Mechanism of Qili Qiangxin Capsule for Heart Failure Based on miR133a-Endoplasmic Reticulum Stress.

OBJECTIVE: To investigate the pharmacological mechanism of Qili Qiangxin Capsule (QLQX) improvement of heart failure (HF) based on miR133a-endoplasmic reticulum stress (ERS) pathway. METHODS: A left coronary artery ligation-induced HF after myocardial infarction model was used in this study. Rats were randomly assigned to the sham group, the model group, the QLQX group [0.32 g/(kg·d)], and the captopril group [2.25 mg/(kg·d)], 15 rats per group, followed by 4 weeks of medication. Cardiac function such as left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), the maximal rate of increase of left ventricular pressure (+dp/dt max), and the maximal rate of decrease of left ventricular pressure (-dp/dt max) were monitored by echocardiography and hemodynamics. Hematoxylin and eosin (HE) and Masson stainings were used to visualize pathological changes in myocardial tissue. The mRNA expression of miR133a, glucose-regulated protein78 (GRP78), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), X-box binding protein1 (XBP1), C/EBP homologous protein (CHOP) and Caspase 12 were detected by RT-PCR. The protein expression of GRP78, p-IRE1/IRE1 ratio, cleaved-ATF6, XBP1-s (the spliced form of XBP1), CHOP and Caspase 12 were detected by Western blot. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the rate of apoptosis. RESULTS: QLQX significantly improved cardiac function as evidenced by increased EF, FS, LVSP, +dp/dt max, -dp/dt max, and decreased LVEDP (P<0.05, P<0.01). HE staining showed that QLQX ameliorated cardiac pathologic damage to some extent. Masson staining indicated that QLQX significantly reduced collagen volume fraction in myocardial tissue (P<0.01). Results from RT-PCR and Western blot showed that QLQX significantly increased the expression of miR133a and inhibited the mRNA expressions of GRP78, IRE1, ATF6 and XBP1, as well as decreased the protein expressions of GRP78, cleaved-ATF6 and XBP1-s and decreased p-IRE1/IRE1 ratio (P<0.05, P<0.01). Further studies showed that QLQX significantly reduced the expression of CHOP and Caspase12, resulting in a significant reduction in apoptosis rate (P<0.05, P<0.01). CONCLUSION: The pharmacological mechanism of QLQX in improving HF is partly attributed to its regulatory effect on the miR133a-IRE1/XBP1 pathway.

Effectiveness and pharmacological mechanisms of Chinese herbal medicine for coronary heart disease complicated with heart failure.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal medicine (CHM) is widely used for treating coronary heart disease complicated with heart failure (CHD-HF). However, the exact mechanisms involved are still not fully understood. AIM OF THE STUDY: To assess the clinical effectiveness and potential pharmacological mechanisms of CHM for treating CHD-HF. METHODS: Eight databases were retrieved for Randomized Controlled Trials of CHM for CHD-HF published from their inception to March 2023. Quality assessment of include studies was performed by the Cochrane risk-of-bias. Meta-analysis was used to assess the effectiveness of CHM for CHD-HF, and then core drugs and active ingredients were selected by data mining and network pharmacology. Finally, cluster and enrichment analysis were adopted to explore the potential targets and signaling pathways. RESULTS: A total of 52 studies enrolling 5216 patients were included. Meta-analysis revealed that CHM treatment groups significantly improved left ventricular ejection fraction (LVEF), 6-min walk test (6-MWT), left ventricular end-diastolic dimension (LVEDD) and left ventricular end systolic diameter (LVESD) than control groups: [LVEF: SMD = 0.7, 95%CI (0.54, 0.87), p < 0.00001, I2 = 80%; 6-MWT: SMD = 0.72, 95%CI (0.58, 0.86), p < 0.0001, I2 = 67%; LVEDD: SMD = -0.79, 95%CI (-0.89, -0.69), p < 0.0001, I2 = 49%; LVESD: SMD = -0.6 (-0.74, -0.46), p < 0.0001, I2 = 0%]. The results of various biological information analysis showed the internal relationship between prescriptions, core drugs, active ingredients and therapeutic targets. Twelve core herbs with the most commonly use and high correlation were selected from 110 CHMs of 52 prescriptions for CHD-HF treatment, and further 65 effective components were screened out according to the most strength value, which were divided into 12 compounds such as terpenoids, flavonoids, steroids and alkaloids and etc. At the same time, 67 therapeutic targets of active ingredients in CHD-HF were filtrated. On these bases, cluster and enrichment analysis of the components and targets were used to explore relevant pharmacological mechanisms, mainly including anti-myocardial cell damage, anti-inflammation, anti-apoptosis, anti-fibrosis, regulation of oxidative stress, anticoagulation and angiogenesis, and improvement of glucose and fatty acid metabolism. CONCLUSION: CHM are effective in treating CHD-HF compared with conventional treatment. Some of the included studies have high risks in the implementation of blinding, so more high-quality studies are needed. The active ingredients of CHM could protect the myocardium and improve pathological environment of CHD-HF in various ways. And CHM has the advantage of multi-component and multi-target treatment for complex diseases.

Cognitive impairment is associated with BDNF-TrkB signaling mediating synaptic damage and reduction of amino acid neurotransmitters in heart failure.

Heart failure (HF) is often accompanied by cognitive impairment (CI). Brain-derived neurotrophic factor (BDNF) deficiency is closely associated with CI. However, the role and mechanism of BDNF in HF with CI is still not fully understood. Here, the case-control study was designed including 25 HF without CI patients (HF-NCI) and 50 HF with CI patients (HF-CI) to investigate the predictive value of BDNF in HF-CI while animal and cell experiments were used for mechanism research. Results found that BDNF levels in serum neuronal-derived exosomes were downregulated in HF-CI patients. There was no significant difference in serum BDNF levels among the two groups. HF rats showed obvious impairment in learning and memory; also, they had reduced thickness and length of postsynaptic density (PSD) and increased synaptic cleft width. Expression of BDNF, TrkB, PSD95, and VGLUT1 was significantly decreased in HF rats brain. In addition, compared with sham rats, amino acids were significantly reduced with no changes in the acetylcholine and monoamine neurotransmitters. Further examination showed that the number of synaptic bifurcations and the expression of BDNF, TrkB, PSD95, and VGLUT1 were all decreased in the neurons that interfered with BDNF-siRNA compared with those in the negative control neurons. Together, our results demonstrated that neuronal-derived exosomal BDNF act as effective biomarkers for prediction of HF-CI. The decrease of BDNF in the brain triggers synaptic structural damage and a decline in amino acid neurotransmitters via the BDNF-TrkB-PSD95/VGLUT1 pathway. This discovery unveils a novel pathological mechanism underlying cognitive impairment following heart failure.

The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy.

Background/aims: To investigate the specific effects of s odium-glucose transporter 2 inhibitor (SGLT2i) on cardiac energy metabolism. Methods: A systematic literature search was conducted in eight databases. The retrieved studies were screened according to the inclusion and exclusion criteria, and relevant information was extracted according to the purpose of the study. Two researchers independently screened the studies, extracted information, and assessed article quality. Results: The results of the 34 included studies (including 10 clinical and 24 animal studies) showed that SGLT2i inhibited cardiac glucose uptake and glycolysis, but promoted fatty acid (FA) metabolism in most disease states. SGLT2i upregulated ketone metabolism, improved the structure and functions of myocardial mitochondria, alleviated oxidative stress of cardiomyocytes in all literatures. SGLT2i increased cardiac glucose oxidation in diabetes mellitus (DM) and cardiac FA metabolism in heart failure (HF). However, the regulatory effects of SGLT2i on cardiac FA metabolism in DM and cardiac glucose oxidation in HF varied with disease types, stages, and intervention duration of SGLT2i. Conclusion: SGLT2i improved the efficiency of cardiac energy production by regulating FA, glucose and ketone metabolism, improving mitochondria structure and functions, and decreasing oxidative stress of cardiomyocytes under pathological conditions. Thus, SGLT2i is deemed to exert a benign regulatory effect on cardiac metabolic disorders in various diseases. Systematic review registration: https://www.crd.york.ac.uk/, PROSPERO (CRD42023484295).

Efficacy of scalp stimulation for multidomain cognitive impairment in patients with post-stroke cognitive impairment and dementia: A network meta-analysis and meta-regression of moderators.

BACKGROUND: Scalp stimulation has gained more traction for post-stroke cognitive impairment and dementia (PSCID); the interaction between stimulation targets and parameters influences the response to the stimulation. However, the most efficacious treatment for improving different domains of cognitive impairment remains unknown. OBJECTIVE: We aimed to conduct a systematic review and network meta-analysis (NMA) to compare the efficacy of various scalp stimulation protocols used in PSCID treatment. METHODS: Randomized controlled trials of scalp stimulation in patients with PSCID were searched in eight databases over the past 20 years. Standardized mean differences (SMDs) for global and subdomain cognitive scores were pooled in Bayesian NMA. Moderators were examined using meta-regression analysis. RESULTS: A total of 90 trials, with 6199 patients, were included. Low-frequency repetitive transcranial magnetic stimulation (rTMS) over the unaffected dorsolateral prefrontal cortex (DLPFC) was highly suggested for alleviating global severity (SMD = 1.11, 95% CI (0.64, 1.57)). High-frequency rTMS over the left DLPFC was recommended for language use (1.85 (1.18, 2.52)), executive function (0.85 (0.36, 1.33)), orientation deficits (0.59 (0.07, 1.13)), and attention (0.85 (0.27, 1.43)). Anodal transcranial direct current stimulation over the affected DLPFC (2.03 (0.72, 3.34)) was recommended for treating memory impairment. Meta-regression analyses showed significant associations within attention, language and orientation. CONCLUSION: Overall, different cognitive domains have different optimal scalp stimulation prescriptions, and activating the affected key brain regions and inhibiting the unaffected area is still the most effective treatment.

Bioinformatics prediction and experimental verification of a novel microRNA for myocardial fibrosis after myocardial infarction in rats.

Background: MicroRNAs (miRNAs) are endogenous noncoding single-stranded small RNAs. Numerous studies have shown that miRNAs have pivotal roles in the occurrence and development of myocardial fibrosis (MF). However, miRNA expression profile in rats with MF after myocardial infarction (MI) is not well understood. The present study aimed to find the potential miRNA for MF post MI. Methods: SPF male Sprague-Dawley (SD) rat models of acute myocardial infarction (AMI) were established by ligating the anterior descending branch of the left coronary artery, while sham-operated rats were only threaded without ligation as a control group. Hematoxylin-eosin and Masson trichrome staining were used to detect myocardial histopathological changes for model evaluation. The differentially expressed miRNAs were detected by using the Agilent Rat miRNA gene chip in the myocardial tissue of the infarct marginal zone. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed by DAVID. The expression of miR-199a-5p was verified by real-time fluorescence quantitative PCR (qRT-PCR). Transfected miR-199a-5p mimics into cardiac fibroblasts (CFs) to construct cell models of miR-199a-5p overexpression. Dual-luciferase reporter assay was employed to validate the target gene of miR-199a-5p. The protein expression of the target gene in CFs transfected with miR-199a-5p mimics were detected by Western blot. Results: Myocardial fibrosis was exacerbated in the model group compared with the control group. Thirteen differentially expressed miRNAs between the two groups were screened and their expression levels in the model group were all higher than those in the control group. The expression of miR-199a-5p was significantly increased in the model group in qRT-PCR, which was consistent with the results of the gene chip. KEGG enrichment analysis showed that the target genes of miR-199a-5p were enriched in the insulin signaling pathway. Furthermore, dual-luciferase reporter assay indicated that miR-199a-5p could negatively regulate the expression of GSK-3ß. After transfection, the expression of miR-199a-5p was increased in the miR-199a-5p mimics group. The protein expression of GSK-3ß was decreased in CFs transfected with miR-199a-5p mimics. Conclusion: Our study identified miR-199a-5p could promote the progression of myocardial fibrosis after myocardial infarction by targeting GSK-3ß, which provides novel targets for diagnosis and treatment of MF.

Effects of Exercise on Extracellular Vesicles in Patients with Metabolic Dysfunction: a Systematic Review.

The aim of this study was to investigate the effect of exercise on extracellular vesicles (EVs) in patients with metabolic dysfunction. The literatures were searched until Apr 28, 2022, and 16 studies that met inclusion criteria were included in this review. The results showed that the concentrations of platelet-derived extracellular vesicles (PEVs) and endothelial cell-derived extracellular vesicles (EEVs) decreased after long-term exercise, especially for CD62E+ EEVs and CD105+ EEVs. Simultaneously, exercise improved the concentration of clinical evaluation indicators of metabolic diseases, and the changes in these indicators were positively correlated with the changes of EEVs and PEVs. The concentration of skeletal muscle-derived extracellular vesicles (SkEVs) increased after a single bout of exercise. The aforementioned results indicated that long-term exercise might improve endothelial function and hypercoagulability in patients with metabolic dysfunction. The changes in concentrations of EVs could assist in assessing effect of exercise on patients with metabolic dysfunction.

Abnormalities of hippocampus and frontal lobes in heart failure patients and animal models with cognitive impairment or depression: A systematic review.

AIMS: This systematic review aimed to study the hippocampal and frontal changes of heart failure (HF) patients and HF animal models with cognitive impairment or depression. METHODS: A systematic review of the literature was conducted independently by reviewers using PubMed, Web of Science, Embase, and the Cochrane Library databases. RESULTS AND CONCLUSIONS: 30 studies were included, involving 17 pieces of clinical research on HF patients and 13 studies of HF animal models. In HF patients, the hippocampal injuries were shown in the reduction of volume, CBF, glucose metabolism, and gray matter, which were mainly observed in the right hippocampus. The frontal damages were only in reduced gray matter and have no difference between the right and left sides. The included HF animal model studies were generalized and demonstrated the changes in inflammation and apoptosis, synaptic reduction, and neurotransmitter disorders in the hippocampus and frontal lobes. The results of HF animal model studies complemented the clinical observations by providing potential mechanistic explanations of the changes in the hippocampus and frontal lobes.

Circulating microparticles are associated with plaque burden and cause eNOS uncoupling in patients with carotid atherosclerosis.

Aims: The study aimed to evaluate the correlation of different microparticle (MP) phenotypes with plaque burden and their diagnostic value and preliminarily explore the role of MPs in atherosclerosis (AS). Methods: Carotid intima-media thickness (CIMT) and maximal plaque area in 23 patients with carotid atherosclerosis (CAS) and 22 healthy subjects were measured by ultrasound. Transmission electron microscopy, nanoparticle tracking analysis and western blot were used to identify MPs. Flow cytometry assay measured absolute number of MPs, and receiver operating characteristic (ROC) analysis was used to assess the relationship between plaque burden and MPs. To study the preliminary mechanism of MPs in AS, MPs were administered to 32 male Kunming mice, which were randomly divided into control, CAS, healthy, and tetrahydrobiopterin (BH4) groups. Hematoxylin-eosin staining, immunohistochemistry staining, and Western blot were adopted to detect relevant indexes 24 h after the injection. Results: The plasma levels of CD45+ leukocyte-derived microparticle (LMP), CD11a+ LMP, CD11a+/CD45+ LMP, and CD31+/CD42b+ platelet-derived microparticle (PMP) in CAS patients were significantly higher than those in healthy subjects, and were positively correlated with the maximal plaque area. Moreover, the levels of CD11a+ LMP, CD11a+/CD45+ LMP were also positively correlated with CIMT. The area under the ROC curve of the four MPs was 0.689, 0.747, 0.741, and 0.701, respectively. Compared with healthy subjects, MPs from CAS patients resulted in a significantly lower expression of endothelial nitric oxide synthase (eNOS) dimer/monomer, and BH4 could improve eNOS uncoupling. Moreover, the level of VCAM-1 in intima in the CAS group was significantly higher than in the other three groups. Conclusion: CD11a+ LMP and CD11a+/CD45+ LMP might be potential biomarkers for CAS prediction. BH4-related eNOS uncoupling occurs in CAS patients, and circulating MPs from them lead to endothelial dysfunction through eNOS uncoupling.

Effect of WenXin KeLi on Improvement of Arrhythmia after Myocardial Infarction by Intervening PI3K-AKT-mTOR Autophagy Pathway.

Background: Myocardial infarction (MI) is an acute and serious cardiovascular disease. Arrhythmia after MI can lead to sudden cardiac death, which seriously affects the survival outcome of patients. WenXin KeLi is a Chinese patent medicine for the treatment of arrhythmia in a clinic, which can significantly improve symptoms of palpitation and play an important role in reducing the risk of arrhythmia after MI. In this study, we aimed to explore the pharmacological mechanism of WenXin KeLi in protecting the heart. Methods: The MI model was established by ligating the left coronary artery and the ventricular fibrillation threshold (VFT) was measured by electrical stimulation. The expression of connexin43 (CX43) and autophagy-related protein were measured by Western Blot, and correlation analysis was conducted to study the relationship between cardiac autophagy, CX43, and arrhythmia in rats after MI. The effects of WenXin KeLi on arrhythmia, cardiac structure, and function in MI rats were respectively observed by electrical stimulation, cardiac gross section, Masson staining, and cardiac ultrasound. The effects of WenXin KeLi on the expression of phosphoinositide 3 kinase-protein kinase B-mammalian targets of rapamycin (PI3K-AKT-mTOR) autophagy pathway and CX43 were observed by Western Blot. Results: After 4 weeks of MI, the VFT in the model group was significantly reduced, the expression levels of yeast ATG6 homolog (Beclin1), microtubule-associated protein 1A/1B-light chain 3 (LC3II/LC3I), and p-CX43 (S368) significantly increased, the expression of sequestosome-1(P62) and CX43 significantly decreased. LC3II/LC3I and Beclin1 expression were significantly negatively correlated with the VFT, and the expression of P62 and CX43 were significantly positively correlated with the VFT. LC3II/LC3I and Beclin1 expression were negatively correlated with CX43 expression, while P62 expression was positively correlated with CX43 expression. WenXin KeLi could significantly increase the VFT, reduce the deposition of collagen fibers, and increase the index levels of the left ventricular end-diastolic anterior wall (LVEDAW), interventricular septum end-diastolic (IVSED), left ventricular end-systolic anterior wall (LVESAW), interventricular septum end-systolic (IVSES), left ventricular end-diastolic posterior wall (LVEDPW), left ventricular end-systolic posterior wall (LVESPW), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and reduce the index levels of the left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). WenXin KeLi could increase the expression of CX43, P62, AKT, p-PI3K, p-AKT (308), p-AKT (473), and p-mTOR and decrease the expression of LC3II/LC3I and Beclin1. Conclusion: WenXin KeLi can activate the PI3K-AKT-mTOR signaling pathway, improve cardiac autophagy and Cx43 expression in rats after MI, reduce the risk of arrhythmia after MI, and play a cardioprotective role.

Separability Criteria Based on the Weyl Operators.

Entanglement as a vital resource for information processing can be described by special properties of the quantum state. Using the well-known Weyl basis we propose a new Bloch decomposition of the quantum state and study its separability problem. This decomposition enables us to find an alternative characterization of the separability based on the correlation matrix. We show that the criterion is effective in detecting entanglement for the isotropic states, Bell-diagonal states and some PPT entangled states. We also use the Weyl operators to construct an detecting operator for quantum teleportation.

Evidence and Characteristics of Traditional Chinese Medicine for Coronary Heart Disease Patients With Anxiety or Depression: A Meta-Analysis and Systematic Review.

Aims: The objective of this study was to assess the efficacy and potential mechanisms of Chinese herbal medicine (CHM) for treating coronary heart disease (CHD) patients with anxiety or depression. Methods: A systematic literature search was performed. Screening studies, extracting data, and assessing article quality were carried out independently by two researchers. The active ingredients of CHM for the treatment of CHD with anxiety or depression were analyzed by the network pharmacology, and the main potential mechanisms were summarized by the database of Web of Science. Results: A total of 32 studies were included. The results showed that compared with the blank control groups, CHM was more beneficial in treating anxiety or depression in patients with CHD [anxiety: OR = 3.22, 95% CI (1.94, 5.35), p < 0.00001, I2 = 0%; depression: OR = 3.27, 95% CI (1.67, 6.40), p = 0.0005, I2 = 0%], and the efficacy of CHM was not inferior to that of Western medicine (WM) [anxiety: OR = 1.58, 95%CI (0.39, 6.35), p = 0.52, I2 = 67%; depression: OR = 1.97, 95%CI (0.73, 5.28), p = 0.18, I2 = 33%,]. Additionally, CHM also showed a significant advantage in improving angina stability (AS) in CHD patients with anxiety or depression compared with blank groups [anxiety: SMD = 0.55, 95%CI (0.32, 0.79), p < 0.00001, I2 = 0%; depression: p = 0.004] and WM groups [anxiety: SMD = 1.14, 95%CI (0.80, 1.47), p < 0.00001, I2 = 0%; depression: SMD = 12.15, 95%CI (6.07, 18.23), p < 0.0001, I2 = 0%]. Angina frequency (AF) and electrocardiogram (ECG) analysis after using CHM demonstrated similar trends. Based on the network pharmacology, quercetin, kaempferol, luteolin, beta-sitosterol, puerarin, stigmasterol, isorhamnetin, baicalein, tanshinone IIa, and nobiletin were most closely and simultaneously related to the pathological targets of CHD, anxiety, and depression. The main underlying mechanisms might involve anti-damage/apoptosis, anti-inflammation, antioxidative stress, and maintaining neurotransmitter homeostasis. Conclusion: CHM exhibited an obvious efficacy in treating CHD patients with anxiety or depression, especially for improving the symptom of angina pectoris. The most active compounds of CHM could simultaneously act on the pathological targets of CHD, anxiety, and depression. Multiple effective components and multiple targets were the advantages of CHM compared with WM.

Effect of Extracellular Vesicles From Multiple Cells on Vascular Smooth Muscle Cells in Atherosclerosis.

Atherosclerosis (AS)-related diseases are still the main cause of death in clinical patients. The phenotype switching, proliferation, migration, and secretion of vascular smooth muscle cells (VSMCs) have a pivotal role in atherosclerosis. Although numerous research studies have elucidated the role of VSMCs in AS, their potential functional regulations continue to be explored. The formation of AS involves various cells, such as endothelial cells, smooth muscle cells, and macrophages. Therefore, intercellular communication of blood vessels cannot be ignored due to closely connected endothelia, media, and adventitia. Extracellular vesicles (EVs), as the vectors of cell-to-cell communication, can deliver proteins and nucleic acids of parent cells to the recipient cells. EVs have emerged as being central in intercellular communication and play a vital role in the pathophysiologic mechanisms of AS. This review summarizes the effects of extracellular vesicles (EVs) derived from multiple cells (endothelial cells, macrophages, mesenchymal stem cells, etc.) on VSMCs in AS. The key findings of this review are as follows: 1) endothelial cell-derived EVs (EEVs) have anti- or pro-atherogenic effects on VSMCs; 2) macrophage-derived EVs (MEVs) aggravate the proliferation and migration of VSMCs; 3) mesenchymal stem cells can inhibit VSMCs; and 4) the proliferation and migration of VSMCs can be inhibited by the treatment of EVs with atherosclerosis-protective factors and promoted by noxious stimulants. These results suggested that EVs have the same functional properties as treated parent cells, which might provide vital guidance for treating AS.

The Improvement of Cardiac and Endothelial Functions of Xue-Fu-Zhu-Yu Decoction for Patients with Acute Coronary Syndrome: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Xue-Fu-Zhu-Yu decoction (XFZYD) is a traditional Chinese prescription that has been used to treat patients with blood stasis in China for many years. The present study aimed to evaluate the improvement of cardiac and endothelial functions of XFZYD for patients with acute coronary syndrome (ACS) through a systematic review and meta-analysis. METHODS: Six databases were searched to collect RCTs related to the treatment of XFZYD for ACS. The primary outcomes were cardiac and endothelial functions, including the levels of left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD) in echocardiography, as well as the changes in the levels of nitric oxide (NO), endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in the serum. The secondary outcomes were the blood levels of oxidative damage markers (including superoxide dismutase (SOD) and malondialdehyde (MDA)), C-reactive protein (CRP), brain natriuretic peptide (BNP), creatine kinase-MB (CK-MB), and cardiac troponin I (cTnI) as well as the incidence of adverse drug reactions (ADRs). Weighted mean difference (WMD) was estimated for all the outcomes with the random effects model. This type of analysis was conducted in the subgroups of the ACS subtypes, and the methodological quality was assessed using the handbook of Cochrane Collaboration. RESULTS: A total of 1,658 records were identified, and 16 randomized controlled trials (1,171 patients) were included. The primary outcomes suggested that XFZYD combined with routine treatment improved LVEF, reduced LVEDD and LVESD, and also improved the serum levels of NO, and reduced the levels of ET-1 and ICAM-1. XFZYD combination therapy significantly ameliorated the blood levels of SOD, MDA, BNP, CK-MB, and cTnI. However, the results indicated no significant difference between XFZYD plus routine treatment and routine treatment for the levels of VCAM-1 and CRP. Moreover, all the ADRs reported in the included studies were slight and the patients recovered soon. CONCLUSIONS: The present study suggested that XFZYD may improve the cardiac and endothelial functions of ACS patients without serious ADRs. However, based on the mediocre methodological quality, the aforementioned conclusion should be confirmed in a multicenter, large-scale, and accurately designed clinical trial.

Mesenchymal Stem Cell Exosomes in the Treatment of Myocardial Infarction: a Systematic Review of Preclinical In Vivo Studies.

Several prior studies have highlighted the promise of mesenchymal stem cells (MSCs) as tools for treating myocardial infarction (MI) patients. While MSCs were initially thought to mediate post-MI repair through differentiation and replacement of injured cells, they are now thought to function by releasing exosomes carrying important cargos which can prevent apoptosis and facilitate revascularization in the context of MI. Herein, we comprehensively survey prior preclinical studies examining MSC-derived exosomes (MSC-Exos) utility for the repair of MI-related tissue injury. In total, 24 relevant studies were identified in the PubMed, Web of Science, Embase, and Cochrane Library databases as per the PRISMA guidelines. In most studies, exosome-treated rodents exhibited improved cardiac function and angiogenesis together with decreased apoptotic cell death. MSC-Exos thus offer beneficial therapeutic efficacy when treating MI injury. However, further work will be necessary to standardize experimental preclinical models and to validate these results. This systematic review provides a comprehensive overview of previous preclinical studies on the utility of exosomes derived from mesenchymal stem cells (MSCs) in the repair of myocardial infarction (MI) injury.

Atheroprotective Effects and Mechanisms of Postmarketing Chinese Patent Formulas in Atherosclerosis Models: A Systematic Review.

BACKGROUND: Some postmarketing Chinese patent formulas have been widely used to treat atherosclerosis (AS) and play critical roles in Chinese healthcare. However, the usage of these herbs is yet controversial due to unclear effects and lack of understanding of the mechanism of action. With the modernization of traditional Chinese formulas, we are to elucidate the atheroprotective properties of these remedies from successful postmarketing experiments in vivo. METHODS: In this systematic review, we critically searched the databases, applied stringent criteria, assessed the methodological quality, and examined the current evidence in vivo. RESULTS: Consequently, 60 studies were included in the present qualitative synthesis. Data on models, high-fat diet, intervention time, outcome measures, efficacy, and mechanisms were collected. Finally, 23 formulas that could alleviate AS were correlated to the amelioration of plaques, improvement of plaque stability, modification of lipid level and lipid metabolism, and the effects of anti-inflammation and antioxidant stress with multiple components and targets. However, the methodological quality was low and incomplete among the included literature. CONCLUSIONS: Thus, taken together, the studies on postmarketing Chinese patent formulas would provide a novel approach to improve the treatment of AS, and rigorously designed studies would provide high-quality evidence.

Advances of Traditional Chinese Medicine Regulating Connexin43 in the Prevention and Treatment of Myocardial Infarction.

Gap junctions are the main form of interaction between cardiomyocytes, through which the electrochemical activities between cardiomyocytes can be synchronized to maintain the normal function of the heart. Connexins are the basis of gap junctions. Changes in the expression, structural changes (e.g., phosphorylation and dephosphorylation), and distribution of connexins can affect the normal electrophysiological activities of the heart. Myocardial infarction (MI) and concurrent arrhythmia, shock, or heart failure can endanger life. The structural and functional damage of connexin (Cx) 43 in cardiomyocytes is a central part of the pathological progression of MI and is one of the main pathological mechanisms of arrhythmia after MI. Therefore, increasing Cx43 expression has become one of the main measures to prevent MI. Also, intervention in Cx43 expression can improve the structural and electrical remodeling of the myocardium to improve MI prognosis. Here, research progress of Cx43 in MI and its prevention and treatment using Traditional Chinese Medicine formulations is reviewed.

Wenxin Granules Regulate Endoplasmic Reticulum Stress Unfolded Protein Response and Improve Ventricular Remodeling on Rats with Myocardial Infarction.

Background. Arrhythmia after myocardial infarction is the leading cause of death in clinical heart disease. Increasing studies have shown that the response to endoplasmic reticulum (ER) stress (ERS) caused by myocardial infarction is related to prognosis and the development of arrhythmias. The unfolded protein response (UPR) could serve as an important regulatory signaling pathway following myocardial infarction. The traditional Chinese medicine Wenxin Granules improve arrhythmias following myocardial infarction, which may be related to ERS intervention and the activation of the UPR and apoptosis. We aimed to investigate the involvement of Wenxin Granules in the activation of the UPR and apoptosis following myocardial infarction. Left coronary artery ligation was established as a rat model of myocardial infarction. The rats were randomly divided into the model group, low-dose Wenxin Granule group, high-dose Wenxin Granule group, and metoprolol group. Rats with only wire insertion and no ligature were used as the sham group. Small animal ultrasound systems were used to detect changes in heart structure and function, and the electrical stimulation threshold for ventricular fibrillation was detected. The expression of glucose-regulated protein (GRP)78, activating transcription factor (ATF)6, X-box binding protein (XBP)1, protein kinase-like ER kinase (PERK), phosphorylated (p)-PERK, Bax, Bcl2, C/EBP homologous protein (CHOP), caspase 12, caspase 8, and caspase 3 were detected by western blot, and terminal deoxynucleotidyl transferase dUTP Nick end labeling (TUNEL) was used to determine the cardiomyocyte apoptosis index. Compared with the sham group, rats in the model group displayed immediate ST-segment elevation and pathological Q waves after 24 hours. After 2 weeks, the left ventricular (LV) anterior wall thickness (LVAW) became thinner, and the inner diameter (LVID) increased. The end-diastolic LVAW (LVAWd), end-systolic LVAW (LVAWs), ejection fraction (EF), and fractional shortening (FS) were significantly reduced (P < 0.01), whereas the LVIDd, LVIDs, diastolic LV volume (LV Vold), and systolic LV volume (LV Vols) significantly increased (P < 0.01). The ventricular fibrillation threshold decreased significantly (P < 0.01). ERS proteins GRP78, p-PERK, PERK, ATF6, and XBP1 and apoptotic proteins CHOP, Bax, caspase 12, caspase 8, and caspase 3 significantly increased (P < 0.01, P < 0.05), whereas Bcl-2 expression and the Bcl-2/Bax ratio decreased (P < 0.01). Compared with the sham group, LVAWd, LVAWs, FS, and Bcl-2 protein expression were significantly increased in the low-dose Wenxin Granule group (P < 0.01, P < 0.05), and p-PERK and ATF6 decreased (P < 0.01, P < 0.05). Compared with the sham group, LVAWd, LVAWs, EF, FS, and the ventricular fibrillation threshold significantly increased in the high-dose Wenxin Granule and metoprolol groups (P < 0.01, P < 0.05), whereas LVIDs, LV Vols, and ERS proteins were significantly decreased (P < 0.01, P < 0.05). CHOP, Bax, caspase 12, caspase 8, and caspase 3 protein expression decreased in the Wenxin Granule group (P < 0.01, P < 0.05), whereas Bcl-2 and the Bcl-2/Bax ratio increased (P < 0.01, P < 0.05). LVIDd and Bax decreased in the metoprolol group (P < 0.01, P < 0.05), and the Bcl-2/Bax ratio increased (P < 0.05). The cardiomyocyte apoptosis index values for the low- and high-dose Wenxin Granule and metoprolol groups were significantly reduced (P < 0.05). This study suggested that the UPR is an essential mechanism underlying pathological injury after myocardial infarction. Wenxin Granule treatment can improve ventricular remodeling and cardiac function and inhibit arrhythmia by preventing excessive ERS from activating the UPR and apoptosis.

Comparison of the Clinical Value of miRNAs and Conventional Biomarkers in AMI: A Systematic Review.

Background/Aims: This study aimed to compare the clinical value of the peak time point and area under the curve (AUC) of miRNAs and conventional biomarkers in acute myocardial infarction (AMI). Methods: A literature search was carried out in PubMed, Web of Science, Embase, and Cochrane systematically. Screening studies, extracting data, and assessing article quality were performed independently by two researchers. Also, the names of miRNAs in the included studies were standardized by the miRBase database. Results: A total of 40 studies, encompassing 6,960 participants, were included in this systematic review. The samples of circulating miRNAs were mainly from the plasma. The results of this systematic review displayed that miR-1-3p, miR-19b-3p, miR-22-5p, miR-122-5p, miR-124-3p, miR-133a/b, miR-134-5p, miR-150-5p, miR-186-5p, miR-208a, miR-223-3p, miR-483-5p, and miR-499a-5p reached peak time earlier and showed a shorter time window than the conventional biomarkers despite the different collection times of initial blood samples. miR-1-3p, miR-19b-3p, miR-133a/b, miR-208a/b, miR-223-3p, miR-483-5p, and miR-499a-5p were shown to be more valuable than classical biomarkers for the early diagnosis of AMI, and these miRNAs appeared to have the most potential biomarkers within 4 h of the onset of symptoms except miR-133a/b and miR-208b. Moreover, combined miRNAs or miRNAs combined with classical biomarkers could compensate for the deficiency of single miRNA and conventional biomarker in sensitivity or specificity for an optimal clinical value. Conclusions: miR-1-3p, miR-19b-3p, miR-208a, miR-223-3p, miR-483-5p, and miR-499a-5p are promising biomarkers for AMI due to their satisfactory diagnostic accuracy and short time window (within 4 h of the onset of symptoms).

Modelling of integrated scheduling problem of capacitated equipment systems with a multi-lane road network.

The coordination of different container-handling equipment is an important method for improving the overall efficiency of automated container terminals. In the real terminal, we should consider many real-life issues, such as the equipment capacity, the equipment collision, changing lanes in the multi-lane road, and choosing one of container-handling lanes for each container. This paper proposes the integrated scheduling problem of three container-handling equipment with the capacity constraint and the dual-cycle strategy, for simultaneously solving the equipment scheduling problem, the assignment problem of the container-handling lane and the conflict-free route planning problem of automated guided vehicles (AGVs). With the objective of minimizing the ship's berth time, we propose a mixed-integer programming model based on the space-time network representation method and two bilevel optimization algorithms based on conflict resolution rules. Finally, numerical experiments are conducted to verify the effectiveness of the proposed model and two bilevel optimization algorithms.