scholarly journals Pro-Angiogenic Activity of Monocytic-Type Myeloid-Derived Suppressor Cells from Balb/C Mice Infected with Echinococcus Granulosus and the Regulatory Role of miRNAs

2018 ◽  
Vol 51 (3) ◽  
pp. 1207-1220 ◽  
Author(s):  
Jian-hai Yin ◽  
Cong-shan Liu ◽  
Ai-ping Yu ◽  
Jia-qing Yao ◽  
Yu-juan Shen ◽  
...  
Keyword(s):  
Quantitative Pcr ◽  
Echinococcus Granulosus ◽  
Protein Transport ◽  
Target Genes ◽  
Suppressor Cells ◽  
Differentially Expressed ◽  
Signalling Pathways ◽  
Myeloid Derived Suppressor Cells ◽  
Differentially Expressed Mirnas

Background/Aims: This study aims to predict the pro-angiogenic functions of monocytic-type myeloid-derived suppressor cells (M-MDSCs) derived from mice infected with Echinococcus granulosus. Methods: M-MDSCs were collected from Balb/c mice infected with E. granulosus and normal mice (control) and cultured in vitro. Human umbilical vein endothelial cells (HUVECs) were stimulated with the cell supernatant, and angiogenesis was investigated and analysed by the Angiogenesis module of the software NIH Image J. RNA was extracted from fresh isolated M-MDSCs and analysed with miRNA microarray; differentially expressed miRNAs and their potential functions were analysed through several bioinformatics tools. Finally, quantitative PCR was used to confirm the results of microarray analysis. Results: M-MDSCs from mice infected with E. granulosus could promote the formation of tubes from HUVECs in vitro. Moreover, vascular endothelial growth factor (VEGF) showed significantly high expression, whereas soluble fms-like tyrosine kinase-1 (sFlt-1) showed low expression at the transcriptional level in M-MDSCs from mice infected with E. granulosus. Microarray analysis of miRNAs showed that 28 miRNAs were differentially expressed in M-MDSCs from the two experimental mice groups, and 272 target genes were predicted using the microRNA databases TargetScan, PITA and microRNAorg. These target genes were mainly involved in the biological processes of intracellular protein transport, protein targeting to the lysosome and protein transport, and mainly located in the cytoplasm, neuronal cell body and membrane. Moreover, they were mainly involved in the molecular functions of protein binding, metal ion binding and SH3 domain binding. Further, the differentially expressed miRNAs were mainly enriched in the endocytosis, Wnt and axon guidance pathways, as well as the MAPK, focal adhesion, PI3K-Akt, cAMP, mTOR and TGF-β signalling pathways, which are linked to immunoregulation and angiogenesis based on the results of bioinformatics analysis with DIANA-miRPath 3.0. In addition, the expression of eight miRNAs was randomly verified by quantitative PCR independently in three mice infected with E. granulosus and three normal mice. Conclusion: M-MDSCs have a potential angiogenic role during E. granulosus infection, and miRNAs may play a role in the immune response and angiogenesis functions of M-MDSCs through regulation of the identified signalling pathways.

scholarly journals Identification of New miRNA-mRNA Networks in the Development of Non-syndromic Cleft Lip With or Without Cleft Palate

2021 ◽  
Vol 9 ◽  
Author(s):  
Chengyi Fu ◽  
Shu Lou ◽  
Guirong Zhu ◽  
Liwen Fan ◽  
Xin Yu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cleft Palate ◽  
Negative Correlation ◽  
Cell Apoptosis ◽  
Cleft Lip ◽  
Target Genes ◽  
Craniofacial Development ◽  
Differentially Expressed ◽  
Differentially Expressed Mirnas

Objective: To identify new microRNA (miRNA)-mRNA networks in non-syndromic cleft lip with or without cleft palate (NSCL/P).Materials and Methods: Overlapping differentially expressed miRNAs (DEMs) were selected from cleft palate patients (GSE47939) and murine embryonic orofacial tissues (GSE20880). Next, the target genes of DEMs were predicted by Targetscan, miRDB, and FUNRICH, and further filtered through differentially expressed genes (DEGs) from NSCL/P patients and controls (GSE42589), MGI, MalaCards, and DECIPHER databases. The results were then confirmed by in vitro experiments. NSCL/P lip tissues were obtained to explore the expression of miRNAs and their target genes.Results: Let-7c-5p and miR-193a-3p were identified as DEMs, and their overexpression inhibited cell proliferation and promoted cell apoptosis. PIGA and TGFB2 were confirmed as targets of let-7c-5p and miR-193a-3p, respectively, and were involved in craniofacial development in mice. Negative correlation between miRNA and mRNA expression was detected in the NSCL/P lip tissues. They were also associated with the occurrence of NSCL/P based on the MGI, MalaCards, and DECIPHER databases.Conclusions: Let-7c-5p-PIGA and miR-193a-3p-TGFB2 networks may be involved in the development of NSCL/P.

scholarly journals Astaxanthin Treatment Induces Maturation and Functional Change of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 350
Author(s):  
Seong Mun Jeong ◽  
Yeon-Jeong Kim
Keyword(s):  
Mhc Class Ii ◽  
Target Genes ◽  
Suppressor Cells ◽  
Functional Change ◽  
Related Factor ◽  
Mrna Levels ◽  
Myeloid Derived Suppressor Cells ◽  
Antitumor Effects

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells which accumulate in stress conditions such as infection and tumor. Astaxanthin (ATX) is a well-known antioxidant agent and has a little toxicity. It has been reported that ATX treatment induces antitumor effects via regulation of cell signaling pathways, including nuclear factor erythroid-derived 2-related factor 2 (Nrf2) signaling. In the present study, we hypothesized that treatment with ATX might induce maturation of MDSCs and modulate their immunosuppressive activity. Both in vivo and in vitro treatment with ATX resulted in up-regulation of surface markers such as CD80, MHC class II, and CD11c on both polymorphonuclear (PMN)-MDSCs and mononuclear (Mo)-MDSCs. Expression levels of functional mediators involved in immune suppression were significantly reduced, whereas mRNA levels of Nrf2 target genes were increased in ATX-treated MDSCs. In addition, ATX was found to have antioxidant activity reducing reactive oxygen species level in MDSCs. Finally, ATX-treated MDSCs were immunogenic enough to induce cytotoxic T lymphocyte response and contributed to the inhibition of tumor growth. This demonstrates the role of ATX as a regulator of the immunosuppressive tumor environment through induction of differentiation and functional conversion of MDSCs.

The high expression of miR-564 in patients with systemic lupus erythematosus promotes differentiation and maturation of DC cells by negatively regulating TP53 expression in vitro

Lupus ◽  
2021 ◽  
pp. 096120332110203
Author(s):  
Ziyue Teng ◽  
Xiaoying Lin ◽  
Chunyan Luan ◽  
Yixuan Sun ◽  
Xiaolan Li
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Target Genes ◽  
Differentially Expressed ◽  
Systemic Lupus ◽  
Differentially Expressed Mirnas ◽  
And Migration ◽  
Si Rna

Background miRNA is involved in the occurrence and progression of systemic lupus erythematosus (SLE), but the regulatory effect of miRNA on dendritic cells in SLE patients is still unclear. Material and methods Bioinformatics methods were used to analyze the differentially expressed miRNA and its target genes in SLE patients. In vitro experiments were conducted to explore the effects and mechanisms of differentially expressed miRNAs in SLE patients on the differentiation and maturation of monocyte-derived dendritic cells. Results Bioinformatics analysis showed that miR-564 was up-regulated in SLE patients, and TP53 was the core target gene of miR-564. The expression level of miR-564 showed a rising trend during the differentiation and maturation of monocytes into Mo-DC cells. The differentiation, maturation and proliferation of Mo-DC cells were significantly inhibited by transfection with miR-564 antagomir. The expression of TP53 is negatively regulated by miR-564. In rescue experiments, the proliferation and migration of DC cells were significantly restored by co-transfection of miR-564 antagomir and TP53 si-RNA. Conclusion Highly expressed miR-564 promotes the maturation, proliferation of Mo-DC cells by negatively regulating the expression of TP53.

scholarly journals A combined microRNA and target protein-based panel for predicting the probability and severity of uraemic vascular calcification: a translational study

2020 ◽  
Author(s):  
Chia-Ter Chao ◽  
Hsiang-Yuan Yeh ◽  
You-Tien Tsai ◽  
Chih-Kang Chiang ◽  
Huei-Wen Chen
Keyword(s):  
Vascular Calcification ◽  
Target Genes ◽  
Ex Vivo ◽  
Target Protein ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Target Proteins ◽  
Differentially Expressed Mirnas

Abstract Aims  Vascular calcification (VC) increases the future risk of cardiovascular events in uraemic patients, but effective therapies are still unavailable. Accurate identification of those at risk of developing VC using pathogenesis-based biomarkers is of particular interest and may facilitate individualized risk stratification. We aimed to uncover microRNA (miRNA)-target protein-based biomarker panels for evaluating uraemic VC probability and severity. Methods and results  We created a three-tiered in vitro VC model and an in vivo uraemic rat model receiving high phosphate diet to mimic uraemic VC. RNAs from the three-tiered in vitro and in vivo uraemic VC models underwent miRNA and mRNA microarray, with results screened for differentially expressed miRNAs and their target genes as biomarkers. Findings were validated in original models and additionally in an ex vivo VC model and human cells, followed by functional assays of identified miRNAs and target proteins, and tests of sera from end-stage renal disease (ESRD) and non-dialysis-dependent chronic kidney disease (CKD) patients without and with VC. Totally 122 down-regulated and 119 up-regulated miRNAs during calcification progression were identified initially; further list narrowing based on miRNA–mRNA pairing, anti-correlation, and functional enrichment left 16 and 14 differentially expressed miRNAs and mRNAs. Levels of four miRNAs (miR-10b-5p, miR-195, miR-125b-2-3p, and miR-378a-3p) were shown to decrease throughout all models tested, while one mRNA (SULF1, a potential target of miR-378a-3p) exhibited the opposite trend concurrently. Among 96 ESRD (70.8% with VC) and 59 CKD patients (61% with VC), serum miR-125b2-3p and miR-378a-3p decreased with greater VC severity, while serum SULF1 levels increased. Adding serum miR-125b-2-3p, miR-378a-3p, and SULF1 into regression models for VC substantially improved performance compared to using clinical variables alone. Conclusion  Using a translational approach, we discovered a novel panel of biomarkers for gauging the probability/severity of uraemic VC based on miRNAs/target proteins, which improved the diagnostic accuracy.

scholarly journals Identification of the TF-miRNA-mRNA Co-regulatory Networks Involved in Sepsis

2021 ◽  
Author(s):  
Xiaoqian Luo ◽  
Weina Lu ◽  
Jianfeng Zhao ◽  
Jun Hu ◽  
Enjiang Chen ◽  
...  
Keyword(s):  
Expression Analysis ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Mirna Target ◽  
Target Genes ◽  
Medical Condition ◽  
Differentially Expressed ◽  
Biological Targets ◽  
Differentially Expressed Mirnas

Abstract BackgroundSepsis is a life-threatening medical condition caused by a dysregulated host response to infection. Recent studies have found that the expression of miRNAs is associated with the pathogenesis of sepsis and septic shock. Our study aimed to reveal which miRNAs may be involved in the dysregulated immune response in sepsis and how these miRNAs interact with transcription factors (TFs) using a computational approach with in vitro validation studies. MethodsTo determine the network of TFs, miRNAs and target genes involved in sepsis, GEO datasets GSE94717 and GSE131761 were used to identify differentially expressed miRNAs and DEGs. TargetScan and miRWalk databases were used to predict biological targets that overlap with the identified DEGs of differentially expressed miRNAs. The TransmiR database was used to predict the differential miRNA TFs that overlap with the identified DEGs. The TF-miRNA-mRNA network was constructed and visualized. Finally, qRT-PCR was used to verify the expression of TFs and miRNA in HUVECs. ResultBetween the healthy and sepsis groups, there were 146 upregulated and 98 downregulated DEGs in the GSE131761 dataset, and there were 1 upregulated and 183 downregulated DEMs in the GSE94717 dataset. A regulatory network of the TF-miRNA-target genes was established. According to the experimental results, RUNX3 was found to be downregulated while MAPK14 was upregulated, which corroborates the result of the computational expression analysis. In a HUVECs model, miR-19b-1-5p and miR-5009-5p were found to be significantly downregulated. Other TFs and miRNAs did not correlate with our bioinformatics expression analysis. ConclusionWe constructed a TF-miRNA-target gene regulatory network and identified potential treatment targets RUNX3, MAPK14, miR-19b-1-5p and miR-5009-5p. This information provides an initial basis for understanding the complex sepsis regulatory mechanisms.

scholarly journals Downregulation of Hsa-miR-3616-3p in Triple-Negative Breast Cancer is Associated with Cell Migration and Invasion

2021 ◽  
Author(s):  
Keqian Wu ◽  
Rui Peng ◽  
Zheng Zhang ◽  
Handeng Liu ◽  
Yan Sun
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Target Genes ◽  
Triple Negative ◽  
Micro Rna ◽  
Differentially Expressed ◽  
Migration And Invasion ◽  
Candidate Mirnas ◽  
Differentially Expressed Mirnas

Abstract Background: Micro RNA (miRNA), a class of endogenous small RNAs with a length of about 20-24 nucleotides, have been played a variety of important regulatory roles in cells and have attracted the attention of researchers because involvement of initiation and progression of diverse kinds of human diseases, especially cancer. However, the regulatory role of miRNA in triple negative breast cancer (TNBC), its clinical significance and potential mechanism are still largely unknown.Methods: In this study, the differentially expressed miRNAs were analyzed using GEO2R from GSE57897 and GSE97811 of the Gene Expression Omnibus (GEO). Then, we performed the overall survival (OS) analysis of four candidate miRNAs. And the expressions of four candidate miRNAs in TNBC and non-TNBC tissues were tested by Quantitative real-time PCR. We determined the level and prognostic values of hsa-miR-3616-3p in TNBC patients. Then, TNBC cells migration and invasion were studied in vitro with hsa-miR-3616-3p by using wounding heal assays and transwell assays. Next, target genes and transcription factors of hsa-miR-3616-3p enrichment analysis, were performed by the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway.Results: Based on GSE57897 and GSE97811, we found 962 differentially expressed miRNAs including 943 up-regulated miRNAs and 19 down-regulated miRNAs. We selected top2 up-regulated miRNAs as hsa-miR-4428 and hsa-miR-575, and top2 down-regulated miRNAs as hsa-miR-3616-3p and hsa-miR-3909, and then we found that low expression of 4 candidated miRNAs had a worse prognosis in TNBC subtype. Next, we verified that the expression of hsa-miR-3616-3p was the most downregulated in TNBC tissues compared with matched surrounding tissues by qRT-PCR. Moerover, our results showed that overexpression of hsa-miR-3616-3p inhibited TNBC cells migration, and invasion in vitro.Conclusions: Our study might reveal important roles of hsa-miR-3616-3p plays in TNBC migration and invasion.

Bioinformatics Analysis Reveals Functions of MicroRNAs in Rice Under the Drought Stress

2021 ◽  
Vol 15 (8) ◽  
pp. 927-936 ◽  
Author(s):  
Yan Peng ◽  
Yuewu Liu ◽  
Xinbo Chen
Keyword(s):  
Drought Stress ◽  
Target Genes ◽  
Hot Spot ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Differentially Expressed ◽  
Protein Protein Interaction ◽  
Promising Tool ◽  
Differentially Expressed Mirnas ◽  
Aba Biosynthesis

Background: Drought is one of the most damaging and widespread abiotic stresses that can severely limit the rice production. MicroRNAs (miRNAs) act as a promising tool for improving the drought tolerance of rice and have become a hot spot in recent years. Objective: In order to further extend the understanding of miRNAs, the functions of miRNAs in rice under drought stress are analyzed by bioinformatics. Method: In this study, we integrated miRNAs and genes transcriptome data of rice under the drought stress. Some bioinformatics methods were used to reveal the functions of miRNAs in rice under drought stress. These methods included target genes identification, differentially expressed miRNAs screening, enrichment analysis of DEGs, network constructions for miRNA-target and target-target proteins interaction. Results: (1) A total of 229 miRNAs with differential expression in rice under the drought stress, corresponding to 73 rice miRNAs families, were identified. (2) 1035 differentially expressed genes (DEGs) were identified, which included 357 up-regulated genes, 542 down-regulated genes and 136 up/down-regulated genes. (3) The network of regulatory relationships between 73 rice miRNAs families and 1035 DEGs was constructed. (4) 25 UP_KEYWORDS terms of DEGs, 125 GO terms and 7 pathways were obtained. (5) The protein-protein interaction network of 1035 DEGs was constructed. Conclusion: (1) MiRNA-regulated targets in rice might mainly involve in a series of basic biological processes and pathways under drought conditions. (2) MiRNAs in rice might play critical roles in Lignin degradation and ABA biosynthesis. (3) MiRNAs in rice might play an important role in drought signal perceiving and transduction.

755 CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A803-A803 ◽  
Author(s):  
Alvaro Teijeira ◽  
Saray Garasa ◽  
Itziar Migueliz ◽  
Assunta Cirella ◽  
Ignacio Melero
Keyword(s):  
Cancer Patients ◽  
Tumor Cells ◽  
Mouse Models ◽  
Chemokine Receptor ◽  
Suppressor Cells ◽  
Neutrophil Extracellular Traps ◽  
Myeloid Derived Suppressor Cells ◽  
Extracellular Traps ◽  
Tumor Associated Neutrophils

BackgroundNeutrophils are expanded and abundant in an important fraction (up to 35% of patients) in cancer-bearing hosts. When neutrophils are expanded, they usually promote exert immunomodulatory functions promoting tumor progression and the generation of metastases. Neutrophils can undergo a specialized form of cell death called NETosis that is characterized by the extrusion of their DNA to contain infections. In cancer NETs have been described to promote metastases in mouse models. IL-8, a CXCR1/2 ligand clinically targeted by blocking antibodies, has been described to induce NETosis and is upregulated in many cancer patients. Our hypothesis is that chemokines secreted by cancer cells can mediate NETosis in tumor associated neutrophils and that NETs can be one of the immunomodulatory mechanisms provided by tumor associated neutrophils.MethodsNETosis induction of peripheral neutrophils and granulocytic myeloid derived suppressor cells by different chemotactic stimuli, tumor cell supernatants and cocultures upon CXCR1/2 blockade. NET immunodetection in mouse models and xenograft tumors upon CXCR1/2 blockade. In vitro tumor cytotoxicity assays in the presence/absence of NETs, and videomicroscopy studies in vitro and by intravital imaging to test NETs inhibition of immune cytotoxicity by immune-cell/target-cell inhibition. Tumor growth studies and metastases models in the presence of NETosis inhibitors and in combination with checkpoint blockade in mouse cancer models.ResultsUnder the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.ConclusionsCXCR1 and 2 are the main receptors mediating NETosis of tumor associated neutrophils in our in-vitro and in vivo systems expressing high levels of CXCR1 and 2 ligands. NETs limit cancer cell cytotoxicity by impeding contacts with cancer cells.

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