Myeloperoxidase-derived Hypochlorous Acid Antagonizes the Oxidative Stress-mediated Activation of Iron Regulatory Protein 1
Bibliographic record
Abstract
Hypochlorous acid (HOCl) is a highly reactive product generated by the myeloperoxidase reaction during the oxidative burst of activated neutrophils, which is implicated in many bactericidal and cytotoxic responses. Recent evidence suggests that HOCl may also play a role in the modulation of redox sensitive signaling pathways. The short half-life of HOCl and the requirement for a continuous presence of H2O2 as a substrate for its myeloperoxidase-catalyzed generation make the study of HOCl-mediated responses very difficult. We describe here an enzymatic model consisting of glucose/glucose oxidase, catalase, and myeloperoxidase (GOX/CAT/MPO) that allows the controlled generation of both HOCl and H2O2 and thus, mimics the oxidative burst of activated neutrophils. By employing this model we show that HOCl prevents the H2O2-mediated activation of iron regulatory protein 1 (IRP1), a central post-transcriptional regulator of mammalian iron metabolism. Activated IRP1 binds to (R)iron-responsive elements" (IREs) within the mRNAs encoding proteins of iron metabolism and thereby controls their translation or stability. The inhibitory effect of HOCl is not a result of a direct modification of IRP1 by this oxidant. Kinetics experiments provide evidence that HOCl intervenes with the signaling cascade, which results in the activation of IRP1. We further demonstrate that HOCl antagonizes the H2O2-mediated increase in the levels of transferrin receptor, which is a downstream target of IRP1. Our findings suggest that HOCl can modulate signaling pathways in a concerted action with H2O2. The GOX/CAT/MPO system provides a valuable tool for studying the regulatory function of HOCl.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".