[1]许鑫,杨君,赵金金,等.雷帕霉素对多囊卵巢综合征大鼠子宫内膜的作用及机制[J].新乡医学院学报,2023,40(9):818-823.[doi:10.7683/xxyxyxb.2023.09.003]
　XU Xin,YANG Jun,ZHAO Jinjin,et al.Effect and mechanism of rapamycin on endometrium of rats with polycystic ovary syndrome[J].Journal of Xinxiang Medical University,2023,40(9):818-823.[doi:10.7683/xxyxyxb.2023.09.003]
点击复制

雷帕霉素对多囊卵巢综合征大鼠子宫内膜的作用及机制
分享到：

《新乡医学院学报》[ISSN:1004-7239/CN:41-1186/R]

卷:
40卷
期数:
2023年9
页码:
818-823
栏目:
基础研究
出版日期:
2023-09-05

文章信息/Info

Title:
Effect and mechanism of rapamycin on endometrium of rats with polycystic ovary syndrome
作者:
许鑫1; 杨君1; 2; 赵金金3; 吴霏霏1; 张瑾1; 李柯欣1
（1.新乡医学院第一附属医院妇科，河南　卫辉　453100；2.新乡市妇科恶性肿瘤防治重点实验室，河南　卫辉　453100； 3.新乡医学院第一附属医院生命科学研究中心，河南　卫辉　453100）
Author(s):
XU Xin1; YANG Jun1; 2; ZHAO Jinjin3; WU Feifei1; ZHANG Jin1; LI Kexin1
（1.Department of Gynecology,the First Affiliated Hospital of Xinxiang Medical University,Weihui 453100,Henan Province,China;2.Xinxiang Key Laboratory of Prevention and Treatment of Gynecological Malignant Tumor,Weihui 453100,Henan Province,China;3.Life Science Research Center,the First Affiliated Hospital of Xinxiang Medical University,Weihui 453100,Henan Province,China）
关键词:
多囊卵巢综合征; 子宫; 脱氢表雄酮; 雷帕霉素
Keywords:
polycystic ovary syndrome; uterus; dehydroepiandrosterone; rapamycin
分类号:
R711.75
DOI:
10.7683/xxyxyxb.2023.09.003
文献标志码:
A
摘要:
目的　探讨雷帕霉素对多囊卵巢综合征（PCOS）大鼠子宫内膜的作用及机制。
方法　将30只Sprague Dawley雌性大鼠随机分为对照组、PCOS组、雷帕霉素组，每组10只。PCOS组和雷帕霉素组大鼠经颈背部皮下注射脱氢表雄酮（60 mg·kg-1）构建PCOS模型，每日1次，连续注射28 d；对照组大鼠每日注射等量生理盐水。造模成功后，雷帕霉素组大鼠每日腹腔注射雷帕霉素10 mg·kg-1，PCOS组和对照组大鼠每日腹腔注射等量生理盐水，连续注射28 d。于造模前、造模后和给药28 d后称各组大鼠体质量。给药28 d后，采用苏木精-伊红染色法观察各组大鼠子宫内膜病理学变化，采用Masson染色法检测大鼠子宫内膜纤维化情况，采用免疫组织化学法检测大鼠子宫内膜中哺乳动物雷帕霉素靶蛋白（mTOR）、磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）及磷酸化p70核糖体蛋白S6（p-p70S6）表达，采用末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记测定法检测大鼠子宫内膜细胞凋亡情况。
结果　造模前各组大鼠体质量比较差异无统计学意义（F=0.506，P>0.05）；造模后，PCOS组、雷帕霉素组大鼠的体质量显著高于对照组（P<0.05）；PCOS 组与雷帕霉素组大鼠的体质量比较差异无统计学意义（P>0.05）；给药28 d后，PCOS组大鼠的体质量显著高于对照组和雷帕霉素组，雷帕霉素组大鼠的体质量显著低于对照组（P<0.05）。给药28 d后，对照组大鼠子宫内膜腺体为多个腺体簇状排列，腺腔较大且迂曲较多；PCOS组大鼠子宫内膜腺体数目较对照组减少，为单个腺体分散排列，腺腔小且少有迂曲；雷帕霉素组大鼠子宫内膜腺体数目较多，呈簇状排列，但腺腔多小而直，部分可见到一些皱褶和分支。PCOS组和雷帕霉素组大鼠子宫内膜纤维化面积占比显著高于对照组（P<0.05）；PCOS组与雷帕霉素组大鼠子宫内膜纤维化面积占比比较差异无统计学意义（P>0.05）。PCOS组大鼠子宫内膜组织中mTOR、p-mTOR及p-p70S6的相对表达量显著高于对照组和雷帕霉素组（P<0.05）；雷帕霉素组大鼠子宫内膜组织中p-mTOR的相对表达量显著低于对照组（P<0.05）；对照组与雷帕霉素组大鼠子宫内膜组织中mTOR、p-p70S6 的相对表达量比较差异无统计学意义（P>0.05）。 PCOS组大鼠的子宫内膜细胞凋亡率显著高于对照组和雷帕霉素组（P<0.05）；对照组与雷帕霉素组大鼠的子宫内膜细胞凋亡率比较差异无统计学意义（P>0.05）。
结论　雷帕霉素能抑制PCOS大鼠体质量增加，改善子宫内膜病理形态改变，减少子宫内膜细胞凋亡，其作用机制可能与抑制mTOR信号通路异常激活有关。
Abstract:
Objective　To investigate the effect and mechanism of rapamycin on endometrium of rats with polycystic ovary syndrome (PCOS).
Methods　A total of 30 female Sprague Dawley rats were randomly divided into control group,PCOS group and rapamycin group,with 10 rats in each group.The rats in the PCOS group and rapamycin group were injected subcutaneously with 60 mg·kg-1 dehydroepiandrosterone once a day for 28 days to establish the PCOS model;the rats in the control group were injected with the same amount of normal saline.After the modeling was successful,the rats in the rapamycin group were intraperitoneally injected with 10 mg·kg-1 rapamycin daily,and the rats in the PCOS group and control group were intraperitoneally injected with the same amount of normal saline daily for 28 consecutive days.The body mass of the rats in each group was measured before and after modeling and after 28 days of administration.After 28 days of administration,the pathological change of endometrium of rats in each group was observed by hematoxylin and eosin staining,and the endometrial fibrosis of rats in each group was detected by Masson staining.The expressions of mammalian target of rapamycin (mTOR),phosphory-lated-mammalian target of rapamycin (p-mTOR)and phosphorylated-p70 ribosomal protein S6 (p-p70S6) in endometrium of rats were detected by immunohistochemistry.The apoptosis of endometrial cells of rats was detected by terminal-deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick-end labeling.
Results　There was no significant difference in body mass of rats among the three groups before modeling (F=0.506,P>0.05);after modeling,the body mass of rats in the PCOS group and rapamycin group was significantly higher than that in the control group (P<0.05);there was no significant difference in body mass of rats between PCOS group and rapamycin group (P>0.05);after 28 days of administration,the body mass of rats in the PCOS group was significantly higher than that in the control group and rapamycin group,while the body mass of rats in the rapamycin group was significantly lower than that in the control group (P<0.05).After 28 days of administration,the endometrial glands of rats in the control group were arranged in clusters,with larger and more tortuous glandular cavities;the number of endometrial glands of rats in the PCOS group was less than that in control group,and the single glands were scattered,and the glandular cavity was small and seldom tortuous;the number of endometrial glands of rats in rapamycin group was more,and they were arranged in clusters,but the gland cavities were mostly small and straight,and some folds and branches could be seen.The proportion of area of endometrial fibrosis of rats in the PCOS group and rapamycin group was significantly higher than that in the control group (P<0.05);there was no significant difference in proportion of area of endometrial fibrosis between the PCOS group and rapamycin group (P>0.05).The relative expressions of mTOR,p-MTOR and p-p70S6 in endometrium of rats in the PCOS group were significantly higher than those in the control group and rapamycin group (P<0.05);the relative expression of p-MTOR in endometrium of rats in the rapamycin group was significantly lower than that in the control group (P<0.05)；there was no significant difference in the relative expressions of mTOR and p-p70S6 in endometrium between the control group and the rapamycin group (P>0.05).The apoptosis rate of endometrium cells in the PCOS group was significantly higher than that in the control group and rapamycin group (P<0.05)；there was no significant difference in apoptosis rate of endometrium cells between the control group and the rapamycin group (P>0.05).
Conclusion　Rapamycin can inhibit the increase of body mass and improve the pathological morphological changes of endometrium,reduce apoptosis of endometrium cells in PCOS rats.Its mechanism may be related to the inhibition of abnormal activation of mTOR signaling pathway.

参考文献/References:

［1］　AMJADI F,MEHDIZADEH M,ASHRAFI M,et al.Distinct changes in the proteome profile of endometrial tissues in polycystic ovary syndrome compared with healthy fertile women［J］.Reprod Biomed Online,2018,37(2):184-200.
［2］　WANG F,XIE N,WU Y,et al.Association between circadian rhythm disruption and polycystic ovary syndrome［J］.Fertil Steril,2021,115(3):771-781.
［3］　ROSENFIELD R L,EHRMANN D A.The pathogenesis of polycystic ovary syndrome (PCOS):the hypothesis of PCOS as functional ovarian hyperandrogenism revisited［J］.Endocr Rev,2016,37(5):467-520.
［4］　GOODARZI M O,DUMESIC D A,CHAZENBALK G,et al.Polycystic ovary syndrome:etiology,pathogenesis and diagnosis［J］.Nat Rev Endocrinol,2011,7(4):219-231.
［5］　COONEY L G,DOKRAS A.Beyond fertility:polycystic ovary syndrome and long-term health［J］.Fertil Steril,2018,110(5):794-809.
［6］　EKIZCELI G,INAN S,OKTEM G,et al.Immunohistochemical determination of mTOR pathway molecules in ovaries and uterus in rat estrous cycle stages［J］.Histol Histopathol,2020,35(11):1337-1351.
［7］　PATEL S.Polycystic ovary syndrome (PCOS),an inflammatory,systemic,lifestyle endocrinopathy［J］.J Steroid Biochem Mol Biol,2018，182:27-36.
［8］　杨坤,王子豪,马晓欣.多囊卵巢综合征与子宫内膜病变关系研究进展［J］.中国计划生育和妇产科,2021,13(2):33-36.
YAGN K,WANG Z H,MA X X.Research progress on the relationship between polycystic ovary syndrome and endometrial lesions［J］.Chin J Family Plan Gynecotok,2021,13(2):33-36.
［9］　王立群,周月希,张娟.多囊卵巢综合征大鼠子宫内膜细胞凋亡及VEGF-A的表达［J］.暨南大学学报（自然科学与医学版）,2019,40(2):143-149.
WANG L Q,ZHOU Y X,ZHANG J.Apoptosis of endometrial cells and expression of VEGF-A in rats with polycystic ovary syndrome［J］.J Jinan Univ（Natural Sci Med Edit）,2019,40(2):143-149.
［10］　LIU J,WU D C,QU L H,et al.The role of mTOR in ovarian neoplasms,polycystic ovary syndrome,and ovarian aging［J］.Clin Anat,2018,31(6):891-898.
［11］　YABA A,DEMIR N.The mechanism of mTOR (mammalian target of rapamycin) in a mouse model of polycystic ovary syndrome (PCOS)［J］.J Ovarian Res,2012,5(1):38.
［12］　WANG Y,ZHU L,KUOKKANEN S,et al.Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17β is mediated by a PKC-ERK1/2-mTOR signaling pathway［J］.Proc Natl Acad Sci U S A,2015,112(11):E1382-E1391.
［13］　张萍,王维斌,邵岩飞,等.不同时长脱氢表雄酮诱导多囊卵巢综合征大鼠模型的比较［J］.福建中医药,2020,51(3):37-41.
ZHANG P,WANG W B,SHAO Y F,et al.Comparison of different time dependent dehydroepiandrosterone induced polycystic ovary syndrome in rats［J］.Fujian J Trad Chin Med,2020,51(3):37-41.
［14］　段沁芳.多囊卵巢综合征患者临床内分泌代谢改变对子宫膜病变的影响［J］.世界复合医学,2019,5(1):70-72.
DUAN Q F.Effect of clinical endocrine and metabolic changes on endometrial lesions in patients with polycystic ovary syndrome［J］.World J Compl Med,2019,5(1):70-72.
［15］　YIN D,WANG N,ZHANG S L,et al.Specific siRNA inhibits XIAP expression in human endometrial carcinoma cell apoptosis［J］.Cell Biochem Biophys,2015,71(1):161-165.
［16］　陈秀英,管海云,李斌,等.雷帕霉素对小鼠始基卵泡激活及生长发育的作用研究［J］.中华生殖与避孕杂志,2020,40(1):24-29.
CHEN X Y,GUAN H Y,LI B,et al.Effects of rapamycin on the activation and growth of primordial follicles in mice［J］.Chin J Reprod Contracept,2020,40(1):24-29.
［17］　周咏,许丽,肖月,等.雷帕霉素对肥胖小鼠卵巢功能的影响［J］.南京医科大学学报（自然科学版）,2020,40(9):1245-1251,1262.
ZHOU Y,XU L,XIAO Y,et al.Effects of rapamycin on ovarian function in obese mice［J］.J Nanjing Med Univ (Nat Sci),2020,40(9):1245-1251,1262.

相似文献/References:

[1]王晓慧,彭芝兰.子宫下段妊娠3例[J].新乡医学院学报,2005,22(04):312.
[2]张婷婷,杨　君,王慧玲.血清维生素D和C-反应蛋白水平与多囊卵巢综合征发病的相关性分析[J].新乡医学院学报,2021,38(10):949.[doi:10.7683/xxyxyxb.2021.10.010]
　ZHANG Tingting,YANG Jun,WANG Huiling.Correlation analysis of serum vitamin D and C-reactive protein levels with polycystic ovary syndrome[J].Journal of Xinxiang Medical University,2021,38(9):949.[doi:10.7683/xxyxyxb.2021.10.010]
[3]孙家珍,段予新,潘瑞洋,等.子宫腔灌注人绒毛膜促性腺激素对多囊卵巢综合征患者植入窗期子宫内膜容受性的影响[J].新乡医学院学报,2019,36(7):642.[doi:10.7683/xxyxyxb.2019.07.010]
　SUN Jia-zhen,DUAN Yu-xin,PAN Rui-yang,et al.Effect of intrauterine perfusion of human chorionic gonadotropin on endometrial receptivity in patients with polycystic ovary syndrome during implantation window[J].Journal of Xinxiang Medical University,2019,36(9):642.[doi:10.7683/xxyxyxb.2019.07.010]
[4]张小琼,谢　涛,汪文雁,等.肥胖型多囊卵巢综合征孕妇血清β细胞营养因子和性激素水平与不良妊娠结局的关系[J].新乡医学院学报,2021,38(9):851.[doi:10.7683/xxyxyxb.2021.09.011]
　ZHANG Xiaoqiong,XIE Tao,WANG Wenyan,et al.Relationship between the serum betatrophin and sex hormones levels and adverse pregnancy outcomes in pregnant women with obese polycystic ovary syndrome[J].Journal of Xinxiang Medical University,2021,38(9):851.[doi:10.7683/xxyxyxb.2021.09.011]
[5]李晓凡,张　宁.多囊卵巢综合征与心理应激中西医研究进展[J].新乡医学院学报,2021,38(12):1185.[doi:10.7683/xxyxyxb.2021.12.016]
[6]张颖颖,王慧玲,杨　君.多囊卵巢综合征患者血清磷酸化哺乳动物雷帕霉素靶蛋白表达及临床意义[J].新乡医学院学报,2022,39(1):025.[doi:10.7683/xxyxyxb.2022.01.006]
　ZHANG Yingying,WANG Huiling,YANG Jun.Expression and clinical significance of serum phosphorylated mammal target of rapamycin of patients with polycystic ovary syndrome[J].Journal of Xinxiang Medical University,2022,39(9):025.[doi:10.7683/xxyxyxb.2022.01.006]
[7]周婷婷,谈　勇.维生素D及氧化应激在多囊卵巢综合征中的作用研究进展[J].新乡医学院学报,2019,36(2):198.[doi:10.7683/xxyxyxb.2019.02.025]
[8]冯塬媛,刘　煜,李　沫,等.多囊卵巢综合征患者发病机制及其治疗研究进展[J].新乡医学院学报,2017,34(6):548.[doi:10.7683/xxyxyxb.2017.06.027]
[9]孙畅,潘紫萌,韩鹏光,等.多囊卵巢综合征患者肠道微生物群结构变化及其在代际效应中的作用机制研究进展[J].新乡医学院学报,2023,40(1):084.[doi:10.7683/xxyxyxb.2023.01.015]
　SUN Chang,PAN Zimeng,HAN Pengguang,et al.Research progress on structural changes of intestinal microbiota in patients with polycystic ovary syndrome and its mechanism in intergenerational effect[J].Journal of Xinxiang Medical University,2023,40(9):084.[doi:10.7683/xxyxyxb.2023.01.015]
[10]邢冠琳,王芳,柳胜贤.维生素D缺乏对多囊卵巢综合征患者糖脂代谢及妊娠结局的影响[J].新乡医学院学报,2024,(4):372.[doi:10.7683/xxyxyxb.2024.04.014]
　XING Guanlin,WANG Fang,LIU Shengxian.Effect of vitamin D deficiency on glycolipid metabolism and pregnancy outcome of patients with polycystic ovary syndrome[J].Journal of Xinxiang Medical University,2024,(9):372.[doi:10.7683/xxyxyxb.2024.04.014]

更新日期/Last Update: 2023-09-05