Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-03675-z
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Funding
- Fondo Nacional de Desarrollo Cientifico y Tecnologico from the Government of Chile [FONDECYT 1150327, 1161646, 1150311, 1150106, PD3140396]
- Comision Nacional de Investigacion Cientifica y Tecnologica from the Government of Chile [CONICYT PIA/Basal PFB12/2007]
- Association-Francaise Contre Les Myopathies [AFM 16670]
- Millennium Institute on Immunology and Immunotherapy [P09-016-F]
- UNAB [DI-741-15/N]
- National Institutes of Health [R01 DK082451, U01 AA022489]
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Therapy for nonalcoholic steatohepatitis (NASH) is limited. Andrographolide (ANDRO), a botanical compound, has a potent anti-inflammatory activity due to its ability to inhibit NF-kB. ANDRO has been also shown to inhibit the NLRP3 inflammasome, a relevant pathway in NASH. Our aim was to evaluate the effects of ANDRO in NASH and its influence on inflammasome activation in this setting. Thus, mice were fed a choline-deficient-amino-acid-defined (CDAA) diet with/without concomitant ANDRO administration (1 mg/kg, 3-times/week). Also, we assessed serum levels of alanine-aminotransferase (ALT), liver histology, hepatic triglyceride content (HTC) and hepatic expression of pro-inflammatory, pro-fibrotic and inflammasome genes. Inflammasome activation was also evaluated in fat-laden HepG2 cells. Our results showed that ANDRO administration decreased HTC and attenuated hepatic inflammation and fibrosis in CDAA-fed mice. ANDRO treatment determined a strong reduction in hepatic macrophage infiltration and reduced hepatic mRNA levels of both pro-inflammatory and profibrotic genes. In addition, mice treated with ANDRO showed reduced expression of inflammasome genes. Finally, ANDRO inhibited LPS-induced interleukin-1 beta expression through NF-kB inhibition in fat-laden HepG2 cells and inflammasome disassembly. In conclusion, ANDRO administration reduces inflammation and fibrosis in experimental NASH. Inflammasome modulation by a NF-kB-dependent mechanism may be involved in the therapeutic effects of ANDRO.
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