补肾健脾化痰方调控Keap1/Nrf2/HO-1通路对多囊卵巢综合征大鼠性激素水平及胰岛素抵抗的影响

doi:10.3969/j.issn.1006-6233.2026.02.05

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摘要 目的: 探讨补肾健脾化痰方调控环氧氯丙烷相关蛋白1(Keap1)/核因子E2相关因子2(Nrf2)/血红素加氧酶-1(HO-1)通路对多囊卵巢综合征(PCOS)大鼠性激素水平及胰岛素抵抗的影响。方法: 通过来曲唑和高脂饮食构建PCOS大鼠模型,并将其分为模型组、二甲双胍组、补肾健脾化痰方组、补肾健脾化痰方+Nrf2抑制剂组,每组10只,另取10只喂养普通饲料作为正常组。二甲双胍组灌胃剂量为0.3g/kg,补肾健脾化痰方灌胃剂量为16g/kg,补肾健脾化痰方+Nrf2抑制剂组灌胃16g/kg补肾健脾化痰方并腹腔注射Nrf2抑制剂10mg/kg,均1次/d,持续4周。苏木精伊红(HE)染色检测动情周期和卵巢组织病变;血糖仪检测血清空腹血糖(FBG)水平,酶联免疫吸附测定(ELISA)法检测血清空腹胰岛素(FINS)、性激素[睾酮(T)、雌二醇(E2)、促黄体生成素(LH)、促卵泡素(FSH)]、血脂指标[甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)]、炎性因子[肿瘤坏死因子α(TNF-α)、白细胞介素18(IL-18)]以及卵巢组织中氧化应激指标[总超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、丙二醛(MDA)]变化,并计算胰岛素抵抗指数(HOMA-IR);实时定量聚合酶链反应(qRT-PCR)检测卵巢组织Keap1、Nrf2、HO-1 mRNA水平;Western blot检测卵巢组织Keap1、Nrf2、HO-1蛋白表达水平。结果: 与正常组相比,模型组大鼠动情周期紊乱,卵泡可见囊性扩增,T、LH、LH/FSH、TG、TC、LDL-C、FINS、FBG、HOMA-IR、TNF-α、IL-18、MDA水平、keap1 mRNA及其蛋白表达水平均升高,E2、HDL-C、SOD、GSH-Px水平、Nrf2、HO-1 mRNA及其蛋白表达水平均降低(P<0.05);与模型组相比,补肾健脾化痰方组大鼠卵泡囊性扩增减少,T、LH、LH/FSH、TG、TC、LDL-C、FINS、FBG、HOMA-IR、TNF-α、IL-18、MDA水平、keap1 mRNA及其蛋白表达水平均降低,E2、HDL-C、SOD、GSH-Px水平、Nrf2、HO-1 mRNA及其蛋白表达水平均升高(P<0.05);补肾健脾化痰方+Nrf2抑制剂组大鼠卵泡囊性扩增增多,血清和卵巢中各指标变化与补肾健脾化痰方组相反(P<0.05)。结论: 补肾健脾化痰方可能通过调控Keap1/Nrf2/HO-1通路缓解PCOS大鼠性激素紊乱和胰岛素抵抗。

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关键词 ：多囊卵巢综合征, 补肾健脾化痰方, Keap1/Nrf2/HO-1通路, 性激素

Abstract：Objective: To discuss the effects of the Bushen Jianpi Huatan Formula on sex hormone and insulin resistance in polycystic ovary syndrome (PCOS) rats by regulating the Kelch-like epichlorohydrin-associated protein 1 (Keap1)/nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)signaling pathway. Methods: A PCOS rat model was established via letrozole combined with a high-fat diet, then the model rats were assigned to a model group, a metformin group, a Bushen Jianpi Huatan Formula group, and a Bushen Jianpi Huatan Formula+Nrf2 inhibitor group, each with 10 rats. Another 10 rats fed with regular feed were served as the normal group. The gavage dose for the metformin group was 0.3g/kg,16g/kg for the Bushen Jianpi Huatan Formula group, and for the Bushen Jianpi Huatan Formula +Nrf2 inhibitor group, 16g/kg of the Bushen Jianpi Huatan Formula was gavage along with an intraperitoneal injection of Nrf2 inhibitor 10mg/kg, all regiments were given once a day for 4 weeks. Hematoxylin eosin (HE) staining was used to detect the estrous cycle and ovarian tissue lesions. The blood glucose meter was used to detect fasting blood glucose (FBG) in rat serum. Enzyme-linked immunosorbent assay (ELISA) was used to detect changes in serum fasting insulin (FINS), sex hormones [testosterone (T), estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH)], blood lipid indicators [triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)], inflammatory factors [tumor necrosis factor -α (TNF-α), interleukin-18 (IL-18)], as well as the levels of oxidative stress indicators [total superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA)] in ovarian tissues, and the homeostatic model assessment of insulin resistance index (HOMA-IR) was calculated. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of Keap1, Nrf2, and HO-1 mRNAs in ovarian tissue. While Western blot was used to detect the protein levels of Keap1, Nrf2, and HO-1 in ovarian tissue. Results: Compared with the normal group,Rats in the model group showed dysregulation of the estrous cycle, cystic expansion of follicles, increased levels of T, LH, LH/FSH, TG, TC, LDL-C, FINS, FBG, HOMA-IR, TNF-α, IL-18, MDA,and the Keap1 mRNA and protein, and meanwhile showed the decreased levels of E2, HDL-C, SOD, GSH-Px, the Nrf2 and the HO-1 mRNAs and protein(P<0.05). Compared with the model group, The Bushen Jianpi Huatan Formula group showed a decreased follicular cystic expansion, decreased levels of T, LH, LH/FSH, TG, TC, LDL-C, FINS, FBG, HOMA-IR, TNF-α, IL-18, MDA, the Keap1 mRNA and protein, and meanwhile showed increased levels of E2, HDL-C, SOD, GSH-Px, the Nrf2, HO-1 mRNAs and protein(P<0.05). The Bushen Jianpi Huatan Formula and Nrf2 inhibitor group showed an increased follicular cystic expansion, and the changes in various indicators in serum and ovaries were opposite to those in the Bushen Jianpi Huatan Formula group (P<0.05). Conclusion: Bushen Jianpi Huatan Formula may alleviate sex hormone disorders and insulin resistance in PCOS rats by regulating Keap1/Nrf2/HO-1 signaling pathway.

Key words： Polycystic ovary syndrome Bushen jianpi huatan formula Keap1/Nrf2/HO-1 signaling pathway Sex hormone

基金资助:湖北省武汉市中医药科研项目,(编号:WZ24B45)

通讯作者: 朱梦妮

引用本文:

定晓雯, 詹小霜, 杨文静, 宋倩, 朱梦妮. 补肾健脾化痰方调控Keap1/Nrf2/HO-1通路对多囊卵巢综合征大鼠性激素水平及胰岛素抵抗的影响[J]. 河北医学, 2026, 32(2): 203-213.
DING Xiaowen, ZHAN Xiaoshuang, YANG Wenjing, et al. Effects of Bushen Jianpi Huatan Formula on Sex Hormones and Insulin Resistance in Polycystic Ovary Syndrome Rats by Regulating the Keap1/Nrf2/HO-1 Signaling Pathway. HeBei Med, 2026, 32(2): 203-213.

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http://www.hbyxzzs.cn/CN/10.3969/j.issn.1006-6233.2026.02.05 或 http://www.hbyxzzs.cn/CN/Y2026/V32/I2/203

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