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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., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-23-86/coif). The authors have no conflicts of interest to declare., (2023 Cardiovascular Diagnosis and Therapy. All rights reserved.)

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

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 (m 6 A) in DM and its complications were the developing areas of study., Conclusion: Studies on RNA methylation, especially m 6 A 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Zhang, Dong, Guo, Jia, Jiang, Wang, Zhou and Gong.)

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., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Fuyong Chu et al.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

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-1β, 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-1β, 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Liu, Li, Qin, Li, Shang, Xing, Gong, Liu and Zhou.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cao, Zhou, Liu, Chen, Li and Jia.)

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.

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.

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Sinai Li et al.)

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., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

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.

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.

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.

Background and Aim: The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway plays a crucial role in autophagy and inflammation. Our previous studies demonstrated that Shen-Yuan-Dan Capsule (SYDC), a Chinese medicine used for treating angina pectoris, has anti-atherosclerotic and anti-inflammatory effects in mice. However, its effects on autophagy and the PI3K/Akt/mTORC1 signaling pathway remain unclear. This study aimed to explore the effects of SYDC on autophagy and PI3K/Akt/mTORC1 signaling in the apolipoprotein E knockout (ApoE -/- ) mouse model and in macrophage-derived foam cells to delineate the underlying mechanism. Methods: After 6 weeks of high-fat diet, ApoE -/- mice were randomly grouped into control, Lipitor, low-SYDC (SYDC-L), middle-SYDC (SYDC-M), and high-SYDC (SYDC-H) groups (n = 10). The mice were intragastrically administered the respective treatment for 6 weeks. Murine RAW264.7 cells were stimulated with oxidized low-density lipoprotein (ox-LDL) (80 µg/ml) for 24 h and then pretreated with SYDC freeze-dried powder for another 24 h. Cells treated with SYDC were co-cultured for 24 h with LY294002, tricirbine, and rapamycin to investigate the effects on the PI3K/Akt/mTORC1 signaling pathway. Results: SYDC ameliorated blood lipid levels, reduced the atherosclerotic index and plaque areas in the aortic root in mice, and inhibited total cholesterol (TC) levels and cholinesterase (ChE)/TC ratios in ox-LDL stimulated macrophages. Moreover, SYDC up-regulated Beclin1 and LC3II/I proteins in mice and in the ox-LDL-stimulated macrophages. Moreover, SYDC inhibited AKT phosphorylation at Ser473 and mTOR phosphorylation at Ser2448 in mice and in ox-LDL-stimulated macrophages. Furthermore, SYDC's inhibitory of ChE/TC ratios in ox-LDL-stimulated macrophages was not changed by selective inhibition of the PI3K/Akt/mTORC1 pathway. Conclusions: Our results highlight that SYDC treatment attenuates foam cell formation by promoting autophagy via inhibiting activation of the PI3K/Akt/mTORC1 signaling pathway. This study provides new insights into the molecular mechanism underlying SYDC's therapeutic potential for treating atherosclerosis.

Background: Shen-Yuan-Dan Capsule (SYDC), a traditional Chinese medicine, is proposed to have the capacity to prevent angina pectoris. However, the effects and the related mechanisms of SYDC on atherosclerosis (AS) are still unknown. This study was designed to investigate the effects of SYDC on AS and inflammatory reaction in the apoliprotein E-knockout (ApoE -/- ) mice fed with a high-fat diet., Methods: Thirty eight-week-old male ApoE -/- mice were randomly divided into three groups (n = 10) 6 weeks after being fed with a high-fat diet: the control group, the lipitor group, and the SYDC group. The hearts were collected for hematoxylin and eosin (HE) or Van Gieson (VG) staining, and the aortas were collected for quantitative reverse transcription polymerase chain reaction (RT-PCR) and western-blotting., Results: The data showed that the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), atherosclerotic indexes (AI) and the corrected areas of atherosclerotic plaque of the mice on SYDC group were significantly decreased compared with those of the mice in the control group (p < 0.01, p < 0.05). SYDC can significantly increase collagen proportion in plaques as compared to the untreated mice (p < 0.01). In addition, the messenger ribonucleic acid (mRNA) expressions of insulin receptor substrate 1 (IRS-1), PI3K, Akt, NF-κB and tumor necrosis factor-α (TNF-α) in the mice fed with a high-fat diet were significantly reduced by SYDC (p < 0.05, p < 0.01)., Conclusions: SYDC can exert an anti-atherosclerotic effect on ApoE -/- mice fed with a high-fat diet. The action mechanism of SYDC was attributed to its ability to inhibit inflammatory reaction by regulating IRS-1/PI3K/Akt/NF-κB signaling pathway.

Lipid metabolism dysregulation plays a crucial role in the occurrence of atherosclerosis (As). SCAP/SREBP signaling is the main pathway for regulating lipid metabolism. Tetramethylpyrazine (TMP), a Traditional Chinese Medicine (TCM) for treating angina pectoris, has antiatherosclerotic effects and ameliorates blood lipids disturbance. However, its precise mechanism remains unclear. This study investigated the mechanism of TMP in ameliorating As in mice model. After six weeks of high-fat diet, 30 ApoE -/- mice were randomized ( n = 10) and treated with Lipitor, TMP, or distilled water for six weeks. The serum blood lipids and insulin levels were measured. The expressions of PAQR3, Insig-1, SCAP, SREBP-1c, IRS-1, PI3K, Akt, and mTORC-1 in the adipose tissues were determined. The results showed that TMP could significantly decrease blood lipids levels, insulin, and corrected plaque area of the ApoE -/- mice as compared to the untreated mice ( P < 0.05, P < 0.01). Moreover, TMP could significantly downregulate the expressions of SCAP, SREBP-1c, PAQR3, IRS-1, PI3K, Akt, and mTORC1 ( P < 0.01). Thus, TMP may ameliorate lipid metabolism disorder and As by downregulating PAQR3 and inhibiting SCAP/SREBP-1c signaling pathway. In addition, PI3K/Akt/mTORC1 signaling pathway may be involved in this process.

Background: Astragalus was broadly used for treating heart failure (HF) and arrhythmias in East Asia for thousands of years. Astragalus granule (AG), extracted from Astragalus , shows beneficial effect on the treatment of HF in clinical research. We hypothesized that administration of AG prevents the remodeling of L-type Ca 2+ current ( I Ca-L ) in HF mice by the downregulation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII)., Methods: HF mice were induced by thoracic aortic constriction (TAC). After 4 weeks of AG treatment, cardiac function and QT interval were evaluated. Single cardiac ventricular myocyte was then isolated and whole-cell patch clamp was used to record action potential (AP) and I Ca-L . The expressions of L-type calcium channel alpha 1C subunit (Cav1.2), CaMKII, and phosphorylated protein kinase A (p-PKA) were examined by western blot., Results: The failing heart manifested distinct electrical remodeling including prolonged repolarization time and altered I Ca-L kinetics. AG treatment attenuated this electrical remodeling, supported by AG-related shortened repolarization time, decreased peak I Ca-L , accelerated I Ca-L inactivation, and positive frequency-dependent I Ca-L facilitation. In addition, AG treatment suppressed the overexpression of CaMKII, but not p-PKA, in the failing heart., Conclusion: AG treatment protected the failing heart against electrical remodeling and I Ca-L remodeling by downregulating CaMKII.

Abnormal collagen deposition, as well as collagen metabolism, plays a crucial role in the formation and progression of vulnerable atherosclerotic plaques (VAPs), which are susceptible to rupture. According to our previous findings, rosiglitazone, a thiazolidinedione, can promote the stability of atherosclerotic plaques in fat-fed ApoE-knockout mice; however, it is unknown whether it can modulate collagen deposition and metabolism in VAPs. The present study was designed to determine the effect of rosiglitazone on collagen deposition and metabolism in the plaques of fat-fed ApoE-knockout mice. Following 13 weeks of the high-fat diet, the mice were randomized into three groups (10 mice/group) and intragastrically administered rosiglitazone, simvastatin and distilled water, respectively, for a further 13 weeks. The category of the collagen present in the plaques was evaluated using the picro-Sirius red polarization method. Additionally, the protein expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the plaques was determined using immunohistochemistry. The results showed that rosiglitazone reduced the lipid to collagen and type III to type I collagen ratios in the plaques, and these reductions were correlated with the reduction in the plaque MMP-9 to TIMP-1 ratio. These results suggest that rosiglitazone can modulate collagen deposition and metabolism and promote the stabilization of VAPs.

Background: Renalase is a protein that can regulate sympathetic nerve activity by metabolizing catecholamines, while redundant catecholamines are thought to contribute to atherosclerosis (As). Catecholamine release can be facilitated by angiotensin (Ang) II by binding to Ang II type 1 (AT1) receptors. Valsartan, a special AT1 antagonist, can dilate blood vessels and reduce blood pressure, but it remained unclear whether valsartan can promote the stability of atherosclerotic plaque by affecting renalase., Objective: This study examined the tissue distribution of renalase in ApoE(-/-) mice fed with a high-fat diet and the effect of valsartan on expression of renalase., Methods: ApoE(-/-) mice were fed with a high-fat diet for 13 or 26 weeks. As a control, 10 C57BL mice were fed with a standard chow diet. After 13 weeks on the high-fat diet, the ApoE(-/-) mice were randomized (10 mice/group) and treated with valsartan, simvastatin, or distilled water (control group) for an additional 13 weeks accompanied by a high-fat diet., Results: Knockout of ApoE caused a dramatic increase in expression of renalase in mice adipose tissue. With the disturbance of lipid metabolism induced by a high-fat diet, renalase expression decreased in the liver. Renalase can be expressed in smooth muscle cells and M2 macrophages in atherosclerotic plaque, and its expression gradually decreases in the fibrous cap during the transition from stable to vulnerable atherosclerotic plaque. Valsartan, an AT1 receptor antagonist, promotes the stabilization of atherosclerotic plaque by increasing the levels of renalase in serum and the expression of renalase in the fibrous cap of atherosclerotic plaque. It also reduces triglyceride levels in serum and increases the expression of renalase in the liver., Conclusions: Renalase may be a potential-related gene of lipid metabolism and As, and it may be the possible molecular target of valsartan to help stabilize atherosclerotic plaque., (© The Author(s) 2015.)

Compound Chuanxiong Capsule (CCC), a Chinese herbal compound, can exhibit antiatherosclerotic effect; however, its mechanism is still unclear. This study is designed to study the mechanism of CCC on atherosclerosis in the ApoE-knockout (ApoE(-/-)) mice fed with a high-fat diet. After 6 weeks of high-fat feeding, 40 ApoE(-/-) mice were randomized (n = 10) and treated with lipitor, high-dose or low-dose CCC, or distilled water (ApoE(-/-) group) for 7 weeks. The blood lipids in serum and the plaque areas of the mice were measured and the mRNA expressions of phosphatidylinositol-3-kinases (PI3K), Akt, nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) of the aortae were determined. The data showed that CCC can significantly decrease the levels of blood lipids, atherosclerosis index, and plaque areas and increase collagen proportion in plaques as compared with the untreated mice (p < 0.05, p < 0.01). In addition, CCC can significantly reduce the mRNA expressions of PI3K, Akt, NF-κB, IL-6, and TNF-α in the mice fed with a high-fat diet (p < 0.001). Thus, we concluded that CCC can inhibit inflammatory reaction in the ApoE(-/-) mice fed with a high-fat diet. This mechanism may be attributed to regulating PI3K/Akt/NF-κB signaling pathway.

Renalase was initially identified in human kidney as a soluble monoamine oxidase. Here we show that renalase is predominantly expressed in reproductive/steroidogenic systems, with particularly substantial expression in oocytes, granulosa, interstitial and luteal cells of ovary, spermatogenic cells of testis, and cortex of adrenal gland, suggesting its function(s) in maturation of germ cells and steroid hormone regulation. Renalase expression increases in testes and ovaries as mice develop and its expression is further enhanced in the ovaries of pregnant mice, indicating an activity of renalase in reproduction. Gonadotropin-releasing hormone (GnRH) antagonist, cetrorelix, repressed renalase expression in mice ovaries and testes, suggesting that steroids regulate renalase expression. Leptin is an effector and modulator of steroid hormones and reproduction. Surprisingly, knockout of leptin causes a dramatic increase of renalase expression in mice testes. Taken together, our results suggest that reproductive/steroidogenic systems are also the sources for renalase secretion and renalase may play a critical role in reproduction and hormone regulation. This provides a novel insight into understanding the function of renalase.

The hypothalamic-pituitary-gonadal (HPG) axis exerts a profound effect on animal development, reproduction, and response to stress, and new insights into its complicated functional activities are continuously being made. In the present study, by using immunohistochemical studies and different mouse models (ovariectomy and ob/ob mice), we systemically analyzed the expression of a novel mitochondria-localized glutamic acid-rich protein (MGARP)/ovary-specific acid protein and demonstrated that MGARP is under the regulation of the HPG axis. MGARP is highly enriched in steroidogenic tissues and the visual system. Interestingly, its expression increases as mice develop. Early in development, MGARP is mainly detected in the retina and adrenal gland. At this early developmental stage, its expression is not detectable in the gonads, but its expression in the gonads dramatically increases during the first 2-4 wk after birth. Importantly, MGARP levels correlate with estrogen levels in the ovaries during the estrous cycle, and estrogen regulates the expression of MGARP in a tissue-specific manner and through a feedback regulatory mechanism. Functional inhibition of GnRH with an antagonist strongly reduces MGARP levels, and knockout of leptin (ob/ob) significantly reduces the MGARP expression in follicular granular cells. We proposed a model that elucidates the role MGARP plays in the HPG axis. Within the HPG axis loop, MGARP participates in hormone biosynthesis while being under the regulation of the hormones derived from the HPG axis.

Study of retina specific genes would offer insights into retinal diseases and treatment. Based on the information from the gene expression profiles of mouse retinas, we here identified a mitochondria-localized glutamic acid-rich protein (MGARP/OSAP) as one of the highly expressed proteins in retina. Sequence analysis revealed that mouse and rat MGARPs have an extra insertion of four consecutive amino acid repeats at the C-terminus, while other homologues do not. MGARP was demonstrated to be localized to the mitochondria and overexpression of MGARP missing N-terminal region causes severe mitochondrial aggregation, implying an important role of MGARP in maintaining mitochondrial morphology. MGARP is highly expressed in mitochondria-rich layers, including inner segment of the photoreceptor, outer plexiform layer and ganglion cell layers of mouse retina. Far-UV CD spectrum analysis suggested that MGARP exhibits a large area of intrinsic disorder and the unusual position of its Tyr fluorescence suggested that Tyr residues in MGARP might form excimer and exist in an ionized state. These findings implied that MGARP be a good candidate for assembling certain ion channels on mitochondria membrane and have great potential to be involved in retinal energetic metabolism through mitochondria related pathway.

Type 2 diabetes is considered a "risk equivalent" for cardiovascular disease, rosiglitazone, as an insulin sensitizer, has been explored as a novel therapeutic drug for the prevention of cardiovascular disease, but whether it can stabilize vulnerable atherosclerotic plaques is still unknown. Our study aims to investigate the effect of rosiglitazone on plaque stability in fat-fed ApoE-knockout mice. Our findings showed that rosiglitazone can stabilize the vulnerable atherosclerotic plaques in fat-fed ApoE-knockout mice by modifying the plaque composition as well as decreasing the number of buried fibrous caps and its anti-inflammatory effect probably is the key mechanism through which promotes the plaque more stable.

Increasing evidence indicated that plaque stabilization is attributed to the composition of the atherosclerotic plaque, and inflammation plays an important role in the formation and progress of vulnerable atherosclerotic plaque (VAP), which is prone to rupture. Emodin, an important component of traditional Chinese herb rhubarb, has obvious anti-inflammatory effect, although its effect on atherosclerotic plaque stabilization is unknown. Apolipoprotein E (ApoE) is an important component of plasma lipoprotein with anti-atherosclerosis function, and the plaque in the aorta of ApoE-deficient mice has been demonstrated with characteristics of VAP. Therefore, this study was designed to determine whether emodin can stabilize the VAP in the ApoE-deficient mice and explain the possible mechanism. After fat-fed for 13 weeks, mice were randomized into three groups (11 animals/group) and intragastrically administrated with emodin, simvastatin or distilled water for 13 weeks, respectively. The plaque stability was evaluated by the morphology and composition of atherosclerotic plaques. Additionally, the expression of peroxisomal proliferator-activated receptor-gamma (PPAR-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), and matrix metalloproteinase 9 (MMP-9) in plaques was determined by the immunohistochemistry method. We showed that emodin could decrease the lipid core area and the ratio of lipid to collagen content in plaques. In addition, emodin significantly inhibited the expression of GM-CSF and MMP-9, whereas it induced the expression of PPAR-gamma in plaques. In conclusion, these results suggest that emodin can stabilize the VAP in the aortic root of ApoE-knockout mice, which is probably due to its anti-inflammatory effect.