NRF2 ACTIVATORS FOR AGE-RELATED CHRONIC DISEASES: THEORETICAL LIMITATIONS AND PRACTICAL APPROACHES (Nrf2 peptide)
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PROVIDER: PRJNA1130996 | ENA |
REPOSITORIES: ENA
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Project description:NRF2 ACTIVATORS FOR AGE-RELATED CHRONIC DISEASES: THEORETICAL LIMITATIONS AND PRACTICAL APPROACHES (HPPE and protoporphyrins)
| PRJNA1214707 | ENA
Project description:One of the major metabolic responses to counteract aging, inflammation, and various chronic diseases including neurodegeneration, is the so call antioxidant pathway controlled by Nrf2 transcription factor. Nrf2 protein stability is regulated via interaction with the redox sensor Keap1, an adapter protein in Cullin III ubiquitin ligase complex. The search for Nrf2 activators is mainly focused on compounds that either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered as the most appropriate one for continuous administration without side effects, which are unavoidable in case of non-specific chemical modifiers of Keap1. However, true displacement activators show a significant offset, by many orders of magnitude, when switched from homogeneous assay to cell-based assays. This phenomenon originates, as we show here, from high micromolar intracellular concentrations of Keap1. A guarantee for high specificity of an alkylating Nrf2 activator is its targeted delivery. A transcriptomic analysis for a cell-permeable Nrf2-peptide bearing a fumarate moiety shows the activation of the antioxidant program only, confirming the high specificity of such approach. However, aging-linked neurodegeneration is also known to build-up Bach1, an Nrf2 target gene and competitive transcriptional repressor for Nrf2. Therefore, an ideal combination could be a benign Nrf2 activator and Bach1 inhibitor in one molecule, as represented by the recently developed HPPE. HPPE demonstrates an intersection of the activated antioxidant pathway with the Nrf2 peptide, and, in addition to that, shows a big pool of genes overlapping with the known inhibitors of Bach1 - zinc and tin protoporphyrins. Hence, at present moment, HPPE presents a unique combination of the two desired activities beneficial for age-related neurodegeneration.
2025-08-20 | GSE271364 | GEO
Project description:One of the major metabolic responses to counteract aging, inflammation, and various chronic diseases including neurodegeneration, is the so call antioxidant pathway controlled by Nrf2 transcription factor. Nrf2 protein stability is regulated via interaction with the redox sensor Keap1, an adapter protein in Cullin III ubiquitin ligase complex. The search for Nrf2 activators is mainly focused on compounds that either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered as the most appropriate one for continuous administration without side effects, which are unavoidable in case of non-specific chemical modifiers of Keap1. However, true displacement activators show a significant offset, by many orders of magnitude, when switched from homogeneous assay to cell-based assays. This phenomenon originates, as we show here, from high micromolar intracellular concentrations of Keap1. A guarantee for high specificity of an alkylating Nrf2 activator is its targeted delivery. A transcriptomic analysis for a cell-permeable Nrf2-peptide bearing a fumarate moiety shows the activation of the antioxidant program only, confirming the high specificity of such approach. However, aging-linked neurodegeneration is also known to build-up Bach1, an Nrf2 target gene and competitive transcriptional repressor for Nrf2. Therefore, an ideal combination could be a benign Nrf2 activator and Bach1 inhibitor in one molecule, as represented by the recently developed HPPE. HPPE demonstrates an intersection of the activated antioxidant pathway with the Nrf2 peptide, and, in addition to that, shows a big pool of genes overlapping with the known inhibitors of Bach1 - zinc and tin protoporphyrins. Hence, at present moment, HPPE presents a unique combination of the two desired activities beneficial for age-related neurodegeneration.
2025-08-20 | GSE287793 | GEO
Project description:Nrf2 is an important therapeutic target as activation of this pathway detoxifies harmful insults and reduces oxidative stress. However, the role of Nrf2 in cancer biology is controversial. Protection against oxidative stress and inflammation can confer a survival advantage to tumor cells, leading to a poor prognosis, and constitutive activation of Nrf2 has been detected in numerous tumors. In our study, we examined the role of two clinically relevant classes of Nrf2 activators, the synthetic triterpenoids (CDDO-Im and CDDO-Me) and dimethyl fumarate (DMF) in lung cancer. Using microarrays, we attempt to examine whether these Nrf2 activators have an effect on the same subset of Nrf2 genes.
2015-05-31 | GSE65623 | GEO
Project description:The transcription factor NRF2 plays an important role in many biological processes and is a promising therapeutic target. NRF2 is highly expressed in the skin and is known to play a critical role in diabetic wound healing, a disease state with limited treatment options. However, many existing NRF2 activators display off-target effects due to their electrophilic mechanism, underscoring the need for alternative approaches. In this work, we investigated two recently described, non-electrophilic NRF2 activators, ADJ-310 and PRL-295, and demonstrated their efficacy in vitro and in vivo. Both ADJ-310 and PRL-295 maintained human keratinocyte cell viability at increasing concentrations and maintained or improved cell proliferation over time. Both compounds also increased cell migration, improving in vitro wound closure. ADJ-310 and PRL-295 enhanced the oxidative stress response in vitro, and RNA-sequencing data showed that PRL-295 activated NRF2 with a narrower transcriptomic effect than the widely used electrophilic NRF2 activator, CDDO-Me. In vivo, both ADJ-310 and PRL-295 improved wound healing in Leprdb/db diabetic mice. The non-electrophilic compounds ADJ-310 and PRL-295 are effective, innovative tools for the investigation of the function of NRF2 that directly address the need for alternative NRF2 activators. They offer a new approach to studying the role of NRF2 in human diseases and its potential as a therapeutic. Both non-electrophilic NRF2 activators promoted wound healing functions in human keratinocytes and improved wound healing in diabetic mice, demonstrating their efficacy both in vitro and in vivo. RNA sequencing showed that PRL-295 upregulated downstream target genes that favorably compared with those of CDDO-Me.
2023-08-23 | GSE241267 | GEO
Project description:WGS and RNA-seq data for Nrf2 study
| EGAS00001001740 | EGA
Project description:NFE2L2/NRF2 is a transcription factor and master regulator of the cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, resulting in increased cellular fitness, chemo-radiation resistance, metabolic reprogramming and immune evasion. NRF2 protein levels and activity is governed primarily by the KEAP1/CUL3 ubiquitin ligase and subsequent proteasomal degradation. To what extent parallel signaling pathways and protein classes impact NRF2 activity remains to be fully explored. Also, because NRF2-directed therapies remain in the discovery and early development stages, continued identification and validation of NRF2 regulators is of potential clinical value. Here we used a gain-of-function genetic screen of the kinome to identify druggable activators and inhibitors of NRF2 signaling. We found that the understudied Brain Selective Kinase 1 and 2 (BRSK1/2) proteins suppress NRF2-dependent transcription and NRF2 protein levels in a kinase-dependent fashion. Integrative phospho-proteomic screens, RNAseq profiling and follow-up validation studies revealed BRSK1/2-driven activation of AMPK and suppression of MTOR signaling. BRSK2 over-expression suppressed global protein synthesis and decreased ribosome-RNA associations, which results in decreased NRF2 protein levels. Overall, our data establish the BRSK1 and BRSK2 kinases as negative regulators of NRF2 via the AMPK/MTOR signaling axis. Strategies which exploit these relationships may prove useful for therapeutically targeting NRF2 in cancer.
2020-06-24 | PXD015884 | Pride
Project description:Theoretical and practical refinements of sans spike-in quantitative ChIP-seq with application to p300/CBP inhibition
| PRJNA857063 | ENA
Project description:We identified RNA binding motif protein 47 (RBM47) as a target gene of transforming growth factor (TGF)-beta in mammary gland epithelial cells (NMuMG cells) that have undergone the epithelial-to-mesenchymal transition (EMT). TGF-beta repressed RBM47 expression in NMuMG cells and lung cancer cell lines. Expression of RBM47 correlated with good prognosis in patients with lung, breast, and gastric cancer. RBM47 suppressed the expression of cell metabolism-related genes, which were the direct targets of nuclear factor erythroid 2-related factor 2 (Nrf2; also known as NFE2L2). RBM47 bound to KEAP1 and Cullin3 mRNAs, and knockdown of RBM47 inhibited their protein expression, which led to enhanced binding of Nrf2 to target genomic regions. Knockdown of RBM47 also enhanced the expression of some Nrf2 activators, p21/CDKN1A and MafK induced by TGF-beta. Both mitochondrial respiration rates and the side population cells in lung cancer cells increased in the absence of RBM47. Our findings, together with the enhanced tumor formation and metastasis of xenografted mice by knockdown of the RBM47 expression, suggested tumor suppressive roles for RBM47 through the inhibition of Nrf2 activity. Effect of shRNA for RBM47 and TGF-beta on gene expression was evaluated by RNA-seq and RBM47-bound RNAs were identified by RIP-seq in A549 cells.
2016-03-01 | E-GEOD-61910 | biostudies-arrayexpress
Project description:Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator, Kelch-like ECH associated protein 1 (Keap1), are at the interface between redox and intermediary metabolism, allowing adaptation and survival under conditions of oxidative, inflammatory and metabolic stress. Nrf2 is the principal determinant of redox homeostasis, and contributes to mitochondrial function and integrity, and cellular bioenergetics. Using proteomics and lipidomics, we show that genetic downregulation of Keap1 in mice, and the consequent Nrf2 activation to pharmacologically-relevant levels, leads to upregulation of carboxylesterase 1 (Ces1) and acyl-CoA oxidase 2 (Acox2), decreases triglycerides levels, and alters the lipidome. This is accompanied by downregulation of hepatic ATP-citrate lyase (Acly) and decreased levels of acetyl-CoA, a trigger for autophagy. These findings suggest that downregulation of Keap1 confers features of a fasted metabolic state, which is an important consideration in the drug development of Keap1-targeting pharmacologic Nrf2 activators.
2020-11-11 | PXD021639 | Pride