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Effect of a point mutation at Keap1 C151 on hepatic gene expression in mice treated with Bardoxolone Methyl (CDDO-Me)

ABSTRACT: Effect of a point mutation at Keap1 C151 on hepatic gene expression in mice treated with Bardoxolone Methyl (CDDO-Me)

PROVIDER: PRJNA918689 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22990855_1.fastq.gz	Fastqsanger.gz
	SRR22990855_2.fastq.gz	Fastqsanger.gz
	SRR22990856_1.fastq.gz	Fastqsanger.gz
	SRR22990856_2.fastq.gz	Fastqsanger.gz
	SRR22990857_1.fastq.gz	Fastqsanger.gz

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Effect of a point mutation at Keap1 C151 on hepatic gene expression in mice treated with Bardoxolone Methyl (CDDO-Me)

Project description:To investigate the role of Keap1 C151 for induction of gene expression in mouse liver, comprehensive gene expression profiles were compared in the livers of wild-type, Nrf2 knockout, and mice harboring a point mutation at Keap1 C151 (C151S) treated with either CDDO-Me or vehicle

2023-03-07 | GSE222256 | GEO

Effect of KEAP1 knockout and CDDO-2P-Im Treatment in ARH-77 Cells

Project description:ARH-77 cells were genetically editted with CRISPR-Cas9 to knock out KEAP1 and treated with various doses of CDDO-2P-Im or DMSO.

2023-04-20 | GSE229914 | GEO

CDDO drives transcriptomic and epigenetic reprogramming in response to TPA-induced JB6 cell neoplastic transformation [Methyl-seq]

Project description:12-O-tetradecanoylphorbol-13-acetate (TPA) promotes skin carcinogenesis. CDDO is a potential antioxidative and antiinflammatory agent to prevent the TPA-induced skin cell transformation at nanomolar scale. We characterized the transcriptome, CpG methylome, and pathway network of JB6 cells treated with TPA and TPA + CDDO using RNA sequencing, methyl sequencing, and QIAGEN Ingenuity Pathway Analysis.

2022-06-18 | GSE206166 | GEO

Transcription profiling of mouse Keap1-null (CKO) to investigate genetic and pharmacologic activation of Nrf2 signaling

Project description:Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct hepatic gene expression profiles between Keap1 knockout and triterpenoid treated mice; Loss of Nrf2 signaling increases susceptibility to acute toxicity, inflammation, and carcinogenesis in mice due to the inability to mount adaptive responses. By contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice; although dominant negative mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. This analysis also enables a global characterization of the pharmacodynamic action of CDDO-Im at a low dose that is relevant to chemoprevention. Experiment Overall Design: Liver-targeted conditional Keap1-null (CKO) mice provide a model of genetic activation of Nrf2 signaling. By coupling global gene expression analysis of CKO mice with analysis of pharmacologic activation using the synthetic oleanane triterpenoid CDDO-Im, we are able to gain insight into pathways affected by Nrf2 activation. CDDO-Im is an extremely potent activator of Nrf2 signaling. CKO mice were used to identify genes modulated by genetic activation of Nrf2 signaling. The CKO response was compared to hepatic global gene expression changes in wild-type mice treated with CDDO-Im at a maximal Nrf2 activating dose. n=3/group, male 9 week old mice were used. Mice were treated with a single dose of vehicle (10% Cremophor-EL, 10% DMSO, and PBS) or 30 umol CDDO-Im/kg body weight by gavage and sacrificed 6 h later.

2009-05-11 | E-GEOD-15633 | biostudies-arrayexpress

The NRF2 inducer CDDO-2P-Im provokes a reduction in amyloid beta levels in Alzheimer’s disease model mice

Project description:Alzheimer’s disease (AD) is the most common etiology of dementia. The transcription factor NF-E2-related factor 2 (NRF2) induces the expression of genes encoding phase II detoxification and antioxidant genes. NRF2 is regulated by Kelch-like ECH-associated protein 1 (KEAP1), and the KEAP1-NRF2 system is the key regulatory system involved in cytoprotection. To examine whether pharmacological induction of NRF2 expression alleviates AD phenotypes in vivo, we employed two AD mouse models, i.e., AppNL-G-F/NL-G-F (AppNLGF) and APPV717I::TAUP301L (APP/TAU) mice. As the synthetic oleanane triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11-dien-28-oyl)] (CDDO)-4(-pyridin-2-yl)-imidazole (CDDO-2P-Im) exhibits strong NRF2-inducing activity, in this study, we treated AD model mice with CDDO-2P-Im.

2024-09-09 | GSE271154 | GEO

Effect of KEAP1 knockout and CDDO-2P-Im Treatment in ARH-77 Cells

Project description:Effect of KEAP1 knockout and CDDO-2P-Im Treatment in ARH-77 Cells

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Pharmacogenomic comparison between D3T- and CDDO-Im in mouse liver tissue

Project description:The Keap1/Nrf2 signaling pathway is a tractable target for the pharmacological prevention of tumorigenesis. 3H-1,2-dithiole-3-thione (D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are representative members of two classes of Nrf2-activating chemopreventive agents. Natural dithiolethiones have been widely used in clinical trials for cancer chemoprevention. Synthetic triterpenoids, however, have been shown to be significantly more potent Nrf2 activators and are under clinical evaluation for the treatment of chronic kidney disease. This study seeks to characterize the structure-activity relationship between D3T and CDDO-Im in mouse liver tissue. To this end we treated Wt and Nrf2-null mice with 300 umol/kg bw D3T and 3, 10, and 30 umol/kg bw CDDO-Im every other day for 5 days and evaulated global gene expression changes as a product of both treamtent and genotype using Affymetrix microarray.

2018-02-25 | GSE99199 | GEO

CDDO drives transcriptomic and epigenetic reprogramming in response to TPA-induced JB6 cell neoplastic transformation [RNA-seq]

2022-06-18 | GSE206167 | GEO

Bardoxolone methyl improves nonalcoholic steatohepatitis through inhibition of macrophage recruitment

Project description:Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease caused by excess fat accumulation, closely associated with obesity and metabolic syndrome.Bardoxolone methyl (2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me) is a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2). Some clinical trials of CDDO-Me were conducted for chronic kidney diseases and pulmonary arterial hypertension, whereas the hepatoprotective effect of CDDO-Me on nonalcoholic steatohepatitis (NASH) has not yet been elucidated. The purpose of this study was to determine the hepatoprotective potential and mechanisms of CDDO-Me in a diet-induced NASH mouse model. Whole transcriptome analysis revealed that CDDO-Me markedly inhibited the expressions of chemokine ligands, Ccl3 and Ccl4, and the chemokine receptors, Ccr1 and Ccr5 that increased in NASH mice while activating Nrf2-dependent pathway. Serum protein levels of CCL3 and CCL4 upregulated in NASH mice were inhibited in a dose-dependent manner by treatment with CDDO-Me. CDDO-Me inhibited the expression levels of Ccr1 and Ccr5, and simultaneously blocked Ccl3 and Ccl4 the ligands of the receptors, respectively in RAW264.7 cell line. Taken together with the observations, CDDO-Me directly inhibits the expression of CCL3-CCR1 and CCL4-CCR5 axes in macrophages of NASH mice, which might contribute to the improvement of nonalcoholic steatohepatitis and fibrosis through the interference of monocyte-derived macrophage migration.

2024-08-02 | GSE239861 | GEO

Characterization of RA839, a non-covalent small-molecule binder to Keap1 and selective activator of Nrf2 signalling

Project description:The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors the activity of Nrf2 is inhibited by its interaction with the kelch-like ECH-associated protein 1 (Keap1). Here, we describe RA839, a small molecule that binds non-covalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of approximately 6 µM, as demonstrated by X-ray co-crystallization and isothermal titration calorimetry. Whole-genome DNA arrays showed that at 10 µM RA839 significantly regulated 105 genes in bone marrow-derived macrophages. Canonical pathway mapping of these genes revealed an activation of pathways linked with Nrf2 signalling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knockout macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound CDDO-Me, RA839 prevented the induction of both inducible nitric oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice RA839 acutely induced Nrf2-target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2. Gene expression profile of bone marrow derived murine macrophages (BMDM) from Nrf2+/+ or Nrf2-/- mice treated with RA838, siKeap1-1 or siKeap1-2 were compared to untreated DMSO control or siControl. Four biological replicates were used for each sample group.

2015-10-31 | E-GEOD-71695 | biostudies-arrayexpress

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