Exosomal miR-223-3p from bone marrow mesenchymal stem cells targets HDAC2 to downregulate STAT3 phosphorylation to alleviate HBx-induced ferroptosis in podocytes
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PROVIDER: S-EPMC10912342 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:IntroductionHepatitis B virus-associated glomerulonephritis (HBV-GN) is a common secondary kidney disease in China, the pathogenesis of which is not completely clear, and there is still a lack of effective treatment.MethodsThe mechanism of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) was investigated by using HBx-transfected human renal podocytes. Cell viability was detected by CCK8 assay. Iron and malondialdehyde (MDA) contents were detected by using commercial kits. Reactive oxygen species (ROS) levels were measured by flow cytometry analysis. The expression of ferroptosis related molecules was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. The effect of miR-223-3p transferred by BMSC-derived exosomes on HBx-overexpressing podocytes was proved by using miR-223-3p inhibitor.ResultsThe cell viability of podocytes reduced at 72 h or 96 h after the transfection of lentivirus overexpressing HBx protein (p < 0.05). Ferroptosis-related proteins, including glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) were down-regulated upon HBx overexpression, while acyl-CoA synthetase long-chain family member 4 (ACSL4) was up-regulated (p < 0.05). Intracellular levels of iron, MDA, and ROS were also enhanced (p < 0.05). BMSC-derived exosomes protected against ferroptosis induced by HBx overexpression in podocytes. miR-223-3p was enriched in BMSC-derived exosomes. Application of miR-223-3p inhibitor reversed the protective effect of BMSC-derived exosomes on HBx-induced ferroptosis in podocytes.ConclusionBMSC-derived exosomes inhibit HBx-induced podocyte ferroptosis by transferring miR-223-3p.
| S-EPMC10183163 | biostudies-literature
Project description:BackgroundCerebrovascular disease is a common clinical illness. Many patients with cerebrovascular disease can be accompanied by cognitive impairment. The exosomal microRNA (miRNA)-223-3p is related to vascular endothelial injury, synaptic function, inflammatory response, and other mechanisms. In this study, we investigated the levels of plasma exosomal miRNA-223-3p in patients with cerebral small vessel disease (CSVD), in order to determine whether it could be used as a more accessible potential biomarker for the early diagnosis and treatment of CSVD. This study aimed to explore whether the development of cognitive impairment can be explained by differentially expressed miRNA-223-3p by detecting the level of miRNA-223-3p, which is abundant in peripheral blood exosomes related to cognitive impairment in CSVD.MethodsThe three groups of participants included 40 patients with CSVD cognitive impairment (CSVDCI), 38 patients with CSVD, and 35 normal controls (NC). The real-time polymerase chain reaction (RT-PCR) was used to detect the expression level of blood exosomal miRNA-223-3p. In addition, we also studied the relationship between exosomal miRNA-223-3p and blood Hcy and C-reactive protein (CRP). Receiver-operating characteristic (ROC) curve analysis was used to evaluate the diagnostic efficacy of plasma exosomal miRNA-223-3p.ResultsThe expression of exosomal miRNA-223-3p in CSVD increased, and the expression of miRNA-223-3p increased significantly with the occurrence of cognitive impairment. Exosomal miRNA-223-3p was positively correlated with the expression levels of Hcy and CRP in the blood.ConclusionsThe expression of plasma exosomal miRNA-223-3p is associated with the development of cognitive impairment in patients with CSVD. It may be involved in the pathogenesis of CSVD and cognitive impairment, and can be used as a sensitive predictive biomarker.
| S-EPMC8756253 | biostudies-literature
Project description:Research about the effect of exosomes derived from tumor associated macrophages (TAM-exos) in the distant organ metastasis of breast cancer is limited. In this study, we found that TAM-exos could promote the migration of 4T1 cells. Through comparing the expression of microRNAs in 4T1 cells, TAM-exos, and exosomes from bone marrow derived macrophages (BMDM-exos) by sequencing, miR-223-3p and miR-379-5p were screened out as two noteworthy differentially expressed microRNAs. Furthermore, miR-223-3p was confirmed to be the reason for the improved migration and metastasis of 4T1 cells. The expression of miR-223-3p was also increased in 4T1 cells isolated from the lung of tumor-bearing mice. Cbx5, which has been reported to be closely related with metastasis of breast cancer, was identified to be the target of miR-223-3p. Based on the information of breast cancer patients from online databases, miR-223-3p had a negative correlation with the overall survival rate of breast cancer patients within a three-year follow-up, while Cbx5 showed an opposite relationship. Taken together, miR-223-3p in TAM-exos can be delivered into 4T1 cells and exosomal miR-223-3p promotes pulmonary metastasis of 4T1 cells by targeting Cbx5.
| S-EPMC10366638 | biostudies-literature
Project description:The etiology of Parkinson's disease (PD) is poorly understood, and is strongly suspected to include both genetic and environmental factors. In this context, it is essential to investigate possible biomarkers for both prognostic and diagnostic purposes. Several studies reported dysregulated microRNA expression in neurodegenerative disorders, including PD. Using ddPCR, we investigated the concentrations of miR-7-1-5p, miR-499-3p, miR-223-3p and miR-223-5p-miRNAs involved in the α-synuclein pathway and in inflammation-in the serum and serum-isolated exosomes of 45 PD patients and 49 age- and sex-matched healthy controls (HC). While miR-499-3p and miR-223-5p showed no differences (1), serum concentration of miR-7-1-5p was significantly increased (p = 0.0007 vs. HC) and (2) miR-223-3p serum (p = 0.0006) and exosome (p = 0.0002) concentrations were significantly increased. ROC curve analysis showed that miR-223-3p and miR-7-1-5p serum concentration discriminates between PD and HC (p = 0.0001, in both cases). Notably, in PD patients, both miR-223-3p serum (p = 0.0008) and exosome (p = 0.006) concentrations correlated with levodopa equivalent daily dosage (LEDD). Finally, serum α-synuclein was increased in PD patients compared to HC (p = 0.025), and in patients correlated with serum miR-7-1-5p in (p = 0.05). Our results suggest that both miR-7-1-5p and miR-223-3p, distinguishing PD from HC, have the potential to be useful and non-invasive biomarkers in Parkinson's disease.
| S-EPMC10216839 | biostudies-literature
Project description:Background and objectivesAcute myocardial infarction (AMI) often occurs suddenly and leads to fatal consequences. Ferroptosis is closely related to the progression of AMI. However, the specific mechanism of ferroptosis in AMI remains unclear.MethodsWe constructed a cell model of AMI using AC16 cells under oxygen and glucose deprivation (OGD) conditions and a mice model of AMI using the left anterior descending (LAD) ligation. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide was employed to determine cell viability. The levels of lactate dehydrogenase, creatine kinase, reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and iron were measured using corresponding kits. Dual luciferase reporter gene assay, RNA-binding protein immunoprecipitation, and RNA pull-down were performed to validate the correlations among AC005332.7, miR-331-3p, and cyclin D2 (CCND2). Hematoxylin and eosin staining was employed to evaluate myocardial damage.ResultsAC005332.7 and CCND2 were lowly expressed, while miR-331-3p was highly expressed in vivo and in vitro models of AMI. AC005332.7 sufficiency reduced ROS, MDA, iron, and ACSL4 while boosting the GSH and GPX4, indicating that AC005332.7 sufficiency impeded ferroptosis to improve cardiomyocyte injury in AMI. Mechanistically, AC005332.7 interacted with miR-331-3p, and miR-331-3p targeted CCND2. Additionally, miR-331-3p overexpression or CCND2 depletion abolished the suppressive impact of AC005332.7 on ferroptosis in OGD-induced AC16 cells. Moreover, AC005332.7 overexpression suppressed ferroptosis in mice models of AMI.ConclusionsAC005332.7 suppressed ferroptosis in OGD-induced AC16 cells and LAD ligation-operated mice through modulating miR-331-3p/CCND2 axis, thereby mitigating the cardiomyocyte injury in AMI, which proposed novel targets for AMI treatment.
| S-EPMC10011218 | biostudies-literature
Project description:Increasing studies have identified the potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in non-alcoholic fatty liver disease (NAFLD) treatment. Hence, we further focused on the potential of adipose-derived MSC (ADSC)-EVs in NAFLD by delivering miR-223-3p. The uptake of isolated ADSC-EVs by hepatocytes was assessed, and the expression of miR-223-3p in ADSC-EVs and hepatocytes was characterized. It was established that miR-223-3p, enriched in ADSC-EVs, could be delivered by ADSC-EVs into hepatocytes. Using co-culture system and gain-of-function approach, we evaluated the effect of ADSC-EVs carrying miR-223-3p on lipid accumulation and liver fibrosis in pyrrolizidine alkaloids (PA)-induced hepatocytes and a high-fat diet-induced NAFLD mouse model. Bioinformatics websites and dual-luciferase reporter gene assay were performed to determine the interactions between miR-223-3p and E2F1, which was further validated by rescue experiments. ADSC-EVs containing miR-223-3p displayed suppressive effects on lipid accumulation and liver fibrosis through E2F1 inhibition, since E2F1 was demonstrated as a target gene of miR-223-3p. The protective role of ADSC-EVs by delivering miR-223-3p was then confirmed in the mouse model. Collectively, this study elucidated that ADSC-EVs delayed the progression NAFLD through the delivery of anti-fibrotic miR-223-3p and subsequent E2F1 suppression, which may suggest miR-223-3p-loaded ADSC-EVs to be a potential therapeutic approach for NAFLD.
| S-EPMC9481107 | biostudies-literature
Project description:Chronic cerebral hypoperfusion (CCH) is a major contributor to vascular dementia, with neuroinflammation playing a central role in its pathogenesis. Sinomenine (SINO), a natural alkaloid derived from traditional Chinese medicine, has shown significant anti-inflammatory and neuroprotective properties. However, its efficacy and mechanism of action in CCH remain unclear. In this study, we established a CCH rat model through bilateral common carotid artery occlusion and administered 10 mg/kg of SINO daily. Behavioral tests demonstrated that SINO significantly improved cognitive and memory functions in CCH rats. Histological analysis revealed that SINO effectively reduced neuroinflammation and damage in the hippocampal CA1, CA3, and DG regions. Mechanistically, SINO promoted microglial polarization from the M1 to M2 phenotype, markedly inhibiting the release of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Further exploration of its neuroprotective mechanism showed that exosomes from SINO-treated microglia were enriched with miRNA-223-3p, which suppressed NLRP3-mediated pyroptosis in neurons. While our findings highlight the therapeutic potential of SINO, further studies are needed to validate its safety and efficacy in diverse populations and chronic settings. In summary, this study not only demonstrates SINO's regulatory effect on microglial polarization in CCH but also unveils a novel neuroprotective mechanism through exosomal miRNA-223-3p delivery, providing a solid theoretical foundation for SINO's potential as a treatment for CCH.
| S-EPMC11881310 | biostudies-literature
Project description:MicroRNAs (miRNAs) present frequently altered expression in urologic cancers including prostate, bladder, and kidney cancer. The altered expression of miR-223 has been reported in cancers and other diseases in recent researches. MiR-223 is up-regulated in systemic lupus erythematosus and rheumatoid arthritis. In neoplastic diseases, miR-223 is proved to be up-expressed in plasma or serum and cancer tissues compared with normal tissues in pancreatic cancer, gastric cancer, et al. However, whether altered expression of miR-223 is associated with prostate cancer (PCa) and what it is potential functions in PCa remained unveiled. In this study, we firstly found miR-223-3p were up-regulated in prostate cancer tissues and then we study functional role of miR-223-3p in PCa using DU145, PC3 and LNCaP cell lines. Our data suggested that miR-223-3p might target gene SEPT6 and promoted the biological behavior of prostate cancer. Notably, we found increasing SEPT6 expression might reverse the biological activity induced by miR-223-3p, which might be a potential therapeutic target for PCa.
| S-EPMC4269886 | biostudies-other
Project description:BackgroundMicroRNAs have an important role in diverse biological processes including tumorigenesis. MiR-223 has been reported to be deregulated in several human cancer types. However, its biological role has not been functionally characterized in lung squamous cell carcinoma (LSCC). The following study investigates the role of miR-223-3p in LSCC growth and metastasis and its underlying mechanism.MethodsMicroRNA profiling analyses were conducted to determine differential miRNAs expression levels in LSCC tumor tissues that successfully formed xenografts in immunocompromised mice (XG) and failed tumor tissues (no-XG). RT-PCR and in situ hybridization (ISH) was performed to evaluate the expression of miR-223-3p in 12 paired adjacent normal tissues and LSCC specimens. Cell proliferation and migration were assessed by CCK-8, colony formation and Transwell assay, respectively. The role of miR-223-3p in LSCC tumorigenesis was examined using xenograft nude models. Bioinformatics analysis, Dual-luciferase reporter assays, Chromatin immunoprecipitation (ChIP) assay and Western blot analysis were used to identify the direct target of miR-223-3p and its interactions.ResultsMiR-223-3p was downregulated in LSCC tissues that successfully formed xenografts (XG) compared with tumor tissues that failed (no-XG), which was also significantly reduced in LSCC tissues compared with the adjacent normal tissues. Gain- and loss-of function experiments showed that miR-223-3p inhibited proliferation and migration in vitro. More importantly, miR-223-3p overexpression greatly suppressed tumor growth in vivo. Mechanistically, we found that mutant p53 bound to the promoter region of miR-223 and reduced its transcription. Meanwhile, p53 is a direct target of miR-223-3p. Thus, miR-223-3p regulated mutant p53 expression in a feedback loop that inhibited cell proliferation and migration.ConclusionsOur study identified miR-223-3p, as a tumor suppressor gene, markedly inhibited cell proliferation and migration via miR-223-3p-mutant p53 feedback loop, which suggested miR-223-3p might be a new therapeutic target in LSCC bearing p53 mutations.
| S-EPMC6373043 | biostudies-literature
Project description:It has recently been established that exosomes can mediate intercellular cross-talk under normal and pathological conditions through the transfer of specific miRNAs. As muscle cells secrete exosomes, we addressed the question of whether skeletal muscle (SkM) exosomes contained specific miRNAs, and whether they could act as "endocrine signals" during myogenesis. We compared the miRNA repertoires found in exosomes released from C2C12 myoblasts and myotubes and found that 171 and 182 miRNAs were exported into exosomes from myoblasts and myotubes, respectively. Interestingly, some miRNAs were expressed at higher levels in exosomes than in their donor cells and vice versa, indicating a selectivity in the incorporation of miRNAs into exosomes. Moreover miRNAs from C2C12 exosomes were regulated during myogenesis. The predicted target genes of regulated exosomal miRNAs are mainly involved in the control of important signaling pathways for muscle cell differentiation (e.g., Wnt signaling pathway). We demonstrated that exosomes from myotubes can transfer small RNAs (C. elegans miRNAs and siRNA) into myoblasts. Moreover, we present evidence that exosome miRNAs secreted by myotubes are functionally able to silence Sirt1 in myoblasts. As Sirt1 regulates muscle gene expression and differentiation, our results show that myotube-exosome miRNAs could contribute to the commitment of myoblasts in the process of differentiation. Until now, myokines in muscle cell secretome provided a conceptual basis for communication between muscles. Here, we show that miRNA exosomal transfer would be a powerful means by which gene expression is orchestrated to regulate SkM metabolic homeostasis.
| S-EPMC3925739 | biostudies-literature