Correlation analysis of circular RNAs involved in liver injury in mice with autoimmune hepatitis / 中国组织工程研究

BACKGROUND:The pathogenesis of autoimmune hepatitis has not been clearly elucidated.Circular RNA(CircRNA)is a research hotspot in the field of RNA and is involved in the pathogenesis of many autoimmune diseases.However,the role of CircRNA in autoimmune hepatitis remains unclear. OBJECTIVE:To investigate the relationship between CircRNA(CircRNA)and concanavalin A induced liver injury in mice with autoimmune hepatitis. METHODS:Bioinformatics analysis was performed on CircRNA profiles selected by previous microarray technology,including gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses,so as to explore the potential biological functions of these differentially expressed genes.Twelve C57BL/6 mice were randomized into normal group and model group(n=6 per group).Autoimmune hepatitis model was established by tail vein injection of concanavalin A in the model group.Mice were killed at 12 hours after modeling to extract mouse liver and peripheral blood.The expression levels of CircRNAs were verified by qRT-PCR.Serum alanine aminotransferase and aspartate aminotransferase levels were detected by colorimetric method.The levels of oxidative stress indexes malondialdehyde and nitric oxide in mouse liver were detected by microplate method.The correlation between oxidative stress level and liver injury index was analyzed. RESULTS AND CONCLUSION:The results of GO analysis showed that the target genes with up-regulated CircRNAs expression were mainly involved in the biological processes of SNARE complex assembly regulation(P=0.004),their molecular functions were mainly metal ion binding(P=0.000 29),and the cell components were mainly enriched in CORVET complex(P=0.075).The biological processes involved in the down-regulated circRNAs target genes were mainly"negative regulation of pancreatic secretion"(P=0.000 42),the molecular functions were mainly"transcriptional activator activity"(P=0.025),and the cell components were mainly enriched in"extracellular components"(P=0.006).KEGG results showed that the target genes with up-regulated CircRNAs expression were mainly enriched in the"base excision-repair"signaling pathways(P=0.026).Compared with the normal group,serum alanine aminotransferase and aspartate aminotransferase levels and the levels of malondialdehyde and nitric oxide in mouse liver in the model group were significantly increased(P＜0.01).Compared with the normal group,the expression of two selected CircRNAs(mmu-circ-0001520 and mmu-circ-0001577)was increased in the model group(P＜0.05).Spearman correlation analysis showed that the expression of mmu-circ-0001520 and mmu-circ-0001577 was positively correlated with alanine aminotransferase,aspartate aminotransferase,malondialdehyde and nitric oxide.To conclude,the differential expression of CircRNAs is correlated with liver injury in autoimmune hepatitis mice.mmu-circ-0001520 and mmu-circ-0001577 are expected to be diagnostic biomarkers and therapeutic targets for autoimmune hepatitis.

Circular RNAs Involved in The Development of Nasopharyngeal Carcinoma / 生物化学与生物物理进展

Circular RNAs (circRNAs) are a kind of non-coding RNA (ncRNA) with covalent closed-loop structure. They have attracted more and more attention because of their high stability, evolutionary conservatism, and tissue expression specificity. It has shown that circRNAs are involved in the development of a variety of diseases including malignant tumors recently. Nasopharyngeal carcinoma (NPC) is a malignant tumor that occurs in the nasopharynx and has a unique ethnic and geographical distribution in South China and Southeast Asia. Epstein-Barr virus (EBV) infection is closely related to the development of NPC. Radiotherapy and chemotherapy are the mainstays of treatment for NPC. But tumor recurrence or distant metastasis is the leading cause of death in patients with NPC. Several studies have shown that circRNAs, as gene expression regulators, play an important role in NPC and affect the progression of NPC. This review mainly summarized the research status of abnormally expressed circRNAs in NPC and EBV-encoded circRNAs. We also discussed the possibility of circRNAs as a therapeutic target, diagnostic and prognostic marker for NPC.

Role of circTmeff-1 in morphine addiction memory of mice / 中国药理学与毒理学杂志

In addition to the essential pharmacologi-cal effects of opioids,situational cues associated with drug addiction memory are key triggers for drug seeking.CircRNAs,an emerging hotspot regulator in crown genet-ics-play an important role in central nervous system-relat-ed diseases.However,the internal mediating mechanism of circRNA in the field of drug reward and addiction mem-ory remains unknown.Here,we trained mice on a condi-tional place preference(CPP)model and collected nucle-us accumbens(NAc)tissues from day 1(T0)and day 8(T1)for high-throughput RNA sequencing.qRT-PCR 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 reverse regulation of circTmeff-1 by adeno-associated viruses could both inhibit the formation of addiction mem-ory in the NAc core or shell.Subsequently,the GO and KEGG analyses indicated 21 that circTmeff-1 might regu-late the addiction memory via the MAPK and AMPK path-ways.These findings suggest that circTmeff-1 in NAc plays a crucial role in morphine-dependent memory for-mation.

Research progress of circular RNA in drug resistance of liver cancer / 中国药理学通报

Circular RNAs are novel non-coding RNAs with multiple biological functions, which can participate in biological processes such as the occurrence, development, invasion, and metastasis of liver cancer, as well as drug resistance of liver cancer. This article reviews the roles and mechanisms of circR-NAs in chemotherapy resistance, targeted therapy resistance and immunotherapy resistance in liver cancer, in order to provide new ideas for solving liver cancer resistance.

Construction of endogenous RNA regulatory network for colorectal cancer based on bioinformatics / 中南大学学报(医学版)

OBJECTIVES@#The high morbidity and mortality of colorectal cancer (CRC) have posed great threats to human health. Circular RNA (circRNA) and microRNA (miRNA), acting as competing endogenous RNAs (ceRNAs), have been found to play vital roles in carcinogenesis. This paper aims to construct a circRNA/miRNA/mRNA regulatory network so as to explore the molecular mechanism of CRC.@*METHODS@#The sequencing data of circRNA from CRC were obtained from Gene Expression Omnibus (GEO). The differential circRNA was screened and its structure was identified by Cancer-specific CircRNA Database (CSCD); the sequencing data of miRNA and messenger RNA (mRNAs) were downloaded from The Cancer Genome Atlas (TCGA) database and the differentially expressed genes were screened; the corresponding miRNA of differential circRNAs were predicted by CircInteractome database; DIANA, Miranda, PicTar, and TargetScan databases were used to predict the target genes of different miRNAs; the target genes from Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were enriched by R language; String database combined with Cytoscape 3.7.2 software was used to construct protein-protein interaction (PPI) network and hub genes were screened; the expressions of mRNAs in the Top10 hub genes were verified in CRC. The network diagrams of circRNAs/miRNAs/mRNAs and circRNAs/miRNAs/Top10 hub mRNAs were constructed by Cytoscape3.7.2. Real-time PCR was used to examine the expression levels of hsa_circRNA_0065173, hsa-mir-450b, hsa-mir-582, adenylate cyclase 5 (ADCY5), muscarinic acetylcholine receptor M2 (CHRM2), cannabinoid receptor 1 (CNR1), and lysophosphatidic acid receptor 1 (LPAR1) in the CRC tissues and the adjacent normal tissues.@*RESULTS@#A total of 14 differential circRNAs were identified, and 8 were found in CSCD; 34 miRNAs targeted by circRNAs were obtained. The PPI network was constructed, and the Top10 hub genes were identified, which were CHRM2, melanin concentrating hormone receptor 2 (MCHR2), G-protein gamma 3 subunit (GNG3), neuropeptide Y receptor Y1 (NPY1R), CNR1, LPAR1, ADCY5, adenylate cyclase 2 (ADCY2), gamma 7 (GNG7) and chemokine 12 (CXCL12), respectively. The expressions of Top 10 hub genes were also verified, and the results showed that the Top 10 hub genes were down-regulated in CRC; the constructed network diagram showed that hsa_circRNA_0065173 may regulate ADCY5, CHRM2, and Hsa-mir-450b by modulating hsa-mir-450b and hsa-mir-582. CNR1 and LPAR1 genes might serve as potentially relevant targets for the treatment of CRC. Real-time PCR results showed that the expression levels of hsa_circRNA_0065173, ADCY5, CHRM2, CNR1 and LPAR1 in the CRC tissues were significantly reduced compared with the adjacent normal tissues (all P<0.05); the expression levels of hsa-mir-450b and hsa-miR-582 were significantly increased (both P<0.05).@*CONCLUSIONS@#In this study, a potential circRNAs/miRNAs/mRNAs network is successfully constructed, which provides a new insight for CRC development mechanism through ceRNA mediated by circRNAs.

Research progress on the regulatory mechanism of non-coding RNA in arsenic toxicity / 中华劳动卫生职业病杂志

Arsenic is a non-metallic element, and the International Agency for Research on Cancer has identified arsenic and its compounds as carcinogens. Arsenic and its compounds can be absorbed through the respiratory tract, skin and digestive tract, distributed in the liver, kidney, lung and skin, and cause damage. Non-coding RNAs are closely related to arsenic-induced nervous system disorders, cell necrosis, reproductive toxicity, and carcinogenesis. In recent years, the network regulation of microRNAs (miRNAs) , long non-coding RNAs (lncRNAs) , and circular RNAs (circRNAs) among non-coding RNAs in various diseases induced by arsenic has become a new research field. This paper summarizes the existing scientific research results, and expounds the mechanism of miRNAs, lncRNAs and circRNAs in arsenic toxicity, and provides basic data and theoretical basis for the prevention and treatment of arsenic poisoning.

Research progress and application prospects of circRNA in cardiovascular diseases / 中国临床药理学与治疗学

CircRNA is a single-stranded, covalently closed non-coding RNA, whose mechanism mainly involves sponge adsorption of micro RNA (miRNA), regulation of protein transcription and post-transcriptional levels, interaction with RNA-binding proteins and few coding proteins of circRNA. Meanwhile, because of its abundant expression, highly conserved and dynamic changes, circRNAs have promising applications such as becoming biomarkers of diseases, developing circRNA vaccines and gene editing therapies for circRNAs. Cardiovascular diseases are the leading cause of death from diseases worldwide, and existing therapeutic approaches can delay the development of heart diseases, but are still limited by the unknown pathogenesis and therapeutic targets. Many studies have reported the mechanistic link between circRNAs and cardiac diseases, therefore, this review is to explain the progress of circRNA research in cardiovascular diseases and to illustrate the three clinical applications in which circRNAs are currently involved.

Research Progress on Energy Metabolism and Radiosensitivity of Glioma / 肿瘤防治研究

Radiotherapy is an important auxiliary treatment for glioma. Although comprehensive treatment of glioma has made some progress in recent years, the prognosis is still poor. How to improve the radiosensitivity of glioma is one of the hot spots in current glioma research. The changes of energy metabolism in gliomas promote malignant progression and resistance to chemoradiotherapy, but the exact mechanism is still unclear. This paper reviews the research progress of energy metabolism in gliomas and its relation with radiosensitivity of gliomas, in order to lay a foundation for further exploration of improving radiosensitivity of gliomas.

Mechanism of action of circular RNAs in hepatocellular carcinoma / 临床肝胆病杂志

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide and has high mortality and recurrence rates and low survival rates. Circular RNAs (circRNAs) are a class of single-stranded closed circular RNA molecules with tissue- and development-specific expression and play a regulatory role in organisms. These circRNAs regulate the progression of HCC by acting as miRNA sponges and targeted protein-coding genes, but the basic mechanism is still unclear. This article summarizes the formation mechanism and biological functions of circRNAs, reviews the research advances in the role of circRNAs in the pathogenesis of HCC, and points out their potential value as diagnostic markers and therapeutic targets for HCC.

Bioinformatics analysis of differentially expressed circRNAs and microRNA-1 in HepG2 cells / 医学研究生学报

ObjectivecircRNAs play an important role in tumor development, but the relationship between circRNAs and hepatocellular carcinoma remains to be further explored. The present study aimed to bioinformatically analyze the target gene of microRNA-1. Another aim was to screen circRNAs that are associated with target genes and differentially expressed in hepatocellular carcinoma cells, as well as provide theoretical basis for clinical screening of molecular markers and targeted therapies related to hepatocellular carcinoma.MethodsThe miRNA related database used for the prediction of microRNA-1 target genes, and the bioinformatic analysis of the target genes of microRNA-1 involved functional enrichment analysis and signal transduction pathway enrichment. Then, the circRNAs, which are related to the downstream target genes of microRNA-1, are screened through the circRNA database.ResultsThe number of microRNA-1 target genes was 230 in miRNA related database. Through GO analysis, it was found that the target genes of microRNA-1 had a strong tendency in regulation, and were mainly enriched in three aspects: biological function, biological process and cell localization.The target genes of microRNA-1 are involved in the function of proteins, regulation of biosynthesis, cofactor binding, enzyme regulation and other biological processes. Predicted target genes of miRNA-1 were significantly enriched in cancer signaling pathways, hepatitis B occurrence, endocytosis and splicing pathways. Further, 21 circRNAs related to the target gene of microRNA-1 were found in three circRNA databases, wherein hsa_circ_0004651 was highly expressed in hepatocellular carcinoma cell line HepG2 and its pavent gene was hnRNPD.ConclusionMicroRNA-1 influence the occurrence of hepatocellular carcinoma development through the regulation of protein and enzyme. Hsa_circ_0004651 may affect the development of hepatocellular carcinoma with microRNA-1 and its parental gene hnRNPD.

Research Progress in the translation ability of circular RNAs / 国际生物医学工程杂志

With the development of the next-generation sequencing technology, circular RNAs (circRNAs) are again receiving attention. Circular RNAs have a circular structure that without 5' and a 3' ending. This special structural characteristics and unique formation mechanism (backsplicing) has been known well, but few studies aim to its biological functions. Related researches are mainly focused on its functions as a regulator of the splicing of pre-mRNAs and the expression of parental gene in nucleus or as a competitive inhibitor of miRNAs absorbed by the circRNAs in cytoplasm. The related diseases include Parkinson disease, diabetes, cancers, cardiomyopathy and so on. According to the nature of the sequence contained in the ring, circRNAs can be divided into circular exonic RNA, circular intronic RNA, and ElciRNAs. The sequences contained within the circRNAs are mainly exons, whose ability of guiding the protein synthesis still remains controversial. In this paper, the current researches on the translation ability of circRNAs were reviewed, and the possible biological information tools and lab methods to identify such ability were recommended.

Hsa-circ-000094 in Peripheral blood can be used as a biomarker for the diagnosis of type 2 diabetes / 中华内分泌代谢杂志

Objective The purpose of this study was to investigate the differential expression of circRNAs in human blood, as a diagnostic marker for pre-diabetes and type 2 diabetes mellitus( T2DM). Methods Microarray analysis was used to select several differentially expressed circRNAs from three normal patients and three T2DM patients. Enlarge the sample size(normal controls,n=20;subjects with impaired glucose regulation,n=20;and type 2 diabetes mellitus,n=20) to determine a circRNA which the most evident differentially expressed by fluorescence quantitative PCR( Q-PCR). Then they were verified with expanded samples ( normal controls, n= 50; impaired glucose regulations,n=50;type 2 diabetes mellitus, n=50) by Q-PCR. Results A total of 2 953 differentially expressed circRNAs were found in microarray analysis, of which 1 439 were up-regulated and 1 514 were down-regulated. Nine differentially expressed circRNAs were selected from the 1 439 circRNAs that were up-regulated(hsa-circ-103838, hsa-circ-103965, hsa-circ-104227, hsa-circ-002117, hsa-circ-000094, hsa-circ-101226, hsa-circ-101720, hsa-circ-400029, and hsa-circ-100633). The Q-PCR results of the expanded sample( n=60) showed that the difference expression of hsa-circ-000094(Alias:has-circ-0000247) in the nine circRNAs was the most obvious one among the 3 groups, the area under the maximum curve was found by ROC curve analysis, SIGR=0. 802 5[ 95% confidence interval (0.665 5-0.939 5), P=0.001]; ST2DM=0.77[95% confidence interval (0.624-0.916), P=0.003]. In order to verify the clinical diagnostic ability of hsa-circ-000094, the experiment was conducted to further expand the sample ( n=150). The results showed that the expression of hsa-circ-000094 in the three groups was different, the difference and ROC curve analysis were statistically significant, SIGR=0. 673 3 [ 95% confidence interval (0.575 7-0. 771 0), P＜0. 01]; ST2DM=0. 723 1 [ 95% confidence interval ( 0. 632 7-0. 813 4), P＜ 0.01]. Conclusion The higher expression of hsa-circ-000094 in peripheral blood provides a certain diagnostic basis for pre-diabetes as well as type 2 diabetes mellitus.

Identification and characterization of CircRNAs involved in the regulation of wheat root length

BACKGROUND: Recent studies indicate that circular RNAs (circRNAs) may play important roles in the regulation of plant growth and development. Plant roots are the main organs of nutrient and water uptake. However, whether circRNAs involved in the regulation of plant root growth remains to be elucidated. METHODS: LH9, XN979 and YN29 are three Chinese wheat varieties with contrasting root lengths. Here, the root circRNA expression profiles of LH9, XN979 and YN29 were examined by using high-throughput sequencing technology. RESULTS: Thirty-three and twenty-two differentially expressed circRNAs (DECs) were identified in the YN29-LH9 comparison and YN29-XN979 comparison, respectively. Among them, ten DECs coexisted in both comparisons. As the roots of both LH9 and XN979 were significantly larger and deeper than YN29, the ten DECs coexisting in the two comparisons were highly likely to be involved in the regulation of wheat root length. Moreover, three of the ten DECs have potential miRNA binding sites. Real-time PCR analysis showed that the expression levels of the potential binding miRNAs exhibited significant differences between the long root plants and the short root plants. CONCLUSIONS: The expression levels of some circRNAs exhibited significant differences in wheat varieties with contrasting root phenotypes. Ten DECs involved in the regulation of wheat root length were successfully identified in which three of them have potential miRNAs binding sites. The expression levels of putative circRNA-binding miRNAs were correlated with their corresponding circRNAs. Our results provide new clues for studying the potential roles of circRNAs in the regulation of wheat root length.

circRNAs:post-transcription regulation in cerebrovascular diseases / 中国病理生理杂志

Circular RNAs(circRNAs)are a type of covalently closed circular non-coding RNAs that are ex-pressed across varieties of life forms.CircRNAs have a variety of characteristics such as stable structures, tissue-specific expression and the function of microRNA sponges in the regulation of genes.CircRNAs are abundant,highly expressed in neural tissues,emerging evidence also indicates that circRNAs play an important role in the pathophysiologic process of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other neurological diseases.As one of the most important neurological diseases,the pathogenesis of brain damage and repair after ischemia has not yet been evalua -ted,and stroke related circRNAs are of great significance.In this review,we summarize related regulations,and the poten-tial regulatory mechanisms of cicrcRNAs in cerebrovascular diseases, and the important role of circRNAs in post stroke pathophysiologic process is also discussed.CircRNAs are expected to be a new drug target,and provide new theoretical ba-sis for the diagnosis and treatment of cerebrovascular diseases.

Study on relationship between lncRNAs and circRNAs in tumor / 中国药理学通报

With the development of whole genome and transcrip-tome sequencing technologies, a growing body of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) has been i-dentified and is receiving increasing attention. LncRNAs and circRNAs are non-protein encoding transcripts whose functions are crucial for advancing our comprehensive understanding of bi-ological processes in human health and diseases, specifically tumor. And there is a close relationship between circRNAs and lncRNAs in their origin and function. In this paper, we have re-viewed the recent advances of lncRNAs and circRNAs in tumor by focusing on their relationships, which may help to distinguish them and identify tumor biomarkers further.

An Emerging Role for Circular RNAs in Osteoarthritis

Circular RNAs (circRNAs) are currently classed as non-coding RNAs that, unlike the better known canonical linear RNAs, form a covalently closed continuous loop without 5′ or 3′ polarities. With the development of high throughput sequencing technology, a large number of circRNAs have been discovered in many species. More importantly, growing evidence suggests that circRNAs are abundant, evolutionally conserved, and relatively stable in cells and tissues. Strikingly, recent studies have discovered that circRNAs can serve as microRNA sponges, interact with RNA-binding protein, and regulate gene transcription, as well as protein translation. Osteoarthritis (OA) is the most common chronic degenerative joint disease. CircRNAs are differentially expressed in OA cartilage. Moreover, some circRNAs are involved in multiple pathological processes during OA, mainly extracellular matrix degradation, inflammation, and apoptosis. In this review, we briefly delineate the biogenesis, characteristics, and biofunctions of circRNAs, and then, focus on the role of circRNAs in the occurrence and progression OA.

Identification and characterization of circRNAs involved in the regulation of low nitrogen-promoted root growth in hexaploid wheat

BACKGROUND: CircRNAs are widespread in plants and play important roles in response to abiotic stresses. Low nitrogen (LN) promotes the growth of plant root system, allowing it to explore more nitrogen. However, whether circRNAs involved in the response to LN stress and the regulation of LN-promoted root growth in wheat remains unclear. METHODS: Two wheat varieties (LH9 and XN979) with contrasting root phenotypes to LN stress were used as materials to identify circRNAs under control and LN conditions by using high-throughput sequencing technology. RESULTS: Six differentially expressed circRNAs (DECs) involved in the common response to LN stress and 23 DECs involved in the regulation of LN-promoted root growth were successfully identified. GO analysis of the DEC-host genes involved in the regulation of LN-promoted root growth showed that GO terms related to biological regulation, responses to stimuli and signalling were significantly enriched. Moreover, seven DECs were predicted to have miRNA binding sites and may serve as miRNA sponges to capture miRNAs from their target genes. CONCLUSIONS: LN stress altered the expression profiles of circRNAs in wheat. This is the first report of LN stress responsive circRNAs in plants. Our results provided new clues for investigating the functions of circRNAs in response to LN stress and in the regulation of LN-promoted wheat root growth.