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Abstract Background The miR-208 gene is one of the microRNAs now under active studies, and has been found to play significant roles in an array of cardiovascular diseases. Nevertheless, until now, no studies have examined the relationship between the susceptibility to ischemic stroke (IS) and genetic variations in miR-208. This study explored the association between the miR-208 polymorphisms (rs178642, rs8022522, and rs12894524) and the risk of IS. Methods A total of 205 cases of IS and 211 control subjects were included. The SNPscans genotyping test was employed to determine the genotypes of the three polymorphisms. Results Significant correlation was observed between rs8022522 polymorphism and risk of IS on the basis of analyses of genotypes, models and alleles (GA vs. GG: adjusted OR = 2.159, 95% CI: 1.052–4.430, P = 0. 036; AA vs. GG: adjusted OR = 5.154, 95% CI: 1.123–23.660, P = 0.035; dominant model: adjusted OR = 1.746, 95% CI, 1.075–2.838, P = 0.025; G vs. A: adjusted OR = 2.451, 95% CI: 1.374–4.370, P = 0.002). Conclusions The rs8022522 polymorphism of the miR-208 gene is significantly associated with an elevated risk of ischemic stroke in Chinese.

Background: The miR-208 gene is one of the microRNAs now under active studies, and has been found to play significant roles in an array of cardiovascular diseases. Nevertheless, until now, no studies have examined the relationship between the susceptibility to ischemic stroke (IS) and genetic variations in miR-208. This study explored the association between the miR-208 polymorphisms (rs178642, rs8022522, and rs12894524) and the risk of IS. Methods: A total of 205 cases of IS and 211 control subjects were included. The SNPscans genotyping test was employed to determine the genotypes of the three polymorphisms. Results: Significant correlation was observed between rs8022522 polymorphism and risk of IS on the basis of analyses of genotypes, models and alleles (GA vs. GG: adjusted OR = 2.159, 95% CI: 1.052–4.430, P = 0. 036; AA vs. GG: adjusted OR = 5.154, 95% CI: 1.123–23.660, P = 0.035; dominant model: adjusted OR = 1.746, 95% CI, 1.075–2.838, P = 0.025; G vs. A: adjusted OR = 2.451, 95% CI: 1.374–4.370, P = 0.002). Conclusions: The rs8022522 polymorphism of the miR-208 gene is significantly associated with an elevated risk of ischemic stroke in Chinese. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) regulate gene expression and play a significant role in cancer progression. Previously, downregulation of lncRNA MEG3 was shown to associate with poor clinical outcomes in melanoma patients. The basis for this association has not been described and the aims of this study were to identify a role for lncRNA MEG3 in melanoma and to describe its regulatory mechanism of action. RT-qPCR was used to detect lncRNA MEG3 expression in melanoma cells and tissues. Luciferase reporter assays were used to identify lncRNA MEG3 downstream targets. Melanoma cells were transfected with various expression vectors and these transfected cells were assessed for; migration, colony formation, proliferation, in vivo tumorigenesis, and metastatic potential. Melanoma cell lines were found to be sensitive to lncRNA MEG3 expression levels and overexpression was found to inhibit melanoma cell proliferation and invasion, both in vitro and in vivo. Luciferase reporter assays identified miR-208 and SOX4 as downstream targets of lncRNA MEG3. Overexpression of miR-208 and silencing of SOX4 rescued invasion and proliferation by cells that overexpressed lncRNA MEG3. Moreover, lncRNA MEG3 inhibited cancer stem cell differentiation and suppressed melanoma progression and metastasis through inhibition of miR-208 by SOX4. [ABSTRACT FROM AUTHOR]

This article aimed to investigate the role of miR‐208 in the apoptosis of myocardial tissues in acute myocardial infarction (AMI) mice. The AMI mouse model was constructed. Then, miR‐208 expression in AMI mice was regulated by transfection. The mouse myocardial tissues were subject to hematoxylin–eosin (HE) staining, TUNEL assay, and immunofluorescence analysis. H9c2 cell transfection and hypoxia induction were then completed, and cell apoptosis and cytokine levels were tested. Additionally, RNA pull‐down and dual luciferase reporter gene assays were conducted for exploring the relation of miR‐208 with programmed cell death 4 (PDCD4). Additionally, fluorescence in situ hybridization (FISH) was conducted for investigating miR‐208 and PDCD4 colocalization within H9c2 cells. AMI mice had severe damage, apoptosis, decreased miR‐208 expression, increased IL‐1β, IL‐6, IL‐8 levels, whereas reduced IL‐10 level within myocardial tissues. H9c2 cells under hypoxia induction exhibited decreased miR‐208 expression, promoted apoptosis, increased protein expression of Bax and cleaved‐caspase‐3, decreased protein expression of Bcl‐2 and caspase‐3, elevated IL‐1β, IL‐6, IL‐8 levels and decreased IL‐10 level. miR‐208 upregulation alleviated the damage and apoptosis of myocardial tissues in AMI mice. AMI mice with miR‐208 upregulation showed decreased expression of Bax and cleaved‐caspase‐3, increased expression of Bcl‐2 and caspase‐3, reduced levels of IL‐1β, IL‐6, IL‐8, whereas an increased level of IL‐10. miR‐208 showed direct inhibition of PDCD4. PDCD4 and miR‐208 were mainly co‐expressed in the cytoplasm. The upregulated PDCD4 expression abolished miR‐208's suppression of H9c2 cell apoptosis induced by hypoxia. Besides this, miR‐208 inhibited myocardial tissue apoptosis in AMI mice by inhibiting PDCD4 expression. [ABSTRACT FROM AUTHOR]

The prognostic characteristics of pancreatic cancer (PC) are determined by the contributing factors from the tumor microenvironment. Leptin is a critical oncogenic factor released by adipocytes as an adipokine into the tumor microenvironment, where it promotes tumor development by activating cancer stem cell (CSC) molecular regulators Notch, Hedgehog, and Wnt/β-catenin signaling. One of the downstream targets of these pathways is CDK4/6 and cyclin D which is controlled by P16 INK4A that is highly mutated in PC. Therefore, the purpose of this study was to determine the effect of a CDK4/6 inhibitor, palbociclib, on Leptin-induced PC cells and to target the Notch, Hedgehog, and Wnt/β-catenin signaling pathways via miR-150, miR-506, and miR-208 modulation. Leptin treatment increased the ability of Panc-1, MiaPaCa-2, and Capan-2 cells to proliferate and decreased the effect of palbociclib. Additionally, tumorspheres were generated from Leptin-treated (Leptin+) and Leptin-untreated (Leptin-) Panc-1 and MiaPaCa-2 cells and transfected with miR-506, miR-150 (tumorsuppressor miRNAs), or anti-miR-208 (oncomiR), followed by palbociclib treatment. Forced expression of miR-506 or miR-150 significantly increased the susceptibility of Leptin+ cells to palbociclib treatment by inhibiting colony and tumor spheroid formation, and CD44 expression in Panc-1 and MiaPaCa-2 cells. Additionally, the increased miR-150 expression is more effective at inhibiting N-cadherin, β-catenin, p-GSK3β, Notch, and Wnt5a/b expression in Leptin-/+ Panc-1 and MiaPaCa-2 cells. As a result, palbociclib suppressed the CSC profile induced by leptin treatment, inhibiting both tumorsphere forms and leptin-targeted signaling pathways, thereby disabling the Panc-1 and MiaPaCa-2 cells' resistance mechanism. Increased expression of miR-506 or miR-150 and inhibition of miR-208 enhanced sensitivity of Panc-1 and MiaPaCa-2 Leptin-/+ cells to palbociclib treatment. As a result, this study proved that combining inhibitors of CSC molecular regulators with palbociclib improves the success rate of inhibition of PC cell proliferation. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are strongly up‐regulated under pathological stress and in a wide range of diseases. In recent years, miRNAs are under investigation for their potential use as biomarkers in cardiovascular diseases. We investigate whether specific cardio‐miRNAs are overexpressed in heart samples from subjects deceased for acute myocardial infarction (AMI) or sudden cardiac death (SCD), and whether miRNA could help differentiate between them. Forty four cases of death due to cardiovascular disease were selected, respectively, 19 cases categorized as AMI and 25 as SCD. Eighteen cases of traumatic death without pathological cardiac involvement were selected as control. Immunohistochemical investigation was performed for CD15, IL‐15, Cx43, MCP‐1, tryptase, troponin C and troponin I. Reverse transcription and quantitative real‐time PCR were performed for miR‐1, miR‐133, miR‐208 and miR‐499. In AMI group, stronger immunoreaction for the CD15, IL‐15 and MCP‐1 antibodies was detectable compared with SCD and control. Cx43 showed a negative reaction with respect to the other groups. Real‐time PCR results showed a down‐regulation of all miRNAs in the AMI group compared with SCD and control. The selected miRNAs presented high accuracy in discriminating SCD from AMI (miR‐1 and miR‐499) and AMI from control (miR‐208) representing a potential aid for both clinicians and pathologists for differential diagnosis. [ABSTRACT FROM AUTHOR]

Background/Aims: Ginsenoside Rb1 (GS-Rb1) is one of the most important active pharmacological extracts of the Traditional Chinese Medicine ginseng, with extensive evidence of its cardioprotective properties. Mir-208 has been shown to act as a biomarker of acute myocardial infarction in vivo studies including man. However the impact of miR-208 on the protective effect of GS-Rb1 in hypoxia/ischemia injured cardiomyocytes remains unclear. The current study aims to investigate the target gene of miR-208 and the impact on the protective effect of GS-Rb1 in hypoxia/ischemia (H/I) injuried cardiomyocytes. Materials and Methods: Primary cultures of neonatal rat cardiomyocytes (NRCMs) was subjected to the H/I conditions with or without GS-Rb1. Cell viability was calculated by MTT assay and confirmed by flow cytometry analysis. Mir-208 was then detected by qRT-PCR. Luciferase reporter assay was carried out to detect the target gene of Mir-208. Then the NRCMs were transfected with miR-208 mimics and inhibitors to evaluate the impact on cardioprotective properties of Rb1. Results: The miR-208 expression level was clearly upregulated in the H/I treated NRCMs accompanied by the percentage of the apoptotic cells which could be reversed by GS-Rb1 pretreatment. The nemo-like kinase (NLK) mRNA and protein expression levels were decreased in H/I group measured by RT-PCR and western blotting. Luciferase activity assay was then carried out to identify that NLK may be a direct target of mir-208. MTT assay showed that miR-208 inhibitor slightly decreased the protective effect of Rb1 on the H/I impaired NRCMs. However, results showed no statistical difference. Conclusions: These findings proved that NLK was a direct target of mir-208 and miR-208 act indirectly during Rb1 protecting H/I impaired NRCMs and further researches were needed to explore the relationship that microRNAs and other signal pathways in the protective effect of GS-Rb1 on the hypoxia/ischemia injuries in cardiomyocytes.

In this study, we tested the hypothesis that extracellular vesicles (EVs)-mediated transfer of miR-208a/b can exacerbate apoptosis of cardiomyocytes (CMs) induced by hypoxia/reoxygenation (H/R) injury by reducing the expression of the RNA-binding protein Quaking (QKI). EVs were isolated from culture medium of hypoxic H9c2 cells (EVs-H). In in vitro H9c2 cell model, the EVs-H could be taken up by normoxic CMs and exacerbated cell apoptosis induced by H/R injury. In addition, miR-208a and miR-208b were enriched in EVs-H. Suppression of miR-208a and miR-208b loading significantly suppressed the detrimental effect of EVs-H on H/R injury in H9c2 cells. Inhibition of endogenous miR-208a and miR-208b restored QKI5 and QKI6 after H/R treatment. Dual-luciferase assay confirmed direct bindings between miR-208a/b and QKI 3′UTR. Functionally, QKI5 overexpression significantly suppressed H/R-induced CM apoptosis and suppressed the enhancing effect of EVs-H on CM apoptosis. Therefore, we infer that EVs-mediated transfer of miR-208a/b can exaggerate H/R injury in CMs by reducing QKI expression. This represents a previously unrecognized pathway of H/R injury in CMs. [ABSTRACT FROM AUTHOR]

Conventional circulating biomarkers of cardiac and skeletal muscle (SKM) toxicity lack specificity and/or have a short half-life. MicroRNAs (miRNAs) are currently being assessed as biomarkers of tissue injury based on their long half-life in blood and selective expression in certain tissues. To assess the utility of miRNAs as biomarkers of cardiac and SKM injury, male Sprague–Dawley rats received a single dose of isoproterenol (ISO); metaproterenol (MET); allylamine (AAM); mitoxantrone (MIT); acetaminophen (APAP) or vehicle. Blood and tissues were collected from rats in each group at 4, 24 and 48 h. ISO, MET, and AAM induced cardiac and SKM lesions and APAP induced liver specific lesions. There was no evidence of tissue injury with MIT by histopathology. Serum levels of candidate miRNAs were compared to conventional serum biomarkers of SKM/cardiac toxicity. Increases in heart specific miR-208 only occurred in rats with cardiac lesions alone and were increased for a longer duration than cardiac troponin and FABP3 (cardiac biomarkers). ISO, MET and AAM induced increases in MyL3 and skeletal muscle troponin (sTnl) (SKM biomarkers). MIT induced large increases in sTnl indicative of SKM toxicity, but sTnl levels were also increased in APAP-treated rats that lacked SKM toxicity. Serum levels of miR-133a/b (enriched in cardiac and SKM) increased following ISO, MET, AAM and MIT treatments but were absent in APAP-treated rats. Our results suggest that miR-133a/b are sensitive and specific markers of SKM and cardiac toxicity and that miR-208 used in combination with miR-133a/b can be used to differentiate cardiac from SKM toxicity. [ABSTRACT FROM AUTHOR]

Healthy, premenopausal women have the advantage of female-specific cardiovascular protection compared to age-matched healthy men. However, pathologies such as obesity and Type 2 diabetes mellitus (T2DM) cause losing of this female-specific cardiovascular protection in young, obese and diabetic females. Molecular mechanisms underlying this loss of female-specific cardiovascular protection in young, obese and diabetic females are not clearly elucidated. This review takes a close look at the latest advances in our understanding of sex differences in adult cardiac gene expression patterns in health and disease. Based on the emerging data, this review proposes that female biased gene expression patterns in healthy adult hearts of human and pre-clinical models support the existence of active fetal gene program in healthy, premenopausal female heart compared to age-matched healthy male heart. However, the misalignment of gene expression pattern in this female-specific active cardiac fetal gene program caused by pathologies such as obesity and T2DM may contribute to the loss of female-specific cardiovascular protection in young, obese and diabetic females., Competing Interests: The author declares 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 © 2023 Pulakat.)

Background/Aims: Ginsenoside Rb1 (GS-Rb1) is one of the most important active pharmacological extracts of the Traditional Chinese Medicine ginseng, with extensive evidence of its cardioprotective properties. Mir-208 has been shown to act as a biomarker of acute myocardial infarction in vivo studies including man. However the impact of miR-208 on the protective effect of GS-Rb1 in hypoxia/ischemia injured cardiomyocytes remains unclear. The current study aims to investigate the target gene of miR-208 and the impact on the protective effect of GS-Rb1 in hypoxia/ischemia (H/I) injuried cardiomyocytes. Materials and Methods: Primary cultures of neonatal rat cardiomyocytes (NRCMs) was subjected to the H/I conditions with or without GS-Rb1. Cell viability was calculated by MTT assay and confirmed by flow cytometry analysis. Mir-208 was then detected by qRT-PCR. Luciferase reporter assay was carried out to detect the target gene of Mir-208. Then the NRCMs were transfected with miR-208 mimics and inhibitors to evaluate the impact on cardioprotective properties of Rb1. Results: The miR-208 expression level was clearly upregulated in the H/I treated NRCMs accompanied by the percentage of the apoptotic cells which could be reversed by GS-Rb1 pretreatment. The nemo-like kinase (NLK) mRNA and protein expression levels were decreased in H/I group measured by RT-PCR and western blotting. Luciferase activity assay was then carried out to identify that NLK may be a direct target of mir-208. MTT assay showed that miR-208 inhibitor slightly decreased the protective effect of Rb1 on the H/I impaired NRCMs. However, results showed no statistical difference. Conclusions: These findings proved that NLK was a direct target of mir-208 and miR-208 act indirectly during Rb1 protecting H/I impaired NRCMs and further researches were needed to explore the relationship that microRNAs and other signal pathways in the protective effect of GS-Rb1 on the hypoxia/ ischemia injuries in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Background Heart chamber-specific mRNA expression patterns have been extensively studied, and dynamic changes have been reported in many cardiovascular diseases. MicroRNAs (miRNAs) are also important regulators of normal cardiac development and functions that generally suppress gene expression at the posttranscriptional level. Recent focus has been placed on circulating miRNAs as potential biomarkers for cardiac disorders. However, miRNA expression levels in human normal hearts have not been thoroughly studied, and chamber-specific miRNA expression signatures in particular remain unclear. Methods and results We performed miRNA deep sequencing on human paired left atria (LA) and ventricles (LV) under normal physiologic conditions. Among 438 miRNAs, miR-1 was the most abundant in both chambers, representing 21% of the miRNAs in LA and 26% in LV. A total of 25 miRNAs were differentially expressed between LA and LV; 14 were upregulated in LA, and 11 were highly expressed in LV. Notably, the miR-208 family in particular showed prominent chamber specificity; miR-208a-3p and miR-208a-5p were abundant in LA, whereas miR-208b-3p and miR-208b-5p were preferentially expressed in LV. Subsequent real-time polymerase chain reaction analysis validated the predominant expression of miR-208a in LA and miR-208b in LV. Conclusions Human atrial and ventricular tissues display characteristic miRNA expression signatures under physiological conditions. Notably, miR-208a and miR-208b show significant chamber-specificity as do their host genes, α-MHC and β-MHC, which are mainly expressed in the atria and ventricles, respectively. These findings might also serve to enhance our understanding of cardiac miRNAs and various heart diseases. [ABSTRACT FROM AUTHOR]

Background It has been demonstrated that circulating muscle-enriched miR-1 and the cardiac-specific miR-208 and miR-499 might leak out of the necrotic myocardium and release into the circulation during the early stages of acute myocardial infarction (AMI). This study aims to investigate potential predictive value of the three miRNAs in AMI. Methods Plasma samples were taken from 70 AMI patients and 72 healthy controls. The expression levels of target miRNAs were measured by qRT-PCR. Student's t test and χ 2 test were applied to test the significance of the differences between AMI patients and controls. Additionally, a meta-analysis about the prediction accuracy of the three miRNAs in AMI was performed to summarize all the results from available studies. Results The expression of plasma miR-1, miR-208 and miR-499 were all significantly elevated in AMI patients compared with controls. By receiver operating characteristic (ROC) curve analysis, plasma miR-1, miR-208 and miR-499 were demonstrated to be potential biomarkers for the prediction of AMI with AUC values of 0.81, 0.72, and 0.88, respectively. The meta-analysis consisted of nine studies for miR-1, eight studies for miR-208 and eight studies for miR-499. The summary estimates of miR-1, miR-208 and miR-499 were 0.73, 0.80 and 0.83 for sensitivity, 0.82, 0.95 and 0.90 for specificity, 0.84, 0.89 and 0.91 for AUC, respectively. Conclusion In summary, we confirmed the predictive values of plasma miR-1, miR-208 and miR-499 in AMI. In contrast to miR-1, the cardiac-specific miR-208 and miR-499 were supposed to be more reliable as biomarkers in AMI screening and prediction. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is a prevalent cancer in aged men. Curcumin is an active ingredient that has been extracted from the rhizome of the plant Curcuma longa. Recently, a potential of Curcumin against PC has been reported in PC, whereas the underlying molecular mechanisms are not completely understood. Here, we studied the effects of low-dose Curcumin on PC cell growth. Curcumin (from 0.2 to 0.8 μmol/l) dose-dependently inhibited the proliferation of PC cells, without affecting cell apoptosis. Further analyses showed that Curcumin dose-dependently increased a cell cycle suppressor CDKN1A at protein levels, but not mRNA levels, in PC cells, suggesting that Curcumin may regulate the translation of CDKN1A, as well as a possible involvement of miRNA intervention. From all CDKN1A-3′-UTR-binding miRNAs, we found that miR-208 was specifically inhibited in PC cells dose-dependently by Curcumin. Moreover, miR-208 was found to bind CDKN1A to suppress its expression. In a loss-of-function experiment, PC cells that overexpressed miR-208 failed to decrease cell proliferation in response to Curcumin. Together, these data suggest that Curcumin inhibits growth of PC via miR-208-mediated CDKN1A activation. [ABSTRACT FROM AUTHOR]

Cardiovascular disease remains to be a severe and yet unsolved health problem that has become a leading threat to human health. It is urgent to explore early diagnostic biomarker and innovative therapeutic strategy to prevent the progression of cardiovascular diseases. MicroRNAs (miRNAs) are conserved endogenous, non-coding small RNAs that are essential modulators of gene expression by inhibiting translation or promoting degradation of messenger RNAs (mRNAs). A large range of functions has been attributed to miRNAs, such as cell proliferation, differentiation, apoptosis, and invasion. So far, miRNAs have shown characteristic changes in expression during the process of cardiovascular disease that may act as potential biomarkers. A series of studies have clearly discovered that the miR-208 family is closely associated with the development of cardiac diseases, such as myocardial hypertrophy, cardiac fibrosis, myocardial infarction, arrhythmia, and heart failure. In this review, we will highlight novel insights into miR-208 family functions and discuss it as potential biomarker and therapeutic target in cardiovascular diseases. [ABSTRACT FROM AUTHOR]

ABSTRACT Cardiotoxicity is one of the major safety concerns in drug development. Therefore, detecting and monitoring cardiotoxicity throughout preclinical and clinical studies is important for pharmaceutical companies. The present study was conducted in order to explore a plasma miRNA biomarker for cardiotoxicity in rats. As organ specificity is an important factor for a biomarker, we analyzed the miRNA microarray dataset in 55 organs/tissues in normal male rats. Based on this analysis, 5 miRNAs consisting of miR-208 (heart-specific), miR-1, miR-133a, miR-133b (heart and skeletal muscle-specific) and miR-206 (skeletal muscle-specific) were selected. Next, we evaluated the usefulness of those 5 miRNAs as circulating biomarkers in rats administered with single-dose isoproterenol or doxorubicin. Plasma miR-208 was consistently increased through 24 h after dosing in rats administered with isoproterenol, whereas plasma concentrations of cardiac troponin (cTn) showed transient elevation. In contrast, the plasma levels of miR-1, miR-133a, miR-133a and miR-206 were elevated after treatment with doxorubicin, probably as a result of skeletal muscle toxicity. Additionally, the plasma miR-208 level was elevated even after repeat-dose administration (once daily for 7 days) of isoproterenol under which the pathological condition proceeded to the sub-chronic phase such as fibrosis. Thus, our data suggest that miR-208 is a promising plasma biomarker for cardiotoxicity in rats. Monitoring of plasma miR-208 levels in rats may lead to more accurate evaluation of cardiotoxicity in preclinical studies. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the role of miR-208 in the invasion and metastasis of pancreatic cancer cells and the underlying molecular mechanism. miR-208 mimic, miR-208 inhibitor and NC were transfected into pancreatic cancer cell line Bxpc3 using liposome. Transwell invasion and scratch assays were used to test cell migratory and invasive abilities. Western blotting and quantitative PCR methods were used to detect E-cadherin, fibronectin and vimentin protein and mRNA expression in pancreatic cancer cell line BxPC3 after transfection by miR-208 mimic, miR-208 inhibitor and NC. Transwell invasion and scratch assays showed that after overexpressing miR-208, pancreatic cancer cell line BxPC3 exhibited enhanced in vitro migratory and invasive abilities, while after downregulating miR-208 expression, cell migratory and invasive abilities were decreased. Western blotting and quantitative PCR showed that after overexpressing miR-208, expression of E-cadherin, an epithelial cell marker, was decreased and expression of fibronectin and vimentin, interstitial cell markers, was increased in pancreatic cancer cell line BxPC3; however, after inhibiting miR-208, increased E-cadherin expression and decreased fibronectin and vimentin expression were observed in pancreatic cancer cell line BxPC3. After overexpressing miR-208, p-AKT and p-GSK-3β expression was altered by activating AKT/GSK-3β/snail signaling pathway. miR-208 induces epithelial to mesenchymal transition of pancreatic cancer cell line BxPC3 by activating AKT/GSK-3β/snail signaling pathway and thereby promotes cell metastasis and invasion. [ABSTRACT FROM AUTHOR]

Background and Aims: Thyroid hormones exert important effects on heart remodeling through mir-208. The process may have a role in myocardial changes in chronic kidney disease where thyroid abnormalities are common. In this study the effect of T4 supplementation on left ventricle (LV) remodeling in 5/6 nephrectomized rats (5/6Nx) was analyzed. Methods: 5/6Nx rats and 5/6Nx under T4 supplementation (5/6Nx + T4) were compared with control (C) and thyroidectomized (Tx) rats. After 8 weeks of follow-up, LV was analyzed for α-MHC, β-MHC, TGF-β, and mir-208 expression, hydroxyproline content, and myocardial fibrosis. Serum collagenase activity was also analyzed. Results: Heart weight increased in 5/6Nx rats compared to C, which was prevented with T4 supplementation (C, 1.5 ± 0.04; 5/6Nx, 1.8 ± 0.09; 5/6Nx + T4, 1.6 ± 0.07 g, p <0.05). The same pattern was seen for LV wall thickness, hydroxyproline content, LV fibrosis, and mRNA TGF-β expression (C, 0.47 ± 0.17; 5/6Nx, 10.55 ± 3.4; 5/6Nx + T4, 3.01 ± 0.52, p <0.01). Tx rats had reduction in heart weight, increased LV wall thickness, and fibrosis. Collagenase activity did not change in any group. mRNA expression of α-, β-MHC, and TGF-β increased in 5/6Nx in comparison to C and 5/6Nx + T4. Expression of mir-208 decreased in 5/6Nx groups, and levels were restored with T4 supplementation (4.21 ± 0.28, 3.39 ± 0.29, and 4.26 ± 0.37 RU, respectively, p <0.01). Conclusions: Decreased plasma level of thyroid hormones or sensitivity at tissue level observed in chronic kidney disease induced by 5/6Nx has an important effect in heart remodeling processes, some of it related or mediated by mir-208 and TGF-β expression in the heart. [ABSTRACT FROM AUTHOR]

Abstract: The currently used biomarkers for acute myocardial infarction (AMI) are blood creatinine phosphokinase-muscle band (CPK-MB), troponin-T (TnT), and troponin I (TnI). However, no good biomarkers are identified in urine after AMI, because these blood protein biomarkers are difficult to be filtered into urine. In this study, the role of urine microRNAs in the diagnosis of AMI and the mechanism involved were determined. We found that urine miR-1 was quickly increased in rats after AMI with peak at 24h after AMI, in which an over 50-fold increase was demonstrated. At 7days after AMI, the urine miR-1 level was returned to the basal level. No miR-208 was found in normal urine. In urine from rats with AMI, miR-208 was easily detected. To determine the mechanism involved, we determined the levels of heart-released miR-1 in the liver, spleen and kidney after AMI in rats and found that the kidney was an important metabolic organ. To determine the renal elimination of blood miRNAs, we isolated serum exosomes from rats after AMI and injected these exosomes into the circulating blood of normal rats. We found that the urine miR-1 was significantly increased in exosome-injected animals. Moreover, PKH67-labeled exosomes injected into circulating blood could enter into the kidney tissues and cells, as well as urine. Furthermore, the levels of urine miR-1 were significantly increased in patients with AMI. The results suggest that urine miRNAs such as miR-1 could be novel urine biomarkers for AMI. [Copyright &y& Elsevier]

Background: Subcutaneous immunotherapy (SCIT) is widely used in the treatment of allergic rhinitis (AR). This study aimed to determine the expression of 48 miRNAs in patients with AR undergoing grass pollen SCIT and investigate relations with clinical outcomes. Methodology: Expression of selected miRNAs was determined using RT-PCR in the full blood of 16 patients with AR and seven healthy controls. Results:  miR-136, miR-208 and miR-190 were upregulated in the AR group. After 6 months of SCIT, significant downregulation of some proinflammatory miRNAs and upregulation of several miRNAs regulating Th1/Th2 balance were found. No differences were found between good and poor responders. Conclusion:  miRNAs may play a regulatory role in SCIT, leading to tolerance induction.

Cardiovascular disease is a major chronic complication of obesity and diabetes. Due to several patients with obesity and diabetes, it is necessary to urgently explore early diagnostic biomarkers and innovative therapeutic strategies to prevent the progression of cardiovascular diseases. Recently, microRNAs (also known as miRNAs) have emerged as important players in heart disease and energy regulation. MiRNAs are a group of small, highly conserved non-coding RNA molecules that regulate gene expression by suppressing the translation of messenger RNA of target genes or by promoting mRNA degradation. These act as a class of potential biomarkers and may provide key information in diagnosing common diseases such as tumors, tissue damage, and autoimmune diseases. Among all the known miRNAs, microRNA-208 (miR-208) is specifically expressed in myocardial cells and showed close association with the development of cardiac diseases, such as myocardial hypertrophy, cardiac fibrosis, myocardial infarction, arrhythmia, and heart failure. However, the functions and underlying mechanisms of miR-208 in heart are still unclear. In this review, we highlighted the novel insights of miR-208 functions and associated mechanisms in the regulation of cardiac diseases. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is a prevalent cancer in aged men. Curcumin is an active ingredient that has been extracted from the rhizome of the plant Curcuma longa. Recently, a potential of Curcumin against PC has been reported in PC, whereas the underlying molecular mechanisms are not completely understood. Here, we studied the effects of low-dose Curcumin on PC cell growth. Curcumin (from 0.2 to 0.8 μmol/l) dose-dependently inhibited the proliferation of PC cells, without affecting cell apoptosis. Further analyses showed that Curcumin dose-dependently increased a cell cycle suppressor CDKN1A at protein levels, but not mRNA levels, in PC cells, suggesting that Curcumin may regulate the translation of CDKN1A, as well as a possible involvement of miRNA intervention. From all CDKN1A-3'-UTR-binding miRNAs, we found that miR-208 was specifically inhibited in PC cells dose-dependently by Curcumin. Moreover, miR-208 was found to bind CDKN1A to suppress its expression. In a loss-of-function experiment, PC cells that overexpressed miR-208 failed to decrease cell proliferation in response to Curcumin. Together, these data suggest that Curcumin inhibits growth of PC via miR-208-mediated CDKN1A activation.

Several clinical observations have demonstrated a link between heart rate and anxiety or panic disorders. In these patients, β-adrenergic receptor function was altered. This prompted us to investigate whether the β-adrenergic receptor agonist isoproterenol, at a dose that stimulates peripheral β-adrenergic system but has no effects at the central nervous system, can induce anxiety-like behavior in rats. Moreover, some possible messengers involved in the peripheral to brain communication were investigated. Our results showed that isoproterenol (5 mg kg(-1) i.p.) increased heart rate, evoked anxiety-like behavior, did not result in motor impairments and increased extracellular vesicle content in the blood. Plasma corticosterone level was unmodified as well as vesicular Hsp70 content. Vesicular miR-208 was also unmodified indicating a source of increased extracellular vesicles different from cardiomyocytes. We can hypothesize that peripheral extracellular vesicles might contribute to the β-adrenergic receptor-evoked anxiety-like behavior, acting as peripheral signals in modulating the mental state., (Copyright © 2015 Elsevier Inc. All rights reserved.)