Danhong Injection Up-regulates miR-125b in Endothelial Exosomes and Attenuates Apoptosis in Post-Infarction Myocardium.

OBJECTIVE: To investigate the involvement of endothelial cells (ECs)-derived exosomes in the anti-apoptotic effect of Danhong Injection (DHI) and the mechanism of DHI-induced exosomal protection against postinfarction myocardial apoptosis. METHODS: A mouse permanent myocardial infarction (MI) model was established, followed by a 14-day daily treatment with DHI, DHI plus GW4869 (an exosomal inhibitor), or saline. Phosphate-buffered saline (PBS)-induced ECs-derived exosomes were isolated, analyzed by miRNA microarray and validated by droplet digital polymerase chain reaction (ddPCR). The exosomes induced by DHI (DHI-exo), PBS (PBS-exo), or DHI+GW4869 (GW-exo) were isolated and injected into the peri-infarct zone following MI. The protective effects of DHI and DHI-exo on MI hearts were measured by echocardiography, Masson's trichrome staining, and TUNEL apoptosis assay. The Western blotting and quantitative reverse transcription PCR (qRT-PCR) were used to evaluate the expression levels of miR-125b/p53-mediated pathway components, including miR-125b, p53, Bak, Bax, and caspase-3 activities. RESULTS: DHI significantly improved cardiac function and reduced infarct size in MI mice (P<0.01), which was abolished by the GW4869 intervention. DHI promoted the exosomal secretion in ECs (P<0.01). According to the results of exosomal miRNA microarray assay, 30 differentially expressed miRNAs in the DHI-exo were identified (28 up-regulated miRNAs and 2 down-regulated miRNAs). Among them, DHI significantly elevated miR-125b level in DHI-exo and DHI-treated ECs, a recognized apoptotic inhibitor impeding p53 signaling (P<0.05). Remarkably, treatment with DHI and DHI-exo attenuated apoptosis, elevated miR-125b expression level, inhibited capsase-3 activity, and down-regulated the expression levels of proapoptotic effectors (p53, Bak, and Bax) in post-MI hearts, whereas these effects were blocked by GW4869 (P<0.05 or P<0.01). CONCLUSION: DHI and DHI-induced exosomes inhibited apoptosis, promoted the miR-125b expression level, and regulated the p53 apoptotic pathway in post-infarction myocardium.

Protective effects of Shen Yuan Dan on myocardial ischemia-reperfusion injury via the regulation of mitochondrial quality control.

Background: Myocardial cell death resulting from ischemia-reperfusion (I/R) injury has been a predominant contributor to morbidity and mortality globally. The mitochondria-centered mechanism plays an important role in the formation of I/R injury. This study intended to discuss the protective mechanism of Shen Yuan Dan (SYD) on cardiomyocytes hypoxia-reoxygenation (H/R) injury via the regulation of mitochondrial quality control (MQC). Additionally, this study clarified the mechanism by which SYD suppressed mitophagy activity through the suppression of the PTEN-induced kinase 1 (PINK1)/Parkin pathway. Methods: To induce cellular injury, H9c2 cardiomyocytes were exposed to H/R stimulation. Following the pretreatment with SYD, cardiomyocytes were subjected to H/R stimulation. Mitochondrial membrane potential (MMP), adenosine triphosphate (ATP), superoxide dismutase (SOD), and methane dicarboxylic aldehyde (MDA) were detected to evaluate the degree of cardiomyocyte mitochondrial damage. Laser confocal microscopy was applied to observe the mitochondrial quality, and the messenger (mRNA) levels of mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), optic atrophy protein 1 (Opa1), dynamin-related protein 1 (Drp1), fission 1 (Fis1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in cardiomyocytes were assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Western blotting was employed for the estimation of light chain 3 (LC3)-I, LC3-II, PINK1, and Parkin in cardiomyocytes. Results: It was discovered that SYD pretreatment elevated MMP in H/R injury cardiomyocytes, enhanced ATP content, activated SOD activity, and reduced MDA level. SYD treatment increased the mRNA levels of Mfn1, Mfn2, Opa1 and PGC-1α decreased the mRNA levels of Drp1 and Fis1, and reduced the protein levels of LC3, PINK1, and Parkin. Conclusions: SYD plays a protective role in H/R injury to cardiomyocytes by regulating mitochondrial quality. Meanwhile, SYD may inhibit mitophagy activity through inhibiting the PINK1/Parkin pathway. This study provides insights into the underlying mechanism of SYD in alleviating myocardial I/R injury.

Continuous venovenous hemodiafiltration versus standard medical therapy for the prevention of rhabdomyolysis-induced acute kidney injury: a retrospective cohort study.

AIM: To determine whether continuous venovenous hemodiafiltration (CVVHDF) plus standard medical therapy (SMT) vs. SMT alone prevents rhabdomyolysis (RM)-induced acute kidney injury (AKI) and analyze the related health economics. METHODS: This retrospective cohort study involved 9 RM patients without AKI, coronary heart disease, or chronic kidney disease treated with CVVHDF plus SMT (CVVHDF + SMT group). Nine matched RM patients without AKI treated with SMT only served as controls (SMT group). Baseline characteristics, biochemical indexes, renal survival data, and health economic data were compared between groups. In the CVVHDF + SMT group, biochemical data were compared at different time points. RESULTS: At 2 and 7 days after admission, serum biochemical indices (e.g., myoglobin, creatine kinase, creatinine, and blood urea nitrogen) did not differ between the groups. Total (P = 0.011) and daily hospitalization costs (P = 0.002) were higher in the CVVHDF + SMT group than in the SMT group. After 53 months of follow-up, no patient developed increased serum creatinine, except for 1 CVVHDF + SMT-group patient who died of acute myocardial infarction. In the CVVHDF + SMT group, myoglobin levels significantly differed before and after the first CVVHDF treatment (P = 0.008), and serum myoglobin, serum creatinine, and blood urea nitrogen decreased significantly at different time points after CVVHDF. CONCLUSIONS: Although CVVHDF facilitated myoglobin elimination, its addition to SMT did not improve biochemical indices like serum myoglobin, serum creatine kinase, creatinine, blood urea nitrogen, and lactate dehydrogenase or the long-term renal prognosis. Despite similar hospitalization durations, both total and daily hospitalization costs were higher in the CVVHDF + SMT group.

Efficacy and safety of Tonifying Qi and activating blood Chinese herbal prescriptions for myocardial infarction: Study protocol for a multi-centered RCT.

INTRODUCTION: Acute myocardial infarction (AMI) is a common cause of death worldwide and heart failure (HF) is the main complication. Although the increase in percutaneous coronary intervention and drug treatment can reduce in-hospital mortality after AMI, the incidence of HF after AMI and the resulting risk of death are still rising, which causes difficulties in the rehabilitation of AMI patients after reperfusion. METHODS: In this prospective, multicenter, randomized, double-blind, double-dummy, placebo-controlled trial, we will assigned 673 eligible patients with AMI after reperfusion into 4 groups: receiving Nao-Xin-Tong capsule (NXT), Bu-Yang-Huan-Wu (BYHW) granule (BYHW), Yang-Yin-Tong-Nao granule (YYTN), or placebo. The course of treatment will be 3 months. The primary outcome is HF incidence within 180 days. Nao-Xin-Tong capsule, BYHW granule, and Yang-Yin-Tong-Nao granule are different traditional Chinese medicines used for tonifying Qi and activating blood (TQAB). RESULTS: Three months of TQAB combined with Western medicine may reduce the incidence of HF after reperfusion of AMI and improve patients' quality of life. DISCUSSION: This study will provide an important basis for the application of traditional Chinese medicine in patients with AMI after reperfusion and provide an evidence-based basis for the prevention and treatment strategy of HF after AMI.

A bibliometric analysis of RNA methylation in diabetes mellitus and its complications from 2002 to 2022.

Background: RNA methylation has emerged as an active research field in diabetes mellitus (DM) and its complications, while few bibliometric analyses have been performed. We aimed to visualize the hotspots and trends using bibliometric analysis to provide a comprehensive and objective overview of the current search state in this field. Methods: The articles and reviews regarding RNA methylation in DM and its complications were from the Web of Science Core Collection. A retrospective bibliometric analysis and science mapping was performed using the CiteSpace software to plot the knowledge maps and predict the hotspots and trends. Results: Three hundred seventy-five qualified records were retrieved. The annual publications gradually increased over the past 20 years. These publications mainly came from 66 countries led by Canada and 423 institutions. Leiter and Sievenpiper were the most productive authors, and Jenkins ranked first in the cited authors. Diabetes Care was the most co-cited journal. The most common keywords were "Type 2 diabetes", "cardiovascular disease", "diabetes mellitus", and "n 6 methyladenosine". The extracted keywords mainly clustered in "beta-cell function", "type 2 diabetes", "diabetic nephropathy", "aging", and "n6-methyladenosine". N6-methyladenosine (m6A) in DM and its complications were the developing areas of study. Conclusion: Studies on RNA methylation, especially m6A modification, are the current hotspots and the future trends in type 2 diabetes (T2D) and diabetic nephropathy (DN), as well as a frontier field for other complications of DM. Strengthening future cooperation and exchange between countries and institutions is strongly advisable to promote research developments in this field.

Purple tea water extract blocks RANKL-induced osteoclastogenesis through modulation of Akt/GSK3ß and Blimp1-Irf8 pathways.

A number of studies demonstrated that some tea extracts exert inhibitory effects on osteoclastogenesis induced by receptor activator of nuclear factor κB ligand (RANKL). However, the effect of purple tea, a famous tea in China, on osteoclastogenesis remains unclear. In this study, a water-based purple tea extract (PTE) was found to suppress osteoclast formation, osteoclastic resorption pit area formation, and F-actin ring formation within RANKL-stimulated bone marrow macrophages (BMMs). Furthermore, our results demonstrated that PTE could inhibit expression of master transcription factors NFATc1 and c-Fos and their target genes DC-STAMP, Ctsk, and Atp6v0d2. Western blot analysis revealed that PTE treatment led to reduced RANKL-induced phosphorylation of Akt and GSK3ß without altering transient activation of NF-κB and MAPKs (p38, JNK, ERK1/2) signaling. In addition, the results demonstrated that PTE treatment of RANKL-stimulated BMMs could down-regulate Blimp1 expression and up-regulate Irf8 expression. In summary, these results suggest that PTE treatment of RANKL-stimulated BMMs inhibited osteoclast differentiation via modulation of Blimp1-Irf8 and Akt/GSK3ß signaling pathways. Aligning with our in vitro results, in vivo PTE administration ameliorated bone loss in LPS-treated mice. Taken together, the results presented in this work suggest that PTE treatment possesses anti-osteolytic activity.

Sec-O-Glucosylhamaudol Inhibits RANKL-Induced Osteoclastogenesis by Repressing 5-LO and AKT/GSK3ß Signaling.

Sec-O-glucosylhamaudol (SOG), an active flavonoid compound derived from the root of Saposhnikovia divaricata (Turcz. ex Ledeb.) Schischk., exhibits analgesic, anti-inflammatory, and high 5-lipoxygenase (5-LO) inhibitory effects. However, its effect on osteoclastogenesis was unclear. We demonstrated that SOG markedly attenuated RANKL-induced osteoclast formation, F-actin ring formation, and mineral resorption by reducing the induction of key transcription factors NFATc1, c-Fos, and their target genes such as TRAP, CTSK, and DC-STAMP during osteoclastogenesis. Western blotting showed that SOG significantly inhibited the phosphorylation of AKT and GSK3ß at the middle-late stage of osteoclastogenesis without altering calcineurin catalytic subunit protein phosphatase-2ß-Aα expression. Moreover, GSK3ß inhibitor SB415286 partially reversed SOG-induced inhibition of osteoclastogenesis, suggesting that SOG inhibits RANKL-induced osteoclastogenesis by activating GSK3ß, at least in part. 5-LO gene silencing by small interfering RNA in mouse bone marrow macrophages markedly reduced RANKL-induced osteoclastogenesis by inhibiting NFATc1. However, it did not affect the phosphorylation of AKT or GSK3ß, indicating that SOG exerts its inhibitory effects on osteoclastogenesis by suppressing both the independent 5-LO pathway and AKT-mediated GSK3ß inactivation. In support of this, SOG significantly improved bone destruction in a lipopolysaccharide-induced mouse model of bone loss. Taken together, these results suggest a potential therapeutic effect for SOG on osteoclast-related bone lysis disease.

Traditional Chinese Medicine Shen-Yuan-Dan (SYD) Improves Hypoxia-Induced Cardiomyocyte Apoptosis in Neonatal Rats by Upregulating miR-24/Bim Pathway.

Background: Acute myocardial infarction (AMI) is the leading cause of malignant arrhythmia, heart failure, and sudden death. However, safe and effective drugs for the treatment of AMI are unavailable to date. The present study aimed to investigate the role of traditional Chinese medicine shen-yuan-dan (SYD) in hypoxia-induced cardiomyocyte apoptosis in neonatal rats. In addition, the study explored the possible mechanism through which SYD could reduce myocardial ischemia apoptosis and regulate the expression of the miR-24/Bim pathway. Methods: Hypoxia-induced neonatal rat cardiomyocytes were used for the experiments. These cardiomyocytes were transfected with an miR-24 mimic and an miR-24 inhibitor and then cocultured with SYD-containing serum. MTT and lactate dehydrogenase (LDH) assays, AnnexinV/PI double staining, flow cytometry, and TUNEL staining were used to determine the cell viability and apoptosis under hypoxic conditions. Furthermore, the expression level of Bim in the hypoxia-induced cardiomyocytes was determined through western blotting and quantitative real-time polymerase chain reaction. Results: After 48 h of hypoxia, LDH and creatine phosphokinase (CPK) activities increased, cell viability decreased, and miR-24 expression upregulated in the cardiomyocytes. SYD alleviated hypoxia-induced cardiomyocyte injury, decreased LDH and CPK activities, increased cell viability, and reduced apoptosis in the neonatal rat cardiomyocytes. Moreover, SYD could upregulate miR-24 expression and downregulate Bim expression. Upregulation of miR-24 expression significantly enhanced the effect of SYD, thereby improving myocardial cell apoptosis. Dual-luciferase reporter assay and western blot analysis confirmed that Bim was a direct target of miR-24. Conclusion: SYD treatment reduces hypoxia-induced myocardial apoptosis by upregulating miR-24 expression. This study provides new insights into the molecular mechanism underlying the therapeutic potential of SYD in promoting the recovery of myocardial function and delaying the incidence of heart failure.

Comparative efficacy of five Chinese medicine injections for treating dilated cardiomyopathy with heart failure: A Bayesian network meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese medicine injections (CMIs) are widely used by clinicians in China as an adjuvant treatment in dilated cardiomyopathy with heart failure (DCM-HF). However, comprehensive and systematic evidence supporting the beneficial effects of CMIs combined with Western medicine (WM) against DCM-HF was lacking. OBJECTIVE: This network meta-analysis aimed to assess the effectiveness of five different CMIs in the treatment of DCM-HF. METHODS: The Cochrane Library, Embase, PubMed, China National Knowledge Infrastructure (CNKI), Allied and Alternative Medieine Database (AMED), Chinese Biological Medicine Database (CBM), Wanfang Database, and Chinese Scientific Journal Database (VIP) were comprehensively searched from their inception to March 10, 2020, for randomized controlled trials (RCTs) focusing on the use of CMIs combined with WM to treat DCM-HF. The quality of the included RCTs was assessed using the Cochrane Handbook 5.1.0. Bayesian network meta-analysis were designed to access the effectiveness of different CMIs. RESULTS: A total of 38 eligible RCTs involving 3247 patients were enrolled. The study showed that Huangqi injection, Shengmai injection, Shenfu injection, Shenmai injection, and Xinmailong injection combined with WM significantly improved performance compared with WM alone in treating DCM-HF. Xinmailong injection + WM had the highest likelihood of being the best treatment in terms of the improvement in the clinical effectiveness rate, left ventricular end-diastolic dimension, and 6-min walking distance. Huangqi injection + WM had the highest probability of being the best treatment on account of the enhancement of left ventricular ejection fraction. Shenmai injection + WM had the highest likelihood of being the best treatment considering the improvement in cardiac output and the reduction in brain natriuretic peptide. CONCLUSIONS: The combination between CMIs and WM exerted a more positive effect in DCM-HF treatment. Xinmailong injection + WM had the best performance in treating DCM-HF, followed by Shenmai injection and Huangqi injection. However, due to the low qualities of the original studies, more high-quality studies are needed to support the findings.

Qing-Xue-Xiao-Zhi formula attenuates atherosclerosis by inhibiting macrophage lipid accumulation and inflammatory response via TLR4/MyD88/NF-κB pathway regulation.

BACKGROUND: Atherosclerosis is a progressive chronic disease characterised by aberrant lipid metabolism and a maladaptive inflammatory response. As atherosclerosis-driven cardiovascular disease remains the major cause of morbidity and mortality worldwide, more effective clinical therapies are urgently needed. Traditional Chinese Medicine (TCM) has demonstrated efficacy against atherosclerosis, with Qing-Xue-Xiao-Zhi formula (QXXZF) having been approved for clinical treatment of patients with atherosclerosis. However, the mechanisms underlying the anti-atherosclerotic activity of QXXZF remain unknown. PURPOSE: To investigate the anti-atherosclerotic effect of QXXZF and reveal its mechanisms using preclinical models. METHODS: In vivo, apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-choline diet (HHD) to induce atherosclerosis. Serum metabolomic profiling was used to identify the concentration of trimethylamine N-oxide (TMAO) in mice. In vitro, RAW264.7 macrophages and bone marrow-derived macrophages (BMDMs) from WT and TLR4-/- C57BL/6 mice were used to explore the effects of QXXZF on macrophages. After confirming the therapeutic effects of QXXZF, mass spectrometry and network pharmacology analyses were used to predict and investigate the main components and the anti-atherogenic mechanisms of QXXZF in the context of atherosclerosis. RESULTS: Our results showed QXXZF significantly suppressed the development of atherosclerosis, as evidenced by the decreased atherosclerotic plaques in the aorta and aortic root, reduced plasma lipid levels and decreased serum TMAO content in HHD-fed ApoE-/- mice. Meanwhile, QXXZF effectively reduced foam cell formation in oxidized low-density lipoprotein (ox-LDL) and TMAO-stimulated RAW264.7 macrophages and BMDMs. Moreover, QXXZF facilitated reverse cholesterol transport (RCT) in macrophages by upregulating the expression of cholesterol efflux-related genes PPARγ/LXRα/ABCA1/ABCG1. Mechanistic studies revealed that QXXZF influenced cholesterol metabolism by inhibiting the TLR4-mediated nuclear factor kappa B (NF-κB) axis. Importantly, TLR4 knockout abolished the influence of QXXZF on macrophages. CONCLUSION: QXXZF promotes lipid efflux and inhibits macrophage-mediated inflammation, producing a therapeutic effect against atherosclerosis. Our study provides new insight into the mechanism of QXXZF against atherosclerosis.

Distinct Nuclear Architecture of Photoreceptors and Light-Induced Behaviors in Different Strains of Mice.

Purpose: The mouse retina is considered a remarkable model for studying gene functions. However, variations in genetic background influence phenotypes in the mammalian retina. Therefore this study aimed to investigate the effects of the genetic background on the nuclear architecture of photoreceptor cells and the light-induced behavior in C57BL/6, 129 × 1/svj, and ICR mice. Methods: The nuclear architecture of photoreceptor cells was investigated using various staining methods on postnatal day 21 (P21). Murine behavior was observed using a light-dark compartment test. Results: The outer nuclear layer and retina were significantly thicker in C57BL/6 mice than in 129 × 1/svj mice. The percentage of photoreceptors with one chromocenter was significantly higher in C57BL/6 mice than in 129 × 1/svj and ICR mice on P21. The numbers of photoreceptor cells in C57BL/6 and ICR mice were significantly higher than those in 129 × 1/svj mice. The behavior test revealed that the walking distance and velocity in the light compartment were increased in C57BL/6 and ICR mice compared to 129 × 1/svj mice. Conclusions: Different mouse strains had a distinct nuclear architecture of photoreceptors on P21, and C57BL/6 and ICR mice were more active than 129 × 1/svj mice in response to light-induced stress. Translational Relevance: This study demonstrates a technique for assessing retinal structures and nuclear architecture in various strains of mice, which are often used to model human retinal disease. Hence, this study may help to elucidate the effect of genetic or disease-induced variance in retinal architecture and the organization of photoreceptor nuclear content on visual function in humans.

Shen-Yuan-Dan Capsule Attenuates Verapamil-Induced Zebrafish Heart Failure and Exerts Antiapoptotic and Anti-Inflammatory Effects via Reactive Oxygen Species-Induced NF-κB Pathway.

Background: Heart failure (HF) is the end stage of ischemic cardiovascular diseases; nonetheless, safe and effective therapeutic agents for HF are still lacking, and their discovery remains challenging. Our previous studies demonstrated that Shen-Yuan-Dan Capsule (SYDC), a hospital preparation of traditional Chinese herbal, effectively protected ischemic injury in cardiovascular diseases. However, its therapeutic effects and possible mechanisms on HF remain unclear. Methods: A zebrafish HF model treated with verapamil was developed to assess the therapeutic effect of SYDC on HF zebrafish. Zebrafish were administered with SYDC and digoxin (positive control) by direct soaking. After drug treatment, zebrafish were randomly assigned to the visual observation and image acquisition using a Zebralab Blood Flow System. The reactive oxygen species (ROS), MDA, and SOD levels were determined by fluorescence signal detection, TBA, and WST-8 methods. RT-PCR determined the mRNA expressions of Caspase-3, Caspase-1, Bcl-2, Bax, IL-1ß, NF-κB, and TNF-α. Results: SYDC significantly inhibited the levels of heart dilatation and venous congestion and markedly increased the levels of cardiac output, blood flow dynamics, and heart rates in HF zebrafish (p < 0.05, p < 0.01, and p < 0.001). Moreover, SYDC also significantly decreased the levels of MDA and ROS and increased the level of SOD in HF zebrafish. The RT-PCR results revealed that SYDC decreased the expression of Caspase-1, Caspase-3, Bax, IL-1ß, NF-κB, and TNF-α but increased the expression of Bcl-2 in HF zebrafish (p < 0.05, p < 0.01, and p < 0.001). Conclusions: SYDC improved the heart function in verapamil-induced HF zebrafish and alleviated inflammation and apoptosis by inhibiting the ROS-mediated NF-κB pathway.

Clinical Efficacy and Safety of Shensong Yangxin Capsule-Amiodarone Combination on Heart Failure Complicated by Ventricular Arrhythmia: A Meta-Analysis of Randomized Controlled Trials.

Background: Shensong Yangxin capsule (SSYX) is a well-known traditional Chinese patent medicine for treating arrhythmia. Recently, a flurry of randomized controlled trials (RCTs) of SSYX combined with amiodarone (SSYX-amiodarone) was reported in the treatment of heart failure (HF) complicated by ventricular arrhythmia (VA) in China. However, these RCTs have not been systematically evaluated. Therefore, this study aimed to evaluate the efficacy and safety of SSYX-amiodarone in the treatment of heart failure complicated by ventricular arrhythmia (HF-VA). Methods: Seven electronic literature databases (the Cochrane Library, PubMed, EMBASE, China Biomedical database web, China National Knowledge Infrastructure Databases, Chinese Scientific Journal database and Wanfang database) were searched from their inceptions to June 1, 2020 to identify RCTs of SSYX-amiodarone in the treatment of HF-VA. The primary outcomes included the total effective rate and adverse events (ADRs). The secondary outcomes included the frequency of ventricular premature complexes, left ventricular ejection fraction, N terminal pro Btype natriuretic peptide (NT-proBNP), and QT dispersion (QTd). The quality of the included RCTs was assessed using the Cochrane risk-of-bias tool. All data was analyzed using RevMan 5.3 software. The registration number of this protocol is PROSPERO CRD42020196689. Results: There are Eighteen trials involving 1,697 patients were included in this study. Meta-analysis showed that SSYX-amiodarone group was superior to the amiodarone group in improving the total effective rate [RR = 1.21; 95%CI (1.16, 1.27); p < 0.01], meanwhile reducing the ADRs [RR = 0.65; 95%CI (0.45, 0.95); p = 0.03], VPCs [MD = 170.96; 95%CI (159.88, 182.04); p < 0.01] and QTd [MD = 8.39; 95%CI (6.91, 9.87); p < 0.01]. No significant difference of enhancing LVEF [MD = 4.32; 95%CI (-0.56, 9.20); p = 0.08] and reducing NT-proBNP [SMD = 0.17; 95%CI (-0.81, 1.14); p = 0.73] was observed between SSYX-amiodarone and amiodarone group. Conclusions: Despite the apparent positive findings reported, the evidence provided by this meta-analysis was still insufficient to support the routine use of SSYX-amiodarone for HF-VA due to the poor methodological quality of included studies. The overall effect should to be verified in further through more well-design clinical studies with reasonable sample and good methodological quality.

Dynamic Disintegration of Explosively-Driven Metal Cylinder with Internal V-Grooves.

Machining V-shaped grooves to the internal surface of cylindrical shells is one of the most common technologies of controlled fragmentation for improving warhead lethality against targets. The fracture strain of grooved shells is a significant concern in warhead design. However, there is as yet no reasonable theory for predicting the fracture strain of a specific grooved shell; existing approaches are only able to predict this physical regularity of non-grooved shells. In this paper, through theoretical analysis and numerical simulations, a new model was established to study the fracture strain of explosively driven cylindrical shells with internal longitudinal V-grooves. The model was built based on an energy conservation equation in which the energy consumed to create a new fracture surface in non-grooved shells was provided by the elastic deformation energy stored in shells. We modified the energy approach so that it can be applicable to grooved shells by adding the elastic energy liberated for crack penetration and reducing the required fracture energy. Cylinders with different groove geometric parameters were explosively expanded to the point of disintegration to verify the proposed model. Theoretical predictions of fracture strain showed good agreement with experimental results, indicating that the model is suitable for predicting the fracture strain of explosively driven metal cylinders with internal V-grooves. In addition, this study provides an insight into the mechanism whereby geometric defects promote fracturing.

Roles and mechanisms of renalase in cardiovascular disease: A promising therapeutic target.

Cardiovascular disease (CVD) is prevalent worldwide and remains a leading cause of death. Although substantial progress has been made in the diagnosis and treatment of CVD, the prognosis remains unsatisfactory. Renalase is a newly discovered cytokine that is synthesized by the kidney and then secreted into blood. Numerous studies have suggested the efficacy of renalase in treating CVD by metabolizing catecholamines in the circulatory system. As a new biomarker of heart disease, renalase is normally recognized as a signalling molecule that activates cytoprotective intracellular signals to lower blood pressure, protect ischaemic heart muscle and promote atherosclerotic plaque stability in CVD, which subsequently improves cardiac function. Due to its important regulatory role in the circulatory system, renalase has gradually become a potential target in the treatment of CVD. This review summarizes the structure, mechanism and function of renalase in CVD, thereby providing preclinical evidence for alternative approaches and new prospects in the development of renalase-related drugs against CVD.

Acceleration Characteristics of Discrete Fragments Generated from Explosively-Driven Cylindrical Metal Shells.

The acceleration characteristics of fragments generated from explosively-driven cylindrical shells are important issues in warhead design. However, there is as yet no reasonable theory for predicting the acceleration process of a specific metallic shell; existing approaches either ignore the effects of shell disintegration and the subsequent gas leakage on fragment acceleration or treat them in a simplified manner. In this paper, a theoretical model was established to study the acceleration of discrete fragments under the combined effect of shell disintegration and gas leakage. Firstly, an equation of motion was developed, where the acceleration of a cylindrical shell and the internal detonation gas was determined by the motive force impacting the inner surface of the metallic cylinder. To account for the force decrease induced by both the change in fragment area after the shell disintegrates and the subsequent drop in gas pressure due to gas leakage, the equation of motion was then associated with an equation for the locally isentropic expansion of the detonation gas and a modified gas-leakage equation. Finally, theoretical analysis was conducted by solving the associated differential equations. The proposed model showed good agreement with experimental data and numerical simulations, indicating that it was suitable for predicting the acceleration of discrete fragments generated from a disintegrated warhead shell. In addition, this study facilitated a better understanding of the complicated interaction between fragment acceleration and gas outflow.

The Effect of Shen-Yuan-Dan Capsule on Autophagy-Related Gene Atg13 Promoter Methylation and Genomic Methylation Levels in Atherosclerotic Mice.

BACKGROUND: Moderate autophagy plays a positive role in the prevention of atherosclerosis. Aberrant promoter methylation of autophagic genes can affect autophagy. Shen-Yuan-Dan Capsule (SYDC), a traditional Chinese medicine, can prevent atherosclerosis in high-fat-fed mice. However, its precise mechanism remains unclear. This study investigated the mechanism of SYDC in ameliorating atherosclerosis in a mice model. METHODS: After 6 weeks of a high-fat diet, apolipoprotein E knockout (apoE-/-) mice were randomly grouped into control, Lipitor, and SYDC groups (n = 10). The mice were intragastrically administered with the respective drugs for 6 weeks. The expressions of Beclin1 and Atg5-Atg12 complex in atherosclerotic plaques of the mice were measured. The levels of 5-mC and DNA methyltransferase 1 (DNMT1) in the plasma of the mice were determined. The average methylation rate of CpG islands in the promoter region of autophagy-related protein (Atg13) and the mRNA expression of Atg13 in the aortas of the mice were determined. RESULTS: SYDC up-regulated the expressions of Atg5-Atg12 complex and Beclin-1 in atherosclerotic plaques (p < 0.01). Moreover, SYDC decreased the 5-mC and DNMT1 levels in plasma and atherosclerotic plaques of the mice (p < 0.01), and also decreased the average methylation rate of CpG islands in the promoter region of Atg13 and increased the mRNA levels of Atg13 in the aortas of atherosclerotic mice (p < 0.01). CONCLUSIONS: SYDC attenuates atherosclerosis by promoting autophagy, probably through regulating genomic DNA methylation and Atg13 promoter demethylation.

Danhong Injection Alleviates Cardiac Fibrosis via Preventing the Hypermethylation of Rasal1 and Rassf1 in TAC Mice.

BACKGROUND/AIM: Danhong injection (DHI) is a Chinese patent drug used for relieving cardiovascular diseases. Recent studies have suggested that DNA methylation plays a pivotal role in the maintenance of cardiac fibrosis (CF) in cardiovascular diseases. This study was aimed at identifying the effect and the underlying mechanism of DHI on CF, especially the DNA methylation. METHODS: A CF murine model was established by thoracic aortic constriction (TAC). A 28-day daily treatment with or without DHI via intraperitoneal injection was carried out immediately following TAC surgery. The changes in cardiac function, pathology, and fibrosis following TAC were measured by echocardiography and immunostaining. We used methyl-seq analysis to assess the DNA methylation changes in whole genes and identified the methylation changes of two Ras signaling-related genes in TAC mice, including Ras protein activator like-1 (Rasal1) and Ras-association domain family 1 (Rassf1). Next, the methylation status and expression levels of Rasal1 and Rassf1 genes were consolidated by bisulfite sequencing, quantitative reverse transcription polymerase chain reaction (RT-qPCR), and Western blotting, respectively. To determine the underlying molecular mechanism, the expressions of DNA methyltransferases (DNMTs), Tet methylcytosine dioxygenase 3 (TET3), fibrosis-related genes, and the activity of Ras/ERK were measured by RT-qPCR and Western blotting. RESULTS: DHI treatment alleviated CF and significantly improved cardiac function on day 28 of TAC. The methyl-seq analysis identified 42,606 differential methylated sites (DMSs), including 19,618 hypermethylated DMSs and 22,988 hypomethylated DMSs between TAC and sham-operated mice. The enrichment analysis of these DMSs suggested that the methylated regulation of Ras signal transduction and focal adhesion-related genes would be involved in the TAC-induced CF development. The results of bisulfite sequencing revealed that the TAC-induced methylation affected the CpG site in both of Rasal1 and Rassf1 genes, and DHI treatment remarkably downregulated the promoter methylation of Rasal1 and Rassf1 in CF hearts. Furthermore, DHI treatment upregulated the expressions of Rasal1 and Rassf1, inhibited the hyperactivity of Ras/ERK, and decreased the expressions of fibrosis-related genes. Notably, we found that DHI treatment markedly downregulated the expression of DNMT3B in CF hearts, while it did not affect the expressions of DNMT1, DNMT3A, and TET3. CONCLUSION: Aberrant DNA methylation of Rasal1 and Rassf1 genes was involved in the CF development. DHI treatment alleviated CF, prevented the hypermethylation of Rasal1 and Rassf1, and downregulated DNMT3B expression in CF hearts.

Danhong injection enhances angiogenesis after myocardial infarction by activating MiR-126/ERK/VEGF pathway.

BACKGROUND/AIM: Danhong injection (DHI) is a Chinese drug used for relieving cardiovascular diseases. This study aimed to identify the effect and mechanism of action of DHI on post-infarct angiogenesis, especially the epigenetic regulation of angiogenesis. METHODS: A myocardial infarction (MI) mouse model was induced by ligating the left anterior descending coronary artery. A 4-week daily treatment with or without DHI via intraperitoneal injection was started immediately following MI. The changes in cardiac function, pathology, and angiogenesis following MI were measured by echocardiography and immunostaining. Matrigel tube formation and scratch wound assays were used to evaluate the effect of DHI on the proliferation and migration of hypoxic human umbilical vein endothelial cells (HUVECs). The expression of miR-126, Spred-1, and angiogenesis-related mRNAs was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of related proteins and the phosphorylated levels of extracellular signal-regulated kinase (ERK) and protein kinase B were detected by Western blot analysis. The loss-of-function study was performed using antagomir-126. RESULTS: The DHI-treated mice had significantly reduced infarct area, improved ejection fraction, and increased capillary density 4 weeks after MI. Also, DHI promoted the proliferation and migration of hypoxic HUVECs. The qRT-PCR and Western blot analysis revealed that DHI intervention upregulated miR-126, suppressed Spred-1 expression, and activated the ERK pathway, but not the Akt pathway. The loss-of-function study showed the blockade of the pro-angiogenic effect of DHI by antagomir-126 involving the ERK/vascular endothelial growth factor (VEGF) pathway. CONCLUSION: DHI enhanced post-infarct angiogenesis after MI by activating the miR-126/ERK/VEGF pathway.

Danhong Injection Attenuates High-Fat-Induced Atherosclerosis and Macrophage Lipid Accumulation by Regulating the PI3K/AKT Insulin Pathway.

BACKGROUND AND AIMS: High-fat diet (HFD) is reported to induce atherosclerosis and insulin resistance. Macrophage lipid accumulation has been implicated as key mediators during the development of HFD-induced atherosclerosis. Traditional Chinese formula, which has long been used to improve disorder of glucose and lipid metabolism of patients, is now gradually being used as complementary therapy. This study aimed to investigate the effect of Danhong injection (DHI), a Chinese medicine used for the treatment of coronary artery disease, on atherosclerosis and its underlying mechanisms. METHODS AND RESULTS: We observed the effects of DHI on HFD-induced atherosclerosis in a mice model, macrophage lipid accumulation in an ox-LDL-stimulated macrophage model, and the role of PI3K/AKT insulin pathway in the process of DHI ameliorating atherosclerosis. The data demonstrated that DHI attenuated atherosclerosis by ameliorating blood lipids, reducing the atherosclerotic index and atherosclerotic plaque area in HFD-induced atherosclerotic mice, and inhibiting TC levels in an ox-LDL-induced macrophage model. By estimating the levels of serum insulin resistance-related indexes and protein expression of GLUT-4, DHI treatment dramatically inhibited the levels of fasting serum NEFA and fasting serum insulin and promoted the protein expression of GLUT-4 in aortas of the HFD-induced atherosclerotic mice. Moreover, according to the hints provided by microarray-based transcriptional profiling, the results demonstrated that DHI treatment also promoted the activation of PI3K/AKT insulin signaling pathway induced by IRS-1 in aortas of HFD-induced atherosclerotic mice. Furthermore, in an ox-LDL-induced macrophage model, the activation of PI3k/AKT signaling pathway also effectively functioned in the process of DHI inhibiting macrophage lipid accumulation. CONCLUSIONS: These results highlight that DHI treatment attenuates atherosclerosis and macrophage lipid accumulation by promoting the activation of PI3K/AKT insulin signaling pathway. It provides new insights into the molecular mechanism of DHI and its therapeutic potential in the treatment of atherosclerosis.