Genome-wide analysis of miRNAs suggests a differential microRNAs signature associated with Normal and Diabetic limbal human corneas
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE97069 | GEO | 2023/03/14
REPOSITORIES: GEO
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Project description:The main cause of morbidity and mortality in diabetes mellitus (DM) are cardiovascular complications. Diabetic cardiomyopathy (DCM) remains incompletely understood. Animal models have been crucial in exploring DCM pathophysiology while identifying potential therapeutic targets. Streptozotocin (STZ) has been widely used to produce experimental models of both type 1 and type 2 DM (T1DM and T2DM). Here we compared these two models for their effects on cardiac structure, function, and transcriptome. Different doses of STZ and different diet chows were used to generate T1DM and T2DM in C57BL/6J mice. Normal euglycemic and non-obese sex and age-matched mice served as controls (CTRL). Immunohistochemistry, RT-PCR, and RNA-Seq were employed to compare hearts from the three animal groups. STZ-induced T1DM and T2DM differently affect left ventricular function and myocardial performance. T1DM displays an exaggerated apoptotic cardiomyocyte (CM) death and reactive hypertrophy and fibrosis along with increased cardiac oxidative stress, CM DNA damage and senescence when compared to T2DM mice. T1DM and T2DM differently affect whole cardiac transcriptome. In conclusion, STZ-induced T1DM and T2DM mouse models show significant differences in cardiac remodeling, function and whole transcriptome. These differences could be of key relevance when choosing an animal model to study specific features of DCM.
2023-02-20 | E-MTAB-12558 | biostudies-arrayexpress
Project description:MicroRNAs are powerful gene expression regulators, but their corneal repertoire and potential changes in corneal diseases remain unknown. Our purpose was to identify miRNAs altered in the human diabetic cornea by microarray analysis, and to examine their effects on wound healing in cultured telomerase-immortalized human corneal epithelial cells (HCEC) in vitro. Using microarrays, 29 miRNAs were identified as differentially expressed in diabetic samples. Two miRNA candidates showing the highest fold increased in expression in the diabetic cornea were confirmed by Q-PCR and further characterized. HCEC transfection with h-miR-146a or h-miR-424 significantly retarded wound closure, but their respective antagomirs significantly enhanced wound healing vs. controls. Cells treated with h-miR-146a or h-miR-424 had decreased p-p38 and p-EGFR staining, but these increased over control levels close to the wound edge upon antagomir treatment. In conclusion, several miRNAs with increased expression in human diabetic central corneas were found. Two such miRNAs inhibited cultured corneal epithelial cell wound healing. Dysregulation of miRNA expression in human diabetic cornea may be an important mediator of abnormal wound healing. Total RNA was extracted from age-matched human autopsy normal (n=6) and diabetic (n=6) central corneas, Flash Tag end-labeled, and hybridized to Affymetrix® GeneChip® miRNA Arrays. Select miRNAs associated with diabetic cornea were validated by quantitative RT-PCR (Q-PCR) and by in situ hybridization (ISH) in independent samples.
2013-11-09 | E-GEOD-52233 | biostudies-arrayexpress
Project description:Purpose: We compared the levels of miRNA specific for DEGs in isograft corneas with those in normal corneas, as well as the levels of miRNA specific for DEGs in allograft corneas with those in isograft corneas, to gain a better understanding of molecular variables that affect corneal graft rejection pathways. Methods: Illumina Hiseq 2500 deep sequencing was used to screen for differentially expressed genes (DEGs) in matched pairs of isograft corneas and normal corneas, allograft corneas and isograft corneas. Potential target genes among the DEGs were predicted using target prediction software (TargetScan, Miranda, miRDB, and CLIP), and the overlay portion was analyzed using the Gene Ontology (GO) database and the Kyoto Encyclopedia of Genes and Genomes (KEGG). An analysis of the interactions between DEG proteins (PPI analysis) and a MetaCore software analysis. Results: Our results showed that 22 miRNAs were significantly upregulated and 4 were significantly downregulated in the isograft group when compared with the control group (P < 0.01), while 17 miRNAs were significantly upregulated and 3 were significantly downregulated in the allograft group when compared with the isograft group (P < 0.01). Among the miRNAs with altered expression levels, miR-155-5p, miR-142-3p, miR-142-5p, and miR-223-3p displayed simultaneous changes in the above two comparisons. Potential target genes among the DEGs were predicted using target prediction software, and the overlay portion was analyzed using the Gene Ontology (GO) database and the Kyoto Encyclopedia of Genes and Genomes (KEGG). GO and KEGG analyses showed that the DEGs were mainly involved in metabolic pathways, cytokine secretion, and tumor immunity functions. An analysis of the interactions between DEG proteins (PPI analysis) and a MetaCore software analysis of 4 key DEGs revealed that the genes regulated by miR-155-5p played important roles in the miRNA-mRNA regulatory network. Furthermore, the MetaCore analysis identified C/EBP beta, p53, and sp1 as key transcription factors in that network. Conclusions: Our study identified transplanted corneas-specific miRNA in matched pairs of isograft corneas and normal corneas, allograft corneas and isograft corneas. Furthermore, bioinformatics analysis of the key miRNA regulatory network revealed the molecular mechanisms, which suggests miRNAs may as new molecular targets for treating corneal injuries and corneal transplant rejection
2018-04-28 | GSE113787 | GEO
Project description:Using microarray, we compared the expression of miRNAs from the peripheral blood of male subjects with T1DM and T2DM with healthy controls. Healthy male controls used were age-matched to the T2DM group patients with mean(SD) 37.3 (7.1) years. Subjects with T1DM were younger [23.3(1.6) years]. Expression was compared and validated using quantitative real-time PCR. Statistical testing (ANOVA, P-value <0.05) was performed and fold changes with respect to the control were calculated Systolic BP, fasting glucose, HbA1c, total cholesterol and LDL-cholesterol levels were significantly higher in T2DM subjects compared with controls (P-value <0.05). Compared with controls, we identified 37 differentially regulated miRNAs in DM subjects. Among them, 21 miRNAs were upregulated (2-5 fold change, p-value < 0.05) and 16 miRNAs were downregulated (1.5-2 fold change, p-value < 0.05). These miRNAs had gene putative targets primarily involved in regulating pancreatic development and functions, adipocyte differentiation, insulin signaling and glucose-dependent insulin secretion. peripheral blood of male subjects with T1DM and T2DM with healthy controls
2011-03-05 | E-GEOD-27645 | biostudies-arrayexpress
Project description:Type 1 diabetes mellitus (T1DM) results from immune mediated destruction of pancreatic beta cells. However, clinical and immunologic phenotypes of T1DM are variable. Several auto-antibodies including GADA, IA-2A, and ZnT8A, were identified in T1DM, but the prevalence of these auto-antibodies varied for a broad spectrum of T1DM. Here, we systemically profiled auto-antibodies from serum samples of 16 T1DM, 16 type 2 diabetes (T2DM) patients, and 27 healthy controls with normal glucose tolerance (NGT) using protein microarrays containing 9,480 proteins. Among 9,480 different proteins on the array, we identified novel auto-antibody candidates (EEF1A1-AAb and UBE2L3-AAb) by M-test coupled with PLS-DA. These auto-antibodies were highly present in T1DM than controls and detected in 40% of T1DM without GADA. Furthermore, these auto-antibodies might help to differentiate subtype of T1DM when combined with GADA. These novel auto-antibodies provide new diagnostic information of T1DM, as well as new insights into the pathogenesis of T1DM. Auto-antibodies from serum samples were profiled using a high-density, fluorescence-based protein microarray containing duplicate spots of 9,480 human proteins derived from the Ultimate ORF collection The cohort of patients and controls consisted of 16 T1DM, 16 T2DM patients, and 27 healthy controls with NGT. This cohort was used to screen candidate auto-antibodies using protein microarrays (ProtoArray platform version 5.0, Invitrogen Corp., Carlsbad, CA). Serum samples were drawn from T1DM patients who have 1) fasting C-peptide level <0.3 nmol/L or serum C-peptide <0.6 nmol/L after glucagon loading, 2) initiation of insulin treatment within six months after diagnosis, and 3) duration of diabetes M-bM-^IM-$12 months. Mean age of T1DM in the first cohort was 42 M-BM-1 16 years. The control serum samples were obtained from T2DM patients who were treated only with oral anti-diabetic drug at least 5 years and from NGTs who had no history of diabetes, no first-degree relatives with diabetes, a fasting plasma glucose concentration of <6.1 mmol/l, and a HbA1c value of <5.8%.
2014-07-30 | E-GEOD-50866 | biostudies-arrayexpress
Project description:Limbal stem cells including epithelial and stromal/Mesenchymal stem cells that contribute to sustained corneal homeostasis, maintain their ability to act as self-renewal progenitor cells by virtue of their limbal niche and intercellular communication. Extracellular vehicles (EVs), including exosomes (Exos), are important paracrine mediators through their cargo transfer for intercellular communication in various stem cell niches. Previously we have shown the differential cargos and regulatory roles of limbal stromal cell (LSC)-derived Exos, in limbal epithelial cells (LEC) in normal (N) and diabetic (DM) limbal niche. In the present study, to have a comprehensive knowledge of reciprocal LEC-LSC crosstalk, we investigated the proteomics and miRNA profile of exosomes derived from LEC and their regulatory roles in LSC in N and DM limbus. Our study showed wound healing and proliferation rates in primary N-LSC were significantly enhanced upon treatment by normal LEC-derived Exos (N-Exos), but not by diabetic Exos (DM-Exos). Further, N-Exos treated LSC showed downregulation of keratocyte markers, ALDH3A1 and lumican, but not keratocan, and upregulation of MSC markers, CD105, CD90, and CD73 compared to the DM-Exos treated LSC. Using next generation sequencing (NGS) and proteomics analysis, we revealed some miRNAs and proteins in the Exos that affect the cellular crosstalk and the function of the cornea. We also documented differences in DM vs. normal LEC-derived Exo’s cargos. Overall, DM-Exos have less effect on LSC proliferation, wound healing, and stem cell maintenance than N-Exos, likely by transferring their cargo proteins and/or regulatory miRNAs targeting cell cycle, ERK/MAPK, TGF-β, EMT, PI3K-Akt-mTOR signaling molecules. This suggests that the small RNA and protein cargo differences in DM vs. N LEC-derived Exos could contribute to the disease state. Our study revealed a complex contribution of Exos to health and diabetic state of corneal homeostasis and suggests the potential of EV therapeutics for diabetic cornea regenerative medicine
2023-10-23 | PXD040918 | Pride
Project description:Using microarray, we compared the expression of miRNAs from the peripheral blood of male subjects with T1DM and T2DM with healthy controls. Healthy male controls used were age-matched to the T2DM group patients with mean(SD) 37.3 (7.1) years. Subjects with T1DM were younger [23.3(1.6) years]. Expression was compared and validated using quantitative real-time PCR. Statistical testing (ANOVA, P-value <0.05) was performed and fold changes with respect to the control were calculated Systolic BP, fasting glucose, HbA1c, total cholesterol and LDL-cholesterol levels were significantly higher in T2DM subjects compared with controls (P-value <0.05). Compared with controls, we identified 37 differentially regulated miRNAs in DM subjects. Among them, 21 miRNAs were upregulated (2-5 fold change, p-value < 0.05) and 16 miRNAs were downregulated (1.5-2 fold change, p-value < 0.05). These miRNAs had gene putative targets primarily involved in regulating pancreatic development and functions, adipocyte differentiation, insulin signaling and glucose-dependent insulin secretion.
2011-03-05 | GSE27645 | GEO
Project description:MicroRNAs are powerful gene expression regulators, but their corneal repertoire and potential changes in corneal diseases remain unknown. Our purpose was to identify miRNAs altered in the human diabetic cornea by microarray analysis, and to examine their effects on wound healing in cultured telomerase-immortalized human corneal epithelial cells (HCEC) in vitro. Using microarrays, 29 miRNAs were identified as differentially expressed in diabetic samples. Two miRNA candidates showing the highest fold increased in expression in the diabetic cornea were confirmed by Q-PCR and further characterized. HCEC transfection with h-miR-146a or h-miR-424 significantly retarded wound closure, but their respective antagomirs significantly enhanced wound healing vs. controls. Cells treated with h-miR-146a or h-miR-424 had decreased p-p38 and p-EGFR staining, but these increased over control levels close to the wound edge upon antagomir treatment. In conclusion, several miRNAs with increased expression in human diabetic central corneas were found. Two such miRNAs inhibited cultured corneal epithelial cell wound healing. Dysregulation of miRNA expression in human diabetic cornea may be an important mediator of abnormal wound healing.
2013-11-09 | GSE52233 | GEO
Project description:To understand the association between systemic factors and the diabetic retinopathy, blood samples were collected in 50 healthy controls, 74 diabetic patients without diabetic retinopathy (DM group), and 69 diabetic retinopathy (DR Group). T1DM and T2DM in this study was based on the diagnostic criteria for diabetes proposed by the WHO in 1999. The diagnosis of DR was based on the international clinical classification of DR proposed at the 2002 International Ophthalmology Conference. We then performed gene expression profiling analysis using data obtained from RNA-seq of three patient groups.
2023-05-26 | GSE221521 | GEO
Project description:Circulating miRNAs constitute a novel class of disease biomarkers, which are altered in diabetes but the effect of diabetes associated inflammation as seen in chronic wounds is unknown. We here compared the miRNA pattern in diabetic patients in presence or absence of chronic wound with PAD. The clinical plasma samples were obtained from Heart and Diabetes centre, NRW and compared for plasma miRNA levels in 2 pools of 17 T2DM+PAD+Wound patients vs 2 pools from 20 T2DM controls
2015-06-09 | E-GEOD-49885 | biostudies-arrayexpress