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Título
Melatonin inhibits the sphingosine kinase 1/sphingosine-1-phosphate signaling pathway in rabbits with fulminant hepatitis of viral origin
Autor
Facultad/Centro
Área de conocimiento
Datos de la obra
Journal of Pineal Research, 2016
Editor
Wiley
Fecha
2016-04-23
Abstract
The sphingosine kinase (SphK)1/sphingosine-1-phosphate (S1P) pathway is involved in
multiple biological processes, including liver diseases. This study investigate whether modulation
of the SphK1/S1P system associates to the beneficial effects of melatonin in an animal model of
acute liver failure (ALF) induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were
experimentally infected with 2x104 hemagglutination units of a RHDV isolate and received 20
mg/kg of melatonin at 0 hr, 12 hr and 24 hr postinfection. Liver mRNA levels, protein
concentration and immunohistochemical labelling for SphK1 increased in RHDV-infected rabbits.
S1P production and protein expression of the S1PR1 receptor were significantly elevated following
RHDV infection. These effects were significantly reduced by melatonin. Rabbits also exhibited
increased expression of toll-like receptor (TLR)4, tumor necrosis factor alpha (TNF-α), interleukin
(IL)-6, nuclear factor-kappa B (NF-κB) p50 and p65 subunits and phosphorylated inhibitor of kappa
B (IκB)α. Melatonin administration significantly inhibited those changes and induced a decreased
immunoreactivity for RHDV viral VP60 antigen in the liver. Results obtained indicate that the
SphK1/S1P system activates in parallel to viral replication and the inflammatory process induced by
the virus. Inhibition of the lipid signaling pathway by the indole reveals novel molecular pathways
that may account for the protective effect of melatonin in this animal model of ALF, and supports
the potential of melatonin as an antiviral agent
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