A53 NOVEL PROTEASE–HISTAMINE INTERACTIONS POTENTIATE PAIN SIGNALING EVOKED BY FECAL SUPERNATANTS FROM IBS PATIENTS
Notice bibliographique
Résumé
Abstract Background Proteases and histamine, originating from intestinal tissue and/or the microbiota, have each been implicated in the severe pain symptoms reported by patients with irritable bowel syndrome (IBS). However, the effects of their combined signaling and the mechanisms involved have not been studied. Aims To determine whether histamine and trypsin synergistically enhance colonic nociceptive signaling and, if so, to study the mechanisms involved. Methods Fecal supernatants (FS) were obtained from IBS patients with low and high pain scores. Responses to luminal application of FS, histamine and protease (trypsin) and antagonists (H1R-pyrilamine, PAR2-GB83) were studied using ex vivo mouse colonic afferent nerve recordings. In mechanistic studies, excitability of isolated mouse dorsal root ganglia (DRG) neurons was measured using patch clamp recordings of rheobase after combined or sequential application of agonists. To study endosomal signaling, neurons were incubated with clathrin inhibitor, pitstop2, before agonists. Using HEK cells, recruitment of mGαq to PAR2 and H1R at the plasma membrane (CAAX) or early endosome (Rab5) was measured using bioluminescence resonance energy transfer (BRET) in response to sequential application of increasing doses of trypsin and histamine. Results In colonic afferent nerve recordings, FS from IBS patients with high pain scores increased mechanosensitivity (50%; p <0.001) and this was blocked by either a PAR2 and H1R antagonist, whereas FS from those with low pain scores had no effect. Trypsin and histamine at subthreshold concentrations (30 μM) alone had no effect. However, their co-application increased afferent mechanosensitivity (46%; p <0.001); similar effects were observed in patch clamp recordings from DRG neurons (rheobase decreased 33%; p <0.05). To study the mechanism of this synergistic interaction, DRG neurons were recorded after a sequential incubation with histamine and proteases. Incubation first with histamine had no effect (p=0.55) on the subsequent trypsin-mediated PAR2 excitability but incubation first with trypsin amplified the histamine response by 42 % (p<0.01). This PAR2-mediated action was blocked by inhibitors of endosomal signaling. In keeping with these findings, BRET studies revealed that incubation first with trypsin promoted mGαq recruitment to the plasma membrane and early endosomes, whereas histamine did not. Conclusions Conclusion: FS from IBS patients with high pain scores caused exaggerated pain signaling from the mouse colon and was mediated by the synergistic action of histamine and proteases. Mechanistic studies revealed a novel pathway where trypsin-mediated PAR2 endosomal signaling amplified histamine-evoked pain signaling. These findings could inform future studies of IBS therapies and biomarkers. Funding Agencies CIHR
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,002 |
| 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) | 0,000 | 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 tête enseignante, 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 ».