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1.
Nat Commun ; 12(1): 5763, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599158

RESUMO

Signals from the central circadian pacemaker, the suprachiasmatic nucleus (SCN), must be decoded to generate daily rhythms in hormone release. Here, we hypothesized that the SCN entrains rhythms in the paraventricular nucleus (PVN) to time the daily release of corticosterone. In vivo recording revealed a critical circuit from SCN vasoactive intestinal peptide (SCNVIP)-producing neurons to PVN corticotropin-releasing hormone (PVNCRH)-producing neurons. PVNCRH neurons peak in clock gene expression around midday and in calcium activity about three hours later. Loss of the clock gene Bmal1 in CRH neurons results in arrhythmic PVNCRH calcium activity and dramatically reduces the amplitude and precision of daily corticosterone release. SCNVIP activation reduces (and inactivation increases) corticosterone release and PVNCRH calcium activity, and daily SCNVIP activation entrains PVN clock gene rhythms by inhibiting PVNCRH neurons. We conclude that daily corticosterone release depends on coordinated clock gene and neuronal activity rhythms in both SCNVIP and PVNCRH neurons.


Assuntos
Ritmo Circadiano/fisiologia , Glucocorticoides/metabolismo , Neurônios/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Cálcio/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Corticosterona/farmacologia , Hormônio Liberador da Corticotropina/metabolismo , Fezes/química , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Fotometria , Núcleo Supraquiasmático/fisiologia
2.
Am J Physiol Regul Integr Comp Physiol ; 321(5): R802-R811, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34612088

RESUMO

Hospitalized preterm infants experience painful medical procedures. Oral sucrose is the nonpharmacological standard of care for minor procedural pain relief. Infants are treated with numerous doses of sucrose, raising concerns about potential long-term effects. The objective of this study was to determine the long-term effects of neonatal oral sucrose treatment on growth and liver metabolism in a mouse model. Neonatal female and male mice were randomly assigned to one of two oral treatments (n = 7-10 mice/group/sex): sterile water or sucrose. Pups were treated 10 times/day for the first 6 days of life with 0.2 mg/g body wt of respective treatments (24% solution; 1-4 µL/dose) to mimic what is given to preterm infants. Mice were weaned at age 3 wk onto a control diet and fed until age 16 wk. Sucrose-treated female and male mice gained less weight during the treatment period and were smaller at weaning than water-treated mice (P ≤ 0.05); no effect of sucrose treatment on body weight was observed at adulthood. However, adult sucrose-treated female mice had smaller tibias and lower serum insulin-like growth factor-1 than adult water-treated female mice (P ≤ 0.05); these effects were not observed in males. Lower liver S-adenosylmethionine, phosphocholine, and glycerophosphocholine were observed in adult sucrose-treated compared with water-treated female and male mice (P ≤ 0.05). Sucrose-treated female, but not male, mice had lower liver free choline and higher liver betaine compared with water-treated female mice (P < 0.01). Our findings suggest that repeated neonatal sucrose treatment has long-term sex-specific effects on growth and liver methionine and choline metabolism.


Assuntos
Analgésicos/toxicidade , Colina/metabolismo , Glucocorticoides/metabolismo , Fígado/efeitos dos fármacos , Sacarose/toxicidade , Tíbia/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos , Administração Oral , Fatores Etários , Analgésicos/administração & dosagem , Animais , Animais Recém-Nascidos , Betaína/metabolismo , Feminino , Glicerilfosforilcolina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fosforilcolina/metabolismo , S-Adenosilmetionina/metabolismo , Fatores Sexuais , Sacarose/administração & dosagem , Tíbia/crescimento & desenvolvimento
3.
Cells ; 10(9)2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34572025

RESUMO

BACKGROUND: Most work in endocrinology focus on the action of a single hormone, and very little on the cross-talks between two hormones. Here we characterize the nature of interactions between thyroid hormone and glucocorticoid signaling during Xenopus tropicalis metamorphosis. METHODS: We used functional genomics to derive genome wide profiles of methylated DNA and measured changes of gene expression after hormonal treatments of a highly responsive tissue, tailfin. Clustering classified the data into four types of biological responses, and biological networks were modeled by system biology. RESULTS: We found that gene expression is mostly regulated by either T3 or CORT, or their additive effect when they both regulate the same genes. A small but non-negligible fraction of genes (12%) displayed non-trivial regulations indicative of complex interactions between the signaling pathways. Strikingly, DNA methylation changes display the opposite and are dominated by cross-talks. CONCLUSION: Cross-talks between thyroid hormones and glucocorticoids are more complex than initially envisioned and are not limited to the simple addition of their individual effects, a statement that can be summarized with the pseudo-equation: TH ∙ GC > TH + GC. DNA methylation changes are highly dynamic and buffered from genome expression.


Assuntos
Glucocorticoides/metabolismo , Metamorfose Biológica/fisiologia , Transdução de Sinais/fisiologia , Hormônios Tireóideos/metabolismo , Transcriptoma/genética , Xenopus/genética , Xenopus/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento/genética , Genoma/genética
4.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576214

RESUMO

Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. GC actions are principally mediated through the GC receptor (GR), a ligand-dependent transcription factor. Despite the ubiquitous expression of GR, imbalances in GC signalling affect tissues differently, and with variable degrees of severity through mechanisms that are not completely deciphered. Congenital or acquired GC hypersensitivity or resistance syndromes can impact responsiveness to endogenous or pharmacological GCs, causing disease or inadequate therapeutic outcomes, respectively. Acquired GC resistance is defined as loss of efficacy or desensitization over time, and arises as a consequence of chronic inflammation, affecting around 30% of GC-treated patients. It represents an important limitation in the management of chronic inflammatory diseases and cancer, and can be due to impairment of multiple mechanisms along the GC signalling pathway. Among them, activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), have been identified as common mechanisms of GC resistance. While many of the anti-inflammatory actions of GCs rely on GR-mediated inhibition of MAPKs and/or induction of DUSPs, the GC anti-inflammatory capacity is decreased or lost in conditions of excessive MAPK activation, contributing to disease susceptibility in tissue- and disease- specific manners. Here, we discuss potential strategies to modulate GC responsiveness, with the dual goal of overcoming GC resistance and minimizing the onset and severity of unwanted adverse effects while maintaining therapeutic potential.


Assuntos
Regulação da Expressão Gênica , Glucocorticoides/metabolismo , Sistema de Sinalização das MAP Quinases , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Animais , Doenças Autoimunes/terapia , Doença Crônica , Ativação Enzimática , Heterozigoto , Humanos , Inflamação/metabolismo , Leucemia/terapia , Erros Inatos do Metabolismo/metabolismo , Camundongos , Mutação , Polimorfismo Genético , Isoformas de Proteínas , Receptores de Glucocorticoides/deficiência , Transtornos Respiratórios/terapia , Transdução de Sinais , Dermatopatias/terapia , Resultado do Tratamento
5.
Int J Mol Sci ; 22(18)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34575930

RESUMO

Low body weight at birth has been shown to be a risk factor for future metabolic disorders, as well as stress response abnormalities and depression. We showed that low-birthweight rats had prolonged high blood corticosterone levels after stress exposure, and that an increase in Gas5 lncRNA, a decoy receptor for glucocorticoid receptors (GRs), reduces glucocorticoid responsiveness. Thus, we concluded that dampened pituitary glucocorticoid responsiveness disturbed the glucocorticoid feedback loop in low-birthweight rats. However, it remains unclear whether such glucocorticoid responsiveness is suppressed solely in the pituitary or systemically. The expression of Gas5 lncRNA increased only in the pituitary, and the intact induction of expression of the GR co-chaperone factor Fkbp5 against dexamethasone was seen in the liver, muscle, and adipose tissue. Intervention with a methyl-modulator diet (folate, VB12, choline, betaine, and zinc) immediately before or one week after delivery reversed the expression level of Gas5 lncRNA in the pituitary of the offspring. Consequently, it partially normalized the blood corticosterone levels after restraint stress exposure. In conclusion, the mode of glucocorticoid response in low-birthweight rats is impaired solely in the pituitary, and intervention with methyl-modulators ameliorates the impairment, but with a narrow therapeutic time window.


Assuntos
Biomarcadores , Peso ao Nascer , Glucocorticoides/metabolismo , Estresse Fisiológico , Estresse Psicológico , Animais , Suplementos Nutricionais , Feminino , Expressão Gênica , Glucocorticoides/sangue , Metilação , Especificidade de Órgãos , Hipófise/metabolismo , Gravidez , RNA Nucleolar Pequeno/genética , Ratos , Receptores de Glucocorticoides/metabolismo
6.
Cells ; 10(9)2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34571982

RESUMO

Programmed cell death protein 1 (PD-1) and its ligands, PD-L1/2, control T cell activation and tolerance. While PD-1 expression is induced upon T cell receptor (TCR) activation or cytokine signaling, PD-L1 is expressed on B cells, antigen presenting cells, and on non-immune tissues, including cancer cells. Importantly, PD-L1 binding inhibits T cell activation. Therefore, the modulation of PD-1/PD-L1 expression on immune cells, both circulating or in a tumor microenvironment and/or on the tumor cell surface, is one mechanism of cancer immune evasion. Therapies that target PD-1/PD-L1, blocking the T cell-cancer cell interaction, have been successful in patients with various types of cancer. Glucocorticoids (GCs) are often administered to manage the side effects of chemo- or immuno-therapy, exerting a wide range of immunosuppressive and anti-inflammatory effects. However, GCs may also have tumor-promoting effects, interfering with therapy. In this review, we examine GC signaling and how it intersects with PD-1/PD-L1 pathways, including a discussion on the potential for GC- and PD-1/PD-L1-targeted therapies to "confuse" the immune system, leading to a cancer cell advantage that counteracts anti-cancer immunotherapy. Therefore, combination therapies should be utilized with an awareness of the potential for opposing effects on the immune system.


Assuntos
Glucocorticoides/metabolismo , Sistema Imunitário/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Glucocorticoides/imunologia , Humanos , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia
7.
Am J Physiol Endocrinol Metab ; 321(5): E606-E620, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34541876

RESUMO

Circadian rhythms are central to optimal physiological function, as disruption contributes to the development of several chronic diseases. Alcohol (EtOH) intoxication disrupts circadian rhythms within liver, brain, and intestines, but it is unknown whether alcohol also disrupts components of the core clock in skeletal muscle. Female C57BL/6Hsd mice were randomized to receive either saline (control) or alcohol (EtOH) (5 g/kg) via intraperitoneal injection at the start of the dark cycle [Zeitgeber time (ZT12)], and gastrocnemius was collected every 4 h from control and EtOH-treated mice for the next 48 h following isoflurane anesthetization. In addition, metyrapone was administered before alcohol intoxication in separate mice to determine whether the alcohol-induced increase in serum corticosterone contributed to circadian gene regulation. Finally, synchronized C2C12 myotubes were treated with alcohol (100 mM) to assess the influence of centrally or peripherally mediated effects of alcohol on the muscle clock. Alcohol significantly disrupted mRNA expression of Bmal1, Per1/2, and Cry1/2 in addition to perturbing the circadian pattern of clock-controlled genes, Myod1, Dbp, Tef, and Bhlhe40 (P < 0.05), in muscle. Alcohol increased serum corticosterone levels and glucocorticoid target gene, Redd1, in muscle. Metyrapone prevented the EtOH-mediated increase in serum corticosterone but did not normalize the EtOH-induced change in Per1, Cry1 and Cry2, and Myod1 mRNA expression. Core clock gene expression (Bmal, Per1/2, and Cry1/2) was not changed following 4, 8, or 12 h of alcohol treatment on synchronized C2C12 myotubes. Therefore, binge alcohol disrupted genes of the core molecular clock independently of elevated serum corticosterone or direct effects of EtOH on the muscle.NEW & NOTEWORTHY Alcohol is a myotoxin that impairs skeletal muscle metabolism and function following either chronic consumption or acute binge drinking; however, mechanisms underlying alcohol-related myotoxicity have not been fully elucidated. Herein, we demonstrate that alcohol acutely interrupts oscillation of skeletal muscle core clock genes, and this is neither a direct effect of ethanol on the skeletal muscle, nor an effect of elevated serum corticosterone, a major clock regulator.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Ritmo Circadiano/efeitos dos fármacos , Glucocorticoides/metabolismo , Músculo Esquelético/metabolismo , Intoxicação Alcoólica/sangue , Animais , Ritmo Circadiano/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Metirapona/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
8.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360746

RESUMO

Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies.


Assuntos
Resistência à Doença , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipóxia Encefálica/metabolismo , Precondicionamento Isquêmico , Sistema Hipófise-Suprarrenal/metabolismo , Transdução de Sinais , Animais , Humanos , Sistema Hipotálamo-Hipofisário/patologia , Hipóxia Encefálica/prevenção & controle , Sistema Hipófise-Suprarrenal/patologia
9.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445209

RESUMO

Glucocorticoids (GCs) are hormones that aid the body under stress by regulating glucose and free fatty acids. GCs maintain energy homeostasis in multiple tissues, including those in the liver and skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). WAT stores energy as triglycerides, while BAT uses fatty acids for heat generation. The multiple genomic and non-genomic pathways in GC signaling vary with exposure duration, location (adipose tissue depot), and species. Genomic effects occur directly through the cytosolic GC receptor (GR), regulating the expression of proteins related to lipid metabolism, such as ATGL and HSL. Non-genomic effects act through mechanisms often independent of the cytosolic GR and happen shortly after GC exposure. Studying the effects of GCs on adipose tissue breakdown and generation (lipolysis and adipogenesis) leads to insights for treatment of adipose-related diseases, such as obesity, coronary disease, and cancer, but has led to controversy among researchers, largely due to the complexity of the process. This paper reviews the recent literature on the genomic and non-genomic effects of GCs on WAT and BAT lipolysis and proposes research to address the many gaps in knowledge related to GC activity and its effects on disease.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Genômica , Glucocorticoides , Lipogênese , Lipólise , Animais , Glucocorticoides/genética , Glucocorticoides/metabolismo , Humanos
10.
Nat Commun ; 12(1): 5068, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417460

RESUMO

p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.


Assuntos
Acetilglucosamina/metabolismo , Glucose/metabolismo , Fígado/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Sequência de Bases , Restrição Calórica , Linhagem Celular , Colforsina/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Epinefrina/metabolismo , Glucagon/metabolismo , Glucocorticoides/metabolismo , Gluconeogênese/efeitos dos fármacos , Glicosilação , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hidrocortisona/metabolismo , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/complicações , Obesidade/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Ácido Pirúvico/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética
11.
J Med Chem ; 64(16): 11958-11971, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34378927

RESUMO

Glucocorticoids (GCs) are widely used to treat a variety of autoimmune and inflammatory diseases; however, systemic delivery of GCs is associated with side effects that affect essentially every organ system, reflecting the nearly ubiquitous expression of the glucocorticoid receptor (GR). Targeted delivery of GCs to diseased tissues using antibody-glucocorticoid conjugates (GC-ADCs) offers a therapeutic alternative to overcome these adverse effects. Herein, we describe novel classes of GCs that exhibited greater potency than dexamethasone and budesonide, a 100-fold selectivity toward the GR over other nuclear receptors, and no in vitro safety liability in pharmacology assays (hERG, AMES) and that demonstrated a substantial reduction in tumor necrosis factor-α (TNF-α) release in mice challenged with lipopolysaccharide (LPS). The site-specific conjugated GC-ADCs via cathepsin-cleavable linkers were highly stable in plasma and specifically released GCs in antigen-positive cells, suggesting that these novel GCs can serve as ADC payloads to treat autoimmune and inflammatory diseases.


Assuntos
Budesonida/análogos & derivados , Budesonida/uso terapêutico , Glucocorticoides/uso terapêutico , Imunoconjugados/uso terapêutico , Inflamação/tratamento farmacológico , Animais , Budesonida/metabolismo , Budesonida/farmacocinética , Catepsina B/metabolismo , Glucocorticoides/síntese química , Glucocorticoides/metabolismo , Glucocorticoides/farmacocinética , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Imunoconjugados/metabolismo , Inflamação/induzido quimicamente , Inflamação/imunologia , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores de Glucocorticoides/metabolismo , Receptores da Prolactina/imunologia , Relação Estrutura-Atividade
12.
BMC Pregnancy Childbirth ; 21(1): 490, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233642

RESUMO

BACKGROUND: It was reported that steroid-related gene expressions in the adipose tissue (AT) of women differ between women affected with polycystic ovary syndrome (PCOS) and non-PCOS. Although association between PCOS in mother and offspring's health is a crucial issue, there are few studies focusing on AT of pregnant women suffering from PCOS. Our objectives were to determine the differences between mRNA expression levels of key steroid-converting enzymes in abdominal subcutaneous AT of pregnant women afflicted with PCOS and non-PCOS. METHODS: Twelve pregnant women with PCOS (case) and thirty six non-PCOS pregnant women (control) (1:3 ratio; age- and BMI-matched) undergoing cesarean section were enrolled for the present study. Expressions of fifteen genes related to steriodogenesis in abdominal subcutaneous AT were investigated using quantitative real-time PCR. RESULTS: No significant differences were detected with respect to age, BMI (prior pregnancy and at delivery day), gestational period and parity among pregnant women with PCOS and non-PCOS. Most of the sex steroid-converting genes except 17ß-Hydroxysteroid dehydrogenases2 (17BHSD2), were highly expressed on the day of delivery in subcutaneous AT. Women with PCOS showed significantly higher mRNA levels of steroidgenic acute regulator (STAR; P < 0.001), cytochrome P450 monooxygenase (CYP11A1; P < 0.05), 17α-hydroxylase (CYP17A1; P < 0.05), and 11ß-Hydroxysteroid dehydrogenase (11BHSD1 and 11BHSD2; P < 0.05). The expression of steroid 21-hydroxylase (CYP21) in non-PCOS was fourfold higher than those of women with PCOS (P < 0.001). There were no significant differences between relative expression of aromatase cytochrome P450 (CYP19A1), 3ß-hydroxysteroid dehydrogenase (3BHSD1 and 3BHSD2), and 17BHSD family (1, 3, 5, 7, and 12) between the two groups. CONCLUSION: The expression levels of genes related to sex steroids metabolism were similar to age-matched and BMI- matched pregnant non-PCOS and pregnant women with PCOS at delivery day. However, the alterations in gene expressions involved in glucocorticoids and mineralocorticoids metabolism were shown. It is necessary to point out that further studies regarding functional activity are required. More attention should be given to AT of pregnant women with PCOS that was previously ignored.


Assuntos
Hormônios Esteroides Gonadais/metabolismo , Hidroxiesteroide Desidrogenases/metabolismo , Síndrome do Ovário Policístico/genética , Esteroide Hidroxilases/metabolismo , Gordura Subcutânea Abdominal/metabolismo , Adulto , Estudos de Casos e Controles , Cesárea , Feminino , Expressão Gênica/genética , Glucocorticoides/metabolismo , Humanos , Mineralocorticoides/metabolismo , Fosfoproteínas/metabolismo , Gravidez , RNA Mensageiro/metabolismo
13.
Am J Physiol Regul Integr Comp Physiol ; 321(3): R413-R428, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34260302

RESUMO

Elephant seals experience natural periods of prolonged food deprivation while breeding, molting, and undergoing postnatal development. Prolonged food deprivation in elephant seals increases circulating glucocorticoids without inducing muscle atrophy, but the cellular mechanisms that allow elephant seals to cope with such conditions remain elusive. We generated a cellular model and conducted transcriptomic, metabolic, and morphological analyses to study how seal cells adapt to sustained glucocorticoid exposure. Seal muscle progenitor cells differentiate into contractile myotubes with a distinctive morphology, gene expression profile, and metabolic phenotype. Exposure to dexamethasone at three ascending concentrations for 48 h modulated the expression of six clusters of genes related to structural constituents of muscle and pathways associated with energy metabolism and cell survival. Knockdown of the glucocorticoid receptor (GR) and downstream expression analyses corroborated that GR mediates the observed effects. Dexamethasone also decreased cellular respiration, shifted the metabolic phenotype toward glycolysis, and induced mitochondrial fission and dissociation of mitochondria-endoplasmic reticulum (ER) interactions without decreasing cell viability. Knockdown of DNA damage-inducible transcript 4 (DDIT4), a GR target involved in the dissociation of mitochondria-ER membranes, recovered respiration and modulated antioxidant gene expression in myotubes treated with dexamethasone. These results show that adaptation to sustained glucocorticoid exposure in elephant seal myotubes involves a metabolic shift toward glycolysis, which is supported by alterations in mitochondrial morphology and a reduction in mitochondria-ER interactions, resulting in decreased respiration without compromising cell survival.


Assuntos
Metabolismo Energético/fisiologia , Glucocorticoides/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Adaptação Fisiológica , Animais , Antioxidantes/metabolismo , Jejum/metabolismo , Privação de Alimentos/fisiologia , Fenótipo , Receptores de Glucocorticoides/genética , Focas Verdadeiras/metabolismo , Transcriptoma/fisiologia
14.
Nature ; 595(7867): 409-414, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34194038

RESUMO

Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence1,2. The gut microbiota contribute to social activity in mice3,4, but the gut-brain connections that regulate this complex behaviour and its underlying neural basis are unclear5,6. Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical stress responses and social behaviours. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activation of the hypothalamus-pituitary-adrenal (HPA) axis. Adrenalectomy, antagonism of glucocorticoid receptors, or pharmacological inhibition of corticosterone synthesis effectively corrects social deficits following microbiome depletion. Genetic ablation of glucocorticoid receptors in specific brain regions or chemogenetic inactivation of neurons in the paraventricular nucleus of the hypothalamus that produce corticotrophin-releasing hormone (CRH) reverse social impairments in antibiotic-treated mice. Conversely, specific activation of CRH-expressing neurons in the paraventricular nucleus induces social deficits in mice with a normal microbiome. Via microbiome profiling and in vivo selection, we identify a bacterial species, Enterococcus faecalis, that promotes social activity and reduces corticosterone levels in mice following social stress. These studies suggest that specific gut bacteria can restrain the activation of the HPA axis, and show that the microbiome can affect social behaviours through discrete neuronal circuits that mediate stress responses in the brain.


Assuntos
Encéfalo/citologia , Encéfalo/fisiologia , Microbioma Gastrointestinal/fisiologia , Neurônios/metabolismo , Comportamento Social , Estresse Psicológico , Animais , Corticosterona/sangue , Hormônio Liberador da Corticotropina/metabolismo , Enterococcus faecalis/metabolismo , Vida Livre de Germes , Glucocorticoides/metabolismo , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais
15.
Biochemistry (Mosc) ; 86(6): 641-656, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225588

RESUMO

The review discusses molecular and cellular mechanisms common to the temporal lobe epileptogenesis/epilepsy and depressive disorders. Comorbid temporal lobe epilepsy and depression are associated with dysfunction of the hypothalamic-pituitary-adrenocortical axis. Excessive glucocorticoids disrupt the function and impair the structure of the hippocampus, a brain region key to learning, memory, and emotions. Selective vulnerability of the hippocampus to stress, mediated by the reception of glucocorticoid hormones secreted during stress, is the price of the high functional plasticity and pleiotropy of this limbic structure. Common molecular and cellular mechanisms include the dysfunction of glucocorticoid receptors, neurotransmitters, and neurotrophic factors, development of neuroinflammation, leading to neurodegeneration and loss of hippocampal neurons, as well as disturbances in neurogenesis in the subgranular neurogenic niche and formation of aberrant neural networks. These glucocorticoid-dependent processes underlie altered stress response and the development of chronic stress-induced comorbid pathologies, in particular, temporal lobe epilepsy and depressive disorders.


Assuntos
Transtorno Depressivo/metabolismo , Epilepsia/metabolismo , Glucocorticoides/metabolismo , Hipocampo/metabolismo , Estresse Psicológico , Animais , Transtorno Depressivo/fisiopatologia , Emoções , Epilepsia/complicações , Epilepsia/fisiopatologia , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/fisiopatologia , Glucocorticoides/fisiologia , Hipocampo/fisiopatologia , Humanos , Inflamação , Aprendizagem , Memória
16.
Biochemistry (Mosc) ; 86(6): 729-736, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225595

RESUMO

Comparative analysis of available literature data on the pathogenetic neuroendocrine mechanisms of depression and post-traumatic stress disorder (PTSD) is provided in this review to identify their common features and differences. We discuss the multidirectional modifications of the activity of cortical and subcortical structures of the brain, levels of neurotransmitters and their receptors, and functions of the hypothalamic-pituitary-adrenocortical axis in depression and PTSD. The analysis shows that these disorders are examples of opposite failures in the system of adaptive stress response of the body to stressful psychotraumatic events. On this basis, it is concluded that the currently widespread use of similar approaches to treat these disorders is not justified, despite the significant similarity of their anxiety-depressive symptoms; development of differential therapeutic strategies is required.


Assuntos
Encéfalo/metabolismo , Transtorno Depressivo Maior/metabolismo , Glucocorticoides/metabolismo , Neurotransmissores/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtorno Depressivo Maior/etiologia , Humanos , Transtornos de Estresse Pós-Traumáticos/etiologia , Estresse Psicológico
17.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203717

RESUMO

It is well understood that sex differences exist between females and males even before they are born. These sex-dependent differences may contribute to altered growth and developmental outcomes for the fetus. Based on our initial observations in the human placenta, we hypothesised that the male prioritises growth pathways in order to maximise growth through to adulthood, thereby ensuring the greatest chance of reproductive success. However, this male-specific "evolutionary advantage" likely contributes to males being less adaptable to shifts in the in-utero environment, which then places them at a greater risk for intrauterine morbidities or mortality. Comparatively, females are more adaptable to changes in the in-utero environment at the cost of growth, which may reduce their risk of poor perinatal outcomes. The mechanisms that drive these sex-specific adaptations to a change in the in-utero environment remain unclear, but an increasing body of evidence within the field of developmental biology would suggest that alterations to placental function, as well as the feto-placental hormonal milieu, is an important contributing factor. Herein, we have addressed the current knowledge regarding sex-specific intrauterine growth differences and have examined how certain pregnancy complications may alter these female- and male-specific adaptations.


Assuntos
Desenvolvimento Embrionário , Desenvolvimento Fetal/fisiologia , Placenta/fisiologia , Caracteres Sexuais , Androgênios/metabolismo , Animais , Feminino , Glucocorticoides/metabolismo , Humanos , Masculino , Gravidez
18.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201279

RESUMO

Epigenetics is one of the mechanisms by which environmental factors can alter brain function and may contribute to central nervous system disorders. Alterations of DNA methylation and miRNA expression can induce long-lasting changes in neurobiological processes. Hence, we investigated the effect of chronic stress, by employing the chronic mild stress (CMS) and the chronic restraint stress protocol, in adult male rats, on the glucocorticoid receptor (GR) function. We focused on DNA methylation specifically in the proximity of the glucocorticoid responsive element (GRE) of the GR responsive genes Gadd45ß, Sgk1, and Gilz and on selected miRNA targeting these genes. Moreover, we assessed the role of the antipsychotic lurasidone in modulating these alterations. Chronic stress downregulated Gadd45ß and Gilz gene expression and lurasidone normalized the Gadd45ß modification. At the epigenetic level, CMS induced hypermethylation of the GRE of Gadd45ß gene, an effect prevented by lurasidone treatment. These stress-induced alterations were still present even after a period of rest from stress, indicating the enduring nature of such changes. However, the contribution of miRNA to the alterations in gene expression was moderate in our experimental conditions. Our results demonstrated that chronic stress mainly affects Gadd45ß expression and methylation, effects that are prolonged over time, suggesting that stress leads to changes in DNA methylation that last also after the cessation of stress procedure, and that lurasidone is a modifier of such mechanisms.


Assuntos
Epigênese Genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/metabolismo , Cloridrato de Lurasidona/farmacologia , Córtex Pré-Frontal/metabolismo , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico , Animais , Antipsicóticos/farmacologia , Modelos Animais de Doenças , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , RNA Mensageiro , Ratos , Ratos Wistar , Receptores de Glucocorticoides/genética
19.
Int J Mol Sci ; 22(13)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34281257

RESUMO

The modern lifestyle brings both excessive fructose consumption and daily exposure to stress which could lead to metabolic disturbances and type 2 diabetes. Muscles are important points of glucose and lipid metabolism, with a crucial role in the maintenance of systemic energy homeostasis. We investigated whether 9-week fructose-enriched diet, with and without exposure to 4-week unpredictable stress, disturbs insulin signaling in the skeletal muscle of male rats and evaluated potential contributory roles of muscle lipid metabolism, glucocorticoid signaling and inflammation. The combination of fructose-enriched diet and stress increased peroxisome proliferator-activated receptors-α and -δ and stimulated lipid uptake, lipolysis and ß-oxidation in the muscle of fructose-fed stressed rats. Combination of treatment also decreased systemic insulin sensitivity judged by lower R-QUICKI, and lowered muscle protein content and stimulatory phosphorylations of insulin receptor supstrate-1 and Akt, as well as the level of 11ß-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor. At the same time, increased levels of protein tyrosine phosphatase-1B, nuclear factor-κB, tumor necrosis factor-α, were observed in the muscle of fructose-fed stressed rats. Based on these results, we propose that decreased glucocorticoid signaling in the skeletal muscle can make a setting for lipid-induced inflammation and the development of insulin resistance in fructose-fed stressed rats.


Assuntos
Frutose/administração & dosagem , Glucocorticoides/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos , Músculo Esquelético/metabolismo , Estresse Fisiológico/fisiologia , Animais , Frutose/efeitos adversos , Humanos , Inflamação/etiologia , Resistência à Insulina/fisiologia , Masculino , Modelos Biológicos , Ratos , Ratos Wistar , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais
20.
Nat Commun ; 12(1): 4398, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285226

RESUMO

Studies in rodents and captive primates suggest that the early-life social environment affects future phenotype, potentially through alterations to DNA methylation. Little is known of these associations in wild animals. In a wild population of spotted hyenas, we test the hypothesis that maternal care during the first year of life and social connectedness during two periods of early development leads to differences in DNA methylation and fecal glucocorticoid metabolites (fGCMs) later in life. Here we report that although maternal care and social connectedness during the den-dependent life stage are not associated with fGCMs, greater social connectedness during the subadult den-independent life stage is associated with lower adult fGCMs. Additionally, more maternal care and social connectedness after den independence correspond with higher global (%CCGG) DNA methylation. We also note differential DNA methylation near 5 genes involved in inflammation, immune response, and aging that may link maternal care with stress phenotype.


Assuntos
Epigênese Genética/fisiologia , Hyaenidae/psicologia , Comportamento Materno/fisiologia , Meio Social , Estresse Psicológico/diagnóstico , Envelhecimento/genética , Envelhecimento/psicologia , Animais , Metilação de DNA/fisiologia , Fezes/química , Feminino , Glucocorticoides/análise , Glucocorticoides/metabolismo , Hyaenidae/genética , Hyaenidae/crescimento & desenvolvimento , Masculino , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia
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