Peroxynitrite is key to Cylindrospermopsin-mediated MASLD to MASH progression via triggering TXNIP binding to NLRP3 and subsequent inflammasome activation
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Le résumé fourni par la source
Harmful algal bloom (HAB) toxins are shown to be associated with Metabolic dysfunction-associated steatohepatitis (MASH) progression. Several studies link the HAB toxin microcystin to hepatic inflammasome activation, but the role of cylindrospermopsin (CYN) in Metabolic dysfunction-associated steatotic liver disease (MASLD) pathology remains unknown. Using a mouse model of MASLD, we show that CYN exposure served as a second hit for MASLD to MASH progression, as shown by histopathology and NAS scoring. The pathology was attenuated by the use of NADPH oxidase 2 (NOX2) inhibitor apocynin and peroxynitrite inhibitor phenylboronic acid. Inhibition of peroxynitrite and other redox signaling processes decreased stellate cell activation and fibronectin protein in the hepatic lobules, thus confirming the involvement of the above nitrosative moiety in early fibrotic remodeling, crucial for MASH progression. Redox inhibitors also decreased the endothelial Nitric Oxide Synthase (eNOS)/inducible Nitric Oxide Synthase (iNOS) protein ratio, thus raising the yield of inducible nitric oxide and facilitating the uncoupling of eNOS. Mechanistically, peroxynitrite inhibitors coupled with attenuation of redox processes prevented Thioredoxin-interacting protein (TXNIP) colocalization with NLRP3 and resulted in the inhibition of NLRP3 inflammasome activation, a crucial mediator of hepatic inflammation in MASH. Hepatocyte-hepatic macrophage crosstalk, crucial for MASH progression, was shown to induce NOX2 activation, the generation of 3-nitrotyrosine in close proximity to iNOS, a predictive nitric oxide source, thus confirming the role of these cells in activating the inflammation cascade. The results show a crucial role of peroxynitrite in TXNIP-NLRP3 induced inflammasome activation and can be a crucial therapeutic target in treating MASH etiology from environmental exposure.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Peroxynitrite is key to Cylindrospermopsin-mediated MASLD to MASH progression via triggering TXNIP binding to NLRP3 and subsequent inflammasome activation
- Date Crossref
- 01/11/2025
- 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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Baylor University Department of Environmental Science pays non établi dans la noticeUniversité ou école supérieure
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The State University of New Jersey Rutgers pays non établi dans la noticeUniversité ou école supérieure
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University of the Basque Country pays non établi dans la noticeUniversité ou école supérieure
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Duke University Division of Gastroenterology pays non établi dans la noticeUniversité ou école supérieure
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Joe C. Wen School of Population & Public Health Environmental Health and Disease Laboratory pays non établi dans la noticeUniversité ou école supérieure
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Ernest Mario School of Pharmacy Department of Pharmacology and Toxicology pays non établi dans la noticeUniversité ou école supérieure
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Saint Louis University School of Medicine Department of Internal Medicine pays non établi dans la noticeUniversité ou école supérieure
Department of Environmental Science — Baylor University, Rutgers — The State University of New Jersey et University of the Basque Country, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.