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二甲基乙酰胺经口服给药激活 Nrf2/Keap1 通路，减轻氧化应激，可能延缓小鼠卵巢的衰老相关不孕。

Activation of Nrf2/Keap1 pathway by oral Dimethylfumarate administration alleviates oxidative stress and age-associated infertility might be delayed in the mouse ovary.

机构信息

Department of Obstetrics and Gynecology, Graduate school of Medicine, The University of Tokyo, Tokyo, 1138655, Japan.

Department of Obstetrics and Gynecology, Mizonokuchi Hospital, Teikyo University, Kawasaki, 2138507, Japan.

出版信息

Reprod Biol Endocrinol. 2019 Feb 13;17(1):23. doi: 10.1186/s12958-019-0466-y.

DOI:10.1186/s12958-019-0466-y
PMID:30760288
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6375213/
Abstract

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. 20 mg/kg DMF was administrated to female mice from 32 to 48 weeks, 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.

摘要

背景

与年龄相关的不孕是一个全球性问题，已知氧化应激的管理至关重要。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）信号通路是对抗氧化应激的基本防御机制，已知口服药物二甲基富马酸（DMF）可激活该途径。

方法

我们检验了这样一个假设，即口服 DMF 可以减轻卵巢中的氧化应激，从而挽救生殖年龄小鼠模型中与年龄相关的不孕，我们检查了 DMF 给药的效果。从 32 周到 48 周，给雌性小鼠口服 20mg/kg 的 DMF，检查 Nrf2 水平、抗氧化水平、卵巢储备、DNA 损伤和氧化应激。

结果

DMF 给药导致 Nrf2、抗氧化剂和端粒的 mRNA 和蛋白水平升高，血清 Nrf2 和抗苗勒管激素水平也升高。TUNEL 检测和小鼠卵巢组织免疫组化的结果表明，DMF 给药可减少 DNA 损伤和氧化应激，收集的卵母细胞数量显著增加，原始卵泡保留增加了 60%。

结论

我们的数据表明，DMF 给药可激活 Nrf2/Keap1 途径，提高抗氧化剂水平，减少 DNA 损伤和氧化应激，从而改善小鼠卵巢中的卵巢储备。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/efe5c9e06762/12958_2019_466_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/89ddf0a2b4cf/12958_2019_466_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/4ce60ea2071b/12958_2019_466_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/c87d93605bc7/12958_2019_466_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/c02ebcd69bdc/12958_2019_466_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/9da95df429ce/12958_2019_466_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/ee01484a117e/12958_2019_466_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/03e666f0497a/12958_2019_466_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/efe5c9e06762/12958_2019_466_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/89ddf0a2b4cf/12958_2019_466_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/4ce60ea2071b/12958_2019_466_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/c87d93605bc7/12958_2019_466_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/c02ebcd69bdc/12958_2019_466_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/9da95df429ce/12958_2019_466_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/ee01484a117e/12958_2019_466_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/03e666f0497a/12958_2019_466_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdf2/6375213/efe5c9e06762/12958_2019_466_Fig8_HTML.jpg

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