菱壳生物活性成分分析及抗胃癌机制研究
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摘要
水生植物菱在我国已有上千年的栽培历史,其果实菱角是人们喜食的一种蔬果。作为食用和加工副产物而丢弃的菱壳,目前尚未有效的利用途径,一定程度上造成了资源浪费和环境污染。大量的研究表明,植物果实的外皮(壳)富含多酚、黄酮、生物碱等活性成分,具有广泛的生物活性。目前国内与菱壳相关的报道已证实其丰富的活性成分和功效,但缺乏系统的研究。本文选取无角菱(南湖菱)、二角菱和四角菱三个我国南方主要栽植品种的外壳为原料,系统分析其生物活性成分及其机制。
对三种菱壳粉碎后进行70%甲醇和沸水提取,测定其活性成分含量,结果表明总多酚含量为140.4±3.1-201.7±3.4mg/g、总黄酮含量为34.3±1.9-54.6+4.0mg/g、总皂苷含量为21.7±2.1-36.3+2.5mg/g粗多糖含量为42.2±2.5-123.16±5.8mg/g; HPLC分析发现,三种菱壳的主要酚酸为没食子酸和阿魏酸。经DPPH、ABTS、FRAP和还原力体系评价发现,菱壳提取物均具有较强的自由基清除和金属离子还原能力；抑菌圈和最低抑菌浓度实验表明,菱壳提取物对蜡样芽孢杆菌、枯草芽孢杆菌、金黄色葡萄球菌和大肠杆菌等致病细菌具有较好的抑制作用,对酿酒酵母和青霉等真菌效果较差；MTT结果显示,菱壳提取物对胃癌、肝癌、前列腺癌和结肠癌细胞具有显著的体外抑制作用,尤其是胃癌细胞,而对胃上皮细胞、前列腺上皮细胞和人脐静脉内皮细胞等正常细胞无明显毒性；
构建H202氧化损伤和连二亚硫酸钠缺氧损伤HUVEC细胞模型,考察菱壳提取物对血管内皮细胞的保护作用。结果表明,菱壳提取物对两种模型引起的血管内皮细胞损伤具有良好的修复作用,使HUVEC细胞的生长和状态恢复,SOD、CAT和GSH-Px等抗氧化酶活性增强,脂质过氧化物MDA生成量显著下降,NO释放量增加,保护了HUVEC细胞的正常功能；
将三种菱壳经95%乙醇浸提、不同极性溶剂萃取后发现,多酚和黄酮类物质主要富集到乙酸乙酯相,皂苷类物质富集到氯仿和石油醚相,乙酸乙酯相和氯仿相显示出较强的抑制胃癌SGC7901细胞生长的效果,以无角菱壳的乙酸乙酯相效果最佳；采用硅胶柱层析、Sephadex LH-20和制备液相色谱对其抗胃癌活性成分追踪分离纯化,获得两个化合物；经ESI-MS、FT-IR和NMR波谱检测,鉴定为没食子酸(GA)和没食子酸二聚体(GAD),均为无角菱壳中首次报道；
探讨了GA和GAD对胃癌细胞的抑制机制。以两株胃癌细胞SGC7901和MGC803及胃正常上皮细胞GES-1为模型,结果表明,GA和GAD对两株胃癌细胞的生长均有显著的抑制作用,IC50分别为SGC7901(7.67,4.31μg/mL)和MGC(3.22,2.67μg/mL),活性略低于抗癌药物5-FU；在测试浓度范围内对GES-1基本无抑制作用,而5-FU则对其毒性较大；流式细胞和DNA电泳结果显示,GA和GAD对胃癌细胞具有s期细胞周期阻抑和诱导凋亡的作用；GA和GAD可引起线粒体膜电位丧失,导致ATP合成下降和细胞色素C释放,激活Caspase-3活性；GA和GAD还使胃癌细胞的GSH-Px活性降低,GSH耗竭,ROS激增；RT-PCR结果显示,GA和GAD对抗癌靶点基因p53和AMPKa有显著的上调作用；
研究了GA和GAD对胃癌细胞迁移和血管生成的影响。划痕实验显示GA和GAD对两株胃癌细胞的迁移有显著的抑制作用,ELISA结果表明二者均可抑制迁移相关蛋白MMP-9的活性；GA和GAD不仅可显著抑制HUVEC细胞的生长,且对其迁移、NO释放和体外管腔形成均具有显著的抑制作用；ELISA检测发现GA和GAD处理后的两株胃癌细胞和HUVEC的VEGF分泌量均显著降低；同时,GA和GAD处理后还使胃癌细胞的TNF-a和IL-6分泌量显著下降,而IL-12分泌量显著上升；
作为创新点,本文系统分析了无角、二角和四角菱壳的生物活性成分,从无角菱壳中分离出两个抗癌活性单体,并研究其对胃癌细胞凋亡、迁移和血管生成的影响,均为国内外首次报道。
Trapa sp. is widely cultivated aquatic free-floating plant in China. Its fruit, named water caltrop, is popular Chinese traditional edible vegetable. As processing by-products, the pericarps are commonly considered to be waste and polluted to environment. Recent studies showed that pericarps of many fruits and vegetables contain numerous bioactive compounds, such as polyphenols, flavonoids and alkanoids, etc, which contribute to various related bioactivities. Limited studies indicated that water caltrop pericarps possess abundant bioactivities and functions. In this paper, the pericaips of three mainly cultivars,'Wujiaoling'(Trapa. acornis Nakano.),'Erjiaoling'(T. bispinosa Roxb.) and'Sijiaoling'(T. quadrispinosa Roxb.), from Southern areas of China were collected and analyzed.
The pericarps were ground to power and extracted by70%CH3OH and hot water. The bioactive components determination showed that total phenolics content varied from140.4±3.1to201.7±3.4mg GAE/g, total flavonoids content from34.3±1.9to54.6±4.0mg RE/g, total saponins content from21.7±2.1to36.3±2.5mg RE/g and total crude sugar content from42.2±2.5to123.16±5.8mg GE/g. The major phenolic acids in water caltrops were gallic acid and feruic acid analyzed by HPLC. All extracts exhibited strong antioxidant capacity tested by DPPH, ABTS, FRAP and Reducing power. Antimicrobial activities of water caltrop pericarp extracts were evaluated by inhibition zone and minimum inhibitory concentration, and all extracts showed inhibitory activities to four bacteria strains, Baclillus cereus, B. sublilis, Staphyloccocus aureus and Escherichia coli, but not to two fungi, Saccharomyces cerevisiae and Penicillium sp.. All extracts inhibit proliferation of gastic, liver, prostate and colon cancer cell lines, especially gastric cancer cells, without detectable cytotoxicity to three normal cell lines, gastric epithelial, prostate epithelial and human umbilical vein endothelial cells.
H2O2and hyposulfite were employed to induce oxidative and hypoxia injury to HUVEC cells. After treated with water caltrop pericarp extracts, the proliferation and morphology of HUVEC cells were recovered nearly to be normal. Besides these, the activities of antioxidant enzymes, including SOD, CAT and GSH-Px were increased, the contents of MDA produced by lipoperoxidation were reduced, and the NO releases were elevated. From these results, we concluded that water caltrop pericarp extracts could attenuate oxidative and hypoxia injury to vascular endothelial cells, which are important for cardiovascular system.
Three pericarps were extracted using95%ethanol and separated to different polar fractions. The determination of bioactive components indicated that polyphenols, flavonoids and saponins were concentrated in ethyl acetate and chloroform fractions, respectively. Among these, ethyl acetate fraction of'Wujiaoling'pericarps showed strongest antiproliferative activity to gastric cancer cell SGC7901. Afterwards, chromatography of silica gel, Sephadex LH-20and preparative HPLC were employed for bioactivity-guided purification of this fraction. Two bioactive compounds were obtained and identified to be Gallic acid (GA) and Gallidc acid dimmer (GAD) by ESI-MS, FT-IR and NMR, and this is a first report for them from this species.
Then, the mechanisms of GA and GAD against gastric cancer were discussed. Gastric cancer cell lines SGC7901and MGC803and normal gastric epithelial cell line GES-1were used. GA and GAD exhibited significant antiproliferative effects to SGC7901and MGC803with IC50SGC7901(7.67,4.31μg/mL) and MGC (3.22,2.67μg/mL), and these effects were a little lower than anticancer drug5-FU. On the other hand, GA and GAD did not show any detectable cytotoxicity to GES-1in same concentrations, but5-FU is fairly toxic. Flow cytometry and DNA fragmentation analysis showed that GA and GAD exhibited S phase cell cycle arrest and apoptosis induction. GA and GAD could also induce collapse of mitochondrial membrane potential, decrease of ATP synthesis, release of cytochrome c and activation of Caspase-3in gastric cancer cells. In addition, GA and GAD caused GSH-Px activity reduction, GSH deleption and ROS level raise of gastric cancer cells, which could destroy their oxidative stress defense system and damage to cells. RT-PCR results indicated that the gene expression of p53and AMPKa were significant up-regulated, and these two genes were proved to be anticancer potential. These results suggested that GA and GAD would induce gastric cancer cell apoptosis through combination of different pathways with little damage to normal gastric epithelial cell.
Further mechanisms were studied in the effects of GA and GAD on the migration and angiogenesis of gastric cancer cells. Would healing assays showed GA and GAD could significantly inhibit migration of gastric cancer cells, and activity of related protein MMP-9were also decreased when test by ELISA. Meanwhile, GA and GAD could not only inhibit antiproliferation of HUVEC cells, but also their migration, NO release and tube formation in vitro. The VEGF levels of gastric cancer cells and HUVEC cell were reduced when treated by GA and GAD. Cytokines associated with migration and angiogenesis were also determined by ELISA, and the results showed that the secretion TNF-a and IL-6were significantly reduced and IL-12was elevated.
Overall, this is the first paper to screen the bioactivities of three water caltrop pericarps, identify two bioactive compounds against gastric cancer from Wujiaoling pericarps, and elucidate the mechanisms of these two compounds in apoptosis, migration and angiogenesis of gastric cancer cells.
对三种菱壳粉碎后进行70%甲醇和沸水提取,测定其活性成分含量,结果表明总多酚含量为140.4±3.1-201.7±3.4mg/g、总黄酮含量为34.3±1.9-54.6+4.0mg/g、总皂苷含量为21.7±2.1-36.3+2.5mg/g粗多糖含量为42.2±2.5-123.16±5.8mg/g; HPLC分析发现,三种菱壳的主要酚酸为没食子酸和阿魏酸。经DPPH、ABTS、FRAP和还原力体系评价发现,菱壳提取物均具有较强的自由基清除和金属离子还原能力；抑菌圈和最低抑菌浓度实验表明,菱壳提取物对蜡样芽孢杆菌、枯草芽孢杆菌、金黄色葡萄球菌和大肠杆菌等致病细菌具有较好的抑制作用,对酿酒酵母和青霉等真菌效果较差；MTT结果显示,菱壳提取物对胃癌、肝癌、前列腺癌和结肠癌细胞具有显著的体外抑制作用,尤其是胃癌细胞,而对胃上皮细胞、前列腺上皮细胞和人脐静脉内皮细胞等正常细胞无明显毒性；
构建H202氧化损伤和连二亚硫酸钠缺氧损伤HUVEC细胞模型,考察菱壳提取物对血管内皮细胞的保护作用。结果表明,菱壳提取物对两种模型引起的血管内皮细胞损伤具有良好的修复作用,使HUVEC细胞的生长和状态恢复,SOD、CAT和GSH-Px等抗氧化酶活性增强,脂质过氧化物MDA生成量显著下降,NO释放量增加,保护了HUVEC细胞的正常功能；
将三种菱壳经95%乙醇浸提、不同极性溶剂萃取后发现,多酚和黄酮类物质主要富集到乙酸乙酯相,皂苷类物质富集到氯仿和石油醚相,乙酸乙酯相和氯仿相显示出较强的抑制胃癌SGC7901细胞生长的效果,以无角菱壳的乙酸乙酯相效果最佳；采用硅胶柱层析、Sephadex LH-20和制备液相色谱对其抗胃癌活性成分追踪分离纯化,获得两个化合物；经ESI-MS、FT-IR和NMR波谱检测,鉴定为没食子酸(GA)和没食子酸二聚体(GAD),均为无角菱壳中首次报道；
探讨了GA和GAD对胃癌细胞的抑制机制。以两株胃癌细胞SGC7901和MGC803及胃正常上皮细胞GES-1为模型,结果表明,GA和GAD对两株胃癌细胞的生长均有显著的抑制作用,IC50分别为SGC7901(7.67,4.31μg/mL)和MGC(3.22,2.67μg/mL),活性略低于抗癌药物5-FU；在测试浓度范围内对GES-1基本无抑制作用,而5-FU则对其毒性较大；流式细胞和DNA电泳结果显示,GA和GAD对胃癌细胞具有s期细胞周期阻抑和诱导凋亡的作用；GA和GAD可引起线粒体膜电位丧失,导致ATP合成下降和细胞色素C释放,激活Caspase-3活性；GA和GAD还使胃癌细胞的GSH-Px活性降低,GSH耗竭,ROS激增；RT-PCR结果显示,GA和GAD对抗癌靶点基因p53和AMPKa有显著的上调作用；
研究了GA和GAD对胃癌细胞迁移和血管生成的影响。划痕实验显示GA和GAD对两株胃癌细胞的迁移有显著的抑制作用,ELISA结果表明二者均可抑制迁移相关蛋白MMP-9的活性；GA和GAD不仅可显著抑制HUVEC细胞的生长,且对其迁移、NO释放和体外管腔形成均具有显著的抑制作用；ELISA检测发现GA和GAD处理后的两株胃癌细胞和HUVEC的VEGF分泌量均显著降低；同时,GA和GAD处理后还使胃癌细胞的TNF-a和IL-6分泌量显著下降,而IL-12分泌量显著上升；
作为创新点,本文系统分析了无角、二角和四角菱壳的生物活性成分,从无角菱壳中分离出两个抗癌活性单体,并研究其对胃癌细胞凋亡、迁移和血管生成的影响,均为国内外首次报道。
Trapa sp. is widely cultivated aquatic free-floating plant in China. Its fruit, named water caltrop, is popular Chinese traditional edible vegetable. As processing by-products, the pericarps are commonly considered to be waste and polluted to environment. Recent studies showed that pericarps of many fruits and vegetables contain numerous bioactive compounds, such as polyphenols, flavonoids and alkanoids, etc, which contribute to various related bioactivities. Limited studies indicated that water caltrop pericarps possess abundant bioactivities and functions. In this paper, the pericaips of three mainly cultivars,'Wujiaoling'(Trapa. acornis Nakano.),'Erjiaoling'(T. bispinosa Roxb.) and'Sijiaoling'(T. quadrispinosa Roxb.), from Southern areas of China were collected and analyzed.
The pericarps were ground to power and extracted by70%CH3OH and hot water. The bioactive components determination showed that total phenolics content varied from140.4±3.1to201.7±3.4mg GAE/g, total flavonoids content from34.3±1.9to54.6±4.0mg RE/g, total saponins content from21.7±2.1to36.3±2.5mg RE/g and total crude sugar content from42.2±2.5to123.16±5.8mg GE/g. The major phenolic acids in water caltrops were gallic acid and feruic acid analyzed by HPLC. All extracts exhibited strong antioxidant capacity tested by DPPH, ABTS, FRAP and Reducing power. Antimicrobial activities of water caltrop pericarp extracts were evaluated by inhibition zone and minimum inhibitory concentration, and all extracts showed inhibitory activities to four bacteria strains, Baclillus cereus, B. sublilis, Staphyloccocus aureus and Escherichia coli, but not to two fungi, Saccharomyces cerevisiae and Penicillium sp.. All extracts inhibit proliferation of gastic, liver, prostate and colon cancer cell lines, especially gastric cancer cells, without detectable cytotoxicity to three normal cell lines, gastric epithelial, prostate epithelial and human umbilical vein endothelial cells.
H2O2and hyposulfite were employed to induce oxidative and hypoxia injury to HUVEC cells. After treated with water caltrop pericarp extracts, the proliferation and morphology of HUVEC cells were recovered nearly to be normal. Besides these, the activities of antioxidant enzymes, including SOD, CAT and GSH-Px were increased, the contents of MDA produced by lipoperoxidation were reduced, and the NO releases were elevated. From these results, we concluded that water caltrop pericarp extracts could attenuate oxidative and hypoxia injury to vascular endothelial cells, which are important for cardiovascular system.
Three pericarps were extracted using95%ethanol and separated to different polar fractions. The determination of bioactive components indicated that polyphenols, flavonoids and saponins were concentrated in ethyl acetate and chloroform fractions, respectively. Among these, ethyl acetate fraction of'Wujiaoling'pericarps showed strongest antiproliferative activity to gastric cancer cell SGC7901. Afterwards, chromatography of silica gel, Sephadex LH-20and preparative HPLC were employed for bioactivity-guided purification of this fraction. Two bioactive compounds were obtained and identified to be Gallic acid (GA) and Gallidc acid dimmer (GAD) by ESI-MS, FT-IR and NMR, and this is a first report for them from this species.
Then, the mechanisms of GA and GAD against gastric cancer were discussed. Gastric cancer cell lines SGC7901and MGC803and normal gastric epithelial cell line GES-1were used. GA and GAD exhibited significant antiproliferative effects to SGC7901and MGC803with IC50SGC7901(7.67,4.31μg/mL) and MGC (3.22,2.67μg/mL), and these effects were a little lower than anticancer drug5-FU. On the other hand, GA and GAD did not show any detectable cytotoxicity to GES-1in same concentrations, but5-FU is fairly toxic. Flow cytometry and DNA fragmentation analysis showed that GA and GAD exhibited S phase cell cycle arrest and apoptosis induction. GA and GAD could also induce collapse of mitochondrial membrane potential, decrease of ATP synthesis, release of cytochrome c and activation of Caspase-3in gastric cancer cells. In addition, GA and GAD caused GSH-Px activity reduction, GSH deleption and ROS level raise of gastric cancer cells, which could destroy their oxidative stress defense system and damage to cells. RT-PCR results indicated that the gene expression of p53and AMPKa were significant up-regulated, and these two genes were proved to be anticancer potential. These results suggested that GA and GAD would induce gastric cancer cell apoptosis through combination of different pathways with little damage to normal gastric epithelial cell.
Further mechanisms were studied in the effects of GA and GAD on the migration and angiogenesis of gastric cancer cells. Would healing assays showed GA and GAD could significantly inhibit migration of gastric cancer cells, and activity of related protein MMP-9were also decreased when test by ELISA. Meanwhile, GA and GAD could not only inhibit antiproliferation of HUVEC cells, but also their migration, NO release and tube formation in vitro. The VEGF levels of gastric cancer cells and HUVEC cell were reduced when treated by GA and GAD. Cytokines associated with migration and angiogenesis were also determined by ELISA, and the results showed that the secretion TNF-a and IL-6were significantly reduced and IL-12was elevated.
Overall, this is the first paper to screen the bioactivities of three water caltrop pericarps, identify two bioactive compounds against gastric cancer from Wujiaoling pericarps, and elucidate the mechanisms of these two compounds in apoptosis, migration and angiogenesis of gastric cancer cells.
引文
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