Identification of Blood Let-7e-5p as a Biomarker for Ischemic Stroke

<div><p>Circulating microRNAs (miRNAs) are emerging as novel disease biomarkers. Using a miRNA microarray, we previously showed that the whole blood level of let-7e-5p was significantly higher in ischemic stroke patients than in control subjects. However, the association between let-7e-5p expression and the occurrence of ischemic stroke remains unknown. In this study, we validated the expression levels of let-7e-5p in two case-control populations using miRNA TaqMan assays and further investigated the potential targets of let-7e-5p. The results suggest that the blood level of let-7e-5p was significantly higher in patients with ischemic stroke than in controls (p<0.05). Higher levels of let-7e-5p were associated with increased occurrence of ischemic stroke (adjusted OR, 1.89; 95% CI, 1.61~2.21, p<0.001) in the combined population. The addition of let-7e-5p to traditional risk factors led to an improvement in the area under the curve, which increased from 0.74 (95% CI, 0.70~0.78) to 0.82 (95% CI, 0.78~0.85), with a net reclassification improvement of 16.76% (p<0.0001) and an integrated discrimination improvement of 0.10 (p<0.0001) for patients with ischemic stroke. Bioinformatics prediction and cell experiments suggested that the expression levels of four genes enriched in the MAPK signaling pathway were down-regulated by let-7e-5p transfection. Specifically, the expression levels of the genes CASP3 and NLK were significantly lower in ischemic stroke patients than in controls and were negatively correlated with let-7e-5p expression. In summary, our study suggests the potential use of blood let-7e-5p as a biomarker for ischemic stroke and indicates its involvement in the related pathomechanism.</p></div

Association of the expression level of let-7e-5p with ischemic stroke.

<p>Association of the expression level of let-7e-5p with ischemic stroke.</p

The expression levels of let-7e-5p in stage I and II populations.

<p>Let-7e-5p expression was detected in (A) stage I (n = 44 patients and controls) and (B) stage II (n = 302 patients and controls) population. The relative expression levels were normalized to U6 and then log-transformed. The whiskers of the plots represent the 2.5 to 97.5 percentiles.</p

Correlation analysis of let-7e-5p and gene expression.

<p>Correlation analysis of let-7e-5p and gene expression.</p

Correlations between let-7e-5p expression and platelet parameters.

<p>The correlation was evaluated by the Spearman test in the combined patient population.</p

The mRNA levels of the target genes in different cell groups.

<p>U937 cells were transfected with 50 nM control mimics (negative control) or 50 nM let-7e-5p mimics. The normal control is normal cultured cells. *p<0.05 compared to the negative control; **p<0.01 compared to the negative control.</p

AUC, NRI, and IDI calculations for let-7e-5p in the combined population.

<p>AUC, NRI, and IDI calculations for let-7e-5p in the combined population.</p

General characteristics of the study population.

<p>General characteristics of the study population.</p

The whole blood mRNA levels of the target genes in control subjects (n = 20) and ischemic stroke patients (n = 20).

<p>The relative expression levels were normalized to beta-actin. *p<0.05; **p<0.01.</p

The Dose–Response Decrease in Heart Rate Variability: Any Association with the Metabolites of Polycyclic Aromatic Hydrocarbons in Coke Oven Workers?

<div><h3>Background</h3><p>Air pollution has been associated with an increased risk of cardiopulmonary mortality and decreased heart rate variability (HRV). However, it is unclear whether coke oven emissions (COEs) and polycyclic aromatic hydrocarbons (PAHs) are associated with HRV.</p> <h3>Objectives</h3><p>Our goal in the present study was to investigate the association of exposure to COEs and the urinary metabolite profiles of PAHs with HRV of coke oven workers.</p> <h3>Methods</h3><p>We measured benzene soluble matter, carbon monoxide, sulfur dioxide, particulate matters, and PAHs at different workplaces of a coke oven plant. We determined 10 urinary PAH metabolites and HRV indices of 1333 workers using gas chromatography–mass spectrometry and a 3-channel digital Holter monitor, respectively.</p> <h3>Results</h3><p>Our results showed that there was a significant COEs-related dose-dependent decrease in HRV, and an inverse relationship between the quartiles of urinary 2-hydroxynaphthalene and five HRV indices (<em>p</em>_trend<0.01 for all). After adjustment for potential confounders, elevation per interquartile range (IQR) (1.81 µg/mmol creatinine) of urinary 2-hydroxynaphthalene was associated with a 5.46% (95% CI, 2.50–8.32) decrease in standard deviation of NN intervals (SDNN). As workers worked more years, SDNN gradually declined in the same quartiles of 2-hydroxynaphthalene levels (<em>p</em>_trend = 1.40×10⁻⁴), especially in workers with the highest levels of 2-hydroxynaphthalene.</p> <h3>Conclusions</h3><p>Occupational exposure to COEs is associated with a dose-response decrease in HRV. In particular, increased exposure to 2-hydroxynaphthalene is associated with significantly decreased HRV. Increase of working years and exposure levels has resulted in a gradual decline of HRV.</p> </div