Semaglutide Alleviates Ovarian Oxidative Stress and Autophagy via the PI3K/AKT/mTOR Pathway in Mice with Polycystic Ovary Syndrome.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-05-23 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S522730

Sili Guo, Xiaohan Li, Mei Liu, Meiqi Feng, Xi Wang, Haibo Xue, Lei Zhang

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引用次数: 0

Abstract

Background: Polycystic ovary syndrome (PCOS) is a typical reproductive endocrine system disease with high incidence rate among childbearing age women. Several clinical data show that glucagon-like peptide-1 receptor agonists (GLP-1RAs) might have therapeutic effects on PCOS, but the mechanisms are still unclear. Here, we aim to assess the effects of semaglutide (a weekly preparation of GLP-1RAs) on PCOS in vivo.

Methods: C57BL/6J female mice aged 3 weeks were subcutaneously injected with dehydroepiandrosterone and fed high-fat diet for 3 weeks to establish PCOS model. Then, we randomly divided the modeled mice into PCOS group (n=6), S-Low group (n=6), and S-High group (n=6). Additionally, six normal mice served as controls. Mice in S-Low and S-High group were intraperitoneally injected with corresponding dose of semaglutide every week for 4 weeks. The estrus cycle was observed daily. At the end of the experiment, body weight, blood glucose, and serum hormone levels were measured. Ovarian morphology was also observed. Then, the oxidative stress markers, autophagy-related proteins and CYP19A1, StAR, and CYP17A1 expression in ovarian tissue were measured. Finally, we used Western blot to detect the expression of PI3K/AKT/mTOR and downstream proteins.

Results: After treatment with semaglutide, the estrous rhythm of PCOS mice was restored, the number of ovarian vesicles decreased, serum hormone imbalance corrected, and glucose tolerance improved. The relative expression of CYP17A1, StAR, Beclin-1, and LC3B, as well as MDA, were significantly reduced, while CYP19A1, p62, GSH, and SOD were significantly increased. Finally, semaglutide alleviates ovarian oxidative stress and autophagy via the PI3K/AKT/mTOR pathway.

Conclusion: Semaglutide alleviates autophagy and ovarian oxidative stress via the PI3K/AKT/mTOR pathway in mice with PCOS.

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西马鲁肽通过PI3K/AKT/mTOR通路减轻多囊卵巢综合征小鼠卵巢氧化应激和自噬

背景：多囊卵巢综合征（PCOS）是育龄妇女中一种典型的高发生殖内分泌系统疾病。一些临床数据显示胰高血糖素样肽-1受体激动剂（GLP-1RAs）可能对PCOS有治疗作用，但其机制尚不清楚。在这里，我们的目的是评估西马鲁肽（每周一次的GLP-1RAs制剂）对体内PCOS的影响。方法：3周龄C57BL/6J雌性小鼠皮下注射脱氢表雄酮，饲喂高脂饲料3周，建立PCOS模型。然后将模型小鼠随机分为PCOS组（n=6）、S-Low组（n=6）和S-High组（n=6）。另外，6只正常小鼠作为对照。S-Low和S-High组小鼠每周腹腔注射相应剂量的西马鲁肽，连续4周。每日观察发情周期。实验结束时，测量体重、血糖和血清激素水平。观察卵巢形态。然后检测卵巢组织中氧化应激标志物、自噬相关蛋白及CYP19A1、StAR、CYP17A1的表达。最后，我们用Western blot检测PI3K/AKT/mTOR及其下游蛋白的表达。结果：经西马鲁肽治疗后，PCOS小鼠的情期节律恢复，卵巢囊泡数量减少，血清激素失衡得到纠正，糖耐量提高。CYP17A1、StAR、Beclin-1、LC3B及MDA的相对表达量显著降低，CYP19A1、p62、GSH、SOD的相对表达量显著升高。最后，semaglutide通过PI3K/AKT/mTOR通路缓解卵巢氧化应激和自噬。结论：西马鲁肽通过PI3K/AKT/mTOR通路减轻PCOS小鼠自噬和卵巢氧化应激。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.