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Zheng: A systems biology approach to diagnosis and treatments








Traditional Chinese medicine (TCM) is an ancient medical practice system which emphasizes regulating the integrity of the human body and its interrelationship with natural environments. As a key concept in TCM, Zheng (meaning syndrome or pattern) is the overall physiological and/or pathological pattern of the human body in response to a given internal and external condition, which usually is an abstraction of internal disharmony defined by a comprehensive analysis of the clinical symptoms and signs gathered by a practitioner using inspection, auscultation, olfaction, interrogation, and palpation of the pulses (1). Correctly identifying the Zheng is fundamental for the diagnosis and treatment of diseases. Moreover, Zheng has been historically applied as the key pathological principle guiding the prescription of herbal formulas (Figure 1).




A lack of research on Zheng has left us with little understanding of its underlying biology or the relationships between different Zhengs, diseases, and drugs. Moreover,there have been attempts to integrate Zheng differentiation with modern biomedical diagnostic methods, though these efforts have not achieved the desired results (2). Many well-known herbal recipes, such as Liu Wei Di Huang Wan and Jin Kui Shen Qi Wan, have long been used for the clinical treatment of Zheng disorders; however, Zheng-guided treatments are still scarce due to the lack of evidence-based interpretations of syndromes and treatment efficacies. Thus,investigating the biological basis of Zhengs from a molecular to systems level is important for advancing the identification and treatment of these syndromes, and for providing more objective and quantitative diagnostic criteria.








Zheng-guided disease research




In Western medicine, a disease is a particular abnormal and pathological condition that affects part or all of the human body and is often construed as a medical condition associated with specific symptoms. By contrast, Zheng puts forth a very different definition of a disease and encompasses all of the symptoms a patient presents.




Because of the highly interconnected nature of the human interactome, it is difficult to study different diseases at the molecular level completely independent of one another (3),and this issue also applies to Zhengs. Moreover, Zhengs are dynamic with changing boundaries, overlapping symptoms,and a multiscale nature, which makes them difficult to understand at a biological and mechanistic level. Thus, we propose that a comprehensive Zheng map be constructed that links together all the Zhengs based on their molecular and cellular relationships. Further, we suggest creating the “Zhengome” as a new 'omics field, in which a network is the basic research unit used to investigate the hierarchy present in the human body,from the molecular to the systems level. A comprehensive understanding of the Zhengome requires us to bring together multiple sources of evidence, from shared genes to proteinprotein interactions, shared environmental factors, common treatments, and phenotypic and clinical manifestations, in order to capture the relationships between the different Zhengs.




Zheng uses the Yin-Yang, exterior-interior, cold-heat, and deficiency-excess definitions to describe patients’ conditions,which are then managed by Zheng-specific recipes (Figure 1).Modern 'omics techniques combined with bioinformatics and bionetwork models through a systems biology approach have been applied to investigate the differences between Zhengs and to identify novel biomarkers. For instance, rheumatoid arthritis (RA) patients differentiated on the basis of “hot” and “cold” Zhengs have been shown to be associated with different underlying genomic and metabolomic profiles, with the RA hot group showing more apoptotic activity than the cold group (4). Additionally, Li et al. used a network-based computational model to understand Zheng in the context of the neuro-endocrine-immune network and found that cold and hot Zhengs were closely related to a metabolism-immune imbalance (5). Wang and colleagues investigated the urine




metabolome of patients with jaundice syndrome and its two subtypes of Yang Huang (acute) and Yin Huang (chronic), and identified several biomarker metabolites (6). However, most of the current studies have relied on only one or two approaches for molecular profiling and have lacked an efficient method to integrate data obtained at different 'omic levels.These studies also did not look at combining the analysis of molecular data with clinical variables, possibly missing an opportunity to generate more convincing conclusions. Considering the limitations of past studies, future efforts should integrate an analysis for all levels of 'omics (e.g., genomics,transcriptomics, epigenomics, and proteomics) data from a large number of patient samples for different Zhengs and include an investigation of the prognostic and therapeutic utilities of the data as a whole. Moreover, combining these molecular data with patients’ clinical information could provide evidence-based theoretical interpretations for Zhengs and enable an assessment of Zheng-based therapeutic approaches.




Zhengs may change dynamically during disease progression.Differentiating the specific Zheng involved in each stage of a disease could provide valuable guidance for prescribing a dynamic therapeutic recipe. Using dynamic network modeling, a disease process can be conceptualized as spatio-temporal changes in network structures. The changes associated with a Zheng under dynamic therapy can be used to identify the key factors in the dynamic biological




networks. Appropriate network perturbation models and subsequent robustness and topology analysis could help unveil potential disease-related genes or therapeutic targets involved in a disease’s progression or evolution (7). The relationships between the different aspects of a disease (e.g.,main symptoms versus complications) in a specific Zheng as well as the psychological, social, and even environmental factors should be taken into account during the modeling and simulation process in order to uncover the dynamic nature of complex diseases. Combining a Zhengome approach with dynamic modeling has the potential for establishing an accurate and quantitative Zheng research model, as well as for creating a new system for performing disease research.








Zheng-driven drug discovery




Despite considerable progress in genome, transcriptome,proteome, and metabolome-based high throughput screening methods and in rational drug design, drug discovery often encounters considerable costly failures that challenge the fidelity of the modern drug discovery system. Zheng-driven drug discovery has shown tremendous success for traditional drug discovery throughout Chinese medicine’s history.However, since this concept is completely new to Western medicine, it is no easy task to incorporate Zheng-driven drug discovery into modern drug discovery workflows.




Here, we propose the “Zheng to TCM” and “TCM to Zheng” strategies within the framework of systems pharmacology to investigate biological systems and develop new therapeutics(Figure 2). The first strategy, Zheng to TCM, proposes developing a pipeline from Zheng diagnoses to TCM drugs,including differentiating Zhengs, identifying Zheng-related diseases and the associated genes and proteins, reverse targeting of drug effects, constructing and analyzing network/systems, and finally identifying effective herbal medicines (8). In effect, this strategy can be considered a reverse targeting and screening approach that is designed to uncover drugs from natural products that can target multiple Zhengs or related diseases. The goal of this method is to help researchers identify the active components within medicinal plants and multi-ingredient synergistic herbal formulas or drug combinations (9). In fact, this novel strategy has already been successfully applied in a qi-blood study, where we identified the active compounds in the qi-enriching and blood-tonifying herbs, their targets, and the corresponding pathways involved in the treatment of qi and blood deficiency syndromes (8).




The second strategy, TCM to Zheng, consists of a wholesystem evaluation process starting with herbs or herbal formulas and culminating in identifying the Zhengs. This process includes the initial collection and classification of herbal medicines; screening the ingredients for absorption,distribution, metabolism, excretion, and toxicity (ADME/T);performing targeted drug screenings and tissue localization; constructing and analyzing networks; and finally identifying Zhengs/diseases (10). Using this strategy, it is possible to identify novel multitarget drugs in natural products (11). One particularly striking example is the systematic analysis of blood stasis and qi deficiency syndrome in coronary heart disease and the herbal drugs used to treat the syndromes. The results indicate that the herbs for eliminating blood stasis have pharmacological activity that acts to dilate blood vessel, improve the microcirculation, reduce blood viscosity,and regulate blood lipid, while qi-enhancing herbs have the potential for enhancing energy metabolism and anti-inflammatory activity (12). The TCM to Zheng strategy can also help to elucidate the pharmacological effectiveness of herbs and formulas.




In our ongoing work investigating Pi-deficiency syndrome (PDS) in the context of Zheng, we are analyzing patient samples using the sequencing alternative polyadenylation sites (SAPAS) method, RNA sequencing (13), lipid metabolomics,proteomics, and transcriptomics in order to decipher the pathogenesis and complex responses of the human body to PDS. From a drug development perspective, we plan to systematically investigate the Si Jun Zi decoction, a widely used herbal recipe for PDS, within the framework of the “TCM to Zheng” strategy, so as to understand why this recipe can regulate the immune response, stimulate blood circulation,and adjust gastrointestinal digestive functions. Despite the progress in Zheng-guided drug discovery, its future success requires the integration of multidisciplinary technologies,together with further innovations in these technologies, to facilitate the understanding of multifactorial diseases and the development of new therapies.












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“证”—— 疾病诊疗的系统生物学方法
























    纵观中医药发展史,在传统药物的研发中,以证候为导向的药物研发取得了巨大的成就。但是这对于西方医学来说是一种全新的模式。因此,如何将以证候为导向的药物研发融入到现代药物研发的潮流中,将是一大难题。在此,大家提出在系统药理学框架中建立“从证到中医”和“从中医到证”的策略,旨在研究生物系统和开发新型的治疗方法。 “从证到中医”为从证候的诊断到中药处方之间提供了渠道,包括证候的辨别、证候和相关的基因、蛋白及药效反向定位的识别、网状结构系统的构建与分析和最终找出有效的中药疗法。实际上,这样的策略可作为一种反向定位和筛选的途径,从适用于多种证型及相关疾病的天然药物中寻找并研发新药,目的是为了帮助研究者找出药用植物、多成分中药处方或复方合剂的活性成分。而这种新策略已经成功应用于大家的一个研究中。大家在补益气血的中药中找到其有效成分、靶点及在治疗气血不足证中的作用途径。“从中医到证”是指从中药或中药复方到证候辨别的整个系统评估的过程,包括中药的采集与分类,药物吸取、分布、代谢、排泄和具有毒性的成分,药物靶向的检查和组织定位,构建和分析网状结构系统,最终辨别证候/疾病。这种策略可能有助于在天然药物中找出新型的多靶点药物。举个非常显著的例子,就是冠心病气虚血瘀证和相应辨证用药的系统分析,结果提示该类用药中的活血药具有扩张血管、改善循环、降低血液粘度、调节血脂的作用,而补气药具有促进能量代谢和抗炎的疗效。“从中医到证”的策略有助于阐释中药及其复方的药理学作用。在大家正在开展的“脾虚证”研究中,大家采用SAPAS、RNA测序、脂类代谢组学、蛋白质代谢组学和转录组学的方法对患者提供的标本进行分析,以说明脾虚证的发病机制和人体复杂反应。