miRNA Gene Expression Research Articles

Tetra aniline-based polymers ameliorate BPA-induced cardiotoxicity in Sprague Dawley rats, in silico and in vivo analysis

AimsBisphenol A (BPA), xenoestrogen, is an environmental toxicant, that generates oxidative stress leading to cardiotoxicity. The oxidative stress can be neutralized by natural and synthetic antioxidants. The present study elucidates the highly selective antioxidative potential of synthetic tetra aniline polymers Es-37 and L-37 against Bisphenol A-induced cardiac cellular impairments and the role of miRNA-15a-5p in the regulation of different apoptotic proteins. Materials and methodsThe molecular docking of L-37 and Es-37 with three proteins (p53, Cytochrome c, and Bcl-2) were performed. The dose of 1 mg/kg BW of BPA, 1 mg/kg BW Es-37 and L-37 and 50 mg/kg BW N-acetyl cysteine (NAC) was administered to Sprague Dawley rats. The miRNA and target gene expression were confirmed by qRt-PCR and Immunoblotting. Key findingsIn our results, BPA administration significantly elevated the reactive oxygen species (ROS), p53, cytochrome c, and particularly miRNA-15a-5p expression; however: these changes were notably reversed by Es-37 and L-37 treatment. Additionally, molecular docking of synthetic polymers validated that L-37 has a greater binding affinity with the target proteins compared to Es-37, with the highest binding values reported for the enzymatic protein cytochrome c. SignificanceThese results suggest that both synthetic polymers Es-37 and L-37 have the potential to scavenge free radicals, boost-up antioxidant enzyme activities, and avert (BPA-induced) toxicity, thus, may serve as cardioprotective agents. Moreover, this study first time proposes that miRNA-15a-5p overexpression is associated with oxidative stress and coincides with BPA induced cardiotoxicity, thus may serve as potential therapeutic target in future.

Breast Tumor Diagnosis Based on Molecular Learning Vector Quantization Neural Networks.

DNA nanotechnology plays a crucial role in precise cancer medicine. Currently, molecular logic circuits are applied to detect tumor-specific biomarkers and control the release of therapeutic drugs. However, these systems lack self-learning capabilities for intelligent diagnostics in biological samples, and their data processing capabilities are limited. Here, a molecular learning vector quantization neural network (LVQNN) model based on DNA strand displacement (DSD) technology for breast tumor diagnosis is developed. Compared to previous work, the molecular LVQNN boasts powerful computing abilities, handling high-dimensional data for intelligent cancer diagnosis. To verify the feasibility and versatility of the network, two distinct typical datasets are selected: one from a single source with cell morphology data from 569 cases, and a more extensive one spanning different populations and ages, with miRNA gene expression data from 1881 cases. By using the molecular LVQNN, diagnostic experiments are conducted on 50 and 120 public individuals from these two datasets, respectively, achieving accuracy rates of 94% and 97.5%. This study demonstrates that the LVQNN model exhibits significant advantages in breast cancer diagnosis and enhances diagnostic accuracy while introducing new approaches for intelligent cancer diagnosis, anticipated to bring significant breakthroughs and application prospects to precise cancermedicine.

First-trimester predictive models for adverse pregnancy outcomes-a base for implementation of strategies to prevent cardiovascular disease development.

This study aimed to establish efficient, cost-effective, and early predictive models for adverse pregnancy outcomes based on the combinations of a minimum number of miRNA biomarkers, whose altered expression was observed in specific pregnancy-related complications and selected maternal clinical characteristics. This retrospective study included singleton pregnancies with gestational hypertension (GH, n = 83), preeclampsia (PE, n = 66), HELLP syndrome (n = 14), fetal growth restriction (FGR, n = 82), small for gestational age (SGA, n = 37), gestational diabetes mellitus (GDM, n = 121), preterm birth in the absence of other complications (n = 106), late miscarriage (n = 34), stillbirth (n = 24), and 80 normal term pregnancies. MiRNA gene expression profiling was performed on the whole peripheral venous blood samples collected between 10 and 13 weeks of gestation using real-time reverse transcription polymerase chain reaction (RT-PCR). Most pregnancies with adverse outcomes were identified using the proposed approach (the combinations of selected miRNAs and appropriate maternal clinical characteristics) (GH, 69.88%; PE, 83.33%; HELLP, 92.86%; FGR, 73.17%; SGA, 81.08%; GDM on therapy, 89.47%; and late miscarriage, 84.85%). In the case of stillbirth, no addition of maternal clinical characteristics to the predictive model was necessary because a high detection rate was achieved by a combination of miRNA biomarkers only [91.67% cases at 10.0% false positive rate (FPR)]. The proposed models based on the combinations of selected cardiovascular disease-associated miRNAs and maternal clinical variables have a high predictive potential for identifying women at increased risk of adverse pregnancy outcomes; this can be incorporated into routine first-trimester screening programs. Preventive programs can be initiated based on these models to lower cardiovascular risk and prevent the development of metabolic/cardiovascular/cerebrovascular diseases because timely implementation of beneficial lifestyle strategies may reverse the dysregulation of miRNAs maintaining and controlling the cardiovascular system.

CircHIRA sponges miR-196b-5p to promote porcine early embryonic development

Circular RNA (circRNA) is abundantly expressed in preimplantation embryos and embryonic stem cells in mice and humans. However, its function and mechanism in early development of mammalian embryos remain unclear. Here, we showed that circHIRA mediated miR-196b-5p to regulate porcine early embryonic development. We verified the circular feature of circHIRA by sanger sequencing, and proved the authenticity of circHIRA by enzyme digestion test. HIRA and circHIRA were expressed in porcine early embryos, and its expression levels significantly increased from 8-cell stage onwards and reached the maximum at the blastocyst stage. Functional studies revealed that circHIRA knockdown not only significantly reduced the developmental efficiency of embryos from 8-cell stage to blastocyst stage, but also impaired the blastocyst quality. Mechanistically, integrated analysis of miRNA prediction and gene expression showed that circHIRA knockdown significantly increased the expression of miR-196b-5p in porcine early embryos. Furthermore, miR-196b-5p inhibitor injection could rescue the early development of circHIRA knockdown embryos. Taken together, the findings reveal that circHIRA regulates porcine early embryonic development via inhibiting the expression of miR-196b-5p.

*Re-Print: The NS-3 Mixture of δ-Tocotrienol, Vitamin D3 and Resveratrol Modulates Gene Expression of Several Novel MicroRNAs Identified by Transcriptomic Analyses in People with Type 2 Diabetes

Aims: Type 2 diabetes mellitus is due to hyperglycemia, therefore fasting glucose and glycosylated hemoglobin (HbA1c) levels are used as biomarkers to determine onset of diabetes. RT-PCR estimation of pooled total mRNAs of EDTA treated whole blood (plasma) obtained after the treatment of NS-3 mixture of d-tocotrienol, vitamin D3, resveratrol of people with type 2 diabetes mellitus (T2DM) for 24 weeks, showed significant down-regulation of gene expression of several diabetes biomarkers (IRS-1, SOD-2, GCKR, IGFBP-2) and cytokines (IL-4, IL-6) as compared to pre-treatment values. Present study investigates the effectiveness of NS-3 on gene expression of mRNAs, miRNAs, and paired mRNA-miRNA in people with T2DM. Methods: Present study is an extension of a randomized placebo controlled double-blinded clinical trial of T2DM (n = 56/group) given two capsules/d of cellulose/olive oil (placebo), or NS-3 for 24-weeks. Pure mRNAs and miRNAs of plasma of pre-dose versus post-dose of NS-3 treated samples were analyzed by next generation sequencing (NGS). Data was uploaded into “Ingenuity Pathways Analyses”. Results: A total of 4000 genes are considered significant, based on > 2-fold gene expression changes. Out of which 1373 genes are significantly differentially expressed in pre-dose vs post-dose (P < 0.02) samples, 20 are up-regulated and 27 are down-regulated of NS-3 treated RNAs of T2DM. Gene expression of up-regulated miR-29b-3p modulates (GLUT4, insulin resistance), miR-624-5p (nephropathy biomarker), miR-361-5p (chronic inflammation), miR-130a-3p (glucose metabolism, insulin secretion), miR-3912-3p (lipid metabolism), and miR-11401 (cellular transcription). The miR-374c-5p (insulin resistance), miR-4326 (HbA1c level)), miR-874-3p (b-cell function) are down-regulated of NS-3 treated people with T2DM. Whereas messengerR-ML-1621513 (oxidative/stress), mR-CTD-2349P217 (insulin-mediated glucose-uptake), are up-regulated, and mR-CTC-246B1810 (b-cell/biology) are down-regulated in T2DM after NS-3 treatment. Venn diagrams have established genetic regulatory network images and canonical signaling pathways for mRNA, miRNA, and paired mRNA-miRNA of gene expression profiles of pre-dose vs post-dose of NS-3 treatment group. Conclusions: The NS-3 treatment of people with T2DM indicates up- or down-regulation of several new miRNAs (miR-29b-3p, miR-624-5p, miR-361-5p, miR-130a-3p, miR-3912-3p, miR-374c-5p, miR-4326 [HbA1c], miR-1247-3p, miR-874-5p) which may be used to identify onset of T2DM. Overexpression of mRNA-AL1621513 indicates oxidative stress in people with T2DM, resulting in complications of diabetes (neuropathy, retinopathy, and stroke).

Evaluation of changes in exhausted T lymphocytes and miRNAs expression in the different trimesters of pregnancy in pregnant women.

Throughout the three trimesters of a typical pregnancy, we looked at changes in the expression of miRNAs and exhausted T lymphocytes for this study. Fifty healthy subjects were included in this study. The frequency of exhausted T lymphocytes was measured in isolated PBMCs using flow cytometry. PD-1, TIM-3, and related miRNAs gene expression were assessed using qRT-PCR. The analyses revealed a significant decline in PD-1 and Tim-3 expression in PBMCs from RPL women (p = 0.0003 and p = 0.001, respectively). In addition, PD-1 and TIM-3 expression increased significantly in the 2nd trimester compared with the 1st trimester of healthy pregnant women (p < 0.0001 and p = 0.0002, respectively). PD-1 and TIM-3 expression was down-regulated in the 3rd trimester compared with the 1st and 2nd trimesters. In the present study, we demonstrated that TIM-3+/CD4+, TIM-3+/CD8+, PD-1+/CD4+, and PD-1+/CD8 + exhausted T lymphocytes increased in the circulation of women in the 2nd trimester compared to the 1st and 3rd trimester. In the 3rd trimester, the expression of miR-16-5p increased significantly (p < 0.0001). miR-125a-3p expression was down and upregulated in 2nd (p < 0.0001) and 3rd (p = 0.0007) trimesters compared to 1st trimester, respectively. This study showed a significant elevation of miR-15a-5p in 3rd trimester compared to 1st trimester of pregnant women (p = 0.0002). Expression pattern of PD-1 and TIM3 in exhausted T lymphocytes is different not only between normal pregnant and RPL women but also in different trimesters of pregnancy. So, our results showed the role of these markers in the modulation lymphocytes activity in different stages of pregnancy.

Screening and analysis of single nucleotide polymorphismin the 3'-UTR microRNA target regions and its implications for lung tumorigenesis.

Aim: The study aims to identify high-impact single nucleotide polymorphisms (SNPs) in miRNA target sites of genes associated with lung cancer.Materials & methods: Lung cancer genes were obtained from Uniprot KB. miRNA target site SNPs were mined from MirSNP, miRdSNP and TargetScan. SNPs were shortlisted based on binding impact, minor allele frequencyand conservation. Gene expression was analyzed in genes with high-impact SNPs in healthy versus lung cancer tissue. Additionally, enrichment, pathwayand network analyzes were performed.Results: 19 high-impact SNPs were identified in miRNA target sites of lung cancer-associated genes. These SNPs affect miRNA binding and gene expression. The genes are involved in key cancerrelated pathways.Conclusion: The identified high-impact miRNA target site SNPs and associated genes provide a starting point for case-control studies in lung cancer patients in different populations.

Dgcr8 functions in the secondary heart field for outflow tract and right ventricle development in mammals

The DGCR8 gene, encoding a critical miRNA processing protein, maps within the hemizygous region in patients with 22q11.2 deletion syndrome. Most patients have malformations of the cardiac outflow tract that is derived in part from the anterior second heart field (aSHF) mesoderm. To understand the function of Dgcr8 in the aSHF, we inactivated it in mice using Mef2c-AHF-Cre. Inactivation resulted in a fully penetrant persistent truncus arteriosus and a hypoplastic right ventricle leading to lethality by E14.5. To understand the molecular mechanism for this phenotype, we performed gene expression profiling of the aSHF and the cardiac outflow tract with right ventricle in conditional null versus normal mouse littermates at stage E9.5 prior to morphology changes. We identified dysregulation of mRNA gene expression, of which some are relevant to cardiogenesis. Many pri-miRNA genes were strongly increased in expression in mutant embryos along with reduced expression of mature miRNA genes. We further examined the individual, mature miRNAs that were decreased in expression along with pri-miRNAs that were accumulated that could be direct effects due to loss of Dgcr8. Among these genes, were miR-1a, miR-133a, miR-134, miR143 and miR145a, which have known functions in heart development. These early mRNA and miRNA changes may in part, explain the first steps that lead to the resulting phenotype in Dgcr8 aSHF conditional mutant embryos.

MicroRNAs as Potential Biomarkers of Environmental Exposure to Polycyclic Aromatic Hydrocarbons and Their Link with Inflammation and Lung Cancer

Exposure to atmospheric air pollution containing volatile organic compounds such as polycyclic aromatic hydrocarbons (PAHs) has been shown to be a risk factor in the induction of lung inflammation and the initiation and progression of lung cancer. MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules of ~20–22 nucleotides that regulate different physiological processes, and their altered expression is implicated in various pathophysiological conditions. Recent studies have shown that the regulation of gene expression of miRNAs can be affected in diseases associated with outdoor air pollution, meaning they could also be useful as biomarkers of exposure to environmental pollution. In this article, we review the published evidence on miRNAs in relation to exposure to PAH pollution and discuss the possible mechanisms that may link these compounds with the expression of miRNAs.

The Diagnostic Value of Stool-Based MicroRNA-135b in the Early Detection of Colorectal Cancer and the Potent Neuro Function of MiR-146a

Background: Detecting microRNA (miRNA) in stool is a non-invasive approach for colorectal cancer (CRC) screening. This study aims to assess the diagnostic performance of stool-based microRNA-135b in detection of colorectal cancer and the role of miR-146a. Methods: To identify eligible studies that are well suited for diagnostic value of miR-135b in stool of colorectal cancer patients, we have evaluated 3 papers after systematic literature search of public database. The sensitivity and specificity were used to plot the summary receiver operator characteristic (SROC) curve and calculate the area under the SROC curve (AUC). The between-study heterogeneity was evaluated by Q test and I2 statistics. Importantly, we have also identified microRNA (miRNA) gene expression patterns by expression profiling. Moreover, we execute the pathway analysis to find the function of miR-146a. Results: A total of 3 studies from 19 articles were included for the meta-analysis according to the inclusion criteria. The overall analysis showed that microRNA-135b has a relatively good diagnostic performance in colorectal cancer, with a sensitivity of 0.685, a specificity of 0.813 and a partial AUC of 0.658. In stool samples, level of microRNA-135b was 2.21 fold change higher in subjects with CRC (P &lt; 0.0001). Moreover, our study proved that miR-146a involved in the neuro and immune function. Interpretation: In conclusion, stool-based microRNA-135b shows a moderate level of overall diagnostic accuracy in diagnosis of CRC, which may present as auxiliary means for the diagnosis of colorectal cancer compare with colonoscopy. Further large-scale prospective studies are necessary to validate their potential applicability (miR-135b and miR-146a) combined with FBT methods in human cancer diagnosis.

Differential gene expression of cytokines, receptors, and miRNAs in individuals living with HIV-1 and vaccinated against yellow fever

Between 2016 and 2018, Brazil faced a yellow fever (YF) outbreak, which led to an expansion of vaccination coverage. The coexistence of the YF outbreak and the HIV-1 epidemic in Brazil raised concerns regarding the immune response and vaccine effectiveness in individuals living with HIV (PLWH). The aim of this study was to investigate the immune response to YF vaccination in PLWH and HIV-uninfected individuals as controls. Transcript levels of immunomodulatory molecules, including IL-6, IL-10, IL-21, TGF-β, CD19, CD163, miR-21, miR-146, and miR-155, were measured using RTqPCR. TCD4+ cells were evaluated by cytometry, and neutralizing antibody (Nab) titers were detected by a micro plaque-reduction neutralization test. The findings of our study revealed several noteworthy observations. First, there was a notable reduction in the circulation of TCD4+ cells postvaccination. Among people living with HIV (PLWH), we observed an increase in the expression of IL-10 following vaccination, while IL-6 expression was diminished in PLWH with lower TCD4+ counts. Furthermore, we identified the downregulation of CD19 and TGF-β, along with the upregulation of IL-21 and CD163. Notably, we observed positive correlations between the levels of IL-10/IL-21, IL-10/CD163, and IL-6/CD19. Additionally, there was a positive correlation between miRNAs 146 and 155. It is important to emphasize that all participants exhibited robust neutralizing antibody responses after receiving 17DD YF vaccination. In this context, the gene expression data presented can be useful for biomarker studies of protective antibodies induced by YF vaccination. This study sheds light on immune mechanisms in individuals living with HIV and YF vaccination.

The protective impact of curcumin, vitamin D and E along with manganese oxide and Iron (III) oxide nanoparticles in rats with scrotal hyperthermia: Role of apoptotic genes, miRNA and circRNA

BackgroundInfertility is one of the major factors affecting most people around the world. Short-term exposure to high temperatures can cause hyperthermia, which is one of the causes of male infertility. The aim of this study was to investigate the protective effect of curcumin, vitamins D and E along with Iron (III) oxide nanoparticles (Fe2O3-NPs) and manganese oxide nanoparticles (MnO2-NPs) on semen parameters and its effect on miRNA21 and circRNA0001518 expression. Material and methodsIn this study, the lower part of the rat was exposed to 43 °C for 5 weeks every other day for 5 weeks. Then the animals were killed. Tissue samples were collected for sperm parameters analysis, and tissue samples were taken for evaluation of apoptosis levels in germ cells, and RNA extraction in order to examine the expression of Bax, Bcl-2, miRNA, and CircRNA genes. ResultsThe results of this study showed that administration of curcumin, vitamin D, and vitamin E with Fe2O3-NPs and MnO2-NPs can improve the parameters of semen, Bax gene expression, Bcl-2 as well as miRNA and CircRNA in rats with testicular hyperthermia. In addition, curcumin by reducing the toxicity of Fe2O3 nanoparticles was able to reduce its negative effects and also reduce apoptosis in germ cells. This decrease in apoptosis was attributed to decreased Bcl-2 gene expression and increased expression of Bax, miRNA-21, and circRNA0001518. ConclusionAll the results of this study confirmed that Fe2O3-NPs and Mno2-NPs containing antioxidants or vitamins are useful in improving fertility in rats due to scrotal hyperthermia. Although Fe2O3-NPs and Mno2-NPs containing both antioxidants and vitamins had a greater effect on improving fertility and reducing the toxic effects of nanoparticles.

Loss of Key EMT-Regulating miRNAs Highlight the Role of ZEB1 in EGFR Tyrosine Kinase Inhibitor-Resistant NSCLC.

Despite recent advances in the treatment of non-small cell lung cancer (NSCLC), acquired drug resistance to targeted therapy remains a major obstacle. Epithelial-mesenchymal transition (EMT) has been identified as a key resistance mechanism in NSCLC. Here, we investigated the mechanistic role of key EMT-regulating small non-coding microRNAs (miRNAs) in sublines of the NSCLC cell line HCC4006 adapted to afatinib, erlotinib, gefitinib, or osimertinib. The most differentially expressed miRNAs derived from extracellular vesicles were associated with EMT, and their predicted target ZEB1 was significantly overexpressed in all resistant cell lines. Transfection of a miR-205-5p mimic partially reversed EMT by inhibiting ZEB1, restoring CDH1 expression, and inhibiting migration in erlotinib-resistant cells. Gene expression of EMT-markers, transcription factors, and miRNAs were correlated during stepwise osimertinib adaptation of HCC4006 cells. Temporally relieving cells of osimertinib reversed transition trends, suggesting that the implementation of treatment pauses could provide prolonged benefits for patients. Our results provide new insights into the contribution of miRNAs to drug-resistant NSCLC harboring EGFR-activating mutations and highlight their role as potential biomarkers and therapeutic targets.

Upregulation of miR-21 and pro-inflammatory cytokine genes IL-6 and TNF-[formula omitted] in promoting a pro-tumorigenic microenvironment in canine mammary carcinomas

This study evaluated the gene expression of the pro-inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in canine mammary tumors (CMTs), and correlated them with gene expression of miRNAs expected to regulate the secretion of pro-inflammatory cytokines within the tumor microenvironment (TME). Furthermore, gene expression of cytokines and miRNAs involved in tumor cell proliferation and invasion (i.e. miR-21; miR-124; miR-145) were correlated with tumor proliferation index (Ki67 index) to determine the prognostic value in CMTs. Twenty-six canine mammary samples were used, including 22 CMTs and 4 control samples. MiR-21, IL-6 and TNF-α were upregulated in mammary carcinomas compared with controls (p < 0.05). MiR-146b was downregulated in CMTs compared with control cases (p < 0.05). IL-6 expression showed a significant positive correlation with miR-21 and a negative correlation with miR-146b; while, TNF-α gene expression was positively correlated with miR-21 and miR-145 in mammary carcinomas. In carcinomas, the Ki67 index correlated positively with gene expression of IL-6 and miR-21 and negatively correlated with miR-145 and miR-146b. Specifically, gene expression of IL-6 and miR-21 was positively correlated with ki67 index >33.3%, whereas, expression of miR-145 and miR-146b was negatively correlated with ki67 index <33.3%. Results reinforce the concept of interaction between tumor cells and inflammatory cells within the TME, with a central role of IL-6 and TNF-α. Since the upregulation of miR-21 reflects the gene overexpression of interleukins and the high proliferation index of tumor cells, this miRNA may be considered a biomarker with prognostic value in CMTs.

An updated review on cell signaling pathways regulated by candidate miRNAs in coronary artery disease

MicroRNAs (miRNAs) are small endogenous non-coding RNA, size range from 17 to 25 nucleotides that regulate gene expression at the post-transcriptional level. More than 2000 different types of miRNAs have been identified in humans which regulate about 60% of gene expression, since the discovery of the first miRNA in 1993. MicroRNA performs many functions such as being involved in the regulation of various biological pathways for example cell migration, cell proliferation, cell differentiation, disease progression, and initiation. miRNAs also play an important role in the development of atherosclerosis lesions, cardiac fibroblast, cardiac hypertrophy, cancer, and neurological disorders. Abnormal activation of many cell signaling pathways has been observed in the development of coronary artery disease. Abnormal expression of these candidate miRNA genes leads to up or downregulation of specific genes, these specific genes play an important role in the regulation of cell signaling pathways involved in coronary artery disease. Many studies have found that miRNAs play a key role in the regulation of crucial signaling pathways that are involved in the pathophysiology of coronary artery disease. This review is designed to investigate the role of cell signaling pathways regulated by candidate miRNAs in Coronary artery disease.

Myc-regulated miRNAs modulate p53 expression and impact animal survival under nutrient deprivation.

The conserved transcription factor Myc regulates cell growth, proliferation and apoptosis, and its deregulation has been associated with human pathologies. Although specific miRNAs have been identified as fundamental components of the Myc tumorigenic program, how Myc regulates miRNA biogenesis remains controversial. Here we showed that Myc functions as an important regulator of miRNA biogenesis in Drosophila by influencing both miRNA gene expression and processing. Through the analysis of ChIP-Seq datasets, we discovered that nearly 56% of Drosophila miRNA genes show dMyc binding, exhibiting either the canonical or non-canonical E-box sequences within the peak region. Consistently, reduction of dMyc levels resulted in widespread downregulation of miRNAs gene expression. dMyc also modulates miRNA processing and activity by controlling Drosha and AGO1 levels through direct transcriptional regulation. By using in vivo miRNA activity sensors we demonstrated that dMyc promotes miRNA-mediated silencing in different tissues, including the wing primordium and the fat body. We also showed that dMyc-dependent expression of miR-305 in the fat body modulates Dmp53 levels depending on nutrient availability, having a profound impact on the ability of the organism to respond to nutrient stress. Indeed, dMyc depletion in the fat body resulted in extended survival to nutrient deprivation which was reverted by expression of either miR-305 or a dominant negative version of Dmp53. Our study reveals a previously unrecognized function of dMyc as an important regulator of miRNA biogenesis and suggests that Myc-dependent expression of specific miRNAs may have important tissue-specific functions.

Changes in Multiple microRNA Levels with Antidepressant Treatment Are Associated with Remission and Interact with Key Pathways: A Comprehensive microRNA Analysis.

Individual treatment outcomes to antidepressants varies widely, yet the determinants to this difference remain elusive. MicroRNA (miRNA) gene expression regulation in major depressive disorder (MDD) has attracted interest as a biomarker. This 4-week randomized controlled trial examined changes in the plasma miRNAs that correlated with the treatment outcomes of mirtazapine (MIR) and selective serotonin reuptake inhibitor (SSRI) monotherapy. Pre- and post- treatment, we comprehensively analyzed the miRNA levels in MDD patients, and identified the gene pathways linked to these miRNAs in 46 patients. Overall, 141 miRNA levels significantly demonstrated correlations with treatment remission after 4 weeks of MIR, with miR-1237-5p showing the most robust and significant correlation after Bonferroni correction. These 141 miRNAs displayed a negative correlation with remission, indicating a decreasing trend. These miRNAs were associated with 15 pathways, including TGF-β and MAPK. Through database searches, the genes targeted by these miRNAs with the identified pathways were compared, and it was found that MAPK1, IGF1, IGF1R, and BRAF matched. Alterations in specific miRNAs levels before and after MIR treatment correlated with remission. The miRNAs mentioned in this study have not been previously reported. No other studies have investigated treatment with MIR. The identified miRNAs also correlated with depression-related genes and pathways.

P-346 Migration-associated microRNAs are dysregulated in endometriosis: potential diagnostic biomarkers

Abstract Study question What is the role of dysregulated endometrial microRNAs (miRNAs) in the development of endometriosis? Summary answer Dysregulated miRNAs in the endometrium of women with endometriosis can also be found in endometriomas and may affect the migratory ability of endometriotic cells. What is known already The molecular mechanisms underlying the pathogenesis of endometriosis are poorly understood. One of the hypotheses is that changes in cell properties observed in endometriotic lesions could be initiated already in the endometrium. Dysregulation of miRNAs in the endometrium of women with endometriosis has been reported in previous microarray-based studies. However, little overlap has been seen between published miRNA expression data. Moreover, the potential role of dysregulated miRNAs in the endometrium of women with endometriosis and whether these changes are also present in the endometrioma are largely unknown. Study design, size, duration In this experimental case-control study miRNA gene expression in proliferative phase endometrium was compared between 15 women with laparoscopically confirmed endometriosis (stage III–IV) and 17 age-matched controls who were laparoscopically confirmed to be free of endometriosis. Selected miRNAs were further compared between paired proliferative-phase endometrium and endometrioma from a new cohort of women with endometriosis (stage III–IV) and studied in vitro to understand their effect on cell migration. Participants/materials, setting, methods Samples were collected during laparoscopic operations performed at Tartu University Hospital, Estonia. Dysregulated endometrial miRNAs were detected with small RNA sequencing and differential gene expression analysis. Target genes and biological pathways were predicted to understand their potential role in the disease. Selected miRNAs were further studied for their expression in endometriomas using qRT-PCR and in-vitro for their proliferation and migration ability using a transwell-migration assay after miRNA mimic transfection of the 12Z endometriotic cell line. Main results and the role of chance In total, we identified 9 upregulated and 5 downregulated (-2 &amp;lt;fold change &amp;gt; 2, FDR &amp;lt; 0.05) miRNAs in the endometrium of women with endometriosis compared to controls. In-silico analyses showed that predicted target genes of the dysregulated miRNAs were significantly enriched in migration-related KEGG pathways such as adherens junctions, focal adhesion, MAPK-, PI3-AKT-, and TGF-beta signaling. The most down-regulated miRNA, miR-193b-5p, and the most up-regulated miRNA, miR-374b-5p, were selected for further characterization. Validation of their expression in endometriomas showed a significant up-regulation of both miRNAs compared to paired endometrium (Fold change &amp;gt; 2, FDR &amp;lt; 0.05). Since it has been reported that altered cell migratory ability could be involved in the pathogenesis of endometriosis and our dysregulated miRNA were associated with migration-related pathways, we explored if miR-193b-5p mimic transfection affects the migration capacity of 12Z cells. A 2-fold decrease in cell migration (p-value 0.0021) was observed after 12Z cell mimic transfection. No change in proliferation was demonstrated. Limitations, reasons for caution Although our findings both in-silico and in-vitro suggest a link between dysregulated miRNAs and cell migration, further in-vitro studies in primary cells and in-vivo studies in animal models are needed to reveal the specific pathways that these miRNAs regulate to explain the observed functional changes in the context of endometriosis. Wider implications of the findings This study gives molecular insight into the pathogenesis of endometriosis, a poorly understood disease, by demonstrating changes in miRNA expression in both the endometrium and endometrioma that potentially can be linked to a changed cell migratory ability. Furthermore, identified miRNAs could be further evaluated as diagnostic biomarkers in larger studies. Trial registration number Not applicable

Circulating microRNA signatures in patients with chronic Urticaria.

Background: Chronic Urticaria (CU) is a complex skin disease that appears as recurrent raised itchy rash/angioedema or both for more than six weeks. The pathophysiology of CU is complex and has yet to be understood entirely. It is predominantly a mast cell-driven disease with the possible involvement of type 2 inflammation. Current evidence largely favors mast cell activation by an IgE-mediated autoallergic mechanism or an autoimmune mechanism by IgG autoantibodies to IgE/ high-affinity receptor of IgE. MicroRNAs (miRNA) are small coding RNAs regulating gene expression at the post-transcription level. This study aimed to investigate the circulating miRNA as potential biomarkers in CU patients compared to healthy controls. Methods: The miRNA gene expression was done in seven patients with CU and seven healthy controls. The expression of miRNA is done using TaqMan openArray human advanced miRNA Panel. ExpressionSuite Software (Thermo Fischer Scientific, Waltham, MA, USA) is used for data analysis to quantify the miRNA expressions. P<0.05 is considered to be statistically significant. Results: A significant upregulation (p<0.05) in the miR-451a, miR-9-5p, miR-150-5p, miR-296-5p, and miR-182-5p was observed in CU compared to controls. Dysregulation of miR-451a is identified as an early biomarker in allergic diseases. Functional enrichment analysis with the KEGG pathway and disease ontology databases showed that these miRNAs were associated with skin diseases and inflammation. The differentially expressed miRNAs contribute to determining the genes regulated in CU. miRNA-based therapies that target different genes in a given pathway might be a potential candidate for treating CU. Conclusion: miRNA field has grown steadily over the past few years, but the role of circulating miRNAs in CU remains relatively unexplored. This study showed that the upregulated circulating miRNA might play an essential role in CU pathogenesis and inflammation. Also, our study highlights the importance of miRNAs as a future biomarker and potential therapeutic target to be investigated.

Temporal expression analysis of microRNAs and their target GRAS genes induced by osmotic stress in two contrasting wheat genotypes.

MicroRNAs (miRNAs) are important nonprotein-coding genes in plants which participate in almost all biological processes during abiotic and biotic stresses. Understanding how plants respond to various environmental conditions requires the identification of stress-related miRNAs. In recent years, there has been an increased interest in studying miRNA genes and gene expression. Drought is one of the common environmental stresses limiting plant growth and development. Stress-specific miRNAs and their GRAS gene targets were validated to understand the role of miRNAs in response to osmotic stress. In this study, expression patterns of the ten stress-responsive miRNAs involved in osmotic stress adaptation were examined in order to undertand the regulation behavior of abiotic stress and miRNAs in two contrasting wheat genotype C-306 (drought tolerant) and WL-711 (drought sensitive). Three miRNAs were discovered to be upregulated under stress, whereas seven miRNAs were showed to be down-regulated as a consequence of the study. In contrast to miRNA, it was also discovered that GRAS genes as their targets were up-regulated during osmotic stress. In addition, the expression level of miR159, miR408 along with their targets, TaGRAS178 and TaGRAS84 increased in response to osmotic stress. Nevertheless, miR408 is highly conserved miRNA that regulates plant growth, development and stress response. As a result, variation in the expression levels of studied miRNAs in the presence of target genes provides a plausible explanation for miRNA-based abiotic stress regulation. A regulatory network of miRNA and their targets revealed that fourteen miRNA interact with 55 GRAS targets from various subfamilies that contribute in the plant growth and development. These findings provide evidence for temporal and variety-specific differential regulation of miRNAs and their targets in wheat in response to osmotic shock, and they may aid in determining the potential.