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Preeclampsia (PE) is a high morbidity and lethality disease specific to pregnancy, and insufficient placental trophoblast invasion acts as a crucial factor contributing to PE development. The present study investigated the function and potential mechanism of microRNA (miR)-224-5p within PE. In the study, miR-224-5p expression was reduced within placental tissue samples of the PE mouse model and PE cell model. Restoration of miR-224-5p expression markedly inhibited ROS levels and ferroptosis, lowered blood pressure in pregnant mice, increased the live birth rate, and enhanced trophoblast cell proliferation and invasion as well as suppressed their apoptosis. miR-224-5p could target and suppress PANX1, and overexpression of PANX1 could significantly advance ferroptosis and cause trophoblast dysfunction, a process that might be relieved via restoring miR-224-5p expression. In conclusion, miR-224-5p/PANX1 ameliorates trophoblast dysfunction by inhibiting ferroptosis, which provides a potential new option for clinical treatment of PE. • miR-224–5p expression showed to be down-regulated within PE tissues. • miR-224–5p ameliorates PE mice symptoms via the inhibition of ferroptosis. • miR-224–5p enhances trophoblast cell proliferation and invasive ability through inhibiting ferroptosis. • miR-224–5p targets PANX1. [ABSTRACT FROM AUTHOR]

There is increasing evidence that circular RNAs (circRNAs) play significant roles in various biological processes, yet few reports have examined their roles and molecular mechanisms in ketamine-induced cystitis (KIC). This study examines the possible molecular mechanisms underlying the circRNA-microRNA-mRNA regulatory network in the development of KIC. Transcriptome data were collected, and bioinformatics analysis was conducted to create a circRNA-miRNA-mRNA regulatory network (ceRNA network) associated with the occurrence of KIC. Human bladder epithelial cells (SV-HUC-1) were used in in vitro cell assays. The binding affinity among circ-SFMBT2, miR-224-5p, and Metadherin (MTDH) was identified. To investigate the effects of circ-SFMBT2/miR-224-5p/MTDH on bladder function, KIC mouse models were induced by intraperitoneal injection of ketamine, and gain- or loss-of-function experiments were conducted. Our results demonstrate that MTDH may be a key gene involved in the occurrence of KIC. Both bioinformatics analysis and in vitro cell assays verified that circ-SFMBT2 can competitively bind to miR-224-5p, and miR-224-5p can target and inhibit MTDH. In the bladder tissues of KIC mice, circ-SFMBT2 and MTDH were up-regulated, while miR-224-5p was down-regulated. Animal experiments further confirmed that circ-SFMBT2 can up-regulate MTDH expression by sponging miR-224-5p, thereby exacerbating bladder dysfunction in KIC mice. This study proved that circ-SFMBT2 up-regulates MTDH by competitively binding to miR-224-5p, thereby exacerbating the bladder dysfunction of KIC. [ABSTRACT FROM AUTHOR]

MicroRNAs play a crucial role in regulating cartilage extracellular matrix (ECM) metabolism and are being explored as potential therapeutic targets for osteoarthritis (OA). The present study indicated that microRNA-224-5p (miR-224-5p) could balance the homeostasis of OA via regulating cartilage degradation and synovium inflammatory simultaneously. Multifunctional polyamidoamine dendrimer with amino acids used as efficient vector to deliver miR-224-5p. The vector could condense miR-224-5p into transfected nanoparticles, which showed higher cellular uptake and transfection efficiency compared to lipofectamine 3000, and also protected miR-224-5p from RNase degradation. After treatment with the nanoparticles, the chondrocytes showed an increase in autophagy rate and ECM anabolic components, as evidenced by the upregulation of autophagy-related proteins and OA-related anabolic mediators. This led to a corresponding inhibition of cell apoptosis and ECM catabolic proteases, ultimately resulting in the alleviation of ECM degradation. In addition, miR-224-5p also inhibited human umbilical vein endothelial cells angiogenesis and fibroblast-like synoviocytes inflammatory hyperplasia. Integrating the above synergistic effects of miR-224-5p in regulating homeostasis, intra-articular injection of nanoparticles performed outstanding therapeutic effect by reducing articular space width narrowing, osteophyte formation, subchondral bone sclerosis and inhibiting synovial hypertrophy and proliferation in the established mouse OA model. The present study provides a new therapy target and an efficient intra-articular delivery method for improving OA therapy. Osteoarthritis (OA) is the most prevalent joint disease worldwide. Gene therapy, which involves delivering microRNAs, has the potential to treat OA. In this study, we demonstrated that miR-224-5p can simultaneously regulate cartilage degradation and synovium inflammation, thereby restoring homeostasis in OA gene therapy. Moreover, compared to traditional transfection reagents such as lipofectamine 3000, G5-AHP showed better efficacy in both microRNA transfection and protection against degradation due to its specific surface structure. In summary, G5-AHP/miR-224-5p was developed to meet the clinical needs of OA patients and the high requirement of gene transfection efficiency, providing a promising paradigm for the future application and development of gene therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background The proliferation of airway smooth muscle cells (ASMCs) contributes to the contractility and inflammation in the pathophysiology of asthma. This intrigued us to clarify the effect of microRNA (miR)-224-5p on biological characteristics of ASMCs in mice with asthma-like airway inflammation and responses through the FHL1-dependent MAPK pathway. Methods An ovalbumin (OVA)-induced asthma mouse model was established, where ASMCs were isolated. The expression of FHL1 was determined in asthmatic mice. Artificial modulation of FHL1 expression was performed to explore its effect on airway inflammation of asthmatic mice and ASMC proliferation and apoptosis. Afterwards, we analyzed the interaction among miR-224-5p, FHL1 and the MAPK pathway, and explored their combined impacts on airway inflammation of asthmatic mice and ASMC proliferation and apoptosis. Results FHL1 was highly expressed and miR-224-5p was poorly expressed in asthmatic mice. FHL1 was verified to be a target of miR-224-5p. Loss of FHL1 function reduced airway inflammation in asthmatic mice and proliferation of ASMCs while inducing their apoptosis. Besides, miR-224-5p inhibited the MAPK pathway by binding to FHL1. Overexpression of miR-224-5p relieved airway inflammation, inhibited ASMC proliferation, and increased apoptosis, which could be reversed by overexpression of FHL1. Conclusion Altogether, miR-224-5p inhibited airway inflammation in asthmatic mice and ASMC proliferation through blocking the MAPK pathway by down-regulating FHL1.

Background: The proliferation of airway smooth muscle cells (ASMCs) contributes to the contractility and inflammation in the pathophysiology of asthma. This intrigued us to clarify the effect of microRNA (miR)-224-5p on biological characteristics of ASMCs in mice with asthma-like airway inflammation and responses through the FHL1-dependent MAPK pathway. Methods: An ovalbumin (OVA)-induced asthma mouse model was established, where ASMCs were isolated. The expression of FHL1 was determined in asthmatic mice. Artificial modulation of FHL1 expression was performed to explore its effect on airway inflammation of asthmatic mice and ASMC proliferation and apoptosis. Afterwards, we analyzed the interaction among miR-224-5p, FHL1 and the MAPK pathway, and explored their combined impacts on airway inflammation of asthmatic mice and ASMC proliferation and apoptosis. Results: FHL1 was highly expressed and miR-224-5p was poorly expressed in asthmatic mice. FHL1 was verified to be a target of miR-224-5p. Loss of FHL1 function reduced airway inflammation in asthmatic mice and proliferation of ASMCs while inducing their apoptosis. Besides, miR-224-5p inhibited the MAPK pathway by binding to FHL1. Overexpression of miR-224-5p relieved airway inflammation, inhibited ASMC proliferation, and increased apoptosis, which could be reversed by overexpression of FHL1. Conclusion: Altogether, miR-224-5p inhibited airway inflammation in asthmatic mice and ASMC proliferation through blocking the MAPK pathway by down-regulating FHL1. [ABSTRACT FROM AUTHOR]

The relevance of circular RNAs (circRNAs) has been indicated in the progression of various diseases. Nevertheless, the precise function of circRNAs in osteoarthritis (OA) remains to be established. Therefore, we aimed to investigate changes in the expression of a specific circRNA, hsa_circ_0134111 (circ_PDE1C) and predict its functions in OA. A rat model of OA was constructed to detect circ_PDE1C expression in knee joint tissues. Subsequently, CHON-001 chondrocytes were treated with IL-1β to mimic OA in vitro. circ_PDE1C was significantly overexpressed in knee cartilage tissues from OA patients relative to amputation patients. Knockdown of circ_PDE1C inhibited extracellular matrix (ECM) degradation and chondrocyte apoptosis. Furthermore, circ_PDE1C could target miR-224-5p, and miR-224-5p expressed poorly in knee cartilage tissues from OA patients. Overexpression of miR-224-5p inhibited ECM degradation and apoptosis in chondrocytes. miR-224-5p also targeted CCL2, which activated the JAK2/STAT signaling pathway, thereby promoting cartilage degradation and exacerbating the symptoms of OA patients. In conclusion, our findings underscore a novel role of circ_PDE1C in OA pathogenesis and suggest that targeting circ_PDE1C/miR-224-5p/CCL2 axis might provide an attractive approach for OA therapy. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia (FRDA) is a genetic neurodegenerative disease that is caused by guanine-adenine-adenine (GAA) nucleotide repeat expansions in the first intron of the frataxin (FXN) gene. Although present in the intron, this mutation leads to a substantial decrease in protein expression. Currently, no effective treatment is available for FRDA, and, in addition to FXN, other targets with therapeutic potential are continuously sought. As miRNAs can regulate the expression of a broad spectrum of genes, are used as biomarkers, and can serve as therapeutic tools, we decided to identify and characterize differentially expressed miRNAs and their targets in FRDA cells compared to unaffected control (CTRL) cells. In this study, we performed an integrated miRNAseq and RNAseq analysis using the same cohort of primary FRDA and CTRL cells. The results of the transcriptome studies were supported by bioinformatic analyses and validated by qRT-PCR. miRNA interactions with target genes were assessed by luciferase assays, qRT-PCR, and immunoblotting. In silico analysis identified the FXN transcript as a target of five miRNAs upregulated in FRDA cells. Further studies confirmed that miRNA-224-5p indeed targets FXN, resulting in decreases in mRNA and protein levels. We also validated the ability of miRNA-10a-5p to bind and regulate the levels of brain-derived neurotrophic factor (BDNF), an important modulator of neuronal growth. We observed a significant decrease in the levels of miRNA-10a-5p and increase in the levels of BDNF upon correction of FRDA cells via zinc-finger nuclease (ZFN)-mediated excision of expanded GAA repeats. Our comprehensive transcriptome analyses identified miRNA-224-5p and miRNA-10a-5p as negative regulators of the FXN and BDNF expression, respectively. These results emphasize not only the importance of miRNAs in the pathogenesis of FRDA but also their potential as therapeutic targets for this disease. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the potential role and regulatory mechanism of long non-coding RNA ferritin heavy polypeptide 1 pseudogene 3 (FTH1P3) in glioma development. The expression of FTH1P3 in low- and high-grade glioma tissues was investigated using reverse transcription-quantitative polymerase chain reaction. FTH1P3 expression was overexpressed or suppressed in U251 glioma cells to examine the involvement of FTH1P3 in glioma cell proliferation and apoptosis using MTT assay and flow cytometry respectively. In addition, the regulatory association between FTH1P3, microRNA (miR)-224-5p and tumor protein (TP) D52 was investigated to elucidate the potential underlying mechanisms of FTH1P3 in glioma by luciferase reporter assay. The results revealed that FTH1P3 was up-regulated in glioma tissues, and FTH1P3 expression in high-grade glioma tissues was significantly higher compared with that in low-grade glioma tissues. Upregulation of FTH1P3 promoted glioma cell proliferation and inhibited apoptosis. Furthermore, FTH1P3 inhibited miR-224-5p expression, which in turn negatively regulated TPD52 expression. Overexpression of miR-224-5p significantly inhibited U251 cell proliferation and induced cellular apoptosis; this effect was clearly reversed following co-transfection of miR-224-5p and TPD52. These data revealed that upregulation of FTH1P3 may have promoted glioma cell proliferation and inhibited apoptosis. Thus, the miR-224-5p/TPD52 axis may be a downstream mechanism of FTH1P3 in glioma progression. The findings of the present study may provide a theoretical basis for the study of the treatment of glioma in the future. [ABSTRACT FROM AUTHOR]

Pancreatic mucinous cystadenocarcinoma (MCC) is a rare malignant tumor, with a limited number of studies. The present study aimed to investigate the function and mechanism of microRNA (miR)-224-5p on proliferation, migration and invasion of MCC of the pancreas. Reverse transcription-quantitative PCR was used to explorethe expression of miR-224-5p and the PTEN gene. MTT, wound healing, Transwell and tumorigenesis assays were conducted to investigate the proliferation, migration and invasion of MCC1 cells in vitro and in vivo. Western blot analysis was employed to test the protein expression of PTEN. The target gene of miR-224-5p was assessed and verified by luciferase assay. miR-224-5p expression was notably higher, while PTEN expression was lower, in MCC1 cells compared with normal tissues and cells. Overexpression of miR-224-5p promoted the proliferation, migration and invasion of MCC and knockdown of miR-224-5p inhibited these functions. Bioinformatics analysis and luciferase assay indicated that PTEN was the direct target gene of miR-224-5p. The negative correlation between miR-224-5p and PTEN was confirmed both in vitro and in vivo. PTEN reversed the effects of miR-224-5p on proliferation, migration and invasion of MCC1 cells. The present study revealed for the first time, to the best of the authors' knowledge, that miR-224-5p was highly expressed and served an oncogenic role in MCC. miR-224-5p not only regulated the proliferation, migration and invasion of pancreatic MCC but may also be a potential therapeutic target for MCC. [ABSTRACT FROM AUTHOR]

The prognosis of invasive pancreatic mucinous cystadenocarcinoma (MCC) is poor, and the molecular mechanism underlying its development remains unclear. The present study aimed to explore the potential role of autophagy in pancreatic MCC. The results demonstrated an increase in autophagy signaling in pancreatic MCC tissues and the MCC1 cell line compared with adjacent tissues and normal human pancreatic ductal epithelium (HPDE) cells. In addition, abnormal autophagy activation facilitated the migration and invasion of MCC1 cells. MicroRNA (miR)-224-5p expression levels were significantly higher in MCC1 cells compared with those in HPDE cells. Treatment with rapamycin further demonstrated that high levels of autophagy elevated miR-224-5p expression in MCC1 cells in a time-dependent manner. BCL2 was identified as a downstream target gene of miR-224-5p, which binds to the 3′-untranslated region of BCL2. In addition, the results of the present study demonstrated that BCL2 knockdown reversed the inhibition of autophagy mediated by the miR-224-5p inhibitor. To the best of our knowledge, this is the first study to evaluate the role of autophagy in pancreatic MCC. Thus, these results suggested that autophagy may be hyperactivated in pancreatic MCC. In addition, the present study identified a positive feedback loop between autophagy signaling and miR-224-5p, which may promote the aggressive migration and invasion of MCC1. These results may provide a new insight into the relationship between autophagy and tumor metastasis in pancreatic MCC. [ABSTRACT FROM AUTHOR]

Several long intergenic noncoding RNAs (lincRNAs) have been linked to carcinogenesis; however, little is known about the role of LINC00619 in gastric cancer (GC). LINC00619 was identified among differentially expressed lncRNAs linked to gastric cancer based on microarray analysis and its relationships with miR-224-5p and opioid binding protein/cell adhesion molecule-like gene (OPCML) were investigated. LINC00619, miR-224-5p, and OPCML expression were measured in GC tissues and cells. Ectopic expression and depletion experiments were conducted to assess the effects of LINC00619, miR-224-5p and OPCML on cell proliferation, invasion, migration and apoptosis as well as their effects on the expression of apoptosis- and metastasis-related genes (Bcl-2, Bax, MMP-2 and MMP-9). Tumorigenicity in the nude mice was also examined. Gastric cancer was characterized by downregulation of LINC00619 and OPCML and upregulation of miR-224-5p. Additionally, we found that miR-224-5p could interact with both LINC00619 and OPCML. Upregulation of LINC00619, which binds to miR-224-5p, led to decreased miR-224-5p expression while increasing the expression of OPCML, a target gene of miR-224-5p. Overexpression of LINC00619 or OPCML or downregulation of miR-224-5p suppressed cell proliferation, invasion, migration and tumorigenicity while promoting apoptosis in GC. Our results indicated that LINC00619 functions as a tumor suppressor in GC by impairing miR-224-5p-mediated inhibition of OPCML. [ABSTRACT FROM AUTHOR]