Xiao-Chai-Hu-Tang Research Articles

Network pharmacology and bioinformatics approach to unravel the mechanism of Xiao-chai-hu-tang herbal formula in tinnitus treatment

BackgroundTinnitus treatment remains a global challenge, and current therapeutic approaches are still controversial. This study aims to elucidate the potential mechanisms of Xiao-Chai-Hu-Tang (XCHT) in treating tinnitus through the analysis of network pharmacology, mendelian randomization and molecular docking, and molecular dynamics simulation analysis. We hope to contribute to the research on the target of action of traditional Chinese medicine and exploration of the mechanism of tinnitus. MethodsWe utilized network pharmacology to screen potential targets of action of XCHT on tinnitus. Mendelian randomization was employed to determine the causal relationship between potential targets of action and tinnitus. Finally, molecular docking and molecular dynamics simulation with clear targets and the combination of the active ingredient in effectiveness. ResultsThrough network pharmacology, we identified 38 potential targets of action. Mendelian randomization analysis revealed that HIF1A (OR [95 % CI] = 0.78 [0.65, 0.94], P = 0.008) and CCND1 (OR [95 % CI] = 1.22 [1.00, 1.49], P = 0.04) exhibited significant results with tinnitus. Molecular docking and molecular dynamics simulation of HIF1A and active ingredients demonstrated good binding efficacy. ConclusionHIF1A may play a key role in the treatment of tinnitus by XCHT, which may play a certain protective role in tinnitus patients and may inhibit the occurrence and development of tinnitus. However, the specific mechanism and effect need to be further studied and verified.

Insight into the mechanism of Xiao–Chai–Hu–Tang alleviates irinotecan-induced diarrhea based on regulating the gut microbiota and inhibiting Gut β-GUS

BackgroundIrinotecan (CPT-11, Camptosar@) is a first-line drug for metastatic colorectal cancer. CPT-11-induced diarrhea, which is closely related to the concentrations of β-glucuronidase (β-GUS) and SN-38 in the gut, largely limits its clinical application. PurposeHerein, Xiao–Chai–Hu–Tang (XCHT), a traditional Chinese formula, was applied to mitigate CPT-11-induced toxicity. This study initially explored the mechanism by which XCHT alleviated diarrhea, especially for β-GUS from the gut microbiota. MethodsFirst, we examined the levels of the proinflammatory cytokines and the anti-inflammatory cytokines in the intestine. Furthermore, we researched the community abundances of the gut microbiota in the CPT-11 and XCHT-treated mice based on 16S rRNA high-throughput sequencing technology. Meanwhile, the level of SN-38 and the concentrations of β-GUS in intestine were examined. We also resolved the 3D structure of β-GUS from gut microbiota by X-ray crystallography technology. Moreover, we used virtual screening, SPR analysis, and enzyme activity assays to confirm whether the main active ingredients from XCHT could selectively inhibit β-GUS. ResultsIn XCHT-treated mice, the levels of the proinflammatory cytokines decreased, the anti-inflammatory cytokines increased, and the community abundances of beneficial Firmicutes and Bacteroidota improved in the gut microbiota. We also found that the concentrations of β-GUS and the level of SN-38, the major ingredient that induces diarrhea in the gut, significantly decreased after coadministration of XCHT with CPT-11 in the intestine. Additionally, we revealed the structural differences of β-GUS from different gut microbiota. Finally, we found that EcGUS had good affinity with baicalein and meanwhile could be selectively inhibited by baicalein from XCHT. ConclusionsOverall, XCHT could relieve the delayed diarrhea induced by CPT-11 through improving the abundance of beneficial gut microbiota and reduced inflammation. Furthermore, based on the three-dimensional structure, baicalein, especially, could be used as a candidate EcGUS inhibitor to alleviate CPT-11-induced diarrhea.

Xiao Chai Hu Tang alleviates the pancreatic tumorigenesis via improving the mtDNA N6-Methyladenine modification mediated mitochondrial dysfunction in Syrian hamster model

BackgroundPancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which is a highly malignant tumor and lack of effective treatment. Although Xiao Chai Hu Tang (XCHT) has a good therapeutic effect on pancreatic cancer patients with advanced stage, the effect and mechanism of XCHT remains unclear in pancreatic tumorigenesis. PurposeTo assess the therapeutic effects of XCHT on the malignant transformation from PanIN to PDAC and to reveal its mechanisms of pancreatic tumorigenesis. MethodsSyrian golden hamster were induced by N-Nitrosobis (2-oxopropyl) amine (BOP) to establish the pancreatic tumorigenesis model. The morphological changes of pancreatic tissue were observed by H&E and Masson staining; the Gene ontology (GO) analysis the transcriptional profiling changes; the mitochondrial ATP generation, mitochondrial redox status, mitochondrial DNA (mtDNA) N6-methyladenine (6mA) level and relative mtDNA genes expressions were examined. In addition, immunofluorescence detect the cell localization of 6mA in human pancreatic cancer PANC1 cell. Using the TCGA database, the prognostic effect of mtDNA 6mA demethylation ALKBH1 expression on pancreatic cancer patients was analyzed. ResultsWe confirmed the mtDNA 6mA levels were gradually increased with the mitochondrial dysfunction in PanINs progression. XCHT showed the effect to inhibit the occurrence and development of pancreatic cancer in Syrian hamster pancreatic tumorigenesis model. In addition, the lack of ALKBH1 mediated mtDNA 6mA increase, mtDNA coded genes down-expression and abnormal redox status were rescued by XCHT. ConclusionsALKBH1/mtDNA 6mA mediated mitochondrial dysfunction to induce the occurrence and progression of pancreatic cancer. XCHT can improve ALKBH1 expression and mtDNA 6mA level, regulate the oxidative stress and expression of mtDNA coded genes. This study investigated a new molecular mechanism of pancreatic tumorigenesis, and revealed the therapeutic efficacy of XCHT in pancreatic tumorigenesis for the first time.

Effects and mechanisms of Xiaochaihu Tang against liver fibrosis: An integration of network pharmacology, molecular docking and experimental validation

Ethnopharmacological relevanceLiver fibrosis is a potentially harmful chronic liver disease caused by various etiologies. There is currently no specific drug for liver fibrosis. Xiaochaihu Tang (XCHT) is a traditional formula combined of seven herbs, which was first recorded in the Treatise on Febrile Diseases in Han Dynasty of ancient China. It is widely used in clinic to hepatic protection, analgesic, antipyretic and anti-inflammatory treatment. And it has been recommended for treating chronic hepatitis and chronic cholecystitis in the latest guidelines for the diagnosis and treatment of liver fibrosis with integrated traditional and western medicine. However, the underlying regulatory mechanisms remain elusive. Aim of the studyThis study aims to explore the therapeutic effects of XCHT on liver fibrosis and its underlying molecular mechanisms from the perspective of network pharmacology and experimental research. Materials and methodsCarbon tetrachloride (CCl4) induced and bile duct ligation (BDL) induced liver fibrosis models in mice were established to evaluate the anti-fibrosis effects of XCHT in vivo. Potential anti-fibrosis targets of XCHT were screened via network establishment. The underlying mechanisms were uncovered through GO and pathway enrichment analysis. Then, the core targets were identified from protein-protein interaction network by means of the Cytohubba plug-in of Cytoscape. Furthermore, two effective monomer components of XCHT were recognized by molecular docking. Moreover, the predicted components and pathways were verified by in vitro experiments. ResultsWhen treated with XCHT, liver fibrosis was alleviated in both mice models, showing as the improvement of liver function, the protection of hepatocytes, the inhibition of HSC activation and the reduction of hepatic collagen accumulation. 540 monomer components, 300 therapeutic targets, 109 signaling pathways, 246 GO biological processes, 77 GO cellular components, 107 GO molecular functions items and core targets were identified by network analysis. Then, 6-gingerol and baicalein were identified as the core components of anti-fibrosis effects of XCHT via leptin or Nrf2 signaling pathway. Furthermore, the experiment in vitro also validated the results. ConclusionsOur study suggests XCHT could alleviate liver fibrosis through multi-targets and multi-pathways; 6-gingerol and baicalein are its core components which may play an important role via leptin or Nrf2 signaling pathway.

The Pharmacological Mechanisms of Xiaochaihutang in Treating Breast Cancer Based on Network Pharmacology.

Background As a classic prescription in Chinese medicine treatment, Xiaochaihutang (XCHT) can improve the clinical effect and reduce serum tumor markers in patients with breast cancer (BC). However, there has not been any study to confirm the mechanism. We used bioinformatics analysis and network pharmacology to find the potential targets. Methods The differentially expressed genes (DEGs) of BC were identified from the Cancer Genome Atlas (TCGA) dataset. Then, we utilized weighted coexpression network analysis (WGCNA) with the same dataset. The target genes of BC were obtained by comparing genes of DEGs and in significant modules of WGCNA. Drug targets of XCHT from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database were intersected with the targets of BC. The protein-protein interaction (PPI) of the drug targets was analysed by using the STRING database. We utilized the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analysis (KEGG) enrichment analysis to identify the specific pathways and key target proteins. Receiver operator characteristic (ROC) curve was used as the verification of drug targets. Molecular docking was performed to visualize the patterns of interactions between the effective molecule and targeted protein. Results We obtained a set of 21 target genes, which mainly encode neurotransmitter receptors or related transporters, such as OPRD1, 5-HT2A, and so on. In addition, enrichment analyses of 21 target genes showed that they were mainly concentrated in pathways related to the nervous system. Molecular docking was performed on the target gene of BC. Six active compounds can enter the active pocket of target gene, namely, naringenin, beta-sitosterol, coumestrol, nuciferine, beta-sitosterol, and protopine, thereby exerting potential therapeutic effects in BC. Conclusions Our analysis shows that the mechanism of XCHT in the treatment of BC is mainly acting on the neurogenesis in the microenvironment of breast tumor tissue.

Tandem mass tag-based quantitative proteomic analysis of the liver reveals potential protein targets of Xiaochaihutang in CUMS model of depression

Depression is a global mental disorder disease and greatly threatened human health. Xiaochaihutang (XCHT) has been used successfully in treatment of depression for many years in China, but the mechanism is unclear. Using the chronic unpredictable mild stress (CUMS) mice model of depression, the present study aimed to reveal possible antidepressant mechanisms of XCHT from the perspective of liver by analyzing hepatic proteomics in mice. Bioinformatics analysis identified 31 differentially expressed proteins (DEPs), including 5 upregulated and 26 downregulated proteins, between the CUMS model and XCHT groups. The bile secretion pathway was found by KEGG pathway analysis of these DEPs. Four of the 31 differentially expressed proteins, including 2 active proteins involved in bile secretion, carbonic anhydrase 2 (CA2) and cystic fibrosis transmembrane conductance regulator (CFTR), were selected to verify their genes. Four genes (Cyp7a1, Fxr, Shp and Ntcp) related to bile acid synthesis and transport were further investigated by quantitative real-time polymerase chain reaction (qRT-PCR). Both biochemical tests and gene studies demonstrated that CUMS affected bile acid synthesis and transport, while XCHT regulated this pathway. The results indicated that there may be a potential relationship between CUMS induced depression and hepatic injury caused by increased bile acid, and also provide a novel insight to understand the underlying anti-depression mechanisms of XCHT.

Network pharmacology and molecular docking study on the mechanism of colorectal cancer treatment using Xiao-Chai-Hu-Tang.

Background and objectiveWe aimed to predict the targets and signal pathways of Xiao-Chai-Hu-Tang (XCHT) in the treatment of colorectal cancer (CRC) based on network pharmacology, just as well as to further analyze its anti-CRC material basis and mechanism of action.MethodsWe adopted Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and Traditional Chinese Medicine Integrated Database (TCMID) databases to screen the active ingredients and potential targets of XCHT. CRC-related targets were retrieved by analyzing published microarray data (accession number GSE110224) from the Gene Expression Omnibus (GEO) database. The common targets were used to construct the “herb-active ingredient-target” network using the Cytoscape 3.8.0 software. Next, we constructed and analyzed protein-to-protein interaction (PPI) using BisoGenet and CytoNCA plug-in in Cytoscape. We then performed Gene Ontology (GO) functional and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses of target genes using the R package of clusterProfiler. Furthermore, we used the AutoDock Tools software to conduct molecular docking studies on the active ingredients and key targets to verify the network pharmacological analysis results.ResultsWe identified a total of 71 active XCHT ingredients and 20 potential anti-CRC targets. The network analysis revealed quercetin, stigmasterol, kaempferol, baicalein, and acacetin as potential key compounds, and PTGS2, NR3C2, CA2, and MMP1 as potential key targets. The active ingredients of XCHT interacted with most CRC disease targets. We showed that XCHT’s therapeutic effect was attributed to its synergistic action (multi-compound, multi-target, and multi-pathway). Our GO enrichment analysis showed 46 GO entries, including 20 biological processes, 6 cellular components, and 20 molecular functions. We identified 11 KEGG signaling pathways, including the IL-17, TNF, Toll-like receptor, and NF-kappa B signaling pathways. Our results showed that XCHT could play a role in CRC treatment by regulating different signaling pathways. The molecular docking experiment confirmed the correlation between five core compounds (quercetin, stigmasterol, kaempferol, baicalein, and acacetin) just as well as PTGS2, NR3C2, CA2, and MMP1.ConclusionIn this study, we described the potential active ingredients, possible targets, and key biological pathways responsible for the efficacy of XCHT in CRC treatment, providing a theoretical basis for further research.

Xiao-Chai-Hu-Tang ameliorates tumor growth in cancer comorbid depressive symptoms via modulating gut microbiota-mediated TLR4/MyD88/NF-κB signaling pathway

BackgroundDepressive symptoms are thought to promote cancer development and depressive remission has been reported to be effective for defeating cancer. The herbal formula Xiao-Chai-Hu-Tang (XCHT), that has an anti-depressive efficacy, has been widely utilized in China. However, its anti-cancer effect and underlying mechanisms remain unclear. PurposeThe present study aims to investigate the effects of XCHT on the depression-associated tumor and its potential mechanisms. MethodsA placebo-controlled trial was conducted in cancer patients comorbid with depressive symptoms to evaluate the effects of XCHT on depressive scales, tumor-related immune indicators, and gut microbial composition. A xenografted colorectal cancer (CRC) mouse model exposure to chronic restraint stress (CRS) was established to examine XCHT effects on tumorigenesis in vivo. Further, by manipulating gut bacteria with fecal microbial transplantation (FMT) or antibiotics-induced bacterial elimination in CRS-associated xenografted model, gut microbiota-mediated anti-tumor mechanism was explored. ResultsIn cancer patients comorbid with depressive symptoms, XCHT showed substantial effects on improvement of depressive scales, system inflammatory levels and gut dysbiosis. In vivo, XCHT inhibited tumor growth and prolonged survival time in addition to showing anti-depressive effect. Similarly, in our clinical trial, XCHT partially reversed gut dysbiosis, particularly through reducing abundances of Parabacteroides, Blautia and Ruminococcaceae bacterium. Manipulation of gut bacteria in CRS-associated xenografted model further proved that the inhibition of XCHT on tumor progression was mediated by gut microbiota and that the underlying mechanism involves in downregulation of TLR4/MyD88/NF-κB signaling. ConclusionsWe demonstrated that gut microbiota mediates the anti-tumor action of the formula XCHT in cancer patients and models that were comorbid with depressive symptoms. This study implies a novel clinical significance of anti-depressive herbal medicine in the cancer treatment and clarifies the important role of gut microbiota in treating cancer accompanied by depressive symptoms.

Xiao Chai Hu Tang for Peptic Ulcers: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

A peptic ulcer (PU) is a digestive disorder most commonly found in clinical practice. An oriental herbal formula, Xiao Chai Hu Tang (XCHT), has been used to treat PU for an extended period in China. The effectiveness and safety of XCHT in treating peptic ulcers was evaluated using a systematic review of randomized controlled trials (RCTs). Studies were systematically retrieved from CNKI, Embase, Medline, PubMed, SinoMed, VIP, Wanfang, and Web of Science. The following information was extracted from the relevant RCTs: the clinical efficacy rate, recurrence rate, clinical efficacy of traditional Chinese medicine, and the adverse effects. 13 RCTs, including 1334 patients, were included in this review. The meta-analysis showed that treatment with XCHT was superior to conventional pharmacotherapy (CPT) in improving the clinical efficacy rate (RR: 1.20, 95% confidence intervals (CIs): 1.08–1.34, P=0.0007), poor appetite (RR: 0.30, 95% CI: 0.15–0.61, P=0.0009), abdominal distension (RR: 0.61, 95% CI: 0.39–0.96, P=0.03), vomiting (RR: 0.33, 95% CI: 0.19–0.55, P < 0.0001), and stomach pain (RR: 0.36, 95% CI: 0.19–0.68, P=0.002) and reducing adverse events (RR: 0.23, 95% CI: 0.07–0.69, P=0.009). XCHT considerably increased the total clinical efficacy rate (RR: 1.22, 95% CI: 1.15–1.30, P < 0.00001) as both monotherapy and adjunctive therapy. The recurrence rate (RR = 0.29; 95% CI: 0.16–0.52, P < 0.0001) was remarkably decreased in the XCHT plus CPT group. The meta-analysis did not show a significant beneficial effect of XCHT compared with CPT in reducing the recurrence rate (RR = 0.45; 95% CI: 0.07–3.10, P=0.42) and acid reflux (RR: 0.76, 95% CI: 0.47–1.23, P=0.26). Our findings show that XCHT can treat peptic ulcers as part of an alternative medicine approach.

Hepatoprotective and antioxidative properties of chinese herbal medicine Xiao-Chai-Hu-Tang formulated with Bupleurum kaoi Liu on carbon tetrachloride-induced acute hepatotoxicity in rats

The Chinese herbal medicine, Xiao-Chai-Hu-Tang (XCHT), with Bupleurum radix as the main ingredient, is used for treating hepatitis. Although there are many varieties of Bupleurum in the herbal market, Bupleurum kaoi is the only indigenous species belonging to the Bupleurum genus plant in Taiwan which is commercially cultivated for making health-promoting products. The present study examined the hepatoprotective and antioxidative properties of XCHT formulated with commercially cultivated B. kaoi. The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GRd) and glutathione-S-transferase (GST) as well as lipid peroxidation in rats treated with CCl4 were analyzed to evaluate the hepatoprotective property of XCHT. The results showed that the enzyme levels in the serum of rats treated with XCHT extract prior to receiving CCl4 were significantly lower (p < 0.05) than those in the rats that received CCl4 only. Malondialdehyde formation was also reduced when XCHT extract was given. In comparison with the extract of XCHT, the extract of B. kaoi showed similar hepatoprotective abilities. Since the levels of SOD, catalase, GPx, GRd and GST were compensation increased in CCl4 treatment, it was suggested that XCHT or B. kaoi markedly suppressed lipid peroxidation and reversed the activities of the antioxidant enzymes to the normal levels.

Network Pharmacology Analysis of Anticonvulsant Effect of Xiao Chai Hu Tang

Epilepsy is the second largest disease after headache in the neurology department of the hospital. Previous studies have shown that Xiao Chai Hu Tang (XCHT) has a certain therapeutic effect on epilepsy. We used the gene expression array data of epilepsy patients, and the relevant data of the Chinese medicine components in the TCMSP database and DrugBank database, combined with bioinformatics analysis methods, to construct herbs-compounds-targets (HCT) network and protein-protein interaction (PPI) core network of XCHT. The result suggests that Caveolin 1 (CAV1) may be a key target in the treatment of epilepsy, and β-carotene may have potential antiepileptic activity. In addition, the PPI core function network is enriched in the process of transcription factor regulation, and the related protein is located on the nuclear chromosome and closely related to the immune process, which provides a reference for other researchers.

Favorable outcome of adjunctive traditional Chinese medicine therapy in liver cirrhosis: A large cohort study in Southwest China

ObjectiveTo assess the effects of traditional Chinese medicine (TCM) on the survival of patients with liver cirrhosis (LC) in Southwest China. DesignSingle-center, ambispective cohort study conducted from 2012 to 2019. SettingTraditional Chinese Medicine Hospital of Dianjiang Chongqing, Southwest China. Main outcome measureThe primary outcome was the effect of TCM on the survival of patients with LC, as assessed with survival analysis and Cox regression model. ResultsAmong the 691 patients with LC, 364 (52.68 %) received TCM treatment. The mean (standard deviation) follow-up period was 3.53 (1.62) years for non-TCM users and 4.17 (1.53) years for TCM users (P = 0.184). Multivariate analysis revealed that the use of TCM was associated with a significantly decreased risk of mortality (adjusted hazard ratio [HR] = 0.41, 95 % confidence interval [CI] = 0.30 – 0.54) compared with no TCM use. Similarly, the cumulative mortality rates were significantly lower among TCM users, across various subgroups of LC aetiologies. Among the commonly used TCM prescriptions, Xiao Chaihu Tang (XCHT, adjusted HR = 0.17, 95 % CI = 0.07 – 0.42), Yinchen Wuling San (adjusted HR = 0.31, 95 % CI = 0.14 – 0.66), Biejia Ruan Gan Jian (adjusted HR = 0.31, 95 % CI = 0.13 – 0.75), and Chaihu Shu Gan San (adjusted HR = 0.33, 95 % CI = 0.19 – 0.57) were the most effective in improving survival. ConclusionsOur results provide evidence for supporting that adjunctive TCM therapy may potentially improve the survival of patients with liver cirrhosis, and XCHT was the most effective TCM prescription in this study.

Xiaochaihutang Improves the Cortical Astrocyte Edema in Thioacetamide-Induced Rat Acute Hepatic Encephalopathy by Activating NRF2 Pathway.

Oxidative stress induced by high ammonia, which leads to astrocyte edema, is the key to acute hepatic encephalopathy (AHE). Nuclear factor erythroid 2-related factor 2 (NRF2) has been implicated in oxidative stress, but the mechanism of NRF2 against ammonia-induced astrocytes edema has not been fully studied. We confirmed that the NRF2 pathway is related to brain edema caused by AHE and found that Xiaochaihutang (XCHT) could effectively activate the NRF2 pathway to treat AHE. The model of AHE was established with thioacetamide (TAA) in rats. Rat behaviors were observed, brain water content, blood ammonia levels, glutamine synthetase (GS), malondialdehyde (MDA), and total superoxide dismutase (T-SOD) were determined after XCHT treatment. Furthermore, the expression of NRF2 pathway proteins and mRNA, glial fibrillary acidic protein (GFAP) and aquaporins 4 (AQP4) were examined. In order to determine whether XCHT has a direct effect on cerebral edema caused by high ammonia, we examined the effect of XCHT compound serum on cortical astrocytes in the presence of ammonia, through microscopic observation and immunofluorescence (IF). Results showed that AHE induced by TAA changed the behavior of the rats, and increased brain water content, blood ammonia levels, GS and MDA content meanwhile decreasing T-SOD, but these symptoms were improved by treatment with XCHT. XCHT protected brain edema by activating the NRF2 pathway and increasing the expression of downstream proteins and genes. Astrocytes treated with 5 mM ammonia also showed an increase in the AQP4 protein expression but a decrease in XCHT compound serum and ammonia-induced cell edema groups. This study demonstrates that the NRF2 pathway is involved in the brain edema in AHE, and XCHT may represent a useful prescription for the treatment of AHE.

How does Xiao Chai Hu Tang (XCHT) formula compare with no intervention for adults with chronic hepatitis B virus (HBV)?

How does Xiao Chai Hu Tang (XCHT) formula compare with no intervention for adults with chronic hepatitis B virus (HBV)?

Precise Application of the Xiao-Chai-Hu-Tang in 98 Cases of Patients with the Major Syndrome of Feeling Pain and Tenderness under the Right Costal Arch

Xiao-Chai-Hu-Tang (XCHT), a representative of previous edition of Formulas of Traditional Chinese Medicine and harmonizing formulas, has multiple pharmacological functions. However, a variety of side effects could be caused by misuse or abuse, ignoring the theory of diagnosis and treatment based on the combination of syndrome and disease differentiation. Therefore, we conducted a retrospective study to evaluate the efficacy of XCHT, depending upon the individual patient’s condition. Among 98 patients treated with XCHT, most of the patients of syndromes could be cured after about two course. The therapeutic effect rate of prescribed XCHT in our 98 cases of treatment is 91.84% (90/98). In addition, the high frequently syndromes are consistent with Shanhanlun. With multiple years of experience, we believe that: patient feel pain and tenderness under the right costal arch is one of the symptoms of patients who fit for the treatment with XCHT.

Advances in anti hepatic fibrotic therapy with Traditional Chinese Medicine herbal formula.

The process of liver fibrogenesis includes a number of common and etiology-dependent or independent mechanisms and events. Up to now, there are still insufficient approved biological or chemical therapies directly targeting and reversing advanced fibrosis. The key is that once liver fibrosis is triggered, it presents a complex network control model with the activation of HSCs as the core, resulting in poor efficacy of treatment. Traditional Chinese medicine (TCM) has unique advantages in treating hepatic fibrosis because of its syndrome differentiation and treatment and comprehensive pharmacological effects of multi-channel, multi-level and multi-target. However, TCM's advantages were rarely discussed as previous reviews focused on the active ingredients of TCM and single Chinese Medicine. Therefore, this paper focuses on TCM herbal formulae's pharmacological role, target and related mechanisms in the treatment of liver fibrosis. This paper will focus on the pharmacological role, target and related mechanisms of TCM herbal formulae in the treatment of liver fibrosis. We collect English literatures or Chinese literatures with English Abstract on the treatment of liver fibrosis with TCM herbal formulae from databases including PubMed, Wiley InterScience, Science Direct OnSite/Elsevier, Ovid, Excerpta Medica Database, SpringLink, CNKI and China Biomedical Literature Database. Based on previous literatures, we summarize the TCM herbal formulae with definite anti-hepatic fibrosis effects. To some extent, classical or modern TCM herbal formulae including Yinchenhao Decoction (YCHD), Xiayuxue Decoction (XYXD), Xiaochaihutang (XCHT), Yiguanjian Decoction (YGJ), Huangqi Decoction (HQD), Dahuang Zhechong Pills (DHZC), Fuzheng Huayu Formula (FZHY), Fufang Biejia Ruangan Tablets (FFBJRG), Anluo Huaxian Pills (ALHX) and Compound 861 (Cpd861) have anti-hepatic fibrosis effect both on patients with liver fibrosis and animal models with liver fibrosis. According to the principle of syndrome differentiation and treatment, Liver fibrosis patients with different syndromes are treated with different herbal formula, which increases the difficulty of clinical efficacy research. YCHD and XYXD research lack randomized and controlled clinical trials. XCHT, YGJ and HQD research has small sample sizes despite randomized and controlled clinical trials. In contrast, most modern herbal formulae have randomized and controlled clinical trials. For instance, FZHY and ALHX recently published the research results of the combination of entecavir in the treatment of patients with chronic hepatitis B liver fibrosis or cirrhosis. Compared to anti-viral treatment with entecavir alone, this method has improved the reversion rate of liver fibrosis but still needs syndrome classification therapy of TCM. TCM Herbal formulae have a good prospect in treating liver fibrosis, but its composition of multiple drugs and a wide range of targets intensify the difficulty of studying their anti-hepatic fibrosis mechanisms. Future research needs to further study the anti-hepatic fibrosis mechanisms and select corresponding TCM herbal formula to treat patients with different syndromes of liver fibrosis or the same patient with different syndromes at different stages to achieve better curative results.

Safety evaluation of heavy metals contaminated Xiaochaihu Tang using health risk assessment model

In order to further improve the quality and safety evaluation standards of traditional Chinese medicine compound preparation,Xiaochaihu Tang compound preparations were selected to analyze the pollution level of heavy metals deeply,and the potential health risks were evaluated under taking such kind of compound preparations. In this study,the contents of copper( Cu),arsenic( As),cadmium( Cd),mercury( Hg),and lead( Pb) in different Xiaochaihu Tang compound preparations were determinated by the method of inductively coupled plasma mass spectrometry( ICP-MS). Moreover,combined with target hazard coefficient method and in vitro artificial system,the bioaccessibility and health risk level was investigated in three main consumption ways including powder,decoction and granule. The result was showed that,under the maximum residual limit set by International Standard Organization,only one batch of raw herb was eight times exceeded the Hg MRL,however,in water decoctions and granules,the heavy metal residue rate was reduced to 2. 02%( Hg in granules)-42. 85%( Cd in granules). So,the heavy metal pollutions and health risks can be reduced to safe region in spite of the serious pollution in raw herbs. Besides,the THQ and CR values of the three consumption methods were lower than the standard values of non-carcinogenic and carcinogenic risks of each heavy metal. It can be seen that even if the heavy metals in the raw herbs exceed the standard,the use of Xiaochaihu Tang decoction and granules can reduce the harm of heavy metals to the human body. Above all,the establishment of this health risk assessment model can be provided experimental basis and reference value for improving the safety evaluation standard of other heavy metals contained traditional Chinese medicine( TCM) compound preparations,and further improving the quality control methods of other different toxic compounds in clinical use.

Antidepressant-like effects of Xiaochaihutang in perimenopausal mice.

Xiaochaihutang (XCHT) is a traditional Chinese medicine prescription for thousand years in China. Our previous researches show that XCHT has antidepressant-like effects in several depression models, but effect and mechanism of XCHT in perimenopausal depression are still vague. To reveal the antidepressant-like effect and mechanism of XCHT in perimenopausal mice. Perimenopausal depression model is executed by ovariectomy combined with chronic unpredictable mild stress (OVX-CUMS). Tail suspension test (TST), forced swim test (FST), elevated plus-maze (EPM), novelty suppressed feeding (NSF) and locomotor activity are used to assess antidepressant-like effects of XCHT. The Level of estradiol (E2), follicle-stimulating hormone (FSH), gonadotrophin releasing hormone (GnRH), corticosterone (CORT), adrenocorticotrophic hormone (ACTH) and corticotropin releasing hormone (CRH) are evaluated by ELISA. Antidepressant mechanisms of XCHT in OVX-CUMS mice are analyzed by 5-hydroxytryptamine (5-HT), tryptophan hydroxylase 2 (TPH2) and estrogen receptor α and β (ERα/β). The results show that OVX-CUMS significantly increases the immobility time in TST and FST, increases latency to feed, decreases food consumption in NSF and both the time spend and number of entries in open arms in EPM. While, oral administration of XCHT can significantly normalize above depression-like behaviors in OVX-CUMS mice. Moreover, XCHT also remarkably normalized levels of 5-HT, 5-HIAA, E2, GnRH, CORT, ACTH and CRH in OVX-CUMS mice. Finally, the expression of ERβ and TPH2 are decreased by OVX-CUMS in prefrontal cortex and hypothalamus, and XCHT can restore these decrease. Current findings suggest XCHT can alleviate perimenopausal depression-like behaviors, restore 5-HT and hormones in OVX-CUMS mice, which may be related to normalizing the functions of HPA/HPO axis and enhancing expression of ERβ and TPH2 in prefrontal cortex and hypothalamus.

Metabolic profiles of Xiao Chai Hu Tang in mouse plasma, bile and urine by the UHPLC–ESI-Q-TOF/MS technique

Xiao Chai Hu Tang (XCHT) is sold as traditional medicine or dietary supplement in worldwide. To understand metabolism profile of traditional medicine is key point in their logical pharmacological research and clinical application. Based on our previous research of the chemical and absorption signature of XCHT in vitro, we proposed a novel strategy to identify the bioactive components of XCHT in vivo. This strategy have two steps: firstly, based on the parents' database in vitro, built-in and editable biotransformations for phase I and phase II metabolism reactions with MassHunter Metabolite ID software (building metabolites database). Secondly, mouse plasma, bile and urine samples were analyzed by UHPLC–ESI-Q-TOF/MS technique, and the absorbed parents and metabolites were compared and identified with the XCHT's digital library using MassHunter Metabolite ID software. In total, 27 parent compounds and 26 metabolites of XCHT were identified in vivo, 2′-O-xylosyl saikosaponin b2 or b1 was reported for the first time. Saponins and their related metabolites were predominantly excreted into the bile, but flavonoids were excreted by both hepatic as well as renal excretion. Flavonoids, saponins, gingerol and their related metabolites were the absorbed components in cardiovascular system and bioactive components of XCHT. Phase I reactions (hydrolysis, hydroxylation and oxidation) and phase II reactions (glucuronidation) were identified and involved in the mouse metabolism of XCHT.

Xiao-Chai-Hu-Tang (XCHT) Intervening Irinotecan's Disposition: The Potential of XCHT in Alleviating Irinotecan-Induced Diarrhea.

Diarrhea is a severe side effect of irinotecan, a pro-drug of SN-38 used for the treatment of many types of cancers. Pre-clinical and clinical studies showed that decreasing the colonic exposure of SN-38 can mitigate irinotecan-induced diarrhea. The purpose of this study is to evaluate the anti-diarrhea potential of Xiao-Chai-Hu-Tang (XCHT), a traditional Chinese herbal formula, against irinotecan-induced diarrhea by determining if and how XCHT alters the disposition of SN-38. LC-MS/MS was used to quantify the concentrations of irinotecan and its major metabolites (i.e., SN-38, SN-38G). An Intestinal perfusion model was used to determine the effect of XCHT on the biliary and intestinal secretions of irinotecan, SN-38, and SN-38G. Pharmacokinetic (PK) studies were performed to determine the impact of XCHT on the blood and fecal concentrations of irinotecan, SN-38, and SN-38G. The results showed that XCHT significantly inhibits both biliary and intestinal excretions of irinotecan, SN-38, and SN-38G (range: 35% to 95%). PK studies revealed that the fecal concentrations of irinotecan and SN-38 were significantly decreased from 818.35 ± 120.2 to 411.74 ± 138.83 µg/g or from 423.95 ± 76.44 to 245.63 ± 56.72 µg/g (p<0.05) by XCHT, respectively, suggesting the colonic exposure of SN-38 is significantly decreased by XCHT. PK studies also showed that the plasma concentrations of irinotecan, SN-38, and SN-38G were not affected by XCHT. In conclusion, XCHT significantly decreased the exposure of SN-38 in the gut without affecting its plasma level, thereby possessing the potential of alleviating irinotecan-induced diarrhea without negatively impacting its therapeutic efficacy.