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PI3-kinase/Akt 通路调控酸性敏感离子通道 1a/钙离子内流/内质网应激激活在血小板衍生生长因子诱导的肝星状细胞激活中的膜转运。

PI3-kinase/Akt pathway-regulated membrane transportation of acid-sensing ion channel 1a/Calcium ion influx/endoplasmic reticulum stress activation on PDGF-induced HSC Activation.

机构信息

Department of Pharmacy, Hospital of Armed Police of Anhui Province, Hefei, China.

School of Pharmacy, Anhui Medical University, Hefei, China.

出版信息

J Cell Mol Med. 2019 Jun;23(6):3940-3950. doi: 10.1111/jcmm.14275. Epub 2019 Apr 2.

Abstract

Acid-sensing ion channel 1a (ASIC1a) allows Na and Ca flow into cells. It is expressed during inflammation, in tumour and ischaemic tissue, in the central nervous system and non-neuronal injury environments. Endoplasmic reticulum stress (ERS) is caused by the accumulation of misfolded proteins that interferes with intracellular calcium homoeostasis. Our recent reports showed ASIC1a and ERS are involved in liver fibrosis progression, particularly in hepatic stellate cell (HSC) activation. In this study, we investigated the roles of ASIC1a and ERS in activated HSC. We found that ASIC1a and ERS-related proteins were up-regulated in carbon tetrachloride (CCl )-induced fibrotic mouse liver tissues, and in patient liver tissues with hepatocellular carcinoma with severe liver fibrosis. The results show silencing ASIC1a reduced the expression of ERS-related biomarkers GRP78, Caspase12 and IREI-XBP1. And, ERS inhibition by 4-PBA down-regulated the high expression of ASIC1a induced by PDGF, suggesting an interactive relationship. In PDGF-induced HSCs, ASIC1a was activated and migrated to the cell membrane, leading to extracellular calcium influx and ERS, which was mediated by PI3K/AKT pathway. Our work shows PDGF-activated ASIC1a via the PI3K/AKT pathway, induced ERS and promoted liver fibrosis progression.

摘要

酸感应离子通道 1a(ASIC1a)允许 Na 和 Ca 流入细胞。它在炎症、肿瘤和缺血组织、中枢神经系统和非神经元损伤环境中表达。内质网应激(ERS)是由错误折叠的蛋白质积累引起的,这些蛋白质会干扰细胞内钙稳态。我们最近的报告表明,ASIC1a 和 ERS 参与肝纤维化的进展,特别是在肝星状细胞(HSC)激活中。在这项研究中,我们研究了 ASIC1a 和 ERS 在激活的 HSC 中的作用。我们发现,在四氯化碳(CCl )诱导的纤维化小鼠肝组织和伴有严重肝纤维化的肝细胞癌患者肝组织中,ASIC1a 和 ERS 相关蛋白上调。结果表明,沉默 ASIC1a 降低了 ERS 相关生物标志物 GRP78、Caspase12 和 IREI-XBP1 的表达。并且,用 4-PBA 抑制 ERS 下调了 PDGF 诱导的 ASIC1a 的高表达,表明存在相互作用关系。在 PDGF 诱导的 HSCs 中,ASIC1a 被激活并迁移到细胞膜,导致细胞外钙内流和 ERS,这是由 PI3K/AKT 途径介导的。我们的工作表明,PDGF 通过 PI3K/AKT 途径激活 ASIC1a,诱导 ERS,并促进肝纤维化的进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d09/6533492/e88d9b8f12b8/JCMM-23-3940-g001.jpg

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