A44 PGC1-α INHIBITION WORSENS DSS-INDUCED COLITIS IN MICE
Bibliographic record
Abstract
Abstract Background Inflammatory bowel diseases (IBD) represent a wide range of gastrointestinal diseases that are characterized by chronic inflammation of the gastrointestinal tract (GIT). Affecting more than 6 million individuals globally, the most prevalent forms of IBD are Ulcerative colitis (UC), characterized by inflammation and ulceration of the colon and rectum, and Crohn’s disease (CD), characterized by inflammation of several areas of the GIT. Due to the morbidity and occasionally mortality arising from IBD, as well as its increasing global prevalence, the search for novel treatments and cures for IBD presents great importance. Loss of immune tolerance significantly contributes to the inflammatory patterns observed in IBD patients. Dendritic Cells (DCs), key antigen-presenting cells, are important mediators of tolerance in the gut when polarized to tolerogenic DCs (tolDCs). The phenotype of tolDCs has been shown to directly depend on their intracellular metabolism, mostly by adopting mitochondrial oxidative phosphorylation. Peroxisome proliferator-activated receptor-gamma coactivator (PGC)1-α is a transcription coactivator that plays a crucial role in mediating cellular energy metabolism. Evidence shows that activation of PGC1-α stimulates mitochondrial biogenesis and promotes oxidative metabolism in a variety of biological processes. Aims The aim of this project was to evaluate whether activation or inhibition of PGC1-α impacts inflammatory response in DSS-induced colitic in mice. We hypothesize that the PGC1-α pharmacological activator ZLN005 would ameliorate colitis as a result of tolDC polarization. On other hand, the PGC1-α pharmacological inhibitor SR18292 would increase inflammatory responses and decrease tolerance. Methods C57/b6 mice received DSS in drinking water for 5 days, followed by 3 days of tap water. Mice were treated with vehicle, ZLN005 (10 mg/kg), or SR18292 treatment (25 mg/kg) for the 3 days of drinking tap water. Under necropsy, colitis was assessed by disease activity score (DAS), colon length, weight change, myeloperoxidase (MPO) activity assay, histopathology score, and cytokines by ELISA. Intestinal tolerance was accessed by evaluating T cells polarization to Treg, TH1, TH2, or TH17 by qPCR of the transcription factors Foxp3 (Treg), Tbx21 (TH1), Gata3 (TH2), and Rorγt (TH17) expressed in the colon. Results Our results demonstrated that ZLN005 did not alter the inflammatory response induced by DSS, gauged by MPO assay, DAS, and histopathology, suggesting that ZLN005 was ineffective in polarizing tolDCs. However, we observed a worsening of inflammatory conditions with treatment with SR18292 with a decrease in IL-10 levels and increased MPO values, potentially stemming from the loss of tolDCs and intestinal tolerance. Conclusions PGC1-α inhibition worsens inflammatory response in DSS-induced colitis potentially by inhibiting tolDC polarization and loss of intestinal tolerance. Funding Agencies None
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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 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.006 | 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".