Comparisons of serum miRNA expression profiles in patients with diabetic retinopathy and type 2 diabetes mellitus

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"identificador" => "c1-cln_72p111" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Shenzhen Nanshan Center for Chronic Disease Control, Department of Chronic Disease Prevention and Control, Shenzhen, 518054, China" "etiqueta" => "I" "identificador" => "af1-cln_72p111" ] 1 => array:3 [ "entidad" => "Ningbo Medical Center Lihuili Eastern Hospital, Department of Endocrinology, Ningbo 315040, China" "etiqueta" => "II" "identificador" => "af2-cln_72p111" ] 2 => array:3 [ "entidad" => "Ningbo University, School of Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo 315211, China" "etiqueta" => "III" "identificador" => "af3-cln_72p111" ] 3 => array:3 [ "entidad" => "Kunming Medical University, Department of Science and Technology, Kunming, 650500, China" "etiqueta" => "IV" "identificador" => "af4-cln_72p111" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig1-cln_72p111" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "cln-72-02-111-g001.jpeg" "Alto" => 370 "Ancho" => 777 "Tamanyo" => 28753 ] ] "descripcion" => array:1 [ "en" => "A-B: Comparison of miRNA expression levels (2-ΔΔCt) in the serum of DR patients (n=45) and controls (n=45). Expression levels of selected miRNAs were analyzed by qRT-PCR." ] ] ] "textoCompleto" => "INTRODUCTIONDiabetic retinopathy (DR) is a common microvascular complication of diabetes and the leading cause of legal blindness among people of working age in the Western world <a class="elsevierStyleCrossRef" href="#bib1">1</a>. Due to the increased lifespan of diabetic patients, the prevalence of DR will continue to increase as a result of the longer duration of diabetes. However, the molecular mechanisms underlying DR are not clearly understood. It has been reported that 28.8% of diabetic patients develop DR, whereas 22.2% of individuals with a history of diabetes do not develop DR regardless of glycemic exposure, indicating that genetic factors may play a role in the development of DR <a class="elsevierStyleCrossRef" href="#bib2">2</a>.MicroRNAs (miRNAs) are a class of highly conserved, endogenous RNA sequences that regulate the activity of target mRNAs and control gene expression at the post-transcriptional level <a class="elsevierStyleCrossRef" href="#bib3">3</a>. Dysregulated miRNA expression has been identified as a risk factor for hepatocellular carcinoma and ischemic stroke <a class="elsevierStyleCrossRef" href="#bib4">4</a>,<a class="elsevierStyleCrossRef" href="#bib5">5</a>, and studies have shown that miRNAs play a significant role in the development of diabetes and its associated complications <a class="elsevierStyleCrossRef" href="#bib6">6</a>. For example, circulating levels of miR-126-3p were found to be lower in patients with type 2 diabetes mellitus (T2DM) than in healthy controls <a class="elsevierStyleCrossRef" href="#bib7">7</a>, while circulating miR-146a levels were significantly elevated in newly diagnosed T2DM patients compared with healthy controls <a class="elsevierStyleCrossRef" href="#bib8">8</a>.To date, few studies have investigated the relationship between circulating miRNA levels and the development of DR <a class="elsevierStyleCrossRef" href="#bib9">9</a>, with most studies focusing on diabetic rat models or endothelial cells cultured in high-glucose conditions <a class="elsevierStyleCrossRef" href="#bib10">10</a>. Circulating miRNA levels can be used for the early prediction of DR with high sensitivity and specificity <a class="elsevierStyleCrossRef" href="#bib11">11</a>, and aberrant circulating miRNA levels may represent a novel non-invasive biomarker for the early detection of DR <a class="elsevierStyleCrossRef" href="#bib12">12</a>. Therefore, the aim of this study was to compare the circulating miRNA profiles of DR cases and matched T2DM controls.MATERIALS AND METHODSStudy subjectsThe subjects were identified by community health service centers (CHSCs) under supervision of the Shenzhen Nanshan Center for Chronic Disease Control in the Nanshan district. All of the subjects provided informed consent, and the study was approved by the Ethical Committee of the Shenzhen Nanshan Center for Chronic Disease Control (2011001). All of the subjects underwent fundus fluorescein angiography, which was completed by certified ophthalmologists. The cases were T2DM patients with DR, and the controls were T2DM patients without DR. T2DM was diagnosed according to the 2010 guidelines from the American Diabetes Association <a class="elsevierStyleCrossRef" href="#bib13">13</a>. Subjects with acute or chronic inflammatory disease, type 1 diabetes, maturity-onset diabetes of the young, or mitochondrial diabetes were excluded.Additionally, age, sex, BMI (body mass index), and family history of diabetes were recorded. All of the subjects underwent a general physical examination. Peripheral blood samples were collected following a 12-hour fast, and glycosylated hemoglobin (HbA1c), low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), and triglyceride (TG) levels were estimated. TC, LDL, HDL and TG were measured using standard enzymatic methods and a HITACHI 7080 automatic biochemical analyzer. BMI was calculated as [weight (kg)/ height (m)2].miRNA microarraysThe RNA samples from the 5 DR cases and 5 T2DM controls were analyzed using a μParaflo™ MicroRNA microarray assay. Fluorescence images were collected using a laser scanner (GenePix 4000B, Molecular Devices) and digitized using Array-Pro image analysis software (Media Cybernetics, Washington, USA) (<a class="elsevierStyleCrossRef" href="#fig2-cln_72p111">Figure 2</a>). The data were analyzed by first subtracting the background and then normalizing the signals using a LOWESS filter (Locally Weighted Regression). The results were then filtered according to the following criteria: ① p-value<0.05; ② at least a two-fold (|log2|>1) difference between the samples (groups), with an ideal difference ≥4 (|log2| ≥2); and ③ two groups present in the sample and a strong hybridization signal (average value≥2000). The two identified miRNAs and their target sequences (5′ to 3′) are shown in <a class="elsevierStyleCrossRef" href="#t1-cln_72p111">Table 1</a>.<elsevierMultimedia ident="fig2-cln_72p111"></elsevierMultimedia><elsevierMultimedia ident="t1-cln_72p111"></elsevierMultimedia>RNA extractionThe serum (400 μL) isolated from each sample was centrifuged at 6,000 g and at 4°C for 15 min prior to RNA extraction. miRNA was isolated from 45 DR and 45 matched T2DM serum samples using QIAzol Lysis Reagent (Qiagen, Hilden, Germany) as part of the miRNeasy Serum/Plasma Kit (Qiagen). Then, 3.5 μl of synthetic miRNA-39 from Caenorhabditis elegans (cel-microRNA-39) was added to the extracted miRNA as a spike-in control (1.6 x 108 copies/μl working solution) before the samples were reverse transcribed to complementary DNA. RNA concentration and purity were determined using an Agilent 2100 Bioanalyzer and RNA 6000 Nano/Pico LabChip (Agilent Technologies, Boeblingen, Germany).Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR)Total RNA extracted from the isolated serum was initially reverse transcribed using a miScript® II RT Kit (Qiagen, Germany) according to the manufacturer's instructions. Each reverse transcription (RT) reaction contained 1 µl of miScript Reverse Transcriptase Mix, 4 µl of 5x miScript RT Buffer, 13 µl of RNase-free water and 2 µl of RNA template. The 20 µl RT reaction was incubated at 37°C for 1 hour followed by 5 min at 95°C using an iCycler system (Bio-Rad, Hercules, CA). The cDNA was diluted 10-fold before being added to each quantitative polymerase chain reaction (qPCR), with the spiked-in cel-miR-39 serving as the external control for normalization. To improve quantification accuracy, each sample was analyzed in triplicate, and both the melting curve and amplification plot analyses were used to confirm the specificity of the reactions. Each 12.5 µl quantitative real-time PCR reaction contained 6.2 µl of SYBR Green PCR Master Mix, 1.2 µl of miScript universal primer, 1.2 µl of specific primer, 2 µl of cDNA and 1.9 µl of RNase-free water. The amplification protocol consisted of an initial activation step at 95°C for 15 min, followed by 40 cycles of 94°C for 15 s, 55°C for 30 s, and 70°C for 30 s, and was carried out on the Mx3005P qPCR system (Stratagene, USA). The levels of circulating miR-3939 (Hs_miR-3939 miScript Primer Assay, MS00023688 Qiagen, Germany) and miR-1910-3p (Hs_miR-1910-3p miScript Primer Assay, MS00016464 Qiagen, Germany) were analyzed quantitatively using the 2-ΔΔCt (cycle threshold) method after normalization to the cel-microRNA-39 control <a class="elsevierStyleCrossRef" href="#bib14">14</a>.Statistical analysisQuantitative data are expressed as the mean±standard deviation, while threshold cycle (Ct) values were determined using the melting curve analysis to measure the expression of target miRNAs. Triplicate Ct values were averaged, and the relative expression level of each miRNA was calculated using the comparative threshold cycle (Ct) method (2-ΔΔCt). All of the miRNA values are expressed as the mean±SD. A paired t-test was used to evaluate differences in serum miRNA levels between the two groups. Differences were considered statistically significant at p<0.05. The statistical analysis was performed using SPSS Statistics Version 18 (SPSS Inc., Chicago, USA) and GraphPad Prism 5 (GraphPad Software, Inc., La Jolla, CA, USA).RESULTSCharacteristics of the included subjectsThe demographic characteristics of the study subjects are presented in <a class="elsevierStyleCrossRef" href="#t2-cln_72p111">Table 2</a>. A total of 45 DR cases and 45 T2DM controls (matched by age, sex, BMI and duration of diabetes) were included in the validation stage. There were no significant differences in family history of diabetes or in levels of TC, HDL, LDL, TG or HbA1c between the two groups.<elsevierMultimedia ident="t2-cln_72p111"></elsevierMultimedia>Comprehensive miRNA profiling and qRT-PCR validationTo identify a DR-specific serum miRNA expression profile, the μParaflo™ MicroRNA microarray assay was used to screen for miRNAs that were differentially expressed in 5 DR cases and 5 T2DM controls. Two miRNAs (miR-3939 and miR-1910-3p) were higher in DR patients than in T2DM patients, with |log2| values of 8.58 and 8.59, respectively (<a class="elsevierStyleCrossRef" href="#t1-cln_72p111">Table 1</a>). We further validated these 2 serum miRNAs in 45 DR cases and 45 matched T2DM controls using RT-qPCR; however, no statistically significant difference was found (<a class="elsevierStyleCrossRef" href="#fig1-cln_72p111">Figure 1A-B</a>).<elsevierMultimedia ident="fig1-cln_72p111"></elsevierMultimedia>DISCUSSIONAlthough miR-3939 and miR-1910-3p appeared to be differentially expressed in the screening stage, qRT-PCR did not confirm these results. Consistent with our findings, Zampetaki et al. did not find a significant association between plasma miR-146a levels and T2DM <a class="elsevierStyleCrossRef" href="#bib15">15</a>. However, a double-blind, parallel design, placebo-controlled randomized clinical trial found that serum miR-27b and miR-320a levels were independently associated with DR susceptibility in patients with type 1 diabetes <a class="elsevierStyleCrossRef" href="#bib16">16</a>. Additionally, Pescador et al. <a class="elsevierStyleCrossRef" href="#bib17">17</a> identified serum miR-15b, miR-138 and miR-376a as potential predictive biomarkers for obesity and T2DM. Moreover, Zhang et al. <a class="elsevierStyleCrossRef" href="#bib18">18</a> showed that plasma miR-126 levels were a potential biomarker for the early prediction of T2DM susceptibility. These contradictory results may be due to differences in study design, sample collection, sample size, participant ethnicities and detection methods.Importantly, the biological role of miRNAs in the development of DR should be noted. McArthur et al. <a class="elsevierStyleCrossRef" href="#bib19">19</a> found that miR-200b regulates vascular endothelial growth factor (VEGF)-mediated abnormalities in cultured ECs and streptozotocin (STZ)-induced diabetic rats. Zhuang et al. <a class="elsevierStyleCrossRef" href="#bib20">20</a> revealed that the downregulation of miR-155 attenuates retinal neovascularization via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, while Chen et al. <a class="elsevierStyleCrossRef" href="#bib21">21</a> suggested that miR-410 inhibits oxygen-induced retinal neovascularization by suppressing VEGF expression. Additionally, Xiong et al. <a class="elsevierStyleCrossRef" href="#bib22">22</a> determined that 17 miRNAs were dysregulated in the retinas of diabetic Sprague–Dawley rats, suggesting that miRNAs play a significant role in the progression of DR. Moreover, in high-glucose conditions, miR-152 represses VEGF and TGFβ1 expression in human retinal endothelial cells through post-transcriptional inhibition of the (pro)renin receptor <a class="elsevierStyleCrossRef" href="#bib23">23</a>. These studies suggest that miRNAs play a substantial role in the pathogenesis of DR.Kong et al. reported that 7 serum miRNAs (miR-9, miR-29a, miR-30d, miR-34a, miR-124a, miR-146a and miR-375) were elevated in T2DM subjects compared to healthy controls <a class="elsevierStyleCrossRef" href="#bib24">24</a>, while Qing et al. <a class="elsevierStyleCrossRef" href="#bib25">25</a> revealed that serum miR-21, miR-181c and miR-1179 levels could be sensitive and cost-effective biomarkers for the early detection of proliferative DR (PDR). Thus, further investigation into the circulating levels of miRNAs in samples obtained from patients with different stage disease is warranted <a class="elsevierStyleCrossRef" href="#bib10">10</a>.Interestingly, Liu et al. <a class="elsevierStyleCrossRef" href="#bib26">26</a> identified serum miR-126 as a biomarker for pre-diabetes and T2DM and found that six months of treatment (diet control and exercise in subjects with prediabetes or insulin plus diet control and exercise in T2DM patients) significantly increased miR-126 levels, indicating that therapeutic treatments have a significant effect on circulating miRNA levels. However, the plasma levels of 13 miRNAs (miR-15a, miR-20b, miR-21, miR-24, miR-126, miR-191, miR-197, miR-223, miR-28-3p, miR-150, miR-29b, miR-320 and miR-486) in T2DM subjects were similar before and after drug treatment (mainly sulfonylureas) <a class="elsevierStyleCrossRef" href="#bib15">15</a>. Further studies exploring the effects of therapeutic treatments on circulating miRNA expression levels are recommended. One limitation of the present study was the relatively small sample size. Another limitation was that the use of anti-diabetic medications was not analyzed, and pharmacological treatments may influence the expression of circulating miRNAs.In conclusion, although the serum levels of miR-3939 and miR-1910-3p differed significantly between DR cases and T2DM controls in the screening stage, these results were not validated in the validation stage. Therefore, the above two circulating miRNAs may not play important roles in the development of DR. Further research is required to determine whether the analysis of circulating miRNA levels holds predictive value for the early detection of DR, and prospective studies investigating the biological mechanisms and effects of different therapeutic treatments should be encouraged.AUTHOR CONTRIBUTIONSYou D and Han L conceived and designed the study and had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Ma J, Wang J, Liu Y, Wang C, Duan D and Lu N were responsible for the data acquisition. Wang K, Zhang L, Gu K, Chen S and Zhang T were responsible for the data analysis and interpretation. Ma J, Wang C, Wang J and Liu Y were responsible for the manuscript drafting. You D and Han L were responsible for the critical revision of the manuscript for important intellectual content. Ma J, Wang C, Wang J and Liu Y were responsible for the statistical analysis. You D and Han L supervised the study." "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "xpalclavsec1580231" "titulo" => "KEYWORDS" ] 1 => array:2 [ "identificador" => "cesec10" "titulo" => "INTRODUCTION" ] 2 => array:3 [ "identificador" => "cesec20" "titulo" => "MATERIALS AND METHODS" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "cesec30" "titulo" => "Study subjects" ] 1 => array:2 [ "identificador" => "cesec40" "titulo" => "miRNA microarrays" ] 2 => array:2 [ "identificador" => "cesec50" "titulo" => "RNA extraction" ] 3 => array:2 [ "identificador" => "cesec60" "titulo" => "Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR)" ] 4 => array:2 [ "identificador" => "cesec70" "titulo" => "Statistical analysis" ] ] ] 3 => array:3 [ "identificador" => "cesec80" "titulo" => "RESULTS" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "cesec90" "titulo" => "Characteristics of the included subjects" ] 1 => array:2 [ "identificador" => "cesec100" "titulo" => "Comprehensive miRNA profiling and qRT-PCR validation" ] ] ] 4 => array:2 [ "identificador" => "cesec110" "titulo" => "DISCUSSION" ] 5 => array:2 [ "identificador" => "cesec120" "titulo" => "AUTHOR CONTRIBUTIONS" ] 6 => array:2 [ "identificador" => "xack638188" "titulo" => "ACKNOWLEDGMENTS" ] 7 => array:1 [ "titulo" => "REFERENCES" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-09-13" "fechaAceptado" => "2016-12-15" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "KEYWORDS" "identificador" => "xpalclavsec1580231" "palabras" => array:3 [ 0 => "Type 2 diabetes mellitus" 1 => "Diabetic retinopathy" 2 => "Serum miRNAs" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "resumen" => "OBJECTIVES:The aim of this study was to compare the expression levels of serum miRNAs in diabetic retinopathy and type 2 diabetes mellitus. METHODS:Serum miRNA expression profiles from diabetic retinopathy cases (type 2 diabetes mellitus patients with diabetic retinopathy) and type 2 diabetes mellitus controls (type 2 diabetes mellitus patients without diabetic retinopathy) were examined by miRNA-specific microarray analysis. Quantitative real-time polymerase chain reaction was used to validate the significantly differentially expressed serum miRNAs from the microarray analysis of 45 diabetic retinopathy cases and 45 age-, sex-, body mass index- and duration-of-diabetes-matched type 2 diabetes mellitus controls. The relative changes in serum miRNA expression levels were analyzed using the 2-ΔΔCt method. RESULTS:A total of 5 diabetic retinopathy cases and 5 type 2 diabetes mellitus controls were included in the miRNA-specific microarray analysis. The serum levels of miR-3939 and miR-1910-3p differed significantly between the two groups in the screening stage; however, quantitative real-time polymerase chain reaction did not reveal significant differences in miRNA expression for 45 diabetic retinopathy cases and their matched type 2 diabetes mellitus controls. CONCLUSION:Our findings indicate that miR-3939 and miR-1910-3p may not play important roles in the development of diabetic retinopathy; however, studies with a larger sample size are needed to confirm our findings." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "ceabs10" "titulo" => "OBJECTIVES:" ] 1 => array:2 [ "identificador" => "ceabs20" "titulo" => "METHODS:" ] 2 => array:2 [ "identificador" => "ceabs30" "titulo" => "RESULTS:" ] 3 => array:2 [ "identificador" => "ceabs40" "titulo" => "CONCLUSION:" ] ] ] ] "NotaPie" => array:1 [ 0 => array:1 [ "nota" => "No potential conflict of interest was reported." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig1-cln_72p111" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "cln-72-02-111-g001.jpeg" "Alto" => 370 "Ancho" => 777 "Tamanyo" => 28753 ] ] "descripcion" => array:1 [ "en" => "A-B: Comparison of miRNA expression levels (2-ΔΔCt) in the serum of DR patients (n=45) and controls (n=45). Expression levels of selected miRNAs were analyzed by qRT-PCR." ] ] 1 => array:7 [ "identificador" => "fig2-cln_72p111" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "cln-72-02-111-g002.jpeg" "Alto" => 2122 "Ancho" => 760 "Tamanyo" => 274678 ] ] "descripcion" => array:1 [ "en" => "Chip cluster analysis for analyzing the differential expression of miRNAs between DR cases and T2DM controls." ] ] 2 => array:7 [ "identificador" => "t1-cln_72p111" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "SD: standard deviation; log2: the difference between the groups (DR/T2DM), which should be larger than 2; Target Sequence: the miRNA sequence." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">T2DM</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">DR</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Assay \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Mean \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">SD \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Mean \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">SD \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">p-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">|log2| \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Target Sequence (5′ to 3′) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">hsa-miR-3939 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">876 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">812 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">UACGCGCAGACCA CAGGAUGUC \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">hsa-miR-1910-3p \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">697 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">788 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.09 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GAGGCAGAAGC AGGAUGACA \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Differential expression of serum miRNAs based on the miRNA expression microarray." ] ] 3 => array:7 [ "identificador" => "t2-cln_72p111" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">DR (n=45) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">T2D (n=45) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">p \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66.24±8.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65.42±7.96 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.606 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMI (kg/m2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24.48±3.71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23.9±3.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.293 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Duration of diabetes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16.78±7.42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15.96±9.50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.638 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TC (mmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.50±0.84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.63±1.81 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.52 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HDL (mmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.22±0.39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.15±0.31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.347 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LDL (mmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.97±0.96 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.64±0.67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.54 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TG (mmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.50±1.23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.43±1.05 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.925 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HbA1c \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.63±2.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.62±1.68 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.157 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical characteristics of the included DR cases and T2DM controls." ] ] ] "bibliografia" => array:2 [ "titulo" => "REFERENCES" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec10" "bibliografiaReferencia" => array:26 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetic retinopathy: global prevalence, major risk factors, screening practices and public health challenges: a review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ DS Ting \n \t\t\t\t\t\t\t\t """ 1 => """ GC Cheung \n \t\t\t\t\t\t\t\t """ 2 => """ TY Wong \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1111/ceo.12696" "Revista" => array:7 [ "tituloSerie" => "Clin Exp Ophthalmol" "fecha" => "2016" 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C. Wong Magna Fund in Ningbo University; the Ministry of Education, Humanities and Social Sciences (14YJC630046); and the China Postdoctoral Science Foundation (156458)." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/18075932/0000007200000002/v1_202211290931/S1807593222010067/v1_202211290931/en/main.assets" "Apartado" => null "PDF" => "https://static.elsevier.es/multimedia/18075932/0000007200000002/v1_202211290931/S1807593222010067/v1_202211290931/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222010067?idApp=UINPBA00004N"]

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CLINICAL SCIENCE

Jianping MaI,#, Jufang WangII,#, Yanfen LiuIII,#, Changyi WangI,#, Donghui DuanIII, Nanjia LuIII, Kaiyue WangIII, Lu ZhangIII, Kaibo GuIII, Sihan ChenI, Tao ZhangI, Dingyun YouIV,

, Liyuan HanIII,

I Shenzhen Nanshan Center for Chronic Disease Control, Department of Chronic Disease Prevention and Control, Shenzhen, 518054, China

II Ningbo Medical Center Lihuili Eastern Hospital, Department of Endocrinology, Ningbo 315040, China

III Ningbo University, School of Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo 315211, China

IV Kunming Medical University, Department of Science and Technology, Kunming, 650500, China

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Diabetic retinopathy &#40;DR&#41; is a common microvascular complication of diabetes and the leading cause of legal blindness among people of working age in the Western world <a class="elsevierStyleCrossRef" href="#bib1">1</a>&#46; Due to the increased lifespan of diabetic patients&#44; the prevalence of DR will continue to increase as a result of the longer duration of diabetes&#46; However&#44; the molecular mechanisms underlying DR are not clearly understood&#46; It has been reported that 28&#46;8&#37; of diabetic patients develop DR&#44; whereas 22&#46;2&#37; of individuals with a history of diabetes do not develop DR regardless of glycemic exposure&#44; indicating that genetic factors may play a role in the development of DR <a class="elsevierStyleCrossRef" href="#bib2">2</a>&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">MicroRNAs &#40;miRNAs&#41; are a class of highly conserved&#44; endogenous RNA sequences that regulate the activity of target mRNAs and control gene expression at the post-transcriptional level <a class="elsevierStyleCrossRef" href="#bib3">3</a>&#46; Dysregulated miRNA expression has been identified as a risk factor for hepatocellular carcinoma and ischemic stroke <a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#44; and studies have shown that miRNAs play a significant role in the development of diabetes and its associated complications <a class="elsevierStyleCrossRef" href="#bib6">6</a>&#46; For example&#44; circulating levels of miR-126-3p were found to be lower in patients with type 2 diabetes mellitus &#40;T2DM&#41; than in healthy controls <a class="elsevierStyleCrossRef" href="#bib7">7</a>&#44; while circulating miR-146a levels were significantly elevated in newly diagnosed T2DM patients compared with healthy controls <a class="elsevierStyleCrossRef" href="#bib8">8</a>&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">To date&#44; few studies have investigated the relationship between circulating miRNA levels and the development of DR <a class="elsevierStyleCrossRef" href="#bib9">9</a>&#44; with most studies focusing on diabetic rat models or endothelial cells cultured in high-glucose conditions <a class="elsevierStyleCrossRef" href="#bib10">10</a>&#46; Circulating miRNA levels can be used for the early prediction of DR with high sensitivity and specificity <a class="elsevierStyleCrossRef" href="#bib11">11</a>&#44; and aberrant circulating miRNA levels may represent a novel non-invasive biomarker for the early detection of DR <a class="elsevierStyleCrossRef" href="#bib12">12</a>&#46; Therefore&#44; the aim of this study was to compare the circulating miRNA profiles of DR cases and matched T2DM controls&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">MATERIALS AND METHODS</span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">Study subjects</span><p id="para40" class="elsevierStylePara elsevierViewall">The subjects were identified by community health service centers &#40;CHSCs&#41; under supervision of the Shenzhen Nanshan Center for Chronic Disease Control in the Nanshan district&#46; All of the subjects provided informed consent&#44; and the study was approved by the Ethical Committee of the Shenzhen Nanshan Center for Chronic Disease Control &#40;2011001&#41;&#46; All of the subjects underwent fundus fluorescein angiography&#44; which was completed by certified ophthalmologists&#46; The cases were T2DM patients with DR&#44; and the controls were T2DM patients without DR&#46; T2DM was diagnosed according to the 2010 guidelines from the American Diabetes Association <a class="elsevierStyleCrossRef" href="#bib13">13</a>&#46; Subjects with acute or chronic inflammatory disease&#44; type 1 diabetes&#44; maturity-onset diabetes of the young&#44; or mitochondrial diabetes were excluded&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">Additionally&#44; age&#44; sex&#44; BMI &#40;body mass index&#41;&#44; and family history of diabetes were recorded&#46; All of the subjects underwent a general physical examination&#46; Peripheral blood samples were collected following a 12-hour fast&#44; and glycosylated hemoglobin &#40;HbA1c&#41;&#44; low-density lipoprotein &#40;LDL&#41;&#44; high-density lipoprotein &#40;HDL&#41;&#44; total cholesterol &#40;TC&#41;&#44; and triglyceride &#40;TG&#41; levels were estimated&#46; TC&#44; LDL&#44; HDL and TG were measured using standard enzymatic methods and a HITACHI 7080 automatic biochemical analyzer&#46; BMI was calculated as &#91;weight &#40;kg&#41;&#47; height &#40;m&#41;<span class="elsevierStyleSup">2</span>&#93;&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">miRNA microarrays</span><p id="para60" class="elsevierStylePara elsevierViewall">The RNA samples from the 5 DR cases and 5 T2DM controls were analyzed using a &#956;Paraflo&#8482; MicroRNA microarray assay&#46; Fluorescence images were collected using a laser scanner &#40;GenePix 4000B&#44; Molecular Devices&#41; and digitized using Array-Pro image analysis software &#40;Media Cybernetics&#44; Washington&#44; USA&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig2-cln_72p111">Figure 2</a>&#41;&#46; The data were analyzed by first subtracting the background and then normalizing the signals using a LOWESS filter &#40;Locally Weighted Regression&#41;&#46; The results were then filtered according to the following criteria&#58; &#9312; <span class="elsevierStyleItalic">p</span>-value&#60;0&#46;05&#59; &#9313; at least a two-fold &#40;&#124;log2&#124;&#62;1&#41; difference between the samples &#40;groups&#41;&#44; with an ideal difference &#8805;4 &#40;&#124;log2&#124; &#8805;2&#41;&#59; and &#9314; two groups present in the sample and a strong hybridization signal &#40;average value&#8805;2000&#41;&#46; The two identified miRNAs and their target sequences &#40;5&#8242; to 3&#8242;&#41; are shown in <a class="elsevierStyleCrossRef" href="#t1-cln_72p111">Table 1</a>&#46;</p><elsevierMultimedia ident="fig2-cln_72p111"></elsevierMultimedia><elsevierMultimedia ident="t1-cln_72p111"></elsevierMultimedia></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">RNA extraction</span><p id="para70" class="elsevierStylePara elsevierViewall">The serum &#40;400 &#956;L&#41; isolated from each sample was centrifuged at 6&#44;000 g and at 4&#176;C for 15 min prior to RNA extraction&#46; miRNA was isolated from 45 DR and 45 matched T2DM serum samples using QIAzol Lysis Reagent &#40;Qiagen&#44; Hilden&#44; Germany&#41; as part of the miRNeasy Serum&#47;Plasma Kit &#40;Qiagen&#41;&#46; Then&#44; 3&#46;5 &#956;l of synthetic miRNA-39 from <span class="elsevierStyleItalic">Caenorhabditis elegans</span> &#40;cel-microRNA-39&#41; was added to the extracted miRNA as a spike-in control &#40;1&#46;6 x 10<span class="elsevierStyleSup">8</span> copies&#47;&#956;l working solution&#41; before the samples were reverse transcribed to complementary DNA&#46; RNA concentration and purity were determined using an Agilent 2100 Bioanalyzer and RNA 6000 Nano&#47;Pico LabChip &#40;Agilent Technologies&#44; Boeblingen&#44; Germany&#41;&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Quantitative Real-Time Polymerase Chain Reaction &#40;qRT-PCR&#41;</span><p id="para80" class="elsevierStylePara elsevierViewall">Total RNA extracted from the isolated serum was initially reverse transcribed using a miScript&#174; II RT Kit &#40;Qiagen&#44; Germany&#41; according to the manufacturer&#39;s instructions&#46; Each reverse transcription &#40;RT&#41; reaction contained 1 &#181;l of miScript Reverse Transcriptase Mix&#44; 4 &#181;l of 5x miScript RT Buffer&#44; 13 &#181;l of RNase-free water and 2 &#181;l of RNA template&#46; The 20 &#181;l RT reaction was incubated at 37&#176;C for 1 hour followed by 5 min at 95&#176;C using an iCycler system &#40;Bio-Rad&#44; Hercules&#44; CA&#41;&#46; The cDNA was diluted 10-fold before being added to each quantitative polymerase chain reaction &#40;qPCR&#41;&#44; with the spiked-in cel-miR-39 serving as the external control for normalization&#46; To improve quantification accuracy&#44; each sample was analyzed in triplicate&#44; and both the melting curve and amplification plot analyses were used to confirm the specificity of the reactions&#46; Each 12&#46;5 &#181;l quantitative real-time PCR reaction contained 6&#46;2 &#181;l of SYBR Green PCR Master Mix&#44; 1&#46;2 &#181;l of miScript universal primer&#44; 1&#46;2 &#181;l of specific primer&#44; 2 &#181;l of cDNA and 1&#46;9 &#181;l of RNase-free water&#46; The amplification protocol consisted of an initial activation step at 95&#176;C for 15 min&#44; followed by 40 cycles of 94&#176;C for 15 s&#44; 55&#176;C for 30 s&#44; and 70&#176;C for 30 s&#44; and was carried out on the Mx3005P qPCR system &#40;Stratagene&#44; USA&#41;&#46; The levels of circulating miR-3939 &#40;Hs&#95;miR-3939 miScript Primer Assay&#44; MS00023688 Qiagen&#44; Germany&#41; and miR-1910-3p &#40;Hs&#95;miR-1910-3p miScript Primer Assay&#44; MS00016464 Qiagen&#44; Germany&#41; were analyzed quantitatively using the 2<span class="elsevierStyleSup">-&#916;&#916;Ct</span> &#40;cycle threshold&#41; method after normalization to the cel-microRNA-39 control <a class="elsevierStyleCrossRef" href="#bib14">14</a>&#46;</p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Statistical analysis</span><p id="para90" class="elsevierStylePara elsevierViewall">Quantitative data are expressed as the mean&#177;standard deviation&#44; while threshold cycle &#40;Ct&#41; values were determined using the melting curve analysis to measure the expression of target miRNAs&#46; Triplicate Ct values were averaged&#44; and the relative expression level of each miRNA was calculated using the comparative threshold cycle &#40;Ct&#41; method &#40;2<span class="elsevierStyleSup">-&#916;&#916;Ct</span>&#41;&#46; All of the miRNA values are expressed as the mean&#177;SD&#46; A paired t-test was used to evaluate differences in serum miRNA levels between the two groups&#46; Differences were considered statistically significant at <span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#46; The statistical analysis was performed using SPSS Statistics Version 18 &#40;SPSS Inc&#46;&#44; Chicago&#44; USA&#41; and GraphPad Prism 5 &#40;GraphPad Software&#44; Inc&#46;&#44; La Jolla&#44; CA&#44; USA&#41;&#46;</p></span></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">RESULTS</span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Characteristics of the included subjects</span><p id="para100" class="elsevierStylePara elsevierViewall">The demographic characteristics of the study subjects are presented in <a class="elsevierStyleCrossRef" href="#t2-cln_72p111">Table 2</a>&#46; A total of 45 DR cases and 45 T2DM controls &#40;matched by age&#44; sex&#44; BMI and duration of diabetes&#41; were included in the validation stage&#46; There were no significant differences in family history of diabetes or in levels of TC&#44; HDL&#44; LDL&#44; TG or HbA1c between the two groups&#46;</p><elsevierMultimedia ident="t2-cln_72p111"></elsevierMultimedia></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">Comprehensive miRNA profiling and qRT-PCR validation</span><p id="para110" class="elsevierStylePara elsevierViewall">To identify a DR-specific serum miRNA expression profile&#44; the &#956;Paraflo&#8482; MicroRNA microarray assay was used to screen for miRNAs that were differentially expressed in 5 DR cases and 5 T2DM controls&#46; Two miRNAs &#40;miR-3939 and miR-1910-3p&#41; were higher in DR patients than in T2DM patients&#44; with &#124;log2&#124; values of 8&#46;58 and 8&#46;59&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#t1-cln_72p111">Table 1</a>&#41;&#46; We further validated these 2 serum miRNAs in 45 DR cases and 45 matched T2DM controls using RT-qPCR&#59; however&#44; no statistically significant difference was found &#40;<a class="elsevierStyleCrossRef" href="#fig1-cln_72p111">Figure 1A-B</a>&#41;&#46;</p><elsevierMultimedia ident="fig1-cln_72p111"></elsevierMultimedia></span></span><span id="cesec110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">DISCUSSION</span><p id="para120" class="elsevierStylePara elsevierViewall">Although miR-3939 and miR-1910-3p appeared to be differentially expressed in the screening stage&#44; qRT-PCR did not confirm these results&#46; Consistent with our findings&#44; Zampetaki et al&#46; did not find a significant association between plasma miR-146a levels and T2DM <a class="elsevierStyleCrossRef" href="#bib15">15</a>&#46; However&#44; a double-blind&#44; parallel design&#44; placebo-controlled randomized clinical trial found that serum miR-27b and miR-320a levels were independently associated with DR susceptibility in patients with type 1 diabetes <a class="elsevierStyleCrossRef" href="#bib16">16</a>&#46; Additionally&#44; Pescador et al&#46; <a class="elsevierStyleCrossRef" href="#bib17">17</a> identified serum miR-15b&#44; miR-138 and miR-376a as potential predictive biomarkers for obesity and T2DM&#46; Moreover&#44; Zhang et al&#46; <a class="elsevierStyleCrossRef" href="#bib18">18</a> showed that plasma miR-126 levels were a potential biomarker for the early prediction of T2DM susceptibility&#46; These contradictory results may be due to differences in study design&#44; sample collection&#44; sample size&#44; participant ethnicities and detection methods&#46;</p><p id="para130" class="elsevierStylePara elsevierViewall">Importantly&#44; the biological role of miRNAs in the development of DR should be noted&#46; McArthur et al&#46; <a class="elsevierStyleCrossRef" href="#bib19">19</a> found that miR-200b regulates vascular endothelial growth factor &#40;VEGF&#41;-mediated abnormalities in cultured ECs and streptozotocin &#40;STZ&#41;-induced diabetic rats&#46; Zhuang et al&#46; <a class="elsevierStyleCrossRef" href="#bib20">20</a> revealed that the downregulation of miR-155 attenuates retinal neovascularization via the phosphatidylinositol 3-kinase &#40;PI3K&#41;&#47;Akt pathway&#44; while Chen et al&#46; <a class="elsevierStyleCrossRef" href="#bib21">21</a> suggested that miR-410 inhibits oxygen-induced retinal neovascularization by suppressing VEGF expression&#46; Additionally&#44; Xiong et al&#46; <a class="elsevierStyleCrossRef" href="#bib22">22</a> determined that 17 miRNAs were dysregulated in the retinas of diabetic Sprague&#8211;Dawley rats&#44; suggesting that miRNAs play a significant role in the progression of DR&#46; Moreover&#44; in high-glucose conditions&#44; miR-152 represses VEGF and TGF&#946;1 expression in human retinal endothelial cells through post-transcriptional inhibition of the &#40;pro&#41;renin receptor <a class="elsevierStyleCrossRef" href="#bib23">23</a>&#46; These studies suggest that miRNAs play a substantial role in the pathogenesis of DR&#46;</p><p id="para140" class="elsevierStylePara elsevierViewall">Kong et al&#46; reported that 7 serum miRNAs &#40;miR-9&#44; miR-29a&#44; miR-30d&#44; miR-34a&#44; miR-124a&#44; miR-146a and miR-375&#41; were elevated in T2DM subjects compared to healthy controls <a class="elsevierStyleCrossRef" href="#bib24">24</a>&#44; while Qing et al&#46; <a class="elsevierStyleCrossRef" href="#bib25">25</a> revealed that serum miR-21&#44; miR-181c and miR-1179 levels could be sensitive and cost-effective biomarkers for the early detection of proliferative DR &#40;PDR&#41;&#46; Thus&#44; further investigation into the circulating levels of miRNAs in samples obtained from patients with different stage disease is warranted <a class="elsevierStyleCrossRef" href="#bib10">10</a>&#46;</p><p id="para150" class="elsevierStylePara elsevierViewall">Interestingly&#44; Liu et al&#46; <a class="elsevierStyleCrossRef" href="#bib26">26</a> identified serum miR-126 as a biomarker for pre-diabetes and T2DM and found that six months of treatment &#40;diet control and exercise in subjects with prediabetes or insulin plus diet control and exercise in T2DM patients&#41; significantly increased miR-126 levels&#44; indicating that therapeutic treatments have a significant effect on circulating miRNA levels&#46; However&#44; the plasma levels of 13 miRNAs &#40;miR-15a&#44; miR-20b&#44; miR-21&#44; miR-24&#44; miR-126&#44; miR-191&#44; miR-197&#44; miR-223&#44; miR-28-3p&#44; miR-150&#44; miR-29b&#44; miR-320 and miR-486&#41; in T2DM subjects were similar before and after drug treatment &#40;mainly sulfonylureas&#41; <a class="elsevierStyleCrossRef" href="#bib15">15</a>&#46; Further studies exploring the effects of therapeutic treatments on circulating miRNA expression levels are recommended&#46; One limitation of the present study was the relatively small sample size&#46; Another limitation was that the use of anti-diabetic medications was not analyzed&#44; and pharmacological treatments may influence the expression of circulating miRNAs&#46;</p><p id="para160" class="elsevierStylePara elsevierViewall">In conclusion&#44; although the serum levels of miR-3939 and miR-1910-3p differed significantly between DR cases and T2DM controls in the screening stage&#44; these results were not validated in the validation stage&#46; Therefore&#44; the above two circulating miRNAs may not play important roles in the development of DR&#46; Further research is required to determine whether the analysis of circulating miRNA levels holds predictive value for the early detection of DR&#44; and prospective studies investigating the biological mechanisms and effects of different therapeutic treatments should be encouraged&#46;</p></span><span id="cesec120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle160">AUTHOR CONTRIBUTIONS</span><p id="para170" class="elsevierStylePara elsevierViewall">You D and Han L conceived and designed the study and had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis&#46; Ma J&#44; Wang J&#44; Liu Y&#44; Wang C&#44; Duan D and Lu N were responsible for the data acquisition&#46; Wang K&#44; Zhang L&#44; Gu K&#44; Chen S and Zhang T were responsible for the data analysis and interpretation&#46; Ma J&#44; Wang C&#44; Wang J and Liu Y were responsible for the manuscript drafting&#46; You D and Han L were responsible for the critical revision of the manuscript for important intellectual content&#46; Ma J&#44; Wang C&#44; Wang J and Liu Y were responsible for the statistical analysis&#46; You D and Han L supervised the study&#46;</p></span></span>"
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          "titulo" => "KEYWORDS"
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        1 => array:2 [
          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
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        2 => array:3 [
          "identificador" => "cesec20"
          "titulo" => "MATERIALS AND METHODS"
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              "titulo" => "Study subjects"
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            1 => array:2 [
              "identificador" => "cesec40"
              "titulo" => "miRNA microarrays"
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            2 => array:2 [
              "identificador" => "cesec50"
              "titulo" => "RNA extraction"
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            3 => array:2 [
              "identificador" => "cesec60"
              "titulo" => "Quantitative Real-Time Polymerase Chain Reaction &#40;qRT-PCR&#41;"
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            4 => array:2 [
              "identificador" => "cesec70"
              "titulo" => "Statistical analysis"
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          ]
        ]
        3 => array:3 [
          "identificador" => "cesec80"
          "titulo" => "RESULTS"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "cesec90"
              "titulo" => "Characteristics of the included subjects"
            ]
            1 => array:2 [
              "identificador" => "cesec100"
              "titulo" => "Comprehensive miRNA profiling and qRT-PCR validation"
            ]
          ]
        ]
        4 => array:2 [
          "identificador" => "cesec110"
          "titulo" => "DISCUSSION"
        ]
        5 => array:2 [
          "identificador" => "cesec120"
          "titulo" => "AUTHOR CONTRIBUTIONS"
        ]
        6 => array:2 [
          "identificador" => "xack638188"
          "titulo" => "ACKNOWLEDGMENTS"
        ]
        7 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-09-13"
    "fechaAceptado" => "2016-12-15"
    "PalabrasClave" => array:1 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "KEYWORDS"
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          "palabras" => array:3 [
            0 => "Type 2 diabetes mellitus"
            1 => "Diabetic retinopathy"
            2 => "Serum miRNAs"
          ]
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    "resumen" => array:1 [
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVES&#58;</span><p id="spara60" class="elsevierStyleSimplePara elsevierViewall">The aim of this study was to compare the expression levels of serum miRNAs in diabetic retinopathy and type 2 diabetes mellitus&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">Serum miRNA expression profiles from diabetic retinopathy cases &#40;type 2 diabetes mellitus patients with diabetic retinopathy&#41; and type 2 diabetes mellitus controls &#40;type 2 diabetes mellitus patients without diabetic retinopathy&#41; were examined by miRNA-specific microarray analysis&#46; Quantitative real-time polymerase chain reaction was used to validate the significantly differentially expressed serum miRNAs from the microarray analysis of 45 diabetic retinopathy cases and 45 age-&#44; sex-&#44; body mass index- and duration-of-diabetes-matched type 2 diabetes mellitus controls&#46; The relative changes in serum miRNA expression levels were analyzed using the 2<span class="elsevierStyleSup">-&#916;&#916;Ct</span> method&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">A total of 5 diabetic retinopathy cases and 5 type 2 diabetes mellitus controls were included in the miRNA-specific microarray analysis&#46; The serum levels of miR-3939 and miR-1910-3p differed significantly between the two groups in the screening stage&#59; however&#44; quantitative real-time polymerase chain reaction did not reveal significant differences in miRNA expression for 45 diabetic retinopathy cases and their matched type 2 diabetes mellitus controls&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSION&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">Our findings indicate that miR-3939 and miR-1910-3p may not play important roles in the development of diabetic retinopathy&#59; however&#44; studies with a larger sample size are needed to confirm our findings&#46;</p></span>"
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            "titulo" => "RESULTS&#58;"
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        "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">No potential conflict of interest was reported&#46;</p>"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">A-B&#58; Comparison of miRNA expression levels &#40;2<span class="elsevierStyleSup">-&#916;&#916;Ct</span>&#41; in the serum of DR patients &#40;n&#61;45&#41; and controls &#40;n&#61;45&#41;&#46; Expression levels of selected miRNAs were analyzed by qRT-PCR&#46;</p>"
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Chip cluster analysis for analyzing the differential expression of miRNAs between DR cases and T2DM controls&#46;</p>"
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          "leyenda" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">SD&#58; standard deviation&#59; log2&#58; the difference between the groups &#40;DR&#47;T2DM&#41;&#44; which should be larger than 2&#59; Target Sequence&#58; the miRNA sequence&#46;</p>"
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                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col">T2DM</th><th class="td" title="\n
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                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">Assay&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col">Mean&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col">Mean&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col">SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col"><span class="elsevierStyleItalic">p</span>-value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&#124;log2&#124;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Target Sequence &#40;5&#8242; to 3&#8242;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">hsa-miR-3939&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">876&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">812&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">0&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">UACGCGCAGACCA CAGGAUGUC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">hsa-miR-1910-3p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">697&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">788&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;09&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">GAGGCAGAAGC AGGAUGACA&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Differential expression of serum miRNAs based on the miRNA expression microarray&#46;</p>"
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                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">DR &#40;n&#61;45&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">T2D &#40;n&#61;45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&#46;24&#177;8&#46;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">65&#46;42&#177;7&#46;96&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">0&#46;606&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMI &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#46;48&#177;3&#46;71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&#46;9&#177;3&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;293&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Duration of diabetes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;78&#177;7&#46;42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;96&#177;9&#46;50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">0&#46;638&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TC &#40;mmol&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;50&#177;0&#46;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">4&#46;63&#177;1&#46;81&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">0&#46;52&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">HDL &#40;mmol&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">1&#46;22&#177;0&#46;39&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">1&#46;15&#177;0&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">0&#46;347&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">2&#46;97&#177;0&#46;96&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">2&#46;64&#177;0&#46;67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">0&#46;54&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">TG &#40;mmol&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">1&#46;50&#177;1&#46;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;157&nbsp;\t\t\t\t\t\t\n
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                          "etal" => false
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                              """
                            1 => """
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                              """
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                              TY Wong \n
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                              JM Mercader \n
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                              JM Moreno-Navarrete \n
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                              E Guerra \n
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        "texto" => "<p id="para180" class="elsevierStylePara elsevierViewall">This research was supported by grants from the Shenzhen Science and Technology Innovation committee &#40;JCYJ20150402095940017&#41;&#59; the Nanshan Technology Bureau &#40;2015035&#41;&#59; the National Natural Science Foundation of China &#40;81402745&#41;&#59; the Natural Science Foundation of Zhejiang Province &#40;LR13H020003&#41;&#59; the K&#46; C&#46; Wong Magna Fund in Ningbo University&#59; the Ministry of Education&#44; Humanities and Social Sciences &#40;14YJC630046&#41;&#59; and the China Postdoctoral Science Foundation &#40;156458&#41;&#46;</p>"
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Article information

ISSN: 18075932
Original language: English

DOI:10.6061/clinics/2017(02)08

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Year/Month	Html	Pdf	Total

2024 October	22	11	33
2024 September	27	21	48
2024 August	46	23	69
2024 July	41	23	64
2024 June	39	9	48
2024 May	32	14	46
2024 April	36	15	51
2024 March	26	15	41
2024 February	31	13	44
2024 January	18	13	31
2023 December	9	18	27
2023 November	11	21	32
2023 October	19	21	40
2023 September	30	19	49
2023 August	9	6	15
2023 July	9	16	25
2023 June	16	6	22
2023 May	27	2	29
2023 April	30	1	31
2023 March	23	7	30
2023 February	12	2	14
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2022 December	6	3	9
2022 November	1	0	1

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