Bioactivity of Phytosterols and Their Production in Plant in Vitro Cultures

Journal of Agricultural and Food Chemistry

Volumn 64, Issue 38, 2016, Pages 7049-7058

  Miras Moreno, Begona ^a   Sabater Jara, Ana Belén ^a   Pedreno, M A ^a   Almagro, Lorena ^a  

^a UNIVERSITY OF MURCIA   (Spain)

Author keywords

biosynthethic pathway; in vitro cultures; phytosterols

Indexed keywords

BIOCHEMISTRY; BIOMOLECULES; BIOSYNTHESIS; BIOTECHNOLOGY; CHEMICAL COMPOUNDS; METABOLITES;

ANTI-INFLAMMATORIES; ANTICANCER ACTIVITIES; BENEFICIAL EFFECTS; BIOSYNTHETHIC PATHWAY; COMMERCIAL EXPLOITATION; IN-VITRO; PHYTOSTEROLS; PLASMA CHOLESTEROL;

ALCOHOLS;

ANTIDIABETIC AGENT; ANTIINFLAMMATORY AGENT; ANTINEOPLASTIC AGENT; CAMPESTEROL; CHOLESTEROL; GAMMA-SITOSTEROL; PHYTOSTEROL; SITOSTEROL DERIVATIVE; STIGMASTEROL;

ANALOGS AND DERIVATIVES; BIOAVAILABILITY; BIOSYNTHESIS; BIOTECHNOLOGY; BLOOD; CHEMISTRY; EMPIRICAL RESEARCH; HUMAN; PLANT; PLANT CELL;

ANTI-INFLAMMATORY AGENTS; ANTINEOPLASTIC AGENTS; BIOLOGICAL AVAILABILITY; BIOTECHNOLOGY; CHOLESTEROL; EMPIRICAL RESEARCH; HUMANS; HYPOGLYCEMIC AGENTS; PHYTOSTEROLS; PLANT CELLS; PLANTS; SITOSTEROLS; STIGMASTEROL;

EID: 84989249003     PISSN: 00218561     EISSN: 15205118     Source Type: Journal    
DOI: 10.1021/acs.jafc.6b02345     Document Type: Review

References (81)

1. Gylling, H.; Simonen, P. Phytosterols, phytostanols, and lipoprotein metabolism Nutrients 2015, 7, 7965-7977 10.3390/nu7095374
2. Hartmann, M. A. Plant sterols and the membrane environment Trends Plant Sci. 1998, 3, 170-175 10.1016/S1360-1385(98)01233-3
3. Piironen, V.; Lindsay, D. G.; Miettinen, T. A.; Toivo, J.; Lampi, A. M. Plant sterols: biosynthesis, biological function and their importance to human nutrition J. Sci. Food Agric. 2000, 80, 939-966 10.1002/(SICI)1097-0010(20000515)80:7<939::AID-JSFA644>3.0.CO;2-C
4. Santas, J.; Codony, R.; Rafecas, M. Phytosterols: beneficial effects. In Natural Products; Ramawat, K. G.; Mérillon, J. M., Eds.; Springer: Berlin, Heidelberg, 2013; pp 3437-3464.
5. Vranová, E.; Coman, D.; Gruissem, W. Network analysis of the MVA and MEP pathways for isoprenoid synthesis Annu. Rev. Plant Biol. 2013, 64, 665-700 10.1146/annurev-arplant-050312-120116
6. Opitz, S.; Nes, W. D.; Gershenzon, J. Both methylerythritol phosphate and mevalonate pathways contribute to biosynthesis of each of the major isoprenoid classes in young cotton seedlings Phytochemistry 2014, 98, 110-119 10.1016/j.phytochem.2013.11.010
7. Flores-Sánchez, I. J.; Ortega-López, J.; del Carmen Montes-Horcasitas, M.; Ramos-Valdivia, A. C. Biosynthesis of sterols and triterpenes in cell suspension cultures of Uncaria tomentosa Plant Cell Physiol. 2002, 43, 1502-1509 10.1093/pcp/pcf181
8. 3-dimethylallyl pyrophosphate by Mycoplasma J. Bacteriol. 1966, 92, 701-706
9. Ohyama, K.; Suzuki, M.; Kikuchi, J.; Saito, K.; Muranaka, T. Dual biosynthetic pathways to phytosterol via cycloartenol and lanosterol in Arabidopsis Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 725-730 10.1073/pnas.0807675106
10. Boutté, Y.; Grebe, M. Cellular processes relying on sterol function in plants Curr. Opin. Plant Biol. 2009, 12, 705-713 10.1016/j.pbi.2009.09.013
11. Neelakandan, A. K.; Nguyen, H. T.; Kumar, R.; Tran, L. S. P.; Guttikonda, S. K.; Quach, T. N.; Aldrich, D. L.; Nes, W. D.; Nguyen, H. T. Molecular characterization and functional analysis of Glycine max sterol methyl transferase 2 genes involved in plant membrane sterol biosynthesis Plant Mol. Biol. 2010, 74, 503-518 10.1007/s11103-010-9692-6
12. Grandmougin-Ferjani, A.; Schuler-Muller, I.; Hartmann, M. A. Sterol modulation of the plasma membrane H+-ATPase activity from corn roots reconstituted into soybean lipids Plant Physiol. 1997, 113, 163-174
13. Roche, Y.; Gerbeau-Pissot, P.; Buhot, B.; Thomas, D.; Bonneau, L.; Gresti, J.; Mongrand, S.; Perrier-Cornet, J. M.; Simon-Plas, F. Depletion of phytosterols from the plant plasma membrane provides evidence for disruption of lipid rafts FASEB J. 2008, 22, 3980-3991 10.1096/fj.08-111070
14. Mongrand, S.; Stanislas, T.; Bayer, E. M.; Lherminier, J.; Simon-Plas, F. Membrane rafts in plant cells Trends Plant Sci. 2010, 15, 656-663 10.1016/j.tplants.2010.09.003
15. Asami, T.; Nakano, T.; Fujioka, S. Plant brassinosteroid hormones Vitam. Horm. 2005, 72, 479-504 10.1016/S0083-6729(05)72014-8
16. Gudesblat, G. E.; Russinova, E. Plants grow on brassinosteroids Curr. Opin. Plant Biol. 2011, 14, 530-537 10.1016/j.pbi.2011.05.004
17. Fridman, Y.; Savaldi-Goldstein, S. Brassinosteroids in growth control: how, when and where Plant Sci. 2013, 209, 24-31 10.1016/j.plantsci.2013.04.002
18. Devarenne, T. P.; Ghosh, A.; Chappell, J. Regulation of squalene synthase, a key enzyme of sterol biosynthesis, in tobacco Plant Physiol. 2002, 129, 1095-1106 10.1104/pp.001438
19. Griebel, T.; Zeier, J. A role for β-sitosterol to stigmasterol conversion in plant-pathogen interactions Plant J. 2010, 63, 254-268 10.1111/j.1365-313X.2010.04235.x
20. Wang, K.; Senthil-Kumar, M.; Ryu, C. M.; Kang, L.; Mysore, K. S. Phytosterols play a key role in plant innate immunity against bacterial pathogens by regulating nutrient efflux into the apoplast Plant Physiol. 2012, 158, 1789-1802 10.1104/pp.111.189217
21. Moreau, R. A.; Whitaker, B. D.; Hicks, K. B. Phytosterols, phytostanols, and their conjugates in foods: structural diversity, quantitative analysis, and health-promoting uses Prog. Lipid Res. 2002, 41, 457-500 10.1016/S0163-7827(02)00006-1
22. García-Llatas, G.; Rodríguez-Estrada, M. T. Current and new insights on phytosterol oxides in plant sterol-enriched food Chem. Phys. Lipids 2011, 164, 607-624 10.1016/j.chemphyslip.2011.06.005
23. Woyengo, T. A.; Ramprasath, V. R.; Jones, P. J. H. Anticancer effects of phytosterols Eur. J. Clin. Nutr. 2009, 63, 813-820 10.1038/ejcn.2009.29
24. Rozner, S.; Garti, N. The activity and absorption relationship of cholesterol and phytosterols Colloids Surf., A 2006, 282, 435-456 10.1016/j.colsurfa.2005.12.032
25. Jones, P. J.; AbuMweis, S. S. Phytosterols as functional food ingredients: linkages to cardiovascular disease and cancer Curr. Opin. Clin. Nutr. Metab. Care 2009, 12, 147-151 10.1097/MCO.0b013e328326770f
26. Rocha, M.; Banuls, C.; Bellod, L.; Jover, A.; Victor, V. M.; Hernandez-Mijares, A. A review on the role of phytosterols: new insights into cardiovascular risk Curr. Pharm. Des. 2011, 17, 4061-4075 10.2174/138161211798764852
27. Bouic, P. J.; Lamprecht, J. H. Plant sterols and sterolins: a review of their immune-modulating properties Altern. Med. Rev. 1999, 4, 170-177
28. Alappat, L.; Valerio, M.; Awad, A. B. Effect of vitamin D and β-sitosterol on immune function of macrophages Int. Immunopharmacol. 2010, 10, 1390-1396 10.1016/j.intimp.2010.08.003
29. Aherne, S. A.; O'Brien, N. M. Modulation of cytokine production by plant sterols in stimulated human Jurkat T cells Mol. Nutr. Food Res. 2008, 52, 664-673 10.1002/mnfr.200700385
30. Devaraj, S.; Jialal, I.; Rockwood, J.; Zak, D. Effect of orange juice and beverage with phytosterols on cytokines and PAI-1 activity Clin. Nutr. 2011, 30, 668-671 10.1016/j.clnu.2011.03.009
31. Misawa, E.; Tanaka, M.; Nomaguchi, K.; Yamada, M.; Toida, T.; Takase, M.; Iwatsuki, K.; Kawada, T. Administration of phytosterols isolated from Aloe vera gel reduce visceral fat mass and improve hyperglycemia in Zucker diabetic fatty (ZDF) rats Obes. Res. Clin. Pract 2008, 2, 239-245 10.1016/j.orcp.2008.06.002
32. Misawa, E.; Tanaka, M.; Nomaguchi, K.; Nabeshima, K.; Yamada, M.; Toida, T.; Iwatsuki, K. Oral ingestion of Aloe vera phytosterols alters hepatic gene expression profiles and ameliorates obesity-associated metabolic disorders in Zucker diabetic fatty rats J. Agric. Food Chem. 2012, 60, 2799-2806 10.1021/jf204465j
33. Awad, A. B.; Fink, C. S.; Williams, H.; Kim, U. In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells Eur. J. Cancer Prev. 2001, 10, 507-513 10.1097/00008469-200112000-00005
34. Choi, J. M.; Lee, E. O.; Lee, H. J.; Kim, K. H.; Ahn, K. S.; Shim, B. S.; Kim, N. I.; Song, M. C.; Baek, N. I.; Kim, S. H. Identification of campesterol from Chrysanthemum coronarium L. and its antiangiogenic activities Phytother. Res. 2007, 21, 954-959 10.1002/ptr.2189
35. Awad, A. B.; Toczek, J.; Fink, C. S. Phytosterols decrease prostaglandin release in cultured P388D 1/MAB macrophages Prostaglandins, Leukotrienes Essent. Fatty Acids 2004, 70, 511-520 10.1016/j.plefa.2003.11.005
36. Vivancos, M.; Moreno, J. J. β-Sitosterol modulates antioxidant enzyme response in RAW 264.7 macrophages Free Radical Biol. Med. 2005, 39, 91-97 10.1016/j.freeradbiomed.2005.02.025
37. Awad, A. B.; Burr, A. T.; Fink, C. S. Effect of resveratrol and β-sitosterol in combination on reactive oxygen species and prostaglandin release by PC-3 cells Prostaglandins, Leukotrienes Essent. Fatty Acids 2005, 72, 219-226 10.1016/j.plefa.2004.11.005
38. Park, C.; Moon, D. O.; Rhu, C. H.; Choi, B. T.; Lee, W. H.; Kim, G. Y.; Choi, Y. H. β-Sitosterol Induces anti-proliferation and apoptosis in human leukemic U937 cells through activation of caspase-3 and induction of Bax/Bcl-2 ratio Biol. Pharm. Bull. 2007, 30, 1317-1323 10.1248/bpb.30.1317
39. Bradford, P. G.; Awad, A. B. Phytosterols as anticancer compounds Mol. Nutr. Food Res. 2007, 51, 161-170 10.1002/mnfr.200600164
40. Salen, G.; Starc, T.; Sisk, C. M.; Patel, S. B. Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemia and xanthomatosis Gastroenterology 2006, 130, 1853-1857 10.1053/j.gastro.2006.02.027
41. Lees, A. M.; Mok, H. Y.; Lees, R. S.; McCluskey, M. A.; Grundy, S. M. Plant sterols as cholesterol-lowering agents: clinical trials in patients with hypercholesterolemia and studies of sterol balance Atherosclerosis 1977, 28, 325-338 10.1016/0021-9150(77)90180-0
42. Jansen, D.; Zerbi, V.; Janssen, C.; Zinnhardt, B.; van Rooij, D.; Broersen, L.; Liu, Y.; Heerschap, A.; Kiliaan, A. Effects of specific lipid-based diets on behavior, cognition, cerebral metabolism and hemodynamics, and inflammatory markers in APP/PS1, ApoE4 and ApoE knockout mice Alzheimer's Dementia 2011, 7, S650 10.1016/j.jalz.2011.05.1864
43. Vanmierlo, T.; Weingärtner, O.; van der Pol, S.; Husche, C.; Kerksiek, A.; Friedrichs, S.; Sijbrands, E.; Steinbusch, H.; Grimm, M.; Hartmann, T.; Laufs, U.; Böhm, M.; de Vries, H. E.; Mulder, M.; Lütjohann, D. Dietary intake of plant sterols stably increases plant sterol levels in the murine brain J. Lipid Res. 2012, 53, 726-735 10.1194/jlr.M017244
44. Richelle, M.; Enslen, M.; Hager, C.; Groux, M.; Tavazzi, I.; Godin, J. P.; Berger, A.; Métairon, S.; Quaile, S.; Piguet-Welsch, C.; Sagalowicz, L.; Green, H.; Sagalowicz, L. Both free and esterified plant sterols reduce cholesterol absorption and the bioavailability of β-carotene and α-tocopherol in normocholesterolemic humans Am. J. Clin. Nutr. 2004, 80, 171-177
45. Kritchevsky, D.; Tepper, S. A.; Czarnecki, S. K.; Wolfe, B.; Setchell, K. D. Serum and aortic levels of phytosterols in rabbits fed sitosterol or sitostanol ester preparations Lipids 2003, 38, 1115-1118 10.1007/s11745-003-1168-8
46. Normen, L.; Andersson, S. W. Does phytosterol lntake affect the development of cancer? In Phytosterols as Functional Food Components and Nutraceuticals; Dutta, P. C., Ed.; Marcel Dekker: 2003; p 191.
47. Noakes, M.; Clifton, P.; Ntanios, F.; Shrapnel, W.; Record, I.; McInerney, J. An increase in dietary carotenoids when consuming plant sterols or stanols is effective in maintaining plasma carotenoid concentrations Am. J. Clin. Nutr. 2002, 75, 79-86
48. Piironen, V.; Lindsay, D. G.; Miettinen, T. A.; Toivo, J.; Lampi, A. M. Plant sterols: biosynthesis, biological function and their importance to human nutrition J. Sci. Food Agric. 2000, 80, 939-966 10.1002/(SICI)1097-0010(20000515)80:7<939::AID-JSFA644>3.0.CO;2-C
49. Llamos, B. R. H.; Morejón, A. F.; Bolanos, C. P.; Morales, S. T.; Quinones, Y. B.; Rodríguez, M. P. Fitosteroles. Parte 2: Fuentes de obtención, formas de uso y posición actual en el mercado Rev. CENIC, Cienc. Biol. 2008, 39 (2) 97-104
50. Novak, A. C.; Sydney, E. B.; Soccol, C. R. Biocosmetics. In Biotransformation of waste biomass into high value biochemicals, Brar, S. K., et al., Eds.; Springer: New York; pp 389-411.
51. Doering, T.; Holtkötter, O.; Schlotmann, K.; Jassoy, C.; Petersohn, D.; Wadle, A.; Waldmann-Laue, M. Cutaneous restructuration by apple seed phytosterols: from DNA chip analysis to morphological alterations Int. J. Cosmet. Sci. 2005, 27, 142-142 10.1111/j.1467-2494.2005.00259-1.x
52. Riedel, J. H.; Korbacher, K.; Hengel, R.; Schmidt-Lewerkuhne, H. (2000. U.S. Patent 6,156,296.
53. Fernandes, P.; Cabral, J. M. S. Phytosterols: applications and recovery methods Bioresour. Technol. 2007) 98, 2335-2350 10.1016/j.biortech.2006.10.006
54. Huibers, D. T. A.; Robbins, A. M.; Sullivan, D. H. Method for separating sterols from tall oil. 2000. U.S. Patent WO 0015652.
55. Uddin, M.; Sarker, M.; Islam, Z.; Ferdosh, S.; Akanda, J. H.; Easmin, S.; Shamsudin, S. H. B.; Yunus, K. B. Phytosterols and their extraction from various plant matrices using supercritical carbon dioxide: a review J. Sci. Food Agric. 2015, 95, 1385-1394 10.1002/jsfa.6833
56. Verpoorte, R.; Contin, A.; Memelink, J. Biotechnology for the production of plant secondary metabolites Phytochem. Rev. 2002, 1, 13-25 10.1023/A:1015871916833
57. Saiman, M. Z.; Mustafa, N. R.; Pomahočová, B.; Verberne, M.; Verpoorte, R.; Choi, Y. H.; Schulte, A. E. Analysis of metabolites in the terpenoid pathway of Catharanthus roseus cell suspensions Plant Cell, Tissue Organ Cult. 2014, 117, 225-239 10.1007/s11240-014-0435-2
58. Dyas, L.; Threlfall, D. R.; Goad, L. J. The sterol composition of five plant species grown as cell suspension cultures Phytochemistry 1994, 35, 655-660 10.1016/S0031-9422(00)90581-8
59. Cunha, A.; Ferreira, M. F. Differences in free sterols content and composition associated with somatic embryogenesis, shoot organogenesis and calli growth of flax Plant Sci. 1997, 124, 97-105 10.1016/S0168-9452(97)04587-1
60. Meyer, W.; Spiteller, G. Oxidized phytosterols increase by ageing in photoautotrophic cell cultures of Chenopodium rubrum Phytochemistry 1997, 45, 297-302 10.1016/S0031-9422(96)00818-7
61. Sharma, N.; Nathawat, R. S.; Gour, K.; Patni, V. Establishment of callus tissue and effect of growth regulators on enhanced sterol production in Cissus quadrangularis L Int. J. Pharmacol. 2011, 7, 653-658 10.3923/ijp.2011.653.658
62. Fernandes-Ferreira, M.; Pais, M. S.; Novais, J. M. The effects of medium composition on biomass, sterols and triterpenols production by in-vitro cultures of Euphorbia characias Bioresour. Technol. 1992, 42, 67-73 10.1016/0960-8524(92)90089-G
63. Mangas, S.; Moyano, E.; Osuna, L.; Cusidó, R. M.; Bonfill, M.; Palazón, J. Triterpenoid saponin content and the expression level of some related genes in calli of Centella asiatica Biotechnol. Lett. 2008, 30, 1853-1859 10.1007/s10529-008-9766-6
64. Bonfill, M.; Mangas, S.; Moyano, E.; Cusidó, R. M.; Palazón, J. Production of centellosides and phytosterols in cell suspension cultures of Centella asiatica Plant Cell, Tissue Organ Cult. 2011, 104, 61-67 10.1007/s11240-010-9804-7
65. Flores-Sánchez, I. J.; Ortega-López, J.; del Carmen Montes-Horcasitas, M.; Ramos-Valdivia, A. C. Biosynthesis of sterols and triterpenes in cell suspension cultures of Uncaria tomentosa Plant Cell Physiol. 2002, 43, 1502-1509 10.1093/pcp/pcf181
66. Almagro, L.; García-Pérez, P.; Belchí-Navarro, S.; Sánchez-Pujante, P. J.; Pedreno, M. A. New strategies for the use of Linum usitatissimum cell factories for the production of bioactive compounds Plant Physiol. Biochem. 2016, 99, 73-78 10.1016/j.plaphy.2015.12.009
67. Briceno, Z.; Almagro, L.; Sabater-Jara, A. B.; Calderón, A. A.; Pedreno, M. A.; Ferrer, M. A. Enhancement of phytosterols, taraxasterol and induction of extracellular pathogenesis-related proteins in cell cultures of Solanum lycopersicum cv Micro-Tom elicited with cyclodextrins and methyl jasmonate J. Plant Physiol. 2012, 169, 1050-1058 10.1016/j.jplph.2012.03.008
68. Sabater-Jara, A. B.; Pedreno, M. A. Use of β-cyclodextrins to enhance phytosterol production in cell suspension cultures of carrot (Daucus carota L.) Plant Cell, Tissue Organ Cult. 2013, 114, 249-258 10.1007/s11240-013-0320-4
69. Wu, J.; Seliskar, D. M.; Gallagher, J. L. The response of plasma membrane lipid composition in callus of the halophyte Spartina patens (Poaceae) to salinity stress Am. J. Bot. 2005, 92, 852-858 10.3732/ajb.92.5.852
70. Burlini, N.; Iriti, M.; Daghetti, A.; Faoro, F.; Ruggiero, A.; Bernasconi, S. Benzothiadiazole (BTH) activates sterol pathway and affects vitamin D3 metabolism in Solanum malacoxylon cell cultures Plant Cell Rep. 2011, 30, 2131-2141 10.1007/s00299-011-1119-6
71. Bru, R.; Sellés, S.; Casado-Vela, J.; Belchí-Navarro, S.; Pedreno, M. A. Modified cyclodextrins are chemically defined glucan inducers of defense responses in grapevine cell cultures J. Agric. Food Chem. 2006, 54, 65-71 10.1021/jf051485j
72. Sabater-Jara, A. B.; Almagro, L.; Belchí-Navarro, S.; Ferrer, M. A.; Ros-Barceló, A.; Pedreno, M. A. Induction of sesquiterpenes, phytoesterols and extracellular pathogenesis-related proteins in elicited cell cultures of Capsicum annuum J. Plant Physiol. 2010, 167, 1273-1281 10.1016/j.jplph.2010.04.015
73. Belchí-Navarro, S.; Almagro, L.; Lijavetzky, D.; Bru, R.; Pedreno, M. A. Enhanced extracellular production of trans-resveratrol in Vitis vinifera suspension cultured cells by using cyclodextrins and methyljasmonate Plant Cell Rep. 2012, 31, 81-89 10.1007/s00299-011-1141-8
74. Suh, H. W.; Hyun, S. H.; Kim, S. H.; Lee, S. Y.; Choi, H. K. Metabolic profiling and enhanced production of phytosterols by elicitation with methyl jasmonate and silver nitrate in whole plant cultures of Lemna paucicostata Process Biochem. 2013, 48, 1581-1586 10.1016/j.procbio.2013.06.032
75. Sabater-Jara, A. B.; Almagro, L.; Bru, R.; Pedreno, M. A. Uso de las ciclodextrinas para la producción y extracción de fitoesteroles en cultivos celulares. Patent number WO2010049563 A1.
76. Kim, O. T.; Kim, S. H.; Ohyama, K.; Muranaka, T.; Choi, Y. E.; Lee, H. Y.; Kim, M. Y.; Hwang, B. Upregulation of phytosterol and triterpene biosynthesis in Centella asiatica hairy roots overexpressed ginseng farnesyl diphosphate synthase Plant Cell Rep. 2010, 29, 403-411 10.1007/s00299-010-0831-y
77. Kim, Y. K.; Kim, J. K.; Kim, Y. B.; Lee, S.; Kim, S. U.; Park, S. U. Enhanced accumulation of phytosterol and triterpene in hairy root cultures of Platycodon grandiflorum by overexpression of Panax ginseng 3-hydroxy-3-methylglutaryl-coenzyme A reductase J. Agric. Food Chem. 2013, 61, 1928-1934 10.1021/jf304911t
78. Kim, Y. K.; Kim, Y. B.; Uddin, M. R.; Lee, S.; Kim, S. U.; Park, S. U. Enhanced triterpene accumulation in Panax ginseng hairy roots overexpressing mevalonate-5-pyrophosphate decarboxylase and farnesyl pyrophosphate synthase ACS Synth. Biol. 2014, 3, 773-779 10.1021/sb400194g
79. Lee, M. H.; Jeong, J. H.; Seo, J. W.; Shin, C. G.; Kim, Y. S.; In, J. G.; Yang, D. C.; Yi, J. S.; Choi, Y. E. Enhanced triterpene and phytosterol biosynthesis in Panax ginseng overexpressing squalene synthase gene Plant Cell Physiol. 2004, 45, 976-984 10.1093/pcp/pch126
80. Kim, Y. S.; Cho, J. H.; Park, S.; Han, J. Y.; Back, K.; Choi, Y. E. Gene regulation patterns in triterpene biosynthetic pathway driven by overexpression of squalene synthase and methyl jasmonate elicitation in Bupleurum falcatum Planta 2011, 233, 343-355 10.1007/s00425-010-1292-9
81. Seo, J. W.; Jeong, J. H.; Shin, C. G.; Lo, S. C.; Han, S. S.; Yu, K. W.; Harada, E.; Han, J. Y.; Choi, Y. E. Overexpression of squalene synthase in Eleutherococcus senticosus increases phytosterol and triterpene accumulation Phytochemistry 2005, 66, 869-877 10.1016/j.phytochem.2005.02.016