Vitamin D can mitigate sepsis-associated neurodegeneration by inhibiting exogenous histone-induced pyroptosis and ferroptosis: Implications for brain protection and cognitive preservation
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BACKGROUND: Sepsis-induced neurodegeneration and cognitive dysfunction remain critical challenges worldwide. Vitamin D was reported to reduce neuronal injury and neurotoxicity and its deficiency was associated with neurocognitive disorders. This study investigates the mechanisms by which vitamin D exerts neuroprotective potential against damage-associated molecular patterns (DAMPs), specifically extracellular histones, in sepsis-related brain dysfunction. METHODS: The cultured mouse hippocampal neuronal HT22 cells were exposed to 20 µg/ml exogenous histone for 24 h to induce pyroptosis and ferroptosis in the presence or absence of the active form of vitamin D, calcitriol (1 nM). A cecal ligation and puncture mouse sepsis model was used to evaluate histone release and pyroptosis/ferroptosis biomarkers in the brain together with neurobehavioral performance with or without calcitriol treatment (1 µg/kg, i.p. injection) at 24 h or 1 week after sepsis onset. RESULTS: In vitro, histone exposure triggered both pyroptosis and ferroptosis in neuronal cells, which was significantly suppressed by calcitriol treatment with the reduced expression of caspase-1 by 38 %, GSDMD by 30 %, ACSL4 by 33 %, and the increased expression of GPX4 by 35 % (n = 6, P < 0.05). Similarly, in vivo, calcitriol treatment inhibited both neuronal pyroptosis and ferroptosis by reducing expression of pyroptosis marker, GSDMD/NeuN (11.6 ± 1.2 % vs. 19.4 ± 1.1 %) and increasing expression of ferroptosis marker, GPX4/NeuN (21.4 ± 1.7 % vs. 13.5 ± 1.1 %), in the brain of septic mice (n = 6, P < 0.01). In addition, calcitriol increased survival rate (72 % vs. 41 %) and ameliorated cognitive dysfunction of septic mice (n = 8-13, P < 0.05). CONCLUSIONS: This study demonstrates that vitamin D exerts a neuroprotective effect against sepsis by attenuating histone-induced pyroptosis and ferroptosis. These findings highlight the potential therapeutic role of vitamin D supplementation in mitigating brain dysfunction associated with sepsis which needs for further investigation.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Vitamin D can mitigate sepsis-associated neurodegeneration by inhibiting exogenous histone-induced pyroptosis and ferroptosis: Implications for brain protection and cognitive preservation
- Date Crossref
- 01/02/2025
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Capital Medical University Department of Anesthesiology pays non établi dans la noticeUniversité ou école supérieure
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Beijing Tian Tan Hospital pays non établi dans la noticeÉtablissement de santé
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Beijing Institute of Neurosurgery pays non établi dans la noticeStructure de recherche
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Chelsea and Westminster Hospital pays non établi dans la noticeÉtablissement de santé
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Imperial College London pays non établi dans la noticeUniversité ou école supérieure
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Children's Hospital of Zhejiang University pays non établi dans la noticeÉtablissement de santé
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Faculty of Medicine Department of Surgery and Cancer pays non établi dans la noticeUniversité ou école supérieure
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Zhejiang University School of Medicine Perioperative and Systems Medicine Laboratory pays non établi dans la noticeUniversité ou école supérieure
Department of Anesthesiology — Capital Medical University, Beijing Tian Tan Hospital et Beijing Institute of Neurosurgery, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.