BackgroundXiaoyao pills (XYP) is a commercial Chinese patent medicine used in the treatment of depression. However, the mechanisms underlying its therapeutic effects, as well as the patients who can benefit from XYP, have not been evaluated so far.ObjectivesTo this end, we conducted a double-blinded, random, and placebo-controlled clinical trial of orally administered XYP in patients with depression.MethodsThe 17-item Hamilton Depression Rating Scale (HAMD-17) scores were recorded at baseline, and every 2 weeks after the start of treatment. To further elucidate the epigenetic mechanism of XYP, we performed mRNA sequencing and genome-wide DNA methylation sequencing using peripheral blood leukocytes of patients and healthy.ResultsXYP effectively alleviated the symptoms in patients with mild or moderate depressive disorders, particularly that of psychomotor retardation. XYP restored aberrant gene expression and DNA methylation patterns associated with depression, and the normalization of DNA methylation correlated with downregulation of several genes. In addition, altered DNA methylation levels in the XYP-treated samples were attributed to increased expression of the DNA methyltransferase DNMT1.ConclusionsOur study provides new insights into the epigenetic mechanism underlying depression and the therapeutic effects of XYP, along with an experimental basis for using XYP in the treatment of depression.Trial Registration InformationThe name of the registry and number: U.S. Clinical Trials Registry. The link to the registration: ClinicalTrials.gov ISRCTN12746343 (https://www.isrctn.com/ISRCTN12746343). The name of the trial register is “Efficacy and safety of the Xiaoyao pill for improving the clinical symptoms of stagnation of liver qi (chi) and spleen deficiency”. The clinical trial registration number is ISRCTN12746343.

BackgroundXiaoyaosan has been used to treat mental disorders in China for thousands of years. Xiaoyaosan may also provide a potential therapeutic advantage in the treatment of premenstrual dysphoric disorder (PMDD) with few adverse events, but its mechanism of action remains unclear.Aim of this studyThe present study explored the clinical efficacy of the Xiaoyaosan in the treatment of patients with PMDD. Additionally, the metabolomic features and small-molecule marker compounds related to PMDD pathogenesis were investigated.MethodsThirty patients with PMDD were recruited as the treatment group, and sixteen healthy individuals were recruited as the control group. The treatment group was treated with Xiaoyaosan for three menstrual cycles. The Daily Record of Severity of Problems and the PMDD symptom score scale of traditional Chinese medicine were used to evaluate the clinical efficacy of Xiaoyaosan. The urine of all patients was collected for metabolomics analysis using ultra-liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF MS).ResultsTreating PMDD using Xiaoyaosan had significant clinical efficacy compared to the control group. Compared to the control group, urine UPLC-Q-TOF MS test results showed that 39 endogenous differential metabolites were detected in patients with PMDD, which were mainly enriched in ABC transporter proteins, amino acid and nucleotide sugar metabolism, galactose metabolism, fructose and mannose metabolism, arginine and proline metabolism, and the C-type lectin receptor signalling pathway. Compared with the pre-treatment period, 14 endogenous differential metabolites were detected after Xiaoyaosan treatment, which were primarily enriched in riboflavin metabolism, the AMPK signalling pathway, and the caffeine metabolism pathway.ConclusionXiaoyaosan has a curative effect on PMDD. The therapeutic mechanism of Xiaoyaosan may be related to regulating energy metabolism in the nervous system.

Background: Xiaoer Chaige Tuire Oral Liquid (XCT) is a compound preparation composed of 7 traditional Chinese medicines including Bupleuri Radix, Puerariae Lobatae Radix, Scutellariae Radix, Gypsum Fibrosum, Artemisiae Annuae Herba, Paeoniae Radix Alba and Zhigancao in proportion. It is mainly aimed at treating upper respiratory tract infection in children caused by exogenous wind-heat. Modern pharmacological studies have indicated that XCT has a variety of activities such as antibacterial, anti-inflammatory, antiviral and immune regulation.Purpose: To analyze the oral administration metabolism process of XCT by means of sequential metabolism in vitro and verification experiment in vivo, and to screen potential quality control components of XCT.Methods: The main components of prepared XCT were analyzed by high performance liquid chromatography with diode-array detection (HPLC-DAD). The employed models in vitro of XCT sequential metabolism were artificial gastric fluid, artificial intestinal fluid, intestinal bacteria, Caco-2 cells and liver S9 in order. The quantitative analysis of sequential metabolism samples were also analyzed by HPLC-DAD. Ultra performance liquid chromatography QExactive Orbitrap tandem mass spectrometry (LC-QExactive-HF-x-Orbitrap-MS) was used to determine the components in medicated plasma and metabolites in liver S9 of rats after applying XCT orally.Results: A total of 25 components were identified from XCT, of which 19 with high content. Sequential metabolism studies in vitro indicated that baicalin, baicalein, genistin and saikosaponin A were digested in artificial gastric fluid. Albiflorin, glycyrrhizic acid, gallic acid and baicalein were unstable in artificial intestinal fluid. Daidzin, liquiritin and genistin were severally hydrolyzed into daidzein, liquiritigenin and genistein by intestinal bacteria. In addition, there were 7 well absorbed components were detected in the samples of Caco-2 cell model. After incubated by liver S9 system, 7 metabolites which were mainly the products of hydroxylation and glycosylation were identified. A total of 10 components were determined in the drug-containing plasma of rats, among which daidzein, puerarin and benzoic acid were the common components both in absorption model samples and the plasma samples.Conclusions: A sequential metabolism methodology of XCT in vitro and in vivo was established. Puerarin, daidzein, benzoic acid, baicalin, baicalein, wogonin, wogonoside, oroxylin A, 3′-methoxypuerarin, paeoniflorin, scopoletin and liquiritigenin were screened to be potential quality control components of XCT, which provides a material basis for quality control standard and redevelopment of XCT.

Bipolar disorder (BD) is a psychiatric disorder that affects an increasing number of people worldwide. The mechanisms of BD are unclear, but some studies have suggested that it may be related to genetic factors with high heritability. Moreover, research has shown that chronic stress can contribute to the development of major illnesses. In this paper, we used bioinformatics methods to analyze the possible mechanisms of chronic stress affecting BD through various aspects. We obtained gene expression data from postmortem brains of BD patients and healthy controls in datasets GSE12649 and GSE53987, and we identified 11 chronic stress-related genes (CSRGs) that were differentially expressed in BD. Then, we screened five biomarkers (IGFBP6, ALOX5AP, MAOA, AIF1 and TRPM3) using machine learning models. We further validated the expression and diagnostic value of the biomarkers in other datasets (GSE5388 and GSE78936) and performed functional enrichment analysis, regulatory network analysis and drug prediction based on the biomarkers. Our bioinformatics analysis revealed that chronic stress can affect the occurrence and development of BD through many aspects, including monoamine oxidase production and decomposition, neuroinflammation, ion permeability, pain perception and others. In this paper, we confirm the importance of studying the genetic influences of chronic stress on BD and other psychiatric disorders and suggested that biomarkers related to chronic stress may be potential diagnostic tools and therapeutic targets for BD.

目的:探讨逍遥散对慢性束缚应激抑郁大鼠海马神经再生的影响.方法:60只大鼠随机分为正常组、模型组、逍遥散组、氟西汀组,每组15只.21 d慢性束缚应激方法造抑郁模型,旷场实验、糖水消耗实验进行模型评价,免疫荧光双标法检测观察各组大鼠海马神经再生的情况.结果:模型组大鼠旷场实验活动能力、糖水消耗率、BrdU/DCX、BrdU/NeuN双标阳性细胞数目显著低于正常组(P＜0.05,P＜0.01);逍遥散组、氟西汀组大鼠旷场实验活动能力、糖水消耗率、BrdU/DCX、BrdU/NeuN双标阳性细胞数目显著高于模型组(P＜0.05,P＜0.01).结论:逍遥散能够改善慢性束缚应激抑郁大鼠的抑郁状态,其机制可能与增强海马神经再生密切相关.

Background Many studies about depression have focused on the dysfunctional synaptic signaling in the hippocampus that drives the pathophysiology of depression. Radix Bupleuri has been used in China for over 2000 years to regulate liver-qi. Extracted from Radix Bupleuri, Saikosaponin D (SSD) is a pharmacologically active substance that has antidepressant effects. However, its underlying mechanism remains unknown. Materials and methods A chronic unpredictable mild stress (CUMS) paradigm was used as a rat model of depression. SD rats were randomly assigned to a normal control (NC) group or one exposed to a CUMS paradigm. Of the latter group, rats were assigned to four subgroups: no treatment (CUMS), fluoxetine-treated (FLU), high-dose and low-dose SSD-treated (SSDH and SSDL). SSD was orally administrated of 1.50 mg/kg and 0.75 mg/kg/days for three weeks in the SSDH and SSDL groups, respectively. Fluoxetine was administrated at a dose of 2.0 mg/kg/days. SSD's antidepressant effects were assessed using the open field test, forced swim test, and sucrose preference test. Glutamate levels were quantified by ELISA. Western blot and immunochemical analyses were conducted to quantify proteins in the Homer protein homolog 1 (Homer1)-metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) pathways in the hippocampal CA1 region. To measure related gene expression, RT-qPCR was employed. Results CUMS-exposed rats treated with SSD exhibited increases in food intake, body weight, and improvements in the time spent in the central are and total distance traveled in the OFT, and less pronounced pleasure-deprivation behaviors. SSD also decreased glutamate levels in CA1. In CA1 region of CUMS-exposed rats, SSD treatment increased mGluR5 expression while decreasing Homer1 expression. SSD also increased expressions of postsynaptic density protein 95 (PSD95) and synapsin I (SYP), and the ratios of p-mTOR/mTOR, p-p70S6k/p70S6k, and p-4E-BP1/4E-BP1 in the CA1 region in CUMS-exposed rats. Conclusions SSD treatment reduces glutamate levels in the CA1 region and promotes the expression of the synaptic proteins PSD-95 and SYP via the regulation of the Homer1-mGluR5 and downstream mTOR signaling pathways. These findings suggest that SSD could act as a natural neuroprotective agent in the prevention of depression.

•Xiaoyaosan effectively regulates metabolic disorders in patients with mild to moderate depression.•Xiaoyaosan demonstrates the ability to regulate metabolic disorders in depressed rats.•The administration of Xiaoyaosan results in the up-regulation of XDH and GRIA2 expression in CUMS rats.

中医要自强,教育需先行.中医药既在抗击新型冠状病毒肺炎(简称"新冠肺炎")疫情的过程中发挥了重要作用,同时也暴露出诸多亟需解决的问题.中医药教育如何应对新冠肺炎疫情引发医学教育的新形势、新要求是中医药教育工作者应当思考的问题.文章立足于新冠肺炎疫情背景,反思和总结中医药教育当前存在的问题,有针对性地从教育模式、师资培养、学科建设、中医药管理及评价体制等方面提出改革的对策和建议,并对中医药教育发展前景进行了预测,以期为我国中医药教育事业改革和发展提供参考.

肝气郁结与抑郁症的关系已得到历代中医的认可,但单纯疏肝解郁治疗并不能完全改善抑郁症患者的不适症状.临床中发现部分抑郁症患者的症状具有秋、冬季加重,春、夏季减轻的规律,综合其主要临床表现,呈现出阳气虚弱的病症特点,这为进一步探讨抑郁症的病因、病机提供了新的线索.现基于重阳理论,在分析肝郁与抑郁症发病关系的基础上,揭示阳虚在抑郁症发病中扮演的角色,探讨光照疗法治疗抑郁症,强调阳气在抑郁症发病与治疗中的作用.

玄府理论是起源于《黄帝内经》的中医原创理论。文章首先对《黄帝内经》中的“玄府”及其近似概念的意义进行辨析；然后分析玄府的生理功能及生理特性，主要有“排出汗液，为泄热之门户”“阳气主外，司玄府之开闭”“卫外为固，开泄则易感邪气”“内合三焦，协助水液运输”等方面；最后基于《黄帝内经》原著探讨玄府的临床应用，认为《黄帝内经》中的开玄府法主要有开玄府以消水肿、退身热、通水道、发疮疡等临床应用。

Background Depression is one of the most frequent and severe psychiatric conditions. Many chemical drugs to treat depression are associated with adverse reactions and have shortcomings. Traditional Chinese medicine is of great significance in the prevention and treatment of depression. Xiaoyao pills has achieved good results in clinical application, which has the advantages of quick effect and no obvious adverse reactions. The aim of our study is to evaluate the efficacy and safety of Xiaoyao pills on mild to moderate depression patients. Methods This study is a multi-centre, double-blinded, randomized and placebo-controlled clinical trial. A total of 108 participants are assigned to three groups: Xiaoyao pill group taking Xiaoyao pills twice daily for 4 weeks, placebo group taking placebos twice daily for 4 weeks and normal group without taking any drug. The primary and secondary outcome measures are the Hamilton Depression Scale (HAMD) and Traditional Chinese Medicine (TCM) Syndrome Scale. The assessment is at baseline (before treatment initiation), 1 week, 2 weeks 4 weeks after the first treatment. Exploratory outcome is also assessed to explore the mechanism of Xiaoyao pills at baseline and 4 weeks. Discussion The results from this study will provide clinical evidence on the efficacy and safety of Xiaoyao pills in patients with mild to moderate depression with syndrome of liver stagnation and spleen deficiency. Trial registration ClinicalTrials.gov ISRCTN12746343. Registered on September 25, 2020.

玄府理论是起源于《黄帝内经》的中医原创理论.文章首先对《黄帝内经》中的"玄府"及其近似概念的意义进行辨析;然后分析玄府的生理功能及生理特性,主要有"排出汗液,为泄热之门户""阳气主外,司玄府之开闭""卫外为固,开泄则易感邪气""内合三焦,协助水液运输"等方面;最后基于《黄帝内经》原著探讨玄府的临床应用,认为《黄帝内经》中的开玄府法主要有开玄府以消水肿、退身热、通水道、发疮疡等临床应用.

抑郁症低动力症状是指抑郁症患者表现出劳累感增加、活动减少、稍事活动即感明显倦怠等症状.肝与抑郁症的关系已得到历代中医的认可,但单纯疏肝解郁并不能完全改善抑郁症低动力患者的不适症状.脾作为后天之本,脾主运化、脾胃为气机升降之枢纽、脾藏意,为后天活动提供物质基础,调理脾胃在抑郁症低动力症状的治疗中发挥着重要作用.从肝郁是抑郁症发病的关键病机、脾病是低动力症状发病的基础对抑郁症低动力症状的病机进行分析.从健脾则助肝升、醒脾则助肝疏探讨从脾治疗抑郁症低动力.辨治抑郁症低动力症状,应在疏肝理气的基础上,联合应用健脾法、醒脾法等.

The mechanism of berberine hydrochloride (BBH) inhibiting the biofilm formation of Hafnia alvei was investigated in this study. The antibiofilm potential of BBH was evaluated by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) as well as crystal violet staining. The quorum-sensing (QS) inhibition was revealed by determination of QS-related genes expression and related signal molecules production using real-time quantitative PCR (RT-qPCR) and high performance liquid chromatography (HPLC). The binding of BBH to receptor proteins was simulated by molecular docking and molecular dynamics simulations. It was found that BBH at sub-minimum inhibitory concentrations (sub-MICs) significantly reduced the biofilm formation of H. alvei in a dose dependent manner. BBH inhibited the bacterial swimming motility, decreased the transcription of halI and halR genes, and reduced the production of signal molecule C14-HSL. It bound to HalR protein mainly through Van der Waals force and electrostatic interaction force. Based on these results, it was concluded that BBH inhibits the biofilm formation of H. alvei and the mechanism is related to its interference with QS through down-regulating the expression of halI and halR genes.

目的 基于Notch信号通路探讨柴胡皂苷a对肝郁脾虚型抑郁症大鼠模型的影响变化及内在的神经保护调节机制.方法 建立肝郁脾虚型大鼠抑郁模型,利用HE染色观察海马组织形态学变化,运用Western Blotting和RT-PCR法检测Notch信号通路上大鼠海马Notch1、Jagged1、Hes1的蛋白及基因表达情况.结果 HE染色提示模型组大鼠海马区发生不同程度的神经细胞稀疏、排列松散等病理变化.Western Blotting与RT-PCR提示模型组大鼠Notch信号通路上基因及蛋白表达明显下降(P＜0.01),柴胡皂苷a对上述结果变化可表现出一定的逆转作用(P＜0.01).结论 柴胡皂苷a干预治疗后可以改善肝郁脾虚型抑郁症状,其内在机制可能是通过调节Notch信号通路发挥海马神经细胞的保护作用来实现.

Background: Paeoniflorin (PF) represents the major bioactive constituent of the traditional Chinese medicine plant Paeonia suffruticosa (Ranunculaceae), which has a long history as a folk medicine in Asian. Paeoniflorin, a bitter pinene monoterpene glycoside, has antidepressant effects, but its potential therapeutic mechanism has not been thoroughly explored.Methods: Experimental depression in rats was established by the chronic unpredictable mild stress (CUMS) combined with orphan method, and the efficacy of paeoniflorin on depression was evaluated by the sucrose preference test and open field test. The antidepressant mechanism of paeoniflorin was investigated by metabolomic and network pharmacology. The relevant pathways of biomarkers highlighted in metabolomics were explored, and the possible targets of paeoniflorin in the treatment of depression were further revealed through network analysis. The binding activity of paeoniflorin to key targets was verified by molecular docking.Results: Metabolomics showed that rats with CUMS-induced depression had urine metabolic disorders, which were reversed by paeoniflorin through the regulation of metabolic pathways. Metabolites that play a key role in the function of paeoniflorin include citric acid, thiamine monophosphate, gluconolactone, 5-hydroxyindoleacetic acid and stachyose. Key predicted targets are SLC6A4, TNF, IL6 and SLC6A3. An important metabolic pathway is the Citrate cycle (TCA cycle).Conclusion: Network integrative analysis in this study showed that paeoniflorin could improve depressive-like symptoms in model rats with CUMS-induced depression and overall correct the disordered metabolic profile through multiple metabolic pathways.

抑郁症作为一种最常见的心理疾病,具有一定的社会功能损害性.中医认为抑郁症多因肝郁气滞、脏腑失和所致."少阳为枢"强调少阳在气的运动中起到至关重要的调控作用,而胆属少阳,其对于抑郁症发病的重要性常被忽略.笔者通过搜集整理相关文献,发现"少阳为枢"功能异常造成气机失和会导致一系列抑郁表现.本文将从少阳为枢的涵义、少阳为枢与抑郁症的联系出发,科学阐释从胆治疗抑郁症的理论依据,以期对抑郁症的诊疗有所裨益.

基于"六异识候"症状标准化理论体系,明确了中医症状标准化的3个阶段任务和基于人工智能的技术路径.第1阶段任务是明确症状类型;第2阶段任务是明确不同症状类型描述公式中的具体内容;第3阶段任务是构建标准化症状数据库以及各类标准化症状描述公式数据库.这3个阶段任务均可以采用人工智能技术自动完成,技术路径是:文本分类-文本理解-知识提取.本课题组提出了一个基于LFText与TextCNN的自动文本分类模型来自动化症状分类(第1阶段任务),模型整体效果评价指标:分类别平均准确率(MAP)、宏平均F1值(Macro F1)、宏平均准确率(Macro Accuracy)分别是0.8107、0.8117、0.8290,证明了本课题组提出的中医症状标准化路径的有效性,并为后续两阶段的标准化任务奠定了数据与技术基础.