丙酮酸乙酯对急性肝损伤保护作用的研究
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摘要
目的:通过研究丙酮酸乙酯对急性肝损伤大鼠肠粘膜紧密连接蛋白ZO-1表达和肝枯否细胞炎症因子释放以及对血管内皮细胞炎症因子释放的影响,探讨丙酮酸乙酯对急性肝损伤的保护作用及其机制。
材料与方法:第一部分实验:Wistar大鼠30只,随机分为对照组(腹腔注射等量生理盐水)、急性肝损伤组(D-GalN/LPS 700mg/5ug/kg腹腔注射)、EP预防组(于D-GalN/LPS注射前1h,EP40mg/kg腹腔注射)。以上各组于注射造模后48h自腹主动脉采皿做血浆ALT及内毒素水平的检测,并留取一段肠组织HIE染色观察并采用免疫组化方法测定肠粘膜上皮细胞紧密连接蛋白ZO-1的表达。第二部分实验:Wistar大鼠30只,随机分为对照组(腹腔注射等量生理盐水)、急性肝损伤组(D-GalN/LPS 700mg/5ug/kg腹腔注射)、EP治疗组(于注射D-GalN/LPS后24h,EP40mg/kg腹腔注射)。各组于注射造模后48h腹主动脉取血,分别用自动生化仪测血浆ALT含量、ELISA方法检测血浆TNF-α含量、Western blot方法检测血浆HMGB1含量。第三部分实验:1、新生儿脐静脉内皮细胞体外原代培养与鉴定:将新生儿脐静脉通过酶消化法使内皮细胞脱落,进行原代培养并采用免疫组化方法对内皮细胞vWF因子进行鉴定。2、细胞免疫组化实验分为三组:对照组、LPS刺激组、EP组,采用免疫组化方法检测脐静脉内皮细胞HMGB1、ICAM-1的表达;3、HMGB1在人脐静脉内皮细胞分泌的时间规律以及丙酮酸乙酯抑制人脐静脉内皮细胞分泌HMGB1的作用:细胞分三组,对照组、LPS刺激组(LPS100ng/ml)与EP组(LPS100ng/ml+EP10mM),每组设5个复孔,设0h、6h、12h、24h、48h五个时问点。采用Western blot方法检测培养上清液HMGB1的含量。4、不同剂量的EP对人脐静脉内皮细胞分泌HMGB1的作用。细胞分三组(EP0uM组、5uM组、10uM组),采用Western blot方法检测培养上清液HMGB1的含量。
结果:第一部分实验:急性肝损伤组ALT、Endotoxin含量显著高于正常对照组(P＜0.01),丙酮酸乙酯预防组ALT、Endotoxin含量仍高于正常对照组,但显著低于急性肝损伤组(P＜0.05)。病理组织HE染色观察可见对照组大鼠肠粘膜表面绒毛排列整齐、柱状上皮细胞结构完整;肝损伤组大鼠肠粘膜表现为问质充血水肿,绒毛顶端下间隙增宽,绒毛脱落坏死;EP预防组改变较损伤组减轻。免疫组化结果可见ZO-1正常时均匀一致地分布于小肠上皮细胞连接处的尖端:肝损伤组ZO-1分布不均、染色变淡,EP预防组介于二者之间。第二部分实验:急性肝损伤组ALT、TNF-α含量显著高于正常对照组(P＜0.01),丙酮酸乙酯治疗组ALT、TNF-α含量仍高于正常对照组,但显著低于急性肝损伤组(P＜0.01)。各时间点血浆HMGB1含量变化Western blot检测结果显示,对照组大鼠血浆中未检测到HMGB1;ALI组HMGB1含量为171.75±18.80ng/ml;EP组HMGB1含量为78.79±8.55ng/ml。EP组HMGB1含量显著低于ALI组(P＜0.01)。第三部分实验:原代培养脐静脉内皮细胞vWF因子经免疫组化检测证实原代及传代培养的细胞为人脐静脉内皮细胞。脐静脉内皮细胞ICAM-1、HMGB1表达免疫组化结果显示:未刺激时HMGB1聚集在细胞核内,细胞核呈棕色深染;LPS组刺激后HMGB1从细胞核释放,胞浆染色加深;EP组HMGB1释放被部分抑制,胞浆染色变浅。未刺激时细胞膜、胞浆表面ICAM-1微弱表达;LPS组ICAM-1在胞膜及胞浆中的表达呈强阳性,胞浆呈深棕色染色;EP组ICAM-1在胞膜及胞浆中的表达明显减弱。培养上清液中HMGB1含量变化检测:LPS组上清液HMGB1含量随诱导时间延长明显增高,呈时间依赖方式,24h达分泌高峰;EP组上清液HMGB1含量变化趋势与LPS组一致,但HMGB1含量明显降低(P＜0.05)。不同剂量的EP对人脐静脉内皮细胞分泌HMGB1的作用结果显示各细胞组于LPS100ng/ml刺激16h后,EP5uM剂量组对HMGB1分泌具有一定的抑制作用,与EP0uM组比,HMGB1含量明显降低(P＜0.05);10uM剂量组与0uM组比P＜0.01:而且10uM剂量组与5uM剂量组比p＜0.05,具有显著差异。
结论:
1、丙酮酸乙酯可以增加急性肝损伤时肠粘膜上皮细胞紧密连接蛋白ZO-1的表达,可以阻止肠源性内毒素血症的发生。
2、丙酮酸乙酯可以抑制急性肝损伤时枯否细胞释放TNF-α、HMGB1,减轻由炎症因子引起的肝损伤。
3、丙酮酸乙酯可以减少血管内皮细胞释放ICAM-1、HMGB1,对急性肝损伤时肝脏微循坏障碍有改善作用。
Objective:To study effects of ethyl pyruvte on expression of the tight junction associated protein-ZO-1 between epithelial cells of intestinal mucosa and on release of cytokins from kupffer cells or from human umbilical vein endothelial cells,in order to explore the protective role and pathogenesis of ethyl pyruvte in.acute liver injury.
Materials and Methods:The first part of the experiment:Thirty BW 190～250g male wistar rats were randomly divided into three groups(n=10 for each group),normal contral group,acute liver injury group(D-GalN/LPS,700mg/5ug/kg,i.p.)and EP group(pretreatment with EP,40mg/kg,lhour befor i.p with D-GalN/LPS).48 hours after D-GalN/LPS was administered,the parameters of plasma's ALT and Endotoxin were measured and historical staining of intestinal tissue was evaluated and ZO-1 was observed by immunohistochemistry. The second part of the experiment:Thirty BW 190～250g male wistar rats were randomly divided into three groups.(n=10for each group),normal contral group,acute liver injury group(D-GalN/LPS,700mg/5ug/kg,i.p.)and EP group(treatment with EP,40mg/kg,24 hour after i.p with D-GalN/LPS)48 hours after D-GalN/LPS was administered,the parameters of plasma's ALT,TNF-αand HMGB1 were measured respectively.The third part of the experiment:Neonate umbilical vein endothelial cells were primary cultured and identified in vitro,Firstly,the cells were divided into three groups in every experiments,LPS stimulation group,EP group and normal contral group,then the expression of HMGB1,ICAM-1 between umbilical vein endothelial cells were measured by immunohistochemistry.Secondly,the cells were divided into normal contral group,LPS stimulation group and EP group,on every time points(Ohour,6hour,12hour,24hour,48hour),the level of HMGB1 in the supernatant were measured by Western blot.Thirdly,the cells were divided into three groups,0uM EP group, 5uM EP group and 10uM EP group,and the level of HMGB1 in the supematant were measured by Western blot.
Results:The first part of the experiment:The levels of ALT and Endotoxin were markly higher in the acute liver injury group than that in the nomal contral group(P＜0.01).In EP group, the levels of ALT and Endotoxin were still higher than that in the nomal contral group but were obviously lower than that in the acute liver injury group(P＜0.05).The staining of ZO-1 in the control rats was similar to a honeycomb,which reflected a continuous and uniform distribution localized at the apical portion of cell-to-cell contact of the enterocytes.In the acute liver injury group,the signals of ZO-1 were disrupted and irregularly distributed at the outer enterocyte periphery.The content of ZO-1 was obviously lower in the acute liver injury group than that in the control group.Meanwhile,the level of ZO-1 in EP,prevention group was higher than that in the acute liver injury group.The second part of the experiment:The levels of ALT and TNF-αin plasma of contral group had no difference in various times,however,the ALT and TNF-αlevels in the acute liver injury group were much higher than that in nomal group.Pretreat with EP could reduce the release of ALT and TNF-α.We evaluated HMGB1 protein levels by Western blot analysis,and couldn't detect the expression of it in contral group.The HMGB1 levels in the EP group(78.79±8.55ng/ml)were much lower than that in the acute liver injury group(171.75±18.80ng/ml)(P＜0.01).The third part of the experiment:The primary cultured cells were verified as vascular endothelial cells by the examination of the immunohistochemical staining of the factorⅧrelated antigen(vWF).The expression of ICAM-1 and HMGB1 in HUVEC which were analysed by immunohistochemistry was very low without stimulation,however,increased obviously after stimulated with LPS,Pretreat with EP could reduce the release of ICAM-1 and HMGB1.After stimulation HUVEC for 6hour,12hour,24hour and 48hour with 100 ng/ml LPS,HMGB1 in the supernate were increased in a time-dependent manner,and reach the peak at 24hour.When pretreated with EP,the HMGB1 protein levels decreased accordingly.After stimulation HUVEC for 16hour with 100 ng/ml LPS,as compared with 0uM EP group,The HMGB1 levels in the 10uM EP group were much lower than that iri the 5uMEP group.
Conclusion:1、Ethyl pyruvate could upregulate the expression of ZO-1 between umbilical vein endothelial cells and inhibit the genesis of intestinal endotoxemia.2、Ethyl pyruvate could reduce the release of TNF-αand HMGB1 from kupffer cells and protect acute liver injury.3、Ethyl pyruvate could reduce the expression of HMGB1 and ICAM-1 from human umbilical vein endothelial cells and ameliorate the hepatic microcirculatory disturbance.
材料与方法:第一部分实验:Wistar大鼠30只,随机分为对照组(腹腔注射等量生理盐水)、急性肝损伤组(D-GalN/LPS 700mg/5ug/kg腹腔注射)、EP预防组(于D-GalN/LPS注射前1h,EP40mg/kg腹腔注射)。以上各组于注射造模后48h自腹主动脉采皿做血浆ALT及内毒素水平的检测,并留取一段肠组织HIE染色观察并采用免疫组化方法测定肠粘膜上皮细胞紧密连接蛋白ZO-1的表达。第二部分实验:Wistar大鼠30只,随机分为对照组(腹腔注射等量生理盐水)、急性肝损伤组(D-GalN/LPS 700mg/5ug/kg腹腔注射)、EP治疗组(于注射D-GalN/LPS后24h,EP40mg/kg腹腔注射)。各组于注射造模后48h腹主动脉取血,分别用自动生化仪测血浆ALT含量、ELISA方法检测血浆TNF-α含量、Western blot方法检测血浆HMGB1含量。第三部分实验:1、新生儿脐静脉内皮细胞体外原代培养与鉴定:将新生儿脐静脉通过酶消化法使内皮细胞脱落,进行原代培养并采用免疫组化方法对内皮细胞vWF因子进行鉴定。2、细胞免疫组化实验分为三组:对照组、LPS刺激组、EP组,采用免疫组化方法检测脐静脉内皮细胞HMGB1、ICAM-1的表达;3、HMGB1在人脐静脉内皮细胞分泌的时间规律以及丙酮酸乙酯抑制人脐静脉内皮细胞分泌HMGB1的作用:细胞分三组,对照组、LPS刺激组(LPS100ng/ml)与EP组(LPS100ng/ml+EP10mM),每组设5个复孔,设0h、6h、12h、24h、48h五个时问点。采用Western blot方法检测培养上清液HMGB1的含量。4、不同剂量的EP对人脐静脉内皮细胞分泌HMGB1的作用。细胞分三组(EP0uM组、5uM组、10uM组),采用Western blot方法检测培养上清液HMGB1的含量。
结果:第一部分实验:急性肝损伤组ALT、Endotoxin含量显著高于正常对照组(P＜0.01),丙酮酸乙酯预防组ALT、Endotoxin含量仍高于正常对照组,但显著低于急性肝损伤组(P＜0.05)。病理组织HE染色观察可见对照组大鼠肠粘膜表面绒毛排列整齐、柱状上皮细胞结构完整;肝损伤组大鼠肠粘膜表现为问质充血水肿,绒毛顶端下间隙增宽,绒毛脱落坏死;EP预防组改变较损伤组减轻。免疫组化结果可见ZO-1正常时均匀一致地分布于小肠上皮细胞连接处的尖端:肝损伤组ZO-1分布不均、染色变淡,EP预防组介于二者之间。第二部分实验:急性肝损伤组ALT、TNF-α含量显著高于正常对照组(P＜0.01),丙酮酸乙酯治疗组ALT、TNF-α含量仍高于正常对照组,但显著低于急性肝损伤组(P＜0.01)。各时间点血浆HMGB1含量变化Western blot检测结果显示,对照组大鼠血浆中未检测到HMGB1;ALI组HMGB1含量为171.75±18.80ng/ml;EP组HMGB1含量为78.79±8.55ng/ml。EP组HMGB1含量显著低于ALI组(P＜0.01)。第三部分实验:原代培养脐静脉内皮细胞vWF因子经免疫组化检测证实原代及传代培养的细胞为人脐静脉内皮细胞。脐静脉内皮细胞ICAM-1、HMGB1表达免疫组化结果显示:未刺激时HMGB1聚集在细胞核内,细胞核呈棕色深染;LPS组刺激后HMGB1从细胞核释放,胞浆染色加深;EP组HMGB1释放被部分抑制,胞浆染色变浅。未刺激时细胞膜、胞浆表面ICAM-1微弱表达;LPS组ICAM-1在胞膜及胞浆中的表达呈强阳性,胞浆呈深棕色染色;EP组ICAM-1在胞膜及胞浆中的表达明显减弱。培养上清液中HMGB1含量变化检测:LPS组上清液HMGB1含量随诱导时间延长明显增高,呈时间依赖方式,24h达分泌高峰;EP组上清液HMGB1含量变化趋势与LPS组一致,但HMGB1含量明显降低(P＜0.05)。不同剂量的EP对人脐静脉内皮细胞分泌HMGB1的作用结果显示各细胞组于LPS100ng/ml刺激16h后,EP5uM剂量组对HMGB1分泌具有一定的抑制作用,与EP0uM组比,HMGB1含量明显降低(P＜0.05);10uM剂量组与0uM组比P＜0.01:而且10uM剂量组与5uM剂量组比p＜0.05,具有显著差异。
结论:
1、丙酮酸乙酯可以增加急性肝损伤时肠粘膜上皮细胞紧密连接蛋白ZO-1的表达,可以阻止肠源性内毒素血症的发生。
2、丙酮酸乙酯可以抑制急性肝损伤时枯否细胞释放TNF-α、HMGB1,减轻由炎症因子引起的肝损伤。
3、丙酮酸乙酯可以减少血管内皮细胞释放ICAM-1、HMGB1,对急性肝损伤时肝脏微循坏障碍有改善作用。
Objective:To study effects of ethyl pyruvte on expression of the tight junction associated protein-ZO-1 between epithelial cells of intestinal mucosa and on release of cytokins from kupffer cells or from human umbilical vein endothelial cells,in order to explore the protective role and pathogenesis of ethyl pyruvte in.acute liver injury.
Materials and Methods:The first part of the experiment:Thirty BW 190～250g male wistar rats were randomly divided into three groups(n=10 for each group),normal contral group,acute liver injury group(D-GalN/LPS,700mg/5ug/kg,i.p.)and EP group(pretreatment with EP,40mg/kg,lhour befor i.p with D-GalN/LPS).48 hours after D-GalN/LPS was administered,the parameters of plasma's ALT and Endotoxin were measured and historical staining of intestinal tissue was evaluated and ZO-1 was observed by immunohistochemistry. The second part of the experiment:Thirty BW 190～250g male wistar rats were randomly divided into three groups.(n=10for each group),normal contral group,acute liver injury group(D-GalN/LPS,700mg/5ug/kg,i.p.)and EP group(treatment with EP,40mg/kg,24 hour after i.p with D-GalN/LPS)48 hours after D-GalN/LPS was administered,the parameters of plasma's ALT,TNF-αand HMGB1 were measured respectively.The third part of the experiment:Neonate umbilical vein endothelial cells were primary cultured and identified in vitro,Firstly,the cells were divided into three groups in every experiments,LPS stimulation group,EP group and normal contral group,then the expression of HMGB1,ICAM-1 between umbilical vein endothelial cells were measured by immunohistochemistry.Secondly,the cells were divided into normal contral group,LPS stimulation group and EP group,on every time points(Ohour,6hour,12hour,24hour,48hour),the level of HMGB1 in the supernatant were measured by Western blot.Thirdly,the cells were divided into three groups,0uM EP group, 5uM EP group and 10uM EP group,and the level of HMGB1 in the supematant were measured by Western blot.
Results:The first part of the experiment:The levels of ALT and Endotoxin were markly higher in the acute liver injury group than that in the nomal contral group(P＜0.01).In EP group, the levels of ALT and Endotoxin were still higher than that in the nomal contral group but were obviously lower than that in the acute liver injury group(P＜0.05).The staining of ZO-1 in the control rats was similar to a honeycomb,which reflected a continuous and uniform distribution localized at the apical portion of cell-to-cell contact of the enterocytes.In the acute liver injury group,the signals of ZO-1 were disrupted and irregularly distributed at the outer enterocyte periphery.The content of ZO-1 was obviously lower in the acute liver injury group than that in the control group.Meanwhile,the level of ZO-1 in EP,prevention group was higher than that in the acute liver injury group.The second part of the experiment:The levels of ALT and TNF-αin plasma of contral group had no difference in various times,however,the ALT and TNF-αlevels in the acute liver injury group were much higher than that in nomal group.Pretreat with EP could reduce the release of ALT and TNF-α.We evaluated HMGB1 protein levels by Western blot analysis,and couldn't detect the expression of it in contral group.The HMGB1 levels in the EP group(78.79±8.55ng/ml)were much lower than that in the acute liver injury group(171.75±18.80ng/ml)(P＜0.01).The third part of the experiment:The primary cultured cells were verified as vascular endothelial cells by the examination of the immunohistochemical staining of the factorⅧrelated antigen(vWF).The expression of ICAM-1 and HMGB1 in HUVEC which were analysed by immunohistochemistry was very low without stimulation,however,increased obviously after stimulated with LPS,Pretreat with EP could reduce the release of ICAM-1 and HMGB1.After stimulation HUVEC for 6hour,12hour,24hour and 48hour with 100 ng/ml LPS,HMGB1 in the supernate were increased in a time-dependent manner,and reach the peak at 24hour.When pretreated with EP,the HMGB1 protein levels decreased accordingly.After stimulation HUVEC for 16hour with 100 ng/ml LPS,as compared with 0uM EP group,The HMGB1 levels in the 10uM EP group were much lower than that iri the 5uMEP group.
Conclusion:1、Ethyl pyruvate could upregulate the expression of ZO-1 between umbilical vein endothelial cells and inhibit the genesis of intestinal endotoxemia.2、Ethyl pyruvate could reduce the release of TNF-αand HMGB1 from kupffer cells and protect acute liver injury.3、Ethyl pyruvate could reduce the expression of HMGB1 and ICAM-1 from human umbilical vein endothelial cells and ameliorate the hepatic microcirculatory disturbance.
引文
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[19]Weiler F,Marbe T,Scheppach W,Schauber J.Influence of protein kinase,C on transcription of the tight junction elements ZO-1 and occludin.J Cell Physiol 2005;204:83-86
[20]Cruz N,Qi L,Alvarez X,Berg RD,Deitch EA.The Caco-2 cell monolayer system as an in vitro model for studying bacterialenterocyte interactions and bacterial translocation.J Burn Care Rehabil 1994;15:207-212
[21]Sappington PL,Han X,Yang R,Delude RL,Fink MR Ethyl pyruvate ameliorates intestinal epithelial barrier dysfunction in endotoxemic mice and immunostimulated caco-2 enterocytic monolayers.J Pharmacol Exp Ther 2003;304:464-476
[22]Raschperger E,Engstrom U,Pettersson RF,Fuxe J.CLMP,a novel member of the CTX family and a new component of epithelial tight junctions.J Biol Chem 2004;279:796-804
[23]Neunlist M,Toumi F,Oreschkova T,Denis M,Leborgne J,Laboisse CL,Galmiche JP,Jarry A.Human ENS regulates the intestinal epithelial barrier permeability and a tight junctionassociated protein ZO-1 via VIPergic pathways.Am J Physiol Gastrointest Liver Physiol 2003;285:G1028-1036
[24]Sappington PL,Tracey K J,Yang H,Delude RL,and Fink MP(2002)HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice.Gastroenterology 123:790-802.
[25]Salzman AL,Denenberg AG,Ueta I,O'Connor M,Linn SC,and Szabo C(1996)Induction and activity of nitric oxide synthase in cultured human intestinal epithelial monolayers.Am J Physiol 270:G565-G573.
[26]韩德伍.肝功能衰竭发病机制的研究—肠源性内毒素血症假说[J].中华肝脏病杂志,1995,3(3):134-137
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[28]McKessar SJ,Betty AM,Bell JM,et al.Genetic charactcrimion of VanG,a novel vanemycin resistance locus of Entericous faecalis.Antimietob Agents Chernuther,2 000,44(11):3224-3228
[29]Andersson U,Wang H,Palmblad K,et al.High mobility group 1 protein(HMG-1)stimulates proinflammatory cytokin synthesis in human monocytes.J Exp Med,2000,192(14):565-570
[30]Wang H,Bloom O,Zhang M,et al.HMG-1 as a late mediator of endotoxin lethality in mice.Science 1999.285:248-251
[31]Mullins GE,Sunden-Cullberg J,Johansson AS,et al.Activation of human umbilical vein endothelial cells leads to relocation and release of highmobility group box chromosomal protein 1.Scand J Immunol,2004,60(6):566-573
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[33]Yang H,Ochani M,Li Jet al.Reversifig established sepsis with antagonists of endogenous high-mobility group box 1.Proc.Natl.Acad.Sci.U S A 2004.101:296-301.
[34]Kokkola R,Sundberg E,Ulfgren AK,et al.High mobility group box chromosomal protein 1:a novel proinflammatory mediator in synovitis.Arthritis Rheum.2002.46:2598-2603.
[35]Taniguchi N,Kawahara K,Yone K,et al.High mobility group box chromosomal protein 1plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine.Arthritis Rheum.2003.48:971-981.
[36]Rahman I,MacNee W.Regulation redox glutathione levels and gene transcription in lung inflammation:therapeutic approaches[J].Free Radic Biol Med,2000,28:1405-1420.
[37]姚咏明,姚胜,陈劲松,等.NF-κB抑制剂对烫伤脓毒症大鼠致炎/抗炎细胞因子表达的影响[J].解放军医学杂志,2004,29:33 35.
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[43]Du XL,Sui GZ,Stockklauser FK,et al.Induction of apoptosis by high proinsulin and glucose in cultured human umbilical vein endothelial cells is mediated by reactive oxygen species[J].Diabetologia,1998,41:249
[44]董玉兰,陈铁镇,王铁吉,等.人脐带静脉内皮细胞的继代培养.中国医科大学学报, 1989,18(2):81-85
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[48]Gimbrone MA.Human vascular endothelial cells in culture,growth and DNA synthesis.J Cell BioL,1974;60:673
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[50]谢平初,陆家齐,孙大铭,陆连荣,等.猪内毒素休克外周与内脏微循环灌注的动态变化.中国危重病急救医学,1999,11:718-720
[51]Schmid SGW.Capillary plugging by granulocytes and the no-reflow phenomenon in the microcirculation.Proc Fed Am Soc Exp Biol,1987,46:2379-2401
[52]McKessar SJ,Betty AM,Bell JM,et al.Genetic charactcrimion of VanG,a novel v anemycin resistance locus of Entericous faecalis.Antimietob Agents Chernuther,2000,44(11):3224-3228
[53]Andersson U,Wang H,Palmblad K,et al.High mobility group 1 protein(HMG-1)stimulates proinflammatory cytokin synthesis in human monocytes.J Exp Med,2000,192(14):565-570
[54]Wang H,Bloom O,Zhang M,et al.HMG-1 as a late mediator of endotoxin lethality in mice.Science 1999.285:248-251
[1]周爱儒.主编.生物化学[M].第六版.北京:人民卫生出版社.2004.77-88
[2]Desagher,S.,et al.Pyruvate Protects Neurons against Hydrogen Peroxide-Induced Toxicity.J.Neuroscience.1997,17(23):9060-9067
[3]Montgomery CM and Webb JL.Metabolic studies on heart mitochondria.Ⅱ.The inhibitory action of parapyruvate on the tricarboxylic acid cycle.J Biol Chem,1956,221:359-368
[4]Sims CA,Wattanasirichaigoon S,Menconi M J,Ajami AM and Fink ME Ringer's ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats.Crit Care Med,2001,29:1513-1518
[5]Varma SD,Devamanoharan PS and Ali AH.Prevention of intracellular oxidative stress to lens by pyruvate and its ester.Free Rad Res,1998,28:131-135
[6]Adickes F and Andresen G,Zur kenntnis der reihe der normalen aliphatischen β-oxysauren und der α-ketosauren.Ann Chem(Justus Liebigs),1943,50:41-57.
[7]Dobsak,P.,Courderot-Masuyer,C.,Zeller,M.,et al.Antioxidative properties of pyruvate and protection of the ischemic rat heart during cardioplegia.J Cardiovasc Pharmacol,1999;34(5):651-659.
[8]Song,M.,Kellum,J.A.Kaldas,H.,et al.Evidence That Glutathione Depletion Is a Mechanism Responsible for the Anti-Inflammatory Effects of Ethyl Pyruvate in Cultured Lipopolysaccharide-Stimulated RAW 264.7 Cells.J.Pharmacol.Exp.Ther.,2004;308: 307-316.
[9]钟慈声,孙安阳.一氧化氮的生物医学.上海:上海医科大学出版社,1997;3-250.
[10]Livolsi,A.,V.Busuttil,V.Imbert,R.T.et al.Tyrosine phosphorylation- dependent activation of NF-κB:Requirement for p56 LCK and ZAP-70 protein tyrosine kinases.Eur.J.Biochem.2001.268,1508-1515.
[11]Rahman,I.,B.Mulier,RS.Gilmour,T.Watchorn,etal.Oxidant-mediated lung epithelial cell tolerance:the role of intracellular glutathione and nuclear factor-kappaB.Biochem.Pharmacol,2001;62:787-794.
[12]Schoonbroodt,S.,V.Ferreira,M.Best-Belpomme,et al.Crucial role of the amino-terminal tyrosine residue 42 and the carboxyl-terminal PEST domain of IκBα in NF-κB activation by oxidative stress.J.Immunol.2000,164:4292-4300.
[13]Schreck,R.,B.Meier,D.N.Mannel,et al.Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells.J.Exp.Med.1992.175:1181-1194.
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