GL1001 Inhibition of ACE2 is Gastroprotective in Rat Models of Gastritits
Bibliographic record
Abstract
GL1001 is a potent and selective inhibitor of ACE2 (angiotensin converting enzyme 2), a monocar boxy peptidase that is expressed in epithelial and submucosal cells throughout the gastrointestinal tract. The initial aim of the present work was to investigate whether GL1001 and ACE2 have a role in gastric diseases. Using an in silico approach we observed elevated levels of ACE2 mRNA in stomach tissue samples from human subjects with chronic gastritis compared to samples from non-gastritis subjects. Subsequently, using NF-κB-luciferase reporter mice we observed a strong inhibition of LPS-induced NF-κB activity in the stomach of reporter mice treated with GL1001. These observations suggested a gastrointestinal anti-inflammatory action of GL1001. The second and main purpose of the present study was therefore, to evaluate the efficacy of GL1001 in rat models of gastritis. First, an acute NSAID-induced gastric toxicity model with indomethacin or diclofenac was performed. The studies involved pretreatment of fasted rats with a single oral dose of GL1001 (900 mg/kg), escalating single oral GL1001 doses (from 100 to 900 mg/kg) or control substances for 30 minutes, followed by treatment with indomethacin (20 mg/kg) or diclofenac (50 mg/kg) for 3 hours. Animals were then sacrificed, gastric damage scores were determined, and stomachs were extracted to determine GL1001 and NSAID pharmacodynamic effects. Second, a chronic gastric ulcer healing model was used; after 3 days of disease induction by serosal application of acetic acid, animals were given subcutaneous BID doses of GL1001 (150 and 450 mg/kg) or controls, for 7 days, and were then sacrificed to determine gastric ulcer areas. Oral administration of GL1001 prior to indomethacin or diclofenac treatment resulted in a significant reduction of the severity of indomethacin (61% decrease, p<0.05), or diclofenac-induced gastric damage (85% decrease, p<0.02). Gastroprotection correlated with full inhibition of gastric ACE2 activity by GL1001 and that of gastric PGE2 by NSAIDs. Expression analyses revealed increased mRNA levels of TNF-α, IL-1 and ICAM-1 in diclofenac-treated samples which had a significant positive correlation with gastric scores. Additionally, ELISA determinations of pro-inflammatory cytokines and chemokines in plasma and stomach homogenates revealed that MCP-1 and RANTES were significantly reduced in GL1001 samples compared with diclofenac samples. In the chronic gastric ulcer healing study, the subcutaneous low dose of GL1001 significantly enhanced healing of gastric ulcers (>30% increase healing, p<0.05) compared to its vehicle group. This study shows significant gastroprotection of orally administered GL1001 against NSAID-induced gastric damage and significant efficacy of subcutaneous dosing of GL1001 in enhancing gastric ulcer healing. GL1001 effects could therefore be due to prevention of gastric erosion and/or to acceleration of healing of the gastric mucosa. In aggregate, the data are consistent with a target-specific, gastroprotective, anti-inflammatory effect by GL1001 and underline its possible therapeutic application in gastrointestinal diseases.
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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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".