Melatonin ameliorates ovarian dysfunction by regulating autophagy in PCOS via the PI3K-Akt pathway

Reproduction ◽  
2021 ◽  
Author(s):  
Fenfen Xie ◽  
Junhui Zhang ◽  
Muxin Zhai ◽  
Yajing Liu ◽  
Hui Hu ◽  
...  
Keyword(s):  
Rat Model ◽  
Follicular Fluid ◽  
Molecular Mechanisms ◽  
Ovarian Function ◽  
Polycystic Ovary ◽  
Akt Pathway ◽  
Therapeutic Drug ◽  
Ovarian Dysfunction ◽  
Protective Function ◽  
Expression Levels

Emerging evidence has demonstrated that melatonin (MT) plays a crucial role in regulating mammalian reproductive functions. It has been reported that MT has a protective effect on polycystic ovary syndrome (PCOS). However, the protective mechanisms of MT remain poorly understood. This study aims to explore the effect of MT on ovarian function in PCOS and to elucidate the relevant molecular mechanisms in vivo and in vitro. Here, we first analysed MT expression levels in the follicular fluid of PCOS patients. A significant reduction in MT expression levels was noted in PCOS patients. Intriguingly, reduced MT levels correlated with serum testosterone and inflammatory cytokine levels in follicular fluid. Moreover, we confirmed the protective function of MT through regulating autophagy in a dehydroepiandrosterone (DHEA)-induced PCOS rat model. Autophagy was activated in the ovarian tissue of the PCOS rat model, whereas additional MT inhibited autophagy by increasing PI3K-Akt pathway expression. In addition, serum-free testosterone, inflammatory and apoptosis indexes were reduced after MT supplementation. Furthermore, we also found that MT suppressed autophagy and apoptosis by activating the PI3K-Akt pathway in the DHEA-exposed human granulosa cell line KGN. Our study showed that MT ameliorated ovarian dysfunction by regulating autophagy in DHEA-induced PCOS via the PI3K-Akt pathway, revealing a potential therapeutic drug target for PCOS.

GPR120 agonist ameliorated insulin resistance and improved ovarian function

Zygote ◽  
2021 ◽  
pp. 1-6
Author(s):  
Yang Liu ◽  
Jiayi Ding ◽  
Xiaofang Tan ◽  
Ya Shen ◽  
Li Xu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Rat Model ◽  
Lipid Accumulation ◽  
Ovarian Function ◽  
Polycystic Ovary ◽  
Vital Role ◽  
Expression Levels ◽  
Glucose And Lipid Metabolism

Summary GPR120 is implicated in the regulation of glucose and lipid metabolism, and insulin resistance. In the current study, we aimed to investigate the role of GPR120 in polycystic ovary syndrome (PCOS). With the adoption of dehydroepiandrosterone, a rat model was established to simulate PCOS in vitro. mRNA and protein expression levels of GPR120 were measured using RT-qPCR and western blot, respectively. In addition, expression levels of testosterone, estradiol, luteinizing hormone and follicle-stimulating hormone, serum total cholesterol and triglyceride were assessed using the corresponding kits. Moreover, haematoxylin and eosin staining was used to detect pathological changes in ovary or liver and oil red staining was utilized to evaluate lipid accumulation. In the present study, GPR120 was downregulated in plasma, liver and ovary in the PCOS rat model. In addition, the GPR120 agonist regulated lipid metabolism in the liver and weight in the PCOS rat model. Furthermore, the GPR120 agonist decreased insulin resistance in the PCOS rat model but improved the ovarian function. It is suggested that GPR120 plays a vital role in suppressing insulin resistance, regulating ovary function and decreasing lipid accumulation in the liver, demonstrating that targeting GPR120 could be an effective method for the improvement of PCOS.

scholarly journals Total flavonoids extracted from Nervilia Fordii function in polycystic ovary syndrome through IL-6 mediated JAK2/STAT3 signaling pathway

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Yanyuan Zhou ◽  
Liang Lv ◽  
Qinghua Liu ◽  
Jiale Song
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Rat Model ◽  
Molecular Mechanisms ◽  
Polycystic Ovary ◽  
Serum Levels ◽  
Cytokine Signaling ◽  
Therapeutic Drug ◽  
Total Flavonoids ◽  
Ovary Syndrome

Abstract Large doses of flavonoids could cure many diseases with no serious side effects. However, the role of flavonoids in the treatment of polycystic ovary syndrome (PCOS) has not been reported. Therefore, total flavonoids extracted from Nervilia Fordii were selected to explore its therapeutic efficiency in PCOS. PCOS rat model was constructed to explore the role of total flavonoids in the treatment of PCOS. ELISA was used to assess the changes of ovulation function under the treatment of total flavonoids with or without exogenous interleukin-6 (IL-6). Western blot, real-time PCR and immunohistochemistry were carried out to assess the related molecular mechanisms. We explored that total flavonoids obviously increased the serum levels of follicle-stimulating hormone (FSH), and sharply decreased the serum levels of luteinizing hormone (LH), testosterone (T) and insulin (INS) in the PCOS-IR rats via partly inhibiting the activation of JAK2/STAT3 pathway, partially up-regulating the IL-6 expression and partially down-regulating the suppressor of cytokine signaling 3 (SOCS3) expression in ovaries of PCOS rats. The effect of total flavonoids on estrous cycles, serum levels of FSH, LH, T and INS were partially attenuated by IL-6 in PCOS rat model. Moreover, IL-6 significantly reversed the effect of total flavonoids on the phosphorylation of JAK2/STAT3, the expression of IL-6 and SOCS3 in ovaries of PCOS rats. Total flavonoids extracted from Nervilia Fordii might induce the expression of IL-6 in ovary and act as a potential therapeutic drug for the treatment of PCOS.

Humanin alleviates insulin resistance in polycystic ovary syndrome: a human and rat model-based study

Endocrinology ◽  
2021 ◽  
Author(s):  
Yingying Wang ◽  
Zhengyan Zeng ◽  
Shuhua Zhao ◽  
Li Tang ◽  
Jin Yan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Rat Model ◽  
Follicular Fluid ◽  
Polycystic Ovary ◽  
Glucose Consumption ◽  
Cell Types ◽  
Reproductive Age ◽  
Therapeutic Drug ◽  
Ovary Syndrome

Abstract Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenism and insulin resistance (IR); however, the pathogenesis of local ovarian IR in PCOS remains largely unclear. Humanin, a mitochondria-derived peptide, has been reported to be associated with IR. Our previous study confirmed that humanin is expressed in multiple cell types and is present in follicular fluid. However, it remains unknown whether humanin participates in the pathogenesis of local ovarian IR or whether humanin supplementation can improve IR in PCOS patients. In this study, we compared humanin concentrations in follicular fluid from PCOS patients with and without IR. We further investigated the effect of humanin analogue (HNG) supplementation on IR in a rat model of dehydroepiandrosterone-induced PCOS. Humanin concentrations in the follicular fluid were found to be significantly lower in PCOS patients with IR than in those without IR. HNG supplementation attenuated both the increases in the levels of fasting plasma glucose and fasting insulin in rats with PCOS and the decreases in phosphorylation of IRS1, PI3K, AKT, and GLUT4 proteins in the granulosa cells of these rats. Combined supplementation with HNG and insulin significantly improved glucose consumption in normal and humanin-siRNA-transfected COV434 cells. In conclusion, downregulated humanin in the ovaries may be involved in the pathogenesis of IR in PCOS, and exogenous supplementation with HNG improved local ovarian IR through modulation of the IRS1/PI3K/Akt signaling pathway in a rat model. This finding supports the potential future use of HNG as a therapeutic drug for PCOS.

scholarly journals Ganoderic Acid A Protects Rat H9c2 Cardiomyocytes from Hypoxia-Induced Injury via Up-Regulating miR-182-5p

2018 ◽  
Vol 50 (6) ◽  
pp. 2086-2096 ◽  
Author(s):  
Xiaohong  Zhang ◽  
Can Xiao ◽  
Hong Liu
Keyword(s):  
Cell Viability ◽  
Molecular Mechanisms ◽  
Akt Pathway ◽  
H9c2 Cell ◽  
H9c2 Cells ◽  
Ganoderic Acid ◽  
Expression Levels ◽  
Protein Levels ◽  
Viability Loss ◽  
H9c2 Cardiomyocytes

Background/Aims: Ganoderic acid A (GAA) isolated from Ganoderma lucidum, shows various benefit activities, such as anti-tumor activity, anti-HIV activity and hepatoprotective activity. However, the potential effects of GAA on hypoxia-induced injury of cardiomyocytes are still unclear. In this study, we aimed to reveal the effects of GAA on hypoxic-induced H9c2 cell injury, as well as potential underlying molecular mechanisms. Methods: Rat H9c2 cardiomyocytes were cultured in hypoxia condition with different doses of GAA. Cell viability and apoptosis were detected by CCK-8 assay and flow cytometry, respectively. qRT-PCR was performed to assess the expression levels of microRNA-182-5p (miR-182-5p) and phosphatase and tensin homologue (PTEN). Cell transfection was conducted to change the expression levels of miR-182-5p and PTEN in H9c2 cells. Finally, protein levels of key factors involved in cell proliferation, cell apoptosis and PTEN/PI3K/AKT pathway were evaluated using western blotting. Results: Hypoxia treatment significantly induced H9c2 cell viability loss and apoptosis. GAA incubation remarkably protected H9c2 cells from hypoxia-induced viability loss, proliferation inhibition and apoptosis. In addition, GAA obviously enhanced the expression level of miR-182-5p in H9c2 cells. Suppression of miR-182-5p notably alleviated the protective effects of GAA on hypoxia-treated H9c2 cells. Furthermore, miR-182-5p negatively regulated the mRNA and protein levels of PTEN in H9c2 cells. GAA attenuated hypoxia-induced inactivation of PI3K/AKT pathway in H9c2 cells by up-regulating miR-182-5p and then down-regulating PTEN. Conclusion: GAA protected rat H9c2 cardiomyocytes from hypoxia-induced injury might via up-regulating miR-182-5p, down-regulating PTEN and then activating PI3K/AKT signaling pathway.

Increased Expression of KISS1 and KISS1 Receptor in Human Granulosa Lutein Cells—Potential Pathogenesis of Polycystic Ovary Syndrome

2018 ◽  
Vol 26 (11) ◽  
pp. 1429-1438 ◽  
Author(s):  
Kai-Lun Hu ◽  
Hongcui Zhao ◽  
Zheying Min ◽  
Yilei He ◽  
Tianjie Li ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Follicular Fluid ◽  
Polycystic Ovary ◽  
Expression Patterns ◽  
Serum Levels ◽  
Recent Experimental Data ◽  
Ovary Syndrome ◽  
Expression Levels ◽  
Highly Correlated

Kisspeptins are a family of neuropeptides that are essential for fertility. Recent experimental data suggest a putative role of kisspeptin signaling in the direct control of ovarian function. To explore the expression of KISS1 and KISS1 receptor (KISS1R) in human granulosa lutein cells and the potential role of KISS1/KISS1R system in the pathogenesis of polycystic ovary syndrome (PCOS), we measured the concentration of KISS1 in follicular fluid, the expression of KISS1 and KISS1R in granulosa lutein cells, and the circulating hormones. The expression levels of KISS1 and KISS1R were significantly upregulated in human granulosa lutein cells obtained from women with PCOS. The expression levels of KISS1 in human granulosa lutein cells highly correlated with those of KISS1R in non-PCOS patients, but not in patients with PCOS, most likely due to the divergent expression patterns in women with PCOS. Additionally, the expression levels of KISS1 highly correlated with the serum levels of anti-Müllerian hormone (AMH). The expression levels of KISS1 and KISS1R, as well as the follicular fluid levels of KISS1, were not significantly different between the pregnant and nonpregnant patients in both PCOS and non-PCOS groups. In conclusion, the increased expression of KISS1 and KISS1R in human granulosa lutein cells may contribute to the pathogenesis of PCOS. The expression levels of KISS1 highly correlated with the serum levels of AMH. The KISS1 and KISS1R system in the ovary may not have a remarkable role in predicting the in vitro fertilization (IVF) outcome.

Determine Cyp17a1 and Ki67 Expressions in Pcos Induced Rat Model Treated with Sepia pharaonis Ink Extract Proves Effective

2020 ◽  
Author(s):  
J. Leonoline Ebenezer ◽  
R. Gunapriya ◽  
K. Ranganathan ◽  
R. Vijayaraghavan ◽  
M. Karthik Ganesh
Keyword(s):  
Rat Model ◽  
Polycystic Ovary ◽  
Clomiphene Citrate ◽  
Drug Effects ◽  
Female Rats ◽  
Therapeutic Drug ◽  
Control Group ◽  
Vaginal Smears ◽  
Sepia Pharaonis ◽  
Pcos Group

Background: The present study aims to evaluate the therapeutic action of Sepia pharaonis ink extract in experimentally induced polycystic ovary syndrome (PCOS) rat model and perform Immunohistochemistry to confirm the findings.Methods: The female rats were grouped into 5 consisting of six animals each. Only water was given to the control group. For inducing PCOS, Letrozole 1mg/kg.b.wt was administered to the subsequent four groups for 21 days. To the third group, an allopathic drug, clomiphene citrate 1mg/kg was given for 19 days after PCOS induction. The SPIE was subjected to lyophilisation to make a black powder and next two groups were administered orally with two different dosages of SPIE (100mg and 200mg respectively) mixed with water after PCOS induction. Vaginal smears were taken from all groups till 21 days and then treatment was started with clomiphene citrate (CC) and SPIE. After 21 days, vaginal smears were taken from all groups till ovulation was induced. The test drug effects were studied using ovary weight both right and left, body weight, hormonal levels, histopathology of ovary and Immunohistochemistry. Result: PCOS group showed rapid increase in the ovarian weight when compared to control and was reduced by CC and SPIE treatment. The levels of progesterone and estradiol were found lower and testosterone levels were found higher in PCOS rats which were favourably altered. Vaginal smears coincided with the histopathology and immunohistochemistry findings. SPIE can be used as a therapeutic drug for PCOS in future, reduce infertility complaint of females and prevent early inception of diabetes mellitus.

scholarly journals PI3K–AKT Signaling Activation and Icariin: The Potential Effects on the Perimenopausal Depression-Like Rat Model

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3700 ◽  
Author(s):  
Li-Hua Cao ◽  
Jing-Yi Qiao ◽  
Hui-Yuan Huang ◽  
Xiao-Yan Fang ◽  
Rui Zhang ◽  
...  
Keyword(s):  
Rat Model ◽  
Significant Risk ◽  
B Cell Lymphoma ◽  
Brain Homogenate ◽  
Serum Levels ◽  
Akt Signaling ◽  
Akt Pathway ◽  
Expression Levels ◽  
Increased Risk ◽  
The Brain

Icariin is a prenylated flavonol glycoside isolated from Epimedium herb, and has been shown to be its main bioactive component. Recently, the antidepressant-like mechanism of icariin has been increasingly evaluated and demonstrated. However, there are few studies that have focused on the involvement of the phosphatidylinositol 3-kinase (PI3K)/serine-threonine protein kinase (AKT) signaling in mediating the perimenopausal depression effects of icariin. Perimenopausal depression is a chronic recurrent disease that leads to an increased risk of suicide, and poses a significant risk to public health. The aim of the present study was to explore the effect of icariin on the expression of the PI3K–AKT pathway related to proteins in a rat model of perimenopausal depression. Eighty percent of the left ovary and the entire right ovary were removed from the model rats. A perimenopausal depression model was created through 18 days of chronic unpredictable stimulation, followed by the gavage administration of target drugs for 30 consecutive days. We found that icariin administered at various doses significantly improved the apparent symptoms in the model rats, increased the organ indices of the uterus, spleen, and thymus, and improved the pathological changes in the ovaries. Moreover, icariin administration elevated the serum levels of female hormone estradiol (E2), testosterone (T), and interleukin (IL)-2, decreased those of follicle stimulating hormone (FSH) and luteotropic hormone (LH), promoted the expression levels of estrogen receptor (ER) and ERα in the hypothalamus, and increased those of serotonin (5-HT), dopamine (DA), and noradrenaline (NA) in the brain homogenate. Furthermore, icariin elevated the expression levels of AKT, phosphorylation-akt (p-AKT), PI3K (110 kDa), PI3K (85 kDa), and B-cell lymphoma 2 (Bcl-2) in the ovaries, and inhibited those of Bax. These results show that icariin administration rebalanced the disordered sex hormones in perimenopausal depression rats, regulated the secretion of neurotransmitters in the brain, boosted immune function, and improved the perimenopausal syndrome. The mechanism of action may be related to the regulation of the expression of PI3K–AKT pathway-related proteins.

scholarly journals Circulating leptin concentrations and ovarian function in polycystic ovary syndrome

2001 ◽  
pp. 289-294 ◽  
Author(s):  
IR Pirwany ◽  
R Fleming ◽  
N Sattar ◽  
IA Greer ◽  
AM Wallace
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Ovarian Function ◽  
Polycystic Ovary ◽  
Ovarian Dysfunction ◽  
Ovary Syndrome ◽  
Cross Sectional ◽  
Serum Leptin ◽  
Significant Difference ◽  
The Relationship

OBJECTIVE: Polycystic ovary syndrome (PCOS) is characterized by ovarian dysfunction. Although the role of leptin in the control of reproduction is unclear, it may be involved in the control of ovulation. The aim of this cross-sectional study was to determine the relationship between circulating leptin concentrations, and anthropometric, metabolic and endocrine variables as well as to examine a possible role of leptin in ovarian dysfunction associated with PCOS. DESIGN: Prospective observational study. METHODS: Seventy-one subjects with PCOS and 23 body mass index (BMI)-matched control subjects were recruited from infertility clinics. The association between serum leptin concentrations and the above variables was measured outwith the luteal phase. A subgroup of 24 PCOS subjects underwent more frequent blood sampling to monitor follicular growth and ovulation. The association between variables was measured by univariate, multivariate and partial correlation analyses. RESULTS: Serum leptin concentrations were not different in subjects with PCOS and controls, and were strongly associated with BMI in both groups. Twelve patients ovulated during the study period. There was no significant difference in serum leptin concentrations between ovulatory and anovulatory subjects. The relationship between BMI and leptin was similar in both groups. CONCLUSION: The results indicated that circulating leptin concentrations relate principally to total body fat in subjects with PCOS and controls, and that this is not associated with the facility for follicular development and ovulation in these patients.

scholarly journals Angiopoietins/TIE2 System and VEGF Are Involved in Ovarian Function in a DHEA Rat Model of Polycystic Ovary Syndrome

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3446-3456 ◽  
Author(s):  
Dalhia Abramovich ◽  
Griselda Irusta ◽  
Diana Bas ◽  
Natalia Isabel Cataldi ◽  
Fernanda Parborell ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Rat Model ◽  
Ovarian Function ◽  
Polycystic Ovary ◽  
Fetal Liver ◽  
Follicular Development ◽  
Tyrosine Kinase Receptor ◽  
Ovary Syndrome ◽  
Pcos Group ◽  
Vegf Inhibition

Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age. It is characterized by anovulation, oligo- or amenorrhea, hyperandrogenism, obesity, and insulin resistance. PCOS patients present with elevated levels of vascular endothelial growth factor (VEGF) in serum and follicular fluid. In this study, we examined the ovarian expression of angiopoietins (ANGPT) and their receptor tyrosine kinase receptor (TIE2), involved in the stabilization of blood vessels, in a rat model of dehydroepiandrosterone-induced PCOS. We also analyzed the effect of ovarian VEGF inhibition on ANGPT/TIE2, follicular development, and vascular stability. VEGF levels were increased in the PCOS ovaries, whereas the levels of its receptor fetal liver kinase-1 were decreased. In addition, the periendothelial cell area and the ANGPT1 to ANGPT2 ratio in the ovary were increased in the PCOS group. Percentage of primary follicles was increased and the percentage of preantral follicles and corpora lutea was decreased in the PCOS group. VEGF inhibition decreased the percentage of primary follicles close to control values. Interestingly, despite the presence of cysts in the ovaries from VEGF inhibitor-treated PCOS rats, its percentage was lower than the PCOS group without treatment. In summary, this study describes an alteration not only in the VEGF/fetal liver kinase-1 system but also in the ANGPT/TIE2 system in a dehydroepiandrosterone-induced PCOS rat model. This leads to an increase in periendothelial cell recruitment. We also demonstrated that ovarian VEGF inhibition can partially restore the accumulation of small follicles in PCOS rats and reduces cyst formation, improving ovulation and follicular development. Therefore, the inhibition of VEGF could be considered, in addition to other currently applied treatments, as a new strategy to be studied in PCOS patients to restore ovarian function.

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