Study on the mechanism of qingre huoxue prescription in the intervention and treatment of acute myocardial infarction based on network pharmacology

Abstract

Objective: The objective is to study the mechanism of Qingre Huoxue prescription in the intervention and treatment of acute myocardial infarction (AMI) based on the method of network pharmacology. Materials and Methods: Five databases were used to screen the chemical compounds and targets of Ligusticum wallichii (chuanxiong), Radix Paeoniae Rubra (chishao), Lignum acronychiae (jiangxiang), Safflower (honghua), Salvia miltiorrhiza (danshen), Scutellaria baicalensis (huangqin), and Ilex pubescens (mao dong qing) in Qingre Huoxue prescription. Furthermore, Cytoscape-V3.2.1 software was used to construct the drug-component-target network. Functional protein association networks' database and the Database for Annotation, Visualization, and Integrated Discovery (DAVID) were used to visualize the protein interaction, pathway enrichment, and analysis. Results: A total of 44 active ingredients were screened out in Qingre Huoxue prescription. Among them, 178 targets and 41 compounds related to Qingre Huoxue prescription's function in treating AMI were obtained. After the analysis of the drug-component-action target network on Qingre Huoxue prescription, 14 key compounds and nine key targets with three scores above average were obtained. In addition, pathway enrichment and biological processes were conducted with the aid of the DAVID; and 8 related pathways and 10 biological processes were associated with AMI and related diseases; the PI3K-AKT signaling pathway, MAPK signaling pathway, and HIF-1 signaling pathway are the main pathways of Qingre Huoxue prescription for the treatment of AMI and related diseases. Conclusion: Qingre Huoxue prescription could treat AMI by multiple components, targets, and pathways. This study provides ideas and theoretical basis for further clinical studies on Qingre Huoxue prescription in treating AMI.

Full text

World J Tradit Chin Med | Volume 5 | Issue 4 | October-December 2019
220
Original Article
IntroductIon
In recent years, the incidence of cardiovascular disease in
China was increasing year by year. The number of patients
with coronary heart disease is over 1 million every year in
China,whichseriouslyaectsthenormallivingstandards
of people. Acute myocardial infarction (AMI) is a common
cardiovascular disease. It could cause harm in a short period
and lead to death in severe cases.[1] AMI is an acute myocardial
necrosis caused by myocardial ischemia and hypoxia
induced by coronary artery disease. Some studies have
shownthatAMIiscloselyrelatedto plaque inammation.
Animal experiments have proved that the use of traditional
Chinesemedicine(TCM) with eect of clearing heat and
activating blood circulation could suppress the occurrence
and development of plaque.[2-4]
Qingre Huoxue prescription is composed of Ligusticum
wallichii(chuanxiong,10 g); Radix Paeoniae Rubra
Study on the Mechanism of Qingre Huoxue Prescription in
the Intervention and Treatment of Acute Myocardial Infarction
Based on Network Pharmacology
Cai‑Xia Jiaa, Jin‑Ping Wanga, Fei‑Long Zhanga, Xiao‑Han Panga, Wei‑Lu Wanga, Paulin‑Xue Xub, Kuo Gaoc, Jian‑Xin Chena
aPharmacology Major of Integrated Traditional Chinese and Western Medicine, School of Preclinical Medicine, Beijing University of Chinese Medicine, cScientific Research
and Experiment Center, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China, bHarvard Medical School, 25 Shattuck Street Boston, MA 02115, USA
Objective:TheobjectiveistostudythemechanismofQingreHuoxueprescriptionin theinterventionandtreatmentofacutemyocardial
infarction (AMI) based on the method of network pharmacology. Materials and Methods:Fivedatabaseswereusedtoscreen the
chemicalcompoundsandtargetsofLigusticumwallichii(chuanxiong),RadixPaeoniaeRubra(chishao),Lignumacronychiae(jiangxiang),
Saower(honghua),Salvia miltiorrhiza (danshen), Scutellaria baicalensis (huangqin), and Ilex pubescens (mao dong qing) in Qingre Huoxue
prescription.Furthermore,Cytoscape‑V3.2.1softwarewasusedtoconstructthedrug‑component‑targetnetwork.Functionalproteinassociation
networks’ database and the Database for Annotation, Visualization, and Integrated Discovery (DAVID) were used to visualize the protein
interaction, pathway enrichment, and analysis. Results: A total of 44 active ingredients were screened out in Qingre Huoxue prescription.
Among them, 178 targets and 41 compounds related to Qingre Huoxue prescription’s function in treating AMI were obtained. After the analysis
of the drug-component-action target network on Qingre Huoxue prescription, 14 key compounds and nine key targets with three scores above
average were obtained. In addition, pathway enrichment and biological processes were conducted with the aid of the DAVID; and 8 related
pathwaysand10biologicalprocesseswereassociatedwithAMIandrelateddiseases;thePI3K‑AKTsignalingpathway,MAPKsignaling
pathway,andHIF‑1signalingpathwayarethemainpathwaysofQingreHuoxueprescriptionforthetreatmentofAMIandrelateddiseases.
Conclusion: Qingre Huoxue prescription could treat AMI by multiple components, targets, and pathways. This study provides ideas and
theoretical basis for further clinical studies on Qingre Huoxue prescription in treating AMI.
Keywords: Acute myocardial infarction, mechanism, network pharmacology, Qingre Huoxue prescription
Address for correspondence: Dr. Kuo Gao,
Scientific Research and Experiment Center, Dongfang Hospital,
Beijing University of Chinese Medicine, Beijing, China.
E‑mail: 515123134@qq.com
Dr. Jian‑Xin Chen,
Pharmacology Major of Integrated Traditional Chinese and Western
Medicine, School of Preclinical Medicine, Beijing University of Chinese
Medicine, Beijing, China.
E‑mail: cjx@bucm.edu.cn
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DOI:
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Abstract
How to cite this article: JiaCX,WangJP,ZhangFL,PangXH,WangWL,
XuPX,et al. Study on the mechanism of qingre huoxue prescription in the
intervention and treatment of acute myocardial infarction based on network
pharmacology. World J Tradit Chin Med 2019;5:220-7.
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Received: 09-11-2018, Revised: 29-03-2019,
Accepted: 08-04-2019, Published: 03-12-2019
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Jia, et al. Study on the mechanism of Qingre Huoxue Prescription in AMI
World J Tradit Chin Med | Volume 5 | Issue 4 | October-December 2019 221
(chishao,12g);Lignum acronychiae (jiangxiang, 10 g);
Saower(honghua,10g);Salvia miltiorrhiza (danshen, 30 g);
S. baicalensis (huangqin, 15 g); and Ilex pubescens (mao dong
qing, 30 g).[5] Among them, Ligusticum wallichii is warm
natured, which could activate blood and circulation of qi, expel
wind,andalleviatepain;RadixPaeoniaeRubraiscold‑natured,
which could clear heat and cool blood as well as dispel stasis
and alleviate pain; Lignum acronychiae is warm-natured, which
could not only dispel blood stasis and stanch bleeding but also
regulateqitoalleviatepain;Saoweriswarm‑natured,which
could activate blood to regulate menstruation and dispel stasis to
relieve pain; Salvia miltiorrhiza is slightly cold-natured, which
could activate blood and dispel stasis, regulate menstruation and
relieve dysmenorrhea, and cool blood and eliminate carbuncle;
S. baicalensis is bitter and cold-natured, which could clear heat
anddampness,purgereandresolvetoxin,andrelievepainand
tranquilize mind;[6] Ilex pubescens is slightly cold-natured, which
could activate blood circulation, clear heat and resolve toxin,
and disperse swelling and relieve pain.[7] Wu et al.[5] collected
60 patients with AMI and treated them with routine western
medicine and add Qingre Huoxue prescription; in addition, it
was found that Qingre Huoxue prescription could improve the
level of proof factors in vivo and the score of clinical syndromes
compared with routine treatment alone. However, there are many
herbs and complex chemical components in this prescription.
The mechanism of multi-target and multi-channel treatment for
AMIofcoronaryheartdiseasestillneedsfurtherclarication.
Network pharmacology integrates multi-disciplinary techniques
and methods’ it explores the relationship between drugs and
diseases from the whole and is consistent with the overall
concept of TCM.[8]
This paper adopts the method of network pharmacology
to study the mechanism of Qingre Huoxue prescription in
treating AMI of coronary heart disease, aiming to provide
more information and ideas for the clinical treatment of AMI
of coronary heart disease.
materIals and methods
Selection of objective compounds from Qingre Huoxue
prescription
Qingre Huoxue prescription consists of Ligusticum wallichii,
RadixPaeoniaeRubra,Lignumacronychiae,Saower,Salvia
miltiorrhiza, S. baicalensis, and Ilex pubescens. TCM Systems
PharmacologyDatabaseandAnalysisPlatform(TCMSP
database, http://lsp.nwu.edu.cn/tcmsp.php) and literature were
used to collect chemical constituents;, the names of TCMs,
such as “chuanxiong,” “chishao,” and “honghua” were input
intheTCMSPdatabase.LiteraturesearchmadeuseofCNKI
andPubMedtosearcharticlesonsevenTCMs;thoseKeyword
Advertisingswere“chuanxiong,chishao,jiangxiang,honghua,
danshen, huangqin, mao dong qing,” “Ligusticum wallichii,
RadixPaeoniaeRubra,Lignumacronychiae, Safflower,
Salvia miltiorrhiza, S. baicalensis, and Ilex pubescens” and
then obtained relevant ingredients of TCM according to the
contents and inquired whether the obtained ingredients were
related to AMI and related diseases. According to other reports,
chemical constituents were selected under the conditions
of drug-likeness (DL) >0.18 and oral bioavailability (OB)
>30%.[9] Compounds that are inconsistent with OB and DL
conditions were retained because these compounds have been
reportedtohaveimportanteectsoncardiovasculardiseases
such as AMI. After obtaining seven alternative compounds
ofTCM, PubChemdatabasewasused tofurtherscreenthe
compoundswithexperimentalvericationtargetsforreserve.
The acquisition of Qingre Huoxue prescription targets and
related targets of acute myocardial infarction
PubChemdatabasewasusedtoquerythetargetinformation
of compounds screened in the previous step, and active targets
were selected. Gene names corresponding to each target
proteinwereobtained in UniProt database (https://www.
uniprot.org/).Unlesshumantargetswereexcluded,UniProt
numbers corresponding to the target were recorded. Drugbank
database (https://www.drugbank.ca/), Online Mendelian
Inheritance in Man database (OMIM, http://www.omim.org/)
and GeneCards database (The Human Gene Database, https://
www.genecards.org/) were used to search related targets of
AMI and to delete duplication. And then, these targets related
to acute myocardial infarction were mapped with the targets
ofQingreHuoxue Prescription, targets of Qingre Huoxue
PrescriptionintreatingAMIwereobtainednally.
Network construction and analysis
The obtained targets were processed with Cytoscape-V3.2.1
software, and the network diagram of TCM component target
was obtained through the Merge function. In addition, the
functional protein association networks’ database (String
database) was used for the construction of protein mutual
network.
Kyoto Encyclopedia of Genes and Genomes pathway
enrichment and gene ontology biological process analysis
Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway
enrichment and gene ontology (GO) biological analysis
were conducted through using The Database for Annotation,
Visualization, and Integrated Discovery (DAVID database),
to predict the mechanism of Qingre Huoxue prescription in
the treatment of AMI.
results
Selection of objective compounds from Qingre Huoxue
prescription
DL refers to the similarity between compound molecules and
known drug molecules, which integrates pharmacokinetics and
safetyandhas agreatinuenceonpharmacology research.
At the same time, oral availability (OB) is an important
parameter for drugs entering the circulatory system through
oraladministration,andithasimportantguidingsignicance
for drug research and development.[10] The chemical
constituents were screened under the conditions of DL >0.18
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Jia, et al. Study on the mechanism of Qingre Huoxue Prescription in AMI
World J Tradit Chin Med | Volume 5 | Issue 4 | October-December 2019
222
andOB>30%.ThroughthescreeningofTCMSP,superadd
literature,andPubChem, a total of 53 compounds were
obtained (The duplication between the herbs is not removed).
After removing duplication, 44 compounds were obtained, as
shown in Figure 1. Among the compounds collected, luteolin,
beta sterols, baicalin, and others appeared in a variety of
medicinal materials with extensive pharmacological activities.
The acquisition of Qingre Huoxue prescription targets and
related targets of acute myocardial infarction
PubChemdatabasewasusedtosearchtargetinformationof
compounds screened from Qingre Huoxue prescription and to
selectactivetargets.Forcompoundssharingatarget,removing
duplicates, and retaining only one, then 29 targets related to
Ligusticumwallichii,190 targetsrelatedto RadixPaeoniae
Rubra, 37 targets related to Lignum acronychiae, 154 targets
relatedtoSaower,173targetsrelatedtoS. miltiorrhiza,
154 targets related to S. baicalensis, and 69 targets related
to Ilex pubescens were obtained. Combining the targets of
all compounds, 409 targets were obtained after removal of
duplication. Drugbank database, OMIM, and Genecards
database were used to search acute myocardial infarct-related
targets; a total of 2661 targets of AMI were obtained after
removing duplicates. By mapping the targets corresponding
to Qingre Huoxue prescription, 178 targets and 41 compounds
related to Qingre Huoxue prescription in treating AMI were
obtained as shown in Table 1.
Network construction and analysis
CytoscapeV3.2.1(U.S. National Institute of General Medical
Sciences (NIGMS)) was used to construct the drug component
action-target network of Qingre Huoxue prescription, as shown
in Figure2.Thegreensquaresrepresentveherbs,theorange
rhomboids represent 41 compounds, and the yellow circles
represent 178 targets. Based on the Cytoscape-V3.2.1 network
analysis data, compounds and targets were screened according
to degrees of freedom, median centrality, and tight centrality,
and 14 key compounds and 9 key targets with three scores
above average were obtained at last (shows a large scale),
and most of these were from S. miltiorrhizaandSaoweras
shown in Tables 2 and 3.
The String database could be used to search known interactions
between proteins and to predict direct interactions between
Figure 1: Objective active compounds of Qingre Huoxue prescription
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Jia, et al. Study on the mechanism of Qingre Huoxue Prescription in AMI
World J Tradit Chin Med | Volume 5 | Issue 4 | October-December 2019 223
proteins. We used String database to construct protein interaction
network for the treatment of AMI targets about Qingre Huoxue
prescription excluding nonhuman targets, as shown in Figure 2.
The top three of these compounds in terms of degrees of
freedom were ellagic acid, luteolin, and chrysin. Ellagic acid
has been reported to be able to prevent dietary atherosclerosis
in wild-type mice,[11]luteolincouldsignicantlyimprove
cardiac function and reduce the release of myocardial enzymes
andinammatorycytokinesaftermyocardialinfarction,[12] and
chrysinisanaturalavonoidthatcouldreduceinfarctsizeand
alleviateinammationandoxidativestressinmiceafteracute
ischemic stroke.[13]
Among these nine key targets screened out according to degrees
of freedom, median centrality, and tight centrality, androgen
receptor (AR) is widely presented in the cardiovascular
and cerebrovascular system. Studies have shown that bone
marrow mesenchymal stem cells (bm-mscs) could improve
the cardiac function of AMI, and bm-mscs also have ARs.[14,15]
Aldose reductase (gene AKR1B1) exists in nerve, heart,
and other tissues. Inhibiting aldose reductase can improve
the energy supply of ischemic myocardium and can reduce
ischemicinjuryofmyocardium.[16] Glycogen synthase
kinase-3 (GSK-3) beta belongs to the highly conserved
serine/threonine phosphokinase family and it plays a key role in
the cardiovascular system. Many myocardial protective drugs
arenallyfocusingonthetargetofGSK‑3throughavarietyof
signaling pathways, which could increase the phosphorylation
ofSer9,reducemPTPopeningtoprotectthemyocardium,and
aectthedierentiationofstemcellsintocardiacmyocytes.[17]
The treatment of AMI by Qingre Huoxue prescription may
be related to the inhibited expression of aldose reductase,
increased expression of AR, and overexpression of GSK-3 of
themyocardialstemcellsaboutdierentiatemyocardialcells
to repair damaged cardiac tissue, thereby improving cardiac
function.
The String database could be used to search for known
interactions between proteins and to predict direct interactions
between proteins. We used String database to construct protein
interaction network for the treatment of AMI targets with
Qingre Huoxue prescription excluding nonhuman targets,
as shown in Figure 3. In the network, nodes with a high
degree of values play important roles in the connection of the
network,theMAPTgenerankedtherstindegreeandplays
animportantroleintheMAPKsignalingpathway,andMAPK
inhibitors could inhibit endoplasmic reticulum stress and could
reduce myocardial apoptosis.
Enrichment of Kyoto Encyclopedia of Genes and Genomes
pathway and biological process analysis of gene ontology
KEGG pathway enrichment and GO bioassay were conducted
through using DAVID database; a total of 115 pathways
were enriched by KEGG pathway. According to P < 0.05
and literature screening, eight KEGG pathways and 10
biological pathways were associated with AMI and related
diseases, as shown in Figure 4a and b. The numbers in
Figure 4a and b represent the number of predicted targets
enriched in this pathway. That is to say, the target of TCM
ingredients may play a role in the pathways.
As can be seen from Figure4aandb,thePI3K‑AKT
signalingpathway,MAPKsignalingpathway,HIF‑1signaling
Table 1: 178 targets and 41 compounds related to
Qingre Huoxue prescription in treating acute myocardial
infarction
41 compounds AMI infarction‑related targets
Esculetin ITGB1;MMP1;TRPA1;IGF1R
Hydroquinone TEK;INSR;MET;EGFR
Scopoletin KDR;CCND1;PDGFRB;tat
Homovanillicacid BRAF;EPHB4;Lyn;PLK4
Formononetin PTK2;AKT1;CDK2;CCNA2
Beta-sitosterol HBB;MAPK1;EPHX2;GSR
Naringenin Dusp6;HSPA8;EIF4G1;PPP1CA
Isoliquiritigenin GRK2;ACP1;IL1B;F2
Baicalein lrp6;IL2;Ppara;Tnfsf11
Acacetin PIM1;BCHE;Plcg1;Prkaa2
Ent-epicatechin CHRM1;ADAM10;ADAM17;P4HB
Epiberberine TTR;Top1;MMP12;TNKS2
Oroxylin a Slc6a3; Adora1; TNKS; WRN
Wogonin MMP2;PARP1;SYK;MMP9
Chrysin MMP13;ALOX15B;MMP3;DAPK1
Quercetagetin RAPGEF3;MAPK10;FXN;PNLIP
Kaempferol JUN; CES1; STAT3; ACHE
Luteolin PTPN11;PTPN1;PTPRC;STAT1
Quercetin Kcnj2;MAPK13;MAPK14;EZH2
Rutin TERT;CASP9;MDM2;Ppp1r15a
Cryptotanshinone DNMT1;SRC;cacna1c;CYP1B1
Danshenola CYP1A1;CYP3A4;SMAD3;CYP2D6
DihydrotanshinoneⅠXDH;CYP2C19;AR;NR3C1
Isoimperatorin CASP3;CDK9;SMARCA2;ALOX5
Miltirone ⅡRELA;TP53;UGT1A1;CYP2C9
Miltirone MAPT;BLM;FEN1;GAPDH
Przewaquinonee MGAM; ABL1; EGLN1; ALOX12
Sclareol DPP4;GSK3B;PTGS1;BACE1
Tanshinone IIa OPRK1;OPRM1;OPRD1;POLB
Danshenol b BCL2L1; JAK2; Trpc4; Trpc6
Salvianolic acid a APAF1;FLT3;Ptgs2;Nos2
Tanshinone ii a sodium
sulfonate
Gabra3; MAOB; ABCG2; CDK5R1
Tanshinone i CDK1; CCNB1; AKR1B1; ABCB1
Sitosterol HDAC9; ESR1; NR1I2; TYR
Chlorogenic acid PPARG;NR1H4;VDR;CYBB
Caeicacid ESR2; DLD; DRD1; GAA
Ligustilide RUNX1;UHRF1;RGS8;PLA2G7
Ellagic acid TPM1;TNNI3;TNNT2;TNNC1
(+)‑Catechin AHR; CA2; CA3; CXCL8
Arbutin CYP19A1;ESRRA;GLI3;GLS
Ethyl gallate HIF1A;HTT;NFE2L2;NFKB1
RORC;THPO;ALOX15;PTGER2
CA9;CYP1A2;ERAP1;GNAI1
IMPA1;NOD2;RGS12;RIPK2
HSP90AA1;HSP90AB1
AMI: Acute myocardial infarction
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Jia, et al. Study on the mechanism of Qingre Huoxue Prescription in AMI
World J Tradit Chin Med | Volume 5 | Issue 4 | October-December 2019
224
pathway, and other pathways are the main pathways for the
treatment of AMI and related diseases by Qingre Huoxue
prescription. Biological processes involve cellular response
to hypoxia and positive regulation of angiogenesis, etc.,
Studieshaveshown that PI3K‑AKT signaling pathway
plays a role in promoting angiogenesis and in improving
cardiac function after myocardial infarction was activated.
Vascularendothelialgrowthfactor(VEGF)isanimportant
regulatorofneovascularization.Itcouldeectivelypromote
ischemicmyocardialcollateralcirculation,increaseVEGF
expression, and promote angiogenesis.[18] In the Qingre
Huoxueprescription,27targetswereinvolvedinPI3K‑AKT
signaling pathway, which is the highest. It plays a role in
promoting angiogenesis after myocardial infarction and
in improving cardiac function after activation, and it is
an important signaling regulation pathway in platelet
activation.[19,20]Plateletactivationpathwayplaysaregulatory
roleintheprocess of Platelet adhesion and aggregation.
In the biological process of GO, positive regulation of
angiogenesis also indicated that the treatment of AMI with
Qingre Huoxue prescription might be related to angiogenesis
and platelet activation, which may be achieved through the
activationofPI3K‑AKTsignalingpathway.Themortalityof
heart failure after AMI is extremely high, which is related to
theapoptosisofcardiacmyocytes. MAPKinhibitorscould
inhibit endoplasmic reticulum stress and reduce myocardial
apoptosis,suggestingthatMAPKsignalingpathwayplaysan
important role in AMI myocardial apoptosis. Qingre Huoxue
prescription may treat AMI by weakening the apoptosis of
AMIcellsdamagedby MAPK signaling pathway.HIF‑1
is a nucleoprotein produced by cells under hypoxia that
consistsofalphaandbetasubunits.Ithasaprotectiveeect
on myocardial cells, and it can promote angiogenesis and
glycolysis.Increasedexpression of HIF‑1alphagenecould
increasecontentofVEGFintheblood,increasemyocardial
capillary density, and reduce myocardial infarction area.[21]
The expression of proteins related to the JAK-STAT channel
hasaprotectiveeect on myocardialischemia‑reperfusion
injury,andstudieshaveshownthatthemyocardialinfarction
area can be reduced through the mediation of the JAK-STAT
cell signaling pathway.[22] In addition, myocardial infarction
could cause death and loss of myocardial cells, immune system
disorders,andinammation.Toll‑likereceptorsplayacrucial
roleininducingimmuneandinammatoryresponses.[23]
Figure 2: Drug‑component‑target network map
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Jia, et al. Study on the mechanism of Qingre Huoxue Prescription in AMI
World J Tradit Chin Med | Volume 5 | Issue 4 | October-December 2019 225
dIscussIon
At present, cardiovascular diseases are still top in the world
list of fatal diseases, and the fatality rate caused by AMI is
alsoincreasingyearbyyear.ForAMI,conventionalchemical
therapy has certain limitations in clinical treatment.[24] In the
eldofTCM,AMIbelongstothecategoryof“eclampsia”and
“genuine heartache.” It is very promising to use Chinese herbs
such as Spina date seed, Dalbergia odorifera, Radix puerariae,
and Angelica sinensis as a complementary therapy to the
treatment and prevention of cardiac remodeling after AMI.[25]
According to relevant studies, Qingre Huoxue prescription
couldimprovethelevelofinammatoryfactorsinpatientswith
AMI on the basis of Western medicine treatment, and it is good
in terms of safety.[5] Modern pharmacological studies have
shownthatSaowerhasantithrombosisandantiatherosclerosis
eects.[26] S. miltiorrhizahasprotectiveeectsonmyocardium,
vasodilation, and antiatherosclerosis.[27]RadixPaeoniae
Rubra has antithrombosis, antioxidation, and cardioprotection
effects.[28] Ligusticum wallichii has protective effect on
myocardium and antiplatelet aggregation;[29] S. baicalensis
has anti-inflammatory, antitumor, and antiangiogenesis
eects.[30] Lignum acronychiae has vasodilation, antioxidation,
Table 2: Results of network analysis on key active components of Qingre Huoxue prescription in the treatment of acute
myocardial infarction
Number Drug Compound Degree Median centrality Tight centrality
1 Radix paeoniae rubra Ellagic acid 61 2.366 0.423
2Saower;Salvia miltiorrhiza Luteolin 48 2.551 0.392
3Scutellaria baicalensis Chrysin 39 2.597 0.385
4Saower;Radixpaeoniaerubra Kaempferol 38 2.625 0.381
5Scutellaria baicalensis;saower;Radixpaeoniaerubra Baicalein 24 2.866 0.349
6Scutellaria baicalensis Acacetin 17 3.005 0.333
7 Ilex pubescens Hydroquinone 16 3.171 0.315
8Salvia miltiorrhiza Tanshinone IIa 15 2.977 0.336
9Salvia miltiorrhiza Cryptotanshinone 15 2.995 0.334
10 Lignum acronychiae Formononetin 14 3.051 0.328
11 Ligusticum wallichii Caeicacid 12 2.995 0.334
12 Salvia miltiorrhiza Tanshinone I 8 2.053 0.487
13 Saower Rutin 6 2.789 0.358
14 Lignum acronychiae Isoliquiritigenin 5 3 0.333
Table 3: The key target information and network analysis results of Qingre Huoxue prescription in the treatment of acute
myocardial infarction
Number Target name Gene Degree Median centrality Tight centrality
1 Microtubule-associated protein tau MAPT 8 0.411 0.073
2CytochromeP4501A2 CYP1A2 8 0.411 0.055
3 Androgen receptor AR 8 0.362 0.035
4 Aldose reductase AKR1B1 8 0.400 0.068
5 Carbonic anhydrase 2 CA2 7 0.397 0.052
6 Vitamin D3 receptor VDR 6 0.353 0.033
7 DNA polymerase beta POLB 6 0.372 0.044
8 Glycogen synthase kinase-3 beta GSK3B 6 0.384 0.046
9 Glyceraldehyde-3-phosphate
dehydrogenase
GAPDH 6 0.333 0.026
Figure 3: Protein interaction network of Qingre Huoxue prescription in
the treatment of acute myocardial infarction
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Jia, et al. Study on the mechanism of Qingre Huoxue Prescription in AMI
World J Tradit Chin Med | Volume 5 | Issue 4 | October-December 2019
226
anti‑inammatory,and other eects.[31] Ilex pubescens has
effects of lowering blood pressure, anticoagulation, and
anti‑inammationandimprovingimmunity.[32] However, the
mechanism of Qingre Huoxue prescription in treating AMI
is not clear.
Based on the method of network pharmacology, this study
investigated the relevant targets of Qingre Huoxue prescription
in the intervention of AMI and speculated the possible
mechanism of Qingre Huoxue prescription in the treatment of
AMI.Theresultsshowedthatthedierentcomponentsinthe
Qingre Huoxue prescription have similar or common targets and
maybehavesynergisticeects.SaowerandS. miltiorrhiza are
the compounds with the largest number of targets; they might
betheimportanteectiveChinesemedicineforclearingheat
and activating blood circulation. Targets of intervention for
AMI include androgen receptor, aldose reductase, and GSK-3
beta.Further,studiesonthetreatmentofAMI with Qingre
Huoxue prescription-related pathways involved arachidonic
acidmetabolism,VEGFsignalingpathway,JAK‑STAT
signaling pathway, Toll-like receptor signaling pathway, platelet
activation,HIF‑1signalingpathway,MAPKsignalingpathway,
andPI3K‑Aktsignalingpathway.
This study revealed the molecular basis and mechanism of
Qingre Huoxue prescription in the intervention of AMI, laying
a foundation for the development of TCM. However, there are
also some limitations, such as imperfect database information
may lead to omission of compounds and targets; because of
theauthor’scognitivedeciencies,theinterpretationmight
notbecomprehensive;lackofexperimentalvericationto
prove the accuracy of prediction. Therefore, it is imperative
to further study compounds and targets in the future from the
experimental perspective on the intervention of Qingre Huoxue
prescription in the treatment of AMI.
Financial support and sponsorship
Nil.
Conflicts of interest
Therearenoconictsofinterest.
references
1. CuiXQ, LingD, JingC,LiXM.Eectanalysisof Chinesemedicine
comprehensive nursing in acute infarction patients. J Mod Med Health
Res 2017;1:136.
2. VersaciF,GaspardoneA, TomaiF, CreaF,ChiarielloL,GiorèPA,
et al.PredictivevalueofC‑reactive protein in patients with unstable
angina pectoris undergoing coronary artery stent implantation. Am J
Cardiol 2000;85:92-5, A8.
3. WuH, Liu YD,WuW,Dong XG, HuangYS. The eect ofclearing
heatanddetoxication onatherosclerosisin rabbitsdueto chlamydia
pneumonia. J Guangzhou Univ Tradit Chin Med 2006;23:151-4.
4. Wu W, Liu Y D, Li R, Wu H, Wang S, Huang YS, et al.Theinuence
of chlamydia pneumonia infection on the area of atherosclerotic plaques
andtheinterventioneectofBaicalin.JGuangzhouUnivTraditChin
Med 2006;23:322-4.
5. Wu W, Peng Y, Li R, Wu H, Huang YS. Clinical observation of 60
cases of acute myocardial infarction with coronary heart disease treated
by clearing heat and activating blood circulation. J Tradit Chin Med
2010;51:905-8.
6. GaoXM.TraditionalChineseMedicine.Vol.1.Beijing:ChinaPressof
Tradition Chinese Medicine; 2007. p. 96-323.
7. WuW,LuoChJ,LR,WuH,ChenYP,HuangYS.Clinicalobservation
of qingre huoxue prescription in the treatment of acute coronary
syndrome. New Chin Med 2012:912.
8. Hopkins AL. Network pharmacology. Nat Biotechnol 2007;25:1110-1.
9. Zhang GB, Li QY, Chen QL, Su SB. Network pharmacology: A new
approach for Chinese herbal medicine research. Evid Based Complement
Alternat Med 2013;2013:621423.
10. TianS.TheoreticalPredictionofDrug‑LikePropertyandBioavailability.
Suzhou University; 2011.
11. Ding Y, Zhang B, Zhou K, Chen M, Wang M, Jia Y, et al. Dietary
ellagic acid improves oxidant-induced endothelial dysfunction and
atherosclerosis: Role of Nrf2 activation. Int J Cardiol 2014;175:508-14.
12. Hu J, Man W, Shen M, Zhang M, Lin J, Wang T, et al. Luteolin alleviates
post-infarction cardiac dysfunction by up-regulating autophagy through
mst1 inhibition. J Cell Mol Med 2016;20:147-56.
13. Yao Y, Chen L, Xiao J, Wang C, Jiang W, Zhang R, et al. Chrysin
protects against focal cerebral ischemia/reperfusion injury in mice
throughattenuationofoxidativestressandinammation.IntJMolSci
2014;15:20913-26.
14. Wang C, Du H, Hou J, Yan S, Yang J, Wang Y, et al. Chaihulonggumulitang
shows psycho‑cardiology therapeutic eects on acute myocardial
infarction by enhancing bone marrow mesenchymal stem cells
mobilization. Sci Rep 2018;8:3724.
15. Ma JP. A Preliminary Clinical and Basic Study on the Relationship
Between Androgen Receptors and Ischemic Cardiovascular Disease;
2013.
16. WangJJ,Kang Z,Li FM,YangTL,OuYangDS.Aldose reductase:A
newtargetforinterventionofmyocardialischemiainjury.IntJ Pathol
Clin Sci 2007;3:211-3.
17. Zhao CH, Li YM, Zhong XM, He RL, Cheng GC. Myocardial stem
cell transplantation with glycogen synthase kinase 3 overexpression
in the treatment of myocardial infarction. Tissue Eng Res China
2016;20:6203-8.
Figure 4: (a) Kyoto Encyclopedia of Genes and Genomes pathway
diagram of Qingre Huoxue prescription in the treatment of acute
myocardial infarction. (b) gene ontology biological process diagram of
Qingre Huoxue prescription in the treatment of acute myocardial infarction
b
a
[Downloaded free from http://www.wjtcm.net on Wednesday, January 8, 2020, IP: 10.232.74.23]

Jia, et al. Study on the mechanism of Qingre Huoxue Prescription in AMI
World J Tradit Chin Med | Volume 5 | Issue 4 | October-December 2019 227
18. YangF,LiuW,YanX,ZhouH,ZhangH,LiuJ,et al.Eectsofmir‑21
on cardiac microvascular endothelial cells after acute myocardial
infarction in rats: Role of phosphatase and tensin homolog (PTEN)/
Vascular endothelial growth factor (VEGF) signal pathway.Med Sci
Monit 2016;22:3562-75.
19. Cheng SY. Experimental Study of Astragaloside Regulating
PTEN/PI3K/Akt Signaling Pathway to Mediate Angiogenesis and
MyocardialProtectionafterMyocardialInfarction.NanjingUniversity
of Traditional Chinese Medicine; 2018.
20. Xu L, Jiang X, Wei F, Zhu H. Leonurine protects cardiac function
following acute myocardial infarction through antiapoptosis by the
PI3K/AKT/GSK3β signaling pathway. Mol Med Rep 2018;18:1582-90.
21. Semenza GL. Hypoxia-inducible factor 1 and cardiovascular disease.
AnnuRevPhysiol2014;76:39‑56.
22. Das A, Salloum FN, Durrant D, Ockaili R, Kukreja RC. Rapamycin
protects against myocardial ischemia‑reperfusion injury through
JAK2-STAT3 signaling pathway. J Mol Cell Cardiol 2012;53:858-69.
23. OmiyaS,OmoriY,TaneikeM,ProttiA,YamaguchiO,AkiraS,et al.
Toll-like receptor 9 prevents cardiac rupture after myocardial infarction
inmiceindependentlyofinammation.AmJPhysiolHeartCircPhysiol
2016;311:H1485-H1497.
24. Wang CL, Qin JB, Song HJ, Guan Y, Zhang J. Clinical study of
tongxinluo capsule combined with clopidogrel in the treatment of acute
myocardialinfarction. Mod Med Clin 2018;33:496-501.
25. Lu S, Zhang JN. Eects of traditional Chinese medicine on
cardiovascular receptors. Chin J Integr Tradit West Med 1998;18:699.
26. Chen M, Zhao PW, Sun YL, Sun LP. Pharmacological eects of
safoweranditsmaincomponents.GlobJTraditChinMed2012;5:556.
27. Wang L, Ma R, Liu C, Liu H, Zhu R, Guo S, et al. Salvia miltiorrhiza:
APotentialredlighttothedevelopmentofcardiovasculardiseases.Curr
PharmDes2017;23:1077‑97.
28. Lu XH, Ma X, Wang J, Zhu Y, Zhou ZY, Chen Z, et al. Research
progressonchemicalcomponents and pharmacologicaleectsofred
peony root. Chin Herb Med 2015;46:595-602.
29. Tang YF, Yang AX. Study on the active ingredients and
pharmacological eects of Ligusticum wallichii. Mod Chin Pharm
Appl 2018;12:219-20.
30. Ma LL, Sun Y. Advances in pharmacological eects of Scutellaria
baicalensis. J Shenyang Med Coll 2016;18:115-7.
31. FanZM,WangYH,XieRF,WangDY,ZhouX.Advancesinthestudyof
chemicalconstituentsandpharmacologicaleectsofDaphneodorifera.
Shizhen Tradit Chin Med 2016;27:247-880.
32. Li XR. Overview of pharmacological studies on ilex pubescens. Glob
Chin Med 2011;4:238-40.
[Downloaded free from http://www.wjtcm.net on Wednesday, January 8, 2020, IP: 10.232.74.23]