title: Potent inhibition of superoxide anion production in activated human neutrophils by isopedicin, a bioactive component of the Chinese medicinal herb Fissistigma oldhamii.
abstract: Fissistigma oldhamii is widely used in traditional Chinese medicine to treat rheumatoid arthritis. Activation of neutrophils is a key feature of inflammatory diseases. Herein, the anti-inflammatory functions of isopedicin, a flavanone derived from F. oldhamii, and its underlying mechanisms were investigated in human neutrophils. Isopedicin potently and concentration-dependently inhibited superoxide anion (O(2)(*)(-)) production in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-activated human neutrophils with an IC(50) value of 0.34+/-0.03 microM. Furthermore, isopedicin displayed no superoxide-scavenging ability, and it failed to alter subcellular NADPH oxidase activity. The inhibitory effect of isopedicin on O(2)(*)(-) production was reversed by protein kinase A (PKA) inhibitors. Moreover, isopedicin increased cAMP formation and PKA activity in FMLP-activated human neutrophils, which occurred through the inhibition of phosphodiesterase (PDE) activity but not an increase in adenylate cyclase function. In addition, isopedicin reduced FMLP-induced phosphorylation of extracellular regulated kinase and c-Jun N-terminal kinase, which was reversed by the PKA inhibitor. In contrast, isopedicin failed to alter FMLP-induced phosphorylation of p38 mitogen-activated protein kinase and calcium mobilization. In summary, these results demonstrate that inhibition of O(2)(*)(-) production in human neutrophils by isopedicin is associated with an elevation of cellular cAMP and activation of PKA through its inhibition of cAMP-specific PDE.
authors.affiliation: Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan. htl@mail.cgu.edu.tw
authors.forename: Tsong-Long
authors.initials: TL
authors.lastname: Hwang
authors.forename: Guo-Long
authors.initials: GL
authors.lastname: Li
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Lan
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Chia
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsieh
authors.forename: Yi-Hsiu
authors.initials: YH
authors.lastname: Wu
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
mesh_terms: D029061:Annonaceae; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000276:immunology / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D044950:Flavanones / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000276:immunology; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D018547:Plant Stems; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004365:Drugs, Chinese Herbal; D044950:Flavanones; C544922:isopedicin; D013481:Superoxides; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; C028610:flavanone