α-硫辛酸抗大鼠心肌缺血再灌注损伤中的保护作用及其机制的研究
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摘要
背景：
近年来心血管系统疾病特别是冠心病的发病率逐年攀升，严重的危害了人类健康。一旦出现冠状动脉阻塞，其首要的治疗措施即为及时恢复其血供，改善心肌血液灌注。但心肌缺血再次恢复血液供应后常常会出现缺血再灌注（I/R）损伤，即恢复血供后出现心肌梗死面积增大、发生心室颤动等恶性心律失常、心脏收缩功能降低等心肌受损现象。目前认为心肌的缺血再灌注损伤多与再灌注后氧自由基的增加、心肌细胞的凋亡、钙离子超载、炎性介质浸润等因素相关。α-硫辛酸（LA）是一种在蔬菜及肉类中发现的万能抗氧化剂，是同时具有脂溶性及水溶性的抗氧化剂，可清除体内自由基、螯合金属离子等。目前已有相关研究表明LA在治疗氧化应激相关疾病方面有明显的作用，而针对LA对心肌缺血再灌注损伤后心肌的保护作用方面的研究也在进展中，但其具体保护效果及作用机制仍不清楚。因此，通过构建大鼠心肌缺血再灌注损伤研究LA对灌注后心肌的保护作用及其作用机制对于充分认识LA有深远的意义。
目的：
（1）明确LA是否在大鼠心肌I/R损伤中起到了保护性作用；
（2）明确LA在大鼠心肌I/R损伤后是否通过抗氧化、抗炎等途径减少心肌损伤；
（3）明确PI3K/Akt/Nrf2信号通路是否在LA对抗心肌I/R损伤中起到信号转导的作用。
方法：
（1）选取成年雄性Sprague-Dawley（SD）大鼠随机分为假手术组（sham I/R）、I/R损伤+盐水对照组（I/R+V）、I/R损伤+LA组（I/R+LA）、I/R损伤+LA+wortmannin组（I/R+LA+W）。LA给药量为15mg/kg，在进行心肌缺血手术前30分钟通过大鼠尾静脉给药。Wortmannin为PI3K通路阻滞剂给药量为15ug/kg，在给予LA前5分钟通过大鼠尾静脉给药。大鼠麻醉后切断左侧第4肋骨，暴露心脏，选择性结扎冠状动脉左前降支，进行缺血30分钟，打开结扎线进行再灌注，进行各项检测。
（2）再灌注后3小时后提取血清进行乳酸脱氢酶（LDH）及肌酸激酶（CK）的活性检测；提取心肌左室缺血组织，通过末端脱氧核苷基转移酶介导的dUTP原位末端标记法（TUNEL）及DAPI细胞核染色测定心肌细胞凋亡指数（AI）及Caspase-3凋亡蛋白的活性。检测心肌组织及血浆中血清髓过氧化物酶（MPO）及肿瘤坏死因子-α（TNF-α）的活性。
（3）灌注24小时后取心肌组织标本通过伊文氏蓝-TTC染色法测定心肌梗死面积。
（4）灌注72小时后通过M型超声测定大鼠左室收缩末、舒张末容积及左室射血分数。
（5）通过免疫印迹技术检测心肌组织中Akt、iNOS含量及磷酸化水平，测定HO-1、Nrf2、p38-MAPK、NOx等蛋白成分的水平。
结果：
（1）与对照组相比，LA减少再灌注3小时后血清中CK及LDH含量，两组之间有非常显著差异（P<0.01）；给予PI3K通路阻滞剂Wortmannin后，CK及LDH较LA组均升高，差异有显著性（P<0.05）。其次，与对照组相比，LA组心肌梗死区大小（P<0.01）、凋亡指数（P<0.01）、Caspase-3活性均明显降低（P<0.05）；LA组大鼠心脏收缩功能上比生理盐水组明显升高，其左室射血分数高于其他各组（P<0.05），提示LA对I/R损伤后的心肌组织起到了明显的保护作用。而PI3K通路阻滞剂Wortmannin组的保护效果均被所阻断。
（2） LA组大鼠I/R损伤后局部及全身炎症反应明显减轻，MPO及血清、心肌组此作用被明显抑制。
（3） LA组大鼠心肌组织中p38-MAPK、NOx、iNOS等的水平与盐水组相比无明显差异，提示其可能未介导LA的心肌保护作用。
（4） LA组大鼠心肌组织磷酸化程度增加，Akt、核Nrf2及HO-1含量均增加（P<0.05），且此作用可被PI3K通路阻滞剂Wortmannin所阻断，提示PI3K/Akt/Nrf2通路在心肌I/R损伤后的心肌保护中起到了重要作用。
结论：
（1） LA可明显减轻大鼠I/R损伤后的心肌细胞及全身炎症反应，有效减轻再灌注后的氧化应激，提高了大鼠心肌对抗I/R损伤的能力。
（2）研究证实LA可明显减轻大鼠I/R损伤后心肌梗死面积，减少心肌细胞凋亡，改善心肌收缩功能，明显减轻了心肌细胞缺血再灌注后的损伤。
（3）本研究首次发现LA增加了心肌细胞中Akt、核Nrf2及HO-1的表达，且其作用可被PI3K通路阻滞剂Wortmannin所阻断，说明PI3K/Akt/Nrf2通路在LA对I/R损伤后心肌的保护作用中起到了重要作用。
Objective
In recent years, cardiovascular diseases, especially coronary heart disease, increasedwhich serious harm to human health. When the coronary arteries blocked, the primarytreatment shall be restore its blood supply, to improve myocardial blood perfusion. Thereperfusion could make the ischemia/reperfusion injury happen, which could increase theinfarct size, cause the malignant arrhythmias and reduce the heart function. Now, weconsidered that the ischemia/reperfusion injury likely associated with oxygen free radicalsincreases, apoptosis of myocardial cells, calcium overload, infiltration of inflammatorymediators and other relevant factors. Alpha-lipoic acid(LA) is a kind of universalantioxidant which found in vegetables and meat. It can reduce the free radicals, chelatingmetal ions. There are some studies shown that LA plays an obvious role in the treatment ofsome oxidative stress-related disease. And the studies of LA’s protective effects onmyocardial ischemia/reperfusion injury are in progress. The present study attempted toinvestigate the protection effects and its underlying mechanism of LA on myocardialischemia/reperfusion injury.
Methods
1. Adult male Sprague-Dawley (SD) rats, weight220to250g were randomly dividedinto the following groups (n=10):(1) sham operation group (sham I/R);(2)I/R+vehicle group (I/R+V);(3)I/R+a-Lipoic acid group (I/R+LA); and (4) a-Lipoicacid+I/R+wortmannin group (I/R+LA+W). LA (99%, Sigma, USA,15mg/kg) wasgiven by tail vein injection30min before ischemia. Wortmannin (Sigma, USA,15mg/kg) was injected via tail vein5min before LA injection. The MI/R animal modelwas constructed by left anterior descending coronary artery (LAD) ligation.
2. After3h of reperfusion, myocardial cellular damage was evaluated by measuringlactate dehydrogenase (LDH) and creatinine kinase (CK) activity in plasma.Myocardial apoptosis was determined by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling(TUNEL) staining and caspase-3activity. And after3h of reperfusion, myocardial samples were taken from the AARzones for MPO activity analysis and TNF-a level measurement.
3. After24h of reperfusion, myocardial infarct size was evaluated by Evans Blue andTTC staining.
4. After72h of reperfusion, left ventricular end-systolic volume (LVESV), leftventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction(LVEF) were calculated by M-mode echocardiography.
5. The expression and activation of HO-1, Nrf2, iNOS, Akt, phospho-Akt (Ser-473),p38-MAPK, phospho-p38-MAPK, eNOS, phosphoeNOS, were extracted from themyocardium after3h or24h of reperfusion by western blot.
Results
Our results reveal that LA administration significantly reduced LDH and CK release(P<0.01), attenuated myocardial infarct size(P<0.01), decreased cardiomyocytesapoptosis(P<0.01), and partially preserved heart function(P<0.05). Western blot analysisshowed that LA pretreatment up-regulated Akt phosphorylation and Nrf2nucleartranslocation while producing no impact on p38MAPK activation or nitric oxide (NO)production. LA pretreatment also increased expression of HO-1, a major target of Nrf2. LA treatment inhibited neutrophil accumulation and release of TNF-a. Moreover, PI3Kinhibition abolished the beneficial effects of LA.
Conclusions
This study indicates that LA attenuates cardiac dysfunction by reducingcardiomyoctyes necrosis, apoptosis and inflammation after MI/R. LA exerts its action byactivating the PI3K/Akt pathway as well as subsequent Nrf2nuclear translocation andinduction of cytoprotective genes such as HO-1.
近年来心血管系统疾病特别是冠心病的发病率逐年攀升，严重的危害了人类健康。一旦出现冠状动脉阻塞，其首要的治疗措施即为及时恢复其血供，改善心肌血液灌注。但心肌缺血再次恢复血液供应后常常会出现缺血再灌注（I/R）损伤，即恢复血供后出现心肌梗死面积增大、发生心室颤动等恶性心律失常、心脏收缩功能降低等心肌受损现象。目前认为心肌的缺血再灌注损伤多与再灌注后氧自由基的增加、心肌细胞的凋亡、钙离子超载、炎性介质浸润等因素相关。α-硫辛酸（LA）是一种在蔬菜及肉类中发现的万能抗氧化剂，是同时具有脂溶性及水溶性的抗氧化剂，可清除体内自由基、螯合金属离子等。目前已有相关研究表明LA在治疗氧化应激相关疾病方面有明显的作用，而针对LA对心肌缺血再灌注损伤后心肌的保护作用方面的研究也在进展中，但其具体保护效果及作用机制仍不清楚。因此，通过构建大鼠心肌缺血再灌注损伤研究LA对灌注后心肌的保护作用及其作用机制对于充分认识LA有深远的意义。
目的：
（1）明确LA是否在大鼠心肌I/R损伤中起到了保护性作用；
（2）明确LA在大鼠心肌I/R损伤后是否通过抗氧化、抗炎等途径减少心肌损伤；
（3）明确PI3K/Akt/Nrf2信号通路是否在LA对抗心肌I/R损伤中起到信号转导的作用。
方法：
（1）选取成年雄性Sprague-Dawley（SD）大鼠随机分为假手术组（sham I/R）、I/R损伤+盐水对照组（I/R+V）、I/R损伤+LA组（I/R+LA）、I/R损伤+LA+wortmannin组（I/R+LA+W）。LA给药量为15mg/kg，在进行心肌缺血手术前30分钟通过大鼠尾静脉给药。Wortmannin为PI3K通路阻滞剂给药量为15ug/kg，在给予LA前5分钟通过大鼠尾静脉给药。大鼠麻醉后切断左侧第4肋骨，暴露心脏，选择性结扎冠状动脉左前降支，进行缺血30分钟，打开结扎线进行再灌注，进行各项检测。
（2）再灌注后3小时后提取血清进行乳酸脱氢酶（LDH）及肌酸激酶（CK）的活性检测；提取心肌左室缺血组织，通过末端脱氧核苷基转移酶介导的dUTP原位末端标记法（TUNEL）及DAPI细胞核染色测定心肌细胞凋亡指数（AI）及Caspase-3凋亡蛋白的活性。检测心肌组织及血浆中血清髓过氧化物酶（MPO）及肿瘤坏死因子-α（TNF-α）的活性。
（3）灌注24小时后取心肌组织标本通过伊文氏蓝-TTC染色法测定心肌梗死面积。
（4）灌注72小时后通过M型超声测定大鼠左室收缩末、舒张末容积及左室射血分数。
（5）通过免疫印迹技术检测心肌组织中Akt、iNOS含量及磷酸化水平，测定HO-1、Nrf2、p38-MAPK、NOx等蛋白成分的水平。
结果：
（1）与对照组相比，LA减少再灌注3小时后血清中CK及LDH含量，两组之间有非常显著差异（P<0.01）；给予PI3K通路阻滞剂Wortmannin后，CK及LDH较LA组均升高，差异有显著性（P<0.05）。其次，与对照组相比，LA组心肌梗死区大小（P<0.01）、凋亡指数（P<0.01）、Caspase-3活性均明显降低（P<0.05）；LA组大鼠心脏收缩功能上比生理盐水组明显升高，其左室射血分数高于其他各组（P<0.05），提示LA对I/R损伤后的心肌组织起到了明显的保护作用。而PI3K通路阻滞剂Wortmannin组的保护效果均被所阻断。
（2） LA组大鼠I/R损伤后局部及全身炎症反应明显减轻，MPO及血清、心肌组此作用被明显抑制。
（3） LA组大鼠心肌组织中p38-MAPK、NOx、iNOS等的水平与盐水组相比无明显差异，提示其可能未介导LA的心肌保护作用。
（4） LA组大鼠心肌组织磷酸化程度增加，Akt、核Nrf2及HO-1含量均增加（P<0.05），且此作用可被PI3K通路阻滞剂Wortmannin所阻断，提示PI3K/Akt/Nrf2通路在心肌I/R损伤后的心肌保护中起到了重要作用。
结论：
（1） LA可明显减轻大鼠I/R损伤后的心肌细胞及全身炎症反应，有效减轻再灌注后的氧化应激，提高了大鼠心肌对抗I/R损伤的能力。
（2）研究证实LA可明显减轻大鼠I/R损伤后心肌梗死面积，减少心肌细胞凋亡，改善心肌收缩功能，明显减轻了心肌细胞缺血再灌注后的损伤。
（3）本研究首次发现LA增加了心肌细胞中Akt、核Nrf2及HO-1的表达，且其作用可被PI3K通路阻滞剂Wortmannin所阻断，说明PI3K/Akt/Nrf2通路在LA对I/R损伤后心肌的保护作用中起到了重要作用。
Objective
In recent years, cardiovascular diseases, especially coronary heart disease, increasedwhich serious harm to human health. When the coronary arteries blocked, the primarytreatment shall be restore its blood supply, to improve myocardial blood perfusion. Thereperfusion could make the ischemia/reperfusion injury happen, which could increase theinfarct size, cause the malignant arrhythmias and reduce the heart function. Now, weconsidered that the ischemia/reperfusion injury likely associated with oxygen free radicalsincreases, apoptosis of myocardial cells, calcium overload, infiltration of inflammatorymediators and other relevant factors. Alpha-lipoic acid(LA) is a kind of universalantioxidant which found in vegetables and meat. It can reduce the free radicals, chelatingmetal ions. There are some studies shown that LA plays an obvious role in the treatment ofsome oxidative stress-related disease. And the studies of LA’s protective effects onmyocardial ischemia/reperfusion injury are in progress. The present study attempted toinvestigate the protection effects and its underlying mechanism of LA on myocardialischemia/reperfusion injury.
Methods
1. Adult male Sprague-Dawley (SD) rats, weight220to250g were randomly dividedinto the following groups (n=10):(1) sham operation group (sham I/R);(2)I/R+vehicle group (I/R+V);(3)I/R+a-Lipoic acid group (I/R+LA); and (4) a-Lipoicacid+I/R+wortmannin group (I/R+LA+W). LA (99%, Sigma, USA,15mg/kg) wasgiven by tail vein injection30min before ischemia. Wortmannin (Sigma, USA,15mg/kg) was injected via tail vein5min before LA injection. The MI/R animal modelwas constructed by left anterior descending coronary artery (LAD) ligation.
2. After3h of reperfusion, myocardial cellular damage was evaluated by measuringlactate dehydrogenase (LDH) and creatinine kinase (CK) activity in plasma.Myocardial apoptosis was determined by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling(TUNEL) staining and caspase-3activity. And after3h of reperfusion, myocardial samples were taken from the AARzones for MPO activity analysis and TNF-a level measurement.
3. After24h of reperfusion, myocardial infarct size was evaluated by Evans Blue andTTC staining.
4. After72h of reperfusion, left ventricular end-systolic volume (LVESV), leftventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction(LVEF) were calculated by M-mode echocardiography.
5. The expression and activation of HO-1, Nrf2, iNOS, Akt, phospho-Akt (Ser-473),p38-MAPK, phospho-p38-MAPK, eNOS, phosphoeNOS, were extracted from themyocardium after3h or24h of reperfusion by western blot.
Results
Our results reveal that LA administration significantly reduced LDH and CK release(P<0.01), attenuated myocardial infarct size(P<0.01), decreased cardiomyocytesapoptosis(P<0.01), and partially preserved heart function(P<0.05). Western blot analysisshowed that LA pretreatment up-regulated Akt phosphorylation and Nrf2nucleartranslocation while producing no impact on p38MAPK activation or nitric oxide (NO)production. LA pretreatment also increased expression of HO-1, a major target of Nrf2. LA treatment inhibited neutrophil accumulation and release of TNF-a. Moreover, PI3Kinhibition abolished the beneficial effects of LA.
Conclusions
This study indicates that LA attenuates cardiac dysfunction by reducingcardiomyoctyes necrosis, apoptosis and inflammation after MI/R. LA exerts its action byactivating the PI3K/Akt pathway as well as subsequent Nrf2nuclear translocation andinduction of cytoprotective genes such as HO-1.
引文
[1]. Topol EJ, O’Neill WW, Langburd AB, Walton JAJr, Bourdillon PD, Bates ER, GrinesCL, Schork AM, Kline E, Pitt B. A randomized, placebo-controlled trial ofintravenous recombinant tissue-type plasminogen activator and emergency coronaryangioplasty in patients with acute myocardial infarction. Circulation198775:420–428.
[2]. Skyschally A, van Caster P, Boengler K, Gres P, Musiolik J, Schilawa D, Schulz R,Heusch G. Ischemic post-conditioning in pigs: no causal role for RISK activation.Circ Res2009104:15–18.
[3]. Castedo E,Segovia J,Escudero C,et a1.Ischemia-reperfusion injury duringexperimental heart transplantation. Evaluation of trimetazidine's cytoprotectiveeffect[J].Rev Esp Cardiol.2005,58(8):941-950.
[4]. Turer AT, Hill JA. Pathogenesis of myocardial ischemia-reperfusion injury andrationale for therapy. Am J Cardiol.2010;106:360–8.
[5]. Derek M, Yellon DS. Myocardial Reperfusion Injury[J]. N Engl J Med,2007,357:1121-1135.
[6]. Fedinandy P, Schulz R, Baxter GF. Interaction of cardiovascular risk factors withmyocardial ischemia/reperfusion injury, preconditioning and post conditioning[J].Pharmacol Rev,2007,59:418-458.
[7]. Gorczyca W, Melamed MR, Darzynkiewicz Z. Programmed death ofcell(apoptosis)[J]. Patol Pol,1993,44(3):113-119.
[8]. Levi AJ, Dalton GR, Hancox JC. Role of intracellular sodium overload in the genesisof cardiac arrhythmias[J]. J Cardiovasc Electrophysiol,1997,8(6):700-721.
[9]. Turer A T, Hilll JA. Pathogenesis of Myocardial Ischemia-Reperfusion Injury andRationale for Therapy. The American Journal of Cardiology2010(106):360-368.
[10]. Holmqist L, Stubury G, Berbaum K. Lipoic acid as a novel treatment for Azheimer’sdisease and related dementias [J]. Pharmacol Ther,2007,113(1):154-157.
[11]. Ghibu S, Richard C, Delemasure Sl. An endogenous dithiol with antioxidantproperties: alpha lipoic acid. potential uses in cardiovascular diseases [J].AnnCardiol Anreiol (Paris),2008,57(3):161-165.
[12]. Pari L, Murugavel P. Protective effect of alpha-lipoic acid againstchloroquine-induced hepatotoxicity in rats [J]. J Appl Toxicol2004,24(1):21-26.
[13]. Smfh AR，Shenvi SV，Widlansky M．Lipoic acid as a potential therapy for chronicdisease associated with oxidative stress[J]．Current Medicinal Chemist，2004，11(9)：1135-1146.
[14]. Packer L, Witt EH, Tritschler HJ. alpha-Lipoic acid as a biological antioxidant. FreeRadic Biol Med1995;19:227–50.
[15]. Sola S, Mir MQ, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S, KhanBV. Irbesartan and lipoic acid improve endothelial function and reduce markers ofinflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid inEndothelial Dysfunction (ISLAND) study. Circulation2005;111:343–8.
[16]. Ikeda U, Ito T, Shimada K. Interleukin-6and acute coronary syndrome. Clin Cardiol2001;24:701–4.
[17]. Zweier JL, Talukder M AH.The role of oxidants and free radicals in reperfusioninjury. Cardiovascular Research2006(70):181-190.
[18]. Moens AL, Claeys M J, Timmemmans JP, Vrints CJ. Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiologicalprocess.International Journal of Cardiology2005(100):179-190.
[19]. Trujillo M, Radi R. Peroxynitrite react ionwith the reduced and the oxdized forms oflipoic acid: New insight into the reaction of peroxynitrite with thiols[J]. ArchBiochem Biophys,2002,397(1):91-98.
[20]. Navar Izzo F, Quartacci MF, Sgherri C. Lipoic acid: a unique antiox-idant in thedetoxification of activated oxygen species[J]. Plant Physiol Biochem,2002,40:463-470.
[21]. Schabbauer G, Tencati M, Pedersen B, Pawlinski R, Mackman N.ArteriosclerThromb Vasc Biol2004(24):1963–1969.
[22]. Williams DL, Li C, Ha T, Ozment-Skelton T, Kalbfleisch JH, Preiszner J, Brooks L,Breuel K, Schweitzer JB.J Immunol2004(172):449–456.
[23]. Rajaram MV, Ganesan LP, Parsa KV, Butchar JP, Gunn JS, Tridandapani S JImmunol2006(177):6317–6324.
[24]. Matsuda N, Hayashi Y, Takahashi Y, Hattori Y J Pharmacol Exp Ther(2006)319:1348–1354.
[25]. D. Ramzy, V. R.D. Weisel. Clinical applicability of preconditioning andpostconditioning:the cardiothoracic surgeons’s view, Cardiovascular research2006(70)174-180.
[26]. P. Saikumar, Z. Dong, V. Mikhailov, M. Denton, JM. Weinberg, M.A. Venkatachalam,Apoptosis: definition, mechanisms, and relevance to disease, The American journalof medicine1999(107):489-506.
[27]. Chen AF,Chen DD,Daiber A,et a1.Free radical biology of the cardiovascularsystem[J].Clin Sci (Lond),2012,123(2):73-91.
[28]. Valko M,Leibf r it z D,Moncol J,et a1.Free radicals and antioxidants in normalphysiological functions and human disease [J].Int J Biochem Cell Biol,2007,39(1):44-84.
[29]. Dr ge W.Free radicals in the physiological control of cell function[J].Physiol Rev,2002,82(1):47-95.
[30]. Guha M, Mackman N. The phosphate dylinositol3-kinase-Akt pathway limitslipopolysaccharide activation of signaling pathways and expression of inflammatorymediators in human monocytic cells. J Biol Chem.2002(277):32124-32132.
[31]. Arslan F,de Kleijn DP,Timmers L,et a1.Bridging innate immunity and myocardialischemia/reperfusion injury: the search for therapeutic targets[J].Curr Pharm Des,2008,14(12):1205-1216.
[32]. Sjaastad I, Bentzen JG, Semb SO. Reduced calcium tolerance in rat cardiomyocytesafter myocardial infarction [J].Acta Physiol Scand,2002,175(4):261-269.
[33]. Levi AJ,Dalton GR,Hancox JC,et a1. Role of intracellular sodium overload in thegenesis of cardiac arrhythmias[J].J Cardiovasc Electrophysiol,1997,8(6):700-721.
[34]. Gorczyca W, Melamed MR, Darzynkiewicz Z. Programmed death of cells (apoptosis)[J].Patol Pol,1993,44(3):113-119.
[35]. Saikummar P, Dong Z, Mikhailov V, Denton M, Weinberg JM, Venkatachalam MA.Apoptosis: definition, mechanisms, and Relevance to disease. Am J Med1999;107(5):489-506.
[36]. Orrenius S. Apoptosis: molecular mechanisms and implications for human disease. JInter Med1995;237(6):529-536.
[37]. J.F. Kerr, A.H. Wylllie, A.R. Currie. Apoptosis: a basic biological phenomenon withwide-ranging implications in tissue kinetics. British journal of cancer1972(26):239-257.
[38]. Fliss H, Gattinger D. Apoptosis in ischemic and reperfused rat myocardium. Cric Res1996;79(5):949-956.
[39]. Gottieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injuryinduces apoptosis in rabbit cardiomyocytes. J Clin Invest1994;94(4):1621-1628.
[40]. Tomei LD, Umansky SR. Apoptosis and the heart: a brief review. Ann N Y Acad Sci2001;946:160-168.
[41]. Abbate A, Biondi-Zoccai GG, Baldi A. pathophysiologic role of myocardialapoptosis in post-infarction left ventricular remodeling. J Cell Physiol2002;193(2):145-153.
[42]. Z.Q. Zhao, J. Vinten-Johansen. Myocardial apoptosis and ischemic preconditioning,Cardiovascular research2002;55:438-455.
[43]. Heineke J, Kempf T et al. Down regulation of cytoskeletal muscle LIM protein bynitric oxide: impact on cardiac myocyte hypertrophy. Circulation2003;107(10)1424-1432.
[44]. Hamnstetter A, Izumo S. Future perspectives and potential implications of cardiacmyocyte apoptosis. Cardiovasc Res2000;45(3):795-810.
[45].Yaoita H, Ogawa K, Maechara K, Maruyama Y. Apoptosis in relevant clinicalsituations: contribution of apoptosis in myocardial infarction. Cardiovasc Res2000;45(3):630-641.
[46]. E. Farber, Programmed cell death: necrosis versus apoptosis, Mod Pathol1994(7)605-609.
[47]. N. Joza, G. Kroemer, J.M. Penninger. Genetic analysis of the mammalian cell deathmachinery. Trends Genet2002(18)142-149.
[48]. Reed LJ, DeBusk BG, Gansalus IC, Hornberger Jr CS: Crystallineα-lipoic acid: acatalytic agent associated with pyruvate dehydrogenase. Ciences,1951,114,93–94.
[49]. Carreau JP: Biosynthesis of lipoic acid via unsaturatedfatty acids. Meth Enzymol,1979,62,152–158.
[50]. Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM. Lipoic acid as a otentialtherapy for chronic diseases associated with oxidative stress. Curr Med Chem2004;11:1135–46.
[51]. Scott BC, Aruoma OI, Evans PJ, O’Neill C, Van der Vliet A, Cross CE, Tritschler H,Halliwell B. Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation.Free Radic Res1994;20:119–33.
[52]. Devasagayam TP, Subramanian M, Pradhan DS, Sies H. Prevention of singletoxygen-induced DNA damage by lipoate. Chem Biol Interact1993;86:79–92.
[53]. Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, AmesBN. Memory loss in old rats is associated with brain mitochondrial decay andRNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha-lipoic acid. Proc Natl Acad Sci U S A2002;99:2356–61.
[54]. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM. Decline intranscriptional activity of Nrf2causes age-related loss of glutathione synthesis, whichis reversible with lipoic acid. Proc Natl Acad Sci U S A2004;101:3381–6.
[55]. Lodge JK, Traber MG, Packer L. Thiol chelation of Cu2+by dihydrolipoic acidprevents human low density lipoprotein peroxidation. Free Radic Biol Med1998;25:287–97.
[56]. Anuradha B, Varalakshmi P. Protective role of DL-alpha-lipoic acid againstmercury-induced neural lipid peroxidation. Pharmacol Res1999;39:67–80.
[57]. Han D, Sen CK, Roy S, Kobayashi MS, Tritschler HJ, Packer L. Protection againstglutamate-induced cytotoxicity in C6glial cells by thiol antioxidants. Am J Physiol1997;273:R1771–8.
[58]. Cremer DR, Rabeler R, Roberts A, Lynch B.: Safety evaluation of alpha-lipoic acid(ALA). Regul Toxicol Pharmacol,2006,46,29–41.
[59]. Miadokova E, Vlckova V, Duhova V: Antimutagenic effect of alpha-lipoic acid onthree model test systems. Pharmazie,2000,55,862–863.
[60]. Novotny L, Rauko P, Cojocel C:α-Lipoic acid–the potential for use in cancertherapy. Neoplasma,2008,55,81–86.
[61]. Packer L,Witt EH, Tritschler HJ:α-Lipoic acid as a biological antioxidant. Free RadicBiol Med,1995,19,227–250.
[62]. Bast A, Haenen GR: Lipoic acid: a multifunctional antioxidant. Biofactors,2003,17,207–213.
[63]. Biewenga G, Haenen G, Bast A: The pharmacology of the antioxidant lipoic acid.Gen Pharmacol,1997,29,315–331.
[64]. Bilska A, W3odek L: Lipoic acid-the drug of the future. Pharmacol Rep,2005,57,570–577.
[65]. Ghibu S, Richard C, Vergely C, Zeller M, Cottin Y, Rochette L: Antioxidantproperties of an endogenous thiol: Alpha-lipoic acid, useful in the prevention ofcardiovascular diseases. J Cardiovasc Pharmacol,2009,54,391–398.
[66]. Bitar MS, Ayed AK, Abdel-Halim SM, Isenovic ER, Al-Mulla F: Inflammation andapoptosis in aortic tissues of aged type II diabetes: amelioration withα-lipoic acidthrough phosphatidylinositol3-kinase/Akt-dependent mechanism. Life Sci,2010,86,844–853.
[67]. Gorca A, As3anowicz-Antkowiak K: Prophylaxis with alpha-lipoic acid againstlipopolisaccharide-induced brain injury in rats. Arch Immunol Ther Exp (Warsz),2009,57,141–146.
[68]. Gorca A, Piechota A, Huk-Kolega H: Effect of alphalipoic acid on LPS-inducedoxidative stress in the heart. J Physiol Pharmacol,2009,60,61–68.
[69]. Skibska B, Józefowicz-Okonkwo G, Gor1ca A: Protective effects of earlyadministration of alpha-lipoic acid against lipopolysaccharide-induced plasma lipidperoxidation. Pharmacol Rep,2006,58,399–404.
[70]. Suzuki YJ, Aggarwal BB, Packer L: Alpha-lipoic acid is a potent inhibitor ofNF-kappa B activation in human T cells. Biochem Biophys Res Commun,1992,189,1709–1715.
[71]. Yan LJ, Traber MG, Kobuchi H, Matsugo S, Tritscher HJ, Packer L: Efficacy ofhypochlorous acid scavengers in the prevention of protein carbonyl formation. ArchBiochem Biophys,1996,327,330–334.
[72]. Valko M, Morris H, Cronin MT: Metals, toxicity and oxidative stress. Curr MedChem,2005,12,1161–1208.
[73]. Doraiswamy PM, Finefrock AE: Metals in our minds: therapeutic implications forneurodegenerative disorders. Lance Neurol,2004,3,431–434.
[74]. Goralska M, Dackor R, Holley B, McGahan MC. Alpha lipoic acid changes ironuptake and storage in lens epithelial cells. Exp Eye Res2003;76:241–8.
[75]. Suh JH, Moreau R, Heath SH, Hagen TM. Dietary supplementation with(R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion ofantioxidants in the rat cerebral cortex. Redox Rep2005;10:52–60.
[76]. Baldwin AS Jr: NFκB and ILB proteins: new discoveries and insights. Annu RevImmunol,1996,14,649–681.
[77]. Hofmann MA, Schiekofer S, Kanitz M, Klevesath MS, Joswig M, Lee V, Morcos M:Insufficient glycemic control increases nuclear factor kappa B binding activity inperipheral blood mononuclear cells isolated from patients with type1diabetes.Diabetes Care,1998,21,1310–1316.
[78]. Kim HJ, Chang EJ, Kim HM, Lee SB, Kim HD, Kim GS, Kim HH:Antioxidantα-lipoic acid inhibits osteoclast differentiation by reducing nuclearfactorκB DNA binding and prevents in vivo bone resorption induced by receptoractivator of nuclear factorκB ligand and tumor necrosis factorα. Free Radic Biol Med,2006,40,1483–1493.
[79]. Kim HY, Or Y, Kim M, Yokozawa T: Protective effect of lipoic acid againstmethylglyoxal-induced oxidative stress in LLC-PK1cells. J Nutr Sci Vitaminol,2008,54,99–104.
[80]. Suzuki YJ, Tsachya M, Packer L: Thioctic acid and dihydrolipoic acid are novelantioxidants which interact with reactive oxygen species. Free Radic Res Commun,1991,15,255–263.
[81]. Ying Z, Kherada N, Farrar B, Kampfrath T, Chung Y, Simonetti O, Deiuliis J et al.:Lipoic acid effects on established atherosclerosis. Life Sci,2010,86,95–102.
[82]. Suzuki YJ, Tsachya M, Packer L: Thioctic acid and dihydrolipoic acid are novelantioxidants which interact with reactive oxygen species. Free Radic Res Commun,1991,15,255–263.
[83]. Vig-Varga E, Benson EA, Limbil TL, Allison BM, Goebl MG, Harrington MA:Alpha-lipoic acid modulates ovarian surface epithelial cell growth. Gynecol Oncol,2006,103,45–52.
[84]. Zhang WJ, Frei B:α-Lipoic acid inhibits TNF-αinduced NFκB activation andadhesion molecule expression in human aortic endothelial cells. FASEB J,2001,15,2423–2432.
[85]. Kim HS, Kim HJ, Park KG, Kim YN, Kwon TK, Park JY:α-Lipoic acid inhibitsmatrix metalloproteinase-9expression by inhibiting NFκB transcriptionalactivity.Exp Mol Med,2007,39,106–113.
[86]. Holmquist L, Stuchbury G, Berbaun K: Lipoic acid as a novel treatment forAlzheimer’s disease and related dementias. Pharmacol Ther,2007,113,154–164.
[87]. Kilic F, Handelman GJ, Traber K, Tsang K, Packer L, Trevithick JR. Modellingcortical cataractogenesis XX. In vitro effect of alpha-lipoic acid on glutathioneconcentrations in lens in model diabetic cataractogenesis. Biochem Mol Biol Int1998;46:585–95.
[88]. Wolz P, Krieglstein J. Neuroprotective effects of alpha-lipoic acid and itsenantiomers demonstrated in rodent models of focal cerebral ischemia.Neuropharmacology1996;35:369–75.
[89]. Biewenga GP, Dorstijn MA, Verhagen JV, Haenen GR, Bast A. Reduction of lipoicacid by lipoamide dehydrogenase. Biochem Pharmacol1996;51:233–8.
[90]. Hagen TM, Vinarsky V, Wehr CM, Ames BN.(R)-alpha-lipoic acid reverses theage-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxideboth in vitro and in vivo. Antioxid Redox Signal2000;2:473–83.
[91]. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM. Decline intranscriptional activity of Nrf2causes age-related loss of glutathione synthesis, whichis reversible with lipoic acid. Proc Natl Acad Sci U S A2004;101:3381–6.
[92]. Moini H, Tirosh O, Park YC, Cho KJ, Packer L. R-alpha-lipoic acid action on cellredox status, the insulin receptor, and glucose uptake in3T3-L1adipocytes. ArchBiochem Biophys2002;397:384–91.
[93]. Beckman MA, Creager P, Libby P: Diabetes and atherosclerosis: epidemiology,pathophysiology, and management. J Am Med Assoc,2002,287,2570–2581.
[94]. Clavreul N, Bachschmid MM, Hou X, Shi C, Idrizovic A, Ido Y, Pimentel D et al.:S-glutathiolation of p21ras by peroxynitrite mediates endothelial insulin resistancecaused by oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol,2006,26,2454–2461.
[95]. Andreozzi F, Laratta E, Sciacqua A, Perticone F, Sesti G: Angiotensin II impairs theinsulin signaling pathway promoting production of nitric oxide by inducingphosphorylation of insulin receptor substrate-1on Ser312and Ser616in humanumbilical vein endothelial cells. Circ Res,2004,94,1211–1218.
[96]. Eason RC, Archer HE, Akhtar S, Bailey CJ: Lipoic acid increases glucose uptake byskeletal muscles of obesediabetic ob/ob mice. Diabetes Obes Metab,2002,4,29–35.
[97]. Ghibu S, Richard C, Vergely C, Zeller M, Cottin Y, Rochette L: Antioxidantproperties of an endogenous thiol: Alpha-lipoic acid, useful in the prevention ofcardiovascular diseases. J Cardiovasc Pharmacol,2009,54,
[98]. Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler HJ. Differentialeffects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletalmuscle. Am J Physiol1997;273:E185–91.
[99]. Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ, Dietze GJ, Henriksen EJ.The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose metabolism ininsulin-resistant rat skeletal muscle. Diabetes1996;45:1024–9.
[100]. Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung WI,Augustin HJ, Dietze GJ. Enhancement of glucose disposal in patients with type2diabetes by alpha-lipoic acid. Arzneimittelforschung1995;45:872–4.
[101]. Konrad T, Vicini P, Kusterer K, Hoflich A, Assadkhani A, Bohles HJ, Sewell A,Tritschler HJ, Cobelli C, Usadel KH. alpha-Lipoic acid treatment decreases serumlactate and pyruvate concentrations and improves glucose effectiveness in lean andobese patients with type2diabetes. Diabetes Care1999;22:280–7.
[102]. Bitar MS, Ayed AK, Abdel-Halim SM, Isenovic ER, Al-Mulla F: Inflammation andapoptosis in aortic tissues of aged type II diabetes: amelioration withα-lipoic acidthrough phosphatidylinositol3-kinase/Akt-dependent mechanism. Life Sci,2010,86,844–853.
[103]. Heinisch BB, Francesconi M, Mittermayer F, Schaller G, Gouya G, Wolzt M,Pleiner: Alpha-lipoic acid improves vascular endothelial function in patients withtype2diabetes: a placebo-controlled randomized trial, Eur J Clin Invest,2010,40,148–154.
[104]. Mijnhout GS, Alkhalaf A, Kleefstra N, Bilo HJ: Alpha lipoic acid: a new treatmentfor neuropathic pain in patients with diabetes? Neth J Med,2010,68,158–162.
[105]. Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Yorek MA: Effect ofantioxidant treatment of streptozotocin-induced diabetic rats on endoneurial bloodflow, motor nerve conduction velocity, and vascular reactivity of epineurial arteriolesof the sciatic nerve. Diabetes,2001,50,1927–1937.
[106]. Zhu X, Su B, Wang X, Smith MA, Perry G: Causes of oxidative stress in Alzheimerdisease. Cell Mol Life Sci,2007,64,2202–2210.
[107]. Marishka K Brown，et al. Beneficial effects of natural antioxidants EGCG andα-lipoic acid on life span and age-dependent behavioral declines in Caenorhabditiselegans［J］， Pharmacology Biochemistry and Behavior，2006，85（3）：620-628.
[108]. Arivazhagan P, Ramanathan K, Panneerselvam C: Effect of DL-α-lipoic acid onmitochondrial enzymes in aged rats. Chem Biol Interact,2001,138,189–198.
[109]. Arivazhagan P, Panneerselvam SR, Panneerselvam C: Effect of DL-α-lipoic acid onthe status of lipid peroxidation and lipids in aged rats. J Gerontol A Biol Sci Med Sci,2003,58, B788–B791.
[110]. Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S,Nair KS: Decline in skeletal muscle mitochondrial function with aging inhumans.Proc Natl Acad Sci USA,2005,102,5618–5623.
[111]. Janson M: Orthomolecular medicine: the therapeutic use of dietary supplements foranti-aging. Clin Interv Aging,2006,13,261–265.
[112]. Mc Carthy MF, Barroso-Aranda J, Contreras F: The "rejuvenatory" impact of lipoicacid on mitochondrial function in aging rats may reflect induction and activation ofPPAR-α coactivator-1. Med Hypotheses,2009,72,29–33.
[113]. Christie LA, Studzinski CM, Araujo JA, Leung CS, Ikeda-Douglas CJ, Head E,Cotman CW, Milgram NW: A comparison of egocentric and allocentric agedependentspatial learning in the beagle dogs. Prog Neuropsychpharmacol Biol Psychiatry,2005,29,361–369.
[114]. Studzinski CM, Christie LA, Araujo JA, Burnham WM, Head E, Cotman CW,Milgram NW: Visuospatial function in the beagle dog: an early marker of cognitivedecline in a model of human aging and dementia. Neurobiol Learn Mem,2006,86,197–204.
[115]. Tapp PD, Siwak CT, Estrada J, Muggenburg BA, Head E, Cotman CW, MilgramNW: Size and reversal learning in the beagle dog as a measure of executive functionand inhibitory control in aging. Learn Mem,2003,10,64–73.
[116]. Bickford PC, Gould T, Briederick L, Chadman K, Pollock A, Young D,Shukitt-Hale B et al.: Antioxidantrich diets improve cerebellar physiology and motorlearning in aged rats. Brain Res,2000,866,211–217
[117]. Roudebush P, Zicker SC, Cotman CW, Milgram NW, Muggenburg BA, Head E:Nutritional management of brain aging in dogs. J Am Vet Med Assoc,2005,227,722–728.
[118]. Head E, Nukala VN, Fenoglio KA, Muggenburg BA, Cotman CW, Sullivan PG:Effects of age, dietary and behavioral enrichment on brain mitochondria in a caninemodel of human aging. Exp Neurol,2009,220,171–176.
[119]. Stoll S, Hartmann H, Cohen SA, Muller WE: The potent free radical scavengeralpha-lipoic acid improves memory in aged mice: putative relationship toNMDAreceptor deficits. Pharmacol Biochem Behav,1993,46,799–805.
[120]. Bitar MS, Ayed AK, Abdel-Halim SM, Isenovic ER, Al-Mulla F: Inflammation andapoptosis in aortic tissues of aged type II diabetes: amelioration withα-lipoic acidthrough phosphatidylinositol3-kinase/Akt-dependent mechanism. Life Sci,2010,86,844–853.
[121]. Vasdev S, Gill V, Longerich L, Parai S, Gadag V. Salt-induced hypertension inWKY rats: prevention by alpha-lipoic acid supplementation. Mol Cell Biochem2003;254:319–26.
[122]. Vasdev S, Ford CA, Parai S, Longerich L, Gadag V. Dietary lipoic acidsupplementation prevents fructose-induced hypertension in rats. Nutr MetabCardiovasc Dis2000;10:339–46.
[123]. Vasdev S, Ford CA, Parai S, Longerich L, Gadag V. Dietary alpha-lipoic acidsupplementation lowers blood pressure in spontaneously hypertensive rats. JHypertens2000;18:567–73.
[124]. Vasdev S, Gill V, Parai S, Gadag V. Dietary lipoic acid supplementation attenuateshypertension in Dahl salt sensitive rats. Mol Cell Biochem2005;275:135–41.
[125]. Louhelainen M, Merasto S, Finckenberg P, Lapatto R, Cheng ZJ, Mervaala EM.Lipoic acid supplementation prevents cyclosporine-induced hypertension andnephrotoxicity in spontaneously hypertensive rats. J Hypertens2006;24:947–56.
[126]. El Midaoui A, de Champlain J. Prevention of hypertension, insulin r esistance, andoxidative stress by alpha-lipoic acid. Hypertension2002;39:303–7.
[127]. Midaoui AE, Elimadi A, Wu L, Haddad PS, de Champlain J. Lipoic acid preventshypertension, hyperglycemia, and the increase in heart mitochondrial superoxideproduction. Am J Hypertens2003;16:173–9.
[128]. Takaoka M, Kobayashi Y, Yuba M, Ohkita M, Matsumura Y. Effects of alpha-lipoicacid on deoxycorticosterone acetate-salt-induced hypertension in rats. Eur JPharmacol2001;424:121–9.
[129]. Shay, K. Petersen; Moreau, RF.; Smith, EJ.; Hagen, TM. Is alpha-lipoic acid ascavenger of reactive oxygen species in vivo? Evidence for its initiation of stresssignaling pathways that promote endogenous antioxidant capacity. IUBMB Life2008;60:362–7.
[130]. McMackin CJ, Widlansky ME, Hamburg NM, Huang AL, Weller S, Holbrook M,Gokce N, Hagen TM, Keaney JF Jr. Vita JA. Effect of combined treatment withalpha-Lipoic acid and acetyl-Lcarnitine on vascular function and blood pressure inpatients with coronary artery disease. J Clin Hypertens (Greenwich)2007;9:249–55.
[131]. Sola S, Mir MQ, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S,Khan BV. Irbesartan and lipoic acid improve endothelial function and reduce markersof inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acidin Endothelial Dysfunction (ISLAND) study. Circulation2005;111:343–8.
[132]. Heitzer T, Finckh B, Albers S, Krohn K, Kohlschutter A, Meinertz T. Beneficialeffects of alphalipoic acid and ascorbic acid on endothelium-dependent, nitricoxide-mediated vasodilation in diabetic patients: relation to parameters of oxidativestress. Free Radic Biol Med2001;31:53–61.
[133]. Sena CM, Nunes E, Louro T, Proenca T, Fernandes R, Boarder MR, Seica RM.Effects of alphalipoic acid on endothelial function in aged diabetic and high-fat fedrats. Br J Pharmacol.2007
[134]. Montagnani M, Ravichandran LV, Chen H, Esposito DL, Quon MJ. Insulin receptorsubstrate-1and phosphoinositide-dependent kinase-1are required forinsulin-stimulated production of nitric oxide in endothelial cells. Mol Endocrinol2002;16:1931–42.
[135]. Federici M, Menghini R, Mauriello A, Hribal ML, Ferrelli F, Lauro D, Sbraccia P,Spagnoli LG, Sesti G, Lauro R. Insulin-dependent activation of endothelial nitricoxide synthase is impaired by O-linked glycosylation modification of signalingproteins in human coronary endothelial cells. Circulation2002;106:466–72.
[136]. Hagen TM, Moreau R, Suh JH, Visioli F. Mitochondrial decay in the aging rat heart:evidence for improvement by dietary supplementation with acetyl-L-carnitine and/orlipoic acid. Ann N Y Acad Sci2002;959:491–507.
[137]. Smith AR, Hagen TM. Vascular endothelial dysfunction in aging: loss ofAkt-dependent endothelial nitric oxide synthase phosphorylation and partialrestoration by (R)-alpha-lipoic acid. Biochem Soc Trans2003;31:1447–9.
[138]. Kunt T, Forst T, Wilhelm A, Tritschler H, Pfuetzner A, Harzer O, Engelbach M,Zschaebitz A, Stofft E, Beyer J. Alpha-lipoic acid reduces expression of vascular celladhesion molecule-1and endothelial adhesion of human monocytes after stimulationwith advanced glycation end products. Clin Sci (Lond)1999;96:75–82.
[139].Kim HS, Kim HJ, Park KG, Kim YN, Kwon TK, Park JY, Lee KU, Kim JG, Lee IK.Alpha-lipoic acid inhibits matrix metalloproteinase-9expression by inhibitingNF-kappaB transcriptional activity. Exp Mol Med2007;39:106–13.
[140]. Chaudhary P, Marracci GH, Bourdette DN. Lipoic acid inhibits expression ofICAM-1and VCAM-1by CNS endothelial cells and T cell migration into the spinalcord in experimental autoimmune encephalomyelitis. J Neuroimmunol2006;175:87–96.
[141]. Ikeda U, Ito T, Shimada K. Interleukin-6and acute coronary syndrome. ClinCardiol2001;24:701–4.
[142]. Novotny L, Rauko P, Cojocel C:α-Lipoic acid–the potential for use in cancertherapy. Neoplasma,2008,55,81–86.
[143]. De Marco VG, Bosanquet JP, Rawlani VR, Skimming JW: Lipoic acid decreasesexhaled nitric oxide concentrations in anesthetized endotoxemic rats. Vasc Pharmacol,2005,43,4040–10.
[144]. Van de Mark K, Chen JS, Steliou K, Perrine SP, Faller DV: Alpha-lipoic acidinduces p27Kip-dependent cell cycle arrest in non-transformed cell lines andapoptosis in tumor cell lines. J Cell Physiol,2003,194,325–340.
[145]. Packer L:α-Lipoic acid: a metabolic antioxidant which regulates NFκB signaltransduction and protects against oxidative injury. Drug Metab Rev,1998,30,245–275.
[146]. Vig-Varga E, Benson EA, Limbil TL, Allison BM, Goebl MG, Harrington MA:Alpha-lipoic acid modulates ovarian surface epithelial cell growth. Gynecol Oncol,2006,103,45–52.
[147]. Pack RA, Hardy K, Madigan MC, Hunt NH: Differential effects of theantioxidantα-lipoic acid on the proliferation of mitogen-stimulated peripheral bloodlymphocytes and leukaemic T cells. Mol Immunol,2002,38,733–745.
[148]. Lee HS, Na MH, Kim WK:_-Lipoic acid reduces matrix metalloproteinase activityin MDA-MB-231human breast cancer line. Nutr Res,2010,30,403–409.
[150]. Marianna Zana. Oxidative stress： A bridge between Down's syndrome andAlzheimer's disease ［J］Neurobiology of Aging，2007，28（5）：648-679.
[151]. Lina Holmquist， Grant Stuchbury，Katrin Berbaum.αLipoic acid as a noveltreatment for Alzheimer’s disease and related dementias［J］. Pharmacology andTherapeutics，2007，113（1）：154-164.
[152]. Xuesen Li， Zhongbo Liu， Cheng Luo，et al. Lipoamide protects retinal pigmentepithelial cells from oxidative stress and mitochon-drial dysfunction ［J］.FreeRadical Biology&Medicine，2008，44：1465-1474.
[153]. Munsterman AS, Bertone AL, Zachos TA. Effects of theomega23fatty acid,alpha-linolenic acid, on lipopolysaccharide challenged synovial explants from horses[J]. Am J Vet Res,2005,66(9):1503-1508.
[154].McCulloch V, Seidel Rogool BL. A human mitochondrial transcription of nucleargenes encoding the mammalian cytochrome complex. Prog Nucleic Acid Res MolBiol.2002;2:1116-1125.
[155]. Black SC, Rodger IW. Methods for studying experimental myocardial ischemic andreperfusion injury. J Pharmacol Toxicol Methods199635:179–190.
[156]. Sun Z, Shen L, Sun X, Tong G, Sun D, et al. Variation of NDRG2and c-Mycexpression in rat heart during the acute stage of ischemia/reperfusion injury.Histochem Cell Biol2011135:27–35.
[157]. Oh SK, Yun KH, Yoo NJ, Kim NH, Kim MS, et al. Cardioprotective effects ofalpha-lipoic Acid on myocardial reperfusion injury: suppression of reactive oxygenspecies generation and activation of mitogen-activated protein kinase. Korean Circ J200939:359–366.
[158]. Muller C, Dunschede F, Koch E, Vollmar AM, Kiemer AK. Alpha-lipoic acidpreconditioning reduces ischemia-reperfusion injury of the rat liver via thePI3-kinase/Akt pathway. Am J Physiol Gastrointest Liver Physiol2003285:G769–778.
[159]. Demarco VG, Scumpia PO, Bosanquet JP, Skimming JW. Alpha-lipoic acid inhibitsendotoxin-stimulated expression of iNOS and nitric oxide independent of the heatshock response in RAW264.7cells. Free Radic Res200438:675–682.
[160]. Yamada M, Kaibori M, Tanaka H, Habara K, Hijikawa T, et al. alphalipoic acidprevents the induction of iNOS gene expression through destabilization of its mRNAin proinflammatory cytokine-stimulated hepatocytes. Dig Dis Sci201257:943–951.
[161]. Wildhirt SM, Weismueller S, Schulze C, Conrad N, Kornberg A, et al. Induciblenitric oxide synthase activation after ischemia/reperfusion contributes to myocardialdysfunction and extent of infarct size in rabbits: evidence for a late phase of nitricoxide-mediated reperfusion injury. Cardiovasc Res199943:698–711.
[162]. Kensler TW, Wakabayashi N, Biswal S Cell survival responses to environmentalstresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol200747:89–116.
[163]. Melo LG, Agrawal R, Zhang L, Rezvani M, Mangi AA, et al. Gene therapy strategyfor long-term myocardial protection using adeno-associated virus-mediated deliveryof heme oxygenase gene. Circulation2002105:602–607.
[164]. Dudek M, Bednarski M, Bilska A, Iciek M, Sokolowska-Jezewicz M, et al. The roleof lipoic acid in prevention of nitroglycerin tolerance. Eur J Pharmacol2008591:203–210.
[165]. Ghibu S, Richard C, Vergely C, Zeller M, Cottin Y, et al. Antioxidant properties ofan endogenous thiol: Alpha-lipoic acid, useful in the prevention of cardiovasculardiseases. J Cardiovasc Pharmacol200954:391–398.
[166]. Coleman MD, Eason RC, Bailey CJ. The therapeutic use of lipoic acid in diabetes:a current perspective. Environ Toxicol Pharmacol200110:167–172.
[167]. Konrad D, Somwar R, Sweeney G, Yaworsky K, Hayashi M, et al. Theantihyperglycemic drug alpha-lipoic acid stimulates glucose uptake via both GLUT4translocation and GLUT4activation: potential role of p38mitogenactivated proteinkinase in GLUT4activation. Diabetes200150:1464–1471.
[168]. Pugazhenthi S, Akhov L, Selvaraj G, Wang M, Alam J. Regulation of hemeoxygenase-1expression by demethoxy curcuminoids through Nrf2by aPI3-kinase/Akt-mediated pathway in mouse beta-cells. Am J Physiol EndocrinolMetab2007293: E645–655.
[169]. Huang HC, Nguyen T, Pickett CB. Phosphorylation of Nrf2at Ser-40by proteinkinase C regulates antioxidant response element-mediated transcription. J Biol Chem2002277:42769–42774.
[170]. Steffens S, Montecucco F, Mach F. The inflammatory response as a target toreduce myocardial ischaemia and reperfusion injury. Thromb Haemost2009102:240–247.
[171]. Rojo AI, Sagarra MR, Cuadrado A. GSK-3beta down-regulates the transcriptionfactor Nrf2after oxidant damage: relevance to exposure of neuronal cells to oxidativestress. J Neurochem2008105:192–202.
[172]. Wu CC, Hsu MC, Hsieh CW, Lin JB, Lai PH, et al. Upregulation of hemeoxygenase-1by Epigallocatechin-3-gallate via the phosphatidylinositol3-kinase/Aktand ERK pathways. Life Sci200678:2889–2897.
[173]. Na HK, Kim EH, Jung JH, Lee HH, Hyun JW, et al.(2)-Epigallocatechin gallateinduces Nrf2-mediated antioxidant enzyme expression via activation of PI3K andERK in human mammary epithelial cells. Arch Biochem Biophys2008476:171–177.
[174]. Hausenloy DJ, Yellon DM. New directions for protecting the heart againstischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase(RISK)-pathway. Cardiovasc Res200461:448–460.
[175]. Chan TO, Rittenhouse SE, Tsichlis PN. AKT/PKB and other D3phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependentphosphorylation. Annu Rev Biochem199968:965–1014.
[176]. Apopa PL, He X, Ma Q. Phosphorylation of Nrf2in the transcription activationdomain by casein kinase2(CK2) is critical for the nuclear translocation andtranscription activation function of Nrf2in IMR-32neuroblastoma cells. J BiochemMol Toxicol200822:63–76.
[177]. Surh YJ, Kundu JK, Na HK. Nrf2as a master redox switch in turning on thecellular signaling involved in the induction of cytoprotective genes by somechemopreventive phytochemicals. Planta Med200874:1526–1539.
[178]. Jain AK, Jaiswal AK. GSK-3beta acts upstream of Fyn kinase in regulation ofnuclear export and degradation of NF-E2related factor2. J Biol Chem2007282:16502–16510.
[179]. Ashrafian H, Czibik G, Bellahcene M, Aksentijevic D, Smith AC, et al. Fumarate iscardioprotective via activation of the Nrf2antioxidant pathway. Cell Metab201215:361–371.
[180]. Kim J, Cha YN, Surh YJ. A protective role of nuclear factor-erythroid2-relatedfactor-2(Nrf2) in inflammatory disorders. Mutat Res2010690:12–23.
[181]. Pickering AM, Linder RA, Zhang H, Forman HJ, Davies KJ. Nrf2-dependentinduction of proteasome and Pa28alphabeta regulator are required for adaptation tooxidative stress. J Biol Chem2012287:10021–10031.
[182]. Shay KP, Michels AJ, Li W, Kong AN, Hagen TM. Cap-independent Nrf2translation is part of a lipoic acid-stimulated detoxification stress response. BiochimBiophys Acta20121823:1102–1109.
[2]. Skyschally A, van Caster P, Boengler K, Gres P, Musiolik J, Schilawa D, Schulz R,Heusch G. Ischemic post-conditioning in pigs: no causal role for RISK activation.Circ Res2009104:15–18.
[3]. Castedo E,Segovia J,Escudero C,et a1.Ischemia-reperfusion injury duringexperimental heart transplantation. Evaluation of trimetazidine's cytoprotectiveeffect[J].Rev Esp Cardiol.2005,58(8):941-950.
[4]. Turer AT, Hill JA. Pathogenesis of myocardial ischemia-reperfusion injury andrationale for therapy. Am J Cardiol.2010;106:360–8.
[5]. Derek M, Yellon DS. Myocardial Reperfusion Injury[J]. N Engl J Med,2007,357:1121-1135.
[6]. Fedinandy P, Schulz R, Baxter GF. Interaction of cardiovascular risk factors withmyocardial ischemia/reperfusion injury, preconditioning and post conditioning[J].Pharmacol Rev,2007,59:418-458.
[7]. Gorczyca W, Melamed MR, Darzynkiewicz Z. Programmed death ofcell(apoptosis)[J]. Patol Pol,1993,44(3):113-119.
[8]. Levi AJ, Dalton GR, Hancox JC. Role of intracellular sodium overload in the genesisof cardiac arrhythmias[J]. J Cardiovasc Electrophysiol,1997,8(6):700-721.
[9]. Turer A T, Hilll JA. Pathogenesis of Myocardial Ischemia-Reperfusion Injury andRationale for Therapy. The American Journal of Cardiology2010(106):360-368.
[10]. Holmqist L, Stubury G, Berbaum K. Lipoic acid as a novel treatment for Azheimer’sdisease and related dementias [J]. Pharmacol Ther,2007,113(1):154-157.
[11]. Ghibu S, Richard C, Delemasure Sl. An endogenous dithiol with antioxidantproperties: alpha lipoic acid. potential uses in cardiovascular diseases [J].AnnCardiol Anreiol (Paris),2008,57(3):161-165.
[12]. Pari L, Murugavel P. Protective effect of alpha-lipoic acid againstchloroquine-induced hepatotoxicity in rats [J]. J Appl Toxicol2004,24(1):21-26.
[13]. Smfh AR，Shenvi SV，Widlansky M．Lipoic acid as a potential therapy for chronicdisease associated with oxidative stress[J]．Current Medicinal Chemist，2004，11(9)：1135-1146.
[14]. Packer L, Witt EH, Tritschler HJ. alpha-Lipoic acid as a biological antioxidant. FreeRadic Biol Med1995;19:227–50.
[15]. Sola S, Mir MQ, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S, KhanBV. Irbesartan and lipoic acid improve endothelial function and reduce markers ofinflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid inEndothelial Dysfunction (ISLAND) study. Circulation2005;111:343–8.
[16]. Ikeda U, Ito T, Shimada K. Interleukin-6and acute coronary syndrome. Clin Cardiol2001;24:701–4.
[17]. Zweier JL, Talukder M AH.The role of oxidants and free radicals in reperfusioninjury. Cardiovascular Research2006(70):181-190.
[18]. Moens AL, Claeys M J, Timmemmans JP, Vrints CJ. Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiologicalprocess.International Journal of Cardiology2005(100):179-190.
[19]. Trujillo M, Radi R. Peroxynitrite react ionwith the reduced and the oxdized forms oflipoic acid: New insight into the reaction of peroxynitrite with thiols[J]. ArchBiochem Biophys,2002,397(1):91-98.
[20]. Navar Izzo F, Quartacci MF, Sgherri C. Lipoic acid: a unique antiox-idant in thedetoxification of activated oxygen species[J]. Plant Physiol Biochem,2002,40:463-470.
[21]. Schabbauer G, Tencati M, Pedersen B, Pawlinski R, Mackman N.ArteriosclerThromb Vasc Biol2004(24):1963–1969.
[22]. Williams DL, Li C, Ha T, Ozment-Skelton T, Kalbfleisch JH, Preiszner J, Brooks L,Breuel K, Schweitzer JB.J Immunol2004(172):449–456.
[23]. Rajaram MV, Ganesan LP, Parsa KV, Butchar JP, Gunn JS, Tridandapani S JImmunol2006(177):6317–6324.
[24]. Matsuda N, Hayashi Y, Takahashi Y, Hattori Y J Pharmacol Exp Ther(2006)319:1348–1354.
[25]. D. Ramzy, V. R.D. Weisel. Clinical applicability of preconditioning andpostconditioning:the cardiothoracic surgeons’s view, Cardiovascular research2006(70)174-180.
[26]. P. Saikumar, Z. Dong, V. Mikhailov, M. Denton, JM. Weinberg, M.A. Venkatachalam,Apoptosis: definition, mechanisms, and relevance to disease, The American journalof medicine1999(107):489-506.
[27]. Chen AF,Chen DD,Daiber A,et a1.Free radical biology of the cardiovascularsystem[J].Clin Sci (Lond),2012,123(2):73-91.
[28]. Valko M,Leibf r it z D,Moncol J,et a1.Free radicals and antioxidants in normalphysiological functions and human disease [J].Int J Biochem Cell Biol,2007,39(1):44-84.
[29]. Dr ge W.Free radicals in the physiological control of cell function[J].Physiol Rev,2002,82(1):47-95.
[30]. Guha M, Mackman N. The phosphate dylinositol3-kinase-Akt pathway limitslipopolysaccharide activation of signaling pathways and expression of inflammatorymediators in human monocytic cells. J Biol Chem.2002(277):32124-32132.
[31]. Arslan F,de Kleijn DP,Timmers L,et a1.Bridging innate immunity and myocardialischemia/reperfusion injury: the search for therapeutic targets[J].Curr Pharm Des,2008,14(12):1205-1216.
[32]. Sjaastad I, Bentzen JG, Semb SO. Reduced calcium tolerance in rat cardiomyocytesafter myocardial infarction [J].Acta Physiol Scand,2002,175(4):261-269.
[33]. Levi AJ,Dalton GR,Hancox JC,et a1. Role of intracellular sodium overload in thegenesis of cardiac arrhythmias[J].J Cardiovasc Electrophysiol,1997,8(6):700-721.
[34]. Gorczyca W, Melamed MR, Darzynkiewicz Z. Programmed death of cells (apoptosis)[J].Patol Pol,1993,44(3):113-119.
[35]. Saikummar P, Dong Z, Mikhailov V, Denton M, Weinberg JM, Venkatachalam MA.Apoptosis: definition, mechanisms, and Relevance to disease. Am J Med1999;107(5):489-506.
[36]. Orrenius S. Apoptosis: molecular mechanisms and implications for human disease. JInter Med1995;237(6):529-536.
[37]. J.F. Kerr, A.H. Wylllie, A.R. Currie. Apoptosis: a basic biological phenomenon withwide-ranging implications in tissue kinetics. British journal of cancer1972(26):239-257.
[38]. Fliss H, Gattinger D. Apoptosis in ischemic and reperfused rat myocardium. Cric Res1996;79(5):949-956.
[39]. Gottieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injuryinduces apoptosis in rabbit cardiomyocytes. J Clin Invest1994;94(4):1621-1628.
[40]. Tomei LD, Umansky SR. Apoptosis and the heart: a brief review. Ann N Y Acad Sci2001;946:160-168.
[41]. Abbate A, Biondi-Zoccai GG, Baldi A. pathophysiologic role of myocardialapoptosis in post-infarction left ventricular remodeling. J Cell Physiol2002;193(2):145-153.
[42]. Z.Q. Zhao, J. Vinten-Johansen. Myocardial apoptosis and ischemic preconditioning,Cardiovascular research2002;55:438-455.
[43]. Heineke J, Kempf T et al. Down regulation of cytoskeletal muscle LIM protein bynitric oxide: impact on cardiac myocyte hypertrophy. Circulation2003;107(10)1424-1432.
[44]. Hamnstetter A, Izumo S. Future perspectives and potential implications of cardiacmyocyte apoptosis. Cardiovasc Res2000;45(3):795-810.
[45].Yaoita H, Ogawa K, Maechara K, Maruyama Y. Apoptosis in relevant clinicalsituations: contribution of apoptosis in myocardial infarction. Cardiovasc Res2000;45(3):630-641.
[46]. E. Farber, Programmed cell death: necrosis versus apoptosis, Mod Pathol1994(7)605-609.
[47]. N. Joza, G. Kroemer, J.M. Penninger. Genetic analysis of the mammalian cell deathmachinery. Trends Genet2002(18)142-149.
[48]. Reed LJ, DeBusk BG, Gansalus IC, Hornberger Jr CS: Crystallineα-lipoic acid: acatalytic agent associated with pyruvate dehydrogenase. Ciences,1951,114,93–94.
[49]. Carreau JP: Biosynthesis of lipoic acid via unsaturatedfatty acids. Meth Enzymol,1979,62,152–158.
[50]. Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM. Lipoic acid as a otentialtherapy for chronic diseases associated with oxidative stress. Curr Med Chem2004;11:1135–46.
[51]. Scott BC, Aruoma OI, Evans PJ, O’Neill C, Van der Vliet A, Cross CE, Tritschler H,Halliwell B. Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation.Free Radic Res1994;20:119–33.
[52]. Devasagayam TP, Subramanian M, Pradhan DS, Sies H. Prevention of singletoxygen-induced DNA damage by lipoate. Chem Biol Interact1993;86:79–92.
[53]. Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, AmesBN. Memory loss in old rats is associated with brain mitochondrial decay andRNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha-lipoic acid. Proc Natl Acad Sci U S A2002;99:2356–61.
[54]. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM. Decline intranscriptional activity of Nrf2causes age-related loss of glutathione synthesis, whichis reversible with lipoic acid. Proc Natl Acad Sci U S A2004;101:3381–6.
[55]. Lodge JK, Traber MG, Packer L. Thiol chelation of Cu2+by dihydrolipoic acidprevents human low density lipoprotein peroxidation. Free Radic Biol Med1998;25:287–97.
[56]. Anuradha B, Varalakshmi P. Protective role of DL-alpha-lipoic acid againstmercury-induced neural lipid peroxidation. Pharmacol Res1999;39:67–80.
[57]. Han D, Sen CK, Roy S, Kobayashi MS, Tritschler HJ, Packer L. Protection againstglutamate-induced cytotoxicity in C6glial cells by thiol antioxidants. Am J Physiol1997;273:R1771–8.
[58]. Cremer DR, Rabeler R, Roberts A, Lynch B.: Safety evaluation of alpha-lipoic acid(ALA). Regul Toxicol Pharmacol,2006,46,29–41.
[59]. Miadokova E, Vlckova V, Duhova V: Antimutagenic effect of alpha-lipoic acid onthree model test systems. Pharmazie,2000,55,862–863.
[60]. Novotny L, Rauko P, Cojocel C:α-Lipoic acid–the potential for use in cancertherapy. Neoplasma,2008,55,81–86.
[61]. Packer L,Witt EH, Tritschler HJ:α-Lipoic acid as a biological antioxidant. Free RadicBiol Med,1995,19,227–250.
[62]. Bast A, Haenen GR: Lipoic acid: a multifunctional antioxidant. Biofactors,2003,17,207–213.
[63]. Biewenga G, Haenen G, Bast A: The pharmacology of the antioxidant lipoic acid.Gen Pharmacol,1997,29,315–331.
[64]. Bilska A, W3odek L: Lipoic acid-the drug of the future. Pharmacol Rep,2005,57,570–577.
[65]. Ghibu S, Richard C, Vergely C, Zeller M, Cottin Y, Rochette L: Antioxidantproperties of an endogenous thiol: Alpha-lipoic acid, useful in the prevention ofcardiovascular diseases. J Cardiovasc Pharmacol,2009,54,391–398.
[66]. Bitar MS, Ayed AK, Abdel-Halim SM, Isenovic ER, Al-Mulla F: Inflammation andapoptosis in aortic tissues of aged type II diabetes: amelioration withα-lipoic acidthrough phosphatidylinositol3-kinase/Akt-dependent mechanism. Life Sci,2010,86,844–853.
[67]. Gorca A, As3anowicz-Antkowiak K: Prophylaxis with alpha-lipoic acid againstlipopolisaccharide-induced brain injury in rats. Arch Immunol Ther Exp (Warsz),2009,57,141–146.
[68]. Gorca A, Piechota A, Huk-Kolega H: Effect of alphalipoic acid on LPS-inducedoxidative stress in the heart. J Physiol Pharmacol,2009,60,61–68.
[69]. Skibska B, Józefowicz-Okonkwo G, Gor1ca A: Protective effects of earlyadministration of alpha-lipoic acid against lipopolysaccharide-induced plasma lipidperoxidation. Pharmacol Rep,2006,58,399–404.
[70]. Suzuki YJ, Aggarwal BB, Packer L: Alpha-lipoic acid is a potent inhibitor ofNF-kappa B activation in human T cells. Biochem Biophys Res Commun,1992,189,1709–1715.
[71]. Yan LJ, Traber MG, Kobuchi H, Matsugo S, Tritscher HJ, Packer L: Efficacy ofhypochlorous acid scavengers in the prevention of protein carbonyl formation. ArchBiochem Biophys,1996,327,330–334.
[72]. Valko M, Morris H, Cronin MT: Metals, toxicity and oxidative stress. Curr MedChem,2005,12,1161–1208.
[73]. Doraiswamy PM, Finefrock AE: Metals in our minds: therapeutic implications forneurodegenerative disorders. Lance Neurol,2004,3,431–434.
[74]. Goralska M, Dackor R, Holley B, McGahan MC. Alpha lipoic acid changes ironuptake and storage in lens epithelial cells. Exp Eye Res2003;76:241–8.
[75]. Suh JH, Moreau R, Heath SH, Hagen TM. Dietary supplementation with(R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion ofantioxidants in the rat cerebral cortex. Redox Rep2005;10:52–60.
[76]. Baldwin AS Jr: NFκB and ILB proteins: new discoveries and insights. Annu RevImmunol,1996,14,649–681.
[77]. Hofmann MA, Schiekofer S, Kanitz M, Klevesath MS, Joswig M, Lee V, Morcos M:Insufficient glycemic control increases nuclear factor kappa B binding activity inperipheral blood mononuclear cells isolated from patients with type1diabetes.Diabetes Care,1998,21,1310–1316.
[78]. Kim HJ, Chang EJ, Kim HM, Lee SB, Kim HD, Kim GS, Kim HH:Antioxidantα-lipoic acid inhibits osteoclast differentiation by reducing nuclearfactorκB DNA binding and prevents in vivo bone resorption induced by receptoractivator of nuclear factorκB ligand and tumor necrosis factorα. Free Radic Biol Med,2006,40,1483–1493.
[79]. Kim HY, Or Y, Kim M, Yokozawa T: Protective effect of lipoic acid againstmethylglyoxal-induced oxidative stress in LLC-PK1cells. J Nutr Sci Vitaminol,2008,54,99–104.
[80]. Suzuki YJ, Tsachya M, Packer L: Thioctic acid and dihydrolipoic acid are novelantioxidants which interact with reactive oxygen species. Free Radic Res Commun,1991,15,255–263.
[81]. Ying Z, Kherada N, Farrar B, Kampfrath T, Chung Y, Simonetti O, Deiuliis J et al.:Lipoic acid effects on established atherosclerosis. Life Sci,2010,86,95–102.
[82]. Suzuki YJ, Tsachya M, Packer L: Thioctic acid and dihydrolipoic acid are novelantioxidants which interact with reactive oxygen species. Free Radic Res Commun,1991,15,255–263.
[83]. Vig-Varga E, Benson EA, Limbil TL, Allison BM, Goebl MG, Harrington MA:Alpha-lipoic acid modulates ovarian surface epithelial cell growth. Gynecol Oncol,2006,103,45–52.
[84]. Zhang WJ, Frei B:α-Lipoic acid inhibits TNF-αinduced NFκB activation andadhesion molecule expression in human aortic endothelial cells. FASEB J,2001,15,2423–2432.
[85]. Kim HS, Kim HJ, Park KG, Kim YN, Kwon TK, Park JY:α-Lipoic acid inhibitsmatrix metalloproteinase-9expression by inhibiting NFκB transcriptionalactivity.Exp Mol Med,2007,39,106–113.
[86]. Holmquist L, Stuchbury G, Berbaun K: Lipoic acid as a novel treatment forAlzheimer’s disease and related dementias. Pharmacol Ther,2007,113,154–164.
[87]. Kilic F, Handelman GJ, Traber K, Tsang K, Packer L, Trevithick JR. Modellingcortical cataractogenesis XX. In vitro effect of alpha-lipoic acid on glutathioneconcentrations in lens in model diabetic cataractogenesis. Biochem Mol Biol Int1998;46:585–95.
[88]. Wolz P, Krieglstein J. Neuroprotective effects of alpha-lipoic acid and itsenantiomers demonstrated in rodent models of focal cerebral ischemia.Neuropharmacology1996;35:369–75.
[89]. Biewenga GP, Dorstijn MA, Verhagen JV, Haenen GR, Bast A. Reduction of lipoicacid by lipoamide dehydrogenase. Biochem Pharmacol1996;51:233–8.
[90]. Hagen TM, Vinarsky V, Wehr CM, Ames BN.(R)-alpha-lipoic acid reverses theage-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxideboth in vitro and in vivo. Antioxid Redox Signal2000;2:473–83.
[91]. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM. Decline intranscriptional activity of Nrf2causes age-related loss of glutathione synthesis, whichis reversible with lipoic acid. Proc Natl Acad Sci U S A2004;101:3381–6.
[92]. Moini H, Tirosh O, Park YC, Cho KJ, Packer L. R-alpha-lipoic acid action on cellredox status, the insulin receptor, and glucose uptake in3T3-L1adipocytes. ArchBiochem Biophys2002;397:384–91.
[93]. Beckman MA, Creager P, Libby P: Diabetes and atherosclerosis: epidemiology,pathophysiology, and management. J Am Med Assoc,2002,287,2570–2581.
[94]. Clavreul N, Bachschmid MM, Hou X, Shi C, Idrizovic A, Ido Y, Pimentel D et al.:S-glutathiolation of p21ras by peroxynitrite mediates endothelial insulin resistancecaused by oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol,2006,26,2454–2461.
[95]. Andreozzi F, Laratta E, Sciacqua A, Perticone F, Sesti G: Angiotensin II impairs theinsulin signaling pathway promoting production of nitric oxide by inducingphosphorylation of insulin receptor substrate-1on Ser312and Ser616in humanumbilical vein endothelial cells. Circ Res,2004,94,1211–1218.
[96]. Eason RC, Archer HE, Akhtar S, Bailey CJ: Lipoic acid increases glucose uptake byskeletal muscles of obesediabetic ob/ob mice. Diabetes Obes Metab,2002,4,29–35.
[97]. Ghibu S, Richard C, Vergely C, Zeller M, Cottin Y, Rochette L: Antioxidantproperties of an endogenous thiol: Alpha-lipoic acid, useful in the prevention ofcardiovascular diseases. J Cardiovasc Pharmacol,2009,54,
[98]. Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler HJ. Differentialeffects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletalmuscle. Am J Physiol1997;273:E185–91.
[99]. Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ, Dietze GJ, Henriksen EJ.The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose metabolism ininsulin-resistant rat skeletal muscle. Diabetes1996;45:1024–9.
[100]. Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung WI,Augustin HJ, Dietze GJ. Enhancement of glucose disposal in patients with type2diabetes by alpha-lipoic acid. Arzneimittelforschung1995;45:872–4.
[101]. Konrad T, Vicini P, Kusterer K, Hoflich A, Assadkhani A, Bohles HJ, Sewell A,Tritschler HJ, Cobelli C, Usadel KH. alpha-Lipoic acid treatment decreases serumlactate and pyruvate concentrations and improves glucose effectiveness in lean andobese patients with type2diabetes. Diabetes Care1999;22:280–7.
[102]. Bitar MS, Ayed AK, Abdel-Halim SM, Isenovic ER, Al-Mulla F: Inflammation andapoptosis in aortic tissues of aged type II diabetes: amelioration withα-lipoic acidthrough phosphatidylinositol3-kinase/Akt-dependent mechanism. Life Sci,2010,86,844–853.
[103]. Heinisch BB, Francesconi M, Mittermayer F, Schaller G, Gouya G, Wolzt M,Pleiner: Alpha-lipoic acid improves vascular endothelial function in patients withtype2diabetes: a placebo-controlled randomized trial, Eur J Clin Invest,2010,40,148–154.
[104]. Mijnhout GS, Alkhalaf A, Kleefstra N, Bilo HJ: Alpha lipoic acid: a new treatmentfor neuropathic pain in patients with diabetes? Neth J Med,2010,68,158–162.
[105]. Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Yorek MA: Effect ofantioxidant treatment of streptozotocin-induced diabetic rats on endoneurial bloodflow, motor nerve conduction velocity, and vascular reactivity of epineurial arteriolesof the sciatic nerve. Diabetes,2001,50,1927–1937.
[106]. Zhu X, Su B, Wang X, Smith MA, Perry G: Causes of oxidative stress in Alzheimerdisease. Cell Mol Life Sci,2007,64,2202–2210.
[107]. Marishka K Brown，et al. Beneficial effects of natural antioxidants EGCG andα-lipoic acid on life span and age-dependent behavioral declines in Caenorhabditiselegans［J］， Pharmacology Biochemistry and Behavior，2006，85（3）：620-628.
[108]. Arivazhagan P, Ramanathan K, Panneerselvam C: Effect of DL-α-lipoic acid onmitochondrial enzymes in aged rats. Chem Biol Interact,2001,138,189–198.
[109]. Arivazhagan P, Panneerselvam SR, Panneerselvam C: Effect of DL-α-lipoic acid onthe status of lipid peroxidation and lipids in aged rats. J Gerontol A Biol Sci Med Sci,2003,58, B788–B791.
[110]. Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S,Nair KS: Decline in skeletal muscle mitochondrial function with aging inhumans.Proc Natl Acad Sci USA,2005,102,5618–5623.
[111]. Janson M: Orthomolecular medicine: the therapeutic use of dietary supplements foranti-aging. Clin Interv Aging,2006,13,261–265.
[112]. Mc Carthy MF, Barroso-Aranda J, Contreras F: The "rejuvenatory" impact of lipoicacid on mitochondrial function in aging rats may reflect induction and activation ofPPAR-α coactivator-1. Med Hypotheses,2009,72,29–33.
[113]. Christie LA, Studzinski CM, Araujo JA, Leung CS, Ikeda-Douglas CJ, Head E,Cotman CW, Milgram NW: A comparison of egocentric and allocentric agedependentspatial learning in the beagle dogs. Prog Neuropsychpharmacol Biol Psychiatry,2005,29,361–369.
[114]. Studzinski CM, Christie LA, Araujo JA, Burnham WM, Head E, Cotman CW,Milgram NW: Visuospatial function in the beagle dog: an early marker of cognitivedecline in a model of human aging and dementia. Neurobiol Learn Mem,2006,86,197–204.
[115]. Tapp PD, Siwak CT, Estrada J, Muggenburg BA, Head E, Cotman CW, MilgramNW: Size and reversal learning in the beagle dog as a measure of executive functionand inhibitory control in aging. Learn Mem,2003,10,64–73.
[116]. Bickford PC, Gould T, Briederick L, Chadman K, Pollock A, Young D,Shukitt-Hale B et al.: Antioxidantrich diets improve cerebellar physiology and motorlearning in aged rats. Brain Res,2000,866,211–217
[117]. Roudebush P, Zicker SC, Cotman CW, Milgram NW, Muggenburg BA, Head E:Nutritional management of brain aging in dogs. J Am Vet Med Assoc,2005,227,722–728.
[118]. Head E, Nukala VN, Fenoglio KA, Muggenburg BA, Cotman CW, Sullivan PG:Effects of age, dietary and behavioral enrichment on brain mitochondria in a caninemodel of human aging. Exp Neurol,2009,220,171–176.
[119]. Stoll S, Hartmann H, Cohen SA, Muller WE: The potent free radical scavengeralpha-lipoic acid improves memory in aged mice: putative relationship toNMDAreceptor deficits. Pharmacol Biochem Behav,1993,46,799–805.
[120]. Bitar MS, Ayed AK, Abdel-Halim SM, Isenovic ER, Al-Mulla F: Inflammation andapoptosis in aortic tissues of aged type II diabetes: amelioration withα-lipoic acidthrough phosphatidylinositol3-kinase/Akt-dependent mechanism. Life Sci,2010,86,844–853.
[121]. Vasdev S, Gill V, Longerich L, Parai S, Gadag V. Salt-induced hypertension inWKY rats: prevention by alpha-lipoic acid supplementation. Mol Cell Biochem2003;254:319–26.
[122]. Vasdev S, Ford CA, Parai S, Longerich L, Gadag V. Dietary lipoic acidsupplementation prevents fructose-induced hypertension in rats. Nutr MetabCardiovasc Dis2000;10:339–46.
[123]. Vasdev S, Ford CA, Parai S, Longerich L, Gadag V. Dietary alpha-lipoic acidsupplementation lowers blood pressure in spontaneously hypertensive rats. JHypertens2000;18:567–73.
[124]. Vasdev S, Gill V, Parai S, Gadag V. Dietary lipoic acid supplementation attenuateshypertension in Dahl salt sensitive rats. Mol Cell Biochem2005;275:135–41.
[125]. Louhelainen M, Merasto S, Finckenberg P, Lapatto R, Cheng ZJ, Mervaala EM.Lipoic acid supplementation prevents cyclosporine-induced hypertension andnephrotoxicity in spontaneously hypertensive rats. J Hypertens2006;24:947–56.
[126]. El Midaoui A, de Champlain J. Prevention of hypertension, insulin r esistance, andoxidative stress by alpha-lipoic acid. Hypertension2002;39:303–7.
[127]. Midaoui AE, Elimadi A, Wu L, Haddad PS, de Champlain J. Lipoic acid preventshypertension, hyperglycemia, and the increase in heart mitochondrial superoxideproduction. Am J Hypertens2003;16:173–9.
[128]. Takaoka M, Kobayashi Y, Yuba M, Ohkita M, Matsumura Y. Effects of alpha-lipoicacid on deoxycorticosterone acetate-salt-induced hypertension in rats. Eur JPharmacol2001;424:121–9.
[129]. Shay, K. Petersen; Moreau, RF.; Smith, EJ.; Hagen, TM. Is alpha-lipoic acid ascavenger of reactive oxygen species in vivo? Evidence for its initiation of stresssignaling pathways that promote endogenous antioxidant capacity. IUBMB Life2008;60:362–7.
[130]. McMackin CJ, Widlansky ME, Hamburg NM, Huang AL, Weller S, Holbrook M,Gokce N, Hagen TM, Keaney JF Jr. Vita JA. Effect of combined treatment withalpha-Lipoic acid and acetyl-Lcarnitine on vascular function and blood pressure inpatients with coronary artery disease. J Clin Hypertens (Greenwich)2007;9:249–55.
[131]. Sola S, Mir MQ, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S,Khan BV. Irbesartan and lipoic acid improve endothelial function and reduce markersof inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acidin Endothelial Dysfunction (ISLAND) study. Circulation2005;111:343–8.
[132]. Heitzer T, Finckh B, Albers S, Krohn K, Kohlschutter A, Meinertz T. Beneficialeffects of alphalipoic acid and ascorbic acid on endothelium-dependent, nitricoxide-mediated vasodilation in diabetic patients: relation to parameters of oxidativestress. Free Radic Biol Med2001;31:53–61.
[133]. Sena CM, Nunes E, Louro T, Proenca T, Fernandes R, Boarder MR, Seica RM.Effects of alphalipoic acid on endothelial function in aged diabetic and high-fat fedrats. Br J Pharmacol.2007
[134]. Montagnani M, Ravichandran LV, Chen H, Esposito DL, Quon MJ. Insulin receptorsubstrate-1and phosphoinositide-dependent kinase-1are required forinsulin-stimulated production of nitric oxide in endothelial cells. Mol Endocrinol2002;16:1931–42.
[135]. Federici M, Menghini R, Mauriello A, Hribal ML, Ferrelli F, Lauro D, Sbraccia P,Spagnoli LG, Sesti G, Lauro R. Insulin-dependent activation of endothelial nitricoxide synthase is impaired by O-linked glycosylation modification of signalingproteins in human coronary endothelial cells. Circulation2002;106:466–72.
[136]. Hagen TM, Moreau R, Suh JH, Visioli F. Mitochondrial decay in the aging rat heart:evidence for improvement by dietary supplementation with acetyl-L-carnitine and/orlipoic acid. Ann N Y Acad Sci2002;959:491–507.
[137]. Smith AR, Hagen TM. Vascular endothelial dysfunction in aging: loss ofAkt-dependent endothelial nitric oxide synthase phosphorylation and partialrestoration by (R)-alpha-lipoic acid. Biochem Soc Trans2003;31:1447–9.
[138]. Kunt T, Forst T, Wilhelm A, Tritschler H, Pfuetzner A, Harzer O, Engelbach M,Zschaebitz A, Stofft E, Beyer J. Alpha-lipoic acid reduces expression of vascular celladhesion molecule-1and endothelial adhesion of human monocytes after stimulationwith advanced glycation end products. Clin Sci (Lond)1999;96:75–82.
[139].Kim HS, Kim HJ, Park KG, Kim YN, Kwon TK, Park JY, Lee KU, Kim JG, Lee IK.Alpha-lipoic acid inhibits matrix metalloproteinase-9expression by inhibitingNF-kappaB transcriptional activity. Exp Mol Med2007;39:106–13.
[140]. Chaudhary P, Marracci GH, Bourdette DN. Lipoic acid inhibits expression ofICAM-1and VCAM-1by CNS endothelial cells and T cell migration into the spinalcord in experimental autoimmune encephalomyelitis. J Neuroimmunol2006;175:87–96.
[141]. Ikeda U, Ito T, Shimada K. Interleukin-6and acute coronary syndrome. ClinCardiol2001;24:701–4.
[142]. Novotny L, Rauko P, Cojocel C:α-Lipoic acid–the potential for use in cancertherapy. Neoplasma,2008,55,81–86.
[143]. De Marco VG, Bosanquet JP, Rawlani VR, Skimming JW: Lipoic acid decreasesexhaled nitric oxide concentrations in anesthetized endotoxemic rats. Vasc Pharmacol,2005,43,4040–10.
[144]. Van de Mark K, Chen JS, Steliou K, Perrine SP, Faller DV: Alpha-lipoic acidinduces p27Kip-dependent cell cycle arrest in non-transformed cell lines andapoptosis in tumor cell lines. J Cell Physiol,2003,194,325–340.
[145]. Packer L:α-Lipoic acid: a metabolic antioxidant which regulates NFκB signaltransduction and protects against oxidative injury. Drug Metab Rev,1998,30,245–275.
[146]. Vig-Varga E, Benson EA, Limbil TL, Allison BM, Goebl MG, Harrington MA:Alpha-lipoic acid modulates ovarian surface epithelial cell growth. Gynecol Oncol,2006,103,45–52.
[147]. Pack RA, Hardy K, Madigan MC, Hunt NH: Differential effects of theantioxidantα-lipoic acid on the proliferation of mitogen-stimulated peripheral bloodlymphocytes and leukaemic T cells. Mol Immunol,2002,38,733–745.
[148]. Lee HS, Na MH, Kim WK:_-Lipoic acid reduces matrix metalloproteinase activityin MDA-MB-231human breast cancer line. Nutr Res,2010,30,403–409.
[150]. Marianna Zana. Oxidative stress： A bridge between Down's syndrome andAlzheimer's disease ［J］Neurobiology of Aging，2007，28（5）：648-679.
[151]. Lina Holmquist， Grant Stuchbury，Katrin Berbaum.αLipoic acid as a noveltreatment for Alzheimer’s disease and related dementias［J］. Pharmacology andTherapeutics，2007，113（1）：154-164.
[152]. Xuesen Li， Zhongbo Liu， Cheng Luo，et al. Lipoamide protects retinal pigmentepithelial cells from oxidative stress and mitochon-drial dysfunction ［J］.FreeRadical Biology&Medicine，2008，44：1465-1474.
[153]. Munsterman AS, Bertone AL, Zachos TA. Effects of theomega23fatty acid,alpha-linolenic acid, on lipopolysaccharide challenged synovial explants from horses[J]. Am J Vet Res,2005,66(9):1503-1508.
[154].McCulloch V, Seidel Rogool BL. A human mitochondrial transcription of nucleargenes encoding the mammalian cytochrome complex. Prog Nucleic Acid Res MolBiol.2002;2:1116-1125.
[155]. Black SC, Rodger IW. Methods for studying experimental myocardial ischemic andreperfusion injury. J Pharmacol Toxicol Methods199635:179–190.
[156]. Sun Z, Shen L, Sun X, Tong G, Sun D, et al. Variation of NDRG2and c-Mycexpression in rat heart during the acute stage of ischemia/reperfusion injury.Histochem Cell Biol2011135:27–35.
[157]. Oh SK, Yun KH, Yoo NJ, Kim NH, Kim MS, et al. Cardioprotective effects ofalpha-lipoic Acid on myocardial reperfusion injury: suppression of reactive oxygenspecies generation and activation of mitogen-activated protein kinase. Korean Circ J200939:359–366.
[158]. Muller C, Dunschede F, Koch E, Vollmar AM, Kiemer AK. Alpha-lipoic acidpreconditioning reduces ischemia-reperfusion injury of the rat liver via thePI3-kinase/Akt pathway. Am J Physiol Gastrointest Liver Physiol2003285:G769–778.
[159]. Demarco VG, Scumpia PO, Bosanquet JP, Skimming JW. Alpha-lipoic acid inhibitsendotoxin-stimulated expression of iNOS and nitric oxide independent of the heatshock response in RAW264.7cells. Free Radic Res200438:675–682.
[160]. Yamada M, Kaibori M, Tanaka H, Habara K, Hijikawa T, et al. alphalipoic acidprevents the induction of iNOS gene expression through destabilization of its mRNAin proinflammatory cytokine-stimulated hepatocytes. Dig Dis Sci201257:943–951.
[161]. Wildhirt SM, Weismueller S, Schulze C, Conrad N, Kornberg A, et al. Induciblenitric oxide synthase activation after ischemia/reperfusion contributes to myocardialdysfunction and extent of infarct size in rabbits: evidence for a late phase of nitricoxide-mediated reperfusion injury. Cardiovasc Res199943:698–711.
[162]. Kensler TW, Wakabayashi N, Biswal S Cell survival responses to environmentalstresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol200747:89–116.
[163]. Melo LG, Agrawal R, Zhang L, Rezvani M, Mangi AA, et al. Gene therapy strategyfor long-term myocardial protection using adeno-associated virus-mediated deliveryof heme oxygenase gene. Circulation2002105:602–607.
[164]. Dudek M, Bednarski M, Bilska A, Iciek M, Sokolowska-Jezewicz M, et al. The roleof lipoic acid in prevention of nitroglycerin tolerance. Eur J Pharmacol2008591:203–210.
[165]. Ghibu S, Richard C, Vergely C, Zeller M, Cottin Y, et al. Antioxidant properties ofan endogenous thiol: Alpha-lipoic acid, useful in the prevention of cardiovasculardiseases. J Cardiovasc Pharmacol200954:391–398.
[166]. Coleman MD, Eason RC, Bailey CJ. The therapeutic use of lipoic acid in diabetes:a current perspective. Environ Toxicol Pharmacol200110:167–172.
[167]. Konrad D, Somwar R, Sweeney G, Yaworsky K, Hayashi M, et al. Theantihyperglycemic drug alpha-lipoic acid stimulates glucose uptake via both GLUT4translocation and GLUT4activation: potential role of p38mitogenactivated proteinkinase in GLUT4activation. Diabetes200150:1464–1471.
[168]. Pugazhenthi S, Akhov L, Selvaraj G, Wang M, Alam J. Regulation of hemeoxygenase-1expression by demethoxy curcuminoids through Nrf2by aPI3-kinase/Akt-mediated pathway in mouse beta-cells. Am J Physiol EndocrinolMetab2007293: E645–655.
[169]. Huang HC, Nguyen T, Pickett CB. Phosphorylation of Nrf2at Ser-40by proteinkinase C regulates antioxidant response element-mediated transcription. J Biol Chem2002277:42769–42774.
[170]. Steffens S, Montecucco F, Mach F. The inflammatory response as a target toreduce myocardial ischaemia and reperfusion injury. Thromb Haemost2009102:240–247.
[171]. Rojo AI, Sagarra MR, Cuadrado A. GSK-3beta down-regulates the transcriptionfactor Nrf2after oxidant damage: relevance to exposure of neuronal cells to oxidativestress. J Neurochem2008105:192–202.
[172]. Wu CC, Hsu MC, Hsieh CW, Lin JB, Lai PH, et al. Upregulation of hemeoxygenase-1by Epigallocatechin-3-gallate via the phosphatidylinositol3-kinase/Aktand ERK pathways. Life Sci200678:2889–2897.
[173]. Na HK, Kim EH, Jung JH, Lee HH, Hyun JW, et al.(2)-Epigallocatechin gallateinduces Nrf2-mediated antioxidant enzyme expression via activation of PI3K andERK in human mammary epithelial cells. Arch Biochem Biophys2008476:171–177.
[174]. Hausenloy DJ, Yellon DM. New directions for protecting the heart againstischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase(RISK)-pathway. Cardiovasc Res200461:448–460.
[175]. Chan TO, Rittenhouse SE, Tsichlis PN. AKT/PKB and other D3phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependentphosphorylation. Annu Rev Biochem199968:965–1014.
[176]. Apopa PL, He X, Ma Q. Phosphorylation of Nrf2in the transcription activationdomain by casein kinase2(CK2) is critical for the nuclear translocation andtranscription activation function of Nrf2in IMR-32neuroblastoma cells. J BiochemMol Toxicol200822:63–76.
[177]. Surh YJ, Kundu JK, Na HK. Nrf2as a master redox switch in turning on thecellular signaling involved in the induction of cytoprotective genes by somechemopreventive phytochemicals. Planta Med200874:1526–1539.
[178]. Jain AK, Jaiswal AK. GSK-3beta acts upstream of Fyn kinase in regulation ofnuclear export and degradation of NF-E2related factor2. J Biol Chem2007282:16502–16510.
[179]. Ashrafian H, Czibik G, Bellahcene M, Aksentijevic D, Smith AC, et al. Fumarate iscardioprotective via activation of the Nrf2antioxidant pathway. Cell Metab201215:361–371.
[180]. Kim J, Cha YN, Surh YJ. A protective role of nuclear factor-erythroid2-relatedfactor-2(Nrf2) in inflammatory disorders. Mutat Res2010690:12–23.
[181]. Pickering AM, Linder RA, Zhang H, Forman HJ, Davies KJ. Nrf2-dependentinduction of proteasome and Pa28alphabeta regulator are required for adaptation tooxidative stress. J Biol Chem2012287:10021–10031.
[182]. Shay KP, Michels AJ, Li W, Kong AN, Hagen TM. Cap-independent Nrf2translation is part of a lipoic acid-stimulated detoxification stress response. BiochimBiophys Acta20121823:1102–1109.
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