RESUMO
Abnormally high circulating androgen levels have been considered a causative factor for benign prostatic hypertrophy and prostate cancer in men. Recent animal studies on gut microbiome suggested that gut bacteria are involved in sex steroid metabolism; however, the underlying mechanisms and bacterial taxa remain elusive. Denitrifying betaproteobacteria Thauera spp. are metabolically versatile and often distributed in the animal gut. Thauera sp. strain GDN1 is an unusual betaproteobacterium capable of catabolizing androgen under both aerobic and anaerobic conditions. We administered C57BL/6 mice (aged 7 weeks) with strain GDN1 through oral gavage. The strain GDN1 administration caused a minor increase in the relative abundance of Thauera (≤0.1%); however, it has profound effects on the host physiology and gut bacterial community. The results of our ELISA assay and metabolite profile analysis indicated an approximately 50% reduction in serum androgen levels in the strain GDN1-administered male mice. Moreover, androgenic ring-cleaved metabolites were detected in the fecal extracts of the strain GDN1-administered mice. Furthermore, our RT - qPCR results revealed the expression of the androgen catabolism genes in the gut of the strain GDN1-administered mice. We found that the administered strain GDN1 regulated mouse serum androgen levels, possibly because it blocked androgen recycling through enterohepatic circulation. This study discovered that sex steroids serve as a carbon source of gut bacteria; moreover, host circulating androgen levels may be regulated by androgen-catabolizing gut bacteria. Our data thus indicate the possible applicability of androgen-catabolic gut bacteria as potent probiotics in alternative therapy of hyperandrogenism.
Assuntos
Androgênios , Microbioma Gastrointestinal , Camundongos , Masculino , Animais , Androgênios/metabolismo , Microbioma Gastrointestinal/genética , Camundongos Endogâmicos C57BL , Bactérias , Metabolismo dos LipídeosRESUMO
BACKGROUND: Patients with polycystic ovarian syndrome (PCOS) are associated with known alterations in mitochondria DNA copy number (mtDNA-CN). The aim of this study is to study the change in mtDNA-CN in patients with PCOS who were treated with metformin. METHODS: This is a prospective cohort of patients with PCOS, who received metformin for one year. From 2009 to 2015, 88 women diagnosed with PCOS, based on the Rotterdam criteria, were enrolled. Serial measurements of mtDNA-CN, 8-hydroxydeoxyguanosine (8-OHdG), anthropometric, metabolic, endocrine, and inflammatory markers were obtained before and after 3, 6, and 12 months of treatment. RESULTS: A significant decrease in mtDNA-CN was seen over the course of one year. Other markers, including 8-OHdG, testosterone, free androgen index, blood pressure and liver enzymes, also decreased in the same interval. On regression analysis, there was a significant association between the change in mtDNA-CN and serum total testosterone, and no association between mtDNA-CN and metabolic factors. CONCLUSIONS: Treatment with metformin is associated with a time-dependent decrease in mtDNA-CN in patients with PCOS who are treated over the course of one year. This may signify a reduction in mitochondria dysfunction. The change in mtDNA-CN corresponds to a similar change in serum total testosterone, and suggests a possible relationship between mtDNA-CN and testosterone. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00172523 . Registered September 15, 2005.
Assuntos
Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Adolescente , Adulto , Índice de Massa Corporal , Variações do Número de Cópias de DNA/efeitos dos fármacos , DNA Mitocondrial/análise , DNA Mitocondrial/efeitos dos fármacos , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Resistência à Insulina/fisiologia , Estudos Longitudinais , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/patologia , Adulto JovemRESUMO
Ovarian follicular cell undergoes extensive proliferation and differentiation during the period that the follicle evolved from the primordial state to its ovulatory phase and then corpus luteum status. During this process, different and various levels of steroid hormones in follicular fluid, or obtained from circulation and adjacent cells as granulosa and theca cells, or from environment and diet will all affect the process of follicular growth and development. Differential steroid hormones might have differential effects on ovarian folliculogenesis via the effect on granulosa cell growth and follicular fluid formation that involves cell proliferation, apoptosis, and angiogenesis within the follicle. In this chapter we further discuss the role of various steroid hormones such as estrogens, progesterone, and androgens on ovarian follicular growth and development. Various stages of follicle development that might be disturbed by the steroid hormones are also discussed in this chapter.
Assuntos
Androgênios/farmacologia , Estrogênios/farmacologia , Fármacos para a Fertilidade Feminina/farmacologia , Fase Folicular/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Ovário/efeitos dos fármacos , Progestinas/farmacologia , Androgênios/metabolismo , Animais , Apoptose/efeitos dos fármacos , Corpo Lúteo/citologia , Corpo Lúteo/efeitos dos fármacos , Corpo Lúteo/crescimento & desenvolvimento , Corpo Lúteo/fisiologia , Estrogênios/metabolismo , Ciclo Estral/efeitos dos fármacos , Ciclo Estral/metabolismo , Feminino , Fase Folicular/metabolismo , Humanos , Ciclo Menstrual/efeitos dos fármacos , Ciclo Menstrual/metabolismo , Ovário/citologia , Ovário/crescimento & desenvolvimento , Ovário/fisiologia , Progestinas/metabolismoRESUMO
Iron is an essential nutrient that may exert toxic effects when it accumulates in tissues. Little is known regarding its effects on gonadal function. Both Fe2+ and Fe3+ could be released from iron deposition. We employed mouse nonluteinized granulosa cell for in vitro studies and human ovarian tissues for Prussian blue and immunohistochemical staining to identify the iron deposition and effect in vivo. After treatment with FeSO4-7H2O or FeCl3 in granulosa cell cultured with follicle-stimulating hormone (FSH) for 48 h, we found that Fe2+ significantly suppressed FSH-induced granulosa cell proliferation and arrested the cell cycle at the G2/M phase by cell proliferation assay and flow cytometry. Fe2+ significantly increased intracellular reactive oxygen species (ROS) and ferritin levels of mouse granulosa cells. The increases in p21 and p53 messenger RNA and protein expression facilitated by Fe2+ treatment in mouse granulosa cells were significantly suppressed by separate treatments with p53 small interfering RNA and p38 mitogen-activated protein kinase (MAPK) inhibitors. An ROS inhibitor downregulated Fe2+-induced increases in p38MAPK expression in mouse granulosa cells. Quantitative analysis of immunohistochemical staining revealed that human ovarian tissue sections with positive Prussian blue staining had lower levels of proliferating cell nuclear antigen expression, but higher levels of p21, p53, and CDC25C expression than those with negative Prussian blue staining. Conclusively, Fe2+ could directly arrest the cell cycle and inhibit granulosa cell proliferation by regulating the ROS-mediated p38MAPK/p53/p21 pathway. Therefore, iron can directly affect female gonadal function.
Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Células da Granulosa/efeitos dos fármacos , Ferro/farmacologia , Ovário/citologia , Proteína Supressora de Tumor p53/genética , Quinases Ativadas por p21/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Apoptose , Proliferação de Células/efeitos dos fármacos , Feminino , Ferritinas/metabolismo , Hormônio Foliculoestimulante/sangue , Camundongos , Camundongos Endogâmicos ICR , Ovário/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Nitrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Sphingosine 1-phosphate (S1P) is a multifunctional phospholipid which acts through a specific family of G protein-coupled receptors. Platelet/endothelial cell adhesion molecule-1 (PECAM-1) form trans-homophilic binding at lateral cell border. Upon stimulation, its cytoplasmic tyrosine residues could be phosphorylated and interact with various downstream signaling molecules. In this study, we demonstrated that S1P induced PECAM-1 tyrosine phosphorylation in human umbilical cord vein cells (HUVECs). By pharmacological inhibitors, it was suggested that G(i) and Src family kinases were involved in PECAM-1 phosphorylation. Moreover, cSrc and Fyn siRNA significantly suppressed S1P-induced PECAM-1 phosphorylation. These results suggested that S1P-induced PECAM-1 phosphorylation through G(i) and subsequent cSrc and Fyn. Our findings provide further understanding of S1P and PECAM-1 signaling as well as their functions in endothelial cells.