白背三七降血糖物质基础研究
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摘要
白背三七(Gynura divaricata (L.) DC.)是菊科菊三七属植物,在福建,民间以茎叶冲茶煮水服用,对治疗糖尿病有较好的疗效。我们考察了白背三七不同提取物的降血糖活性,确定了其有效部位,结果显示白背三七提取物中正丁醇部分和大孔树脂90%乙醇洗脱部分低剂量的药效最好。
我们从白背三七茎叶中分离得到25个化合物,并根据化合物的理化性质分析、波谱解析、对照品比较及与文献报道对比鉴定了其中的23个化合物,分别为2-[2′-羟基(2′R)-二十四碳酰胺]-3,4-二羟基-(2S,3S,4R,10Z)-十八碳烯-1-O-β-D-吡喃葡萄糖苷(1)、2-[2′-羟基(2′R)-二十二碳酰胺]-3,4-二羟基-(2S,3S,4R,10E)-十八碳烯-1-O-β-D-吡喃葡萄糖苷(2)、山奈酚(3)、紫云英苷(4)、烟花苷(5)、山奈酚-3,7- O -双-β-D-吡喃葡萄糖苷(6)、山奈酚-5-O-(6′′-O-乙酰基)-β-D-吡喃葡萄糖苷(7)、4-羟基-5-羟甲基-γ-丁内酯(8)、2-(1′, 2′, 3′, 4′-四羟基丁基)-6-(2′′, 3′′, 4′′-三羟基丁基)-吡嗪(9)、掌叶半夏碱庚(10)、烟酸(11)、5-羟基吡啶羧酸(12)、5-羟基吡啶-2-甲酸甲酯(13)、腺苷(14)、尿苷(15)、β-谷甾醇-5-O-β-D-葡萄糖-6′- O-十七烷酸酯(16)、β-谷甾醇(17)、豆甾醇(18)、胡萝卜苷(19)、豆甾醇葡萄糖苷(20)、对苯二甲酸二丁酯(21)、绿原酸甲酯(22)、正二十烷(23)。其中化合物1、2为未见文献报道的新化合物,化合物6,7,8,9,10,13,16,21,22为首次从该属植物中分离得到,化合物3,4,11,12为首次从该植物中分离得到。
建立了HPLC测定白背三七中三种黄酮(山奈酚、紫云英苷、烟花苷)的方法,并测定了不同采收期药材中三种黄酮的含量,结果表明:白背三七以9月份采集为宜。
采用单因素试验法和正交试验法筛选得到白背三七的最佳提取工艺:用40倍量60%的乙醇,在60℃下超声提取2次;然后纯化得到白背三七总黄酮(黄酮含量达70%以上)。
以SPF级雄性SD大鼠高糖高脂喂养合并小剂量链脲佐菌素(STZ)诱导制备2型糖尿病模型,分组灌胃给予白背三七总黄酮及阳性对照药物,连续30d。给药结束后取材并检测血糖(BG)、血脂(甘油三酯TC、总胆固醇TG)、血清胰岛素(Ins)、超氧化物歧化酶(SOD)、丙二醛(MDA)、一氧化氮(NO)、血浆内皮素(ET)等指标,剖取胰腺行HE和免疫组化染色观察,考察白背三七总黄酮对各项指标的影响。结果表明:白背三七总黄酮可显著降低2型糖尿病模型大鼠血糖,改善其脂代谢紊乱和高胰岛素血症,增加机体抗氧化酶活性,减轻脂质过氧化,保护T2DM血管内皮功能,促进胰岛β细胞的修复。降血糖机制可能是通过增强机体清除活性氧自由基的能力从而抑制自由基对胰岛β细胞的损伤,促进胰岛β细胞的修复。
Gynura divaricata (L.) DC. is an important folk medicine. The leaf of Gynura divaricata is a commonly tea for reducing blood glucose. It could significantly decrease the blood glucose of diabetic patient.
The experiment determined some validation sections of Gynura divaricata (L.) DC. that could reduce the blood glucose in the model animals. In the advanced study, 4g/kg of the 90% alcohol eluted fractionⅤand the n-butanol extract fraction F of Gynura medica reducing blood glucose were better than other.
The chemical constituents of the plant were studied. Various modern chromatographic techniques, spectral methods as well as physical and chemical means were used to isolate and identify constituents from Gynura divaricata. 25 compounds were obtained. 23 were determined to be 1-O-β-D-glucopyranosyl-(2S,3S,4R,10Z)-2-[(2′R)-2′-hydroxylignocenoyl-amino]-10-octadecene- 1,3,4– triol ( 1 )、1-O-β-D-glucopyranosyl-(2S,3S,4R,10E)-2-[(2′R)-2′-hydroxyldocosanoyl -amino]-10-octadecene-1,3,4-trio(l2)、kaempfero(l3)、astragulin(4)、nicotiflorin (5)、kaempferol 3,7-O-di-β-D-glucopyranside(6)、kaempferol 5-O-(6′′-O-acetyl)-β-D- glucoside (7)、5-hydroxyl-4-hydroxymethyl-γ-butyrolactone (8)、2-(1′, 2′, 3′, 4′-tetrahydroxybutyl)-6-(2′′, 3′′, 4′′-trihydroxybutyl)-pyrazine (9)、2-(1′, 2′, 3′, 4′-tetrahydroxybutyl)-5-(2′′, 3′′, 4′′-trihydroxybutyl)-pyrazine (10)、nicotinic acid (11)、5-hydroxy-picolinic acid (12)、methyl-5-hydroxy-2- pyridinecarboxylate (13)、adenosine (14)、uridine(15)、β-sitosteryl glucoside- 6′-O-heptadecoicate(16)、β-sitostero(l17)、stigmastero(l18)、daucostero(l19)、stigmasterol-5-O-β-D-glucoside(20)、dibutyl terephthalat(e21)、methyl chlorogenat(e22)、n-eicosan(e23). Among them, compound 1、2 was new compound. and 6,7,8,9,10,13,16,21,22 was obtained for the first time from Gynura genus,3, 4,11,12 was obtained for the first time from Gynura divaricata.
RE-HPLC was used to determine the contents of kaempferol,astragulin and nicotiflorin in Gynura divaricata (L.) DC, the results show that the contents of three flavones in Gynura divaricata (L.) DC. Collected in september is highest.
The extracting process was studied by single factor method and orthogonal method, The optimal extracting techniques: 60% ethanol by ultrasonic extracting at 60℃with material and solvent ratio 1:40 for 2 times. Total flavones of Gynura divaricata(FGD) were obtained using polyamide, with content of kaempferol,astragulin and nicotiflorin more than 70%.
Male Sprague Dawley(SD) rats were fed with high fatty and high sugar diet for 4 weeks,then Streptozotocin(STZ) was injected intraperitioneally to m-ake rat model of T2DM.. The diabetic rats were randomly divided into six gr-oups:normal control group、diabetic model group、Glibenclamide group、Met-formin group、high dose of FGD and low dose of FGD. Blood glucose、TC、TG、blood serum insulin、SOD、MDA、NO and ET were detected after the rats given drugs for 4 weeks. The islands of Langerhans were dying with HE and immunohistochemistry to observate the beta cells of islands of Langerhans.The results showed that FGD has obvious glucose-lowering effect on T2DM rats. It can improve T2DM lipid peroxidation and hyperinsulinism ,and it can increase the level of SOD and reduce production of MDA in serum which were related to protecting the blood vessel endothelium injury and repairing the beta cells of T2DM islands of Langerhans. FGD has good effect for preventi-on and curing of T2DM. it also can protect the blood vessel endothelium inj-ury,The mechnism of hypoglycemic effect may relate to improve serum SOD、lipidperoxidation and hyperinsulinism that can repair the beta cells of T2DM islands of Langerhans.
我们从白背三七茎叶中分离得到25个化合物,并根据化合物的理化性质分析、波谱解析、对照品比较及与文献报道对比鉴定了其中的23个化合物,分别为2-[2′-羟基(2′R)-二十四碳酰胺]-3,4-二羟基-(2S,3S,4R,10Z)-十八碳烯-1-O-β-D-吡喃葡萄糖苷(1)、2-[2′-羟基(2′R)-二十二碳酰胺]-3,4-二羟基-(2S,3S,4R,10E)-十八碳烯-1-O-β-D-吡喃葡萄糖苷(2)、山奈酚(3)、紫云英苷(4)、烟花苷(5)、山奈酚-3,7- O -双-β-D-吡喃葡萄糖苷(6)、山奈酚-5-O-(6′′-O-乙酰基)-β-D-吡喃葡萄糖苷(7)、4-羟基-5-羟甲基-γ-丁内酯(8)、2-(1′, 2′, 3′, 4′-四羟基丁基)-6-(2′′, 3′′, 4′′-三羟基丁基)-吡嗪(9)、掌叶半夏碱庚(10)、烟酸(11)、5-羟基吡啶羧酸(12)、5-羟基吡啶-2-甲酸甲酯(13)、腺苷(14)、尿苷(15)、β-谷甾醇-5-O-β-D-葡萄糖-6′- O-十七烷酸酯(16)、β-谷甾醇(17)、豆甾醇(18)、胡萝卜苷(19)、豆甾醇葡萄糖苷(20)、对苯二甲酸二丁酯(21)、绿原酸甲酯(22)、正二十烷(23)。其中化合物1、2为未见文献报道的新化合物,化合物6,7,8,9,10,13,16,21,22为首次从该属植物中分离得到,化合物3,4,11,12为首次从该植物中分离得到。
建立了HPLC测定白背三七中三种黄酮(山奈酚、紫云英苷、烟花苷)的方法,并测定了不同采收期药材中三种黄酮的含量,结果表明:白背三七以9月份采集为宜。
采用单因素试验法和正交试验法筛选得到白背三七的最佳提取工艺:用40倍量60%的乙醇,在60℃下超声提取2次;然后纯化得到白背三七总黄酮(黄酮含量达70%以上)。
以SPF级雄性SD大鼠高糖高脂喂养合并小剂量链脲佐菌素(STZ)诱导制备2型糖尿病模型,分组灌胃给予白背三七总黄酮及阳性对照药物,连续30d。给药结束后取材并检测血糖(BG)、血脂(甘油三酯TC、总胆固醇TG)、血清胰岛素(Ins)、超氧化物歧化酶(SOD)、丙二醛(MDA)、一氧化氮(NO)、血浆内皮素(ET)等指标,剖取胰腺行HE和免疫组化染色观察,考察白背三七总黄酮对各项指标的影响。结果表明:白背三七总黄酮可显著降低2型糖尿病模型大鼠血糖,改善其脂代谢紊乱和高胰岛素血症,增加机体抗氧化酶活性,减轻脂质过氧化,保护T2DM血管内皮功能,促进胰岛β细胞的修复。降血糖机制可能是通过增强机体清除活性氧自由基的能力从而抑制自由基对胰岛β细胞的损伤,促进胰岛β细胞的修复。
Gynura divaricata (L.) DC. is an important folk medicine. The leaf of Gynura divaricata is a commonly tea for reducing blood glucose. It could significantly decrease the blood glucose of diabetic patient.
The experiment determined some validation sections of Gynura divaricata (L.) DC. that could reduce the blood glucose in the model animals. In the advanced study, 4g/kg of the 90% alcohol eluted fractionⅤand the n-butanol extract fraction F of Gynura medica reducing blood glucose were better than other.
The chemical constituents of the plant were studied. Various modern chromatographic techniques, spectral methods as well as physical and chemical means were used to isolate and identify constituents from Gynura divaricata. 25 compounds were obtained. 23 were determined to be 1-O-β-D-glucopyranosyl-(2S,3S,4R,10Z)-2-[(2′R)-2′-hydroxylignocenoyl-amino]-10-octadecene- 1,3,4– triol ( 1 )、1-O-β-D-glucopyranosyl-(2S,3S,4R,10E)-2-[(2′R)-2′-hydroxyldocosanoyl -amino]-10-octadecene-1,3,4-trio(l2)、kaempfero(l3)、astragulin(4)、nicotiflorin (5)、kaempferol 3,7-O-di-β-D-glucopyranside(6)、kaempferol 5-O-(6′′-O-acetyl)-β-D- glucoside (7)、5-hydroxyl-4-hydroxymethyl-γ-butyrolactone (8)、2-(1′, 2′, 3′, 4′-tetrahydroxybutyl)-6-(2′′, 3′′, 4′′-trihydroxybutyl)-pyrazine (9)、2-(1′, 2′, 3′, 4′-tetrahydroxybutyl)-5-(2′′, 3′′, 4′′-trihydroxybutyl)-pyrazine (10)、nicotinic acid (11)、5-hydroxy-picolinic acid (12)、methyl-5-hydroxy-2- pyridinecarboxylate (13)、adenosine (14)、uridine(15)、β-sitosteryl glucoside- 6′-O-heptadecoicate(16)、β-sitostero(l17)、stigmastero(l18)、daucostero(l19)、stigmasterol-5-O-β-D-glucoside(20)、dibutyl terephthalat(e21)、methyl chlorogenat(e22)、n-eicosan(e23). Among them, compound 1、2 was new compound. and 6,7,8,9,10,13,16,21,22 was obtained for the first time from Gynura genus,3, 4,11,12 was obtained for the first time from Gynura divaricata.
RE-HPLC was used to determine the contents of kaempferol,astragulin and nicotiflorin in Gynura divaricata (L.) DC, the results show that the contents of three flavones in Gynura divaricata (L.) DC. Collected in september is highest.
The extracting process was studied by single factor method and orthogonal method, The optimal extracting techniques: 60% ethanol by ultrasonic extracting at 60℃with material and solvent ratio 1:40 for 2 times. Total flavones of Gynura divaricata(FGD) were obtained using polyamide, with content of kaempferol,astragulin and nicotiflorin more than 70%.
Male Sprague Dawley(SD) rats were fed with high fatty and high sugar diet for 4 weeks,then Streptozotocin(STZ) was injected intraperitioneally to m-ake rat model of T2DM.. The diabetic rats were randomly divided into six gr-oups:normal control group、diabetic model group、Glibenclamide group、Met-formin group、high dose of FGD and low dose of FGD. Blood glucose、TC、TG、blood serum insulin、SOD、MDA、NO and ET were detected after the rats given drugs for 4 weeks. The islands of Langerhans were dying with HE and immunohistochemistry to observate the beta cells of islands of Langerhans.The results showed that FGD has obvious glucose-lowering effect on T2DM rats. It can improve T2DM lipid peroxidation and hyperinsulinism ,and it can increase the level of SOD and reduce production of MDA in serum which were related to protecting the blood vessel endothelium injury and repairing the beta cells of T2DM islands of Langerhans. FGD has good effect for preventi-on and curing of T2DM. it also can protect the blood vessel endothelium inj-ury,The mechnism of hypoglycemic effect may relate to improve serum SOD、lipidperoxidation and hyperinsulinism that can repair the beta cells of T2DM islands of Langerhans.
引文
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