RESUMEN
Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is closely associated with chronic low-grade inflammation and insulin resistance. To clarify the contribution of prepubertal weight gain to the development of insulin resistance in PCOS, we investigated the effects of early postnatal overfeeding on inflammatory and energy-sensing pathways as well as on markers of insulin signaling in the liver of the PCOS rat model. Methods: Obesity induced by overfeeding was achieved by reducing litter size, while the PCOS-like condition was developed by treatment with 5α-dihydrotestosterone (DHT). Western blot and qPCR were used to analyze the expression of pro-inflammatory transcription factors and cytokines, as well as markers of the energy sensing and insulin signaling pathways. Results: The results showed that hepatic insulin sensitivity was impaired only in DHT-treated rats raised in small litters, as evidenced by increased phosphorylation of IRS1 on Ser307 and decreased expression of total IRS1. Postnatal overfeeding stimulated JNK1 activation independent of hyperandrogenemia; nevertheless, the synergistic effect of both factors triggered NLRP3 activation and increased IL1ß expression in the small litter DHT-treated group. This pro-inflammatory state was accompanied by decreased activatory phosphorylation of AMPK and reduced levels of its protein targets. Conclusions: Overfeeding in the early postnatal period leads to a decrease in hepatic insulin sensitivity in the rat model of PCOS, which is associated with decreased activation of AMPK and stimulation of the hepatic NLRP3-IL1ß signaling pathway. Accordingly, the inhibition of NLRP3 activation could provide a basis for the development of new therapeutic strategies for the treatment of insulin resistance in women with PCOS.
Asunto(s)
Dihidrotestosterona , Modelos Animales de Enfermedad , Inflamación , Resistencia a la Insulina , Hígado , Hipernutrición , Síndrome del Ovario Poliquístico , Animales , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/patología , Femenino , Ratas , Dihidrotestosterona/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Inflamación/metabolismo , Inflamación/patología , Hipernutrición/metabolismo , Hipernutrición/complicaciones , Ratas Wistar , Obesidad/metabolismo , Animales Recién Nacidos , Transducción de Señal/efectos de los fármacos , Proteínas Sustrato del Receptor de Insulina/metabolismoRESUMEN
This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.
Asunto(s)
Hipotálamo , Subunidad alfa del Factor 1 Inducible por Hipoxia , Síndrome del Ovario Poliquístico , Piroptosis , Ratas Wistar , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/patología , Femenino , Animales , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/patología , Piroptosis/efectos de los fármacos , Ratas , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Resistencia a la Insulina , Factor 2 Relacionado con NF-E2/metabolismo , Modelos Animales de Enfermedad , Letrozol/farmacología , Triglicéridos/sangre , Triglicéridos/metabolismo , Hormona Luteinizante/sangre , Hormona Folículo Estimulante/sangre , Adiponectina/metabolismo , Adiponectina/sangre , Testosterona/sangre , Leptina/sangre , Leptina/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age globally. Emerging evidence suggests that the dysregulation of microRNAs (miRNAs) and gut dysbiosis are linked to the development of PCOS. In this study, the effects of Lacticaseibacillus paracasei subsp. paracasei DSM 27449 (DSM 27449) were investigated in a rat model of PCOS induced by letrozole. The administration of DSM 27449 resulted in improved ovarian function, reduced cystic follicles, and lower serum testosterone levels. Alterations in miRNA expressions and increased levels of the pro-apoptotic protein Bax in ovarian tissues were observed in PCOS-like rats. Notably, the administration of DSM 27449 restored the expression of miRNAs, including miR-30a-5p, miR-93-5p, and miR-223-3p, leading to enhanced ovarian function through the downregulation of Bax expressions in ovarian tissues. Additionally, 16S rRNA sequencing showed changes in the gut microbiome composition after letrozole induction. The strong correlation between specific bacterial genera and PCOS-related parameters suggested that the modulation of the gut microbiome by DSM 27449 was associated with the improvement of PCOS symptoms. These findings demonstrate the beneficial effects of DSM 27449 in ameliorating PCOS symptoms in letrozole-induced PCOS-like rats, suggesting that DSM 27449 may serve as a beneficial dietary supplement with the therapeutic potential for alleviating PCOS.
Asunto(s)
Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Letrozol , MicroARNs , Síndrome del Ovario Poliquístico , Animales , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Femenino , Ratas , Microbioma Gastrointestinal/efectos de los fármacos , MicroARNs/genética , MicroARNs/metabolismo , Ovario/efectos de los fármacos , Ovario/metabolismo , Ovario/patología , Probióticos , Testosterona/sangre , Ratas Sprague-Dawley , ARN Ribosómico 16S/genética , Proteína X Asociada a bcl-2/metabolismo , Proteína X Asociada a bcl-2/genéticaRESUMEN
The most common cause of anovulatory infertility is polycystic ovarian syndrome (PCOS), which is closely associated with obesity and metabolic syndrome. Artificial sweetener, notably saccharin sodium (SS), has been utilized in management of obesity in PCOS. However, accumulating evidence points towards SS deleterious effects on ovarian physiology, potentially through activation of ovarian sweet and bitter taste receptors, culminating in a phenotype reminiscent of PCOS. This research embarked on exploration of SS influence on ovarian functions within a PCOS paradigm. Rats were categorized into six groups: Control, Letrozole-model, two SS groups at 2 dose levels, and two groups receiving 2 doses of SS with Letrozole. The study underscored SS capability to potentiate PCOS-related anomalies. Elevated cystic profile with outer thin granulosa cells, were discernible. This owed to increased apoptotic markers as cleaved CASP-3, mirrored by high BAX and low BCL-2, with enhanced p38-MAPK/ERK1/2 pathway. This manifestation was accompanied by activation of taste receptors and disruption of steroidogenic factors; StAR, CYP11A1, and 17ß-HSD. Thus, SS showed an escalation in testosterone, progesterone, estrogen, and LH/FSH ratio, insinuating a perturbation in endocrine regulation. It is found that there is an impact of taste receptor downstream signaling on ovarian steroidogenesis and apoptosis instigating pathophysiological milieu of PCOS.
Asunto(s)
Modelos Animales de Enfermedad , Letrozol , Síndrome del Ovario Poliquístico , Sacarina , Animales , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/metabolismo , Femenino , Ratas , Sacarina/administración & dosificación , Receptores Acoplados a Proteínas G/metabolismo , Apoptosis/efectos de los fármacos , Ratas Sprague-Dawley , Edulcorantes/toxicidad , Ovario/efectos de los fármacos , Ovario/metabolismoRESUMEN
Growing evidence supports the role of gut microbiota in chronic inflammation, insulin resistance (IR) and sex hormone production in polycystic ovary syndrome (PCOS). Adropin plays a pivotal role in the regulation of glucose and lipid metabolism and is negatively correlated with IR, which affects intestinal microbiota and sex hormones. However, the effect of adropin administration in PCOS has yet to be investigated. The present study aimed to assess the effects of adropin on letrozole (LTZ)-induced PCOS in rats and the potential underlying mechanisms. The experimental groups were normal, adropin, letrozole and LTZ + adropin. At the end of the experiment, adropin significantly ameliorated PCOS, as evidenced by restoring the normal ovarian structure, decreasing the theca cell thickness in antral follicles, as well as serum testosterone and luteinizing hormone levels and luteinizing hormone/follicle-stimulating hormone ratios, at the same time as increasing granulosa cell thickness in antral follicles, oestradiol and follicle-stimulating hormone levels. The ameliorating effect could be attributed to its effect on sex hormone-binding globulin, key steroidogenic genes STAR and CYP11A1, IR, lipid profile, gut microbiota metabolites-brain-ovary axis components (short chain fatty acids, free fatty acid receptor 3 and peptide YY), intestinal permeability marker (zonulin and tight junction protein claudin-1), lipopolysaccharides/Toll-like receptor 4/nuclear factor kappa B inflammatory pathway and oxidative stress makers (malondialdehyde and total antioxidant capacity). In conclusion, adropin has a promising therapeutic effect on PCOS by regulating steroidogenesis, IR, lipid profile, the gut microbiota inflammatory axis and redox homeostasis. KEY POINTS: Adropin treatment reversed endocrine and ovarian morphology disorders in polycystic ovary syndrome (PCOS). Adropin regulated the ovarian steroidogenesis and sex hormone-binding globulin in PCOS. Adropin improved lipid profile and decreased insulin resistance in PCOS. Adropin modulated the components of the gut-brain-ovary axis (short chain fatty acids, free fatty acid receptor 3 and peptide YY) in PCOS. Adropin improved intestinal barrier integrity, suppressed of lipopolysaccharides/Toll-like receptor 4/nuclear factor kappa B signalling pathway and oxidative stress in PCOS.
Asunto(s)
Microbioma Gastrointestinal , Letrozol , Síndrome del Ovario Poliquístico , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/metabolismo , Femenino , Letrozol/farmacología , Ratas , Microbioma Gastrointestinal/efectos de los fármacos , Ratas Sprague-Dawley , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Ovario/efectos de los fármacos , Ovario/metabolismo , Péptidos/farmacología , Resistencia a la Insulina , Proteínas SanguíneasRESUMEN
Polycystic ovary syndrome (PCOS) is one of the leading causes of infertility in women. Animal models are widely used to study the etiologic mechanisms of PCOS and for related drug development. Letrozole-induced mouse models replicate the metabolic and reproductive phenotypes of patients with PCOS. The traditional method of letrozole treatment in PCOS mice requires daily dosing over a certain period, which can be labor-intensive and cause significant stress to the mice. This study describes a simple and effective method for inducing PCOS in mice by implanting a controlled letrozole-releasing mini-pump. A mini-pump capable of stable, continuous release of a quantitative amount of letrozole was fabricated and implanted subcutaneously in mice under anesthesia. This study demonstrated that the mouse model successfully mimicked PCOS features after letrozole mini-pump implantation. The materials and equipment used in this study are readily available to most laboratories, requiring no special customization. Collectively, this article provides a unique, easy-to-perform method for inducing PCOS in mice.
Asunto(s)
Ratones , Síndrome del Ovario Poliquístico , Síndrome del Ovario Poliquístico/inducido químicamente , Letrozol/administración & dosificación , Femenino , Implantes de Medicamentos , Inhibidores de la Aromatasa/administración & dosificaciónRESUMEN
BACKGROUND: This study aimed to explore the impact of Diacerein (DIC) on endocrine and cardio-metabolic changes in polycystic ovarian syndrome (PCOS) mouse model. METHODS: A total of 18 adult female mice (Parkes strain), aged 4-5 weeks, were randomly assigned to three groups, each comprising 6 animals, as follows: Group I (control), received normal diet and normal saline as vehicle for 51 days; Group II received Letrozole (LET; 6 mg/kg bw) for 21 days to induce PCOS; Group III received LET, followed by daily oral gavage administration of DIC (35 mg/kg bw) for 30 days. RESULTS: This study indicates that treatment with LET resulted in PCOS with characteristics such as polycystic ovaries, elevated testosterone, weight gain, visceral adiposity, high levels of insulin as well as fasting blood glucose in addition to insulin resistance, improper handling of ovarian lipids, atherogenic dyslipidemia, impaired Na + /K + -ATPase activity and serum, cardiac, and ovarian oxidative stress. Serum/ovarian adiponectin levels were lowered in LET-treated mice. In mice treated with LET, we also discovered a reduction in cardiac and serum paraoxonase 1 (PON1). Interestingly, DIC restored ovarian andcardio-metabolic abnormalities in LET-induced PCOS mice. DIC prevented the endocrine and cardio-metabolic changes brought on by letrozole-induced PCOS in mice. CONCLUSION: The ameliorative effects of DIC on letrozole-induced PCOS with concurrent oxidative stress, abdominal fat deposition, cardiac and ovarian substrate mishandling, glucometabolic dysfunction, and adiponectin/PON1 activation support the idea that DIC perhaps, restore compromised endocrine and cardio-metabolic regulators in PCOS.
Asunto(s)
Antraquinonas , Arildialquilfosfatasa , Modelos Animales de Enfermedad , Resistencia a la Insulina , Síndrome del Ovario Poliquístico , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/metabolismo , Femenino , Ratones , Antraquinonas/farmacología , Antraquinonas/uso terapéutico , Arildialquilfosfatasa/metabolismo , Letrozol , Receptores de Adiponectina/metabolismo , Estrés Oxidativo/efectos de los fármacos , Adiponectina/metabolismoRESUMEN
Polycystic ovary syndrome (PCOS) is the most common gynaecological, endocrine disorder that occurs during reproductive age and is a significant cause of anovulatory infertility. Letrozole is an aromatase inhibitor which negates the action of the aromatase enzyme, which results in the buildup of male hormones (testosterone) in the females, causing hyperandrogenism, which is a hallmark of Polycystic Ovarian Syndrome. Mifepristone (RU486) is a progestin antagonist that acts to arrest the actions of the progesterone hormone, resulting in follicular atresia and anovulation. DHEA is an androgen which was also administered in a bid to cause hyperandrogenism in the rats.This study aimed to evaluate the effects of these hormones on the cytoarchitecture of the ovaries and uterus to assess their various PCOS-like histological features.Animals were grouped mainly into three: Letrozole, Mifepristone and DHEA groups, which were further divided into two subgroups each, administered low and high doses of letrozole orally, Mifepristone and Dehydroepiandosterone (DHEA) subcutaneously. Each of the subgroups also had a comparison control group. Following the completion of administration, the Wistar rats were euthanized, and their ovaries and uterus were collected for histological analysis.Increased proliferation of ovarian follicles was noted in the treated groups compared to control, as well as thickening of the endometrial layer.
Asunto(s)
Modelos Animales de Enfermedad , Letrozol , Mifepristona , Ovario , Síndrome del Ovario Poliquístico , Ratas Wistar , Útero , Animales , Femenino , Síndrome del Ovario Poliquístico/patología , Síndrome del Ovario Poliquístico/inducido químicamente , Ratas , Letrozol/farmacología , Ovario/patología , Ovario/efectos de los fármacos , Mifepristona/farmacología , Útero/patología , Útero/efectos de los fármacos , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/patología , Folículo Ovárico/metabolismo , Deshidroepiandrosterona/farmacologíaRESUMEN
BACKGROUND: Polycystic ovary syndrome (PCOS) is a common and complex endocrine disease in women, with a prevalence of 5% to 18% worldwide. HeQi San (HQS) is a Chinese medicine compound prescription, which has been applied to treat various endocrine and metabolic diseases. OBJECTIVE: The study was intended to investigate the effect of HQS on PCOS, and clarify the potential mechanism via in vivo and in vitro experiments. METHODS: The PCOS mouse model was established by injecting the dehydroepiandrosterone (DHEA) subcutaneously and fading high-fat diet for 3 weeks. After making model, PCOS mice were treated with HQS (8.75 g/kg and 17.5 g/kg, ig.) for 4 weeks. Firstly, we assessed the histopathological changes in ovary tissues and detected the hormone level. Subsequently, the study evaluated the capability of anti-inflammatory and regulating macrophage polarization of HQS in vivo and in vitro. The secretion of inflammation indicators was measured with Elisa kits, and the expression level of phosphorylated nuclear factor kappa-B (P-NFκB) and B-lymphocyte activation antigen B7 (CD80) was measured by immunofluorescence and Western blot. Meanwhile, the apoptosis of ovarian granulosa cells was detected via tunel staining and Western blot. The co-culture model in vitro was utilized to assess the effect between macrophage polarization and human ovarian granulosa cells (KGN cells) apoptosis. Furthermore, 16S rDNA sequencing was utilized to elevate gut microbiota change in PCOS mice. RESULTS: HQS reversed the abnormal hormone increase, ameliorated insulin resistance, and improved histopathological changes of the ovary tissue to exert the therapeutic effect. HQS inhibited the expression of P-NF-κB and decreased the production of interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) to further prohibit the macrophage M1 polarization in ovary tissues and macrophages. The apoptosis-positive cells, Bcl-2 Assaciated X protein (BAX), and cleaved-caspase 3 expression were also decreased in the treatment group. The B-cell lymphoma-2 (Bcl2) expression was enhanced after HQS treatment in vivo. The co-culture experiments also verified that HQS could prevent the apoptosis of KGN cells. Furthermore, HQS mediated the abundance of gut flora. The abundance of bifldobacterium and parasutterella was increased and the abundance of lachnoclostridium was decreased. CONCLUSION: The study verified that HQS has the effect of anti-inflammation and inhibits macrophage M1 polarization. Besides, HQS could mediate the abundance of gut microbiota in mice with PCOS. Thus, this study would provide more reasonable basis of HQS for clinical use. In conclusion, HQS might be a potential candidate for PCOS treatment.
Asunto(s)
Antiinflamatorios , Deshidroepiandrosterona , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Síndrome del Ovario Poliquístico , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/inmunología , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ovario/patología , Ovario/efectos de los fármacos , Ovario/inmunología , Ovario/metabolismo , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Células RAW 264.7 , Citocinas/metabolismo , Apoptosis/efectos de los fármacos , FN-kappa B/metabolismo , Dieta Alta en Grasa/efectos adversos , Inflamación/tratamiento farmacológico , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a widespread endocrine disorder among women, characterized by symptoms like ovarian cysts, hormonal imbalance, and metabolic issues. This research evaluates the therapeutic potential of Bone Marrow Mesenchymal Stem Cell-derived exosomes (BMSC-Exo) in treating PCOS symptoms within a mouse model. METHODS: BMSC-Exo were isolated from NMRI mice, characterized using Transmission Electron Microscopy (TEM) and Nanoparticle Tracking Analysis (NTA), and administered to a PCOS mouse model induced by dehydroepiandrosterone (DHEA). The efficacy of BMSC-Exo was assessed in three groups of mice: a control group, a PCOS group, and a PCOS group treated with intravenous BMSC-Exo. Morphological changes in ovarian tissue were examined by Hematoxylin and Eosin (H&E) staining, apoptosis was determined using the TUNEL assay, and CD31 expression was analyzed through immunofluorescent staining to assess angiogenic activity. RESULTS: The existence of BMSCs-Exo was confirmed via TEM and NTA, revealing their distinct cup-shaped morphology and a size range of 30 to 150 nanometers. H&E staining revealed that BMSCs-Exo treatment improved ovarian morphology in PCOS models, increasing corpora lutea and revitalizing granulosa cell layers, suggesting a reversal of PCOS-induced damage. TUNEL assays showed that BMSCs-Exo treatment significantly reduced apoptosis in PCOS-affected ovarian cells to levels comparable with the control group, highlighting its role in mitigating PCOS-induced cellular apoptosis. Immunofluorescence for CD31 indicated that BMSCs-Exo treatment normalized endothelial marker expression and angiogenic activity in PCOS models, suggesting its effectiveness in modulating the vascular irregularities of PCOS. Collectively, these findings demonstrate the therapeutic potential of BMSCs-Exo in addressing ovarian dysfunction, cellular apoptosis, and aberrant angiogenesis associated with PCOS. CONCLUSION: The study substantiates the role of BMSC-Exo in mitigating the deleterious effects of PCOS on ovarian tissue, with implications for enhanced follicular development and reduced cellular stress. The modulation of CD31 by BMSC-Exo further highlights their potential in normalizing PCOS-induced vascular anomalies. These findings propel the need for clinical investigations to explore BMSC-Exo as a promising therapeutic avenue for PCOS management.
Asunto(s)
Apoptosis , Exosomas , Células Madre Mesenquimatosas , Síndrome del Ovario Poliquístico , Animales , Femenino , Ratones , Angiogénesis , Deshidroepiandrosterona , Modelos Animales de Enfermedad , Exosomas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Neovascularización Fisiológica , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/terapiaRESUMEN
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.
Asunto(s)
Quimiocina CCL2 , Cinamatos , Depsidos , Modelos Animales de Enfermedad , Letrozol , Síndrome del Ovario Poliquístico , Ácido Rosmarínico , Factor A de Crecimiento Endotelial Vascular , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Femenino , Cinamatos/farmacología , Depsidos/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratas , Quimiocina CCL2/metabolismo , Letrozol/farmacología , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Inmunohistoquímica , Testosterona/sangre , Ratas Sprague-DawleyRESUMEN
The present study was conducted to evaluate the combination effect of apple cider vinegar (ACV) and metformin against letrozole-induced polycystic ovary syndrome (PCOS). Female Wistar rats were administered letrozole (1 mg/kg/day, p.o) for 21 days, except for the control group of animals. On the 22nd day, PCOS-induced animals were segregated into 4 groups and administered with CMC, ACV, metformin, and a combination of ACV and metformin, respectively. The treatments were continued for 15 days, and on the 36th day, all the animals were sacrificed for biochemical (blood glucose, lipid profile), hormonal (sex hormones and adiponectin), and pro-inflammatory mediator estimations in blood samples. The ovarian tissue samples were used for oxidative stress parameters and histological alterations. The PCOS control animals showed a significant alteration in the estrous cycle. The administration of letrozole resulted in the alteration of hormonal balance and elevation of body weights, glycemic state, lipid profile, pro-inflammatory mediators in serum, and oxidative stress in ovarian samples. Individual treatment groups and combination treatment groups reversed the letrozole-induced alterations in PCOS animals, and more promising results were observed with combination therapy than with individual treatment groups. Further, the therapeutic potential of the combination treatment group was also confirmed by the histological observations in the ovarian samples. The study showed that the combination of ACV and metformin significantly alleviated letrozole-induced PCOS complications in rats. This might have been achieved by mitigating the hormonal imbalance, pro-inflammatory, hyperglycemic, and hyperlipidemic states in serum, and oxidative stress in the ovary samples.
Asunto(s)
Ácido Acético , Sinergismo Farmacológico , Quimioterapia Combinada , Hipoglucemiantes , Letrozol , Metformina , Estrés Oxidativo , Síndrome del Ovario Poliquístico , Ratas Wistar , Animales , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/patología , Femenino , Letrozol/administración & dosificación , Metformina/farmacología , Metformina/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Ratas , Hipoglucemiantes/farmacología , Hipoglucemiantes/administración & dosificación , Ovario/efectos de los fármacos , Ovario/patología , Ovario/metabolismo , Malus/química , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/administración & dosificación , Ciclo Estral/efectos de los fármacosRESUMEN
Polycystic ovary syndrome (PCOS) is a gynecological disorder among reproductive-aged women and a major cause of infertility. Different treatment options are being employed but with side effects. This has mandated alternative treatment options, especially complementary therapy. This study therefore investigated the possible protective effects of methanol extract of Drymaria cordata in Letrozole-induced PCOS. The plant is folklorically used in the treatment of diverse ailments including PCOS, fibroids, uterine/ovarian/breast tumors, and cancers. Forty-eight female Wistar rats were acclimatized and initially divided into two groups: group I(control group) and group II(PCOS group). PCOS was induced by the oral administration of letrozole/high-fat diet for 21 days. After the induction, the PCOS group was sub-divided into four groups (n = 4): group II (positive control with PCOS), group III (MET 2mg/kg), group IV (MEDC 200mg/kg), and group V (MEDC 400mg/kg). Rats were orally treated with MET and MEDC for six weeks after the PCOS induction. At the end of the experimental period, blood samples were collected, sera were separated, mitochondria were isolated, and the mPT, some apoptotic biomarkers, hormonal and lipid profiles, and oxidative stress markers were determined. Ovarian histological evaluation and GC-MS analysis of MEDC were carried out. There was no significant mPT pore opening in the PCOS (untreated) group. However, treatments with MEDC caused significant mPT pore opening, upraised caspase 9, caspase 3, and Bax, and decreased anti-apoptotic Bcl-2 levels. The MEDC treatments restored the hormonal and lipid profiles, increased the levels of GSH-Px and SOD and decreased TBARS. Histological examination revealed resolved ovarian cysts and improved follicular growth with MEDC treatments. Comparable results were observed for both MEDC and metformin. The GC-MS analysis revealed the presence of some major pharmacologically relevant compounds. These findings suggest that MEDC contains phytochemicals that can protect against letrozole-induced PCOS possibly by normalizing the impaired hormonal balance, restoring the lipid profile, and improving the antioxidant milieu of the system.
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Antioxidantes , Apoptosis , Letrozol , Extractos Vegetales , Síndrome del Ovario Poliquístico , Ratas Wistar , Animales , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Femenino , Extractos Vegetales/farmacología , Apoptosis/efectos de los fármacos , Antioxidantes/farmacología , Ratas , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Triazoles/farmacología , Hormonas Esteroides Gonadales/sangre , Ovario/efectos de los fármacos , Ovario/patología , Ovario/metabolismo , Nitrilos/farmacología , Metanol/químicaRESUMEN
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.
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Ghrelina , Inflamación , Resistencia a la Insulina , FN-kappa B , Síndrome del Ovario Poliquístico , Transducción de Señal , Receptor Toll-Like 4 , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/patología , Femenino , Receptor Toll-Like 4/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Inflamación/metabolismo , Humanos , Modelos Animales de Enfermedad , Células de la Granulosa/metabolismo , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/patologíaRESUMEN
AIMS: Polycystic ovarian syndrome (PCOS) is one of the most common (about 5-20%) reproductive disorders in women of reproductive age; it is characterized by polycystic ovaries, hyperandrogenism, and oligo/ anovulation. The levels and expression of ovarian adipokines are deregulated in the PCOS. Apelin is an adipokine that acts through its receptor (APJ) and is known to express in the various tissues including the ovary. It has also been suggested that apelin and APJ could be targeted as therapeutic adjuncts for the management of PCOS. However, no study has been conducted on the management of PCOS by targeting the apelin system. Thus, we aimed to evaluate its impact on combating PCOS-associated ovarian pathogenesis. METHODS: The current work employed a letrozole-induced-hyperandrogenism PCOS-like mice model to investigate the effects of apelin13 and APJ, antagonist ML221. The PCOS model was induced by oral administration of letrozole (1 mg/kg) for 21 days. A total of four experimental groups were made, control, PCOS control, PCOS + aplein13, and PCOS + ML221. The treatment of apelin13 and ML221 was given from day 22 for two weeks. KEY FINDINGS: The letrozole-induced PCOS-like features such as hyperandrogenism, cystic follicle, decreased corpus luteum, elevated levels of LH/FSH ratio, and up-regulation of ovarian AR expression were ameliorated by apelin13 and ML221 treatment. However, the PCOS-augmented oxidative stress and apoptosis were suppressed by apelin 13 treatments only. ML221 treatment still showed elevated oxidative stress and stimulated apoptosis as reflected by decreased antioxidant enzymes and increased active caspase3 and Bax expression. The expression of ERs was elevated in all groups except control. Furthermore, the PCOS model showed elevated expression of APJ and apelin13 treatment down-regulated its own receptor. Overall, observing the ovarian histology, corpus luteum formation, and decreased androgen levels by both apelin13 and ML221 showed ameliorative effects on the cystic ovary. SIGNIFICANCE: Despite the similar morphological observation of ovarian histology, apelin13 and ML221 exhibited opposite effects on oxidative stress and apoptosis. Therefore, apelin13 (which down-regulates APJ) and ML221 (an APJ antagonist) may have suppressed APJ signalling, which would account for our findings on the mitigation of polycystic ovarian syndrome. In conclusion, both apelin13 and ML221 mediated mitigation have different mechanisms, which need further investigation.
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Receptores de Apelina , Apelina , Letrozol , Ovario , Síndrome del Ovario Poliquístico , Letrozol/farmacología , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Animales , Femenino , Receptores de Apelina/metabolismo , Ratones , Apelina/metabolismo , Ovario/metabolismo , Ovario/patología , Ovario/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Hiperandrogenismo/metabolismo , Hiperandrogenismo/inducido químicamente , Apoptosis/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with reproductive dysfunction and metabolic abnormalities, particularly characterized by insulin resistance and chronic low-grade inflammation. Multiple clinical studies have clearly demonstrated the significant efficacy and safety of the combination of Bailing capsules (BL) in the treatment of PCOS, but its pharmacological effects and mechanisms still require further study. AIM OF THE STUDY: To evaluate the effect of BL on improving PCOS in mice and explore the mechanism. METHODS: In this study, Dehydroepiandrosterone (DHEA) injection was administered alone and in combination with a high-fat and high-sugar diet to induce PCOS-like mouse. They were randomly divided into five groups: normal group (N), PCOS group (P), Bailing capsule low-dose group (BL-L), Bailing capsule high-dose group (BL-H) and Metformin + Daine-35 group (M + D). Firstly, the effects of BL on ovarian lesions, serum hormone levels, HOMA-IR, intestinal barrier function, inflammation levels, along with the expression of IRS1, PI3K, AKT, TLR4, Myd88, NF-κB p65, TNF-α, IL-6, and Occludin of the ovary, liver and colon were investigated. Finally, the composition of the gut microbiome of fecal was tested. RESULTS: The administration of BL significantly reduced body weight, improved hormone levels, improved IR, and attenuated pathological damage to ovarian tissues, up-regulated the expression of IRS1, PI3K, and AKT in liver. It also decreased serum LPS, TNF-α, and IL-6 levels, while downregulating the expression of Myd88, TLR4, and NF-κB p65. Additionally, BL improved intestinal barrier damage and upregulated the expression of Occludin. Interestingly, the abundance of norank_f__Muribaculacea and Lactobacillus was down-regulated, while the abundance of Akkermansia was significantly up-regulated. CONCLUSION: The results of the study showed that BL exerts a treatment PCOS effect, which may be related to the modulation of the gut microbiota, the improvement of insulin resistance and the intestinal-derived LPS-TLR4 inflammatory pathway. Our research will provide a theoretical basis for the clinical treatment of PCOS.
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Medicamentos Herbarios Chinos , Lipopolisacáridos , Síndrome del Ovario Poliquístico , Transducción de Señal , Receptor Toll-Like 4 , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/inducido químicamente , Animales , Femenino , Receptor Toll-Like 4/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Resistencia a la Insulina , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Deshidroepiandrosterona/farmacología , Cápsulas , Intestinos/efectos de los fármacos , Ratones Endogámicos C57BL , Ovario/efectos de los fármacos , Ovario/metabolismo , Ovario/patologíaRESUMEN
Polycystic ovary syndrome (PCOS) is a condition resulting from the interaction between environmental factors and hereditary components, profoundly affecting offspring development. Although the etiology of this disease remains unclear, aberrant in utero androgen exposure is considered one of the pivotal pathogenic factors. Herein, we demonstrate the intergenerational inheritance of PCOS-like phenotypes in F2 female offspring through F1 males caused by maternal testosterone exposure in F0 mice. We found impaired serum hormone expression and reproductive system development in prenatal testosterone-treated F1 male and F2 female mice (PTF1 and PTF2). In addition, downregulated N6-methyladenosine (m6A) methyltransferase and binding proteins induced mRNA hypomethylation in the PTF1 testis, including frizzled-6 (Fzd6). In the PTF2 ovary, decreased FZD6 protein expression inhibited the mammalian target of rapamycin (mTOR) signaling pathway and activated Forkhead box O3 (FoxO3) phosphorylation, which led to impaired follicular development. These data indicate that epigenetic modification of the mTOR signaling pathway could be involved in the intergenerational inheritance of maternal testosterone exposure-induced impairments in the PTF2 ovary through male PTF1 mice.
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Herencia Paterna , Efectos Tardíos de la Exposición Prenatal , Testosterona , Animales , Femenino , Masculino , Ratones , Efectos Tardíos de la Exposición Prenatal/genética , Embarazo , Testosterona/sangre , Herencia Paterna/genética , Exposición Materna/efectos adversos , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/inducido químicamente , Epigénesis Genética , Andrógenos/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Ovario/metabolismo , Ovario/efectos de los fármacos , Testículo/metabolismo , Testículo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Metilación de ADN/efectos de los fármacos , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/genéticaRESUMEN
Polycystic ovary syndrome (PCOS) is a prevalent endocrinologic and gynecologic disorder that affects women of reproductive age; besides, insulin resistance (IR) occurs in 50-70 % of PCOS cases. Metformin (Met) is commonly prescribed for IR management; however, it does not affect IR with some gastrointestinal symptoms. Spirulina platensis (SP) is a blue-green alga that may increase insulin sensitivity. Therefore, our study aims to evaluate SP as an alternative treatment to Met for improving glucose homeostasis by assessing the expression of 11 crucial genes involved in the insulin signaling pathway. After induction of the PCOS model using dehydroepiandrosterone (DHEA) (60 mg/kg bwt) for 30 consecutive days, rats were allocated into six groups. Relative liver weight, glutamic pyruvic transaminase (GPT) serum levels, glutamic-oxaloacetic transaminase (GOT), and insulin were determined. Furthermore, the gene expression of Ins1, Irs1, Pik3ca, Prkcz, Foxo1, Srebf1, Ppargc1a, Pklr, Gk, G6pc, and Pepck in the rat's liver tissue was determined using qRT-PCR. Treatment of the PCOS control group with Met or SP revealed a decrease in all these parameters compared with the PCOS model. Additionally, we found a statistically significant difference in the expression of both the Gk and Prkcz genes. To summarize our study results, SP or Met supplementation to PCOS rats had almost the same effect on assessed relative liver weight, GOT, GPT, and insulin levels compared with PCOS control rats. If further studies confirm and detect more impact of SP on IR in PCOS, SP could be used instead of Met since the latter causes many side effects.
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Modelos Animales de Enfermedad , Resistencia a la Insulina , Insulina , Metformina , Síndrome del Ovario Poliquístico , Transducción de Señal , Spirulina , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/metabolismo , Femenino , Metformina/farmacología , Ratas , Transducción de Señal/efectos de los fármacos , Insulina/sangre , Hígado/metabolismo , Hígado/efectos de los fármacos , Ratas Wistar , Hipoglucemiantes/farmacología , Regulación de la Expresión Génica/efectos de los fármacosRESUMEN
Polycystic ovary syndrome (PCOS) is the most common cause of anovulation and infertility in women. Inflammation and oxidative stress are considered to be the causes of ovarian dysfunction in PCOS. Dimethyl itaconate, as a macrophage-derived immunometabolite, has anti-inflammatory and antioxidative properties, but limited data are available about its effect on female reproductive dysfunctions. The present study aimed to determine the effects of dimethyl itaconate, a cell-permeable derivative of itaconate, on the histological changes, oxidative stress, and inflammation in the ovaries of PCOS rats. In this experimental study, 48 mature female Wistar rats (160-180â¯g) were randomly divided into the six groups including control, PCOS, PCOS+DMI, PCOS+ metformin, control DMI and control metformin. Following PCOS induction by using testosterone enanthate (1â¯mg/100â¯g/day for 35 days), the animals were treated with DMI (50â¯mg/kg) or metformin (300â¯mg/kg) for 30 days. At the end of the experimental period, the insulin resistance markers (serum insulin and glucose concentrations, and the homeostasis model assessment of basal insulin resistance (HOMA-IR), oxidative stress index (OSI), and inflammatory cytokines were measured. The process of Folliculogenesis was evaluated by histological examination of the ovary. The results showed that DMI improved insulin resistance and decreased TNF- and IL-1ß levels and OSI in the ovarian tissue of rats following androgen-induced PCOS. It also improved steroidogenesis and Folliculogenesis by reducing cystic follicles and ovarian tissue structure. Results indicated that DMI may be a potential candidate to ameliorate PCOS adverse effects by reducing insulin resistance, inflammation, and oxidative stress and restoring ovarian Folliculogenesis.
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Inflamación , Resistencia a la Insulina , Metformina , Ovario , Estrés Oxidativo , Síndrome del Ovario Poliquístico , Ratas Wistar , Succinatos , Animales , Femenino , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/patología , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Ratas , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Succinatos/farmacología , Ovario/efectos de los fármacos , Ovario/patología , Ovario/metabolismo , Metformina/farmacología , Modelos Animales de Enfermedad , Antioxidantes/farmacología , Insulina/metabolismo , Insulina/sangreRESUMEN
INTRODUCTION: In humans, prenatal androgen excess can lead to a broad spectrum of pathologies in adulthood, including polycystic ovary syndrome (PCOS). Women with PCOS present a variety of reproductive and metabolic disturbances and they also face increased risk to develop neuropsychiatric disorders such as depression and anxiety. Despite the high prevalence, the cause of depressive and anxiety symptoms is not fully elucidated. The use of androgenized ewe models can provide valuable insights into the pathogenesis of PCOS, as they closely mimic the reproductive, neuroendocrine, and metabolic characteristics observed in women with this condition. METHOD: We studied the impact of prenatal exposure to testosterone propionate on cognitive and behavioral performances of Ile-de-France ewes, using a plethora of behavioral tests for anxiety and cognitive performances. RESULTS: Our findings indicate that prenatal androgenized ewes exhibit markedly elevated levels of anxiety-like behavior compared to control animals, while showing no discernible differences in cognitive performance. CONCLUSION: These discoveries offer novel perspectives on how maternal androgen excess contributes to anxiogenic effects in PCOS preclinical models, underscoring the ewe's significance as a model for conducting mechanistic studies to unravel the physiological and molecular aspects of anxiety.