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1.
Elife ; 122023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36695573

RESUMO

Skeletal muscle exhibits remarkable plasticity in response to environmental cues, with stress-dependent effects on the fast-twitch and slow-twitch fibers. Although stress-induced gene expression underlies environmental adaptation, it is unclear how transcriptional and epigenetic factors regulate fiber type-specific responses in the muscle. Here, we show that flavin-dependent lysine-specific demethylase-1 (LSD1) differentially controls responses to glucocorticoid and exercise in postnatal skeletal muscle. Using skeletal muscle-specific LSD1-knockout mice and in vitro approaches, we found that LSD1 loss exacerbated glucocorticoid-induced atrophy in the fast fiber-dominant muscles, with reduced nuclear retention of Foxk1, an anti-autophagic transcription factor. Furthermore, LSD1 depletion enhanced endurance exercise-induced hypertrophy in the slow fiber-dominant muscles, by induced expression of ERRγ, a transcription factor that promotes oxidative metabolism genes. Thus, LSD1 serves as an 'epigenetic barrier' that optimizes fiber type-specific responses and muscle mass under the stress conditions. Our results uncover that LSD1 modulators provide emerging therapeutic and preventive strategies against stress-induced myopathies such as sarcopenia, cachexia, and disuse atrophy.


Assuntos
Glucocorticoides , Doenças Musculares , Camundongos , Animais , Glucocorticoides/metabolismo , Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fatores de Transcrição/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo
2.
Mol Cell Endocrinol ; 563: 111855, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36646303

RESUMO

The pro-inflammatory cytokine, chemokine (C-C motif) ligand 20 (CCL20), is emerging as a therapeutic target for immune-based therapies. Cooperative regulation of CCL20 by glucocorticoids and progestins used in endocrine therapy and pro-inflammatory mediators could modulate immune function and affect disease outcomes. We show that glucocorticoids as well as medroxyprogesterone acetate (MPA), the progestin widely used in injectable contraception in sub-Saharan Africa, cooperate with pro-inflammatory mediators to upregulate CCL20 protein and/or mRNA in human peripheral blood mononuclear cells (PBMCs) and human cervical cell lines. Changes in CCL20 mRNA levels were shown to be synergistic, as assessed by Chou analysis, cell- and gene-specific and to involve transcriptional regulation, with a requirement for a nuclear factor kappa B (NF-κB) site and glucocorticoid receptor (GR) involvement. The novel results suggest a mechanism whereby MPA, like glucocorticoids, may impact inflammation both systemically and in the genital tract in patients using MPA and/or glucocorticoid therapy.


Assuntos
Glucocorticoides , Acetato de Medroxiprogesterona , Humanos , Acetato de Medroxiprogesterona/farmacologia , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Leucócitos Mononucleares/metabolismo , Progestinas/metabolismo , Receptores de Glucocorticoides/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Quimiocina CCL20/genética , Quimiocina CCL20/metabolismo
3.
Mol Cell Endocrinol ; 563: 111864, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36690169

RESUMO

Prenatal exposure to synthetic glucocorticoids (sGCs) reprograms brain development and predisposes the developing fetus towards potential adverse neurodevelopmental outcomes. Using a mouse model of sGC administration, previous studies show that these changes are accompanied by sexually dimorphic alterations in the transcriptome of neural stem and progenitor cells (NSPCs) derived from the embryonic telencephalon. Because cell type-specific gene expression profiles tightly regulate cell fate decisions and are controlled by a flexible landscape of chromatin domains upon which transcription factors and enhancer elements act, we multiplexed data from four genome-wide assays: RNA-seq, ATAC-seq (assay for transposase accessible chromatin followed by genome wide sequencing), dual cross-linking ChIP-seq (chromatin immunoprecipitation followed by genome wide sequencing), and microarray gene expression to identify novel relationships between gene regulation, chromatin structure, and genomic glucocorticoid receptor (GR) action in NSPCs. These data reveal that GR binds preferentially to predetermined regions of accessible chromatin to influence gene programming and cell fate decisions. In addition, we identify SOX2 as a transcription factor that impacts the genomic response of select GR target genes to sGCs (i.e., dexamethasone) in NSPCs.


Assuntos
Glucocorticoides , Células-Tronco Neurais , Feminino , Gravidez , Humanos , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Genômica , Cromatina/metabolismo , Regulação da Expressão Gênica , Células-Tronco Neurais/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Receptores de Glucocorticoides/metabolismo
4.
Biomolecules ; 13(1)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36671556

RESUMO

The etiology of osteonecrosis of the femoral head (ONFH) is not yet fully understood. However, ONFH is a common disease with high morbidity, and approximately one-third of cases are caused by glucocorticoids. We performed single-cell RNA sequencing of bone marrow to explore the effect of glucocorticoid on ONFH. Bone marrow samples of the proximal femur were extracted from four participants during total hip arthroplasty, including two participants diagnosed with ONFH for systemic lupus erythematosus (SLE) treated with glucocorticoids (the case group) and two participants with femoral neck fracture (the control group). Unbiased transcriptome-wide single-cell RNA sequencing analysis and computational analyses were performed. Seventeen molecularly defined cell types were identified in the studied samples, including significantly dysregulated neutrophils and B cells in the case group. Additionally, fatty acid synthesis and aerobic oxidation were repressed, while fatty acid beta-oxidation was enhanced. Our results also preliminarily clarified the roles of the inflammatory response, substance metabolism, vascular injury, angiogenesis, cell proliferation, apoptosis, and dysregulated coagulation and fibrinolysis in glucocorticoid-induced ONFH. Notably, we list the pathways that were markedly altered in glucocorticoid-induced ONFH with SLE compared with femoral head fracture, as well as their common genes, which are potential early therapeutic targets. Our results provide new insights into the mechanism of glucocorticoid-induced ONFH and present potential clues for effective and functional manipulation of human glucocorticoid-induced ONFH, which could improve patient outcomes.


Assuntos
Necrose da Cabeça do Fêmur , Lúpus Eritematoso Sistêmico , Humanos , Glucocorticoides/metabolismo , Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/genética , Necrose da Cabeça do Fêmur/metabolismo , Cabeça do Fêmur/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Análise de Sequência de RNA , Ácidos Graxos/metabolismo
5.
Int J Mol Sci ; 24(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36674678

RESUMO

Since depression produces a long-term negative impact on quality of life, understanding the pathophysiological changes implicated in this disorder is urgent. There is growing evidence that demonstrates a key role for dysfunctional energy metabolism in driving the onset of depression; thus, bioenergetic alterations should be extensively studied. Brain metabolism is known to be a glucocorticoid-sensitive process, but the long-lasting consequences in adulthood following high levels of glucocorticoids at the early stages of life are unclear. We examined a possible association between brain energetic changes induced by synthetic glucocorticoid-dexamethasone treatment in the prenatal period and depressive-like behavior. The results show a reduction in the oxidative phosphorylation process, Krebs cycle impairment, and a weakening of the connection between the Krebs cycle and glycolysis in the frontal cortex of animals receiving dexamethasone, which leads to ATP reduction. These changes appear to be mainly due to decreased expression of pyruvate dehydrogenase, impairment of lactate transport to neurons, and pyruvate to the mitochondria. Acute stress in adulthood only slightly modified the observed alterations in the frontal cortex, while in the case of the hippocampus, prenatal exposure to dexamethasone made this structure more sensitive to future adverse factors.


Assuntos
Glucocorticoides , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Gravidez , Humanos , Glucocorticoides/metabolismo , Dexametasona/efeitos adversos , Dexametasona/metabolismo , Depressão/metabolismo , Qualidade de Vida , Encéfalo/metabolismo , Homeostase , Piruvatos/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo
6.
Methods Mol Biol ; 2587: 467-478, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36401044

RESUMO

In vivo testing of glucocorticoid steroids in dystrophic mice offers important insights in benefits and risks of those drugs in the pathological context of muscular dystrophy. Frequency of dosing changes the spectrum of glucocorticoid effects on muscle and metabolic homeostasis. Here, we describe a combination of non-invasive and invasive methods to quantitatively discriminate the specific effects of intermittent (once-weekly) versus mainstay (once-daily) regimens on muscle fibrosis, muscle function, and metabolic homeostasis in murine models of Duchenne and limb-girdle muscular dystrophies.


Assuntos
Distrofia Muscular do Cíngulo dos Membros , Distrofia Muscular de Duchenne , Camundongos , Animais , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Modelos Animais de Doenças , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular do Cíngulo dos Membros/tratamento farmacológico , Distrofia Muscular do Cíngulo dos Membros/patologia
7.
Gen Comp Endocrinol ; 330: 114141, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36272446

RESUMO

Living in variable and unpredictable environments, organisms face recurrent stressful situations. The endocrine stress response, which includes the secretion of glucocorticoids, helps organisms to cope with these perturbations. Although short-term elevations of glucocorticoid levels are often associated with immediate beneficial consequences for individuals, long-term glucocorticoid elevation can compromise key physiological functions such as immunity. While laboratory works highlighted the immunosuppressive effect of long-term elevated glucocorticoids, it remains largely unknown, especially in wild animals, whether this relationship is modulated by individual and environmental characteristics. In this study, we explored the co-variation between integrated cortisol levels, assessed non-invasively using faecal cortisol metabolites (FCMs), and 12 constitutive indices of innate, inflammatory, and adaptive immune functions, in wild roe deer living in three populations with previously known contrasting environmental conditions. Using longitudinal data on 564 individuals, we further investigated whether age and spatio-temporal variations in the quantity and quality of food resources modulate the relationship between FCMs and immunity. Negative covariation with glucocorticoids was evident only for innate and inflammatory markers of immunity, while adaptive immunity appeared to be positively or not linked to glucocorticoids. In addition, the negative covariations were generally stronger in individuals facing harsh environmental constraints and in old individuals. Therefore, our results highlight the importance of measuring multiple immune markers of immunity in individuals from contrasted environments to unravel the complex relationships between glucocorticoids and immunity in wild animals. Our results also help explain conflicting results found in the literature and could improve our understanding of the link between elevated glucocorticoid levels and disease spread, and its consequences on population dynamics.


Assuntos
Cervos , Animais , Cervos/metabolismo , Animais Selvagens/metabolismo , Glucocorticoides/metabolismo , Hidrocortisona/metabolismo , Imunidade Adaptativa
8.
Gen Comp Endocrinol ; 330: 114147, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36272448

RESUMO

African penguins (Spheniscus demersus) are an endangered species, with approximately 70,000 mature adults remaining in the wild. Population loss is linked to a combination of environmental and anthropogenic stressors. The aim of the study was to validate a commercially available enzyme immunoassay (EIA) to assess adrenal activity and measure the response to stressors in the feces of African penguins. Fecal samples (n = 609) were collected from 12 African penguins housed at Mystic Aquarium throughout their natural lifecycle, including breeding and molt, where measurable changes in fecal glucocorticoid metabolite (FGM) levels are predicted to occur. Fecal samples collected post-veterinary exam were used for biological validation. Longitudinal analysis shows a significant difference (p = <0.0001) between the average FGM levels during baseline and breeding season, 33.97 ± 1.30 ng/g and 50.21 ± 3.18 ng/g, respectively. Females displayed significantly higher FGM levels than males during both baseline (p = 0.0386; females = 38.80 ± 2.19 ng/g; males = 29.34 ± 1.37 ng/g) and breeding periods (p = 0.0175; females = 57.53 ± 4.84 ng/g; males = 42.69 ± 3.95 ng/g). Average FGM levels decreased significantly over the three-week molting period, from 85.40 ± 20.35 ng/g at week one to 20.23 ± 5.30 ng/g at week three. A seasonal difference in FGM levels was observed in both male and female fecal samples, with Fall having the highest average FGM levels, 54.38 ± 3.64 ng/g, and Summer the lowest, 30.87 ± 2.21 ng/g. General linear mixed model analysis determined that lifecycle (females) and visitor presence (males) were the two factors which best explained the variation in FGM levels observed, however neither factor was found to be significant. These results show FGM analysis can detect physiologically meaningful changes in endocrine activity in African penguins and can be used to monitor health for penguins in aquaria and in the wild, thus contributing to conservation efforts for the survival of the species.


Assuntos
Spheniscidae , Animais , Masculino , Feminino , Spheniscidae/metabolismo , Glucocorticoides/metabolismo , Técnicas Imunoenzimáticas , Fezes/química , Espécies em Perigo de Extinção
9.
FASEB J ; 37(1): e22709, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36527388

RESUMO

Glucocorticoids (GCs) exert potent antiproliferative and anti-inflammatory properties, explaining their therapeutic efficacy for skin diseases. GCs act by binding to the GC receptor (GR) and the mineralocorticoid receptor (MR), co-expressed in classical and non-classical targets including keratinocytes. Using knockout mice, we previously demonstrated that GR and MR exert essential nonoverlapping functions in skin homeostasis. These closely related receptors may homo- or heterodimerize to regulate transcription, and theoretically bind identical GC-response elements (GRE). We assessed the contribution of MR to GR genomic binding and the transcriptional response to the synthetic GC dexamethasone (Dex) using control (CO) and MR knockout (MREKO ) keratinocytes. GR chromatin immunoprecipitation (ChIP)-seq identified peaks common and unique to both genotypes upon Dex treatment (1 h). GREs, AP-1, TEAD, and p53 motifs were enriched in CO and MREKO peaks. However, GR genomic binding was 35% reduced in MREKO , with significantly decreased GRE enrichment, and reduced nuclear GR. Surface plasmon resonance determined steady state affinity constants, suggesting preferred dimer formation as MR-MR > GR-MR ~ GR-GR; however, kinetic studies demonstrated that GR-containing dimers had the longest lifetimes. Despite GR-binding differences, RNA-seq identified largely similar subsets of differentially expressed genes in both genotypes upon Dex treatment (3 h). However, time-course experiments showed gene-dependent differences in the magnitude of expression, which correlated with earlier and more pronounced GR binding to GRE sites unique to CO including near Nr3c1. Our data show that endogenous MR has an impact on the kinetics and differential genomic binding of GR, affecting the time-course, specificity, and magnitude of GC transcriptional responses in keratinocytes.


Assuntos
Receptores de Glucocorticoides , Receptores de Mineralocorticoides , Animais , Camundongos , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Cinética , Queratinócitos/metabolismo , Camundongos Knockout , Genômica
10.
Psychopharmacology (Berl) ; 240(2): 283-293, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36580134

RESUMO

BACKGROUND: Depression is associated with circadian disturbances in which melanopsin was a key mechanism. Further studies have demonstrated that melanopsin gene variations are associated with some depressive disorders and aberrant light can impair mood through melanopsin-expressing retinal ganglion cells (mRGCs). The goal of this study was to explore the direct relationship between depression and melanopsin. METHODS: Adult C57BL/6 male mice were physically restrained for 16 h in a 50-ml polypropylene centrifuge tube and all behavioral tests were performed after CRS treatment. Western blot analysis and immunofluorescence were used to detect melanopsin expression in the retina of C57BL/6 mice. And we observed the change of the electrophysiological function and release of glutamate of mRGCs. RESULTS: The melanopsin expression upregulate in mRGCs of chronic restraint stress (CRS)-treating mice which exhibit depression-like behavior. The frequency of blue light-induced action potentials and light-induced glutamate release mediated by melanopsin also increase significantly. This change of melanopsin is mediated by the CRS-induced glucocorticoid. CONCLUSIONS: CRS may induce the depression-like behavior in mice via glucocorticoid-melanopsin pathway. Our findings provide a novel mechanistic link between CRS-induced depression and melanopsin in mice.


Assuntos
Depressão , Glucocorticoides , Masculino , Camundongos , Animais , Regulação para Cima , Depressão/etiologia , Glucocorticoides/metabolismo , Camundongos Endogâmicos C57BL , Retina/metabolismo
11.
Life Sci ; 313: 121304, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36535402

RESUMO

AIMS: Adhesion molecules play vital roles in the induction of airway hyperresponsiveness (AHR) or airway inflammation. The down-regulation of catenin alpha-like 1 (CTNNAL1) in the bronchial epithelial cells of asthma patients and mice models has been noted in our previous study. In this work, we further explore the underlying mechanism of CTNNAL1 in asthma. MAIN METHODS: We constructed a house dust mite (HDM)-induced asthma animal model on control mice and applied CTNNAL1-siRNA transfection to create CTNNAL1-deficient mice. KEY FINDINGS: We documented much more severe airway inflammation and increased leukocyte infiltration in the lungs of the CTNNAL1-deficient mice comparing to control mice, along with elevated expression of inflammatory cytokines. Dexamethasone (DEX) treatment led to less reduced inflammation in CTNNAL1-deficient mice compared with control mice. Immunoprecipitation confirmed the interaction between heat shock protein90 (hsp90) and CTNNAL1. The expression of hsp90 was upregulated after CTNNAL1 silencing. Meanwhile, the use of hsp90 inhibitor geldanamycin significantly decreased the expression of NR3C1, ICAM-1 and the ratio of p-p65/p65 in CTNNAL1-silenced 16HBE14o- cells. Both geldanamycin and DEX could function to suppress the expression of ICAM-1 and the phosphorylation level of p65. Nevertheless, the anti-inflammatory effect of DEX proved less potent than geldanamycin in the CTNNAL1-silenced group. The combined therapy of geldanamycin and DEX significantly decreased the inflammatory responses in CTNNAL1-deficient HBE cells than DEX monotherapy. SIGNIFICANCE: Our study corroborates that CTNNAL1 deficiency induced aggravated airway inflammation and rendered insensitivity to glucocorticoids via triggering hsp90 signaling pathway.


Assuntos
Asma , Glucocorticoides , Camundongos , Animais , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Asma/metabolismo , Pulmão/metabolismo , Transdução de Sinais , Resposta ao Choque Térmico , Inflamação/metabolismo , Pyroglyphidae , Modelos Animais de Doenças , alfa Catenina/genética , alfa Catenina/metabolismo
12.
J Immunol ; 209(12): 2287-2291, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36469844

RESUMO

The mechanistic target of rapamycin is an essential regulator of T cell metabolism and differentiation. In this study, we demonstrate that serum- and glucocorticoid-regulated kinase 1 (SGK1), a downstream node of mechanistic target of rapamycin complex 2 signaling, represses memory CD8+ T cell differentiation. During acute infections, murine SGK1-deficient CD8+ T cells adopt an early memory precursor phenotype leading to more long-lived memory T cells. Thus, SGK1-deficient CD8+ T cells demonstrate an enhanced recall capacity in response to reinfection and can readily reject tumors. Mechanistically, activation of SGK1-deficient CD8+ T cells results in decreased Foxo1 phosphorylation and increased nuclear translocation of Foxo1 to promote early memory development. Overall, SGK1 might prove to be a powerful target for enhancing the efficacy of vaccines and tumor immunotherapy.


Assuntos
Glucocorticoides , Complexos Multiproteicos , Camundongos , Animais , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Glucocorticoides/metabolismo , Complexos Multiproteicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células T de Memória , Linfócitos T CD8-Positivos , Sirolimo , Diferenciação Celular , Memória Imunológica/genética
13.
Int J Mol Sci ; 23(23)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36499341

RESUMO

Glucocorticoids are steroids involved in key physiological processes such as development, metabolism, inflammatory and stress responses and are mostly used exogenously as medications to treat various inflammation-based conditions. They act via the glucocorticoid receptor (GR) expressed in most cells. Exogenous glucocorticoids can negatively impact the function of the Leydig cells in the testis, leading to decreased androgen production. However, endogenous glucocorticoids are produced by the adrenal and within the testis, but whether their action on GR in Leydig cells regulates steroidogenesis is unknown. This study aimed to define the role of endogenous GR signalling in adult Leydig cells. We developed and compared two models; an inducible Cre transgene driven by expression of the Cyp17a1 steroidogenic gene (Cyp17-iCre) that depletes GR during development and a viral vector-driven Cre (AAV9-Cre) to deplete GR in adulthood. The delivery of AAV9-Cre ablated GR in adult mouse Leydig cells depleted Leydig cell GR more efficiently than the Cyp17-iCre model. Importantly, adult depletion of GR in Leydig cells caused reduced expression of luteinising hormone receptor (Lhcgr) and of steroidogenic enzymes required for normal androgen production. These findings reveal that Leydig cell GR signalling plays a physiological role in the testis and highlight that a normal balance of glucocorticoid activity in the testis is important for steroidogenesis.


Assuntos
Células Intersticiais do Testículo , Receptores de Glucocorticoides , Camundongos , Masculino , Animais , Células Intersticiais do Testículo/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Glucocorticoides/genética , Glucocorticoides/metabolismo , Androgênios/metabolismo , Camundongos Knockout , Testículo/metabolismo , Expressão Gênica
14.
Nat Commun ; 13(1): 7858, 2022 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-36543805

RESUMO

SUMOylation is a dynamic posttranslational modification, that provides fine-tuning of protein function involved in the cellular response to stress, differentiation, and tissue development. In the adrenal cortex, an emblematic endocrine organ that mediates adaptation to physiological demands, the SUMOylation gradient is inversely correlated with the gradient of cellular differentiation raising important questions about its role in functional zonation and the response to stress. Considering that SUMO-specific protease 2 (SENP2), a deSUMOylating enzyme, is upregulated by Adrenocorticotropic Hormone (ACTH)/cAMP-dependent Protein Kinase (PKA) signalling within the zona fasciculata, we generated mice with adrenal-specific Senp2 loss to address these questions. Disruption of SENP2 activity in steroidogenic cells leads to specific hypoplasia of the zona fasciculata, a blunted reponse to ACTH and isolated glucocorticoid deficiency. Mechanistically, overSUMOylation resulting from SENP2 loss shifts the balance between ACTH/PKA and WNT/ß-catenin signalling leading to repression of PKA activity and ectopic activation of ß-catenin. At the cellular level, this blocks transdifferentiation of ß-catenin-positive zona glomerulosa cells into fasciculata cells and sensitises them to premature apoptosis. Our findings indicate that the SUMO pathway is critical for adrenal homeostasis and stress responsiveness.


Assuntos
Transdiferenciação Celular , Cisteína Endopeptidases , Glucocorticoides , Animais , Camundongos , Córtex Suprarrenal/metabolismo , Corticosteroides/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , beta Catenina/metabolismo , Transdiferenciação Celular/genética , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Glucocorticoides/metabolismo , Via de Sinalização Wnt
15.
Front Endocrinol (Lausanne) ; 13: 1064024, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36578966

RESUMO

Congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase deficiency (21OHD) or 11ß-hydroxylase deficiency (11OHD) are congenital conditions with affected adrenal steroidogenesis. Patients with classic 21OHD and 11OHD have a (nearly) complete enzyme deficiency resulting in impaired cortisol synthesis. Elevated precursor steroids are shunted into the unaffected adrenal androgen synthesis pathway leading to elevated adrenal androgen concentrations in these patients. Classic patients are treated with glucocorticoid substitution to compensate for the low cortisol levels and to decrease elevated adrenal androgens levels via negative feedback on the pituitary gland. On the contrary, non-classic CAH (NCCAH) patients have more residual enzymatic activity and do generally not suffer from clinically relevant glucocorticoid deficiency. However, these patients may develop symptoms due to elevated adrenal androgen levels, which are most often less elevated compared to classic patients. Although glucocorticoid treatment can lower adrenal androgen production, the supraphysiological dosages also may have a negative impact on the cardiovascular system and bone health. Therefore, the benefit of glucocorticoid treatment is questionable. An individualized treatment plan is desirable as patients can present with various symptoms or may be asymptomatic. In this review, we discuss the advantages and disadvantages of different treatment options used in patients with NCCAH due to 21OHD and 11OHD.


Assuntos
Hiperplasia Suprarrenal Congênita , Humanos , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/diagnóstico , Glucocorticoides/uso terapêutico , Glucocorticoides/metabolismo , Hidrocortisona , Androgênios , Oxigenases de Função Mista
16.
J Med Chem ; 65(24): 16818-16828, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36484727

RESUMO

The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein-protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators.


Assuntos
Glucocorticoides , Receptores de Glucocorticoides , Glucocorticoides/metabolismo , Receptores de Glucocorticoides/metabolismo , Proteínas 14-3-3/metabolismo , Regulação da Expressão Gênica , Sítios de Ligação , Esteroides , Dexametasona
17.
Int J Mol Sci ; 23(24)2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36555315

RESUMO

Glucocorticoids are steroid hormones that play diverse roles in numerous normal and pathological processes. They are actively used to treat a wide variety of diseases, including neurodegenerative and inflammatory diseases, cancers, and COVID-19, among others. However, the long-term use of glucocorticoids is associated with numerous side effects. Molecular mechanisms of these negative side effects are not completely understood. Recently, arguments have been made that one such mechanisms may be related to the influence of glucocorticoids on O-glycosylated components of the cell surface and extracellular matrix, in particular on proteoglycans and glycosaminoglycans. The potential toxic effects of glucocorticoids on these glycosylated macromolecules are particularly meaningful for brain physiology because proteoglycans/glycosaminoglycans are the main extracellular components of brain tissue. Here, we aim to review the known effects of glucocorticoids on proteoglycan expression and glycosaminoglycan content in different tissues, with a specific focus on the brain.


Assuntos
Glucocorticoides , Glicosaminoglicanos , Proteoglicanas , Humanos , Glucocorticoides/metabolismo , Glicosaminoglicanos/metabolismo , Proteoglicanas/metabolismo
18.
Biomolecules ; 12(12)2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36551249

RESUMO

While topical corticosteroid (TCS) treatment is widely used for many skin diseases, it can trigger adverse side effects, and some of such effects can last for a long time after stopping the treatment. However, molecular changes induced by TCS treatment remain largely unexplored, although transient changes in histology and some major ECM components have been documented. Here, we investigated transcriptomic and proteomic changes induced by fluocinolone acetonide (FA) treatment in the mouse skin by conducting RNA-Seq and quantitative proteomics. Chronic FA treatment affected the expression of 4229 genes, where downregulated genes were involved in cell-cycle progression and ECM organization, and upregulated genes were involved in lipid metabolism. The effects of FA on transcriptome and histology of the skin largely returned to normal by two weeks after the treatment. Only a fraction of transcriptomic changes were reflected by proteomic changes, and the expression of 46 proteins was affected one day after chronic FA treatment. A comparable number of proteins were differentially expressed between control and FA-treated skin samples even at 15 and 30 days after stopping chronic FA treatment. Interestingly, proteins affected during and after chronic FA treatment were largely different. Our results provide fundamental information of molecular changes induced by FA treatment in the skin.


Assuntos
Fluocinolona Acetonida , Transcriptoma , Camundongos , Animais , Fluocinolona Acetonida/farmacologia , Fluocinolona Acetonida/uso terapêutico , Proteômica , Pele/metabolismo , Glucocorticoides/metabolismo , Corticosteroides/metabolismo
19.
Int J Mol Sci ; 23(24)2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36555435

RESUMO

Abnormalities in hematological parameters of peripheral blood have been noted in patients with endogenous Cushing's Syndrome (CS) in the corticotropin (ACTH)-dependent and ACTH-independent forms. Nevertheless, the exact mechanism of glucocorticoids (GCs) action on human hematopoiesis is still not entirely clear. The aim of the study was to determine whether endogenous excessive production of GCs could affect apoptosis of CD34+ cells enriched in hematopoietic stem and progenitor cells (HSPCs) collected from the peripheral blood of newly diagnosed CS patients. Flow cytometry, Annexin-V enzyme-linked immunosorbent assay, TUNEL assay, real-time quantitative PCR, and microarray RNA/miRNA techniques were used to characterize CS patients' HSPCs. We found that the glucocorticoid receptor (GR) protein expression levels in CS were higher than in healthy controls. A complex analysis of apoptotic status of CS patients' HSPC cells showed that GCs significantly augmented apoptosis in peripheral blood-derived CD34+ cells and results obtained using different methods to detect early and late apoptosis in analyzed cell population were consistent. CS was also associated with significant upregulation in several members of the BCL-2 superfamily and other genes associated with apoptosis control. Furthermore, global gene expression analysis revealed significantly higher expression of genes associated with programmed cell death control in HSPCs from CS patients. These findings suggest that human endogenous GCs have a direct pro-apoptotic activity in hematopoietic CD34+ cells derived from CS subjects before treatment.


Assuntos
Síndrome de Cushing , Glucocorticoides , Humanos , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Síndrome de Cushing/metabolismo , Antígenos CD34/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Apoptose/fisiologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Hormônio Adrenocorticotrópico/metabolismo
20.
Nucleic Acids Res ; 50(20): 11635-11653, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36399508

RESUMO

Understanding the function of non-coding genomic sequence variants represents a challenge for biomedicine. Many diseases are products of gene-by-environment interactions with complex mechanisms. This study addresses these themes by mechanistic characterization of non-coding variants that influence gene expression only after drug or hormone exposure. Using glucocorticoid signaling as a model system, we integrated genomic, transcriptomic, and epigenomic approaches to unravel mechanisms by which variant function could be revealed by hormones or drugs. Specifically, we identified cis-regulatory elements and 3D interactions underlying ligand-dependent associations between variants and gene expression. One-quarter of the glucocorticoid-modulated variants that we identified had already been associated with clinical phenotypes. However, their affected genes were 'unmasked' only after glucocorticoid exposure and often with function relevant to the disease phenotypes. These diseases involved glucocorticoids as risk factors or therapeutic agents and included autoimmunity, metabolic and mood disorders, osteoporosis and cancer. For example, we identified a novel breast cancer risk gene, MAST4, with expression that was repressed by glucocorticoids in cells carrying the risk genotype, repression that correlated with MAST4 expression in breast cancer and treatment outcomes. These observations provide a mechanistic framework for understanding non-coding genetic variant-chemical environment interactions and their role in disease risk and drug response.


Assuntos
Glucocorticoides , Sequências Reguladoras de Ácido Nucleico , Glucocorticoides/genética , Glucocorticoides/metabolismo , Fatores de Risco
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