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1.
Endocrinology ; 160(10): 2215-2229, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398249

RESUMO

The circadian glucocorticoid (GC) rhythm is dependent on a molecular clock in the suprachiasmatic nucleus (SCN) and an adrenal clock that is synchronized by the SCN. To determine whether the adrenal clock modulates GC responses to stress, experiments used female and male Cyp11A1Cre/+::Bmal1Fl/Fl knockout [side-chain cleavage (SCC)-KO] mice, in which the core clock gene, Bmal1, is deleted in all steroidogenic tissues, including the adrenal cortex. Following restraint stress, female and male SCC-KO mice demonstrate augmented plasma corticosterone but not plasma ACTH. In contrast, following submaximal scruff stress, plasma corticosterone was elevated only in female SCC-KO mice. Adrenal sensitivity to ACTH was measured in vitro using acutely dispersed adrenocortical cells. Maximal corticosterone responses to ACTH were elevated in cells from female KO mice without affecting the EC50 response. Neither the maximum nor the EC50 response to ACTH was affected in male cells, indicating that female SCC-KO mice show a stronger adrenal phenotype. Parallel experiments were conducted using female Cyp11B2 (Aldosterone Synthase)Cre/+::Bmal1Fl/Fl mice and adrenal cortex-specific Bmal1-null (Ad-KO) mice. Plasma corticosterone was increased in Ad-KO mice following restraint or scruff stress, and in vitro responses to ACTH were elevated in adrenal cells from Ad-KO mice, replicating data from female SCC-KO mice. Gene analysis showed increased expression of adrenal genes in female SCC-KO mice involved in cell cycle control, cell adhesion-extracellular matrix interaction, and ligand receptor activity that could promote steroid production. These observations underscore a role for adrenal Bmal1 as an attenuator of steroid secretion that is most prominent in female mice.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Córtex Suprarrenal/metabolismo , Corticosterona/sangue , Glucocorticoides/metabolismo , Fatores de Transcrição ARNTL/genética , Hormônio Adrenocorticotrópico , Animais , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Feminino , Genótipo , Masculino , Camundongos , Camundongos Knockout , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Fatores Sexuais , Estresse Fisiológico
2.
Toxicol Lett ; 314: 63-74, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306741

RESUMO

This study aimed to verify the toxic effects of prenatal caffeine exposure (PCE) on the podocyte development in male offspring, and to explore the underlying intrauterine programming mechanisms. The pregnant rats were administered with caffeine (30 to 120 mg/kg⋅d) during gestational day (GD) 9 to 20. The male fetus on GD20 and the offspring at postnatal week (PW) 6 and PW28 were sacrificed. The results indicated that PCE caused ultrastructural abnormalities on podocyte, and inhibited the expression of podocyte marker genes such as Nephrin, Wilms tumor 1 (WT1), the histone 3 lysine 9 acetylation (H3K9ac) level in the Kruppel-like factor 4 (KLF4) promoter and its expression in the male offspring from GD20 to PW28. Meanwhile, the expression of glucocorticoid receptor (GR) and histone deacetylase 7 (HDAC7) in the fetus were increased by PCE. In vitro, corticosterone increased GR and HDAC7 whereas reduced the H3K9ac level of KLF4 and KLF4/Nephrin expression. KLF4 over-expression reversed the reduction of Nephrin expression, knockdown of HDAC7 and GR antagonist RU486 partially reversed the inhibitory effects of corticosterone on H3K9ac level and KLF4 expression. In conclusion, PCE caused podocyte developmental toxicity in male offspring, which was associated with corticosterone-induced low-functional programming of KLF4 through GR/HDAC7/H3K9ac pathway.


Assuntos
Cafeína/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Histonas/metabolismo , Nefropatias/induzido quimicamente , Fatores de Transcrição Kruppel-Like/metabolismo , Podócitos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Acetilação , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Idade Gestacional , Glucocorticoides/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Nefropatias/embriologia , Nefropatias/genética , Nefropatias/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Lisina , Masculino , Exposição Materna , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fenótipo , Podócitos/metabolismo , Podócitos/ultraestrutura , Gravidez , Regiões Promotoras Genéticas , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Zoo Biol ; 38(4): 334-342, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173396

RESUMO

We characterized behavioral and adrenocortical activities of Tamandua tetradactyla under human care driven by the hypothesis that they vary between males and females. We also assessed the potential association between natural or abnormal behaviors and adrenocortical activity. We kept females and males T. tetradactyla in individual, contiguous enclosures at Córdoba Zoo (Argentina), under natural photoperiod and temperature. During 29 consecutive days we monitored the animals' behavior by recording their activity pattern every 5 min using infrared cameras (8352 records/individual). We collected all feces and measured fecal glucocorticoid metabolites (FGM) with an 11-oxoaetiocholanolone enzyme immunoassay. We found individual differences in all behavioral variables. We detected that females exhibited lower total activity than males (23.8 ± 0.2% and 32.3 ± 0.3%, respectively; p = .005). Females were more active at night and males during the day (p < .05) and exhibited less abnormal behaviors than males (p = .05). Although we did not find sex-related differences for average FGM, we detected individual differences (p < .0001). We found that daily FGM showed negative (-0.39) and positive (0.38) correlations with natural and abnormal behaviors, respectively (p < .0001). Thus, we consider that individual input and sex are factors to be considered in stress responses of the species in captivity. Natural and abnormal behaviors may demand different levels of adrenocortical activity. Our findings may prove useful as normative data for ex situ management of conservation programs.


Assuntos
Comportamento Animal/fisiologia , Fezes/química , Glucocorticoides/metabolismo , Xenartros , Animais , Animais de Zoológico/metabolismo , Feminino , Glucocorticoides/química , Abrigo para Animais , Masculino , Caracteres Sexuais , Estresse Fisiológico
4.
Int J Mol Sci ; 20(11)2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31181590

RESUMO

In modern societies, high fructose intake from sugar-sweetened beverages has contributed to obesity development. In the diet, sucrose and high fructose corn syrup are the main sources of fructose and can be metabolized in the intestine and transported into the systemic circulation. The liver can metabolize around 70% of fructose intake, while the remaining is metabolized by other tissues. Several tissues including adipose tissue express the main fructose transporter GLUT5. In vivo, chronic fructose intake promotes white adipose tissue accumulation through activating adipogenesis. In vitro experiments have also demonstrated that fructose alone induces adipogenesis by several mechanisms, including (1) triglycerides and very-low-density lipoprotein (VLDL) production by fructose metabolism, (2) the stimulation of glucocorticoid activation by increasing 11ß-HSD1 activity, and (3) the promotion of reactive oxygen species (ROS) production through uric acid, NOX and XOR expression, mTORC1 signaling and Ang II induction. Moreover, it has been observed that fructose induces adipogenesis through increased ACE2 expression, which promotes high Ang-(1-7) levels, and through the inhibition of the thermogenic program by regulating Sirt1 and UCP1. Finally, microRNAs may also be involved in regulating adipogenesis in high fructose intake conditions. In this paper, we propose further directions for research in fructose participation in adipogenesis.


Assuntos
Adipogenia , Xarope de Milho Rico em Frutose/metabolismo , Obesidade/etiologia , Animais , Glucocorticoides/metabolismo , Xarope de Milho Rico em Frutose/efeitos adversos , Humanos , Metabolismo dos Lipídeos , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo
5.
Drugs ; 79(10): 1065-1087, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31201710

RESUMO

Glucocorticoids (GCs) are often used for improvement of quality of life, particularly in the elderly, but long-term GC use may cause harm; bone loss and fractures are among the most devastating side effects. Fracture risk is particularly high in patients with a severe underlying disease with an urgent need for treatment with high-dose GCs. Moreover, it is important to realize that these patients suffer from an augmented background fracture risk as these patients have a high presence of traditional risk factors for osteoporosis, such as high age, low body mass index (BMI), smoking and relatives with osteoporosis or hip fractures. It is thus crucial for prevention of osteoporotic fractures to use the lowest dose of GC for a short period of time to prevent fractures. Another important task is optimal treatment of the underlying disease; for instance, fracture risk is higher in patients with active rheumatoid arthritis than in patients in whom rheumatoid arthritis is in remission. Thus, fracture risk is generally highest in the early phase, when GC dosage and the disease activity of the underlying disease are high. Finally, some of the traditional risk factors can be modulated, e.g., smoking and low BMI. Life-style measures, such as adequate amounts of calcium and vitamin D and exercise therapy are also crucial. In some patients, anti-osteoporotic drugs are also indicated. In general, oral bisphosphonates (BPs) are the first choice, because of their efficacy and safety combined with the low cost of the drug. However, for those patients who do not tolerate oral BPs, alternatives ("second-line therapies") are available: BP intravenously (zoledronic acid), denosumab (Dmab), and teriparatide. Both zoledronic acid and Dmab have been proven to be superior to oral bisphosphonates like risedronate in improvement of bone mineral density. For teriparatide, vertebral fracture reduction has been shown in comparison with alendronate. Thus, to reduce the global burden of GC use and fracture risk, fracture risk management in GC users should involve at least involve life-style measures and the use of the lowest possible dose of GC. In high-risk patients, anti-osteoporotic drugs should be initiated. First choice drugs are oral BPs; however, in those with contraindications and those who do not tolerate oral BPs, second-line therapies should be started. Although this is a reasonable treatment algorithm, an unmet need is that the most pivotal (second-line) drugs are not used in daily clinical practice at the initial phase, usually characterized by high-dose GC and active underlying disease, when they are most needed. In some patients second-line drugs are started later in the disease course, with lower GC dosages and higher disease activity. As this is a paradox, we think it is a challenge for physicians and expert committees to develop an algorithm with clear indications in which specific patient groups second-line anti-osteoporotic drugs should or could be initiated as first-choice treatment.


Assuntos
Glucocorticoides/metabolismo , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/tratamento farmacológico , Cálcio/metabolismo , Denosumab/efeitos adversos , Denosumab/farmacocinética , Difosfonatos/farmacologia , Terapia por Exercício/métodos , Feminino , Glucocorticoides/genética , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Teriparatida/efeitos adversos , Teriparatida/farmacocinética , Resultado do Tratamento , Vitamina D/metabolismo , Ácido Zoledrônico/farmacologia
6.
Mol Med Rep ; 20(1): 401-408, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115574

RESUMO

Osteoblast apoptosis has been identified as an important event in the development of glucocorticoid (GC)­induced osteoporosis and osteonecrosis of the femoral head. Crocin, a bioactive ingredient of saffron, has been demonstrated to induce antiapoptotic effects on numerous types of cell in vitro; however, the effects of crocin on the dexamethasone (Dex)­induced apoptosis of osteoblasts remain unclear. In the present study, the protective effects of crocin during Dex­induced apoptosis of MC3T3­E1 osteoblasts, and the underlying mechanisms, were investigated. MTT and Annexin V­FITC/PI flow cytometry assays were performed to evaluate the viability and apoptosis of cells, respectively. The mitochondrial transmembrane potential, reactive oxygen species (ROS), intracellular Ca2+ levels and apoptosis­associated protein expression were assessed via flow cytometry, fluorescence microscopy and western blotting. It was demonstrated that crocin pretreatment inhibited Dex­induced apoptosis of osteoblasts in a dose­dependent manner. Crocin reversed Dex­induced decreases in the mitochondrial transmembrane potential, and increases in ROS and intracellular Ca2+ levels. Furthermore, crocin upregulated the expression levels of B­cell lymphoma-2 (Bcl­2) and mitochondrial cytochrome c (Cyt C), and downregulated those of cleaved caspase­9, cleaved caspase­3, Bcl­2­associated X protein and cytoplasmic Cyt C. N­acetylcysteine, a ROS inhibitor, and 1,2­bis(2­aminophenoxy)ethane­N,N,N',N'­tetraacetic acid, a calcium chelator, attenuated Dex­induced osteoblast apoptosis, whereas H2O2 and ionomycin, a calcium ionophore that increases intracellular calcium levels, reversed the antiapoptotic effects of crocin on Dex­treated osteoblasts. These results indicated that crocin may protect osteoblasts from Dex­induced apoptosis by inhibiting the ROS/Ca2+­mediated mitochondrial pathway, thus suggesting that crocin has potential value as a treatment for GC­induced bone diseases.


Assuntos
Apoptose/efeitos dos fármacos , Carotenoides/farmacologia , Glucocorticoides/metabolismo , Osteonecrose/tratamento farmacológico , Osteoporose/tratamento farmacológico , Acetilcisteína/farmacologia , Animais , Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dexametasona/toxicidade , Fraturas do Fêmur/tratamento farmacológico , Fraturas do Fêmur/genética , Fraturas do Fêmur/patologia , Humanos , Peróxido de Hidrogênio/farmacologia , Ionomicina/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Osteonecrose/induzido quimicamente , Osteonecrose/genética , Osteonecrose/patologia , Osteoporose/induzido quimicamente , Osteoporose/genética , Osteoporose/patologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
7.
Toxicol Lett ; 311: 17-26, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31039417

RESUMO

Prenatal ethanol exposure (PEE) causes intrauterine growth retardation (IUGR), and the occurrence of glomerulosclerosis is closely related to IUGR. This study aimed to confirm the kidney toxic effect of PEE and explore its intrauterine programming mechanism in female offspring. The Wistar female fetuses on gestational day (GD) 20 and the adult offspring at postnatal week 24 were anesthetized and decapitated. The adult offspring kidneys in the PEE group displayed glomerular hyperplasia and glomerulosclerosis. Blood urea nitrogen (BUN) and the BUN / Serum creatinine (Scr) concentration ratio in the PEE group was increased significantly compared to the control group (P<0.01, P<0.05). Meanwhile, the renal glucocorticoid-activation system was inhibited, whereas the insulin-like growth factor 1 (IGF1) signaling pathway was activated in the female adult offspring of the PEE group. In the fetal kidney of the PEE group, pathological observation showed kidney dysplasia, and the gene expression of the glial-cell-line-derived neurotrophic factor/tyrosine kinase receptor (GDNF/c-Ret) signaling pathway was reduced compared to that of the control group. Moreover, the glucocorticoid-activation system was activated, whereas the IGF1 signaling pathway was inhibited in the fetal kidneys of the PEE group. In conclusion, PEE caused fetal kidney dysplasia and adult glomerulosclerosis in the female offspring rats, and the intrauterine programming alteration of glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis might be involved in fetal-originated glomerulosclerosis.


Assuntos
Etanol/toxicidade , Glucocorticoides/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Nefropatias/induzido quimicamente , Glomérulos Renais/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Idade Gestacional , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator de Crescimento Insulin-Like I/genética , Nefropatias/genética , Nefropatias/metabolismo , Nefropatias/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Gravidez , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Ratos Wistar , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacos
8.
Gen Comp Endocrinol ; 280: 91-96, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31002827

RESUMO

Faecal glucocorticoid measurement is a potentially important tool for improving wildlife conservation, but its use is still limited by methodological issues including the need to avoid modifications of steroids by faecal microorganisms during storage. The freezing of faeces is recommended as a means of avoiding such alterations, but this is costly under non-controlled environmental conditions. The present study was designed to determine whether the application of thymol reduced the proliferation of microorganisms in the faeces of Tamandua tetradactyla and whether it influenced faecal glucocorticoid metabolite (FGM) measurements. Tamandua tetradactyla faeces were individually collected after defaecation, divided into fractions (5.5 g each) and kept in sealed glass Petri dishes at 22 ±â€¯2 °C. A thymol solution (550 µL; 5 mg g-1 feces; 80% ethanol) or an 80% ethanol solution (550 µL, control) was added before storage of faeces. Negative controls for FGM consisted of samples without thymol or ethanol solutions. All samples were evaluated at 0, 24, 48 and 72 h post-defaecation. Thymol was first incubated with a glucocorticoid standard in a faeces-free tube or in a faecal sample in order to determine whether it interfered with FGM measurements. Data showed that thymol did not affect FGM measurements. Post-defaecation time caused a significant reduction in FGM measurements in the negative control, an increment at 48 h in the control, and no change in FGM measurements in thymol treatment. FGM measurements were significantly different between groups (negative control > control - treatment). Thymol caused a significant reduction of up to three orders of magnitude in total coliforms, total aerobic and anaerobic heterotrophic mesophilic bacteria, mold and yeast per gram of faeces at 24, 48 and 72 h. The reduction in microbial activity presumably contributed to the stability of FGM over time. Spore-forming bacteria (SFB) in faeces were not reduced by thymol. We propose thymol as an alternative to freezing since it stabilizes FGMs for at least 3 days after collection in the faeces of Tamandua tetradactyla.


Assuntos
Fezes/microbiologia , Glucocorticoides/metabolismo , Metaboloma/efeitos dos fármacos , Timol/farmacologia , Xenartros/metabolismo , Animais , Contagem de Colônia Microbiana , Enterobacteriaceae/efeitos dos fármacos , Etiocolanolona/análogos & derivados , Etiocolanolona/metabolismo , Feminino , Masculino , Padrões de Referência
9.
Gen Comp Endocrinol ; 280: 147-157, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31009603

RESUMO

Monitoring glucocorticoids in faeces and hair is increasingly used in ecological studies and provides a powerful and minimally intrusive mean to identify physiological challenges faced by wild animals. Using a cortisol and a corticosterone immunoassays, we conducted an adrenocorticotropic (ACTH) challenge with five weekly repeated injections to validate the use of faecal glucocorticoid metabolites and hair cortisol concentration as biological markers of the HPA-axis activity in captive mountain goats (Oreamnos americanus). We also investigated the effect of endogenous (age, sex, reproductive status) and methodological (faecal sample collection date, freezing delay and hair type) variables on cortisol values using faecal and hair samples collected from marked wild mountain goats during a long-term study. The cortisol enzyme immunoassay was reliable for mountain goat faeces and hair, and was sensitive enough to detect a clear rise in glucocorticoid concentration following ACTH injections for both matrices. Age and sex had no detectable effect on faecal glucocorticoid metabolites, but hair cortisol concentration was higher in kids and yearlings than in older goats, and lower in adult males compared to adult females. Reproductive status had no detectable effect on both faecal and hair measurements. Faecal metabolite concentrations increased with sample collection date in late spring until mid-summer and decreased afterward until early fall. Guard hair had nearly twice as much cortisol per gram as undercoat hair. Prolonged delay to freezing reduced the concentration of faecal glucocorticoid metabolites, but degradation seemed limited when samples were exposed to wind and sun or when ambient temperature was low. We conclude that faeces and hair can be used as valid biomarkers of the HPA-axis activity in mountain goat provided that confounding variables are taken into account when interpreting measurements.


Assuntos
Biomarcadores/metabolismo , Fezes/química , Cabras/metabolismo , Cabelo/metabolismo , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Metaboloma , Hormônio Adrenocorticotrópico/farmacologia , Envelhecimento/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Corticosterona/metabolismo , Feminino , Glucocorticoides/metabolismo , Cabelo/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Técnicas Imunoenzimáticas , Masculino , Reprodutibilidade dos Testes , Reprodução
10.
Gen Comp Endocrinol ; 280: 24-34, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30951726

RESUMO

Fecal hormone analysis shows high potential for noninvasive assessment of population-level patterns in stress and reproduction of marine mammals. However, the marine environment presents unique challenges for fecal sample collection. Data are still lacking on collection methodology and assay validations for most species, particularly for those mysticete whales that have variable diets. In this study we tested collection techniques for fecal samples of free-swimming humpback whales (Megaptera novaeangliae), and validated immunoassays for five steroid and thyroid hormones. Resulting data were used for preliminary physiological validations, i.e., comparisons to independently confirmed sex and reproductive state. Pregnant females had significantly higher fecal progestins and glucocorticoids than did other demographic categories of whales. Two possible cases of previously undetected pregnancies were noted. Males had significantly higher fecal testosterone metabolites than nonpregnant females. Fecal glucocorticoids were significantly elevated in pregnant females and mature males compared to nonpregnant females. Calf fecal samples had elevated concentrations of all fecal hormones. Fecal thyroid hormones showed a significant seasonal decline from spring to summer. Though sample sizes were small, and sampling was necessarily opportunistic, these patterns indicate that noninvasive fecal hormone analysis may facilitate studies of reproduction, stress and potentially energetics in humpback whales.


Assuntos
Fezes/química , Hormônios/metabolismo , Jubarte/fisiologia , Estresse Fisiológico , Animais , Feminino , Glucocorticoides/metabolismo , Masculino , Metaboloma , Gravidez , Progestinas/metabolismo , Reprodutibilidade dos Testes , Reprodução/fisiologia , Natação/fisiologia , Testosterona/metabolismo , Hormônios Tireóideos/metabolismo
11.
Gen Comp Endocrinol ; 280: 82-90, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31002829

RESUMO

Conspicuous coloration can indicate phenotypic quality, and may reflect exposure or vulnerability to stress, or access to essential nutrients such as pigments. Although the production of pigmented colours is well understood, much less is known about how structural colours are affected by physiological state. In this study, we tested whether glucocorticoids (corticosterone) predicted expression of plumage coloration in an Australian parrot, the crimson rosella (Platycercus elegans). Parrots provide an interesting and unique test, as they possess conspicuous coloration produced by distinctive pigments known as psittacofulvins, in addition to structural coloration. We have previously documented that coloration in P. elegans is condition-dependent and responds to dietary manipulation. Here, n = 21 P. elegans underwent a dietary manipulation (including food restriction or carotenoid supplementation) during which they moulted, and the change in reflectance was measured for three structural and three pigmentary plumage patches. Stress-induced corticosterone (10 min after handling) measured at the start of the experiment predicted change in coloration in two pigmentary patches (crown and front). We also found that change in stress-induced corticosterone during the experiment was associated with the change in coloration of the crown and two structural patches (cheek and epaulette). Baseline corticosterone (<3 min after handling) was not associated with any measure of coloration. We found no effects of dietary manipulation on baseline or stress-induced corticosterone, but carotenoid supplementation was associated with an increase in a measure of chronic stress (heterophil/lymphocyte ratio), and the corticosterone response to handling decreased over the course of the study. Our results suggest that corticosterone may be linked to colour expression more broadly than previously recognised, including psittacofulvin and structural coloration in parrots, and they confirm the independence of plumage pigmentation in parrots from carotenoid accumulation. Moreover, our study provides new insight into the stress responses of Psittaciformes, one of the most highly threatened avian orders.


Assuntos
Carotenoides/metabolismo , Plumas/metabolismo , Glucocorticoides/metabolismo , Papagaios/metabolismo , Pigmentação , Animais , Cor , Corticosterona/metabolismo , Dieta , Plumas/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Papagaios/imunologia , Fito-Hemaglutininas/farmacologia , Pigmentação/fisiologia , Estresse Fisiológico/efeitos dos fármacos , Fatores de Tempo
12.
Neuron ; 102(1): 60-74, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30946827

RESUMO

Threat processing is central to understanding debilitating fear- and trauma-related disorders such as posttraumatic stress disorder (PTSD). Progress has been made in understanding the neural circuits underlying the "engram" of threat or fear memory formation that complements a decades-old appreciation of the neurobiology of fear and threat involving hub structures such as the amygdala. In this review, we examine key recent findings, as well as integrate the importance of hormonal and physiological approaches, to provide a broader perspective of how bodily systems engaged in threat responses may interact with amygdala-based circuits in the encoding and updating of threat-related memory. Understanding how trauma-related memories are encoded and updated throughout the brain and the body will ultimately lead to novel biologically-driven approaches for treatment and prevention.


Assuntos
Encéfalo/fisiopatologia , Medo/fisiologia , Memória/fisiologia , Trauma Psicológico/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/fisiopatologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Tonsila do Cerebelo/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Núcleo Central da Amígdala/fisiologia , Núcleo Central da Amígdala/fisiopatologia , Hormônio Liberador da Corticotropina/metabolismo , Medo/psicologia , Glucocorticoides/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiologia , Hipocampo/fisiopatologia , Humanos , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Hipotálamo/fisiopatologia , Interneurônios/metabolismo , Interneurônios/fisiologia , Trauma Psicológico/metabolismo , Trauma Psicológico/psicologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Tálamo/metabolismo , Tálamo/fisiologia , Tálamo/fisiopatologia
13.
Nature ; 567(7749): 540-544, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30867597

RESUMO

Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy1-3. Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade4, remain poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intra-patient tumour heterogeneity and metastasis is crucial for the success of personalized cancer therapy. Here, using transcriptional profiling of tumours and matched metastases in patient-derived xenograft models in mice, we show cancer-site-specific phenotypes and increased glucocorticoid receptor activity in distant metastases. The glucocorticoid receptor mediates the effects of stress hormones, and of synthetic derivatives of these hormones that are used widely in the clinic as anti-inflammatory and immunosuppressive agents. We show that the increase in stress hormones during breast cancer progression results in the activation of the glucocorticoid receptor at distant metastatic sites, increased colonization and reduced survival. Our transcriptomics, proteomics and phospho-proteomics studies implicate the glucocorticoid receptor in the activation of multiple processes in metastasis and in the increased expression of kinase ROR1, both of which correlate with reduced survival. The ablation of ROR1 reduced metastatic outgrowth and prolonged survival in preclinical models. Our results indicate that the activation of the glucocorticoid receptor increases heterogeneity and metastasis, which suggests that caution is needed when using glucocorticoids to treat patients with breast cancer who have developed cancer-related complications.


Assuntos
Neoplasias da Mama/patologia , Glucocorticoides/efeitos adversos , Glucocorticoides/metabolismo , Metástase Neoplásica/patologia , Animais , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Dexametasona/efeitos adversos , Dexametasona/metabolismo , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taxa de Sobrevida
14.
Gen Comp Endocrinol ; 276: 60-68, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30836104

RESUMO

Using faecal matter to monitor stress levels in animals non-invasively is a powerful technique for elucidating the effects of biotic and abiotic stressors on free-living animals. To validate the use of droppings for measuring stress in southern pied babblers (Turdoides bicolor) we performed an ACTH challenge on captive individuals and determined the effect of temporary separation from their social group on their faecal glucocorticoid metabolite (fGCM) concentration. Additionally, we compared fGCM concentrations of captive babblers to those of wild conspecifics and examined the effects of dominance rank on fGCM concentration. We found droppings to be a suitable matrix for measuring physiological stress in babblers and that individual separation from the group caused an increase in fGCM levels. In addition, babblers temporarily held in captivity had substantially higher fGCM concentrations than wild individuals, indicating that babblers kept in captivity experience high levels of stress. In wild, free-living individuals, dominant males showed the highest levels of stress, suggesting that being the dominant male of a highly territorial social group is stressful. Non-invasive sampling allows field-based researchers to reduce disturbance related to monitoring adrenocortical function, thereby avoiding artificially increasing circulating corticosterone concentration as it is not necessary to physically restrain study animals.


Assuntos
Passeriformes/fisiologia , Estresse Fisiológico , Clima Tropical , Hormônio Adrenocorticotrópico/farmacologia , Animais , Corticosterona/sangue , Fezes/química , Feminino , Glucocorticoides/metabolismo , Técnicas Imunoenzimáticas , Masculino , Metaboloma , Passeriformes/sangue
15.
Proc Natl Acad Sci U S A ; 116(14): 7077-7082, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30877244

RESUMO

Extensive evidence indicates that the basolateral amygdala (BLA) interacts with other brain regions in mediating stress hormone and emotional arousal effects on memory consolidation. Brain activation studies have shown that arousing conditions lead to the activation of large-scale neural networks and several functional connections between brain regions beyond the BLA. Whether such distal interactions on memory consolidation also depend on BLA activity is not as yet known. We investigated, in male Sprague-Dawley rats, whether BLA activity enables prelimbic cortex (PrL) interactions with the anterior insular cortex (aIC) and dorsal hippocampus (dHPC) in regulating glucocorticoid effects on different components of object recognition memory. The glucocorticoid receptor (GR) agonist RU 28362 administered into the PrL, but not infralimbic cortex, immediately after object recognition training enhanced 24-hour memory of both the identity and location of the object via functional interactions with the aIC and dHPC, respectively. Importantly, posttraining inactivation of the BLA by the noradrenergic antagonist propranolol abolished the effect of GR agonist administration into the PrL on memory enhancement of both the identity and location of the object. BLA inactivation by propranolol also blocked the effect of GR agonist administration into the PrL on inducing changes in neuronal activity within the aIC and dHPC during the postlearning consolidation period as well as on structural changes in spine morphology assessed 24 hours later. These findings provide evidence that BLA noradrenergic activity enables functional interactions between the PrL and the aIC and dHPC in regulating stress hormone and emotional arousal effects on memory.


Assuntos
Androstanóis/farmacologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Córtex Cerebral/metabolismo , Glucocorticoides/metabolismo , Memória/efeitos dos fármacos , Rede Nervosa/metabolismo , Receptores de Glucocorticoides/agonistas , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/metabolismo
16.
PLoS One ; 14(3): e0210537, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30865634

RESUMO

We previously found relationships between body condition and physiological function affecting health and welfare of female tourist camp elephants in Thailand, and used that approach to conduct a similar study of bull elephants in the same camps (n = 13). A body condition score (BCS) was done every other month, and fecal glucocorticoid metabolite (FGM) concentrations were measured twice monthly for 1 year. Effects of season, camp management and tourist activity on lipid profiles [total cholesterol (TC), low density lipoproteins (LDL), high density lipoproteins (HDL), triglycerides (TG)] and metabolic factors [insulin, glucose, fructosamine, glucose to insulin ratio (G:I)] were determined and correlated to measures of body condition, testosterone and FGM. Positive correlations were found between BCS and TG, between FGM and TG, HDL and glucose, and between testosterone and HDL, whereas BCS and testosterone were negatively associated with the G:I. There was a significant positive relationship between FGM and testosterone. Elevated FGM concentrations were associated with altered lipid and metabolic profiles and were higher in winter compared to summer and rainy seasons. Insulin and glucose levels were higher, while the G:I was lowest in the winter season. Strong positive associations were found between TC and HDL, LDL and HDL and glucose, and glucose and insulin. By contrast, negative relationships were found between the G:I and HDL and glucose, and between insulin and G:I. Differences also were found between High and Low tourist season months for FGM, insulin, and G:I. Last, there was notable variation among the camps in measured parameters, which together with tourist season effects suggests camp management may affect physiological function and welfare; some negatively like feeding high calorie treats, others positively, like exercise. Last, compared to females, bull elephants appear to be in better physical health based on normal BCSs, lower insulin levels and higher G:I ratios.


Assuntos
Animais de Zoológico/fisiologia , Glucocorticoides/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Lipídeos/análise , Testículo/química , Testosterona/análise , Bem-Estar do Animal , Animais , Elefantes , Fezes/química , Nível de Saúde , Atividades Humanas , Masculino , Metabolômica , Estações do Ano , Tailândia
17.
J Steroid Biochem Mol Biol ; 189: 73-80, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30817990

RESUMO

Hereditary adrenocorticotropin (ACTH) resistance syndromes encompass the genetically heterogeneous isolated or Familial Glucocorticoid Deficiency (FGD) and the distinct clinical entity known as Triple A syndrome. The molecular basis of adrenal resistance to ACTH includes defects in ligand binding, MC2R/MRAP receptor trafficking, cellular redox balance, cholesterol synthesis and sphingolipid metabolism. Biochemically, this manifests as ACTH excess in the setting of hypocortisolaemia. Triple A syndrome is an inherited condition involving a tetrad of adrenal insufficiency, achalasia, alacrima and neuropathy. FGD is an autosomal recessive condition characterized by the presence of isolated glucocorticoid deficiency, classically in the setting of preserved mineralocorticoid secretion. Primarily there are three established subtypes of the disease: FGD 1, FGD2 and FGD3 corresponding to mutations in the Melanocortin 2 receptor MC2R (25%), Melanocortin 2 receptor accessory protein MRAP (20%), and Steroidogenic acute regulatory protein STAR (5-10%) respectively. Together, mutations in these 3 genes account for approximately half of cases. Whole exome sequencing in patients negative for MC2R, MRAP and STAR mutations, identified mutations in minichromosome maintenance 4 MCM4, nicotinamide nucleotide transhydrogenase NNT, thioredoxin reductase 2 TXNRD2, cytochrome p450scc CYP11A1, and sphingosine 1-phosphate lyase SGPL1 accounting for a further 10% of FGD. These novel genes have linked replicative and oxidative stress and altered redox potential as a mechanism of adrenocortical damage. However, a genetic diagnosis is still unclear in about 40% of cases. We describe here an updated list of FGD genes and provide a description of relevant mouse models that, despite some being flawed, have been precious allies in the understanding of FGD pathobiology.


Assuntos
Insuficiência Adrenal/genética , Acalasia Esofágica/genética , Glucocorticoides/genética , Erros Inatos do Metabolismo de Esteroides/genética , Insuficiência Adrenal/metabolismo , Insuficiência Adrenal/patologia , Hormônio Adrenocorticotrópico/genética , Hormônio Adrenocorticotrópico/metabolismo , Animais , Modelos Animais de Doenças , Acalasia Esofágica/metabolismo , Acalasia Esofágica/patologia , Predisposição Genética para Doença , Glucocorticoides/metabolismo , Humanos , Mutação , Erros Inatos do Metabolismo de Esteroides/metabolismo , Erros Inatos do Metabolismo de Esteroides/patologia
18.
Pharmacol Rep ; 71(2): 347-350, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30831440

RESUMO

BACKGROUND: Corticosteroid-binding globulin (CBG), albumin and 11ß-hydroxysteroid dehydrogenase (11ß-HSD) enzymes play crucial roles in the bioavailability of glucocorticoids. Downstream of the adrenal glands, these proteins affect glucocorticoid levels in target tissues. Early-life stress (ELS) is known to program glucocorticoid action at many levels. The effects of ELS on the concentrations and synthesis of CBG and albumin and on the expression of 11ß-HSD remain unclear. METHODS: The maternal separation (MS) procedure in rats on postnatal days 1-14 was used as a model of ELS. On postnatal day 35 (adolescence), the serum corticosterone, CBG and albumin concentrations of male rats were measured by ELISA, while the mRNA and protein levels of CBG, albumin and 11ß-HSD1 in the liver and brain were examined by RT-qPCR and Western blot, respectively. RESULTS: Under basal conditions, MS rats displayed lower levels of serum CBG and albumin. However, MS did not affect CBG or albumin synthesis in the liver, suggesting that the half-life and/or secretion of these proteins were influenced by MS. Additionally, MS rats showed increased protein expression of 11ß-HSD1, specifically in the medial prefrontal cortex. CONCLUSIONS: These results indicate that ELS may potentially program glucocorticoid action through its effects on glucocorticoid bioavailability in tissues.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/isolamento & purificação , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Privação Materna , Estresse Psicológico/fisiopatologia , Animais , Encéfalo/metabolismo , Corticosterona/sangue , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Glucocorticoides/metabolismo , Fígado/metabolismo , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Transcortina/metabolismo
19.
Int J Mol Sci ; 20(6)2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30889819

RESUMO

Male osteoporosis is a significant but undetermined healthcare problem. Men suffer from a higher mortality rate post-fracture than women and they are marginalized in osteoporosis treatment. The current prophylactic agents for osteoporosis are limited. Functional food components such as tocotrienol may be an alternative option for osteoporosis prevention in men. This paper aims to review the current evidence regarding the skeletal effects of tocotrienol in animal models of male osteoporosis and its potential antiosteoporotic mechanism. The efficacy of tocotrienol of various sources (single isoform, palm and annatto vitamin E mixture) had been tested in animal models of bone loss induced by testosterone deficiency (orchidectomy and buserelin), metabolic syndrome, nicotine, alcoholism, and glucocorticoid. The treated animals showed improvements ranging from bone microstructural indices, histomorphometric indices, calcium content, and mechanical strength. The bone-sparing effects of tocotrienol may be exerted through its antioxidant, anti-inflammatory, and mevalonate-suppressive pathways. However, information pertaining to its mechanism of actions is superficial and warrants further studies. As a conclusion, tocotrienol could serve as a functional food component to prevent male osteoporosis, but its application requires validation from a clinical trial in men.


Assuntos
Osteoporose/prevenção & controle , Tocotrienóis/uso terapêutico , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Reabsorção Óssea/patologia , Glucocorticoides/metabolismo , Humanos , Masculino , Fumar/efeitos adversos , Tocotrienóis/química , Tocotrienóis/farmacologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-30702391

RESUMO

Member States of the EU are required to monitor the use of pharmacologically active substances in food-producing animals. There is evidence, however, that the target-based approach currently applied in official monitoring plans might under-estimate the real incidence of growth promoter abuse in livestock. As demonstrated for sex hormones, the association of effect-oriented biological screening with chemical confirmatory techniques could be the best strategy in revealing the abuse of veterinary drugs. Here we demonstrate the reliability of a cell-based assay to screen calf urine samples for synthetic glucocorticoids. The validation included the most widely used synthetic drugs (flumethasone, dexamethasone, betamethasone, methylprednisolone and prednisolone) and was developed according to the Commission Decision 2002/657/EC, thus including the verification of cut-off level, the ß error, the specificity, ruggedness and stability. The study was carried out using prednisolone as representative substance at 5 ng mL-1 concentration. All blank and spiked urine fulfilled the EU criteria, moreover the method resulted in being specific and sound, and the analytes in urine were stable for at least 30 days. The assay results indicated its suitability for a qualitative analysis of calf urine samples. This method enabled the detection of low doses of synthetic glucocorticoids (GCs) in matrix (<2 ng mL-1 for flumethasone, dexamethasone, betamethasone; < 4 ng mL-1 for methylprednisolone; 5 ng mL-1 for prednisolone), with the possibility of detecting new or unknown molecules and cumulative effects of low-level mixtures with glucocorticoid bioactivity.


Assuntos
Bioensaio , Glucocorticoides/urina , Animais , Bovinos , Cromatografia Líquida , Glucocorticoides/síntese química , Glucocorticoides/metabolismo , Luciferases/genética , Luciferases/metabolismo , Espectrometria de Massas por Ionização por Electrospray
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