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

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 (40 mg/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.

Research Highlights
► Geniposide is isolated from Gardenia jasminoides Ellis under the guidance of affinity sensor technology.
► Geniposide binds to lipid A and neutralizes LPS.
► Geniposide attenuates LPS-induced over-production of pro-inflammatory cytokines.
► Geniposide protects sepsis model mice.