Activation of Nrf2/Keap1 pathway by oral Dimethylfumarate administration alleviates oxidative stress and age-associated infertility might be delayed in the mouse ovary
Activation of Nrf2/Keap1 pathway by oral Dimethylfumarate administration alleviates oxidative stress and age-associated infertility might be delayed in the mouse ovary
复制标题
DOI：
10.1186/s12958-019-0466-y
复制
发表时间：
2019-02-13
影响因子：
4.4
通讯作者：
Osuga, Yutaka
中科院分区：
文献类型：
--
作者：
Akino, Nana;Wada-Hiraike, Osamu;Osuga, Yutaka
背景：年龄相关性不孕症是一个世界性的问题，众所周知，氧化应激的管理是必不可少的。核因子-E2相关因子2(Nrf2)/Kelch样ECH相关蛋白1(Keap1)-抗氧化反应元件(ARE)信号通路是机体抵抗氧化应激的重要机制，口服药物富马酸二甲酯(DMF)可激活该通路。方法：我们在一只育龄小鼠模型上验证了口服DMF可减轻卵巢氧化应激，从而挽救与年龄相关的不孕症的假说，并考察了DMF的作用。20 mg/kg DMF染毒32~48周雌性小鼠，检测Nrf2水平、抗氧化剂水平、卵巢储备、DNA损伤和氧化应激。结果：DMF使Nrf2、抗氧化剂和端粒的mRNA和蛋白水平升高，血清Nrf2和抗苗勒氏激素水平升高。小鼠卵巢组织原位末端标记法和免疫组织化学检测结果显示，DMF组小鼠卵巢组织DNA损伤和氧化应激明显减轻，卵母细胞数量显著增加，原始卵泡的保存率增加60%。结论：DMF可激活Nrf2/Keap1途径，提高抗氧化剂水平，减轻DNA损伤和氧化应激，从而改善卵巢储备功能。
Background: Age-associated infertility is a problem worldwide, and management of oxidative stress is known to be essential. Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway works as an essential defense mechanism against oxidative stress, and an oral drug Dimethylfumarate (DMF) is known to activate the pathway.Methods: We tested the hypothesis that oral DMF could alleviate oxidative stress in the ovary, resulting in salvation of age-associated infertility in a mouse model of reproductive age, and we examined the effects of DMF administration. 20mg/kg DMF was administrated to female mice from 32 to 48weeks, and Nrf2 levels, antioxidant levels, ovarian reserve, DNA damage, and oxidative stress were examined.Results: DMF administration resulted in elevated mRNA and protein levels of Nrf2, antioxidants, and telomere, and serum levels of Nrf2 and anti-mullerian hormone were also elevated. Results of TUNEL assay and Immunohistochemistry of mice ovarian tissues showed that DNA damage and oxidative stress were decreased by DMF administration, and significantly more oocytes were collected along with preservation of 60% more primordial follicles.Conclusions: Our data suggest that DMF administration activates the Nrf2/Keap1 pathway, elevate levels of antioxidants, and decrease DNA damage and oxidative stress, resulting in improved ovarian reserve in the mouse ovary.