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1. 发明申请

WO2007147168A3 ATTENUATION OF HYPEROXIA-INDUCED CELL DEATH WITH MITOCHONDRIAL ALDEHYDE DEHYDROGENASE 审中-公开
标题翻译：超氧化物歧化酶诱导的细胞死亡与麻醉醛糖脱氢酶的衰减
公开(公告)号：WO2007147168A3
公开(公告)日：2008-08-07
申请号：PCT/US2007071492
申请日：2007-06-18
申请人： CHILDRENS MERCY HOSPITAL , XU DONG , TRUOG WILLIAM E
发明人： XU DONG , TRUOG WILLIAM E
IPC分类号： C12Q1/68 , A01N63/00 , A01N65/00 , A61K48/00 , C12N15/00 , C12N15/74
CPC分类号： C12N9/0008 , A61K48/00 , C12N2510/00
摘要： Oxygen toxicity is one of the major risk factors in Jhe development of the chronic lung disease or bronchopulmonary dysplasia in premature infants. Using proteoraic analysis, we discovered mitochondria! aldehyde dehydrogenase (mtALDR or ALDB2) was down-regulated in neonatal rat lung after hyperoxic exposure. To study the role of mtALDH in hyperoxie lung injury, we overexpressed ratALDH in human lung epithelial ceils (A549) and found thai mtALDH significantly reduced hyperoxia-induced cell death. Compared to control cells (Neo- A549), the.necrotic cell death in mtALDH overexpressing cells (mtALDH-A549) decreased from 25.3% to 6.5%, 50.5% to 9.1% and 52,4% to 15.06% after 24-, 48- and 72-hour hyperoxic exposure, respectively. The levels of intracellular and mitochondria-derived reactive oxygen species (ROS) in ratALDH-A549 cells after hyperoxic exposure were significantly lowered compared to Neo-A549 cells. mtALDH overexpreasion significantly stimulated extracellular signal regulated kinase (HRK) phosphorylation, under nontoxic and hyperoxic conditions. inhibition of ERK phosphorylation partially eliminated the protective effect of mtALDH in hyperoxia-induced cell death, suggesting ERK activation by ratALDH conferred cellular resistance to hyperoxia. mtALDH overexpresaion augmented Akt phosphorylation and maintained She total Akt level in mt ALDH- A549 cells under.nonnoxie and hyperoxic conditions. Inhibition of FBK activation by LY294002 in miALüH-A549 cells significantly increased necrotic cell death after hyperoxic exposure, indicating that. POKVAkt activation by mtALDH played an important role in cell survival after hyperoxia. Taken together, these data demonstrate that puALDH overexpression attenuates hyperøxia-induced cell death in lung epithelial cells through reduction of ROS, activation of ERK/MAPK and PBK/Akt cell survival signaling pathways.
摘要翻译：氧气毒性是早产儿慢性肺部疾病或支气管肺发育异常的主要危险因素之一。使用蛋白质分析，我们发现线粒体！醛脱氢酶（mtALDR或ALDB2）在高氧暴露后新生大鼠肺中下调。为了研究mtALDH在高氧肺损伤中的作用，我们在人肺上皮细胞（A549）中过表达大鼠ALDH，发现mtALDH显着降低高氧诱导的细胞死亡。与对照细胞（Neo-A549）相比，mtALDH过表达细胞（mtALDH-A549）中坏死性细胞死亡率从24.3％下降到25.3％，达到6.5％，分别为50.5％，9.1％和52.4％，降至15.06％ - 和72小时高氧暴露。与Neo-A549细胞相比，高氧暴露后大鼠ALDH-A549细胞中细胞内和线粒体衍生的活性氧（ROS）水平显着降低。在无毒和高氧条件下，mtALDH过表达显着刺激细胞外信号调节激酶（HRK）磷酸化。抑制ERK磷酸化部分消除了mtALDH在高氧诱导的细胞死亡中的保护作用，表明大鼠ALD的ERK活化赋予细胞对高氧的抗性。 mtALDH过表达增强了Akt磷酸化，并维持了在无氧和高氧条件下的mt ALDH-A549细胞中的总Akt水平。 LY294002在miALüH-A549细胞中抑制FBK活化显着增加了高氧暴露后的坏死细胞死亡，表明。 mtALDH的POKVAkt激活在高氧后细胞存活中起重要作用。总之，这些数据表明，puALDH过表达通过减少ROS，激活ERK / MAPK和PBK / Akt细胞存活信号通路来减弱肺上皮细胞中的眼眶诱导的细胞死亡。

2. 发明申请

WO2007147168A8 ATTENUATION OF HYPEROXIA-INDUCED CELL DEATH WITH MITOCHONDRIAL ALDEHYDE DEHYDROGENASE 审中-公开
标题翻译：超氧化物歧化酶诱导的细胞死亡与麻醉醛糖脱氢酶的衰减
公开(公告)号：WO2007147168A8
公开(公告)日：2009-11-05
申请号：PCT/US2007071492
申请日：2007-06-18
申请人： CHILDRENS MERCY HOSPITAL , XU DONG , TRUOG WILLIAM E
发明人： XU DONG , TRUOG WILLIAM E
IPC分类号： C12Q1/68 , A01N63/00 , A01N65/00 , A61K48/00 , C12N15/00 , C12N15/74
CPC分类号： C12N9/0008 , A61K48/00 , C12N2510/00
摘要： Oxygen toxicity is one of the major risk factors in Jhe development of the chronic lung disease or bronchopulmonary dysplasia in premature infants. Using proteoraic analysis, we discovered mitochondria! aldehyde dehydrogenase (mtALDR or ALDB2) was down-regulated in neonatal rat lung after hyperoxic exposure. To study the role of mtALDH in hyperoxie lung injury, we overexpressed ratALDH in human lung epithelial ceils (A549) and found thai mtALDH significantly reduced hyperoxia-induced cell death. Compared to control cells (Neo- A549), the.necrotic cell death in mtALDH overexpressing cells (mtALDH-A549) decreased from 25.3% to 6.5%, 50.5% to 9.1% and 52,4% to 15.06% after 24-, 48- and 72-hour hyperoxic exposure, respectively. The levels of intracellular and mitochondria-derived reactive oxygen species (ROS) in ratALDH-A549 cells after hyperoxic exposure were significantly lowered compared to Neo-A549 cells. mtALDH overexpreasion significantly stimulated extracellular signal regulated kinase (HRK) phosphorylation, under nontoxic and hyperoxic conditions. inhibition of ERK phosphorylation partially eliminated the protective effect of mtALDH in hyperoxia-induced cell death, suggesting ERK activation by ratALDH conferred cellular resistance to hyperoxia. mtALDH overexpresaion augmented Akt phosphorylation and maintained She total Akt level in mt ALDH- A549 cells under.nonnoxie and hyperoxic conditions. Inhibition of FBK activation by LY294002 in miALüH-A549 cells significantly increased necrotic cell death after hyperoxic exposure, indicating that. POKVAkt activation by mtALDH played an important role in cell survival after hyperoxia. Taken together, these data demonstrate that puALDH overexpression attenuates hyperøxia-induced cell death in lung epithelial cells through reduction of ROS, activation of ERK/MAPK and PBK/Akt cell survival signaling pathways.
摘要翻译：氧气毒性是早产儿慢性肺部疾病或支气管肺发育异常的主要危险因素之一。使用蛋白质分析，我们发现线粒体！醛脱氢酶（mtALDR或ALDB2）在高氧暴露后新生大鼠肺中下调。为了研究mtALDH在高氧肺损伤中的作用，我们在人肺上皮细胞（A549）中过表达大鼠ALDH，发现mtALDH显着降低高氧诱导的细胞死亡。与对照细胞（Neo-A549）相比，mtALDH过表达细胞（mtALDH-A549）中坏死性细胞死亡率从24.3％下降到25.3％，达到6.5％，分别为50.5％，9.1％和52.4％，降至15.06％ - 和72小时高氧暴露。与Neo-A549细胞相比，高氧暴露后大鼠ALDH-A549细胞中细胞内和线粒体衍生的活性氧（ROS）水平显着降低。在无毒和高氧条件下，mtALDH过表达显着刺激细胞外信号调节激酶（HRK）磷酸化。抑制ERK磷酸化部分消除了mtALDH在高氧诱导的细胞死亡中的保护作用，表明大鼠ALD的ERK活化赋予细胞对高氧的抗性。 mtALDH过表达增强了Akt磷酸化，并维持了在无氧和高氧条件下的mt ALDH-A549细胞中的总Akt水平。 LY294002在miALüH-A549细胞中抑制FBK活化显着增加了高氧暴露后的坏死细胞死亡，表明。 mtALDH的POKVAkt激活在高氧后细胞存活中起重要作用。总之，这些数据表明，puALDH过表达通过减少ROS，激活ERK / MAPK和PBK / Akt细胞存活信号通路来减弱肺上皮细胞中的眼眶诱导的细胞死亡。

3. 发明申请

WO2007147168A2 ATTENUATION OF HYPEROXIA-INDUCED CELL DEATH WITH MITOCHONDRIAL ALDEHYDE DEHYDROGENASE 审中-公开
标题翻译：超氧化物歧化酶诱导的细胞死亡与麻醉醛糖脱氢酶的衰减
公开(公告)号：WO2007147168A2
公开(公告)日：2007-12-21
申请号：PCT/US2007/071492
申请日：2007-06-18
申请人： THE CHILDREN'S MERCY HOSPITAL , XU, Dong , TRUOG, William, E.
发明人： XU, Dong , TRUOG, William, E.
IPC分类号： C12N15/09
CPC分类号： C12N9/0008 , A61K48/00 , C12N2510/00
摘要： Oxygen toxicity is one of the major risk factors in Jhe development of the chronic lung disease or bronchopulmonary dysplasia in premature infants. Using proteoraic analysis, we discovered mitochondria! aldehyde dehydrogenase (mtALDR or ALDB2) was down-regulated in neonatal rat lung after hyperoxic exposure. To study the role of mtALDH in hyperoxie lung injury, we overexpressed ratALDH in human lung epithelial ceils (A549) and found thai mtALDH significantly reduced hyperoxia-induced cell death. Compared to control cells (Neo- A549), the.necrotic cell death in mtALDH overexpressing cells (mtALDH-A549) decreased from 25.3% to 6.5%, 50.5% to 9.1% and 52,4% to 15.06% after 24-, 48- and 72-hour hyperoxic exposure, respectively. The levels of intracellular and mitochondria-derived reactive oxygen species (ROS) in ratALDH-A549 cells after hyperoxic exposure were significantly lowered compared to Nεo-A549 cells. mtALDH overexpreasion significantly stimulated extracellular signal regulated kinase (HRK) phosphorylation, under nontoxic and hyperoxic conditions. inhibition of ERK phosphorylation partially eliminated the protective effect of mtALDH in hyperoxia-induced cell death, suggesting ERK activation by ratALDH conferred cellular resistance to hyperoxia. mtALDH overexpresaion augmented Akt phosphorylation and maintained She total Akt level in mt ALDH- A549 cells under.nonnoxie and hyperoxic conditions. Inhibition of FBK activation by LY294002 in miALüH-A549 cells significantly increased necrotic cell death after hyperoxic exposure, indicating that. POKVAkt activation by mtALDH played an important role in cell survival after hyperoxia. Taken together, these data demonstrate that πuALDH overexpression attenuates hyperøxia-induced cell death in lung epithelial cells through reduction of ROS, activation of ERK/MAPK and PBK/Akt cell survival signaling pathways.
摘要翻译：氧气毒性是早产儿慢性肺部疾病或支气管肺发育异常的主要危险因素之一。使用蛋白质分析，我们发现线粒体！醛脱氢酶（mtALDR或ALDB2）在高氧暴露后新生大鼠肺中下调。为了研究mtALDH在高氧肺损伤中的作用，我们在人肺上皮细胞（A549）中过表达大鼠ALDH，发现mtALDH显着降低高氧诱导的细胞死亡。与对照细胞（Neo-A549）相比，mtALDH过表达细胞（mtALDH-A549）中坏死性细胞死亡率从24.3％下降到25.3％，分别为25.5％，9.1％和52.4％，降幅达到15.06％ - 和72小时高氧暴露。与Neo-A549细胞相比，高氧暴露后大鼠HDH-A549细胞中细胞内和线粒体来源的活性氧（ROS）水平显着降低。在无毒和高氧条件下，mtALDH过表达显着刺激细胞外信号调节激酶（HRK）磷酸化。抑制ERK磷酸化部分消除了mtALDH在高氧诱导的细胞死亡中的保护作用，表明大鼠ALD的ERK活化赋予细胞对高氧的抗性。 mtALDH过表达增强Akt磷酸化，并维持她在无氧和高氧条件下的总ALDH-A549细胞中的总Akt水平。在miALüH-A549细胞中LY294002对FBK活化的抑制显着增加了高氧暴露后的坏死细胞死亡，表明。 mtALDH的POKVAkt激活在高氧后细胞存活中起重要作用。总之，这些数据表明，puALDH过表达通过减少ROS，激活ERK / MAPK和PBK / Akt细胞存活信号通路来减弱肺上皮细胞中的眼眶诱导的细胞死亡。

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