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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.

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.

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.

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

Current medication for depression is inadequate and far from ideal. Development of novel antidepressant drugs is a pressing task. The discovery of ketamine and related agents represents a new era in drug discovery for the rapid treatment of depression. Due to potential neurotoxicity, short-lasting efficacy, the limitation of a single target approach, and a limited role in depression prevention of these agents, additional approaches or drugs that exert synergy and compatibility, with the rapid-acting agents are required for better treatment of depression. Traditional Chinese Medicine (TCM) is a systems medicine and its clinical experience and integrated theory for diagnosis and treatment provides an alternative method of novel drug discovery in depression treatment. In TCM, there are numerous claimed effective antidepressant formulas, but comprehensive research and evidence-based clinical studies are required for their acceptance as a treatment. In this essay, we review current attempts in the discovery of new agents, TCM drug formulation, and TCM treatment of depression, and discuss the challenges and opportunities of TCM in the new era of antidepressant discovery. TCM could provide an important resource in the discovery of novel agents, assistance of the rapid-acting antidepressants, development of new agents for female patients, and the prevention of depression at its early stages. The study of depression in conjunction with TCM therefore not only provides an opportunity to scientifically evaluate the benefits and risks of TCM, but also accelerates the development of novel antidepressant agents by combining the principle of modern molecular medicine with the ideas of empirical systems medicine.

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.

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.

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.

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.

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).

The efficacy of traditional medicine such as traditional Chinese medicine (TCM) had been confirmed by many years of clinical use. However, the mechanisms of traditional medicine remained obscure. Since the development of systems biology in 2000, systems biology technologies have been popularly used in the mechanism study of traditional medicine. In this special issue, we particularly picked reviews and research papers related to mechanism study of TCM, TCM diagnosis, or TCM therapy methods using proteomics as well as other systems biology technologies. There are 10 papers collected in this special issue, in which 3 papers are reviews and 7 papers are original research papers. The 3 reviews in the present issue introduce the advancements in applications of proteomics technologies in the study of TCM and the achievements in the mechanism study of TCM. Q. Ji et al. summarized the applications of proteomics technologies in TCM syndrome research as well as the mechanistic study of TCM treatments, including Chinese herbal medicine, Chinese herbal formula, and acupuncture. Furthermore, they introduced the combined analyses of proteomics with other “-omics” technologies in the study of TCM. Y. A. Sulistio and K. Heese discussed the utility of comparative proteomics for a better understanding of the mechanisms involved in TCM activities and its potential application as complementary therapy for the treatment of Alzheimer's disease (AD). Additionally, they reviewed the data from comparative proteomics studies of AD patients and established the relevance of the data with available AD hypotheses and potential TCM-based treatments, most notably regarding the ubiquitin proteasome system. Y. Yang et al. focused on discussing various results of proteomics studies of mechanisms of anticancer TCM, including terpenes, flavonoids, and glycosides. And they suggested future research strategies such as integrating translating mRNA analysis with proteomics in the study of the mechanisms of anticancer TCM. Four of the research papers reported results of mechanism studies of TCM. J.-Y. Shiau et al. studied the mechanism of 2-β-D-glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tetrayne, an active component of Bidens pilosa, in human T-cell acute lymphocytic leukemia cells by using combined differential proteomics and bioinformatics approaches. M.-N. Shi et al. reported the protective effects of scutellarin, a flavone isolated from Erigeron breviscapus (Vant.) Hand.-Mazz, on human cardiac microvascular endothelial cells against hypoxia-reoxygenation injury. Possible target-related proteins of scutellarin were searched using proteomics analysis and a possible interaction network was predicted using bioinformatics analysis. C.-C. Guo et al. studied the antiosteoporotic effects and possible target-related proteins of Huangqi Sanxian decoction, a traditional Chinese formula composed of Radix astragali, Epimedii folium, Cistanche herba, Radix notoginseng, Radix Salviae Miltiorrhiae, Corydalis rhizoma, Radix Angelicae sinensis, and Radix Clematidis, in cultured rat osteoblasts. Z. Bo et al. investigated the molecular mechanism of fibroblast regulation and the treatment of recurrent oral ulcer by Shuizhongcao granule-containing serum. Shuizhongcao granule is a TCM formula composed of buffalo horn, urine sediment, callicarpa, and so forth, and it exhibited great efficacy in the clinical treatment of recurrent oral ulcer. In the present issue, there are also 3 research papers reporting about the mechanisms of TCM used for the diagnosis of diseases or specialized TCM therapy methods such as moxibustion. In the TCM system, tongue diagnosis has been an important diagnostic method. X. Liu et al. used the GC/MS technology to determine the potential changes of metabolites and identify special metabolic biomarkers in the tongue coating of H. pylori infected chronic gastritis patients. W.-T. Dang et al. studied the expression of caspase-1 gene transcript variant mRNA in peripheral blood mononuclear cells of patients with primary gout in different TCM syndromes. X.-L. Shi et al. investigated the effects of moxibustion, a traditional Chinese practice that involves heated Artemisia vulgaris (mugwort) stimulation, on hormonal imbalance and ovarian granulosa cell apoptosis in a rat model of perimenopause. In summary, this special issue provides a snapshot of the current status of mechanism studies of traditional medicine, especially TCM, using proteomics and other systems biology technologies. Authors of the present issue highlight both the achievements and challenges faced in the field of the mechanism study of traditional medicine. Hopefully, this publication will help readers to follow mechanism studies of traditional medicine and will contribute to improved applications of proteomics or other systems biology technologies in research of traditional medicine.

For the first time, the principal actions or effects of individual herbs defined by traditional Chinese medicine (TCM) are considered to describe an herbal formula. Principal effects, natures, flavors, meridian affinity, l ifting, l owering, f loating and s inking (LLFS) and toxicity of single herbs are then combined with their dosages to generate formula descriptors in a linear manner. Herbal actions and properties defined by TCM theory are foundations of formula prescriptions. Therefore, the resulted formula descriptors will simulate a TCM doctor's knowledge well. Moreover, during the development of TCM for thousands of years, herbal actions and properties are well understood and one can generate descriptors for any TCM formula based on our method. To validate and demonstrate the usefulness of the newly proposed formula descriptors, a case study of quantitative formula–activity relationship (QFAR) of hypertension formulas is performed. Based on 64 general formula descriptors, least squares support vector machine (LS-SVM) is used to discriminate the effective hypertension formulas from the negative ones. An external validation set is used to optimize LS-SVM parameters and evaluate the performance of classification models. The prediction accuracy of independent positive formulas and negative formulas are 93.1% and 96.5%, respectively. The new formula descriptors and the corresponding QFAR model can be used for preliminary screening of effective formulas from the massive TCM formula data distributed in various literatures and databases.

Objective The aim of this study is to determine the effects of aromatic acids on stimulating blood circulation and removing blood stasis. Methods A systematic study of aromatic acids concentration in the herbs frequently used in Traditional Chinese Medicine (TCM) formula to stimulate blood circulation and remove blood stasis is performed to help to establish a bio-activity basis and a compatibility principle for TCM formula. Results Through the study, we find that aromatic acids' effect of stimulating blood circulation and removing blood stasis may be increased by combing with alkali. Besides, aromatic acid esters can better stimulate blood circulation and remove blood stasis. What's more, the solubilization of aromatic acids helps stimulating blood circulation and removing blood stasis. Conclusions Aromatic acids have been proved to be effective in preventing platelet aggregation and anti-thrombus. On the one hand, they have a biological contribution to TCM formula and on the other hand they improve blood circulation through working with other elements in the TCM formula. Aromatic acids make a lot of contributions to the whole TCM formula.

The authors of this paper discussed different thoughts and methods of system biology and its applications in TCM formula study. The research and development of traditional Chinese medicine (TCM) formula has attracted increasing attention in the TCM industry for many years. But the basis and mechanism of TCM has not been explained clearly yet, due to its multicomponent and multitarget nature. System biology could provide novel insights into the TCM research. Therefore, some difficulties in TCM formula study including physical basis of TCM therapeutic effects, rules of compatibility, pharmacology, and action mechanism will be well illustrated in an effective manner. The problem of "black box" in TCM study will be fully understood with the help of system biology.

Along with an indispensable role in healthcare system of China for centuries, Traditional Chinese Medicine (TCM) shows increasing usages as complementary therapy in western countries. To improve our understanding on their therapeutic effects, it’s critical to unveil chemical compositions of TCM formula, the predominant form of therapy in TCM. However, intrinsic chemical complexity makes it a challenging task to perform analysis on each individual TCM formula even with most current state-of-art analytic techniques available. In this work we approached this question by focusing on analogous formulae, a unique category of TCM formulae grouped together based on shared herbs and/or similar TCM syndromes. Systematic chemical profiling on five Si-Ni decoctions (SNs) for cardiovascular diseases was performed by multistage MS and high-resolution MS (HR-MS) experiments. A total of 83 compounds, including alkaloids, flavonoids, ginsenosides, bile acids and triterpenoids, were described. Analysis on SNs-treated rats detected 55 prototype compounds and 39 metabolites in the systemic circulation in vivo, which may contribute directly to their observed clinical efficacies. This approach offers great advantage to speed up identification of chemical compositions of formula and reveal the difference among these analogous formulae that may be related to diverse clinical effects.

Compound identification is the essential step in the mechanistic research of traditional Chinese medicine (TCM). As the most common mode of practice in the clinic, TCM formula (Fangji or FJ in Chinese) is often utilized to treat diseases. With the proved therapeutic efficacies by century-long clinical applications, these TCM formulas have been the valuable resource of drug discovery and it is important to understand their mechanisms of action systemically in order to broaden their utilizations in modern system of medicine. Structure elucidation of compounds in FJs has been a very difficult and time-consuming task due to the extremely complex composition. In this work we developed a pre-classification strategy on multiple spectrums (high-performance liquid chromatography-mass spectrometry) of TCM analogous formulas to assist compound identification from FJs. Here Ma Huang decoction group (Herba Ephedrae, MHs, widely used in respiratory diseases) were analyzed as an example of TCM analogous formulas to demonstrate the accuracy and speed of our method. The results showed this strategy is very effective and powerful for this kind of complex sample analysis. Additionally, we carried out the chemical differentiation study of this formula group, which was reported for the first time and would be useful to further pharmacological studies.

Traditional Chinese medicine (TCM) formula has been playing a very important role in health protection and disease control for thousands of years. Guided by TCM syndrome theories, formula are designed to contain a combination of various kinds of crude drugs that, when combined, will achieve synergistic efficacy. However, the precise mechanism of synergistic action remains poorly understood. One example is a famous TCM formula Yinchenhao Tang (YCHT), whose efficacy in treating hepatic injury (HI) and Jaundice syndrome, has recently been well established as a case study. We also conducted a systematic analysis of synergistic effects of the principal compound using biochemistry, pharmacokinetics and systems biology, to explore the key molecular mechanisms. We had found that the three component (6,7-dimethylesculetin (D), geniposide (G), and rhein (R)) combination exerts a more robust synergistic effect than any one or two of the three individual compounds by hitting multiple targets. They can regulate molecular networks through activating both intrinsic and extrinsic pathways to synergistically cause intensified therapeutic effects. This paper provides an overview of the recent and potential developments of chemical fingerprinting coupled with systems biology advancing drug discovery towards more agile development of targeted combination therapies for the YCHT.

Ethnopharmacology relevance The main therapeutic concept in Traditional Chinese Medicine (TCM) is herb formula, which treats various diseases via potential herb interactions to maximize the efficacy and minimize the adverse effects. However, the combination principle of herb formula still remains a mystery due to the lack of appropriate methods. Methods A systems pharmacology method integrating the pharmacokinetic analysis, drug targeting, and drug–target–disease network is developed to dissect this rule embedded in the herbal formula. All these are exemplified by a representative TCM formula, Ma-huang decoction, made up of four botanic herbs. Results Based on the deep investigation of the function and compatibility of each herb, in a molecular/systems level, we demonstrate the different pharmacological roles that each herb might play in the prescription. By the way of enhancing the bioavailability and/or making the pharmacological synergy among different herbs, the four herbs effectively combine together to be suitable for treating diseases. Conclusions The present work lays foundations for a more comprehensive understanding of the combination rule of TCM, which might also be beneficial to drug development and applications.

Traditional Chinese medicine (TCM) is a complex system, which consists of numerous compounds with related mechanisms to maximize therapeutic efficacy with minimal adverse effects. Some new methods disclosing the contribution of these constituents as well as their relationship in the formula are necessary for elucidating the bio-active constituents and the working mechanisms of TCM. In this study, depletion of target components using preparative HPLC followed by antiplatelet and anticoagulation activities evaluation was first applied to investigate the roles of paeoniflorin and senkyunolide I in a well-known formula, SiWu decoction. The results showed that both paeoniflorin and senkyunolide I not only directly brought about some bio-activities, but also indirectly made the contribution to the total bio-activity reflection of SiWu decoction, especially the latter should deserve to be drawn attention to the research of complicated bio-active constituents of TCM or its formula. So, the significant and effective approach will be very useful for the elucidation of the contribution of each different chemical constituent to the bio-activity of a TCM formula. Furthermore, this study demonstrated the potential utilization of preparative HPLC in the research of TCM.

Traditional Chinese medicine (TCM) is a discipline with its own distinct methodologies and philosophical principles. The main method of treatment in TCM is to use herb prescriptions. Typically, a number of herbs are combined to form a formula and different formulae are prescribed for different patients. Regularities on the mixture of herbs in the prescriptions are important for both clinical treatment and novel patent medicine development. In this study, we analyze TCM formula data using latent tree (LT) models. Interesting regularities are discovered. Those regularities are of interest to students of TCM as well as pharmaceutical companies that manufacture medicine using Chinese herbs.

Background - Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures. PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906. Methods - Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of CPT-11 (CPT-11) by PHY906 in a well-characterized pre-clinical model; the administration of PHY906 and CPT-11 to female BDF-1 mice bearing subcutaneous Colon 38 tumors. Results - We observed that 1) individually PHY906 and CPT-11 induce distinct alterations in tumor, liver and spleen; 2) PHY906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of CPT-11, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection. Conclusions - PHY906 together with CPT-11 triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response.