Establishment of a transgenic mouse line for monitoring exposure history to electrophilic stress
Bibliographic record
Abstract
Abstract Background KEAP1‐NRF2 system is a major response mechanism against electrophilic stress. In normal condition, NRF2 is ubiquitinated by the KEAP1‐CUL3 ubiquitin E3 ligase complex in the cytoplasm, resulting in degradation through the proteasome. On the exposure to electrophilic stress, KEAP1 is inactivated leading to nuclear translocation of NRF2 and inducible expression of antioxidant proteins and detoxification enzymes. NRF2 activation caused by electrophilic phytochemicals has been shown beneficial for various human disorders including neurodegeneration such as Alzheimer’s disease. However, due to the transient and fluctuating nature of the NRF2 activation, it has not been easy to detect the electrophilic response, i.e., NRF2 activation, at a single‐cell resolution. Method In order to establish an in vivo detection system of NRF2 activation at a single‐cell resolution, we generated a unique mouse model by utilizing Neh2 domain of NRF2. Neh2 domain is located at the N‐terminus of Nrf2 and known as a degron mediating ubiquitination and degradation of NRF2 in KEAP1 dependent manner. We first established a transgenic mouse line expressing Neh2‐Cre recombinase fusion protein ubiquitously under the regulation of mouse Mafg gene regulatory region (MGRD‐Neh2‐Cre mouse). Secondly, we crossed the transgenic mouse with Rosa‐CAG‐LSL‐tdTomato mouse and obtained MGRD‐Neh2‐Cre:Rosa‐CAG‐LSL‐tdTomaato (Neh2‐Cre:tdTomato) mouse. In this mouse, Neh2‐Cre was expected to be stabilized under electrophilic stress and subsequently induce expression of tdTomato by recombining the Rosa locus. Result Although a single dose of an electrophilic compound, CDDO‐Im, did not induce tdTomato expression in Neh2‐Cre:tdTomato mice, repeated administration of CDDO‐Im gradually increase the number of cells expressing tdTomato in various organs. Furthermore, the mice continuously treated with 6‐methylsulfinylhexyl Isothiocyanate (6‐MSITC) in drinking water for 4‐5 months, which is a weak electrophile compared with CDDO‐Im, exhibited tdTomato expression in various organs including brain. These results suggest that 6‐MSITC as well as CDDO‐Im activates KEAP1‐NRF2 system in the central nervous system. Conclusion We consider that the established Neh2‐Cre:tdTomato mouse is especially useful to monitor the cumulative weak response to chronic/repetitive electrophilic stimuli. Our study suggests that 6‐MSITC as well as CDDO‐Im can be applied for therapeutic approaches of aging‐related neurodegenerative disorders by activating NRF2 in the central nervous system.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.009 | 0.003 |
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".