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Screening of circular RNAs and validation of circANKRD36 associated with inflammation in patients with type 2 diabetes mellitus.

ABSTRACT: Circular RNAs (circRNAs) are an abundant class of endogenous non?coding RNAs and are associated with numerous diseases, including cancer, cardiovascular diseases, and type 2 diabetes mellitus (T2DM). However, the association between circRNAs and inflammation or inflammatory cytokines in patients with T2DM remains to be fully elucidated. The purpose of the present study was to investigate the expression profiles of circRNAs in peripheral leucocytes of patients with T2DM and their association with inflammatory cytokines. Peripheral blood from patients with T2DM (n=43) and healthy individuals (n=45) were collected for RNA sequencing and later verification. Reverse transcription?polymerase chain reaction (RT?PCR) and reverse transcription?quantitative polymerase chain reaction (RT?qPCR) analyses were used to detect the expression levels of circRNAs. The expression of inflammatory factors, including interleukin (IL)?1, (IL)?6, and tumor necrosis factor (TNF)?? were measured via enzyme?linked immunosorbent assay. Furthermore, the mRNA expression level of ankyrin repeat domain 36 (ANKRD36), a protein located at 2q11.2 that interacts with the GAPDH gene, was measured using RT?qPCR analysis. The circRNA/microRNA (miRNA) interaction was predicted using RegRNA and mirPath software. In total, 220 circRNAs were found to be differentially expressed between patients with T2DM and healthy individuals, of which 107 were upregulated and 113 were downregulated. Among the nine selected circRNAs, circANKRD36 was significantly upregulated in patients with T2DM compared with control subjects (P=0.02). The expression level of circANKRD36 was positively correlated with glucose and glycosylated hemoglobin (r=0.3250, P=0.0047 and r=0.3171, P=0.0056, respectively). The expression level of IL?6 was significantly different between the T2DM group and control group (P=0.028) and was positively correlated with circANKRD36. The difference of circANKRD36 host gene expression between patients with T2DM and healthy controls was significant (P=0.04). Taken together, circANKRD36 may be involved in T2DM and inflammation?associated pathways via interaction with miRNAs, including hsa?miR?3614?3p, hsa?miR?498, and hsa?miR?501?5p. The expression of circANKRD36 was up-regulated in peripheral blood leucocytes and was correlated with chronic inflammation in T2DM. Therefore, circANKRD36 can be used as a potential biomarker for screening chronic inflammation in patients with T2DM.

SUBMITTER: Fang Y

PROVIDER: S-EPMC6108858 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Screening of circular RNAs and validation of circANKRD36 associated with inflammation in patients with type 2 diabetes mellitus.

Fang Yuan Y Wang Xiaoxia X Li Wenqing W Han Jingli J Jin Junhua J Su Fei F Zhang Junhua J Huang Wei W Xiao Fei F Pan Qi Q Zou Lihui L

International journal of molecular medicine 20180718 4

Circular RNAs (circRNAs) are an abundant class of endogenous non‑coding RNAs and are associated with numerous diseases, including cancer, cardiovascular diseases, and type 2 diabetes mellitus (T2DM). However, the association between circRNAs and inflammation or inflammatory cytokines in patients with T2DM remains to be fully elucidated. The purpose of the present study was to investigate the expression profiles of circRNAs in peripheral leucocytes of patients with T2DM and their association with ...[more]

PMID: 30066828

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Project description:BackgroundDiabetes mellitus, a metabolic disorder characterised by hyperglycaemia and associated with a heavy burden of microvascular and macrovascular complications, frequently remains undiagnosed. Screening of apparently healthy individuals may lead to early detection and treatment of type 2 diabetes mellitus and may prevent or delay the development of related complications.ObjectivesTo assess the effects of screening for type 2 diabetes mellitus.Search methodsWe searched CENTRAL, MEDLINE, LILACS, the WHO ICTRP, and ClinicalTrials.gov from inception. The date of the last search was May 2019 for all databases. We applied no language restrictions.Selection criteriaWe included randomised controlled trials involving adults and children without known diabetes mellitus, conducted over at least three months, that assessed the effect of diabetes screening (mass, targeted, or opportunistic) compared to no diabetes screening.Data collection and analysisTwo review authors independently screened titles and abstracts for potential relevance and reviewed the full-texts of potentially relevant studies, extracted data, and carried out 'Risk of bias' assessment using the Cochrane 'Risk of bias' tool. We assessed the overall certainty of the evidence using the GRADE approach.Main resultsWe screened 4651 titles and abstracts identified by the search and assessed 92 full-texts/records for inclusion. We included one cluster-randomised trial, the ADDITION-Cambridge study, which involved 20,184 participants from 33 general practices in Eastern England and assessed the effects of inviting versus not inviting high-risk individuals to screening for diabetes. The diabetes risk score was used to identify high-risk individuals; it comprised variables relating to age, sex, body mass index, and the use of prescribed steroid and anti-hypertensive medication. Twenty-seven practices were randomised to the screening group (11,737 participants actually attending screening) and 5 practices to the no-screening group (4137 participants). In both groups, 36% of participants were women; the average age of participants was 58.2 years in the screening group and 57.9 years in the no-screening group. Almost half of participants in both groups were on antihypertensive medication. The findings from the first phase of this study indicate that screening compared to no screening for type 2 diabetes did not show a clear difference in all-cause mortality (hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.90 to 1.25, low-certainty evidence). Screening compared to no screening for type 2 diabetes mellitus showed an HR of 1.26, 95% CI 0.75 to 2.12 (low-certainty evidence) for diabetes-related mortality (based on whether diabetes was reported as a cause of death on the death certificate). Diabetes-related morbidity and health-related quality of life were only reported in a subsample and did not show a substantial difference between the screening intervention and control. The included study did not report on adverse events, incidence of type 2 diabetes, glycosylated haemoglobin A1c (HbA1c), and socioeconomic effects.Authors' conclusionsWe are uncertain about the effects of screening for type 2 diabetes on all-cause mortality and diabetes-related mortality. Evidence was available from one study only. We are therefore unable to draw any firm conclusions relating to the health outcomes of early type 2 diabetes mellitus screening. Furthermore, the included study did not assess all of the outcomes prespecified in the review (diabetes-related morbidity, incidence of type 2 diabetes, health-related quality of life, adverse events, socioeconomic effects).

Project description:Rationale: Macrophages play critical roles in the pathogenesis of type 1 diabetes mellitus (T1DM). Circular RNAs (circRNAs) are a novel class of endogenous RNAs with covalently closed loop structures, implicated in various disease processes. However, their impact on macrophage activation and T1DM pathogenesis remains elusive. Methods: circRNA expression profiles of peripheral blood mononuclear cells (PBMCs) from T1DM children were determined by whole transcriptome microarray. Bioinformatics, quantitative real-time PCR, Western blot, RNA immunoprecipitation (RIP), cell co-culture, cell proliferation, and cell apoptosis assays were performed to investigate the expression, function, and regulatory mechanisms of circPPM1F in vitro. The regulatory role of circPPM1F in vivo was evaluated in the streptozocin-induced diabetic mouse model. Results: We identified 27 upregulated and 31 downregulated differentially expressed circRNAs in T1DM patients. circPPM1F, a circRNA with unknown function, was dominantly expressed in monocytes and significantly upregulated in T1DM patients. Functionally, circPPM1F promoted lipopolysaccharide (LPS)-induced M1 macrophage activation via enhancement of the NF-κB signaling pathway. Mechanistically, circPPM1F competitively interacted with HuR to impair the translation of protein phosphatase, Mg2+/Mn2+ dependent 1F (PPM1F), thus alleviating the inhibitory effect of PPM1F on the NF-κB pathway. Moreover, eukaryotic initiation factor 4A-III (EIF4A3) and fused in sarcoma (FUS) coordinately regulated circPPM1F expression during M1 macrophage activation. In addition, circPPM1F could exacerbate pancreas injury in the streptozocin-induced diabetic mice by activation of M1 macrophages in vivo. Conclusions: circPPM1F is a novel positive regulator of M1 macrophage activation through the circPPM1F-HuR-PPM1F-NF-κB axis. Overexpression of circPPM1F could promote pancreatic islet injury by enhancing M1 macrophage activation and circPPM1F may serve as a novel potential therapeutic target for T1DM in children.

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Screening of circular RNAs and validation of circANKRD36 associated with inflammation in patients with type 2 diabetes mellitus.

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Screening of circular RNAs and validation of circANKRD36 associated with inflammation in patients with type 2 diabetes mellitus.

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