title: Identification of a new anti-LPS agent, geniposide, from Gardenia jasminoides Ellis, and its ability of direct binding and neutralization of lipopolysaccharide in vitro and in vivo.
abstract: Lipopolysaccharide (LPS/endotoxin) is a key pathogen recognition molecule for sepsis. Currently, one of the therapeutic approaches for severe sepsis is focusing on the neutralization of LPS, and clinical trials have shown a lot of traditional Chinese herbs possess anti-sepsis function. Herein, to elucidate the bioactive components of traditional Chinese herbs that can neutralize LPS, the lipid A-binding abilities of sixty herbs were tested using affinity biosensor technology. The aqueous extract of Gardenia jasminoides Ellis, traditionally used to treat inflammation in Asian countries for centuries, was further investigated. Subsequently, a monomer, identified as geniposide, was isolated. In vitro, geniposide was found to directly bind LPS and neutralize LPS. It dose-dependently inhibited cytokines release from RAW264.7 cells induced by LPS without affecting the cell viability, and inhibited TNF-α mRNA expression up-regulated by LPS. However, geniposide did not decrease TNF-α release induced by CpG DNA, Poly I:C or IL-1β. Significantly, geniposide dose-dependently down-regulated TLR4 mRNA expression up-regulated by LPS, and suppressed the phosphorylations of p38 MAKP induced by LPS but not by IL-1β. In vivo, geniposide (40mg/kg) could significantly protect mice challenge with lethal heat-killed E. coli, and dose-dependently decreased the level of serum endotoxin which was tightly associated with the cytokine levels in endotoxemia mice. In summary, we successfully isolated geniposide from G. jasminoides Ellis. Geniposide directly bound LPS and neutralized LPS in vitro, and significantly protected sepsis model mice. Therefore, geniposide could be as a useful lead compound for anti-sepsis drug development.
authors.affiliation: Medical Research Center, Southwestern Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xinchuan
authors.initials: X
authors.lastname: Zheng
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cao
authors.forename: Yongling
authors.initials: Y
authors.lastname: Lu
authors.forename: Guo
authors.initials: G
authors.lastname: Wei
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Jiang
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D019446:Endotoxemia / Q000188:drug therapy; D005260:Female; D032062:Gardenia / Q000737:chemistry*; D005786:Gene Expression Regulation / Q000187:drug effects; D039823:Iridoids / Q000737:chemistry* / Q000494:pharmacology*; D008050:Lipid A / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D039823:Iridoids; D008050:Lipid A; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C007835:geniposide