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CircHivep2 contributes to microglia activation and inflammation via miR-181a-5p/SOCS2 signalling in mice with kainic acid-induced epileptic seizures.

ABSTRACT: Epilepsy is a chronic brain disease characterized by recurrent seizures. Circular RNA (circRNA) is a novel family of endogenous non-coding RNAs that have been proposed to regulate gene expression. However, there is a lack of data on the role of circRNA in epilepsy. In this study, the circRNA profiles were evaluated by microarray analysis. In total, 627 circRNAs were up-regulated, whereas 892 were down-regulated in the hippocampus in mice with kainic acid (KA)-induced epileptic seizures compared with control. The expression of circHivep2 was significantly down-regulated in hippocampus tissues of mice with KA-induced epileptic seizures and BV-2 microglia cells upon KA treatment. Bioinformatics analysis predicted that circHivep2 interacts with miR-181a-5p to regulate SOCS2 expression, which was validated using a dual-luciferase reporter assay. Moreover, overexpression of circHivep2 significantly inhibited KA-induced microglial activation and the expression of inflammatory factors in vitro, which was blocked by miR-181a-5p, whereas circHivep2 knockdown further induced microglia cell activation and the release of pro-inflammatory proteins in BV-2 microglia cells after KA treatment. The application of circHivep2+ exosomes derived from adipose-derived stem cells (ADSCs) exerted significant beneficial effects on the behavioural seizure scores of mice with KA-induced epilepsy compared to control exosomes. The circHivep2+ exosomes also inhibited microglial activation, the expression of inflammatory factors, and the miR-181a-5p/SOCS2 axis in vivo. Our results suggest that circHivep2 regulates microglia activation in the progression of epilepsy by interfering with miR-181a-5p to promote SOCS2 expression, indicating that circHivep2 may serve as a therapeutic tool to prevent the development of epilepsy.

SUBMITTER: Xiaoying G

PROVIDER: S-EPMC7701587 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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CircHivep2 contributes to microglia activation and inflammation via miR-181a-5p/SOCS2 signalling in mice with kainic acid-induced epileptic seizures.

Xiaoying Gao G Guo Mian M Jie Liu L Yanmei Zhu Z Ying Cui C Shengjie Shu S Haiyan Gou G Feixiang Sun S Sihua Qi Q Jiahang Sun S

Journal of cellular and molecular medicine 20201001 22

Epilepsy is a chronic brain disease characterized by recurrent seizures. Circular RNA (circRNA) is a novel family of endogenous non-coding RNAs that have been proposed to regulate gene expression. However, there is a lack of data on the role of circRNA in epilepsy. In this study, the circRNA profiles were evaluated by microarray analysis. In total, 627 circRNAs were up-regulated, whereas 892 were down-regulated in the hippocampus in mice with kainic acid (KA)-induced epileptic seizures compared ...[more]

PMID: 33002329

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Project description:BackgroundThe development of drug resistance and high mortality rates are the major problems observed in non-small cell lung cancer (NSCLC). Biomarkers indicating and predicting disease development towards these unfavorable directions are therefore on high demand. Many studies have demonstrated that changes in miRNAs expression may be associated with a response to treatment and disease prognosis, thus suggesting its potential biomarker value for a broad spectrum of clinical applications. The aim of the present study was to investigate the expression level of miR-181a-5p, miR-630, and its targets in NSCLC tumor tissue and plasma samples; and to analyze its association with NSCLC patient's response to treatment and disease prognosis.MethodsThe study was performed in 89 paired tissue specimens and plasma samples obtained from NSCLC patients who underwent surgical treatment at the Department of Thoracic Surgery and Oncology of the National Cancer Institute. Analysis of miR-181a-5p and miR-630 expression was performed by qRT-PCR using TaqMan miRNA specific primers. Whereas BCL2, LMO3, PTEN, SNAI2, WIF1 expression levels were identified with KAPA SYBR FAST qPCR Kit. Each sample was examined in triplicate and calculated following the 2-ΔΔCt method. When the p-value was less than 0.05, the differences were considered statistically significant.ResultsIt was found that miR-181a-5p and miR-630 expression levels in NSCLC tissue and plasma samples were significantly decreased compared with control samples. Moreover, patients with low miR-181a-5p expression in tumor tissue and plasma had longer PFS rates than those with high miRNA expression. Decreased miR-630 expression in tumor was statistically significantly associated with better NSCLC patients' OS. In addition, the expression of miR-181a-5p, as well as miR-630 in tumor tissue, are the statistically significant variables for NSCLC patients' OS. Moreover, in NSCLC patient plasma samples circulating miR-181a-5p can be evaluated as significant independent prognostic factors for OS and PFS.ConclusionsOur findings indicate the miR-181a-5p and miR-630 expression levels have the potential to prognose and predict and therefore improve the treatment individualization and the outcome of NSCLC patients. Circulating miR-181a-5p has the potential clinical value as a non-invasive biomarker for NSCLC.

Project description:Objective: Our study aimed to explore whether gasdermin D (GSDMD)-mediated pyroptosis is involved in the mechanism of kainic acid-induced seizures. Methods: C57BL/6 mice were randomly divided into sham and epilepsy groups. The epilepsy group was intrahippocampally injected with kainic acid to induce status epilepticus (SE), and the sham group was injected with an equal volume of saline. Dimethyl fumarate (DMF) was used as the GSDMD N-terminal fragments (GSDMD-N) inhibitor and suspended in 0.5% sodium carboxymethyl cellulose (CMC) for orally administration. The epilepsy group was divided into SE + CMC and SE + DMF groups. In the SE + DMF group, DMF was orally administered for 1 week before SE induction and was continued until the end of the experiment. An equal volume of CMC was administered to the sham and SE + CMC groups. Recurrent spontaneous seizures (SRSs) were monitored for 21 days after SE. Western blot analysis and immunofluorescent staining was performed. Results: The expression of GSDMD increased at 7-21 days post-SE, and GSDMD-N expression was significantly elevated 7 days after SE in both ipsilateral and contralateral hippocampus. GSDMD-positive cells were co-labeled with astrocytes, but not neurons or microglia. Astroglial damage occurs following status epilepticus (SE). Damaged astrocytes showed typical clasmatodendrosis in the CA1 region containing strong GSDMD expression at 7-21 days post-SE, accompanied by activated microglia. In the SE + DMF group, the expression of GSDMD-N was significantly inhibited compared to that in the SE + CMC group. After administration of DMF, SRSs at 7-21 days after SE were significantly decreased, and the number of clasmatodendritic astrocytes, microglia, and the expression of inflammatory factors such as IL-1β and IL-18 were significantly attenuated. Conclusion: GSDMD-mediated pyroptosis is involved in the mechanism of kainic acid-induced seizures. Our study provides a new potential therapeutic target for seizure control.

Dataset Information

CircHivep2 contributes to microglia activation and inflammation via miR-181a-5p/SOCS2 signalling in mice with kainic acid-induced epileptic seizures.

Publications

CircHivep2 contributes to microglia activation and inflammation via miR-181a-5p/SOCS2 signalling in mice with kainic acid-induced epileptic seizures.

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