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1.
Artigo em Chinês | MEDLINE | ID: mdl-38973050

RESUMO

Glucocorticoids(GC) are widely used in the clinical treatment of autoimmune inner ear diseases, sudden sensorineural hearing loss, Meniere's disease, sinusitis and other otolaryngology diseases. However, GC resistance remains a major factor contributing to the poor efficacy of clinical treatments. The mechanism of GC resistance is still unclear. This paper reviews the related mechanisms of GC resistance from the perspectives of GC receptor factors and non-GC receptor factors. Additionally, it summarizes the latest research progress on GC resistance in otolaryngological diseases, with the aim of identifying effective clinical alternative treatment options for reversing GC resistance in the future.


Assuntos
Resistência a Medicamentos , Glucocorticoides , Otorrinolaringopatias , Receptores de Glucocorticoides , Humanos , Glucocorticoides/uso terapêutico , Otorrinolaringopatias/tratamento farmacológico , Receptores de Glucocorticoides/metabolismo , Doença de Meniere/tratamento farmacológico
2.
Adipocyte ; 13(1): 2369776, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38982594

RESUMO

BACKGROUND: Bariatric surgery is the most effective treatment for severe obesity. There can be variation in the degree of weight reduction following bariatric surgery. It is unknown whether single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor locus (GRL) affect postoperative weight loss and metabolic outcomes. MATERIALS/METHODS: We studied the association between selected candidate SNPs and postoperative weight loss and metabolic outcomes in patients with severe obesity undergoing bariatric surgery. The polymorphisms rs41423247 (Bcl1), rs56149945 (N363S) and rs6189/rs6190 (ER22/23EK) were analysed. RESULTS: The 139 participants included 95 women (68.3%) and had a median (interquartile range) age of 53.0 (46.0-60.0) years and mean (SD) weight of 140.8 (28.8) kg and body mass index of 50.3 (8.6) kg/m2. At baseline, 59 patients had type 2 diabetes (T2D), 60 had hypertension and 35 had obstructive sleep apnoea syndrome treated with continuous positive airway pressure (CPAP). 84 patients (60.4%) underwent gastric bypass and 55 (39.6%) underwent sleeve gastrectomy. There were no significant differences in weight loss, glycated haemoglobin (HbA1c) or lipid profile categorized by genotype status, sex or median age. There was significant weight reduction after bariatric surgery with a postoperative BMI of 34.1 (6.8) kg/m2 at 24 months (p < 0.001). CONCLUSION: While GRL polymorphisms with a known deleterious effect on adipose tissue mass and function may have a small, additive effect on the prevalence of obesity and related metabolic disorders in the population, we suggest that the relatively weak biological influence of these SNPs is readily overcome by bariatric surgery.


Assuntos
Cirurgia Bariátrica , Polimorfismo de Nucleotídeo Único , Receptores de Glucocorticoides , Redução de Peso , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Redução de Peso/genética , Estudos Prospectivos , Resultado do Tratamento , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirurgia , Obesidade Mórbida/cirurgia , Obesidade Mórbida/genética , Obesidade Mórbida/metabolismo , Adulto
3.
Front Endocrinol (Lausanne) ; 15: 1437179, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39027480

RESUMO

Prostate cancer is one of the most prevalent malignancies and is primarily driven by aberrant androgen receptor (AR) signaling. While AR-targeted therapies form the cornerstone of prostate cancer treatment, they often inadvertently activate compensatory pathways, leading to therapy resistance. This resistance is frequently mediated through changes in transcription factor (TF) crosstalk, reshaping gene regulatory programs and ultimately weakening treatment efficacy. Consequently, investigating TF interactions has become crucial for understanding the mechanisms driving therapy-resistant cancers. Recent evidence has highlighted the crosstalk between the glucocorticoid receptor (GR) and AR, demonstrating that GR can induce prostate cancer therapy resistance by replacing the inactivated AR, thereby becoming a driver of the disease. In addition to this oncogenic role, GR has also been shown to act as a tumor suppressor in prostate cancer. Owing to this dual role and the widespread use of glucocorticoids as adjuvant therapy, it is essential to understand GR's actions across different stages of prostate cancer development. In this review, we explore the current knowledge of GR in prostate cancer, with a specific focus on its crosstalk with other TFs. GR can directly and indirectly interact with a variety of TFs, and these interactions vary significantly depending on the type of prostate cancer cells. By highlighting these crosstalk interactions, we aim to provide insights that can guide the research and development of new GR-targeted therapies to mitigate its harmful effects in prostate cancer.


Assuntos
Neoplasias da Próstata , Receptores de Glucocorticoides , Fatores de Transcrição , Humanos , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Transdução de Sinais , Animais , Receptor Cross-Talk/fisiologia , Regulação Neoplásica da Expressão Gênica
4.
PeerJ ; 12: e17539, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38952964

RESUMO

The association between sleep and the immune-endocrine system is well recognized, but the nature of that relationship is not well understood. Sleep fragmentation induces a pro-inflammatory response in peripheral tissues and brain, but it also activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing glucocorticoids (GCs) (cortisol in humans and corticosterone in mice). It is unclear whether this rapid release of glucocorticoids acts to potentiate or dampen the inflammatory response in the short term. The purpose of this study was to determine whether blocking or suppressing glucocorticoid activity will affect the inflammatory response from acute sleep fragmentation (ASF). Male C57BL/6J mice were injected i.p. with either 0.9% NaCl (vehicle 1), metyrapone (a glucocorticoid synthesis inhibitor, dissolved in vehicle 1), 2% ethanol in polyethylene glycol (vehicle 2), or mifepristone (a glucocorticoid receptor antagonist, dissolved in vehicle 2) 10 min before the start of ASF or no sleep fragmentation (NSF). After 24 h, samples were collected from brain (prefrontal cortex, hypothalamus, hippocampus) and periphery (liver, spleen, heart, and epididymal white adipose tissue (EWAT)). Proinflammatory gene expression (TNF-α and IL-1ß) was measured, followed by gene expression analysis. Metyrapone treatment affected pro-inflammatory cytokine gene expression during ASF in some peripheral tissues, but not in the brain. More specifically, metyrapone treatment suppressed IL-1ß expression in EWAT during ASF, which implies a pro-inflammatory effect of GCs. However, in cardiac tissue, metyrapone treatment increased TNF-α expression in ASF mice, suggesting an anti-inflammatory effect of GCs. Mifepristone treatment yielded more significant results than metyrapone, reducing TNF-α expression in liver (only NSF mice) and cardiac tissue during ASF, indicating a pro-inflammatory role. Conversely, in the spleen of ASF-mice, mifepristone increased pro-inflammatory cytokines (TNF-α and IL-1ß), demonstrating an anti-inflammatory role. Furthermore, irrespective of sleep fragmentation, mifepristone increased pro-inflammatory cytokine gene expression in heart (IL-1ß), pre-frontal cortex (IL-1ß), and hypothalamus (IL-1ß). The results provide mixed evidence for pro- and anti-inflammatory functions of corticosterone to regulate inflammatory responses to acute sleep loss.


Assuntos
Glucocorticoides , Metirapona , Camundongos Endogâmicos C57BL , Mifepristona , Privação do Sono , Animais , Masculino , Metirapona/farmacologia , Privação do Sono/metabolismo , Privação do Sono/tratamento farmacológico , Camundongos , Mifepristona/farmacologia , Glucocorticoides/farmacologia , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Corticosterona/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/genética
5.
Pharmacol Res ; 206: 107294, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38992851

RESUMO

Liver fibrosis is a determinant-stage process of many chronic liver diseases and affected over 7.9 billion populations worldwide with increasing demands of ideal therapeutic agents. Discovery of active molecules with anti-hepatic fibrosis efficacies presents the most attacking filed. Here, we revealed that hepatic L-aspartate levels were decreased in CCl4-induced fibrotic mice. Instead, supplementation of L-aspartate orally alleviated typical manifestations of liver injury and fibrosis. These therapeutic efficacies were alongside improvements of mitochondrial adaptive oxidation. Notably, treatment with L-aspartate rebalanced hepatic cholesterol-steroid metabolism and reduced the levels of liver-impairing metabolites, including corticosterone (CORT). Mechanistically, L-aspartate treatment efficiently reversed CORT-mediated glucocorticoid receptor ß (GRß) signaling activation and subsequent transcriptional suppression of the mitochondrial genome by directly binding to the mitochondrial genome. Knockout of GRß ameliorated corticosterone-mediated mitochondrial dysfunction and hepatocyte damage which also weakened the improvements of L-aspartate in suppressing GRß signaling. These data suggest that L-aspartate ameliorates hepatic fibrosis by suppressing GRß signaling via rebalancing cholesterol-steroid metabolism, would be an ideal candidate for clinical liver fibrosis treatment.


Assuntos
Ácido Aspártico , Tetracloreto de Carbono , Cirrose Hepática , Fígado , Camundongos Endogâmicos C57BL , Receptores de Glucocorticoides , Animais , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Masculino , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Ácido Aspártico/metabolismo , Camundongos , Corticosterona , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Colesterol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/patologia , Camundongos Knockout
6.
Clin Epigenetics ; 16(1): 90, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38978139

RESUMO

BACKGROUND: Stress during pregnancy can lead to adverse maternal and infant health outcomes through epigenetic changes in the hypothalamic-pituitary-adrenal axis. Among farmers in low-income countries, one important stressor is food insecurity, which can be reduced using hermetic storage bags. This study aimed to determine, for the first time, whether a hermetic storage bag intervention during pregnancy positively affects maternal and infant DNA methylation of the hypothalamic-pituitary-adrenal axis-related genes FKBP5 and NR3C1. We further analyzed whether anthropometrics, stress, and mental health were associated with DNA methylation. METHODS: This study was part of a larger matched-pair randomized controlled trial focusing on the impact of improved on-farm storage on food security, poverty, and net income of smallholder farming households. A total of N = 149 mothers were recruited by telephone and invited to attend a study appointment at health facilities in Kakamega County, Western Kenya, with their infants in April or May 2021. During the appointment, anthropometric measurements were taken, questionnaires on stress and mental health were administered, and saliva samples were collected. Logistic and multiple linear regression were used to examine the effect of the intervention and related measures on DNA methylation. RESULTS: Mothers in the intervention group showed higher mean NR3C1 methylation levels than those in the control group, corrected for multiple testing. Maternal postpartum body mass index was positively associated with infant NR3C1 CpG3 DNA methylation. The more stressful life events a mother had experienced in the previous 12 months (including during pregnancy), the lower her FKBP5 CpG3 methylation levels. CONCLUSIONS: Food insecurity and stressful life events during pregnancy seem to exert significant effects on maternal DNA methylation. While these stressors did not appear to impact infant DNA methylation in the present study, maternal postpartum body mass index was significantly related to infant methylation. These findings suggest that while infants may be protected from excessive maternal glucocorticoids by placental barrier activity, maternal metabolic status is still reflected in their epigenetic make-up. Trial registration This study was part of a larger matched-pair randomized controlled trial on the impact of improved on-farm crop storage on welfare, nutrition, and human health. Registration can be found in the American Economic Association (AEA) RCT Registry, RCT ID: AEARCTR-0005845.


Assuntos
Metilação de DNA , Epigênese Genética , Receptores de Glucocorticoides , Humanos , Metilação de DNA/genética , Feminino , Quênia , Adulto , Gravidez , Lactente , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Proteínas de Ligação a Tacrolimo/genética , Mães/psicologia , Masculino , Estresse Psicológico/genética , Fazendas , Sistema Hipotálamo-Hipofisário/metabolismo , Adulto Jovem , Insegurança Alimentar , Sistema Hipófise-Suprarrenal/metabolismo , Recém-Nascido , Produtos Agrícolas/genética
7.
Int J Mol Sci ; 25(13)2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-39000204

RESUMO

Fear conditioning evokes a physiologic release of glucocorticoids that assists learning. As a cochaperone in the glucocorticoid receptor complex, FKBP51 modulates stress-induced glucocorticoid signaling and may influence conditioned fear responses. This study combines molecular and behavioral approaches to examine whether locally reducing FKBP51 expression in the ventral hippocampus is sufficient to affect fear-related behaviors. We hypothesized that reducing FKBP51 expression in the VH would increase glucocorticoid signaling to alter auditory fear conditioning. Adult male rats were injected with an adeno-associated virus (AAV) vector expressing short hairpin - RNAs (shRNA) targeting FKBP5 into the ventral hippocampus to reduce FKBP5 levels or a control AAV. Infusion of FKBP5-shRNA into the ventral hippocampus decreased auditory fear acquisition and recall. Although animals injected with FKBP5-shRNA showed less freezing during extinction recall, the difference was due to a reduced fear recall rather than improved extinction. Reducing ventral hippocampus FKBP51 did not affect exploratory behavior in either the open field test or the elevated zero maze test but did increase passive behavior in the forced swim test, suggesting that the reduction in auditory fear recall was not due to more active responses to acute stress. Furthermore, lower ventral hippocampus FKBP51 levels did not alter corticosterone release in response to restraint stress, suggesting that the reduced fear recall was not due to lower corticosterone release. Our findings suggest FKBP51 in the ventral hippocampus plays a selective role in modulating fear-learning processes and passive behavioral responses to acute stress rather than hypothalamic-pituitary-adrenal axis reactivity or exploratory responses.


Assuntos
Medo , Hipocampo , Proteínas de Ligação a Tacrolimo , Animais , Masculino , Medo/fisiologia , Proteínas de Ligação a Tacrolimo/metabolismo , Proteínas de Ligação a Tacrolimo/genética , Hipocampo/metabolismo , Ratos , Corticosterona/metabolismo , Corticosterona/sangue , Ratos Sprague-Dawley , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/genética , Receptores de Glucocorticoides/metabolismo , Extinção Psicológica/fisiologia
8.
Physiol Rep ; 12(14): e16124, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39016119

RESUMO

Alpha-1-antitrypsin (AAT) plays a homeostatic role in attenuating excessive inflammation and augmenting host defense against microbes. We demonstrated previously that AAT binds to the glucocorticoid receptor (GR) resulting in significant anti-inflammatory and antimycobacterial consequences in macrophages. Our current investigation aims to uncover AAT-regulated genes that rely on GR in macrophages. We incubated control THP-1 cells (THP-1control) and THP-1 cells knocked down for GR (THP-1GR-KD) with AAT, performed bulk RNA sequencing, and analyzed the findings. In THP-1control cells, AAT significantly upregulated 408 genes and downregulated 376 genes. Comparing THP-1control and THP-1GR-KD cells, 125 (30.6%) of the AAT-upregulated genes and 154 (41.0%) of the AAT-downregulated genes were significantly dependent on GR. Among the AAT-upregulated, GR-dependent genes, CSF-2 that encodes for granulocyte-monocyte colony-stimulating factor (GM-CSF), known to be host-protective against nontuberculous mycobacteria, was strongly upregulated by AAT and dependent on GR. We further quantified the mRNA and protein of several AAT-upregulated, GR-dependent genes in macrophages and the mRNA of several AAT-downregulated, GR-dependent genes. We also discussed the function(s) of selected AAT-regulated, GR-dependent gene products largely in the context of mycobacterial infections. In conclusion, AAT regulated several genes that are dependent on GR and play roles in host immunity against mycobacteria.


Assuntos
Macrófagos , Receptores de Glucocorticoides , alfa 1-Antitripsina , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Humanos , Macrófagos/metabolismo , Macrófagos/imunologia , Células THP-1 , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética
9.
Cell Rep Methods ; 4(7): 100818, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38986614

RESUMO

Protein-protein interactions play an important biological role in every aspect of cellular homeostasis and functioning. Proximity labeling mass spectrometry-based proteomics overcomes challenges typically associated with other methods and has quickly become the current state of the art in the field. Nevertheless, tight control of proximity-labeling enzymatic activity and expression levels is crucial to accurately identify protein interactors. Here, we leverage a T2A self-cleaving peptide and a non-cleaving mutant to accommodate the protein of interest in the experimental and control TurboID setup. To allow easy and streamlined plasmid assembly, we built a Golden Gate modular cloning system to generate plasmids for transient expression and stable integration. To highlight our T2A Split/link design, we applied it to identify protein interactions of the glucocorticoid receptor and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid and non-structural protein 7 (NSP7) proteins by TurboID proximity labeling. Our results demonstrate that our T2A split/link provides an opportune control that builds upon previously established control requirements in the field.


Assuntos
Peptídeos , Proteômica , SARS-CoV-2 , Proteômica/métodos , Humanos , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , Peptídeos/metabolismo , Peptídeos/química , COVID-19/metabolismo , COVID-19/virologia , Células HEK293 , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/química , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/genética , Proteínas do Nucleocapsídeo de Coronavírus/química , Plasmídeos/genética , Plasmídeos/metabolismo , Espectrometria de Massas/métodos , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Mapeamento de Interação de Proteínas/métodos
10.
Cell Rep ; 43(6): 114330, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38865241

RESUMO

The human genome has many short tandem repeats, yet the normal functions of these repeats are unclear. The 5' untranslated region (UTR) of the fragile X messenger ribonucleoprotein 1 (FMR1) gene contains polymorphic CGG repeats, the length of which has differing effects on FMR1 expression and human health, including the neurodevelopmental disorder fragile X syndrome. We deleted the CGG repeats in the FMR1 gene (0CGG) in human stem cells and examined the effects on differentiated neurons. 0CGG neurons have altered subcellular localization of FMR1 mRNA and protein, and differential expression of cellular stress proteins compared with neurons with normal repeats (31CGG). In addition, 0CGG neurons have altered responses to glucocorticoid receptor (GR) activation, including FMR1 mRNA localization, GR chaperone HSP90α expression, GR localization, and cellular stress protein levels. Therefore, the CGG repeats in the FMR1 gene are important for the homeostatic responses of neurons to stress signals.


Assuntos
Proteína do X Frágil da Deficiência Intelectual , Neurônios , RNA Mensageiro , Humanos , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Neurônios/metabolismo , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Estresse Fisiológico/genética , Regiões 5' não Traduzidas/genética , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico HSP90/genética , Repetições de Trinucleotídeos/genética , Expansão das Repetições de Trinucleotídeos/genética
11.
Nucleic Acids Res ; 52(13): 7740-7760, 2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-38932701

RESUMO

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.


Assuntos
Adenocarcinoma , Benzamidas , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Nitrilas , Neoplasias da Próstata , Receptores Androgênicos , Receptores de Glucocorticoides , Masculino , Humanos , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/tratamento farmacológico , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Benzamidas/farmacologia , Linhagem Celular Tumoral , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Feniltioidantoína/análogos & derivados , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Epigênese Genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/tratamento farmacológico , Animais , Linhagem da Célula/genética , Camundongos
12.
Cancer Res Commun ; 4(7): 1643-1654, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38912926

RESUMO

Despite lower rates and intensity of smoking, Black men experience a higher incidence of lung cancer compared to white men. The racial disparity in lung cancer is particularly pronounced in Chicago, a highly segregated urban city. Neighborhood conditions, particularly social stress, may play a role in lung tumorigenesis. Preliminary studies indicate that Black men residing in neighborhoods with higher rates of violent crime have significantly higher levels of hair cortisol, an indicator of stress response. To examine the relationship between social stress exposure and gene expression in lung tumors, we investigated glucocorticoid receptor (GR) binding in 15 lung tumor samples in relation to GR target gene expression levels and zip code level residential violent crime rates. Spatial transcriptomics and a version of ChIP sequencing known as CUT&RUN were used. Heatmap of genes, pathway analysis, and motif analysis were conducted at the statistical significance of P < 0.05. GR recruitment to chromatin was correlated with zip code level residential violent crime rate and overall GR binding increased with higher violent crime rates. Our findings suggest that exposure to residential violent crime may influence tumor biology via reprogramming GR recruitment. Prioritizing lung cancer screening in neighborhoods with increased social stress, such as high levels of violent crime, may reduce racial disparities in lung cancer. SIGNIFICANCE: Exposure to neighborhood violent crime is correlated with glucocorticoid signaling and lung tumor gene expression changes associated with increased tumor aggressiveness, suggesting social conditions have downstream biophysical consequences that contribute to lung cancer disparities.


Assuntos
Neoplasias Pulmonares , Receptores de Glucocorticoides , Características de Residência , Transdução de Sinais , Estresse Psicológico , Violência , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/metabolismo , Masculino , Características de Residência/estatística & dados numéricos , Estresse Psicológico/genética , Estresse Psicológico/epidemiologia , Estresse Psicológico/metabolismo , Violência/estatística & dados numéricos , Violência/etnologia , Chicago/epidemiologia , Negro ou Afro-Americano/genética , Negro ou Afro-Americano/estatística & dados numéricos , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade
13.
Sci Rep ; 14(1): 13543, 2024 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866996

RESUMO

The objective of this study was to investigate spleen pathology and immune cell subset alterations in mice exposed to acute and chronic restraint stress over various timeframes. A deeper understanding of stress-induced spleen injuries can provide new insights into the mechanisms underlying stress-induced disorders. C57BL/6N mice were restrained for different durations (1, 3, 7, 14 and 21 days) for 6-8 h daily. The control mice were observed at the same time points. Post restraint, behavioural experiments were conducted to assess spleen weight, gross morphology and microscopic histological changes. Immunohistochemical staining was used to detect changes in glucocorticoid receptor (GR) expression, immune cell subsets and cell proliferation in response to stress. Our analysis revealed significant behavioural abnormalities in the stressed mice. In particular, there was an increase in the nuclear expression of GR beginning on Day 3, and it peaked on Day 14. The spleens of stressed mice displayed a reduction in size, disordered internal tissue structure and reduced cell proliferation. NK cells and M2-type macrophages exhibited immune cell subset alterations under stress, whereas T or B cells remained unaltered. Restraint stress can lead to pathomorphological alterations in spleen morphology, cell proliferation and immune cell counts in mice. These findings suggest that stress-induced pathological changes can disrupt immune regulation during stress.


Assuntos
Camundongos Endogâmicos C57BL , Receptores de Glucocorticoides , Restrição Física , Baço , Estresse Psicológico , Animais , Baço/patologia , Baço/metabolismo , Receptores de Glucocorticoides/metabolismo , Camundongos , Masculino , Estresse Psicológico/imunologia , Proliferação de Células , Fatores de Tempo , Células Matadoras Naturais/imunologia , Estresse Fisiológico , Macrófagos/imunologia , Macrófagos/metabolismo
14.
Front Endocrinol (Lausanne) ; 15: 1397081, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38887268

RESUMO

Introduction: Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear, prior research suggested an intermediary role for increased circulating glucocorticoids. Methods: In this study, we utilized a recently described mouse model (BMAd-Cre) to exclusively target bone marrow adipocytes (BMAds) for elimination of the glucocorticoid receptor (GR) (i.e. Nr3c1) whilst maintaining GR expression in other adipose depots. Results: Mice lacking GR in BMAds (BMAd-Nr3c1 -/-) and control mice (BMAd-Nr3c1 +/+) were fed ad libitum or placed on a 30% CR diet for six weeks. On a normal chow diet, tibiae of female BMAd-Nr3c1-/- mice had slightly elevated proximal trabecular metaphyseal bone volume fraction and thickness. Both control and BMAd-Nr3c1-/- mice had increased circulating glucocorticoids and elevated numbers of BMAds in the proximal tibia following CR. However, no significant differences in trabecular and cortical bone were observed, and quantification with osmium tetroxide and µCT revealed no difference in BMAT accumulation between control or BMAd-Nr3c1 -/- mice. Differences in BMAd size were not observed between BMAd-Nr3c1-/- and control mice. Interestingly, BMAd-Nr3c1-/- mice had decreased circulating white blood cell counts 4 h into the light cycle. Discussion: In conclusion, our data suggest that eliminating GR from BMAd has minor effects on bone and hematopoiesis, and does not impair BMAT accumulation during CR.


Assuntos
Adipócitos , Adiposidade , Medula Óssea , Restrição Calórica , Hematopoese , Receptores de Glucocorticoides , Animais , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/deficiência , Camundongos , Adipócitos/metabolismo , Adiposidade/fisiologia , Feminino , Medula Óssea/metabolismo , Camundongos Knockout , Osso e Ossos/metabolismo , Camundongos Endogâmicos C57BL , Tecido Adiposo/metabolismo , Masculino , Erros Inatos do Metabolismo
15.
Int J Mol Sci ; 25(11)2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38892090

RESUMO

Fetal hypoxia and maternal stress frequently culminate in neuropsychiatric afflictions in life. To replicate this condition, we employed a model of prenatal severe hypoxia (PSH) during days 14-16 of rat gestation. Subsequently, both control and PSH rats at 3 months old were subjected to episodes of inescapable stress to induce learned helplessness (LH). The results of the open field test revealed an inclination towards depressive-like behavior in PSH rats. Following LH episodes, control (but not PSH) rats displayed significant anxiety. LH induced an increase in glucocorticoid receptor (GR) levels in extrahypothalamic brain structures, with enhanced nuclear translocation in the hippocampus (HPC) observed both in control and PSH rats. However, only control rats showed an increase in GR nuclear translocation in the amygdala (AMG). The decreased GR levels in the HPC of PSH rats correlated with elevated levels of hypothalamic corticotropin-releasing hormone (CRH) compared with the controls. However, LH resulted in a reduction of the CRH levels in PSH rats, aligning them with those of control rats, without affecting the latter. This study presents evidence that PSH leads to depressive-like behavior in rats, associated with alterations in the glucocorticoid system. Notably, these impairments also contribute to increased resistance to severe stressors.


Assuntos
Ansiedade , Depressão , Glucocorticoides , Efeitos Tardios da Exposição Pré-Natal , Receptores de Glucocorticoides , Animais , Ratos , Feminino , Ansiedade/metabolismo , Gravidez , Glucocorticoides/metabolismo , Depressão/metabolismo , Depressão/etiologia , Receptores de Glucocorticoides/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Estresse Psicológico/metabolismo , Masculino , Hormônio Liberador da Corticotropina/metabolismo , Hipocampo/metabolismo , Hipóxia/metabolismo , Fenótipo , Comportamento Animal , Desamparo Aprendido , Modelos Animais de Doenças , Tonsila do Cerebelo/metabolismo , Hipóxia Fetal/metabolismo , Hipóxia Fetal/complicações
16.
Ann Endocrinol (Paris) ; 85(3): 259-262, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38871499

RESUMO

Glucocorticoids (GCs) play an important role in metabolic adaptation, regulating carbohydrate-lipid homeostasis and the immune system. Because they also have anti-inflammatory and immunosuppressive properties, synthetic analogues of GCs have been developed and are widely used in the treatment of chronic inflammatory conditions and in organ transplantation. GCs are among the most commonly prescribed drugs in the world. However, long term and high GC doses can cause side effects such as GC-induced diabetes and lipodystrophy. In recent years, a large number of independent studies have reported the effects of constitutive and adipocyte-specific deletion of the GC receptor (GR) in mice under different diets and treatments, resulting in contrasting phenotypes. To avoid potential compensatory mechanisms associated with the constitutive adipocyte GR silencing during adipose tissue development, our team has generated an inducible mouse model of GR deletion specifically in the adipocyte (AdipoGR-KO). Using this mouse model, we were able to demonstrate the critical role of the adipocyte GR in GC-induced metabolic changes. Indeed, under conditions of hypercorticism, AdipoGR-KO mice showed an improvement in glucose tolerance and insulin sensitivity, as well as in lipid profile, despite a massive increase in adiposity. This result is explained by a densification of adipose tissue vascularization, highlighting the repressive role of adipocyte GR in the healthy expansion of this tissue. Our work has largely contributed to the demonstration of the important role of the adipocyte GR in the physiology and pathophysiology of the adipose tissue and its impact on energy homeostasis.


Assuntos
Tecido Adiposo , Glucocorticoides , Animais , Glucocorticoides/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Humanos , Camundongos , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Camundongos Knockout , Resistência à Insulina/fisiologia
17.
Pharmacol Biochem Behav ; 241: 173794, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38834160

RESUMO

Psychological stress affects the neuroendocrine regulation, which modulates mental status and behaviors. Melatonin, a hormone synthesized primarily by the pineal gland, regulates many brain functions, including circadian rhythms, pain, sleep, and mood. Selective pharmacological melatonin agonist ramelteon has been clinically used to treat mood and sleep disorders. Posttraumatic stress disorder (PTSD) is a psychiatric condition associated with severe trauma; it is generally triggered by traumatic events, which lead to severe anxiety and uncontrollable trauma recall. We recently reported that repeated social defeat stress (RSDS) may induce robust anxiety-like behaviors and social avoidance in mice. In the present study, we investigated whether melatonin receptor activation by melatonin and ramelteon regulates RSDS-induced behavioral changes. Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. Moreover, treatment of the non-selective MT1/MT2 receptor agonist, ramelteon, markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. Moreover, activating melatonin receptors also balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. Taken together, our findings indicate that the activation of both melatonin and ramelteon regulates RSDS-induced anxiety-like behaviors and PTSD symptoms. The current study also showed that the regulatory effects of neuroendocrine mechanisms and cognitive behaviors on melatonin receptor activation in repeated social defeat stress.


Assuntos
Ansiedade , Indenos , Melatonina , Derrota Social , Estresse Psicológico , Animais , Indenos/farmacologia , Camundongos , Masculino , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , Melatonina/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/agonistas , Receptor MT1 de Melatonina/agonistas , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/agonistas , Receptor MT2 de Melatonina/metabolismo , Camundongos Endogâmicos C57BL , Monoaminoxidase/metabolismo , Receptores de Melatonina/agonistas , Receptores de Melatonina/metabolismo , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos de Estresse Pós-Traumáticos/metabolismo
18.
Biochem Biophys Res Commun ; 725: 150219, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-38941883

RESUMO

BACKGROUND: Neonates undergo numerous painful procedures throughout their hospitalization. Repeated procedural pain may cause adverse long-term effects. Glucose as a non-pharmacological analgesia, is used for neonate pain management. In this study, potential mechanism of attenuate pain induced by glucose in neurodevelopment effect of neonate pain stimulus was investigated. METHODS: Neonatal rats to perform a repetitive injury model and glucose intervention model in the postnatal day 0-7(P0-7). Pain thresholds were measured by von Frey test weekly. The puberty behavioral outcome, tissue loss and protein expression in hippocampus were analyzed. RESULTS: Oral administration of glucose after repeated pain stimulation can maintain the hippocampal structure in, and reduce the expressions of corticotropin releasing factor (CFR) and glucocorticoid receptor (GR), therefore, resulted in long-term threshold of pain and cognitive improvement. CONCLUSION: Exposure to neonatal repeated procedural pain causes persistent mechanical hypersensitivity and the dysfunction of spatial memory retention at puberty. In addition, glucose can relieve these adverse effects, possibly via decreasing CRF/GR levels to change the hypothalamus-pituitary-adrenal (HPA) axis.


Assuntos
Animais Recém-Nascidos , Hormônio Liberador da Corticotropina , Glucose , Hipocampo , Dor , Ratos Sprague-Dawley , Receptores de Glucocorticoides , Animais , Glucose/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Receptores de Glucocorticoides/metabolismo , Dor/metabolismo , Dor/etiologia , Ratos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Limiar da Dor/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Feminino
19.
Prostaglandins Other Lipid Mediat ; 173: 106840, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38830399

RESUMO

We have previously demonstrated that the glucocorticoid receptor ß (GRß) isoform induces hepatic steatosis in mice fed a normal chow diet. The GRß isoform inhibits the glucocorticoid-binding isoform GRα, reducing responsiveness and inducing glucocorticoid resistance. We hypothesized that GRß regulates lipids that cause metabolic dysfunction. To determine the effect of GRß on hepatic lipid classes and molecular species, we overexpressed GRß (GRß-Ad) and vector (Vec-Ad) using adenovirus delivery, as we previously described. We fed the mice a normal chow diet for 5 days and harvested the livers. We utilized liquid chromatography-mass spectrometry (LC-MS) analyses of the livers to determine the lipid species driven by GRß. The most significant changes in the lipidome were monoacylglycerides and cholesterol esters. There was also increased gene expression in the GRß-Ad mice for lipogenesis, eicosanoid synthesis, and inflammatory pathways. These indicate that GRß-induced glucocorticoid resistance may drive hepatic fat accumulation, providing new therapeutic advantages.


Assuntos
Eicosanoides , Glucocorticoides , Inflamação , Lipogênese , Fígado , Receptores de Glucocorticoides , Animais , Camundongos , Fígado/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Eicosanoides/metabolismo , Glucocorticoides/metabolismo , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Metabolismo dos Lipídeos
20.
Psychoneuroendocrinology ; 167: 107088, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38924829

RESUMO

BACKGROUND: Changes in NR3C1 and IGF2/H19 methylation patterns have been associated with behavioural and psychiatric outcomes. Maternal mental state has been associated with offspring NR3C1 promotor and IGF2/H19 imprinting control region (ICR) methylation patterns. However, there is a lack of prospective studies with long-term follow-up. METHODS: 52 mother-offspring pairs were studied from 12 to 22 weeks of pregnancy and offspring was followed-up until 28-29 years-of-age. During pregnancy, mothers filled in a Life Event Scale and a Daily Hassles Scale measuring perceived stress; i.e., appraisal or subjectively experienced severity of impact of important life events and of daily hassles in several life domains during pregnancy, respectively. Green space was quantified around the residence, using high-resolution (1 m2) map data. Saliva and blood samples were obtained from the adult offspring. Absolute DNA methylation levels were determined in blood and saliva on four NR3C1 amplicons, and one IGF2/H19 ICR amplicon using a bisulfite PCR and sequencing method. Linear mixed effect models were used to test the associations between perceived stress and green spaces during pregnancy, and adult offspring methylation patterns. RESULTS: We found associations between maternal perceived stress during pregnancy and methylation patterns on two out of the four NR3C1 amplicons, measured in blood, from offspring in adulthood, but not with IGF2/H19 methylation. For an interquartile-range (IQR) increase in maternal perceived life event or daily hassles stress scores, absolute methylation levels on several NR3C1 CpG sites were significantly changed (-1.62 % to +5.89 %, p<0.05). Maternal perceived stress scores were not associated with IGF2/H19 methylation, neither in blood nor in saliva. Maternal exposure to green spaces surrounding the residence during the pregnancy was associated with IGF2/H19 ICR methylation (-0.80 % to -1.04 %, p<0.05) in saliva, but not with NR3C1 promotor methylation. CONCLUSION: We observed significant long-term effects of maternal perceived stress during pregnancy on the methylation patterns of the NR3C1 promotor in offspring well into adulthood. This may imply that maternal psychological distress during pregnancy may influence the regulation of the HPA-axis well into adulthood. Additionally, maternal proximity to green spaces was associated with IGF2/H19 ICR methylation patterns, which is a novel finding.


Assuntos
Metilação de DNA , Fator de Crescimento Insulin-Like II , Efeitos Tardios da Exposição Pré-Natal , RNA Longo não Codificante , Receptores de Glucocorticoides , Estresse Psicológico , Humanos , Feminino , Gravidez , Metilação de DNA/genética , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Projetos Piloto , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Adulto , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Masculino , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Filhos Adultos/psicologia , Mães/psicologia , Regiões Promotoras Genéticas/genética , Impressão Genômica/genética , Estudos Prospectivos
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