AJPS  Vol.4 No.5 , May 2013
Towards Application of Bioactive Natural Products Containing Isoprenoids for the Regulation of HMG-CoA Reductase—A Review
Abstract: Recognition of the biological properties of numerous “natural products” has fueled the current focus of this field, namely, the search for new drugs, antibiotics, insecticides, and herbicides. Based on their biosynthetic origins, natural products can be divided into three major groups: the isoprenoids, alkaloids, and phenolic compounds. Isoprenoids are structurally the most diverse group of secondary natural metabolites with different roles in the growth, development, and reproduction of a diverse range of prokaryotic and eukaryotes cells. Mevalonate and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways are known to be responsible for biosynthesis of numerous isoprenoids. HMG-CoA reductase is a rate-determining enzyme in mevalonate pathway, producing intermediates such as farnesyl and geranylgeranyl pyrophosphates, which lead to by-products such as cholesterol. Earlier studies have demonstrated that the inhibition of HMG-CoA reductase is one of the most effective approaches for treating hypercholesterolemia and eventually cardiovascular disease (CVD). Statins are HMG-CoA reductase inhibitors and the most prescribed group of drugs worldwide in treating hypercholesterolemia; however the application of this group of drugs may be expensive and has side effects including rashes and gastrointestinal symptoms. For these reasons, there is an important need to examine the viability of natural products as an alternative to statin treatment. This article is a review of different aforementioned areas with a focus on isoprenoids that can be used for the regulation of HMG-CoA reductase.
Cite this paper: S. Pakpour, "Towards Application of Bioactive Natural Products Containing Isoprenoids for the Regulation of HMG-CoA Reductase—A Review," American Journal of Plant Sciences, Vol. 4 No. 5, 2013, pp. 1116-1126. doi: 10.4236/ajps.2013.45138.

[1]   C. C. Correll, L. Ng and P. A. Edwards, “Identification of Farnesolas the Nonsterol Derivative of Mevalonic Acid Required for the Accelerated Degradation of 3-Hydroxy-3- Methylglutaryl-Coenzyme A Reductase,” Journal of Biological Chemistry, Vol. 269, No. 7, 1994, pp. 17390- 17393.

[2]   S. A. Holstein and R. J. Hohl, “Isoprenoids: Remarkable Diversity of Form and Function,” Lipids, Vol. 39, No. 4, 2004, pp. 293-309. doi:10.1007/s11745-004-1233-3

[3]   Y. G. Lin, M. A. Vermeer and E. A. Trautwein, “Triterpenic Acids Present in Hawthorn Lower Plasma Cholesterol by Inhibiting Intestinal ACAT Activity in Hamsters,” Evidence-Based Complementary and Alternative Medicine, Vol. 2011, 2011, Article ID 801272. doi:10.1093/ecam/nep007

[4]   P. M. Dewick, “Medicinal Natural Products,” John Wiley & Sons, Chichester, 2009. doi:10.1002/9780470742761

[5]   P. A. Edwards, “Sterols and Isoprenoids: Signaling Molecules Derived from the Cholesterol Biosynthetic Pathway,” Annual Review of Biochemistry, Vol. 69, 1999, pp. 157-185. doi:10.1146/annurev.biochem.68.1.157

[6]   T. Kuwabara, K. H. Han, N. Hashimoto, H. Yamauchi, K. Shimada, M. Sekikawa and M. Fukushima, “Tartary Buckwheat Sprout Powder Lowers Plasma Cholesterol Level in Rats,” Journal of Nutritional Science and Vitaminology. Vol. 53, No. 6, 2007, pp. 501-507. doi:10.3177/jnsv.53.501

[7]   B. A. Stermer, G. M. Bianchini and K. L. Korth, “Regulation of HMG-COA Reductase Activity in Plants,” Journal of Lipid Research, Vol. 35, No. 7, 1994, pp. 1133- 1140.

[8]   S. C. Hashimoto, A. Drevon, D. B. Weinstein, J. S. Bernett, S. Dayton and D. Steinberg., “Activity of Acyl-CoA- Cholesterol Acyltransferaseand 3-Hydroxy-3-Methylglutaryl-CoA Reductase in Subfractions of Hepatic Microsomes Enriched with Cholesterol,” Biochimica Et BiophysicaActa, Vol. 754, No. 2, 1983, pp. 126-133. doi:10.1016/0005-2760(83)90153-4

[9]   E. Cordoba, M. Salmi and P. Leon, “Unravellingthe Regulatory Mechanisms that Modulate the MEP Pathway in Higher Plants,” Journal of Experimental Botany, Vol. 60, No. 10, 2009, pp. 2933-2943. doi:10.1093/jxb/erp190

[10]   Y. V. Ershov, “2-C-Methylerythritol Phosphate Pathway of Isoprenoid Biosynthesis as a Target in Identifying New Antibiotics, Herbicides, and Immunomodulators: A Review,” Applied Biochemistry and Microbiology, Vol. 43, 2007, pp. 115-138. doi:10.1134/S0003683807020019

[11]   M. Rohmer, “The Discovery of a Mevalonate-Independent Pathway for Isoprenoid Biosynthesis in Bacteria, Algae and Higher Plants,” Natural Product Reports, Vol. 16, No. 5, 1999, pp. 565-574. doi:10.1039/a709175c

[12]   J. Roitelman, E. H. Olender, S. Bar-Nun, J. William A. Dunn and R. D. Simoni, “Immunological Evidence for Eight Spans in the Membrane Domain of 3-Hydroxy-3- Methylglutaryl Conzyme A Reductase: Implications for Enzyme Degradation in the Endoplasmic Reticulum,” Rockefeller University Press, Rockefeller, 1992, pp. 959- 973. doi:10.1083/jcb.117.5.959

[13]   Y. Chen, “Cholesterol-Lowering Nutraceuticalsand Functional Foods,” Journal of Agricultural and Food Chemistry, Vol. 56, No. 19, 2008, pp. 8761-8773. doi:10.1021/jf801566r

[14]   J. Kirby and J. D. Keasling, “Biosynthesis of Plant Isoprenoids: Perspectives for Microbial Engineering,” Annual Review of Plant Biology, Vol. 60, 2009, pp. 335-355. doi:10.1146/annurev.arplant.043008.091955

[15]   Bjorkelid, T. Bergfors, L. M. Henriksson, A. L. Stern, T. Unge, S. L. Mowbray and T. A. Jones, “Structural and Functional Studies of Mycobacterial IspD Enzymes,” Acta Crystallographica Section D: Biological Crystallography, Vol. 67, 2011, pp. 403-414. doi:10.1107/S0907444911006160

[16]   E. J. Park, D. Lee, Y. G. Shin, D. D. Lantvit, R. B. van Breemen, A. D. Kinghorn and J. M. Pezzuto, “Analysis of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Using Liquid Chromatography-Electrospray Mass Spectrometry,” Journal of Chromatography, Vol. 754, No. 2, 2001, pp. 327-332. doi:10.1016/S0378-4347(00)00620-4

[17]   K. Vonbergmann, A. Beck, C. Engel and O. Leiss, “Administration of a Terpene Mixture Inhibits Cholesterol Nucleation in Bile from Patients with Cholesterol Gallstones,” Klinische Wochenschrift, Vol. 65, No. 10, 1987, pp. 458-462. doi:10.1007/BF01712838

[18]   D. Rozman and M. R. Waterman, “Sterol Biosynthesis” In: J. I. Mason, Ed., Genetics of Steroid Biosynthesis and Function, 2002. http://

[19]   E. Oldfield, “Targeting Isoprenoid Biosynthesis for Drug Discovery: Bench to Bedside,” Accounts of Chemical Research, Vol. 43, No. 9, 2010, pp. 1216-1226. doi:10.1021/ar100026v

[20]   Z. Y. Chen, K. Y. Ma, Y. T. Liang, C. Peng and Y. Y. Zuo, “Role and Classification of Cholesterol-Lowering Functional Foods,” Journal of Functional Foods, Vol. 3, No. 2, 2011, pp. 61-69. doi:10.1016/j.jff.2011.02.003

[21]   A. Atzel and J. R. Wetterau, “Mechanism of Microsomal Triglyceride Transfer Protein Catalyzed Lipid Transport,” Biochemistry, Vol. 32, No. 39, 1993, pp. 10444-10450. doi:10.1021/bi00090a021

[22]   H. R. Davis, L. J. Zhu, L. M. Hoos, G. Tetzloff, M. Maguire, J. J. Liu, X. R. Yao, S. P. N. Iyer, M. H. Lam, E. G. Lund, P. A. Detmers, M. P. Graziano and S. W. Altmann, “Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-Body Cholesterol Homeostasis,” Journal of Biological Chemistry, Vol. 279, 2004, pp. 33586-33592. doi:10.1074/jbc.M405817200

[23]   K. A. Do, A. Green, J. R. Guthrie, E. C. Dudley, H. G. Burger and L. Dennerstein, “Longitudinal Study of Risk Factors for Coronary Heart Disease Across the Menopausal Transition,” American Journal of Epidemiology, Vol. 151, No. 6, 2000, pp. 584-593. doi:10.1093/oxfordjournals.aje.a010246

[24]   K. Y. Ma, N. Yang, R. Jiao, C. Peng, L. Guan, Y. Huang, and Z. Y. Chen, “Dietary Calcium Decreases Plasma Cholesterol by Down-Regulation of Intestinal Niemann- Pick C1 Like 1 and Microsomal Triacylglycerol Transport Protein and Up-Regulation of CYP7A1 and ABCG 5/8 in Hamsters,” Molecular Nutrition & Food Research, Vol. 55, No. 2, 2011, pp. 247-258. doi:10.1002/mnfr.201000161

[25]   C. Messa, M. Notarnicola, F. Russo, A. Cavallini, V. Pallottini, A. Trentalance, M. Bifulco, C. Laezza and M. G. Caruso, “Estrogenic Regulation of Cholesterol Biosynthesis and Cell Growth in DLD-1 Human Colon Cancer Cells,” Scandinavian Journal of Gastroenterology, Vol. 40, No. 12, 2005, pp. 1454-1461. doi:10.1080/00365520510024007

[26]   P. Mirmiran, N. Noori, M. B. Zavareh and F. Azizi, “Fruit and Vegetable Consumption and Risk Factors for Cardiovascular Disease,” Metabolism-Clinical and Experimental, Vol. 58, No. 4, 2009, pp. 460-468. doi:10.1016/j.metabol.2008.11.002

[27]   H. Suido, T. Tanaka, T. Tabei, A. Takeuchi, M. Okita, T. Kishimoto, S. Kasayama and K. Higashino, “A Mixed Green Vegetable and Fruit Beverage Decreased the Serum Level of Low-Density Lipoprotein Cholesterol in Hypercholesterolemic Patients,” Journal of Agricultural and Food Chemistry, Vol. 50, No. 11, 2002, pp. 3346- 3350. doi:10.1021/jf0116698

[28]   S. W. Andersson, J. Skinner, L. Ellegard, A. A. Welch, S. Bingham, A. Mulligan, H. Andersson and K. T. Khaw, “Intake of Dietary Plant Sterols Is Inversely Related to Serum Cholesterol Concentration in Men and Women in the EPIC Norfolk Population: A Cross-Sectional Study,” European Journal of Clinical Nutrition, Vol. 58, 2004, pp. 1378-1385. doi:10.1038/sj.ejcn.1601980

[29]   M. B. Katan, S. M. Grundy, P. Jones, M. Law, T. Miettinen, R. Paoletti and P. Stresa Workshop, “Efficacy and Safety of Plant Stanols and Sterols in the Management of Blood Cholesterol Levels,” Mayo Clinic Proceedings, Vol. 78, No. 8, 2003, pp. 965-978. doi:10.4065/78.8.965

[30]   R. P. Mensink and M. B. Katan, “Effect of Dietary Fatty Acids on Serum Lipids and Lipoproteins. A Meta- Analysis of 27 Trials,” Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 12, No. 8, 1992, pp. 911-919.

[31]   C. K. Lam, J. N. Chen, Y. Cao, L. Yang, Y. M. Wong, S. Y. V. Yeung, X. Q. Yao, Y. Huang, and Z. Y. Chen, “Conjugated and Non-Conjugated Octadecaenoic Acids Affect Differently Intestinal Acyl Coenzyme A: Cholesterol Acyltransferase Activity,” Atherosclerosis, Vol. 198, No. 1, 2008, pp. 85-93. doi:10.1016/j.atherosclerosis.2007.11.001

[32]   M. S. Lee, J. Y. Park, H. Freake, I. S. Kwun and Y. Kim, “Green Tea Catechin Enhances Cholesterol 7 Alpha-Hydroxylase Gene Expression in HepG2 Cells,” The British Journal of Nutrition, Vol. 99, No. 6, 2008, pp. 1182-1185. doi:10.1017/S0007114507864816

[33]   S. Pal, N. Ho, C. Santos, P. Dubois, J. Mamo, K. Croft, and E. Allister, “Red Wine Polyphenolics Increase LDL Receptor Expression and Activity and Suppress the Secretion of ApoB100 from Human HepG2 Cells,” Journal of Nutrition, Vol. 133, No. 3, 2003, pp. 700-706.

[34]   C. A. Bursill, M. Abbey and P. D. Roach, “A Green Tea Extract Lowers Plasma Cholesterol by Inhibiting Cholesterol Synthesis and Up Regulating the LDL Receptor in the Cholesterol-Fed Rabbit,” Atherosclerosis, Vol. 193, No. 1, 2007, pp. 86-93. doi:10.1016/j.atherosclerosis.2006.08.033

[35]   H. J. Kim and P. J. White, “In Vitro Bile-Acid Binding and Fermentation of High, Medium, and Low Molecular Weight Beta-Glucan,” Journal of Agricultural and Food Chemistry, Vol. 58, No. 1, 2010, pp. 628-634. doi:10.1021/jf902508t

[36]   M. J. Kwon, Y. S. Song, M. S. Choi, S. J. Park, K. S. Jeong and Y. O. Song, “Cholesteryl Ester Transfer Protein Activity and Atherogenic Parameters in Rabbits Supplemented with Cholesterol and Garlic Powder,” Life Sciences, Vol. 72, No. 26, 2003, pp. 2953-2964. doi:10.1016/S0024-3205(03)00234-0

[37]   M. J. Kwon, Y. S. Song, M. S. Choi and Y. O. Song, “Red Pepper Attenuates Cholesteryl Ester Transfer Protein Activity and Atherosclerosis in Cholesterol-Fed Rabbits,” Clinica Chimica Acta, Vol. 332, No. 1-2, 2003, pp. 37-44. doi:10.1016/S0009-8981(03)00118-9

[38]   M. Kim and Y. Kim, “Hypocholesterolemic Effects of Curcumin via Up-Regulation of Cholesterol 7a-Hydroxylase in Rats Fed a High Fat Diet,” Nutrition Research and Practice, Vol. 4, No. 3, 2010, pp. 191-195. doi:10.4162/nrp.2010.4.3.191

[39]   R. Jiao, Z. S. Zhang, H. J. Yu, Y. Huang and Z. Y. Chen, “Hypocholesterolemic Activity of Grape Seed Proanthocyanidin is Mediated by Enhancement of Bile Acid Excretion and Up-Regulation of CYP7A1,” Journal of Nutritional Biochemistry, Vol. 21, No. 11, 2010, pp. 1134- 1139. doi:10.1016/j.jnutbio.2009.10.007

[40]   N. Singh, J. Tamariz, G. Chamorro and J. L.Medina- Franco, “Inhibitors of HMG-CoA Reductase: Current and Future Prospects,” Medicinal Chemistry, Vol. 9, No. 11, 2009, pp. 1272-1283. doi:10.2174/138955709789878105

[41]   D. A. Bochar, C. V. Stauffacher and V. W. Rodwell, “Sequence Comparisons Reveal Two Classes of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase,” Molecular Genetics and Metabolism, Vol. 66, No. 2, 1999, pp. 122-127. doi:10.1006/mgme.1998.2786

[42]   L. Tabernero, V. W. Rodwell and C. V. Stauffacher, “Crystal Structure of a Statin Bound to a Class II Hydroxy-Methylglutaryl-CoA Reductase,” Journal of Biological Chemistry, Vol. 278, No. 22, 2003, pp. 19933- 19938. doi:10.1074/jbc.M213006200

[43]   J. A. Friesen and V. W. Rodwell, “The 3-Hydroxy-3- Methylglutaryl Coenzyme-A (HMG-CoA) Reductases,” Genome Biology, Vol. 5, No. 11, 2004, p. 248. doi:10.1186/gb-2004-5-11-248

[44]   P. Leivar, V. M. Gonzalez, S. Castel, R. N. Trelease, C. Lopez-Iglesias, M. Arro, A. Boronat, N. Campos, A. Ferrer and X. Fernandez-Busquets, “Subcellular Localization of Arabidopsis 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase,” Plant Physiology, Vol. 137, No. 1, 2005, pp. 57-69. doi:10.1104/pp.104.050245

[45]   N. Cunillera, M. Arro, D. Delourme, F. Karst, A. Boronat and A. Ferrer, “Arabidopsis thaliana Contains Two Differentially Expressed Farnesyl-Diphosphate Synthase Genes,” Journal of Biological Chemistry, Vol. 271, No. 13, 1996, pp. 7774-7780. doi:10.1074/jbc.271.13.7774

[46]   J. G. Jelesko, S. M. Jenkins, M. Rodriguez-Concepcion and W. Gruissem, “Regulation of Tomato HMG1 during Cell Proliferation and Growth,” Planta, Vol. 208, No. 3, 1999, pp. 310-318. doi:10.1007/s004250050564

[47]   Y. M. Crane and K. L. Korth, “Regulated Accumulation of 3-Hydroxy-3-Methylglutaryl CoA Reductase Protein in Potato Cell Cultures: Effects of Calcium and Enzyme Inhibitors,” Journal of Plant Physiology, Vol. 159, No. 12, 2002, pp. 1301-1307. doi:10.1078/0176-1617-00874

[48]   V. Lumbreras, N. Campos and A. Boronat, “The Use of an Alternative Promoter in the Arabidopsis thaliana HMG1 Gene Generates a Messenger-RNA that Encodes a Novel 3-Hydroxy-3-Methylglutaryl Coenzyme-A Reductase Isoform with an Extended N-Terminal Region,” Plant Journal, Vol. 8, No. 4, 1995, pp. 541-549. doi:10.1046/j.1365-313X.1995.8040541.x

[49]   P. A. Edwards and J. Ericsson, “Signaling Molecules Derived from the Cholesterol Biosynthetic Pathway: Mechanisms of Action and Possible Roles in Human Disease,” Current Opinion in Lipidology, Vol. 9, No. 5, 1998, pp. 433-440. doi:10.1097/00041433-199810000-00007

[50]   C. E. Elson, D. M. Peffley, P. Hentosh and H. B. Mo, “Isoprenoid-Mediated Inhibition of Mevalonate Synthesis: Potential Application to Cancer,” Proceedings of the Society for Experimental Biology and Medicine, Vol. 221, No. 4, 1999, pp. 294-311. doi:10.1046/j.1525-1373.1999.d01-87.x

[51]   T. J. Bach, D. H. Rogers and H. Rudney, “Detergent- Solubilization, Purification, and Characterization of Membrane-Bound 3-Hydroxy-3-Methylglutaryl-Coenzyme- A Reductase from Radish Seedlings,” European Journal of Biochemistry, Vol. 154, No. 1, 1986, pp. 103-111. doi:10.1111/j.1432-1033.1986.tb09364.x

[52]   J. D. Brooker and D. W. Russell, “Properties of microsomal 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase from Pisum-Sativum Seedlings,” Archives of Biochemistry and Biophysics, Vol. 167, No. 2, 1975, pp. 723- 729. doi:10.1016/0003-9861(75)90517-2

[53]   J. O. Narita and W. Gruissem, “Tomato Hydroxymethylglutaryl-CoA Reductase Is Required Early in Fruit Development but not During Ripening,” Plant Cell, Vol. 1, No. 2, 1989, pp. 181-190. doi:10.2307/3869034

[54]   M. Gleizes, G. Pauly, C. Bernarddagan and R. Jacques, “Effects of Light on Terpene Hydrocarbon Synthesis in Pinus-Pinaster,” Physiologia Plantarum, Vol. 50, No. 1, 1980, pp. 16-20. doi:10.1111/j.1399-3054.1980.tb02676.x

[55]   B. R. Loveys and P. F. Wareing, “Red Light Controlled Production of Gibberllin in Etiolated Wheat Leaves,” Planta, Vol. 98, No. 2, 1971, pp. 109-116. doi:10.1007/BF00385343

[56]   S. Tanaka, T. Yamaura, R. Shigemoto and M. Tabata, “Phytochrome-Mediated Production of Monoterpenes in Thyme Seedlings,” Phytochemistry, Vol. 28, No. 11, 1989, pp. 2955-2957. doi:10.1016/0031-9422(89)80260-2

[57]   B. A. Stermer and R. M. Bostock, “Involvement of 3- Hydroxy-3-Methylglutaryl Coenzyme-A Reductase in the Regulation of Sesquiterpenoid Phytoalexin Synthesis in Potato,” Plant Physiology, Vol. 84, No. 2, 1987, pp. 404- 408. doi:10.1104/pp.84.2.404

[58]   H. Suzuki, K. Oba and I. Uritani, “Occurrence and Some Properties of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Sweet-Potato Roots Infected by Ceratocystis Fimbriata,” Physiological Plant Pathology, Vol. 7, No. 3, 1975, pp. 265-276. doi:10.1016/0048-4059(75)90031-4

[59]   B. I. Cohen, R. F. Raicht and E. H. Mosbach, “Sterol Metabolism Studies in the Rat. Effects of Dietary Plant Sterols and Bile Acids on Sterol Metabolism,” Biochimica Et Biophysica Acta, Vol. 487, No. 2, 1977, pp. 287- 296. doi:10.1016/0005-2760(77)90005-4

[60]   L. L. Smith and B. H. Johnson, “Biological-Activities of Oxysterols,” Free Radical Biology and Medicine, Vol. 7, No. 3, 1989, pp. 285-332. doi:10.1016/0891-5849(89)90136-6

[61]   J. D. Horton, J. L. Goldstein and M. S. Brown, “SREBPs: Activators of the Complete Program of Cholesterol and Fatty Acid Synthesis in the Liver,” Journal of Clinical Investigation, Vol. 109, No. 9, 2002, pp. 1125-1131. doi:10.1172/JCI200215593

[62]   J. X. Wang, Z. L. Lu, J. M. Chi, W. H. Wang, M. Z. Su, W. R. Kou, P. L. Yu, L. J. Yu, J. S. Zhu and J. Chang, “Multicenter Clinical Trial of the Serum Lipid-Lowering Effects of a Monascus Purpureus (Red Yeast) Rice Preparation from Traditional Chinese Medicine,” Current Therapeutic Research-Clinical and Experimental, Vol. 58, No. 12, 1997, pp. 964-978. doi:10.1016/S0011-393X(97)80063-X

[63]   A. Leszczynska, B. Burzynska, D. Plochocka, J. Kaminska, M. Zimnicka, M. Kania, M. Kiliszek, M. Wysocka- Kapcinska, W. Danikiewicz and A. Szkopinska, “Investigating the Effects of Statins on Cellular Lipid Metabolism Using a Yeast Expression System,” PloS ONE, Vol. 4, No. 12, 2009, Article ID: e8499. doi:10.1371/journal.pone.0008499

[64]   R. J. Clegg, B. Middleton, G. D. Bell and D. A. White, “The Mechanism of Cyclic Monoterpene Inhibition of Hepatic 3-Hydroxy-3-Methylglutaryl Coenzyme-A Reductase in Vivo in the Rat,” Journal of Biological Chemistry, Vol. 257, No. 5, 1982, pp. 2294-2299.

[65]   A. Hemmerlin and T. J. Bach, “Farnesol-Induced Cell Death and Stimulation of 3-Hydroxy-3-Methylglutaryl -Coenzyme A Reductase Activity in Tobacco cv Bright Yellow-2 Cells,” Plant Physiology, Vol. 123, No. 4, 2000, pp. 1257-1268. doi:10.1104/pp.123.4.1257

[66]   M. J. Chung, K. W. Park, K. H. Kim, C. T. Kim, J. P. Baek, K. H. Bang, Y. M. Choi and S. J. Lee, “Asian Plantain (Plantago asiatica) Essential Oils Suppress 3- Hydroxy-3-Methylglutaryl-Co-Enzyme A Reductase Expression in Vitro and in Vivo and Show Hypocholesterolaemic Properties in Mice,” British Journal of Nutrition, Vol. 99, No. 1, 2008, pp. 67-75. doi:10.1017/S0007114507798926

[67]   S. Das, K. Nesaretnam and D. K. Das, “Tocotrienols in Cardioprotection”, In: G. Litwack, Ed., Vitamin E: Vitamins and Hormones Advances in Research and Applications, American Medical Association, Chicago, 2007, p. 419-433. doi:10.1001/jama.1945.02860260070044

[68]   J. L. Goldstein and M. S. Brown, “Regulation of the Mevalonate Pathway,” Nature, Vol. 343, No. 6257, 1990, pp. 425-430. doi:10.1038/343425a0

[69]   Z. Y. Chen, K. Y. Ma, Y. Liang, C. Peng and Y. Zuo, “Role and Classification of Cholesterol-Lowering Functional Foods,” Journal of Functional Foods, Vol. 3, No. 2, 2011, pp. 61-69. doi:10.1016/j.jff.2011.02.003

[70]   C. Dobetsberger and G. Buchbauer, “Actions of Essential Oils on the Central Nervous System: An updated review,” Flavour and Fragrance Journal, Vol. 26, No. 5, 2011, pp. 300-316.

[71]   D. P. D. Sousa, “Analgesic like Activity of Essential Oils Constituents,” Molecules, Vol. 16, No. 3, 2011, pp. 2233- 2252. doi:10.3390/molecules16032233

[72]   D. J. Newman, G. M. Cragg and K. M. Snader, “The Influence of Natural Products upon Drug Discovery,” Natural Product Reports, Vol. 17, No. 3, 2000, pp. 215- 234. doi:10.1039/a902202c

[73]   Interactive European Network for Industrial Crops and their Applications, “Summary Report for the European Union 2000-2005,” IENICA, 2005.