Background: Depression is a common complication of cardiovascular disease, which deteriorates cardiac function. Shuangxinfang (psycho-cardiology formula, PCF) was reported to alleviate myocardial ischemia injury and improve depression-like behavior. Interestingly, our previous proteomics study predicted that the protein S100A9 appeared as an important target, and macrophage/microglial inflammation might be involved in the process of PCF improving depression induced by acute myocardial infarction (AMI). This study aims to validate the proteomics results.Methods: AMI rat models were established in vivo, followed by the administration of PCF or ABR-215757 (also named paquinimod, inhibiting S100A9 binding to TLR4) for 5 days. Forced swimming test (FST) and open field test (OFT) were applied to record depression-like behavior, and echocardiography was employed to evaluate cardiac function. Morphological changes of cardiomyocytes were assessed by HE staining and TUNEL staining on day 7 after cardiac surgery, as well as Masson trichrome staining on day 21. Hippocampal neurogenesis was determined by Nissl staining, while 5-hydroxytryptamine (5-HT), tryptophan/kynurenine ratio, and brain-derived neurotrophic factor (BDNF) in the hippocampus were analyzed as biochemical indicators of depression. We employed RT-qPCR, western blotting, and immunofluorescence to detect the expression of pathway-related genes and proteins. Myocardial and hippocampal expression of inflammatory factors were performed by ELISA. The activation of macrophage and microglia was assessed via immunoreaction using CD68 and Iba1, respectively. For in vitro confirmation, BV2 cells were primed with recombinant protein S100A9 and then treated with PCF serum or ferulic acid to determine alterations in microglial inflammation.Results: Rats in the AMI group showed heart function deterioration and depression-like behavior. Coronary ligation not only brought about myocardial inflammation, cell apoptosis, and fibrosis but also reduced the neurogenesis, elevated the tryptophan/kynurenine ratio, and decreased the content of 5-HT. PCF could ameliorate the pathological and phenotypic changes in the heart and brain and inhibit the expression of the S100A9 protein, the activation of the microglial cell, and the secretion of IL-1β and TNF-α raised by AMI. ABR-215757 showed therapeutic effect and molecular biological mechanisms similar to PCF. Treatment with PCF serum or ferulic acid in vitro was proved to efficiently block the hyperactivation of BV2 cells and increment of cytokine contents induced by recombinant protein S100A9.Conclusion: We identify S100A9 as a novel and potent regulator of inflammation in both the heart and brain. Macrophage/microglia inflammation mediated by S100A9 is considered a pivotal pathogenic in depression after AMI and a major pathway for the treatment of PCF, suggesting that PCF is a promising therapeutic candidate for psycho-cardiology disease.
Background & Aims: Carotid atherosclerotic plaque is an important cause of carotid artery stenosis. The features of carotid atherosclerotic plaque detected by relevant magnetic resonance imaging (MRI), such as lipid core, plaque hemorrhage, and fibrous cap rupture, have been confirmed to be associated with the occurrence of the first cerebral ischemic event. Meanwhile, the features of carotid atherosclerotic plaque can be used as biomarkers to predict the occurrence of cerebral ischemic event. However, the mechanism of recurrent stroke is still unclear. A systematic review and meta-analysis will be performed to summarize the association between features of carotid artery plaque detected by MRI and recurrent stroke, so as to find biomarkers that can predict recurrent stroke. Methods: Electronic search will be performed in PUBMED, EMBASE, Cochrane Controlled Register of Trials (CENTRAL) from inception to October 30, 2018. We will include cohort studies with an average follow-up time of >1 month in which lipid-rich/necrotic cores (LRNC), intraplaque hemorrhage (IPH), and thinned or ruptured fibrous caps (TRFC) are associated with recurrent ipsilateral stroke or ischemic events. We will perform heterogeneity assessment before carrying out meta-analysis. According to the heterogeneity, we select random effect model or fixed effect model for meta-analysis of the included cohort studies. Results: Review Manager 5.3 software will be used to calculate the combined hazard ratio value and 95% confidence interval (CI). This meta-analysis will provide high-quality data analysis of LRNC, IPH, and TRFC and ipsilateral recurrent stroke or ischemic events, including biomarkers as major predictors. Conclusion: The systematic review will provide evidence to assess the association between features of carotid plaque and ipsilateral recurrent stroke or ischemic events. PROSPERO registration number: PROSPERO CRD42019124043.
Introduction: Recurrent angina pectoris after percutaneous coronary intervention (PCI) is a common clinical syndrome, which seriously reduces the quality of life and health of patients, increases medical costs, and causes the risk of cardiogenic death. The efficacy of various western medicine improving angina symptoms has not been fully confirmed at the moment, whereas Chinese patent medicine capsules (CPMC) have been generally used in clinical practice due to the therapeutic efficacy and safety. This study evaluates the efficacy and safety of CPMC for stable angina after PCI, designed to provide more evidence for clinical treatment. Methods: This protocol was based on the previous reporting items. We will search 3 English databases (PubMed, Excerpta Medica Database, and the Cochrane Library) and 3 Chinese databases (China Network Knowledge Infrastructure, Wan Fang Database, and Chinese Biomedicine) until January 2020. RCTs to evaluate the efficacy and safety of CPMC for recurrent stable angina pectoris after PCI will be included. The primary outcome will be assessed by major adverse cardiovascular events and angina attack frequency. We will use the criteria provided by Cochrane risk of bias tool for quality evaluation and risk assessment, and use the Revman 5.3 for meta-analysis. Ethics and Dissemination: Ethical approval is not required for systematic review and meta-analysis. The results of this review will be disseminated in a peer-review journal. PROSPERO registration number: CRD42020164005.
Background Depression is a common complication of cardiovascular disease, which deteriorated the cardiac function. Shuangxinfang (Psycho-cardiology Formula, PCF) was reported to alleviate myocardial ischemia injury and improve depression-like behavior. Interestingly, our previous proteomics study predicted that the protein S100A9 appeared as an important target, and macrophage/microglial inflammation might be involved in the process of PCF treating depressive disorder induced by acute myocardial infarction (AMI). The aim of this study is to validate the proteomics results. Methods AMI rat models were established in vivo, followed by the administration of PCF or ABR-215757 (also named paquinimod, inhibiting S100A9 binding to TLR4) for 5 days. Forced swimming test (FST) and open field test (OFT) were applied to record depression-like behavior, and echocardiography was employed to evaluate cardiac function. Morphological changes of cardiomyocytes were assessed by HE staining and TUNEL staining on day 7 after cardiac surgery, as well as masson trichrome staining on day 21. Hippocampal neurogenesis was determined by Nissl staining, while 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) in the hippocampus were detected as biochemical indicators of depression. Myocardial and hippocampal expression of inflammatory factors were analyzed by western blotting, immunofluorescence, and ELISA. The activation state of macrophage and microglia was assessed via immunoreaction respectively using CD68 and Iba1. For in vitro confirmation, BV2 cells were primed with recombinant protein S100A9, and then pretreated with PCF serum, to determine alterations in microglial activation and inflammation. Results Rats in the AMI group showed heart function deterioration, as well as depression-like behavior. Coronary ligation not only brought about myocardial inflammation, cell apoptosis and fibrosis, but also reduced the neurogenesis and decreased the content of 5-HT. PCF could ameliorate the pathological and phenotypic changes of the heart and brain, and inhibited the expression of S100A9/TLR4/NF-κB pathway, the activation of microglial cell and the secretion of IL-1β and TNF-α raised by AMI. ABR-215757 showed therapeutic effect and molecular biological mechanisms similar to PCF. Pretreatment with PCF serum in vitro was proved to efficiently block the hyperactivation of BV2 cells and increasement of cytokine contents induced by recombinant protein S100A9. Conclusion We identify S100A9 as a novel and potent regulator of inflammation in both heart and brain. Macrophage/microglia inflammation mediated by S100A9 is considered as a pivotal pathogenic in depression post-AMI, as well as a major pathway for the treatment of PCF, suggesting that PCF is a promising therapeutic candidate for psycho-cardiology disease.
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