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1.
Biomed Pharmacother ; 153: 113385, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076523

RESUMO

Female menopause is a hormone deficiency phenomenon that causes hot flashes, vaginal dryness, depression, nervous tension, insomnia, obesity, and bone loss. There are various hormone replacement therapy (HRT)-based menopausal treatments, but they are accompanied by side effects such as endometrial cancer and hyperplasia. To confirm the menopausal improvement effect of Polygonatum sibiricum (PS), we prepared an ovariectomized animal model, administered 17ß-estradiol (E2) and PS, and analyzed various menopausal symptoms. PS restored vaginal epithelium thickness, by increasing the expression of estrogen receptors ERα (ESR1) and ERß (ESR2), and increased serotonin concentration by reducing serotonin receptor 1 A (5-HT1A) and glucocorticoid receptor (Gr) expression. In addition, PS suppressed obesity by increasing HDL-C and decreasing LDL-C levels and improved the osteoporosis induced by ovariectomy. In particular, by controlling Hand2, Fgf2, and Faf9 expression through PR, the antiproliferative signal was suppressed in uterine epithelium, thereby reducing the risk of side effects of the administration of E2 alone. These results demonstrate that PS alleviates menopausal symptoms without causing endometrial hyperplasia.


Assuntos
Polygonatum , Animais , Modelos Animais de Doenças , Estradiol/farmacologia , Estrogênios/farmacologia , Feminino , Humanos , Menopausa , Camundongos , Obesidade/tratamento farmacológico , Ovariectomia
2.
Adv Exp Med Biol ; 1390: 297-309, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36107326

RESUMO

Estrogen Receptor alpha (ERα) stands as one of the most successfully prosecuted drug targets in oncology, beginning with the approval of tamoxifen for women with ERα positive (ER+) breast cancer over 40 years ago. The field continued to advance with the development of aromatase inhibitors and the pure antiestrogen fulvestrant. With multiple endocrine therapies approved for the treatment of ER+ breast cancer, efforts to generate novel ERα-targeted therapeutics somewhat diminished in the early 2000s. Today however, there are at least eight new molecular entities targeting ERα under active clinical investigation, each with the aim of bringing further benefit to patients. This remarkable re-energizing of the field was spurred in part by the discovery of highly prevalent ERα mutations as a mechanism of resistance to standard-of-care therapies, which provided unequivocal evidence of the continued, and broad, dependence of tumors on ERα, despite relapsing after earlier lines of endocrine therapy. Re-engagement of the pharmaceutical and biotechnology industries with ERα as a drug target has been further underpinned by the impressive advances made in medicinal chemistry, enabling desirable mechanistic features - high potency full ERα antagonism - to be combined with improved drug-like properties - oral bioavailability and optimized pharmacokinetics. In this chapter, we describe the rich history and science behind the currently evolving landscape of ERα targeting in breast cancer.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estradiol/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Receptor alfa de Estrogênio/genética , Feminino , Fulvestranto/uso terapêutico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Preparações Farmacêuticas , Receptores de Estrogênio/genética , Tamoxifeno/uso terapêutico
3.
Cancer Chemother Pharmacol ; 90(4): 345-356, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36050497

RESUMO

PURPOSE: The DNA alkylating agent temozolomide (TMZ), is the first-line therapeutic for the treatment of glioblastoma (GBM). However, its use is confounded by the occurrence of drug resistance and debilitating adverse effects. Previously, we observed that letrozole (LTZ), an aromatase inhibitor, has potent activity against GBM in pre-clinical models. Here, we evaluated the effect of LTZ on TMZ activity against patient-derived GBM cells. METHODS: Employing patient-derived G76 (TMZ-sensitive), BT142 (TMZ-intermediately sensitive) and G43 and G75 (TMZ-resistant) GBM lines we assessed the influence of LTZ and TMZ on cell viability and neurosphere growth. Combination Index (CI) analysis was performed to gain quantitative insights of this interaction. We then assessed DNA damaging effects by conducting flow-cytometric analysis of Ë H2A.X formation and induction of apoptotic signaling pathways (caspase3/7 activity). The effects of adding estradiol on LTZ-induced cytotoxicity and DNA damage were also evaluated. RESULTS: Co-treatment with LTZ at a non-cytotoxic concentration (40 nM) reduced TMZ IC50 by 8, 37, 240 and 640 folds in G76, BT-142, G43 and G75 cells, respectively. The interaction was deemed to be synergistic based on CI analysis. LTZ co-treatment also significantly increased DNA damaging effects of TMZ. Addition of estradiol abrogated these LTZ effects. CONCLUSIONS: LTZ increases DNA damage and synergistically enhances TMZ activity in TMZ sensitive and TMZ-resistant GBM lines. These effects are abrogated by the addition of exogenous estradiol underscoring that the observed effects of LTZ may be mediated by estrogen deprivation. Our study provides a strong rationale for investigating the clinical potential of combining LTZ and TMZ for GBM therapy.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Inibidores da Aromatase/farmacologia , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Estradiol/farmacologia , Glioblastoma/metabolismo , Humanos , Letrozol/farmacologia , Letrozol/uso terapêutico , Temozolomida/farmacologia , Temozolomida/uso terapêutico
4.
Sci Rep ; 12(1): 13881, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35974048

RESUMO

Porphyromonas gingivalis has been strongly associated to active periodontitis sites. A number of studies have tried to elucidate the association between female steroid sex hormones and gingival health. However, until now, there is limited knowledge on estradiol effects on the virulence traits of P. gingivalis. The aim of the study was to investigate the impact of estradiol exposure on the virulence characteristics of P. gingivalis strain W50. We found that a pre- and postmenopausal concentration of estradiol increased the growth and biofilm formation of P. gingivalis W50. We also found that estradiol increased the release of lysine and arginine gingipains from W50. We then showed that IL-1ß, CXCL10 and TGF-ß1 release from gingival epithelial cells was significantly lowered by W50 pre-exposed to estradiol compared to W50 alone. Real time-qPCR showed that the gene expression of IL-18, IL-6, IL-8, TGF-ß1 and NLRP3 in gingival epithelial cells was significantly lowered by W50 pre-exposed to estradiol compared to W50 alone. We also found that estradiol in a dose-dependent manner increased P. gingivalis colonization and invasion of gingival epithelial cells. Taken together, our findings show that estradiol has the ability to alter the virulence traits of P. gingivalis.


Assuntos
Porphyromonas gingivalis , Fator de Crescimento Transformador beta1 , Estradiol/metabolismo , Estradiol/farmacologia , Feminino , Cisteína Endopeptidases Gingipaínas , Humanos , Porphyromonas gingivalis/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Virulência
5.
PLoS One ; 17(8): e0271131, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35939438

RESUMO

Estrogens are thought to contribute to cognitive function in part by promoting the function of basal forebrain cholinergic neurons that project to the hippocampus and cortical regions including the entorhinal cortex. Reductions in estrogens may alter cognition by reducing the function of cholinergic inputs to both the hippocampus and entorhinal cortex. In the present study, we assessed the effects of ovariectomy on proteins associated with cholinergic synapses in the entorhinal cortex. Ovariectomy was conducted at PD63, and tissue was obtained on PD84 to 89 to quantify changes in the degradative enzyme acetylcholinesterase, the vesicular acetylcholine transporter, and muscarinic M1 receptor protein. Although the vesicular acetylcholine transporter was unaffected, ovariectomy reduced both acetylcholinesterase and M1 receptor protein, and these reductions were prevented by chronic replacement of 17ß-estradiol following ovariectomy. We also assessed the effects of ovariectomy on the cholinergic modulation of excitatory transmission, by comparing the effects of the acetylcholinesterase inhibitor eserine on evoked excitatory synaptic field potentials in brain slices obtained from intact rats, and from ovariectomized rats with or without 17ß-estradiol replacement. Eserine is known to prolong the effects of endogenously released acetylcholine, resulting in an M1-like mediated reduction of glutamate release at excitatory synapses. The reduction in excitatory synaptic potentials in layer II of the entorhinal cortex induced by 15-min application of 10 µM eserine was greatly reduced in slices from ovariectomized rats as compared to intact rats and ovariectomized rats with replacement of 17ß-estradiol. The reduced modulatory effect of eserine is consistent with the observed changes in cholinergic proteins, and suggests that reductions in 17ß-estradiol following ovariectomy lead to impaired cholinergic function within the entorhinal cortex.


Assuntos
Acetilcolinesterase , Córtex Entorrinal , Animais , Colinérgicos/farmacologia , Córtex Entorrinal/fisiologia , Estradiol/farmacologia , Estrogênios/farmacologia , Potenciais Pós-Sinápticos Excitadores , Feminino , Humanos , Ovariectomia , Fisostigmina/farmacologia , Ratos , Receptor Muscarínico M1 , Transmissão Sináptica/fisiologia , Proteínas Vesiculares de Transporte de Acetilcolina
6.
Transl Psychiatry ; 12(1): 354, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36045119

RESUMO

Posttraumatic stress disorder (PTSD) is characterised by dysregulated hypothalamic-pituitary-adrenal axis activity and altered glucocorticoid receptor sensitivity. Early treatment with glucocorticoids may reduce PTSD risk, although the effect of such treatment on the aetiologically critical step of traumatic-memory-formation remains unclear. Here we examine the effects of exogenous cortisol (hydrocortisone) in a preclinical model of PTSD, using a factorial (Drug × Sex), randomised-controlled, double-blind design. Healthy men and women (n = 120) were randomised to receive 30 mg oral hydrocortisone or matched placebo immediately after watching a stressful film. Effects on film-related intrusions were assessed acutely in the lab, and ecologically using daily memory diaries for one week. We found that participants receiving hydrocortisone showed a faster reduction in daily intrusion frequency. Voluntary memory was assessed once, at the end of the week, but was unaffected by hydrocortisone. Exploratory analyses indicated sex-dependent associations between intrusions and baseline estradiol and progesterone levels. In men receiving hydrocortisone, higher baseline estradiol levels were associated with fewer intrusions, whereas women exhibited the opposite pattern. By contrast, progesterone levels were positively associated with intrusions only in men treated with hydrocortisone. The findings suggest that hydrocortisone promotes an accelerated degradation of sensory-perceptual representations underlying traumatic intrusive memories. In addition, while sex alone was not an important moderator, the combination of sex and sex-hormone levels (especially estradiol) influenced hydrocortisone's effects on involuntary aversive memories. Future well-powered experimental studies may provide a basis for a precision-psychiatry approach to optimising early post-traumatic glucocorticoid treatments that target intrusive memories, based on individual endocrinological profiles.


Assuntos
Hidrocortisona , Transtornos de Estresse Pós-Traumáticos , Estradiol/farmacologia , Feminino , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Memória , Sistema Hipófise-Suprarrenal/metabolismo , Progesterona/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico
7.
J Am Chem Soc ; 144(33): 15059-15071, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-35952371

RESUMO

Photopharmacology is an emerging approach in drug design and pharmacological therapy. Light is used to switch a pharmacophore between a biologically inactive and an active isomer with high spatiotemporal resolution at the site of illness, thus potentially avoiding side effects in neighboring healthy tissue. The most frequently used strategy to design a photoswitchable drug is to replace a suitable functional group in a known bioactive molecule with azobenzene. Our strategy is different in that the photoswitch moiety is closer to the drug's scaffold. Docking studies reveal a very high structural similarity of natural 17ß-estradiol and the E isomers of dihydroxy diazocines, but not their Z isomers, respectively. Seven dihydroxy diazocines were synthesized and subjected to a biological estrogen reporter gene assay. Four derivatives exhibit distinct estrogenic activity after irradiation with violet light, which can be shut off with green light. Most remarkably, the photogenerated, active E form of one of the active compounds isomerizes back to the inactive Z form with a half-life of merely several milliseconds in water, but nevertheless is active for more than 3 h in the presence of the estrogen receptor. The results suggest a significant local impact of the ligand-receptor complex toward back-isomerization. Thus, drugs that are active when bound but lose their activity immediately after leaving the receptor could be of great pharmacological value because they strongly increase target specificity. Moreover, the drugs are released into the environment in their inactive form. The latter argument is particularly important for drugs that act as endocrine disruptors.


Assuntos
Desenho de Fármacos , Estrogênios , Estradiol/farmacologia , Isomerismo , Ligantes
8.
Anim Reprod Sci ; 244: 107048, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35914333

RESUMO

Thrombospondin-1 (THBS1) is involved in the process of angiogenesis and is down-regulated by insulin-like growth factor 1 (IGF1) in porcine granulosa cells (GC), but what other hormones regulate GC THBS1 and its role in follicular growth is unclear. Thus, six experiments were conducted to determine the influence of other hormones on THBS1 gene expression in porcine GC, and to determine if THBS1 mRNA changes during follicular development. For Exp. 1-5, small (1-5 mm) follicles from ovaries of abattoir gilts were aspirated, GC collected and treated with FSH, IGF1, fibroblast growth factor 9 (FGF9), Sonic hedgehog (SHH), estradiol, cortisol, and/or prostaglandin E2 (PGE2). FSH, IGF1 and FGF9 each decreased (P < 0.05) THBS1 mRNA abundance. Alone, PGE2 increased (P < 0.05) THBS1 mRNA abundance. PGE2 significantly attenuated the FSH-induced inhibition of THBS1 mRNA expression. Estradiol, cortisol, and SHH had no effect on THBS1 mRNA abundance. In Exp. 6, small (1-3 mm), medium (4-6 mm) and large (7-14 mm) follicles were aspirated to measure abundance of THBS1 mRNA in GC which did not differ (P > 0.10) between small and medium-sized follicles but was threefold greater (P < 0.05) in large compared to small or medium follicles. We hypothesize that the inhibitory effects of FSH, IGF1 and FGF9 on the antiangiogenic gene THBS1 could contribute to promoting angiogenesis in the developing follicle, while stimulation of THBS1 mRNA by PGE2 may help reduce angiogenesis during the preovulatory period when PGE2 and THBS1 mRNA are at their greatest levels.


Assuntos
Dinoprostona , Hidrocortisona , Animais , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Estradiol/metabolismo , Estradiol/farmacologia , Feminino , Hormônio Foliculoestimulante/metabolismo , Hormônio Foliculoestimulante/farmacologia , Regulação da Expressão Gênica , Células da Granulosa , Proteínas Hedgehog/genética , Hidrocortisona/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Suínos
9.
Viruses ; 14(8)2022 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-36016428

RESUMO

BACKGROUND AND AIMS: Sex hormones are widely recognised to act as protective factors against several viral infections. Specifically, females infected by the hepatitis C virus display higher clearance rates and reduced disease progression than those found in males. Through modulation of particle release and spread, 17ß-oestradiol controls HCV's life cycle. We investigated the mechanism(s) behind oestrogen's antiviral effect. METHODS: We used cell culture-derived hepatitis C virus in in vitro assays to evaluate the effect of 17ß-oestradiol on the innate immune response. Host immune responses were evaluated by enumerating gene transcripts via RT-qPCR in cells exposed to oestrogen in the presence or absence of viral infection. Antiviral effects were determined by focus-forming unit assay or HCV RNA quantification. RESULTS: Stimulation of 17ß-oestradiol triggers a pre-activated antiviral state in hepatocytes, which can be maintained for several hours after the hormone is removed. This induction results in the elevation of several innate immune genes, such as interferon alpha and beta, tumour necrosis factor, toll-like receptor 3 and interferon regulatory factor 5. We demonstrated that this pre-activation of immune response signalling is not affected by a viral presence, and the antiviral state can be ablated using an interferon-alpha/beta receptor alpha inhibitor. Finally, we proved that the oestrogen-induced stimulation is essential to generate an antiviral microenvironment mediated by activation of type I interferons. CONCLUSION: Resulting in viral control and suppression, 17ß-oestradiol induces an interferon-mediated antiviral state in hepatocytes. Oestrogen-stimulated cells modulate the immune response through secretion of type I interferon, which can be countered by blocking interferon-alpha/beta receptor alpha signalling.


Assuntos
Hepatite C , Interferon Tipo I , Antivirais/uso terapêutico , Estradiol/metabolismo , Estradiol/farmacologia , Estradiol/uso terapêutico , Estrogênios/metabolismo , Estrogênios/farmacologia , Estrogênios/uso terapêutico , Feminino , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatócitos/metabolismo , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Interferon-alfa/farmacologia , Masculino , Replicação Viral
10.
Int J Mol Sci ; 23(15)2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35955769

RESUMO

During their breeding season, estrogen induces vitellogenin (VTG) production in the liver of teleost fish through estrogen receptors (ERs) that support oocyte vitellogenesis. There are at least three ER subtypes in teleost fish, but their roles in mediating E2-induced VTG expression have yet to be ascertained. In this study, we investigated the expression of vtgs and ers in the liver of orange-spotted grouper (Epinephelus coioides). Their expression levels were significantly increased in the breeding season and were upregulated by an estradiol (E2) injection in female fish, except for the expression of erß1. The upregulation of vtgs, erα and erß2 by E2 was also observed in primary hepatocytes, but these stimulatory effects could be abolished by ER antagonist ICI182780 treatment. Subsequent studies showed that ERß antagonist Cyclofenil downregulated the E2-induced expression of vtg, erα, and erß2, while the ERß agonist DPN simulated their expression. Knockdown of erß2 by siRNA further confirmed that ERß2 mediated the E2-induced expression of vtgs and erα. To reveal the mechanism of ERß2 in the regulation of erα expression, the erα promoter was cloned, and its activity was examined in cells. E2 treatment simulated the activity of the erα promoter in the presence of ERß2. Deletions and site-directed mutations showed that the E2 up-regulated transcriptional activity of erα occurs through a classical half-estrogen response element- (ERE) dependent pathway. This study reveals the roles of ER subtypes in VTG expression in orange-spotted grouper and provides a possible explanation for the rapid and efficient VTG production in this species during the breeding season.


Assuntos
Bass , Vitelogeninas , Animais , Bass/genética , Bass/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios , Feminino , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Vitelogeninas/genética , Vitelogeninas/metabolismo
11.
Transfusion ; 62(9): 1882-1893, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35929193

RESUMO

BACKGROUND: Female sex confers a survival advantage following severe injury in the setting of trauma-induced coagulopathy, with female platelets having heightened responsiveness likely due to estrogen. The effects of testosterone on platelet biology are unknown, and platelets express both estradiol and androgen receptors on the plasma membrane. We hypothesize testosterone decreases platelet responses in vitro, and there are baseline differences in platelet function and metabolism stratified by sex/age. STUDY DESIGN AND METHODS: Apheresis platelets were collected from: older males (OM) ≥45 years, younger males (YM) <45 years, older females (OF) ≥54 years, and younger females (YF) <54 years, and testosterone and estradiol were measured. Platelets were incubated with testosterone (5.31 ng/ml), estradiol (105 pg/ml) or vehicle and stimulated with buffer, adenosine diphosphate (20 µM), platelet activating factor (2 µM), or thrombin (0.3 U/ml). Aggregation, CD62P surface expression, fibrinogen receptor surface expression, and platelet mitochondrial metabolism were measured. RESULTS: Testosterone significantly inhibited aggregation in OF and OM (p < .05), inhibited CD41a expression in YF, YM, and OM (p < .05), and affected a few of the baseline amounts of CD62P surface expression but not platelet activation to platelet-activating factor and adenosine diphosphate, and variably changed platelet metabolism. DISCUSSION: Platelets have sex- and age-specific aggregation, receptor expression, and metabolism. Testosterone decreases platelet function dependent on the stimulus, age, and sex. Similarly, platelet metabolism has varying responses to sex hormones with baseline metabolic differences dependent upon sex and age.


Assuntos
Plaquetas , Agregação Plaquetária , Difosfato de Adenosina/farmacologia , Plaquetas/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Feminino , Humanos , Masculino , Testosterona/farmacologia
12.
Biochem Biophys Res Commun ; 625: 181-187, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35970078

RESUMO

Pathological vascular remodeling and cell proliferation play vital roles in many proliferative vascular diseases. Estrogen can protect the cardiovascular system, but its exact molecular mechanism is unknown. Here we report that 17ß-estradiol (E2) suppressed vascular smooth muscle cells (VSMCs) proliferation and inflammation. qRT-PCR and Western blot demonstrated that E2 decreased NF-κB p50 expression and reduced VSMCs proliferation and inflammation. Mechanistically, a dual luciferase reporter assay and chromatin immunoprecipitation suggested that KLF5 promoted NF-κB p50 expression by binding to the NF-κB p50 promoter, whereas E2 reduced the effect of KLF5 binding to the NF-κB p50 promoter and inhibited NF-κB p50 expression. Furthermore, a coimmunoprecipitation assay and immunofluorescence staining showed that the interaction between KLF5 and ERα increased in VSMCs treated with E2, which in turn decreased NF-κB p50 expression levels. Altogether, we reveal that E2 inhibits VSMCs proliferation and inflammation by reducing NF-κB expression induced by an increased interaction between KLF5 and ERα. These data provide further insights into how E2 inhibits vascular proliferation and inflammation.


Assuntos
Músculo Liso Vascular , NF-kappa B , Animais , Células Cultivadas , Estradiol/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Humanos , Inflamação/patologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo
13.
Biochem Biophys Res Commun ; 626: 129-134, 2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-35988296

RESUMO

Taurine, acting as a free amino acid, is widely distributed and plays multiple functions, including its regulating effect on estrogen synthesis in ovary. However, the mechanisms of taurine regulating estrogen synthesis in granulosa cells are not well understood. In this study, we identify whether microRNA-7a2 (miR-7a2) is involved in the signaling of taurine regulating estrogen synthesis in mouse granulosa cells for the first time. The results demonstrated that taurine transporter (TauT) co-localized with miR-7a in mouse ovarian granulose cells. Further, taurine treatment markedly enhanced the expression of miR-7a and Cyp19a1 in mouse ovaries and increased serum 17ß-estradiol (E2) concentration. Meanwhile, miR-7a2 knockout reversed the effect of taurine on E2. In addition, Golgi apparatus protein 1 (Glg1), a downstream target gene of miR-7a2, was significantly down-regulated by taurine, while Glg1 knockdown markedly increased the Cyp19a1 expression and E2 synthesis. Moreover, taurine affected miR-7a expression via activating p38 signaling. These results suggest that taurine promotes E2 synthesis through p38/miR-7a/Glg1/Cyp19a1 signaling pathway, which is crucial to understand the function and mechanism of taurine on estrogen synthesis.


Assuntos
MicroRNAs , Animais , Estradiol/farmacologia , Estrogênios/metabolismo , Estrogênios/farmacologia , Feminino , Células da Granulosa/metabolismo , Camundongos , MicroRNAs/metabolismo , Taurina/farmacologia
14.
Front Cell Infect Microbiol ; 12: 941014, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909974

RESUMO

Women with cystic fibrosis (CF) have a significantly lower life expectancy compared to men, which is indicated by an earlier impairment of lung function due to chronic colonization with biofilm formed by Pseudomonas aeruginosa. There is growing evidence that blood serum concentrations of the steroid sex hormone estradiol (E2) correlate with the occurrence of pulmonary exacerbations in CF but also play a role in the mucoid switch of P. aeruginosa. This study aims to shed light on possible microbiological reasons for sexual dimorphism in CF by investigating the influence of E2 on biofilm formation of P. aeruginosa CF isolates. For this purpose, 10 CF isolates of the respiratory tract derived from different CF patients have been treated with E2 in a microtiter plate biofilm model. Biofilms have been examined by crystal violet assays, field emission scanning electron microscopy (FE-SEM), 3D laser scanning microscopy (LSM), and quorum sensing (QS) reporter assays of the supernatants taken from biofilms. This allowed us to simultaneously investigate the effects of E2 on attached biofilm mass, biofilm ultrastructure, and QS activity. Upon E2 treatment, six out of 10 investigated CF isolates showed an increase of attached biofilm mass, whereas biofilms from two tested non-CF laboratory strains (PAO1 and ATCC19660) did not. Moreover, FE-SEM and 3D LSM analyses of the E2 responsive CF biofilms revealed ultrastructural remodeling of biofilm structure at different scales with increased formation of prominent biofilm spots, enhanced coverage with extracellular polymeric substance (EPS), and extended average surface roughness. QS activity measurements performed in biofilm supernatants via luminescence acyl homoserine lactone (AHL) reporter assays further showed that E2 treatment may also modulate QS signaling, as shown in an E2 sensitive CF isolate. Together, our results suggest the biofilm modulating effects of E2 on various clinical CF isolates that are documented by both biomass and ultrastructural changes of biofilms. The gained new insight into the influence of steroid hormones on P. aeruginosa biofilm phenotypes might pave the way for novel future approaches in personalized medicine based on the patients' sex and hormonal status.


Assuntos
Fibrose Cística , Infecções por Pseudomonas , Biofilmes , Fibrose Cística/microbiologia , Estradiol/farmacologia , Matriz Extracelular de Substâncias Poliméricas , Feminino , Humanos , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa
15.
J Endocrinol ; 255(2): 39-51, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35993439

RESUMO

Among patients with knee osteoarthritis (OA), postmenopausal women are over-represented. The purpose of this study was to determine whether deficiency of female sex steroids affects OA progression and to evaluate the protective effect of treatment with a physiological dose of 17ß-estradiol (E2) on OA progression using a murine model. Ovariectomy (OVX) of female mice was used to mimic a postmenopausal state. OVX or sham-operated mice underwent surgery for destabilization of the medial meniscus (DMM) to induce OA. E2 was administered in a pulsed manner for 2 and 8 weeks. OVX of OA mice did not influence the cartilage phenotype or synovial thickness, while both cortical and trabecular subchondral bone mineral density (BMD) decreased after OVX compared with sham-operated mice at 8 weeks post-DMM surgery. Additionally, OVX mice displayed decreased motor activity, reduced threshold of pain sensitivity, and increased number of T cells in the inguinal lymph nodes compared to sham-operated mice 2 weeks after OA induction. Eight weeks of treatment with E2 prevented cartilage damage and thickening of the synovium in OVX OA mice. The motor activity was improved after E2 replacement at the 2 weeks time point, which was also associated with lower pain sensitivity in the OA paw. E2 treatment protected against OVX-induced loss of subchondral trabecular bone. The number of T cells in the inguinal lymph nodes was reduced by E2 treatment after 8 weeks. This study demonstrates that treatment with a physiological dose of E2 exerts a protective role by reducing OA symptoms.


Assuntos
Estradiol , Osteoartrite , Animais , Cartilagem , Modelos Animais de Doenças , Estradiol/farmacologia , Estradiol/uso terapêutico , Feminino , Humanos , Camundongos , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Ovariectomia , Dor
16.
Pharmacol Biochem Behav ; 218: 173431, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35850178

RESUMO

Ovarian hormones influence the activity of endogenous opioids, and exogenous administration of estradiol reduces opioid intake and opioid seeking in animal models of opioid reward and reinforcement. The purpose of this study was to examine the effects of ovarian hormones on the discriminative stimulus effects of morphine and naloxone-precipitated opioid withdrawal. To this end, separate groups of ovariectomized female rats were trained to discriminate the stimulus effects of either 3.0 or 10 mg/kg morphine, and substitution tests were conducted with estradiol or progesterone alone and in combination with morphine. At the conclusion of discrimination testing, rats were treated chronically with estradiol, progesterone, or their combination, and challenged with naloxone to measure opioid-like withdrawal symptoms. Finally, the effects of estradiol, progesterone, and their combination were examined on naloxone-precipitated withdrawal in morphine-dependent rats. Neither estradiol nor progesterone substituted for the morphine discriminative stimulus, but estradiol significantly increased the potency of morphine in rats trained to discriminate 10 mg/kg but not 3 mg/kg morphine. When administered chronically, neither hormone nor their combination produced an opioid-like withdrawal syndrome following a naloxone challenge. Acute administration of estradiol, but not progesterone or a combination of estradiol and progesterone, significantly reduced naloxone-precipitated weight loss in morphine-dependent rats. These data indicate that estradiol influences the behavioral effects of morphine, possibly by increasing endogenous tone at mu opioid receptors.


Assuntos
Dependência de Morfina , Síndrome de Abstinência a Substâncias , Transtornos Relacionados ao Uso de Substâncias , Analgésicos Opioides/farmacologia , Animais , Estradiol/farmacologia , Feminino , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Progesterona/farmacologia , Ratos , Receptores Opioides mu
17.
Neurobiol Aging ; 118: 13-24, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35843109

RESUMO

Female APOE4 carriers are at greatest risk of Alzheimer's disease (AD). The potent estrogen 17ß-estradiol (E2) may mediate AD risk, as the onset of memory decline coincides with the menopausal transition. Whether APOE genotype mediates E2's effects on memory and neuronal morphology is poorly understood. We used the APOE+/+/5xFAD+/- (EFAD) mouse model to examine how APOE3 homozygote (E3FAD), APOE3/4 heterozygote (E3/4FAD), and APOE4 homozygote (E4FAD) genotypes modulate effects of E2 on object and spatial memory consolidation, dendritic spine density, and dorsal hippocampal estrogen receptor expression in 6-month-old ovariectomized EFAD mice. Dorsal hippocampal E2 infusion enhanced memory consolidation and increased CA1 apical spine density in E3FAD and E3/4FAD, but not E4FAD, mice. CA1 basal mushroom spines were also increased by E2 in E3FADs. E4FAD mice exhibited reduced CA1 and mPFC basal spine density, and increased dorsal hippocampal ERα protein, independent of E2. Overall, E2 benefitted hippocampal memory and structural plasticity in females bearing one or no APOE4 allele, whereas two APOE4 alleles impeded the memory-enhancing and spinogenic effects of E2.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E3/farmacologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Estradiol/metabolismo , Estradiol/farmacologia , Estrogênios/metabolismo , Estrogênios/farmacologia , Feminino , Homozigoto , Camundongos , Camundongos Transgênicos
18.
Int J Mol Sci ; 23(14)2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35886868

RESUMO

Polyamine levels decrease with menopause; however, little is known about the mechanisms regulated by menopause. In this study, we found that among the genes involved in the polyamine pathway, polyamine oxidase (PAOX) mRNA levels were the most significantly reduced by treatment with 17ß-estradiol in estrogen receptor (ESR)-positive MCF-7 breast cancer cells. Treatment with 17ß-estradiol also reduced the PAOX protein levels. Treatment with selective ESR antagonists and knockdown of ESR members revealed that estrogen receptor 2 (ESR2; also known as ERß) was responsible for the repression of PAOX by 17ß-estradiol. A luciferase reporter assay showed that 17ß-estradiol downregulates PAOX promoter activity and that 17ß-estradiol-dependent PAOX repression disappeared after deletions (-3126/-2730 and -1271/-1099 regions) or mutations of activator protein 1 (AP-1) binding sites in the PAOX promoter. Chromatin immunoprecipitation analysis showed that ESR2 interacts with AP-1 bound to each of the two AP-1 binding sites. These results demonstrate that 17ß-estradiol represses PAOX transcription by the interaction of ESR2 with AP-1 bound to the PAOX promoter. This suggests that estrogen deficiency may upregulate PAOX expression and decrease polyamine levels.


Assuntos
Neoplasias da Mama , Receptor beta de Estrogênio , Oxirredutases atuantes sobre Doadores de Grupo CH-NH , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Células MCF-7/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Poliaminas , Fator de Transcrição AP-1/genética
19.
Endocrinology ; 163(8)2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35789268

RESUMO

Luteinizing hormone (LH) secretion during the ovarian cycle is governed by fluctuations in circulating estradiol (E2) that oppositely regulate kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) of the hypothalamus. However, how these effects are orchestrated to achieve fertility is unknown. Here, we have tested the hypothesis that AVPV and ARC neurons have different sensitivities to E2 to coordinate changes in LH secretion. Cycling and ovariectomized rats with low and high E2 levels were used. As an index of E2 responsiveness, progesterone receptor (PR) was expressed only in the AVPV of rats with high E2, showing the preovulatory LH surge. On the other hand, kisspeptin neurons in the ARC responded to low E2 levels sufficient to suppress LH release. Notably, the Esr1/Esr2 ratio of gene expression was higher in the ARC than AVPV, regardless of E2 levels. Accordingly, the selective pharmacological activation of estrogen receptor α (ERα) required lower doses to induce PR in the ARC. The activation of ERß, in turn, amplified E2-induced PR expression in the AVPV and the LH surge. Thus, ARC and AVPV neurons are differently responsive to E2. Lower E2 levels activate ERα in the ARC, whereas ERß potentiates the E2 positive feedback in the AVPV, which appears related to the differential Esr1/Esr2 ratio in these 2 brain areas. Our findings provide evidence that the distinct expression of ER isoforms in the AVPV and ARC plays a key role in the control of periodic secretion of LH required for fertility in females.


Assuntos
Estradiol , Kisspeptinas , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Hipotálamo/metabolismo , Kisspeptinas/metabolismo , Hormônio Luteinizante/metabolismo , Isoformas de Proteínas/metabolismo , Ratos , Receptores de Estrogênio/metabolismo
20.
J Assist Reprod Genet ; 39(8): 1739-1747, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35819576

RESUMO

PURPOSE: The effect of PTEN inhibitor (Bpv(HOpic); Bpv) and mTOR activators (phosphatidic acid (PA) and propranolol (PP)), were evaluated on the activation and subsequent development of human primordial follicles in ovarian tissue culture. METHODS: Slow frozen-thawed human ovarian cortical strips were incubated for 24 h in different groups: (1) Control (base medium), (2) Bpv (100 µM), (3) PA (200 µM), (4) PA + PP (50 µm), and (5) Bpv + PA + PP. Afterward, the medium was exchanged, and all groups were cultured without stimulators for 6 additional days. The proportion of normal and degenerated follicles, estradiol secretion, and expression of RPS6, FOXO3a, and AKT proteins was evaluated and compared between groups. RESULTS: After 24 h of culture, there was no significant difference between the proportion of primordial and growing follicles in either of the experimental groups. This non-significant change was also observed for the phosphorylated protein to total protein ratios of RPS6, FOXO3a, and AKT proteins. After 7 days of culture, the proportion of the transitional follicles was significantly higher in comparison to the primordial follicles for the PA, PA + PP, and Bpv + PA + PP groups. The estradiol level was significantly higher on the last day compared to the first day, in PA, PA + PP, and Bpv + PA + PP groups. Hormonal secretion was significantly higher in the PA and PA + PP groups and lower in the Bpv and Bpv + PA + PP groups compared to the control on day 7 of culture. CONCLUSION: Temporary in vitro treatment of human ovarian tissue with mTOR activators enhances the initiation of primordial follicle development and positively influences steroidogenesis after short-term culture.


Assuntos
Folículo Ovariano , Proteínas Proto-Oncogênicas c-akt , Estradiol/metabolismo , Estradiol/farmacologia , Feminino , Humanos , Ovário/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
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