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1.
J Agric Food Chem ; 69(40): 11847-11855, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34609142

RESUMO

Estrogen and its analogues are ubiquitous in agricultural environments, with large biological functions of oocyte development. Gap junction intercellular communications (GJICs) are the structural basis in cumulus-oocyte complexes (COCs) and regulate oocyte maturation and developmental material transport through a number of pathways. This study mainly determines the effect and potential mechanism of estrogen (17ß-estradiol) in regulating GJICs in porcine COCs. In our study, 17ß-estradiol increased porcine nuclear maturation in a time-dependent manner. The analysis revealed that 17ß-estradiol upregulated the autophagy in COCs during in vitro maturation. In contrast with the control, 17ß-estradiol decreased GJICs in a time-dependent manner between cumulus cells and oocytes, while it was consistent with the control group at 24 h. Carbenoxolone (CBX) blocks GJICs as a negative control group used in our system. Autophagy inhibitor autophinib decreased oocyte maturation, and the reduced nuclear maturation treated with autophinib was abolished by 17ß-estradiol. Besides, the upregulation effect of autophinib on GJICs and transzonal projections (TZPs) was decreased by 17ß-estradiol. 17ß-Estradiol could reduce serine 368 phosphorylation of connexin 43 (Cx43) protein by autophinib in porcine COCs. These results were dependent upon the MEK/ERK signaling pathway. Furthermore, 17ß-estradiol-induced GJICs and Cx43 phosphorylation were inhibited by autophinib or the MEK/ERK pathway inhibitors (Trametinib and FR 180204), indicating that 17ß-estradiol regulated GJICs through the MEK/ERK signaling pathway. In conclusion, 17ß-estradiol improves the autophagy-mediated nuclear maturation with downregulating GJICs and TZPs in porcine COCs. Such an effect occurs by phosphorylation of Cx43, which was regulated via the MEK/ERK signaling pathway.


Assuntos
Conexina 43 , Sistema de Sinalização das MAP Quinases , Animais , Autofagia , Conexina 43/genética , Conexina 43/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Feminino , Junções Comunicantes/metabolismo , Meiose , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Oócitos/metabolismo , Fosforilação , Transdução de Sinais , Suínos
2.
J Water Health ; 19(5): 796-807, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34665772

RESUMO

Sulfate radical (•SO4-)-based advanced oxidation processes are widely used for wastewater treatment. This study explored the potential use of UV/persulfate (UV/PS) system for the degradation of 17ß-estradiol (E2). The pH of the reaction system can affect the degradation rate of E2 by UV/PS and the optimum pH was 7.0; Br- and Cl- in water can promote the degradation rate, HCO3- has an inhibitory effect on the reaction, SO42- and cations (Na+, Mg2+, K+) have no effect on the degradation rate. The degradation of E2 by UV/PS was a mineralization process, with the mineralization rate reaching 90.97% at 8 h. E2 in the UV/PS system was mainly degraded by hydroxylation, deoxygenation, and hydrogenation. E2 reaction sites were mainly located on benzene rings, mainly carbonylation on quinary rings, and bond breakage between C10 and C5 resulted in the removal of benzene rings and carboxyl at C2 and C3 sites. In the presence of halogen ions, halogenated disinfection by-products were not formed in the degradation process of E2 by UV/PS. E2 in the UV/PS system could inhibit the formation of bromate. The results of this study suggest that UV/PS is a safe and reliable method to degrade E2.


Assuntos
Poluentes Químicos da Água , Purificação da Água , Estradiol , Oxirredução , Sulfatos , Raios Ultravioleta , Água , Poluentes Químicos da Água/análise
3.
Cells ; 10(9)2021 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-34571963

RESUMO

Stroke is the third leading cause of mortality in women and it kills twice as many women as breast cancer. A key role in the pathophysiology of stroke plays the disruption of the blood-brain barrier (BBB) within the neurovascular unit. While estrogen induces vascular protective actions, its influence on stroke remains unclear. Moreover, experiments assessing its impact on endothelial cells to induce barrier integrity are non-conclusive. Since pericytes play an active role in regulating BBB integrity and function, we hypothesize that estradiol may influence BBB by regulating their activity. In this study using human brain vascular pericytes (HBVPs) we investigated the impact of estradiol on key pericyte functions known to influence BBB integrity. HBVPs expressed estrogen receptors (ER-α, ER-ß and GPER) and treatment with estradiol (10 nM) inhibited basal cell migration but not proliferation. Since pericyte migration is a hallmark for BBB disruption following injury, infection and inflammation, we investigated the effects of estradiol on TNFα-induced PC migration. Importantly, estradiol prevented TNFα-induced pericyte migration and this effect was mimicked by PPT (ER-α agonist) and DPN (ER-ß agonist), but not by G1 (GPR30 agonist). The modulatory effects of estradiol were abrogated by MPP and PHTPP, selective ER-α and ER-ß antagonists, respectively, confirming the role of ER-α and ER-ß in mediating the anti-migratory actions of estrogen. To delineate the intracellular mechanisms mediating the inhibitory actions of estradiol on PC migration, we investigated the role of AKT and MAPK activation. While estradiol consistently reduced the TNFα-induced MAPK and Akt phosphorylation, only the inhibition of MAPK, but not Akt, significantly abrogated the migratory actions of TNFα. In transendothelial electrical resistance measurements, estradiol induced barrier function (TEER) in human brain microvascular endothelial cells co-cultured with pericytes, but not in HBMECs cultured alone. Importantly, transcriptomics analysis of genes modulated by estradiol in pericytes showed downregulation of genes known to increase cell migration and upregulation of genes known to inhibit cell migration. Taken together, our findings provide the first evidence that estradiol modulates pericyte activity and thereby improves endothelial integrity.


Assuntos
Encéfalo/irrigação sanguínea , Movimento Celular/efeitos dos fármacos , Estradiol/farmacologia , Perfilação da Expressão Gênica , Pericitos/citologia , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Estrogênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502321

RESUMO

We examined the vasoactive effect of estradiol in a rat model of early PCOS and the influence of vitamin D deficiency (VDD). We created a model of chronic hyperandrogenism and VDD in adolescent female Wistar rats (N = 46) with four experimental groups: vitamin D supplemented (T-D+), VDD (T-D-), hyperandrogenic and vitamin D supplemented (T+D+), and hyperandrogenic and VDD (T+D-). T+ groups received an 8-week-long transdermal Androgel treatment, D-animals were on vitamin D-reduced diet and D+ rats were supplemented orally with vitamin D3. Estrogen-induced vasorelaxation of thoracic aorta segments were measured with a wire myograph system with or without the inhibition of endothelial nitric oxide synthase (eNOS) or cyclooxygenase-2 (COX-2). The distribution of estrogen receptor (ER), eNOS and COX-2 in the aortic wall was assessed by immunohistochemistry. VDD aortas showed significantly lower estradiol-induced relaxation independently of androgenic status that was further decreased by COX-2 inhibition. COX-2 inhibition failed to alter vessel function in D+ rats. Inhibition of eNOS abolished the estradiol-induced relaxation in all groups. Changes in vascular function in VDD were accompanied by significantly decreased ER and eNOS staining. Short-term chronic hyperandrogenism failed to, but VDD induced vascular dysfunction, compromised estrogen-dependent vasodilatation and changes in ER and eNOS immunostaining.


Assuntos
Colecalciferol/farmacologia , Estradiol/farmacologia , Síndrome do Ovário Policístico/tratamento farmacológico , Vasodilatação , Deficiência de Vitamina D/complicações , Animais , Aorta/efeitos dos fármacos , Modelos Animais de Doenças , Estrogênios/farmacologia , Feminino , Óxido Nítrico Sintase Tipo III/metabolismo , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/patologia , Ratos , Ratos Wistar , Vitaminas/farmacologia
6.
Theriogenology ; 175: 7-22, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34481229

RESUMO

Metformin is a commonly used for treating type 2 diabetes and it acts on a variety of organs including the male reproductive system. 17ß-estradiol plays an important role in Sertoli cell (SC) proliferation which determines the germ cell development and spermatogenesis. The aim of this study is to investigate the effect of metformin on immature chicken SC proliferation and the potential mechanisms by which 17ß-estradiol regulate this process. Results showed that metformin significantly inhibited SC proliferation, whereas 17ß-estradiol weakened the inhibitory effects of metformin on SC viability, cell growth, and cell cycle progression. SC proliferation-inhibiting effect of metformin exposure was regulated by decreasing adenosine triphosphate level and respiratory enzyme activity in the mitochondria; this process was possibly mediated by the adenosine monophosphate-activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2)/mammalian target of rapamycin (mTOR) signaling pathway, which was regulated by the down-expressed miR-1764 and by the decreased antioxidant enzyme activity and excessive reactive oxygen species generation. In addition, SCs transfected with the miR-1764 agomir led to an improvement of proliferation capacity through down-regulating AMPKα2 level, which further decreased TSC2 expression and induced mTOR activation. However, the anti-proliferative effect of miR-1764 antagomir can be alleviated by 17ß-estradiol treatment via the up-expression of miR-1764 in transfected SCs. Our findings suggest appropriate dose of exogenous 17ß-estradiol treatment can ameliorate the inhibitory effect of metformin on SC proliferation via the regulation of AMPK/TSC2/mTOR signaling pathway, this might reduce the risk of poor male fertility caused by the abuse of anti-diabetic agents.


Assuntos
Estradiol , Metformina , Células de Sertoli/efeitos dos fármacos , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proliferação de Células , Galinhas , Estradiol/farmacologia , Masculino , Metformina/farmacologia , Células de Sertoli/citologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa
7.
Biomed J ; 44(4): 461-470, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34507919

RESUMO

BACKGROUND: Type2 Diabetes (T2D) remains one of the most important causes of cardiovascular diseases (CVD). Menopause leads to an increase in CVD and metabolic syndrome, which indicates the role of sex steroids as a protective factor. In the present study, we surveyed the effects of 17ß-estradiol (E2) alone and in combination with progesterone (P4) on cardiovascular dysfunction in T2D. METHODS: Female ovariectomized (OVX) diabetic rats were divided into eight groups: Sham-Control, Diabetes (Dia), OVX + Dia, OVX + Dia + Vehicle, OVX + Dia + E2, OVX + Dia + P4, OVX + Dia + E2+P4, and OVX + Dia + E2+Vehicle. T2D was induced by a high-fat diet and streptozotocin. E2 and P4 were administrated every four days for four weeks. The heart cytokines and angiotensin II, lipid profile, insulin, water, and food intake and cardiovascular indices were measured. RESULTS: Results showed that single treatment with E2 decreased fasting blood glucose, water, and food intake, atherogenic and cardiac risk indices, and blood pressure. Also, P4 led to a decrease in atherogenic and cardiac risk indices. TNFα and IL-6 levels were increased and IL-10 was decreased in the Dia group, while E2 alone was able to inhibit these changes. The combined use of E2 and P4 eliminated the beneficial effects of E2 on these indices. Although diabetes results in an increment of cholesterol, LDL and triglyceride, hormone therapy with E2 was associated with improved dyslipidemia. CONCLUSION: The use of E2 alone, and not the individual use of P4, and its combination with E2 improved cardiovascular function in OVX diabetic animals, possibly by reducing the amount of inflammatory cytokines and improving metabolic parameters.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Experimental , Animais , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Estradiol/farmacologia , Estradiol/uso terapêutico , Feminino , Humanos , Ovariectomia , Progesterona/farmacologia , Progesterona/uso terapêutico , Ratos
8.
Int J Mol Sci ; 22(17)2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34502280

RESUMO

Estrogen receptor alpha (ERα) is a ligand-dependent transcriptional factor in the nuclear receptor superfamily. Many structures of ERα bound with agonists and antagonists have been determined. However, the dynamic binding patterns of agonists and antagonists in the binding site of ERα remains unclear. Therefore, we performed molecular docking, molecular dynamics (MD) simulations, and quantum mechanical calculations to elucidate agonist and antagonist dynamic binding patterns in ERα. 17ß-estradiol (E2) and 4-hydroxytamoxifen (OHT) were docked in the ligand binding pockets of the agonist and antagonist bound ERα. The best complex conformations from molecular docking were subjected to 100 nanosecond MD simulations. Hierarchical clustering was conducted to group the structures in the trajectory from MD simulations. The representative structure from each cluster was selected to calculate the binding interaction energy value for elucidation of the dynamic binding patterns of agonists and antagonists in the binding site of ERα. The binding interaction energy analysis revealed that OHT binds ERα more tightly in the antagonist conformer, while E2 prefers the agonist conformer. The results may help identify ERα antagonists as drug candidates and facilitate risk assessment of chemicals through ER-mediated responses.


Assuntos
Estradiol/metabolismo , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Tamoxifeno/análogos & derivados , Estradiol/química , Receptor alfa de Estrogênio/química , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Teoria Quântica , Tamoxifeno/química , Tamoxifeno/metabolismo
9.
Neurosci Biobehav Rev ; 130: 529-542, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34517034

RESUMO

Anxiety and stress-related disorders are more prevalent in women and associated with negative emotional memory consolidation as well as impaired fear extinction recall. Recent research has identified a role of gonadal steroid hormones in influencing emotional memories and fear extinction, however most individual studies have small samples and employed various protocols. A systematic review and meta-analysis were conducted on studies that examined sex hormones (estrogen, progesterone, testosterone, allopregnanolone, dehydroepiandrosterone) on four aspects of memory, namely, intentional recall (k = 13), recognition memory (k = 7), intrusive memories (k = 9), and extinction recall (k = 11). The meta-analysis on natural cycling women revealed that progesterone level was positively associated with negative recall and negative intrusive memories, and this effect on intentional recall was enhanced under stress induction. Estradiol level was positively associated with extinction recall. This study reveals an important role of progesterone and estradiol in influencing emotional memory consolidation. It highlights the need to control for these hormonal effects and examine progesterone and estradiol concurrently across all menstrual phases in future emotional memory paradigms.


Assuntos
Consolidação da Memória , Estradiol , Extinção Psicológica , Medo , Feminino , Hormônios Esteroides Gonadais , Humanos , Ciclo Menstrual , Progesterona
10.
Nat Commun ; 12(1): 5565, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552089

RESUMO

Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors probably controls the sex discrepancy in the immune response, but the underlying mechanisms are unclear. Here we positionally identify a polymorphic estrogen receptor binding site that regulates Cd2 expression, leading to female-specific differences in T cell-dependent mouse models of autoimmunity. Female mice with reduced Cd2 expression have impaired autoreactive T cell responses. T cells lacking Cd2 costimulation upregulate inhibitory Lag-3. These findings help explain sexual dimorphism in human autoimmunity, as we find that CD2 polymorphisms are associated with rheumatoid arthritis and 17-ß-estradiol-regulation of CD2 is conserved in human T cells. Hormonal regulation of CD2 might have implications for CD2-targeted therapy, as anti-Cd2 treatment more potently affects T cells in female mice. These results demonstrate the relevance of sex-genotype interactions, providing strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.


Assuntos
Doenças Autoimunes/genética , Antígenos CD2/genética , Predisposição Genética para Doença/genética , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Sítios de Ligação/genética , Antígenos CD2/imunologia , Antígenos CD2/metabolismo , Modelos Animais de Doenças , Estradiol/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Ativação Linfocitária , Masculino , Camundongos , Polimorfismo Genético , Caracteres Sexuais , Linfócitos T/imunologia
11.
Talanta ; 235: 122782, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34517640

RESUMO

Previous 17ß-estradiol sensors required expensive reagents or complicated fabrication of sensing probes. In this work, a cheap, simple, and reusable electrochemical sensor based on commercially available polyaniline (PANI) and carbon dots (CDs) synthesized from iota-carrageenan was developed for the sensitive detection of 17ß-estradiol. The sensor was simply prepared by drop-casting CDs/PANI composite on a glassy carbon electrode (GCE) using poly(vinylidene fluoride) as a binder. With synergistic contributions from both CDs and PANI, the CDs-PANI/GCE was much more electrochemically stable than the CDs/GCE or PANI/GCE. The CDs-PANI/GCE was sensitive to 17ß-estradiol across a linear range from 0.001 to 100 µmol L-1 with a detection limit of 43 nmol L-1. The electrochemical measurement can be performed in 2 min and the probe can be reused for several hundred times. The CDs-PANI/GCE was selective towards 17ß-estradiol against several interferences and gave excellent recovery between 94.4 and 103.7 % from real sample analysis. From intensive investigation on electron transfer process and energy levels, the oxidation reaction of 17ß-estradiol occurred on the surface of CDs-PANI/GCE via favorable energy levels and dominantly surface adsorption process through π-π stacking and hydrogen bonding between 17ß-estradiol and CDs/PANI. Such unique interfacial interactions also resulted in the synergistically enhanced electrochemical stability of the modified electrode.


Assuntos
Carbono , Técnicas Eletroquímicas , Compostos de Anilina , Eletrodos , Estradiol
12.
J Hazard Mater ; 416: 125862, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492810

RESUMO

Di (2-ethylhexyl) phthalate (DEHP) is widely used as a plastic additive and it could induce reproduction defects and fertility in mammals as environmental endocrine disruptor. However, the effects and potential mechanism of DEHP exposure during lactation stage on follicular development of offspring are still unclear. In this study, we found that the total primordial follicle number and antral follicles in the suckling of mice exposed to DEHP during lactation was significantly reduced. RNA-seq analysis results showed that the transcription levels of genes related to steroid production, ovarian hormone secretion and oxidative stress were significantly changed, which led to a decrease in 17ß-estradiol and an increase in oxidative stress. The proportion of DNA damage marker γH2AX in the ovary of female suckling exposed to DEHP was significantly increased. We also found an increase in the level of ovarian apoptosis, and the proliferation of ovarian granulosa cells was inhibited. These alterations also lead to abnormal spindle and chromosome misalignment during oocyte maturation. Overall, our data indicate that lactation exposure to DEHP can affect the secretion of hormones and the development of antral follicles in suckling mice by affecting the secretion pathways of ovarian hormone enzymes and oxidative stress pathway.


Assuntos
Dietilexilftalato , Ovário , Animais , Dietilexilftalato/toxicidade , Estradiol , Feminino , Lactação , Camundongos , Folículo Ovariano
13.
Life Sci ; 284: 119874, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34390725

RESUMO

AIM: To investigate the effect of 17ß-Estradiol (E2) on intervertebral disc degeneration (IVDD) and the related mechanism. MATERIALS AND METHODS: Immunohistochemistry was used to detect the expression of estrogen receptor ß (ERß) within intervertebral discs of humans and rats. After that, rat IVDD model was established by needle puncture and bilateral ovariectomy. Then, the serum E2 level was detected by enzyme linked immunosorbent assay, and the degree of IVDD was evaluated by X-ray, magnetic resonance imaging, hematoxylin and eosin staining, and Safranin O-Fast Green staining. Finally, we used immunohistochemistry and immunofluorescence staining to determine the effect of E2 on nuclear factor kappa-B (NF-κB) signal pathway both in vivo and in vitro. KEY FINDINGS: We identified that IVDD was associated with lower levels of ERß and ERß levels were inversely correlated with IVDD. The histological staining and radiological results showed that E2 supplement could alleviate IVDD progression. Additionally, immunohistochemistry staining demonstrated that E2 could inhibit nucleus pulposus cell (NPC) apoptosis, matrix metalloproteinases (MMPs) synthesis, and degradation of extracellular matrix (ECM) by inhibiting the activation of NF-κB signal pathway. Furthermore, immunofluorescence staining showed that the above effects of E2 on the NF-κB signal pathway could be blocked by the estrogen receptor antagonist ICI182780 in vitro. Finally, inhibition of NF-κB signal pathway by BAY11-7082 could reduce MMPs synthesis and ECM degradation of NPCs. SIGNIFICANCE: Collectively, these findings indicated that E2 could effectively ameliorate IVDD by inhibiting NPC apoptosis via inhibition of NF-κB signal pathway.


Assuntos
Estradiol/farmacologia , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , NF-kappa B/metabolismo , Transdução de Sinais , Adolescente , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Receptor beta de Estrogênio/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Humanos , Interleucina-1beta/metabolismo , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Núcleo Pulposo/patologia , Ovariectomia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
14.
Am J Physiol Heart Circ Physiol ; 321(3): H592-H598, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415188

RESUMO

The endothelin-B (ETB) receptor is a key regulator of vascular endothelial function in women. We have previously shown that the ETB receptor mediates vasodilation in young women, an effect that is lost after menopause. However, the direct impact of changes in estradiol (E2) on ETB receptor function in women remains unclear. Therefore, the purpose of this study was to test the hypothesis that E2 exposure modulates ETB receptor-mediated dilation in young women. Fifteen young women (24 ± 4 yr, 24 ± 3 kg/m2) completed the study. Endogenous sex hormone production was suppressed with daily administration of a gonadotropin-releasing hormone antagonist (GnRHant; Ganirelix) for 10 days; E2 (0.1 mg/day, Vivelle-Dot patch) was added back on days 4-10. We measured vasodilation in the cutaneous microcirculation (microvascular endothelial function) via local heating (42°C) on day 4 (GnRHant) and day 10 (GnRHant + E2) using laser Doppler flowmetry coupled with intradermal microdialysis during perfusions of lactated Ringer's (control) and ETB receptor antagonist (BQ-788, 300 nM). During GnRHant, vasodilatory responses to local heating were enhanced with ETB receptor blockade (control: 83 ± 9 vs. BQ-788: 90 ± 5%CVCmax, P = 0.004). E2 administration improved vasodilation in the control site (GnRHant: 83 ± 9 vs. GnRHant + E2: 89 ± 8%CVCmax, P = 0.036). Furthermore, cutaneous vasodilatory responses during ETB receptor blockade were blunted after E2 administration (control: 89 ± 8 vs. BQ-788: 84 ± 8%CVCmax, P = 0.047). These data demonstrate that ovarian hormones, specifically E2, modulate ETB receptor function and contribute to the regulation of microvascular endothelial function in young women.NEW & NOTEWORTHY The endothelin-B (ETB) receptor mediates vasodilation in young women, an effect lost following menopause. It is unclear whether these alterations are due to aging or changes in estradiol (E2). During endogenous hormone suppression (GnRH antagonist), blockade of ETB receptors enhanced cutaneous microvascular vasodilation. However, during E2 administration, blockade of ETB receptors attenuated vasodilation, indicating that the ETB receptor mediates dilation in the presence of E2. In young women, ETB receptors mediate vasodilation in the presence of E2, an effect that is lost when E2 is suppressed.


Assuntos
Antagonistas do Receptor de Endotelina B/farmacologia , Estradiol/farmacologia , Estrogênios/farmacologia , Receptor de Endotelina B/metabolismo , Vasodilatação , Adulto , Feminino , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Antagonistas de Hormônios/farmacologia , Humanos , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/fisiologia , Oligopeptídeos/farmacologia , Piperidinas/farmacologia , Pele/irrigação sanguínea
15.
Am J Physiol Regul Integr Comp Physiol ; 321(3): R454-R468, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34346723

RESUMO

We evaluated maternal pregnancy adaptations and their relationships with circulating hormones in women who conceived with or without in vitro fertilization (IVF). Pregnancies were grouped by corpus luteum (CL) number: 1 CL with physiological plasma relaxin concentration (PRLN; spontaneous pregnancies); 0 CL without circulating RLN (programmed cycles); >1 CL with elevated PRLN (ovarian stimulation). Major findings were that declines in plasma osmolality (Posm) and plasma sodium concentration ([Formula: see text]) were comparable in the 1 CL and 0 CL cohorts, correlated with plasma estradiol and progesterone concentrations but not PRLN; gestational declines in plasma uric acid (UA) concentration (PUA) were attenuated after IVF, especially programmed cycles, partly because of subdued increases of renal UA clearance; and PRLN and cardiac output (CO) were inversely correlated when plasma estradiol concentration was below ∼2.5 ng/mL but positively correlated above ∼2.5 ng/mL. Unexpectedly, PRLN and plasma sFLT1 (PsFLT1) were directly correlated. Although PsFLT1 and CO were not significantly associated, CO was positively correlated with plasma placental growth factor (PLGF) concentration after the first trimester, particularly in women who conceived with 0 CL. Major conclusions are that 1) circulating RLN was unnecessary for gestational falls in Posm and [Formula: see text]; 2) PRLN and CO were inversely correlated during early gestation, suggesting that PRLN in the lower range may have contributed to systemic vasodilation, whereas at higher PRLN RLN influence became self-limiting; 3) evidence for cooperativity between RLN and estradiol on gestational changes in CO was observed; and 4) after the first trimester in women who conceived without a CL, plasma PLGF concentration was associated with recovery of CO, which was impaired during the first trimester in this cohort.


Assuntos
Fertilização In Vitro , Hormônios Gonadais/sangue , Hemodinâmica , Infertilidade/terapia , Adaptação Fisiológica , Adulto , Biomarcadores/sangue , Débito Cardíaco , Estradiol/sangue , Feminino , Humanos , Infertilidade/sangue , Infertilidade/fisiopatologia , Pessoa de Meia-Idade , Concentração Osmolar , Fator de Crescimento Placentário/sangue , Gravidez , Primeiro Trimestre da Gravidez/sangue , Relaxina/sangue , Sódio/sangue , Ácido Úrico/sangue , Vasodilatação , Adulto Jovem
16.
Behav Neurosci ; 135(5): 668-679, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34398621

RESUMO

Estradiol (E2) is involved in the regulation of emotional behavior, cognitive function, and neuroplasticity. However, peripheral E2 and central E2 levels do not always fluctuate together. The relationships of peripheral and central E2 with cognitive function are not clear. The aim of this study was to investigate whether peripheral E2, hippocampal E2, or both play a critical role in novel object recognition (NOR), and whether Kalirin-7, an important regulator of spine plasticity, is involved in the modulation of E2 on cognitive behavior. Our results showed that ovariectomy (OVX) significantly reduced serum E2 levels in the 14 weeks following the procedure. However, hippocampal E2 levels did not decrease in the OVX group compared to the sham group until after 14 weeks. Consistent with the changes in hippocampal E2 levels, the investigation ratio in the NOR test and hippocampal Kalirin-7 expression was also not lower in the OVX group than in the sham group until 14 weeks after the procedure. To confirm the relationship between hippocampal E2 levels and NOR ability, we inhibited the production of hippocampal E2 via microinjection of letrozole (LTZ; an aromatase inhibitor) into the hippocampi of rats in the control group and 8-week OVX group. The data indicated that a reduction in E2 levels in the hippocampus significantly impaired NOR ability and simultaneously decreased Kalirin-7 levels in the hippocampus. In conclusion, our study strongly demonstrates that hippocampal E2, but not peripheral E2, plays a critical role in NOR ability and that Kalirin-7 may be involved in this mechanism. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Estradiol , Hipocampo , Animais , Estrogênios , Feminino , Humanos , Plasticidade Neuronal , Ovariectomia , Ratos
17.
Clinics (Sao Paulo) ; 76: e3042, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34406272

RESUMO

OBJECTIVES: Lung transplantation is limited by the systemic repercussions of brain death (BD). Studies have shown the potential protective role of 17ß-estradiol on the lungs. Here, we aimed to investigate the effect of estradiol on the long-lasting lung inflammatory state to understand a possible therapeutic application in lung donors with BD. METHODS: Female Wistar rats were separated into 3 groups: BD, subjected to brain death (6h); E2-T0, treated with 17ß-estradiol (50 µg/mL, 2 mL/h) immediately after brain death; and E2-T3, treated with 17ß-estradiol (50 µg/ml, 2 ml/h) after 3h of BD. Complement system activity and macrophage presence were analyzed. TNF-α, IL-1ß, IL-10, and IL-6 gene expression (RT-PCR) and levels in 24h lung culture medium were quantified. Finally, analysis of caspase-3 gene and protein expression in the lung was performed. RESULTS: Estradiol reduced complement C3 protein and gene expression. The presence of lung macrophages was not modified by estradiol, but the release of inflammatory mediators was reduced and TNF-α and IL-1ß gene expression were reduced in the E2-T3 group. In addition, caspase-3 protein expression was reduced by estradiol in the same group. CONCLUSIONS: Brain death-induced lung inflammation in females is modulated by estradiol treatment. Study data suggest that estradiol can control the inflammatory response by modulating the release of mediators after brain death in the long term. These results strengthen the idea of estradiol as a therapy for donor lungs and improving transplant outcomes.


Assuntos
Morte Encefálica , Pneumonia , Animais , Estradiol/farmacologia , Estrogênios , Feminino , Ratos , Ratos Wistar
18.
Emerg Microbes Infect ; 10(1): 1807-1818, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34402750

RESUMO

Male sex was repeatedly identified as a risk factor for death and intensive care admission. However, it is yet unclear whether sex hormones are associated with disease severity in COVID-19 patients. In this study, we analysed sex hormone levels (estradiol and testosterone) of male and female COVID-19 patients (n = 50) admitted to an intensive care unit (ICU) in comparison to control non-COVID-19 patients at the ICU (n = 42), non-COVID-19 patients with the most prevalent comorbidity (coronary heart diseases) present within the COVID-19 cohort (n = 39) and healthy individuals (n = 50). We detected significantly elevated estradiol levels in critically ill male COVID-19 patients compared to all control cohorts. Testosterone levels were significantly reduced in critically ill male COVID-19 patients compared to control cohorts. No statistically significant differences in sex hormone levels were detected in critically ill female COVID-19 patients, albeit similar trends towards elevated estradiol levels were observed. Linear regression analysis revealed that among a broad range of cytokines and chemokines analysed, IFN-γ levels are positively associated with estradiol levels in male and female COVID-19 patients. Furthermore, male COVID-19 patients with elevated estradiol levels were more likely to receive ECMO treatment. Thus, we herein identified that disturbance of sex hormone metabolism might present a hallmark in critically ill male COVID-19 patients.


Assuntos
COVID-19/mortalidade , COVID-19/patologia , Estradiol/sangue , Testosterona/sangue , Idoso , Idoso de 80 Anos ou mais , COVID-19/sangue , Cuidados Críticos , Estado Terminal , Oxigenação por Membrana Extracorpórea , Feminino , Humanos , Hipogonadismo/patologia , Unidades de Terapia Intensiva , Interferon gama/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Distribuição por Sexo
19.
Commun Biol ; 4(1): 954, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376799

RESUMO

Longitudinal menstrual cycle studies allow to investigate the effects of ovarian hormones on brain organization. Here, we use spectral dynamic causal modelling (spDCM) in a triple network model to assess effective connectivity changes along the menstrual cycle within and between the default mode, salience and executive control networks (DMN, SN, and ECN). Sixty healthy young women were scanned three times along their menstrual cycle, during early follicular, pre-ovulatory and mid-luteal phase. Related to estradiol, right before ovulation the left insula recruits the ECN, while the right middle frontal gyrus decreases its connectivity to the precuneus and the DMN decouples into anterior/posterior parts. Related to progesterone during the mid-luteal phase, the insulae (SN) engage to each other, while decreasing their connectivity to parietal ECN, which in turn engages the posterior DMN. When including the most confident connections in a leave-one out cross-validation, we find an above-chance prediction of the left-out subjects' cycle phase. These findings corroborate the plasticity of the female brain in response to acute hormone fluctuations and may help to further understand the neuroendocrine interactions underlying cognitive changes along the menstrual cycle.


Assuntos
Estradiol/metabolismo , Ciclo Menstrual/fisiologia , Vias Neurais/fisiologia , Progesterona/metabolismo , Adulto , Mapeamento Encefálico , Feminino , Humanos , Adulto Jovem
20.
eNeuro ; 8(5)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34385153

RESUMO

Kisspeptin-expressing neurons in the anteroventral-periventricular nucleus (AVPV) are part of a neural circuit generating the gonadotropin-releasing hormone (GnRH) surge. This process is estradiol-dependent and occurs on the afternoon of proestrus in female mice. On proestrus, AVPV kisspeptin neurons express more kisspeptin and exhibit higher frequency action potentials and burst firing compared with diestrus, which is characterized by a pulsatile rather than a prolonged surge of GnRH secretion. We hypothesized changes in voltage-gated potassium conductances shape activity profiles of these cells in a cycle-dependent manner. Whole-cell voltage-clamp recordings of GFP-identified AVPV kisspeptin neurons in brain slices from diestrous and proestrous mice revealed three subcomponents of the voltage-sensitive K+ current: fast-transient slow-transient, and residual. During proestrus, the V50 of inactivation of the fast-transient current was depolarized and the amplitude of the slow-transient component was reduced compared with diestrus; the residual component was consistent across both stages. Computational models were fit to experimental data, including published estrous-cycle effects on other voltage-gated currents. Computer simulations suggest proestrus-typical K+ currents are suppressive compared with diestrus. Interestingly, larger T-type, persistent-sodium, and hyperpolarization-activated currents during proestrus compensate for this suppressive effect while also enabling postinhibitory rebound bursting. These findings suggest modulation of voltage-gated K+ and multiple subthreshold depolarizing currents across the negative to positive feedback transition maintain AVPV kisspeptin neuron excitability in response to depolarizing stimuli. These changes also enable firing in response to hyperpolarization, providing a net increase in neuronal excitability, which may contribute to activation of this population leading up to the preovulatory GnRH surge.


Assuntos
Kisspeptinas , Potássio , Animais , Estradiol/farmacologia , Ciclo Estral , Feminino , Hormônio Liberador de Gonadotropina , Hipotálamo Anterior/metabolismo , Kisspeptinas/metabolismo , Camundongos , Neurônios/metabolismo
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