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Circular RNA (CircRNA), as a classical noncoding RNA, has been proven to regulate skeletal muscle development (SMD). However, the molecular genetic basis of circRNA regulation in muscle cells remains unclear. In this study, the expression patterns of circRNAs in the longissimus dorsi muscle at embryonic day 75 and postnatal day 1 in DBGs were investigated to identify the key circRNAs that play an important role in SMD in goats. A total of 140 significantly and differentially expressed circRNAs (DEcircRNAs) were identified among the groups at different developmental stages. Among the 116 host genes (HGs) of DEcircRNAs, 76 were significantly and differentially expressed, which was confirmed by previous RNA_seq data. Furthermore, the expression pattern of 10 DEcircRNAs with RT-qPCR was verified, which showed 80% concordance rate with that of RNA_seq datasets. Moreover, the authenticity of seven randomly selected DEcircRNAs was verified by PCR Sanger sequencing. Based on the functional annotation results, among the 76 significantly and differentially expressed HGs, 74 were enriched in 845 GO terms, whereas 35 were annotated to 85 KEGG pathways. The results of this study could provide a comprehensive understanding of the genetic basis of circRNAs involved in SMD and muscle growth.

Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia in the elderly, and the mechanisms of AD have not been fully defined. Circular RNAs (circRNAs), covalently closed RNAs produced by reverse splicing, have critical effects in the pathogenesis of AD. CircRNAs participate in production and clearance of Aβ and tau, regulate neuroinflammation, synaptic plasticity and the process of apoptosis and autophagy, indicating that circRNAs may be alternative biomarkers and therapeutic targets. Our review summarizes the functions of circRNAs in the progression and development of AD, which provide insights into the prospect of circRNAs in the diagnosis and treatment of AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A ring-stabilized endogenous non-coding RNA is called circular RNA (circRNA). Intercellular communication is mediated by exosomes, and circRNA is enriched and stabilized in exosomes. It has recently been demonstrated that cancer cells and tissues exhibit abnormal expression of exosomal circRNAs. By controlling angiogenesis, metabolism, metastasis, epithe-lial mesenchymal transition (EMT), tumor chemoresistance, immune evasion, and cell prolifera-tion, it may also have an impact on the development of different malignancies. Furthermore, ex-osomal circRNAs have strong tissue selectivity, stability, and other qualities that make them useful for diagnostic purposes. Consequently, exosomal circRNAs offer a wide range of poten-tial applications in the therapy of cancer and can be utilized as biomarkers and anti-tumor tar-gets. The features and purposes of circRNAs and exosomes are briefly discussed in this review, which also methodically explains the function and possible mechanism of the function of exo-somal circRNA in the onset of gastric cancer (GC). Furthermore, their clinical uses as targets and biomarkers for gastric cancers are also summarized and discussed in this work., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Circular RNAs (circRNAs) are now recognized as key regulators in the epigenetic control of genetic expression, being involved in a wide range of cellular activities such as proliferation, differentiation, and apoptosis. Their unique closed-loop structure endows them with stability and resistance to exonuclease degradation, making them not only key regulatory molecules within the cell but also promising biomarkers for disease diagnosis and prognosis, particularly in hematological malignancies. This review comprehensively explores the role of circRNAs in the pathogenesis, progression, and therapeutic resistance of common hematological malignancies. Furthermore, the review delves into the prognostic significance of circRNAs, underscoring their potential in predicting disease outcomes and treatment response. Given their extensive involvement in cancer biology, circRNAs present a frontier for novel therapeutic strategies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Competing Interests: Conflict of interest statement. None declared.

Circular ribonucleic acids (CircRNAs) represent a category of noncoding RNAs characterized by a circular structure bonded through covalent bonds. Unlike linear RNAs, CircRNAs are not affected by exonucleases and exhibit more stable expression. Research suggests that CircRNAs may have the ability to be translated through the internal ribosome entry sites (IRESs) mechanism and it could enable CircRNAs to produce proteins despite lacking a 5' cap structure. They have gained attention due to their diverse functions, including acting as miRNA sponges, participating in complex gene expression regulation, and disease markers. CircRNAs play crucial roles in various biological processes, including cancer development and progression. These cyclic molecules have garnered significant interest for their diverse effects in humans. Furthermore, CircRNAs have been implicated in human genetic diseases, offering insights into potential diagnostic and therapeutic avenues. They are formed through back-splicing of pre-mRNA transcripts, resulting in covalently closed loops. Recent studies have highlighted the significance of CircRNAs in cancer biology, such as their involvement in modulating gene expression, acting as micro RNA (miRNA) sponges, and regulating cellular processes. There are some detection methods including computational models, experimental techniques, and advanced RNA-based and CLIP-Seq-based methods. This review could help to understand the key points regarding biogenesis, biological function, literature trend and biological function of CircRNAs.

Jinyan Yu,1,* Shulun Huang,1,* Weiyu Shen,1,* Zheming Zhang,1 Shugao Ye,2 Yuan Chen,2 Yue Yang,3 Tao Bian,3 Yan Wu3 1The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, People’s Republic of China; 2Transplant Centre, the Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, People’s Republic of China; 3Department of Respiratory Medicine, the Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Wu; Tao Bian, Department of Respiratory Medicine, the Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, People’s Republic of China, Email wuyanphd@163.com; btaophd@sina.comIntroduction: Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), which can worsen the prognosis and increase the mortality of COPD patients. Circular RNA (circRNA) has been discovered to participate in the occurrence and progression of PH in COPD and may have significant prospects for advanced diagnostics and prognosis evaluation. However, the expression profile of circRNAs in human lung tissues with definite diagnosis of COPD-PH remains to be further explored and validated.Methods: Twelve human lung tissue samples (6 each from COPD-PH and control groups) were collected and subjected to high-throughput sequencing. QRT-PCR was performed to validate the differential expression levels of the top 10 dysregulated circRNAs in patients’ plasma samples, HPAECs and HPASMCs. Functional and pathway enrichment analysis on target genes was performed to explore the potential functions and pathways of those circRNAs. Hub genes obtained after conducting bioinformatics analysis on the predicted target mRNAs were verified by qRT-PCR in HPAECs and HPASMCs, and then we selected VCAN as a potential key gene involved in the pathogenesis of COPD-PH for immunohistochemistry validation in lung tissue.Results: A total of 136 circRNAs (39 up-regulated and 97 down-regulated) were differentially expressed between the two groups. Following qRT-PCR validation, two circRNAs (hsa_circ_0007608 and hsa_circ_0064656) were believed to be involved in the pathogenesis. GO and KEGG pathway analysis suggested that these two DECs were mainly related to the celluar proliferation, migration and EndMT. PPI network revealed 11 pairs of key mRNAs. VCAM1, VCAN and THBS1, three hub mRNAs with the highest reliability among all, were validated and proven to be up-regulated in COPD-PH. We innovatively found that VCAN may be involved in COPD-PH.Conclusion: This study identified the functional circRNAs, providing insights into the molecular mechanisms and predictions of COPD-PH, and may provide potential diagnostic biomarkers or therapeutic targets for COPD-PH.Keywords: pulmonary hypertension, chronic obstructive pulmonary disease, circular RNA, RNA-sequencing, biomarker, bioinformatics analysis

Objective To investigate the effects of intraperitoneal injection of islet amyloid polypeptide (IAPP) on the expression profiles of circular RNAs (circRNAs) and messenger RNAs (mRNAs) in the brain tissue of Alzheimer's disease (AD) mice and wild-type (WT) mice. Methods Six 10-month-old male APP/PS1 transgenic AD model and C57 WT mice (20~30 g) were employed in this study. They were randomly divided into 2 groups, and further assigned into AD+IAPP (AD mice with IAPP intraperitoneal injection), WT+IAPP (WT mice with IAPP intraperitoneal injection), AD+PBS (AD mice injected with same dose of PBS intraperitoneally) and WT+PBS (WT mice with intraperitoneal injection of PBS) groups (n=3). After the intervention, total RNA was extracted from the brain tissue of 4 groups of mice, and gene chip sequencing was performed to screen differentially expressed circRNAs and mRNAs between AD+IAPP and WT+IAPP mice and between AD+PBS and WT+PBS mice. Among the differentially expressed circRNAs between AD+IAPP and WT+IAPP mice, 6 circRNAs were selected and subjected to real-time quantitative polymerase chain reaction (qRT-PCR) to verify the reliability of the microarray results. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomics (KEGG) pathway enrichment analysis were performed on the differentially expressed mRNAs. Subsequently, a competitive endogenous RNA (ceRNA) network was constructed for significantly differentially expressed circRNA_45921. Results There were 237 circRNAs significantly differentially expressed between AD+IAPP and WT+IAPP mice, of which 157 were up-regulated and 80 were down-regulated. Totally 663 significantly differentially expressed mRNAs were found, including 348 up-regulated and 315 down-regulated. The results of qRT-PCR showed that the differential expression of 6 circRNAs was consistent with the results of gene chip, indicating that the results of gene chip sequencing were reliable. GO enrichment analysis revealed that differentially up-regulated mRNAs were significantly enriched in nucleoside phosphate binding, organelles and metabolism processes of phosphate containing compounds. The differentially down-regulated mRNAs were significantly enriched in transmembrane signal receptor activity, supramolecular fibers and tissue development. KEGG enrichment analysis indicated that differentially upregulated mRNAs were mainly enriched in signal pathways such as insulin secretion, oxidative phosphorylation, and Parkinson's disease, while those down-regulated ones in signal pathways such as neuroactive ligand receptor interactions, calcium signaling pathways, tyrosine metabolism and phenylalanine metabolism. CeRNA network displayed that the circRNA_45921/miR-34c-5p/Eef2k regulatory network may play a role in the functioning of IAPP. Conclusion Intraperitoneal injection of IAPP alters the expression profiles of circRNA and mRNA in the brain tissues of AD mice and WT mice. Differentially expressed Paip2, Cdon, Ttr, and circRNA_45921/miR-34c-5p/Eef2k regulatory network may have regulatory roles in IAPP regulating the development of AD.

Abstract Circular RNAs (circRNAs) are a class of covalently closed, endogenous ncRNAs. Most circRNAs are derived from exonic or intronic sequences by precursor RNA back-splicing. Advanced high-throughput RNA sequencing and experimental technologies have enabled the extensive identification and characterization of circRNAs, such as novel types of biogenesis, tissue-specific and cell-specific expression patterns, epigenetic regulation, translation potential, localization and metabolism. Increasing evidence has revealed that circRNAs participate in diverse cellular processes, and their dysregulation is involved in the pathogenesis of various diseases, particularly cancer. In this review, we systematically discuss the characterization of circRNAs, databases, challenges for circRNA discovery, new insight into strategies used in circRNA studies and biomedical applications. Although recent studies have advanced the understanding of circRNAs, advanced knowledge and approaches for circRNA annotation, functional characterization and biomedical applications are continuously needed to provide new insights into circRNAs. The emergence of circRNA-based protein translation strategy will be a promising direction in the field of biomedicine.

Abstract Glaucoma is the leading cause of irreversible blindness globally. Circular RNAs (circRNAs) play vital roles in various biological processes as microRNA (miRNA) sponges and, thus, have been investigated as potential biomarkers and therapeutic targets in numerous human diseases. However, the underlying mechanisms of circRNAs in the pathogenesis of glaucoma remain unclear. Therefore, transcriptome sequencing was performed to identify relevant circRNAs in peripheral blood samples from patients with primary angle-closure glaucoma. Bioinformatics analysis was performed to investigate the potential roles of differentially expressed circRNAs (DEcircRNAs) in the pathogenesis of glaucoma. In total, 481 differentially expressed genes in addition to 345 DEcircRNAs were identified in patients with glaucoma. Based on a public database, targeted gene analysis identified 11 DEcircRNAs that potentially regulate the expression of five genes as miRNA sponges in glaucoma. In addition, quantitative reverse transcription PCR analysis verified that expression of the circRNA hsa-circ-0000745 was positively correlated with the expression of NEAT1 as a potential target gene. These results suggest that DEcircRNAs are involved in a gene expression regulatory network related to immune cell function and progression of glaucoma. Thus, DEcircRNAs in peripheral blood are potential biomarkers and therapeutic targets for glaucoma.

Abstract Background Evidence showed that N6-methyladenosine (m6A) is strongly associated with male germline development. However, the role of m6A methylation on circRNAs in amphibians remains unknown. In this study, we conducted m6A sequencing analysis to explore the m6A transcriptome-wide profile of circRNAs in testis tissues of Xenopus laevis (X. laevis) with and without treatment with 100 µg/L atrazine (AZ). Results The analysis showed that m6A modification of circRNAs enriched in sense overlapping in testes of X. laevis. We identified the differential m6A modification sites within circRNAs in testes of AZ-exposed X. laevis and compared that with animals from control group. The results showed that a total of 1507 methylated m6A sites was induced by AZ (760 up-methylated and 747 down-methylated). The cross-analysis exhibited a negative correlation of differentially methylated m6A peaks and circRNAs expression level. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that 20 key pathways may be involved in the mechanism of testis damage of AZ-exposed X. laevis. Conclusions These findings indicated that differentially m6A-methylated circRNAs may play important roles in abnormal testis development of AZ-exposed X. laevis. This study is the first report about a map of m6A modification of circRNAs in male X. laevis and provides a basis for further studying on the function and mechanism of m6A methylation of circRNAs in the testis development of amphibian.

Atherosclerosis is a significant risk factor for coronary heart disease (CHD) and myocardial infarction (MI). Atherosclerosis develops during foam cell generation, which is caused by an imbalance in cholesterol uptake, esterification, and efflux. LOX-1, SR-A1, and CD36 all increased cholesterol uptake. ACAT1 and ACAT2 promote free cholesterol (FC) esterification to cholesteryl esters (CE). The hydrolysis of CE to FC was aided by nCEH. FC efflux was promoted by ABCA1, ABCG1, ADAM10, and apoA-I. SR-BI promotes not only cholesterol uptake but also FC efflux. Circular RNAs (circRNAs), which are single-stranded RNAs with a closed covalent circular structure, have emerged as promising biomarkers and therapeutic targets for atherosclerosis due to their highly tissue, cell, and disease state-specific expression profiles. Numerous studies have shown that circRNAs regulate foam cell formation, acting as miRNA sponges to influence atherosclerosis development by regulating the expression of SR-A1, CD36, ACAT2, ABCA1, ABCG1, ADAM10, apoA-I, SR-B1. Several circRNAs, including circ-Wdr91, circ 0004104, circRNA0044073, circRNA_0001805, circDENND1B, circRSF1, circ 0001445, and circRNA 102682, are potential biomarkers for atherosclerosis to better evaluate cardiovascular risk. It is difficult to deliver synthetic therapeutic circRNAs to the desired target tissues. Nanotechnology, such as GA-RM/GZ/PL, may be an important solution to this problem. In this review, we focus on the potential role and mechanism of circRNA/miRNA axis in foam cell formation in the hopes of discovering new targets for the diagnosis, prevention, and treatment of atherosclerosis.

Liquid biopsy strategies enable the noninvasive detection of changes in the levels of circulating biomarkers in body fluid samples, providing an opportunity to diagnose, dynamically monitor, and treat a range of diseases, including cancers. Glioma is among the most common forms of intracranial malignancy, and affected patients exhibit poor prognostic outcomes. As such, diagnosing and treating this disease in its early stages is critical for optimal patient outcomes. Exosomal circular RNAs (circRNAs) are involved in both the onset and progression of glioma. Both the roles of exosomes and methods for their detection have received much attention in recent years and the detection of exosomal circRNAs by liquid biopsy has significant potential for monitoring dynamic changes in glioma. The present review provides an overview of the circulating liquid biopsy biomarkers associated with this cancer type and the potential application of exosomal circRNAs as tools to guide the diagnosis, treatment, and prognostic evaluation of glioma patients during disease progression.

ABSTRACT: Pigeon has the specific biological ability to produce pigeon milk (also known as crop milk) by its crop. Circular RNAs (circRNAs) are important noncoding RNAs acting as the sponges of miRNAs, but the molecular mechanism of circRNAs regulating crop milk production has not been reported in pigeon. We compared expression profiles of crops during lactating and nonlactating crops, and networks of competing endogenous RNAs (ceRNAs) were constructed. The results showed a total of 8,723 circRNAs were identified, and there were 770 differentially expressed circRNAs (DECs) between these two different periods of crops. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the host genes of DECs were enriched in GnRH, MAPK, Insulin, Wnt, and AMPK signaling pathways. Furthermore, gga_circ_0000300 interacted with miR-92-2-5p, which targeted genes participating in lactation and milk composition synthesis. Gga_circ_0003018, gga_circ_0003019 and gga_circ_0003020 could bind with let-7c-5p regulating SOCS3 in crop milk production. These findings provide the circRNAs expression profiles and facilitate the analysis of molecular mechanism of crop milk production in pigeon.

Altered autophagy is a hallmark of neurodegeneration but how autophagy is regulated in the brain and dysfunctional autophagy leads to neuronal death has remained cryptic. Being a key cellular waste-recycling and housekeeping system, autophagy is implicated in a range of brain disorders and altering autophagy flux could be an effective therapeutic strategy and has the potential for clinical applications down the road. Tight regulation of proteins and organelles in order to meet the needs of complex neuronal physiology suggests that there is distinct regulatory pattern of neuronal autophagy as compared to non-neuronal cells and nervous system might have its own separate regulator of autophagy. Evidence has shown that circRNAs participates in the biological processes of autophagosome assembly. The regulatory networks between circRNAs, autophagy, and neurodegeneration remains unknown and warrants further investigation. Understanding the interplay between autophagy, circRNAs and neurodegeneration requires a knowledge of the multiple steps and regulatory interactions involved in the autophagy pathway which might provide a valuable resource for the diagnosis and therapy of neurodegenerative diseases. In this review, we aimed to summarize the latest studies on the role of brain-protective mechanisms of autophagy associated circRNAs in neurodegenerative diseases (including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Friedreich’s ataxia) and how this knowledge can be leveraged for the development of novel therapeutics against them. Autophagy stimulation might be potential one-size-fits-all therapy for neurodegenerative disease as per considerable body of evidence, therefore future research on brain-protective mechanisms of autophagy associated circRNAs will illuminate an important feature of nervous system biology and will open the door to new approaches for treating neurodegenerative diseases.

Cerebral ischaemiareperfusion injury is an important pathological process in nervous system diseases during which neurons undergo oxygenglucose deprivation and reoxygenation (OGD/R) injury. No study has used epitranscriptomics to explore the characteristics and mechanism of injury. N6methyladenosine (m6A) is the most abundant epitranscriptomic RNA modification. However, little is known about m6A modifications in neurons, especially during OGD/R. m6A RNA immunoprecipitation sequencing (MeRIPseq) and RNA-sequencing data for normal and OGD/R-treated neurons were analysed by bioinformatics. MeRIP quantitative real-time polymerase chain reaction was used to determine the m6A modification levels on specific RNAs. We report the m6A modification profiles of the mRNA and circRNA transcriptomes of normal and OGD/R-treated neurons. Expression analysis revealed that the m6A levels did not affect m6A mRNA or m6A circRNA expression. We found crosstalk between m6A mRNAs and m6A circRNAs and identified three patterns of m6A circRNA production in neurons; thus, distinct OGD/R treatments induced the same genes to generate different m6A circRNAs. Additionally, m6A circRNA biogenesis during distinct OGD/R processes was found to be time specific. These results expand our understanding of m6A modifications in normal and OGD/R-treated neurons, providing a reference to explore epigenetic mechanisms and potential treatments for OGD/R-related diseases.

Litter size is a crucial quantitative trait in animals, closely linked to follicular development. Circular RNA (circRNA), a type of single-stranded closed-loop endogenous RNA with stable expression, plays pivotal roles in various biological processes, yet its function in goat follicular development remains unclear. In this study, we collected large (follicle diameter > 3 mm) and small (1 mm < follicle diameter < 3 mm) follicles from black goats in the Chuanzhong region for circRNA sequencing, with the aim of elucidating the functional circRNAs that influence follicle development in goats. Differential analysis revealed that 17 circRNAs were upregulated in large follicles, and 28 circRNAs were upregulated in small follicles. Functional enrichment analysis revealed significant enrichment of pathways related to reproduction, including cellular response to follicle-stimulating hormone stimulus, the PI3K-Akt signaling pathway, the MAPK signaling pathway, and the Notch signaling pathway. Based on the ceRNA mechanism, 45 differentially expressed circRNAs were found to target and bind a total of 418 miRNAs, and an intercalation network including miR-324-3p (circRNA2497, circRNA5650), miR-202-5p (circRNA3333, circRNA5501), and miR-493-3p (circRNA4995, circRNA5508) was constructed. In addition, conservation analysis revealed that 2,239 circRNAs were conserved between goats and humans. Prediction of translation potential revealed that 154 circRNAs may potentially utilize both N6-methyladenosine (m6A) and internal ribosome entry site (IRES) translation mechanisms. Furthermore, the differential expression and circularization cleavage sites of five circRNAs were validated through RT-qPCR and DNA sequencing. Our study constructed a circRNA map in goat follicle development, offering a theoretical foundation for enhancing goat reproductive performance. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) is one of the most prevalent and conserved RNA modifications. It controls several biological processes, including the biogenesis and function of circular RNAs (circRNAs), which are a class of covalently closed-single stranded RNAs. Several studies have revealed that proteotoxic stress response induction could be a relevant anticancer therapy in Acute Myeloid Leukemia (AML). Furthermore, a strong molecular interaction between the m6A mRNA modification factors and the suppression of the proteotoxic stress response has emerged. Since the proteasome inhibition leading to the imbalance in protein homeostasis is strictly linked to the stress response induction, we investigated the role of Bortezomib (Btz) on m6A regulation and in particular its impact on the modulation of m6A-modified circRNAs expression. Here, we show that treating AML cells with Btz downregulated the expression of the m6A regulator WTAP at translational level, mainly because of increased oxidative stress. Indeed, Btz treatment promoted oxidative stress, with ROS generation and HMOX-1 activation and administration of the reducing agent N-acetylcysteine restored WTAP expression. Additionally, we identified m6A-modified circRNAs modulated by Btz treatment, including circHIPK3, which is implicated in protein folding and oxidative stress regulation. These results highlight the intricate molecular networks involved in oxidative and ER stress induction in AML cells following proteotoxic stress response, laying the groundwork for future therapeutic strategies targeting these pathways. [ABSTRACT FROM AUTHOR]

Yichen Liu, Lei Wang, Wen Liu Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of ChinaCorrespondence: Yichen Liu; Wen Liu, Email yc-liu@outlook.com; wen2liu@126.comAbstract: Circular RNAs (circRNAs) are a class of non-coding RNAs with loop structures that are stable and widely distributed in different tumor tissues. The development of high-throughput sequencing and in silico tools has enabled the discovery of numerous functional circRNAs. Hepatocellular carcinoma (HCC) is a malignant tumor, and the mechanism involved in its progression has remained unclear. In recent years, an increasing number of circRNAs have been identified in HCC, contributing to tumorigenesis and metastasis and with the potential role as biomarkers through competitive endogenous RNAs (ceRNAs) as miRNA sponges or by interacting with RNA binding proteins (RBPs). In this review, we summarize the regulatory roles of circRNAs in HCC development as well as the use of bioinformatics tools in the annotation and prioritization of circRNA and highlight the participation of exosomal circRNAs in HCC metastasis and drug resistance.Keywords: circRNAs, HCC, tumorigenesis, metastasis, exosome, biomarker

Abstract Exosomes are microvesicles secreted by cells. They contain a variety of bioactive substances with important roles in intercellular communication. Circular RNA (circRNA), a type of nucleic acid molecule found in exosomes, forms a covalently bonded closed loop without 5′ caps or 3′ poly(A) tails. It is structurally stable, widely distributed, and tissue specific. CircRNAs mainly act as microRNA sponges and have important regulatory roles in gene expression; they are superior to other non-coding RNAs as molecular diagnostic markers and drug treatment targets. Exosomal-derived circRNAs in the body fluids of tumor patients can modulate tumor proliferation, invasion, metastasis, and drug resistance. They can be used as effective biomarkers for early non-invasive diagnosis and prognostic evaluation of tumors, and also represent ideal targets for early precision therapeutic intervention. This review provides a theoretical basis for exploring the applications of exosomal circRNAs in malignant tumor diagnosis and treatment. We describe the biological functions of exosomal circRNAs in the occurrence and development of malignant tumors, their potential utility in diagnosis and treatment, and possible mechanisms.

Breakthroughs in surgical and medical techniques have significantly improved outcomes for children with congenital heart disease (CHD), but research continues to address the ongoing challenge of organ dysfunction after surgery, particularly in neonates and infants. Our study explored circular RNAs (circRNAs) within plasma-derived extracellular vesicles (EVs) in neonates and infants undergoing CHD surgery. Post-surgery EV circRNAs showed dramatic expression changes between organ dysfunction (OD) and control groups. Tissue injury-related pathways were consistent across pre- and post-surgery in OD. The top two significant predicted tissue sources of these circRNAs originated from the respiratory system, aligning with the fact that all patients in the OD arm experienced respiratory dysfunction. Five of these circRNAs, namely circ-CELSR1, circ-PLXNA1, circ-OBSL1, circ-DAB2IP, and circ-KANK1, significantly correlated with PELOD (Pediatric Logistic Organ Dysfunction) score and demonstrated high performance (AUC = 0.95), supporting the potential of circRNAs as prognostic markers. These findings pave the way for EV circRNAs as promising tools for managing post-surgical organ dysfunction and potentially guiding therapeutic strategies in children with CHD.

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease leading to progressive demyelination and neuronal loss, with extensive neurological symptoms. As one of the most widespread neurodegenerative disorders, with an age onset of about 30 years, it turns out to be a socio-health and economic issue, thus necessitating therapeutic interventions currently unavailable. Loss of integrity in the blood–brain barrier (BBB) is one of the distinct MS hallmarks. Brain homeostasis is ensured by an endothelial cell-based monolayer at the interface between the central nervous system (CNS) and systemic bloodstream, acting as a selective barrier. MS results in enhanced barrier permeability, mainly due to the breakdown of tight (TJs) and adherens junctions (AJs) between endothelial cells. Specifically, proinflammatory mediator release causes failure in cytoplasmic exposure of junctions, resulting in compromised BBB integrity that enables blood cells to cross the barrier, establishing iron deposition and neuronal impairment. Cells with a compromised cytoskeletal protein network, fiber reorganization, and discontinuous junction structure can occur, resulting in BBB dysfunction. Recent investigations on spatial transcriptomics have proven circularRNAs (circRNAs) to be powerful multi-functional molecules able to epigenetically regulate transcription and structurally support proteins. In the present review, we provide an overview of the recent role ascribed to circRNAs in maintaining BBB integrity/permeability via cytoskeletal stability. Increased knowledge of the mechanisms responsible for impairment and circRNA’s role in driving BBB damage and dysfunction might be helpful for the recognition of novel therapeutic targets to overcome BBB damage and unrestrained neurodegeneration.

The hypothalamic–pituitary–ovarian (HPO) axis plays a pivotal role in the regulation of egg production in chickens. In addition to the traditional understanding of the HPO axis, emerging research highlights the significant role of circRNAs in modulating the functions of this axis. In the study, we collected hypothalamus, pituitary, and ovarian tissues from low-yielding and high-yielding Bian chickens for transcriptome sequencing. We identified 339, 339, and 287 differentially expressed (DE) circRNAs with p_value < 0.05 and |log2 (fold change)| ≥ 1 in hypothalamus, pituitary, and ovarian tissues. The Gene Ontology (GO) enrichment analysis for the source genes of DE circRNAs has yielded multiple biological process (BP) entries related to cell development, the nervous system, and proteins, including cellular component morphogenesis, cell morphogenesis, nervous system development, neurogenesis, protein modification process, and protein metabolic process. In the top 30 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we observed the enrichment of the GnRH signaling pathway in both the hypothalamus and the pituitary, solely identified the GnRH secretion pathway in the pituitary, and discovered the pathway of oocyte meiosis in the ovary. Furthermore, given that circRNA primarily functions through the ceRNA mechanism, we constructed ceRNA regulatory networks with DE circRNAs originating from the GnRH signaling pathway, GnRH secretion, ovarian steroidogenesis, steroid hormone biosynthesis, and the estrogen signaling pathway. Finally, several important ceRNA regulatory networks related to reproduction were discovered, such as novel_circ_003662-gga-let-7b/miR-148a-3p/miR-146a-5p/miR-146b-5p and novel_circ_003538-gga-miR-7464-3p-SLC19A1. This study will contribute to advancements in understanding the involvement of circRNAs in the HPO axis, potentially leading to innovations in improving egg production and poultry health.

Litter size is a crucial quantitative trait in animals, closely linked to follicular development. Circular RNA (circRNA), a type of single-stranded closed-loop endogenous RNA with stable expression, plays pivotal roles in various biological processes, yet its function in goat follicular development remains unclear. In this study, we collected large (follicle diameter > 3 mm) and small (1 mm < follicle diameter < 3 mm) follicles from black goats in the Chuanzhong region for circRNA sequencing, with the aim of elucidating the functional circRNAs that influence follicle development in goats. Differential analysis revealed that 17 circRNAs were upregulated in large follicles, and 28 circRNAs were upregulated in small follicles. Functional enrichment analysis revealed significant enrichment of pathways related to reproduction, including cellular response to follicle-stimulating hormone stimulus, the PI3K-Akt signaling pathway, the MAPK signaling pathway, and the Notch signaling pathway. Based on the ceRNA mechanism, 45 differentially expressed circRNAs were found to target and bind a total of 418 miRNAs, and an intercalation network including miR-324-3p (circRNA2497, circRNA5650), miR-202-5p (circRNA3333, circRNA5501), and miR-493-3p (circRNA4995, circRNA5508) was constructed. In addition, conservation analysis revealed that 2,239 circRNAs were conserved between goats and humans. Prediction of translation potential revealed that 154 circRNAs may potentially utilize both N6-methyladenosine (m6A) and internal ribosome entry site (IRES) translation mechanisms. Furthermore, the differential expression and circularization cleavage sites of five circRNAs were validated through RT-qPCR and DNA sequencing. Our study constructed a circRNA map in goat follicle development, offering a theoretical foundation for enhancing goat reproductive performance.

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 Background Circular RNAs (circRNAs) are a new category of endogenous non‐protein coding RNAs (ncRNAs), and show the characteristics of high conservation, stability, and tissue specificity. Due to rapid advances in next‐generation sequencing and transcriptome profiling technologies, circRNAs have been widely discovered in many organisms and participated in the development and progress of a variety of diseases. As a type of molecular sponge, circRNAs mainly absorb micro RNAs competitively and interplay with RNA‐binding proteins to modulate the splicing as well as transcription of target genes. Methods This review is based on a literature search using the Medline database. Search terms used were “circular RNAs and leukemia,” “circRNAs and leukemia,” “circRNAs and acute lymphoblastic leukemia,” “circRNAs and chronic lymphoblastic leukemia,” “circRNAs and acute myeloid leukemia,” “circRNAs and chronic myeloid leukemia,” and “circRNAs, biomarker, and hematological system.” Results CircRNAs have been proven as potential biomarkers and therapeutic targets in a variety of tumors. Recent research has found that circRNAs aberrantly exist in hematological cancers, especially leukemia, and are significantly associated with the incidence, progress, and metastasis of diseases as well as the prognosis of patients. Conclusion The current work summarizes the latest findings on circRNAs in various types of leukemia, aiming to propose prospective therapies and new drug screening methods for the treatment of leukemia.

Objective(s): Huntington’s disease (HD) is identified as a progressive genetic disorder caused by a mutation in the Huntington gene. Although the pathogenesis of this disease has not been fully understood, investigations have demonstrated the role of various genes and non-coding RNAs in the disease progression. In this study, we aimed to discover the potential promising circRNAs which can bind to miRNAs of HD. Materials and Methods: We used several bioinformatics tools such as ENCORI, Cytoscape, circBase, Knime, and Enrichr to collect possible circRNAs and then evaluate their connections with target miRNAs to reach this goal. We also found the probable relationship between parental genes of these circRNAs and the disease progress. Results: According to the data collected, more than 370 thousand circRNA-miRNA interactions were found for 57 target miRNAs. Several of circRNAs were spliced out of parental genes involved in the etiology of HD. Some of them need to be further investigated to elucidate their role in this neurodegenerative disease.Conclusion: This in silico investigation highlights the potential role of circRNAs in the progression of HD and opens up new horizons for drug discovery as well as diagnostic approaches for the disease.

Abstract Unlike improved treatment response in multiple myeloma (MM), the mortality rate in MM is still high. The study’s aim is to investigate the potential role of circRNAs as a new biomarker for diagnosis, prognosis, and clinicopathological features of MM. We identified studies through Web of Science, Scopus, PubMed and ProQuest databases, and Google Scholar to August 2022. The SEN, SPE, PLR, NLR, DOR, and AUC were combined to investigate the diagnostic performance of circRNAs in MM. Also, HR and RR were used for prognostic and clinicopathological indicators, respectively. 12 studies for prognosis, 9 studies about diagnosis, and 13 studies regarding clinicopathological features. The pooled SEN, SPE, DOR, and AUC were 0.82, 0.76, 14.70, and 0.86, respectively for the diagnostic performance of circRNAs. For the prognostic performance, oncogene circRNAs showed a poor prognosis for the patients (HR = 3.71) and tumor suppressor circRNAs indicated a good prognosis (HR = 0.31). Finally, we discovered that dysregulation of circRNAs is associated with poor clinical outcomes in beta-2-microglobulin (RR = 1.56), Durie-Salmon stage (RR = 1.36), and ISS stage (RR = 1.79). Furthermore, the presence of del(17p) and t(4;14) is associated with circRNA dysregulation (RR = 1.44 and 1.44, respectively). Our meta-analysis demonstrates that the expression analysis of circRNAs is valuable for MM’s diagnosis and prognosis determination. Also, dysregulation of circRNAs is associated with poor clinicopathological features and can be used as the applicable biomarkers for evaluating treatment effectiveness.

Abstract N7‐methylguanosine (m7G) modification is closely related to the occurrence of tumors. However, the m7G modification of circRNAs in oral squamous cell carcinoma (OSCC) remains to be investigated. Methylated RNA immunoprecipitation sequencing (MeRIP‐seq) was used to measure the methylation levels of m7G and identify m7G sites in circRNAs in human OSCC and normal tissues. The host genes of differentially methylated and differentially expressed circRNAs were analyzed by Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, and circRNA–miRNA–mRNA networks were predicted using the miRanda and miRDB databases. The analysis identified 2348 m7G peaks in 624 circRNAs in OSCC tissues. In addition, the source of m7G‐methylated circRNAs in OSCC was mainly the sense overlap region compared with normal tissues. The most conserved m7G motif in OSCC tissues was CCUGU, whereas the most conserved motif in normal tissues was RCCUG (R = G/A). Importantly, GO enrichment and KEGG pathway analysis showed that the host genes of differentially methylated and differentially expressed circRNAs were involved in many cellular biological functions. Furthermore, the significantly differentially expressed circRNAs were analyzed to predict the circRNA–miRNA–mRNA networks. This study revealed the whole profile of circRNAs of differential m7G methylation in OSCC and suggests that m7G‐modified circRNAs may impact the development of OSCC.

Abstract Background One of the most critical periods for the loss of pig embryos is the 12th day of gestation when implantation begins. Recent studies have shown that non-coding RNAs (ncRNAs) play important regulatory roles during pregnancy. Circular RNAs (circRNAs) are a kind of ubiquitously expressed ncRNAs that can directly regulate the binding proteins or regulate the expression of target genes by adsorbing micro RNAs (miRNA). Results We used the Illumina Novaseq6,000 technology to analyze the circRNA expression profile in the endometrium of three Erhualian (EH12) and three Yorkshire (YK12) pigs on day 12 of gestation. Overall, a total of 22,108 circRNAs were identified. Of these, 4051 circRNAs were specific to EH12 and 5889 circRNAs were specific to YK12, indicating a high level of breed specificity. Further analysis showed that there were 641 significant differentially expressed circRNAs (SDEcircRNAs) in EH12 compared with YK12 (FDR

Abstract Circular RNAs (circRNAs) play a role in sepsis-related autophagy. However, the role of circRNAs in autophagy after sepsis-induced cardiomyopathy (SICM) is unknown, so we explored the circRNA expression profiles associated with autophagy in an acute sepsis mouse model. At a dose of 10 mg/kg, mice were intraperitoneally administered with lipopolysaccharides. The myocardial tissue was harvested after 6 h for microarray analysis, qRT-PCR, and western blotting. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis were evaluated, and a competing endogenous RNA network was constructed, to evaluate the role of circRNAs related to autophagy in SICM. In total, 1,735 differently expressed circRNAs were identified in the LPS-treated group, including 990 upregulated and 745 downregulated circRNAs. The expression level of the autophagy-specific protein p62 decreased, while the ratio of LC3 II to LC3 I increased. Additionally, 309 mRNAs and 187 circRNAs were correlated with autophagy in myocardial tissue after SICM. Of these, 179 circRNAs were predicted to function as “miRNA sponges”. Some distinctive circRNAs and mRNAs found by ceRNA analysis might be involved in autophagy in SICM. These findings provide insights into circRNAs and identified new research targets that may be used to further explore the pathogenesis of SICM.

Abstract Reproductive traits play a vital role in determining the production efficiency of sheep. Maximizing the production is of paramount importance for breeders worldwide due to the growing population. Circular RNAs (circRNAs) act as miRNA sponges by absorbing miRNA activity through miRNA response elements (MREs) and participate in ceRNA regulatory networks (ceRNETs) to regulate mRNA expression. Despite of extensive research on role of circRNAs as miRNA sponges in various species, their specific regulatory roles and mechanism in sheep ovarian tissue are still not well understood. In this study, we performed whole genome sequencing of circRNAs, miRNA and mRNA employing bioinformatic techniques on ovine tissues of two contrasting sheep breeds "Small tail Han (X_LC) and Dolang sheep (D_LC)", which results into identification of 9,878 circRNAs with a total length of 23,522,667 nt and an average length of 2,381.32 nt. Among them, 44 differentially expressed circRNAs (DECs) were identified. Moreover, correlation between miRNA-mRNA and lncRNA-miRNA provided us with to prediction of miRNA binding sites on nine differentially expressed circRNAs and 165 differentially expressed mRNAs using miRanda. miRNA-mRNA and lncRNA-miRNA pairs with negative correlation were selected to determine the ceRNA score along with positively correlated pairs from lncRNA and mRNA network. Integration of ceRNA score and positively correlated pairs exhibit a significant ternary relationship among circRNAs-miRNA-mRNA demonestrated by ceRNA, comprising of 50 regulatory pairs sharring common nodes and predicted potential differentially expressed circRNAs-miRNAs-mRNAs regulatory axis. Based on functional enrichment analysis shortlisted key ceRNA regulatory pairs associated with reproduction including circRNA_3257-novel579_mature-EPHA3, circRNA_8396-novel130_mature-LOC101102473, circRNA_4140- novel34_mature > novel661_mature-KCNK9, and circRNA_8312-novel339_mature-LOC101110545. Furthermore, expression profiling, functional enrichments and qRT-PCR analysis of key target genes infer their implication in reproduction and metabolism. ceRNA target mRNAs evolutionary trajectories, expression profiling, functional enrichments, subcellular localizations following genomic organizations will provide new insights underlying molecular mechanisms of reproduction, and establish a solid foundation for future research. Graphical Abstract Graphical abstract summarizing the scheme of study