参与多个信号途径, 如细胞凋亡、趋化因子信号通路、结肠直肠癌、子宫内膜癌、ErbB信号通路、Fc-ε受体RI信号通路、黏着斑、胶质瘤、胰岛素信号通路、黑色素瘤、mTOR信号通路、神经营养素信号通路、非小细胞肺癌、癌症通路、孕酮介导的卵母细胞成熟、前列腺癌、T细胞受体信号通路、Toll样受体信号通路等。为此, 选择细胞凋亡途径中的PI3K/Akt信号通路进行生物学验证, 考察瓜蒌薤白滴丸预处理对心肌缺血-再灌注损伤大鼠心肌细胞凋亡及凋亡相关信号通路PI3K/Akt中蛋白表达的影响。
5 瓜蒌薤白滴丸对大鼠心肌缺血再灌注心肌组织细胞凋亡的影响
按心肌细胞凋亡测定方法处理, 检测大鼠心肌细胞的凋亡指数。结果见图 2。统计各组凋亡指数, 结果见表 5。
与模型组比较, wortmannin组心肌细胞凋亡指数差异无统计学意义, 瓜蒌薤白滴丸心肌细胞凋亡指数显著减少(P < 0.01);与瓜蒌薤白滴丸组比较, 瓜蒌薤白滴丸与wortmannin合用组心肌细胞凋亡指数增加(P < 0.01)。
6 瓜蒌薤白滴丸对大鼠缺血再灌注心肌PI3K/Akt信号通路影响
观察各组大鼠心肌缺血再灌注后caspase-3、Akt、p-Akt表达(图 3), 与假手术组比较, 模型组caspase-3的活性明显升高(P < 0.05), 提示造模成功; 与模型组比较, wortmannin组caspase-3和p-Akt/Akt表达无明显差异, 说明wortmannin对caspase-3、Akt、p-Akt表达的影响可忽略; 与模型组比较, 瓜蒌薤白滴丸组能显著抑制caspase-3的活性(P < 0.01), 激活PI3K/Akt磷酸化过程, 上调p-Akt蛋白表达水平; 与瓜蒌薤白滴丸组比较, 瓜蒌薤白滴丸与wortmannin合用组p-Akt/Akt值显著减小(P < 0.01), 提示wortmannin能阻断Akt蛋白的磷酸化过程, 抑制PI3K/Akt信号通路的激活, 促进细胞凋亡。
讨论
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本研究借助DRAR-CPI及DAVID等数据库, 对瓜蒌薤白中22个化合物进行网络药理学分析, 发现10α-cucurbita-5, 24-diene-3β-ol和macrostemonoside等22个化合物通过多靶点、多生物途径及多通路方式协同抗心力衰竭, 涉及激素刺激反应、磷酸化、细胞凋亡调控等生物学途径和胰岛素、MAPK、细胞凋亡等信号通路, 部分功能已有文献报道, 如瓜蒌薤白通过3种MAPKs信号通路参与抗大鼠急性心肌缺血所致的心肌损伤[8];瓜蒌薤白煎液通过抑制大鼠被激活的p38、c-Jun氨基末端激酶信号通路, 降低心肌损伤, 磷酸化过程有着重要的作用[9];此外, 瓜蒌薤白汤通过下调Fas/Fas-L的表达对抗异丙肾上腺素诱导的心肌细胞凋亡[10];通过小鼠离体MIRI模型实验证明, 瓜蒌薤白白酒汤可通过促进Akt/糖原合成酶激酶-3β磷酸化、增加Bcl-2/Bax比值、下调cleaved-caspase-3表达而抑制心肌细胞凋亡等[11]。
细胞凋亡是心肌缺血再灌注损伤的主要细胞死亡形式, 有多种基因参与。通过本文网络药理学研究可知, 瓜蒌薤白中5-dehydrokarounidiol、7-oxo- dihydrokaro-unidiol、quercetin (来自瓜蒌)及sitosteryl acetate (来自薤白) 4种成分通过调控Akt1、TNFRSF1A、IL1R1、CASP3和PRKACA等基因参与细胞凋亡过程。其中caspase-3 (CASP3)是半胱氨酸天冬氨酸蛋白酶家族中最重要的成员之一, 是细胞凋亡及级联反应的必经之路[12]。PI3K/Akt信号通路是抑制细胞凋亡的重要信号通路[13], Akt的磷酸化程度非常关键[14], 活化的Akt可激活下游靶点, 抑制CASP3导致的细胞凋亡[15]。特异性信号通路阻断剂wortmannin可抑制PI3K/Akt的磷酸化过程。
本实验结果显示, 与模型组相比, wortmannin对心肌细胞凋亡水平的影响无统计学意义, 瓜蒌薤白滴丸组可降低心肌细胞凋亡指数(P < 0.01)。与瓜蒌薤白滴丸组相比, 瓜蒌薤白滴丸与wortmannin合用组凋亡指数增加(P < 0.01), 说明wortmannin能抑制瓜蒌薤白滴丸抗心肌细胞凋亡作用。瓜蒌薤白滴丸能有效抑制大鼠急性心肌缺血-再灌注损伤时心肌中CASP3蛋白的表达, 促进Akt蛋白的磷酸化。综上, 瓜蒌薤白配伍可通过细胞凋亡调控和磷酸化等生物学途径发挥抗心力衰竭作用, 进一步验证了网络药理学的预测结果, 对于下一步深入研究瓜蒌薤白配伍抗心力衰竭的作用机制具有重要意义。
基金
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  • 安徽高校省级自然科学研究重大项目(KJ2015ZD41)
  • 安徽高校省级自然科学研究重大项目(KJ2016SD60)
文献
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参考文献 引证文献
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2018年第53卷第9期
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doi: 10.16438/j.0513-4870.2018-0394
  • 接收时间：2018-04-27
  • 首发时间：2026-01-15
  • 出版时间：2018-09-15
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  • 收稿日期：2018-04-27
  • 修回日期：2018-06-03
基金
安徽高校省级自然科学研究重大项目(KJ2015ZD41)
安徽高校省级自然科学研究重大项目(KJ2016SD60)
作者信息
    1.皖南医学院药学院, 安徽 芜湖 241002
    2.安徽省第二人民医院药学部, 安徽 合肥 230041

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2种不同金属材料的力学参数
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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
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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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