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Objective: Alzheimer’s disease (AD) is a neurodegenerative ailment that launches insidiously and progresses slowly, and its prevalence gradually increases with age. In a former study, we explored the plasma exosomal circular RNA (circRNA)-micro RNAs (miRNA) expression profiles in AD patients derived from next-generation sequencing data by scanning experimentally validated miRNA-target interaction databases. The current paper focused on computing the integration of circRNA-miRNA and RNA binding proteins (RBP) into the plasma exosomes using the output of our earlier study. Methods: We identified 24 upregulated circRNAs and 12 downregulated miRNAs from our previous paper. These were then subjected to prediction of circRNA-miRNA via the circMine web server and MiRNet. Subsequently, the circRNA Interactome web server was used to integrate the 24 circRNAs with RBPs. Finally, the obtained numeric scale results were visualized using R studio, ensuring the validity and reliability of our findings. Results: As an overall outcome of calculations, we found CNTN4, SH3BGRL, THOC2, CGGBP1, FLNA, ATP6V1A, and UBN1 from queried 24 circRNAs linked to AD pathology, proposing that circRNAs complexes composed of RBPs and miRNAs might be considered empirically under oncoming studies. Conclusion: Basically, our calculations claim that it may be examined whether these complexes behave as sponge miRNA in AD.

Circular RNA (circRNA) is a class of non-coding RNA molecules that form a covalently closed loop, lacking the 5' cap and 3' poly(A) tail structures. CircRNAs are generated through back splicing and are widely present in eukaryotic cells. They are known to function as miRNA sponges, participate in protein translation, interact with proteins, and regulate gene expression. Ovarian cancer (OC) is the most lethal gynecological malignancy, often diagnosed at an advanced stage due to the lack of specific early symptoms, resulting in a poor overall prognosis. Understanding the molecular mechanisms underlying OC and identifying potential diagnostic markers and therapeutic targets are crucial. Studies have shown that circRNAs are differentially expressed in OC tissues, serum, and cell lines, functioning as either oncogenes or tumor suppressors. Some circRNAs are involved in various biological processes linked to OC pathogenesis, making them promising candidates as novel diagnostic markers, therapeutic targets, and prognostic indicators. This review summarizes the biogenesis, biological functions, and latest research on circRNAs in OC, aiming to provide new insights. into potential strategies for OC diagnosis and treatment. [ABSTRACT FROM AUTHOR]

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INTRODUCTION. The development of malignant neoplasms is associated with changes in the expression of small non-coding RNAs (miRNAs). This emphasises the need for research into the development of miRNA-targeted inhibitors as a promising approach to cancer treatment.AIM. This study aimed to compare current strategies for suppressing the functional activity of tumour-associated miRNAs based on the use of therapeutic nucleic acids and to determine the application potential of these strategies.DISCUSSION. This study analysed known oligonucleotide-based miRNA inhibitors with different mechanisms of action. Based on their mechanism of action, miRNA-targeted inhibitors can be classified into two groups. The first group of miRNA-targeted inhibitors exhibits an indirect inhibitory effect, either by blocking functional connections between miRNAs and specific mRNA targets through the use of miRNA-masking oligonucleotides or by introducing mutations into miRNA genes and disrupting gene biosynthesis processes through the use of the CRISPR/Cas system. Despite their relatively high biological potential, these strategies are mostly used as search tools to study miRNA functional roles and molecular interactions in carcinogenesis. The second group of oligonucleotide constructs interacts with miRNA targets directly, which leads to steric blocking or degradation of oncogenic microRNAs. These miRNA-binding oligonucleotide constructs come in a variety of structural variants, including miRNA sponges, RNA zippers, antisense oligonucleotides, and miRNases, which demonstrate high therapeutic potential in vitro and in vivo.CONCLUSION. The described analysis of the biological properties, therapeutic potential, and key advantages of the developed miRNA-targeted oligonucleotide constructs helps outline the areas for their potential practical application in cancer treatment.

The scientific review provides the mechanisms of drug regulation of microRNA in the human body. To write the article, information was searched using Scopus, Web of Science, MEDLINE, PubMed, Google Scholar, Embase, Global Health, The Cochrane Library databases. To restore the reduced functional activity of microRNAs, replacement therapy is used, with modified synthetic analogs of endogenous microRNAs, and drugs that enhance the production of the body’s own microRNAs. The authors state that numerous studies have confirmed the effectiveness of miRNA replacement therapy. It is known that there are several groups of drugs among miRNA inhibitors: anti-miRNA oligonucleotides, miRNA traps, miRNA mimics that prevent miRNA binding; peptide nucleic acids, small-molecule inhibitors. The authors suggest that the expression of drug-metabolizing enzymes is controlled by nuclear receptors and transcription factors, epigenetic regulation such as DNA methylation and histone acetylation, and post-translational modification. It is emphasized that ursodeoxycholic acid modulates the expression of some miRNAs. It is known that probiotic bacteria can modulate the expression level of miRNA genes. The use of probiotics is accompanied by a change in the expression of nume­rous genes of the body involved in the regulation of the inflammatory response, allergic reactions, metabolism and other biological processes. Thus, modern science is intensively studying the potential of using drugs that restore miRNA content or inhibit miRNA acti­vity for the therapy of miRNA-dependent conditions. The results of scientific research confirmed the therapeutic effect of ursodeoxycholic acid and probiotic preparations due to the effect on the acti­vity of miRNA generation in hepatobiliary diseases. Therefore, the introduction into clinical practice of drugs than can modulate the content and expression of specific miRNAs will certainly open new perspectives in the treatment of patients with hepatobiliary diseases.

CircRNAs are a category of regulatory RNAs that have garnered significant attention in the field of regulatory RNA research due to their structural stability and tissue-specific expression. Their circular configuration, formed via back-splicing, results in a covalently closed structure that exhibits greater resistance to exonucleases compared to linear RNAs. The distinctive regulation of circRNAs is closely associated with several physiological processes, as well as the advancement of pathophysiological processes in several human diseases. Despite a good understanding of the biogenesis of circular RNA, details of their biological roles are still being explored. With the steady rise in the number of investigations being carried out regarding the involvement of circRNAs in various regulatory pathways, understanding the biological and clinical relevance of circRNA-mediated regulation has become challenging. Given the vast landscape of circRNA research in the development of the heart and vasculature, we evaluated cardiovascular system research as a model to critically review the state-of-the-art understanding of the biologically relevant functions of circRNAs. We conclude the review with a discussion of the limitations of current functional studies and provide potential solutions by which these limitations can be addressed to identify and validate the meaningful and impactful functions of circRNAs in different physiological processes and diseases. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) represent single-stranded RNA species that contain covalently closed 3′ and 5′ ends that provide them more stability than linear RNA, which has free ends. Emerging evidence indicates that circRNAs perform essential functions in many DNA viruses, including coronaviruses, Epstein–Barr viruses, cytomegalovirus, and Kaposi sarcoma viruses. Recent studies have confirmed that circRNAs are present in viruses, including DNA and RNA viruses, and play various important functions such as evading host immune response, disease pathogenesis, protein translation, miRNA sponges, regulating cell proliferation, and virus replication. Studies have confirmed that circRNAs can be biological signatures or pathological markers for autoimmune diseases, neurological diseases, and cancers. However, our understanding of circRNAs in DNA and RNA viruses is still limited, and functional evaluation of viral and host circRNAs is essential to completely understand their biological functions. In the present review, we describe the metabolism and cellular roles of circRNA, including its roles in various diseases and viral and cellular circRNA functions. Circular RNAs are found to interact with RNA, proteins, and DNA, and thus can modulate cellular processes, including translation, transcription, splicing, and other functions. Circular RNAs interfere with various signaling pathways and take part in vital functions in various biological, physiological, cellular, and pathophysiological processes. We also summarize recent evidence demonstrating cellular and viral circRNA's roles in DNA and RNA viruses in this growing field of research. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are regulatory elements that are involved in orchestrating gene expression and protein functions and are implicated in various biological processes including cancer. Notably, breast cancer has a significant mortality rate and is one of the most common malignancies in women. CircRNAs have been demonstrated to contribute to the pathogenesis of breast cancer including its initiation, progression, metastasis, and resistance to drugs. By acting as miRNA sponges, circRNAs can indirectly influence gene expression by disrupting miRNA regulation of their target genes, ultimately altering the course of cancer development and progression. Additionally, circRNAs can interact with proteins and modulate their functions including signaling pathways involved in the initiation and development of cancer. Recently, circRNAs can encode peptides that play a role in the pathophysiology of breast cancer and other diseases and their potential as diagnostic biomarkers and therapeutic targets for various cancers including breast cancer. CircRNAs possess biomarkers that differentiate, such as stability, specificity, and sensitivity, and can be detected in several biological specimens such as blood, saliva, and urine. Moreover, circRNAs play an important role in various cellular processes including cell proliferation, differentiation, and apoptosis, all of which are integral factors in the development and progression of cancer. This review synthesizes the functions of circRNAs in breast cancer, scrutinizing their contributions to the onset and evolution of the disease through their interactions with exosomes and cancer-related intracellular pathways. It also delves into the potential use of circRNA as a biomarker and therapeutic target against breast cancer. It discusses various databases and online tools that offer crucial circRNA information and regulatory networks. Lastly, the challenges and prospects of utilizing circRNAs in clinical settings associated with breast cancer are explored. [ABSTRACT FROM AUTHOR]

Converging evidence indicates heavy metal–induced genes, transcription factors (TFs), and microRNAs (miRNAs) are critical pathological components of metabolic syndrome (MetS) and cognitive impairment. Thus, our goals are to identify the interaction of mixed heavy metals (cadmium + lead + mercury) with genes, TFs, and miRNAs involved in MetS and its components, as well as cognitive impairment development. The most commonly retrieved genes for each disease were different, but essential biological pathways such as oxidative stress, altered lipoprotein metabolism, fluid shear stress and atherosclerosis, apoptosis, the IL-6 signaling pathway, and Alzheimer's disease were highlighted. The genes CASP3, BAX, BCL2, IL6, TNF, APOE, HMOX1, and IGF were found to be mutually affected by the heavy metal mixture studied, suggesting the importance of apoptosis, inflammation, lipid, heme, and glucose metabolism in MetS and cognitive impairment, as well as the potentiality of targeting these genes in prospective therapeutic intervention for these diseases. EGR2, ATF3, and NFE2L2 were noted as the most key TFs implicated in the etiology of MetS and its components, as well as cognitive impairment. We also found six miRNAs induced by studied heavy metals were the mutual miRNAs linked to MetS, its components, and cognitive impairment. In particular, we used miRNAsong to construct and verify a miRNA sponge sequence for these miRNAs. These sponges are promising molecules for the treatment of MetS and its components, as well as cognitive impairment. [ABSTRACT FROM AUTHOR]

Abstract Circular RNAs (circRNAs) are endogenous RNAs with a covalently closed single‐stranded transcript. They are a novel class of genomic regulators that are linked to many important development and disease processes and are being pursued as clinical and therapeutic targets. Using the most powerful RNA sequencing and bioinformatics techniques, a large number of circRNAs have been identified and further functional studies have been performed. It is known that circRNAs act as potential biomarkers, sponges for microRNAs (miRNAs) and RNA‐binding proteins (RBPs), and regulators of mRNA transcription. They also participate in the translation of peptides or proteins. Many types of circRNAs are dysregulated in plasma or lung tissues, and they may be involved in regulating the proliferation and apoptosis of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs), leading to pulmonary vascular remodeling in pulmonary hypertension (PH). One possible mechanism is that circRNAs can regulate the function of PAECs and PASMCs by acting as miRNA sponge. However, other potential mechanisms of action of circRNAs are still being actively explored in PH. This paper presents a systematic review of the biogenesis, biological characterization, relevant underlying functions, and future perspectives for studies of circRNAs in the pathogenesis of PH.

Abstract Background Triple-negative breast cancer (TNBC) is a special type of breast cancer that lacks effective therapeutic targets. There is a significant need to clarify its pathogenesis, so as to bring new targeted approaches for TNBC management. Here, we identified a long-non coding RNA (lncRNA) ASMTL-AS1 that linked to TNBC development and progression. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assays were used to test gene and protein levels, respectively. The regulatory axis of miR-1228-3p/SOX17/β-catenin was determined by luciferase reporter and RNA pull-down assays. In vivo assay was conducted by using the nude mice model via subcutaneous transplantation of tumor cells. Results ASMTL-AS1 was significantly downregulated in TNBC tissues compared to normal tissues, which was closely associated with aggressive clinical features and unfavorable prognosis. Lentivirus-mediated ASMTL-AS1 overexpression evidently reduced the ability of TNBC cell colony formation, activity and invasion by more than 2.5 times. RNA pull-down and luciferase reporter assays revealed that miR-1228-3p directly bound to ASMTL-AS1, ASMTL-AS1 increased SOX17 expression via sponging and repressing miR-1228-3p. Subsequently, the upregulated SOX17 trans-suppressed β-catenin expression, resulting in the inactivation of carcinogenic Wnt/β-catenin signaling, thereby restraining TNBC cell growth and dissemination. Importantly, the xenograft tumor model showed that the ASMTL-AS1 overexpression significantly retarded tumor growth, and negatively regulated Wnt/β-catenin pathway. Conclusions Our data characterize a novel tumor suppressor in TNBC, restoration of ASMTL-AS1 may be a candidate therapeutic intervention for TNBC patients.

Stem cells are a class of undifferentiated cells with great self-renewal and differentiation capabilities that can differentiate into mature cells in specific tissue types. Stem cell differentiation plays critical roles in body homoeostasis, injury repair and tissue generation. The important functions of stem cell differentiation have resulted in numerous studies focusing on the complex molecular mechanisms and various signalling pathways controlling stem cell differentiation. Circular RNAs (circRNAs) are a novel class of noncoding RNAs with a covalently closed structure present in eukaryotes. Numerous studies have highlighted important biological functions of circRNAs, and they play multiple regulatory roles in various physiological and pathological processes. Importantly, multiple lines of evidence have shown the abnormal expression of numerous circRNAs during stem cell differentiation, and some play a role in regulating stem cell differentiation, highlighting the role of circRNAs as novel biomarkers of stem cell differentiation and novel targets for stem cell-based therapy. In this review, we systematically summarize and discuss recent advances in our understanding of the roles and underlying mechanisms of circRNAs in modulating stem cell differentiation, thus providing guidance for future studies to investigate stem cell differentiation and stem cell-based therapy. Abbreviations: CircRNAs: circular RNAs; ESCs: embryonic stem cells; ADSCs: adipose-derived mesenchymal stem cells; ecircRNAs: exonic circRNAs; EIciRNAs: exon-intron circRNAs; eiRNAs: circular intronic RNAs; tricRNAs: tRNA intronic circRNAs; pol II: polymerase II; snRNP: small nuclear ribonucleoprotein; m6A: N6-methyladenosine; AGO2: Argonaute 2; RBPs: RNA-binding proteins; MBNL: muscleblind-like protein 1; MSCs: mesenchymal stem cells; hiPSCs: human induced pluripotent stem cells; hiPSC-CMs: hiPSC-derived cardiomyocytes; hBMSCs: human bone marrow mesenchymal stem cells; hADSCs: human adipose-derived mesenchymal stem cells; hDPSCs: human dental pulp stem cells; RNA-seq: high-throughput RNA sequencing; HSCs: haematopoietic stem cells; NSCs: neural stem cells; EpSCs: epidermal stem cells; hESCs: human embryonic stem cells; mESCs: murine embryonic stem cells; MNs: motor neurons; SSUP: small subunit processome; BMSCs: bone marrow-derived mesenchymal stem cells; OGN: osteoglycin; GIOP: glucocorticoid‑induced osteoporosis; CDR1as: cerebellar degeneration-related protein 1 transcript; SONFH: steroid-induced osteogenesis of the femoral head; rBMSCs: rat bone marrow-derived mesenchymal stem cells; QUE: quercetin; AcvR1b: activin A receptor type 1B; BSP: bone sialoprotein; mADSCs: mouse ADSCs; PTBP1: polypyrimidine tract-binding protein; ER: endoplasmic reticulum; hUCMSCs: MSCs derived from human umbilical cord; MSMSCs: maxillary sinus membrane stem cells; SCAPs: stem cells from the apical papilla; MyoD: myogenic differentiation protein 1; MSTN: myostatin; MEF2C: myocyte enhancer factor 2C; BCLAF1: BCL2-associated transcription factor 1; EpSCs: epidermal stem cells; ISCs: intestinal stem cells; NSCs: neural stem cells; Lgr5+ ISCs: crypt base columnar cells; ILCs: innate lymphoid cells. [ABSTRACT FROM AUTHOR]

Our lab and others have shown that chronic alcohol use leads to gene and miRNA expression changes across the mesocorticolimbic (MCL) system. Circular RNAs (circRNAs) are noncoding RNAs that form closed‐loop structures and are reported to alter gene expression through miRNA sequestration, thus providing a potentially novel neurobiological mechanism for the development of alcohol dependence (AD). Genome‐wide expression of circRNA was assessed in the nucleus accumbens (NAc) from 32 AD‐matched cases/controls. Significant circRNAs (unadj. p ≤ 0.05) were identified via regression and clustered in circRNA networks via weighted gene co‐expression network analysis (WGCNA). CircRNA interactions with previously generated mRNA and miRNA were detected via correlation and bioinformatic analyses. Significant circRNAs (N = 542) clustered in nine significant AD modules (FWER p ≤ 0.05), within which we identified 137 circRNA hubs. We detected 23 significant circRNA–miRNA–mRNA interactions (FDR ≤ 0.10). Among these, circRNA‐406742 and miR‐1200 significantly interact with the highest number of mRNA, including genes associated with neuronal functioning and alcohol addiction (HRAS, PRKCB, HOMER1, and PCLO). Finally, we integrate genotypic information that revealed 96 significant circRNA expression quantitative trait loci (eQTLs) (unadj. p ≤ 0.002) that showed significant enrichment within recent alcohol use disorder (AUD) and smoking genome‐wide association study (GWAS). To our knowledge, this is the first study to examine the role of circRNA in the neuropathology of AD. We show that circRNAs impact mRNA expression by interacting with miRNA in the NAc of AD subjects. More importantly, we provide indirect evidence for the clinical importance of circRNA in the development of AUD by detecting a significant enrichment of our circRNA eQTLs among GWAS of substance abuse. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) is a special type of breast cancer that lacks effective therapeutic targets. There is a significant need to clarify its pathogenesis, so as to bring new targeted approaches for TNBC management. Here, we identified a long-non coding RNA (lncRNA) ASMTL-AS1 that linked to TNBC development and progression. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assays were used to test gene and protein levels, respectively. The regulatory axis of miR-1228-3p/SOX17/β-catenin was determined by luciferase reporter and RNA pull-down assays. In vivo assay was conducted by using the nude mice model via subcutaneous transplantation of tumor cells. Results: ASMTL-AS1 was significantly downregulated in TNBC tissues compared to normal tissues, which was closely associated with aggressive clinical features and unfavorable prognosis. Lentivirus-mediated ASMTL-AS1 overexpression evidently reduced the ability of TNBC cell colony formation, activity and invasion by more than 2.5 times. RNA pull-down and luciferase reporter assays revealed that miR-1228-3p directly bound to ASMTL-AS1, ASMTL-AS1 increased SOX17 expression via sponging and repressing miR-1228-3p. Subsequently, the upregulated SOX17 trans-suppressed β-catenin expression, resulting in the inactivation of carcinogenic Wnt/β-catenin signaling, thereby restraining TNBC cell growth and dissemination. Importantly, the xenograft tumor model showed that the ASMTL-AS1 overexpression significantly retarded tumor growth, and negatively regulated Wnt/β-catenin pathway. Conclusions: Our data characterize a novel tumor suppressor in TNBC, restoration of ASMTL-AS1 may be a candidate therapeutic intervention for TNBC patients. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are an evolutionarily conserved novel class of non-coding endogenous RNAs (ncRNAs) found in the eukaryotic transcriptome, originally believed to be aberrant RNA splicing by-products with decreased functionality. However, recent advances in high-throughput genomic technology have allowed circRNAs to be characterized in detail and revealed their role in controlling various biological and molecular processes, the most essential being gene regulation. Because of the structural stability, high expression, availability of microRNA (miRNA) binding sites and tissue-specific expression, circRNAs have become hot topic of research in RNA biology. Compared to the linear RNA, circRNAs are produced differentially by backsplicing exons or lariat introns from a pre-messenger RNA (mRNA) forming a covalently closed loop structure missing 3′ poly-(A) tail or 5′ cap, rendering them immune to exonuclease-mediated degradation. Emerging research has identified multifaceted roles of circRNAs as miRNA and RNA binding protein (RBP) sponges and transcription, translation, and splicing event regulators. CircRNAs have been involved in many human illnesses, including cancer and neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, due to their aberrant expression in different pathological conditions. The functional versatility exhibited by circRNAs enables them to serve as potential diagnostic or predictive biomarkers for various diseases. This review discusses the properties, characterization, profiling, and the diverse molecular mechanisms of circRNAs and their use as potential therapeutic targets in different human malignancies.

Background/Aims: A growing body of evidence has suggested that circular RNAs (circRNAs) have crucial functions in the regulation of gene expression, and their dysregulation has been implicated in various types of cancers. However, the roles of circRNAs in laryngeal cancer remain largely unknown. This study investigated the global changes in the expression pattern of circRNAs in laryngeal squamous cell carcinoma (LSCC) to identify potential differentially expressed circRNAs. Methods: Microarray-based circRNA expression was determined in LSCC and paired normal laryngeal tissues. Pathway analyses of the genes producing differentially expressed circRNAs were performed to predict the function of circRNAs using standard enrichment computational methods. Expression levels of candidate circRNAs and microRNAs (miRNAs) were detected by quantitative real-time PCR. The circRNA/ miRNA interactions were constructed using bioinformatics methods to predict the binding of miRNA with circRNA. Results: We identified 506 differentially expressed circRNAs from human LSCC and normal laryngeal mucosa tissues. We confirmed that hsa_circ_0044520 and hsa_circ_0044529 were significantly upregulated in LSCC tissues. The most likely potential target miRNAs for hsa_ circ_0044520 and hsa_circ_0044529 were hsa-miR-4726-5p and hsa-miR-4640-5p, respectively. Functional analysis showed that hsa_circ_0044520 and hsa_circ_0044529 were involved in the process of collagen synthesis. Conclusion: Competitive endogenous RNA network prediction and bioinformatics functional analysis revealed that hsa_circ_0044520 and hsa_circ_0044529 play important regulatory roles by sponging hsa-miR-4726-5p and hsa-miR-4640-5p, thereby providing novel insights into the tumorigenesis of LSCC.

Cold viruses have generally been considered fairly innocuous until the appearance of the severe acute respiratory coronavirus 2 (SARS-CoV-2) in 2019, which caused the coronavirus disease 2019 (COVID-19) global pandemic. Two previous viruses foreshadowed that a coronavirus could potentially have devastating consequences in 2002 [severe acute respiratory coronavirus (SARS-CoV)] and in 2012 [Middle East respiratory syndrome coronavirus (MERS-CoV)]. The question that arises is why these viruses are so different from the relatively harmless cold viruses. On the basis of an analysis of the current literature and using bioinformatic approaches, we examined the potential human miRNA interactions with the SARS-CoV2’s genome and compared the miRNA target sites in seven coronavirus genomes that include SARS-CoV-2, MERS-CoV, SARS-CoV, and four nonpathogenic coronaviruses. Here, we discuss the possibility that pathogenic human coronaviruses, including SARS-CoV-2, could modulate host miRNA levels by acting as miRNA sponges to facilitate viral replication and/or to avoid immune responses. [ABSTRACT FROM AUTHOR]

Being the center of the hypothalamus-pituitary-ovary (HPO) axis, the pituitary plays a key role in the onset of puberty. Recent studies show that circular RNAs (circRNAs) can perform as miRNA sponges to regulate development in animals. However, the function of pituitary-derived circRNAs in first estrus remains unclear in pigs. In this study, we performed a genome-wide identification and characterization of circRNAs using pituitaries from Landrace × Yorkshire crossbred pigs at three stages: pre-, in-, and post-puberty, to describe such pituitary-derived circRNAs in pigs. A total of 5148 circRNAs were found in the gilts' pituitaries, averaging 18 682 bp in genomic distance, which consisted of approximately 91% exonic, 6% intergenic, and 3% intronic circRNAs. Furthermore, 158 novel circRNAs were identified for the first time and classified as putative pituitary-specific circRNAs. Their expression levels during the onset of puberty, significantly exceeded those of the other circRNAs, and the parental genes of these putative pituitary-specific circRNAs were enriched in “ssc04917: prolactin signaling pathway,” “ssc04080: neuroactive ligand-receptor interaction,” and “ssc04728: dopaminergic synapse” pathways, all of which were consistent with pituitary functioning. Additionally, 17 differentially regulated circRNAs were found and investigated for their potential interaction with miRNAs, along with genes, by constructing a circRNA-targeted miRNA-gene network. Taken together, these results provide new insight into the circRNA-mediated timing of puberty in gilts at the pituitary level.

Being the center of the hypothalamus-pituitary-ovary (HPO) axis, the pituitary plays a key role in the onset of puberty. Recent studies show that circular RNAs (circRNAs) can perform as miRNA sponges to regulate development in animals. However, the function of pituitary-derived circRNAs in first estrus remains unclear in pigs. In this study, we performed a genome-wide identification and characterization of circRNAs using pituitaries from Landrace × Yorkshire crossbred pigs at three stages: pre-, in-, and post-puberty, to describe such pituitary-derived circRNAs in pigs. A total of 5148 circRNAs were found in the gilts' pituitaries, averaging 18 682 bp in genomic distance, which consisted of approximately 91% exonic, 6% intergenic, and 3% intronic circRNAs. Furthermore, 158 novel circRNAs were identified for the first time and classified as putative pituitary-specific circRNAs. Their expression levels during the onset of puberty, significantly exceeded those of the other circRNAs, and the parental genes of these putative pituitary-specific circRNAs were enriched in "ssc04917: prolactin signaling pathway," "ssc04080: neuroactive ligand-receptor interaction," and "ssc04728: dopaminergic synapse" pathways, all of which were consistent with pituitary functioning. Additionally, 17 differentially regulated circRNAs were found and investigated for their potential interaction with miRNAs, along with genes, by constructing a circRNA-targeted miRNA-gene network. Taken together, these results provide new insight into the circRNA-mediated timing of puberty in gilts at the pituitary level. [ABSTRACT FROM AUTHOR]

Non-coding circular RNAs (circRNAs) have been shown to have important roles in many diseases; however, no study has indicated circRNAs are involved in Chlamydia trachomatis infection. In this study, we used circRNA microarray to measure the global circRNA expression profiles in HeLa cells with or without C. trachomatis serovar E (Ct.E) infection. CircRNA/miRNA/mRNA interactions were predicted and bioinformatics analyses were performed. The differentially expressed circRNAs were selected according to our criterion for validation by reverse-transcription and quantitative polymerase chain reaction (RT-qPCR). The mRNA microarray was used to detect the mRNA expression profiles after Ct.E infection. Among 853 differentially expressed circRNAs, 453 were upregulated and 400 were downregulated after Ct.E infection. Target miRNAs and miRNA-targeted mRNAs of these circRNAs were predicted. RT-qPCR analysis indicated hsa_circRNA_001226, hsa_circRNA_007046 and hsa_circRNA_400027 were elevated similar to those determined in the circRNA microarray analysis. The mRNA microarray results showed 915 genes were upregulated and 619 genes were downregulated after Ct.E infection. Thirty-four differentially expressed genes overlapped in the bioinformatics and mRNA microarray results. KEGG pathway analysis revealed several signaling pathways, including endocytosis, MAPK and PI3P-Akt signaling pathways, that were targeted by circRNAs may play important roles in Chlamydia infection. This study provides evidence that circRNAs in host cells are involved in the process of Chlamydia infection. Identification of the differentially expressed circular RNAs and circular RNA-targeted pathways involved in the interaction between host cells and Chlamydia infection for the first time. [ABSTRACT FROM AUTHOR]

Recent studies have found that known functions of circular RNAs (circRNAs) include sequestration of microRNAs (miRNAs) or proteins, modulation of transcription and interference with splicing, and even translation to produce polypeptides. The zebrafish model is also demonstrably similar to humans in many studies. To explore the changes in circRNAs during embryonic development and to further research the mechanism of action of circRNAs in development‐related diseases, Zebrafish embryos at the blastula period, gastrula period, segmentation period, throat stage, and incubation period were collected. Illumina deep‐sequencing technology and CircRNA Identifier (CIRI) algorithm were used to detect circRNAs. In total, we identified 1,028 circRNAs (junction reads ≥5 and p < 0.05). Considering that the function of circRNAs is related to host genes, a bioinformatics analysis revealed these differentially expressed host genes are involved in NOTCH signaling pathways, cardiovascular system development, retinal ganglion cell axon guidance, and so on. Moreover, circRNAs can participate in biological regulation through the function of miRNA sponges. TargetScan and miRanda were used to predict 73 miRNAs binding to circRNAs such as miR‐19b, miR‐124, and so on. Some miRNAs play important roles in embryogenesis. The peak expression of circRNAs is distributed at different time points, suggesting that it may be involved in embryogenesis at different stages. Our study provides a foundation for understanding the dynamic regulation of circRNA transcriptomes during embryogenesis and identifies novel key circRNAs that might control embryonic development in a zebrafish model. [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC) is characterized by chronic inflammation in the colon and epigenetic factors underlying the occurrence. Circular RNAs (circRNAs) have been under intensive focus due to the circular construct and gene-regulating functions. However, the changes and roles of circRNAs in UC remain unknown.Methods: Microarrays were used to detect the differentially expressed genes, and quantitative real-time PCR was used to identify the changes in UC. In silico analyses were performed to predict the functions of circRNAs and mRNAs. In vitro, epithelial cell lines were stimulated by pro-inflammation effectors to test the alterations in circRNAs. CircRNAs-microRNAs-mRNAs network clarified the potential mechanisms underlying circRNAs in UC. The binding site between hsa_circ_0007919 and miR-138 or let-7a was verified using dual-luciferase assay.Results: A total of 264 significantly dysregulated circRNAs and 1869 differentially expressed mRNAs in inflamed mucosa were compared with the non-inflamed mucosa in UC. Hsa_circ_0004662 and hsa_circ_0007919 were altered largely in UC tissues. Hsa_circ_0007919 was reduced persistently after inflammatory treatments, and it was relevant to Mayo endoscopic subscores and the expression of tight junction molecules. Finally, hsa_circ_0007919 could harbor miR-138, and let-7a to regulate the targeted mRNAs EPC1 and VIPR1.Conclusions: Several circRNAs were differentially expressed in UC. Hsa_circ_0007919 is related to clinical characteristics and epithelial integrity by binding to hsa-let-7a, hsa-miR-138 to regulate the target genes. CircRNAs, especially hsa_circ_0007919, are associated with the pathogenesis and development of UC, with potential diagnostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are non-coding RNAs newly identified and play important roles in RNA regulation. The mechanism and function of circRNAs have been reported in some species. However, little is known regarding circRNAs in honey bees. In this study, we analyzed circRNAs through bioinformatics, and predicted 12,211 circRNAs in the ovary of honey bee queens. 1340, 175 and 100 circRNAs were differentially expressed in comparisons of egg-laying queens vs virgin queens, egg-laying inhibited queens vs egg-laying queens and egg-laying recovery queens vs egg-laying inhibited queens. Further, functional annotation of differentially expressed circRNAs revealed several pathways that are closely related to ovary activation and oviposition, including insulin secretion and calcium signaling pathways. Moreover, the potential interactions among circRNAs, miRNAs, lncRNAs and mRNAs were investigated. Ame_circ_0005197 and ame_circ_0016640 were observed to sponge several reproductive related miRNAs. These findings demonstrate that circRNAs have potential effects in ovary activation and oviposition of honey bees. • The expression of circRNAs, miRNAs, lncRNAs and mRNAs in ovary of honey bee queens were investigated. [ABSTRACT FROM AUTHOR]

Orf, caused by Orf virus (ORFV), is a globally distributed zoonotic disease responsible for serious economic losses in the agricultural sector. However, the mechanism underlying ORFV infection remains largely unknown. Circular RNAs (circRNAs), a novel type of endogenous non-coding RNAs, play important roles in various pathological processes but their involvement in ORFV infection and host response is unclear. In the current study, whole transcriptome sequencing and small RNA sequencing were performed in ORFV-infected goat skin fibroblast cells and uninfected cells. A total of 151 circRNAs, 341 messenger RNAs (mRNAs), and 56 microRNAs (miRNAs) were differently expressed following ORFV infection. Four circRNAs: circRNA1001, circRNA1684, circRNA3127 and circRNA7880 were validated by qRT-PCR and Sanger sequencing. Gene ontology (GO) analysis indicated that host genes of differently expressed circRNAs were significantly enriched in regulation of inflammatory response, epithelial structure maintenance, positive regulation of cell migration, positive regulation of ubiquitin-protein transferase activity, regulation of ion transmembrane transport, etc. The constructed circRNA-miRNA-mRNA network suggested that circRNAs may function as miRNA sponges indirectly regulating gene expression following ORFV infection. Our study presented the first comprehensive profiles of circRNAs in response to ORFV infection, thus providing new clues for the mechanisms of interactions between ORFV and the host.

MicroRNAs (miRNAs) are RNA molecules at about 22 nucleotide in length that are non-coding, which regulate gene expression in the post-transcriptional level by performing degradation or blocks translation of the target mRNA. It is known that they play roles in mechanisms such as metabolic regulation, embryogenesis, organogenesis, differentiation and growth control by providing post-transcriptional regulation of gene expression. With these properties, miRNAs play important roles in the regulation of biological processes such as proliferation, differentiation, apoptosis, drug resistance mechanisms in eukaryotic cells. In addition, there are miRNAs that can be used for cancer therapy. Tumor cells and tumor microenvironment have different miRNA expression profiles. Some miRNAs are known to play a role in the onset and progression of the tumor. miRNAs with oncogenic or tumor suppressive activity specific to different cancer types are still being investigated. This review summarizes the role of miRNAs in tumorigenesis, therapeutic strategies in human cancer and current studies. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a new class of non-coding RNAs in animals and are a novel target of non-coding RNA (ncRNA) regulation. The mechanism and function of circRNAs have been reported in some species and tissues. However, there is little available information on the functions of circRNAs in the goat reproductive system. In the present study, we deeply sequenced and analyzed circRNAs through bioinformatics to reveal the expression profiles, and predicted 13,950 circRNAs in the pre-ovulatory ovarian follicles of goats for the first time. Thirty-seven circRNAs were differentially expressed in the Boer goat compared with the Macheng black goat. The chi_circ_0008219 was involved in a vast circRNA-miRNA-mRNA co-expression network. Via a luciferase activity assay, chi_circ_0008219 is observed to sponge to 3 ovarian follicle-related miRNAs. These findings demonstrate that circRNAs have potential effects in the ovarian follicles of ewes and may represent a promising new research field in ovarian follicular development. [ABSTRACT FROM AUTHOR]

Little information about the roles of circular RNAs (circRNAs) during potato-Pectobacterium carotovorum subsp. brasiliense (Pcb) interaction is currently available. In this study, we conducted the systematic identification of circRNAs from time series samples of potato cultivars Valor (susceptible) and BP1 (disease tolerant) infected by Pcb. A total of 2098 circRNAs were detected and about half (931, 44.38%) were intergenic circRNAs. And differential expression analysis detected 429 significantly regulated circRNAs. circRNAs play roles by regulating parental genes and sponging miRNAs. Gene Ontology (GO) enrichment of parental genes and miRNAs targeted mRNAs revealed that these differentially expressed (DE) circRNAs were involved in defense response (GO:0006952), cell wall (GO:0005199), ADP binding (GO:0043531), phosphorylation (GO:0016310), and kinase activity (GO:0016301), suggesting the roles of circRNAs in regulating potato immune response. Furthermore, weighted gene co-expression network analysis (WGCNA) found that circRNAs were closely related with coding-genes and long intergenic noncoding RNAs (lincRNAs). And together they were cultivar-specifically regulated to strengthen immune response of potato to Pcb infection, implying the roles of circRNAs in reprogramming disease responsive transcriptome. Our results will provide new insights into the potato-Pcb interaction and may lead to novel disease control strategy in the future. [ABSTRACT FROM AUTHOR]

• CircRNAs seem to play important roles in various biological functions. • CircRNAs have been shown to be able to regulate many cellular pathways. • circRNAs might be a suitable inducer to promote osteogenic differentiation of stem cells in bone tissue. The extracellular matrixes (ECM), as well as the microenvironmental signals, play an essential role in osteogenesis by regulating intercellular pathways. Recently, it has been demonstrated that a newly identified RNA, circular RNA, contributes to the osteogenesis process. Circular RNA (circRNA), the most recently identified RNA, is involved in the regulation of gene expression at transcription to translation levels. The dysregulation of circRNAs has been observed in several tumors and diseases. Also, various studies have shown that circRNAs expression is changed during osteogenic differentiation of progenitor cells. Therefore, understanding the role of circRNAs in osteogenesis might help the diagnosis as well as treatment of bone diseases such as bone defects and osteoporosis. In this review, circRNA functions and the related pathways in osteogenesis have been discussed. [ABSTRACT FROM AUTHOR]

In recent years, breakthroughs in bioinformatics have been made with the discovery of many functionally significant non-coding RNAs (ncRNAs). The discovery of these ncRNAs has further demonstrated the multi-level characteristics of intracellular gene expression regulation, which plays an important role in assisting diagnosis, guiding clinical drug use and determining prognosis in the treatment process of various diseases. microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are the three major types of ncRNAs that interact with each other. Studies have shown that lncRNAs and circRNAs can sponge miRNAs, thereby influencing normal physiological processes and regulating mRNA expression and, thus, the physiological state of cells. This paper summarizes the mechanism of action and research progress of the three ncRNA and seven types of modalities. This summary is intended to provide new ideas for diagnosing and treating diseases and researching and developing new drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

Normal cell proliferation is controlled by a balance between signals that promote or halt cell proliferation. Micro RNAs are emerging as key elements in providing fine signal balance in different physiological situations. Here we report that STAT5 signaling induces the miRNAs miR-19 and miR-155, which potentially antagonize the tumor suppressor axis composed by the STAT5 target gene SOCS1 (suppressor of cytokine signaling-1) and its downstream effector p53. MiRNA sponges against miR-19 or miR-155 inhibit the functions of these miRNAs and potentiate the induction of SOCS1 and p53 in mouse leukemia cells and in human myeloma cells. Adding a catalytic RNA motif of the hammerhead type within miRNA sponges against miR-155 leads to decreased miR-155 levels and increased their ability of inhibiting cell growth and cell migration in myeloma cells. The results indicate that antagonizing miRNA activity can reactivate tumor suppressor pathways downstream cytokine stimulation in tumor cells. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are widely known as a class of non-coding RNA (ncRNA), which regulate gene expression, largely at the post-transcriptional level, but rarely also at the transcription level. During the last few years, a new class of ncRNA has been discovered, which counteracts the repressive activity of miRNA, by sequestering miRNA within a cell. These novel ncRNA molecules have been variously described as 'miRNA sponges/decoys', 'target mimics' or 'competing endogenous RNA'. Several reports of the occurrence of these ceRNAs and their role in regulating gene expression were published recently, which are briefly described in this article. These discoveries will keep scientists busy for many years to generate new information. [ABSTRACT FROM AUTHOR]

The specification of motor neuron (MN) subtypes and columnar organization in developing spinal cord is controlled by multiple transcription factors. FoxP1 drives specification of lateral motor neuron (LMN) subtypes, and we demonstrated in our previous work that FoxP1 expression levels are regulated by the microRNA miR-9. Here we show that ectopic FoxP1 expression can rescue altered LMN development caused by miR-9 over-expression, demonstrating that FoxP1 is the critical interaction partner for miR-9 in LMN development. Moreover, we have optimized this technique, called a miRNA sponge, to permit easy discovery of the role of individual miRNA in vivo using a loss-of-function approach. We here show that narrow spacing between binding sites and inclusion of a coding gene, and optimizing the number of miRNA binding sites can significantly increase the blocking ability of a sponge. We go on to show that a miR-9 sponge reduces detectable miR-9 in the ventral horn, preventing miR-9 silencing of FoxP1 in vivo, and in turn modifies MN subtypes in the spinal cord. Our designs for optimized sponges provide a knockdown tool that is ready to be used to study the function of miRNA in vivo, and in particular for generating transgenic animal models.

Endogenously expressed transcripts that are posttranscriptionally regulated by the same microRNAs (miRNAs) will, in principle, compete for the binding of their shared small noncoding RNA regulators and modulate each other's abundance. Recently, the levels of some coding as well as noncoding transcripts have indeed been found to be regulated in this way. Transcripts that engage in such regulatory interactions are referred to as competitive endogenous RNAs (ceRNAs). This novel layer of posttranscriptional regulation has been shown to contribute to diverse aspects of organismal and cellular biology, despite the number of functionally characterized ceRNAs being as yet relatively low. Importantly, increasing evidence suggests that the dysregulation of some ceRNA interactions is associated with disease etiology, most preeminently with cancer. Here we review how posttranscriptional regulation by miRNAs contributes to the cross-talk between transcripts and review examples of known ceRNAs by highlighting the features underlying their interactions and what might be their biological relevance. [ABSTRACT FROM AUTHOR]

Background: microRNA 21 (miR-21) has been demonstrated to be significantly elevated in many types of cancers, including the hepatocellular carcinoma (HCC). In the present study, we investigated the role of miR-21 in HCC by identifying its novel targets, as well as its underlying molecular mechanism.Methods: The expression of mitogen-activated protein kinase-kinase 3 (MAP2K3) in human HCC tumor tissues and adjacent non-tumor tissues was determined by immunohistochemistry staining (IHC) analysis. The 3'-untranslated region (3'-UTR) of MAP2K3 combined with miR-21 was experimentally verified by a miRNA luciferase reporter approach. Moreover, the role of miR-21 in regulating HCC cell proliferation was analyzed by an MTT assay infected with miR-21mimics/sponge inhibitor Adenoviral viral vectors.Results: By immunohistochemistry staining analysis, we found that mitogen-activated protein kinase-kinase 3 (MAP2K3) was strikingly repressed in the human HCC tumor tissues, in comparison with the adjacent non-tumor tissues in clinical settings. More importantly, the repression of MAP2K3 was inversely correlated with the expression of miR-21 in HCC. Further study demonstrated that the MAP2K3 was a novel direct target of miR-21, which was experimentally validated by a miRNA luciferase reporter approach. In HepG2 cells, inhibition of miR-21 expression with an adenoviral miR-21 sponge vector profoundly suppressed cell proliferation by up-regulating MAP2K3 expression at both mRNA and protein levels.Conclusions: These results provide a clinical evidence that MAP2K3 may be a tumor repressor gene, and it is a direct target of miR-21 in HCC, indicating an underlying mechanism by which miR-21 is able to directly target MAP2K3 and inhibit its expression during the carcinogenesis of HCC, at both transcriptional and post-translational levels. This study also suggests that targeting miR-21-MAP2K3 pathway may be a promising strategy in the prevention and treatment of HCC. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are widely involved in plant growth and development. However, the function of circRNAs in plant somatic embryogenesis (SE) remains elusive. Here, by using high-throughput sequencing, a total of 5029 circRNAs were identified in the three stages of longan (Dimocarpus longan Lour.) early SE. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that differentially expressed (DE) circRNA host genes were enriched in the 'non-homologous end-joining' (NHEJ) and 'butanoate metabolism' pathways. In addition, the reactive oxygen species (ROS) content during longan early SE was determined. The results indicated that ROS-induced DNA double-strand breaks may not depend on the NHEJ repair pathway. Correlation analyses of the levels of related metabolites (glutamate, γ-aminobutyrate and pyruvate) and the expression levels of circRNAs and their host genes involved in butanoate metabolism were performed. The results suggested that circRNAs may act as regulators of the expression of cognate mRNAs, thereby affecting the accumulation of related compounds. A competing endogenous RNA (ceRNA) network of DE circRNAs, DE mRNAs, DE long noncoding RNAs (lncRNAs) and DE microRNAs (miRNAs) was constructed. The results showed that the putative targets of the noncoding RNA (ncRNAs) were significantly enriched in the KEGG pathways 'mitogen-activated protein kinase signaling' and 'nitrogen metabolism'. Furthermore, the expression patterns of the candidate circRNAs, lncRNAs, miRNAs and mRNAs confirmed the negative correlation between miRNAs and ceRNAs. In addition, two circRNA overexpression vectors were constructed to further verify the ceRNA network correlations in longan early SE. Our study revealed the potential role of circRNAs in longan early SE, providing new insights into the intricate regulatory mechanism underlying plant SE., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

MicroRNAs (miRNAs) are about 19-24 nucleotide small single-stranded noncoding RNAs that are involved in crucial cell processes such as proliferation, apoptosis, and differentiation. Several studies reported show the involvement of miRNA in cancer. It has been suggested that miRNA profiling has the potential to classify a variety of tumors and possibly predict outcome. MicroRNA can act as an oncogene as well as tumor suppressor gene and this dual function of miRNA can be utilized as a therapeutic tool. The oncogenic character of miRNA can be silenced through various RNA interference-type strategies. The involvement of miRNA in the tumorogenesis processes makes them an important therapeutic tool and a novel biomarker. In this review, we have highlighted the role of miRNA in hematological malignancies and its utility in targeted therapy. [ABSTRACT FROM AUTHOR]

Converging evidence demonstrates that microRNAs (miRNAs) play an important role in the etiology of cognitive impairment. Thus, we aim to: (i) identify the molecular mechanisms of heavy metals, particularly miRNAs involved in the development of cognitive impairment; and (ii) generate miRNA sponges to prevent them from binding with their target messenger RNAs. The Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org), MicroRNA ENrichment TURned NETwork (MIENTURNET, http://userver.bio.uniroma1.it/apps/mienturnet/) and the microRNA sponge generator and tester (miRNAsong, http://www.med.muni.cz/histology/miRNAsong) were used as the core data-mining approaches in the current study. We observed that lead acetate, arsenic, gold, copper, iron, and aluminum, as well as their mixtures, had significant effects on the development of cognitive impairment. Although prevalent genes obtained from investigated heavy metals of cognitive impairment were different, the "PI3K-Akt signaling pathway", "pathways of neurodegeneration-multiple diseases", "apoptosis", "apoptosis-multiple species", "p53 signaling pathway", "NF-kappa B signaling pathway", and "Alzheimer's disease pathway" were highlighted. The mixed heavy metals altered the genes BAX, CASP3, BCL2, TNF, and IL-1B, indicating the significance of apoptosis and pro-inflammatory cytokines in the pathogenesis of cognitive impairment and the possibility of targeting these genes in future neuroprotective therapy. In addition, we used a network-based approach to identify key genes, miRNAs, pathways, and diseases related to the development of cognitive impairment. We also found 16 significant miRNAs related to cognitive impairment (hsa-miR-1–3p, hsa-let-7a-5p, hsa-miR-9–5p, hsa-miR-16–5p, hsa-miR-17–5p, hsa-miR-20a-5p, hsa-miR-26a-5p, hsa-miR-26b-5p, hsa-miR-34a-5p, hsa-miR-101–3p, hsa-miR-106a-5p, hsa-miR-128–3p, hsa-miR-144–3p, hsa-miR-199a-3p, hsa-miR-204–5p, and hsa-miR-335–5p). Finally, we created and evaluated miRNA sponge sequences for these miRNAs in silico. Further studies, including in vivo and in vitro, are needed to assess the link between these genes, miRNAs, pathways, and cognitive impairment. [Display omitted] [ABSTRACT FROM AUTHOR]