Hwang Tsong-Long, Li Guo-Long, Lan Yu-Hsuan, Chia Yi-Chen, Hsieh Pei-Wen, Wu Yi-Hsiu, Wu Yang-Chang
Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan.
Free Radic Biol Med. 2009 Feb 15;46(4):520-8. doi: 10.1016/j.freeradbiomed.2008.11.014. Epub 2008 Dec 6.
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.
乌藤在传统中药中被广泛用于治疗类风湿性关节炎。中性粒细胞的激活是炎症性疾病的一个关键特征。在此，我们研究了从乌藤中提取的一种黄酮类化合物异水飞蓟宾在人中性粒细胞中的抗炎功能及其潜在机制。异水飞蓟宾能有效且浓度依赖性地抑制甲酰 - L - 蛋氨酰 - L - 亮氨酰 - L - 苯丙氨酸（FMLP）激活的人中性粒细胞中超氧阴离子（O₂⁻*）的产生，IC₅₀值为0.34±0.03微摩尔。此外，异水飞蓟宾没有超氧阴离子清除能力，也未能改变亚细胞NADPH氧化酶活性。蛋白激酶A（PKA）抑制剂可逆转异水飞蓟宾对O₂⁻*产生的抑制作用。此外，异水飞蓟宾可增加FMLP激活的人中性粒细胞中cAMP的形成和PKA活性，这是通过抑制磷酸二酯酶（PDE）活性而非增加腺苷酸环化酶功能实现的。另外，异水飞蓟宾可降低FMLP诱导的细胞外调节激酶和c - Jun N端激酶的磷酸化，PKA抑制剂可逆转这一作用。相比之下，异水飞蓟宾未能改变FMLP诱导的p38丝裂原活化蛋白激酶的磷酸化和钙动员。总之，这些结果表明，异水飞蓟宾对人中性粒细胞中O₂⁻*产生的抑制作用与细胞内cAMP的升高以及通过抑制cAMP特异性PDE激活PKA有关。
