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1.
Chemosphere ; 262: 127841, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32784060

RESUMO

Environmental pollutants suspected of disrupting the endocrine system are considered etiologic factors in the epidemic of metabolic disorders. As regulation of energy metabolism relies on the integrated action of a large number of hormones, we hypothesized that certain chemicals could trigger changes in glucocorticoid signaling. To this end, we exposed C57Bl6/J female and male mice between 5 and 20 weeks of age to a mixture of 2,3,7,8- tetrachlorodibenzo-p-dioxin (20 pg/kg body weight/day [bw/d]), polychlorobiphenyl 153 (200 ng/kg bw/d), di-[2-ethylhexyl]-phthalate (500 µg/kg bw/d) and bisphenol A (40 µg/kg bw/d). In female mice fed a standard diet (ST), we observed a decrease in plasma levels of leptin as well as a reduced expression of corticoid receptors Nr3c1 and Nr3c2, of leptin and of various canonical genes related to the circadian clock machinery in visceral (VAT) but not subcutaneous (SAT) adipose tissue. However, Nr3c1 and Nr3c2 mRNA levels did not change in high-fat-fed females exposed to pollutants. In ST-fed males, pollutants caused the same decrease of Nr3c1 mRNA levels in VAT observed in ST-fed females but levels of Nr3c2 and other clock-related genes found to be down-regulated in female VAT were enhanced in male SAT and not affected in male VAT. The expression of corticoid receptors was not affected in the livers of both sexes in response to pollutants. In summary, exposure to a mixture of pollutants at doses lower than the no-observed adverse effect levels (NoAELs) resulted in sex-dependent glucocorticoid signaling disturbances and clock-related gene expression modifications in the adipose tissue of ST-fed mice.


Assuntos
Poluentes Ambientais/toxicidade , Glucocorticoides/metabolismo , Tecido Adiposo/metabolismo , Animais , Compostos Benzidrílicos , Peso Corporal , Poluentes Ambientais/metabolismo , Feminino , Expressão Gênica , Leptina/sangue , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenóis , Dibenzodioxinas Policloradas/metabolismo , RNA Mensageiro/metabolismo , Sensibilidade e Especificidade
2.
Gene ; 766: 145128, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32911026

RESUMO

BACKGROUND: The pathogenesis of osteonecrosis of the femoral head (ONFH) is unclear. Our previous study demonstrated that upregulated miR-335 in bone microvascular endothelial cells (BMECs) might be associated with the disease of steroid-induced ONFH. Here, we study the preventive effect of ICA on steroid-induced ONFH in rats. METHOD: 90 rats were separated into three groups: control group, methylprednisolone (MPS) group, and MPS + Icariin (ICA) group. Four weeks later, histological analyses were performed. Thrombomodulin (TM) and vascular endothelial growth factor (VEGF) were tested. MiRNA-335 expression was screened in the three groups using Agilent Gene Spring GX software. Target genes of miRNA-335 were detected by bioinformatics analysis. The functions of BMECs were analyzed by scratch, angiogenesis and cell survival rate. RESULTS: ICA can prevent the occurrence of steroid-associated ONFH in rats and reduce the amount of TM and VEGF in serum induced by glucocorticoids. ICA could regulate the overexpression of miRNA-335 induced by glucocorticoids. We predicted the Gene ontology (GO) and signaling pathways of target genes. At 24 hours, we found that ICA significantly promoted BMECs migration abilities. We also found that ICA could promote the angioplasty ability of BMECs. ICA could improve the survival rate of BMECs after steroid-induced injury. CONCLUSIONS: ICA is effective to prevent the occurrence of steroidinduced ONFH. ICA has a protective effect against steroid-induced BMECs injury. ICA regulated the imbalance of miRNA-335 expression induced by the glucocorticoid in BMECs, which provides a new viewpoint to explore the mechanism of ICA in preventing steroid-induced ONFH.


Assuntos
Células Endoteliais/efeitos dos fármacos , Necrose da Cabeça do Fêmur/tratamento farmacológico , Cabeça do Fêmur/efeitos dos fármacos , Flavonoides/farmacologia , MicroRNAs/metabolismo , Neovascularização Patológica/tratamento farmacológico , Substâncias Protetoras/farmacologia , Adipogenia/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Cabeça do Fêmur/metabolismo , Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/metabolismo , Glucocorticoides/metabolismo , Metilprednisolona/farmacologia , Neovascularização Patológica/metabolismo , Osteócitos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Esteroides/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Eur J Endocrinol ; 183(6): 669-676, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33112256

RESUMO

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


Assuntos
Cortisona/metabolismo , Síndrome de Cushing/etiologia , Glicopeptídeos/metabolismo , Hidrocortisona/metabolismo , Obesidade/metabolismo , Adulto , Arginina Vasopressina/metabolismo , Biomarcadores/metabolismo , Índice de Massa Corporal , Hormônio Liberador da Corticotropina/metabolismo , Estudos Transversais , Feminino , Glucocorticoides/metabolismo , Cabelo/química , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Obesidade/complicações , Sistema Hipófise-Suprarrenal/metabolismo
4.
Proc Natl Acad Sci U S A ; 117(35): 21667-21672, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817534

RESUMO

Extensive pharmacologic, genetic, and epigenetic research has linked the glucocorticoid receptor (GR) to memory processes, and to risk and symptoms of posttraumatic stress disorder (PTSD). In the present study we investigated the epigenetic pattern of 12 genes involved in the regulation of GR signaling in two African populations of heavily traumatized individuals: Survivors of the rebel war in northern Uganda (n = 463) and survivors of the Rwandan genocide (n = 350). The strongest link between regional methylation and PTSD risk and symptoms was observed for NTRK2, which encodes the transmembrane receptor tropomyosin-related kinase B, binds the brain-derived neurotrophic factor, and has been shown to play an important role in memory formation. NTRK2 methylation was not related to trauma load, suggesting that methylation differences preexisted the trauma. Because NTRK2 methylation differences were predominantly associated with memory-related PTSD symptoms, and because they seem to precede traumatic events, we next investigated the relationship between NTRK2 methylation and memory in a sample of nontraumatized individuals (n = 568). We found that NTRK2 methylation was negatively associated with recognition memory performance. Furthermore, fMRI analyses revealed NTRK2 methylation-dependent differences in brain network activity related to recognition memory. The present study demonstrates that NTRK2 is epigenetically linked to memory functions in nontraumatized subjects and to PTSD risk and symptoms in traumatized populations.


Assuntos
Glicoproteínas de Membrana/genética , Receptor trkB/genética , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Idoso , Encéfalo/metabolismo , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Glucocorticoides/metabolismo , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Memória/fisiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptor trkB/metabolismo , Receptores de Glucocorticoides/metabolismo , Fatores de Risco , Ruanda/epidemiologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Sobreviventes , Uganda/epidemiologia
5.
Proc Natl Acad Sci U S A ; 117(33): 20052-20062, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747546

RESUMO

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


Assuntos
Fezes/química , Glucocorticoides/análise , Papio/psicologia , Comportamento Social , Animais , Animais Selvagens/metabolismo , Feminino , Glucocorticoides/metabolismo , Estudos Longitudinais , Masculino , Apego ao Objeto , Papio/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Estudos Prospectivos , Estresse Psicológico
6.
Proc Natl Acad Sci U S A ; 117(29): 17166-17176, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632016

RESUMO

Signaling of 17ß-estradiol (estrogen) through its two nuclear receptors, α and ß (ERα, ERß), is an important mechanism of transcriptional regulation. Although ERs are broadly expressed by cells of the immune system, the mechanisms by which they modulate immune responses remain poorly understood. ERß-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease, and our previous work suggests that dysregulation of ERß-specific signaling contributes to enhanced intestinal inflammation in female SAMP/YitFC mice, a spontaneous model of Crohn's disease-like ileitis. The present study builds on these prior observations to identify a nonredundant, immunoprotective role for ERß-specific signaling in TGF-ß-dependent regulatory T cell (Treg) differentiation. Using a strain of congenic SAMP mice engineered to lack global expression of ERß, we observed dramatic, female-specific exacerbation of intestinal inflammation accompanied by significant reductions in intestinal Treg frequency and function. Impaired Treg suppression in the absence of ERß was associated with aberrant overexpression of Tsc22d3 (GILZ), a glucocorticoid-responsive transcription factor not normally expressed in mature Tregs, and ex vivo data reveal that forced overexpression of GILZ in mature Tregs inhibits their suppressive function. Collectively, our findings identify a pathway of estrogen-mediated immune regulation in the intestine, whereby homeostatic expression of ERß normally functions to limit Treg-specific expression of GILZ, thereby maintaining effective immune suppression. Our data suggest that transcriptional cross-talk between glucocorticoid and steroid sex hormone signaling represents an important and understudied regulatory node in chronic inflammatory disease.


Assuntos
Receptor beta de Estrogênio/metabolismo , Estrogênios/metabolismo , Inflamação/imunologia , Intestinos/imunologia , Transdução de Sinais/fisiologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Animais , Doença de Crohn/imunologia , Modelos Animais de Doenças , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Feminino , Glucocorticoides/metabolismo , Humanos , Ileíte/patologia , Doenças Inflamatórias Intestinais/imunologia , Intestinos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
7.
Am J Physiol Heart Circ Physiol ; 319(2): H488-H506, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618516

RESUMO

Although chronic stress is an important risk factor for cardiovascular diseases (CVD) onset, the underlying mechanisms driving such pathophysiological complications remain relatively unknown. Here, dysregulation of innate stress response systems and the effects of downstream mediators are strongly implicated, with the vascular endothelium emerging as a primary target of excessive glucocorticoid and catecholamine action. Therefore, this review article explores the development of stress-related endothelial dysfunction by focusing on the following: 1) assessing the phenomenon of stress and complexities surrounding this notion, 2) discussing mechanistic links between chronic stress and endothelial dysfunction, and 3) evaluating the utility of various preclinical models currently employed to study mechanisms underlying the onset of stress-mediated complications such as endothelial dysfunction. The data reveal that preclinical models play an important role in our efforts to gain an increased understanding of mechanisms underlying stress-mediated endothelial dysfunction. It is our understanding that this provides a good foundation going forward, and we propose that further efforts should be made to 1) more clearly define the concept of stress and 2) standardize protocols of animal models with specific guidelines to better indicate the mental complications that are simulated.


Assuntos
Doenças Cardiovasculares/etiologia , Endotélio Vascular/fisiopatologia , Estresse Psicológico/complicações , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/psicologia , Catecolaminas/metabolismo , Doença Crônica , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Glucocorticoides/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Fatores de Risco , Transdução de Sinais , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia
8.
Nucleic Acids Res ; 48(15): 8393-8407, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32619221

RESUMO

The glucocorticoid receptor is an important immunosuppressive drug target and metabolic regulator that acts as a ligand-gated transcription factor. Generally, GR's anti-inflammatory effects are attributed to the silencing of inflammatory genes, while its adverse effects are ascribed to the upregulation of metabolic targets. GR binding directly to DNA is proposed to activate, whereas GR tethering to pro-inflammatory transcription factors is thought to repress transcription. Using mice with a point mutation in GR's zinc finger, that still tether via protein-protein interactions while being unable to recognize DNA, we demonstrate that DNA binding is essential for both transcriptional activation and repression. Performing ChIP-Seq, RNA-Seq and proteomics under inflammatory conditions, we show that DNA recognition is required for the assembly of a functional co-regulator complex to mediate glucocorticoid responses. Our findings may contribute to the development of safer immunomodulators with fewer side effects.


Assuntos
Proteínas de Ligação a DNA/genética , DNA/genética , Inflamação/genética , Receptores de Glucocorticoides/genética , Animais , DNA/metabolismo , Regulação da Expressão Gênica/genética , Glucocorticoides/genética , Glucocorticoides/metabolismo , Humanos , Inflamação/patologia , Camundongos , Domínios e Motivos de Interação entre Proteínas/genética , RNA-Seq , Ativação Transcricional/genética
9.
Toxicol Lett ; 331: 167-177, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32535229

RESUMO

Prenatal ethanol exposure (PEE) could increase offspring's susceptibility to adult liver lipid-metabolism diseases. This study aimed to confirm intrauterine programming mechanism of glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis for liver dysfunction in offspring rats induced by PEE. The results showed that levels of hepatic IGF1, lipid metabolism-related enzymes (e.g. FASN and HMGCR) and serum phenotype (TG, TCH, HDL-C, and LDL-C) were low in fetal rats of PEE but high in adult offspring except for HDL-C, meanwhile, hepatic H3K9ac and expression levels of IGF1 were low in fetal rats but high in adult offspring. Furthermore, levels of serum corticosterone and hepatic glucocorticoid-activation system (mainly including expression of 11ß-HSD1, GR, and C/EBPα as well as 11ß-HSD1/11ß-HSD2 ratio) were high in fetal rats of PEE but low or unchanged in adult offspring. The adult F2 generation of PEE maintained the same GC-IGF1 axis programming alteration as the F1 generation despite gender differences. In vitro, cortisol was proved to activate hepatocyte glucocorticoid-activation system and decrease H3K9ac and expression levels of IGF1 by GR. Therefore, PEE has a long-term effect on the offspring's liver functional development, which may be mainly related to the epigenetic programming alteration of the GC-IGF1 axis mediated by the glucocorticoid-activation system.


Assuntos
Etanol/toxicidade , Glucocorticoides/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Peso Corporal , Corticosterona/sangue , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/metabolismo , Células Hep G2 , Humanos , Lipídeos/sangue , Fígado/embriologia , Fígado/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Ratos Wistar , Transdução de Sinais
10.
J Allergy Clin Immunol ; 146(2): 330-331, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32593491
11.
PLoS Genet ; 16(5): e1008757, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32379754

RESUMO

In the last decades in vitro studies highlighted the potential for crosstalk between Hypoxia-Inducible Factor-(HIF) and glucocorticoid-(GC) signalling pathways. However, how this interplay precisely occurs in vivo is still debated. Here, we use zebrafish larvae (Danio rerio) to elucidate how and to what degree hypoxic signalling affects the endogenous glucocorticoid pathway and vice versa, in vivo. Firstly, our results demonstrate that in the presence of upregulated HIF signalling, both glucocorticoid receptor (Gr) responsiveness and endogenous cortisol levels are repressed in 5 days post fertilisation larvae. In addition, despite HIF activity being low at normoxia, our data show that it already impedes both glucocorticoid activity and levels. Secondly, we further analysed the in vivo contribution of glucocorticoids to HIF activity. Interestingly, our results show that both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) play a key role in enhancing it. Finally, we found indications that glucocorticoids promote HIF signalling via multiple routes. Cumulatively, our findings allowed us to suggest a model for how this crosstalk occurs in vivo.


Assuntos
Glucocorticoides/farmacologia , Fator 1 Induzível por Hipóxia/fisiologia , Receptor Cross-Talk/fisiologia , Peixe-Zebra , Animais , Animais Geneticamente Modificados , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Glucocorticoides/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Larva/genética , Larva/metabolismo , Receptor Cross-Talk/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
12.
Am J Physiol Lung Cell Mol Physiol ; 319(2): L239-L255, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32460513

RESUMO

While antenatal glucocorticoids are widely used to enhance lung function in preterm infants, cellular and molecular mechanisms by which glucocorticoid receptor (GR) signaling influences lung maturation remain poorly understood. Deletion of the glucocorticoid receptor gene (Nr3c1) from fetal pulmonary mesenchymal cells phenocopied defects caused by global Nr3c1 deletion, while lung epithelial- or endothelial-specific Nr3c1 deletion did not impair lung function at birth. We integrated genome-wide gene expression profiling, ATAC-seq, and single cell RNA-seq data in mice in which GR was deleted or activated to identify the cellular and molecular mechanisms by which glucocorticoids control prenatal lung maturation. GR enhanced differentiation of a newly defined proliferative mesenchymal progenitor cell (PMP) into matrix fibroblasts (MFBs), in part by directly activating extracellular matrix-associated target genes, including Fn1, Col16a4, and Eln and by modulating VEGF, JAK-STAT, and WNT signaling. Loss of mesenchymal GR signaling blocked fibroblast progenitor differentiation into mature MFBs, which in turn increased proliferation of SOX9+ alveolar epithelial progenitor cells and inhibited differentiation of mature alveolar type II (AT2) and AT1 cells. GR signaling controls genes required for differentiation of a subset of proliferative mesenchymal progenitors into matrix fibroblasts, in turn, regulating signals controlling AT2/AT1 progenitor cell proliferation and differentiation and identifying cells and processes by which glucocorticoid signaling regulates fetal lung maturation.


Assuntos
Diferenciação Celular/fisiologia , Glucocorticoides/metabolismo , Pulmão/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células Epiteliais Alveolares/metabolismo , Animais , Proliferação de Células/fisiologia , Fibroblastos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/fisiologia
13.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L173-L184, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432919

RESUMO

The alveolar epithelium is comprised of two cell types, alveolar epithelial type 1 (AT1) and type 2 (AT2) cells, the latter being capable of self-renewal and transdifferentiation into AT1 cells for normal maintenance and restoration of epithelial integrity following injury. MicroRNAs (miRNAs) are critical regulators of several biological processes, including cell differentiation; however, their role in establishment/maintenance of cellular identity in adult alveolar epithelium is not well understood. To investigate this question, we performed genome-wide analysis of sequential changes in miRNA and gene expression profiles using a well-established model in which human AT2 (hAT2) cells transdifferentiate into AT1-like cells over time in culture that recapitulates many aspects of transdifferentiation in vivo. We defined three phases of miRNA expression during the transdifferentiation process as "early," "late," and "consistently" changed, which were further subclassified as up- or downregulated. miRNAs with altered expression at all time points during transdifferentiation were the largest subgroup, suggesting the need for consistent regulation of signaling pathways to mediate this process. Target prediction analysis and integration with previously published gene expression data identified glucocorticoid signaling as the top pathway regulated by miRNAs. Serum/glucocorticoid-regulated kinase 1 (SGK1) emerged as a central regulatory factor, whose downregulation correlated temporally with gain of hsa-miR-424 and hsa-miR-503 expression. Functional validation demonstrated specific targeting of these miRNAs to the 3'-untranslated region of SGK1. These data demonstrate the time-related contribution of miRNAs to the alveolar transdifferentiation process and suggest that inhibition of glucocorticoid signaling is necessary to achieve the AT1-like cell phenotype.


Assuntos
Diferenciação Celular , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Genoma Humano , MicroRNAs/metabolismo , Alvéolos Pulmonares/metabolismo , Transcriptoma/genética , Sequência de Bases , Diferenciação Celular/genética , Linhagem Celular , Transdiferenciação Celular/genética , Regulação da Expressão Gênica , Glucocorticoides/metabolismo , Humanos , Proteínas Imediatamente Precoces/metabolismo , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/metabolismo
14.
Metabolism ; 108: 154250, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32335074

RESUMO

BACKGROUND: Chronic steroid treatment causes an increase in visceral adiposity and osteoporosis. It is believed that steroids may alter a balance between differentiation of mesenchymal stem cells (MSCs) into either adipocytes or osteoblasts; however, the detailed molecular mechanisms are unclear. We previously identified Dexras1 as a critical factor that potentiates adipogenesis in response to glucocorticoids. Thus, in this study, we investigated the role of Dexras1 in maintaining the balance between chronic steroid treatment-associated adipogenesis and osteoporosis. MATERIAL AND METHODS: We treated wild type (WT) and Dexras1 knockout (KO) mice with dexamethasone for five weeks followed by 60% HFD for additional two weeks with dexamethasone. The changes of glucocorticoid-induced body weight gain and osteoporosis were analyzed. Bone marrow derived stromal cells (BMSCs) and mouse embryonic fibroblasts (MEFs) extracted from WT and Dexras1 KO mice, as well as MC3T3-E1 pre-osteoblasts and osteoclasts differentiated from RAW264.7 were analyzed to further define the role of Dexras1 in osteoblasts and osteoclasts. RESULTS: Dual-energy X-ray absorptiometry and micro-computed tomography analyses in murine femurs revealed that Dexras1 deficiency was associated with increased osteogenesis, concurrent with reduced adipogenesis. Furthermore, Dexras1 deficiency promoted osteogenesis of BMSCs and MEFs in vitro, suggesting that Dexras1 deficiency prevents steroid-induced osteoporosis. We also observed that Dexras1 downregulated SMAD signaling pathways, which reduced the osteogenic differentiation capacity of pre-osteoblast MC3T3-E1 cells into mature osteoblasts. CONCLUSION: We propose that Dexras1 is critical for maintaining the equilibrium between adipogenesis and osteogenesis upon steroid treatment.


Assuntos
Adipogenia/fisiologia , Osteogênese/fisiologia , Proteínas ras/metabolismo , Células 3T3 , Adipócitos/metabolismo , Animais , Diferenciação Celular/fisiologia , Linhagem Celular , Fêmur/metabolismo , Glucocorticoides/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporose/metabolismo , Células RAW 264.7 , Transdução de Sinais/fisiologia
15.
Chemosphere ; 254: 126785, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32334250

RESUMO

Fetal overexposure to active glucocorticoid (GC) is the major cause for fetal growth restriction (FGR). This study investigated the influences of cadmium (Cd) exposure on active GC and its mechanism in placental trophoblasts. Pregnant mice were exposed to CdCl2 (4.5 mg/kg, i.p.). Human JEG-3 cells were treated with CdCl2 (0-20 µM). Prenatal Cd exposure significantly increased active GC level in amniotic fluid and placenta. Similarly, Cd treatment also elevated active GC level in medium. Expectedly, the expression of 11ß-HSD2 protein was markedly downregulated in Cd-exposed placental trophoblasts. We further found that Cd activated the PERK/p-eIF2α signaling pathway in placental trophoblasts. Mechanistically, PERK siRNA pretreatment completely blocked PERK/p-eIF2α signaling, and thereby restoring Cd-downregulated 11ß-HSD2 protein expression in human placental trophoblasts. We further found that N-acetylcysteine, a well-known antioxidant, obviously reversed Cd-downregulated 11ß-HSD2 protein expression by inhibiting p-PERK/p-eIF2α signaling in placental trophoblasts. Overall, our data suggest that Cd activates the PERK/p-eIF2α signaling, down-regulates the protein expression of 11ß-HSD2, and thereby elevating active GC level in placental trophoblast.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Animais , Cádmio/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Retardo do Crescimento Fetal , Glucocorticoides/metabolismo , Humanos , Camundongos , Placenta/metabolismo , Gravidez , Trofoblastos/fisiologia
16.
Int J Mol Sci ; 21(2)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32284519

RESUMO

Maternal stress before or during the sensitive preimplantation phase is associated with reproduction failure. Upon real or perceived threat, glucocorticoids (classic stress hormones) as cortisol are synthesized. The earliest "microenvironment" of the embryo consists of the oviduct epithelium and the oviductal fluid generated via the epithelial barrier. However, to date, the direct effects of cortisol on the oviduct are largely unknown. In the present study, we used a compartmentalized in vitro system to test the hypothesis that a prolonged stimulation with cortisol modifies the physiology of the oviduct epithelium. Porcine oviduct epithelial cells were differentiated at the air-liquid interface and basolaterally stimulated with physiological levels of cortisol representing moderate and severe stress for 21 days. Epithelium structure, transepithelial bioelectric properties, and gene expression were assessed. Furthermore, the distribution and metabolism of cortisol was examined. The polarized oviduct epithelium converted basolateral cortisol to cortisone and thereby reduced the amount of bioactive cortisol reaching the apical compartment. However, extended cortisol stimulation affected its barrier function and the expression of genes involved in hormone signaling and immune response. We conclude that continuing maternal stress with long-term elevated cortisol levels may alter the early embryonic environment by modification of basic oviductal functions.


Assuntos
Microambiente Celular , Desenvolvimento Embrionário , Células Epiteliais/fisiologia , Hidrocortisona/metabolismo , Suínos/fisiologia , Animais , Diferenciação Celular , Epitélio/fisiologia , Tubas Uterinas/embriologia , Tubas Uterinas/fisiologia , Feminino , Glucocorticoides/metabolismo , Gravidez , Estresse Fisiológico , Suínos/embriologia
17.
Am J Physiol Endocrinol Metab ; 319(1): E48-E66, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315214

RESUMO

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


Assuntos
Citocinas/imunologia , Glucocorticoides/imunologia , Receptores de Glucocorticoides/imunologia , Transtornos de Estresse Pós-Traumáticos/imunologia , Hormônio Adrenocorticotrópico/imunologia , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Campanha Afegã de 2001- , Proteína C-Reativa/imunologia , Estudos de Casos e Controles , Ritmo Circadiano , Metilação de DNA , Dexametasona , Glucocorticoides/metabolismo , Humanos , Hidrocortisona/imunologia , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Inflamação , Concentração Inibidora 50 , Interleucina-6/imunologia , Guerra do Iraque 2003-2011 , Masculino , Modelos Teóricos , Testes de Função Adreno-Hipofisária , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Regiões Promotoras Genéticas , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Veteranos
18.
Gen Comp Endocrinol ; 293: 113494, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32333913

RESUMO

Integrative behavioral ecology requires accurate and non-invasive measures of hormone mediators for the study of wild animal populations. Biologically sensitive assay systems for the measurement of hormones and their metabolites need to be validated for the species and sample medium (e.g. urine, feces, saliva) of interest. Where more than one assay is available for hormone (metabolite) measurement, antibody selection is useful in identifying the assay that tracks changes in an individuals endocrine activity best, i.e., the most biologically sensitive assay. This is particularly important when measuring how glucocorticoids (GCs) respond to the subtle, additive effects of acute stressors during a predictable metabolic challenge, such as gestation. Here, we validate a group-specific enzyme immunoassay, measuring immunoreactive 11ß-hydroxyetiocholanolone, for use in a wild primate, geladas (Theropithecus gelada). This group-specific assay produced values correlated with those from a previously validated double-antibody, corticosterone 125I radioimmunoassay. However, the results with the group-specific assay showed a stronger response to an ACTH challenge and identified greater variation in gelada immunoreactive fecal glucocorticoid metabolites (iGCMs) compared with the corticosterone assay, indicating a higher biological sensitivity for assessing adrenocortical activity. We then used the group-specific assay to: (1) determine the normative pattern of iGCM levels across gelada gestation, and (2) identify the ecological, social, and individual factors that influence GC output for pregnant females. Using a general additive mixed model, we found that higher iGCM levels were associated with low rank (compared to high rank) and first time mothers (compared to multiparous mothers). This study highlights the importance of assay selection and the efficacy of group-specific assays for hormonal research in non-invasively collected samples. Additionally, in geladas, our results identify some of the factors that increase GC output over and above the already-elevated GC concentrations associated with gestation. In the burgeoning field of maternal stress, these factors can be examined to identify the effects that GC elevations may have on offspring development.


Assuntos
Fezes/química , Glucocorticoides/metabolismo , Metaboloma , Paridade , Theropithecus/metabolismo , Animais , Animais Selvagens/metabolismo , Corticosterona/metabolismo , Feminino , Técnicas Imunoenzimáticas , Masculino , Modelos Biológicos , Gravidez , Radioimunoensaio , Reprodutibilidade dos Testes
19.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188359, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32222610

RESUMO

Advanced cancer patients exhibit cachexia, a condition characterized by a significant reduction in the body weight predominantly from loss of skeletal muscle and adipose tissue. Cachexia is one of the major causes of morbidity and mortality in cancer patients. Decreased food intake and multi-organ energy imbalance in cancer patients worsen the cachexia syndrome. Cachectic cancer patients have a low tolerance for chemo- and radiation therapies and also have a reduced quality of life. The presence of tumors and the current treatment options for cancer further exacerbate the cachexia condition, which remains an unmet medical need. The onset of cachexia involves crosstalk between different organs leading to muscle wasting. Recent advancements in understanding the molecular mechanisms of skeletal muscle atrophy/hypertrophy and adipose tissue wasting/browning provide a platform for the development of new targeted therapies. Therefore, a better understanding of this multifactorial disorder will help to improve the quality of life of cachectic patients. In this review, we summarize the metabolic mediators of cachexia, their molecular functions, affected organs especially with respect to muscle atrophy and adipose browning and then discuss advanced therapeutic approaches to cancer cachexia.


Assuntos
Estimulantes do Apetite/uso terapêutico , Caquexia/patologia , Atrofia Muscular/patologia , Neoplasias/complicações , Apoio Nutricional/métodos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/efeitos da radiação , Antineoplásicos/efeitos adversos , Estimulantes do Apetite/farmacologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Osso e Ossos/efeitos da radiação , Caquexia/etiologia , Caquexia/metabolismo , Caquexia/terapia , Citocinas/metabolismo , Suplementos Nutricionais , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/efeitos da radiação , Glucocorticoides/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos da radiação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/efeitos da radiação , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/efeitos da radiação , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Neoplasias/terapia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Pâncreas/efeitos da radiação , Hormônio Paratireóideo/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Qualidade de Vida , Radioterapia/efeitos adversos , Ganho de Peso/efeitos dos fármacos
20.
Cell ; 180(5): 847-861.e15, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142678

RESUMO

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


Assuntos
Infecções Bacterianas/imunologia , Desenvolvimento Embrionário/imunologia , Glucocorticoides/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Dexametasona/farmacologia , Desenvolvimento Embrionário/genética , Feminino , Glucocorticoides/imunologia , Glucocorticoides/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Interleucina-4/farmacologia , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Neoplasias/induzido quimicamente , Neoplasias/genética , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Receptores de Glucocorticoides/genética , Transdução de Sinais/genética
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