Qing-Xin-Jie-Yu Granule inhibits ferroptosis and stabilizes atherosclerotic plaques by regulating the GPX4/xCT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Qing-Xin-Jie-Yu Granule (QXJYG) is an integrated traditional Chinese medicine formula used to treat atherosclerotic (AS) cardiovascular diseases. A randomized controlled trial found that QXJYG reduced cardiovascular events and experiments also verified that QXJYG attenuated AS by remodeling the intestinal flora. AIM OF THE STUDY: To determine whether QXJYG would attenuate AS and plaque vulnerability by regulating ferroptosis in high-fat diet-induced atherosclerotic ApoE-/- mice and to investigate the effects of QXJYG on macrophage ferroptosis in RAS-selective lethal 3 (RSL3)-induced J744A.1 cells. METHODS: AS models in ApoE-/- mice and RSL3-induced ferroptosis in J744A.1 cells were established to measure the protective and anti-ferroptotic effects of QXJYG in vivo and in vitro. The glutathione peroxidase 4 (GPX4)/cystine glutamate reverse transporter (xCT) signal pathway was examined by immunohistochemistry and western blotting. RESULTS: QXJYG attenuated AS progression and plaque vulnerability. Characteristic morphological changes of ferroptosis in the QXJYG-treated animals were rare. Total iron was significantly lower in the QXJYG group than in the model group (P < 0.05); QXJYG suppressed the lipid peroxidation (LPO) levels (malondialdehyde), enhanced the antioxidant capacity (superoxide dismutase and glutathione), and reduced inflammatory factors (interleukin [IL]-6, IL-1ß, tumor necrosis factor-α) associated with ferroptosis. Expression of GPX4/xCT in aorta tissues was remarkably increased in the QXJYG group. QXJYG inhibited ferroptosis in J744A.1 macrophages disturbed using RSL3. The Fe2+, LPO, and reactive oxygen species levels were lower in the QXJYG group than in the RSL3 group (P < 0.05). The QXJYG group showed higher expression of the GPX4/xCT signal pathway. CONCLUSION: QXJYG inhibits ferroptosis in vulnerable AS plaques partially via the GPX4/xCT signaling pathway.

Chinese Herbal Medicines and Active Metabolites: Potential Antioxidant Treatments for Atherosclerosis.

Atherosclerosis is a complex chronic disease that occurs in the arterial wall. Oxidative stress plays a crucial role in the occurrence and progression of atherosclerotic plaques. The dominance of oxidative stress over antioxidative capacity generates excess reactive oxygen species, leading to dysfunctions of the endothelium and accelerating atherosclerotic plaque progression. Studies showed that Chinese herbal medicines and traditional Chinese medicine (TCM) might regulate oxidative stress; they have already been used to treat diseases related to atherosclerosis, including stroke and myocardial infarction. This review will summarize the mechanisms of oxidative stress in atherosclerosis and discuss studies of Chinese herbal medicines and TCM preparations treating atherosclerosis, aiming to increase understanding of TCM and stimulate research for new drugs to treat diseases associated with oxidative stress.

Chaihu Longgu Muli decoction, a Chinese herbal formula, for the treatment of insomnia: A systematic review and meta-analysis.

PURPOSE: To review the literature on the efficacy and safety of Chaihu Longgu Muli decoction (CLMD) for insomnia. METHODS: A systematic literature search was performed for five databases up to May of 2019 to identify randomized control trials involving CLMD for patients with insomnia. The experimental group was CLMD monotherapy or CLMD plus conventional treatment. Comparators were placebo, no treatment, or conventional medicine. The main comparison was CLMD against conventional drugs. The primary outcome was sleep quality (assessed using the Pittsburgh Sleep Quality Index, PSQI). The secondary outcomes were clinical effectiveness rate, total sleep time, and adverse event rate. RevMan 5.3 software was used for meta-analysis with effect estimate presented as relative risk (RR) and mean difference (MD) with 95% confidence interval (CI). RESULTS: A total of 22 studies involving 2029 patients were included. All the included studies presented some risk of bias, especially risks of performance, and detection bias. The main meta-analysis showed that CLMD alone was more effective than conventional medications by reducing PSQI (MD = -2.80, 95% CI [-5.48, -0.13], P = .04), improving the clinical effectiveness rate (RR = 1.23, 95% CI [1.16, 1.31], P < .00001), and prolonging total sleep time (MD = 1.01, 95% CI [0.19, 1.83], P = .002). The adverse event rate in the CLMD group was lower than that of the control group (RR = 0.22, 95% CI [0.09, 0.51], P = .0005). CLMD also improved sleep quality better than conventional medications as an adjunct therapy (P < .05). The funnel plot was symmetrical, representing a low risk of publication bias. CONCLUSION: CLMD presented better efficacy and safety than conventional medications and had the potential to become an alternative to conventional medications for the treatment of insomnia. However, as the included studies showed significant risks of bias, these results will need to be confirmed by future double-blind randomized controlled trials. PROSPERO REGISTRATION NUMBER: CRD42019133103.

[Network pharmacology-based study on mechanisms of Danhong Injection in treatment of aspirin resistance].

This paper aims to discuss the potential targets,pathways and possible mechanisms of Danhong Injection in treatment of aspirin resistance by using network pharmacology concept and network analysis technique. Active ingredients and potential targets of Danhong Injection were collected from TCMSP database and the ingredients were further screened based on their topological characteristics. The active ingredients with nodal degree of freedom≥9 were selected as the main active ingredients. Targets related to aspirin resistance were collected from Genecards database. Drug-active ingredient-target-disease network was constructed by using Cytoscape3. 7. 0,and Funrich 3. 1. 3 software was used for gene enrichment analysis. Sixty main active ingredients were screened out from 110 active ingredients of Danhong Injection,including 51 ingredients in Salviae Miltiorrhizae Radix et Rhizoma and 11 ingredients in Carthami Flos,2 of which were both in Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos. In addition,159 potential targets were collected. The results of gene enrichment analysis showed that Danhong Injection could improve aspirin resistance mainly through21 pathways involving coagulation process,inflammatory response and metabolism. This study revealed the effects of Danhong Injection for improving aspirin resistance in multi-component,multi-target and multi-pathway means mainly through regulation in coagulation process,inflammatory response and metabolism,providing more abundant information and basis for subsequent research and experimental work.

Oral Chinese Herbal Medicine for Heart Failure with Preserved Ejection Fraction: A Meta-Analysis.

OBJECTIVE: To evaluate the effectiveness and safety of oral Chinese herbal medicine (OCHM) for heart failure with preserved ejection fraction (HFpEF). METHODS: PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Chinese Biological Medicine Database (CBM), Wanfang Database, Chongqing VIP Information (VIP) and China National Knowledge Infrastructure (CNKI) were searched for appropriate articles from respective inceptions until June 3, 2018. Randomized controlled trials (RCTs) investigating the effectiveness of OCHM for the patients with HFpEF were eligible. Quality assessment was performed by employing the Cochrane Risk of Bias assessment tool. Papers were independently reviewed by two reviewers and analyzed using Cochrane software Revman 5.3. Dichotomous data were analyzed by relative risk (RR) with a 95% confidence interval (CI), while continuous variables were analyzed by using mean difference (MD) with 95% CI for effect size. RESULTS: A total of 16 RCTs involving 1,320 participants were identified. Fourteen of the trials used conventional Western medicine (CWM) as the control, the control of 1 trial was no treatment, and another was placebo. Three of the trials served Chinese patent medicine (CPM) as interventions, and other OCHM were Chinese medicine decoctions (CMDs). Only limited evidence showed experimental group with OCHM may get better effect on brain natriuretic peptide (BNP: MD -37.29, 95% CI -53.08 to -21.50, P<0.00001) or N terminal pro B type natriuretic peptide (NT-proBNP: MD -236.04, 95% CI -356.83 to -115.25, P=0.0001), Minnesota Living with Heart Failure questionnaire (MLHFQ, MD -9.94, 95% CI -16.77 to -3.11, P=0.004), but the results had high heterogeneities. With concerns on 12 of 16 trials, the meta-analysis found that the adjuvant therapy of OCHM might be more effective in increasing overall response rate (RR 1.17, 95% CI 1.11 to 1.24, P<0.00001), when compared with CWM alone. Subgroup meta-analysis between CPMs and CMDs showed that the two CPMs may have more therapeutic effect on MLHFQ, but not on NT-proBNP, and CMD came to the opposite conclusion. No significant differences were found between experimental groups and control groups on 6-min walk test (6MWT). Adverse events, such as more defecation, weakness, cardiopalmus, edema, cough and hypotension, were mild in all groups and disappeared after the easement of pharmacological intervention. CONCLUSIONS: Due to the insufficient quality of trials that were analyzed, it is not appropriate to confirm or deny the potency of OCHMs in treating HFpEF at the present time. More rigorously designed RCTs focusing on primary endpoints with long-term follow-up are warranted to validate the effect of OCHMs for patients with HFpEF.

Efficacy and safety of berberine for dyslipidaemias: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: In recent years, berberine has become widely used as an effective alternative to treat dyslipidaemias; much clinical evidence has emerged. It is important to systematically and critically evaluate the existing evidence. PURPOSE: This study aims to evaluate the efficacy and safety of berberine in patients with dyslipidaemias. STUDY DESIGN: A systematic review and meta-analysis of randomized clinical trials. METHODS: Five electronic databases were searched up to Apr 15, 2018 to identify randomized controlled trials (RCTs) of berberine in treatment of dyslipidaemias. The outcomes were lipid profile parameters and adverse events. Study selection, data collection, risk of bias assessment, data analyses and interpretations were conducted according to the Cochrane handbook. RESULTS: Sixteen trials with total of 2147 participants were judged to be eligible and were included in the meta-analysis. The included trials were assessed to be of high clinical heterogeneity. The methodological quality of the majority of the trials was generally low in terms of random sequence generation, allocation concealment, blinding and incomplete outcome data. Thus, selection bias, performance bias, detection bias, attrition bias and confounding bias might exist. Meta-analysis showed that berberine significantly reduced levels of total cholesterol (TC) (MD = -0.47  mmol/l 95% CI [-0.64, -0.31], p < 0.00001), low-density lipoprotein cholesterol (LDL-C) (MD =-0.38  mmol/l 95% CI [-0.53, -0.22], p < 0.00001) and triglycerides (TG) (MD = -0.28  mmol/l 95% CI [-0.46, -0.10], p = 0.002). Berberine also increased the level of high-density lipoprotein cholesterol (HDL-C) when used alone (MD = 0.08  mmol/l 95% CI [0.03, 0.12], p = 0.001). No significant differences were found between groups in terms of incidence of adverse events (RR = 0.64 95% CI [0.31, 1.30], p = 0.22). No severe adverse effects were reported in either group. CONCLUSION: Berberine improves lipid profiles in dyslipidaemias with satisfactory safety. Nevertheless, these findings should be interpreted with caution because of the high clinical heterogeneity and high risk of bias in the included trials. Rigorous clinical trials should be carried out to provide more reliable evidence.

Serum Metabolomics Study Based on LC-MS and Antihypertensive Effect of Uncaria on Spontaneously Hypertensive Rats.

Our previous studies have shown that Uncaria has an important role in lowering blood pressure, but its intervention mechanism has not been clarified completely in the metabolic level. Therefore, in this study, a combination method of HPLC-TOF/MS-based metabolomics and multivariate statistical analyses was employed to explore the mechanism and evaluate the antihypertensive effect of Uncaria. Serum samples were analyzed and identified by HPLC-TOF/MS, while the acquired data was further processed by partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA) to discover the perturbed metabolites. A clear cluster among the different groups was obtained, and 7 significantly changed potential biomarkers were screened out. These biomarkers were mainly associated with lipid metabolism (dihydroceramide, ceramide, PC, LysoPC, and TXA2) and vitamin and amino acids metabolism (nicotinamide riboside, 5-HTP). The result indicated that Uncaria could decrease the blood pressure effectively, partially by regulating the above biomarkers and metabolic pathways. Analyzing and verifying the specific biomarkers, further understanding of the therapeutic mechanism and antihypertensive effect of Uncaria was acquired. Metabolomics provided a new insight into estimate of the therapeutic effect and dissection of the potential mechanisms of traditional Chinese medicine (TCM) in treating hypertension.

Guanxinning tablet for patients who switch from dual antiplatelet therapy to aspirin alone after percutaneous coronary intervention: study protocol for a cluster randomized controlled trial.

BACKGROUND: One-year dual antiplatelet therapy (DAPT), generally aspirin in combination with a P2Y12 receptor inhibitor, has been a standard treatment for patients undergoing percutaneous coronary intervention (PCI). Prolonged DAPT has proven itself effective in further reducing cardiovascular events, yet with increased risk of bleeding. Thus, it is of great necessity to find an alternative drug that is as effective but safer and more economic than the P2Y12 inhibitors after termination of one-year DAPT. METHODS: We will conduct a cluster randomized controlled trial in 3600 eligible post-PCI patients from 36 tertiary hospitals (100 patients per hospital) across mainland China. The hospitals served as clusters are randomized in a 2:1 ratio to Guanxinning tablet (GXNT) plus aspirin or aspirin alone for 12 months, with other conventional treatment applied in both groups. After the treatment period, all patients will be followed up for another 12 months. The primary outcome measure is composite cardiovascular events including cardiovascular death, non-fatal myocardial infarction, stent thrombosis, revascularization, ischemic stroke, and re-admission due to unstable angina. Secondary outcome measures are all-cause mortality, each individual component of the primary outcome measure, and stopping or reducing the rate of nitroglycerin administration. Adverse events, including bleeding, will be closely monitored during the whole trial period. In addition, a cost-effectiveness study of GXNT for the study population will be conducted along with this trial. DISCUSSION: This trial aims to determine whether the addition of GXNT will further improve prognosis without increasing bleeding risk for patients with coronary artery disease who have switched from DAPT to aspirin alone after PCI. Completion of this clinical trial might provide a novel, promising, and safer alternative to P2Y12 inhibitors for prolonged antiplatelet therapy in post-PCI patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IIR-17010688 . Registered on 20 February 2017.

Oral Chinese Herbal Medicine for Treatment of Dilated Cardiomyopathy: A Systematic Review and Meta-Analysis.

Dilated cardiomyopathy (DCM) is one of the main causes of heart failure and could increase death, hospitalization, and rehospitalization rate. The effect of conventional medicine treatment (CMT) is limited; meanwhile, the combination of CMT and Oral Chinese Herbal Medicine (OCHM) represents exciting adjunctive therapies. In this study, we ascertained the therapeutic effect of OCHM in combination with CMT for dilated cardiomyopathy by using meta-analysis methods for controlled clinical trials. We searched studies from five databases and extracted data from these studies. We also assessed the methodological quality of the included studies. We evaluated the following outcome measures to estimate the prognosis in patients with DCM: left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), stroke volume (SV), brain natriuretic peptide (BNP), 6-minute walk test (6MWT), and overall efficacy. The result showed that OCHM combined with CMT for the improvement of therapeutic effect in DCM patients. However, the evidence remains weak due to the small sample size, high clinical heterogeneity, and poor methodological quality of the included trials. Further, large sample size and well-designed trials are needed.

A metabolomic study using HPLC-TOF/MS coupled with ingenuity pathway analysis: Intervention effects of Rhizoma Alismatis on spontaneous hypertensive rats.

Rhizoma Alismatis, an important crude herb component in traditional Chinese medicine, has been commonly used for treating hypertension, but its mechanism has not been clarified in level of metabolic. Therefore, in the present work, metabolomics study coupled with ingenuity pathway analysis (IPA) have been performed to explore the potential mechanism in anti-hypertensive effect of Rhizoma Alismatis. Serum samples from SHRs and WKYs were analyzed with the use of high performance liquid chromatography coupled with time of flight mass spectrometry detection (HPLC-TOF/MS) in positive polarity. The obtained data sets were statistically analyzed using univariate and multivariate statistical analyses including the principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) for pattern recognition and selection of significant metabolites. 12 potential biomarkers in rat serum were screened out from HMDB, METLIN and KEGG databases. Furthermore, IPA was introduced and Glycerophospholipid metabolism and Purine metabolism were filtered out as potential target pathways. This metabolomic approach coupled with IPA provided a feasible way to understand the therapeutic mechanism of Rhizoma Alismatis on spontaneous hypertensive rats.

Serum metabolomics research of the anti-hypertensive effects of Tengfu Jiangya tablet on spontaneously hypertensive rats.

A HPLC/TOF-MS-based metabolomic study was conducted to investigate the holistic therapeutic effects of Tengfu Jiangya Tablet (TJT) on spontaneously hypertensive rats (SHRs). The SHRs were divided into valsartan (VST) group, TJT group and model group, in addition, the Wistar-Kyoto rats (WKY) were taken as normal control. Serum samples were separated and identified by HPLC/TOF-MS, while the obtained data was further processed by partial least-squares discriminant analysis (PLS-DA). A clear cluster among the four groups was observed, and we identified thirteen biomarkers involved involved in sphingolipid metabolism (sphinganine, lysosphingomyelin, ceramide), glycerophospholipid metabolism (phosphatidylcholines, phosphatidylethanolamine, lysophosphatidylcholines), arginine and proline metabolism (l-proline, citrulline), tryptophan metabolism (xanthuiulrenic acid, l-kynurenine, l-tryptophan), arachidonic acid metabolism(leukotriene D4), and linoleic acid metabolism (gamma-linolenic acid). Altered metabolic pathways involved in impaired NO production, inflammation and vascular smooth muscle cells (VSMCs) apoptosis and proliferation, which suggesting the possible pathological state in SHRs. TJT as well as VST altered the metabolic state, suggesting a possible anti-hypertension role by improving NO production, and an extra cardiovascular protection role possibly by amelioration of inflammatory state and vascular remodeling.

[Study on Optimum Extraction Process of Water Soluble Protein from Coicis Semen].

OBJECTIVE: To optimize the extraction process of water soluble protein from Coicis Semen. METHODS: Coicis Semen was used to extract protein with cysteine hydrochloride aqueous solution in alkaline environment. The single factor test was conducted with the factors of extraction temperature, extraction pH, solid-liquid ratio and extraction time. In combination with single factor test results, a 4 factors 3 levels orthogonal experiment was designed with the factors of extraction temperature, extraction pH, solid-liquid ratio and extraction time. The effect of various factors on the results and the interactions were analyzed by range analysis, variance analysis and partial least squares regression analysis. RESULTS: The optimum extraction process of water soluble protein from Coicis Semen was as follows: the extraction temperature was 40 °C , the extraction pH was 10, the solid-liquid ratio was 1:20 and the extraction time was 4 h. The interaction of temperature and solid-liquid ratio, as well as temperature and extraction time would lower protein extraction rate. CONCLUSION: The optimized extraction process is economical, simple, reasonable and practicable.

Efficacy of Chinese herbal medicine on health-related quality of life (SF-36) in hypertensive patients: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: This study aims to evaluate published randomized controlled trials (RCTs) of Chinese Herbal Medicine (CHM) improving health-related quality of life (HRQL) in hypertensive patients that employ the Short-Form 36-Item Health questionnaire (SF-36) as an outcome measure. METHODS: Five electronic databases were searched up to October 2013 to identify RCTs of CHM for hypertension. The primary outcome was SF-36. Trial selection, data extraction, methodological quality assessment, and data analyses were conducted according to the Cochrane handbook. RESULTS: Eleven RCTs with total of 1043 participants were identified. The majority of the included trials were assessed to be of poor methodological quality and high clinical heterogeneity. Meta-analysis shows a significant improvement both in physical component summary (PCS) measure and mental component summary (MCS) measure of SF-36, with physical functioning (WMD=8.54[5.34, 11.74], p<0.001), role physical (WMD=13.32[7.03, 19.61], p<0.001), bodily pain (WMD=10.53[6.46, 14.60], p<0.001), general health (WMD=-5.56[2.09, 9.02], p<0.001), vitality (WMD=6.84[4.33, 9.53], p<0.001), social functioning (WMD=7.50[2.63, 12.36], p<0.001), role emotional (WMD=12.06[4.45, 19.68], p<0.001) and mental health (WMD=-5.68[2.90, 8.47], p<0.001). CHM can also decrease systolic blood pressure (WMD=-4.45 [-6.71, -2.19], p<0.001) and relieve symptoms related to hypertension. CONCLUSIONS: CHM appears to have beneficial effects on improvement of HRQL in hypertensive patients. However, the findings should be interpreted with caution due to the poor methodological quality and high clinical heterogeneity of the included trials. Further clinical trials should be carried out to provide more reliable evidence.

Oral Chinese herbal medicine for improvement of quality of life in patients with chronic heart failure: a systematic review and meta-analysis.

PURPOSE: Chronic heart failure (CHF) is not only a leading cause of death, hospitalization, and rehospitalization, but also significantly decreases quality of life (QoL). This study aims to evaluate published clinical trials of oral Chinese herbal medicine (OCHM) for improvement of QoL in patients with CHF that employ the Minnesota Living with Heart Failure Questionnaire (MLHFQ) score as an outcome measure. METHODS: A systematic literature search was performed using five databases up to June 2013 to identify randomized control trials (RCTs). RCTs involving OCHM plus conventional medicine treatment (CMT) with or without blinding, compared with CMT with or without placebo, with MLHFQ score as an outcome measure were identified. The methodological quality of RCTs was assessed independently using the Cochrane Handbook for Systematic Review of Interventions. RevMan 5.2.5 and Stata 11.0 were used for data analysis. RESULTS: Thirty-eight RCTs with a total of 3,170 participants were identified. The majority of the included trials were assessed to be of high clinical heterogeneity and poor methodological quality. The main results of meta-analysis showed improvement of total MLHFQ score when OCHM plus CMT compared with CMT with or without placebo [MD = -5.71 (-7.07, -4.36), p < 0.01]. CONCLUSIONS: There is some encouraging evidence of OCHM combined with CMT for the improvement of QoL in CHF patients. However, the evidence remains weak due to the small sample size, high clinical heterogeneity, and poor methodological quality of the included trials. Further, large sample size and well-designed trials are needed.