A269 SEX-DEPENDENT EFFECT OF PANCREASTATIN INHIBITION ON COLON MUCOSAL INTEGRITY IN HOMEOSTATIC CONDITION
Bibliographic record
Abstract
Abstract Background Sex bias in inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) epidemiology is well known. Pancreastatin (PST), an epithelial cells-derived peptide overexpressed in IBD patients, regulates the endoplasmic reticulum (ER) and survival signalling involved in CRC. Pancreastatin inhibitor 8 (PSTi8), an inhibitor of PST, showed promising anti-inflammatory effects in IBD male mice model. However, no data exists regarding PST’s role in colon mucosal regeneration and epithelium maintenance. Aims Here, we investigated the impact of PSTi8 treatment on colonic epithelial cells in male and female mice under homeostatic conditions. Methods Male and female C57BL/6 mice were treated with PSTi8 (2.5mg/mL/kg, i.r.) or PBS for six days. Epithelial cells’ proliferation (Ki67) and differentiation (cytokeratin-20) were measured by immunofluorescence. Genetic markers for differentiated epithelial cells (goblet Muc2 and Tuft Dclk1), stem cells (fast-cycling Lgr5, reserve Hopx and fetal-like Ly6a), stem cell regulator (BMP4), epithelial cells lineage commitment (Atoh1, Hes1, Gfl1), ER activation (ATF6), and apoptosis (CHOP) were tested by qRT-PCR. Results PSTi8 treatment decreased epithelial cell proliferation in both sexes. The inhibition of PST lowered the differentiation of epithelial cells and mucus production and increased tuft cell gene expression in females but not in male mice. In females, PSTi8 treatment increased fast-cycling stem cells but lower reserve and fetal-like stem cells in both sexes. In addition, PST inhibition significantly downregulated BMP4, which regulates epithelial cell differentiation, in females while not altering its expression in males. In contrast, PSTi8 treatment significantly increased transcription factors regulating epithelial cells' self-renewal and lineage commitments Hes1 and GFI1 in females but decreased Atoh1 in both sexes. PST inhibition enhanced gene expression of ER stress molecules ATF6 and CHOP in female and ATF6 in male mice. CHOP remained unaltered by PST inhibition in males. Conclusions PSTi8 alters colonic epithelial regeneration, differentiation, and thus maintenance in a sex-dependent manner. Funding Agencies CIHRChildren’s Hospital Research Institute of Manitoba (CHRIM)/Research Manitoba
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.006 | 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".