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Cell Reports Dec 2023Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3, and AGO4) are...
Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3, and AGO4) are required for miRNA activity. We generate Ago1, Ago3, and Ago4-deficient mice (Ago134) and find AGO1/3/4 to be redundant for miRNA biogenesis, homeostasis, or function, a role that is carried out by AGO2. Instead, AGO1/3/4 regulate the expansion of type 2 immunity via precursor mRNA splicing in CD4 T helper (Th) lymphocytes. Gain- and loss-of-function experiments demonstrate that nuclear AGO3 interacts directly with SF3B3, a component of the U2 spliceosome complex, to aid global mRNA splicing, and in particular the isoforms of the gene Nisch, resulting in a dysregulated Nisch isoform ratio. This work uncouples AGO1, AGO3, and AGO4 from miRNA-mediated RNA interference, identifies an AGO3:SF3B3 complex in the nucleus, and reveals a mechanism by which AGO proteins regulate inflammatory diseases.
Topics: Animals; Mice; Argonaute Proteins; Imidazoline Receptors; Mammals; MicroRNAs; RNA Interference; RNA Precursors; RNA Splicing; RNA, Messenger
PubMed: 38096048
DOI: 10.1016/j.celrep.2023.113515 -
International Journal of Oncology Oct 2023MicroRNAs (miRNAs) are non‑coding RNAs (ncRNAs) that can post‑transcriptionally suppress targeted genes. Dysregulated miRNAs are associated with a variety of... (Review)
Review
MicroRNAs (miRNAs) are non‑coding RNAs (ncRNAs) that can post‑transcriptionally suppress targeted genes. Dysregulated miRNAs are associated with a variety of diseases. MiR‑181a‑5p is a conserved miRNA with the ability to regulate pathological processes, such as angiogenesis, inflammatory response and obesity. Numerous studies have demonstrated that miR‑181a‑5p exerts regulatory influence on cancer development and progression, acting as an oncomiR or tumor inhibitor in various cancer types by impacting multiple hallmarks of tumor. Generally, miR‑181a‑5p binds to target RNA sequences with partial complementarity, resulting in suppression of the targeted genes of miR‑181a‑5p. However, the precise role of miR‑181a‑5p in cancer remains incompletely understood. The present review aims to provide a comprehensive summary of recent research on miR‑181a‑5p, focusing on its involvement in different types of cancer and its potential as a diagnostic and prognostic biomarker, as well as its function in chemoresistance.
Topics: Humans; MicroRNAs; Neoplasms
PubMed: 37539738
DOI: 10.3892/ijo.2023.5556 -
Cells Dec 2023Mesenchymal stem cell (MSC)-based therapy is one of the most promising modalities for cardiac repair. Accumulated evidence suggests that the therapeutic value of MSCs is... (Review)
Review
Mesenchymal stem cell (MSC)-based therapy is one of the most promising modalities for cardiac repair. Accumulated evidence suggests that the therapeutic value of MSCs is mainly attributable to exosomes. MSC-derived exosomes (MSC-Exos) replicate the beneficial effects of MSCs by regulating various cellular responses and signaling pathways implicated in cardiac regeneration and repair. miRNAs constitute an important fraction of exosome content and are key contributors to the biological function of MSC-Exo. MSC-Exo carrying specific miRNAs provides anti-apoptotic, anti-inflammatory, anti-fibrotic, and angiogenic effects within the infarcted heart. Studying exosomal miRNAs will provide an important insight into the molecular mechanisms of MSC-Exo in cardiac regeneration and repair. This significant information can help optimize cell-free treatment and overcome the challenges associated with MSC-Exo therapeutic application. In this review, we summarize the characteristics and the potential mechanisms of MSC-derived exosomal miRNAs in cardiac repair and regeneration.
Topics: Humans; MicroRNAs; Myocardial Infarction; Mesenchymal Stem Cell Transplantation; Heart; Mesenchymal Stem Cells
PubMed: 38132135
DOI: 10.3390/cells12242815 -
Clinical and Translational Medicine Nov 2023MicroRNAs (miRNAs) have been implicated in the pathobiology of preeclampsia, a common hypertensive disorder of pregnancy. In a nested matched case-control cohort within...
BACKGROUND
MicroRNAs (miRNAs) have been implicated in the pathobiology of preeclampsia, a common hypertensive disorder of pregnancy. In a nested matched case-control cohort within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we previously identified peripheral blood mRNA signatures related to preeclampsia and vitamin D status (≤30 ng/mL) during gestation from 10 to 18 weeks, using differential expression analysis.
METHODS
Using quantitative PCR arrays, we conducted profiling of circulating miRNAs at 10-18 weeks of gestation in the same VDAART cohort to identify differentially expressed (DE) miRNAs associated with preeclampsia and vitamin D status. For the validation of the expression of circulating miRNA signatures in the placenta, the HTR-8/SVneo trophoblast cell line was used. Targets of circulating miRNA signatures in the preeclampsia mRNA signatures were identified by consensus ranking of miRNA-target prediction scores from four sources. The connected component of target signatures was identified by mapping to the protein-protein interaction (PPI) network and hub targets were determined. As experimental validation, we examined the gene and protein expression of IGF1R, one of the key hub genes, as a target of the DE miRNA, miR-182-5p, in response to a miR-182-5p mimic in HTR-8/SVneo cells.
RESULTS
Pregnant women with preeclampsia had 16 circulating DE miRNAs relative to normal pregnancy controls that were also DE under vitamin D insufficiency (9/16 = 56% upregulated, FDR < .05). Thirteen miRNAs (13/16 = 81.3%) were detected in HTR-8/SVneo cells. Overall, 16 DE miRNAs had 122 targets, of which 87 were unique. Network analysis demonstrated that the 32 targets of DE miRNA signatures created a connected subnetwork in the preeclampsia module with CXCL8, CXCL10, CD274, MMP9 and IGF1R having the highest connectivity and centrality degree. In an in vitro validation experiment, the introduction of an hsa-miR-182-5p mimic resulted in significant reduction of its target IGF1R gene and protein expression within HTR-8/SVneo cells.
CONCLUSIONS
The integration of the circulating DE miRNA and mRNA signatures associated preeclampsia added additional insights into the subclinical molecular signature of preeclampsia. Our systems and network biology approach revealed several biological pathways, including IGF-1, that may play a role in the early pathophysiology of preeclampsia. These pathways and signatures also denote potential biomarkers for the early stages of preeclampsia and suggest possible preventive measures.
Topics: Humans; Female; Pregnancy; Transcriptome; Pre-Eclampsia; Circulating MicroRNA; MicroRNAs; Vitamin D; Biomarkers; RNA, Messenger
PubMed: 37905457
DOI: 10.1002/ctm2.1446 -
International Journal of Molecular... Dec 2023Substance addiction is a chronic and relapsing brain disorder characterized by compulsive seeking and continued substance use, despite adverse consequences. The high... (Review)
Review
Substance addiction is a chronic and relapsing brain disorder characterized by compulsive seeking and continued substance use, despite adverse consequences. The high prevalence and social burden of addiction are indisputable; however, the available intervention is insufficient. The modulation of gene expression and aberrant adaptation of neural networks are attributed to the changes in brain functions under repeated exposure to addictive substances. Considerable studies have demonstrated that miRNAs are strong modulators of post-transcriptional gene expression in substance addiction. The emerging role of microRNA (miRNA) provides new insights into many biological and pathological processes in the central nervous system: their variable expression in different regions of the brain and tissues may play a key role in regulating the pathophysiological events of addiction. This work provides an overview of the current literature on miRNAs involved in addiction, evaluating their impaired expression and regulatory role in neuroadaptation and synaptic plasticity. Clinical implications of such modulatory capacities will be estimated. Specifically, it will evaluate the potential diagnostic role of miRNAs in the various stages of drug and substance addiction. Future perspectives about miRNAs as potential novel therapeutic targets for substance addiction and abuse will also be provided.
Topics: Humans; MicroRNAs; Substance-Related Disorders; Behavior, Addictive; Brain
PubMed: 38069445
DOI: 10.3390/ijms242317122 -
Minerva Obstetrics and Gynecology Feb 2024MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules that play a role in regulating gene expression in a tissue-specific manner. Placental miRNAs... (Review)
Review
MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules that play a role in regulating gene expression in a tissue-specific manner. Placental miRNAs expression pattern dynamically changes during pregnancy influencing cell proliferation, differentiation and apoptosis. Changes of specific miRNA levels have been described in pregnancies complicated by hypertensive disorders or gestational diabetes and a growing interest in understanding miRNA role on placental development and placental disorders is currently going on. The present review evaluates the possible roles of miRNAs in trophoblastic invasion and placental development as well as their potential role as biomarkers for the prediction of placental disorders focusing the attention on intrauterine growth restriction.
Topics: Pregnancy; Humans; Female; MicroRNAs; Pre-Eclampsia; Placenta; Fetal Growth Retardation; Trophoblasts; Placenta Diseases
PubMed: 36222784
DOI: 10.23736/S2724-606X.22.05109-0 -
Biomedicine & Pharmacotherapy =... Sep 2023Circular RNAs (circRNAs) are single-stranded, covalently closed RNA molecules formed by mRNA exon back-splicing. Although the circRNA functions remain largely unknown,... (Review)
Review
Circular RNAs (circRNAs) are single-stranded, covalently closed RNA molecules formed by mRNA exon back-splicing. Although the circRNA functions remain largely unknown, their currently known biological activities include: acting as competing endogenous RNA (ceRNA) to adsorb microRNA (miRNA), binding proteins, regulating transcription or splicing, and ability to be translated into proteins or peptides. A growing number of studies have found that many circRNAs are abnormally expressed in various cancers, and their dysregulation is highly correlated with tumor progression. Therefore, diagnosis and treatment using circRNAs as biomarkers and therapeutic targets, respectively, has gradually become an attractive research topic. In this review, we introduced the canonical biogenesis pathways and degradation mechanisms of circRNAs. In addition, we examined the biological functions of circRNAs in vivo. Finally, we discussed the current clinical applications and challenges faced by circRNA, and proposed future directions for this promising research field.
Topics: Humans; RNA, Circular; MicroRNAs; Neoplasms; RNA Splicing; Exons
PubMed: 37506578
DOI: 10.1016/j.biopha.2023.115217 -
Pathology, Research and Practice Aug 2023MicroRNAs (miRNAs) are gaining recognition as potential therapeutic agents due to their small size, ability to target a wide range of genes, and significant role in... (Review)
Review
MicroRNAs (miRNAs) are gaining recognition as potential therapeutic agents due to their small size, ability to target a wide range of genes, and significant role in disease progression. However, despite their promising potential, nearly half of the miRNA drugs developed for therapeutic purposes have been discontinued or put on hold, and none have advanced to phase III clinical trials. The development of miRNA therapeutics has faced obstacles such as difficulties in validating miRNA targets, conflicting evidence regarding competition and saturation effects, challenges in miRNA delivery, and determining appropriate dosages. These hurdles primarily arise from the intricate functional complexity of miRNAs. Acupuncture, a distinct, complementary therapy, offers a promising avenue to overcome these barriers, particularly by addressing the fundamental issue of preserving functional complexity through acupuncture regulatory networks. The acupuncture regulatory network consists of three main components: the acupoint network, the neuro-endocrine-immune (NEI) network, and the disease network. These networks represent the processes of information transformation, amplification, and conduction that occur during acupuncture. Notably, miRNAs serve as essential mediators and shared biological language within these interconnected networks. Harnessing the therapeutic potential of acupuncture-derived miRNAs can help reduce the time and economic resources required for miRNA drug development and alleviate the current developmental challenges miRNA therapeutics face. This review provides an interdisciplinary perspective by summarizing the interactions between miRNAs, their targets, and the three acupuncture regulatory networks mentioned earlier. The aim is to illuminate the challenges and opportunities in developing miRNA therapeutics. This review paper presents a comprehensive overview of miRNAs, their interactions with acupuncture regulatory networks, and their potential as therapeutic agents. By bridging the miRNA research and acupuncture fields, we aim to offer valuable insights into the obstacles and prospects of developing miRNA therapeutics.
Topics: Humans; MicroRNAs; Gene Regulatory Networks; Acupuncture Therapy
PubMed: 37406378
DOI: 10.1016/j.prp.2023.154652 -
Nanoscale Aug 2023Bone loss is prevalent in clinical pathological phenomena such as osteoporosis, which is characterized by decreased osteoblast function and number, increased osteoclast... (Review)
Review
Bone loss is prevalent in clinical pathological phenomena such as osteoporosis, which is characterized by decreased osteoblast function and number, increased osteoclast activity, and imbalanced bone homeostasis. However, current treatment strategies for bone diseases are limited. Regulated cell death (RCD) is a programmed cell death pattern activated by the expression of specific genes in response to environmental changes. Various studies have shown that RCD is closely associated with bone diseases, and manipulating the death fate of osteoblasts could contribute to effective bone treatment. Recently, microRNA-targeting therapy drugs have emerged as a potential solution because of their precise targeting, powerful curative effect, and limited side effects. Nevertheless, their clinical application is limited by their inherent instability, easy enzymatic degradation, and poor membrane penetrability. To address this challenge, a self-assembling tetrahedral DNA nanostructure (TDN)-based microRNA (Tmi) delivery system has been proposed. TDN features excellent biocompatibility, cell membrane penetrability, serum stability, and modification versatility, making it an ideal nucleic acid carrier for miRNA protection and intracellular transport. Once inside cells, Tmi can dissociate and release miRNAs to manipulate key molecules in the RCD signaling pathway, thereby regulating bone homeostasis and curing diseases caused by abnormal RCD activation. In this paper, we discuss the impact of the miRNA network on the initiation and termination of four critical RCD programs in bone tissues: apoptosis, autophagy, pyroptosis, and ferroptosis. Furthermore, we present the Tmi delivery system as a miRNA drug vector. This provides insight into the clinical translation of miRNA nucleic acid drugs and the application of miRNA drugs in bone diseases.
Topics: Humans; MicroRNAs; Pharmaceutical Preparations; Osteoclasts; Bone and Bones; Bone Diseases
PubMed: 37482769
DOI: 10.1039/d3nr02318d -
Briefings in Bioinformatics Jul 2023MicroRNAs (miRNAs) are human post-transcriptional regulators in humans, which are involved in regulating various physiological processes by regulating the gene...
MicroRNAs (miRNAs) are human post-transcriptional regulators in humans, which are involved in regulating various physiological processes by regulating the gene expression. The subcellular localization of miRNAs plays a crucial role in the discovery of their biological functions. Although several computational methods based on miRNA functional similarity networks have been presented to identify the subcellular localization of miRNAs, it remains difficult for these approaches to effectively extract well-referenced miRNA functional representations due to insufficient miRNA-disease association representation and disease semantic representation. Currently, there has been a significant amount of research on miRNA-disease associations, making it possible to address the issue of insufficient miRNA functional representation. In this work, a novel model is established, named DAmiRLocGNet, based on graph convolutional network (GCN) and autoencoder (AE) for identifying the subcellular localizations of miRNA. The DAmiRLocGNet constructs the features based on miRNA sequence information, miRNA-disease association information and disease semantic information. GCN is utilized to gather the information of neighboring nodes and capture the implicit information of network structures from miRNA-disease association information and disease semantic information. AE is employed to capture sequence semantics from sequence similarity networks. The evaluation demonstrates that the performance of DAmiRLocGNet is superior to other competing computational approaches, benefiting from implicit features captured by using GCNs. The DAmiRLocGNet has the potential to be applied to the identification of subcellular localization of other non-coding RNAs. Moreover, it can facilitate further investigation into the functional mechanisms underlying miRNA localization. The source code and datasets are accessed at http://bliulab.net/DAmiRLocGNet.
Topics: Humans; MicroRNAs; Algorithms; Computational Biology; Software; Semantics
PubMed: 37332057
DOI: 10.1093/bib/bbad212