Pharmacological effects and pharmacokinetic properties of icariin, the major bioactive component in Herba Epimedii

Life Sciences

Volumn 126, Issue , 2015, Pages 57-68

  Li, Chenrui ^a   Li, Qiang ^b   Mei, Qibing ^a   Lu, Tingli ^a  

^a NORTHWESTERN POLYTECHNICAL UNIVERSITY   (China)

^b FOURTH MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

Epimedii; Herba; Icariin; Icaritin; Pharmacokinetic; Pharmacological effects

Indexed keywords

CALPONIN; DEMETHYLICARITIN; DRUG METABOLITE; EPIMEDIUM EXTRACT; ICARIIN; ICARITIN; UNCLASSIFIED DRUG; ANTIINFLAMMATORY AGENT; FLAVONOID; HERBACEOUS AGENT;

ALZHEIMER DISEASE; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; BONE TISSUE; EPIMEDIUM; HEART PROTECTION; HERBA EPIMEDII; HUMAN; IMMUNITY; NEUROPROTECTION; NONHUMAN; OSSIFICATION; OSTEOPOROSIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REPRODUCTION; REVIEW; SEXUAL DYSFUNCTION; ANIMAL; CHEMISTRY; CHINESE MEDICINE; MEDICINAL PLANT; SEXUAL DYSFUNCTION, PHYSIOLOGICAL;

EPIMEDIUM;

ANIMALS; ANTI-INFLAMMATORY AGENTS; DRUGS, CHINESE HERBAL; FLAVONOIDS; HUMANS; MEDICINE, CHINESE TRADITIONAL; OSTEOPOROSIS; PLANTS, MEDICINAL; SEXUAL DYSFUNCTION, PHYSIOLOGICAL;

EID: 84924027908     PISSN: 00243205     EISSN: 18790631     Source Type: Journal    
DOI: 10.1016/j.lfs.2015.01.006     Document Type: Review

References (170)

1. H. Cao, Y. Ke, Y. Zhang, C.J. Zhang, W. Qian, and G.L. Zhang Icariin stimulates MC3T3-E1 cell proliferation and differentiation through up-regulation of bone morphogenetic protein-2 Int. J. Mol. Med. 29 2012 435 439
2. Y.F. Cao, R.R. He, J. Cao, J.X. Chen, T. Huang, and Y. Liu Drug-drug interactions potential of icariin and its intestinal metabolites via inhibition of intestinal UDP-glucuronosyltransferases Evid. Based Complement. Alternat. Med. 2012 395912
3. Q. Chang, G.N. Wang, Y. Li, L. Zhang, C. You, and Y. Zheng Oral absorption and excretion of icaritin, an aglycone and also active metabolite of prenylflavonoids from the Chinese medicine Herba Epimedii in rats Phytomedicine 19 2012 1024 1028
4. K.M. Chen, B.F. Ge, X.Y. Liu, P.H. Ma, M.B. Lu, and M.H. Bai Icariin inhibits the osteoclast formation induced by RANKL and macrophage-colony stimulating factor in mouse bone marrow culture Pharmazie 62 2007 388 391
5. K.M. Chen, B.F. Ge, H.P. Ma, X.Y. Liu, M.H. Bai, and Y. Wang Icariin, a flavonoid from the herb Epimedium enhances the osteogenic differentiation of rat primary bone marrow stromal cells Pharmazie 60 2005 939 942
6. K.M. Chen, H.P. Ma, B.F. Ge, X.Y. Liu, L.P. Ma, and M.H. Bai Icariin enhances the osteogenic differentiation of bone marrow stromal cells but has no effects on the differentiation of newborn calvarial osteoblasts of rats Pharmazie 62 2007 785 789
7. M. Chen, J. Hao, Q. Yang, and G. Li Effects of icariin on reproductive functions in male rats Molecules 19 2014 9502 9514
8. Y. Chen, J. Wang, X. Jia, X. Tan, and M. Hu Role of intestinal hydrolase in the absorption of prenylated flavonoids present in Yinyanghuo Molecules 16 2011 1336 1348
9. Y. Chen, Y.H. Zhao, X.B. Jia, and M. Hu Intestinal absorption mechanisms of prenylated flavonoids present in the heat-processed Epimedium koreanum nakai (Yin Yanghuo) Pharm. Res. 25 2008 2190 2199
10. China TPCoPR Pharmacopeia of the People's Republic of China Version 2010 2010 306 308
11. B.H. Chung, J.D. Kim, C.K. Kim, J.H. Kim, M.H. Won, and H.S. Lee Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells Biochem. Biophys. Res. Commun. 376 2008 404 408
12. J. Cui, M. Zhu, S. Zhu, G. Wang, Y. Xu, and D. Geng Inhibitory effect of icariin on Ti-induced inflammatory osteoclastogenesis J. Surg. Res. 2014
13. L. Cui, E. Sun, Z. Zhang, Q. Qian, X. Tan, and F. Xu Metabolite profiles of epimedin B in rats by ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry J. Agric. Food Chem. 61 2013 3589 3599
14. L. Cui, E. Sun, Z. Zhang, X. Tan, F. Xu, and X. Jia Metabolite profiles of epimedin C in rat plasma and bile by ultra-performance liquid chromatography coupled with quadrupole-TOF-MS Biomed. Chromatogr. 2014
15. M. Dell'Agli, G.V. Galli, E. Dal Cero, F. Belluti, R. Matera, and E. Zironi Potent inhibition of human phosphodiesterase-5 by icariin derivatives J. Nat. Prod. 71 2008 1513 1517
16. L. Ding, X.G. Liang, Y. Hu, D.Y. Zhu, and Y.J. Lou Involvement of p38 MAPK and reactive oxygen species in icariin-induced cardiomyocyte differentiation of murine embryonic stem cells in vitro Stem Cells Dev. 17 2008 751 760
17. L. Ding, X.G. Liang, D.Y. Zhu, and Y.J. Lou Icariin promotes expression of PGC-1alpha, PPARalpha, and NRF-1 during cardiomyocyte differentiation of murine embryonic stem cells in vitro Acta Pharmacol. Sin. 28 2007 1541 1549
18. J.J. Fan, L.G. Cao, T. Wu, D.X. Wang, D. Jin, and S. Jiang The dose-effect of icariin on the proliferation and osteogenic differentiation of human bone mesenchymal stem cells Molecules 16 2011 10123 10133
19. R. Feng, L. Feng, Z. Yuan, D. Wang, F. Wang, and B. Tan Icariin protects against glucocorticoid-induced osteoporosis in vitro and prevents glucocorticoid-induced osteocyte apoptosis in vivo Cell Biochem. Biophys. 67 2013 189 197
20. J.L. Geng, Y. Dai, Z.H. Yao, Z.F. Qin, X.L. Wang, and L. Qin Metabolites profile of Xian-Ling-Gu-Bao capsule, a traditional Chinese medicine prescription, in rats by ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry analysis J. Pharm. Biomed. Anal. 96 2014 90 103
21. J. Guo, F. Li, Q. Wu, Q. Gong, Y. Lu, and J. Shi Protective effects of icariin on brain dysfunction induced by lipopolysaccharide in rats Phytomedicine 17 2010 950 955
22. X.L. He, W.Q. Zhou, M.G. Bi, and G.H. Du Neuroprotective effects of icariin on memory impairment and neurochemical deficits in senescence-accelerated mouse prone 8 (SAMP8) mice Brain Res. 1334 2010 73 83
23. J. Hong, Z. Zhang, W. Lv, M. Zhang, C. Chen, and S. Yang Icaritin synergistically enhances the radiosensitivity of 4T1 breast cancer cells PLoS One 8 2013 e71347
24. T.P. Hsieh, S.Y. Sheu, J.S. Sun, and M.H. Chen Icariin inhibits osteoclast differentiation and bone resorption by suppression of MAPKs/NF-kappaB regulated HIF-1alpha and PGE(2) synthesis Phytomedicine 18 2011 176 185
25. T.P. Hsieh, S.Y. Sheu, J.S. Sun, M.H. Chen, and M.H. Liu Icariin isolated from Epimedium pubescens regulates osteoblasts anabolism through BMP-2, SMAD4, and Cbfa1 expression Phytomedicine 17 2010 414 423
26. J. Huang, L. Yuan, X. Wang, T.L. Zhang, and K. Wang Icaritin and its glycosides enhance osteoblastic, but suppress osteoclastic, differentiation and activity in vitro Life Sci. 81 2007 832 840
27. J.G. Huang, L. Pang, Z.R. Chen, and X.P. Tan Dual-delivery of vancomycin and icariin from an injectable calcium phosphate cement-release system for controlling infection and improving bone healing Mol. Med. Rep. 8 2013 1221 1227
28. J.H. Huang, W.J. Cai, X.M. Zhang, and Z.Y. Shen Icariin promotes self-renewal of neural stem cells: an involvement of extracellular regulated kinase signaling pathway Chin. J. Integr. Med. 20 2014 107 115
29. Z. Jiang, B. Hu, J. Wang, Q. Tang, Y. Tan, and J. Xiang Effect of icariin on cyclic GMP levels and on the mRNA expression of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in penile cavernosum J. Huazhong Univ. Sci. Technol. Med. Sci. 26 2006 460 462
30. F. Jin, Q.H. Gong, Y.S. Xu, L.N. Wang, H. Jin, and F. Li Icariin, a phosphodiesterase-5 inhibitor, improves learning and memory in APP/PS1 transgenic mice by stimulation of NO/cGMP signalling Int. J. Neuropsychopharmacol. 17 2014 871 881
31. M.S. Jin, S. Shi, Y. Zhang, Y. Yan, X.D. Sun, and W. Liu Icariin-mediated differentiation of mouse adipose-derived stem cells into cardiomyocytes Mol. Cell. Biochem. 344 2010 1 9
32. X. Jin, Z.H. Zhang, E. Sun, X.B. Tan, F.X. Zhu, and S.L. Li Preparation of icariside II-phospholipid complex and its absorption across Caco-2 cell monolayers Pharmazie 67 2012 293 298
33. H.K. Kang, S.B. Lee, H. Kwon, C.K. Sung, Y.I. Park, and M.S. Dong Peripubertal administration of icariin and icaritin advances pubertal development in female rats Biomol. Ther. (Seoul) 20 2012 189 195
34. H. Koizumi, J. Yu, R. Hashimoto, Y. Ouchi, and T. Okabe Involvement of androgen receptor in nitric oxide production induced by icariin in human umbilical vein endothelial cells FEBS Lett. 584 2010 2440 2444
35. C.J. Lee, Y.T. Wu, T.Y. Hsueh, L.C. Lin, and T.H. Tsai Pharmacokinetics and oral bioavailability of epimedin C after oral administration of epimedin C and Herba Epimedii extract in rats Biomed. Chromatogr. 28 2014 630 636
36. M.K. Lee, Y.J. Choi, S.H. Sung, D.I. Shin, J.W. Kim, and Y.C. Kim Antihepatotoxic activity of icariin, a major constituent of Epimedium koreanum Planta Med. 61 1995 523 526
37. B. Li, X. Duan, C. Xu, J. Wu, B. Liu, and Y. Du Icariin attenuates glucocorticoid insensitivity mediated by repeated psychosocial stress on an ovalbumin-induced murine model of asthma Int. Immunopharmacol. 19 2014 381 390
38. D. Li, T. Yuan, X. Zhang, Y. Xiao, R. Wang, and Y. Fan Icariin: a potential promoting compound for cartilage tissue engineering Osteoarthr. Cartil. 20 2012 1647 1656
39. F. Li, Q.H. Gong, Q. Wu, Y.F. Lu, and J.S. Shi Icariin isolated from Epimedium brevicornum Maxim attenuates learning and memory deficits induced by d-galactose in rats Pharmacol. Biochem. Behav. 96 2010 301 305
40. G.W. Li, Z. Xu, S.X. Chang, H. Nian, X.Y. Wang, and L.D. Qin Icariin prevents ovariectomy-induced bone loss and lowers marrow adipogenesis. Menopause 2014
41. L. Li, L. Peng, J. Miao, Y. Qiu, Y. Zhou, and X. Gao Icariin induces the expression of toll-like receptor 9 in ana-1 murine macrophages Phytother. Res. 25 2011 1732 1735
42. L. Li, H.J. Tsai, L. Li, and X.M. Wang Icariin inhibits the increased inward calcium currents induced by amyloid-beta(25-35) peptide in CA1 pyramidal neurons of neonatal rat hippocampal slice Am. J. Chin. Med. 38 2010 113 125
43. L. Li, Q.X. Zhou, and J.S. Shi Protective effects of icariin on neurons injured by cerebral ischemia/reperfusion Chin. Med. J. 118 2005 1637 1643
44. S. Li, P. Dong, J. Wang, J. Zhang, J. Gu, and X. Wu Icariin, a natural flavonol glycoside, induces apoptosis in human hepatoma SMMC-7721 cells via a ROS/JNK-dependent mitochondrial pathway Cancer Lett. 298 2010 222 230
45. W. Li, M. Wang, L. Wang, S. Ji, J. Zhang, and C. Zhang Icariin synergizes with arsenic trioxide to suppress human hepatocellular carcinoma Cell Biochem. Biophys. 68 2014 427 436
46. W.W. Li, X.M. Gao, X.M. Wang, H. Guo, and B.L. Zhang Icariin inhibits hydrogen peroxide-induced toxicity through inhibition of phosphorylation of JNK/p38 MAPK and p53 activity Mutat. Res. 708 2011 1 10
47. X.F. Li, H. Xu, Y.J. Zhao, D.Z. Tang, G.H. Xu, and J. Holz Icariin augments bone formation and reverses the phenotypes of osteoprotegerin-deficient mice through the activation of Wnt/beta-catenin-BMP signaling Evid. Based Complement. Alternat. Med. 2013 652317
48. Y. Li, J. Duan, T. Guo, W. Xie, S. Yan, and B. Li In vivo pharmacokinetics comparisons of icariin, emodin and psoralen from gan-kang granules and extracts of herba Epimedii, Nepal dock root, Ficus hirta yahl J. Ethnopharmacol. 124 2009 522 529
49. Y. Li, J. Jiang, Y. He, R. Jiang, J. Liu, and Z. Fan Icariin combined with breviscapine improves the erectile function of spontaneously hypertensive rats J. Sex Med. 2014
50. Y. Li, Z. Xiong, and F. Li Determination of epimedin C in rat plasma by reversed-phase high-performance chromatography after oral administration of Herba Epimedii extract J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 821 2005 235 239
51. Y.C. Li, X.S. Ding, H.M. Li, and C. Zhang Icariin attenuates high glucose-induced type IV collagen and fibronectin accumulation in glomerular mesangial cells by inhibiting transforming growth factor-beta production and signalling through G protein-coupled oestrogen receptor 1 Clin. Exp. Pharmacol. Physiol. 40 2013 635 643
52. Z. Li, F.S. Cheung, J. Zheng, T. Chan, L. Zhu, and F. Zhou Interaction of the bioactive flavonol, icariin, with the essential human solute carrier transporters J. Biochem. Mol. Toxicol. 28 2014 91 97
53. Z.H. Li, D. Alex, S.O. Siu, I.K. Chu, J. Renn, and C. Winkler Combined in vivo imaging and omics approaches reveal metabolism of icaritin and its glycosides in zebrafish larvae Mol. BioSyst. 7 2011 2128 2138
54. D.L. Liang, and S.L. Zheng Effects of icaritin on cytochrome P450 enzymes in rats Pharmazie 69 2014 301 305
55. W. Liang, M. Lin, X. Li, C. Li, B. Gao, and H. Gan Icariin promotes bone formation via the BMP-2/Smad4 signal transduction pathway in the hFOB 1.19 human osteoblastic cell line Int. J. Mol. Med. 30 2012 889 895
56. C.C. Lin, L.T. Ng, F.F. Hsu, D.E. Shieh, and L.C. Chiang Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth Clin. Exp. Pharmacol. Physiol. 31 2004 65 69
57. B. Liu, H. Zhang, C. Xu, G. Yang, J. Tao, and J. Huang Neuroprotective effects of icariin on corticosterone-induced apoptosis in primary cultured rat hippocampal neurons Brain Res. 1375 2011 59 67
58. J. Liu, and Y.J. Lou Determination of icariin and metabolites in rat serum by capillary zone electrophoresis: rat pharmacokinetic studies after administration of icariin J. Pharm. Biomed. Anal. 36 2004 365 370
59. J. Liu, H. Ye, and Y. Lou Determination of rat urinary metabolites of icariin in vivo and estrogenic activities of its metabolites on MCF-7 cells Pharmazie 60 2005 120 125
60. K. Liu, L. Wang, Y. Li, B. Yang, C. Du, and Y. Wang Preparation, pharmacokinetics, and tissue distribution properties of icariin-loaded stealth solid lipid nanoparticles in mice Chin. Herb. Med. 4 2012 170 174
61. M. Liu, H. Liu, X. Lu, C. Li, Z. Xiong, and F. Li Simultaneous determination of icariin, icariside II and osthole in rat plasma after oral administration of the extract of Gushudan (a Chinese compound formulation) by LC-MS/MS J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 860 2007 113 120
62. M. Liu, S. Zhao, Z. Wang, H. Wang, X. Shi, and Z. Lu Tentative identification of new metabolites of epimedin C by liquid chromatography-mass spectrometry J. Sep. Sci. 34 2011 3200 3207
63. M. Liu, C. Zhong, R.X. He, and L.F. Chen Icariin associated with exercise therapy is an effective treatment for postmenopausal osteoporosis Chin. Med. J. 125 2012 1784 1789
64. M.H. Liu, J.S. Sun, S.W. Tsai, S.Y. Sheu, and M.H. Chen Icariin protects murine chondrocytes from lipopolysaccharide-induced inflammatory responses and extracellular matrix degradation Nutr. Res. 30 2010 57 65
65. T. Liu, H. Xin, W.R. Li, F. Zhou, G.Y. Li, and Y.Q. Gong Effects of icariin on improving erectile function in streptozotocin-induced diabetic rats J. Sex Med. 8 2011 2761 2772
66. W.J. Liu, Z.C. Xin, H. Xin, Y.M. Yuan, L. Tian, and Y.L. Guo Effects of icariin on erectile function and expression of nitric oxide synthase isoforms in castrated rats Asian J. Androl. 7 2005 381 388
67. Z.Q. Liu, X.Y. Luo, Y.X. Sun, W. Wu, C.M. Liu, and Z.Q. Liu The antioxidative effect of icariin in human erythrocytes against free-radical-induced haemolysis J. Pharm. Pharmacol. 56 2004 1557 1562
68. Y. Luo, J. Nie, Q.H. Gong, Y.F. Lu, Q. Wu, and J.S. Shi Protective effects of icariin against learning and memory deficits induced by aluminium in rats Clin. Exp. Pharmacol. Physiol. 34 2007 792 795
69. X.C. Lv, L.J. Bi, Y. Jiang, and X. Wang Effects of icariin on the alkaline phosphatase activity of human periodontal ligament cells inhibited by lipopolysaccharide Mol. Med. Rep. 8 2013 1411 1415
70. H. Ma, X. He, Y. Yang, M. Li, D. Hao, and Z. Jia The genus Epimedium: an ethnopharmacological and phytochemical review J. Ethnopharmacol. 134 2011 519 541
71. H.P. Ma, L.G. Ming, B.F. Ge, Y.K. Zhai, P. Song, and C.J. Xian Icariin is more potent than genistein in promoting osteoblast differentiation and mineralization in vitro J. Cell. Biochem. 112 2011 916 923
72. X.N. Ma, J. Zhou, B.F. Ge, P. Zhen, H.P. Ma, and W.G. Shi Icariin induces osteoblast differentiation and mineralization without dexamethasone in vitro Planta Med. 79 2013 1501 1508
73. F.H. Meng, Y.B. Li, Z.L. Xiong, Z.M. Jiang, and F.M. Li Osteoblastic proliferative activity of Epimedium brevicornum Maxim Phytomedicine 12 2005 189 193
74. L.G. Ming, K.M. Chen, and C.J. Xian Functions and action mechanisms of flavonoids genistein and icariin in regulating bone remodeling J. Cell. Physiol. 228 2013 513 521
75. S.K. Mok, W.F. Chen, W.P. Lai, P.C. Leung, X.L. Wang, and X.S. Yao Icariin protects against bone loss induced by oestrogen deficiency and activates oestrogen receptor-dependent osteoblastic functions in UMR 106 cells Br. J. Pharmacol. 159 2010 939 949
76. Y. Nan, X. Zhang, G. Yang, J. Xie, Z. Lu, and W. Wang Icariin stimulates the proliferation of rat Sertoli cells in an ERK1/2-dependent manner in vitro Andrologia 2012
77. H. Nian, M.H. Ma, S.S. Nian, and L.L. Xu Antiosteoporotic activity of icariin in ovariectomized rats Phytomedicine 16 2009 320 326
78. J. Nie, Y. Luo, X.N. Huang, Q.H. Gong, Q. Wu, and J.S. Shi Icariin inhibits beta-amyloid peptide segment 25-35 induced expression of beta-secretase in rat hippocampus Eur. J. Pharmacol. 626 2010 213 218
79. H. Ning, Z.C. Xin, G. Lin, L. Banie, T.F. Lue, and C.S. Lin Effects of icariin on phosphodiesterase-5 activity in vitro and cyclic guanosine monophosphate level in cavernous smooth muscle cells Urology 68 2006 1350 1354
80. Y. Pan, Y. Hong, Q.Y. Zhang, and L.D. Kong Impaired hypothalamic insulin signaling in CUMS rats: restored by icariin and fluoxetine through inhibiting CRF system Psychoneuroendocrinology 38 2013 122 134
81. Y. Pan, L. Kong, X. Xia, W. Zhang, Z. Xia, and F. Jiang Antidepressant-like effect of icariin and its possible mechanism in mice Pharmacol. Biochem. Behav. 82 2005 686 694
82. Y. Pan, L.D. Kong, Y.C. Li, X. Xia, H.F. Kung, and F.X. Jiang Icariin from Epimedium brevicornum attenuates chronic mild stress-induced behavioral and neuroendocrinological alterations in male Wistar rats Pharmacol. Biochem. Behav. 87 2007 130 140
83. Y. Pan, F.M. Wang, L.Q. Qiang, D.M. Zhang, and L.D. Kong Icariin attenuates chronic mild stress-induced dysregulation of the LHPA stress circuit in rats Psychoneuroendocrinology 35 2010 272 283
84. Y. Pan, W.Y. Zhang, X. Xia, and L.D. Kong Effects of icariin on hypothalamic-pituitary-adrenal axis action and cytokine levels in stressed Sprague-Dawley rats Biol. Pharm. Bull. 29 2006 2399 2403
85. Z. Pei, F. Zhang, Z. Niu, and S. Shi Effect of icariin on cell proliferation and the expression of bone resorption/formation-related markers in human periodontal ligament cells Mol. Med. Rep. 8 2013 1499 1504
86. M.Y. Qi, C. Kai, H.R. Liu, Y.H. Su, and S.Q. Yu Protective effect of icariin on the early stage of experimental diabetic nephropathy induced by streptozotocin via modulating transforming growth factor beta1 and type IV collagen expression in rats J. Ethnopharmacol. 138 2011 731 736
87. Q. Qian, S.L. Li, E. Sun, K.R. Zhang, X.B. Tan, and Y.J. Wei Metabolite profiles of icariin in rat plasma by ultra-fast liquid chromatography coupled to triple-quadrupole/time-of-flight mass spectrometry J. Pharm. Biomed. Anal. 66 2012 392 398
88. L. Qin, T. Han, Q. Zhang, D. Cao, H. Nian, and K. Rahman Antiosteoporotic chemical constituents from Er-Xian Decoction, a traditional Chinese herbal formula J. Ethnopharmacol. 118 2008 271 279
89. K.Y. Rhew, and Y. Han Immunoadjuvant activity of icariin that induces Th1-type antibody in mice Arch. Pharm. Res. 35 2012 1685 1691
90. D. Sha, L. Li, L. Ye, R. Liu, and Y. Xu Icariin inhibits neurotoxicity of beta-amyloid by upregulating cocaine-regulated and amphetamine-regulated transcripts Neuroreport 20 2009 1564 1567
91. P. Shen, S.P. Wong, J. Li, and E.L. Yong Simple and sensitive liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of five Epimedium prenylflavonoids in rat sera J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 877 2009 71 78
92. P. Shen, S.P. Wong, and E.L. Yong Sensitive and rapid method to quantify icaritin and desmethylicaritin in human serum using gas chromatography-mass spectrometry J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 857 2007 47 52
93. D.B. Shi, X.X. Li, H.T. Zheng, D.W. Li, G.X. Cai, and J.J. Peng Icariin-mediated inhibition of NF-kappaB activity enhances the in vitro and in vivo antitumour effect of 5-fluorouracil in colorectal cancer Cell Biochem. Biophys. 69 2014 523 530
94. A.W. Shindel, Z.C. Xin, G. Lin, T.M. Fandel, Y.C. Huang, and L. Banie Erectogenic and neurotrophic effects of icariin, a purified extract of horny goat weed (Epimedium spp.) in vitro and in vivo J. Sex Med. 7 2010 1518 1528
95. L. Song, J. Zhao, X. Zhang, H. Li, and Y. Zhou Icariin induces osteoblast proliferation, differentiation and mineralization through estrogen receptor-mediated ERK and JNK signal activation Eur. J. Pharmacol. 714 2013 15 22
96. Y.H. Song, H. Cai, N. Gu, C.F. Qian, S.P. Cao, and Z.M. Zhao Icariin attenuates cardiac remodelling through down-regulating myocardial apoptosis and matrix metalloproteinase activity in rats with congestive heart failure J. Pharm. Pharmacol. 63 2011 541 549
97. L. Sun, W. Chen, L. Qu, J. Wu, and J. Si Icaritin reverses multidrug resistance of HepG2/ADR human hepatoma cells via downregulation of MDR1 and P-glycoprotein expression Mol. Med. Rep. 8 2013 1883 1887
98. P. Sun, Y. Liu, X. Deng, C. Yu, N. Dai, and X. Yuan An inhibitor of cathepsin K, icariin suppresses cartilage and bone degradation in mice of collagen-induced arthritis Phytomedicine 20 2013 975 979
99. X. Sun, X. Sun, X. Jin, X. Zhang, C. Liu, and L. Lei Icariin induces mouse embryonic stem cell differentiation into beating functional cardiomyocytes Mol. Cell. Biochem. 349 2011 117 123
100. F. Tao, C. Qian, W. Guo, Q. Luo, Q. Xu, and Y. Sun Inhibition of Th1/Th17 responses via suppression of STAT1 and STAT3 activation contributes to the amelioration of murine experimental colitis by a natural flavonoid glucoside icariin Biochem. Pharmacol. 85 2013 798 807
101. C. Tohda, and A. Nagata Epimedium koreanum extract and its constituent icariin improve motor dysfunction in spinal cord injury Evid. Based Complement. Alternat. Med. 2012 2012 731208
102. T. Urano, and C. Tohda Icariin improves memory impairment in Alzheimer's disease model mice (5xFAD) and attenuates amyloid beta-induced neurite atrophy Phytother. Res. 24 2010 1658 1663
103. F. Wang, Z. Liu, S. Lin, H. Lu, and J. Xu Icariin enhances the healing of rapid palatal expansion induced root resorption in rats Phytomedicine 19 2012 1035 1041
104. L. Wang, L. Zhang, Z.B. Chen, J.Y. Wu, X. Zhang, and Y. Xu Icariin enhances neuronal survival after oxygen and glucose deprivation by increasing SIRT1 Eur. J. Pharmacol. 609 2009 40 44
105. Q. Wang, J. Hao, J. Pu, L. Zhao, Z. Lu, and J. Hu Icariin induces apoptosis in mouse MLTC-10 Leydig tumor cells through activation of the mitochondrial pathway and down-regulation of the expression of piwil4 Int. J. Oncol. 39 2011 973 980
106. X. Wang, J. Li, L. Qian, X.F. Zang, S.Y. Zhang, and X.Y. Wang Icariin promotes histone acetylation and attenuates post-stroke cognitive impairment in the central cholinergic circuits of mice Neuroscience 236 2013 281 288
107. Y. Wang, H. Dong, M. Zhu, Y. Ou, J. Zhang, and H. Luo Icariin exerts negative effects on human gastric cancer cell invasion and migration by vasodilator-stimulated phosphoprotein via Rac1 pathway Eur. J. Pharmacol. 635 2010 40 48
108. 2 in vitro Pharmacol. Res. 52 2005 174 182
109. H. Wei, L. Zili, C. Yuanlu, Y. Biao, L. Cheng, and W. Xiaoxia Effect of icariin on bone formation during distraction osteogenesis in the rabbit mandible Int. J. Oral Maxillofac. Surg. 40 2011 413 418
110. Y. Wei, P. Li, H. Fan, E. Sun, C. Wang, and L. Shu Metabolite profiling of four major flavonoids of Herba Epimedii in zebrafish Molecules 17 2012 420 432
111. Y. Wo, D. Zhu, Y. Yu, and Y. Lou Involvement of NF-kappaB and AP-1 activation in icariin promoted cardiac differentiation of mouse embryonic stem cells Eur. J. Pharmacol. 586 2008 59 66
112. Y.B. Wo, D.Y. Zhu, Y. Hu, Z.Q. Wang, J. Liu, and Y.J. Lou Reactive oxygen species involved in prenylflavonoids, icariin and icaritin, initiating cardiac differentiation of mouse embryonic stem cells J. Cell. Biochem. 103 2008 1536 1550
113. S.P. Wong, P. Shen, L. Lee, J. Li, and E.L. Yong Pharmacokinetics of prenylflavonoids and correlations with the dynamics of estrogen action in sera following ingestion of a standardized Epimedium extract J. Pharm. Biomed. Anal. 50 2009 216 223
114. B. Wu, Y. Chen, J. Huang, Y. Ning, Q. Bian, and Y. Shan Icariin improves cognitive deficits and activates quiescent neural stem cells in aging rats J. Ethnopharmacol. 142 2012 746 753
115. C. Wu, J. Zhang, T. Zhou, B. Guo, Y. Wang, and J. Hou Simultaneous determination of seven flavonoids in dog plasma by ultra-performance liquid chromatography-tandem mass spectrometry and its application to a bioequivalence study of bioactive components in Herba Epimedii and Er-Xian Decoction J. Pharm. Biomed. Anal. 54 2011 186 191
116. J. Wu, J. Du, C. Xu, J. Le, Y. Xu, and B. Liu Icariin attenuates social defeat-induced down-regulation of glucocorticoid receptor in mice Pharmacol. Biochem. Behav. 98 2011 273 278
117. L. Xia, Y. Li, Z. Zhou, Y. Dai, H. Liu, and H. Liu Icariin delivery porous PHBV scaffolds for promoting osteoblast expansion in vitro Mater. Sci. Eng. 33 2013 3545 3552
118. D. Xiao-Hong, X. Chang-Qin, H. Jian-Hua, Z. Wen-Jiang, and S. Bing Icariin delays homocysteine-induced endothelial cellular senescence involving activation of the PI3K/AKT-eNOS signaling pathway Pharm. Biol. 51 2013 433 440
119. H.H. Xiao, C.Y. Fung, S.K. Mok, K.C. Wong, M.X. Ho, and X.L. Wang Flavonoids from Herba epimedii selectively activate estrogen receptor alpha (ERalpha) and stimulate ER-dependent osteoblastic functions in UMR-106 cells J. Steroid Biochem. Mol. Biol. 143C 2014 141 151
120. Q. Xiao, A. Chen, and F. Guo Effects of icariin on expression of OPN mRNA and type I collagen in rat osteoblasts in vitro J. Huazhong Univ. Sci. Technol. Med. Sci. 25 2005 690 692
121. H. Xin, F. Zhou, T. Liu, G.Y. Li, J. Liu, and Z.Z. Gao Icariin ameliorates streptozotocin-induced diabetic retinopathy in vitro and in vivo Int. J. Mol. Sci. 13 2012 866 878
122. Z.C. Xin, E.K. Kim, C.S. Lin, W.J. Liu, L. Tian, and Y.M. Yuan Effects of icariin on cGMP-specific PDE5 and cAMP-specific PDE4 activities Asian J. Androl. 5 2003 15 18
123. C.Q. Xu, J.J. Le, X.H. Duan, W.J. Du, B.J. Liu, and J.F. Wu Molecular mechanism of icariin on rat asthmatic model Chin. Med. J. 124 2011 2899 2906
124. C.Q. Xu, B.J. Liu, J.F. Wu, Y.C. Xu, X.H. Duan, and Y.X. Cao Icariin attenuates LPS-induced acute inflammatory responses: involvement of PI3K/Akt and NF-kappaB signaling pathway Eur. J. Pharmacol. 642 2010 146 153
125. H.B. Xu, and Z.Q. Huang Icariin enhances endothelial nitric-oxide synthase expression on human endothelial cells in vitro Vasc. Pharmacol. 47 2007 18 24
126. H.B. Xu, and Z.Q. Huang Vasorelaxant effects of icariin on isolated canine coronary artery J. Cardiovasc. Pharmacol. 49 2007 207 213
127. R.X. Xu, Q. Wu, Y. Luo, Q.H. Gong, L.M. Yu, and X.N. Huang Protective effects of icariin on cognitive deficits induced by chronic cerebral hypoperfusion in rats Clin. Exp. Pharmacol. Physiol. 36 2009 810 815
128. S.F. Xu, T. Jin, Y.F. Lu, L.S. Li, J. Liu, and J.S. Shi Effect of icariin on UDP-glucuronosyltransferases in mouse liver Planta Med. 80 2014 387 392
129. L. Xue, L. Jiao, Y. Wang, Y. Nie, T. Han, and Y. Jiang Effects and interaction of icariin, curculigoside, and berberine in er-xian decoction, a traditional Chinese medicinal formula, on osteoclastic bone resorption Evid. Based Complement. Alternat. Med. 2012 490843
130. L. Xue, Y. Wang, Y. Jiang, T. Han, Y. Nie, and L. Zhao Comparative effects of er-xian decoction, Epimedium herbs, and icariin with estrogen on bone and reproductive tissue in ovariectomized rats Evid. Based Complement. Alternat. Med. 2012 241416
131. C.R. Yang, and J.D. Chen Preparation and biological evaluation of chitosan-collagen-icariin composite scaffolds for neuronal regeneration Neurol. Sci. 34 2013 941 947
132. L. Yang, D. Lu, J. Guo, X. Meng, G. Zhang, and F. Wang Icariin from Epimedium brevicornum Maxim promotes the biosynthesis of estrogen by aromatase (CYP19) J. Ethnopharmacol. 145 2013 715 721
133. L. Yang, Z. Yu, H. Qu, and M. Li Comparative effects of hispidulin, genistein, and icariin with estrogen on bone tissue in ovariectomized rats Cell Biochem. Biophys. 2014
134. Y. Ye, G.X. Chou, H. Wang, J.H. Chu, and Z.L. Yu Flavonoids, apigenin and icariin exert potent melanogenic activities in murine B16 melanoma cells Phytomedicine 18 2010 32 35
135. X.X. Yin, Z.Q. Chen, Z.J. Liu, Q.J. Ma, and G.T. Dang Icariine stimulates proliferation and differentiation of human osteoblasts by increasing production of bone morphogenetic protein 2 Chin. Med. J. 120 2007 204 210
136. K.W. Zeng, H. Fu, G.X. Liu, and X.M. Wang Icariin attenuates lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting TAK1/IKK/NF-kappaB and JNK/p38 MAPK pathways Int. Immunopharmacol. 10 2010 668 678
137. K.W. Zeng, H. Ko, H.O. Yang, and X.M. Wang Icariin attenuates beta-amyloid-induced neurotoxicity by inhibition of tau protein hyperphosphorylation in PC12 cells Neuropharmacology 59 2010 542 550
138. L. Zeng, W. Wang, X.F. Rong, Y. Zhong, P. Jia, and G.Q. Zhou Chondroprotective effects and multi-target mechanisms of icariin in IL-1 beta-induced human SW 1353 chondrosarcoma cells and a rat osteoarthritis model Int. Immunopharmacol. 18 2014 175 181
139. Y.K. Zhai, X.Y. Guo, B.F. Ge, P. Zhen, X.N. Ma, and J. Zhou Icariin stimulates the osteogenic differentiation of rat bone marrow stromal cells via activating the PI3K-AKT-eNOS-NO-cGMP-PKG Bone 66C 2014 189 198
140. C. Zhang, Y.R. Shi, X.R. Liu, Y.C. Cao, J.L. Tian, and Z.Y. Jia The regulatory role of icariin on apoptosis in mouse preimplantation embryos with reduced microRNA-21 Theriogenology 82 2014 461 468
141. D. Zhang, J. Zhang, C. Fong, X. Yao, and M. Yang Herba epimedii flavonoids suppress osteoclastic differentiation and bone resorption by inducing G2/M arrest and apoptosis Biochimie 94 2012 2514 2522
142. D.C. Zhang, J.L. Liu, Y.B. Ding, J.G. Xia, and G.Y. Chen Icariin potentiates the antitumor activity of gemcitabine in gallbladder cancer by suppressing NF-kappaB Acta Pharmacol. Sin. 34 2013 301 308
143. D.W. Zhang, Y. Cheng, N.L. Wang, J.C. Zhang, M.S. Yang, and X.S. Yao Effects of total flavonoids and flavonol glycosides from Epimedium koreanum Nakai on the proliferation and differentiation of primary osteoblasts Phytomedicine 15 2008 55 61
144. G. Zhang, L. Qin, and Y. Shi Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a 24-month randomized, double-blind and placebo-controlled trial J. Bone Miner. Res. 22 2007 1072 1079
145. J. Zhang, Y. Li, J. Sun, C. Liu, and D. Zhang Synergistic or antagonistic effect of MTE plus TF or icariin from Epimedium koreanum on the proliferation and differentiation of primary osteoblasts in vitro Biol. Trace Elem. Res. 143 2011 1746 1757
146. L. Zhang, S. Huang, Y. Chen, Z. Wang, E. Li, and Y. Xu Icariin inhibits hydrogen peroxide-mediated cytotoxicity by up-regulating sirtuin type 1-dependent catalase and peroxiredoxin Basic Clin. Pharmacol. Toxicol. 107 2010 899 905
147. L. Zhang, C. Shen, J. Chu, R. Zhang, Y. Li, and L. Li Icariin decreases the expression of APP and BACE-1 and reduces the beta-amyloid burden in an APP transgenic mouse model of Alzheimer's disease Int. J. Biol. Sci. 10 2014 181 191
148. L. Zhang, X. Zhang, K.F. Li, D.X. Li, Y.M. Xiao, and Y.J. Fan Icariin promotes extracellular matrix synthesis and gene expression of chondrocytes in vitro Phytother. Res. 26 2012 1385 1392
149. Q. Zhang, H. Li, S. Wang, M. Liu, Y. Feng, and X. Wang Icariin protects rat cardiac H9c2 cells from apoptosis by inhibiting endoplasmic reticulum stress Int. J. Mol. Sci. 14 2013 17845 17860
150. W.P. Zhang, X.J. Bai, X.P. Zheng, X.L. Xie, and Z.Y. Yuan Icariin attenuates the enhanced prothrombotic state in atherosclerotic rabbits independently of its lipid-lowering effects Planta Med. 79 2013 731 736
151. X. Zhang, Y. Guo, D.X. Li, R. Wang, H.S. Fan, and Y.M. Xiao The effect of loading icariin on biocompatibility and bioactivity of porous beta-TCP ceramic J. Mater. Sci. Mater. Med. 22 2011 371 379
152. X. Zhang, T. Liu, Y. Huang, D. Wismeijer, and Y. Liu Icariin: does it have an osteoinductive potential for bone tissue engineering? Phytother. Res. 28 2014 498 509
153. Y. Zhang, Q.S. Wang, Y.L. Cui, F.C. Meng, and K.M. Lin Changes in the intestinal absorption mechanism of icariin in the nanocavities of cyclodextrins Int. J. Nanomedicine 7 2012 4239 4249
154. Y. Zhang, Y. Wei, Z. Zhu, W. Gong, X. Liu, and Q. Hou Icariin enhances radiosensitivity of colorectal cancer cells by suppressing NF-kappaB activity Cell Biochem. Biophys. 69 2014 303 310
155. Z.B. Zhang, and Q.T. Yang The testosterone mimetic properties of icariin Asian J. Androl. 8 2006 601 605
156. F. Zhao, Y.Z. Tang, and Z.Q. Liu Protective effect of icariin on DNA against radical-induced oxidative damage J. Pharm. Pharmacol. 59 2007 1729 1732
157. H. Zhao, M. Fan, L. Fan, J. Sun, and D. Guo Liquid chromatography-tandem mass spectrometry analysis of metabolites in rats after administration of prenylflavonoids from Epimediums J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 878 2010 1113 1124
158. J. Zhao, S. Ohba, Y. Komiyama, M. Shinkai, U.I. Chung, and T. Nagamune Icariin: a potential osteoinductive compound for bone tissue engineering Tissue Eng. A 16 2010 233 243
159. J. Zhao, S. Ohba, M. Shinkai, U.I. Chung, and T. Nagamune Icariin induces osteogenic differentiation in vitro in a BMP- and Runx2-dependent manner Biochem. Biophys. Res. Commun. 369 2008 444 448
160. D. Zheng, S. Peng, S.H. Yang, Z.W. Shao, C. Yang, and Y. Feng The beneficial effect of icariin on bone is diminished in osteoprotegerin-deficient mice Bone 51 2012 85 92
161. M. Zheng, L. Qu, and Y. Lou Effects of icariin combined with Panax notoginseng saponins on ischemia reperfusion-induced cognitive impairments related with oxidative stress and CA1 of hippocampal neurons in rat Phytother. Res. 22 2008 597 604
162. H. Zhou, Y. Yuan, Y. Liu, W. Deng, J. Zong, and Z.Y. Bian Icariin attenuates angiotensin II-induced hypertrophy and apoptosis in H9c2 cardiomyocytes by inhibiting reactive oxygen species-dependent JNK and p38 pathways Exp. Ther. Med. 7 2014 1116 1122
163. J. Zhou, Y. Chen, Y. Wang, X. Gao, D. Qu, and C. Liu A comparative study on the metabolism of Epimedium koreanum Nakai-prenylated flavonoids in rats by an intestinal enzyme (lactase phlorizin hydrolase) and intestinal flora Molecules 19 2013 177 203
164. L. Zhou, Y. Huang, Y. Zhang, Q. Zhao, B. Zheng, and Y. Lou mGluR5 stimulating Homer-PIKE formation initiates icariin induced cardiomyogenesis of mouse embryonic stem cells by activating reactive oxygen species Exp. Cell Res. 319 2013 1505 1514
165. L. Zhou, B. Zheng, L. Tang, Y. Huang, and D. Zhu Involvement of PIKE in icariin induced cardiomyocyte differentiation from murine embryonic stem cells Pharmazie 69 2014 198 202
166. D. Zhu, L. Qu, X. Zhang, and Y. Lou Icariin-mediated modulation of cell cycle and p53 during cardiomyocyte differentiation in embryonic stem cells Eur. J. Pharmacol. 514 2005 99 110
167. D.Y. Zhu, R. Cui, Y.Y. Zhang, H. Li, L.M. Zhou, and Y.J. Lou Involvement of ubiquitin-proteasome system in icariin-induced cardiomyocyte differentiation of embryonic stem cells using two-dimensional gel electrophoresis J. Cell. Biochem. 112 2011 3343 3353
168. D.Y. Zhu, and Y.J. Lou Inducible effects of icariin, icaritin, and desmethylicaritin on directional differentiation of embryonic stem cells into cardiomyocytes in vitro Acta Pharmacol. Sin. 26 2005 477 485
169. D.Y. Zhu, and Y.J. Lou Icariin-mediated expression of cardiac genes and modulation of nitric oxide signaling pathway during differentiation of mouse embryonic stem cells into cardiomyocytes in vitro Acta Pharmacol. Sin. 27 2006 311 320
170. H.R. Zhu, Z.Y. Wang, X.L. Zhu, X.X. Wu, E.G. Li, and Y. Xu Icariin protects against brain injury by enhancing SIRT1-dependent PGC-1alpha expression in experimental stroke Neuropharmacology 59 2010 70 76