三种中药化学成分抗糖尿病心肌病变的作用初探
摘要
糖尿病心肌病(Diabetic Cardiomyopathy,DC)是糖尿病心脏病(Diabetic heart disease,DHD)的一种特异性病变,是由代谢紊乱触发,引起心肌超微结构改变,最终引起左心室肥厚、舒张期和(或)收缩期功能障碍的一种疾病状态,是独立于冠脉病变、微血管病变和心脏神经病变之外的心肌功能失调,为一类独立的病理生理状态。随着糖尿病(Diabetes Mellitus,DM)的发病率逐年增高,病程的延长,继发于DM的糖尿病心肌病已成为糖尿病晚期患者死亡的主要原因。因此,探明糖尿病心肌病的发生机制,寻求防治糖尿病心肌病的药物,是糖尿病心血管领域研究的重要课题。
近年,中医药对糖尿病及糖尿病心血管并发症的积极治疗作用受到广泛关注。临床常用方剂有葛根芩连汤、大柴胡汤、黄连解毒汤、三黄汤等,其中黄连、黄芩、苦参是临床运用较多的中药。现代药理研究显示,这三种中药及其主要化学成分在治疗糖尿病及心血管病方面具有一定的疗效。
小檗碱(Berberine,Ber)是黄连、黄柏、三棵针等植物中所含的主要生物碱,有大量研究证实其具有抗心律失常、降压、强心等心血管药理活性,同时还具有降血糖、调血脂、改善胰岛素抵抗、抑制蛋白糖基化等方面作用。但小檗碱是否改善糖尿病心肌病变尚未见研究报道。
黄芩苷(Baicalin,Bai)是植物黄芩中的一种主要黄酮类化合物。近年来研究发现,黄芩苷除了具有降压、镇静、消炎等药理作用外,还有抗脂质过氧化、拮抗儿茶酚胺和钙离子通道阻滞,抑制醛糖还原酶(AR)、抑制蛋白非酶糖基化作用、抑制蛋白激酶C的激活,调节脂代谢和细胞因子,保护内皮细胞,抑制血管平滑肌细胞增殖,保护心肌缺血/再灌注损伤作用,可防治糖尿病心血管并发症。
苦参碱(Matrine,Mat)是豆科植物苦参、苦豆子、广豆根等中草药的活性成分,是苦参碱类生物碱的代表。苦参碱具有较为广泛的心血管药理作用,其中抗心律失常、降血脂、正性肌力作用的研究较为深入。体外研究发现苦参碱能抑制醛固酮、血管紧张素Ⅱ诱导的离体心肌成纤维细胞的增殖,因此,苦参碱可能有一定的抗心室重构作用。
本课题采用高糖及高糖加高胰岛素制备DC细胞模型,通过体外细胞实验研究小檗碱、黄芩苷、苦参碱对DC细胞模型心肌细胞和心肌成纤维细胞形态结构、细胞增殖以及分泌病理活性产物的影响,评价其对于糖尿病心肌病变的防治作用,探讨小檗碱抗糖尿病心肌病变的机制,为阐明糖尿病心肌病的发病机制、药物治疗的作用环节以及小檗碱对糖尿病心肌病的防治作用提供科学依据。
1乳鼠心肌细胞(MC)和心肌成纤维细胞(CFB)的分离培养与鉴定
目的:分离培养符合实验要求的心肌细胞以及心肌成纤维细胞,确立细胞实验的最佳期。
方法:采用机械消化和酶消化相结合的方法将心肌组织消化为单细胞悬液,利用差速贴壁法和化学试剂抑制法分别获得纯度高、活力强的心肌细胞和心肌成纤维细胞。对细胞进行形态学和免疫化学鉴定,台盼蓝染色法和MTT比色法检测细胞活力,并绘制细胞增殖曲线。
结果:①心肌细胞呈梭形或不规则形,细胞核凸出明显,可见节律性搏动。细胞活力≥90%,α-Sarcomeric actin抗体染色阳性(阳性率≥90%),Fibronectin抗体染色染色阴性,分离后144h内生长状态良好。②心肌成纤维细胞呈梭形或不规则三角形,胞体较大通常有2-3个细胞核,胞质稀薄。细胞活力≥95%,Fibronectin抗体染色阳性(阳性率≥95%),α-Sarcomeric actin抗体染色阴性,分离后120h内呈指数增长。
结论:心肌细胞以及心肌成纤维细胞的纯度和活力符合实验要求,细胞实验的最佳时间段在分离后48-120h。
2小檗碱、黄芩苷、苦参碱对正常MC及CFB的影响
目的:观察不同浓度小檗碱、黄芩苷、苦参碱对正常MC及CFB的影响。
方法:用MTT比色法测定细胞活力,考马斯亮兰法测定细胞内蛋白含量,分别观察小檗碱(0.47μmol/L～60μmol/L)、黄芩苷(0.47μmol/L～120μmol/L)、苦参碱(62.5μmol/L～2000μmol/L)对正常MC及CFB作用48h的影响。
结果:①小檗碱(0.47μmol/L～30μmol/L),黄芩苷(0.47μmol/L～30μmol/L),苦参碱(62.5μmol/L～500μmol/L)、罗格列酮(1.6μmol/L～2μmol/L)、格列齐特(96μmol/L～120μmol/L)、卡托普利(32μmol/L～40μmol/L)对MC活力、细胞内蛋白含量无抑制作用。②小檗碱(7.5μmol/L～60μmol/L)、黄芩苷(0.94μmol/L～120μmol/L)、苦参碱(125μmol/L～2000μmol/L)、罗格列酮(1.6μmol/L～2μmol/L)、格列齐特96μmol/L以及卡托普利(32μmol/L～40μmol/L)对正常CFB活力、细胞内蛋白含量有一定的抑制作用。
结论:小檗碱(7.5μmol/L～30μmol/L),黄芩苷(0.94μmol/L～30μmol/L),苦参碱(125μmol/L～500μmol/L),罗格列酮(1.6μmol/L～2μmol/L),格列齐特96μmol/L,卡托普利(32μmol/L～40μmol/L)对正常MC增殖无抑制作用,而对CFB的增殖具有一定的抑制作用。
3小檗碱、黄芩苷、苦参碱对高糖致MC及CFB病变的影响
目的:建立高糖MC及高糖CFB模型,分别观察小檗碱、黄芩苷、苦参碱对高糖致MC病变及CFB病变的影响。
方法:采用葡萄糖25mmol/L建立高糖MC及CFB模型,通过测定细胞活力、面积(图像分析法)、蛋白含量以及CFB分泌的胶原蛋白含量(羟脯氨酸-碱水解法),分别观察小檗碱、黄芩苷、苦参碱、罗格列酮、格列齐特及卡托普利对高糖诱导的MC病变及CFB病变的影响。
结果:①葡萄糖25mmol/L可明显增加MC和CFB的细胞内蛋白含量,促进CFB增殖和胶原蛋白的分泌。②小檗碱(3.75μmol/L～30μmol/L)可明显抑制高糖所致的MC及CFB面积、蛋白含量的增加,抑制CFB增殖及胶原蛋白分泌的增加,而对MC增殖无明显影响。③黄芩苷(3.75μmol/L～30μmot/L)对高糖所致的MC和CFB的蛋白、面积的增加均有明显的抑制作用,30μmol/L组可明显抑制高糖所致的CFB增殖、胶原蛋白含量的增加,对MC增殖无抑制作用。④苦参碱62.5μmol/L可促进MC增殖,500μmol/L对高糖所致的MC蛋白、面积以及CFB的增殖、蛋白的增加有一定的抑制作用,苦参碱各浓度组对高糖所致的CFB增加面积均有明显的抑制作用,而对高糖所致的胶原蛋白含量增加无明显的抑制作用。⑤阳性药各组对MC以及CFB的活力、蛋白、面积以及胶原蛋白含量亦有一定的抑制作用。
结论:小檗碱、黄芩苷、苦参碱可抑制高糖诱导的MC和CFB面积和蛋白含量的增加,此外,小檗碱和黄芩苷还可抑制CFB增殖和胶原蛋白的分泌,而苦参碱对CFB分泌胶原蛋白含量无明显影响。
4小檗碱、黄芩苷、苦参碱对高糖加高胰岛素致MC/RCFB病变的影响
目的:分别观察小檗碱、黄芩苷、苦参碱对高糖加高胰岛素致MC及CFB病变的影响。
方法:采用葡萄糖25mmol/L加胰岛素10~(-4)mmol/L建立高糖高胰岛素MC及CFB病变模型,通过测定细胞活力、面积、蛋白含量以及胶原蛋白含量,分别观察小檗碱、黄芩苷、苦参碱、罗格列酮、格列齐特及卡托普利对高糖加高胰岛素诱导的MC病变及CFB病变的影响。
结果:①高糖加高胰岛素使MC及CFB活力、蛋白、面积和胶原蛋白明显增加。②小檗碱(15μmol/L～30μmol/L)对高糖加高胰岛素所致MC和CFB蛋白、面积增加均有明显抑制作用,30μmol/L对MC的活力有一定的抑制作用。③黄芩苷(15μmol/L～30μmol/L)对高糖加高胰岛素所致MC及CFB面积增加均有显著的抑制作用,30μmol/L对MC及CFB活力、蛋白含量、胶原蛋白增加有一定的抑制作用。④苦参碱(250μmol/L～500μmol/L)对高糖加高胰岛素模型MC活力和CFB活力有一定的抑制作用,500μmol/L对高糖加高胰岛素所致的MC蛋白含量、面积以及CFB蛋白含量增加有一定的抑制作用,苦参碱各浓度组对CFB面积均有明显的抑制作用,而对胶原蛋白含量无明显影响。⑤阳性药组对高糖加高胰岛素所致的MC活力、面积以及CFB活力、面积蛋白、胶原蛋白含量增加有明显的抑制作用,而对高糖加高胰岛素所致的MC蛋白含量增加无明显影响。
结论:小檗碱、黄芩苷、苦参碱可抑制高糖加高胰岛素诱导的MC和CFB增殖、面积和蛋白含量的增加,此外,小檗碱和黄芩苷还可抑制CFB分泌胶原蛋白,而苦参碱对此无明显抑制作用。
5小檗碱抗糖尿病心肌病的作用机制初探
目的:观察小檗碱对高糖加高胰岛素致MC分泌TNF-α及CFB分泌NO和TGF-β1的影响。
方法:采用葡萄糖25mmol/L加胰岛素10~(-4)mmol/L建立MC及CFB病变模型,通过测定MC培养液中TNF-α含量(ELISA法),CFB培养液中NO含量(硝酸还原法)以及TGF-β1含量(ELISA法),分别观察小檗碱、罗格列酮、格列齐特及卡托普利对高糖加高胰岛素诱导的MC及CFB病变的影响。
结果:小檗碱各浓度组对高糖加高胰岛素所致MC的TNF-α含量增加、CFB的TGF-β1含量增加以及CFB的NO含量减少均有明显的抑制作用。阳性药各组亦具有一定的抑制作用。
结论:小檗碱保护心肌细胞,抗心肌间质纤维化,改善心室重构的作用可能与降低TNF-α、TGF-β1含量,提高NO含量有关。
综上所述,高糖高胰岛素可诱导心肌细胞及心肌成纤维细胞活力、细胞面积、蛋白含量以及成纤维细胞分泌胶原蛋白含量增加,是引起糖尿病患者出现心脏结构和功能改变的重要致病因素。小檗碱、黄芩苷、苦参碱可通过抑制心肌细胞活力、细胞面积和蛋白含量的增加,抑制心肌成纤维细胞增殖和胶原蛋白含量的增加,进而抑制心肌细胞肥大和心肌间质纤维化,改善心脏结构和心肌细胞功能。其中小檗碱改善心室重构的作用可能与抑制高糖高胰岛素诱导的心肌细胞及心肌成纤维细胞分泌TNF-α、TGF-β_1含量的增高,提高NO含量有关,有关机制还有待进一步深入研究。
Diabetic Cardiomyopathy(DC),which triggered by metabolic disturbance,is a specific kind of diabetic heart disease,and it can cause the change of myocardial ultra structure,finally leads to left ventricular hypertrophy,dysfunction during diastolic and/or systolic.It is a kind of cardiac dysfunction that different from coronary artery disease,microvascular disease and cardiac neuropathy.With the incidence of Diabetes Mellitus(DM) increased and the course extended year by year,DC along with DM has become a leading cause of death.Therefore,the main research area in the field of diabetic angiocardiopathy is proving up the pathogenesis of DC and seeking for the prophylactic agent of DC.
Recently,Traditional Chinese Medicine has attracted more and more attention in the treatment of DM and diabetic angiocardiopathy.Commonly used clinical prescriptions are Gegenqinlian decoction,Dachaihu decoction Huanglianjiedu decoction,Sanhuang decoction, etc,and Berberine,baicalin,matrine is a commonly used clinical prescriptions.Modern pharmacological studies have shown that these three kinds of Chinese medicine and its main chemical constituents in the treatment of diabetes and cardiovascular disease have a certain effect.
Berberine(Ber) is the primary alkaloid inside Coptis chinensis Franch,cortex phellodendri\ Radix Berberidis.Large quantity,of studies have proved that Ber has the cardiovascular pharmacological activity of anti-arrhythmic,lowering blood pressure and cardiac,it also have the ability to lowering blood sugar,regulate blood fat,reform IR and restrain glycosylated protein.But there's no research report about whether Ber has the ability to cure DC.
Baicalin(Bai) is a chief flavanoid in the Plant of Baicalin,it can generate baicalein and glucuronic acid after hydrolyze.According to the recent research,Bai not only has the pharmacological action of lowering blood pressure,and anti-inflammatory,but also has the ability to anti-lipid peroxidation,calcium antagonists and Catecholamine channel blockers, inhibit aldose reduction enzyme(AR),inhibitory protein non-enzymatic glycation,inhibition of protein kinase C activation,regulation of lipid metabolism and cytokines,the protection of endothelial cells,inhibition of vascular smooth muscle cell proliferation,protect myocardial ischemia / reperfusion injury.
Matrine(Mat) is the active constituent of Chinese herbal medicine like Sophora alopecuroides L\Matrine and Subprostrate Sophora Root,and it is the primary matrine alkaloid. Mat has wide cardiovascular pharmacological action,and deeply research has been made in the field of antiarrhythmic,hypolipidemic,positive inotropic effect.In vitro study showed that Mat can inhibit aldosterone and the hyperplasia of cardiac fibroblasts caused by angiotensin-Ⅱ. Therefore,Mat may have the pharmacological action of anti ventricular remodeling.
The topic established DC cell model by high sugar and high glucose plus high insulin. Through the in vitro experimental study of Ber,Bai,Mat on myocardial cells and cardiac fibroblasts in DC morphology,cell proliferation and the impact of pathology,this paper would evaluate their preventive and therapeutic effect on DC and discuss the metabolic mechanism of Ber during curing DC.Finally clarify the pathogenesis of DC,the role of drug therapy,as well as aspects of berberine on the prevention and treatment of diabetic cardiomyopathy.
1 Cultured and identified of cardiomyocyte cell(MC) and cardiac fibroblast(CFB) in neonatal rat ventricular
Objective:Isolation culture cardiomyocyte cell and cardiac fibroblast that-meet the experimental requirements and establish the best period of the experimental.
Methods:Cardiac tissue was digested to single cell suspension by mechanical and enzyme.Cardiomyocyte cell and cardiac fibroblast was separated according to different adherence time and inhibition of chemical reagents in order to get high purity,and strong activity of myocardial cells and cardiac fibroblasts.Cell was identified by morphology and immunochemistry.Cytoactive was detected by trypan blue.Detected the cytoactive by MTT colorimetric,and mapped the cell proliferation curves.
Results:①Cardiomyocyte was looked like fusiform or irregularity,cell nucleus was obviously bulged,and rhythmic mpulse was seen.Cytoactive＞90%;α-Sarcomeric actin antibody dyeing was positive(rate≥90%),90%,Fibronectin antibody dyeing was negative.After separation it grew in good condition within 144 hours.②Cardiac fibroblasts was looked like fusiform or irregularity triangle,Cell body was larger and kytoplasm was tenuity.Fibronectin antibody dyeing was positive,(rate≥95%),α-Sarcomeric actin antibody dyeing was negative. After the separation it reached a exponentially growth within 120 hours.
Conclusion:Myocardial cells and cardiac fibroblasts purity and activity in line with the experimental requirements,the best experimental time period is 48 hours to 120 hours after separation.
2 Effect of Bet,Bai and Mat on normal MC and CFB
Objective:Observing how the Ber,Bai,Mat impact ordinary MC and CFB with different density.
Methods:Measure the cell activity via MTT colormetric and Measure intracellular protein content through Coomassie brilliant blue method.Observe Ber with density 0.47μmol/L～60μmol/L,Bai with the density 0.47μmol/L～120μmol/L and Mat with the density 62.5μmol/L～2000μmol/L,find the effectiveness on ordinary MC and CFB after 48 hours.
Results:①Ber with the density 7.5μmol/L～30μmol/L,Bai with the density 0.47μmol/L～30μmol/L,Mat with the density 125μmol/L～500μmol/L,Rosiglitazone with the density 1.6μmol/L～2μmol/L,gliclazide with the density 96μmol/L～120μmol/L and captopril with the density 32μmol/L～40μmol/L have no effect on MC cytoactive and protein.②Ber with the density 7.5μmol/L～60μmol/L,Bai with the density 0.94μmol/L～120μmol/L,Mat with the density 125μmol/L～500μmol/L,Rosiglitazone with the density 1.6μmol/L～2μmol/L,gliclazide with the density 96μmol/L and captopril with the density 32μmol/L～40μmol/L can inhibit ordinary CFB cytoactive and protein.
Conclusion:Ber with the density 7.5μmol/L～30μmol/L,Bai with the density 0.94μmol/L～30μmol/L,Mat with the density 125μmol/L～500μmol/L,Rosiglitazone with the density 1.6μmol/L,2μmol/L,gliclazide with the density 96μmol/L and captopril with the density 32μmol/L～40μmol/L have no effect on ordinary MC cytoactive,but they can inhibit CFB proliferate.
3 Effect of Bet,Bai and Mat on MC and CFB models induced by high glucose
Objective:Construct a model of MC and CFB induced by high glucose,then observe the effectiveness of Ber,Bai and Mat on MC induced by high glucose and CFB.
Methods:Construct a model of MC and CFB induced by high glucose model with glucose with density 25mmol/L.Observe the effectiveness of Ber,Bai,Mat,rosiglitazone, gliclazide and captopril on MC and CFB induced by high glucose through testing cytoactive, area(image analysis method),protein content and collagen protein content that secreted by CFB(hydroxyproline-alkaline hydrolysis method)
Results:①Glucose with density 25mmol/L can significantly increase the intracellular protein content of MC and CFB and stimulate CFB proliferation and collagen protein content that secreted by CFB.②Bet with density 3.75μmol/L～30μmol/L can effectively inhibit collagen protein content,area of MC induced by high glucose.It also inhibit cytoactive,area and collagen protein content of CFB,but has no effect on cytoactive of MC.③Bai with density 3.75μmot/L～30μmol/L can significantly inhibit collagen protein content,area of MC and CFB induced by high glucose.Bai with density 30μmol/L can effectively inhibit proliferation,collagen protein content Of CFB induced by high glucose.④Mat with density 62.5μmol/L can stimulate MC proliferation.Mat with density 500～μmol/L can inhibit protein content,area of MC induced by high glucose,it also inhibit proliferation and protein content of CFB.All Mat testing group can inhibit the area of CFB induced by high glucose,but they have no effect on collagen protein content increasing that induced by high glucose.⑤All testing group can inhibit the cytoactive,protein content,area,collagen protein content of MC and CFB.
Conclusion:Ber,Bai,Mat can inhibit the area,protein content of MC and CFB induced by high-glucose.Ber and Bai can also inhibit cytoactive,area,protein content and collagen protein content of CFB,but Mat have no effect on it.
4 Effect of Bet,Bai and Mat on MC and CFB models induced by high glucose and high Insulin
Objective:Observe separately the effectiveness of Ber,Bai,Mat on MC and CFB induced by high glucose plus high insulin.
Methods:Use glucose with density 25mmol/L plus insulin with density 10-7mol/L to construct a model of MC and CFB induced by high glucose plus high insulin,and then observe the effectiveness of Ber,Bai and Mat on MC and CFB induced by high glucose plus high insulin.
Results:①High glucose plus high insulin can significantly increase the cytoactive, protein content,area and collagen protein content of MC and CFB.②Ber with density 1.5μmol/L～30μmol/L can inhibit protein,area of MC and CFB induced by high glucose plus high insulin.Ber with density 30μmol/L can inhibit cytoactive of MC.③Bai with density 15μmol/L～30μmol/L can significantly inhibit,the area of MC and CFB induced by high glucose plus high insulin.Bai with density 30μmol/L can inhibit cytoactive,protein content and collagen protein content of MC and CFB.④Mat with density 250μmol/L～500μmol/L can inhibit cytoactive of MC and CFB induced by high glucose plus high insulin.Mat with density 500μmol/L can inhibit protein content,area of MC induced by high glucose plus high insulin,it also can inhibit protein content of CFB induced by high glucose plus high insulin. All testing group of Mat can inhibit the area of CFB,but they have no significant effect on collagen protein content.⑤All testing group can inhibit the cytoactive,area of MC induced by high glucose plus high insulin,they can also inhibit cytoactive,area,protein content and collagen protein content of CFB induced by high glucose plus high insulin.But they all have no significant effect on protein content of MC induced by high glucose plus high insulin.
Conclusion:Ber,Bai and Mat can inhibit MC and CFB cell proliferation and hyperplasia induced by high glucose plus high insulin.Ber and Bai can also inhibit collagen protein content of CFB,but Mat have no effect on it.
5 The mechanism of Berberine anti-diabetic cardiomyopathy
Objective:Observe the effectiveness of Ber on MC induced by high glucose plus high insulin secreting TNF-αand CFB secreting TGF-β1.
Methods:Using Glucose with density 25mmol/L plus insulin with density 10~(-4)mmol/L to construct MC and CFB model.Observe the effectiveness of Ber,Bai and Mat on MC and CFB induced by high glucose plus high insulin through testing the content of TNF-αinside MC culture solution(ELISA-method),testing the content of NO inside CFB culture solution (Nitrate reduction method) and testing the content of TGF-β1(Nitrate reduction method).
Results:All testing group of Ber can inhibit the content of TNF-αinside MC induced by high glucose plus high insulin and inhibit the content of TGF-β1 inside CFB,they can also inhibit the NO.content decreasing inside CFB.The positive drug also have the inhibition.
Conclusion:The effectiveness of Ber on protecting myocardial cell,anti myocardial fibrosis and assisting cardiac ventricular remodeling may have relative with decreasing the content of TNF-α,TGF-β1,and increasing the content of NO.
As a consequence of the above,High glucose and high insulin can active myocardial cell and cardiac fibroblasts,area,protein content and CFB secretion collagen.Ber,Bai and Mat can inhibit hyperplasia and myocardial fibrosis through inhibiting myocardial cell cytoactive, area,protein content and inhibiting CFB proliferation,area,protein,content and collagen protein content.The effectiveness of Ber on protecting myocardial cell,anti myocardial fibrosis and assisting cardiac ventricular remodeling may have relative with decreasing the content of TNF-α,TGF-β1,and increasing the content of NO,but need to do a future study on it.
近年,中医药对糖尿病及糖尿病心血管并发症的积极治疗作用受到广泛关注。临床常用方剂有葛根芩连汤、大柴胡汤、黄连解毒汤、三黄汤等,其中黄连、黄芩、苦参是临床运用较多的中药。现代药理研究显示,这三种中药及其主要化学成分在治疗糖尿病及心血管病方面具有一定的疗效。
小檗碱(Berberine,Ber)是黄连、黄柏、三棵针等植物中所含的主要生物碱,有大量研究证实其具有抗心律失常、降压、强心等心血管药理活性,同时还具有降血糖、调血脂、改善胰岛素抵抗、抑制蛋白糖基化等方面作用。但小檗碱是否改善糖尿病心肌病变尚未见研究报道。
黄芩苷(Baicalin,Bai)是植物黄芩中的一种主要黄酮类化合物。近年来研究发现,黄芩苷除了具有降压、镇静、消炎等药理作用外,还有抗脂质过氧化、拮抗儿茶酚胺和钙离子通道阻滞,抑制醛糖还原酶(AR)、抑制蛋白非酶糖基化作用、抑制蛋白激酶C的激活,调节脂代谢和细胞因子,保护内皮细胞,抑制血管平滑肌细胞增殖,保护心肌缺血/再灌注损伤作用,可防治糖尿病心血管并发症。
苦参碱(Matrine,Mat)是豆科植物苦参、苦豆子、广豆根等中草药的活性成分,是苦参碱类生物碱的代表。苦参碱具有较为广泛的心血管药理作用,其中抗心律失常、降血脂、正性肌力作用的研究较为深入。体外研究发现苦参碱能抑制醛固酮、血管紧张素Ⅱ诱导的离体心肌成纤维细胞的增殖,因此,苦参碱可能有一定的抗心室重构作用。
本课题采用高糖及高糖加高胰岛素制备DC细胞模型,通过体外细胞实验研究小檗碱、黄芩苷、苦参碱对DC细胞模型心肌细胞和心肌成纤维细胞形态结构、细胞增殖以及分泌病理活性产物的影响,评价其对于糖尿病心肌病变的防治作用,探讨小檗碱抗糖尿病心肌病变的机制,为阐明糖尿病心肌病的发病机制、药物治疗的作用环节以及小檗碱对糖尿病心肌病的防治作用提供科学依据。
1乳鼠心肌细胞(MC)和心肌成纤维细胞(CFB)的分离培养与鉴定
目的:分离培养符合实验要求的心肌细胞以及心肌成纤维细胞,确立细胞实验的最佳期。
方法:采用机械消化和酶消化相结合的方法将心肌组织消化为单细胞悬液,利用差速贴壁法和化学试剂抑制法分别获得纯度高、活力强的心肌细胞和心肌成纤维细胞。对细胞进行形态学和免疫化学鉴定,台盼蓝染色法和MTT比色法检测细胞活力,并绘制细胞增殖曲线。
结果:①心肌细胞呈梭形或不规则形,细胞核凸出明显,可见节律性搏动。细胞活力≥90%,α-Sarcomeric actin抗体染色阳性(阳性率≥90%),Fibronectin抗体染色染色阴性,分离后144h内生长状态良好。②心肌成纤维细胞呈梭形或不规则三角形,胞体较大通常有2-3个细胞核,胞质稀薄。细胞活力≥95%,Fibronectin抗体染色阳性(阳性率≥95%),α-Sarcomeric actin抗体染色阴性,分离后120h内呈指数增长。
结论:心肌细胞以及心肌成纤维细胞的纯度和活力符合实验要求,细胞实验的最佳时间段在分离后48-120h。
2小檗碱、黄芩苷、苦参碱对正常MC及CFB的影响
目的:观察不同浓度小檗碱、黄芩苷、苦参碱对正常MC及CFB的影响。
方法:用MTT比色法测定细胞活力,考马斯亮兰法测定细胞内蛋白含量,分别观察小檗碱(0.47μmol/L～60μmol/L)、黄芩苷(0.47μmol/L～120μmol/L)、苦参碱(62.5μmol/L～2000μmol/L)对正常MC及CFB作用48h的影响。
结果:①小檗碱(0.47μmol/L～30μmol/L),黄芩苷(0.47μmol/L～30μmol/L),苦参碱(62.5μmol/L～500μmol/L)、罗格列酮(1.6μmol/L～2μmol/L)、格列齐特(96μmol/L～120μmol/L)、卡托普利(32μmol/L～40μmol/L)对MC活力、细胞内蛋白含量无抑制作用。②小檗碱(7.5μmol/L～60μmol/L)、黄芩苷(0.94μmol/L～120μmol/L)、苦参碱(125μmol/L～2000μmol/L)、罗格列酮(1.6μmol/L～2μmol/L)、格列齐特96μmol/L以及卡托普利(32μmol/L～40μmol/L)对正常CFB活力、细胞内蛋白含量有一定的抑制作用。
结论:小檗碱(7.5μmol/L～30μmol/L),黄芩苷(0.94μmol/L～30μmol/L),苦参碱(125μmol/L～500μmol/L),罗格列酮(1.6μmol/L～2μmol/L),格列齐特96μmol/L,卡托普利(32μmol/L～40μmol/L)对正常MC增殖无抑制作用,而对CFB的增殖具有一定的抑制作用。
3小檗碱、黄芩苷、苦参碱对高糖致MC及CFB病变的影响
目的:建立高糖MC及高糖CFB模型,分别观察小檗碱、黄芩苷、苦参碱对高糖致MC病变及CFB病变的影响。
方法:采用葡萄糖25mmol/L建立高糖MC及CFB模型,通过测定细胞活力、面积(图像分析法)、蛋白含量以及CFB分泌的胶原蛋白含量(羟脯氨酸-碱水解法),分别观察小檗碱、黄芩苷、苦参碱、罗格列酮、格列齐特及卡托普利对高糖诱导的MC病变及CFB病变的影响。
结果:①葡萄糖25mmol/L可明显增加MC和CFB的细胞内蛋白含量,促进CFB增殖和胶原蛋白的分泌。②小檗碱(3.75μmol/L～30μmol/L)可明显抑制高糖所致的MC及CFB面积、蛋白含量的增加,抑制CFB增殖及胶原蛋白分泌的增加,而对MC增殖无明显影响。③黄芩苷(3.75μmol/L～30μmot/L)对高糖所致的MC和CFB的蛋白、面积的增加均有明显的抑制作用,30μmol/L组可明显抑制高糖所致的CFB增殖、胶原蛋白含量的增加,对MC增殖无抑制作用。④苦参碱62.5μmol/L可促进MC增殖,500μmol/L对高糖所致的MC蛋白、面积以及CFB的增殖、蛋白的增加有一定的抑制作用,苦参碱各浓度组对高糖所致的CFB增加面积均有明显的抑制作用,而对高糖所致的胶原蛋白含量增加无明显的抑制作用。⑤阳性药各组对MC以及CFB的活力、蛋白、面积以及胶原蛋白含量亦有一定的抑制作用。
结论:小檗碱、黄芩苷、苦参碱可抑制高糖诱导的MC和CFB面积和蛋白含量的增加,此外,小檗碱和黄芩苷还可抑制CFB增殖和胶原蛋白的分泌,而苦参碱对CFB分泌胶原蛋白含量无明显影响。
4小檗碱、黄芩苷、苦参碱对高糖加高胰岛素致MC/RCFB病变的影响
目的:分别观察小檗碱、黄芩苷、苦参碱对高糖加高胰岛素致MC及CFB病变的影响。
方法:采用葡萄糖25mmol/L加胰岛素10~(-4)mmol/L建立高糖高胰岛素MC及CFB病变模型,通过测定细胞活力、面积、蛋白含量以及胶原蛋白含量,分别观察小檗碱、黄芩苷、苦参碱、罗格列酮、格列齐特及卡托普利对高糖加高胰岛素诱导的MC病变及CFB病变的影响。
结果:①高糖加高胰岛素使MC及CFB活力、蛋白、面积和胶原蛋白明显增加。②小檗碱(15μmol/L～30μmol/L)对高糖加高胰岛素所致MC和CFB蛋白、面积增加均有明显抑制作用,30μmol/L对MC的活力有一定的抑制作用。③黄芩苷(15μmol/L～30μmol/L)对高糖加高胰岛素所致MC及CFB面积增加均有显著的抑制作用,30μmol/L对MC及CFB活力、蛋白含量、胶原蛋白增加有一定的抑制作用。④苦参碱(250μmol/L～500μmol/L)对高糖加高胰岛素模型MC活力和CFB活力有一定的抑制作用,500μmol/L对高糖加高胰岛素所致的MC蛋白含量、面积以及CFB蛋白含量增加有一定的抑制作用,苦参碱各浓度组对CFB面积均有明显的抑制作用,而对胶原蛋白含量无明显影响。⑤阳性药组对高糖加高胰岛素所致的MC活力、面积以及CFB活力、面积蛋白、胶原蛋白含量增加有明显的抑制作用,而对高糖加高胰岛素所致的MC蛋白含量增加无明显影响。
结论:小檗碱、黄芩苷、苦参碱可抑制高糖加高胰岛素诱导的MC和CFB增殖、面积和蛋白含量的增加,此外,小檗碱和黄芩苷还可抑制CFB分泌胶原蛋白,而苦参碱对此无明显抑制作用。
5小檗碱抗糖尿病心肌病的作用机制初探
目的:观察小檗碱对高糖加高胰岛素致MC分泌TNF-α及CFB分泌NO和TGF-β1的影响。
方法:采用葡萄糖25mmol/L加胰岛素10~(-4)mmol/L建立MC及CFB病变模型,通过测定MC培养液中TNF-α含量(ELISA法),CFB培养液中NO含量(硝酸还原法)以及TGF-β1含量(ELISA法),分别观察小檗碱、罗格列酮、格列齐特及卡托普利对高糖加高胰岛素诱导的MC及CFB病变的影响。
结果:小檗碱各浓度组对高糖加高胰岛素所致MC的TNF-α含量增加、CFB的TGF-β1含量增加以及CFB的NO含量减少均有明显的抑制作用。阳性药各组亦具有一定的抑制作用。
结论:小檗碱保护心肌细胞,抗心肌间质纤维化,改善心室重构的作用可能与降低TNF-α、TGF-β1含量,提高NO含量有关。
综上所述,高糖高胰岛素可诱导心肌细胞及心肌成纤维细胞活力、细胞面积、蛋白含量以及成纤维细胞分泌胶原蛋白含量增加,是引起糖尿病患者出现心脏结构和功能改变的重要致病因素。小檗碱、黄芩苷、苦参碱可通过抑制心肌细胞活力、细胞面积和蛋白含量的增加,抑制心肌成纤维细胞增殖和胶原蛋白含量的增加,进而抑制心肌细胞肥大和心肌间质纤维化,改善心脏结构和心肌细胞功能。其中小檗碱改善心室重构的作用可能与抑制高糖高胰岛素诱导的心肌细胞及心肌成纤维细胞分泌TNF-α、TGF-β_1含量的增高,提高NO含量有关,有关机制还有待进一步深入研究。
Diabetic Cardiomyopathy(DC),which triggered by metabolic disturbance,is a specific kind of diabetic heart disease,and it can cause the change of myocardial ultra structure,finally leads to left ventricular hypertrophy,dysfunction during diastolic and/or systolic.It is a kind of cardiac dysfunction that different from coronary artery disease,microvascular disease and cardiac neuropathy.With the incidence of Diabetes Mellitus(DM) increased and the course extended year by year,DC along with DM has become a leading cause of death.Therefore,the main research area in the field of diabetic angiocardiopathy is proving up the pathogenesis of DC and seeking for the prophylactic agent of DC.
Recently,Traditional Chinese Medicine has attracted more and more attention in the treatment of DM and diabetic angiocardiopathy.Commonly used clinical prescriptions are Gegenqinlian decoction,Dachaihu decoction Huanglianjiedu decoction,Sanhuang decoction, etc,and Berberine,baicalin,matrine is a commonly used clinical prescriptions.Modern pharmacological studies have shown that these three kinds of Chinese medicine and its main chemical constituents in the treatment of diabetes and cardiovascular disease have a certain effect.
Berberine(Ber) is the primary alkaloid inside Coptis chinensis Franch,cortex phellodendri\ Radix Berberidis.Large quantity,of studies have proved that Ber has the cardiovascular pharmacological activity of anti-arrhythmic,lowering blood pressure and cardiac,it also have the ability to lowering blood sugar,regulate blood fat,reform IR and restrain glycosylated protein.But there's no research report about whether Ber has the ability to cure DC.
Baicalin(Bai) is a chief flavanoid in the Plant of Baicalin,it can generate baicalein and glucuronic acid after hydrolyze.According to the recent research,Bai not only has the pharmacological action of lowering blood pressure,and anti-inflammatory,but also has the ability to anti-lipid peroxidation,calcium antagonists and Catecholamine channel blockers, inhibit aldose reduction enzyme(AR),inhibitory protein non-enzymatic glycation,inhibition of protein kinase C activation,regulation of lipid metabolism and cytokines,the protection of endothelial cells,inhibition of vascular smooth muscle cell proliferation,protect myocardial ischemia / reperfusion injury.
Matrine(Mat) is the active constituent of Chinese herbal medicine like Sophora alopecuroides L\Matrine and Subprostrate Sophora Root,and it is the primary matrine alkaloid. Mat has wide cardiovascular pharmacological action,and deeply research has been made in the field of antiarrhythmic,hypolipidemic,positive inotropic effect.In vitro study showed that Mat can inhibit aldosterone and the hyperplasia of cardiac fibroblasts caused by angiotensin-Ⅱ. Therefore,Mat may have the pharmacological action of anti ventricular remodeling.
The topic established DC cell model by high sugar and high glucose plus high insulin. Through the in vitro experimental study of Ber,Bai,Mat on myocardial cells and cardiac fibroblasts in DC morphology,cell proliferation and the impact of pathology,this paper would evaluate their preventive and therapeutic effect on DC and discuss the metabolic mechanism of Ber during curing DC.Finally clarify the pathogenesis of DC,the role of drug therapy,as well as aspects of berberine on the prevention and treatment of diabetic cardiomyopathy.
1 Cultured and identified of cardiomyocyte cell(MC) and cardiac fibroblast(CFB) in neonatal rat ventricular
Objective:Isolation culture cardiomyocyte cell and cardiac fibroblast that-meet the experimental requirements and establish the best period of the experimental.
Methods:Cardiac tissue was digested to single cell suspension by mechanical and enzyme.Cardiomyocyte cell and cardiac fibroblast was separated according to different adherence time and inhibition of chemical reagents in order to get high purity,and strong activity of myocardial cells and cardiac fibroblasts.Cell was identified by morphology and immunochemistry.Cytoactive was detected by trypan blue.Detected the cytoactive by MTT colorimetric,and mapped the cell proliferation curves.
Results:①Cardiomyocyte was looked like fusiform or irregularity,cell nucleus was obviously bulged,and rhythmic mpulse was seen.Cytoactive＞90%;α-Sarcomeric actin antibody dyeing was positive(rate≥90%),90%,Fibronectin antibody dyeing was negative.After separation it grew in good condition within 144 hours.②Cardiac fibroblasts was looked like fusiform or irregularity triangle,Cell body was larger and kytoplasm was tenuity.Fibronectin antibody dyeing was positive,(rate≥95%),α-Sarcomeric actin antibody dyeing was negative. After the separation it reached a exponentially growth within 120 hours.
Conclusion:Myocardial cells and cardiac fibroblasts purity and activity in line with the experimental requirements,the best experimental time period is 48 hours to 120 hours after separation.
2 Effect of Bet,Bai and Mat on normal MC and CFB
Objective:Observing how the Ber,Bai,Mat impact ordinary MC and CFB with different density.
Methods:Measure the cell activity via MTT colormetric and Measure intracellular protein content through Coomassie brilliant blue method.Observe Ber with density 0.47μmol/L～60μmol/L,Bai with the density 0.47μmol/L～120μmol/L and Mat with the density 62.5μmol/L～2000μmol/L,find the effectiveness on ordinary MC and CFB after 48 hours.
Results:①Ber with the density 7.5μmol/L～30μmol/L,Bai with the density 0.47μmol/L～30μmol/L,Mat with the density 125μmol/L～500μmol/L,Rosiglitazone with the density 1.6μmol/L～2μmol/L,gliclazide with the density 96μmol/L～120μmol/L and captopril with the density 32μmol/L～40μmol/L have no effect on MC cytoactive and protein.②Ber with the density 7.5μmol/L～60μmol/L,Bai with the density 0.94μmol/L～120μmol/L,Mat with the density 125μmol/L～500μmol/L,Rosiglitazone with the density 1.6μmol/L～2μmol/L,gliclazide with the density 96μmol/L and captopril with the density 32μmol/L～40μmol/L can inhibit ordinary CFB cytoactive and protein.
Conclusion:Ber with the density 7.5μmol/L～30μmol/L,Bai with the density 0.94μmol/L～30μmol/L,Mat with the density 125μmol/L～500μmol/L,Rosiglitazone with the density 1.6μmol/L,2μmol/L,gliclazide with the density 96μmol/L and captopril with the density 32μmol/L～40μmol/L have no effect on ordinary MC cytoactive,but they can inhibit CFB proliferate.
3 Effect of Bet,Bai and Mat on MC and CFB models induced by high glucose
Objective:Construct a model of MC and CFB induced by high glucose,then observe the effectiveness of Ber,Bai and Mat on MC induced by high glucose and CFB.
Methods:Construct a model of MC and CFB induced by high glucose model with glucose with density 25mmol/L.Observe the effectiveness of Ber,Bai,Mat,rosiglitazone, gliclazide and captopril on MC and CFB induced by high glucose through testing cytoactive, area(image analysis method),protein content and collagen protein content that secreted by CFB(hydroxyproline-alkaline hydrolysis method)
Results:①Glucose with density 25mmol/L can significantly increase the intracellular protein content of MC and CFB and stimulate CFB proliferation and collagen protein content that secreted by CFB.②Bet with density 3.75μmol/L～30μmol/L can effectively inhibit collagen protein content,area of MC induced by high glucose.It also inhibit cytoactive,area and collagen protein content of CFB,but has no effect on cytoactive of MC.③Bai with density 3.75μmot/L～30μmol/L can significantly inhibit collagen protein content,area of MC and CFB induced by high glucose.Bai with density 30μmol/L can effectively inhibit proliferation,collagen protein content Of CFB induced by high glucose.④Mat with density 62.5μmol/L can stimulate MC proliferation.Mat with density 500～μmol/L can inhibit protein content,area of MC induced by high glucose,it also inhibit proliferation and protein content of CFB.All Mat testing group can inhibit the area of CFB induced by high glucose,but they have no effect on collagen protein content increasing that induced by high glucose.⑤All testing group can inhibit the cytoactive,protein content,area,collagen protein content of MC and CFB.
Conclusion:Ber,Bai,Mat can inhibit the area,protein content of MC and CFB induced by high-glucose.Ber and Bai can also inhibit cytoactive,area,protein content and collagen protein content of CFB,but Mat have no effect on it.
4 Effect of Bet,Bai and Mat on MC and CFB models induced by high glucose and high Insulin
Objective:Observe separately the effectiveness of Ber,Bai,Mat on MC and CFB induced by high glucose plus high insulin.
Methods:Use glucose with density 25mmol/L plus insulin with density 10-7mol/L to construct a model of MC and CFB induced by high glucose plus high insulin,and then observe the effectiveness of Ber,Bai and Mat on MC and CFB induced by high glucose plus high insulin.
Results:①High glucose plus high insulin can significantly increase the cytoactive, protein content,area and collagen protein content of MC and CFB.②Ber with density 1.5μmol/L～30μmol/L can inhibit protein,area of MC and CFB induced by high glucose plus high insulin.Ber with density 30μmol/L can inhibit cytoactive of MC.③Bai with density 15μmol/L～30μmol/L can significantly inhibit,the area of MC and CFB induced by high glucose plus high insulin.Bai with density 30μmol/L can inhibit cytoactive,protein content and collagen protein content of MC and CFB.④Mat with density 250μmol/L～500μmol/L can inhibit cytoactive of MC and CFB induced by high glucose plus high insulin.Mat with density 500μmol/L can inhibit protein content,area of MC induced by high glucose plus high insulin,it also can inhibit protein content of CFB induced by high glucose plus high insulin. All testing group of Mat can inhibit the area of CFB,but they have no significant effect on collagen protein content.⑤All testing group can inhibit the cytoactive,area of MC induced by high glucose plus high insulin,they can also inhibit cytoactive,area,protein content and collagen protein content of CFB induced by high glucose plus high insulin.But they all have no significant effect on protein content of MC induced by high glucose plus high insulin.
Conclusion:Ber,Bai and Mat can inhibit MC and CFB cell proliferation and hyperplasia induced by high glucose plus high insulin.Ber and Bai can also inhibit collagen protein content of CFB,but Mat have no effect on it.
5 The mechanism of Berberine anti-diabetic cardiomyopathy
Objective:Observe the effectiveness of Ber on MC induced by high glucose plus high insulin secreting TNF-αand CFB secreting TGF-β1.
Methods:Using Glucose with density 25mmol/L plus insulin with density 10~(-4)mmol/L to construct MC and CFB model.Observe the effectiveness of Ber,Bai and Mat on MC and CFB induced by high glucose plus high insulin through testing the content of TNF-αinside MC culture solution(ELISA-method),testing the content of NO inside CFB culture solution (Nitrate reduction method) and testing the content of TGF-β1(Nitrate reduction method).
Results:All testing group of Ber can inhibit the content of TNF-αinside MC induced by high glucose plus high insulin and inhibit the content of TGF-β1 inside CFB,they can also inhibit the NO.content decreasing inside CFB.The positive drug also have the inhibition.
Conclusion:The effectiveness of Ber on protecting myocardial cell,anti myocardial fibrosis and assisting cardiac ventricular remodeling may have relative with decreasing the content of TNF-α,TGF-β1,and increasing the content of NO.
As a consequence of the above,High glucose and high insulin can active myocardial cell and cardiac fibroblasts,area,protein content and CFB secretion collagen.Ber,Bai and Mat can inhibit hyperplasia and myocardial fibrosis through inhibiting myocardial cell cytoactive, area,protein content and inhibiting CFB proliferation,area,protein,content and collagen protein content.The effectiveness of Ber on protecting myocardial cell,anti myocardial fibrosis and assisting cardiac ventricular remodeling may have relative with decreasing the content of TNF-α,TGF-β1,and increasing the content of NO,but need to do a future study on it.
引文
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