Human microRNA Research Articles

Serum expression of mirnas in obese and lean patients with heart failure

Abstract Background Heart Failure (HF) is a progressive disease that results in increased morbidity and mortality, and clinical studies have demonstrated that body mass index (BMI) is an independent risk factor for the development of HF. Evidence has suggested that human obesity is associated with reduced mortality among patients with HF, a clinical phenomenon known as the "Obesity Paradox." MicroRNAs (miRNAs) have been underscored for their pivotal regulatory roles in numerous diseases, particularly in the context of HF. Nevertheless, our understanding of the impact of these miRNAs on obesity in conjunction with HF remains limited. Purpose The objective of this study was to evaluate the serum expression of miRNAs in obese and lean patients with HF and establish the relationship between these miRNAs and BMI. Additionally, we explored this association within two distinct phenotypes: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Methods Sixty-five patients with symptomatic HF (all NYHA >/=II, mean-LVFE 44.4 %), 29 lean (BMI= 25.87 ± 2.52 Kg/m2) and 36 obese (BMI= 34.52 ± 4.15 Kg/m2), were prospectively evaluated by clinical, laboratory and echocardiographic analyses. Serum expression of miRNAs was assessed by the TaqMan OpenArray Human MicroRNA system, a polymerase chain reaction-based quantitative platform that contains 754 microRNAs in a microfluidic platform. Results Among the studied miRNAs, seventeen were upregulated and one downregulated in obese HF patients compared to lean HF patients (Figure 1A). Ten miRNAs were differentially expressed in the serum of obese HFpEF patients compared to lean HFrEF patients (Figure 1B) and five were differentially expressed in the serum of obese HFpEF patients when compared to lean HFpEF patients (Figure 1C). miR-132 was upregulated in obese patients with HFrEF and HFpEF compared to lean patients, whereas miR-1291 was downregulated only in obese patients with HFpEF. Correlation analysis demonstrated a positive association between BMI and miR-132 (r=0.502; p=0.001), miR-148b (r=0.510; p<0.001), miR-103a-3p (r=0.373; p =0.011) and miR-374b-5p (r=0.325; p=0.034) in HF patients and gene set enrichment analysis identified seventy-nine potential target genes common to at least three of these four miRNAs, with the EIF4E3 and TRA2B genes common to the four miRNAs. Conclusions Our study reveals a profile of miRNAs that are differentially expressed in obese patients with HF when compared to lean patients with HF. Furthermore, four of these miRNAs showed a positive correlation with BMI in patients with HF. Although the literature indicates that miR-132 presents reduced expression in obesity models, our study identified increased serum expression of this miRNA, suggesting that it might be a potential "missing link" in the obesity paradox in patients with HF. Further studies with a larger sample are needed to confirm and explore the mechanisms linking these miRNAs to the obesity paradox.

Early Cancer Detection via Multi-microRNA Profiling of Urinary Exosomes Captured by Nanowires.

Multiple microRNAs encapsulated in extracellular vesicles (EVs) including exosomes, unique subtypes of EVs, differ in healthy and cancer groups of people, and they represent a warning sign for various cancer scenarios. Since all EVs in blood cannot be transferred from donor to recipient cells during a single blood circulation, kidney filtration could pass some untransferred EVs from blood to urine. Previously, we reported on the ability of zinc oxide nanowires to capture EVs based on surface charge and hydrogen bonding; these nanowires extracted massive numbers of microRNAs in urine, seeking cancer-related microRNAs through statistical analysis. Here, we report on the scalability of the nanowire performance capability to comprehensively capture EVs, including exosomes, in urine, extract microRNAs from the captured EVs in situ, and identify multiple microRNAs in the extracted microRNAs differing in noncancer and lung cancer subjects through machine learning-based analysis. The nanowire-based extraction allowed the presence of about 2500 species of urinary microRNAs to be confirmed, meaning that urine includes almost all human microRNA species. The machine learning-based analysis identified multiple microRNAs from the extracted microRNA species. The ensembles could classify cancer and noncancer subjects with the area under the receiver operating characteristic curve of 0.99, even though the former were staged early.

The impact of host microRNAs on the development of conserved mutations of SARS-CoV-2.

SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has undergone various genetic alterations due to evolutionary pressures exerted by host cells, including intracellular antiviral mechanisms such as targeting by human microRNAs (miRNAs). This study investigates the impact of miRNAs hsa-miR-3132 and hsa-miR-4650 on the viral genome. Sequence alignment revealed conserved mutations in the binding sites of these miRNAs in adapted strains compared to the original Wuhan-Hu-1 strain, leading to their deletion. Despite modest expression of these miRNAs in SARS-CoV-2 target tissues, their efficacy against mutant strains is reduced due to the loss of binding sites. Structural analysis indicates that the mutant genome is more stable than the Wuhan-Hu-1 genome. Luciferase and virus titration assays demonstrate that hsa-miR-3132 and hsa-miR-4650 effectively target the Nsp3 gene in the Wuhan-Hu-1 strain but not in mutant strains lacking their binding sites. These findings suggest that the observed mutations help the virus evade selective pressure from human miRNAs, contributing to its adaptation.

Role of HPV E7/miR-143-3p/SH2D3A pathway in regulating the occurrence and development of cervical cancer.

This study aims to explore the role of SH2D3A in cervical cancer, as well as its potential interaction with human papillomavirus (HPV) E7 and microRNA (miRNA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were used to compare the expressions of SH2D3A in tissues. To assess the effects of SH2D3A on cervical cancer cell phenotypes, SH2D3A was knocked down in SiHa and HeLa cells, followed by cell proliferation (Cell Counting Kit-8 assay), apoptosis (flow cytometry), and invasion (Transwell assay) analyses. A transplantation tumor model was established to compare the tumorigenic ability of cervical cancer cells before and after SH2D3A silencing. Bioinformatics analysis predicted and dual-luciferase reporter assays verified the sponge adsorption effect of SH2D3A on miRNA. Western blot and qRT-PCR analyses were conducted to examine the impact on target genes following the downregulation of HPV E7 and SH2D3A. SH2D3A expression was significantly elevated in cervical cancer tissues. SH2D3A silencing inhibited cell proliferation and invasion, induced apoptosis, and reduced tumorigenesis in nude mice. Bioinformatics tools identified a binding relationship between SH2D3A and miR-143-3p, confirmed by the luciferase reporter assays. Western blot analysis revealed that SH2D3A knockdown led to decreased levels of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) proteins. Additionally, qRT-PCR showed that SH2D3A mRNA levels decreased after HPV E7 silencing, whereas miR-143-3p levels significantly increased. HPV E7 influences SH2D3A expression through miR-143-3p, thereby regulating the JAK1/STAT3 pathway. This mechanism promotes the occurrence and development of cervical cancer.

Dual-neighbourhood information aggregation and feature fusion for prediction of miRNA–disease association

Studying the intricate relationship between miRNAs and diseases is crucial to prevent and treat miRNA-related disorders. Existing computational methods often overlook the importance of features of different nodes and the propagation of features among heterogeneous nodes. Many prediction models focus only on the feature coding of miRNA and diseases and ignore the importance of feature aggregation. We propose a prediction method via dual-neighbourhood feature aggregation and feature fusion, which uses multiple sources of information, aggregates information on homogeneous and heterogeneous nodes and fuses learned features to predict multiple representations of disease nodes. We constructed similarity networks of multiple homogeneous nodes based on different similarity computation methods respectively, and fused the attention mechanism by using graph convolutional networks to obtain information of different levels of importance. To alleviate the problem of sparse connectivity in the dataset, we built a two-neighbourhood heterogeneous graph neural network model to integrate the homogeneous similarity network into a miRNA-disease heterogeneous network by using known miRNA–disease association information. We used the neighbourhood information associated with the nodes in the network to perform feature aggregation. In addition, we used a feature fusion module to learn the importance of different types of nodes to predict miRNA–disease associations. Our experimental results on the Human microRNA Disease Database (HMDD v3.2) show that the model demonstrates superior performance. This work demonstrates the capability of our model to identify potential miRNAs associated with diseases through a case study of two common cancers.

ExomiRHub: A comprehensive database for hosting and analyzing human disease-related extracellular microRNA transcriptomics data

Extracellular microRNA (miRNA) expression data generated by different laboratories exhibit heterogeneity, which poses challenges for biologists without bioinformatics expertise. To address this, we introduce ExomiRHub (http://www.biomedical-web.com/exomirhub/), a user-friendly database designed for biologists. This database incorporates 191 human extracellular miRNA expression datasets associated with 112 disease phenotypes, 62 treatments, and 24 genotypes, encompassing 29,198 and 23 sample types. ExomiRHub also integrates 16,012 miRNA transcriptomes of 156 cancer subtypes from The Cancer Genome Atlas. All the data in ExomiRHub were further standardized and curated with annotations. The platform offers 25 analytical functions, including differential expression, co-expression, Weighted Gene Co-Expression Network Analysis (WGCNA), feature selection, and functional enrichment, enabling users to select samples, define groups, and customize parameters for analyses. Moreover, ExomiRHub provides a web service that allows biologists to analyze their uploaded miRNA expression data. Four additional tools were developed to evaluate the functions and targets of miRNAs and miRNA variations. Through ExomiRHub, we identified extracellular miRNA biomarkers associated with angiogenesis for monitoring glioma progression, demonstrating its potential to significantly accelerate the discovery of extracellular miRNA biomarkers.

Human Leukocyte Antigen and microRNAs as Key Orchestrators of Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review.

The expression of inflamma-miRs and human leukocyte antigen (HLA) haplotypes could indicate mild cognitive impairment (MCI) and Alzheimer's disease (AD). We used international databases to conduct a systematic review of studies on HLA variants and a meta-analysis of research on microRNAs (miRNAs). We aimed to analyze the discriminative value of HLA variants and miRNAs in MCI, AD and controls to evaluate the protective or causative effect of HLA in cognitive decline, establish the role of miRNAs as biomarkers for the early detection of AD, and find a possible link between miRNAs and HLA. Statistical analysis was conducted using Comprehensive Meta-analysis software, version 2.2.050 (Biostat Inc., Englewood, NJ, USA). The effect sizes were estimated by the logarithm base 2 of the fold change. The systematic review revealed that some HLA variants, such as HLA-B*4402, HLA-A*33:01, HLA-A*33:01, HLA-DPB1, HLA-DR15, HLA-DQB1*03:03, HLA-DQB1*06:01, HLA-DQB1*03:01, SNPs on HLA-DRB1/DQB1, and HLA-DQA1, predisposed to cognitive decline before the occurrence of AD, while HLA-A1*01, HLA-DRB1∗13:02, HLA-DRB1*04:04, and HLA-DRB1*04:01 demonstrated a protective role. The meta-analysis identified let-7 and miR-15/16 as biomarkers for the early detection of AD. The association between these two miRNA families and the HLA variants that predispose to AD could be used for the early screening and prevention of MCI.

Evaluation of Micro-RNA Expression Profiling Level as Biomarkers for Diagnosis and Gene Sequencing in Patients Suffering from Breast Cancer

Background: Human bloodstream microRNAs (miRNAs) have emerged as a promising predictive and diagnostic biomarker for a range of cancers, including breast cancer. Our objective was to look into new miRNA biomarkers for diagnosis in the serum of patients with breast cancer and track the expression levels at different stages using miRNA profiling.Methods: 53 breast cancer patients and 10 healthy controls had blood samples tested for three miRNAs. miRNAs were extracted from blood and evaluated using real-time quantitative polymerase chain reaction. After extracting genomic DNA, miRNA primer-produced PCR products were sequenced to discover point mutations that may contribute to the illness.Results: After examining miR195, miR200b, and miR331, breast cancer patients had a significantly lower miR195 level than healthy persons. In addition, miR200b expression levels were significantly lower in breast cancer patients than in healthy individuals. In advanced stages, miR331 expression was substantially higher than in healthy people.Conclusion: The findings of our study demonstrated a significant association between the expression of miRNAs and the prognosis of breast cancer. Additional research is necessary to study better the correlation between these circulating miRNAs and the stages of breast cancer.Keywords: Breast cancer; Circulating miRNAs; miR195; miR200b; miR331 RT PCR; Gene Sequencing

Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity

Background:The development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes are still missing.Methods:Liver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice.Results:Here, we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182–5 p was the most associated with whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene LRP6 was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182–5 p overexpression. Weight loss in obese mice decreased hepatic miR-182–5 p and restored Lrp6 expression and other miR-182–5 p target genes. Hepatic overexpression of miR-182–5 p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days.Conclusions:By mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of LRP6 by miR-182–5 p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182–5 p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis.Funding:This work was supported by research funding from the Deutsche Forschungsgemeinschaft (KI 1887/2-1, KI 1887/2-2, KI 1887/3-1 and CRC-TR296), the European Research Council (ERC, CoG Yoyo LepReSens no. 101002247; PTP), the Helmholtz Association (Initiative and Networking Fund International Helmholtz Research School for Diabetes; MB) and the German Center for Diabetes Research (DZD Next Grant 82DZD09D1G).

Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity.

The development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes are still missing. Liver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice. Here, we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182-5 p was the most associated with whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene LRP6 was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5 p overexpression. Weight loss in obese mice decreased hepatic miR-182-5 p and restored Lrp6 expression and other miR-182-5 p target genes. Hepatic overexpression of miR-182-5 p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days. By mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of LRP6 by miR-182-5 p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182-5 p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis. This work was supported by research funding from the Deutsche Forschungsgemeinschaft (KI 1887/2-1, KI 1887/2-2, KI 1887/3-1 and CRC-TR296), the European Research Council (ERC, CoG Yoyo LepReSens no. 101002247; PTP), the Helmholtz Association (Initiative and Networking Fund International Helmholtz Research School for Diabetes; MB) and the German Center for Diabetes Research (DZD Next Grant 82DZD09D1G).

Identification of potential pathogenic genes related to osteoporosis and osteoarthritis.

Osteoarthritis (OA) and osteoporosis (OS) are the most common orthopedic diseases. To identify important genes as biomarkers for the pathogenesis of OA and OS. Microarray data for OA and OS were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between the OA and healthy control groups and between the OS and healthy control groups were identified using the Limma software package. Overlapping hub DEGs were selected using MCC, MNC, DEGREE, and EPC. Weighted gene co-expression network analysis (WGCNA) was used to mine OA- and OS-related modules. Shared hub DEGs were identified, human microRNA disease database was used to screen microRNAs associated with OA and OS, and an miRNA-target gene network was constructed. Finally, the expression of shared hub DEGs was evaluated. A total of 104 overlapping DEGs were identified in both the OA and OS groups, which were mainly related to inflammatory biological processes, such as the Akt and TNF signaling pathways Forty-six hub DEGs were identified using MCC, MNC, DEGREE, and EPC modules using different algorithms. Seven modules with 392 genes that highly correlated with disease were identified in the WGCNA. Furthermore, 10 shared hub DEGs were identified between the OA and OS groups, including OGN, FAP, COL6A3, THBS4, IGFBP2, LRRC15, DDR2, RND3, EFNB2, and CD48. A network consisting of 8 shared hub DEGs and 55 miRNAs was constructed. Furthermore, CD48 was significantly upregulated in the OA and OS groups, whereas EFNB2, DR2, COL6A3, and RND3 were significantly downregulated in OA and OS. Other hub DEGs were significantly upregulated in OA and downregulated in OS. The ten genes may be promising biomarkers for modulating the development of both OA and OS.

Differential Expression of Circulating miRNAs and Carfilzomib-Related Cardiovascular Adverse Events in Patients with Multiple Myeloma.

This study investigates the association between circulating microRNA (miRNA) expression and cardiovascular adverse events (CVAE) in multiple myeloma (MM) patients treated with a carfilzomib (CFZ)-based regimen. A cohort of 60 MM patients from the Prospective Observation of Cardiac Safety with Proteasome Inhibitor (PROTECT) study was analyzed. Among these, 31 patients (51.6%) developed CVAE post-CFZ treatment. The Taqman OpenArray Human microRNA panels were used for miRNA profiling. We identified 13 differentially expressed miRNAs at baseline, with higher expressions of miR-125a-5p, miR-15a-5p, miR-18a-3p, and miR-152-3p and lower expression of miR-140-3p in patients who later developed CVAE compared to those free of CVAE, adjusting for age, gender, race, and higher B-type natriuretic peptide levels. We also identified three miRNAs, including miR-150-5p, that were differentially expressed in patients with and without CVAE post-treatment. Additionally, five miRNAs responded differently to CFZ treatment in CVAE vs. non-CVAE patients, including significantly elevated post-treatment expression of miR-140-3p and lower expressions of miR-598, miR-152, miR-21, and miR-323a in CVAE patients. Pathway enrichment analysis highlighted the involvement of these miRNAs in cardiovascular diseases and vascular processes. These findings suggest that specific miRNAs could serve as predictive biomarkers for CVAE and provide insights into the underlying mechanisms of CFZ-CVAE. Further investigation is warranted before these findings can be applied in clinical settings.

Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human microRNA mutation.

Mutations in microRNA-96 (MIR96) cause autosomal dominant deafness-50 (DFNA50), a form of delayed-onset hearing loss. Genome editing has shown efficacy in hearing recovery through intervention in neonatal mice, yet editing in the adult inner ear is necessary for clinical applications, which has not been done. Here, we developed a genome editing therapy for the MIR96 mutation 14C>A by screening different CRISPR systems and optimizing Cas9 expression and the sgRNA scaffold for efficient and specific mutation editing. AAV delivery of the KKH variant of Staphylococcus aureus Cas9 (SaCas9-KKH) and sgRNA to the cochleae of presymptomatic (3-week-old) and symptomatic (6-week-old) adult Mir9614C>A/+ mutant mice improved hearing long term, with efficacy increased by injection at a younger age. Adult inner ear delivery resulted in transient Cas9 expression without evidence of AAV genomic integration, indicating the good safety profile of our in vivo genome editing strategy. We developed a dual-AAV system, including an AAV-sgmiR96-master carrying sgRNAs against all known human MIR96 mutations. Because mouse and human MIR96 sequences share 100% homology, our approach and sgRNA selection for efficient and specific hair cell editing for long-term hearing recovery lay the foundation for the development of treatment for patients with DFNA50 caused by MIR96 mutations.

Human cytomegalovirus microRNAs: strategies for immune evasion and viral latency.

Viruses use various strategies and mechanisms to deal with cells and proteins of the immune system that form a barrier against infection. One of these mechanisms is the encoding and production of viral microRNAs (miRNAs), whose function is to regulate the gene expression of the host cell and the virus, thus creating a suitable environment for survival and spreading viral infection. miRNAs are short, single-stranded, non-coding RNA molecules that can regulate the expression of host and viral proteins, and due to their non-immunogenic nature, they are not eliminated by the cells of the immune system. More than half of the viral miRNAs are encoded and produced by Orthoherpesviridae family members. Human cytomegalovirus (HCMV) produces miRNAs that mediate various processes in infected cells to contribute to HCMV pathogenicity, including immune escape, viral latency, and cell apoptosis. Here, we discuss which cellular and viral proteins or cellular pathways and processes these mysterious molecules target to evade immunity and support viral latency in infected cells. We also discuss current evidence that their function of bypassing the host's innate and adaptive immune system is essential for the survival and multiplication of the virus and the spread of HCMV infection.

Deciphering the landscape of lncRNA-driven ceRNA network in schizophrenia etiology

BackgroundThe unifying hypothesis of competing endogenous RNA (ceRNA) wherein crosstalk between coding (mRNAs) and long non-coding RNAs (lncRNAs) via microRNA (miRNA) response elements, creates a pervasive regulatory network across the transcriptome, has been implicated in complex disorders including schizophrenia. Even with a wide range of high-throughput data, the etiology of schizophrenia remains elusive, necessitating a more holistic understanding of the altered genetic landscape, shifting focus from solely candidate gene studies and protein-coding variants.ObjectiveWe developed lncRNA-associated ceRNA networks to elucidate global molecular/regulatory signatures underlying schizophrenia using diverse data in the public domain.MethodsMicroarray dataset associated with peripheral blood mononuclear cells (PBMCs) of schizophrenia and control patients was used to identify differentially expressed mRNAs. Weighted gene co-expression network analysis (WGCNA) was used to identify highly correlated hubs, and genes from these overlapping Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) term genesets were considered key mRNA players. StarBase, Human MicroRNA Disease Database, and miRWalk were used to derive mRNA-miRNA and miRNA-lncRNA relationships. Finally, the key mRNAs, interacting lncRNAs and miRNAs were chosen to reconstruct sub-ceRNA networks based on network centrality scores.ResultsBioinformatics analysis revealed the involvement of three differentially expressed mRNAs, namely ADRA1A, HAP1 and HOMER3 in the schizophrenia ceRNA networks with lncRNAs NEAT1, XIST, and KCNQ1OT1 modulating their activity by a suggestive sequestering of miR-3163, miR-214-3p and miR-2467-3p, respectively.ConclusionsFurthermore, based on contextual evidence, we propose how ceRNAs could orchestrate crosstalk between neurostructural dynamics and immune/inflammatory processes and enable unifying these disparate models of schizophrenia etiology.

Identification of New, Translatable ProtectomiRs against Myocardial Ischemia/Reperfusion Injury and Oxidative Stress: The Role of MMP/Biglycan Signaling Pathways.

Ischemic conditionings (ICon) were intensively investigated and several protective signaling pathways were identified. Previously, we have shown the role of matrix metalloproteinases (MMP) in myocardial ischemia/reperfusion injury (MIRI) and the cardioprotective role of biglycan (BGN), a small leucine-rich proteoglycan in vitro. Here, we hypothesized that cardiac MMP and BGN signaling are involved in the protective effects of ICon. A reverse target-microRNA prediction was performed by using the miRNAtarget™ 2.0 software to identify human microRNAs with a possible regulatory effect on MMP and BGN, such as on related genes. To validate the identified 1289 miRNAs in the predicted network, we compared them to two cardioprotective miRNA omics datasets derived from pig and rat models of MIRI in the presence of ICons. Among the experimentally measured miRNAs, we found 100% sequence identity to human predicted regulatory miRNAs in the case of 37 porcine and 24 rat miRNAs. Upon further analysis, 42 miRNAs were identified as MIRI-associated miRNAs, from which 24 miRNAs were counter-regulated due to ICons. Our findings highlight 24 miRNAs that potentially regulate cardioprotective therapeutic targets associated with MMPs and BGN in a highly translatable porcine model of acute myocardial infarction.

IL-2RG as a possible immunotherapeutic target in CRC predicting poor prognosis and regulated by miR-7-5p and miR-26b-5p

Despite advances in treatment strategies, colorectal cancer (CRC) continues to cause significant morbidity and mortality, with mounting evidence a close link between immune system dysfunctions issued. Interleukin-2 receptor gamma (IL-2RG) plays a pivotal role as a common subunit receptor in the IL-2 family cytokines and activates the JAK-STAT pathway. This study delves into the role of Interleukin-2 receptor gamma (IL-2RG) within the tumor microenvironment and investigates potential microRNAs (miRNAs) that directly inhibit IL-2RG, aiming to discern their impact on CRC clinical outcomes. Bioinformatics analysis revealed a significant upregulation of IL-2RG mRNA in TCGA-COAD samples and showed strong correlations with the infiltration of various lymphocytes. Single-cell analysis corroborated these findings, highlighting IL-2RG expression in critical immune cell subsets. To explore miRNA involvement in IL-2RG dysregulation, mRNA was isolated from the tumor tissues and lymphocytes of 258 CRC patients and 30 healthy controls, and IL-2RG was cloned into the pcDNA3.1/CT-GFP-TOPO vector. Human embryonic kidney cell lines (HEK-293T) were transfected with this construct. Our research involved a comprehensive analysis of miRPathDB, miRWalk, and Targetscan databases to identify the miRNAs associated with the 3′ UTR of human IL-2RG. The human microRNA (miRNA) molecules, hsa-miR-7-5p and hsa-miR-26b-5p, have been identified as potent suppressors of IL-2RG expression in CRC patients. Specifically, the downregulation of hsa-miR-7-5p and hsa-miR-26b-5p has been shown to result in the upregulation of IL-2RG mRNA expression in these patients. Prognostic evaluation of IL-2RG, hsa-miR-7-5p, and hsa-miR-26b-5p, using TCGA-COAD data and patient samples, established that higher IL-2RG expression and lower expression of both miRNAs were associated with poorer outcomes. Additionally, this study identified several long non-coding RNAs (LncRNAs), such as ZFAS1, SOX21-AS1, SNHG11, SNHG16, SNHG1, DLX6-AS1, GAS5, SNHG6, and MALAT1, which may act as competing endogenous RNA molecules for IL2RG by sequestering shared hsa-miR-7-5p and hsa-miR-26b-5p. In summary, this investigation underscores the potential utility of IL-2RG, hsa-miR-7-5p, and hsa-miR-26b-5p as serum and tissue biomarkers for predicting CRC patient prognosis while also offering promise as targets for immunotherapy in CRC management.Graphical

Exploration of the Shared Gene Signatures and Molecular Mechanisms Between Ischemic Stroke and Atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory vascular disease and the predominant cause of ischemic stroke (IS). AS is a potential pathogenetic factor in IS. However, the processes by which they interact remain unknown. The purpose of this paper was to investigate the shared gene signatures and putative molecular processes in AS and IS. Gene Expression Omnibus (GEO) data for AS and IS microarrays were retrieved. The co-expression modules associated with AS and IS were identified using the Weighted Gene Co-Expression Network Analysis (WGCNA). We constructed an interaction network of shared differentially expressed genes in AS and IS and conducted an enrichment analysis using ClueGO software. We validated the results in a separate cohort through differential gene analysis. Additionally, we retrieved AS and IS-related miRNAs from the Human microRNA Disease Database (HMDD) and predicted their target genes using miRWalk. We then built a network of miRNAs-mRNAs-KEGG pathways using the shared genes. Through WGCNA, we identified five modules and six modules as significant in AS and IS, respectively. A ClueGO enrichment analysis of common genes showed that highly active CCR1 chemokine receptor binding is critical to AS and IS pathogenesis. The differential analysis expression results in another cohort closely matched these findings. The miRNA-mRNA network suggested that hsa-miR-330-5p, hsa-miR-143-3p, hsa-miR-16-5p, hsa-miR-152-3p might regulate the shared gene KRAS, which could be a key player in AS and IS. We integrated ischemic stroke and carotid atherosclerosis public database data and found that ATF3, CCL3, CCL4, JUNB, KRAS, and ZC3H12A may affect both, making them novel biomarkers or therapeutic target genes. Clinical samples and expression trends supported our analyses of pivotal genes.

Uncovering the shared neuro-immune-related regulatory mechanisms between spinal cord injury and osteoarthritis

Adults with spinal cord injury (SCI), a destructive neurological injury, have a significantly higher incidence of osteoarthritis (OA), a highly prevalent chronic joint disorder. This study aimed to dissect the neuroimmune-related regulatory mechanisms of SCI and OA using bioinformatics analysis. Using microarray data from the Gene Expression Omnibus database, differentially expressed genes (DEGs) were screened between SCI and sham samples and between OA and control samples. Common DEGs were used to construct a protein-protein interaction (PPI) network. Weighted gene co-expression network analysis (WGCNA) was used to mine SCI- and OA-related modules. Shared miRNAs were identified, and target genes were predicted using the Human MicroRNA Disease Database (HMDD) database. A miRNA-gene-pathway regulatory network was constructed with overlapping genes, miRNAs, and significantly enriched pathways. Finally, the expression of the identified genes and miRNAs was verified using RT-qPCR. In both the SCI and OA groups, 185 common DEGs were identified, and three hub clusters were obtained from the PPI network. WGCNA revealed three SCI-related modules and two OA-related modules. There were 43 overlapping genes between the PPI network clusters and the WGCNA network modules. Seventeen miRNAs shared between patients with SCI and OA were identified. A regulatory network consisting of five genes, six miRNAs, and six signaling pathways was constructed. Upregulation of CD44, TGFBR1, CCR5, and IGF1, while lower levels of miR-125b-5p, miR-130a-3p, miR-16-5p, miR-204-5p, and miR-204-3p in both SCI and OA were successfully verified using RT-qPCR. Our study suggests that a miRNA-gene-pathway network is implicated in the neuroimmune-related regulatory mechanisms of SCI and OA. CD44, TGFBR1, CCR5, and IGF1, and their related miRNAs (miR-125b-5p, miR-130a-3p, miR-16-5p, miR-204-5p, and miR-204-3p) may serve as promising biomarkers and candidate therapeutic targets for SCI and OA.

Exploration of the core pathway of inflammatory bowel disease complicated with metabolic fatty liver and two-sample Mendelian randomization study of the causal relationships behind the disease.

Inflammatory bowel disease (IBD) is often associated with complex extraintestinal manifestations. The incidence of nonalcoholic fatty liver disease (NAFLD) in IBD populations is increasing yearly. However, the mechanism of interaction between NAFLD and IBD is not clear. Consequently, this study aimed to explore the common genetic characteristics of IBD and NAFLD and identify potential therapeutic targets. Gene chip datasets for IBD and NAFLD were obtained from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to identify modules in those datasets related to IBD and NAFLD. ClueGO was used for biological analysis of the shared genes between IBD and NAFLD. Based on the Human MicroRNA Disease Database (HMDD), microRNAs (miRNAs) common to NAFLD and IBD were obtained. Potential target genes for the miRNAs were predicted using the miRTarbase, miRDB, and TargetScan databases. Two-sample Mendelian randomization (MR) and two-way MR were used to explore the causal relationship between Interleukin-17 (IL-17) and the risk of IBD and NAFLD using data from GWAS retrieved from an open database. Through WGCNA, gene modules of interest were identified. GO enrichment analysis using ClueGO suggested that the abnormal secretion of chemokines may be a common pathophysiological feature of IBD and NAFLD, and that the IL-17-related pathway may be a common key pathway for the pathological changes that occur in IBD and NAFLD. The core differentially expressed genes (DEGs) in IBD and NAFLD were identified and included COL1A1, LUM, CCL22, CCL2, THBS2, COL1A2, MMP9, and CXCL8. Another cohort was used for validation. Finally, analysis of the miRNAs identified potential therapeutic targets. The MR results suggested that although there was no causal relationship between IBD and NAFLD, there were causal relationships between IL-17 and IBD and NAFLD. We established a comorbid model to explain the potential mechanism of IBD with NAFLD and identified the chemokine-related pathway mediated by cytokine IL-17 as the core pathway in IBD with NAFLD, in which miRNA also plays a role and thus provides potential therapeutic targets.