Research Article
Print
Research Article
Exploring the pharmacological mechanism of Qishen Yiqi dropping pills in treating chronic heart failure based on network pharmacology and molecular docking
expand article infoDaqiu Chen‡, Yanqing Wu‡, Yixing Chen‡, Tao Ye‡, Shunxiang Luo‡, Fanglin Luo‡
‡ Fujian Medical University, Nanping, China

Corresponding author: Shunxiang Luo ( 15959755605@139.com )

Corresponding author: Fanglin Luo ( lflbobby@163.com )

Academic editor: Emilio Mateev
© 2024 Daqiu Chen, Yanqing Wu, Yixing Chen, Tao Ye, Shunxiang Luo, Fanglin Luo.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation: Chen D, Wu Y, Chen Y, Ye T, Luo S, Luo F (2024) Exploring the pharmacological mechanism of Qishen Yiqi dropping pills in treating chronic heart failure based on network pharmacology and molecular docking. Pharmacia 71: 1-11. https://doi.org/10.3897/pharmacia.71.e135014
Open Access

Abstract

Chronic heart failure (CHF) is a severe condition that affects millions of people worldwide. Despite standardized treatments, patients often face recurrent symptoms such as dyspnea, edema, and fatigue, which impair their quality of life and contribute to high mortality and hospital readmission rates. Traditional Chinese Medicine (TCM) offers alternative therapies, and Qishen Yiqi Dropping Pills (QYDP) has emerged as a potential treatment for CHF. QYDP is composed of Danshen, Huangqi, Jiangxiang, and Sanqi and is known for its ability to promote circulation, enhance Qi, and support cardiac health. Although clinical studies have suggested that QYDP can alleviate CHF symptoms, the underlying molecular mechanisms are not fully understood. In this study, network pharmacology and molecular docking were used to explore the pharmacological targets of QYDP for CHF treatment. Four core genes were identified: AKT1, HIF1A, STAT3, and MYC. Molecular docking confirmed the interactions between these genes and active compounds in QYDP, such as kaempferol, luteolin, quercetin, tanshinone IIa, and cryptotanshinone. These findings suggest that QYDP may treat CHF through a multitarget mechanism, offering new insights into its therapeutic potential and providing a basis for further clinical research.

Keywords

CHF, cardiovascular disease, QYDP, traditional Chinese medicine

Introduction

Chronic heart failure (CHF) is a challenging and multifaceted clinical syndrome characterized by progressive deterioration of cardiac structure and function due to various factors (Ponikowski et al. 2016). Statistics indicate that by 2019, the number of reported heart failure cases worldwide had increased to approximately 56.19 million (Liu et al. 2024). Patients with CHF and patients with malignant tumors are similar in their 5-year survival rates (Lam et al. 2011). In recent years, the “fantastic four” drugs, beta-blockers, angiotensin receptor/neprilysin, sodium-glucose cotransporter-2, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists, have been used in clinical practice to treat patients with CHF (Bauersachs 2021; Bauersachs and Soltani 2023; Chinese Society of Cardiology et al. 2024). However, the prolonged use of these medications may result in a number of side effects, including electrolyte imbalance, hypotension, and fluid loss, necessitating the use of different medications for CHF treatment (Chinese Society of Cardiology et al. 2024). Therefore, there is an urgent need to identify adjunctive therapies to further improve the mortality rate of CHF, especially in patients with concomitant hypotension. (Greene et al. 2020; Liang and Gu 2021; He et al. 2023; Chinese Society of Cardiology et al. 2024).

Qishen Yiqi Dropping Pills (QYDP) have been widely used for the treatment of CHF because they can improve certain symptoms caused by insufficient Qi and blood as a type of Traditional Chinese medicine (TCM), renowned for having few adverse effects and long-lasting benefits (Hao et al. 2015). Many randomized controlled clinical trials (RCTs) have shown that QYDP is an efficient and safe treatment for persistent cardiovascular diseases (Chen et al. 2021). QYDP is composed of Danshen (Radix Salviae), Huangqi (Hedysarum multijugum Maxim), Jiangxiang (Dalbergia odorifera [Lignum]), and Sanqi (Panax notoginseng). Various herbal treatments offer therapeutic benefits for heart failure, particularly following acute myocardial infarction. For instance, Salvia miltiorrhiza helps alleviate inflammatory damage in heart failure by regulating the MD2/TLR4-MyD88 complex and the TLR4-TRAF6-NF-κB signaling pathway (Wang et al. 2020). Similarly, Astragalus mongholicus improves heart failure by modulating extracellular vesicle miR-27a-3p derived from pericardial adipose tissue, which activates AMPKα2-mediated mitophagy (Chen et al. 2024). Additionally, Panax notoginseng saponins protect against both acute myocardial infarction and heart failure by inducing autophagy (Wang et al. 2021).

Collectively, these findings highlight the pharmacological effects of QYDP in treating CHF. Several studies have shown that QYDP protects the myocardium in rats with CHF by enhancing cardiac angiogenesis, reducing myocardial fibrosis, improving cardiomyocyte hypertrophy, and inhibiting myocardial apoptosis (Lu et al. 2019; Wang et al. 2019; Chen et al. 2022); however, the specific pharmacological pathways through which QYDP exerts its effects in CHF remain unclear. Network pharmacology is an extremely powerful and innovative approach to elucidate the mechanisms of action of TCM at the molecular level (Zhang et al. 2013; Xu et al. 2020). This study was designed using network pharmacology and molecular docking to systematically search for the core target genes of the QYDP in treating CHF.

Materials and methods

Target preacquisition

The traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was used to identify the active QYDP constituents (Ru et al. 2014). Using UniProt, the gene targets of the identified compounds were determined (UniProt Consortium T 2017). We identified genes related to “chronic heart failure” from GeneCards (Zhou et al. 2024), OMIM (Amberger and Hamosh 2017), TTD (Barbarino et al. 2018), and PharmGKB databases. Overlapping genes were removed using the Venn package, and a final set of candidate genes associated with CHF was obtained.

Network construction

The Venn package (Jia et al. 2021) was used to determine the intersection of genes related to CHF and the active compounds of QYDP. The STRING database was used to analyze the intersecting genes and create a protein interaction network, using “humans” as the target species and a combined score of > 0.95 (Szklarczyk et al. 2023). Gene Ontology (GO) functional (Gene Ontology Consortium et al. 2012) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses (Kanehisa et al. 2017) were conducted for these genes using the screening criterion (q < 0.05) (Yu et al. 2012).

Network characterization and key gene acquisition

To further explore the network characteristics of the protein-protein interaction (PPI), we used the STRING database and CytoNCA plugin in Cytoscape 3.8.0 software (Tang et al. 2015). Key genes in this network were screened based on six parameters: 1) betweenness centrality (BC), 2) closeness centrality (CC), 3) degree centrality (DC), 4) eigenvector centrality, 5) local average connectivity-based method centrality, and 6) network centrality. We obtained key nodes (genes) based on their network scores and retained the genes whose expression was greater than the median value.

Molecular docking

For molecular docking, we collected the core chemical compounds of QYDP and selected the core genes from gene enrichment and network characteristic analyses. We obtained the 2D structures of these compounds using PubChem (Kim 2016) and converted them into 3D chemical structures using ChemOffice software. PDB was used to obtain the 3D structure of the core gene proteins (Burley et al. 2017). Water molecules and protein molecular ligands were removed using PyMol (Rosignoli and Paiardini 2022). The format of the core chemical compounds and core gene proteins was converted into pdbqt format, and their active pockets were determined using AutoDock Vina and AutoDockTools 1.5.6 software. Molecular docking data were generated using AutoDock Vina according to their active pockets. Finally, the 3D structures of the molecular docking were visualized using PyMol software. To validate the molecular docking method, a compound known to bind to target proteins was selected as a positive control.

Results

Target acquisition

Compounds in QYDP and corresponding target genes

A total of 108 active QYDP constituents were identified: 65 from Danshen, 20 from Huangqi, 15 from Jiangxiang, and eight from Sanqi. A total of 2390 target genes associated with the active compounds of QYDP were identified, including 932 target genes of Danshen, 953 target genes of Huangqi, 252 target genes of Jiangxiang, and 253 target genes of Sanqi. Ultimately, we obtained 1631 target genes. A total of 218 gene targets were obtained after the deletion of duplicate genes, as shown in Fig. 1.

Figure 1. 

Gene targets for QYDP compounds.

After removing the overlapping genes, we obtained a total of 2915 genes related to CHF, including 2818 genes from the GeneCards database (the screening criterion was a relevance score > 10), 152 genes from the DrugBank database, 268 genes from the OMIM database, 16 genes from the PharmGKB database, and 13 genes from the TTD database (Fig. 2).

Figure 2. 

Gene targets of the CHF from the databases.

Network construction

After eliminating duplicate genes using the R language Venn package, 218 therapeutic gene targets for QYDP and 2915 disease-related gene targets for CHF were identified. As illustrated in Fig. 3, we identified 157 intersecting genes linked to the active ingredients in QYDP that were associated with CHF.

Figure 3. 

One hundred and fifty-seven overlapping genes between QYDP and CHF.

PPI network of the disease and drug target genes

The results of the PPI analysis of the 157 intersecting genes show that a total of 117 genes were found to interact with other proteins (Fig. 4).

Figure 4. 

117 genes interacting with other proteins from the results of the PPI network.

GO enrichment analysis

From the GO enrichment analysis of the intersecting genes, we obtained 2283 biological processes, 218 molecular functions, and 77 cellular components using a screening criterion of a q value < 0.05. The top ten terms were visualized according to the q value (Fig. 5).

Figure 5. 

The GO enrichment results of the top 10 terms.

KEGG pathway enrichment analysis

We obtained 162 pathways using a screening criterion of a q value < 0.05 from the KEGG pathway enrichment analysis. According to the q value, the top 30 KEGG items were visualized, as shown in Fig. 6.

Figure 6. 

The top 30 KEGG pathway enrichment results.

Acquisition of key genes based on network characteristics analysis

Based on six parameters of the CytoNCA plugin, a PPI network of 117 overlapping genes was constructed using two filters. We acquired 36 nodes (genes) and 151 edges using the first filter (Fig. 7A). Using the second filter, we identified 12 core genes: CDKN1A, STAT3, JUN, AKT1, HIF1A, MAPK1, RB1, TP53, MAPK14, CCND1, MYC, and RELA (Fig. 7B, C).

Figure 7. 

PPI network of overlapping genes (yellow squares highlight important genes). A PPI network of the 117 overlapping genes; B The 36 genes obtained using the first filter of the CytoNCA plugin; C The acquisition of 12 key genes using the second filter of the CytoNCA plugin.

Molecular docking

We selected the core compounds of QYDP, namely kaempferol, luteolin, quercetin, tanshinone IIa, and cryptotanshinone, and four genes for molecular docking, namely HIF1A, MYC, STAT3, and AKT1. Combining the results of network characteristics and gene enrichment analyses, as shown in Table 1, Fig. 8. Trimetazidine, a compound experimentally validated to bind to the aforementioned targets, was used as a positive control. The validation results indicated favorable molecular docking interactions between trimetazidine and AKT1, Myc, HIF-1α, and STAT3 using the aforementioned method, as illustrated in Table 2, Fig. 9.

Table 1.
Download as
CSV
XLSX

The molecular docking results in the compounds of QYDP and four core genes.

Number Core targets Compounds Docking affinity (kcal/mol)
1 AKT1 kaempferol -8.1
Luteolin -8.2
Quercetin -8.2
2 Myc Quercetin -6.2
tanshinone IIa -7.4
3 HIF1A Quercetin -8.0
4 STAT3 cryptotanshinone -7.6
Table 2.
Download as
CSV
XLSX

The molecular docking results in the trimetazidine and four core genes.

Number Core genes Compound Docking affinity (kcal/mol)
1 AKT1 trimetazidine -6.6
2 Myc trimetazidine -5.1
3 HIF1A trimetazidine -5.4
4 STAT3 trimetazidine -4.8
Figure 8. 

Results of active chemicals binding to putative target proteins using molecular docking.

Figure 9. 

Results of the positive control, trimetazidine binding to putative target proteins using molecular docking.

Discussion

Previous research has demonstrated that CHF patient mortality is increasing globally, and optimizing CHF treatment may improve patient survival rates (Crowley et al. 2017; Lin et al. 2017; Yohannes et al. 2017). Based on practical clinical applications and related clinical studies, QYDP can improve cardiac function in patients with CHF (Chang et al. 2019; Mao et al. 2020; Wang et al. 2020; Chen et al. 2021; He et al. 2023; Xingmeng et al. 2023). Existing pharmacological mechanism studies show that QYDP improves cardiac function by regulating long noncoding RNA TINCR (Chen et al. 2022) or XIST gene (Luo et al. 2022) expression. Some studies have investigated the potential mechanism of QYDP by examining the expression of proteins such as Bax, VEGF (Wang et al. 2019), caspase-3, α-SMA, and TGF-β1 (Lu et al. 2019). However, it is unclear whether there are more pharmacological routes by which QYDP treats CHF. Network pharmacology studies make it possible to further identify the target genes and proteins of QYDP therapy in CHF.

According to our network pharmacology investigation, QYDP improved cardiac function through multiple targets and pathways. Moreover, we also observed some targets that have been experimentally verified to be related to the efficacy of QYDP, such as Bax, VEGF, and caspase-3, although the corresponding genes of the above proteins were excluded during the screening of the key genes, confirming to a certain extent that our study has reference value for the discovery of the pharmacological effects of QYDP in CHF. GO analysis revealed that the majority of the overlapping genes were responsible for phosphatase binding, oxidative stress, and other processes. According to KEGG analysis, fluid shear stress, atherosclerosis, and the TNF, IL-17, and PI3K-Akt signaling pathways were the major enriched pathways for the overlapping genes. Overall, network pharmacology revealed 12 key genes, including CDKN1A, JUN, MAPK1, RB1, TP53, MAPK14, CCND1, and RELA, and in particular, STAT3, HIF1A, MYC, and AKT1.

All four core gene targets have proven roles in CHF treatment. The signal transducer and activator of transcription 3 (STAT3) is necessary for several biological processes, notably cell proliferation and death. According to a previous study, astragaloside IV can reduce HF through the JAK-STAT3 pathway (Sui et al. 2019). The MYC proto-oncogene (also known as MYC or c-Myc) contributes to cellular transformation and cell cycle progression (Thompson 1998; Gomes et al. 2017). Analysis of GSE1145 microarray data revealed that MYC is closely related to heart failure (Chen et al. 2013). The Wnt/β-catenin/c-myc axis is closely related to abnormal cardiac remodeling and can prevent and treat heart failure (Hou et al. 2017). AKT serine/threonine kinase 1 (AKT1) controls various cellular processes such as angiogenesis, metabolism, cell division, and survival. A previous study reported that cardiac function was improved by regulating the angiogenic regulatory network via AKT1 induction in endothelial cells (Schiekofer et al. 2008). According to a previous study, sphingosylphosphorylcholine uses the lipid raft/PTEN/Akt1/mTOR-mediated autophagy to shield cardiomyocytes from ischemia-induced death (Yue et al. 2015). Apoptosis, energy metabolism, and angiogenesis are significantly affected by hypoxia-inducible factor-1 subunit alpha (HIF1A), a subunit of HIF-1. Muscone enhanced angiogenesis by upregulating HIF-1α and VEGFA expression, which in turn improved heart function (Du et al. 2018). Silter et al. (2010) reported that HIF-1α has a major part in protecting cardiac function against chronic pressure overload.

In this study, quercetin, kaempferol, luteolin, tanshinone IIA, and cryptotanshinone were screened from the compounds of QYDP using the TCMSP based on their better OB and DL. Many studies have shown that these compounds have anti-apoptotic, antioxidative, and anti-inflammatory effects. The TNF and the PI3K-Akt pathway are involved in treating multiple cardiovascular diseases with quercetin (Muhammad and Fatima 2015; Patel et al. 2018; Guo et al. 2019). Kaempferol is a flavonoid with both anti-inflammatory and antioxidant properties. According to a report, kaempferol shields cardiomyocytes from heart failure by regulating the NF-κB/mitogen-activated protein kinase and AMPK/Nrf2 pathways (Zhang et al. 2019). Luteolin has been reported to improve cardiac function by adjusting sarcoplasmic reticulum Ca2+-ATPase 2a levels in rats with heart failure (Hu et al. 2017). Tanshinone IIA regulates angiogenesis, inflammation resistance, and antioxidant activity and has anti-apoptotic effects (Gao et al. 2019; Zhao et al. 2019; Zhou et al. 2019). Although there is little research on the role of cryptotanshinone in heart failure, a study reported that cryptotanshinone can inhibit STAT3, resulting in the blockade of the NF-κB pathway (He et al. 2019).

Trimetazidine directly improves myocardial metabolism in both clinical and basic studies (Kantor et al. 2000). Therefore, trimetazidine was used as a positive control to validate the molecular docking method for active compounds of QYDP. The results showed that the propensity of core targets to bind kaempferol, luteolin, tanshinone IIa, quercetin, and cryptotanshinone was similar to that for trimetazidine. In brief, the findings of this study showed that AKT1, Myc, HIF-1α, and STAT3 may be the core targets of QYDP in treating cardiovascular disease. Nevertheless, this study was based on a network pharmacology method to mine and analyze the data. In the future, we plan to perform further clinical validation of the role of QYDP in CHF.

Conclusions

This network pharmacology study provides evidence for the use of QYDP in the treatment of CHF by identifying potential targets and providing insights into the mechanisms of action of QYDP in the treatment of CHF. AKT1, Myc, HIF1A, and STAT3 are potential targets of QYDP in CHF treatment, highlighting the potential of QYDP as an alternative and complementary therapy. Further experimental validation is warranted to confirm these findings and to elucidate the specific roles of the identified targets and pathways.

Acknowledgments

Our thanks go to Sijiang Li, who corrected the mistakes in English grammar in this article.

Additional information

Conflict of interest

The authors have declared that no competing interests exist.

Ethical statements

The authors declared that no clinical trials were used in the present study.

The authors declared that no experiments on humans or human tissues were performed for the present study.

The authors declared that no informed consent was obtained from the humans, donors or donors’ representatives participating in the study.

The authors declared that no experiments on animals were performed for the present study.

The authors declared that no commercially available immortalised human and animal cell lines were used in the present study.

Funding

This research was Supported by Fujian Provincial Natural Science Foundation of China (grant number: 2021J011421) and the training project for Young and Middle-aged backbone talents of Fujian Provincial Health Commission (grant number: 2020GGB051).

Author contributions

Conceptualization, Daqiu Chen and Fanglin Luo; methodology, Daqiu Chen; software, Yanqing Wu; validation, Daqiu Chen, Yixing Chen and Tao Ye; formal analysis, Daqiu Chen; investigation, Shunxiang Luo; resources, Daqiu Chen and Fanglin Luo; data curation, Daqiu Chen; writing—original draft preparation, Daqiu Chen; writing—review and editing, Yanqing Wu and Shunxiang Luo; visualization, Daqiu Chen; supervision, Fanglin Luo; project administration, Shunxiang Luo; funding acquisition, Daqiu Chen and Fanglin Luo. All authors have read and agreed to the published version of the manuscript.

Data availability

All data generated or analyzed during this study are included in this published article.

References

  • Amberger JS, Hamosh A (2017) Searching Online Mendelian Inheritance in Man (OMIM): A Knowledgebase of Human Genes and Genetic Phenotypes. Current protocols in bioinformatics 58: 1.2.1–1.2.12. https://doi.org/10.1002/cpbi.27
  • Barbarino JM, Whirl-Carrillo M, Altman RB, Klein TE (2018) PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdisciplinary Reviews. Systems Biology and Medicine 10(4): e1417. https://doi.org/10.1002/wsbm.1417
  • Burley SK, Berman HM, Kleywegt GJ, Markley JL, Nakamura H, Velankar S (2017) Protein data bank (PDB): The single global macromolecular structure archive. Methods in Molecular Biology 1607: 627–641. https://doi.org/10.1007/978-1-4939-7000-1_26
  • Chang M, Cheng L, Shen Y, Zhang Y, Zhang Z, Hao P (2019) Qishenyiqi dripping pill improves ventricular remodeling and function in patients with chronic heart failure: A pooled analysis. Medicine (Baltimore) 98(2): e13906A-F. https://doi.org/10.1097/MD.0000000000013906
  • Chen HB, Wang L, Jiang JF (2013) Re-analysis of expression profiles for revealing new potential candidate genes of heart failure. European Review for Medical and Pharmacological Sciences 17(7): 903–911. https://www.europeanreview.org/article/3677
  • Chen L, Wang R, Liu H, Wei S, Jing M, Wang M, Zhao Y (2021) Clinical efficacy and safety of qishen yiqi dropping pill combined with conventional western medicine in the treatment of chronic heart failure: A systematic review and meta-analysis. Evidence-Based Complementary and Alternative Medicine 202: 13. https://doi.org/10.1155/2021/6612653
  • Chen L, Pan L, Zhang Y, Chen Y, Su Y, Luo Y, Wu Z, Zheng W, Cai S, Liu X, Wu X (2022) Qishen Yiqi dropping pills improve cardiomyocyte hypertrophy via the lncRNA TINCR/miR-193b-3p/RORA axis. Journal of Thoracic Disease 14(11): 4372–4383. https://doi.org/10.21037/jtd-22-1322
  • Chen Z, Zhang M, Xu Q, Lu P, Liu M, Yin R, Liu X, Dai Y, Gao X, Gong J, Zhang S, Wang X (2024) Huangqi-Danshen decoction improves heart failure by regulating pericardial adipose tissue derived extracellular vesicular miR-27a-3p to activate AMPKα2 mediated mitophagy. Phytomedicine 135: 156187. [Epub ahead of print] https://doi.org/10.1016/j.phymed.2024.156187
  • Chinese Society of Cardiology,Chinese Medical Association,Chinese College of Cardiovascular Physician,Chinese Heart Failure Association of Chinese Medical Doctor Association,Editorial Board of Chinese Journal of Cardiology (2024) Chinese guidelines for the diagnosis and treatment of heart failure 2024. Zhonghua Xin Xue Guan Bing Za Zhi 52 (3): 235–275. [Chinese]
  • Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB, Stanifer JW, Mock CK, Wang X, Tang S, Nagi A, Kosinski AS, Williams Jr JW (2017) clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: A systematic review. Annals of Internal Medicine 166(3): 191–200. https://doi.org/10.7326/M16-1901
  • Du Y, Ge Y, Xu Z, Aa N, Gu X, Meng H, Lin Z, Zhu D, Shi J, Zhuang R, Wu X, Wang X, Yang Z (2018) Hypoxia-Inducible Factor 1 alpha (HIF-1α)/Vascular Endothelial Growth Factor (VEGF) Pathway Participates in Angiogenesis of Myocardial Infarction in Muscone-Treated Mice: Preliminary Study. Medical Science Monitor 24: 8870–8877. https://doi.org/10.12659/MSM.912051
  • Gao S, Li L, Li L, Ni J, Guo R, Mao J, Fan G (2019) Effects of the combination of tanshinone IIA and puerarin on cardiac function and inflammatory response in myocardial ischemia mice. Journal of Molecular and Cellular Cardiology 137: 59–70. https://doi.org/10.1016/j.yjmcc.2019.09.012
  • Blake JA, Dolan M, Drabkin H, Hill DP, Li N, Sitnikov D, Bridges S, Burgess S, Buza T, McCarthy F, Peddinti D, Pillai L, Carbon S, Dietze H, Ireland A, Lewis SE, Mungall CJ, Gaudet P, Chrisholm RL, Fey P, Kibbe WA, Basu S, Siegele DA, McIntosh BK, Renfro DP, Zweifel AE, Hu JC, Brown NH, Tweedie S, Alam-Faruque Y, Apweiler R, Auchinchloss A, Axelsen K, Bely B, Blatter M-, Bonilla C, Bouguerleret L, Boutet E, Breuza L, Bridge A, Chan WM, Chavali G, Coudert E, Dimmer E, Estreicher A, Famiglietti L, Feuermann M, Gos A, Gruaz-Gumowski N, Hieta R, Hinz C, Hulo C, Huntley R, James J, Jungo F, Keller G, Laiho K, Legge D, Lemercier P, Lieberherr D, Magrane M, Martin MJ, Masson P, Mutowo-Muellenet P, O’Donovan C, Pedruzzi I, Pichler K, Poggioli D, Porras Millán P, Poux S, Rivoire C, Roechert B, Sawford T, Schneider M, Stutz A, Sundaram S, Tognolli M, Xenarios I, Foulgar R, Lomax J, Roncaglia P, Khodiyar VK, Lovering RC, Talmud PJ, Chibucos M, Giglio MG, Chang H-, Hunter S, McAnulla C, Mitchell A, Sangrador A, Stephan R, Harris MA, Oliver SG, Rutherford K, Wood V, Bahler J, Lock A, Kersey PJ, McDowall DM, Staines DM, Dwinell M, Shimoyama M, Laulederkind S, Hayman T, Wang S-, Petri V, Lowry T, D’Eustachio P, Matthews L, Balakrishnan R, Binkley G, Cherry JM, Costanzo MC, Dwight SS, Engel SR, Fisk DG, Hitz BC, Hong EL, Karra K, Miyasato SR, Nash RS, Park J, Skrzypek MS, Weng S, Wong ED, Berardini TZ, Huala E, Mi H, Thomas PD, Chan J, Kishore R, Sternberg P, Van Auken K, Howe D, Westerfield M (2012) Gene Ontology annotations and resources. Nucleic acids research 41(D1): D530–D535. https://doi.org/10.1093/nar/gks1050
  • Guo G, Gong L, Sun L, Xu H (2019) Quercetin supports cell viability and inhibits apoptosis in cardiocytes by down-regulating miR-199a. Artificial Cells, Nanomedicine, and Biotechnology 47(1): 2909–2916. https://doi.org/10.1080/21691401.2019.1640711
  • Hao PP, Jiang F, Chen YG, Yang J, Zhang K, Zhang MX, Zhang C, Zhao YX, Zhang Y (2015) Traditional Chinese medication for cardiovascular disease. Nature Reviews Cardiology 12(2): 115–122. https://doi.org/10.1038/nrcardio.2014.177
  • He J, Zhong X, Zhao L, Gan H (2019) JAK2/STAT3/BMP-2 axis and NF-κB pathway are involved in erythropoietin-induced calcification in rat vascular smooth muscle cells. Clinical and Experimental Nephrology 23(4): 501–512. https://doi.org/10.1007/s10157-018-1666-z
  • He X, Jiang Y, Li S, Liu D, Li Z, Han X, Zhang X, Dong X, Liu H, Huang J, Wang X, Long W, Ni S, Yang Z, Ye T (2023) Efficacy and Safety of QiShen YiQi Dripping Pills in the Treatment of Coronary Heart Disease Complicating Chronic Heart Failure (Syndrome of Qi Deficiency with Blood Stasis): Study Protocol for a Randomized, Placebo-Controlled, Double-Blind and Multi-Centre Phase II Clinical Trial. International Journal of General Medicine 16: 6177–6188. https://doi.org/10.2147/IJGM.S436999
  • Hou N, Ye B, Li X, Margulies KB, Xu H, Wang X, Li F (2016) Transcription Factor 7-like 2 Mediates Canonical Wnt/β-Catenin Signaling and c-Myc Upregulation in Heart Failure. Circulation: Heart Failure 9(6): e003010. https://doi.org/10.1161/CIRCHEARTFAILURE.116.003010
  • Hu W, Xu T, Wu P, Pan D, Chen J, Chen J, Zhang B, Zhu H, Li D (2017) Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca2+-ATPase 2a. Scientific Reports 7(1): 41017. https://doi.org/10.1038/srep41017
  • Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K (2017) KEGG: New perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Research 45(D1): D353–D361. https://doi.org/10.1093/nar/gkw1092
  • Kantor PF, Lucien A, Kozak R, Lopaschuk GD (2000) The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circulation Research 86(5): 580–588. https://doi.org/10.1161/01.RES.86.5.580
  • Lam CS, Donal E, Kraigher-Krainer E, Vasan RS (2011) Epidemiology and clinical course of heart failure with preserved ejection fraction. European Journal of Heart Failure 13(1): 18–28. https://doi.org/10.1093/eurjhf/hfq121
  • Liang B, Gu N (2021) Traditional chinese medicine for coronary artery disease treatment: Clinical evidence from randomized controlled trials. Frontiers in Cardiovascular Medicine 8: 702110. https://doi.org/10.3389/fcvm.2021.702110
  • Lin MH, Yuan WL, Huang TC, Zhang HF, Mai JT, Wang JF (2017) Clinical effectiveness of telemedicine for chronic heart failure: a systematic review and meta-analysis. Journal of investigative medicine: the official publication of the American Federation for Clinical Research 65(5): 899–911. https://doi.org/10.1136/jim-2016-000199
  • Liu Z, Li Z, Li X, Yan Y, Liu J, Wang J, Guan J, Xin A, Zhang F, Ouyang W, Wang S, Xia R, Li Y, Shi Y, Xie J, Zhang Y, Pan X (2024) Global trends in heart failure from 1990 to 2019: An age-period-cohort analysis from the Global Burden of Disease study. ESC Heart Failure 11(5): 3264–3278. https://doi.org/10.1002/ehf2.14915 [Epub 2024 Jun 27. PMID: 38937863; PMCID: PMC11424301]
  • Lu Y, Wang D, Yuan X, Wang M, Li Z, Bao X, Zhang C, Jing H (2019) Protective effect of Qishen Yiqi dropping pills on the myocardium of rats with chronic heart failure. Experimental and Therapeutic Medicine 17(1): 378–382. https://doi.org/10.3892/etm.2018.6957
  • Luo Y, Chen J, Chen Y, Su Y, Wu X, Zheng W, Liu X, Chen L (2022) Qishen Yiqi dropping pills improve isoproterenol-induced cardiomyocyte hypertrophy by regulating X-inactive specific transcript (XIST) expression in rats. Journal of Thoracic Disease 14(6): 2213–2223. https://doi.org/10.21037/jtd-22-606
  • Mao J, Zhang J, Lam CSP, Zhu M, Yao C, Chen S, Liu Z, Wang F, Wang Y, Dai X, Niu T, An D, Miao Y, Xu T, Dong B, Ma X, Zhang F, Wang X, Fan R, Zhao Y, Jiang T, Zhang Y, Wang X, Hou Y, Zhao Z, Su Q, Zhang J, Wang B, Zhang B (2020) Qishen Yiqi dripping pills for chronic ischaemic heart failure: Results of the CACT-IHF randomized clinical trial. ESC Heart Failure 7(6): 3881–3890. https://doi.org/10.1002/ehf2.12980
  • Muhammad SA, Fatima N (2015) In silico analysis and molecular docking studies of potential angiotensin-converting enzyme inhibitor using quercetin glycosides. Pharmacognosy Magazine 11(Suppl 1): S123–S126. https://doi.org/10.4103/0973-1296.157712
  • Patel RV, Mistry BM, Shinde SK, Syed R, Singh V, Shin HS (2018) Therapeutic potential of quercetin as a cardiovascular agent. European Journal of Medicinal Chemistry 155: 889–904. https://doi.org/10.1016/j.ejmech.2018.06.053
  • Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Heart Journal 37(27): 2129–2200. https://doi.org/10.1093/eurheartj/ehw128
  • Ru J, Li P, Wang J, Zhou W, Li B, Huang C, Li P, Guo Z, Tao W, Yang Y, Xu X, Li Y, Wang Y, Yang L (2014) TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. Journal of Cheminformatics 6(1): 13. https://doi.org/10.1186/1758-2946-6-13
  • Schiekofer S, Belisle K, Galasso G, Schneider JG, Boehm BO, Burster T, Schmitz G, Walsh K (2008) Angiogenic-regulatory network revealed by molecular profiling heart tissue following Akt1 induction in endothelial cells. Angiogenesis 11(3): 289–299. https://doi.org/10.1007/s10456-008-9112-6
  • Silter M, Kögler H, Zieseniss A, Wilting J, Schäfer K, Toischer K, Rokita AG, Breves G, Maier LS, Katschinski DM (2010) Impaired Ca(2+)-handling in HIF-1alpha(+/-) mice as a consequence of pressure overload. Pflügers Archiv 459(4): 569–577. https://doi.org/10.1007/s00424-009-0748-x
  • Sui YB, Wang Y, Liu L, Liu F, Zhang YQ (2019) Astragaloside IV alleviates heart failure by promoting angiogenesis through the JAK-STAT3 pathway. Pharmaceutical Biology 57(1): 48–54. https://doi.org/10.1080/13880209.2019.1569697
  • Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, Gable AL, Fang T, Doncheva NT, Pyysalo S, Bork P, Jensen LJ, von Mering C (2023) The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Research 51(D1): D638–D646. https://doi.org/10.1093/nar/gkac1000
  • Wang L, Wang L, Zhou X, Ruan G, Yang G (2019) Qishen Yiqi Dropping Pills Ameliorates Doxorubicin-induced Cardiotoxicity in Mice via Enhancement of Cardiac Angiogenesis. Medical Science Monitor 25: 2435–2444. https://doi.org/10.12659/MSM.915194
  • Wang C, Yang Y, Zhang G, Li J, Wu X, Ma X, Shan G, Mei Y (2019) Long noncoding RNA EMS connects c-Myc to cell cycle control and tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 116(29): 14620–14629. https://doi.org/10.1073/pnas.1903432116
  • Wang H, Li L, Qing X, Zhang S, Li S (2020) Efficacy of qishen yiqi drop pill for chronic heart failure: An updated meta-analysis of 85 studies. Cardiovascular Therapeutics 8138764: 1–14. https://doi.org/10.1155/2020/8138764
  • Wang X, Guo D, Li W, Zhang Q, Jiang Y, Wang Q, Li C, Qiu Q, Wang Y (2020) Danshen (Salvia miltiorrhiza) restricts MD2/TLR4-MyD88 complex formation and signalling in acute myocardial infarction-induced heart failure. Journal of Cellular and Molecular Medicine 24(18): 10677–10692. https://doi.org/10.1111/jcmm.15688
  • Wang D, Lv L, Xu Y, Jiang K, Chen F, Qian J, Chen M, Liu G, Xiang Y (2021) Cardioprotection of Panax notoginseng saponins against acute myocardial infarction and heart failure through inducing autophagy. Biomedicine and Pharmacotherapy 136: 111287. https://doi.org/10.1016/j.biopha.2021.111287
  • Xingmeng W, Guohua D, Hui G, Wulin G, Huiwen Q, Maoxia F, Runmin L, Lili R (2023) Clinical efficacy and safety of adjunctive treatment of chronic ischemic heart failure with Qishen Yiqi dropping pills: A systematic review and meta-analysis. Frontiers in Cardiovascular Medicine 10: 1271608. https://doi.org/10.3389/fcvm.2023.1271608
  • Xu M, Li Z, Yang L, Zhai W, Wei N, Zhang Q, Chao B, Huang S, Cui H (2020) Elucidation of the Mechanisms and Molecular Targets of Sanhuang Xiexin Decoction for Type 2 Diabetes Mellitus Based on Network Pharmacology. BioMed Research International 5848497: 1–13. https://doi.org/10.1155/2020/5848497
  • Yohannes AM, Chen W, Moga AM, Leroi I, Connolly MJ (2017) Cognitive Impairment in Chronic Obstructive Pulmonary Disease and Chronic Heart Failure: A Systematic Review and Meta-analysis of Observational Studies. Journal of the American Medical Directors Association 18(5): 451.e1–451.e11. https://doi.org/10.1016/j.jamda.2017.01.014
  • Yu G, Wang LG, Han Y, He QY (2012) clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS: A Journal of Integrative Biology 16(5): 284–287. https://doi.org/10.1089/omi.2011.0118
  • Yue HW, Liu J, Liu PP, Li WJ, Chang F, Miao JY, Zhao J (2015) Sphingosylphosphorylcholine protects cardiomyocytes against ischemic apoptosis via lipid raft/PTEN/Akt1/mTOR mediated autophagy. Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1851(9): 1186–1193. https://doi.org/10.1016/j.bbalip.2015.04.001
  • Zhang GB, Li QY, Chen QL, Su SB (2013) Network pharmacology: a new approach for chinese herbal medicine research. Evidence-based complementary and alternative medicine 2013: 621423. https://doi.org/10.1155/2013/621423
  • Zhang L, Guo Z, Wang Y, Geng J, Han S (2019) The protective effect of kaempferol on heart via the regulation of Nrf2, NF-κβ, and PI3K/Akt/GSK-3β signaling pathways in isoproterenol-induced heart failure in diabetic rats. Drug Development Research 80(3): 294–309. https://doi.org/10.1002/ddr.21495
  • Zhao M, Luo M, Xie Y, Jiang H, Cagliero C, Li N, Ye H, Wu M, Hao S, Sun T, Yang H, Zhang M, Lin T, Lu H, Zhu J (2019) Development of a recombinant human IL-15·sIL-15Rα/Fc superagonist with improved half-life and its antitumor activity alone or in combination with PD-1 blockade in mouse model. Biomedicine and Pharmacotherapy 112: 108677. https://doi.org/10.1016/j.biopha.2019.108677
  • Zhou ZY, Zhao WR, Zhang J, Chen XL, Tang JY (2019) Sodium tanshinone IIA sulfonate: A review of pharmacological activity and pharmacokinetics. Biomedicine and Pharmacotherapy 118: 109362. https://doi.org/10.1016/j.biopha.2019.109362
  • Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F (2024) TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Research 52(D1): D1465–D1477. https://doi.org/10.1093/nar/gkad751
login to comment