Natural isoprenoids inhibit LPS-induced-production of cytokines and nitric oxide in aminobisphosphonate-treated monocytes
Natural isoprenoids inhibit LPS-induced-production of cytokines and nitric oxide in aminobisphosphonate-treated monocytes
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DOI：
10.1016/j.intimp.2010.03.008
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发表时间：
2010-06-01
影响因子：
5.6
通讯作者：
Pontillo, Alessandra
中科院分区：
文献类型：
--
作者：
Marcuzzi, Annalisa;Tommasini, Alberto;Pontillo, Alessandra
通过遗传缺陷（甲羟戊酸激酶缺乏症）抑制甲羟戊酸途径。MKD）或药理学药物（氨基二膦酸盐）导致中间体化合物的短缺，特别是与半胱天冬酶-1和IL-1 β释放的激活相关的香叶基香叶基焦磷酸（GGPP）的短缺。香叶醇（GOH）、法尼醇（FOH）、香叶基香叶醇（GGOH）和薄荷醇（MOH）由于它们的类异戊二烯结构，被认为进入甲羟戊酸途径并绕过生化阻断，重建该途径。考虑到氨基二膦酸盐已知的副作用，以及缺乏对MKD的特异性治疗，我们评估了这些天然类异戊二烯化合物在用氨基二膦酸盐阿仑膦酸盐化学处理的RAW细胞系中以及在从2名受MKD影响的患者中分离的单核细胞中的影响。GOH、FOH、GGOH和MOH均能降低LPS诱导的炎症标志物水平。这些天然类异戊二烯可以被提议作为仍然是孤儿药MKD的新的治疗方法，但也可以考虑用于评估氨基二膦酸盐的可能的炎症副作用。(C)2010 Elsevier B. V.保留所有权利。
The inhibition of mevalonate pathway through genetic defects (mevalonate kinase deficiency. MKD) or pharmacologic drugs (aminobisphosphonates) causes a shortage of intermediate compounds and, in particular, of geranylgeranyl-pyrophosphate (GGPP) associated to the activation of caspase-1 and IL-1 beta release. Geraniol (GOH), farnesol (FOH),geranylgeraniol (GGOH) and menthol (MOH), due to their isoprenoid structure, are supposed to enter the mevalonate pathway and to by-pass the biochemical block, reconstituting the pathway. Considering the already known side effects of aminobisphosphonates, and the lack of a specific treatment for MKD, we evaluated the impact of these natural isoprenoids compounds in a RAW cell lines chemically treated with the aminobisphosphonate alendronate, and in monocytes isolated from 2 patients affected by MKD. GOH, FOH, GGOH and MOH were all capable to diminish inflammatory marker levels induced by LPS. These natural isoprenoids could be proposed as novel therapeutic approach for the still orphan drug MKD, but also considered for the evaluation of possible inflammatory side effects of aminobisphosphonates. (C) 2010 Elsevier B.V. All rights reserved.