3,4-Dihydroxy-benzohydroxamic acid (Didox) suppresses pro-inflammatory profiles and oxidative stress in TLR4-activated RAW264.7 murine macrophages.
3,4-Dihydroxy-benzohydroxamic acid (Didox) suppresses pro-inflammatory profiles and oxidative stress in TLR4-activated RAW264.7 murine macrophages.
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DOI：
10.1016/j.cbi.2015.03.027
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发表时间：
2015-05-25
影响因子：
5.1
通讯作者：
Rice, Charles D.
中科院分区：
文献类型：
--
作者：
Matsebatlela, Thabe M.;Anderson, Amy L.;Gallicchio, Vincent S.;Elford, Howard;Rice, Charles D.
Didox（3，4-dihydroxy-benzohydroxamic acid）是一种合成的核糖核苷酸还原酶（RR）抑制剂，来源于多羟基取代的苯并异羟肟酸，最初开发为抗癌剂。一些研究表明，didox可能具有抗氧化应激样特性，而其他研究暗示，didox可能具有抗炎特性。使用响应于LPS处理的一氧化氮产生作为抗炎化合物的敏感筛选测定，我们表明didox在低至6.25 μM的水平下非常有效，在100 μM时具有最大抑制作用。然后采用qRT-PCR阵列筛选didox的其他潜在抗炎和抗氧化应激相关性质。Didox是非常有效的抑制这些排列的mRNA的表达响应LPS，并在某些情况下，Didox单独抑制表达。使用qRT-PCR作为阵列的后续，我们证明了didox在处理24 h后抑制LPS诱导的iNOS、IL-6、IL-1、TNF-α、NF-κβ（p65）和p38-α的mRNA水平。用didox治疗还抑制一氧化氮、IL-6和IL-10的分泌。此外，通过响应于巨噬细胞活化剂LPS和佛波酯（PMA）以及谷胱甘肽消耗剂BSO的细胞内ROS水平来量化的氧化应激通过用didox处理而降低。此外，我们还证实，Didox可抑制LPS诱导的NF-κβ（p65）核转位。这些发现得到了氧化应激基因SOD 1和过氧化氢酶qRT-PCR的支持。总的来说，这项研究支持的结论是，didox可能有一个未来的作用，在管理急性和慢性炎症性疾病和氧化应激，由于高生产的活性氧。
Didox (3,4-dihydroxy-benzohydroxamic acid), is a synthetic ribonucleotide reductase (RR) inhibitor derived from polyhydroxy-substituted benzohydroxamic acid, and originally developed as an anti-cancer agent. Some studies indicate that didox may have anti-oxidative stress-like properties, while other studies hint that didox may have anti-inflammatory properties. Using nitric oxide production in response to LPS treatment as a sensitive screening assay for anti-inflammatory compounds, we show that didox is very potent at levels as low as 6.25 μM, with maximal inhibition at 100 μM. A qRT-PCR array was then employed to screen didox for other potential anti-inflammatory and anti-oxidative stress-related properties. Didox was very potent in suppressing the expression of these arrayed mRNA in response to LPS, and in some cases didox alone suppressed expression. Using qRT-PCR as a follow up to the array, we demonstrated that didox suppresses LPS-induced mRNA levels of iNOS, IL-6, IL-1, TNF-α, NF-κβ (p65), and p38-α, after 24 h of treatment. Treatment with didox also suppresses the secretion of nitric oxide, IL-6, and IL-10. Furthermore, oxidative stress, as quantified by intracellular ROS levels in response to macrophage activators LPS and phorbol ester (PMA), and the glutathione depleting agent BSO, is reduced by treatment with didox. Moreover, we demonstrate that nuclear translocation of NF-κβ (p65) in response to LPS is inhibited by didox. These findings were supported by qRT-PCR for oxidative stress genes SOD1 and catalase. Overall, this study supports the conclusion that didox may have a future role in managing acute and chronic inflammatory diseases and oxidative stress due to high production of ROS.
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影响因子：
4.4
作者：
Chandel, NS;Trzyna, WC;Schumacker, PT
通讯作者：
Schumacker, PT
影响因子：
158.5
作者：
Harrison, CN;Campbell, PJ;Murray, M
通讯作者：
Murray, M
DOI：
10.1186/1476-9255-7-1
发表时间：
2010-01-08
期刊：
Journal of inflammation (London, England)
影响因子：
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作者：
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通讯作者：
Festy F
影响因子：
2.8
作者：
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通讯作者：
Jaillon, Sebastien
影响因子：
14.2
作者：
Escribano, Luis;Alvarez-Twose, Ivan;Orfao, Alberto
通讯作者：
Orfao, Alberto