Abstract
Alpinia pricei Hayata is a Formosan plant which has been popularly used as nutraceutical or folk medicine for inflammation and various disorders. An active compound of the plant rhizomes, desmethoxyyangonin (DMY), was identified in this study for its novel effect against endotoxin lipopolysaccharide (LPS)-stimulated inflammation in murine macrophages and LPS/D-galactosamine (LPS/D-GalN)-induced fulminant hepatitis in mice. DMY was observed to significantly inhibit proliferation and activation of T cells ex vivo and the activity of several pro-inflammatory mediators in vitro. DMY also protected LPS/D-GalN−induced acute hepatic damages in mice through inhibiting aminotransferases activities and infiltrations of inflammatory macrophages, neutrophils and pathogenic T cells into the liver tissues. In addition, pretreatment with DMY significantly improved the survival rate of LPS/D-GalN−treated mice to 90% (9/10), compared to LPS/D-GalN−treated group (40%, 4/10). UPLC/MS platform-based comparative metabolomics approach was used to explore the serum metabolic profile in fulminant hepatic failure (FHF) mice with or without the DMY pretreatment. The results showed that LPS/D-GalN−induced hepatic damage is likely through perturbing amino acid metabolism, which leads to decreased pyruvate formation via catalysis of aminotransferases, and DMY treatment can prevent to a certain degree of these alterations in metabolic network in mouse caused by LPS/D-GalN. Mechanistic investigation demonstrated that DMY protects LPS or LPS/D-GalN−induced damages in cell or liver tissues mainly through de-regulating IKK/NFκB and Jak2/STAT3 signaling pathways. This report provides evidence-based knowledge to support the rationale for the use of A. pricei root extract in anti-inflammation and also its new function as hepatoprotetive agent against fulminant hepatitis.
Highlights
Inflammation is a syndrome responsive to pathogen infection or injury
Fulminant hepatitis is associated with a high mortality rate; we studied the protective effect of DMY on LPS/DGalN−induced mortality in ICR mice
The results showed that 62% to 88% of iNOS mRNA expression was inhibited by 150~200 μM DMY as compared with LPS alone (Figure 1C), and the iNOS protein level was more significantly inhibited by DMY in a dosedependent manner, with more than 60% of the protein level of iNOS inhibited at > 75 μM DMY as compared with LPS alone (Figure 1D)
Summary
Inflammation is a syndrome responsive to pathogen infection or injury. Stimuli−induced production of pro-inflammatory mediators in macrophages, such as TNF-α and NO can cause acute inflammatory responses and may result in inflammatory diseases. LPS from the outer membrane of Gram-negative bacteria promotes secretion of the pro-inflammatory mediators by interacting with the CD14/Toll-like receptor 4/MD2 receptor complex in many cell types such as macrophages and endothelial cells [1]. LPS can induce mRNA or protein levels of iNOS, which catalyzes oxidative deamination of L-arginine to produce NO. LPS promotes NO production to induce inflammation and liver toxicity by activating iNOS in Kupffer cells, endothelial cells and hepatocytes [2]. Some plant natural compounds such as curcumin and tea polyphenols possess hepatoprotective functions by inhibiting iNOS in LPS–induced liver damage [3]
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