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微小 RNA-143 通过靶向重症肌无力小鼠模型中的 CXCL13 抑制胸腺细胞增殖并促进其凋亡。

Micro-RNA-143 inhibits proliferation and promotes apoptosis of thymocytes by targeting CXCL13 in a myasthenia gravis mouse model.

机构信息

Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University , Xuzhou , People's Republic of China.

College of Health Sciences, Jiangsu Normal University , Xuzhou , People's Republic of China.

出版信息

Am J Physiol Cell Physiol. 2019 Jan 1;316(1):C70-C80. doi: 10.1152/ajpcell.00090.2018. Epub 2018 Nov 7.

Abstract

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder, affecting the quality of life of millions of people worldwide. The present study aims to determine the relationship between micro-RNA-143 (miR-143) and C-X-C motif chemokine 13 (CXCL13) and whether it influences the pathogenesis of myasthenia gravis (MG). Thymus specimens were resected from patients with thymic hyperplasia combined with MG and then infused into normal mouse cavities to establish MG mouse models. Immunohistochemistry, reverse transcription-quantitative PCR, in situ hybridization detection, and Western blot analysis were employed to identify the expression of miR-143 and CXCL13 in MG and normal mice. The obtained thymocytes were cultured in vitro and transfected with a series of miR-143 mimic, miR-143 inhibitor, overexpression of CXCL13, or siRNA against CXCL13. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and flow cytometry assays were employed to assess cell viability, cycle entry, and apoptosis of the thymocytes. Dual-luciferase reporter assay provided verification, confirming that CXCL13 was the target gene of miR-143. Low miR-143 expression in the thymus tissues of the MG mice was detected, which presented with a reciprocal relationship with the expression rate of CLCX13. Observations in relation to the interactions between miR-143 mimic or siRNA-CXCL13 exposure showed reduced cell viability, with a greater number of cells arrested at the G0/G1 phase and a greater rate of induced apoptosis. Furthermore, overexpression of CXCL13 rescued miR-143 mimic-induced apoptosis. The findings have identified the potential role of miR-143 as a MG development mediator by targeting CXCL13. The key results obtained provide a promising experimental basis for targeted intervention treatment with miR-143.

摘要

重症肌无力(MG)是一种影响全球数百万人生活质量的自身免疫性神经肌肉疾病。本研究旨在确定 microRNA-143(miR-143)和 C-X-C 基序趋化因子 13(CXCL13)之间的关系,以及它们是否影响重症肌无力(MG)的发病机制。从伴有胸腺瘤的 MG 患者中切除胸腺组织,然后注入正常小鼠腔中,建立 MG 小鼠模型。采用免疫组织化学、逆转录定量 PCR、原位杂交检测和 Western blot 分析鉴定 MG 和正常小鼠中 miR-143 和 CXCL13 的表达。体外培养获得的胸腺细胞,并转染一系列 miR-143 模拟物、miR-143 抑制剂、CXCL13 过表达或 siRNA 靶向 CXCL13。MTT [3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴盐]和流式细胞术检测评估胸腺细胞的活力、细胞周期进入和凋亡。双荧光素酶报告基因检测提供了验证,证实 CXCL13 是 miR-143 的靶基因。检测到 MG 小鼠胸腺组织中 miR-143 表达降低,与 CXCL13 的表达率呈相反关系。miR-143 模拟物或 siRNA-CXCL13 暴露的相互作用观察表明,细胞活力降低,更多的细胞停滞在 G0/G1 期,诱导凋亡的比例增加。此外,CXCL13 的过表达挽救了 miR-143 模拟物诱导的凋亡。这些发现确定了 miR-143 通过靶向 CXCL13 作为 MG 发展调节剂的潜在作用。关键结果为 miR-143 的靶向干预治疗提供了有前景的实验基础。

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