生物转化银杏叶提取物提高其降血糖活性
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摘要
在我国,银杏叶(Ginkgo biloba Leaf)资源非常丰富,其作为一种中药,具有降血糖、调节血脂、清除自由基、改善血液循环和保护心肌及血管内皮细胞等功效。但由于一般中药的作用往往较缓慢,效果也并不显著,因此,如何提高中药的作用效果已成为中医药治疗的重要问题。如采用药用真菌对中药进行生物转化,能有效提高药用真菌和中药的功效或产生新的疗效,目前已受到广泛的关注。
本文首先通过实验比较了四氧嘧啶糖尿病模型大鼠与正常大鼠血清中葡萄糖、果糖胺、NADH、血红蛋白、糖基化血红蛋白含量,以及肝脏和肾脏中与糖代谢相关的己糖激酶、丙酮酸脱氢酶和柠檬酸合成酶活性。结果显示四氧嘧啶诱导的糖尿病模型大鼠中果糖胺含量显著高于正常鼠,说明非酶糖基化反应在糖尿病模型大鼠中显著增强;总血红蛋白的含量显著减少,以及糖基化血红蛋白与总血红蛋白比例显著增加、NADH水平增加,而肝脏和肾脏中与糖代谢相关的己糖激酶、丙酮酸脱氢酶和柠檬酸合成酶活性显著减弱,说明糖代谢的三羧酸循环途径和糖酵解途径受到抑制,从而加速血糖升高。据此,我们提出了非酶糖基化反应能加速模型鼠血糖升高的假说。
分别优化了检测非酶糖基化反应、羟自由基产生Fenton反应体系,并利用以上两个体系以及体外抑制α-葡萄糖苷酶活性试验,对比了灵芝、猴头、香菇、红曲霉、蛹虫草、桑黄、竹黄、竹荪和云芝等11种菌株对银杏叶提取物(EGB)转化前后的活性变化情况。结果表明,猴头菌转化EGB后,体外活性的各项指标都得到加强,并且抑制非酶糖基化反应效果最好。
采用非酶糖基化反应平台,通过单因子试验确定了影响抑制率的最适工艺参数:pH为6.0,温度为27℃,发酵周期6天,EGB添加量为0.5%;并确定了显著影响抑制率的4个培养基因素:葡萄糖、蛋白胨、麸皮和玉米粉,四因子三水平正交试验设计优化的适合猴头菌转化EGB的培养基组成为:葡萄糖2%、蛋白胨0.4%、麸皮2%、玉米粉1.5%、KH_2PO_4 0.012%、MgSO_4 0.006%和CaCO_3 1%。20L发酵罐扩大培养最佳工艺条件为:72小时前通气量为8L/min,72小时后为4.8L/min,转速为120rpm。
通过四氧嘧啶诱导的糖尿病模型大鼠试验,比较了猴头菌转化EGB发酵液、EGB、猴头菌发酵液和添加EGB的猴头菌发酵液等四组试验材料对大鼠血糖、非酶糖基化反应、血脂和氧化趋势的作用。结果表明:①猴头菌转化EGB发酵液试验组血清中的血糖(14.59mmol/L)、果糖胺含量(3.10mmol/L)显著低于其他实验组,表明转化EGB发酵液在四氧嘧啶诱导的1型糖尿病鼠体内具有显著的抑制非酶糖基化反应的能力;②提高了糖耐量的水平;③降低了血糖、甘油三酯和总胆固醇的含量,提高了高密度胆固醇含量,各受试组在血清中均有明显的抗氧化作用,并无显著差异。猴头菌转化EGB发酵液降血糖机理分析显示,转化组血清中的血红蛋白含量(14.86g/L)显著高于模型对照组和二甲双胍组,而糖基化血红蛋白含量(2.93g/L)显著低于其他药物组,肝脏和肾脏中己糖激酶(158.16和97.34umol/min/g protein)、丙酮酸脱氢酶(90.25和69.85umol/min/g protein)和柠檬酸合成酶活性(776.5和643.2umol/min/g protein)显著高于模型鼠和二甲双胍组,由此推断猴头菌转化EGB发酵液组通过抑制体内非酶糖基化反应,提高血清中血红蛋白浓度,降低糖基化血红蛋白比例,增加氧的供给,降低NADH含量,减低NADH对糖代谢的反馈抑制作用,提高了与糖代谢有关的酶活性,结合对胰岛素分泌的促进作用降低血糖。
采用链脲佐菌素诱导高脂饲料胁迫的2型糖尿病模型大鼠,研究了上述四组药物对2型糖尿病的作用。结果显示:猴头转化EGB组果糖胺含量显著低于其它药物组,因而在2型糖尿病鼠体内同样具有显著的抑制非酶糖基化反应的功能。模型鼠给药后,转化组血清中血糖值(5.92 mmol/L)显著低于其他药物组,超氧化物岐化酶活性显著提高(182.3UN/mL),而对体重和脂代谢的作用与其它组之间无显著差异。转化组血清中胰岛素含量低于其它药物组(P＜0.01)。
通过对比九种不同类型树脂对猴头菌转化EGB产物的分离效果,确定AB-8型吸附树脂较为合适,其最适的吸附条件为:发酵液pH 2.0、流速为4%的树脂体积/min。最适解吸条件为:40%乙醇洗脱组分抑制率最高,重复性实验证明树脂洗脱性能稳定。并研究了粗提物体外抑制非酶糖基化反应、α-葡萄糖苷酶活性和清除自由基的能力。其半抑制浓度分别为1.223mg/mL,15.1 mg/mL和6.3mg/mL。该粗提物能通过迅速与非酶糖基化反应产物结合改变其结构,抑制产物的荧光强度。
Ginkgo biloba,as one of the most popular herbal medicines,was planted in China widely,and the annual production of its leaf was approximately 70%in the world. Ginkgo biloba Leaf has attracted great attention as agents for decreasing the blood glucose level,balancing the blood lipid level,scavenging the free radicals,improving circulation,particularly cerebral circulation.However,due to the inefficiency of Ginkgo biloba Leaf directly ulitilized as the herb medicines,the problem how to elevate the efficiency of the herb seems to be more serious.Now increasing interests has attracted on the biotransformation of Ginkgo biloba Leaf by the medicinal mushrooms which might improve the bioactive components and their medical effects of the herbs.
In current investigation,the comparisons of various indexes such as glucose, fructosamine,sugar,NADH,haemoglobin,glycosylated haemoglobin in blood,the systemic enzymes related to the glycolytic metabolism such as hexokinase,citratse synthase and pyruvate dehydrogenase in kidney and liver in the normal and alloxan-induced hyperglycemic rats were carried out.Results showed that the fructosamine level was significant higher in the model rats than that in the normal group, which indicated that the non-enzymatic glycation reaction was enhanced in the model rats.Significant declining of the content of total haemoglobin,increasing of the ratsio of glycosylated haemoglobin/total haemoglobin and NADH level,and decreasing of the related enzymes such as hexokinase,citratse synthase and pyruvate dehydrogenase activities of hexokinase,citratse synthase and pyruvate dehydrogenase showed that the Tricarboxylic acid cycle(TCA) and Embden-Meyerhof pathway(EMP) of glycolytic metabolism were inhibited and finally accelerates the blood glucose levels.According to above results,the hypothesis that non-enzymatic glycosylation reaction could increase the blood glucose of the diabetic rats was put forward.
The reaction systems to detect the non-enzyme glycation reaction and Fenton reactive system were optimized,respectively,and based on the bioactivities scavenging the free radicals and inhibition of non-enzymatic glycation reaction andα-glucosidase activity,11 strains such as Hericium erinaceus,Coriolus versicolor,and yeast were chosen to biotransformate extract of Ginkgo biloba L.(EGB).Results showed that comparing with other strains,all three indexes were enhanced after the biotransformation of EGB by Hericium erinaceus,and especially,the inhibition of non-enzymatic glycation reaction was most significantly improved.
Based on the results of inhibition of non-enzymatic glycation reaction in vitro, optimization of the operating parameters such as pH,temperature,fermentation period and media composition were carded out by on-factor-at-a-time method,and the suitable culture conditions was set as:pH 6.0,temperature 27℃,fermentation period,and 0.5% EGB addition content.And four media factors were also confirmed as glucose,peptone, wheat bran,and corn powder.The orthogonal test design L_9(3~4) demonstrated the optimal composition containing 2%glucose,0.4%peptone,2%wheat bran,1.5%corn powder 0.12%KH_2PO_4、0.06%MgSO_4 and CaCO_3 1%.The temperature and initial pH for highest inhibitory ratio were 27℃and 6.0,respectively.In 20-L scale fermenter,the optimal operating factors were:8 L before 72 h,4.8 L after 72 h,and agitation rate was 120rpm.
The hypoglycemic,inhibiting nonenzymatic glycosylation reaction,hypolipidemic, and antioxidant effects of various treatments,such as extract of Ginkgo biloba Leaf (EGB),biotransformation products of EGB by H.erinaceus,submerged culture of H. erinaceus and the culture combined with EGB,were compared in alloxan-induced hyperglycemic rats.Results showed that in the group treated with biotransformation products of EGB by H.erinaceus:①The levels of blood sugar(14.59mmol/L) and fructosamine(3.10mmol/L) were significant lower that other groups,which indicated that the biotransformation products of EGB by H.erinaceus could remarkably inhibit the non-enzyme glycation reaction in the TypeⅠdiabetes rats;②the ability of glucose tolerance was enhanced;③the levels of blood sugar,TC and TG were decreased and that of HDLC were increased.The mechanism analysis of anti-hyperglycemic activities of biotransformation products of EGB by H.erinaceus was conducted,and the results revealed that haemoglobin in blood,hexokinase(58.16and 97.34umol/min/g protein), citratse synthase(776.5 and 643.2umol/min/g protein) and pyruvate dehydrogenase (90.25 and 69.85umol/min/g protein) in kidney and liver of the group treated with biotransformation products of EGB by H.erinaceus was significantly higher than those in the control group and the mefformin treated group,synchronously,the content of glycosylated haemoglobin in blood was significantly lower than that of the control group and the metformin-treated group.According to these results,it could be concluded that the biotransformation products of EGB by H.erinaceus could generate significant anti-hyperglycermic and hypoglycemic effect on alloxan induced diabetic rats by inhibiting non-enzymatic glycosylated reaction,decreasing glycosylated haemoglobin level,improving total haemoglobin level and supply of oxygen,enhancing respiration of tissue,decreasing the levels of NADH,speeding up catabolism of glucose, and regulating the enzymes activities related to the glycolytic metabolism coupled with its elevating level of insulin of plasma.
The hypoglycemic,inhibiting nonenzymatic glycosylation reaction,hypolipidemic, and antioxidant effects of various treatments,such as extract of Ginkgo biloba Leaf (EGB),biotransformation products of EGB by H.erinaceus,submerged culture of H. erinaceus and the culture combined with EGB,were compared in streptozotocin-induced type 2 diabetic rats.Results prove that the biotransformation products of EGB by H.erinaceus could inhibit nonenzymatic glycosylation reaction of protein in vivo by reducing the content of fructosamine in the treated group,decrease the blood glucose level(5.92 mmol/L) and enhance SOD activity(182.3UN/mL) compared with control group and other treated-group.However,no significant influences were observed on body weight and lipid,and the blood insulin level was higher in transformation group than in model group,but distinctly lower than other treated group.
The isolation effects of 9 types macro-porous resins were compared and results revealed that AB-8 resin was most suitable to extract the active compositions with inhibitory activity on non-enzymatic glycation reaction from the broth of H.erinaceus. And the optimum technological conditions for adsorption were as fellows:pH=2.0, flow ratio=4%volume of resin/min,40%ethanol was selected as the most suitable agent for resolving the main bioactive fractions,and 10-cycle repeating experiments were also carried out and the results showed that the eluting factors were stable enough for the future applicant.The crude extraction resolving from the AB-8 resin biotransformation products of EGB by H.erinaceus,had been testified to inhibit non-enzymatic glycation reaction andα-glucosidase,as well as to scavenge free radical in vitro.The corresponding IC_(50) values were 1.223mg/mL,15.1 mg/mL and 6.3mg/mL, respectively.It was presume d that the crude extraction could combine with products of non-enzymatic glycation reaction,change their structure and finally attenuate their fluorescence intensive.
本文首先通过实验比较了四氧嘧啶糖尿病模型大鼠与正常大鼠血清中葡萄糖、果糖胺、NADH、血红蛋白、糖基化血红蛋白含量,以及肝脏和肾脏中与糖代谢相关的己糖激酶、丙酮酸脱氢酶和柠檬酸合成酶活性。结果显示四氧嘧啶诱导的糖尿病模型大鼠中果糖胺含量显著高于正常鼠,说明非酶糖基化反应在糖尿病模型大鼠中显著增强;总血红蛋白的含量显著减少,以及糖基化血红蛋白与总血红蛋白比例显著增加、NADH水平增加,而肝脏和肾脏中与糖代谢相关的己糖激酶、丙酮酸脱氢酶和柠檬酸合成酶活性显著减弱,说明糖代谢的三羧酸循环途径和糖酵解途径受到抑制,从而加速血糖升高。据此,我们提出了非酶糖基化反应能加速模型鼠血糖升高的假说。
分别优化了检测非酶糖基化反应、羟自由基产生Fenton反应体系,并利用以上两个体系以及体外抑制α-葡萄糖苷酶活性试验,对比了灵芝、猴头、香菇、红曲霉、蛹虫草、桑黄、竹黄、竹荪和云芝等11种菌株对银杏叶提取物(EGB)转化前后的活性变化情况。结果表明,猴头菌转化EGB后,体外活性的各项指标都得到加强,并且抑制非酶糖基化反应效果最好。
采用非酶糖基化反应平台,通过单因子试验确定了影响抑制率的最适工艺参数:pH为6.0,温度为27℃,发酵周期6天,EGB添加量为0.5%;并确定了显著影响抑制率的4个培养基因素:葡萄糖、蛋白胨、麸皮和玉米粉,四因子三水平正交试验设计优化的适合猴头菌转化EGB的培养基组成为:葡萄糖2%、蛋白胨0.4%、麸皮2%、玉米粉1.5%、KH_2PO_4 0.012%、MgSO_4 0.006%和CaCO_3 1%。20L发酵罐扩大培养最佳工艺条件为:72小时前通气量为8L/min,72小时后为4.8L/min,转速为120rpm。
通过四氧嘧啶诱导的糖尿病模型大鼠试验,比较了猴头菌转化EGB发酵液、EGB、猴头菌发酵液和添加EGB的猴头菌发酵液等四组试验材料对大鼠血糖、非酶糖基化反应、血脂和氧化趋势的作用。结果表明:①猴头菌转化EGB发酵液试验组血清中的血糖(14.59mmol/L)、果糖胺含量(3.10mmol/L)显著低于其他实验组,表明转化EGB发酵液在四氧嘧啶诱导的1型糖尿病鼠体内具有显著的抑制非酶糖基化反应的能力;②提高了糖耐量的水平;③降低了血糖、甘油三酯和总胆固醇的含量,提高了高密度胆固醇含量,各受试组在血清中均有明显的抗氧化作用,并无显著差异。猴头菌转化EGB发酵液降血糖机理分析显示,转化组血清中的血红蛋白含量(14.86g/L)显著高于模型对照组和二甲双胍组,而糖基化血红蛋白含量(2.93g/L)显著低于其他药物组,肝脏和肾脏中己糖激酶(158.16和97.34umol/min/g protein)、丙酮酸脱氢酶(90.25和69.85umol/min/g protein)和柠檬酸合成酶活性(776.5和643.2umol/min/g protein)显著高于模型鼠和二甲双胍组,由此推断猴头菌转化EGB发酵液组通过抑制体内非酶糖基化反应,提高血清中血红蛋白浓度,降低糖基化血红蛋白比例,增加氧的供给,降低NADH含量,减低NADH对糖代谢的反馈抑制作用,提高了与糖代谢有关的酶活性,结合对胰岛素分泌的促进作用降低血糖。
采用链脲佐菌素诱导高脂饲料胁迫的2型糖尿病模型大鼠,研究了上述四组药物对2型糖尿病的作用。结果显示:猴头转化EGB组果糖胺含量显著低于其它药物组,因而在2型糖尿病鼠体内同样具有显著的抑制非酶糖基化反应的功能。模型鼠给药后,转化组血清中血糖值(5.92 mmol/L)显著低于其他药物组,超氧化物岐化酶活性显著提高(182.3UN/mL),而对体重和脂代谢的作用与其它组之间无显著差异。转化组血清中胰岛素含量低于其它药物组(P＜0.01)。
通过对比九种不同类型树脂对猴头菌转化EGB产物的分离效果,确定AB-8型吸附树脂较为合适,其最适的吸附条件为:发酵液pH 2.0、流速为4%的树脂体积/min。最适解吸条件为:40%乙醇洗脱组分抑制率最高,重复性实验证明树脂洗脱性能稳定。并研究了粗提物体外抑制非酶糖基化反应、α-葡萄糖苷酶活性和清除自由基的能力。其半抑制浓度分别为1.223mg/mL,15.1 mg/mL和6.3mg/mL。该粗提物能通过迅速与非酶糖基化反应产物结合改变其结构,抑制产物的荧光强度。
Ginkgo biloba,as one of the most popular herbal medicines,was planted in China widely,and the annual production of its leaf was approximately 70%in the world. Ginkgo biloba Leaf has attracted great attention as agents for decreasing the blood glucose level,balancing the blood lipid level,scavenging the free radicals,improving circulation,particularly cerebral circulation.However,due to the inefficiency of Ginkgo biloba Leaf directly ulitilized as the herb medicines,the problem how to elevate the efficiency of the herb seems to be more serious.Now increasing interests has attracted on the biotransformation of Ginkgo biloba Leaf by the medicinal mushrooms which might improve the bioactive components and their medical effects of the herbs.
In current investigation,the comparisons of various indexes such as glucose, fructosamine,sugar,NADH,haemoglobin,glycosylated haemoglobin in blood,the systemic enzymes related to the glycolytic metabolism such as hexokinase,citratse synthase and pyruvate dehydrogenase in kidney and liver in the normal and alloxan-induced hyperglycemic rats were carried out.Results showed that the fructosamine level was significant higher in the model rats than that in the normal group, which indicated that the non-enzymatic glycation reaction was enhanced in the model rats.Significant declining of the content of total haemoglobin,increasing of the ratsio of glycosylated haemoglobin/total haemoglobin and NADH level,and decreasing of the related enzymes such as hexokinase,citratse synthase and pyruvate dehydrogenase activities of hexokinase,citratse synthase and pyruvate dehydrogenase showed that the Tricarboxylic acid cycle(TCA) and Embden-Meyerhof pathway(EMP) of glycolytic metabolism were inhibited and finally accelerates the blood glucose levels.According to above results,the hypothesis that non-enzymatic glycosylation reaction could increase the blood glucose of the diabetic rats was put forward.
The reaction systems to detect the non-enzyme glycation reaction and Fenton reactive system were optimized,respectively,and based on the bioactivities scavenging the free radicals and inhibition of non-enzymatic glycation reaction andα-glucosidase activity,11 strains such as Hericium erinaceus,Coriolus versicolor,and yeast were chosen to biotransformate extract of Ginkgo biloba L.(EGB).Results showed that comparing with other strains,all three indexes were enhanced after the biotransformation of EGB by Hericium erinaceus,and especially,the inhibition of non-enzymatic glycation reaction was most significantly improved.
Based on the results of inhibition of non-enzymatic glycation reaction in vitro, optimization of the operating parameters such as pH,temperature,fermentation period and media composition were carded out by on-factor-at-a-time method,and the suitable culture conditions was set as:pH 6.0,temperature 27℃,fermentation period,and 0.5% EGB addition content.And four media factors were also confirmed as glucose,peptone, wheat bran,and corn powder.The orthogonal test design L_9(3~4) demonstrated the optimal composition containing 2%glucose,0.4%peptone,2%wheat bran,1.5%corn powder 0.12%KH_2PO_4、0.06%MgSO_4 and CaCO_3 1%.The temperature and initial pH for highest inhibitory ratio were 27℃and 6.0,respectively.In 20-L scale fermenter,the optimal operating factors were:8 L before 72 h,4.8 L after 72 h,and agitation rate was 120rpm.
The hypoglycemic,inhibiting nonenzymatic glycosylation reaction,hypolipidemic, and antioxidant effects of various treatments,such as extract of Ginkgo biloba Leaf (EGB),biotransformation products of EGB by H.erinaceus,submerged culture of H. erinaceus and the culture combined with EGB,were compared in alloxan-induced hyperglycemic rats.Results showed that in the group treated with biotransformation products of EGB by H.erinaceus:①The levels of blood sugar(14.59mmol/L) and fructosamine(3.10mmol/L) were significant lower that other groups,which indicated that the biotransformation products of EGB by H.erinaceus could remarkably inhibit the non-enzyme glycation reaction in the TypeⅠdiabetes rats;②the ability of glucose tolerance was enhanced;③the levels of blood sugar,TC and TG were decreased and that of HDLC were increased.The mechanism analysis of anti-hyperglycemic activities of biotransformation products of EGB by H.erinaceus was conducted,and the results revealed that haemoglobin in blood,hexokinase(58.16and 97.34umol/min/g protein), citratse synthase(776.5 and 643.2umol/min/g protein) and pyruvate dehydrogenase (90.25 and 69.85umol/min/g protein) in kidney and liver of the group treated with biotransformation products of EGB by H.erinaceus was significantly higher than those in the control group and the mefformin treated group,synchronously,the content of glycosylated haemoglobin in blood was significantly lower than that of the control group and the metformin-treated group.According to these results,it could be concluded that the biotransformation products of EGB by H.erinaceus could generate significant anti-hyperglycermic and hypoglycemic effect on alloxan induced diabetic rats by inhibiting non-enzymatic glycosylated reaction,decreasing glycosylated haemoglobin level,improving total haemoglobin level and supply of oxygen,enhancing respiration of tissue,decreasing the levels of NADH,speeding up catabolism of glucose, and regulating the enzymes activities related to the glycolytic metabolism coupled with its elevating level of insulin of plasma.
The hypoglycemic,inhibiting nonenzymatic glycosylation reaction,hypolipidemic, and antioxidant effects of various treatments,such as extract of Ginkgo biloba Leaf (EGB),biotransformation products of EGB by H.erinaceus,submerged culture of H. erinaceus and the culture combined with EGB,were compared in streptozotocin-induced type 2 diabetic rats.Results prove that the biotransformation products of EGB by H.erinaceus could inhibit nonenzymatic glycosylation reaction of protein in vivo by reducing the content of fructosamine in the treated group,decrease the blood glucose level(5.92 mmol/L) and enhance SOD activity(182.3UN/mL) compared with control group and other treated-group.However,no significant influences were observed on body weight and lipid,and the blood insulin level was higher in transformation group than in model group,but distinctly lower than other treated group.
The isolation effects of 9 types macro-porous resins were compared and results revealed that AB-8 resin was most suitable to extract the active compositions with inhibitory activity on non-enzymatic glycation reaction from the broth of H.erinaceus. And the optimum technological conditions for adsorption were as fellows:pH=2.0, flow ratio=4%volume of resin/min,40%ethanol was selected as the most suitable agent for resolving the main bioactive fractions,and 10-cycle repeating experiments were also carried out and the results showed that the eluting factors were stable enough for the future applicant.The crude extraction resolving from the AB-8 resin biotransformation products of EGB by H.erinaceus,had been testified to inhibit non-enzymatic glycation reaction andα-glucosidase,as well as to scavenge free radical in vitro.The corresponding IC_(50) values were 1.223mg/mL,15.1 mg/mL and 6.3mg/mL, respectively.It was presume d that the crude extraction could combine with products of non-enzymatic glycation reaction,change their structure and finally attenuate their fluorescence intensive.
引文
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