糖尿病对缺血后适应脑保护作用的影响及机制研究
|
摘要
背景：中风是由于脑血流中断导致的以急性神经功能受损为特征的一组综合征，具有发病率高，致残率高及死亡率高的特点。治疗中风最有效的方法是血管再通，通过溶栓及介入治疗实现早期再灌注，尽早实现缺血组织的血液供应。但是，再灌注本身产生大量的活性氧簇或自由基，导致发生再灌注损伤。脑缺血后适应是指脑组织缺血一段时间后，在进行再灌注时实施几次短暂的、重复的缺血与再灌注，能够对缺血的脑组织提供保护作用，减轻脑缺血再灌注损伤。Zhao等研究证实：在大鼠永久性大脑中动脉阻塞联合15min、30min及60min颈总动脉阻塞的局灶性脑缺血模型，缺血后适应能够减少脑梗死面积分别达80%、51%及17%；Pignataro等采用大脑中动脉梗塞100min的脑缺血模型大鼠，同样证实缺血后适应能够减少脑梗死体积最高达70%。上述缺血后适应的保护作用均是在血糖正常的动物模型上获得的。但是在临床上，缺血性脑卒中合并糖尿病的患者非常多见。糖尿病是目前公认的脑卒中的重要危险因素之一。探讨糖尿病状态下，缺血后适应是否仍具有抑制缺血再灌注损伤的作用，对于缺血后适应的临床应用具有重要意义。
目的：探讨缺血后适应在糖尿病状态下是否仍然具有脑保护作用，并进一步探讨高血糖对缺血后适应作用机制的影响。
方法：本研究采用高脂喂养4周加链脲佐菌素注射的方法制备糖尿病大鼠，采用线栓法制备大脑中动脉梗死模型。缺血再灌注组：缺血时间为1h，然后进行再灌注；后适应组为再灌注开始时立即进行再灌注10s/缺血10s，共5次循环，在缺血/再灌注24h留取标本。我们比较了缺血后适应对血糖正常大鼠和糖尿病大鼠局灶性脑缺血再灌注损伤是否都有保护作用。我们通过TTC染色法测定脑梗死体积，大鼠的神经功能评分及光镜下观察脑组织病理改变，判断缺血后适应对脑缺血的保护作用，并进一步探讨了缺血后适应对血糖正常大鼠及糖尿病大鼠的脑组织氧化应激反应及细胞凋亡、凋亡相关蛋白Bcl-2、Bax及凋亡执行蛋白caspase-3表达的影响，同时我们还探讨了缺血后适应对PI3K-Akt通路中的关键蛋白Akt、p-Akt表达的影响。
结果：对于血糖正常的大鼠，缺血后适应能够明显降低局灶性脑缺血再灌注24h的脑梗死体积百分比，明显改善大鼠的神经功能评分，减少脑缺血周围区域的细胞凋亡数量。而对于糖尿病大鼠，缺血后适应的上述脑保护作用不明显。对于血糖正常的大鼠，缺血后适应能够明显降低脑组织脂质过氧化产物丙二醛（MDA）的水平，升高脑组织超氧化物歧化酶（SOD）和谷胱甘肽还原酶（GSH-pX）的活性，提高抗凋亡蛋白Bcl-2的表达，降低促凋亡蛋白Bax及凋亡执行蛋白caspase-3的表达，同时能够使再灌注损伤抢救激酶途径中的p-Akt蛋白表达明显增加；而对于糖尿病大鼠，缺血后适应对脑组织MDA水平及SOD、GSH-pX活性及上述凋亡相关蛋白及p-Akt的蛋白表达无明显的改变。
结论：缺血后适应对血糖正常的大鼠局灶性脑缺血再灌注损伤有明显的保护作用，其主要机制为抑制氧化应激及细胞凋亡；而慢性高血糖抵消了缺血后适应的这种保护作用，其机制可能与高血糖诱发氧化应激、细胞凋亡及Akt的磷酸化障碍有关。
Backgrounds：Stroke is a group of syndromes due to the interruption ofcerebral blood flow. It is characterized by a high incidence and high morbidityand high mortality. Advances in intravascular techniques and thrombolyticagents have reduced functional deficits within an optimal time window instroke patients. However, reperfusion itself generates an overproduction ofreactive oxygen species (ROS) or free radicals, leading to reperfusion injury.Ischemic postconditioning is defined in the field of cerebral ischemia researchas a series of brief occlusions and reperfusions applied at the onset ofestablishing reflow, which has proved to be effective against cerebral ischemia.Zhao et al found that postconditioning reduced the infarct size by80%,51%,and17%, respectively, in15,30, or60-min common carotid artery occlusioncombined with permanent distal middle cerebral artery occlusion. Pignataro etal had also shown a very strong protection with postconditioning in anotherfocal ischemic model, in which the middle cerebral artery was occluded for100min. Clinical ischemic stroke in diabetic patients is very common. Diabetesmellitus (DM) is widely recognized as important risk factor for stroke. It is ofgreat significance for ischemic postconditioning in the clinical application toinvestigate whether ischemic postconditioning still has the role of inhibition ofischemia-reperfusion injury in diabetic state.
Objective: To investigate whether ischemic postconditioning in thediabetic state still has a protective effect on focal cerebral ischemia and discussthe probable mechanism of ischemic postconditioning in normal blood glucosestate and diabetic state.
Methods: We fed the male Sprague-Dawley rats with high fat diet for4 weeks and then injected streptozotocin (STZ) in order to establish diabetic ratmodels. Normal SD rats and diabetic SD rats were treated with ischemicpostconditioning after60minutes of middle cerebral artery occlusion at theonset of reperfusion. Neurologic scores, infarct volumes with TTC staining andhistopathology of cerebral ischemia were assessed at24hours. Oxidative stresswas evaluated by detecting the activity of superoxidase dismutase (SOD),glutathione peroxidase (GSH-pX) and malondialdehyde (MDA) assay.Apoptosis-related molecules such as Bcl-2, Bax and caspase-3were studied byimmunohistochemical staining. Protein kinase B (PKB/Akt) was also tested byWestern blotting and immunohistochemical staining. We compared the effect ofischemic postconditioning in normal rats and diabetic rats.
Results: Our results showed that compared with ischemia/reperfusiongroup, ischemic postconditioning significantly reduced the size of ischemicinfarction and improved the neurologic scores at24hours of ischemic/reperfusion injury in normal blood glucose state. Ischemic postconditioningcould also reduce the number of TUNEL positive cells in the ischemicpenumbra in normal rats. But the protective effect of ischemic postconditioningwas not seen in the diabetic state. Postconditioning failed to decrease infarctvolume or improve the neurologic scores in diabetic rats. Postconditioningincreased the activity of SOD and GSH-pX in the brain tissue in the normalstate but not in the diabetic rats when measured at ischemia-reperfusion24hours; Postconditioning decreased the level of MDA in the brain tissue innormal rats but not in the diabetic rats; Postconditioning treatment upregulatedBcl-2and p-Akt protein expression and downregulated Bax and caspase-3activity in normal rats but not in the diabetic rats.
Conclusions: Ischemic postconditioning has protective effect for focalischemia-reperfusion injury in normal rats. Chronic hyperglycemia canabrogate the protection of postconditioning at least in part via oxidative stress, cell apoptosis and Akt phosphorylation dysfunction.
目的：探讨缺血后适应在糖尿病状态下是否仍然具有脑保护作用，并进一步探讨高血糖对缺血后适应作用机制的影响。
方法：本研究采用高脂喂养4周加链脲佐菌素注射的方法制备糖尿病大鼠，采用线栓法制备大脑中动脉梗死模型。缺血再灌注组：缺血时间为1h，然后进行再灌注；后适应组为再灌注开始时立即进行再灌注10s/缺血10s，共5次循环，在缺血/再灌注24h留取标本。我们比较了缺血后适应对血糖正常大鼠和糖尿病大鼠局灶性脑缺血再灌注损伤是否都有保护作用。我们通过TTC染色法测定脑梗死体积，大鼠的神经功能评分及光镜下观察脑组织病理改变，判断缺血后适应对脑缺血的保护作用，并进一步探讨了缺血后适应对血糖正常大鼠及糖尿病大鼠的脑组织氧化应激反应及细胞凋亡、凋亡相关蛋白Bcl-2、Bax及凋亡执行蛋白caspase-3表达的影响，同时我们还探讨了缺血后适应对PI3K-Akt通路中的关键蛋白Akt、p-Akt表达的影响。
结果：对于血糖正常的大鼠，缺血后适应能够明显降低局灶性脑缺血再灌注24h的脑梗死体积百分比，明显改善大鼠的神经功能评分，减少脑缺血周围区域的细胞凋亡数量。而对于糖尿病大鼠，缺血后适应的上述脑保护作用不明显。对于血糖正常的大鼠，缺血后适应能够明显降低脑组织脂质过氧化产物丙二醛（MDA）的水平，升高脑组织超氧化物歧化酶（SOD）和谷胱甘肽还原酶（GSH-pX）的活性，提高抗凋亡蛋白Bcl-2的表达，降低促凋亡蛋白Bax及凋亡执行蛋白caspase-3的表达，同时能够使再灌注损伤抢救激酶途径中的p-Akt蛋白表达明显增加；而对于糖尿病大鼠，缺血后适应对脑组织MDA水平及SOD、GSH-pX活性及上述凋亡相关蛋白及p-Akt的蛋白表达无明显的改变。
结论：缺血后适应对血糖正常的大鼠局灶性脑缺血再灌注损伤有明显的保护作用，其主要机制为抑制氧化应激及细胞凋亡；而慢性高血糖抵消了缺血后适应的这种保护作用，其机制可能与高血糖诱发氧化应激、细胞凋亡及Akt的磷酸化障碍有关。
Backgrounds：Stroke is a group of syndromes due to the interruption ofcerebral blood flow. It is characterized by a high incidence and high morbidityand high mortality. Advances in intravascular techniques and thrombolyticagents have reduced functional deficits within an optimal time window instroke patients. However, reperfusion itself generates an overproduction ofreactive oxygen species (ROS) or free radicals, leading to reperfusion injury.Ischemic postconditioning is defined in the field of cerebral ischemia researchas a series of brief occlusions and reperfusions applied at the onset ofestablishing reflow, which has proved to be effective against cerebral ischemia.Zhao et al found that postconditioning reduced the infarct size by80%,51%,and17%, respectively, in15,30, or60-min common carotid artery occlusioncombined with permanent distal middle cerebral artery occlusion. Pignataro etal had also shown a very strong protection with postconditioning in anotherfocal ischemic model, in which the middle cerebral artery was occluded for100min. Clinical ischemic stroke in diabetic patients is very common. Diabetesmellitus (DM) is widely recognized as important risk factor for stroke. It is ofgreat significance for ischemic postconditioning in the clinical application toinvestigate whether ischemic postconditioning still has the role of inhibition ofischemia-reperfusion injury in diabetic state.
Objective: To investigate whether ischemic postconditioning in thediabetic state still has a protective effect on focal cerebral ischemia and discussthe probable mechanism of ischemic postconditioning in normal blood glucosestate and diabetic state.
Methods: We fed the male Sprague-Dawley rats with high fat diet for4 weeks and then injected streptozotocin (STZ) in order to establish diabetic ratmodels. Normal SD rats and diabetic SD rats were treated with ischemicpostconditioning after60minutes of middle cerebral artery occlusion at theonset of reperfusion. Neurologic scores, infarct volumes with TTC staining andhistopathology of cerebral ischemia were assessed at24hours. Oxidative stresswas evaluated by detecting the activity of superoxidase dismutase (SOD),glutathione peroxidase (GSH-pX) and malondialdehyde (MDA) assay.Apoptosis-related molecules such as Bcl-2, Bax and caspase-3were studied byimmunohistochemical staining. Protein kinase B (PKB/Akt) was also tested byWestern blotting and immunohistochemical staining. We compared the effect ofischemic postconditioning in normal rats and diabetic rats.
Results: Our results showed that compared with ischemia/reperfusiongroup, ischemic postconditioning significantly reduced the size of ischemicinfarction and improved the neurologic scores at24hours of ischemic/reperfusion injury in normal blood glucose state. Ischemic postconditioningcould also reduce the number of TUNEL positive cells in the ischemicpenumbra in normal rats. But the protective effect of ischemic postconditioningwas not seen in the diabetic state. Postconditioning failed to decrease infarctvolume or improve the neurologic scores in diabetic rats. Postconditioningincreased the activity of SOD and GSH-pX in the brain tissue in the normalstate but not in the diabetic rats when measured at ischemia-reperfusion24hours; Postconditioning decreased the level of MDA in the brain tissue innormal rats but not in the diabetic rats; Postconditioning treatment upregulatedBcl-2and p-Akt protein expression and downregulated Bax and caspase-3activity in normal rats but not in the diabetic rats.
Conclusions: Ischemic postconditioning has protective effect for focalischemia-reperfusion injury in normal rats. Chronic hyperglycemia canabrogate the protection of postconditioning at least in part via oxidative stress, cell apoptosis and Akt phosphorylation dysfunction.
引文
[1] Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: adelay of lethal cell injury in ischemic myocardium. Circulation.1986;74:1124-1136.
[2] Schaller B, Graf R. Cerebral ischemic preconditioning: an experimentalphenomenon or a clinical important entity of stroke prevention. J Neurol.2002;249:1503-1511.
[3] Na HS, Kim YI, Yoon YW, et al. Ventricular premature beat-drivenintermittent restoration of coronary blood flow reduces the incidence ofreperfusion-induced ventricular fibrillation in a cat model of regionalischemia. Am Heart,1996;132:78-83,.
[4] Zhao ZQ, Corvera JS, Halkos ME. Inhibition of myocardial injury byischemic postconditioning during reperfusion: comparison with ischemicpreconditioning. Am J Physiol.2003;285:579-588.
[5] Darling CE, Jiang R, Maynard M. Postconditioning via stutteringreperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2.Am J Physiol.2005;289: H1618-1626.
[6] Kin H, Zatta AJ, Lofye MT. Postconditioning reduces infarct size viaadenosine receptor activation by endogenous adenosine. Cardiovasc Res.2005;67:124-133.
[7] Sun HY, Wang NP, Kerendi F. Hypoxic postconditioning reducescardiomyocyte loss by inhibiting ROS generation and intracellularCa2+overload. Am J Physiol.2005;288:1900-1908.
[8] Bopassa JC, Ferrera R, Gateau-Roesch O. PI3-kinase regulates themitochondrial transition pore in controlled reperfusion and postcondi-tioning. Cardiovasc Res.2006;69:178-185.
[9] Kin H, Zhao ZQ, Sun HY. Postconditioning attenuates myocardialischemia-reperfusion injury by inhibiting events in the early minutes ofreperfusion. Cardiovasc Res.2004;62:74–85.
[10] Tsang A, Hausenloy DJ, Mocanu MM. Postconditioning: a form of‘modified reperfusion’ protects the myocardium by activating thephosphatidylinositol3-kinase-Akt pathway. Circ Res.2004;95:230-232.
[11] Sun HY, Wang NP, Halkos M. Postconditioning attenuatescardiomyocyte apoptosis via inhibition of JNK and p38mitogen-activated proteinkinase signaling pathways. Apoptosis.2006;11:1583-1593.
[12] Staat P, Rioufol G, Piot C. Postconditioning the human heart.Circulation.2005;112:2143-2148.
[13] Zhao H, Sapolsky RM, Steinberg GK. Interrupting reperfusion as astroke therapy: ischemic postconditioning reduces infarct size after focalischemia in rats. J Cerebr Blood F Met2006;26(9):1114-1121,
[14] Pignataro G, Meller R, Inoue K, et al, In vivo and in vitro characterizationof a novel neuroprotective strategy for stroke: ischemic postconditioning.J Cereb Blood Flow Metab,2008;28:232-41
[15] Argaud L, Gateau-Roesch O, Raisky O, et al. Postconditioning inhibitsmitochondrial permeability transition. Circulation2005;111:194-199
[16] Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeabilitytransition pore opening during myocardial reperfusion are target forcardioprotection. Cardiovasc Res2004;61:372-385.
[17] Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis:epidemiology, pathophysiology, and management. JAMA2002;287:2570–2581.
[18] Barrett-Connor E, Khaw KT. Diabetes mellitus: an independent riskfactor for stroke? Am J Epidemiol1988;128:116-123
[19] Tuomilehto J, Rastenyte D, Jousilahti P, et al. Diabetes mellitus as a riskfactor for death from stroke. Prospective study of the middle-agedFinnish population. Stroke1996;27:210-215.
[20] Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: adelay of lethal cell injury in ischemic myocardium. Circulation1986;74:1124-1136
[21] Perez-Pinzon MA. Neuroprotective effects of ischemic preconditioning inbrain mitochondria following cerebral ischemia. J Bioenerg Biomem-branes2004;36:323–327
[22] Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injuryby ischemic postconditioning during reperfusion: comparison withischemic preconditioning. Am J Physiol Heart Circ Physiol2003;285:H579-H588
[23] Sewell WH, Koth DR, Huggins CE. Ventricular fibrillation in dogs aftersudden return of flow to the coronary artery. Surgery1955;38:1050-1053
[24] Na HS, Kim YI, Yoon YW, et al. Ventricular premature beat-drivenintermittent restoration of coronary blood flow reduces the incidence ofreperfusion-induced ventricular fibrillation in a cat model of regionalischemia. Am Heart1996;132:78-83
[25] Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injuryby ischemic postconditioning during reperfusion: comparison withischemic preconditioning. Am J Physiol Heart Circ Physiol2003;285:H579-88
[26] Zhao ZQ, Vinten-Johansen J. Postconditioning: reduction of reperfusion-induced injury. Cardiovasc Res2006;70:200–211
[27] Obal D, Dettwiler S, Favoccia C, et al. The influence of mitochondrialKATP-channels in the cardioprotection of preconditioning and postcondi-tioning by sevoflurane in the rat in vivo. Anesth Analg2005;101:1252-1260
[28] Kin H, Zatta AJ, Lofye MT, et al. Postconditioning reduces infarct sizevia adenosine receptor activation by endogenous adenosine. CardiovascRes2005;67:124-133
[29] Krolikowski JG, Weihrauch D, Bienengraeber M, et al. Role of Erk1/2,p70s6K, and eNOS in isoflurane-induced cardioprotection during earlyreperfusion in vivo. Can J Anaesth2006;53:174–182
[30] Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart.Circulation2005;112:2143-2148
[31] J. Moncayo, G.R. de Freitas, J. Bogousslavsky, et al. Do transientischemic attacks have a neuroprotective effect? Neurology,2000;54(11):2089-2094
[32] Kinouchi H, Epstein CJ, Mizui T, et al. Attenuation of focal cerebralischemic injury in transgenic mice overexpressing CuZn superoxidedismutase. Proc Natl Acad Sci USA1991;88:11158-62
[33] Yamashima T. Implication of cysteine proteases calpain, cathepsin andcaspase in ischemic neuronal death of primates. Prog Neurobiol2000;62:273-295
[34] Chen J, Nagayama T, Jin K, et al. Induction of caspase-3-like proteasemay mediate delayed neuronal death in the hippocampus after transientcerebral ischemia. J Neurosci1998;18:4914-28
[35] Noshita N, Sugawara T, Hayashi T, et al. Copper/zinc superoxidedismutase attenuates neuronal cell death by preventing extracellularsignalregulated kinase activation after transient focal cerebral ischemia inmice. J Neurosci2002;22:7923-30
[36] Shimohata T, Zhao H, Steinberg GK. Epsilon PKC may contribute to theprotective effect of hypothermia in a rat focal cerebral ischemia model.Stroke2007;38:375-80
[37] Zhao H, Shimohata T, Wang JQ, et al. Akt contributes to neuroprotectionby hypothermia against cerebral ischemia in rats. J Neurosci2005;25(9):794-806
[38] Nan Wang, Jian G. Lu, Xian L. et al. Effects of ischemic postcondi-tioning on reperfusion injury in rat liver grafts after orthotopic livertransplantation.2009;39(4):382-390
[39] Zhao H, Shimohata T, Wang JQ, et al. Akt contributes to neuroprotectionby hypothermia against cerebral ischemia in rats. J Neurosci2005;25:9794-9806
[40] Zhao H, YenariMA, Cheng D, et al. Bcl-2overexpression protectsagainst neuron loss within the ischemic margin following experimentalstroke and inhibits cytochrome c translocation and caspase-3activity. JNeurochem2003;85:1026–1036
[41] Zhao H，Sapolsky RM，Steinberg GK. Interrupting reperfusion as astroke therapy: ischemic Posteonditioning reduces infarct size after focalischemia in rats.[J]Cereb Blood Flow Metab，2006;26(9):1114-1121
[42] Ren C, Gao X, Niu G, et al. Delayed Postconditioning Protects againstFocal Ischemic Brain Injury in Rats. PLoS ONE2008;3(12):38-51.
[43] Pignataro G, Meller R, Inoue K, et al. In vivo and in vitrocharacterization of a novel neuroprotective strategy for stroke: ischemicpostconditioning. J Cereb Blood Flow Metab2008;28:232-41
[44] Wang JY, Shen J, Gao Q, et al. Ischemic postconditioning protectsagainst global cerebral ischemia/reperfusion induced injury in rats.Stroke2008;39:983-90
[45] Rehni AK, Singh N. Role of phosphoinositide3-kinase in ischemicpostconditioning-induced attenuation of cerebral ischemia-evokedbehaveioral deficits in mice. Pharmacol Rep2007;59:192–8
[46] Tsang A, Hausenloy DJ, Mocanu MM, et al. Postconditioning: a form of“modified reperfusion” protects the myocardium by activating thephosphatidylinositol3-kinase-Akt pathway. Circ Res2004;95:230-232
[47] Bianzhi Xing, Hui Chen; Min Zhang, et al. Ischemic PostconditioningInhibits Apoptosis After Focal Cerebral Ischemia/Reperfusion Injury inthe Rat. Stroke.2008;39:2362-2369
[48] Zhao Z-Q, Corvera JS, Halkos ME, et al. Inhibition of myocardial injuryby ischemic postconditioning during reperfusion: comparison withischemic preconditioning. Am J Physiol (Heart Circ Physiol)2003;285:579-88
[49] Okamoto F, Allen BS, Buckberg GD, et al. Reperfusion conditions:importance of ensuring gentle versus sudden reperfusion during relief ofcoronary occlusion. J Thorac Cardiovasc Surg1986;92:613-620
[50] Hori M, Kitakaze M, Sato H, et al. Staged reperfusion attenuatesmyocardial stunning in dogs. Role of transient acidosis during earlyreperfusion.Circulation1991;84:2135-2145
[51] Gao X, Ren C, Zhao H. Protective effects of ischemic postconditioningcompared with gradual reperfusion or preconditioning. J NeurosciRes2008;86:2505-11
[52] Vandenberg JI, Metcalfe JC, Grace AA. Mechanisms of pH recoveryafter global ischemia in the perfused heart. Circ Res1993;72:993-1003.
[53] Garcia-Dorado D, Ruiz-Meana M, Piper HM. Lethal reperfusion injuryin acute myocardial infarction: facts and unresolved issues. CardiovascRes2009;83:165-168
[54] Ruiz-Maena M, Pina P, Garcia-Dorado D, et al. Glycine protectscardiomyocytes against lethal reoxygenation injury by inhibitingmitochondrial permeability transition. J Physiol2004;558:873-882
[55] Garcia-Dorado D, Ruiz-Meana M, Piper HM. Lethal reperfusion injuryin acute myocardial infarction: facts and unresolved issues. CardiovascRes2009;83:165-168.
[56] Heusch G. Postconditioning: Old wine in a new bottle? J Am CollCardiol2004;44:1111-1112.
[57] Cohen MV, Yang XM, Downey JM. The pH hypothesis of postcondi-tioning: staccato reperfusion reintroduces oxygen and perpe-tuatesmyocardial acidosis. Circulation2007;115:1895–1903.
[58] Inserte J, Barba I, Hernando V, Garcia-Dorado D. Delayed recovery ofintracellular acidosis during reperfusion prevents calpain activation anddetermines protection in postconditioned myocardium. Cardiovasc Res2009;81:116-122.
[59] B Olafsson, MB Forman, DW Puett, et al. Reduction of reperfusioninjury in the canine preparation by intracoronary adenosine: importanceof the endothelium and the no-reflow phenomenon.Circulation.1987,76:1135-1145
[60] Sebastian Philippa, Xi-Ming Yanga, Lin Cuia, et al. Postconditioningprotects rabbit hearts through a protein kinase C-adenosine A2b receptorcascade. Cardiovasc Res2006;70(2):308-314
[61] Hajime Kina, Amanda J. Zattaa, Mark T. et al. Postconditioning reducesinfarct size via adenosine receptor activation by endogenous adenosine.Cardiovasc Res2005;67(1):124-133
[62] R. Ray Morrison, M. A. Hassan Talukder, Catherine Ledent,et al.Cardiaceffects of adenosine in A2A receptor knockout hearts: uncovering A2Breceptors. AJP-Heart2002;282(2): H437-H444
[63] Joel Linden. Adenosine in tissue protection and tissue regeneration.Molecular Pharmacology2005;67(5):1385-1387
[64] Zatta AJ, Kin H, Yoshishige D, et al. Evidence that cardioprotection bypostconditioning involves preservation of myocardial opioid content andselective opioid receptor activation. Am J Physiol Heart Circ Physiol2008;294: H1444-H1451
[65] Chen Z, Li T, Zhang B. Morphine postconditioning protects againstreperfusion injury in the isolated rat hearts. J Surg Res2008;145:287-294
[66] Penna C, Mancardi D, Rastaldo R, Losano G, Pagliaro P. Intermittentactivation of bradykinin B(2) receptors and mitochondrial K(ATP)channels trigger cardiac postconditioning through redox signaling.Cardiovasc Res2007;75:168-177
[67] Penna C, Mancardi D, Tullio F, Pagliaro P. Postconditioning andintermittent bradykinin induced cardioprotection require cyclooxygenaseactivation and prostacyclin release during reperfusion. Basic Res Cardiol2008;103:368–377.
[68] Bell RM, Yellon DM. Bradykinin limits infarction when administered asan adjunct to reperfusion in mouse heart: the role of PI3K, Akt and eNOS.J Mol Cell Cardiol2003;35:185–193.
[69] Cross TG, Scheel-Toellner D, Henriquez NV, et al. Serine/threonineproteinkinases and apoptosis. Exp CellRes2000;(256):34-41.
[70] Hausenloy D, Jand Y, ellon DM. New directions for protecting the heartagainst ischaemia-reperfusion injury: targeting the reperfusion injurysalvage kinase(RISK) pathway. Cardiovasc Res2004;(61):448-460
[71] Tsang A, Hausenloy DJ, Mocanu MM, et al. Postconditioning:a form of‘modified reperfusion’ protects the myocardium by activating thephosphatidylinosit3-kinase-Akt pathway. Circ Res2004(95):230-232.
[72] Xi-Ming Yang, Sebastian Philipp, James M. et al. Postconditioning’sprotection is not dependent on circulating blood factors or cells butinvolves adenosine receptors and requires PI3–kinase and guanylylcyclase activation Basic Research in Cardiology,2005,100(1):57-63
[73] Andrew Tsang, Derek J. Hausenloy, Mihaela M. Mocanu, et al.Postconditioning: A Form of “Modified Reperfusion” Protects theMyocardium by Activating the Phosphatidylinositol3-Kinase-AktPathway. Circulation Research.2004,95:230-232
[74] Laurent Argaud, Odile Gateau-Roesch, Olivier Raisky, et al. Postcondi-tioning Inhibits Mitochondrial Permeability Transition. Circu-lation.2005;111:194-197
[75] Xi-Ming Yang, J. Bradley Proctor, Lin Cui, et al. Multiple brief coronaryocclusions during early reperfusion protect rabbit hearts by targeting cellsignaling pathways. Journal of the American College of Cardiology.2004;44(5):1103-1110
[76] Chad E. Darling, Rong Jiang, Michelle Maynard, et al. Postconditioningvia stuttering reperfusion limits myocardial infarct size in rabbit hearts:role of ERK1/2. AJP-Heart2005,289(4): H1618-1626
[77] Heng Zhao. Ischemic postconditioning as a novel avenue to protectagainst brain injury after stroke. Journal of Cerebral Blood Flow andMetabolism2009,29:873–885
[78] Sawe N, Steinberg G, Zhao H Dual roles of the MAPK/ERK1/2cellsignaling pathway after stroke.J Neurosci Res.2008;86:1659–69
[79] Gao X, Zhang H, Takahashi T, et al. The Akt signaling pathwaycontributes to postconditioning’s protection against stroke; the protectionis associated with the MAPK and PKC pathways. J Neurochem,2008;105:943–55
[80] J. Mykytenko, F. Kerendi, J. G. Reeves, et al. Long-term inhibition ofmyocardial infarction by postconditioning during reperfusion. BasicResearch in Cardiology,2006,102(1):90-100
[81] AP. Halestrap, E. Doran, J. P. Gillespie and A. O'Toole. Mitochondriaand cell death.Biochemical Society Transactions.2000,28(2):170-178
[82] Griffiths EJ and Halestrap AP. Mitochondrial non-specific pores remainclosed during cardiac ischaemia, but open upon reperfusion. Biochem J1995;307:93–98,.
[83] Laurent Argaud,Odile Gateau-Roesch, Olivier Raisky, et al. Postcondi-tioning Inhibits Mitochondrial Permeability Transition. Circulation.2005;111:194-197
[84] James Mykytenko, James G. Reeves, Hajime Kin, et al. Persistentbeneficial effect of postconditioning against infarct size: role ofmitochondrial KATP channels during reperfusion. Basic Research inCardiology2007,103,(5):472-484
[85] Ludovic Gomez, Bo Li, Nathan Mewton, Ingrid Sanchez, ChristophePiot, Meier Elbaz and Michel Ovize. Inhibition of mitochondrialpermeability transition pore opening: translation to patients.CardiovascRes (2009)83(2):226-233.
[86] Hausenloy DJ, Duchen MR, and Yellon DM. Inhibiting mitochondrialpermeability transition pore opening at reperfusion protects againstischaemia-reperfusion injury. Cardiovasc Res60:617–625,2003.
[87] Penna C, Rastaldo R, Mancardi D, et al. Postconditioning inducedcardioprotection requires signaling through a redox-sensitive mechanism,mitochondrial ATP-sensitive K+channel and protein kinase Cactivation.Basic Res Cardiol2006;101:180–189.
[88] Zatta AJ, Kin H, Lee G, et al. Infarct-sparing effect of myocardialpostconditioning is dependent on protein kinase C signalling. CardiovascRes2006,70:315–324.
[89] Raval A. P, Dave K. R, Prado R, et al. Protein kinase C delta cleavageinitiates an aberrant signal transduction pathway after cardiac arrest andoxygen glucose deprivation.J. Cereb. Blood Flow Metab.2005,25:730-741.
[90] Xuwen Gao,Hanfeng Zhang,Tetsuya Takahashi, et al.The Akt signalingpathway contributes to postconditioning’s protection against stroke; theprotection is associated with the MAPK and PKC pathways.Journal ofNeurochemistry.2008,105(3):943-955
[91] M.V. Cohen, X.M. Yang, J.M. Downey. Acidosis, oxygen, andinterference with mitochondrial permeability transition pore formation inthe early minutes of reperfusion are critical to postconditioning'ssuccess.Basic Res Cardiol,2008;103:464–471
[92] L. Gomez, M. Paillard, H. Thibault, et al. Inhibition of GSK3beta bypostconditioning is required to prevent opening of the mitochondrialpermeability transition pore during reperfusion.Circulation,2008;(117):2761–2768
[93] Y. Nishino, I.G. Webb, S.M. Davidson, et al.Glycogen synthase kinase-3inactivation is not required for ischemic preconditioning or postcondi-tioning in the mouse. Circ Res,2008;103:307-314
[94] Negoro S, Kunisada K, Fujio Y, et al. Activation of signal transducer andactivator of transcription3protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation ofmanganese superoxide dismutase. Circulation2001;104:979-981
[95] Boengler K, Buechert A, Heinen Y, et al. Cardioprotection by ischemicpostconditioning is lost in aged and STAT3-deficient mice. Circ Res2008;102:131-135.
[96] Suleman N, Opie L, Lecour S. Ischemic postconditioning conferscardioprotection via phosphorylation of STAT-3. J Mol Cell Cardiol2006;40:977
[97] Torbenson M, Yang SQ, Liu HZ, et al. STAT-3overexpression and p21up-regulation accompany impaired regeneration of fatty livers. Am JPathol2002;161:155–61
[98] Hattori R, Maulik N, Otani H, et al. Role of STAT3in ischemicpreconditioning. J Mol Cell Cardiol2001,33:1929–36
[99] Lecour S, Suleman N, Deuchar GA, et al.Pharmacologicalpreconditioning with tumor necrosis factor-alpha activates signaltransducer and activator of transcription-3at reperfusion withoutinvolving classic prosurvival kinases (Akt and extracellular signal-regulated kinase).Circulation2005,112:3911-3918.
[100] Gross ER, Hsu AK, Gross GJ. The JAK/STAT pathway is essential foropioid-induced cardioprotection: JAK2as a mediator of STAT3, Akt,and GSK-3beta. Am J Physiol Heart Circ Physiol2006;291: H827-834
[101] Penna C, Tullio F, Merlino A, et al. Postconditioning cardioprotectionagainst infarct size and post-ischemic systolic dysfunction is influencedby gender. Basic Res Cardiol2009;104:390–402
[102] Crisostomo PR,Wang M,Wairiuko GM, et al. Postconditioning infemales depends on injury severity. J Surg Res2006;134:342–347
[103] Przyklenk K, Maynard M, Darling CE, Whittaker P. Aging mouse heartsare refractory to infarct size reduction with post-conditioning. J Am CollCardiol2008;51:1393-1398
[104] Boengler K, Buechert A, Heinen Y, et al. Cardioprotection by ischemicpostconditioning is lost in aged and STAT3-deficient mice. Circ Res2008;102:131–135
[105] Ferdinandy P, Schulz R, Baxter GF. Interaction of cardiovascular riskfactors with myocardial ischemia/reperfusion injury, preconditioning,and postconditioning. Pharmacol Rev2007;59:418–458
[106] Iliodromitis EK, Zoga A, Vrettou A, et al. The effectiveness ofpostconditioning and preconditioning on infarct size in hypercholester-olemic and normal anesthetized rabbits. Atherosclerosis2006,188:356-362
[107] Kupai K, Csonka C, Fekete V, et al. Cholesterol diet-inducedhyperlipidemia impairs the cardioprotective effect of postconditioning:role of peroxynitrite. Am J Physiol Heart Circ Physiol2009;297:H1729–H1735
[108] Donato M, D’Annunzio V, Berg G, et al. Ischemic postconditioningreduces infarct size by activation of A1receptors and K+(ATP)channels in both normal and hypercholesterolemic rabbits. J CardiovascPharmacol2007,49:287-292
[109] Penna C, Tullio F, Moro F, et al. Effects of a protocol of ischemicpostconditioning and/or captopril in hearts of normotensive andhypertensive rats. Basic Res Cardiol2010,105:181-192
[110] Feng J, Fischer G, Lucchinetti E, et al. Infarct-remodeled myocardium isreceptive to protection by isoflurane postconditioning:role of proteinkinase B/Akt signaling. Anesthesiology2006;104:1004–1014
[111] Wagner C, Kloeting I, Strasser RH, et al. Cardioprotection bypostconditioning is lost in WOKW rats with metabolic syndrome: role ofglycogen synthase kinase3beta. J Cardiovasc Pharmacol2008;52:430–437
[112] Bouhidel O, Pons S, Souktani R, et al. Myocardial ischemicpostconditioning against ischemia/reperfusion is impaired in ob/ob mice.Am J Physiol Heart Circ Physiol2008;295: H1580–H1586
[113] Huhn R, Heinen A, Hollmann MW, et al. Cyclosporine A administeredduring reperfusion fails to restore cardioprotection in prediabetic Zuckerobese rats in vivo. Nutr Metab Cardiovasc Dis2009;10:1016
[114] Hoyte, L; Kaur, J; Buchan, A.M. Lost in translation: takingneuroprotection from animal models to clinical trials. Exp. Neurol,2004,188(2):200-204
[115] Zhao, H. The protective effect of ischemic postconditioning againstischemic injury: from the heart to the brain. J. Neuroimmune. Pharmacol,2007,2(4):313-318
[116] Wang, J.Y, Shen, J, Gao, Q, et al. Ischemic postconditioning protectsagainst global cerebral ischemia/reperfusion-induced injury in rats.Stroke,2008,39(3):983-990
[117] Scartabelli, T, Gerace, E, Landucci, E, et al. Neuroprotection by group ImGlu receptors in a rat hippocampal slice model of cerebral ischemia isassociated with the PI3K-Akt signaling pathway: a novel postcondi-tioning strategy? Neuropharmacology,2008,55(4):509-516
[118] Pignataro, G, Meller, R, Inoue, K, et al. In vivo and in vitrocharacterization of a novel neuroprotective strategy for stroke: ischemic,postconditioning. J. Cereb. Blood Flow Metab,2008,28(2):232-241
[119] Kitagawa, K, Matsumoto, M, Tagaya, M, et al.‘Ischemic tolerance’phenomenon found in the brain. Brain Res,1990,528(1):21-24
[120] Burda,J, Danielisova, V,Nemethova, M,et al. Delayed postconditioniginitiates additive mechanism necessary for survival of selectivelyvulnerable neurons after transient Ischemia in Rat Brain. Cellular andmolecular neurobiology.2006;26(7-8):1139-1149
[120] Ren, C; Gao, X; Niu, G; et al. Delayed postconditioning protects againstfocal ischemic brain injury in rats. PLoS One,2008,3(12):e3851
[121] Lee, J.J; Li, L; Jung, H.H; et al. Postconditioning with isoflurane reducedischemia-induced brain injury in rats.Anesthesiology,2008,108(6):1055-1062
[122] Leconte, C; Tixier, E; Freret, T; et al. Delayed hypoxic postconditioningprotects against cerebral ischemia in the mouse. Stroke,2009,40(10):3349-3355.
[123] Feng, Jianhua; Lucchinetti, Eliana; Ahuja, Preeti; et al. IsofluranePostconditioning Prevents Opening of the Mitochondrial PermeabilityTransition Pore through Inhibition of Glycogen Synthase Kinase3β.Anesthesiology.2005;103(5):987-995
[124] Perez-Pinzon, M.A. Mechanisms of neuroprotection during ischemicpreconditioning: lessons from anoxic tolerance. Comp.Biochem. Physiol.A. Mol. Integr. Physiol,2007,147(2):291-299.
[125] Oxman, T; Arad, M; Klein, R; et al. Limb ischemia preconditions theheart against reperfusion tachyarrhythmia. Am. J. Physiol,1997,273(4Pt2): H1707-1712
[126] Birnbaum, Y; Hale, S.L; Kloner, R.A. Ischemic preconditioning at adistance: reduction of myocardial infarct size by partial reduction ofblood supply combined with rapid stimulation of the gastrocnemiusmuscle in the rabbit. Circulation,1997,96(5):1641-1646
[127] Ren, C; Yan, Z; Wei, D; et al. Limb remote ischemic postconditioningprotects against focal ischemia in rats. Brain Res,2009,128(8):88-94
[128] Dietrich, W.D; Busto, R; Alonso, O; et al. Intraischemic but notpostischemic brain hypothermia protects chronically following globalforebrain ischemia in rats. J Cereb. Blood Flow Metab.,1993,13(4):541-549
[129] Halkos, M.E.; Kerendi, F.; Corvera, J.S.; et al. Myocardial protectionwith postconditioning is not enhanced by ischemic preconditioning. Ann.Thorac. Surg.,2004,78(3),961-969; discussion96
[130] Danielisova, V; Nemethova, M; Gottlieb, M; et al. The changes inendogenous antioxidant enzyme activity after postconditioning. Cell Mol.Neurobiol,2006,26(7):1181-1191
[131] Xing, B; Chen, H; Zhang, M; et al. Ischemic post-conditioning protectsbrain and reduces inflammation in a rat model of focal cerebralischemia/reperfusion.J. Neurochem,2008,105(5):1737-1745
[132] Casabona, G. Intracellular signal modulation: a pivotal role for proteinkinase C. Prog. Neuropsychopharmacol. Biol. Psychiatry,1997,21(3):407-425
[133] Wolfrum, S, Schneider, K,Heidbreder, M,et al. Remote preconditioningprotects the heart by activating myocardial PKCepsilon-isoform.Cardiovasc. Res.2002,55(3):583-589
[134] Schoemaker, R.G; van Heijningen, C.L. Bradykinin mediates cardiacpreconditioning at a distance. Am. J. Physiol. Heart Circ. Physiol,2000,278(5):H1571-1576
[135] Barone, F.C; White, R.F; Spera, P.A; et al. Ischemic preconditioning andbrain tolerance: temporal histological and functional outcomes, proteinsynthesis requirement, and interleukin-1receptor antagonist and earlygene expression. Stroke,1998,29(9):1937-1950
[136]叶燕丽,王辉云,王莲桂,黄丽惜,冯启胜.四氧嘧啶制作大鼠糖尿病模型--剂量探讨与方法改进,实验动物科学与管理,2001,18(2):54-55
[137]马常升,马文领,戴维国,等.插线法制备大鼠局灶性脑缺血再灌注模型的研究[J].解剖学杂志,1999,22:209-211
[138]曹秋云,潘旭东.线栓法大鼠大脑中动脉闭塞模型的研究进展[J].滨州医学院学报,2000,23:100-101
[139] Elsaesser RS, Zausinger S, Hungerhuber E, et al. A critical reevaluationof the intraluminal thread model of focal cerebral ischemia. Evidence ofinadvertent premature reperfusion and subarachnoid hemorrhage in ratsby Laser-Doppler Flowmetry[J]. Stroke,1998;29:2162-2170
[140] Keman WN，Inzueehi SE. Type2diabetes mellitus and insulin resistance:Stroke Prevention and management. Curr Treat Options Neurol，2004;6(6):443-450
[141] Cavallini A,Micieli G,Marcheselli S,et a1.Role of monitoring inmanagement of acute ischemic stroke patients[J].Stroke,2003;34(11):2599-2603
[142] Li PA,Shuaib A,Miyashita H,et al. Hyperglycemia enhances extracellularglutamate accumulation in rats subjected to forebrain ischemia[J]· Stroke,2000,31(1):183-192
[143] Zhao JL, Yang YJ, You SJ. Different effects of postconditioning onmyocardial no-reflow in the normal and hypercholesterolemic mini-swines. Microvasc. Res.2007;73:137-142
[144] Hausenloy DJ, Tsang A, Yellon D.M. Postconditioning does not protectthe diabetic heart. J. Mol. Cell. Cardiol.2006;40:958
[145] Youqing Hu, Gladys Block, Edward P Norkus, et al. Relations ofglycemic index and glycemic load with plasma oxidative stressmarkers[J]. Am.J.clinical Nutrition,2006;84(1):70-76
[146] Sophie Richier, Paola Furla, Amandine Plantivaux, et al. Symbiosis-induced adaptation to oxidative stress[J].J.Exp.Biol,2005;208(2):277-285
[2] Schaller B, Graf R. Cerebral ischemic preconditioning: an experimentalphenomenon or a clinical important entity of stroke prevention. J Neurol.2002;249:1503-1511.
[3] Na HS, Kim YI, Yoon YW, et al. Ventricular premature beat-drivenintermittent restoration of coronary blood flow reduces the incidence ofreperfusion-induced ventricular fibrillation in a cat model of regionalischemia. Am Heart,1996;132:78-83,.
[4] Zhao ZQ, Corvera JS, Halkos ME. Inhibition of myocardial injury byischemic postconditioning during reperfusion: comparison with ischemicpreconditioning. Am J Physiol.2003;285:579-588.
[5] Darling CE, Jiang R, Maynard M. Postconditioning via stutteringreperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2.Am J Physiol.2005;289: H1618-1626.
[6] Kin H, Zatta AJ, Lofye MT. Postconditioning reduces infarct size viaadenosine receptor activation by endogenous adenosine. Cardiovasc Res.2005;67:124-133.
[7] Sun HY, Wang NP, Kerendi F. Hypoxic postconditioning reducescardiomyocyte loss by inhibiting ROS generation and intracellularCa2+overload. Am J Physiol.2005;288:1900-1908.
[8] Bopassa JC, Ferrera R, Gateau-Roesch O. PI3-kinase regulates themitochondrial transition pore in controlled reperfusion and postcondi-tioning. Cardiovasc Res.2006;69:178-185.
[9] Kin H, Zhao ZQ, Sun HY. Postconditioning attenuates myocardialischemia-reperfusion injury by inhibiting events in the early minutes ofreperfusion. Cardiovasc Res.2004;62:74–85.
[10] Tsang A, Hausenloy DJ, Mocanu MM. Postconditioning: a form of‘modified reperfusion’ protects the myocardium by activating thephosphatidylinositol3-kinase-Akt pathway. Circ Res.2004;95:230-232.
[11] Sun HY, Wang NP, Halkos M. Postconditioning attenuatescardiomyocyte apoptosis via inhibition of JNK and p38mitogen-activated proteinkinase signaling pathways. Apoptosis.2006;11:1583-1593.
[12] Staat P, Rioufol G, Piot C. Postconditioning the human heart.Circulation.2005;112:2143-2148.
[13] Zhao H, Sapolsky RM, Steinberg GK. Interrupting reperfusion as astroke therapy: ischemic postconditioning reduces infarct size after focalischemia in rats. J Cerebr Blood F Met2006;26(9):1114-1121,
[14] Pignataro G, Meller R, Inoue K, et al, In vivo and in vitro characterizationof a novel neuroprotective strategy for stroke: ischemic postconditioning.J Cereb Blood Flow Metab,2008;28:232-41
[15] Argaud L, Gateau-Roesch O, Raisky O, et al. Postconditioning inhibitsmitochondrial permeability transition. Circulation2005;111:194-199
[16] Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeabilitytransition pore opening during myocardial reperfusion are target forcardioprotection. Cardiovasc Res2004;61:372-385.
[17] Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis:epidemiology, pathophysiology, and management. JAMA2002;287:2570–2581.
[18] Barrett-Connor E, Khaw KT. Diabetes mellitus: an independent riskfactor for stroke? Am J Epidemiol1988;128:116-123
[19] Tuomilehto J, Rastenyte D, Jousilahti P, et al. Diabetes mellitus as a riskfactor for death from stroke. Prospective study of the middle-agedFinnish population. Stroke1996;27:210-215.
[20] Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: adelay of lethal cell injury in ischemic myocardium. Circulation1986;74:1124-1136
[21] Perez-Pinzon MA. Neuroprotective effects of ischemic preconditioning inbrain mitochondria following cerebral ischemia. J Bioenerg Biomem-branes2004;36:323–327
[22] Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injuryby ischemic postconditioning during reperfusion: comparison withischemic preconditioning. Am J Physiol Heart Circ Physiol2003;285:H579-H588
[23] Sewell WH, Koth DR, Huggins CE. Ventricular fibrillation in dogs aftersudden return of flow to the coronary artery. Surgery1955;38:1050-1053
[24] Na HS, Kim YI, Yoon YW, et al. Ventricular premature beat-drivenintermittent restoration of coronary blood flow reduces the incidence ofreperfusion-induced ventricular fibrillation in a cat model of regionalischemia. Am Heart1996;132:78-83
[25] Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injuryby ischemic postconditioning during reperfusion: comparison withischemic preconditioning. Am J Physiol Heart Circ Physiol2003;285:H579-88
[26] Zhao ZQ, Vinten-Johansen J. Postconditioning: reduction of reperfusion-induced injury. Cardiovasc Res2006;70:200–211
[27] Obal D, Dettwiler S, Favoccia C, et al. The influence of mitochondrialKATP-channels in the cardioprotection of preconditioning and postcondi-tioning by sevoflurane in the rat in vivo. Anesth Analg2005;101:1252-1260
[28] Kin H, Zatta AJ, Lofye MT, et al. Postconditioning reduces infarct sizevia adenosine receptor activation by endogenous adenosine. CardiovascRes2005;67:124-133
[29] Krolikowski JG, Weihrauch D, Bienengraeber M, et al. Role of Erk1/2,p70s6K, and eNOS in isoflurane-induced cardioprotection during earlyreperfusion in vivo. Can J Anaesth2006;53:174–182
[30] Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart.Circulation2005;112:2143-2148
[31] J. Moncayo, G.R. de Freitas, J. Bogousslavsky, et al. Do transientischemic attacks have a neuroprotective effect? Neurology,2000;54(11):2089-2094
[32] Kinouchi H, Epstein CJ, Mizui T, et al. Attenuation of focal cerebralischemic injury in transgenic mice overexpressing CuZn superoxidedismutase. Proc Natl Acad Sci USA1991;88:11158-62
[33] Yamashima T. Implication of cysteine proteases calpain, cathepsin andcaspase in ischemic neuronal death of primates. Prog Neurobiol2000;62:273-295
[34] Chen J, Nagayama T, Jin K, et al. Induction of caspase-3-like proteasemay mediate delayed neuronal death in the hippocampus after transientcerebral ischemia. J Neurosci1998;18:4914-28
[35] Noshita N, Sugawara T, Hayashi T, et al. Copper/zinc superoxidedismutase attenuates neuronal cell death by preventing extracellularsignalregulated kinase activation after transient focal cerebral ischemia inmice. J Neurosci2002;22:7923-30
[36] Shimohata T, Zhao H, Steinberg GK. Epsilon PKC may contribute to theprotective effect of hypothermia in a rat focal cerebral ischemia model.Stroke2007;38:375-80
[37] Zhao H, Shimohata T, Wang JQ, et al. Akt contributes to neuroprotectionby hypothermia against cerebral ischemia in rats. J Neurosci2005;25(9):794-806
[38] Nan Wang, Jian G. Lu, Xian L. et al. Effects of ischemic postcondi-tioning on reperfusion injury in rat liver grafts after orthotopic livertransplantation.2009;39(4):382-390
[39] Zhao H, Shimohata T, Wang JQ, et al. Akt contributes to neuroprotectionby hypothermia against cerebral ischemia in rats. J Neurosci2005;25:9794-9806
[40] Zhao H, YenariMA, Cheng D, et al. Bcl-2overexpression protectsagainst neuron loss within the ischemic margin following experimentalstroke and inhibits cytochrome c translocation and caspase-3activity. JNeurochem2003;85:1026–1036
[41] Zhao H，Sapolsky RM，Steinberg GK. Interrupting reperfusion as astroke therapy: ischemic Posteonditioning reduces infarct size after focalischemia in rats.[J]Cereb Blood Flow Metab，2006;26(9):1114-1121
[42] Ren C, Gao X, Niu G, et al. Delayed Postconditioning Protects againstFocal Ischemic Brain Injury in Rats. PLoS ONE2008;3(12):38-51.
[43] Pignataro G, Meller R, Inoue K, et al. In vivo and in vitrocharacterization of a novel neuroprotective strategy for stroke: ischemicpostconditioning. J Cereb Blood Flow Metab2008;28:232-41
[44] Wang JY, Shen J, Gao Q, et al. Ischemic postconditioning protectsagainst global cerebral ischemia/reperfusion induced injury in rats.Stroke2008;39:983-90
[45] Rehni AK, Singh N. Role of phosphoinositide3-kinase in ischemicpostconditioning-induced attenuation of cerebral ischemia-evokedbehaveioral deficits in mice. Pharmacol Rep2007;59:192–8
[46] Tsang A, Hausenloy DJ, Mocanu MM, et al. Postconditioning: a form of“modified reperfusion” protects the myocardium by activating thephosphatidylinositol3-kinase-Akt pathway. Circ Res2004;95:230-232
[47] Bianzhi Xing, Hui Chen; Min Zhang, et al. Ischemic PostconditioningInhibits Apoptosis After Focal Cerebral Ischemia/Reperfusion Injury inthe Rat. Stroke.2008;39:2362-2369
[48] Zhao Z-Q, Corvera JS, Halkos ME, et al. Inhibition of myocardial injuryby ischemic postconditioning during reperfusion: comparison withischemic preconditioning. Am J Physiol (Heart Circ Physiol)2003;285:579-88
[49] Okamoto F, Allen BS, Buckberg GD, et al. Reperfusion conditions:importance of ensuring gentle versus sudden reperfusion during relief ofcoronary occlusion. J Thorac Cardiovasc Surg1986;92:613-620
[50] Hori M, Kitakaze M, Sato H, et al. Staged reperfusion attenuatesmyocardial stunning in dogs. Role of transient acidosis during earlyreperfusion.Circulation1991;84:2135-2145
[51] Gao X, Ren C, Zhao H. Protective effects of ischemic postconditioningcompared with gradual reperfusion or preconditioning. J NeurosciRes2008;86:2505-11
[52] Vandenberg JI, Metcalfe JC, Grace AA. Mechanisms of pH recoveryafter global ischemia in the perfused heart. Circ Res1993;72:993-1003.
[53] Garcia-Dorado D, Ruiz-Meana M, Piper HM. Lethal reperfusion injuryin acute myocardial infarction: facts and unresolved issues. CardiovascRes2009;83:165-168
[54] Ruiz-Maena M, Pina P, Garcia-Dorado D, et al. Glycine protectscardiomyocytes against lethal reoxygenation injury by inhibitingmitochondrial permeability transition. J Physiol2004;558:873-882
[55] Garcia-Dorado D, Ruiz-Meana M, Piper HM. Lethal reperfusion injuryin acute myocardial infarction: facts and unresolved issues. CardiovascRes2009;83:165-168.
[56] Heusch G. Postconditioning: Old wine in a new bottle? J Am CollCardiol2004;44:1111-1112.
[57] Cohen MV, Yang XM, Downey JM. The pH hypothesis of postcondi-tioning: staccato reperfusion reintroduces oxygen and perpe-tuatesmyocardial acidosis. Circulation2007;115:1895–1903.
[58] Inserte J, Barba I, Hernando V, Garcia-Dorado D. Delayed recovery ofintracellular acidosis during reperfusion prevents calpain activation anddetermines protection in postconditioned myocardium. Cardiovasc Res2009;81:116-122.
[59] B Olafsson, MB Forman, DW Puett, et al. Reduction of reperfusioninjury in the canine preparation by intracoronary adenosine: importanceof the endothelium and the no-reflow phenomenon.Circulation.1987,76:1135-1145
[60] Sebastian Philippa, Xi-Ming Yanga, Lin Cuia, et al. Postconditioningprotects rabbit hearts through a protein kinase C-adenosine A2b receptorcascade. Cardiovasc Res2006;70(2):308-314
[61] Hajime Kina, Amanda J. Zattaa, Mark T. et al. Postconditioning reducesinfarct size via adenosine receptor activation by endogenous adenosine.Cardiovasc Res2005;67(1):124-133
[62] R. Ray Morrison, M. A. Hassan Talukder, Catherine Ledent,et al.Cardiaceffects of adenosine in A2A receptor knockout hearts: uncovering A2Breceptors. AJP-Heart2002;282(2): H437-H444
[63] Joel Linden. Adenosine in tissue protection and tissue regeneration.Molecular Pharmacology2005;67(5):1385-1387
[64] Zatta AJ, Kin H, Yoshishige D, et al. Evidence that cardioprotection bypostconditioning involves preservation of myocardial opioid content andselective opioid receptor activation. Am J Physiol Heart Circ Physiol2008;294: H1444-H1451
[65] Chen Z, Li T, Zhang B. Morphine postconditioning protects againstreperfusion injury in the isolated rat hearts. J Surg Res2008;145:287-294
[66] Penna C, Mancardi D, Rastaldo R, Losano G, Pagliaro P. Intermittentactivation of bradykinin B(2) receptors and mitochondrial K(ATP)channels trigger cardiac postconditioning through redox signaling.Cardiovasc Res2007;75:168-177
[67] Penna C, Mancardi D, Tullio F, Pagliaro P. Postconditioning andintermittent bradykinin induced cardioprotection require cyclooxygenaseactivation and prostacyclin release during reperfusion. Basic Res Cardiol2008;103:368–377.
[68] Bell RM, Yellon DM. Bradykinin limits infarction when administered asan adjunct to reperfusion in mouse heart: the role of PI3K, Akt and eNOS.J Mol Cell Cardiol2003;35:185–193.
[69] Cross TG, Scheel-Toellner D, Henriquez NV, et al. Serine/threonineproteinkinases and apoptosis. Exp CellRes2000;(256):34-41.
[70] Hausenloy D, Jand Y, ellon DM. New directions for protecting the heartagainst ischaemia-reperfusion injury: targeting the reperfusion injurysalvage kinase(RISK) pathway. Cardiovasc Res2004;(61):448-460
[71] Tsang A, Hausenloy DJ, Mocanu MM, et al. Postconditioning:a form of‘modified reperfusion’ protects the myocardium by activating thephosphatidylinosit3-kinase-Akt pathway. Circ Res2004(95):230-232.
[72] Xi-Ming Yang, Sebastian Philipp, James M. et al. Postconditioning’sprotection is not dependent on circulating blood factors or cells butinvolves adenosine receptors and requires PI3–kinase and guanylylcyclase activation Basic Research in Cardiology,2005,100(1):57-63
[73] Andrew Tsang, Derek J. Hausenloy, Mihaela M. Mocanu, et al.Postconditioning: A Form of “Modified Reperfusion” Protects theMyocardium by Activating the Phosphatidylinositol3-Kinase-AktPathway. Circulation Research.2004,95:230-232
[74] Laurent Argaud, Odile Gateau-Roesch, Olivier Raisky, et al. Postcondi-tioning Inhibits Mitochondrial Permeability Transition. Circu-lation.2005;111:194-197
[75] Xi-Ming Yang, J. Bradley Proctor, Lin Cui, et al. Multiple brief coronaryocclusions during early reperfusion protect rabbit hearts by targeting cellsignaling pathways. Journal of the American College of Cardiology.2004;44(5):1103-1110
[76] Chad E. Darling, Rong Jiang, Michelle Maynard, et al. Postconditioningvia stuttering reperfusion limits myocardial infarct size in rabbit hearts:role of ERK1/2. AJP-Heart2005,289(4): H1618-1626
[77] Heng Zhao. Ischemic postconditioning as a novel avenue to protectagainst brain injury after stroke. Journal of Cerebral Blood Flow andMetabolism2009,29:873–885
[78] Sawe N, Steinberg G, Zhao H Dual roles of the MAPK/ERK1/2cellsignaling pathway after stroke.J Neurosci Res.2008;86:1659–69
[79] Gao X, Zhang H, Takahashi T, et al. The Akt signaling pathwaycontributes to postconditioning’s protection against stroke; the protectionis associated with the MAPK and PKC pathways. J Neurochem,2008;105:943–55
[80] J. Mykytenko, F. Kerendi, J. G. Reeves, et al. Long-term inhibition ofmyocardial infarction by postconditioning during reperfusion. BasicResearch in Cardiology,2006,102(1):90-100
[81] AP. Halestrap, E. Doran, J. P. Gillespie and A. O'Toole. Mitochondriaand cell death.Biochemical Society Transactions.2000,28(2):170-178
[82] Griffiths EJ and Halestrap AP. Mitochondrial non-specific pores remainclosed during cardiac ischaemia, but open upon reperfusion. Biochem J1995;307:93–98,.
[83] Laurent Argaud,Odile Gateau-Roesch, Olivier Raisky, et al. Postcondi-tioning Inhibits Mitochondrial Permeability Transition. Circulation.2005;111:194-197
[84] James Mykytenko, James G. Reeves, Hajime Kin, et al. Persistentbeneficial effect of postconditioning against infarct size: role ofmitochondrial KATP channels during reperfusion. Basic Research inCardiology2007,103,(5):472-484
[85] Ludovic Gomez, Bo Li, Nathan Mewton, Ingrid Sanchez, ChristophePiot, Meier Elbaz and Michel Ovize. Inhibition of mitochondrialpermeability transition pore opening: translation to patients.CardiovascRes (2009)83(2):226-233.
[86] Hausenloy DJ, Duchen MR, and Yellon DM. Inhibiting mitochondrialpermeability transition pore opening at reperfusion protects againstischaemia-reperfusion injury. Cardiovasc Res60:617–625,2003.
[87] Penna C, Rastaldo R, Mancardi D, et al. Postconditioning inducedcardioprotection requires signaling through a redox-sensitive mechanism,mitochondrial ATP-sensitive K+channel and protein kinase Cactivation.Basic Res Cardiol2006;101:180–189.
[88] Zatta AJ, Kin H, Lee G, et al. Infarct-sparing effect of myocardialpostconditioning is dependent on protein kinase C signalling. CardiovascRes2006,70:315–324.
[89] Raval A. P, Dave K. R, Prado R, et al. Protein kinase C delta cleavageinitiates an aberrant signal transduction pathway after cardiac arrest andoxygen glucose deprivation.J. Cereb. Blood Flow Metab.2005,25:730-741.
[90] Xuwen Gao,Hanfeng Zhang,Tetsuya Takahashi, et al.The Akt signalingpathway contributes to postconditioning’s protection against stroke; theprotection is associated with the MAPK and PKC pathways.Journal ofNeurochemistry.2008,105(3):943-955
[91] M.V. Cohen, X.M. Yang, J.M. Downey. Acidosis, oxygen, andinterference with mitochondrial permeability transition pore formation inthe early minutes of reperfusion are critical to postconditioning'ssuccess.Basic Res Cardiol,2008;103:464–471
[92] L. Gomez, M. Paillard, H. Thibault, et al. Inhibition of GSK3beta bypostconditioning is required to prevent opening of the mitochondrialpermeability transition pore during reperfusion.Circulation,2008;(117):2761–2768
[93] Y. Nishino, I.G. Webb, S.M. Davidson, et al.Glycogen synthase kinase-3inactivation is not required for ischemic preconditioning or postcondi-tioning in the mouse. Circ Res,2008;103:307-314
[94] Negoro S, Kunisada K, Fujio Y, et al. Activation of signal transducer andactivator of transcription3protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation ofmanganese superoxide dismutase. Circulation2001;104:979-981
[95] Boengler K, Buechert A, Heinen Y, et al. Cardioprotection by ischemicpostconditioning is lost in aged and STAT3-deficient mice. Circ Res2008;102:131-135.
[96] Suleman N, Opie L, Lecour S. Ischemic postconditioning conferscardioprotection via phosphorylation of STAT-3. J Mol Cell Cardiol2006;40:977
[97] Torbenson M, Yang SQ, Liu HZ, et al. STAT-3overexpression and p21up-regulation accompany impaired regeneration of fatty livers. Am JPathol2002;161:155–61
[98] Hattori R, Maulik N, Otani H, et al. Role of STAT3in ischemicpreconditioning. J Mol Cell Cardiol2001,33:1929–36
[99] Lecour S, Suleman N, Deuchar GA, et al.Pharmacologicalpreconditioning with tumor necrosis factor-alpha activates signaltransducer and activator of transcription-3at reperfusion withoutinvolving classic prosurvival kinases (Akt and extracellular signal-regulated kinase).Circulation2005,112:3911-3918.
[100] Gross ER, Hsu AK, Gross GJ. The JAK/STAT pathway is essential foropioid-induced cardioprotection: JAK2as a mediator of STAT3, Akt,and GSK-3beta. Am J Physiol Heart Circ Physiol2006;291: H827-834
[101] Penna C, Tullio F, Merlino A, et al. Postconditioning cardioprotectionagainst infarct size and post-ischemic systolic dysfunction is influencedby gender. Basic Res Cardiol2009;104:390–402
[102] Crisostomo PR,Wang M,Wairiuko GM, et al. Postconditioning infemales depends on injury severity. J Surg Res2006;134:342–347
[103] Przyklenk K, Maynard M, Darling CE, Whittaker P. Aging mouse heartsare refractory to infarct size reduction with post-conditioning. J Am CollCardiol2008;51:1393-1398
[104] Boengler K, Buechert A, Heinen Y, et al. Cardioprotection by ischemicpostconditioning is lost in aged and STAT3-deficient mice. Circ Res2008;102:131–135
[105] Ferdinandy P, Schulz R, Baxter GF. Interaction of cardiovascular riskfactors with myocardial ischemia/reperfusion injury, preconditioning,and postconditioning. Pharmacol Rev2007;59:418–458
[106] Iliodromitis EK, Zoga A, Vrettou A, et al. The effectiveness ofpostconditioning and preconditioning on infarct size in hypercholester-olemic and normal anesthetized rabbits. Atherosclerosis2006,188:356-362
[107] Kupai K, Csonka C, Fekete V, et al. Cholesterol diet-inducedhyperlipidemia impairs the cardioprotective effect of postconditioning:role of peroxynitrite. Am J Physiol Heart Circ Physiol2009;297:H1729–H1735
[108] Donato M, D’Annunzio V, Berg G, et al. Ischemic postconditioningreduces infarct size by activation of A1receptors and K+(ATP)channels in both normal and hypercholesterolemic rabbits. J CardiovascPharmacol2007,49:287-292
[109] Penna C, Tullio F, Moro F, et al. Effects of a protocol of ischemicpostconditioning and/or captopril in hearts of normotensive andhypertensive rats. Basic Res Cardiol2010,105:181-192
[110] Feng J, Fischer G, Lucchinetti E, et al. Infarct-remodeled myocardium isreceptive to protection by isoflurane postconditioning:role of proteinkinase B/Akt signaling. Anesthesiology2006;104:1004–1014
[111] Wagner C, Kloeting I, Strasser RH, et al. Cardioprotection bypostconditioning is lost in WOKW rats with metabolic syndrome: role ofglycogen synthase kinase3beta. J Cardiovasc Pharmacol2008;52:430–437
[112] Bouhidel O, Pons S, Souktani R, et al. Myocardial ischemicpostconditioning against ischemia/reperfusion is impaired in ob/ob mice.Am J Physiol Heart Circ Physiol2008;295: H1580–H1586
[113] Huhn R, Heinen A, Hollmann MW, et al. Cyclosporine A administeredduring reperfusion fails to restore cardioprotection in prediabetic Zuckerobese rats in vivo. Nutr Metab Cardiovasc Dis2009;10:1016
[114] Hoyte, L; Kaur, J; Buchan, A.M. Lost in translation: takingneuroprotection from animal models to clinical trials. Exp. Neurol,2004,188(2):200-204
[115] Zhao, H. The protective effect of ischemic postconditioning againstischemic injury: from the heart to the brain. J. Neuroimmune. Pharmacol,2007,2(4):313-318
[116] Wang, J.Y, Shen, J, Gao, Q, et al. Ischemic postconditioning protectsagainst global cerebral ischemia/reperfusion-induced injury in rats.Stroke,2008,39(3):983-990
[117] Scartabelli, T, Gerace, E, Landucci, E, et al. Neuroprotection by group ImGlu receptors in a rat hippocampal slice model of cerebral ischemia isassociated with the PI3K-Akt signaling pathway: a novel postcondi-tioning strategy? Neuropharmacology,2008,55(4):509-516
[118] Pignataro, G, Meller, R, Inoue, K, et al. In vivo and in vitrocharacterization of a novel neuroprotective strategy for stroke: ischemic,postconditioning. J. Cereb. Blood Flow Metab,2008,28(2):232-241
[119] Kitagawa, K, Matsumoto, M, Tagaya, M, et al.‘Ischemic tolerance’phenomenon found in the brain. Brain Res,1990,528(1):21-24
[120] Burda,J, Danielisova, V,Nemethova, M,et al. Delayed postconditioniginitiates additive mechanism necessary for survival of selectivelyvulnerable neurons after transient Ischemia in Rat Brain. Cellular andmolecular neurobiology.2006;26(7-8):1139-1149
[120] Ren, C; Gao, X; Niu, G; et al. Delayed postconditioning protects againstfocal ischemic brain injury in rats. PLoS One,2008,3(12):e3851
[121] Lee, J.J; Li, L; Jung, H.H; et al. Postconditioning with isoflurane reducedischemia-induced brain injury in rats.Anesthesiology,2008,108(6):1055-1062
[122] Leconte, C; Tixier, E; Freret, T; et al. Delayed hypoxic postconditioningprotects against cerebral ischemia in the mouse. Stroke,2009,40(10):3349-3355.
[123] Feng, Jianhua; Lucchinetti, Eliana; Ahuja, Preeti; et al. IsofluranePostconditioning Prevents Opening of the Mitochondrial PermeabilityTransition Pore through Inhibition of Glycogen Synthase Kinase3β.Anesthesiology.2005;103(5):987-995
[124] Perez-Pinzon, M.A. Mechanisms of neuroprotection during ischemicpreconditioning: lessons from anoxic tolerance. Comp.Biochem. Physiol.A. Mol. Integr. Physiol,2007,147(2):291-299.
[125] Oxman, T; Arad, M; Klein, R; et al. Limb ischemia preconditions theheart against reperfusion tachyarrhythmia. Am. J. Physiol,1997,273(4Pt2): H1707-1712
[126] Birnbaum, Y; Hale, S.L; Kloner, R.A. Ischemic preconditioning at adistance: reduction of myocardial infarct size by partial reduction ofblood supply combined with rapid stimulation of the gastrocnemiusmuscle in the rabbit. Circulation,1997,96(5):1641-1646
[127] Ren, C; Yan, Z; Wei, D; et al. Limb remote ischemic postconditioningprotects against focal ischemia in rats. Brain Res,2009,128(8):88-94
[128] Dietrich, W.D; Busto, R; Alonso, O; et al. Intraischemic but notpostischemic brain hypothermia protects chronically following globalforebrain ischemia in rats. J Cereb. Blood Flow Metab.,1993,13(4):541-549
[129] Halkos, M.E.; Kerendi, F.; Corvera, J.S.; et al. Myocardial protectionwith postconditioning is not enhanced by ischemic preconditioning. Ann.Thorac. Surg.,2004,78(3),961-969; discussion96
[130] Danielisova, V; Nemethova, M; Gottlieb, M; et al. The changes inendogenous antioxidant enzyme activity after postconditioning. Cell Mol.Neurobiol,2006,26(7):1181-1191
[131] Xing, B; Chen, H; Zhang, M; et al. Ischemic post-conditioning protectsbrain and reduces inflammation in a rat model of focal cerebralischemia/reperfusion.J. Neurochem,2008,105(5):1737-1745
[132] Casabona, G. Intracellular signal modulation: a pivotal role for proteinkinase C. Prog. Neuropsychopharmacol. Biol. Psychiatry,1997,21(3):407-425
[133] Wolfrum, S, Schneider, K,Heidbreder, M,et al. Remote preconditioningprotects the heart by activating myocardial PKCepsilon-isoform.Cardiovasc. Res.2002,55(3):583-589
[134] Schoemaker, R.G; van Heijningen, C.L. Bradykinin mediates cardiacpreconditioning at a distance. Am. J. Physiol. Heart Circ. Physiol,2000,278(5):H1571-1576
[135] Barone, F.C; White, R.F; Spera, P.A; et al. Ischemic preconditioning andbrain tolerance: temporal histological and functional outcomes, proteinsynthesis requirement, and interleukin-1receptor antagonist and earlygene expression. Stroke,1998,29(9):1937-1950
[136]叶燕丽,王辉云,王莲桂,黄丽惜,冯启胜.四氧嘧啶制作大鼠糖尿病模型--剂量探讨与方法改进,实验动物科学与管理,2001,18(2):54-55
[137]马常升,马文领,戴维国,等.插线法制备大鼠局灶性脑缺血再灌注模型的研究[J].解剖学杂志,1999,22:209-211
[138]曹秋云,潘旭东.线栓法大鼠大脑中动脉闭塞模型的研究进展[J].滨州医学院学报,2000,23:100-101
[139] Elsaesser RS, Zausinger S, Hungerhuber E, et al. A critical reevaluationof the intraluminal thread model of focal cerebral ischemia. Evidence ofinadvertent premature reperfusion and subarachnoid hemorrhage in ratsby Laser-Doppler Flowmetry[J]. Stroke,1998;29:2162-2170
[140] Keman WN，Inzueehi SE. Type2diabetes mellitus and insulin resistance:Stroke Prevention and management. Curr Treat Options Neurol，2004;6(6):443-450
[141] Cavallini A,Micieli G,Marcheselli S,et a1.Role of monitoring inmanagement of acute ischemic stroke patients[J].Stroke,2003;34(11):2599-2603
[142] Li PA,Shuaib A,Miyashita H,et al. Hyperglycemia enhances extracellularglutamate accumulation in rats subjected to forebrain ischemia[J]· Stroke,2000,31(1):183-192
[143] Zhao JL, Yang YJ, You SJ. Different effects of postconditioning onmyocardial no-reflow in the normal and hypercholesterolemic mini-swines. Microvasc. Res.2007;73:137-142
[144] Hausenloy DJ, Tsang A, Yellon D.M. Postconditioning does not protectthe diabetic heart. J. Mol. Cell. Cardiol.2006;40:958
[145] Youqing Hu, Gladys Block, Edward P Norkus, et al. Relations ofglycemic index and glycemic load with plasma oxidative stressmarkers[J]. Am.J.clinical Nutrition,2006;84(1):70-76
[146] Sophie Richier, Paola Furla, Amandine Plantivaux, et al. Symbiosis-induced adaptation to oxidative stress[J].J.Exp.Biol,2005;208(2):277-285