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Airway smooth muscle reponse to dexamathasone at 4 and 24 hours

ABSTRACT: Glucocorticoids, which activate glucocorticoid receptor signaling and thus modulate gene expression, are widely used to treat asthma. Glucocorticoids exert their therapeutic effects in part through modulating airway smooth muscle structure and function. However, the effects of genes that are regulated by GCs on airway function are not fully understood. Here, we used transcription profiling to characterize the effects of a potent glucocorticoid, dexamethasone, on cultured human airway smooth muscle gene expression at 4 and 24 hours. This study examined differential gene expression induced by treatment of cultured human airway smooth muscle cells with dexamethasone. There were 3 groups of samples and each group had 4 biological replicates. Group 1 was no treatment, Group 2 was dexamethasone (dex) treatment for 4 hours, Group 3 was dex treatment for 24 hours. Cultures were synchronized so harvest occurred at the same time for all three groups. 2 samples are not included in this analysis (based on unsupervised clustering of samples and diagnostic plots).

ORGANISM(S): Homo sapiens

SUBMITTER: Anthony Gerber

PROVIDER: E-GEOD-34313 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Airway smooth muscle reponse to dexamathasone at 4 and 24 hours

Project description:Glucocorticoids, which activate glucocorticoid receptor signaling and thus modulate gene expression, are widely used to treat asthma. Glucocorticoids exert their therapeutic effects in part through modulating airway smooth muscle structure and function. However, the effects of genes that are regulated by GCs on airway function are not fully understood. Here, we used transcription profiling to characterize the effects of a potent glucocorticoid, dexamethasone, on cultured human airway smooth muscle gene expression at 4 and 24 hours.

2011-12-10 | GSE34313 | GEO

Human Airway Smooth Muscle Transcriptome Changes in Response to Asthma Medications

Project description:Rationale: Asthma is a chronic inflammatory airway disease. The most common medications used for its treatment are β2-agonists and glucocorticosteroids, and one of the primary tissues that these drugs target in the treatment of asthma is the airway smooth muscle. We used RNA-Seq to characterize the human airway smooth muscle (HASM) transcriptome at baseline and under three asthma treatment conditions. Methods: The Illumina TruSeq assay was used to prepare 75bp paired-end libraries for HASM cells from four white male donors under four treatment conditions: 1) no treatment; 2) treatment with a β2-agonist (i.e. Albuterol, 1μM for 18h); 3) treatment with a glucocorticosteroid (i.e. Dexamethasone (Dex), 1μM for 18h); 4) simultaneous treatment with a β2-agonist and glucocorticoid, and the libraries were sequenced with an Illumina Hi-Seq 2000 instrument. The Tuxedo Suite Tools were used to align reads to the hg19 reference genome, assemble transcripts, and perform differential expression analysis using the protocol described in https://github.com/blancahimes/taffeta mRNA profiles obtained via RNA-Seq for four primary human airway smooth muscle cell lines that were treated with dexamethasone, albuterol, dexamethasone+albuterol or were left untreated.

2014-01-01 | E-GEOD-52778 | biostudies-arrayexpress

Human Airway Smooth Muscle Transcriptome Changes in Response to Asthma Medications

2014-01-01 | GSE52778 | GEO

The auophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages

Project description:Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy characteristics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for the anti-inflammatory capacity of CpdA, at least in this cell type. Together, these results demonstrate how off-target mechanisms of selective NR3C1 ligands may contribute to a more efficient anti-inflammatory therapy.

2019-06-11 | PXD012121 | Pride

Crosstalk between the glucocorticoid and mineralocorticoid receptor boosts glucocorticoid-induced killing of multiple myeloma cells

Project description:The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR’s action in myeloma. Here we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells, while in a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk is arising from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR MR homodimerization but leaves GR-GR homodimerization intact. Unbiased transcriptomics further reveals that c-myc and many of its target genes are downregulated most by Dex and Spi combined, while proteomics analyses identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex+Spi downregulated genes and proteins that may predict prognosis in the CoMMpass patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies towards glucocorticoid-based dose-reduction.

2023-10-24 | PXD043635 | Pride

Comparative analysis of gene expression profiles in lymphoma cells after treatment by Dexamethasone or CpdA

Project description:The project is directed to the development of selective glucocorticoid receptor agonists for anticancer therapy. Glucocorticoids (GC) are widely used in treatment of many types of cancer due to its ability to induce apoptosis in malignant cells (in blood cancer therapy) and to prevent nausea and emesis (in the chemotherapy of solid tumors). However, severe dose-limiting side effects occur, including osteoporosis, muscle wasting, diabetes and other metabolic complications. Both beneficial and harmful effects of glucocorticoids are due to selective activation or repression of particular genes by glucocorticoid receptor (GR). GR regulates gene expression via transactivation that requires GR homodimer binding to gene promoters and transrepression mediated via negative interaction between GR and other transcription factors as well as binding with negative glucocorticoid response elements (nGRE) in genes. GR transactivation is linked to metabolic side effects, while GR transrepression underlies glucocorticoid therapeutic action. Novel selective GR agonist Compound A (CpdA) prevents GR dimerization and transactivation, specifically activates GR transrepression, and has fewer side effects compared to glucocorticoids. Here we compare the gene expression profiles in lymphoma cells treated with glucocorticoid Dexamethasone (Dex) or CpdA

2015-07-21 | GSE71102 | GEO

Comparative analysis of gene expression profiles in prostate cancer cells after treatment by Dexamethasone or CpdA

Project description:The project is directed to the development of selective glucocorticoid receptor agonists for anticancer therapy. Glucocorticoids (GC) are widely used in treatment of many types of cancer due to its ability to induce apoptosis in malignant cells (in blood cancer therapy) and to prevent nausea and emesis (in the chemotherapy of solid tumors). However, severe dose-limiting side effects occur, including osteoporosis, muscle wasting, diabetes and other metabolic complications. Both beneficial and harmful effects of glucocorticoids are due to selective activation or repression of particular genes by glucocorticoid receptor (GR). GR regulates gene expression via transactivation that requires GR homodimer binding to gene promoters and transrepression mediated via negative interaction between GR and other transcription factors as well as binding with negative glucocorticoid response elements (nGRE) in genes. GR transactivation is linked to metabolic side effects, while GR transrepression underlies glucocorticoid therapeutic action. Novel selective GR agonist Compound A (CpdA) prevents GR dimerization and transactivation, specifically activates GR transrepression, and has fewer side effects compared to glucocorticoids. Here we compare the gene expression profiles in prostate cancer cells treated with glucocorticoid Dexamethasone (Dex) or CpdA

2015-07-21 | GSE71099 | GEO

Expression data from the stomach of mice treated with dexamethasone.

Project description:Glucocorticoids are used for the treatment of inflammatory conditions but they also cause many side-effects. We used microarrays to detail the changes in gene expression induced in the stomach upon oral glucocorticoid treatment. Female wildtype Balb/c mice were treated for three days with 50 mg/l dexamethasone (dex) via the drinking water. Control mice were left untreated. The stomach was dissected and RNA prepared from the corpus.

2014-07-18 | E-GEOD-51669 | biostudies-arrayexpress

Exploiting crosstalk between glucocorticoid and mineralocorticoid receptors enhances glucocorticoid-induced killing of multiple myeloma cells

Project description:Long-term glucocorticoid treatment in multiple myeloma is hampered by deleterious side effects. Glucocorticoids bind to the glucocorticoid receptor (GR), which is a crucial drug target because its activation triggers myeloma cell death. The mineralocorticoid receptor (MR) is a closely related nuclear receptor but its impact on glucocorticoid responsiveness in myeloma is unknown. Here we reveal a functional crosstalk between GR and MR that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone enhances Dex-induced cell killing in (primary) myeloma cells. The crosstalk is further evidenced by an endogenous interaction between GR and MR in myeloma cells that is ligand-inducible and by a distinctive gene expression profile. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma and presents a glucocorticoid-based dose-reduction strategy that could diminish glucocorticoid-related side effects in patients.

2023-08-23 | GSE200313 | GEO

Effect of glucocorticoid chemical structure and receptor potency on human trabecular meshwork cells

Project description:Glucocorticoids with different chemical structures but similar glucocorticoid receptor potency regulate subsets of common and unique genes in human trabecular meshwork cells. Gene expression changes of human trabecular meshwork cells, TM 86 and TM 93, due to treatment with dexamethasone (Dex), fluocinolone acetonide (FA), and triamcinolone acetonide (TA).

2010-02-15 | GSE16643 | GEO

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