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With recent advances in mass spectrometry-based proteomics technologies, deep profiling of hundreds of proteomes has become increasingly feasible. However, deriving biological insights from such valuable datasets is challenging. Here we introduce a systems biology-based software JUMPn, and its associated protocol to organize the proteome into protein co-expression clusters across samples and protein-protein interaction (PPI) networks connected by modules (e.g., protein complexes). Using the R/Shiny platform, the JUMPn software streamlines the analysis of co-expression clustering, pathway enrichment, and PPI module detection, with integrated data visualization and a user-friendly interface. The main steps of the protocol include installation of the JUMPn software, the definition of differentially expressed proteins or the (dys)regulated proteome, determination of meaningful co-expression clusters and PPI modules, and result visualization. While the protocol is demonstrated using an isobaric labeling-based proteome profile, JUMPn is generally applicable to a wide range of quantitative datasets (e.g., label-free proteomics). The JUMPn software and protocol thus provide a powerful tool to facilitate biological interpretation in quantitative proteomics.

This paper studies the differences between different types of newspapers in expressing temporal information, which is a topic that has not received much attention. Techniques from the fields of temporal processing and pattern mining are employed to investigate this topic. First, a corpus annotated with temporal information is created by the author. Then, sequences of temporal information tags mixed with part-of-speech tags are extracted from the corpus. The TKS algorithm is used to mine skip-gram patterns from the sequences. With these patterns, the signatures of the four newspapers are obtained. In order to make the signatures uniquely characterize the newspapers, we revise the signatures by removing reference patterns. Through examining the number of patterns in the signatures and revised signatures, the proportion of patterns containing temporal information tags and the specific patterns containing temporal information tags, it is found that newspapers differ in ways of expressing temporal information., 19 pages

Long non-coding RNA (lncRNA)-mediated competitive endogenous RNA (ceRNA) networks act as essential mechanisms in tumor initiation and progression, but their diagnostic and prognostic significance in prostate cancer (PCa) remains poorly understood. Presently, using the RNA expression data derived from multiple independent PCa-related studies, we constructed a high confidence and PCa-specific core ceRNA network by employing three lncRNA-gene inference approaches and key node filter strategies and then established a logistic model and risk score formula to evaluate its diagnostic and prognostic values, respectively. The core ceRNA network consists of 10 nodes, all of which are significantly associated with clinical outcomes. Combination of expression of the 10 ceRNAs with a logistic model achieved AUC of ROC and PR curve up to ∼96 and 99% in excluding normal prostate samples, respectively. Additionally, a risk score formula constructed with the ceRNAs exhibited significant association with disease-free survival. More importantly, utilizing the expression of RNAs in the core ceRNA network as a molecular signature, the TCGA-PRAD cohort was divided into four novel clinically relevant subgroups with distinct expression patterns, highlighting a feasible way for improving patient stratification in the future. Overall, we constructed a PCa-specific core ceRNA network, which provides diagnostic and prognostic value.

Coronary heart disease (CHD) is often accompanied with diabetes mellitus, which leads the limited effect of monotherapy. Drug combinations are deemed to a promising approach for treating CHD, and traditional Chinese medicine (TCM) formulas are important source of drug combinations discovery. In this study, to dissect the synergic bioactive compounds from TCM formula for CHD, Gualou Xiebai Decoction (GXD), is exemplified by employing a systems pharmacology strategy. 16 potential bioactive compounds are screened out by ADME evaluation. The Probability Ensemble Approach is used to predict potential drug combination pairs. Then, we exploit network analysis to dissect the synergistic mechanisms and find compound combinations act on multiple pathways. In vitro experiments confirm that the three compound combinations alleviate high-glucose induced myocardial injury. In summary, the integrated systems pharmacology method supplies accurate illustration of the molecular mechanisms of GXD to treat CHD and provides a new way for developing combination therapeutics.

Psychiatric disorders have become the biggest cause of non-fatal health burden and are the major contributor to suicide worldwide. The currently limitations of standard psychotherapy lead to an increasing attention in complementary and alternative therapies, in particular the traditional herbal medicine. Lonicerae Japonicae Flos (LJF) is one of the most consumed herbal tea beverages for medical purposes. LJF contains flavonoids and phenolic acid as the major constituents, hence the anti-inflammatory and anti-oxidative properties reported earlier. Nevertheless, the neuro-pharmacological properties of LJF are largely unknown. In this study, combined systems pharmacology strategy and RNA-Seq technology, we uncovered psychotherapeutic effects of LJF. In brief, LJF and its active ingredient luteolin can reversed depressive/anxiety-like behavior in rats exposed to chronic mild stress (CMS), restored abnormal gene expression changes and neurotransmission in the striatum of CMS rats, these effects were mediated through triggering the activation of the HTR2A/PLCγ/ERK/CREB pathway.

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.

BackgroundAddition and subtraction theory (AST), a basic theory of herb combination in traditional Chinese medicine (TCM), is often used to add or subtract the "fundamental formulae" to generate more targeted prescriptions. This theory plays a core role in individualized medicine and compound compatibility of TCM. However, the mechanisms underlying AST have largely remained elusive. MethodsAn integrated platform of systems pharmacology was proposed for revealing how the oral administration, drug half-life, and target interactions affect the pharmacological functions of herbal medicines. This platform was further applied on two classical prescriptions, i.e., Xiao Chaihu decoction (XCHD) and Da Chaihu decoction (DCHD) to dissect the addition and subtraction theory (AST). ResultsWe uncovered the candidate compounds, key molecular targets and interaction network involved in XCHD and DCHD, and summarized its pharmacological characters and therapeutic indications. The results show that the "fundamental formula" is responsible for the major therapeutic effects, whereas the "additive herbs" synergistically enhance the treatment outcomes by targeting the same or complementary proteins between the foundational and additive herbs. ConclusionThis work has established a novel method to comprehensively understand the mechanism of AST, which would be beneficial for the TCM recipe optimization as well as the production of new herbal formula with desirable therapeutic effects. Candidate compounds, targets and interaction network involved in XCHD and DCHD."Fundamental formula" is mainly responsible for basic therapeutic effects."Additive herbs" exhibit reinforced function to the foundational formula.

Identified as a treasure of natural herbal products, traditional Chinese medicine (TCM) has attracted extensive attention for their moderate treatment effect and lower side effect. Cardio-cerebrovascular diseases (CCVD) are a leading cause of death. TCM is used in China to prevent and treat CCVD. However, the complexity of TCM poses challenges in understanding the mechanisms of herbs at a systems-level, thus hampering the modernization and globalization of TCM. A novel model, termed traditional Chinese medicine systems pharmacology (TCMSP) analysis platform, which relies on the theory of systems pharmacology and integrates absorption, distribution, metabolism, excretion and toxicity (ADME/T) evaluation, target prediction and network/pathway analysis, was proposed to address these problems. Here, we review the development of systems pharmacology, the TCMSP approach and its applications in the investigations of CCVD and compare it with other methods. TCMSP assists in uncovering the mechanisms of action of herbal formulas used in treating CCVD. It can also be applied in ascertaining the different syndrome patterns of coronary artery disease, decoding the multi-scale mechanisms of herbs, and in understanding the mechanisms of herbal synergism.

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.

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.

Background.Viral hemorrhagic fevers (VHF) are a group of systemic diseases characterized by fever and bleeding, which have posed a formidable potential threat to public health with high morbidity and mortality. Traditional Chinese Medicine (TCM) formulas have been acknowledged with striking effects in treatment of hemorrhagic fever syndromes in China’s history. Nevertheless, their accurate mechanisms of action are still confusing.Objective.To systematically dissect the mechanisms of action of Chinese medicinal formula Xijiao Dihuang (XJDH) decoction as an effective treatment for VHF.Methods.In this study, a systems pharmacology method integrating absorption, distribution, metabolism, and excretion (ADME) screening, drug targeting, network, and pathway analysis was developed.Results.23 active compounds of XJDH were obtained and 118 VHF-related targets were identified to have interactions with them. Moreover, systematic analysis of drug-target network and the integrated VHF pathway indicate that XJDH probably acts through multiple mechanisms to benefit VHF patients, which can be classified as boosting immune system, restraining inflammatory responses, repairing the vascular system, and blocking virus spread.Conclusions.The integrated systems pharmacology method provides precise probe to illuminate the molecular mechanisms of XJDH for VHF, which will also facilitate the application of traditional medicine in modern medicine.

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.

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.