RESUMO
Hypoglycemia causes sex-reliant changes in hypothalamic astrocyte glycogen metabolism in vivo. The role of nuclear versus membrane astrocyte estrogen receptors (ER) in glucoprivic regulation of glycogen is unclear. Here, primary hypothalamic astrocyte cultures were treated with selective ER antagonists during glucoprivation to investigate the hypothesis that ER mediate sex-specific glycogen responses to glucoprivation. Results show that glucoprivic down-regulation of glycogen synthase expression is mediated by transmembrane G protein-coupled ER-1 (GPER) signaling in each sex and estrogen receptor (ER)-beta (ERß) activity in females. Glucoprivic inhibition of glycogen phosphorylase involves GPER and ERß in females, but ER-independent mechanisms in males. GPER, ERß, and ER-alpha (ERα) inhibit or stimulate AMPK protein expression in male versus female astrocytes, respectively. Glucoprivic augmentation of phospho-AMPK profiles in male glia was opposed by GPER activation, whereas GPER and ERß suppress this protein in females. Astrocyte ERα and GPER content was down-regulated in each sex during glucose deficiency, whereas ERß levels was unaltered (males) or increased (females). Glucoprivation correspondingly elevated or diminished male versus female astrocyte glycogen content; ER antagonism reversed this response in males, but not females. Results identify distinctive ER variants involved in sex-similar versus sex-specific astrocyte protein responses to withdrawal of this substrate fuel. Notably, glucoprivation elicits a directional switch or gain-of-effect of GPER and ERß on specific glial protein profiles. Outcomes infer that ERs are crucial for glucoprivic regulation of astrocyte glycogen accumulation in males. Alternatively, estradiol may act independently of ER signaling to disassemble this reserve in females.
Assuntos
Astrócitos/metabolismo , Glicogênio/metabolismo , Hipoglicemia/metabolismo , Hipotálamo/metabolismo , Animais , Astrócitos/citologia , Células Cultivadas , Estradiol/farmacologia , Feminino , Glucose/deficiência , Glucose/farmacologia , Glicogenólise/fisiologia , Hipotálamo/citologia , Masculino , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/fisiologia , Caracteres Sexuais , Transdução de Sinais/efeitos dos fármacosRESUMO
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
Injúria Renal Aguda/metabolismo , Estrogênios/metabolismo , Receptores de Estrogênio/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Injúria 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 de Estrogênio/fisiologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Marantodes pumilum (Blume) Kuntze has traditionally been used to firm the uterus after delivery, however scientific evidences behind this claim is still lacking. AIMS OF STUDY: To demonstrate Marantodes pumilum leaves aqueous extract (MPE) has an effect on uterine contraction after delivery and to elucidate the molecular mechanisms involved. METHODS: Day-1 post-delivery female rats were given MPE (100, 250 and 500â¯mg/kg/day) orally for seven consecutive days. A day after the last treatment (day-8), rats were sacrificed and uteri were harvested and subjected for ex-vivo contraction study using organ bath followed by protein expression and distribution study by Western blotting and immunohistochemistry techniques, respectively. The proteins of interest include calmodulin-CaM, myosin light chain kinase-MLCK, sarcoplasmic reticulum Ca2+-ATPase (SERCA), G-protein α and ß (Gα and Gß), inositol-triphosphate 3-kinase (IP3K), oxytocin receptor-OTR, prostaglandin (PGF)2α receptor-PGFR, muscarinic receptor-MAChR and estrogen receptor (ER) isoforms α and ß. Levels of estradiol and progesterone in serum were determined by enzyme-linked immunoassay (ELISA). RESULTS: Ex-vivo contraction study revealed the force of uterine contraction increased with increasing doses of MPE. In addition, expression of CaM, MLCK, SERCA, Gα, Gß, IP3K, OTR, PGF2α, MAChR, Erα and ERß in the uterus increased with increasing doses of MPE. Serum analysis indicate that estradiol levels decreased while progesterone levels remained low at day-8 post-partum in rats receiving 250 and 500â¯mg/kg/day MPE. CONCLUSIONS: These findings support the claims that MPE help to firm the uterus and pave the way for its use as a uterotonic agent after delivery.
Assuntos
Extratos Vegetais/farmacologia , Primulaceae , Contração Uterina/efeitos dos fármacos , Animais , Estradiol/sangue , Estrogênios/sangue , Feminino , Folhas de Planta , Período Pós-Parto/sangue , Período Pós-Parto/fisiologia , Progesterona/sangue , Ratos Sprague-Dawley , Receptores de Estrogênio/fisiologia , Útero/efeitos dos fármacos , Útero/fisiologiaRESUMO
Mitochondrial dysfunction is increasingly recognized as a critical determinant of both hereditary and acquired kidney diseases. However, it remains poorly understood how mitochondrial metabolism is regulated to support normal kidney function and how its dysregulation contributes to kidney disease. Here, we show that the nuclear receptor estrogen-related receptor gamma (ERRγ) and hepatocyte nuclear factor 1 beta (HNF1ß) link renal mitochondrial and reabsorptive functions through coordinated epigenomic programs. ERRγ directly regulates mitochondrial metabolism but cooperatively controls renal reabsorption via convergent binding with HNF1ß. Deletion of ERRγ in renal epithelial cells (RECs), in which it is highly and specifically expressed, results in severe renal energetic and reabsorptive dysfunction and progressive renal failure that recapitulates phenotypes of animals and patients with HNF1ß loss-of-function gene mutations. Moreover, ERRγ expression positively correlates with renal function and is decreased in patients with chronic kidney disease (CKD). REC-ERRγ KO mice share highly overlapping renal transcriptional signatures with human patients with CKD. Together these findings reveal a role for ERRγ in directing independent and HNF1ß-integrated programs for energy production and use essential for normal renal function and the prevention of kidney disease.
Assuntos
Cistos/prevenção & controle , Metabolismo Energético , Epigenômica , Regulação da Expressão Gênica , Fator 1-beta Nuclear de Hepatócito/genética , Receptores de Estrogênio/genética , Insuficiência Renal Crônica/prevenção & controle , Animais , Cistos/metabolismo , Cistos/patologia , Fator 1-beta Nuclear de Hepatócito/metabolismo , Fator 1-beta Nuclear de Hepatócito/fisiologia , Humanos , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Regiões Promotoras Genéticas , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/fisiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologiaRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by a cascade of pathologic changes. A widely discussed theory indicates that amyloid ß (Aß) peptides are the causative agents of AD. Silibinin, a flavonoid derived from milk thistle, is well known for its hepato-protective activities and we have reported the neuroprotective effects of silibinin. In this study, we investigated the role of estrogen receptors (ERs) in silibinin's neuroprotective effect on Aß1-42-injected rats. Results of Morris water maze and novel object-recognition tests demonstrated that silibinin significantly attenuated Aß1-42-induced memory impairment. Silibinin attenuated ERs and PI3K-Akt pathways, as well as modulated mitogen-activated protein kinases in the hippocampus of Aß1-42-injected rats. Taken together, silibinin is a potential candidate in the treatment of Alzheimer's disease.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/toxicidade , Receptores de Estrogênio/fisiologia , Silimarina/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Relação Dose-Resposta a Droga , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Ratos , SilibinaRESUMO
The first record of ginseng use dates back over two millennia, and ginseng is now popular in more than 35 countries. Ginsenosides are the pharmacological constituents responsible for the beneficial effects of ginseng. There is increasing evidence that ginseng and its bioactive ingredients are involved in the regulation of nuclear receptors, molecules that act in response to the specific binding of hormones, which link to a diverse array of signaling pathways, such as the ERK and PI3K/Akt pathways. Knowledge of the mechanism of how ginseng mediates these complexes is essential for the development of multi-target phytomedicine as possible therapy for different diseases. Here, we discuss the literature on the effects of ginseng and its constituents on estrogen, glucocorticoid, peroxisome proliferator-activated, and androgen nuclear hormone receptors, as well as how ginseng and its constituents exert their biological function in the treatment of cancer, obesity, and cardiovascular and neurological disorders. The accumulated results definitely show that the nuclear receptors are cellular targets of ginsenosides, but more rigorous data are required to establish and provide a scientific basis to confirm the suggested efficacy of ginseng or products with ginsenosides.
Assuntos
Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Panax/química , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Animais , Doenças Cardiovasculares/tratamento farmacológico , Feminino , Ginsenosídeos/isolamento & purificação , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Obesidade/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/fisiologia , Extratos Vegetais/isolamento & purificação , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/fisiologia , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/fisiologiaRESUMO
IGF-IIR plays important roles as a key regulator in myocardial pathological hypertrophy and apoptosis, which subsequently lead to heart failure. Salvia miltiorrhiza Bunge (Danshen) is a traditional Chinese medicinal herb used to treat cardiovascular diseases. Tanshinone IIA is an active compound in Danshen and is structurally similar to 17[Formula: see text]-estradiol (E[Formula: see text]. However, whether tanshinone IIA improves cardiomyocyte survival in pathological hypertrophy through estrogen receptor (ER) regulation remains unclear. This study investigates the role of ER signaling in mediating the protective effects of tanshinone IIA on IGF-IIR-induced myocardial hypertrophy. Leu27IGF-II (IGF-II analog) was shown in this study to specifically activate IGF-IIR expression and ICI 182,780 (ICI), an ER antagonist used to investigate tanshinone IIA estrogenic activity. We demonstrated that tanshinone IIA significantly enhanced Akt phosphorylation through ER activation to inhibit Leu27IGF-II-induced calcineurin expression and subsequent NFATc3 nuclear translocation to suppress myocardial hypertrophy. Tanshinone IIA reduced the cell size and suppressed ANP and BNP, inhibiting antihypertrophic effects induced by Leu27IGF-II. The cardioprotective properties of tanshinone IIA that inhibit Leu27IGF-II-induced cell hypertrophy and promote cell survival were reversed by ICI. Furthermore, ICI significantly reduced phospho-Akt, Ly294002 (PI3K inhibitor), and PI3K siRNA significantly reduced the tanshinone IIA-induced protective effect. The above results suggest that tanshinone IIA inhibited cardiomyocyte hypertrophy, which was mediated through ER, by activating the PI3K/Akt pathway and inhibiting Leu27IGF-II-induced calcineurin and NFATC3. Tanshinone IIA exerted strong estrogenic activity and therefore represented a novel selective ER modulator that inhibits IGF-IIR signaling to block cardiac hypertrophy.
Assuntos
Abietanos/farmacologia , Cardiotônicos , Fator de Crescimento Insulin-Like II/antagonistas & inibidores , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Calcineurina/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/metabolismo , Fulvestranto , Hipertrofia/genética , Hipertrofia/prevenção & controle , Fator de Crescimento Insulin-Like II/efeitos adversos , Miócitos Cardíacos/efeitos dos fármacos , Fatores de Transcrição NFATC/metabolismo , Fitoterapia , Ratos , Receptor IGF Tipo 2/metabolismo , Receptor IGF Tipo 2/fisiologia , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/fisiologia , Salvia miltiorrhiza/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
OBJECTIVE: Estrogen plays an important role in the control of energy balance in the hypothalamus. Leptin-independent STAT3 activation (i.e., tyrosine(705)-phosphorylation of STAT3, pSTAT3) in the hypothalamus is hypothesized as the primary mechanism of the estrogen-induced anorexic response. However, the type of estrogen receptor that mediates this regulation is unknown. We investigated the role of the G protein-coupled receptor 30 (GPR30) in estradiol (E2)-induced STAT3 activation in the hypothalamus. MATERIALS/METHODS: Regulation of STAT3 activation by E2, G-1, a specific agonist of GPR30 and G-15, a specific antagonist of GPR30 was analyzed in vitro and in vivo. Effect of GPR30 activation on eating behavior was analyzed in vivo. RESULTS: E2 stimulated pSTAT3 in cells expressing GPR30, but not expressing estrogen receptor ERα and ERß. G-1 induced pSTAT3, and G-15 inhibited E2-induced pSTAT3 in primary cultures of hypothalamic neurons. A cerebroventricular injection of G-1 increased pSTAT3 in the arcuate nucleus of mice, which was associated with a decrease in food intake and body weight gain. CONCLUSIONS: These results suggest that GPR30 is the estrogen receptor that mediates the anorectic effect of estrogen through the STAT3 pathway in the hypothalamus.
Assuntos
Anorexia/fisiopatologia , Estrogênios/fisiologia , Hipotálamo/fisiopatologia , Receptores de Estrogênio/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Animais , Sequência de Bases , Primers do DNA , Células HeLa , Humanos , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
INTRODUCTION: Osteoporosis is a disease characterized by low bone mineral density (BMD) and increased risk of fractures. Studies have demonstrated the use of phytoestrogens, or plant-derived estrogens, such as genistein and daidzein, to effectively increase osteogenic activity of bone marrow-derived mesenchymal stem cells (BMSCs). Herein, the effects of daidzein analogs on the osteogenic differentiation efficiency of human BMSC and adipose-derived stromal/stem cells (ASC) were explored. METHODS: BMSCs and ASCs underwent osteogenic differentiation in the presence of vehicle, 17ß-estradiol (E2), phytoestrogens, or daidzein analogs. Cells were stained for alkaline phosphatase (ALP) enzymatic activity, calcium deposition by alizarin red s, and phosphate mineralization by silver nitrate. Gene expression analysis was conducted on cells treated with daidzein analogs. RESULTS: Cells treated with E2, daidzein, or genistein increased calcium deposition by 1.6-, 1.5-, and 1.4-fold, respectively, relative to vehicle-treated BMSCs and 1.6-, 1.7-, and 1.4-fold relative to vehicle-treated ASCs, respectively. BMSCs treated with daidzein analog 2c, 2g, and 2l demonstrated a 1.6-, 1.6-, and 1.9-fold increase in calcium deposition relative to vehicle-treated BMSCs, respectively, while ASCs treated with daidzein analog 2c, 2g, or 2l demonstrated a 1.7-, 2.0-, and 2.2-fold increase in calcium deposition relative to vehicle-treated ASCs, respectively. Additional analysis with BMSCs and ASCs was conducted in the more efficient compounds: 2g and 2l. ALP activity and phosphate mineralization was increased in 2g- and 2l-treated cells. The analysis of lineage specific gene expression demonstrated increased expression of key osteogenic genes (RUNX2, c-FOS, SPARC, DLX5, SPP1, COL1A1, IGF1, SOST, and DMP1) and earlier induction of these lineage specific genes, following treatment with 2g or 2l, relative to vehicle-treated cells. Estrogen receptor (ER) inhibitor studies demonstrated that ER antagonist fulvestrant inhibited the osteogenic differentiation of 2g in BMSCs and ASCs, while fulvestrant only attenuated the effects of 2l, suggesting that 2l acts by both ER dependent and independent pathways. CONCLUSIONS: These studies provide support for exploring the therapeutic efficacy of daidzein derivatives for the treatment of osteoporosis. Furthermore, the patterns of gene induction differed following treatment with each daidzein analog, suggesting that these daidzein analogs activate distinct ER and non-ER pathways to induce differentiation in BMSCs and ASCs.
Assuntos
Células-Tronco Adultas/fisiologia , Conservadores da Densidade Óssea/farmacologia , Isoflavonas/farmacologia , Células-Tronco Mesenquimais/fisiologia , Receptores de Estrogênio/fisiologia , Células-Tronco Adultas/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Células da Medula Óssea/fisiologia , Diferenciação Celular , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Fulvestranto , Humanos , Concentração Inibidora 50 , Osteogênese , Osteoporose/tratamento farmacológico , Fitoestrógenos/farmacologiaRESUMO
Er-xian Decoction (EXD), containing Herba epimedii Maxim (HEP) and Curculigo orchioides Gaertn (XM) as principal drugs, is a traditional Chinese medicine (TCM) formula prescribed for the treatment of postmenopausal osteoporosis. In the present study, the in vivo anti-osteoporosis effects of EXD, HEP and XM on four-month-old ovariectomized (OVX) Sprague-Dawley rats were investigated. Micro-computed tomography analysis showed that EXD could significantly improve the micro-architectural parameters (BMD, BV/TV, Tb.N, Tb.Th, and Tb.Sp) of trabecular bone in the distal femur and proximal tibia in OVX rats (p < 0.05). The biomechanical parameters of the distal femur in rats treated with EXD were also improved significantly (p < 0.05 vs. OVX group). The in vivo efficacy of EXD was found to be superior to HEP or XM alone in improving the bone properties of OVX rats. Treatment of rat osteoblastic-like UMR-106 cells with EXD, HEP, and XM significantly promoted the cell proliferation rate (p < 0.05) with the most promising effects observed in cells treated with EXD (p < 0.001). The proliferative effect in UMR-106 cells induced by EXD, HEP, and XM were abolished in the presence of the estrogen antagonist, ICI182780, suggesting that their effects were mediated by estrogen receptor (ER). Additionally, EXD could activate ER-α and ER-ß mediated estrogen-response element (ERE)-dependent luciferase activity as well as phosphorylate ER-α at serine 118 in UMR-106 cells. Taken together, EXD offered better osteoprotective effects than its single principal herb, and the beneficial effects of EXD in preventing bone deteriorations are, at least partially, through the ER signaling pathway.
Assuntos
Conservadores da Densidade Óssea/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/prevenção & controle , Fitoterapia , Animais , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Luciferases/metabolismo , Osteoblastos/citologia , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/patologia , Ovariectomia , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/fisiologia , Estimulação Química , Tomografia Computadorizada por Raios XRESUMO
To study gene function in neural progenitors and radial glia of the retina and hypothalamus, we developed a Rax-CreERT2 mouse line in which a tamoxifen-inducible Cre recombinase is inserted into the endogenous Rax locus. By crossing Rax-CreER(T2) with the Cre-dependent Ai9 reporter line, we demonstrate that tamoxifen-induced Cre activity recapitulates the endogenous Rax mRNA expression pattern. During embryonic development, Cre recombinase activity in Rax-CreER(T2) is confined to retinal and hypothalamic progenitor cells, as well as progenitor cells of the posterior pituitary. At postnatal time points, selective Cre recombinase activity is seen in radial glial-like cell types in these organs--specifically Müller glia and tanycytes--as well as pituicytes. We anticipate that this line will prove useful for cell lineage analysis and investigation of gene function in the developing and mature retina, hypothalamus and pituitary.
Assuntos
Proteínas do Olho/fisiologia , Deleção de Genes , Proteínas de Homeodomínio/fisiologia , Hipotálamo/metabolismo , Integrases/metabolismo , Neuroglia/metabolismo , Receptores de Estrogênio/fisiologia , Retina/metabolismo , Células-Tronco/metabolismo , Fatores de Transcrição/fisiologia , Animais , Antineoplásicos Hormonais/farmacologia , Southern Blotting , Linhagem da Célula , Feminino , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroglia/citologia , Neuroglia/efeitos dos fármacos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Recombinação Genética , Retina/citologia , Retina/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Tamoxifeno/farmacologiaRESUMO
Several medical conditions exhibit age- and sex-based differences. Whether or not traumatic shock exhibits such differences with regard to vascular responsiveness is not clear. In a cohort of 177 healthy subjects and 842 trauma patients (21-82 years) as well as different ages (4, 8, 10, 14, 18, and 24 wk; 1 and 1.5 years) and sexes of Sprague-Dawley normal and traumatic shock rats, the age- and sex-based differences of vascular responsiveness and the underlying mechanisms were investigated. Middle-aged and young women as well as female rats of reproductive age had higher vascular responsiveness in the normal condition and a lower decrease in vascular responsiveness after traumatic shock than older men and male rats of identical age. Exogenous supplementation of 17ß-estrdiol increased vascular reactivity in both male and femal rats of 8-24 wk and preserved vascular responsiveness in rats following traumatic shock. No effect was observed in rats 1 to 1.5 years. These protective effects of estrogen were closely related to G protein-coupled receptor (GPR)30, estrogen receptor-mediated Rho kinase, and PKC pathway activation. Vascular responsiveness exhibits age- and sex-based differences in healthy subjects and trauma patients. Estrogen and its receptor (GPR30) mediated activation of Rho kinase and PKC using genomic and nongenomic mechanisms to elicit protective effects in vascular responsiveness. This finding is important for the personalized treatment for several age- and sex-related diseases involving estrogen.
Assuntos
Fatores Etários , Hemodinâmica/fisiologia , Receptores de Estrogênio/fisiologia , Fatores Sexuais , Ferimentos e Lesões/fisiopatologia , Quinases Associadas a rho/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Estradiol/administração & dosagem , Estrogênios/fisiologia , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Quinase C/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/fisiologia , Choque Hemorrágico/fisiopatologiaRESUMO
Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERß and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD.
Assuntos
Vasos Sanguíneos/fisiopatologia , Terapia de Reposição de Estrogênios , Estrogênios/fisiologia , Receptores de Estrogênio/fisiologia , Doenças Vasculares/fisiopatologia , Relação Dose-Resposta a Droga , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Receptores de Estrogênio/agonistas , Receptores de Estrogênio/antagonistas & inibidoresRESUMO
Puerarin, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. Puerarin promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERß. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Isoflavonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Estrogênio/fisiologia , Fosfatase Alcalina/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Colágeno/metabolismo , Feminino , Humanos , Isoflavonas/uso terapêutico , Sistema de Sinalização das MAP Quinases/fisiologia , Osteoblastos/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêuticoRESUMO
Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Suplementos Nutricionais , Fitoestrógenos/farmacologia , Receptores de Estrogênio/fisiologia , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MenopausaRESUMO
Isoflavones (genistein, daidzein, and glycitein) are suggested to have benefits as well as risks for human health. Approximately one-third of the Western population is able to metabolize daidzein into the more potent metabolite equol. Having little endogenous estradiol, equol-producing postmenopausal women who use isoflavone supplements to relieve their menopausal symptoms could potentially be at high risk of adverse effects of isoflavone supplementation. The current trial aimed to study the effects of intake of an isoflavone supplement rich in daidzein compared with placebo on whole-genome gene expression profiles of peripheral blood mononuclear cells (PBMCs) in equol-producing, postmenopausal women. Thirty participants received an isoflavone supplement or a placebo for 8 wk each in a double-blind, randomized cross-over design. The isoflavone supplement was rich in daidzein (60%) and provided 94 mg isoflavones (aglycone equivalents) daily. Gene expression in PBMCs was significantly changed (P < 0.05) in 357 genes after the isoflavone intervention compared with placebo. Gene set enrichment analysis revealed downregulated clusters of gene sets involved in inflammation, oxidative phosphorylation, and cell cycle. The expression of estrogen receptor (ER) target genes and gene sets related to ER signaling were not significantly altered, which may be explained by the low ERα and ERß expression in PBMCs. The observed downregulated gene sets point toward potential beneficial effects of isoflavone supplementation with respect to prevention of cancer and cardiovascular disease. However, whether ER-related effects of isoflavones are beneficial or harmful should be studied in tissues that express ERs.
Assuntos
Equol/biossíntese , Isoflavonas/efeitos adversos , Leucócitos Mononucleares/metabolismo , Pós-Menopausa/metabolismo , Receptores de Estrogênio/fisiologia , Transcriptoma/efeitos dos fármacos , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Feminino , Expressão Gênica , Humanos , Isoflavonas/administração & dosagem , Isoflavonas/sangue , Placebos , Receptores de Estrogênio/genéticaRESUMO
Our knowledge of membrane estrogenic signaling mechanisms and their interactions that regulate physiology and behavior has grown rapidly over the past three decades. The discovery of novel membrane estrogen receptors and their signaling mechanisms has started to reveal the complex timing and interactions of these various signaling mechanisms with classical genomic steroid actions within the nervous system to regulate physiology and behavior. The activation of the various estrogenic signaling mechanisms is site specific and differs across the estrous cycle acting through both classical genomic mechanisms and rapid membrane-initiated signaling to coordinate reproductive behavior and physiology. This review focuses on our current understanding of estrogenic signaling mechanisms to promote: (1) sexual receptivity within the arcuate nucleus of the hypothalamus, (2) estrogen positive feedback that stimulates de novo neuroprogesterone synthesis to trigger the luteinizing hormone surge important for ovulation and estrous cyclicity, and (3) alterations in energy balance.
Assuntos
Estradiol/fisiologia , Hipotálamo/fisiologia , Progesterona/biossíntese , Receptores de Estrogênio/fisiologia , Reprodução/fisiologia , Transdução de Sinais/fisiologia , Animais , Estradiol/metabolismo , Estradiol/farmacologia , Feminino , Hipotálamo/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
When hormones during the ovulatory cycle are shown in phase plane graphs, reported FSH and estrogen values form a specific pattern that resembles the leaning "&" symbol, while LH and progesterone (Pg) values form a "boomerang" shape. Graphs in this paper were made using data reported by Stricker et al. [Clin Chem Lab Med 2006;44:883-887]. These patterns were used to construct a simplistic model of the ovulatory cycle without the conventional "positive feedback" phenomenon. The model is based on few well-established relations:hypothalamic GnRH secretion is increased under estrogen exposure during two weeks that start before the ovulatory surge and lasts till lutheolysis.the pituitary GnRH receptors are so prone to downregulation through ligand binding that this must be important for their function.in several estrogen target tissue progesterone receptor (PgR) expression depends on previous estrogen binding to functional estrogen receptors (ER), while Pg binding to the expressed PgRs reduces both ER and PgR expression.Some key features of the presented model are here listed:High GnRH secretion induced by the recovered estrogen exposure starts in the late follicular phase and lasts till lutheolysis. The LH and FSH surges start due to combination of accumulated pituitary GnRH receptors and increased GnRH secretion. The surges quickly end due to partial downregulation of the pituitary GnRH receptors (64% reduction of the follicular phase pituitary GnRH receptors is needed to explain the reported LH drop after the surge). A strong increase in the lutheal Pg blood level, despite modest decline in LH levels, is explained as delayed expression of pituitary PgRs. Postponed pituitary PgRs expression enforces a negative feedback loop between Pg levels and LH secretions not before the mid lutheal phase.Lutheolysis is explained as a consequence of Pg binding to hypothalamic and pituitary PgRs that reduces local ER expression. When hypothalamic sensitivity to estrogen is diminished due to lack of local ERs, hypothalamus switches back to the low GnRH secretion rate, leading to low secretion of gonadotropins and to lutheolysis. During low GnRH secretion rates, previously downregulated pituitary GnRH receptors recover to normal levels and thus allow the next cycle.Possible implications of the presented model on several topics related to reproductive physiology are shortly discussed with some evolutionary aspects including the emergence of menopause.
Assuntos
Ciclo Menstrual/fisiologia , Modelos Biológicos , Ovulação/fisiologia , Ativinas/fisiologia , Evolução Biológica , Estrogênios/fisiologia , Retroalimentação Fisiológica , Feminino , Hormônio Foliculoestimulante/fisiologia , Humanos , Hipotálamo/fisiologia , Inibinas/fisiologia , Leptina/fisiologia , Hormônio Luteinizante/fisiologia , Luteólise/fisiologia , Masculino , Hipófise/fisiologia , Progesterona/fisiologia , Puberdade/fisiologia , Receptores de Estrogênio/fisiologia , Receptores LHRH/fisiologia , Receptores de Progesterona/fisiologia , Caracteres SexuaisRESUMO
It is well known that many of the actions of estrogens in the central nervous system are mediated via intracellular receptor/transcription factors that interact with steroid response elements on target genes. However, there now exists compelling evidence for membrane estrogen receptors in hypothalamic and other brain neurons. But, it is not well understood how estrogens signal via membrane receptors, and how these signals impact not only membrane excitability but also gene transcription in neurons. Indeed, it has been known for sometime that estrogens can rapidly alter neuronal activity within seconds, indicating that some cellular effects can occur via membrane delimited events. In addition, estrogens can affect second messenger systems including calcium mobilization and a plethora of kinases to alter cell signaling. Therefore, this review will consider our current knowledge of rapid membrane-initiated and intracellular signaling by estrogens in the hypothalamus, the nature of receptors involved and how they contribute to homeostatic functions.
Assuntos
Temperatura Corporal/fisiologia , Metabolismo Energético/fisiologia , Estradiol/fisiologia , Homeostase/fisiologia , Hipotálamo/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores de Estrogênio/fisiologia , Reprodução/fisiologia , Feminino , Humanos , Hipotálamo/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
This study compared ex vivo relaxing responses to the naturally occurring human hormone estetrol (E(4)) vs 17ß-estradiol (E(2)) in eight different vascular beds. Arteries were mounted in a myograph, contracted with either phenylephrine or serotonin, and cumulative concentration-response curves (CRCs) to E(4) and E(2) (0·1-100 âµmol/l) were constructed. In all arteries tested, E(4) had lower potency than E(2), although the differential effect was less in larger than smaller arteries. In uterine arteries, the nonselective estrogen receptor (ER) blocker ICI 182â780 (1â µmol/l) caused a significant rightward shift in the CRC to both E(4) and E(2), indicating that the relaxation responses were ER dependent. Pharmacological blockade of nitric oxide (NO) synthases by N(ω)-nitro-L-arginine methyl ester (L-NAME) blunted E(2)-mediated but not E(4)-mediated relaxing responses, while inhibition of prostaglandins and endothelium-dependent hyperpolarization did not alter relaxation to either E(4) or E(2) in uterine arteries. Combined blockade of NO release and action with L-NAME and the soluble guanylate cyclase (sGC) inhibitor ODQ resulted in greater inhibition of the relaxation response to E(4) compared with E(2) in uterine arteries. Endothelium denudation inhibited responses to both E(4) and E(2), while E(4) and E(2) concentration-dependently blocked smooth muscle cell Ca(2)(+) entry in K(+)-depolarized and Ca(2)(+)-depleted uterine arteries. In conclusion, E(4) relaxes precontracted rat arteries in an artery-specific fashion. In uterine arteries, E(4)-induced relaxations are partially mediated via an endothelium-dependent mechanism involving ERs, sGC, and inhibition of smooth muscle cell Ca(2)(+) entry, but not NO synthases or endothelium-dependent hyperpolarization.