湖北巴戟天抗衰老化学成分及作用机制的研究
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摘要
湖北巴戟天,为茜草科植物虎刺(Damnacanthus officinarum Huang, DOH)的干燥根,故称“四川虎刺”。在湖北恩施地区长期作巴戟天药用,故又名恩施巴戟。民间广泛药用证实其具有补肾阳、强筋骨、祛风湿之功能,临床上用于治疗阳萎、风湿痹痛、少腹冷痛、腰膝酸痛等疾病。为了证实湖北巴戟天的延缓衰老和对神经保护的作用,筛选湖北巴戟天的活性部位和成分,本研究对湖北巴戟天进行了系统的药理和化学成分研究。
本研究建立了秀丽隐杆线虫神经元保护和寿命实验的实验模型。根和叶的乙醇、正丁醇和水提取物均能明显提高HA759线虫对毒性化合物的趋让性。神经元存活实验中,DOH根的乙醇、正丁醇、水提取物的高低两个浓度组和叶的正丁醇部位,均对ASH神经元具有一定的保护作用,能避免被PolyQ蛋白聚集所介导的毒性所损害。神经元存活和趋化实验结果具有一致性,并确定湖北巴戟天的活性部位为中高极性提取物,正丁醇部位最优。并且,湖北巴戟天根提取物对神经元的保护作用要强于叶提取物,这在一定程度上印证了湖北巴戟天抗衰老活性有效部位在其“肉质根部”的传统中医药理论。
进一步观察DOH中具有神经元保护作用的提取物对线虫寿命的影响,发现在秀丽线虫整体模型上,ER, BR, AR和BL四个不同部位的提取物都能使生存曲线右移,延缓线虫的寿命。且提取物的高剂量组(1200ug/mL)较之低剂量组(800ug/mL)的延长秀丽线虫寿命的效果显著。根的正丁醇部位高剂量组(1200ug/mL)能使线虫的平均寿命最大延长30.3%。
多种神经退行性疾病的病理生理过程与ROS相关,特别是衰老的脑组织,易遭受ROS氧化损伤。DOH测试的八个提取物中根的水和正丁醇的高剂量提取物具有抗百草枯诱导的氧化应激作用。提示巴戟天抗衰老的机制和神经元保护密切相关,而部分通过抗氧化和清除自由基的途径来对秀丽线虫起到延寿作用。
本研究对湖北巴戟天进行了系统的化学成分研究,在湖北巴戟天各部位分离得到17个单体化合物,利用NMR、MS、IR、UV等光谱学方法鉴定了结构。分别为p-谷甾醇(DOH 1)、二十四烷酸(DOH 2)、1-羟基-2-羟甲基蒽醌(DOH3)、齐墩果酸乙酸酯(DOH 4)、茜素二甲醚(DOH 5)、百眼藤A (DOH6)、β-胡萝卜苷(DOH 7)、2-羟基-1-甲氧基蒽醌(DOH 8)、2,5-二羟基-1-甲氧基-蒽醌(DOH 9)、正丁基-O-β-D-吡喃果糖苷(DOH 10)、水晶兰苷(DOH11)、(1S,5S,9S)-△3(4),7(8)-10-(二羟甲基)。4-环烯醚萜酸-1-O-β-D-葡萄糖(DOH 12)、1-甲氧基-2-羟甲基蒽醌-龙胆二糖苷(DOH 13)、1-羟基-2-羟甲基蒽醌-龙胆二糖苷(DOH 14)、硬脂酸(DOH 15)、a-D-葡萄糖(DOH 16)和p-D-葡萄糖(DOH 17)。其中包括7个蒽醌类化合物和蒽醌苷类,2个环烯醚萜类,1个三萜类。分离得到的化合物中DOH 12为一个新的天然产物,DOH2、4、5、7、9、10、11、13、14、15、16、17这12个化合物是湖北巴戟天植物中首次发现,也是虎刺属植物中首次发现。本课题进一步明确了湖北巴戟天的物质基础,为民间用药一湖北巴戟天作为一新的植物药在全国市场流通奠定了一定的科学基础。
Damnacanthus officinarum Huang (DOH; Ensi Ba-jitian) is a plant of Rubiaceae family, which has been extensively used as a valuable Yang-tonic agent in Hubei, Hunan and Sichuan provinces for medicinal purposes as an alternative of M. officinalis root, which is one of four famous "southern medicines" in China. As a Yang-tonic agent, DOH root has been used to nourish "kidney" and strengthen "bone and muscle", which are important indices for impotence and infertility in traditional Chinese medicine. To evaluate the neuroprotective and anti-aging activity of extracts in Caenorhabditis elegans from the roots and leaves of Damnacanthus officinarum Huang, and to provide the pharmacological basis in traditional medicine, we systematically studied the chemical constituents and the medicinal effect of DOH.
It has been shown that the ethanol, n-butanol and aqueous extracts in the roots and leaves possessed significantly neuroprotective effect both in chemosensory behavior test. In ASH neuron survival model, the ER, BR, AR and EL extracts were able to protect ASH neuron from polyQ-mediated death. Results of neuroprotective and chemosensory behavior test were consistent, among which the n-butanol extracts showed best efficacy. Moreover, the neuroprotective and lifespan-extention activity effects of root extracts are superior to leave extracts, supporting the traditional application of above-ground parts of DOH in treating various diseases associated with brain disorders and anti-aging.
Four candidate extracts, possessing excellent neuroprotective activity, extend lifespan in C. elegans. Compared with the lower dose group (800ug/ml), the higher dose group (1200ug/ml) showed better significant effect of extending lifespan in C. elegans. The root of the n-butanol of the higher dose group (1200ug/mL) enabled nematodes to extend the average life expectancy of 30.3%.
The pathophysiological process of a variety of neurodegenerative diseases associated with ROS, especially the aging brain tissue vulnerable to ROS oxidative damage. Treatment with BR and AR(1200ug/ml) extracts increased the survival rate of the worms exposed to paraquat. It should be speculated that the anti-aging mechanisms of DOH would be closely related with neuronal protection, in part related to antioxidant and free radical scavenging pathways in Caenorhabditis elegans.
Our chemical constituents study of DOH afforded 17 compounds. They were isolated and purified by chemical and spectroscopic methods (NMR、MS、IR、UV etc.) to identify their structures. They wereβ-sitosteol(DOH 1), Lignoceric acid (DOH 2), 1-hydroxy-2-hydroxy-methylanthraquinone (DOH 3), Oleanolic acid acetate (DOH 4), Alizarin dimethyl ether (DOH 5), Morindaparvin A (DOH 6), Daucosterol (DOH 7),2-hydroxy-l-methoxyanthraquinone (DOH 8),2,5-dihydroxy-1-methoxy-anthraquinone (DOH 9), n-butyl-β-D-fructopyranoside (DOH 10), Monotropein (DOH 11), (1S,5S,9S)-Δ3(4)，7(8)-10-dihydroxymethyl-4-iridoid acid-1-O-β-D-glucose (DOH 12), (digiferruginol-l-methylether-11-O-β-gentiobioside, (DOH 13), digiferruginol-11-O-β-primeveroside (DOH 14), stearic acid (DOH 15), a-D-Glucose (DOH 16), (3-D-Glucose (DOH 17), Including seven anthraquinones and anthraquinone glycosides, two iridoids, a triterpenoid. In this thesis, DOH 12 was a new compound, DOH 2、4、5、7、9、10、11、13、14、15、16、17 were obtained from Damnacanthus officinarum Huang for the first time, and were discovered from the Damnacanthus species for the first time. This subject further clarified the material basis of Damnacanthus officinarum Huang, this may provide valuable evidence for its traditional use in treating various diseases or dietary therapy in China.
本研究建立了秀丽隐杆线虫神经元保护和寿命实验的实验模型。根和叶的乙醇、正丁醇和水提取物均能明显提高HA759线虫对毒性化合物的趋让性。神经元存活实验中,DOH根的乙醇、正丁醇、水提取物的高低两个浓度组和叶的正丁醇部位,均对ASH神经元具有一定的保护作用,能避免被PolyQ蛋白聚集所介导的毒性所损害。神经元存活和趋化实验结果具有一致性,并确定湖北巴戟天的活性部位为中高极性提取物,正丁醇部位最优。并且,湖北巴戟天根提取物对神经元的保护作用要强于叶提取物,这在一定程度上印证了湖北巴戟天抗衰老活性有效部位在其“肉质根部”的传统中医药理论。
进一步观察DOH中具有神经元保护作用的提取物对线虫寿命的影响,发现在秀丽线虫整体模型上,ER, BR, AR和BL四个不同部位的提取物都能使生存曲线右移,延缓线虫的寿命。且提取物的高剂量组(1200ug/mL)较之低剂量组(800ug/mL)的延长秀丽线虫寿命的效果显著。根的正丁醇部位高剂量组(1200ug/mL)能使线虫的平均寿命最大延长30.3%。
多种神经退行性疾病的病理生理过程与ROS相关,特别是衰老的脑组织,易遭受ROS氧化损伤。DOH测试的八个提取物中根的水和正丁醇的高剂量提取物具有抗百草枯诱导的氧化应激作用。提示巴戟天抗衰老的机制和神经元保护密切相关,而部分通过抗氧化和清除自由基的途径来对秀丽线虫起到延寿作用。
本研究对湖北巴戟天进行了系统的化学成分研究,在湖北巴戟天各部位分离得到17个单体化合物,利用NMR、MS、IR、UV等光谱学方法鉴定了结构。分别为p-谷甾醇(DOH 1)、二十四烷酸(DOH 2)、1-羟基-2-羟甲基蒽醌(DOH3)、齐墩果酸乙酸酯(DOH 4)、茜素二甲醚(DOH 5)、百眼藤A (DOH6)、β-胡萝卜苷(DOH 7)、2-羟基-1-甲氧基蒽醌(DOH 8)、2,5-二羟基-1-甲氧基-蒽醌(DOH 9)、正丁基-O-β-D-吡喃果糖苷(DOH 10)、水晶兰苷(DOH11)、(1S,5S,9S)-△3(4),7(8)-10-(二羟甲基)。4-环烯醚萜酸-1-O-β-D-葡萄糖(DOH 12)、1-甲氧基-2-羟甲基蒽醌-龙胆二糖苷(DOH 13)、1-羟基-2-羟甲基蒽醌-龙胆二糖苷(DOH 14)、硬脂酸(DOH 15)、a-D-葡萄糖(DOH 16)和p-D-葡萄糖(DOH 17)。其中包括7个蒽醌类化合物和蒽醌苷类,2个环烯醚萜类,1个三萜类。分离得到的化合物中DOH 12为一个新的天然产物,DOH2、4、5、7、9、10、11、13、14、15、16、17这12个化合物是湖北巴戟天植物中首次发现,也是虎刺属植物中首次发现。本课题进一步明确了湖北巴戟天的物质基础,为民间用药一湖北巴戟天作为一新的植物药在全国市场流通奠定了一定的科学基础。
Damnacanthus officinarum Huang (DOH; Ensi Ba-jitian) is a plant of Rubiaceae family, which has been extensively used as a valuable Yang-tonic agent in Hubei, Hunan and Sichuan provinces for medicinal purposes as an alternative of M. officinalis root, which is one of four famous "southern medicines" in China. As a Yang-tonic agent, DOH root has been used to nourish "kidney" and strengthen "bone and muscle", which are important indices for impotence and infertility in traditional Chinese medicine. To evaluate the neuroprotective and anti-aging activity of extracts in Caenorhabditis elegans from the roots and leaves of Damnacanthus officinarum Huang, and to provide the pharmacological basis in traditional medicine, we systematically studied the chemical constituents and the medicinal effect of DOH.
It has been shown that the ethanol, n-butanol and aqueous extracts in the roots and leaves possessed significantly neuroprotective effect both in chemosensory behavior test. In ASH neuron survival model, the ER, BR, AR and EL extracts were able to protect ASH neuron from polyQ-mediated death. Results of neuroprotective and chemosensory behavior test were consistent, among which the n-butanol extracts showed best efficacy. Moreover, the neuroprotective and lifespan-extention activity effects of root extracts are superior to leave extracts, supporting the traditional application of above-ground parts of DOH in treating various diseases associated with brain disorders and anti-aging.
Four candidate extracts, possessing excellent neuroprotective activity, extend lifespan in C. elegans. Compared with the lower dose group (800ug/ml), the higher dose group (1200ug/ml) showed better significant effect of extending lifespan in C. elegans. The root of the n-butanol of the higher dose group (1200ug/mL) enabled nematodes to extend the average life expectancy of 30.3%.
The pathophysiological process of a variety of neurodegenerative diseases associated with ROS, especially the aging brain tissue vulnerable to ROS oxidative damage. Treatment with BR and AR(1200ug/ml) extracts increased the survival rate of the worms exposed to paraquat. It should be speculated that the anti-aging mechanisms of DOH would be closely related with neuronal protection, in part related to antioxidant and free radical scavenging pathways in Caenorhabditis elegans.
Our chemical constituents study of DOH afforded 17 compounds. They were isolated and purified by chemical and spectroscopic methods (NMR、MS、IR、UV etc.) to identify their structures. They wereβ-sitosteol(DOH 1), Lignoceric acid (DOH 2), 1-hydroxy-2-hydroxy-methylanthraquinone (DOH 3), Oleanolic acid acetate (DOH 4), Alizarin dimethyl ether (DOH 5), Morindaparvin A (DOH 6), Daucosterol (DOH 7),2-hydroxy-l-methoxyanthraquinone (DOH 8),2,5-dihydroxy-1-methoxy-anthraquinone (DOH 9), n-butyl-β-D-fructopyranoside (DOH 10), Monotropein (DOH 11), (1S,5S,9S)-Δ3(4)，7(8)-10-dihydroxymethyl-4-iridoid acid-1-O-β-D-glucose (DOH 12), (digiferruginol-l-methylether-11-O-β-gentiobioside, (DOH 13), digiferruginol-11-O-β-primeveroside (DOH 14), stearic acid (DOH 15), a-D-Glucose (DOH 16), (3-D-Glucose (DOH 17), Including seven anthraquinones and anthraquinone glycosides, two iridoids, a triterpenoid. In this thesis, DOH 12 was a new compound, DOH 2、4、5、7、9、10、11、13、14、15、16、17 were obtained from Damnacanthus officinarum Huang for the first time, and were discovered from the Damnacanthus species for the first time. This subject further clarified the material basis of Damnacanthus officinarum Huang, this may provide valuable evidence for its traditional use in treating various diseases or dietary therapy in China.
引文
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