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Publication Record


DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: a prospective analysis.
Humphreys KL, Moore SR, Davis EG, MacIsaac JL, Lin DTS, Kobor MS, Gotlib IH
(2019) Transl Psychiatry 9: 245
MeSH Terms: Adolescent, CpG Islands, DNA Methylation, Depressive Disorder, Major, Epigenesis, Genetic, Female, Genotype, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prospective Studies, Receptors, Corticotropin-Releasing Hormone, Receptors, Glucocorticoid
Show Abstract · Added March 3, 2020
The stress response system is disrupted in individuals with major depressive disorder (MDD) as well as in those at elevated risk for developing MDD. We examined whether DNA methylation (DNAm) levels of CpG sites within HPA-axis genes predict the onset of MDD. Seventy-seven girls, approximately half (n = 37) of whom were at familial risk for MDD, were followed longitudinally. Saliva samples were taken in adolescence (M age = 13.06 years [SD = 1.52]) when participants had no current or past MDD diagnosis. Diagnostic interviews were administered approximately every 18 months until the first onset of MDD or early adulthood (M age of last follow-up = 19.23 years [SD = 2.69]). We quantified DNAm in saliva samples using the Illumina EPIC chip and examined CpG sites within six key HPA-axis genes (NR3C1, NR3C2, CRH, CRHR1, CRHR2, FKBP5) alongside 59 genotypes for tagging SNPs capturing cis genetic variability. DNAm levels within CpG sites in NR3C1, CRH, CRHR1, and CRHR2 were associated with risk for MDD across adolescence and young adulthood. To rule out the possibility that findings were merely due to the contribution of genetic variability, we re-analyzed the data controlling for cis genetic variation within these candidate genes. Importantly, methylation levels in these CpG sites continued to significantly predict the onset of MDD, suggesting that variation in the epigenome, independent of proximal genetic variants, prospectively predicts the onset of MDD. These findings suggest that variation in the HPA axis at the level of the methylome may predict the development of MDD.
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15 MeSH Terms
Loss of αB-crystallin function in zebrafish reveals critical roles in the development of the lens and stress resistance of the heart.
Mishra S, Wu SY, Fuller AW, Wang Z, Rose KL, Schey KL, Mchaourab HS
(2018) J Biol Chem 293: 740-753
MeSH Terms: Animals, Cardiomyopathies, Edema, Glucocorticoids, Image Processing, Computer-Assisted, Lens, Crystalline, Molecular Chaperones, Mutation, Myocardium, Pericardium, Phenotype, Receptors, Glucocorticoid, Signal Transduction, Stress, Physiological, Transgenes, Zebrafish, alpha-Crystallin A Chain, alpha-Crystallin B Chain
Show Abstract · Added April 3, 2018
Genetic mutations in the human small heat shock protein αB-crystallin have been implicated in autosomal cataracts and skeletal myopathies, including heart muscle diseases (cardiomyopathy). Although these mutations lead to modulation of their chaperone activity , the functions of αB-crystallin in the maintenance of both lens transparency and muscle integrity remain unclear. This lack of information has hindered a mechanistic understanding of these diseases. To better define the functional roles of αB-crystallin, we generated loss-of-function zebrafish mutant lines by utilizing the CRISPR/Cas9 system to specifically disrupt the two αB-crystallin genes, α and α We observed lens abnormalities in the mutant lines of both genes, and the penetrance of the lens phenotype was higher in α than α mutants. This finding is in contrast with the lack of a phenotype previously reported in αB-crystallin knock-out mice and suggests that the elevated chaperone activity of the two zebrafish orthologs is critical for lens development. Besides its key role in the lens, we uncovered another critical role for αB-crystallin in providing stress tolerance to the heart. The αB-crystallin mutants exhibited hypersusceptibility to develop pericardial edema when challenged by crowding stress or exposed to elevated cortisol stress, both of which activate glucocorticoid receptor signaling. Our work illuminates the involvement of αB-crystallin in stress tolerance of the heart presumably through the proteostasis network and reinforces the critical role of the chaperone activity of αB-crystallin in the maintenance of lens transparency.
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
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18 MeSH Terms
G6PC2 Modulates the Effects of Dexamethasone on Fasting Blood Glucose and Glucose Tolerance.
Boortz KA, Syring KE, Lee RA, Dai C, Oeser JK, McGuinness OP, Wang JC, O'Brien RM
(2016) Endocrinology 157: 4133-4145
MeSH Terms: Animals, Blood Glucose, Cell Line, Cell Line, Tumor, Cricetinae, Dexamethasone, Fasting, Glucose-6-Phosphatase, Maf Transcription Factors, Large, Mice, Mice, Inbred C57BL, Mice, Knockout, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Rats, Receptors, Glucocorticoid
Show Abstract · Added March 14, 2018
The glucose-6-phosphatase catalytic subunit 2 (G6PC2) gene encodes an islet-specific glucose-6-phosphatase catalytic subunit. G6PC2 forms a substrate cycle with glucokinase that determines the glucose sensitivity of insulin secretion. Consequently, deletion of G6pc2 lowers fasting blood glucose (FBG) without affecting fasting plasma insulin. Although chronic elevation of FBG is detrimental to health, glucocorticoids induce G6PC2 expression, suggesting that G6PC2 evolved to transiently modulate FBG under conditions of glucocorticoid-related stress. We show, using competition and mutagenesis experiments, that the synthetic glucocorticoid dexamethasone (Dex) induces G6PC2 promoter activity through a mechanism involving displacement of the islet-enriched transcription factor MafA by the glucocorticoid receptor. The induction of G6PC2 promoter activity by Dex is modulated by a single nucleotide polymorphism, previously linked to altered FBG in humans, that affects FOXA2 binding. A 5-day repeated injection paradigm was used to examine the chronic effect of Dex on FBG and glucose tolerance in wild-type (WT) and G6pc2 knockout mice. Acute Dex treatment only induces G6pc2 expression in 129SvEv but not C57BL/6J mice, but this chronic treatment induced G6pc2 expression in both. In 6-hour fasted C57BL/6J WT mice, Dex treatment lowered FBG and improved glucose tolerance, with G6pc2 deletion exacerbating the decrease in FBG and enhancing the improvement in glucose tolerance. In contrast, in 24-hour fasted C57BL/6J WT mice, Dex treatment raised FBG but still improved glucose tolerance, with G6pc2 deletion limiting the increase in FBG and enhancing the improvement in glucose tolerance. These observations demonstrate that G6pc2 modulates the complex effects of Dex on both FBG and glucose tolerance.
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16 MeSH Terms
Of mothers and myelin: Aberrant myelination phenotypes in mouse model of Angelman syndrome are dependent on maternal and dietary influences.
Grier MD, Carson RP, Lagrange AH
(2015) Behav Brain Res 291: 260-267
MeSH Terms: Angelman Syndrome, Animals, Cerebral Cortex, Diet, High-Fat, Disease Models, Animal, Female, Heterozygote, Male, Maternal Nutritional Physiological Phenomena, Mice, Inbred C57BL, Mice, Knockout, Myelin Proteins, Phenotype, Receptors, Glucocorticoid, Sciatic Nerve, Spinal Cord, Ubiquitin-Protein Ligases
Show Abstract · Added March 14, 2018
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by a number of neurological problems, including developmental delay, movement disorders, and epilepsy. AS results from the loss of UBE3A (an imprinted gene) expressed from the maternal chromosome in neurons. Given the ubiquitous expression of Ube3a and the devastating nature of AS, the role of environmental and maternal effects has been largely ignored. Severe ataxia, anxiety-like behaviors and learning deficits are well-documented in patients and AS mice. More recently, clinical imaging studies of AS patients suggest myelination may be delayed or reduced. Utilizing a mouse model of AS, we found disrupted expression of cortical myelin proteins, the magnitude of which is influenced by maternal status, in that the aberrant myelination in the AS pups of AS affected mothers were more pronounced than those seen in AS pups raised by unaffected (Ube3a (m+/p-)) Carrier mothers. Furthermore, feeding the breeding mothers a higher fat (11% vs 5%) diet normalizes these myelin defects. These effects are not limited to myelin proteins. Since AS mice have abnormal stress responses, including altered glucocorticoid receptor (GR) expression, we measured GR expression in pups from Carrier and affected AS mothers. AS pups had higher GR expression than their WT littermates. However, we also found an effect of maternal status, with reduced GR levels in pups from affected mothers compared to genotypically identical pups raised by unaffected Carrier mothers. Taken together, our findings suggest that the phenotypes observed in AS mice may be modulated by factors independent of Ube3a genotype.
Published by Elsevier B.V.
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1 Members
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17 MeSH Terms
Glucocorticoid effects on skeletal muscle: benefit and risk in patients with autoimmune inflammatory rheumatoid diseases.
Hanaoka BY, Peterson CA, Crofford LJ
(2012) Expert Rev Clin Immunol 8: 695-7
MeSH Terms: Anti-Inflammatory Agents, Arthritis, Rheumatoid, Autoimmunity, Genetic Predisposition to Disease, Glucocorticoids, Homeostasis, Humans, Immunosuppression, Muscle, Skeletal, Polymorphism, Genetic, Precision Medicine, Receptors, Glucocorticoid, Risk, Treatment Outcome, Wound Healing
Added September 18, 2013
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15 MeSH Terms
A potential role for insulin resistance in experimental pulmonary hypertension.
West J, Niswender KD, Johnson JA, Pugh ME, Gleaves L, Fessel JP, Hemnes AR
(2013) Eur Respir J 41: 861-71
MeSH Terms: Animals, Body Composition, Bone Morphogenetic Protein Receptors, Type II, Cell Line, Dexamethasone, Diet, High-Fat, Disease Models, Animal, Energy Metabolism, Humans, Hypertension, Pulmonary, Insulin Resistance, Male, Mice, Mice, Transgenic, Mutation, Phenotype, Protein Transport, Rats, Receptors, Glucocorticoid
Show Abstract · Added May 20, 2014
Patients with pulmonary arterial hypertension have increased prevalence of insulin resistance. We aimed to determine whether metabolic defects are associated with bone morphogenic protein receptor type 2 (Bmpr2) mutations in mice, and whether these may contribute to pulmonary vascular disease development. Metabolic phenotyping was performed on transgenic mice with inducible expression of Bmpr2 mutation, R899X. Phenotypic penetrance in Bmpr2(R899X) was assessed in a high-fat diet model of insulin resistance. Alterations in glucocorticoid responses were assessed in murine pulmonary microvascular endothelial cells and Bmpr2(R899X) mice treated with dexamethasone. Compared to controls, Bmpr2(R899X) mice showed increased weight gain and demonstrated insulin resistance as assessed by the homeostatic model assessment insulin resistance (1.0 ± 0.4 versus 2.2 ± 1.8) and by fat accumulation in skeletal muscle and decreased oxygen consumption. Bmpr2(R899X) mice fed a high-fat diet had strong increases in pulmonary hypertension penetrance (seven out of 11 versus three out of 11). In cell culture and in vivo experiments, Bmpr2 mutation resulted in a combination of constitutive glucocorticoid receptor activation and insensitivity. Insulin resistance is present as an early feature of Bmpr2 mutation in mice. Exacerbated insulin resistance through high-fat diet worsened pulmonary phenotype, implying a possible causal role in disease. Impaired glucocorticoid responses may contribute to metabolic defects.
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3 Members
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19 MeSH Terms
Ligand structural motifs can decouple glucocorticoid receptor transcriptional activation from target promoter occupancy.
Blind RD, Pineda-Torra I, Xu Y, Xu HE, Garabedian MJ
(2012) Biochem Biophys Res Commun 420: 839-44
MeSH Terms: 17-alpha-Hydroxyprogesterone, 3T3-L1 Cells, Adipocytes, Adipogenesis, Adrenal Cortex Hormones, Aldosterone, Animals, Cell Line, Tumor, Corticosterone, Desoxycorticosterone, Dexamethasone, Hydrocortisone, Ligands, Mice, Molecular Structure, Progesterone, Promoter Regions, Genetic, Protein Conformation, Rats, Receptors, Glucocorticoid, Transcriptional Activation
Show Abstract · Added August 18, 2015
Glucocorticoid (GC) induction of the tyrosine aminotransferase (TAT) gene by the glucocorticoid receptor (GR) is a classic model used to investigate steroid-regulated gene expression. Classic studies analyzing GC-induction of the TAT gene demonstrated that despite having very high affinity for GR, some steroids cannot induce maximal TAT enzyme activity, but the molecular basis for this phenomenon is unknown. Here, we used RT-PCR and chromatin immunoprecipitation to determine TAT mRNA accumulation and GR recruitment to the TAT promoter (TAT-GRE) in rat hepatoma cells induced by seven GR ligands: dexamethasone (DEX), cortisol (CRT), corticosterone (CCS), 11-deoxycorticosterone (DOC), aldosterone (ALD), progesterone (PRG) and 17-hydroxyprogesterone (17P). As expected, DEX, CRT, CCS and ALD all induced both TAT mRNA and GR recruitment to the TAT-GRE, while PRG and 17P did not. However, while DOC could not induce significant TAT mRNA, it did induce robust GR occupancy of the TAT-GRE. DOC also induced recruitment of the histone acetyltransferase p300 to the TAT-GRE as efficiently as DEX. These DOC-induced effects recapitulated at another GR target gene (sulfonyltransferase 1A1), and DOC also failed to promote the multiple changes in gene expression required for glucocorticoid-dependent 3T3-L1 adipocyte differentiation. Structural simulations and protease sensitivity assays suggest that DOC and DEX induce different conformations in GR. Thus, although steroids that bind GR with high affinity can induce GR and p300 occupancy of target promoters, they may not induce a conformation of GR capable of activating transcription.
Copyright © 2012 Elsevier Inc. All rights reserved.
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21 MeSH Terms
The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress.
Hartmann J, Wagner KV, Liebl C, Scharf SH, Wang XD, Wolf M, Hausch F, Rein T, Schmidt U, Touma C, Cheung-Flynn J, Cox MB, Smith DF, Holsboer F, Müller MB, Schmidt MV
(2012) Neuropharmacology 62: 332-9
MeSH Terms: Analysis of Variance, Animals, Corticosterone, Disease Models, Animal, Exploratory Behavior, Gene Expression Regulation, HSP90 Heat-Shock Proteins, Locomotion, Male, Maze Learning, Mice, Mice, Knockout, Neurosecretory Systems, Receptors, Glucocorticoid, Receptors, Mineralocorticoid, Stress, Psychological, Swimming, Tacrolimus Binding Proteins
Show Abstract · Added March 9, 2015
Chronic stress is increasingly considered to be a main risk factor for the development of a variety of psychiatric diseases such as depression. This is further supported by an impaired negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which has been observed in the majority of depressed patients. The effects of glucocorticoids, the main hormonal endpoint of the HPA axis, are mediated via the glucocorticoid receptor (GR) and the mineralocorticoid receptor. The FK506-binding protein 51 (FKBP5), a co-chaperone of the Hsp90 and component of the chaperone-receptor heterocomplex, has been shown to reduce ligand sensitivity of the GR. This study aimed to investigate the function of FKBP5 as a possible mediator of the stress response system and its potential role in the development of stress-related diseases. Therefore, we assessed whether mice lacking the gene encoding FKBP5 (51KO mice) were less vulnerable to the adverse effects of three weeks of chronic social defeat stress. Mice were subsequently analyzed with regards to physiological, neuroendocrine, behavioral and mRNA expression alterations. Our results show a less vulnerable phenotype of 51KO mice with respect to physiological and neuroendocrine parameters compared to wild-type animals. 51KO mice demonstrated lower adrenal weights and basal corticosterone levels, a diminished response to a novel acute stimulus and an enhanced recovery, as well as more active stress-coping behavior. These results suggest an enhanced negative glucocorticoid feedback within the HPA axis of 51KO mice, possibly modulated by an increased sensitivity of the GR. This article is part of a Special Issue entitled 'Anxiety and Depression'.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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18 MeSH Terms
Dexamethasone protects auditory hair cells against TNFalpha-initiated apoptosis via activation of PI3K/Akt and NFkappaB signaling.
Haake SM, Dinh CT, Chen S, Eshraghi AA, Van De Water TR
(2009) Hear Res 255: 22-32
MeSH Terms: Animals, Apoptosis, Benzyl Compounds, Caspase Inhibitors, Dexamethasone, Dose-Response Relationship, Drug, Hair Cells, Auditory, Hydrocarbons, Fluorinated, In Vitro Techniques, NF-kappa B, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Rats, Rats, Sprague-Dawley, Receptors, Glucocorticoid, Signal Transduction, Tumor Necrosis Factor-alpha
Show Abstract · Added April 18, 2017
BACKGROUND - Tumor necrosis factor alpha (TNFalpha) is associated with trauma-induced hearing loss. Local treatment of cochleae of trauma-exposed animals with a glucocorticoid is effective in reducing the level of hearing loss that occurs post-trauma (e.g., electrode insertion trauma-induced hearing loss/dexamethasone treatment).
HYPOTHESIS - Dexamethasone (Dex) protects auditory hair cells (AHCs) from trauma-induced loss by activating cellular signal pathways that promote cell survival.
MATERIALS AND METHODS - Organ of Corti explants challenged with an ototoxic level of TNFalpha was the trauma model with Dex the otoprotective drug. A series of inhibitors were used in combination with the Dex treatment of TNFalpha-exposed explants to investigate the signal molecules that participate in Dex-mediated otoprotection. The otoprotective capacity of Dex against TNFalpha ototoxicity was determined by hair cell counts obtained from fixed explants stained with FITC-phalloidin labeling with investigators blinded to specimen identity.
RESULTS - The general caspase inhibitor Boc-d-fmk prevented TNFalpha-induced AHC death. There was a significant reduction (p<0.05) in the efficacy of Dex otoprotection against TNFalpha ototoxicity when the following cellular events were blocked: (1) glucocorticoid receptors (Mif); (2) PI3K (LY294002); (3) Akt/PKB (SH-6); and (4) NFkappaB (NFkappaB-I).
CONCLUSION - Dex treatment protects hair cells against TNFalpha apoptosis in vitro by activation of PI3K/Akt and NFkappaB signaling.
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18 MeSH Terms
Inhibition of 11beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans.
Zhang MZ, Xu J, Yao B, Yin H, Cai Q, Shrubsole MJ, Chen X, Kon V, Zheng W, Pozzi A, Harris RC
(2009) J Clin Invest 119: 876-85
MeSH Terms: 11-beta-Hydroxysteroid Dehydrogenase Type 2, Adenocarcinoma, Adenoma, Animals, Base Sequence, Cell Line, Tumor, Colonic Neoplasms, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Enzyme Inhibitors, Gene Silencing, Genes, APC, Glycyrrhizic Acid, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Mutant Strains, Models, Biological, Neovascularization, Pathologic, RNA, Small Interfering, Receptors, Glucocorticoid
Show Abstract · Added February 24, 2014
Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. Studies have shown that COX-2-derived PGE2 promotes CRC progression, and both nonselective COX inhibitors (NSAIDs) and selective COX-2 inhibitors (such as glucocorticoids) reduce the number and size of colonic adenomas. However, increased gastrointestinal side effects of NSAIDs and increased cardiovascular risks of selective COX-2 inhibitors limit their use in chemoprevention of CRC. We found that expression of 11beta-hydroxysteroid dehydrogenase type II (11betaHSD2), which converts active glucocorticoids to inactive keto-forms, increased in human colonic and Apc+/min mouse intestinal adenomas and correlated with increased COX-2 expression and activity. Furthermore, pharmacologic inhibition or gene silencing of 11betaHSD2 inhibited COX-2-mediated PGE2 production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice. Inhibition of 11betaHSD2 did not reduce systemic prostacyclin production or accelerate atherosclerosis in mice, thereby avoiding the major cardiovascular side effects seen with systemic COX-2 inhibitors. Therefore, 11betaHSD2 inhibition represents what we believe to be a novel approach for CRC chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity.
1 Communities
6 Members
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22 MeSH Terms