Silencing of Long Noncoding RNA MIAT Contributes to Relieving Sepsis-Induced Myocardial Depression via the NF-κB Axis.

INTRODUCTION: Sepsis represents a life-threatening disease caused by a series of infections, which may be complicated with severe myocardial depression (MD). Long noncoding RNAs (lncRNAs) are closely related to sepsis-induced myocardial depression (SIMD). This study aimed to seek out the mechanism of lncRNA myocardial infarction-associated transcript (MIAT) in the growth of SIMD. METHODS: Venous blood samples were collected from 62 patients with sepsis; the sepsis rat model was established with 15 mg/kg lipopolysaccharide (LPS), and the H9C2 cardiomyocyte injury model was established with 1 µg/mL LPS. In the rat and cardiomyocyte models, MIAT was inhibited. The expression of MIAT in normal tissues and SIMD tissues was detected. Then, the functional assays of MIAT were performed in rats and H9C2 cells for detection of cardiac function, hemodynamics, inflammation response, myocardial function, oxidative stress, tissue stainings, and cardiomyocyte viability and apoptosis. Western blot analysis was used to measure the levels of apoptosis-related proteins and the nuclear factor kappa B (NF-κB) axis-related proteins. RESULTS: MIAT was highly expressed in SIMD patients. Silencing MIAT alleviated inflammation and apoptosis and improved myocardial function in SIMD rats by downregulating the NF-κB axis. In LPS-induced H9C2 cardiomyocytes, silencing MIAT alleviated inflammation and oxidative stress and inhibited apoptosis by downregulating the NF-κB axis, thus mitigating cardiomyocyte injury. CONCLUSIONS: MIAT could assist the diagnosis of SIMD and might affect the progression of SIMD by regulating the NF-κB pathway.

Periostin renders cardiomyocytes vulnerable to acute myocardial infarction via pro-apoptosis.

AIMS: As a severe cardiovascular disease, acute myocardial infarction (AMI) could trigger congestive heart failure. Periostin (Postn) has been elucidated to be dramatically up-regulated in myocardial infarction. Abundant expression of Postn was also observed in the infarct border of human and mouse hearts with AMI. This work is dedicated to explore the mechanism through which Postn exerts its functions on AMI. METHODS AND RESULTS: The expression of Postn in AMI mice and hypoxia-treated neonatal mouse cardiomyocytes (NMCMs) was quantified by qRT-PCR. The biological functions of Postn in AMI were explored by trypan blue, TUNEL, flow cytometry analysis, and JC-1 assays. Luciferase activity or MS2-RIP or RNA pull-down assay was performed to study the interaction between genes. Postn exhibited up-regulated expression in AMI mice and hypoxia-treated NMCMs. Functional assays indicated that cell apoptosis in NMCMs was promoted via the treatment of hypoxia. And Postn shortage could alleviate cell apoptosis in hypoxia-induced NMCMs. Postn was verified to bind to mmu-miR-203-3p and be down-regulated by miR-203-3p overexpression. Postn and miR-203-3p were spotted to coexist with small nucleolar RNA host gene 8 (Snhg8) in RNA-induced silencing complex. The affinity between Snhg8 and miR-203-3p was confirmed. Afterwards, Snhg8 was validated to promote cell apoptosis in hypoxia-induced NMCMs partially dependent on Postn. Furthermore, vascular endothelial growth factor A (Vegfa) was revealed to bind to miR-203-3p and be implicated in the Snhg8-mediated AML cell apoptosis and angiogenesis. CONCLUSIONS: miR-203-3p availability is antagonized by Snhg8 for Postn and Vegfa-induced AMI progression.

miR-30c-5p acts as a therapeutic target for ameliorating myocardial ischemia-reperfusion injury.

Coronary heart disease (CHD) is one of the most vital reasons for death and disability all over the world. miRNA, as a plasma index, is quite valuable for disease screening and prognosis prediction in CHD. Mining the molecular mechanism behind miRNA is also helpful for us to find molecular therapeutic strategies. In this research, we found that the expression of plasma miR-30c-5p in CHD patients was obviously lower than that in the control group (CG), which had a high differential value for CHD. We also discovered that miR-30c-5p was obviously correlated with clinical characteristics of CHD patients such as age, NYHA grade, smoking history, hypertension, hyperlipidemia, etc. In prognosis analysis, the miR-30c-5p expression in patients with poor prognosis was dramatically lower than that in those with good one, and the AUC for predicting poor prognosis of CHD was not lower than 0.850. In addition, we also induced myocardial ischemia/reperfusion (I/R) injury model of H9C2 cells through hypoxia/reoxygenation, and found that H9C2 cells also had abnormally down-regulated miR-30c-5p and up-regulated BCL2-like 11 (BCL2L11). Up-regulating miR-30c-5p or down-regulating BCL2L11 were helpful to improve proliferation and apoptosis of I/R injury model. Mechanically, BCL2L11 was also negatively regulated by miR-30c-5p, and up-regulating the former could cancel the in vitro protective effect of up-regulating the latter on H9C2 cell I/R injury model. In vivo research, up-regulating miR-30c-5p or down-regulating BCL2L11 can improve myocardial injury, histopathological changes and apoptosis in rat I/R model.

Association Between Nitrite and Nitrate Intake and Risk of Gastric Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND Studies have shown inconsistent associations of nitrite and nitrate intake with the risk of gastric cancer or its associated mortality. We performed a meta-analysis of observational studies to evaluate the correlation of nitrite and nitrate intake with the risk of gastric cancer. MATERIAL AND METHODS We searched for studies reporting effect estimates and 95% confidence intervals (CIs) of gastric cancer in PubMed, EMBASE, and the Cochrane Library through November 2018. The summary results of the included studies were pooled using a random-effects model. RESULTS Eighteen case-control and 6 prospective cohort studies recruiting 800 321 participants were included in this study. The summary results indicated that the highest (odds ratio [OR], 1.27; 95%CI, 1.03-1.55; P=0.022) or moderate (OR: 1.12; 95%CI, 1.01-1.26; P=0.037) nitrite intake were associated with a higher risk of gastric cancer. However, we noted that high (OR, 0.81; 95%CI, 0.68-0.97; P=0.021) or moderate (OR, 0.86; 95%CI, 0.75-0.99; P=0.036) nitrate intakes were associated with a reduced risk of gastric cancer. These associations differed when stratified by publication year, study design, country, the percentage of male participants, assessment of exposure, adjusted model, and study quality. CONCLUSIONS High or moderate nitrite intake was associated with higher risk of gastric cancer, whereas high or moderate nitrate intake was correlated with lower risk of gastric cancer.

MicroRNA-26b relieves inflammatory response and myocardial remodeling of mice with myocardial infarction by suppression of MAPK pathway through binding to PTGS2.

BACKGROUND: Myocardial infarction (MI) is a common cardiovascular disease caused by myocardial ischemia. Also, microRNA (miRNA) participates in the pathophysiology of many cardiovascular diseases, which can affect stem cell transplantation in the treatment of MI. In this study, our aim is to explore effect of miR-26b on inflammatory response and myocardial remodeling through the MAPK pathway by targeting PTGS2 in mice with MI. METHODS: Microarray data analysis was conducted to screen MI-related differentially expressed gens (DEGs). Relationship between miR-26b and PTGS2 was testified. Cardiac function, inflammatory reaction, infarct size, and myocardial fibrosis were observed. The miR-26b expression and mRNA and protein levels of, PTGS2, ERK, JNK and p38 and Bcl-2/Bax were examined. The effect of miR-26b on cell apoptosis was also analyzed. RESULTS: MiR-26b was predicted to target PTGS2 further to mediate the MAPK pathway, thus affecting MI. MiR-26b negatively targeted PTGS2. MI mice showed decreased cardiac function, as well as increased inflammatory reaction, myocardial injury, area of fibrosis and myocardial cell apoptosis. After injection of miR-26b agomir or NS-398 (PTGS2 inhibitor), inflammatory response of MI mice was attenuated and myocardial remodeling induced by MI was alleviated. CONCLUSION: These findings indicate that miR-26b inhibits PTGS2 to activate the MAPK pathway, so as to reduce inflammatory response and improve myocardial remodeling in mice with MI.

IRAK3 gene silencing prevents cardiac rupture and ventricular remodeling through negative regulation of the NF-κB signaling pathway in a mouse model of acute myocardial infarction.

Cardiac rupture and ventricular remodeling are recognized as the severe complications and major risk factors of acute myocardial infarction (AMI). This study aims to evaluate the regulatory roles of interleukin-1 receptor-associated kinase 3 (IRAK3) and nuclear factor-κB (NF-κB) signaling pathway in cardiac rupture and ventricular remodeling. Microarray analysis was performed to screen AMI-related differentially expressed genes and IRAK3 was identified. The models of AMI were established in male C57BL/6 mice to investigate the functional role of IRAK3. Afterwards, lentivirus recombinant plasmid si-IRAK3 was constructed for IRAK3 silencing. Next, cardiac function parameters were measured in response to IRAK3 silencing. The regulatory effects that IRAK3 had on myocardial infarct size and the content of myocardial interstitial collagen were analyzed. The regulation of IRAK3 silencing on the NF-κB signaling pathway was further assayed. The obtained results indicated that highly expressed IRAK3 and activated NF-κB signaling pathway were observed in myocardial tissues of mouse models of AMI, accompanied by increased expression of matrix metalloproteinase (MMP)-2/9 and tissue inhibitor of metalloproteinase 2 (TIMP-2). Notably, IRAK3 gene silencing inhibited the activation of NF-κB signaling pathway. Furthermore, IRAK3 gene silencing led to the decreased thickness of infarct area and collagen content of myocardial interstitium, alleviated diastolic, and systolic dysfunctions, as well as, facilitated cardiac functions in mice with AMI, corresponding to decreased expression of MMP-2/9 expression and increased expression of TIMP-2. Taken together, silencing of IRAK3 inactivates the NF-κB signaling pathway, and thereby impeding the cardiac rupture and ventricular remodeling, which eventually prevents AMI progression.