Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats.
Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats.
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长期摄入 2-脱氧-D-葡萄糖会诱导心脏空泡化并增加大鼠的死亡率。
DOI：
10.1016/j.taap.2009.11.025
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发表时间：
2010-03-15
影响因子：
3.8
通讯作者：
Mattison, Julie A.
中科院分区：
文献类型：
--
作者：
Minor, Robin K.;Smith, Daniel L., Jr.;Sossong, Alex M.;Kaushik, Susmita;Poosala, Suresh;Spangler, Edward L.;Roth, George S.;Lane, Mark;Allison, David B.;de Cabo, Rafael;Ingram, Donald K.;Mattison, Julie A.
热量限制（CR），有目的地减少能量摄入，保持足够的微量营养素摄入，是众所周知的，以延长实验室动物的寿命。像2-脱氧-D-葡萄糖（2DG）这样的化合物可以概括CR的代谢作用，由于其延长寿命的潜力而引起了极大的兴趣。2DG治疗已被证明对治疗癌症和癫痫发作具有潜在的治疗益处。2DG还概括了CR表型的一些特征，包括在短期啮齿动物试验中降低体温和循环胰岛素，但一项大鼠慢性喂养研究发现了毒性作用。本研究旨在进一步探讨2DG在体内的长期作用。首先，我们证明了2DG增加雄性Fischer-344大鼠的死亡率。在2DG处理的大鼠中还观察到肾上腺髓质中嗜铬细胞瘤的发生率增加。我们再次确认心脏毒性的2DG在6周的后续研究中评估雄性布朗挪威大鼠和天然形式的2DG，除了再次检查在Fischer-344大鼠和原始合成2DG的影响。高水平的两个2DG来源减少体重增加继发于减少食物摄入量在两个菌株。心脏组织学分析显示心肌细胞空泡化随剂量增加而增加，组织染色显示空泡不含糖原和脂质。然而，我们确实观察到组织蛋白酶D和LC 3在2DG处理的大鼠的心脏中的更高表达，这表明自噬通量增加。虽然一个显着的CR样表型可以用2DG治疗再现，2DG的最终毒性严重挑战2DG作为一个潜在的CR模拟在哺乳动物中，也引起了对该化合物的其他治疗应用的关注。
Calorie restriction (CR), the purposeful reduction of energy intake with maintenance of adequate micronutrient intake, is well known to extend the lifespan of laboratory animals. Compounds like 2-deoxy-D-glucose (2DG) that can recapitulate the metabolic effects of CR are of great interest for their potential to extend lifespan. 2DG treatment has been shown to have potential therapeutic benefits for treating cancer and seizures. 2DG has also recapitulated some hallmarks of the CR phenotype including reduced body temperature and circulating insulin in short-term rodent trials, but one chronic feeding study in rats found toxic effects. The present studies were performed to further explore the long-term effects of 2DG in vivo. First we demonstrate that 2DG increases mortality of male Fischer-344 rats. Increased incidence of pheochromocytoma in the adrenal medulla was also noted in the 2DG treated rats. We reconfirm the cardiotoxicity of 2DG in a 6-week follow-up study evaluating male Brown Norway rats and a natural form of 2DG in addition to again examining effects in Fischer-344 rats and the original synthetic 2DG. High levels of both 2DG sources reduced weight gain secondary to reduced food intake in both strains. Histopathological analysis of the hearts revealed increasing vacuolarization of cardiac myocytes with dose, and tissue staining revealed the vacuoles were free of both glycogen and lipid. We did, however, observe higher expression of both cathepsin D and LC3 in the hearts of 2DG-treated rats which indicates an increase in autophagic flux. Although a remarkable CR-like phenotype can be reproduced with 2DG treatment, the ultimate toxicity of 2DG seriously challenges 2DG as a potential CR mimetic in mammals and also raises concerns about other therapeutic applications of the compound.
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影响因子：
11.2
作者：
Andringa, KK;Coleman, NC;Spitz, DR
通讯作者：
Spitz, DR
影响因子：
3.9
作者：
Hagopian, K;Ramsey, JJ;Weindruch, R
通讯作者：
Weindruch, R
DOI：
10.1016/s0360-3016(96)85017-6
发表时间：
1996-04-01
影响因子：
7
作者：
Mohanti, BK;Rath, GK;Jain, V
通讯作者：
Jain, V
影响因子：
11.2
作者：
Stafstrom, Carl E.;Ockuly, Jeffrey C.;Murphree, Lauren;Valley, Matthew T.;Roopra, Avtar;Sutula, Thomas P.
通讯作者：
Sutula, Thomas P.
DOI：
10.1152/ajpendo.00102.2007
发表时间：
2007-07-01
影响因子：
5.1
作者：
Fontana, Luigi;Villareal, Dennis T.;Holloszy, John O.
通讯作者：
Holloszy, John O.