Tubastatin A通过磷脂酰肌醇-3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR）信号通路抑制硬膜外纤维化中成纤维细胞的增殖,Journal of Pharmacy and Pharmacology

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Tubastatin A通过磷脂酰肌醇-3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR）信号通路抑制硬膜外纤维化中成纤维细胞的增殖
Journal of Pharmacy and Pharmacology ( IF 2.8 ) Pub Date : 2022-02-21 , DOI: 10.1093/jpp/rgab106
Yang Liu ₁ , Ruihong Wang ₁ , Huimin Han ₁ , Li Li ₁

Affiliation

目的本研究旨在探讨 tubastatin A (Tub A) 对硬膜外纤维化的影响及其潜在机制。方法构建组蛋白去乙酰化酶6（HDAC6）过表达的成纤维细胞，采用Cell Counting Kit-8、5-乙炔基-2'-脱氧尿苷（EdU）和细胞周期测定法检测Tub A对活化成纤维细胞增殖的影响。此外，对 20 只 Sprague-Dawley 大鼠进行动物椎板切除术模型构建，然后分别用 4% 二甲基亚砜 (DMSO)（用 0.9% 盐水稀释）或 Tub A（10 mg/kg/天）随机处理。测量硬膜外纤维化组织中 HDAC6 和磷脂酰肌醇-3-激酶/蛋白激酶 B/哺乳动物雷帕霉素靶蛋白 (PI3K/AKT/mTOR) 通路相关蛋白的表达。主要发现 HDAC6 在大鼠模型的活化成纤维细胞和硬膜外瘢痕组织中过度表达。在 HDAC6 过表达的成纤维细胞中，细胞增殖显着升高，这反映在细胞活力、EdU 和基于流式细胞术的细胞周期测定中，并且与磷酸化 PI3K、AKT 和 mTOR 的表达增加平行，这在 Tub A 处理后显着逆转. 添加 740Y-P 激活剂显着逆转了 Tub A 诱导的成纤维细胞增殖下降。在 Tub A 处理的大鼠模型中，PI3K/AKT/mTOR 通路相关蛋白的表达也在硬膜外组织中降低。结论 Tub A可通过介导PI3K/AKT/mTOR通路抑制成纤维细胞增殖来预防硬膜外纤维化形成。在 HDAC6 过表达的成纤维细胞中，细胞增殖显着升高，这反映在细胞活力、EdU 和基于流式细胞术的细胞周期测定中，并且与磷酸化 PI3K、AKT 和 mTOR 的表达增加平行，这在 Tub A 处理后显着逆转. 添加 740Y-P 激活剂显着逆转了 Tub A 诱导的成纤维细胞增殖下降。在 Tub A 处理的大鼠模型中，PI3K/AKT/mTOR 通路相关蛋白的表达也在硬膜外组织中降低。结论 Tub A可通过介导PI3K/AKT/mTOR通路抑制成纤维细胞增殖来预防硬膜外纤维化形成。在 HDAC6 过表达的成纤维细胞中，细胞增殖显着升高，这反映在细胞活力、EdU 和基于流式细胞术的细胞周期测定中，并且与磷酸化 PI3K、AKT 和 mTOR 的表达增加平行，这在 Tub A 处理后显着逆转. 添加 740Y-P 激活剂显着逆转了 Tub A 诱导的成纤维细胞增殖下降。在 Tub A 处理的大鼠模型中，PI3K/AKT/mTOR 通路相关蛋白的表达也在硬膜外组织中降低。结论 Tub A可通过介导PI3K/AKT/mTOR通路抑制成纤维细胞增殖来预防硬膜外纤维化形成。AKT 和 mTOR，在 Tub A 治疗后显着逆转。添加 740Y-P 激活剂显着逆转了 Tub A 诱导的成纤维细胞增殖下降。在 Tub A 处理的大鼠模型中，PI3K/AKT/mTOR 通路相关蛋白的表达也在硬膜外组织中降低。结论 Tub A可通过介导PI3K/AKT/mTOR通路抑制成纤维细胞增殖来预防硬膜外纤维化形成。AKT 和 mTOR，在 Tub A 治疗后显着逆转。添加 740Y-P 激活剂显着逆转了 Tub A 诱导的成纤维细胞增殖下降。在 Tub A 处理的大鼠模型中，PI3K/AKT/mTOR 通路相关蛋白的表达也在硬膜外组织中降低。结论 Tub A可通过介导PI3K/AKT/mTOR通路抑制成纤维细胞增殖来预防硬膜外纤维化形成。

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Tubastatin A suppresses the proliferation of fibroblasts in epidural fibrosis through phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway

Objectives This study was designed to explore the effect of tubastatin A (Tub A) on epidural fibrosis and the underlying mechanism. Methods Histone deacetylase 6 (HDAC6)-overexpressed fibroblasts were constructed, and the effect of Tub A on the proliferation of activated fibroblasts was detected by Cell Counting Kit-8, 5-ethynyl-2′-deoxyuridine (EdU) and cell cycle assay. Besides, 20 Sprague–Dawley rats were subjected to animal laminectomy model construction and then randomly treated with 4% dimethyl sulfoxide (DMSO) (diluted in 0.9% saline) or Tub A (10 mg/kg/day), separately. The expression of HDAC6 and phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway-related proteins was measured in epidural fibrosis tissues. Key findings HDAC6 was overexpressed in activated fibroblasts and epidural scar tissues of rat models. Cell proliferation was remarkably elevated in HDAC6-overexpressed fibroblasts, which was reflected by cell viability, EdU and flow cytometry-based cell cycle assay, and paralleled with the increased expression of phosphorylated PI3K, AKT and mTOR, which was remarkably reversed following Tub A treatment. 740Y-P activator addition significantly reversed the declined fibroblast proliferation induced by Tub A. The expressions of PI3K/AKT/mTOR pathway-related proteins were also reduced in epidural tissues in rat models with Tub A treatment. Conclusion Tub A could prevent epidural fibrosis formation by inhibiting fibroblast proliferation through mediating PI3K/AKT/mTOR pathway.

更新日期：2022-02-21

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