ArticleChemical research in toxicology2012
Quinone-induced activation of Keap1/Nrf2 signaling by aspirin prodrugs masquerading as nitric oxide.
Article in Chemical research in toxicology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
15 citing papers in PubMed, 22 citations in OpenAlex.
- Covalent Modification of Keap1 by the Key Metabolic Cofactor Coenzyme A Under Oxidative and Metabolic Stress.Antioxidants (Basel, Switzerland) · 2026Article
- Antioxidant Metabolism Pathways in Vitamins, Polyphenols, and Selenium: Parallels and Divergences.International journal of molecular sciences · 2024Review
- Post-translational modifications of Keap1: the state of the art.Frontiers in cell and developmental biology · 2023Review
- Identification of a potent Nrf2 displacement activator among aspirin-containing prodrugs.Neurochemistry international · 2021Article
- An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation.Molecules (Basel, Switzerland) · 2020Review
- Unraveling Reversible DNA Cross-Links with a Biological Machine.Chemical research in toxicology · 2020Article
- Directing Quinone Methide-Dependent Alkylation and Cross-Linking of Nucleic Acids with Quaternary Amines.Bioconjugate chemistry · 2020Article
- Pharmacological manipulation of cGMP and NO/cGMP in CNS drug discovery.Nitric oxide : biology and chemistry · 2019Review
- Cytotoxic Effect of Thymoquinone-Loaded Nanostructured Lipid Carrier (TQ-NLC) on Liver Cancer Cell Integrated with Hepatitis B Genome, Hep3B.Evidence-based complementary and alternative medicine : eCAM · 2018Article
- Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects.Chemical research in toxicology · 2017Article
- Review
- Prodrugs Bioactivated to Quinones Target NF-κB and Multiple Protein Networks: Identification of the Quinonome.Chemical research in toxicology · 2016Article
- Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid.Scientific reports · 2015Article
- A novel aspirin prodrug inhibits NFκB activity and breast cancer stem cell properties.BMC cancer · 2015Article
- Quinone Methide Bioactivation Pathway: Contribution to Toxicity and/or Cytoprotection?Current organic chemistry · 2014Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
The promising therapeutic potential of the NO-donating hybrid aspirin prodrugs (NO-ASA) includes induction of chemopreventive mechanisms and has been reported in almost 100 publications. One example, NCX-4040 (pNO-ASA), is bioactivated by esterase to a quinone methide (QM) electrophile. In cell cultures, pNO-ASA and QM-donating X-ASA prodrugs that cannot release NO rapidly depleted intracellular GSH and caused DNA damage; however, induction of Nrf2 signaling elicited cellular defense mechanisms including upregulation of NAD(P)H:quinone oxidoreductase-1 (NQO1) and glutamate-cysteine ligase (GCL). In HepG2 cells, the "NO-specific" 4,5-diaminofluorescein reporter, DAF-DA, responded to NO-ASA and X-ASA, with QM-induced oxidative stress masquerading as NO. LC-MS/MS analysis demonstrated efficient alkylation of Cys residues of proteins including glutathione-S-transferase-P1 (GST-P1) and Kelch-like ECH-associated protein 1 (Keap1). Evidence was obtained for alkylation of Keap1 Cys residues associated with Nrf2 translocation to the nucleus, nuclear translocation of Nrf2, activation of antioxidant response element (ARE), and upregulation of cytoprotective target genes. At least in cell culture, pNO-ASA acts as a QM donor, bioactivated by cellular esterase activity to release salicylates, NO(3)(-), and an electrophilic QM. Finally, two novel aspirin prodrugs were synthesized, both potent activators of ARE, designed to release only the QM and salicylates on bioactivation. Current interest in electrophilic drugs acting via Nrf2 signaling suggests that QM-donating hybrid drugs can be designed as informative chemical probes in drug discovery.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.