title: The hederagenin saponin SMG-1 is a natural FMLP receptor inhibitor that suppresses human neutrophil activation.
abstract: The pericarp of Sapindus mukorossi Gaertn is traditionally used as an expectorant in Japan, China, and Taiwan. Activated neutrophils produce high concentrations of the superoxide anion (O(2)(-)) and elastase known to be involved in airway mucus hypersecretion. In the present study, the anti-inflammatory functions of hederagenin 3-O-(3,4-O-di-acetyl-alpha-L-arabinopyranoside)-(1-->3)-alpha-l-rhamnopyranosyl-(1-->2)-alpha-l-arabinopyranoside (SMG-1), a saponin isolated from S. mukorossi, and its underlying mechanisms were investigated in human neutrophils. SMG-1 potently and concentration-dependently inhibited O(2)(*-) generation and elastase release in N-Formyl-Met-Leu-Phe (FMLP)-activated human neutrophils. Furthermore, SMG-1 reduced membrane-associated p47(phox) expression in FMLP-induced intact neutrophils, but did not alter subcellular NADPH oxidase activity in reconstituted systems. SMG-1 attenuated FMLP-induced increase of cytosolic calcium concentration and phosphorylation of p38 MAPK, ERK, JNK, and AKT. However, SMG-1 displayed no effect on cellular cAMP levels and activity of adenylate cyclase and phosphodiesterase. Significantly, receptor-binding analysis showed that SMG-1 inhibited FMLP binding to its receptor in a concentration-dependent manner. In contrast, neither phorbol myristate acetate-induced O(2)(*-) generation and MAPKs activation nor thapsigargin-caused calcium mobilization was altered by SMG-1. Taken together, our results demonstrate that SMG-1 is a natural inhibitor of the FMLP receptor, which may have the potential to be developed into a useful new therapeutic agent for treating neutrophilic inflammatory diseases.
authors.affiliation: Graduate Institute of Natural Products, Chang Gung University, Taoyuan 333, Taiwan. htl@mail.cgu.edu.tw
authors.forename: Tsong-Long
authors.initials: TL
authors.lastname: Hwang
authors.forename: Chien-Chiao
authors.initials: CC
authors.lastname: Wang
authors.forename: Yao-Haur
authors.initials: YH
authors.lastname: Kuo
authors.forename: Hui-Chi
authors.initials: HC
authors.lastname: Huang
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
authors.forename: Liang-Mou
authors.initials: LM
authors.lastname: Kuo
authors.forename: Yi-Hsiu
authors.initials: YH
authors.lastname: Wu
mesh_terms: D002118:Calcium; D000242:Cyclic AMP; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010196:Pancreatic Elastase; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors*; D032127:Sapindus / Q000737:chemistry; D012503:Saponins / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D044042:Receptors, Formyl Peptide; D012503:Saponins; C552533:hederagenin 3-O-(3,4-O-diacetylarabinopyranoside)-1-3-rhamnopyranosyl-1-2-arabinopyranoside; D009828:Oleanolic Acid; D000242:Cyclic AMP; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D010196:Pancreatic Elastase; C025763:hederagenin; D002118:Calcium