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1.
Endocrinology ; 160(10): 2471-2484, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398247

RESUMO

Prenatal testosterone (T)-treated sheep, similar to women with polycystic ovary syndrome (PCOS), manifest oligo-/anovulation, hyperandrogenism, and polyfollicular ovary. The polyfollicular ovarian morphology, a result of persistence of antral follicles, arises, in part, by transcriptional changes in key mediators of follicular development that, in turn, are driven by epigenetic mechanisms. We hypothesized that prenatal T excess induces, in a cell-specific manner, transcriptional changes in key mediators of follicular development associated with relevant changes in epigenetic machinery. Expression levels of key mediators of follicular development, DNA methyltransferases (DNMTs), and histone de-/methylases and de-/acetylases were determined in laser-capture microdissection-isolated antral follicular granulosa and theca and ovarian stromal cells from 21 months of age control and prenatal T-treated sheep (100 mg IM twice weekly from gestational day 30 to 90; term: 147 days). Changes in histone methylation were determined by immunofluorescence. Prenatal T treatment induced the following: (i) cell-specific changes in gene expression of key mediators of follicular development and steroidogenesis; (ii) granulosa, theca, and stromal cell-specific changes in DNMTs and histone de-/methylases and deacetylases, and (iii) increases in histone 3 trimethylation at lysine 9 in granulosa and histone 3 dimethylation at lysine 4 in theca cells. The pattern of histone methylation was consistent with the expression profile of histone de-/methylases in the respective cells. These findings suggest that changes in expression of key genes involved in the development of the polyfollicular phenotype in prenatal T-treated sheep are mediated, at least in part, by cell-specific changes in epigenetic-modifying enzymes.


Assuntos
Epigênese Genética/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Síndrome do Ovário Policístico/veterinária , Doenças dos Ovinos/induzido quimicamente , Propionato de Testosterona/toxicidade , Animais , Feminino , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ovinos , Doenças dos Ovinos/metabolismo
2.
Int J Dev Neurosci ; 78: 33-44, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31400491

RESUMO

To further reveal the molecular mechanism underlying sexual differentiation of the mouse cerebral cortex and hippocampus, we reanalyzed our previous microarray study with Gene Ontology (GO) term enrichment and found that the GO term "RNA binding" was over-represented among the 89 sexually dimorphic candidate genes. Thus, we selected 16 autosomal genes annotated to the term RNA binding and profiled their mRNA expression in the developing male and female mouse cortex/hippocampus. During the first three weeks after birth, sex differences in mRNA levels of Khdrbs2, Nanos2, Rbm48, and Tdrd3 were observed in the mouse cortex/hippocampus. Of these genes, only the female-biased expression of Rbm48 in neonates was abolished by prenatal exposure to testosterone propionate (TP), while postnatal treatment of TP three weeks after birth increased Rbm48 and Tdrd3 mRNA levels in both sexes. Regardless of sex, the postnatal cortex/hippocampus also showed a marked increase in the content of androgen receptor (Ar) and estrogen receptor ß (Esr2), but a decrease in estrogen receptor α (Esr1) and aromatase (Cyp19a1), which might confer the different responses of Rbm48 to prenatal and postnatal TP. Our results suggest that androgen-regulated, sexually dimorphic Rbm48 expression might present a novel molecular mechanism by which perinatal androgens control development of sexual dimorphism in cortical and hippocampal structure and function.


Assuntos
Androgênios/farmacologia , Córtex Cerebral/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Propionato de Testosterona/farmacologia , Animais , Aromatase/metabolismo , Córtex Cerebral/metabolismo , Feminino , Hipocampo/metabolismo , Masculino , Camundongos , Proteínas/genética , Proteínas/metabolismo , Proteínas de Ligação a RNA/genética , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Caracteres Sexuais , Fatores Sexuais
3.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1953-1959, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342726

RESUMO

In this study,mouse models of benign prostatic hyperplasia induced by subcutaneous injection of testosterone propionate was used to investigate the therapeutic effect and mechanism of Urtica hyperborean( UW) extracts on prostate hyperplasia in mice. The effects of UW extracts on prostate index,serum epidermal growth factor( EGF) and dihydrotestosterone( DHT) in model mice were observed,and the EGF and anti-apoptotic factor( Bcl-2) mRNA expression levels were detected as well as pathological changes in prostate tissue. The results showed that the ethyl acetate extraction and alcohol soluble fraction of the UW could significantly reduce the prostate index,reduce the serum DHT and EGF levels( P<0. 01),and significantly decrease the EGF and Bcl-2 mRNA expression( P<0. 01),significantly improved the morphological structure of prostate tissue. The above results confirmed that ethyl acetate extract and alcohol-soluble parts of UW have a good preventive effect on mice prostatic hyperplasia model,and its mechanism may be to reduce androgen levels by regulating polypeptide growth factors and/or inhibiting cell hyperproliferation and promoting apoptosis. This study laid the foundation for the further research on UW.


Assuntos
Medicina Tradicional Tibetana , Extratos Vegetais/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Urticaceae/química , Animais , Di-Hidrotestosterona/sangue , Fator de Crescimento Epidérmico/sangue , Masculino , Camundongos , Hiperplasia Prostática/induzido quimicamente , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Propionato de Testosterona
4.
Am J Physiol Heart Circ Physiol ; 317(2): H243-H254, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31149843

RESUMO

Vessels of female rats constrict less and relax more to adrenergic stimulation than vessels of males. Although we have reported that these sex-specific differences rely on endothelial ß-adrenoceptors, the role of sex hormones in ß-adrenoceptor expression and related vessel tone regulation is unknown. We investigated the role of estrogen, progesterone and testosterone on ß-adrenoceptor expression and adrenergic vessel tone regulation, along with sex-specific differences in human mammary arteries. The sex-specific differences in vasoconstriction and vasorelaxation in rat vessels were eliminated after ovariectomy in females. Ovariectomy increased vessel vasoconstriction to norepinephrine more than twofold. Vasorelaxations by isoprenaline and a ß3-agonist were reduced after ovariectomy. Estrogen, but not progesterone substitution, restored sex-specific differences in vasoconstriction and vasorelaxation. Vascular mRNA levels of ß1- and ß3- but not ß2-adrenoreceptors were higher in vessels of females compared with males. Ovariectomy reduced these differences by decreasing ß1- and ß3- but not ß2-adrenoreceptor expression in females. Consistently, estrogen substitution restored ß1- and ß3-adrenoreceptor expression. Orchiectomy or testosterone treatment affected neither vasoconstriction and vasorelaxation nor ß-adrenoceptor expression in vessels of male rats. In human mammary arteries, sex-specific differences in vasoconstriction and vasorelaxation were reduced after removal of endothelium or treatment with l-NMMA. Vessels of women showed higher levels of ß1- and ß3-adrenoceptors than in men. In conclusion, the sex-specific differences in vasoconstriction and vasorelaxation are common for rat and human vessels. In rats, these differences are estrogen but not testosterone or progesterone dependent. Estrogen determines these differences via regulation of vascular endothelial ß1- and ß3-adrenoreceptor expression. NEW & NOTEWORTHY This study proposes a mechanistic concept regulating sex-specific differences in adrenergic vasoconstriction and vasorelaxation. Estrogen increases vascular ß1- and ß3-adrenoceptor expression in female rats. This and our previous studies demonstrate that these receptors are located primarily on endothelium and when activated by norepinephrine act via nitric oxide (NO). Therefore, ß-adrenergic stimulation leads to a more pronounced vasorelaxation in females. Coactivation of endothelial ß1- and ß3-adrenoreceptors leads to higher NO release in vessels of females, ultimately blunting vasoconstriction triggered by activation of smooth muscle α-adrenoceptors.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Estradiol/administração & dosagem , Terapia de Reposição de Estrogênios , Artéria Torácica Interna/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Sistema Vasomotor/efeitos dos fármacos , Animais , Endotélio Vascular/metabolismo , Feminino , Humanos , Masculino , Artéria Torácica Interna/metabolismo , Pessoa de Meia-Idade , Orquiectomia , Ovariectomia , Progesterona/administração & dosagem , Ratos Wistar , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Fatores Sexuais , Transdução de Sinais , Propionato de Testosterona/administração & dosagem , Sistema Vasomotor/metabolismo
5.
Andrologia ; 51(9): e13344, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31206753

RESUMO

To investigate whether low androgen status affects erectile function by regulating the expression of adenosine A2A and A2B receptors in rat penile corpus cavernosum. Thirty-six 8-week-old male Sprague-Dawley rats were randomly divided into six groups: sham-operated group (4w-sham, 8w-sham), castration group (4w-cast, 8w-cast) and androgen replacement group (4w-cast+T, 8w-cast+T). The rats in the androgen replacement groups were subcutaneously injected with testosterone propionate (3 mg/kg) every other day after castration. The maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP), the expression of A2A , A2B , AKT and eNOS and the concentrations of cAMP and cGMP in the corpus cavernosum were detected at the 4th and 8th weeks after the operation. The serum testosterone level and the ratio of ICPmax/MAP decreased significantly in the castration group as compared to other groups (p < 0.01). There was no significant difference in the expression of A2A receptor among groups, while the expression of A2B , AKT and eNOS and the concentrations of cAMP and cGMP in the castration group were significantly lower than in other groups (p < 0.01). Low androgen status inhibits the AKT/eNOS/cGMP signalling pathways and the production of cAMP in the corpus cavernosum of castrated rats by down-regulating the expression of A2B receptor, and results in decreased of ICPmax/MAP.


Assuntos
Androgênios/metabolismo , Disfunção Erétil/fisiopatologia , Pênis/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismo , Androgênios/sangue , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/etiologia , Terapia de Reposição Hormonal/métodos , Humanos , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Orquiectomia/efeitos adversos , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/fisiologia , Pênis/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Propionato de Testosterona/administração & dosagem
6.
Probl Endokrinol (Mosk) ; 65(1): 19-30, 2019 05 14.
Artigo em Russo | MEDLINE | ID: mdl-31091047

RESUMO

BACKGROUND: Anabolic androgenic steroids (AASs) are often used by individuals engaged in physical recreational activity. AASs inhibit the hypothalamus-pituitary-gonad axis and can cause erectile dysfunction and reduced fertility. There is no data on the use of AASs in this category of people in the Russian Federation; therefore, a study exploring the rate and patterns of using steroids for non-medical purposes is topical. Aim - of this study was to investigate the rate and patterns of using AASs in males attending gyms in Saint Petersburg. MATERIAL AND METHODS: We used individual anonymous postal survey of males attending gyms. We analyzed demographic and anthropometric data, information on the use of AASs, awareness of their side effects, used agents, patterns and duration of their use, and rehabilitation therapy. RESULTS: Out of 1,815 sent questionnaires, we received back 762 ones. The criteria were met by 550 questionnaires. The mean age was 29.3±7.4 years. The use of AASs was reported by 30.4% of respondents. The main AAS (74.3%) consumers were males aged 22 to 35 years. The most popular drug was Testosterone Propionate (51.5%); the drug was often combined with Oxandrolone (19.7%). In 70.6% of cases, drugs were administered by injection or injection combined with tablet intake. The injectable testosterone dose ranged from 500 to 2,000 mg/week and above. The most common dose was 1,000 mg/week (23.9%). AAS administration for more than 1 year was reported in 16.1% of males. Anastrozole (55%), hCG (51.3%), Clomiphene (41.3%), and Tamoxifen (30.5%) were used during the recovery period. The main source of information on AASs, doses, and dosage patterns was the Internet (48.7%). A negative attitude towards AASs was found in 17.3% of respondents. The desire to receive qualified information about AASs and their impact on health was reported by 54.8% of the surveyed respondents. CONCLUSION: Almost every fourth gym visitor has experience in using AASs. These are males of an optimal reproductive age. The common pattern of using AASs is an aggressive steroid course followed by a recovery period. The list of used drugs and their doses indicate a significant pharmacological intervention and a high risk to health.


Assuntos
Anabolizantes/administração & dosagem , Androgênios/administração & dosagem , Atletas/estatística & dados numéricos , Uso de Medicamentos/estatística & dados numéricos , Exercício Físico , Oxandrolona/administração & dosagem , Propionato de Testosterona/administração & dosagem , Adulto , Anabolizantes/efeitos adversos , Androgênios/efeitos adversos , Atletas/psicologia , Conscientização , Esquema de Medicação , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Oxandrolona/efeitos adversos , Federação Russa , Autoadministração/estatística & dados numéricos , Automedicação/estatística & dados numéricos , Inquéritos e Questionários , Propionato de Testosterona/efeitos adversos
7.
Exp Parasitol ; 202: 15-21, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31078550

RESUMO

Toxoplasma gondii is an opportunistic zoonotic protozoan that exceeds neurological and congenital impact sequence to reactivating latent toxoplasmosis especially under immunosuppression. Sex-associated hormones influence the severity of Toxoplasma infection. Thus, our study aimed to compare toxoplasmosis associated morbidity in both male and female mice and to monitor the response to anti-Toxoplasma therapeutics fortified with sex hormones in comparison to presently used drugs. Twenty male and 20 female mice were infected with ME49 Toxoplasma strain. The morbidity was assessed in the chronic stage in both sexes by estimating brain cyst burden, brain histopathological examination and monitoring serum anti-Toxoplasma IL-12 using ELISA method. Another 40 male and 40 female mice were infected with ME49 Toxoplasma strain then after 6 weeks received different treatment regimens including Atovaquone, Spiramycin, Metronidazole, Estradiol benzoate and Testoserone propionate either as a monotherapy or as a combination. Treatment response was monitored by scoring mice activity and brain cyst burden. This study showed that female mice demonstrated higher cyst burden and manifested more pathological reactions than male mice. While, the IL-12 serum level was significantly higher in male than female mice. Also, it is proved that the Toxoplasma cyst number was reduced significantly when used testosterone/atovaquone, or testosterone/spiramycin/metronidazole combined regimen in female mice groups. While for male mice, the combined therapy of spiramycin/metronidazole was the superior one. Accordingly, combined therapy with sex hormones is a promising strategy for discovering new therapeutic regimens for treating latent toxoplasmosis especially in female.


Assuntos
Coccidiostáticos/uso terapêutico , Toxoplasmose Animal/epidemiologia , Animais , Anticorpos Antiprotozoários/sangue , Atovaquona/uso terapêutico , Encéfalo/parasitologia , Encéfalo/patologia , Doença Crônica , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Estradiol/análogos & derivados , Estradiol/uso terapêutico , Feminino , Imunoglobulina G/sangue , Interleucina-12/sangue , Masculino , Metronidazol/uso terapêutico , Camundongos , Morbidade , Fatores Sexuais , Espiramicina/uso terapêutico , Propionato de Testosterona/uso terapêutico , Toxoplasma/fisiologia , Toxoplasmose Animal/tratamento farmacológico
8.
Biol Pharm Bull ; 42(1): 1-9, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30381617

RESUMO

Veratrum maackii (VM), a perennial plant in the Melanthiaceae family, has anti-hypertensive, anti-cholinergic, anti-asthmatic, anti-tussive, anti-fungal, anti-melanogenesis, and anti-tumor activities. Here, we investigated the therapeutic effect of VM on benign prostatic hyperplasia (BPH) in human normal prostate cell line (WPMY-1) and a testosterone propionate-induced BPH animal model. WPMY-1 cells were treated with VM (1-10 µg/mL) and testosterone propionate (100 nM). BPH in rats was generated via daily subcutaneous injections of testosterone propionate (3 mg/kg) dissolved in corn oil, for 4 weeks. VM (150 mg/kg) was administered daily for 4 weeks by oral gavage concurrently with the testosterone propionate. All rats were sacrificed and the prostates were dissected, weighed, and subjected to histological, immunohistochemical, and biochemical examinations. Immunoblotting experiments indicated that WPMY-1 cells treated testosterone propionate had increased expression of prostate specific antigen (PSA) and androgen receptor (AR), and treatment with VM or finasteride blocked this effect. In rat model, VM significantly reduced prostate weight, prostatic hyperplasia, prostatic levels of dihydrotestosterone (DHT), and expression of proliferation markers such as proliferating cell nuclear antigen (PCNA) and cyclin D1, but increased the expression of pro-apoptotic Bcl-2-associated X protein (Bax) and the cleavage of caspase-3. VM administration also suppressed the testosterone propionate-induced activation of nuclear factor-kappaB (NF-κB). Our results indicate that VM effectively represses the development of testosterone propionate-induced BPH, suggesting it may be a useful treatment agent for BPH.


Assuntos
Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Propionato de Testosterona/toxicidade , Veratrum , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Hiperplasia Prostática/patologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
9.
Andrologia ; 51(1): e13167, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30295340

RESUMO

The aim of this study was to investigate the relationship between sulphur dioxide (SO2 ) signalling pathway and the changes in erectile function under low androgen levels. Thirty-six healthy male Sprague Dawley (SD) rats aged eight weeks were randomly divided into androgen replacement group, castration group and sham group. Rats in the androgen replacement group were subcutaneously injected with testosterone propionate at 3 mg/kg every other day postcastration. The maximum intracavernous pressure/mean arterial pressure (ICPmax /MAP) and the relative content of SO2 in the penile corpus cavernosum were measured. The mRNA and protein expressions of aspartate aminotransferase (AAT1 and AAT2), cysteine oxidase (CDO), endothelial nitric oxide synthase (eNOS) and phosphorylation of endothelial nitric oxide synthase (P-eNOS) were detected. ICPmax /MAP, P-eNOS/eNOS and the level of SO2 decreased significantly in the castration group compared to the other groups (p < 0.05). The expressions of mRNA and protein decreased significantly in the castration group compared to the androgen replacement group and the sham group (p < 0.05), while there was no significant difference between the androgen replacement group and sham group. Low androgen levels can inhibit erectile function by downregulating the SO2 signalling pathway.


Assuntos
Androgênios/sangue , Ereção Peniana/fisiologia , Pênis/metabolismo , Transdução de Sinais/fisiologia , Dióxido de Enxofre/metabolismo , Propionato de Testosterona/farmacologia , Androgênios/farmacologia , Animais , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Ereção Peniana/efeitos dos fármacos , Pênis/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
10.
Physiol Behav ; 203: 70-80, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29106989

RESUMO

Alcohol use disorder (AUD) is a chronic, relapsing disease characterized by maladaptive patterns of alcohol drinking and seeking. Though sex differences exist in the etiology of AUD, much remains to be elucidated concerning the mechanisms underlying sex-related vulnerability to developing excessive alcohol-motivated behavior. While a large body of evidence points to an important role of circulating gonadal hormones in mediating cocaine reinforcement, findings are less consistent with respect to ethanol. Critically, the effects of gonadal hormones on the reinstatement of ethanol seeking, a model of "craving"-like behavior that reveals pronounced sex differences, has not yet been examined. Thus, the goal of the present experiment was to directly compare manipulations of gonadal hormones in male and female rats on ethanol-motivated behavior. Rats received sham or gonadectomy surgery with or without hormone replacement prior to and throughout three weeks of operant ethanol self-administration to determine the effects of chronically high or low gonadal hormone levels on ethanol drinking. Hormone treatment ceased during extinction training, and the effects of an acute injection of either testosterone (in males) or estradiol (in females) on cue+yohimbine-induced reinstatement of ethanol seeking was determined. Separate groups of gonadally-intact female rats went through similar training, but the effects of either the antiestrogen, fulvestrant, the selective estrogen receptor modulator, clomiphene, or the estrogen receptor ß antagonist, PHTPP, on the reinstatement of ethanol seeking were determined. Chronic estradiol replacement produced significant increases in ethanol drinking in female rats, while chronic testosterone significantly decreased ethanol drinking in male rats. Gonadectomy alone only produced modest shifts in drinking towards the opposite-sex pattern, and did not eliminate the robust sex differences that persisted regardless of hormone manipulations. Neither prior chronic nor acute hormone manipulations altered cue+yohimbine-induced reinstatement of ethanol seeking, though blockade of estrogen receptors tended to reduce reinstatement in gonadally-intact females. Overall, our findings indicate that gonadal hormones at least partially mediate, but do not totally account for the sex differences evident in ethanol self-administration, and circulating gonadal hormones have little effect on the reinstatement of ethanol seeking. These results provide a foundation for future studies examining the neuronal mechanisms underlying sex differences in ethanol drinking and seeking.


Assuntos
Consumo de Bebidas Alcoólicas , Comportamento de Procura de Droga/efeitos dos fármacos , Estradiol/farmacologia , Etanol/administração & dosagem , Propionato de Testosterona/farmacologia , Ioimbina/farmacologia , Animais , Clomifeno/farmacologia , Sinais (Psicologia) , Antagonistas do Receptor de Estrogênio/farmacologia , Feminino , Fulvestranto/farmacologia , Masculino , Motivação/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Autoadministração , Caracteres Sexuais
11.
J Ethnopharmacol ; 233: 115-122, 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30508623

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ulmus macrocarpa Hance (UMH), of the family Ulmaceae, is a deciduous tree, widely distributed throughout Korea. UMH has been used as a traditional oriental medicine in Korea for the treatment of urological disorders, including bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), diuresis, and hematuria. To date, its possible protective effects against benign prostatic hyperplasia (BPH) have not been analyzed. AIM OF THE STUDY: This study investigated the effects of UMH on the development of BPH using a rat model of testosterone propionate (TP)-induced BPH. MATERIALS AND METHODS: BPH was induced by daily subcutaneous injections of testosterone propionate (TP) for four weeks. UMH was administrated daily by oral gavage at a dose of 150 mg/kg during the four weeks of TP injections. Animals were sacrificed, and their prostates were weighed and subjected to histopathological examination, TUNEL assay, and western blot analysis. RESULTS: Treatment of BPH-model rats with UMH significantly reduced prostate weight, serum testosterone concentration and dihydrotestosterone (DHT) concentration in prostate tissue. TP-induced prostatic hyperplasia and the expression of proliferating cell nuclear antigen (PCNA) were significantly attenuated in UMH-treated rats. In addition, UMH administration markedly induced the activation of caspases-3, - 8, and - 9 in prostate tissues of BPH rats, accompanied by upregulation of expression of Fas, Fas-associated protein with death domain (FADD), and Fas ligand (FasL) and a reduction in the ratio of B-cell lymphoma 2 (Bcl-2) to Bcl-2-associated X protein (Bax). CONCLUSIONS: UMH effectively inhibited the proliferation and promoted the apoptosis of prostate cells, suggesting it may be useful for the treatment of BPH.


Assuntos
Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Ulmus , Animais , Apoptose/efeitos dos fármacos , Di-Hidrotestosterona/metabolismo , Masculino , Fitoterapia , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Próstata/patologia , Próstata/fisiologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Ratos Sprague-Dawley , Testosterona/sangue , Propionato de Testosterona
12.
Psychoneuroendocrinology ; 102: 84-94, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30529907

RESUMO

Estrogens play important roles in regulating brain development, brain function, and behavior. Many studies have evaluated these effects using ovariectomized (OVX) rats or mice with different doses of estrogen replacement, assuming that estradiol levels in all regions of the brain are the same as levels achieved in the serum. It is well known, however, that the brain contains all the enzymes necessary to produce estrogens, and that estrogen levels in the brain are determined by both systemic and local production and are region-specific. The present study conducted a detailed analysis of the relationship between systemic levels of 17-ß-estradiol (E2) achieved by estrogen replacement and levels achieved in specific regions of the brain. Levels of E2 were measured in both brain and serum in OVX rats treated with different doses of estradiol benzoate (EB) using a novel and recently validated UPLC-MS/MS method. Results confirmed significantly higher levels of E2 in the brain than in serum in brain regions known to contain aromatase (ARO) activity, both in OVX controls and in rats treated with physiological doses of EB. Additional studies compared the level of E2 and testosterone (T) in the brain and serum between testosterone propionate (TP) treated OVX and male. This demonstrated higher levels of E2 in certain brain regions of males than in TP treated OVX females even though T levels in the brain and serum were similar between the two groups. Studies also demonstrated that the differences between serum and brain levels of E2 can be eliminated by letrozole (ARO inhibitor) treatment, which indicates that the differences are due to local ARO activity. Collectively the results provide a detailed analysis of brain region-specific E2 concentrations in OVX, E2-, and T-treated rats and demonstrate the degree to which these concentrations are ARO-dependent.


Assuntos
Encéfalo/metabolismo , Estradiol/análise , Estradiol/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Aromatase/metabolismo , Inibidores da Aromatase/metabolismo , Encéfalo/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cromatografia/métodos , Cromatografia Líquida/métodos , Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Estrogênios , Feminino , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Letrozol/farmacologia , Masculino , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos , Testosterona/farmacologia , Propionato de Testosterona
13.
Nutrients ; 10(12)2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30544543

RESUMO

Benign prostatic hyperplasia (BPH) is a common disease in the elderly male population throughout the world. Among other factors, androgen dysregulation has been known to play major roles in its pathogenesis. HX109 is a botanical formulation prepared from a mixture of Taraxacum officinale, Cuscuta australis, and Nelumbo nucifera, which have traditionally been used-usually along with other plants-to treat urinary diseases. An ethanol extract was prepared from a mixture of these three plants, and its quality was controlled through cell-based bioassays and by quantification of several marker compounds by high-performance liquid chromatography (HPLC). In the testosterone propionate (TP)-induced prostate hyperplasia rat model, oral administration of HX109 ameliorated prostate enlargement and histological changes induced by TP. In LNCaP cells, a human prostate epithelial cell line, HX109 repressed AR-mediated cell proliferation and the induction of androgen receptor (AR) target genes at the transcriptional level without affecting the translocation or expression of AR. Such effects of HX109 on AR signaling were mediated through the control of activating transcriptional factor 3 (ATF3) expression, phosphorylation of calcium/calmodulin-dependent protein kinase kinase ß (CaMKKß), and increases in intracellular calcium, as evidenced by data from experiments involving ATF3-specific siRNA, CaMKKß inhibitor, and calcium chelator, respectively. Taken together, our data suggest that HX109 might be used as a starting point for developing therapeutic agents for the treatment of BPH.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Preparações de Plantas/farmacologia , Hiperplasia Prostática , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Propionato de Testosterona/efeitos adversos
14.
Endocrinology ; 159(12): 4056-4064, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30376052

RESUMO

The main clinical feature associated with hyperandrogenism in polycystic ovary syndrome (PCOS) in humans is hirsutism, where hair increases its length, pigmentation, and particularly its diameter. Currently, it is not known whether PCOS animal models also exhibit changes in the hair. Therefore, the aim of this study was to explore the wool characteristics in sheep prenatally androgenized (PA) with testosterone propionate. After 4 and 13 months of life, wool was collected from the top of the shoulder of both females and males (both androgenized and controls). The offspring sheep were followed for up to 19 months of life to evaluate testosterone and androstenedione serum levels by ultra-high-performance liquid chromatography-tandem mass spectrometry, determine insulin and glucose response to intravenous glucose tolerance test, and address estrus cyclicity during the second breeding season. PA male animals showed a reduction in wool fiber diameter at 4 months of age compared with controls (P = 0.02) but not at 13 months, whereas PA females showed increased hair diameter at 13 months (P = 0.002), with no difference at 4 months. No substantial changes in other hair parameters (length, color, and medullation) were identified. In addition, increased levels of serum testosterone were observed in PA female sheep compared with controls at 12 months (P = 0.03). Our results indicate for the first time, to our knowledge, that changes in wool fiber diameter observed in PA ewes replicate, at the translational level, the increase in hair diameter in hirsute women with PCOS.


Assuntos
Androgênios , Modelos Animais de Doenças , Hirsutismo , Síndrome do Ovário Policístico , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ovinos , Virilismo/induzido quimicamente , Animais , Feminino , Teste de Tolerância a Glucose , Hirsutismo/sangue , Hirsutismo/induzido quimicamente , Hirsutismo/complicações , Hirsutismo/patologia , Hiperandrogenismo/sangue , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/patologia , Masculino , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/patologia , Propionato de Testosterona , Virilismo/sangue , Virilismo/patologia
15.
Molecules ; 23(10)2018 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-30322186

RESUMO

Benign prostatic hyperplasia (BPH), an age-dependent disorder with a prevalence percentage of 60% in the 60s, has been found to involve an androgenic hormone imbalance that causes confusion between cell apoptosis and proliferation. Because general medications for BPH treatment have undesirable side effects, the development of effective alternative medicines has been considered. HBX-5 is a newly developed formula with the aim of improving BPH, and is composed of nine medicinal herbs. BPH was induced in the rats by intramuscular injection of testosterone propionate after castration. Rats were divided into six groups, and the efficacy of HBX-5 on testosterone-induced BPH in rats was estimated. In addition, RWPE-1 and WPMY-1 cells were used to demonstrate the effect of HBX-5 on BPH in vitro model. Compared with the control group, HBX-5 administration group suppressed BPH manifestations, such as excessive development of prostate, and increase of serum dihydrotestosterone and 5α-reductase concentrations. Furthermore, immunohistochemistry analysis revealed that HBX-5 significantly decreased the expression of androgen receptor (AR) and proliferating cell nuclear antigen (PCNA). In addition, results of RWPE-1 and WPMY-1 cells showed that HBX-5 inhibited the over-expression of AR and PSA in DHT-induced prostate hyperplastic microenvironments.


Assuntos
Extratos Vegetais/administração & dosagem , Plantas Medicinais/química , Hiperplasia Prostática/tratamento farmacológico , Propionato de Testosterona/efeitos adversos , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Animais , Linhagem Celular , Di-Hidrotestosterona/sangue , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções Intramusculares , Masculino , Extratos Vegetais/farmacologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Hiperplasia Prostática/sangue , Hiperplasia Prostática/induzido quimicamente , Ratos , Receptores Androgênicos/metabolismo
16.
Biomed Pharmacother ; 107: 1641-1647, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30257382

RESUMO

Gestational androgen excess has been implicated in the development of cardiac dysfunction with poor mechanistic delineation. The role of sodium acetate on cardiac uric acid (UA) production and glucose-6-phosphate dehydrogenase (G6PD)-dependent antioxidant defense in pregnancy is not known. The study therefore sought to test the hypothesis that rats exposed to elevated testosterone in late pregnancy would have increased cardiac UA production and defective G6PD-dependent antioxidant defense. We also hypothesized that sodium acetate (SAc) or androgen receptor blocker, flutamide (Flu) would ameliorate these effects through endoglin inhibition. Twenty-four pregnant Wistar rats were treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with SAc (200 mg/kg; po) or Flu (7.5 mg/kg; po) in the late gestation between gestational day 14 and 19. The results showed that in the late gestation, testosterone exposure led to increased plasma and cardiac endoglin. In the heart of rats exposed to gestational testosterone there were elevated lactate dehydrogenase, adenosine deaminase, xanthine oxidase, uric acid (UA), cardiac injury markers and decreased G6PD-dependent antioxidant defense. However, either SAc or Flu comparably ameliorated these testosterone-induced effects. The data from the present study revealed that testosterone exposure in the late gestation causes elevated cardiac Eng that is accompanied by increased UA production and defective G6PD-dependent anti-oxidant defenses. Besides, the findings also suggest that the inhibitory effect of SAc or Flu on endoglin attenuates UA production and enhances the G6PD-dependent anti-oxidant barrier, thereby implying that endoglin may be a potentially novel therapeutic intervention for cardiac dysfunction particularly in pregnancy.


Assuntos
Endoglina/antagonistas & inibidores , Flutamida/farmacologia , Acetato de Sódio/farmacologia , Propionato de Testosterona/administração & dosagem , Antagonistas de Androgênios/farmacologia , Animais , Antioxidantes/metabolismo , Feminino , Glucosefosfato Desidrogenase/metabolismo , Coração/efeitos dos fármacos , Exposição Materna/efeitos adversos , Gravidez , Ratos , Ratos Wistar , Propionato de Testosterona/toxicidade , Ácido Úrico/metabolismo
17.
Am J Physiol Heart Circ Physiol ; 315(5): H1393-H1401, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30095996

RESUMO

Polycystic ovary syndrome is a complex and common disorder in women, and those affected experience an increased burden of cardiovascular disease. It is an intergenerational syndrome, as affected women with high androgen levels during pregnancy "program" fetal development, leading to a similar phenotype in their female offspring. The effect of excess maternal testosterone exposure on fetal cardiomyocyte growth and maturation is unknown. Pregnant ewes received biweekly injections of vehicle (control) or 100 mg testosterone propionate between 30 and 59 days of gestation (early T) or between 60 and 90 days of gestation (late T). Fetuses were delivered at ~135 days of gestation, and their hearts were enzymatically dissociated to measure cardiomyocyte growth (dimensional measurements), maturation (proportion binucleate), and proliferation (nuclear Ki-67 protein). Early T depressed serum insulin-like growth factor 1 and caused intrauterine growth restriction (IUGR; P < 0.0005). Hearts were smaller with early T ( P < 0.001) due to reduced cardiac myocyte maturation ( P < 0.0005) and proliferation ( P = 0.017). Maturation was also lower in male than female fetuses ( P = 0.004) independent of treatment. Late T did not affect cardiac growth. Early excess maternal testosterone exposure depresses circulating insulin-like growth factor 1 near term and causes IUGR in both female and male offspring. These fetuses have small, immature hearts with reduced proliferation, which may reduce cardiac myocyte endowment and predispose to adverse cardiac growth in postnatal life. While excess maternal testosterone exposure leads to polycystic ovary syndrome and cardiovascular disease in female offspring, it may also predispose to complications of IUGR and cardiovascular disease in male offspring. NEW & NOTEWORTHY Using measurements of cardiac myocyte growth and maturation in an ovine model of polycystic ovary syndrome, this study demonstrates that early gestation excess maternal testosterone exposure reduces near-term cardiomyocyte proliferation and maturation in intrauterine growth-restricted female and male fetuses. The effect of testosterone is restricted to exposure during a specific period early in pregnancy, and the effects appear mediated through reduced insulin-like growth factor 1 signaling. Furthermore, male fetuses, regardless of treatment, had fewer mature cardiomyocytes than female fetuses.


Assuntos
Diferenciação Celular , Proliferação de Células , Retardo do Crescimento Fetal/patologia , Coração Fetal/patologia , Miócitos Cardíacos/patologia , Propionato de Testosterona , Animais , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/induzido quimicamente , Coração Fetal/metabolismo , Idade Gestacional , Fator de Crescimento Insulin-Like I/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Exposição Materna , Miócitos Cardíacos/metabolismo , Gravidez , Fatores Sexuais , Carneiro Doméstico
18.
Sci Rep ; 8(1): 10726, 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30013094

RESUMO

Androgen plays a pivotal role in the progression of renal fibrosis. However, whether exogenous androgen treatment to aged male rats can improve the age-related renal fibrosis was not explored. In our study, the changes of morphological structure, renal fibrosis, ultrastructure and renal function, the expressions of extracellular matrix (ECM), matrix metalloproteinases (MMPs) and its tissue inhibitors of metalloproteinases (TIMPs), the expressions of tumor growth factor ß1 (TGF-ß1)/Smad signaling and oxidative stress parameters as well as nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) signaling were tested in kidney of aged male Wistar rats after subcutaneous testosterone propionate (TP, 2 mg/kg/d, 84-day) injection. Aged rats showed significantly renal histopathological changes, increased renal fibrosis, increased thickening of the glomerular basement membrane and the Bowman's capsule basement membrane, declined renal functional, increased ECM, lower expressions of MMP-2 and MMP-9 and higher expressions of TIMP-1 and TIMP-2 in renal tissues and higher expressions of TGF-ß1/Smad signaling, as well as lower expressions of Nrf2-ARE signaling compared to young rats. TP treatment significantly improved age-related above indexes. These results suggested that TP supplement may alleviate age-related renal fibrosis via suppression of TGF-ß1/Smad signaling and activation of Nrf2-ARE signaling in aged rats.


Assuntos
Envelhecimento/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/patologia , Transdução de Sinais/efeitos dos fármacos , Propionato de Testosterona/administração & dosagem , Animais , Elementos de Resposta Antioxidante/genética , Fibrose , Regulação da Expressão Gênica/fisiologia , Rim/efeitos dos fármacos , Rim/ultraestrutura , Masculino , Microscopia Eletrônica de Transmissão , Modelos Animais , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
19.
J Chromatogr A ; 1566: 51-63, 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-29958683

RESUMO

Anabolic and androgenic steroids (AAS) are banned substances in both human and equine sports. They are often administered intramuscularly to horses in esterified forms for the purpose of extending their time of action. The authors' laboratory has previously reported an UHPLC/HRMS method using quadrupole-Orbitrap mass spectrometer in full scan and parallel reaction monitoring (PRM) mode for the detection of 48 AAS and/or their esters in horse hair. However, two injections were required due to the long duty cycle time. In this paper, an UHPLC/HRMS method using multiplexed targeted MS2 mode was developed and validated to improve the coverage to 65 AAS and/or their esters in a single injection. In addition, a GC/MS/MS method in selected reaction monitoring (SRM) mode was developed to screen for another seven AAS and/or their esters not adequately covered by the UHPLC/HRMS method using the same sample extract after derivatisation with pentafluoropropionic anhydride. The UHPLC/HRMS and GC/MS/MS methods in combination allowed the detection of 72 AAS and/or their esters with estimated limits of detection down to sub to low ppb levels with good interday precision. Method applicability was demonstrated by the detection of boldione and 4-androstenedione in two out-of-competition hair samples and testosterone propionate in a referee hair sample.


Assuntos
Cromatografia Líquida de Alta Pressão , Ésteres/análise , Cromatografia Gasosa-Espectrometria de Massas , Cabelo/química , Esteroides/análise , Espectrometria de Massas em Tandem , Androstenodiona/análise , Animais , Doping nos Esportes , Ésteres/química , Cavalos , Esteroides/química , Propionato de Testosterona/análise
20.
Arch Biochem Biophys ; 649: 53-59, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29733810

RESUMO

The effects of testosterone propionate (TP) on the oxidative stress and mitochondrial function, as well as on mitochondria associated apoptotic signaling, were analyzed in the gastric mucosa in orchiectomized male rats. The present study showed that testosterone deficiency triggered apoptosis by damaging the mitochondrial function (ROS overload generation, membrane potential loss, ATP depletion, etc.), increasing both the release of mitochondrial cytochrome c (Cyt c) and the Bax/Bcl-2 ratio, and activating caspase-9 and caspase-3. Supplements of testosterone propionate to castrated male rats ameliorated mitochondrial function and confirmed the involvement of the mitochondrial pathway in the gastric mucosa. These results suggest that testosterone could maintain the mitochondrial function of the gastric mucosa and mediate mitochondria-associated apoptotic signaling.


Assuntos
Apoptose/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Propionato de Testosterona/farmacologia , Animais , Mucosa Gástrica/metabolismo , Masculino , Mitocôndrias/metabolismo , Orquiectomia , Ratos , Ratos Sprague-Dawley
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