Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Screening of Phenolic Compounds with Inhibitory Activities against HMG-CoA Reductase

페놀 화합물로부터 HMG-CoA reductase 저해 활성 물질 탐색

  • Son, Kun Ho (Department of Food Science and Nutrition, Andong National University) ;
  • Lee, Ju Yeon (Department of Food Science and Nutrition, Andong National University) ;
  • Lee, Jeong Soon (Forest Resources Development Institute of Gyeongsangbuk-do) ;
  • Kang, Sam Sik (Natural Products Research Institute, Seoul National University) ;
  • Sohn, Ho Yong (Department of Food Science and Nutrition, Andong National University) ;
  • Kwon, Chong Suk (Department of Food Science and Nutrition, Andong National University)
  • 손건호 (안동대학교 생활과학대학 식품영양학과) ;
  • 이주연 (안동대학교 생활과학대학 식품영양학과) ;
  • 이정순 (경상북도산림자원개발원) ;
  • 강삼식 (서울대학교 천연물과학연구소) ;
  • 손호용 (안동대학교 생활과학대학 식품영양학과) ;
  • 권정숙 (안동대학교 생활과학대학 식품영양학과)
  • Received : 2016.10.27
  • Accepted : 2016.12.01
  • Published : 2017.03.30
Download PDF
⟨ Previous Next ⟩

Abstract

High level of plasma cholesterol is strongly associated with the development of atherosclerosis and coronary heart disease. Clinical trials designed to reduce plasma cholesterol level by diet or pharmacological intervention have resulted in marked reduction of disease incidence. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which reduces cholesterol biosynthesis in the liver is the key enzyme of the mevalonate pathway that produces cholesterol. In this study, 71 naturally occurring phenolic compounds were tested for inhibitory activities against HMG-CoA reductase. Eleven compounds out of 71 showed inhibitory activities: three hydrolyzable tannin (geraniin, acetonyl geraniin and pentagalloyl ${\beta}-D-glucose$), four benzoic acid derivatives (benzoic acid, trans-cinnamic acid, 2,4-dihydroxybenzoic acid and 2,5-dihydroxybenzoic acid), and four naphthoquinone derivatives (1,2-naphthoquinone, 1,4-naphthoquinone, plumbagin and shikonin). At the concentration of $10{\mu}g/ml$, 1,4-naphthoquinone inhibited HMG-CoA reductase by 99.4%, and then plumbagin 91.4%, pentagalloyl ${\beta}-D-glucose$ 46.6%, 2,4-dihydroxybenzoic acid 40.9%, shikonin 37.7%, 1,2-naphthoquinone 36.6%, trans-cinnamic acid 32.0%, acetonyl geraniin 30.2%, benzoic acid 28.5%, geraniin 28.3% and 2,5-dihydroxybenzoic acid 22.3%, respectively. $IC_{50}$ values of 1,4-naphthoquinone and plumbagin was $2.1{\mu}g/ml$ and $5.8{\mu}g/ml$, respectively.

심혈관계 질환은 질환별 사망률 순위에 있어서 세계에서는 1위이며, 우리나라에서는 2위인 질병이다. 심혈관계 질환 발생의 주 위험 요인인 콜레스테롤은 HMG-CoA reductase에 의해 간에서 신생합성이 조절된다. 현재 고콜레스테롤혈증 치료에 statin이 널리 사용되고 있지만 광범위한 부작용이 보고되고 있어서 이를 대체하거나 보조할 수 있는 천연물 유래의 기능성 물질 개발이 필요한 실정이다. 따라서 본 연구에서는 혈장 콜레스테롤 감소 활성을 가지는 물질을 발굴하고자 71종의 페놀 및 그와 관련된 화합물들을 대상으로 10ug/ml 농도에서 HMG-CoA reductase 저해 활성을 탐색하였다. 그 결과, 1,4-naphthoquinone의 HMG-CoA reductase 저해율이 99.4%로 가장 높았고, 다음으로 plumbagin 91.4%, pentagalloyl ${\beta}-D-glucose$ 46.6%, 2,4-dihydroxybenzoic acid 40.9%, shikonin 37.7%, 1,2-naphthoquinone 36.6%, trans-cinnamic acid 32.0%, acetonylgeraniin 30.2%, benzoic acid 28.5%, geraniin 28.3%, gentisic acid 22.3%의 순이었다. $IC_{50}$값을 계산한 결과, 1,4-naphthoquinone가 $2.1{\mu}g/ml$로 가장 낮았으며, plumbagin과 pentagalloyl ${\beta}-D-glucose$은 각각 $5.8{\mu}g/ml$과 $13.1{\mu}g/ml$으로 나타났다. 1,4-naphthoquinone과 plumbagin의 경우, $5{\mu}g/ml$에서도 각각 90.3%와 43.3%의 저해율을 나타내었다.

Keywords

References

  1. Ahan, B. T., Lee, S. C., Park, W. Y., Lee, S. H., Ro, J. S., Lee, K. S. and Ryu, E. K. 1992. Pharmacognostical study on Euphorbia ebracteolata (II)-On the chemical study of the tannins and related compounds. Kor. J. Pharmacogn. 23, 211-217.
  2. Ahn, B. T. and Kang, S. S. 1996. Phenolic compounds from Aerial Parts of Euphorbia pekinensis. Kor. J. Pharmacogn. 27, 142-145.
  3. Ahn, E. M., Park, S. J., Choi, W. C., Choi, S. H. and Baek, N. I. 2007. Antioxidant activity of isolated compounds from the heartwoods of Rhus verniciflua. J. Kor. Soc. Appl. Biol. Chem. 50, 358-361.
  4. Anderson, K. M., Wilson, P. W., Garrison, R. J. and Castelli, W. P. 1987. Longitudinal and secular trends in lipoprotein cholesterol measurements in a general population sample. The Framingham offspring study. Atherosclerosis 68, 59-66. https://doi.org/10.1016/0021-9150(87)90094-3
  5. Ansell, B. J., Watson, K. E. and Fogelman, A. M. 1999. An evidence-based assessment of the NCEP adult treatment panel II guidelines. JAMA 282, 2051-2057. https://doi.org/10.1001/jama.282.21.2051
  6. Ashidate, K., Mimura, M. D., Tohda, H., Miyazaki, S., Teramoto, T., Yamamoto, Y. and Hirata, Y. 2005. Gentisic acid, an aspirin metabolite, inhibits oxidation of low-density lipoprotein and the formation of cholesterol ester hydroperoxides in human plasma. Eur. J. Pharmacol. 513, 173-179. https://doi.org/10.1016/j.ejphar.2005.03.012
  7. Babula, P., Adam, V., Havel, L. and Kizek, R. 2007. Naphthoquinones and their pharmacological properties. Ceska a Slovenska Farmacie (in Czech) 56, 114-120.
  8. Barger, G. and Silberschmidt, R. 1928. CCCLXXXIV.-The constitution of laurotetanine. J. Chem. Soc. 17, 2919-2927.
  9. Blankenhorn, D. H., Johnson, R. L., Nessim, S. A., Azen, S. P., Sanmarco, M. E. and Selzer, R. H. 1987. The cholesterol lowering atherosclerosis study (CLAS): design, methods and baseline results. Control Clin. Trials. 8, 356-387. https://doi.org/10.1016/0197-2456(87)90156-5
  10. Cho, J. Y., Park, K. Y., Lee, K. H., Lee, H. J., Lee, S. H., Cho, J. A., Kim, W. S., Shin, S. C., Park, K. H. and Moon, J. H. 2011. Recovery of arbutin in high purity from fruit peels of pear (Pyrus pyrifolia Nakai). Food Sci. Biotec. 20, 801-807. https://doi.org/10.1007/s10068-011-0111-9
  11. Cho, J. Y., Xing, Y., Park, K. H., Park, H. J., Park, S. Y., Moon, J. H. and Ham, K. S. 2013. Isolization and identification of antioxidative compounds and their activities from Suaeda japonica. Food Sci. Biotechnol. 22, 1547-1557. https://doi.org/10.1007/s10068-013-0250-2
  12. Chung, A. P. Y. S., Ton, S. H., Gurtu, S. and Palanisamy, U. D. 2014. Ellagitannin geraniin supplementation ameliorates metabolic risks in high-fat diet-induced obese Sprague Dawley rats. J. Funct. Food 9, 173-182. https://doi.org/10.1016/j.jff.2014.03.029
  13. Dai, J., Kardono, L. B. S, Tsauri, S., Padmawinata, K., Pezzuto, J. M. and Kinghorn, A. D. 1991. Phenylacetic acid derivatives and a thioamide glycoside from Entada phaseoloides. Phytochemistry 30, 3749-3752. https://doi.org/10.1016/0031-9422(91)80102-7
  14. De Koster, C. G., Niemann, G. J. and Heerma, W. 1986. Fast atom bombardment mass spectrometry of hydroxybenzoic acids. Fresenius' Z. Anal. Chem. 323, 321-325. https://doi.org/10.1007/BF00474593
  15. Ding, Y., Chen, Z. J., Liu, S., Che, D., Vetter, M. and Chang, C. H. 2005. Inhibition of Nox-4 activity by plumbagin, a plant-derived bioactive naphthoquinone. J. Pharm. Pharmacol. 57, 111-116. https://doi.org/10.1211/0022357055119
  16. Egawa, T., Akiyo, K. and Hiroshi, T. 2006. Structural determination of vanillin, isovanillin and ethylvanillin by means of gas electron diffraction and theoretical calculations. J. Mol. Struct. 794, 92-102. https://doi.org/10.1016/j.molstruc.2006.01.042
  17. Endo, A. 1992. The discovery and development of HMG-CoA reductase inhibitors. J. Lipid Res. 33, 1569-1582.
  18. Eom, J. E., Kwon, S. C. and Moon, G. S. 2012. Detection of 1,4-dihydroxy-2-naphthoic acid from commercial makgeolli products. Prev. Nutr. Food Sci. 17, 83-86. https://doi.org/10.3746/pnf.2012.17.1.083
  19. Giugliano, D. 2000. Dietary antioxidants for cardiovascular prevention. Nut. Metab. Cardivasc. Dis. 10, 38-44.
  20. Gordon, T. and Kannel, W. B. 1972. Predisposition to atherosclerosis in the head, heart, and legs. The Framingham study. JAMA 221, 661-666. https://doi.org/10.1001/jama.1972.03200200011003
  21. Grundy, S. M. 1977. Treatment of hypercholesterolemia. Am. J. Clin. Nutr. 30, 985-992. https://doi.org/10.1093/ajcn/30.6.985
  22. Grundy, S. M. 1998. Statin trials and goals of cholesterol-lowering therapy. Circulation 97, 1436-1439. https://doi.org/10.1161/01.CIR.97.15.1436
  23. Han, S. Y. and Choi, S. C. 2002. Antibacterial activity and identification of the active compound from Turmeric extract. J. Kor. Soc. Dyers Finishers 14, 11-17.
  24. Haslam, E., Haworth, R. D., Mills, S. D., Rogers, H. J., Armitage, R. and Searle, T. 1961. 359. Gallotannins. Part II. Some esters and depsides of gallic acid. J. Chem. Soc. 1836-1842. https://doi.org/10.1039/jr9610001836
  25. Hiroshige. Y., Miyuki, Y., Yukiko, S., Masatake, I., Mutsuko, O., Yohko, F., Keiki, K., Yukio, O. and Yo, U. 1979. Tautomerism of 4-amino- and 4-arylamino-1,2-naphthoquinones. Chem. Pharm. Bull. 28, 207-1213.
  26. Jeon, J. H., Song, H. Y., Kim, M. G. and Lee, H. S. 2009. Anticoagulant properties of alizarin and its derivatives derived from the seed extract of Cassia obtusifolia. J. Kor. Soc. Appl. Biol. Chem. 52, 163-167.
  27. Jeong, D. M., Jung, H. A., Kang, H. S. and Choi, J. S. 2008. Peroxynitrite scavengers from Phellinus linteus. Nat. Prod. Sci. 14, 1-11.
  28. Jeong, O. J. and Jung, I. C. 2006. Phenolic compounds of ligustrum japonicum leaves. J. Kor. Soc. Food Sci. Nut. 35, 713-720. https://doi.org/10.3746/jkfn.2006.35.6.713
  29. Jung, D. Y., Ha, H. K., Lee, H. Y., Kim, C. S., Lee, J. H., Bae, K. H., Kim, J. S. and Kang, S. S. 2008. Triterpenoid saponins from the seeds of Pharbitis nil. Chem. Pharm. Bull. 56, 203-206. https://doi.org/10.1248/cpb.56.203
  30. Jung, H. W., Choi, J. Y., Lee, J. G., Choi, E. H., Oh, J. S., Kim, D. C., Kim, J. A., Park, S. H., Son, H. K. and Lee, S. H. 2007. Isolation of melanogenesis inhibitors from Cinnamomi cortex. Kor. J. Pharmacogn. 38, 382-386.
  31. Kang, S. S. and Woo, W. S. 1982. Anthraquinones from the leaves of Polygonum sachalinense. Kor. J. Pharmacogn. 13, 7-9.
  32. Kashiwada, Y., Nonaka, G. I., Nishioka, I. and Yamagishi, T. 1988. Galloyl and hydroxycinnamoylglucoses from rhubarb. Phytochemistry 27, 1473-1477. https://doi.org/10.1016/0031-9422(88)80218-8
  33. Kim, J. S., Yean, M. H., Seo, H. K., Lee, J. H. and Kang, S. S. 2009. Phytochemical studies on lonicera caulis (2) - Aliphatic and phenolic compounds. Kor. J. Pharmacogn. 40, 326-333.
  34. Kim, J. S., Shim, S. H., Xu, Y. N., Kang, S. S., Son, K. H., Chang, H. W., Kim, H. P. and Bae, K. H. 2004. Phenolic glycosides from Pyrola japonica. Chem. Pharm. Bull. 52, 714-717. https://doi.org/10.1248/cpb.52.714
  35. Kim, J. S., Han, S. J., Byun, J. H., Xu, Y. N., Yoo, S. W., Kang, S. S., Son, K. H., Chang, H. W. and Kim, H. P. 2001. Minor constituents from the roots of Sophora flavescens. Nat. Prod. Sci. 7, 5-8.
  36. Kim, J. S., Kim, Y. J., Lee, J. Y. and Kang, S. S. 2008. Phytochemical studies on Paeoniae radix (2); Phenolic and related compounds. Kor. J. Pharmacogn. 39, 28-36.
  37. Kim, J. S., Han, Y. S. and Kang, M. H. 2006. Identification of shikonin and its derivatives from Lithospermum erythrorhizon. J. Kor. Soc. Food Sci. Nutr. 35, 177-181. https://doi.org/10.3746/jkfn.2006.35.2.177
  38. Kim, K. T., Kim, J. G., Park, S. H., Lee, J. H., Lee, S. H., Kim, K. H. and Park, S. N. 2004. Anti-melanogenesis Effect of phenolic compounds isolated from Gastrodia elata. J. Soc. Cosmet. Scientists Korea 30, 33-38.
  39. Kim, T. H., Shin, S. R., Kim, T. W., Lee, I. C., Park, M. Y. and Jo, C. 2009. A tyrosinase inhibitor isolated from the seeds of Eriobotrya japonica. Kor. J. Food Preserv. 16, 435-441.
  40. Kim, W. J., Veriansyah, B., Lee, Y. W., Kim, J. H. and Kim, J. D. 2010. Extraction of mangiferin from Mahkota Dewa (Phaleria macrocarpa) using subcritical water. J. Ind. Eng. Chem. 16, 425-430. https://doi.org/10.1016/j.jiec.2009.08.008
  41. Kim, W. J., Lee, K. T., Lee, H. J. and Cho, S. T. 2014. Extractives from wood of Euonymus japonica. J. Kor. For. Soc. 103, 133-121.
  42. Kiuchi F., Goto, Y., Sugimoto, N., Akao, N., Kondo, K. and Tsuda, Y. 1993. Nematocidal activity of turmeric: synergistic action of curcuminoids. Chem. Pharm. Bull. 41, 1640-1643. https://doi.org/10.1248/cpb.41.1640
  43. Kobayashi, M., Terui, Y., Tori, K. and Tsuji, N. 1976. Carbon-13 NMR spectra of juglone, naphthazarin and their derivatives. Tetrahedron Lett. 17, 619-620. https://doi.org/10.1016/S0040-4039(00)77927-5
  44. Lau, C. K., Patrice, P. C., Dufresne, C. and Scheigetz, J. 1987. Novel cyclization of S-(0-acetylaryl) dimethylthiocarbamates. A new synthesis of 3-hydroxybenzothiophenes and 2-hydroxythiochromones. J. Org. Chem. 52, 1670-1673. https://doi.org/10.1021/jo00385a005
  45. Lee, E. J., Kim, J. S., Kim, H. P., Lee, J. H. and Kang, S. S. 2010. Phenolic constituents from the flower buds of Lonicera japonica and their 5-lipoxygenase inhibitory activities. Food Chem. 120, 134-139. https://doi.org/10.1016/j.foodchem.2009.09.088
  46. Lee, H. S. 2010. Suppressive effects of dihydroxyanthraquinone derivatives against inducible nitric oxide synthase. J. Kor. Soc. Appl. Biol. Chem. 53, 831-837. https://doi.org/10.3839/jksabc.2010.126
  47. Lee, J. Y., Lee, E. J., Kim, J. S., Lee, J. H. and Kang, S. S. 2011. Phytochemical studies on Rehmanniae radix preparata. Kor. J. Pharmacogn. 42, 117-126.
  48. Lee, M. K., Park, Y. B., Moon, S. S., Bok, S. H., Kim, D. J., Ha, T. Y., Jeong, T. S., Jeong, K. S. and Choi, M. S. 2007. Hypocholesterolemic and antioxidant properties of 3-(4-hydroxyl) propanoic acid derivatives in high-cholesterol fed rats. Chem. Biol. Interact. 170, 9-19. https://doi.org/10.1016/j.cbi.2007.06.037
  49. Lee, S. H., Shim S. H., Kim, J. S., Shin, K. H. and Kang, S. S. 2005. Aldose reductase inhibitors from the fruiting bodies of Ganoderma applanatum. Biol. Pharm. Bull. 28, 1103-1105. https://doi.org/10.1248/bpb.28.1103
  50. Lee, S. H., Kang, S. S., Cho, S. H., Ryu, S. N. and Lee, B. J. 2005. Determination of eleutherosides B and E in various parts of Acanthopanax species. Kor. J. Pharmacogn. 36, 70-74.
  51. Lee, S. H., Kim, W. S., Park, K. H. and Moon, J. H. 2013. Isolation and identification of 3 low-molecular compounds from pear (Pyrus pyrifolia Nakai cv. Chuhwangbae) fruit peel. Kor. J. Food Sci. Technol. 45, 174-179. https://doi.org/10.9721/KJFST.2013.45.2.174
  52. Lee, S. Y., Yean, M. H., Kim, J. S., Lee, J. H. and Kang, S. S. 2011. Phytochemical studies on Rehmanniae radix. Kor. J. Pharmacogn. 42, 127-137.
  53. Li, Y., Yang, S. and Bai, S. 2009. Studies on chemical constituents from roots of Angelica polymorpha. Zhong Yao Cai 34, 854-857.
  54. Limpe, J. W. 1999. Health effects of vegetables and fruit: assessing mechanisms of action in human experimental studies. Am. J. Clin. Nutr. 70, 475S-490S. https://doi.org/10.1093/ajcn/70.3.475s
  55. Liu, J. C., Hsu, F. L., Tsai, J. C., Chan, P., Liu, J. Y., Thomas, G. N., Tomlinsonm, B., Lo, M. Y. and Lin, J. Y. 2003. Antihypertensive effects of tannins isolated from traditional Chinese herbs as non-specific inhibitors of angiontensin converting enzyme. Life Sci. 73, 1543-1555. https://doi.org/10.1016/S0024-3205(03)00481-8
  56. Liu, X., Zhang, B., Chou, G., Yang, L. and Wang, Z. 2012. Chemical constituents from Imperata cylindrica. Zhong Yao Cai 37, 2296-2300.
  57. Massow, F. V. and Smith, M. A. 1976. Indirect 13C-1H coupling in asymmetrically trisubstituted benzenes: a carbon-13 nuclear magnetic resonance study. J. Chem. Soc. 9, 977-980.
  58. Neering, H., Vitányi, B. E., Malten, K. E., van Ketel, W. G. and van Dijk, E. 1975. Allergens in sesame oil contact dermatitis. Acta. Derm. Venereol. 55, 31-34.
  59. Ning, Y., Sun, J., Lv, H. N., Tu, P. F. and Jiang, Y. 2013. Chemical constituents from seeds of Vigna umbellata. Zhong Yao Cai. 38, 1938-1941.
  60. O'Rourke, Y., VanderZanden, A., Shepard, D. and Leach-Kemon, K. 2015. Cardiovascular disease worldwide, 1990-2013. JAMA 314, 1905. https://doi.org/10.1001/jama.2015.14994
  61. Padhye, S. B and Kulicarni, B. A. 1974. PMR evidence for hydrogen bonding in naturally occurring isomeric juglones. J. Magn. Reson. 16, 150-152.
  62. Park, J. K., Cho, H. J., Lim, Y., Cho, Y. H. and Lee, C. H. 2002. Hypocholestrolemic effect of CJ90002 in hamsters: A potent inhibitor for squalene synthase from Paeonia moutan. J. Microbiol. Biotechnol. 12, 222-227.
  63. Quick, J. and Meltz, C. 1978. Treatment of cinnamic acids with polyphosphoric acid. Chem. Commun. 8, 355.
  64. Sayed, H. M., Mohamed, M. H., Farag, S. F., Mohamed, G. A. and Proksch, P. 2007. A new steroid glycoside and furochromones from Cyperus rotundus L. Nat. Prod. Res. 21, 343-350. https://doi.org/10.1080/14786410701193056
  65. Scalbert, A. and Williamson, G. 2000. Dietary intake and bioavailability of polyphenols. J. Nutr. 130, 2073S-85S. https://doi.org/10.1093/jn/130.8.2073S
  66. Schulte, K. E., Reisch, J. and Hopmann, J. 1963. Polyacetylene und Phenoläther als inhaltsstoffe der Wurzeln von Pulicaria-Arten. Arch. Pharm. Ber. Dtsch. Pharm. Ges. 296, 353-364. https://doi.org/10.1002/ardp.19632960602
  67. Sharma, I., Gusain, D. and Dixit, V. P. 1991. Hypolipidaemic and antiatherosclerotic effects of plumbagin in rabbits. Indian J. Physiol Pharmacol. 35, 10-14.
  68. Shin, H. J., Lee, S. Y., Kim, J. S., Lee, S. H., Choi, R. J., Chung, H. S., Kim, Y. S. and Kang, S. S. 2012. Sesquiterpenes and other constituents from Dendranthema zawadskii var. latilobum. Chem. Pharm. Bull. 60, 306-314. https://doi.org/10.1248/cpb.60.306
  69. Statistics Korea. 2013. Statistics of the cause of death.
  70. Sydiskis, R. J., Owen, D. G., Lohr, J. L., Rosler, K. H. and Blomster, R. N. 1991. Inactivation of enveloped viruses by anthraquinones extracted from plants. Antimicrob. Agents. Chemother. 35, 2463-2466. https://doi.org/10.1128/AAC.35.12.2463
  71. Vermes, B., Farkas, L., Nogradi, M., Wagner, H. and Dirscherl, R. 1976. The synthesis of afzelin, paeonoside and kaempferol 3-O-$\beta$-rutinoside. Phytochemistry 15, 1320-1321. https://doi.org/10.1016/0031-9422(76)85106-0
  72. Wang, Y. N., Shi, G. L., Ren, J. J., Zhao, L., Du, J., Liu, Y. B. and Zhao, L. L. 2009. Structure identification of an acaricidal active ingredient from green walnuts husks (Juglans regia). Bioinform. Biomed. Eng. 3, 1-4.
  73. Wee, J. J., Park, J. D., Kim, M. W. and Lee, H. J. 1989. Identification of phenolic antioxidant components isolated from Panax ginseng. J. Kor. agric. Chem. Soc. 32, 50-56.
  74. Wierzbicki, A. S. 2003. New lipid-lowering agents. Expert Opin. Emerg. Drugs. 8, 365-376. https://doi.org/10.1517/14728214.8.2.365
  75. Woo, W. S. and Kang, S. S. 1979. A new phenolic aldehyde from the seeds of Phytolacca americana. Kor. J. Pharmacogn. 10, 83-84.
  76. Xu, R., Yokoyama, W. H., Irving, D., Rein, D., Walzem, R. L. and German, J. B. 1998. Effect of dietary catechin and vitamin E on aortic fatty streak accumulation in hypercholesterolemic hamsters. Atherosclerosis 137, 29-36. https://doi.org/10.1016/S0021-9150(97)00248-7
  77. Yamaloshi, J., Ktaoka, S., Koga, T. and Ariga, T. 1999. Proanthocyanidinrich extract from grape seed attenuates the development of arotic atherosclerosis in cholesterol-fed rabbits. Atheroscelerosis 142, 139-149. https://doi.org/10.1016/S0021-9150(98)00230-5
  78. Yean, M. H., Kim, J. S., Hyun, Y. J., Hyun, J. W., Bae, K. H. and Kang, S. S. 2012. Terpenoids and phenolics from Geum japonicum. Kor. J. Pharmacogn. 43, 107-121.