FKBP5 mRNA Expression Is a Biomarker for GR Antagonism

Bali, Utsav; Phillips, Tim; Hunt, Hazel; Unitt, John

doi:10.1210/jc.2016-1624

Cited by 34 publications

(32 citation statements)

References 19 publications

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“…10 had also indicated that expression of GILZ, a key GR-responsive endogenous regulator of immune responses, and FKBP5, a key regulator of steroid hormone receptors as part of the heat shock protein 90 steroid receptor complex mRNA, had potential roles as biomarkers specifically linked to GR activation. 12 In the present study prednisone was clearly demonstrated to have the expected effects on all the biomarkers examined. Mifepristone was used as an active control in the single-dose study.…”

Section: Pharmacodynamicssupporting

confidence: 61%

“…Compared with the effect of prednisone alone, coadministration with a single 600‐mg dose of mifepristone decreased FKBP5 expression approximately 10‐fold and GILZ expression approximately 3‐fold, which were to near preprednisone dose levels. Coadministration of CORT125134 (500 mg as a single dose or 250 mg daily for 14 days) with prednisone showed effects similar to those observed with mifepristone in combination with prednisone …”

Section: Resultsmentioning

confidence: 65%

“…The impact of a single dose of prednisone on a variety of parameters, including white blood cell differential (neutrophil, lymphocyte, and eosinophil) counts and osteocalcin, has been reported previously and provided a convenient method to assess GR antagonism in healthy subjects . Nonclinical investigations had also indicated that expression of GILZ, a key GR‐responsive endogenous regulator of immune responses, and FKBP5, a key regulator of steroid hormone receptors as part of the heat shock protein 90 steroid receptor complex mRNA, had potential roles as biomarkers specifically linked to GR activation …”

Section: Discussionmentioning

confidence: 78%

“…Coadministration of CORT125134 (500 mg as a single dose or 250 mg daily for 14 days) with prednisone showed effects similar to those observed with mifepristone in combination with prednisone. 12 Mean (SD) pre-OGTT plasma glucose concentrations (ie, 5 hours after dosing and 1 hour postprandial), following prednisone alone, prednisone plus mifepristone, and prednisone plus CORT125134 were 7.79 (1.006) mmol/L, 6.30 (1.006) mmol/L (P = .0118 compared with prednisone alone; paired t-test), and 5.55 (0.431) mmol/L (P = .0006 compared with prednisone alone; P = .0483 compared with prednisone plus mifepristone), respectively (data not presented).…”

Section: Pharmacodynamic Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Clinical Study

Hunt

Donaldson

Strem

et al. 2017

Clinical Pharm in Drug Dev

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CORT125134 is an orally active, high‐affinity, selective antagonist of the glucocorticoid receptor that is being developed for indications that may benefit from the modulation of cortisol activity. This first‐in‐human study was conducted to evaluate the dose‐related safety, tolerability, pharmacokinetics and pharmacological effects of CORT125134 and its active metabolite CORT125201. Eighty‐one healthy male or female subjects received a single dose of 5 to 500 mg CORT125134 or matching placebo across 9 cohorts; 1 cohort received 150 mg CORT125134 after a high‐fat breakfast; and 46 subjects received 50 to 500 mg CORT125134 or matching placebo once daily for up to 14 days across 4 cohorts. CORT125134 was well tolerated at doses up to 250 mg per day for 14 days. CORT125134 was absorbed rapidly and eliminated with a mean half‐life ranging from 11 to 19 hours. Steady state was achieved by day 7. Exposure increased in a greater than proportional manner, particularly at lower doses. Exposure to CORT125201 at steady state was less than 5% that of parent CORT125134. Evidence for the desired pharmacological effect (glucocorticoid receptor antagonism) was demonstrated by the ability of CORT125134 to prevent several effects of the glucocorticoid receptor agonist prednisone.

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Section: Pharmacodynamicssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 78%

Section: Pharmacodynamic Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Clinical Study

Hunt

Donaldson

Strem

et al. 2017

Clinical Pharm in Drug Dev

Self Cite

View full text Add to dashboard Cite

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“…GCs cause the mobilization of energetic substrates from peripheral sources such as the liver, skeletal muscle, and adipose tissue [ 10 ]. Among the genes regulated by GCs, FK506-binding protein 51 (FKBP51) has been described as an important marker for GR sensitivity and bioavailability [ 11 , 12 ]. FKBP51 is a co-chaperone that modulates GC responses by negatively regulating GR activity, with their role in inflammation, autophagy, and insulin resistance having recently been discovered [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Moderate Aerobic Exercise Training Prevents the Augmented Hepatic Glucocorticoid Response Induced by High-Fat Diet in Mice

Dassonvalle

Díaz-Castro

Donoso-Barraza

et al. 2020

IJMS

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Glucocorticoids (GCs) are critical regulators of energy balance. Their deregulation is associated with the development of obesity and metabolic syndrome. However, it is not understood if obesity alters the tissue glucocorticoid receptor (GR) response, and moreover whether a moderate aerobic exercise prevents the alteration in GR response induced by obesity. Methods: To evaluate the GR response in obese mice, we fed C57BL6J mice with a high-fat diet (HFD) for 12 weeks. Before mice were sacrificed, we injected them with dexamethasone. To assess the exercise role in GR response, we fed mice an HFD and subjected them to moderate aerobic exercise three times a week. Results: We found that mice fed a high-fat diet for 12 weeks developed hepatic GC hypersensitivity without changes in the gastrocnemius or epididymal fat GR response. Therefore, moderate aerobic exercise improved glucose tolerance, increased the corticosterone plasma levels, and prevented hepatic GR hypersensitivity with an increase in epididymal fat GR response. Conclusion: Collectively, our results suggest that mice with HFD-induced obesity develop hepatic GR sensitivity, which could enhance the metabolic effects of HFD in the liver. Moreover, exercise was found to be a feasible non-pharmacological strategy to prevent the deregulation of GR response in obesity.

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A Novel Methodology Using Dexamethasone to Induce Neuronal Differentiation in the CNS-Derived Catecholaminergic CAD Cells

et al. 2021

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The Cath.a-differentiated (CAD) cell line is a central nervous system-derived catecholaminergic cell line originating from tyrosine hydroxylase (TH)-producing neurons located around the locus coeruleus area of the mouse brain. CAD cells have been used as an in vitro model for cellular and molecular studies due to their ability to differentiate under serum-free media conditions. However, the lack of serum-derived survival factors, limits the longevity for differentiated CAD cells to be maintained in healthy conditions; thereby, limiting their use in long-term culture studies. Here, we present a novel differentiation method that utilizes dexamethasone (Dex), a synthetic glucocorticoid receptor agonist. Speci cally, we discovered that the addition of 100 µM of Dex into the 1% fetal bovine serum (FBS)-supplemented media effectively induced neuronal differentiation of CAD cells, as characterized by neurite formation and elongation. Dexdifferentiated CAD cells exited the cell cycle, stopped proliferating, extended the neurites, and expressed neuronal markers. These effects were dependent on the glucocorticoid receptors (GR) as they were abolished by GR knockdown. Importantly, Dex-differentiated CAD cells showed longer survival duration than serum-free differentiated CAD cells. In addition, RNA-sequencing and qPCR data demonstrate that several genes involved in proliferation, neuronal differentiation, and survival pathways were differentially expressed in the Dex-differentiated cells. This is the rst study to reveal Dex as a novel differentiation methodology used to generate postmitotic neuronal CAD cells, which may be utilized as an in vitro neuronal model for cellular and molecular neurobiology research.Glucocorticoid receptor, GSTA3 = Glutathione S-transferase A3, HCN1 = Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1, IL6 = Interleukin-6, KCNT1 = Potassium channel subfamily T, member 1, MAP2= Microtubule associated protein type 2, MAPT = Microtubule associated protein tau, KEGG = Kyoto Encyclopedia of Genes and Genomes, MF = Molecular functions, MTT = 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromidefor, NDRG2 = N-myc downstream-

show abstract

FKBP5 mRNA Expression Is a Biomarker for GR Antagonism

Abstract: The inhibition of FKBP5 mRNA expression by a selective GR antagonist is a potential clinical biomarker of GR antagonism.

Cited by 34 publications

References 19 publications

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Clinical Study

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Clinical Study

Moderate Aerobic Exercise Training Prevents the Augmented Hepatic Glucocorticoid Response Induced by High-Fat Diet in Mice

A Novel Methodology Using Dexamethasone to Induce Neuronal Differentiation in the CNS-Derived Catecholaminergic CAD Cells

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