Reshaping the gut microbiome and bile acid composition by Gyejibongnyeong-hwan ameliorates western diet-induced dyslipidemia.

Gyejibongnyeong-hwan (GBH), a traditional Chinese medicine, is used in clinical practice to treat blood stasis in metabolic diseases. Herein, we examined the effects of GBH on dyslipidemia and investigated the underlying mechanisms by focusing on modulation of the gut microbiota-bile acid axis by GBH. We utilized a Western diet-induced dyslipidemia mouse model and divided animals into the following four groups (n = 5 each): the normal chow diet, vehicle control (WD), simvastatin (Sim, 10 mg/kg/day simvastatin; positive control), and GBH (GBH, 300 mg/kg/day) groups. The drugs were administered for 10 weeks, and morphological changes in the liver and aorta were analyzed. The mRNA expression of genes related to cholesterol metabolism, gut microbiota, and bile acid profiles were also evaluated. The GBH group showed significantly lower levels of total cholesterol, accumulation of lipids, and inflammatory markers in the liver and aorta of Western diet-fed mice. Low-density lipoprotein cholesterol levels were significantly lower in the GBH group than in the WD group (P < 0.001). The expression of cholesterol excretion-associated genes such as liver X receptor alpha and ATP-binding cassette subfamily G member 8, as well as the bile acid synthesis gene cholesterol 7 alpha-hydroxylase, which lowers cholesterol in circulation, was increased. Furthermore, GBH inhibited the intestinal farnesoid X receptor (FXR)-fibroblast growth factor 15 signaling pathway through the interactions of gut microbiota with bile acids acting as FXR ligands, which included chenodeoxycholic acid and lithocholic acid. Overall, GBH improved dyslipidemia induced by a Western diet by modulating the gut microbiota-bile acid axis.

Anti-Obesity Effects of Aqueous Extracts of Sunbanghwalmyung-Eum in High-Fat- and High-Cholesterol-Diet-Induced Obese C57BL/6J Mice.

Sunbanghwalmyung-eum (SBH) is a traditional herbal medicine that exhibits various pharmacological properties, such as antioxidant, anti-inflammatory, and anticancer activities. In this study, we investigated the systemic anti-obesity effects of an aqueous extract of SBH in the liver, adipose, and muscle tissue from high-fat and high-cholesterol diet (HFHCD)-induced obese C57BL/6J mice. After 6 weeks of an HFHCD, the mice were continuously fed HFHC with oral administration of SBH (100 mg/kg/day), Sim (simvastatin, 5 mg/kg/day, positive control), or water (HFHC only) for another 6 weeks. Our results showed that SBH attenuated the HFHCD-induced body weight gain and fat accumulation in the liver, and improved plasma lipid levels, such as those of triglycerides (TGs), blood total cholesterol (TC), and low-density lipoprotein (LDL-c). SBH and Sim inhibited the inflammation accompanied by obesity via decreasing inflammatory cytokine interleukin (IL)-1ß, tumor necrosis factor α (TNFα), and monocyte chemoattractant protein 1 (MCP1). Moreover, SBH downregulated the expression of protein levels of adipogenic-related factors, including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), in the liver, adipose, and muscle tissue. The SBH and Sim treatment also significantly upregulated the phosphorylation of AMP-activated protein kinase α (AMPKα) in the liver and hormone-sensitive lipase (HSL) in the adipose tissue. Overall, the effects of SBH on HFHCD-induced obesity were similar to or more potent than those of simvastatin. These results indicated that SBH has great potential as a therapeutic herbal medicine for obesity.

Metabolomic analysis of Gyejibongnyeong-Hwan for shoulder pain: A randomized, wait-list controlled pilot trial.

BACKGROUND: In Korea, Gyejibongnyeong-Hwan (GBH), a herbal decoction used to treat blood stasis (BS), is widely used to treat shoulder pain in clinics. Nevertheless, the therapeutic mechanism of GBH in alleviating shoulder pain has not yet been elucidated. PURPOSE: In this study, we applied mass spectrometry-based metabolomics to explore the therapeutic mechanism of GBH in BS-induced shoulder pain. STUDY DESIGN: We conducted a two-center, randomized, wait-list controlled pilot trial to explore the therapeutic effect of GBH on shoulder discomfort related to BS. METHODS: A total of 40 participants with shoulder pain were randomly assigned to either the immediate treatment (GBH-Treat; n = 20) or waiting treatment (Wait-List; n = 20) group. A non-targeted metabolomics approach was then applied to investigate the therapeutic mechanism of GBH. RESULTS: After 8 weeks of treatment, the visual analog scale (VAS) scores for shoulder pain decreased significantly in the GBH-Treat and Wait-List groups compared with baseline VAS scores (p = 0.004 and p = 0.013, respectively). However, the VAS and BS scores were significantly more reduced in the GBH-Treat group than in the Wait-List group. The plasma metabolic pattern between GBH-Treat and Wait-List groups also differed significantly, which was shown by the score plot of a partial least-squared-discriminant analysis (R2 = 0.806 and Q2 = 0.229, p = 0.016). Arginine, bilirubin, carnitine, glutamine, maltol, mystic acid, N,N dimethylarginine, trimethylamine N-oxide, valine, kynurenine, and linoleic acid significantly contributed to the different metabolic patterns between the GBH-Treat and Wait-List groups (all p < 0.05). Pathway analysis revealed that these metabolites were involved in arginine biosynthesis and tryptophan metabolism, which are related to pain generation and transmission. We also confirmed that the ratio of kynurenine to tryptophan, one of the indicators for chronic pain and neuro-inflammation, was significantly lower in the GBH-Treat group than in the Wait-List group (p = 0.02). CONCLUSION: These results demonstrated that GBH may be a potential treatment option for shoulder pain, and it acts by regulating metabolic patterns. In particular, our study provides evidence for the use of GBH treatment for patients with should pain caused by BS, and we believe that our findings can provide evidence for precision medicine based on traditional Chinese medicine (TCM) or traditional Korean medicine (TKM). We also verified that metabolomics studies provide comprehensive understanding of herbal decoctions in TCM or TKM.

Effects of Bojungikgi-tang on anorexic patients with atopic dermatitis: A protocol for a randomized, usual care-controlled, assessor-blinded, parallel, pilot clinical trial.

BACKGROUND: Anorexia and atopic dermatitis (AD) are highly prevalent diseases, and the herbal medicine Bojungikgi-tang (BJT) has been frequently used for the treatment of both anorexia and AD. However, no study has simultaneously evaluated the effects of BJT for both anorexia and AD. METHODS: A prospective, randomized, usual care-controlled, assessor-blinded. parallel, pilot clinical trial has been designed to explore the feasibility, preliminary effectiveness, and safety of BJT for the treatment of anorexic patients with AD. Forty anorexic patients with AD will be randomly assigned (1:1) to BJT or the usual care group. The BJT group will be administered BJT granules twice a day for 8 weeks and followed up for 4 weeks whereas the usual care group will not receive BJT granules. All participants in both groups will be provided with over-the-counter topical corticosteroids as a relief drug. Data will be collected at baseline and at 4, 8, and 12 weeks after randomization. The primary outcome is the score on the anorexia visual analog scale at 8 weeks post-treatment. The secondary outcomes include body weight, body fat percentage, body fat mass, skeletal muscle mass, SCORing of Atopic Dermatitis index, Validated Investigator Global Assessment scale for Atopic Dermatitis, Dermatology Life Quality Index, EuroQoL 5 Dimension 5 Level, deficiency and excess pattern identification questionnaire, total immunoglobulin E, eosinophil count, and frequency and amount of use of topical corticosteroids. Adverse events and laboratory test results will be monitored to assess safety. Fecal samples to check for gut microbiome changes and blood samples to check immune and metabolic markers will be collected before and after taking BJT. DISCUSSION: This is the first trial that explores the preliminary effectiveness and safety of BJT for the treatment of anorexic patients with AD. The results of this pilot study will provide the basic evidence for large-scale, confirmatory, multicenter, high-quality clinical trials. TRIAL REGISTRATION: Clinical Research Information Service, KCT0006784 (registered on November 26, 2021).

Modulation of the Gut Microbiota by Sihocheonggan-Tang Shapes the Immune Responses of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by complex immune dysregulation and closely related to the gut microbiome. The present study investigated the microbiome-mediated effect of Sihocheonggan-Tang (SHCGT) on AD-like symptoms induced by 2,4-dinitrochlorobenzene (DNCB) in BALB/c mice. DNCB was applied regularly to the ear and dorsal skin of BALB/c mice, and SHCGT was administered orally daily for 2 weeks. The composition of the gut microbiota was analyzed using 16S rRNA sequencing, and the effect of gut microbiome-derived metabolites, specifically short-chain fatty acids (SCFAs), was evaluated in tumor necrosis factor-alpha (TNF-α)- and interferon-gamma (IFN-γ)-treated HaCaT cells. SHCGT alleviated DNCB-induced symptoms of AD and the immune response to AD by decreasing the plasma immunoglobulin E level and splenic interleukin-4, interleukin-10, TNF-α, and IFN-γ levels. The gut microbiome composition and the damaged gut epithelial barrier in mice with AD were also significantly altered by SHCGT, and the reduced SCFA levels therein were elevated. We found that SFCAs directly inhibited the mRNA expression of IL-6 and ICAM-1 in TNF-α- and INF-γ-treated HaCaT cells. The finding that SHCGT regulates the gut microbiome and improves DNCB-induced AD in mice suggests that this herbal medicine has therapeutic potential in patients with AD.

Electromyographic changes in masseter and sternocleidomastoid muscles can be applied to diagnose of temporomandibular disorders: An observational study.

BACKGROUND: The diagnosis of temporomandibular disorders (TMDs) is an important part of the functional cerebrospinal technique (FCST). In addition, surface electromyography (sEMG) is an important candidate for diagnosing TMD. In FCST, despite the importance of the cranio-cervical-mandibular system, few sEMG parameters consider TMDs. Thus, this study evaluated the possibility of TMD diagnosis by sEMG. METHODS: The study was conducted as an assessor-blinded cross-sectional study. Each of 35 participants were recruited for patient group and normal group separately based on the Diagnostic Criteria for TMD Symptoms Questionnaire (DC/TMD SQ). The sEMG was measured by attaching electrodes to sternocleidomastoid muscles (SCMM) and masseter muscles (MM) before and after wearing the temporomandibular joint balance appliance (TBA). RESULTS: The percentage overlapping coefficient (POC) value of the healthy control group was increased compared with the TMD group. Receiver operating characteristic (ROC) analysis revealed that the area under the curve (AUC) value of the SCMM was greater than that of the MM. POC values before and after the SCMM also revealed significant changes compared to the MM. CONCLUSION: This study showed that the sEMG measurement of the SCMM is useful for TMD diagnosis in traditional Korean medicine.

Association of serum resistin with blood stasis syndrome in traditional Korean medicine for metabolic diseases: A cross-sectional multicenter observational study.

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.

Lipidomics reveals that acupuncture modulates the lipid metabolism and inflammatory interaction in a mouse model of depression.

Depression is a serious disease that has considerable impact on lipid metabolism and inflammatory responses. Recent studies have shown that leptin, which is well known as a mediator of energy homeostasis and is a cytokine in inflammatory response, plays an important role in depression. Acupuncture is widely used to treat depression; however, the underlying mechanisms and the effect of acupuncture on depression remain poorly understood. In this study, we utilized the chronic restraint stress (CRS) induced depression model and acupuncture treatment was performed at KI10, LR8, LU8, LR4 (AP) or non-acupoint (NP). Then, lipidomics was applied to investigate the effects of acupuncture on lipid metabolism and analyze leptin signals in the brain and changes of immune markers. Acupuncture treatment at AP improved depression-like behavior in an open-field test, forced swimming test, and marble burying test. Concurrently, CRS mice treated with AP acupuncture (CRS + AP) had significantly lower levels of aspartate aminotransaminase (AST, liver injury markers) and exhibited different lipid patterns in liver lipidomic profiles. In particular, triglycerides (TGs) contributed the change of lipid patterns. Compared to the CRS mice, TGs with relatively high degrees of unsaturated fatty acids increased in the CRS + AP mice, but did not change in CRS mice treated with NP acupuncture (CRS + NP). The levels of leptin in plasma and leptin receptor positive cells in the brain (hypothalamus and hippocampus) decreased and increased, respectively, in the CRS + AP mice, while opposite patterns were exhibited in the CRS and CRS + NP mice. These results indicated that acupuncture treatment at AP attenuated leptin insensitivity in CRS mice. Additionally, expression of pro-inflammatory cytokines such as interleukin-1 beta and tumor necrosis factor-alpha were decreased in the spleen, plasma, and liver of CRS + AP mice, which was one of results of alleviation of leptin resistance. In conclusion, these results show that AP acupuncture treatment effectively alleviated the depression-like behavior, affected immune responses, and altered hepatic lipid metabolism through the attenuation of leptin insensitivity.

Tongqiaohuoxue Hinders Development and Progression of Atherosclerosis: A Possible Role in Alzheimer's Disease.

Atherosclerosis is closely associated with Alzheimer's disease (AD). Tongqiaohuoxue decoction (THD) is a classical herbal prescription in traditional Chinese medicine widely used for the prevention and treatment of cerebrovascular disease. This study aimed to explore the therapeutic effects of THD on atherosclerosis and AD. Eight-week-old C57BL6/J wild-type and ApoE-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for eight weeks, followed by oral phosphate-buffered saline vehicle or THD treatment for eight weeks further. In ApoE-/- mice, THD attenuated lipid deposition in the aorta and the brain, and abrogated atherosclerotic changes without affecting serum lipid profiles while decreasing amyloid plaque formation. In vitro assays undertaken to understand THD's effects on lipid clearance in the aorta and brain vessels revealed that THD treatment inhibited the lipid uptake, stimulated by oxidized low-density lipoprotein, resulted in decreased endothelial cell activation through reduction in intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 levels. Serum analysis revealed inhibitory effects of THD on resistin production, which has important roles in the development of both atherosclerosis and AD. In conclusion, the current study demonstrates beneficial effects of THD on the development and progression of atherosclerosis, and a possible protective role against AD.

Integrated omics analysis unraveled the microbiome-mediated effects of Yijin-Tang on hepatosteatosis and insulin resistance in obese mouse.

BACKGROUND: Gut microbiota play important roles in insulin homeostasis and the pathogenesis of non-alcoholic fatty liver diseases (NAFLD). Yijin-Tang (YJT), a traditional Korean and Chinese medicine, is used in the treatment of gastrointestinal diseases and obesity-related disorders such as insulin resistance (IR) and NAFLD. PURPOSE: Our aim was to identify the microbiome-mediated effects of YJT on IR and associated NAFLD by integrating metagenomics and hepatic lipid profile. METHODS: C57BL/6J mice were fed a normal chow diet (NC) or high-fat/high-cholesterol (HFHC) diet with or without YJT treatment. Hepatic lipid profiles were analyzed using liquid chromatography/mass spectrometry, and the composition of gut microbiota was investigated using 16S rRNA sequencing. Then, hepatic lipid profiles, gut microbiome, and inflammatory marker data were integrated using multivariate analysis and bioinformatics tools. RESULTS: YJT improved NAFLD, and 39 hepatic lipid metabolites were altered by YJT in a dose-dependent manner. YJT also altered the gut microbiome composition in HFHC-fed mice. In particular, Faecalibaculum rodentium and Bacteroides acidifaciens were altered by YJT in a dose-dependent manner. Also, we found significant correlation among hepatic phosphatidylglycerol metabolites, F. rodentium, and γδ-T cells. Moreover, interleukin (IL)-17, which is secreted by the γδ-T cell when it recognizes lipid antigens, were elevated in HFHC mice and decreased by YJT treatment. In addition, YJT increased the relative abundance of B. acidifaciens in NC or HFHC-fed mice, which is a gut microbiota that mediates anti-obesity and anti-diabetic effects by modulating the gut environment. We also confirmed that YJT ameliorated the gut tight junctions and increased short chain fatty acid (SCFA) levels in the intestine, which resulted in improved IR. CONCLUSION: These data demonstrated that gut microbiome and hepatic lipid profiles are regulated by YJT, which improved the IR and NAFLD in mice with diet-induced obesity.

An observational study on diagnosis index of metabolic disease with blood-stasis.

INTRODUCTION: Treating blood stasis is effective in treating obesity and metabolic diseases in traditional Korean medicine. The aim of this prospective observational study is to determine the effectiveness of the diagnosis index for metabolic diseases with blood stasis by analyzing clinical data and blood samples. METHODS AND ANALYSIS: We will perform a prospective observational study. Participants who meet the inclusion criteria will be recruited from the Dongguk university Ilsan Oriental hospital. The outcomes are resistin, serum amyloid P component, C-reactive protein, D-dimer, and blood stasis scores. In addition, the blood pressure, ankle-brachial pressure index, brachial-ankle pulse wave velocity, body mass index, waist circumference, and levels of blood lipid will be assessed. DISCUSSION: Through this study, we could collect specific data for diagnosing metabolic diseases with blood stasis. Therefore, the findings of this study will provide a summary of the current state of evidence regarding the effectiveness of the diagnosis index in managing metabolic disease with blood stasis. ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Board of the Dongguk University Ilsan Oriental Hospital (DUIOH-2018-09-001-007). The results will be published in a peer-reviewed journal and will be disseminated electronically and in print. TRIAL REGISTRATION NUMBER: Clinical Research Information Service: KCT0003548.

Safety and efficacy of an herbal formula, Gwakhyangjeonggi-san on atopic dermatitis with gastrointestinal symptoms: Protocol for a randomized controlled trial.

INTRODUCTION: Gwakhyangjeonggi-san (GJS) is an herbal formula with anti-inflammatory and anti-allergic properties that is broadly used to treat a wide range of diseases including gastrointestinal disorders and allergic diseases. There have been several clinical studies conducted on its effects on atopic dermatitis (AD). So far, no randomized controlled trials have been conducted. Here, we describe the protocol for a randomized controlled study designed to investigate the efficacy and safety of GJS for treating patients with AD that have gastrointestinal symptoms. METHODS AND ANALYSIS: A randomized, double-blind, placebo-controlled, parallel-group, clinical trial has been designed to investigate the clinical efficacy and safety of GJS on patients with AD that have gastrointestinal symptoms. A total of 58 participants with AD will be recruited and randomly allocated to the GJS or placebo group in a 1:1 ratio. The participants will be administered GJS or placebo granules 3 times a day for 8 weeks. Data will be collected from the participants at baseline and after 4 and 8 weeks. The primary outcome measure will be the mean change in the SCORing of Atopic Dermatitis (SCORAD) index from baseline to 8 weeks. The secondary outcomes will include the eczema area and severity index (EASI), dermatology life quality index (DLQI), EuroQoL 5 dimensions 5 levels (EQ-5D-5L), and immunological factors. The Korean Gastrointestinal Symptom Rating Scale (KGSRS), Nepean Dyspepsia Index will also be obtained for assessing the gastrointestinal status. DISCUSSION: The findings of this study are expected to provide evidence on the safety and effectiveness of GJS and for treating patients with AD that have gastrointestinal symptoms. Additionally, the study will explore the mechanism of GJS action via gut microbiome. This study will provide new perspectives on approaching treatment for AD. ETHICS AND DISSEMINATION: The study protocol was approved by the Institutional Review Board of Kyung Hee University Korean Medicine Hospital at Gangdong (KHNMCOH2019-06-002-001). TRIAL REGISTRATION NUMBER: This study has been registered at the Korean National Clinical Trial Registry, Clinical Research Information Service (KCT0004299).

An unbiased lipidomics approach identifies key lipid molecules as potential therapeutic targets of Dohongsamul-tang against non-alcoholic fatty liver diseases in a mouse model of obesity.

ETHNOPHARMACOLOGICAL RELEVANCE: Dohongsamul-tang (DST) is a traditional herbal formula used to promote the blood circulation and inhibit inflammation, and also widely has been used in the treatment of patients with chronic liver diseases in Korea and China. AIM OF THE STUDY: This study aimed to investigate the effect of DST on regulation of lipid metabolism of chronic liver diseases in mouse model of non-alcoholic fatty liver diseases (NAFLD). MATERIALS AND METHODS: In this study, we evaluated the effect of DST on high-fat and high-cholesterol diet (HFHC, 40% fat and 1% cholesterol)-induced NAFLD, and applied unbiased lipidomics using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF MS) coupled with multivariate analysis. RESULTS: DST improved hepatic morphology and reduced levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In addition, DST inhibited hepatic lipid accumulation through the downregulation of C/EBPα, PPARγ, and pAMPK. To further elucidate the effect of DST on hepatic lipid metabolism, we applied UPLC/Q-TOF MS-based lipidomics. The score plots of partial least squares-discriminant analysis (PLS-DA) showed that DST changed the lipid metabolic pattern of high-fat and high-cholesterol diet (HFHC) mice. Twenty-two lipid metabolites were selected as biomarkers regulated by DST and pathway analysis revealed that sphingolipid metabolism and glycerophospholipid metabolism were associated with the effect of DST on NAFLD. Among the 22 selected biomarkers, 14 were phospholipids, and DST significantly reversed the increased expression of lysophospholipase 3 (LYPLA3) and neuropathy target esterase (NTE), which are key enzymes in glycerophospholipid metabolism. Given that alterations in sphingolipids and phospholipids can have effects on apoptosis and insulin resistance (IR), we subsequently investigated changes in the expression of apoptosis-related proteins, including Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl2), and IR-related markers after DST treatment. We accordingly found that the ratio of Bax to Bcl-2 expression, a maker of apoptosis, was also elevated in HFHC mice and reduced by DST treatment. In addition, DST enhanced hepatic insulin signaling by upregulating the expression of insulin receptor substrate 1 (IRS-1) and phospho-protein kinase B (pAKT), and oral glucose tolerance test (OGTT) analysis indicated that this herbal preparation also ameliorated systemic IR. CONCLUSIONS: This study suggested that DST might have an effect on NAFLD by regulating the metabolism of lipids such as phospholipids and sphingolipids and demonstrated that lipidomic profiling is useful to investigate the therapeutic effects of herbal decoctions from traditional Korean and Chinese medicine.

Effectiveness of Gyejibongnyeong-Hwan for shoulder pain: study protocol for a randomised, wait-list controlled pilot trial.

BACKGROUND: Shoulder pain is an uncomfortable feeling in the muscle around the shoulder. The cause of myalgia is the accumulation of lactic acid in muscles and impaired blood circulation, which is called blood stasis in traditional East Asian medicine. This study aimed to explore the therapeutic effect of Gyejibongnyeong-Hwan (GBH) for shoulder discomfort related to blood stasis before and after treatment. METHODS/DESIGN: This study will be a double-centre, randomised, wait-list controlled pilot trial. Participants with shoulder pain and with a visual analogue scale score of 4 or higher out of 10, blood stasis score of 9 or higher, and triglyceride level of ≥150 mg/dl or total cholesterol level of ≥200 mg/dl will be recruited from two university hospitals. A total of 40 participants will be assigned to the immediate and waiting treatment groups. The immediate treatment group will receive GBH for 8 weeks on enrolment while the waiting treatment group will receive GBH for 8-16 weeks after 8 weeks of controlled waiting. The primary outcome is shoulder pain, and the secondary outcomes are the blood stasis score, blood pressure, ankle-brachial pressure index, brachial-ankle pulse wave velocity, body mass index, waist circumference, indexes of oximetry, and levels of blood lipid, blood sugar, resistin, C-reactive protein, serum amyloid P, and D-dimer. DISCUSSION: The results of this pilot trial will be the bases for a full-scale clinical trial of GBH. TRIAL REGISTRATION: Clinical Research Information Service, KCT0003837. Registered on 23 April 2019. https://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=14258.

Lipidomic analysis reveals therapeutic effects of Yijin-Tang on high-fat/high-cholesterol diet-induced obese mice.

BACKGROUND: In Traditional Korean and Chinese medicine, the herbal remedy Yijin (Erchen)-Tang (YJT) is widely used to treat obesity-related disorders, and its therapeutic potential has been demonstrated in numerous studies. However, the systemic effect of YJT on obesity status and change of lipid metabolism by YJT still remains unknown. PURPOSE: This study aimed to investigate the therapeutic mechanism of the YJT on obesity by using lipidomics. METHODS: To evaluate the effects of treatment with YJT on obesity, C57BL/6 J mice were fed a high-fat and high-cholesterol (HFHC, 40% fat and 1% cholesterol) diet for 8 weeks and treated them with YJT for an additional 6 weeks. We then performed untargeted lipidomic analysis using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry mass spectroscopy coupled with multivariate statistical analysis. RESULTS: YJT ameliorated obesity induced systemic inflammation and improved insulin resistance. Additionally, YJT protected against HFHC-diet-induced hepatic inflammation. To explore specific changes in lipid metabolism associated with the therapeutic effects of YJT, we performed untargeted lipid profiling of the plasma. Partial least squares-discriminant analysis (PLS-DA) score plots showed that YJT altered the lipid metabolic pattern of HFHC mice. In particular, ceramides and triglycerides with saturated fatty acids and monounsaturated fatty acids were significantly changed by YJT, which were significantly associated with insulin resistance, the AGE-RAGE signaling pathway in diabetic complications and adipocytokine signaling pathway in pathway enrichment analysis. Thus, we analyzed the changes in adipocytes and adipokine caused by YJT, and confirmed that YJT alleviated adipocytes inflammation and macrophage infiltration, and reversed HFHC-induced alterations in leptin and adiponectin levels in adipose tissue and plasma. CONCLUSION: These data suggest that YJT ameliorates obesity-induced systemic inflammation and insulin resistance by regulating lipid metabolism, and demonstrated that lipidomic profiling is a useful method to investigate the therapeutic effects of herbal decoctions in traditional Korean and Chinese medicine.

Treating nasal symptoms associated with rhinitis using the intranasal herbal ointment Biyeom-go: A prospective observational study.

OBJECTIVES: The aim of the current study was to investigate the effectiveness and clinical feasibility of Biyeom-go for the treatment of nasal symptoms associated with rhinitis. DESIGN: Prospective observational study. SETTING: This study was conducted at the Woosuk Korean Medicine Medical Center in South Korea. PARTICIPANTS: Fifty-eight patients with rhinitis participated in this study. All patients received Biyeom-go treatment >3 times daily for a total of 4 weeks. MAIN OUTCOME MEASURES: The primary outcome was the total nasal symptom score. Mini-rhinoconjunctivitis quality of life questionnaire, nasal endoscopy index, total serum immunoglobulin E levels and immunologic factors in nasal lavage fluid were also measured. RESULTS: Biyeom-go administration was associated with significant improvements in total nasal symptoms scores (P < .0001) and mini-rhinoconjunctivitis quality of life questionnaire scores (P < .0001) in a time-dependent manner. The nasal endoscopy index also significantly improved at weeks 2 (P = .0049), 3 (P < .0001) and 4 (P = .0001) after Biyeom-go treatment. Significantly, increased interleukin-2 levels (P = .005) and decreased interleukin-8, chemokine (C-C motif) ligand (CCL) 5, chemokine (C-X-C motif) ligand (CXCL) 9, CCL2 and CXCL10 levels were observed in the nasal lavage fluid. CONCLUSIONS: The present findings suggest that Biyeom-go may be beneficial for the management of rhinitis symptoms and rhinitis-associated quality of life. Further well-designed randomised controlled trials are needed to evaluate the effectiveness of Biyeom-go for rhinitis.

A Study on the Development of a Korean Metabolic Syndrome Questionnaire Using Blood Stasis Clinical Data.

OBJECTIVE: The aims of this study were to extract clinical indicators related to metabolic diseases using the Blood Stasis Questionnaires I and II (BSQ-I and II) developed in 2013 and 2014, respectively, and to develop a BSQ on metabolic syndrome (BSQ-MS). METHODS: A total of 2,158 patients, comprising 1,214 from 7 traditional Korean medical hospitals in 2013 and 944 from 3 traditional Korean medical hospitals in 2014, were asked to complete the BSQ-I and BSQ-II. For the 370 patients who met the metabolic syndrome criteria, reliability and validity of the BSQ-MS were assessed using Cronbach's alpha, while prediction accuracy was determined by logistic regression. RESULTS: The BSQ-MS included a total of 15 clinical signs and symptoms. It showed satisfactory internal consistency (Cronbach's α coefficient=0.70) and validity, with significant differences in mean scores between the blood stasis (14.09±6.14) and non-blood stasis (9.09±5.60) subject groups. The cut-off value of BSQ-MS score was 9 points, the area under the receiver operating characteristic curve was approximately 77%, the sensitivity and specificity of the diagnostic accuracy according to the cut-off value were 82.9% and 49.7%, respectively, and the sensitivity and specificity of the prediction accuracy by logistic regression were 72.2% and 71.6%, respectively. CONCLUSION: These results suggest that the BSQ-MS is an appropriate instrument for estimating blood stasis in patients with metabolic syndrome, although its sensitivity for diagnosis according to the cut-off value is low.

Effects of Acupuncture on Chronic Stress-Induced Depression-Like Behavior and Its Central Neural Mechanism.

Depression is a serious psychiatric disorder with an enormous socioeconomic burden, and it is commonly comorbid with pain, chronic fatigue, or other inflammatory diseases. Recent studies have shown that acupuncture is an effective therapeutic method for reducing depressive symptoms; however, the underlying mechanism remains unknown. In this study, we investigated the effects of acupuncture on chronic stress-induced depression-like behavior and its central neural mechanisms in the brain. We induced chronic restraint stress (CRS) in male C57BL/6 mice for 14 or 28 consecutive days. Acupuncture treatment was performed at KI10·LR8·LU8·LR4 or control points for 7 or 14 days. Depression-like behavior was assessed with the open field test. Then, brain neural activity involving c-Fos and serotonin-related mechanisms via the 5-HT1A and 5-HT1B receptors were investigated. Acupuncture treatment at KI10·LR8·LU8·LR4 points rescued the depressive-like behavior, while control points (LU8·LR4·HT8·LR2) and non-acupoints on the hips did not. Brain neural activity was changed in the hippocampus, cingulate cortex, motor cortex, insular cortex, thalamus, and the hypothalamus after acupuncture treatment. Acupuncture treatment increased expression of 5-HT1A receptor in the cortex, hippocampus, thalamus, and the hypothalamus, and of 5-HT1B in the cortex and thalamus. In conclusion, acupuncture treatment at KI10·LR8·LU8·LR4 was effective in alleviating the depressive-like behavior in mice, and this therapeutic effect was produced through central brain neural activity and serotonin receptor modulation.

Four Subgroups of Blood Stasis Syndrome Are Identified by Manifestation Cluster Analysis in Males.

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.

Herbal medicines for metabolic diseases with blood stasis: A protocol for a systematic review and meta-analysis.

BACKGROUND: Herbal medicines have the potential to be alternative treatments for metabolic diseases. This systematic review will assess the efficacy of herbal medicines in treating metabolic diseases with blood stasis. METHODS AND ANALYSIS: We will search MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, 2 Korean medical databases (OASIS, NDSL), a Chinese database (China National Knowledge Infrastructure, CNKI), and a Japanese database (J-STAGE) for relevant literature. We will include all randomized controlled trials (RCTs) or quasi-RCTs evaluating the effectiveness of herbal medicine. Participants of both sexes and of any age with clinically diagnosed metabolic disease with blood stasis will be included. Primary outcomes will include Blood-stasis syndrome score, TC, TG, HDL-C and LDL-C. Secondary outcomes will Blood pressure, FBS. ECG, prevalence rate of heart disease, and response rate. The risk of bias will be assessed using the Cochrane tool for assessing risk of bias. DISCUSSION: The findings of this study will provide a summary of the current state of evidence regarding the effectiveness of types of herbal medicine in managing metabolic disease with blood stasis. In addition, this review will be expected to provide a base for clinical trials to confirm the efficacy of herbal medicine for treatments of metabolic disease with blood stasis. TRIAL REGISTRATION NUMBER: PROSPERO 2018 CRD42018090179.