RESUMEN
Estradiol (E2) deficiency arising from menopause is closely related to changes in body composition and declines of muscle mass and strength in elderly women. Whole-body vibration training (WBV) is an emerging approach expected to improve muscle mass and strength of older person, but the underlying mechanisms remain unclear. The balance between protein synthesis and degradation is a determining factor for muscle mass and strength, which is regulated by Akt-mTOR and FoxO1 signal pathway, respectively. In the present study, we firstly determined whether the effects of WBV on muscle mass and strength in ovariectomized female mice was affected by estrogen level, then investigated whether this was associated with Akt-mTOR and FoxO1 signal pathways. We found that (1) WBV, E2 supplementation (E) and WBV combined with E2 supplementation (WBV+E) significantly increased serum estradiol content, quadriceps muscle mass and grip strength in ovariectomized mice, accompanied with alterations of body composition (reducing fat content, increasing lean body mass and lean percent), furthermore, the altered degrees of these indicators by WBV+E were greater than WBV alone; (2) WBV, E and WBV+E remarkably increased the activities of Akt and mTOR and decreased FoxO1 activity, and the changed degrees by WBV+E were greater than WBV alone; (3) Pearson correlation coefficient revealed that serum estradiol content was positively correlated with Akt and mTOR activities, while inversely associated with FoxO1 activity. We concluded that WBV could significantly increase muscle mass and strength in ovariectomized mice, which might achieve through activating Akt-mTOR and suppressing FoxO1 signal pathways, and the improving effect of WBV on muscle mass and strength was better when in the presence of estrogen.
Asunto(s)
Estradiol , Estrógenos , Proteína Forkhead Box O1 , Fuerza Muscular , Ovariectomía , Serina-Treonina Quinasas TOR , Vibración , Animales , Femenino , Vibración/uso terapéutico , Ratones , Fuerza Muscular/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Estradiol/sangre , Proteína Forkhead Box O1/metabolismo , Estrógenos/sangre , Estrógenos/metabolismo , Transducción de Señal , Composición Corporal/fisiología , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Condicionamiento Físico Animal/fisiología , Condicionamiento Físico Animal/métodosRESUMEN
Female fertility signals are found across taxa, and the precision of such signals may be influenced by the relative strength of different sexual selection mechanisms. Among primates, more precise signals may be found in species with stronger direct male-male competition and indirect female mate choice, and less precise signals in species with stronger indirect male-male competition (e.g. sperm competition) and direct female mate choice. We tested this hypothesis in a wild population of Kinda baboons in Zambia, combining data on female signals with reproductive hormones (estrogen and progesterone metabolites) and intra- and inter-cycle fertility. We predicted that Kinda baboons will exhibit less precise fertility signals than other baboon species, as they experience weaker direct and stronger indirect male-male competition. The frequency of copulation calls and proceptive behavior did not vary with hormones or intra- or inter-cycle fertility in almost all models. Sexual swelling size was predicted by the ratio of estrogen to progesterone metabolites, and was largest in the fertile phase, but differences in size across days were small. Additionally, there was variability in the timing of ovulation relative to the day of sexual swelling detumescence across cycles and swelling size did not vary with inter-cycle fertility. Our results suggest that female Kinda baboon sexual swellings are less precise indicators of fertility compared to other baboon species, while signals in other modalities do not reflect variation in intra- and inter-cycle fertility. Female Kinda baboon sexual signals may have evolved as a strategy to reduce male monopolizability, allowing for more female control over reproduction by direct mate choice.
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Fertilidad , Progesterona , Conducta Sexual Animal , Animales , Femenino , Fertilidad/fisiología , Masculino , Conducta Sexual Animal/fisiología , Progesterona/metabolismo , Progesterona/sangre , Estrógenos/metabolismo , Copulación/fisiología , Ovulación/fisiología , Comunicación AnimalRESUMEN
Sexual dimorphism in plumage is widespread among avian species. In chickens, adult females exhibit countershading, characterized by dull-colored round feathers lacking fringe on the saddle, while adult males display vibrant plumage with deeply fringed bright feathers. This dimorphism is estrogen-dependent, and administering estrogen to males transforms their showy plumage into cryptic female-like plumage. Extensive studies have shown that estrogen's role in female plumage formation requires thyroid hormone; however, the precise mechanisms of their interaction remain unclear. In this study, we investigated the roles of estrogen and thyroid hormone in creating sexual dimorphism in the structure and coloration of saddle feathers by administering each hormone to adult males and observing the resulting changes in regenerated feathers induced by plucking. RT-PCR analysis revealed that the expression of type 3 deiodinase (DIO3), responsible for thyroid hormone inactivation, correlates with fringing. Estrogen suppressed DIO3 and agouti signaling protein (ASIP) expression while stimulating BlSK1, a marker of barbule cells, resulting in female-like feathers with mottled patterns and lacking fringes. Administration of thyroxine (T4) stimulated BlSK1 and proopiomelanocortin (POMC) expression, with no effect on ASIP, leading to the formation of solid black feathers lacking fringes. Triiodothyronine (T3) significantly increased POMC expression in pulp cells in culture. Taken together, these findings suggest that estrogen promotes the formation of solid vanes by suppressing DIO3 expression, while also inducing the formation of mottled patterns through inhibition of ASIP expression and indirect stimulation of melanocortin expression via changes in local T3 concentration. This is the first report describing molecular mechanism underlying hormonal crosstalk in creating sexual dimorphism in feathers.
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Pollos , Plumas , Caracteres Sexuales , Animales , Plumas/metabolismo , Pollos/metabolismo , Masculino , Femenino , Hormonas Tiroideas/metabolismo , Estrógenos/metabolismo , Estrógenos/farmacologíaRESUMEN
Long-term administration of exogenous estrogen is known to cause urinary retention and marked, often fatal, bladder distention in both male and female mice. Estrogen-treated mice have increased bladder pressure and decreased urine flow, suggesting that urinary retention in estrogen-treated mice is due to infravesicular obstruction to urine outflow. Thus, the condition is commonly referred to as bladder outlet obstruction (BOO). Obesity can also lead to urinary retention. As the effects of estrogen are mediated by multiple receptors, including estrogen receptors ERα and ERß and the G protein-coupled estrogen receptor (GPER), we sought to determine whether GPER plays a role in estrogen-induced BOO, particularly in the context of obesity. Wild type and GPER knockout (KO) mice fed a high-fat diet were ovariectomized or left ovary-intact (sham surgery) and supplemented with slow-release estrogen or vehicle-only pellets. Supplementing both GPER KO and wild type obese mice with estrogen for 8 weeks resulted in weight loss, splenic enlargement, and thymic atrophy, as expected. However, estrogen-treated obese GPER KO mice developed abdominal distension, debilitation, and ulceration of the skin surrounding the urogenital opening. At necropsy, these mice had prominently distended bladders and hydronephrosis. In contrast, estrogen-treated obese wild type mice only rarely displayed these signs. Our results suggest that, under conditions of obesity, estrogen induces BOO as a result of ERα-driven pathways and that GPER expression is protective against BOO.
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Estrógenos , Ratones Noqueados , Obesidad , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Retención Urinaria , Animales , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/genética , Estrógenos/metabolismo , Femenino , Obesidad/metabolismo , Obesidad/complicaciones , Obesidad/genética , Ratones , Retención Urinaria/metabolismo , Retención Urinaria/genética , Ratones Endogámicos C57BL , Ratones Obesos , Dieta Alta en Grasa/efectos adversos , Ovariectomía , Masculino , Obstrucción del Cuello de la Vejiga Urinaria/metabolismo , Obstrucción del Cuello de la Vejiga Urinaria/patología , Obstrucción del Cuello de la Vejiga Urinaria/genéticaRESUMEN
Transgender is a term for people whose gender identity or expression differs from their natal sex. These individuals often seek cross-hormonal therapy to simulate the individual´s desired gender. However, the use of estrogens and testosterone has side effects such as a higher propensity to cancer, weight changes and cardiovascular diseases. Testosterone has also been linked with hypertension. Still, little is known about the outcomes and prevalence of metabolic perturbations in the trans community. Here we aim to analyze if cross-administering sexual hormones affects heart mitochondrial function. Mitochondria produces the ATP needed for heart function. In fact, different studies show that mitochondrial dysfunction precedes cardiac damage. In this work we used either female rats castrated and injected with testosterone or male rats castrated and injected with estrogens for 4 months. We performed an electrocardiogram, and then we isolated heart mitochondria to measure the rate of oxygen consumption, calcium fluxes, membrane potential, superoxide dismutase activity, lipoperoxidation and cytokines. We detected wide modifications in all parameters associated to cross-hormonal administration.
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Mitocondrias Cardíacas , Testosterona , Animales , Femenino , Masculino , Ratas , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Testosterona/farmacología , Estrógenos/farmacología , Estrógenos/metabolismo , Ratas Wistar , Consumo de Oxígeno/efectos de los fármacos , Calcio/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Terapia de Reemplazo de HormonasRESUMEN
Alzheimer's disease (AD) is a long-term neurodegenerative condition that leads to the deterioration of neurons and synapses in the cerebral cortex, resulting in severe dementia. AD is significantly more prevalent in postmenopausal women, suggesting a neuroprotective role for estrogen. Estrogen is now known to regulate a wide array of physiological functions in the body by interacting with three known estrogen receptors (ERs) and with the ß-amyloid precursor protein, a key factor in AD pathogenesis. Recent experimental evidence indicates that new selective ER modulators and phytoestrogens may be promising treatments for AD for their neuroprotective and anti-apoptotic properties. These alternatives may offer fewer side effects compared to traditional hormone therapies, which are associated with risks such as cardiovascular diseases, cancer, and metabolic dysfunctions. This review sheds light on estrogen-based treatments that may help to partially prevent or control the neurodegenerative processes characteristic of AD, paving the way for further investigation in the development of estrogen-based treatments.
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Enfermedad de Alzheimer , Receptores de Estrógenos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Receptores de Estrógenos/metabolismo , Animales , Estrógenos/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fitoestrógenos/uso terapéutico , Fitoestrógenos/farmacología , Fitoestrógenos/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Moduladores Selectivos de los Receptores de Estrógeno/farmacologíaRESUMEN
Oestrogen plays a crucial physiological role in both women and men. It regulates reproductive functions and maintains various non-reproductive tissues through its receptors, such as oestrogen receptor 1/oestrogen receptor α (ESR1/Erα), oestrogen receptor 2/oestrogen receptor ß (ESR2/Erß), and G protein-coupled oestrogen receptor 1 (GPER). This hormone is essential for the proper functioning of women's ovaries and uterus. Oestrogen supports testicular function and spermatogenesis in men and contributes to bone density, cardiovascular health, and metabolic processes in both sexes. Nuclear receptors Er-α and Er-ß belong to the group of transcription activators that stimulate cell proliferation. In the environment, compounds similar in structure to the oestrogens compete with endogenous hormones for binding sites to receptors and to disrupt homeostasis. The lack of balance in oestrogen levels can lead to infertility, cancer, immunological disorders, and other conditions. Exogenous endocrine-active compounds, such as bisphenol A (BPA), phthalates, and organic phosphoric acid esters, can disrupt signalling pathways responsible for cell division and apoptosis processes. The metabolism of oestrogen and its structurally similar compounds can produce carcinogenic substances. It can also stimulate the growth of cancer cells by regulating genes crucial for cell proliferation and cell cycle progression, with long-term elevated levels linked to hormone-dependent cancers such as breast cancer. Oestrogens can also affect markers of immunological activation and contribute to the development of autoimmune diseases. Hormone replacement therapy, oral contraception, in vitro fertilisation stimulation, and hormonal stimulation of transgender people can increase the risk of breast cancer. Cortisol, similar in structure to oestrogen, can serve as a biomarker associated with the risk of developing breast cancer. The aim of this review is to analyse the sources of oestrogens and their effects on the endogenous and exogenous process of homeostasis.
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Estrógenos , Humanos , Estrógenos/metabolismo , Animales , Receptores de Estrógenos/metabolismo , Femenino , MasculinoRESUMEN
Several risk factors contribute to the development of Alzheimer's disease (AD), including genetics, metabolic health, cardiovascular history, and diet. It has been observed that women appear to face a higher risk of developing AD. Among the various hypotheses surrounding the gender disparity in AD, one pertains to the potential neuroprotective properties of estrogen. Compared to men, women are believed to be more susceptible to neuropathology due to the significant decline in circulating estrogen levels following menopause. Studies have shown, however, that estrogen replacement therapies in post-menopausal women do not consistently reduce the risk of AD. While menopause and estrogen levels are potential factors in the elevated incidence rates of AD among women, this review highlights the possible roles estrogen has in other pathways that may also contribute to the sex disparity observed in AD such as olfaction, sleep, and glymphatic functionality.
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Enfermedad de Alzheimer , Estrógenos , Sistema Glinfático , Sueño , Olfato , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Estrógenos/metabolismo , Sistema Glinfático/metabolismo , Sistema Glinfático/fisiopatología , Sueño/fisiología , Olfato/fisiología , Femenino , Masculino , Factores SexualesRESUMEN
The metastasis-associated protein (MTA) family plays a crucial role in the development of breast cancer, a common malignancy with a high incidence rate among women. However, the mechanism by which each member of the MTA family contributes to breast cancer progression is poorly understood. In this study, we aimed to investigate the roles of MTA1, MTA3, and tripartite motif-containing 21 (TRIM21) in the proliferation, invasion, epithelial-mesenchymal transition (EMT), and stem cell-like properties of breast cancer cells in vivo and in vitro. The molecular mechanisms of the feedback loop between MTA1 and MTA3/TRIM21 regulated by estrogen were explored using Chromatin immunoprecipitation (ChIP), luciferase reporter, immunoprecipitation (IP), and ubiquitination assays. These findings demonstrated that MTA1 acts as a driver to promote the progression of breast cancer by repressing the transcription of tumor suppressor genes, including TRIM21 and MTA3. Conversely, MTA3 inhibited MTA1 transcription and TRIM21 regulated MTA1 protein stability in breast cancer. Estrogen disrupted the balance between MTA1 and MTA3, as well as between MTA1 and TRIM21, thereby affecting stemness and the EMT processes in breast cancer. These findings suggest that MTA1 plays a vital role in stem cell fate and the hierarchical regulatory network of EMT through negative feedback loops with MTA3 or TRIM21 in response to estrogen, supporting MTA1, MTA3, and TRIM21 as potential prognostic biomarkers and MTA1 as a treatment target for future breast cancer therapies.
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Neoplasias de la Mama , Transición Epitelial-Mesenquimal , Estrógenos , Histona Desacetilasas , Células Madre Neoplásicas , Proteínas Represoras , Transactivadores , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Transactivadores/metabolismo , Transactivadores/genética , Estrógenos/farmacología , Estrógenos/metabolismo , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Animales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Retroalimentación Fisiológica/efectos de los fármacos , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , Ratones Desnudos , Células MCF-7 , Ratones Endogámicos BALB C , Proteínas de NeoplasiasRESUMEN
Hyperactive osteoclasts and hypoactive osteoblasts usually result in osteolytic conditions such as estrogen-deficiency bone loss. Few natural compounds that both attenuating bone resorption and enhancing bone formation could exert effects on this imbalance. 5-Deoxycajanin (5-D), an isoflavonoid extracted from Cajan leaf with estrogen-like properties, were found to have beneficial pharmacological effects on rebalancing the activities of osteoclasts and osteoblasts. This study revealed that 5-D at the same concentration could inhibit osteoclastogenesis of BMMs and promoted osteoblast differentiation of BMSCs. 5-D not only attenuated the fluorescent formation of RANKL-induced F-actin belts and NFATc1, but also activated ALP and RUNX2 expressions. As to downstream factor expressions, 5-D could block osteoclast-specific genes and proteins including NFATc1 and CTSK, while increased osteogenic genes and proteins including OPG and OCN, as confirmed by Real-time PCR and Western Blotting. Additionally, the network pharmacology and molecular docking identified the involvement of 5-D in the MIF and MAPK signaling pathways and the stable binding between 5-D and MAPK2K1. Further Western blot studies showed that 5-D decreased the phosphorylation of p38 and ERK in osteoclasts, but promoted these phosphorylations in osteoblasts. In a female C57BL/6J mouse model of estrogen deficiency-induced bone loss, 5-D demonstrated efficacy in enhancing BMD through attenuating osteoclast activities and promoting osteogenesis. These results underscore the potential application of 5-D on treating osteolysis resulting from hyperactive osteoclasts and hypoactive osteoblasts, shedding light on modulating osteoclast-osteoblast homeostasis.
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Resorción Ósea , Estrógenos , Osteoblastos , Osteoclastos , Animales , Osteoclastos/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Ratones , Femenino , Estrógenos/deficiencia , Estrógenos/metabolismo , Resorción Ósea/tratamiento farmacológico , Osteogénesis/efectos de los fármacos , Homeostasis/efectos de los fármacos , Ratones Endogámicos C57BL , Células Cultivadas , Diferenciación Celular/efectos de los fármacos , Ovariectomía , Isoflavonas/farmacología , Isoflavonas/uso terapéutico , Ligando RANK/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismoRESUMEN
It is well understood that the balance of bone formation and resorption is dependent on both mechanical and biochemical factors. In addition to cell-secreted cytokines and growth factors, sex hormones like estrogen are critical to maintaining bone health. Although the direct osteoprotective function of estrogen and estrogen receptors (ERs) has been reported extensively, evidence that estrogen signaling also has a role in mediating the effects of mechanical loading on maintenance of bone mass and healing of bone injuries has more recently emerged. Recent studies have underscored the role of estrogen and ERs in many pathways of bone mechanosensation and mechanotransduction. Estrogen and ERs have been shown to augment integrin-based mechanotransduction as well as canonical Wnt/b-catenin, RhoA/ROCK, and YAP/TAZ pathways. Estrogen and ERs also influence the mechanosensitivity of not only osteocytes but also osteoblasts, osteoclasts, and marrow stromal cells. The current review will highlight these roles of estrogen and ERs in cellular mechanisms underlying bone mechanobiology and discuss their implications for management of osteoporosis and bone fractures. A greater understanding of the mechanisms behind interactions between estrogen and mechanical loading may be crucial to addressing the shortcomings of current hormonal and pharmaceutical therapies. A combined therapy approach including high-impact exercise therapy may mitigate adverse side effects and allow an effective long-term solution for the prevention, treatment, and management of bone fragility in at-risk populations. Furthermore, future implications to novel local delivery mechanisms of hormonal therapy for osteoporosis treatment, as well as the effects on bone health of applications of sex hormone therapy outside of bone disease, will be discussed.
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Estrógenos , Mecanotransducción Celular , Receptores de Estrógenos , Humanos , Estrógenos/metabolismo , Receptores de Estrógenos/metabolismo , Mecanotransducción Celular/fisiología , Animales , Enfermedades Óseas/metabolismo , Enfermedades Óseas/fisiopatología , Huesos/metabolismo , Huesos/fisiología , Fenómenos BiomecánicosRESUMEN
The endometrium is crucial for the perpetuation of human species. It is a complex and dynamic tissue lining the inner wall of the uterus, regulated throughout a woman's life based on estrogen and progesterone fluctuations. During each menstrual cycle, this multicellular tissue undergoes cyclical changes, including regeneration, differentiation in order to allow egg implantation and embryo development, or shedding of the functional layer in the absence of pregnancy. The biology of the endometrium relies on paracrine interactions between epithelial and stromal cells involving complex signaling pathways that are modulated by the variations of estrogen and progesterone levels across the menstrual cycle. Understanding the complexity of estrogen and progesterone receptor signaling will help elucidate the mechanisms underlying normal reproductive physiology and provide fundamental knowledge contributing to a better understanding of the consequences of hormonal imbalances on gynecological conditions and tumorigenesis. In this narrative review, we delve into the physiology of the endometrium, encompassing the complex signaling pathways of estrogen and progesterone.
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Endometrio , Estrógenos , Progesterona , Transducción de Señal , Humanos , Femenino , Endometrio/metabolismo , Progesterona/metabolismo , Estrógenos/metabolismo , Animales , Receptores de Progesterona/metabolismoRESUMEN
The menopause transition is an important period in a woman's life, during which she is at an increased risk of mood disorders. Estrogen and progesterone fluctuations during the menopausal transition and very low levels of estradiol after menopause have a profound effect on the central nervous system (CNS), causing an imbalance between excitatory and inhibitory inputs. Changes in neurotransmission and neuronal interactions that occur with estradiol withdrawal disrupt the normal neurological balance and may be associated with menopausal symptoms. Hot flushes, depressed mood and anxiety are all symptoms of menopause that are a consequence of the complex changes that occur in the CNS, involving many signaling pathways and neurotransmitters (i.e. γ-aminobutyric acid, serotonin, dopamine), neurosteroids (i.e. allopregnanolone), and neuropeptides (i.e. kisspeptin, neurokinin B). All these pathways are closely linked, and the complex interactions that exist are not yet fully understood. This review summarizes the neuroendocrine changes in the CNS during the menopausal transition, with particular emphasis on those that underlie mood changes.
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Menopausia , Trastornos del Humor , Sistemas Neurosecretores , Humanos , Femenino , Trastornos del Humor/etiología , Menopausia/fisiología , Menopausia/psicología , Sistemas Neurosecretores/fisiopatología , Sistema Nervioso Central , Sofocos , Estrógenos/metabolismo , Estradiol , Neuropéptidos/metabolismo , Neurotransmisores/metabolismo , Progesterona/metabolismoRESUMEN
Leukaemia-related protein 16 (LRP16) has been found to be highly expressed in various tumours and to be related to poor prognosis. However, the role of LRP16 in endometrial carcinoma remains to be explored. We aimed to investigate the prognosis and role of LRP16 in endometrial carcinoma. Overall, 160 endometrial carcinoma (EC) tissues and 60 benign samples were collected. The expression of LRP16 protein in EC tissues was significantly increased compared with that in normal endometrial tissues, and high LRP16 expression was related to poor patient prognosis. Reduced LRP16 expression markedly inhibited cancer cell growth. The proliferation rates in the prophylactic bilateral salpingectomy (PBS) group and the shNon group were 0.727 ±0.015 and 0.743 ±0.009, respectively, while the proliferation rate in the shLRP16 group was only 0.373 ±0.012. The migration experiment showed that the number of cells passing through the basement membrane in the shLRP16 group was 34.2 ±5.1, which was significantly different to the shNon (161.6 ±7.8) and PBS groups (138.0 ±7.2). The results of the invasion experiment showed that the number of cells was 39.2 ±6.2 in the shLRP16 group, 146.7 ±8.2 in the shNon group, and 141.2 ±8.1 in the PBS group ( p < 0.05). Leukaemia-related protein 16 is highly expressed in oestrogen-dependent EC and may promote cancer cell growth.
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Biomarcadores de Tumor , Proliferación Celular , Neoplasias Endometriales , Humanos , Femenino , Neoplasias Endometriales/patología , Neoplasias Endometriales/metabolismo , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Anciano , Línea Celular Tumoral , Movimiento Celular , Adulto , Neoplasias Hormono-Dependientes/patología , Neoplasias Hormono-Dependientes/metabolismo , Estrógenos/metabolismo , Hidrolasas de Éster CarboxílicoRESUMEN
BACKGROUND: Patients prone to psoriasis suffer after a breakdown of the epidermal barrier and develop poorly healing lesions with abnormal proliferation of keratinocytes. Strong inflammatory reactions with genotoxicity (short telomeres) suggest impaired immune defenses with DNA damage repair response (DDR) in patients with psoriasis. Recent evidence indicates the existence of crosstalk mechanisms linking the DDR machinery and hormonal signaling pathways that cooperate to influence both progressions of many diseases and responses to treatment. The aim of this study was to clarify whether steroid biosynthesis and genomic stability markers are altered in parallel during the formation of psoriatic skin. Understanding the interaction of the steroid pathway and DNA damage response is crucial to addressing underlying fundamental issues and managing resulting epidermal barrier disruption in psoriasis. METHODS: Skin (Lesional, non-lesional) and blood samples from twenty psoriasis patients and fifteen healthy volunteers were collected. Real-Time-PCR study was performed to assess levels of known transcripts such as: estrogen (ESR1, ESR2), androgen (AR), glucocorticoid/mineralocorticoid receptors (NR3C1, NR3C2), HSD11B1/HSD11B2, and DNA damage sensors (SMC1A, TREX1, TREX2, SSBP3, RAD1, RAD18, EXO1, POLH, HUS1). RESULTS: We found that ESR1, ESR2, HSD11B1, NR3C1, NR3C2, POLH, and SMC1A transcripts were significantly decreased and AR, TREX1, RAD1, and SSBP3 transcripts were increased dramatically in the lesional skin compared to skin samples of controls. CONCLUSION: We found that the regulation of the steroidogenic pathway was disrupted in the lesional tissue of psoriasis patients and that a sufficient glucocorticoid and mineralocorticoid response did not form and the estrogen/androgen balance was altered in favour of androgens. We suggest that an increased androgen response in the presence of DDR increases the risk of developing psoriasis. Although this situation may be the cause or the consequence of a disruption of the epidermal barrier, our data suggest developing new therapeutic strategies.
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Andrógenos , Daño del ADN , Psoriasis , Humanos , Daño del ADN/genética , Psoriasis/genética , Psoriasis/metabolismo , Femenino , Adulto , Andrógenos/metabolismo , Masculino , Persona de Mediana Edad , Cortisona/metabolismo , Piel/metabolismo , Piel/patología , Hidrocortisona/sangre , Hidrocortisona/metabolismo , Estrógenos/metabolismo , Reparación del ADN/genética , Fenotipo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismoRESUMEN
Introduction. Lactobacillus species predominate the human vagina and are associated with positive vaginal health, including an acidic pH (<4.5). The prevalence of vaginal Lactobacilli increases with increased oestrogen due to increased glycogen production within the vagina. Lactobacilli produce lactic acid, thereby lowering vaginal pH, preventing growth of other bacteria, and lowering microbial diversity. Lower placental oestrogen levels in obese pregnant women could dampen the mechanism to initiate this process, which may be associated with vaginal dysbiosis and unfavourable pregnancy outcomes.Hypothesis. We hypothesize that oestrogen and glycogen levels will be lower, vaginal pH will be higher, and vaginal microbiome diversity will be greater during pregnancy in obese and overweight women compared to healthy weight women.Aim. Pregnancy complications (e.g. preterm birth) are more common in overweight and obese women. If vaginal dysbiosis plays a role, and quantifiable predictors of this increased risk can be determined, these measures could be used to prospectively identify women at risk for pregnancy complications early in pregnancy.Methodology. Vaginal samples were collected at 10-14, 18-24, 26-30, and 34-37 weeks gestation and at delivery from 67 pregnant participants (23 healthy weight, 22 overweight, 22 obese). A blood sample to quantify serum oestrogen was collected at 10-14 weeks. Vaginal samples were collected to test vaginal pH using pH paper, glycogen abundance using fluorometry, and the vaginal microbiome using 16S rRNA amplicon sequencing.Results. Vaginal pH was higher in obese participants compared to healthy weight participants (P=<0.001). Vaginal glycogen levels increased over time in obese participants (P=0.033). The vaginal bacterial alpha diversity was higher in obese participants compared to healthy weight participants (P=0.033). The relative abundances of Peptoniphilus and Anaerococcus were increased in overweight and obese participants, as well as in complicated pregnancies, at 10-14 weeks gestation.Conclusion. The relative abundance of specific vaginal bacteria, like Peptoniphilus and Anaerococcus, in early pregnancy could predict pregnancy outcomes. Our goal is to use the information gathered in this pilot study to further determine the feasibility of assessing the vaginal environment during pregnancy to identify women at risk for negative pregnancy and birth outcomes in the context of a larger study.
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Microbiota , Obesidad , Resultado del Embarazo , Vagina , Humanos , Femenino , Vagina/microbiología , Embarazo , Obesidad/microbiología , Adulto , Concentración de Iones de Hidrógeno , Disbiosis/microbiología , Complicaciones del Embarazo/microbiología , Estrógenos/sangre , Estrógenos/metabolismo , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Glucógeno/metabolismo , Glucógeno/análisis , Adulto Joven , Lactobacillus/aislamiento & purificación , Nacimiento Prematuro , ARN Ribosómico 16S/genéticaRESUMEN
Breast cancer is the most diagnosed cancer in the world, and it is the primary cause of cancer death for women. The risk of breast cancer is increased by endogenous factors like hormones and exogenous factors like radiation exposure that causes damage to the mammary epithelial cells leading to an inflammatory response. Chronic inflammation creates a microenvironment composed of, among other factors, chemokines, and interleukins, which promote cancer. The gene expression of the interleukin 1 receptor type 1, the interleukin 1 receptor antagonist, the Interleukin 1 Receptor Accessory Protein, the interleukin 6 cytokine family signal transducer, the C-X-C motif chemokine ligand 3, the C-X-C motif chemokine ligand 5, and the C-X-C motif chemokine ligand 6 were analyzed in an estrogen and radiation experimental breast cancer model. Furthermore, the expression of these genes was correlated with immune cell infiltration, estrogen receptor expression, and their clinical relevance in breast cancer patients based on data provided by The Cancer Genome Atlas database online. Results given by the experimental breast cancer model showed that all genes related to inflammation respond to ionizing radiation alone or in combination with estrogen. On the other hand, the immune response depended on the breast cancer type and on the expression of the gene that encoded the estrogen receptor. Finally, the importance of the expression of these genes in breast cancer is such that high IL1R1 or IL1RAP is strongly related to patient survival. These findings may help to improve the understanding of the role of immune molecules in carcinogenesis and enhance therapeutic approaches.
Asunto(s)
Neoplasias de la Mama , Receptor alfa de Estrógeno , Estrógenos , Inflamación , Radiación Ionizante , Femenino , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/genética , Estrógenos/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Inflamación/metabolismo , Humanos , Ratones , Regulación Neoplásica de la Expresión Génica , Microambiente TumoralRESUMEN
Ovarian granulosa cells are essential to gonadotrophin-regulated estrogen production, female cycle maintenance and fertility. The epithelial Na+ channel (ENaC) is associated with female fertility; however, whether and how it plays a role in ovarian cell function(s) remained unexplored. Here, we report patch-clamp and Na+ imaging detection of ENaC expression and channel activity in both human and mouse ovarian granulosa cells, which are promoted by pituitary gonadotrophins, follicle stimulating hormone (FSH) or luteinizing hormone (LH). Cre-recombinase- and CRISPR-Cas9-based granulosa-specific knockout of ENaC α subunit (Scnn1a) in mice resulted in failed estrogen elevation at early estrus, reduced number of corpus luteum, abnormally extended estrus phase, reduced litter size and subfertility in adult female mice. Further analysis using technologies including RNA sequencing and Ca2+ imaging revealed that pharmacological inhibition, shRNA-based knockdown or the knockout of ENaC diminished spontaneous or stimulated Ca2+ oscillations, lowered the capacity of intracellular Ca2+ stores and impaired FSH/LH-stimulated transcriptome changes for estrogen production in mouse and/or human granulosa cells. Together, these results have revealed a previously undefined role of ENaC in modulating gonadotrophin signaling in granulosa cells for estrogen homeostasis and thus female fertility.
Asunto(s)
Calcio , Canales Epiteliales de Sodio , Estrógenos , Fertilidad , Células de la Granulosa , Homeostasis , Femenino , Animales , Células de la Granulosa/metabolismo , Canales Epiteliales de Sodio/metabolismo , Canales Epiteliales de Sodio/genética , Humanos , Estrógenos/metabolismo , Ratones , Fertilidad/genética , Calcio/metabolismo , Gonadotropinas/metabolismo , Transducción de Señal , Ratones Noqueados , Señalización del CalcioRESUMEN
Menopause is induced by spontaneous ovarian failure and leads to life quality deterioration with various irritating symptoms. Hormonal treatment can alleviate these symptoms, but long-term treatment is closely associated with breast and uterine cancer, and stroke. Therefore, developing alternative therapies with novel anti-menopausal substances and improved safety is needed. In our study, heat-killed Bifidobacterium breve HDB7040 significantly promoted MCF-7 cell proliferation in a dose-dependent manner under estrogen-free conditions, similar to 17ß-estradiol. This strain also triggered ESR2 expression, but not ESR1, in MCF-7 cells. Moreover, administrating HDB7040 to ovariectomized (OVX) Sprague-Dawley (SD) female rats reduced estrogen deficiency-induced weight gain, fat mass, blood triglyceride, and total cholesterol levels. It also recovered collapsed trabecular microstructure by improving trabecular morphometric parameters (bone mineral density, bone volume per tissue volume, trabecular number, and trabecular separation) and decreasing blood alkaline phosphatase levels with no significant changes in uterine size and blood estradiol. HDB7040 also significantly regulated the expression of Tff1, Pgr, and Esr2, but not Esr1 in uteri of OVX rats. Heat-killed B. breve HDB7040 exerts an anti-menopausal effect via the specific regulation of ERß in vitro and in vivo, suggesting its potential as a novel substance for improving and treating menopausal syndrome.