Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Uniformed Services University, Bethesda, Maryland, USA.
Cell Biosci. 2011 Jun 3;1(1):21. doi: 10.1186/2045-3701-1-21.
Hemorrhage increases inducible nitric oxide synthase (iNOS) and depletes ATP levels in various tissues. Previous studies have shown that geldanamycin, an inducer of heat shock protein 70kDa (HSP-70) and inhibitor of iNOS, limits both processes. Reduction in NO production limits lipid peroxidation, apoptosome formation, and caspase-3 activation, thereby increasing cellular survival and reducing the sequelae of hemorrhage. The poor solubility of geldanamycin in aqueous solutions, however, limits its effectiveness as a drug. 17-DMAG is a water-soluble analog of geldanamycin that might have greater therapeutic utility. This study investigated the effectiveness of 17-DMAG at reducing hemorrhagic injury in mouse small intestine.
In mice, the hemorrhage-induced iNOS increase correlated with increases in Kruppel-like factor 6 (KLF6) and NF-kB and a decrease in KLF4. As a result, increases in NO production and lipid peroxidation occurred. Moreover, hemorrhage also resulted in decreased Bcl-2 and increased TNF-α, IL-6, and IL-10 concentrations, p53 protein, caspase-3 activation, and cellular ATP depletion. A shortening and widening of villi in the small intestine was also observed. Treatment with 17-DMAG significantly reduced the hemorrhage-induced increases in iNOS protein, jejunal alteration, and TNF-α and IL-10 concentrations, but 17-DMAG did not affect the hemorrhage-induced increases in p53 and IL-6 concentration. 17-DMAG treatment by itself upregulated HSP-70, Bcl-2, and p53.
Since 17-DMAG is water soluble, bioactive, and not toxic, 17-DMAG may prove useful as a prophylactic drug for hemorrhage.
出血会增加诱导型一氧化氮合酶（iNOS）的含量并降低各种组织中的三磷酸腺苷（ATP）水平。先前的研究表明，格尔德霉素（一种诱导热休克蛋白 70kDa（HSP-70）和 iNOS 抑制剂）可以限制这两个过程。减少一氧化氮（NO）的产生可以限制脂质过氧化、凋亡小体形成和半胱天冬酶-3 的激活，从而提高细胞存活率并减少出血的后遗症。然而，格尔德霉素在水溶液中的溶解度较差，限制了其作为药物的效果。17-DMAG 是格尔德霉素的水溶性类似物，可能具有更大的治疗效果。本研究旨在探讨 17-DMAG 对减少小鼠小肠出血损伤的效果。
在小鼠中，出血诱导的 iNOS 增加与 Kruppel 样因子 6（KLF6）和 NF-kB 的增加以及 KLF4 的减少相关。结果，NO 产生和脂质过氧化增加。此外，出血还导致 Bcl-2 减少和 TNF-α、IL-6 和 IL-10 浓度增加、p53 蛋白、半胱天冬酶-3 激活和细胞内 ATP 耗竭。还观察到小肠绒毛缩短和变宽。用 17-DMAG 治疗可显著降低出血引起的 iNOS 蛋白增加、空肠改变以及 TNF-α 和 IL-10 浓度，但 17-DMAG 对出血引起的 p53 和 IL-6 浓度增加没有影响。17-DMAG 本身的治疗可上调 HSP-70、Bcl-2 和 p53。
由于 17-DMAG 水溶性好、具有生物活性且无毒，因此 17-DMAG 可能是一种有用的出血预防药物。
