Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35.096
Filtrar
1.
Zebrafish ; 21(2): 223-230, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38621217

RESUMO

Obesity is a public health concern resulting in a variety of health complications, including heart disease and insulin resistance. Estrogens have been associated with a reduced risk of obesity, but this relationship remains incompletely understood. We assessed the role of 17ß-estradiol (E2) in mitigating complications associated with obesity by supplementing E2 in the diets of overfed zebrafish. We report that dietary E2 supplementation protects against weight gain and modulates de novo cholesterol synthesis in a sex-specific manner. Our studies lead us to propose a model in which E2 regulates hmgcr expression independently of unsaturated fat consumption. These data can be used to develop sex-specific treatments for obesity-related health conditions.


Assuntos
Gorduras Insaturadas , Peixe-Zebra , Masculino , Feminino , Animais , Peixe-Zebra/metabolismo , Gorduras Insaturadas/metabolismo , Estradiol/farmacologia , Estradiol/metabolismo , Estrogênios/metabolismo , Obesidade/etiologia , Colesterol/metabolismo , Suplementos Nutricionais
2.
BMC Biol ; 22(1): 77, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589878

RESUMO

BACKGROUND: Ten percent of the female population suffers from congenital abnormalities of the vagina, uterus, or oviducts, with severe consequences for reproductive and psychological health. Yet, the underlying causes of most of these malformations remain largely unknown. ADGRA3 (GPR125) is involved in WNT signaling and planar cell polarity, mechanisms vital to female reproductive tract development. Although ADGRA3 is a well-established spermatogonial stem cell marker, its role within the female urogenital system remains unclear. RESULTS: In this study, we found Adgra3 to be expressed throughout the murine female urogenital system, with higher expression pre-puberty than after sexual maturation. We generated a global Adgra3-/- mouse line and observed imperforate vagina in 44% of Adgra3-/- females, resulting in distension of the reproductive tract and infertility. Ovarian morphology, plasma estradiol, ovarian Cyp19a1, and vaginal estrogen receptor α (Esr1) expression were unaffected. However, compared to controls, a significantly lower bone mineral density was found in Adgra3-/- mice. Whereas vaginal opening in mice is an estrogen-dependent process, 17ß-estradiol treatment failed to induce vaginal canalization in Adgra3-/- mice. Furthermore, a marked reduction in vaginal and ovarian progesterone receptor expression was observed concomitant with an upregulation of apoptotic regulators Bcl2, Bid, and Bmf in adult Adgra3-/- females with a closed vagina. CONCLUSIONS: Our collective results shed new insights into the complex mechanisms by which the adhesion receptor ADGRA3 regulates distal vaginal tissue remodeling during vaginal canalization via altered sex hormone responsiveness and balance in apoptotic regulators. This highlights the potential of ADGRA3 as a target in diagnostic screening and/or therapy for obstructive vaginal malformations in humans.


Assuntos
Estrogênios , Vagina , Humanos , Animais , Camundongos , Feminino , Incidência , Vagina/anormalidades , Estrogênios/metabolismo , Útero/metabolismo , Estradiol/farmacologia
3.
Se Pu ; 42(4): 333-344, 2024 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-38566422

RESUMO

17ß-Estradiol (E2), an important endocrine hormone in the mammalian body, participates in the regulation of the physiological functions of the reproductive system, mammary glands, bone, and cardiovascular system, among others. Paradoxically, despite the physiological actions of endogenous E2 (0.2-1.0 nmol/L), numerous clinical and experimental studies have demonstrated that high-dose E2 treatment can cause tumor regression and exert pro-apoptotic actions in multiple cell types; however, the underlying mechanism remains undescribed. In particular, little information of the cellular processes responding to the lethality of E2 is available. In the present study, we attempted to characterize the cellular processes responding to high-dose (µmol/L) E2 treatment using quantitative phosphoproteomics to obtain a better understanding of the regulatory mechanism of E2-induced cell death. First, the cell phenotype induced by high-dose E2 was determined by performing Cell Counting Kit-8 assay (CCK8), cell cytotoxicity analysis by trypan blue staining, and microscopic imaging on HeLa cells treated with 1-10 µmol/L E2 or dimethyl sulfoxide (DMSO) for 1-3 d. E2 inhibited cell proliferation and induced cell death in a dose- and time-dependent manner. Compared with the DMSO-treated HeLa cells, the cells treated with 5 µmol/L E2 for 2 d demonstrated >74% growth inhibition and approximately 50% cell death. Thus, these cells were used for quantitative phosphoproteomic analysis. Next, a solid-phase extraction (SPE)-based immobilized titanium ion affinity chromatography (Ti4+-IMAC) phosphopeptide-enrichment method coupled with data-independent acquisition (DIA)-based quantitative proteomics was employed for the in-depth screening of high-dose E2-regulated phosphorylation sites to investigate the intracellular processes responding to high-dose E2 treatment. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified over 10000 phosphorylation sites regulated by E2 and DMSO in HeLa cells. In comparison with the DMSO-treated cells, the cells treated with 5 µmol/L E2 showed 537 upregulated phosphorylation sites and 387 downregulated phosphorylation sites, with a threshold of p<0.01 and |log2(fold change)|≥1. A total of 924 phosphorylation sites on 599 proteins were significantly regulated by high-dose E2, and these sites were subjected to enrichment analysis. In addition, 453 differently regulated phosphorylation sites on 325 proteins were identified only in the E2- or DMSO-treated cell samples. These phosphorylation sites may be phosphorylated or dephosphorylated in response to high-dose E2 stimulation and were subjected to parallel enrichment analyses. Taken together, 1218 phosphorylation sites on 741 proteins were significantly regulated by high-dose E2 treatment. The functional phosphoproteins in these two groups were then analyzed using Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) to determine the biological processes in which they participate and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Consistent with the cell-phenotype data, cell cycle-related proteins were highly enriched in the two groups of E2-regulated phosphoproteins (p<0.05), indicating that high-dose E2 treatment can regulate cell proliferation. In addition, E2-regulated phosphoproteins were highly enriched in the cellular processes of ribosome biogenesis, nucleocytoplasmic transport, and messenger ribonucleic acid (mRNA) processing/splicing (p<0.05), indicating that the activation of these processes may contribute to high-dose E2-induced cell death. These results further confirm that high-dose E2 treatment inhibits protein translation and induces cell death. Furthermore, the significant upregulation of multiple phosphorylation sites associated with epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (MAPKs) MAPK1, MAPK4, and MAPK14 by high-dose E2 indicates that the EGFR and MAPK signaling pathways are likely involved in the regulation of E2-induced cell death. These phosphorylation sites likely play vital roles in E2-induced cell death in HeLa cells. Overall, our phosphoproteomic data could be a valuable resource for uncovering the regulatory mechanisms of E2 in the micromolar range.


Assuntos
Dimetil Sulfóxido , Espectrometria de Massas em Tandem , Animais , Humanos , Cromatografia Líquida , Células HeLa , Estradiol/farmacologia , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Receptores ErbB/metabolismo , Fosforilação , Mamíferos/metabolismo
4.
J Biochem Mol Toxicol ; 38(4): e23697, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38578078

RESUMO

Genistein, an isoflavone has the potential to mimic, augment, or dysregulate the steroid hormone production pathways. We hypothesized that genistein affects the granulosa cell (GCs) functions through a series of biochemical, molecular, and genomic cascades. The present study was conducted to evaluate the impact of genistein exposure on GCs viability, apoptosis, and steroidogenesis. The present study involved 3/5 days of exposure to genistein on GCs collected from abattoir-derived ovine ovaries at doses of 0, 1, 10, 25, 50, and 100 µM. The harvested GCs were used for growth, cytotoxicity, and gene expression studies related to apoptosis, growth, and steroidogenesis. We observed that genistein had both stimulatory at 10 and 25 µM levels as well as inhibitory effects at 50 and 100 µM levels on the growth and proliferation of GCs. Genistein significantly decreased the levels of 17ß-estradiol at higher exposure (50 and 100 µM), whereas the progesterone level increased significantly as the genistein exposure increased. Additionally, genistein could also alter the mRNA expression of the steroidogenic receptor, enzymes, proteins, and growth-related genes suggesting that genistein could potentially alter the steroidogenic pathways. We conclude that genistein can interfere with cell survival and steroidogenesis by exhibiting a dose-dependent biphasic response on the viability, growth-related parameters, and the synthesis of 17ß-estradiol in the cultured GCs.


Assuntos
Genisteína , Isoflavonas , Feminino , Ovinos , Animais , Genisteína/farmacologia , Progesterona/metabolismo , Células da Granulosa/metabolismo , Estradiol/farmacologia , Estradiol/metabolismo , Isoflavonas/farmacologia , Carneiro Doméstico/metabolismo , Células Cultivadas
5.
Reprod Domest Anim ; 59(3): e14553, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38501644

RESUMO

This study evaluated the efficacy of the administration of different doses of equine chorionic gonadotropin (eCG; 0 IU, 200 IU, or 300 IU) at the time of the progesterone device removal in 2-year-old Nelore (Bos indicus) heifers synchronized for fixed-timed artificial insemination (FTAI). On day 0 (D0), a total of 398 heifers received 2 mg of oestradiol benzoate i.m., 0.53 mg of cloprostenol i.m., and an eight-day previously used (second use) intravaginal device containing 1 g of progesterone (P4). Eight days later (D8), simultaneous with the P4 device removal, 0.5 mg of oestradiol cypionate i.m. and 0.53 mg of cloprostenol i.m. were administered. At the same time, heifers were randomly assigned to receive one of the following treatments: G-0 IU (n = 141; no eCG treatment), G-200 IU (n = 132; treated with 200 IU of eCG), and G-300 IU (n = 125; treated with 300 IU of eCG). FTAI was performed 48 h after the P4 device removal (D10). Ultrasonographic evaluations were performed at D0, D10, and D17. Heifers were scanned to measure the size of the largest follicle (LF), the presence, number, and size of the corpus luteum (CL), and the ovulation rate. Subsequently, at D40, the heifers underwent scanning to determine the pregnancy rate and identify any twin pregnancies. Additionally, at D70, scans were performed to assess pregnancy loss (PG). Data were analysed by orthogonal contrasts [C1 (eCG effect): control x (200 IU + 300 IU) and C2 (eCG dose effect): 200 IU × 300 IU]. On D0, CL presence was similar between the groups [G-0 IU = 65.2% (92/141), G-200 IU = 55.3% (73/132), and G-300 IU = 63.2% (79/125); p = .16]. No interactions between the presence of CL on D0 and eCG treatment were found for any of the variables (p > .05). The diameter of the LF at FTAI (D10) was not influenced by eCG treatment (p = .22) or eCG dose (p = .18). However, treatment with eCG increased the diameter of the CL at D17 (G-0 IU = 15.7 ± 0.3 mmb , G-200 IU = 16.6 ± 0.2 mma , and G-300 IU = 16.6 ± 0.3 mma ; p = .001), regardless of the dose used (p = .94). The ovulation rate was higher in heifers treated with eCG [G-0 IU = 79.4%b (112/141), G-200 IU = 90.2%a (119/132), and G-300 IU = 93.6%a (117/125); p = .002], but there was no effect of eCG dose (p = .36). Pregnancy per AI (P/AI) on D40 [G-0 IU = 32.6%b (46/141), G-200 IU = 42.4%a (56/132), and G-300 IU = 42.4%a (53/125); P = 0.05] and D70 [G-0 IU = 29.1%b (41/141), G-200 IU = 40.9%a (54/132), and G-300 IU = 40.8%a (51/125); p = .02] were higher on heifers that received eCG; however, no dose effect was observed for P/AI on D40 (p = .89) nor D70 (p = .98). Pregnancy loss between D40 and D70 tended to reduce (p = .07) in eCG-treated heifers without dose effect (p = .91). Heifers with CL at D0 presented a greater follicle diameter (LF) on D10 (With CL = 11.2 ± 0.2 mm and Without CL = 10.2 ± 0.2 mm; p = .05), CL diameter on D17 (With CL = 15.8 ± 0.03 mm and Without CL = 11.8 ± 0.6 mm; p = .01), and ovulation rate [With CL = 95.5% (233/244) and Without CL = 74.7% (115/154); p = .01]. However, no difference in pregnancy rate at D40 (p = .52) and D70 (p = .84) was found. In conclusion, eCG treatment increases ovulation and pregnancy rates of heifers submitted to a FTAI protocol. Furthermore, eCG treatment increases the diameter of the CL after FTAI and reduces pregnancy losses. No dose effect was observed, suggesting Nelore (Bos indicus) heifers respond to 200 IU of eCG treatment for FTAI.


Assuntos
Doenças dos Bovinos , Doenças dos Cavalos , Gravidez , Bovinos , Animais , Feminino , Cavalos , Progesterona/farmacologia , Aborto Animal , Ovulação , Estradiol/farmacologia , Cloprostenol/farmacologia , Inseminação Artificial/veterinária , Inseminação Artificial/métodos , Sincronização do Estro/métodos
6.
Gen Comp Endocrinol ; 351: 114482, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38432348

RESUMO

In black porgy (Acanthopagrus schlegelii), the brain-pituitary-testis (Gnrh-Gths-Dmrt1) axis plays a vital role in male fate determination and maintenance, and then inhibiting female development in further (puberty). However, the feedback of gonadal hormones on regulating brain signaling remains unclear. In this study, we conducted short-term sex steroid treatment and surgery of gonadectomy to evaluate the feedback regulation between the gonads and the brain. The qPCR results show that male phase had the highest gths transcripts; treatment with estradiol-17ß (E2) or 17α-methyltestosterone (MT) resulted in the increased pituitary lhb transcripts. After surgery, apart from gnrh1, there is no difference in brain signaling genes between gonadectomy and sham fish. In the diencephalon/mesencephalon transcriptome, de novo assembly generated 283,528 unigenes; however, only 443 (0.16%) genes showed differentially expressed between sham and gonadectomy fish. In the present study, we found that exogenous sex steroids affect the gths transcription; this feedback control is related to the gonadal stage. Furthermore, gonadectomy may not affect gene expression of brain signaling (Gnrh-Gths axis). Our results support the communication between ovotestis and brain signaling (Gnrh-Gths-testicular Dmrt1) for the male fate.


Assuntos
Perciformes , Processos de Determinação Sexual , Animais , Feminino , Masculino , Maturidade Sexual , Gônadas/metabolismo , Perciformes/metabolismo , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Estradiol/farmacologia , Estradiol/metabolismo , Peixes/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Encéfalo/metabolismo , Expressão Gênica
7.
Toxicol In Vitro ; 97: 105803, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38431060

RESUMO

Dexamethasone (DEX) is a synthetic glucocorticoid widely used as pharmaceutical and usually exists in effluents with varying degrees of concentrations. In this study, cultivated Brain, ovary and testis cells from Arabian Sea bream, Acanthopagrus arabicus, were treated by DEX at concentrations of 0, 0.3, 3.0, 30.0 and 300.0 µg/ml for 48 h. The aromatase activity and steroid (17-ß-estradiol (E2), progesterone (P) and testosterone (T)) production by cells were measured at 12, 24 and 48 h of the experiment. The results showed that the sensitivity of cultivated ovarian, testicular and brain cells to DEX increased dose dependently. DEX was potent inhibitor of aromatase activity at specially 30.0 and 300.0 µg/ml in the cultivated ovarian and testicular cells at different sampling time. On the other hand, DEX was found to stimulate the aromatase activity of fish brain. DEX also decreased E2, P and T production by cultivated ovarian and testicular cells during the experiment. While, DEX caused an increase in the production of E2 and P by brain cells, which seems logical considering the stimulating effect of this drug on brain aromatase activity. In conclusion, results highlight that DEX is able to change the activity of aromatase, and disrupt the biosynthesis of estrogens and thus affect reproduction in fish.


Assuntos
Dourada , Masculino , Feminino , Animais , Dourada/metabolismo , Aromatase/metabolismo , Oceano Índico , Gônadas , Estradiol/farmacologia , Esteroides , Encéfalo/metabolismo , Técnicas de Cultura de Células , Dexametasona/toxicidade
8.
Theriogenology ; 220: 77-83, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38490112

RESUMO

The present study evaluated follicular and endocrine dynamics during ReBreed21, a reproductive strategy that allows resynchronization of ovulation every 21 days in Bos indicus (Nelore) heifers. A synchronized estrous cycle was induced using a standard timed ovulation protocol (d -10: P4 implant inserted + 2 mg estradiol benzoate; d -2: P4 removed+ 0.5 mg cloprostenol + 0.6 mg estradiol cypionate + 200 IU equine chorionic gonadotropin (eCG); d0: 8.4 µg buserelin) without AI to ensure nonpregnancy in heifers. Day of GnRH was designated d0 of estrous cycle. On d12, heifers (n = 80) were randomized into three experimental groups: (1) ReBreed21 (n = 28) d12 P4 device inserted, d19 P4 device withdrawal plus 200 IU eCG, and d21 8.4 µg buserelin (GnRH); (2) ReBreed21+G (n = 26) same as ReBreed21 plus GnRH (16.8 µg) treatment on d12; and (3) Control (n = 26) no treatment. ReBreed21+G increased two-fold (62.9%; 18/26) percentage of heifers with synchronized follicular wave emergence compared to Control (34.6%; 9/26) whereas ReBreed21 (53.6%; 15/28) was intermediate. The ReBreeed21 groups (eCG on d19) increased (P < 0.01) follicular growth between d19 and d21 in ReBreed21 (2.3 ± 0.2 mm) and ReBreed21+G (3.4 ± 0.2 mm) compared with Control (1.2 ± 0.3 mm), resulting in greater (P < 0.01) follicle diameter on d21 for ReBreed21 (10.7 ± 0.4 mm) and ReBreed21+G (10.8 ± 0.4 mm) compared with Control (9.1 ± 0.5 mm). Structural luteolysis was similar among groups (P = 0.51), although the average day when P4 was <1 ng/mL was later (P < 0.01) for ReBreed21 (20.5 ± 0.2) and ReBreed21+G (20.7 ± 0.2) compared to Control (19.2 ± 0.4). Overall ovulation at the end of the estrous cycle was increased (P = 0.03) for ReBreed21 groups (83.3%; 45/54) compared with Control (57.7%; 15/26). Synchronized ovulation on day 22-23 was greater (P < 0.01) for ReBreed21 (78.6%; 22/28) and ReBreed21+G (76.9%; 20/26) compared with Control (30.8%; 8/26). Thus, the ReBreed21 resynchronization program produced acceptable endocrine and follicular dynamics, including synchronized ovulation at the end of the protocol in nonpregnant heifers providing good rationale for testing the fertility and practical implementation of this protocol under field conditions.


Assuntos
Busserrelina , Sincronização do Estro , Animais , Bovinos , Feminino , Busserrelina/farmacologia , Estradiol/farmacologia , Sincronização do Estro/métodos , Gonadotropinas Equinas/farmacologia , Cavalos , Inseminação Artificial/veterinária , Inseminação Artificial/métodos , Folículo Ovariano , Ovário , Ovulação , Progesterona/farmacologia
9.
Horm Mol Biol Clin Investig ; 45(1): 1-15, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38507353

RESUMO

OBJECTIVES: Studies suggest that both genomic and nongenomic pathways are involved in mediating the salutary effects of steroids following traumatic brain injury (TBI). This study investigated the nongenomic effects of 17ß-estradiol (E2) mediated by the PI3K/p-Akt pathway after TBI. METHODS: Ovariectomized rats were apportioned to E2, E2-BSA (E2 conjugated to bovine serum albumin), G1 [G-protein-coupled estrogen receptor agonist (GPER)] or their vehicle was injected following TBI, whereas ICI (classical estrogen receptor antagonist), G15 (GPER antagonist), ICI + G15, and their vehicles were injected before the induction of TBI and injection of drugs. Diffuse TBI was induced by the Marmarou model. Evans blue (EBC, 5 h), brain water contents (BWC), histopathological changes, and brain PI3K and p-Akt protein expressions were measured 24 h after TBI. The veterinary comma scale (VCS) was assessed before and at different times after TBI. RESULTS: The results showed a reduction in BWC and EBC and increased VCS in the E2, E2-BSA, and G1 groups. Also, E2, E2-BSA, and G1 reduced brain edema, inflammation, and apoptosis. The ICI and G15 inhibited the beneficial effects of E2, E2-BSA, and G1 on these parameters. All drugs, following TBI, prevented the reduction of brain PI3K/p-Akt expression. The individual or combined use of ICI and G15 eliminated the beneficial effects of E2, E2-BSA, and G1 on PI3K/p-Akt expressions. CONCLUSIONS: These findings indicated that PI3K/p-Akt pathway plays a critical role in mediating the salutary effects of estradiol on histopathological changes and neurological outcomes following TBI, suggesting that GPER and classic ERs are involved in regulating the expression of PI3K/p-Akt.


Assuntos
Lesões Encefálicas Traumáticas , Fármacos Neuroprotetores , Soroalbumina Bovina , Ratos , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Estrogênios/farmacologia , Estradiol/farmacologia , Estradiol/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Receptores Acoplados a Proteínas G
10.
PLoS One ; 19(3): e0298184, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38547301

RESUMO

ß-catenin is an important regulator of malignant progression. 17ß-Estradiol (E2), an important sex hormone in women, promotes the growth and metastasis of triple-negative breast cancer (TNBC). However, whether ß-catenin is involved in E2-induced metastasis of TNBC remains unknown. In this study, we show that E2 induces the proliferation, migration, invasion, and metastasis of TNBC cells. E2 induces ß-catenin protein expression and nuclear translocation, thereby regulating the expression of target genes such as Cyclin D1 and MMP-9. The inhibition of ß-catenin reversed the E2-induced cell malignant behaviors. Additionally, E2 activated Calpain by increasing intracellular Ca2+ levels and reducing calpastatin levels. When Calpain was inhibited, E2 did not induce the proliferation, migration, invasion, or metastasis of TNBC cells. In addition, E2 promoted translocation of YAP into the nucleus by inhibiting its phosphorylation. Calpain inhibition reversed the E2-induced YAP dephosphorylation. Inhibition of YAP transcriptional activity reversed the effects of E2 on the proliferation, migration, invasion, and ß-catenin of TNBC cells. In conclusion, we demonstrated that E2 induced metastasis-related behaviors in TNBC cells and this effect was mediated through the Calpain/YAP/ß-catenin signaling pathway.


Assuntos
Neoplasias de Mama Triplo Negativas , beta Catenina , Feminino , Humanos , beta Catenina/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Calpaína/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Estradiol/farmacologia , Proliferação de Células
11.
J Pharmacol Sci ; 155(1): 1-13, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38553133

RESUMO

BACKGROUND: Gallic acid (GA) is an organic compound with phenolic properties that occurs naturally and can be found in Guizhi Fuling capsules, showcasing a wide range of biological functionalities. PURPOSE: The objective of this study was to examine the influence of GA on endometrial hyperplasia (EH) and elucidate its underlying mechanism. METHODS: Initially, the induction of EH was achieved by administering estradiol to mice via continuous subcutaneous injection for a duration of 21 days. Concurrently, GA treatment was administered, and subsequently, the uterine tissue structure was assessed using hematoxylin and eosin (H&E) staining. Following this, the proliferation of human endometrial cells treated by GA was determined utilizing the CCK-8 method. Furthermore, network pharmacology and single-cell-RNA-seq data were employed to identify the target of GA action. In addition, we will employ immunofluorescence (IF), immunohistochemistry (IHC), flow cytometry, western blot and RT-qPCR methodologies to investigate the impact of GA on the expression level of cyclin D1, PI3K, p-PI3K, AKT, p-AKT. RESULTS: GA treatment ameliorated histopathological alterations in the uterus and suppress proliferation. Estradiol stimulation can activate the PI3K/AKT pathway, leading to up-regulation of cyclin D1 expression, whereas GA treatment results in down-regulation of its expression. CONCLUSIONS: The expression of cyclin D1 is down-regulated by GA through the inhibition of the PI3K/AKT pathway, effectively mitigating estradiol-induced EH in mice.


Assuntos
Hiperplasia Endometrial , Transdução de Sinais , Feminino , Humanos , Camundongos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proliferação de Células , Fosfatidilinositol 3-Quinases/metabolismo , Hiperplasia Endometrial/tratamento farmacológico , Regulação para Baixo , Ciclina D1/genética , Ciclina D1/metabolismo , Estradiol/farmacologia
12.
J Nanobiotechnology ; 22(1): 122, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38504208

RESUMO

Endocrine therapy is standard for hormone receptor-positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer.


Assuntos
Neoplasias da Mama , Flavanonas , Nanopartículas , Humanos , Camundongos , Animais , Feminino , Neoplasias da Mama/patologia , Peixe-Zebra/metabolismo , Receptores de Estrogênio/metabolismo , Estrogênios/metabolismo , Estrogênios/uso terapêutico , Tamoxifeno/farmacologia , Estradiol/farmacologia , Fígado/metabolismo
13.
Int J Mol Sci ; 25(6)2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38542355

RESUMO

Breast cancer brain metastasis (BCBM) is a challenging condition with limited treatment options and poor prognosis. Understanding the interactions between tumor cells and the blood-brain barrier (BBB) is critical for developing novel therapeutic strategies. One promising target is estrogen receptor ß (ERß), which promotes the expression of key tight junction proteins, sealing the BBB and reducing its permeability. In this study, we investigated the effects of 17ß-estradiol (E2) and the selective ERß agonist diarylpropionitrile (DPN) on endothelial and cancer cells. Western blot analysis revealed the expression patterns of ERs in these cell lines, and estrogen treatment upregulated claudin-5 expression in brain endothelial cells. Using in vitro models of the BBB, we found that DPN treatment significantly increased BBB tightness about suppressed BBB transmigration activity of representative Her2-positive (BT-474) and triple-negative (MDA-MB-231) breast cancer cell lines. However, the efficacy of DPN treatment decreased when cancer cells were pre-differentiated in the presence of E2. Our results support ERß as a potential target for the prevention and treatment of BCBM and suggest that targeted vector-based approaches may be effective for future preventive and therapeutic implications.


Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Humanos , Feminino , Barreira Hematoencefálica/metabolismo , Estrogênios/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor beta de Estrogênio/metabolismo , Células Endoteliais/metabolismo , Encéfalo/metabolismo , Estradiol/farmacologia , Estradiol/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/metabolismo , Células MCF-7 , Receptor alfa de Estrogênio/metabolismo
14.
Theriogenology ; 220: 35-42, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38471389

RESUMO

Estrogens have proven to be effective in bovine estrus induction protocols. Considering the extensive use of these products in large-scale estrus synchronization, the primary objective of the present study was to assess their effects on pregnancy rate (PR) using a meta-analysis approach. A total of 797 papers were screened from three major databases (PubMed, Web of Science, Scopus). Sixty-one studies were eligible for inclusion in the meta-analysis. The pregnancy status (success or failure) at 30 days post-insemination was considered as the effect size data. The odds ratios (OR) of PR were evaluated by considering the effects of estrogens in groups with or without estrogen intervention. The impact of estrogen (including factors such as type, dose, and time of administration) and animal characteristics (such as breed, type, and parity) was taken into account when assessing the effectiveness of estrogen response as PR. The results showed an OR of 1.25 (95% CI: 1.15-1.36; P = 0.000) for PR in animals that received estrogen compared to cattle that did not receive estrogen. Estradiol benzoate (OR = 1.3) and estradiol cypionate (OR = 1.2), with doses ranging from 1 to 3 mg (OR = 1.13-1.7), significantly increased the OR of PR. In terms of PR, beef cattle exhibited a higher odds ratio (OR = 1.4; P = 0.000) compared to dairy cattle (OR = 1.1; P = 0.09). The administration of estrogens in the estrus synchronization protocol significantly improved PR in both artificial insemination (OR = 1.2; P = 0.000) and embryo transfer (OR = 1.3; P = 0.033) programs. In summary, incorporating estrogens into estrus induction protocols led to an enhancement of the OR of PR among cattle.


Assuntos
Estrogênios , Progesterona , Feminino , Gravidez , Bovinos , Animais , Estrogênios/farmacologia , Taxa de Gravidez , Progesterona/farmacologia , Estradiol/farmacologia , Estro/fisiologia , Sincronização do Estro/métodos , Inseminação Artificial/veterinária , Inseminação Artificial/métodos , Dinoprosta/farmacologia , Hormônio Liberador de Gonadotropina/farmacologia
15.
ScientificWorldJournal ; 2024: 5338212, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38304042

RESUMO

Endometriosis (EM) is a gynecological disorder that causes morbidity in women and is characterized by endometrial tissue in the uterus cavity. This study investigated the mechanism of genistein in the VEGF-A and ER-α expression through in vivo and in silico approaches. An in vivo study was conducted by thirty-six mice that were divided into six groups including control, EM, and EM treatment with genistein with the doses of 1.3, 1.95, 2.6, and 3.25 mg/day for 14 days. Peritoneal tissues with lesions were collected and analyzed by immunohistochemistry to measure the VEGF-A and ER-α expression. The data were analyzed using a statistical approach using one-way ANOVA followed by Tukey HSD test with a significant value p < 0.05. In silico study was conducted for investigating the inhibition mechanism of genistein in VEGF-A and ER-α protein. Genistein significantly reduced the VEGF-A and ER-α expression with the optimum dose of 3.25 mg/day. Molecular docking showed that genistein inhibited VEGF-A in several active site residues of VEGF-A, also blocked the ER-α protein in estradiol binding sites. This study concluded that genistein prevented endometriosis by performing the antiangiogenic activity and showed a similar function to estradiol.


Assuntos
Endometriose , Fator A de Crescimento do Endotélio Vascular , Humanos , Feminino , Camundongos , Animais , Genisteína/farmacologia , Genisteína/uso terapêutico , Endometriose/tratamento farmacológico , Endometriose/patologia , Simulação de Acoplamento Molecular , Receptores de Estrogênio/metabolismo , Receptor alfa de Estrogênio/metabolismo , Estradiol/farmacologia , Modelos Animais de Doenças
16.
Physiol Plant ; 176(1): e14155, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38342490

RESUMO

Leucine-rich repeat receptor kinases (LRR-RKs) play a pivotal role in diverse aspects of growth, development, and immunity in plants by sensing extracellular signals. Typically, LRR-RKs are activated through the ligand-induced interaction with a SOMATIC EMBRYOGENESIS RECEPTOR KINASE (SERK) coreceptor, triggering downstream signaling. ROOT MERISTEM GROWTH FACTOR1 (RGF1) INSENSITIVEs (RGIs) LRR-RLK receptors promote primary root meristem activity while inhibiting lateral root (LR) development in response to RGF peptide. In this study, we employed rapamycin-induced dimerization (RiD) and BAK1-INTERACTING RECEPTOR-LIKE KINASE3 (BIR3) chimera approaches to explore the gain-of-function of RGI1, RGI4, and RGI5. Rapamycin induced the association of cytosolic kinase domains (CKDs) of RGI1 and the BAK1 coreceptor, activating both mitogen-activated protein kinase 3 (MPK3) and MPK6. Rapamycin significantly inhibited LR formation in RiD-RGI1/RGI4/RGI5-BAK1 plants. Using transgenic Arabidopsis expressing RGI1CKD fused to the BIR3-LRR chimera under estradiol control, we observed a substantial reduction in LR density upon ß-estradiol treatment. Additionally, we identified a decrease in root gravitropism in BIR3 chimera plants. In contrast, RiD-RGI/BAK1 plants did not exhibit defects in root gravitropism, implying the importance of combinatorial interactions between RGIs and SERK coreceptors in the inhibition of root gravitropism. Constitutive activation of RGIs with BAK1 in RiD-RGI/BAK1 plants by rapamycin treatment resulted in the inhibition of primary root growth, resembling the inhibitory effects observed with high concentrations of phytohormones on primary root elongation. Our findings highlight that the interactions between CKDs of RGIs and BAK1, constitutively induced by rapamycin or BIR3 chimera, efficiently control LR development.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/farmacologia , Proteínas de Arabidopsis/metabolismo , Dimerização , Plantas/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia
17.
Physiol Behav ; 276: 114484, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38331374

RESUMO

It is well documented that estrogens inhibit fluid intake. Most of this research, however, has focused on fluid intake in response to dipsogenic hormone and/or drug treatments in euhydrated rats. Additional research is needed to fully characterize the fluid intake effects of estradiol in response to true hypovolemia. As such, the goals of this series of experiments were to provide a detailed analysis of water intake in response to water deprivation in ovariectomized female rats treated with estradiol. In addition, these experiments also tested if activation of estrogen receptor alpha is sufficient to reduce water intake stimulated by water deprivation and tested for a role of glucagon like peptide-1 in the estrogenic control of water intake. As expected, estradiol reduced water intake in response to 24 and 48 h of water deprivation. The reduction in water intake was associated with a reduction in drinking burst number, with no change in drinking burst size. Pharmacological activation of estrogen receptor alpha reduced intake. Finally, estradiol-treatment caused a leftward shift in the behavioral dose response curve of exendin-4, the glucagon like peptide-1 agonist. While the highest dose of exendin-4 reduced 10 min intake in both oil and estradiol-treated rats, the intermediate dose only reduced intake in rats treated with estradiol. Together, this series of experiments extends previous research by providing a more thorough behavioral analysis of the anti-dipsogenic effect of estradiol in dehydrated rats, in addition to identifying the glucagon like peptide-1 system as a potential bioregulator involved in the underlying mechanisms by which estradiol reduces water intake in the female rat.


Assuntos
Ingestão de Líquidos , Peptídeo 1 Semelhante ao Glucagon , Animais , Feminino , Ratos , Desidratação , Ingestão de Líquidos/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio , Exenatida/farmacologia , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Fatores de Transcrição
18.
Int J Mol Sci ; 25(3)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38338656

RESUMO

Amyloid beta 1-42 (Aß42) aggregates acutely impair hippocampal long-term potentiation (LTP) of synaptic transmission, and 17ß-estradiol is crucial for hippocampal LTP. We tested whether boosting the synthesis of neural-derived 17ß-estradiol (nE2) saves hippocampal LTP by the neurotoxic action of Aß42. Electrophysiological recordings were performed to measure dentate gyrus (DG) LTP in rat hippocampal slices. Using a pharmacological approach, we tested the ability of nE2 to counteract the LTP impairment caused by acute exposure to soluble Aß42 aggregates. nE2 was found to be required for LTP in DG under physiological conditions. Blockade of steroid 5α-reductase with finasteride, by increasing nE2 synthesis from testosterone (T), completely recovered LTP in slices treated with soluble Aß42 aggregates. Modulation of the glutamate N-methyl-D aspartate receptor (NMDAR) by memantine effectively rescued the LTP deficit observed in slices exposed to Aß42, and memantine prevented LTP reduction observed under the blocking of nE2 synthesis. nE2 is able to counteract Aß42-induced synaptic dysfunction. This effect depends on a rapid, non-genomic mechanism of action of nE2, which may share a common pathway with glutamate NMDAR signaling.


Assuntos
Estradiol , Potenciação de Longa Duração , Ratos , Animais , Estradiol/farmacologia , Estradiol/metabolismo , Peptídeos beta-Amiloides/metabolismo , Memantina/farmacologia , Hipocampo/metabolismo , Glutamatos/metabolismo
19.
Int J Mol Sci ; 25(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38339098

RESUMO

Diabetes mellitus is clinically defined by chronic hyperglycemia. Sex differences in the presentation and outcome of diabetes exist with premenopausal women having a reduced risk of developing diabetes, relative to men, or women after menopause. Accumulating evidence shows a protective role of estrogens, specifically 17-beta estradiol, in the maintenance of pancreatic beta cell health; however, the mechanisms underlying this protection are still unknown. To elucidate these potential mechanisms, we used a pancreatic beta cell line (BTC6) and a mouse model of hyperglycemia-induced atherosclerosis, the ApoE-/-:Ins2+/Akita mouse, exhibiting sexual dimorphism in glucose regulation. In this study we hypothesize that 17-beta estradiol protects pancreatic beta cells by modulating the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress. We observed that ovariectomized female and male ApoE-/-:Ins2+/Akita mice show significantly increased expression of apoptotic UPR markers. Sham operated female and ovariectomized female ApoE-/-:Ins2+/Akita mice supplemented with exogenous 17-beta estradiol increased the expression of adaptive UPR markers compared to non-supplemented ovariectomized female ApoE-/-:Ins2+/Akita mice. These findings were consistent to what was observed in cultured BTC6 cells, suggesting that 17-beta estradiol may protect pancreatic beta cells by repressing the apoptotic UPR and enhancing the adaptive UPR activation in response to pancreatic ER stress.


Assuntos
Diabetes Mellitus , Hiperglicemia , Células Secretoras de Insulina , Humanos , Feminino , Camundongos , Masculino , Animais , Células Secretoras de Insulina/metabolismo , Estradiol/farmacologia , Estradiol/metabolismo , Resposta a Proteínas não Dobradas , Diabetes Mellitus/metabolismo , Estresse do Retículo Endoplasmático , Hiperglicemia/metabolismo , Apolipoproteínas E/metabolismo
20.
Eur Rev Med Pharmacol Sci ; 28(2): 571-576, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38305601

RESUMO

OBJECTIVE: This study aims to compare the effects of vaginal estrogen and hyaluronic acid on vulvovaginal atrophy. PATIENTS AND METHODS: This randomized controlled study included a total of 300 patients, with 150 patients in each group (Group E and Group H). The VHI score was determined based on a pre-treatment evaluation conducted by a gynecologist. After one month of receiving vaginal estrogen in Group E and vaginal hyaluronic acid in Group H, the patients were re-evaluated by their physicians. RESULTS: A statistically significant difference was found between the pre- and post-treatment VHI scores in Group E and Group H (p = 0.000; p = 0.000). No statistical difference was found between Group E and Group H in terms of treatment efficacy (p = 0.712). The pre- and post-treatment complaints of dryness, itching, dyspareunia, burning, and dysuria were found to be statistically significant in Group E and Group H (p = 0.000; p = 0.000; p = 0.000; p = 0.000; p = 0.000 in Group E, respectively) (p = 0.000; p = 0.000; p = 0.000; p = 0.000; p = 0.000 in Group H, respectively). No statistical difference was observed regarding dyspareunia, dysuria, and burning complaints (p = 0.632; p = 0.106; p = 0.128, respectively). However, hyaluronic acid was found to be significantly more effective for itching complaints (p = 0.002), while estrogen was found to be significantly more effective for dryness complaints (p = 0.012). CONCLUSIONS: Hyaluronic acid and estrogen were equally effective in vaginal treatment. Hyaluronic acid may be preferred for patients in whom hormonal therapy is contraindicated or for those who prefer non-hormonal therapy.


Assuntos
Dispareunia , Ácido Hialurônico , Feminino , Humanos , Estradiol/uso terapêutico , Estradiol/farmacologia , Dispareunia/patologia , Disuria/induzido quimicamente , Disuria/patologia , Pós-Menopausa , Vagina/patologia , Estrogênios/uso terapêutico , Estrogênios/farmacologia , Resultado do Tratamento , Atrofia/tratamento farmacológico , Atrofia/patologia , Prurido/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...