20（S）-人参皂苷Rg3对糖尿病大鼠心脏的保护作用研究
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摘要
研究背景：
糖尿病是世界上主要的健康问题之一,糖尿病的根本危害在于其各种并发症，主要有大血管病变，糖尿病肾病及视网膜病变，神经病变和糖尿病足，尤以心血管系统最为严重。流行病学研究发现糖尿病人群心血管病患病率比非糖尿病人群高2～4倍，心肌梗死的患病率高10倍，而且患有慢性心力衰竭和猝死的发生率明显升高。糖尿病心肌病（DCM）是指糖尿病慢性并发症中排除了高血压、冠心病及其他已知疾病所致的心肌损伤而独立存在的特征性心肌病。DCM发生的病理改变有多种因素参与，其中包括高糖血症，脂肪酸代谢紊乱，钙离子的稳定失调，RAAS系统激活，NADPH氧化系统紊乱和线粒体代谢障碍，氧化应激的增加，糖基化终产物（AGEs）增多等。
近年来研究表明，氧化应激反应及下游信号通路在糖尿病心肌病的发病机制中起着重要的作用，氧化应激反应介导的RAGEs受体蛋白引起促细胞生长因子的增加，使细胞外基质成分和基因表达发生改变，引起心肌细胞肥大，心脏微血管病变和间质纤维化，影响心脏的收缩舒张功能，因此抑制氧化应激表达水平对防治糖尿病心肌病有着重要的意义。
人参皂苷是人参的主要生物活性成分，目前发现有30多种皂苷单体，其中20(S)-人参皂苷Rg3（20(S)-ginsenoside Rg3，20(S)-Rg3）被认为是具有多种药理作用的化合物。其作用主要包括调控血糖、改善微循环、抗肿瘤、抑制内皮细胞凋亡等。近年来随着对20(S)-Rg3研究的不断深入，发现在缺血性脑损伤和内皮细胞中有较强的抗氧化活性，对糖尿病引起的肾脏损伤亦有保护作用，但20(S)-Rg3对糖尿病心肌病是否有保护作用及其相关机制目前尚未明确，由此展开本实验。
研究目的：
1．20(S)-Rg3能否降低糖尿病心脏损伤重要因素之一氧化应激反应。
2．从氧化应激/AGEs-RAGEs/NF-κB介导的纤维化信号通路角度探讨20(S)-Rg3对糖尿病心肌病的保护作用。
3．寻找到20(S)-Rg3治疗糖尿病心肌病大鼠尿液中药物代谢的标记产物，为进一步探讨其治疗机制奠定分子基础。
研究方法：
通过建立糖尿病大鼠模型，观察药物治疗前后体重、心脏重量/体重及生化指标变化及心肌超微结构改变，检测氧化应激相关蛋白MDA、SOD、GSH及CAT活性水平，Masson染色观察心肌纤维化程度，应用免疫印迹方法检测RAGE、NF-κB、TGF-β1和CTGF四个信号蛋白的表达及RT-PCR方法测RAGE、NF-κB mRNA水平。应用代谢组学方法通过液相质谱检测找到20(S)-Rg3治疗糖尿病心肌病尿液中发生变化的标记物质。
研究结果：
1．20(S)-Rg3三个治疗组均降低糖尿病大鼠血清中血糖、血脂、心肌酶水平，改善心肌超微结构的损伤，且存在剂量依赖性，高剂量组改善最明显。
2．20(S)-Rg3三个治疗组均能提高糖尿病心脏组织中抗氧化系统中SOD、GSH和CAT活性，降低氧化损伤标志物MDA水平、并且具有剂量依赖性，高剂量组抗氧水平最显著。
3．20(S)-Rg3三个剂量组均可改善糖尿病心肌组织中胶原的过度沉积、减低I、III型胶原蛋白的水平，高剂量组效果最显著。
4．20(S)-Rg3可降低糖尿病心肌组织中RAGE、NF-ΚB、TGF-β1、CTGF的蛋白表达及RAGE、NF-ΚB的mRNA表达，并且具有剂量依赖性，高剂量组降低明显。
5．应用尿液代谢组学方法找出20(S)-Rg3治疗糖尿病心肌病的三种标记物，分别是3-甲基鸟嘌呤、L-肉毒碱和肌肽。
结论：
1．20(S)-Rg3改善糖尿病心肌病大鼠代谢紊乱及心肌细胞超微结构损害。
2．20(S)-Rg3可通过降低血清和组织中氧化应激水平发挥保护糖尿病心脏作用。
3．20(S)-Rg3可逆转心肌间质纤维化，机制可能与抑制氧化应激/AGEs-RAGE/NF-κB信号通路有关。
4．尿液代谢组学研究20(S)-Rg3治疗糖尿病心肌病机制与能量代谢和氧化应激作用相关。
创新点：
1．本研究应用20(S)-Rg3干预STZ诱导糖尿病大鼠，从蛋白、基因水平进行研究，结果显示20(S)-Rg3通过阻断氧化应激介导的AGEs-RAGE/NF-κB纤维化通路，通过抑制促生长因子的表达减低I和Ⅲ胶原蛋白在心肌的含量，对糖尿病大鼠心肌起到保护作用。
2．本研究通过尿液代谢组学方法找到20(S)-Rg3治疗糖尿病心肌病药物代谢的标志物，为进一步研究药物的治疗机制奠定分子基础。
3．20(S)-Rg3为天然的草本植物提取物，本研究为预防和治疗糖尿病心肌损害的新药研发提供了重要的理论参考依据。
综上所述，本研究显示20(S)-Rg3可通过抑制糖尿病心肌组织中氧化应激介导的AGEs-RAGE/NF-κB信号通路抵抗糖尿病引起的心肌损伤的作用，并通过尿液组学研究进一步发现其保护与能量代谢和氧化应激作用相关，20(S)-Rg3有可能成为新的心脏保护药物，有望应用于糖尿病心肌损伤或其它心脏疾病的治疗。
Background:
Diabetes is one of the world's major health problems, diabetes fundamentalhazards in its various complications, mainly macrovascular disease, diabeticnephropathy and retinopathy, neuropathy and diabetic foot, especially in thecardiovascular system is the most serious. Epidemiological studies have found that thediabetic population of patients with cardiovascular disease rates2to4times higherthan the non-diabetic population,10times higher prevalence of myocardial infarction,and suffers from chronic heart failure and significantly increased the incidence ofsudden death. Diabetic cardiomyopathy (DCM) is to exclude myocardial injurycaused by high blood pressure, coronary heart disease and other known diseases existindependently of the characteristics of cardiomyopathy in the chronic complicationsof diabetes. DCM occurrence of pathological changes of a variety of factors involvedinclude: hyperglycemia, fatty acid metabolism disorders, disorders of calcium ionstability, activation of the RAAS system, NADPH oxidation system disorders andmitochondrial metabolism, increased oxidative stress, glycosylation end products(AGEs) increase.
In recent years, studies have shown that oxidative stress and the downstreamsignaling pathway plays an important role in the pathogenesis of diabeticcardiomyopathy, RAGEs receptor protein mediated oxidative stress caused promotecell growth factor increases, so that the extracellular matrix composition and geneexpression changes, causing cardiac myocyte hypertrophy, cardiac microvasculardisease and interstitial fibrosis, affecting systolic and diastolic function of the heart,thus inhibiting the expression levels of oxidative stress has an important significance to the prevention and treatment of diabetic cardiomyopathy.
Ginseng saponin is the main biologically active components of ginseng, found30kinds of saponin monomer, of which20(S)-ginsenoside Rg3(20(S)-ginsenosideRg3,20(S)-Rg3) is considered to be a multi-The colors of the pharmacologicaleffects of the compound. Its main function,including the regulation of blood sugar,improve microcirculation, anti-tumor, inhibition of endothelial cell apoptosis. Inrecent years, with the deepening of the20(S)-Rg3study found that there is a strongantioxidant activity in ischemic brain injury and endothelial cells, kidney damagecaused by diabetes mellitus also have protective effects, but the20(S)-Rg3on diabeticcardiomyopathy has a protective effect and its mechanism is not yet clear, thus givingrise to this experiment.
Objective:
1.20(S)-Rg3ability to reduce one of the important factors of diabetic heartdamage oxidative stress.
2. Fibrosis from the oxidation stress/AGEs-RAGEs/NF-κB, mediated signalingpathways angle to explore the protective effect of20(S)-Rg3on diabeticcardiomyopathy.
3. Seeking to lay the molecular basis of the labeled product of20(S)-Rg3treatment of diabetic cardiomyopathy in rat urine drug metabolism, in order to furtherexplore its therapeutic mechanism
Methods:
Through the establishment of diabetic rats were observed before and aftertreatment weight, heart weight/body weight and changes in biochemical markers ofmyocardial ultrastructural changes, detection of oxidative stress-related proteins MDA,SOD, GSH and CAT activity level, Masson staining myocardial fibrosis application toWestern blot detection Rage, four signals in the NF-kappaB, TGF-beta1and CTGFprotein expression by RT-PCR measurement of RAGE and NF-kappaB mRNA level.Application of metabolomics methods by liquid mass spectrometric detection foundthat20(S)-Rg3treatment change the labeling substance in the urine of diabetic cardiomyopathy.
Results:
1.20(S)-Rg3three treatment groups decreased level of diabetic rats serumglucose, lipids, enzymes, improve myocardial ultrastructural damage, and there is adose-dependent, high-dose group improved the most obvious.
2.20(S)-Rg3three treatment groups could improve the antioxidant system indiabetic heart tissue SOD, GSH and CAT activity, MDA levels reduce the markers ofoxidative damage, and a dose-dependent oxidation level of the high-dose group themost significant.
3.20(S)-the Rg3three dose groups can improve the excessive deposition ofcollagen in diabetic myocardial tissue, reduce the I and type III collagen level, theeffect of high-dose group significantly.
4.20(S)-Rg3can reduce diabetic myocardial tissue RAGE, NF-kappaB,TGF-beta1, CTGF protein expression of RAGE, NF-kappaB mRNA expression, and adose-dependent, high-dose group reduced significantly.
5. Application urine metabolomics approach to identify three of the20(S)-Rg3treatment of diabetic cardiomyopathy markers, namely3-methylguanine, L-carnitineand carnosine.
Conclusions:
1.20(S)-Rg3to improve the diabetic cardiomyopathy the rat metabolic disordersand myocardial ultrastructure damage.
2.20(S)-Rg3may play a protective role of diabetes heart by reducing oxidativestress in serum and tissues.
3.20(S)-Rg3can reverse the myocardial interstitial fibrosis, the mechanism maybe related to the inhibition of oxidative stress/AGEs-RAGE/NF-κB signalingpathway.
Urine metabolomics studies20(S)-Rg3treatment related to the the diabeticcardiomyopathy mechanism of the energy metabolism and oxidative stress. Innovation:
1. In this study,20(S)-Rg3intervention STZ-induced diabetic rats, protein, genelevel study, results showed that20(S)-Rg3by blocking oxidative stress-mediatedAGEs-RAGE/NF-κB fibrosis pathway through inhibition of pro reduce the expressionof growth factors I and III collagen content in myocardial, myocardium of diabeticrats play a protective role.
2．In this study, urine metabolomics methods to find the20(S)-Rg3treatment ofdiabetic cardiomyopathy drug metabolism markers laid molecular basis for the furtherstudy of the drug treatment mechanism.
3.20(S)-Rg3as a natural herb extracts, this study for the research anddevelopment of new drugs for the prevention and treatment of diabetic myocardialdamage provides an important theoretical basis.
In summary, this study shows that20(S)-Rg3can by inhibiting oxidativestress-mediated diabetes myocardial tissue AGEs-RAGE/NF-kappaB signalingpathway resistant to diabetes-induced myocardial injury and learn through urine groupThe study further found that protection and energy metabolism and oxidative stress20(S)-Rg3may become the new heart drug protection, may be used in the treatment ofdiabetes myocardial injury or other heart disease.
糖尿病是世界上主要的健康问题之一,糖尿病的根本危害在于其各种并发症，主要有大血管病变，糖尿病肾病及视网膜病变，神经病变和糖尿病足，尤以心血管系统最为严重。流行病学研究发现糖尿病人群心血管病患病率比非糖尿病人群高2～4倍，心肌梗死的患病率高10倍，而且患有慢性心力衰竭和猝死的发生率明显升高。糖尿病心肌病（DCM）是指糖尿病慢性并发症中排除了高血压、冠心病及其他已知疾病所致的心肌损伤而独立存在的特征性心肌病。DCM发生的病理改变有多种因素参与，其中包括高糖血症，脂肪酸代谢紊乱，钙离子的稳定失调，RAAS系统激活，NADPH氧化系统紊乱和线粒体代谢障碍，氧化应激的增加，糖基化终产物（AGEs）增多等。
近年来研究表明，氧化应激反应及下游信号通路在糖尿病心肌病的发病机制中起着重要的作用，氧化应激反应介导的RAGEs受体蛋白引起促细胞生长因子的增加，使细胞外基质成分和基因表达发生改变，引起心肌细胞肥大，心脏微血管病变和间质纤维化，影响心脏的收缩舒张功能，因此抑制氧化应激表达水平对防治糖尿病心肌病有着重要的意义。
人参皂苷是人参的主要生物活性成分，目前发现有30多种皂苷单体，其中20(S)-人参皂苷Rg3（20(S)-ginsenoside Rg3，20(S)-Rg3）被认为是具有多种药理作用的化合物。其作用主要包括调控血糖、改善微循环、抗肿瘤、抑制内皮细胞凋亡等。近年来随着对20(S)-Rg3研究的不断深入，发现在缺血性脑损伤和内皮细胞中有较强的抗氧化活性，对糖尿病引起的肾脏损伤亦有保护作用，但20(S)-Rg3对糖尿病心肌病是否有保护作用及其相关机制目前尚未明确，由此展开本实验。
研究目的：
1．20(S)-Rg3能否降低糖尿病心脏损伤重要因素之一氧化应激反应。
2．从氧化应激/AGEs-RAGEs/NF-κB介导的纤维化信号通路角度探讨20(S)-Rg3对糖尿病心肌病的保护作用。
3．寻找到20(S)-Rg3治疗糖尿病心肌病大鼠尿液中药物代谢的标记产物，为进一步探讨其治疗机制奠定分子基础。
研究方法：
通过建立糖尿病大鼠模型，观察药物治疗前后体重、心脏重量/体重及生化指标变化及心肌超微结构改变，检测氧化应激相关蛋白MDA、SOD、GSH及CAT活性水平，Masson染色观察心肌纤维化程度，应用免疫印迹方法检测RAGE、NF-κB、TGF-β1和CTGF四个信号蛋白的表达及RT-PCR方法测RAGE、NF-κB mRNA水平。应用代谢组学方法通过液相质谱检测找到20(S)-Rg3治疗糖尿病心肌病尿液中发生变化的标记物质。
研究结果：
1．20(S)-Rg3三个治疗组均降低糖尿病大鼠血清中血糖、血脂、心肌酶水平，改善心肌超微结构的损伤，且存在剂量依赖性，高剂量组改善最明显。
2．20(S)-Rg3三个治疗组均能提高糖尿病心脏组织中抗氧化系统中SOD、GSH和CAT活性，降低氧化损伤标志物MDA水平、并且具有剂量依赖性，高剂量组抗氧水平最显著。
3．20(S)-Rg3三个剂量组均可改善糖尿病心肌组织中胶原的过度沉积、减低I、III型胶原蛋白的水平，高剂量组效果最显著。
4．20(S)-Rg3可降低糖尿病心肌组织中RAGE、NF-ΚB、TGF-β1、CTGF的蛋白表达及RAGE、NF-ΚB的mRNA表达，并且具有剂量依赖性，高剂量组降低明显。
5．应用尿液代谢组学方法找出20(S)-Rg3治疗糖尿病心肌病的三种标记物，分别是3-甲基鸟嘌呤、L-肉毒碱和肌肽。
结论：
1．20(S)-Rg3改善糖尿病心肌病大鼠代谢紊乱及心肌细胞超微结构损害。
2．20(S)-Rg3可通过降低血清和组织中氧化应激水平发挥保护糖尿病心脏作用。
3．20(S)-Rg3可逆转心肌间质纤维化，机制可能与抑制氧化应激/AGEs-RAGE/NF-κB信号通路有关。
4．尿液代谢组学研究20(S)-Rg3治疗糖尿病心肌病机制与能量代谢和氧化应激作用相关。
创新点：
1．本研究应用20(S)-Rg3干预STZ诱导糖尿病大鼠，从蛋白、基因水平进行研究，结果显示20(S)-Rg3通过阻断氧化应激介导的AGEs-RAGE/NF-κB纤维化通路，通过抑制促生长因子的表达减低I和Ⅲ胶原蛋白在心肌的含量，对糖尿病大鼠心肌起到保护作用。
2．本研究通过尿液代谢组学方法找到20(S)-Rg3治疗糖尿病心肌病药物代谢的标志物，为进一步研究药物的治疗机制奠定分子基础。
3．20(S)-Rg3为天然的草本植物提取物，本研究为预防和治疗糖尿病心肌损害的新药研发提供了重要的理论参考依据。
综上所述，本研究显示20(S)-Rg3可通过抑制糖尿病心肌组织中氧化应激介导的AGEs-RAGE/NF-κB信号通路抵抗糖尿病引起的心肌损伤的作用，并通过尿液组学研究进一步发现其保护与能量代谢和氧化应激作用相关，20(S)-Rg3有可能成为新的心脏保护药物，有望应用于糖尿病心肌损伤或其它心脏疾病的治疗。
Background:
Diabetes is one of the world's major health problems, diabetes fundamentalhazards in its various complications, mainly macrovascular disease, diabeticnephropathy and retinopathy, neuropathy and diabetic foot, especially in thecardiovascular system is the most serious. Epidemiological studies have found that thediabetic population of patients with cardiovascular disease rates2to4times higherthan the non-diabetic population,10times higher prevalence of myocardial infarction,and suffers from chronic heart failure and significantly increased the incidence ofsudden death. Diabetic cardiomyopathy (DCM) is to exclude myocardial injurycaused by high blood pressure, coronary heart disease and other known diseases existindependently of the characteristics of cardiomyopathy in the chronic complicationsof diabetes. DCM occurrence of pathological changes of a variety of factors involvedinclude: hyperglycemia, fatty acid metabolism disorders, disorders of calcium ionstability, activation of the RAAS system, NADPH oxidation system disorders andmitochondrial metabolism, increased oxidative stress, glycosylation end products(AGEs) increase.
In recent years, studies have shown that oxidative stress and the downstreamsignaling pathway plays an important role in the pathogenesis of diabeticcardiomyopathy, RAGEs receptor protein mediated oxidative stress caused promotecell growth factor increases, so that the extracellular matrix composition and geneexpression changes, causing cardiac myocyte hypertrophy, cardiac microvasculardisease and interstitial fibrosis, affecting systolic and diastolic function of the heart,thus inhibiting the expression levels of oxidative stress has an important significance to the prevention and treatment of diabetic cardiomyopathy.
Ginseng saponin is the main biologically active components of ginseng, found30kinds of saponin monomer, of which20(S)-ginsenoside Rg3(20(S)-ginsenosideRg3,20(S)-Rg3) is considered to be a multi-The colors of the pharmacologicaleffects of the compound. Its main function,including the regulation of blood sugar,improve microcirculation, anti-tumor, inhibition of endothelial cell apoptosis. Inrecent years, with the deepening of the20(S)-Rg3study found that there is a strongantioxidant activity in ischemic brain injury and endothelial cells, kidney damagecaused by diabetes mellitus also have protective effects, but the20(S)-Rg3on diabeticcardiomyopathy has a protective effect and its mechanism is not yet clear, thus givingrise to this experiment.
Objective:
1.20(S)-Rg3ability to reduce one of the important factors of diabetic heartdamage oxidative stress.
2. Fibrosis from the oxidation stress/AGEs-RAGEs/NF-κB, mediated signalingpathways angle to explore the protective effect of20(S)-Rg3on diabeticcardiomyopathy.
3. Seeking to lay the molecular basis of the labeled product of20(S)-Rg3treatment of diabetic cardiomyopathy in rat urine drug metabolism, in order to furtherexplore its therapeutic mechanism
Methods:
Through the establishment of diabetic rats were observed before and aftertreatment weight, heart weight/body weight and changes in biochemical markers ofmyocardial ultrastructural changes, detection of oxidative stress-related proteins MDA,SOD, GSH and CAT activity level, Masson staining myocardial fibrosis application toWestern blot detection Rage, four signals in the NF-kappaB, TGF-beta1and CTGFprotein expression by RT-PCR measurement of RAGE and NF-kappaB mRNA level.Application of metabolomics methods by liquid mass spectrometric detection foundthat20(S)-Rg3treatment change the labeling substance in the urine of diabetic cardiomyopathy.
Results:
1.20(S)-Rg3three treatment groups decreased level of diabetic rats serumglucose, lipids, enzymes, improve myocardial ultrastructural damage, and there is adose-dependent, high-dose group improved the most obvious.
2.20(S)-Rg3three treatment groups could improve the antioxidant system indiabetic heart tissue SOD, GSH and CAT activity, MDA levels reduce the markers ofoxidative damage, and a dose-dependent oxidation level of the high-dose group themost significant.
3.20(S)-the Rg3three dose groups can improve the excessive deposition ofcollagen in diabetic myocardial tissue, reduce the I and type III collagen level, theeffect of high-dose group significantly.
4.20(S)-Rg3can reduce diabetic myocardial tissue RAGE, NF-kappaB,TGF-beta1, CTGF protein expression of RAGE, NF-kappaB mRNA expression, and adose-dependent, high-dose group reduced significantly.
5. Application urine metabolomics approach to identify three of the20(S)-Rg3treatment of diabetic cardiomyopathy markers, namely3-methylguanine, L-carnitineand carnosine.
Conclusions:
1.20(S)-Rg3to improve the diabetic cardiomyopathy the rat metabolic disordersand myocardial ultrastructure damage.
2.20(S)-Rg3may play a protective role of diabetes heart by reducing oxidativestress in serum and tissues.
3.20(S)-Rg3can reverse the myocardial interstitial fibrosis, the mechanism maybe related to the inhibition of oxidative stress/AGEs-RAGE/NF-κB signalingpathway.
Urine metabolomics studies20(S)-Rg3treatment related to the the diabeticcardiomyopathy mechanism of the energy metabolism and oxidative stress. Innovation:
1. In this study,20(S)-Rg3intervention STZ-induced diabetic rats, protein, genelevel study, results showed that20(S)-Rg3by blocking oxidative stress-mediatedAGEs-RAGE/NF-κB fibrosis pathway through inhibition of pro reduce the expressionof growth factors I and III collagen content in myocardial, myocardium of diabeticrats play a protective role.
2．In this study, urine metabolomics methods to find the20(S)-Rg3treatment ofdiabetic cardiomyopathy drug metabolism markers laid molecular basis for the furtherstudy of the drug treatment mechanism.
3.20(S)-Rg3as a natural herb extracts, this study for the research anddevelopment of new drugs for the prevention and treatment of diabetic myocardialdamage provides an important theoretical basis.
In summary, this study shows that20(S)-Rg3can by inhibiting oxidativestress-mediated diabetes myocardial tissue AGEs-RAGE/NF-kappaB signalingpathway resistant to diabetes-induced myocardial injury and learn through urine groupThe study further found that protection and energy metabolism and oxidative stress20(S)-Rg3may become the new heart drug protection, may be used in the treatment ofdiabetes myocardial injury or other heart disease.
引文
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