scholarly journals Peripheral Circulating Exosomal miRNAs Potentially Contribute to the Regulation of Molecular Signaling Networks in Aging

2020 ◽  
Vol 21 (6) ◽  
pp. 1908 ◽  
Author(s):  
Hongxia Zhang ◽  
Kunlin Jin

People are living longer than ever. Consequently, they have a greater chance for developing a functional impairment or aging-related disease, such as a neurodegenerative disease, later in life. Thus, it is important to identify and understand mechanisms underlying aging as well as the potential for rejuvenation. Therefore, we used next-generation sequencing to identify differentially expressed microRNAs (miRNAs) in serum exosomes isolated from young (three-month-old) and old (22-month-old) rats and then used bioinformatics to explore candidate genes and aging-related pathways. We identified 2844 mRNAs and 68 miRNAs that were differentially expressed with age. TargetScan revealed that 19 of these miRNAs are predicated to target the 766 mRNAs. Pathways analysis revealed signaling components targeted by these miRNAs: mTOR, AMPK, eNOS, IGF, PTEN, p53, integrins, and growth hormone. In addition, the most frequently predicted target genes regulated by these miRNAs were EIF4EBP1, insulin receptor, PDK1, PTEN, paxillin, and IGF-1 receptor. These signaling pathways and target genes may play critical roles in regulating aging and lifespan, thereby validating our analysis. Understanding the causes of aging and the underlying mechanisms may lead to interventions that could reverse certain aging processes and slow development of aging-related diseases.

2021 ◽  
Author(s):  
Li Xia ◽  
Huang He

Abstract Backguound: To screen the signaling axis of epigenetic modification in serum exosomes of ovarian cancer patients based on sequencing technology and raw signal analysis, in depth study of the potential mechanism of action of ovarian cancer, prediction of potential therapeutic targets and survival prognosis analysis of potential targets.Methods: Serum exosomes from three ovarian cancer patients were selected as the experimental group, and serum exosomes from three uterine fibroid patients as the control group, and whole transcriptome of serum exosomes was performed to obtain differentially expressed lncRNA and mRNA in ovarian cancer,The miRcode database and miRNA target gene prediction website were used to predict the target genes, Cytoscape software was used to draw a ceRNA network model of epigenetic modification of ovarian cancer serum exosomes, and the R language was used for GO and KEGG enrichment analysis of the target genes. Finally, the TCGA website was used to download clinical and expression data related to ovarian cancer, and the common potential target genes obtained in the previous period were analyzed for survival。Results: A total of 117 differentially expressed lncRNAs as well as 513 differentially expressed mRNAs (P < 0.05, |log2 FC|≥ 1.0) were obtained by combining sequencing data and raw signal analysis, and 841 predicted target genes were reciprocally mapped by combining mircode database and miRNA target gene prediction website, resulting in 11 potential target genes related to ovarian cancer (FGFR3, BMPR1B, TRIM29, FBN2, PAPPA, CCDC58, IGSF3, FBXO10, GPAM, HOXA10, LHFPL4), and survival prognosis analysis of the above 11 target genes revealed that the survival curve was statistically significant (P < 0.05) for HOXA10 only genes, but not for the other genes, and through enrichment analysis, we found that the above target genes were mainly involved in biological processes such as regulation of transmembrane receptor protein kinase activity, structural molecule activity with elasticity, transforming growth factor - activated receptor activity, and GABA receptor binding, and were mainly enriched in signaling pathways regulating stem cell pluripotency, bladder cancer, glycerolipid metabolism, central carbon metabolism of cancer, tyrosine stimulation to EGFR in signaling pathways such as resistance to enzyme inhibitors.Conclusions: The serum exosomal DIO3OS-hsa-miR-27a-3p-HOXA10 epigenetic modification signaling axis affects ovarian cancer development and disease survival prognosis by targeting transcriptional dysregulation pathways in cancer.


2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Danli Zhong ◽  
Chanyuan Wu ◽  
Dong Xu ◽  
Jingjing Bai ◽  
Qian Wang ◽  
...  

The present study is aimed at profiling circulating exosome-derived microRNAs (miRNAs/miRs) from patients with dermatomyositis (DM), in particular those complicated with interstitial lung disease (ILD) with anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive. Fifteen participants were enrolled, including five patients with DM complicated with ILDs prior to treatment with circulating anti-MDA5 antibody-positive status [DM-ILD-MDA5 Ab(+)], five DM patients without ILDs who were negative for 16 detectable myositis-specific antibodies [DM-nonILD-MSA16(-)], and five age- and gender-matched healthy donor controls (HCs). The characteristics of the exosomes extracted by Ribo™ Exosome Isolation Reagent were identified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and flow cytometry. Differentially expressed miRNAs, determined by next-generation deep sequencing, were identified through the criteria of ∣ log 2   fold   change ∣ ≥ 1 and P < 0.01 . A total of 38 miRNAs were significantly upregulated in exosomes from patients with DM-ILD-MDA5 Ab(+) compared to those from HC, while 21 miRNAs were significantly downregulated. Compared to exosomes derived from patients with DM-nonILD-MSA16(-), 51 miRNAs were significantly upregulated and 33 miRNAs were significantly downregulated from patients with DM-ILD-MDA5 Ab(+). A total of 73 exosomal miRNAs were significantly differentially expressed between DM-nonILD-MSA16(-) and HC. In particular, two miRNAs, Homo sapiens- (hsa-) miR-4488 and hsa-miR-1228-5p, were common differentially expressed miRNAs among three comparisons. GO and KEGG analyses suggested that several pathways may contribute the pathogenesis of DM-ILD-MDA5 Ab(+) and DM-nonILD-MSA16(-), while PPI network analysis of hsa-miR-4488 and hsa-miR-1228-5p indicated that their predicted target genes, DExD-box helicase 39B and MDM2, may be involved in the mechanisms of DM-ILD-MDA5 Ab(+).


2021 ◽  
Author(s):  
Hai-Tao Pan ◽  
Xiao-Liang Shi ◽  
Min Fang ◽  
Xiang-Mei Sun ◽  
Pan-Pan Chen ◽  
...  

Abstract Background: Epidemiological and experimental studies suggest that preeclampsia has a negative impact on maternity and offspring health. Previous studies report that dysregulation in utero-environment increases risk for elderly disease such as cardiovascular disease. However, the underlying mechanisms remain elusive. Specific microRNAs (miRNAs) are packaged in exosomes may regulate processes in offspring microvascular dysfunction.Methods: A comprehensive miRNA sequence-based approach to compare exosomes carry miRNAs (Exo-miRNAs) expression levels in umbilical serum between normal and preeclampsia patients was performed to explore mechanisms for development of cardiovascular dysfunction in offspring exposed to preeclampsia. by ExoQuick precipitations were used to isolate serum exosomes. Serum exosomes were then viewed under electron microscopy, and their characteristics determined by western blotting and nanoparticle-tracking analysis. Illumina platform was used to perform sequencing. Bioinformatics analysis was used to explore differentially expressed Exo-miRNAs in umbilical serum.Results: Based on sequence similarity, 1733 known miRNAs were retrieved. Furthermore, 157 mature miRNAs in serum exosomes were significantly differential expressed between PE and those control groups (P<0.05, log2|FC|>1). Out, of the 157 miRNAs, 96 were upregulated miRNAs whereas 61 miRNAs were downregulated. The 157 differentially expressed miRNAs targeted 51424 differentially expressed genes. Functional analysis through KEGG pathway and Gene Ontology results uncovered that target genes of miRNAs with differential expression were significantly linked to several pathways and biological processes.Conclusion: The findings of this study showed differential expression of umbilical serum Exo-miRNAs in normal compared with PE patients, implying that these Exo-miRNAs play an important function in offspring microvascular dysfunction of preeclampsia.


2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Wei-xian Chen ◽  
Ling-yun Xu ◽  
Qi Qian ◽  
Xiao He ◽  
Wen-ting Peng ◽  
...  

A major cause of failure in chemotherapy is drug resistance of cancer cells. Exosomes have been introduced to spread chemoresistance through delivering miRNAs. However, a systematic evaluation of the exosomal miRNA expression profiles responsible for chemoresistance is still lacking. In the present study, miRNA signature differentially expressed in exosomes derived from adriamycin-resistant (A/exo) and parental breast cancer cells (S/exo) were analyzed by microarray and the results were confirmed by PCR. A total of 309 miRNAs were increased and 66 miRNAs were decreased significantly in A/exo compared with S/exo. Specifically, 52 novel miRNAs with increased expression levels >16.0-fold in A/exo were identified. After prediction of target genes for 13 of 52 selected novel miRNAs, pathway analysis, gene ontology (GO) terms, and protein–protein interactions (PPIs) were constructed. The results implied that these selected exosomal miRNAs inhibited target genes involved in transcriptional misregulation in cancer, MAPK, and Wnt signaling pathways. Functional enrichment analysis demonstrated that the target genes were mainly responsible for protein phosphorylation, transcription regulation, molecular binding, and kinase activity. In summary, the current bioinformatics study of exosomal miRNAs may offer a new understanding into mechanisms of chemoresistance, which is helpful to find potential exosomal miRNAs to overcome drug insensitivity in future breast cancer treatment.


2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yong Zhao ◽  
Hao Wang ◽  
Ming Lu ◽  
Xin Qiao ◽  
Bei Sun ◽  
...  

Macrophage activation plays an important role in the inflammatory response in acute pancreatitis. In the present study, the activation of AR42J pancreatic acinar cells was induced by taurolithocholate treatment. The results showed that the culture medium from the activated AR42J cells significantly enhanced NFκB activation in the macrophages compared to that without taurolithocholate treatment. Additionally, the precipitates obtained from ultracentrifugation of the culture media that were rich in exosomes were markedly more potent in activating macrophages compared with the supernatant fraction lacking exosomes. The results indicated that the mediators carried by the exosomes played important roles in macrophage activation. Exosomal miRNAs were extracted and examined using microarrays. A total of 115 differentially expressed miRNAs were identified, and 30 showed upregulated expression, while 85 displayed downregulated expression. Target genes of the differentially expressed miRNAs were predicted using TargetScan, MiRanda, and PicTar software programs. The putative target genes were subjected to KEGG functional analysis. The functions of the target genes were primarily enriched in MAPK pathways. Specifically, the target genes regulated macrophage activation through the TRAF6-TAB2-TAK1-NIK/IKK-NFκB pathway. As the mediators of signal transduction, miRNAs and their predicted target mRNAs regulate every step in the MAPK pathway.


2021 ◽  
Author(s):  
Qian Yang ◽  
Shulei He ◽  
Lu Huang ◽  
Ci Shao ◽  
Tiejian Nie ◽  
...  

Abstract BackgroundBlood-based test for disease progression and early diagnosis of Parkinson’s disease (PD) is a long awaited but unsolved key problem in the clinic. The profiles of microRNAs (miRNAs) are regarded as potential diagnostic biomarkers in human diseases whereas the miRNAs in the periphery are susceptible to the influence of various components. MiRNAs enriched in serum exosomes have revealed disease-specific advantages for the diagnosis due to their high abundance, stability and resistant to degradation. This study aimed to screen differentially expressed exosomal miRNAs between healthy controls and PD patients to aid in diagnosis. MethodsA total of 103 healthy controls and diagnosed PD patients at different Hoehn and Yahr (H&Y) stages in Tangdu Hospital were included. In total, 185 differentially expressed miRNAs were obtained through miRNA sequencing of serum exosomes as well as edgeR and t-test analyses. Subsequently, the weighted gene co-expression network analysis (WGCNA) was utilized to identify the commonly expressed miRNAs in all stages of PD by constructing connections between modules and specifically expressed miRNAs in each stage of PD by functional enrichment analysis. The obtained miRNAs were further validated by quantitative real-time polymerase chain reaction (qRT-PCR) with peripheral blood exosomes from 30 more participants. ResultsUsing WGCNA, it was found that 4 miRNAs were commonly associated with all the stages of PD and 13 miRNAs were specifically associated with different stages of PD. Among the 17 miRNAs, 2 were commonly expressed in all the stages of PD and 5 were specifically expressed in different stages of PD via qRT-PCR; 5 were also specifically expressed in different stages of PD by WGCNA, but validation by qRT-PCR showed inconsistent results; the remaining 5 miRNAs did not exhibit significant differences by qRT-PCR. ConclusionsThis study revealed that the 7 serum exosomal miRNAs (hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-199a-3p, hsa-miR-195-5p, hsa-miR-28-5p, hsa-miR-22-5p and hsa-miR-151a-5p) we screened out may potentially be used as biomarkers for progression and early grading diagnosis of PD in the population.


2019 ◽  
Vol 244 (14) ◽  
pp. 1149-1161 ◽  
Author(s):  
Shu-Qin Ding ◽  
Jing Chen ◽  
Sai-Nan Wang ◽  
Fei-Xiang Duan ◽  
Yu-Qing Chen ◽  
...  

It is important to find specific and easily detectable diagnostic markers in acute stage of spinal cord injury for guiding treatment and estimating prognosis. Although, microRNAs are attractive biomarkers, there is still no uniform standard for clinical evaluation of spinal cord injury based on “free circulation” miRNA spectrum. The reason may be that miRNA analysis from biological fluids is influenced by many pre-analysis variables. Exosome miRNAs are widely distributed in body fluids and have many advantages comparing with free miRNAs. The specific miRNAs in the central nervous system can be transported to the peripheral circulation and concentrated in exosomes. Therefore, we hypothesized that there might be some physiological changes associated with spinal cord injury in serum exosomal miRNAs. Using next-generation sequencing, miRNA profiles in serum exosomes of sham and acute spinal cord injury rats were analyzed, and integrative bioinformatics were used to analyze the function and regulation of putative target genes. The results showed that acute spinal cord injury can lead to changes in miRNA expression in the circulating exosomes. The changed miRNAs and their associated pathways may explain the pathology of acute spinal cord injury. More importantly, we determined serum exosomal miR-125b-5p, miR-152-3p, and miR-130a-3p are specific and easily detectable diagnostic markers in acute spinal cord injury. More interestingly, we also found some valuable known and novel miRNAs. Further bioinformatics analysis and functional research will be of great help to make clear their role in the pathological process of spinal cord injury and judging whether they can be used as diagnostic markers. Impact statement This research hypothesized that there might be some physiological changes associated with SCI in serum exosomal miRNAs. Using next-generation sequencing, miRNA profiles in serum exosomes of sham and acute SCI rats were analyzed, and integrative bioinformatics were used to analyze the function and regulation of putative target genes. The results showed that acute SCI can lead to changes in miRNA expression in the circulating exosomes. The changed miRNAs and their associated pathways may explain the pathology of acute SCI. More importantly, we determined serum exosomal miR-125b-5p, miR-152-3p, and miR-130a-3p are specific and easily detectable diagnostic markers in acute SCI.


2021 ◽  
Vol 15 (8) ◽  
pp. e0009633
Author(s):  
Li-Min Xie ◽  
Xin Yin ◽  
Jie Bi ◽  
Huan-Min Luo ◽  
Xun-Jie Cao ◽  
...  

Dengue fever virus (DENV) is a global health threat that is becoming increasingly critical. However, the pathogenesis of dengue has not yet been fully elucidated. In this study, we employed bioinformatics analysis to identify potential biomarkers related to dengue fever and clarify their underlying mechanisms. The results showed that there were 668, 1901, and 8283 differentially expressed genes between the dengue-infected samples and normal samples in the GSE28405, GSE38246, and GSE51808 datasets, respectively. Through overlapping, a total of 69 differentially expressed genes (DEGs) were identified, of which 51 were upregulated and 18 were downregulated. We identified twelve hub genes, including MX1, IFI44L, IFI44, IFI27, ISG15, STAT1, IFI35, OAS3, OAS2, OAS1, IFI6, and USP18. Except for IFI44 and STAT1, the others were statistically significant after validation. We predicted the related microRNAs (miRNAs) of these 12 target genes through the database miRTarBase, and finally obtained one important miRNA: has-mir-146a-5p. In addition, gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out, and a protein–protein interaction (PPI) network was constructed to gain insight into the actions of DEGs. In conclusion, our study displayed the effectiveness of bioinformatics analysis methods in screening potential pathogenic genes in dengue fever and their underlying mechanisms. Further, we successfully predicted IFI44L and IFI6, as potential biomarkers with DENV infection, providing promising targets for the treatment of dengue fever to a certain extent.


PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10998
Author(s):  
Feng Zhang ◽  
Su-Ping Li ◽  
Tao Zhang ◽  
Bin Yu ◽  
Juan Zhang ◽  
...  

Background Polycystic ovary syndrome (PCOS) is the most common type of endocrine disorder, affecting 5–11% of women of reproductive age worldwide. microRNAs (miRNAs) stably exist in circulating blood encapsulated in extracellular vesicles such as exosomes; therefore, serum miRNAs have the potential to serve as novel PCOS biomarkers. Methods To identify miRNA biomarkers that are associated with PCOS, we performed a comprehensive sequence-based characterization of the PCOS serum miRNA landscape. The serum exosomes were successfully isolated and characterized in a variety of ways. Next, sequence-based analysis was performed on serum exosomes to screen the differentially expressed miRNAs in women with and without PCOS. Results The sequence data revealed that the levels of 54 miRNAs significantly differed between PCOS patients and normal controls. The levels of these miRNAs were detected by RT-qPCR. The results show that hsa-miR-1299, hsa-miR-6818-5p hsa-miR-192-5p, and hsa-miR-145-5p are significantly differentially expressed in PCOS patients serum exosomes and identify these microRNAs as potential biomarkers for PCOS. Furthermore, Gene Ontology (GO) analyses and KEGG pathway analyses of the miRNA targets further allowed to explore the potential implication of the miRNAs in PCOS. Conclusion Our findings suggest that serum exosomal miRNAs serve important roles in PCOS and may be used as novel molecular biomarkers for clinical diagnosis.


2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Shun Wang ◽  
Zhenkuan Xu ◽  
Chao Zhang ◽  
Rui Yu ◽  
Jun Jiang ◽  
...  

Objective. At present, no effective noninvasive method is currently available for the differential diagnosis of high-grade glioma and intracranial lymphoma. In the present study, we aimed to screen microRNA (miRNA) markers in serum exosomes for differential diagnosis of high-grade glioma and intracranial lymphoma using high-throughput sequencing technology. Methods. Patients with intracranial lymphoma or high-grade glioma and healthy controls were included in this study (training cohort ( n = 10 ) and validation cohort: intracranial lymphoma ( n = 10 ), high-grade glioma ( n = 32 ), and healthy controls ( n = 20 )). After RNA was extracted from serum exosomes, the high-throughput sequencing was used to determine the expression profiles of serum exosomal miRNAs and screen the differentially expressed miRNAs. RT-qPCR was used to verify the expressions of the selected miRNAs. The differences of miRNA expressions between groups were assessed by the Kruskal-Wallis test. The diagnostic value was analyzed using the receiver operating characteristic (ROC) curve. Results. High-throughput sequencing demonstrated that 170 miRNAs, including 109 upregulated ones and 61 downregulated ones, were differentially expressed in serum exosomes between the patients with intracranial lymphoma and high-grade glioma. Compared with the healthy controls, the number of differential serum exosomal miRNAs in the high-grade glioma group and intracranial lymphoma group was 130 and 173, respectively. RT-qPCR proved that both miR-766-5p and miR-376b-5p were significantly downregulated in high-grade glioma and intracranial lymphoma patients compared with the healthy controls (all p < 0.001 ), and the expression of serum exosomal miR-766-5p in the intracranial lymphoma group was lower compared with the high-grade glioma group ( p < 0.05 ). The areas under ROC curve (AUCs) of serum exosomal miR-766-5p and miR-376b-5p for the diagnosis of glioma were 0.8883 ( p < 0.001 ) and 0.7688 ( p = 0.001 ), respectively, and they were 0.9271 ( p < 0.001 ) and 0.8542 ( p < 0.001 ), respectively, for the diagnosis of intracranial lymphoma. Moreover, the AUC value of serum exosomal miR-766-5p for the differential diagnosis of glioma and intracranial lymphoma was 0.7201 ( p = 0.026 ). Conclusions. miR-766-5p and miR-376b-5p in serum exosomes might be used as auxiliary diagnostic indicators for high-grade glioma and intracranial lymphoma, and miR-766-5p might be used as a differential diagnostic marker for both diseases.


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