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Magnesium isoglycyrrhizinate ameliorates high fructose-induced liver fibrosis in rat by increasing miR-375-3p to suppress JAK2/STAT3 pathway and TGF-β1/Smad signaling.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-12-19 , DOI: 10.1038/s41401-018-0194-4
Yan-Zi Yang 1 , Xiao-Juan Zhao 1 , Hong-Jiang Xu 2 , Shan-Chun Wang 2 , Ying Pan 1 , Shui-Juan Wang 1 , Qiang Xu 1 , Rui-Qing Jiao 1 , Hong-Mei Gu 2 , Ling-Dong Kong 1
Affiliation  

Increasing evidence has demonstrated that excessive fructose intake induces liver fibrosis. Epithelial-mesenchymal transition (EMT) driven by transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (Smad) signaling activation promotes the occurrence and development of liver fibrosis. Magnesium isoglycyrrhizinate is clinically used as a hepatoprotective agent to treat liver fibrosis, but its underlying molecular mechanism has not been identified. Using a rat model, we found that high fructose intake reduced microRNA (miR)-375-3p expression and activated the janus-activating kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) cascade and TGF-β1/Smad signaling, which is consistent with the EMT and liver fibrosis. To further verify these observations, BRL-3A cells and/or primary rat hepatocytes were exposed to high fructose and/or transfected with a miR-375-3p mimic or inhibitor or treated with a JAK2 inhibitor, and we found that the low expression of miR-375-3p could induce the JAK2/STAT3 pathway to activate TGF-β1/Smad signaling and promote the EMT. Magnesium isoglycyrrhizinate was found to ameliorate high fructose-induced EMT and liver fibrosis in rats. More importantly, magnesium isoglycyrrhizinate increased miR-375-3p expression to suppress the JAK2/STAT3 pathway and TGF-β1/Smad signaling in these animal and cell models. This study provides evidence showing that magnesium isoglycyrrhizinate attenuates liver fibrosis associated with a high fructose diet.

中文翻译:

异甘草酸镁通过增加 miR-375-3p 抑制 JAK2/STAT3 通路和 TGF-β1/Smad 信号传导,改善大鼠高果糖诱导的肝纤维化。

越来越多的证据表明,过多的果糖摄入会导致肝纤维化。由转化生长因子-β1(TGF-β1)/母体对抗十五位麻痹同系物(Smad)信号激活驱动的上皮-间质转化(EMT)促进肝纤维化的发生和发展。异甘草酸镁在临床上被用作治疗肝纤维化的保肝剂,但其潜在的分子机制尚未确定。使用大鼠模型,我们发现高果糖摄入量降低了 microRNA (miR)-375-3p 表达并激活了 janus 激活激酶 2 (JAK2)/信号转导和转录激活因子 3 (STAT3) 级联和 TGF-β1/Smad信号,这与 EMT 和肝纤维化一致。为了进一步验证这些观察结果,BRL-3A 细胞和/或原代大鼠肝细胞暴露于高果糖和/或转染 miR-375-3p 模拟物或抑制剂或用 JAK2 抑制剂处理,我们发现 miR-375-3p 的低表达可以诱导 JAK2/STAT3 通路激活 TGF-β1/Smad 信号并促进 EMT。发现异甘草酸镁可改善大鼠高果糖诱导的 EMT 和肝纤维化。更重要的是,异甘草酸镁增加了 miR-375-3p 的表达,以抑制这些动物和细胞模型中的 JAK2/STAT3 通路和 TGF-β1/Smad 信号传导。该研究提供的证据表明,异甘草酸镁可减轻与高果糖饮食相关的肝纤维化。我们发现miR-375-3p的低表达可以诱导JAK2/STAT3通路激活TGF-β1/Smad信号并促进EMT。发现异甘草酸镁可改善大鼠高果糖诱导的 EMT 和肝纤维化。更重要的是,异甘草酸镁增加了 miR-375-3p 的表达,以抑制这些动物和细胞模型中的 JAK2/STAT3 通路和 TGF-β1/Smad 信号传导。该研究提供的证据表明,异甘草酸镁可减轻与高果糖饮食相关的肝纤维化。我们发现miR-375-3p的低表达可以诱导JAK2/STAT3通路激活TGF-β1/Smad信号并促进EMT。发现异甘草酸镁可改善大鼠高果糖诱导的 EMT 和肝纤维化。更重要的是,异甘草酸镁增加了 miR-375-3p 的表达,以抑制这些动物和细胞模型中的 JAK2/STAT3 通路和 TGF-β1/Smad 信号传导。该研究提供的证据表明,异甘草酸镁可减轻与高果糖饮食相关的肝纤维化。在这些动物和细胞模型中,异甘草酸镁增加 miR-375-3p 表达以抑制 JAK2/STAT3 通路和 TGF-β1/Smad 信号传导。该研究提供的证据表明,异甘草酸镁可减轻与高果糖饮食相关的肝纤维化。在这些动物和细胞模型中,异甘草酸镁增加 miR-375-3p 表达以抑制 JAK2/STAT3 通路和 TGF-β1/Smad 信号传导。该研究提供的证据表明,异甘草酸镁可减轻与高果糖饮食相关的肝纤维化。
更新日期:2019-05-16
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