Centella asiatica (L.) Urb. attenuates cardiac hypertrophy and improves heart function through multi-level mechanisms revealed by systems pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiac hypertrophy (CH) is an incurable heart disease, contributing to an increased risk of heart failure due to the lack of safe and effective strategies. Therefore, searching for new approaches to treat CH is urgent. Centella asiatica (L.) Urb. (CA), a traditional food and medicinal natural plant, has been turned out to be effective in the treatment of cardiovascular disease, but its efficacy and potential mechanisms in alleviating CH have not yet been investigated. AIM OF STUDY: In this study, we aimed to elucidate the multi-level mechanisms underlying the effect of CA against CH. STUDY DESIGN AND METHODS: A systems pharmacology approach was employed to screen active ingredients, identify potential targets, construct visual networks and systematically investigate the pathways and mechanisms of CA for CH treatment. The cardiac therapeutic potential and mechanism of action of CA on CH were verified with in vivo and in vitro experiments. RESULTS: Firstly, we demonstrated the therapeutic effect of CA on CH and then screened 13 active compounds of CA according to the pharmacokinetic properties. Then, asiatic acid (AA) was identified as the major active molecule of CA for CH treatment. Afterwards, network and functional enrichment analyses showed that CA exerted cardioprotective effects by modulating multiple pathways mainly involved in anti-apoptotic, antioxidant and anti-inflammatory processes. Finally, in vivo, the therapeutic effects of AA and its action on the YAP/PI3K/AKT axis and NF-κB signaling pathway were validated using an isoproterenol-induced CH mouse model. In vitro, AA decreased ROS levels in hydrogen peroxide-treated HL-1 cells. CONCLUSION: Overall, the multi-level mechanisms of CA for CH treatment were demonstrated by systems pharmacology approach, which provides a paradigm for systematically deciphering the mechanisms of action of natural plants in the treatment of diseases and offers a new idea for the development of medicinal and food products.

Systems pharmacology reveals the multi-level synergetic mechanism of action of Ginkgo biloba L. leaves for cardiomyopathy treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiomyopathy is a common cause of heart failure and may lead to increased risk of sudden cardiac death, lacking simple, safe and effective treatment strategies due to unclear pathogenesis. Ginkgo biloba L. leaves (GBLs), a traditional Chinese medicine (TCM), has been widely used in clinical medicine for improving blood circulation, and was demonstrated to be effective on cardiomyopathy in preclinical studies. However, because of the widely known holistic therapeutic philosophy via multi-target and multi-pathway effect for most TCMs, to explore its underlying molecular mechanisms of action (MoA) remains a great challenge. AIM OF STUDY: Decipher the underlying MoA of GBLs for cardiomyopathy treatment: Study design and methods: An integrated systems pharmacology framework was employed to screen potential active compounds, identify therapeutic targets, explore the action pathways and verify mechanisms of GBLs with in vitro experiments. RESULTS: We firstly confirmed the therapeutic effect of GBLs on cardiomyopathy and subsequently screened 27 active compounds from GBLs according to their pharmacokinetic properties. Then Probability Ensemble Approach was applied to identify the compound combinations that exert synergetic effect from GBLs. Network analysis and functional enrichment analysis demonstrated that these compounds exhibit synergistic therapeutic effect by acting on multiple targets and thereby regulating multiple pathways mainly involved in pro-survival, anti-apoptotic and anti-inflammatory processes. Finally, using a doxorubicin-induced myocardial injury model, therapeutic effect of ginkgolide A, ginkgolide B, isorhamnetin, as well as their synergistic effect on PI3K-AKT and NF-κB signaling pathways were validated in vitro. Importantly, we demonstrated that Ginkgo diterpene lactone meglumine injection (GDJ), an approved injection derived from GBLs, could be a promising agent for cardiomyopathy treatment. CONCLUSION: Collectively, the multi-level synergetic mechanism of GBLs on cardiomyopathy treatment was demonstrated with systems pharmacology approach, providing a paradigm for deciphering the complicated MoA of TCMs.

System-Pharmacology Dissection of Traditional Chinese herbs SINI Decoction for Treatment of Cardiovascular Diseases.

Abstract: Cardiovascular diseases (CVDs) are leading causes of death in the world, owing to noticeable incidence and mortality. Traditional Chinese Medicine (TCM) SINI Decoction (SND) is used to prevent and treat CVDs, which has attracted extensive attention for its moderate and little side effects. However, the involved molecular mechanisms are exceedingly complicated and remain unclear. Systems pharmacology, as a novel approach that integrates systems biology and pharmacology plays a significant role in investigating the molecular mechanism of TCM. In systems pharmacology approach, we use to systematically uncover the mechanisms of action in Chinese medicinal formula SND as an effective treatment for CVDs, which mainly includes:1) molecular database building; 2) ADME evaluation; 3) target-fishing 4) network construction and analysis. The results show that 78 underlying valid ingredients and their corresponding 71 direct targets of SND were obtained. And SND take part in cardiomyocyte protection, blood pressure regulation, and lipid regulation module in treatment of CVDs by cooperative way. Systems pharmacology as an emerging field that investigates the molecular mechanisms of TCM through pharmacokinetic evaluation target prediction, and pathway analysis, which will facilitate the development of traditional Chinese herbs in modern medicine.

Systems-Mapping of Herbal Effects on Complex Diseases Using the Network-Perturbation Signatures.

The herbs have proven to hold great potential to improve people's health and wellness during clinical practice over the past millennia. However, herbal medicine for the personalized treatment of disease is still under investigation owing to the complex multi-component interactions in herbs. To reveal the valuable insights for herbal synergistic therapy, we have chosen Traditional Chinese Medicine (TCM) as a case to illustrate the art and science behind the complicated multi-molecular, multi-genes interaction systems, and how the good practices of herbal combination therapy are applicable to personalized treatment. Here, we design system-wide interaction map strategy to provide a generic solution to establish the links between diseases and herbs based on comprehensive testing of molecular signatures in herb-disease pairs. Firstly, we integrated gene expression profiles from 189 diseases to characterize the disease-pathological feature. Then, we generated the perturbation signatures from the huge chemical informatics data and pharmacological data for each herb, which were represented the targets affected by the ingredients in the herb. So that we could assess the effects of herbs on the individual. Finally, we integrated the data of 189 diseases and 502 herbs, yielding the optimal herbal combinations for the diseases based on the strategy, and verifying the reliability of the strategy through the permutation testing and literature verification. Furthermore, we propose a novel formula as a candidate therapeutic drugs of rheumatoid arthritis and demonstrate its therapeutic mechanism through the systematic analysis of the influencing targets and biological processes. Overall, this computational method provides a systematic approach, which blended herbal medicine and omics data sets, allowing for the development of novel drug combinations for complex human diseases.

Clarifying of the potential mechanism of Sinisan formula for treatment of chronic hepatitis by systems pharmacology method.

Chronic hepatitis is a general designation class of diseases, which results in different degrees of liver necrosis and inflammatory reaction, followed by liver fibrosis, may eventually develop into cirrhosis. However, the molecular pathogenesis of chronic hepatitis is too complex to elucidate. Herbal medicines, featured with multiple targets and compounds, have long displayed therapeutic effect in treating chronic hepatitis, though their molecular mechanisms of contribution remain indistinct. This research utilized the network pharmacology to confirm the molecular pathogenesis of chronic hepatitis through providing a comprehensive analysis of active chemicals, drug targets and pathways' interaction of Sinisan formula for treating chronic hepatitis. The outcomes showed that 80 active ingredients of Sinisan formula interacting with 91 therapeutic proteins were authenticated. Sinisan formula potentially participates in immune modulation, anti-inflammatory and antiviral activities, even has regulating effects on lipid metabolism. These mechanisms directly or indirectly are involved in curing chronic hepatitis by an interaction way. The network pharmacology based analysis demonstrated that Sinisan has multi-scale curative activity in regulating chronic hepatitis related biological processes, which provides a new potential way for modern medicine in the treatment of chronic diseases.

Dengue virus causes changes of MicroRNA-genes regulatory network revealing potential targets for antiviral drugs.

BACKGROUND: Dengue virus (DENV) is an increasing global health threat and associated with induction of both a long-lived protective immune response and immune-suppression. So far, the potency of treatment of DENV via antiviral drugs is still under investigation. Recently, increasing evidences suggest the potential role of microRNAs (miRNAs) in regulating DENV. The present study focused on the function of miRNAs in innate insusceptible reactions and organization of various types of immune cells and inflammatory responses for DENV. Three drugs were tested including antiviral herbal medicine ReDuNing (RDN), Loratadine (LRD) and Acetaminophen. RESULTS: By the microarray expression of miRNAs in 165 Patients. Results showed that 89 active miRNAs interacted with 499 potential target genes, during antiviral treatment throughout the critical stage of DENV. Interestingly, reduction of the illness threats using RDN combined with LRD treatment showed better results than Acetaminophen alone. The inhibitions of DENV was confirmed by decrease concentrations of cytokines and interleukin parameters; like TNF-α, IFN-γ, TGF-ß1, IL-4, IL-6, IL-12, and IL-17; after treatment and some coagulants factors increased. CONCLUSIONS: This study showed a preliminary support to suggest that the herbal medicine RDN combined with LRD can reduce both susceptibility and the severity of DENV.

Elucidation of the Anti-Inflammatory Mechanisms of Bupleuri and Scutellariae Radix Using System Pharmacological Analyses.

Objective. This study was aimed at elucidating the molecular mechanisms underlying the anti-inflammatory effect of the combined application of Bupleuri Radix and Scutellariae Radix and explored the potential therapeutic efficacy of these two drugs on inflammation-related diseases. Methods. After searching the databases, we collected the active ingredients of Bupleuri Radix and Scutellariae Radix and calculated their oral bioavailability (OB) and drug-likeness (DL) based on the absorption-distribution-metabolism-elimination (ADME) model. In addition, we predicted the drug targets of the selected active components based on weighted ensemble similarity (WES) and used them to construct a drug-target network. Gene ontology (GO) analysis and KEGG mapper tools were performed on these predicted target genes. Results. We obtained 30 compounds from Bupleuri Radix and Scutellariae Radix of good quality as indicated by ADME assays, which possess potential pharmacological activity. These 30 ingredients have a total of 121 potential target genes, which are involved in 24 biological processes related to inflammation. Conclusions. Combined application of Bupleuri Radix and Scutellariae Radix was found not only to directly inhibit the synthesis and release of inflammatory cytokines, but also to have potential therapeutic effects against inflammation-induced pain. In addition, a combination therapy of these two drugs exhibited systemic treatment efficacy and provided a theoretical basis for the development of drugs against inflammatory diseases.

Systems Pharmacology Dissection of the Integrated Treatment for Cardiovascular and Gastrointestinal Disorders by Traditional Chinese Medicine.

Though cardiovascular diseases (CVDs) and gastrointestinal disorders (GIDs) are different diseases associated with different organs, they are highly correlated clinically. Importantly, in Traditional Chinese Medicine (TCM), similar treatment strategies have been applied in both diseases. However, the etiological mechanisms underlying them remain unclear. Here, an integrated systems pharmacology approach is presented for illustrating the molecular correlations between CVDs and GIDs. Firstly, we identified pairs of genes that are associated with CVDs and GIDs and found that these genes are functionally related. Then, the association between 115 heart meridian (HM) herbs and 163 stomach meridian (SM) herbs and their combination application in Chinese patent medicine was investigated, implying that both CVDs and GIDs can be treated by the same strategy. Exemplified by a classical formula Sanhe Decoration (SHD) treating chronic gastritis, we applied systems-based analysis to introduce a drug-target-pathway-organ network that clarifies mechanisms of different diseases being treated by the same strategy. The results indicate that SHD regulated several pathological processes involved in both CVDs and GIDs. We experimentally confirmed the predictions implied by the effect of SHD for myocardial ischemia. The systems pharmacology suggests a novel integrated strategy for rational drug development for complex associated diseases.

Systematic understanding the mechanisms of vitiligo pathogenesis and its treatment by Qubaibabuqi formula.

ETHNOPHARMACOLOGICAL RELEVANCE: Vitiligo is a depigmentation disorder, which results in substantial cosmetic disfigurement and poses a detriment to patients' physical as well as mental. Now the molecular pathogenesis of vitiligo still remains unclear, which leads to a daunting challenge for vitiligo therapy in modern medicine. Herbal medicines, characterized by multi-compound and multi-target, have long been shown effective in treating vitiligo, but their molecular mechanisms of action also remain ambiguous. MATERIALS AND METHODS: Here we proposed a systems pharmacology approach using a clinically effective herb formula as a tool to detect the molecular pathogenesis of vitiligo. This study provided an integrative analysis of active chemicals, drug targets and interacting pathways of the Uygur medicine Qubaibabuqi formula for curing Vitiligo. RESULTS: The results show that 56 active ingredients of Qubaibabuqi interacting with 83 therapeutic proteins were identified. And Qubaibabuqi probably participate in immunomodulation, neuromodulation and keratinocytes apoptosis inhibition in treatment of vitiligo by a synergistic/cooperative way. CONCLUSIONS: The drug-target network-based analysis and pathway-based analysis can provide a new approach for understanding the pathogenesis of vitiligo and uncovering the molecular mechanisms of Qubaibabuqi, which will also facilitate the application of traditional Chinese herbs in modern medicine.

Systems-Pharmacology Dissection of Traditional Chinese Medicine Compound Saffron Formula Reveals Multi-scale Treatment Strategy for Cardiovascular Diseases.

Cardiovascular diseases (CVDs) have been regarding as "the world's first killer" of human beings in recent years owing to the striking morbidity and mortality, the involved molecular mechanisms are extremely complex and remain unclear. Traditional Chinese medicine (TCM) adheres to the aim of combating complex diseases from an integrative and holistic point of view, which has shown effectiveness in CVDs therapy. However, system-level understanding of such a mechanism of multi-scale treatment strategy for CVDs is still difficult. Here, we developed a system pharmacology approach with the purpose of revealing the underlying molecular mechanisms exemplified by a famous compound saffron formula (CSF) in treating CVDs. First, by systems ADME analysis combined with drug targeting process, 103 potential active components and their corresponding 219 direct targets were retrieved and some key interactions were further experimentally validated. Based on this, the network relationships among active components, targets and diseases were further built to uncover the pharmacological actions of the drug. Finally, a "CVDs pathway" consisted of several regulatory modules was incorporated to dissect the therapeutic effects of CSF in different pathological features-relevant biological processes. All this demonstrates CSF has multi-scale curative activity in regulating CVD-related biological processes, which provides a new potential way for modern medicine in the treatment of complex diseases.

Systems Pharmacology Based Study of the Molecular Mechanism of SiNiSan Formula for Application in Nervous and Mental Diseases.

Background. Mental disorder is a group of systemic diseases characterized by a variety of physical and mental discomfort, which has become the rising threat to human life. Herbal medicines were used to treat mental disorders for thousand years in China in which the molecular mechanism is not yet clear. Objective. To systematically explain the mechanisms of SiNiSan (SNS) formula on the treatment of mental disorders. Method. A systems pharmacology method, with ADME screening, targets prediction, and DAVID enrichment analysis, was employed as the principal approach in our study. Results. 60 active ingredients of SNS formula and 187 mental disorders related targets were discovered to have interactions with them. Furthermore, the enrichment analysis of drug-target network showed that SNS probably acts through "multi-ingredient, multitarget, and multisystems" holistic coordination in different organs pattern by indirectly regulating the nutritional and metabolic pathway even their serial complications. Conclusions. Our research provides a reference for the molecular mechanism of medicinal herbs in the treatment of mental disease on a systematic level. Hopefully, it will also provide a theoretical basis for the discovery of lead compounds of natural medicines for other diseases based on traditional medicine.

CancerHSP: anticancer herbs database of systems pharmacology.

The numerous natural products and their bioactivity potentially afford an extraordinary resource for new drug discovery and have been employed in cancer treatment. However, the underlying pharmacological mechanisms of most natural anticancer compounds remain elusive, which has become one of the major obstacles in developing novel effective anticancer agents. Here, to address these unmet needs, we developed an anticancer herbs database of systems pharmacology (CancerHSP), which records anticancer herbs related information through manual curation. Currently, CancerHSP contains 2439 anticancer herbal medicines with 3575 anticancer ingredients. For each ingredient, the molecular structure and nine key ADME parameters are provided. Moreover, we also provide the anticancer activities of these compounds based on 492 different cancer cell lines. Further, the protein targets of the compounds are predicted by state-of-art methods or collected from literatures. CancerHSP will help reveal the molecular mechanisms of natural anticancer products and accelerate anticancer drug development, especially facilitate future investigations on drug repositioning and drug discovery. CancerHSP is freely available on the web at http://lsp.nwsuaf.edu.cn/CancerHSP.php.

TCMSP: a database of systems pharmacology for drug discovery from herbal medicines.

BACKGROUND: Modern medicine often clashes with traditional medicine such as Chinese herbal medicine because of the little understanding of the underlying mechanisms of action of the herbs. In an effort to promote integration of both sides and to accelerate the drug discovery from herbal medicines, an efficient systems pharmacology platform that represents ideal information convergence of pharmacochemistry, ADME properties, drug-likeness, drug targets, associated diseases and interaction networks, are urgently needed. DESCRIPTION: The traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was built based on the framework of systems pharmacology for herbal medicines. It consists of all the 499 Chinese herbs registered in the Chinese pharmacopoeia with 29,384 ingredients, 3,311 targets and 837 associated diseases. Twelve important ADME-related properties like human oral bioavailability, half-life, drug-likeness, Caco-2 permeability, blood-brain barrier and Lipinski's rule of five are provided for drug screening and evaluation. TCMSP also provides drug targets and diseases of each active compound, which can automatically establish the compound-target and target-disease networks that let users view and analyze the drug action mechanisms. It is designed to fuel the development of herbal medicines and to promote integration of modern medicine and traditional medicine for drug discovery and development. CONCLUSIONS: The particular strengths of TCMSP are the composition of the large number of herbal entries, and the ability to identify drug-target networks and drug-disease networks, which will help revealing the mechanisms of action of Chinese herbs, uncovering the nature of TCM theory and developing new herb-oriented drugs. TCMSP is freely available at http://sm.nwsuaf.edu.cn/lsp/tcmsp.php.