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一种从番荔枝茎中提取的具有抗炎作用的对映贝壳杉烷,可抑制多种人类中性粒细胞功能。

An anti-inflammatory ent-kaurane from the stems of Annona squamosa that inhibits various human neutrophil functions.

作者信息

Yeh Shang-Hsin, Chang Fang-Rong, Wu Yang-Chang, Yang Yu-Liang, Zhuo Shi-Kai, Hwang Tsong-Long

机构信息

Graduate Institute of Natural Products, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan 333, Taoyuan, Taiwan, ROC.

出版信息

Planta Med. 2005 Oct;71(10):904-9. doi: 10.1055/s-2005-871234.

Abstract

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.

摘要

我们之前已经表明,从番荔枝茎中分离出的11种对映-贝壳杉烷类化合物在白细胞中表现出免疫调节作用。在本研究中,为了阐明16β,17-二羟基-对映-贝壳杉烷-19-酸(1)的抗炎功能,建立了一个使用分离的人中性粒细胞的细胞模型,人中性粒细胞在类风湿性关节炎、缺血-再灌注损伤、慢性阻塞性肺疾病、哮喘和其他炎症性疾病的发病机制中起重要作用。中性粒细胞产生的活性氧(ROS)和颗粒蛋白酶有助于炎症性疾病的发病机制。化合物1以浓度依赖性方式抑制甲酰-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的产生、ROS的形成以及弹性蛋白酶的释放,IC(50)值分别为3.95±0.68、12.20±2.16和12.52±2.26μM。抗炎作用并非归因于细胞毒性,因为用1孵育人中性粒细胞不会导致乳酸脱氢酶释放。化合物1不具有抗氧化或超氧阴离子清除活性。此外,1对亚细胞NADPH氧化酶活性和cAMP依赖性途径均无影响。化合物1显著抑制FMLP诱导的细胞内钙库快速钙释放,但对毒胡萝卜素诱导的钙释放无抑制作用。总之,所示结果表明,1对人中性粒细胞呼吸爆发和脱颗粒的抑制作用是通过抑制胞质钙动员,而不是通过cAMP依赖性途径。

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