Huoxue Qingre decoction used for treatment of coronary heart disease network analysis and metabolomic evaluation.

Objective: Network pharmacology provides new methods and references for the research of traditional Chinese medicine, but some problems remain, such as single evaluation components and index methods, imperfect relevant databases, unscientific prediction results, and lack of verification of results. Herein, we used a modified network pharmacology research method to explore the potential network analysis mechanism of Huoxue Qingre decoction in the treatment of coronary heart disease and utilized clinical trials for assessment. Methods: Based on literature research, the targets corresponding to the drug were obtained with the assistance of the TCMSP database and Swiss Target Prediction, and the target proteins were corrected using the UniProt database. The targets related to coronary heart disease was obtained through the GeneCards database. A protein-protein interaction network diagram was constructed, and a "component-intersection target" network diagram was drawn based on Cytoscape 3.6.2 software. The mapped targets were imported into the DAVID bioinformatics platform, which underwent Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and the network pharmacology prediction results were evaluated through clinical trials. Results: We obtained 151 compounds related to Huoxue Qingre decoction, 286 genes after evaluation and deduplication, and 426 genes related to coronary heart disease. Finally, 81 common target genes were obtained with 32 pathways according to the KEGG pathway enrichment analysis. The validation results of the clinical trials showed that a total of 98 differential metabolites were found in the treatment of coronary heart disease with Huoxue Qingre decoction, involving a total of 16 metabolic pathways. Compared with the network pharmacology prediction results, it was found that only the pathways in cancer (hsa05200) were the common pathways in the top 32 signaling pathways predicted by network pharmacology. The expanded network pharmacology prediction results revealed that the sphingolipid signaling pathway (hsa04071) and prostate cancer pathway (hsa05215) matched the predicted metabolic pathways, with differential metabolites of N-oleoyl-D-sphingomyelin and 1-methyl-6-phenyl-1h-imidazole[4,5-b]pyridine-2-amine. Conclusion: Through the network analysis and metabolomic evaluation, there may be three signaling pathways that involve the Huoxue Qingre decoction in the treatment of coronary heart disease: pathways in cancer (hsa05200), sphingolipid signaling pathway (hsa04071), and prostate cancer pathway (hsa05215).

Analysis of the Efficacy and Mechanism of Action of Xuebijing Injection on ARDS Using Meta-Analysis and Network Pharmacology.

OBJECTIVE: Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory process known as cytokine storm. Xuebijing injection (hereinafter referred to as Xuebijing) is a patent drug that was used to treat ARDS or severe pneumonia (SP) in China. However, its efficacy and mechanism of actions remain unclear. In this study, we used meta-analysis and network pharmacology to assess these traits of Xuebijing. METHODS: We searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang databases for randomized controlled trials (RCTs) that evaluated Xuebijing therapy for ARDS or SP. The outcomes were total mortality, intensive care unit (ICU) stay time, and TNF-α and IL-6 levels. We performed a meta-analysis using RevMan 5.3 software. The putative targets, top 10 proteins, and possible pathway of Xuebinjing on ARDS were analyzed by network pharmacology. TNF-α and IL-6 were further docked with the six main active components of Xuebinjing using AutoDock 4.2.6 and PyMol 1.5.0.3 software. RESULTS: Fifteen RCTs involving 2778 patients (13 ARDS and 2 SP) were included. Compared with the control, Xuebijing treatment significantly reduced the mortality rate (risk ratio, 0.64 (95% credible interval (CrI), 0.54-0.77)), reduced the ICU stay time (mean difference (MD), -4.51 (95% CrI, -4.97--4.06)), reduced the TNF-α ((MD), -1.23 (95% CrI, -1.38--1.08)) and IL-6 ((MD), -1.15 (95% CrI, -1.52--0.78)) levels. The 56 putative targets, top 10 proteins (MAPK1 (mitogen-activated protein kinase 1), MAPK8 (mitogen-activated protein kinase 8), RELA (transcription factor p65), NFKB1 (nuclear factor NF-kappa-B p105 subunit), JUN (transcription factor AP-1), SRC (proto-oncogene tyrosine-protein kinase), TNF (tumor necrosis factor), HRAS (GTPase HRas), IL6 (interleukin-6), and APP (amyloid-beta A4 protein)), and possible pathways (Ret tyrosine kinase, IL2-mediated signaling events, CD4+/CD8+ T cell-related TCR signaling, p75(NTR)-mediated signaling, CXCR4-mediated signaling events, LPA receptor-mediated events, IL12-mediated signaling events, FAS (CD95) signaling pathway, and immune system) of Xuebinjing's action on ARDS were obtained. The molecular docking results showed that all the six components of Xuebinjing docked with TNF-α, and two components docked with IL-6 got the binding energies lower than -5. CONCLUSION: Our results recommended Xuebijing treatment for patients with ARDS. Xuebijing has therapeutic effects on ARDS patients partly by regulating the immune cell/cytokine pathways and thus inhibiting the cytokine storm. TNF-α is the cytokine both directly and indirectly inhibited by Xuebijing, and IL-6 is the cytokine mainly indirectly inhibited by Xuebijing.

Huoxue Huatan Decoction Ameliorates Myocardial Ischemia/Reperfusion Injury in Hyperlipidemic Rats via PGC-1α-PPARα and PGC-1α-NRF1-mtTFA Pathways.

OBJECTIVE: The aim of this study was to eluc\idate the preventive and therapeutic effects and the underlying mechanisms of Huoxue Huatan Decoction (HXHT) on myocardial ischemia/reperfusion (I/R) injury in hyperlipidemic rats. METHODS: An I/R model was established in hyperlipidemic Wistar rats. After 4-8 weeks of HXHT treatment, the physical signs of rats were observed. Lipid metabolism, myocardial enzyme spectrum, cardiac function, myocardial histomorphology, and mitochondrial biosynthesis were investigated by a biochemical method, ultrasonography, electron microscopy, pathological examination, real-time PCR, and Western blot. RESULTS: HXHT can affect lipid metabolism at different time points and significantly reduce the levels of cholesterol (CHO), triglyceride (TG), high-density lipid-cholesterol (HDL-C), and low-density lipid-cholesterol (LDL-C) in hyperlipidemic rats (P < 0.05 or P < 0.01); it can significantly reduce the levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), reduce the myocardial infarct size and myocardial ischemic area, and improve cardiac function. The results of myocardial histomorphology showed that HXHT could protect myocardial cells, relieve swelling, reduce the number of cardiac lipid droplets, and improve myocardial mitochondrial function. HXHT could significantly increase the levels of total superoxide dismutase (T-SOD) and succinate dehydrogenase (SDH) (P < 0.05 or P < 0.01), increase CuZn-superoxide dismutase (CuZn-SOD) and glutathione-peroxidase (GSH-Px) levels, and decrease the levels of malondialdehyde (MDA) (P < 0.05); it could increase the mRNA and protein expression levels of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), peroxisome proliferator-activated receptor alpha (PPARα), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (mtTFA) (P < 0.05 or P < 0.01), and increase the synthesis of mitochondrial DNA (mtDNA) (P < 0.01). CONCLUSION: HXHT can reduce myocardial I/R injury in hyperlipidemic rats. The protective mechanisms may involve a reduction in blood lipids, enhancement of PGC-1α-PPARα pathway activity, and, subsequently, an increase in fatty acid ß-oxidation, which may provide the required input for mitochondrial energy metabolism. HXHT can additionally enhance PGC-1α-NRF1-mtTFA pathway activity and, subsequently, increase the antioxidant capacity, promote mtDNA synthesis, and reduce mitochondrial damage. The two pathways use PGC-1α as the intersection point to protect mitochondrial structure and function, reduce I/R-induced injury, and improve cardiac function.

Advances in Research on the circRNA-miRNA-mRNA Network in Coronary Heart Disease Treated with Traditional Chinese Medicine.

There has been an increase in morbidity and mortality related to coronary heart disease (CHD) in China in recent years. Numerous clinical experiences and studies have shown that traditional Chinese medicine (TCM) plays an important role in the prevention, treatment, and prognosis of CHD. However, the mechanism of TCM in the treatment of CHD has not yet been elucidated. The circRNA-miRNA-mRNA network consists of miRNA that is competitively bound by circRNA, and miRNA regulates the transcription level of mRNA. Through literature review, we found that the circRNA-miRNA-mRNA network acts to contribute to certain effects to CHD such as myocardial hypertrophy, myocardial fibrosis, and heart failure. TCM contains constituents that act against CHD by antiatherosclerosis and apoptosis inhibition action, cardiac and cardiomyocyte protection, and these components also promote cell growth and protection of the vascular system by regulating miRNAs. Therefore, we consider that the circRNA-miRNA-mRNA network may be a new regulatory mechanism for the effective treatment of CHD by TCM.

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.

Sesquiterpenes and a monoterpenoid with acetylcholinesterase (AchE) inhibitory activity from Valeriana officinalis var. latiofolia in vitro and in vivo.

Acetylcholinesterase Inhibitor (AchEI) is the most extensive in all anti-dementia drugs. The extracts and isolated compounds from the Valeriana genus have shown anti-dementia bioactivity. Four new sesquiterpenoids (1-4) and a new monoterpenoid (5) were isolated from the root of Valeriana officinalis var. latiofolia. The acetylcholinesterase (AchE) inhibitory activity of isolates was evaluated by modified Ellman method in vitro. Learning and memory ability of compound 4 on mice was evaluated by the Morris water maze. The contents of acetylcholine (Ach), acetylcholine transferase (ChAT) and AchE in mice brains were determined by colorimetry. The results showed IC50 of compound 4 was 0.161 µM in vitro. Compared with the normal group, the learning and memory ability of mice and the contents of Ach and ChAT decreased in model group mice (P<0.01), while the AchE increased (P<0.01). Compared with the model group, Ach and ChAT in the positive control group, the high-dose group and the medium-dose group increased (P<0.01), while the AchE decreased (P<0.01). Compound 4 can improve the learning and memory abilities of APPswe/PSΔE9 double-transgenic mice, and the mechanism may be related to the regulation of the relative enzyme in the cholinergic system.

Chemical Components and Cardiovascular Activities of Valeriana spp.

Valeriana spp. is a flowering plant that is well known for its essential oils, iridoid compounds such as monoterpenes and sesquiterpenes, flavonoids, alkaloids, amino acids, and lignanoids. Valeriana spp. exhibits a wide range of biological activities such as lowering blood pressure and heart rate, antimyocardial ischemia reperfusion injury, antiarrhythmia, and regulation of blood lipid levels. This review focuses on the chemical constituents and cardiovascular activities of Valeriana spp.

Two new flavonols from Cudrania cochinchinensis.

Two new flavonols, 6-p-hydroxybenzyl kaempferol (1) and 6-p-hydroxybenzyl quercetin (2), together with six known compounds were isolated from the roots of Cudrania cochinchinensis and their structures elucidated on the basis of spectroscopic methods. Their antioxidant capacities were evaluated by 1,1-diphenyl-2-picryl-hydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical-scavenging assays. The results suggested that compounds 2, 4, and 7 showed significant radical-scavenging activities.

[Effect of the chelator Zn-DTPA on the excretion of lead in lead intoxication mice detected with ICP-MS].

To study the lead excretion effect of the chelator Zn-DTPA on the lead intoxication mice, inductively coupled plasma mass spectrometry (ICP-MS) was applied to detect the lead content of biological samples. The acute lead intoxication mice model was established by injecting lead acetate intraperitoneally with the dose of 1 mg. Zn-DTPA was administered intraperitoneally to mice once daily for five consecutive days 4 h after intoxication. Control group, model group, combination of Zn-DTPA and Ca-DTPA group were evaluated at the same time. The urine was collected every day. The mice were sacrificed in batches in the 2rd, 4th, 6th day. Biological samples including urine, whole blood, femur and brain were prepared and nitrated. Lead concentration was detected by ICP-MS. The result showed that Zn-DTPA could increase lead content in urine markedly and reduce lead content in blood, femur and brain.