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1.
Eur J Endocrinol ; 182(3): 265-273, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32038030

RESUMO

Objectives: We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA). Design: Multicenter retrospective study by Japan PA study. Method: We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI <2 with ACTH-stimulated LI ≥4 (Bilateral (B) to U group, n = 15); and basal LI ≥2 with ACTH-stimulated LI <4 (U to B group, n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria. Results: Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI. Conclusions: Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group.


Assuntos
Glândulas Suprarrenais/metabolismo , Cosintropina/farmacologia , Hiperaldosteronismo/cirurgia , Adenoma/patologia , Neoplasias das Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/efeitos dos fármacos , Adrenalectomia , Adenoma Adrenocortical/patologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Sensibilidade e Especificidade , Resultado do Tratamento
2.
Biosci Biotechnol Biochem ; 84(3): 606-612, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31746674

RESUMO

Royal jelly (RJ) is used as a dietary supplement for human health promotion. Recently, a clinical trial has reported that RJ improved mental health. The present study was conducted to experimentally support the clinical effect of RJ on mental health and to further elucidate the mechanisms of action of RJ. RJ and an ethanol extract of RJ, which contains fatty acids but not proteins, inhibited an unpredictable chronic mild stress (UCMS)-induced increase in immobility time, a depression-like behavior, in the tail suspension test. DNA microarray analysis of the adrenal grand revealed that the expression of genes involved in cholesterol metabolism was up-regulated in response to UCMS exposure and that RJ suppressed expression of genes related to cholesterol synthesis and transport. These results suggested that RJ improves stress-induced depression-like behavior by regulating adrenal steroidogenesis and that fatty acids contained in RJ partly contribute to the antidepressant effect of RJ.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Corticosterona/biossíntese , Depressão/prevenção & controle , Ácidos Graxos/farmacologia , Estresse Fisiológico , Glândulas Suprarrenais/metabolismo , Animais , Peso Corporal , Doença Crônica , Corticosterona/sangue , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C
3.
Bull Exp Biol Med ; 167(5): 624-627, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31606806

RESUMO

We studied the effect of LPS on the state of stress-marker organs in rats at various periods after a single exposure to long-term stress on the model of 24-h immobilization. The animals were intraperitoneally injected with LPS in a dose of 100 µg/kg immediately after the negative emotiogenic exposure. Changes in physiological parameters were evaluated 3 h, 1 day, and 8 days after immune stimulation. Acute stress was accompanied by a decrease in the weight of the thymus during all stages of the post-stress period. An increase in the relative weight of theadrenal glands in animals under these conditions was observed only on day 8 after restraint stress. The induction of immune reactions due to systemic treatment with LPS was shown to prevent involution of the spleen in the late stage after a single exposure to long-term stress (day 8). Hypertrophy of the adrenal glands, which serves as one of the typical reactions of mammals to negative emotiogenic factors, was not revealed during the post-stress period after antigenic stimulation. These data hold much promise for the development of new approaches to the use of immunoactive substances to prevent or reduce the severity of physiological changes after emotiogenic loads.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Estresse Psicológico/fisiopatologia , Timo/efeitos dos fármacos , Glândulas Suprarrenais/fisiopatologia , Animais , Imobilização/métodos , Injeções Intraperitoneais , Masculino , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/imunologia , Ratos , Ratos Wistar , Baço/efeitos dos fármacos , Baço/fisiopatologia , Estresse Psicológico/imunologia , Estresse Psicológico/prevenção & controle , Timo/fisiopatologia
4.
Eur J Endocrinol ; 181(4): C13-C15, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505455

RESUMO

A study has examined the rates of adrenal crises in patients treated with pituitary or adrenal surgery. Rates were substantial (approximately 9 per 100 patient years), perhaps representing suppression of corticotrope ACTH secretion and deprivation of normal corticotrope number postoperatively. Hormone withdrawal syndrome may have contributed to the rates of apparent adrenal crises given the definition used. Higher rates were seen in patients given relatively high dose glucocorticoids postoperatively in one of the two centres where patients were treated - perhaps some of the patients in the high dose centre had longer periods of corticotrope suppression from exogenous glucocorticoids, increasing the risk period for adrenal crises. The question of optimal glucocorticoid dose and weaning rate after cure of Cushing's syndrome remains a balance between weaning at a rate sufficiently rapid to allow resumption of normal corticotrope function thereby preventing adrenal crises and providing sufficient glucocorticoid support to avoid hormone withdrawal syndrome or even precipitating an adrenal crisis, in the vulnerable 4-6 month period after successful surgery. There is likely to be considerable inter-individual variability in optimum glucocorticoid dose and weaning rate so that close clinical and biochemical monitoring is currently a practical approach.


Assuntos
Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Síndrome de Cushing/metabolismo , Síndrome de Cushing/terapia , Glândulas Suprarrenais/efeitos dos fármacos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Estudos Multicêntricos como Assunto/métodos , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Resultado do Tratamento
5.
Regul Toxicol Pharmacol ; 108: 104472, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494191

RESUMO

The OECD guideline 407 outlines the conduct of 28-day studies in rodents to detect systemic toxicity with focus on endocrine and immunotoxic effects. It was validated with the rat as preferred model species. Justification is required for other rodent species, as an increased variability is expected compared to the rat. We investigated the variability of organ weights in the mouse and compared this to data published for the rat in the validation report of test guideline 407. Furthermore, the influence of the immunotoxic model substance cyclophosphamide on spleen and thymus weights in the mouse in immunotoxicity studies (duration 28 days) is reported and discussed, an immunotoxic model substance was not included in the validation report. Historical control data were compiled for mouse studies performed according to OECD 407 and for immunotoxicity studies between 2008 and 2013 at BASF SE. For absolute weights, the coefficient of variation was determined for each study group and compared with the rat. Adrenal glands, ovaries and to lesser degree testes and prostate showed higher coefficients of variation in the mouse (most pronounced in adrenal glands in male animals: rat 5%-17%, CD1 mouse 20%-51%). Effects of cyclophosphamide were best detected measuring the thymus weight.


Assuntos
Variação Biológica Individual , Peso Corporal , Grupos Controle , Tamanho do Órgão , Testes de Toxicidade Subaguda , Glândulas Suprarrenais/anatomia & histologia , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Ciclofosfamida/toxicidade , Feminino , Genitália/anatomia & histologia , Genitália/efeitos dos fármacos , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Imunossupressores/toxicidade , Rim/anatomia & histologia , Rim/efeitos dos fármacos , Fígado/anatomia & histologia , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Ratos , Especificidade da Espécie , Baço/anatomia & histologia , Baço/efeitos dos fármacos , Timo/anatomia & histologia , Timo/efeitos dos fármacos
6.
J Toxicol Sci ; 44(9): 575-584, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474739

RESUMO

The adrenal gland is the most common toxicological target of drugs within the endocrine system, and inhibition of adrenal steroidogenesis can be fatal in humans. However, methods to evaluate the adrenal toxicity are limited. The aim of the present study was to verify the usefulness of simultaneous measurement of blood levels of multiple adrenal steroids, including precursors, as a method to evaluate drug effects on adrenal steroidogenesis in cynomolgus monkeys. With this aim, physiological and drug-induced changes in blood levels of adrenal steroids, including cortisol, aldosterone, androgen, and their precursors were examined. First, for physiological changes, intraday and interday changes in blood steroid levels were examined in male and female cynomolgus monkeys. The animals showed circadian changes in steroid levels that are similar to those in humans, while interday changes were relatively small in males. Next, using males, changes in blood steroid levels induced by ketoconazole and metyrapone were examined, which suppress adrenal steroidogenesis via inhibition of CYP enzymes. Consistent with rats and humans, both ketoconazole and metyrapone increased the deoxycorticosterone and deoxycortisol levels, probably via CYP11B1 inhibition, and the increase was observed earlier and with greater dynamic range than the changes in cortisol level. Changes in other steroid levels reflecting the drug mechanisms were also observed. In conclusion, this study showed that in cynomolgus monkeys, simultaneous measurement of blood levels of adrenal steroids, including precursors, can be a valuable method to sensitively evaluate drug effects on adrenal steroidogenesis and to investigate the underlying mechanisms.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Aldosterona/sangue , Aldosterona/metabolismo , Androgênios/sangue , Androgênios/metabolismo , Cromatografia Líquida/métodos , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Cetoconazol/toxicidade , Metirapona/toxicidade , Espectrometria de Massas em Tandem/métodos , Animais , Ritmo Circadiano , Desoxicorticosterona/metabolismo , Feminino , Humanos , Macaca fascicularis , Masculino , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores
7.
J Toxicol Sci ; 44(9): 601-610, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474741

RESUMO

To verify simultaneous measurement of blood levels of adrenal steroids as a tool to evaluate drug effects on adrenal steroidogenesis, dose- and time-dependent changes in blood levels of corticosterone and its precursors (pregnenolone, progesterone and deoxycorticosterone), as well as their relationship with the pathological changes in the adrenal gland, were examined in rats dosed with ketoconazole (KET). Also examined were whether effects on adrenal steroidogenesis that were not obvious in the blood steroid levels after sole administration of KET could be revealed by post-administration of ACTH, and the correlation between the blood and adrenal steroid levels. Male rats were dosed with 15, 50, or 150 mg/kg of KET for 1 or 7 days with or without ACTH, and the blood and adrenal concentrations of the steroids were measured. KET increased the blood deoxycorticosterone level even at a dose level and time point at which histopathological changes were not obvious. KET-induced changes in blood levels of other steroids were revealed by ACTH, and the blood and adrenal levels were generally correlated especially after ACTH post-administration. Thus, blood levels of adrenal steroids, including precursors, can be a sensitive and early marker of drug effects on the adrenal steroidogenesis that reflect adrenal levels of steroids. The usefulness of the multiple steroid measurement as a method for mechanism investigation of drug effects on the adrenal gland can be further enhanced by ACTH.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/farmacologia , Desoxicorticosterona/sangue , Desoxicorticosterona/metabolismo , Cetoconazol/toxicidade , Pregnenolona/sangue , Pregnenolona/metabolismo , Progesterona/sangue , Progesterona/metabolismo , Glândulas Suprarrenais/patologia , Hormônio Adrenocorticotrópico/administração & dosagem , Animais , Cromatografia Líquida , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Fatores de Tempo
8.
Biol Pharm Bull ; 42(8): 1402-1408, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366875

RESUMO

Beta-cryptoxanthin (ß-CRX, (3R)-ß, ß-caroten-3-ol) is an oxygenated carotenoid and a potent antioxidant that is abundant in Satsuma mandarin orange (Citrus unshiu MARC.), which is the most popular fruit in Japan. Since our preliminary data suggested that the ingestion of ß-CRX had an anti-stress effect in female participants, the effect was evaluated in another set of female participants. The study design was a double-blind group comparison and participants (n = 23) were randomly assigned to ß-CRX-rich orange juice or placebo (ß-CRX was removed from orange juice) groups. ß-CRX or placebo juice (125 mL, after breakfast) were consumed from 1 week prior to pharmacy practice and continued for 5 d into the practice period. Salivary α-amylase activity (sAA), a marker of sympathetic nervous system activity, was significantly higher in the evening than in the morning in the placebo-group during pharmacy practice, but not in the ß-CRX-group. This result supports the anti-stress effect of ß-CRX. The dose-dependency of ß-CRX was observed in male mice that were loaded with stress. These results indicate that the ingestion of ß-CRX is helpful to reduce stress.


Assuntos
beta-Criptoxantina/farmacologia , Citrus , Sucos de Frutas e Vegetais , alfa-Amilases Salivares/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Glândulas Suprarrenais/efeitos dos fármacos , Adulto , Animais , Método Duplo-Cego , Feminino , Frutas , Humanos , Masculino , Camundongos , Estresse Psicológico/metabolismo , Adulto Jovem
11.
Endocrinology ; 160(7): 1719-1730, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31166572

RESUMO

The control of steroidogenesis in the neonatal adrenal gland is of great clinical interest. We have previously demonstrated that the postnatal day (PD) 2 rat exhibits a large plasma corticosterone response to hypoxia in the absence of an increase in plasma ACTH measured by RIA, whereas the corticosterone response to exogenous ACTH is intact. By PD8, the corticosterone response to hypoxia is clearly ACTH-dependent. We hypothesized that this apparently ACTH-independent response to hypoxia in the newborn rat is due to an increase in a bioactive, nonimmunoassayable form of ACTH. To evaluate this phenomenon, we pretreated neonatal rats with a novel, specific, neutralizing anti-ACTH antibody (ALD1611) (20 mg/kg or 1 mg/kg IP) on the morning of PD1, PD7, and PD14. Twenty-four hours later, we measured hypoxia- or ACTH-stimulated plasma ACTH and corticosterone. For long-term effects, ALD1611 was given on PD1 and pups were studied on PD8 and PD15. Pretreatment with ALD1611 significantly decreased baseline corticosterone and completely blocked the corticosterone response to hypoxia and exogenous ACTH stimulation at all ages. The effect of 1 mg/kg ALD1611 on PD1 had dissipated by PD15. The decrease in corticosterone in ALD1611-treated pups was associated with decreases in baseline and hypoxia- and ACTH-stimulated adrenal Ldlr, Mrap, and Star mRNA expression at all ages. The adrenal response to hypoxia in the newborn rat is ACTH-dependent, suggesting the release of nonimmunoassayable, biologically active forms of ACTH. ALD1611 is useful as a tool to attenuate stress-induced, ACTH-dependent adrenal steroidogenesis in vivo.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Hormônio Adrenocorticotrópico/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Corticosterona/sangue , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/farmacologia , Animais , Animais Recém-Nascidos , Feminino , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Hipóxia/metabolismo , Masculino , Fosfoproteínas/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de LDL/metabolismo
12.
Eur J Endocrinol ; 181(3): D15-D26, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31176302

RESUMO

Notwithstanding the high prevalence of primary aldosteronism (PA), probably the most common form of secondary hypertension, the diagnosis of PA is often neglected or delayed, thus precluding target treatment, which is curative in many cases. For selection of the most appropriate treatment, a fundamental step is the distinction between a lateralized form, mainly aldosterone-producing adenoma (APA), and bilateral adrenocortical hyperplasia (BAH), also known as idiopathic hyperaldosteronism (IHA). To this aim all current guidelines recommend adrenal vein sampling (AVS), a technically challenging procedure that often fails, particularly in non-experienced hands. Cosyntropin (synthetic ACTH) is administered in the attempt to maximize adrenal cortisol secretion and avoid pulsatile adrenocortical hormone secretion in about 40% of the referral centres around the world. However, the Endocrine Society guidelines do not advise about the use or not of cosyntropin as stimulus during AVS, as there are arguments in favour and against its use. These arguments are presented in this debate article reflecting the views of groups that currently use and do not use cosyntropin.


Assuntos
Glândulas Suprarrenais/irrigação sanguínea , Glândulas Suprarrenais/metabolismo , Aldosterona/metabolismo , Cosintropina/administração & dosagem , Hiperaldosteronismo/metabolismo , Flebotomia/métodos , Glândulas Suprarrenais/efeitos dos fármacos , Hormônios/administração & dosagem , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/tratamento farmacológico
13.
Can J Physiol Pharmacol ; 97(10): 924-931, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31132324

RESUMO

Sensitized stress-induced corticosterone (CORT) secretion in chronically stressed rats involves 5-HT7 receptor activation. The effect of 14-day chronic CORT and vehicle (VEH) administration on 5-HT7 receptor expression in adrenal glands, adrenal 5-HT content, and adrenocorticotropic hormone and CORT secretion was analysed. On day 15, VEH- and CORT-treated animals were perfused or decapitated without stress exposure (0 min) or after 10 and 30 min of restraint for collection of trunk blood and tissues. 5-HT7 receptor-like immunoreactivity (5-HT7R-LI), 5-HT7 receptor protein, and mRNA levels were determined by immunohistochemistry, Western blot, and reverse transcription polymerase chain reaction assays, respectively; 5-HT levels and hormones were quantified using HPLC and ELISA kits, respectively. An undisturbed control group was included for most experimental comparisons. Chronic CORT strongly increased 5-HT7R-LI in the outer adrenal cortex, as well as 5-HT7 receptor protein and mRNA in whole adrenal glands; adrenal 5-HT content also increased in these animals. Decreased adrenocorticotropic hormone and CORT secretion at 30 min of restraint occurred in CORT-treated rats. The results support the notion that chronic stress-induced increase of adrenocortical 5-HT7 receptors and adrenal 5-HT content is a glucocorticoid-dependent phenomenon; the development of magnified stress-induced 5-HT7 receptor-mediated CORT responses in chronically stressed animals nevertheless likely involves additional mechanisms.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Corticosterona/administração & dosagem , Receptores de Serotonina/metabolismo , Estresse Psicológico/metabolismo , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/análise , Hormônio Adrenocorticotrópico/metabolismo , Animais , Corticosterona/metabolismo , Modelos Animais de Doenças , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Receptores de Serotonina/análise , Restrição Física/psicologia , Serotonina/análise , Serotonina/metabolismo , Estresse Psicológico/etiologia , Estresse Psicológico/psicologia
14.
Nutrients ; 11(5)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31035471

RESUMO

The consumption of high levels of dietary caffeine has increased in children and adolescents. Human and animal studies have shown that chronic intake of high doses of caffeine affects serum glucocorticoid levels. Given that glucocorticoids play a role in peripubertal organ growth and development, chronic high doses of caffeine during puberty might impair maturation of the adrenal glands. To evaluate any effects of caffeine exposure on growing adrenal glands, 22-day-old male (n = 30) and female Sprague Dawley rats (n = 30) were divided into three groups (n = 10/group); group 1 received tap water (control) and groups 2 and 3 received water containing 120 and 180 mg/kg/day caffeine, respectively, via gavage for 4 weeks. At the end of the experiment, adrenal glands were weighed and processed for histological analysis. Relative adrenal weights increased in both groups of caffeine-fed males and females, whereas absolute weights were decreased in the females. In the female caffeine-fed groups the adrenal cortical areas resembled irregularly arranged cords and the medullary area was significantly increased, whereas no such effects were seen in the male rats. Our results indicate that the harmful effects of caffeine on the adrenal glands of immature rats differ between females and males. Although female rats seemed to be more susceptible to damage based on the changes in the microarchitecture of the adrenal glands, caffeine affected corticosterone production in both female and male rats. In addition, increased basal adrenocorticotropic hormone levels in caffeine-fed groups may reflect decreased cortical function. Therefore, caffeine may induce an endocrine imbalance that disturbs the establishment of the hypothalamo-pituitary adrenal axis during puberty, thereby leading to abnormal stress responses.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Cafeína/efeitos adversos , Maturidade Sexual , Glândulas Suprarrenais/patologia , Hormônio Adrenocorticotrópico/sangue , Animais , Cafeína/administração & dosagem , Corticosterona/sangue , Relação Dose-Resposta a Droga , Feminino , Masculino , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley
15.
Ecotoxicol Environ Saf ; 180: 326-332, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31100596

RESUMO

Aniline and aniline derivatives have been widely used in the production of pesticides, pharmaceuticals, cosmetic, dyes, rubber, and adhesives products. These chemicals can easily be released into the environment through industrial and municipal discharges or as degradation byproducts. Several studies have suggested that aniline and some of its derivatives could cause reproductive toxicity in aquatic organisms. However, knowledge on the endocrine disruption potentials of these chemicals is limited only to aniline and associated mechanisms are rarely investigated. The objective of this study was to investigate the potential of major aniline derivatives, i.e., 3,4-dichloroaniline (3,4-DCA), 1-naphthylamine (1-NPA), and 4,4'-methylenedianiline (4,4'-MDA), to disrupt sex steroid production and other biological processes. For this purpose, the human adrenal H295R cell line and adult male zebrafish (Danio rerio) were used. In the H295R cell line, all tested aniline derivatives decreased testosterone (T) levels. Regulatory changes of several steroidogenic genes, i.e., down-regulation of StAR or CYP17 genes, and up-regulation of CYP19A, observed in the H295R cells could explain the sex hormone disruption. In male zebrafish, generally similar directions of changes, i.e., decreases in T levels and increased E2/T ratios, were observed. Again, down-regulation of key steroidogenic genes such as cyp17 or 3ß-hsd, but slight up-regulation of cyp19a gene observed in the fish could explain the sex hormone changes. The results of our study demonstrate that all tested aniline derivatives could influence steroidogenesis and disrupt sex hormone balance toward reduced androgenicity. Consequences of anti-androgenicity following long-term exposure warrant further investigation.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Compostos de Anilina/toxicidade , Disruptores Endócrinos/toxicidade , Testosterona/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Glândulas Suprarrenais/metabolismo , Animais , Aromatase/genética , Linhagem Celular , Família 17 do Citocromo P450/genética , Relação Dose-Resposta a Droga , Humanos , Masculino , Fosfoproteínas/genética
16.
Phytomedicine ; 58: 152874, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30889421

RESUMO

BACKGROUND: The fruits of Psoralea corylifolia L. (Fructus Psoraleae, FP) has a long history and a wide range of applications in the treatment of osteoporosis and leukoderma. Although it is well known that FP could cause hepatotoxicity and reproductive toxicity, less is known about its potential toxicity on multiple organs. PURPOSE: This study aims to determine the multiorgan toxicity of EtOH extract of FP (EEFP) and to investigate the underlying mechanisms through a systematic evaluation in Wistar rats. STUDY DESIGN AND METHODS: Wistar rats were orally administered with the EEFP at doses of 1.5, 1.0 and 0.5 g/kg for 28 days. Histopathologic and clinicopathologic analyses were performed, and the hormone levels in serum and the mRNA levels of enzymes related to the production of steroid hormones in adrenal glands were detected. The area of each band of adrenal glands and the steroid levels in the adrenal glands were also measured. RESULTS: After the treatment, both the histopathologic and clinicopathologic examination showed that EEFP caused liver, prostate, seminal vesicle and adrenal gland damage. Among the enzymes involved in the regulation of adrenal steroid hormone production, NET, VMAT2, and CYP11B1 were upregulated, while CYP17A1 was downregulated. Among the adrenal steroid hormones, COR and NE were upregulated, while levels of DHT and serum ACRH and CRH decreased. CONCLUSION: Our results indicated that adrenal gland, prostate, and seminal vesicles could also be the target organs of FP-induced toxicity. Abnormal enzyme and hormone production related to the hypothalamic pituitary adrenal (HPA) axis caused by the EEFP may be the potential toxic mechanism for changes in the adrenal gland and secondary sex organs of male rats.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Enzimas/metabolismo , Extratos Vegetais/toxicidade , Esteroides/metabolismo , Administração Oral , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Animais , Enzimas/genética , Etanol/química , Feminino , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Próstata/efeitos dos fármacos , Próstata/patologia , Ratos Wistar , Testes de Toxicidade/métodos
17.
Res Vet Sci ; 124: 137-148, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30901666

RESUMO

The present study evaluated the toxic effects of Tilmicosin (TIL) on adult rats. The rats received a single subcutaneous injection of TIL at different doses (10, 25, 50, 75 and 100 mg/kg bw). TIL altered the biochemical parameters including liver and kidney function markers, glucose level and lipid profile as well as resulted in histopathological lesions in liver and adrenal glands mostly in rats exposed to 75 and 100 mg/kg bw. Then the role of Astragalus polysaccharide (APS) at 100 and 200 mg/kg bw, in modulating the toxic effects induced by high dose of TIL was evaluated. Single injection of TIL at a dose of 75 mg/kg bw was found to increase the activity of ALT, AST and ALP enzymes, induce the generation of reactive oxygen species (ROS) and decrease the total antioxidant capacity (TAC). TIL upregulated the hepatic mRNA expression of heat shock protein 70 (HSP70) and nuclear factor kappa B (NF-kB) while blocked the Nrf2/HO-1 mediated response. These changes were also associated with increasing tumer necrosis factor-alpha (TNF-α), interlukin1-beta (IL-1ß) and nitric oxide levels. On the other hand, the results indicate that APS has a beneficial role particularly at high level in alleviating the stress and the hepatotoxic effects elicited by TIL injection in rats.


Assuntos
Antibacterianos/toxicidade , Astrágalo (Planta)/química , Polissacarídeos/farmacologia , Substâncias Protetoras/farmacologia , Tilosina/análogos & derivados , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/fisiopatologia , Animais , Análise Química do Sangue , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Testes Hematológicos , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tilosina/toxicidade
18.
Endocrine ; 64(1): 169-175, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30729424

RESUMO

INTRODUCTION: Glucocorticoid release by adrenals has been described as significant to survive sepsis. The activation of transient receptor potential vanilloid type 1 (TRPV1) inhibited ACTH-induced glucocorticoid release by adrenal glands in vitro. OBJECTIVE: The aim of this study was to investigate if capsaicin, an activator of TRPV1, would prevent LPS-induced glucocorticoid production by adrenals. METHODS: Male Swiss-Webster mice were treated with capsaicin intraperitoneally (0.2 or 2 mg/kg) 30 min before LPS injection. All analyses were performed 2 h after the LPS stimulation, including plasma corticosterone and peritoneal IL-1ß and TNF-α levels. Furthermore, murine adrenocortical Y1 cells were used to assess the effects of capsaicin on LPS-induced corticosterone production in vitro. RESULTS: Capsaicin (2 mg/kg, i.p.) significantly reduced plasma corticosterone levels and adrenal hypertrophy induced by LPS without alter the levels of pro-steroidogenic cytokines IL-1ß and TNF-α in peritoneal cavity of mice, while the dose of 0.2 mg/kg of capsaicin did not interfere with adrenal steroidogenesis, attested by RIA and ELISA, respectively. Y1 cells express TRPV1, measured by immunofluorescence and western blot, and capsaicin decreased LPS-induced corticosterone production by these cells in vitro. Capsaicin also induces calcium mobilization in Y1 cells in vitro. CONCLUSIONS: These findings suggest that capsaicin inhibits corticosterone production induced by LPS by acting directly on adrenal cells producing glucocorticoids, in a mechanism probably associated with induction of a cytoplasmic calcium increase in these cells.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Cálcio/metabolismo , Capsaicina/farmacologia , Glucocorticoides/biossíntese , Lipopolissacarídeos/farmacologia , Glândulas Suprarrenais/metabolismo , Animais , Líquido Ascítico/metabolismo , Linhagem Celular , Corticosterona/biossíntese , Interleucina-1beta/metabolismo , Masculino , Camundongos , Canais de Cátion TRPV/agonistas , Fator de Necrose Tumoral alfa/metabolismo
19.
Can J Physiol Pharmacol ; 97(7): 685-690, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30773040

RESUMO

This study investigated the effects of melatonin treatment on adrenal catecholamine content, synthesis, uptake, and vesicular transport induced by the chronic unpredictable mild stress (CUMS) model of depression in rats. This entailed quantifying the norepinephrine, epinephrine, mRNA, and protein levels of tyrosine hydroxylase (TH), dopamine-ß-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT), norepinephrine transporter (NET), and vesicular monoamine transporter 2 (VMAT2) in the adrenal medulla. CUMS caused a significant depletion of norepinephrine stores and protein levels of TH, DBH, and NET, whereas the gene expression of PNMT was increased. It was observed that melatonin treatment in the CUMS rats prevented the stress-induced decrease in norepinephrine content and the protein expression of TH, DBH, and NET in the adrenal medulla of chronically stressed rats. The present study demonstrates the stimulatory effect of melatonin on adrenomedullary synthesis, the uptake and content of catecholamine in the rat model of chronic stress-induced depression.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Catecolaminas/biossíntese , Depressão/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Melatonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Estresse Psicológico/complicações , Glândulas Suprarrenais/metabolismo , Animais , Doença Crônica , Depressão/etiologia , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Masculino , Melatonina/uso terapêutico , Ratos , Ratos Wistar
20.
ACS Chem Neurosci ; 10(3): 1369-1379, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30698015

RESUMO

The classical small molecule neurotransmitters are essential for cell-cell signaling in the nervous system for regulation of behaviors and physiological functions. Metabolomics approaches are ideal for quantitative analyses of neurotransmitter profiles but have not yet been achieved for the repertoire of 14 classical neurotransmitters. Therefore, this study developed targeted metabolomics analyses by full scan gas chromatography/time-of-flight mass spectrometry (GC-TOF) and hydrophilic interaction chromatography-QTRAP mass spectrometry (HILIC-MS/MS) operated in positive ionization mode for identification and quantitation of 14 neurotransmitters consisting of acetylcholine, adenosine, anandamide, aspartate, dopamine, epinephrine, GABA, glutamate, glycine, histamine, melatonin, norepinephrine, serine, and serotonin. GC-TOF represents a new metabolomics method for neurotransmitter analyses. Sensitive measurements of 11 neurotransmitters were achieved by GC-TOF, and three neurotransmitters were analyzed by LC-MS/MS (acetylcholine, anandamide, and melatonin). The limits of detection (LOD) and limits of quantitation (LOQ) were assessed for linearity for GC-TOF and LC-MS/MS protocols. In neurotransmitter-containing dense core secretory vesicles of adrenal medulla, known as chromaffin granules (CG), metabolomics measured the concentrations of 9 neurotransmitters consisting of the catecholamines dopamine, norepinephrine, and epinephrine, combined with glutamate, serotonin, adenosine, aspartate, glycine, and serine. The CG neurotransmitters were constitutively secreted from sympathoadrenal chromaffin cells in culture. Nicotine- and KCl-stimulated release of the catecholamines and adenosine. Lithium, a drug used for the treatment of bipolar disorder, decreased the constitutive secretion of dopamine and norepinephrine and decreased nicotine-stimulated secretion of epinephrine. Lithium had no effect on other secreted neurotransmitters. Overall, the newly developed GC-TOF with LC-MS/MS metabolomics methods for analyses of 14 neurotransmitters will benefit investigations of neurotransmitter regulation in biological systems and in human disease conditions related to drug treatments.


Assuntos
Comunicação Celular/fisiologia , Células Cromafins/química , Lítio/farmacologia , Metabolômica/métodos , Neurotransmissores/análise , Espectrometria de Massas em Tandem/métodos , Glândulas Suprarrenais/química , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Animais , Bovinos , Comunicação Celular/efeitos dos fármacos , Células Cromafins/efeitos dos fármacos , Células Cromafins/metabolismo , Cromatografia Gasosa/métodos , Cromatografia Líquida/métodos , Neurotransmissores/metabolismo , Paragânglios Cromafins/química , Paragânglios Cromafins/efeitos dos fármacos , Paragânglios Cromafins/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
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