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Cachexia is a late consequence of various diseases that is characterized by systemic muscle loss, with or without fat loss, leading to significant mortality. Multiple signaling pathways and molecules that increase catabolism, decrease anabolism, and interfere with muscle regeneration are activated. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play vital roles in cachexia muscle atrophy. This review mainly provides the mechanisms of specific ncRNAs to regulate muscle loss during cachexia and discusses the role of ncRNAs in cachectic biomarkers and novel therapeutic strategies that could offer new insights for clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is difficult to treat. This is partly because each tumor is different and there are few drugs that are effective against this disease. Further, the high mortality from TNBC is primarily attributable to its spread beyond the primary tumor site, or metastasis. There has been a lack of understanding of common factors affecting metastasis in TNBC and, consequently, continued difficulty in effectively treating this deadly disease. A re-emerging concept regarding the broad regulation of factors affecting disease is that of competitive endogenous RNA networks. The recent study of these networks and how they regulate metastatic processes in TNBC is providing new insights into the predominant molecular factors and cellular signaling pathways involved in the progression of this disease. Here, we review this research and what it may mean for patients with metastatic TNBC (mTNBC) and advancements that may improve their treatment. Triple-negative breast cancer is aggressive and challenging to treat because of a lack of targets and heterogeneity among tumors. A paramount factor in the mortality from breast cancer is metastasis, which is driven by genetic and phenotypic alterations that drive epithelial–mesenchymal transition, stemness, survival, migration and invasion. Many genetic and epigenetic mechanisms have been identified in triple-negative breast cancer that drive these metastatic phenotypes; however, this knowledge has not yet led to the development of effective drugs for metastatic triple-negative breast cancer (mTNBC). One that may not have received enough attention in the literature is post-translational regulation of broad sets of cancer-related genes through inhibitory microRNAs and the complex competitive endogenous RNA (ceRNA) regulatory networks they are influenced by. This field of study and the resulting knowledge regarding alterations in these networks is coming of age, enabling translation into clinical benefit for patients. Herein, we review metastatic triple-negative breast cancer (mTNBC), the role of ceRNA network regulation in metastasis (and therefore clinical outcomes), potential approaches for therapeutic exploitation of these alterations, knowledge gaps and future directions in the field. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are cardinal players in numerous physiological and pathological processes. CircRNAs play dual roles as tumor suppressors and oncogenes in different oncological contexts, including hepatocellular carcinoma (HCC). Their roles significantly impact the disease at all stages, including initiation, development, progression, invasion, and metastasis, in addition to the response to treatment. In this review, we discuss the biogenesis and regulatory functional roles of circRNAs, as well as circRNA–protein–mRNA ternary complex formation, elucidating the intricate pathways tuned by circRNAs to modulate gene expression and cellular processes through a comprehensive literature search, in silico search, and bioinformatics analysis. With a particular focus on the interplay between circRNAs, epigenetics, and HCC pathology, the article sets the stage for further exploration of circRNAs as novel investigational theranostic agents in the dynamic realm of HCC. [ABSTRACT FROM AUTHOR]

Circular RNA (circRNA) is a type of non-coding RNA with multiple biological functions. Whole circRNA genomes in plants have been identified, and circRNAs have been demonstrated to be widely present and highly expressed in various plant tissues and organs. CircRNAs are highly stable and conserved in plants, and exhibit tissue specificity and developmental stage specificity. CircRNAs often interact with other biomolecules, such as miRNAs and proteins, thereby regulating gene expression, interfering with gene function, and affecting plant growth and development or response to environmental stress. CircRNAs are less studied in plants than in animals, and their regulatory mechanisms of biogenesis and molecular functions are not fully understood. A variety of circRNAs in plants are involved in regulating growth and development and responding to environmental stress. This review focuses on the biogenesis and regulatory mechanisms of circRNAs, as well as their biological functions during growth, development, and stress responses in plants, including a discussion of plant circRNA research prospects. Understanding the generation and regulatory mechanisms of circRNAs is a challenging but important topic in the field of circRNAs in plants, as it can provide insights into plant life activities and their response mechanisms to biotic or abiotic stresses as well as new strategies for plant molecular breeding and pest control. [ABSTRACT FROM AUTHOR]

m6A methylation, a ubiquitous modification on circRNAs, exerts a profound influence on RNA function, intracellular behavior, and diverse biological processes, including disease development. While prediction algorithms exist for mRNA m6A modifications, a critical gap remains in the prediction of circRNA m6A modifications. Therefore, accurate identification and prediction of m6A sites are imperative for understanding RNA function and regulation. This study presents a novel hybrid model combining a convolutional neural network (CNN) and a bidirectional long short-term memory network (BiLSTM) for precise m6A methylation site prediction in circular RNAs (circRNAs) based on data from HEK293 cells. This model exploits the synergy between CNN's ability to extract intricate sequence features and BiLSTM's strength in capturing long-range dependencies. Furthermore, the integrated attention mechanism empowers the model to pinpoint critical biological information for studying circRNA m6A methylation. Our model, exhibiting over 78% prediction accuracy on independent datasets, offers not only a valuable tool for scientific research but also a strong foundation for future biomedical applications. This work not only furthers our understanding of gene expression regulation but also opens new avenues for the exploration of circRNA methylation in biological research. [ABSTRACT FROM AUTHOR]

Cancer has been one of the most problematic health issues globally. Typically, all cancers share a common characteristic or cancer hallmark, such as sustaining cell proliferation, evading growth suppressors, and enabling replicative immortality. Indeed, cell cycle regulation in cancer is often found to be dysregulated, leading to an increase in aggressiveness. These dysregulations are partly due to the aberrant cellular signaling pathway. In recent years, circular RNAs (circRNAs) have been widely studied and classified as one of the regulators in various cancers. Numerous studies have reported that circRNAs antagonize or promote cancer progression through the modulation of cell cycle regulators or their associated signaling pathways, directly or indirectly. Mostly, circRNAs are known to act as microRNA (miRNA) sponges. However, they also hold additional mechanisms for regulating cellular activity, including protein binding, RNA-binding protein (RBP) recruitment, and protein translation. This review will discuss the current knowledge of how circRNAs regulate cell cycle-related proteins through the abovementioned mechanisms in different cancers. [ABSTRACT FROM AUTHOR]

Eggshell color plays important biological roles and attracts the attention of both egg retailers and researchers. However, whether non-coding RNAs are involved in pigment deposition among different eggshell colors remains unknown. In this study, RNA sequencing was used to analyse the uterine gland transcriptome (CircRNA and miRNA) of Changshun chicken blue-shell hens producing four different eggshell color eggs including dark blue PK(DB) and light blue (LB), dark brown and greenish (between blue and pink, DP) and pink (p). We found that miR-192-x, targeting SLC16a7, was expressed in DB, DP, and LB groups compared with the PK group, which indicates that miR-192-x may play a role in the blue eggshell color. KEGG and GO analyses showed that the "metabolic pathways" with targeted genes such BLVRA and HMOX1 were detected in dark and light blue color eggshell chickens, which confirms the different ratios of biliverdin and HO-1 involved in the deposition of blue color. As annotated by connectivity analysis, RASGRF1 and RASGRF2, belonging to the RASGRF family, are involved in the Ras signaling pathway, which plays an important role in cell growth, differentiation, metastasis and apoptosis. Our findings enrich the database of circRNA, miRNAs and genes for chicken uterine tissue, which will be useful in accelerating molecular selection for blue eggshell color layers. [ABSTRACT FROM AUTHOR]

This manuscript summarizes information on the diverse range of RNA molecules and their role as competing endogenous RNAs (ceRNAs). Moreover, it provides an overview of ceRNA regulatory networks and their applications in ruminant biology. Knowledge of co-expression networks has increased with microarrays, RNA-seq, and scRNA-seq characterizing molecular mediators across various biological scales, using sequences from numerous blood and tissue samples. By synthesizing existing knowledge, this study summarizes interactions between coding and non-coding RNAs through microRNA response elements (MREs), elucidating large-scale regulatory networks throughout the transcriptome that influence the expression and activities of various ceRNAs. Identification of non-coding RNAs with important regulatory functions will revolutionize understanding of RNA biology, shifting from an mRNA-centric model to a complex network of RNA crosstalk. The ceRNA networks offer a more comprehensive and arguably more realistic perspective compared to protein–protein interaction (PPI) networks and weighted gene co-expression networks (WGCN). These ceRNA regulatory networks can describe potential molecular regulatory mechanisms related to functional and economically important traits in ruminants, plus contribute to disease and pathology research, by elucidating pathogenesis and potential drug effects in disease and cancer models. Furthermore, they can provide insights into farm animal biology, e.g., reproductive traits in goats and sheep, regulation of fat metabolism in beef cattle, heat stress responses, and lactation regulation in dairy cattle, fertility and muscle characteristics in buffalo, and resistance to high-salt and water-deprivation conditions in camels. In conclusion, ceRNA and associated regulatory networks should promote a new understanding of molecular mechanisms and identify candidate genes and metabolic-signaling pathways in ruminants. [ABSTRACT FROM AUTHOR]

Historically, the Y chromosome has presented challenges to classical methodology and philosophy of understanding the differences between males and females. A genetic unsolved puzzle, the Y chromosome was the last chromosome to be fully sequenced. With the advent of the Human Genome Project came a realization that the human genome is more than just genes encoding proteins, and an entire universe of RNA was discovered. This dark matter of biology and the black box surrounding the Y chromosome have collided over the last few years, as increasing numbers of non-coding RNAs have been identified across the length of the Y chromosome, many of which have played significant roles in disease. In this review, we will uncover what is known about the connections between the Y chromosome and the non-coding RNA universe that originates from it, particularly as it relates to long non-coding RNAs, microRNAs and circular RNAs. [ABSTRACT FROM AUTHOR]

Our previous study has reported that metastasis-associated protein 2 (MTA2) plays essential roles in tumorigenesis and aggressiveness of gastric cancer (GC). However, the underlying molecular mechanisms of MTA2-mediated GC and its upstream regulation mechanism remain elusive. In this study, we identified a novel circular RNA (circRNA) generated from the MTA2 gene (circMTA2) as a crucial regulator in GC progression. CircMTA2 was highly expressed in GC tissues and cell lines, and circMTA2 promoted the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circMTA2 interacted with ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) to restrain MTA2 ubiquitination and stabilize MTA2 protein expression, thereby facilitating tumor progression. Moreover, circMTA2 was mainly encapsulated and transported by exosomes to promote GC cell progression. Taken together, these findings uncover that circMTA2 suppresses MTA2 degradation by interacting with UCHL3, thereby promoting GC progression. In conclusion, we identified a cancer-promoting axis (circMTA2/UCHL3/MTA2) in GC progression, which paves the way for us to design and synthesize targeted inhibitors as well as combination therapies. [ABSTRACT FROM AUTHOR]

The concept of competitive endogenous RNA regulation has brought on a change in the way we think about transcriptional regulation by miRNA–mRNA interactions. Rather than the relatively simple idea of miRNAs negatively regulating mRNA transcripts, mRNAs and other non-coding RNAs can regulate miRNAs and, therefore, broad networks of gene products through competitive interactions. While this concept is not new, its significant roles in and implications on cancer have just recently come to light. The field is now ripe for the extrapolation of technologies with a substantial clinical impact on cancer. With the majority of the genome consisting of non-coding regions encoding regulatory RNAs, genomic alterations in cancer have considerable effects on these networks that have been previously unappreciated. Triple-negative breast cancer (TNBC) is characterized by high mutational burden, genomic instability and heterogeneity, making this aggressive breast cancer subtype particularly relevant to these changes. In the past few years, much has been learned about the roles of competitive endogenous RNA network regulation in tumorigenesis, disease progression and drug response in triple-negative breast cancer. In this review, we present a comprehensive view of the new knowledge and future perspectives on competitive endogenous RNA networks affected by genomic alterations in triple-negative breast cancer. An overview of the competitive endogenous RNA (ceRNA) hypothesis and its bearing on cellular function and disease is provided, followed by a thorough review of the literature surrounding key competitive endogenous RNAs in triple-negative breast cancer, the genomic alterations affecting them, key disease-relevant molecular and functional pathways regulated by them and the clinical implications and significance of their dysregulation. New knowledge of the roles of these regulatory mechanisms and the current acceleration of research in the field promises to generate insights into the diagnosis, classification and treatment of triple-negative breast cancer through the elucidation of new molecular mechanisms, therapeutic targets and biomarkers. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are defined as subcellular structures limited by a bilayer lipid membrane that function as important intercellular communication by transporting active biomolecules, such as proteins, amino acids, metabolites, and nucleic acids, including long non-coding RNAs (lncRNAs). These cargos can effectively be delivered to target cells and induce a highly variable response. LncRNAs are functional RNAs composed of at least 200 nucleotides that do not code for proteins. Nowadays, lncRNAs and circRNAs are known to play crucial roles in many biological processes, including a plethora of diseases including cancer. Growing evidence shows an active presence of lnc- and circRNAs in EVs, generating downstream responses that ultimately affect cancer progression by many mechanisms, including angiogenesis. Moreover, many studies have revealed that some tumor cells promote angiogenesis by secreting EVs, which endothelial cells can take up to induce new vessel formation. In this review, we aim to summarize the bioactive roles of EVs with lnc- and circRNAs as cargo and their effect on cancer angiogenesis. Also, we discuss future clinical strategies for cancer treatment based on current knowledge of circ- and lncRNA-EVs. [ABSTRACT FROM AUTHOR]

CircRNAs are a class of non-coding RNAs able to regulate gene expression at multiple levels. Their involvement in physiological processes, as well as their altered regulation in different human diseases, both tumoral and non-tumoral, is well documented. However, little is known about their involvement in female reproduction. This study aims to identify circRNAs potentially involved in reproductive women's health. Candidate circRNAs expressed in ovary and sponging miRNAs, already known to be expressed in the ovary, were selected by a computational approach. Using real time PCR, we verified their expression and identified circPUM1 as the most interesting candidate circRNA for further analyses. We assessed the expression of circPUM1 and its linear counterpart in all the follicle compartments and, using a computational and experimental approach, identified circPUM1 direct and indirect targets, miRNAs and mRNAs, respectively, in cumulus cells. We found that both circPUM1 and its mRNA host gene are co-expressed in all the follicle compartments and proposed circPUM1 as a potential regulator of PTEN, finding a strong positive correlation between circPUM1 and PTEN mRNA. These results suggest a possible regulation of PTEN by circPUM1 in cumulus cells and point out the important role of circRNA inside the pathways related to follicle growth and oocyte maturation. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are noncoding RNAs with diverse functions. However, most Mycobacterium tuberculosis (M.tb)-related circRNAs remain undiscovered. In this study, we infected THP-1 cells with virulent and avirulent M.tb strains and then sequenced the cellular circRNAs. Bioinformatic analysis predicted 58,009 circRNAs in all the cells. In total, 2035 differentially expressed circRNAs were identified between the M.tb-infected and uninfected THP-1 cells and 1258 circRNAs were identified in the virulent and avirulent M.tb strains. Further, the top 10 circRNAs were confirmed by Sanger sequencing, among which four circRNAs, namely circSOD2, circCHSY1, circTNFRSF21, and circDHTKD1, which were highly differentially expressed in infected cells compared with those in uninfected cells, were further confirmed by ring formation, specific primers, and RNase R digestion. Next, circRNA-miRNA-mRNA subnetworks were constructed, such as circDHTKD1/miR-660-3p/IL-12B axis. Some of the individual downstream genes, such as miR-660-3p and IL-12B, were previously reported to be associated with cellular defense against pathological processes induced by M.tb infection. Because macrophages are important immune cells and the major host cells of M.tb, these findings provide novel ideas for exploring the M.tb pathogenesis and host defense by focusing on the regulation of circRNAs during M.tb infection. [ABSTRACT FROM AUTHOR]

Chemotherapy based on taxane-class drugs is the gold standard for treating advanced stages of various oncological diseases. However, despite the favorable response trends, most patients eventually develop resistance to this therapy. Drug resistance is the result of a combination of different events in the tumor cells under the influence of the drug, a comprehensive understanding of which has yet to be determined. In this review, we examine the role of the major classes of non-coding RNAs in the development of chemoresistance in the case of prostate cancer, one of the most common and socially significant types of cancer in men worldwide. We will focus on recent findings from experimental studies regarding the prognostic potential of the identified non-coding RNAs. Additionally, we will explore novel approaches based on machine learning to study these regulatory molecules, including their role in the development of drug resistance. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are a leading cause of worldwide mortality, and exosomes have recently gained attention as key mediators of intercellular communication in these diseases. Exosomes are double-layered lipid vesicles that can carry biomolecules such as miRNAs, lncRNAs, and circRNAs, and the content of exosomes is dependent on the cell they originated from. They can be involved in the pathophysiological processes of cardiovascular diseases and hold potential as diagnostic and monitoring tools. Exosomes mediate intercellular communication, stimulate or inhibit the activity of target cells, and affect myocardial hypertrophy, injury and infarction, ventricular remodeling, angiogenesis, and atherosclerosis. Exosomes can be released from various types of cells, including endothelial cells, smooth muscle cells, cardiomyocytes, fibroblasts, platelets, adipocytes, immune cells, and stem cells. In this review, we highlight the communication between different cell-derived exosomes and cardiovascular cells, with a focus on the roles of RNAs. This provides new insights for further exploring targeted therapies in the clinical management of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Brain damage can be induced by oxygen deprivation. It is known that hypoxic or anoxic conditions can lead to changes in the expression levels of non-coding RNAs (ncRNAs), which, in turn, can be related to Central Nervous System (CNS) injuries. Therefore, it could be useful to investigate the involvement of non-coding RNAs (ncRNAs), as well as the underlying mechanisms which are able to modulate them in brain damage induced by hypoxic or anoxic conditions. In this review, we focused on recent research that associates these conditions with long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). The results of this review demonstrate that the expression of both lncRNAs and circRNAs can be influenced by oxygen deprivation conditions and so they can contribute to inducing damage or providing neuroprotection by affecting specific molecular pathways. Furthermore, several experimental studies have shown that ncRNA activity can be regulated by compounds, thus also modifying their transcriptomic profile and their effects on CNS damages induced by hypoxic/anoxic events. [ABSTRACT FROM AUTHOR]

CircRNAs have become a novel scientific research hotspot, and an increasing number of studies have shed light on their involvement in malignant progression. Prompted by the apparent scientific gap in circRNAs from apoptosis-related genes, such as BOK, we focused on the identification of novel BOK circRNAs in human ovarian and prostate cancer cells. Total RNA was extracted from ovarian and prostate cancer cell lines and reversely transcribed using random hexamer primers. A series of PCR assays utilizing gene-specific divergent primers were carried out. Next, third-generation sequencing based on nanopore technology followed by extensive bioinformatics analysis led to the discovery of 23 novel circRNAs. These novel circRNAs consist of both exonic and intronic regions of the BOK gene. Interestingly, the exons that form the back-splice junction were truncated in most circRNAs, and multiple back-splice sites were found for each BOK exon. Moreover, several BOK circRNAs are predicted to sponge microRNAs with a key role in reproductive cancers, while the presence of putative open reading frames indicates their translational potential. Overall, this study suggests that distinct alternative splicing events lead to the production of novel BOK circRNAs, which could come into play in the molecular landscape and clinical investigation of ovarian and prostate cancer. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a type of non-coding RNA that play a crucial role in the development and lactation of mammary glands in mammals. A total of 107 differentially expressed circRNAs (DE circRNAs) were found, of which 52 were up-regulated and 55 were down-regulated. We also found that DE circRNA host genes were mainly involved in GO terms related to the development process of mammary epithelial cells and KEGG pathways were mostly related to mammary epithelial cells, lactation, and gland development. Protein network analysis found that DE circRNAs can competitively bind to miRNAs as key circRNAs by constructing a circRNA–miRNA–mRNA network. CircRNAs competitively bind to miRNAs (miR-10b-3p, miR-671-5p, chi-miR-200c, chi-miR-378-3p, and chi-miR-30e-5p) involved in goat mammary gland development, mammary epithelial cells, and lactation, affecting the expression of core genes (CDH2, MAPK1, ITGB1, CAMSAP2, and MAPKAPK5). Here, we generated CiMECs and systematically explored the differences in the transcription profile for the first time using whole-transcriptome sequencing. We also analyzed the interaction among mRNA, miRNA, and cirRNA and predicted that circRNA plays an important role in the maintenance of mammary epithelial cells. [ABSTRACT FROM AUTHOR]

As a novel form of regulated cell death, ferroptosis is characterized by intracellular iron and lipid peroxide accumulation, which is different from other regulated cell death forms morphologically, biochemically, and immunologically. Ferroptosis is regulated by iron metabolism, lipid metabolism, and antioxidant defense systems as well as various transcription factors and related signal pathways. Emerging evidence has highlighted that ferroptosis is associated with many physiological and pathological processes, including cancer, neurodegeneration diseases, cardiovascular diseases, and ischemia/reperfusion injury. Noncoding RNAs are a group of functional RNA molecules that are not translated into proteins, which can regulate gene expression in various manners. An increasing number of studies have shown that noncoding RNAs, especially miRNAs, lncRNAs, and circRNAs, can interfere with the progression of ferroptosis by modulating ferroptosis-related genes or proteins directly or indirectly. In this review, we summarize the basic mechanisms and regulations of ferroptosis and focus on the recent studies on the mechanism for different types of ncRNAs to regulate ferroptosis in different physiological and pathological conditions, which will deepen our understanding of ferroptosis regulation by noncoding RNAs and provide new insights into employing noncoding RNAs in ferroptosis-associated therapeutic strategies. [ABSTRACT FROM AUTHOR]

Effective viral clearance requires fine-tuned immune responses to minimize undesirable inflammatory responses. Circular RNAs (circRNAs) are a class of non-coding RNAs that are abundant and highly stable, formed by backsplicing pre-mRNAs, and expressed ubiquitously in eukaryotic cells, emerging as critical regulators of a plethora of signaling pathways. Recent progress in high-throughput sequencing has enabled a better understanding of the physiological and pathophysiological functions of circRNAs, overcoming the obstacle of the sequence overlap between circRNAs and their linear cognate mRNAs. Some viruses also encode circRNAs implicated in viral replication or disease progression. There is increasing evidence that viral infections dysregulate circRNA expression and that the altered expression of circRNAs is critical in regulating viral infection and replication. circRNAs were shown to regulate gene expression via microRNA and protein sponging or via encoding small polypeptides. Recent studies have also highlighted the potential role of circRNAs as promising diagnostic and prognostic biomarkers, RNA vaccines and antiviral therapy candidates due to their higher stability and lower immunogenicity. This review presents an up-to-date summary of the mechanistic involvement of circRNAs in innate immunity against viral infections, the current understanding of their regulatory roles, and the suggested applications. [ABSTRACT FROM AUTHOR]

In addition to the essential pharmacological effects of opioids, situational cues associated with drug addiction memory are key triggers for drug seeking. CircRNAs, an emerging hotspot regulator in crown genetics, play an important role in central nervous system-related diseases. However, the internal mediating mechanism of circRNAs in the field of drug reward and addiction memory remains unknown. Here, we trained mice on a conditional place preference (CPP) model and collected nucleus accumbens (NAc) tissues from day 1 (T0) and day 8 (T1) for high-throughput RNA sequencing. QRT-PCR analysis revealed that circTmeff-1 was highly expressed in the NAc core but not in the NAc shell, suggesting that it plays a role in addiction memory formation. Meanwhile, the down-regulation of circTmeff-1 by adeno-associated viruses in the NAc core or shell could inhibit the morphine CPP scores. Subsequently, the GO and KEGG analyses indicated that circTmeff-1 might regulate the addiction memory via the MAPK and AMPK pathways. These findings suggest that circTmeff-1 in NAc plays a crucial role in morphine-dependent memory formation. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive disorder that causes low fertility in females. Despite its detrimental effects on women's health, care for PCOS has been impeded by its undefined pathogenesis. Thus, there is an urgent need to explore novel biomarkers and therapeutic targets for the diagnosis and treatment of PCOS. Circular RNAs (circRNAs) are a class of noncoding RNAs with covalently closed cyclic structures, present in high abundance, and show development-stage specific expression patterns. Recent studies have demonstrated that circRNAs participate in PCOS progression by modulating various biological functions, including cell proliferation, apoptosis, and steroidogenesis. In addition, circRNAs are widely present in the follicular fluid of women with PCOS, indicating their potential as diagnostic biomarkers and therapeutic targets for PCOS. This review provides the current knowledge of circRNAs in PCOS, including their regulatory functions and molecular mechanisms, and explores their potential as diagnostic biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

This study conducted transcriptome sequencing of goat-mammary-gland tissue at the late lactation (LL), dry period (DP), and late gestation (LG) stages to reveal the expression characteristics and molecular functions of circRNAs during mammary involution. A total of 11,756 circRNAs were identified in this study, of which 2528 circRNAs were expressed in all three stages. The number of exonic circRNAs was the largest, and the least identified circRNAs were antisense circRNAs. circRNA source gene analysis found that 9282 circRNAs were derived from 3889 genes, and 127 circRNAs' source genes were unknown. Gene Ontology (GO) terms, such as histone modification, regulation of GTPase activity, and establishment or maintenance of cell polarity, were significantly enriched (FDR < 0.05), which indicates the functional diversity of circRNAs' source genes. A total of 218 differentially expressed circRNAs were identified during the non-lactation period. The number of specifically expressed circRNAs was the highest in the DP and the lowest in LL stages. These indicated temporal specificity of circRNA expression in mammary gland tissues at different developmental stages. In addition, this study also constructed circRNA–miRNA–mRNA competitive endogenous RNA (ceRNA) regulatory networks related to mammary development, immunity, substance metabolism, and apoptosis. These findings help understand the regulatory role of circRNAs in mammary cell involution and remodeling. [ABSTRACT FROM AUTHOR]

Despite the substantial improvement in diagnosis and treatment within the last decades, ischemic stroke still represents a challenge, responsible still for a high burden of morbidity and mortality. Among the unmet clinical needs are the difficulties in identifying those subjects with the greatest risk of developing a stroke, the challenges in obtaining a timely diagnosis, the prompt recognition of the different clinical forms of stroke, the assessment of the response to treatments and the prognostic assessment. All these issues might be improved with appropriate smart biomarkers that could better inform clinical management. The present article offers an overview of the potential role of circular RNAs as disease biomarkers in stroke. A systematic approach was adopted to gather all potentially relevant information in order to provide a panoramic view on this class of promising molecules. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a recently discovered class of RNAs derived from protein-coding genes that have important biological and pathological roles. They are formed through backsplicing during co-transcriptional alternative splicing; however, the unified mechanism that accounts for backsplicing decisions remains unclear. Factors that regulate the transcriptional timing and spatial organization of pre-mRNA, including RNAPII kinetics, the availability of splicing factors, and features of gene architecture, have been shown to influence backsplicing decisions. Poly (ADP-ribose) polymerase I (PARP1) regulates alternative splicing through both its presence on chromatin as well as its PARylation activity. However, no studies have investigated PARP1's possible role in regulating circRNA biogenesis. Here, we hypothesized that PARP1's role in splicing extends to circRNA biogenesis. Our results identify many unique circRNAs in PARP1 depletion and PARylation-inhibited conditions compared to the wild type. We found that while all genes producing circRNAs share gene architecture features common to circRNA host genes, genes producing circRNAs in PARP1 knockdown conditions had longer upstream introns than downstream introns, whereas flanking introns in wild type host genes were symmetrical. Interestingly, we found that the behavior of PARP1 in regulating RNAPII pausing is distinct between these two classes of host genes. We conclude that the PARP1 pausing of RNAPII works within the context of gene architecture to regulate transcriptional kinetics, and therefore circRNA biogenesis. Furthermore, this regulation of PARP1 within host genes acts to fine tune their transcriptional output with implications in gene function. [ABSTRACT FROM AUTHOR]

Obesity is a pathophysiological disorder associated with adiposity accumulation, oxidative stress, and chronic inflammation state that is progressively increasing in younger population worldwide, negatively affecting male reproductive skills. An emerging topic in the field of male reproduction is circRNAs, covalently closed RNA molecules produced by backsplicing, actively involved in a successful spermatogenesis and in establishing high-quality sperm parameters. However, a direct correlation between obesity and impaired circRNA cargo in spermatozoa (SPZ) remains unclear. In the current work, using C57BL6/J male mice fed with a high-fat diet (HFD, 60% fat) as experimental model of oxidative stress, we investigated the impact of HFD on sperm morphology and motility as well as on spermatic circRNAs. We performed a complete dataset of spermatic circRNA content by a microarray strategy, and differentially expressed (DE)-circRNAs were identified. Using a circRNA/miRNA/target network (ceRNET) analysis, we identified circRNAs potentially involved in oxidative stress and sperm motility pathways. Interestingly, we demonstrated an enhanced skill of HFD sperm in backsplicing activity together with an inefficient epididymal circRNA biogenesis. Fused protein in sarcoma (FUS) and its ability to recruit quaking (QKI) could be involved in orchestrating such mechanism. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common cancer types, ranking third after lung and breast cancers. As such, it demands special attention for better characterization, which may eventually result in the development of early detection strategies and preventive measures. Currently, components of bodily fluids, which may reflect various disease states, are being increasingly researched for their biomarker potential. One of these components is the circulating extracellular vesicles, namely, exosomes, which are demonstrated to carry various cargo. Of importance, the non-coding RNA cargo of circulating exosomes, especially long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and micro RNAs (miRNAs), may potentially serve as significant diagnostic and prognostic/predictive biomarkers. In this review, we present existing evidence on the diagnostic and prognostic/predictive biomarker value of exosomal non-coding RNAs in CRC. In addition, taking advantage of the miRNA sponging functionality of lncRNAs and circRNAs, we demonstrate an experimentally validated CRC exosomal non-coding RNA-regulated target gene axis benefiting from published miRNA sponging studies in CRC. Hence, we present a set of target genes and pathways downstream of the lncRNA/circRNA–miRNA–target axis along with associated significant Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, which may collectively serve to better characterize CRC and shed light on the significance of exosomal non-coding RNAs in CRC diagnosis and prognosis/prediction. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a newly discovered class of endogenously expressed non-coding RNAs (ncRNAs). They are highly stable, covalently closed molecules that frequently exhibit tissue-specific expression in eukaryotes. A small number of circRNAs are abundant and have been remarkably conserved throughout evolution. Numerous circRNAs are known to play important biological roles by acting as microRNAs (miRNAs) or protein inhibitors ('sponges'), by regulating the function of proteins, or by being translated themselves. CircRNAs have distinct cellular functions due to structural and production differences from mRNAs. Recent advances highlight the importance of characterizing circRNAs and their targets in a variety of insect species in order to fully understand how they contribute to the immune responses of these insects. Here, we focus on the recent advances in our understanding of the biogenesis of circRNAs, regulation of their abundance, and biological roles, such as serving as templates for translation and in the regulation of signaling pathways. We also discuss the emerging roles of circRNAs in regulating immune responses to various microbial pathogens. Furthermore, we describe the functions of circRNAs encoded by microbial pathogens that play in their hosts. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) have gained recent attraction due to their functional versatility and particular structure connected to human diseases. Current investigations are focused on the interplay between their ability to sponge smaller species of RNAs, such as microRNAs (miRNAs), thus influencing their regulatory activity on gene expression and protein templates. Therefore, their reported implication in various biological processes axis has resulted in an accumulating number of studies. While the testing and annotation methods of novel circular transcripts are still under development, there is still a plethora of transcript candidates suitable for investigation in human disease. The discordance in the literature regarding the approaches used in circRNAs quantification and validation methods, especially regarding qRT-PCR, the current golden standard procedure, leads to high result variability and undermines the replicability of the studies. Therefore, our study will offer several valuable insights into bioinformatic data for experimental design for circRNA investigation and in vitro aspects. Specifically, we will highlight key aspects such as circRNA database annotation divergent primer design and several processing steps, such as RNAse R treatment optimization and circRNA enrichment assessment. Additionally, we will provide insights into the exploration of circRNA-miRNA interactions, a prerequisite for further functional investigations. With this, we aim to contribute to the methodological consensus in a currently expanding field with possible implications for assessing therapeutic targets and biomarker discovery. [ABSTRACT FROM AUTHOR]

Deregulation of RNA metabolism has emerged as one of the key events leading to the degeneration of motor neurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) disease. Indeed, mutations on RNA-binding proteins (RBPs) or on proteins involved in aspects of RNA metabolism account for the majority of familiar forms of ALS. In particular, the impact of the ALS-linked mutations of the RBP FUS on many aspects of RNA-related processes has been vastly investigated. FUS plays a pivotal role in splicing regulation and its mutations severely alter the exon composition of transcripts coding for proteins involved in neurogenesis, axon guidance, and synaptic activity. In this study, by using in vitro-derived human MNs, we investigate the effect of the P525L FUS mutation on non-canonical splicing events that leads to the formation of circular RNAs (circRNAs). We observed altered levels of circRNAs in FUSP525L MNs and a preferential binding of the mutant protein to introns flanking downregulated circRNAs and containing inverted Alu repeats. For a subset of circRNAs, FUSP525L also impacts their nuclear/cytoplasmic partitioning, confirming its involvement in different processes of RNA metabolism. Finally, we assess the potential of cytoplasmic circRNAs to act as miRNA sponges, with possible implications in ALS pathogenesis. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a highly conserved and specifically expressed novel class of covalently closed non-coding RNAs. CircRNAs can function as miRNA sponges, protein scaffolds, and regulatory factors, and play various roles in development and other biological processes in mammals. With the rapid development of high-throughput sequencing technology, thousands of circRNAs have been discovered in farm animals; some reportedly play vital roles in skeletal muscle and adipose development. These are critical factors affecting meat yield and quality. In this review, we have highlighted the recent advances in circRNA-related studies of skeletal muscle and adipose in farm animals. We have also described the biogenesis, properties, and biological functions of circRNAs. Furthermore, we have comprehensively summarized the functions and regulatory mechanisms of circRNAs in skeletal muscle and adipose development in farm animals and their effects on economic traits such as meat yield and quality. Finally, we propose that circRNAs are putative novel targets to improve meat yield and quality traits during animal breeding. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a family of noncoding RNAs (ncRNAs) that are endogenous and widely distributed in different species, performing several functions, mainly their association with microRNAs (miRNAs) and RNA-binding proteins. CVDs remain the leading cause of death worldwide; therefore, the development of new therapies and strategies, such as gene therapies or nonpharmacological therapies, with low cost, such as physical exercise, to alleviate these diseases is of extreme importance for society. With increasing evidence of ncRNA participating in the progression of CVDs, several studies have reported these RNAs as promising targets for diagnosis and treatment. There are several studies of CVDs and the role of miRNAs and lncRNAs; however, little is known about the new class of RNAs, called circRNAs, and CVDs. In this mini review, we focus on the mechanisms of circRNAs and CVDs. [ABSTRACT FROM AUTHOR]

Litter size is an important indicator to measure the reproductive performance of goats, which is affected by the reproductive function of animals. The hypothalamus, as the regulatory center of the endocrine system, plays an important role in the reproduction of female animals. Here, we performed high-throughput RNA sequencing using hypothalamic tissue from high-fecundity and low-fecundity Leizhou goats to explore critical functional genes associated with litter size. Differentially expressed mRNA, lncRNA, and circRNAs were screened using DESeq and were enriched, and then analyzed by Gene Ontology and Kyoto Encyclopedia of Gene and Genome. Results showed that some of these differentially expressed mRNAs could be enriched in reproductive processes, jak-STAT, prolactin signaling pathway, and other signaling pathways related to reproduction, such as SOCS3. Furthermore, the central proteins POSTN, MFAP5, and DCN from protein–protein interaction may regulate animal reproductive activity by affecting cell proliferation and apoptosis. lncRNA MSTRG.33887.2 as well as circRNAs chicirc_098002, chicirc_072583, and chicirc_053531 may be able to influence animal reproduction by participating in folate metabolism and energy metabolism homeostasis through their respective target genes. Our results expand the molecular mechanism of hypothalamic regulation on animal reproduction. [ABSTRACT FROM AUTHOR]

Atherosclerosis and non-alcoholic fatty liver disease (NAFLD) are pathologies related to ectopic fat accumulation, both of which are continuously increasing in prevalence. These threats are prompting researchers to develop effective therapies for their clinical management. One of the common pathophysiological alterations that underlies both diseases is oxidative stress (OxS), which appears as a result of lipid deposition in affected tissues. However, the molecular mechanisms that lead to OxS generation are different in each disease. Non-coding RNAs (ncRNAs) are RNA transcripts that do not encode proteins and function by regulating gene expression. In recent years, the involvement of ncRNAs in OxS modulation has become more recognized. This review summarizes the most recent advances regarding ncRNA-mediated regulation of OxS in atherosclerosis and NAFLD. In both diseases, ncRNAs can exert pro-oxidant or antioxidant functions by regulating gene targets and even other ncRNAs, positioning them as potential therapeutic targets. Interestingly, both diseases have common altered ncRNAs, suggesting that the same molecule can be targeted simultaneously when both diseases coexist. Finally, since some ncRNAs have already been used as therapeutic agents, their roles as potential drugs for the clinical management of atherosclerosis and NAFLD are analyzed. [ABSTRACT FROM AUTHOR]

Endometrial receptivity is one of the main factors underlying a successful pregnancy, with reports substantiating the fact that suboptimal endometrial receptivity accounts for two-thirds of early implantation event failures. The association between circRNAs and endometrial receptivity in the goat remains unclear. This study aims to identify potential circRNAs and regulatory mechanisms related to goat endometrial receptivity. Therefore, the endometrial samples on day 16 of pregnancy and day 16 of the estrous cycle were analyzed using high-throughput RNA-seq and bioinformatics. The results show that 4666 circRNAs were identified, including 7 downregulated and 11 upregulated differentially expressed circRNAs (DE-circRNAs). Back-splicing and RNase R resistance verified the identified circRNAs. We predicted the competing endogenous RNA (ceRNA) regulatory mechanism and potential target genes of DE-circRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of these predicted target genes suggest that DE-circRNAs were significantly involved in establishing endometrial receptivity. Furthermore, Sanger sequencing, qPCR, correlation analysis and Fluorescence in Situ Hybridization (FISH) show that circ_MYRF derived from the host gene myelin regulatory factor (MYRF) might regulate the expression of interferon stimulating gene 15 (ISG15), thereby promoting the formation of endometrial receptivity. These novel findings may contribute to a better understanding of the molecular mechanisms regulating endometrial receptivity and promoting the maternal recognition of pregnancy (MRP). [ABSTRACT FROM AUTHOR]

Simple Summary: Angioplasty is a procedure where a stent is inserted to open a blocked blood vessel that is causing issues for a patient. Restenosis is a medical condition that reverses the benefits of angioplasty, and it is caused by injury from the stent, with inflammation, excessive smooth muscle cell growth and the movement of cells to accumulate inside the vessel, as part of a disproportionate healing response to the foreign object. The current treatments for restenosis stop the growth of all cells in the area, which is an issue as endothelial cells are required to keep growing in order to heal the inner layer of the blood vessel, which was damaged by the stent, and prevent issues in the future, such as blood clots. Noncoding RNAs are small pieces of genetic material that are not translated into proteins; however, they are important in controlling different biological processes, some of which are the growth and movement of specific cells involved in restenosis. Therefore, we may be able to target certain noncoding RNAs to only slow down the growth and movement of the type of cell causing the condition, namely smooth muscle cells, while allowing for endothelial cells to keep growing and healing the blood vessel. In-stent restenosis (ISR), characterised by ≥50% re-narrowing of the target vessel, is a common complication following stent implantation and remains a significant challenge to the long-term success of angioplasty procedures. Considering the global burden of cardiovascular diseases, improving angioplasty patient outcomes remains a key priority. Noncoding RNAs (ncRNAs) including microRNA (miRNA), long noncoding RNA (lncRNA) and circular RNA (circRNA) have been extensively implicated in vascular cell biology and ISR through multiple, both distinct and overlapping, mechanisms. Vascular smooth muscle cells, endothelial cells and macrophages constitute the main cell types involved in the multifactorial pathophysiology of ISR. The identification of critical regulators exemplified by ncRNAs in all these cell types and processes makes them an exciting therapeutic target in the field of restenosis. In this review, we will comprehensively explore the potential functions and underlying molecular mechanisms of ncRNAs in vascular cell biology in the context of restenosis, with an in-depth focus on vascular cell dysfunction during restenosis development and progression. We will also discuss the diagnostic biomarker and therapeutic target potential of ncRNAs in ISR. Finally, we will discuss the current shortcomings, challenges, and perspectives toward the clinical application of ncRNAs. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute myeloid leukemia (AML), especially the FLT3-ITD mutation subtype, has a poorer prognosis and higher risk of recurrence, which seriously threatens human health. Ferroptosis, an iron-dependent regulated cell death, is involved in the development and progression of AML. The mechanism by which circRNAs regulate the pathogenesis and prognosis of FLT3-ITD mutant-type AML through ferroptosis-related genes (FerRGs) remains unclear. In the present study, we aimed to decipher the pathogenic role of circRNAs in AML with FLT3-ITD mutation. Encouragingly, we discovered a circRNA, hsa_circ_0015278, that regulates ferroptosis-related genes by sponging miRNAs to promote FLT3-ITD AML progression. Furthermore, ferroptosis-related genes with prognostic value contribute to FLT3-ITD AML progression by regulating the tumor microenvironment. In conclusion, we constructed a ceRNA regulatory network involving hsa_circ_0015278/miRNAs/FerRGs, and the hsa_circ_0015278 signaling axis contributes to the identification of potential diagnostic and prognostic biomarkers and provides new insight into the pathogenesis and therapeutic targets of AML with FLT3-ITD mutation. AML with the FLT3-ITD mutation seriously threatens human health. The mechanism by which circRNAs regulate the pathogenesis of FLT3-ITD mutant-type AML through ferroptosis-related genes (FerRGs) remains unclear. Differentially expressed circRNAs and mRNAs were identified from multiple integrated data sources. The target miRNAs and mRNAs of the circRNAs were predicted using various databases. The PPI network, ceRNA regulatory network, GO, and KEGG enrichment analyses were performed. The "survival" and the "pROC" R packages were used for K-M and ROC analysis, respectively. GSEA, immune infiltration analysis, and clinical subgroup analysis were performed. Finally, circRNAs were validated by Sanger sequencing and qRT-PCR. In our study, 77 DECircs-1 and 690 DECircs-2 were identified. Subsequently, 11 co-up-regulated DECircs were obtained by intersecting DECircs-1 and DECircs-2. The target miRNAs of the circRNAs were screened by CircInteractome, circbank, and circAtlas. Utilizing TargetScan, ENCORI, and miRWalk, the target mRNAs of the miRNAs were uncovered. Ultimately, 73 FerRGs were obtained, and the ceRNA regulatory network was constructed. Furthermore, MAPK3 and CD44 were significantly associated with prognosis. qRT-PCR results confirmed that has_circ_0015278 was significantly overexpressed in FLT3-ITD mutant-type AML. In summary, we constructed the hsa_circ_0015278/miRNAs/FerRGs signaling axis, which provides new insight into the pathogenesis and therapeutic targets of AML with FLT3-ITD mutation. [ABSTRACT FROM AUTHOR]

Breast cancer is a major health threat and the second leading cause of cancer-related deaths in women worldwide. The detailed mechanisms involved in the initiation and progression of breast cancer remain unclear. In recent years, amounting evidence indicated that long non-coding RNAs (lncRNAs) played crucial roles in regulating various biological processes and malignancy tumors, including breast cancer. In this review, we briefly introduce the functions and underlying mechanisms by which lncRNAs are involved in breast cancer. We summarize the roles of the lncRNAs in regulating malignant behaviors of breast cancer, such as cell proliferation, migration and invasion, epithelial–mesenchymal transition (EMT), apoptosis, and drug resistance. Additionally, we also briefly summarize the roles of circular RNAs (circRNAs) in breast cancer carcinogenesis. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a class of noncoding RNAs with a covalently closed loop. Studies have demonstrated that circRNA can function as microRNA (miRNA) sponges or competing endogenous RNAs. Although circRNA has been explored in some species and tissues, the genetic basis of testis development and spermatogenesis in donkeys remain unknown. We performed RNA-seq to detect circRNA expression profiles of adult donkey testes. Length distribution and other characteristics were shown a total of 1971 circRNAs were differentially expressed and 12,648 and 6261 circRNAs were detected from the testis and caput epididymis, respectively. Among these circRNAs, 1472 circRNAs were downregulated and 499 circRNAs were upregulated in the testis. Moreover, KEGG pathway analyses and Gene Ontology were performed for host genes of circRNAs. A total of 39 upregulated circRNA host genes were annotated in spermatogenesis terms, including PIWIL2, CATSPERD, CATSPERB, SPATA6, and SYCP1. Other host genes were annotated in the focal adhesion, Rap1 signaling pathway. Downregulated expressed circRNA host genes participated in the TGF-β signaling pathway, GnRH signaling pathway, estrogen signaling pathway, and calcium signaling pathway. Our discoveries provide a solid foundation for identifying and characterizing critical circRNAs involved in testis development or spermatogenesis. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are an abundant class of endogenous non-coding RNAs (ncRNAs) generated from exonic, intronic, or untranslated regions of protein-coding genes or intergenic regions. The diverse, stable, and specific expression patterns of circRNAs and their possible functions through cis/trans regulation and protein-coding mechanisms make circRNA a research hotspot in various biological and pathological processes. It also shows practical value as biomarkers, diagnostic indicators, and therapeutic targets. This review summarized the characteristics, classification, biogenesis and elimination, detection and confirmation, and functions of circRNAs. We focused on research advances circRNAs in the mammalian ovary under conditions including ovarian cancer, polycystic ovarian syndrome (PCOS), and maternal aging, as well as during reproductive status, including ovarian follicle development and atresia. The roles of circRNAs in high reproductive traits in domestic animals were also summarized. Finally, we outlined some obstructive factors and prospects to work with circRNA, aiming to provide insights into the functional research interests of circRNAs in the reproduction and gynecology areas. [ABSTRACT FROM AUTHOR]

Non-coding RNAs (ncRNAs) regulate cell proliferation, migration, differentiation, inflammation, metabolism of clinically important biomolecules, and other cellular processes. They do not encode proteins but are involved in the regulatory network of various proteins that are directly related to the pathogenesis of diseases. Little is known about the ncRNA-associated mechanisms of atherosclerosis and related cardiovascular disorders. Remodeling of the extracellular matrix (ECM) is critical in the pathogenesis of atherosclerosis and related disorders; however, its regulatory proteins are the potential subjects to explore with special emphasis on epigenetic regulatory components. The activity of regulatory proteins involved in ECM remodeling is regulated by various ncRNA molecules, as evident from recent research. Thus, it is important to critically evaluate the existing literature to enhance the understanding of nc-RNAs-regulated molecular mechanisms regulating ECM components, remodeling, and progression of atherosclerosis. This is crucial since deregulated ECM remodeling contributes to atherosclerosis. Thus, an in-depth understanding of ncRNA-associated ECM remodeling may identify novel targets for the treatment of atherosclerosis and other cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: The analysis of liquid biopsies brings new opportunities in the precision oncology field. Under this context, extracellular vesicle circular RNAs (EV-circRNAs) have gained interest as biomarkers for lung cancer (LC) detection. However, standardized and robust protocols need to be developed to boost their potential in the clinical setting. Although nCounter has been used for the analysis of other liquid biopsy substrates and biomarkers, it has never been employed for EV-circRNA analysis of LC patients. Methods: EVs were isolated from early-stage LC patients (n = 36) and controls (n = 30). Different volumes of plasma, together with different number of pre-amplification cycles, were tested to reach the best nCounter outcome. Differential expression analysis of circRNAs was performed, along with the testing of different machine learning (ML) methods for the development of a prognostic signature for LC. Results: A combination of 500 μL of plasma input with 10 cycles of pre-amplification was selected for the rest of the study. Eight circRNAs were found upregulated in LC. Further ML analysis selected a 10-circRNA signature able to discriminate LC from controls with AUC ROC of 0.86. Conclusions: This study validates the use of the nCounter platform for multiplexed EV-circRNA expression studies in LC patient samples, allowing the development of prognostic signatures. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a class of noncoding RNAs with closed-loop of single-stranded RNA structure. Although most of the circRNAs do not directly encode proteins, emerging evidence suggests that circRNAs play a pivotal and complex role in multiple biological processes by regulating gene expression. As one of the most popular circRNAs, circular homeodomain-interacting protein kinase 3 (circHIPK3) has frequently gained the interest of researchers in recent years. Accumulating studies have demonstrated the significant impacts on the occurrence and development of multiple human diseases including cancers, cardiovascular diseases, diabetes mellitus, inflammatory diseases, and others. The present review aims to provide a detailed description of the functions of circHIPK3 and comprehensively overview the diagnostic and therapeutic value of circHIPK3 in these certain diseases. [ABSTRACT FROM AUTHOR]

This study explores the effects of the coevolution of the host genome (the first genome) and gut microbiome (the second genome) on nutrition stress in Tibetan sheep during the cold season. The rumen epithelial tissue of six Tibetan sheep (Oula-type) was collected as experimental samples during the cold and warm seasons and the study lasted for half a year. The cDNA library was constructed and subjected to high-throughput sequencing. The circRNAs with significant differential expression were identified through bioinformatics analysis and functional prediction, and verified by real-time quantitative PCR (qRT-PCR). The results showed that a total of 56 differentially expressed (DE) circRNAs of rumen epithelial tissue were identified using RNA-seq technology, among which 29 were significantly upregulated in the cold season. The circRNA-miRNA regulatory network showed that DE circRNAs promoted the adaptation of Tibetan sheep in the cold season by targeting miR-150 and oar-miR-370-3p. The results of correlation analysis among circRNAs, microbiota, and metabolites showed that the circRNA NC_040275.1:28680890|28683112 had a very significant positive correlation with acetate, propionate, butyrate, and total volatile fatty acid (VFA) (p < 0.01), and had a significant positive correlation with Ruminococcus-1 (p < 0.05). In addition, circRNA NC_040256.1:78451819|78454934 and metabolites were enriched in the same KEGG pathway biosynthesis of amino acids (ko01230). In conclusion, the host genome and rumen microbiome of Tibetan sheep co-encoded a certain glycoside hydrolase (β-glucosidase) and coevolved efficient VFA transport functions and amino acid anabolic processes; thus, helping Tibetan sheep adapt to nutrient stress in the cold season in high-altitude areas. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a class of covalently circular noncoding RNAs that have been extensively studied in recent years. Aging is a process related to functional decline that is regulated by signal transduction. An increasing number of studies suggest that circRNAs can regulate aging and multiple age-related diseases through their involvement in age-related signaling pathways. CircRNAs perform several biological functions, such as acting as miRNA sponges, directly interacting with proteins, and regulating transcription and translation to proteins or peptides. Herein, we summarize research progress on the biological functions of circRNAs in seven main age-related signaling pathways, namely, the insulin-insulin-like, PI3K-AKT, mTOR, AMPK, FOXO, p53, and NF-κB signaling pathways. In these pathways, circRNAs mainly function as miRNA sponges. In this review, we suggest that circRNAs are widely involved in the regulation of the main age-related pathways and are potential biomarkers for aging and age-related diseases. [ABSTRACT FROM AUTHOR]

Polarized microglia play a vital role in neurodegenerative diseases. However, the effects of polarized microglia-derived small extracellular vesicles (SEVs) on neuronal cells and the regulatory mechanisms of circular RNAs (circRNAs) in SEVs remain incompletely defined. In the present study, we carried out high-throughput sequencing and differential expression analysis of circRNAs in the SEVs of M0-phenotype BV2 microglia (M0-BV2) and polarized M1-phenotype BV2 microglia (M1-BV2). Hub circRNAs in the SEVs and their functions were screened using multiple bioinformatics methods. We further validated the effects of SEVs on neuronal PC12 cells by co-culturing M0-BV2 SEVs and M1-BV2 SEVs with neuronal PC12 cells. Among the differentially expressed circRNAs, the target mRNAs of six hub circRNAs (circ_0000705, circ_0001313, circ_0000229, circ_0001123, circ_0000621, and circ_0000735) were enriched in apoptosis-related biological processes. Furthermore, western blot and flow cytometry analysis demonstrated that M0-BV2 SEVs had no distinct effect on apoptosis of neuronal PC12 cells, while M1-BV2 SEVs remarkably increased the apoptosis of neuronal PC12 cells. We then constructed the competing endogenous RNA (ceRNA) networks of the six hub circRNAs. Taken together, the results suggest that polarized M1-BV2 microglia can induce apoptosis of neuronal PC12 cells through secreted SEVs, and this regulatory effect may be achieved by the circRNAs circ_0000705, circ_0001313, circ_0000229, circ_0001123, circ_0000621, and circ_0000735 through ceRNAs regulatory networks. These findings provide new potential targets for the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are capable of finely modulating gene expression at transcriptional and post-transcriptional levels; however, their characters in dermal papilla cells (DPCs)—the signaling center of hair follicle—are still obscure. Herein, we established a comprehensive atlas of circRNAs in DPCs and their skin counterparts—dermal fibroblasts (DFs)—from cashmere goats. In terms of the results, a sum of 3706 circRNAs were bioinformatically identified. Subsequent analysis suggested that the detected transcripts exhibited several prominent genomic features, including exons as their main sources. Compared with DFs, 76 circRNAs significantly displayed higher abundances in goat DPCs, with 45 transcripts markedly exhibiting adverse trends (p < 0.05). Furthermore, potential roles and underlying molecular mechanisms of circRNAs in goat DPCs were speculated through constructing their possible regulatory networks with mRNAs and microRNAs (miRNAs). We found that the circRNAs may serve as miRNA sponges to alleviate three hair growth-related functional genes (HOXC8, RSPO1, and CCBE1) of DPCs from miRNAs-imposed post-transcriptional modulation, further facilitating two critical processes (HOXC8 and RSPO1: hair follicle stem cell activation; CCBE1: follicular angiogenesis) closely involved in hair growth. In addition, we also speculated that two intron-derived circRNAs (chi_circ_0005569 and chi_circ_0005570) possibly affect the expression of their host gene CCBE1 at a transcriptional level in the nucleus. The above results demonstrated that circRNAs are abundantly expressed in goat DPCs, and certain circRNAs are potential participators in hair growth via the effects on the levels of related functional genes. Our study offers a preliminary clue for researchers hoping to untangle the roles of non-coding RNAs in hair growth. [ABSTRACT FROM AUTHOR]

Non-coding RNAs (ncRNAs) are an abundant class of RNA with varying nucleotide lengths. They have been shown to have great potential in eutherians/human disease diagnosis and treatments and are now gaining more importance for the improvement of diseases in livestock. To date, thousands of ncRNAs have been discovered in the bovine genome and the continuous advancement in deep sequencing technologies and various bioinformatics tools has enabled the elucidation of their roles in bovine health. Among farm animals' diseases, mastitis, a common inflammatory disease in cattle, has caused devastating economic losses to dairy farmers over the last few decades. Here, we summarize the biology of bovine mastitis and comprehensively discuss the roles of ncRNAs in different types of mastitis infection. Based on our findings and relevant literature, we highlighted various evidence of ncRNA roles in mastitis. Different approaches (in vivo versus in vitro) for exploring ncRNA roles in mastitis are emphasized. More particularly, the potential applications of emerging genome editing technologies, as well as integrated omics platforms for ncRNA studies and implications for mastitis are presented. [ABSTRACT FROM AUTHOR]

Genetic variants in TREM2, a microglia-related gene, are well-known risk factors for Alzheimer's disease (AD). Here, we report that TREM2 originates from circular RNAs (circRNAs), a novel class of non-coding RNAs characterized by a covalent and stable closed-loop structure. First, divergent primers were designed to amplify circRNAs by RT-PCR, which were further assessed by Sanger sequencing. Then, additional primer sets were used to confirm back-splicing junctions. In addition, HMC3 cells were used to assess the microglial expression of circTREM2s. Three candidate circTREM2s were identified in control and AD human entorhinal samples. One of the circRNAs, circTREM2_1, was consistently amplified by all divergent primer sets in control and AD entorhinal cortex samples as well as in HMC3 cells. In AD cases, a moderate negative correlation (r = −0.434) was found between the global average area of Aβ deposits in the entorhinal cortex and circTREM2_1 expression level. In addition, by bioinformatics tools, a total of 16 miRNAs were predicted to join with circTREM2s. Finally, TREM2 mRNA corresponding to four isoforms was profiled by RT-qPCR. TREM2 mRNA levels were found elevated in entorhinal samples of AD patients with low or intermediate ABC scores compared to controls. To sum up, a novel circRNA derived from the TREM2 gene, circTREM2_1, has been identified in the human entorhinal cortex and TREM2 mRNA expression has been detected to increase in AD compared to controls. Unraveling the molecular genetics of the TREM2 gene may help to better know the innate immune response in AD. [ABSTRACT FROM AUTHOR]