An anti-inflammatory ent-kaurane from the stems of Annona squamosa that inhibits various human neutrophil functions.
We have previously shown that 11 ent-kauranes isolated from the stems of Annona squamosa exhibited immunomodulating effects in leukocytes. In this study, a cellular model using isolated human neutrophils, which are important in the pathogenesis of rheumatoid arthritis, ischemia-reperfusion injury, chronic obstructive pulmonary disease, asthma and other inflammatory diseases, was established in order to elucidate the anti-inflammatory functions of 16beta,17-dihydroxy-ent-kauran-19-oic acid (1). Reactive oxygen species (ROS) and granule proteases produced by neutrophils contribute to the pathogenesis of inflammatory diseases. Compound 1 inhibited the generation of superoxide anion, the formation of ROS, and the release of elastase in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-activated human neutrophils in a concentration-dependent manner with IC (50) values of 3.95 +/- 0.68, 12.20 +/- 2.16, and 12.52 +/- 2.26 microM, respectively. The anti-inflammatory actions were not attributable to cytotoxicity because incubation of the neutrophils with 1 did not result in lactate dehydrogenase release. Compound 1 did not display antioxidant or superoxide anion-scavenging activity. Furthermore, neither subcellular NADPH oxidase activity nor cAMP-dependent pathways were altered by 1. Compound 1 significantly inhibited rapid calcium release from internal calcium stores induced by FMLP but not by thapsigargin. In summary, the presented results indicate that the inhibitory effects of 1 on respiratory burst and degranulation of human neutrophils are through the inhibition of cytosolic calcium mobilization, but not via the cAMP-dependent pathways.
Yeh
Shang-Hsin
SH
Graduate Institute of Natural Products, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan 333, Taoyuan, Taiwan, ROC.
Chang
Fang-Rong
FR
Wu
Yang-Chang
YC
Yang
Yu-Liang
YL
Zhuo
Shi-Kai
SK
Hwang
Tsong-Long
TL
D000328:Adult; D031041:Annona; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds; D002118:Calcium / Q000378:metabolism; D045786:Diterpenes, Kaurane / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D008517:Phytotherapy; D010851:Picrates / Q000737:chemistry; D018547:Plant Stems; D016897:Respiratory Burst / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D045786:Diterpenes, Kaurane; D010851:Picrates; C004931:1,1-diphenyl-2-picrylhydrazyl; D002118:Calcium