Abstract
Fulminant hepatic failure (FHF) is a rare, life-threatening liver disease with a poor prognosis. Administration of D-galactosamine (GalN) and lipopolysaccharide (LPS) triggers acute liver injury in mice, simulating many clinical features of FHF in humans; therefore, this disease model is often used to investigate potential therapeutic interventions to treat FHF. Recently, suppression of the nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome, was shown to alleviate the severity of GalN/LPS-induced liver damage in mice. Therefore, the goal of this study was to find dietary exosome-like nanoparticles (ELNs) with therapeutic potential in curbing FHF by suppressing the NLRP3 inflammasome. Seven commonly consumed mushrooms were used to extract ELNs. These mushrooms were found to contain ELNs composed of RNAs, proteins, and lipids. Among these mushroom-derived ELNs, only shiitake mushroom-derived ELNs (S-ELNs) substantially inhibited NLRP3 inflammasome activation by preventing inflammasome formation in primary macrophages. S-ELNs also suppressed the secretion of interleukin (IL)-6, as well as both protein and mRNA levels of the Il1b gene. Remarkably, pre-treatment with S-ELNs protected mice from GalN/LPS-induced acute liver injury. Therefore, S-ELNs, identified as potent new inhibitors of the NLRP3 inflammasome, represent a promising class of agents with the potential to combat FHF.
Highlights
Fulminant hepatic failure (FHF) is a rare liver disease characterized by abrupt and extensive death of hepatocytes, as well as inflammation, coagulopathy, and hepatic encephalopathy [1,2]
The nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome has been found to play a critical role in GalN/LPS-induced acute liver injury in mice. mRNA and protein levels of the Nlrp3 gene are increased in mice after GalN/LPS challenge [8,9], and inhibition of the NLRP3 inflammasome with its specific inhibitor MCC950 ameliorates the severity of GalN/LPS-induced acute liver injury in mice [6]
exosome-like nanoparticles (ELNs) were extracted from all seven mushrooms
Summary
Fulminant hepatic failure (FHF) is a rare liver disease characterized by abrupt and extensive death of hepatocytes, as well as inflammation, coagulopathy, and hepatic encephalopathy [1,2]. Liver transplantation has been the most effective therapeutic modality for treating FHF in clinical practice, but the availability of donor livers is often limited [1,2]. Identifying new agents that have therapeutic potential in treating FHF is highly desirable. Administration of D-galactosamine (GalN) and a low dose of lipopolysaccharide (LPS) triggers acute liver damage in mice, simulating many of the clinical manifestations of FHF in humans [4]. GalN/LPS-induced acute liver injury in mice is used extensively to investigate the molecular mechanisms and potential therapeutic interventions of FHF [5,6,7]. The nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome has been found to play a critical role in GalN/LPS-induced acute liver injury in mice. The nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome has been found to play a critical role in GalN/LPS-induced acute liver injury in mice. mRNA and protein levels of the Nlrp gene are increased in mice after GalN/LPS challenge [8,9], and inhibition of the NLRP3 inflammasome with its specific inhibitor MCC950 ameliorates the severity of GalN/LPS-induced acute liver injury in mice [6]
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