Target network differences between western drugs and Chinese herbal ingredients in treating cardiovascular disease
© Fu et al; licensee BioMed Central Ltd. 2014
Published: 19 March 2014
Western drugs have achieved great successes in CVDs treatment. However, they may lead to some side effects and drug resistance. On the other hand, more and more studies found that Traditional Chinese herbs have efficient therapeutic effects for CVDs, while their therapeutic mechanism is still not very clear. It may be a good view towards molecules, targets and network to decipher whether difference exists between anti-CVD western drugs and Chinese herbal ingredients.
Anti-CVD western drugs and Chinese herbal ingredients, as well as their targets were thoroughly collected in this work. The similarities and the differences between the herbal ingredients and the western drugs were deeply explored based on three target-based perspectives including biochemical property, regulated pathway and disease network. The biological function of herbal ingredients' targets is more complex than that of the western drugs' targets. The signal transduction and immune system associated signaling pathways, apoptosis associated pathways may be the most important pathway for herbal ingredients, however the western drugs incline to regulate vascular smooth muscle contraction associated pathways. Chinese herbal ingredients prefer to regulate the downstream proteins of apoptosis associated pathway; while the western drugs incline to regulate the upstream proteins of VECC (Vascular Epidermal Cells Contraction) related pathways.
In summary, the characteristics identified in this study would be valuable for designing new network-based multi-target CVD drugs or vaccine adjuvants.
According to the statistics of The World Health Organization (WHO), CVDs are the world's largest killers of human health, since these disorders lead to 17.1 million deaths per year and the death number is still rising . Cardiovascular diseases (CVDs) is the general term that describes a number of circulatory system diseases, which mainly include ischemic heart disease, hypertension, cardiac arrhythmias, stroke, myocardial infarction, coronary artery disease, hypertrophic cardiomyopathy, hyperlipidemia, etc [2, 3]. Both genetic abnormalities and environmental factors play important roles in CVDs development. Their pathological mechanisms often refer to many complex physiological processes, such as inflammation , apoptosis [4, 5], oxidative stress , and lipid metabolism .
There have been various anti-CVD drugs approved by US FDA. One of the most-used examples is the statins. They have reduced the mortality and morbidity from atherosclerotic heart disease by about 30%, but the remaining 70% CVDs still need novel therapies . In recent years, with the development of genomics  and proteomics , a large number of associated genomic and gene regulation data make it possible to develop new drugs for CVDs. Bezafibrate , Lisinopril , Quinapril  and so on, have been developed as new drugs of CVDs. Although western drugs have achieved great successes in CVDs treatment, they may lead to serious side effects  and drug resistance .
On the other hand, more and more studies found that Chinese herbs have efficient therapeutic effect for CVDs, such as Danshen Pian [16, 17], Yin Xing Ye Pian [16, 18], Shengmai Yin  and Xinning Pian . For instance, Danshen has a range of potentially beneficial effects, including causing coronary vasodilatation, suppressing the formation of thromboxane, and inhibiting platelet adhesion and aggregation . G. biloba extract (GBE) was found to decrease capillary permeability, inhibit platelet-activating factors, and decrease vascular resistance . Herbal ingredients have been expected as a potential drug like database . In addition, increased research has been carried out in search of new adjuvant candidates from traditional Chinese medicinal herbs [22, 23]. Although great promise has been shown for Chinese herbs, their therapeutic mechanism is still not very clear.
Before demystify the mechanism of anti-CVD Chinese herbs, researchers want to know whether there is any difference between herbal ingredients and western drugs? It may be a good view towards molecules and their targets to decipher these questions. In this study, herbal ingredients (active compounds in herb which have been reported with anti-CVD effects) and western drugs (FDA-approved drugs with anti-CVD effectiveness) have been comprehensively collected. Their corresponding target proteins were retrieved from DrugBank  and HIT . Then, the similarities and the differences of molecular mechanism between those herbal ingredients and western drugs were probed from 3 target-based perspectives: biochemical property, regulated pathway, and disease related network.
Methods and materials
Molecules, targets and related diseases
Western drugs whose first letter of ATC code is "C" and their associated targets were downloaded from DrugBank. The keywords such as: "Hypertension", "Hyperlipidemia", "Coronary heart disease", "Stroke", "Myocardial infarction", "Angina", "Atherosclerosis", "Cardiomyopathy", "Heart failure" and "Thrombosis" have been used to search anti-CVD herbs in Chinese Pharmacopoeia . The ingredients of anti-CVD herbs and their corresponding targets were extracted from HIT . Two kinds of ingredients' targets have been collected from HIT: direct targets and indirect targets.
Targets and associated diseases were collected from Therapeutic Target Database (TTD) . As targets are under different stages of study, they have been classified into three categories in TTD: Successful targets, Clinical trial targets and Research targets.
Protein biochemical family, structure domain and cell location
Protein Biochemical family data was downloaded from UniProtKB . Protein structure domain data was obtained from Pfam . Protein cell location data was collected from The Gene Ontology (GO) . GO provides an ontology of defined terms representing gene product properties, cell location information for the targets was extracted from Cellular component item.
Protein transcription factor
TRANSFAC database records eukaryotic transcription regulating DNA sequence elements and the transcription factors binding to and acting through them . Information of transcription factor was retrieved from TRANSFAC, 618 transcription factors have been included in TRANSFAC.
Network construction and analysis
Construction of target-pathway network and compound-pathway network
Firstly, target proteins of herbal ingredients and western drugs were mapped onto KEGG pathways  respectively. Targets were considered to participate in a specific pathway if they appear in the pathway. Through regulating those targets, western drugs or herbal ingredients act on pathways. A bipartite graph was constructed by linked pathways and targets, which represents the association of targets and pathways . In the same way, the compound (a compound means an herbal ingredient or a western drug)-pathway network was generated.
Degree distribution of network
In network, the number of edges linked to a node was defined as degree. The degree distribution f(x) of network is the frequency of nodes with degree x. It is reported that degree distribution of the majority of real world networks especially biological networks obey power law. In another word, the majority of nodes in network would only influence few nodes, while few nodes would affect a lot of nodes and play important roles in whole network [32, 33].
Pathway enrichment for targets of herbal ingredients and western drugs
Pathway enrichment analysis  has been applied to query whether a compound regulate a pathway by chance or not. Fisher's exact test was used. A significance level with a Pvalue less than 0.01 means the compound would regulate the pathway at a high probability .
Construction of disease network
In previous reported studies, inflammation, apoptosis and Ca2 + channel caused vascular epidermal cells contraction disorder were the main pathogenesis for cardiovascular diseases. Firstly, two CVDs local networks were constructed: the CVDs-Apoptosis-Network and the CVDs-VECC (vascular epidermal cells contraction)-Network. Secondly, the whole-CVDs-network was built which integrates CVDs associated pathways in KEGG, BioCarta  and Therapeutically Relevant Multiple Pathways (TRMP) .
Results and discussions
Targets of herbal ingredients and western drugs
184 FDA-approved anti-CVD western drugs as well as their 204 protein targets were collected from DrugBank. 40 anti-CVD herbs were collected in the Chinese Pharmacopoeia as well. For these anti-CVD herbs, 172 herbal ingredients and 862 protein targets were identified from the HIT, among which 118 were direct targets.
Protein targets of herbal ingredients and western drugs in TTD.
herbal ingredients-direct targets(118)
herbal ingredients-all targets(862)
number of targets
number of targets
number of targets
Clinical trial targets
Sum of targets in TTD
Drug targets related diseases from TTD.
Type of targets
Number of diseases
Clinical trial target(15)
Clinical trial target(10)
As shown in Additional file 1, figure S1, 27% of western drugs bind different subtypes of the same type of protein targets such as inhibitors of calcium ion channel etc. The other 28% of western drugs regulate different targets in the same biological process. That is to say, besides one-target-drugs, most targets of multi-targets western drugs either belong to the same protein type or participate in the same biological process. This might hint why western drugs are often used for a certain disorder.
targets of 118 herbal ingredients' direct targets were TFs (transcript factor), while only 10 out of 204 western drugs targets were TFs (Table 3). Fisher's exact test was used to quantitatively measure which kind of targets is more enriched with TFs. The P-value of herbal ingredients is less than 0.01, however western drugs' is greater than 0.05. It implies that herbal ingredients prefer to target TFs than western drugs.
Transcription factor distribution for targets of western drug and herbal ingredients
Num for Transcriptional genes
As summarized from the above protein family analysis, cellular location analysis, and the TF enrichment analysis, the targets of western drugs are enriched in channels and transporters, receptors, and they tend to locate on the plasma membrane, which agrees with the common sense about western drug discovery. On the other hand, the targets of herbal ingredients are enriched in enzymes, factors and regulators, and they prefer to locate in cytoplasm and nucleus. This suggests that herbal ingredients may provide new insights for CVDs therapy. In addition, as the herbal ingredients' targets locate in cytoplasm and nucleus, this may meet difficulties in exploring herbal ingredients' mechanism.
It can be inferred from both target-pathway and compound-pathway analysis that signal transduction and immune system associated signaling pathways, apoptosis associated pathways are always the most important pathway of herbal ingredients, while for the western drugs, the most important pathways are cardiac and vascular smooth muscle contraction associated pathways. These herbal ingredients can be exerted along with the vaccine to elicit a faster and stronger immune response .
The CVDs-Whole-Network and the two local networks provide an overview that western drugs prefer to target the upstream of CVDs, while the herbal ingredients prefer to modulate the downstream of CVDs.
Use of adjuvant in the vaccine preparation is a long standing practice. Despite major advances in vaccine adjuvants, vaccines seem to depend on aluminium salts. However, these adjuvants would lead to serious adverse effects . Herbal ingredients as immuno-modulator are paving its way as a safe alternative.
From the results of pathway enrichment, herbal ingredient s' direct target significantly enriched in seven immune system pathways, while no immune system pathway was enriched by western drugs' targets. For example, curcumin (the extractive of radix curcumae) would not only regulate interleukin 1(IL1), interleukin 6(IL6), interleukin 8(IL8), interferon-γ(IFN-γ) and Transforming Growth Factor beta(TGF-β) in T and B cell, but also target some immune proteins such as, Toll-like receptor 4(TLR4), CD80 and CD28. Styrene (the extractive of storax) can affect IL4, IL5, IL13 and TGF-β expression. Resveratrol (the extractive of polygonum cuspidatum) can regulate IL1, IL6, IL8, IL10, IFN-γ, TGF-β, CD80 and CD28. What's more, ginseng saponins have adjuvant effects on the specific immune responses, which due to their can promote IL1 production by pertoneal macrophages, stimulate secretion of cytokine such as IL2, IL4, IL6, IL8, IL10, IFN-γ and TNF-α, regulate TLR4 to produce proinflammatory cytokines, and affect TGF-β to enhance lymphocyte proliferation [42–45]. Therefore, those herbal ingredients could regulate one or several kinds of cytokine such as IL1, IL4, IL6, IL8, IL10, IFN-γ, TGF-β and immune related protein TLR4 have the potential to promote both humoral and cellular immune responses. Some ingredients of anti-CVD herbs might be the candidate adjuvant.
Herbal ingredients and western drugs, as well as their targets were thoroughly collected in this work. The similarities and the differences between herbal ingredients and western drugs were deeply explored. From biochemical property analysis, the biological function of herbal ingredients' targets is more complex than that of the targets of western drugs. Herbal ingredients tend to target enzymes, factors, regu-lators protein in cytoplasm and nucleus, while western drugs lean towards targeting the protein of channels and transporters, receptors in plasma membrane. From pathway analysis, the signal transduction and immune system associated signaling pathways, apoptosis associated pathways are always the most important pathway for herbal ingredients, however western drugs incline to regulate vascular smooth muscle contraction associated pathways. From disease network analysis, herbal ingredients prefer to regulate the downstream proteins of apoptosis associated pathway, while the western drugs incline to regulate the upstream proteins of VECC related pathways.
According to some statistics, nearly one-third of the top-selling drugs in the world are nature products or their derivatives, and nature products are the most consistently successful source of drug leads [46, 47]. Herbal ingredients may provide some new clues to drugs development for CVDs. Herbal ingredients may also have the potential to be used in design of new vaccines.
The work was partly supported by Ministry of Science and Technology China (2012AA020404), and National Natural Science Foundation of China (30900832). The publication of paper was funded by grants from Ministry of Health (2012ZX10005001-008).
The publication of this work was funded by Ministry of Health (2012ZX10005001-008).
This article has been published as part of BMC Bioinformatics Volume 15 Supplement 4, 2014: Selected articles on Computational Vaccinology 2013. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcbioinformatics/supplements/15/S4.
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