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Background Fire needle therapy is a characteristic treatment in traditional Chinese medicine (TCM). An increasing number of studies have indicated that fire needle treatment for psoriasis provides satisfactory results with few side effects and a low recurrence rate. We herein describe the protocol for a multicenter, randomized, single-blind, placebo-controlled trial that will provide high-quality evidence on the efficacy and safety of fire needle therapy for plaque psoriasis. Methods Ninety-two patients with blood stasis syndrome (BSS) of plaque psoriasis will be enrolled and randomly assigned to receive fire needle therapy (intervention group) or fire needle control therapy (control group) once a week for 4 weeks. The Psoriasis Area and Severity Index (PASI) score will serve as the major efficacy index, while the body surface area (BSA), Physician Global Assessment (PGA) score, Dermatology Life Quality Index (DLQI) score, patient-reported quality of life (PRQoL), visual analog scale (VAS) score for itching, TCM symptom score, and relapse rate will be assessed as secondary outcomes. The PASI score, BSA, PGA score, and VAS score for itching will be evaluated at baseline and during the 4-week treatment and follow-up periods. DLQI score, PRQoL, and TCM symptom score will be assessed at baseline and during the treatment period. Recurrence will be evaluated during the follow-up period. Safety assessments include vital sign monitoring, routine blood tests, blood biochemistry, routine urine tests, pregnancy tests, physical examinations, and adverse-event recording. SAS software will be used for data analysis. The data network platform will be designed by the data management center of Nanjing Ningqi Medical Technology Co., Ltd. Discussion It is believed that fire needle therapy can activate the meridians, promote blood circulation, and regulate skin immunity. BSS of plaque psoriasis is related to not only immune dysfunction but also poor or stagnant blood flow. We anticipate that the results of the trial described in this protocol will provide strong evidence for the safety and efficacy of fire needle therapy for BSS of plaque psoriasis. Trial registration Clinicaltrials.govNCT03953885. Registered on May 15, 2019. Name: Fire Needle Therapy on Plaque Psoriasis with Blood Stasis Syndrome

Objectives: The aim of this study was to establish a quantitative syndrome differentiation model with logistic regression analysis for phlegm and blood stasis syndrome (PBSS) in coronary heart disease (CHD) to offer methodology guidance for the quantitative syndrome differentiation of Traditional Chinese Medicine (TCM). Design: Tongue, face, and pulse information of each subject was obtained using the TCM-intelligent diagnosis instruments. Logistic regression model was used to construct the syndrome diagnosis model. The area under receiver operating characteristic curve (ROC-AUC) was used to evaluate the diagnostic value of the model. Subjects: Among the 141 subjects, 83 belonged to the PBSS group, and 58 belonged to the non-PBSS group. Results: The independent indexes used to predict PBSS in patients with CHD were length of the crack (LC) (p = 0.002), number of ecchymosis (NE) (p

Background Coronary heart disease (CHD) has become one of the biggest health problems in the world. Stable angina is a common clinical type of CHD with poor prognosis and high mortality. Although there are various interventions for stable angina, none of them can significantly reduce mortality. Both basic and clinical research have shown that Suxiao Jiuxin Pill (SJP) can relieve the symptoms of angina pectoris and improve the clinical efficacy, but there is a lack of high-quality clinical research to provide research-based evidence. We design a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of SJP for stable angina. Methods/design This is a prospective, randomized, double-blind, placebo-controlled, and multicenter trial. The trial will enroll 324 participants with chronic stable angina (Qi Stagnation and Blood Stasis syndrome). All participants will have received the conventional therapy of chronic stable angina. Participants will be randomized into two groups, conventional therapy plus SJP group and conventional therapy plus placebo group. Eligible participants will receive either SJP or placebo (five pills administered orally, three times daily) in addition to conventional treatment for 24 weeks. The primary outcomes are the symptom improvement rate of angina from baseline to 4 weeks after inclusion and major adverse cardiovascular events (MACE). The secondary outcomes are angina classification (CCS), improvement of traditional Chinese medicine (TCM) syndromes, Seattle Angina Scale score, the dosage of emergency drugs and the stopping rate, and electrocardiogram (EKG) efficacy. Adverse events will be monitored throughout the trial. Discussion Integrated traditional Chinese and Western Medicine is commonly used for angina in China. This study will evaluate the clinical effectiveness and safety of SJP for angina. The results of the trial will provide high-level clinical research-based evidence for the application of SJP instable angina. Trial registration This study protocol was registered on 14 March 2019. The registration number is ChiCTR1900021876 on the Chinese Clinical Trial Registry.

Supplemental Digital Content is available in the text, Introduction: Unstable angina pectoris is an acute exacerbation secondary to coronary artery occlusion. In routine clinical treatment, patients with unstable angina pectoris are prone to recurrence or aggravation of symptoms. Based on the traditional Chinese medicine (TCM) theory, phlegm, and blood stasis are one of the main pathological factors of unstable angina pectoris. The treatment of unstable angina pectoris with phlegm-blood stasis syndrome by Gualou Danshen granules (GLDS) has been the focus of many clinical trials. However, there is no evidence to prove the safety or clinical efficacy of GLDS. Methods and analysis: In this study, we will conduct a 4-week randomized, controlled feasibility study, with participants recruited from Guang’anmen Hospital, Chinese Academy of Traditional Chinese Medicine. Sixty subjects are to be diagnosed as having phlegm-blood stasis syndrome and randomly divided into a treatment group (GLDS) and placebo group in a 1:1 ratio. Result measurements will include therapeutic indicators (Clinical Symptom Rating Scale, Phlegm-Blood Stasis Syndrome Scale, and Seattle Angina Questionnaire) and safety indicators (blood routine, urine routine, electrocardiogram, liver function, and kidney function). The clinical data management system (http://www.tcmcec.net/) will be used to collect and manage data. Quality control will be implemented according to good clinical practice. Discussion: Previous TCM clinical trials have investigated if adding GLDS to standard routine treatment can improve the therapeutic effect in patients with unstable angina pectoris. This study focuses on the safety and efficacy of GLDS on unstable angina pectoris of phlegm-blood stasis type, in order to obtain relevant clinical evidence. Trial registration: This study is approved by the Ethics Committee of Guang’anmen Hospital of the China Academy of Chinese Medical Sciences (no. 2019–187-KY-02) and is registered with chictr.org (registration number ChiCTR2000031780).

Psoriasis is a chronic, refractory, systemic inflammatory skin disease. Traditional Chinese medicine (TCM) shows unique advantage in the treatment of psoriasis based on syndrome differentiation. An untargeted high-throughput metabonomics method based on liquid chromatography coupled to mass spectrometry was applied to study the serum metabolic characteristics in different TCM syndrome types in patients with psoriasis vulgaris (PV), and to discover potential serum biomarkers for its pathogenesis on the endogenous metabolite differentiation basis. The serum metabolic profiles of 45 healthy controls and 124 patients with PV (50 in the blood-stasis group, 30 in the blood-heat group, and 44 in the blood-dryness group) were acquired. The raw spectrometric data were processed using multivariate statistical analysis, and 14 biomarkers related to TCM syndrome differentiation and psoriasis types were screened and identified. The blood-stasis syndrome group showed abnormal lipid metabolism, which was characterized by a low level of phosphatidylcholine (PC) and a high level of lysophosphatidylcholine (LPC). We propose that platelet-activating factor can be applied as a potential biomarker in clinical diagnosis and differentiation of PV with blood-stasis syndrome. The difference in the serum metabolites among PV types with different TCM syndromes and healthy control group illustrated the objective material basis in TCM syndrome differentiation and classification of psoriasis.

The drug preparations from dried flower of Carthamus tinctorius L. (CTL) are widely used as an adjuvant medication in cardiovascular diseases in China. In this research, Safflower yellow extract (SYE), a CTL drug in market, was studied through components analysis and two animal experiments with different dosages to assess its pharmacodynamic effects. The whole constituents of SYE were characterized through ultra-fast liquid chromatography–diode array detector–quadrupole time-of-flight tandem mass spectrometry. Cerebral arteriole thrombus was induced in C57BL/6J mouse by laser irradiation in vivo using two-photon laser-scanning microscopy. The time of thrombus formation and vessel diameter were calculated to evaluate the antithrombotic effect. In the model of blood stasis syndrome, rats were injected with adrenaline injection before and after ice-bath to induce hemorheology disorders. The results identified 29 constituents in SYE and hydroxysafflor yellow A was the main component (19.8%). In the mouse model, SYE inhibited thrombus formation in a dose-dependent manner and postponed the occlusion time in brain arteriole at dosages of 26.0 and 52.0 mg/kg. In the rat model of blood stasis syndrome, SYE significantly decreased the whole blood viscosity, suppressed red blood cell aggregation and platelet aggregation in high-dose (p < 0.01). The activated partial thromboplast in time was prolonged at a dosage of 7.0 mg/kg (p < 0.05) as well. In conclusion, SYE administration could inhibit the thrombus formation and beneficially influence the blood rheologyin blood stasis syndromes at relevant low dosages.

Background Post-stroke depression (PSD) is the most common psychiatric complication after a stroke. The most frequently used antidepressants are selective serotonin receptor inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), however, these exhibit a series of side effects. Traditional Chinese medicine has been used to treat PSD with few side effects. The aim of this study is to evaluate the efficacy and safety of Jiedu Tongluo granules for treating PSD with qi deficiency and blood stasis syndrome. Methods The planned study is a double-blind, randomized, placebo-controlled pilot trial. Eighty participants will be randomly assigned to receive either treatment or placebo. The treatment group will receive Jiedu Tongluo granules (JDTLG) with conventional treatment, and the placebo group will receive placebo with conventional treatment for 8 weeks. The primary outcome is the effectiveness of JDTLG on depression after 8 weeks treatment, which is defined as a decrease of 50% or more in 17-item Hamilton Depression Scale (HAMD-17) score or clinical recovery (score

Ischemic stroke (IS) is characterized by high morbidity and high mortality. The integration of Traditional Chinese medicine (TCM) and western medicine has shown promising benefits in relieving symptoms, promoting neurological recovery, and improving the quality of life of patients with IS. In TCM, Qi-deficiency along with blood-stasis (QDBS) syndrome is one of the common types of IS that is treated by invigorating Qi and activating blood circulation. In TCM theory, improving the corresponding degree of prescription–syndrome correlation (PSC) is helpful to improve clinical efficacy. In this study, we intend to use similar prescriptions that invigorate Qi and activate blood circulation: Buyang Huanwu granules (BHG), Naoxintong capsules (NXTC), and Yangyin Tongnao granules (YTG). The goal is to evaluate their level of PSC inpatients with IS with QDBS syndrome and find relevant biomarkers to provide an objective basis for precise treatment of TCM and improve the clinical therapeutic effects. A multicenter, randomized, double-blinded, and placebo-controlled intervention trial will be conducted in IS patients with QDBS syndrome, followed by an add-on of Chinese patent medicine. A total of 160 subjects will be randomly assigned to the BHG, NXTC, YTG, and placebo groups in a 1:2:1:1 allocation ratio. All subjects will undergo 28 days of treatment and then followed for another 180 days. The primary outcome is the changes in the National Institutes of Health Stroke Scale score after 28 days of medication. The secondary outcomes include the modified Rankin scale score, activity of daily living scale score, and TCM symptom score. Data will be analyzed in accordance with a predefined statistical analysis plan. Ethical approval of this trial has been granted by the Research Ethics Committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (ID: 2017-Y-004-02). Written informed consent of patients will be required. This trial is registered in the Chinese Clinical Trial Registry (ChiCTR1800015189), and the results will be disseminated to the public through peer-reviewed journals and academic conferences.

Background Blood stasis syndrome (BSS) is considered as the cause of several chronic disease including metabolic diseases in traditional East Asian medicine. In this study, we investigated the levels of serum resistin and other proteins related to metabolic syndrome (MS) and several other diseases categories to identify the association with BSS. Methods This was a cross-sectional, multicenter study of patients recruited from seven traditional Korean Medicine (TKM) hospitals. To identify whether there was an association with BSS in specific disease conditions, including MS, serum protein levels were evaluated using the multiplex method. Results A total of 885 patients (419 patients with BSS, 376 patients without BSS, and 90 healthy controls) participated in the study, and 139 patients had MS. The resistin and insulin levels were significantly higher in patients with BSS than in patients without BSS and normal subjects (P = 0.002 and P = 0.046, respectively). Patients with BSS who had MS exhibited significantly higher resistin levels than those in patients without BSS and normal subjects (P = 0.049). In addition, the levels of serum resistin were significantly correlated with symptoms of the BSS, especially dark red gums, dark facial complexion, and nocturnal pain. Conclusions Despite several limitations, these results demonstrated that resistin levels are potentially associated with the pathogenesis of BSS in MS. Trial registration number Clinical Research Information Service (CRIS): KCT0000916.

To evaluate the efficacy and safety of Yangyin Yiqi Huoxue Granule (养阴益气活血颗粒, YYHG) in the treatment of ischemic stroke (IS) patients with qi-yin deficiency and blood stasis syndrome (QYDBSS), and to explore its effective dosage. The total of 288 patients were randomly assigned to the YYHG high-dose, YYHG low-dose, positive control (administered Xiaoshuantong Granule, XSTG, 消栓通颗粒), or placebo control (administered inert granule) groups (72 cases per group) by software-drived competitive block randomization. The trial was conducted for a 28-day period, with a 180-day follow-up period. The primary outcome was the comprehensive curative evaluation, and secondary outcomes were the National Institute of Health Stroke Scale (NIHSS) score, Barthel activities of daily living (ADL) index score, the quality of life index (QLI) score, and the Chinese medicine syndrome (CMS) score. All analyses were done on an intention-to-treat basis. The clinical safety was also assessed. The total of 288 participants were recruited between June 1, 2008 and September 30, 2009, and 287 patients received intervention; the treatment groups were well balanced at baseline. The comprehensive cure rates of YYHG high-dose, low-dose, positive and placebo control groups were 63.38%, 31.94%, 36.11% and 6.14%, respectively; there was a statistical difference between the two groups (P

Background: Plaque psoriasis (PSO) is a common clinical chronic inflammatory skin disease. The incidence rate is increasing year by year due to the fast pace of work and unhealthy diet. Fire needle has been widely used in the treatment of PSO. However, the efficacy of fire needle for PSO is uncertain. Thus, the purpose of this systematic review is to evaluate the effectiveness and safety of fire needle for PSO (blood stasis syndrome). Methods: The following electronic databases will be searched from inception to October 2020:PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, WangFang Database, Chinese Science Journal Database, Chinese Biomedical Literature Database. In addition, other documents that meet the requirements will be manually searched, including conference papers, dissertations, etc. All randomized controlled trials using fire needle to treat PSO (blood stasis syndrome) that meet the criteria for inclusion will be included. The primary outcomes are clinical efficacy, Psoriasis area and severity index. Secondary outcomes include Itchy, TCM evaluation standard syndrome score, Dermatological quality of life index, and adverse events. To complete data synthesis and assess the risk of bias, we will use the RevMan V.5.3 software. Results: The review results will be published in a peer-reviewed journal. Conclusion: This study will provide high-quality evidence based medicine to evaluate the effectiveness and safety of fire needle for PSO (blood stasis syndrome), and further seek its scientific and effective chinese medicine treatment methods. INPLASY registration number: INPLASY202120007.

Background Coronary heart disease (CHD) remains highly prevalent and is one of the largest causes of death worldwide. Blood stasis syndrome (BSS) is the main syndrome associated with CHD. However, the underlying biological basis of BSS with CHD is not yet been fully understood. Materials and Methods We proposed a metabolomics method based on 1H-NMR and random forest (RF) models to elucidate the underlying biological basis of BSS with CHD. Firstly, 58 cases of CHD patients, including 27 BSS and 31 phlegm syndrome (PS), and 26 volunteers were recruited from Xiangya Hospital affiliated to Central South University. A 1 mL venous blood sample was collected for NMR analysis. Secondly, principal component analysis (PCA), partial least squares discrimination analysis (PLS-DA) and RF was applied to observe the classification of each group, respectively. Finally, RF and multidimensional scaling (MDS) were utilized to discover the plasma potential biomarkers in CHD patients and CHD–BSS patients. Results The models constructed by RF could visually discriminate BSS from PS in CHD patients. Simultaneously, we obtained 12 characteristic metabolites, including lysine, glutamine, taurine, tyrosine, phenylalanine, histidine, lipid, citrate, choline, lactate, α-glucose, β-glucose related to the CHD patients, and Choline, β-glucose, α-glucose and tyrosine were considered as potential biomarkers of CHD–BSS. Conclusion The combining of 1H-NMR profiling with RF models was a useful approach to analyze complex metabolomics data (should be deleted). Choline, β-glucose, α-glucose and tyrosine were considered as potential biomarkers of CHD–BSS.

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

To assess the effect and safety of Hydroxysafflor Yellow A for Injection (HSYAI) in treating patients with acute ischemic stroke (AIS) and blood stasis syndrome (BSS).A multicenter, randomized, double-blind, multiple-dose, active-controlled phase II trial was conducted at 9 centers in China from July 2013 to September 2015. Patients with moderate or severe AIS and BSS were randomly assigned to low-, medium-, high-dose HSYAI groups (25, 50 and 70 mg/d HSYAI by intravenous infusion, respectively), and a control group (Dengzhan Xixin Injection (, DZXXI) 30 mL/d by intravenous infusion), for 14 consecutive days. The primary outcome was the Modified Rankin Scale (mRS) score ⩽1 at days 90 after treatment. The secondary outcomes included the National Institute of Health Stroke Scale (NIHSS) score ⩽1, Barthel Index (BI) score ⩾95, and BSS score reduced ⩾30% from baseline at days 14, 30, 60, and 90 after treatment. The safety outcomes included any adverse events during 90 days after treatment.Of the 266 patients included in the effectiveness analysis, 66, 67, 65 and 68 cases were in the low-, medium-, and high-dose HSYAI and control groups, respectively. The proportions of patients in the medium- and high-dose HSYAI groups with mRS score ⩽1 at days 90 after treatment were significantly larger than the control group (P0.05). The incidences of favorable outcomes of NIHSS and BI at days 90 after treatment as well as satisfactory improvement of BSS at days 30 and 60 after treatment in the medium- and high-dose HSYAI groups were all significantly higher than the control group (P0.05). No significant difference was reported among the 4 groups in any specific adverse events (P0.05).HSYAI was safe and well-tolerated at all doses for treating AIS patients with BSS. The medium (50 mg/d) or high dose (75 mg/d) might be the optimal dose for a phase III trial. (Registration No. ChiCTR-2000029608).

Naoxintong Capsule (NXT), a Chinese medicine, has been widely used for the treatment of cardiovascular diseases in clinic. The present study was designed to clarify the effects of NXT on haemorheology, blood coagulation, hepatic function, antioxidant capacity and inflammatory responses in a rat model of blood stasis syndrome. Rats were placed in ice-cold water for 5 min during the time interval of two adrenaline injections to induce blood circulation disorders after intragastric administration of 10 consecutive days. Blood was collected from abdominal aorta to determine whole blood viscosity (WBV), plasma viscosity (PV), activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (FIB), total antioxidant capacity (T-AOC), superoxide dismutase (SOD), malonaldehyde (MDA), alanine transaminase (ALT), aspartate transaminase (AST), interleukin-1β (IL-1β), interleukin-6 (IL-6), platelet activating factor (PAF). The results showed that NXT could significantly decrease the WBV, PV, FIB and prolong the APTT and PT. Meanwhile, NXT significantly decreased the serum contents of MDA, IL-1β, IL-6, ALT, AST and PAF, while elevating T-AOC and SOD levels. These results indicate that NXT could improve coagulation function, enhance antioxidant capacity and suppress inflammation, which might partly account for its mechanisms of action in preventing and treating cardiovascular diseases.

In this study, we employed a previously developed in vivo assay system to determine whether the flowers and leaves of Syringa vulgaris (S. vulgaris; commonly known as "lilac") can prevent blood stasis syndrome, known as oketsu in Japanese. This syndrome is considered an important pathology in traditional Chinese and Japanese medicine, and is related to diseases such as peripheral vascular disorders, blood vessel inflammation, and platelet aggregation, whose severities are augmented owing to lipid peroxidation, free radicals, and oxidative stress. The assay system employed in this study monitored the blood flow decrease in the tail vein of mice subjected to sensitization with hen egg white lysozyme. Through bioassay-guided fractionation of different S. vulgaris extracts, five polyphenols were isolated and identified. Among them, quercetine 3-glucoside, quercetin 3-rutinoside, and acteoside were identified as active compounds, as they significantly mitigated blood flow reduction. These findings indicate that the polyphenols obtained from S. vulgaris could be useful for preventing oketsu and improve the quality of life of individuals with disorders and diseases such as gynecopathy, cold sensitivity, poor circulation, allergy, and lifestyle-related diseases.

This study was performed to elucidate the potential influence of He Qi San (HQS) on glucose and lipid metabolism in type 2 diabetes mellitus (T2DM) patients with phlegm-blood stasis syndrome (PBSS), and to determine DNA methylation changes. Sixty T2DM patients with PBSS were randomly divided into control and HQS groups. The control group received conventional treatments, and the HQS group received conventional treatments plus HQS. Glucose metabolism (FPG, 2hPG, FINS, and HbA1c) and lipid metabolism indexes (TG, TC and LDL-C) were determined. Genes with differential DNA methylation were subjected to GO and KEGG analyses. Glucose and lipid metabolism indexes in both groups were reduced, but were much more pronounced in the HQS group. Differential promoter CpG methylation regions were identified in 682 genes, including 426 genes with high-CpG promoters, 150 genes with intermediate CpG promoters, and 106 genes with low CpG promoters. Genes with differential DNA methylation were mainly enriched in the AMPK and insulin signaling pathways, terpenoid backbone biosynthesis, and renin secretion. We concluded that HQS remarkably improved indexes of glucose and lipid metabolism in T2DM patients with PBSS through regulating the DNA methylation of genes in the AMPK and insulin signaling pathways and terpenoid backbone biosynthesis.

Introduction Unstable angina pectoris (UAP) is the common type of coronary heart disease with the risk of developing into acute myocardial infarction (AMI). Currently, there are still numerous patients suffering from recurrent angina after revascularization or conventional medication due to the microvascular lesions, endothelial dysfunction, chronic inflammation, in-stent restenosis, and other factors. As an important part of China’s medical and health care system, traditional Chinese medicine (TCM) has rich clinical experience in the treatment of UAP. According to the theory of TCM, Yang deficiency and blood stasis syndrome is a common type of UAP. Wen Xin decoction, as a type of Chinese herbal medicine, has been used in the clinic for years and shown great efficacy in the treatment of UAP with Yang deficiency and blood stasis syndrome. This study aims to evaluate the efficacy and safety of Wen Xin granular in patients with UAP. Methods and analysis This is a double-blinded, randomized, placebo-controlled clinical trial. A total of 502 participants will be randomly allocated to the intervention group and the placebo group. Based on conventional medication, the intervention group will be treated with Wen Xin granular and the placebo group will be treated with Wen Xin granular placebo. The primary outcomes are major adverse cardiovascular events (MACE). Assessments will be performed 1 year after the treatment. The secondary outcomes include TCM symptom scale score, Seattle angina questionnaire, and thromboelastography. Assessments will be performed at baseline (before randomization) and 4 and 8 weeks after randomization. Discussion This trial will provide high-quality data on the benefits and risks of Wen Xin granular in patients with UAP. Trial registration ClinicalTrials.govNCT04661709. Registered on 30 November 2020

Qi stagnation and blood stasis syndrome (QS&BSS) is one of the common Zhengs in traditional Chinese medicine (TCM), which manifests as various symptoms and signs, such as distending pain or a tingling sensation in a fixed position. In recent years, a number of clinical trials have focused on the effectiveness and safety of XFZYC in patients with a QS&BSS subtype disease, such as coronary heart disease, hyperlipidaemia, ischaemic cerebrovascular disease, gastritis, dysmenorrhoea, or arthritis, in terms of the outcomes of relevant diseases. However, there is lack of evidence of the effects of XFZYC in patients with QS&BSS with different diseases, focusing on the outcomes of Zhengs. A randomised, controlled, pilot and feasibility trial will be employed in this study, using a 7-week study period. Participants will be recruited from Guang’anmen Hospital, Huguosi TCM Hospital, Wangjing Hospital in China. One hundred and twenty participants will be randomised to a treatment group (Xue-Fu-Zhu-Yu Capsule (XFZYC)) and placebo group in a 1:1 ratio. Participants included in the study must be diagnosed with Qi stagnation and blood stasis syndrome criteria. The outcome measurements will include the traditional Chinese medicine patient-reported outcome (PRO) scale for QS&BSS, the single symptom and sign scale of QS&BSS, and the pain scale of QS&BSS. The clinical data management system ( http://www.tcmcec.net /) will be used to collect and manage the data. Quality control will be used, according to Good Clinical Practice (GCP). Previous studies were expected to evaluate whether the addition of XFZYC to standard routine treatment would enhance the treatment effectiveness and improve the biomedical parameters pertaining to relevant disease. However, this trial is focused on the outcome of Zhengs, and we chose a range of outcome measurements to assess the improvement of relevant symptoms and signs. This trial is the first study designed to define and optimise the outcome measurements of Zhengs of XFZYC in the treatment of patients with QS&BSS. ClinicalTrials.gov, NCT03091634 . Registered on 12 August 2018. Release date 6 May 2017.

In traditional Chinese medicine (TCM), blood stasis syndrome (BSS) is mainly manifested by the increase of blood viscosity, platelet adhesion rate and aggregation, and the change of microcirculation, resulting in vascular endothelial injury. It is an important factor in the development of diabetes mellitus (DM). The aim of the present study was to screen out the potential candidate microRNAs (miRNAs) in DM patients with BSS by high-throughput sequencing (HTS) and bioinformatics analysis. Human umbilical vein endothelial cells (HUVECs) were incubated with 10% human serum to establish models of DM with BSS, DM without BSS (NBS), and normal control (NC). Total RNA of each sample was extracted and sequenced by the Hiseq2000 platform. Differentially expressed miRNAs (DE-miRNAs) were screened between samples and compared with known changes in mRNA abundance. Target genes of miRNAs were predicted by softwares. Gene Ontology (GO) and pathway enrichment analysis of the target genes were conducted. According to the significantly enriched GO annotations and pathways (P-value ≤ 0.001), we selected the key miRNAs of DM with BSS. It showed that the number of DE-miRNAs in BSS was 32 compared with non-blood stasis syndrome (NBS) and NC. The potential candidate miRNAs were chosen from GO annotations in which target genes were significantly enriched (−log10 (P-value) > 5), which included miR-140-5p, miR-210, miR-362-5p, miR-590-3p, and miR-671-3p. The present study screened out the potential candidate miRNAs in DM patients with BSS by HTS and bioinformatics analysis. The miRNAs will be helpful to provide valuable suggestions on clinical studies of DM with BSS at the gene level.

Context Naoxintong Capsule (NXT), a Chinese medicine, has been widely used for the treatment of coronary heart disease (CHD) in clinics. Objective This study evaluated the cardioprotective effects of NXT alone and in combination with ticagrelor (TIC) and atorvastatin (ATO). Materials and methods Qi deficiency and blood stasis rats were established by 8 weeks high fat diet feeding and 16 days exhaustive swimming and randomly divided into seven groups, that is, NXT (250, 500 and 1000 mg/kg/d), TIC (20 mg/kg/d), ATO (8 mg/kg/d), NXT (500 mg/kg/d)+TIC (20 mg/kg/d) and NXT (500 mg/kg/d)+ATO (8 mg/kg/d) group, with oral administration for 12 weeks. The contents of TC, TG, LDL-C, HDL-C, IL-1β, IL-6, IL-8, TNF-α, AST, ALT, SOD, MDA, CK-MB, LDH, TXA2, PGI2, IgA, IgG, IgM and C3 in serum were measured. Results NXT + TIC group was significantly superior to the TIC group in decreasing the levels of TC (4.34 vs. 5.54), TG (3.37 vs. 4.66), LDL-C (1.21 vs. 1.35), LDH (4919.71vs. 5367.19) and elevating SOD level (248.54 vs. 192.04). NXT + ATO group was significantly superior to the ATO group in decreasing the levels of AST (195.931 vs. 241.63), ALT (71.26 vs. 83.16), LDH (4690.05 vs. 5285.82), TXA2 (133.73 vs. 158.67), IgG (8.08 vs. 9.80), C3 (2.03 vs. 2.35) and elevating the levels of HDL-C (1.19 vs. 0.91), SOD (241.91vs. 209.49). Conclusions The present findings demonstrate that the combined use of NXT with TIC and ATO had better integrated regulating effects than TIC and ATO, respectively. The mechanism of action requires further research.

Objective. To explore the basic characteristics of intestinal flora, metabolomics, and proteomics of non-small cell lung cancer (NSCLC) in patients with Qi stagnation and blood stasis syndrome. Methods. Twelve NSCLC patients with Qi stagnation and blood stasis syndrome were selected for the QZXY group and 15 healthy volunteers were selected for the control group. Fecal samples from the two groups were collected to evaluate intestinal microecology using the 16s rDNA technique. Serum samples were collected to compare the differences in metabolomics and proteomics between the two groups using liquid chromatography-mass spectrometry (LC-MS). Another 34 NSCLC patients with other syndromes were selected for the nQZXY group and their serum samples were collected. Metabolomics differences between the QZXY and nQZXY groups were compared using LC-MS, and four metabolites with the most obvious differences were selected for receiver operation characteristic curve representation. Finally, multigroup results were analyzed using the WGCNA software. Results. There were two significantly different types of bacteria (Aerococcaceae and Abiotrophia), 11 different proteins (six upregulated and five downregulated), and 38 different metabolites (nine upregulated, 29 downregulated) between the QZXY and control groups. There was a correlation between differential bacteria, proteins, and metabolites. The conjoint analysis found that the different substances were related to MAPK, PI3K/Akt, Ras signaling pathway, cancer pathways, and cytokine-cytokine receptor interaction. There were four significant differences in metabolites (Pseudouridine, phenlacetyl-C0A, L-glutamic, and phospho-anandamide) between the QZXY and nQZXY groups. Conclusions. NSCLC with Qi stagnation and blood stasis syndrome had specific intestinal flora and protein and metabolites, which were closely related to the occurrence and development of tumors.

Background: BuqiTongluo (BQTL) granules are herbal phenotypic drugs for Qi deficiency and blood stasis (QDBS) syndrome. Its discovery relied primarily on knowledge of observable phenotypic changes associated with diseases. Although BQTL granules have been widely advocated by Chinese Medicine (CM) practitioners, its use lacks empirical support.Aim of the study: In this basket trial, the efficacy of BQTL granules in multiple diseases that have the QDBS syndrome in common will be compared with placebo.Materials and Methods: The BuqiTongluo granule for Qi deficiency and blood stasis syndrome (BOSS) study is a basket herbal trial (ClinicalTrials.gov, NCT04408261). It will be a double-blinded, randomized, placebo-controlled, parallel, multicenter, clinical trial. In total, 432 patients (1:1:1 ischemic stroke, stable angina pectoris, and diabetic peripheral neuropathy), who meet the operationalized diagnostic criteria for QDBS syndrome, have been recruited and randomized in a ratio of 1:1 to receive 6 weeks’ treatment with BQTL granules or placebo. The primary outcome is the change in the QDBS syndrome score at week 6 from baseline. Secondary outcomes include objective outcome measures for the three diseases and adverse events. Omics will help to understand these responses by molecular events.Conclusion: QDBS syndrome is a common phenotypic marker that was hypothesized to predict whether patients with multiple diseases would respond to this targeted therapy. No previous basket trial has assessed the potential efficacy of an herbal intervention for multiple diseases. The unique promise of the trial is its ability to exploit a disease phenotype to discover novel treatments for three diseases for which the root cause is unknown, complex, or multifactorial, and for which scientific understanding is insufficient to provide valid molecular targets.

Objectives: To investigate the difference of serum estrogen, serum lipids and inflammatory factors levels in postmenopausal women with coronary heart blood stasis syndrome and non-blood stasis syndrome. Methods: Twenty five healthy postmenopausal women were selected as a healthy control group who were compared with 43 postmenopausal women with coronary heart disease (CHD) first visiting a doctor for the CHD. Among the postmenopausal women with CHD, There were 23 patients with blood stasis syndrome (BSS) and 20 patients with non-blood stasis syndrome (NBSS). The levels of plasma triglyceride (TG), total cholesterol (TC) were determined in blood samples taken after patients’ admission in Beijing Anzhen Hospital. The serum estradiol(E2) was measured by electrochemiluminescence assay and soluble intercellular adhesion molecule-1(sICAM-1) was measured by enzyme-linked immune sorbent assay (ELISA). Results: Compared with the healthy control group, the levels of TG and TC, sICAM-1 in coronary heart disease group were all significantly increased (P0.05), and there was an increasing trend of serum sICAM-1 levels (P>0.05). There were negative significant correlations between serum E2 levels and TC, sICAM-1 levels in patient with coronary heart disease. Conclusion: The estrogen level of menopausal women with coronary heart disease is lower than healthy menopausal women. With the low estrogen levels, postmenopausal women tend to have high levels of blood lipids and sICAM-1, which elucidates that the estrogen could regulate lipids and attenuate inflammatory response to play a protective role on blood vessels.

Blood stasis syndrome is implicated in the development of chronic conditions, including cardio- and cerebrovascular diseases. Cyclo-(Tyr-Leu), named Sparganin A (SA), is a compound isolated from the ethanol extract of Rhizoma Sparganii. Here, the successful extraction of SA from Rhizoma Sparganii was verified by extensive spectral analysis using 1H NMR and 13C NMR. To determine the biological effects of SA, a mouse model of acute blood stasis was established by subcutaneous injection of adrenaline hydrochloride and placing the animals in an ice water bath. In this model, the concentration of TXB2, PAI-1, FIB, ET-1 was measured by ELISA, and thymus index (TI), hepatic index (HI), and spleen index (SI) were calculated. Molecular docking by SYBYL and functional analysis of the putative targets by STRING and Cytoscape were employed to identify the key targets of SA. The accumulated results documented that SA exhibits anticoagulative activity, and its key targets are VEGFA and SERPINE1. SA may be involved in the pathological process of complement and coagulation cascades. This study demonstrates that SA may be a promising drug to control coagulation in blood stasis syndrome.

Objective To investigate the pathological features of blood stasis syndrome (BSS) in non-diabetic peripheral neuropathy. Methods Clinical data of 31 patients with non-diabetic peripheral neuropathy who had undergone nerve biopsy during December 2004 and December 2010 in Xuanwu Hospital Capital Medical University were retrospectively analyzed. According to Chinese medicine (CM) syndrome differentiation and signs, 26 patients were blood stasis type and 5 patients were non-blood stasis type. Clinical and pathological data were compared in detail. Results Clinically, although both groups shared similar symptoms of limb numbness, weakness and sensory disturbances, the prevalence of neuralgia was much grievous in BSS group (73.1%, 26/31) compared with the non-BSS group (0%, 0/5). As for signs, dermal nutrients disturbance (84.6%, 22/26), dark or purple tongue (100.0%, 26/26), and sublingual varices (80.7%, 21/26) were more common in the BSS group than the non-BSS group (0%, 60%, 20%, respectively). The prevalence of qi deficiency cases (19/26) in the BSS group was significantly higher compared with the non-BSS group (1/5). The unique histological manifestations of BSS were axonal degeneration (16/26 vs 2/5 in non-BSS group), which was the hallmark of ischemia. Cases with BSS had prominent microangiopathy (61.5%, 16/26), manifested as epineurium vasculitis (inflammatory cell infiltrated to the vessel wall, obliteration and recanalization, vascular proliferation, extravascular hemosiderin deposition), angiotelectasis, proliferation and hyaline degeneration of endoneurium capillary. In the BSS group, impaired blood-nerve barrier was indicated by sub-perineurial edema (46.2%, 11/26) and endoneurial edema (15.4%, 4/26). The Renaut body (15.4%, 4/26) and amyloid deposition (3.8%, 1/26) found in the BSS group were absent in the non-BSS group. Conclusions BBS was common in non-diabetic peripheral neuropathies. The nerves exhibited ischemic alteration of primary axon degeneration and secondary demyelination. The interstitial tissue revealed microcirculation impairment, blood-nerve barrier disturbance, amyloid deposition and proliferation changes. The high prevalence of qi deficiency also highlights the therapy of promotion of blood circulation and removal of blood stasis.

Blood stasis syndrome (BSS) is one of the most common symptoms of cardiovascular diseases (CVDs) in traditional Chinese medicine (TCM) theory. Previous studies have identified that Salvia miltiorrhiza (Danshen) has beneficial effects on BSS, but there is no relevant research from the perspective of lipidomics to study the mechanism of Danshen against BSS since hyperlipidemia has been the widely accepted risk factor of CVDs. In this study, lipidomics technology combined with network pharmacology was applied to investigate the pathological mechanism of BSS and the protective effects of Danshen. The lipidomics profiling based on the UPLC-QTOF-MS analysis method was applied to identify the differential metabolites in the plasma of blood stasis rats. The related pathway and potential targets involved in the anti-BSS effects of Danshen were predicted by pathway analysis and network pharmacology. The biochemical results showed that Danshen intervention significantly reduced whole blood viscosity (WBV) at all the shear rates and fibrinogen concentration (FIB) p < 0.01 and increased activated partial thromboplastin time (APTT) effectively p < 0.01 . We also found that 52 lipid metabolites, including glycerophospholipid, sphingolipid, glycerolipid, plasmalogen, cholesterol ester, and testosterone, were associated with blood stasis. Moreover, Dgka, Hsd17b3, Hsd3b1, Inppl1, Lpl, Pik3ca, Pik3r1, Pla2g1b, Pla2g2a, Soat1, and Soat2 were predicted as potential targets, while glycerophospholipid metabolism, glycerolipid metabolism, steroid and steroid hormone biosynthesis, phosphatidylinositol signaling system, and ether lipid metabolism were involved as shared critical pathways of lipidomics analysis and network pharmacology. Collectively, this study offered a new understanding of the protection mechanism of Danshen against BSS, which provided new insight to explore the protective effects of Danshen.

Introduction Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM) and the primary cause of end-stage renal disease. Routine medication might result in adverse effects which limit their usage. Laboratory studies have shown that Xiao Zheng San Jie (XZSJ) granules is effective in reducing the levels of urinary protein and blood creatinine in rats with DKD. Hence, we aim to conduct a clinical trial to determine the efficacy and safety of XZSJ granules among patients with DKD Stage IV, who present with the syndromes of qi deficiency and blood stasis. The purpose of this paper is to report the methodology of this trial.Methods and analysisThis is a randomised, double-blind, placebo-controlled, multi-centre clinical trial. A total of 72 patients with DKD Stage IV who have the syndromes of qi deficiency and blood stasis will be randomly assigned to either intervention or placebo group. In addition to routine medication, the intervention group will be given XZSJ formula (in granules) and the control group will be given placebo for 12-weeks. Data collected at baseline as well as weeks 4, 8 and 12 will be recorded in case report forms and subsequently entered into EpiData 3.1 electronic database. Adverse events will also be documented. Primary outcomes – estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, and serum creatinine – will be assessed after 12 weeks. Ethics and disseminationThis trial has been approved by the Research Ethics Committee of Dongzhimen Hospital (DZMEC-KY-2018-60). Informed consent will be obtained from all participants. Results of this study will be disseminated to the public through academic conferences and peer-reviewed journals.DiscussionThis trial might provide information on an effective method for the treatment of DKD, especially for patients who present with the syndromes of qi deficiency and blood stasis. We hope that this trial will serve as a reference for the conception of high-quality Traditional Chinese Medicine trials in the future, which incorporate syndrome diagnosis into the study design.Trial registration Chinese Clinical Trial Registry, ChiCTR1900021391. Registered 18 February 2018, http://www.chictr.org.cn/showproj.aspx?proj=36106.

Objective: Explore the partial mechanisms of cupping therapy by means of the cellular factors in the peripheral blood cells; methods: Replicate the rabbit model of cold stagnation leading to blood stasis by adopting the cold stimulation and randomly dividing 12 rabbits to three groups based on the weight. Observe the sign of the rabbits before and after cupping test, the content of the vascular endothelial growth factor (VEGF), epidermal growth factor (EGF)in the peripheral blood; Results: After replicated the model, the model group and the treatment group gradually appeared the sign of cold stagnation leading to blood stasis. After cupping treatment, the sign of cold stagnation leading to blood stasis of the rabbits gradually disappeared. Compared with the blank controlled group and the model group at the same time, the epidermal growth factor (EGF)in the peripheral blood of the treatment group was much higher after cupping and was statistically difference (p

Background: Blood Stasis syndrome (BSS) is one of the major syndromes in Traditional East Asia medicine (TEAM). Modern research of BSS began in the late1980s. Methods: We searched in PubMed for BSS-related articles published between 1989 and 2015. The publication information, study contents, and bibliometric indicators were documented and analyzed. Results: Most of the BSS-related studies were conducted by Chinese researchers in China. The number of publications on BSS-related increased rapidly in recent years, so did the quality of them. The disease diversity of BSS-related studies increased along with the number of publications. Yet the academic influence of them remained on average low; further, the diagnostic criteria of BSS were not uniform. Conclusions: BSS-related studies have increased in quantity and quality, but there are limitations to them which require improvement in research productivity and academic influence.

Background: Traditional Chinese medicines (TCMs) have been used to manage psoriasis since thousands of years and are associated with advantages such as long remission period and few side effects. PSORI-CM01 is a clinical TCM formula for treating the blood stasis syndrome of psoriasis vulgaris. It is optimised from Yin Xie Ling, a herbal preparation formulated by the Chinese national medical master Xuan Guowei. In the present study, we used microRNA (miRNA) chip technology to analyse the effects of PSORI-CM01 and Yin Xie Ling on miRNA differential expression in the peripheral blood monocytes of patients with blood stasis syndrome of psoriasis vulgaris.Methods: Blood samples collected from healthy subjects and patients with blood stasis syndrome of psoriasis vulgaris were obtained from the Department of Dermatology in the Guangdong Provincial Hospital of Chinese Medicine. These samples were obtained before and after treatment with PSORI-CM01 or Yin Xie Ling. Differentially expressed miRNAs were analysed by performing miRNA expression microarray to evaluate the mechanisms underlying the effects of the two formulations.Results: It was found that hsa-miR-3184-3p, hsa-miR-3653-3p, hsa-miR-20a-3p, hsa-miR-5681b, and hsa-miR-26a-5p were differentially expressed between the PSORI-CM01 and healthy control groups as well as between the Yin Xie Ling and healthy control groups before treatment, without any significant differences in their expression after treatment. The results revealed that the therapeutic effect of PSORI-CM01 on psoriasis was mediated mainly via the regulation of the adherens junction, thyroid hormone signalling, and proteoglycans in cancer pathways, whereas that of Yin Xie Ling was mediated mainly via the regulation of the endoplasmic reticulum protein processing, Hippo signalling, adherens junction, thyroid hormone signalling, cell cycle, proteoglycans in cancer, p53 signalling, oocyte meiosis, and unsaturated fatty acid biosynthesis pathways.Conclusions: The findings demonstrate that PSORI-CM01 and Yin Xie Ling are beneficial for treating blood stasis syndrome of psoriasis vulgaris through the regulation of hsa-miR-20a-3p and hsa-miR-3184-3p expression and, consequently, through the adherens junction, thyroid hormone signalling, and proteoglycans in cancer pathways.Trial registration: Registration number, ChiCTR-TRC-14005185; Date of registration, 8 August 2014.

In Kampo medicine, blood stasis (BS) syndrome is strongly associated with microangiopathy and can lead to atherosclerosis. Vascular endothelial dysfunction (VED), evaluated through flow-mediated dilation (FMD), plays an important role in the early stages of atherosclerosis. However, the association of BS syndrome with VED, as determined using FMD, has not been reported. This study investigated the association between BS syndrome and VED using FMD. Forty-one patients with normal glucose tolerance or impaired glucose tolerance (IGT) and without macrovascular complications were evaluated using FMD from May 2017 to August 2017. Based on the BS score, the patients were divided into the non-BS (n = 19) and BS syndrome (n = 22) groups. Physical and background characteristics, physiological function test results, and laboratory data were compared. Univariate analysis revealed that FMD and a history of dyslipidemia/IGT were significantly different between the two groups ( p < 0.05 ). Multiple logistic regression analysis showed that BS syndrome was significantly associated with FMD (odds ratio: 6.26; p = 0.03 ) after adjusting for the history of dyslipidemia/IGT. The receiver operating characteristic curve showed that the area under the curve for BS syndrome (0.74; p < 0.001 ) and history of IGT ( p < 0.007 ) provided good diagnostic accuracy for FMD. The area under the curve for “BS syndrome + IGT” showed very good accuracy (0.80; p < 0.0001 ) and was higher than that for BS syndrome or IGT alone. In conclusion, the results of this study suggest that the BS score in Kampo medicine could be a useful tool for detecting the early pathogenic stages of atherosclerosis.

Psoriasis is a chronic autoimmune disease. Identification of the biomarkers responsible for Traditional Chinese Medicine (TCM) syndromes of psoriasis can help researchers recognize the different aspects of psoriasis and find novel therapeutic targets for the treatment of psoriasis. The current study investigated the levels of circulating Mo-MDSCs and Mo-MDSC-associated immune factors in the peripheral blood of psoriasis patients with different TCM syndromes. We found that the frequency of Mo-MDSCs (CD14+HLA-DR−/low cells) among CD14+ cells from plaque psoriasis patients with blood-stasis (BS) syndrome was significantly increased when compared with healthy controls p<0.001 and blood-heat (BH) syndrome group p<0.001, respectively. However, serum IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α, IFN-γ, iNOS, Arg-1, and NO concentration showed no statistically significant difference between healthy controls and psoriasis patients as well as no significant difference between the BH and BS syndrome groups. Compared with healthy controls, the mRNA expression of Arg-1, TNF-α, ROR-γ, and PD-L1 was increased, while the mRNA expression of PD-1 and IL-10 was decreased in PBMCs from psoriasis patients. Moreover, the mRNA expression of TNF-α and FOXP3 in PBMCs showed a pronounced statistical difference between the psoriatic BH syndrome group and the BS syndrome group. Therefore, we provide evidence that the percentage of CD14+HLA-DR−/low MDSC/ CD14+ cells and TNF-α and Foxp3 mRNA expression levels in PBMCs are potential biomarkers for distinguishing TCM BH syndrome and BS syndrome.

Erchen plus Huiyanzhuyu decoction (EHD), a Chinese herbal medicine (CHM) formula that consists of Erchen decoction and Huiyanzhuyu decoction, has achieved satisfactory results in the clinic. The main function of EHD is to remove phlegm and blood stasis, and EHD is suitable for phlegm-coagulation-blood-stasis (PCBS) syndrome in laryngeal cancer (LC). In this study, a xenograft mouse model of LC with PCBS syndrome was constructed by feeding a high-fat diet, swimming in ice water, and subcutaneously injecting epinephrine hydrochloride for 2 weeks. Based on the successful Chinese medicine syndrome model, Hep2-luciferase-GFP cells were injected subcutaneously under the armpit of the right upper limb in mice to form tumours. A mouse model of LC with PCBS syndrome was established via heterotopic transplantation. Then, the mice received intragastric administration of different concentrations of EHD daily, and cisplatin (DDP) was intraperitoneally injected every week for 21 days. Tumour fluorescence in mice was measured with a living animal imager on days 7, 14, 21, and 28 during treatment. The results of this experiment confirmed that a mouse model of Chinese medicine syndrome was successfully constructed. Moreover, EHD slowed the growth of xenograft tumours in nude mice; decreased the expression levels of STAT3, p-STAT3, and cyclin D1; and upregulated the expression level of P27. In brief, EHD inhibited laryngeal tumour growth in a xenograft mouse model of PCBS syndrome and regulated the STAT3/cyclin D1 signalling pathway. This study was the first to construct a Chinese medicine xenograft mouse model of LC with PCBS syndrome; in addition, this study clarified that EHD regulated the STAT3/cyclin D1 signalling pathway to inhibit the growth of LC and that EHD may be a promising novel therapeutic compound for the treatment of patients with LC.

Background. Psoriasis has been reported as a high-risk factor for quality of life and survival rate in patients with metabolic disorder. However, there is no animal model for studying this disease. This study aimed to establish and evaluate mouse models of psoriasis with blood stasis syndrome (which is a key to psoriasis pathogenesis, according to Chinese Medicine) complicated with metabolic disorders. Method. Forty-five C57BL/6 mice were randomly divided into the blank control (Control), psoriasis (Imiquimod (IMQ)), psoriasis with metabolic disorders (IMQ + streptozotocin (STZ)), psoriasis with blood stasis syndrome (BSS) (IMQ + BSS), and psoriasis with blood stasis syndrome complicated with metabolic disorders (IMQ + STZ + BSS) groups (n = 9 mice/group). Psoriasis lesions were induced using IMQ cream (on both the ears and back, except in the Control group). Mice of the IMQ + BSS group were fed a half-fat, high-sugar diet and stimulated with ice-water swimming every day. Mice of the IMQ + STZ group were fed a half-fat, high-sugar diet and injected with STZ. Mice of the IMQ + STZ + BSS group were subjected to the same treatments as the IMQ + STZ and IMQ + BSS groups. After induction, the mice in each group were observed for vital signs, ear thickness, body weight, and psoriasis area and severity index (PASI) score. The mice were fasted for 12 h before determination of related laboratory serum indexes. Dorsal skin lesions, aortic arch pathology sections, and signal transducer and activator of transcription 3 (STAT3) were examined by H&E staining and immunohistochemistry. Results. Laboratory indexes in the four model groups were significantly different from those in the Control group (p<0.01); indicators of the IMQ + STZ, IMQ + BSS, and IMQ + STZ + BSS groups showed varying degrees of difference from those of the IMQ group. Conclusions. The established mouse models of psoriasis blood stasis syndrome complicated with glucose and lipid metabolism disorders met the clinical and Chinese Medicine characteristics, and thus they could be used as animal models in future studies of psoriasis complicated with glucose and lipid metabolism disorders.

Supplemental Digital Content is available in the text, Background: Chronic stable angina (CSA) is a cardiovascular disease with high prevalence. At present, drug treatment is still the main measure of stable angina pectoris. Traditional Chinese medicine has a long history in the treatment of CSA. Qi stagnation and Blood stasis syndrome is a common syndrome of CSA. Xinnaoning (XNN) capsule is considered as an effective adjuvant treatment for CSA with the efficacy of promoting qi and blood circulation but lack of high-quality clinical evidence. The purpose of this study is to evaluate the efficacy and safety of XNN capsule compared with placebo by clinical trial. Methods: This multicenter, randomized, double-blind, placebo-controlled trial will be conducted with a total of 240 participants diagnosed with chronic stable angina (qi stagnation and blood stasis syndrome). The participants will be randomized (1:1) into groups receiving either XNN or placebo for 12 weeks. After a 2-week run-in period, they will receive either XNN or placebo (3 pills, 3 times daily) for 12 weeks on the basis of conventional therapy. The primary outcomes include changes in the integral scores of angina symptoms. The secondary outcome measures include changes in the total score of traditional Chinese medicine syndrome, severity grading of angina pectoris, the number of angina pectoris per week, nitroglycerin dosage, score of seattle angina scale, serum homocysteine, incidence of cardiovascular events. Safety outcomes will also be assessed. Adverse events will be monitored throughout the trial. Results: This study will investigate whether XNN capsule can alleviate clinical symptoms, and improve quality of life of patients with chronic stable angina (qi stagnation and blood stasis syndrome). The results of this study will provide clinical evidence for the application of XNN capsule in the treatment of chronic stable angina. Trial registration: ClinicalTrials.gov: NCT 03914131.

To investigate the important diagnostic indicators for blood stasis syndrome (BSS) in patients of childbearing age with gynaecological diseases. A partial least squared-discriminant analysis (PLS-DA) were applied to BSS symptoms data of patients with gynaecological diseases, and the diagnostic indicators used by doctors of Korean medicine (DKMs) among BSS patients with gynaecological diseases were also investigated. A total of 103 patients of childbearing age with gynaecological diseases and 40 healthy controls were enrolled. Among the 103 patients, 63 (61.7%) and 40 (38.8%) were diagnosed with BSS and non-BSS, respectively, and BSS patients exhibited a more severe extent of disease. A score plot of PLS-DA showed clearly different patterns among the 3 groups. Based on the variable importance on projection of PLS-DA model, menstrual pains, dark lumps in the menstrual blood, ileocoecal tenderness and resistance, sharp pains, and sublingual varicosities were selected as the top five most important indicators. Moreover, more than 75% of DKMs chose dark lumps in menstrual blood, menstrual pain, and dark menstrual blood as the diagnostic indicators of BSS in patients with gynaecological diseases, and more than 49% of them also considered sharp pains, dark red tongue, sublingual varicosities, and tendency to bruise easily as diagnostic indicators of BSS. DKMs focused on menstrual symptoms and certain gynaecological symptoms to diagnose BSS patients of childbearing age with female diseases.

Metabonomic analysis has been widely used in the study of traditional Chinese medicine (TCM) syndromes. In this paper, dynamic changes of the metabolic network during the evolution of a syndrome based on the toxic heat and blood stasis syndrome (THBSS) rat model have been elucidated for the first time. It was found that the metabolic trajectories could characterize three stages during THBSS evolution: the metabolic disturbance at 2–5 h, 8–12 h and 24–48 h could reflect the status of the excessive heat and little blood stasis stage, the coexistence of heat and blood stasis stage and the blood stasis stage respectively. The obtained dynamic metabolic network revealed the mechanism of THBSS progression: the inhibition of nicotinate and nicotinamide metabolism may lead to the activation of SIRT1 producing an inflammatory response, which then results in the disorder of energy metabolism and amino acid metabolism, and eventually the blood stasis appears. Nine involved metabolic pathways were found, among which the nicotinate and nicotinamide metabolism and histidine metabolism closely related to the occurrence of the inflammatory response in the early stage and blood stasis in the later stage of THBSS respectively. The former one, which is not reported in other blood stasis syndromes, might be the characteristic pathway of THBSS. This study firstly reveals the essence of THBSS progression, which is conducive to the diagnosis and pharmacotherapeutics of THBSS and related diseases, and also provides a new way to study TCM syndrome evolution.

Introduction The Korea Institute of Oriental Medicine (KIOM) has developed and validated a Blood Stasis Syndrome (BSS) questionnaire by integrating Korean, Chinese and Japanese BSS criteria with a community-based, multi-center trial, called the Convergence Research of the Diagnostic Technology for Blood Stasis (CORE-DITEC-BS). The aims of the current study were to assess the reliability and validity of the CoRe-Ditec-BS Questionnaire-I (BSQ-I). Methods Between May 2013 and November 2013, 607 patients from 6 traditional Korean medical hospitals were asked to complete the BSQ-I. Each patient was independently diagnosed with BSS by two traditional Korean medical physicians from the same site. We estimated the internal consistency using Cronbach’s α coefficient, the inter-rater reliability in each site using the kappa coefficient, the discriminant validity using the means score of BSS, and the predictive validity using logistic regression (sensitivity and specificity). Results The BSQ-I had satisfactory internal consistency (average: 0.701, expert1: α = 0.710, expert2: α = 0.700) and validity, with significant differences in the mean scores between the BSS and non-BSS groups. The overall classification accuracy of the two experts was 78.42%, and the Kappa value was 0.57 (0.50, 0.63), which was considered moderate. The area under the receiver operating curve was 85%, and the sensitivity and specificity were 77.4% and 75.9%, respectively. Conclusion These results suggest that the CoRE-Ditec-BSQ-I is a reliable and valid instrument for estimating BSS.

Background Chinese medicine (CM) classifies psoriasis vulgaris into three syndromes: blood-heat syndrome (BHS), blood-stasis syndrome (BSS), and blood-dryness syndrome (BDS). The levels of several immunological serum markers in BHS have been established. We aimed to investigate the immune status of patients with psoriasis vulgaris of BSS and BDS. Methods Seven databases were searched, covering nearly 40 years. Fifteen studies including 957 individuals (386 patients with psoriasis vulgaris of BSS, 233 patients with BDS, and 338 healthy controls) were identified. Differences in interleukin (IL) levels between subjects and controls were pooled as mean differences (MDs) with 95% confidence intervals (CI) using a random-effects model. Results For BSS, interferon (IFN)-γ (MD 3.85, 95% CI: 1.27 to 6.44), tumor necrosis factor (TNF)-α (MD 1.71, 95% CI: 0.70 to 2.72), IL-4 (MD 7.66, 95% CI: 4.67 to 10.65), IL-17 (MD 5.06, 95% CI: 0.28 to 9.85), IL-6 (MD 99.34, 95% CI: 45.84 to 152.84), and IL-22 (43.88, 95% CI: 28.17 to 59.59) levels were significantly higher in patients than in controls, while pooled IL-10 levels were lower in patients (MD -10.33, 95% CI: -12.03 to -8.63). The MD in IL-8 levels between cases and controls was not significant. Subjects with BDS showed higher levels of IFN-γ (MD 2.33, 95% CI: 0.22 to 4.45), TNF-α (MD 2.33, 95% CI: 1.26 to 3.40), and IL-23 (MD 46.18, 95% CI: -7.60 to 99.97) and lower levels of IL-4 levels (MD -2.47, 95% CI: -4.78 to -0.15) than did controls. The MDs in IL-17, IL-6, and IL-8 levels were not statistically significant. Conclusions Our pooled analysis suggests that the levels of several ILs are specifically altered in BSS and BDS. Larger, well designed, controlled studies are needed to confirm these results and fully clarify these effects.

Background. Qixuehe capsule (QXH), a Chinese patent medicine, has been demonstrated to be effective in the treatment of menstrual disorders. In traditional Chinese medicine (TCM) theory, qi stagnation and blood stasis syndrome (QS-BSS) is the main syndrome type of menstrual disorders. However, the pharmacodynamic effect of QXH in treating QS-BSS is not clear, and the main active compounds and underlying mechanisms remain unknown.Methods. A rat model of QS-BSS was established to evaluate the pharmacodynamic effect of QXH. Thereafter, a network pharmacology approach was performed to decipher the active compounds and underlying mechanisms of QXH.Results. QXH could significantly reduce the rising whole blood viscosity (WBV) and plasma viscosity (PV) but also normalize prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB) content in QS-BSS rats. Based on partial least-squares-discriminant analysis (PLS-DA), the low-dose QXH-intervened (QXH-L) and the high-dose QXH-intervened (QXH-H) groups seemed the most effective by calculating the relative distance to normality. Through network pharmacology, QXH may improve hemorheological abnormality mainly via 185 compounds-51 targets-28 pathways, whereas 184 compounds-68 targets-28 pathways were associated with QXH in improving coagulopathy. Subsequently, 25 active compounds of QXH were verified by UPLC-Q/TOF-MS. Furthermore, 174 active compounds of QXH were shared in improving hemorheological abnormality and coagulopathy in QS-BSS, each of which can act on multiple targets to be mainly involved in complement and coagulation cascades, leukocyte transendothelial migration, PPAR signaling pathway, VEGF signaling pathway, and arachidonic acid metabolism. The attribution of active compounds indicated that Angelicae Sinensis Radix (DG), Paeoniae Radix Rubra (CS), Carthami Flos (HH), Persicae Semen (TR), and Corydalis Rhizoma (YHS) were the vital herbs of QXH in treating QS-BSS.Conclusion. QXH can improve the hemorheology abnormality and coagulopathy of QS-BSS, which may result from the synergy of multiple compounds, targets, and pathways.

High-throughput metabolomics can be used to investigate the therapeutic targets and metabolic mechanisms of traditional Chinese medicine (TCM) formulae, which have multiple targets in disease therapy, but it is a great challenge to explore their mechanism of action. Huaxian capsule (HXC) is a classical formula in TCM that has therapeutic effects on a sepsis-associated Qi deficiency and blood stasis syndrome (SQBS). However, its targets and metabolic mechanisms need more investigation. To investigate the therapeutic effects of HXC in the treatment of SQBS and elucidate the potential mechanism, we used a high-throughput metabolomics strategy based on the ultraperformance liquid chromatography/mass spectrometry combined with chemometrics to analyze and identify differential metabolites and pathways. The pathological examination of organs and biochemical indices was also performed to verify the successful establishment of the rat model and protective effects of HXC. Pathological symptoms and biochemical indicators of SQBS rats were reversed by the HXC treatment. A total of 24 potential biomarkers were identified to indicate the difference between the control and model groups; they were closely associated with ten metabolic pathways and regulated by the HXC administration. From the pathway analysis, we further understood the protective activity of HXC against SQBS, which affected amino acid metabolism, molecular transport, small molecule biochemistry and cell signaling as well as vitamin and mineral metabolism. In conclusion, HXC protects against SQBS by modulating the metabolic biomarkers and functional pathways.

Blood stasis syndrome (BSS) is an important pathological condition in traditional East Asian medicine and is associated with ischemic heart disease, cerebral vascular accident, diabetes mellitus, chronic renal failure, severe traumatic injury, and dysmenorrhea. However, previous studies have been unable to reveal the clinical and biological characteristics or biological markers of BSS. We hypothesized that the heterogeneity among the manifestations of BSS or non-BSS could interfere with an analysis to describe the characteristics of BSS. In this study, male participants based on the severity of BSS-associated symptoms and signs were clustered and classified into four subgroups: BSS subgroups (1), (2), (3), and (4). Non-BSS core subgroup was redefined using manifestation cluster analysis. Biological characteristics of subgroups BSS(1) and BSS(2) belong to the range of the non-BSS core subgroup (1), whereas that of subgroups BSS(3) and BSS(4) are characterized by different biological parameters such as systemic inflammatory conditions and elevated D-dimer level. Our results suggested that patients in subgroups of BSS(3) and BSS(4) are more likely to be exposed in an inflammatory state than other BSS subgroups. We found the heterogeneity among the manifestations which could mask the characteristics of BSS and identified the clinical and biological profiles of the four BSS subgroups through comparisons of the redefined non-BSS and BSS subgroups. This finding could provide accurate diagnostic criteria and new approaches for BSS treatments in different subgroups.

To observe the effect of regulating qi and invigorate blood circulation method on hemorrheology in rats with acute blood stasis syndrome from the perspective of modern pharmacology, and use network pharmacology to explain its mechanism. Forty male Wistar rats were randomly divided into 6 groups. Except the blank control group, the other groups were injected with adrenaline hydrochloride and ice bath to establish the acute blood stasis syndrome model. Each group were administered Xuefu Zhuyu D ecoction, Jinlingzi Powder, Taohong Siwu Decoction, and Yanhusuo Decoction, and t he blank control group and model control group were given the same volume of saline, respectively. The blood rheology indexes such as red blood cell aggregation index of rats were measured. The TCMSP and Batman database were used to search for chemical components and targets of Jinlingzi Powder, and protein interaction analysis, GO enrichment analysis and KEGG analysis were performed on the common targets. The experimental results show that, compared with the model group, the blood rheology index levels of the Yanhusuo group and Taohong Siwu Decoction group are reduced, while the blood rheology index levels of the Xuefu Zhuyu Decoction group and the Jinlingzi S an group are significantly reduced. The network pharmacology predicts that Jinlingzi Powder has 44 active ingredients and 34 drug-disease shared targets, and KEGG analyzes 61 signaling pathways. Conclusion: IN the case of blood stasis syndrome, the effect of regulating qi with invigorate blood circulation is better than that of regulating qi alone. Network pharmacologic prediction showed that TNF signaling pathway was strongly correlated with hemorheology, and its action pathway was closely related to key tar gets IL6, TNF, CASP3.

Objectives : The aims of the current study were to assess the reliability and validity of the CoRe-Ditec-BS Questionnaire-II (BSQ-II; Blood stasis questionnaire-II) with 8 items including 5 items related women added to BSQ-I that was consisted of 36 items and developed in 2013. Methods : Between May...

To investigate the innate characters of 3 endometriosis (EMT) syndromes, blood stasis (BS), qi stagnation and blood stasis (QSBS) as well as Shen (Kidney) deficiency and blood stasis (KDBS) in terms of proteomics, lay a molecular biological basis for the differentiation of various blood stasis syndromes of EMT, establish a EMT microscopic syndrome differentiation and diagnosis system in terms of proteomics, discover the evolution principles and therapeutic targets of these EMT syndromes, and search their signifificant molecular markers and genetic intervention targets. Six specimens from the ectopic and entopic endometrium tissues of patients with EMT in each syndrome, BS, QSBS as well as KDBS, in the early proliferative phase of the menstrual cycle, and 6 specimens from normal endometrium tissues in the early proliferative phase of the menstrual cycle were obtained. Three groups were formed in each syndrome by mixing two random specimens in equal amount, and then their respective two-dimensional electrophoresis graphs were obtained after total protein extraction. Finally, the detected differences in protein expression were identifified through matrix-assisted laser desorption Ionization-time of flflight mass spectrometry (MALDI-TOF/MS) and protein database. The results of differential proteins expressed in each syndrome were shown as follows: BS syndrome had 2 differential proteins in entopic endometrium and 1 differential protein in ectopic endometrium; KDBS syndrome had 3 in entopic endometrium and 3 in ectopic endometrium; and QSBS syndrome had 3 in entopic endometrium and 4 in ectopic endometrium. It was found out that annexin was highly expressed in both entopic and ectopic endometrium of KDBS syndrome; and myosin light chain 3 was highly expressed in both entopic and ectopic endometrium of QSBS syndrome. There are differential protein expressions among the 3 EMT syndromes, which might be the inner origin of syndrome characters, and these differential proteins might be the candidate biomarkers for the pathogenesis of various EMT syndromes.

Objective To screen for mRNAs associated with blood stasis syndrome and to explore the genetic mechanisms of blood stasis syndrome in hypertension. Methods This study involved groups of patients with hypertension and blood stasis, including those with Qi deficiency, Qi stagnation, cold retention and heat retention; as well as hypertensive patients without blood stasis and healthy individuals. Human umbilical vein endothelial cells were co-cultured with the sera of these healthy individuals and patients with blood stasis syndrome. Total RNA was extracted from these cells and assessed by a high-throughput sequencing method (Solexa) and digital gene expression. Differentially expressed genes among these six groups were compared using whole genome sequences, and mRNAs associated with blood stasis syndrome identified. Differences in gene use and gene ontology function were analyzed. Genes enriched significantly and their pathways were determined, as were network interactions, and encoded proteins. Gene identities were confirmed by real-time polymerase chain reactions. Results Compared with cells cultured in sera of the blood stasis groups, those culture in sera of healthy individuals and of the non-blood stasis group showed 11 and 301 differences, respectively in stasis-related genes. Genes identified as differing between the blood stasis and healthy groups included activating transcription factor 4, activating transcription factor 3, DNA-damage inducible transcription factor 3, Tribbles homolog 3, CCAAT/enhancer binding protein-β, and Jun proto-oncogene (JUN). Pathway and protein interaction network analyses showed that these genes were associated with endoplasmic reticulum stress. Cells cultured in sera of patients with blood stasis and Qi deficiency, Qi stagnation, heat retention, and cold retention were compared with cells cultured in sera of patients with the other types blood stasis syndrome. The comparison showed differences in expression of 28,28,34, and 32 specific genes, respectively. Conclusion The pathogenesis of blood stasis syndrome in hypertension is related to endoplasmic reticulum stress and involves the differential expression of the activating transcription factor 4, activating transcription factor 3, DNA-damage inducible transcription factor 3, Tribbles homolog 3, CCAAT/enhancer binding protein-β, and JUN genes.