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李潇,姚伟洁,杨鑫伟,史浩田,高变娥,朱笳悦,许利平.糖络宁对糖尿病周围神经病变大鼠坐骨神经功能及内质网应激IRE1α-XBP-1-CHOP通路的影响[J].湖南中医药大学学报英文版,2019,39(7):841-847.[Click to copy
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| 糖络宁对糖尿病周围神经病变大鼠坐骨神经功能及内质网应激IRE1α-XBP-1-CHOP通路的影响 |
| 李潇,姚伟洁,杨鑫伟,史浩田,高变娥,朱笳悦,许利平 |
| (首都医科大学中医药学院, 北京 100069;中医络病研究北京市重点实验室, 北京 100069) |
| 摘要: |
| 目的 探讨糖络宁对糖尿病周围神经病变（diabetic peripheral neuropathy，DPN）大鼠内质网应激（endoplasmic reticulum stress，ER stress）IRE1α-XBP-1-CHOP通路的影响。方法 建立DPN大鼠模型，设置空白对照组（Control）、模型对照组（Model）、氧化三甲胺组（TMAO）、糖络宁低剂量组（LTLN）和糖络宁高剂量组（HTLN），分别灌胃给药12周。采用放射免疫试剂盒测定稳态胰岛素抵抗指数；采用透射电镜和劳克坚劳蓝染色观察坐骨神经结构；测定鼠尾热痛阈值、神经传导速度和蛋白基因产物9.5（protein gene product 9.5，PGP 9.5）蛋白的表达并检测周围神经功能；采用Western blot法检测葡萄糖调节蛋白78（glucose-regulated protein 78，GRP 78）、X盒结合蛋白1（X-box binding protein1，XBP-1）、凋亡蛋白C/EBP同源蛋白（CCAAT/enhancer binding protein Homologous protein，CHOP）、B细胞淋巴瘤-2（B cell lymphoma-2，Bcl-2）、Bcl-2相关X蛋白（Bcl-2 associated X protein，Bax）和磷酸化真核翻译起始因子2α（phospho-ukaryotic translation initiation factor 2α，P-eIF 2α）的蛋白表达；通过免疫荧光组织化学法检测肌醇激酶1（inositol requiring enzyme1α，IRE 1α）、生长停滞及DNA损伤基因34（growth-arrest and DNA damage-inducible gene 34，GADD 34）和内质网氧化蛋白（endoplasmic oxidoreductin-1-like，Ero1α）指标。结果 与模型组比，糖络宁高、低剂量组能够有效改善坐骨神经的结构和功能，并能够影响内质网应激IRE1α-XBP-1-CHOP凋亡通路提高GRP 78、Bcl-2和P-eIF 2α的表达（P<0.05），降低P-IRE1α、XBP-1、CHOPGADD 34、Bax和Ero1α的表达（P<0.05）。结论 糖络宁能够通过抑制ER stress中IRE1α-XBP-1-CHOP凋亡途径相关蛋白的表达，从而减轻ER stress诱导的细胞凋亡，改善坐骨神经的结构和功能从而防治DPN。 |
| 关键词: 糖络宁 糖尿病周围神经病变 内质网应激 X盒结合蛋白1 凋亡蛋白C/EBP同源蛋白 |
| DOI：10.3969/j.issn.1674-070X.2019.07.011 |
| Received:April 25, 2018 |
| 基金项目:国家自然基金面上项目（81473642，81873125）；国家自然基金青年科学基金（81704014）；北京市优秀人才项目（2017000020124G291）。 |
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| Effects of Tangluoning on IRE1α-XBP-1-CHOP Pathway Under Endoplasmic Reticulum Stress in Diabetic Peripheral Neuropathy Rats |
| LI Xiao,YAO Weijie,YANG Xinwei,SHI Haotian,GAO Bian'e,ZHU Jiayue,XU Liping |
| (School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China;Beijing Key Lab of TCM Collateral Diseases, Beijing 100069, China) |
| Abstract: |
| Objective To explore the effects of Tangluoning (TLN) on the IRE1α-XBP-1-CHOP pathway under endoplasmic reticulum (ER) stress in diabetic peripheral neuropathy (DPN) rats. Methods DPN rat model was established, with Control group, Model group, Trimethylamine oxide (TMAO) group, Low-dose Tangluoning (LTLN) group and High-dose Tangluoning (HTLN) group, and they were treated with intragastric administration for 12 weeks. Homeostasis model of assessment for insulin resistance index(HOMA-IR)was determined by a radioimmune outfit. The sciatic nerve structure was observed by transmission electron microscope (TEM) and luxol fast blue (LFB). Thermal perception threshold (TPT) of the rat tail, motor nerve conduction velocity (MNCV) and sensor nerve conduction velocity (SNCV), and the expression of protein gene product 9.5 (PGP 9.5) were measured. And the peripheral neurological function was determined. Western blot analysis was used to assess the expressions of glucose-regulated protein 78 (GRP 78), X-box binding protein 1 (XBP-1), CCAAT/enhancer binding protein Homologous protein (CHOP), B cell lymphoma-2 (Bcl-2), Bcl-2 Associated X Protein (Bax) and phospho-ukaryotic translation initiation factor 2α (P-eIF2α). Immunohistochemistry was used to detect the expressions of inositol requiring enzyme 1 (IRE1α), growth-arrest and DNA damage-inducible gene 34 (GADD34) and endoplasmic oxidoreductin-1-like (Ero1α). Results Compared with the Model group, TLN could significantly improve the morphological structure and neurological function of the sciatic nerve. TLN had an impact on the IRE1α-XBP-1-CHOP pathway under ER stress by enhancing the expressions of GRP78, Bcl-2 and P-eIF 2α (P<0.01), and reducing the expressions of P-IRE 1α, XBP-1, CHOP, GADD 34, Bax and Ero1α (P<0.01). Conclusion TLN can inhibit the expressions of correlative proteins in the IRE1α-XBP-1-CHOP pathway under ER stress to alleviate the cell apoptosis induced by ER stress, and improve the structure and function of the sciatic nerve, in order to prevent the DPN. |
| Key words: Tangluoning diabetic peripheral neuropathy endoplasmic reticulum stress XBP-1 CHOP |
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