新型自由基清除剂抗高原缺氧作用及保护机制研究
|
摘要
研究背景
我国高原面积辽阔，是世界上高原面积最大、边境线最长的国家。缺氧是高原环境医学中的首要问题。随着我国西部大开发战略的实施、青藏铁路的开通，越来越多的人到达高海拔地区。高原相关疾病正日渐成为一个严重影响公共健康的问题。因此，研发新型高效、低毒的抗高原缺氧损伤防治药物具有重要的现实意义。
通过文献回顾及前期实验基础，课题组发现高原缺氧相关疾病的发生和体内自由基释放增加密切相关。由此提出研究假设：即高原缺氧导致机体氧化应激，线粒体氧化还原途径激活，抗氧化体系失代偿，自由基产生增加是导致高原相关疾病的主要原因之一，自由基清除剂类药物可能通过清除机体产生的过多自由基而对高原缺氧具有保护作用。
研究目的
1.通过研究高原缺氧动物模型，证实课题假设，阐明高原缺氧与体内自由基释放之间的关系，明确自由基清除剂对高原缺氧的保护作用。
2.筛选出全新的抗高原缺氧自由基清除剂，并探讨其作用机制。
3.研究兼具自由基清除和NO释放作用的硝酸酯类化合物的抗高原缺氧作用，并探讨其保护机制。
实验内容及结果
1.自由基清除剂的抗高原缺氧研究
(1)4'-羟基-2-苯基咪唑啉自由基的抗高原缺氧研究
通过常压密闭缺氧筛选试验对多个可能具有抗缺氧活性的化合物和中药提取物进行了筛选。选择了抗缺氧效果较为显著的咪唑啉类自由基清除剂4'-羟基-2-苯基咪唑啉自由基(HPN)进行抗高原缺氧药效及保护机制研究。结果显示HPN具有较好的抗高原缺氧作用，从而证实了课题假设并得出结论，即通过自由基清除剂类化合物对高原缺氧动物模型的干预可以保护机体免受缺氧引起氧化应激所致自由基产生增加的损伤，防止脂质过氧化，保护机体抗氧化酶系维持正常活性，维持线粒体能量代谢功能正常，稳定了线粒体膜，维持线粒体内氧化磷酸化的正常进行，维持Na/K-ATP酶活性，最终防止AMS及HACE的症状出现。以HPN为母核合成的咪唑啉类自由基化合物在常压密闭缺氧实验中也显示了较好的抗缺氧活性。
(2) TEMPOL的抗高原缺氧研究
对TEMPOL的抗高原缺氧作用进行了研究。结果显示TEMPOL同样具有较好的抗高原缺氧作用，能够保护海拔8000m实验动物的大脑及心脏。其保护机制同HPN相似，主要是通过清除过量产生的ROS，抑制脂质过氧化，保护机体抗氧化酶系维持正常活性。该结果再次证明了自由基清除剂类化合物具有抗高原缺氧作用，并首次证实了TEMPOL具有潜在的抗高原缺氧作用。
2. NO供体乙酰阿魏酸单硝酸异山梨酯的抗高原缺氧研究
对兼具自由基清除和NO释放作用的NO供体类化合物乙酰阿魏酸单硝酸异山梨酯(ACMI)进行抗高原缺氧药效及保护机制研究。结果显示，ACMI具有较好的抗高原缺氧作用，能够保护高海拔机体免受缺氧损伤。其机制为清除体内过多的自由基，维持了药物所释放的NO在体内的药理活性，抑制脂质过氧化的同时抑制了因自由基而导致的体内NO失活。以单硝酸异山梨酯为母核，合成的NO供体类自由基清除化合物，同样显示了较好的抗缺氧活性。
本课题通过对两个氮氧自由基类化合物HPN、TEMPOL及NO供体类自由基清除化合物ACMI的抗缺氧作用及机制研究，证实了自由基清除剂可通过清除机体产生的过多自由基而对高原缺氧具有保护作用。同时筛选出了具有潜在药用价值的自由基清除剂及NO供体化合物，为进一步将其开发成为缺氧损伤防护药物奠定了基础，同时也为新型抗缺氧药物研发提供了实验依据和理论根据。
Background
China is the world's largest plateau country with longest high altitude border. Our countryhas vast plateau area. Hypoxia is the most important issue in the plateau environmentalMedicine. With the implementation of the western development strategy in China and theopening of the Qinghai-Tibet Railway, more and more people reach high altitudes. Thehigh altitude related disease is becoming a serious impact on public health problem. Thus,the research and development of new high efficiency, low toxicity anti-altitude hypoxiaimpairment preventive drug has important practical significance.
Base on the literature review and preliminary experimental results, the research groupfound the occurrence of high-altitude hypoxia related disease is closely related to theincrease of free radicals release in the body. Thus proposed research hypotheses:high-altitude hypoxia leads to oxidative stress, mitochondrial redox pathway activation,antioxidant system decompensation. increasing radical generating is one of the major factors that lead to high-altitude related diseases. Radical scavenger drugs may have aprotective effect through clearing the body free radicals on the plateau hypoxia.
Research purposes
1. Through the study of the high altitude anoxic animal models confirmed researchhypothesis, clarified the relationship between the plateau hypoxia and free radicalsrelease and confirmed the protective effect of free radical scavenger compounds toplateau hypoxia.
2. Screening new anti high-altitude radical scavenger and discussing the mechanisms.
3. Study on the anti-altitude hypoxia protective effect of both radical scavenging and NOrelease NO donor compounds and discussing the mechanisms.
Experimental content and results
1. Research for the anti-altitude hypoxia protective effect of radical scavenger
(1) the anti-altitude hypoxia protective effect of4'-hydroxy-2-phenyl imidazoline radical
Screening the activities of multiple compounds and traditional Chinese medicineextracts which may have anti-hypoxia activity through of normobaric hypoxia tests.Imidazoline radical scavenger4'-hydroxy-2-phenyl-imidazoline radical (HPN) withmore significant anti-hypoxia effect was selected in the anti high-altitude hypoxiapharmacodynamic and protective mechanism study. The results showed that HPN hasgood anti high-altitude hypoxia effect. Thus confirming the subject’s assumptions andgetting concluded conclusion. Intervention in animal models of plateau hypoxiacompounds by radical scavenging agents can protect the body from hypoxia inducedoxidative stress caused by free radicals increased injury, preventing lipid peroxidation,protecting the body antioxidant enzyme system to maintain normal activity, maintainmitochondrial energy metabolism functioning properly, stabilizing the mitochondrialmembrane, maintaining mitochondrial oxidative phosphorylation to normal level,maintaining the Na/K-ATP enzyme activity and ultimately prevent AMS and HACEsymptoms. The HPN nucleus synthesized imidazolines radical compound also shows abetter anti-hypoxic activity in the normobaric hypoxia experiment.
(2) the anti-altitude hypoxia protective effect of TEMPOL
Study on the anti Hypoxia effect of of TEMPOL. The results showed that TEMPOLalso had good resistant effect to high altitude hypoxia. TEMPOL can protectexperimental animals’ brain and heart under the altitude of8000m. The protectivemechanism of TEMPOL was similar with HPN, primarily by removing the excessiveproduction of ROS, inhibition of lipid peroxidation and protect the body's antioxidantenzyme system to maintain normal activity. The results proved once again that theradical scavenger compounds has anti-altitude hypoxia effect, and for the first timeconfirmed the potential protective role of TEMPOL under anti-altitude hypoxia.
2. The anti high-altitude hypoxia research of NO donor acetyl ferulic acid isosorbidemononitrate
Study on the anti-altitude hypoxia protective effect of NO donor compounds acetylferulic acid isosorbide mononitrate (ACMI) with both of free radical scavenging andNO release function and discussing the protection mechanisms. The results showedthat ACMI had good resistance to high-altitude hypoxia and could protect the bodyfrom high altitude hypoxic injury. Its proctive mechanism was cleaning excess freeradicals in the body, maintaining the drug release NO in vivo pharmacological activity,Inhibition of lipid peroxidation, while suppressing the inactivation of NO caused byfree radicals in vivo. Using isosorbide mononitrate as parent nucleus structure tosynthesis the radical scavenging NO donor compounds, also showed good anti-hypoxiaactivity.
Through the research on anti-hypoxia effect and radical scavenging mechanism oftwo nitroxide radical compounds of HPN and TEMPOL, and the NO donor ACMI, thisissue confirmed that a free radical scavenger could have a protective effect on theplateau hypoxia by clearing too many free radicals produced by the body. Meanwhilethe issue filtered out the radical scavenging and NO donor compounds with potentialmedicinal value. The study laid the foundation for the further development of hypoxicinjury protection drugs, as well as provided an experimental basis and theoretical basisfor the new anti-hypoxia drug development.
我国高原面积辽阔，是世界上高原面积最大、边境线最长的国家。缺氧是高原环境医学中的首要问题。随着我国西部大开发战略的实施、青藏铁路的开通，越来越多的人到达高海拔地区。高原相关疾病正日渐成为一个严重影响公共健康的问题。因此，研发新型高效、低毒的抗高原缺氧损伤防治药物具有重要的现实意义。
通过文献回顾及前期实验基础，课题组发现高原缺氧相关疾病的发生和体内自由基释放增加密切相关。由此提出研究假设：即高原缺氧导致机体氧化应激，线粒体氧化还原途径激活，抗氧化体系失代偿，自由基产生增加是导致高原相关疾病的主要原因之一，自由基清除剂类药物可能通过清除机体产生的过多自由基而对高原缺氧具有保护作用。
研究目的
1.通过研究高原缺氧动物模型，证实课题假设，阐明高原缺氧与体内自由基释放之间的关系，明确自由基清除剂对高原缺氧的保护作用。
2.筛选出全新的抗高原缺氧自由基清除剂，并探讨其作用机制。
3.研究兼具自由基清除和NO释放作用的硝酸酯类化合物的抗高原缺氧作用，并探讨其保护机制。
实验内容及结果
1.自由基清除剂的抗高原缺氧研究
(1)4'-羟基-2-苯基咪唑啉自由基的抗高原缺氧研究
通过常压密闭缺氧筛选试验对多个可能具有抗缺氧活性的化合物和中药提取物进行了筛选。选择了抗缺氧效果较为显著的咪唑啉类自由基清除剂4'-羟基-2-苯基咪唑啉自由基(HPN)进行抗高原缺氧药效及保护机制研究。结果显示HPN具有较好的抗高原缺氧作用，从而证实了课题假设并得出结论，即通过自由基清除剂类化合物对高原缺氧动物模型的干预可以保护机体免受缺氧引起氧化应激所致自由基产生增加的损伤，防止脂质过氧化，保护机体抗氧化酶系维持正常活性，维持线粒体能量代谢功能正常，稳定了线粒体膜，维持线粒体内氧化磷酸化的正常进行，维持Na/K-ATP酶活性，最终防止AMS及HACE的症状出现。以HPN为母核合成的咪唑啉类自由基化合物在常压密闭缺氧实验中也显示了较好的抗缺氧活性。
(2) TEMPOL的抗高原缺氧研究
对TEMPOL的抗高原缺氧作用进行了研究。结果显示TEMPOL同样具有较好的抗高原缺氧作用，能够保护海拔8000m实验动物的大脑及心脏。其保护机制同HPN相似，主要是通过清除过量产生的ROS，抑制脂质过氧化，保护机体抗氧化酶系维持正常活性。该结果再次证明了自由基清除剂类化合物具有抗高原缺氧作用，并首次证实了TEMPOL具有潜在的抗高原缺氧作用。
2. NO供体乙酰阿魏酸单硝酸异山梨酯的抗高原缺氧研究
对兼具自由基清除和NO释放作用的NO供体类化合物乙酰阿魏酸单硝酸异山梨酯(ACMI)进行抗高原缺氧药效及保护机制研究。结果显示，ACMI具有较好的抗高原缺氧作用，能够保护高海拔机体免受缺氧损伤。其机制为清除体内过多的自由基，维持了药物所释放的NO在体内的药理活性，抑制脂质过氧化的同时抑制了因自由基而导致的体内NO失活。以单硝酸异山梨酯为母核，合成的NO供体类自由基清除化合物，同样显示了较好的抗缺氧活性。
本课题通过对两个氮氧自由基类化合物HPN、TEMPOL及NO供体类自由基清除化合物ACMI的抗缺氧作用及机制研究，证实了自由基清除剂可通过清除机体产生的过多自由基而对高原缺氧具有保护作用。同时筛选出了具有潜在药用价值的自由基清除剂及NO供体化合物，为进一步将其开发成为缺氧损伤防护药物奠定了基础，同时也为新型抗缺氧药物研发提供了实验依据和理论根据。
Background
China is the world's largest plateau country with longest high altitude border. Our countryhas vast plateau area. Hypoxia is the most important issue in the plateau environmentalMedicine. With the implementation of the western development strategy in China and theopening of the Qinghai-Tibet Railway, more and more people reach high altitudes. Thehigh altitude related disease is becoming a serious impact on public health problem. Thus,the research and development of new high efficiency, low toxicity anti-altitude hypoxiaimpairment preventive drug has important practical significance.
Base on the literature review and preliminary experimental results, the research groupfound the occurrence of high-altitude hypoxia related disease is closely related to theincrease of free radicals release in the body. Thus proposed research hypotheses:high-altitude hypoxia leads to oxidative stress, mitochondrial redox pathway activation,antioxidant system decompensation. increasing radical generating is one of the major factors that lead to high-altitude related diseases. Radical scavenger drugs may have aprotective effect through clearing the body free radicals on the plateau hypoxia.
Research purposes
1. Through the study of the high altitude anoxic animal models confirmed researchhypothesis, clarified the relationship between the plateau hypoxia and free radicalsrelease and confirmed the protective effect of free radical scavenger compounds toplateau hypoxia.
2. Screening new anti high-altitude radical scavenger and discussing the mechanisms.
3. Study on the anti-altitude hypoxia protective effect of both radical scavenging and NOrelease NO donor compounds and discussing the mechanisms.
Experimental content and results
1. Research for the anti-altitude hypoxia protective effect of radical scavenger
(1) the anti-altitude hypoxia protective effect of4'-hydroxy-2-phenyl imidazoline radical
Screening the activities of multiple compounds and traditional Chinese medicineextracts which may have anti-hypoxia activity through of normobaric hypoxia tests.Imidazoline radical scavenger4'-hydroxy-2-phenyl-imidazoline radical (HPN) withmore significant anti-hypoxia effect was selected in the anti high-altitude hypoxiapharmacodynamic and protective mechanism study. The results showed that HPN hasgood anti high-altitude hypoxia effect. Thus confirming the subject’s assumptions andgetting concluded conclusion. Intervention in animal models of plateau hypoxiacompounds by radical scavenging agents can protect the body from hypoxia inducedoxidative stress caused by free radicals increased injury, preventing lipid peroxidation,protecting the body antioxidant enzyme system to maintain normal activity, maintainmitochondrial energy metabolism functioning properly, stabilizing the mitochondrialmembrane, maintaining mitochondrial oxidative phosphorylation to normal level,maintaining the Na/K-ATP enzyme activity and ultimately prevent AMS and HACEsymptoms. The HPN nucleus synthesized imidazolines radical compound also shows abetter anti-hypoxic activity in the normobaric hypoxia experiment.
(2) the anti-altitude hypoxia protective effect of TEMPOL
Study on the anti Hypoxia effect of of TEMPOL. The results showed that TEMPOLalso had good resistant effect to high altitude hypoxia. TEMPOL can protectexperimental animals’ brain and heart under the altitude of8000m. The protectivemechanism of TEMPOL was similar with HPN, primarily by removing the excessiveproduction of ROS, inhibition of lipid peroxidation and protect the body's antioxidantenzyme system to maintain normal activity. The results proved once again that theradical scavenger compounds has anti-altitude hypoxia effect, and for the first timeconfirmed the potential protective role of TEMPOL under anti-altitude hypoxia.
2. The anti high-altitude hypoxia research of NO donor acetyl ferulic acid isosorbidemononitrate
Study on the anti-altitude hypoxia protective effect of NO donor compounds acetylferulic acid isosorbide mononitrate (ACMI) with both of free radical scavenging andNO release function and discussing the protection mechanisms. The results showedthat ACMI had good resistance to high-altitude hypoxia and could protect the bodyfrom high altitude hypoxic injury. Its proctive mechanism was cleaning excess freeradicals in the body, maintaining the drug release NO in vivo pharmacological activity,Inhibition of lipid peroxidation, while suppressing the inactivation of NO caused byfree radicals in vivo. Using isosorbide mononitrate as parent nucleus structure tosynthesis the radical scavenging NO donor compounds, also showed good anti-hypoxiaactivity.
Through the research on anti-hypoxia effect and radical scavenging mechanism oftwo nitroxide radical compounds of HPN and TEMPOL, and the NO donor ACMI, thisissue confirmed that a free radical scavenger could have a protective effect on theplateau hypoxia by clearing too many free radicals produced by the body. Meanwhilethe issue filtered out the radical scavenging and NO donor compounds with potentialmedicinal value. The study laid the foundation for the further development of hypoxicinjury protection drugs, as well as provided an experimental basis and theoretical basisfor the new anti-hypoxia drug development.
引文
[1] Hackett, P. H.; Roach, R. C. High-altitude illness. N Engl J Med345:107-114;2001.
[2] Salisbury, R.; Hawley, E. The Himalaya by the numbers: a statistical analysis of mountaineeringin the Nepal Himalaya. Vajra;2011.
[3] Hunt, L. Mount Kilimanjaro: climb and punishment. Telegraph Travel;2010.
[4] Imray, C.; Booth, A.; Wright, A.; Bradwell, A. Acute altitude illnesses. BMJ343:d4943;2011.
[5] Low, E. V.; Avery, A. J.; Gupta, V.; Schedlbauer, A.; Grocott, M. P. Identifying the lowesteffective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematicreview and meta-analysis. BMJ345:e6779;2012.
[6] Dean, A. G.; Yip, R.; Hoffmann, R. E. High incidence of mild acute mountain sickness inconference attendees at10,000foot altitude. J Wilderness Med1:86-92;1990.
[7] Basnyat, B. High-altitude illness. N Engl J Med345:1279; author reply1280-1271;2001.
[8] Huey, R. B. High altitude: an exploration of human adaptation. Integr Comp Biol42:910;2002.
[9] Bartsch, P.; Bailey, D. M.; Berger, M. M.; Knauth, M.; Baumgartner, R. W. Acute mountainsickness: controversies and advances. High Alt Med Biol5:110-124;2004.
[10] Hackett, P. H.; Roach, R. C. High altitude cerebral edema. High Alt Med Biol5:136-146;2004.
[11] Imray, C.; Wright, A.; Subudhi, A.; Roach, R. Acute mountain sickness: pathophysiology,prevention, and treatment. Prog Cardiovasc Dis52:467-484;2010.
[12] Silber, E.; Sonnenberg, P.; Collier, D. J.; Pollard, A. J.; Murdoch, D. R.; Goadsby, P. J. Clinicalfeatures of headache at altitude: a prospective study. Neurology60:1167-1171;2003.
[13] Serrano-Duenas, M. High altitude headache. A prospective study of its clinical characteristics.Cephalalgia25:1110-1116;2005.
[14] Savourey, G.; Guinet, A.; Besnard, Y.; Garcia, N.; Hanniquet, A. M.; Bittel, J. Evaluation of theLake Louise acute mountain sickness scoring system in a hypobaric chamber. Aviat SpaceEnviron Med66:963-967;1995.
[15] Southard, A.; Niermeyer, S.; Yaron, M. Language used in Lake Louise Scoring Systemunderestimates symptoms of acute mountain sickness in4-to11-year-old children. High Alt MedBiol8:124-130;2007.
[16] Sampson, J. B.; Cymerman, A.; Burse, R. L.; Maher, J. T.; Rock, P. B. Procedures for themeasurement of acute mountain sickness. Aviat Space Environ Med54:1063-1073;1983.
[17] Wagner, D. R.; Tatsugawa, K.; Parker, D.; Young, T. A. Reliability and utility of a visual analogscale for the assessment of acute mountain sickness. High Alt Med Biol8:27-31;2007.
[18] Fan, P. C.; Ma, H. P.; Jing, L. L.; Li, L.; Jia, Z. P. The antioxidative effect of a novel free radicalscavenger4'-hydroxyl-2-substituted phenylnitronyl nitroxide in acute high-altitude hypoxia mice.Biol Pharm Bull;2013.
[19] Schneider, M.; Bernasch, D.; Weymann, J.; Holle, R.; Bartsch, P. Acute mountain sickness:influence of susceptibility, preexposure, and ascent rate. Med Sci Sports Exerc34:1886-1891;2002.
[20] Scherrer, U.; Rexhaj, E.; Jayet, P. Y.; Allemann, Y.; Sartori, C. New insights in the pathogenesisof high-altitude pulmonary edema. Prog Cardiovasc Dis52:485-492;2010.
[21] Honigman, B.; Theis, M. K.; Koziol-McLain, J.; Roach, R.; Yip, R.; Houston, C.; Moore, L. G.;Pearce, P. Acute mountain sickness in a general tourist population at moderate altitudes. AnnIntern Med118:587-592;1993.
[22] Gallagher, S. A.; Hackett, P. H. High-altitude illness. Emerg Med Clin North Am22:329-355, viii;2004.
[23] Roach, R. C.; Houston, C. S.; Honigman, B.; Nicholas, R. A.; Yaron, M.; Grissom, C. K.;Alexander, J. K.; Hultgren, H. N. How well do older persons tolerate moderate altitude? West JMed162:32-36;1995.
[24] Wu, T. Y.; Ding, S. Q.; Liu, J. L.; Yu, M. T.; Jia, J. H.; Duan, J. Q.; Chai, Z. C.; Dai, R. C.; Zhang,S. L.; Liang, B. Z.; Zhao, J. Z.; Qi de, T.; Sun, Y. F.; Kayser, B. Reduced incidence and severityof acute mountain sickness in Qinghai-Tibet railroad construction workers after repeated7-month exposures despite5-month low altitude periods. High Alt Med Biol10:221-232;2009.
[25] Singh, I.; Khanna, P. K.; Srivastava, M. C.; Lal, M.; Roy, S. B.; Subramanyam, C. S. Acutemountain sickness. N Engl J Med280:175-184;1969.
[26] Loeppky, J. A.; Roach, R. C.; Maes, D.; Hinghofer-Szalkay, H.; Roessler, A.; Gates, L.; Fletcher,E. R.; Icenogle, M. V. Role of hypobaria in fluid balance response to hypoxia. High Alt Med Biol6:60-71;2005.
[27] Loeppky, J. A.; Icenogle, M.; Scotto, P.; Robergs, R.; Hinghofer-Szalkay, H.; Roach, R. C.Ventilation during simulated altitude, normobaric hypoxia and normoxic hypobaria. RespirPhysiol107:231-239;1997.
[28] Schoonman, G. G.; Sandor, P. S.; Nirkko, A. C.; Lange, T.; Jaermann, T.; Dydak, U.; Kremer, C.;Ferrari, M. D.; Boesiger, P.; Baumgartner, R. W. Hypoxia-induced acute mountain sickness isassociated with intracellular cerebral edema: a3T magnetic resonance imaging study. J CerebBlood Flow Metab28:198-206;2008.
[29] Goadsby, P. J. Pathophysiology of migraine. Neurol Clin27:335-360;2009.
[30] Chen, C. J.; Wang, W. Y.; Wang, X. L.; Dong, L. W.; Yue, Y. T.; Xin, H. L.; Ling, C. Q.; Li, M.Anti-hypoxic activity of the ethanol extract from Portulaca oleracea in mice. J Ethnopharmacol124:246-250;2009.
[31] Xie, Y.; Jiang, S.; Su, D.; Pi, N.; Ma, C.; Gao, P. Composition analysis and anti-hypoxia activityof polysaccharide from Brassica rapa L. Int J Biol Macromol47:528-533;2010.
[32] Shen, Z. B.; Yin, Y. Q.; Tang, C. P.; Yan, C. Y.; Chen, C.; Guo, L. B. Pharmacodynamicscreening and simulation study of anti-hypoxia active fraction of xiangdan injection. JEthnopharmacol127:103-107;2010.
[33] Cai, Y.; Lu, Y.; Chen, R.; Wei, Q.; Lu, X. Anti-hypoxia activity and related components ofRhodobryum giganteum par. Phytomedicine18:224-229;2011.
[34] Ma, H. P.; Fan, P. C.; Jing, L. L.; Yao, J.; He, X. R.; Yang, Y.; Chen, K. M.; Jia, Z. P.Anti-hypoxic activity at simulated high altitude was isolated in petroleum ether extract ofSaussurea involucrata. J Ethnopharmacol137:1510-1515;2011.
[35] Jordan, J.; de Groot, P. W.; Galindo, M. F. Mitochondria: the headquarters in ischemia-inducedneuronal death. Cent Nerv Syst Agents Med Chem11:98-106;2011.
[36] Finkel, T. Radical medicine: treating ageing to cure disease. Nat Rev Mol Cell Biol6:971-976;2005.
[37] Fantinelli, J. C.; Perez Nunez, I. A.; Gonzalez Arbelaez, L. F.; Schinella, G. R.; Mosca, S. M.Participation of mitochondrial permeability transition pore in the effects of ischemicpreconditioning in hypertrophied hearts: Role of NO and mitoK(ATP). Int J Cardiol;2011.
[38] Larsen, G. A.; Skjellegrind, H. K.; Berg-Johnsen, J.; Moe, M. C.; Vinje, M. L. Depolarization ofmitochondria in isolated CA1neurons during hypoxia, glucose deprivation and glutamateexcitotoxicity. Brain Res1077:153-160;2006.
[39] Lee, D. R.; Helps, S. C.; Macardle, P. J.; Nilsson, M.; Sims, N. R. Alterations in membranepotential in mitochondria isolated from brain subregions during focal cerebral ischemia and earlyreperfusion: evaluation using flow cytometry. Neurochem Res34:1857-1866;2009.
[40] Dave, K. R.; Bhattacharya, S. K.; Saul, I.; DeFazio, R. A.; Dezfulian, C.; Lin, H. W.; Raval, A. P.;Perez-Pinzon, M. A. Activation of protein kinase C delta following cerebral ischemia leads torelease of cytochrome C from the mitochondria via bad pathway. PLoS One6:e22057;2011.
[41] Moreira, P. I.; Zhu, X.; Wang, X.; Lee, H. G.; Nunomura, A.; Petersen, R. B.; Perry, G.; Smith, M.A. Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta1802:212-220;2010.
[42] Hota, S. K.; Hota, K. B.; Prasad, D.; Ilavazhagan, G.; Singh, S. B. Oxidative-stress-inducedalterations in Sp factors mediate transcriptional regulation of the NR1subunit in hippocampusduring hypoxia. Free Radic Biol Med49:178-191;2010.
[43] Zaobornyj, T.; Valdez, L. B.; Iglesias, D. E.; Gasco, M.; Gonzales, G. F.; Boveris, A.Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect ofsildenafil, L-NAME, and L-arginine treatments. Am J Physiol Heart Circ Physiol296:H1741-1747;2009.
[44] Chen, J.; Gao, Y.; Liao, W.; Huang, J.; Gao, W. Hypoxia affects mitochondrial protein expressionin rat skeletal muscle. OMICS16:98-104;2012.
[45] Kirpatovskii, V. I.; Kazachenko, A. V.; Plotnikov, E. Y.; Kon'kova, T. A.; Drozhzheva, V. V.;Zorov, D. B. Effects of ischemic and hypoxic preconditioning on the state of mitochondria andfunction of ischemic kidneys. Bull Exp Biol Med143:105-109;2007.
[46] Bailey, D. M.; Bartsch, P.; Knauth, M.; Baumgartner, R. W. Emerging concepts in acutemountain sickness and high-altitude cerebral edema: from the molecular to the morphological.Cell Mol Life Sci66:3583-3594;2009.
[47] Hildebrandt, W.; Alexander, S.; Bartsch, P.; Droge, W. Effect of N-acetyl-cysteine on the hypoxicventilatory response and erythropoietin production: linkage between plasma thiol redox state andO(2) chemosensitivity. Blood99:1552-1555;2002.
[48] Kallenberg, K.; Bailey, D. M.; Christ, S.; Mohr, A.; Roukens, R.; Menold, E.; Steiner, T.; Bartsch,P.; Knauth, M. Magnetic resonance imaging evidence of cytotoxic cerebral edema in acutemountain sickness. J Cereb Blood Flow Metab27:1064-1071;2007.
[49] Reinehr, R.; Gorg, B.; Becker, S.; Qvartskhava, N.; Bidmon, H. J.; Selbach, O.; Haas, H. L.;Schliess, F.; Haussinger, D. Hypoosmotic swelling and ammonia increase oxidative stress byNADPH oxidase in cultured astrocytes and vital brain slices. Glia55:758-771;2007.
[50] Master, S.; Gottstein, J.; Blei, A. T. Cerebral blood flow and the development ofammonia-induced brain edema in rats after portacaval anastomosis. Hepatology30:876-880;1999.
[51] Carlsten, C.; Swenson, E. R.; Ruoss, S. A dose-response study of acetazolamide for acutemountain sickness prophylaxis in vacationing tourists at12,000feet (3630m). High Alt MedBiol5:33-39;2004.
[52] Basnyat, B.; Gertsch, J. H.; Holck, P. S.; Johnson, E. W.; Luks, A. M.; Donham, B. P.;Fleischman, R. J.; Gowder, D. W.; Hawksworth, J. S.; Jensen, B. T.; Kleiman, R. J.; Loveridge,A. H.; Lundeen, E. B.; Newman, S. L.; Noboa, J. A.; Miegs, D. P.; O'Beirne, K. A.; Philpot, K.B.; Schultz, M. N.; Valente, M. C.; Wiebers, M. R.; Swenson, E. R. Acetazolamide125mg BD isnot significantly different from375mg BD in the prevention of acute mountain sickness: theprophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol7:17-27;2006.
[53] van Patot, M. C.; Leadbetter, G.,3rd; Keyes, L. E.; Maakestad, K. M.; Olson, S.; Hackett, P. H.Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountainsickness. High Alt Med Biol9:289-293;2008.
[54] Wright, A. D.; Bradwell, A. R.; Fletcher, R. F. Methazolamide and acetazolamide in acutemountain sickness. Aviat Space Environ Med54:619-621;1983.
[55] Johnson, T. S.; Rock, P. B.; Fulco, C. S.; Trad, L. A.; Spark, R. F.; Maher, J. T. Prevention ofacute mountain sickness by dexamethasone. N Engl J Med310:683-686;1984.
[56] Hackett, P. H.; Roach, R. C.; Wood, R. A.; Foutch, R. G.; Meehan, R. T.; Rennie, D.; Mills, W. J.,Jr. Dexamethasone for prevention and treatment of acute mountain sickness. Aviat Space EnvironMed59:950-954;1988.
[57] Wright, A. D.; Beazley, M. F.; Bradwell, A. R.; Chesner, I. M.; Clayton, R. N.; Forster, P. J.;Hillenbrand, P.; Imray, C. H. Medroxyprogesterone at high altitude. The effects on blood gases,cerebral regional oxygenation, and acute mountain sickness. Wilderness Environ Med15:25-31;2004.
[58] Fischer, R.; Lang, S. M.; Leitl, M.; Thiere, M.; Steiner, U.; Huber, R. M. Theophylline andacetazolamide reduce sleep-disordered breathing at high altitude. Eur Respir J23:47-52;2004.
[59] Kupper, T. E.; Strohl, K. P.; Hoefer, M.; Gieseler, U.; Netzer, C. M.; Netzer, N. C. Low-dosetheophylline reduces symptoms of acute mountain sickness. J Travel Med15:307-314;2008.
[60] Chow, T.; Browne, V.; Heileson, H. L.; Wallace, D.; Anholm, J.; Green, S. M. Ginkgo biloba andacetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial.Arch Intern Med165:296-301;2005.
[61] Esbaugh, A. J.; Tufts, B. L. The structure and function of carbonic anhydrase isozymes in therespiratory system of vertebrates. Respir Physiol Neurobiol154:185-198;2006.
[62] Maren, T. H.; Sanyal, G. The activity of sulfonamides and anions against the carbonic anhydrasesof animals, plants, and bacteria. Annu Rev Pharmacol Toxicol23:439-459;1983.
[63] Swenson, E. R. Carbonic anhydrase inhibitors and hypoxic pulmonary vasoconstriction. RespirPhysiol Neurobiol151:209-216;2006.
[64] Swenson, E. R.; Teppema, L. J. Prevention of acute mountain sickness by acetazolamide: as yetan unfinished story. J Appl Physiol102:1305-1307;2007.
[65] Hackett, P. H.; Roach, R. C. Medical therapy of altitude illness. Ann Emerg Med16:980-986;1987.
[66] Zell, S. C.; Goodman, P. H. Acetazolamide and dexamethasone in the prevention of acutemountain sickness. West J Med148:541-545;1988.
[67] Dumont, L.; Mardirosoff, C.; Tramer, M. R. Efficacy and harm of pharmacological prevention ofacute mountain sickness: quantitative systematic review. BMJ321:267-272;2000.
[68] Kayser, B.; Hulsebosch, R.; Bosch, F. Low-dose acetylsalicylic acid analog and acetazolamidefor prevention of acute mountain sickness. High Alt Med Biol9:15-23;2008.
[69] Hackett, P. H.; Schoene, R. B.; Winslow, R. M.; Peters, R. M., Jr.; West, J. B. Acetazolamide andexercise in sojourners to6,300meters--a preliminary study. Med Sci Sports Exerc17:593-597;1985.
[70] Garske, L. A.; Brown, M. G.; Morrison, S. C. Acetazolamide reduces exercise capacity andincreases leg fatigue under hypoxic conditions. J Appl Physiol94:991-996;2003.
[71] Fulco, C. S.; Muza, S. R.; Ditzler, D.; Lammi, E.; Lewis, S. F.; Cymerman, A. Effect ofacetazolamide on leg endurance exercise at sea level and simulated altitude. Clin Sci (Lond)110:683-692;2006.
[72] Jonk, A. M.; van den Berg, I. P.; Olfert, I. M.; Wray, D. W.; Arai, T.; Hopkins, S. R.; Wagner, P.D. Effect of acetazolamide on pulmonary and muscle gas exchange during normoxic andhypoxic exercise. J Physiol579:909-921;2007.
[73] Schoene, R. B.; Bates, P. W.; Larson, E. B.; Pierson, D. J. Effect of acetazolamide on normoxicand hypoxic exercise in humans at sea level. J Appl Physiol55:1772-1776;1983.
[74] Beck, K. C. Flat beer vs. physiological improvement: effect of acetazolamide during hypoxicexercise. J Physiol579:568-569;2007.
[75] Maren, T. H. Carbonic anhydrase: chemistry, physiology, and inhibition. Physiol Rev47:595-781;1967.
[76] Levine, B. D.; Yoshimura, K.; Kobayashi, T.; Fukushima, M.; Shibamoto, T.; Ueda, G.Dexamethasone in the treatment of acute mountain sickness. N Engl J Med321:1707-1713;1989.
[77] Rock, P. B.; Johnson, T. S.; Larsen, R. F.; Fulco, C. S.; Trad, L. A.; Cymerman, A.Dexamethasone as prophylaxis for acute mountain sickness. Effect of dose level. Chest95:568-573;1989.
[78] Basu, M.; Sawhney, R. C.; Kumar, S.; Pal, K.; Prasad, R.; Selvamurthy, W. Glucocorticoids asprophylaxis against acute mountain sickness. Clin Endocrinol (Oxf)57:761-767;2002.
[79] Bernhard, W. N.; Schalick, L. M.; Delaney, P. A.; Bernhard, T. M.; Barnas, G. M. Acetazolamideplus low-dose dexamethasone is better than acetazolamide alone to ameliorate symptoms ofacute mountain sickness. Aviat Space Environ Med69:883-886;1998.
[80] Chan, C. W.; Hoar, H.; Pattinson, K.; Bradwell, A. R.; Wright, A. D.; Imray, C. H. Effect ofsildenafil and acclimatization on cerebral oxygenation at altitude. Clin Sci (Lond)109:319-324;2005.
[81] Maggiorini, M.; Brunner-La Rocca, H. P.; Peth, S.; Fischler, M.; Bohm, T.; Bernheim, A.;Kiencke, S.; Bloch, K. E.; Dehnert, C.; Naeije, R.; Lehmann, T.; Bartsch, P.; Mairbaurl, H. Bothtadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: arandomized trial. Ann Intern Med145:497-506;2006.
[82] Fischer, R.; Lang, S. M.; Steiner, U.; Toepfer, M.; Hautmann, H.; Pongratz, H.; Huber, R. M.Theophylline improves acute mountain sickness. Eur Respir J15:123-127;2000.
[83] Chen, C. H.; Chen, A. C.; Liu, H. J. Involvement of nitric oxide and N-methyl-D-aspartate inacute hypoxic altitude convulsion in mice. Aviat Space Environ Med68:296-299;1997.
[84] Xie, J.; Lu, G.; Hou, Y. Role of excitatory amino acids in hypoxic preconditioning. Biol SignalsRecept8:267-274;1999.
[85] Lysakowski, C.; Von Elm, E.; Dumont, L.; Junod, J. D.; Tassonyi, E.; Kayser, B.; Tramer, M. R.Effect of magnesium, high altitude and acute mountain sickness on blood flow velocity in themiddle cerebral artery. Clin Sci (Lond)106:279-285;2004.
[86] Dumont, L.; Lysakowski, C.; Tramer, M. R.; Junod, J. D.; Mardirosoff, C.; Tassonyi, E.; Kayser,B. Magnesium for the prevention and treatment of acute mountain sickness. Clin Sci (Lond)106:269-277;2004.
[87] Aoki, V. S.; Robinson, S. M. Body hydration and the incidence and severity of acute mountainsickness. J Appl Physiol31:363-367;1971.
[88] Gray, G. W.; Bryan, A. C.; Frayser, R.; Houston, C. S.; Rennie, I. D. Control of acute mountainsickness. Aerosp Med42:81-84;1971.
[89] Jain, S. C.; Singh, M. V.; Sharma, V. M.; Rawal, S. B.; Tyagi, A. K. Amelioration of acutemountain sickness: comparative study of acetazolamide and spironolactone. Int J Biometeorol30:293-300;1986.
[90] Larsen, R. F.; Rock, P. B.; Fulco, C. S.; Edelman, B.; Young, A. J.; Cymerman, A. Effect ofspironolactone on acute mountain sickness. Aviat Space Environ Med57:543-547;1986.
[91] Dubowitz, G. Effect of temazepam on oxygen saturation and sleep quality at high altitude:randomised placebo controlled crossover trial. BMJ316:587-589;1998.
[92] Nickol, A. H.; Leverment, J.; Richards, P.; Seal, P.; Harris, G. A.; Cleland, J.; Dubowitz, G.;Collier, D. J.; Milledge, J.; Stradling, J. R.; Morrell, M. J. Temazepam at high altitude reducesperiodic breathing without impairing next-day performance: a randomized cross-overdouble-blind study. J Sleep Res15:445-454;2006.
[93] Jafarian, S.; Gorouhi, F.; Salimi, S.; Lotfi, J. Low-dose gabapentin in treatment of high-altitudeheadache. Cephalalgia27:1274-1277;2007.
[94] Jafarian, S.; Gorouhi, F.; Salimi, S.; Lotfi, J. Sumatriptan for prevention of acute mountainsickness: randomized clinical trial. Ann Neurol62:273-277;2007.
[95] Basnyat, B. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med347:1282-1285; author reply1282-1285;2002.
[96] Kumar, D.; Bansal, A.; Thomas, P.; Mongia, S. S.; Sharma, S. K.; Sairam, M.; Grover, S. K.;Singh, M. V.; Prasad, D.; Ilavazhagan, G.; Selvamurthy, W. Improved high altitude hypoxictolerance and amelioration of anorexia and hypophagia in rats on oral glutamate supplementation.Aviat Space Environ Med70:475-479;1999.
[97] Oelz, O.; Maggiorini, M.; Ritter, M.; Waber, U.; Jenni, R.; Vock, P.; Bartsch, P. Nifedipine forhigh altitude pulmonary oedema. Lancet2:1241-1244;1989.
[98]惠锦，刘福玉，高文祥，高钰琪，陈莉.二十八烷醇对小鼠耐缺氧作用的实验研究.西南国防医药17:143-145;2007.
[99]于长青，张国海.二十八烷醇抗大鼠心肌线粒体损伤的研究.中国食品添加剂2:35-37;2003.
[100] Zhang, J.; Liu, A.; Hou, R.; Jia, X.; Jiang, W.; Chen, J. Salidroside protects cardiomyocyteagainst hypoxia-induced death: a HIF-1alpha-activated and VEGF-mediated pathway. Eur JPharmacol607:6-14;2009.
[101] Schriner, S. E.; Avanesian, A.; Liu, Y.; Luesch, H.; Jafari, M. Protection of human cultured cellsagainst oxidative stress by Rhodiola rosea without activation of antioxidant defenses. Free RadicBiol Med47:577-584;2009.
[102] Kong, H. L.; Wang, J. P.; Li, Z. Q.; Zhao, S. M.; Dong, J.; Zhang, W. W. Anti-hypoxic effect ofginsenoside Rbl on neonatal rat cardiomyocytes is mediated through the specific activation ofglucose transporter-4ex vivo. Acta Pharmacol Sin30:396-403;2009.
[103] Patir, H.; Sarada, S. K.; Singh, S.; Mathew, T.; Singh, B.; Bansal, A. Quercetin as a prophylacticmeasure against high altitude cerebral edema. Free Radic Biol Med53:659-668;2012.
[104] Subudhi, A. W.; Jacobs, K. A.; Hagobian, T. A.; Fattor, J. A.; Muza, S. R.; Fulco, C. S.;Cymerman, A.; Friedlander, A. L. Changes in ventilatory threshold at high altitude: effect ofantioxidants. Med Sci Sports Exerc38:1425-1431;2006.
[105] Hagobian, T. A.; Jacobs, K. A.; Subudhi, A. W.; Fattor, J. A.; Rock, P. B.; Muza, S. R.; Fulco, C.S.; Braun, B.; Grediagin, A.; Mazzeo, R. S.; Cymerman, A.; Friedlander, A. L. Cytokineresponses at high altitude: effects of exercise and antioxidants at4300m. Med Sci Sports Exerc38:276-285;2006.
[106] Dubey, A. K.; Shankar, P. R.; Upadhyaya, D.; Deshpande, V. Y. Ginkgo biloba--an appraisal.Kathmandu Univ Med J (KUMJ)2:225-229;2004.
[107] Moraga, F. A.; Flores, A.; Serra, J.; Esnaola, C.; Barriento, C. Ginkgo biloba decreases acutemountain sickness in people ascending to high altitude at Ollague (3696m) in northern Chile.Wilderness Environ Med18:251-257;2007.
[108] van Patot, M. C.; Keyes, L. E.; Leadbetter, G.,3rd; Hackett, P. H. Ginkgo biloba for preventionof acute mountain sickness: does it work? High Alt Med Biol10:33-43;2009.
[109] Leadbetter, G.; Keyes, L. E.; Maakestad, K. M.; Olson, S.; Tissot van Patot, M. C.; Hackett, P. H.Ginkgo biloba does--and does not--prevent acute mountain sickness. Wilderness Environ Med20:66-71;2009.
[110] Schreiber, M.; Trojan, S. Protective effect of flavonoids and tocopherol in high altitude hypoxiain the rat: comparison with ascorbic acid. Cesk Fysiol47:51-52;1998.
[111] Bailey, D. M.; Dehnert, C.; Luks, A. M.; Menold, E.; Castell, C.; Schendler, G.; Faoro, V.;Gutowski, M.; Evans, K. A.; Taudorf, S.; James, P. E.; McEneny, J.; Young, I. S.; Swenson, E. R.;Mairbaurl, H.; Bartsch, P.; Berger, M. M. High-altitude pulmonary hypertension is associatedwith a free radical-mediated reduction in pulmonary nitric oxide bioavailability. J Physiol588:4837-4847;2010.
[112] Vats, P.; Singh, V. K.; Singh, S. N.; Singh, S. B. Glutathione metabolism under high-altitudestress and effect of antioxidant supplementation. Aviat Space Environ Med79:1106-1111;2008.
[113] Al-Hashem, F. H. Potential roles for vitamins E and C in combination in modulating exhaustiveswimming and high altitude-associated lung injury in rats. Saudi Med J33:367-374;2012.
[114] Telford, J. E.; Kilbride, S. M.; Davey, G. P. Decylubiquinone increases mitochondrial function insynaptosomes. J Biol Chem285:8639-8645;2010.
[115] Zhao, K.; Zhao, G. M.; Wu, D.; Soong, Y.; Birk, A. V.; Schiller, P. W.; Szeto, H. H.Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibitmitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem279:34682-34690;2004.
[116] Wright, J. S.; Carpenter, D. J.; McKay, D. J.; Ingold, K. U. Theoretical calculation of substituenteffects on the O-H bond strength of phenolic antioxidants related to vitamin E. J Am Chem Soc119:4245-4252;1997.
[117] Liu, L. M.; Hu, D. Y.; Zhou, X. W.; Liu, J. C.; Li, P. HSD is a better resuscitation fluid forhemorrhagic shock with pulmonary edema at high altitude. Shock30:714-720;2008.
[118] Vats, P.; Singh, V. K.; Singh, S. N.; Singh, S. B. High altitude induced anorexia: effect ofchanges in leptin and oxidative stress levels. Nutr Neurosci10:243-249;2007.
[119] Dosek, A.; Ohno, H.; Acs, Z.; Taylor, A. W.; Radak, Z. High altitude and oxidative stress. RespirPhysiol Neurobiol158:128-131;2007.
[120] Sinha, S.; Singh, S. N.; Saha, M.; Kain, T. C.; Tyagi, A. K. Antioxidant and oxidative stressresponses of sojourners at high altitude in different climatic temperatures. Int J Biometeorol54:85-92;2010.
[121] Parraguez, V. H.; Urquieta, B.; Perez, L.; Castellaro, G.; De Los Reyes, M.; Torres-Rovira, L.;Aguado-Martinez, A.; Astiz, S.; Gonzalez-Bulnes, A. Fertility in a high-altitude environment iscompromised by luteal dysfunction: the relative roles of hypoxia and oxidative stress. ReprodBiol Endocrinol11:24;2013.
[1] Low, E. V.; Avery, A. J.; Gupta, V.; Schedlbauer, A.; Grocott, M. P. Identifying the lowesteffective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic reviewand meta-analysis. BMJ345:e6779;2012.
[2] Ritchie, N. D.; Baggott, A. V.; Andrew Todd, W. T. Acetazolamide for the prevention of acutemountain sickness--a systematic review and meta-analysis. J Travel Med19:298-307;2012.
[3] Kayser, B.; Dumont, L.; Lysakowski, C.; Combescure, C.; Haller, G.; Tramer, M. R. Reappraisalof acetazolamide for the prevention of acute mountain sickness: a systematic review andmeta-analysis. High Alt Med Biol13:82-92;2012.
[4] Inatani, M.; Yano, I.; Tanihara, H.; Ogura, Y.; Honda, Y.; Inui, K. I. Relationship betweenacetazolamide blood concentration and its side effects in glaucomatous patients. J OculPharmacol Ther15:97-105;1999.
[5] Pun, M. Side-effect of acetazolamide in prevention of acute mountain sickness. S Afr Med J102:114; author reply114;2012.
[6] Vahedi, K.; Taupin, P.; Djomby, R.; El-Amrani, M.; Lutz, G.; Filipetti, V.; Landais, P.; Massiou, H.;Bousser, M. G. Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomisedplacebo-controlled trial. J Neurol249:206-211;2002.
[7] Lastnick, G. Metabolic acidosis secondary to acetazolamide therapy a possible hazardous sideeffect after prolonged use of acetazolamide in geriatric patients. A case report. Ariz Med32:19-21;1975.
[8] Dahl, H.; Norskov, K.; Peitersen, E.; Hilden, J. Zinc therapy of acetazolamide-inducedside-effects. Acta Ophthalmol (Copenh)62:739-745;1984.
[9] Theeuwes, F.; Bayne, W.; McGuire, J. Gastrointestinal therapeutic system for acetazolamide.Efficacy and side effects. Arch Ophthalmol96:2219-2221;1978.
[10] Borhani, H.; Rahimy, M. H.; Peyman, G. A. Vitreoretinal toxicity of acetazolamide followingintravitreal administration in the rabbit eye. Ophthalmic Surg25:166-169;1994.
[11] Yang, M. T.; Chien, W. L.; Lu, D. H.; Liou, H. C.; Fu, W. M. Acetazolamide impairs fear memoryconsolidation in rodents. Neuropharmacology67:412-418;2013.
[12] Ellsworth, A. J.; Larson, E. B.; Strickland, D. A randomized trial of dexamethasone andacetazolamide for acute mountain sickness prophylaxis. Am J Med83:1024-1030;1987.
[13] Zhang, J.; Liu, A.; Hou, R.; Jia, X.; Jiang, W.; Chen, J. Salidroside protects cardiomyocyte againsthypoxia-induced death: a HIF-1alpha-activated and VEGF-mediated pathway. Eur J Pharmacol607:6-14;2009.
[14] Schriner, S. E.; Avanesian, A.; Liu, Y.; Luesch, H.; Jafari, M. Protection of human cultured cellsagainst oxidative stress by Rhodiola rosea without activation of antioxidant defenses. Free RadicBiol Med47:577-584;2009.
[15] Patir, H.; Sarada, S. K.; Singh, S.; Mathew, T.; Singh, B.; Bansal, A. Quercetin as a prophylacticmeasure against high altitude cerebral edema. Free Radic Biol Med53:659-668;2012.
[16] Schreiber, M.; Trojan, S. Protective effect of flavonoids and tocopherol in high altitude hypoxia inthe rat: comparison with ascorbic acid. Cesk Fysiol47:51-52;1998.
[17] Kong, H. L.; Wang, J. P.; Li, Z. Q.; Zhao, S. M.; Dong, J.; Zhang, W. W. Anti-hypoxic effect ofginsenoside Rbl on neonatal rat cardiomyocytes is mediated through the specific activation ofglucose transporter-4ex vivo. Acta Pharmacol Sin30:396-403;2009.
[18] Ma, H. P.; Fan, P. C.; Jing, L. L.; Yao, J.; He, X. R.; Yang, Y.; Chen, K. M.; Jia, Z. P. Anti-hypoxicactivity at simulated high altitude was isolated in petroleum ether extract of Saussurea involucrata.J Ethnopharmacol137:1510-1515;2011.
[19] Gupta, V.; Lahiri, S. S.; Sultana, S.; Tulsawani, R. K.; Kumar, R. Anti-oxidative effect ofRhodiola imbricata root extract in rats during cold, hypoxia and restraint (C-H-R) exposure andpost-stress recovery. Food Chem Toxicol48:1019-1025;2010.
[20]景临林.新型氮氧自由基的设计合成及其性能研究.第四军医大学博士论文;2010.
[21]向卓.新型抗心肌缺血/再灌注损伤药物的研究.第四军医大学博士论文;2011.
[22] Wu, Y.; Bi, L.; Bi, W.; Li, Z.; Zhao, M.; Wang, C.; Ju, J.; Peng, S. Novel2-substituted nitronylnitroxides as free radical scavengers: synthesis, biological evaluation and structure-activityrelationship. Bioorg Med Chem14:5711-5720;2006.
[23] Zhao, M.; Li, Z.; Wu, Y.; Tang, Y. R.; Wang, C.; Zhang, Z.; Peng, S. Studies on logP, retentiontime and QSAR of2-substituted phenylnitronyl nitroxides as free radical scavengers. Eur J MedChem42:955-965;2007.
[24] Qian, J.; Jiang, F.; Wang, B.; Yu, Y.; Zhang, X.; Yin, Z.; Liu, C. Ophiopogonin D preventsH2O2-induced injury in primary human umbilical vein endothelial cells. J Ethnopharmacol128:438-445;2010.
[25] Sheng, R.; Gu, Z. L.; Xie, M. L.; Zhou, W. X.; Guo, C. Y. Epigallocatechin gallate protects H9c2cardiomyoblasts against hydrogen dioxides-induced apoptosis and telomere attrition. Eur JPharmacol641:199-206;2010.
[26] Zhao, L.; Shi, L. Metabolism of hydrogen peroxide in univoltine and polyvoltine strains ofsilkworm (Bombyx mori). Comp Biochem Physiol B Biochem Mol Biol152:339-345;2009.
[27] Wang, X. Z.; Liu, S. S.; Sun, Y.; Wu, J. Y.; Zhou, Y. L.; Zhang, J. H. Beta-cypermethrin impairsreproductive function in male mice by inducing oxidative stress. Theriogenology72:599-611;2009.
[28] Huang, X.; Zhuang, J.; Teng, X.; Li, L.; Chen, D.; Yan, X.; Tang, F. The promotion of humanmalignant melanoma growth by mesoporous silica nanoparticles through decreased reactiveoxygen species. Biomaterials31:6142-6153;2010.
[29] Qiao, T.; Liu, C.; Ran, F. The impact of gastrocnemius muscle cell changes in chronic venousinsufficiency. Eur J Vasc Endovasc Surg30:430-436;2005.
[30] Moreira, P. I.; Zhu, X.; Wang, X.; Lee, H. G.; Nunomura, A.; Petersen, R. B.; Perry, G.; Smith, M.A. Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta1802:212-220;2010.
[31] Gruber, J.; Fong, S.; Chen, C. B.; Yoong, S.; Pastorin, G.; Schaffer, S.; Cheah, I.; Halliwell, B.Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions toslow ageing. Biotechnol Adv;2012.
[32] Mukhopadhyay, P.; Horvath, B.; Zsengeller, Z.; Zielonka, J.; Tanchian, G.; Holovac, E.; Kechrid,M.; Patel, V.; Stillman, I. E.; Parikh, S. M.; Joseph, J.; Kalyanaraman, B.; Pacher, P.Mitochondrial-targeted antioxidants represent a promising approach for prevention ofcisplatin-induced nephropathy. Free Radic Biol Med52:497-506;2012.
[33] Zhu, X. J.; Shi, Y.; Peng, J.; Guo, C. S.; Shan, N. N.; Qin, P.; Ji, X. B.; Hou, M. The effects ofBAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia. Blood114:5362-5367;2009.
[34] Keeney, P. M.; Xie, J.; Capaldi, R. A.; Bennett, J. P., Jr. Parkinson's disease brain mitochondrialcomplex I has oxidatively damaged subunits and is functionally impaired and misassembled. JNeurosci26:5256-5264;2006.
[35] Feng, Z.; Zou, X.; Jia, H.; Li, X.; Zhu, Z.; Liu, X.; Bucheli, P.; Ballevre, O.; Hou, Y.; Zhang, W.;Wang, J.; Chen, Y.; Liu, J. Maternal docosahexaenoic acid feeding protects against impairment oflearning and memory and oxidative stress in prenatally stressed rats: possible role of neuronalmitochondria metabolism. Antioxid Redox Signal16:275-289;2012.
[36] Long, J.; Gao, F.; Tong, L.; Cotman, C. W.; Ames, B. N.; Liu, J. Mitochondrial decay in the brainsof old rats: ameliorating effect of alpha-lipoic acid and acetyl-L-carnitine. Neurochem Res34:755-763;2009.
[1] Barriga, S.2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO). Synlett.4:563.;2001.
[2] Bernstein, E. F.; Kong, S. K.; Brown, D. B.; Kwak, B. C.; Takeuchi, T.; Gasparro, F. P.; Uitto, J.The nitroxide Tempol affords protection against ultraviolet radiation in a transgenic murinefibroblast culture model of cutaneous photoaging. Exp Dermatol10:55-61;2001.
[3]严淑贤;胡跃;邓辉;洪新宇;徐昱;廖康煌.紫外线A1对真皮成纤维细胞的损伤及Tempol保护作用的研究.中华皮肤科杂志38:413-415;2005.
[4] Qian, J.; Jiang, F.; Wang, B.; Yu, Y.; Zhang, X.; Yin, Z.; Liu, C. Ophiopogonin D preventsH2O2-induced injury in primary human umbilical vein endothelial cells. J Ethnopharmacol128:438-445;2010.
[5] Sheng, R.; Gu, Z. L.; Xie, M. L.; Zhou, W. X.; Guo, C. Y. Epigallocatechin gallate protects H9c2cardiomyoblasts against hydrogen dioxides-induced apoptosis and telomere attrition. Eur JPharmacol641:199-206;2010.
[6] Zhao, L.; Shi, L. Metabolism of hydrogen peroxide in univoltine and polyvoltine strains ofsilkworm (Bombyx mori). Comp Biochem Physiol B Biochem Mol Biol152:339-345;2009.
[7] Wang, X. Z.; Liu, S. S.; Sun, Y.; Wu, J. Y.; Zhou, Y. L.; Zhang, J. H. Beta-cypermethrin impairsreproductive function in male mice by inducing oxidative stress. Theriogenology72:599-611;2009.
[8] Huang, X.; Zhuang, J.; Teng, X.; Li, L.; Chen, D.; Yan, X.; Tang, F. The promotion of humanmalignant melanoma growth by mesoporous silica nanoparticles through decreased reactiveoxygen species. Biomaterials31:6142-6153;2010.
[9] Qiao, T.; Liu, C.; Ran, F. The impact of gastrocnemius muscle cell changes in chronic venousinsufficiency. Eur J Vasc Endovasc Surg30:430-436;2005.
[1] Ma, X. L.; Gao, F.; Nelson, A. H.; Lopez, B. L.; Christopher, T. A.; Yue, T. L.; Barone, F. C.Oxidative inactivation of nitric oxide and endothelial dysfunction in stroke-prone spontaneoushypertensive rats. J Pharmacol Exp Ther298:879-885;2001.
[2] Munzel, T.; Wenzel, P.; Daiber, A. Do we still need organic nitrates? J Am Coll Cardiol49:1296-1298;2007.
[3] Gao, F.; Yao, C. L.; Gao, E.; Mo, Q. Z.; Yan, W. L.; McLaughlin, R.; Lopez, B. L.; Christopher, T.A.; Ma, X. L. Enhancement of glutathione cardioprotection by ascorbic acid in myocardialreperfusion injury. J Pharmacol Exp Ther301:543-550;2002.
[4] Yan, J.; Feng, Z.; Liu, J.; Shen, W.; Wang, Y.; Wertz, K.; Weber, P.; Long, J. Enhanced autophagyplays a cardinal role in mitochondrial dysfunction in type2diabetic Goto-Kakizaki (GK) rats:ameliorating effects of (-)-epigallocatechin-3-gallate. J Nutr Biochem23:716-724;2012.
[5]向卓.新型抗心肌缺血/再灌注损伤药物的研究.第四军医大学博士论文;2011.
[6] Qian, J.; Jiang, F.; Wang, B.; Yu, Y.; Zhang, X.; Yin, Z.; Liu, C. Ophiopogonin D preventsH2O2-induced injury in primary human umbilical vein endothelial cells. J Ethnopharmacol128:438-445;2010.
[7] Sheng, R.; Gu, Z. L.; Xie, M. L.; Zhou, W. X.; Guo, C. Y. Epigallocatechin gallate protects H9c2cardiomyoblasts against hydrogen dioxides-induced apoptosis and telomere attrition. Eur JPharmacol641:199-206;2010.
[8] Zhao, L.; Shi, L. Metabolism of hydrogen peroxide in univoltine and polyvoltine strains ofsilkworm (Bombyx mori). Comp Biochem Physiol B Biochem Mol Biol152:339-345;2009.
[9] Wang, X. Z.; Liu, S. S.; Sun, Y.; Wu, J. Y.; Zhou, Y. L.; Zhang, J. H. Beta-cypermethrin impairsreproductive function in male mice by inducing oxidative stress. Theriogenology72:599-611;2009.
[10] Huang, X.; Zhuang, J.; Teng, X.; Li, L.; Chen, D.; Yan, X.; Tang, F. The promotion of humanmalignant melanoma growth by mesoporous silica nanoparticles through decreased reactiveoxygen species. Biomaterials31:6142-6153;2010.
[11] Qiao, T.; Liu, C.; Ran, F. The impact of gastrocnemius muscle cell changes in chronic venousinsufficiency. Eur J Vasc Endovasc Surg30:430-436;2005.
[2] Salisbury, R.; Hawley, E. The Himalaya by the numbers: a statistical analysis of mountaineeringin the Nepal Himalaya. Vajra;2011.
[3] Hunt, L. Mount Kilimanjaro: climb and punishment. Telegraph Travel;2010.
[4] Imray, C.; Booth, A.; Wright, A.; Bradwell, A. Acute altitude illnesses. BMJ343:d4943;2011.
[5] Low, E. V.; Avery, A. J.; Gupta, V.; Schedlbauer, A.; Grocott, M. P. Identifying the lowesteffective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematicreview and meta-analysis. BMJ345:e6779;2012.
[6] Dean, A. G.; Yip, R.; Hoffmann, R. E. High incidence of mild acute mountain sickness inconference attendees at10,000foot altitude. J Wilderness Med1:86-92;1990.
[7] Basnyat, B. High-altitude illness. N Engl J Med345:1279; author reply1280-1271;2001.
[8] Huey, R. B. High altitude: an exploration of human adaptation. Integr Comp Biol42:910;2002.
[9] Bartsch, P.; Bailey, D. M.; Berger, M. M.; Knauth, M.; Baumgartner, R. W. Acute mountainsickness: controversies and advances. High Alt Med Biol5:110-124;2004.
[10] Hackett, P. H.; Roach, R. C. High altitude cerebral edema. High Alt Med Biol5:136-146;2004.
[11] Imray, C.; Wright, A.; Subudhi, A.; Roach, R. Acute mountain sickness: pathophysiology,prevention, and treatment. Prog Cardiovasc Dis52:467-484;2010.
[12] Silber, E.; Sonnenberg, P.; Collier, D. J.; Pollard, A. J.; Murdoch, D. R.; Goadsby, P. J. Clinicalfeatures of headache at altitude: a prospective study. Neurology60:1167-1171;2003.
[13] Serrano-Duenas, M. High altitude headache. A prospective study of its clinical characteristics.Cephalalgia25:1110-1116;2005.
[14] Savourey, G.; Guinet, A.; Besnard, Y.; Garcia, N.; Hanniquet, A. M.; Bittel, J. Evaluation of theLake Louise acute mountain sickness scoring system in a hypobaric chamber. Aviat SpaceEnviron Med66:963-967;1995.
[15] Southard, A.; Niermeyer, S.; Yaron, M. Language used in Lake Louise Scoring Systemunderestimates symptoms of acute mountain sickness in4-to11-year-old children. High Alt MedBiol8:124-130;2007.
[16] Sampson, J. B.; Cymerman, A.; Burse, R. L.; Maher, J. T.; Rock, P. B. Procedures for themeasurement of acute mountain sickness. Aviat Space Environ Med54:1063-1073;1983.
[17] Wagner, D. R.; Tatsugawa, K.; Parker, D.; Young, T. A. Reliability and utility of a visual analogscale for the assessment of acute mountain sickness. High Alt Med Biol8:27-31;2007.
[18] Fan, P. C.; Ma, H. P.; Jing, L. L.; Li, L.; Jia, Z. P. The antioxidative effect of a novel free radicalscavenger4'-hydroxyl-2-substituted phenylnitronyl nitroxide in acute high-altitude hypoxia mice.Biol Pharm Bull;2013.
[19] Schneider, M.; Bernasch, D.; Weymann, J.; Holle, R.; Bartsch, P. Acute mountain sickness:influence of susceptibility, preexposure, and ascent rate. Med Sci Sports Exerc34:1886-1891;2002.
[20] Scherrer, U.; Rexhaj, E.; Jayet, P. Y.; Allemann, Y.; Sartori, C. New insights in the pathogenesisof high-altitude pulmonary edema. Prog Cardiovasc Dis52:485-492;2010.
[21] Honigman, B.; Theis, M. K.; Koziol-McLain, J.; Roach, R.; Yip, R.; Houston, C.; Moore, L. G.;Pearce, P. Acute mountain sickness in a general tourist population at moderate altitudes. AnnIntern Med118:587-592;1993.
[22] Gallagher, S. A.; Hackett, P. H. High-altitude illness. Emerg Med Clin North Am22:329-355, viii;2004.
[23] Roach, R. C.; Houston, C. S.; Honigman, B.; Nicholas, R. A.; Yaron, M.; Grissom, C. K.;Alexander, J. K.; Hultgren, H. N. How well do older persons tolerate moderate altitude? West JMed162:32-36;1995.
[24] Wu, T. Y.; Ding, S. Q.; Liu, J. L.; Yu, M. T.; Jia, J. H.; Duan, J. Q.; Chai, Z. C.; Dai, R. C.; Zhang,S. L.; Liang, B. Z.; Zhao, J. Z.; Qi de, T.; Sun, Y. F.; Kayser, B. Reduced incidence and severityof acute mountain sickness in Qinghai-Tibet railroad construction workers after repeated7-month exposures despite5-month low altitude periods. High Alt Med Biol10:221-232;2009.
[25] Singh, I.; Khanna, P. K.; Srivastava, M. C.; Lal, M.; Roy, S. B.; Subramanyam, C. S. Acutemountain sickness. N Engl J Med280:175-184;1969.
[26] Loeppky, J. A.; Roach, R. C.; Maes, D.; Hinghofer-Szalkay, H.; Roessler, A.; Gates, L.; Fletcher,E. R.; Icenogle, M. V. Role of hypobaria in fluid balance response to hypoxia. High Alt Med Biol6:60-71;2005.
[27] Loeppky, J. A.; Icenogle, M.; Scotto, P.; Robergs, R.; Hinghofer-Szalkay, H.; Roach, R. C.Ventilation during simulated altitude, normobaric hypoxia and normoxic hypobaria. RespirPhysiol107:231-239;1997.
[28] Schoonman, G. G.; Sandor, P. S.; Nirkko, A. C.; Lange, T.; Jaermann, T.; Dydak, U.; Kremer, C.;Ferrari, M. D.; Boesiger, P.; Baumgartner, R. W. Hypoxia-induced acute mountain sickness isassociated with intracellular cerebral edema: a3T magnetic resonance imaging study. J CerebBlood Flow Metab28:198-206;2008.
[29] Goadsby, P. J. Pathophysiology of migraine. Neurol Clin27:335-360;2009.
[30] Chen, C. J.; Wang, W. Y.; Wang, X. L.; Dong, L. W.; Yue, Y. T.; Xin, H. L.; Ling, C. Q.; Li, M.Anti-hypoxic activity of the ethanol extract from Portulaca oleracea in mice. J Ethnopharmacol124:246-250;2009.
[31] Xie, Y.; Jiang, S.; Su, D.; Pi, N.; Ma, C.; Gao, P. Composition analysis and anti-hypoxia activityof polysaccharide from Brassica rapa L. Int J Biol Macromol47:528-533;2010.
[32] Shen, Z. B.; Yin, Y. Q.; Tang, C. P.; Yan, C. Y.; Chen, C.; Guo, L. B. Pharmacodynamicscreening and simulation study of anti-hypoxia active fraction of xiangdan injection. JEthnopharmacol127:103-107;2010.
[33] Cai, Y.; Lu, Y.; Chen, R.; Wei, Q.; Lu, X. Anti-hypoxia activity and related components ofRhodobryum giganteum par. Phytomedicine18:224-229;2011.
[34] Ma, H. P.; Fan, P. C.; Jing, L. L.; Yao, J.; He, X. R.; Yang, Y.; Chen, K. M.; Jia, Z. P.Anti-hypoxic activity at simulated high altitude was isolated in petroleum ether extract ofSaussurea involucrata. J Ethnopharmacol137:1510-1515;2011.
[35] Jordan, J.; de Groot, P. W.; Galindo, M. F. Mitochondria: the headquarters in ischemia-inducedneuronal death. Cent Nerv Syst Agents Med Chem11:98-106;2011.
[36] Finkel, T. Radical medicine: treating ageing to cure disease. Nat Rev Mol Cell Biol6:971-976;2005.
[37] Fantinelli, J. C.; Perez Nunez, I. A.; Gonzalez Arbelaez, L. F.; Schinella, G. R.; Mosca, S. M.Participation of mitochondrial permeability transition pore in the effects of ischemicpreconditioning in hypertrophied hearts: Role of NO and mitoK(ATP). Int J Cardiol;2011.
[38] Larsen, G. A.; Skjellegrind, H. K.; Berg-Johnsen, J.; Moe, M. C.; Vinje, M. L. Depolarization ofmitochondria in isolated CA1neurons during hypoxia, glucose deprivation and glutamateexcitotoxicity. Brain Res1077:153-160;2006.
[39] Lee, D. R.; Helps, S. C.; Macardle, P. J.; Nilsson, M.; Sims, N. R. Alterations in membranepotential in mitochondria isolated from brain subregions during focal cerebral ischemia and earlyreperfusion: evaluation using flow cytometry. Neurochem Res34:1857-1866;2009.
[40] Dave, K. R.; Bhattacharya, S. K.; Saul, I.; DeFazio, R. A.; Dezfulian, C.; Lin, H. W.; Raval, A. P.;Perez-Pinzon, M. A. Activation of protein kinase C delta following cerebral ischemia leads torelease of cytochrome C from the mitochondria via bad pathway. PLoS One6:e22057;2011.
[41] Moreira, P. I.; Zhu, X.; Wang, X.; Lee, H. G.; Nunomura, A.; Petersen, R. B.; Perry, G.; Smith, M.A. Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta1802:212-220;2010.
[42] Hota, S. K.; Hota, K. B.; Prasad, D.; Ilavazhagan, G.; Singh, S. B. Oxidative-stress-inducedalterations in Sp factors mediate transcriptional regulation of the NR1subunit in hippocampusduring hypoxia. Free Radic Biol Med49:178-191;2010.
[43] Zaobornyj, T.; Valdez, L. B.; Iglesias, D. E.; Gasco, M.; Gonzales, G. F.; Boveris, A.Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect ofsildenafil, L-NAME, and L-arginine treatments. Am J Physiol Heart Circ Physiol296:H1741-1747;2009.
[44] Chen, J.; Gao, Y.; Liao, W.; Huang, J.; Gao, W. Hypoxia affects mitochondrial protein expressionin rat skeletal muscle. OMICS16:98-104;2012.
[45] Kirpatovskii, V. I.; Kazachenko, A. V.; Plotnikov, E. Y.; Kon'kova, T. A.; Drozhzheva, V. V.;Zorov, D. B. Effects of ischemic and hypoxic preconditioning on the state of mitochondria andfunction of ischemic kidneys. Bull Exp Biol Med143:105-109;2007.
[46] Bailey, D. M.; Bartsch, P.; Knauth, M.; Baumgartner, R. W. Emerging concepts in acutemountain sickness and high-altitude cerebral edema: from the molecular to the morphological.Cell Mol Life Sci66:3583-3594;2009.
[47] Hildebrandt, W.; Alexander, S.; Bartsch, P.; Droge, W. Effect of N-acetyl-cysteine on the hypoxicventilatory response and erythropoietin production: linkage between plasma thiol redox state andO(2) chemosensitivity. Blood99:1552-1555;2002.
[48] Kallenberg, K.; Bailey, D. M.; Christ, S.; Mohr, A.; Roukens, R.; Menold, E.; Steiner, T.; Bartsch,P.; Knauth, M. Magnetic resonance imaging evidence of cytotoxic cerebral edema in acutemountain sickness. J Cereb Blood Flow Metab27:1064-1071;2007.
[49] Reinehr, R.; Gorg, B.; Becker, S.; Qvartskhava, N.; Bidmon, H. J.; Selbach, O.; Haas, H. L.;Schliess, F.; Haussinger, D. Hypoosmotic swelling and ammonia increase oxidative stress byNADPH oxidase in cultured astrocytes and vital brain slices. Glia55:758-771;2007.
[50] Master, S.; Gottstein, J.; Blei, A. T. Cerebral blood flow and the development ofammonia-induced brain edema in rats after portacaval anastomosis. Hepatology30:876-880;1999.
[51] Carlsten, C.; Swenson, E. R.; Ruoss, S. A dose-response study of acetazolamide for acutemountain sickness prophylaxis in vacationing tourists at12,000feet (3630m). High Alt MedBiol5:33-39;2004.
[52] Basnyat, B.; Gertsch, J. H.; Holck, P. S.; Johnson, E. W.; Luks, A. M.; Donham, B. P.;Fleischman, R. J.; Gowder, D. W.; Hawksworth, J. S.; Jensen, B. T.; Kleiman, R. J.; Loveridge,A. H.; Lundeen, E. B.; Newman, S. L.; Noboa, J. A.; Miegs, D. P.; O'Beirne, K. A.; Philpot, K.B.; Schultz, M. N.; Valente, M. C.; Wiebers, M. R.; Swenson, E. R. Acetazolamide125mg BD isnot significantly different from375mg BD in the prevention of acute mountain sickness: theprophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol7:17-27;2006.
[53] van Patot, M. C.; Leadbetter, G.,3rd; Keyes, L. E.; Maakestad, K. M.; Olson, S.; Hackett, P. H.Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountainsickness. High Alt Med Biol9:289-293;2008.
[54] Wright, A. D.; Bradwell, A. R.; Fletcher, R. F. Methazolamide and acetazolamide in acutemountain sickness. Aviat Space Environ Med54:619-621;1983.
[55] Johnson, T. S.; Rock, P. B.; Fulco, C. S.; Trad, L. A.; Spark, R. F.; Maher, J. T. Prevention ofacute mountain sickness by dexamethasone. N Engl J Med310:683-686;1984.
[56] Hackett, P. H.; Roach, R. C.; Wood, R. A.; Foutch, R. G.; Meehan, R. T.; Rennie, D.; Mills, W. J.,Jr. Dexamethasone for prevention and treatment of acute mountain sickness. Aviat Space EnvironMed59:950-954;1988.
[57] Wright, A. D.; Beazley, M. F.; Bradwell, A. R.; Chesner, I. M.; Clayton, R. N.; Forster, P. J.;Hillenbrand, P.; Imray, C. H. Medroxyprogesterone at high altitude. The effects on blood gases,cerebral regional oxygenation, and acute mountain sickness. Wilderness Environ Med15:25-31;2004.
[58] Fischer, R.; Lang, S. M.; Leitl, M.; Thiere, M.; Steiner, U.; Huber, R. M. Theophylline andacetazolamide reduce sleep-disordered breathing at high altitude. Eur Respir J23:47-52;2004.
[59] Kupper, T. E.; Strohl, K. P.; Hoefer, M.; Gieseler, U.; Netzer, C. M.; Netzer, N. C. Low-dosetheophylline reduces symptoms of acute mountain sickness. J Travel Med15:307-314;2008.
[60] Chow, T.; Browne, V.; Heileson, H. L.; Wallace, D.; Anholm, J.; Green, S. M. Ginkgo biloba andacetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial.Arch Intern Med165:296-301;2005.
[61] Esbaugh, A. J.; Tufts, B. L. The structure and function of carbonic anhydrase isozymes in therespiratory system of vertebrates. Respir Physiol Neurobiol154:185-198;2006.
[62] Maren, T. H.; Sanyal, G. The activity of sulfonamides and anions against the carbonic anhydrasesof animals, plants, and bacteria. Annu Rev Pharmacol Toxicol23:439-459;1983.
[63] Swenson, E. R. Carbonic anhydrase inhibitors and hypoxic pulmonary vasoconstriction. RespirPhysiol Neurobiol151:209-216;2006.
[64] Swenson, E. R.; Teppema, L. J. Prevention of acute mountain sickness by acetazolamide: as yetan unfinished story. J Appl Physiol102:1305-1307;2007.
[65] Hackett, P. H.; Roach, R. C. Medical therapy of altitude illness. Ann Emerg Med16:980-986;1987.
[66] Zell, S. C.; Goodman, P. H. Acetazolamide and dexamethasone in the prevention of acutemountain sickness. West J Med148:541-545;1988.
[67] Dumont, L.; Mardirosoff, C.; Tramer, M. R. Efficacy and harm of pharmacological prevention ofacute mountain sickness: quantitative systematic review. BMJ321:267-272;2000.
[68] Kayser, B.; Hulsebosch, R.; Bosch, F. Low-dose acetylsalicylic acid analog and acetazolamidefor prevention of acute mountain sickness. High Alt Med Biol9:15-23;2008.
[69] Hackett, P. H.; Schoene, R. B.; Winslow, R. M.; Peters, R. M., Jr.; West, J. B. Acetazolamide andexercise in sojourners to6,300meters--a preliminary study. Med Sci Sports Exerc17:593-597;1985.
[70] Garske, L. A.; Brown, M. G.; Morrison, S. C. Acetazolamide reduces exercise capacity andincreases leg fatigue under hypoxic conditions. J Appl Physiol94:991-996;2003.
[71] Fulco, C. S.; Muza, S. R.; Ditzler, D.; Lammi, E.; Lewis, S. F.; Cymerman, A. Effect ofacetazolamide on leg endurance exercise at sea level and simulated altitude. Clin Sci (Lond)110:683-692;2006.
[72] Jonk, A. M.; van den Berg, I. P.; Olfert, I. M.; Wray, D. W.; Arai, T.; Hopkins, S. R.; Wagner, P.D. Effect of acetazolamide on pulmonary and muscle gas exchange during normoxic andhypoxic exercise. J Physiol579:909-921;2007.
[73] Schoene, R. B.; Bates, P. W.; Larson, E. B.; Pierson, D. J. Effect of acetazolamide on normoxicand hypoxic exercise in humans at sea level. J Appl Physiol55:1772-1776;1983.
[74] Beck, K. C. Flat beer vs. physiological improvement: effect of acetazolamide during hypoxicexercise. J Physiol579:568-569;2007.
[75] Maren, T. H. Carbonic anhydrase: chemistry, physiology, and inhibition. Physiol Rev47:595-781;1967.
[76] Levine, B. D.; Yoshimura, K.; Kobayashi, T.; Fukushima, M.; Shibamoto, T.; Ueda, G.Dexamethasone in the treatment of acute mountain sickness. N Engl J Med321:1707-1713;1989.
[77] Rock, P. B.; Johnson, T. S.; Larsen, R. F.; Fulco, C. S.; Trad, L. A.; Cymerman, A.Dexamethasone as prophylaxis for acute mountain sickness. Effect of dose level. Chest95:568-573;1989.
[78] Basu, M.; Sawhney, R. C.; Kumar, S.; Pal, K.; Prasad, R.; Selvamurthy, W. Glucocorticoids asprophylaxis against acute mountain sickness. Clin Endocrinol (Oxf)57:761-767;2002.
[79] Bernhard, W. N.; Schalick, L. M.; Delaney, P. A.; Bernhard, T. M.; Barnas, G. M. Acetazolamideplus low-dose dexamethasone is better than acetazolamide alone to ameliorate symptoms ofacute mountain sickness. Aviat Space Environ Med69:883-886;1998.
[80] Chan, C. W.; Hoar, H.; Pattinson, K.; Bradwell, A. R.; Wright, A. D.; Imray, C. H. Effect ofsildenafil and acclimatization on cerebral oxygenation at altitude. Clin Sci (Lond)109:319-324;2005.
[81] Maggiorini, M.; Brunner-La Rocca, H. P.; Peth, S.; Fischler, M.; Bohm, T.; Bernheim, A.;Kiencke, S.; Bloch, K. E.; Dehnert, C.; Naeije, R.; Lehmann, T.; Bartsch, P.; Mairbaurl, H. Bothtadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: arandomized trial. Ann Intern Med145:497-506;2006.
[82] Fischer, R.; Lang, S. M.; Steiner, U.; Toepfer, M.; Hautmann, H.; Pongratz, H.; Huber, R. M.Theophylline improves acute mountain sickness. Eur Respir J15:123-127;2000.
[83] Chen, C. H.; Chen, A. C.; Liu, H. J. Involvement of nitric oxide and N-methyl-D-aspartate inacute hypoxic altitude convulsion in mice. Aviat Space Environ Med68:296-299;1997.
[84] Xie, J.; Lu, G.; Hou, Y. Role of excitatory amino acids in hypoxic preconditioning. Biol SignalsRecept8:267-274;1999.
[85] Lysakowski, C.; Von Elm, E.; Dumont, L.; Junod, J. D.; Tassonyi, E.; Kayser, B.; Tramer, M. R.Effect of magnesium, high altitude and acute mountain sickness on blood flow velocity in themiddle cerebral artery. Clin Sci (Lond)106:279-285;2004.
[86] Dumont, L.; Lysakowski, C.; Tramer, M. R.; Junod, J. D.; Mardirosoff, C.; Tassonyi, E.; Kayser,B. Magnesium for the prevention and treatment of acute mountain sickness. Clin Sci (Lond)106:269-277;2004.
[87] Aoki, V. S.; Robinson, S. M. Body hydration and the incidence and severity of acute mountainsickness. J Appl Physiol31:363-367;1971.
[88] Gray, G. W.; Bryan, A. C.; Frayser, R.; Houston, C. S.; Rennie, I. D. Control of acute mountainsickness. Aerosp Med42:81-84;1971.
[89] Jain, S. C.; Singh, M. V.; Sharma, V. M.; Rawal, S. B.; Tyagi, A. K. Amelioration of acutemountain sickness: comparative study of acetazolamide and spironolactone. Int J Biometeorol30:293-300;1986.
[90] Larsen, R. F.; Rock, P. B.; Fulco, C. S.; Edelman, B.; Young, A. J.; Cymerman, A. Effect ofspironolactone on acute mountain sickness. Aviat Space Environ Med57:543-547;1986.
[91] Dubowitz, G. Effect of temazepam on oxygen saturation and sleep quality at high altitude:randomised placebo controlled crossover trial. BMJ316:587-589;1998.
[92] Nickol, A. H.; Leverment, J.; Richards, P.; Seal, P.; Harris, G. A.; Cleland, J.; Dubowitz, G.;Collier, D. J.; Milledge, J.; Stradling, J. R.; Morrell, M. J. Temazepam at high altitude reducesperiodic breathing without impairing next-day performance: a randomized cross-overdouble-blind study. J Sleep Res15:445-454;2006.
[93] Jafarian, S.; Gorouhi, F.; Salimi, S.; Lotfi, J. Low-dose gabapentin in treatment of high-altitudeheadache. Cephalalgia27:1274-1277;2007.
[94] Jafarian, S.; Gorouhi, F.; Salimi, S.; Lotfi, J. Sumatriptan for prevention of acute mountainsickness: randomized clinical trial. Ann Neurol62:273-277;2007.
[95] Basnyat, B. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med347:1282-1285; author reply1282-1285;2002.
[96] Kumar, D.; Bansal, A.; Thomas, P.; Mongia, S. S.; Sharma, S. K.; Sairam, M.; Grover, S. K.;Singh, M. V.; Prasad, D.; Ilavazhagan, G.; Selvamurthy, W. Improved high altitude hypoxictolerance and amelioration of anorexia and hypophagia in rats on oral glutamate supplementation.Aviat Space Environ Med70:475-479;1999.
[97] Oelz, O.; Maggiorini, M.; Ritter, M.; Waber, U.; Jenni, R.; Vock, P.; Bartsch, P. Nifedipine forhigh altitude pulmonary oedema. Lancet2:1241-1244;1989.
[98]惠锦，刘福玉，高文祥，高钰琪，陈莉.二十八烷醇对小鼠耐缺氧作用的实验研究.西南国防医药17:143-145;2007.
[99]于长青，张国海.二十八烷醇抗大鼠心肌线粒体损伤的研究.中国食品添加剂2:35-37;2003.
[100] Zhang, J.; Liu, A.; Hou, R.; Jia, X.; Jiang, W.; Chen, J. Salidroside protects cardiomyocyteagainst hypoxia-induced death: a HIF-1alpha-activated and VEGF-mediated pathway. Eur JPharmacol607:6-14;2009.
[101] Schriner, S. E.; Avanesian, A.; Liu, Y.; Luesch, H.; Jafari, M. Protection of human cultured cellsagainst oxidative stress by Rhodiola rosea without activation of antioxidant defenses. Free RadicBiol Med47:577-584;2009.
[102] Kong, H. L.; Wang, J. P.; Li, Z. Q.; Zhao, S. M.; Dong, J.; Zhang, W. W. Anti-hypoxic effect ofginsenoside Rbl on neonatal rat cardiomyocytes is mediated through the specific activation ofglucose transporter-4ex vivo. Acta Pharmacol Sin30:396-403;2009.
[103] Patir, H.; Sarada, S. K.; Singh, S.; Mathew, T.; Singh, B.; Bansal, A. Quercetin as a prophylacticmeasure against high altitude cerebral edema. Free Radic Biol Med53:659-668;2012.
[104] Subudhi, A. W.; Jacobs, K. A.; Hagobian, T. A.; Fattor, J. A.; Muza, S. R.; Fulco, C. S.;Cymerman, A.; Friedlander, A. L. Changes in ventilatory threshold at high altitude: effect ofantioxidants. Med Sci Sports Exerc38:1425-1431;2006.
[105] Hagobian, T. A.; Jacobs, K. A.; Subudhi, A. W.; Fattor, J. A.; Rock, P. B.; Muza, S. R.; Fulco, C.S.; Braun, B.; Grediagin, A.; Mazzeo, R. S.; Cymerman, A.; Friedlander, A. L. Cytokineresponses at high altitude: effects of exercise and antioxidants at4300m. Med Sci Sports Exerc38:276-285;2006.
[106] Dubey, A. K.; Shankar, P. R.; Upadhyaya, D.; Deshpande, V. Y. Ginkgo biloba--an appraisal.Kathmandu Univ Med J (KUMJ)2:225-229;2004.
[107] Moraga, F. A.; Flores, A.; Serra, J.; Esnaola, C.; Barriento, C. Ginkgo biloba decreases acutemountain sickness in people ascending to high altitude at Ollague (3696m) in northern Chile.Wilderness Environ Med18:251-257;2007.
[108] van Patot, M. C.; Keyes, L. E.; Leadbetter, G.,3rd; Hackett, P. H. Ginkgo biloba for preventionof acute mountain sickness: does it work? High Alt Med Biol10:33-43;2009.
[109] Leadbetter, G.; Keyes, L. E.; Maakestad, K. M.; Olson, S.; Tissot van Patot, M. C.; Hackett, P. H.Ginkgo biloba does--and does not--prevent acute mountain sickness. Wilderness Environ Med20:66-71;2009.
[110] Schreiber, M.; Trojan, S. Protective effect of flavonoids and tocopherol in high altitude hypoxiain the rat: comparison with ascorbic acid. Cesk Fysiol47:51-52;1998.
[111] Bailey, D. M.; Dehnert, C.; Luks, A. M.; Menold, E.; Castell, C.; Schendler, G.; Faoro, V.;Gutowski, M.; Evans, K. A.; Taudorf, S.; James, P. E.; McEneny, J.; Young, I. S.; Swenson, E. R.;Mairbaurl, H.; Bartsch, P.; Berger, M. M. High-altitude pulmonary hypertension is associatedwith a free radical-mediated reduction in pulmonary nitric oxide bioavailability. J Physiol588:4837-4847;2010.
[112] Vats, P.; Singh, V. K.; Singh, S. N.; Singh, S. B. Glutathione metabolism under high-altitudestress and effect of antioxidant supplementation. Aviat Space Environ Med79:1106-1111;2008.
[113] Al-Hashem, F. H. Potential roles for vitamins E and C in combination in modulating exhaustiveswimming and high altitude-associated lung injury in rats. Saudi Med J33:367-374;2012.
[114] Telford, J. E.; Kilbride, S. M.; Davey, G. P. Decylubiquinone increases mitochondrial function insynaptosomes. J Biol Chem285:8639-8645;2010.
[115] Zhao, K.; Zhao, G. M.; Wu, D.; Soong, Y.; Birk, A. V.; Schiller, P. W.; Szeto, H. H.Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibitmitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem279:34682-34690;2004.
[116] Wright, J. S.; Carpenter, D. J.; McKay, D. J.; Ingold, K. U. Theoretical calculation of substituenteffects on the O-H bond strength of phenolic antioxidants related to vitamin E. J Am Chem Soc119:4245-4252;1997.
[117] Liu, L. M.; Hu, D. Y.; Zhou, X. W.; Liu, J. C.; Li, P. HSD is a better resuscitation fluid forhemorrhagic shock with pulmonary edema at high altitude. Shock30:714-720;2008.
[118] Vats, P.; Singh, V. K.; Singh, S. N.; Singh, S. B. High altitude induced anorexia: effect ofchanges in leptin and oxidative stress levels. Nutr Neurosci10:243-249;2007.
[119] Dosek, A.; Ohno, H.; Acs, Z.; Taylor, A. W.; Radak, Z. High altitude and oxidative stress. RespirPhysiol Neurobiol158:128-131;2007.
[120] Sinha, S.; Singh, S. N.; Saha, M.; Kain, T. C.; Tyagi, A. K. Antioxidant and oxidative stressresponses of sojourners at high altitude in different climatic temperatures. Int J Biometeorol54:85-92;2010.
[121] Parraguez, V. H.; Urquieta, B.; Perez, L.; Castellaro, G.; De Los Reyes, M.; Torres-Rovira, L.;Aguado-Martinez, A.; Astiz, S.; Gonzalez-Bulnes, A. Fertility in a high-altitude environment iscompromised by luteal dysfunction: the relative roles of hypoxia and oxidative stress. ReprodBiol Endocrinol11:24;2013.
[1] Low, E. V.; Avery, A. J.; Gupta, V.; Schedlbauer, A.; Grocott, M. P. Identifying the lowesteffective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic reviewand meta-analysis. BMJ345:e6779;2012.
[2] Ritchie, N. D.; Baggott, A. V.; Andrew Todd, W. T. Acetazolamide for the prevention of acutemountain sickness--a systematic review and meta-analysis. J Travel Med19:298-307;2012.
[3] Kayser, B.; Dumont, L.; Lysakowski, C.; Combescure, C.; Haller, G.; Tramer, M. R. Reappraisalof acetazolamide for the prevention of acute mountain sickness: a systematic review andmeta-analysis. High Alt Med Biol13:82-92;2012.
[4] Inatani, M.; Yano, I.; Tanihara, H.; Ogura, Y.; Honda, Y.; Inui, K. I. Relationship betweenacetazolamide blood concentration and its side effects in glaucomatous patients. J OculPharmacol Ther15:97-105;1999.
[5] Pun, M. Side-effect of acetazolamide in prevention of acute mountain sickness. S Afr Med J102:114; author reply114;2012.
[6] Vahedi, K.; Taupin, P.; Djomby, R.; El-Amrani, M.; Lutz, G.; Filipetti, V.; Landais, P.; Massiou, H.;Bousser, M. G. Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomisedplacebo-controlled trial. J Neurol249:206-211;2002.
[7] Lastnick, G. Metabolic acidosis secondary to acetazolamide therapy a possible hazardous sideeffect after prolonged use of acetazolamide in geriatric patients. A case report. Ariz Med32:19-21;1975.
[8] Dahl, H.; Norskov, K.; Peitersen, E.; Hilden, J. Zinc therapy of acetazolamide-inducedside-effects. Acta Ophthalmol (Copenh)62:739-745;1984.
[9] Theeuwes, F.; Bayne, W.; McGuire, J. Gastrointestinal therapeutic system for acetazolamide.Efficacy and side effects. Arch Ophthalmol96:2219-2221;1978.
[10] Borhani, H.; Rahimy, M. H.; Peyman, G. A. Vitreoretinal toxicity of acetazolamide followingintravitreal administration in the rabbit eye. Ophthalmic Surg25:166-169;1994.
[11] Yang, M. T.; Chien, W. L.; Lu, D. H.; Liou, H. C.; Fu, W. M. Acetazolamide impairs fear memoryconsolidation in rodents. Neuropharmacology67:412-418;2013.
[12] Ellsworth, A. J.; Larson, E. B.; Strickland, D. A randomized trial of dexamethasone andacetazolamide for acute mountain sickness prophylaxis. Am J Med83:1024-1030;1987.
[13] Zhang, J.; Liu, A.; Hou, R.; Jia, X.; Jiang, W.; Chen, J. Salidroside protects cardiomyocyte againsthypoxia-induced death: a HIF-1alpha-activated and VEGF-mediated pathway. Eur J Pharmacol607:6-14;2009.
[14] Schriner, S. E.; Avanesian, A.; Liu, Y.; Luesch, H.; Jafari, M. Protection of human cultured cellsagainst oxidative stress by Rhodiola rosea without activation of antioxidant defenses. Free RadicBiol Med47:577-584;2009.
[15] Patir, H.; Sarada, S. K.; Singh, S.; Mathew, T.; Singh, B.; Bansal, A. Quercetin as a prophylacticmeasure against high altitude cerebral edema. Free Radic Biol Med53:659-668;2012.
[16] Schreiber, M.; Trojan, S. Protective effect of flavonoids and tocopherol in high altitude hypoxia inthe rat: comparison with ascorbic acid. Cesk Fysiol47:51-52;1998.
[17] Kong, H. L.; Wang, J. P.; Li, Z. Q.; Zhao, S. M.; Dong, J.; Zhang, W. W. Anti-hypoxic effect ofginsenoside Rbl on neonatal rat cardiomyocytes is mediated through the specific activation ofglucose transporter-4ex vivo. Acta Pharmacol Sin30:396-403;2009.
[18] Ma, H. P.; Fan, P. C.; Jing, L. L.; Yao, J.; He, X. R.; Yang, Y.; Chen, K. M.; Jia, Z. P. Anti-hypoxicactivity at simulated high altitude was isolated in petroleum ether extract of Saussurea involucrata.J Ethnopharmacol137:1510-1515;2011.
[19] Gupta, V.; Lahiri, S. S.; Sultana, S.; Tulsawani, R. K.; Kumar, R. Anti-oxidative effect ofRhodiola imbricata root extract in rats during cold, hypoxia and restraint (C-H-R) exposure andpost-stress recovery. Food Chem Toxicol48:1019-1025;2010.
[20]景临林.新型氮氧自由基的设计合成及其性能研究.第四军医大学博士论文;2010.
[21]向卓.新型抗心肌缺血/再灌注损伤药物的研究.第四军医大学博士论文;2011.
[22] Wu, Y.; Bi, L.; Bi, W.; Li, Z.; Zhao, M.; Wang, C.; Ju, J.; Peng, S. Novel2-substituted nitronylnitroxides as free radical scavengers: synthesis, biological evaluation and structure-activityrelationship. Bioorg Med Chem14:5711-5720;2006.
[23] Zhao, M.; Li, Z.; Wu, Y.; Tang, Y. R.; Wang, C.; Zhang, Z.; Peng, S. Studies on logP, retentiontime and QSAR of2-substituted phenylnitronyl nitroxides as free radical scavengers. Eur J MedChem42:955-965;2007.
[24] Qian, J.; Jiang, F.; Wang, B.; Yu, Y.; Zhang, X.; Yin, Z.; Liu, C. Ophiopogonin D preventsH2O2-induced injury in primary human umbilical vein endothelial cells. J Ethnopharmacol128:438-445;2010.
[25] Sheng, R.; Gu, Z. L.; Xie, M. L.; Zhou, W. X.; Guo, C. Y. Epigallocatechin gallate protects H9c2cardiomyoblasts against hydrogen dioxides-induced apoptosis and telomere attrition. Eur JPharmacol641:199-206;2010.
[26] Zhao, L.; Shi, L. Metabolism of hydrogen peroxide in univoltine and polyvoltine strains ofsilkworm (Bombyx mori). Comp Biochem Physiol B Biochem Mol Biol152:339-345;2009.
[27] Wang, X. Z.; Liu, S. S.; Sun, Y.; Wu, J. Y.; Zhou, Y. L.; Zhang, J. H. Beta-cypermethrin impairsreproductive function in male mice by inducing oxidative stress. Theriogenology72:599-611;2009.
[28] Huang, X.; Zhuang, J.; Teng, X.; Li, L.; Chen, D.; Yan, X.; Tang, F. The promotion of humanmalignant melanoma growth by mesoporous silica nanoparticles through decreased reactiveoxygen species. Biomaterials31:6142-6153;2010.
[29] Qiao, T.; Liu, C.; Ran, F. The impact of gastrocnemius muscle cell changes in chronic venousinsufficiency. Eur J Vasc Endovasc Surg30:430-436;2005.
[30] Moreira, P. I.; Zhu, X.; Wang, X.; Lee, H. G.; Nunomura, A.; Petersen, R. B.; Perry, G.; Smith, M.A. Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta1802:212-220;2010.
[31] Gruber, J.; Fong, S.; Chen, C. B.; Yoong, S.; Pastorin, G.; Schaffer, S.; Cheah, I.; Halliwell, B.Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions toslow ageing. Biotechnol Adv;2012.
[32] Mukhopadhyay, P.; Horvath, B.; Zsengeller, Z.; Zielonka, J.; Tanchian, G.; Holovac, E.; Kechrid,M.; Patel, V.; Stillman, I. E.; Parikh, S. M.; Joseph, J.; Kalyanaraman, B.; Pacher, P.Mitochondrial-targeted antioxidants represent a promising approach for prevention ofcisplatin-induced nephropathy. Free Radic Biol Med52:497-506;2012.
[33] Zhu, X. J.; Shi, Y.; Peng, J.; Guo, C. S.; Shan, N. N.; Qin, P.; Ji, X. B.; Hou, M. The effects ofBAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia. Blood114:5362-5367;2009.
[34] Keeney, P. M.; Xie, J.; Capaldi, R. A.; Bennett, J. P., Jr. Parkinson's disease brain mitochondrialcomplex I has oxidatively damaged subunits and is functionally impaired and misassembled. JNeurosci26:5256-5264;2006.
[35] Feng, Z.; Zou, X.; Jia, H.; Li, X.; Zhu, Z.; Liu, X.; Bucheli, P.; Ballevre, O.; Hou, Y.; Zhang, W.;Wang, J.; Chen, Y.; Liu, J. Maternal docosahexaenoic acid feeding protects against impairment oflearning and memory and oxidative stress in prenatally stressed rats: possible role of neuronalmitochondria metabolism. Antioxid Redox Signal16:275-289;2012.
[36] Long, J.; Gao, F.; Tong, L.; Cotman, C. W.; Ames, B. N.; Liu, J. Mitochondrial decay in the brainsof old rats: ameliorating effect of alpha-lipoic acid and acetyl-L-carnitine. Neurochem Res34:755-763;2009.
[1] Barriga, S.2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO). Synlett.4:563.;2001.
[2] Bernstein, E. F.; Kong, S. K.; Brown, D. B.; Kwak, B. C.; Takeuchi, T.; Gasparro, F. P.; Uitto, J.The nitroxide Tempol affords protection against ultraviolet radiation in a transgenic murinefibroblast culture model of cutaneous photoaging. Exp Dermatol10:55-61;2001.
[3]严淑贤;胡跃;邓辉;洪新宇;徐昱;廖康煌.紫外线A1对真皮成纤维细胞的损伤及Tempol保护作用的研究.中华皮肤科杂志38:413-415;2005.
[4] Qian, J.; Jiang, F.; Wang, B.; Yu, Y.; Zhang, X.; Yin, Z.; Liu, C. Ophiopogonin D preventsH2O2-induced injury in primary human umbilical vein endothelial cells. J Ethnopharmacol128:438-445;2010.
[5] Sheng, R.; Gu, Z. L.; Xie, M. L.; Zhou, W. X.; Guo, C. Y. Epigallocatechin gallate protects H9c2cardiomyoblasts against hydrogen dioxides-induced apoptosis and telomere attrition. Eur JPharmacol641:199-206;2010.
[6] Zhao, L.; Shi, L. Metabolism of hydrogen peroxide in univoltine and polyvoltine strains ofsilkworm (Bombyx mori). Comp Biochem Physiol B Biochem Mol Biol152:339-345;2009.
[7] Wang, X. Z.; Liu, S. S.; Sun, Y.; Wu, J. Y.; Zhou, Y. L.; Zhang, J. H. Beta-cypermethrin impairsreproductive function in male mice by inducing oxidative stress. Theriogenology72:599-611;2009.
[8] Huang, X.; Zhuang, J.; Teng, X.; Li, L.; Chen, D.; Yan, X.; Tang, F. The promotion of humanmalignant melanoma growth by mesoporous silica nanoparticles through decreased reactiveoxygen species. Biomaterials31:6142-6153;2010.
[9] Qiao, T.; Liu, C.; Ran, F. The impact of gastrocnemius muscle cell changes in chronic venousinsufficiency. Eur J Vasc Endovasc Surg30:430-436;2005.
[1] Ma, X. L.; Gao, F.; Nelson, A. H.; Lopez, B. L.; Christopher, T. A.; Yue, T. L.; Barone, F. C.Oxidative inactivation of nitric oxide and endothelial dysfunction in stroke-prone spontaneoushypertensive rats. J Pharmacol Exp Ther298:879-885;2001.
[2] Munzel, T.; Wenzel, P.; Daiber, A. Do we still need organic nitrates? J Am Coll Cardiol49:1296-1298;2007.
[3] Gao, F.; Yao, C. L.; Gao, E.; Mo, Q. Z.; Yan, W. L.; McLaughlin, R.; Lopez, B. L.; Christopher, T.A.; Ma, X. L. Enhancement of glutathione cardioprotection by ascorbic acid in myocardialreperfusion injury. J Pharmacol Exp Ther301:543-550;2002.
[4] Yan, J.; Feng, Z.; Liu, J.; Shen, W.; Wang, Y.; Wertz, K.; Weber, P.; Long, J. Enhanced autophagyplays a cardinal role in mitochondrial dysfunction in type2diabetic Goto-Kakizaki (GK) rats:ameliorating effects of (-)-epigallocatechin-3-gallate. J Nutr Biochem23:716-724;2012.
[5]向卓.新型抗心肌缺血/再灌注损伤药物的研究.第四军医大学博士论文;2011.
[6] Qian, J.; Jiang, F.; Wang, B.; Yu, Y.; Zhang, X.; Yin, Z.; Liu, C. Ophiopogonin D preventsH2O2-induced injury in primary human umbilical vein endothelial cells. J Ethnopharmacol128:438-445;2010.
[7] Sheng, R.; Gu, Z. L.; Xie, M. L.; Zhou, W. X.; Guo, C. Y. Epigallocatechin gallate protects H9c2cardiomyoblasts against hydrogen dioxides-induced apoptosis and telomere attrition. Eur JPharmacol641:199-206;2010.
[8] Zhao, L.; Shi, L. Metabolism of hydrogen peroxide in univoltine and polyvoltine strains ofsilkworm (Bombyx mori). Comp Biochem Physiol B Biochem Mol Biol152:339-345;2009.
[9] Wang, X. Z.; Liu, S. S.; Sun, Y.; Wu, J. Y.; Zhou, Y. L.; Zhang, J. H. Beta-cypermethrin impairsreproductive function in male mice by inducing oxidative stress. Theriogenology72:599-611;2009.
[10] Huang, X.; Zhuang, J.; Teng, X.; Li, L.; Chen, D.; Yan, X.; Tang, F. The promotion of humanmalignant melanoma growth by mesoporous silica nanoparticles through decreased reactiveoxygen species. Biomaterials31:6142-6153;2010.
[11] Qiao, T.; Liu, C.; Ran, F. The impact of gastrocnemius muscle cell changes in chronic venousinsufficiency. Eur J Vasc Endovasc Surg30:430-436;2005.