牛蒡子的化学成分研究与抗肿瘤作用初步研究
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摘要
牛蒡子(Fructus arctii)为菊科(Compositae)牛蒡属植物牛蒡的干燥成熟果实,属辛凉解表药,具疏散风热、宣肺透疹、消肿解毒之功效;用于治疗风热感冒、咳嗽痰多、咽喉肿痛、斑疹不透、风疹作痒、痈肿疮毒等症。自1929年日本人田川越等从牛蒡子中获得牛蒡苷以来,关于牛蒡化学成分的研究取得了重要进展,前人对化学成分及其抗肿瘤、抗病毒作用进行过研究,从牛蒡种子,茎叶和根中获得了多种化合物,主要有木脂素,脂肪油及有机酸类化合物,硫炔类,挥发油类,倍半萜,三萜,糖,蛋白质等,其中牛蒡子苷和牛蒡子苷元具有多种生物活性。但对其他化学成分的药理报道还不多。为了进一步寻找该植物的有效成分,本项研究对其化学成分进行了分离、鉴定和体外抗肿瘤作用研究,以期有新的发现,为牛蒡子的深入研究和开发应用奠定基础。
牛蒡子乙醇提取物的氯仿萃取部分经过硅胶柱层析、反相硅胶柱层析、SephadexLH-20凝胶柱层析、半制备高效液相色谱分离,得到13个化合物。运用光谱分析(UV、MS、ESIMS、1D-NMR,2D-NMR)鉴定了13个化合物的结构,这些化合物分别是:异牛蒡酚C(isolappaol C)(1)、牛蒡酚C(lappaol C)(2)、牛蒡酚H(lappaol H)(3)、油酸(oleie acid)(4)、牛蒡酚F(lappaol F)(5)、牛蒡子苷元(arctigenin)(6)、罗汉松脂素(matairesinol)(7)、牛蒡酚B(lappaol B)(8)、7,8-双脱氢牛蒡苷元[(+)-7,8-didehydroarctigenin](9)、牛蒡子苷(arctiin)(10)、牛蒡酚E(lappaol E)(11)、异牛蒡酚A(isolappaol A)(12)、牛蒡酚A(lappaol A)(13)。
本研究以人慢性髓原白血病细胞K562为靶标,初步测试了从牛蒡子分得的木脂素类化合物对白血病细胞株K562的影响。实验结果显示,lappaol B,isolappaol A,lappaolA对K562细胞的IC_(50)分别为38.5μg/ml,53.5μg/ml,51.1μg/ml。
Fructus arctii is the dried seeds of Arctium lappa L. (Compositae). In theory of traditional Chinese medicine, this medicine can disperse wind-heat from the superficies, smooth the throat and disperse the mass due to retention of evils. Ventilating the lung and facilitating eruption, and remove toxic materials and relieve pyogenic infection of the skin. Many chemical and pharmacologic studies on Fructus arctii have been reported. The chemical constituents of it are lignans, essential oil, fatty acid, sesquiterpene, triterpene, and so on. It was reported that arctigenin and arctiin could be used for anti-virus and anti-tumor . whereas the pharmacological reports of other chemical constituents were insufficient. In this paper, isolation, purification, structural elucidation, in vitro activities of the lignan isolates against tumor cells were investigated.
Thirteen compounds were isolated from the ethanol extract of Fructus arctii through repeated silica gel, ODS and Sephadex LH-20 and/or separated by preparative HPLC column chromatographies.
From the physico-chemical data, including NMR, MS, UV and IR, the chemical structures of the compounds were determined, as isolappaol C (1), lappaol C (2), lappaol H (3), oleic acid (4), lappaol F (5), arctigenin (6), matairesinol (7), lappaol B (8), (+)-7,8-didehydroarctigenin (9), arctiin.(10) , lappaol E(11), isolappaol A(12), and lappaol A(13).
In this study anti-tumor effect was evaluated for the lignans isolated from the seeds of Arctium lappa L. and the cytotoxicity of lappaol B, lappaol A, and isolappaol A to K562 cells was reported for the first time. The results showed that IC_(50) values of lappaol B, lappaol A, and isolappaol A to K 562 cells were 38.5μg/ml, 53.5μg/ml, 51.1μg/ml, respectively.
牛蒡子乙醇提取物的氯仿萃取部分经过硅胶柱层析、反相硅胶柱层析、SephadexLH-20凝胶柱层析、半制备高效液相色谱分离,得到13个化合物。运用光谱分析(UV、MS、ESIMS、1D-NMR,2D-NMR)鉴定了13个化合物的结构,这些化合物分别是:异牛蒡酚C(isolappaol C)(1)、牛蒡酚C(lappaol C)(2)、牛蒡酚H(lappaol H)(3)、油酸(oleie acid)(4)、牛蒡酚F(lappaol F)(5)、牛蒡子苷元(arctigenin)(6)、罗汉松脂素(matairesinol)(7)、牛蒡酚B(lappaol B)(8)、7,8-双脱氢牛蒡苷元[(+)-7,8-didehydroarctigenin](9)、牛蒡子苷(arctiin)(10)、牛蒡酚E(lappaol E)(11)、异牛蒡酚A(isolappaol A)(12)、牛蒡酚A(lappaol A)(13)。
本研究以人慢性髓原白血病细胞K562为靶标,初步测试了从牛蒡子分得的木脂素类化合物对白血病细胞株K562的影响。实验结果显示,lappaol B,isolappaol A,lappaolA对K562细胞的IC_(50)分别为38.5μg/ml,53.5μg/ml,51.1μg/ml。
Fructus arctii is the dried seeds of Arctium lappa L. (Compositae). In theory of traditional Chinese medicine, this medicine can disperse wind-heat from the superficies, smooth the throat and disperse the mass due to retention of evils. Ventilating the lung and facilitating eruption, and remove toxic materials and relieve pyogenic infection of the skin. Many chemical and pharmacologic studies on Fructus arctii have been reported. The chemical constituents of it are lignans, essential oil, fatty acid, sesquiterpene, triterpene, and so on. It was reported that arctigenin and arctiin could be used for anti-virus and anti-tumor . whereas the pharmacological reports of other chemical constituents were insufficient. In this paper, isolation, purification, structural elucidation, in vitro activities of the lignan isolates against tumor cells were investigated.
Thirteen compounds were isolated from the ethanol extract of Fructus arctii through repeated silica gel, ODS and Sephadex LH-20 and/or separated by preparative HPLC column chromatographies.
From the physico-chemical data, including NMR, MS, UV and IR, the chemical structures of the compounds were determined, as isolappaol C (1), lappaol C (2), lappaol H (3), oleic acid (4), lappaol F (5), arctigenin (6), matairesinol (7), lappaol B (8), (+)-7,8-didehydroarctigenin (9), arctiin.(10) , lappaol E(11), isolappaol A(12), and lappaol A(13).
In this study anti-tumor effect was evaluated for the lignans isolated from the seeds of Arctium lappa L. and the cytotoxicity of lappaol B, lappaol A, and isolappaol A to K562 cells was reported for the first time. The results showed that IC_(50) values of lappaol B, lappaol A, and isolappaol A to K 562 cells were 38.5μg/ml, 53.5μg/ml, 51.1μg/ml, respectively.
引文
[1]国家药典委员会编.中华人民共和国药典.一部.北京:化学工业出版社,2005,48.
[2]Ozawa T.Component of the seed of Arctium lappa[J]J Pharm Soc Japan,1952:551-553
[3]Matsumoto T,Hosono N,Yamaha H,et al.Antiproliferative and apoptotic effects of butyrolaetone lignans from Arctium lappa on leukemic cells[J].Planta Med,2006,72:276-278
[4]Kazuo I,Takeshi K,Sansei N,et al.The Ca2+ antagonist activity of lignans[J].Chem Pharm Bull,1986,34(8):3514-3517.
[5]Sakae Y,Michio T,Ushio S,et al.On the constituents of the fruit of Arctium lappa [J].Yakugaku Zasshi,1976,96(12):1492-93
[6]米靖宇.常用中药牛蒡子的化学、体内外代谢及质量控制研究.上海中医药大学博士学位论文.2002.16-17
[7]Ichihara A,Kengo O,Yoshiaki N,et al.Lappaol A and B,Novel lignans from Arctium lappa L[J].Tetra Lett,1976,44:3961-3961.
[8]Kaoru U,Ariko S,Masanori K,et al.Studies on differentiation-inducers from Arctium Fructus(1)[J]Chem Pharm Bull,1993,41(10):1774-1779
[9]Ichihara A,Numata Y,Kanai S,et al.New sesquilignans from Arctium lappa L.[J].Agric Biol Chem.1977,41(9):1813-14
[10]So Young Park,Seong Su Hong,Xiang Hua Han,et al.Lignans form Arctium lappa and their inhibition of LPS-induced nitric oxide production Chem Pharm Bull,2007,55(1):150-152
[11]Ichihara A,Seiji K,Yasuji N,et al.Structures of Lappaol F and H,dilignans from Arctium Lappa L[J].Tetra Lett.1978,33:3035-38
[12]Kaoru U,Mitsuhrio N,Toshio M,et al.Studies on differentiation-inducers from Arctium Fructus(2)[J]Chem Pharm Bull,1996,44(12):2300
[13]Han BH,Kang YH,Yang HO,et al.A butyrolactone lignan dimmer from arctium Lappa.Phytoehemistry,1994,37(4):1161
[14]HY Wang,JS Yang.Neoarctin A from Aretium lappa L[J].Chin Chem Lett,1995,6(3):217-220
[15]HY Wang,JS Yang.Studies on the chemical constituents of Arctium lappa L.[J].Chin Chem Lett,1993,28(12):911-917
[16]Shiro S et al Stereochemical difference in secoisolariciresinol formation between cell-free extracts from Petioles and from ripening seeds of Arctium Lappa L.Biosci.Biotechnol.Biochem.1998,62(7):1468-1470
[17]Naya keizo,Kazuyasu T,Unsho Haku.The constituent of Arctium Lappa L.[J].Chem Lett,1972,3:235-6
[18]Iochkova I Zakharieva E Zakharieva E.Titerpene alcohols and sterols of Arctium lappa Dokl Boly Akac Nauk,1989,42(10):43.
[19]Lotti G,etal.Agrochimiea,1991,35(1-3):58.
[20]Kang K,Lee HJ,Kim CY,et al.The chemopreventive effects of Saussurea salicifolia through induction of apoptosis and phase Ⅱ detoxification enzyme.[J].Biol.Pharm.Bull.2007,30(12):2352-2359
[21]Awale S,Lu J,Kalauni SK,et al,Identification of arctigenin as an antitumor agent having the ability to eliminate the tolerance of cancer cells to nutrient starvation,Cancer Res.2006 Feb 1;66(3):1751-7.
[22]Hausott B,Greger H,Marian B.Naturally occurring lignans efficiently induce apoptosis in colorectal tumor cells.[J].J Cancer Res Clin Oncol.2003,129(10):569-76
[23]Matsuzaki Y,Koyama M,Hitomi T,et al.Arctiin induces cell growth inhibition through the down-regulation of cyclin D1 expression.[J].Oncol Rep.2008,19(3):721-7.
[24]Huang DM,Guh JH,Chueh SC,et al.Modulation of anti-adhesion molecule MUC-1 is associated with arctiin-induced growth inhibition in PC-3 cells.[J].Prostate,200459(3):260-7.
[25]Moritani S,Nomura M,Takeda Y,et al.Cytotoxic components of bardanae fructus (goboshi)[J].Biol.Pharm.Bull.,1996,Nov,19(11):1515-1517
[26]Hirano T,Gotoh M,Oka K.Natural flavonoids and lignans are potent cytostatic agents against human leukemic HL-60 cells.[J].Life Sci.1994;55(13):1061-9.
[27]佐藤昭彦.国外医学.中医中药分册,1987,9(2):47
[28]Lec DY,Song MC,Yoo KH,et al.Lignans from the fruits of Comus kousa Burg.and their cytotoxic effects on human cancer cell lines.[J].Arch Pharm Res.2007,30(4):402-7.
[29]Yang XJ,Wong MS,Wang NL,et al.Lignans from the stems of Sambucus williamsii and their effects on ostcoblastic UMR106 cells.[J].J Asian Nat Prod Res.2007,9(6-8):583-91.
[30]Yamauchi S,Sugahara T,Nakashima Y,et al.Effect of benzylic oxygen on the cytotoxic activity for colon 26 cell line of phenolic lignans.[J]Biosci Biotechnol Biochem.2006,70(12):2942-7
[31]Chen JJ,Fang HY,Dub CY,ct al.New indolopyridoquinazolinc,benzo[c]phenanthridines and cytotoxic constituents from Zanthoxylum intcgrifoliolum.[J].Planta Med.2005 May;71(5):470-5.
[32]Toyoda T,Tsukamoto T,Mizoshita T,et al.Inhibitory effect of nordihydroguaiaretic acid,a plant lignan,on Helicobacter pylori- associated gastric carcinogenesis in Mongolian gerbils.Cancer Sci.2007,98(11):1689-95.
[33]Hirose M,Nishikawa A,Shibutani M,et al.Chemoprevention of heterocyclic amine-induced mammary carcinogenesis in rats.[J].Environ Mol Mutagen.2002;39(2-3):271-8.
[34]Hirose M,Yamaguchi T,Lin C,et al.Effects of arctiin on PhIP-induced mammary,colonandpancreatic carcinogens is in female Sprague awleyrats and MeLQx-induced hepatocar-cinogenes is in male.F344 rats[J].Cancer Lett.,2000,155(1):79-88
[35]Takasaki M,Konoshima T,Komatsu K,Tokuda H,et al.Anti-tumor-promoting activity of lignans from the aerial part of Saus-sureamedusa[J].Cancer Lett.2000,158(1):53-59
[36]Kato T,Hirose M,Takahashi S,et al.Effects of the lignan,arctiin,on 17-betae thinyle stradiol promotion of preneop lastic liver cell focidevel opmentinrats[J].Anticancer Res.1998,18(2A):1053-1057
[37]杨子峰,刘妮,黄碧松,等.牛蒡子甙元体内抗甲1型流感病毒作用的研究[J]..中药材 2005,28(11):1012-1014
[38]陈铁宏,黄迪.牛蒡子对Epstein-Barr病毒抗原表达的抑制作用[J].中华实验和临床病毒学杂志,1994,8(4):323
[39]Cho JY,Kim AR,Yoo ES,et al.Immunomodulatory effect of arctigenin,a lignan compound,on tumour necrosis factor-alpha and nitric oxide production,and lymphocyte proliferation.J Pharm Pharmacol.1999,51(11):1267-73.
[40]Cho MK,Jang YP,Kim YC,et al.Arctigenin,a phenylpropanoid dibenzylbutyrolactone ignan,inhibits MAP kinases and AP-1 activation via potent MKK inhibition:the role in TNF-alpha inhibition.[J].Int Immunopharmacol.2004,4(10-11):1419-29.
[41]F.D.Gunstone,M.R.Pollard,C.M.Scrimgeour,et al.Fatty acids.Part 50.13C nuclear magnetic resonance studies of olefinic fatty acids and esters[J].Chemistry and Physics of Lipids1977,18(1):115-129
[42]任玉琳,杨峻山.二苄基丁内酯型木脂素类化合物光谱规律分析.[J].波谱学杂志.2002,19(1):15-24
[43]黄震琪,夏瑞祥,曾庆曙.维甲酸联合三氧化二砷对NB4细胞NF—KB1、ROS 表达的影响[J].安徽医科大学学报,2006,41(3):250-3
[44]Corbin A S,Buehdunger E,Pascal F,et al.Analysis of the structural basis of specificity of inhibition of the Ab1 kinase by STI571[J].J Biol Chem,2002,277(35):32214-9.
[45]王伟佳.人白血病K562细胞红系分化的研究进展[J].国际检验医学杂志 2006,27(6):512-516
[46]Singh SK,Shanmugavel M,Kampasi H,et al.Chemically standardized isolates from Cedrus deodara stem wood having anticancer activity.Planta Med.2007Jun;73(6):519-26.
[2]Ozawa T.Component of the seed of Arctium lappa[J]J Pharm Soc Japan,1952:551-553
[3]Matsumoto T,Hosono N,Yamaha H,et al.Antiproliferative and apoptotic effects of butyrolaetone lignans from Arctium lappa on leukemic cells[J].Planta Med,2006,72:276-278
[4]Kazuo I,Takeshi K,Sansei N,et al.The Ca2+ antagonist activity of lignans[J].Chem Pharm Bull,1986,34(8):3514-3517.
[5]Sakae Y,Michio T,Ushio S,et al.On the constituents of the fruit of Arctium lappa [J].Yakugaku Zasshi,1976,96(12):1492-93
[6]米靖宇.常用中药牛蒡子的化学、体内外代谢及质量控制研究.上海中医药大学博士学位论文.2002.16-17
[7]Ichihara A,Kengo O,Yoshiaki N,et al.Lappaol A and B,Novel lignans from Arctium lappa L[J].Tetra Lett,1976,44:3961-3961.
[8]Kaoru U,Ariko S,Masanori K,et al.Studies on differentiation-inducers from Arctium Fructus(1)[J]Chem Pharm Bull,1993,41(10):1774-1779
[9]Ichihara A,Numata Y,Kanai S,et al.New sesquilignans from Arctium lappa L.[J].Agric Biol Chem.1977,41(9):1813-14
[10]So Young Park,Seong Su Hong,Xiang Hua Han,et al.Lignans form Arctium lappa and their inhibition of LPS-induced nitric oxide production Chem Pharm Bull,2007,55(1):150-152
[11]Ichihara A,Seiji K,Yasuji N,et al.Structures of Lappaol F and H,dilignans from Arctium Lappa L[J].Tetra Lett.1978,33:3035-38
[12]Kaoru U,Mitsuhrio N,Toshio M,et al.Studies on differentiation-inducers from Arctium Fructus(2)[J]Chem Pharm Bull,1996,44(12):2300
[13]Han BH,Kang YH,Yang HO,et al.A butyrolactone lignan dimmer from arctium Lappa.Phytoehemistry,1994,37(4):1161
[14]HY Wang,JS Yang.Neoarctin A from Aretium lappa L[J].Chin Chem Lett,1995,6(3):217-220
[15]HY Wang,JS Yang.Studies on the chemical constituents of Arctium lappa L.[J].Chin Chem Lett,1993,28(12):911-917
[16]Shiro S et al Stereochemical difference in secoisolariciresinol formation between cell-free extracts from Petioles and from ripening seeds of Arctium Lappa L.Biosci.Biotechnol.Biochem.1998,62(7):1468-1470
[17]Naya keizo,Kazuyasu T,Unsho Haku.The constituent of Arctium Lappa L.[J].Chem Lett,1972,3:235-6
[18]Iochkova I Zakharieva E Zakharieva E.Titerpene alcohols and sterols of Arctium lappa Dokl Boly Akac Nauk,1989,42(10):43.
[19]Lotti G,etal.Agrochimiea,1991,35(1-3):58.
[20]Kang K,Lee HJ,Kim CY,et al.The chemopreventive effects of Saussurea salicifolia through induction of apoptosis and phase Ⅱ detoxification enzyme.[J].Biol.Pharm.Bull.2007,30(12):2352-2359
[21]Awale S,Lu J,Kalauni SK,et al,Identification of arctigenin as an antitumor agent having the ability to eliminate the tolerance of cancer cells to nutrient starvation,Cancer Res.2006 Feb 1;66(3):1751-7.
[22]Hausott B,Greger H,Marian B.Naturally occurring lignans efficiently induce apoptosis in colorectal tumor cells.[J].J Cancer Res Clin Oncol.2003,129(10):569-76
[23]Matsuzaki Y,Koyama M,Hitomi T,et al.Arctiin induces cell growth inhibition through the down-regulation of cyclin D1 expression.[J].Oncol Rep.2008,19(3):721-7.
[24]Huang DM,Guh JH,Chueh SC,et al.Modulation of anti-adhesion molecule MUC-1 is associated with arctiin-induced growth inhibition in PC-3 cells.[J].Prostate,200459(3):260-7.
[25]Moritani S,Nomura M,Takeda Y,et al.Cytotoxic components of bardanae fructus (goboshi)[J].Biol.Pharm.Bull.,1996,Nov,19(11):1515-1517
[26]Hirano T,Gotoh M,Oka K.Natural flavonoids and lignans are potent cytostatic agents against human leukemic HL-60 cells.[J].Life Sci.1994;55(13):1061-9.
[27]佐藤昭彦.国外医学.中医中药分册,1987,9(2):47
[28]Lec DY,Song MC,Yoo KH,et al.Lignans from the fruits of Comus kousa Burg.and their cytotoxic effects on human cancer cell lines.[J].Arch Pharm Res.2007,30(4):402-7.
[29]Yang XJ,Wong MS,Wang NL,et al.Lignans from the stems of Sambucus williamsii and their effects on ostcoblastic UMR106 cells.[J].J Asian Nat Prod Res.2007,9(6-8):583-91.
[30]Yamauchi S,Sugahara T,Nakashima Y,et al.Effect of benzylic oxygen on the cytotoxic activity for colon 26 cell line of phenolic lignans.[J]Biosci Biotechnol Biochem.2006,70(12):2942-7
[31]Chen JJ,Fang HY,Dub CY,ct al.New indolopyridoquinazolinc,benzo[c]phenanthridines and cytotoxic constituents from Zanthoxylum intcgrifoliolum.[J].Planta Med.2005 May;71(5):470-5.
[32]Toyoda T,Tsukamoto T,Mizoshita T,et al.Inhibitory effect of nordihydroguaiaretic acid,a plant lignan,on Helicobacter pylori- associated gastric carcinogenesis in Mongolian gerbils.Cancer Sci.2007,98(11):1689-95.
[33]Hirose M,Nishikawa A,Shibutani M,et al.Chemoprevention of heterocyclic amine-induced mammary carcinogenesis in rats.[J].Environ Mol Mutagen.2002;39(2-3):271-8.
[34]Hirose M,Yamaguchi T,Lin C,et al.Effects of arctiin on PhIP-induced mammary,colonandpancreatic carcinogens is in female Sprague awleyrats and MeLQx-induced hepatocar-cinogenes is in male.F344 rats[J].Cancer Lett.,2000,155(1):79-88
[35]Takasaki M,Konoshima T,Komatsu K,Tokuda H,et al.Anti-tumor-promoting activity of lignans from the aerial part of Saus-sureamedusa[J].Cancer Lett.2000,158(1):53-59
[36]Kato T,Hirose M,Takahashi S,et al.Effects of the lignan,arctiin,on 17-betae thinyle stradiol promotion of preneop lastic liver cell focidevel opmentinrats[J].Anticancer Res.1998,18(2A):1053-1057
[37]杨子峰,刘妮,黄碧松,等.牛蒡子甙元体内抗甲1型流感病毒作用的研究[J]..中药材 2005,28(11):1012-1014
[38]陈铁宏,黄迪.牛蒡子对Epstein-Barr病毒抗原表达的抑制作用[J].中华实验和临床病毒学杂志,1994,8(4):323
[39]Cho JY,Kim AR,Yoo ES,et al.Immunomodulatory effect of arctigenin,a lignan compound,on tumour necrosis factor-alpha and nitric oxide production,and lymphocyte proliferation.J Pharm Pharmacol.1999,51(11):1267-73.
[40]Cho MK,Jang YP,Kim YC,et al.Arctigenin,a phenylpropanoid dibenzylbutyrolactone ignan,inhibits MAP kinases and AP-1 activation via potent MKK inhibition:the role in TNF-alpha inhibition.[J].Int Immunopharmacol.2004,4(10-11):1419-29.
[41]F.D.Gunstone,M.R.Pollard,C.M.Scrimgeour,et al.Fatty acids.Part 50.13C nuclear magnetic resonance studies of olefinic fatty acids and esters[J].Chemistry and Physics of Lipids1977,18(1):115-129
[42]任玉琳,杨峻山.二苄基丁内酯型木脂素类化合物光谱规律分析.[J].波谱学杂志.2002,19(1):15-24
[43]黄震琪,夏瑞祥,曾庆曙.维甲酸联合三氧化二砷对NB4细胞NF—KB1、ROS 表达的影响[J].安徽医科大学学报,2006,41(3):250-3
[44]Corbin A S,Buehdunger E,Pascal F,et al.Analysis of the structural basis of specificity of inhibition of the Ab1 kinase by STI571[J].J Biol Chem,2002,277(35):32214-9.
[45]王伟佳.人白血病K562细胞红系分化的研究进展[J].国际检验医学杂志 2006,27(6):512-516
[46]Singh SK,Shanmugavel M,Kampasi H,et al.Chemically standardized isolates from Cedrus deodara stem wood having anticancer activity.Planta Med.2007Jun;73(6):519-26.
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