葛根素治疗糖尿病的作用机制研究
摘要
糖尿病是21世纪危害人类健康的主要疾病之一。中药葛根数千年来一直用于糖尿病即消渴症的治疗,其主要的异黄酮活性成分-葛根素近年来用于治疗2型糖尿病及其综合征,证实确有降低血糖、提高胰岛素受体敏感性的疗效。葛根素的药理机制非常复杂,目前研究多集中在整体动物或器官水平,关于细胞特别是胰岛细胞以及分子机制的研究很少。
胰岛β细胞功能紊乱是2型糖尿病发生发展的主要原因之一,导致其发生的中心机制是氧化应激。体内外研究均表明葛根素具有清除自由基、提高抗氧化酶活性、抑制蛋白质非酶糖基化的作用,然而尚不清楚其抗氧化作用是否在保护胰岛细胞功能方面发挥作用。以过氧化氢(500μM)为刺激物诱导急性分离的大鼠胰岛细胞氧化损伤,采用MTT、流式细胞术、AO/EB荧光双染、Rhodamine 123、DCFH-DA荧光探针、酶分析及放射免疫法检测了葛根素(10-100μM)对胰岛细胞的凋亡、线粒体膜电位、自由基水平、抗氧化酶活性及胰岛素分泌功能的影响。结果表明葛根素能明显抑制胰岛细胞特别是β细胞凋亡,恢复胰岛细胞的基础和葡萄糖刺激分泌功能,其机制可能是清除活性氧,保护线粒体功能以及提高细胞在氧化应激下的抗氧化酶(CAT, SOD)活性。
同时依赖于电压和钙的大电导钾通道(BK_(Ca))在维持血管张力,调节血管舒张中起重要作用,研究表明其功能异常是糖尿病血管舒张功能弱化的重要原因。葛根素具有明显的舒血管作用,而且结构与某些BK_(Ca)通道开放剂相似。用膜片钳技术直接检测了葛根素与克隆的BK-α+β1和BK-α通道的相互作用,并考察了葛根素对BK_(Ca)通道的激活作用与其舒张大鼠胸主动脉的关系。结果表明纳摩尔浓度的葛根素能明显激活BK-α+β1通道宏观电流,使通道的GV曲线向负向移动20 mV左右。葛根素呈浓度依赖性的迅速、部分可逆的激活BK-α+β1通道电流,其EC50在10μM Ca~(2+)和0μM Ca~(2+)条件下分别为0.8 nM和12.6 nM。葛根素对通道电流的激活与膜电位成反比,即膜电位越高激活效应越弱,10μM Ca~(2+)时葛根素对ΒΚ?α+β1通道电流的激活主要在负电压下发生。单通道实验表明葛根素主要增加通道的开放几率而不改变单通道电导。在没有β1亚基和0μM Ca~(2+)条件下葛根素也能激活通道电流,但EC50是有β1亚基时的13倍,说明β1亚基能提高通道对葛根素的敏感性。葛根素的脱糖基类似物大豆素也能激活BK-α通道,但其效用弱于葛根素,说明糖基在葛根素对通道的激活中发挥重要作用。微摩尔浓度的葛根素(0.1-1000μM)呈浓度依赖性的舒张由去甲肾上腺素预收缩的大鼠胸主动脉,50 nM IbTX能明显抑制葛根素的舒张效应,说明BK_(Ca)通道的激活是葛根素舒张血管的机制之一。
进一步考察了葛根素对BK_(Ca)通道α亚基(mslo)的作用,并结合分子生物学技术对葛根素与BK_(Ca)通道的结合位点进行了初步研究。结果表明,在10μM Ca~(2+)下,葛根素对mslo电流有阻断作用,使通道的GV曲线向右移动。葛根素在10μM Ca~(2+)下阻断mslo电流的EC50为6.2 nM。葛根素对mslo的阻断作用随钙浓度降低而减弱,但随膜电位的降低而增强。葛根素对dslo没有作用,且将mslo和dslo的S0-S1 Linker交换后,葛根素对mslo的作用消失,说明葛根素与BK_(Ca)通道的结合位点在S0-S1 Linker上。
综上所述,葛根素对胰岛细胞在氧化应激下的功能紊乱及凋亡的抑制以及对表达于血管平滑肌的BK_(Ca)通道的激活可能是其治疗糖尿病及糖尿病血管并发症的重要机制。
Diabetes mellitus is one of the main threats to human health in the 21st century. Ge-gen (also known as“kudzu”) is used in Chinese traditional medicine for the therapy of diabetes for over two thousands years. Puerarin (7– Hydroxy– 3 - ( 4– hydroxyphenyl )– 1– benzopyran– 4– one 8-(β-D-glucopyranoside)) is the main isoflavone glycoside derived from ge-gen. Modern pharmacological researches have demonstrated that puerarin has antihyperglycemic effects and can improve insulin resistance, which has been used to treat diabetes mellitus and its complications. Previous studies about the pharmacological mechanisms of puerarin focused on animal and organ levels. However, the cellular and molecular mechanisms involved in its antidiabetic actions remain unclear.
The pancreaticβcell dysfunction is one of the main causes in diabetes etiology, and the oxidative stress under diabetic conditions is the leading cause ofβcell dysfunction. Puerarin has been shown to possess anti-oxidant properties such as scavenging reactive oxygen species, increasing superoxide dismutase (SOD) activity and inhibiting protein nonenzymatic glycation. This study was designed to investigate the protective effect against hydrogen peroxide (H2O2)-induced pancreatic islets damage by puerarin. Exposure of islets to 500μM H2O2 could cause a significant viability loss by MTT assay and an increase in apoptotic rate by flow cytometry and AO/EB double staining. Pre-treatment of islets with puerarin for 48 h resulted in a reduction in viability loss and apoptotic rate. 100μM puerarin significantly inhibited the apoptosis of islets induced by H2O2. In addition, preincubation with puerarin could improve the H2O2-induced decrease in glucose-induced insulin secretion in pancreatic islets by radioimmunoassay. Puerarin was also found to inhibit the free radicals production and the loss of mitochondrial membrane potential induced by H2O2 using DCFH-DA and Rhodamine123 as the fluorescent probes, respectively and to increase catalase (CAT) and superoxide dismutase (SOD) activities by enzyme assays in the isolated pancreatic islets. These results suggest that puerarin can protect islets against oxidative stress probably partially due to its antioxidative activity. Puerarin may be effective in preventing islet cells from the toxic action of reactive oxygen species (ROS) in diabetes.
The BK_(Ca) channel, the large-conductance voltage- and Ca~(2+)-activated potassium channel, abundantly expressed in vascular smooth muscle cells, plays a critical role in controlling vascular tone. The dysfunction of BK_(Ca) channels in diabetes mellitus has been reported to lead to diminished vascular relaxation. Puerarin has positive vasodilation effect and the structure of which is similar to some BK_(Ca) channel openers. We investigated the direct effects of puerarin on cloned pore forming subunit (α) of BK_(Ca) channel, with or withoutβ1 subunits and on rat thoracic aortas. BK_(Ca) channels encoded with eitherα(BK-α) orα/β1 subunits (BK-α+β1) were heterologously expressed in Xenopus oocytes or HEK293 cells. The activities of BK_(Ca) channels were measured using excised patch-clamp recordings. Puerarin intracellularly activated BK-α+β1 currents with a half-maximal concentration (EC50) of 0.8 nM and a Hill coefficient of 1.11 at 10μM Ca~(2+), and with EC50 of 12.6 nM and a Hill coefficient of 1.08 at 0μM Ca~(2+). Puerarin (1 nM) induced a 16 mV leftward shift in the conductance-voltage curve for BK-α+β1 currents at 10μM Ca~(2+), and at 100 nM induced a 26 mV leftward shift at 0μM Ca~(2+). Puerarin mainly increased the BK-α+β1 channel open probability without changing the unitary conductance. Activation was also detected in the absence of theβ1 subunit. A deglycosylated analog of puerarin, daidzein, also activated BK_(Ca) channels with weaker potency. In addition, puerarin (0.1 to 1000μM) caused concentration-dependent relaxations of rat thoracic aortic rings contracted with 1μM noradrenaline bitartrate (NA) (EC50 = 1.1μM). These were significantly inhibited by 50 nM iberiotoxin, a specific blocker of BK_(Ca) channels, indicating that the activation of the BK_(Ca) channel probably contributes to the puerarin-mediated vasodilation action.
Further, we explored the effect of puerarin on mslo currents in the presence of Ca~(2+) and the binding sites of puerarin on BK_(Ca) channel protein. Puerarin blocked mslo currents with an EC50 of 6.2 nM and a Hill coefficient of 0.86 at 10μM Ca~(2+). Puerarin inhibited mslo currents in a Ca~(2+) and voltage-dependent manners, higher Ca~(2+) concentration, higher inhibition while higher voltage, lower inhibition. The chimera construct with dslo S0-S1 Linker to mslo diminished the effect of puerarin on mslo channels, indicated that the sites for puerarin binding may be located at the region of S0-S1 Linker.
In summary, the present study provides evidences that puerarin could protect islet cells from oxidative damage and stimulate BK_(Ca) channel activity. These beneficial effects of puerarin may contribute to the underlying mechanisms by which it acts as an anti-diabetes compound.
胰岛β细胞功能紊乱是2型糖尿病发生发展的主要原因之一,导致其发生的中心机制是氧化应激。体内外研究均表明葛根素具有清除自由基、提高抗氧化酶活性、抑制蛋白质非酶糖基化的作用,然而尚不清楚其抗氧化作用是否在保护胰岛细胞功能方面发挥作用。以过氧化氢(500μM)为刺激物诱导急性分离的大鼠胰岛细胞氧化损伤,采用MTT、流式细胞术、AO/EB荧光双染、Rhodamine 123、DCFH-DA荧光探针、酶分析及放射免疫法检测了葛根素(10-100μM)对胰岛细胞的凋亡、线粒体膜电位、自由基水平、抗氧化酶活性及胰岛素分泌功能的影响。结果表明葛根素能明显抑制胰岛细胞特别是β细胞凋亡,恢复胰岛细胞的基础和葡萄糖刺激分泌功能,其机制可能是清除活性氧,保护线粒体功能以及提高细胞在氧化应激下的抗氧化酶(CAT, SOD)活性。
同时依赖于电压和钙的大电导钾通道(BK_(Ca))在维持血管张力,调节血管舒张中起重要作用,研究表明其功能异常是糖尿病血管舒张功能弱化的重要原因。葛根素具有明显的舒血管作用,而且结构与某些BK_(Ca)通道开放剂相似。用膜片钳技术直接检测了葛根素与克隆的BK-α+β1和BK-α通道的相互作用,并考察了葛根素对BK_(Ca)通道的激活作用与其舒张大鼠胸主动脉的关系。结果表明纳摩尔浓度的葛根素能明显激活BK-α+β1通道宏观电流,使通道的GV曲线向负向移动20 mV左右。葛根素呈浓度依赖性的迅速、部分可逆的激活BK-α+β1通道电流,其EC50在10μM Ca~(2+)和0μM Ca~(2+)条件下分别为0.8 nM和12.6 nM。葛根素对通道电流的激活与膜电位成反比,即膜电位越高激活效应越弱,10μM Ca~(2+)时葛根素对ΒΚ?α+β1通道电流的激活主要在负电压下发生。单通道实验表明葛根素主要增加通道的开放几率而不改变单通道电导。在没有β1亚基和0μM Ca~(2+)条件下葛根素也能激活通道电流,但EC50是有β1亚基时的13倍,说明β1亚基能提高通道对葛根素的敏感性。葛根素的脱糖基类似物大豆素也能激活BK-α通道,但其效用弱于葛根素,说明糖基在葛根素对通道的激活中发挥重要作用。微摩尔浓度的葛根素(0.1-1000μM)呈浓度依赖性的舒张由去甲肾上腺素预收缩的大鼠胸主动脉,50 nM IbTX能明显抑制葛根素的舒张效应,说明BK_(Ca)通道的激活是葛根素舒张血管的机制之一。
进一步考察了葛根素对BK_(Ca)通道α亚基(mslo)的作用,并结合分子生物学技术对葛根素与BK_(Ca)通道的结合位点进行了初步研究。结果表明,在10μM Ca~(2+)下,葛根素对mslo电流有阻断作用,使通道的GV曲线向右移动。葛根素在10μM Ca~(2+)下阻断mslo电流的EC50为6.2 nM。葛根素对mslo的阻断作用随钙浓度降低而减弱,但随膜电位的降低而增强。葛根素对dslo没有作用,且将mslo和dslo的S0-S1 Linker交换后,葛根素对mslo的作用消失,说明葛根素与BK_(Ca)通道的结合位点在S0-S1 Linker上。
综上所述,葛根素对胰岛细胞在氧化应激下的功能紊乱及凋亡的抑制以及对表达于血管平滑肌的BK_(Ca)通道的激活可能是其治疗糖尿病及糖尿病血管并发症的重要机制。
Diabetes mellitus is one of the main threats to human health in the 21st century. Ge-gen (also known as“kudzu”) is used in Chinese traditional medicine for the therapy of diabetes for over two thousands years. Puerarin (7– Hydroxy– 3 - ( 4– hydroxyphenyl )– 1– benzopyran– 4– one 8-(β-D-glucopyranoside)) is the main isoflavone glycoside derived from ge-gen. Modern pharmacological researches have demonstrated that puerarin has antihyperglycemic effects and can improve insulin resistance, which has been used to treat diabetes mellitus and its complications. Previous studies about the pharmacological mechanisms of puerarin focused on animal and organ levels. However, the cellular and molecular mechanisms involved in its antidiabetic actions remain unclear.
The pancreaticβcell dysfunction is one of the main causes in diabetes etiology, and the oxidative stress under diabetic conditions is the leading cause ofβcell dysfunction. Puerarin has been shown to possess anti-oxidant properties such as scavenging reactive oxygen species, increasing superoxide dismutase (SOD) activity and inhibiting protein nonenzymatic glycation. This study was designed to investigate the protective effect against hydrogen peroxide (H2O2)-induced pancreatic islets damage by puerarin. Exposure of islets to 500μM H2O2 could cause a significant viability loss by MTT assay and an increase in apoptotic rate by flow cytometry and AO/EB double staining. Pre-treatment of islets with puerarin for 48 h resulted in a reduction in viability loss and apoptotic rate. 100μM puerarin significantly inhibited the apoptosis of islets induced by H2O2. In addition, preincubation with puerarin could improve the H2O2-induced decrease in glucose-induced insulin secretion in pancreatic islets by radioimmunoassay. Puerarin was also found to inhibit the free radicals production and the loss of mitochondrial membrane potential induced by H2O2 using DCFH-DA and Rhodamine123 as the fluorescent probes, respectively and to increase catalase (CAT) and superoxide dismutase (SOD) activities by enzyme assays in the isolated pancreatic islets. These results suggest that puerarin can protect islets against oxidative stress probably partially due to its antioxidative activity. Puerarin may be effective in preventing islet cells from the toxic action of reactive oxygen species (ROS) in diabetes.
The BK_(Ca) channel, the large-conductance voltage- and Ca~(2+)-activated potassium channel, abundantly expressed in vascular smooth muscle cells, plays a critical role in controlling vascular tone. The dysfunction of BK_(Ca) channels in diabetes mellitus has been reported to lead to diminished vascular relaxation. Puerarin has positive vasodilation effect and the structure of which is similar to some BK_(Ca) channel openers. We investigated the direct effects of puerarin on cloned pore forming subunit (α) of BK_(Ca) channel, with or withoutβ1 subunits and on rat thoracic aortas. BK_(Ca) channels encoded with eitherα(BK-α) orα/β1 subunits (BK-α+β1) were heterologously expressed in Xenopus oocytes or HEK293 cells. The activities of BK_(Ca) channels were measured using excised patch-clamp recordings. Puerarin intracellularly activated BK-α+β1 currents with a half-maximal concentration (EC50) of 0.8 nM and a Hill coefficient of 1.11 at 10μM Ca~(2+), and with EC50 of 12.6 nM and a Hill coefficient of 1.08 at 0μM Ca~(2+). Puerarin (1 nM) induced a 16 mV leftward shift in the conductance-voltage curve for BK-α+β1 currents at 10μM Ca~(2+), and at 100 nM induced a 26 mV leftward shift at 0μM Ca~(2+). Puerarin mainly increased the BK-α+β1 channel open probability without changing the unitary conductance. Activation was also detected in the absence of theβ1 subunit. A deglycosylated analog of puerarin, daidzein, also activated BK_(Ca) channels with weaker potency. In addition, puerarin (0.1 to 1000μM) caused concentration-dependent relaxations of rat thoracic aortic rings contracted with 1μM noradrenaline bitartrate (NA) (EC50 = 1.1μM). These were significantly inhibited by 50 nM iberiotoxin, a specific blocker of BK_(Ca) channels, indicating that the activation of the BK_(Ca) channel probably contributes to the puerarin-mediated vasodilation action.
Further, we explored the effect of puerarin on mslo currents in the presence of Ca~(2+) and the binding sites of puerarin on BK_(Ca) channel protein. Puerarin blocked mslo currents with an EC50 of 6.2 nM and a Hill coefficient of 0.86 at 10μM Ca~(2+). Puerarin inhibited mslo currents in a Ca~(2+) and voltage-dependent manners, higher Ca~(2+) concentration, higher inhibition while higher voltage, lower inhibition. The chimera construct with dslo S0-S1 Linker to mslo diminished the effect of puerarin on mslo channels, indicated that the sites for puerarin binding may be located at the region of S0-S1 Linker.
In summary, the present study provides evidences that puerarin could protect islet cells from oxidative damage and stimulate BK_(Ca) channel activity. These beneficial effects of puerarin may contribute to the underlying mechanisms by which it acts as an anti-diabetes compound.
引文
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