民族药材雪里见的生物活性及化学成分研究
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摘要
雪里见Arisaema rhizomatum C.E.C. Fischer为天南星科(Araceae)天南星属(Arisaema)植物,为我国特有药材,具有祛风除湿、活血化瘀、解毒止痛的功效,民间常用来治疗风湿麻木疼痛、跌打损伤、毒蛇咬伤、无名肿毒等症,疗效明显,在湖北恩施土家族苗族自治州药用历史渊远。依据民间用药传统和目前已做的研究,我们认为雪里见可以用于治疗类风湿性关节炎。本课题主要对雪里见抗实验小鼠CIA关节炎模型的药理活性、活性部位以及化学/活性成分以及发挥疗效的药理学机制进行系统的研究,以期对雪里见的资源保护和药用开发提供一定的依据。
一.活性部位的筛选
根据民间传统用药和药效学预实验结果,本课题对雪里见甲醇提取物和石油醚、乙酸乙酯、正丁醇、水部位的各个萃取物进行了以下研究：(1)急性毒性试验和最大耐受量试验。供试药物单次经口给药(最大剂量均相当于生药材5 g/Kgb.w),给药后观察小鼠的毒性反应；最大耐受量实验,24 h内经口三次给予甲醇提取物(总剂量为生药材60g/Kg b.w),给药后观察小鼠的反应。在观察期内实验动物均未出现异常行为。(2)抗炎和镇痛作用的研究。通过小鼠耳肿胀急性炎症实验和醋酸扭体实验,考察雪里见总提取物及其各个极性部位抗炎、镇痛作用。结果显示乙酸乙酯和正丁醇萃取部位有较好的抗炎镇痛作用。(3)抗小鼠CIA模型关节炎的作用。通过对小鼠踝关节、后足足垫、脾指数、关节病理切片评估、血清中TNF-α、IL-1β、IL-6、IL-33和RF水平的测定,结果表明雪里见乙酸乙酯和正丁醇萃取部位比总提取物及其他部位活性更强。
二.活性部位化学成分的分离与鉴定
根据活性部位筛选的结果,本课题针对雪里见的乙酸乙酯萃取部位、正丁醇部位萃取部位以及石油醚萃取部位进行了进一步的分离工作。主要运用萃取法、色谱法、重结晶等方法,从雪里见的根茎的甲醇总膏的石油醚、乙酸乙酯和正丁醇萃取物中分离纯化得到12个化合物,鉴定其中了10个化合物。主要有脂肪酸类、黄酮类、神经酰胺类、甾醇类、吡喃酮类。其结构主要有β-sitosterol(xlj-1), (xlj-5),5,7,4'-Hrihydroxy-3'-methoxyflavone(xlj-8),2-[(2-hydroxybexadecanoyl) amido]-4,8-octadecadiene-1,3-diol(xlj-9), Cinnamic acid(xlj-10), Tridecanoic acid(xlj-11), Lauric acid(xlj-13), Pentadecenoic acid(xlj-15), Myristic acid(xlj-16),β-daucosterol(xlj-17)其中吡喃酮类得到2个新化合物。除了β-sitosterol和β-daucosterol之外,所有化合物均首次从该植物中分离得到。
三.活性机制的探索和单体化合物活性成分的筛选
本课题对分离得到的部分化学成分进行了体外细胞活性筛选。单体化合物对细胞炎症、炎性因子抑制作用实验显示xlj5和xlj8对LPS诱导的RAW264.7的炎性因子TNF-α、IL-1β和IL-6均有明显的抑制作用；通过对AA大鼠关节炎模型的原代滑膜细胞培养,甲醇提取物、乙酸乙酯萃取物,正丁醇萃取物和xlj5和xlj8有抑制滑膜细胞增殖并降低滑膜细胞分泌炎性因子TNF-α、IL-1β、PGE2的作用。通过调节巨噬细胞和关节滑膜细胞的生理学行为,最终降低前炎性和炎性细胞因子的水平,可能为雪里见发挥抗类风湿性关节炎的作用途径之一
Arisaema rhizomatum C.E.C. Fischer is a perennial herb of Arisaema genus in Araceae and just growing in China. The herb has been used as a traditional ethnic Chinese medicine for long in history because of it's remarkably activity to eliminate dampness, dispel wind, free the flow of network vessels, quicken blood, reduce toxin or poison and relieve pains. Folk, in Enshi Tujia and Miao autonomous prefecture of Hubei, are commonly used to remedy rheumatism numb pain, treat injuries from falls, contusions and strains, manage viper bite, and alleviate turgescence for a long history because of it's remarkably activity with weak side-effect. Based on traditional folk medicine and researches which some scholars have done, we think that Arisaema rhizomatum C.E.C. Fischer can be effective in the treatment for rheumatoid arthritis (RA). The purpose of our research is to investigate the pharmacological activity of the herb on collagen-induced arthritis in mice, ascertain active site, extract and separate (medicative) compounds, and explore the potential immunological mechanisms. In addition, our studies also provide some basis for protecting and developing medicinal resources of Arisaema rhizomatum C.E.C. Fischer.
1. Screening of active part(s).
According to the traditional medicine and pharmacodynamics experiment results that was done previously, in order to evaluate the activity of methanol extract and extracts from petroleum ether, ethyl acetate, n-butyl alcohol and water of Arisaema rhizomatum C.E.C. Fischer, the following researches were set about. (1) Acute toxicity tests and maximum tolerance tests. In acute toxicity tests, the maximum dose of acute toxicity tests in all groups is 5 g/Kg b.w (crude drug). In maximum tolerance tests, mice were taken methanol extracts for three times in 24 h, and the total dose was 60 g/Kg b.w. After treatment, all mice were observed for one week and no toxic symptom was found. (2) Anti-inflammatory and analgesic action researches. To investigate the anti-inflammatory and analgesic activity, acute ear swelling experiment and body torsion experiment were carry out. The results showed that extracts from ethyl acetate and n-butyl alcohol were good at reducing inflammation and alleviating pain. (3) Atenuate inflammatory response on CIA. During the experiment, edema of mice hind ankle and paws, spleen index, histological changes of hind ankles, and levels of TNF-α, IL-1β, IL-6, IL-33 and RF in the serum were detected and measured. The experimental results indicated that extracts from ethyl acetate and n-butyl alcohol were more effective than the methanol extract and other parts.
2. Isolation of compounds from active parts
According to the results of selecting the active parts,12 compounds were isolated and separated from the extracts from ethyl acetate and n-butyl alcohol by using extraction method, chromatography, re-crystallization, et al.10 of these compounds were identified by various modem spectral analysis, (such as'H-NMR, 13C-NMR, HSQC, H-HCOSY, HMBC) and other classical chemical methods. Their types were fatty acids, galactosyl ceramide, sterol kind, and pyranoid ketone. Their structures were elucidated as:β-sitosterol (xlj-1), (xlj-5),5,7,4'-Hrihydroxy-3'-methoxyflavone (xlj-8),2-[(2-hydroxybexadecanoyl) amido]-4,8-octadecadiene-1, 3-diol (xlj-9), Cinnamic acid (xlj-10), Tridecanoic acid (xlj-11), Lauric acid (xlj-13), Pentadecenoic acid (xlj-15), Myristic acid (xlj-16),β-daucosterol (xlj-17). Exceptβ-sitosterol andβ-daucosterol, all these compounds were isolated from this plant for the first time; especially compound xlj-5 and xlj-18 were new compounds.
3. Exploration of active mechanism and screening the activity of compounds
We studied the activities of the compounds xlj-5, xlj-8 and xlj-9, and explored the active mechanism of extracts of methanol, ethyl acetate and n-butyl alcohol. Experiment in vitro suggested that compounds of xlj-5 and xlj-8 significantly reduced the levels of TNF-α, IL-1βand IL-6 in inflammation cell model reduced by LPS, restrained synovial cell proliferation, reduced levels of TNF-α, IL-1βand PGE2 secreted by synovial cells obtained from AA rats model. Extracts of methanol, ethyl acetate and n-butyl alcohol displayed the same active in RAW264.7 cell and the original generation synovial cells from knee of AA rats model. Adjusting the physiological behavior of macrophages and joint synovial cells, and reducing pre-inflammatory and inflammatory cells factor levels eventually, may be one of the mechanisms by which the Arisaema rhizomatum C.E.C. Fischer play the role of anti-inflammatory and remedy the CIA mice model.
一.活性部位的筛选
根据民间传统用药和药效学预实验结果,本课题对雪里见甲醇提取物和石油醚、乙酸乙酯、正丁醇、水部位的各个萃取物进行了以下研究：(1)急性毒性试验和最大耐受量试验。供试药物单次经口给药(最大剂量均相当于生药材5 g/Kgb.w),给药后观察小鼠的毒性反应；最大耐受量实验,24 h内经口三次给予甲醇提取物(总剂量为生药材60g/Kg b.w),给药后观察小鼠的反应。在观察期内实验动物均未出现异常行为。(2)抗炎和镇痛作用的研究。通过小鼠耳肿胀急性炎症实验和醋酸扭体实验,考察雪里见总提取物及其各个极性部位抗炎、镇痛作用。结果显示乙酸乙酯和正丁醇萃取部位有较好的抗炎镇痛作用。(3)抗小鼠CIA模型关节炎的作用。通过对小鼠踝关节、后足足垫、脾指数、关节病理切片评估、血清中TNF-α、IL-1β、IL-6、IL-33和RF水平的测定,结果表明雪里见乙酸乙酯和正丁醇萃取部位比总提取物及其他部位活性更强。
二.活性部位化学成分的分离与鉴定
根据活性部位筛选的结果,本课题针对雪里见的乙酸乙酯萃取部位、正丁醇部位萃取部位以及石油醚萃取部位进行了进一步的分离工作。主要运用萃取法、色谱法、重结晶等方法,从雪里见的根茎的甲醇总膏的石油醚、乙酸乙酯和正丁醇萃取物中分离纯化得到12个化合物,鉴定其中了10个化合物。主要有脂肪酸类、黄酮类、神经酰胺类、甾醇类、吡喃酮类。其结构主要有β-sitosterol(xlj-1), (xlj-5),5,7,4'-Hrihydroxy-3'-methoxyflavone(xlj-8),2-[(2-hydroxybexadecanoyl) amido]-4,8-octadecadiene-1,3-diol(xlj-9), Cinnamic acid(xlj-10), Tridecanoic acid(xlj-11), Lauric acid(xlj-13), Pentadecenoic acid(xlj-15), Myristic acid(xlj-16),β-daucosterol(xlj-17)其中吡喃酮类得到2个新化合物。除了β-sitosterol和β-daucosterol之外,所有化合物均首次从该植物中分离得到。
三.活性机制的探索和单体化合物活性成分的筛选
本课题对分离得到的部分化学成分进行了体外细胞活性筛选。单体化合物对细胞炎症、炎性因子抑制作用实验显示xlj5和xlj8对LPS诱导的RAW264.7的炎性因子TNF-α、IL-1β和IL-6均有明显的抑制作用；通过对AA大鼠关节炎模型的原代滑膜细胞培养,甲醇提取物、乙酸乙酯萃取物,正丁醇萃取物和xlj5和xlj8有抑制滑膜细胞增殖并降低滑膜细胞分泌炎性因子TNF-α、IL-1β、PGE2的作用。通过调节巨噬细胞和关节滑膜细胞的生理学行为,最终降低前炎性和炎性细胞因子的水平,可能为雪里见发挥抗类风湿性关节炎的作用途径之一
Arisaema rhizomatum C.E.C. Fischer is a perennial herb of Arisaema genus in Araceae and just growing in China. The herb has been used as a traditional ethnic Chinese medicine for long in history because of it's remarkably activity to eliminate dampness, dispel wind, free the flow of network vessels, quicken blood, reduce toxin or poison and relieve pains. Folk, in Enshi Tujia and Miao autonomous prefecture of Hubei, are commonly used to remedy rheumatism numb pain, treat injuries from falls, contusions and strains, manage viper bite, and alleviate turgescence for a long history because of it's remarkably activity with weak side-effect. Based on traditional folk medicine and researches which some scholars have done, we think that Arisaema rhizomatum C.E.C. Fischer can be effective in the treatment for rheumatoid arthritis (RA). The purpose of our research is to investigate the pharmacological activity of the herb on collagen-induced arthritis in mice, ascertain active site, extract and separate (medicative) compounds, and explore the potential immunological mechanisms. In addition, our studies also provide some basis for protecting and developing medicinal resources of Arisaema rhizomatum C.E.C. Fischer.
1. Screening of active part(s).
According to the traditional medicine and pharmacodynamics experiment results that was done previously, in order to evaluate the activity of methanol extract and extracts from petroleum ether, ethyl acetate, n-butyl alcohol and water of Arisaema rhizomatum C.E.C. Fischer, the following researches were set about. (1) Acute toxicity tests and maximum tolerance tests. In acute toxicity tests, the maximum dose of acute toxicity tests in all groups is 5 g/Kg b.w (crude drug). In maximum tolerance tests, mice were taken methanol extracts for three times in 24 h, and the total dose was 60 g/Kg b.w. After treatment, all mice were observed for one week and no toxic symptom was found. (2) Anti-inflammatory and analgesic action researches. To investigate the anti-inflammatory and analgesic activity, acute ear swelling experiment and body torsion experiment were carry out. The results showed that extracts from ethyl acetate and n-butyl alcohol were good at reducing inflammation and alleviating pain. (3) Atenuate inflammatory response on CIA. During the experiment, edema of mice hind ankle and paws, spleen index, histological changes of hind ankles, and levels of TNF-α, IL-1β, IL-6, IL-33 and RF in the serum were detected and measured. The experimental results indicated that extracts from ethyl acetate and n-butyl alcohol were more effective than the methanol extract and other parts.
2. Isolation of compounds from active parts
According to the results of selecting the active parts,12 compounds were isolated and separated from the extracts from ethyl acetate and n-butyl alcohol by using extraction method, chromatography, re-crystallization, et al.10 of these compounds were identified by various modem spectral analysis, (such as'H-NMR, 13C-NMR, HSQC, H-HCOSY, HMBC) and other classical chemical methods. Their types were fatty acids, galactosyl ceramide, sterol kind, and pyranoid ketone. Their structures were elucidated as:β-sitosterol (xlj-1), (xlj-5),5,7,4'-Hrihydroxy-3'-methoxyflavone (xlj-8),2-[(2-hydroxybexadecanoyl) amido]-4,8-octadecadiene-1, 3-diol (xlj-9), Cinnamic acid (xlj-10), Tridecanoic acid (xlj-11), Lauric acid (xlj-13), Pentadecenoic acid (xlj-15), Myristic acid (xlj-16),β-daucosterol (xlj-17). Exceptβ-sitosterol andβ-daucosterol, all these compounds were isolated from this plant for the first time; especially compound xlj-5 and xlj-18 were new compounds.
3. Exploration of active mechanism and screening the activity of compounds
We studied the activities of the compounds xlj-5, xlj-8 and xlj-9, and explored the active mechanism of extracts of methanol, ethyl acetate and n-butyl alcohol. Experiment in vitro suggested that compounds of xlj-5 and xlj-8 significantly reduced the levels of TNF-α, IL-1βand IL-6 in inflammation cell model reduced by LPS, restrained synovial cell proliferation, reduced levels of TNF-α, IL-1βand PGE2 secreted by synovial cells obtained from AA rats model. Extracts of methanol, ethyl acetate and n-butyl alcohol displayed the same active in RAW264.7 cell and the original generation synovial cells from knee of AA rats model. Adjusting the physiological behavior of macrophages and joint synovial cells, and reducing pre-inflammatory and inflammatory cells factor levels eventually, may be one of the mechanisms by which the Arisaema rhizomatum C.E.C. Fischer play the role of anti-inflammatory and remedy the CIA mice model.
引文
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62 Akaogi, J., Nozaki, T., Satoh, M., et al. Role of PGE2 and EP receptors in the pathogenesis of rheumatoid arthritis and as a novel therapeutic strategy. Endocr Metab Immune Disord Drug Targets.2006,6(4):383-394.
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55 Bertolini, D.R., Nedwin, G.E., Bringman, T.S., et al. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature.1986,319,516-518.
56 Deleuran, B.W., Chu, C.Q., Field, M., et al. Localization of tumor necrosis factor receptors in the synovial tissue and cartilage-pannus junction in patients with rheumatoid arthritis. Implications for local actions of tumor necrosis factor alpha. Arthritis and Rheumatism.1992,35,1170-1178.
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1《中国植物志》 13卷116-117
2 中华人民共和国卫生部药典委员会编.中华人民共和国药典(2010年版一部).北京：化学工业出版社,2000,43.
3 Parkash, Sinha, G.k. Chemical examination of Arisaema curvatum kunth (Part Ⅰ) [J]. Nat Appl Sci Bull,1974,26 (2):25.
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