Coronary microvascular dysfunction.

Coronary microvascular dysfunction (CMD) is a key mechanism underlying ischemic heart disease (IHD), yet its diagnosis and treatment remain challenging. This article presents a comprehensive overview of CMD research, covering its pathogenesis, diagnostic criteria, assessment techniques, risk factors, and therapeutic strategies. Additionally, it highlights the prospects for future CMD research. The article aims at advocating early and effective intervention for CMD and improving the prognosis of IHD.

Zedoarondiol inhibits atherosclerosis by regulating monocyte migration and adhesion via CXCL12/CXCR4 pathway.

Atherosclerosis (AS) is an essential pathological changes of ischemic cardio-cerebrovascular disease, and monocyte migration and adhesion to endothelial cells are the critical pathological process in AS. Our previous studies demonstrated a beneficial effect of zedoarondiol in AS, but whether the mechanism is associated with monocyte migration and adhesion to endothelial cells remains unclear. In this study, we investigated whether the anti-atherosclerotic effects of zedoarondiol were associated with decreasing migration and adhesion of monocytes. The oil red O staining demonstrated that zedoarondiol ameliorated AS plaques in en face aorta and aortic root of apolipoprotein E gene knocked (apoE-/-) mice. In vitro, zedoarondiol decreased human monocytic macrophage-like cell line (THP-1) monocytes migration and adhesion to endothelial cells. Single-cell RNA sequencing analysis (scRNA-seq) in mice indicated that zedoarondiol decreased monocytes adhesion to endothelial cells by regulating CXC chemokine ligand 12/CXC chemokine receptor 4 (CXCL12/CXCR4) pathway, which was verified by Western blot of THP-1 monocytes；zedoarondiol also decreased the expressions of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) and nuclear factor-kappa B (NF/κB), the downstream proteins of CXCL12/CXCR4 pathway. In conclusion, zedoarondiol ameliorated AS plaque and inhibited monocyte migration and adhesion to endothelial cells via regulating CXCL12/CXCR4 pathway, suggesting that zedoarondiol might be a new promising drug for AS.

Panax Notoginseng Saponins Combined with Dual Antiplatelet Drugs Potentiates Anti-Thrombotic Effect with Alleviated Gastric Injury in A Carotid Artery Thrombosis Rat Model.

OBJECTIVE: To observe the combination effects of Panax notoginseng saponins (PNS)and dual antiplatelet drugs (DAPT), and to explore the mechanism via cyclooxygenase /prostaglandin pathway. METHODS: Right carotid artery thrombosis was induced in Wistar rats by infiltration with 70% FeCl3, and the animals were randomly divided into sham group, model group, DAPT group and PNS + DAPT group, intragastrically treated for 4 weeks. The cerebral pia mater microcirculation was observed in vivo after anesthetizing by anatomical microscope. The wet weight of carotid artery thrombosis was measured. Gastric mucosal injury was observed by hematoxylin and eosin staining. Platelet aggregation rate was detected with adenosine diphosphate -induced turbidimetry. Platelet CD62p expression was detected by flow cytometry. Concentrations of 6-Ketoprostaglandin F1 alpha, prostaglandin E2 in gastric mucosa and thromboxane B2, 6-Ketoprostaglandin F1 alpha, tissue plasminogen activator, plasminogen activator inhibitor, and fibrin fragment D in the plasma were measured by radioimmunoassay. RESULTS: PNS and DAPT increased the blood flow volume of cerebral pia mater and decreased erythrocyte aggregation and leukocyte adhesion of model rats. Compared to DAPT, PNS and DAPT further reduced the weight of carotid artery thrombosis with enhanced inhibition of platelet aggregation, increased tissue plasminogen activator levels and decreased fibrin fragment D levels. PNS and DAPT alleviated gastric injury induced by dual antiplatelet drugs and upregulated the expression of 6-Ketoprostaglandin F1 alpha in the gastric mucosa compared with DAPT. CONCLUSIONS: PNS combined with DAPT increased anti-thrombosis effects of DAPT and mitigated DAPT-related gastric injury. The underlying mechanisms may be associated with enhanced antiplatelet aggregation and activation of the fibrinolytic system and up-regulation of 6-Ketoprostaglandin F1 alpha expression in gastric mucosa.

The roles of PKC-δ and PKC-ε in myocardial ischemia/reperfusion injury.

Ischemia and reperfusion (I/R) cause a reduction in arterial blood supply to tissues, followed by the restoration of perfusion and consequent reoxygenation. The reestablishment of blood flow triggers further damage to ischemic tissue through reactive oxygen species (ROS) accumulation, interference with cellular ion homeostasis, opening of mitochondrial permeability transition pores (mPTPs) and promotion of cell death (apoptosis or necrosis). PKC-δ and PKC-ε, belonging to a family of serine/threonine kinases, have been demonstrated to play important roles during I/R injury in cardiovascular diseases. However, the cardioprotective mechanisms of PKC-δ and PKC-ε in I/R injury have not been elaborated until now. This article discusses the roles of PKC-δ and PKC-ε during myocardial I/R in redox regulation (redox signaling and oxidative stress), cell death (apoptosis and necrosis), Ca2+ overload, and mitochondrial dysfunction.

DLDTI: a learning-based framework for drug-target interaction identification using neural networks and network representation.

BACKGROUND: Drug repositioning, the strategy of unveiling novel targets of existing drugs could reduce costs and accelerate the pace of drug development. To elucidate the novel molecular mechanism of known drugs, considering the long time and high cost of experimental determination, the efficient and feasible computational methods to predict the potential associations between drugs and targets are of great aid. METHODS: A novel calculation model for drug-target interaction (DTI) prediction based on network representation learning and convolutional neural networks, called DLDTI, was generated. The proposed approach simultaneously fused the topology of complex networks and diverse information from heterogeneous data sources, and coped with the noisy, incomplete, and high-dimensional nature of large-scale biological data by learning the low-dimensional and rich depth features of drugs and proteins. The low-dimensional feature vectors were used to train DLDTI to obtain the optimal mapping space and to infer new DTIs by ranking candidates according to their proximity to the optimal mapping space. More specifically, based on the results from the DLDTI, we experimentally validated the predicted targets of tetramethylpyrazine (TMPZ) on atherosclerosis progression in vivo. RESULTS: The experimental results showed that the DLDTI model achieved promising performance under fivefold cross-validations with AUC values of 0.9172, which was higher than the methods using different classifiers or different feature combination methods mentioned in this paper. For the validation study of TMPZ on atherosclerosis, a total of 288 targets were identified and 190 of them were involved in platelet activation. The pathway analysis indicated signaling pathways, namely PI3K/Akt, cAMP and calcium pathways might be the potential targets. Effects and molecular mechanism of TMPZ on atherosclerosis were experimentally confirmed in animal models. CONCLUSIONS: DLDTI model can serve as a useful tool to provide promising DTI candidates for experimental validation. Based on the predicted results of DLDTI model, we found TMPZ could attenuate atherosclerosis by inhibiting signal transductions in platelets. The source code and datasets explored in this work are available at https://github.com/CUMTzackGit/DLDTI .

Xinyue Capsule in patients with stable coronary artery disease after percutaneous coronary intervention: a multicenter, randomized, placebo-controlled trial.

BACKGROUND: Xinyue capsule, a patented Chinese herbal medicine, has been used to manage coronary artery disease (CAD) for over a decade in China, but whether it can further reduce risk of cardiovascular events beyond conventional treatment is unknown. METHODS: In this multicenter, randomized, placebo-controlled trial, we randomly assigned patients with stable CAD who underwent percutaneous coronary intervention (PCI) within the preceding 3-12 months to receive Xinyue capsule (100 mg panax quinquefolius saponins, three times a day) or placebo for 24 weeks in addition to conventional treatment. The primary endpoint was a composite that included cardiac death, nonfatal myocardial infarction and urgent revascularization with either PCI or coronary artery bypass grafting. The secondary composite endpoints included stroke, re-hospitalization due to acute coronary syndrome (ACS), pulmonary embolism, peripheral vascular events and all-cause mortality. Quality of life was assessed using a 36-item Short-Form Health Survey (SF-36). RESULTS: A total of 1054 participants were included in the analyses. The median follow up was 1 year. The primary endpoint events occurred in 16 patients (3.02%) in the Xinyue group and 34 patients (6.49%) in the placebo group (hazard ratio [HR] 0.455, 95% confidence interval [CI] 0.25 to 0.825; P = 0.009). Secondary end-point events occurred in 5.47% of patients in the Xinyue group and 10.31% in the placebo group (HR 0.515, 95% CI 0.328 to 0.809; P = 0.004). SF-36 subscale scores at 12 months were significantly higher in the Xinyue group than placebo group for general health (P = 0.048) and vitality (P = 0.008). CONCLUSIONS: In patients with stable CAD after PCI within the preceding 3 to 12 months, Xinyue capsule added on conventional treatment reduced the incidence of primary composite endpoint (cardiac death, nonfatal myocardial infarction and urgent revascularization).

ANRIL and atherosclerosis.

WHAT IS KNOWN AND OBJECTIVE: The 3.8-kb-long antisense non-coding RNA at the INK4 locus (ANRIL) is transcribed from the short arm of human chromosome 9 on P21 and is associated with malfunction of the vascular endothelium, vascular smooth muscle cell (VSMC) proliferation/migration/senescence/apoptosis, mononuclear cell adhesion and proliferation, glycolipid metabolism disorder and DNA damage. Hence, ANRIL plays an important role in atherogenesis. Moreover, genome-wide association studies (GWAS) have identified ANRIL as a biomarker that is closely related to coronary heart disease (CHD). The objective of this review was to discuss the pathological mechanism of ANRIL in atherosclerotic development and its significance as a predictor of cardiovascular disease. METHODS: Review of the PubMed, EMBASE and Cochrane databases for articles demonstrating the roles of ANRIL in the development of atherosclerotic diseases. RESULTS AND DISCUSSION: The abnormal expression of ANRIL is linked to vascular endothelium injury; the proliferation, migration, senescence and apoptosis of VSMCs; mononuclear cell adhesion and proliferation; glycolipid metabolism disorder; DNA damage; and competing endogenous RNAs. Moreover, ANRIL accelerates the progression of CHD by regulating its single nucleotide polymorphisms (SNPs). WHAT IS NEW AND CONCLUSION: Considering that ANRIL accelerates atherosclerosis (AS) development and is a risk factor for CHD, it is reasonable for us to explore an efficacious ANRIL-based therapy for AS in CHD.

[Editorial explanation for Expert consensus statement on Diemailing Kudiezi Injection in clinical practice].

Expert consensus statement on Diemailing Kudiezi Injection in clinical practice was approved on April 17,2019 by the Standardadization Office of the Chinese Association of Chinese Medicine. This project,which started in November 2017,has been developed and completed in accordance with the standard developing procedure. This paper will give a detailed introduction to the compilation process about the consensus. The aim is to enable readers to understand the background,purpose and basis of this consensus in a timely manner. Readers can learn about diffferent stages of develping process,including project management system,drafting,consulting,expert consensus,as well as current problems and shortcomings. Such an editorial explanation is just a dynamic follow-up of the whole consensus-making process. It also plays a good supervisory role in the whole consensus-making. It could be a guarantee for the quality of the consensus. There is no doubts that the editorial explanation is an important auxiliary document in the process of consensus-making. It is the extension and supplement of consensus content and a basis for fully understanding the technical content of this consensus. Therefore it is an indispensable document in the process of consensus-making.

[Expert consensus statement on Diemailing~® Kudiezi Injection in clinical practice].

Diemailing~® Kudiezi Injection( DKI) is widely used in the treatment of cerebral infarction,coronary heart disease and angina pectoris. Long-term clinical application and related research evidence showed that DKI has a good effect in improving the clinical symptoms of cardiovascular and cerebrovascular diseases. However,this injection has not been included in any clinical practice guideline. It has been found that the use of DKI is in wrong way in clinical practice in recent years. Therefore,clinical experts from the field of cardiovascular and cerebrovascular diseases nationwide are invited to compile this expert consensus in order to guide clinicians.GRADE system is used to grade the quality of evidence according to different outcomes according to degrading factors. Then it forms the recommendation or consensus suggestion through the nominal group method. The formation of expert consensus mainly considers six factors: quality of evidence,economy,efficacy,adverse reactions,patient acceptability and others. Based on these six aspects,if the evidence is sufficient,a " recommendation" supported by evidence is formed,and GRADE grid voting rule is adopted. If the evidence is insufficient,a " consensus suggestions" will be formed,using the majority voting rule. In this consensus,the clinical indications,efficacy,safety evidences and related preliminary data of DKI were systematically and comprehensively summarized in a concise and clear format,which could provide valuable reference for the clinical use of DKI. This consensus has been approved by China association of Chinese medicine which is numbered GS/CACM 202-2019.

Zedoarondiol Attenuates Endothelial Cells Injury Induced by Oxidized Low-Density Lipoprotein via Nrf2 Activation.

BACKGROUND/AIMS: Zedoarondiol, a sesquiterpene lactone compound, showed an anti-proliferative activity on vascular smooth muscle cells in our previous study. However, whether it has a beneficial effect on endothelial cells injury induced by oxidized low-density lipoprotein (ox-LDL) remains unclear. This study was designed to investigate the protective effect of zedoarondiol on ox-LDL-induced injury of endothelial cells and explored its underlying mechanism. METHODS: The protective effect of zedoarondiol on ox-LDL-induced human umbilical vein endothelial cells (HUVECs) injury were evaluated by Cell Counting Kit-8 (CCK-8) assay and released lactic dehydrogenase (LDH) activity assay. Oxidative stress was determined by malonedialdehyde (MDA) content and superoxide dismutase (SOD) activity. The level of reactive oxygen species (ROS) was measured by dichlorodihydrofluorescin diacetate (DCFH-DA) staining. The culture supernatant was collected for enzyme linked immune-sorbent assays (ELISA) of interleukine-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). Immunofluorescence staining was used to observe NF-E2-related factor 2 (Nrf2) translocation. Western blotting was performed to determine the expression of IL-1ß, TNF-α, MCP-1, Kelch-like ECH associated protein 1 (Keap1), heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase-1 (NQO1), and Nrf2. RESULTS: Zedoarondiol attenuated HUVECs injury, up-regulated SOD activity, suppressed formation of MDA and ROS, and secretion and protein expression of IL-1ß, TNF-α, and MCP-1 in injured HUVECs induced by ox-LDL. Zedoarondiol induced nuclear Nrf2 translocation from cytoplasm into nucleus and up-regulated expression of HO-1, NQO1, and Nrf2 in nucleus. All-trans-retinoic acid (ATRA), an inhibitor of Nrf2, abolished zedoarondiol-mediated anti-oxidative effect. CONCLUSION: Zedoarondiol attenuates ox-LDL-induced endothelial cells injury by inhibiting oxidative stress and inflammation via Nrf2/HO-1 pathway, suggesting that zedoarondiol might be meaningful on prevention and treatment of atherosclerosis.

Panax Quinquefolium Saponins Attenuate Myocardial Dysfunction Induced by Chronic Ischemia.

BACKGROUND/AIMS: Previous studies in rat models of myocardial ischemia showed that Panax quinquefolium saponins (PQS) could attenuate ischemic/reperfusion injury, increase vessel density and improve cardiac function. In the current study, we examined whether PQS could attenuate myocardial dysfunction in a swine model of chronic myocardial ischemia (CMI). METHODS: CMI was established in Bama mini-pigs by placing amroid constrictor on the left anterior descending artery (LAD). Starting from 2 months after the surgery, pigs randomly received PQS (30 mg/kg/day), atorvastatin (1.5 mg/kg/day), or no drug for one month (n=6). A group of pigs receiving sham surgery was included as an additional control. Glucose utilization was assessed with positron emission tomography-computer tomography (PET-CT). Cardiac function was assessed with echocardiography. Myocyte size, nuclear density, and arteriolar density were examined in tissue section obtained from the ischemia area. Potential molecular targets of PQS were identified using proteomic analysis with isobaric tags for relative and absolute quantitation (iTARQ) and network pharmacology. RESULTS: In comparison to the sham controls, pigs implanted with ameroid constrictor had decreased ventricular wall motion, left ventricular ejection fraction (LVEF), and glucose utilization. PQS significantly increased cardiac function and glucose utilization. Arteriole density and myocyte nuclear density were increased. Myocyte diameter was decreased. PQS also attenuated the CMI-induced change of protein expression profile. The effects of atorvastatin were generally similar to that of PQS. However, PQS attenuated the reduction of left ventricular systolic WT induced by CMI more robustly than atorvastatin. CONCLUSION: The results from the current study supports the use of PQS in patients with coronary artery disease.

Obstructive sleep apnea increases the risk of cardiac events after percutaneous coronary intervention: a meta-analysis of prospective cohort studies.

PURPOSE: Recent studies have shown an association between obstructive sleep apnea (OSA) and coronary artery disease; however, the association between OSA and cardiac outcomes in patients after percutaneous coronary intervention (PCI) remains undetermined. METHODS: PubMed, EMBASE, and CENTRAL were searched from inception to July 2016 for cohort studies that followed up with patients after PCI, and evaluated their overnight sleep patterns within 1 month for major adverse cardiac events (MACEs) as primary outcomes including cardiac death, non-fatal myocardial infarction (MI), and coronary revascularization and secondary outcomes including re-admission for heart failure and stroke. Outcomes data were pooled using fixed-effect meta-analysis, and heterogeneity was assessed with the I 2 statistics. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale checklist, and publication bias was evaluated by a visual investigation of funnel plots. RESULTS: We identified seven pertinent studies including 2465 patients from 178 related articles. OSA was associated with MACEs (odds ratio [OR], 1.52, 95% confidence interval [CI], 1.20-1.93, I 2 = 29%), which included cardiac death (OR 2.05, 95% CI, 1.15-3.65, I 2 = 0%), non-fatal MI (OR 1.59, 95% CI, 1.14-2.23, I 2 = 15%), and coronary revascularization (OR 1.69, 95% CI, 1.28-2.23, I 2 = 0%). However, OSA was not associated with re-admission for heart failure (OR 1.71, 95% CI, 0.99-2.96, I 2 = 0%) and/or stroke (OR 1.68, 95% CI, 0.91-3.11, I 2 = 0%) according to the pooled results. CONCLUSIONS: In patients after PCI, OSA appears to increase the risk of cardiac death, non-fatal MI, and coronary revascularization.

miR-941 as a promising biomarker for acute coronary syndrome.

BACKGROUND: Circulating miRNAs can function as biomarkers for diagnosis, treatment, and prevention of diseases. However, it is unclear whether miRNAs can be used as biomarkers for acute coronary syndrome (ACS). To this end, we applied gene chip technology to analyze miRNA expression in patients with stable angina (SA), non-ST elevation ACS (NSTE-ACS), and ST-segment elevation myocardial infarction (STEMI). METHODS: We enrolled patients with chest pain who underwent diagnostic coronary angiography, including five patients each with SA, NSTE-ACS, or STEMI, and five controls without coronary artery disease (CAD) but with three or more risk factors. After microarray analysis, differential miRNA expression was confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Compared with those in patients with STEMI, differentially expressed microRNAs in controls and patients with SA or NSTE-ACS were involved in inflammation, protein phosphorylation, and cell adhesion. Pathway analysis showed that differentially expressed miRNAs were related to the mitogen-activated protein kinase signaling, calcium ion pathways, and cell adhesion pathways. Compared with their expression levels in patients with STEMI, miR-941, miR-363-3p, and miR-182-5p were significantly up-regulated (fold-change: 2.0 or more, P < 0.05) in controls and patients with SA or NSTE-ACS. Further, qRT-PCR showed that plasma miR-941 level was elevated in patients with NSTE-ACS or STEMI as compared with that in patients without CAD (fold-change: 1.65 and 2.28, respectively; P < 0.05). Additionally, miR-941 expression was significantly elevated in the STEMI group compared with that in the SA (P < 0.01) and NSTE-ACS groups (P < 0.05). Similarly, miR-941 expression was higher in patients with ACS (NSTE-ACS or STEMI) than in patients without ACS (without CAD or with SA; P < 0.01). There were no significant differences in miR-182-5p and miR-363-3p expression. The areas under the receiver operating characteristic curves were 0.896, 0.808, and 0.781 for patients in the control, SA, and NSTE-ACS groups, respectively, compared with that for patients with STEMI; that for the ACS group compared with the non-ACS group was 0.734. CONCLUSION: miR-941 expression was relatively higher in patients with ACS and STEMI. Thus, miR-941 may be a potential biomarker of ACS or STEMI.

[Dynamic Visible Microcirculation and Activating Blood Removing Stasis Research].

The technology of dynamic visualization microcirculation is to observe changes of mi- crocirculation by using visualization technology, combined with fluorescence labeling, high-speed video, electronic microscopy and other methods, converting rest images into dynamic visual graphics. In the past ten years, domestic researchers used this technology, and carried out researches on the heart, piamater/mesenteric microcirculation, dynamically observed effects of activating blood removing stasis (ABRS) research monomer, single herb and compound on arteriole/venula diameter, and the velocity of red blood cell, white blood cell adhesion, platelet aggregation, microvascular permeability, superoxide production, and plasma albumin leakage, etc. Microcirculation detection technologies were further opti- mized. Exerting direct advantages of dynamic visualization microcirculation, systematically evaluating ac- tion mechanism of Chinese herbs (multi-sites and multi-targets) , and interaction mechonism between Chinese herbs and Western drugs are important directions for future researches on microcirculation.

Zedoarondiol Inhibits Platelet-Derived Growth Factor-Induced Vascular Smooth Muscle Cells Proliferation via Regulating AMP-Activated Protein Kinase Signaling Pathway.

BACKGROUND/AIMS: Vascular smooth muscle cells (VSMCs) proliferation contributes significantly to atherosclerosis and in-stent restenosis. Platelet-derived growth factor-BB (PDGF-BB) plays a vital role in VSMCs proliferation. Zedoarondiol, a sesquiterpene lactone compound, has an anti-inflammatory activity. However, the role of zedoarondiol in PDGF-BB-mediated VSMCs proliferation remains unclear. In this study, we investigated the effects of zedoarondiol on PDGF-BB-induced VSMCs proliferation and explored the possible mechanisms. METHODS: The inhibitory effects of zedoarondiol on PDGF-BB-induced VSMCs proliferation were evaluated by direct cell counting and the Cell Counting Kit-8 (CCK-8) assay. DNA synthesis was examined by bromodeoxyuridine (BrdU) incorporation assay. Cell cycle was assessed by propidium iodide staining. Western blotting was performed to determine the expression of cyclin-dependent kinase 2 (CDK2), cyclin E, p53, p21, total and phosphorylated adenosine monophosphate-activated protein kinase (AMPK), acetyl CoA carboxylase (ACC), mammalian target of rapamycin (mTOR), and p70 ribosomal protein S6 kinase (p70S6K). RESULTS: Zedoarondiol suppressed PDGF-BB-induced VSMCs proliferation and DNA synthesis, and induced cell cycle arrest in G0/G1 phase. In addition, zedoarondiol activated AMPK and ACC, inhibited the phosphorylation of mTOR and p70S6K, increased the expression of p53 and p21, and decreased the expression of CDK2 and cyclin E. Compound C (an AMPK inhibitor) abrogated, whereas 5-aminoimidazole-4-carboxamide 1-ß-ribofuranoside (AICAR, an AMPK activator) enhanced zedoarondiol-mediated inhibition of VSMCs proliferation and DNA synthesis. CONCLUSION: Zedoarondiol inhibits PDGF-BB-induced VSMCs proliferation via AMPK-mediated down-regulation of the mTOR/p70S6K pathway and up-regulation of the p53/p21 pathway. These findings suggest that zedoarondiol might be a promising compound against atherosclerosis and in-stent restenosis.

Pretreatment with a combination of ligustrazine and berberine improves cardiac function in rats with coronary microembolization.

AIM: We have shown that a combination of ligustrazine and berberine produces more effective inhibition on platelet activation and inflammatory reactions in rat acute myocardial infarction compared with either agent alone. In this study we evaluated the beneficial effects of a combination of ligustrazine and berberine in a rat model of coronary microembolization (CME). METHODS: SD rats were treated with ligustrazine, berberine, ligustrazine+berberine, or clopidogrel for 2 weeks. When the treatment completed, CME was induced by injection of sodium laurate into the left ventricular, while obstructing the ascending aorta. All rats were intubated for hemodynamic measurements. Blood samples were collected for biochemical analyses, flow cytometry, and ELISAs. Heart tissues were isolated for histopathology and subsequent protein analyses. RESULTS: Pretreatment with the combination of ligustrazine (27 mg·kg(-1)·d(-1)) and berberine (90 mg·kg(-1)·d(-1)) significantly improved cardiac function, and decreased myocardial necrosis, inflammatory cell infiltration, microthrombosis and serum CK-MB levels in CME rats. In addition, this combination significantly decreased plasma ET-1 levels and von Willebrand factor, inhibited ADP-induced platelet activation, and reduced TNFα, IL-1ß, ICAM-1 and RANTES levels in serum and heart tissues. The protective effects of this combination were more prominent than those of ligustrazine or berberine alone, but comparable to those of a positive control clopidogrel (6.75 mg·kg(-1)·d(-1)). CONCLUSION: The combination of ligustrazine and berberine significantly improved cardiac function in rat CME model via a mechanism involving antiplatelet and anti-inflammatory effects.

[Research on Precision Medicine, Gene Polymorphism, and Combination of Disease Identification and Syndrome Typing on Cardiovascular Diseases].

With the fusion and application of biological and information technologies in clinical practice, precision medicine has become a more precise positioning and sublimation of individualized medicine. Based on the concept of precision medicine, great developments have taken place in genetic diagnosis and targeted therapy of lung cancer, leukemia, breast cancer and other diseases, genetic diagnosis of cardiovascular diseases, and researches on gene polymorphisms and combination of disease identification and syndrome typing. However, there are still some problems. In the big data analysis era, how to organically combine precision medicine with essence research of syndromes, how to establish a new methodological system based on basic theories of Chinese medicine (CM) in accordance with clinical practice of CM and integrative medicine (IM) are both the difficulties and breakthrough points for Chinese medicine and pharmacy (CMP). They are of significance in promoting modernization of CMP.

[Chinese Herbal Compounds for Supplementing Qi and Activating Blood Circulation Combined with Dual Antiplatelet Drugs Alleviated Human Umbilical Vein Endothelial Cell Injury and Platelet Adhe- sion via Up-regulation of P13K/Akt Pathway].

OBJECTIVE: To observe the effect and underlying mechanism of Chinese herbal com- pound (CHC) for supplementing qi and activating blood circulation (SQABC) combined with dual antiplatelet drugs (DA) on oxidized low density lipoprotein (ox-LDL) induced human umbilical vein endothelial cell (HUVEC) injury and platelet adhesion evoked by injured endothelial cells (ECs) based on P13K/Akt signaling pathway. METHODS: HUVECs were randomly divided into 5 groups, i.e., the blank control group, the model group (80 mg/L ox-LDL) , the DA group (15 µg/mL aspirin +10 µg/ mL clopidogrel +80 mg/L ox-LDL) , the Panax Quinquefolium saponins ( PQS, 160 µLg/mL) + Panax Notoginseng saponins (PNS, 160 µg/mL) +DA group, the LY294002 (30 µg/mL) + PQS + PNS + DA group. HUVEC apoptosis rate and platelet adhesion to HUVECs were detected by flow cytometry. Concentration of lactate dehydrogenase ( LDH) in HUVEC supernatant was detected by biochemical assay. Concentration of intercellular adhesion molecular ([CAM) was detected by radioimmunoassay. Protein expressions of p-P13K and p-Akt in HU- VECs were detected by Western blot. RESULTS: Compared with the blank control group, the apoptosis rate of HUVECs, mean fluorescence indicator ( MFI) , concentrations of both LDH and ICAM increased (P <0. 05) , and p-Akt protein expression decreased (P <0. 05) in the model group. Compared with the model group, the apoptosis rate of HUVECs and LDH concentration increased (P <0. 05), concentrations of MFI and ICAM obviously decreased (P <0. 05) in the DA group. The apoptosis rate, MFI, concentrations of both LDH and ICAM all decreased in the PQS + PNS + DA group (P <0. 05). p-Akt protein. expres- sion in HUVECs obviously increased in the PQS + PNS + DA group (P <0. 05). Compared with the DA group, HUVEC apoptosis rate, MFI, concentrations of both LDH and ICAM in supernatant obviously decreased, p-Akt expression in HUVECs increased in the PQS + PNS + DA group (all P <0. 05). p-Akt protein expression in HUVECs was inhibited after adding specific P13K inhibitor LY294002. Protection men- tioned above all disappeared in the PQS + PNS + DA group (P <0. 05). CONCLUSION: CHC for SQABC combined with DA could alleviate ox-LDL induced apoptosis of endothelial cells and reduce injured ECs e- voked platelet adhesion via up-regulation of P13K/Akt pathway in ECs.

[Thinking on the Relationship of Formulas Corresponding to Diseases in Chinese Medicine].

"Treatment based on diseases identification and formulas corresponding to diseases" is one of important therapy modes of Chinese medicine. Although it originates from Huangdi Neijing, it is seldom systematically discussed. Modern Chinese medicine (CM) now faces diseases mostly with comparatively confirmed Western medical diagnoses. Most of them have specific pathophysiological changes. How to interpret these specific pathophysiological changes, play CM's advantages, and improve clinical efficacies has become an inevitable problem for modern CM in clinic. Authors expounded historic development and clinical application of "formulas corresponding to diseases", and its difference from "formulas corresponding to syndromes", put forward that we should combine "formulas corresponding to diseases" and "formulas corresponding to syndromes" in CM clinics. We should focus on the disease and summarize treatment rules, thereby improving targeted CM formulas.

[Effect of Chinese herbal drug-containing serum for activating blood, activating blood and dispelling toxin on TNF-alpha-induced adherence between endothelial cells and neutrophils and the expression of MAPK pathway].

OBJECTIVE: To explore the effect of drug-containing serum of Chinese herbal compounds [Xiongshao Capsule (XS, for activating blood) and Huanglian Capsule (HL, for dispelling toxin)] on tumor necrosis factor-alpha (TNF-alpha)-induced adherence between human umbilical vein endothelial cells (HUVECs) and polymorphonuclear neutrophils (PMN), inflammatory reaction and expression of related proteins in mitogen-activated protein kinase (MAPK) pathway. METHODS: Thirty-two rats were randomly divided into four groups (8 in each group) using random digit table: the blank control group treated with distilled water, the test group I treated with Chinese herbal compound of XS (0.135 g/kg), the test group II treated with Chinese herbal compound of HL (0.135 g/kg), and the test group Ill treated with Chinese herbal compound of XS (0.135 g/kg) and HL (0.135 g/kg). All medication was given by gastrogavage once a day for a week. Rats' blood serum was harvested 1 h after the last administration to prepare drug-containing serum. HUVECs were exposed to TNF-alpha (100 ng/mL) to induce cell injury model and incubated with corresponding drug-containing serum (10%) for 24 h. Normal rats' serum was given to cells in the blank control group and the model group, while XC + HL containing serum was given to cells in the rest 3 groups. The adherence of HUVECs and PMN cells was detected by using rose bengal strain. Levels of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and interleukin-1beta (IL-1P) in the supernatant of cultured HU-VECs were determined by ELISA. Protein expressions of mitogen-activated protein kinases p38 (p38MAPK) and extracellular signal-regulated kinase 1/2 (ERK 12) were determined by Western blot. RESULTS: Compared with the blank control group, HUVECs were seriously injured; PMN adherence amount significantly increased; levels of E-selectin, ICAM-1, and IL-1beta increased; expression levels of p-p38MAPK and p-ERK 1/2 in the supernatant of HUVECs significantly increased in the model group (all P < 0.01). Compared with the model group, HUVECs-PMN adherence amount decreased (P < 0.05); levels of E-selectin, ICAM-1, and IL-1 beta in the supernatant of HUVECs decreased (P < 0.01, P < 0.05); expression levels of p-p38MAPK and p-ERK 1/2 of endothelial cells decreased in the test group I, II, and III (P < 0.01). CONCLUSIONS: Drug-containing serums of activating blood, activating blood and dispelling toxin could attenuate TNF-alpha induced injury of HUVECs, inhibit HUVECs-PMN adherence and the release of adhesion factors. Its mechanism might be involved with protein phosphorylation of p38MAPK and ERK 1/2 in the MAPK pathway.