药学学报, 2018, 53(12): 2026-2039
程敏, 汤俊, 李姗姗. 紫草萘醌类成分的药理活性及其定量分析方法研究进展[J]. 药学学报, 2018, 53(12): 2026-2039.
CHENG Min, TANG Jun, LI Shan-shan. Recent advances in the research on pharmacological actions and quantitative analyses of naphthoquinones in Chinese medicinal herb “Zicao”[J]. Acta Pharmaceutica Sinica, 2018, 53(12): 2026-2039.

程敏1, 汤俊2, 李姗姗2
1. 武汉药品医疗器械检验所, 湖北 武汉 430075;
2. 武汉大学药学院, 组合生物合成与新药发现教育部重点实验室, 湖北 武汉 430071
Recent advances in the research on pharmacological actions and quantitative analyses of naphthoquinones in Chinese medicinal herb “Zicao”
CHENG Min1, TANG Jun2, LI Shan-shan2
1. Wuhan Institute for Drug and Medical Device Control, Wuhan 430075, China;
2. Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China
Naphthoquinones are a kind of important active ingredients in the traditional Chinese medicinal herb "Zicao". In recent years, researches on pharmacology and clinical application of naphthoquinones in Zicao have been gradually deepened and made extensive progress around the world. On the other hand, the plant origins of the herbal materials of Zicao in market are complex and their qualities are quite different, thus more and more studies have been focused on the quantitative determination and quality assessment of the medicinal herb as well as its products by using various naphthoquinones as quality chemical markers. In this paper, we review recent advances in the research on pharmacological actions and multi-components content determination of shikonin/alkannin and its derivatives in Zicao so as to provide a scientific guidance for further research and development of medicinal resource of Zicao, and to establish more comprehensive and systematic method for their quality control and evaluation.
Key words:   
收稿日期: 2018-06-23
DOI: 10.16438/j.0513-4870.2018-0583
基金项目: 湖北省食品药品监督管理局科研项目(201601021);国家自然科学基金面上项目(31270401).
通讯作者: 汤俊,Tel:86-27-68759315,Fax:86-27-68759850,E-mail:tangj0205@whu.edu.cn
Email: tangj0205@whu.edu.cn
PDF(501KB) Free

[1] Chinese Herbals Editor Board, the State Administrative Bureau of Chinese Medicine of China. Chinese Herbals (中华本草)[M]. Shanghai:Shanghai Science and Technology Press, 1999, 6:525-544.
[2] Wu D, Li CY. Textual research on Arnebia[J]. Lishizhen Med Mater Med Res (时珍国医国药), 2008, 19:2042-2043.
[3] Chinese Pharmacopoeia Commission. Pharmacopoeia of the People's Republic of China (中华人民共和国药典)[S]. Vol I. 2015 Ed. Beijing:China Medicinal Science Press, 2015:340.
[4] The Editor Board of Yunnan Food and Drug Administration Bureau. Yun Nan Chinese Materia Medica Standards (Volume 6 for Yi Nationality Medicine (Ⅲ)) (云南省中药材标准2005年版第六册•彝族药(Ⅲ))[S]. Kunming:Yunnan Science and Technology Press, 2010:99, 485.
[5] The Editor Board of Sichuan Food and Drug Administration Bureau. Si Chuan Chinese Materia Medica Standards (2010 Edition) (四川省中药材标准2010年版)[S]. Chengdu:Sichuan Science and Technology Press, 2011:608-609.
[6] Jiang B. A medicinal plant of Bai Nationality-Onosma paniculatum Bur. et Franch[J]. J Dali Univ (大理大学学报), 2016, 1:102.
[7] Zhan Z, Hu J, Liu T, et al. Advances in studies on chemical compositions and pharmacological activities of Arnebiae Radix[J]. China J Chin Mater Med (中国中药杂志), 2015, 40:4127-4135.
[8] Zhao X, Li N, Song Y, et al. Chemical constituents of Arnebiae Radix[J]. Chin J Exp Tradit Med Form (中国实验方剂学杂志), 2016, 22:47-50.
[9] Liao M, Yao Y, Chen F, et al. Studies on chemical constituents from Arnebia guttata Bunge[J]. J South-Cent Univ Natly (Nat Sci Ed) (中南民族大学学报·自然科学版), 2018, 37:58-60.
[10] Zhang B, Xie Y. Protective effect of Lithospermum erythrorhizon polysaccharide on CCl4-induced acute liver injury in mice and its underlying mechanisms[J]. Curr Immunol (现代免疫学), 2018, 38:135-139.
[11] Andújar I, Ríos JL, Giner RM, et al. Pharmacological properties of shikonin-a review of literature since 2002[J]. Planta Med, 2013, 79:1685-1697.
[12] Papageorgiou VP, Assimopoulou AN, Ballis AC. Alkannins and shikonins:a new class of wound healing agents[J]. Curr Med Chem, 2008, 15:3248-3267.
[13] Gao XM. Chinese Medicines (中药学)[M]. Beijing:People's Medical Publishing House, 2000:445-452.
[14] Liu T, Lv C, Wang S, et al. Transcriptome-based gene mining and bioinformatics analysis of p-hydroxybenzoate geranyltransferase genes in Arnebia euchroma[J]. China J Chin Mater Med (中国中药杂志), 2016, 41:1422-1429.
[15] Liu C, Chen S, Xiao X, et al. A new concept on quality marker of Chinese materia medica:quality control for Chinese medicinal products[J]. Chin Tradit Herb Drugs (中草药), 2016, 47:1443-1457.
[16] Cheng M, Mo Q, Xu Y, et al. Quality evaluation of Arnebiae Radix using multiple qualitative and quantitative methods coupled with multivariate statistical analysis[J]. Curr Pharm Anal, 2013, 9:217-225.
[17] Andujar I, Rios JL, Giner RM, et al. Beneficial effect of shikonin on experimental colitis induced by dextran sulfate sodium in BALB/c mice[J]. Evid Based Complement Alternat Med, 2012, 2012:271606.
[18] Xu YY, Xu YG, Gao XG, et al. Shikonin suppresses IL-17-induced VEGF expression via blockage of JAK2/STAT3 pathway[J]. Int Immunopharmacol, 2014, 19:327-333.
[19] Liu L, Wu Y, Cao K, et al. Shikonin inhibits IFN-g-induced K17 over-expression of HaCaT cells by interfering with STAT3 signaling[J]. Int J Clin Exp Pathol, 2015, 8:9202-9207.
[20] Liu T, Xia Y, Li J, et al. Shikonin attenuates concanavalin A-induced acute liver injury in mice via inhibition of the JNK pathway[J]. Mediat Inflamm, 2016, 2016:2748367.
[21] Tian Y, Li Z, Shen B, et al. The protective effects of shikonin on lipopolysaccharide/D-galactosamine-induced acute liver injury via inhibiting MAPK and NF-κB and activating Nrf2/HO-1 signaling pathways[J]. Rsc Adv, 2017, 7:34846-34856.
[22] Nie Y, Yang Y, Zhang J, et al. Shikonin suppresses pulmonary fibroblasts proliferation and activation by regulating Akt and p38 MAPK signaling pathways[J]. Biomed Pharmacother, 2017, 95:1119-1128.
[23] Li YJ. Anti-inflammatory Effects of Shikonin by TLR4/NF-κB Pathway in Macrophage (紫草素通过TLR4/NF-kB信号通路在巨噬细胞中发挥抗炎作用的研究)[D]. Wuhan:Wuhan University, 2018.
[24] Fan HY, Yang MY, Che X, et al. Activity study of a hydroxynaphthoquinone fraction from Arnebia euchroma in experimental arthritis[J]. Fitoterapia, 2012, 83:1226-1237.
[25] Rajapaksha GP, Kyoung TL, Chang HK, et al. Isobutyrylshikonin inhibits lipopolysaccharide-induced nitric oxide and prostaglandin E2 production in BV2 microglial cells by suppressing the PI3K/Akt-mediated nuclear transcription factor-κB pathway[J]. Nutr Res, 2014, 34:1111-1119.
[26] Guha M, Mackman N. LPS induction of gene expression in human monocytes[J]. Cell Signal, 2001, 13:85-94.
[27] Blaser H, Dostert C, Mak TW, et al. TNF and ROS crosstalk in inflammation[J]. Trends Cell Biol, 2016, 26:249-261.
[28] Qiu HY, Wang PF, Lin HY, et al. Naphthoquinones:a continuing source for discovery of therapeutic antineoplastic agents[J]. Chem Biol Drug Des, 2018, 91:681-690.
[29] Andújar I, Recio MC, Giner RM, et al. Traditional Chinese medicine remedy to jury:the pharmacological basis for the use of shikonin as an anticancer therapy[J]. Curr Med Chem, 2013, 20:2892-2898.
[30] Zhu M, Wang R, Zhou W, et al. Antitumor effect research progress of shikonin and its derivatives[J]. Acta Pharm Sin (药学学报), 2012, 47:588-593.
[31] Yang WB, Luo XL, Hu J, et al. Research progress on anti-tumor components and mechanism of Arnebiae Radix[J]. Pharm J Chin PLA (解放军药学学报), 2017, 33:359-362.
[32] Tian R, Li Y, Gao M. Shikonin causes cell-cycle arrest and induces apoptosis by regulating the EGFR-NF-κB signalling pathway in human epidermoid carcinoma A431 cells[J]. Biosci Rep, 2015, 35:e00189.
[33] Jang SY, Hong D, Jeong SY, et al. Shikonin causes apoptosis by up-regulating p73 and down-regulating ICBP90 in human cancer cells[J]. Biochem Biophys Res Commun, 2015, 465:71-76.
[34] Lee MJ, Kao SH, Hunag JE, et al. Shikonin time-dependently induced necrosis or apoptosis in gastric cancer cells via generation of reactive oxygen species[J]. Chem Biol Interact, 2014, 211:44-53.
[35] Shi SQ, Cao HM. Shikonin promotes autophagy in BXPC-3 human pancreatic cancer cells through the PI3K/Akt signaling pathway[J]. Oncol Lett, 2014, 8:1087-1089.
[36] Kuo LJ, Huang CY, Cheng WL, et al. Glucose-regulated protein 78 mediates the anticancer efficacy of shikonin in hormone-refractory prostate cancer cells[J]. Tumor Biol, 2015, 36:5063-5070.
[37] Li X, Fan XX, Jiang ZB, et al. Shikonin inhibits gefitinib-resistant non-small cell lung cancer by inhibiting TRXR and activating the EGFR proteasomal degradation pathway[J]. Pharmacol Res, 2017, 115:45-55.
[38] Hsieh YS, Liao CH, Chen WS, et al. Shikonin inhibited migration and invasion of human lung cancer cells via suppression of c-met-mediated epithelial-to-mesenchymal transition[J]. J Cell Biochem, 2017, 118:4639-4651.
[39] Kourounakis AP, Assimopoulou AN, Papageorgiou VP, et al. Alkannin and shikonin:effect on free radical processes and on inflammation-a preliminary pharmacochemical investigation[J]. Arch Pharm (Weinheim), 2002, 335:262-266.
[40] Parray JA, Hamid R, Kamili AN, et al. Biological efficacy and radical scavenging potential of shikonin in Arnebia benthamii (Wall ex. G Don) Johnston[J]. Ind Crop Prod, 2015, 74:434-439.
[41] Huang CS, Lin AH, Yang TC, et al. Shikonin inhibits oxidized LDL-induced monocyte adhesion by suppressing NF-κB activation via up-regulation of PI3K/Akt/Nrf2-dependent antioxidation in EA.hy926 endothelial cells[J]. Biochem Pharmacol, 2015, 93:352-361.
[42] Wang ZH, Liu T, Gan L, et al. Shikonin protects mouse brain against cerebral ischemia/reperfusion injury through its antioxidant activity[J]. Eur J Pharmacol, 2010, 643:211-217.
[43] Ding X, Yin B, Qian L, et al. Screening for novel quorum-sensing inhibitors to interfere with the formation of Pseudomonas aeruginosa biofilm[J]. J Med Microbiol, 2011, 60:1827-1834.
[44] Vegara S, Funes L, Martí N, et al. Bactericidal activities against pathogenic bacteria by selected constituents of plant extracts in carrot broth[J]. Food Chem, 2011, 128:872-877.
[45] Li HM, Tang YL, Zhang ZH, et al. Compounds from Arnebia euchroma and their related anti-HCV and antibacterial activeties[J]. Planta Med, 2012, 78:39-45.
[46] Kim JY, Jeong HJ, Park JY, et al. Selective and slow-binding inhibition of shikonin derivatives isolated from Lithospermum erythrorhizon on glycosyl hydrolase 33 and 34 sialidases[J]. Bioorg Med Chem, 2012, 20:1740-1748.
[47] Ho TY, Wu SL, Lai IL, et al. An in vitro system combined with an in-house quantitation assay for screening hepatitis C virus inhibitors[J]. Antivir Res, 2003, 58:199-208.
[48] Zhang MM, Zhao HQ, Zhao ZG, et al. Rapid screening, identification, and purification of neuraminidase inhibitors from Lithospermum erythrorhizon Sieb.et Zucc. by ultrafiltration with HPLC-ESI-TOF-MS combined with semipreparative HPLC[J]. J Sep Sci, 2016, 39:2097-2104.
[49] Chen X, Yang L, Zhang N, et al. Shikonin, a component of Chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1[J]. Antimicrob Agents Chemother, 2003, 47:2810-2816.
[50] Gwon SY, Choi WH, Lee DH, et al. Shikonin protects against obesity through the modulation of adipogenesis, lipogenesis, and β-oxidation in vivo[J]. J Funct Foods, 2015, 16:484-493.
[51] Su ML, Huang WD, Zhu BH, et al. Acetylshikonin from Zicao prevents obesity in rats on a high-fat diet by inhibiting lipid accumulation and inducing lipolysis[J]. PLoS One, 2016, 11:e0146884.
[52] Su ML, He Y, Li QS, et al. Efficacy of acetylshikonin in preventing obesity and hepatic steatosis in db/db mice[J]. Molecules, 2016, 21:976.
[53] He Y, Li QS, Su ML, et al. Acetylshikonin from Zicao exerts antifertility effects at high dose in rats by suppressing the secretion of GTH[J]. Biochem Biophys Res Commun, 2016, 476:560-565.
[54] Zhang L, Feng L, Nie J. A survey on the standards and characteristics of Chinese patent medicines in 2010 edition of Chinese Pharmacopoeia[J]. Chin Pharm J (中国药学杂志), 2010, 45:1284-1286.
[55] Zhang L. Elementary analysis of quality standards of traditional Chinese patent medicines in the Chinese Pharmacopoeia 2015 Edition[J]. Chin Pharm J (中国药学杂志), 2015, 50:1754-1756.
[56] Wang Z, Qian Z, Zhang Q, et al. A technical guideline for the establishment of methodology of quantitative analysis of multi-components by single marker (QAMS)[J]. China J Chin Mater Med (中国中药杂志), 2011, 36:657-658.
[57] Wang J, Zhang L, Guo Q, et al. Quantitative analysis of seven phenolic acids in eight Yinqiao Jiedu serial preparations by quantitative analysis of multi-components with single-marker[J]. Acta Pharm Sin (药学学报), 2015, 50:480-485.
[58] Zhang C, He B, Chen S, et al. Content determination of acetylshikonin in Onosma paniculatum and its two closely related species by HPLC[J]. J Yunnan Univ Tradit Chin Med (云南中医学院学报), 2014, 37:17-22.
[59] Cheng M, Mo Q, Tang J, et al. Determination of β,β'-dimethylacrylalkannin in Arnebiae Radix from different sources and quality evaluation[J]. China Pharm (中国药师), 2013, 16:798-801.
[60] Zhu Y, Dong N, Qu X, et al. Content determination of deoxyshikonin of Arnebia Radix in different producing areas by HPLC[J]. J Taishan Med Coll (泰山医学院学报), 2017, 38:1229-1231.
[61] Zhao W, Wu Z, Wu X, et al. Determination of five naphthaquinones in Arnebia euchroma by quantitative analysis multi-components with single-marker[J]. China J Chin Mater Med (中国中药杂志), 2016, 41:3792-3797.
[62] Liu Y. Simultaneous determination of shikonin and its derivatives in Arnebia euchroma (Royle) Johnst by HPLC[J]. China Brew (中国酿造), 2011, 1:173-176.
[63] Wang XY, Gao SQ, Zhang R, et al. Determination of the active constituents in Arnebia euchroma (Royle) Johnst. by ionic liquid-based ultrasonic-assisted extraction high-performance liquid chromatography[J]. J Chromatogr B, 2011, 879:1833-1838.
[64] Hao H, Li P, Ye H, et al. Simultaneous determination of seven naphthoquinones in crude extract of Arnebia euchroma[J]. Chin J Exp Tradit Med Form (中国实验方剂学杂志), 2013, 19:108-112.
[65] Zan K, Su R, Teng A, et al. HPLC specific chromatogram of Arnebia euchroma and determination of six naphthoquinones in Boraginaceous herbs[J]. Chin J Pharm Anal (药物分析杂志), 2016, 36:1526-1535.
[66] Zan K, Zheng H, Liu J, et al. Simultaneous determination of eight hydroxyl naphthoquinones in different parts of Arnebia euchroma by HPLC[J]. China J Chin Mater Med (中国中药杂志), 2017, 42:2532-2537.
[67] Ding W, Li J, Yan X, et al. Determination of four naphthaquinones in roots of Arnebia decumbens from different origin by HPLC[J]. Nat Prod Res Dev (天然产物研究与开发), 2017, 29:2075-2080.
[68] Aga E, Nie L, Dongzhi Z, et al. Multi-component quantitative analysis combined with chromatographic fingerprint for quality assessment of Onosma hookeri[J]. China J Chin Mater Med (中国中药杂志), 2015, 40:4442-4445.
[69] Jiang L, Aga E, Wang J, et al. Study on fingerprint of Onosma hookeri and its variants[J]. J Tibet U (Nat Sci Ed) (西藏大学学报·自然科学版), 2017, 32:38-44.
[70] Sun J, Wen X, Cai D, et al. Simultaneous determination of shikonin, acetylshikonin and β,β'-dimethylacrylshikonin in Arnebia euchroma by RP-HPLC[J]. China Pharm (中国药房), 2018, 29:455-457.
[71] Han J, Zhu L, Weng X, et al. RP-HPLC determination of shikonin, isobutylshikonin and β,β'-dimethylacrylshikonin in Lithospermum erythrorhizon Sieb.et Zucc.[J]. Chin J Pharm Anal (药物分析杂志), 2008, 28:6-8.
[72] Bozan B, Baser KHC, Kara S. Quantitative determination of naphthaquinones of Arnebia densiflora (Nordm.) Ledeb. by an improved high-performance liquid chromatographic method[J]. J Chromatogr A, 1997, 782:133-136.
[73] Hu YN, Jiang ZH, Leung Y, et al. Simultaneous determination of naphthoquinone derivatives in Boraginaceous herbs by high-performance liquid chromatography[J]. Anal Chim Acta, 2006, 577:26-31.
[74] Li F, Cao X, Hao S. Established HPLC fingerprint of Arnebia euchroma (Royle) Johnst.[J]. J Yantai Univ (Nat Sci Eng Ed) (烟台大学学报·自然科学与工程版), 2016, 29:187-192.
[75] Liao M, Jiang H. Simultaneous determination of 13 shikonins and shikonofurans in medicinal Arnebia plants by HPLC-MS[J]. Chin Pharm J (中国药学杂志), 2016, 51:1212-1218.
[76] Liao M, Li A, Chen C, et al. Systematic identification of shikonins and shikonofurans in medicinal Zicao species using ultra-high performance liquid chromatography quadrupole time of flight tandem mass spectrometry combined with a data mining strategy[J]. J Chromatogr A, 2015, 1425:158-172.
[77] Tao K, Liu L, Guo S, et al. Determination of five naphthaquinones derivatives in Arnebia euchroma by reversed-phase high-performance liquid chromatography with electrochemical detection[J]. J Yangzhou U (Nat Sci Ed) (扬州大学学报·自然科学版), 2017, 20:33-37.
[78] Katoch P, Rana S, Kumar D, et al. Concurrent NP-HPTLC determination of shikonin and β,β'-dimethylacryl shikonin in Arnebia benthamii[J]. J Chromatogr Sci, 2016, 54:1421-1427.
[79] Zhang L, Zhang A, Wang M, et al. Capillary electrophoresis fingerprint of Arnebia euchroma (Royle) Johnst[J]. Chin J Anal Chem (分析化学), 2017, 45:1727-1733.
[80] Jiang L. Study on the Quality Control of Onosma hookeri Using High Performance Liquid Chromatography and Infrared Spectroscopy (高效液相色谱法和近红外光谱法在藏紫草质量控制中的应用)[D]. Tibet:Tibet University, 2017.
[81] Lin JY. Application Research of Infrared Fingerprint Identification in Tibetan Medicine (红外指纹图谱在藏药鉴别中的应用研究)[D]. Lanzhou:Lanzhou University, 2013.
[82] Wang S, Li X, Zhou LY, et al. Breeding biology and artificial cultivation of Arnebia euchroma[J]. Mod Chin Med (中国现代中药), 2011, 13:18-22.
[83] Li SS. Studies on Naphthoquinones Determination in Onosmae Radix et Cortex (滇紫草萘醌类成分含量测定研究)[D]. Wuhan:Wuhan University, 2017.
[84] Li GY, Maierdan M. Distribution of the medicinal Zicao species in Xinjiang and research progress[J]. J Xinjiang Med Univ (新疆医科大学学报), 2009, 32:386-388.
[85] Liu Y. Study on chromatographic detection method for hydroxynaphthoquinone pigments in Arnebia euchroma (Royle) Johnst[J]. Chin J Pharm Anal (药物分析杂志), 2011, 31:1140-1145.
[86] Zhou W, Jiang HG, Peng Y, et al. Comparative study on enantiomeric excess of main akannin/shikonin derivatives isolated from the roots of three endemic Boraginaceae plants in China[J]. Biomed Chromatogr, 2011, 25:1067-1075.
[87] Papadoyannis IN, Samanidou VF, Assimopoulou AN, et al. Analytical methods for the determination of alkannins and shikonins[J]. Curr Org Chem, 2006, 10:583-622.