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1.
Ecotoxicol Environ Saf ; 185: 109683, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31550567

RESUMO

Thiamethoxam has emerged as an environmental contaminant detected in aqueous environments, and its endocrine-disrupting effect at chronic exposure in teleosts remains unknown. In the present study, a docking experiment and an in vivo test were integrated to systematically explore the toxic mechanisms of thiamethoxam in fish. Histological analysis, plasma VTG and hormone level (E2, 11-KT, T3 and T4) determinations, and HPG and HPT gene expression quantification were performed after Chinese rare minnow (Gobiocypris rarus) was exposed to thiamethoxam (0, 0.5, 5, and 50 µg/L) for 90 days. According to the docking study, thiamethoxam had different interactions with ERα, AR and TRα via hydrogen bonding. A decrease in body length and plasma T4 was observed in both genders. The histological damage in liver and delayed gonadal development were observed in both genders at 50 µg/L thiamethoxam treatment. In males, the following HPG axis genes were upregulated: gnrh and cyp19b in the brain; vtg and cyp19a in the liver; and cyp17 and cyp19a in the gonad. In females, erɑ in the liver was significantly upregulated with 0.5 µg/L thiamethoxam treatment, and cyp17 in the gonad was upregulated with all treatment. The suppression of cyp19a, gnrh, cyp11a, and ttr was observed at the concentration of 5 µg/L in the female liver. Taken together, the endocrine system of Chinese rare minnow might be disrupted after chronic exposure to thiamethoxam.


Assuntos
Cyprinidae/metabolismo , Disruptores Endócrinos/toxicidade , Sistema Endócrino/efeitos dos fármacos , Hormônios/metabolismo , Tiametoxam/toxicidade , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Cyprinidae/genética , Sistema Endócrino/metabolismo , Feminino , Gônadas/efeitos dos fármacos , Gônadas/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Simulação de Acoplamento Molecular , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Regulação para Cima , Vitelogeninas/metabolismo
2.
Molecules ; 24(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540539

RESUMO

Treatment of the unpredictable chronic mild stress (UCMS) mice with the ethanol extract of Dipterocarpus alatus leaf attenuated anhedonia (increased sucrose preference) and behavioral despair (decreased immobility time in tail suspension test (TST) and forced swimming test (FST)). The extract not only decreased the elevation of serum corticosterone level and the index of over-activation of the hypothalamic-pituitary-adrenal (HPA) axis, caused by UCMS, but also ameliorated UCMS-induced up-regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) mRNA expression and down-regulation of cyclic AMP-responsive element binding (CREB) and brain-derived neurotrophic factor (BDNF) mRNAs in frontal cortex and hippocampus. In vitro monoamine oxidase (MAO) inhibition assays showed that the extract exhibited the partial selective inhibition on MAO-A. HPLC analysis of the extract showed the presence of flavonoids (luteolin-7-O-glucoside, kaempferol-3-glucoside, rutin) and phenolic acids (gallic acid, ferulic acid, and caffeic acid) as major constituents.


Assuntos
Depressão , Dipterocarpaceae/química , Etanol/química , Extratos Vegetais , Folhas de Planta/química , Estresse Psicológico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/patologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Proteínas Imediatamente Precoces/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos ICR , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteínas Serina-Treonina Quinases/biossíntese , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia
3.
Pediatr Hematol Oncol ; 36(7): 422-431, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31429623

RESUMO

Background: Children with acute lymphocytic leukemia (ALL) are enrolled in advanced treatment protocols involving high doses of glucocorticoids (GCs). Current protocols do not advocate tapering of GCs doses postinduction phase. Prolonged administration of supra-physiologic doses of GCs can induce transient suppression of the hypothalamic pituitary adrenal axis (HPA). Timely recognition of adrenal insufficiency is important in order to ensure that children at risk receive the necessary treatment and follow-up including stress coverage during illness and surgical procedures. Methods: 21 newly diagnosed patients with ALL aged 3-10 years old were prospectively enrolled in the study over a 2-year period. All enrolled patients received high doses of GCs as part of a chemotherapy treatment protocol. The HPA axis was assessed prior to the induction phase of chemotherapy and 1-2 weeks after un-tapered discontinuation of GCs. Results: All children had normal HPA axis at baseline. Postinduction 1 mcg ACTH stimulation test result was normal (cortisol > 500 nmol/L) in 75% of children and partially responsive in 25% (cortisol 300-500 nmol/L). None of the participants demonstrated clinically significant adrenal insufficiency following abrupt cessation of GCs. Conclusion: All children in our cohort had either normal or subnormal cortisol response during a low dose ACTH stimulation test 1 to 2 weeks following abrupt discontinuation of GCs, suggesting that any inhibition of the HPA axis is of short duration. We suggest that future studies investigate the timing of adrenal function recovery following GC discontinuation as well as whether tapering of the GC should be recommended.


Assuntos
Glândulas Suprarrenais/metabolismo , Glucocorticoides/administração & dosagem , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Pré-Escolar , Feminino , Glucocorticoides/efeitos adversos , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Prospectivos
4.
Environ Toxicol ; 34(11): 1255-1262, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31298479

RESUMO

Progesterone (P4) is a biologically active steroid hormone that is involved in the regulation of oocyte growth and maturation, as well as development of the endometrium and implantation in the uterus of humans. It can also stimulate oocyte maturation in female fish, as well as spermatogenesis and sperm motility in male fish. Thus, P4 has been extensively used in human and animal husbandry as a typical progestin. However, P4 remaining in the water environment will pose a potential hazard to aquatic organisms. For example, it can interfere with sex differentiation and reproduction in aquatic vertebrates such as fish. Therefore, we investigated the effects of prolonged progesterone exposure on the expression of genes related to circadian rhythm signaling and the hypothalamic-pituitary-gonadal (HPG) axes in Yellow River Carp, which may have a potential impact on their sex differentiation. Our results suggested that P4 exposure altered the expression of genes related to circadian rhythm signaling, which can lead to disorders in the endocrine system and regulate the HPG axes-related activities. Furthermore, the expression of genes related to the HPG axes was also altered, which might affect gonadal development and the reproductive systems of Yellow River Carp. In addition, these changes may provide a plausible mechanism for the observed shifts in their sex ratio toward females.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Progesterona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Carpas/crescimento & desenvolvimento , Carpas/metabolismo , Feminino , Gônadas/efeitos dos fármacos , Gônadas/patologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Diferenciação Sexual/efeitos dos fármacos , Razão de Masculinidade , Transcrição Genética/efeitos dos fármacos
5.
EBioMedicine ; 46: 411-422, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31358477

RESUMO

BACKGROUND: Severe energy deficits during military operations, produced by significant increases in exercise and limited dietary intake, result in conditions that degrade lean body mass and lower-body muscle function, which may be mediated by concomitant reductions in circulating testosterone. METHODS: We conducted a three-phase, proof-of-concept, single centre, randomised, double-blind, placebo-controlled trial (CinicalTrials.gov, NCT02734238) of non-obese men: 14-d run-in, free-living, eucaloric diet phase; 28-d live-in, 55% exercise- and diet-induced energy deficit phase with (200 mg testosterone enanthate per week, Testosterone, n = 24) or without (Placebo, n = 26) exogenous testosterone; and 14-d recovery, free-living, ad libitum diet phase. Body composition was the primary end point; secondary endpoints included lower-body muscle function and health-related biomarkers. FINDINGS: Following energy deficit, lean body mass increased in Testosterone and remained stable in Placebo, such that lean body mass significantly differed between groups [mean difference between groups (95% CI), 2.5 kg (3.3, 1.6); P < .0001]. Fat mass decreased similarly in both treatment groups [0.2 (-0.4, 0.7), P = 1]. Change in lean body mass was associated with change in total testosterone (r = 0.71, P < .0001). Supplemental testosterone had no effect on lower-body muscle function or health-related biomarkers. INTERPRETATION: Findings suggest that supplemental testosterone may increase lean body mass during short-term severe energy deficit in non-obese, young men, but it does not appear to attenuate lower-body functional decline. FUNDING: Collaborative Research to Optimize Warfighter Nutrition projects I and II, Joint Program Committee-5, funded by the US Department of Defence.


Assuntos
Composição Corporal/efeitos dos fármacos , Dieta , Suplementos Nutricionais , Exercício , Músculos/efeitos dos fármacos , Músculos/metabolismo , Testosterona/administração & dosagem , Adolescente , Adulto , Biomarcadores , Peso Corporal/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Estudo de Prova de Conceito , Adulto Jovem
6.
World Neurosurg ; 131: e81-e87, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31306837

RESUMO

BACKGROUND: Pituitary stalk sectioning is only essential in cases of craniopharyngioma originating from the stalk or metastatic tumor to the stalk. Some patients can discontinue postoperative antidiuretic hormone (ADH) supplementation with special conditions. METHODS: Sixty-three patients with craniopharyngiomas who were treated by surgery with pituitary stalk sectioning were included in this study. Great care was taken to preserve the fine arteries running along the lateral walls of the third ventricle. Removal rates, change of endocrinologic status, and magnetic resonance imaging (MRI) findings were investigated. RESULTS: Total removal was achieved in 52 of 54 patients in initial surgery (96.3%), and in 5 of 9 patients in retreatment (55.6%). ADH supplementation was required in all patients from the day of surgery, but was discontinued in 29 of 54 patients among the initial surgery group (53.7%) and in 2 of 9 patients among the retreatment group (22.2%). Preservation of thyroid hormone secretion was observed in 24 of 31 patients who could discontinue ADH (77.4%), but only in 12 of 32 patients who could not discontinue ADH (37.5%). Recovery from diabetes insipidus (DI) was significantly associated with preservation of thyroid function (P < 0.01). Postoperative MRI showed that part of the hypothalamus was enhanced in patients with recovery from DI. CONCLUSIONS: Total removal was achieved in 91% of all cases. Half of the patients could discontinue ADH supplementation, which was associated with preservation of thyroid function. The findings of hypothalamic enhancement on postoperative MRI may be associated with recovery from DI.


Assuntos
Antidiuréticos/uso terapêutico , Craniofaringioma/cirurgia , Diabetes Insípido/tratamento farmacológico , Sistema Hipotálamo-Hipofisário/metabolismo , Procedimentos Neurocirúrgicos/métodos , Neoplasias Hipofisárias/cirurgia , Complicações Pós-Operatórias/tratamento farmacológico , Recuperação de Função Fisiológica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Desamino Arginina Vasopressina/uso terapêutico , Diabetes Insípido/etiologia , Feminino , Glucocorticoides/deficiência , Glucocorticoides/uso terapêutico , Terapia de Reposição Hormonal , Humanos , Hipopituitarismo/tratamento farmacológico , Hipopituitarismo/etiologia , Sistema Hipotálamo-Hipofisário/diagnóstico por imagem , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/etiologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/efeitos adversos , Hipófise/cirurgia , Complicações Pós-Operatórias/etiologia , Prognóstico , Hormônios Tireóideos/uso terapêutico , Adulto Jovem
7.
PLoS One ; 14(6): e0216679, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31211771

RESUMO

The "ship" of the Arabian and North African deserts, the one-humped dromedary camel (Camelus dromedarius) has a remarkable capacity to survive in conditions of extreme heat without needing to drink water. One of the ways that this is achieved is through the actions of the antidiuretic hormone arginine vasopressin (AVP), which is made in a specialised part of the brain called the hypothalamo-neurohypophyseal system (HNS), but exerts its effects at the level of the kidney to provoke water conservation. Interestingly, our electron microscopy studies have shown that the ultrastructure of the dromedary HNS changes according to season, suggesting that in the arid conditions of summer the HNS is in an activated state, in preparation for the likely prospect of water deprivation. Based on our dromedary genome sequence, we have carried out an RNAseq analysis of the dromedary HNS in summer and winter. Amongst the 171 transcripts found to be significantly differentially regulated (>2 fold change, p value <0.05) there is a significant over-representation of neuropeptide encoding genes, including that encoding AVP, the expression of which appeared to increase in summer. Identification of neuropeptides in the HNS and analysis of neuropeptide profiles in extracts from individual camels using mass spectrometry indicates that overall AVP peptide levels decreased in the HNS during summer compared to winter, perhaps due to increased release during periods of dehydration in the dry season.


Assuntos
Adaptação Fisiológica , Camelus/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Estações do Ano , Animais , Camelus/genética , Perfilação da Expressão Gênica , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/ultraestrutura
8.
Gerontology ; 65(5): 465-473, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31212285

RESUMO

Anxiety disorders are common, yet clinically underrecognized in late life, with estimated prevalence rates ranging from 1.2 to 15%. They are highly comorbid with depression, sleep disorders, and substance use disorders, may accelerate cognitive decline, and potentially catalyze morbidity and mortality risk in the elderly. Thus, a more detailed knowledge about the underlying mechanisms of late-life anxiety disorders is urgently warranted. Age-related genetic, neuroimaging, neuroendocrine, and neuropsychological markers as well as late-life specific psychosocial aspects, particularly loss and isolation, have been identified as prominent pathogenetically relevant and thus potentially targetable factors. Personalized treatments based on individual biological and biographic markers, innovative therapeutic approaches, and preventive strategies have great potential to alleviate the high individual and societal burden of late-life anxiety disorders.


Assuntos
Envelhecimento/psicologia , Transtornos de Ansiedade/psicologia , Idoso , Ansiedade/psicologia , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Envelhecimento Cognitivo/psicologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Comorbidade , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/psicologia , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/psicologia , Isolamento Social/psicologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia
9.
Nat Rev Endocrinol ; 15(9): 525-534, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31249398

RESUMO

The human stress response has evolved to maintain homeostasis under conditions of real or perceived stress. This objective is achieved through autoregulatory neural and hormonal systems in close association with central and peripheral clocks. The hypothalamic-pituitary-adrenal axis is a key regulatory pathway in the maintenance of these homeostatic processes. The end product of this pathway - cortisol - is secreted in a pulsatile pattern, with changes in pulse amplitude creating a circadian pattern. During acute stress, cortisol levels rise and pulsatility is maintained. Although the initial rise in cortisol follows a large surge in adrenocorticotropic hormone levels, if long-term inflammatory stress occurs, adrenocorticotropic hormone levels return to near basal levels while cortisol levels remain raised as a result of increased adrenal sensitivity. In chronic stress, hypothalamic activation of the pituitary changes from corticotropin-releasing hormone-dominant to arginine vasopressin-dominant, and cortisol levels remain raised due at least in part to decreased cortisol metabolism. Acute elevations in cortisol levels are beneficial to promoting survival of the fittest as part of the fight-or-flight response. However, chronic exposure to stress results in reversal of the beneficial effects, with long-term cortisol exposure becoming maladaptive, which can lead to a broad range of problems including the metabolic syndrome, obesity, cancer, mental health disorders, cardiovascular disease and increased susceptibility to infections. Neuroimmunoendocrine modulation in disease states and glucocorticoid-based therapeutics are also discussed.


Assuntos
Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Fisiológico/fisiologia , Estresse Psicológico/metabolismo , Ritmo Circadiano/fisiologia , Terapia de Reposição Hormonal/métodos , Humanos , Estresse Psicológico/psicologia , Estresse Psicológico/terapia
10.
Pharmacol Rep ; 71(4): 636-643, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31176893

RESUMO

BACKGROUND: The inverse relationship between GnRH transcript level and GABA neurons activity has suggested that GABA at the hypothalamic level may exert a suppressive effect on subsequent steps of the GnRH biosynthesis. In the present study, we analyzed the effects of GABA type A receptor agonist (muscimol) or antagonist (bicuculline) on molecular mechanisms governing GnRH/LH secretion in follicular-phase sheep. METHODS: ELISA technique was used to investigate the effects of muscimol and/or bicuculline on levels of post-translational products of genes encoding GnRH ligand and GnRH receptor (GnRHR) in the preoptic area (POA), anterior (AH) and ventromedial (VMH) hypothalamus, stalk/median eminence (SME), and GnRHR in the anterior pituitary (AP). Real-time PCR was chosen for determination of the effect of drugs on kisspeptin (Kiss 1) mRNA level in POA and VMH including arcuate nucleus (VMH/ARC), and on Kiss1 receptor (Kiss1r) mRNA abundance in POA-hypothalamic structures. These analyses were supplemented by RIA method for measurement of plasma LH concentration. RESULTS: The study demonstrated that muscimol and bicuculline significantly decreased or increased GnRH biosynthesis in all analyzed structures, respectively, and led to analogous changes in plasma LH concentration. Similar muscimol- and bicuculline-related alterations were observed in levels of GnRHR. However, the expression of Kiss 1 and Kiss1r mRNAs in selected POA-hypothalamic areas of either muscimol- and bicuculline-treated animals remained unaltered. CONCLUSIONS: Our data suggest that GABAergic neurotransmission is involved in the regulatory pathways of GnRH/GnRHR biosynthesis and then GnRH/LH release in follicular-phase sheep conceivably via indirect mechanisms that exclude involvement of Kiss 1 neurons.


Assuntos
Ciclo Estral/metabolismo , Hormônio Liberador de Gonadotropina/biossíntese , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Kisspeptinas/metabolismo , Receptores de GABA-A/metabolismo , Receptores LHRH/biossíntese , Animais , Bicuculina/farmacologia , Feminino , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Hormônio Liberador de Gonadotropina/sangue , Sistema Hipotálamo-Hipofisário/metabolismo , Muscimol/farmacologia , Neurônios/metabolismo , Ovinos
11.
Biomed Pharmacother ; 117: 109077, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177064

RESUMO

BACKGROUND: Prenatal stress (PS) leads to a wide variety of behavioral and emotional aberration observed in later life, particularly in the impairment of spatial learning and memory in offspring. Icariin (ICA) is a naturally occurring furanocoumarin and exhibits many pharmacological properties, including potent improvement on learning and memory. PURPOSE: We pretend to investigate the improvement of ICA on learning and memory impairment in PS. METHODS: Female PS offspring rats were used to explore the effects of ICA on learning and memory impairment. After 28 days of ICA (20, 40 and 80 mg/kg/day) treatment, we measured Morris water maze and 8-Arm Maze, the HPA axis and the related pathway in the hippocampus. RESULTS: We reported that ICA ameliorated the spatial learning and memory and working memory impairment in the female offspring rats. Correspondingly, ICA prevented adverse changes in the dendritic morphology of CA3 pyramidal neurons in the hippocampus. ICA significantly decreased the serum adrenocorticotropin, corticotropin-releasing hormone and corticosterone levels in offspring rats exposed to PS, associated with increased GR expression. Additionally, ICA treatment significantly increased the neurogranin (Ng) and c-fos protein expression of hippocampus in the offspring rats. Furthermore, the protein of relative content of p-EKR/ERK, p-CaMKIIα/CaMKIIα, p-CREB/CREB were remarkably increased after ICA treatment in the offspring rats. CONCLUSION: Taken together, ICA may be an effective therapeutic for learning and memory dysfunction in female offspring exposed to PS, its neuroprotective effect was mediated in part by normalizing the HPA axis and up-regulating of ERK/CaMKIIα/CREB signaling, Ng and c-fos protein.


Assuntos
Flavonoides/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Animais , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo
12.
Neuropsychobiology ; 78(3): 145-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31189176

RESUMO

BACKGROUND: Dysregulation of leptin secretion and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may be involved in the pathophysiology of suicide. Preclinical and clinical studies have shown interactions between the HPA axis and leptin. There is also evidence for a negative relationship between leptin and anxiety in humans. However, these possible associations have not been studied in individuals with attempted suicide. OBJECTIVES: To examine the relationship between leptin, HPA axis activity, and anxiety in individuals with a recent suicide attempt. METHOD: Sixty-nine individuals with a recent suicide attempt (n = 37 females; n = 32 males) were recruited and subjected to the Dexamethasone Suppression Test (DST), lumbar puncture, and evaluation with the Comprehensive Psychopathological Rating Scale from which the Brief Scale for Anxiety (BSA) was derived. Leptin was analyzed in cerebrospinal fluid (CSF) and cortisol in serum. Leptin was corrected for body mass index (BMI) by dividing CSF-leptin by BMI (CSF-leptin/BMI). Due to gender-related differences in leptin secretion and HPA axis activity, calculations were made for males and females separately. RESULTS: Significant differences were only found among females; CSF-leptin/BMI levels correlated significantly and negatively with BSA (p < 0.05), pre-DST cortisol, and post-DST serum cortisol at 8 a.m. and 3 p.m. (all p < 0.05). Furthermore, CSF-leptin/BMI was significantly lower in nonsuppressors of dexamethasone as compared to suppressors (p < 0.05). CONCLUSIONS: These findings suggest that in females with a recent suicide attempt, low CSF leptin may be related to symptoms of anxiety and a hyperactive HPA axis.


Assuntos
Ansiedade/sangue , Ansiedade/líquido cefalorraquidiano , Sistema Hipotálamo-Hipofisário/metabolismo , Leptina/líquido cefalorraquidiano , Sistema Hipófise-Suprarrenal/metabolismo , Tentativa de Suicídio/psicologia , Adulto , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Caracteres Sexuais
13.
Psychopharmacology (Berl) ; 236(8): 2485-2500, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201478

RESUMO

BACKGROUND: Borderline personality disorder (BPD) is a pervasive psychiatric disorder characterized by emotion dysregulation, impulsivity, impaired self-perceptions, and interpersonal relationships and currently affects 1-3% of the US population as reported by Torgersen et al. (Arch Gen Psychiatry 58:590-596, Torgersen et al. 2001), Lenzenweger et al. (Biol Psychiatry 62:553-564, Lenzenweger et al. 2007), and Tomko et al. (J Personal Disord 28:734-750, Tomko et al. 2014). One major obstacle to our understanding of the neural underpinnings of BPD is a lack of valid animal models that translate the key known features of the disorder to a system that is amenable to study. OBJECTIVE: To summarize the etiology, major symptoms, and symptom triggers of BPD and then propose a blueprint for building an animal model of BPD by choosing key components of the disorder that can be implemented in rodents. RESULTS: We identify the role of early life stress and subsequent mild stress in adulthood as contributing etiological factors and the potential use of altered communication between frontal cortices and the amygdala in extinction and habituation, increased impulsivity, dysregulation of the hypothalamic pituitary axis (HPA), and increased neuroinflammation as biological markers of BPD. Building upon these features of BPD, we propose a two-hit animal model that uses maternal abandonment to alter maturation of the HPA axis and mild secondary adult stress to evoke behavioral symptoms such as increased impulsivity and impaired extinction, habituation, and social interactions. CONCLUSION: Through exploration of the etiology, symptom presentation, and altered neurological function, we propose an animal model of BPD. We believe that a number of existing animal paradigms that model other mental health disorders should be combined in a unique way to reflect the etiology, symptom presentation, and altered neurological function that is evident in BPD. These model, when compared with available human data, will inform research and treatment in humans for better understanding of systems from the micro-molecular level to more global physiology underlying BPD.


Assuntos
Transtorno da Personalidade Borderline/psicologia , Modelos Animais de Doenças , Comportamento Impulsivo/fisiologia , Relações Interpessoais , Tonsila do Cerebelo/metabolismo , Animais , Transtorno da Personalidade Borderline/genética , Transtorno da Personalidade Borderline/metabolismo , Emoções/fisiologia , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/psicologia
14.
Transl Psychiatry ; 9(1): 158, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164628

RESUMO

A particular challenge in the development of a bipolar disorder (BD) model in animals is the complicated clinical course of the condition, characterized by manic, depressive and mixed mood episodes. Ouabain (OUA) is an inhibitor of Na+/K+-ATPase enzyme. Intracerebroventricular (ICV) injection of this drug in rats has been regarded a proper model to study BD by mimic specific manic symptoms, which are reversed by lithium (Li), an important mood stabilizer drug. However, further validation of this experimental approach is required to characterize it as an animal model of BD, including depressive-like behaviors. The present study aimed to assess manic- and depressive-like behaviors, potential alteration in the hypothalamic-pituitary-adrenal (HPA) system and oxidative stress parameters after a single OUA ICV administration in adult male Wistar rats. Moreover, we evaluated Li effects in this experimental setting. Data show that OUA ICV administration could constitute a suitable model for BD since the injection of the drug triggered manic- and depressive-like behaviors in the same animal. Additionally, the OUA model mimics significant physiological and neurochemical alterations detected in BD patients, including an increase in oxidative stress and change in HPA axis. Our findings suggest that decreased Na+/K+-ATPase activity detected in bipolar patients may be linked to increased secretion of glucocorticoid hormones and oxidative damage, leading to the marked behavioral swings. The Li administration mitigated these pathological changes in the rats. The proposed OUA model is regarded as suitable to simulate BD by complying with all validities required to a proper animal model of the psychiatric disorder.


Assuntos
Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Ouabaína/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Injeções Intraventriculares , Compostos de Lítio/farmacologia , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Ratos Wistar
15.
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
16.
Eur J Endocrinol ; 181(2): 201-210, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31167165

RESUMO

Background: Adrenal crisis, the most feared complication of adrenal insufficiency, is a potentially life-threatening state of acute glucocorticoid deficiency. After successful surgery for Cushing's syndrome, many patients develop (transient) adrenal insufficiency. The incidence of adrenal crisis in patients treated for hypercortisolism is unknown. Methods: Cohort study included consecutive patients with Cushing's syndrome with adrenal insufficiency after surgery from Leiden and Berlin from 2000 to 2015. We summarized the incidence of adrenal crisis, compared patients with and without adrenal crisis regarding potential risk factors for its occurrence and assessed the effect of better education in time on incidence of adrenal crisis. Results: We included 106 patients, of whom 19 patients had a total of 41 adrenal crises. There were 9.0 crises per 100 patient-years at risk (95% confidence interval (CI): 6.7-12.0). All crises occurred while on hydrocortisone replacement. The risk ratio for a recurrent crisis was 2.3 (95% CI: 1.2-4.6). No clear change in incidence of adrenal crisis due to better education in time was observed. There was no difference in recurrence rate between patients with, and without any crisis, but patients with adrenal crisis had more often pituitary deficiencies. Conclusions: The incidence of adrenal crises after treatment for Cushing's syndrome is substantial, and patients who suffered from an adrenal crisis have higher risk for recurrent crisis. Adrenal crisis tends to present early after remission of Cushing's syndrome, which is probably the period of severest HPA axis suppression, despite in general higher hydrocortisone replacement doses for withdrawal complaints in this period. Additional pituitary hormone deficiencies may be a risk marker for increased risk of adrenal crisis. However, further risk factor analysis is needed to identify risks for a first crisis. Effective education methods to prevent adrenal crises should be identified and implemented, including stress instructions by trained nursing staff before hospital discharge.


Assuntos
Insuficiência Adrenal/metabolismo , Síndrome de Cushing/metabolismo , Síndrome de Cushing/cirurgia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Complicações Pós-Operatórias/metabolismo , Adolescente , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Síndrome de Cushing/diagnóstico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Adulto Jovem
17.
J Anim Sci ; 97(7): 2940-2951, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31081510

RESUMO

The present study used Escherichia coli lipopolysaccharide (LPS) to investigate whether maternal immune challenge during late gestation altered programming of the offspring hypothalamus and hypothalamic-pituitary-adrenal axis (HPAA). In addition, interactions of maternal diet, supplementation with fish oil (FO) or microalgae (AL), and complex vs. simple weaning diets were investigated. Briefly, Landrace × Yorkshire sows (N = 48) were randomly assigned to diets supplemented with FO, AL, or a standard gestation control diet (CON) from day 75 of gestation (gd 75) until parturition. On gd 112, half the sows from each dietary treatment were immune challenged with LPS (10 µg/kg BW) or saline as a control. At 21 d postpartum, the offspring were weaned, and half the animals from each maternal treatment were allocated to either a complex or simple weaning diet. At 28 d postpartum, the offspring's hourly fever and 2-h cortisol responses to LPS immune challenge (40 µg/kg BW) were measured to assess hypothalamus and HPAA function. Results indicated that the maternal temperature of sows on the FO diet returned to baseline levels faster than sows on the AL and CON diets after LPS immune challenge (P < 0.05). In contrast, there was no difference in the maternal cortisol response across the dietary treatments (P > 0.10). Regardless of the dietary treatments, the maternal LPS immune challenge induced a greater cortisol response in male offspring (P = 0.05) and a greater fever response in female offspring (P = 0.03) when they were LPS immune challenged post-weaning. Male offspring from LPS-immune-challenged sows fed the FO and AL diets had a greater fever response than male offspring from the maternal CON diet group (P ≤ 0.05). Last, no effect of the complex or simple weaning diets was observed for the nursery pig cortisol or fever responses to LPS immune challenge. In conclusion, LPS immune challenge during late pregnancy altered responsiveness of the offspring hypothalamus and HPAA to this same microbial stressor, and a sex-specific response was influenced by maternal dietary supplementation with FO and AL.


Assuntos
Suplementos Nutricionais , Óleos de Peixe/farmacologia , Microalgas , Suínos/fisiologia , Animais , Óleo de Milho/farmacologia , Dieta/veterinária , Escherichia coli/química , Feminino , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Projetos Piloto , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Distribuição Aleatória , Fatores Sexuais , Suínos/imunologia , Desmame
18.
PLoS One ; 14(5): e0216000, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31116735

RESUMO

Hair is an emerging biological matrix in which to measure chronic HPA axis activity, offering a longer term view into an animal's life. We explored effects of exogenous (e.g. lifestyle, medications, social environment) and endogenous (e.g. disease, behaviour) stressors on hair cortisol concentration (HCC) in a population of Border Collies (BCs). Owners of BCs were recruited and reported their dog's lifestyle, clinical history, anxiety-related behaviour, and collected a white hair sample from their dog's dorsal neck region. HCC was determined using established methods with a commercial cortisol assay kit. Samples from 135 BCs were analysed, with 91 healthy controls and 44 diagnosed with epilepsy as a model disease. Factors associated with higher HCC included psychosocial stressors (living with three or more other dogs) and lifestyle (engaging in competitive flyball); while factors associated with lower HCC included anxiety (stranger-directed and non-social), health (epilepsy diagnosis, with number of seizures to date negatively correlated with HCC) and medication (certain anti-epileptic drugs were associated with elevated or reduced HCC). These novel results highlight the potential of chronic stress with frequent or persisting HPA-axis hyperactivity leading to a state of hypocortisolism, and the need to consider stressor recency and recurrence when interpreting HCC data.


Assuntos
Cabelo/metabolismo , Cabelo/fisiologia , Hidrocortisona/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Animais , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , Cães , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiologia
19.
J Assist Reprod Genet ; 36(6): 1273-1280, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31073722

RESUMO

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder mostly characterized by gonadotropins release and/or action deficiencies. Both isolated (idiopathic hypogonadotropic hypogonadism) and syndromic (Kallmann) forms are identified depending on the olfactory ability. Clinical and genetic heterogeneities of CHH have been widely explored, thus improving our understanding of the disease's pathophysiology. This work aims to (1) provide a detailed clinical and hormonal description of normosmic CHH patients and (2) identify the mutation linked to the studied phenotype. PARTICIPANTS AND METHODS: We investigated three affected patients with normosmic CHH, belonging to a consanguineous Tunisian family. Patients underwent an insulin-induced hypoglycemia test. We performed whole exome sequencing to identify the causal mutation. RESULTS: At first diagnosis, a total gonadotropic deficiency was identified in all patients. The insulin-induced hypoglycemia test has also revealed a reduced cortisol secretion and complete growth hormone deficiency. At 20.8 years, one female exhibited a spontaneous recovery of the hypothalamic-pituitary-adrenal axis function, unlike her affected siblings who still depend on corticosteroid replacement therapy. Herein, we identified a novel homozygous nonstop mutation (c.1195T>C) in KISS1R gene in all affected subjects. This mutation led to the substitution of the physiologic stop codon by an arginine (p.X399R). CONCLUSIONS: Our study highlights the importance of the KISS1R signaling, in gonadotropin-releasing hormone neurons, in the control of reproductive function. Additionally, our data suggests a complex central and peripheral metabolic control of puberty, through the hypothalamic KISS1R signaling. We suggest a mutual link between the hypothalamic-pituitary-gonadal, -adrenal, and -somatotropic axes.


Assuntos
Hipogonadismo/genética , Sistema Hipotálamo-Hipofisário/metabolismo , Receptores de Kisspeptina-1/genética , Reprodução/genética , Adolescente , Corticosteroides/uso terapêutico , Adulto , Criança , Feminino , Hormônio Liberador de Gonadotropina/genética , Gonadotropinas/uso terapêutico , Humanos , Hipogonadismo/tratamento farmacológico , Hipogonadismo/patologia , Sistema Hipotálamo-Hipofisário/patologia , Masculino , Mutação , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
20.
Ther Adv Cardiovasc Dis ; 13: 1753944719851950, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31144599

RESUMO

Women are at increased risk for developing depression and cardiovascular disease (CVD) across the lifespan and their comorbidity is associated with adverse outcomes that contribute significantly to rates of morbidity and mortality in women worldwide. Immune-system activity has been implicated in the etiology of both depression and CVD, but it is unclear how inflammation contributes to sex differences in this comorbidity. This narrative review provides an updated synthesis of research examining the association of inflammation with depression and CVD, and their comorbidity in women. Recent research provides evidence of pro-inflammatory states and sex differences associated with alterations in the hypothalamic-pituitary-adrenal axis, the renin-angiotensin-aldosterone system and the serotonin/kynurenine pathway, that likely contribute to the development of depression and CVD. Changes to inflammatory cytokines in relation to reproductive periods of hormonal fluctuation (i.e. the menstrual cycle, perinatal period and menopause) are highlighted and provide a greater understanding of the unique vulnerability women experience in developing both depressed mood and adverse cardiovascular events. Inflammatory biomarkers hold substantial promise when combined with a patient's reproductive and mental health history to aid in the prediction, identification and treatment of the women most at risk for CVD and depression. However, more research is needed to improve our understanding of the mechanisms underlying inflammation in relation to their comorbidity, and how these findings can be translated to improve women's health.


Assuntos
Doenças Cardiovasculares/imunologia , Depressão/imunologia , Sistema Imunitário/imunologia , Inflamação/imunologia , Reprodução/imunologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Depressão/metabolismo , Depressão/fisiopatologia , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Imunitário/metabolismo , Sistema Imunitário/fisiopatologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Cinurenina/imunologia , Cinurenina/metabolismo , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Sistema Renina-Angiotensina/imunologia , Serotonina/imunologia , Serotonina/metabolismo , Transdução de Sinais
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