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1.
Exp Suppl ; 111: 85-102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588529

RESUMO

Primary generalized glucocorticoid resistance or Chrousos syndrome is a rare disorder, which affects all tissues expressing the human glucocorticoid receptor. It is characterized by generalized, partial tissue insensitivity to glucocorticoids caused by genetic defects in the NR3C1 gene. We and others have applied standard methods of molecular and structural biology to investigate the molecular mechanisms and conformational alterations through which the mutant glucocorticoid receptors lead to the broad spectrum of clinical manifestations of Chrousos syndrome. The ever-increasing application of novel technologies, including the next-generation sequencing, will enhance our knowledge in factors that influence the glucocorticoid signal transduction in a positive or negative fashion.


Assuntos
Erros Inatos do Metabolismo/genética , Receptores de Glucocorticoides/deficiência , Glucocorticoides , Humanos , Receptores de Glucocorticoides/genética , Transdução de Sinais
2.
J Agric Food Chem ; 67(39): 10871-10879, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31517482

RESUMO

This study evaluated the effect of triterpenoids from edible mushroom Poria cocos on intestinal epithelium integrity and revealed the transcriptional regulatory pathways that underpin restorative mechanisms in the gut. Based on computational docking studies, transcriptional activation experiments and glucocorticoid receptor (GR) protein immunofluorescence localization assays in cultured cells, 16α-hydroxytrametenolic acid (HTA) was discovered as a novel GR agonist in this study. HTA ameliorates TNF-α-induced Caco-2 monolayer intestinal epithelial barrier damage and suppressed activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt), which attenuated downstream IκB and nuclear factor kappa-B (NF-κB) phosphorylation through GR activation. Moreover, HTA prevented NF-κB translocation into the nucleus and binding to its cis-element and suppressed lipopolysaccharide-induced downstream NO production and pro-inflammatory cytokines at both protein and mRNA expression levels. In conclusion, HTA from P. cocos improves intestinal barrier function through a GR-mediated PI3K/Akt/NF-κB signaling pathway and may be potentially exploited as a supportive dietary therapeutic strategy for restoring gut health.


Assuntos
Mucosa Intestinal/efeitos dos fármacos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Glucocorticoides/metabolismo , Triterpenos/farmacologia , Wolfiporia/química , Células CACO-2 , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Mucosa Intestinal/metabolismo , Simulação de Acoplamento Molecular , NF-kappa B/genética , Fosfatidilinositol 3-Quinase/genética , Fosforilação , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Glucocorticoides/genética , Transdução de Sinais/efeitos dos fármacos , Triterpenos/química , Verduras/química
3.
Toxicol Lett ; 314: 63-74, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306741

RESUMO

This study aimed to verify the toxic effects of prenatal caffeine exposure (PCE) on the podocyte development in male offspring, and to explore the underlying intrauterine programming mechanisms. The pregnant rats were administered with caffeine (30 to 120 mg/kg⋅d) during gestational day (GD) 9 to 20. The male fetus on GD20 and the offspring at postnatal week (PW) 6 and PW28 were sacrificed. The results indicated that PCE caused ultrastructural abnormalities on podocyte, and inhibited the expression of podocyte marker genes such as Nephrin, Wilms tumor 1 (WT1), the histone 3 lysine 9 acetylation (H3K9ac) level in the Kruppel-like factor 4 (KLF4) promoter and its expression in the male offspring from GD20 to PW28. Meanwhile, the expression of glucocorticoid receptor (GR) and histone deacetylase 7 (HDAC7) in the fetus were increased by PCE. In vitro, corticosterone increased GR and HDAC7 whereas reduced the H3K9ac level of KLF4 and KLF4/Nephrin expression. KLF4 over-expression reversed the reduction of Nephrin expression, knockdown of HDAC7 and GR antagonist RU486 partially reversed the inhibitory effects of corticosterone on H3K9ac level and KLF4 expression. In conclusion, PCE caused podocyte developmental toxicity in male offspring, which was associated with corticosterone-induced low-functional programming of KLF4 through GR/HDAC7/H3K9ac pathway.


Assuntos
Cafeína/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Histonas/metabolismo , Nefropatias/induzido quimicamente , Fatores de Transcrição Kruppel-Like/metabolismo , Podócitos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Acetilação , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Idade Gestacional , Glucocorticoides/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Nefropatias/embriologia , Nefropatias/genética , Nefropatias/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Lisina , Masculino , Exposição Materna , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fenótipo , Podócitos/metabolismo , Podócitos/ultraestrutura , Gravidez , Regiões Promotoras Genéticas , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
BMC Plant Biol ; 19(1): 314, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307397

RESUMO

BACKGROUND: LEAFY COTYLEDON 2 (LEC2) acts throughout embryo morphogenesis and maturation phase to maintain embryogenic identity. Our previous study stated that Arabidopsis thaliana LEC2 (AtLEC2) driven by glucocorticoid receptor-dexamethasone (GR-DEX) inducible system (AtLEC2-GR) triggers embryogenic callus formation in tobacco (Nicotiana tabacum). RESULTS: In this study, the adenosine phosphate isopentenyltransferase genes AtIPT3, AtIPT7 and the tRNA isopentenyltransferase gene AtIPT9 were overexpressed in the AtLEC2-GR transgenic background. In the AtIPT7-OE AtLEC2-GR and AtIPT9-OE AtLEC2-GR seedlings, high-quality embryogenic callus was obtained under the DEX condition, and the shoot regeneration efficiency was 2 to 3.5 folds higher than AtLEC2-GR alone on hormone free medium without DEX. Transcriptome analyses showed that up-regulated BBM, L1L, ABI3, and FUS3 might function during embryogenic callus formation. However, at the shoot regeneration stage, BBM, L1L, ABI3, and FUS3 were down-regulated and Type-B ARRs were up-regulated, which might contribute to the increased shoot regeneration rate. CONCLUSIONS: A novel system for inducing shoot regeneration in tobacco has been developed using the GR-DEX system. Induced expression of AtLEC2 triggers embryogenic callus formation and overexpression of AtIPT7 or AtIPT9 improves shoot regeneration without exogenous cytokinin.


Assuntos
Alquil e Aril Transferases/genética , Proteínas de Arabidopsis/genética , Arabidopsis/genética , Brotos de Planta/crescimento & desenvolvimento , Técnicas de Embriogênese Somática de Plantas , Tabaco/genética , Fatores de Transcrição/genética , Dexametasona/farmacologia , Plantas Geneticamente Modificadas , Receptores de Glucocorticoides/genética , Sementes , Tabaco/embriologia , Tabaco/crescimento & desenvolvimento
5.
Invest Ophthalmol Vis Sci ; 60(6): 1967-1978, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31050723

RESUMO

Purpose: Glucocorticoid (GC)-induced ocular hypertension (GC-OHT) is a serious side effect of prolonged GC therapy that can lead to glaucoma and permanent vision loss. GCs cause a plethora of changes in the trabecular meshwork (TM), an ocular tissue that regulates intraocular pressure (IOP). GCs act through the glucocorticoid receptor (GR), and the GR regulates transcription both through transactivation and transrepression. Many of the anti-inflammatory properties of GCs are mediated by GR transrepression, while GR transactivation largely accounts for GC metabolic effects and side effects of GC therapy. There is no evidence showing which of the two mechanisms plays a role in GC-OHT. Methods: GRdim transgenic mice (which have active transrepression and impaired transactivation) and wild-type (WT) C57BL/6J mice received weekly periocular dexamethasone acetate (DEX-Ac) injections. IOP, outflow facilities, and biochemical changes to the TM were determined. Results: GRdim mice did not develop GC-OHT after continued DEX treatment, while WT mice had significantly increased IOP and decreased outflow facilities. Both TM tissue in eyes of DEX-treated GRdim mice and cultured TM cells isolated from GRdim mice had reduced or no change in the expression of fibronectin, myocilin, collagen type I, and α-smooth muscle actin (α-SMA). GRdim mouse TM (MTM) cells also had a significant reduction in DEX-induced cytoskeletal changes, which was clearly seen in WT MTM cells. Conclusions: We provide the first evidence for the role of GR transactivation in regulating GC-mediated gene expression in the TM and in the development of GC-OHT. This discovery suggests a novel therapeutic approach for treating ocular inflammation without causing GC-OHT and glaucoma.


Assuntos
Regulação da Expressão Gênica , Glaucoma/genética , Glucocorticoides/efeitos adversos , Hipertensão Ocular/genética , RNA/genética , Receptores de Glucocorticoides/genética , Animais , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Feminino , Glaucoma/induzido quimicamente , Glaucoma/metabolismo , Imuno-Histoquímica , Pressão Intraocular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Hipertensão Ocular/induzido quimicamente , Hipertensão Ocular/metabolismo , Receptores de Glucocorticoides/biossíntese , Ativação Transcricional
6.
Int J Mol Sci ; 20(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022961

RESUMO

Background: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and manageable lung disease characterized by large heterogeneity in disease presentation and grades impairment. Inhaled corticosteroids (ICS) are commonly used to manage COPD/COPD-exacerbation. The patient's response is characterized by interindividual variability without disease progression/survival modification. Objectives: We hypothesize that a therapeutic intervention may be more effective if single nucleotide polymorphisms (SNPs) are investigated. Methods: In 71 COPD patients under pulmonary rehabilitation, a small number of powerful SNPs, selected according to current literature, were analyzed; namely the glucocorticoid receptor gene NR3C1 (rs6190/rs6189/rs41423247), the glucocorticoid-induced transcript 1 gene (GLCCI1 rs37972), and the related co-chaperone FKBP5 gene (rs4713916). MDR1 rs2032582 was also evaluated. Lung function outcomes were assessed. Results: A significant association with functional outcomes, namely FEV1 (forced expiration volume/one second) and 6MWD (six-minutes walking distance), was found for rs4713916 and weakly for rs37972. The genotype rs4713916(GA) and, in a lesser extent, the genotype rs37972(TT), were more favorable than the wild-type. Conclusions: Our study supports a possible picture of pharmacogenomic control for COPD intervention. rs4713916 and, possibly, rs37972 may be useful predictors of clinical outcome. These results may help to tailor an optimal dose for individual COPD patients based on their genetic makeup.


Assuntos
Corticosteroides/uso terapêutico , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Proteínas de Ligação a Tacrolimo/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Administração por Inalação , Corticosteroides/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Glucocorticoides/genética , Resultado do Tratamento
7.
Molecules ; 24(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018484

RESUMO

Cutaneous wound healing is a well-orchestrated event in which many types of cells and growth factors are involved in restoring the barrier function of skin. In order to identify whether ginsenosides, the main active components of Panax ginseng, promote wound healing, the proliferation and migration activities of 15 different ginsenosides were tested by MTT assay and scratched wound closure assay. Among ginsenosides, gypenoside LXXV (G75) showed the most potent wound healing effects. Thus, this study aimed to investigate the effects of G75 on wound healing in vivo and characterize associated molecular changes. G75 significantly increased proliferation and migration of keratinocytes and fibroblasts, and promoted wound closure in an excision wound mouse model compared with madecassoside (MA), which has been used to treat wounds. Additionally, RNA sequencing data revealed G75-mediated significant upregulation of connective tissue growth factor (CTGF), which is known to be produced via the glucocorticoid receptor (GR) pathway. Consistently, the increase in production of CTGF was confirmed by western blot and ELISA. In addition, GR-competitive binding assay and GR translocation assay results demonstrated that G75 can be bound to GR and translocated into the nucleus. These results demonstrated that G75 is a newly identified effective component in wound healing.


Assuntos
Anti-Inflamatórios/farmacologia , Fator de Crescimento do Tecido Conjuntivo/genética , Fármacos Dermatológicos/farmacologia , Receptores de Glucocorticoides/genética , Ferida Cirúrgica/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fármacos Dermatológicos/química , Fármacos Dermatológicos/isolamento & purificação , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Ginsenosídeos/química , Ginsenosídeos/isolamento & purificação , Ginsenosídeos/farmacologia , Gynostemma/química , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Panax/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Transporte Proteico , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/lesões , Pele/metabolismo , Ferida Cirúrgica/genética , Ferida Cirúrgica/metabolismo , Ferida Cirúrgica/patologia , Cicatrização/fisiologia
8.
Hum Nat ; 30(2): 192-216, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30941597

RESUMO

Examining the costs and motivations of warfare is key to conundrums concerning the relevance of this troubling phenomenon to the evolution of social attachment and cooperation, particularly during adolescence and young adulthood-the developmental time period during which many participants are first recruited for warfare. The study focuses on Samburu, a pastoralist society of approximately 200,000 people occupying northern Kenya's semi-arid and arid lands, asking what role the emotionally sensitized, peer-driven adolescent life stage may have played in the cultural and genetic coevolution of coalitional lethal aggression. Research in small-scale societies provides unparalleled opportunities for sharply defined variables, particularly in age generation societies in which all young men are initiated into "warriorhood." Proposing an epigenetic and component behavior approach, we examine whether raiding activities such as number of raids, killing, and sparing enemy lives associate with DNA methylation in two candidate genes: MAOA, linked to mood and arousal, and NR3C1, linked to stress and immune response. We report statistically significant associations between the epigenetic variables and the combat (exposure) variables of overall raiding activity and reportedly showing mercy to enemies. In contrast, epigenetic variables did not associate with post-traumatic stress disorder (PTSD) symptom scores (a potential outcome measure), and the only combat variable associated with PTSD (but not DNA methylation) was losing one's own livestock in a raid. These findings raise important questions concerning the mechanisms driving warfare's paradoxical mix of violent and altruistic behaviors.


Assuntos
Comportamento do Adolescente/etnologia , Altruísmo , Metilação de DNA/genética , Epigênese Genética/genética , Violência/etnologia , Guerra/etnologia , Adolescente , Homicídio/etnologia , Humanos , Quênia/etnologia , Masculino , Monoaminoxidase/genética , Receptores de Glucocorticoides/genética , Transtornos de Estresse Pós-Traumáticos/etnologia , Transtornos de Estresse Pós-Traumáticos/genética
9.
J Physiol Anthropol ; 38(1): 4, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999951

RESUMO

BACKGROUND: High-altitude pulmonary edema (HAPE) is a life-threatening form of non-cardiogenic edema which occurs in unacclimatized individuals after rapid ascent to high altitude. NR3C1 gene encodes for glucocorticoid receptor (GR) which plays an important role in stress and inflammation. This study aimed to investigate the association of NR3C1 polymorphisms with the susceptibility to HAPE in Han Chinese. METHODS: The 30 SNPs in the NR3C1 gene were genotyped by the Sequenom MassARRAY SNP assay in 133 HAPE patients (HAPE-p) and 135 matched Han Chinese resistant to HAPE (HAPE-r). The genotypic and allele frequencies, odds ratios (ORs), and 95% confidence intervals (95% CIs) were calculated, respectively. RESULTS: The 12 SNPs showed a significant difference between the HAPE-p and HAPE-r groups. In allelic model analysis, we found that the allele "A" of rs17287745, rs17209237, rs17209251, rs6877893, and rs1866388; the allele "C" of rs6191, rs6188, and rs2918417; the allele "T" of rs33388 and rs4634384; and the allele "G" of rs41423247 and rs10052957 were associated with increased the risk of HAPE. In the genetic model analysis, we found that rs17287745, rs6191, rs6188, rs33388, rs2918417, rs6877893, rs1866388, rs41423247, rs4634384, and rs10052957 were relevant to the increased HAPE risk under the dominant model. In addition, the haplotype AACACTCAAGTG of the 12 SNPs was detected to be significantly associated with HAPE risk (OR = 2.044, 95%CI = 1.339~3.120, P = 0.0008), while the haplotype GGAGCACGACCG was associated with the decreased risk of HAPE (OR = 0.573, 95% CI = 0.333~0.985, P = 0.0422). CONCLUSIONS: Our findings provide new evidence for the association between SNPs in NR3C1 and an increased risk of HAPE in the Chinese population. NR3C1 polymorphisms are associated with the susceptibility to HAPE in Han Chinese.


Assuntos
Doença da Altitude/epidemiologia , Doença da Altitude/genética , Grupo com Ancestrais do Continente Asiático/genética , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/genética , Receptores de Glucocorticoides/genética , Adulto , Altitude , China , Predisposição Genética para Doença/genética , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade
10.
Yakugaku Zasshi ; 139(4): 647-650, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30930401

RESUMO

The effectiveness of steroid rotation from dexamethasone to prednisolone for hiccups caused by dexamethasone for antiemetic chemotherapy has been reported overseas, but has not been reported in Japan. The effectiveness of steroid rotation in Japanese individuals is unclear because ethnic differences and variations in glucocorticoid receptors affect sensitivity to dexamethasone. We report a case of the effectiveness of steroid rotation in a Japanese patient with hiccups caused by dexamethasone for antiemetic chemotherapy. A 74-year-old man was diagnosed as having stage IV gastric cancer. Chemotherapy was initiated using S-1 (80 mg/d on Days 1-21) and cisplatin (80 mg on Day 8), with dexamethasone (8 mg/d on Day 8 intravenously and on Days 9-11 orally) as antiemetic. Severe hiccups developed on Day 10 and resolved on Day 11 by the 1st cycle of chemotherapy. Subcutaneous injection of atropine by the 5th cycle and ingestion of Syakuyakukanzouto (Glycyrrhiza extract) by the 6th cycle did not effectively relieve the hiccups. By the 7th cycle, the hiccups resolved after the dose of dexamethasone was decreased from 8 mg/d to 4 mg/d but recurred by the 8th cycle. We then changed to prednisolone 30 mg/d from dexamethasone 4 mg/d by the 9th cycle; the hiccups completely resolved thereafter. Steroid rotation from dexamethasone to prednisolone completely controlled the hiccups, with no further recurrence. No emetic episodes occurred during chemotherapy. Therefore, this demonstrates the effectiveness of steroid rotation in a Japanese patient with hiccups caused by dexamethasone for antiemetic chemotherapy.


Assuntos
Antieméticos/efeitos adversos , Dexametasona/efeitos adversos , Soluço/etiologia , Soluço/prevenção & controle , Prednisolona/administração & dosagem , Idoso , Antieméticos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Cisplatino/administração & dosagem , Dexametasona/administração & dosagem , Combinação de Medicamentos , Humanos , Masculino , Ácido Oxônico/administração & dosagem , Receptores de Glucocorticoides/genética , Neoplasias Gástricas/tratamento farmacológico , Tegafur/administração & dosagem
11.
Curr Protoc Plant Biol ; 4(2): e20089, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30860661

RESUMO

Use of chemically inducible systems for transgene expression is a crucial requirement for modern plant biology research, as it allows (1) expression of transgenes that compromise plant viability or fertility when constitutively expressed and (2) spatiotemporal control of transgene expression levels. We describe the stringently regulated and highly responsive dexamethasone-inducible gene expression system pOp6/LhGR, which comprises the chimeric transcription activator LhGR and the corresponding pOp6 promoter. Upon induction, the LhGR activator binds to the pOp6 promoter and induces expression of the target gene of interest. We provide detailed protocols for inducing transgene expression at different developmental stages and in different plant species and discuss dexamethasone stability and use of its analogs. We also introduce new, versatile, GATEWAY-compatible binary vectors that are now available for the pOp6/LhGR system. © 2019 by John Wiley & Sons, Inc.


Assuntos
Arabidopsis/genética , Plantas Geneticamente Modificadas/genética , Ativação Transcricional , Transgenes , Proteínas de Ligação a DNA/genética , Dexametasona/farmacologia , Proteínas de Escherichia coli/genética , Técnicas Genéticas , Repressores Lac/genética , Regiões Promotoras Genéticas , Receptores de Glucocorticoides/genética , Proteínas de Saccharomyces cerevisiae/genética , Fatores de Transcrição/genética , Ativação Transcricional/efeitos dos fármacos
12.
Early Hum Dev ; 131: 63-74, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30870624

RESUMO

BACKGROUND: Every year, an estimated 15 million babies are born preterm (<37 weeks' gestational age [GA]) globally. These preterm infants are exposed to repeated stressful and often painful procedures as part of routine life-saving care within the neonatal intensive care unit (NICU). Preterm birth continues to be a major health issue associated with increased risk of neurodevelopmental and behavioral disorders such as cerebral palsy, cognitive impairment, autism spectrum disorders and psychiatric disease. OBJECTIVE: This paper identifies epigenetic alterations and incidence of telomere erosion that have been studied in preterm infants while in the NICU and as a long-term outcome measure. Better understanding of epigenetic alterations and telomere erosion might aid in early detection and prevention/alleviation of the negative effects of cumulative painful/stressful experiences in this population. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards were used to guide this review. Systematic searches of databases included PubMed, CINAHL, SCOPUS and PsychInfo. RESULTS: Twenty-one studies were included, appraised and then synthesized into a narrative summary. DISCUSSION: Several putative epigenetic markers were identified although there was a paucity of studies related to telomere length. The interaction of disease entity combined with therapeutic interventions intended to treat may inadvertently increase infant allostatic load or ability to adapt to stress. Future research should include not only human studies but leverage newly available large data sets to conduct additional analysis.


Assuntos
Epigênese Genética , Recém-Nascido Prematuro/fisiologia , Telômero/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Humanos , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Fator de Crescimento Insulin-Like II/genética , Unidades de Terapia Intensiva Neonatal , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Inibidor de NF-kappaB alfa/genética , Transtornos do Neurodesenvolvimento/genética , Receptores de Glucocorticoides/genética , Estresse Fisiológico/genética , Proteínas de Ligação a Tacrolimo/genética
13.
Behav Brain Res ; 363: 126-134, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30707907

RESUMO

To explore the associations between stress response genes and attention deficit hyperactivity disorder (ADHD) in children, we conducted a case-control study consisting of 406 newly diagnosed ADHD cases and 432 controls in Wuhan, China. We genotyped the candidate genes, nuclear receptor subfamily 3 group C member 1(NR3C1) and solute carrier family 6 member 4(SLC6A4), using the Sequenom MassARRAY technology. After correction by Bonferroni (α' = 0.05/6 = 0.008), the rs6191 SNP was found to be associated with a reduced risk of ADHD in the dominant model (OR = 0.564, 95% CI = 0.389-0.819, P = 0.003) while the rs25531 SNP was associated with an increased risk of ADHD in the multiplicative model (OR = 1.380, 95% CI = 1.111-1.714, P = 0.004). Additionally, both the rs6191 and rs25531 SNPs were significantly associated with the attention deficit factor (P = 0.006, P = 0.003, respectively) but not with the hyperactivity/impulsivity factor in the Swanson, Nolan and Pelham-IV Questionnaire (SNAP-IV) scale. Furthermore, we found that these two SNPs were significantly associated with pure ADHD, and not affected by the comorbidities (P = 0.001, P = 0.007, respectively). Besides, there was an interaction between these two SNPs. This study demonstrated the role of NR3C1 and SLC6A4 polymorphisms in ADHD, yet independent replication of the findings of this study in multi-center and multi-stage studies with large samples is warranted in the future.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Receptores de Glucocorticoides/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Estudos de Casos e Controles , Criança , China , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Receptores de Glucocorticoides/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estresse Fisiológico/genética
14.
Eur J Med Chem ; 166: 232-242, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30711833

RESUMO

Prostate cancer (PCa) is the most frequently diagnosed male malignant tumor and remains the second leading cause of male cancer mortality in the western countries. The second-generation antiandrogen enzalutamide (ENZa) can prolong survival time for patients with mCRPC. However, the overexpression of glucocorticoids receptor (GR) in mCRPC cells causes the resistance of antiandrogen and leads to the failure of androgen receptor (AR) targeting therapy. Herein, based on the chemical structures of antiandrogen and crystal structure of GR, we set up to develop GR/AR (GR and AR) dual antagonist by virtual screening and biological evaluation. We identified Z19 as a dual AR/GR antagonist. Z19 inhibited the transcription activity of both AR and GR, reducing both protein and mRNA level of the downstream proteins of GR and AR signaling, and provided a potential lead compound for the development of novel treatment agents of prostate cancer. Our work demonstrates that rational drug design is an efficient strategy in development of the GR/AR dual antagonist for the treatment of prostate cancer.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Desenho de Drogas , Receptores Androgênicos/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Antagonistas de Receptores de Andrógenos/metabolismo , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Simulação de Acoplamento Molecular , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Conformação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Androgênicos/química , Receptores Androgênicos/genética , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transcrição Genética/efeitos dos fármacos , Interface Usuário-Computador
15.
RNA ; 25(4): 407-422, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30655309

RESUMO

Nonsense-mediated mRNA decay (NMD), which is arguably the best-characterized translation-dependent regulatory pathway in mammals, selectively degrades mRNAs as a means of post-transcriptional gene control. Control can be for the purpose of ensuring the quality of gene expression. Alternatively, control can facilitate the adaptation of cells to changes in their environment. The key to NMD, no matter what its purpose, is the ATP-dependent RNA helicase upstream frameshift 1 (UPF1), without which NMD fails to occur. However, UPF1 does much more than regulate NMD. As examples, UPF1 is engaged in functionally diverse mRNA decay pathways mediated by a variety of RNA-binding proteins that include staufen, stem-loop-binding protein, glucocorticoid receptor, and regnase 1. Moreover, UPF1 promotes tudor-staphylococcal/micrococcal-like nuclease-mediated microRNA decay. In this review, we first focus on how the NMD machinery recognizes an NMD target and triggers mRNA degradation. Next, we compare and contrast the mechanisms by which UPF1 functions in the decay of other mRNAs and also in microRNA decay. UPF1, as a protein polymath, engenders cells with the ability to shape their transcriptome in response to diverse biological and physiological needs.


Assuntos
Degradação do RNAm Mediada por Códon sem Sentido , RNA Helicases/genética , RNA Mensageiro/genética , Transativadores/genética , Transcriptoma , Animais , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , RNA Helicases/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Ribonucleases/genética , Ribonucleases/metabolismo , Transativadores/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo
16.
Leukemia ; 33(7): 1650-1662, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30696950

RESUMO

Glucocorticoid (GC) receptor (GR) phosphorylation and signature genes were studied in chronic lymphocytic leukemia (CLL) cells to help place GCs within modern treatment algorithms. In contrast to normal B and T cells, transcription of GC-regulated genes was not rhythmic and the synthetic GC dexamethasone (DEX) could not inhibit toll-like receptor (TLR)-responses in CLL cells. This intrinsic GC-resistance was associated with aberrant GR-phosphorylation on activating Ser211 and inhibitory Ser226 sites. Ibrutinib increased transcription of the GR-signature gene GILZ in circulating CLL cells along with GR(pS211)/GR(pS226) ratios and lytic sensitivity to DEX that were not reversed by the competitive antagonist mifepristone in vitro. However, ibrutinib could not improve GR-responses in circulating CLL cells activated with IL2 and TLR7/8 agonists to mimic conditions in pseudofollicle microenvironments. Addition of the janus kinase inhibitor ruxolitinib to block ibrutinib-insensitive signals increased GILZ transcription in pseudofollicle conditions in vitro and in a clinical trial (NCT02912754), and also increased GR(S211)/GR(S226) ratios and DEX-mediated killing in patient samples in vitro. These observations suggest that intrinsic resistance to endogenous GCs is characteristic of CLL cells and ibrutinib may help increase the therapeutic activity of GCs by non-canonical activation of GR.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Glucocorticoides/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Biomarcadores Tumorais/genética , Ritmo Circadiano , Quimioterapia Combinada , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Fosforilação , Receptores de Glucocorticoides/genética , Receptores Toll-Like/metabolismo , Ativação Transcricional , Células Tumorais Cultivadas
17.
Nat Commun ; 10(1): 306, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659202

RESUMO

Glucocorticoids (GCs) are effective drugs, but their clinical use is compromised by severe side effects including hyperglycemia, hyperlipidemia and obesity. They bind to the Glucocorticoid Receptor (GR), which acts as a transcription factor. The activation of metabolic genes by GR is thought to underlie these adverse effects. We identify the bHLH factor E47 as a modulator of GR target genes. Using mouse genetics, we find that E47 is required for the regulation of hepatic glucose and lipid metabolism by GR, and that loss of E47 prevents the development of hyperglycemia and hepatic steatosis in response to GCs. Here we show that E47 and GR co-occupy metabolic promoters and enhancers. E47 is needed for the efficient recruitment of GR and coregulators such as Mediator to chromatin. Altogether, our results illustrate how GR and E47 regulate hepatic metabolism, and might provide an entry point for novel therapies with reduced side effects.


Assuntos
Glucocorticoides/farmacologia , Fígado/efeitos dos fármacos , Receptores de Glucocorticoides/genética , Fator 3 de Transcrição/genética , Animais , Imunoprecipitação da Cromatina/métodos , Fígado Gorduroso/metabolismo , Perfilação da Expressão Gênica , Glucocorticoides/efeitos adversos , Glucose/genética , Glucose/metabolismo , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Masculino , Camundongos Knockout , Fator 3 de Transcrição/metabolismo
18.
Fish Shellfish Immunol ; 86: 1151-1161, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30597252

RESUMO

The glucocorticoid receptor (GR) is an important feedback regulator of the hypothalamic-pituitary-interrenal (HPI) axis. However, there are a limited number of studies focused on host-pathogen interactions in which an association between GR and immune response has been evaluated in monocytes/macrophages (MO/MФ) after being challenged with highly pathogenic bacteria. Here, we cloned the cDNA sequence of the glucocorticoid receptor (PaGR) gene from ayu fish. The PaGR transcript was expressed in all tissues, and changes in expression were observed in immune tissues and MO/MФ after live Vibrio anguillarum infection. Subsequently, PaGR was expressed and purified to prepare anti-PaGR antibodies. We analyzed the subcellular localization of PaGR. PaGR was expressed not only in the intracellular space but also in the plasma membrane. PaGR activation decreased the expression of pro-inflammatory cytokines and increased the expression of anti-inflammatory cytokines. However, PaGR activation suppressed the phagocytosis activity of V. anguillarum-infected ayu MO/MФ via a non-genomic pathway. Interestingly, PaGR activation could enhance MO/MФ bacterial killing capability and apoptosis. Therefore, PaGR may modulate the immune response in ayu MO/MФ by genomic and non-genomic pathways.


Assuntos
Macrófagos/imunologia , Monócitos/imunologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Vibrioses/veterinária , Animais , Apoptose/imunologia , Membrana Celular/metabolismo , Doenças dos Peixes/imunologia , Osmeriformes , Fagocitose/imunologia , Vibrio , Vibrioses/genética , Vibrioses/imunologia
19.
Transl Psychiatry ; 9(1): 41, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696808

RESUMO

Early-life adversity is an important risk factor for major depressive disorder (MDD) and schizophrenia (SCZ) that interacts with genetic factors to confer disease risk through mechanisms that are still insufficiently understood. One downstream effect of early-life adversity is the activation of glucocorticoid receptor (GR)-dependent gene networks that drive acute and long-term adaptive behavioral and cellular responses to stress. We have previously shown that genetic variants that moderate GR-induced gene transcription (GR-response eSNPs) are significantly enriched among risk variants from genome-wide association studies (GWASs) for MDD and SCZ. Here, we show that the 63 transcripts regulated by these disease-associated functional genetic variants form a tight glucocorticoid-responsive co-expression network (termed GCN). We hypothesized that changes in the correlation structure of this GCN may contribute to early-life adversity-associated disease risk. Therefore, we analyzed the effects of different qualities of social support and stress throughout life on GCN formation across distinct brain regions using a translational mouse model. We observed that different qualities of social experience substantially affect GCN structure in a highly brain region-specific manner. GCN changes were predominantly found in two functionally interconnected regions, the ventral hippocampus and the hypothalamus, two brain regions previously shown to be of relevance for the stress response, as well as psychiatric disorders. Overall, our results support the hypothesis that a subset of genetic variants may contribute to risk for MDD and SCZ by altering circuit-level effects of early and adult social experiences on GCN formation and structure.


Assuntos
Transtorno Depressivo Maior/genética , Redes Reguladoras de Genes , Receptores de Glucocorticoides/genética , Esquizofrenia/genética , Estresse Psicológico/genética , Animais , Comportamento Animal , Encéfalo/metabolismo , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Núcleo Hipotalâmico Paraventricular/metabolismo , Especificidade da Espécie
20.
Genes Brain Behav ; 18(2): e12546, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30548775

RESUMO

Major depressive disorder (MDD) is a leading contributor to the global burden of disease. However, the causal relationship of risk factors, such as genetic predisposition or experience of augmented stress, remain unknown. Numerous studies in humans and rodents have implicated brain-derived neurotrophic factor (BDNF) in MDD pathology, as a genetic risk factor and a factor regulated by stress. Until now, the majority of preclinical studies have employed genetically modified mice as their model of choice. However, mice display a limited behavioural repertoire and lack expression of circulating BDNF, which is present in rats and humans. Therefore, heterozygous BDNF (BDNF+/- ) rats were tested for affective behaviours and accompanying expression of key genes associated with affective disorders in the brain. We found that BDNF+/- rats, which have reduced BDNF levels in brain and plasma, displayed symptoms of anhedonia, a core symptom of MDD, and anxiety-like behaviour, but no behavioural despair or cognitive impairments. This was accompanied by changes in the expression of genes that are implicated in modulation of the stress response and affective disorders. Hence, glucocorticoid receptor, neuregulin 1 and disrupted-in-schizophrenia 1 gene expression were upregulated in the prefrontal cortex of BDFN+/- rats, whereas FK506 binding protein 5 levels were decreased in the hippocampus. We conclude that a reduction in BDNF levels alters expression of genes associated with affective disorders, which may contribute to the development of depressive-like symptoms.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Encéfalo/metabolismo , Transtorno Depressivo Maior/genética , Fenótipo , Animais , Transtorno Depressivo Maior/metabolismo , Feminino , Heterozigoto , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuregulina-1/genética , Neuregulina-1/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Proteínas de Ligação a Tacrolimo/genética , Proteínas de Ligação a Tacrolimo/metabolismo
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