scholarly journals Amoxicillin inactivation by thiol-catalyzed cyclization reduces protein haptenation and antibacterial potency

2019 ◽  
Author(s):  
María A. Pajares ◽  
Tahl Zimmerman ◽  
Francisco J. Sánchez-Gómez ◽  
Adriana Ariza ◽  
María J. Torres ◽  
...  
Keyword(s):  
Residual Activity ◽  
Redox Status ◽  
Adduct Formation ◽  
Protein Adducts ◽  
Cellular Proteins ◽  
Nucleophilic Attack ◽  
Allergic Reactions ◽  
Lactam Antibiotic ◽  
Lower Capacity ◽  
Intracellular Redox Status

AbstractSerum and cellular proteins are targets for the formation of adducts with the β-lactam antibiotic amoxicillin. This process could be important for the development of adverse, and in particular, allergic reactions to this antibiotic. In studies exploring protein haptenation by amoxicillin, we observed that reducing agents influenced the extent of amoxicillin-protein adducts formation. Consequently, we show that thiol-containing compounds, including dithiothreitol, N-acetyl-L-cysteine and glutathione, perform a nucleophilic attack on the amoxicillin molecule that is followed by an internal rearrangement leading to amoxicillin diketopiperazine, a known amoxicillin metabolite with residual activity. The effect of thiols is catalytic and can render complete amoxicillin conversion. Interestingly, this process is dependent on the presence of an amino group in the antibiotic lateral chain, as in amoxicillin and ampicillin. Furthermore, it does not occur for other β-lactam antibiotics, including cefaclor or benzylpenicillin. Biological consequences of thiol-mediated amoxicillin transformation are exemplified by a reduced bacteriostatic action and a lower capacity of thiol-treated amoxicillin to form protein adducts. Finally, modulation of the intracellular redox status through inhibition of glutathione synthesis influenced the extent of amoxicillin adduct formation with cellular proteins. These results open novel perspectives for the understanding of amoxicillin metabolism and actions, including the formation of adducts involved in allergic reactions.

scholarly journals Redox Buffering Capacity of Nanomaterials as an Index of ROS-based Therapeutics and Toxicity: A Preclinical Animal Study

2021 ◽  
Author(s):  
Aniruddha Adhikari ◽  
Susmita Mondal ◽  
Monojit Das ◽  
Ria Ghosh ◽  
Pritam Biswas ◽  
...  
Keyword(s):  
Therapeutic Index ◽  
Redox Status ◽  
Buffering Capacity ◽  
Engineered Nanoparticles ◽  
Ros Generation ◽  
Cellular Functions ◽  
Physiological Level ◽  
Precise Control ◽  
Preclinical Animal Study ◽  
Intracellular Redox Status

Precise control of intracellular redox status, i.e., maintenance of physiological level of reactive oxygen species (ROS) for mediating normal cellular functions (oxidative eustress) while evading the excess ROS stress (distress) is central to the concept of redox medicine. In this regard, engineered nanoparticles with unique ROS generation, transition, or depletion functions have the potential to be the choice of redox therapeutics. However, it is always challenging to estimate whether ROS-induced intracellular events are beneficial or deleterious to the cell. Here, we propose the concept of redox buffering capacity as a therapeutic index of engineered nanomaterials. As a steady redox state is maintained for normal functioning cells, we hypothesize that the ability of a nanomaterial to preserve this homeostatic condition will dictate its therapeutic efficacy. Additionally, the redox buffering capacity is expected to provide information about the nanoparticle toxicity. Here, using citrate functionalized trimanganese tetroxide nanoparticles (C-Mn3O4 NPs) as a model nanosystem we explored its redox buffering capacity in erythrocytes. Furthermore, we went on to study the chronic toxic effect (if any) of this nanomaterial in animal model in order to co-relate with the experimentally estimated redox buffering capacity. This study could function as a framework for assessing the capability of a nanomaterial as redox medicine (whether maintains eustress or damages by creating distress), thus orienting its application and safety for clinical use.

scholarly journals Regulation of CD20 expression by radiation-induced changes in intracellular redox status

2008 ◽  
Vol 44 (4) ◽  
pp. 614-623 ◽  
Author(s):  
Damodar Gupta ◽  
Meredith E. Crosby ◽  
Alexandru Almasan ◽  
Roger M. Macklis
Keyword(s):  
Redox Status ◽  
Cd20 Expression ◽  
Radiation Induced ◽  
Induced Changes ◽  
Intracellular Redox Status ◽  
Intracellular Redox

scholarly journals Redox Regulation of Adenovirus-Induced AP-1 Activation by Overexpression of Manganese-Containing Superoxide Dismutase

2002 ◽  
Vol 76 (1) ◽  
pp. 355-363 ◽  
Author(s):  
Hannah J. Zhang ◽  
Victoria J. Drake ◽  
Linjing Xu ◽  
Jianfang Hu ◽  
Frederick E. Domann ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Dna Binding ◽  
Redox Regulation ◽  
Recombinant Adenovirus ◽  
Redox Status ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Promising Tool ◽  
Gel Shift Assay ◽  
Intracellular Redox Status

ABSTRACT Adenovirus gene therapy is a promising tool in the clinical treatment of many genetic and acquired diseases. However, it has also caused pathogenic effects in organs such as the liver. The redox-sensitive transcription factors AP-1 and NF-κB have been implicated in these effects. To study the mechanisms of adenovirus-mediated AP-1 and NF-κB activation and the possible involvement of oxidative stress in adenovirus transduction, rats were injected with either replication-defective recombinant adenovirus with DNA containing the cytomegalovirus promoter region only (AdCMV), adenovirus containing human manganese-containing superoxide dismutase (MnSOD) cDNA (AdMnSOD), or vehicle. Compared to vehicle and AdCMV transduction, MnSOD gene transfer yielded a fivefold increase in liver MnSOD activity 7 days postinjection. Gel shift assay showed that AdCMV transduction induced DNA binding activity for AP-1 but not NF-κB. MnSOD overexpression abolished this activation. Western blotting analysis of c-Fos and c-Jun suggested that up-regulation of c-fos and c-jun gene expression does not directly contribute to the induction of AP-1 activation. Glutathione/glutathione disulfide ratios were decreased by adenovirus transduction and restored by MnSOD overexpression. The AP-1 binding activity that was induced by AdCMV was decreased by immunoprecipitation of Ref-1 protein. Ref-1 involvement was confirmed by restoration of AP-1 binding activity after the immunoprecipitated Ref-1 protein had been added back. AP-1 DNA binding activity was also elevated in control and AdMnSOD-injected rats after addition of the immunoprecipitated Ref-1 protein. These data indicate that cellular transduction by recombinant adenovirus stimulates AP-1 DNA binding activity. Furthermore, our results suggest that MnSOD overexpression decreases AP-1 DNA binding activity by regulating intracellular redox status, with the possible involvement of Ref-1 in this redox-sensitive pathway.

Redox-based regulation of neural stem cell function and Nrf2

2015 ◽  
Vol 43 (4) ◽  
pp. 627-631 ◽  
Author(s):  
Lalitha Madhavan
Keyword(s):  
Oxidative Stress ◽  
Stress Resistance ◽  
Somatic Mutations ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Redox Status ◽  
Common Theme ◽  
Tissue Microenvironment ◽  
Neural Tissues ◽  
Intracellular Redox Status

Neural stem cells (NSCs) play vital roles in the development and maintenance of brain tissues throughout life. They can also potentially act as powerful sources of regeneration and repair during pathology to replace degenerating cells and counteract deleterious changes in the tissue microenvironment. However, both aging and neurodegeneration involve an up-regulation of processes, such as oxidative stress, inflammation, somatic mutations, and reduction in growth factors in neural tissues, which threaten the robust functioning of NSCs. Nevertheless, recent evidence also indicates that NSCs may possess the intrinsic capability to cope with such stressors in their microenvironment. Whereas the mechanisms governing the responses of NSCs to stress are diverse, a common theme that is emerging suggests that underlying changes in intracellular redox status are crucial. Here we discuss such redox-based regulation of NSCs, particularly in relation to nuclear erythroid factor 2-like 2 (Nrf2), which is a key cellular stress resistance factor, and its implications for successfully harnessing NSC therapeutic potential towards developing cell-based therapeutics for nervous system disorders.

scholarly journals Bromofatty aldehyde derived from bromine exposure and myeloperoxidase and eosinophil peroxidase modify GSH and protein

2018 ◽  
Vol 59 (4) ◽  
pp. 696-705 ◽  
Author(s):  
Mark A. Duerr ◽  
Elisa N. D. Palladino ◽  
Celine L. Hartman ◽  
James A. Lambert ◽  
Jacob D. Franke ◽  
...  
Keyword(s):  
Phorbol Myristate Acetate ◽  
Plasma Levels ◽  
Adduct Formation ◽  
Nucleophilic Attack ◽  
Fatty Aldehyde ◽  
Myristate Acetate ◽  
Protein Adduct ◽  
Protein Thiols ◽  
Hypobromous Acid ◽  
Activated Neutrophils

α-Chlorofatty aldehydes (α-ClFALDs) and α-bromofatty aldehydes (α-BrFALDs) are produced in activated neutrophils and eosinophils. This study investigated the ability of α-BrFALD and α-ClFALD to react with the thiols of GSH and protein cysteinyl residues. Initial studies showed that 2-bromohexadecanal (2-BrHDA) and 2-chlorohexadecanal (2-ClHDA) react with GSH producing the same fatty aldehyde-GSH adduct (FALD-GSH). In both synthetic and cellular reactions, FALD-GSH production was more robust with 2-BrHDA compared with 2-ClHDA as precursor. NaBr-supplemented phorbol myristate acetate (PMA)-activated neutrophils formed more α-BrFALD and FALD-GSH compared with non-NaBr-supplemented neutrophils. Primary human eosinophils, which preferentially produce hypobromous acid and α-BrFALD, accumulated FALD-GSH following PMA stimulation. Mice exposed to Br2 gas had increased levels of both α-BrFALD and FALD-GSH in the lungs, as well as elevated systemic plasma levels of FALD-GSH in comparison to mice exposed to air. Similar relative reactivity of α-ClFALD and α-BrFALD with protein thiols was shown using click analogs of these aldehydes. Collectively, these data demonstrate that GSH and protein adduct formation are much greater as a result of nucleophilic attack of cysteinyl residues on α-BrFALD compared with α-ClFALD, which was observed in both primary leukocytes and in mice exposed to bromine gas.

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