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    多囊1号调控Kiss1/Kiss1R/Akt/FoxO1通路治疗多囊卵巢综合征的作用机制

    Mechanism of Duonang NO.1 Alleviating Polycystic Ovary Syndrome by Modulating the Kiss1/Kiss1R/Akt/FoxO1 Signaling Pathway

      摘要
    • 摘要:
      目的 探讨多囊1号(Duonang NO.1，DNY)治疗多囊卵巢综合征(polycystic ovarian syndrome，PCOS)模型大鼠的潜在作用机制。
      方法 将雌性SD大鼠随机分为空白对照组、模型组、阳性对照组和DNY低、中、高剂量组，每组8只。采用连续灌胃来曲唑21 d建立PCOS大鼠模型，造模期间监测大鼠体质量、动情周期以判断造模情况。造模成功后，空白对照组和模型组灌胃生理盐水，各给药组灌胃相应剂量的药物，持续14 d。记录大鼠体质量、卵巢质量，计算卵巢指数，苏木素-伊红染色观察卵巢组织的形态。酶联免疫吸附测定法测定促黄体生成素(luteinizing hormone，LH)、促卵泡生成素(follicle-stimulating hormone，FSH)等激素水平以及白介素(interleukin 6，IL-6)、丙二醛(malondialdehyde，MDA)、超氧化物歧化酶(superoxide dismutase，SOD)、吻素1(Kiss1)水平。RT-PCR法检测卵巢组织FoxO1、CYP17A1、CYP19A mRNA的表达。免疫组化法检测大鼠卵巢切片中的Kiss1、磷酸化丝苏氨酸蛋白激酶(phosphorylated protein kinase B，P-Akt)、FoxO1的表达情况。Western blotting检测卵巢组织中的Kiss1、吻素受体(Kiss1 receptor，Kiss1R)、丝苏氨酸蛋白激酶(protein kinase B，Akt)、P-Akt、FoxO1蛋白的表达。
      结果 与模型组相比，DNY能降低大鼠的体质量增长率，显著降低血清中LH、T、LH/FSH、IL-6、MDA、Kiss1水平，升高FSH、E2、SOD水平(P<0.05或P<0.01)。DNY给药后能改善卵巢组织病理形态，降低卵巢组织FoxO1、CYP17A1 mRNA表达，增加CYP19A1 mRNA表达(P<0.05或P<0.01)，降低卵巢组织Kiss1、FoxO1蛋白表达，增加Kiss1R、P-Akt/Akt蛋白的表达(P<0.05或P<0.01)。
      结论 DNY能够改善PCOS引起的性激素异常，减轻卵巢组织的病理损伤，其作用机制可能与Kiss1/Kiss1R/Akt/FoxO1信号通路改善性激素分泌有关。

       

      Abstract:
      OBJECTIVE To investigate the potential effect and mechanism of Duonang NO.1 (DNY) in treating polycystic ovary syndrome(PCOS) model rats.
      METHODS Female SD rats were randomly divided into 6 groups: blank control group, model group, positive control group, DNY low-dose group, DNY medium-dose group, and DNY high-dose group, with 8 rats in each group. The PCOS rat model was established by continuous intragastric administration of letrozole for 21 days, and the body weight and estrous cycle of rats were observed to evaluate the modeling status. After successful modeling, the blank control and model groups were given normal saline by intragastric gavage, while the treatment groups received corresponding doses of drugs for 14 days. Body weight and ovarian weight were recorded, and the ovarian weight index was calculated. Hematoxylin-eosin staining was employed to observe ovarian histopathological changes. The levels of hormones including luteinizing hormone(LH) and follicle-stimulating hormone(FSH), as well as interleukin-6(IL-6), malondialdehyde(MDA), superoxide dismutase(SOD), and Kiss1 were measured by ELISA. RT-PCR was used to investigate the expression of FoxO1, CYP17A1, CYP19A1 mRNA in rats ovarian. The protein expression of Kiss1, P-Akt and FoxO1 were detected by immunohistochemistry(IHC). Western blotting was used to detect the protein expression of Kiss1, Kiss1R, Akt, P-Akt, and FoxO1 in ovarian tissue.
      RESULTS Compared with the model group, DNY reduced the body weight growth rate, decreased serum levels of LH, LH/FSH ratio, T, AMH, IL-6, MDA, and Kiss1, and increased serum FSH, E2, and SOD levels(P<0.05 or P<0.01). DNY improved ovarian pathological morphology. Compared with model group, the expression levels of FoxO1 and CYP17A1 mRNA were significantly decreased, the expression level of CYP19A1 mRNA was significantly increased(P<0.05 or P<0.01). Additionally, DNY downregulated the ovarian protein expression of Kiss1 and FoxO1, while upregulating the protein expression of Kiss1R and P-Akt/Akt(P<0.05 or P<0.01).
      CONCLUSION DNY can improve sex hormone levels and alleviate ovarian pathological changes in PCOS rats. Its mechanism may be related to improving sex hormone secretion through the Kiss1/Kiss1R/Akt/FoxO1 signaling pathway.

       

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