A Synthetic External Control Study Comparing the Clinical Efficacy of Wendan Decoction and 19 Antidepressants.

BACKGROUND: Wendan decoction (WDD) has been used as a treatment for depression in China since the Tang Dynasty. However, high-quality evidence for this is lacking. This study proposed a novel synthetic external control method to evaluate its clinical efficacy. METHODS: We searched public databases for clinical trials of WDD for major depression. The rate of change of the Hamilton Depression Scale score from baseline was used as an efficacy indicator, and a model-based meta-analysis was performed to analyze the clinical efficacy of WDD. To establish a reference standard for efficacy, the antidepressant efficacy distributions of a placebo and 19 antidepressants were virtually synthesized based on the same conditions as the clinical trial characteristics of WDD. RESULTS: This study included 5 clinical trials with 177 participants. WDD showed a slow onset, with a time to reach the maximum effect of 9.71 weeks. At 8 weeks, the rate of change in the Hamilton Depression Scale score from baseline was 66.4% (95% CI = 62.3%-70.3%) in the WDD group. The pure effect value of WDD, after deducting the placebo effect, was 26.9% (95%CI = 23.0%-30.9%), which was comparable with 5 types of antidepressants and significantly higher than the others. CONCLUSION: The proposed external synthetic control method provides a solution to the bottleneck problem of clinical efficacy evaluation in real-world research on traditional Chinese medicine. WDD has high clinical development value for the treatment of depression, and large-scale randomized controlled trials are recommended to confirm its antidepressant effect.

Metabolic profile and potential mechanisms of Wendan decoction on coronary heart disease by ultra-high-performance quadrupole time of flight-mass spectrometry combined with network pharmacology analysis.

Wendan decoction, a well-known classical traditional Chinese medicine prescription, has been widely used in the clinical application of coronary heart disease for thousands of years. However, due to a lack of research on the overall metabolism of Wendan decoction, the bioavailable components responsible for the therapeutic effects remain unclear, hindering the revelation of its mechanisms against coronary heart disease. Consequently, an efficient joint research pattern combined with characterization of the metabolic profile and network pharmacology analysis was proposed. As a result, a total of 172 Wendan decoction-related xenobiotics (57 prototypes and 115 metabolites) were detected based on the exploration of the typical metabolic pathways of representative pure compounds in vivo, describing their multi-component metabolic characteristics comprehensively. Subsequently, an integrated network of "herbs-bioavailable compounds-coronary heart disease targets-pathways-therapeutic effects" was constructed, and its seven compounds were finally screened out as the key components acting on five main targets of coronary heart disease. Overall, this work not only provided a crucial biological foundation for interpreting the effective components and action mechanisms of Wendan decoction on coronary heart disease but also showed a reference value for revealing the bioactive components of traditional Chinese medicine prescriptions.

Screening of Active Ingredients from Wendan Decoction in Alleviating Palmitic Acid-Induced Endothelial Cell Injury.

(1) Objective: Traditional Chinese medicine (TCM) plays an important role in the treatment of numerous illnesses. As a classic Chinese medicine, Wendan Decoction (WDD) encompasses a marvelous impact on the remedy of hyperlipidemia. It is known that hyperlipidemia leads to cardiovascular injury, therefore anti-vascular endothelial cell injury (AVECI) may be an underlying molecular mechanism of WDD in the cure of hyperlipidemia. However, there is no relevant research on the effect of WDD on vascular endothelial cells and its pharmacodynamic substances. Therefore, the purpose of this study was to investigate the protective effect of WDD on vascular endothelial cells. (2) Methods: The chemical constituents of WDD were determined by LC-MS/MS technology. The protective effects of 16 batches of WDD on samples from human umbilical vein endothelial cells (HUVECs) were evaluated. Finally, gray relation analysis (GRA) and partial least squares regression (PLSR) were used to analyze the potential correlation between chemical ingredients and AVECI. (3) Results: The results indicated that WDD had apparent protective effect on endothelial cells, and pharmacological properties in 16 batches of WDD tests were apparently discrepant. The GRA and PLSR showed that trigonelline, liquiritin, hesperidin, hesperetin, scopoletin, morin, quercetin, isoliquiritigenin, liquiritigenin and formononetin may be the active ingredients of AVECI in WDD. (4) Conclusions: WDD has a protective effect on endothelial cell injury induced by palmitic acid, which may be related to its component content. This method was suitable for the search of active components in classical TCM.

Characterization of chemical profile and quantification of major representative components of Wendan decoction, a classical traditional Chinese medicine formula.

Wendan decoction, a classical traditional Chinese medicine formula consisting of six herbal medicines, has been widely used in clinical treatments for thousands of years due to the expectorant effects. However, the chemical basis of Wendan decoction remains unclear, which hinders the elucidation of the scientific connotation and mechanism of its effective components. In this study, an ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry method was first developed for characterization of its chemical profile, and a total of 142 chemical components including flavonoids, triterpenoids, alkaloids, coumarins, pungent phytochemicals, and other types were detected, among which 41 components were definitively identified with authentic standards. Furthermore, 14 major representative components were simultaneously quantified by high-performance liquid chromatography with ultraviolet detector, indicating that the content levels of flavonoids were the most abundant in Wendan decoction. In summary, this study established sensitive and practical methods to systematically characterize chemical profile for the first time and simultaneous quantify representative components of Wendan decoction. These findings above would provide a solid chemical basis for disclosure of potential effective components by further in vivo disposal study, and promote therapeutic mechanism researches of Wendan decoction.

[Mechanism of Huanglian Wendan Decoction in intervening IGT IR based on liver cell pyroptosis].

To investigate the mechanism of Huanglian Wendan Decoction in intervening impaired glucose tolerance( IGT) rat insulin resistance( IR) based on the pyroptosis pathway of liver cells. The IGT rat model was established by high-fat diet( 20 weeks) combined with high temperature,humidity environment and inactive lifestyle. The experiment was divided into blank group,model group,metformin hydrochloride group( positive group)( 0. 05 g·kg~(-1)·d~(-1)) and Huanglian Wendan Decoction group( 7. 8 g·kg~(-1)·d~(-1)). After continuous intragastric administration for 4 weeks,the body weight,body length and abdominal circumferences of all the rats were measured,the Lee' s obesity indexes was calculated,and the levels of fasting plasma glucose( FPG) and 2-hour plasma glucose( 2 hPG) in each group were measured. Serum insulin levels( FINS) and tumour necrosis factor-α( TNF-α) levels were detected by ELISA,and insulin sensitivity index( ISI) and insulin resistance index( IRI) values were calculated. The expressions of cysteinyl aspartate specific proteinase-1( caspase-1),gasdermin D( GSDMD),interleukin-1ß( IL-1ß) and interleukin-18( IL-18) m RNA and proteins in liver tissues were detected by Real-time PCR and Western blot. Immunofluorescence was used to detect the expressions of caspase-1 and GSDMD protein in liver tissues. Huanglian Wendan Decoction could effectively reduce the weight of model rats,improve abdominal obesity,FINS,IRI and ISI indexes and correct 2 hPG levels. Compared with blank group,TNF-α levels in serum and caspase-1,GSDMD,IL-1ß and IL-18 expressions in liver tissue of model control group were increased significantly. Huanglian Wendan Decoction could effectively reduce TNF-α level in serum,regulate the expressions of caspase-1,GSDMD,IL-1ß and IL-18 genes and proteins in liver tissues of IGT rats. The above results showed that the occurrence and development of " obesity-IR-abnormal glucose metabolism-type 2 diabetes mellitus" was closely related to inflammatory response and the classical pyroptosis pathway mediated by caspase-1/GSDMD. The mechanism of Huanglian Wendan Decoction in improving IR may be correlated with reduction of the level of inflammatory factors and the alleviation of the state of pyroptosis,and thus reverse the course of IGT.

[Mechanism of Huanglian Wendan Decoction in improving impaired glucose tolerance based on skeletal muscle NLRP3/caspase-1/IL-1ß, IL-18 pathway].

This study investigated the mechanism of improving impaired glucose tolerance(IGT) of rats by Huanglian Wendan Decoction from the perspective of the skeletal muscle Nod-like receptor protein 3(NLRP3)/cysteinyl aspartate specific proteinase-1(caspase-1)/interleukin-1ß(IL-1ß), interleukin-18(IL-18) pathway. Healthy male SD rats were fed with the diet containing 45% fat for 20 weeks, accompanied by a high-temperature and high-humidity environment and an inactive lifestyle, for the establishment of the IGT rat model. The rats were divided into the blank control group, model control group, metformin hydrochloride group(positive drug group, 0.05 g·kg~(-1)·d~(-1)) and Huanglian Wendan Decoction group(7.8 g·kg~(-1)·d~(-1)). After continuous intragastric administration for 4 weeks, the obesity and glycemic indexes of all the rats were measured. The fasting serum insulin(FINS) level was determined by ELISA, with the insulin sensitivity index(ISI) and insulin resistance index(IRI) calculated. The mRNA and protein expression le-vels of nuclear factor kappaB(NF-κB), NLRP3, caspase-1, IL-1ß and IL-18 in skeletal muscle tissue were detected by real-time polymerase chain reaction(PCR), Western blot and immunofluorescence. Compared with the blank control group, the model control group witnessed significantly increased mRNA and protein expression of NF-κB, NLRP3, caspase-1, IL-1ß and IL-18. As revealed by the comparison with the model control group, Huanglian Wendan Decoction could effectively regulate the obesity status, reduce body weight, correct the abnormal levels of 2-hour plasma glucose(2 hPG), insulin resistance index(IRI), insulin sensitivity index(ISI), and lower the mRNA and protein expression of NF-κB, NLRP3, caspase-1, IL-1ß and IL-18 in the skeletal muscle tissue of IGT rats. Combined with previous studies, the above results showed that the occurrence and development of IGT was closely related to inflammatory response and the classic pyroptosis pathway in skeletal muscle, such as NLRP3/caspase-1/IL-1ß, IL-18. It is inferred that the mechanism of Huanglian Wendan Decoction was to alleviate insulin resistance(IR) and then reverse the course of IGT lies in the regulation of the abnormal insulin receptor signaling pathway based on the NLRP3 inflammasome pathway.

Tuling Wendan Decoction combined with flunarizine in the treatment of migraine patients and the effect of intervention on serum cyclooxygenase-2, endothelin-1 and nitric oxide.

This experiment aimed to explore the curative effect of Tuling Wendan Decoction combined with flunarizine on migraine patients and the intervention effect on serum cyclooxygenase-2 (COX-2), endothelin-1 (ET-1), nitric oxide(NO) levels. For this purpose, from January 2019 to January 2020, 96 patients with migraine in our hospital were selected as the research object. Using a simple randomization method, patients who meet the criteria were assigned 1:1, and each patient was assigned a random number, of which the number 1 to 48 were the observation group, and the number 49 to 96 were the control group. The control group was treated with flunarizine, and the observation group was treated with Tuling Wendan Decoction combined with flunarizine. Comparing the efficacy, incidence of adverse reactions, the incidence of headache, cerebral blood flow rate [basal artery (BA), vertebral artery (VA), middle cerebral artery (MCA)], vascular endothelial function (serum COX-2, ET-1, NO levels), neurological function [5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF), calcitonin gene-related peptide (CGRP)] before treatment, 4 weeks and 8 weeks after treatment between the two groups. The results for efficacy showed that after 8 weeks of treatment, the total effective rate of the observation group (93.75%) was higher than that of the control group (77.08%, P<0.05). In regards to the situation of headache attack, the number of headache attacks, duration, pain degree and accompanying symptom scores of the observation group after 4 weeks and 8 weeks of treatment were lower than those of the control group (P<0.05). Results of cerebral blood flow velocity showed that the blood flow velocity of BA, VA, MCA in the observation group was lower than that in the control group after 4 and 8 weeks of treatment (P<0.05). Vascular endothelial function results indicated that the serum COX-2 and ET-1 levels of the observation group were lower than those of the control group after 4 weeks and 8 weeks of treatment, and the serum NO levels were higher than that of the control group (P<0.05). The serum BDNF and CGRP levels of the observation group were lower than those of the control group after 4 weeks and 8 weeks of treatment, and the serum 5-HT levels were higher than the control group (P<0.05). The incidence of adverse reactions between the two groups was not statistically significant (P>0.05). It was concluded that Tuling Wendan Decoction combined with flunarizine is the first treatment for migraine, with definite curative effect and can effectively improve the onset of headache, reduce the speed of cerebral blood flow, regulate vascular endothelial function and nerve function, and ensure safety.

Systematic Understanding of Mechanisms of a Chinese Herbal Formula in Treatment of Metabolic Syndrome by an Integrated Pharmacology Approach.

Metabolic syndrome (MS) is becoming a worldwide health problem. Wendan decoction (WDD)-a famous traditional Chinese medicine formula-has been extensively employed to relieve syndromes related to MS in clinical practice in China. However, its pharmacological mechanisms still remain vague. In this study, a comprehensive approach that integrated chemomics, principal component analysis, molecular docking simulation, and network analysis was established to elucidate the multi-component and multi-target mechanism of action of WDD in treatment of MS. The compounds in WDD were found to possess chemical diversity, complexity and drug-likeness compared to MS drugs. Six nuclear receptors were obtained to have strong binding affinity with 217 compounds of five herbs in WDD. The importance roles of targets and herbs were also identified due to network parameters. Five compounds from Radix Glycyrrhizae Preparata can hit all six targets, which can assist in screening new MS drugs. The pathway network analysis demonstrated that the main pharmacological effects of WDD might lie in maintaining lipid and glucose metabolisms and anticancer activities as well as immunomodulatory and hepatoprotective effects. This study provided a comprehensive system approach for understanding the multi-component, multi-target and multi-pathway mechanisms of WDD during the treatment of MS.

Integrated Network Pharmacology and Molecular Docking to Explore the Mechanisms of Ningshen Wendan Decoction in the Treatment of Schizophrenia.

Objective: Schizophrenia (SCZ) is a prevalent chronic mental disorder characterized by a high recurrence rate and significant disability. Currently, no satisfactory pharmacological treatments have been identified. Although Ningshen Wendan decoction (NSWDD) has shown promising results in improving cognitive function in patients with schizophrenia, its underlying mechanism of action remains unclear. Methods: This study systematically investigated the mechanisms of NSWDD in SCZ treatment using network pharmacology and molecular docking approaches. Results: Analysis of the interaction genes revealed 307 common targets of NSWDD and SCZ. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated the involvement of multiple signaling pathways including interleukin 17 signaling pathway, multiple virus infections, Advanced glycosylation end products (AGEs) - receptor of AGEs (AGEs-RAGE) signaling pathway, tumor necrosis factor signaling pathway, and Hypoxia-inducible factor-1 (HIF-1) signaling pathway as key pathways influenced by NSWDD in treating SCZ. These pathways are associated with various biological processes such as transcriptional regulation, apoptosis regulation, gene expression regulation, and external stimulus-response. Molecular docking simulations indicated favorable binding interactions between components of NSWDD and target proteins via intermolecular forces. Conclusion: The study provided initial insights into the internal molecular mechanisms underlying the beneficial effect of NSWDD on SCZ through multi-target modulation across multiple pathways.

The in vivo study on antioxidant activity of wendan decoction in treating hyperlipidemia: a pharmacokinetic-pharmacodynamic (PK-PD) model.

Background: Wendan Decoction (WDD) is a six-herb Chinese medicine recipe that was first mentioned in about 652 AD. It is frequently used to treat hyperlipidemic patients' clinical complaints. According to reports, oxidative stress has a significant role in hyperlipidemia. Purpose: There has not yet been a thorough pharmacokinetic-pharmacodynamic (PK-PD) examination of the clinical efficacy of WDD in the context of hyperlipemia-related oxidative stress. Therefore, the goal of this research is to explore the antioxidant essence of WDD by developing a PK-PD model, ordering to assure its implication in treating hyperlipidemia in medical practice. Methods: The model rats of foodborne hyperlipidemia were established by feeding with high-fat feed, and the lipid-lowering effect of WDD was explored. The plasma drug concentration of rats at different doses were measured by UPL-MS/MS technology, and PK parameters were calculated using Phoenix WinNonlin 8.1 software. The level of lipid peroxide (LPO) in plasma at different time points was measured by enzyme labeling instrument. Finally, the PK-PD model was established by using Phoenix WinNonlin 8.1 software, to explore the lipid-lowering effect of WDD and the relation between the dynamic changes of chemical components and antioxidant effect. Results: The findings suggested that, WDD can reduce the levels of triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in plasma, and high-density lipoprotein cholesterol (HDL-C) was related to the dosage. Between the peak drug levels and the WDD's maximal therapeutic response, there existed a hysteresis. WDD's effect-concentration curves displayed a counterclockwise delaying loop. Alternatively, among the ten components of WDD, hesperetin, quercetin, naringenin and tangeretin might exert more significant effects in regulating the LPO levels in hyperlipidemic rats. Conclusion: This study can be helpful for other investigators to study the lipid-lowering effect of WDD.

Therapeutic effect of Wendan Decoction combined with mosapride on gastroesophageal reflux disease after esophageal cancer surgery.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common complication of esophageal cancer surgery that can affect quality of life and increase the risk of esophageal stricture and anastomotic leakage. Wendan Decoction (WDD) is a traditional Chinese herbal formula used to treat various gastrointestinal disorders, such as gastritis, functional dyspepsia, and irritable bowel syndrome. Mosapride, a prokinetic agent, functions as a selective 5-hydroxytryptamine 4 agonist, enhancing gastrointestinal motility. AIM: To evaluate the therapeutic effects of WDD combined with mosapride on GERD after esophageal cancer surgery. METHODS: Eighty patients with GERD were randomly divided into treatment (receiving WDD combined with mosapride) and control (receiving mosapride alone) groups. The treatment was conducted from January 2021 to January 2023. The primary outcome was improved GERD symptoms as measured using the reflux disease questionnaire (RDQ). The secondary outcomes were improved esophageal motility (measured using esophageal manometry), gastric emptying (measured using gastric scintigraphy), and quality of life [measured via the Short Form-36 (SF-36) Health Survey]. RESULTS: The treatment group showed a notably reduced RDQ score and improved esophageal motility parameters, such as lower esophageal sphincter pressure, peristaltic amplitude, and peristaltic velocity compared to the control group. The treatment group showed significantly higher gastric emptying rates and SF-36 scores (in both physical and mental domains) compared to the control group. No serious adverse effects were observed in either group. CONCLUSION: WDD combined with mosapride is an effective and safe therapy for GERD after esophageal cancer surgery. It can improve GERD symptoms, esophageal motility, gastric emptying, and the quality of life of patients. Further studies with larger sample sizes and longer follow-up periods are required to confirm these findings.

Activation of GABA type A receptor is involved in the anti-insomnia effect of Huanglian Wendan Decoction.

Huanglian Wendan Decoction (HWD) is a traditional Chinese medicine (TCM) prescribed to patients diagnosed with insomnia, which can achieve excellent therapeutic outcomes. As positively modulating the γ-aminobutyric acid (GABA) type A receptors (GABAARs) is the most effective strategy to manage insomnia, this study aimed to investigate whether the activation of GABAARs is involved in the anti-insomnia effect of HWD. We assessed the metabolites of HWD using LC/MS and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and tested the pharmacological activity in vitro and in vivo using whole-cell patch clamp and insomnia zebrafish model. In HEK293 cells expressing α1ß3γ2L GABAARs, HWD effectively increased the GABA-induced currents and could induce GABAAR-mediated currents independent of the application of GABA. In the LC-MS (QToF) assay, 31 metabolites were discovered in negative ion modes and 37 metabolites were found in positive ion modes, but neither three selected active metabolites, Danshensu, Coptisine, or Dihydromyricetin, showed potentiating effects on GABA currents. 62 active metabolites of the seven botanical drugs were collected based on the TCMSP database and 19 of them were selected for patch-clamp verification according to the virtual docking simulations and other parameters. At a concentration of 100 µM, GABA-induced currents were increased by (+)-Cuparene (278.80% ± 19.13%), Ethyl glucoside (225.40% ± 21.77%), and ß-Caryophyllene (290.11% ± 17.71%). In addition, (+)-Cuparene, Ethyl glucoside, and ß-Caryophyllene could also serve as positive allosteric modulators (PAMs) and shifted the GABA dose-response curve (DRC) leftward significantly. In the PCPA-induced zebrafish model, Ethyl glucoside showed anti-insomnia effects at concentrations of 100 µM. In this research, we demonstrated that the activation of GABAARs was involved in the anti-insomnia effect of HWD, and Ethyl glucoside might be a key metabolite in treating insomnia.

Pharmacokinetics integrated with network pharmacology to clarify effective components and mechanism of Wendan decoction for the intervention of coronary heart disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Coronary heart disease (CHD), one of the leading causes of mortality in the world among chronic non-infectious diseases, is closely associated with atherosclerosis, which ultimately leads to myocardial injury. Wendan decoction (WDD), a classical famous formula, exerted an intervention effect on CHD according to numerous reports. However, the effective components and underlying mechanisms for the treatment of CHD have not been fully elucidated. AIM OF THE STUDY: An in-depth investigation of the effective components and mechanisms of WDD for the intervention of CHD was further explored. MATERIALS AND METHODS: Firstly, based on our previous metabolic profile results, a quantification method for absorbed components was established by ultra-performance liquid chromatography triple quadrupole-mass spectrometry (UPLC-TQ-MS) and applied to the pharmacokinetics study of WDD. Then the network pharmacology analysis for considerable exposure components in rat plasma was employed to screen key components of WDD. Gene ontology and KEGG pathway enrichment analysis were further performed to obtain putative action pathways. The effective components and mechanism of WDD were confirmed by in vitro experiments. RESULTS: A rapid and sensitive quantification method was successfully applied to the pharmacokinetic study of 16 high-exposure components of WDD at three different doses. A total of 235 putative CHD targets were obtained for these 16 components. Then, 44 core targets and 10 key components with high degree values were successively screened out by the investigation of protein-protein interaction and the network of "herbal medicine-key components-core targets". Enrichment analysis suggested that the PI3K-Akt signaling pathway was closely related to this formula's therapeutic mechanism. Furthermore, pharmacological experiments demonstrated that 5 of 10 key components (liquiritigenin, narigenin, hesperetin, 3,5,6,7,8,3',4'-heptamethoxyflavone, and isoliquiritigenin) significantly enhanced DOX-induced H9c2 cell viability. The cardioprotective effects of WDD against DOX-induced cell death through the PI3K-Akt signaling pathway were verified by western blot experiments. CONCLUSION: The integration of pharmacokinetics and network pharmacology approaches successfully clarified 5 effective components and therapeutic mechanism of WDD for the intervention of CHD.

Clinical efficacy and metabolomics study of Wendan Decoction in the treatment of phlegm-dampness obstructive sleep apnea-hypopnea syndrome with type 2 diabetes mellitus.

ETHNOPHARMACOLOGICAL RELEVANCE: Wendan Decoction (WDD) is one of the classic traditional Chinese prescriptions that has been used in the treatment of type 2 diabetes mellitus (T2DM), metabolic syndrome, obstructive sleep apnea-hypopnea syndrome (OSAHS) and so on. The therapeutic effects and mechanism of WDD remain to be explored, especially from the perspective of metabolomics, oxidative stress and inflammation. AIM OF THE STUDY: To investigate the therapeutic and metabolic regulatory effects and the underlying mechanism of WDD in OSAHS with T2DM patients. MATERIALS AND METHODS: All included patients were from Rudong Hospital of Traditional Chinese Medicine, Nantong, Jiangsu Province, China. Both groups received lifestyle interventions; at the same time, all of them were administered metformin (1500 mg/day) and dapagliflozin (10 mg/day), and the treatment group was administered WDD orally. All patients were treated for two months. Before and after treatment, the changes in clinical symptoms and signs of the two groups of patients were evaluated, and the detection indicators such as body mass index (BMI), apnea-hypopnea index (AHI), lowest arterial oxygen saturation (LSaO2), Epworth sleepiness scale (ESS), percentage of total sleep time with oxygen saturation <90% (TST90), fasting plasma glucose (FPG), 2-h post-load glucose(2h-PG), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR)，hemoglobin A1c (HbA1c), blood lipid levels, as well as the adverse reactions and compliance of the patients were observed and detection of serum metabolites in patients to screen out specific biomarkers. The serum metabolic profile of WDD in OSAHS with T2DM patients was explored using ultra-high-performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry (UPLC-Q Orbitrap HRMS). RESULTS: After treatment with WDD for 8 weeks, biochemical indicators, including BMI, FPG, 2h-PG, blood lipid, FINS, HbA1c, AHI, ESS, LSaO2, TST90, and HOMA-IR, were significantly improved. Serum metabolomic analysis showed that metabolites were differentially expressed before and after WDD-treated patients. Metabolomics results revealed that WDD regulated the biomarkers, such as DL-arginine, guaiacol sulfate, azelaic acid, phloroglucinol, uracil, L-tyrosine, cascarillin, Cortisol and L-alpha-lysophosphatidylcholine. Pathway enrichment analysis showed that the metabolites were associated with oxidative stress and inflammation. CONCLUSION: The study based on clinical research and metabolomics indicated that WDD can improve OSAHS with T2DM through multiple targets and pathways, and it may be a useful alternative therapy for the treatment of OSAHS with T2DM patients.

Wendan decoction in the treatment of nonalcoholic fatty liver disease: A systematic review and meta-analysis.

Introduction: The use of Wendan decoction (WDD) as a therapy for nonalcoholic fatty liver disease (NAFLD) has been studied in many clinical trials, and some of them showed that WDD is effective for treating this condition. However, no comprehensive research to evaluate the clinical efficacy of WDD in NAFLD patients had been performed. This systematic review and meta-analysis sought to provide an in-depth inquiry into the data currently available about the safety and effectiveness of WDD to treat NAFLD. Methods: We examined the primary database for any reports of randomized controlled trials (RCTs) including WDD and its effectiveness in treating NAFLD. We used the Jadad rating scale to determine the overall quality of the selected RCTs, and we searched the Cochrane Reviewer's Handbook for criteria for potential bias. The primary findings from the included RCTs were recorded, and the meta-analysis was performed using RevMan5.4 software developed by the Cochrane Collaboration. Results: We retrieved ten RCTs that were suitable for this evaluation and included them in a systematic review and meta-analysis. The quality and risk of bias in the included RCTs were assessed. The meta-analysis showed that the total clinical effective rate was substantially greater in the WDD cohort compared with that in the control cohort, and liver function, blood lipid indices, and blood glucose-related indicators were substantially improved in the WDD-treated cohort compared with those in the control cohort. There was no significant difference in the incidence of adverse events between the two cohorts. Conclusion: WDD is safe and effective for treating NAFLD, which is advantageous for the patients' liver function as well as their blood lipid indices and blood glucose-related indicators.

Network and Experimental Pharmacology to Decode the Action of Wendan Decoction Against Generalized Anxiety Disorder.

Objective: The mechanism of Wendan Decoction (WDD) against Generalized Anxiety Disorder (GAD) was predicted by network pharmacology and validated by in vivo and in vitro experiments. Methods: The targets of WDD for the treatment of GAD were obtained by a search of online databases. Further, PPI network and KEGG enrichment were used to identify the key targets and pathways. Ultimately, these key targets and pathways were validated by in vivo experiments on GAD mice modeled by repeated restraint stress (RRS) and in vitro experiments on inflammatory factor stimulated BV-2 cells. Results: Through searching the databases, the 137 ingredients of WDD that correspond to 938 targets and 4794 targets related to GAD were identified. Among them, 569 overlapping targets were considered as the therapeutic targets of WDD for GAD. PPI analysis showed that the inflammation-related proteins IL-6, TNF, SRC and AKT1 were the key targets, and KEGG enrichment suggested that PI3K/AKT and MAPK signaling pathways were key pathways of WDD in the treatment of GAD. In vivo experiments, RRS mice exhibited abnormality in behavioristics in open field test (OFT) and elevated plus maze (EPM) and increases in serum corticosterone and the percentage of lymphocytes positive for IL-6 in peripheral blood. These abnormal changes can be reversed by WDD and the positive control drug paroxetine. In vitro experiments, WDD can inhibit IL-6 induced activation of PI3K/AKT and MAPK signaling pathways in BV2 cells, and suppress the ensuing release of inflammatory factors TNF-α, IL-1ß and PGE2, and showed a dose-dependent effect. Conclusion: WDD is able to resist GAD by relieving inflammatory response in peripheral and central system.

Efficacy and Safety of Wendan Decoction for Acute Brain Injury: A Randomized Controlled Study.

Objectives: Despite the remarkable advances in critical care management of acute brain injury for the past 20 years, the prognoses remain poor. However, numerous reports indicate the efficacy of Traditional Chinese Medicine (TCM) therapy in stroke rehabilitation. This study aimed to determine the efficacy and safety of integrated TCM (Wendan decoction [WDD]) in patients with acute brain injury as a combination therapy in the early stages. Design: Prospective randomized controlled trial. Setting: Single-center study. Subjects: Sixty patients diagnosed with acute brain injury were randomly assigned to intervention and control groups, equally, and 41 patients completed the study. Interventions: All patients were treated by conventional neurologic intensive care. The 23 patients in the intervention group were administered with an integrated WDD in the early stages three times daily; combination treatment was initiated within 14 days and lasted >1 month. Outcome measures: Duration of ventilator use, intensive care unit stays, Glasgow Coma Scale (GCS) scores, motor response, the best muscle power, disability rating scale (DRS) scores, modified Rankin scale (mRS) scores, and the mortality rate for the first month. The other outcome measures were GCS scores, motor response, the best muscle power, DRS, mRS, and Barthel index (BI) scores 6 months later. Results: There was no mortality in the intervention group, but the rate was 39% in the control group for first month. Comparisons between groups showed significant differences (p < 0.05) in GCS, DRS, mRS, and BI scores, indicating improvements in the intervention group after 6 months. Conclusions: In the early stages of acute brain injury, combination treatment with WDD was found to be safe. Furthermore, this treatment may improve neurologic functional outcomes after 6 months.

Neuroprotective effect of Wendan Decoction on a mouse model of sleep disorders via IKKβ/NF-κB pathway / 中成药

AIM To investigate the effect of Wendan Decoction on nerve injury in a mouse model of sleep disorders and its mechanism.METHODS A mouse model of insomnia was established by the modified multiple platform sleep deprivation method.After successful modeling,the mice were randomly divided into the model group,the estazolam tablet group(0.15 mg/kg)and the low-dose and high-dose Wendan Decoction groups(12.5,50 g/kg),with 6 mice in each group,in contrast to the 6 mice of the control group.After 7 days of drug intervention,the mice had their changes of cerebral cortex,hippocampal CA1 area and hypothalamus observed by HE staining;their neuronal damage observed by Nissl staining;their levels of neurofilament light chain(NEFL),neuron-specific enolase(NSE),S100 calcium-binding protein B(S100B),tumor necrosis factor(TNF-α),interleukin-6(IL-6)and interleukin-1β(IL-1β)in brain tissue and serum detected by ELISA;their cerebral expression of glial fibrillary acidic protein(GFAP)detected by immunohistochemical method;and their cerebral expressions of GFAP,phosphorylated IκB kinase β(p-IKKβ)and phosphorylated nuclear transcription factor-κB(p-NF-κB)detected by Western blot.RESULTS Compared with the model group,the high-dose Wendan Decoction group displayed increased number of neurons,complete and neatly arranged structure;decreased number of neurons with nuclear shrinkage and deformation;increased Nissl bodies,decreased levels of NEFL,NSE,S100B,TNF-α,IL-6 and IL-1β in serum and brain tissue(P＜0.01);decreased cerebral expression of GFAP(P＜0.01);and decreased phosphorylation levels of cerebral p-IKKβ and p-NF-κB(P＜0.01).CONCLUSION Wendan Decoction can reduce the nerve damage and the expression of proinflammatory mediator in sleep disorders mice,and the mechanism may be related to the inhibited activation of IKKβ/NF-κB pathway.

Clinical Observation of Supplemented Wendan Decoction Combined with Western Medicine in Treatment of Insomnia Accompanied by Anxiety and Depression in Phlegm-heat Internal Disturbance Syndrome / 医药导报

Objective To explore the clinical effect of clinical observation of supplemented wendan decoction combined with Western medicine in treating insomnia accompanied by anxiety and depression in phlegm-heat internal disturbance syndrome.Methods A total of 120 cases of insomnia with anxiety and depression comorbiditis with phlegm heat disturbance syndrome were randomly divided into control group and treatment group,60 cases in each group.The control group was given escitalopram oxalate tablet combined with dexzopiclonone tablet,and the observation group was given added Wendan decoction on the basis of the control group.Both groups were treated continuously for 6 weeks.Polysomnography monitoring parameters and heart rate variability were compared between the two groups during baseline period and visit 2(baseline period+3 months).Scale scores of the two groups were compared during baseline period,visit 1(baseline period+6 weeks)and visit 2.The content of heart rate variability includes:time domain analysis(standard deviation of normal interval(SDNN),square root of the square sum of the mean of the difference between adjacent normal interval(RMSSD)and frequency domain analysis(LF,HF,LF/HF).The scale scores included the Pittsburgh Sleep Quality Index(PSQI)and Insomnia Severity Index(ISI)to assess sleep status,and the Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Self-assessment Scale for Depression(PHQ-9)and Generalized Anxiety Disorder Scale(GAD-7)to assess anxiety and depression status.Results(1)Polysomnography monitoring:the wake time of observation group was significantly shorter than that of control group,the number of awakenings was significantly less than that of control group,and the percentage of N3 and REM was significantly higher than these of control group(P＜0.05).(2)Heart rate variability:RMSSD and HF values in the observation group were significantly higher than those in the control group,and LF/HF values were significantly lower than those in the control group(P＜0.05).(3)In terms of sleep:during the interview,PSQI total score,sleep quality,hypnotic drugs and daytime dysfunction in the observation group were significantly lower than those in the control group(P＜0.05);At the 3 months,the sleep quality,hypnotic drugs and daytime dysfunction in the observation group were significantly lower than those in the control group(P＜0.05).In terms of emotion:HAMA,HAMD and GAD-7 scores were significantly lower than those of control group at 6 weeks(P＜0.05);At the 3 months,HAMA and GAD-7 scores were significantly lower than those of control group(P＜0.05).Conclusion Supplemented Wendan decoction combined with western medicine can obviously optimize the sleep structure of insomnia patients with anxiety and depressionof phlegm-heat disturbance syndrome,improve sleep continuity and deepen sleep depth,and improve parasympathetic functional activities,contribute to sympathetic parasympathetic balance,can improve insomniaand depression symptoms recently,and significantly improve anxiety symptoms in the short term,with good safety.

Exploration of Potential Targets and Experimental Verification of Wendan Decoction in Treating Insomnia Based on Network Pharmacology / 世界科学技术-中医药现代化

Objective A network-based pharmacological analysis approach to explore and validate the potential targets of Wendan decoction for the treatment of insomnia.Methods Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform was used to screen active components and corresponding targets of Wendan Decoction.Take the protein corresponding to the target intersection.protein-protein-interaction-network analysis of the interaction between target proteins.Through Database for Annotation,Visualization and Integrated Discovery database.Gene ontology and Kyoto Encyclopedia of Genes and Gnomes(KEGG)were used to analyze the biological process,cellular component,molecular function,and pathway enrichment of Wendan Decoction.The insomnia-related targets were searched through Human gene database,and the common targets of Wendan Decoction and insomnia were obtained.Building a common targets protein-protein interaction network.Cytoscape(visualization software)analyzes the core genes of the common targets,performs biological function and pathway enrichment analysis of the common targets,integrates the biological functions and signal transduction involved in the core genes,and identifies the core targets of Wendan Decoction treatment insomnia.Validation of core target mRNA expression in vivo.Results 97 active components of Wendan Decoction were screened,and 266 targets were identified.There were 2587 insomnia-related targets and 119 targets in total.The core genes in the common targets were AKT1(AKT Serine/Threonine Kinase 1),TNF(Tumor Necrosis Factor),IL-6(Interleukin 6),TP53(Tumor Protein P53),VEGFA(Vascular Endothelial Growth Factor A),CASP3(Caspase 3),MMP9(Matrix metallopeptidase 9),and MAPK3(Mitogen-Activated Protein Kinase 3).PI3K-AKT signaling pathway,apoptosis and p53 signaling pathway play important roles in the treatment of insomnia with Wendan decoction.Compared with the control group,the expression levels of AKT1 and MAPK3 in the brain tissue of the model group were significantly decreased(P<0.05),and the expression levels of TP53,VEGFA,Caspase-3 and TNF were significantly increased(P<0.05).Compared with the model group,the expression levels of AKT1 and MAPK3 in the brain tissue of mice in the high-dose group increased,and the expression levels of P53,VEGFA,Caspase-3 and TNF decreased.Conclusion The potential targets of Wendan decoction in treating insomnia are related to cell proliferation and apoptosis regulated by AKT1,MAPK3,TP53,VEGFA,Caspase-3 and TNF.