Ya-Nan Song

Therapeutic Efficacy of Fuzheng-Huayu Tablet Based Traditional Chinese Medicine Syndrome Differentiation on Hepatitis-B-Caused Cirrhosis: A Multicenter Double-Blind Randomized Controlled Trail

Aim. To evaluate and predict the therapeutic efficacy of Fuzheng-Huayu tablet (FZHY) based traditional Chinese Medicine (TCM) syndrome differentiation or TCM symptoms on chronic hepatitis B caused cirrhosis (HBC). Methods. The trial was designed according to CONSORT statement. It was a multi-center, double-blind, randomized, placebo-controlled trail. Several clinical parameters, Child-Pugh classification and TCM symptoms were detected and evaluated. The FZHY efficacy was predicted by an established Bayes forecasting method following the Bayes classification model. Results. The levels of HA and TCM syndrome score in FZHY group were significantly decreased (P < 0.05) compared to placebo group, respectively. The efficacy of FZHY on TCM syndrome score in HBC patients with some TCM syndromes was better. In TCM syndrome score evaluation, there were 53 effective and 22 invalid in FZHY group. TCM symptoms predicted FZHY efficacy on HBC were close to Child-Pugh score prediction. Conclusion. FZHY decreases the levels of HA and TCM syndrome scores, improves the life quality of HBC patients. Moreover, there were different therapeutic efficacies among different TCM syndromes, indicating that accurate TCM syndrome differentiation might guide the better TCM treatment. Furthermore, the FZHY efficacy was able to predict by Bayes forecasting method through the alteration of TCM symptoms.

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.

Progression from Excessive to Deficient Syndromes in Chronic Hepatitis B: A Dynamical Network Analysis of miRNA Array Data.

Traditional Chinese medicine (TCM) treatment is regarded as a safe and effective method for chronic hepatitis B (CHB), which requires a traditional diagnosis method to distinguish the TCM syndrome. In this study, we study the differences and similarities among excessive, excessive-deficient, and deficient syndromes, by an integrative and comparative analysis of weighted miRNA expression or miRNA-target network in CHB patients. We first calculated the differential expressed miRNAs based on random module t-test and classified three CHB TCM syndromes using SVM method. Then, miRNA target genes were obtained by validated database and predicted programs subsequently, the weighted miRNA-target networks were constructed for different TCM syndromes. Furthermore, prioritize target genes of networks of CHB TCM syndromes progression analyzed using DAVID online analysis. The results have shown that the difference between TCM syndromes is distinctly based on hierarchical cluster and network structure. GO and pathway analysis implicated that three CHB syndromes more likely have different molecular mechanisms, while the excessive-deficient and deficient syndromes are more dangerous than excessive syndrome in the process of tumorigenesis. This study suggested that miRNAs are important mediators for TCM syndromes classification as well as CHB development progression and therefore could be potential diagnosis and therapeutic molecular markers.

Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis.

The classic toxicity of carbon tetrachloride (CCl4) is to induce liver lesion and liver fibrosis. Liver fibrosis is a consequence of chronic liver lesion, which can progress into liver cirrhosis even hepatocarcinoma. However, the toxicological mechanisms of CCl4-induced liver fibrosis remain not fully understood. We combined transcriptomic and proteomic analysis and biological network technology, predicted toxicological targets and regulatory networks of CCl4 in liver fibrosis. Wistar rats were treated with CCl4 for 9 weeks. Histopathological changes, hydroxyproline (Hyp) contents, serum ALT and AST in the CCl4-treated group were significantly higher than that of CCl4-untreated group. CCl4-treated and -untreated liver tissues were examined by microarray and iTRAQ. The results showed that 3535 genes (fold change ≥ 1.5, P < 0.05) and 1412 proteins (fold change ≥ 1.2, P < 0.05) were differentially expressed. Moreover, the integrative analysis of transcriptomics and proteomics data showed 523 overlapped proteins, enriched in 182 GO terms including oxidation reduction, response to oxidative stress, inflammatory response, extracellular matrix organization, etc. Furthermore, KEGG pathway analysis showed that 36 pathways including retinol metabolism, PPAR signaling pathway, glycolysis/gluconeogenesis, arachidonic acid metabolism, metabolism of xenobiotics by cytochrome P450 and drug metabolism. Network of protein-protein interaction (PPI) and key function with their related targets were performed and the degree of network was calculated with Cytoscape. The expression of key targets such as CYP4A3, ALDH2 and ALDH7A1 decreased after CCl4 treatment. Therefore, the toxicological mechanisms of CCl4-induced liver fibrosis may be related with multi biological process, pathway and targets which may provide potential protection reaction mechanism for CCl4 detoxication in the liver.

Classification of Traditional Chinese Medicine Syndromes in Patients with Chronic Hepatitis B by SELDI-Based ProteinChip Analysis

Traditional Chinese medicine (TCM) syndrome, also called ZHENG, is the basis concept of TCM theory. It plays an important role in TCM practice. There are excess and deficiency syndromes in TCM syndrome. They are the common syndromes in chronic hepatitis B (CHB) patients. Here we aim to explore serum protein profiles and potential biomarkers for classification of TCM syndromes in CHB patients. 24 healthy controls and two cohorts of CHB patients of excess syndrome (n = 25) or deficiency syndrome (n = 19) were involved in this study. Protein profiles were obtained by surface-enhanced laser desorption ionization time-flight mass spectrometry (SELDI-TOF/MS) and multiple analyses were performed. Based on SELDI ProteinChip data, healthy controls and CHB patients or excess and deficiency syndromes in CHB patients were obviously differentiated by orthogonal partial least square (OPLS) analysis. Two significant serum proteins (m/z 4187 and m/z 5032) for classifying excess and deficiency syndromes were found. Moreover, the area under the receiver operating characteristic (ROC) curve was 0.887 for classifying excess and nonexcess syndrome, and 0.700 for classifying deficiency and nondeficiency syndrome, respectively. Therefore, the present study provided the possibility of TCM syndrome classification in CHB patients using a universally acceptable scientific approach.

Characteristic Analysis from Excessive to Deficient Syndromes in Hepatocarcinoma Underlying miRNA Array Data

Traditional Chinese medicine (TCM) treatment is regarded as a safe and effective method for many diseases. In this study, the characteristics among excessive, excessive-deficient, and deficient syndromes of Hepatocellular carcinoma (HCC) were studied using miRNA array data. We first calculated the differentially expressed miRNAs based on random module t-test and classified three TCM syndromes of HCC using SVM method. Then, the weighted miRNA-target networks were constructed for different TCM syndromes using predicted miRNA targets. Subsequently, the prioritized target genes of upexpression network of TCM syndromes were analyzed using DAVID online analysis. The results showed that there are distinctly different hierarchical cluster and network structure of TCM syndromes in HCC, but the excessive-deficient combination syndrome is extrinsically close to deficient syndrome. GO and pathway analysis revealed that the molecular mechanisms of excessive-deficient and deficient syndromes of HCC are more complex than excessive syndrome. Furthermore, although excessive-deficient and deficient syndromes have similar complex mechanisms, excessive-deficient syndrome is more involved than deficient syndrome in development of cancer process. This study suggested that miRNAs might be important mediators involved in the changing process from excessive to deficient syndromes and could be potential molecular markers for the diagnosis of TCM syndromes in HCC.

Dynamical Regulation Analysis Identifies Molecular Mechanisms of Fuzheng-Huayu Formula against Hepatitis B-Caused Liver Cirrhosis

Fuzheng-Huayu (FZHY) tablet was formulated based on Chinese medicine theory in treating liver fibrosis. A clinical trial has indicated that FZHY can against hepatitis B-caused liver cirrhosis (HBC), but the underlying mechanism of FZHY efficacy is unclear. Here, we report that miRNA expression levels are remarkably changed when FZHY formula was used in HBC patients treatment as a paradigm of trials. Then, we functionally characterize the significant impact of potential kernel miRNAs by miRNA-target network analysis. Enrichment analysis show that the FZHY formula dramatically effecting the molecular regulated module in HBC. Thus, we infer that FZHY plays a critical function in HBC treatment process and directly regulated many important pathways, including but not limited to cell cycle, p53 signaling pathway, and TGF-β signaling pathway, suggesting a new strategy for investigating the molecular mechanism of FZHY treatment.

Chinese herbal formula Fuzheng Huayu alleviates CCl 4 -induced liver fibrosis in rats: a transcriptomic and proteomic analysis

Liver fibrosis is a consequence of chronic liver disease that can progress to liver cirrhosis or even hepatocarcinoma. Fuzheng Huayu (FZHY), a Chinese herbal formula, has been shown to exert anti-fibrotic effects. To better understand the molecular mechanisms underlying the anti-fibrotic effects of FZHY, we analyzed transcriptomic and proteomic combination profiles in CCl4-induced liver fibrosis in rats, which were treated with extracted FZHY powder (0.35 g·kg−1·d−1, ig) for 3 weeks. We showed that FZHY administration significantly improved liver function, alleviated hepatic inflammatory and fibrotic changes, and decreased the hydroxyproline content in the livers of CCl4-treated rats. When their liver tissues were examined using microarray and iTRAQ, we found 255 differentially expressed genes (fold change ≥1.5, P<0.05) and 499 differentially expressed proteins (fold change ≥1.2, P<0.05) in the FZHY and model groups. Functional annotation with DAVID (The Database for Annotation, Visualization and Integrated Discovery) showed that 15 enriched gene ontology terms, including drug metabolic process, response to extracellular stimulus, response to vitamins, arachidonic acid metabolic process, response to wounding, and oxidation reduction might be involved in the anti-fibrotic effects of FZHY; whereas KEGG pathway analysis revealed that eight enriched pathways, including arachidonic acid metabolism, retinol metabolism, metabolism of xenobiotics by cytochrome P450, and drug metabolism might also be involved. Moreover, the protein-protein interaction network demonstrated that 10 core genes/proteins overlapped, with Ugt2a3, Cyp2b1 and Cyp3a18 in retinol metabolism pathway overlapped to a higher degree. Compared to the model rats, the livers of FZHY-treated rats had significantly higher mRNA and protein expression levels of Ugt2a3, Cyp2b1 and Cyp3a18. Furthermore, the concentration of retinoic acid was significantly higher in the FZHY-treated rats compared with the model rats. The results suggest that the anti-fibrotic effects of FZHY emerge through multiple targets, multiple functions, and multiple pathways, including FZHY-regulated retinol metabolism, xenobiotic metabolism by cytochrome P450, and drug metabolism through up-regulated Ugt2a3, Cyp2b1, and Cyp3a18. These genes may play important anti-fibrotic roles in FZHY-treated rats.

A metabolic mechanism analysis of Fuzheng-Huayu formula for improving liver cirrhosis with traditional Chinese medicine syndromes

Fuzheng-Huayu formula (FZHY), a Chinese herbal mixture prescription, has been proven effective in treating liver fibrosis and cirrhosis in both clinical trials and animal experiments. In this study we assessed the metabolic mechanisms of traditional Chinese medicine (TCM) syndrome-based FZHY treatment in liver cirrhosis (LC). A total of 113 participants, including 50 healthy controls and 63 LC patients, were recruited. According to the diagnosis and differentiation of the TCM syndromes, the LC patients were classified into 5 TCM syndrome groups including the liver stagnation syndrome (LSS), spleen deficiency and damp overabundance syndrome (SDDOS), damp-heat accumulation syndrome (DHAS), liver-kidney Yin deficiency syndrome (LKYDS), and blood stagnation syndrome (BSS), and administered FZHY for 6 months. FZHY treatment significantly decreased serum levels of hyaluronic acid (HA), a biochemical marker for LC, as well as TCM syndrome scores (the TCM syndrome scores were decreased in all the groups with significant decreases in the LSS and LKYDS groups). Furthermore, FZHY treatment gradually shifted the metabolic profiles of LC patients from a pathologic state to a healthy state, especially in LC patients with LSS and LKYDS. Twenty-two differently altered metabolites (DAMs) were identified, including carbohydrates, amino acids, fatty acids, etc with 9 DAMs in LSS patients, 9 in LKYDS patients, and 4 in other patients. The metabolic pathways involved in the conversion of amino acids and the bodys detoxification process were regulated first, followed by the pathways involved in the bodys energy supply process. In conclusion, the evaluation of the effect of TCM syndrome-based FZHY treatment show that FZHY has a better effect on LKYDS and LSS than on the other TCM syndromes, and the metabolic mechanisms might be involved in the increased detoxification function in LKYDS and the improvement of energy supply in LSS, which provides important evidence for the clinical application of TCM syndrome-based treatment.

Complement C4a inhibits the secretion of hepatitis B virus screened by surface-enhanced laser desorption ionization time-flight mass spectrometry-based ProteinChip analysis

Chronic hepatitis B (CHB) is a kind of chronic liver disease caused by persistent hepatitis B virus (HBV) infection. The study aims to seek the factors of host resistance to HBV and investigate their roles.