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Context Owing to the complexity of chemical ingredients in traditional Chinese medicine (TCM), it is difficult to maintain quality and efficacy by relying only on chemical markers. Objective Lianhua Qingwen capsule (LHQW) was selected as an example to discuss the feasibility of a bioassay for quality control. Materials and methods Network pharmacology was used to screen potential targets in LHQW with respect to its anti-inflammatory effects. An in vitro cell model was used to validate the prediction. An anti-inflammatory bioassay was established for the quality evaluation of LHQW in 40 batches of marketed products and three batches of destructed samples. Results The tumor necrosis factor/interleukin-6 (TNF/IL-6) pathway via macrophage was selected as the potential target of LHQW. The IC50 value of LHQW on RAW 264.7 was 799.8 μg/mL. LHQW had significant inhibitory effects on the expression of IL-6 in a dose-dependent manner (p

Depression is a common clinical psychological disease, which is called "yu zheng" in traditional Chinese medicine (TCM). TCM has a long history in the treatment of depression (yu zheng), which has unique advantages. Jieyu pill (JYP), a classical TCM formula, has been widely used for treating depression because of its clear clinical efficacy, low side effects, and high compliance. In this review, we systematically introduce recent clinical and animal experimental studies on JYP and depression, and review the pharmacological mechanism and active ingredients of JYP, as well as its clinical application in depression therapy. This systematic review provides a deep understanding of TCM prescriptions, pharmacological mechanisms, and disease-medicine interactions, and lays the foundation for developing new treatments for depression.

Because traditional Chinese medicine (TCM) is a complex mixture of multiple components, the application of methodologies for evaluating single-component Western medicine in TCM studies may have certain limitations. Appropriate strategies that recognize the integrality of TCM and connect to TCM theories remain to be developed. Yang-Xin-Ding-Ji (YXDJ) capsule is originally from a classical TCM formula used for the treatment of arrhythmia. In this study, we used UPLC-Q-TOF-MS detection method, coupled with the metabolic research and network pharmacology analysis, to study the scientific connotation of the YXDJ capsule. A total of 33 absorbed constituents and 23 metabolites were identified or tentatively characterized in dosed plasma and urine, and the possible metabolic pathways were mainly methylation, oxidation, sulfation, glucuronidation, and deglucosylation. We optimized the conventional process ways of network pharmacology by collecting targets based on absorbed constituents into the blood. The constituents-target disease and Kyoto Encyclopedia of Genes pathway analysis revealed that 24 absorbed constituents, 32 target genes, and 10 key pathways were probably related to the efficacy of the YXDJ capsule against arrhythmia. The results provided a scientific basis for understanding the bioactive compounds and the pharmacological mechanism of the YXDJ capsule.

Traditional Chinese medicine (TCM) has been practiced for thousands of years for treating human diseases. In comparison to modern medicine, one of the advantages of TCM is the principle of herb compatibility, known as TCM formulae. A TCM formula usually consists of multiple herbs to achieve the maximum treatment effects, where their interactions are believed to elicit the therapeutic effects. Despite being a fundamental component of TCM, the rationale of combining specific herb combinations remains unclear. In this study, we proposed a network-based method to quantify the interactions in herb pairs. We constructed a protein–protein interaction network for a given herb pair by retrieving the associated ingredients and protein targets, and determined multiple network-based distances including the closest, shortest, center, kernel, and separation, both at the ingredient and at the target levels. We found that the frequently used herb pairs tend to have shorter distances compared to random herb pairs, suggesting that a therapeutic herb pair is more likely to affect neighboring proteins in the human interactome. Furthermore, we found that the center distance determined at the ingredient level improves the discrimination of top-frequent herb pairs from random herb pairs, suggesting the rationale of considering the topologically important ingredients for inferring the mechanisms of action of TCM. Taken together, we have provided a network pharmacology framework to quantify the degree of herb interactions, which shall help explore the space of herb combinations more effectively to identify the synergistic compound interactions based on network topology.

As a well-established multidrug combinations schema, traditional Chinese medicine (herbal prescription) has been used for thousands of years in real-world clinical settings. This paper uses a complex network approach to investigate the regularities underlying multidrug combinations in herbal prescriptions. Using five collected large-scale real-world clinical herbal prescription datasets, we construct five weighted herbal combination networks with herb as nodes and herbal combinational use in herbal prescription as links. We found that the weight distribution of herbal combinations displays a clear power law, which means that most herb pairs were used in low frequency and some herb pairs were used in very high frequency. Furthermore, we found that it displays a clear linear negative correlation between the clustering coefficients and the degree of nodes in the herbal combination network (HCNet). This indicates that hierarchical properties exist in the HCNet. Finally, we investigate the molecular network interaction patterns between herb related target modules (i.e., subnetworks) in herbal prescriptions using a network-based approach and further explore the correlation between the distribution of herb combinations and prescriptions. We found that the more the hierarchical prescription, the better the corresponding effect. The results also reflected a well-recognized principle called “Jun-Chen-Zuo-Shi” in TCM formula theories. This also gives references for multidrug combination development in the field of network pharmacology and provides the guideline for the clinical use of combination therapy for chronic diseases.

Unlike single-target Western medicines, traditional Chinese medicines (TCMs) exhibit diverse curative effects against multiple diseases through their “multicomponent” and “multitarget” manifestations. However, the material basis of the major therapeutic diseases and TCM underlying molecular mechanisms remain to be challenged. In the current study, we applied, for the first time, an integrated strategy that combines network pharmacology and experimental evaluation and explored and demonstrated the underlying possible mechanisms of a classic TCM formula, Huanglian Jiedu Decoction (HLJD), in the treatment of cerebral ischemia. First, the herb compound, protein compound, and GO-BP and KEGG pathways were constructed to predict the material basis of HLJD in the treatment of cerebral ischemia and explore the underlying molecular mechanisms. Network pharmacology analysis showed that HLJD treats cerebral ischemia mainly through its anti-inflammatory effect. We used molecular docking to verify that HLJD components have good binding activities to the arachidonic acid pathway enzymes, cyclooxylipase-2 (COX-2) and 5-lipoxygenase (5-LOX). Next, based on the prediction by the network pharmacology analysis, the rat model of middle cerebral artery occlusion (MCAO) was established to verify the efficacy of HLJD. The results showed that HLJD reduces the degree of brain injury in MCAO rats, probably by inhibiting the expression of the 5-LOX pathway and inflammatory response. In conclusion, our study demonstrates the effectiveness of integrating network pharmacology with an experimental study for material basis of the major therapeutic diseases and the underlying molecular mechanisms of TCM.

Traditional Chinese medicine (TCM) formulas have a significant clinical efficacy, and the fingerprint technology has been widely accepted to fully reveal the quality of TCM. Whereas, it is a great challenge to establish the fingerprint chromatogram which can fully reflect every single herb material in a short time. In this study, we used Xiaojin capsule (XJC) as a case and developed a rapid fingerprint method based on increasing the column temperature and flow rate simultaneously combined with computer-aided. First, the elution gradient was optimized based on the retention parameters and peak shape parameters of the four linear gradients, and then, the column temperature and flow rate were increased simultaneously to shorten the analysis time. Next, the standard fingerprint chromatogram of XJC, which can reflect every herb material, was generated. Finally, quality markers were screened through unsupervised cluster analysis and supervised orthogonal partial least squares discrimination analysis. Combining computer-aided with increasing column temperature and flow rate simultaneously can develop the rapid method for establishing HPLC fingerprint of XJC, which can fully reflect every single herb material and provide comprehensive quality control. The strategy for establishing HPLC fingerprint of TCM formula could be applied to other traditional Chinese medicine formulas and herbal medicine.

Lianpu drink (LPD) is a traditional Chinese medicine (TCM) formula for the treatment of chronic gastritis (CG), and its clinical effects have been effectively verified. However, due to the complexity of the chemical composition of TCM formulas, its mechanism of action has not yet been clearly explained. Many studies have shown that the principal drugs in the TCM formula play a major therapeutic role. Therefore, in this study, the principal drugs Coptidis Rhizoma (CR) and Magnolia officinalis Rehd. et Wils. (MOR) in LPD were used as the main research objects to predict the mechanism of LPD on CG. We contrasted a “compounds-targets-diseases” network and screened the putative targets of CR and MOR in LPD related to CG, respectively. Furthermore, common targets of CR and MOR related to CG were selected as candidate targets. In this study, the specific target proteins of CR, MOR, and CG were combined by protein-protein interaction (PPI) to construct a pharmacological network of “components-targets-diseases.” In addition, we investigated the effects of CR and MOR on the TNF signaling pathway, which mediated the remission of CG. This study preliminarily revealed that CR and MOR play a key role in the treatment of CG. Animal experiments also showed that CR and MOR could significantly improve CG by inhibiting MKK6/p38 and RIP/p38 pathway.

Background Yellow complexion is a major skin issue that bothers Chinese women. The major factor leading to sallow complexion is the accumulation of advanced glycosylation end products (AGEs). Traditional Chinese medicine (TCM) treats dull, yellow complexion as being associated with liver-, spleen- or stomach-related functional disorders. Through analysis of prescription data, we explored combinations of new prescriptions with yellow-dispelling effects.Methods We extracted the most commonly used drug pairs and core medicine in anti-yellowing formulas, then carry out hierarchical clustering analysis and extract new formula combinations. The combination effect was determined by falvnoe, DPPH radical scavenging activity and Non-enzymatic glycosylation inhibiting activity. Toxicological analysis included HET-CAM, 3T3 phototoxicity, multiple irritation and patch test.Result Three empirical formulas were identified according to drug frequency analysis, and a new formula was identified according to the results of hierarchical clustering analysis. A series of biochemical experiments proved that the best anti-yellow-complexion formula combination was the new one. The results of the safety investigation showed that the new formula at a concentration of 5% had no eye irritation effects, no irritant or corrosive effects on mammalian skin, and no adverse reactions with human skin.Conclusion This study explored and analysed the internal laws of TCM for treatment of yellow complexion and, on this basis, developed a plant combination extract material with an anti-yellowing effect on skin.

Ethnopharmacological relevance Yixin Ningshen tablet is a CFDA-approved TCM formula for treating depression clinically. However, little is known about its active compounds and related potential target proteins, so far, no researches have been performed to investigate its mechanism of action for the treatment of depression. Aim of the study Here we develop an original bioinformatics pipeline composed of text mining tools, database querying and systems biology combinatorial analysis, which is applied to rapidly explore the mechanism of action of Yixin Ningshen tablet in treating depression. Materials and methods Text mining and database query were applied to identify active compounds in Yixin Ningshen tablet for the treatment of depression. Then SwissTargetPrediction was used to predict their potential target proteins. PubMed was retrieved to summarize known depression related systems biology results. Ingenuity Pathway Analysis (IPA) tools and STRING were applied to construct a compound-target protein-gene protein-differential protein-differential metabolite network with the integration of compound-target interaction and systems biology results, as well as enrich the target proteins related pathways. ChEMBL and CDOCKER were used to validate the compound-target interactions. Results 62 active compounds and their 286 potential target proteins were identified in Yixin Ningshen tablet for the treatment of depression. The construction of compound-target protein-gene protein-differential protein-differential metabolite network shrinked the number of potential target proteins from 286 to 133. Pathway enrichment analysis of target proteins indicated that Neuroactive ligand-receptor interaction, Calcium signaling pathway, Serotonergic synapse, cAMP signaling pathway and Gap junction were the common primary pathways regulated by both Yixin Ningshen Tablet and anti-depressant drugs, and MAPK, Relaxin, AGE-RAGE, Estrogen, HIF-1, Jak-STAT signaling pathway, Endocrine resistance, Arachidonic acid metabolism and Regulation of actin cytoskeleton were the specifically main pathways regulated by Yixin Ningshen tablet for the treatment of depression. Further validations based on references and molecular docking results demonstrated that Yixin Ningshen tablet could primarily target MAPT, CHRM1 and DRD1, thus regulating serotonergic neurons, cholinergic transmission, norepinephrine and dopamine reuptake for the treatment of depression. Conclusions This study displays the power of extensive mining of public data and bioinformatical repositories to provide answers for a specific pharmacological question. It furthermore demonstrates how the usage of such a combinatorial approach is advantageous for the biologist in terms of experimentation time and costs.

In traditional Chinese medicine (TCM), type 2 diabetes mellitus (T2DM) is regarded as Xiao Ke disease. Liuwei Dihuang pills (LWP), a classical TCM formula, with the function of nourishing kidney yin, has been used for treating Xiao Ke disease in clinic. In this review, we systematically highlighted recent evidence on LWP and T2DM data from clinical and animal studies, summarized the clinical application, pharmacological mechanism and the active compounds of LWP for the treatment of T2DM. This systematic review will provide an insightful understanding of TCM formulas, pharmacological mechanisms, medicinal-disease interactions, and will lay a foundation for the development of new drug therapy for T2DM.

Background Microbial fermentation has been widely applied in traditional Chinese medicine (TCM) for thousands of years in China. Various beneficial effects of fermentation for applications in TCM or herbals have been reported, such as enhanced anti-ovarian cancer, antioxidative activity, and neuroprotective effects. Ge-Gen-Qin-Lian decoction (GQD), a classic TCM formula, has been used to treat type 2 diabetes mellitus in China. In this study, GQD was fermented with Saccharomyces cerevisiae, and the antidiabetic activities and overall chemical profiles of raw and fermented GQD (FGQD) were systematically compared. Methods First, the antidiabetic effects of GQD and FGQD on high-fat diet and streptozotocin (STZ)-induced diabetic rats were compared. Then, high-performance liquid chromatography Q Exactive MS was applied for rapid characterization of the chemical components of GQD. Additionally, we proposed an integrated chromatographic technique based untargeted metabolomics identifying differential chemical markers between GQD and FGQD and targeted analysis determining the fermenting-induced quantitative variation tendencies of chemical marker strategy for overall chemical profiling of raw and fermented GQD. Results Both GQD and FGQD displayed effects against HFD and STZ-induced diabetes, and FGQD showed a better recovery trend associated with profound changes in the serum lipoprotein profile and body weight gain. In addition, 133 compounds were characterized from GQD. It was demonstrated that the integrated strategy holistically illuminated 30 chemical markers contributed to the separation of GQD and FGQD, and further elucidated the fermenting-induced chemical transformation mechanisms and inherent chemical connections of secondary metabolites. Although there were no new secondary metabolites in FGQD compared with GQD, the amounts of secondary metabolites, which were mostly deglycosylated, were redistributed in FGQD. Conclusion The anti-diabetic activities of GQD could be improved by applying fermentation technology. Moreover, the proposed strategy could serve as a powerful tool for systematically exploring the chemical profiles of raw and fermented formulas. Electronic supplementary material The online version of this article (10.1186/s13020-018-0208-7) contains supplementary material, which is available to authorized users.

Objectives There is an increasing number of complex diseases that are progressively more difficult to be controlled using the conventional "single compound, single target" approach as demonstrated in our current modern drug development. TCM might be the new cornerstone of treatment alternative when the current treatment option is no longer as effective or that we have exhausted it as an option. Orthogonal stimulus-response compatibility group study is one of the most frequently employed formulas to produce optimal herbal combination for treatment of multi-syndromic diseases. This approach could solve the relatively low efficacy single drug therapy usage and chronic adverse effects caused by long terms administration of drugs that has been reported in the field of pharmacology and medicine. Methods The present review was based on the Science Direct database search for those related to the TCM and the development of antihypertensive TCM herbal combination using orthogonal stimulus-response compatibility group studies approach. Results Recent studies have demonstrated that the orthogonal stimulus-response compatibility group study approach was most frequently used to formulate TCM herbal combination based on the TCM principles upon the selection of herbs, and the resulting formulated TCM formula exhibited desired outcomes in treating one of global concerned complex multi-syndromic diseases, the hypertension. These promising therapeutic effects were claimed to have been attributed by the holistic signaling mechanism pathways employed by the crude combination of herbs. Conclusion The present review could serve as a guide and prove the feasibility of TCM principles to be used for future pharmacological drug research development.

Stroke is the leading cause of human disability with limited effective drugs availability. The disruption of multiple signaling pathways in stroke makes developing new drugs be difficult. Traditional Chinese medicine (TCM) has its unique advantage in targeting multiple signaling pathways with multiple components. Many TCM formulas have the potential for neuroprotection and neurogenesis, but well-designed clinical trials are insufficient and underlying mechanisms unclear. Herein, we introduce the commonly used TCM formulas for stroke treatment and selectively introduce two classic formulas, An Gong Niu Huang (AGNH) pill and Bu Yang Huan Wu Decoction (BYHWD) for neuroprotection and neurogenesis, respectively. Current scientific evidence and clinical trials indicate AGNH pill could be an effective neuroprotective formula as adjunct therapy with relative safety. On the other hand, as a representative TCM formula for post stroke disability, BYHWD could improve the neurological outcome with its neuroprotective and neurogenic effects. The underlying mechanisms could be attributed to the modulation of multiple molecular targets with its multiple components. In conclusion, TCM formulas could be potential adjunct therapies for stroke treatment. The clinical efficacies and molecular mechanisms of promoting neuroprotection and neurogenesis remain to be further studies. Keywords: Stroke, Neuroprotection, Neurogenesis, Traditional Chinese Medicine, Bu Yang Huan Wu Decoction, An Gong Niu Huang pill

Introduction On account of the complicated compositions of the products like traditional Chinese medicines (TCMs) and functional foods, it is a common practice to determine different sets of analytes in the same product for different purposes. Objective To efficiently develop the corresponding HPLC methods, a statistical model based analytical method adjustment (SMB-AMA) strategy was proposed. Methods In this strategy, the HPLC data acquired with design of experiments methodology were efficiently utilised to build the retention models for all the analytes and interferences shown in the chromatograms with multivariate statistical modelling methods. According to the set of analytes under research, Monte-Carlo simulations were conducted based on these retention models to estimate the probability of achieving adequate separations between all the analytes and their interferences. Then the analytical parameters were mathematically optimised to the point giving a high value of this probability to compose a robust HPLC method. Radix Angelica Sinensis (RAS) and its TCM formula with Folium Epimedii (FE) were taken as the complicated samples for case studies. Results The retention models for the compounds in RAS and FE were built independently with correlation coefficients all above 0.9799. The analytical parameters were tactfully adjusted to adapt to six cases of different sets of analytes and different sample matrices. In the validation experiments using the adjusted analytical parameters, satisfactory separations were acquired. Conclusion The results demonstrated that the SMB-AMA strategy was able to develop HPLC methods rationally and rapidly in the adaption of different sets of analytes. Copyright © 2017 John Wiley & Sons, Ltd.

Traditional Chinese Medicine (TCM) is widely used and tested in ethnic communities for a long history. A large number of TCM formulae, as the centralized expression of “theory, cure, recipe, and medicine”, were preserved and recorded in way of relatively completed ingredients and lack of well-noted efficacies. The main objective of this paper is to translate dosage of each herb in a TCM formula into intensity of its efficacies in a quantitative and visual way. In this study, firstly, we estimated the intensity between a herb and its efficacies quantitatively based on clinical case data, which can reflect the difference between main and secondary efficacies of a herb. Then, to calculate and visualize the interaction between different efficacies from different herbs, we have proposed a method based on the Efficacy Semantic Network (ESN). It includes three steps: (1) Simple cumulation; (2) Adjustments; (3) Main efficacies selection. We tested on a dataset of 70 TCM formulae, results show that maximum performance measure reaches 0.818 which prove that the proposed approach could help standardize existing and predict potential efficacies of TCM in a quantitative way. It shows a great potential of semantic technologies to represent, calculate and visualize the TCM knowledge. However, more efforts are still required to investigate how to represent other fuzzy and rule-based knowledge and bring more data of TCM formulae for extensive tests.

Huangqi Jianzhong Tang (HQJZ) is a classical traditional Chinese prescription for treating chronic atrophic gastritis (CAG). However, its material basis is still unclear. Thus, we constructed a novel strategy to illustrate its pharmaco basis coupled with metabolomics and serum pharmacochemistry. Plasma metabolic profile including control group, model group, HQJZ treated control group, and HQJZ treated model group were firstly detect by Ultra-high performance liquid chromatography coupled with quadrupole-Exactive mass spectrometry. Eight endogenous metabolites were screened as the pharmaco markers of HQJZ, which were significantly ameliorated by HQJZ in model group but no significant change in control group. A total of 11 prototypical compounds and 13 metabolites of HQJZ were screening and identified in HQJZ intervention groups. Further pearson correlative analysis were applied to discover the effective compounds for HQJZ, which were significantly correlated with those pharmaco markers. At last, 12 prototypical compounds excepting isoliquiritigenin and 7 metabolites were considered as potential pharmacodynamic basis of HQJZ, which could hit more metabolite targets. The results revealed the links between serum exogenous and endogenous metabolites involved into the protection of HQJZ, which showed a powerful tool to obtain the material basis of TCM formula.

Ethnopharmacological relevance Intervertebral disc degeneration (IDD) is one of the most common causes of chronic low back pain that spending a lot of workforces and financial resources, seriously affecting human physical and mental health. Clinically used drug treatments and surgical treatments cannot fundamentally relieve the disease and have a risk of recurrence. Traditional Chinese Medicine (TCM) has a history of more than a thousand years in the prevention and treatment of IDD. However, so far, there are few reviews on the treatment of IDD by TCM. Therefore, it is crucial and necessary to systematically mine the existing literature on the treatment of IDD with TCM. This paper strives to systematically describe the modern medicine and TCM theoretical research on IDD, progress in the treatment of IDD and focuses on the treatment of IDD by TCM, which would lay some theoretical foundation and provide new directions for future research. Materials and methods Information on clinical observations, animal experiments and relevant pharmacology data about the treatment of IDD were gathered from various sources including traditional Chinese books and Chinese Pharmacopoeia, scientific databases (Elsevier, PubMed, Science Direct, Baidu Scholar, CNKI, Spring Link, Web of Science) and from different professional websites. Results This review mainly introduces the current research on the theoretical research on IDD, the combination principle of the TCM formula, and the underlying mechanism of the formula and active ingredients. Conclusions At present, domestic and foreign scholars have carried out a lot of research in different ways, such as the molecular mechanism and predisposing factors of IDD, which provides theoretical development and clinical practice significance for future research. TCM, as a multi-component and multi-targeted drug, can produce synergistic effects to exert its efficacy. Therefore, the development of TCM with more specific functions and practical data will not only become a significant trend in the world market but also has an irreplaceable role in the future treatment of IDD.

Traditional Chinese medicine (TCM) has been practiced for thousands of years in China. TCM formula, usually composed of several or even dozens of herbal medicines, is the main form of TCM practicing, which is extremely complex due to multiple components and therapeutic targets, especially the characteristics of formula compatibility. Thus, it is an enormous challenge for the modernization of TCM. Systems biology is a strategy for investigating the complex interactions between genes, mRNA, proteins, and metabolites by using integrated omics approaches. In recent years, systems biology has been increasingly adopted in TCM study. This review comprehensively summarized status of syndrome and application of TCM formulae in clinical and preclinical studies and discussed the advances of systems biology in TCM research. Then, a “Disease-Syndrome-Formulae-Effect” strategy was proposed for TCM research. Combination of systems biology and “Disease-Syndrome-Formulae-Effect” strategy provided a novel approach to understand the complex interactions among biological systems, drugs, and complex diseases from a network perspective, thus facilitating the modernization of TCM. The objective of this manuscript is to provide comprehensive and up-to-date review on the application of systems biology in TCM research, as well as the perspective of TCM modernization with systems biology.

Pharmacokinetic studies are crucial for elucidating the effective constituents and formula compatibility of traditional Chinese medicines (TCMs). However, studies have usually been limited to single dosages and detection of systemic blood concentrations. To obtain comprehensive pharmacokinetic information, here we propose a multi-dosage and multi-sampling (blood from portal vein or systemic circulation, and liver) strategy to comparatively study the pharmacokinetics of multi-form TCMs, i.e., pure constituents, TCMs, or TCM formula extracts. Based on this strategy, we studied the pharmacokinetics of pure berberine, berberine in Coptidis Rhizoma (CRE), and berberine in Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma extracts (CR-GRE). After simple calculation and comparison of the obtained area under the curve (AUC) values, the results revealed the drastically different pharmacokinetic properties of pure berberine compared to CRE and CR-GRE. The results contribute to explaining the pharmacological loss of berberine activity after purification and the compatibility of the CR-GR drug pair. The results also innovatively showed that it was intestinal absorption that differentiated the pharmacokinetics of CRE and pure berberine, and CRE and CR-GRE. In conclusion, we propose a composite strategy to comparatively study the pharmacokinetics of TCMs, which could provide sufficient information to obtain a comprehensive view, before follow-up mechanism-of-action studies.

Traditional Chinese medicine (TCM) is typically prescribed as formula to treat certain symptoms. A TCM formula contains hundreds of chemical components, which makes it complicated to elucidate the molecular mechanisms of TCM. Here, we proposed a computational systems pharmacology approach consisting of network link prediction, statistical analysis, and bioinformatics tools to investigate the molecular mechanisms of TCM formulae. Taking formula Tian-Ma-Gou-Teng-Yin as an example, which shows pharmacological effects on Alzheimer’s disease (AD) and its mechanism is unclear, we first identified 494 formula components together with corresponding 178 known targets, and then predicted 364 potential targets for these components with our balanced substructure-drug–target network-based inference method. With Fisher’s exact test and statistical analysis we identified 12 compounds to be most significantly related to AD. The target genes of these compounds were further enriched onto pathways involved in AD, such as neuroactive ligand–receptor interaction, serotonergic synapse, inflammatory mediator regulation of transient receptor potential channel and calcium signaling pathway. By regulating key target genes, such as ACHE, HTR2A, NOS2, and TRPA1, the formula could have neuroprotective and anti-neuroinflammatory effects against the progression of AD. Our approach provided a holistic perspective to study the relevance between TCM formulae and diseases, and implied possible pharmacological effects of TCM components.

Multiple components of traditional Chinese medicine (TCM) formulae determine their treatment targets for multiple diseases as opposed to a particular disease. However, discovering the unexplored therapeutic potential of a TCM formula remains challenging and costly. Inspired by the drug repositioning methodology, we propose an integrated strategy to feasibly identify new therapeutic uses for a formula composed of six herbs, Liuweiwuling. First, we developed a comprehensive systems approach to enrich drug compound-liver disease networks to analyse the major predicted diseases of Liuweiwuling and discover its potential effect on liver failure. The underlying mechanisms were subsequently predicted to mainly attribute to a blockade of hepatocyte apoptosis via a synergistic combination of multiple effects. Next, a classical pharmacology experiment was designed to validate the effects of Liuweiwuling on different models of fulminant liver failure induced by D-galactosamine/lipopolysaccharide (GalN/LPS) or thioacetamide (TAA). The results indicated that pretreatment with Liuweiwuling restored liver function and reduced lethality induced by GalN/LPS or TAA in a dose-dependent manner, which was partially attributable to the abrogation of hepatocyte apoptosis by multiple synergistic effects. In summary, the integrated strategy discussed in this paper may provide a new approach for the more efficient discovery of new therapeutic uses for TCM formulae.

Introduction An impediment for the acceptance of Traditional Chinese Medicine (TCM) in the West is that the improper use of some TCM is associated with serious side effects. This is exemplified by Ma Huang Decoction (MHD), a Ma Huang containing TCM formula used to treat asthma. The reported cardiovascular side effects often involve the inappropriate use of Ma Huang in isolation, while in TCM clinical practice Ma Huang is combined with other herbs in MHD to mitigate side effects. The aim of the study was to investigate the potential of Ma Huang as it is used in TCM, explore how it may affect the cardiovascular system and compare this to Ma Huang as it is used in the West. Methods The contractile response of isolated arteries from human placenta to Ma Huang, MHD, and MHD without Ma Huang was used in a bioassay to evaluate their cardiovascular side effects. Results The contractile response by Ma Huang in isolation is much higher than that of Ma Huang in combination with the other herbs in MHD. This confirms that the interplay of the various compounds in MHD may mitigate the side effects of Ma Huang. Previous studies showed that the other herbs in MHD also increase the therapeutic efficacy of Ma Huang. This indicates that the incorrect use of Ma Huang in isolation, and without the supervision of knowledgeable professionals, is likely to be the reasons why the cardiovascular side effects are reported in the West. Conclusion To fully value and appreciate its benefit, TCM should be used appropriately as developed over centuries in China.

Several pathways are crucial in Huntington’s disease (HD). Based on the concept of multitargets, network pharmacology-based analysis was employed to find out related proteins in disease network. The network target method aims to find out related mechanism of efficacy substances in rational design way. Traditional Chinese medicine prescriptions would be used for research and development against HD. Virtual screening was performed to obtain drug molecules with high binding capacity from traditional Chinese medicine (TCM) database@Taiwan. Quantitative structure-activity relationship (QSAR) models were conducted by MLR, SVM, CoMFA, and CoMSIA, constructed to predict the bioactivities of candidates. The compounds with high-dock score were further analyzed compared with control. Traditional Chinese medicine reported in the literature could be the training set provided for constructing novel formula by SVM model. We tried to find a novel formula that can bind well with these targets at the same time, which indicates our design could be highly related to the HD. Additionally, the candidates would validate by a long-term molecular dynamics (MD) simulation, 5 microseconds. Thus, we suggested the herbs Brucea javanica, Holarrhena antidysenterica, Dichroa febrifuga, Erythrophleum guineense, etc. which contained active compounds might be a novel medicine formula toward Huntington’s disease.

Ban-Xia-Xie-Xin-Tang (BXXXT) is a classical formula from Shang-Han-Lun which is one of the earliest books of TCM clinical practice. In this work, we investigated the therapeutic mechanisms of BXXXT for the treatment of multiple diseases using a network pharmacology approach. Here three BXXXT representative diseases (colitis, diabetes mellitus, and gastric cancer) were discussed, and we focus on in silico methods that integrate drug-likeness screening, target prioritizing, and multilayer network extending. A total of 140 core targets and 72 representative compounds were finally identified to elucidate the pharmacology of BXXXT formula. After constructing multilayer networks, a good overlap between BXXXT nodes and disease nodes was observed at each level, and the network-based proximity analysis shows that the relevance between the formula targets and disease genes was significant according to the shortest path distance (SPD) and a random walk with restart (RWR) based scores for each disease. We found that there were 22 key pathways significantly associated with BXXXT, and the therapeutic effects of BXXXT were likely addressed by regulating a combination of targets in a modular pattern. Furthermore, the synergistic effects among BXXXT herbs were highlighted by elucidating the molecular mechanisms of individual herbs, and the traditional theory of “Jun-Chen-Zuo-Shi” of TCM formula was effectively interpreted from a network perspective. The proposed approach provides an effective strategy to uncover the mechanisms of action and combinatorial rules of BXXXT formula in a holistic manner.

The systemic effects of traditional Chinese medicine (TCM) seem to be a Gordian knot, impossible to untie for decades. With the advent of transcriptomics, a useful sword is provided to cut the knot and shed some light on complex bioprocesses and intrinsic connections among them. Here, we revisit studies on TCM ZHENGs using this approach, highlight its applications on elucidating the potential scientific basis of ZHENG and investigating mechanisms of action for the TCM formula, and demonstrating its unique role in novel TCM drug design and discovery through active ingredient detection from TCM and compatibility theory study of TCM. The limitations and future perspectives of transcriptomics approaches to TCM study are also discussed.

Four spiroalkaloids, including a new compound shensongine A (1), were isolated from the anti-arrhythmic TCM formula Shensong Yangxin capsule. Their structures were determined on the basis of spectroscopic analysis. Compounds 1 and 3 displayed cardiovascular activities by shortened APD in rat myocardial cells. These compounds were possibly generated from precursors in different composed herbal medicines during the processing of the TCM formula.

Since traditional Chinese medicine (TCM) is a complex mixture of multiple components, the application of methodologies for evaluating single-components Western medicine in TCM studies may have certain limitations. Appropriate strategies that recognize the integrality of TCM and connect to TCM theories remain to be developed. Here we use multiple unique approaches to study the scientific connotation of a TCM formula Dan-hong injection (DHI) without undermining its prescription integrity. The blood circulation improving and healing promoting effects of DHI were assessed by a qi stagnation blood stasis rat model and a mouse model of laser irradiation induced cerebral microvascular thrombosis. By UFLC-PDA-Triple Q-TOF-MS/MS and relevance analysis between chemical characters and biological effects, 82 chemical constituents and nine core components, whose blood circulation promoting effects were found comparable to that of whole DHI, were successfully identified. What’s more, the rationality of DHI prescription compatibility could be reflected not only in the maximum efficacy of the original ratio, but also in the interactions of compounds from different ingredient herbs, such as complementary activities and facilitating tissues distribution. This study provides scientific evidences in explanation of the clinical benefits of DHI, and also gives a good demonstration for the comprehensive evaluation of other TCM.

Traditional Chinese medicine (TCM) has been an important resource for providing a large number of potential lead compounds for drug discovery, and represents a cornucopia of plant-derived remedies to discover novel lead molecules for the development of new drugs. Because TCM plays an important role in drug discovery and human health, investigation of phytochemical constituents of TCM has become a hotspot. Therefore the detection and identification of components may be equally important for understanding the pharmacological basis. Since almost every TCM is a multicomponent system, it is important to establish selective, sensitive, and feasible analytical methods for recognition, separation, and identification of multicomponents present in TCM. Recent improvements in analytical instrumentation with improved sensitivity and precision to allow greater resolution of multicomponents are driving the investigation of TCM. Ultrahigh performance liquid chromatography mass spectrometry (UHPLC-MS) technology with automated multivariate data processing approach was established for screening and identification of phytochemical constituents in TCM. Simiao Wan (SW), a well-known and widely used TCM formula, has been extensively used as an adjuvant to chemotherapy for rheumatoid arthritis disease treatment in clinics. UHPLC-MS provides a great deal of data, which are best used for structural elucidation and play an important role in the analysis of complex constituents of herbal medicine. In this study, UHPLC coupled with the electrospray ionization quadrupole time-of-flight mass spectrometry system using a C18 column (1.7 μm particle size) was established for rapid separation and structural identification of the constituents in SW.

In light of the emergence and spread of antibiotic resistance and lack of new drugs, herbal drug and antibiotic combination may represent an interesting therapy option for treat multidrug resistant bacteria. The Tanreqing injection is Chinese herbal preparation made from Scutellariae radix (Huang Qin), Ursi fel (Xiong Dan), Naemorhedi cornu (Shan Yang Jiao), Lonicerae flos (Jin Yin Hua) and Forsythiae fructus (Lian Qiao). According to TCM, this formula clears heat and removes phlegm and it is used in China to treat respiratory tract infections (1). The present study was focused on the in vitro antibacterial activity and possible synergistic interactions of Tanreqing injection and selected antibiotics against methicillin-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentrations of Tanreqing injection, vancomycin and linezolid were determined by the broth microdilution method (16.5, 0.005 and 0.005 mg/mL, respectively) and synergy was studied by chequerboard technique and time kill curve assay. Obtained values of fractional inhibitory concentration index suggested no interactive effects of the tested combinations of Tanreqing injection and antibiotics. However, the time-kill experiments which are more informative giving an insight into both the rate and extend of antibacterial activity showed that the antibacterial efficacy of vancomycin and linezolid against MRSA was increased through their combination with Tanreqing injection. Combined application of 1/8 MIC vancomycin with 1/4 MIC Tanreqing or 1/8 MIC linezolid with 1/4 MIC Tanreqing revealed the ΔLC24 value of 2.63, suggesting synergistic effects of the tested TCM formula and antibiotics.

This study aimed to investigate whether the anti-tumor effect of gemcitabine (GEM) in non-small-cell lung cancer (NSCLC) treatment was affected by Danggui Buxue decoction (DBD), and explore the potential mechanisms. The combined use of GEM and DBD showed an enhanced tumor growth inhibition effect in a murine Lewis lung carcinoma (LLC) model. LC-MS/MS results showed that the pharmacokinetic behaviors of a GEM active metabolite, gemcitabine triphosphate (dFdCTP), were found to be altered remarkably in the peripheral blood mononuclear cells (PBMC) of DBD co-administration rats. In addition, after co-administration of DBD with GEM, Western Blot and qPCR results confirmed that the expression of deoxycytidine kinase (dCK) in tumor tissues of LLC-bearing mice were markedly increased. DBD co-administration also reversed the upregulation of P-glycoprotein (P-gp) in tumor tissues induced by GEM. Moreover, DBD could notably up-regulate the IL-12p70 and GM-CSF expression in mice serum, suggesting potential immunomodulatory activities in tumor-bearing mice. Meanwhile, DBD inhibited the P-gp efflux activity in A549 cells. Therefore, the regulation of dCK and P-gp played important roles in the alternation of GEM pharmacokinetics and the enhancement of the anti-tumor effect of GEM. DBD being a potential dCK promoter could work as an adjuvant agent to boost the anticancer effect of GEM.

A traditional Chinese medicine (TCM) formula network including 362 TCM formulas was built by using complex network methodologies. The properties of this network were analyzed including network diameter, average distance, clustering coefficient, and average degree. Meanwhile, we built a TCM chemical space and a TCM metabolism room under the theory of chemical space. The properties of chemical space and metabolism room were calculated and analyzed. The properties of the medicine pairs in “eighteen antagonisms and nineteen mutual inhibitors,” an ancient rule for TCM incompatibility, were studied based on the TCM formula network, chemical space, and metabolism room. The results showed that the properties of these incompatible medicine pairs are different from those of the other TCM based on the analysis of the TCM formula network, chemical space, and metabolism room. The lines of evidence derived from our work demonstrated that the ancient rule of TCM incompatibility, “eighteen antagonisms and nineteen mutual inhibitors,” is probably scientifically based.

Because of the complexity of the components in Traditional Chinese Medicine formula (TCM formula), it is still a challenge to identify its effective components, to elucidate the mechanism of the components, and to discover the relationship between components and therapy objectives. In this paper, a method called directed TCM grammar systems (dTGS) for effective component identification was proposed using entity grammar systems (EGS) as the theoretical framework. The component-disease relationship of a TCM formula (i.e., Bai-Hu decoction plus Wasting-Thirsting formula, BHDWT) and one disease (i.e., type 2 diabetes mellitus) treated with it was studied, and the effective component groups (ECGs) were identified. 19 compounds were found acting on 20 proteins in type 2 diabetes mellitus (T2D) disease network, and 15 compounds were determined as the candidate effective components. Results indicated that this method can be used to identify the effective components and provide an innovative way to elucidate the molecular mechanism of TCM formulas.

Though many studies have been performed to elucidate molecular mechanism of traditional Chinese medicines (TCMs) by identifying protein-compound interactions, no systematic analysis at herb level was reported. TCMs are prescribed by herbs and all compounds from a certain herb should be considered as a whole, thus studies at herb level may provide comprehensive understanding of TCMs. Here, we proposed a computational strategy to study molecular mechanism of TCM at herb level and used it to analyze a TCM anti-HIV formula. Herb-target network analysis was carried out between 17 HIV-related proteins and SH formula as well as three control groups based on systematic docking. Inhibitory herbs were identified and active compounds enrichment was found to contribute to the therapeutic effectiveness of herbs. Our study demonstrates that computational analysis of TCMs at herb level can catch the rationale of TCM formulation and serve as guidance for novel TCM formula design.

To investigate the effects of QuTan HuaYu TongMai granule (QHTG) on the perturbed metabolism of atherosclerosis mini-pig model, a serum metabonomics method based on Liquid chromatography/mass spectrometry was developed. Principal component analysis and partial least squares-discriminate analysis models were established for the metabonomics analysis. The effect of high dose QHTG group is equivalent with those of positive drugs group in PCA score plots. Some significantly changed metabolites, including lyso-PCs, metabolites of vitamin D3 and fatty acids were found to be reasonable in explaining the anti-atherosclerosis mechanism of QHTG. Metabonomic approach is helpful to further understand the pathophysiology of atherosclerosis in mini-pigs and the therapeutic mechanism of QHTG. Our work also indicated that the LC–MS based metabonomics method is a potential tool for performing intervention and mechanism research of traditional Chinese medicine (TCM).