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Your search keyword '"Soft electrophiles"' showing total 3 results
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3 results on '"Soft electrophiles"'

1. Electrophile versus oxidant modification of cysteine residues:Kinetics as a key driver of protein modification

Author

Sauerland, Max B., Davies, Michael J., Sauerland, Max B., and Davies, Michael J.

Abstract

Humans have widespread exposure to both oxidants, and soft electrophilic compounds such as alpha,beta-unsaturated aldehydes and quinones. Electrophilic motifs are commonly found in a drugs, industrial chemicals, pollutants and are also generated via oxidant-mediated degradation of biomolecules including lipids (e.g. formation of 4-hydroxynonenal, 4-hydroxyhexenal, prostaglandin J2). All of these classes of compounds react efficiently with Cys residues, and the particularly the thiolate anion, with this resulting in Cys modification via either oxidation or adduct formation. This can result in deleterious or beneficial effects, that are either reversible (e.g. in cell signalling) or irreversible (damaging). For example, acrolein is a well-established toxin, whereas dimethylfumarate is used in the treatment of multiple sclerosis and psoriasis. This short review discusses the targets of alpha,beta-unsaturated aldehydes, and particularly two prototypic cases, acrolein and dimethylfumarate, and the factors that control the selectivity and kinetics of reaction of these species. Comparison is made between the reactivity of oxidants versus soft electrophiles. These rate constants indicate that electrophiles can be significant thiol modifying agents in some situations, as they have rate constants similar to or greater than species such as H2O2, can be present at higher concentrations, and are less efficiently removed by protective systems when compared to H2O2. They may also induce similar or higher levels of modification than highly reactive oxidants, due to the very low concentrations of oxidants formed in most in vivo situations. more...

Published
2022

2. The Rule of Suppressed Charge Transfer between Heteroaromatic Compounds and Electrophiles.

Author

Gineityte, Viktorija

Subjects
*CHARGE transfer, *AROMATIC compounds, *ELECTROPHILES, *ELECTRONEGATIVITY, *CARBON, *CHEMICAL reactions, *HYDROCARBONS
Abstract

Replacement of a carbon atom of an aromatic compound by a more electronegative heteroatom gives rise to suppression of reactivities of the remaining carbon atoms in electrophilic substitution (SE2) reactions. To prove this experiment-based rule, the reactivities are related to the relevant extents of the intermolecular charge transfer. General algebraic expressions are derived and analyzed for these extents for various directions of the attack of electrophile. The reactant is considered as a perturbed alternant hydrocarbon, the perturbation coinciding with the alteration in the Coulomb parameter of the carbon atom undergoing the replacement, whereas the reagent is represented explicitly by an external vacant orbital. Changes in the intermolecular charge transfer due to introduction of heteroatom are shown to consist of two components, viz. of an initial-population-dependent component contributing increments of alternating signs for shifting positions of electrophile along the hydrocarbon chain and of an additional negative contribution originating from the increased interval between diagonal Hamiltonian matrix elements for orbitals participating in the charge transfer. For soft electrophiles, the negative contribution is shown to predominate over the alternating one. This implies the charge transfer between heteroaromatic reactants and electrophiles to be suppressed vs. the relevant values for hydrocarbons-containing system. [ABSTRACT FROM AUTHOR] more...

Published
2013
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3. A systematic analysis of Nrf2 pathway activation dynamics during repeated xenobiotic exposure

Author

Joost B. Beltman, Jan P. Langenberg, Johannes P Schimming, Luc J M Bischoff, Bob van de Water, Isoude A. Kuijper, Bas ter Braak, Daan Noort, Liesanne Wolters, and TNO Defensie en Veiligheid

Subjects
0301 basic medicine, Health, Toxicology and Mutagenesis, Cell, 010501 environmental sciences, medicine.disease_cause, Toxicology, 01 natural sciences, environment and public health, Green fluorescent protein, Soft electrophiles, Oxidoreductases Acting on Sulfur Group Donors, Gene knockdown, TS - Technical Sciences, Kelch-Like ECH-Associated Protein 1, Chemistry, Nuclear Proteins, Hep G2 Cells, General Medicine, respiratory system, Observation, Weapon & Protection Systems, Molecular Imaging, Cell biology, Protein Transport, medicine.anatomical_structure, Toxicity, Single-Cell Analysis, MafG Transcription Factor, HepG2, NF-E2-Related Factor 2, Green Fluorescent Proteins, Srxn1, Defence Research, Context (language use), Defence, Safety and Security, digestive system, Nrf2, Xenobiotics, Repeated exposure, 03 medical and health sciences, Live cell imaging, Toxicity Tests, medicine, Humans, MafF Transcription Factor, 0105 earth and related environmental sciences, Dose-Response Relationship, Drug, Maleates, CBRN - CBRN Protection, Hydroquinones, Repressor Proteins, 030104 developmental biology, Cell culture, Oxidative stress
Abstract

Oxidative stress leads to the activation of the Nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway. While most studies have focused on the activation of the Nrf2 pathway after single chemical treatment, little is known about the dynamic regulation of the Nrf2 pathway in the context of repeated exposure scenarios. Here we employed single cell live imaging to quantitatively monitor the dynamics of the Nrf2 pathway during repeated exposure, making advantage of two HepG2 fluorescent protein reporter cell lines, expressing GFP tagged Nrf2 or sulfiredoxin 1 (Srxn1), a direct downstream target of Nrf2. High throughput live confocal imaging was used to measure the temporal dynamics of these two components of the Nrf2 pathway after repeated exposure to an extensive concentration range of diethyl maleate (DEM) and tert-butylhydroquinone (tBHQ). Single treatment with DEM or tBHQ induced Nrf2 and Srxn1 over time in a concentration-dependent manner. The Nrf2 response to a second treatment was lower than the response to the first exposure with the same concentration, indicating that the response is adaptive. Moreover, a limited fraction of individual cells committed themselves into the Nrf2 response during the second treatment. Despite the suppression of the Nrf2 pathway, the second treatment resulted in a three-fold higher Srxn1-GFP response compared to the first treatment, with all cells participating in the response. While after the first treatment Srxn1-GFP response was linearly related to Nrf2-GFP nuclear translocation, such a linear relationship was less clear for the second exposure. siRNA-mediated knockdown demonstrated that the second response is dependent on the activity of Nrf2. Several other, clinically relevant, compounds (i.e., sulphorophane, nitrofurantoin and CDDO-Me) also enhanced the induction of Srxn1-GFP upon two consecutive repeated exposure. Together the data indicate that adaptation towards pro-oxidants lowers the Nrf2 activation capacity, but simultaneously primes cells for the enhancement of an antioxidant response which depends on factors other than just Nrf2. These data provide further insight in the overall dynamics of stress pathway activation after repeated exposure and underscore the complexity of responses that may govern repeated dose toxicity. more...

Published
2018