Design of Mn porphyrins for treating oxidative stress injuries and their redox-based regulation of cellular transcriptional activities.
Design of Mn porphyrins for treating oxidative stress injuries and their redox-based regulation of cellular transcriptional activities.
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DOI：
10.1007/s00726-010-0603-6
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发表时间：
2012-01
期刊：
影响因子：
3.5
通讯作者：
Piganelli, Jon D.
中科院分区：
文献类型：
--
作者：
Batinic-Haberle, Ines;Spasojevic, Ivan;Tse, Hubert M.;Tovmasyan, Artak;Rajic, Zrinka;St Clair, Daret K.;Vujaskovic, Zeljko;Dewhirst, Mark W.;Piganelli, Jon D.
关键词：
反应性物质的最有效的Mn（III）卟啉（MNP）清除剂具有接近Mn位点的正电荷，由此它们为与带负电荷的物质如 和ONOO−。它们是Mn（III）meso四（N-烷基吡啶鎓-2-基）卟啉，更具体地说是MnTE-2-PyP 5+（AEOL 10113）和MnTnHex-2-PyP 5+（其中烷基分别是乙基和正己基），以及它们的咪唑鎓类似物MnTDE-2-ImP 5+（AEOL 10150，Mn（III）meso四（N，N '-二乙基咪唑鎓-2-基）卟啉）。MnPs在体内的功效不仅取决于复合抗氧化剂效力，还取决于其生物利用度。前者受化合物的亲油性、大小、结构和整体形状的影响很大。这些卟啉具有消除活性氧物质和影响氧化应激依赖性信号传导事件的进展的能力。这将有效地导致氧化还原依赖性转录因子的调节和继发性炎症和氧化应激介导的免疫应答的抑制。我们已经报道了锰卟啉对主要转录因子HIF-1α、AP-1、SP-1和NF-κB的抑制作用。虽然抑制转录因子活化的流行机制观点是通过抗氧化作用（推测在胞质溶胶中），但MNP在抑制核中NF-κB活化中的促氧化作用已得到证实。影响的大小取决于静电（卟啉电荷）和热力学因素（卟啉氧化还原能力）。已经表明，MnPs的促氧化作用至少部分地有助于MnTE-2-PyP 5+在抗坏血酸盐存在下的体外抗癌作用，以及当与淋巴瘤的化疗组合时的体内抗癌作用。鉴于金属卟啉显着的治疗潜力，未来的研究是必要的，以进一步了解在体内的行动/的锰卟啉，特别是关于其亚细胞分布。
The most efficacious Mn(III) porphyrinic (MnPs) scavengers of reactive species have positive charges close to the Mn site, whereby they afford thermodynamic and electrostatic facilitation for the reaction with negatively charged species such as and ONOO−. Those are Mn(III) meso tetrakis(N-alkylpyridinium-2-yl)porphyrins, more specifically MnTE-2-PyP5+ (AEOL10113) and MnTnHex-2-PyP5+ (where alkyls are ethyl and n-hexyl, respectively), and their imidazolium analog, MnTDE-2-ImP5+ (AEOL10150, Mn(III) meso tetrakis(N,N′-diethylimidazolium-2-yl) porphyrin). The efficacy of MnPs in vivo is determined not only by the compound antioxidant potency, but also by its bio-availability. The former is greatly affected by the lipophilicity, size, structure, and overall shape of the compound. These porphyrins have the ability to both eliminate reactive oxygen species and impact the progression of oxidative stress-dependent signaling events. This will effectively lead to the regulation of redox-dependent transcription factors and the suppression of secondary inflammatory- and oxidative stress-mediated immune responses. We have reported on the inhibition of major transcription factors HIF-1α, AP-1, SP-1, and NF-κB by Mn porphyrins. While the prevailing mechanistic view of the suppression of transcription factors activation is via antioxidative action (presumably in cytosol), the pro-oxidative action of MnPs in suppressing NF-κB activation in nucleus has been substantiated. The magnitude of the effect is dependent upon the electrostatic (porphyrin charges) and thermodynamic factors (porphyrin redox ability). The pro-oxidative action of MnPs has been suggested to contribute at least in part to the in vitro anticancer action of MnTE-2-PyP5+ in the presence of ascorbate, and in vivo when combined with chemotherapy of lymphoma. Given the remarkable therapeutic potential of metalloporphyrins, future studies are warranted to further our understanding of in vivo action/s of Mn porphyrins, particularly with respect to their subcellular distribution.
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影响因子：
7.4
作者：
Gauter-Fleckenstein, Benjamin;Fleckenstein, Katharina;Owzar, Kouros;Jiang, Chen;Reboucas, Julio S.;Batinic-Haberle, Ines;Vujaskovic, Zeljko
通讯作者：
Vujaskovic, Zeljko
影响因子：
4.1
作者：
Ferrer-Sueta, G;Batinic-Haberle, I;Radi, R
通讯作者：
Radi, R
DOI：
10.1161/01.atv.0000258979.92828.bc
发表时间：
2007-04-01
影响因子：
8.7
作者：
Bonello, Steve;Zahringer, Christian;Goerlach, Agnes
通讯作者：
Goerlach, Agnes
影响因子：
4.8
作者：
Batinic-Haberle, I;Benov, L;Fridovich, I
通讯作者：
Fridovich, I
影响因子：
4.8
作者：
Ferrer-Sueta, G;Vitturi, D;Radi, R
通讯作者：
Radi, R