Circular RNA (circRNA) is a novel class of single-stranded RNAs with a closed loop structure. The majority of circRNAs are formed by a back-splicing process in pre-mRNA splicing. Their expression is dynamically regulated and shows spatiotemporal patterns among cell types, tissues and developmental stages. CircRNAs have important biological functions in many physiological processes, and their aberrant expression is implicated in many human diseases. Due to their high stability, circRNAs are becoming promising biomarkers in many human diseases, such as cardiovascular diseases, autoimmune diseases and human cancers. In this review, we focus on the translational potential of using human blood circRNAs as liquid biopsy biomarkers for human diseases. We highlight their abundant expression, essential biological functions and significant correlations to human diseases in various components of peripheral blood, including whole blood, blood cells and extracellular vesicles. In addition, we summarize the current knowledge of blood circRNA biomarkers for disease diagnosis or prognosis.

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The potential of using blood circular RNA as liquid biopsy biomarker for human diseases

The family Enterobacteriaceae has undergone significant morphogenetic changes in its more than 85-year history, particularly during the past 2 decades (2000 to 2020). The development and introduction of new and novel molecular methods coupled with innovative laboratory techniques have led to many advances. We now know that the global range of enterobacteria is much more expansive than previously recognized, as they play important roles in the environment in vegetative processes and through widespread environmental distribution through insect vectors. In humans, many new species have been described, some associated with specific disease processes. Some established species are now observed in new infectious disease settings and syndromes. The results of molecular taxonomic and phylogenetics studies suggest that the current family Enterobacteriaceae should possibly be divided into seven or more separate families. The logarithmic explosion in the number of enterobacterial species described brings into question the relevancy, need, and mechanisms to potentially identify these taxa. This review covers the progression, transformation, and morphogenesis of the family from the seminal Centers for Disease Control and Prevention publication (J. J. Farmer III, B. R. Davis, F. W. Hickman-Brenner, A. McWhorter, et al., J Clin Microbiol 21:46-76, 1985, https://doi.org/10.1128/JCM.21.1.46-76.1985) to the present.

The Changing Face of the Family Enterobacteriaceae (Order: "Enterobacterales"): New Members, Taxonomic Issues, Geographic Expansion, and New Diseases and Disease Syndromes.

CircRNA derived from vacuolar ATPase assembly factor (circVMA21) is a newly-researched circRNA, which is reported to adjust the degeneration of intervertebral disc. But, function of circVMA21 in infantile pneumonia is yet to be explored. The research surveyed the role of circVMA21 in lipopolysaccharide (LPS)-caused WI-38 cell inflammatory injury. LPS (10 μg/ml, 12 hr) was exploited to arouse WI-38 cell inflammatory injury. Subsequently, the mediatory impacts of microRNA (miR)-142-3p and circVMA21 in LPS-evoked cell injury were detected after transfection with the inhibited or overexpressed vectors. In above processes, cell behaviors of cell viability, apoptosis, and pro-inflammatory factors were monitored. NF-κB and JNK pathways were elucidated to showcase the feasible molecular mechanisms. Results displayed that LPS engendered WI-38 cell inflammatory injury was alleviated as well as activated NF-κB and JNK pathways was interdicted by miR-142-3p suppression. Importantly, restrained miR-142-3p expression was discovered in WI-38 cells after overexpressing circVMA21. Moreover, overexpressed circVMA21 exerted the similar functions as miR-142-3p suppression in LPS-triggered WI-38 cell injury. But, the influence was clearly reversed by miR-142-3p overexpression. Hindered NF-κB and JNK pathways caused by overexpressed circVMA21 was also crippled by miR-142-3p overexpression. The research discolsed that circVMA21 protected WI-38 cells to resist LPS-triggered inflammatory injury via miR-142-3p-NF-κB/JNK axis.

Protective impacts of circular RNA VMA21 on lipopolysaccharide-engendered WI-38 cells injury via mediating microRNA-142-3p.

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

/pdf/functions-of-circular-rna-in-human-diseases-and-illnesses-2k0v892v.pdf

Functions of Circular RNA in Human Diseases and Illnesses

Background: Circular RNAs (circRNAs) are a new class of RNAs with medical significance. Compared to that of linear mRNA transcripts, the stability of circRNAs against degradation owing to their circular structure is considered advantageous for their use as biomarkers. As systematic studies on the stability of circRNAs depending on the RNA integrity, determined as RNA integrity number (RIN), in clinical tissue samples are lacking, we have investigated this aspect in the present study under model and clinical conditions. Methods: Total RNA isolated from kidney cancer tissue and cell lines (A-498 and HEK-293) with different RIN after thermal degradation was used in model experiments. Further, RNA isolated from kidney cancer and prostate cancer tissue collected under routine surgical conditions, representing clinical samples with RIN ranging from 2 to 9, were examined. Quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR) analysis of several circRNAs (circEGLN3, circRHOBTB3, circCSNK1G3, circRNA4, and circRNA9), their corresponding linear counterparts, tissue-specific reference genes, and three microRNAs (as controls) was performed. The quantification cycles were converted into relative quantities and normalized to the expression of specific reference genes for the corresponding tissue. The effect of RIN on the expression of different RNA entities was determined using linear regression analysis, and clinical samples were classified into two groups based on RIN greater or lesser than 6. Results: The results of model experiments and clinical sample analyses showed that all relative circRNA expression gradually decreased with reduction in RIN values. The adverse effect of RIN was partially compensated after normalizing the data and limiting the samples to only those with RIN values > 6. Conclusions: Our results suggested that circRNAs are not stable in clinical tissue samples, but are subjected to degradative processes similar to mRNAs. This has not been investigated extensively in circRNA expression studies, and hence must be considered in future for obtaining reliable circRNA expression data. This can be achieved by applying the principles commonly used in mRNA expression studies.

Instability of circular RNAs in clinical tissue samples impairs their reliable expression analysis using RT-qPCR: from the myth of their advantage as biomarkers to reality.

Circular RNAs (circRNAs) have been reported as effective diagnostic and therapeutic biomarkers in many diseases, but the potential of using this easy-to-monitor and highly stable materials for diagnosing Community-acquired pneumonia (CAP) remains unexplored. Here, aiming to identify potential CAP-related circRNAs in peripheral blood and seeking to deepen the understanding of how circRNA-miRNA-mRNA regulatory networks may contribute to CAP, we applied microarrays profiling analysis and identified 8296 differentially expressed (DE) circRNAs between patients with CAP (n = 6) and healthy controls (n = 6). Subsequently, we validated the accumulation trends for the top 100 DE circRNAs based on qPCR in an independent validation cohort (30 patients vs 30 controls), and ultimately identified a panel of four circRNAs that perform extremely well as sensitive and specific biomarkers for diagnosing CAP: hsa_circ_0018429 (area under the curve [AUC] = 0.8216), hsa_circ_0026579 (AUC = 0.7733), hsa_circ_0125357 (AUC = 0.7730), and hsa_circ_0099188 (AUC = 0.6978); combined as a panel (AUC = 0.8776). In addition, hsa_circ_0026579 exhibited good performance in differentiating viral from bacterial or mixed infection, with an AUC of 0.863. We also identified 10 miRNAs that most likely to interact with these four circRNAs, and then predicted 205 mRNA target genes. The KEGG pathway enrichment analysis suggested highly plausible functional implications related to inflammation and to virus-infection-related signaling pathways (such as HTLV-1 infection and hepatitis B infection). Thus, we generated a genetic network of potential CAP-related regulatory interactions that should inform future hypothesis-driven research into the causes and potential treatment of this widespread and frequently fatal disease.

Blood circRNAs as biomarkers for the diagnosis of community‐acquired pneumonia

Opportunistic pathogens are important for clinical practice as they often cause antibiotic-resistant infections. However, little is documented for many emerging opportunistic pathogens and their biological characteristics. Here, we isolated a strain of extended-spectrum β-lactamase-producing Enterobacteriaceae from a patient with a biliary tract infection. We explored the biological and genomic characteristics of this strain to provide new evidence and detailed information for opportunistic pathogens about the co-infection they may cause. The isolate grew very slowly but conferred strong protection for the co-infected cephalosporin-sensitive Klebsiella pneumoniae. As the initial laboratory testing failed to identify the taxonomy of the strain, great perplexity was caused in the etiological diagnosis and anti-infection treatment for the patient. Rigorous sequencing efforts achieved the complete genome sequence of the isolate which we designated as AF18. AF18 is phylogenetically close to a few strains isolated from soil, clinical sewage, and patients, forming a novel species together, while the taxonomic nomenclature of which is still under discussion. And this is the first report of human infection of this novel species. Like its relatives, AF18 harbors many genes related to cell mobility, various genes adaptive to both the natural environment and animal host, over 30 mobile genetic elements, and a plasmid bearing blaCTX-M-3 gene, indicating its ability to disseminate antimicrobial-resistant genes from the natural environment to patients. Transcriptome sequencing identified two sRNAs that critically regulate the growth rate of AF18, which could serve as targets for novel antimicrobial strategies. Our findings imply that AF18 and its species are not only infection-relevant but also potential disseminators of antibiotic resistance genes, which highlights the need for continuous monitoring for this novel species and efforts to develop treatment strategies.

https://www.researchsquare.com/article/rs-12638/v4.pdf?c=1631846952000

Genomic characterization of an emerging Enterobacteriaceae species: the first case of co-infection with a typical pathogen in a human patient

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Blood circRNAs as biomarkers for the diagnosis of community‐acquired pneumonia

Genomic characterization of an emerging Enterobacteriaceae species: the first case of co-infection with a typical pathogen in a human patient