- Open Access
Herb network construction and co-module analysis for uncovering the combination rule of traditional Chinese herbal formulae
© Li et al; licensee BioMed Central Ltd. 2010
- Published: 14 December 2010
Traditional Chinese Medicine (TCM) is characterized by the wide use of herbal formulae, which are capable of systematically treating diseases determined by interactions among various herbs. However, the combination rule of TCM herbal formulae remains a mystery due to the lack of appropriate methods.
From a network perspective, we established a method called Distance-based Mutual Information Model (DMIM) to identify useful relationships among herbs in numerous herbal formulae. DMIM combines mutual information entropy and “between-herb-distance” to score herb interactions and construct herb network. To evaluate the efficacy of the DMIM-extracted herb network, we conducted in vitro assays to measure the activities of strongly connected herbs and herb pairs. Moreover, using the networked Liu-wei-di-huang (LWDH) formula as an example, we proposed a novel concept of “co-module” across herb-biomolecule-disease multilayer networks to explore the potential combination mechanism of herbal formulae.
DMIM, when used for retrieving herb pairs, achieves a good balance among the herb’s frequency, independence, and distance in herbal formulae. A herb network constructed by DMIM from 3865 Collaterals-related herbal formulae can not only nicely recover traditionally-defined herb pairs and formulae, but also generate novel anti-angiogenic herb ingredients (e.g. Vitexicarpin with IC50=3.2 μM, and Timosaponin A-III with IC50=3.4 μM) as well as herb pairs with synergistic or antagonistic effects. Based on gene and phenotype information associated with both LWDH herbs and LWDH-treated diseases, we found that LWDH-treated diseases show high phenotype similarity and identified certain “co-modules” enriched in cancer pathways and neuro-endocrine-immune pathways, which may be responsible for the action of treating different diseases by the same LWDH formula.
DMIM is a powerful method to identify the combination rule of herbal formulae and lead to new discoveries. We also provide the first evidence that the co-module across multilayer networks may underlie the combination mechanism of herbal formulae and demonstrate the potential of network biology approaches in the studies of TCM.
- Traditional Chinese Medicine
- Combination Rule
- Herbal Formula
- Multilayer Network
Traditional Chinese Medicine (TCM) is an important part of the current medical system. It aims to restore the whole-body balance in patients by using herbal formula (Fang-Ji in Mandarin), which is usually composed of two or more medicinal herbs and has the capacity of systematically treating disease . Naturally occurring herbs and herbal ingredients organized into certain formula have been shown to have potential interaction effects. These include mutual enhancement, mutual assistance, mutual restraint and mutual antagonism [2, 3]. For example, synergistic interactions occur when the efficacy of combinations of herbs (or ingredients) is greater than the summed responses of each individual herb or ingredient. Adams et al.  recently reported the synergistic, additive and antagonistic effects exerted by different combinations of six herbal extracts on the viability of prostate cancer cell lines. Wang reported that a Realgar-Indigo naturalis formula is beneficial for the treatment of promyelocytic leukemia; the synergistic effects exerted by several components of this formula are well documented . Ung et al.  conducted an analysis of 394 TCM herb pairs and 2470 non-TCM herb pairs using artificial intelligence methods and considering four classes of herbal properties as features including character, taste, meridian, and toxicity level. Their study revealed that herb pairs in TCM contain features distinguishable from those of non-TCM herb pairs. Schmidt et al. believed that mixtures of interacting compounds produced by plants may become a valuable asset and an important resource for drug discovery, especially for the development of combinational therapeutics.
However, there is still a lack of appropriate methods to learn how and why many herbs are grouped in certain formulae, and the combination rule embedding numerous herbal formulae remain unknown. Traditionally herbs have taken different roles in a typical herbal formula; they are usually expressed in the organization order as Master, Adviser, Soldier and Guide (MASG), each of which is given certain natural properties including Cold, Cool, Neutral, Warm or Hot. Understanding the combination rule of herbal formulae will not only benefit the modernization of TCM but may also be helpful for the way drugs are studied. A good example of the potential of TCM involves angiogenesis. TCM is known to be effective for the treatment of angiogenesis which is the main type of pathological vascular growth associated with various diseases such as cancer and rheumatoid arthritis [8, 9]. We know that more than 60% of the current cancer chemotherapeutic agents are natural products or small molecules based on natural product leads [10, 11]. Many pro-angiogenic and anti-angiogenic plant components are potentially useful for curing angiogenic disorders and are well tolerated . Especially, herbs originally used for treating “Collaterals (Luo in Mandarin) diseases” in TCM have been found to be active on angiogenic disorders . As a consequence, combining traditional herbal formulae with existing biological knowledge might allow researchers to rapidly identify combination treatments for angiogenic disorders.
Recently, a remarkable development has been the use of systems biology, especially network biology, in drug study. This methodology has revealed the systematic mechanisms of complex disease and has highlighted the paradigm shift from “one drug, one target” to “multicomponent therapeutics, biological networks” [13, 14]. Even though the scientific community has high expectations for systems pharmacology, this field is still in its infancy because of a poor understanding of cell behaviours and drug-protein interactions. TCM formula is considered to be an empirical system of multicomponent therapeutics which potentially meets the demands of treating a number of complex diseases in an integrated manner [3, 14, 15]. So, in order to find a relationship between groups of drugs and complex diseases, it is important to introduce a powerful approach to bridge the tradition and the modern, and pursue a priori knowledge about the combination rules embedded in TCM. In this work, we developed a Distance-based Mutual Information Model (DMIM) to extract the herb relationships from plentiful herbal formulae. This method was then used to construct the “herb network” from 3865 Collaterals-related herbal formulae, following by in vitro experiments designed to evaluate the angiogenic effects and synergistic properties of strongly connected herbs and herb pairs. A new concept of “co-module” was further proposed and network biology analyses were conducted to explore the potential combination mechanism of the networked herbal formulae.
Data sources of herbal formulae
Candidate herbal formulae selection
TCM values the “Collaterals” theory and therapy. Using “Collaterals (Luo)” as the keyword, we searched the SIRC-TCM Herbal Formula database (http://www.tcm120.com/1w2k/tcm_recipe.asp) which contains 0.14 million herbal formulae. Then we collected 3865 herbal formulae with formula names and functions, or herb’s meridian tropism (Gui-jing in Mandarin), or targeted syndromes and diseases containing the keyword. We standardized the herbal formulae by substituting all the polysemes, synonyms and acronyms of the herbs in the dataset using the standardized Herb Name list. The standardized Herb Name list consists of 737 herbs. The 3865 Collaterals-related herbal formulae, as examples, will be subject to the following DMIM analysis.
Traditionally-defined herb pairs
The herb pair is the basic unit of a herbal formula. To evaluate the reliability and utility of the DMIM-extracted herb network, 600 traditionally-defined herb pairs recorded in  and 301 herb pairs from  were collected. This resulted in 775 non-redundant traditionally-defined herb pairs made up of 737 separate herbs in the Collaterals-related herbal formulae.
Establishment of DMIM Scoring System
Numerical representation for herbal formulae
Examples for the numerical representation of herbal formulae
From this we had matrix B , where b ij indicates the relative position of herb j in the formula i. Finally, the real data set is represented by a 3865×737 matrix. Then, for given two herbs, x and y, we deduce that the tendency of x and y to form a herb pair is dependent on two factors: mutual information entropy characteristics and the average distance between herbs.
Mutual information entropy
To begin with, we calculate the traditional mutual information entropy  for x and y as: . Here is the frequency that herb x and herb y occurred, and I(x, y,i) is the indicator function of x and y, showing whether herb x and y coexist in the formula i. is the frequency of herb x. It is the same with P(y). A large value of MI(x, y) indicates a strong correlation between herb x and herb y .
Considering a later order indicates a less importance in the organization of Master, Adviser, Soldier or Guide herbs in a herbal formula, we assume that the further the distance between two herbs in a formula, the less likely they are to be relevant to one another. The distance between herb x and herb y in the i th formula, called the “between-herb-distance”, is defined as: d(x, y, i) = |B(x,i) - B(y, i)|. The average distance of herb x and herb y in the dataset is .
DMIM scoring system
The DMIM combines the mutual information (MI) entropy characteristics and the average distance between herbs (d) to form a scoring system, , which describes the tendency of herb x and herb y to form a herb pair. So when two herb pairs share the same information entropy, the one with the smaller average distance shows a stronger connection. When two herb pairs have the same average distance, the one with the larger information entropy shows a greater interaction.
Evaluation of the DMIM-extracted herb network
In vitro assays for evaluating angiogenic activities of DMIM-extracted herbs
We selected major herbal ingredients from DMIM outputs to evaluate angiogenic activities. Two kinds of endothelial cell proliferation assays, namely with or without vascular endothelial growth factor (VEGF) stimulation, were used to evaluate respectively the anti-angiogenic or the pro-angiogenic activity of herbal ingredients. Only the positive results were reported. Human Umbilical Vein Endothelial Cells (HUVECs) from Cascade Biologics (Portland, USA) were cultured in endothelial cell medium (Sciencell Research Laboratory) together with 10% fetal bovine serum and endothelial cell growth supplement. This mixture was sub-cultured using a 1:2 ratio with Trypsin/EDTA solution provided by the manufacturer. Herbal ingredients were purchased from the National Institute for the Control of Pharmaceutical and Biological Products, China. HUVECs (5×103 per well) in a 96-well plate were starved with 0.1% FBS medium and then treated with or without VEGF (5-10 ng/ml) along with different concentrations of herbal ingredients for 48 hours. Cell viability was determined by Cell Counting Kit (CCK-8, Dojindo, Japan) following the measurement of optical density values using MRX Revelation Absorbance Reader.
Herb interaction measurement of DMIM-extracted herb pairs
We investigated whether combination effects were produced by DMIM-extracted herb pairs and whether there was a role for the natural properties of the herbs. The highest single compound model  was used as the reference model for measuring additivity to identify herbal interactions such as synergism or antagonism. The combination effects were determined by selecting the greatest effect produced by each of the combination’s individual compounds using similar concentrations as in the combination. Positive or negative deviations from this predicted additivity demonstrated synergistic or antagonistic interactions.
Co-module analysis for the DMIM-extracted herbal formula
Co-module concept, herbal formula selection and biological data preparation
To further explore the combination mechanism of DMIM-extracted herbal formulae, we propose a new concept of “co-module” based on the assumption that there may exist certain consistent and common biological patterns, which act as “co-modules”, underlying networked herbs and their targeted diseases simultaneously. We took a famous formula, “Liu-wei-di-huang” (LWDH, also known as Rehmannia Six, Six Ingredient Rehmannia or Rokumi-gan), as an example, since we found that all six herbs of this formula are connected closely in the DMIM-extracted herb network including Shan-zhu-yu (Fructus Corni), Ze-xie (Rhizoma Alismatis), Dan-pi (Cortex Moutan), Di-huang (Radix Rehmaniae), Fu-ling (Poria Cocos) and Shan-yao (Rhizoma Dioscoreae). Then, we collected the biological entities (genes or gene products) affected by individual herbs (compounds) of LWDH from PubMed and China National Knowledge Infrastructure (http://www.cnki.net). This resulted in a total of 146 manually collected genes or gene products, called LWDH genes, contributed respectively to the actions of the LWDH constituent six herbs. 127 LWDH genes were nodes of the protein-protein interaction (PPI) network (HPRD, release 7). Next, we collected the documented diseases for which the LWDH formula may serve as a potential treatment. This resulted in 16 diseases containing 9 types of cancer (Prostate cancer, Melanoma, Stomach cancer, Breast cancer, Esophageal cancer, Lung cancer, Hepatocellular carcinoma, Multiple myeloma and Leukemia), 5 diseases with dysfunction of the neuro-endocrine-immune-metabolism system (Parkinson disease, Asthma, Allergy, Rheumatoid arthritis and Diabetes), and 2 cardiovascular disorders (Hypertension and Atherosclerosis) (see literature in Additional file 1). By mapping these 16 diseases into the OMIM database, we identified 73 exclusive phenotypes with OMIM IDs and obtained 224 disease genes called LWDH-disease genes, 173 of which were networked in HPRD.
Performing co-module analysis for LWDH and LWDH-treated diseases
We conducted the co-module analysis from the following three aspects. (1) We analyzed the enriched KEGG pathways for either LWDH genes or LWDH-disease genes with a false discovery rate less than 0.05 by Fisher Exact test in DAVID . (2) We evaluated the “closeness”(average shortest path) between LWDH genes and LWDH-disease genes in the PPI network and used the permutation test to calculate the statistical significance of the average shortest path. Here we kept the original 127 LWDH genes and randomly selected other 173 disease genes from 1273 networked genes in all 3074 non-redundant disease genes stored in the OMIM moridmap.txt (Feb 22, 2008); this was repeated independently 2000 times. (3) We calculated the average phenotype similarity score determined by the cosine of vector angle  of 73 phenotypes of LWDH-diseases, and evaluated the statistical significance by comparison with randomly selected 73 OMIM phenotypes for 2000 times.
The mutual information statistics were transformed to equivalent odds ratios using monotonic transform and then subjected to standard χ2 test. In doing so, we used χ2 test to test whether the occurrence of the two herbs in the formulae is correlated with each other by generating a contingency table. Experimental data from the in vitro assay were presented as mean±SD (Standard Deviation) of four independent experiments with six repeat wells for each experiment. The statistical difference between treatments was determined by the t test.
DMIM-extracted herb network from Collaterals-related formulae
Top 10 herbs in 3865 Collaterals-related formulae
Herbs in Collaterals-related herbal formula
Radix Angelicae Sinensis
Radix Rhizoma Glycyrrhizae
Radix Paeoniae Rubra
Radix et Rhizoma Salviae Miltiorrhizae
Radix Achyranthis Bidentatae
Radix Paeoniae Alba
Top 20 DMIM-extracted herb pairs
Drgon's Bones, Fossilizid
Rhizoma Zingiberis Recens
Radix Angelicae Pubescentis
Rhizoma et Radix Notopterygii
Rhizoma Atractylodis Macrocephalae
Rhizoma Acori Tatarinowii
Radix Paeoniae Rubra
Pericarpium Citri Reticulatae
Radix Angelicae Sinensis
Radix Paeoniae Rubra
Rhizoma Atractylodis Macrocephalae
Radix Paeoniae Alba
Radix Rhizoma Glycyrrhizae
Measurement of angiogenic activities for DMIM-extracted modular herbs
Measurement of DMIM-extracted modular herb interactions
Co-module underlying DMIM-extracted herbal formula in treating different diseases
Enriched pathways of Liu-wei-di-huang genes and Liu-wei-di-huang-treated disease genes identified by DAVID
Enriched KEGG pathway
False discovery rate
hsa05200:Pathways in cancer
hsa05014:Amyotrophic lateral sclerosis
hsa04620:Toll-like receptor signaling pathway
hsa04660:T cell receptor signaling pathway
hsa04621:NOD-like receptor signaling pathway
hsa05222:Small cell lung cancer
hsa04080:Neuroactive ligand-receptor interaction
hsa05200:Pathways in cancer
hsa05221:Acute myeloid leukemia
hsa05220:Chronic myeloid leukemia
hsa04930:Type II diabetes mellitus
hsa05223:Non-small cell lung cancer
hsa04950:Maturity onset diabetes of the young
In this work, we proposed a distance-based mutual information model, DMIM, to uncover the combination rule embedded in herbal formulae, which not only uses mutual information entropy but also introduces a new factor, “between-herb-distance”, into measuring the tendency of two herbs to form an herb pair. This makes DMIM suitable for deciphering herbal formulae and distinguishes it from other analytical methods such as clustering. For example, herb1 and herb2 are often used together to reduce toxicity and side-effects, while herb2 and herb3 may be clustered into a single category because of their co-location in similar organs or meridians. According to the principles of clustering, herb1, herb2 and herb3 may be clustered into one category, but in reality, herb1 and herb3 have no inherent relationship. Moreover, the results of clustering are qualitative rather than quantitative and clustering does not show which herbs have a tendency to form herb pairs. DMIM avoids these pitfalls by calculating the mutual information entropy for each of the herbs and their “between-herb-distance”.
We demonstrated the reliability and usefulness of DMIM by using 3865 Collaterals-related herbal formulae. Firstly, we showed that the DMIM method retains the traditional combination rule of TCM. DMIM identified many herbal pairs which have already been defined (Table 3). We also found that the DMIM-extracted herb network identified six classical herbal formulae from the paired herbs (Figure 1), which are expressed as connected sub-networks. On the other hand, DMIM-extracted herb network can eliminate the disturbance from herbs such as Gan-cao (Radix Rhizoma Glycyrrhizae), a widely used “Guide” herb that coordinates the actions of other herbs in formulae, though it ranks at top 2 in 3865 herbal formulae.
Next, we showed that DMIM has the potential to discover angiogenic herbs and non-addictive herb pairs from TCM. This study found that the 10 most common herbs in the 3865 formulae had potential angiogenic effects (Table 2) [9, 22]. We also conducted in vitro assay to evaluate the extended hub module for Chuan-xiong (Rhizoma Chuanxiong) and Dang-gui (Radix Angelicae Sinensis) in the DMIM-extracted herb network (Figure 2A). As the ingredients of herbs are very complicated and the quality of herbs is still unstable, for simplify, this work used major ingredients of herbs to perform experiments. Results showed that the herbs or herb pairs in the hub modules produced anti-angiogenic or pro-angiogenic activities, suggesting that the modular herbs may have functional dependence. In particular, we detected the novel bioactivity of two herb ingredients which inhibited angiogenesis, including Vitexicarpin (IC50 = 3.2 μM) and Timosaponin A-III (IC50 = 3.4 μM) (Figure 2B). We also validated the synergistic effects produced by DMIM-extracted novel herb pairs such as Chuan-xiong and Hong-hua (Table 3 and Figure 3).
Additionally, in this study, we observed that the active compounds from the herbs with different natural properties might account for their different angiogenic responses (Figure 2B). For instance, major ingredients from Cool/Cold herbs tend to produce anti-angiogenic activities whereas major ingredients from Warm/Hot herbs tend to exert pro-angiogenic activities . The dose-response relationship is another way to understand the characteristics of the herb’s natural properties. We found that Berberine and Tetramethylpyrazine can cause a pro-angiogenic effect at low dose and anti-angiogenic effects at high dose (Figure 2B), suggesting that some herbs may cause biphasic regulation if different dosing regimens are used. For herb interaction effects we assumed that herb pairs in a formula with the same properties were more likely to lead to synergistic interactions, whereas combinations with different properties were inclined to cause antagonism. As shown in Figure 3, combination effects from herb pairs with the same properties (e.g. Chuan-xiong and Hong-hua) and different properties (e.g. Chuan-xiong and Zhi-mu) support our assumption, but the combination of Chuan-xiong and Huang-qi is not the case, making it an open question whether or not herbal properties are related to herb combination behaviours.
Last but not least, we demonstrated that the DMIM-extracted herbal formula, Liu-wei-di-huang, may have its molecular basis for treating different diseases in a co-module manner (Figure 4). LWDH is one of the most famous TCM formulae developed during the Song dynasty in China. Results show that the six herbs in LWDH not only have high DMIM scores, but also connected closely with common responsive genes enriched in cancer pathways and neuro-endocrine-immune pathways (Table 4). Interestingly, LWDH genes show a significantly close relationship with LWDH-disease genes in the PPI network (P<0.0001), forming a co-module underlying herbal formula as well as different diseases. Moreover, the 16 LWDH-treated diseases mainly including cancer, neuro-endocrine-immune-metabolism, and cardiovascular disorders show high phenotype similarity scores (P=0.0248) and might share a overlapped molecular basis associated with the angiogenic processes as well as the imbalance of the human body [23, 24]. Such phenomena of “one formula, different diseases” reinforce the idea that different diseases with similar phenotypes might possess internal coherence [25–27], and a group of diseases with similar mechanisms might be able to be treated by intervening their common network target [28, 29], which in turn illustrates the rationality of multicomponent therapies such as herbal formulae (Figure ). The novel concept of co-module throughout the multilayer networks of herb-biomolecule-diseases may promote our awareness of herbal formulae as well as multicomponent therapies.
DMIM is currently the first step towards building herb network from TCM herbal formula. For future work, DMIM could be generalized to mine synergistic combinations made up of more than two herbs by replacing the “between-herb-distance” with a properly defined index of the distance among multiple herbs in a formula or by introducing multivariate mutual information. As this work treats formula independently, we will take the redundancies and correlations between formulae into consideration for calculating the herb distance. The dose information and natural properties of herbs (as measures of interaction) are also the next step to create a multi-weight herb network. Moreover, we believe that the combination mechanism of herbal formulae will be more deeply identified in a “co-module” manner and contribute to the progression of the modern TCM as well as network pharmacological studies .
DMIM yields a systematic framework for scoring herb pairs and the resulted herb network can uncover some combination rules of TCM. We also provide preliminary clues that the “co-module” across multilayer networks of herb-biomolecule-disease may be responsible for the combination mechanism underlying herbal formulae. This study is the first step forward in exploring the unique theories of TCM herbal formula by network biology approaches and may also benefit the coming network pharmacology as well.
This work is supported by the NSFC (Nos. 30873464 and 60934004).
This article has been published as part of BMC Bioinformatics Volume 11 Supplement 11, 2010: Proceedings of the 21st International Conference on Genome Informatics (GIW2010). The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2105/11?issue=S11.
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