Gene Expression Changes Associated with Nintedanib Treatment in Idiopathic Pulmonary Fibrosis Fibroblasts [miRNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE124787 | GEO | 2019/04/08
REPOSITORIES: GEO
Similar Datasets
Project description:We found strong protein-protein interactions within these dysregulated genes in nintedanib treated IPF fibroblast, with most genes involved in the pathways of cell cycle, mitotic cell cycle, and cell division. In IPF fibroblasts, we found nintedanib treatment was associated with downregulation of has-miR-92a-1-5p, which might de-repress SLC25A23 expression, and upregulation of has-miR-486-5p, which might repress DDX11, E2F1, and PLXNA4 expressions.
2019-04-08 | GSE124786 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a progressing chronic and fibrotic lung response with poor prognosis. The current standard-of-care for IPF is the kinase inhibitor nintedanib, which has a broad target range. The mechanism of nintedanib’s action remains unclear as it inhibits diverse kinases expressed in lung epithelia, endothelia and putatively the immune populations distributed throughout the lung. Given the proposed role of multiple pulmonary macrophage populations in mediating both protective and pathogenic roles in lung fibrosis, we sought to identify repair-associated macrophage populations in mice influenced by nintedanib after bleomycin challenge for 7 and 14 days using single cell RNA sequencing. Bleomycin exposure triggered expansion of inflammatory MHCIIhigh macrophage populations, which was partially reversed after nintedanib treatment. Concurrently, nintedanib promoted the expansion of MHCIIlow macrophages, which were linked to attenuation of lung fibrosis. Concomitantly, nintedanib promoted an increased expression of mRNA for canonical macrophage repair markers in MHCIIlow macrophages. Finally, exposure of inflammatory macrophages to nintedanib in vitro resulted in attenuation of expression of transcripts for MCHII. In conclusion, a component of nintedanib’s protective mode of action in lung fibrosis relies on expanding distinct MHCIIlow macrophage populations and redirecting them toward a reparative phenotype. This study provides a rationale for further refinement of therapeutic kinase inhibition in fibrotic diseases.
2021-05-05 | GSE151374 | GEO
Project description:Background: Acute kidney injury (AKI) is a common clinical event with high morbidity and mortality. We previously demonstrated that injection of cord blood endothelial colony forming cell (ECFC)-derived exosomes, highly enriched in miRNA(miR)-486-5p, prevented ischemic kidney injury in mice. While preclinical models support involvement of several miRs in AKI, the direct effects of miR-486-5p on injury and the kidney transcriptome are unknown. Objective: We studied effects of miR-486-5p in mice with kidney ischemia-reperfusion (IR) injury, and compared the impact of miR-486-5p and ECFC-derived exosomes on the transcriptome of proximal tubules (PTs) and renal endothelial cells. Methods: Adult male mice were subjected to bilateral kidney ischemia (30 min), and injected via tail vein with or without vehicle, miR-486-5p mimic, ECFC-derived exosomes, or scramble miR at the start of reperfusion. Plasma and tissues were collected 24 hrs after reperfusion, and proximal tubular and endothelial cells were isolated for mRNA analysis by RNA-Seq. Results: In mice with kidney IR, injection of miR-486-5p mimic increased levels of miR-486-5p in proximal tubules and endothelial cells, and significantly improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis, compared to vehicle treatment. MiR-486-5p inhibited expression of phosphatase and tensin homolog (PTEN), and activated AKT. Similar results were observed with exosomes, but scramble miR had no effect. In proximal tubules, miR-486-5p or exosomes reduced expression of several AKI genes (e.g. Lcn2, Havcr1 and Krt20) and caused alterations in apoptotic genes compared to IR alone. In endothelium, miR-486-5p or exosomes caused milder effect than in PTs but still impacting on expression of injury-related genes. Conclusion: MiR-486-5p protects mice against ischemic kidney injury. Both miR-486-5p and exosomes reduce expression of apoptotic genes in PTs and endothelium. The results suggest that systemic delivery of miR-486-5p has therapeutic potential in ischemic AKI.
2023-10-10 | GSE159701 | GEO
Project description:Selective removal of senescent cells, or the concept of senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced cell death in primary human diploid fibroblasts undergoing replicative senescence. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without cytotoxicity. Interestingly, compared with ABT263, nintedanib showed a different mode of activating caspase-9 in the intrinsic apoptotic pathway, in that nintedanib did not suppress the levels of Bcl-2 family proteins in senescent cells. In more detail, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused drug-induced cell death in senescent cells. STAT3 knockdown in senescent cells also induced caspase activation. Moreover, nintedanib reduced the number of senescent cells stained based on senescence-associated β-galactosidase activity and airway resistance in a mouse model of bleomycin-induced lung fibrosis. Overall, we identified that nintedanib could be used as a new senolytic agent and that inhibiting STAT3 could be a potential approach for inducing selective cell death in senescent cells. Our findings will pave the way for expanding senolytic toolkits in response to various aging statuses and age-related diseases.
2022-09-06 | GSE210020 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal pulmonary disorder characterized by fibroblast proliferation and the excess deposit of extracellular matrix proteins. The etiology of IPF is unknown, but a central role for microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been recently suggested. We report the upregulation of miR-199a-5p in mouse lungs undergoing bleomycin-induced fibrosis and also in human biopsies from IPF patients. Levels of miR-199a-5p were increased selectively in myofibroblasts and putative profibrotic effects of miR-199a-5p were further investigated in cultured lung fibroblasts. MiR-199a-5p expression was induced upon TGFβ exposure and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts. CAV1, a critical mediator of pulmonary fibrosis, was established as a bona fide target of miR-199a-5p. Finally, we also found an aberrant expression of miR-199a-5p in mouse models of kidney and liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. We propose miR-199a-5p as a major regulator of fibrosis that represents a potential therapeutic target to treat fibroproliferative diseases. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-02-01 | E-GEOD-34818 | biostudies-arrayexpress
Project description:Osteoporosis is a significant health concern, and the role of microRNAs (miRNAs) in cell growth and development regulation is well recognized. High-throughput sequencing technology is widely employed in current research. This study aimed to identify and validate miRNAs associated with osteoporosis. Bone specimens were collected from patients with osteoporosis (n=3) and without osteoporosis (n=3). High-throughput sequencing was utilized to screen for miRNAs, followed by analysis using volcano maps, Wayne maps, gene ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The identified miRNAs were further confirmed using qRT-PCR. Sequencing analysis revealed 12 down-regulated and five upregulated miRNAs in osteoporosis. GO and KEGG analysis indicated the association of these miRNAs with bone metabolism. qRT-PCR results demonstrated a significant decrease in miR-140-5p, miR-127-3p, miR-199b-5p, miR-181a-5p, miR-181d-5p, and miR-542-3p (all P<0.05) in osteoporosis compared to controls, while miR-486-3p and miR-486-5p exhibited a significant increase (P<0.05). This study utilized high-throughput sequencing to identify differential miRNA expression in individuals with osteoporosis. Specifically, six miRNAs (miR-140-5p, miR-127-3p, miR-199b-5p, miR-181a-5p, miR-181d-5p, and miR-542) showed decreased expression, whereas two miRNAs (miR-486-3p and miR-486-5p) exhibited increased expression. The differential expression of these miRNAs may serve as predictive indicators, potentially aiding in the prognosis and management of osteoporosis.
2024-08-28 | GSE273345 | GEO
Project description:Nintedanib is a potent anti-fibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in locally advanced muscle invasive BC patients. Nintedanib inhibits Fibroblast Growth Factor receptors (FGFRs), validated targets in patients with BC harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy their combination (n=4). Reads were mapped separately against the human and mouse genomes to differentiate tumor vs. stromal expression changes
2023-04-13 | GSE218575 | GEO
Project description:Nintedanib is a potent anti-fibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in locally advanced muscle invasive BC patients. Nintedanib inhibits Fibroblast Growth Factor receptors (FGFRs), validated targets in patients with BC harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy their combination (n=4). Reads were mapped separately against the human and mouse genomes to differentiate tumor vs. stromal expression changes
2023-04-13 | GSE182833 | GEO
Project description:Stress fractures are microcracks in bone caused by repetitive loading and these microcracks can increase the risk of developing catastrophic fractures. Early detection of stress fractures can be difficult due to the necessity of accurate clinical detection. MicroRNAs could be used as potential diagnostic and prognostic biomarkers due to their size, abundance, tissue specificity and stability in body fluids. Global profiling of circulating plasma small RNA-sequencing between lame horses (stress fractures and non-stress fractures) and non-lame control horses and the effects and role of selected stress fracture-related miRNAs on equine bone marrow derived mesenchymal stem cells (BMMSCs) were investigated. The miRNA profiles of stress fracture cases and non-lame stress fracture cases were similar. No miRNA was identified for potential usage as a biomarker for differentiating stress fracture from lame cases. However, the miRNA profiles of lame cases and non-lame control horses were significantly different. RNA-sequencing showed three miRNAs (eca-miR-486-5p, eca-miR-26a and eca-miR-23a) were most significantly differentially expressed (p value <0.05) between lame cases and non-lame controls, which was validated by qPCR. Of these, eca-miR-486-5p demonstrated the most abundant and significant increased miRNA in the lame cases compared to non-lame control cases. Cell transfection experiments using the miR-486-5p mimic treatment in equine BMMSCs showed upregulation of the osteogenic transcription factor, Runt-related transcription factor 2 (RUNX2) and insulin-like growth factor type 1 (IGF1). A significant decrease of miR-133a in the miR-486-5p mimic treated cells was also demonstrated. Since RUNX2 is the known target of miR-133a, miR 486-5p together with miR-133a would suggest the biological importance of bone turnover and osteogenesis in equine BMMSCs, but further investigation of role of miR-486-5p and miR-133a in equine bone biology is warranted.
2024-05-23 | GSE268059 | GEO
Project description:We investigated the involvement of microRNAs (miRNAs) in gastric cancers. MiRNA expression was profiled from 40 cancerous and 40 non-cancerous tissues obtained from the National Cancer Centre, Singapore, and Singhealth Tissue Repository, Singapore. We identified 80 differentially expressed miRNAs in tumors compared with normal tissues. Among these miRNAs, we identified hsa-mir-486-5p (mir-486) as a significantly downregulated miRNA in GC. Subsequent functional characterization revealed that mir-486 playing a tumor suppressor role. We also observed frequent genomic deletion of mir-486 in 20-30% of GCs. To our knowledge, mir-486 represents one of the first tumor suppressor miRNAs in GC inactivated through genomic deletion. MiRNA expression was profiled on Agilent Human miRNA Microarrays (V2) representing 723 human and 76 human viral miRNAs in 40 normal and 40 cancerous gastric tissues.
2011-08-01 | E-GEOD-23739 | biostudies-arrayexpress