Xiaoxia Kong1,2,3, Guicheng Wu2,3,4, Sha Chen1, Lihua Zhang2,3, Fengyuan Li2,3, Tuo Shao2,3, Li Ren2,3,5, Shao-Yu Chen2,3, Hongyu Zhang6, Craig J McClain2,3,7, Wenke Feng2,3. 1. School of Basic Medical Sciences, Institute of Hypoxia Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China. 2. Hepatobiology and Toxicology Program, Department of Pharmacology and Toxicology, Alcohol Research Center, University of Louisville, Louisville, Kentucky. 3. Hepatobiology and Toxicology Program, Department of Medicine, Alcohol Research Center, University of Louisville, Louisville, Kentucky. 4. Department of Hepatology, Three Gorges Central Hospital, Chongqing, China. 5. First Affiliate Hospital, Xi'an Jiaotong University, Xi'an, Shanxi, China. 6. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. 7. Robley Rex Louisville VAMC, Louisville, Kentucky.
Abstract
BACKGROUND: Chronic alcohol intake increases circulating endotoxin levels causing excessive inflammation that aggravates the liver injury. (E)-2,3-dimethoxy-4'-methoxychalcone (L6H21), a derivative of chalcone, has been found to inhibit inflammation in cardiac diseases and nonalcoholic fatty liver disease. However, the use of L6H21 in alcoholic liver disease to inhibit exotoxin-associated inflammation has not been explored. In this study, we examined the effects of L6H21 on EtOH + LPS-induced hepatic inflammation, steatosis, and liver injury and investigated the underlying mechanisms. METHODS: C57BL6 mice were treated with 5% EtOH for 10 days, and LPS was given to the mice 6 hours before sacrificing. One group of mice was supplemented with L6H21 with EtOH and LPS. RAW264.7 cells were used to analyze the effects of L6H21 on macrophage activation. RESULTS: EtOH + LPS treatment significantly increased hepatic steatosis and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), which were reduced by L6H21 treatment. EtOH + LPS treatment increased hepatic inflammation, as shown by the increased hepatic protein levels of Toll-like receptor-4, p65, and p-IκB, and increased oxidative stress, as shown by protein carbonyl levels and reactive oxygen species formation, which were reduced by L6H21 treatment. In addition, L6H21 treatment markedly inhibited EtOH + LPS-elevated hepatic protein levels of NLRP3, cleaved caspase-1, cleaved IL-1β, and caspase-1-associated apoptosis. CONCLUSIONS: Our results demonstrate that L6H21 treatment inhibits EtOH + LPS-induced liver steatosis and injury through suppression of NLRP3 inflammasome activation. L6H21 may be used as an alternative strategy for ALD prevention/treatment.
BACKGROUND: Chronic alcohol intake increases circulating endotoxin levels causing excessive inflammation that aggravates the liver injury. (E)-2,3-dimethoxy-4'-methoxychalcone (L6H21), a derivative of chalcone, has been found to inhibit inflammation in cardiac diseases and nonalcoholic fatty liver disease. However, the use of L6H21 in alcoholic liver disease to inhibit exotoxin-associated inflammation has not been explored. In this study, we examined the effects of L6H21 on EtOH + LPS-induced hepatic inflammation, steatosis, and liver injury and investigated the underlying mechanisms. METHODS: C57BL6 mice were treated with 5% EtOH for 10 days, and LPS was given to the mice 6 hours before sacrificing. One group of mice was supplemented with L6H21 with EtOH and LPS. RAW264.7 cells were used to analyze the effects of L6H21 on macrophage activation. RESULTS:EtOH + LPS treatment significantly increased hepatic steatosis and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), which were reduced by L6H21 treatment. EtOH + LPS treatment increased hepatic inflammation, as shown by the increased hepatic protein levels of Toll-like receptor-4, p65, and p-IκB, and increased oxidative stress, as shown by protein carbonyl levels and reactive oxygen species formation, which were reduced by L6H21 treatment. In addition, L6H21 treatment markedly inhibited EtOH + LPS-elevated hepatic protein levels of NLRP3, cleaved caspase-1, cleaved IL-1β, and caspase-1-associated apoptosis. CONCLUSIONS: Our results demonstrate that L6H21 treatment inhibits EtOH + LPS-induced liver steatosis and injury through suppression of NLRP3 inflammasome activation. L6H21 may be used as an alternative strategy for ALD prevention/treatment.
Authors: Mark R Thursz; Paul Richardson; Michael Allison; Andrew Austin; Megan Bowers; Christopher P Day; Nichola Downs; Dermot Gleeson; Alastair MacGilchrist; Allister Grant; Steven Hood; Steven Masson; Anne McCune; Jane Mellor; John O'Grady; David Patch; Ian Ratcliffe; Paul Roderick; Louise Stanton; Nikhil Vergis; Mark Wright; Stephen Ryder; Ewan H Forrest Journal: N Engl J Med Date: 2015-04-23 Impact factor: 91.245
Authors: Heng-Hong Li; Kathryn Doiron; Andrew D Patterson; Frank J Gonzalez; Albert J Fornace Journal: J Transl Med Date: 2013-10-23 Impact factor: 5.531