Tianjiao Shi

Qishenyiqi Protects Ligation-Induced Left Ventricular Remodeling by Attenuating Inflammation and Fibrosis via STAT3 and NF-κB Signaling Pathway

Aim Qi-shen-yi-qi (QSYQ), a formula used for the routine treatment of heart failure (HF) in China, has been demonstrated to improve cardiac function through down-regulating the activation of the Renin-Angiotensin-Aldosterone System (RAAS). However, the mechanisms governing its therapeutic effects are largely unknown. The present study aims to demonstrate that QSYQ treatment can prevent left ventricular remodeling in heart failure by attenuating oxidative stress and inhabiting inflammation. Methods Sprague-Dawley (SD) rats were randomly divided into 6 groups: sham group, model group (LAD coronary artery ligation), QSYQ group with high dosage, middle dosage and low dosage (LAD ligation and treated with QSYQ), and captopril group (LAD ligation and treated with captopril as the positive drug). Indicators of fibrosis (Masson, MMPs, and collagens) and inflammation factors were detected 28 days after surgery. Results Results of hemodynamic alterations (dp/dt value) in the model group as well as other ventricular remodeling (VR) markers, such as MMP-2, MMP-9, collagen I and III elevated compared with sham group. VR was accompanied by activation of RAAS (angiotensin II and NADPHoxidase). Levels of pro-inflammatory cytokines (TNF-α, IL-6) in myocardial tissue were also up-regulated. Treatment of QSYQ improved cardiac remodeling through counter-acting the aforementioned events. The improvement of QSYQ was accompanied with a restoration of angiotensin II-NADPHoxidase-ROS-MMPs pathways. In addition, “therapeutic” QSYQ administration can reduce both TNF-α-NF-B and IL-6-STAT3 pathways, respectively, which further proves the beneficial effects of QSYQ. Conclusions Our study demonstrated that QSYQ protected LAD ligation-induced left VR via attenuating AngII -NADPH oxidase pathway and inhabiting inflammation. These findings provide evidence as to the cardiac protective efficacy of QSYQ to HF and explain the beneficial effects of QSYQ in the clinical application for HF.

DanQi Pill protects against heart failure through the arachidonic acid metabolism pathway by attenuating different cyclooxygenases and leukotrienes B4

BackgroundChinese herbal formulae are composed of complex components and produce comprehensive pharmacological effects. Unlike chemical drugs that have only one clear single target, the components of Chinese herbal formulae have multiple channels and targets. How to discover the pharmacological targets of Chinese herbal formulae and their underlying molecular mechanism are still under investigation.MethodsDanQi pill (DQP), which is one of the widely prescribed traditional Chinese medicines, is applied as an example drug. In this study, we used the drug target prediction model (DrugCIPHER-CS) to examine the underlying molecular mechanism of DQP, followed by experimental validation.ResultsA novel therapeutic effect pattern of DQP was identified. After determining the compounds in DQP, we used DrugCIPHER-CS to predict their potential targets. These potential targets were significantly enriched in well-known cardiovascular disease-related pathways. For example, the biological processes of neuroactive ligand–receptor interaction, calcium-signaling pathway, and aminoacyl–tRNA biosynthesis were involved. A new and significant pathway, arachidonic acid (AA) metabolism, was also identified in this study. This predicted pathway alteration was validated with an animal model of heart failure (HF). Results show that DQP had effect both on thromboxane B2 (TXB2) and Prostaglandin I2 (PGI2) in different patterns. It can down-regulate the TXB2 and up-regulate the PGI2 in diverse way. Remarkably, it also had effect on cyclooxygenase (COX)-1 and COX2 by suppressing their levels, which may be the critical and novel mechanism of cardiacprotective efficacy for DQP. Furthermore, leukotrienes B4 (LTB4) receptor, another key molecule of AA metabolism which finally mediated gastrotoxic leukotrienes, was also reduced by DQP.ConclusionsThe combination of drug target prediction and experimental validation provides new insights into the complicated mechanism of DQP.

Danqi Pill regulates lipid metabolism disorder induced by myocardial ischemia through FATP-CPTI pathway

BackgroundDanqi Pill (DQP), which contains Chinese herbs Salvia miltiorrhiza Bunge and Panax notoginseng, is widely used in the treatment of myocardial ischemia (MI) in China. Its regulatory effects on MI-associated lipid metabolism disorders haven’t been comprehensively studied so far. We aimed to systematically investigate the regulatory mechanism of DQP on myocardial ischemia-induced lipid metabolism disorders.MethodsMyocardial ischemia rat model was induced by left anterior descending coronary artery ligation. The rat models were divided into three groups: model group with administration of normal saline, study group with administration of DanQi aqueous solution (1.5 mg/kg) and positive-control group with administration of pravastatin aqueous solution (1.2 mg/kg). In addition, another sham-operated group was set as negative control. At 28 days after treatment, cardiac function and degree of lipid metabolism disorders in rats of different groups were measured.ResultsPlasma lipid disorders were induced by myocardial ischemia, with manifestation of up-regulation of triglyceride (TG), low density lipoprotein (LDL), Apolipoprotein B (Apo-B) and 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR). DQP could down-regulate the levels of TG, LDL, Apo-B and HMGCR. The Lipid transport pathway, fatty acids transport protein (FATP) and Carnitine palmitoyltransferase I (CPTI) were down-regulated in model group. DQP could improve plasma lipid metabolism by up-regulating this lipid transport pathway. The transcription factors peroxisome proliferator-activated receptor α (PPARα) and retinoid X receptors (RXRs), which regulate lipid metabolism, were also up-regulated by DQP. Furthermore, DQP was able to improve heart function and up-regulate ejection fraction (EF) by increasing the cardiac diastolic volume.ConclusionsOur study reveals that DQP would be an ideal alternative drug for the treatment of dyslipidemia which is induced by myocardial ischemia.

QSYQ Attenuates Oxidative Stress and Apoptosis Induced Heart Remodeling Rats through Different Subtypes of NADPH-Oxidase

We aim to investigate the therapeutic effects of QSYQ, a drug of heart failure (HF) in clinical practice in China, on a rat heart failure (HF) model. 3 groups were divided: HF model group (LAD ligation), QSYQ group (LAD ligation and treated with QSYQ), and sham-operated group. After 4 weeks, rats were sacrificed for cardiac injury measurements. Rats with HF showed obvious histological changes including necrosis and inflammation foci, elevated ventricular remodeling markers levels(matrix metalloproteinases-2, MMP-2), deregulated ejection fraction (EF) value, increased formation of oxidative stress (Malondialdehyde, MDA), and up-regulated levels of apoptotic cells (caspase-3, p53 and tunnel) in myocardial tissue. Treatment of QSYQ improved cardiac remodeling through counter-acting those events. The improvement of QSYQ was accompanied with a restoration of NADPH oxidase 4 (NOX4) and NADPH oxidase 2 (NOX2) pathways in different patterns. Administration of QSYQ could attenuate LAD-induced HF, and AngII-NOX2-ROS-MMPs pathway seemed to be the critical potential targets for QSYQ to reduce the remodeling. Moreover, NOX4 was another key targets to inhibit the p53 and Caspase3, thus to reduce the hypertrophy and apoptosis, and eventually provide a synergetic cardiac protective effect.

The protective effect of the active components of ERPC on diabetic peripheral neuropathy in rats

ETHNOPHARMACOLOGICAL RELEVANCE Euonymus alatus, Radix trichosanthis, Panax notoginseng and Coptis chinensis are popular plants used in traditional Chinese medicine to treat diabetes. AIM OF THE STUDY The aim of the study is to investigate the therapeutic effect of the active components of Euonymus alatus, Radix trichosanthis, Panax notoginseng and Coptis chinensis (cERPC) on diabetic peripheral neuropathy in the rats and explore the underlying mechanism involved. METHODS After diabetes was induced in rats for 20 weeks, cERPC or water was administered for 12 weeks. After a hot plate test, motor nerve conduction velocity and sciatic nerve blood flow were determined; the sciatic nerves were isolated for toluidine blue staining; and the fibre area, fibre diameter, axon area, axon diameter and myelin thickness were evaluated. The levels of the myelin basic protein, myelin protein zero, Oct6 and Krox20 were measured by western blot or immunofluorescence. RESULTS cERPC was efficient in reducing the response latency, increasing motor nerve conduction velocity, enhancing sciatic nerve blood flow and ameliorating the pathological changes in diabetic rats. cERPC also had a role in increasing the levels of myelin basic protein and myelin protein zero and improving the expression of Oct6 and Krox20 in sciatic nerves of diabetic rats. CONCLUSIONS cERPC ameliorates diabetic peripheral neuropathy by attenuating electrophysiological, circulatory and morphological alterations, which is mediated by the Oct6-Krox20 pathway.

Multitarget Effects of Danqi Pill on Global Gene Expression Changes in Myocardial Ischemia

Danqi pill (DQP) is a widely prescribed traditional Chinese medicine (TCM) in the treatment of cardiovascular diseases. The objective of this study is to systematically characterize altered gene expression pattern induced by myocardial ischemia (MI) in a rat model and to investigate the effects of DQP on global gene expression. Global mRNA expression was measured. Differentially expressed genes among the sham group, model group, and DQP group were analyzed. The gene ontology enrichment analysis and pathway analysis of differentially expressed genes were carried out. We quantified 10,813 genes. Compared with the sham group, expressions of 339 genes were upregulated and 177 genes were downregulated in the model group. The upregulated genes were enriched in extracellular matrix organization, response to wounding, and defense response pathways. Downregulated genes were enriched in fatty acid metabolism, pyruvate metabolism, PPAR signaling pathways, and so forth. This indicated that energy metabolic disorders occurred in rats with MI. In the DQP group, expressions of genes in the altered pathways were regulated back towards normal levels. DQP reversed expression of 313 of the 516 differentially expressed genes in the model group. This study provides insight into the multitarget mechanism of TCM in the treatment of complex diseases.

GW24-e0233 NADPHoxidase4-mediated myocardial damage effects to heart failure in rats through the modulation of oxidative stress and cardiac remodelling

Objectives We aim to investigate the myocardial injury effects of different NADPH oxidase subtypes on a rat heart failure (HF) model and possible underlying mechanism. Methods HF model were induced by ligation of left anterior descending coronary (LAD) in Sprague-Dawley rats. 2 groups were divided: CHD group (LAD ligation) and control group. After 4 weeks, rats were sacrificed for cardiac injury measurements. Results Rats with HF showed obvious histological changes including necrosis, elevated ventricular remodeling markers (MMP-9) levels, dysregulated ejection fraction (EF) value, and increased formation of oxidative stress. The radioimmunoassay of SOD shows that at the end of the study, the serum SOD in model group decreased by 32.86% (P < 0.05) compared with control. Results of MDA appeared reverse changes. MDA in model group increased by 33.62% (P < 0.05) compared with control, suggesting an oxidative stress response in HF. The two pathways lead to NADPH oxidases up-regulation which was believed to cause oxidative stress, Nox2 and Nox4 (subtypes of NADPH oxidase) showed different patterns in this model. NOX2 showed no statistical significance compared to control. The Western blot of NADPHoxidase 4(NOX4) showed a 62.00% compensatory increase (P<0.05) in model group, and it had a positive linear correlation with MMP-9. Conclusions In conclusion, the activation of NOX2 and NOX4 showed a distinct pattern in LAD-induced HF model. Oxidative stress and cardiac hypertrophy in this model were induced partly through the NOX4-MMP-9 pathways, but no evidence had showed the change in NOX2, suggesting a NOX4-mediated myocardial injury effects against heart failure, and NOX-4 can be used as potential drug targets for HF.