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2.
Endocrinology ; 161(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31742329

RESUMO

Many neural sex differences are differences in the number of neurons of a particular phenotype. For example, male rodents have more calbindin-expressing neurons in the medial preoptic area (mPOA) and bed nucleus of the stria terminalis (BNST), and females have more neurons expressing estrogen receptor alpha (ERα) and kisspeptin in the ventromedial nucleus of the hypothalamus (VMH) and the anteroventral periventricular nucleus (AVPV), respectively. These sex differences depend on neonatal exposure to testosterone, but the underlying molecular mechanisms are unknown. DNA methylation is important for cell phenotype differentiation throughout the developing organism. We hypothesized that testosterone causes sex differences in neurochemical phenotype via changes in DNA methylation, and tested this by inhibiting DNA methylation neonatally in male and female mice, and in females given a masculinizing dose of testosterone. Neonatal testosterone treatment masculinized calbindin, ERα and kisspeptin cell number of females at weaning. Inhibiting DNA methylation with zebularine increased calbindin cell number only in control females, thus eliminating sex differences in calbindin in the mPOA and BNST. Zebularine also reduced the sex difference in ERα cell number in the VMH, in this case by increasing ERα neuron number in males and testosterone-treated females. In contrast, the neonatal inhibition of DNA methylation had no effect on kisspeptin cell number. We conclude that testosterone normally increases the number of calbindin cells and reduces ERα cells in males through orchestrated changes in DNA methylation, contributing to, or causing, the sex differences in both cell types.


Assuntos
Encéfalo/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos , Testosterona/farmacologia , Animais , Animais Recém-Nascidos , Encéfalo/citologia , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Calbindinas/metabolismo , Citidina/administração & dosagem , Citidina/análogos & derivados , Citidina/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Kisspeptinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Diferenciação Sexual/fisiologia , Fatores Sexuais , Testosterona/administração & dosagem
3.
Biosci Biotechnol Biochem ; 84(1): 95-102, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31478781

RESUMO

D-Aspartate, aspartate racemase activity, and D-aspartate oxidase activity were detected in tissues from several types of starfish. Aspartate racemase activity in male testes of Patiria pectinifera was significantly elevated in the summer months of the breeding season compared with spring months. We also compared aspartate racemase activity with the gonad index and found that activity in individuals with a gonad index ≥6% was four-fold higher than that of individuals with a gonad index <6%. The ratio of the D-form of aspartate to total aspartate was approximately 25% in testes with a gonad index <6% and this increased to approximately 40% in testes with a gonad index ≥6%. However, such changes were not observed in female ovaries. Administration of D-aspartate into male starfish caused testicular growth. These results indicate the possible involvement of aspartate racemase and D-aspartate in testicular maturation in echinoderm starfish.


Assuntos
Isomerases de Aminoácido/metabolismo , Ácido D-Aspártico/metabolismo , Ácido D-Aspártico/farmacologia , Estrelas-do-Mar/fisiologia , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Animais , Ácido Aspártico/administração & dosagem , Ácido Aspártico/farmacologia , Cromatografia Líquida de Alta Pressão , Ácido D-Aspártico/administração & dosagem , Estrona/administração & dosagem , Estrona/farmacologia , Feminino , Masculino , Ovário/crescimento & desenvolvimento , Estações do Ano , Espermatogênese/fisiologia , Testosterona/administração & dosagem , Testosterona/farmacologia
4.
Meat Sci ; 159: 107916, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31476680

RESUMO

Testosterone, as an influential factor in marbling score, requires strict management for uniform development of adipocytes in-between muscle bundles. Present study investigated effect of castration timing and testosterone levels on adipocyte development using SVCs. Isolated SVCs exhibited classical MSC markers, CD31-, CD34-, CD45-, CD90+, and CD105+. ELISA analysis indicated that serum testosterone concentration was highest in non-castrated calves while no significant difference was observed between female, early and late castrated calves. CCK-8 assay showed that concentration of testosterone had no effect on cell proliferation. However, the real-time PCR demonstrated that 20 ng/ml of testosterone suppressed expression of preadipocyte markers, pref-1 and zfp423, but encouraged expression of myoblast markers, myf5 and myoD, via the AR. Consequently, expression of adipogenic markers C/EBPα and PPARγ, as well as accumulation of triglyceride, were decreased in 20 ng/ml testosterone treatment under adipogenic conditions. These findings suggest that by castrating calves before level of testosterone increases, may improve marbling development in the Hanwoo beef industry.


Assuntos
Bovinos , Músculo Esquelético/citologia , Testosterona/farmacologia , Adipócitos , Androgênios/administração & dosagem , Androgênios/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática/veterinária , Feminino , Masculino , Orquiectomia/veterinária , Testosterona/administração & dosagem
5.
PLoS Med ; 16(11): e1002960, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31714912

RESUMO

BACKGROUND: Young male cancer survivors have lower testosterone levels, higher fat mass, and worse quality of life (QoL) than age-matched healthy controls. Low testosterone in cancer survivors can be due to orchidectomy or effects of chemotherapy and radiotherapy. We have undertaken a double-blind, placebo-controlled, 6-month trial of testosterone replacement in young male cancer survivors with borderline low testosterone (7-12 nmol/l). METHODS AND FINDINGS: This was a multicentre United Kingdom study conducted in secondary care hospital outpatients. Male survivors of testicular cancer, lymphoma, and leukaemia aged 25-50 years with morning total serum testosterone 7-12 nmol/l were recruited. A total of 136 men were randomised between July 2012 and February 2015 (42.6% aged 25-37 years, 57.4% 38-50 years, 88% testicular cancer, 10% lymphoma, matched for body mass index [BMI]). Participants were randomised 1:1 to receive testosterone (Tostran 2% gel) or placebo for 26 weeks. A dose titration was performed after 2 weeks. The coprimary end points were trunk fat mass and SF36 Physical Functioning score (SF36-PF) at 26 weeks by intention to treat. At 26 weeks, testosterone treatment compared with placebo was associated with decreased trunk fat mass (-0.9 kg, 95% CI -1.6 to -0.3, p = 0.0073), decreased whole-body fat mass (-1.8 kg, 95% CI -2.9 to -0.7, p = 0.0016), and increased lean body mass (1.5 kg, 95% CI 0.9-2.1, p < 0.001). Decrease in fat mass was greatest in those with a high truncal fat mass at baseline. There was no treatment effect on SF36-PF or any other QoL scores. Testosterone treatment was well tolerated. The limitations of our study were as follows: a relatively short duration of treatment, only three cancer groups included, and no hard end point data such as cardiovascular events. CONCLUSIONS: In young male cancer survivors with low-normal morning total serum testosterone, replacement with testosterone is associated with an improvement in body composition. TRIAL REGISTRATION: ISRCTN: 70274195, EudraCT: 2011-000677-31.


Assuntos
Neoplasias Testiculares/tratamento farmacológico , Testosterona/farmacologia , Testosterona/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Adulto , Composição Corporal/efeitos dos fármacos , Sobreviventes de Câncer , Método Duplo-Cego , Humanos , Leucemia/complicações , Linfoma/complicações , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Qualidade de Vida , Neoplasias Testiculares/complicações , Reino Unido
6.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(9): 1083-1088, 2019 Sep 30.
Artigo em Chinês | MEDLINE | ID: mdl-31640949

RESUMO

OBJECTIVE: To study the expressions of the members of HSP110 family in the testis and epididymis of mice at different stages of development and whether they are regulated by hormones. METHODS: The testicular and epididymis tissues of mice at different ages (14, 21, 28, 35, 42, 49, 70, and 90 days after birth, 3 mice at each age) were collected for RT-PCR detection of the expression levels of HSP110 family members. Forty-eight mice were randomized into 3 groups for sham operation, castration, or castration with testosterone injections every other day (starting at 7 days after castration), and at 1, 3, 5, and 7 days after first testosterone injection, the expressions of HSP110 family in the epididymis were detected using RT-PCR. RESULTS: The mRNA expression levels of HSP110 family members underwent obvious variations with the development of the mice: HSPA4, HSPA4l and HSPH1 expressions in the testicles of the mice first increased and then decreased, and gradually became stable; they also exhibited similar temporal patterns of changes in the epididymis. In the castrated mice, the mRNA expressions of HSPA4 and HSPA4l in the epididymis decreased significantly with the reduction of serum hormone levels (P < 0.05), and became normal after the supplementation of exogenous hormone. CONCLUSIONS: The expression levels of HSP110 family are affected by developmental regulation, and the expressions of HSPA4 and HSPA4l are under the regulation by hormones.


Assuntos
Epididimo/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Choque Térmico HSP110/genética , Testículo/crescimento & desenvolvimento , Animais , Proteínas de Choque Térmico HSP110/metabolismo , Masculino , Camundongos , Orquiectomia , Testosterona/farmacologia
7.
Chem Biol Interact ; 312: 108817, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31499053

RESUMO

Aconitine might have reproductive toxicity and the effects of aconitine on androgen synthesis in Leydig cells remain unclear. Here, we explore how aconitine affects androgen synthesis and metabolism in rat immature Leydig cells in vitro. Immature Leydig cells were isolated from 35-day-old male Sprague Dawley rats and cultured with 0-50 µM aconitine for 3 h in combination with LH, 8Br-cAMP, 22R-hydroxycholesterol, pregnenolone, progesterone, androstenedione, testosterone, and dihydrotestosterone, respectively. Medium androgens were measured. The levels of Leydig cell mRNAs, Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Srd5a1, and Akr1c14, were measured by qPCR. ROS and apoptosis were determined after 24-h aconitine treatment. Aconitine inhibited basal androgen production in Leydig cells at 0.05 µM and the higher concentrations. Aconitine blocked pregnenolone, progesterone, and androstenedione mediated androgen outputs without affecting 22R-hydroxycholesterol-mediated androgen production at 5 µM. Aconitine also inhibited LH and 8Br-cAMP stimulated androgen outputs at 5 µM. Further investigation showed that aconitine blocked androgen synthesis via down-regulating the expression of Scarb1, Hsd3b1, Cyp17a1, and Hsd17b3. At 50 µM, aconitine also induced ROS generation and increased apoptotic rate of Leydig cells. Aconitine lowered serum testosterone levels at 1.5 mg/kg after 7 days of oral exposure from postnatal day 35. In conclusion, aconitine inhibits androgen synthesis.


Assuntos
Aconitina/farmacologia , Androgênios/metabolismo , Regulação para Baixo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptores do LH/genética , Receptores do LH/metabolismo , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Testosterona/sangue , Testosterona/farmacologia
8.
Anim Reprod Sci ; 208: 106116, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405452

RESUMO

Cryptorchidism, the failure of one or both testes to descend to an extra-abdominal location during mammalian development, is a common reproductive malady that often requires surgical intervention to remedy. Leydig cells are responsible for producing insulin-like peptide 3 (INSL3), a peptide hormone that is essential for normal testicular descent. The insl3 promoter in Leydig cells can be activated by cAMP through the transcription factor Nur77, which also regulates the promoters of the steroidogenic enzymes, cyp17 and 3ß-hsd. While the mechanism of LH action on testosterone production is well characterized, the effect of LH on insl3 abundance has not been described. The MA-10 Leydig cell line was used to test the hypothesis that abundance of insl3 mRNA is increased by LH/CG via the cAMP pathway. Cells treated with hCG had a transient robust increase in abundance of nur77 mRNA, while insl3 mRNA abundance remained unchanged. Further, while cAMP addition increased nur77 mRNA abundance, it failed to affect insl3 mRNA. Inhibition of LH-receptor-linked signal transduction pathways in the presence of hCG implicated multiple signaling networks in the regulation of both the insl3 and nur77 genes. Treatment with hCG and cAMP also increased abundance of cyp17 mRNA but not 3ß-hsd. Abundance of insl3 mRNA was not affected by hCG, testosterone or the combination of hCG and testosterone. Collectively, these results provide support for the constitutive regulation of insl3 mRNA abundance in the MA-10 Leydig cell line rather than acute regulation by LH/CG and cAMP.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/metabolismo , Células Intersticiais do Testículo/fisiologia , Proteínas/metabolismo , Animais , Linhagem Celular , Gonadotropina Coriônica/farmacologia , Flavonoides/farmacologia , Regulação da Expressão Gênica/fisiologia , Insulina/genética , Isoquinolinas/farmacologia , Masculino , Camundongos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Perileno/análogos & derivados , Perileno/farmacologia , Proteínas/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sulfonamidas/farmacologia , Testosterona/farmacologia , Wortmanina/farmacologia
9.
Physiol Biochem Zool ; 92(5): 459-462, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31365307

RESUMO

Maternal decisions on egg composition have major consequences for offspring. Maternal egg androgens have diverse, often contrasting, effects depending on offspring trait and life stage, suggesting that mothers face trade-offs in egg hormone transfer. However, the effect of egg androgens on embryonic telomere length, which is a major trait potentially affecting performance, has been never investigated. We administered a physiological dose of testosterone (T) to yellow-legged gull (Larus michahellis) eggs and found that, compared to controls, telomere length shortly before hatching was reduced in the liver but unaffected in the brain, heart, and pectoralis muscle. Telomere length varied across somatic tissues, and, independent of egg treatment, it was not correlated between them, suggesting independent telomere dynamics. Thus, we showed for the first time that increased egg T can increase telomere shortening in the embryo and that maternal T allocation strategies may evolve also in response to such effect. Moreover, contrary to observations in adult birds, at the embryonic stage telomere length in one somatic tissue may not reflect telomere length in other body districts.


Assuntos
Androgênios/farmacologia , Charadriiformes/embriologia , Embrião não Mamífero/efeitos dos fármacos , Homeostase do Telômero/efeitos dos fármacos , Testosterona/farmacologia , Androgênios/administração & dosagem , Animais , Óvulo , Telômero , Testosterona/administração & dosagem
10.
Environ Int ; 132: 105083, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31470217

RESUMO

INTRODUCTION: Human exposure to persistent organic pollutants (POPs) has been linked to genitourinary health-related conditions such as decreased sperm quality, hypospadias, and prostate cancer (PCa). Conventional risk assessment of POPs focuses on individual compounds. However, in real life, individuals are exposed to many compounds simultaneously. This might lead to combinatorial effects whereby the global effect of the mixture is different from the effect of the single elements or subgroups. POP mixtures may act as endocrine disruptors via the androgen receptor (AR) and potentially contribute to PCa development. AIM: To determine the endocrine disrupting activity of a POP mixture and sub-mixtures based upon exposure levels detected in a human Scandinavian population, on AR transactivation and translocation in vitro. MATERIALS AND METHODS: The Total POP mixture combined 29 chemicals modelled on the exposure profile of a Scandinavian population and 6 sub-mixtures: brominated (Br), chlorinated (Cl), Cl + Br, perfluorinated (PFAA), PFAA + Br, PFAA + Cl, ranging from 1/10× to 500× relative to what is found in human blood. Transactivation was measured by reporter gene assay (RGA) and translocation activity was measured by high content analysis (HCA), each using stably transfected AR model cell lines. RESULTS: No agonist activity in terms of transactivation and translocation was detected for any POP mixtures. In the presence of testosterone the Cl + Br mixture at 100× and 500× blood level antagonised AR transactivation, whereas the PFAA mixture at blood level increased AR transactivation (P < 0.05). In the presence of testosterone the Cl and PFAA + Br mixtures at 1/10×, 1×, and 50× blood level antagonised AR translocation (P < 0.05). CONCLUSION: Taken together, some combinations of POP mixtures can interfere with AR translocation. However, in the transactivation assay, these combinations did not affect gene transactivation. Other POP combinations were identified here as modulators of AR-induced gene transactivation without affecting AR translocation. Thus, to fully evaluate the effect of environmental toxins on AR signalling, both types of assays need to be applied.


Assuntos
Antagonistas de Receptores de Andrógenos/sangue , Disruptores Endócrinos/sangue , Poluentes Ambientais/sangue , Poluentes Ambientais/toxicidade , Receptores Androgênicos , Ativação Transcricional/efeitos dos fármacos , Antagonistas de Receptores de Andrógenos/toxicidade , Células Cultivadas , Disruptores Endócrinos/toxicidade , Genes Reporter , Humanos , Testosterona/farmacologia , Translocação Genética/efeitos dos fármacos
11.
Cell Physiol Biochem ; 53(1): 215-228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31299143

RESUMO

BACKGROUND/AIMS: With the prevalence of asthma being greater in women, detrimental effects of female sex steroids have been explored, but potential protective effects of androgens are not established. Airway smooth muscle (ASM) is a key cell type in contractility and remodelling of asthma. There are no data on expression and functionality of androgen receptor (AR) in human ASM cells. METHODS: We used primary human ASM cells from non-asthmatics vs. asthmatics to determine AR expression at baseline and with inflammation measured using Western blotting/qRT-PCR, and the role of AR in regulating intracellular Ca2+ ([Ca2+]i) measured using Fluo-3 loaded real time [Ca2+]i imaging. RESULTS: We found that compared to females, baseline AR is greater in male ASM and increases with inflammation/asthma. Androgens, via AR, blunted TNFα or IL-13-induced enhancement of ASM [Ca2+]i in both males and females, with retained efficacy in asthmatics. AR effects involve reduced Ca2+ influx via L-type channels and store-operated Ca2+ entry, the latter by downregulating STIM1 and Orai1 and increasing TMEM66. CONCLUSION: Our data show AR expression is increased in female ASM with asthma, but has retained functionality that could be used to reduce [Ca2+]i towards alleviating airway hyperresponsiveness.


Assuntos
Cálcio/metabolismo , Receptores Androgênicos/metabolismo , Asma/metabolismo , Asma/patologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Interleucina-13/farmacologia , Masculino , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Androgênicos/química , Receptores Androgênicos/genética , Fatores Sexuais , Molécula 1 de Interação Estromal/metabolismo , Testosterona/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
12.
Theriogenology ; 138: 47-51, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31284221

RESUMO

To test the hypothesis that postnatal sexual steroids induce an impairment of domestic male cat reproductive function, this study describes the physical, endocrine, steroidogenical and histological effects of a single, high dose of a postnatal sexual steroid in this species. Twenty male kittens were randomly assigned within the first 24 h of birth to: Testosterone enanthate 12.5 mg sc (TE; n = 8), medroxyprogesterone acetate 10 mg sc (MA; n = 6), or Placebo sc (PL; n = 6). The cats were followed until puberty when they were castrated. Kittens achieved puberty without age differences among groups (P > 0.05). Two MA cats presented abnormal testicular descent. Histological evaluation of the MA (P < 0.01), but not of TE testes revealed decreased diameter (P < 0.01) and epithelial height (P < 0.01) of the seminiferous tubules. Leydig cell nuclear area was also reduced in this group. Conversely, tubular/intertubular ratio was increased in TE animals (P < 0.01). Quantitative real-time PCR analysis of mRNA expression of testicular tissue revealed no significant differences among groups for StAR, CYP17A1 and androgen receptors. TE animals showed decreased CYP19A1 mRNA expression (P < 0.05). In the first 4 postnatal weeks, fecal testosterone (T) values were high, basal and intermediate in TE, MA and PL (P < 0.05), respectively. These differences progressively diminished and the three groups presented basal T concentrations from the 7th week on (P > 0.05). It was concluded that the postnatal progestagen initially suppressed the gonadal axis and caused an impairment of spermatogenesis and testicular descent at puberty. Androgen treatment caused downregulation of the final steroidogenic cascade.


Assuntos
Disruptores Endócrinos/farmacologia , Reprodução/efeitos dos fármacos , Esteroides/farmacologia , Testículo/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Testosterona/análogos & derivados , Animais , Animais Recém-Nascidos , Constituição Corporal/efeitos dos fármacos , Gatos , Anticoncepção/métodos , Anticoncepção/veterinária , Hormônios Esteroides Gonadais/farmacologia , Masculino , Reprodução/fisiologia , Maturidade Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testosterona/farmacologia
13.
Biomed Res Int ; 2019: 3426092, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281833

RESUMO

Anxiety is one of the most frequent psychiatric disorders. Despite the fact that most studies describe an anxiolytic effect of testosterone, hyperandrogenemia in mothers is assumed to be related to an increased risk of mood disorders in their offspring. An increasing body of scientific evidence suggests that an altered expression of interneuronal markers of the hippocampus may be the cause of anxiety. The aim of this study was to examine the influence of maternal hyperandrogenemia on behavioral parameters of anxiety-like behavior, neuropeptide Y (NPY) and parvalbumin (PV) expression in the hippocampus, and the level of the brain-derived neurotrophic factor (BDNF) in the hippocampus and cerebral cortex. Pregnant female Wistar albino rats were treated with testosterone undecanoate on the 20th day of gestation. Anxiety-like behavior in adult female offspring was evaluated by the elevated plus maze test and the open field. The number of PV and NPY immunoreactive cells in the hippocampus was determined immunohistochemically. The level of BDNF expression in the hippocampus and cerebral cortex was analyzed with the Western blot test. Prenatal hyperandrogenization increased anxiety-like behavior in female offspring and decreased expression of NPY+ and PV+ in the CA1 region of the hippocampus as compared to the control group. BDNF expression in the hippocampus and cerebral cortex of prenatally androgenized female offspring was significantly increased in comparison with the controls. Prenatal hyperandrogenization may be the cause of anxiety-like behavior in female offspring. Decrease in NPY and PV expression in the hippocampus may explain the possible mechanism of hyperandrogenization induced anxiety.


Assuntos
Ansiedade/etiologia , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Interneurônios/fisiologia , Inibição Neural/fisiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Virilismo/complicações , Animais , Ansiedade/sangue , Ansiedade/fisiopatologia , Estradiol/sangue , Feminino , Hipocampo/fisiopatologia , Aprendizagem em Labirinto , Neuropeptídeo Y/metabolismo , Parvalbuminas/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos Wistar , Testosterona/administração & dosagem , Testosterona/sangue , Testosterona/farmacologia , Virilismo/fisiopatologia
14.
J Physiol Sci ; 69(5): 791-798, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301005

RESUMO

Serum testosterone concentration decreases with age in humans and rodents. Accordingly, old male mice show changes in locomotor activity rhythms: a lengthened free-running period and decreased activity levels among others. To investigate whether testosterone replacement improves the age-related decline in circadian rhythmicity, we examined the effects of testosterone on the circadian rhythms of wheel running activity in old male mice. Intact male C57BL/6J mice (18-22 months old) were subcutaneously implanted with silicone tubes packed with testosterone propionate (TP) or cholesterol. TP treatment significantly decreased the daily wheel running revolutions in a normal light/dark (LD) cycle and in constant darkness (DD), but did not affect the free-running period. The same experiment performed on young male gonadectomized mice (3-5 months old) demonstrated that TP treatment significantly increased activity levels in both LD and DD. These results suggest that testosterone replacement exacerbates the age-related decline in circadian rhythmicity.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Testosterona/farmacologia , Animais , Escuridão , Luz , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Fotoperíodo
15.
Eur J Med Chem ; 179: 660-666, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279298

RESUMO

Prostate cancer is the most diagnosed type of cancer in men in Canada. One out of eight men will be stricken with this disease during the course of his life. It is noteworthy that, at initial diagnoses 80-90% of cancers are androgen dependent. Hence, the androgen receptor is a viable biological target to be considered for drug targeting. We have developed a new generation of testosterone-Pt(II) hybrids for site-specific treatment of hormone-dependent prostate cancer. The hybrid molecules are made from testosterone using an eight-step reaction sequence with about 7% overall yield. They are linked with a stronger tether chain between the testosterone moiety and the Pt(II) moiety in comparison to our first generation hybrids. The new hybrids were tested on hormone-dependent and -independent prostate cancer cell lines. The hybrid 3a presents the best antiproliferative activity and was selective on hormone-dependent prostate cancer with IC50 of 2.2 µM on LNCaP (AR+) in comparison to 13.3 µM on PC3 (AR-) and 8.8 µM on DU145 (AR-) prostate cancer cells. On the same cell lines, CDDP displayed IC50 of 2.1 µM, 0.5 µM and 1.0 µM, respectively. Remarkably, hybrid 3a was inactive on both colon carcinoma (HT-29) and normal human adult keratinocyte cells (HaCat) with an IC50 of >25 µM. This is not the case for CDDP showing IC50 of 1.3 µM and 5.1 µM on HT-29 and HaCat cells, respectively. The potential for selective activity on androgen-receptor positive prostate cancer cells is confirmed with hybrid 3a giving new hope for an efficient and less toxic platinum-based treatment of prostate cancer patients.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Compostos Organoplatínicos/farmacologia , Platina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Testosterona/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Platina/química , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Testosterona/química
16.
Nat Hum Behav ; 3(8): 856-866, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31332298

RESUMO

Moral dilemma judgements frequently involve decisions where moral norms and the greater good are in conflict. The current preregistered study tested the effect of the steroid hormone testosterone on moral dilemma judgements using a double-blind administration of testosterone or placebo. Counter to predictions, testosterone administration led to increased inaction in moral dilemmas where harmful actions prohibited by moral norms increase overall well-being. Using a mathematical model to disentangle sensitivity to consequences, sensitivity to moral norms and general preference for inaction versus action, analyses further revealed that testosterone administration influenced judgements by increasing sensitivity to moral norms. Exploratory analyses suggested the opposite pattern for endogenous testosterone measured at baseline, in that higher levels of endogenous testosterone were associated with lower sensitivity to moral norms. The results indicate that the role of testosterone in moral judgements is more complex than suggested by previous findings. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 13 November 2017. The protocol, as accepted by the journal, can be found at https://osf.io/rysbe/ 1.


Assuntos
Androgênios/farmacologia , Tomada de Decisões/efeitos dos fármacos , Teoria Ética , Julgamento/efeitos dos fármacos , Princípios Morais , Testosterona/farmacologia , Adolescente , Método Duplo-Cego , Feminino , Humanos , Masculino , Normas Sociais , Adulto Jovem
17.
Oxid Med Cell Longev ; 2019: 2985956, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182991

RESUMO

Dehydroepiandrosterone (DHEA) is a popular dietary supplement that has well-known benefits in animals and humans, but there is not enough information about the mechanisms underlying its effects. The present study aimed at investigating these mechanisms through in vitro experiments on the effects of DHEA on rat liver BRL-3A cells exposed to oxidative stress through H2O2. The findings showed that DHEA increased the antioxidant enzyme activity, decreased ROS generation, and inhibited apoptosis in H2O2-treated cells. These effects of DHEA were not observed when the cells were pretreated with known antagonists of sex hormones (Trilostane, Flutamide, or Fulvestrant). Furthermore, treatment with estradiol and testosterone did not have the same protective effects as DHEA. Thus, the beneficial effects of DHEA were associated with mechanisms that were independent of steroid hormone pathways. With regard to the mechanism underlying the antiapoptotic effect of DHEA, pretreatment with DHEA was found to induce a significant decrease in the protein expression of Bax and caspase-3 and a significant increase in the protein expression of PI3K and p-Akt in H2O2-treated BRL-3A cells. These effects of DHEA were abolished when the cells were pretreated with the PI3K inhibitor LY294002. No changes were observed on the p-ERK1/2, p-p38, and p-JNK protein levels in H2O2-induced BRL-3A cells pretreated with DHEA. In conclusion, our data demonstrate that DHEA protects BRL-3A cells against H2O2-induced oxidative stress and apoptosis through mechanisms that do not involve its biotransformation into steroid hormones or the activation of sex hormone receptors. Importantly, the protective effect of DHEA on BRL-3A cells was mainly associated with PI3K/Akt signaling pathways, rather than MAPK signaling pathways.


Assuntos
Desidroepiandrosterona/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antioxidantes/metabolismo , Linhagem Celular , Di-Hidrotestosterona/análogos & derivados , Di-Hidrotestosterona/farmacologia , Estradiol/farmacologia , Flutamida/farmacologia , Fulvestranto/farmacologia , Peróxido de Hidrogênio/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Radioimunoensaio , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Testosterona/farmacologia
18.
Endocrinology ; 160(8): 1937-1949, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31180495

RESUMO

The risk of adverse perinatal outcomes with maternal polycystic ovary syndrome may differ among hyperandrogenic and nonhyperandrogenic phenotypes and is likely modulated by maternal obesity and diet. The relative contribution of maternal hyperandrogenism and nutritional status to placental dysfunction is unknown. Female rhesus macaques (N = 39) were assigned at puberty to one of four treatment groups: subcutaneous cholesterol implants and a standard chow diet (controls); testosterone (T) implants and a normal diet; cholesterol implants and a high-fat, Western-style diet (WSD); and testosterone implants in combination with a high-fat diet. After 3.5 years of treatment, contrast-enhanced and Doppler ultrasound analyses of placental blood flow were performed for a representative subset of animals from each treatment group during pregnancy, and placental architecture assessed with stereological analysis. Placental growth factors, cellular nutrient sensors, and angiogenic markers were measured with ELISA and Western blotting. WSD consumption was associated with a 30% increase in placental flux rate relative to that in animals receiving a normal diet. T and WSD treatments were each independently associated with increased villous volume, and T also was associated with an ∼ 40% decrease fetal capillary volume on stereological analysis. T treatment was associated with significantly increased mTOR and SOCS3 expression. WSD consumption was associated with decreased GLUT1 expression and microvillous membrane localization. Hyperandrogenemic and nonhyperandrogenemic phenotypes are associated with altered placental angiogenesis, nutrient sensing, and glucose transport. WSD and T appear to have distinct effects on vascular impedance and capillary angiogenesis.


Assuntos
Dieta Hiperlipídica , Hiperandrogenismo/complicações , Placenta/fisiopatologia , Animais , Doença Crônica , Dieta Ocidental , Feminino , Transportador de Glucose Tipo 1/análise , Macaca mulatta , Placenta/irrigação sanguínea , Placenta/patologia , Síndrome do Ovário Policístico/complicações , Gravidez , Testosterona/farmacologia
19.
J Physiol Pharmacol ; 70(1)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31172974

RESUMO

Within the mammalian reproductive system sirtuin 1 and 6 (SIRT1, SIRT6) are considered to contribute to steroid hormone signaling and control of reproductive physiology. Therefore, the specific question is whether and how a commonly used dicarboximide fungicide with antiandrogenic activity, vinclozolin (Vnz) alters SIRT1 and SIRT6 expression and whether both investigated sirtuins positively affect survival of the follicles after vinclozolin exposure. Immunocytochemistry and immunohistochemistry were performed to localize SIRT1 and SIRT6 expression in cultured granulosa cells (GCs; 48 hours) and whole ovarian follicles (24 hours) after treatment with two androgens, testosterone (T; 10-7 M) and dihydrotestosterone (DHT; 10-7 M), and an antiandrogen, Vnz (1.4 x 10-5 M), separately and in combinations. Granulosal and follicular mRNA and protein expression of both sirtuins was also investigated by real-time PCR and Western blot. In addition, their concentration and activity was studied by immunoenzymatic and fluorescence assays. Our observations: (1) demonstrate the presence of both investigated sirtuins in ovarian cells, (2) show their potential involvement in the control of follicular atresia because of increased SIRT1/SIRT6 expression and SIRT1 activity after exposure to Vnz, (3) represent the first data on the interrelationships between sirtuins and androgens in porcine ovarian cells. Based on these findings and our previous results we can conclude, that SIRT1 and SIRT6 do not exert the protective effects in ovarian follicles after vinclozolin exposure. These novel data on the role of SIRT1/SIRT6 in porcine ovarian follicles shows that in the presence of the investigated fungicide, sirtuins are upregulated, which can induce apoptosis of follicular cells. Furthermore the androgen receptor sensitivity to ligands, especially environmental ones (for example: vinclozolin) might be directly linked with the mechanism of action of both investigated sirtuins in the porcine ovary, which requires further investigation.


Assuntos
Antagonistas de Androgênios/farmacologia , Ovário/efeitos dos fármacos , Oxazóis/farmacologia , Sirtuínas/metabolismo , Androgênios/farmacologia , Animais , Di-Hidrotestosterona/farmacologia , Feminino , Ovário/metabolismo , Sirtuínas/genética , Suínos , Testosterona/farmacologia
20.
Eur J Pharmacol ; 858: 172382, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31112710

RESUMO

Breast cancer is one of the main diagnosis cancers annually worldwide. It is difficult to thorough cure due to drug resistance and the high possibility of metastasis. SM934 is a novel water-soluble artemisinin analog, and has been reported to have a promising therapeutic effect on multiple autoimmune diseases. In this study, SM934 was combined with Testosterone, which is related to prostate cancer, and the reaction product was SM934-Testosterone. We aimed to explore whether SM934, Testosterone and SM934-Testosterone could inhibit tumorigenesis and metastasis of breast cancer cells. Moreover, the mechanism also remains to be clarified. The results of our study showed that among the three compounds, only SM934-Testosterone treatment could lead to the suppression of cell proliferation and metastasis with IC50 = 30.66 ±â€¯2.13 µM at 24 h in MDA-MB-231 and IC50 = 31.11 ±â€¯1.79 µM at 24 h in SK-BR-3, where apoptosis was induced. But SM934-Testosterone showed little effects on breast cancer in vivo due to its poor water-solubility. Furthermore, computational target prediction and experimental validation demonstrated that Cathepsin K was the target of SM934-Testosterone. SM934-Testosterone inhibited the expression of Cathepsin K in breast cancer cells. Then, down-regulation of Cathepsin K in cancer cells by transfected with Cathepsin K shRNA inhibited cell proliferation and metastasis of breast cancer cells. Moreover, pathway enrichment was performed to understand the mechanism of action that Cathepsin K could adjust apoptosis regulator Bcl-X, and knockdown of Cathepsin K by SM934-Testosterone resulted in the reduction of Bcl-xL, which has been reported to be related to the proliferation and metastasis of cells. Collectively, SM934-Testosterone inhibited proliferation and metastasis ability of breast cancer cells via inhibiting the expression of Cathepsin K followed by the inhibition of Bcl-xL.


Assuntos
Artemisininas/farmacologia , Neoplasias da Mama/patologia , Catepsina K/genética , Regulação para Baixo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Metástase Neoplásica , Testosterona/farmacologia , Proteína bcl-X/metabolismo
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