吡格列酮及黄酮类药物抑制2型糖尿病大鼠肾脏泛素蛋白酶复合体系统介导的NF-κB活化作用的研究
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摘要
目的
泛素蛋白酶复合体系统是细胞内氧化蛋白降解的主要途径,糖尿病氧化应激可引起细胞内蛋白空间结构异常,从而进入泛素蛋白酶复合体系统降解。因此,本研究旨在揭示高糖高脂喂养结合小剂量STZ诱导的2型糖尿病大鼠肾脏组织泛素蛋白酶复合体系统介导NF-κB的活化与24小时尿蛋白、肾脏病理改变之间的关系;并通过观察吡格列酮、复方丹参滴丸浸膏、槲皮素药物干预对2型糖尿病大鼠肾脏组织泛素、NF-κB表达的影响,以揭示上述三种药物对2型糖尿病肾脏保护作用的机制。
方法
清洁级SD雄性大鼠52只,适应性喂养1周,随机分为2组,正常对照组(NC组,n=8只)给予普通饲料喂养;造模组44只,给予高糖高脂饲料。喂养4周后,腹腔注射链脲佐菌素(STZ,30mg·kg-1)制备2型糖尿病大鼠模型。72小时后,尾静脉采血随机两次血糖≥16.7mmol/L,视为造模成功,成模大鼠继续给予高糖高脂饲料喂养,并再次随机分为4组:糖尿病对照组(DM组,n=9只)、吡格列酮治疗组(PIO组,n=9只,4 mg·kg-1·d-1)、复方丹参滴丸浸膏治疗组(DSP组,n=9只,500 mg·kg-1·d-1)、槲皮素治疗组(QUE组,n=9只,100 mg·kg-1·d-1);上述三种药物均溶于蒸馏水等量灌胃,NC组和DM组给予等量蒸馏水灌胃。治疗8周后各组大鼠分别脱臼处死,处死前一日收集24小时尿,检测24小时尿蛋白定量;下腔静脉取血检测空腹血糖(GLU)、空腹胰岛素(INS)、胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、尿素氮(BUN)、肌酐(Scr)。取双肾称重,计算肾脏肥大指数(肾重/体重),10%福尔马林固定,石蜡切片, PASM染色观察肾小球细胞外基质的堆积,并分别采用免疫组化、Western-blot方法检测肾脏组织中泛素、NF-κB p65蛋白表达。数据运用SPSS13.0统计软件分析。
结果
实验结束时高糖高脂喂养结合小剂量STZ诱导的2型糖尿病SD大鼠,均表现为持续蛋白尿及肾小球体积增大、基底膜、系膜基质增生、局灶节段性硬化,肾小管空泡变性等糖尿病肾病典型变化。
与NC组相比较,高糖高脂喂养结合小剂量STZ诱导的2型糖尿病大鼠空腹血糖、空腹胰岛素、肌酐、尿素氮、血清胆固醇、甘油三酯、低密度脂蛋白胆固醇水平均明显增高(P<0.01);高密度脂蛋白胆固醇水均明显降低(P<0.05);24小时尿蛋白总量、肾脏肥大指数、肾小球基质堆积指数亦均明显增高(P<0.01);肾脏组织泛素、NF-κB p65蛋白的表达水平均明显增高(P<0.01)。
与DM组比较,三个治疗组空腹血糖、空腹胰岛素、肌酐、尿素氮、血清胆固醇、甘油三酯、低密度脂蛋白胆固醇水平均较低(P﹤0.01);高密度脂蛋白胆固醇水平无明显差异(P﹥0.05);24小时尿蛋白总量、肾脏肥大指数、肾小球基质堆积指数均较低(P﹤0.01);肾脏组织泛素、NF-κB p65蛋白的表达水平均较低(P﹤0.01)。三种药物干预治疗后,上述指标均有不同程度改善,但仍未降至正常,三个治疗组组间上述指标无明显差异(P﹥0.05)。
各组大鼠24小时尿蛋白定量与Western-blot检测泛素、NF-κB p65蛋白表达水平呈正相关(P﹤0.01)。各组大鼠肾小球基质堆积指数与Western-blot检测泛素、NF-κB p65蛋白表达水平呈正相关(P﹤0.01)。
结论
1、2型糖尿病大鼠出现持续蛋白尿、糖尿病肾病早期病理改变,与泛素、NF-κB p65表达呈正相关;
2、吡格列酮、复方丹参浸膏及槲皮素三种药物干预后均可改善糖脂代谢,减轻氧化应激,下调肾组织泛素、NF-κB p65表达,从而减轻肾脏炎症反应,降低24小时尿蛋白,减轻糖尿病肾病病理改变,延缓糖尿病肾病进展。
Objective
The Ubiquitin-proteasome system is principal degration route of intracellular and oxidized proteins, thus diabetes-induced oxidative stress can lead to protein misfolding and degradation by the ubiquitin-proteasome system. The aim of this study was to evaluate the activity of ubiquitin-proteasome system in renal tissues of type 2 diabetic rats in relation to inflammation and its renal structural lesions, and to observe the effecs of Pioglitazone, Danshen dripping pill and Quercetin on the renal expression of ubiquitin and NF-κB p65 and to investigate its renoprotective effects.
Method
After breed adaptively for 1 week, a total of 52 specific pathogen-free male SD rats were randomly divided into 2 groups:normal group for comparison purpose ( group NC, n=8 ) was fed for regular diet and experimental model group ( n=44 ) was fed with fat enriched diets.The rats of experimental model groups were intraperitoneally given low-dose streptozotocin ( STZ, 30 mg/kg ) after having the sucrose and fat enriched diets for 4 weeks. After 72 hours, measured randomly blood glucose twice and the one whose blood glucose was equal or above 16.7mmo1/L was enlisted. The modeling rats were further randomly divided into four groups: type 2 diabetic group ( Group DM, n=9 ) , pioglitazone group ( Group PIO, n=9, 4 mg·kg-1·d-1 ) , danshen dripping pill group ( Group DSP, n=9, 500 mg·kg-1·d-1 ) and quercetin group ( Group QUE, n=9, 100 mg·kg-1·d-1). The rats of treatmental group were performed by intragastric administration for 8 weeks. The rats of two control groups were performed by intragastric administration with equivalent distilled water for 8 weeks. Before the rats were sacrificed, we collected 24 hours urine for measurement of 24h urinary protein, then killed the rats, gathered blood from vein immediately, and measured their fasting plasma glucose, fasting serum insulin, serum creatinine, blood urea nitrogen, triglyceride, total cholesterol, low density lipoprotein cholesterol and high density lipoprotein cholesterol.After that, the kidneys were removed and weighed to calculate the ratio of kidney weight vs body weight ( KW/BW ) . Put the kidney into 10% formalin to be fixed and made paraffinslices. Observed the pathological changes of the kidney and studied the expression of ubiquitin and NF-κB p65 in the kidney with immunohistochemical and Western-blot . The data were analyzed by SPSS13.0 system.
Results
The features of renal involvement in the model included overt persistent proteinuria and typical morphological changes, Histologically the earliest abnormality was mainly glomerular hypertrophy, Vascular changes, mild mesangial expansion and vacuolation of tubularelinal cell were came forth at the end of exprement.
Compared with group NC, the level of fasting plasma glucose, fasting serum insulin, triglyceride, total cholesterol, low density lipoprotein cholesterol, serum creatinine, blood urea nitrogen, 24h urinary protein, the ratio of kidney weight to body weight ( KW/BW ), extracellular matrix accumulation index and the expressions of ubiquitin and NF-κB p65 in type 2 diabetic rats were significantly increased ( P﹤0.01 ), the level of high density lipoprotein cholesterol in group DM was decrease( P﹤0.05 ).
Compared with group DM, the level of fasting plasma glucose, fasting serum insulin, triglyceride, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, serum creatinine, blood urea nitrogen, 24h urinary protein, the ratio of kidney weight to body weight ( KW/BW ), extracellular matrix accumulation index and the expressions of ubiquitin and NF-κB p65 in group PIO, DSP and QUE were significantly decrease( P﹤0.01 ). the level of high density lipoprotein cholesterol in group PIO, DSP and QUE was no significant difference with group DM( P﹥0.05 ). Afer treamwnt, each index was improved, but not reversed to normal level. It has no significant difference between group PIO, DSPand QUE (P﹥0.05).
The expression of ubiquitin and NF-κB p65 were positively related with the level of 24h urinary protein and extracellular matrix accumulation index.
Conclusion
①The features of renal involvement in the type 2 diabetic rats included overt persistent proteinuria and typical morphological changes. Increasing expression of ubiquitin and NF-κB p65 in type 2 diabetic rats were positively related with functional and pathological damage in rats renal.
②Pioglitazone, danshen dripping pill and quercetin can improve glucolipid metabolism, reduce oxidative stress and decrease the expression of ubiquitin and NF-κB p65 in renal tissues of type 2 diabetic rats. Thus they exerts the actions against inflammatory response and to decrease 24h urinary protein, which may have benefit in diabetic nephropathy.
泛素蛋白酶复合体系统是细胞内氧化蛋白降解的主要途径,糖尿病氧化应激可引起细胞内蛋白空间结构异常,从而进入泛素蛋白酶复合体系统降解。因此,本研究旨在揭示高糖高脂喂养结合小剂量STZ诱导的2型糖尿病大鼠肾脏组织泛素蛋白酶复合体系统介导NF-κB的活化与24小时尿蛋白、肾脏病理改变之间的关系;并通过观察吡格列酮、复方丹参滴丸浸膏、槲皮素药物干预对2型糖尿病大鼠肾脏组织泛素、NF-κB表达的影响,以揭示上述三种药物对2型糖尿病肾脏保护作用的机制。
方法
清洁级SD雄性大鼠52只,适应性喂养1周,随机分为2组,正常对照组(NC组,n=8只)给予普通饲料喂养;造模组44只,给予高糖高脂饲料。喂养4周后,腹腔注射链脲佐菌素(STZ,30mg·kg-1)制备2型糖尿病大鼠模型。72小时后,尾静脉采血随机两次血糖≥16.7mmol/L,视为造模成功,成模大鼠继续给予高糖高脂饲料喂养,并再次随机分为4组:糖尿病对照组(DM组,n=9只)、吡格列酮治疗组(PIO组,n=9只,4 mg·kg-1·d-1)、复方丹参滴丸浸膏治疗组(DSP组,n=9只,500 mg·kg-1·d-1)、槲皮素治疗组(QUE组,n=9只,100 mg·kg-1·d-1);上述三种药物均溶于蒸馏水等量灌胃,NC组和DM组给予等量蒸馏水灌胃。治疗8周后各组大鼠分别脱臼处死,处死前一日收集24小时尿,检测24小时尿蛋白定量;下腔静脉取血检测空腹血糖(GLU)、空腹胰岛素(INS)、胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、尿素氮(BUN)、肌酐(Scr)。取双肾称重,计算肾脏肥大指数(肾重/体重),10%福尔马林固定,石蜡切片, PASM染色观察肾小球细胞外基质的堆积,并分别采用免疫组化、Western-blot方法检测肾脏组织中泛素、NF-κB p65蛋白表达。数据运用SPSS13.0统计软件分析。
结果
实验结束时高糖高脂喂养结合小剂量STZ诱导的2型糖尿病SD大鼠,均表现为持续蛋白尿及肾小球体积增大、基底膜、系膜基质增生、局灶节段性硬化,肾小管空泡变性等糖尿病肾病典型变化。
与NC组相比较,高糖高脂喂养结合小剂量STZ诱导的2型糖尿病大鼠空腹血糖、空腹胰岛素、肌酐、尿素氮、血清胆固醇、甘油三酯、低密度脂蛋白胆固醇水平均明显增高(P<0.01);高密度脂蛋白胆固醇水均明显降低(P<0.05);24小时尿蛋白总量、肾脏肥大指数、肾小球基质堆积指数亦均明显增高(P<0.01);肾脏组织泛素、NF-κB p65蛋白的表达水平均明显增高(P<0.01)。
与DM组比较,三个治疗组空腹血糖、空腹胰岛素、肌酐、尿素氮、血清胆固醇、甘油三酯、低密度脂蛋白胆固醇水平均较低(P﹤0.01);高密度脂蛋白胆固醇水平无明显差异(P﹥0.05);24小时尿蛋白总量、肾脏肥大指数、肾小球基质堆积指数均较低(P﹤0.01);肾脏组织泛素、NF-κB p65蛋白的表达水平均较低(P﹤0.01)。三种药物干预治疗后,上述指标均有不同程度改善,但仍未降至正常,三个治疗组组间上述指标无明显差异(P﹥0.05)。
各组大鼠24小时尿蛋白定量与Western-blot检测泛素、NF-κB p65蛋白表达水平呈正相关(P﹤0.01)。各组大鼠肾小球基质堆积指数与Western-blot检测泛素、NF-κB p65蛋白表达水平呈正相关(P﹤0.01)。
结论
1、2型糖尿病大鼠出现持续蛋白尿、糖尿病肾病早期病理改变,与泛素、NF-κB p65表达呈正相关;
2、吡格列酮、复方丹参浸膏及槲皮素三种药物干预后均可改善糖脂代谢,减轻氧化应激,下调肾组织泛素、NF-κB p65表达,从而减轻肾脏炎症反应,降低24小时尿蛋白,减轻糖尿病肾病病理改变,延缓糖尿病肾病进展。
Objective
The Ubiquitin-proteasome system is principal degration route of intracellular and oxidized proteins, thus diabetes-induced oxidative stress can lead to protein misfolding and degradation by the ubiquitin-proteasome system. The aim of this study was to evaluate the activity of ubiquitin-proteasome system in renal tissues of type 2 diabetic rats in relation to inflammation and its renal structural lesions, and to observe the effecs of Pioglitazone, Danshen dripping pill and Quercetin on the renal expression of ubiquitin and NF-κB p65 and to investigate its renoprotective effects.
Method
After breed adaptively for 1 week, a total of 52 specific pathogen-free male SD rats were randomly divided into 2 groups:normal group for comparison purpose ( group NC, n=8 ) was fed for regular diet and experimental model group ( n=44 ) was fed with fat enriched diets.The rats of experimental model groups were intraperitoneally given low-dose streptozotocin ( STZ, 30 mg/kg ) after having the sucrose and fat enriched diets for 4 weeks. After 72 hours, measured randomly blood glucose twice and the one whose blood glucose was equal or above 16.7mmo1/L was enlisted. The modeling rats were further randomly divided into four groups: type 2 diabetic group ( Group DM, n=9 ) , pioglitazone group ( Group PIO, n=9, 4 mg·kg-1·d-1 ) , danshen dripping pill group ( Group DSP, n=9, 500 mg·kg-1·d-1 ) and quercetin group ( Group QUE, n=9, 100 mg·kg-1·d-1). The rats of treatmental group were performed by intragastric administration for 8 weeks. The rats of two control groups were performed by intragastric administration with equivalent distilled water for 8 weeks. Before the rats were sacrificed, we collected 24 hours urine for measurement of 24h urinary protein, then killed the rats, gathered blood from vein immediately, and measured their fasting plasma glucose, fasting serum insulin, serum creatinine, blood urea nitrogen, triglyceride, total cholesterol, low density lipoprotein cholesterol and high density lipoprotein cholesterol.After that, the kidneys were removed and weighed to calculate the ratio of kidney weight vs body weight ( KW/BW ) . Put the kidney into 10% formalin to be fixed and made paraffinslices. Observed the pathological changes of the kidney and studied the expression of ubiquitin and NF-κB p65 in the kidney with immunohistochemical and Western-blot . The data were analyzed by SPSS13.0 system.
Results
The features of renal involvement in the model included overt persistent proteinuria and typical morphological changes, Histologically the earliest abnormality was mainly glomerular hypertrophy, Vascular changes, mild mesangial expansion and vacuolation of tubularelinal cell were came forth at the end of exprement.
Compared with group NC, the level of fasting plasma glucose, fasting serum insulin, triglyceride, total cholesterol, low density lipoprotein cholesterol, serum creatinine, blood urea nitrogen, 24h urinary protein, the ratio of kidney weight to body weight ( KW/BW ), extracellular matrix accumulation index and the expressions of ubiquitin and NF-κB p65 in type 2 diabetic rats were significantly increased ( P﹤0.01 ), the level of high density lipoprotein cholesterol in group DM was decrease( P﹤0.05 ).
Compared with group DM, the level of fasting plasma glucose, fasting serum insulin, triglyceride, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, serum creatinine, blood urea nitrogen, 24h urinary protein, the ratio of kidney weight to body weight ( KW/BW ), extracellular matrix accumulation index and the expressions of ubiquitin and NF-κB p65 in group PIO, DSP and QUE were significantly decrease( P﹤0.01 ). the level of high density lipoprotein cholesterol in group PIO, DSP and QUE was no significant difference with group DM( P﹥0.05 ). Afer treamwnt, each index was improved, but not reversed to normal level. It has no significant difference between group PIO, DSPand QUE (P﹥0.05).
The expression of ubiquitin and NF-κB p65 were positively related with the level of 24h urinary protein and extracellular matrix accumulation index.
Conclusion
①The features of renal involvement in the type 2 diabetic rats included overt persistent proteinuria and typical morphological changes. Increasing expression of ubiquitin and NF-κB p65 in type 2 diabetic rats were positively related with functional and pathological damage in rats renal.
②Pioglitazone, danshen dripping pill and quercetin can improve glucolipid metabolism, reduce oxidative stress and decrease the expression of ubiquitin and NF-κB p65 in renal tissues of type 2 diabetic rats. Thus they exerts the actions against inflammatory response and to decrease 24h urinary protein, which may have benefit in diabetic nephropathy.
引文
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27、VersariD , Herrmann J, Gossl M , et al. Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis. Arterioscler Thromb Vasc Biol. 2006, 26 (9): 2132-2139.
28、Marfella R, Filippo C D, Portoghese M, et al. Proteasome activity as a target of hormone replacement therapy-dependent plaque stabilization in postmenopausal women. Hypertension, 2008, 51 (4): 1135-1141.
29、Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science, 2001, 292(3):1552-1555.
30、Kummar D, Zimpelmann J, Robertson S, et al. Tubular and interstitianl cell in the steptozotocin diabetic rat kidney. [J] . Nephron Exp Nephrol, 2004, 96 (3): 77-88.
31、Li Q, Verma TM. NF-B regulation in the immune system. [J] . Nat Rev Immortal. 2002, 2 (10): 725-734.
32、王扬天,赵明,狄红杰.糖尿病大鼠肾病变过程中核因子-κB及诱导型一氧化氮合酶的表达.医学研究生学报,2006,19(5):416-419.
33、Han HJ, Jeon YJ, Lee YJ. Involvement of NF2kappaB in high glucose induced alteration of alpha-methyl-D-glucopyranoside(alpha-MG) uptake in renal proximal tubule cells. Cell Physiol Biochem,2003,13 (6) :375-384.
34、Rebecca L, Shen ZP, Melissah R, et al. Long term treatment with rosiglitazone and metform in reduces the extent of but not prevent islet amyloid deposition in mice expressing the gene for human islet amyloid polypeptide. Diabetes, 2005, 21 (11): 2235-2444.
35、MoraesLA, Piqueras L, Bishop D, et al. Peroxisome proliferatoractivated receptors and inflammation. Pharmacol Ther, 2005, 14 (1) :2-4.
36、陈丽,郭延云,章秋,et al.吡格列酮对 T2DM 大鼠肾脏超微结构及 NO、CRP 水平的影响.安徽医科大学学报,2007,42(10):494.
37、Ma LJ, Marcatoni C, Linton MF, et al. Peroxisome proliferators-activated receptor -gamma against nondiabetic glomerulosclerosis in rats . [J] .KidneyInt. 2001, 59 (5) :1899-1910.
38、Yamashita H, Nagai Y, Takamura T, et al.Thiazolidinedione derivatives ameliorate albuminuria in streptozotocin-induced diabetic spontaneous hypertensive rat. [J] . Metabo -lism . 2002, 51 (4) : 403-408.
39、田季雨,陈建宗,顾宜,et al.复方丹参滴丸对家兔血脂水平和颈动脉粥样硬化板块的影响.中国临床康复,2004,22(7):437.
40、许晶兰,王孝铭,王东霞.复方丹参滴丸对过氧化氢损伤的人脐静脉血管内皮细胞保护作用.中国病理生理杂志,2006,22(5):929.
41、陈频,徐向进,史道华.复方丹参滴丸对胰岛素抵抗大鼠的保护作用及其机制研究.中国中西医结合心脑血管病杂志,2008,6(5):33-36.
42、陈频,徐向进,史道华.复方丹参滴丸对高糖/高胰岛素诱导兔胸主动脉平滑肌细胞增殖的抑制作用.中国中西医结合急救杂志,2007,14(5):313-316.
43、苏俊峰、郭长江.食物类黄酮槲皮素的抗氧化作用.解放军预防医学杂志,2001,19(3):229.
44、Moon SK, Cho GO, Jung SY, et al. Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2, cell-cycle regulation, and matrixmetalloproteinase-9. Biochem Biophys Res Commun. 2003, 301 (4): 1069-1078.
45、Vessal M, Hemmati M, Vasei M, Antidiabetic effects of quercetin in streptozocin-induced diabetic rats, Comp Biochem physiol Toxicol Pharmacol, 2003, 135 (3) : 357-364.
46、Kamada C, da Silva ZL, Ohnishi-Kmeyama M, et al.Attention of lipid peroxidation and hyperlipidemia by quercetin glucoside in the aorta of high cholesteol-fed rabbit. [J] . Fee Radic Res, 2005 ,39 (2): 185-194.
47、Auger C, Teissedre PL, Gerain P, et al. Dietary wine phenolics catechin, quercetin, and resveratrol efficiently protect hypercholesterolemic hamsters against aortic fatty streak accumulation, [J] . Agric.Food Chem, 2005, 53 (6), 2015-2021.
48、徐向进,郑智勇,张荔群,王庆彪,et al.槲皮素对糖尿病大鼠肾脏的保护作用.中华内分泌代谢杂志,2001,17(5):316-319.
49、徐向进,吴玉水,冯修高,et al.槲皮素对糖尿病大鼠肾脏转化生长因子-β1(TGF-β1)表达的影响.中国糖尿病杂志,2001,9(1):44-48.
50、梅小斌,崔若兰,高从容,et al.槲皮素糖尿病大鼠肾病大鼠的肾小球周期素抑制剂 P27 水平的影响.2002,23(11):1208-1210.
51、李佑生,王文健,马宇滢,et al.复方丹参滴丸防治大鼠早期糖尿病肾脏损害的研究.中成药,2007,29(1):41.
1 、Aguilar RC, Wendland B, Ubiquitin not just for proteasomes anymore. Curropin Cell Biol, 2003. 15(2):184-190.
2 、Smalle j. Vierstra RD. The ubiquitin 26S proteasome proteolytic pathway. Annu Rev Plant Biol. 2004,55 (6): 555～590.
3 、Melikova MS, Filatova MM, Kornilova ES. Cbl-a polyfunctional regulator of cellular processes.[J].Tsitologiia. 2003, 45(11): 1134-1148.
4 、Fang.S, Lorick K L, Jensen J D, Weissman AM. RINGER finger ubiquitin protein ligases:Implications for tumorigenesis metastasis and for molecular targets in caner. Semin Cancer Biol. 2003, 13 (1): 5-14.
5、Petroski MD, Dehshaies RJ, Function and regulation of cullin-RING ubiquitin ligases . Nat Rev Mol Cell. Biol, 2005, 6 (1): 9-20.
6、Ohi MD,Vander kool CW, Rosenberg JA, Chazin WJ, Gould KL. Structural insights into the U-box a domain associated with multi-ubiquitination. Nature Struct Biol. 2003, 10 (4): 250-255.
7、Hatakeyama.S,Nakayama.KI ,U-box proteins as a new family of ubiquitin ligases[J].Biochem Bipphys Res Commun.2003,302(4):635-645.
8、Rui L, Yuan M, Frantz D, Shoelson S. White MF,SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2,J Biol Chem. 2002, 277 (44): 42394-42398.
9、Rome S, Meugnier E, Vidal H. The ubiquitin-proteasome pathway is a new partner for the control of insulin signaling. Curr Opin Clin Nutr Metab Care. 2004, 7 (3) 249-254.
10、叶彦,欧阳静萍,王保华等,IRS-1 的表达和泛素化在 KKAY 及C57BL/6J 小鼠糖尿病发展过程中的意义.武汉大学学报(医学版)2006,27(3):279-282.
11、Juan C, Molero, Samuel G,Waring, Adrian Cooper, Nigel Turner, Ross Laybutt: Casitas b-Lineage Lymphoma-Deficient Mice Are Protected Against High-Fat Diet-Induced Obesity and Insulin Resistance. Diabetes, 2006, 55 (3): 708-715.
12、Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI. Mechanismby which fatty acids inhibit insulin activation of insulin receptor substrate-1(IRS-1)-associated phosphatidylinositol3-kinase activity in musle. J Biol Chem, 2002, 277 (52): 50230-50236.
13、Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R, Defronzo RA, Cusi K. Dose-reponse effect of elevated plasma free fatty acid on insulin signaling. Diabetes, 2005, 54 (6): 1640-1648.
14、Molero JC, Jensen TE, Withers PC, Couzens M, Herzog H, Thien CB, Langdon WY , Walder K, Murphy MA, Bowtell DD, James DE. Cooney Gj:c-Cbl-deficient mice have reduced adiposity, higher energy expenditure and improved peripheral insulin action. J Clin Invest, 2004, 114 (9): 1326-1333.
15、Ling Qi, Jose E Heredia, Judith Y, Altarejos, TRB3 Links the E3 Ubiquitin Ligase COP1 to Lipid Metabolism. Science. 2006, 312 (5781): 1763-1766.
16、Lopez Avalos MD, Duvivier Kali VF, Xu G, Bonner Weir S, Sharma A, Weir GC. Evidence for a role of the ubiquitin-proteasome pathway in pancreatic islets. Diabetes, 2006, 55 (5): 1223-1231.
17、Kawaguchi M, Minami K, Nagashima K, Seino S. Essential role of ubiquitin-proteasome system in normal regulation of insulin secretion. J Biol Chem, 2006, 281 (19): 13015-13020.
18 、 Raffaele Marfella, Michele D Amico, Katherine Esposito, Mario Somoscachi, Ferndinando Carlo Sasso. The Ubiquitin-Proteasome System and Inflammatory Activity in Diabetic Atherosclerotic Plaques.Diabetes. 2006, 55 (3): 622-632.
19、Chunjiang Tan, Yuguang Li, Xuerui Tan, Hongxin Pan, Wen Huang, Inhibition of the ubiquitin-proteasome system: a new avenue foratherosclerosis.Clin Chem Lab Med, 2006, 44 (10): 1218-1225.
20、 Meiners S, Laule M, Rother W, Guenther C, Prauka I, Muschick P, Baumann G, Kloetzel PM, Sangl K. Ubiquitin-proteasome pathway as a new target for the prevention of restenosis.Circulation, 2002, 105(4): 483-489.
21、 Qiu W, Kohen Avramoglu R, Mhapsekar S, Tsai J, Austin RC, Adeli K. Glucosamine-induced endoplasmic reticulum stress promotes ApoB100 degradation: evidence for Grp78-mediated targeting to proteasomal degradation. Arterioscler Thromb Vasc Biol. 2005, 25 (3): 571-577.
22、 Kuhn DJ, Burns AC, Kazi A, Dou QP, Direct inhibition of the ubiquitin-proteasome pathway by ester bond-containing green tea polyphenols is associated with increased expression of sterol regulatory element-binding protein 2 and LDL receptor. Biochim Biophys Acta. 2004, 1682(1-3):1-10.
23、 Ersin Akarsu, Ibrahim Pririm, Ilyas Capoglu, Orhan Deniz, Relationship between electroneurographic changes and serum ubiquitin levels in patients with type 2diabetes. Diabetes Care, 2001, 24 (1): 100-103.
24、 Adachi Uehara N, Kato M, Nimura Y, Seki N, Ishihara A, Matsumoto E, Iwase K, Ohtsuka S, Kodama H, Mizota A, Yamamoto S, Adachi Usami E, Takiguchi M. Up-regulation of genes for oxidative phosphorylation and protein turnover in diabetic mouse retina. Exp Eye Res, 2006, 83 (4): 849-857.
2、Wu LL, Chiou CC, Chang PY, et al.Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics.Clin Chim Acta, 2004, 339 (1): 1 - 9.
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4、Ding Q, Dimayuga E, Keller JN. Oxidative stress, Proteasome regulation of Oxidative stress, Proteasome regulation of oxidative stress in aging and age-related diseases of the CNS. Antioxid Redox Signal. 2006, 8 (1-2): 163–172.
5 、Marfella R, Amico M D, Esposito K, SomoscachiM, et al.The Ubiquitin-Proteasome System and Inflammatory Activity in Diabetic Atherosclerotic Plaques, Diabetes, 2006, 55(3): 622-632.
6 、Fernandes R, Ramalho J, Pereira P. Oxidative stress upregulates the ubiquitin- proteasome pathway in retinal endothelial cells.Molecular Vision, 2006, 12(175): 1526-1535.
7、Kaniuk N A, Kiraly M, Bates H, et al.Ubiquitinated-Protein Aggregates Form in Pancreatic-Cells During Diabetes-Induced Oxidative Stress and Are Regulated by Autophagy, Diabetes, 2007, 56(4):930-939.
8、Marfella R, Amico M D, Esposito K, SomoscachiM, et al.Increased Activity of the Ubiquitin-Proteasome System in Patients With Symptomatic Carotid Disease Is Associated With Enhanced Inflammation and May Destabilize the Atherosclerotic PlaqueEffects of Rosiglitazone Treatment, JACC, 2006, 47 (12): 2444–55.
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11、Bulteau AL, Lundberg KC, Humphries KM, Sadek HA, Szweda PA, Friguet B, Szweda LI. Oxidative modification and inactivation of the proteasome during coronary occlusion reperfusion. J Biol Chem, 2001, 276 (32): 30057–30063.
12、Donaldson KM, Li W, Ching KA, Batalov S, Tsai CC, Joazeiro CA. Ubiquitin mediated sequestration of normal cellular proteins into polyglutamine aggregates. Proc Natl Acad Sci USA, 2003, 100 (15): 8892– 8897.
13、Goellner GM,Rechsteiner M.Are Huntington’s and polyglutamine based ataxias proteasome storage diseases? Int J Biochem Cell Biol, 2003, 35 (5): 562–571.
14、Meiners S, Laule M, Rother W, et al. Ubiquitin-proteasome pathway as a mew target for the prevetion of restenosis. Circulation. 2002,105 (4): 483 –489.
15、Martinet W, De Bie M, Schrijvers DM, et al. 7-ketocholesterol induces protein ubiquitination, myelin figure formation, and light chain 3 processing in vascular smooth musclecells.Arterioscler Thromb Vasc Biol, 2004, 24 (12): 2296 –2301.
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19、Bagi Z, Koller A, Kaley G, PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. Am J Physiol Heart Circ Physiol, 2004, 286 (2): 742 - 748.
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22、Fueger P, Bracy DP, Malbanan CM, et al. Hexokinase ⅡOverexpression improvesexercise-stimulated but notinsulin-stimulated muscleglucose uptake in high-fat-fed C57BL/6J mice. Diabetes, 2004, 53 (2): 306-314.
23、郭啸华,刘志红,李恒,et al.高糖高脂饮食诱导的2型糖尿病大鼠模型及其肾病特点.中国糖尿病杂志,2002,10(5):290-294.
24、Goldberg A L, et al. Protein degradation and protection against misfolded or damaged proteins. Nature, 2003, 426 (6968): 895-899.
25、Fernandes R, Ramalho J, Pereira P. Oxidative stress upregulates the ubiquitin proteasome pathway in retinal endothelial cells. Molecular Vision, 2006, 12 (10): 1526-1535.
26、Wang X N, Hu Z Y, Hu J, et al. Insulin resistance accelerates muscle protein degradation: activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology, 2006, 147 (9): 4160–4168.
27、VersariD , Herrmann J, Gossl M , et al. Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis. Arterioscler Thromb Vasc Biol. 2006, 26 (9): 2132-2139.
28、Marfella R, Filippo C D, Portoghese M, et al. Proteasome activity as a target of hormone replacement therapy-dependent plaque stabilization in postmenopausal women. Hypertension, 2008, 51 (4): 1135-1141.
29、Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science, 2001, 292(3):1552-1555.
30、Kummar D, Zimpelmann J, Robertson S, et al. Tubular and interstitianl cell in the steptozotocin diabetic rat kidney. [J] . Nephron Exp Nephrol, 2004, 96 (3): 77-88.
31、Li Q, Verma TM. NF-B regulation in the immune system. [J] . Nat Rev Immortal. 2002, 2 (10): 725-734.
32、王扬天,赵明,狄红杰.糖尿病大鼠肾病变过程中核因子-κB及诱导型一氧化氮合酶的表达.医学研究生学报,2006,19(5):416-419.
33、Han HJ, Jeon YJ, Lee YJ. Involvement of NF2kappaB in high glucose induced alteration of alpha-methyl-D-glucopyranoside(alpha-MG) uptake in renal proximal tubule cells. Cell Physiol Biochem,2003,13 (6) :375-384.
34、Rebecca L, Shen ZP, Melissah R, et al. Long term treatment with rosiglitazone and metform in reduces the extent of but not prevent islet amyloid deposition in mice expressing the gene for human islet amyloid polypeptide. Diabetes, 2005, 21 (11): 2235-2444.
35、MoraesLA, Piqueras L, Bishop D, et al. Peroxisome proliferatoractivated receptors and inflammation. Pharmacol Ther, 2005, 14 (1) :2-4.
36、陈丽,郭延云,章秋,et al.吡格列酮对 T2DM 大鼠肾脏超微结构及 NO、CRP 水平的影响.安徽医科大学学报,2007,42(10):494.
37、Ma LJ, Marcatoni C, Linton MF, et al. Peroxisome proliferators-activated receptor -gamma against nondiabetic glomerulosclerosis in rats . [J] .KidneyInt. 2001, 59 (5) :1899-1910.
38、Yamashita H, Nagai Y, Takamura T, et al.Thiazolidinedione derivatives ameliorate albuminuria in streptozotocin-induced diabetic spontaneous hypertensive rat. [J] . Metabo -lism . 2002, 51 (4) : 403-408.
39、田季雨,陈建宗,顾宜,et al.复方丹参滴丸对家兔血脂水平和颈动脉粥样硬化板块的影响.中国临床康复,2004,22(7):437.
40、许晶兰,王孝铭,王东霞.复方丹参滴丸对过氧化氢损伤的人脐静脉血管内皮细胞保护作用.中国病理生理杂志,2006,22(5):929.
41、陈频,徐向进,史道华.复方丹参滴丸对胰岛素抵抗大鼠的保护作用及其机制研究.中国中西医结合心脑血管病杂志,2008,6(5):33-36.
42、陈频,徐向进,史道华.复方丹参滴丸对高糖/高胰岛素诱导兔胸主动脉平滑肌细胞增殖的抑制作用.中国中西医结合急救杂志,2007,14(5):313-316.
43、苏俊峰、郭长江.食物类黄酮槲皮素的抗氧化作用.解放军预防医学杂志,2001,19(3):229.
44、Moon SK, Cho GO, Jung SY, et al. Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2, cell-cycle regulation, and matrixmetalloproteinase-9. Biochem Biophys Res Commun. 2003, 301 (4): 1069-1078.
45、Vessal M, Hemmati M, Vasei M, Antidiabetic effects of quercetin in streptozocin-induced diabetic rats, Comp Biochem physiol Toxicol Pharmacol, 2003, 135 (3) : 357-364.
46、Kamada C, da Silva ZL, Ohnishi-Kmeyama M, et al.Attention of lipid peroxidation and hyperlipidemia by quercetin glucoside in the aorta of high cholesteol-fed rabbit. [J] . Fee Radic Res, 2005 ,39 (2): 185-194.
47、Auger C, Teissedre PL, Gerain P, et al. Dietary wine phenolics catechin, quercetin, and resveratrol efficiently protect hypercholesterolemic hamsters against aortic fatty streak accumulation, [J] . Agric.Food Chem, 2005, 53 (6), 2015-2021.
48、徐向进,郑智勇,张荔群,王庆彪,et al.槲皮素对糖尿病大鼠肾脏的保护作用.中华内分泌代谢杂志,2001,17(5):316-319.
49、徐向进,吴玉水,冯修高,et al.槲皮素对糖尿病大鼠肾脏转化生长因子-β1(TGF-β1)表达的影响.中国糖尿病杂志,2001,9(1):44-48.
50、梅小斌,崔若兰,高从容,et al.槲皮素糖尿病大鼠肾病大鼠的肾小球周期素抑制剂 P27 水平的影响.2002,23(11):1208-1210.
51、李佑生,王文健,马宇滢,et al.复方丹参滴丸防治大鼠早期糖尿病肾脏损害的研究.中成药,2007,29(1):41.
1 、Aguilar RC, Wendland B, Ubiquitin not just for proteasomes anymore. Curropin Cell Biol, 2003. 15(2):184-190.
2 、Smalle j. Vierstra RD. The ubiquitin 26S proteasome proteolytic pathway. Annu Rev Plant Biol. 2004,55 (6): 555～590.
3 、Melikova MS, Filatova MM, Kornilova ES. Cbl-a polyfunctional regulator of cellular processes.[J].Tsitologiia. 2003, 45(11): 1134-1148.
4 、Fang.S, Lorick K L, Jensen J D, Weissman AM. RINGER finger ubiquitin protein ligases:Implications for tumorigenesis metastasis and for molecular targets in caner. Semin Cancer Biol. 2003, 13 (1): 5-14.
5、Petroski MD, Dehshaies RJ, Function and regulation of cullin-RING ubiquitin ligases . Nat Rev Mol Cell. Biol, 2005, 6 (1): 9-20.
6、Ohi MD,Vander kool CW, Rosenberg JA, Chazin WJ, Gould KL. Structural insights into the U-box a domain associated with multi-ubiquitination. Nature Struct Biol. 2003, 10 (4): 250-255.
7、Hatakeyama.S,Nakayama.KI ,U-box proteins as a new family of ubiquitin ligases[J].Biochem Bipphys Res Commun.2003,302(4):635-645.
8、Rui L, Yuan M, Frantz D, Shoelson S. White MF,SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2,J Biol Chem. 2002, 277 (44): 42394-42398.
9、Rome S, Meugnier E, Vidal H. The ubiquitin-proteasome pathway is a new partner for the control of insulin signaling. Curr Opin Clin Nutr Metab Care. 2004, 7 (3) 249-254.
10、叶彦,欧阳静萍,王保华等,IRS-1 的表达和泛素化在 KKAY 及C57BL/6J 小鼠糖尿病发展过程中的意义.武汉大学学报(医学版)2006,27(3):279-282.
11、Juan C, Molero, Samuel G,Waring, Adrian Cooper, Nigel Turner, Ross Laybutt: Casitas b-Lineage Lymphoma-Deficient Mice Are Protected Against High-Fat Diet-Induced Obesity and Insulin Resistance. Diabetes, 2006, 55 (3): 708-715.
12、Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI. Mechanismby which fatty acids inhibit insulin activation of insulin receptor substrate-1(IRS-1)-associated phosphatidylinositol3-kinase activity in musle. J Biol Chem, 2002, 277 (52): 50230-50236.
13、Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R, Defronzo RA, Cusi K. Dose-reponse effect of elevated plasma free fatty acid on insulin signaling. Diabetes, 2005, 54 (6): 1640-1648.
14、Molero JC, Jensen TE, Withers PC, Couzens M, Herzog H, Thien CB, Langdon WY , Walder K, Murphy MA, Bowtell DD, James DE. Cooney Gj:c-Cbl-deficient mice have reduced adiposity, higher energy expenditure and improved peripheral insulin action. J Clin Invest, 2004, 114 (9): 1326-1333.
15、Ling Qi, Jose E Heredia, Judith Y, Altarejos, TRB3 Links the E3 Ubiquitin Ligase COP1 to Lipid Metabolism. Science. 2006, 312 (5781): 1763-1766.
16、Lopez Avalos MD, Duvivier Kali VF, Xu G, Bonner Weir S, Sharma A, Weir GC. Evidence for a role of the ubiquitin-proteasome pathway in pancreatic islets. Diabetes, 2006, 55 (5): 1223-1231.
17、Kawaguchi M, Minami K, Nagashima K, Seino S. Essential role of ubiquitin-proteasome system in normal regulation of insulin secretion. J Biol Chem, 2006, 281 (19): 13015-13020.
18 、 Raffaele Marfella, Michele D Amico, Katherine Esposito, Mario Somoscachi, Ferndinando Carlo Sasso. The Ubiquitin-Proteasome System and Inflammatory Activity in Diabetic Atherosclerotic Plaques.Diabetes. 2006, 55 (3): 622-632.
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