4. Discussion
There is an urgent need to develop new strategies for CVD treatment because of the fast growing burden of CVD and the poor efficacy and side effects of the existing approved medicines. Network pharmacology has been used for of interaction between drugs and targets of diseases, and it is capable of comprehensively describing complexities among drugs and diseases[33, 34]. Therefore, the development of network pharmacology techniques that can predict multiple drug-target interactions may hold the key to future drug discoveries in complex diseases such as CVD. TwHF exhibits therapeutic efficacy in preclinical models of CVD has been identified in several studies[35-37]. In this study, the underlying mechanism of protective effects of TwHF on CVD was uncovered by a network pharmacology strategy. Therapeutic targets and the signaling pathways in which they participate were investigated by databases screening, PPI network construction, and pathway enrichment analysis. Furthermore, molecular docking was applied to validate the specific interactions between core targets and CVD.
In this study, 51 active compounds of TwHF were determined based on ADME. Pharmacological analysis suggested that these active components may have protective effects on CVD. Nobiletin has been reported to in H9c2 cardiomyocytes attenuate hypoxia/reoxygenation injury by the inhibition of oxidative stress and apoptosis as well as myocardial ischemia and reperfusion injury in vivo[38, 39]. Triptonide ameliorates diabetic cardiomyopathy via mediating inflammation[40, 41]. Isoxanthohumol regulate vivo vascular proliferation in vivo the -inflammatory crosstalk of vascular cells, contributing to the treatment of angiogenesis and inflammation-related diseases[42]. Stigmasterol protects against Ang II-induced aortic smooth muscle cell proliferation by the arrest of the cell-cycle, promotion of apoptosis and ROS production[43]. Kaempferol attenuates cardiac hypertrophy and isoproterenol-induced heart failure in diabetic rats[44, 45].
Subsequently, targets of TwHF and CVD were also identified. 178 common targets between TwHF and CVD were selected. Finally, we collected 5 cores candidate genes for further analysis. The interactive values and interaction indicate that these targets are tightly contact with other targets in “CVD-target PPI network” and responsible for TwHF actiong on CVD and pathogenesis of CVD. The alterations of Akt signaling play an important role in many cardiovascular pathological processes such as atherosclerosis, cardiac hypertrophy, and vascular remodeling. Several Akt inhibitors have been developed and tested as anti-tumor agents. They could be potential novel therapeutics for the cardiovascular diseases[46]. PIK3R1, MAPK1 and PIK3CA may modulate platelet activation and be involved in CVD[47]. Class I phosphatidylinositol 3-kinases (PI3Ks) are heterodimeric molecules composed of a regulatory subunit (usually p85 regulatory subunit) and a catalytic subunit (usually p110 catalytic subunit)[48, 49]. The catalytic subunit p110α of PI3K is encoded by the gene PIK3CA, which regulates doxorubicin-induced biventricular atrophy and remodeling in right ventricular dysfunction[50]. Indeed, the compounded cardiovascular risk of PI3Kα inhibitor use in breast cancer, is particularly relevant given the prevalence of p110α gain-of-function mutations[51]. MAPK kinases including p38 mitogen activated protein kinase (p38), extracellular signal-regulated kinase1/2 (ERK), and c-Jun NH2 terminal protein kinase (JNK), are major components of pathways controlling embryogenesis, cell differentiation, cell proliferation, and cell death[52]. The inhibition of the phosphorylation of JNK, p38MAPK, and ERK1/2 could block proliferation and migration of vascular smooth muscle cells[53-55]. APP is associated with platelet adhesion to amyloid peptides and potentiation of thrombus formation[56, 57]. It was reported TP53 can differentiate patient with left main coronary artery disease (CAD) from patients healthy participants[58].
Top ten GO of each category (BP, MF, CC) and KEGG pathway associated with TwHF acting on CVD were classified. The results indicated that the major hubs were significantly involved in multiple BPs, including ERBB signaling pathway, regulation of generation of precursor metabolites and energy, peptidyl-serine phosphorylation, aging, peptidyl-serine modification, regulation of developmental growth, neuron death, regulation of DNA metabolic process, cellular response to peptide, and response to oxidative stress. KEGG pathway enrichments analysis showed TwHF may impart therapeutic effects on CVD mainly through cancer pathways. Cancer and cardiovascular disease (CVD) share overlapping pathophysiology and risk factors as well as biological mechanisms[59]. Protein–protein interactions analysis have varied roles in driving and maintaining the growth of cancer and CVD[60, 61]. TwHF was also identified for the treatment of multiple cancer[62-64].
According to screening criteria of high OB, Celaxanthin, Hypodiolide A, Triptofordin B2, Triptofordin B2, Celallocinnine were chosen for the compound-ligand interaction analysis by molecular docking to explore the anti-CVD effects of TwHF. The results molecular docking reflected that these active compounds possess suitable anti-CVD activity. However, the active properties TwHF and the molecular targets of CVD need to be further verified in future studies.