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[PMID]:28460556
[Au] Autor:Perani CV; Langgartner D; Uschold-Schmidt N; Füchsl AM; Neumann ID; Reber SO; Slattery DA
[Ad] Endereço:a Department of Behavioural and Molecular Neurobiology , University of Regensburg , Regensburg , Germany.
[Ti] Título:Adrenal gland plasticity in lactating rats and mice is sufficient to maintain basal hypersecretion of corticosterone.
[So] Source:Stress;20(3):303-311, 2017 May.
[Is] ISSN:1607-8888
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Increased basal glucocorticoid secretion and a reduced glucocorticoid response during acute stress, despite only minor changes in the secretion of the major secretagogue adrenocorticotropic hormone (ACTH), have been documented in the peripartum period in several species. We recently showed that the adrenal gland, the site of glucocorticoid synthesis, undergoes substantial postpartum-associated plasticity in the rat at mid-lactation. Here, we asked the question whether adrenal changes already take place around parturition in the rat and in another species, namely the mouse. After demonstrating that several components of the adrenal machinery mediating cholesterol supply for steroidogenesis, including protein levels of hormone-sensitive lipase, low-density lipoprotein receptor (LDLR) and scavenger receptor class-B type-1 (SRB1), are upregulated, while hydroxymethylglutaryl coenzyme A reductase (HMGCR) is downregulated in the lactating rat one day after delivery, as previously observed at mid-lactation, we demonstrated profound changes in the mouse. In detail, protein expression of LDLR, SRB1, HMGCR and adrenal lipid store density were increased in the mouse adrenal one day after parturition as tested via western blot analysis and oil-red lipid staining, respectively. Moreover, using in vitro culture techniques, we observed that isolated adrenal explants from lactating mice secreted higher levels of corticosterone under basal conditions, but showed impaired responsiveness to ACTH, mimicking the in vivo scenario. These results suggest that mechanisms of adaptation in the maternal adrenal after delivery, namely increased cholesterol availability and decreased ACTH sensitivity, are crucial for the basal increase in circulating glucocorticoids and maternal stress hyporesponsiveness that are typical of this period.
[Mh] Termos MeSH primário: Glândulas Suprarrenais/secreção
Corticosterona/secreção
Lactação/metabolismo
[Mh] Termos MeSH secundário: Hormônio Adrenocorticotrópico/metabolismo
Animais
Colesterol/metabolismo
Feminino
Hidroximetilglutaril-CoA Redutases/metabolismo
Camundongos
Fosfoproteínas/metabolismo
Período Pós-Parto/metabolismo
Ratos
Receptores da Corticotropina/metabolismo
Receptores de LDL/metabolismo
Receptores Depuradores Classe B/metabolismo
Esterol Esterase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phosphoproteins); 0 (Receptors, Corticotropin); 0 (Receptors, LDL); 0 (Scavenger Receptors, Class B); 0 (steroidogenic acute regulatory protein); 9002-60-2 (Adrenocorticotropic Hormone); 97C5T2UQ7J (Cholesterol); EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases); EC 3.1.1.13 (Sterol Esterase); W980KJ009P (Corticosterone)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1080/10253890.2017.1325462


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[PMID]:28542224
[Au] Autor:Pecaut MJ; Mao XW; Bellinger DL; Jonscher KR; Stodieck LS; Ferguson VL; Bateman TA; Mohney RP; Gridley DS
[Ad] Endereço:Department of Basic Sciences, Division of Radiation Research, Loma Linda University School of Medicine, Loma Linda, CA, United States of America.
[Ti] Título:Is spaceflight-induced immune dysfunction linked to systemic changes in metabolism?
[So] Source:PLoS One;12(5):e0174174, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Space Shuttle Atlantis launched on its final mission (STS-135) on July 8, 2011. After just under 13 days, the shuttle landed safely at Kennedy Space Center (KSC) for the last time. Female C57BL/6J mice flew as part of the Commercial Biomedical Testing Module-3 (CBTM-3) payload. Ground controls were maintained at the KSC facility. Subsets of these mice were made available to investigators as part of NASA's Bio-specimen Sharing Program (BSP). Our group characterized cell phenotype distributions and phagocytic function in the spleen, catecholamine and corticosterone levels in the adrenal glands, and transcriptomics/metabolomics in the liver. Despite decreases in most splenic leukocyte subsets, there were increases in reactive oxygen species (ROS)-related activity. Although there were increases noted in corticosterone levels in both the adrenals and liver, there were no significant changes in catecholamine levels. Furthermore, functional analysis of gene expression and metabolomic profiles suggest that the functional changes are not due to oxidative or psychological stress. Despite changes in gene expression patterns indicative of increases in phagocytic activity (e.g. endocytosis and formation of peroxisomes), there was no corresponding increase in genes related to ROS metabolism. In contrast, there were increases in expression profiles related to fatty acid oxidation with decreases in glycolysis-related profiles. Given the clear link between immune function and metabolism in many ground-based diseases, we propose a similar link may be involved in spaceflight-induced decrements in immune and metabolic function.
[Mh] Termos MeSH primário: Glândulas Suprarrenais/metabolismo
Fígado/metabolismo
Voo Espacial
Baço/imunologia
Baço/metabolismo
[Mh] Termos MeSH secundário: Glândulas Suprarrenais/patologia
Animais
Catecolaminas/metabolismo
Sobrevivência Celular
Corticosterona/metabolismo
Feminino
Perfilação da Expressão Gênica
Doenças do Sistema Imune/etiologia
Doenças do Sistema Imune/metabolismo
Doenças do Sistema Imune/patologia
Leucócitos/imunologia
Leucócitos/metabolismo
Leucócitos/patologia
Doenças Metabólicas/etiologia
Doenças Metabólicas/metabolismo
Doenças Metabólicas/patologia
Metaboloma
Metabolômica
Camundongos Endogâmicos C57BL
Modelos Animais
Fagocitose
Espécies Reativas de Oxigênio/metabolismo
Receptores da Corticotropina/metabolismo
Baço/patologia
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Catecholamines); 0 (Reactive Oxygen Species); 0 (Receptors, Corticotropin); W980KJ009P (Corticosterone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0174174


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[PMID]:26820476
[Au] Autor:Barzel B; Lim K; Davern PJ; Burke SL; Armitage JA; Head GA
[Ad] Endereço:aBaker IDI Heart and Diabetes Institute, MelbournebDepartment of Anatomy and Developmental Biology, Monash University, ClaytoncSchool of Medicine (Optometry), Deakin University, GeelongdDepartment of Pharmacology, Monash University, Clayton, Victoria, Australia*Benjamin Barzel and Kyungjoon Lim are joint first authors.†James A. Armitage and Geoffrey A. Head are joint senior authors.
[Ti] Título:Central proopiomelanocortin but not neuropeptide Y mediates sympathoexcitation and hypertension in fat fed conscious rabbits.
[So] Source:J Hypertens;34(3):464-73; discussion 473, 2016 Mar.
[Is] ISSN:1473-5598
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: High-fat diet (HFD)-induced hypertension in rabbits is neurogenic because of the central sympathoexcitatory actions of leptin. Hypothalamic melanocortin and neuropeptide Y (NPY) neurons are recognized as the major signalling pathways through which leptin exerts its central effects. In this study, we assessed the effects of specific antagonists and agonists to melanocortin and NPY receptors on HFD-induced sympathoexcitation and hypertension. METHODS: Rabbits were instrumented with intracerebroventricular cannula, renal sympathetic nerve activity (RSNA) electrode, and blood pressure telemetry transmitter. RESULTS: After 3 weeks HFD (13.5% fat, n = 12) conscious rabbits had higher RSNA (+3.8  nu, P = 0.02), blood pressure (+8.6  mmHg, P < 0.001) and heart rate (+15  b/min, P = 0.01), and brain-derived neurotrophic factor levels in the hypothalamus compared with rabbits fed a control diet (4.2% fat, n = 11). Intracerebroventricular administration of the melanocortin receptor antagonist SHU9119 reduced RSNA (-2.7  nu) and blood pressure (-8.5  mmHg) in HFD but not control rabbits, thus reversing 100% of the hypertension and 70% of the sympathoexcitation induced by a HFD. By contrast, blocking central NPY Y1 receptors with BVD10 increased RSNA only in HFD rabbits. Intracerebroventricular α-melanocortin stimulating hormone increased RSNA and heart rate (P < 0.001) in HFD rabbits but had no effect in control rabbits. CONCLUSION: These findings suggest that obesity-induced hypertension and increased RSNA are dependent on the balance between greater activation of melanocortin signalling through melanocortin receptors and lesser activation of NPY sympathoinhibitory signalling. The amplification of the sympathoexcitatory effects of α-melanocortin stimulating hormone also indicates that the underlying mechanism is related to facilitation of leptin-melanocortin signalling, possibly involving chronic activation of brain-derived neurotrophic factor.
[Mh] Termos MeSH primário: Hipertensão/metabolismo
Hipotálamo/metabolismo
Leptina/metabolismo
Neuropeptídeo Y/metabolismo
Obesidade/metabolismo
Pró-Opiomelanocortina/metabolismo
Receptores de Melanocortina/metabolismo
Receptores de Neuropeptídeo Y/metabolismo
Sistema Nervoso Simpático/metabolismo
[Mh] Termos MeSH secundário: Animais
Pressão Sanguínea/efeitos dos fármacos
Fator Neurotrófico Derivado do Encéfalo/metabolismo
Dieta Hiperlipídica
Frequência Cardíaca/efeitos dos fármacos
Hormônios/farmacologia
Hipertensão/fisiopatologia
Rim/inervação
Masculino
Hormônios Estimuladores de Melanócitos/farmacologia
Obesidade/fisiopatologia
Coelhos
Receptores da Corticotropina/antagonistas & inibidores
Sistema Nervoso Simpático/efeitos dos fármacos
Sistema Nervoso Simpático/fisiopatologia
alfa-MSH/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Brain-Derived Neurotrophic Factor); 0 (Hormones); 0 (Leptin); 0 (Neuropeptide Y); 0 (Receptors, Corticotropin); 0 (Receptors, Melanocortin); 0 (Receptors, Neuropeptide Y); 0 (neuropeptide Y-Y1 receptor); 168482-23-3 (SHU 9119); 581-05-5 (alpha-MSH); 66796-54-1 (Pro-Opiomelanocortin); 9002-79-3 (Melanocyte-Stimulating Hormones)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:160129
[Lr] Data última revisão:
160129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160129
[St] Status:MEDLINE
[do] DOI:10.1097/HJH.0000000000000811


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[PMID]:26577520
[Au] Autor:Shan Y; Wang DD; Xu YX; Wang C; Cao L; Liu YS; Zhu CQ
[Ti] Título:Aging as a Precipitating Factor in Chronic Restraint Stress-Induced Tau Aggregation Pathology, and the Protective Effects of Rosmarinic Acid.
[So] Source:J Alzheimers Dis;49(3):829-44, 2016.
[Is] ISSN:1875-8908
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Stress is an important risk factor of Alzheimer's disease (AD). It has been evidenced that stress could induce tau phosphorylation and increase tau insolubility in brain; however, little is known about the interactional effect of stress with aging on tauopathy. Therefore, we explored the effects of aging on stress-induced tauopathy and the potential mechanism in mouse model of chronic restraint stress (CRS). Here we found that in general, the level of phosphorylated tau (P-tau) was higher in brain of middle-aged mice than that in adult mice under physiological conditions. CRS-induced tau phosphorylation and its insolubility were more prominent in middle-aged mice. The increase of AT8-labeled insoluble P-tau was dramatic in middle-aged mice, which was highly ubiquitinated but did not form PHF structures. The levels of chaperones were relatively lower in middle-aged mice brain; CRS further reduced the expression, especially for HDJ2/HSP40. CRS also suppressed the expression of Pin1, the peptidylprolyl cis/trans isomerase, in middle-aged mice but not in adult mice. Downregulation of HSP40 or Pin1 caused an increase of transfected extraneous tau in 293 cells. Rosmarinic acid (RA) could effectively suppress the elevation of P-tau and insoluble P-tau formation induced by CRS, and reversed the abnormal changes of chaperones and Pin1 particularly in middle-aged mice. Taken together, our findings provided evidence that aging could be a promoting factor in stress-induced tauopathy, which was relevant with malregulation of chaperones and Pin1, and RA might be a promising beneficial agent for stress-induced tauopathy.
[Mh] Termos MeSH primário: Envelhecimento
Antioxidantes/uso terapêutico
Encéfalo/efeitos dos fármacos
Cinamatos/uso terapêutico
Depsídeos/uso terapêutico
Estresse Psicológico/tratamento farmacológico
Estresse Psicológico/metabolismo
Proteínas tau/metabolismo
[Mh] Termos MeSH secundário: Animais
Encéfalo/metabolismo
Encéfalo/ultraestrutura
Hormônio Liberador da Corticotropina/metabolismo
Modelos Animais de Doenças
Células HEK293
Proteínas de Choque Térmico HSP90/metabolismo
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Microscopia Imunoeletrônica
Peptidilprolil Isomerase de Interação com NIMA
Peptidilprolil Isomerase/metabolismo
Fosforilação
Fatores Desencadeantes
Receptores da Corticotropina/metabolismo
Restrição Física/efeitos adversos
Estresse Psicológico/etiologia
Estresse Psicológico/patologia
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antioxidants); 0 (Cinnamates); 0 (Depsides); 0 (HSP90 Heat-Shock Proteins); 0 (NIMA-Interacting Peptidylprolyl Isomerase); 0 (Receptors, Corticotropin); 0 (tau Proteins); 9015-71-8 (Corticotropin-Releasing Hormone); EC 5.2.1.8 (PIN1 protein, human); EC 5.2.1.8 (Peptidylprolyl Isomerase); EC 5.2.1.8 (Pin1 protein, mouse); MQE6XG29YI (rosmarinic acid)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:170103
[Lr] Data última revisão:
170103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151119
[St] Status:MEDLINE
[do] DOI:10.3233/JAD-150486


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[PMID]:25460300
[Au] Autor:Harvey PW
[Ad] Endereço:Toxicology Department, Covance Laboratories Ltd., Otley Road, Harrogate, North Yorkshire HG3 1PY, United Kingdom. Electronic address: philip.harvey@covance.com.
[Ti] Título:Adrenocortical endocrine disruption.
[So] Source:J Steroid Biochem Mol Biol;155(Pt B):199-206, 2016 Jan.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The adrenal has been neglected in endocrine disruption regulatory testing strategy. The adrenal is a vital organ, adrenocortical insufficiency is recognised in life threatening "adrenal crises" and Addison's disease, and the consequences of off-target toxicological inhibition of adrenocortical steroidogenesis is well recognised in clinical medicine, where drugs such as aminoglutethimide and etomidate killed patients via unrecognised inhibition of adrenocortical steroidogenic enzymes (e.g. CYP11B1) along the cortisol and aldosterone pathways. The consequences of adrenocortical dysfunction during early development are also recognised in the congenital salt wasting and adrenogenital syndromes presenting neonatally, yet despite a remit to focus on developmental and reproductive toxicity mechanisms of endocrine disruption by many regulatory agencies (USEPA EDSTAC; REACH) the assessment of adrenocortical function has largely been ignored. Further, every step in the adrenocortical steroidogenic pathway (ACTH receptor, StAR, CYP's 11A1, 17, 21, 11B1, 11B2, and 3-hydroxysteroid dehydrogenase Δ4,5 isomerase) is known to be a potential target with multiple examples of chemicals inhibiting these targets. Many of these chemicals have been detected in human and wildlife tissues. This raises the question of whether exposure to low level environmental chemicals may be affecting adrenocortical function. This review examines the omission of adrenocortical testing in the current regulatory frameworks; the characteristics that make the adrenal cortex particularly vulnerable to toxic insult; chemicals and their toxicological targets within the adrenocortical steroidogenic pathways; the typical manifestations of adrenocortical toxicity (e.g. human iatrogenically induced pharmacotoxicological adrenal insufficiency, manifestations in typical mammalian regulatory general toxicology studies, manifestations in wildlife) and models of adrenocortical functional assessment. The utility of the in vivo ACTH challenge test to prove adrenocortical competency, and the H295R cell line to examine molecular mechanisms of steroidogenic pathway toxicity, are discussed. Finally, because of the central role of the adrenal in the physiologically adaptive stress response, the distinguishing features of stress, compared with adrenocortical toxicity, are discussed with reference to the evidence required to claim that adrenal hypertrophy results from stress rather than adrenocortical enzyme inhibition which is a serious adverse toxicological finding. This article is part of a special issue entitled 'Endocrine disruptors and steroids'.
[Mh] Termos MeSH primário: Córtex Suprarrenal/efeitos dos fármacos
Insuficiência Adrenal/induzido quimicamente
Aminoglutetimida/toxicidade
Disruptores Endócrinos/toxicidade
Etomidato/toxicidade
[Mh] Termos MeSH secundário: Córtex Suprarrenal/fisiopatologia
Insuficiência Adrenal/genética
Insuficiência Adrenal/metabolismo
Insuficiência Adrenal/fisiopatologia
Animais
Linhagem Celular Tumoral
Corticosterona/agonistas
Corticosterona/biossíntese
Sistema Enzimático do Citocromo P-450/genética
Sistema Enzimático do Citocromo P-450/metabolismo
Modelos Animais de Doenças
Regulação da Expressão Gênica
Seres Humanos
Sistema Hipotálamo-Hipofisário/efeitos dos fármacos
Sistema Hipotálamo-Hipofisário/fisiopatologia
Sistema Hipófise-Suprarrenal/efeitos dos fármacos
Sistema Hipófise-Suprarrenal/fisiopatologia
Receptores da Corticotropina/genética
Receptores da Corticotropina/metabolismo
Transdução de Sinais
Estresse Fisiológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Endocrine Disruptors); 0 (Receptors, Corticotropin); 0O54ZQ14I9 (Aminoglutethimide); 9035-51-2 (Cytochrome P-450 Enzyme System); W980KJ009P (Corticosterone); Z22628B598 (Etomidate)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:151215
[Lr] Data última revisão:
151215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE


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[PMID]:26442440
[Au] Autor:Perani CV; Neumann ID; Reber SO; Slattery DA
[Ad] Endereço:Department of Behavioural and Molecular Neurobiology, University of Regensburg, Regensburg, Germany.
[Ti] Título:High-fat diet prevents adaptive peripartum-associated adrenal gland plasticity and anxiolysis.
[So] Source:Sci Rep;5:14821, 2015 Oct 07.
[Is] ISSN:2045-2322
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Maternal obesity is associated with lower basal plasma cortisol levels and increased risk of postpartum psychiatric disorders. Given that both obesity and the peripartum period are characterized by an imbalance between adrenocorticotropic hormone (ACTH) and cortisol, we hypothesized that the adrenal glands undergo peripartum-associated plasticity and that such changes would be prevented by a high-fat diet (HFD). Here, we demonstrate substantial peripartum adrenal gland plasticity in the pathways involved in cholesterol supply for steroidogenesis in female rats. In detail, the receptors involved in plasma lipid uptake, low density lipoprotein (LDL) receptor (LDLR) and scavenger receptor class B type 1 (SRB1), are elevated, intra-adrenal cholesterol stores are depleted, and a key enzyme in de novo cholesterol synthesis, hydroxymethylglutaryl coenzyme A reductase (HMGCR), is downregulated; particularly at mid-lactation. HFD prevented the lactation-associated anxiolysis, basal hypercorticism, and exaggerated the corticosterone response to ACTH. Moreover, we show that HFD prevented the downregulation of adrenal cholesterol stores and HMGCR expression, and LDLR upregulation at mid-lactation. These findings show that the adrenal gland is an important regulator of peripartum-associated HPA axis plasticity and that HFD has maladaptive consequences for the mother, partly by preventing these neuroendocrine and also behavioural changes.
[Mh] Termos MeSH primário: Glândulas Suprarrenais/fisiologia
Ansiedade/fisiopatologia
Dieta Hiperlipídica/efeitos adversos
Período Periparto/fisiologia
[Mh] Termos MeSH secundário: Glândulas Suprarrenais/efeitos dos fármacos
Glândulas Suprarrenais/metabolismo
Hormônio Adrenocorticotrópico/sangue
Animais
Comportamento Animal
Colesterol/metabolismo
Corticosterona/sangue
Feminino
Hidroximetilglutaril-CoA Redutases/metabolismo
Sistema Hipotálamo-Hipofisário/metabolismo
Período Periparto/efeitos dos fármacos
Sistema Hipófise-Suprarrenal/metabolismo
Gravidez
Ratos Wistar
Receptores da Corticotropina/metabolismo
Receptores de LDL/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, Corticotropin); 0 (Receptors, LDL); 9002-60-2 (Adrenocorticotropic Hormone); 97C5T2UQ7J (Cholesterol); EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases); W980KJ009P (Corticosterone)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151008
[St] Status:MEDLINE
[do] DOI:10.1038/srep14821


  7 / 1058 MEDLINE  
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[PMID]:25605722
[Au] Autor:Yang Y; Mishra V; Crasto CJ; Chen M; Dimmitt R; Harmon CM
[Ad] Endereço:From the Department of Surgery, State University of New York at Buffalo, Buffalo, New York 14203 and yingkuiy@buffalo.edu.
[Ti] Título:Third transmembrane domain of the adrenocorticotropic receptor is critical for ligand selectivity and potency.
[So] Source:J Biol Chem;290(12):7685-92, 2015 Mar 20.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The ACTH receptor, known as the melanocortin-2 receptor (MC2R), plays an important role in regulating and maintaining adrenocortical function. MC2R is a subtype of the melanocortin receptor (MCR) family and has unique characteristics among MCRs. Endogenous ACTH is the only endogenous agonist for MC2R, whereas the melanocortin peptides α-, ß-, and γ-melanocyte-stimulating hormone and ACTH are full agonists for all other MCRs. In this study, we examined the molecular basis of MC2R responsible for ligand selectivity using ACTH analogs and MC2R mutagenesis. Our results indicate that substitution of Phe(7) with D-Phe or D-naphthylalanine (D-Nal(2')) in ACTH(1-24) caused a significant decrease in ligand binding affinity and potency. Substitution of Phe(7) with D-Nal(2') in ACTH(1-24) did not switch the ligand from agonist to antagonist at MC2R, which was observed in MC3R and MC4R. Substitution of Phe(7) with D-Phe(7) in ACTH(1-17) resulted in the loss of ligand binding and activity. Molecular analysis of MC2R indicated that only mutation of the third transmembrane domain of MC2R resulted in a decrease in D-Phe ACTH binding affinity and potency. Our results suggest that Phe(7) in ACTH plays an important role in ligand selectivity and that the third transmembrane domain of MC2R is crucial for ACTH selectivity and potency.
[Mh] Termos MeSH primário: Receptores da Corticotropina/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sítios de Ligação
Citometria de Fluxo
Células HEK293
Seres Humanos
Ligantes
Dados de Sequência Molecular
Mutagênese Sítio-Dirigida
Receptores da Corticotropina/química
Receptores da Corticotropina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Receptors, Corticotropin)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:160321
[Lr] Data última revisão:
160321
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150122
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M114.596122


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[PMID]:25517478
[Au] Autor:Gibbison B; Spiga F; Walker JJ; Russell GM; Stevenson K; Kershaw Y; Zhao Z; Henley D; Angelini GD; Lightman SL
[Ad] Endereço:Department of Cardiac Anesthesia, Bristol Heart Institute, Bristol, UK.
[Ti] Título:Dynamic pituitary-adrenal interactions in response to cardiac surgery.
[So] Source:Crit Care Med;43(4):791-800, 2015 Apr.
[Is] ISSN:1530-0293
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: To characterize the dynamics of the pituitary-adrenal interaction during the course of coronary artery bypass grafting both on and off pump. Since our data pointed to a major change in adrenal responsiveness to adrenocorticotropic hormone, we used a reverse translation approach to investigate the molecular mechanisms underlying this change in a rat model of critical illness. CLINICAL STUDIES: Prospective observational study. ANIMAL STUDIES: Controlled experimental study. CLINICAL STUDIES: Cardiac surgery operating rooms and critical care units. ANIMAL STUDIES: University research laboratory. CLINICAL STUDIES: Twenty, male patients. ANIMAL STUDIES: Adult, male Sprague-Dawley rats. CLINICAL STUDIES: Coronary artery bypass graft-both on and off pump. ANIMAL STUDIES: Injection of either lipopolysaccharide or saline (controls) via a jugular vein cannula. CLINICAL STUDIES: Blood samples were taken for 24 hours from placement of the first venous access. Cortisol and adrenocorticotropic hormone were measured every 10 and 60 minutes, respectively, and corticosteroid-binding globulin was measured at the beginning and end of the 24-hour period and at the end of operation. There was an initial rise in both levels of adrenocorticotropic hormone and cortisol to supranormal values at around the end of surgery. Adrenocorticotropic hormone levels then returned toward preoperative values. Ultradian pulsatility of both adrenocorticotropic hormone and cortisol was maintained throughout the perioperative period in all individuals. The sensitivity of the adrenal gland to adrenocorticotropic hormone increased markedly at around 8 hours after surgery maintaining very high levels of cortisol in the face of "basal" levels of adrenocorticotropic hormone. This sensitivity began to return toward preoperative values at the end of the 24-hour sampling period. ANIMAL STUDIES: Adult, male Sprague-Dawley rats were given either lipopolysaccharide or sterile saline via a jugular vein cannula. Hourly blood samples were subsequently collected for adrenocorticotropic hormone and corticosterone measurement. Rats were killed 6 hours after the injection, and the adrenal glands were collected for measurement of steroidogenic acute regulatory protein, steroidogenic factor 1, and dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 messenger RNAs and protein using real-time quantitative polymerase chain reaction and Western immunoblotting, respectively. Adrenal levels of the adrenocorticotropic hormone receptor (melanocortin type 2 receptor) messenger RNA and its accessory protein (melanocortin type 2 receptor accessory protein) were also measured by real-time quantitative polymerase chain reaction. In response to lipopolysaccharide, rats showed a pattern of adrenocorticotropic hormone and corticosterone that was similar to patients undergoing coronary artery bypass grafting. We were also able to demonstrate increased intra-adrenal corticosterone levels and an increase in steroidogenic acute regulatory protein, steroidogenic factor 1, and melanocortin type 2 receptor accessory protein messenger RNAs and steroidogenic acute regulatory protein, and a reduction in dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 and melanocortin type 2 receptor messenger RNAs, 6 hours after lipopolysaccharide injection. CONCLUSIONS: Severe inflammatory stimuli activate the hypothalamic-pituitary-adrenal axis resulting in increased steroidogenic activity in the adrenal cortex and an elevation of cortisol levels in the blood. Following coronary artery bypass grafting, there is a massive increase in both adrenocorticotropic hormone and cortisol secretion. Despite a subsequent fall of adrenocorticotropic hormone to basal levels, cortisol remains elevated and coordinated adrenocorticotropic hormone-cortisol pulsatility is maintained. This suggested that there is an increase in adrenal sensitivity to adrenocorticotropic hormone, which we confirmed in our animal model of immune activation of the hypothalamic-pituitary-adrenal axis. Using this model, we were able to show that this increased adrenal sensitivity results from changes in the regulation of both stimulatory and inhibitory intra-adrenal signaling pathways. Increased understanding of the dynamics of normal hypothalamic-pituitary-adrenal responses to major surgery will provide us with a more rational approach to glucocorticoid therapy in critically ill patients.
[Mh] Termos MeSH primário: Ponte de Artéria Coronária
Sistema Hipófise-Suprarrenal/fisiologia
[Mh] Termos MeSH secundário: Glândulas Suprarrenais/química
Hormônio Adrenocorticotrópico/sangue
Animais
Western Blotting
Ponte de Artéria Coronária sem Circulação Extracorpórea
Corticosterona/sangue
Seres Humanos
Hidrocortisona/sangue
Sistema Hipotálamo-Hipofisário/fisiologia
Lipopolissacarídeos/farmacologia
Masculino
Proteínas de Membrana/análise
Proteínas de Membrana/genética
Fosfoproteínas/análise
Estudos Prospectivos
RNA Mensageiro/análise
Ratos
Ratos Sprague-Dawley
Reação em Cadeia da Polimerase em Tempo Real
Receptores da Corticotropina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Lipopolysaccharides); 0 (MRAP protein, mouse); 0 (Membrane Proteins); 0 (Phosphoproteins); 0 (RNA, Messenger); 0 (Receptors, Corticotropin); 0 (steroidogenic acute regulatory protein); 9002-60-2 (Adrenocorticotropic Hormone); W980KJ009P (Corticosterone); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1505
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:141218
[St] Status:MEDLINE
[do] DOI:10.1097/CCM.0000000000000773


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[PMID]:25392395
[Au] Autor:Walker JJ; Spiga F; Gupta R; Zhao Z; Lightman SL; Terry JR
[Ad] Endereço:College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter EX4 4QF, UK Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Whitson St., Bristol BS1 3NY, UK.
[Ti] Título:Rapid intra-adrenal feedback regulation of glucocorticoid synthesis.
[So] Source:J R Soc Interface;12(102):20140875, 2015 Jan 06.
[Is] ISSN:1742-5662
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The hypothalamic-pituitary-adrenal axis is a vital neuroendocrine system that regulates the secretion of glucocorticoid hormones from the adrenal glands. This system is characterized by a dynamic ultradian hormonal oscillation, and in addition is highly responsive to stressful stimuli. We have recently shown that a primary mechanism generating this ultradian rhythm is a systems-level interaction where adrenocorticotrophin hormone (ACTH) released from the pituitary stimulates the secretion of adrenal glucocorticoids, which in turn feedback at the level of the pituitary to rapidly inhibit ACTH secretion. In this study, we combine experimental physiology and mathematical modelling to investigate intra-adrenal mechanisms regulating glucocorticoid synthesis. Our modelling results suggest that glucocorticoids can inhibit their own synthesis through a very rapid (within minutes), presumably non-genomic, intra-adrenal pathway. We present further evidence for the existence of a short time delay in this intra-adrenal inhibition, and also that at the initiation of each ACTH stimulus, this local feedback mechanism is rapidly antagonized, presumably via activation of the specific ACTH receptor (MC2R) signalling pathway. This mechanism of intra-adrenal inhibition enables the gland to rapidly release glucocorticoids while at the same time preventing uncontrolled release of glucocorticoids in response to large surges in ACTH associated with stress.
[Mh] Termos MeSH primário: Glândulas Suprarrenais/metabolismo
Retroalimentação Fisiológica
Glucocorticoides/metabolismo
[Mh] Termos MeSH secundário: Hormônio Adrenocorticotrópico/metabolismo
Animais
Sistema Hipotálamo-Hipofisário
Masculino
Modelos Biológicos
Sistema Hipófise-Suprarrenal
Ratos
Ratos Sprague-Dawley
Receptor Tipo 2 de Melanocortina/metabolismo
Receptores da Corticotropina/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Glucocorticoids); 0 (Receptor, Melanocortin, Type 2); 0 (Receptors, Corticotropin); 9002-60-2 (Adrenocorticotropic Hormone)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141114
[St] Status:MEDLINE


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[PMID]:25184992
[Au] Autor:Machado ID; Santin JR; Drewes CC; Gil CD; Oliani SM; Perretti M; Farsky SH
[Ad] Endereço:Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil;
[Ti] Título:Alterations in the profile of blood neutrophil membrane receptors caused by in vivo adrenocorticotrophic hormone actions.
[So] Source:Am J Physiol Endocrinol Metab;307(9):E754-63, 2014 Nov 01.
[Is] ISSN:1522-1555
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Elevated levels of adrenocorticotrophic hormone (ACTH) mobilize granulocytes from bone marrow into the blood, although these neutrophils are refractory to a full migratory response into inflamed tissues. Here, we investigated the dependence of glucocorticoid receptor activation and glucocorticoid-regulated protein annexin A1 (ANXA1) on ACTH-induced neutrophilia and the phenotype of blood neutrophil after ACTH injection, focusing on adhesion molecule expressions and locomotion properties. ACTH injection (5 µg ip, 4 h) induced neutrophilia in wild-type (WT) mice and did not alter the elevated numbers of neutrophils in RU-38486 (RU)-pretreated or ANXA1(-/-) mice injected with ACTH. Neutrophils from WT ACTH-treated mice presented higher expression of Ly6G⁺ANXA1(high), CD18(high), CD62L(high), CD49(high), CXCR4(high), and formyl-peptide receptor 1 (FPR1(low)) than those observed in RU-pretreated or ANXA1(-/-) mice. The membrane phenotype of neutrophils collected from WT ACTH-treated mice was paralleled by elevated fractions of rolling and adherent leukocytes to the cremaster postcapillary venules together with impaired neutrophil migration into inflamed air pouches in vivo and in vitro reduced formyl-methionyl-leucyl-phenylalanine (fMLP) or stromal-derived factor-1 (SDF-1α)-induced chemotaxis. In an 18-h senescence protocol, neutrophils from WT ACTH-treated mice had a higher proportion of ANXAV(low)/CXCR4(low), and they were less phagocytosed by peritoneal macrophages. We conclude that alterations on HPA axis affect the pattern of membrane receptors in circulating neutrophils, which may lead to different neutrophil phenotypes in the blood. Moreover, ACTH actions render circulating neutrophils to a phenotype with early reactivity, such as in vivo leukocyte-endothelial interactions, but with impaired locomotion and clearance.
[Mh] Termos MeSH primário: Hormônio Adrenocorticotrópico/metabolismo
Anexina A1/metabolismo
Leucopoese
Neutrófilos/metabolismo
Receptores da Corticotropina/metabolismo
Estresse Fisiológico
Estresse Psicológico/imunologia
[Mh] Termos MeSH secundário: Hormônio Adrenocorticotrópico/administração & dosagem
Hormônio Adrenocorticotrópico/antagonistas & inibidores
Hormônio Adrenocorticotrópico/sangue
Animais
Anexina A1/sangue
Anexina A1/genética
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Células Cultivadas
Quimiotaxia de Leucócito/efeitos dos fármacos
Corticosterona/sangue
Corticosterona/metabolismo
Antagonistas de Hormônios/farmacologia
Leucopoese/efeitos dos fármacos
Macrófagos/efeitos dos fármacos
Macrófagos/imunologia
Macrófagos/metabolismo
Macrófagos/patologia
Masculino
Camundongos Endogâmicos BALB C
Camundongos Knockout
Neutrófilos/efeitos dos fármacos
Neutrófilos/imunologia
Neutrófilos/patologia
Fagocitose/efeitos dos fármacos
Receptores da Corticotropina/agonistas
Receptores da Corticotropina/antagonistas & inibidores
Receptores da Corticotropina/sangue
Estresse Fisiológico/efeitos dos fármacos
Estresse Psicológico/sangue
Estresse Psicológico/metabolismo
Estresse Psicológico/patologia
Propriedades de Superfície/efeitos dos fármacos
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Annexin A1); 0 (Hormone Antagonists); 0 (Receptors, Corticotropin); 0 (annexin A1, mouse); 9002-60-2 (Adrenocorticotropic Hormone); W980KJ009P (Corticosterone)
[Em] Mês de entrada:1502
[Cu] Atualização por classe:141103
[Lr] Data última revisão:
141103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140904
[St] Status:MEDLINE
[do] DOI:10.1152/ajpendo.00227.2014



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