RESUMEN
AIMS: Phytoestrogens can act as natural estrogens owing to their structural similarity to human estrogens. Biochanin-A (BCA) is a well-studied phytoestrogen with a wide variety of pharmacological activities, whereas not reported in the most frequently encountered endocrinopathy called polycystic ovary syndrome (PCOS) in women. PURPOSE: This study aimed to investigate the therapeutic effect of BCA on dehydroepiandrosterone (DHEA) induced PCOS in mice. MAIN METHODS: Thirty-six female C57BL6/J mice were divided into six groups: sesame oil, DHEA-induced PCOS, DHEA + BCA (10 mg/kg/day), DHEA + BCA (20 mg/kg/day), DHEA + BCA (40 mg/kg/day), and metformin (50 mg/kg/day). KEY FINDINGS: The results showed a decrease in obesity, elevated lipid parameters, restoration of hormonal imbalances (testosterone, progesterone, estradiol, adiponectin, insulin, luteinizing hormone, and follicle-stimulating hormone), estrus irregular cyclicity, and pathological changes in the ovary, fat pad, and liver. SIGNIFICANCE: In conclusion, BCA supplementation inhibited the over secretion of inflammatory cytokines (TNF-α, IL-6, and IL-1ß) and upregulated TGFß superfamily markers such as GDF9, BMP15, TGFßR1, and BMPR2 in the ovarian milieu of PCOS mice. Furthermore, BCA reversed insulin resistance by increasing circulating adiponectin levels through a negative correlation with insulin levels. Our results indicate that BCA attenuated DHEA-induced PCOS ovarian derangements, which could be mediated by the TGFß superfamily signaling pathway via GDF9 and BMP15 and associated receptors as first evidenced in this study.
Asunto(s)
Síndrome del Ovario Poliquístico , Animales , Femenino , Ratones , Adiponectina/metabolismo , Proteína Morfogenética Ósea 15/genética , Proteína Morfogenética Ósea 15/metabolismo , Deshidroepiandrosterona/uso terapéutico , Estrógenos/uso terapéutico , Factor 9 de Diferenciación de Crecimiento/genética , Factor 9 de Diferenciación de Crecimiento/metabolismo , Insulina/metabolismo , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Melatonin, as a free radical scavenger exhibiting genomic actions, regulates the antioxidant genes expression and apoptosis mechanisms. In polycystic ovary syndrome (PCOS) patients, an imbalance between free radicals and antioxidants in follicular fluid leads to oxidative stress, aberrant folliculogenesis, and intrinsic defects in PCOS oocytes. In this experimental mouse model study, oocytes of PCOS and the control groups were cultured in different melatonin concentrations (10- 5, 10- 6, and 10- 7 M) to investigate the expression of oocyte maturation-related genes (Gdf9/Bmp15), antioxidant-related genes (Gpx1/Sod1), apoptotic biomarkers (Bcl2/Bax) and total intracellular ROS levels. RESULTS: Gdf9 and Bmp15, Gpx1 and Sod1 were up-regulated in PCOS and control oocytes cultured in all melatonin concentrations compared to those cultured in IVM basal medium (P < 0.05). A significant decrease in the total ROS level was observed in all groups cultured in the supplemented cultures. Melatonin increased Bcl2 and decreased Bax gene expression in PCOS and control oocytes compared to non-treated oocytes. CONCLUSIONS: Melatonin increased antioxidant gene expression and regulated the apoptosis pathway, effectively reducing the adverse effects of culture conditions on PCOS oocytes. Furthermore, it influenced the expression of oocyte maturation-related genes in PCOS, providing valuable support during the IVM process.
Asunto(s)
Antioxidantes/metabolismo , Melatonina/farmacología , Oocitos/efectos de los fármacos , Oogénesis/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteína Morfogenética Ósea 15/genética , Deshidroepiandrosterona/toxicidad , Modelos Animales de Enfermedad , Femenino , Glutatión Peroxidasa/genética , Factor 9 de Diferenciación de Crecimiento/genética , Técnicas de Maduración In Vitro de los Oocitos , Ratones , Oocitos/metabolismo , Oogénesis/genética , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa-1/genética , Proteína X Asociada a bcl-2/genética , Glutatión Peroxidasa GPX1RESUMEN
It is widely known that breast cancer cells eventually develop resistance to hormonal drugs and chemotherapies, which often compromise fertility. This study aimed to investigate the effect of the flavonoid, kaempferol-3-O-apiofuranosyl-7-O-rhamnopyranosyl (KARP), on 1) the viability of MCF-7 breast cancer cells and 2) ovarian function in rats. A dose-dependent decrease in MCF-7 cell survival was observed, and the IC50 value was found to be 48 µg/ml. Cells in the control group or those exposed to increasing concentrations of KARP experienced a similar generation of reactive oxygen species and induction of apoptosis. For the rats, estradiol levels correlated negatively to KARP dosages, although a recovery was obtained at administration of 30 mg/kg per day. Noteworthily, when compared against the control, this dosage led to significant increases in mRNA levels for CYP19, CYP17a, CCND2, GDF9, and INSL3 among the treatment groups, and ER1 and ER2 mRNA levels decreased in a dose-dependent manner. KARP shows great promise as an ideal therapy for breast cancer patients since it induced apoptosis and autophagy in cancerous cells without harming fertility in our animal model. Future investigations on humans are necessary to substantiate these findings and determine its efficacy as a general line of treatment.
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Neoplasias de la Mama , Flavonoides , Animales , Apoptosis , Aromatasa/genética , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Ciclina D2 , Femenino , Factor 9 de Diferenciación de Crecimiento/genética , Humanos , Insulina/genética , Quempferoles/farmacología , Proteínas/genética , Ratas , Esteroide 17-alfa-Hidroxilasa/genéticaRESUMEN
Although previous research has demonstrated the key role of the oocyte-derived factors, bone morphogenetic protein (BMP) 15 and growth differentiation factor (GDF) 9, in follicular development and ovulation, there is a lack of knowledge on the impact of external factors, which females are exposed to during folliculogenesis, on their expression. The present study investigated the effect of the aphrodisiac Tribulus terrestris on the GDF9 and BMP15 expression in the oocytes and cumulus cells at mRNA and protein levels during folliculogenesis in two generations of female rabbits. The experiment was conducted with 28 New Zealand rabbits. Only the diet of the experimental mothers group was supplemented with a dry extract of T. terrestris for the 45 days prior to insemination. The expression of BMP15 and GDF9 genes in the oocytes and cumulus cells of mothers and F1 female offspring was analyzed using real-time polymerase chain reaction (RT-PCR). The localization of the GDF9 and BMP15 proteins in the ovary tissues was determined by immunohistochemical analysis. The BMP15 and GDF9 transcripts were detected in the oocytes and cumulus cells of rabbits from all groups. T. terrestris caused a decrease in the BMP15 mRNA level in the oocytes and an increase in the cumulus cells. The GDF9 mRNA level increased significantly in both oocytes and cumulus cells. The downregulated expression of BMP15 in the treated mothers' oocytes was inherited in the F1 female offspring born to treated mothers. BMP15 and GDF9 show a clearly expressed sensitivity to the bioactive compounds of T. terrestris.
Asunto(s)
Proteína Morfogenética Ósea 15/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Factor 9 de Diferenciación de Crecimiento/metabolismo , Madres , Ovario/efectos de los fármacos , Extractos Vegetales/farmacología , Tribulus/química , Animales , Afrodisíacos/farmacología , Proteína Morfogenética Ósea 15/genética , Femenino , Factor 9 de Diferenciación de Crecimiento/genética , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/metabolismo , Folículo Ovárico/fisiología , Ovario/crecimiento & desarrollo , Ovario/metabolismo , Ovario/fisiología , Ovulación/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , ConejosRESUMEN
OBJECTIVE: To investigate the effect of Soothing liver therapy on infertile women undergoing in vitro fertilization and embryo transfer (IVF-ET) and to explore its mechanism. METHODS: Fifty-eight women with tubal infertility were randomized into two groups: 30 in an experimental group treated with Xiaoyao powder (Shugan) plus gonadotropin-releasing hormone analog (GnRHa)/follicle-stimulating hormone (FSH)/ human chorionic gonadotropin (hCG) and 28 in the control group who were treated with GnRHa/FSH/ hCG only. The total gonadotropin (Gn) doses required, endometrial thickness, oocyte numbers, high quality embryo production rate and pregnancy rate of the two groups were compared. The concentration of growth differentiation factor-9 (GDF-9) in follicular fluid was detected by western blotting and the expression of GDF-9 mRNA in granulosa cells was measured using reverse transcription-polymerase chain reaction amplification. RESULTS: In the experimental group, the Gn dose was significantly lower than that in the control group; the endometrial thickness, high quality embryo production and pregnancy rates were significantly higher and the expression of GDF-9 mRNA was also significantly higher than in the control group (all P < 0.05). CONCLUSION: Shugan treatment can improve the pregnancy rate of women with tubal infertility; its mechanism is possibly related to the increased expression of GDF-9 in granulosa cells.
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Medicamentos Herbarios Chinos/uso terapéutico , Factor 9 de Diferenciación de Crecimiento/genética , Infertilidad Femenina/tratamiento farmacológico , Hígado/efectos de los fármacos , Oocitos/efectos de los fármacos , Adulto , Transferencia de Embrión , Femenino , Fertilización In Vitro , Hormona Folículo Estimulante/uso terapéutico , Hormona Liberadora de Gonadotropina/uso terapéutico , Factor 9 de Diferenciación de Crecimiento/metabolismo , Humanos , Infertilidad Femenina/genética , Infertilidad Femenina/metabolismo , Infertilidad Femenina/terapia , Hígado/fisiopatología , Oocitos/citología , Oocitos/metabolismo , EmbarazoRESUMEN
The multifaceted polycomb group gene Yin-Yang1 (Yy1) has been implicated in a variety of transcriptional regulatory roles both as an activator and silencer of gene expression. Here we examine the role of Yy1 during oocyte growth by conditional deletion of the locus in the growing oocyte. Our results indicate that YY1 is required for oocyte maturation and granulosa cell expansion. In mutant oocytes, we observe severely reduced expression of both Gdf9 and Bmp15, suggesting a mechanism underlying the failure of granulosa cell expansion. Consequently, we observe infertility, failure of estrus cycling, and altered reproductive hormone levels in mutant females. Additionally, we find that YY1-deficient oocytes exhibit altered levels of several oocyte-specific factors, including Pou5f1, Figla, Lhx8, Oosp1, and Sohlh2. These results document YY1's involvement in folliculogenesis and ovarian function in the mouse and indicate that YY1 is required specifically in the oocyte for oocyte-granulosa cell communication.