Dimethyl Fumarate and Monoethyl Fumarate Exhibit Differential Effects on Glutathione, Keap1 and Nrf2 Activation In Vitro (P1.204)
Bibliographic record
Abstract
OBJECTIVE: To evaluate the effects of dimethyl fumarate (DMF) and monoethyl fumarate (MEF) on glutathione conjugation, Keap1 modification and activation of the Nrf2 pathway. BACKGROUND: Delayed-release DMF is approved in the U.S., Canada, and Australia for the treatment of multiple sclerosis. DMF is also one component of combination product with 3 different salts of MEF, and this combination is approved in Germany for the treatment of psoriasis. Previous studies have demonstrated the pharmacologic properties of DMF; however the properties of MEF have been under explored. Characterizing the pharmacodynamic properties of DMF and MEF will provide important insights into the mechanisms of action for delayed-release DMF versus combination products containing DMF and MEF salts. DESIGN/METHODS: DMF and MEF were applied to HEK293 cells expressing Keap1. Keap1 was immunopurified, digested and resultant peptides were analyzed by mass spectrometry to identify specific peptides modified by treatment. Primary human astrocytes were treated with DMF or MEF, and cellular glutathione was measured over 24 hours and cells were also analyzed for pharmacodynamic responses by reverse transcription polymerase chain reaction. RESULTS: DMF treatment resulted in a robust modification of specific cysteine residues in Keap1, an Nrf2 chaperone protein. MEF similarly modified Keap1, but the overall degree was significantly less. DMF produced an acute concentration-dependent depletion of glutathione; however levels recovered and rose above baseline by 24 hours. MEF did not cause acute reductions in glutathione, but did produce an increase by 24 hours. Consistent with Keap1 modification, DMF produced a robust transcriptional response in treated cells as did MEF, however the responses to MEF were of a lower magnitude. CONCLUSIONS: These studies demonstrate that DMF and MEF are both pharmacologically active, but have differing degrees of activities in multiple assay formats. These differences would be expected to result in divergent effects on downstream biology. Study Supported by: Biogen Idec Inc.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".