CHOLESTATIC LIVER DISEASE AND BRAIN DYSFUNCTION: ROLE OF THE ARYL HYDROCARBON RECEPTOR
Notice bibliographique
Résumé
Background Cholestatic liver disease is associated with immune‐mediated inflammatory liver injury and tissue damage. This disorder is also associated with brain dysfunction and behavioural changes, notably fatigue, depression and social withdrawal. The mechanisms leading to these central nervous system abnormalities are unknown, however, they are associated with neuroinflammation in the brain. Microglia and astrocytes are two glial cell populations that play key roles in neuroinflammation. Activated glia display morphological changes, secrete cytokines, and mediate electrophysiological changes, altering the normal functioning of the brain. The aryl hydrocarbon receptor (AhR) is a transcription factor involved in the immune response. AhR is present on glia and its’ activation has been shown to reduce CNS inflammation. The role of the AhR in cholestatic liver disease has yet to examined. Aims To study the function of the AhR and its ligands in an extensively characterized model of cholestic liver disease. We will test the hypothesis that activation of AhR in the brain will reduce neuroinflammation and associated behavioral deficits observed in cholestatic mice. Methods Male C57Bl/6J mice had cholestasis induced by bile duct ligation (BDL); comparisons were made to sham‐operated controls. Mice were tested for social interaction with a 4‐week old juvenile male in their home cage and the number of social interaction attempts quantified. After this behavioral assay, mice were euthanized, brains were removed and processed for immunofluorescence analysis. Brain sections were stained for markers of microglia (IBA‐1) and astrocytes (GFAP). Microglia were counted and astrocyte activation was qualitatively assessed as higher GFAP immunofluorescence. PCR was used to quantify relative gene expression of AhR and its downstream gene targets (eg. CYP1A1) in mice that recived treatment with beta‐napthoflavone (BNF), a potent AhR agonist, or in vehicle treated controls. Results BDL mice made significantly fewer attempts to interact with the juvenile as compared to controls (P<0.05). We also observed a significant increase in IBA‐1 immunoreactive cell numbers in both the CA1 region of the hippocampus and the hypothalamic paraventricular nucleus (PVN, P<0.05). BDL mice also displayed marked increases in GFAP+ staining in the PVN, but not the CA1 region of hippocampus, in contrast to sham controls. Lastly, we found that BNF significantly upregulated CYP1A1 (P<0.05) in the liver and brain prefrontal cortex of mice. We are currently examining whether BNF can downregulate neuroinflammation and improve decreased social interaction behaviors in cholestatic mice. Conclusion Cholestatic liver damage was associated with impaired social behavior. Further, glial activation, an indicator of neuroinflammation was significantly increased in components of the brain limbic system associated with the response to stress, learning, and memory. Future experiments will address whether activation of the AhR will ameliorate neuroinflammation and behavioral changes observed in mice with cholestatic liver injury. Support or Funding Information Canadian Institutes of Health Research
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) | 0,000 | 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 | 0,001 |
| 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 ».