Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+).
Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+).
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DOI：
10.1016/j.redox.2013.12.017
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发表时间：
2014
期刊：
影响因子：
11.4
通讯作者：
Vujaskovic, Zeljko
中科院分区：
文献类型：
--
作者：
Gauter-Fleckenstein, Benjamin;Reboucas, Julio S.;Fleckenstein, Katharina;Tovmasyan, Artak;Owzar, Kouros;Jiang, Chen;Batinic-Haberle, Ines;Vujaskovic, Zeljko
关键词：
为了增强阳离子Mn卟啉在线粒体内的分布，已经合成了亲脂性Mn（III）中四基（n- n-己基吡啶-2-基）卟啉mntnhexx -2- pyp5 +，并在几种不同的疾病模型中进行了测试，在单次或多次剂量低至50µg/kg时显示出显着的疗效。然而，在一项大鼠肺辐射防护研究中，由于其高蓄积和胶束特性，在较高的0.6-1 mg/kg剂量下，它变得有毒。为了避免毒性，本研究评估了MnTnHex-2-PyP5+在50µg/kg时的肺放射保护作用。将Fischer大鼠照射至右半胸（28 Gy），并于照射后2 h开始皮下植入渗透泵，给予0.05 mg/kg/天MnTnHex-2-PyP5+治疗2周。放疗后随访10周，进行组织病理学和免疫组化检查。检测MnTnHex-2-PyP5+对巨噬细胞募集（ED-1）、DNA氧化损伤（8-OHdG）、TGF-β1、VEGF(A)、HIF-1α的影响。MnTnHex-2-PyP5+显著降低辐射引起的肺组织病理学（H&E染色）和功能损伤（呼吸频率），直接或间接抑制氧化应激（8-OHdG），影响TGF-β1、VEGF (A)和HIF-1α途径。其治疗效果与在相同实验条件下使用高120倍~低5000倍的亲脂性Mn（III）中四基（n -乙基吡啶-2-基）卟啉MnTE-2-PyP5+的效果相似。氧化还原活性锰卟啉MnTnHex-2-PyP5+在0.05 mg/kg/天时对大鼠肺具有显著的放射保护作用。MnTnHex-2-PyP5+减少大鼠呼吸频率和肺组织损伤。MnTnHex-2-PyP5+影响基于氧化还原的信号通路，从而减少炎症（巨噬细胞募集、DNA损伤、HIF-1α、TGF-β1和VEGF(A)表达）。显著的功效可能是由于其高细胞和线粒体积累。
With the goal to enhance the distribution of cationic Mn porphyrins within mitochondria, the lipophilic Mn(III)meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP5+ has been synthesized and tested in several different model of diseases, where it shows remarkable efficacy at as low as 50 µg/kg single or multiple doses. Yet, in a rat lung radioprotection study, at higher 0.6–1 mg/kg doses, due to its high accumulation and micellar character, it became toxic. To avoid the toxicity, herein the pulmonary radioprotection of MnTnHex-2-PyP5+ was assessed at 50 µg/kg. Fischer rats were irradiated to their right hemithorax (28 Gy) and treated with 0.05 mg/kg/day of MnTnHex-2-PyP5+ for 2 weeks by subcutaneously-implanted osmotic pumps, starting at 2 h post-radiation. The body weights and breathing frequencies were followed for 10 weeks post-radiation, when the histopathology and immunohistochemistry were assessed. Impact of MnTnHex-2-PyP5+ on macrophage recruitment (ED-1), DNA oxidative damage (8-OHdG), TGF-β1, VEGF(A) and HIF-1α were measured. MnTnHex-2-PyP5+ significantly decreased radiation-induced lung histopathological (H&E staining) and functional damage (breathing frequencies), suppressed oxidative stress directly (8-OHdG), or indirectly, affecting TGF-β1, VEGF (A) and HIF-1α pathways. The magnitude of the therapeutic effects is similar to the effects demonstrated under same experimental conditions with 120-fold higher dose of ~5000-fold less lipophilic Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP5+. Redox-active Mn porphyrin, MnTnHex-2-PyP5+, exerts impressive rat lung radioprotection at 0.05 mg/kg/day. MnTnHex-2-PyP5+ reduces rat breathing frequences and lung tissue damage. MnTnHex-2-PyP5+ affects redox-based signaling pathways whereby reducing inflammation (macrophage recruitment, DNA damage, HIF-1α, TGF-β1 and VEGF(A) expression). Remarkable efficacy is likely due to its high cellular and mitochondrial accumulation.
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影响因子：
5.3
作者：
Drobyshevsky, Alexander;Luo, Kehuan;Tan, Sidhartha
通讯作者：
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影响因子：
4.8
作者：
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影响因子：
7.4
作者：
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阳离子Mn（III）N-取代的吡啶基卟啉的各种功能，被识别为SOD模拟物。
影响因子：
7.4
作者：
Batinic-Haberle I;Rajic Z;Tovmasyan A;Reboucas JS;Ye X;Leong KW;Dewhirst MW;Vujaskovic Z;Benov L;Spasojevic I
通讯作者：
Spasojevic I
影响因子：
3.5
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.
通讯作者：
Piganelli, Jon D.