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Amomum tsao‐ko fruit extract suppresses lipopolysaccharide‐induced inducible nitric oxide synthase by inducing heme oxygenase‐1 in macrophages and in septic mice
Author(s) -
Shin JiSun,
Ryu Suran,
Jang Dae Sik,
Cho YoungWuk,
Chung Eun Kyung,
Lee KyungTae
Publication year - 2015
Publication title -
international journal of experimental pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.671
H-Index - 72
eISSN - 1365-2613
pISSN - 0959-9673
DOI - 10.1111/iep.12159
Subject(s) - heme oxygenase , lipopolysaccharide , nitric oxide synthase , nitric oxide , heme , atp synthase , chemistry , pharmacology , biochemistry , biology , enzyme , immunology , organic chemistry
Summary Amomum tsao‐ko Crevost et Lemarié (Zingiberaceae) has traditionally been used to treat inflammatory and infectious diseases, such as throat infections, malaria, abdominal pain and diarrhoea. This study was designed to assess the anti‐inflammatory effects and the molecular mechanisms of the methanol extract of A. tsao‐ko ( AOM ) in lipopolysaccharide ( LPS )‐induced RAW 264.7 macrophages and in a murine model of sepsis. In LPS ‐induced RAW 264.7 macrophages, AOM reduced the production of nitric oxide ( NO ) by inhibiting inducible nitric oxide synthase ( iNOS ) expression, and increased heme oxygenase‐1 ( HO ‐1) expression at the protein and mRNA levels. Pretreatment with Sn PP (a selective inhibitor of HO ‐1) and silencing HO ‐1 using si RNA prevented the AOM ‐mediated inhibition of NO production and iNOS expression. Furthermore, AOM increased the expression and nuclear accumulation of NF ‐E2‐related factor 2 (Nrf2), which enhanced Nrf2 binding to antioxidant response element ( ARE ). In addition, AOM induced the phosphorylation of extracellular regulated kinase ( ERK ) and c‐Jun N‐terminal kinase ( JNK ) and generated reactive oxygen species ( ROS ). Furthermore, pretreatment with N‐acetyl‐ l ‐cysteine ( NAC ; a ROS scavenger) diminished the AOM ‐induced phosphorylation of ERK and JNK and AOM ‐induced HO ‐1 expression, suggesting that ERK and JNK are downstream mediators of ROS during the AOM ‐induced signalling of HO ‐1 expression. In LPS ‐induced endotoxaemic mice, pretreatment with AOM reduced NO serum levels and liver iNOS expression and increased HO ‐1 expression and survival rates. These results indicate that AOM strongly inhibits LPS ‐induced NO production by activating the ROS / MAPK s/Nrf2‐mediated HO ‐1 signalling pathway, and supports its pharmacological effects on inflammatory diseases.