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孙银辉,何晓,李涵宇,窦娴,陈晟,彭慧婷,杨晓,刘华,李菁,王理槐.扶正口服液对诱导性癌症恶病质裸鼠骨骼肌中ERAD/ERSIA通路的影响[J].湖南中医药大学学报英文版,2022,42(11):1816-1822.[Click to copy
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| 扶正口服液对诱导性癌症恶病质裸鼠骨骼肌中ERAD/ERSIA通路的影响 |
| 孙银辉,何晓,李涵宇,窦娴,陈晟,彭慧婷,杨晓,刘华,李菁,王理槐 |
| (湖南中医药大学, 湖南 长沙 410208;湖南中医药大学第一附属医院, 湖南 长沙 410007) |
| 摘要: |
| 目的 探究扶正口服液对癌症恶病质（cancer cachexia, CC）裸鼠骨骼肌内质网应激相关性降解（ER-associated degradation, ERAD）/内质网应激性凋亡（endoplasmic reticulum stress induced apoptosis, ERSIA）信号通路的影响。方法 选取36只6～7周龄BALB/c-nu SPF级裸鼠建立脾虚证模型，随机抽取12只均分成A组（正常裸鼠生理盐水灌胃56 d）、B组（正常裸鼠扶正口服液灌胃56 d）；剩余24只进行CC造模，分为C组（CC后生理盐水灌胃14 d）、D组（CC后扶正口服液灌胃14 d）、E组（CC后生理盐水灌胃28 d）、F组（CC后扶正口服液灌胃28 d）。比较各组裸鼠的体质量、摄食量、肿瘤体积、骨骼肌病理变化。通过Western blot、RT-PCR检测扶正口服液对不同CC阶段裸鼠骨骼肌中ERSIA通路中CCAAT增强子结合蛋白同源蛋白（CCAAT/enhancer-binding protein-homologous protein, CHOP）、c-Jun氨基末端激酶（c-Jun N-terminal kinase, JNK）表达水平；ERAD通路中X盒结合蛋白1（X-box binding protein-1, XBP1）、内质网跨膜蛋白激酶1（inositol requiring enzyme-1, IRE1）、内质网相关降解蛋白1（Derlin-1）、滑膜细胞凋亡抑制物1（synovial apoptosis inhibitor-1, SYVN1）表达水平。结果 与A、B组比较，C、D、E、F组摄食量均下降（P＜0.05）；与C组比较，D组摄食量增加，E、F组摄食量下降（P＜0.05）；与D组比较，E、F组摄食量下降（P＜0.05）；与E组比较，F组摄食量增加（P＜0.05）。与A、B组比较，第6周C、D组体质量下降（P＜0.05），第8周E、F组体质量下降（P＜0.05）；与C组比较，第6周D组体质量增加（P＜0.05）；与E组比较，第8周F组体质量增加（P＜0.05）。与C组比较，D组肿瘤体积减小（P＜0.05），E组肿瘤体积增大（P＜0.05）；与E组比较，F组肿瘤体积减小（P＜0.05）。与A、B组比较，C、E组裸鼠肌肉组织萎缩，其间隙增大，而D、F组间隙明显缩小，组织萎缩缓解。与A组比较，B组CHOP mRNA，CHOP、p-JNK蛋白表达下降（P＜0.05）；与B组比较，C组CHOP mRNA，CHOP、p-JNK蛋白表达升高（P＜0.05）；与C组比较，D组CHOP mRNA，CHOP、p-JNK蛋白表达下降（P＜0.05）；与E组比较，F组CHOP mRNA，CHOP、p-JNK蛋白表达下降（P＜0.05）。与A组比较，B组XBP1、IRE1、Derlin-1、SYVN1蛋白及mRNA表达升高（P＜0.05）；与B组比较，C组XBP1、Derlin-1、SYVN1蛋白及mRNA表达下降（P＜0.05），IRE1 mRNA及蛋白表达升高（P＜0.05）;与C组比较，D组XBP1、Derlin-1、SYVN1 mRNA及蛋白表达升高（P＜0.05），IRE1 mRNA及蛋白表达下降（P＜0.05）；与E组比较，F组XBP1、IRE1、Derlin-1、SYVN1蛋白及mRNA表达升高（P＜0.05）。结论 扶正口服液可通过上调骨骼肌中ERAD相关蛋白表达，抑制ERSIA凋亡蛋白表达，以逆转ERAD-ERSIA信号稳态失衡。其改善CC的机制可能与提高肌细胞对ERS的耐受能力并保护肌细胞免于凋亡有关。 |
| 关键词: 癌症恶病质 扶正口服液 ERAD/ERSIA通路 裸鼠 骨骼肌 |
| DOI：10.3969/j.issn.1674-070X.2022.11.008 |
| Received:September 01, 2022 |
| 基金项目:湖南省中医肿瘤临床研究中心平台项目（2021SK4023）；湖南省自然科学基金项目（2021JJ30525）；湖南省教育厅优秀青年项目（19B419）；湖南省中医药科研计划项目（2021214）；湖南省卫生健康委员会科研计划项目（C2019092）。 |
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| Effects of Fuzheng Oral Liquid on ERAD/ERSIA pathway in skeletal muscle of induced cancer cachexia nude mice |
| SUN Yinhui,HE Xiao,LI Hanyu,DOU Xian,CHNE Sheng,PENG Huiting,YANG Xiao,LIU Hua,LI Jing,WANG Lihuai |
| (Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China) |
| Abstract: |
| Objective To investigate the effects of Fuzheng Oral Liquid on ER-associated degradation (ERAD)/endoplasmic reticulum stress induced apoptosis (ERSIA) signaling pathway in skeletal muscle of nude mice with cancer cachexia (CC). Methods A total of 36 BALB/c-nu SPF nude mice aged 6-7 weeks were selected to establish spleen deficiency syndrome model and 12 nude mice were randomly divided into group A (normal nude mice were administered with normal saline by gavage for 56 d), group B (normal nude mice were given Fuzheng Oral Liquid for 56 d); the remaining 24 were used for CC modeling, which were equally divided into group C (mice were administered with normal saline by gavage for 14 d after CC), group D (mice were treated with Fuzheng Oral Liquid for 14 d after CC), and group E (mice were treated with normal saline bu gavage for 28 d after CC), group F (mice were treated with Fuzheng Oral Liquid for 28 d after CC). The body weight, food intake, tumor volume and pathological changes of skeletal muscle for each group were compared. Western blot and RT-PCR were used to detect the expression levels of CCAAT/enhancer-binding protein-homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) in ERSIA pathway, and the expression levels of X-box binding protein-1 (XBP1), inositol requiring enzyme-1 (IRE1), Derlin-1, synovial apoptosis inhibitor-1 (SYVN1) in ERAD pathway in skeletal muscle of nude mice at different stages of CC. Results Compared with groups A and B, the food intake of nude mice in groups C, D, E and F decreased (P＜0.05); compared with group C, the food intake of group D increased, and the food intake of groups E and F decreased (P＜0.05); compared with group D, the food intake of groups E and F decreased (P＜0.05); compared with group E, the food intake of group F increased (P＜0.05). Compared with groups A and B, the body weight of groups C and D decreased at 6th week (P＜0.05), the body weight of groups E and F decreased at 8th week (P＜0.05); compared with group C, the body weight of group D increased at 6th week (P＜0.05); compared with group E, the body weight in group F increased at 8th week (P＜0.05). Compared with group C, the tumor volume in group D decreased (P＜0.05), and the tumor volume in group E significantly increased (P＜0.05); compared with group E, the tumor volume in group F decreased (P＜0.05). Compared with groups A and B, the muscle tissue of nude mice in groups C and E was atrophic and the gap increased, while the gap was significantly reduced and the tissue atrophy was alleviated in groups D and F. Compared with group A, the expression levels of CHOP mRNA, CHOP and p-JNK protein in group B decreased (P＜0.05); compared with group B, CHOP mRNA, CHOP and p-JNK protein of group C significantly increased (P＜0.05); compared with group C, the expression levels of CHOP mRNA, CHOP and p-JNK protein of group D decreased (P＜0.05); compared with group E, the expression levels of CHOP mRNA, CHOP and p-JNK protein in group F decreased (P＜0.05). Compared with group A, the protein and mRNA expression levels of XBP1, IRE1, Derlin-1, SYVN1 in group B increased (P＜0.05); compared with group B, the protein and mRNA expression levels of XBP1, Derlin-1 and SYVN1 in group C decreased (P＜0.05), while the mRNA and protein expression of IRE1 increased (P＜0.05); compared with group C, the mRNA and protein expression levels of XBP1, Derlin-1 and SYVN1 in group D increased (P＜0.05), while the mRNA and protein expression of IRE1 decreased (P＜0.05); compared with group E, the protein and mRNA expression levels of XBP1, IRE1, Derlin-1 and SYVN1 of group F significantly increased (P＜0.05). Conclusion Fuzheng Oral Liquid could reverse the homeostasis imbalance of ERAD-ERSIA signaling by up-regulating the expression of ERAD-related proteins in skeletal muscle and inhibiting the expression of ERSIA apoptotic proteins. The mechanism of improving CC may be related to improving the tolerance of myocytes to ERS and protecting myocytes from apoptosis. |
| Key words: cancer cachexia Fuzheng Oral Liquid ERAD/ERSIA pathways nude mice skeletal muscle |
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