GL1001 Inhibition of ACE2 is Gastroprotective in Rat Models of Gastritits
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».