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1.
Ecotoxicol Environ Saf ; 215: 112108, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33799132

RESUMO

Fluoride which is widespread in our environment and food due to its geological origin and industrial pollution has been identified as a developmental neurotoxicant. Gut-brain axis provides new insight into brain-derived injury. We previously found the psychoactive effects of a probiotic strain, Lactobacillus johnsonii BS15 against fluoride-induced memory dysfunction in mice by modulating the gut-brain axis. In this study, we aimed to detect the link between the reconstruction of gut microbiota and gut-brain axis through which probiotic alleviate fluoride-induced memory impairment. We also added an hour of water avoidance stress (WAS) before behavioral tests and sampling, aiming to demonstrate the preventive effects of the probiotic on fluoride-induced memory impairment after psychological stress. Mice were given fluoridated drinking water (sodium fluoride 100 ppm, corresponding to 37.8 ± 2.4 ppm F¯) for 70 days and administered with PBS or a probiotic strain, Lactobacillus johnsonii BS15 for 28 days prior to and throughout a 70 day exposure to sodium fluoride. Results showed that fluoride increases the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis and reduces the exploration ratio in novel object recognition (NOR) test and the spontaneous exploration during the T-maze test in mice following WAS, which were significantly improved by the probiotic. 16S rRNA sequencing showed a significant separation in ileal microbiota between the fluoride-treated mice and control mice. Lactobacillus was the main targeting bacteria and significantly reduced in fluoride-treated mice. BS15 reconstructed the fluoride-post microbiota and increased the relative abundance of Lactobacillus. D-lactate content and diamine oxidase (DAO) activity, two biomarkers of gut permeability were reduced in the serum of probiotic-inoculated mice. ZO-1, an intestinal tight junction protein was reduced by fluoride in mRNA, and its protein levels were increased by the probiotic treatment. Moreover, the hippocampus which is essential to learning and memory, down-regulated mRNA level of both the myelin-associated glycoprotein (MAG), and protein levels of brain-derived neurotrophic factor (BDNF), including the improvement of cAMP response element-binding protein (CREB) by BS15 in fluoride-exposed mice after WAS. Via spearman correlation analysis, Lactobacillus displayed significantly positive associations with the behavioral tests, levels of nerve development related factors, and intestinal tight junction proteins ZO-1, and negative association with TNF-α of the hippocampus, highlighting regulatory effects of gut bacteria on memory potential and gut barrier. These results suggested the psychoactive effects of BS15 on fluoride-induced memory dysfunction after psychological stress. In addition, there may be some correlations between fluoride-induced memory dysfunction and reconstruction of gut microbiota. AVAILABILITY OF DATA AND MATERIALS: 16S rRNA sequencing reads have uploaded to NCBI. The accession code of 16S rRNA sequencing reads in the National Center for Biotechnology Information (NCBI) BioProject database: PRJNA660154.


Assuntos
Fluoretos/metabolismo , Microbioma Gastrointestinal/fisiologia , Probióticos/farmacologia , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Lactobacillus/metabolismo , Masculino , Memória , Transtornos da Memória/induzido quimicamente , Camundongos , Microbiota , Sistema Hipófise-Suprarrenal/metabolismo , RNA Ribossômico 16S/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
2.
Mayo Clin Proc ; 96(3): 788-814, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33673927

RESUMO

Increased life expectancy combined with the aging baby boomer generation has resulted in an unprecedented global expansion of the elderly population. The growing population of older adults and increased rate of age-related chronic illness has caused a substantial socioeconomic burden. The gradual and progressive age-related decline in hormone production and action has a detrimental impact on human health by increasing risk for chronic disease and reducing life span. This article reviews the age-related decline in hormone production, as well as age-related biochemical and body composition changes that reduce the bioavailability and actions of some hormones. The impact of hormonal changes on various chronic conditions including frailty, diabetes, cardiovascular disease, and dementia are also discussed. Hormone replacement therapy has been attempted in many clinical trials to reverse and/or prevent the hormonal decline in aging to combat the progression of age-related diseases. Unfortunately, hormone replacement therapy is not a panacea, as it often results in various adverse events that outweigh its potential health benefits. Therefore, except in some specific individual cases, hormone replacement is not recommended. Rather, positive lifestyle modifications such as regular aerobic and resistance exercise programs and/or healthy calorically restricted diet can favorably affect endocrine and metabolic functions and act as countermeasures to various age-related diseases. We provide a critical review of the available data and offer recommendations that hopefully will form the groundwork for physicians/scientists to develop and optimize new endocrine-targeted therapies and lifestyle modifications that can better address age-related decline in heath.


Assuntos
Envelhecimento Cognitivo/fisiologia , Disfunção Cognitiva/prevenção & controle , Envelhecimento Saudável/fisiologia , Terapia de Reposição Hormonal/estatística & dados numéricos , Estilo de Vida , Idoso , Terapia Comportamental/estatística & dados numéricos , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo
3.
Neurosci Lett ; 746: 135618, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33429002

RESUMO

Stress is a common seizure trigger in persons with epilepsy. The body's physiological response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and involves a hormonal cascade that includes corticotropin releasing hormone (CRH), adrenocorticotropin releasing hormone (ACTH) and the release of cortisol (in humans and primates) or corticosterone (in rodents). The prolonged exposure to stress hormones may not only exacerbate pre-existing medical conditions including epilepsy, but may also increase the predisposition to psychiatric comorbidities. Hyperactivity of the HPA axis negatively impacts the structure and function of the temporal lobe of the brain, a region that is heavily involved in epilepsy and mood disorders like anxiety and depression. Seizures themselves damage temporal lobe structures, further disinhibiting the HPA axis, setting off a vicious cycle of neuronal damage and increasing susceptibility for subsequent seizures and psychiatric comorbidity. Treatments targeting the HPA axis may be beneficial both for epilepsy and for associated stress-related comorbidities such as anxiety or depression. This paper will highlight the evidence demonstrating dysfunction in the HPA axis associated with epilepsy which may contribute to the comorbidity of psychiatric disorders and epilepsy, and propose treatment strategies that may dually improve seizure control as well as alleviate stress related psychiatric comorbidities.


Assuntos
Epilepsia/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Transtornos Mentais/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Hormônio Adrenocorticotrópico/antagonistas & inibidores , Hormônio Adrenocorticotrópico/metabolismo , Animais , Anticonvulsivantes/administração & dosagem , Corticosterona/antagonistas & inibidores , Corticosterona/metabolismo , Desoxicorticosterona/antagonistas & inibidores , Desoxicorticosterona/metabolismo , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Resultado do Tratamento
4.
Artigo em Inglês | MEDLINE | ID: mdl-33466883

RESUMO

The synthesis and secretion of cortisol are controlled by the hypothalamic-pituitary-adrenal axis. Cortisol exhibits a proper 24-h circadian rhythm that affects the brain, the autonomic nervous system, the heart, and the vasculature that prepares the cardiovascular system for optimal function during these anticipated behavioral cycles. A literature search was conducted using databases such as Google Scholar, PubMed, and Scopus. Relevant search terms included "circadian rhythm and cardiovascular", "cortisol", "cortisol and acute coronary syndrome", "cortisol and arrhythmias", "cortisol and sudden cardiac death", "cortisol and stroke", and "cardioprotective agents". A total of 120 articles were obtained on the basis of the above search. Lower levels of cortisol were seen at the beginning of sleep, while there was a rise towards the end of sleep, with the highest level reached at the moment the individual wakes up. In the present review, we discuss the role of 11ß-hydroxysteroid dehydrogenase (11ß-HSD1), which is a novel molecular target of interest for treating metabolic syndrome and type-2 diabetes mellitus. 11ß-HSD1 is the major determinant of cortisol excess, and its inhibition alleviates metabolic abnormalities. The present review highlights the role of cortisol, which controls the circadian rhythm, and describes its effect on the cardiovascular system. The review provides a platform for future potential cardioprotective therapeutic agents.


Assuntos
Sistema Cardiovascular , Hidrocortisona , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Ritmo Circadiano , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo
5.
Zhongguo Zhong Yao Za Zhi ; 45(20): 4971-4977, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33350271

RESUMO

This study aimed to investigate the antidepressant effects of Puyu Capsules and its potential mechanism. The antidepressant activity of Puyu Capsules was evaluated by forced swimming test(FST) and tail suspension test(TST) after subchronic administration in mice. Next, the mice were subjected to a chronic unpredictable stress(CUS) protocol for a period of 28 d to induce depressive-like behaviors. Then, a sucrose preference test, open-field test and novelty-suppressed feeding test were performed to evaluate the antidepressant effect of Puyu Capsules. After the behavioral test, the adrenal index was calculated; the levels of serum corticosterone(CORT) and adrenocorticotropic hormone(ACTH) were detected by enzyme-linked immunosorbent assay(ELISA); the levels of glucocorticoid receptor(GR), protein expression of brain-derived neurotrophic factor(BDNF), and the ratio of phosphorylated cAMP response element binding protein(CREB) to total CREB were detected by Western blot to explore the antidepressant function and mechanism of Puyu Capsules. The results suggested that Puyu Capsules had significant antidepressant effects on both the depression model and CUS model. At the same time, the drug could prevent the change of adrenal index induced by CUS and reverse the abnormal activation of CORT and ACTH in the serum of depressed mice. Finally, Puyu Capsules could also reverse the lower expression of pCREB, BDNF and GR in the hippocampus of CUS mice. In conclusion, Puyu Capsules produced significant antidepressant effects, and the mechanism was closely related to hypothalamic pituitary adrenal(HPA) axis activity, GR and CREB-BDNF pathway expression.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Sistema Hipotálamo-Hipofisário , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cápsulas , Depressão/tratamento farmacológico , Depressão/genética , Modelos Animais de Doenças , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Camundongos , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Psicológico
6.
Eur J Endocrinol ; 183(6): 669-676, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33112256

RESUMO

Context: Obesity and cardiometabolic diseases are associated with higher long-term glucocorticoid levels, measured as scalp hair cortisol (HairF) and cortisone (HairE). Cardiometabolic diseases have also been associated with copeptin, a stable surrogate marker for the arginine-vasopressin (AVP) system. Since AVP is, together with corticotropin-releasing hormone (CRH) an important regulator of the hypothalamic-pituitary adrenal axis (HPA axis), we hypothesize that AVP contributes to chronic hypercortisolism in obesity. Objective: To investigate whether copeptin levels are associated with Higher HairF and HairE levels in obesity. Design: A cross-sectional study in 51 adults with obesity (BMI ≥30 kg/m2). Methods: Associations and interactions between copeptin, HairF, HairE, and cardiometabolic parameters were cross-sectionally analyzed. Results: Copeptin was strongly associated with BMI and waist circumference (WC) (rho = 0.364 and 0.530, P = 0.008 and <0.001, respectively), also after correction for confounders. There were no associations between copeptin and HairF or HairE on a continuous or dichotomized scale, despite correction for confounders. Conclusion: In patients with obesity, AVP seems not a major contributor to the frequently observed high cortisol levels. Other factors which stimulate the HPA axis or affect cortisol synthesis or breakdown may be more important than the influence of AVP on long-term glucocorticoid levels in obesity.


Assuntos
Cortisona/metabolismo , Síndrome de Cushing/etiologia , Glicopeptídeos/metabolismo , Hidrocortisona/metabolismo , Obesidade/metabolismo , Adulto , Arginina Vasopressina/metabolismo , Biomarcadores/metabolismo , Índice de Massa Corporal , Hormônio Liberador da Corticotropina/metabolismo , Estudos Transversais , Feminino , Glucocorticoides/metabolismo , Cabelo/química , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Obesidade/complicações , Sistema Hipófise-Suprarrenal/metabolismo
7.
BMC Med Genet ; 21(1): 184, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32957930

RESUMO

BACKGROUND: Two important aspects for the development of anxiety disorders are genetic predisposition and alterations in the hypothalamic-pituitary-adrenal (HPA) axis. In order to identify genetic risk-factors for anxiety, the aim of this exploratory study was to investigate possible relationships between genetic polymorphisms in genes important for the regulation and activity of the HPA axis and self-assessed anxiety in healthy individuals. METHODS: DNA from 72 healthy participants, 37 women and 35 men, were included in the analyses. Their DNA was extracted and analysed for the following Single Nucleotide Polymorphisms (SNP)s: rs41423247 in the NR3C1 gene, rs1360780 in the FKBP5 gene, rs53576 in the OXTR gene, 5-HTTLPR in SLC6A4 gene and rs6295 in the HTR1A gene. Self-assessed anxiety was measured by the State and Trait Anxiety Inventory (STAI) questionnaire. RESULTS: Self-assessed measure of both STAI-S and STAI-T were significantly higher in female than in male participants (p = 0.030 and p = 0.036, respectively). For SNP rs41423247 in the NR3C1 gene, there was a significant difference in females in the score for STAI-S, where carriers of the G allele had higher scores compared to the females that were homozygous for the C allele (p < 0.01). For the SNP rs53576 in the OXTR gene, there was a significant difference in males, where carriers of the A allele had higher scores in STAI-T compared to the males that were homozygous for the G allele (p < 0.01). CONCLUSION: This study shows that SNP rs41423247 in the NR3C1 gene and SNP rs53576 in the OXTR gene are associated with self-assessed anxiety in healthy individuals in a gender-specific manner. This suggests that these SNP candidates are possible genetic risk-factors for anxiety.


Assuntos
Transtornos de Ansiedade/genética , Predisposição Genética para Doença/genética , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de Glucocorticoides/genética , Receptores de Ocitocina/genética , Adulto , Alelos , Ansiedade/psicologia , Transtornos de Ansiedade/psicologia , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
8.
Proc Natl Acad Sci U S A ; 117(33): 20052-20062, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747546

RESUMO

In humans and other animals, harsh conditions in early life can have profound effects on adult physiology, including the stress response. This relationship may be mediated by a lack of supportive relationships in adulthood. That is, early life adversity may inhibit the formation of supportive social ties, and weak social support is itself often linked to dysregulated stress responses. Here, we use prospective, longitudinal data from wild baboons in Kenya to test the links between early adversity, adult social bonds, and adult fecal glucocorticoid hormone concentrations (a measure of hypothalamic-pituitary-adrenal [HPA] axis activation and the stress response). Using a causal inference framework, we found that experiencing one or more sources of early adversity led to a 9 to 14% increase in females' glucocorticoid concentrations across adulthood. However, these effects were not mediated by weak social bonds: The direct effects of early adversity on adult glucocorticoid concentrations were 11 times stronger than the effects mediated by social bonds. This pattern occurred, in part, because the effect of social bonds on glucocorticoids was weak compared to the powerful effects of early adversity on glucocorticoid levels in adulthood. Hence, in female baboons, weak social bonds in adulthood are not enough to explain the effects of early adversity on glucocorticoid concentrations. Together, our results support the well-established notions that early adversity and weak social bonds both predict poor adult health. However, the magnitudes of these two effects differ considerably, and they may act independently of one another.


Assuntos
Fezes/química , Glucocorticoides/análise , Papio/psicologia , Comportamento Social , Animais , Animais Selvagens/metabolismo , Feminino , Glucocorticoides/metabolismo , Estudos Longitudinais , Masculino , Apego ao Objeto , Papio/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Estudos Prospectivos , Estresse Psicológico
9.
ACS Chem Neurosci ; 11(13): 1868-1870, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32605374

RESUMO

Cytokine storm in COVID-19 is characterized by an excessive inflammatory response to SARS-CoV-2 that is caused by a dysregulated immune system of the host. We are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of nucleus tractus solitarius (NTS) may be responsible for the cytokine storm in COVID 19. The inflamed NTS may result in a dysregulated cholinergic anti-inflammatory pathway and hypothalamic-pituitary-adrenal axis.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Citocinas/metabolismo , Pneumonia Viral/metabolismo , Núcleo Solitário/metabolismo , Axônios/imunologia , Axônios/metabolismo , Axônios/virologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Nervos Cranianos/imunologia , Nervos Cranianos/metabolismo , Nervos Cranianos/virologia , Citocinas/imunologia , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/virologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Pandemias , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/virologia , Pneumonia Viral/imunologia , Núcleo Solitário/imunologia , Núcleo Solitário/virologia
10.
PLoS One ; 15(6): e0233718, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497103

RESUMO

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


Assuntos
Experiências Adversas da Infância , Desidroepiandrosterona/análise , Hidrocortisona/análise , Adolescente , Desidroepiandrosterona/metabolismo , Feminino , Cabelo/química , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Saliva/química , Autorrelato , Fatores Sexuais , Estresse Psicológico/metabolismo
11.
BMC Cardiovasc Disord ; 20(1): 245, 2020 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32450805

RESUMO

BACKGROUND: Cortisol is the main stress hormone mobilised during surgery to establish homeostasis. Our current understanding of the hypothalamic-pituitary-adrenal axis physiology in children undergoing cardiopulmonary bypass is very limited due to: (1) very few cortisol time point measurements over long periods (2) difficulties of sampling in low weight babies and (3) the concomitant use of glucocorticoids at anaesthesia induction. This lack of understanding is reflected in a lack of consensus on the utility of glucocorticoids perioperatively in cardiac surgery with the use of cardiopulmonary bypass. METHODS: The Peacock Study is a prospective, two-centre, observational cohort study of 78 children (undergoing cardiopulmonary bypass procedures and non-surgical procedures - split by age/cyanosis) that aims to characterise in detail the hypothalamic-pituitary-adrenal axis physiology of children using the stress model of paediatric cardiac surgery. Also, we aim to correlate cortisol profiles with clinical outcome data. We herein describe the main study design and report the full cortisol profile of one child undergoing heart surgery, thus proving the feasibility of the method. RESULTS: We used an automated, 24-h tissue microdialysis system to measure cortisol and cortisone, every 20 min. We herein report one cortisol profile of a child undergoing heart surgery. Besides, we measured serum cortisol and adrenocorticotrophic hormone at seven-time points for correlation. Tissue concentrations of cortisol increased markedly several hours after the end of surgery. We also noted an increase in the tissue cortisol/cortisone ratio during this response. CONCLUSION: We report for the first time, the use of an automated microdialysis sampling system to evaluate the paediatric adrenal response in children. Changes in cortisol and cortisone could be measured, and the concentration of cortisol in the tissues increased after the end of cardiac surgery. The method has wide application to measure other hormones dynamically and frequently without the limitation of the circulating blood volume. The data from the main study will clarify how these cortisol profiles vary with age, pathology, type of procedure and correlation to clinical outcomes. TRIAL REGISTRATION: ISCRTN registry, number: 982586.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Cortisona/metabolismo , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Adolescente , Fatores Etários , Biomarcadores/metabolismo , Ponte Cardiopulmonar , Criança , Pré-Escolar , Inglaterra , Estudos de Viabilidade , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Lactente , Recém-Nascido , Masculino , Microdiálise , Sistema Hipófise-Suprarrenal/fisiopatologia , Estudos Prospectivos , Projetos de Pesquisa , Fatores de Tempo , Resultado do Tratamento
12.
Toxicol Lett ; 331: 33-41, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32445661

RESUMO

This study was intended to demonstrate that prenatal dexamethasone exposure (PDE) can induce low basal activity of the hypothalamic-pituitary-adrenal axis (HPAA) in male offspring rats and explore the underlying mechanism. Pregnant rats were subcutaneously administered 0.2 mg/kg/d dexamethasone from gestational day (GD) 9 to GD20. Male GD20 fetuses and postnatal day 85 adult male offspring rats were sacrificed under anesthesia. Hypothalamic cells were from GD20∼postnatal day (PD) 7 fetal male rats, treated with different concentrations of dexamethasone and the glucocorticoid receptor (GR) antagonist mifepristone for 5 days. The results suggested that dexamethasone enhanced the expression of hypothalamic L-glutamic acid decarboxylase (GAD) 67 by activating GR, further stimulating the conversion of glutamate to gamma-aminobutyric acid (GABA) and inducing an imbalance in glutamatergic/GABAergic afferents in the hypothalamic paraventricular nucleus (PVN). This imbalance change was maintained postnatally, leading to the inhibition of parvocellular neurons, and mediating the low basal activity of the HPAA in PDE offspring rats, which was manifested by decreased levels of blood adrenocorticotropic hormone and corticosterone as well as reduced expression levels of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) in the hypothalamus. Programming of a developmental imbalance in glutamatergic/GABAergic afferents in the PVN is a potential mechanism responsible for low basal activity of the HPAA in male PDE rats.


Assuntos
Dexametasona/toxicidade , Ácido Glutâmico/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ácido gama-Aminobutírico/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Animais Recém-Nascidos , Arginina Vasopressina/metabolismo , Corticosterona/sangue , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/metabolismo , Glutamato Descarboxilase/metabolismo , Sistema Hipotálamo-Hipofisário/embriologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Neurônios Aferentes/metabolismo , Núcleo Hipotalâmico Paraventricular/embriologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Sistema Hipófise-Suprarrenal/embriologia , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos
13.
Psychopharmacology (Berl) ; 237(7): 2187-2199, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32399633

RESUMO

RATIONALE: Dysregulation of the endocannabinoid (eCB) system by high doses of Δ9-tetrahydrocannabinol (THC) is hypothesized to generate a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis contributing to cannabinoid hyperemesis syndrome (CHS). OBJECTIVES AND METHODS: Using the conditioned gaping model of nausea, we aimed to determine if pre-treatments that interfere with stress, or an anti-emetic drug, interfere with THC-induced nausea in male rats. The corticotropin-releasing hormone (CRH) antagonist, antalarmin, was given to inhibit the HPA axis during conditioning. Since eCBs inhibit stress, MJN110 (which elevates 2-arachidonylglycerol (2-AG)) and URB597 (which elevates anandamide (AEA)) were also tested. Propranolol (ß-adrenergic antagonist) and WAY-100635 (5-HT1A antagonist) attenuate HPA activation by cannabinoids and, therefore, were assessed. In humans, CHS symptoms are not alleviated by anti-emetic drugs, such as ondansetron (5-HT3 antagonist); however, benzodiazepines are effective. Therefore, ondansetron and chlordiazepoxide were tested. To determine if HPA activation by THC is dose-dependent, corticosterone (CORT) was analyzed from serum of rats treated with 0.0, 0.5, or 10 mg/kg THC. RESULTS: Antalarmin (10 and 20 mg/kg), MJN110 (10 mg/kg), URB597 (0.3 mg/kg), propranolol (2.5 and 5 mg/kg), WAY-100635 (0.5 mg/kg), and chlordiazepoxide (5 mg/kg) interfered with THC-induced conditioned gaping, but the anti-emetic ondansetron (0.1 and 0.01 mg/kg) did not. THC produced significantly higher CORT levels at 10 mg/kg than at 0.0 and 0.5 mg/kg THC. CONCLUSIONS: Treatments that interfere with the stress response also inhibit THC-induced conditioned gaping, but a typical anti-emetic drug does not, supporting the hypothesis that THC-induced nausea, and CHS, is a result of a dysregulated stress response.


Assuntos
Dronabinol/toxicidade , Endocanabinoides/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Náusea/induzido quimicamente , Náusea/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Animais , Antieméticos/farmacologia , Antieméticos/uso terapêutico , Agonistas de Receptores de Canabinoides/toxicidade , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Náusea/tratamento farmacológico , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
14.
Psychopharmacology (Berl) ; 237(7): 2031-2042, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32388622

RESUMO

RATIONALE: Cocaine use disorder (CUD) is associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which plays a critical role in the human stress response. Men and women with CUD differ in reactivity to social stressors. The hypothalamic neuropeptide oxytocin is involved in anxiolytic and natural reward processes, and has shown therapeutic potential for addictive disorders and stress reduction. OBJECTIVES: To examine the impact of oxytocin (oxytocin (OXY) vs. placebo (PBO)) and gender (female (F) vs. male (M)) on response to a social stress task in individuals with CUD. To explore whether ovarian hormones moderate this stress response. METHODS: One hundred twelve adults with CUD were randomized to receive 40 IU intranasal oxytocin (n = 56) or matching placebo (n = 56). Forty minutes after drug administration, participants were exposed to a social stressor. Generalized linear mixed models were used to examine neuroendocrine (cortisol) and subjective (craving, stress) response at pre-stressor, stressor + 0, + 10, + 30, + 60 min. RESULTS: Gender moderated the effect of oxytocin on neuroendocrine response (p = 0.048); women receiving oxytocin (F + OXY) showed blunted cortisol response compared to the other three groups (F + PBO; M + OXY; M + PBO). There was a main effect of gender on subjective stress response; women reported greater stress following the stressor compared to men (p = 0.016). Oxytocin had no significant effect on craving or stress, and gender did not moderate the effect of oxytocin on either measure. Higher endogenous progesterone was associated with lower craving response in women (p = 0.033). CONCLUSIONS: Oxytocin may have differential effects in men and women with CUD. Women may be at greater risk for relapse in response to social stressors, but ovarian hormones may attenuate this effect.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Hormônios Esteroides Gonadais/sangue , Ovário/metabolismo , Ocitocina/administração & dosagem , Caracteres Sexuais , Estresse Psicológico/tratamento farmacológico , Administração Intranasal , Adulto , Transtornos Relacionados ao Uso de Cocaína/sangue , Método Duplo-Cego , Estradiol/sangue , Feminino , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Pessoa de Meia-Idade , Ovário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Progesterona/sangue , Estresse Psicológico/sangue , Resultado do Tratamento , Adulto Jovem
15.
Cell Prolif ; 53(5): e12806, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32281722

RESUMO

The regulation of insulin on depression and depression-like behaviour has been widely reported. Insulin and activation of its receptor can promote learning and memory, affect the hypothalamic-pituitary-adrenal axis (HPA) balance, regulate the secretion of neurotrophic factors and neurotransmitters, interact with gastrointestinal microbiome, exert neuroprotective effects and have an impact on depression. However, the role of insulin on depression remains largely unclear. Therefore, in this review, we summarized the potential role of insulin on depression. It may provide new insight for clarifying role of insulin on the pathogenesis of depression.


Assuntos
Depressão/metabolismo , Depressão/patologia , Insulina/metabolismo , Animais , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/patologia
16.
Am J Physiol Endocrinol Metab ; 319(1): E48-E66, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315214

RESUMO

Although glucocorticoid resistance contributes to increased inflammation, individuals with posttraumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation coexists with a hyperresponsive hypothalamic-pituitary-adrenal (HPA) axis. To understand this better, we developed and analyzed an integrated mathematical model for the HPA axis and the immune system. We performed mathematical simulations for a dexamethasone (DEX) suppression test and IC50-dexamethasone for cytokine suppression by varying model parameters. The model analysis suggests that increasing the steepness of the dose-response curve for GR activity may reduce anti-inflammatory effects of GRs at the ambient glucocorticoid levels, thereby increasing proinflammatory response. The adaptive response of proinflammatory cytokine-mediated stimulatory effects on the HPA axis is reduced due to dominance of the GR-mediated negative feedback on the HPA axis. To verify these hypotheses, we analyzed the clinical data on neuroendocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, proinflammatory cytokines TNFα and IL6, high-sensitivity C-reactive protein, promoter methylation of GR gene, and IC50-DEX for lysozyme suppression. Causal inference modeling revealed significant associations between cortisol suppression and post-DEX cortisol decline, promoter methylation of human GR gene exon 1F (NR3C1-1F), IC50-DEX, and proinflammatory cytokines. We noted significant mediation effects of NR3C1-1F promoter methylation on inflammatory cytokines through changes in GR sensitivity. Our findings suggest that increased GR sensitivity may contribute to increased inflammation; therefore, interventions to restore GR sensitivity may normalize inflammation in PTSD.


Assuntos
Citocinas/imunologia , Glucocorticoides/imunologia , Receptores de Glucocorticoides/imunologia , Transtornos de Estresse Pós-Traumáticos/imunologia , Hormônio Adrenocorticotrópico/imunologia , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Campanha Afegã de 2001- , Proteína C-Reativa/imunologia , Estudos de Casos e Controles , Ritmo Circadiano , Metilação de DNA , Dexametasona , Glucocorticoides/metabolismo , Humanos , Hidrocortisona/imunologia , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Inflamação , Concentração Inibidora 50 , Interleucina-6/imunologia , Guerra do Iraque 2003-2011 , Masculino , Modelos Teóricos , Testes de Função Adreno-Hipofisária , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Regiões Promotoras Genéticas , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Veteranos
17.
Georgian Med News ; (299): 39-43, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32242842

RESUMO

Cancer in children, and mainly the acute lymphoblastic leukemia (ALL), is considered as one of the leading public health problems in Mexico. Glucocorticoids used to treat ALL may cause suppression of the hypothalamic-pituitary-adrenal axis. The aim of the present study was to determine whether cortisol levels in saliva of the patients with ALL are related to the response to the remission induction therapy. The authors have conducted a clinical, prospective and comparative study. The Mann-Whitney U test was used to compare the variables values by gender or type of evolution. According to the patients' evolution, ROC curves were made for salivary cortisol levels and uric acid. An absolute value of 1000 blasts in peripheral blood count after a week of prednisone regimen was defined as a satisfactory response to the treatment. Review of the data has shown that area under the salivary cortisol levels' curve (AUC) was greater than that under the uric acid levels', as a predictor of a poor response to the remission induction. There were no statistically significant gender-associated differences in any variables except in erythrocytes. High levels of cortisol in saliva at the time of diagnosis of ALL seem to be of bad prognosis of the response to the remission induction therapy.


Assuntos
Hidrocortisona/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Saliva/química , Criança , Humanos , Hidrocortisona/análise , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Estudos Prospectivos , Indução de Remissão , Saliva/metabolismo
18.
Dermatol Online J ; 26(2)2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32239884

RESUMO

Skin is the largest peripheral endocrine organ and functions as a hormone target and endocrine gland. A cutaneous hypothalamus-pituitary-adrenal (HPA)-like axis enables the skin to respond to stress and regulates its steroidogenic activity. The pilosebaceous unit is a site for production and metabolism of a number of steroid hormones, including stress and sex hormones. This is an overview of the important role that the cutaneous HPA-like-axis plays in the pathogenesis and treatment of inflammatory pilosebaceous disorders, including acne, rosacea, seborrheic dermatitis, and hidradenitis suppurativa.


Assuntos
Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Doenças das Glândulas Sebáceas/metabolismo , Hidradenite Supurativa/tratamento farmacológico , Hidradenite Supurativa/metabolismo , Humanos , Rosácea/tratamento farmacológico , Rosácea/metabolismo , Doenças das Glândulas Sebáceas/tratamento farmacológico , Pele/metabolismo
19.
Cell ; 180(5): 847-861.e15, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142678

RESUMO

Early life environmental exposure, particularly during perinatal period, can have a life-long impact on organismal development and physiology. The biological rationale for this phenomenon is to promote physiological adaptations to the anticipated environment based on early life experience. However, perinatal exposure to adverse environments can also be associated with adult-onset disorders. Multiple environmental stressors induce glucocorticoids, which prompted us to investigate their role in developmental programming. Here, we report that perinatal glucocorticoid exposure had long-term consequences and resulted in diminished CD8 T cell response in adulthood and impaired control of tumor growth and bacterial infection. We found that perinatal glucocorticoid exposure resulted in persistent alteration of the hypothalamic-pituitary-adrenal (HPA) axis. Consequently, the level of the hormone in adults was significantly reduced, resulting in decreased CD8 T cell function. Our study thus demonstrates that perinatal stress can have long-term consequences on CD8 T cell immunity by altering HPA axis activity.


Assuntos
Infecções Bacterianas/imunologia , Desenvolvimento Embrionário/imunologia , Glucocorticoides/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Dexametasona/farmacologia , Desenvolvimento Embrionário/genética , Feminino , Glucocorticoides/imunologia , Glucocorticoides/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Interleucina-4/farmacologia , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Neoplasias/induzido quimicamente , Neoplasias/genética , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Receptores de Glucocorticoides/genética , Transdução de Sinais/genética
20.
Arch Endocrinol Metab ; 64(1): 82-88, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32187262

RESUMO

Objective The insulin tolerance test (ITT) has been accepted as the gold standard test for assessing the integrity of the growth hormone (GH) - insulin-like growth factor (IGF-1) axis and the hypothalamic-pituitary-adrenal (HPA) axis. The goal of the test is to achieve clinical and biochemical hypoglycemia at a blood glucose level ≤ 40 mg/dL to effectively and correctly assess the HPA and GH-IGF-1 axes. In this study, the GH and cortisol responses of patients who achieved and failed to achieve biochemical hypoglycemia during an ITT were compared. Subjects and methods One hundred thirty-five patients with pituitary disorders were included in the study. Samples for blood glucose levels were obtained after clear symptoms of clinical hypoglycemia developed. The patients were enrolled in the hypoglycemic and nonhypoglycemic groups according to whether their plasma glucose level ≤ 40 mg/dL or > 40 mg/dL during an ITT, and the groups were compared in terms of their GH and cortisol responses. Results The mean age, body mass index and waist circumference of the two patient groups were found to be similar. The mean blood glucose level was significantly lower in the hypoglycemic group than in the nonhypoglycemic group (19.3 and 52.0 mg/dL, respectively). When the two groups were compared in terms of peak cortisol and GH responses, no statistically significant differences were found. Conclusion The data presented suggest that clinically symptomatic hypoglycemia is as effective as biochemically confirmed hypoglycemia during an ITT. Arch Endocrinol Metab. 2020;64(1):82-8.


Assuntos
Teste de Tolerância a Glucose/métodos , Hormônio do Crescimento Humano/sangue , Hidrocortisona/sangue , Hipoglicemia/sangue , Hipoglicemiantes/administração & dosagem , Fator de Crescimento Insulin-Like I/análise , Insulina/administração & dosagem , Adulto , Automonitorização da Glicemia , Feminino , Teste de Tolerância a Glucose/efeitos adversos , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/metabolismo , Estudos Retrospectivos
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