Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.050
Filtrar
1.
PLoS One ; 15(6): e0233718, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497103

RESUMO

BACKGROUND: Person and environment-related childhood adverse events have been demonstrated to increase the risk of impaired mental health in later life differently for boys and girls. Altered hypothalamic pituitary adrenal (HPA)-axis functioning has been suggested as a key mechanism underlying this association. Cortisol and dehydroepiandrosterone (DHEA) are both output hormones of the HPA-axis. DHEA may have a protective function against long-term exposure to increased levels of cortisol, but has been little investigated in relation to childhood adversity. OBJECTIVE: We aimed to test the associations between person-, and environment-related childhood adversity and levels of cortisol, DHEA and cortisol/DHEA ratio in adolescent boys and girls. METHODS: A total of 215 Dutch adolescents participated in the study and filled out the 27-item Adverse Life Events Questionnaire for the assessment of childhood adversity, which was split up in separate scores for person-related and environment-related events. Cortisol and DHEA concentrations and cortisol/DHEA ratio were determined in proximal 3 cm long hair segments. Additionally, saliva samples were collected immediately and 30 minutes after waking up, at noon and at 8 pm. Multiple linear regression analyses were used to test associations between childhood adversity and cortisol and DHEA concentrations, for boys and girls separately, with age, BMI and pubertal development as covariates. RESULTS: Data were available for 74 boys and 116 girls with a mean age of 15.7 years (SD = 2.0). Higher levels of person-related childhood adversity were associated with higher hair DHEA levels in girls and with higher hair cortisol levels in boys. A trend towards a significant association was observed between higher levels of environment-related childhood adversity and higher DHEA levels in boys. Neither person- nor environment related childhood adversity was associated with cortisol/DHEA ratio. A trend was observed for environment-related childhood adversity and lower daily cortisol output in boys. CONCLUSION: We found differential associations between childhood adversity and cortisol and DHEA levels in girls and boys, for respectively person-related and environment-related childhood adversity. Our findings suggest that different types of childhood adversity are not only linked to levels of cortisol, but also to DHEA concentrations, in a sex-specific manner, with possible future implications for mental health.


Assuntos
Experiências Adversas da Infância , Desidroepiandrosterona/análise , Hidrocortisona/análise , Adolescente , Desidroepiandrosterona/metabolismo , Feminino , Cabelo/química , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Saliva/química , Autorrelato , Fatores Sexuais , Estresse Psicológico/metabolismo
2.
PLoS One ; 15(4): e0230053, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298279

RESUMO

Although anxiety disorders are among the most prevalent of psychiatric disorders, childhood trauma-related studies seldom consider anxiety proneness as distinct aetiological contributor. We aimed to distinguish between trauma- and anxiety-associated physiological profiles. South African adolescent volunteers were categorised for trauma exposure (CTQ, mean score 39±11) and anxiety proneness (AP)(CASI, mean score 37±7, STAI-T, mean score 41±8). Circulating hormone and leukocyte glucocorticoid receptor levels, as well as leukocyte functional capacity, were assessed. AP was associated with lower DHEAs (P<0.05) and higher leukocyte GR expression (P<0.05). DHEAs was also negatively correlated with anxiety sensitivity (CASI, P<0.05). In conclusion, AP may have more predictive power than trauma in terms of health profile. Increased glucocorticoid sensitivity previously reported after trauma, may be a unique function of anxiety and not trauma exposure per se. DHEAs concentration was identified as potentially useful marker for monitoring progressive changes in HPA-axis sensitivity and correlated with psychological measures of anxiety.


Assuntos
Transtornos de Ansiedade/sangue , Desidroepiandrosterona/sangue , Regulação da Expressão Gênica , Leucócitos/metabolismo , Receptores de Glucocorticoides/sangue , Estresse Psicológico/sangue , Adolescente , Transtornos de Ansiedade/psicologia , Feminino , Humanos , Masculino , África do Sul , Estresse Psicológico/psicologia
3.
Eur J Endocrinol ; 182(5): 459-471, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32130202

RESUMO

Objective: To evaluate the independent impact of age, obesity and metabolic risk factors on 13 circulating steroid levels; to generate reference intervals for adult men. Design: Cross-sectional study. Methods: Three hundred and fifteen adults, drug-free and apparently healthy men underwent clinical and biochemical evaluation. Thirteen steroids were measured by LC-MS/MS and compared among men with increasing BMI. Moreover, the independent impact of age, BMI and metabolic parameters on steroid levels was estimated. Upper and lower reference limits were generated in steroid-specific reference sub-cohorts and compared with dysmetabolic sub-cohorts. Results: We observed lower steroid precursors and testosterone and increase in estrone levels in men with higher BMI ranges. By multivariate analysis, 17-hydroxyprogesterone and dihydrotestosterone decreased with BMI, while cortisol decreased with waist circumference. Estrone increased with BMI and systolic blood pressure. Testosterone decreased with worsening insulin resistance. 17-hydroxypregnenolone and corticosterone decreased with increasing total/HDL-cholesterol ratio. Age-related reference intervals were estimated for 17-hydroxypregnenolone, DHEA, 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol, cortisol and androstenedione, while age-independent reference intervals were estimated for progesterone, 11-deoxycorticosterone, testosterone, dihydrotestosterone, estrone and estradiol. Testosterone lower limit was 2.29 nmol/L lower (P = 0.007) in insulin resistant vs insulin sensitive men. Furthermore, the upper limits for dihydrotestosterone (-0.34 nmol/L, P = 0.045), cortisol (-87 nmol/L, P = 0.045-0.002) and corticosterone (-10.1 nmol/L, P = 0.048-0.016) were lower in overweight/obese, in abdominal obese and in dyslipidaemic subjects compared to reference sub-cohorts, respectively. Conclusions: Obesity and mild unmedicated metabolic risk factors alter the circulating steroid profile and bias the estimation of reference limits for testosterone, dihydrotestosterone, cortisol and corticosterone. Applying age-dependent reference intervals is mandatory for steroid precursors and corticosteroids.


Assuntos
Peso Corporal/fisiologia , 17-alfa-Hidroxiprogesterona/sangue , Fatores Etários , Androstenodiona/sangue , Índice de Massa Corporal , Cromatografia Líquida , Corticosterona/sangue , Cortodoxona/sangue , Estudos Transversais , Desidroepiandrosterona/sangue , Di-Hidrotestosterona/sangue , Humanos , Hidrocortisona/sangue , Masculino , Análise Multivariada , Obesidade/sangue , Sobrepeso/sangue , Fatores de Risco , Espectrometria de Massas em Tandem
4.
Life Sci ; 249: 117515, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32147428

RESUMO

AIMS: This study investigated the effects of curcumin-loaded super-paramagnetic iron oxide (Fe3O4) nanoparticles (NPs) (SPIONs) on histological parameters and apoptosis-inducing factors (AIFs) in an experimental mouse model of polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: A total number of 40 female prepuberal BALB/c mice were randomly divided into four groups. Group 1 was selected as control and Group 2 was considered as a vehicle taking sesame oil, in the form of a curcumin carrier. Moreover, Group 3 was administered with dehydroepiandrosterone (DHEA) at 6 mg/100 g of the body weight and Group 4 received the DHEA plus the NPs of curcumin (5.4 mg/100 g) for twenty consecutive days. Finally, histology, stereology, and apoptosis of the ovary were evaluated. KEY FINDINGS: The results revealed that the NPs of curcumin had reduced ovarian volume (p < 0.05) and a total number of primary, secondary, antral, and primordial follicles in comparison with the PCOS and vehicle groups (p < 0.05). Furthermore, curcumin treatment following administration of the DHEA resulted in a significant decrease in BAX (p < 0.001) and levels of expression of Caspase3 (CASP3) protein, increased levels of B-cell lymphoma 2 (Bcl2) expression (p < 0.05), and moderated apoptosis in granulosa cells in comparison with the ones seen in the PCOS group. SIGNIFICANCE: Ovarian injuries and DHEA-induced apoptosis were efficiently suppressed by curcumin, indicating the probable protective property of NPs of curcumin against PCOS.


Assuntos
Apoptose/efeitos dos fármacos , Curcumina/administração & dosagem , Desidroepiandrosterona/administração & dosagem , Compostos Férricos/administração & dosagem , Nanopartículas Metálicas/química , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Maturidade Sexual , Animais , Antioxidantes/administração & dosagem , Apoptose/genética , Caspase 3/metabolismo , Modelos Animais de Doenças , Feminino , Compostos Férricos/química , Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Estresse Oxidativo
5.
Environ Res ; 182: 109101, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32069767

RESUMO

BACKGROUND: Fetal programming of the endocrine system may be affected by exposure to perfluoroalkyl substances (PFAAs), as they easily cross the placental barrier. In vitro studies suggest that PFAAs may disrupt steroidogenesis. "Mini puberty" refers to a transient surge in circulating androgens, androgen precursors, and gonadotropins in infant girls and boys within the first postnatal months. We hypothesize that prenatal PFAA exposure may decrease the concentrations of androgens in mini puberty. OBJECTIVES: To investigate associations between maternal serum PFAA concentrations in early pregnancy and serum concentrations of androgens, their precursors, and gonadotropins during mini puberty in infancy. METHODS: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAAs: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured at median gestational week 12 (IQR: 10, 15) in 1628 women. Among these, offspring serum concentrations of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS), androstenedione, 17-hydroxyprogesterone (17-OHP), testosterone, luteinizing (LH) and follicle stimulating hormones (FSH) were measured in 373 children (44% girls; 56% boys) at a mean age of 3.9 (±0.9 SD) months. Multivariate linear regression models were performed to estimate associations. RESULTS: A two-fold increase in maternal PFDA concentration was associated with a reduction in DHEA concentration by -19.6% (95% CI: -32.9%, -3.8%) in girls. In girls, also, the androstenedione and DHEAS concentrations were decreased, albeit non-significantly (p < 0.11), with a two-fold increase in maternal PFDA concentration. In boys, no significant association was found between PFAAs and concentrations of androgens, their precursors, and gonadotropins during mini puberty. CONCLUSION: Prenatal PFDA exposure was associated with significantly lower serum DHEA concentrations and possibly also with lower androstenedione and DHEAS concentrations in female infants at mini puberty. The clinical significance of these findings remains to be elucidated.


Assuntos
Ácidos Alcanossulfônicos , Ácidos Decanoicos , Desidroepiandrosterona , Poluentes Ambientais , Fluorcarbonetos , Efeitos Tardios da Exposição Pré-Natal , Puberdade , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Criança , Ácidos Decanoicos/toxicidade , Desidroepiandrosterona/sangue , Feminino , Fluorcarbonetos/toxicidade , Humanos , Lactente , Masculino , Gravidez , Estudos Prospectivos
6.
J Immunol ; 204(5): 1214-1224, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31980574

RESUMO

Leukocytes are rapidly recruited to sites of inflammation via interactions with the vascular endothelium. The steroid hormone dehydroepiandrosterone (DHEA) exerts anti-inflammatory properties; however, the underlying mechanisms are poorly understood. In this study, we show that an anti-inflammatory mechanism of DHEA involves the regulation of developmental endothelial locus 1 (DEL-1) expression. DEL-1 is a secreted homeostatic factor that inhibits ß2-integrin-dependent leukocyte adhesion, and the subsequent leukocyte recruitment and its expression is downregulated upon inflammation. Similarly, DHEA inhibited leukocyte adhesion to the endothelium in venules of the inflamed mouse cremaster muscle. Importantly, in a model of lung inflammation, DHEA limited neutrophil recruitment in a DEL-1-dependent manner. Mechanistically, DHEA counteracted the inhibitory effect of inflammation on DEL-1 expression. Indeed, whereas TNF reduced DEL-1 expression and secretion in endothelial cells by diminishing C/EBPß binding to the DEL-1 gene promoter, DHEA counteracted the inhibitory effect of TNF via activation of tropomyosin receptor kinase A (TRKA) and downstream PI3K/AKT signaling that restored C/EBPß binding to the DEL-1 promoter. In conclusion, DHEA restrains neutrophil recruitment by reversing inflammation-induced downregulation of DEL-1 expression. Therefore, the anti-inflammatory DHEA/DEL-1 axis could be harnessed therapeutically in the context of inflammatory diseases.


Assuntos
Proteínas de Ligação ao Cálcio/imunologia , Moléculas de Adesão Celular/imunologia , Desidroepiandrosterona/farmacologia , Leucócitos/imunologia , Transdução de Sinais/imunologia , Animais , Proteína beta Intensificadora de Ligação a CCAAT/imunologia , Antígenos CD18/imunologia , Adesão Celular/imunologia , Endotélio Vascular/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Leucócitos/citologia , Camundongos , Fosfatidilinositol 3-Quinases/imunologia , Regiões Promotoras Genéticas/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptor trkA/imunologia
7.
J Biomed Sci ; 27(1): 20, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906962

RESUMO

BACKGROUND: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), affecting approximately one third of the world's population. Development of an adequate immune response will determine disease progression or progress to chronic infection. Risk of developing TB among human immunodeficiency virus (HIV)-coinfected patients (HIV-TB) is 20-30 times higher than those without HIV infection, and a synergistic interplay between these two pathogens accelerates the decline in immunological functions. TB treatment in HIV-TB coinfected persons is challenging and it has a prolonged duration, mainly due to the immune system failure to provide an adequate support for the therapy. Therefore, we aimed to study the role of the hormone 7-oxo-dehydroepiandrosterone (7-OD) as a modulator of anti-tuberculosis immune responses in the context of HIV-TB coinfection. METHODS: A cross-sectional study was conducted among HIV-TB patients and healthy donors (HD). We characterized the ex vivo phenotype of CD4 + T cells and also evaluated in vitro antigen-specific responses by Mtb stimulation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of 7-OD. We assessed lymphoproliferative activity, cytokine production and master transcription factor profiles. RESULTS: Our results show that HIV-TB patients were not able to generate successful anti-tubercular responses in vitro compared to HD, as reduced IFN-γ/IL-10 and IFN-γ/IL-17A ratios were observed. Interestingly, treatment with 7-OD enhanced Th1 responses by increasing Mtb-induced proliferation and the production of IFN-γ and TNF-α over IL-10 levels. Additionally, in vitro Mtb stimulation augmented the frequency of cells with a regulatory phenotype, while 7-OD reduced the proportion of these subsets and induced an increase in CD4 + T-bet+ (Th1) subpopulation, which is associated with clinical data linked to an improved disease outcome. CONCLUSIONS: We conclude that 7-OD modifies the cytokine balance and the phenotype of CD4 + T cells towards a more favorable profile for mycobacteria control. These results provide new data to delineate novel treatment approaches as co-adjuvant for the treatment of TB.


Assuntos
Coinfecção/imunologia , Desidroepiandrosterona/análogos & derivados , Infecções por HIV/imunologia , HIV-1/imunologia , Mycobacterium tuberculosis/imunologia , Células Th1/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Doença Crônica , Coinfecção/patologia , Estudos Transversais , Desidroepiandrosterona/imunologia , Desidroepiandrosterona/farmacologia , Feminino , Infecções por HIV/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Células Th1/patologia , Tuberculose Pulmonar/patologia
8.
Expert Opin Pharmacother ; 21(4): 409-415, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31928093

RESUMO

Introduction: Dyspareunia caused by vulvovaginal atrophy is a primary symptom of genitourinary syndrome of menopause (GSM), a chronic, progressive medical condition that results from estrogen and androgen deficiency at menopause. Dehydroepiandrosterone (DHEA, prasterone) is an endogenous precursor steroid hormone that is metabolized into both androgens and estrogens that has been recently been approved by the FDA for the treatment of moderate to severe dyspareunia caused by vulvovaginal atrophy secondary to menopause.Areas covered: This is a comprehensive drug evaluation describing the chemical composition, pharmacokinetics, metabolism, clinical efficacy and safety of dehydroepiandrosterone (prasterone) in the treatment of dyspareunia and VVA secondary to menopause. Preclinical and clinical data suggesting further potential uses, benefits, and contraindications in the genitourinary health of postmenopausal women are also considered.Expert opinion: Intravaginal dehydroepiandrosterone (prasterone) is effective for the management of dyspareunia secondary to menopause and may be effective in the treatment of other types of sexual dysfunction that are secondary to menopause. Further studies should explore additional dosing regimens and different indications.


Assuntos
Desidroepiandrosterona/uso terapêutico , Doenças Urogenitais Femininas/tratamento farmacológico , Menopausa/metabolismo , Vagina/efeitos dos fármacos , Administração Intravaginal , Androgênios/metabolismo , Atrofia , Desidroepiandrosterona/administração & dosagem , Dispareunia/tratamento farmacológico , Dispareunia/metabolismo , Estrogênios/metabolismo , Feminino , Doenças Urogenitais Femininas/metabolismo , Humanos , Resultado do Tratamento , Vagina/patologia
9.
Chemosphere ; 241: 124899, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31586830

RESUMO

Recent studies have found elevated dioxin levels inside some former US military air bases in Vietnam, known as hotspots. The aim of the present study was to evaluate the association of dioxin exposure and steroid hormone in preschool children in Vietnam. In 2010, 2011, 52 primiparae mother-infant pairs in the hotspot and 52 pairs in a non-exposure region were enrolled. For the final analysis, 26 vs 26 pairs were selected, who participated at all three surveys. Univariable and multivariable linear regressions were used to evaluate associations between hormone and dioxin congeners. Geometric mean total TEQ of PCDD/DFs in the hotspot were significantly higher than in the non-exposure region, 8.7 and 3.4 pg TEQ/g lipid, respectively. In the hotspot, salivary dehydroepiandrosterone (DHEA) was significantly higher in 1-year-old children (Boys = 123 pg/mL, Girls = 120 pg/mL) than in the non-exposure region (Boys = 28 pg/mL, Girls = 27 pg/mL). In contrast, DHEA was significantly lower in 5-year-old children (Boys = 70 pg/mL, Girls = 106 pg/mL) in the hotspot than in the non-exposure region (Boys = 496 pg/mL, Girls = 654 pg/mL). Salivary testosterone was significantly lower in the hotspot (Boys = 1.9 pg/mL, Girls = 1.9 pg/m; Boys = 1.0 pg/mL, Girls = 1.1 pg/mL, respectively) than in the non-exposure region (Boys = 3.7 pg/mL, Girls = 3.8 pg/m; Boys = 5.7 pg/mL, Girls = 7.0 pg/mL, respectively) at 3 years and 5 years of age. Higher levels of highly chlorinated dioxins in breast milk were associated with higher DHEA in 1-year-old and lower DHEA and testosterone levels in 5-year-old children. Our findings indicated that dioxins were associated with changes of DHEA and testosterone levels in preschool Vietnamese children.


Assuntos
Dioxinas/análise , Poluentes Ambientais/análise , Leite Humano/química , Esteroides/análise , Pré-Escolar , Estudos de Coortes , Desidroepiandrosterona/análise , Feminino , Seguimentos , Humanos , Lactente , Masculino , Saliva/química , Testosterona/análise , Vietnã
10.
Am J Obstet Gynecol ; 222(2): 114-122, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31513780

RESUMO

Vaginitis is one of the most common causes of patient visits to gynecologists, primary care providers, and urgent care centers. However, many women leave without a clear diagnosis or experience recurrent symptoms despite treatment. The 3 most common etiologies of vaginitis are trichomonas, bacterial vaginosis, and vulvovaginal candidiasis, which account for an estimated 70% of cases. The remaining 30% may be related to other causes of vaginitis, including atrophic vaginitis, desquamative inflammatory vaginitis, and vaginal erosive disease. The purpose of this review is to describe the noncandidal causes of acute and recurrent vaginitis, with the goal of improving the likelihood of accurate diagnosis as well as efficient and effective therapy. We excluded candidal vaginitis from our review because there was a recently published review on this topic in the Journal. The clinical presentation and evaluation of patients with symptoms of vaginitis can be triaged into 1 of 2 diagnostic pathways: noninflammatory and inflammatory vaginitis. The most common noninflammatory cause is bacterial vaginosis. Features such as irritation, purulent discharge, and the presence of polymorphonuclear neutrophils are more suggestive of an inflammatory process. Trichomoniasis is the most common cause of inflammatory vaginitis. Other well-described forms of inflammatory vaginitis include atrophic vaginitis, desquamative inflammatory vaginitis, and erosive disease. We present a review of the pathogenesis, symptoms, examination findings, diagnostic testing, and treatment for each of these causes of noncandidal vaginitis.


Assuntos
Anti-Infecciosos/uso terapêutico , Vaginite Atrófica/diagnóstico , Candidíase Vulvovaginal/diagnóstico , Vaginite por Trichomonas/diagnóstico , Vaginose Bacteriana/diagnóstico , Administração Intravaginal , Administração Oral , Anti-Inflamatórios/uso terapêutico , Vaginite Atrófica/terapia , Clindamicina/uso terapêutico , Desidroepiandrosterona/uso terapêutico , Diagnóstico Diferencial , Terapia de Reposição de Estrogênios , Estrogênios/uso terapêutico , Feminino , Humanos , Hidrocortisona/uso terapêutico , Inflamação , Líquen Plano/diagnóstico , Líquen Plano/terapia , Metronidazol/análogos & derivados , Metronidazol/uso terapêutico , Penfigoide Mucomembranoso Benigno/diagnóstico , Penfigoide Mucomembranoso Benigno/terapia , Penfigoide Bolhoso/diagnóstico , Penfigoide Bolhoso/terapia , Pênfigo/diagnóstico , Pênfigo/terapia , Tamoxifeno/análogos & derivados , Tamoxifeno/uso terapêutico , Tinidazol/uso terapêutico , Vaginite por Trichomonas/terapia , Vaginite/diagnóstico , Vaginite/terapia , Vaginose Bacteriana/terapia
11.
J Steroid Biochem Mol Biol ; 198: 105570, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31883924

RESUMO

So far, there have been no analyses of correlations between the level of water-soluble vitamins in women with polycystic ovary syndrome (PCOS) and hormone and lipid profiles as well as carbohydrate metabolism. The unpopular concept that PCOS may also be conditioned by a chronic infection leads to a suspicion that water-soluble vitamins may be involved in the struggle against PCOS. This is why the aim of this research was to determine whether there are any indications that could confirm this hypothesis. The study included 64 women of Caucasian race: 50 patients aged 29.52 ±â€¯7.01 years with PCOS, diagnosed according to the Rotterdam criteria. The control group consisted of 14 women aged 30.23 ±â€¯6.3 years with correct BMI. HPLC Infinity1260 Binary LC (Agilent Technologies, Waldbronn, Germany) was used to analyze nine vitamins. The vitamins were separated using the gradient method, a buffer of 25 mM HK2PO4 with pH equal to 7.0, and 100 % methanol buffer. The acquired results were compared using Statistica 12.0 (Statsoft, Tulsa, Oklahoma, USA). Non-parametric tests were used: Mann-Whitney tests for comparisons between groups (PCOS and control group, CG), in which p < 0.05 was considered statistically significant. Subsequently, we performed a correlation matrix of the biochemical parameters of blood with vitamins at p ≤ 0.05. Higher concentrations of ascorbic acid were observed in PCOS. The content of the remaining vitamins was higher in the control group, and the statistical differences were significant in reference to thiamine, riboflavin, pyridoxine and folic acid in comparison to the control group. A significant positive correlation was observed between vitamin C and testosterone/insulin, another between riboflavin and androstenedione/testosterone, next between biotin and thyrotropic hormone (TSH), between pantothenic acid and dehydroepiandrosteron (DHEA-SO4), and finally between pyridoxine and androstenedione. A negative correlation was observed in the case of niacin with sex hormone binding protein (SHBG) and high density lipoprotein (HDL). Water-soluble vitamins play an important role in the therapy of women with PCOS through the reduction of antioxidative stress and low-intensity inflammation caused by various factors, including chronic infection.


Assuntos
Metabolismo dos Carboidratos , Hormônios/sangue , Lipídeos/química , Lipoproteínas HDL/sangue , Síndrome do Ovário Policístico/sangue , Vitaminas/sangue , Adulto , Androstenodiona/sangue , Antioxidantes/química , Desidroepiandrosterona/sangue , Feminino , Ácido Fólico/sangue , Humanos , Piridoxina/sangue , Globulina de Ligação a Hormônio Sexual/análise , Solubilidade , Tiamina/sangue , Tireotropina/sangue , Vitamina B 6/sangue , Água/química , Adulto Jovem
12.
Mol Immunol ; 118: 60-72, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31855808

RESUMO

Dehydroepiandrosterone (DHEA) possess anti-inflammatory, anti-oxidant and immune-regulating function in animals and humans, but there is not enough information about the mechanisms underlying its beneficial effects. The present study investigated the effect and mechanism of DHEA in dextran sulfate sodium (DSS)-induced colitis mice. The findings showed that DHEA relieved the decreasing of body weight, the increasing of disease activity index, the enhancing of spleen weight, the shortening of colon length and the rising of myeloperoxidase activity; meanwhile, histopathological analysis showed that DHEA maintained a relatively intact structure of colon in DSS-induced colitis mice. DHEA decreased the malondialdehyde content, superoxide dismutase activity and inducible nitric oxide synthase protein level; meanwhile, DHEA also inhibited the secretion of tumor necrosis factor-α, interleukin-1ß and interleukin-6 in DSS-induced colitis mice. Importantly, our results showed that DHEA blocked the activation of nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) pathways; and it inhibited the Nod-like receptor protein 3 inflammasome activation in DSS-induced colitis mice. Furthermore, DHEA markedly promoted the intestinal barrier function by up-regulation zonula occludens-1 expression level. The 16S rDNA gene sequencing demonstrated that DHEA decreased the Pseudomonas abundance in DSS-induced colitis mice. In conclusion, our data demonstrated that DHEA reduces oxidative damage through regulating antioxidant enzyme activity; inhibits pro-inflammatory cytokines production by blocking the activation of p38 MAPK and NF-κB signal pathway; protects colon barrier integrity via increasing tight junction protein expression and modulating gut microbiota taxa; all that finally alleviates DSS-induced experimental colitis in mice.


Assuntos
Colite/induzido quimicamente , Colite/tratamento farmacológico , Desidroepiandrosterona/farmacologia , Sulfato de Dextrana/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Colite/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Microbioma Gastrointestinal/imunologia , Imunidade/imunologia , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
13.
Biol Aujourdhui ; 213(3-4): 131-140, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31829933

RESUMO

Discovered in the eighties by Pr Baulieu and colleagues, neurosteroids are a class of neuroactive brain-born steroids, which comprises the steroid hormones, their biosynthesis precursors and their metabolites. They can act through genomic as well as non-genomic pathways. Genomic pathways, only triggered by the neurosteroid hormones, are, in the brain, the same as those largely described in the periphery: the binding of these steroid hormones to nuclear receptors leads to transcription regulations. On the other hand, their precursors and metabolites, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), their respective sulfate esters, pregnenolone sulfate (PREG-S) and DHEA sulfate (DHEA-S) and allopregnanolone (ALLOP), are defined as neurosteroids, but no corresponding nuclear receptors have been identified so far. In fact, they trigger non-genomic pathways which consist in (i) inhibitory ionotropic receptors, (ii) excitatory ionotropic receptors and (iii) the microtubular system. Hence, inhibitory neurosteroids, whose mostly studied representative is ALLOP, positively modulate, or directly activate, the ionotropic GABA-A receptors. In contrast, excitatory neurosteroids, represented by PREG-S, DHEA-S and DHEA, inhibit the GABA-A receptors, and activate, directly or indirectly, through the sigma-1 receptors, the NMDA glutamate receptors. Neurosteroids of the third group, the microtubular neurosteroids, are able to bind microtubule associated proteins, in particular MAP2, to promote microtubule assembly, neurite outgrowth and in fine structural neuroplasticity. So far, PREG, DHEA and progesterone are the three identified microtubular neurosteroids. The pharmacological properties of neurosteroids have led to specific investigations for assessing their therapeutic potentialities in psychiatric diseases, using validated animal models. In some cases, clinical trials were also performed. These studies showed that ALLOP, the main inhibitory neurosteroid, displayed clear-cut anxiolytic-like and antidepressant-like efficacy in animals. It has been subsequently developed as Brexanolone and tested with success in phase III of clinical trials for the treatment of post-partum depression. Although showing pro-cognitive properties in animals, the sulfated neurosteroids, PREG-S and DHEA-S, were, in contrast, never tested in clinical trials, probably due to their poor stability and proconvulsivant side effects. Their respective non-sulfated forms, PREG and DHEA, showed antidepressant and antipsychotic efficacies in clinical trials, but these drugs never reached the phase III of clinical development because their therapeutic uses would have led to an overproduction of active metabolites responsible for intolerable side effects. The alternative strategy which has been selected consists of the development of non-metabolizable synthetic derivatives of these natural steroids, which keep the same neuroactive properties as their parent molecules, but are devoid of any hormonal side effects. An example of such innovative drugs is MAP4343, a synthetic derivative of PREG, which exhibits potent antidepressant-like efficacy in validated animal models. It is currently tested in depressed patients.


Assuntos
Transtornos Mentais/tratamento farmacológico , Neuroesteroides/uso terapêutico , Psiquiatria/tendências , Animais , Desidroepiandrosterona/farmacologia , Sulfato de Desidroepiandrosterona/farmacologia , Depressão/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Humanos , Plasticidade Neuronal/efeitos dos fármacos , Pregnanolona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Terapias em Estudo/métodos , Terapias em Estudo/tendências
14.
J Neuroinflammation ; 16(1): 243, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779639

RESUMO

BACKGROUND: Microglia are resident immune cells in the central nervous system and central to the innate immune system. Excessive activation of microglia after subarachnoid haemorrhage (SAH) contributes greatly to early brain injury, which is responsible for poor outcomes. Dehydroepiandrosterone (DHEA), a steroid hormone enriched in the brain, has recently been found to regulate microglial activation. The purpose of this study was to address the role of DHEA in SAH. METHODS: We used in vivo models of endovascular perforation and in vitro models of haemoglobin exposure to illustrate the effects of DHEA on microglia in SAH. RESULTS: In experimental SAH mice, exogenous DHEA administration increased DHEA levels in the brain and modulated microglial activation. Ameliorated neuronal damage and improved neurological outcomes were also observed in the SAH mice pretreated with DHEA, suggesting neuronal protective effects of DHEA. In cultured microglia, DHEA elevated the mRNA and protein levels of Jumonji d3 (JMJD3, histone 3 demethylase) after haemoglobin exposure, downregulated the H3K27me3 level, and inhibited the transcription of proinflammatory genes. The devastating proinflammatory microglia-mediated effects on primary neurons were also attenuated by DHEA; however, specific inhibition of JMJD3 abolished the protective effects of DHEA. We next verified that DHEA-induced JMJD3 expression, at least in part, through the tropomyosin-related kinase A (TrkA)/Akt signalling pathway. CONCLUSIONS: DHEA has a neuroprotective effect after SAH. Moreover, DHEA increases microglial JMJD3 expression to regulate proinflammatory/anti-inflammatory microglial activation after haemoglobin exposure, thereby suppressing inflammation.


Assuntos
Desidroepiandrosterona/farmacologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Hemorragia Subaracnóidea/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Histona Desmetilases com o Domínio Jumonji/genética , Masculino , Camundongos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Nutrients ; 11(11)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694190

RESUMO

BACKGROUND: Flavonoids potentially exert anti-cancer effects, as suggested by their chemical structures and supported by animal studies. In observational studies, however, the association between flavonoids and breast cancer, and potential underlying mechanisms, remain unclear. OBJECTIVE: To examine the relationship between flavonoid intake and sex hormone levels using timed blood samples in follicular and luteal phases in the Nurses' Health Study II among premenopausal women. METHODS: Plasma concentrations of estrogens, androgens, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), prolactin, and sex hormone-binding globulin (SHBG) were measured in samples collected between 1996 and 1999. Average flavonoid were calculated from semiquantitative food frequency questionnaires collected in 1995 and 1999. We used generalized linear models to calculate geometric mean hormone concentrations across categories of the intake of flavonoids and the subclasses. RESULTS: Total flavonoid intake generally was not associated with the hormones of interest. The only significant association was with DHEAS (p-trend = 0.02), which was 11.1% (95% confidence interval (CI): -18.6%, -3.0%) lower comparing the highest vs. lowest quartile of flavonoid intake. In subclass analyses, the highest (vs. lowest) quartile of flavan-3-ol intake was associated with significantly lower DHEAS concentrations (-11.3% with 95% CI: -18.3%, -3.7%, p-trend = 0.01), and anthocyanin intake was associated with a significant inverse trend for DHEA (-18.0% with 95% CI: -27.9%, -6.7%, p-trend = 0.003). CONCLUSION: Flavonoid intake in this population had limited impact on most plasma sex hormones in premenopausal women. Anthocyanins and flavan-3-ols were associated with lower levels of DHEA and DHEAS.


Assuntos
Ingestão de Alimentos/fisiologia , Flavonoides/análise , Hormônios Esteroides Gonadais/sangue , Pré-Menopausa/sangue , Prolactina/sangue , Globulina de Ligação a Hormônio Sexual/análise , Adulto , Androgênios/sangue , Antocianinas/análise , Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/sangue , Inquéritos sobre Dietas , Estrogênios/sangue , Feminino , Inquéritos Epidemiológicos , Humanos , Modelos Lineares , Pessoa de Meia-Idade
16.
Drug Test Anal ; 11(11-12): 1629-1643, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31701664

RESUMO

7-keto-DHEA (3ß-hydroxy-androst-5-ene-7,17-dione) is included in section S1 of the World Antidoping Agency (WADA) List of Prohibited Substances. The detection of its misuse in sports needs special attention, since it is naturally present in urine samples. The main goal of this study is to investigate the in vivo metabolism of 7-keto-DHEA after a single administration to healthy volunteers and to better describe the relationship between arimistane (androst-5-ene-7,17-dione) and 7-keto-DHEA after the application of the common routine procedures to detect anabolic steroids in WADA accredited antidoping laboratories. Free, glucuro-, and sulpho-conjugated steroids extracted from urine samples obtained before and after the administration of 7-keto-DHEA were analyzed by different gas chromatographic (GC)-mass spectrometric (MS) techniques. Gas chromatography coupled to tandem MS to study the effect on the endogenous steroid profile, coupled to isotope ratio mass spectrometry (IRMS) to investigate the potential formation of androgens derived from DHEA and coupled to high resolution accurate mass spectrometry (HRMS) to investigate new diagnostic metabolites. The analysis by IRMS confirmed that there is no formation of DHEA from 7-keto-DHEA. Ten proposed metabolites, not previously reported, were described. These include reduced and hydroxylated structures that are not considered part of the steroid profile in antidoping analyses. They showed considerable responses in all fractions analyzed. Some deoxidation reactions (including arimistane formation) were found and most probably can be linked to the sample preparation or instrumental analysis. This is important when interpreting the results after the application of procedures to detect steroids in urine currently used in antidoping laboratories. 7-keto-DHEA metabolism in humans for antidoping purposes was studied and unexpected results were found. This could lead to a misinterpretation of the data, depending on the procedure applied and the analytical instrumentation used.


Assuntos
Anabolizantes/metabolismo , Desidroepiandrosterona/análogos & derivados , Anabolizantes/administração & dosagem , Anabolizantes/urina , Cromatografia Líquida de Alta Pressão , Desidroepiandrosterona/administração & dosagem , Desidroepiandrosterona/metabolismo , Desidroepiandrosterona/urina , Doping nos Esportes , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Hidroxilação , Detecção do Abuso de Substâncias/métodos
17.
Span J Psychol ; 22: E40, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31640831

RESUMO

Recent studies have highlighted the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity and its end products, cortisol and dehydroepiandrosterone (DHEA), in women with a history of intimate partner violence (IPV) victimization. These studies analyzed several coping styles, but they neglected to examine the use of violent strategies to confront IPV and the way these strategies affect HPA functioning. This latter proposal would be based on the gender symmetry model of IPV, which sustains that IPV is generally symmetrical, but that women's violence tends to be a reaction to male violence. Hence, the main objective of the present study was to examine whether women's violent reactions to IPV would significantly predict salivary cortisol and DHEA levels, as well as the cortisol/DHEA ratio (assessed through two saliva samples per day on four consecutive work days), controlling for the women's prior IPV abuse, psychopathology, and demographic variables. Our data demonstrated that, specifically, psychological confrontation strategies predicted vespertine cortisol levels (adj R2 = .18, ß = .447, p < .01) and the cortisol/DHEA ratio (adj R2 = .08, ß = .322, p < .05), even after controlling several confounding variables, whereas physical and total confrontation in response to IPV did not predict these hormonal parameters.


Assuntos
Adaptação Psicológica/fisiologia , Vítimas de Crime , Desidroepiandrosterona/metabolismo , Hostilidade , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Maus-Tratos Conjugais , Adulto , Feminino , Humanos
18.
PLoS One ; 14(10): e0224081, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622417

RESUMO

Steroid hormones and their respective nuclear receptors are essential mediators in numerous physiologic and pathophysiologic processes, ranging from regulation of metabolism, immune function, and reproductive processes to the development of hormone-dependent cancers such as those of the breast and prostate. Because steroids must enter cells before activating nuclear receptors, understanding the mechanisms by which cellular uptake occurs is critical, yet a clear understanding of these mechanisms has been elusive. It is generally assumed that diffusion-driven uptake is similar across various steroids whereas an elevated cellular concentration is thought to reflect active uptake, but these assumptions have not been directly tested. Here we show that intact cells rapidly accumulate free steroids to markedly elevated concentrations. This effect varies widely depending on steroid structure; more lipophilic steroids reach more elevated concentrations. Strong preferences exist for 3ß-OH, Δ5-steroids vs. 3-keto, Δ4-structural features and for progestogens vs. androgens. Surprisingly, steroid-structure-specific preferences do not require cell viability, implying a passive mechanism, and occur across cells derived from multiple tissue types. Physiologic relevance is suggested by structure-specific preferences in human prostate tissue compared with serum. On the other hand, the presence of serum proteins in vitro blocks much, but not all, of the passive accumulation, while still permitting a substantial amount of active accumulation for certain steroids. Our findings suggest that both passive and active uptake mechanisms make important contributions to the cellular steroid uptake process. The role of passive, lipophilicity-driven accumulation has previously been largely unappreciated, and its existence provides important context to studies on steroid transport and action both in vitro and in vivo.


Assuntos
Esteroides/metabolismo , Androgênios/análise , Androgênios/sangue , Androgênios/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Desidroepiandrosterona/análise , Desidroepiandrosterona/metabolismo , Humanos , Cinética , Pregnenolona/análise , Pregnenolona/metabolismo , Progesterona/análise , Progesterona/metabolismo , Progesterona/farmacologia , Esteroides/análise , Esteroides/farmacologia , Espectrometria de Massas em Tandem
19.
J Vet Intern Med ; 33(5): 2286-2293, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31489708

RESUMO

BACKGROUND: Transient hypothalamic-pituitary-adrenal axis dysfunction occurs in critically ill foals with sepsis and neonatal maladjustment syndrome (NMS). Cortisol is the most commonly measured steroid. However, a complex interaction of various steroid compounds might play a role in pathophysiology of this disorder. OBJECTIVE: To identify steroid compounds present at high concentrations at birth that rapidly and steadily decrease within the first 7 days of life in healthy foals and that might be supportive diagnosis of NMS and other neonatal disorders. ANIMALS: Ten healthy neonatal Quarter Horse foals (5 females and 5 males). METHODS: Prospective study. Blood was collected in heparinized tubes within 30 minutes after birth, and at 12, 24, 48, 72, 96, 120, 144, and 168 hours of age. Plasma was separated and a panel of steroid compounds was analyzed using liquid chromatography-mass spectrometry. A nonlinear regression model was used to determine decay concentrations over time. Confidence intervals (CIs) were calculated and significance was set a P ≤ .05. RESULTS: Five compounds were identified: pregnenolone, progesterone, deoxycorticosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. Pregnenolone and progesterone concentrations rapidly decreased by 24 hours of age and remained low throughout the first 7 days of life. Their half-life (95% CI) was short at 3.7 (3.4, 4.0) and 4.5 (2.8, 6.1) hours, respectively. No statistical differences in the concentrations of these compounds were found between males and females. CONCLUSIONS AND CLINICAL RELEVANCE: Progesterone might be a useful marker for identifying continuous endogenous production of neuroactive steroids in foals with suspected NMS and other neonatal diseases.


Assuntos
Animais Recém-Nascidos/sangue , Cavalos/sangue , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Animais , Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/sangue , Desoxicorticosterona/sangue , Feminino , Masculino , Pregnenolona/sangue , Progesterona/sangue , Estudos Prospectivos
20.
Graefes Arch Clin Exp Ophthalmol ; 257(11): 2429-2436, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31512044

RESUMO

PURPOSE: Diabetic retinopathy (DR) is a complex eye disease associated with diabetes mellitus. It is characterized by three pathophysiological components, namely microangiopathy, neurodegeneration, and inflammation. We recently reported that intraperitoneal administration of BNN27, a novel neurosteroidal microneurotrophin, reversed the diabetes-induced neurodegeneration and inflammation in rats treated with streptozotocin (STZ), by activating the NGF TrkA and p75 receptors. The aim of the present study was to investigate the efficacy of BNN27 to protect retinal neurons when applied topically as eye drops in the same model. METHODS: The STZ rat model of DR was employed. BNN27 was administered as eye drops to diabetic Sprague-Dawley rats for 7 days, 4 weeks post-STZ (70 mg/kg) injection. Immunohistochemistry and western blot analyses were employed to examine the viability of retinal neurons in control, diabetic, and diabetic-treated animals and the involvement of the TrkA receptor and its downstream signaling ERK1/2 kinases, respectively. RESULTS: BNN27 reversed the STZ-induced attenuation of the immunoreactive brain nitric oxide synthetase (bNOS)- and tyrosine hydroxylase (TH)-expressing amacrine cells and neurofilament (NFL)-expressing ganglion cell axons in a dose-dependent manner. In addition, BNN27 activated/phosphorylated the TrkA receptor and its downstream prosurvival signaling pathway, ERK1/2 kinases. CONCLUSIONS: The results of this study provide solid evidence regarding the efficacy of BNN27 as a neuroprotectant to the diabetic retina when administered topically, and suggest that its pharmacodynamic and pharmacokinetic profiles render it a putative therapeutic for diabetic retinopathy.


Assuntos
Desidroepiandrosterona/administração & dosagem , Diabetes Mellitus Experimental , Retinopatia Diabética/tratamento farmacológico , Retina/patologia , Administração Tópica , Animais , Western Blotting , Desidroepiandrosterona/farmacocinética , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/metabolismo , Relação Dose-Resposta a Droga , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/metabolismo , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA