Arzanol, a prenylated heterodimeric phloroglucinyl pyrone, inhibits eicosanoid biosynthesis and exhibits anti-inflammatory efficacy in vivo
Arzanol, a prenylated heterodimeric phloroglucinyl pyrone, inhibits eicosanoid biosynthesis and exhibits anti-inflammatory efficacy in vivo
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DOI：
10.1016/j.bcp.2010.09.025
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发表时间：
2011-01-15
影响因子：
5.8
通讯作者：
Werz, Oliver
中科院分区：
文献类型：
--
作者：
Bauer, Julia;Koeberle, Andreas;Werz, Oliver
基于其在体外抑制HIV-1在T细胞中的复制和单核细胞中促炎细胞因子释放的能力，戊烯基异二聚体间苯三酚被确定为意大利蜡菊中主要的抗炎和抗病毒成分。我们现在研究了arzanol对促炎类二十烷醇生物合成的活性，评估了其体外和体内的抗炎功效。Arzanol在体外抑制中性粒细胞5-脂氧合酶（EC 7.13.1134）活性和相关白三烯形成，以及环氧合酶(COX)-1 （EC 1.14.99.1）活性和COX-2衍生的前列腺素（PG）E-2的形成（IC50 = 2.3 ~ 9 μ M）。详细研究表明，arzanol主要抑制微粒体PGE(2)合成酶(mPGES)-1 (EC 5.3.99.3, IC50 = 0.4 μ M)，而不是COX-2。事实上，在脂多糖刺激的人单核细胞和人全血中，arzanol可以阻断COX-2/mPGES-1介导的PGE(2)的生物合成，但不能阻断COX-2衍生的血栓素B-2或6-酮PGF（1 α）的生物合成，COX-2或mPGES-1蛋白的表达不受影响。Arzanol能有效抑制卡拉胶诱导的大鼠胸膜炎的炎症反应（3.6 mg/kg, i.p），显著降低胸膜渗出液中PGE(2)的水平。综上所述，我们的数据表明，arzanol在体外和体内都能有效抑制促炎脂质介质如PGE(2)的生物合成，这为意大利红草的抗炎活性提供了机制基础，并为进一步临床前评估这种新型抗炎药物提供了基础。(C) 2010爱思唯尔公司版权所有。
Based on its capacity to inhibit in vitro HIV-1 replication in T cells and the release of pro-inflammatory cytokines in monocytes, the prenylated heterodimeric phloroglucinyl alpha-pyrone arzanol was identified as the major anti-inflammatory and anti-viral constituent from Helichrysum italicum. We have now investigated the activity of arzanol on the biosynthesis of pro-inflammatory eicosanoids, evaluating its anti-inflammatory efficacy in vitro and in vivo. Arzanol inhibited 5-lipoxygenase (EC 7.13.1134) activity and related leukotriene formation in neutrophils, as well as the activity of cyclooxygenase (COX)-1 (EC 1.14.99.1) and the formation of COX-2-derived prostaglandin (PG)E-2 in vitro (IC50 = 2.3-9 mu M). Detailed studies revealed that arzanol primarily inhibits microsomal PGE(2) synthase (mPGES)-1 (EC 5.3.99.3, IC50 = 0.4 mu M) rather than COX-2. In fact, arzanol could block COX-2/mPGES-1-mediated PGE(2) biosynthesis in lipopolysaccharide-stimulated human monocytes and human whole blood, but not the concomitant COX-2-derived biosynthesis of thromboxane B-2 or of 6-keto PGF(1 alpha) and the expression of COX-2 or mPGES-1 protein was not affected. Arzanol potently suppressed the inflammatory response of the carrageenan-induced pleurisy in rats (3.6 mg/kg, i.p.), with significantly reduced levels of PGE(2) in the pleural exudates. Taken together, our data show that arzanol potently inhibits the biosynthesis of pro-inflammatory lipid mediators like PGE(2) in vitro and in vivo, providing a mechanistic rationale for the anti-inflammatory activity of H. italicum, and a rationale for further pre-clinical evaluation of this novel anti-inflammatory lead. (C) 2010 Elsevier Inc. All rights reserved.