Therapeutic effect and mechanism of danshensu on coronary heart disease using liquid chromatography combined with mass spectrometry metabolomics.

Metabolomics can discover the biomarkers and metabolic pathways, provides the possibility for insights into the pharmacological action and mechanism of natural products. The therapeutic effect and mechanism of danshensu (DSS) on total metabolic pathways has not been well investigated. The aim of this study was to explore the disturbed endogenous biomarkers and metabolic pathways reflecting the pharmacological activity of DSS, and mechanism of action of DSS using comprehensive metabolome analysis based on high-throughput metabolomics technology combined with ultra-high performance liquid chromatography (UPLC) coupled with quadrupole tandem time-of-flight mass spectrometry (Q-TOF-MS) and pattern recognition method. Through the changes of the overall metabolic profile and the related biomarkers, the intervention effect of natural product danshensu (DSS) treatment on CHD model rats was revealed. The results showed that after the model replication was established, the metabolic profile was clearly separated, and a total of 26 potential biomarkers were screened out, and involving 8 metabolic pathways. After different doses of DSS solution were given, a total of 20 biomarkers could be significantly regulated, mainly involving primary bile acid biosynthesis, glycerophospholipid metabolism, and lipid metabolism. It showed UPLC-MS-based metabolomics can be used for discovering potential biomarkers and metabolic pathways of CHD, and to further understand and dissecting pharmacological effects and mechanisms of natural products via metabolomics techniques.

Mechanisms of Xiong-Pi-Fang in treating coronary heart disease associated with depression: A systematic pharmacology strategy and in vivo pharmacological validation.

BACKGROUND: Coronary heart disease (CHD) and depression are very common and often co-existing disorders. Xiong-Pi-Fang (XPF), a therapeutic classical traditional Chinese medicine (TCM) formula, has shown satisfactory efficacy in treating CHD associated with depression. However, its mechanism of action is still unknown. PURPOSE: To employ a systematic pharmacology approach for identifying the action mechanisms of XPF in treating CHD associated with depression. METHODS: We used a systematic pharmacology approach to identify the potential active mechanisms of XPF in treating CHD with depression. Potential active compounds in XPF and the diseases targets were screened using relevant databases to build corresponding pathways, following the experiments that were conducted to confirm whether the presumptive results of systemic pharmacology were correct. RESULTS: Network pharmacology predicted 42 key targets and 20 signaling pathways involved in XPF-mediated treatment, with IL-6/JAK2/STAT3/HIF-1α/VEGF-A pathway significantly affected. The common influences were hypothalamic-pituitary-adrenal axis (HPA axis) and glucocorticoid signaling, validated through chronic unexpected mild stress (CUMS) with isoprenaline (ISO) for inducing CHD within the depression model in rats. In addition, XPF intake reduced depressive-like behaviors and improved ECG ischemic changes. Furthermore, XPF exerted some anti-inflammatory effects by inhibiting the interleukin-6 (IL-6) induced phosphorylation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), ultimately downregulating hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A) activation. The dysfunctional HPA axis feedback loop was also regulated, which enhanced the glucocorticoid receptor (GR) expression. In contrast, it improved glucocorticoid resistance by reducing the mineralocorticoid receptor expression. CONCLUSIONS: Suppressing IL-6 release and maintaining the HPA feedback loop balance could be the primary mechanism of XPF against CHD with depression. The significance of the IL-6 and HPA axis identified indicates their potential as essential targets for CHD therapy with depression.

Urinary metabolomic profiling reveals difference between two traditional Chinese medicine subtypes of coronary heart disease.

The World Health Organization has shown that coronary heart disease (CHD) is a more common cause of death than cancer. In traditional Chinese medicine (TCM), CHD is classified as a form of thoracic obstruction that can be divided in different subtypes including Qi stagnation with blood stasis (QS) and Qi deficiency with blood stasis (QD). Different treatment strategies are used based on this subtyping. Owing to the lack of scientific markers in the diagnosis of these subtypes, subjective judgments made by clinicians have limited the objective manner for utility of TCM in the treatment of CHD. Untargeted (UHPLC-QTOF-MS) and targeted (UHPLC-MS/MS) metabolomics approaches were employed to search significantly different metabolites related to the QS or QD subtypes of CHD with angina pectoris in this study. A total of 42 metabolites were obtained in the untargeted metabolomics analysis and 34 amino acids were detected in the targeted metabolomics analysis. In total, 16 metabolites were found significantly different among different groups. The results showed distinct metabolic profiles of urine samples not only between CHD patients and healthy controls, but also between the two subtypes of CHD. Pathway analysis of the significantly varied metabolites revealed that there were subtype-related differences in the activity of pathways. Therefore, urinary metabolomics can reveal the pathological changes of CHD in different subtypes, make the diagnosis of CHD in different subtypes in an objective manner and comprehensive and contribute to personalized treatment by providing scientific evidence.

Exploring lipid biomarkers of coronary heart disease for elucidating the biological effects of gelanxinning capsule by lipidomics method based on LC-MS.

High-throughput lipidomics technology was used to explore the potential therapeutic targets and mechanism of action of gelanxinning capsule on rat model with coronary heart disease (CHD). This study attempts to provide a novel method to interpret the molecular mechanism of traditional medicine. The lipid markers of CHD were determined by full-scan analysis based on ultra-performance liquid chromatography-high-definition mass spectrometry. Then, the metabolic changes associated with gelanxinning capsule treatment via the modulation of lipid biomarkers and pathway in rats were characterized. After gelanxinning treatment, the metabolic profile tended to recover compared with the model group. A total of 26 potential biomarkers were identified to represent the disorders of lipid metabolism in CHD animal model, of which 19 were regulated by gelanxinning capsule administration, and four metabolic pathways such as glycerophospholipid metabolism, sphingolipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, and glycerolipid metabolism were involved. From the pathway analysis, it was found that glycerophospholipid metabolism and sphingolipid metabolism with significant differences have the potential to be regarded as new targets for the treatment of CHD. Gelanxinning capsule with its good therapeutic effect protects against CHD by regulating lipid biomarkers and pathway from lipidomics-guided biochemical analysis.

Combination of Panax notoginseng saponins and aspirin potentiates platelet inhibition with alleviated gastric injury via modulating arachidonic acid metabolism.

High platelet reactivity and gastric mucosal injury after aspirin (ASA) treatment are associated with poor compliance and an increased risk of cardiovascular events. Panax notoginseng saponins (PNS) have been widely used for the treatment of coronary heart disease (CHD) in addition to antiplatelet drugs in China; however, the joint effect and possible mechanism of PNS in addition to ASA on platelet activation and gastric injury remain unclear. This study was designed to investigate the combinational effects of PNS with ASA, and to explore the underlying mechanism via arachidonic acid (AA) metabolism pathway using lipidomic analysis. In a randomized, assessor-blinded trial, 42 patients with stable coronary heart disease (SCHD) and chronic gastritis were randomly assigned to receive ASA (n = 21) or PNS + ASA (n = 21) for 2 months. Compared with ASA alone, PNS + ASA further inhibited CD62p expression, GPIIb-IIIa activation and platelet aggregation and led to increased platelet inhibition rate. PNS + ASA suppressed the activity of platelet cyclooxygenase (COX)-1, and decreased the production of TXB2, PGD2, PGE2, 11-HETE, the downstream oxylipids of AA/COX-1 pathway in platelets, compared with ASA alone. The severity of dyspepsia assessment (SODA) results showed that patients in PNS + ASA group exhibited relieved dyspeptic symptoms as compared with those in ASA group, which might be associated with enhanced secretion of gastrin and motilin. In vivo study of myocardial infarction rats demonstrated that PNS attenuated ASA-induced gastric mucosal injury, which was related to markedly boosted gastric level of 6,15-diketo-13,14-dihydro-prostaglandin (PG)F1α, 13,14-dihydro-15-keto-PGE2 and PGE2 from AA/PG pathway in response to PNS + ASA compared with ASA alone. In summary, our study demonstrated that the combination of PNS and ASA potentiated the antiplatelet effect of ASA via AA/COX-1/TXB2 pathway in platelets, and mitigated ASA-related gastric injury via AA/PG pathway in gastric mucosa.

The Role of the Gut Microbiota in Coronary Heart Disease.

PURPOSE OF REVIEW: This review focuses on recent evidence examining the role gut microbiota play in coronary heart disease. It also provides a succinct overview of current and future therapies targeting the gut microbiota for coronary heart disease risk reduction. RECENT FINDINGS: A consensus has been reached that differences exist in the gut microbiotas of patients with coronary heart disease. Studies have shown that the gut microbiota is associated with obesity, diabetes, dyslipidemia, and hypertension, which are risk factors for coronary heart disease. The gut microbiota is involved in mediating basic metabolic processes, such as cholesterol metabolism, uric acid metabolism, oxidative stress, and inflammatory reactions, through its metabolites, which can induce the development of atherosclerosis and coronary heart disease. Interfering with the composition of gut microbiota, supplementing probiotics, and fecal donation are active areas of research to potentially prevent and treat coronary heart disease. Gut microbiota are causally associated with coronary heart disease. We analyzed the gut microbiota's effects on risk factors for coronary heart disease and studied the effects of gut microbiota metabolites on coronary heart disease. Gut microbiota is a potential target for preventing and treating coronary heart disease.

Association of the 1q25 Diabetes-Specific Coronary Heart Disease Locus With Alterations of the γ-Glutamyl Cycle and Increased Methylglyoxal Levels in Endothelial Cells.

A chromosome 1q25 variant (rs10911021) has been associated with coronary heart disease (CHD) in type 2 diabetes. In human umbilical vein endothelial cells (HUVECs), the risk allele "C" is associated with lower expression of the adjacent gene GLUL encoding glutamine synthase, converting glutamic acid to glutamine. To further investigate the mechanisms through which this locus affects CHD risk, we measured 35 intracellular metabolites involved in glutamic acid metabolism and the γ-glutamyl cycle in 62 HUVEC strains carrying different rs10911021 genotypes. Eight metabolites were positively associated with the risk allele (17-58% increase/allele copy, P = 0.046-0.002), including five γ-glutamyl amino acids, ß-citryl-glutamate, N-acetyl-aspartyl-glutamate, and ophthalmate-a marker of γ-glutamyl cycle malfunction. Consistent with these findings, the risk allele was also associated with decreased glutathione-to-glutamate ratio (-9%, P = 0.012), decreased S-lactoylglutathione (-41%, P = 0.019), and reduced detoxification of the atherogenic compound methylglyoxal (+54%, P = 0.008). GLUL downregulation by shRNA caused a 40% increase in the methylglyoxal level, which was completely prevented by glutamine supplementation. In summary, we have identified intracellular metabolic traits associated with the 1q25 risk allele in HUVECs, including impairments of the γ-glutamyl cycle and methylglyoxal detoxification. Glutamine supplementation abolishes the latter abnormality, suggesting that such treatment may prevent CHD in 1q25 risk allele carriers.

A Quantitative Diagnostic Method for Phlegm and Blood Stasis Syndrome in Coronary Heart Disease Using Tongue, Face, and Pulse Indexes: An Exploratory Pilot Study.

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 < 0.001), length of philtrum (LEP) (p = 0.022), and right hand pulse h1 (Rh1) (p = 0.021). The expression of combining predictor L in this study was L = LC +57.58 NE +4.53 LEP +2.68 Rh1. The ROC curve analysis indicated that the AUC values of LC, NE, LEP, and Rh1 were 0.646, 0.710, 0.619, and 0.613, respectively. The AUC = 0.825 of the syndrome diagnosis model was the largest. Conclusions: The quantitative study of TCM syndrome based on logistic regression analysis provides a good method for the objective analysis and application of TCM syndrome.

Dual-screening of anti-inflammatory and antioxidant active ingredients of shenxiang suhe pill and its potential multi-target therapy for coronary heart disease.

BACKGROUND: Shenxiang Suhe Pill (SXSHP), a Chinese medicine formula, is widely used in clinic to treat coronary heart disease (CHD). However, due to the complex composition of SXSHP, its underlying mechanisms and pharmacodynamic properties are still unknown. In this paper, we try to define the compounds of SXSHP by dual-screening the active ingredients with anti-inflammation and antioxidant effects and predict its multi-target-pathway in CHD therapy using network pharmacology. METHODS: The chemical constituents in SXSHP were analyzed by UPLC/Q-TOF. Then, the active ingredients with the anti-inflammation and antioxidant effects were dual-screened by in vitro experiments. Ingenuity pathway analysis (IPA) was used to analyze and predict the potential targets and pathways of the anti-inflammatory and antioxidant effects of SXSHP. RESULTS: A total of 38 chemical constituents were identified in SXSHP, among which we screened six anti-inflammatory compounds: luteolin, isorhamnetin-3-O-beta-d-glucoside, 4-hydroxy-3-methoxycinnamaldehyde, benzoic acid, kaempferol-3-O-glucuronide acid, and blumeatin; and five antioxidant compounds: vanillin, eugenol, muscone, luteolin, and asiatic acid. IPA showed that eugenol, muscone, and 4-hydroxy-3-methoxycinnamaldehyde were closely related to the HIF-1 and IL-15 signaling pathways, which protect against oxidative stress and inflammation, respectively. CONCLUSIONS: Among the 38 ingredients in SXSHP, the anti-inflammatory pharmacological effects of isorhamnetin-3-O-beta-d-glucoside, blumeatin and 4-hydroxy-3-methoxycinnamaldehyde were reported for the first time. According to the network pharmacology analysis, eugenol, 4-hydroxy-3-methoxycinnamaldehyde and muscone are involved in the antioxidant HIF-1 pathway and the anti-inflammatory IL-15 pathway, and that may be the mechanism of SXSHP in the treatment of CHD.

Exploring the mechanism of TCM formulae in the treatment of different types of coronary heart disease by network pharmacology and machining learning.

Traditional Chinese medicine (TCM) has long been used in the clinical treatment of coronary heart disease (CHD). TCM is characterized by syndrome-based medication, which is, using different TCM formulae for different syndromes. However, the underlying mode of action remains unclear. In this work, we utilized network pharmacology and machine learning to explore the mechanism of eight classic TCM formulae in the treatment of different types of CHD. First, by integrating multiple databases, a total of 669 potential bioactive compounds and 581 targets of the eight formulae were screened. Then, the effectiveness of these formulae on CHD was evaluated using two network-based indicators. The results showed that each formula's targets were significantly correlated with CHD associated genes and overlapped with the targets of 9 classes of drugs for cardio vascular diseases (CVD) to some degree. Next, from 5 different levels, i.e., herb, symptom, compound, target, and pathway level, we systematically compared the eight formulae using network clustering and hierarchical clustering. We found that all the formulae could be grouped into five clusters and the clustering results were approximately consistent at different levels. All the formulae were involved in 7 pathways closely related to CHD and may exhibit the common effect of relieving angina. Formulae in the same group collectively regulated some unique pathways and suggest further specific indications. For example, the three formulae used for Qi stagnation and blood stasis, Qi deficiency and blood stasis, and Qi-Yin deficiency syndromes acted on two special pathways (TNF signaling pathway, NF-kappa B signaling pathway) and may exert anti-inflammatory and immune-enhancing effects; the two formulae for Yin deficiency of heart and kidney, and Yang deficiency of heart and kidney syndromes regulated two special pathways (PPAR signaling pathway, thyroid hormone signaling pathway) in endocrine system and could improve renal function. Subsequently, we designed a rank algorithm, which integrated network topology with biological function, to identify important targets of these formulae. The results were consistent with the multi-level clustering results. At last, our literature mining validated about 20 % putative targets, as well as clustering results and effects of the formulae by experimental evidences. This study explained the medication patterns and scientific significance of TCM formulae on different types of CHD from perspective of systems biology. It may facilitate the understanding of different types of CHD described by traditional Chinese medicine from the perspectives of modern biology.

Exploring the mechanism of Shengmai Yin for coronary heart disease based on systematic pharmacology and chemoinformatics.

OBJECTIVE: To explore the mechanism of Shengmai Yin (SMY) for coronary heart disease (CHD) by systemic pharmacology and chemoinformatics. METHODS: Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), traditional Chinese medicine integrative database (TCMID) and the traditional Chinese medicine (TCM) Database@Taiwan were used to screen and predict the bioactive components of SMY. Pharmmapper were utilized to predict the potential targets of SMY, the TCMSP was utilized to obtain the known targets of SMY. The Genecards and OMIM database were utilized to collect CHD genes. Cytoscape was then used for network construction and analysis, and DAVID was used for Gene Ontology (GO) and pathway enrichment analysis. After that, animal experiments were then performed to further validate the results of systemic pharmacology and chemoinformatics. RESULTS: Three major networks were constructed: (1) CHD genes' protein-protein interaction (PPI) network; (2) SMY-CHD PPI network; (3) SMY known target-CHD PPI network. The other networks are minor networks generated by analyzing the three major networks. Experimental results showed that compared with the model group, the Shengmai injection (SMI) can reduce the myocardial injury score and the activities of serum aspartate aminoconvertase (AST), CK and lactate dehydrogenase (LDH) in rats (P<0.05), and reduce serum lipid peroxide (LPO) content and increase serum superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in myocardial infarction rats (P<0.05). SMI can also decrease the expression of MMP-9 mRNA and increase that of TIMP-1 mRNA (P<0.01). CONCLUSION: SMY may regulate the signaling pathways (such as PPAR, FoxO, VEGF signaling), biological processes (such as angiogenesis, blood pressure formation, inflammatory response) and targets (such as AKT1, EGFR, MAPK1) so as to play a therapeutic role in CHD.

Effects of Astragalus injection and Salvia Miltiorrhiza injection on serum inflammatory markers in patients with stable coronary heart disease: a randomized controlled trial protocol.

BACKGROUND: Coronary heart disease (CHD) is a clinical syndrome caused by coronary atherosclerosis (AS) or functional changes in coronary arteries. We have previously reported that astragaloside IV (in astragalus) and tanshinone IIA (in Salvia miltiorrhiza) improve myocardial ischemic injury. METHODS: This study will employ the randomized, blinded, prospective, single-center experiments approach. Briefly, a total of 160 eligible patients will be equally randomized into three treatment groups and placebo control groups. Patients will receive appropriate treatments every 24 h for seven days after enrollment and followed up for 28 days. The main evaluation indicators will be cell count, serum high-sensitivity C-reactive protein (hs-CRP) level, monocyte chemoattractant protein 1 (MCP-1), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), interleukin-8 (IL-8), interleukin-18 (IL-18), interleukin-10 (IL-10), tumor necrosis factor (TNF)-α, oxidized low density lipoprotein (OX-LDL), angina grade, and Traditional Chinese Medicine (TCM) symptom changes scale. Secondary indicators to be evaluated will include B-type natriuretic peptide (BNP) levels, troponin (cTn), muscle enzyme isoenzyme (CK-MB), heart-type fatty acid binding protein (H-FABP), liver and renal functions, as well as blood coagulation. Close monitoring of adverse events during the trial will also be conducted. DISCUSSION: This randomized controlled trial of Chinese herbal extracts for the treatment of coronary heart disease will generate results that are expected to provide valuable clinical evidence to inform future development of therapies towards management of CHD. TRIAL REGISTRATION: China Clinical Trial Registration Center, ChiCTR1900021590. Registered on 28 February 2019.

Uncovering the protective mechanism of Huoxue Anxin Recipe against coronary heart disease by network analysis and experimental validation.

Coronary heart disease (CHD) is a leading cause of death and disability worldwide. Huoxue Anxin Recipe (HAR) is a novel Chinese Herbal Medicine formula of that has been used to treat CHD for several decades. Our previous study found that HAR had anti-oxidative effects, and could promote myocardial angiogenesis and improve cardiac function following myocardial infarction (MI) in rats. However, the active compounds, potential targets, and biological processes related to HAR have not been systematically investigated. Here, network pharmacology and experimental validation were used to study the protective mechanisms of HAR against CHD. We identified 124 active components, 124 verified targets, and 111 predictive targets. A total of 1192 genes related to CHD were identified by cDNA microarray and database analysis. A total of 47 putative targets of HAR against CHD were identified, including 32 verified targets and 15 predictive targets. ClueGo enrichment analysis identified 49 biological processes involved in the anti-CHD effects of HAR. Among them, the negative regulation of blood coagulation and regulation of collagen biosynthetic process were experimentally validated. After constructing a protein-protein interaction network and clustering with MECODE and ClusterONE, 162 key proteins (from ClueGo and clustering) were used to construct an internal interaction network. Complement C3 (C3), Fibrinogen alpha (FGA), Fibrinogen gamma (FGG), interleukin-6 (IL6), and Apolipoprotein A1 (APOA1) were the top 5 hub proteins identified by cytoHubber analysis. HAR limited the concentrations of C3, FGA, FGG, and IL6 and increased APOA1 levels. The results indicated that HAR could down-regulate blood coagulation, regulate collagen biosynthesis, inhibit peroxidation and inflammation injury, and promote cholesterol efflux. HAR could be a potential source of novel and effective drugs for CHD.

Network Medicine: A Clinical Approach for Precision Medicine and Personalized Therapy in Coronary Heart Disease.

Early identification of coronary atherosclerotic pathogenic mechanisms is useful for predicting the risk of coronary heart disease (CHD) and future cardiac events. Epigenome changes may clarify a significant fraction of this "missing hereditability", thus offering novel potential biomarkers for prevention and care of CHD. The rapidly growing disciplines of systems biology and network science are now poised to meet the fields of precision medicine and personalized therapy. Network medicine integrates standard clinical recording and non-invasive, advanced cardiac imaging tools with epigenetics into deep learning for in-depth CHD molecular phenotyping. This approach could potentially explore developing novel drugs from natural compounds (i.e. polyphenols, folic acid) and repurposing current drugs, such as statins and metformin. Several clinical trials have exploited epigenetic tags and epigenetic sensitive drugs both in primary and secondary prevention. Due to their stability in plasma and easiness of detection, many ongoing clinical trials are focused on the evaluation of circulating miRNAs (e.g. miR-8059 and miR-320a) in blood, in association with imaging parameters such as coronary calcifications and stenosis degree detected by coronary computed tomography angiography (CCTA), or functional parameters provided by FFR/CT and PET/CT. Although epigenetic modifications have also been prioritized through network based approaches, the whole set of molecular interactions (interactome) in CHD is still under investigation for primary prevention strategies.

The effect of crocetin supplementation on markers of atherogenic risk in patients with coronary artery disease: a pilot, randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND AND PURPOSE: Molecular mechanisms of atherogenesis are considered to be emerging therapeutic targets for atherosclerosis prevention. Cell and animal studies have shown that crocetin can decelerate atherogenesis. However, the anti-atherogenic properties of crocetin in humans are still ambiguous. METHODS AND RESULTS: Fifty clinically diagnosed CAD patients were randomly divided into two parallel groups, crocetin and placebo, who received one capsule of crocetin (10 mg) and placebo per day, respectively, for two months. Serum circulating homocysteine (Hcy) [-1.09 (-1.64 to -0.54) µM, P = 0.001], heart-type fatty acid binding protein (h-FABP) [-2.07 (-2.72 to -1.43) ng mL-1, P = 0.001], intercellular adhesion molecule 1 [-14.92 (-21.92 to -7.92) ng mL-1, P = 0.001], vascular cell adhesion molecule 1 [-18.61 (-29.73 to -7.49) ng mL-1, P = 0.002], and monocyte chemoattractant protein 1 [-4.67 (-6.50 to -2.83) pg mL-1, P = 0.001] decreased significantly after the trial in the crocetin group, while high-density lipoprotein (HDL) significantly increased [+4.21 (0.68 to 7.73) mg mL-1, P = 0.021]. Also, systolic [-0.21 (-0.32 to -0.10) mmHg, P = 0.001] and diastolic [-0.20 (-0.34 to -0.07) mmHg, P = 0.004] blood pressures decreased significantly in the crocetin group. Nevertheless, clinically significant percentage changes were only observed in Hcy (-15.25 ± 3.15, µM), HDL (-10.70 ± 5.06, mg dL-1), and h-FABP (-21.10 ± 3.09, ng mL-1) in the crocetin group. Furthermore, the relative increase in the gene expressions of sirtuin1 and AMP-activated protein kinase and a decrease in the lectin-type oxidized LDL receptor 1 and nuclear factor-kappa B expression in isolated peripheral blood mononuclear cells in the crocetin group were significant at the end of the trial in comparison with the placebo. CONCLUSION: As the first human study, we showed the ability of crocetin to alter the expression of atherogenic genes and endothelial cell adhesion molecules in CAD patients. It appears that crocetin could be considered as a promising anti-atherogenic candidate for future studies.

Metabolomic Markers in Tongue-Coating Samples from Damp Phlegm Pattern Patients of Coronary Heart Disease and Chronic Renal Failure.

In this paper, we used tongue coating to obtain metabolites in patients with coronary heart disease (CHD) and chronic renal failure (CRF). The metabolites were analyzed to discover the substance that serves as the underlying basis of the damp phlegm pattern. This analysis is based on the Traditional Chinese Medicine (TCM) theory of "different diseases have the same pattern." The metabolic spectrum was obtained through the Gas Chromatography Mass Spectrometry coupling techniques and analyzed by searching the METLIN and HMDB databases. Some metabolites related to amino acids and glucose metabolism were identified in the tongue-coating samples from damp phlegm pattern patients by comparing them to nondamp phlegm pattern patients and healthy subjects. In addition, there were five common metabolites in the tongue-coating samples from CHD damp phlegm pattern patients compared to CRF damp phlegm pattern patients, which allowed us to understand the theory of "different diseases have the same pattern." In the future, the metabolites identified in this study may be used as noninvasive and convenient biomarkers to distinguish the damp phlegm pattern of CHD and CRF patients.

Metabolomics study on the therapeutic effect of traditional Chinese medicine Xue-Fu-Zhu-Yu decoction in coronary heart disease based on LC-Q-TOF/MS and GC-MS analysis.

The present study aims is to investigate the metabolic mechanism of Xue-Fu-Zhu-Yu decoction (XFZYD) in the treatment of blood-stasis syndrome in Coronary Heart Disease (CHD). To that end, 30 CHD patients with Blood-Stasis Syndrome (BSS) and 20 healthy subjects were enrolled. LC-Q-TOF/MS analysis determined that in comparison between CHD with BSS patients (Group A) and healthy subjects (Group C), 59 significantly differential metabolites in the positive mode and 18 significantly differential metabolites in the negative mode. The metabolite constituents in the plasma of 30 CHD with BSS patients before (group A) and after 30 days of treatment (Group B), and 20 healthy subjects (Group C) were analyzed using LC-Q-TOF/MS and GC-MS. Based on multivariate statistical analysis (PCA, PLS-DA and OPLS-DA), we determined 69 differential metabolites. The levels of hemorheology indexes were significantly down-regulated after treatment. Metabolic pathway attribution analysis showed that lipid metabolism, amino acid metabolism and bile acid metabolism pathways are involved. Our study identifies the metabolic networks of CHD and demonstrates the efficacy of this metabolomics approach to systematically study the therapeutic effect of XFZYC on CHD.

The effects of resveratrol on metabolic status in patients with type 2 diabetes mellitus and coronary heart disease.

This study was performed to investigate the effects of resveratrol on metabolic status in patients with type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD). This randomized, double-blind, placebo-controlled trial was performed with 56 patients having T2DM and CHD. The patients were randomly divided into two groups to receive either 500 mg resveratrol per day (n = 28) or placebo (n = 28) for 4 weeks. Resveratrol reduced fasting glucose (ß-10.04 mg dL-1; 95% CI, -18.23, -1.86; P = 0.01), insulin (ß-1.09 µIU mL-1; 95% CI, -1.93, -0.24; P = 0.01) and insulin resistance (ß-0.48; 95% CI, -0.76, -0.21; P = 0.001) and significantly increased insulin sensitivity (ß 0.006; 95% CI, 0.001, 0.01; P = 0.02) when compared with the placebo. Resveratrol also significantly increased HDL-cholesterol levels (ß 3.38 mg dL-1; 95% CI, 1.72, 5.05; P < 0.001) and significantly decreased the total-/HDL-cholesterol ratio (ß-0.36; 95% CI, -0.59, -0.13; P = 0.002) when compared with the placebo. Additionally, resveratrol caused a significant increase in total antioxidant capacity (TAC) (ß 58.88 mmol L-1; 95% CI, 17.33, 100.44; P = 0.006) and a significant reduction in malondialdehyde (MDA) levels (ß-0.21 µmol L-1; 95% CI, -0.41, -0.005; P = 0.04) when compared with the placebo. Resveratrol upregulated PPAR-γ (P = 0.01) and sirtuin 1 (SIRT1) (P = 0.01) in the peripheral blood mononuclear cells (PBMCs) of T2DM patients with CHD. Resveratrol supplementation did not have any effect on inflammatory markers. Four-week supplementation of resveratrol in patients with T2DM and CHD had beneficial effects on glycemic control, HDL-cholesterol levels, the total-/HDL-cholesterol ratio, TAC and MDA levels. Resveratrol also upregulated PPAR-γ and SIRT1 in the PBMCs of T2DM patients with CHD.

A network pharmacology integrated pharmacokinetics strategy for uncovering pharmacological mechanism of compounds absorbed into the blood of Dan-Lou tablet on coronary heart disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Dan-Lou tablet (DLT) is developed from the traditional Chinese medicine (TCM) formula Gualou Xiebai Baijiu Tang which has been used for at least 2000 years in China. DLT has been widely used in clinical practice to treat cardiovascular diseases. AIM OF THE STUDY: This study aimed to uncover the pharmacological mechanism of the compounds absorbed into the blood of Dan-Lou tablet (DLT) on coronary heart disease (CHD) using a network pharmacology integrated pharmacokinetics strategy. MATERIALS AND METHODS: A rapid and sensitive method was developed for the simultaneous determination of the six compounds (puerarin, formononetin, calycosin, paeoniflorin, cryptotanshinone and tanshinone IIA) in rat plasma by liquid chromatography tandem mass spectrometry (LC-MS/MS). Then, the pharmacology network was established based on the relationship between five compounds absorbed into the blood targets (puerarin, formononetin, calycosin, cryptotanshinone and tanshinone IIA) and CHD targets. RESULTS: The intra-and inter-day precision were less than 11% and the accuracy ranged from 88.2% to 112%, which demonstrated that the LC-MS/MS method could be used to evaluate the pharmacokinetic feature of the six compounds in rats after oral administration of DLT. The pathway enrichment analysis revealed that the significant bioprocess networks of DLT on CHD were positive regulation of estradiol secretion, negative regulation of transcription from RNA polymerase II promoter, lipopolysaccharide-mediated signaling pathway and cytokine activity. CONCLUSION: The proposed network pharmacology integrated pharmacokinetics strategy provides a combination method to explore the therapeutic mechanism of the compounds absorbed into the blood of multi-component drugs on a systematic level.

Anti-inflammatory and antioxidative effects of Dan-Lou tablets in the treatment of coronary heart disease revealed by metabolomics integrated with molecular mechanism studies.

ETHNOPHARMACOLOGICAL EVIDENCE: The Dan-Lou tablet (DLT), a well-known Chinese prescription, has definitive clinical efficacy in the treatment of precordial discomfort and pain caused by coronary heart disease (CHD). However, the pharmacological mechanism of DLT in the treatment of CHD has not been clearly elucidated and needs to be further explored. AIM OF THE STUDY: We aimed to identify relevant biological pathways by assessing changes in biomarkers in response to DLT intervention in CHD to reveal the potential biological mechanism of DLT treatment for CHD. MATERIALS AND METHODS: The major chemical components in DLT were qualitatively analyzed using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), and a model of CHD in rats was subsequently established with a high-fat diet and left anterior coronary artery ligation (LADCA) followed by DLT intervention. Next, the metabolic profile of rat serum samples was analyzed using nontargeted metabolomics, wherein changes in the metabolites in serum samples before and after DLT administration were measured by PLS-DA, and two pathways of DLT treatment for CHD were predicted. Finally, predicted metabolomic pathways were verified by detecting and analyzing tissues from the rat model, revealing the mechanism of DLT in the treatment of CHD. RESULTS: Forty-five major chemical components were identified by the chemical characterization of DLT. In terms of metabolism, 17 biomarkers of CHD in rats were identified. Among these biomarkers, linoleic acid, γ-linolenic acid and lysophosphatidylcholines (LPCs) were found to play an important role in energy metabolism and glycerophospholipid metabolism. Protein analysis revealed that EGFR phosphorylation was inhibited in CHD rats after DLT treatment, which lowered the expression of TNF-α, IL-6 and MMP9, decreased the expression levels of ox-LDL and MDA, and increased the expression of SOD. CONCLUSION: The mechanism of DLT in the treatment of CHD involves inhibiting the expression of EGFR and the activation of the MAPK signaling pathway by regulating glycerophospholipid metabolism (LPCs) and energy metabolism (linoleic acid and γ-linolenic acid). Therefore, inflammation-related (TNF-α, IL-6, MMP9) and oxidative stress-related (ox-LDL, MDA, SOD) indicators are affected, leading to the regulation of the oxidative stress state and anti-inflammatory effects.