Semaglutide Alleviates Ovary Inflammation via the AMPK/SIRT1/NF‑κB Signaling Pathway in Polycystic Ovary Syndrome Mice.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-09-04 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S484531

Mei Liu, Sili Guo, Xiaohan Li, Yang Tian, Yanjie Yu, Lili Tang, Qimei Sun, Ting Zhang, Mingwei Fan, Lili Zhang, Yingjiang Xu, Jiajia An, Xiangqian Gao, Lei Han, Lei Zhang

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Abstract

Background: GLP-1 receptor agonists (GLP-1 RA) have been proven to treat several metabolic diseases; however, the effects of GLP-1 RA on polycystic ovary syndrome (PCOS) remain unclear. Here, we aimed to investigate whether semaglutide, a novel GLP-1 RA, could alleviate ovarian inflammation in PCOS mice.

Methods: Female C57BL/6J mice were subcutaneously injected with dehydroepiandrosterone for 21 days to establish the PCOS model. Then the mice were randomly divided into three groups: PCOS group (n = 6), S-0.42 group (semaglutide 0.42 mg/kg/w, n = 6), and S-0.84 group (semaglutide 0.84 mg/kg/w, n = 6). The remaining six mice were used as controls (NC). After 28 days of intervention, serum sex hormones and inflammatory cytokine levels were measured. Hematoxylin and eosin staining was used to observe the ovarian morphology. Immunohistochemical staining was used to detect the relative expression of CYP19A1, TNF-α, IL-6, IL-1β, and NF-κB in ovaries. CYP17A1 and StAR were detected using immunofluorescence staining. Finally, the relative expressions of AMPK, pAMPK, SIRT1, NF-κB, IκBα, pIκBα, TNF-α, IL-6, and IL-1β were measured using Western blotting.

Results: First, after intervention with semaglutide, the weight of the mice decreased, insulin resistance improved, and the estrous cycle returned to normal. Serum testosterone and IL-1β levels decreased significantly, whereas estradiol and progestin levels increased significantly. Follicular cystic dilation significantly improved. The expression of TNF-α, IL-6, IL-1β, NF-κB, CYP17A1, and StAR in the ovary was significantly downregulated, whereas CYP19A1 expression was upregulated after the intervention. Finally, we confirmed that semaglutide alleviates ovarian tissue inflammation and improves PCOS through the AMPK/SIRT1/NF-κB signaling pathway.

Conclusion: Semaglutide alleviates ovarian inflammation via the AMPK/SIRT1/NF‑κB signaling pathway in PCOS mice.

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塞马鲁肽通过AMPK/SIRT1/NF-κB信号通路缓解多囊卵巢综合征小鼠的卵巢炎症

背景：GLP-1 受体激动剂（GLP-1 RA）已被证实可治疗多种代谢性疾病；然而，GLP-1 RA 对多囊卵巢综合征（PCOS）的影响仍不清楚。在此，我们旨在研究新型 GLP-1 RA semaglutide 是否能缓解 PCOS 小鼠的卵巢炎症：方法：雌性 C57BL/6J 小鼠皮下注射脱氢表雄酮 21 天，建立 PCOS 模型。然后将小鼠随机分为三组：PCOS 组（n = 6）、S-0.42 组（semaglutide 0.42 mg/kg/w，n = 6）和 S-0.84 组（semaglutide 0.84 mg/kg/w，n = 6）。其余六只小鼠作为对照组（NC）。干预 28 天后，测量血清性激素和炎症细胞因子水平。采用苏木精和伊红染色法观察卵巢形态。免疫组化染色用于检测卵巢中 CYP19A1、TNF-α、IL-6、IL-1β 和 NF-κB 的相对表达。采用免疫荧光染色法检测了CYP17A1和StAR。最后，用 Western 印迹法测定了 AMPK、pAMPK、SIRT1、NF-κB、IκBα、pIκBα、TNF-α、IL-6 和 IL-1β 的相对表达量：首先，使用塞马鲁肽干预后，小鼠体重减轻，胰岛素抵抗得到改善，发情周期恢复正常。血清睾酮和IL-1β水平显著下降，而雌二醇和孕激素水平显著上升。卵泡囊性扩张明显改善。干预后，卵巢中TNF-α、IL-6、IL-1β、NF-κB、CYP17A1和StAR的表达明显下调，而CYP19A1的表达上调。最后，我们证实塞马鲁肽可通过AMPK/SIRT1/NF-κB信号通路缓解卵巢组织炎症并改善多囊卵巢综合征：结论：塞马鲁肽可通过AMPK/SIRT1/NF-κB信号通路缓解PCOS小鼠的卵巢炎症。

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.