28. Ketotifen Inhibits Dermal Fibroblast Responses To The Pro-fibrotic Effects Of TGF-beta
Notice bibliographique
Résumé
Purpose: During tissue repair, dermal fibroblasts become activated, begin to differentiate, and synthesize extracellular matrix (ECM) proteins to restore tissue integrity. Transforming growth factor (TGF)-beta is a major regulator in tissue repair and fibrosis, activating fibroblasts and eliciting many tissue repair processes. These include increases in alpha-smooth muscle actin (SMA), fibroblast differentiation into myofibroblasts, and increased collagen deposition. Dysregulated TGF-beta signaling has been implicated in scarring, chronic wounds, and other fibrotic conditions. Previously, the clinically-approved mast cell (MC) stabilizing agent ketotifen has been reported to decrease fibrous band thickness and myofibroblast numbers in the skin through MC-associated mechanisms of action. Our research examined the direct effects of ketotifen on human dermal fibroblasts. Methods: Human dermal fibroblasts (HDFs) were activated with recombinant TGF-beta [10ng/mL] for 48 hours to induce a pro-repair phenotype. Ketotifen [25uM] was added to fibroblasts 24 hours after TGF-beta activation. Untreated and ketotifen treatment-only groups served as controls. Gene expression and protein analyses were performed through qPCR, immunofluorescence, and western blotting. Fibroblast-populated collagen lattices were generated for functional assessments of contraction. Bleomycin-induced skin fibrosis was produced in mice. Ketotifen-supplemented or regular water was provided during bleomycin treatment. Skin collagen density was determined, after 21 days, using Masson’s Trichrome histological staining. Results: TGF-beta-activated HDFs treated with ketotifen showed significant decreases in cytoskeletal and contractility-associated genes ACTA2 (alpha-SMA), CNN1 (calponin 1), and TAGLN (transgelin) compared to TGF-beta-treated controls. Significantly reduced alpha-SMA protein expression was observed with ketotifen treatment in TGF-beta-activated HDFs, indicating impaired differentiation into myofibroblasts. Ketotifen increased phosphorylation of Yes-associated protein (YAP1) and decreased total transcriptional co-activator with PDZ-binding motif (TAZ) protein, suggesting impairment of transcriptional co-regulators involved in cytoskeletal-associated changes. Ketotifen also reduced phosphorylation of protein kinase B (AKT) in activated HDFs. Collagen lattice contraction was decreased with ketotifen treatment, further corroborating decreased contractility of activated HDFs given ketotifen. Using a murine model of skin fibrosis, ketotifen reduced dermal collagen density compared to controls. Conclusion: Previously, anti-fibrotic effects of ketotifen have been attributed to effects on MC stabilization. Here we show that ketotifen directly influences activated dermal fibroblasts by inhibiting differentiation and function through impairment of cytoskeletal and contractility-associated mechanisms in vitro and impairs collagen deposition in vivo. These results demonstrate a previously unknown mechanism and effect of a clinically-approved MC stabilizer in fibrotic settings.
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 | 0,000 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| 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 ».