Theophylline derivatives promote primordial follicle activation via cAMP-PI3K/Akt pathway and ameliorate fertility deficits in naturally aged mice.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Biological Sciences Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.99936
Wenbo Zhang, Longwei Gao, Xiaodan Zhang, Yashuang Weng, Yan Du, Yan-Li Sun, Hongwei Wei, Tiantian Hao, Yuezhou Chen, Xiaoyan Liang, Meijia Zhang
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Abstract

In elderly women and patients with premature ovarian insufficiency (POI), activating their remaining dormant primordial follicles in vivo is challenging. In this study, we found that phosphodiesterase (PDE) subtypes were expressed mainly in primordial follicle oocytes. The specific PDE inhibitors and theophylline derivatives (aminophylline, dyphylline, and enprofylline) activated primordial follicles in neonatal mice by ovary culture and intraperitoneal injection. These inhibitors also increased the levels of ovarian cyclic adenosine monophosphate (cAMP) and oocyte phosphorylated protein kinase B (p-Akt). The blockade of gap junctions using carbenoxolone (CBX) increased the levels of ovarian cAMP and pre-granulosa cell phosphorylated mammalian target of rapamycin (p-mTOR), suggesting that oocyte PDEs hydrolyze cAMP from pre-granulosa cells through gap junctions to maintain primordial follicle dormancy. Importantly, oral aminophylline improved ovulated oocyte quantity and quality, and increased offspring numbers in naturally aged mice. In addition, theophylline derivatives also activated human primordial follicles and increased p-Akt levels. Thus, theophylline derivatives activate primordial follicles by accumulating cAMP levels and activating phosphatidylinositol 3-kinase (PI3K)/Akt pathway in oocytes, and oral aminophylline increased fertility in naturally aged female mice by improving ovulated oocyte quantity and quality. As oral medications, theophylline derivatives may be used to improve fertility in elderly women and patients with POI.

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茶碱衍生物通过cAMP-PI3K/Akt途径促进原始卵泡活化,改善自然老龄小鼠的生育能力缺陷。
对于老年妇女和早衰性卵巢功能不全(POI)患者来说,在体内激活其剩余的休眠原始卵泡是一项挑战。在这项研究中,我们发现磷酸二酯酶(PDE)亚型主要在原始卵泡卵母细胞中表达。通过卵巢培养和腹腔注射,特异性 PDE 抑制剂和茶碱衍生物(氨茶碱、二茶碱和恩丙茶碱)激活了新生小鼠的原始卵泡。这些抑制剂还能提高卵巢环磷酸腺苷(cAMP)和卵母细胞磷酸化蛋白激酶 B(p-Akt)的水平。使用羧甲唑龙(CBX)阻断间隙连接可提高卵巢cAMP和前颗粒细胞磷酸化哺乳动物雷帕霉素靶标(p-mTOR)的水平,这表明卵母细胞PDE通过间隙连接水解前颗粒细胞的cAMP,以维持原始卵泡休眠。重要的是,口服氨茶碱可改善排卵卵母细胞的数量和质量,并增加自然衰老小鼠的后代数量。此外,茶碱衍生物还能激活人类原始卵泡,提高p-Akt水平。因此,茶碱衍生物通过积累cAMP水平和激活卵母细胞中的磷脂酰肌醇3-激酶(PI3K)/Akt通路来激活原始卵泡,而口服氨茶碱通过改善排卵卵母细胞的数量和质量来提高自然老龄雌性小鼠的生育能力。作为口服药物,茶碱衍生物可用于改善老年妇女和 POI 患者的生育能力。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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