<br>山奈酚通过调节 HSP90/NRF2 通路在与年龄相关的卵巢储备功能下降中发挥抗氧化作用,Chemical Biology & Drug Design

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山奈酚通过调节 HSP90/NRF2 通路在与年龄相关的卵巢储备功能下降中发挥抗氧化作用
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2023-11-01 , DOI: 10.1111/cbdd.14385
Zhoujia Hua ₁ , Wei Zhang ₁ , Lin Han ₁ , Yuwei Zhang ₂ , Xuejuan Jiang ₁ , Caifei Ding ₁

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山奈酚是临床上用于治疗卵巢功能障碍的中药配方二仙汤（EXD）的活性成分，但山奈酚缓解年龄相关性卵巢储备功能减退（AR-DOR）的机制尚不清楚。在这项研究中，36名志愿者和78名DOR患者（37名接受EXD治疗的患者）参与了临床研究。同时，采用32周龄雌性小鼠建立AR-DOR模型，在存在或不存在200mg/kg香叶基香叶丙酮(GGA)或1mg/kg的情况下，给这些模型小鼠灌胃给予100mg/kg山奈酚。公斤格尔德霉素（GDA）。采用酶联免疫吸附法检测山奈酚对血清激素水平及氧化应激相关指标的影响。通过苏木精-伊红染色测定窦卵泡计数（AFC）。通过Western blot检测HSP90和核因子红细胞2相关因子2（NRF2）的蛋白水平。本研究显示，接受EXD治疗的DOR患者血清抗苗勒管激素（AMH）水平高于未接受EXD治疗的DOR患者。山奈酚治疗逆转了低水平的 AMH、雌二醇 (E2)、AFC、超氧化物歧化酶 (SOD) 和过氧化氢酶 (CAT)，以及高水平的促卵泡激素 (FSH)、活性氧 (ROS)、和丙二醛（MDA）。结果表明，HSP90预计与山奈酚具有高亲和力，其表达被山奈酚抑制，而HSP90的靶标NRF2的表达被山奈酚上调。然而，山奈酚的上述作用被GGA逆转了。相反，GDA增强了山奈酚对AR-DOR小鼠的治疗效果。此外，山奈酚的处理导致热休克因子1（HSF1）（与HSP90相关的转录因子）的磷酸化水平降低，以及HSP90的客户蛋白Src的磷酸化水平增加。综上所述，山奈酚通过抑制HSP90表达从而上调NRF2表达而对AR-DOR发挥抗氧化作用。本研究为山奈酚在AR-DOR中的临床应用提供理论依据。

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Kaempferol exerts antioxidant effects in age-related diminished ovarian reserve by regulating the HSP90/NRF2 pathway

Kaempferol is the active ingredient of Er-Xian decoction (EXD), a traditional Chinese medicine formula used clinically to treat ovarian dysfunction, but the mechanism of kaempferol relieving age-related diminished ovarian reserve (AR-DOR) is still unclear. In this study, 36 volunteers and 78 DOR patients (37 patients with EXD treatment) were enrolled in the clinical research. Meanwhile, 32-week-old female mice were used to establish the AR-DOR model, and these model mice were intragastrically administered with 100 mg/kg kaempferol in the presence or absence of 200 mg/kg geranylgeranylacetone (GGA) or 1 mg/kg geldanamycin (GDA). The effects of kaempferol on serum hormone levels and oxidative stress-related indexes were detected by enzyme-linked immunosorbent assay. Antral follicle count (AFC) was determined by hematoxylin–eosin staining. The protein levels of HSP90 and nuclear factor erythroid 2-related factor 2 (NRF2) were assayed by Western blot. This study displayed that the serum anti-Mullerian hormone (AMH) level in DOR patients with EXD treatment was higher than that in DOR patients without EXD treatment. Kaempferol treatment reversed the low levels of AMH, estradiol (E2), AFC, superoxide dismutase (SOD), and catalase (CAT), as well as the high levels of follicle-stimulating hormone (FSH), reactive oxygen species (ROS), and malonaldehyde (MDA). The results showed that HSP90 was predicted to have high affinity with kaempferol, and its expression was inhibited by kaempferol, while the expression of NRF2, the target of HSP90, was up-regulated by kaempferol. However, the above effects of kaempferol were reversed by GGA. On the contrary, GDA enhanced the therapeutic effects of kaempferol on AR-DOR mice. Moreover, the treatment of kaempferol resulted in a reduction in the phosphorylation level of heat shock factor 1 (HSF1), the transcription factor associated with HSP90, and an increase in the phosphorylation level of Src, a client protein of HSP90. In summary, kaempferol exerts an antioxidant effect on AR-DOR by inhibiting HSP90 expression to up-regulate NRF2 expression. This study provides a theoretical basis for the clinical application of kaempferol in AR-DOR.

更新日期：2023-11-01

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