ABSTRACT
Objective
The study was to investigate the possible mechanism of Lu'an GuaPian tea in treating heart failure (HF) via network pharmacology and molecular docking.
Method
The target of Lu'an GuaPian tea were screened. The GeneCards, NCBI, and DisGeNET databases were searched for HF targets. The GO and KEGG pathway analysis were used to obtain the targets and pathways. Molecular docking was used to verify the most likely targets and flavonoids.
Results
The Venn diagram revealed that AKT1, TNF, SRC, EGFR, ESR1, PTGS2, MMP9, and KDR were the top 8 target genes. GO and KEGG analysis suggested that Lu'an GuaPian tea could treat HF through PI3K-Akt pathway. Molecular docking predicted that compounds 1 and 7 have the highest binding affinity.
Conclusion
Lu'an GuaPian tea can be used to treat HF via PI3K-Akt signaling pathway, and the compound 1 and 7 were the most active lead compounds for regulating PI3K.
1. Introduction
Heart failure (HF) refers to various cardiac functional or organic diseases caused by cardiac insufficiency or dysfunction, which may result in cardiac output failing to meet the metabolic requirements (Kowalska et al., Citation2021). Following HF, organ function defect, dyspnea, fluid retention, and other major hazards to life safety (Krzesinski et al., Citation2021). HF is exacerbated by a prolonged inflammatory response caused by ventricular remodelling (VR) following a myocardial infarction (MI). Because a persistent inflammatory response after MI exacerbates HF, reducing MI and inflammation might be an important therapeutic focus for HF research (Mouton et al., Citation2018).
The daily drinking of green tea is connected with cardiovascular health and a lower risk of cardiovascular disease (Landini et al., Citation2021). Green tea is one of the most extensively consumed beverages in the world. Green tea or its extracts are considered safe because no side effects have been reported in clinical trials (Oyama et al., Citation2017; Zhang et al., Citation2018). Flavonoids are natural chemical substances and secondary plant metabolites that are commonly found in fruits, vegetables, grains, bark, flowers, tea, and wine (Zhou et al., Citation2020). A diet rich in flavonoids is associated with a reduced risk of HF. Flavonoids’ structural hydroxyl groups can play a role in scavenging free radicals, mediating antioxidant effects, and modulating the function of inflammatory cells (Yamagata & Yamori, Citation2020). Lu’an GuaPian tea, produced in Lu’an City, China, is one of the top ten famous teas in China. Previous research has demonstrated that flavonoids in Lu’an GuaPian tea primarily consist of flavonoid aglycones, flavonoid glycosides, and acetylated flavonoid glycosides (Bai et al., Citation2017). Flavonoids in Lu’an GuaPian tea have a wide variety of biological activities, as demonstrated by the potent inhibition of lipid accumulation in 3T3-L1 adipocytes (Bai et al., Citation2017), inhibition of α-glucosidase and α-amylase (Hua et al., Citation2018), inhibition of TMA-lyase (Hua, Zhou et al., Citation2022), and protection of myocardial injury (Hua et al., Citation2021; Hua, Li et al., Citation2022). Impressively, our prior research indicated that flavonoids in Lu’an GuaPian tea exert myocardial protection by inhibiting the TLR4/MyD88/NF-κB and NLRP3/Caspase-1 signalling pathways (Hua et al., Citation2021; Hua, Li et al., Citation2022). However, the mechanisms by which Lu’an GuaPian tea protects against HF are yet unclear. In addition, it is crucial to determine which flavonoids have function in Lu’an GuaPaian tea ().
Table 1. The chemical structures of flavonoids in Lu’an GuaPian tea.
Network pharmacology is a new field based on systems biology and multidirectional pharmacology that integrates virtual computing, high-throughput omics analysis, and network database search methods to construct biomolecular networks and provides guidance for drug discovery and disease treatment mechanisms through network analysis (Noor et al., Citation2022; Yang et al., Citation2022). Through network pharmacology analysis, we can systematically examine the possible targets, mechanisms, and active components of Lu’an GuaPian tea, giving a theoretical foundation for extensive research on functional foods and the in-depth development of tea.
In this study, network pharmacology was utilized to anticipate the target and mechanism of Lu’an GuaPian tea in the prevention and treatment of HF. Molecular docking was performed to determine the most likely targets and pathways of Lu’an Gu’Pian tea and to identify which flavonoids with high binding affinity.
2. Methods
2.1. The ingredients in Lu’an GuaPian tea and targets
The flavonoids (1-21) in Lu’an GuaPian tea were mainly from the previous studies (Bai et al., Citation2017). The structures of the flavonoids were mapped by ChemDraw software. The chemical structures of flavonoids were imported into the Swiss Target Prediction database to screen the targets (Probability > 0) (Gfeller et al., Citation2014).
2.2. Disease targets
The “Heart Failure” keyword was used to obtain the human genes from the GeneCards database (https://www.genecards.org/), NCBI databases (https://www.ncbi.nlm.nih.gov/), and DisGeNET database (Piñero et al., Citation2017). The targets obtained from GeneCards database were screened by median values according to scores to obtain more relevant targets.
2.3. Construction of “ingredient-disease-target” network
The common target genes of flavonoids in Lu’an GuaPian tea and HF were collected by Venny (version 2.1). The “ingredient-disease-target” network was constructed and visualized using Cytoscape software (version 3.7.2).
2.4. Protein–protein interaction (PPI) network construction
The potential targets of Lu’an GuaPian tea in the treatment of HF were imported into the STRING database (https://string-db.org/cgi/input.pl) (Szklarczyk et al., Citation2017). The protein type was set to “Homo sapiens” and PPI network data was obtained. The results were visualized using Cytoscape software, and the topological properties were analyzed by network analyzer, and the core targets of Lu’an GuaPian tea in the treatment of HF were screened.
2.5. Gene Ontology (GO) analysis
The GO enrichment analysis includes the biological process (BP), cellular component (CC), and molecular function (MF), with corrected P < 0.05 were selected as screening indexes (Ashburner et al., Citation2000). R software (version R 4.0.3), clusterProfiler, enrichplot, and ggplot2 were used to draw the histogram and bubble diagram.
2.6. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis
KEGG pathway enrichment analysis was performed on the common targets of drug and diseases (Kanehisa et al., Citation2017), and the corrected P < 0.05 was screened by using String database. R software (version R 4.0.3), and clusterProfiler was used to draw the histogram and bubble diagram.
2.7. Molecular docking
Flavonoids have good myocardial protection and are also the effective components of tea. Our previous study found that 21 kinds of flavonoids and flavonoid glycosides could be isolated from Lu’an GuaPian tea, therefore, we chose these flavonoids for molecular docking. CB-dock website was used to predict the binding affinity of flavonoids in Lu’an GuaPian tea and phosphatidylinositol 3-kinase (PI3 K). (1) PI3 K (PDB ID: 4L23) (Zhao et al., Citation2013) was downloaded from RCSB PDB database. (2) The structures of flavonoids were mapped by ChemDraw software. (3) PI3 K and flavonoids were input to CB-Dock for molecular docking (Liu et al., Citation2020). PI-103 as a specific inhibitor of PI3 K was used as a control (Helwa et al., Citation2020). VINA scores represented the binding affinity between compounds and targets (Zhang, Tang, et al., Citation2021).
3. Results
3.1. Integration of Lu’an GuaPian tea and heart failure targets
After Swiss Target Prediction database screening, 118 potential drug targets were obtained for flavonoids in Lu’an GuaPian tea after deduplication. The GeneCards database, NCBI databases, and DisGeNET database were then searched for disease targets, yielding 7193 genes associated with HF. Finally, the targets of flavonoids were combined with the targets of HF to obtain the common targets. The common targets were plotted by Venn diagrams (). The Venn diagram showed that 95 targets were potential targets of flavonoids in Lu’an GuaPian tea for the treatment of HF.
Figure 1. The Venn diagram of the common targets. The 95 overlapping targets for Lu’an GuaPian tea in the treatment of HF.
3.2. PPI network and core target analysis
The information on protein interactions obtained from the String database was put into the Cytoscape to generate the PPI network (). The nodes represent the target genes, and the colour depth and node size correlate positively with the degree value. The network has 95 nodes and 509 edges with an average degree value of 10.7. Notably, AKT1, TNF, SRC, EGFR, ESR1, PTGS2, MMP9, and KDR were the top 8 targets that participated in treating HF with Lu’an GuaPian tea. AKT1 was detected as the most considerable protein in the PPI network.
Figure 2. PPI network diagram. The graph shows the interrelationships among 95 common targets.
3.3. Go enrichment analysis
The results of GO enrichment analysis showed that there were 1395 BP terms, 97 CC terms and 51 MF terms. According to the number of enriched genes, the top 10 entries in each section were displayed (). The main BP terms were involved in response to oxidative stress, cellular to chemical stress, and cellular response to oxidative stress. The CC terms primarily included apical part of cell, apical plasma membrane, and transferase complex, transferring phosphorus-containing groups. The MF terms were mainly related to protein serine/threonine kinase activity, protein tyrosine kinase activity, and lyase activity.
Figure 3. GO enrichment analysis. BP diagram, CC diagram, and MF diagram. BP, CC, and MF column colours indicate enrichment significance based on adjusted P-value.
3.4. Kegg enrichment analysis
According to the KEGG analysis, a total of 94 enrichment pathways were screened. The importance of the top 20 pathways is evaluated and ranked by the bubble diagram (). The colour corresponds to the size of the adjusted P-value. This suggests that Lu’an GuaPian tea can be used to treat HF through multiple pathways, such as PI3K-Akt signalling pathway, proteoglycans in cancer, endocrine resistance, EGFR tyrosine kinase inhibitor resistance, and nitrogen metabolism. PI3K-Akt signalling pathway may be the main mechanism. In the PI3K-Akt signalling pathway, PI3 K is the most important key target. Therefore, we chose PI3 K as our research target, and the flavonoids in Lu’an GuaPian tea with PI3 K via molecular docking to clarify the possible mechanism of HF.
Figure 4. KEGG enrichment analysis. The significance of the top 20 pathways is evaluated and ranked via a bubble diagram. The horizontal axis represents importance according to the corrected P-value.
3.5. Molecular docking results
Molecular docking showed that the VINA scores of (1), (2), (4), (7), (8), (9), (10), (11), (12), (14), (15), (16), (17), (18), (19), (20) were higher than that of the PI3 K inhibitor (PI-103) ( and ). Among them, the combination of compounds in Lu’an GuaPian tea with higher VINA scores with amino acid residues were shown in . Molecular docking results showed that the compound 1 and 7 has high binding affinity. Hence, the compound 1 and 7 were the most active and could be used as lead compounds for inhibiting PI3 K in the prevention and treatment of HF.
Figure 5. The 3D pictures of the flavonoids in Lu’an GuaPian tea with PI3K. (A) 1-PI3 K complex, (B) 2-PI3 K complex, (C) 4-PI3 K complex, (D) 7-PI3 K complex, (E) 8-PI3 K complex, (F) 9-PI3 K complex, (G) 10-PI3 K complex, (H) 11-PI3 K complex, (I) 12-PI3 K complex, (J) 14-PI3 K complex, (K) 15-PI3 K complex, (L) 16-PI3 K complex, (M) 17-PI3 K complex, (N) 18-PI3 K complex, (O) 19-PI3 K complex, (P) 20-PI3 K complex, (Q) PI-103-PI3 K complex.
Figure 6. Binding of the flavonoids in Lu’an GuaPian tea to amino acid residues of PI3K. (A) 1, (B) 7, (C) 8, (D) 9, (E) 10, (F) 11, (G) 15, (H) 16, (I) 17, (J) PI-103.
Table 2. Docking of the flavonoids in Lu’an GuaPian tea with PI3K.
4. Discussion
Network pharmacology is a promising method for elucidating the mechanisms underlying functional food (Zhang, Hu, et al., Citation2021). In this study, 7193 disease-related potential targets related to HF were identified based on the network pharmacology, and the common 95 targets of flavonoids in Lu’an GuaPian tea and chronic heart failure were found. We found that the effects of Lu’an GuaPian tea in treating HF involved severa major signalling pathways, such as PI3 K/Akt signalling pathway, proteoglycans in cancer, endocrine resistance, EGFR tyrosine kinase inhibitor resistance, and nitrogen metabolism. More importantly, the network pharmacological analysis revealed that Lu’an GuaPian tea could improve heart functions using the PI3 K/Akt signalling pathway.
The PI3 K/Akt pathway is the most important pathway in the enrichment study and a crucial mechanism in HF. PI3 K/Akt is a traditional signal transduction system that can directly affect the expression of Bcl-2/Bax and plays a crucial role in regulating cardiomyocyte survival, cardiac remodelling, and inflammation (Zhao et al., Citation2021). Activation of the PI3 K/Akt pathway is a mechanism shared by both healthy and pathological cardiac hypertrophy, and physiological hypertrophy may improve systolic and diastolic heart function (Li et al., Citation2021). However, long-term sustained activation of the PI3 K/Akt pathway in HF under pathological conditions promotes excessive cardiac development, mitochondrial dysfunction, ROS generation, and impaired Ca2+ handling (Nakamura & Sadoshima, Citation2018). Therefore, PI3 K/Akt pathway plays an important role in the pathogenesis of HF.
Our previous study found that 21 kinds of flavonoids and flavonoid glycosides could be isolated from Lu’an GuaPian tea. Drinking green tea daily is strongly associated with cardiovascular health and a reduced risk of cardiovascular disease. The myocardial protective effect of kaempferol was mainly reflected in the obvious reduction of lipid distribution, infarct size and oxidative stress in myocardial ischemic injury model rats (Vishwakarma et al., Citation2018). Quercetin may reduce ROS-mediated mitochondrial damage and inflammation through Nrf2/HO-1 and p38MAPK/NF-κBp65/IL-8 signalling pathways, thereby antagonizing cisplatin induced cardiotoxicity (Wang et al., Citation2022). Kaempferol-3-O-rutinoside can prevent and treat VR after AMI, and the protective effect is related to its regulatory NF-κB/NLRP3/Caspase-1 signalling pathway (Hua, Li et al., Citation2022). Flavonoids have good cardioprotective effects, we performed molecular docking of these compounds to predict their binding ability to PI3 K. Molecular docking technology can be used to verify the binding affinity of flavonoids in Lu’an GuaPian tea to PI3 K. In this paper, PI-103, a specific inhibitor of PI3 K, was used as a control. The docking results showed that the binding affinity of most flavonoid glycosides to PI3 K was higher than that of PI-103, and the binding affinity of acetylated flavonoid glycosides were higher. (1) and (7) had the highest binding affinity to PI3 K, which were the most active and could be used as lead compounds for regulating PI3 K in the prevention and treatment of HF.
5. Conclusion
Lu’an GuaPian tea can be used to treat HF through PI3K-Akt signalling pathway, and acetylated flavonoid glycosides (1 and 7) were the most active and could be used as lead compounds for regulating PI3 K in the prevention and treatment of HF. These findings can further improve the mechanisms underlying the Lu’an GuaPian tea as a functional food against HF.
Acknowledgements
Peng Zhou contributed to the study concept and design. Fang Hua performed the experiments and data analyses. Ling-li Shi contributed to literature review and data analyses. All authors read and approved the final manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
References
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