A99 SYSTEMIC DELIVERY OF AN INHIBITOR OF MITOCHONDRIAL FISSION REDUCES THE SEVRITY OF CHEMICALLY-INDUCED COLITIS IN MICE
Bibliographic record
Abstract
Mitochondria exist as a dynamic network that is continually remodelling by the controlled processes of fission and fusion that are critical to cell health, regulating metabolic activity, proliferation and apoptosis. Excessive mitochondrial fission can be a feature of neurological and metabolic diseases. Perturbed mitochondrial form and function can occur in IBD, yet nothing is known of mitochondrial dynamics in the context of these inflammatory conditions. The peptide drug P110 is an inhibitor of the Dynamin-Related Protein 1 (Drp1) fission-inducing protein. We hypothesized that mitochondrial fragmentation (i.e. fission) would contribute to enteric inflammatory disease and sought to test this using P110 in murine models of colitis. Determine if systemic delivery of the inhibitor of mitochondrial fission, P110, would ameliorate, to any significant degree, disease severity and inflammation in chemically-induced colitis in mice. Balb/c mice were treated with (i) 5% dextran-sodium sulfate (DSS) in drinking water for 5 days, followed by 3 days of water recovery or (ii) dinitrobenzene sulphonic acid (DNBS; 3 mg ir, 72h) ± daily P110 (ip., 3mg/kg/day). Disease was assessed by (a) colonic length, (b) weight change, and (c) macroscopic and histological damage scores. Both DSS and DNBS induced substantial disease in mice (n=8 and 4, respectively). Co-treatment with the inhibitor of mitochondrial fission, P110, significantly reduced the severity of DSS-induced colitis as gauged by colon length macroscopic disease score, although histopathology was not different from DSS-only treated mice. In DNBS-induced colitis P110 co-treatment was also beneficial, with mice displaying less wasting, a longer colon and less macroscopic damage and colonic histopathology. There is a re-emergence of interest in mitochondria in enteric inflammatory disease, where excessive fragmentation could be of pathophysiological significance. Use of a peptide engineered to inhibit pathological mitochondrial fission, reduced the severity of disease in two models of colitis. While the target cell for the P110 drug awaits identification, we speculate that suppression of mitochondrial fission is worthy of consideration as a new option to treat IBD. CCC, CIHRUniversity of Calgary Eyes High Program
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".