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.