A102 REGULATION OF ENDPLASMIC RETICULUM STRESS/P53-APOPTITIC PATHWAYS BY CHROMOFUNGIN IN THE CONTEXT OF EXPERIEMENTAL COLITIS
Bibliographic record
Abstract
Chromogranin-A produced by epithelial enterochromaffin cells is implicated in the development of ulcerative colitis (UC). In an animal model of UC, the lack of CHGA regulates the plasticity of macrophages and p/53 caspase activation in colitis. Over the last years, progresses have been done in understanding the implications of multiple chromogranin-A derived peptides in several pathologies. In UC and macrophages, the transcription factor X-linked binding protein (XBP1) is a key component of the endoplasmic reticulum (ER) stress response, which induces intestinal mucosal injury and epithelial apoptosis. Intestinal epithelial apoptosis is mediated by p53-apoptotic pathway through the activation of p53-upregulated modulator of apoptosis (PUMA), Bcl-2 associated-X protein (BAX), Bcl-2 associated death promoter (BAD) and Bcl-2 antagonist/killer-1 (BAK1) proteins. Previously, we showed that chromofungin (CHGA47-66; CHR) protects against acute colitis by regulating macrophage-cytokines production. However, the effects of CHR on ER stress/p53-dependent apoptosis in colitis are still unknown. We aimed to investigate whether CHR suppress inflammation-induced epithelial apoptosis through ER stress/p53-apoptosis in colitis UC-related colitis was induced in C57BL/6 mice (7 weeks) by administering DSS (5%, 5 days). Preventive CHR (2.5 mg/kg/day) or vehicle (Saline) treatments started 1-day before colitis induction and lasted for 5-days. Disease activity index, histologic scores, XBP1, and modulator of apoptosis, PUMA, BAD, BAX, BAK1were quantified using whole colonic sections and q-RT-PCR. Naive peritoneal macrophages were exposed to CHR (200 ng/ml, 2h) or PBS and then to LPS (100 ng/ml, 6h) to promote classically activated macrophages (M1) and the same markers were studied. In colitic conditions, CHR treatment ameliorated the onset and severity of colitis, which was associated with a significant reduction in ER stress/p53-dependent apoptosis as reflected by a significant decrease of Xbp1, Puma, Bad, Bax and Bak1. In vitro, compared to untreated group, LPS-stimulated macrophages treated with CHR demonstrated a significant decrease of Xbp1, Puma, Bad, Bax and Bak1 when compared to LPS PBS-treated macrophages. CHR decreases the severity of colitis and the inflammatory process via the suppression of mucosal and pro-inflammatory macrophages-related ER stress and p53-dependent apoptosis. Functional analysis of CHGA may lead to a novel therapy for IBD. CCC
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".