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2.
PLoS One ; 15(9): e0239218, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32931507

RESUMO

Endocrine profiling is an increasingly utilized tool for detecting pregnancies in wild populations of mammals. Given the difficulty in calculating reproductive rates of Pacific walruses (Odobenus rosmarus divergens) the use of endocrine techniques for determining pregnancy rates could be particularly useful for management of the population. The goals of this study were to 1) determine if progesterone and total estrogen concentrations in ovarian tissues of female walruses could be used to determine reproductive state and 2) determine if walruses undergo a functional postpartum estrus, as is seen in other pinnipeds. Ovaries were collected from female walruses (n = 13) hunted in subsistence hunts by Alaska Native communities. Females were categorized as postpartum, full-term pregnant, pregnant diapause or unbred. Total estrogen concentrations were greatest in unbred (n = 2) and pregnant (n = 2) females. Progesterone concentrations were also nominally larger in unbred (n = 2) than pregnant (n = 2) and postpartum (n = 9) animals. Small samples sizes precluded the use of statistical comparisons among groups. Corpora lutea tissue samples in this study did not reflect the presence of a postpartum estrus in the month of May as postpartum females yielded lower total estrogen concentrations than unbred or pregnant animals. Both unbred animals were in a state of pseudopregnancy, which has not been physiologically described for this species before. The progesterone profiles in late (59 ng/g) and early (140 ng/g) pregnancy were lower than expected and fell within the range of the postpartum females (36-210 ng/g), suggesting low production of the hormone by the corpus luteum during these phases of pregnancy. Profiling reproductive hormones in free-ranging walruses demonstrates that an endocrine approach may be a valuable tool for determining reproductive status of females, however increased sample sizes and time of year must be considered to accurately separate pregnant versus pseudopregnant individuals.


Assuntos
Estrogênios/fisiologia , Progesterona/fisiologia , Pseudogravidez/veterinária , Morsas/fisiologia , Animais , Biomarcadores , Feminino
3.
Proc Natl Acad Sci U S A ; 117(37): 22962-22966, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32868418

RESUMO

Gonadal hormones are linked to mechanisms that govern appetitive behavior and its suppression. Estrogens are synthesized from androgens by the enzyme aromatase, highly expressed in the ovaries of reproductive-aged women and in the brains of men and women of all ages. We measured aromatase availability in the amygdala using positron emission tomography (PET) with the aromatase inhibitor [11C]vorozole in a sample of 43 adult, normal-weight, overweight, or obese men and women. A subsample of 27 also completed personality measures to examine the relationship between aromatase and personality traits related to self-regulation and inhibitory control. Results indicated that aromatase availability in the amygdala was negatively associated with body mass index (BMI) (in kilograms per square meter) and positively correlated with scores of the personality trait constraint independent of sex or age. Individual variations in the brain's capacity to synthesize estrogen may influence the risk of obesity and self-control in men and women.


Assuntos
Apetite/fisiologia , Estrogênios/metabolismo , Obesidade/metabolismo , Adulto , Idoso , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/metabolismo , Androgênios , Aromatase/análise , Inibidores da Aromatase , Índice de Massa Corporal , Encéfalo/metabolismo , Estrogênios/fisiologia , Feminino , Humanos , Lipogênese , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Autocontrole
4.
Med Hypotheses ; 143: 110148, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32759016

RESUMO

Estrogen hormone acts as a potential key player in providing immunity against certain viral infection. It is found to be associated in providing immunity against acute lungs inflammation and influenza virus by modulating cytokines storm and mediating adaptive immune alterations respectively. Women are less affected by SARS-CoV-2 infection because of the possible influence of estrogen hormone as compared to men. We hypothesized that SARS-CoV-2 causes stress in endoplasmic reticulum (ER) which in turn aggravates the infection, estrogen hormone might play key role in decreasing ER stress by activating estrogen mediated signaling pathways, results in unfolded protein response (UPR). Estrogen governs degradation of phosphotidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol triphosphate (IP3) with the help of phospholipase C. IP3 start in-fluxing Ca+2 ions that helps in UPR activation. To support our hypothesis, we analyzed the data of 162,392 COVID-19 patients to determine the relation of this disease with gender. We observed that 26% of women and 74% of men were affected by SARS-CoV-2. It indicated that women are less affected because of the possible influence of estrogen hormone in women.


Assuntos
Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Estresse do Retículo Endoplasmático/fisiologia , Estrogênios/fisiologia , Modelos Biológicos , Pandemias , Pneumonia Viral/fisiopatologia , Adulto , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Conjuntos de Dados como Assunto/estatística & dados numéricos , Diglicerídeos/metabolismo , Resistência à Doença , Feminino , Humanos , Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Fosfatidilinositol 4,5-Difosfato/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Caracteres Sexuais , Distribuição por Sexo , Transdução de Sinais , Fosfolipases Tipo C/metabolismo , Resposta a Proteínas não Dobradas , Proteínas Virais/biossíntese , Proteínas Virais/genética
5.
Med Hypotheses ; 143: 110150, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32763660

RESUMO

COVID-19 due to the SARS-CoV-2 infection is a multi-systemic immune syndrome affecting mainly the lungs, oropharyngeal region, and other vascular endothelial beds. There are tremendous ongoing efforts for the aim of developing drugs against the COVID-19 syndrome-associated inflammation. However, currently no specific medicine is present for the absolute pharmacological cure of COVID-19 mucositis. The re-purposing/re-positioning of already existing drugs is a very important strategy for the management of ongoing pandemy since the development of a new drug needs decades. Apart from altering angiotensin signaling pathways, novel drug candidates for re-purposing comprise medications shall target COVID-19 pathobiology, including pharmaceutical formulations that antagonize proteinase-activated receptors (PARs), mainly PAR-1. Activation of the PAR-1, mediators and hormones impact on the hemostasis, endothelial activation, alveolar epithelial cells and mucosal inflammatory responses which are the essentials of the COVID-19 pathophysiology. In this context, Ankaferd hemostat (Ankaferd Blood Stopper, ABS) which is an already approved hemostatic agent affecting via vital erythroid aggregation and fibrinogen gamma could be a potential topical remedy for the mucosal management of COVID-19. ABS is a clinically safe and effective topical hemostatic agent of plant origin capable of exerting pleiotropic effects on the endothelial cells, angiogenesis, cell proliferation and vascular dynamics. ABS had been approved as a topically applied hemostatic agent for the management of post-surgical/dental bleedings and healing of infected inflammatory mucosal wounds. The anti-inflammatory and proteinase-activated receptor axis properties of ABS with a considerable amount of oestrogenic hormone presence highlight this unique topical hemostatic drug regarding the clinical re-positioning for COVID-19-associated mucositis. Topical ABS as a biological response modifier may lessen SARS-CoV-2 associated microthrombosis, endothelial dysfunction, oropharyngeal inflammation and mucosal lung damage. Moreover, PAR-1 inhibition ability of ABS might be helpful for reducing the initial virus propagation and mocasal spread of COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Estrogênios/fisiologia , Hemostáticos/uso terapêutico , Mucosite/tratamento farmacológico , Pandemias , Fitoestrógenos/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Pneumonia Viral/complicações , Receptor PAR-1/antagonistas & inibidores , Administração Tópica , Distribuição por Idade , Anti-Inflamatórios/administração & dosagem , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/fisiopatologia , Reposicionamento de Medicamentos , Endotélio Vascular/efeitos dos fármacos , Estrogênios/agonistas , Hemostáticos/administração & dosagem , Humanos , Mucosite/etiologia , Fitoestrógenos/administração & dosagem , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Receptor PAR-1/fisiologia , Estomatite/tratamento farmacológico , Estomatite/etiologia , Trombofilia/sangue , Trombofilia/etiologia
6.
Curr Hypertens Rep ; 22(9): 62, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32852624

RESUMO

PURPOSE OF REVIEW: Angiotensin-converting enzyme 2 (ACE2), a specific high-affinity angiotensin II-hydrolytic enzyme, is the vector that facilitates cellular entry of SARS-CoV-1 and the novel SARS-CoV-2 coronavirus. SARS-CoV-2, which crossed species barriers to infect humans, is highly contagious and associated with high lethality due to multi-organ failure, mostly in older patients with other co-morbidities. RECENT FINDINGS: Accumulating clinical evidence demonstrates that the intensity of the infection and its complications are more prominent in men. It has been postulated that potential functional modulation of ACE2 by estrogen may explain the sex difference in morbidity and mortality. We review here the evidence regarding the role of estrogenic hormones in ACE2 expression and regulation, with the intent of bringing to the forefront potential mechanisms that may explain sex differences in SARS-CoV-2 infection and COVID-19 outcomes, assist in management of COVID-19, and uncover new therapeutic strategies.


Assuntos
Infecções por Coronavirus/etiologia , Estrogênios/fisiologia , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/etiologia , Fatores Sexuais , Betacoronavirus , Feminino , Humanos , Masculino , Pandemias
7.
Mayo Clin Proc ; 95(8): 1710-1714, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32753145

RESUMO

Given the rapid spread of the coronavirus disease 2019 (COVID-19) pandemic and its overwhelming effect on health care systems and the global economy, innovative therapeutic strategies are urgently needed. The proposed primary culprit of COVID-19 is the intense inflammatory response-an augmented immune response and cytokine storm-severely damaging the lung tissue and rendering some patients' conditions severe enough to require assisted ventilation. Sex differences in the response to inflammation have been documented and can be attributed, at least in part, to sex steroid hormones. Moreover, age-associated decreases in sex steroid hormones, namely, estrogen and testosterone, may mediate proinflammatory increases in older adults that could increase their risk of COVID-19 adverse outcomes. Sex hormones can mitigate the inflammation response and might provide promising therapeutic potential for patients with COVID-19. In this article, we explore the possible anti-inflammatory effects of estrogen and testosterone and the anabolic effect of testosterone, with particular attention to the potential therapeutic role of hormone replacement therapy in older men and women with COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Estrogênios/fisiologia , Pneumonia Viral/fisiopatologia , Testosterona/fisiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Estrogênios/uso terapêutico , Feminino , Terapia de Reposição Hormonal , Humanos , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Inflamação/virologia , Masculino , Pandemias , Pneumonia Viral/tratamento farmacológico , Testosterona/uso terapêutico
8.
Med Hypotheses ; 143: 110129, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32721814

RESUMO

In trying to understand the biochemical mechanism involved in the recent pandemic COVID-19, there is currently growing interest in angiotensin-converting enzyme II (ACE2). Nevertheless, the attempts to counteract COVID-19 interference with this enzymatic cascade are frustrating, and the results have thus far been inconclusive. Let's start again by considering the involved factors in an alternative way: we could postulate that COVID-19 could be more aggressive/fatal due to a high level of "basal" inflammation with low Nitric Oxide (NO) levels in hypertensive, diabetic and obese patients. Interestingly, the "protective" effects of several factors (such as estrogens) may play a role by increasing the formation of endogenous NO. From a therapeutic point of view, phosphodiesterase type 5 inhibitors such as oral Tadalafil, could be used in order to increase the basal NO levels. In this way, we don't fight the virus, but we may be able to mitigate its effects.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Óxido Nítrico/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Animais , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/fisiopatologia , Estrogênios/fisiologia , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Inflamação , Interleucinas/fisiologia , Modelos Animais , Modelos Biológicos , Óxido Nítrico/uso terapêutico , Obesidade/complicações , Obesidade/fisiopatologia , Uso Off-Label , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/fisiologia , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Pneumonia Viral/complicações , Receptores Virais/efeitos dos fármacos , Receptores Virais/fisiologia , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Tadalafila/farmacologia , Tadalafila/uso terapêutico
9.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276444

RESUMO

During pregnancy, the maternal cardiovascular system undergoes significant changes, including increased heart rate, cardiac output, plasma volume, and uteroplacental blood flow (UPBF) that are required for a successful pregnancy outcome. The increased UPBF is secondary to profound circumferential growth that extends from the downstream small spiral arteries to the upstream conduit main uterine artery. Although some of the mechanisms underlying uterine vascular remodeling are, in part, known, the factors that drive the remodeling are less clear. That higher circulating levels of estrogens are positively correlated with gestational uterine vascular remodeling suggests their involvement in this process. Estrogens binding to the estrogen receptors expressed in cytotrophoblast cells and in the uterine artery wall stimulate an outward hypertrophic remodeling of uterine vasculature. In preeclampsia, generally lower concentrations of estrogens limit the proper uterine remodeling, thereby reducing UPBF increases and restricting the growth of the fetus. This review aims to report estrogenic regulation of the maternal uterine circulatory adaptation in physiological and pathological pregnancy that favors vasodilation, and to consider the underlying molecular mechanisms by which estrogens regulate uteroplacental hemodynamics.


Assuntos
Estrogênios/fisiologia , Pré-Eclâmpsia/fisiopatologia , Receptores Estrogênicos/fisiologia , Útero/irrigação sanguínea , Remodelação Vascular , Estrogênios/metabolismo , Feminino , Hemodinâmica , Humanos , Gravidez , Receptores Estrogênicos/metabolismo , Útero/fisiologia
10.
Curr Hypertens Rep ; 22(3): 23, 2020 02 29.
Artigo em Inglês | MEDLINE | ID: mdl-32114652

RESUMO

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is a non-subsiding disease that remains a leading cause of morbidity and mortality. CVD has been associated with endocrine disruptors, such as bisphenol A (BPA). This review critically summarizes existing findings on BPA and hypertension, with particular attention to genomic, non-genomic, molecular, and cellular mechanisms of action that render BPA as a cardiovascular estrogenic disruptor. RECENT FINDINGS: Owing to its similar estrogenic structure, BPA has been shown to affect various phenotypes that are regulated by the natural hormone, estrogen. Indeed, BPA has been shown to interact with estrogen receptors, located both in the cell membrane and in the cytoplasm/nucleus. Given that estrogen plays an important role in cardiovascular physiology, a contributing role for BPA in CVD would not be unexpected. Existing literature, though limited, established BPA as a source of disruption in cardiovascular health, particularly hypertension. However, effects of BPA are largely dependent on the dose, patient gender, tissue, and developmental stage of the exposed tissue/organ. Accumulating evidence argues for an adverse effect of BPA on blood pressure, with this effect being gender, dose, and time specific. Thus, comprehensive studies which take these factors and other parameters, like epigenetic factors, into account are warranted before a thorough understanding is at hand.


Assuntos
Compostos Benzidrílicos , Estrogênios , Hipertensão , Fenóis , Compostos Benzidrílicos/efeitos adversos , Estrogênios/fisiologia , Humanos , Hipertensão/induzido quimicamente , Fenóis/efeitos adversos
11.
PLoS One ; 15(2): e0228894, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32078667

RESUMO

Lymphangioleiomyomatosis (LAM) is a devastating lung disease caused by inactivating gene mutations in either TSC1 or TSC2 that result in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). As LAM occurs predominantly in women during their reproductive age and is exacerbated by pregnancy, the female hormonal environment, and in particular estrogen, is implicated in LAM pathogenesis and progression. However, detailed underlying molecular mechanisms are not well understood. In this study, utilizing human pulmonary LAM specimens and cell culture models of TSC2-deficient LAM patient-derived and rat uterine leiomyoma-derived cells, we tested the hypothesis that estrogen promotes the growth of mTORC1-hyperactive cells through pyruvate kinase M2 (PKM2). Estrogen increased the phosphorylation of PKM2 at Ser37 and induced the nuclear translocation of phospho-PKM2. The estrogen receptor antagonist Faslodex reversed these effects. Restoration of TSC2 inhibited the phosphorylation of PKM2 in an mTORC1 inhibitor-insensitive manner. Finally, accumulation of phosphorylated PKM2 was evident in pulmonary nodule from LAM patients. Together, our data suggest that female predominance of LAM might be at least in part attributed to estrogen stimulation of PKM2-mediated cellular metabolic alterations. Targeting metabolic regulators of PKM2 might have therapeutic benefits for women with LAM and other female-specific neoplasms.


Assuntos
Estrogênios/metabolismo , Piruvato Quinase/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Animais , Linhagem Celular Tumoral , Estrogênios/fisiologia , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Linfangioleiomiomatose/genética , Linfangioleiomiomatose/fisiopatologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Fosforilação , Piruvato Quinase/fisiologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Proteínas Supressoras de Tumor/genética
12.
Sheng Li Xue Bao ; 72(1): 105-114, 2020 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-32099988

RESUMO

Embryo implantation is crucial for the establishment and maintenance of successful pregnancy and requires the synchronization between implantation-competent blastocyst and receptive uterus. In assisted reproductive technologies, recognition of uterine receptivity is the limiting factor for improving pregnancy rate. It has been previously reported that embryo implantation involves the activation and inactivation of numerous signaling molecules which may influence the proliferation and differentiation of uterine epithelial cells, epithelial polarity, luminal closure, embryo orientation, epithelial-stromal interactions, gland development, etc. Here we summarize the function of estrogen, progesterone, leukemia inhibitory factor (LIF), microRNA (miRNA), channel protein and signaling pathways in embryo implantation and explore their regulatory network to provide theoretical basis for the treatment of infertility and development of safe and efficient contraceptives.


Assuntos
Implantação do Embrião , Útero/fisiologia , Blastocisto/fisiologia , Estrogênios/fisiologia , Feminino , Humanos , Fator Inibidor de Leucemia/fisiologia , MicroRNAs/genética , Gravidez , Progesterona/fisiologia , Transdução de Sinais
13.
Development ; 147(4)2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32001440

RESUMO

Sex determination and differentiation are complex processes controlled by many different factors; however, the relationships among these factors are poorly understood. Zebrafish gonadal differentiation exhibits high plasticity involving multiple factors and pathways, which provides an excellent model for investigating the interactions between them. Ovarian aromatase (cyp19a1a) and dmrt1 are key factors in directing vertebrate ovary and testis differentiation, respectively. Knockout of zebrafish cyp19a1a leads to all-male offspring, whereas the loss of dmrt1 results in a female-biased sex ratio. In the present study, we established dmrt1-/- ;cyp19a1a-/- double mutant zebrafish and discovered that the introduction of the dmrt1 mutation into the cyp19a1a mutant could rescue the all-male phenotype of the latter. Interestingly, despite the lack of aromatase/estrogens, the follicles in the ovary of the rescued cyp19a1a mutant could develop normally up to the previtellogenic stage. Further evidence suggested the ovarian aromatase directed ovarian differentiation by suppressing dmrt1 expression via nuclear estrogen receptors (nERs). Our results provide solid evidence for an interaction between cyp19a1a and dmrt1 in zebrafish gonadal differentiation, and for the dispensability of estrogens in controlling early folliculogenesis.


Assuntos
Aromatase/genética , Aromatase/fisiologia , Folículo Ovariano/embriologia , Testículo/embriologia , Fatores de Transcrição/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologia , Alelos , Animais , Animais Geneticamente Modificados , Diferenciação Celular , Estrogênios/fisiologia , Feminino , Técnicas de Inativação de Genes , Genótipo , Heterozigoto , Masculino , Mutação , Fenótipo , Receptores Estrogênicos/fisiologia , Processos de Determinação Sexual , Diferenciação Sexual , Peixe-Zebra
14.
Development ; 147(4)2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32001442

RESUMO

In chickens, the embryonic ovary differentiates into two distinct domains before meiosis: a steroidogenic core (the female medulla), overlain by the germ cell niche (the cortex). The differentiation of the medulla is a cell-autonomous process based on chromosomal sex identity (CASI). In order to address the extent to which cortex differentiation depends on intrinsic or extrinsic factors, we generated models of gonadal intersex by mixing ZW (female) and ZZ (male) cells in gonadal chimeras, or by altering oestrogen levels of ZW and ZZ embryos. We found that CASI does not apply to the embryonic cortex. Both ZW and ZZ cells can form the cortex and this can happen independently of the phenotypic sex of the medulla as long as oestrogen is provided. We also show that the cortex-promoting activity of oestrogen signalling is mediated via estrogen receptor alpha within the left gonad epithelium. However, the presence of a medulla with an 'intersex' or male phenotype may compromise germ cell progression into meiosis, causing cortical germ cells to remain in an immature state in the embryo.


Assuntos
Estrogênios/fisiologia , Oogênese , Ovário/embriologia , Animais , Embrião de Galinha , Galinhas/genética , Cromossomos/genética , Eletroporação , Células Epiteliais/citologia , Feminino , Células Germinativas/citologia , Gônadas/citologia , Masculino , Meiose , Mitose , Fenótipo , Cromossomos Sexuais , Diferenciação Sexual/genética , Transdução de Sinais
15.
Biol Sex Differ ; 11(1): 2, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31918752

RESUMO

Estrogen plays substantial roles in pain modulation; however, studies concerning sex hormones and nociception often yield confusing results. The discrepancy could be a result of lack of consensus to regard estrogen as a variable when working with animal models; thus, the influence of hormones' fluctuations on nociception has continually been neglected. In the present study, we designed a novel hormone substitution model to aid us to evaluate the effects of estrogen's long-term alterations on ovariectomy (OVX)-induced mechanical hyperalgesia and the expression of estrogen receptors(ERs). OVX rats were implanted with slow-release estrogen pellets at differently arranged time points and doses, such that a gradual elevation or decrease of serum estrogen levels following a relatively stable period of estrogen replacement was achieved in rats. Our results demonstrated that gradual estrogen depletion rather than elevation following the stable period of estrogen substitution in OVX rats alleviated OVX-induced mechanical hyperalgesia in a dose-independent manner, and the opposite estrogen increase or decrease paradigms differently regulate the expression of spinal ERs. Specifically, in rats rendered to continuously increased serum estrogen, the early phase estrogen-induced anti-nociception effect in OVX rats was eliminated, which was accompanied by an over-activation of ERα and a strong depression of ERß, while in the OVX rats subject to gradual decrease of estrogen replacement, both ERα and ERß increased modestly compared with the OVX group. Thus, the present study demonstrated that estrogen increase or decrease modulate nociception differently through change of spinal ERs.


Assuntos
Estradiol/administração & dosagem , Estrogênios/fisiologia , Hiperalgesia/fisiopatologia , Nociceptividade/fisiologia , Percepção da Dor/fisiologia , Animais , Receptor alfa de Estrogênio/fisiologia , Receptor beta de Estrogênio/fisiologia , Estrogênios/sangue , Feminino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Nociceptividade/efeitos dos fármacos , Ovariectomia , Percepção da Dor/efeitos dos fármacos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia
16.
Life Sci ; 239: 117082, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31756345

RESUMO

AIM: Investigating the impact of 17ß-Estradiol/estrogen receptors in gentamicin-induced nephrotoxicity. MAIN METHODS: Three weeks post-ovariectomy or sham surgery for the Wistar albino female rats, thirty sham rats were randomly grouped (n = 6), received either vehicle or gentamicin; the estrogen receptors down regulator (fulvestrant); gentamicin plus fulvestrant; gentamicin plus the phytoestrogen (genistein). Forty-eight ovariectomized rats were randomly grouped (n = 6), treated with either vehicle or gentamicin; fulvestrant; gentamicin plus fulvestrant; genistein; gentamicin plus genistein; estradiol benzoate; gentamicin plus estradiol benzoate. Just post-treatment termination, the traditional kidney injury biomarkers (serum creatinine and blood urea nitrogen) and novel biomarkers (serum Kidney injury molecule -1, cystatin C, lactate dehydrogenase and, gamma-glutamyl transferase) were determined. Bovine serum albumin labeled with fluorescence isothiocyanate assessed megalin expression/endocytic functionality in the proximal tubules epithelial cells (PTECs). The immunohistochemical investigation for the same-sectioned slides of PTECs assessed the correlation between estrogen receptors α and megalin receptors expression. Histopathological examination of PTECs and subjective scoring system graded the damage markers. KEY FINDINGS: Estrogen receptor α expression was markedly dimensioned post-ovariectomy, co-localized and inversely correlated to megalin expression. Serum levels of the novel biomarkers were directly proportional to megalin expression in the PTECs and inversely correlated with estrogen receptor α expression. The injury was exaggerated in ovariectomized and intact rats received fulvestrant. Supplementation with estrogen or genistein ameliorated this injury. SIGNIFICANCE: Estrogen/estrogen receptors have a protective impact on gentamicin-induced acute kidney injury. Estrogen receptors antagonist exacerbate the injury, and oppositely, estrogens or phytoestrogens improve it.


Assuntos
Lesão Renal Aguda/metabolismo , Estrogênios/metabolismo , Receptores Estrogênicos/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Lesão Renal Aguda/prevenção & controle , Animais , Estradiol/metabolismo , Receptor beta de Estrogênio/metabolismo , Estrogênios/fisiologia , Feminino , Fulvestranto/metabolismo , Genisteína/farmacologia , Gentamicinas/efeitos adversos , Gentamicinas/farmacologia , Rim/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Ovariectomia , Fitoestrógenos/farmacologia , Ratos , Ratos Wistar , Receptores Estrogênicos/fisiologia
17.
Basic Res Cardiol ; 115(1): 1, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31741053

RESUMO

Preserving mitochondrial activity is crucial in rescuing cardiac function following acute myocardial ischemia/reperfusion (I/R). The sex difference in myocardial functional recovery has been observed after I/R. Given the key role of mitochondrial connexin43 (Cx43) in cardiac protection initiated by ischemic preconditioning, we aimed to determine the implication of mitochondrial Cx43 in sex-related myocardial responses and to examine the effect of estrogen (17ß-estradiol, E2) on Cx43, particularly mitochondrial Cx43-involved cardiac protection following I/R. Mouse primary cardiomyocytes and isolated mouse hearts (from males, females, ovariectomized females, and doxycycline-inducible Tnnt2-controlled Cx43 knockout without or with acute post-ischemic E2 treatment) were subjected to simulated I/R in culture or Langendorff I/R (25-min warm ischemia/40-min reperfusion), respectively. Mitochondrial membrane potential and mitochondrial superoxide production were measured in cardiomyocytes. Myocardial function and infarct size were determined. Cx43 and its isoform, Gja1-20k, were assessed in mitochondria. Immunoelectron microscopy and co-immunoprecipitation were also used to examine mitochondrial Cx43 and its interaction with estrogen receptor-α by E2 in mitochondria, respectively. There were sex disparities in stress-induced cardiomyocyte mitochondrial function. E2 partially restored mitochondrial activity in cardiomyocytes following acute injury. Post-ischemia infusion of E2 improved functional recovery and reduced infarct size with increased Cx43 content and phosphorylation in mitochondria. Ablation of cardiac Cx43 aggravated mitochondrial damage and abolished E2-mediated cardiac protection during I/R. Female mice were more resistant to myocardial I/R than age-matched males with greater protective role of mitochondrial Cx43 in female hearts. Post-ischemic E2 usage augmented mitochondrial Cx43 content and phosphorylation, increased mitochondrial Gja1-20k, and showed cardiac protection.


Assuntos
Conexina 43/metabolismo , Estrogênios/fisiologia , Mitocôndrias Cardíacas/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Receptor alfa de Estrogênio/metabolismo , Feminino , Masculino , Potencial da Membrana Mitocondrial , Camundongos Endogâmicos C57BL , Camundongos Knockout , Caracteres Sexuais , Superóxidos/metabolismo
18.
Presse Med ; 48(11 Pt 1): 1244-1248, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31732361

RESUMO

Before menopause, women are protected from the risk of hypertension and atherosclerosis by endogenous estrogens. Estrogens have a vasoprotective role, while progesterone seems to have a neutral effect. Exogenous estrogens used in menopausal treatment have vascular effects. These effects depend of type, dose and administration type, and with age and atherosclerosis stages. Synthetic progestins have varying clinical effects. Each drug must be evaluated separately.


Assuntos
Aterosclerose/prevenção & controle , Estrogênios/farmacologia , Estrogênios/fisiologia , Hipertensão/prevenção & controle , Pré-Menopausa , Progestinas/farmacologia , Artérias/efeitos dos fármacos , Artérias/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Terapia de Reposição de Estrogênios , Etinilestradiol/farmacocinética , Etinilestradiol/farmacologia , Feminino , Humanos , Menopausa/fisiologia , Pré-Menopausa/fisiologia , Progesterona/fisiologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia
19.
Proc Natl Acad Sci U S A ; 116(46): 23132-23142, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31666317

RESUMO

The human endometrium is essential in providing the site for implantation and maintaining the growth and survival of the conceptus. An unreceptive endometrium and disrupted maternal-conceptus interactions can cause infertility due to pregnancy loss or later pregnancy complications. Despite this, the role of uterine glands in first trimester human pregnancy is little understood. An established organoid protocol was used to generate and comprehensively analyze 3-dimensional endometrial epithelial organoid (EEO) cultures from human endometrial biopsies. The derived EEO expand long-term, are genetically stable, and can be cryopreserved. Using endometrium from 2 different donors, EEO were derived and then treated with estrogen (E2) for 2 d or E2 and medroxyprogesterone acetate (MPA) for 6 d. EEO cells were positive for the gland marker, FOXA2, and exhibited appropriate hormonal regulation of steroid hormone receptor expression. Real-time qPCR and bulk RNA-sequencing analysis revealed effects of hormone treatment on gene expression that recapitulated changes in proliferative and secretory phase endometrium. Single-cell RNA sequencing analysis revealed that several different epithelial cell types are present in the EEO whose proportion and gene expression changed with hormone treatment. The EEO model serves as an important platform for studying the physiology and pathology of the human endometrium.


Assuntos
Endométrio/fisiologia , Organoides/metabolismo , Epitélio/fisiologia , Estrogênios/fisiologia , Feminino , Perfilação da Expressão Gênica , Humanos , Organoides/citologia , Progesterona/fisiologia , Análise de Sequência de RNA , Análise de Célula Única
20.
Front Neuroendocrinol ; 55: 100785, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31430485

RESUMO

Since the beginning of this century, research methods in neuroendocrinology enjoyed extensive refinements and innovation. These advances allowed collection of huge amounts of new data and the development of new ideas but have not led to this point, with a few exceptions, to the development of new conceptual advances. Conceptual advances that took place largely resulted from the ingenious insights of several investigators. I summarize here some of these new ideas as they relate to the sexual differentiation and activation by sex steroids of reproductive behaviors and I discuss how our research contributed to the general picture. This selective review clearly demonstrates the importance of conceptual changes that have taken place in this field since beginning of the 21st century. The recent technological advances suggest that our understanding of hormones, brain and behavior relationships will continue to improve in a very fundamental manner over the coming years.


Assuntos
Aromatase/metabolismo , Encéfalo/metabolismo , Estrogênios/fisiologia , Neuroendocrinologia , Plasticidade Neuronal/fisiologia , Diferenciação Sexual , Comportamento Sexual Animal/fisiologia , Animais , Encéfalo/enzimologia , Feminino , História do Século XX , História do Século XXI , Masculino , Neuroendocrinologia/história
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