Genipin protects d-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the necroptosis-mediated inflammasome signaling

Jul 16, 2017European journal of pharmacology

Genipin may protect the liver from damage caused by d-galactosamine and bacterial toxins by blocking a form of programmed cell death and inflammation

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Abstract

Genipin at doses of 25, 50, and 100 mg/kg improved survival rates in mice with acute liver failure induced by d-galactosamine and lipopolysaccharide.

Genipin reduced increases in serum aminotransferase activities and inflammatory cytokines following acute liver failure.
The compound decreased the expression of proteins associated with necroptosis, including RIP3 and phosphorylated RIP1.
Genipin diminished the formation of the RIP1/RIP3 necrosome complex in the context of liver injury.
Serum levels of high-mobility group box 1 and interleukin-33, elevated by liver damage, were reduced with genipin treatment.
Genipin also lowered the expression of inflammasome components, such as NLRP3, ASC, and caspase-1, which are linked to inflammatory responses.

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Acute liver failure (ALF) is a life-threatening syndrome resulting from massive inflammation and hepatocyte death. Necroptosis, a programmed cell death controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, has been shown to play an important role in regulating inflammation via crosstalk between other intracellular signaling. The inflammasome is a major intracellular multiprotein that induces inflammatory responses by mediating immune cell infiltration, thus potentiating injury. Genipin, a major active compound of the gardenia fruit, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties. This study investigated the hepatoprotective mechanisms of genipin on d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced ALF, particularly focusing on interaction between necroptosis and inflammasome. Mice were given an intraperitoneal injection of genipin (25, 50, and 100mg/kg) or necrostatin-1 (Nec-1, a necroptosis inhibitor; 1.8mg/kg) 1h prior to GalN (800mg/kg)/LPS (40μg/kg) injection and were killed 3h after GalN/LPS injection. Genipin improved the survival rate and attenuated increases in serum aminotransferase activities and inflammatory cytokines after GalN/LPS injection. Genipin reduced GalN/LPS-induced increases in RIP3, phosphorylated RIP1 and RIP3 protein expression, and RIP1/RIP3 necrosome complex, similar to the effects of Nec-1. GalN/LPS significantly increased serum levels of high-mobility group box 1 and interleukin (IL)-33, which were attenuated by genipin and Nec-1. Moreover, similar to Nec-1, genipin attenuated GalN/LPS-induced increases in the protein expression levels of NLRP3, ASC, and caspase-1, inflammasome components, and levels of liver and serum IL-1β. Taken together, our findings suggest that genipin ameliorates GalN/LPS-induced hepatocellular damage by suppressing necroptosis-mediated inflammasome signaling.

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Genipin protects d-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the necroptosis-mediated inflammasome signaling

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