Traditional Chinese Medicine ZHENG Research Articles

Identification of differentially expressed non-coding RNAs and mRNAs involved in Qi stagnation and blood stasis syndrome.

Qi stagnation and blood stasis syndrome (QSBSS) is a common Zheng in Traditional Chinese Medicine (TCM), describes the condition of unsmooth flow of Qi and blood, which manifests as distending pain in a fixed body part and emotional disorders, including irritability and depression. However, the underlying molecular mechanisms remain largely elusive. RNAs are the connection between DNA and proteins, which reflect the interaction between the genotypes and the phenotype. Of note, non-coding (nc)RNA is a type of RNA that is not translated into any protein, but has regulatory functions. Despite the growing interest in exploring the biological basis of TCM Zhengs, the specific roles of ncRNAs in QSBSS have remained largely elusive. In the present study, next-generation sequencing was performed to investigate the ncRNA profile in patients with three different types of disease, but who had QSBSS. A total of 104 long non-coding RNAs, 2 circular RNAs and 697 mRNAs were identified to be significantly differentially expressed in QSBSS patients. Further bioinformatics analysis revealed that the most significantly enriched pathways by the differentially expressed RNAs in QSBSS were the sphingolipid signaling pathway, the neurotrophin signaling pathway, 5′AMP-activated protein kinase and endocytosis. In addition, a network pharmacology analysis indicated that several of the differentially expressed RNAs were included in the targets of TCM herbs for treating QSBSS. The present study was the first to identify ncRNAs that are deregulated in QSBSS by next-generation sequencing technology. The results may offer insight into the biological basis of TCM Zheng and the optimization of ancient formulae, as well as the discovery of novel drugs, to pave the way toward advanced TCM theory and improved health care delivery.

The Classification of Sini Decoction Pattern in Traditional Chinese Medicine by Gene Expression Profiling.

We investigated the syndromes of the Sini decoction pattern (SDP), a common ZHENG in traditional Chinese medicine (TCM). The syndromes of SDP were correlated with various severe Yang deficiency related symptoms. To obtain a common profile for SDP, we distributed questionnaires to 300 senior clinical TCM practitioners. According to the survey, we concluded 2 sets of symptoms for SDP: (1) pulse feels deep or faint and (2) reversal cold of the extremities. Twenty-four individuals from Taipei City Hospital, Linsen Chinese Medicine Branch, Taiwan, were recruited. We extracted the total mRNA of peripheral blood mononuclear cells from the 24 individuals for microarray experiments. Twelve individuals (including 6 SDP patients and 6 non-SDP individuals) were used as the training set to identify biomarkers for distinguishing the SDP and non-SDP groups. The remaining 12 individuals were used as the test set. The test results indicated that the gene expression profiles of the identified biomarkers could effectively distinguish the 2 groups by adopting a hierarchical clustering algorithm. Our results suggest the feasibility of using the identified biomarkers in facilitating the diagnosis of TCM ZHENGs. Furthermore, the gene expression profiles of biomarker genes could provide a molecular explanation corresponding to the ZHENG of TCM.

Transcriptomics: a sword to cut the Gordian knot of traditional Chinese medicine.

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.

Urinary metabolite profiling offers potential for differentiation of liver-kidney yin deficiency and dampness-heat internal smoldering syndromes in posthepatitis B cirrhosis patients.

Zheng is the basic theory and essence of traditional Chinese medicine (TCM) in diagnosing diseases. However, there are no biological evidences to support TCM Zheng differentiation. In this study we elucidated the biological alteration of cirrhosis with TCM “Liver-Kidney Yin Deficiency (YX)” or “Dampness-Heat Internal Smoldering (SR)” Zheng and the potential of urine metabonomics in TCM Zheng differentiation. Differential metabolites contributing to the intergroup variation between healthy controls and liver cirrhosis patients were investigated, respectively, and mainly participated in energy metabolism, gut microbiota metabolism, oxidative stress, and bile acid metabolism. Three metabolites, aconitate, citrate, and 2-pentendioate, altered significantly in YX Zheng only, representing the abnormal energy metabolism. Contrarily, hippurate and 4-pyridinecarboxylate altered significantly in SR Zheng only, representing the abnormalities of gut microbiota metabolism. Moreover, there were significant differences between two TCM Zhengs in three metabolites, glycoursodeoxycholate, cortolone-3-glucuronide, and L-aspartyl-4-phosphate, among all differential metabolites. Metabonomic profiling, as a powerful approach, provides support to the understanding of biological mechanisms of TCM Zheng stratification. The altered urinary metabolites constitute a panel of reliable biological evidence for TCM Zheng differentiation in patients with posthepatitis B cirrhosis and may be used for the potential biomarkers of TCM Zheng stratification.

Evidence-Based ZHENG: A Traditional Chinese Medicine Syndrome 2013

The traditional Chinese medicine (TCM) ZHENG, also known as TCM syndrome or TCM pattern, is an integral and essential part of TCM theory. A TCM ZHENG is in essence a characteristic profile of all clinical manifestations that can be identified by a TCM practitioner. Clinical treatments of a patient rely on the successful differentiation of a specific ZHENG. Recent advances in systems biology have allowed the application of new phenotyping technologies in the study of the ZHENG differentiation with plausible biological interpretations. Understanding of the characteristic changes in biochemistry associated with a specific TCM ZHENG will facilitate the development of ZHENG identification and a novel disease diagnostic and stratification approach that will potentially lead to personalized healthcare strategies for a range of diseases that lack therapeutic solutions. Here, we have grouped together 28 excellent papers in this field and put forward for publication in this special issue on TCM ZHENG. Firstly, there are 3 review or research papers in this special issue addressed the concept, origin, and development of ZHENG, the recent advances in ZHENG identification and its clinical applications, and latest technologies and methods such as omics methods and data mining for ZHENG identification and outcome measurement. Two papers reviewed the clinical characterization and molecular basis of TCM ZHENG in cancer and TCM management in hepatic encephalopathy, respectively. Moreover, a review paper reviewed systematically the classification of TCM ZHENGs associated with insomnia. In TCM, the clinical diagnosis of ZHENG relies on the gathering of clinical information through inspection, auscultation and olfaction, inquiry, and palpation. For the acquisition of ZHENG-related clinical information, 2 research articles presented the established ZHENG questionnaire in the posthepatic cirrhosis and advanced cancer patients with constipation, respectively. Moreover, the patient stratification and personalized treatment by means of the ZHENG identification and approaches in patients with allergic rhinitis and subhealthy people with fatigue were presented. Additionally, the correlation between Blood-stasis syndrome score and cardio-ankle vascular index in stroke patients was also discussed. ZHENG is not merely an assembly of many disease symptoms but an organization of interrelated clinical manifestations following the TCM theories. The interrelated symptoms and signs of diseases in the ZHENG measurement should be analyzed using appropriate statistical tools to better understand the ZHENG classification. Six research articles of this special issue presented the data mining of ZHENG differentiation using the combination of wavelet packet transform and sample entropy, the clinical phenotypic network in angina pectoris of coronary heart disease, a multilabel learning using the relevant feature for each label algorithm in chronic gastritis, and a structural equation modeling approach in suboptimal health status. To objectively differentiate ZHENGs, 7 research articles in this issue presented the ZHENG classification using genes, proteins, metabolites, and/or their profiles. These are system strategies in investigating ZHENG classification and treatment evaluation by means of gene polymorphism, transcriptomics, proteomics, metabonomics, bioinformatics, and network pharmacology. The methods include IL-10genotypes in ZHENG, the metabonomic evaluation of ZHENG classification and treatment by Chinese herbal formula, and a combined ZHENG theory and high-throughout gene chip data to predict new effects of the formula in hepatitis B-caused cirrhosis. Additionally, the molecular mechanisms of “Same ZHENG for Different Diseases” and “Different ZHENGs for Same Disease” in chronic hepatitis B and liver cirrhosis and the ZHENG classification in chronic hepatitis B patients by SELDI-based protein chip analysis were also discussed in these papers. To experimentally evaluate ZHENG, various pharmacological models of ZHENG are to be established. In this special issue, 4 papers discussed the establishment and/or the application of ZHENG animal models, encompassing the preparation of blood-deficient syndrome model in chicken, the castration-induced kidney deficiency syndrome model in arthritic rats, the kidney-yang deficiency syndrome model in Alzheimer's disease rats, and their applications. Moreover, it was also presented that Chinese herbal medicines were used to treat the established mouse xenograft pancreatic cancer models with dampness-heat, spleen-deficiency and Blood-stasis syndromes. In summary, the concept of TCM ZHENG, as a diagnostic approach in TCM, would provide invaluable guidance about the therapeutic choices and personalized disease management, not only in traditional medical practices but in modern healthcare systems as well. We look forward to an increasing number and sizes of clinical trials utilizing TCM ZHENG that will be conducted in the future to further promote the development of evidence-based personalized medicine. Shi-Bing Su Aiping Lu Shao Li Wei Jia

MicroRNA expression in salivary supernatant of patients with pancreatic cancer and its relationship with ZHENG.

In traditional Chinese medicine (TCM), diagnosis and prescriptions are based on the signs and symptoms which are recognized as ZHENG. The cornerstone of TCM is to differentially treat one ZHENG from others, which is also known as syndrome differentiation, and this relies on the gathering of clinical information through inspection, auscultation and olfaction, inquiry, and palpation. However, the biomolecular basis of the ZHENG remains unclear. In this study, the expressions of 384 cancer-related miRNAs in salivary supernatant of patients with pancreatic cancer were assessed by miRNA polymerase chain reaction (PCR) array, and the different expression patterns of miRNA in three different groups of ZHENG were studied with use of real-time quantitative PCR (qRT-PCR). Some miRNAs were found to be specifically expressed in some ZHENGs, for instance, miR-17, miR-21, and miR-181b in Shi-Re ZHENG and miR-196a in Pi-Xu ZHENG. This indicates that these miRNAs may play important roles in different ZHENG condition. Therefore, this study to some extent revealed the molecular basis of TCM ZHENG in pancreatic cancer.

Traditional Chinese Medicine ZHENG and OMICS Convergence: A Systems Approach to Post-Genomics Medicine in a Global World

Traditional Chinese medicine (TCM) is a comprehensive system of medical practice that has been used to diagnose, treat, and prevent illnesses for more than 3000 years. ZHENG (also known as "syndrome") differentiation remains the essence of TCM. In China, TCM shares equal status, and integrated with Western medicine in the healthcare system to treat many types of diseases. Yet, compared to biomolecular science and Western medicine, the ZHENG/TCM approach to diagnostics might appear unobjective, but offers at the same time long-standing clinical and phenotypic-rich insights. With the current globalization of life sciences and the arrival of "Big Data" research and development, these two silos of medical lore are rapidly coalescing. The applications of multi-omics strategies to TCM have begun to provide novel insights into the essence and molecular basis of TCM ZHENG. We searched the Chinese electronic databases and PubMed for published articles related to "Omics" and "TCM ZHENG" and observed a dramatic increase in studies over the past few years. In this article, we provide a timely synthesis of the lessons learned, and the emerging applications of omics science in TCM ZHENG research. We suggest that the global health scholarship and the field of "developing world Omics" can usefully draw from TCM, and vice versa.

Clinical Applications of Omics Technologies on ZHENG Differentiation Research in Traditional Chinese Medicine.

Traditional Chinese medicine (TCM) ZHENG is the basic concept of TCM theory. The effectiveness of TCM treatment depends on the accuracy of ZHENG differentiation. ZHENG differentiation, using the “four diagnostic methods,” has the drawbacks of subjectivity and variability. Following development of omics technologies, which study the functional activities of human body from a system-wide perspective, it has been more and more applied in study of objectivity differentiating TCM ZHENG and understanding its biological mechanisms. This paper reviewed the literatures of clinical TCM ZHENG differentiation researches, underlying omics technologies, and indicated the increased trends of related articles with four kinds of omics technologies, including genomics, transcriptomics, proteomics and metabolomics, and the correlations between ZHENG differentiation and findings in omics studies. Moreover, the paper summarized the typical omics application in common studied diseases and TCM ZHENGs and discussed the main problems and countermeasure of ZHENG differentiation researches. The work here may provide a reference for further research of TCM ZHENG differentiation using omics technologies.

Classification and Progression Based on CFS-GA and C5.0 Boost Decision Tree of TCM Zheng in Chronic Hepatitis B

Chronic hepatitis B (CHB) is a serious public health problem, and Traditional Chinese Medicine (TCM) plays an important role in the control and treatment for CHB. In the treatment of TCM, zheng discrimination is the most important step. In this paper, an approach based on CFS-GA (Correlation based Feature Selection and Genetic Algorithm) and C5.0 boost decision tree is used for zheng classification and progression in the TCM treatment of CHB. The CFS-GA performs better than the typical method of CFS. By CFS-GA, the acquired attribute subset is classified by C5.0 boost decision tree for TCM zheng classification of CHB, and C5.0 decision tree outperforms two typical decision trees of NBTree and REPTree on CFS-GA, CFS, and nonselection in comparison. Based on the critical indicators from C5.0 decision tree, important lab indicators in zheng progression are obtained by the method of stepwise discriminant analysis for expressing TCM zhengs in CHB, and alterations of the important indicators are also analyzed in zheng progression. In conclusion, all the three decision trees perform better on CFS-GA than on CFS and nonselection, and C5.0 decision tree outperforms the two typical decision trees both on attribute selection and nonselection.

Recent Advances in ZHENG Differentiation Research in Traditional Chinese Medicine

ZHENG, also known as traditional Chinese medicine (TCM) syndrome or TCM pattern, is an integral and essential part of TCM theory. A TCM ZHENG, in essence, is a characteristic profile of all clinical manifestations that can be identified by a TCM practitioner. Clinical treatments of a patient rely on the successful differentiation of a specific ZHENG. Recently, some new technologies and methods such as the System‐ Omics approach were introduced in ZHENG research, which significantly facilitate the development of ZHENG theory. This review focuses on a brief introduction of these new technologies and methods and their application in TCM ZHENG differentiation research. Also, some of the latest progress and applications in this area, such as ZHENG measurement, information collection, data analysis and mining, ZHENG differentiation based TCM treatment, and mechanisms of ZHENG differentiation based on biological networks

Relationship betweenEGF,TGFA, andEGFRGene Polymorphisms and Traditional Chinese Medicine ZHENG in Gastric Cancer

In traditional Chinese medicine (TCM), correct syndrome differentiation is the most important principle guiding the prescription of Chinese herbal formulae for the treatment of gastric cancer (GC). We aimed to reveal the genetic mechanisms underlying GC syndrome differentiation (ZHENG) in a population of 387 GC patients. Twenty-nine single nucleotide polymorphisms (SNPs) in EGF, TGFA, and EGFR were investigated. Two SNPs, rs11466285 in TGFA and rs884225 in EGFR, were significantly associated with the distribution of ZHENG (P < 0.05). The rs11466285 TT genotype increased the risk of damp heat with toxin (DHT) and deficiency of both Qi and yin (DQY) compared with obstruction of blood stasis (OBS). The rs884225 AA genotype could increase the risk of DQY and deficiency of both Qi and blood (DQB) compared with yin deficiency due to stomach heat (YDSH). Parallel comparison among the SNPs and syndrome types revealed that DQB was distinct from YDSH, disharmony between the liver and stomach, stagnation of phlegm muddiness (SPM), OBS, and other syndromes at several SNP loci (P < 0.05). The rs11466285 TT and rs884225 AA genotypes exhibit increased risk of DQB compared with OBS and SPM (P < 0.05), respectively. In conclusion, the formation of GC ZHENG was related to EGF, TGFA, and EGFR gene polymorphisms.

Evidence-Based ZHENG: A Traditional Chinese Medicine Syndrome

The traditional Chinese medicine (TCM) ZHENG, also known as TCM syndrome or TCM pattern, is an integral and essential part of TCM theory. A TCM ZHENG is in essence a characteristic profile of all clinical manifestations that can be identified by a TCM practitioner. Clinical treatments of a patient rely on the successful differentiation of a specific ZHENG. Recent advances in systems biology have allowed the application of new phenotyping technologies in the study of the ZHENG differentiation with plausible biological interpretations. Understanding of the characteristic changes in biochemistry associated with a specific TCM ZHENG will facilitate the development of ZHENG identification and a novel disease diagnostic and stratification approach that will potentially lead to personalized healthcare strategies for a range of diseases that lack therapeutic solutions. Here, we have grouped together 28 excellent papers in this field and put forward for publication in this special issue on TCM ZHENG. Firstly, there are 3 review or research papers in this special issue addressed the concept, origin, and development of ZHENG, the recent advances in ZHENG identification and its clinical applications, and latest technologies and methods such as omics methods and data mining for ZHENG identification and outcome measurement. Two papers reviewed the clinical characterization and molecular basis of TCM ZHENG in cancer and TCM management in hepatic encephalopathy, respectively. Moreover, a review paper reviewed systematically the classification of TCM ZHENGs associated with insomnia. In TCM, the clinical diagnosis of ZHENG relies on the gathering of clinical information through inspection, auscultation and olfaction, inquiry, and palpation. For the acquisition of ZHENG-related clinical information, 2 research articles presented the established ZHENG questionnaire in the posthepatic cirrhosis and advanced cancer patients with constipation, respectively. Moreover, the patient stratification and personalized treatment by means of the ZHENG identification and approaches in patients with allergic rhinitis and subhealthy people with fatigue were presented. Additionally, the correlation between Blood-stasis syndrome score and cardio-ankle vascular index in stroke patients was also discussed. ZHENG is not merely an assembly of many disease symptoms but an organization of interrelated clinical manifestations following the TCM theories. The interrelated symptoms and signs of diseases in the ZHENG measurement should be analyzed using appropriate statistical tools to better understand the ZHENG classification. Six research articles of this special issue presented the data mining of ZHENG differentiation using the combination of wavelet packet transform and sample entropy, the clinical phenotypic network in angina pectoris of coronary heart disease, a multilabel learning using the relevant feature for each label algorithm in chronic gastritis, and a structural equation modeling approach in suboptimal health status. To objectively differentiate ZHENGs, 7 research articles in this issue presented the ZHENG classification using genes, proteins, metabolites, and/or their profiles. These are system strategies in investigating ZHENG classification and treatment evaluation by means of gene polymorphism, transcriptomics, proteomics, metabonomics, bioinformatics, and network pharmacology. The methods include IL-10genotypes in ZHENG, the metabonomic evaluation of ZHENG classification and treatment by Chinese herbal formula, and a combined ZHENG theory and high-throughout gene chip data to predict new effects of the formula in hepatitis B-caused cirrhosis. Additionally, the molecular mechanisms of “Same ZHENG for Different Diseases” and “Different ZHENGs for Same Disease” in chronic hepatitis B and liver cirrhosis and the ZHENG classification in chronic hepatitis B patients by SELDI-based protein chip analysis were also discussed in these papers. To experimentally evaluate ZHENG, various pharmacological models of ZHENG are to be established. In this special issue, 4 papers discussed the establishment and/or the application of ZHENG animal models, encompassing the preparation of blood-deficient syndrome model in chicken, the castration-induced kidney deficiency syndrome model in arthritic rats, the kidney-yang deficiency syndrome model in Alzheimer's disease rats, and their applications. Moreover, it was also presented that Chinese herbal medicines were used to treat the established mouse xenograft pancreatic cancer models with dampness-heat, spleen-deficiency and Blood-stasis syndromes. In summary, the concept of TCM ZHENG, as a diagnostic approach in TCM, would provide invaluable guidance about the therapeutic choices and personalized disease management, not only in traditional medical practices but in modern healthcare systems as well. We look forward to an increasing number and sizes of clinical trials utilizing TCM ZHENG that will be conducted in the future to further promote the development of evidence-based personalized medicine. Shi-Bing Su Aiping Lu Shao Li Wei Jia

The Molecular Mechanisms of Traditional Chinese Medicine ZHENG Syndromes on Pancreatic Tumor Growth

Traditional Chinese medicine (TCM) syndromes (ZHENG in Chinese) are the abstraction from the comprehensive analysis of clinical information gained by the four main diagnostic TCM methods: observation, listening, questioning, and pulse analyses. Proper TCM diagnosis is the most important principle to guide the prescribing of Chinese herbs. To evaluate the specific effect of TCM ZHENG on tumor growth and to examine the molecular mechanisms underlying ZHENG and tumor growth. The authors established subcutaneous tumor models of pancreatic cancer ZHENG syndromes of Damp heat (Shi-Re) and Spleen deficiency (Pi-Xu). Tissue samples of the subcutaneous transplanted tumors from each model were studied versus control tumors. CCR5 and CXCR4 proteins in these tissues were assayed by immunohistochemical staining. The expression of CCR5/CCL5/CCL4/CCL3 and CXCR4/SDF-1 mRNA was investigated by reverse transcriptase-polymerase chain reaction (RT-PCR). SDF-1, CCL4, CCL5, and CCL3, which are ligands of CXCR4 and CCR5, were examined by ELISA. The study found that tumor models with different ZHENG were successfully established in each group; the tumor growth of Shi-Re group was slower than that of the control group. It was found that there was a significant difference in CCR5 mRNA expression levels among the Pi-Xu, Shi-Re, and control groups. The results of immunohistochemistry staining revealed that the positive rate of CCR5 protein in Shi-Re group, Pi-Xu group, and control group was 25.00%, 53.33%, 83.33%, respectively. The Shi-Re group expressed the lowest levels of CCL5 and CCL4. The results of the study suggest that the existence of TCM ZHENG may influence the tumor growth in pancreatic cancer, which might be mediated by the expression of CCR5/CCL5/CCL4. This finding may lead to the development of TCM ZHENG as a prognostic indicator in pancreatic tumor growth.