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1.
Cell Biochem Funct ; 42(4): e4073, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38863227

ABSTRACT

Polycystic ovary syndrome (PCOS) is a multidisciplinary endocrinopathy that affects women of reproductive age. It is characterized by menstrual complications, hyperandrogenism, insulin resistance, and cardiovascular issues. The current research investigated the efficacy of rosmarinic acid in letrozole-induced PCOS in adult female rats as well as the potential underlying molecular mechanisms. Forty female rats were divided into the control group, the rosmarinic acid group (50 mg/kg per orally, po) for 21 days, PCOS group; PCOS was induced by administration of letrozole (1 mg/kg po) for 21 days, and rosmarinic acid-PCOS group, received rosmarinic acid after PCOS induction. PCOS resulted in a marked elevation in both serum luteinizing hormone (LH) and testosterone levels and LH/follicle-stimulating hormone ratio with a marked reduction in serum estradiol and progesterone levels. A marked rise in tumor necrosis factor-α (TNF-α), interleukin-1ß, monocyte chemotactic protein-1, and vascular endothelial growth factor (messenger RNA) in the ovarian tissue was reported. The histological analysis displayed multiple cystic follicles in the ovarian cortex with markedly thin granulosa cell layer, vacuolated granulosa and theca cell layers, and desquamated granulosa cells. Upregulation in the immune expression of TNF-α and caspase-3 was demonstrated in the ovarian cortex. Interestingly, rosmarinic acid ameliorated the biochemical and histopathological changes. In conclusion, rosmarinic acid ameliorates letrozole-induced PCOS through its anti-inflammatory and antiangiogenesis effects.


Subject(s)
Chemokine CCL2 , Cinnamates , Depsides , Disease Models, Animal , Letrozole , Polycystic Ovary Syndrome , Rosmarinic Acid , Vascular Endothelial Growth Factor A , Animals , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/pathology , Female , Cinnamates/pharmacology , Depsides/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Rats , Chemokine CCL2/metabolism , Letrozole/pharmacology , Luteinizing Hormone/blood , Luteinizing Hormone/metabolism , Immunohistochemistry , Testosterone/blood , Rats, Sprague-Dawley
2.
Tissue Cell ; 88: 102404, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38759521

ABSTRACT

Follicular maturation arrest is a prevalent endocrine disorder characterized by hormonal imbalance, ovarian dysfunction, and metabolic disturbances leading to Polycystic ovarian syndrome (PCOS). Tanshinone IIA (TIIA), a bioactive compound derived from Salvia miltiorrhiza, has shown promising therapeutic potential in various diseases, including cardiovascular diseases and cancer. However, its effects on reproductive health and gynecological disorders, particularly PCOS, remain poorly understood. In this study, we investigated the potential therapeutic effects of TIIA on ovarian function. Using a combination of experimental and computational approaches, we elucidated the molecular mechanisms underlying TIIA's pharmacological impact on ovarian function, follicular development, and androgen receptor signaling. Molecular docking and dynamics simulations revealed that TIIA interacts with the human androgen receptor (HAR), modulating its activity and downstream signaling pathways. Our results demonstrate that TIIA treatment alleviates PCOS-like symptoms in a zebrafish model, including improved follicular development, lowered GSI index, improved antioxidant status (SOD, CAT), decreased LDH levels, and enhanced AChE levels by regulating Tox3 and Dennd1a pathway. Our findings suggest that TIIA may hold promise as a novel therapeutic agent for the management of PCOS or ovulation induction.


Subject(s)
Abietanes , Ovarian Follicle , Polycystic Ovary Syndrome , Receptors, Androgen , Salvia miltiorrhiza , Zebrafish , Animals , Humans , Abietanes/pharmacology , Receptors, Androgen/metabolism , Salvia miltiorrhiza/chemistry , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/pathology , Ovarian Follicle/drug effects , Ovarian Follicle/metabolism , Ovarian Follicle/pathology , Female , Molecular Docking Simulation , Zebrafish Proteins/metabolism , Signal Transduction/drug effects , Protein Binding/drug effects
3.
Front Endocrinol (Lausanne) ; 15: 1368494, 2024.
Article in English | MEDLINE | ID: mdl-38745948

ABSTRACT

Decidualisation, the process whereby endometrial stromal cells undergo morphological and functional transformation in preparation for trophoblast invasion, is often disrupted in women with polycystic ovary syndrome (PCOS) resulting in complications with pregnancy and/or infertility. The transcription factor Wilms tumour suppressor 1 (WT1) is a key regulator of the decidualization process, which is reduced in patients with PCOS, a complex condition characterized by increased expression of androgen receptor in endometrial cells and high presence of circulating androgens. Using genome-wide chromatin immunoprecipitation approaches on primary human endometrial stromal cells, we identify key genes regulated by WT1 during decidualization, including homeobox transcription factors which are important for regulating cell differentiation. Furthermore, we found that AR in PCOS patients binds to the same DNA regions as WT1 in samples from healthy endometrium, suggesting dysregulation of genes important to decidualisation pathways in PCOS endometrium due to competitive binding between WT1 and AR. Integrating RNA-seq and H3K4me3 and H3K27ac ChIP-seq metadata with our WT1/AR data, we identified a number of key genes involved in immune response and angiogenesis pathways that are dysregulated in PCOS patients. This is likely due to epigenetic alterations at distal enhancer regions allowing AR to recruit cofactors such as MAGEA11, and demonstrates the consequences of AR disruption of WT1 in PCOS endometrium.


Subject(s)
Endometrium , Polycystic Ovary Syndrome , Receptors, Androgen , WT1 Proteins , Humans , Female , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/genetics , Polycystic Ovary Syndrome/pathology , Endometrium/metabolism , Endometrium/pathology , WT1 Proteins/metabolism , WT1 Proteins/genetics , Receptors, Androgen/metabolism , Receptors, Androgen/genetics , Stromal Cells/metabolism , Stromal Cells/pathology , Adult , Regulatory Sequences, Nucleic Acid
4.
Discov Med ; 36(184): 946-958, 2024 May.
Article in English | MEDLINE | ID: mdl-38798254

ABSTRACT

BACKGROUND: Polycystic ovary syndrome (PCOS) commonly impacts fertile females with potentially severe effects on fertility and metabolism. Blood ghrelin levels are lower in PCOS patients, and exogenous supplements have been proposed for their potential to trigger anti-inflammatory effects at the cellular level. This study aimed to investigate whether pretreatment with ghrelin reduced inflammation, insulin resistance, and reproductive abnormalities in PCOS and the underlying mechanism of this disorder. METHODS: Ghrelin supplementation was first tested in an inflammation model using human ovarian granulosa cells (KGN cells) that were built by treated with Lipolyaccharide. KGN cells were pretreated with ghrelin and exposed to lipopolysaccharide (LPS). Inflammatory gene expression and cytokine production were analyzed by Enzyme-linked immunosorbent assay (ELISA). Based on these results, the PCOS mice model was built with Dehydroepiandrosterone (DHEA) and a high-fat diet. The mRNA and protein expressions of inflammatory factors including Toll-like receptor 4 (TLR4), nuclear factor kappa-B-p65 (NF-κB-p65), Phospho-NF-κB-p65 (p-NF-κB-p65) and myeloid differentiation factor 88 (MYD88) related to the TLR4/NF-κB signaling pathway were evaluated in KGN cells and mouse ovarian tissues using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and western blot, respectively. Lipid metabolism was quantified via an automated biochemical analyzer. RESULTS: The mRNA and protein expressions of interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), and tumor necrosis factor alpha (TNF-α) in ghrelin pretreated KGN cells were lower than the LPS group (p < 0.05). Protein expression was reduced for TLR4, NF-κB-p65, and MYD88 within KGN cells of ghrelin groups compared to the LPS group (p < 0.05). Ghrelin treatment restored the estrous cycle and slowed weight gain and abdominal fat weight of PCOS mice (p < 0.05). Ghrelin treatment decreased the serum concentrations of testosterone, luteinizing hormone, insulin, IL-6, IL-1ß, and TNF-α compared to the PCOS group (p < 0.05). Estradiol concentrations of mice treated with ghrelin were higher than the PCOS group (p < 0.05). The concentrations of low and high-density lipoprotein, triglyceride, and cholesterol in mice treated with ghrelin were lower than in the PCOS mice (p < 0.05). Inflammatory gene expression for IL-6, IL-1ß, TNF-α, TLR4, NF-κB-p65, and MYD88 decreased in the ovarian tissues of ghrelin-treated mice compared to the PCOS group (p < 0.05), along with reduced protein expression of TLR4, p-NF-κB-p65, and MYD88 (p < 0.05). CONCLUSIONS: In the present study, ghrelin treatment effectively reduced inflammation in vitro, and attenuated insulin resistance and reproductive abnormalities in PCOS mice through the TLR4/NF-κB signaling pathway, highlighting potential therapeutic avenues for future PCOS treatments and research directions.


Subject(s)
Ghrelin , Inflammation , Insulin Resistance , NF-kappa B , Polycystic Ovary Syndrome , Signal Transduction , Toll-Like Receptor 4 , Animals , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/pathology , Female , Toll-Like Receptor 4/metabolism , Mice , Signal Transduction/drug effects , NF-kappa B/metabolism , Inflammation/metabolism , Humans , Disease Models, Animal , Granulosa Cells/metabolism , Granulosa Cells/drug effects , Granulosa Cells/pathology
5.
Tissue Cell ; 88: 102375, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38604038

ABSTRACT

Polycystic Ovary Syndrome (PCOS) is a multifactorial reproductive, endocrine and metabolic disturbance which is very commonly observed in females of reproductive age group. The disease is still incurable however the use of synthetic drugs in combination with lifestyle is recommended. Accordingly, the present study was conducted to investigate the possible beneficial effects of sitagliptin on PCOS induced rats on control diet (CD)/high fat- high fructose diet (HFFD). PCOS was induced by giving testosterone propionate (TP) for 28 days to both the CD/HFFD rats and treated with STG i.p. for last 15 days. At the end of the experiment lipid profile, inflammatory markers, expression of NF-κB-p65, miR-24 and miR-29a, fibrotic and apoptotic proteins from ovary tissue were examined. Moreover, lipid accumulation and fibrosis of ovary tissue was further confirmed using Sudan III and Masson's trichrome stain. STG treated rats exerted a significant decrease in levels of cholesterol, TG, LDL-C, VLDL-C, IL-6 and TNF-α and increased HDL-C level, miR-24 and miR-29a expression. STG treated groups expressed significantly decreased expression of NF-κB-p65, TGF-ß1, p-Smad 2 and p-Smad 3 followed by no significant changes in the expression of BAX, caspase-9, caspase-3 and Bcl-2 in all the PCOS induced groups. Among all the CD/ HFFD fed groups, rats on HFFD showed more devastating effect which suggests that diet plays a major role in genesis of PCOS. In conclusion, current results reflect the potential impact of STG against dyslipidaemia, inflammation and fibrosis in PCOS rats via regulating dyslipidaemia and fibrosis via DPP 4 mediated miR-29a expression.


Subject(s)
Diet, High-Fat , Fructose , MicroRNAs , Polycystic Ovary Syndrome , Signal Transduction , Sitagliptin Phosphate , Transforming Growth Factor beta , Animals , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/pathology , MicroRNAs/metabolism , MicroRNAs/genetics , Female , Fructose/adverse effects , Rats , Sitagliptin Phosphate/pharmacology , Diet, High-Fat/adverse effects , Signal Transduction/drug effects , Transforming Growth Factor beta/metabolism , Rats, Wistar , Dipeptidyl Peptidase 4
6.
Tissue Cell ; 88: 102394, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38663112

ABSTRACT

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic dysfunction. This study aims to compare the oral and local treatments of metformin or its nanoparticles (NPs11) for ameliorating PCOS in rats. Rats were divided into 4 groups: the control group with no drug treatment; the PCOS group, where subcutaneous testosterone was given (10 mg/kg/day) for 28 days; the MET group, where metformin was administered orally or locally; and the NP group, where metformin NPs11 were also administered orally or locally. Oral administrations were for 21 days, while local injection was performed once surgically. After 7 weeks, all rats were sacrificed; blood glucose and serum hormonal levels and lipid profile were estimated, and the ovaries were assessed by histopathological, Ki-67 immunohistochemical, and histomorphometric evaluations. Blood glucose levels were significantly decreased in groups of orally administered metformin or NPs11 only, while the most efficient option for modulating PCOS-induced hormonal and lipid profile changes was intraovarian injection of NPs11. The ovaries of PCOS rats demonstrated large follicular cysts, massive collagen depositions, and attenuated Ki-67 immunoexpression. Also, the PCOS group revealed a significant decrease in the count of all stages of growing follicles, corpora lutea, granulosa cell layer thickness, and surface area of corpora lutea, in addition to an increase in the number of atretic follicles and follicular cysts, theca cell layer thickness, and surface area of the follicular cysts. All these parameters were recovered with metformin or their NPs11 treatments in different degrees, while local injection of NPs11 was the best option.


Subject(s)
Metformin , Nanoparticles , Ovary , Polycystic Ovary Syndrome , Testosterone , Animals , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/pathology , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/metabolism , Metformin/pharmacology , Metformin/administration & dosage , Female , Testosterone/blood , Rats , Administration, Oral , Ovary/metabolism , Ovary/drug effects , Ovary/pathology , Blood Glucose/metabolism , Blood Glucose/drug effects , Rats, Wistar
7.
Steroids ; 206: 109424, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38642598

ABSTRACT

OBJECTIVE: This study aimed to evaluate the effects of dehydroepiandrosterone (DHEA) and DHEA combined with a high-fat diet (HFD) treatment of reproductive and endocrine metabolism in rats and then identify an ideal model of polycystic ovary syndrome (PCOS). METHODS: Three-week-old female Sprague-Dawley rats were injected subcutaneously with DHEA or oil, fed with or without a HFD, for 21 days, during which body weight, feed intake, and estrous cycle monitoring were carried out. Fasting blood glucose was measured, and serum fasting insulin, testosterone, dihydrotestosterone (DHT), estradiol, progesterone, luteinizing hormone (LH), anti-Müllerian hormone (AMH), and follicle-stimulating hormone (FSH) were estimated by ELISA. Serum total cholesterol (TC), total triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured by colorimetric assay. Whereas, histologic changes in rat ovaries were evaluated by H&E staining. Ovarian steroid hormone synthases and their protein levels (StAR, 3ß-HSD2, 17ß-HSD1, CYP11A1, CYP17A1, and CYP19A1) were examined by Western blotting. RESULTS: Both DHEA and DHEA + HFD-treated rats lost a regular estrous cycle; had polycystic ovarian changes, significantly higher serum fasting insulin and testosterone levels; and increased ovarian StAR, 3ß-HSD2, and CYP11A1 protein levels. Additionally, rats in the DHEA + HFD-treated group were obese; had elevated fasting blood glucose, TG, DHT, AMH levels and LH:FSH ratios; increased ovarian 17ß-HSD1 protein levels. CONCLUSION: DHEA combined with HFD treatment is more effective at inducing PCOS than DHEA alone. The reproductive and endocrine metabolic aspects of this method are more consistent with the clinical characteristics of PCOS patients.


Subject(s)
Dehydroepiandrosterone , Diet, High-Fat , Disease Models, Animal , Polycystic Ovary Syndrome , Rats, Sprague-Dawley , Animals , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/pathology , Polycystic Ovary Syndrome/blood , Female , Dehydroepiandrosterone/blood , Diet, High-Fat/adverse effects , Rats , Ovary/metabolism , Ovary/drug effects , Ovary/pathology , Estrous Cycle/drug effects
8.
Biochem Biophys Res Commun ; 715: 150005, 2024 Jun 30.
Article in English | MEDLINE | ID: mdl-38678785

ABSTRACT

BACKGROUND: Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder among women of reproductive age, is characterized by disturbances in hormone levels and ovarian dysfunction. Ferroptosis, a unique form of regulated cell death characterized by iron-dependent lipid peroxidation. Emerging evidence indicates that ferroptosis may have a significant role in the pathogenesis of PCOS, highlighting the importance of studying this mechanism to better understand the disorder and potentially develop novel therapeutic interventions. METHODS: To create an in vivo PCOS model, mice were injected with dehydroepiandrosterone (DHEA) and the success of the model was confirmed through further assessments. Ferroptosis levels were evaluated through detecting ferroptosis-related indicators. Ferroptosis-related genes were found through bioinformatic analysis and identified by experiments. An in vitro PCOS model was also established using DHEA treated KGN cells. The molecular binding relationship was confirmed using a chromatin immunoprecipitation (ChIP) assay. RESULTS: In PCOS model, various ferroptosis-related indicators such as MDA, Fe2+, and lipid ROS showed an increase, while GSH, GPX4, and TFR1 exhibited a decrease. These findings indicate an elevated level of ferroptosis in the PCOS model. The ferroptosis-related gene FADS2 was identified and validated. FADS2 and PPAR-α were shown to be highly expressed in ovarian tissue and primary granulosa cells (GCs) of PCOS mice. Furthermore, the overexpression of both FADS2 and PPAR-α in KGN cells effectively suppressed the DHEA-induced increase in ferroptosis-related indicators (MDA, Fe2+, and lipid ROS) and the decrease in GSH, GPX4, and TFR1 levels. The ferroptosis agonist erastin reversed the suppressive effect, suggesting the involvement of ferroptosis in this process. Additionally, the FADS2 inhibitor SC26196 was found to inhibit the effect of PPAR-α on ferroptosis. Moreover, the binding of PPAR-α to the FADS2 promoter region was predicted and confirmed. This indicates the regulatory relationship between PPAR-α and FADS2 in the context of ferroptosis. CONCLUSIONS: Our study indicates that PPAR-α may have an inhibitory effect on DHEA-induced ferroptosis in GCs by enhancing the expression of FADS2. This discovery provides valuable insights into the pathophysiology and potential therapeutic targets for PCOS.


Subject(s)
Dehydroepiandrosterone , Ferroptosis , Granulosa Cells , PPAR alpha , Polycystic Ovary Syndrome , Up-Regulation , Ferroptosis/drug effects , Female , Animals , Granulosa Cells/metabolism , Granulosa Cells/drug effects , Dehydroepiandrosterone/pharmacology , Mice , Up-Regulation/drug effects , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/pathology , Polycystic Ovary Syndrome/genetics , PPAR alpha/metabolism , PPAR alpha/genetics , Humans , Mice, Inbred C57BL , Disease Models, Animal
9.
J Assist Reprod Genet ; 41(5): 1387-1401, 2024 May.
Article in English | MEDLINE | ID: mdl-38656738

ABSTRACT

OBJECTIVE: Women who are of reproductive age can suffer from polycystic ovary syndrome (PCOS), an endocrine disorder. Anovulatory infertility is mostly caused by aberrant follicular development, which is seen in PCOS patients. Due to the dysfunction of reproductive and endocrine function in PCOS patients, assisted reproduction treatment is one of the main means to obtain clinical pregnancy for PCOS patients. Long non-coding RNA (lncRNA) as a group of functional RNA molecules have been found to participate in the regulation of oocyte function, hormone metabolism, and proliferation and apoptosis of granulosa cells. In this study, we investigated the role of lncRNAs in follicular fluid-derived exosomes and the underlying mechanism of lncRNA LIPE-AS1. METHODS: We used RNA sequencing to analyze the lncRNA profiles of follicular fluid-derived exosomes in PCOS patients and controls. RT-qPCR was performed to detect the expression levels of these lncRNAs in control (n = 30) and PCOS (n = 30) FF exosome samples. Furthermore, we validated the performance of lncRNA LIPE-AS1 in oocyte maturation by in vitro maturation (IVM) experiments in mouse and steroid metabolism in granulosa cells. RESULTS: We found 501 lncRNAs were exclusively expressed in the control group and another 273 lncRNAs were found to be specifically expressed in the PCOS group. LncRNA LIPE-AS1, highly expressed in PCOS exosomes, was related to a poor oocyte maturation and embryo development in PCOS patients. Reduced number of MII oocytes were observed in the LIPE-AS1 group by in vitro maturation (IVM) experiments in mouse. LIPE-AS1 was also shown to modulate steroid metabolism and granulosa cell proliferation and apoptosis by LIPE-AS1/miR-4306/LHCGR axis. CONCLUSION: These findings suggested that the increased expression of LIPE-AS1, facilitated by follicular fluid exosomes, had a significant impact on both oocyte maturation and embryo development. We demonstrated the ceRNA mechanism involving LIPE-AS1, miR-4306, and LHCGR as a regulator of hormone production and metabolism. These findings indicate that LIPE-AS1 is essential in PCOS oocyte maturation and revealed a ceRNA network of LIPE-AS1 and provided new information on abnormal steroid metabolism and oocyte development in PCOS.


Subject(s)
Exosomes , Follicular Fluid , Granulosa Cells , Oocytes , Polycystic Ovary Syndrome , RNA, Long Noncoding , Polycystic Ovary Syndrome/genetics , Polycystic Ovary Syndrome/pathology , Polycystic Ovary Syndrome/metabolism , Female , Follicular Fluid/metabolism , RNA, Long Noncoding/genetics , Granulosa Cells/metabolism , Granulosa Cells/pathology , Humans , Exosomes/genetics , Exosomes/metabolism , Oocytes/metabolism , Oocytes/growth & development , Mice , Animals , In Vitro Oocyte Maturation Techniques , Adult , Steroids/metabolism , Oogenesis/genetics , Apoptosis/genetics , Cell Proliferation/genetics
10.
NanoImpact ; 34: 100507, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38663500

ABSTRACT

Polystyrene microplastics, extensively considered endocrine disrupting chemicals, disturb the reproductive system of living organisms. Polycystic ovary syndrome (PCOS), the reproductive endocrinopathy, is longstanding concern due to its eternal impacts as reproductive disorder and infertility. Despite several reports in reproductive and endocrine toxicity, there is inadequate literature regarding the daily intake of polystyrene-microplastics via drinking water in causing PCOS and leading to ovarian fibrosis in long-term. The present study investigated whether daily consumption of polystyrene-microplastics at doses equivalent to human exposure can cause PCOS and progress to ovarian fibrosis, using female zebrafish as model. Resembling letrozole-PCOS zebrafish model, daily intake of polystyrene-microplastics displayed hallmark PCOS pathophysiology; like excess body weight and %Gonadosomatic index, decreased Follicle Stimulating Hormone and ß-estradiol, increased Luteinising Hormone, brain and ovarian Testosterone (39.3% and 75% respectively). Correspondingly, ovarian histology revealed more developing (stage I and II) oocytes and less mature oocytes alongwith cystic lesions; like follicular membrane disorganization, zona pellucida invagination, theca hypertrophy, basophilic granular accumulation and oocyte buddings. Lipid deposition in intestinal and ovarian tissues was evidenced and increased fasting blood glucose manifesting insulin resistance. The expression of PCOS biomarkers (tox3, dennd1a, fem1a) was significantly disturbed. Polystyrene microplastics played vital role in inducing PCOS further enhancing oxidative stress, which positively influences inflammation and aggravate ovarian mitophagy, shedding light on its ability to harshen PCOS into ovarian fibrosis, which is characterized by collagen deposition and upregulation of pro-fibrogenic biomarker genes. These findings illustrate the potential of daily microplastics intake via drinking water in triggering PCOS and its progression to ovarian fibrosis.


Subject(s)
Drinking Water , Fibrosis , Microplastics , Ovary , Polycystic Ovary Syndrome , Polystyrenes , Zebrafish , Animals , Female , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/pathology , Microplastics/toxicity , Microplastics/adverse effects , Polystyrenes/adverse effects , Polystyrenes/toxicity , Drinking Water/adverse effects , Drinking Water/chemistry , Ovary/pathology , Ovary/drug effects , Ovary/metabolism , Fibrosis/chemically induced , Water Pollutants, Chemical/toxicity , Water Pollutants, Chemical/adverse effects , Disease Models, Animal
11.
Mol Med Rep ; 29(6)2024 06.
Article in English | MEDLINE | ID: mdl-38666538

ABSTRACT

Polycystic ovary syndrome (PCOS) is a globally prevalent gynecological disorder among women of childbearing age. The present study aimed to investigate the role of tenascin C (TNC) in PCOS and its potential mechanisms. Fasting blood glucose and serum insulin, the homeostasis model assessment of insulin resistance and the serum hormone levels were determined in PCOS rats. In addition, H&E staining was used for assessing pathology. In addition, the effects of TNC on oxidative stress and inflammation response in PCOS rat and cell models was assessed. Furthermore, the roles of TNC on KGN cell proliferation and apoptosis were determined employing EdU assay and flow cytometry. TLR4/NF­κB pathway­related proteins were measured using western blotting, immunofluorescence and immunohistochemistry. It was found that the mRNA and protein expression was upregulated in PCOS rats and in KGN cells induced by dihydrotestosterone (DHT). Knockdown of TNC relieved the pathological characteristics and the endocrine abnormalities of PCOS rats. Knockdown of TNC inhibited ovarian cell apoptosis, oxidative stress and inflammation in PCOS rats. Knockdown of TNC reversed the DHT­induced reduction in cell proliferation and increase in apoptosis in KGN cells. Furthermore, knockdown of TNC alleviated oxidative stress and inflammatory responses induced by DHT in KGN cells. Additionally, knockdown of TNC inhibited the toll­like receptor 4 (TLR4)/NF­κB signaling pathway in PCOS rats and DHT­treated KGN cells. In conclusion, knockdown of TNC could ameliorate PCOS in both rats and a cell model by inhibiting cell apoptosis, oxidative stress and inflammation via the suppression of the TLR4/NF­κB signaling pathway.


Subject(s)
Apoptosis , Cell Proliferation , NF-kappa B , Oxidative Stress , Polycystic Ovary Syndrome , Signal Transduction , Tenascin , Toll-Like Receptor 4 , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/pathology , Polycystic Ovary Syndrome/genetics , Female , Animals , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/genetics , NF-kappa B/metabolism , Rats , Tenascin/metabolism , Tenascin/genetics , Disease Models, Animal , Rats, Sprague-Dawley , Insulin Resistance , Humans , Cell Line
12.
J Ovarian Res ; 17(1): 78, 2024 Apr 10.
Article in English | MEDLINE | ID: mdl-38600539

ABSTRACT

BACKGROUND: This study investigated the association between Anti-Müllerian Hormone (AMH) and relevant metabolic parameters and assessed its predictive value in the clinical diagnosis of polycystic ovarian syndrome (PCOS). METHODS: A total of 421 women aged 20-37 years were allocated to the PCOS (n = 168) and control (n = 253) groups, and their metabolic and hormonal parameters were compared. Spearman correlation analysis was conducted to investigate associations, binary logistic regression was used to determine PCOS risk factors, and receiver operating characteristic (ROC) curves were generated to evaluate the predictive value of AMH in diagnosing PCOS. RESULTS: The PCOS group demonstrated significantly higher blood lipid, luteinizing hormone (LH), and AMH levels than the control group. Glucose and lipid metabolism and hormonal disorders in the PCOS group were more significant than in the control group among individuals with and without obesity. LH, TSTO, and AMH were identified as independent risk factors for PCOS. AMH along with LH, and antral follicle count demonstrated a high predictive value for diagnosing PCOS. CONCLUSION: AMH exhibited robust diagnostic use for identifying PCOS and could be considered a marker for screening PCOS to improve PCOS diagnostic accuracy. Attention should be paid to the effect of glucose and lipid metabolism on the hormonal and related parameters of PCOS populations.


Subject(s)
Anti-Mullerian Hormone , Polycystic Ovary Syndrome , Female , Humans , Anti-Mullerian Hormone/blood , Glucose/metabolism , Luteinizing Hormone/blood , Polycystic Ovary Syndrome/blood , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/pathology , Sensitivity and Specificity , Adult
13.
J Ovarian Res ; 17(1): 72, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38566229

ABSTRACT

BACKGROUND: Polycystic ovarian syndrome (PCOS) is the most common endocrine disease in women of childbearing age which is often associated with abnormal proliferation or apoptosis of granulosa cells (GCs). Studies proved that long non-coding RNA SNHG12 (lncRNA SNHG12) is significantly increased in ovarian cancer and cervical cancer patients and cells. The inhibition of lncRNA SNHG12 restrains the proliferation, migration, and invasion in tumor cells. OBJECTIVE: This study explores the role of lncRNA SNHG12 in the apoptosis of GCs in PCOS and the underlying regulated mechanism. METHODS: In this study, the injection of dehydroepiandrosterone (DHEA) successfully induced the PCOS model in SD rats. The human granulosa-like tumor cell line KGN was incubated with insulin to assess the effects of lncRNA SNHG12 on GC proliferation and apoptosis. RESULTS: Overexpression of lncRNA SNHG12 influenced the body weight, ovary weight, gonadal hormone, and pathological changes, restrained the expressions of microRNA (miR)-129 and miR-125b, while downregulation of lncRNA SNHG12 exerted the opposite effects in PCOS rats. After silencing lncRNA SNHG12 in cells, the cell viability and proliferation were lessened whereas apoptosis of cells was increased. A loss-of-functions test was implemented by co-transfecting miR-129 and miR-125b inhibitors into lncRNA SNHG12-knocking down cells to analyze the effects on cell viability and apoptosis. Next, the existence of binding sites of SNHG12 and miR-129/miR-125b was proved based on the pull-down assay. CONCLUSION: lncRNA SNHG12 might be a potential regulatory factor for the development of PCOS by sponging miR-129 and miR-125b in GCs.


Subject(s)
MicroRNAs , Polycystic Ovary Syndrome , RNA, Long Noncoding , Humans , Female , Rats , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , Polycystic Ovary Syndrome/pathology , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Rats, Sprague-Dawley , Granulosa Cells/metabolism , Cell Proliferation , Apoptosis/genetics
14.
DNA Cell Biol ; 43(4): 158-174, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38588493

ABSTRACT

Polycystic ovary syndrome (PCOS) refers to an endocrine disorder syndrome that are correlated with multiple organs and systems. PCOS has an effect on women at all stages of their lives, and it has an incidence nearly ranging from 6% to 20% worldwide. Mitochondrial dysfunctions (e.g., oxidative stress, dynamic imbalance, and abnormal quality control system) have been identified in patients and animal models of PCOS, and the above processes may play a certain role in the development of PCOS and its associated complications. However, their specific pathogenic roles should be investigated in depth. In this review, recent studies on the mechanisms of action of mitochondrial dysfunction in PCOS and its associated clinical manifestations are summarized from the perspective of tissues and organs, and some studies on the treatment of the disease by improving mitochondrial function are reviewed to highlight key role of mitochondrial dysfunction in this syndrome.


Subject(s)
Mitochondrial Diseases , Polycystic Ovary Syndrome , Animals , Female , Humans , Polycystic Ovary Syndrome/pathology , Mitochondria/metabolism , Oxidative Stress , Mitochondrial Diseases/pathology
15.
Mol Hum Reprod ; 30(5)2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38603629

ABSTRACT

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, but its pathology has not been fully characterized and the optimal treatment strategy remains unclear. Cellular senescence is a permanent state of cell-cycle arrest that can be induced by multiple stresses. Senescent cells contribute to the pathogenesis of various diseases, owing to an alteration in secretory profile, termed 'senescence-associated secretory phenotype' (SASP), including with respect to pro-inflammatory cytokines. Senolytics, a class of drugs that selectively eliminate senescent cells, are now being used clinically, and a combination of dasatinib and quercetin (DQ) has been extensively used as a senolytic. We aimed to investigate whether cellular senescence is involved in the pathology of PCOS and whether DQ treatment has beneficial effects in patients with PCOS. We obtained ovaries from patients with or without PCOS, and established a mouse model of PCOS by injecting dehydroepiandrosterone. The expression of the senescence markers p16INK4a, p21, p53, γH2AX, and senescence-associated ß-galactosidase and the SASP-related factor interleukin-6 was significantly higher in the ovaries of patients with PCOS and PCOS mice than in controls. To evaluate the effects of hyperandrogenism and DQ on cellular senescence in vitro, we stimulated cultured human granulosa cells (GCs) with testosterone and treated them with DQ. The expression of markers of senescence and a SASP-related factor was increased by testosterone, and DQ reduced this increase. DQ reduced the expression of markers of senescence and a SASP-related factor in the ovaries of PCOS mice and improved their morphology. These results indicate that cellular senescence occurs in PCOS. Hyperandrogenism causes cellular senescence in GCs in PCOS, and senolytic treatment reduces the accumulation of senescent GCs and improves ovarian morphology under hyperandrogenism. Thus, DQ might represent a novel therapy for PCOS.


Subject(s)
Cellular Senescence , Granulosa Cells , Polycystic Ovary Syndrome , Quercetin , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/pathology , Female , Cellular Senescence/drug effects , Humans , Animals , Granulosa Cells/metabolism , Granulosa Cells/drug effects , Granulosa Cells/pathology , Quercetin/pharmacology , Mice , Senescence-Associated Secretory Phenotype , Adult , Dasatinib/pharmacology , Disease Models, Animal , Senotherapeutics/pharmacology , Hyperandrogenism/pathology , Hyperandrogenism/metabolism , Interleukin-6/metabolism , Dehydroepiandrosterone/pharmacology
16.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167182, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38653359

ABSTRACT

OBJECTIVE: This work aimed to investigate the role of rhythm gene PER1 in mediating granulosa cell ferroptosis and lipid metabolism of polycystic ovary syndrome (PCOS). METHODS: We injected dehydroepiandrosterone and Ferrostatin-1 (Fer-1) into mice to explore the mechanism of ferroptosis in PCOS. The effect of PER1 on ferroptosis-like changes in granulosa cells was explored by overexpression of PER1 plasmid transfection and Fer-1 treatment. RESULTS: We found that Fer-1 ameliorated the characteristic polycystic ovary morphology, suppressed ferroptosis in the PCOS mice. PER1 and ALOX15 were highly expressed in PCOS, whereas SREBF2 was lowly expressed. Overexpression of PER1 decreased granulosa cell viability and inhibited proliferation. Meanwhile, overexpression of PER1 increased lipid reactive oxygen species, 4-Hydroxynonenal (4-HNE), Malondialdehyde (MDA), total Fe, and Fe2+ levels in granulosa cells and decreased Glutathione (GSH) content. Fer-1, SREBF2 overexpression, or ALOX15 silencing treatment reversed the effects of PER1 overexpression on granulosa cells. PER1 binds to the SREBF2 promoter and represses SREBF2 transcription. SREBF2 binds to the ALOX15 promoter and represses ALOX15 transcription. Correlation analysis of clinical trials showed that PER1 was positively correlated with total cholesterol, low-density lipoprotein cholesterol, luteinizing hormone, testosterone, 4-HNE, MDA, total Fe, Fe2+, and ALOX15. In contrast, PER1 was negatively correlated with SREBF2, high-density lipoprotein cholesterol, follicle-stimulating hormone, progesterone, and GSH. CONCLUSION: This study demonstrates that the rhythm gene PER1 promotes ferroptosis and dysfunctional lipid metabolism in granulosa cells in PCOS by inhibiting SREBF2/ALOX15 signaling.


Subject(s)
Ferroptosis , Granulosa Cells , Lipid Metabolism , Polycystic Ovary Syndrome , Animals , Female , Humans , Mice , Arachidonate 12-Lipoxygenase , Arachidonate 15-Lipoxygenase/metabolism , Arachidonate 15-Lipoxygenase/genetics , Cyclohexylamines/pharmacology , Dehydroepiandrosterone/metabolism , Ferroptosis/genetics , Granulosa Cells/metabolism , Granulosa Cells/pathology , Lipid Metabolism/genetics , Phenylenediamines/pharmacology , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/genetics , Polycystic Ovary Syndrome/pathology , Reactive Oxygen Species/metabolism
17.
Reproduction ; 167(6)2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38520750

ABSTRACT

In brief: Brown adipose tissue impaired in polycystic ovary syndrome (PCOS) plays a crucial role in the treatment of PCOS. This study shows that myricetin potently improves PCOS by activating brown adipose tissue (BAT). Abstract: PCOS is a complex endocrine disease characterized by hyperandrogenism, anovulation and polycystic ovary, and is often accompanied by metabolic disorder such as insulin resistance. BAT has been considered as a promising target for the treatment of obesity and other metabolic disease. In this study, we showed that 3 weeks of myricetin (a compound from natural product) treatment improved metabolic capacity and insulin sensitivity by activating BAT in dehydroepiandrosterone (DHEA)-induced PCOS mice. Furthermore, increased number of corpus luteum and decreased cystic formation were observed in PCOS mice. With the hormone levels such as luteinizing hormone (LH) were reversed, estrous cycle was also normalized after myricetin treatment. Eventually, myricetin markedly improved reproductive defects in PCOS mice. In short, our results suggest that myricetin treatment dramatically ameliorates ovarian dysfunction and metabolic disturbances in PCOS and provides a novel perspective for the treatment of PCOS.


Subject(s)
Adipose Tissue, Brown , Flavonoids , Insulin Resistance , Polycystic Ovary Syndrome , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/pathology , Animals , Female , Flavonoids/pharmacology , Flavonoids/therapeutic use , Adipose Tissue, Brown/drug effects , Adipose Tissue, Brown/metabolism , Mice , Mice, Inbred C57BL
18.
F S Sci ; 5(2): 204-211, 2024 May.
Article in English | MEDLINE | ID: mdl-38484797

ABSTRACT

OBJECTIVE: To study the combined and isolated effects of melatonin and metformin in the ovarian tissue of rats with PCOS. DESIGN: Experimental study using a rat model of PCOS induced by continuous light exposure. INTERVENTION(S): Forty adult female rats were divided into 5 groups: physiological estrus phase (Sham); permanente estrus with PCOS induced by continuous lighting exposure for 60 consecutive days (control); with PCOS treated with melatonin; with PCOS treated with metformin; with PCOS treated with melatonin + metformin. After 60 days of treatments, all rats were killed, and ovaries were collected and processed for paraffin-embedding. Formalin-fixed paraffin-embedded sections were stained with hematoxylin and eosin or subjected to immunohistochemistry for proliferation (Ki-67) and apoptosis (cleaved caspase 3) detection markers. SETTING: Federal University of São Paulo, Brazil. ANIMALS: Forty adult female Wistar rats (Rattus norvegicus albinus). MAIN OUTCOME MEASURE(S): Number of corpus luteum and ovarian cysts, number of ovarian follicles (primary and antral follicles), number of interstitial cells, percentage of ovarian follicles (primary and antral follicles), and of interstitial cells immunostained to cleaved caspase-3 and Ki-67. RESULTS: Absence of corpus luteum, a higher number of cysts, and increased nuclear volume and area of interstitial cells, along with a decrease in primary and antral follicle numbers, were noticed in the control group compared with the Sham group. Melatonin and metformin treatments attenuated these effects, although the combined treatment did not mitigate the increased number of cysts and ovaries induced by PCOS. An increase in theca interna cell apoptosis was observed in the control group, whereas melatonina and metformin treatments reduced it significantly. A higher percentage of caspase-3-immunostained granulosa cells was noted in the Sham and all treated groups compared with the control group; no aditive effects on ovarian cell apoptosis were observed in the combined treatment. The percentage of Ki-67- immunostained granulosa cells was significantly higher in the control group compared with the Sham group. However, the combined treatment, not melatonin and metformin alone, mitigated this effect. A higher percentage of Ki-67-immunostained interstitial cells was observed in all treated groups compared with the Sham and control groups, whereas no additive effects in that immunoreactivity were observed in the combined treatment. CONCLUSIONS: Melatonin and metformin may improve ovarian function in rats with PCOS. The combined melatonin and metformin treatment is more effective in attenuating excessive granulosa cell proliferation, but it is not more effective in improving ovarian function than these drugs applied alone in rats with PCOS.


Subject(s)
Melatonin , Metformin , Ovary , Polycystic Ovary Syndrome , Rats, Wistar , Animals , Female , Metformin/pharmacology , Metformin/administration & dosage , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/pathology , Polycystic Ovary Syndrome/chemically induced , Melatonin/pharmacology , Melatonin/administration & dosage , Ovary/drug effects , Ovary/pathology , Rats , Apoptosis/drug effects , Caspase 3/metabolism , Disease Models, Animal , Ki-67 Antigen/metabolism , Ki-67 Antigen/analysis
19.
Biomed Pharmacother ; 174: 116504, 2024 May.
Article in English | MEDLINE | ID: mdl-38552442

ABSTRACT

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The aim of this study was to investigate the therapeutic potential of vitamin C, glutamine, mesalazine, hydralazine, and alendronate as new drug candidates for the treatment of letrozole-induced PCOS in female Wistar rats. PCOS was induced in rats by intramuscular injection of estradiol valerate (2 mg/kg body weight for 28 days). The rats then received normal saline (PCOS group), letrozole (0.5 mg/kg), vitamin C (100 mg/kg), glutamine (1000 mg/kg), mesalazine (200 mg/kg), hydralazine (30 mg/kg), and alendronate (17.5 mg/kg). Serum testosterone, LH, FSH, estradiol and progesterone levels were determined by ELISA method. H&E staining was used for histological analysis in the ovarian tissues. The groups treated with hydralazine and alendronate, show a significant decrease in testosterone, LH hormone, cystic and atretic follicles, and a significant increase in the number of single layer, multilayer, antral, graafian follicles and the volume of corpus luteum as compared to the PCOS group. Hydrolazine and alendronate appear to be effective in restoring folliculogenesis and increasing ovulation in PCOS rat. So that the natural process of ovulation and the improvement of the histology of polycystic ovaries and its shift towards healthy and active ovaries were observed. This finding supports the potential beneficial effect of hydrolazine and alendronate on improving PCOS complication.


Subject(s)
Alendronate , Aromatase Inhibitors , Hydralazine , Polycystic Ovary Syndrome , Animals , Female , Rats , Alendronate/pharmacology , Aromatase Inhibitors/pharmacology , Disease Models, Animal , Estradiol/blood , Hydralazine/pharmacology , Hydralazine/therapeutic use , Letrozole , Luteinizing Hormone/blood , Ovary/drug effects , Ovary/pathology , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/pathology , Rats, Wistar , Testosterone/blood
20.
J Ovarian Res ; 17(1): 29, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38302986

ABSTRACT

BACKGROUND: Polycystic ovary syndrome (PCOS) is a frequent and complicated endocrine disease that remains a major reason for infertility. Bushenhuoluo Decotion (BSHLD) has been validated to exhibit curative effects on PCOS. This study was aimed to explore the potential mechanism underlying the therapeutic action of BSHLD. METHODS: PCOS rat model was induced by dehydroepiandrosterone (DHEA). Serum hormone and cytokines levels and ovarian pathological alterations were measured to assess ovarian function. Exosomes (Exos) were identified by Transmission electron microscopy and Nanoparticle Tracking Analysis. RT-qPCR, Western blotting, immunohistochemical staining, and immunofluorescence staining were performed to detect molecule expressions. Proliferation and pyroptosis of granulosa cells (GCs) were evaluated by CCK-8 and flow cytometry, respectively. The binding relationship between miR-30a-5p and suppressor of cytokine signaling 3 (SOCS3) was verified by dual luciferase reporter and RIP assays. RESULTS: BSHLD treatment improved serum hormone abnormality, insulin sensitivity, and ovarian morphologic changes of PCOS rats. Moreover, BSHLD treatment restrained the excessive autophagy and pyroptosis in ovarian tissues of PCOS rats. Moreover, BSHLD reduced the expression of miR-30a-5p in serum, serum-derived Exos, and ovarian tissues, thus inhibiting autophagy and NLRP3-mediated pyroptosis in GCs. Mechanistically, SOCS3 was proved as a target of miR-30a-5p and could activate mTOR/P70S6K pathway to repress autophagy. The inhibitory effect of miR-30a-5p deficiency on autophagy and pyroptosis of GCs was attenuated by rapamycin. CONCLUSION: Collectively, BSHLD suppressed autophagy and pyroptosis to improve POCS by regulating exosomal miR-30a-5p/SOCS3/mTOR signaling.


Subject(s)
Drugs, Chinese Herbal , MicroRNAs , Plant Extracts , Polycystic Ovary Syndrome , Animals , Female , Humans , Rats , Autophagy , Hormones , MicroRNAs/genetics , MicroRNAs/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Polycystic Ovary Syndrome/pathology , Pyroptosis , Suppressor of Cytokine Signaling 3 Protein/genetics , Suppressor of Cytokine Signaling 3 Protein/metabolism , TOR Serine-Threonine Kinases/metabolism , Plant Extracts/therapeutic use , Drugs, Chinese Herbal/therapeutic use
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