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1.
Int J Nanomedicine ; 16: 315-327, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33469288

RESUMO

Background: Castration-resistant prostate cancer (CRPC) is still considered incurable, even though the mechanisms of CRPC had been extensively researched. Studies have demonstrated that exosomes in the tumor microenvironment contribute to prostate cancer development and progression. However, the role of exosomes in the process of CRPC progression has not yet been determined. Methods: Co-culturing and exosome treatment assays combined with in vitro and in vivo assays were performed to determine the function of exosomes in the transformation of androgen-dependent prostate cancer (ADPC) cells into androgen-independent cells. Then, the mRNA expression profiles of ADPC cells and ADPC cells co-cultured with androgen-independent prostate cancer (AIPC) cell-derived exosomes were studied using microarrays. After silencing the expression of heme oxygenase-1 (HMOX1), Western blotting, quantitative real-time PCR, immunohistochemistry (IHC) studies, and MTS assay were used to confirm the mechanisms of exosome participation in CRPC progression. Results: The results showed that ADPC cells acquired tolerance for androgen deprivation due to the exosome-mediated communication between cells. AIPC cell-derived exosomes promoted the transformation of ADPC cells into androgen-independent cells in vivo and in vitro. Microarray analysis revealed that HMOX1 in ADPC cells was up-regulated after treatment with AIPC cell-derived exosomes. Further results showed that HMOX1 is overexpressed in human AIPC specimens and protects ADPC cells from androgen deprivation. Conclusions: Our findings revealed that exosomes contribute to CRPC progression via promoting the transition of prostate cancer cells into an androgen-independent growth stage by activating HMOX1.


Assuntos
Androgênios/farmacologia , Exossomos/metabolismo , Heme Oxigenase-1/metabolismo , Neoplasias da Próstata/patologia , Regulação para Cima/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Progressão da Doença , Exossomos/ultraestrutura , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Microambiente Tumoral
2.
Braz J Biol ; 81(3): 526-536, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33470295

RESUMO

To investigate the optimal androgen concentration for culturing Hetian sheep wool follicle and to detect effects of androgen concentration on wool follicle cell proliferation and apoptosis using immunofluorescence labeling and real-time quantitative fluorescence determinations of wool keratin-associated protein gene expression levels. Wool follicles were isolated by microdissection and wool follicles and skin pieces were cultured in various concentrations of dihydrotestosterone (DHT) in culture medium. Next, daily lengthwise growth measurements of wool follicles were obtained using a microscopic micrometer. Cultured Hetian wool follicles were stained using the SACPIC method to reveal wool follicle structure, while sheep skin slices were used to observe cell proliferation by immunostaining and cell apoptosis using the TUNEL method. At the molecular biological level, keratin-associated protein (Kap) gene expression was studied using wool follicles cultured for various numbers of days in vitro. Effects of androgen concentrations on Hetian wool follicle growth and development were experimentally studied. EdU proliferation assays revealed that androgen promoted cell proliferation within wool follicle dermal papillae. TUNEL apoptosis detection demonstrated that androgen treatment could delay cell apoptosis. Quantitative reverse transcription polymerase chain reaction (qPCR) results demonstrated that gene expression level patterns of Hetian mountain sheep super-high sulfur protein. Kap1.1, KIF1.2, Kap2.12 and Kap4.2 gene expression level of the mountainous experimental group was significantly higher than plains Hetian sheep. An androgen concentration of 100 nM can promote the growth of Hetian wool follicle cells in vitro, resulting in overexpression of some genes of the Kap family.


Assuntos
Queratinas , , Androgênios/farmacologia , Animais , Folículo Piloso , Queratinas/genética , Ovinos
3.
Life Sci ; 269: 119040, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33453241

RESUMO

AIMS: Low testosterone in men is associated with increased cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors including cholesterol, endothelial dysfunction and inflammation as key mediators of atherosclerosis. Although evidence suggests testosterone is anti-atherogenic, its mechanism of action is unknown. The present study investigates whether testosterone exerts anti-atherogenic effects by stimulating cholesterol clearance from macrophages via activation of liver X receptor (LXRα), a nuclear master regulator of cellular cholesterol homeostasis, lipid regulation, and inflammation. MAIN METHODS: Using human monocyte THP-1 cells differentiated into macrophages, the effect of testosterone (1-10 nM) treatment (24-72 h) on the expression of LXRα and LXR- targets apolipoprotein E (APOE), ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding transcription factor 1 (SREBF1) and fatty acid synthase (FAS), was investigated via qPCR and western blotting, with or without androgen receptor blockade with flutamide or LXR antagonism with CPPSS-50. Cholesterol clearance was measured by monitoring fluorescent dehydroergosterol (DHE) cellular clearance and ABCA1 cellular translocation was observed via immunocytochemistry in testosterone treated macrophages. KEY FINDINGS: Testosterone increased mRNA and protein expression of LXRα, APOE, ABCA1, SREBF1 and FAS. These effects were blocked by flutamide and independently by LXR antagonism with CPPSS-50. Furthermore testosterone stimulated cholesterol clearance from the macrophages and promoted the translocation of ABCA1 toward the cell membrane. SIGNIFICANCE: Testosterone acts via androgen receptor-dependent pathways to stimulate LXRα and downstream targets to induce cholesterol clearance in human macrophages. This may, in part, explain the anti-atherogenic effects of testosterone frequently seen clinically.


Assuntos
Colesterol/metabolismo , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Monocítica Aguda/metabolismo , Receptores X do Fígado/metabolismo , Macrófagos/metabolismo , Receptores Androgênicos/metabolismo , Testosterona/farmacologia , Androgênios/farmacologia , Humanos , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Monocítica Aguda/patologia , Receptores X do Fígado/genética , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Receptores Androgênicos/genética , Células Tumorais Cultivadas
4.
Nat Med ; 27(2): 310-320, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33462444

RESUMO

The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.


Assuntos
Androgênios/farmacologia , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Receptores Androgênicos/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/genética , Feminino , Humanos , Células MCF-7 , Coativador 3 de Receptor Nuclear/genética , Receptores Androgênicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
5.
Development ; 148(1)2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33318148

RESUMO

Androgens/androgen receptor (AR)-mediated signaling pathways are essential for prostate development, morphogenesis and regeneration. Specifically, stromal AR signaling has been shown to be essential for prostatic initiation. However, the molecular mechanisms underlying AR-initiated mesenchymal-epithelial interactions in prostate development remain unclear. Here, using a newly generated mouse model, we have directly addressed the fate and role of genetically marked AR-expressing cells during embryonic prostate development. Androgen signaling-initiated signaling pathways were identified in mesenchymal niche populations at single-cell transcriptomic resolution. The dynamic cell-signaling networks regulated by stromal AR were additionally characterized in relation to prostatic epithelial bud formation. Pseudotime analyses further revealed the differentiation trajectory and fate of AR-expressing cells in both prostatic mesenchymal and epithelial cell populations. Specifically, the cellular properties of Zeb1-expressing progenitors were assessed. Selective deletion of AR signaling in a subpopulation of mesenchymal rather than epithelial cells dysregulated the expression of the master regulators and significantly impaired prostatic bud formation. These data provide novel, high-resolution evidence demonstrating the important role of mesenchymal androgen signaling in the cellular niche controlling prostate early development by initiating dynamic mesenchyme-epithelia cell interactions.


Assuntos
Androgênios/farmacologia , Comunicação Celular , Linhagem da Célula , Próstata/citologia , Análise de Célula Única , Animais , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/genética , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Genes Controladores do Desenvolvimento , Masculino , Mesoderma/citologia , Camundongos , Próstata/efeitos dos fármacos , RNA-Seq , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo
6.
Chemosphere ; 262: 128313, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33182081

RESUMO

Androgens and androgen receptor regulate a variety of biological effects in the human body. The impaired functioning of androgen receptor may have different adverse health effects from cancer to infertility. Therefore, it is important to determine whether new chemicals have any binding activity and act as androgen agonists or antagonists before commercial use. Due to the large number of chemicals that require experimental testing, the computational methods are a viable alternative. Therefore, the aim of the present study was to develop predictive QSAR models for classifying compounds according to their activity at the androgen receptor. A large data set of chemicals from the CoMPARA project was used for this purpose and random forest classification models have been developed for androgen binding, agonistic, and antagonistic activity. In addition, a unique effort has been made for multi-class approach that discriminates between inactive compounds, agonists and antagonists simultaneously. For the evaluation set, the classification models predicted agonists with 80% of accuracy and for the antagonists' and binders' the respective metrics were 72% and 78%. Combining agonists, antagonists and inactive compounds into a multi-class approach added complexity to the modelling task and resulted to 64% prediction accuracy for the evaluation set. Considering the size of the training data sets and their imbalance, the achieved evaluation accuracy is very good. The final classification models are available for exploring and predicting at QsarDB repository (https://doi.org/10.15152/QDB.236).


Assuntos
Antagonistas de Receptores de Andrógenos/classificação , Androgênios/classificação , Modelos Químicos , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios/química , Androgênios/farmacologia , Humanos , Aprendizado de Máquina , Ligação Proteica , Relação Quantitativa Estrutura-Atividade
7.
Zhonghua Nan Ke Xue ; 26(6): 487-498, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-33356036

RESUMO

Objective: To observe the effects of different concentrations of testosterone on the differentiation of human embryonic stem cells (hESCs) into early male germ cells and investigate the potential impact of high-level androgen exposure in early pregnancy in women with polycystic ovary syndrome (PCOS) on the fertility and primordial germ cell reserve of the male offspring in adulthood. METHODS: We used 2 µmol/L retinoic acid to induce the differentiation of hESCs (46, XY) into male germ cells in vitro and meanwhile treated them with testosterone (T) at 0 mol/L, 3×10-7 mol/L, 5×10-7 mol/L, 15×10-7 mol/L, 45×10-7 mol/L, and 135×10-7 mol/L, respectively. We collected the cell samples at 0, 4, 7 and 14 days to determine the expressions of the specific genes and compare the differentiation process and efficiency of the male germ cells in different stages. RESULTS: There was no difference in the morphology of the hESCs treated with different concentrations of testosterone in the same differentiation stage. The expression of the marker gene DAZL in the primordial germ cells peaked on the 4th day of differentiation, significantly higher in the 15×10-7, 45×10-7 and 135×10-7 mol/L groups than in the 3×10-7 mol/L group (P < 0.05), and that of the specific gene SCP3 in the early-meiosis germ cells began to increase on the same day, more significantly in the 45×10-7mol/L than in the 3×10-7 mol/L and 5×10-7 mol/L groups (P < 0.01), and peaked on the 7th day, dramatically higher in the 15×10-7, 45×10-7 and 135×10-7 mol/L groups than in the 3×10-7 mol/L group (P < 0.01). Immunofluorescence staining and flow cytometry showed a T concentration-dependent increase in the expression of DAZL at 4 days and those of SCP3 and VASA at 7 days. Moreover, the expression of the androgen receptor (AR) in the hESCs began to rise on the 4th day and kept going up till the 14th day, higher in the high-concentration than in the low-concentration T groups in the same stage of differentiation, though with no statistically significant difference (P > 0.05). CONCLUSIONS: Exposure to high-level androgen during the differentiation of hESCs into early male germ cells can induce earlier expression of AR and earlier differentiation of hESCs into early male germ cells, which may result in insufficient reserve of male primary germ cells in the male offspring of PCOS women and affect their fertility after adulthood. hESCs can be used as an in vitro model to study the effects of intrauterine hyperandrogen on the reproductive development of male offspring in PCOS patients, which is also contributive to researches on the etiology of male infertility.


Assuntos
Androgênios/farmacologia , Diferenciação Celular , Células Germinativas/citologia , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Proteínas de Ciclo Celular/fisiologia , Células Cultivadas , RNA Helicases DEAD-box/fisiologia , Proteínas de Ligação a DNA/fisiologia , Células-Tronco Embrionárias Humanas/citologia , Humanos , Masculino , Meiose , Proteínas de Ligação a RNA/fisiologia
8.
Nutr. hosp ; 37(5): 1033-1038, sept.-oct. 2020. tab
Artigo em Inglês | IBECS | ID: ibc-198020

RESUMO

INTRODUCTION: indiscriminate use of anabolic steroids is associated with cardiovascular diseases, renal damage, and hepatic toxicity. Contrastingly, nutraceutical foods such as avocados prevent and control several diseases, as they can reduce the effects of oxidative stress. OBJECTIVE: this study evaluates the benefits of consuming an avocado oil-based diet to attenuate the systemic damage caused by supraphysiological doses of testosterone, by analyzing the biochemical profile of 28 42-day-old male Wistar rats. METHODS: silicone pellets containing testosterone were surgically implanted, and they received control or avocado oil-based feed. After 20 weeks, all the male rats were anesthetized and their blood samples collected. RESULTS: although the high hormone concentration had a negative influence on the biochemical profile of these animals, the groups that consumed avocado oil exhibited a reduction in serum triacylglycerols (-21 %; p = 0.0001), VLDL (-20 %; p = 0.0085), LDL (-78 %; p < 0.0001), and total cholesterol (-12 %; p < 0.0001), along with positive changes in their HDL concentrations (+7 %; p = 0.001). The avocado oil groups also manifested a reduction in the total concentration of serum proteins (-24 %; p = 0.0357), albumin (-26 %; p = 0.0015), urea (-14 %; p = 0.04), and creatinine (-33 %; p < 0.0001). The concentration of liver transaminases was found to be higher in the animals included in the induced group (ALT, +66 %; p = 0.0005, and AST, +23 %; p = 0.0021), whereas they remained stable in the avocado oil group. CONCLUSION: from the above, it may be concluded that supraphysiological doses of testosterone are related to increased risk factors for cardiovascular, renal, and hepatic diseases, and that the consumption of avocado oil shields the biochemical profile, thus reducing the associated risk factors


INTRODUCCIÓN: el uso indiscriminado de esteroides anabólicos se asocia con enfermedades cardiovasculares, daño renal y toxicidad hepática. En cambio, los alimentos nutracéuticos como el aguacate previenen y controlan varias enfermedades, ya que pueden reducir los efectos del estrés oxidativo. OBJETIVO: este estudio evalúa los beneficios de consumir una dieta basada en aceite de aguacate para atenuar el daño sistémico causado por dosis suprafisiológicas de testosterona mediante el análisis del perfil bioquímico de 28 ratas Wistar macho de 42 días de edad. MÉTODOS: se implantaron quirúrgicamente perdigones de silicona que contenían propionato de testosterona y los animales recibieron una alimentación de control o una basada en el aceite de aguacate. Después de 20 semanas se anestesiaron todos los animales y se recogieron sus muestras de sangre. RESULTADOS: aunque la alta concentración de hormonas tuvo una influencia negativa en el perfil bioquímico de estos animales, los grupos que consumieron aceite de aguacate mostraron una reducción de los triglicéridos séricos (-21 %; p = 0,0001), las VLDL (-20 %; p = 0,0085), las LDL (-78 %; p < 0,0001) y el colesterol total (-12 %; p < 0,0001), con cambios positivos en las LDL (+7 %; p = 0,001). Los grupos alimentados con aceite de aguacate manifestaron una reducción de la concentración total de proteínas séricas (-24 %; p = 0,0357), albúmina (-26 %; p = 0,0015), urea (-14 %; p = 0,04) y creatinina (-33 %; p < 0,0001). Se encontró que la concentración sérica de transaminasas hepáticas era mayor en los animales del grupo inducido (ALT: +66 %; p = 0,0005, y AST: +23 %; p = 0,0021), mientras que en los grupos con aceite de aguacate, los parámetros hepáticos se mantuvieron estables. CONCLUSIÓN: de todo ello se puede concluir que las dosis suprafisiológicas de testosterona están relacionadas con un aumento de los factores de riesgo de sufrir enfermedades cardiovasculares, renales y hepáticas, y que el consumo de aceite de aguacate protege el perfil bioquímico, lo que reduce los factores de riesgo asociados


Assuntos
Animais , Masculino , Ratos , Persea/metabolismo , Óleos Vegetais/administração & dosagem , Androgênios/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Óleos Vegetais/química , Óleos Vegetais/farmacologia , Suplementos Nutricionais , Ratos Wistar , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/veterinária
9.
Proc Natl Acad Sci U S A ; 117(38): 23751-23761, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32917815

RESUMO

Mast cell (MC)-associated diseases, including allergy/anaphylaxis and neuroinflammatory pain disorders, exhibit a sex bias, with females at increase risk. While much attention has been directed toward adult sex hormones as drivers of sex differences, that female sex bias in MC-associated diseases is evident in prepubertal children, suggesting early-life origins of sex differences which have yet to be explored. Utilizing rodent models of MC-mediated anaphylaxis, our data here reveal that, 1) compared with females, males exhibit significantly reduced severity of MC-mediated anaphylactic responses that emerge prior to puberty and persist into adulthood, 2) reduced severity of MC-mediated anaphylaxis in males is linked with the naturally high level of perinatal androgens and can be recapitulated in females by perinatal exposure to testosterone proprionate, 3) perinatal androgen exposure guides bone marrow MC progenitors toward a masculinized tissue MC phenotype characterized by decreased concentration of prestored MC granule mediators (e.g., histamine, serotonin, and proteases) and reduced mediator release upon degranulation, and 4) engraftment of MC-deficient Kit W-sh/W-sh mice with adult male, female, or perinatally androgenized female MCs results in MC-mediated anaphylaxis response that reflects the MC sex and not host sex. Together, these data present evidence that sex differences in MC phenotype and resulting disease severity are established in early life by perinatal androgens. Thus, factors affecting levels of perinatal androgens could have a significant impact on MC development and MC-associated disease risk across the life span.


Assuntos
Anafilaxia , Androgênios/farmacologia , Mastócitos/efeitos dos fármacos , Fatores Sexuais , Animais , Modelos Animais de Doenças , Feminino , Inflamação , Masculino , Mastócitos/fisiologia , Camundongos , Camundongos Transgênicos , Testículo/citologia , Testículo/efeitos dos fármacos
10.
Artigo em Inglês | MEDLINE | ID: mdl-32654587

RESUMO

The 17 alpha methyltestosterone (MT) hormone is fed to Oreochromis niloticus larvae in fish farms with the purpose of inducing sex reversal. The aim of this study was to evaluate the toxicity and sub-lethality of MT (99.9% purity) and cMT (a commercial MT with 90% purity) in zebrafish (Danio rerio) adults, where the animals were exposed to concentrations of 0, 4, 23, 139, 833 and 5000 µg/L for 96 hours. Genotoxicity was evaluated by micronucleus test (MN), nuclear abnormalities (NA) and comet assay. A low genotoxic potential of MT was showed, inducing micronucleus, nuclear abnormalities and DNA damage in Danio rerio, depending on the use of MT or cMT, gender and tested concentrations. In the sub-lethality trials, there was a basal difference in the activity of the enzymatic biochemical markers for males and females, while the Glutatione S transferase (GST) activity decreased in all analyzed tissues, and for males the enzymatic activity decreased only in the intestine. Results suggest that MT has a toxic potential to fish because it alters enzymatic metabolic pathways and may pose a risk to the ecosystems.


Assuntos
Androgênios/toxicidade , Dano ao DNA , Metiltestosterona/toxicidade , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/genética , Androgênios/farmacologia , Animais , Ciclídeos/crescimento & desenvolvimento , Ensaio Cometa , Relação Dose-Resposta a Droga , Ecossistema , Feminino , Pesqueiros , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Masculino , Metiltestosterona/farmacologia , Poluentes Químicos da Água/farmacologia
11.
J Int Acad Periodontol ; 22(3): 146-155, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32655040

RESUMO

BACKGROUND: Skin-related disorders and periodontitis are distinct diseases that have been associated with altered levels of testosterone. Understanding the mechanisms through which testosterone mediates gingival enlargement in animals and humans is crucial for preventing or treating this condition. In this study, we investigated the impact of different doses of androgens, the role of aromatase inhibition, and the effects of testosterone association with sex hormone receptor antagonists or aromatase inhibitors on human gingival fibroblast proliferation and migration in vitro. METHODS: Fibroblasts were cultivated in Dulbecco's Modified Eagle's Medium in a humidified atmosphere and treated with different doses of testosterone or dihydrotestosterone, and testosterone in association with: aromatase inhibitor - anastrozole; antagonist of androgen receptors - flutamide; and antagonist of estrogen receptors - fulvestrant. RESULTS: Low (1nM) and high (1µM) doses of testosterone significantly increased cell migration, but the higher dose did not alter cell proliferation. Those effects were related to both androgen and estrogen receptors activation, as evidenced by the dihydrotestosterone and drug interaction groups. CONCLUSIONS: Testosterone association with sex hormone receptor antagonists flutamide and fulvestrant suggests that not only androgen receptors, but also estrogen receptors, may take part in fibroblast cell proliferation and migration in vitro.


Assuntos
Androgênios , Testosterona , Antagonistas de Androgênios/farmacologia , Androgênios/farmacologia , Animais , Proliferação de Células , Estradiol/farmacologia , Fibroblastos , Humanos , Receptores de Estrogênio , Testosterona/farmacologia
12.
Nat Commun ; 11(1): 3459, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651360

RESUMO

Hepatic amebiasis, predominantly occurring in men, is a focal destruction of the liver due to the invading protozoan Entamoeba histolytica. Classical monocytes as well as testosterone are identified to have important functions for the development of hepatic amebiasis in mice, but a link between testosterone and monocytes has not been identified. Here we show that testosterone treatment induces proinflammatory responses in human and mouse classical monocytes. When treated with 5α-dihydrotestosterone, a strong androgen receptor ligand, human classical monocytes increase CXCL1 production in the presence of Entamoeba histolytica antigens. Moreover, plasma testosterone levels of individuals undergoing transgender procedure correlate positively with the TNF and CXCL1 secretion from their cultured peripheral blood mononuclear cells following lipopolysaccharide stimulation. Finally, testosterone substitution of castrated male mice increases the frequency of TNF/CXCL1-producing classical monocytes during hepatic amebiasis, supporting the hypothesis that the effects of androgens may contribute to an increased risk of developing monocyte-mediated pathologies.


Assuntos
Androgênios/farmacologia , Quimiocina CXCL1/metabolismo , Animais , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Di-Hidrotestosterona/farmacologia , Entamoeba histolytica/química , Voluntários Saudáveis , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
13.
Proc Biol Sci ; 287(1931): 20200976, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32673552

RESUMO

Several studies have implicated testosterone in the modulation of altruistic behaviours instrumental to advancing social status. Independent studies have also shown that people tend to behave more altruistically when being watched (i.e. audience effect). To date, little is known about whether testosterone could modulate the audience effect. In the current study, we tested the effect of testosterone on altruistic behaviour using a donation task, wherein participants were asked to either accept or reject a monetary transfer to a charity organization accompanying a personal cost either in the presence or absence of an observer. We administered testosterone gel or placebo to healthy young men (n = 140) in a double-blind, placebo-controlled, mixed design. Our results showed that participants were more likely to accept the monetary transfer to the charity when being observed compared to when they completed the task alone. More importantly, this audience effect was amplified among people receiving testosterone versus placebo. Our findings suggest that testosterone administration increases the audience effect and further buttress the social status hypothesis, according to which testosterone promotes status-seeking behaviour in a context-dependent manner.


Assuntos
Androgênios/farmacologia , Testosterona/farmacologia , Adolescente , Adulto , Humanos , Masculino , Comportamento Social , Meio Social , Adulto Jovem
14.
Prostate ; 80(11): 885-894, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32483877

RESUMO

BACKGROUND: Eradication of persistent androgen receptor (AR) activity in castration-resistant prostate cancer may be a promising strategy to overcome castration resistance. We aimed to identify novel compounds that inhibit AR activity and could be potential therapeutic agents for prostate cancer. METHODS: A high-throughput screening system involving cell lines stably expressing AR protein and AR-responsive luciferase was employed for the 1260 compound library. Molecular and antitumor effects on candidate pathways that interacted with AR signaling were examined in prostate cancer cells expressing AR. RESULTS: The high-throughput screening identified various potential compounds that interfered with AR signaling through known and novel pathways. Among them, a 5-hydroxytryptamine 5A (5-HT5A) receptor antagonist suppressed AR activity through protein kinase A signaling, which was confirmed by 5-HT5A receptor knockdown. Consistently, 5-HT5A receptor inhibitors showed cytotoxic effects toward prostate cancer cells. CONCLUSIONS: Taken together, this study identifies 5-HT5A receptor as a promising therapeutic target for prostate cancer via its interaction with AR signaling.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Ensaios de Triagem em Larga Escala/métodos , Humanos , Masculino , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo
15.
Adv Gerontol ; 33(2): 385-390, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32593257

RESUMO

There are changes in the metabolism, reproductive and nervous systems with ageing, which have a systemic and interrelated nature. The purpose of this work was to demonstrate the effectiveness of audiovisual correction and therapy with testosterone drugs in addition to the standard therapy in patients with polymorbid pathology. 89 men aged 35-55 years old with diabetes mellitus, polymorbid cardiovascular disease, obesity, anxiety and depressive disorders were examined. They were divided into 3 groups depending on the treatment: the 1st - standard therapy and escitalopram / tofisopam; the 2nd - standard therapy + audiovisual correction; the 3rd - standard therapy + audiovisual correction + testosterone undecanoate. Laboratory examination was carried out in all patients before the start of treatment and 9 months after the treatment. The severity of androgen deficiency was determined using IIEF-5 questionnaire and the AMS male aging scale. In was shown a decrease in testosterone levels, signs of erectile dysfunction and symptoms of moderate to severe androgen deficiency, increased proatherogenic and decreased antiatherogenic lipoproteins, increased glucose, glycated hemoglobin, insulin, HOMA index in our study. In group of audiovisual correction we saw a more significant improvement in the lipid profile after treatment. Audiovisual correction and androgen therapy contributed to the improvement of erectile function indices and a decrease in the severity of the symptoms of ageing in men.


Assuntos
Senilidade Prematura/prevenção & controle , Androgênios/uso terapêutico , Recursos Audiovisuais , Terapia de Reposição Hormonal , Idoso , Androgênios/deficiência , Androgênios/farmacologia , Disfunção Erétil/terapia , Humanos , Masculino , Ereção Peniana/efeitos dos fármacos , Testosterona/análogos & derivados , Testosterona/farmacologia , Testosterona/uso terapêutico
16.
J Steroid Biochem Mol Biol ; 202: 105710, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32534106

RESUMO

The androgen receptor (AR) is a transcription factor that drives prostate cancer (PCa) by modulating the expression of thousands of genes to promote proliferation and survival and to reprogram metabolism. However, how AR activation controls alternative splicing is mostly unknown. Our objective was to define its role in the transcriptome-wide regulation of alternative splicing. Three human PCa models-LNCaP, LAPC4, and 22Rv1 cells-were treated with and without androgens, and RNA was purified for deep-sequencing analyses (RNA-seq). Several bioinformatic tools were then used to study alternative splicing. We demonstrate that in the absence of androgens, alternative splicing complexity is similar among AR-positive PCa cells, with 48 % of all transcripts having various levels of alternative splicing. We also describe alternative splicing differences among cell lines, such as specific splicing of AR, REST, TSC2, and CTBP1. Interestingly, AR activation changed the alternative splicing of thousands of genes in all the PCa cell lines tested. Overlap between AR-sensitive alternative splicing events revealed that genes linked to cell metabolism are major targets for this specific modulation. These genes encode metabolic enzymes such as the prostate-specific membrane antigen, encoded by FOLH1, and the malate dehydrogenase 1 (MDH1). Overall, our study presents a comprehensive analysis of the PCa cell transcriptome and its modulation by AR, revealing a significant enrichment of metabolic genes in this AR-dependent regulation of alternative splicing.


Assuntos
Processamento Alternativo , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Processamento Alternativo/efeitos dos fármacos , Androgênios/farmacologia , Linhagem Celular Tumoral , Humanos , Masculino , RNA-Seq , Transcriptoma
17.
Anticancer Res ; 40(5): 2559-2565, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366400

RESUMO

BACKGROUND/AIM: Androgens are essential for the growth of most prostate cancers (PCa). As a result, androgen ablation is the mainstay of the treatment of PCa. Proteins of the polycomb and trithorax family are master epigenetic regulators of cell type specific gene expression including androgen receptor. MATERIALS AND METHODS: We interrogated epigenetic changes of a 24-gene panel corresponding to polycomb and trithorax genes by PCR array and differential gene expression by quantitative real time-PCR on prostate cancer cell line (LNCaP) treated with the synthetic ligand R1881. RESULTS: We observed the highest methylation for CBX2, PCGF6, PHC2, EZH2 and TRIM27 genes and the lowest methylation for CBX8 and PCGF2 (p<0.05), and a modest decrease in the expression of EZH2. CONCLUSION: Differential methylation profiles of polycomb and trithorax genes may contribute to the dynamics of prostate carcinogenesis.


Assuntos
Androgênios/farmacologia , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas do Grupo Polycomb/genética , Neoplasias da Próstata/genética , Androgênios/metabolismo , Linhagem Celular Tumoral , Metilação de DNA , Humanos , Masculino , Receptores Androgênicos/metabolismo
18.
Gen Comp Endocrinol ; 292: 113435, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32057909

RESUMO

In orange-spotted grouper, androgen can promote the development of testis and spermatogenesis, but the effect of androgen on testis development is unclear. Forkhead box L 3 (Foxl3) is important in the development of fish testis. Rec8 and fbxo47 are involved in meiosis, which impacts spermatogenesis. The present study investigated the plausible role of testis development through the Foxl3 transcriptional regulation of rec8 and fbxo47. The results of tissue distribution showed that rec8 and fbxo47 are highly expressed in gonad. In addition, the highest expression of foxl3, rec8, and fbxo47 was in the testis and intersex compared with the other stages of gonadal development, suggesting that foxl3, rec8, and fbxo47 are important in testis development. In addition, by using dual-luciferase assays, we found that the androgen can increase foxl3 promoter activity and Foxl3 can upregulate rec8 and fbxo47 promoter activity. Furthermore, the addition of ß-testosterone significantly increased foxl3, rec8, and fbxo47 promoter activity. Together, these results suggest that foxl3 plays a decisive role in testis development by regulating the expression of rec8 or fbxo47 and imply that AR-foxl3-rec8/fbxo47 affects the testis development pathway.


Assuntos
Androgênios/farmacologia , Bass/metabolismo , Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Receptores Androgênicos/metabolismo , Testículo/crescimento & desenvolvimento , Fatores de Transcrição/metabolismo , Animais , Bass/genética , Proteínas de Ciclo Celular/genética , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Regiões Promotoras Genéticas/genética , Testículo/citologia , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testosterona/farmacologia , Distribuição Tecidual/efeitos dos fármacos , Fatores de Transcrição/genética
19.
Endocrinology ; 161(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105330

RESUMO

Studies show that a subset of transgender men desire children; however, there is a paucity of literature on the effect of gender-affirming testosterone therapy on reproductive function. In this manuscript, we will review the process of gender-affirming hormone therapy for transgender men and what is known about ovarian and uterine consequences of testosterone exposure in transgender men; draw parallels with existing animal models of androgen exposure; summarize the existing literature on parenting experiences and desires in transgender people; discuss considerations for assisted reproductive technologies and fertility preservation; and identify gaps in the literature and opportunities for further research.


Assuntos
Androgênios/farmacologia , Genitália Feminina/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Testosterona/farmacologia , Pessoas Transgênero , Animais , Feminino , Humanos , Masculino , Modelos Animais , Procedimentos de Readequação Sexual
20.
Am J Physiol Endocrinol Metab ; 318(3): E371-E380, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31910029

RESUMO

Excess androgen-induced obesity has become a public health problem, and its prevalence has increased substantially in recent years. Chemokine-like receptor 1 (CMKLR1), a receptor of chemerin secreted by adipose tissue, is linked to adipocyte differentiation, adipose tissue development, and obesity. However, the effect of CMKLR1 signaling on androgen-mediated adiposity in vivo remains unclear. Using CMKLR1-knockout mice, we constructed an androgen-excess female mouse model through 5α-dihydrotestosterone (DHT) treatment and an androgen-deficient male mouse model by orchidectomy (ORX). For mechanism investigation, we used 2-(α-Naphthoyl) ethyltrimethylammonium iodide (α-NETA), an antagonist of CMKLR1, to suppress CMKLR1 in vivo and wortmannin, a PI3K signaling antagonist, to treat brown adipose tissue (BAT) explant cultures in vitro. Furthermore, we used histological examination and quantitative PCR, as well as Western blot analysis, glucose tolerance tests, and biochemical analysis of serum, to describe the phenotypes and the changes in gene expression. We demonstrated that excess androgen in the female mice resulted in larger cells in the white adipose tissue (WAT) and the BAT, whereas androgen deprivation in the male mice induced a reduction in cell size. Both of these adipocyte size effects could be attenuated in the CMKLR1-knockout mice. CMKLR1 deficiency influenced the effect of androgen treatment on adipose tissue by regulating the mRNA expression of the androgen receptor (AR) and adipocyte markers (such as Fabp4 and Cidea). Moreover, suppression of CMKLR1 by α-NETA could also reduce the extent of the adipocyte cell enlargement caused by DHT. Furthermore, we found that DHT could reduce the levels of phosphorylated ERK (pERK) in the BAT, while CMKLR1 inactivation inhibited this effect, which had been induced by DHT, through the PI3K signaling pathway. These findings reveal an antiobesity role of CMKLR1 deficiency in regulating lipid accumulation, highlighting the scientific importance for the further development of small-molecule CMKLR1 antagonists as fundamental research tools and/or as potential drugs for use in the treatment of adiposity.


Assuntos
Androgênios/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Receptores de Quimiocinas/deficiência , Adipócitos/metabolismo , Adipócitos/ultraestrutura , Tecido Adiposo Marrom/efeitos dos fármacos , Androgênios/deficiência , Animais , Peso Corporal , Tamanho Celular , Di-Hidrotestosterona/farmacologia , Feminino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naftalenos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Compostos de Amônio Quaternário/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/genética , Wortmanina/farmacologia
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