A review on the current literature regarding the value of exosome miRNAs in various diseases.

Exosome microRNAs (miRNAs) have great research outlook in clinical therapy and biomarkers, they have been found to have a close to multiple diseases. A growing number of studies have attempted to alleviate or treat diseases through exosomes. It indicates that miRNAs in exosomes have great significance in preventing and controlling diseases in clinical research. We summarise these studies below to better understand their implications.We screened and analyzed more than 100 articles from PubMed, Web of Science, and other databases from 1987 to 2022. Data of the clinical trials are collected from clinicaltrials.gov.In this review, we introduce the source, type, and characteristics of several exosomes, summarising current research on their role in cardiovascular, nervous system disease, tumour, and other diseases. Further, we discuss their mechanism of action and future directions for development of treatments in several diseases, and highlight the significant research value and potential use of exosomes in clinical diagnosis and treatment.An increasing number of researchers have begun to explore the link between exosomal miRNAs and diseases. More exosome therapeutics will be used in future clinical trials, which may bring new hope for the diagnosis and treatment of several diseases.KEY MESSAGESExosomes have unique advantages in molecular transport and cell signal transduction.miRNAs play an essential role in the formation of multiple diseases.Research on the clinical application and potential value of exosomes is growing.

Development and validation using NHANES data of a predictive model for depression risk in myocardial infarction survivors.

BACKGROUND: Depression after myocardial infarction (MI) is associated with poor prognosis. This study aimed to develop and validate a nomogram to predict the risk of depression in patients with MI. METHODS: This retrospective study included 1615 survivors of MI aged >20 years who were selected from the 2005-2018 National Health and Nutrition Examination Survey database. The 899 subjects from the 2005-2012 survey comprised the development group, and the remaining 716 subjects comprised the validation group. Univariate and multivariate analyses identified variables significantly associated with depression. The least absolute shrinkage and selection operator (LASSO) binomial regression model was used to select the best predictive variables. RESULTS: A full predictive model and a simplified model were developed using multivariate analysis and LASSO binomial regression results, respectively, and validated using data from the validation group. The receiver operator characteristic curve and Hosmer-Lemeshow goodness of fit test were used to assess the nomogram's performance. The full nomogram model included 8 items: age, BMI, smoking, drinking, diabetes, exercise, insomnia, and PIR. The area under the curve for the development group was 0.799 and for the validation group was 0.731, indicating that our model has good stability and predictive accuracy. The goodness of fit test showed a good model calibration for both groups. The simplified model includes age, smoking, PIR, and insomnia. The AUC of the simplified model was 0.772 and 0.711 in the development and validation groups, respectively, indicating that the simplified model still possessed good predictive accuracy. CONCLUSION: Our nomogram helped assess the individual probability of depression after MI and can be used as a complement to existing depression screening scales to help physicians make better treatment decisions.

IFN regulatory Factor-1 induced macrophage pyroptosis by modulating m6A modification of circ_0029589 in patients with acute coronary syndrome.

BACKGROUND: Pyroptosis is identified as a novel form of inflammatory programmed cell death and has been recently found to be closely related to atherosclerosis (AS). We found that IFN regulatory factor-1(IRF-1) effectively promotes macrophage pyroptosis in patients with acute coronary syndrome (ACS). Subsequent studies have demonstrated that circRNAs are implicated in AS. However, the underlying mechanisms of circRNAs in macrophage pyroptosis remain elusive. METHODS: We detected the RNA expression of hsa_circ_0002984, hsa_circ_0010283 and hsa_circ_0029589 in human PBMC-derived macrophages from patients with coronary artery disease (CAD). The lentiviral recombinant vector for hsa_circ_0029589 overexpression (pLC5-GFP-circ_0029589) and small interference RNAs targeting hsa_circ_0029589 and METTL3 were constructed. Then, macrophages were transfected with pLC5-GFP-circ_0029589, si-circ_0029589 or si-METTL3 after IRF-1 was overexpressed and to explore the potential mechanism of hsa_circ_0029589 involved in IRF-1 induced macrophage pyroptosis. RESULTS: The relative RNA expression level of hsa_circ_0029589 in macrophages was decreased, whereas the N6-methyladenosine (m6A) level of hsa_circ_0029589 and the expression of m6A methyltransferase METTL3 were validated to be significantly elevated in macrophages in patients with ACS. Furthermore, overexpression of IRF-1 suppressed the expression of hsa_circ_0029589, but induced its m6A level along with the expression of METTL3 in macrophages. Additionally, either overexpression of hsa_circ_0029589 or inhibition of METTL3 significantly increased the expression of hsa_circ_0029589 and attenuated macrophage pyroptosis. CONCLUSION: Our observations suggest a novel mechanism by which IRF-1 facilitates macrophage pyroptosis and inflammation in ACS and AS by inhibiting circ_0029589 through promoting its m6A modification.

Implications of C1q/TNF-related protein superfamily in patients with coronary artery disease.

The C1q complement/TNF-related protein superfamily (CTRPs) displays differential effects on the regulation of metabolic homeostasis, governing cardiovascular function. However, whether and how they may serve as predictor/pro-diagnosis factors for assessing the risks of coronary artery disease (CAD) remains controversial. Therefore, we performed a clinical study to elaborate on the implication of CTRPs (CTRP1, CTRP5, CTRP7, and CTRP15) in CAD. CTRP1 were significantly increased, whereas CTRP7 and CTRP15 levels were decreased in CAD patients compared to the non-CAD group. Significant differences in CTRP1 levels were discovered between the single- and triple-vascular-vessel lesion groups. ROC analysis revealed that CTRP7 and CTRP15 may serve as CAD markers, while CTRP1 may serve as a marker for the single-vessel lesion of CAD. CTRP1 and CTRP5 can serve as markers for the triple-vessel lesion. CTRP1 may serve as an independent risk predictor for triple-vessel lesion, whereas CTRP15 alteration may serve for a single-vessel lesion of CAD. CTRP1 may serve as a novel superior biomarker for diagnosis of severity of vessel-lesion of CAD patients. CTRP7, CTRP15 may serve as more suitable biomarker for the diagnosis of CAD patients, whereas CTRP5 may serve as an independent predictor for CAD. These findings suggest CTRPs may be the superior predictive factors for the vascular lesion of CAD and represent novel therapeutic targets against CAD.

IFN Regulatory Factor 1 Mediates Macrophage Pyroptosis Induced by Oxidized Low-Density Lipoprotein in Patients with Acute Coronary Syndrome.

BACKGROUND: Atherosclerosis (AS) is recognized as a chronic inflammatory disease. It is caused by the interaction between inflammatory cells such as macrophages, dendritic cells, and lipoproteins. Evidence has revealed that macrophage pyroptosis in lesion contributes to the formation of the necrotic core and thinning of the fibrous cap, which plays crucial roles in the onset of acute coronary syndrome (ACS). IFN regulatory factor 1 (IRF-1) is a pleiotropic transcription factor involved in various immune processes and cell death. We propose that IRF-1 may be implicated in macrophage pyroptosis in the pathogenesis of AS and ACS. METHODS: Patients with stable angina, unstable angina, acute myocardial infarction, and clinical presentation of chest pain were enrolled. The expression of IRF-1 in human PBMC-derived macrophages was analyzed. Then, overexpression and inhibition of IRF-1 was performed in macrophages from patients with ACS to explore the possible role and mechanism of IRF-1 involvement in macrophage pyroptosis. RESULTS: The expression of IRF-1 in macrophages was upregulated in ACS patients. The overexpression or inhibition of IRF-1 effectively modulated caspase-1 activation, as well as macrophage lysis, expression of gasdermin D-N (GSDMD-N), production of IL-1ß and IL-18, and activation of NLRP3-ASC inflammasome, which were all inhibited by caspase-1 inhibitor. Further experiments revealed that pyroptosis and the downstream inflammatory response in AS induced by IRF-1 is a process that is dependent on reactive oxygen species (ROS) generation. CONCLUSION: Our observations suggest that IRF-1 potently activates ox-LDL-induced macrophage pyroptosis and may play an important role in AS and ACS.

Adiponectin inhibits proliferation of vascular endothelial cells induced by Ox-LDL by promoting dephosphorylation of Caveolin-1 and depolymerization of eNOS and up-regulating release of NO.

Oxidized low density lipoprotein (ox-LDL) can induce the proliferation and differentiation of endothelial cells, which is one of the important mechanisms of ox-LDL atherosclerosis. Adiponectin is an endogenous bioactive polypeptide secreted by adipocytes, it participates in the metabolism of fat and glucose. It has the effect of reducing blood triglyceride and LDL content. Adiponectin also inhibits the abnormal proliferation and migration of endothelial cells, but its molecular mechanism is unclear. In this study, we used cell model of Ox-LDL-induced human aortic endothelial cells (HAECs) proliferation to analyze the molecular mechanism of APN inhibiting HAECs abnormal proliferation. The results showed that APN could inhibit the cell viability and DNA synthesis of HAECs after Ox-LDL treatment, up-regulate the apoptosis level and reduce the proportion of S + G2 phase cells. Further analysis showed that adiponectin could promote the dephosphorylation of Caveolin-1, which could dissociate eNOS and Caveolin-1, promote the phosphorylation of eNOS and enhance the synthesis of NO. NO increased expression levels of cleaved caspase 3 and p21 in the cells and inhibited the abnormal proliferation of HAECs. The regulation of phosphorylation and dephosphorylation of Caveolae-1 plays a key role in this process. Further study of the molecular mechanism of Caveolae-1 in the inhibition of HAECs abnormal proliferation by APN may reveal the potential of APN in the treatment of cardiovascular diseases.

MicroRNA-148b-3p is involved in regulating hypoxia/reoxygenation-induced injury of cardiomyocytes in vitro through modulating SIRT7/p53 signaling.

Accumulating evidence has suggested that microRNAs (miRNAs) are emerging as critical regulators in myocardial ischemia/reperfusion injury. miR-148b-3p has been reported to regulate cell apoptosis of various cell types. However, whether miR-148b-3p is involved in regulating cardiomyocyte apoptosis in myocardial ischemia/reperfusion injury remains unknown. In this study, we aimed to investigate the potential role and molecular mechanism of miR-148b-3p in regulating cardiomyocyte apoptosis induced by hypoxia/reoxygenation (H/R) injury in vitro, a cellular model of myocardial ischemia/reperfusion injury. We found that miR-148b-3p expression was significantly up-regulated in response to H/R treatment in cardiomyocytes. Functional experiments showed that miR-148b-3p overexpression significantly decreased the viability, increased LDH release and promoted the apoptosis of H/R-treated cardiomyocytes. In contrast, miR-148b-3p inhibition improved the viability, decreased LDH release and reduced the apoptosis of H/R-treated cardiomyocytes, showing a protective effect against H/R-induced injury. Bioinformatics analysis predicted that Sirtuin7 (SIRT7), a critical stress survival gene of cardiomyocytes, was a potential target gene of miR-148b-3p, which was then validated by dual-luciferase reporter assay, real-time quantitative polymerase chain reaction and Western blot analysis. Moreover, our results showed that miR-148b-3p regulated the acetylation of the p53 protein and modulated p53-mediated pro-apoptotic signaling through targeting SIRT7. Notably, the silencing of SIRT7 significantly abrogated miR-148b-3p inhibition-mediated cardio-protective effects, while SIRT7 overexpression rescued miR-148b-3p-induced cell apoptosis in cardiomyocytes with H/R treatment. Overall, our results indicate that miR-148b-3p contributes to the regulation of H/R-induced cardiomyocyte apoptosis in vitro through targeting SIRT7 and modulating p53-mediated pro-apoptotic signaling.