Clinical and Translational Research Open Access
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Cardiol. Jul 26, 2024; 16(7): 422-435
Published online Jul 26, 2024. doi: 10.4330/wjc.v16.i7.422
Network pharmacology-based exploration of molecular mechanisms underlying therapeutic effects of Jianpi Huatan Quyu recipe on chronic heart failure with spleen Qi deficiency syndrome
Si-Qi Li, Dong-Yu Min, Jun-Wen Jiang, Xiao-Ying Li, Xu-Na Yang, Wen-Bo Gu, Jia-Hui Jiang, Li-Hao Chen, Han Nan, Ze-Yu Chen, Second Department of Cardiology, The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110000, Liaoning Province, China
ORCID number: Si-Qi Li (0009-0009-4222-716X).
Author contributions: Li SQ designed the study and drafted the manuscript; all authors contributed to revising and proofreading the manuscript.
Supported by 2021 Shenyang Science and Technology Program-Public Health R&D Special Project (Joint Project) of Shenyang Municipal Science and Technology Bureau, No. 21-174-9-04.
Conflict-of-interest statement: There is no conflict of interest to disclose.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Si-Qi Li, MD, Chief Physician, Second Department of Cardiology, The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, No. 33 Beiling Street, Huanggu District, Shenyang 110000, Liaoning Province, China. pangdun66@163.com
Received: May 23, 2024
Revised: July 2, 2024
Accepted: July 4, 2024
Published online: July 26, 2024
Processing time: 62 Days and 5.4 Hours

Abstract
BACKGROUND

Chronic heart failure is a complex clinical syndrome. The Chinese herbal compound preparation Jianpi Huatan Quyu recipe has been used to treat chronic heart failure; however, the underlying molecular mechanism is still not clear.

AIM

To identify the effective active ingredients of Jianpi Huatan Quyu recipe and explore its molecular mechanism in the treatment of chronic heart failure.

METHODS

The effective active ingredients of eight herbs composing Jianpi Huatan Quyu recipe were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The target genes of chronic heart failure were searched in the Genecards database. The target proteins of active ingredients were mapped to chronic heart failure target genes to obtain the common drug-disease targets, which were then used to construct a key chemical component-target network using Cytoscape 3.7.2 software. The protein-protein interaction network was constructed using the String database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed through the Metascape database. Finally, our previously published relevant articles were searched to verify the results obtained via network pharmacology.

RESULTS

A total of 227 effective active ingredients for Jianpi Huatan Quyu recipe were identified, of which quercetin, kaempferol, 7-methoxy-2-methyl isoflavone, formononetin, and isorhamnetin may be key active ingredients and involved in the therapeutic effects of TCM by acting on STAT3, MAPK3, AKT1, JUN, MAPK1, TP53, TNF, HSP90AA1, p65, MAPK8, MAPK14, IL6, EGFR, EDN1, FOS, and other proteins. The pathways identified by KEGG enrichment analysis include pathways in cancer, IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, calcium signaling pathway, cAMP signaling pathway, NF-kappaB signaling pathway, AMPK signaling pathway, etc. Previous studies on Jianpi Huatan Quyu recipe suggested that this Chinese compound preparation can regulate the TNF-α, IL-6, MAPK, cAMP, and AMPK pathways to affect the mitochondrial structure of myocardial cells, oxidative stress, and energy metabolism, thus achieving the therapeutic effects on chronic heart failure.

CONCLUSION

The Chinese medicine compound preparation Jianpi Huatan Quyu recipe exerts therapeutic effects on chronic heart failure possibly by influencing the mitochondrial structure of cardiomyocytes, oxidative stress, energy metabolism, and other processes. Future studies are warranted to investigate the role of the IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, and other pathways in mediating the therapeutic effects of Jianpi Huatan Quyu recipe on chronic heart failure.

Key Words: Jianpi Huatan Quyu recipe; Traditional Chinese medicine; Chronic heart failure; Data mining; Network pharmacology; Bioinformatics; Spleen Qi deficiency syndrome

Core Tip: Based on the clinical characteristics of patients, the dialectical treatment of chronic heart failure is often performed primarily by strengthening Qi and nourishing Yin, promoting blood circulation and removing blood stasis, resolving phlegm and alleviating water retention, and warming and tonifying heart Yang. In this study, the authors found that the Chinese medicine compound preparation Jianpi Huatan Quyu recipe exerts therapeutic effects on chronic heart failure possibly by influencing the mitochondrial structure of cardiomyocytes, oxidative stress, energy metabolism, and other processes.



INTRODUCTION

Chronic heart failure is a complex clinical syndrome due to abnormal changes in cardiac structure and/or function caused by multiple factors, resulting in ventricular systolic and/or diastolic dysfunction[1]. Its main manifestations are dyspnea, fatigue, and fluid retention. As the end-stage manifestation of cardiovascular disease and the main cause of death, chronic heart failure is thought to belong to "chest impediment", "palpitation", "true heart pain", and other categories in traditional Chinese medicine (TCM). Based on the clinical characteristics of patients, the dialectical treatment of chronic heart failure is often performed primarily by strengthening Qi and nourishing Yin, promoting blood circulation and removing blood stasis, resolving phlegm and alleviating water retention, and warming and tonifying heart Yang[2]. We have been studying the curative effect and mechanism of the Chinese herbal compound preparation Jianpi Huatan Quyu recipe, which has the effects of strengthening the spleen, dissolving phlegm, and removing blood stasis, in the treatment of chronic heart failure. In order to further explore the therapeutic mechanism of this compound recipe, network pharmacology was applied in the present study to identify the effective active ingredients of eight herbs composing Jianpi Huatan Quyu recipe, as well as common target proteins shared by Jianpi Huatan Quyu recipe and chronic heart failure. In addition, our previous studies on the mechanism of action of Jianpi Huayu Qutan recipe in different conditions were searched to provide support for the results obtained via network pharmacology.

MATERIALS AND METHODS
Analysis of effective active components of Jianpi Huatan Quyu recipe

Jianpi Huatan Quyu recipe is composed of eight Chinese herbs: Dangshen, Fuling, Baizhu, Zhigancao, Danshen, Qingbanxia, and Gualou. The effective active components of these eight herbs were searched using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP)[3]. Oral bioavailability ≥ 30% and drug-likeness ≥ 0.18 were used as the screening criteria to ensure that the selected active ingredients have good oral absorption and high druggability.

Identification of common targets shared by Jianpi Huatan Quyu recipe and chronic heart failure

The TCMSP database was used to identify the targets of the effective active ingredients as mentioned above. Human gene names and corresponding target proteins were downloaded from the UniProt database (https://www.uniprot.org/)[4]. The target genes of chronic heart failure were searched in the Genecards database (https://www.genecards.org/)[5]. The target proteins of active ingredients were mapped to chronic heart failure target genes to obtain the common drug-disease targets and to find out the key chemical components corresponding to these targets.

Key chemical component-target network construction

Common drug-disease targets and their corresponding key chemical components were sorted into a table, which was then imported into Cytoscape 3.7.2 software to obtain their relationship network.

Protein-protein interaction network construction

Protein-protein interaction (PPI) networks can graphically describe the interactions between common drug-disease targets. The common drug-disease targets identified above were input into the String database (https://string-db.org/ Version 10.5)[6] to obtain the PPI network. The protein interaction score was further set to 0.9 to optimize the network diagram. Data on protein interactions were downloaded to screen out the top 15 core proteins.

Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis

The common drug-disease targets identified above were imported into the Metascape database (http: //metascape.org/gp/index.html)[7] for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, with the parameters set as follows: P value = 0.01, minimum overlap = 3, and minimum enrichment = 1.5, GO biological process (BP), cellular component (CC), and molecular function (MF) and KEGG pathways were enriched, respectively. Bubble maps were generated online using the ImageGP website tool. The target-pathway network was constructed with Cytoscape software.

Confirmatory study

According to the key targets and proteins belonging to the signal pathways identified above, our previously published relevant articles were analyzed to verify the therapeutic mechanism of Jianpi Huatan Quyu recipe in the treatment of chronic heart failure.

RESULTS
Identification of effective active ingredients of Jianpi Huatan Quyu recipe

There are eight herbs in the Chinese herbal compound preparation Jianpi Huatan Quyu recipe: Huangqi, Dangshen, Fuling, Baizhu, Zhigancao, Danshen, Qingbanxia, and Gualou. As shown in Table 1, a total of 227 active ingredients were identified in the TCMSP database according to the oral bioavailability and drug-likeness.

Table 1 Active ingredients of herbs composing Jianpi Huatan Quyu recipe.
Molecule ID
Molecule name
Drug(s)
Molecule ID
Molecule name
Drug(s)
MOL0070593-β-hydroxymethyllenetanshiquinoneDanshen, DangshenMOL001792DFVGancao
MOL004355SpinasterolDangshen, GualouMOL001484InermineGancao
MOL0038967-methoxy-2-methyl isoflavoneDangshen, GancaoMOL000500VestitolGancao
MOL002776BaicalinBanxia, DanshenMOL000497Licochalcone aGancao
MOL000449StigmasterolBanxia, DangshenMOL000359SitosterolGancao
MOL000422KaempferolGancao, HuangqiMOL000300Dehydroeburicoic acidFuling
MOL000417CalycosinGancao, HuangqiMOL000292Poricoic acid CFuling
MOL000392FormononetinGancao, HuangqiMOL000291Poricoic acid BFuling
MOL000354IsorhamnetinGancao, HuangqiMOL000290Poricoic acid AFuling
MOL000296HederageninFuling, HuangqiMOL000289Pachymic acidFuling
MOL000239JaranolGancao, HuangqiMOL0002873-β-hydroxy-24-methylene-8-lanostene-21-oic acidFuling
MOL000211MairinGancao, HuangqiMOL000285(2R)-2-[(5R,10S,13R,14R,16R,17R)-16-hydroxy-3-keto-4,4,10,13,14-pentamethyl-1,2,5,6,12,15,16,17-octahydrocyclopenta[a]phenanthren-17-yl]-5-isopropyl-hex-5-enoic acidFuling
MOL000098QuercetinGancao, HuangqiMOL000283Ergosterol peroxideFuling
MOL000033(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R,5S)-5-propan-2-yloctan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-olBaizhu, HuangqiMOL000282Ergosta-7,22E-dien-3beta-olFuling
MOL000006LuteolinDanshen, DangshenMOL000280(2R)-2-[(3S,5R,10S,13R,14R,16R,17R)-3,16-dihydroxy-4,4,10,13,14-pentamethyl-2,3,5,6,12,15,16,17-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-5-isopropyl-hex-5-enoic acidFuling
MOL0004421,7-dihydroxy-3,9-dimethoxy pterocarpeneHuangqiMOL000279CerevisterolFuling
MOL000439Isomucronulatol-7,2'-di-O-glucosioleHuangqiMOL0002767,9(11)-Dehydropachymic acidFuling
MOL000438(3R)-3-(2-hydroxy-3,4-dimethoxyphenyl)chroman-7-olHuangqiMOL000275Trametenolic acidFuling
MOL000433FAHuangqiMOL000273(2R)-2-[(3S,5R,10S,13R,14R,16R,17R)-3,16-dihydroxy-4,4,10,13,14-pentamethyl-2,3,5,6,12,15,16,17-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-6-methylhept-5-enoic acidFuling
MOL000398IsoflavanoneHuangqiMOL00841111-HydroxyrankinidineDangshen
MOL000387BifendateHuangqiMOL008407(8S,9S,10R,13R,14S,17R)-17-[(E,2R,5S)-5-ethyl-6-methylhept-3-en-2-yl]-10,13-dimethyl-1,2,4,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-oneDangshen
MOL000380(6aR,11aR)-9,10-dimethoxy-6a,11a-dihydro-6H-benzofurano[3,2-c]chromen-3-olHuangqiMOL008406Spinoside ADangshen
MOL0003799,10-dimethoxypterocarpan-3-O-β-D-glucosideHuangqiMOL008400GlyciteinDangshen
MOL0003787-O-methylisomucronulatolHuangqiMOL008397DaturilinDangshen
MOL0003745'-hydroxyiso-muronulatol-2',5'-di-O-glucosideHuangqiMOL0083937-(β-xylosyl)cephalomannine_qtDangshen
MOL0003713,9-di-O-methylnissolinHuangqiMOL0083915α-Stigmastan-3,6-dioneDangshen
MOL007180Vitamin EGualouMOL007514Methyl icosa-11,14-dienoateDangshen
MOL007179Linolenic acid ethyl esterGualouMOL006774Stigmast-7-enolDangshen
MOL007175Karounidiol 3-O-benzoateGualouMOL006554TaraxerolDangshen
MOL0071727-oxo-Dihydrokaro-unidiolGualouMOL005321Frutinone ADangshen
MOL0071715-DehydrokarounidiolGualouMOL004492ChrysanthemaxanthinDangshen
MOL00716510α-cucurbita-5,24-diene-3β-olGualouMOL003036ZINC03978781Dangshen
MOL006756SchottenolGualouMOL002879DiopDangshen
MOL005530hydroxygenkwaninGualouMOL002140PerlolyrineDangshen
MOL002881DiosmetinGualouMOL001006Poriferasta-7,22E-dien-3β-olDangshen
MOL001494MandenolGualouMOL007156Tanshinone ⅥDanshen
MOL005020Dehydroglyasperins CGancaoMOL007155(6S)-6-(hydroxymethyl)-1,6-Dimethyl-8,9-dihydro-7H-naphtho[8,7-g]benzofuran-10,11-dioneDanshen
MOL005018XambioonaGancaoMOL007154Tanshinone iiaDanshen
MOL005017PhaseolGancaoMOL007152Przewaquinone EDanshen
MOL005016OdoratinGancaoMOL007151Tanshindiol BDanshen
MOL00501318α-hydroxyglycyrrhetic acidGancaoMOL007150(6S)-6-hydroxy-1-methyl-6-methylol-8,9-dihydro-7H-naphtho[8,7-g]benzofuran-10,11-quinoneDanshen
MOL005012LicoagroisoflavoneGancaoMOL007149NSC 122421Danshen
MOL005008Glycyrrhiza flavonol AGancaoMOL007145SalvioloneDanshen
MOL005007Glyasperins MGancaoMOL007143Salvilenone IDanshen
MOL005003LicoagrocarpinGancaoMOL007142Salvianolic acid JDanshen
MOL005001Gancaonin HGancaoMOL007141Salvianolic acid GDanshen
MOL005000Gancaonin GGancaoMOL007140(Z)-3-[2-[(E)-2-(3,4-dihydroxyphenyl)vinyl]-3,4-dihydroxy-phenyl]acrylic acidDanshen
MOL004996Gadelaidic acidGancaoMOL007132(2R)-3-(3,4-dihydroxyphenyl)-2-[(Z)-3-(3,4-dihydroxyphenyl)acryloyl]oxy-propionic acidDanshen
MOL0049938-prenylated eriodictyolGancaoMOL007130Prolithospermic acidDanshen
MOL0049917-acetoxy-2-methylisoflavoneGancaoMOL0071271-methyl-8,9-dihydro-7H-naphtho[5,6-g]benzofuran-6,10,11-trioneDanshen
MOL0049907,2',4'-trihydroxy-5-methoxy-3-arylcoumarinGancaoMOL007125NeocryptotanshinoneDanshen
MOL0049896-prenylated eriodictyolGancaoMOL007124Neocryptotanshinone IIDanshen
MOL004988Kanzonol FGancaoMOL007123Miltirone IIDanshen
MOL004985Icos-5-enoic acidGancaoMOL007122MiltironeDanshen
MOL004980Inflacoumarin AGancaoMOL007121MiltipoloneDanshen
MOL0049782-[(3R)-8,8-dimethyl-3,4-dihydro-2H-pyrano[6,5-f]chromen-3-yl]-5-methoxyphenolGancaoMOL007120Miltionone IIDanshen
MOL0049743'-methoxyglabridinGancaoMOL007119Miltionone IDanshen
MOL0049663'-hydroxy-4'-O-methylglabridinGancaoMOL007118MicrostegiolDanshen
MOL004961Quercetin der.GancaoMOL007115ManoolDanshen
MOL0049591-methoxyphaseollidinGancaoMOL007111Isotanshinone IIDanshen
MOL004957HMOGancaoMOL007108Isocryptotanshi-noneDanshen
MOL004949IsolicoflavonolGancaoMOL007107C09092Danshen
MOL004948IsoglycyrolGancaoMOL007105EpidanshenspiroketallactoneDanshen
MOL004945(2S)-7-hydroxy-2-(4-hydroxyphenyl)-8-(3-methylbut-2-enyl)chroman-4-oneGancaoMOL007101Dihydrotanshinone IDanshen
MOL004941(2R)-7-hydroxy-2-(4-hydroxyphenyl)chroman-4-oneGancaoMOL007100DihydrotanshinlactoneDanshen
MOL004935Sigmoidin-BGancaoMOL007098DeoxyneocryptotanshinoneDanshen
MOL004924(-)-medicocarpinGancaoMOL007094DanshenspiroketallactoneDanshen
MOL004917GlycyrosideGancaoMOL007093Dan-shexinkum dDanshen
MOL004915Eurycarpin AGancaoMOL007088CryptotanshinoneDanshen
MOL0049141,3-dihydroxy-8,9-dimethoxy-6-benzofurano[3,2-c]chromenoneGancaoMOL007085SalvilenoneDanshen
MOL0049131,3-dihydroxy-9-methoxy-6-benzofurano[3,2-c]chromenoneGancaoMOL007082Danshenol ADanshen
MOL004912GlabroneGancaoMOL007081Danshenol BDanshen
MOL004911GlabreneGancaoMOL007079TanshinaldehydeDanshen
MOL004910GlabraninGancaoMOL007077SclareolDanshen
MOL004908GlabridinGancaoMOL007071Przewaquinone fDanshen
MOL004907GlyzaglabrinGancaoMOL007070(6S,7R)-6,7-dihydroxy-1,6-dimethyl-8,9-dihydro-7H-naphtho[8,7-g]benzofuran-10,11-dioneDanshen
MOL0049053,22-dihydroxy-11-oxo-delta(12)-oleanene-27-α-methoxycarbonyl-29-oic acidGancaoMOL007069Przewaquinone CDanshen
MOL004904LicopyranocoumarinGancaoMOL007068Przewaquinone BDanshen
MOL004903LiquiritinGancaoMOL007064Przewalskin BDanshen
MOL004898(E)-3-[3,4-dihydroxy-5-(3-methylbut-2-enyl)phenyl]-1-(2,4-dihydroxyphenyl)prop-2-en-1-oneGancaoMOL007063przewalskin aDanshen
MOL004891ShinpterocarpinGancaoMOL007061MethylenetanshinquinoneDanshen
MOL004885LicoisoflavanoneGancaoMOL007058FormyltanshinoneDanshen
MOL004884Licoisoflavone BGancaoMOL0070516-O-syringyl-8-o-acetyl shanzhiside methyl esterDanshen
MOL004883LicoisoflavoneGancaoMOL0070502-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-7-methoxy-3-benzofurancarboxaldehydeDanshen
MOL004882LicocoumaroneGancaoMOL0070494-methylenemiltironeDanshen
MOL004879GlycyrinGancaoMOL007048(E)-3-[2-(3,4-dihydroxyphenyl)-7-hydroxy-benzofuran-4-yl]acrylic acidDanshen
MOL0048662-(3,4-dihydroxyphenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)chromoneGancaoMOL0070453α-hydroxytanshinone IIaDanshen
MOL0048645,7-dihydroxy-3-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)chromoneGancaoMOL0070412-isopropyl-8-methylphenanthrene-3,4-dioneDanshen
MOL0048633-(3,4-dihydroxyphenyl)-5,7-dihydroxy-8-(3-methylbut-2-enyl)chromoneGancaoMOL0070365,6-dihydroxy-7-isopropyl-1,1-dimethyl-2,3-dihydrophenanthren-4-oneDanshen
MOL004860Licorice glycoside EGancaoMOL006824α-amyrinDanshen
MOL004857Gancaonin BGancaoMOL002651Dehydrotanshinone IIADanshen
MOL004856Gancaonin AGancaoMOL002222SugiolDanshen
MOL004855LicoriconeGancaoMOL001942IsoimperatorinDanshen
MOL0048493-(2,4-dihydroxyphenyl)-8-(1,1-dimethylprop-2-enyl)-7-hydroxy-5-methoxy-coumarinGancaoMOL001771Poriferast-5-en-3β-olDanshen
MOL004848Licochalcone GGancaoMOL001659PoriferasterolDanshen
MOL004841Licochalcone BGancaoMOL0016011,2,5,6-tetrahydrotanshinoneDanshen
MOL0048388-(6-hydroxy-2-benzofuranyl)-2,2-dimethyl-5-chromenolGancaoMOL000569DigallateDanshen
MOL004835GlypallichalconeGancaoMOL006967β-D-Ribofuranoside, xanthine-9Banxia
MOL004833PhaseolinisoflavanGancaoMOL006957(3S,6S)-3-(benzyl)-6-(4-hydroxybenzyl)piperazine-2,5-quinoneBanxia
MOL004829Glepidotin BGancaoMOL00693712,13-epoxy-9-hydroxynonadeca-7,10-dienoic acidBanxia
MOL004828Glepidotin AGancaoMOL00693610,13-eicosadienoicBanxia
MOL004827Semilicoisoflavone BGancaoMOL005030Gondoic acidBanxia
MOL004824(2S)-6-(2,4-dihydroxyphenyl)-2-(2-hydroxypropan-2-yl)-4-methoxy-2,3-dihydrofuro[3,2-g]chromen-7-oneGancaoMOL003578CycloartenolBanxia
MOL004820Kanzonols WGancaoMOL002714BaicaleinBanxia
MOL004815(E)-1-(2,4-dihydroxyphenyl)-3-(2,2-dimethylchromen-6-yl)prop-2-en-1-oneGancaoMOL002670CavidineBanxia
MOL004814IsotrifoliolGancaoMOL00175524-ethylcholest-4-en-3-oneBanxia
MOL004811Glyasperin CGancaoMOL000519ConiferinBanxia
MOL004810Glyasperin FGancaoMOL000358β-sitosterolBanxia
MOL004808Glyasperin BGancaoMOL0000728β-ethoxy atractylenolide ⅢBaizhu
MOL004806EuchrenoneGancaoMOL0000493β-acetoxyatractyloneBaizhu
MOL004805(2S)-2-[4-hydroxy-3-(3-methylbut-2-enyl)phenyl]-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4-oneGancaoMOL000028α-amyrinBaizhu
MOL004328NaringeninGancaoMOL00002214-acetyl-12-senecioyl-2E,8Z,10E-atractylentriolBaizhu
MOL003656LupiwighteoneGancaoMOL00002114-acetyl-12-senecioyl-2E,8E,10E-atractylentriolBaizhu
MOL002565MedicarpinGancaoMOL00002012-senecioyl-2E,8E,10E-atractylentriolBaizhu
MOL002311GlycyrolGancao
Identification of common drug-disease targets

A total of 4123 genes were downloaded from the Genecard database and screened for genes with a score of 5 or greater, which might be associated with chronic heart failure. Mapping of the target proteins of active ingredients of Jianpi Huatan Quyu recipe to chronic heart failure target genes led to the identification of 201 common targets. The Venn diagram indicating these common targets is shown in Figure 1.

Figure 1
Figure 1  Venn diagram showing common targets of chronic heart failure and Jianpi Huatan Quyu recipe.
Construction of key chemical component-target network

Cytoscape software was used to construct the relationship network of key active components in Jianpi Huatan Quyu recipe and chronic heart failure associated genes. As shown in Figure 2, the top 5 key chemical components are as follows: Quercetin (MOL000098, degree = 236), kaempferol (MOL000422, degree = 94), 7-methoxy-2-methyl isoflavone, (MOL003896, degree = 60), formononetin (MOL000392, degree = 53), and isorhamnetin (MOL000354, degree = 47). The top 15 common target proteins are as follows: PTGS2, ESR1, AR, PTGS1, NOS2, SCN5A, PRSS1, GSK3B, PPARG, CCNA2, ESR2, ADRB2, DPP4, F10, and RXRA.

Figure 2
Figure 2 Network of target proteins shared by key active components in Jianpi Huatan Quyu recipe and chronic heart failure. Boxes represent target genes, and diamonds represent active ingredients. The size of the text in boxes and diamonds indicates "degree".
PPI network analysis

The PPI network was obtained by inputting the common drug-disease targets into the String database. As shown in Figure 3, the PPI network contains 200 nodes and 906 edges. Among them, the interacting protein pairs with a PPI score equal to 0.999 are AKT1-NOS3, AKT1-GSK3B, BCL2 L1-TP53, BCL2 L1-CASP8, CASP3-CASP8, CASP7-CASP8, CCNA2-CDK2, CCNA2-CDKN1A, CCND1-CDKN1A, CCND1-CDK2, CDK2-RB1, CDK2-CDKN1A, CDKN1A-TP53, CDKN1A-PCNA, E2F1-RB1, EDN1-EDNRA, EGF-EGFR, F3-F7, FOS-JUN, IKBKB-NFKBIA, IKBKB-TNF, JUN-MAPK8, KDR-VEGFA, MDM2-TP53, PLAT-SERPINE1, and PLAU-SERPINE1. By calculating the number of connection points in the network, the top 15 core proteins were identified: STAT3, MAPK3, AKT1, JUN, MAPK1, TP53, TNF, HSP90AA1, RELA, MAPK8, MAPK14, IL6, EGFR, EDN1, and FOS, which may be the core proteins mediating the therapeutic effects of Jianpi Huatan Quyu recipe in treating chronic heart failure (Figure 4).

Figure 3
Figure 3  Protein-protein interaction protein interaction network.
Figure 4
Figure 4  Core proteins identified by protein-protein interaction.
GO enrichment analysis

BP enrichment analysis results are shown in Figure 5A. The BPs enriched include response to lipopolysaccharide, inflammatory response, response to drug, reactive oxygen species metabolic process, response to wounding, cellular response to organic cyclic compound, response to inorganic substance, cellular response to nitrogen compound, circulatory system process, positive regulation of cellular component movement, response to oxygen levels, apoptotic signaling pathway, response to extracellular stimulus, positive regulation of ion transport, regulation of MAPK cascade, regulation of DNA-binding transcription factor activity, regulation of cell adhesion, response to growth factor, response to steroid hormone, fine negative regulation of cell differentiation, etc.

Figure 5
Figure 5 GO and KEGG enrichment analyses. A: GO biological process enrichment analysis; B: GO cellular component enrichment analysis; C: GO molecular function enrichment analysis; D: KEGG enrichment analysis.

Figure 5B shows the results of CC enrichment analysis. The CCs enriched are membrane raft, receptor complex, vesicle lumen, postsynaptic membrane, dendrite, perinuclear region of cytoplasm, side of membrane, extracellular matrix, protein kinase complex, cytoplasmic vesicle membrane, organelle outer membrane, focal adhesion, basal part of cell, RNA polymerase II transcription regulator complex, dendrite membrane, endocytic vesicle, dopaminergic synapse, etc.

Figure 5C shows the results of MF enrichment analysis. The MFs enriched include nuclear receptor activity, protein homodimerization activity, DNA-binding transcription factor binding, G protein-coupled amine receptor activity, protein domain specific binding, protein kinase activity, cytokine receptor binding, protein heterodimerization activity, oxidoreductase activity, transcription coactivator binding, amide binding, neurotransmitter receptor activation activity, endopeptidase activity, drug binding, phosphatase binding, protease binding, core promoter sequence-specific DNA binding, MAP kinase activity, repressing transcription factor binding, kinase regulator activity, etc.

KEGG pathway enrichment analysis

KEGG pathway enrichment analysis demonstrated that the pathways enriched include pathways in cancer, IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, calcium signaling pathway, cAMP signaling pathway, NF-kappaB signaling pathway, AMPK signaling pathway, etc. (Figure 5D).

Target-pathway network construction

The target-pathway network constructed is shown in Figure 6. The selected core targets are IKBKB, RELA, AKT1, MAPK8, MAPK10, CHUK, JUN, MAPK1, TNF, CASP3, IL6, MAPK3, NFKBIA, MAPK14, TP53, CASP8, etc.

Figure 6
Figure 6 Target-pathway network diagram. The size of the node text is proportional to the number of lines connecting the node, with larger text indicating more targets or pathways associated with the target.
Confirmatory results of our previous studies

Our previous studies have explored the mechanism of action of Jianpi Huayu Qutan recipe in different conditions, which demonstrated that this recipe functions by regulating the expression of proteins involved in the TNF-α, IL-6, MAPK, cAMP, and AMPK pathways[8-11].

DISCUSSION

From the perspective of TCM, chronic heart failure is a disease characterized by deficiency in origin and excess in superficiality, which initially occurs in the heart, and then involves the lungs, spleen, and kidneys. With deficiency of heart Qi as the root cause, chronic heart failure mainly manifests as phlegm turbidity, fluid retention, and blood stasis[12]. The Chinese herbal compound preparation Jianpi Huatan Quyu recipe, derived from the TCM preparation Sijunzi decoction, was initially used to treat the syndrome of deficiency of spleen Qi[13]. Correcting the deficiency of Qi and blood is essential for the treatment of diseases. The spleen and stomach are the sources of Qi and blood. In Jianpi Huatan Quyu recipe, Huangqi, Dangshen, Baizhu, Fuling, and Zhigancao have strong spleen-strengthening effects and can promote blood circulation by flourishing the spleen Qi. Spleen dysfunction will lead to the accumulation of phlegm, so Qingbanxia is included in the recipe for removing dampness to reduce phlegm, and Gualou is used to relieve depression in the chest and regulate the flow of Qi, both of which can help eliminate the phlegm accumulated in the chest. Qi deficiency results in poor blood circulation and stagnation of blood stasis. Zhang et al[14] wrote in the ancient book "Thoroughly Revised Materia Medica" that "Danshen tonifies the heart, removes blood stasis, and promotes fresh blood production......having multiple therapeutic effects". Therefore, Danshen is included in the Jianpi Huatan Quyu recipe to tonify the heart, promote blood circulation, and remove blood stasis. Combined use of all these herbs can achieve the effects of strengthening the spleen, tonifying the heart, eliminating phlegm, and removing blood stasis. Our previous studies have shown that Jianpi Huatan Quyu recipe can effectively improve patients' blood lipids, improve myocardial function, and affect patients' myocardial mitochondrial energy metabolism[15,16]. This study further explored the molecular mechanism underlying the therapeutic effects of Jianpi Huatan Quyu recipe in chronic heart failure.

In the present study, according to oral bioavailability and drug-likeness, 227 active ingredients of eight herbs composing Jianpi Huatan Quyu recipe were identified, among which quercetin, kaempferol, 7-methoxy-2-methyl isoflavone, formononetin, and isorhamnetin may be the key active ingredients. These chemical components can be highly matched with the following targets of chronic heart failure: PTGS2, ESR1, AR, PTGS1, NOS2, SCN5A, PRSS1, GSK3B, PPARG, CCNA2, ESR2, ADRB2, DPP4, F10, and RXRA. Further analysis of the relationship between these targets and chronic heart failure revealed that STAT3, MAPK3, AKT1, JUN, MAPK1, TP53, TNF, HSP90AA1, p65, MAPK8, MAPK14, IL6, EGFR, EDN1, and FOS may be involved in the development and progression of chronic heart failure. These proteins may also play an important role in the treatment of chronic heart failure. The molecular mechanisms that are involved in the therapeutic effects of Jianpi Huatan Quyu recipe on chronic heart failure include nuclear receptor activity, protein homodimerization activity, DNA-binding transcription factor activity, G protein-coupled amine receptor activity, protein domain specific binding, protein kinase activity, cytokine receptor binding, protein heterodimerization activity, oxidoreductase activity, transcription coactivator binding, amide binding, and neurotransmitter receptor activity, endopeptidase activity, drug binding, phosphatase binding, protease binding, core promoter sequence-specific DNA binding, MAP kinase activity, repressing transcription factor binding, kinase regulator activity, etc. KEGG signaling pathway enrichment analysis indicated that the compound may act on multiple pathways, such as pathways in cancer, IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, calcium signaling pathway, cAMP signaling pathway, NF-kappaB signaling pathway, and AMPK signaling pathway. Among these pathways, IKBKB, RELA, AKT1, MAPK8, MAPK10, CHUK, JUN, MAPK1, TNF, CASP3, IL6, MAPK3, NFKBIA, MAPK14, TP53, CASP8, etc. may be the key protein targets of Jianpi Huatan Quyu recipe.

CONCLUSION

To sum up, the Chinese herbal compound preparation Jianpi Huatan Quyu recipe acts on multiple targets through a variety of active ingredients, exerting therapeutic effects on chronic heart failure via multiple pathways. The TNF-α, IL-6, MAPK, cAMP, and AMPK pathways have been experimentally verified to be involved in the therapeutic effects of Jianpi Huatan Quyu recipe on chronic heart failure in previous studies. The pathways such as the IL-17, PI3K-Akt, and HIF-1 signaling pathways can be used as the targets in the treatment of chronic heart failure. Future research is warranted to further explore the mechanism of Jianpi Huatan Quyu recipe in the treatment of chronic heart failure.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Cardiac and cardiovascular systems

Country of origin: China

Peer-review report’s classification

Scientific Quality: Grade C

Novelty: Grade B

Creativity or Innovation: Grade C

Scientific Significance: Grade B

P-Reviewer: Chhipa AS S-Editor: Lin C L-Editor: Wang TQ P-Editor: Wang WB

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