title: Suppression of nuclear factor-kappa B and mitogen-activated protein kinase signalling pathways by goshonoside-F5 extracted from Rubi Fructus.
abstract: Rubi Fructus, a traditional Chinese medicine, was considered as an anti-inflammatory agent in folk medicine. In the present study, we investigated the signalling pathways involved in the anti-inflammatory effects of goshonoside-F5 (GF5), isolated from Rubi Fructus, in peritoneal macrophages and examined its therapeutic effect in a mouse endotoxic shock model. GF5 decreased NO and PGE2 production in LPS-stimulated macrophages (IC50=3.84 and 3.16μM). This effect involved the suppression of NOS-2 and COX-2 gene expression at the transcriptional level. Examination of the effects of GF5 on NF-κB signalling demonstrated that it inhibits the phosphorylation of IκB-α and IκB-β, blocking their degradation and the nuclear translocation of the NF-κB p65 subunit. Moreover, inhibition of MAPK signalling was also observed, and phosphorylation of p38 and JNK was suppressed in the presence of GF5. Inflammatory cytokines, including IL-6 and TNF-α, were down-regulated by this compound after activation with LPS (IC50=17.04 and 4.09μM). Additionally, GF5 (30 and 90mg/kg, i.p.) significantly reduced the circulating cytokine levels (IL-6 and TNF-α) and increased survival in a mouse model of endotoxemia. These results show that GF5 significantly inhibits the pro-inflammatory response induced by LPS, both in vitro and in vivo. Our results provide a strong pharmacological basis for further understanding the potential therapeutic role of GF5 in inflammatory disease and shed new light on the bioactivity of ent-labdane diterpene glucoside.
authors.affiliation: Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: He
authors.affiliation: Department of Otorhinolaryngology, Changhai Hospital, Shanghai 200433, China. Electronic address: docchen5775@yahoo.com.cn.
authors.forename: Shi-Cai
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Department of Diving Medicine, Faculty of Navy Medicine, Second Military Medical University, Shanghai 200433, China.
authors.forename: Run-Ping
authors.initials: RP
authors.lastname: Li
authors.affiliation: Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Liang-Xi
authors.initials: LX
authors.lastname: Yuan
authors.affiliation: Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: drbaojm@gmail.com.
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Bao
authors.affiliation: Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: mlguo@126.com.
authors.forename: Mei-Li
authors.initials: ML
authors.lastname: Guo
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D002478:Cells, Cultured; D005419:Flavonoids / Q000008:administration & dosage*; D007165:Immunosuppression Therapy; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D008516:Medicine, Chinese Traditional / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D065856:Rubus / Q000276:immunology; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005419:Flavonoids; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C000588444:goshonoside-F5; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases
keywords: Anti-inflammatory; Ent-labdane diterpene glucoside; MAPK; Macrophage; NF-κB; Rubi Fructus