大豆异黄酮调节Nrf2/HO-1信号通路对多囊卵巢综合征大鼠卵巢组织损伤的影响  

Impact of Soy Isoflavones on Ovarian Tissue Damage in Rats with Polycystic Ovary Syndrome by Regulating Nrf2/HO-1 Signaling Pathway

作　　者：赵洪强 时敬爱 王金权 成海红 常珍珍 ZHAO Hong-qiang;SHI Jing-ai;WANG Jin-quan;CHENG Hai-hong;CHANG Zhen-zhen(School of Medicine,Shandong Modern University,Jinan 250104,China;Department of TCM Gynecology,Jinzhong Hospital of Traditional Chinese Medicine,Jinzhong 030600,China;Reproductive Center,Shanxi Bethune Hospital,Taiyuan 030032,China)

机构地区：[1]山东现代学院医学院,济南250104 [2]山西晋中市中医院中医妇科,山西晋中030600 [3]山西白求恩医院生殖中心,太原030032

出　　处：《中国药学杂志》2023年第8期699-707,共9页Chinese Pharmaceutical Journal

基　　金：国家中医药管理局项目资助(LP0104007)。

摘　　要：目的 基于核因子E2相关因子2(nuclear factor-E2-related factor 2, Nrf2)/血红素加氧酶1(heme oxygenase 1, HO-1)通路探究大豆异黄酮(soy isoflavones, SIF)对多囊卵巢综合征(polycystic ovary syndrome, PCOS)大鼠卵巢组织损伤的保护作用。方法 雌性SD大鼠采用来曲唑(1 mg·kg^(-1))诱导建立PCOS模型,实验分为对照组、PCOS组、低剂量SIF组(L-SIF组50 mg·kg^(-1))、高剂量SIF组(H-SIF组100 mg·kg^(-1))和SIF+ML385组(SIF 100 mg·kg^(-1)+Nrf2抑制剂ML385 30 mg·kg^(-1)),每组12只。各组给予相应的药物进行干预,每日1次,连续干预4周。检测各组大鼠体重、空腹血糖(fasting blood glucose, FBG)、空腹胰岛素(fasting insulin, FINS)水平,计算胰岛素抵抗指数(homeostasis model assessment for insulin resistance, HOMA-IR);检测血清睾酮(testosterone, T)、雌二醇(estradiol, E2)、促卵泡激素(follicle stimulating hormone, FSH)和促黄体激素(luteinizing hormone, LH)水平以及卵巢组织谷胱甘肽过氧化物酶(glutathione peroxidase, GPx)、超氧化物歧化酶(superoxide dismutase, SOD)和过氧化氢酶(catalase, CAT)活性,计算LH/FSH比值;HE染色观察卵巢组织病理学改变,并计数囊性卵泡和黄体的数量;TUNEL染色观察卵巢组织细胞凋亡,计算凋亡指数(AI);Western blot检测卵巢组织Nrf2、HO-1蛋白表达。结果 与PCOS组相比,L-SIF组和H-SIF组体重、FBG、FINS水平和HOMA-IR、T、LH水平以及LH/FSH比值、囊性卵泡数量、AI降低,E2水平、卵巢组织GPx、SOD、CAT活性和黄体数量以及Nrf2、HO-1蛋白水平升高,且H-SIF组优于L-SIF组;ML385可抑制Nrf2/HO-1通路的激活,明显减弱SIF对PCOS大鼠卵巢组织损伤的保护作用。结论 SIF可能通过激活Nrf2/HO-1通路,抑制氧化应激,减轻PCOS大鼠卵巢组织损伤。OBJECTIVE To explore the protection of soy isoflavones(SIF)on ovarian tissue damage in polycystic ovary syndrome(PCOS)rats based on the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway.METHODS Female SD rats were treated with letrozole(1 mg·kg^(-1))to establish PCOS model,and the experiment rats were divided into control group,PCOS group,low-concentration SIF group(L-SIF group,50 mg·kg^(-1)),and high-concentration SIF group(H-SIF group,100 mg·kg^(-1))and SIF+ML385 group(SIF 100 mg·kg^(-1)+Nrf2 inhibitor ML38530 mg·kg^(-1)),12 rats per group.Each group was given corresponding drugs for intervention,once a day,for 4 weeks in total.The body weight,fasting blood glucose(FBG)and fasting insulin(FINS)levels of the rats were measured,and the insulin resistance index(HOMA-IR)was calculated;the serum testosterone(T),estradiol(E2),follicle-stimulating hormone(FSH)and luteinizing hormone(LH)levels,ovarian tissue glutathione peroxidase(GPx),superoxide dismutase(SOD)and catalase(CAT)activity were measured to calculate the LH/FSH ratio;the pathological changes of ovarian tissue were observed by HE staining,and the number of cystic follicles and corpus luteum was counted;the apoptosis of ovarian tissue cells was observed by TUNEL staining,and the apoptosis index(AI)was calculated;the expression of Nrf2 and HO-1 proteins in ovarian tissue was measured by Western blot.RESULTS Compared with the PCOS group,the body weight,levels of FBG,FINS,HOMA-IR,T,LH,LH/FSH ratio,the number of cystic follicles,and AI in the L-SIF and H-SIF groups were decreased,the level of E2,ovarian tissue GPx,SOD,CAT activities,corpus luteum number,and the protein levels of Nrf2 and HO-1 were increased,and the H-SIF group was better than the L-SIF group;ML385 was able to inhibit the activation of Nrf2/HO-1 pathway and obviously attenuate the protective effect of SIF on ovarian tissue damage in PCOS rats.CONCLUSION SIF may inhibit oxidative stress and reduce ovarian tissue damage in PCOS rats by activating the Nrf2/HO-1 pathway.

关 键 词：多囊卵巢综合征 大豆异黄酮 氧化应激 核因子E2相关因子2 血红素加氧酶1 

分 类 号：R966[医药卫生—药理学]