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Frontiers of Medicine Oct 2023Long noncoding RNAs (lncRNAs) play a crucial regulatory role in the development and progression of multiple cancers. However, the potential mechanism by which lncRNAs...
Long noncoding RNAs (lncRNAs) play a crucial regulatory role in the development and progression of multiple cancers. However, the potential mechanism by which lncRNAs affect the recurrence and metastasis of ovarian cancer remains unclear. In the current study, the lncRNA LOC646029 was markedly downregulated in metastatic ovarian tumors compared with primary tumors. Gain- and loss-of-function assays demonstrated that LOC646029 inhibits the proliferation, invasiveness, and metastasis of ovarian cancer cells in vivo and in vitro. Moreover, the downregulation of LOC646029 in metastatic ovarian tumors was strongly correlated with poor prognosis. Mechanistically, LOC646029 served as a miR-627-3p sponge to promote the expression of Sprouty-related EVH1 domain-containing protein 1, which is necessary for suppressing tumor metastasis and inhibiting KRAS signaling. Collectively, our results demonstrated that LOC646029 is involved in the progression and metastasis of ovarian cancer, which may be a potential prognostic biomarker.
Topics: Humans; Female; MicroRNAs; RNA, Long Noncoding; RNA, Competitive Endogenous; Cell Line, Tumor; Ovarian Neoplasms; Cell Proliferation; Gene Expression Regulation, Neoplastic; Cell Movement; Adaptor Proteins, Signal Transducing
PubMed: 37434064
DOI: 10.1007/s11684-023-1004-z -
Chemico-biological Interactions Dec 2023Bone marrow-derived mesenchymal stem cells (BMSCs) transplantation is a promising therapeutic strategy for cerebral ischemia/reperfusion (I/R) injury; however, the...
Growth differentiation factor 7 pretreatment enhances the therapeutic capacity of bone marrow-derived mesenchymal stromal cells against cerebral ischemia-reperfusion injury.
Bone marrow-derived mesenchymal stem cells (BMSCs) transplantation is a promising therapeutic strategy for cerebral ischemia/reperfusion (I/R) injury; however, the clinical outcome is barely satisfactory and demands further improvement. The present study aimed to investigate whether preconditioning of BMSCs by recombinant human growth differentiation factor 7 (rhGDF7) could enhance its therapeutic capacity against cerebral I/R injury. Mouse BMSCs and primary neurons were co-cultured and exposed to oxygen glucose deprivation/reperfusion (OGD/R) stimulation. To investigate the role of exosomal microRNA-369-3p (miR-369-3p), inhibitors, RNAi and the miR-369-3p antagomir were used. Meanwhile, mice were intravenously injected with rhGDF7-preconditioned BMSCs and then received cerebral I/R surgery. Markers of inflammation, oxidative stress and neural damage were evaluated. To inhibit AMP-activated protein kinase (AMPK), compound C was used in vivo and in vitro. Compared with cell-free transwell or vehicle-preconditioned BMSCs, rhGDF7-preconditioned BMSCs significantly prevented OGD/R-induced inflammation, oxidative stress and neural damage in vitro. Meanwhile, rhGDF7-preconditioned BMSCs could prevent I/R-induced cerebral inflammation and oxidative stress in vivo. Mechanistically, rhGDF7 preconditioning significantly increased exosomal miR-369-3p expression in BMSCs and then transferred exosomal miR-369-3p to primary neurons, where it bound to phosphodiesterase 4 D (Pde4d) 3'-UTR and downregulated PDE4D expression, thereby preventing I/R-induced inflammation, oxidative stress and neural damage through activating AMPK pathway. Our study identify GDF7 pretreatment as a promising adjuvant reagent to improve the therapeutic potency of BMSCs for cerebral I/R injury and ischemic stroke.
Topics: Mice; Humans; Animals; AMP-Activated Protein Kinases; Bone Marrow; Mesenchymal Stem Cells; Inflammation; Reperfusion Injury; MicroRNAs; Apoptosis
PubMed: 37879595
DOI: 10.1016/j.cbi.2023.110779 -
Journal of Extracellular Vesicles Dec 2023In the central nervous system (CNS), including in the retina, neuronal-to-glial communication is critical for maintaining tissue homeostasis including signal...
In the central nervous system (CNS), including in the retina, neuronal-to-glial communication is critical for maintaining tissue homeostasis including signal transmission, transfer of trophic factors, and in the modulation of inflammation. Extracellular vesicle (EV)-mediated transport of molecular messages to regulate these processes has been suggested as a mechanism by which bidirectional communication between neuronal and glial cells can occur. In this work we employed multiomics integration to investigate the role of EV communication pathways from neurons to glial cells within the CNS, using the mouse retina as a readily accessible representative CNS tissue. Further, using a well-established model of degeneration, we aimed to uncover how dysregulation of homeostatic messaging between neurons and glia via EV can result in retinal and neurodegenerative diseases. EV proteomics, glia microRNA (miRNA) Open Array and small RNA sequencing, and retinal single cell sequencing were performed, with datasets integrated and analysed computationally. Results demonstrated that exogenous transfer of neuronal miRNA to glial cells was mediated by EV and occurred as a targeted response during degeneration to modulate gliotic inflammation. Taken together, our results support a model of neuronal-to-glial communication via EV, which could be harnessed for therapeutic targeting to slow the progression of retinal-, and neuro-degenerations of the CNS.
Topics: Mice; Animals; Multiomics; Extracellular Vesicles; Neurons; MicroRNAs; Inflammation
PubMed: 38082562
DOI: 10.1002/jev2.12393 -
Cell Reports Mar 2024Brain functionality relies on finely tuned regulation of gene expression by networks of non-coding RNAs (ncRNAs) such as the one composed by the circular RNA ciRS-7...
Brain functionality relies on finely tuned regulation of gene expression by networks of non-coding RNAs (ncRNAs) such as the one composed by the circular RNA ciRS-7 (also known as CDR1as), the microRNA miR-7, and the long ncRNA Cyrano. We describe ischemia-induced alterations in the ncRNA network both in vitro and in vivo and in transgenic mice lacking ciRS-7 or miR-7. Our data show that cortical neurons downregulate ciRS-7 and Cyrano and upregulate miR-7 expression during ischemia. Mice lacking ciRS-7 exhibit reduced lesion size and motor impairment, while the absence of miR-7 alone results in increased ischemia-induced neuronal death. Moreover, miR-7 levels in pyramidal excitatory neurons regulate neurite morphology and glutamatergic signaling, suggesting a potential molecular link to the in vivo phenotype. Our data reveal the role of ciRS-7 and miR-7 in modulating ischemic stroke outcome, shedding light on the pathophysiological function of intracellular ncRNA networks in the brain.
Topics: Mice; Animals; MicroRNAs; RNA, Untranslated; RNA, Circular; Signal Transduction; RNA, Long Noncoding; Ischemia
PubMed: 38446664
DOI: 10.1016/j.celrep.2024.113862 -
Scientific Reports Oct 2023Renal interstitial fibrosis (RIF) considered the primary irreversible cause of chronic kidney disease. Recently, accumulating studies demonstrated that lncRNAs play an...
Renal interstitial fibrosis (RIF) considered the primary irreversible cause of chronic kidney disease. Recently, accumulating studies demonstrated that lncRNAs play an important role in the pathogenesis of RIF. However, the underlying exact mechanism of lncRNA MALAT1 in RIF remains barely known. Here, the aim of our study was to investigate the dysregulate expression of lncRNA MALAT1 in TGF-β1 treated HK2/NRK-49F cells and unilateral ureteral obstruction (UUO) mice model, defining its effects on HK2/NRK-49F cells and UUO mice fibrosis process through the miR-124-3p/ITGB1 signaling axis. It was found that lncRNA MALAT1 and ITGB1 was significantly overexpression, while miR-124-3p was downregulated in HK2/NRK-49F cells induced by TGF-β1 and in UUO mice model. Moreover, knockdown of lncRNA MALAT1 remarkably downregulated the proteins level of fibrosis-related markers, ITGB1, and upregulated the expression of epithelial marker E-cadherin. Consistently, mechanistic studies showed that miR-124-3p can directly binds to lncRNA MALAT1 and ITGB1. And the protect effect of Len-sh-MALAT1 on fibrosis related protein levels could be partially reversed by co-transfected with inhibitor-miR-124-3p. Moreover, the expression trend of LncRNA MALAT1/miR-124-3p/ITGB1 in renal tissues of patients with obstructive nephropathy (ON) was consistent with the results of cell and animal experiments. Taken together, these results indicated that lncRNA MALAT1 could promote RIF process in vitro and in vivo via the miR-124-3p/ITGB1 signaling pathway. These findings suggest a new regulatory pathway involving lncRNA MALAT1, which probably serves as a potential therapeutic target for RIF.
Topics: Animals; Humans; Mice; Fibrosis; Kidney Diseases; MicroRNAs; RNA, Long Noncoding; Transforming Growth Factor beta1; Ureteral Obstruction
PubMed: 37872392
DOI: 10.1038/s41598-023-45188-y -
Behavioural Neurology 2023MicroRNAs (miRNAs) are the smallest class of noncoding RNAs, which widely exist in animals and plants. They can inhibit translation or overexpression by combining with... (Review)
Review
MicroRNAs (miRNAs) are the smallest class of noncoding RNAs, which widely exist in animals and plants. They can inhibit translation or overexpression by combining with mRNA and participate in posttranscriptional regulation of genes, resulting in reduced expression of target proteins, affecting the development, growth, aging, metabolism, and other physiological and pathological processes of animals and plants. It is a powerful negative regulator of gene expression. It mediates the information exchange between different cellular pathways in cellular homeostasis and stress response and regulates the differentiation, plasticity, and neurotransmission of neurons. In neurodegenerative diseases, in addition to the complex interactions between genetic susceptibility and environmental factors, miRNAs can serve as a promising diagnostic tool for diseases. They can also increase or reduce neuronal damage by regulating the body's signaling pathways, immune system, stem cells, gut microbiota, etc. They can not only affect the occurrence of diseases and exacerbate disease progression but also promote neuronal repair and reduce apoptosis, to prevent and slow down the development of diseases. This article reviews the research progress of miRNAs on the mechanism and treatment of neurodegenerative diseases in the nervous system. This trial is registered with NCT01819545, NCT02129452, NCT04120493, NCT04840823, NCT02253732, NCT02045056, NCT03388242, NCT01992029, NCT04961450, NCT03088839, NCT04137926, NCT02283073, NCT04509271, NCT02859428, and NCT05243017.
Topics: Animals; MicroRNAs; Neurodegenerative Diseases; RNA, Messenger; Signal Transduction; Clinical Trials as Topic; Humans
PubMed: 38058356
DOI: 10.1155/2023/8537296 -
Free Radical Biology & Medicine Nov 2023Satellite cells are bona fide muscle stem cells that are indispensable for successful post-natal muscle growth and regeneration after severe injury. These cells also... (Review)
Review
Satellite cells are bona fide muscle stem cells that are indispensable for successful post-natal muscle growth and regeneration after severe injury. These cells also participate in adult muscle adaptation in several capacities. MicroRNAs (miRNAs) are post-transcriptional regulators of mRNA that are implicated in several aspects of stem cell function. There is evidence to suggest that miRNAs affect satellite cell behavior in vivo during development and myogenic progenitor behavior in vitro, but the role of miRNAs in adult skeletal muscle satellite cells is less studied. In this review, we provide evidence for how miRNAs control satellite cell function with emphasis on satellite cells of adult skeletal muscle in vivo. We first outline how miRNAs are indispensable for satellite cell viability and control the phases of myogenesis. Next, we discuss the interplay between miRNAs and myogenic cell redox status, senescence, and communication to other muscle-resident cells during muscle adaptation. Results from recent satellite cell miRNA profiling studies are also summarized. In vitro experiments in primary myogenic cells and cell lines have been invaluable for exploring the influence of miRNAs, but we identify a need for novel genetic tools to further interrogate how miRNAs control satellite cell behavior in adult skeletal muscle in vivo.
Topics: MicroRNAs; Satellite Cells, Skeletal Muscle; Muscle, Skeletal; Stem Cells; Cell Differentiation
PubMed: 37879420
DOI: 10.1016/j.freeradbiomed.2023.10.403 -
Acta Biochimica Et Biophysica Sinica Feb 2024MicroRNAs (miRNAs) are small noncoding RNAs (ncRNAs) that play their roles in the regulation of physiological and pathological processes. Originally, it was assumed that... (Review)
Review
MicroRNAs (miRNAs) are small noncoding RNAs (ncRNAs) that play their roles in the regulation of physiological and pathological processes. Originally, it was assumed that miRNAs only modulate gene expression posttranscriptionally in the cytoplasm by inducing target mRNA degradation. However, with further research, evidence shows that mature miRNAs also exist in the cell nucleus, where they can impact gene transcription and ncRNA maturation in several ways. This review provides an overview of novel models of nuclear miRNA functions. Some of the models remain to be verified by experimental evidence, and more details of the miRNA regulation network remain to be discovered in the future.
Topics: MicroRNAs; Gene Expression Regulation; Cytoplasm
PubMed: 38167929
DOI: 10.3724/abbs.2023268 -
Histology and Histopathology Dec 2023Mesenchymal stem cell (MSC)-dependent biological effects in the tumor microenvironment mainly rely on the activity of MSC-sourced microRNAs (MSC-miRNAs) which modulate... (Review)
Review
Mesenchymal stem cell (MSC)-dependent biological effects in the tumor microenvironment mainly rely on the activity of MSC-sourced microRNAs (MSC-miRNAs) which modulate protein synthesis in target tumor cells, endothelial cells and tumor-infiltrated immune cells, regulating their phenotype and function. Several MSC-sourced miRNAs (miR-221, miR-23b, miR-21-5p, miR-222/223, miR-15a miR-424, miR-30b, miR-30c) possess tumor-promoting properties and are able to enhance viability, invasiveness and metastatic potential of malignant cells, induce proliferation and sprouting of tumor endothelial cells and suppress effector functions of cytotoxic tumor-infiltrated immune cells, crucially contributing to the rapid growth and progression of tumor tissue. On the contrary, MSCs also produce "anti-tumorigenic" miRNAs (miR-100, miR-222-3p, miR-146b miR-302a, miR-338-5p, miR-100-5p and miR-1246) which suppress tumor growth and progression by: Up-regulating expression of chemoresistance-related genes in tumor cells, by suppressing neo-angiogenesis and by inducing generation of tumorotoxic phenotypes in tumor-infiltrated lymphocytes. In this review article, we summarize the current knowledge about molecular mechanisms that are responsible for MSC-miRNA-dependent alterations of intracellular signaling in tumor and immune cells and we discuss different insights regarding the therapeutic potential of MSC-derived miRNAs in cancer treatment.
Topics: Humans; MicroRNAs; Endothelial Cells; Signal Transduction; Phenotype; Mesenchymal Stem Cells
PubMed: 37306386
DOI: 10.14670/HH-18-633 -
International Journal of Molecular... Jan 2024Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain... (Review)
Review
Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain poorly understood, but multiple factors, including the renin-angiotensin-aldosterone system (RAAS), play a key role in its progression. Aldosterone, a mineralocorticoid steroid hormone, is one of the key components of RAAS and a potential mediator of renal damage and inflammation in DKD. miRNAs, small noncoding RNA molecules, have attracted interest due to their regulatory roles in numerous biological processes. These processes include aldosterone signaling and mineralocorticoid receptor (MR) expression. Numerous miRNAs have been recognized as crucial regulators of aldosterone signaling and MR expression. These miRNAs affect different aspects of the RAAS pathway and subsequent molecular processes, which impact sodium balance, ion transport, and fibrosis regulation. This review investigates the regulatory roles of particular miRNAs in modulating aldosterone signaling and MR activation, focusing on their impact on kidney injury, inflammation, and fibrosis. Understanding the complex interaction between miRNAs and the RAAS could lead to a new strategy to target aldosterone signaling and MR activation using miRNAs. This highlights the potential of miRNA-based interventions for DKD, with the aim of enhancing kidney outcomes in individuals with diabetes.
Topics: Humans; Aldosterone; Diabetic Nephropathies; Fibrosis; Inflammation; MicroRNAs; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 38255942
DOI: 10.3390/ijms25020869