A novel, hydrogen sulfide-releasing mesalamine derivative (ATB-429) exhibits enhanced anti-inflammatory and analgesic activity in experimental colitis
Notice bibliographique
Résumé
Mesalamine is the most common first-line therapy for IBD, but lacks potency. This limits the effectiveness of mesalamine, even when used at doses of 2-4 gram/day, to mild-to-moderate IBD. Hydrogen sulfide (H2S) has recently been shown to be an endogenous anti-inflammatory mediator, which inhibits leukocyte extravasation and reduces pain perception. We tested the hypothesis that an H2S-releasing derivative of mesalamine (ATB-429) would exert enhanced anti-inflammatory potency and efficacy in experimental colitis. The mouse models of DSS- and TNBS-induced colitis were used. After colitis was established, groups of mice were orally treated with mesalamine (0.33 mmol/kg) or ATB-429 (0.08 - 0.33 mmol/kg) daily for up to 10 days. In addition to macroscopic and microscopic scoring, tissue MPO activity and expression of mRNA for a variety of proand anti-inflammatory cytokines, chemokines and enzymes were measured. In separate studies, the effects of mesalamine vs. ATB-429 were compared in a rat model of colorectal-distention-induced visceral pain. Studies were performed in healthy rats and rats that had recovered from TNBS-induced colitis. ATB-429 exhibited an increase in potency and a broadening of efficacy as compared to mesalamine in both models of colitis. When a dose of 2 mg of TNBS was used, we observed mortality in vehicle-treated rats of 30%, which was not significantly reduced by treatment with mesalamine (25%) but was by ATB-429 (0%). Therapeutic administration of ATB-429 was more effective than equimolar doses of mesalamine in reducing the various parameters of TNBS-or DSS-induced colitis in mice (disease activity, macroscopic and microscopic scoring). In addition, ATB-429 more effectively reduced granulocyte infiltration (MPO) and mucosal expression of mRNA for TNFα, IFNγ, IL-2, IL-6, RANTES and iNOS. However, ATB-429 did not affect expression of mRNA for IL-10. Furthermore, ATB-429 but not mesalamine reduced the accumulation of CD11b+/Gr1+ cells in the lamina propria. In human peripheral blood monocytes, ATB-429 (but not mesalamine) concentration-dependently suppressed LPS-induced TNFα release. These effects of ATB-429 may be attributable to its ability to suppress NF-kB translocation, which was also observed. Mesalamine exerts only a minor analgesic effect in the colorectal-distention model in rats. In contrast, ATB-429 markedly reduced pain perception in this model, whether the studies were performed in healthy rats or rats that had recovered from colitis (the latter exhibited visceral hyperalgesia). These results demonstrate that the addition of an H2S-releasing moiety to mesalamine results in a significant increase in its potency (˜4-fold) as well as a marked broadening of its anti-inflammatory effects. Of particular importance in terms of potential use in the treatment of human disease is the observation that ATB-429 is able to significantly reduce visceral pain
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) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 ».