黄芪注射液拮抗高糖损伤作用机制的研究
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摘要
糖尿病(DM)是目前威胁人类健康的主要慢性病之一。在糖尿病的治疗中,如何充分利用我国传统的医药资源,开辟糖尿病治疗的新途径具有重要意义。氧化应激是糖尿病并发症发生的重要机制之一,抗氧化剂的应用,尤其是中药抗氧化剂的应用,对糖尿病病情的影响报道较少。本研究通过体内外实验,探讨了黄芪(RA)对链脲佐菌素(STZ)诱导的糖尿病大鼠的治疗作用以及拮抗高糖损伤作用的机制,为临床应用RA治疗糖尿病提供了理论与实验依据。
为了观察RA对糖尿病及其并发症的防治作用,我们应用STZ制备了糖尿病大鼠模型,并应用RA治疗糖尿病大鼠,主要从治疗前后糖尿病大鼠的血清学指标、尿常规、各器官的病理改变以及Rho A在各组织器官的表达情况等几个方面,观察了RA对糖尿病的治疗作用。实验结果表明:糖尿病病程中,RA能够参与调节脂代谢,降低TC、TG、LDL、血糖水平,提高HDL、胰岛素水平;RA治疗组大鼠13h尿量显著少于DM组,同时RA治疗组大鼠尿液的白细胞计数、细菌计数、红细胞计数显著低于DM组大鼠;DM组大鼠的胰腺和肾脏的组织结构变化明显,腹腔注射RA 60d后, RA治疗组大鼠胰腺、肾脏的组织结构与正常大鼠相似;RhoA在正常组大鼠肾脏上皮细胞呈阴性或弱阳性表达,而在DM组大鼠的肾脏上皮细胞中呈强阳性表达,经过RA治疗60d后,RhoA表达减弱,呈阴性或弱阳性。上述动物实验结果显示,经过RA治疗的糖尿病大鼠脂代谢得到一定程度的纠正,RA能明显降低糖尿病大鼠的血糖,提高胰岛素水平,RA对糖尿病大鼠的胰腺和肾脏具有积极的保护作用。这一结果提示,在糖尿病治疗中,黄芪可作为治疗糖尿病的一种手段,预防和延缓并发症的发生。
为了探讨黄芪拮抗高糖损伤作用以及对内皮细胞保护作用的机制。我们将人脐静脉内皮细胞ECV304随机分为正常组、高糖组、RA处理组和甘露醇组,观察了RA对高糖诱导的人脐静脉内皮细胞ECV304的细胞凋亡、细胞膜流动性、细胞内Ca2+浓度、细胞线粒体膜电位以及细胞产生氧自由基的影响,并做了电镜观察。实验结果表明:高糖能够导致内皮细胞凋亡,RA处理组细胞发生凋亡的比例与高糖组细胞相比较显著下降;高糖组细胞膜流动性、线粒体膜电位显著下降,显著低于正常细胞组、RA处理组和甘露醇组;高糖组细胞的细胞内钙离子浓度显著高于正常细胞组、RA组和甘露醇组;高糖组细胞产生MDA、OH-、O2-的水平显著高于正常细胞组、RA组、甘露醇组;高糖组细胞的损伤亦较其它组显著,电镜观察的结果表明,高糖组细胞的损伤较重,细胞死亡增多,细胞核中异染色质增多,线粒体数目减少、结构异常,线粒体发生肿胀,线粒体内的嵴消失。上述结果充分表明,高糖对内皮细胞可造成非常显著的损伤,甚至导致细胞死亡。RA能够在高糖环境下对内皮细胞的功能和形态提供很好的保护。
综上所述,糖尿病发病率高,并发症危害大,糖尿病及其相关疾病耗资巨大,目前对糖尿病的治疗主要采取胰岛素注射的方法,而有关中药在糖尿病治疗中的作用报道较少,我国具有丰富的中药资源,黄芪是其中较常用的一种,且黄芪具有毒副作用小、药源丰富的特点,本研究探讨了黄芪对糖尿病动物的治疗和保护作用以及黄芪拮抗高糖损伤的机制,为在糖尿病治疗领域广泛应用中药黄芪提供了理论和实验依据。
Diabetes mellitus is a metabolic disease featured by chronic elevation of blood glucose level. The prevalence of diabetes is increasing and has become the most challenging health problem in the 21st centrury. Worldwidely, diabetes affected the health of 2300 million people, and the number is estimated to shoot up to 3500 million by 2025. Diabetes is top 4 death cause for the whole population at present, there will be one person dead because of diabetes related disease every 10 second. In America, it is estimated that more than 20 million people have diabetes, among therm 14 million people are diagnosed, 6 million people are not. Persistent high level of blood glucose attacks microvessel and macrovessels along the body. In developoing countries, diabetes is the main cause for adult blindness, visioin damage, non-trauma amputation and kidney failure. Diabetes threatens the vision, the patients with diabetes develop cataract earlier and the chances to develp glaucoma doubles, diabetes is also a major cause for delayed wound healing.
In the mechanisms of diabetes complication, oxidative stress plays an important role.Oxidative stress comes from glucose autooxidation, Fenton reaction, advanced glycation end products, polyol pathway, mitochondria respiratory chain deficiency, hexasine, peroxisome, nitric oxide synthase and NADPH oxidase. Pancreaticβcells are more sensitive to oxidative stress because the level of antioxidase, such as catalase, glutathione peroxidase and superoxide dismutase inβcells is very low, which results in the weaker ability to resist oxidative stress. Oxidative stress can damage pancreaticβcells and induce the insulin secretion obstacles, moreover cause the development of complications by inducing pathologic metabolic pathways.
Due to the important role of oxidative stress in the development and progression of diabetes complications, it is necessary to explore the effects of antioxidative agents on the process and progression of diabetes, especially traditional Chinese medicine, so the present study is to explore the therapeutic effects of Radix Astragali on diabetes mellitus and its mechanisms of actions through animal and cell experiments.
In animal experiments, Wistar rats were injected STZ at the dose of 50 mg?kg-1 to establish diabetes rat model, the blood sugar level were tested three times on day 3, 5, and 7, those which had blood sugar level more than 16.7 mmol?L-1 three times were determined diabetes rats. The diabetes rats were classified into diabetes grou, DM and Radix Astragali group, RA; rats in DM group were given 3.3 ml/kg saline and RA group 3.3 ml/kg RA every day through IP. Normal rats were in control group, C.
Blood samples were collected on day 7, 14, 30, 60 of RA injection to test the level of triglyceride(TG), high density lipoprotein(HDL-C), low density lipoprotein(LDL-C) and insulin, each time 5 rats from each group including normal rats.
Human umbilical vein endothelial cells were used to explore the protective effects of RA against high level of glucose. ECV 304 cells were exposed to high glucose concentration (35mM), high glucose concentration and RA(35mM glucose and 500μg/ml), an osmetic control was set up by mannitol(25Mm). The cells were collected 24 hours later after the glucose, mannitol and RA were added to the cells, cell membrane fluidity, intracellular Ca2+ concentration, mitochondrial membrane potential, ROS production and morphology under electronic microscope were tested.
On day 7 and 14 of RA injection, there was no significant difference in blood index in rats between RA and DM group(P>0.05); On day 30 and 60 of RA injection, the level of HDL-C and insulin in rats of RA groups was significantly higher than that of DM group(P<0.05), the level of LDL-C, TG, and TC lower(P<0.05).
On day 7, 14 and 30 of RA injection, there was no significant difference in the morphology of liver, kidney and heart between RA group and DM group rats, which were similar to the normal rats. On day 60 of RA injection, the morphology of liver and heart in rats of RA and DM groups was similar to normal one. But in kidney and pancreas, remarkable changes were seen, for rats in DM group, glomeruli capsular spaced were narrower, matrix hyperplasia, cell number increased while for rats in RA group, the morphology of kidney was similar to that of normal rats.
In cell experiment, intracellular calcium concentration was significantly higher in the presence of high glucose concentration when compared with normal, RA and mannitol control; there was significant decrease in intracellular calcium concentration in the presence of combined high glucose concentration and RA compared to mannitol control (P<0.05). Cells exposed to high glucose concentration had lower mitochondrial membrane potential compared to normal control, RA and mannitol control(P<0.05), cells exposed to combined RA and high glucose concentration had higher mitochondrial membrane potential compared to mannitol control(P<0.05).There was a significant increase in the number of apoptotic cells in the presence of high glucose concentration compared to normal control, RA and mannitol control(P<0.05), there was a significant decrease in the number of apoptotic cells in the presence of RA and high glucose concentration compared to mannitol control. Cellls exposed to high glucose concentration had higher level of MDA, OH- , O2- and lower level of SOD、CAT、GSH activities compared to normal control, RA and mannitol(P<0.05), Cells exposed to combined RA and high glucose concentration had lower level of MDA, OH, O2- and higher level of SOD, CAT, GSH activities compared to mannitol control(P<0.05). Cells exposed to mannitol had lower level of MDA, OH-, O2- and higher level of SOD, CAT, GSH activities compared to high glucose concentration(P<0.05). Under electronic microscope, the cells exposed to high glucose concentration were abnormal with swollen mitochondria and decrease in the number of mitochondria, and cristae disappeared, while the cells exposed to combined RA and high glucose concentration had normal structure and number of mitochondria with clear cristae.
The results of the present research indicated that Radix Astragali could produce therapeutic effects on diabetes rats and one of the mechanisms of action was its ability to eliminate free radicals and participation in the lipid metabolism of diabetes rats.
为了观察RA对糖尿病及其并发症的防治作用,我们应用STZ制备了糖尿病大鼠模型,并应用RA治疗糖尿病大鼠,主要从治疗前后糖尿病大鼠的血清学指标、尿常规、各器官的病理改变以及Rho A在各组织器官的表达情况等几个方面,观察了RA对糖尿病的治疗作用。实验结果表明:糖尿病病程中,RA能够参与调节脂代谢,降低TC、TG、LDL、血糖水平,提高HDL、胰岛素水平;RA治疗组大鼠13h尿量显著少于DM组,同时RA治疗组大鼠尿液的白细胞计数、细菌计数、红细胞计数显著低于DM组大鼠;DM组大鼠的胰腺和肾脏的组织结构变化明显,腹腔注射RA 60d后, RA治疗组大鼠胰腺、肾脏的组织结构与正常大鼠相似;RhoA在正常组大鼠肾脏上皮细胞呈阴性或弱阳性表达,而在DM组大鼠的肾脏上皮细胞中呈强阳性表达,经过RA治疗60d后,RhoA表达减弱,呈阴性或弱阳性。上述动物实验结果显示,经过RA治疗的糖尿病大鼠脂代谢得到一定程度的纠正,RA能明显降低糖尿病大鼠的血糖,提高胰岛素水平,RA对糖尿病大鼠的胰腺和肾脏具有积极的保护作用。这一结果提示,在糖尿病治疗中,黄芪可作为治疗糖尿病的一种手段,预防和延缓并发症的发生。
为了探讨黄芪拮抗高糖损伤作用以及对内皮细胞保护作用的机制。我们将人脐静脉内皮细胞ECV304随机分为正常组、高糖组、RA处理组和甘露醇组,观察了RA对高糖诱导的人脐静脉内皮细胞ECV304的细胞凋亡、细胞膜流动性、细胞内Ca2+浓度、细胞线粒体膜电位以及细胞产生氧自由基的影响,并做了电镜观察。实验结果表明:高糖能够导致内皮细胞凋亡,RA处理组细胞发生凋亡的比例与高糖组细胞相比较显著下降;高糖组细胞膜流动性、线粒体膜电位显著下降,显著低于正常细胞组、RA处理组和甘露醇组;高糖组细胞的细胞内钙离子浓度显著高于正常细胞组、RA组和甘露醇组;高糖组细胞产生MDA、OH-、O2-的水平显著高于正常细胞组、RA组、甘露醇组;高糖组细胞的损伤亦较其它组显著,电镜观察的结果表明,高糖组细胞的损伤较重,细胞死亡增多,细胞核中异染色质增多,线粒体数目减少、结构异常,线粒体发生肿胀,线粒体内的嵴消失。上述结果充分表明,高糖对内皮细胞可造成非常显著的损伤,甚至导致细胞死亡。RA能够在高糖环境下对内皮细胞的功能和形态提供很好的保护。
综上所述,糖尿病发病率高,并发症危害大,糖尿病及其相关疾病耗资巨大,目前对糖尿病的治疗主要采取胰岛素注射的方法,而有关中药在糖尿病治疗中的作用报道较少,我国具有丰富的中药资源,黄芪是其中较常用的一种,且黄芪具有毒副作用小、药源丰富的特点,本研究探讨了黄芪对糖尿病动物的治疗和保护作用以及黄芪拮抗高糖损伤的机制,为在糖尿病治疗领域广泛应用中药黄芪提供了理论和实验依据。
Diabetes mellitus is a metabolic disease featured by chronic elevation of blood glucose level. The prevalence of diabetes is increasing and has become the most challenging health problem in the 21st centrury. Worldwidely, diabetes affected the health of 2300 million people, and the number is estimated to shoot up to 3500 million by 2025. Diabetes is top 4 death cause for the whole population at present, there will be one person dead because of diabetes related disease every 10 second. In America, it is estimated that more than 20 million people have diabetes, among therm 14 million people are diagnosed, 6 million people are not. Persistent high level of blood glucose attacks microvessel and macrovessels along the body. In developoing countries, diabetes is the main cause for adult blindness, visioin damage, non-trauma amputation and kidney failure. Diabetes threatens the vision, the patients with diabetes develop cataract earlier and the chances to develp glaucoma doubles, diabetes is also a major cause for delayed wound healing.
In the mechanisms of diabetes complication, oxidative stress plays an important role.Oxidative stress comes from glucose autooxidation, Fenton reaction, advanced glycation end products, polyol pathway, mitochondria respiratory chain deficiency, hexasine, peroxisome, nitric oxide synthase and NADPH oxidase. Pancreaticβcells are more sensitive to oxidative stress because the level of antioxidase, such as catalase, glutathione peroxidase and superoxide dismutase inβcells is very low, which results in the weaker ability to resist oxidative stress. Oxidative stress can damage pancreaticβcells and induce the insulin secretion obstacles, moreover cause the development of complications by inducing pathologic metabolic pathways.
Due to the important role of oxidative stress in the development and progression of diabetes complications, it is necessary to explore the effects of antioxidative agents on the process and progression of diabetes, especially traditional Chinese medicine, so the present study is to explore the therapeutic effects of Radix Astragali on diabetes mellitus and its mechanisms of actions through animal and cell experiments.
In animal experiments, Wistar rats were injected STZ at the dose of 50 mg?kg-1 to establish diabetes rat model, the blood sugar level were tested three times on day 3, 5, and 7, those which had blood sugar level more than 16.7 mmol?L-1 three times were determined diabetes rats. The diabetes rats were classified into diabetes grou, DM and Radix Astragali group, RA; rats in DM group were given 3.3 ml/kg saline and RA group 3.3 ml/kg RA every day through IP. Normal rats were in control group, C.
Blood samples were collected on day 7, 14, 30, 60 of RA injection to test the level of triglyceride(TG), high density lipoprotein(HDL-C), low density lipoprotein(LDL-C) and insulin, each time 5 rats from each group including normal rats.
Human umbilical vein endothelial cells were used to explore the protective effects of RA against high level of glucose. ECV 304 cells were exposed to high glucose concentration (35mM), high glucose concentration and RA(35mM glucose and 500μg/ml), an osmetic control was set up by mannitol(25Mm). The cells were collected 24 hours later after the glucose, mannitol and RA were added to the cells, cell membrane fluidity, intracellular Ca2+ concentration, mitochondrial membrane potential, ROS production and morphology under electronic microscope were tested.
On day 7 and 14 of RA injection, there was no significant difference in blood index in rats between RA and DM group(P>0.05); On day 30 and 60 of RA injection, the level of HDL-C and insulin in rats of RA groups was significantly higher than that of DM group(P<0.05), the level of LDL-C, TG, and TC lower(P<0.05).
On day 7, 14 and 30 of RA injection, there was no significant difference in the morphology of liver, kidney and heart between RA group and DM group rats, which were similar to the normal rats. On day 60 of RA injection, the morphology of liver and heart in rats of RA and DM groups was similar to normal one. But in kidney and pancreas, remarkable changes were seen, for rats in DM group, glomeruli capsular spaced were narrower, matrix hyperplasia, cell number increased while for rats in RA group, the morphology of kidney was similar to that of normal rats.
In cell experiment, intracellular calcium concentration was significantly higher in the presence of high glucose concentration when compared with normal, RA and mannitol control; there was significant decrease in intracellular calcium concentration in the presence of combined high glucose concentration and RA compared to mannitol control (P<0.05). Cells exposed to high glucose concentration had lower mitochondrial membrane potential compared to normal control, RA and mannitol control(P<0.05), cells exposed to combined RA and high glucose concentration had higher mitochondrial membrane potential compared to mannitol control(P<0.05).There was a significant increase in the number of apoptotic cells in the presence of high glucose concentration compared to normal control, RA and mannitol control(P<0.05), there was a significant decrease in the number of apoptotic cells in the presence of RA and high glucose concentration compared to mannitol control. Cellls exposed to high glucose concentration had higher level of MDA, OH- , O2- and lower level of SOD、CAT、GSH activities compared to normal control, RA and mannitol(P<0.05), Cells exposed to combined RA and high glucose concentration had lower level of MDA, OH, O2- and higher level of SOD, CAT, GSH activities compared to mannitol control(P<0.05). Cells exposed to mannitol had lower level of MDA, OH-, O2- and higher level of SOD, CAT, GSH activities compared to high glucose concentration(P<0.05). Under electronic microscope, the cells exposed to high glucose concentration were abnormal with swollen mitochondria and decrease in the number of mitochondria, and cristae disappeared, while the cells exposed to combined RA and high glucose concentration had normal structure and number of mitochondria with clear cristae.
The results of the present research indicated that Radix Astragali could produce therapeutic effects on diabetes rats and one of the mechanisms of action was its ability to eliminate free radicals and participation in the lipid metabolism of diabetes rats.
引文
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