Berberine (BRB) is commonly used in herbal medicine, but its mechanisms of action are poorly understood. In the present study, we tested BRB in steatohepatitis induced by a methionine- and choline-deficient (MCD) diet, in acute acetaminophen intoxication and in cultured murine macrophages. BRB markedly improved parameters of liver injury and necroinflammation induced by the MCD diet, although increased mortality was observed by mechanisms independent of bacterial infections or plasma levels of BRB. The MCD diet induced up-regulation of all components of the NLRP3 (NACHT, LRR and PYD domain-containing protein 3) inflammasome, and increased hepatic levels of mature IL-1β (interleukin 1β). All of these parameters were significantly reduced in mice treated with BRB. In mice administered an acetaminophen overdose, a model dependent on inflammasome activation, BRB reduced mortality and ALT (alanine aminotransferase) elevation, and limited the expression of inflammasome components. In vitro, LPS (lipopolysaccharide)-induced activation of NLRP3 inflammasome in RAW264.7 murine macrophages was markedly decreased by pre-incubation with BRB. BRB significantly limited the activation of the purinergic receptor P2X7, involved in the late phases of inflammasome activation. Upon P2X7 knockdown, the ability of BRB to block LPS-induced secretion of IL-1β was lost. These data indicate that administration of BRB ameliorates inflammation and injury in two unrelated murine models of liver damage. We demonstrate for the first time that BRB interferes with activation of the NLRP3 inflammasome pathway in vivo and in vitro, through a mechanism based on interference with activation of P2X7, a purinergic receptor involved in inflammasome activation.
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Research Article|
September 09 2016
NLRP3 inflammasome as a target of berberine in experimental murine liver injury: interference with P2X7 signalling
Elisa Vivoli;
Elisa Vivoli
*Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy
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Andrea Cappon;
Andrea Cappon
*Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy
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Stefano Milani;
Stefano Milani
†Dipartimento di Scienze Biomediche, Sperimentali e Cliniche “Mario Serio”, University of Florence, Florence, Italy
‡Centro di Ricerca Denothe, University of Florence, Florence, Italy
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Benedetta Piombanti;
Benedetta Piombanti
*Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy
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Angela Provenzano;
Angela Provenzano
*Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy
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Erica Novo;
Erica Novo
§Dipartimento di Scienze Cliniche e Biologiche, University of Turin, Turin, Italy
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Alessio Masi;
Alessio Masi
║Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, University of Florence, Florence, Italy
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Nadia Navari;
Nadia Navari
*Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy
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Roberto Narducci;
Roberto Narducci
║Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, University of Florence, Florence, Italy
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Guido Mannaioni;
Guido Mannaioni
║Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, University of Florence, Florence, Italy
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Gloriano Moneti;
Gloriano Moneti
¶Dipartimento di Scienze della Salute, University of Florence, Florence, Italy
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Claudia P. Oliveira;
Claudia P. Oliveira
**Department of Gastroenterology (LIM07), University of São Paulo School of Medicine, São Paulo, Brazil
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Maurizio Parola;
Maurizio Parola
§Dipartimento di Scienze Cliniche e Biologiche, University of Turin, Turin, Italy
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Fabio Marra
*Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy
‡Centro di Ricerca Denothe, University of Florence, Florence, Italy
Correspondence: Dr Fabio Marra (email [email protected]).
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Publisher: Portland Press Ltd
Received:
May 28 2016
Revision Received:
July 18 2016
Accepted:
July 20 2016
Accepted Manuscript online:
July 20 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2016) 130 (20): 1793–1806.
Article history
Received:
May 28 2016
Revision Received:
July 18 2016
Accepted:
July 20 2016
Accepted Manuscript online:
July 20 2016
Citation
Elisa Vivoli, Andrea Cappon, Stefano Milani, Benedetta Piombanti, Angela Provenzano, Erica Novo, Alessio Masi, Nadia Navari, Roberto Narducci, Guido Mannaioni, Gloriano Moneti, Claudia P. Oliveira, Maurizio Parola, Fabio Marra; NLRP3 inflammasome as a target of berberine in experimental murine liver injury: interference with P2X7 signalling. Clin Sci (Lond) 1 October 2016; 130 (20): 1793–1806. doi: https://doi.org/10.1042/CS20160400
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