Activation of NRF2 Signaling in HEK293 Cells by a First-in-Class Direct KEAP1-NRF2 Inhibitor

Wen, Xiaozhong; Thorne, Gabriell; Joy, Melanie S.; Aleksunes, Lauren M.

doi:10.1002/jbt.21693

Cited by 20 publications

(12 citation statements)

References 22 publications

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“…From the large number of compounds indexed in the available libraries, the compounds LH601, benzenesulfonylpyrimidone 2, N-phenyl-benzenesulfonamide, and a series of 1,4-diphenyl-1,2,3-triazoles might be very well-suited candidates to inhibit the PPI with KEAP1 (Hu et al, 2013;Jnoff et al, 2014;Bertrand et al, 2015;Wen et al, 2015;Nasiri et al, 2016). These studies described in detail the atomic interaction with KEAP1, the affinity, and the thermodynamics parameters of binding.…”

Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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“…This showed that it was more potent than compound 1 (1.9 μM). The cellular Nrf2‐inducing activity of compound 2 has been validated . Jnoff et al.…”

Section: Strategies For Modulating the Keap1–nrf2–are Pathwaymentioning

confidence: 99%

The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update

Jiang

et al. 2016

Medicinal Research Reviews

585

391

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The Keap1-Nrf2-ARE ((Kelch-like ECH-Associating protein 1) nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway is one of the most important defense mechanisms against oxidative and/or electrophilic stresses, and it is closely associated with inflammatory diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, and aging. In recent years, progress has been made in strategies aimed at modulating the Keap1-Nrf2-ARE pathway. The Nrf2 activator DMF (Dimethylfumarates) has been approved by the FDA as a new first-line oral drug to treat patients with relapsing forms of multiple sclerosis, while a phase 3 study of another promising candidate, CDDO-Me, was terminated for safety reasons. Directly inhibiting Keap1-Nrf2 protein-protein interactions as a novel Nrf2-modulating strategy has many advantages over using electrophilic Nrf2 activators. The development of Keap1-Nrf2 protein-protein interaction inhibitors has become a topic of intense research, and potent inhibitors of this target have been identified. In addition, inhibiting Nrf2 activity has attracted an increasing amount of attention because it may provide an alternative cancer therapy. This review summarizes the molecular mechanisms and biological functions of the Keap1-Nrf2-ARE system. The main focus of this review is on recent progress in studies of agents that target the Keap1-Nrf2-ARE pathway and the therapeutic applications of such agents.

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“…Under normal circumstances, Nrf2 is found and degraded in the cytoplasm attached to KEAP1. Following oxidative stress or drug intervention, Nrf2 is cleaved from KEAP1 and transported to the nucleus, activating transcription of protective genes to defend against organ damage (34). Our results found that BPA in L6 cells causes oxidative stress by activating KEAP1 and suppressing Nrf2.…”

Section: Discussionmentioning

confidence: 65%

Protective Potential of Adiponectin and Quercetin on Alleviating Bisphenol-A-Induced Toxicity in Muscle Cells Through the KEAP1/NRF2 Pathway

Mohammadi

Mashayekhi

Nedaei

et al. 2021

Preprint

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Background: Bisphenol A (BPA) is a toxic environmental estrogenic compound which exerts its detrimental effects by increasing oxidative stress and decreasing levels of antioxidants. This study aimed to evaluate beneficial effect of adiponectin and quercetin in reducing BPA-induced oxidative stress by assessing the Prooxidant-antioxidant balance (PAB) assay, catalase activity and KEAP1/NRF2 expression in muscle cells.Methods and Results: L6 rat muscle cells were exposed to BPA (50 an100 μM) with and without treatment with different concentrations of adiponectin (10 and 100 ng/ml) and quercetin (10 and 25 ng/ml) for 24 and 48 hours. Cell viability was assessed using MTT assay, and the PAB was evaluated with the ELISA at 540 nm. Catalase level was also evaluated in all groups. Furtheremore, the expression of KEAP1/Nrf2 genes was assessed using qRT-PCR. The results showed a significant reduction in L6 cells survival after being treated with 100 μM BPA. Adiponectin and quercetin treatment also increased cell survival compared to BPA-treated cells. It was also found that PAB increased with BPA exposure, and quercetin treatment significantly reduced it compared to BPA treatment. The catalase activity was reduced in BPA-treated cells, which was significantly increased by treatment with adiponectin and quercetin. A significant decrease in Nrf2 gene expression was observed in BPA-treated cells compared to the control group. It was further found that cell treatment with quercetin and adiponectin significantly increased the expression of Nrf2 gene compared to the control group.Conclusions: Taking together, our results implied that adiponectin and quercetin could modulate BPA-induced oxidative stress in muscle cells through KEAP1/Nrf2 pathway. Accordingly, it can be concluded that adiponectin in low dose and quercetin, may have significant impact in reducing toxicity due to BPA.

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Activation of NRF2 Signaling in HEK293 Cells by a First-in-Class Direct KEAP1-NRF2 Inhibitor

Cited by 20 publications

References 22 publications

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update

Protective Potential of Adiponectin and Quercetin on Alleviating Bisphenol-A-Induced Toxicity in Muscle Cells Through the KEAP1/NRF2 Pathway

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