Large numbers and quantities of different, small RNA molecules are present in the cytoplasm of animal and plant cells. One subclass of these molecules is represented by the noncoding microRNAs. Since their discovery in the 1990s a multitude of basic information has accumulated, which has identified their function in post-transcriptional control, either via degradation or translational inhibition of target mRNAs. This function is in most of the cases a finetuning of gene expression, working in parallel with transcriptional regulatory processes. MicroRNA expression profiles are highly dynamic during embryonic development and in adulthood. Misexpression of microRNAs can perturb embryogenesis, organogenesis, tissue homeostasis and the cell cycle. Evidence from gain- and loss-of function studies indicates roles for microRNAs in pathophysiologic states including cardiac hypertrophy, muscle dystrophy, hepatitis infection, diabetes, Parkinson syndrome, hematological malignancies and other types of cancer. In this review, we focus on studies addressing the role of various microRNAs in heart, muscle, liver, pancreas, central nervous system, and hematopoiesis.
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... 2 Small molecules refer to some relatively small organic molecules, including compounds and metabolites. 3 A wealth of research has demonstrated the critical role that miRNA plays in numerous aspects of human life, such as gene expression regulation, 4 cell-cycle control, 5 development and organogenesis, 6 immune response regulation, 7 metabolic control, 8 and even the initiation and progression of tumors. 9 It is precisely because of the key role of miRNA in the human body that more and more researchers are devoting themselves to the invention of miRNA-targeted drugs. ...
Inferring small molecule-miRNA associations (MMAs) is crucial for revealing the intricacies of biological processes and disease mechanisms. Deep learning, renowned for its exceptional speed and accuracy, is extensively used for predicting MMAs. However, given their heavy reliance on data, inaccuracies during data collection can make these methods susceptible to noise interference. To address this challenge, we introduce the joint masking and self-supervised (JMSS)-MMA model. This model synergizes graph autoencoders with a probability distribution-based masking strategy, effectively countering the impact of noisy data and enabling precise predictions of unknown MMAs. Operating in a self-supervised manner, it deeply encodes the relationship data of small molecules and miRNA through the graph autoencoder, delving into its latent information. Our masking strategy has successfully reduced data noise, enhancing prediction accuracy. To our knowledge, this is the pioneering integration of a masking strategy with graph autoencoders for MMA prediction. Furthermore, the JMSS-MMA model incorporates a node-degree–based decoder, deepening the understanding of the network’s structure. Experiments on two mainstream datasets confirm the model’s efficiency and precision, and ablation studies further attest to its robustness. We firmly believe that this model will revolutionize drug development, personalized medicine, and biomedical research.
... Yao et al., 2019), cellular proliferation (Hayashita et al., 2005), metabolism (Ye et al., 2018), homeostasis (Fernandez-Hernando & Suarez, 2018), differentiation (S. Yao, 2016), organogenesis, and development (Asli et al., 2008). Therefore, dysregulation of miRNAs induces various clinically important human diseases such as cancer, autoimmune disease, and cardiovascular diseases (Colpaert & Calore, 2019;Esquela-Kerscher & Slack, 2006). ...
Doxorubicin (DOX) is considered one of the most effective chemotherapy drug and is used to treat many types of cancer. On the other hand, the effectiveness of this drug is restricted due to its adverse effects such as cardiotoxicity. However, the exact mechanism of DOX-induced cardiotoxicity has not been fully understood. To better understand the molecular mechanism of DOX-induced cardiotoxicity, this study focused on identifying a heart-specific miRNA and its target genes in the heart. Publicly available data was downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were extracted by using the online bioinformatics tool iPathwayGuide. Using eight different prediction tools, target genes of miR-130a-3p were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for DEGs intersected with miR-130a-3p targets. Among the HF and non-HF groups, a total of 29 DEGs targeted by miR-130a-3p were identified. We found that SLC8A1, which is among the intersecting genes, might be a crucial gene that is shaped in impaired myocardial function and cardiotoxicity. In conclusion, the findings of the study provided new insights into the potential targets for DOX-induced cardiotoxicity diagnosis, treatment, and/or attenuation.
Non-coding RNAs with a length of 22-24 nt are known as microRNAs (miRNAs or miRs), which are critical regulators of protein translation. Over the past 10 years, the roles of miRNAs have been extensively investigated in several human cancer types. There is evidence to indicate that miRNAs regulate gene expression by concentrating on a number of substances that have an impact on the physiology and development of cancer cells. Thus, miRNAs as regarded as effective targets for further studies on the design of novel therapeutic strategies. Hepatocellular carcinoma, breast, prostate, and ovarian cancer are only a few of the cancers that miR-124 suppresses. Furthermore, it has been shown that miR-124 is linked to the development and aggressive spread of malignancies. The aim of the present review was to clarify and highlight the role of miR-124 in the development and progression of cancer, emphasizing recent research illustrating how miR-124 has been used as a therapeutic agent against cancer, as well as the diagnostic potential, regulatory mechanisms and clinical application of miR-124.
Bioactive molecules and their effects have been influenced by their solubility and administration route. In many therapeutic reagents, the performance of therapeutics is dependent on physiological barriers in the human body and delivery efficacy. Therefore, an effective and stable therapeutic delivery promotes pharmaceutical advancement and suitable biological usage of drugs. In the biological and pharmacological industries, lipid nanoparticles (LNPs) have emerged as a potential carrier to deliver therapeutics. Since studies reported doxorubicin-loaded liposomes (Doxil®), LNPs have been applied to numerous clinical trials. Lipid-based nanoparticles, including liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid nanoparticles, have also been developed to deliver active ingredients in vaccines. In this review, we present the type of LNPs used to develop vaccines with attractive advantages. We then discuss messenger RNA (mRNA) delivery for the clinical application of mRNA therapeutic-loaded LNPs and recent research trend of LNP-based vaccine development.
Objective:
Circular RNAs (circRNAs) have been extensively implicated in the progression of osteoarthritis (OA). Therefore, this study explores the impact of hsa_circ_00046621 on OA progression and the related molecular mechanism.
Methods:
Human articular chondrocyte injury was induced by IL-1β to construct the OA model in vitro. hsa_circ_0004662 and microRNA (miR)-424-5p expression in chondrocytes was evaluated with qRT-PCR. Vascular endothelial growth factors A (VEGFA) expression was examined with qRT-PCR and western blot after hsa_circ_0004662 knockdown or miR-424-5p overexpression in chondrocytes. Subsequent to loss- and gain-of-function assays in IL-1β-induced chondrocytes, the proliferation and apoptosis of chondrocytes were assessed with CCK-8 assay and flow cytometry, respectively. The expression of MMP13, Aggrecan, and apoptosis-related proteins Bax and Bcl-2 was measured with western blot. The binding of miR-424-5p to hsa_circ_0004662 and VEGFA was assessed with a dual-luciferase reporter gene assay.
Results:
Hsa_circ_0004662 was up-regulated, but miR-424-5p was down-regulated in IL-1β-induced chondrocytes. Mechanistically, both hsa_circ_0004662 and VEGFA bound to miR-424-5p, and hsa_circ_0004662 enhanced VEGFA expression by down-regulating miR-424-5p. Hsa_circ_0004662 knockdown elevated cell proliferation, decreased apoptosis and MMP13 and Bax expression, and increased Aggrecan and Bcl-2 expression in IL-1β-induced chondrocytes, which was counteracted by further miR-424-5p down-regulation or VEGFA overexpression.
Conclusion:
Hsa_circ_0004662 facilitates OA progression via the miR-424-5p/VEGFA axis.
MicroRNAs are non-coding ribonucleic acids that are evolutionarily protected. MiRNAs control the expression of genes after transcription by mRNA decomposition or inhibition of their translation. These molecular structures control physiological and pathological processes; therefore, many of them can play vital roles as oncogenes or tumor inhibitors. Besides, the occurrence of various mutations in miRNAs can lead to cancer. In this review article, we want to peruse the role of miR-491-5p in various cancers. In recent years, many experiments and studies have been performed on the involvement of miR-491-5p in cancer, invasion, and cell metastasis. Metastasis is an event that makes cancer more advanced and harder to treat. When cancer is invasive, the cancer cells invade nearby tissues or other organs and develop cancer. Tumor studies have shown that miR-491-5p can inhibit cell growth, invasion, and metastasis. Thus, expression enhancement of miR-491-5p disrupts cell migration and improves cancer.
As a transcriptional regulation element, the microRNA plays a crucial role in any aspect of molecular biological processes like cellular metabolism, cell division, cell death, cell movement, intracellular signaling, and immunity was discovered. Previous studies have been suggested that microRNA-214 (miR-214) probably is a valuable marker in cancer. Here, in this perspective, we provide a brief updated overview of the vital dual role of miR-214 in cancer as a tumor suppressor or oncogene. We also collected target genes and signaling pathways related to the dysregulation of miR-214 by previous experimental research in various human diseases. To highlight the critical function of miR-214 in the prognostic, diagnostic, and pathogenesis of cancer diseases, we focused on the probable clinical biomarker and drug resistance function of miR-214. The current research provides a comprehensive perspective of the regulatory mechanisms governed by miR-214 in human disease pathogenesis and a list of probable candidates for future study.
The poor outcomes of babies with congenital diaphragmatic hernia (CDH) are directly related to pulmonary hypoplasia, a cosndition characterized by impaired lung development. Although the pathogenesis of pulmonary hypoplasia is not fully elucidated, there is now evidence that CDH patients have missing or dysregulated microRNAs (miRNAs) that regulate lung development. A prenatal therapy that supplements these missing/dysregulated miRNAs could be a strategy to rescue normal lung development. Extracellular vesicles (EVs), also known as exosomes when of small dimensions, are lipid-bound nanoparticles that can transfer their heterogeneous cargo (proteins, lipids, small RNAs) to target cells to induce biological responses. Herein, we review all studies that show evidence for stem cell-derived EVs as a regenerative therapy to rescue normal development in CDH fetal lungs. Particularly, we report studies showing that administration of EVs derived from amniotic fluid stem cells (AFSC-EVs) to models of pulmonary hypoplasia promotes fetal lung growth and maturation via transfer of miRNAs that are known to regulate lung developmental processes. We also describe that stem cell-derived EVs exert effects on vascular remodeling, thus possibly preventing postnatal pulmonary hypertension. Finally, we discuss future perspectives and challenges to translate this promising stem cell EV-based therapy to clinical practice. This article is protected by copyright. All rights reserved.
Through the regulation of gene expression, microRNAs (miRNAs) are capable of modulating vital biological processes, such as proliferation, differentiation, and apoptosis. Several mechanisms control the function of miRNAs, including translational inhibition and targeted miRNA degradation. Through utilizing high-throughput screening methods, such as small RNA sequencing and microarray, alterations in miRNA expression of kidneys have recently been observed both in rodent models and humans throughout the development of chronic kidney disease (CKD) and acute kidney injury (AKI). The levels of miRNAs in urine supernatant, sediment, and exosomal fraction could predict novel biomarker candidates in different diseases of kidneys, including IgA nephropathy, lupus nephritis, and diabetic nephropathy. The therapeutic potential of administrating anti-miRNAs and miRNAs has also been reported recently. The present study is aimed at reviewing the state-of-the-art research with regards to miRNAs involved in renal disorders related to primary podocyte dysfunction by laying particular emphasis on Focal Segmental Glomerulosclerosis (FSGS), Minimal Change Disease (MCD) and Membranous Nephropathy (MN).
Approaches to induce tumor differentiation often result in manageable and therapy‐naïve cellular states in cancer cells. This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non‐coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic regimen in one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely resulting from heterogeneity in the genetic and physiological landscapes of tumor types necessitating an approach designed for each cancer's unique genetic and phenotypic build‐up. Forced induction of terminal differentiation in tumors is an alternative therapy for cancer. Tumour differentiation occurs at the interface of three key regulatory components, signalling pathways, epigenetics and the non‐coding transcripts. The differentiation outcome, often acts in an opposing direction to tumor metastasis, invasion and proliferation, driving prognostic benefits.
MicroRNAs (miRNAs) are 21-23 nucleotide RNA molecules that regulate the stability or translational efficiency of target messenger RNAs. miRNAs have diverse functions, including the regulation of cellular differentiation, proliferation and apoptosis. Although strict tissue- and developmental-stage-specific expression is critical for appropriate miRNA function, mammalian transcription factors that regulate miRNAs have not yet been identified. The proto-oncogene c-MYC encodes a transcription factor that regulates cell proliferation, growth and apoptosis. Dysregulated expression or function of c-Myc is one of the most common abnormalities in human malignancy. Here we show that c-Myc activates expression of a cluster of six miRNAs on human chromosome 13. Chromatin immunoprecipation experiments show that c-Myc binds directly to this locus. The transcription factor E2F1 is an additional target of c-Myc that promotes cell cycle progression. We find that expression of E2F1 is negatively regulated by two miRNAs in this cluster, miR-17-5p and miR-20a. These findings expand the known classes of transcripts within the c-Myc target gene network, and reveal a mechanism through which c-Myc simultaneously activates E2F1 transcription and limits its translation, allowing a tightly controlled proliferative signal.
Neuronal gene expression is tightly regulated in developing CNS. Here, we demonstrate the anti-neural function of phosphatase SCP1 (small C-terminal domain phosphatase 1) during development. We further show that the neuron-enriched microRNA miR-124 directly targets SCP1-3' untranslated region (UTR) to suppress SCP1 expression. In developing spinal cord, expression of miR-124 and SCP1 is complementary, and miR-124 antagonism phenocopies SCP1 overexpression and vice versa. In P19 cells, miR-124 suppresses SCP1 expression and induces neurogenesis, and SCP1 counteracts this proneural activity of miR-124. Our results suggest that, during CNS development, timely down-regulation of SCP1 is critical for inducing neurogenesis, and miR-124 contributes to this process at least in part by down-regulating SCP1 expression.
MicroRNAs (miRNAs) constitute a growing class of non-coding RNAs that are thought to regulate gene expression by translational repression. Several miRNAs in animals exhibit tissue-specific or developmental-stage-specific expression, indicating that they could play important roles in many biological processes. To study the role of miRNAs in pancreatic endocrine cells we cloned and identified a novel, evolutionarily conserved and islet-specific miRNA (miR-375). Here we show that overexpression of miR-375 suppressed glucose-induced insulin secretion, and conversely, inhibition of endogenous miR-375 function enhanced insulin secretion. The mechanism by which secretion is modified by miR-375 is independent of changes in glucose metabolism or intracellular Ca2+-signalling but correlated with a direct effect on insulin exocytosis. Myotrophin (Mtpn) was predicted to be and validated as a target of miR-375. Inhibition of Mtpn by small interfering (si)RNA mimicked the effects of miR-375 on glucose-stimulated insulin secretion and exocytosis. Thus, miR-375 is a regulator of insulin secretion and may thereby constitute a novel pharmacological target for the treatment of diabetes.
Skeletal muscle differentiation is controlled by associations between myogenic basic-helix-loop-helix and MEF2 transcription factors. We show that chromatin associated with muscle genes regulated by these transcription factors becomes acetylated during myogenesis and that class II histone deacetylases (HDACs), which interact with MEF2, specifically suppress myoblast differentiation. These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2. Elevating the level of MyoD can override the repression imposed by HDACs on muscle genes. HDAC-mediated repression of myogenesis also can be overcome by CaM kinase and insulin-like growth factor (IGF) signaling. These findings reveal central roles for HDACs in chromatin remodeling during myogenesis and as intranuclear targets for signaling pathways controlled by IGF and CaM kinase.
MicroRNAs (miRNAs) are endogenous noncoding RNAs, about 22 nucleotides in length, that mediate post-transcriptional gene silencing by annealing to inexactly complementary sequences in the 3'-untranslated regions of target mRNAs. Our current understanding of the functions of miRNAs relies mainly on their tissue-specific or developmental stage-dependent expression and their evolutionary conservation, and therefore is primarily limited to their involvement in developmental regulation and oncogenesis. Of more than 300 miRNAs that have been identified, miR-1 and miR-133 are considered to be muscle specific. Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis. miR-1 overexpression slowed conduction and depolarized the cytoplasmic membrane by post-transcriptionally repressing KCNJ2 (which encodes the K(+) channel subunit Kir2.1) and GJA1 (which encodes connexin 43), and this likely accounts at least in part for its arrhythmogenic potential. Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.
MicroRNAs (miRNAs) are genomically encoded small RNAs used by organisms to regulate the expression of proteins generated from messenger RNA transcripts. The in vivo requirement of specific miRNAs in mammals through targeted deletion remains unknown, and reliable prediction of mRNA targets is still problematic. Here, we show that miRNA biogenesis in the mouse heart is essential for cardiogenesis. Furthermore, targeted deletion of the muscle-specific miRNA, miR-1-2, revealed numerous functions in the heart, including regulation of cardiac morphogenesis, electrical conduction, and cell-cycle control. Analyses of miR-1 complementary sequences in mRNAs upregulated upon miR-1-2 deletion revealed an enrichment of miR-1 "seed matches" and a strong tendency for potential miR-1 binding sites to be located in physically accessible regions. These findings indicate that subtle alteration of miRNA dosage can have profound consequences in mammals and demonstrate the utility of mammalian loss-of-function models in revealing physiologic miRNA targets.
dHAND and eHAND are related basic helix-loop-helix (bHLH) transcription factors that are expressed in mesodermal and neural crest-derived structures of the developing heart. In contrast to their homogeneous expression during avian cardiogenesis, during mouse heart development we show that dHAND and eHAND are expressed in a complementary fashion and are restricted to segments of the heart tube fated to form the right and left ventricles, respectively. dHAND and eHAND represent the earliest cardiac chamber-specific transcription factors yet identified. Targeted gene deletion of dHAND in mouse embryos resulted in embryonic lethality at embryonic day 10.5 from heart failure. Our description of the cardiac phenotype of dHAND mutant embryos is the first demonstration of a single gene controlling the formation of the mesodermally derived right ventricle and the neural crest-derived aortic arches and reveals a novel cardiogenic subprogramme for right ventricular development.
The lin-4 and let-7 antisense RNAs are temporal regulators that control the timing of developmental events inCaenorhabditis elegans by inhibiting translation of target mRNAs. let-7 RNA is conserved among bilaterian animals, suggesting that this class of small RNAs [microRNAs (miRNAs)] is evolutionarily
ancient. Using bioinformatics and cDNA cloning, we found 15 new miRNA genes in C. elegans. Several of these genes express small transcripts that vary in abundance during C. elegans larval development, and three of them have apparent homologs in mammals and/or insects. Small noncoding RNAs of the miRNA
class appear to be numerous and diverse.
MicroRNAs (miRNAs) are a new class of noncoding RNAs, which are encoded as short inverted repeats in the genomes of invertebrates and vertebrates. It is believed that miRNAs are modulators of target mRNA translation and stability, although most target mRNAs remain to be identified. Here we describe the identification of 34 novel miRNAs by tissue-specific cloning of approximately 21-nucleotide RNAs from mouse. Almost all identified miRNAs are conserved in the human genome and are also frequently found in nonmammalian vertebrate genomes, such as pufferfish. In heart, liver, or brain, it is found that a single, tissue-specifically expressed miRNA dominates the population of expressed miRNAs and suggests a role for these miRNAs in tissue specification or cell lineage decisions. Finally, a miRNA was identified that appears to be the fruitfly and mammalian ortholog of C. elegans lin-4 stRNA.
![Feedback regulation between microRNAs and transcriptional regulators. A. Promotion of muscle fate through a feedback loop, repressing the translation of myoblast proteins after differentiation [28, 34, 40, 44, 45]. B. Balancing between a non-neural and a neuronal fate through a double negative feedback loop repressing in neuronal cells the translation of the REST complex members, which themselves would maintain a non-neural fate [65, 66, 68]. C. Double negative feedback inhibition involved in the differentiation of a neural progenitor to a mature neuron [73]. D. Differentiation of promyelocytes into monocyte/macrophages upon downregulation of NFI-A [80]. E. The balance of NFI-A and C/EBP-in the differentiation of undifferentiated cord blood cells into granulocytes. C/EBPcompetes NFI-A in binding the microRNA promoter and results in a higher microRNA expression [81]. F. Feedback inhibition of E2F transcription factors by microRNAs after depletion of c-myc from B-cells. The microRNA genes are under positive control in the presence of c-myc [85, 86, 89, 91]. For a detailed discussion please see the main text.](https://www.researchgate.net/profile/Naisana-Asli/publication/23656544/figure/fig3/AS:394439425052675@1471053095461/Fig-3-Feedback-regulation-between-microRNAs-and-transcriptional-regulators-A_Q320.jpg)
