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

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

Liu M ，Guo S ，Li X ，Tian Y ，Yu Y ，Tang L ，Sun Q ，Zhang T ，Fan M ，Zhang L ，Xu Y ，An J ，Gao X ，Han L ，Zhang L ... -  《Drug Design Development and Therapy》

Ghrelin Alleviates Inflammation, Insulin Resistance, and Reproductive Abnormalities in Mice with Polycystic Ovary Syndrome via the TLR4-NF-κB Signaling Pathway.

Liu F ，Wang X ，Zhao M ，Zhang K ，Li C ，Lin H ，Xu L ... -  《-》

Effect of resveratrol and metformin on ovarian reserve and ultrastructure in PCOS: an experimental study.

Furat Rencber S ，Kurnaz Ozbek S ，Eraldemır C ，Sezer Z ，Kum T ，Ceylan S ，Guzel E ... -  《Journal of Ovarian Research》

Dulaglutide, a long-acting GLP-1 receptor agonist, can improve hyperandrogenemia and ovarian function in DHEA-induced PCOS rats.

The purpose of this study was to explore the effect of dulaglutide on DHEA induced PCOS rats and its mechanism, to provide new drugs and research directions for clinical treatment of PCOS. In this study, the PCOS model was established by giving female SD rats subcutaneous injection of DHEA for 21 consecutive days. After modeling, the treatment group was injected subcutaneously with three doses of dulaglutide for 3 weeks. The model group was injected with sterile ultrapure water, and the normal group did not get any intervention. The body weight changes of rats in each group were recorded from the first day when rats received the administration of dulaglutide. Three weeks later, the rats were fasted the night after the last treatment, determined fasting insulin and fasting glucose the next day. After the rats were anesthetized by chloral hydrate, more blood was collected from the heart of the rat. The serum insulin, testosterone and sex hormone binding globulin (SHBG) levels were detected by the enzyme-linked immunoassay method. After removing the adipose tissue, the obtained rat ovary tissue was used for subsequent experimental detection, using HE staining for morphology and follicular development analysis; qRT-PCR for the detection of 3βHSD, CYP17α1, CYP19α1, and StAR gene expression in ovarian tissue; and western blotting analysis of CYP17α1, CYP19α1, StAR protein expression and insulin level to verify whether dulaglutide has a therapeutic effect on PCOS in rats. After treated with different concentrations of dulaglutide, we found that the body weight of rats in the treatment groups were reduced. Compared with the rats in PCOS group, the serum androgen level of rats in the treatment groups was significantly decreased, and the serum sex hormone binding protein content was significantly increased, and there was statistically significant difference between these groups and PCOS group. In terms of protein expression and gene regulation, the expression of 3βHSD, CYP19α1 and StAR in the ovarian tissue of rats in treatment groups were decreased significantly after received the treatment of dulaglutide, and there was statistically significant difference between these groups and PCOS group. In addition, dulaglutide reduced the insulin content in the ovarian tissue of PCOS rats. Dulaglutide may reduce the hyperandrogenemia of PCOS rats by regulating the content of serum SHBG and the expression of 3βHSD, CYP19α1, and StAR related genes and proteins, thereby inhibiting the excessive development of small follicles and the formation of cystic follicles in the ovaries of PCOS rats, thereby improving polycystic ovary in PCOS rats. In addition, dulaglutide may reduce the weight of PCOS rats, further reducing the level of high androgen in PCOS rats, and improving the morphology of their polycystic ovaries.

Wu LM ，Wang YX ，Zhan Y ，Liu AH ，Wang YX ，Shen HF ，Wang YF ，Wang LY ，Tao ZB ，Wang YQ ... -  《-》

Liuwei Dihuang Pills alleviate the polycystic ovary syndrome with improved insulin sensitivity through PI3K/Akt signaling pathway.

Polycystic ovary syndrome (PCOS) is a complex gynecological endocrine disease commonly occurred in women of childbearing age. The main hallmark of PCOS includes elevated androgen production and insulin resistance (IR). Liuwei Dihuang Pills (LWDH Pills), a commonly prescribed traditional Chinese medicine (TCM) is widely used as a tonic prescription to treat diabetes, female menopause syndrome and other symptoms with'Kidney-Yin' deficiency. It has been reported the effects LWDH pills on PI3K/Akt signaling pathway in T2DM treatment. Recent studies have also indicated that the treatment of menopausal syndrome may be associated with the ovarian sexual hormone levels regulated by LWDH pills to alleviate female infertility. However, its potential benefits on PCOS have not been fully elucidated. The primary aim of this study was to investigate the alterations of PI3K/Akt pathway in polycystic ovary syndrome-insulin resistance (PCOS-IR) progression induced by letrozole combined with high fat diet (HFD) and then to explore the detailed mechanism of LWDH Pills to alleviate PCOS. The female Sprague-Dawley rats were continuously treated with letrozole (p.o administration at 1 mg kg-1·day-1) and HFD for 21 days to establish the PCOS-IR model. Concurrently, metformin (200 mg kg-1·day-1) or LWDH Pills was orally administrated (1.2 or 3.6 g kg-1·day-1) to intervene disease progression. The ovarian pathology was evaluated by HE (hematoxylin-eosin) staining. The serum sexual hormones, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, progesterone and fasting insulin (FINS) were determined by radioimmunoassay. The protein expressions of IRS-1, PI3Kp85α, Akt and FoxO1a were analyzed by western blotting, while the mRNA levels of follicle-stimulating hormone receptor (FSHR) and Cyp19a1 in ovarian tissue were measured by qPCR. The upregulated phosphorylation of IRS-1 (S307), down-regulated phosphorylation of PI3Kp85α, Akt, and FoxO1a were significantly reversed by LWDH Pills (3.6 g kg-1·day-1) in PCOS-IR rats with up-regulated mRNA levels of FSHR and Cyp19a1 in ovary. Also, the index of insulin resistance was gradually adjusted to normal by LWDH Pills. The serum levels of FSH, estradiol, progesterone levels were significantly raised while LH, testosterone were reduced. The ovarian polycystic changes were alleviated while the atresia follicles were reduced. LWDH Pills therapy obviously improved the ovarian polycystic pathogenesis and regained the development of follicles via upregulating Cyp19a1, alleviated insulin resistance through acting on PI3K/Akt signaling pathway. These findings have provided scientific evidence for LWDH Pills to treat PCOS.

Qiu Z ，Dong J ，Xue C ，Li X ，Liu K ，Liu B ，Cheng J ，Huang F ... -  《-》