A Review of the Medicinal Uses and Pharmacology of Ashitaba

Abstract

Angelica keiskei Koidzumi, or ashitaba, is a popular botanical medicine in Japan containing diverse bioactive components including prenylated chalcones, linear and angular coumarins, and flavanones. This review provides an overview of the current knowledge of ashitaba metabolites and their biological activities to prioritize future studies. Ashitaba is purported to possess cytotoxic, antidiabetic, antioxidative, anti-inflammatory, antihypertensive, and antimicrobial properties. Although many in vitro studies have been conducted on ashitabaʼs chemical constituents, the in vivo efficacy and clinical relevance of this plant has yet to be confirmed for most of these activities. Here we describe the chemical composition of ashitaba and present the pharmacological effects of this botanical as supported by the current literature. The experimental results demonstrate promise for the medical use of ashitaba, but considerable work needs to be done to understand the mechanisms of action of its metabolites. Additionally, in vivo and clinical trials as well as additional studies on less abundant bioactive compounds are warranted.

Key words

Angelica keiskei - Apiaceae - bioactivity studies - coumarins - prenylated chalcones

• References

• 1 Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the Use of complementary Health approaches among Adults: United States, 2002 – 2012. National Health Statistics Report, No. 79. Hyattsville, MD: National Center for Health Statistics; 2015
• 2 Sarkar SD, Nahar L. Natural medicine: the genus Angelica . Curr Med Chem 2004; 11: 1479-1500
• 3 Akihisa T, Tokuda H, Hasegawa D, Ukiya M, Kimura Y, Enjo F, Suzuki T, Nishino H. Chalcones and other compounds from the exudates of Angelica keiskei and their cancer chemopreventive effects. J Nat Prod 2006; 29: 38-42
• 4 Kim DW, Curtis-Long MJ, Yuk HR, Wang Y, Song YH, Jeong SH, Park KH. Quantitative analysis of phenolic metabolites from different parts of Angelica keiskei by HPLC-ESI MS/MS and their xanthine oxidase inhibition. Food Chem 2014; 153: 20-27
• 5 Winkel-Shirley B. Flavonoid biosynthesis. A colorful model for genetics, biochemistry, cell biology, and biotechnology. Plant Physiol 2011; 126: 485-493
• 6 Zhang H, Liu JJ, Sun J, Yang XH, Zhao TT, Lu X, Gong HB, Zhu HL. Design, synthesis, and biological evaluation of novel chalcone derivatives as antitubulin agents. Bioorg Med Chem 2012; 20: 3212-3218
• 7 Mahapatra DK, Asati V, Bharti SK. Chalcones and their therapeutic targets for the management of diabetes: structural and pharmacological perspectives. Eur J Med Chem 2015; 92: 839-865
• 8 Battenberg OA, Yang Y, Verhelst SH, Sieber SA. Target profiling of 4-hydroxyderricin in S. aureus reveals seryl-tRNA synthetase binding and inhibition by covalent modification. Mol Biosyst 2013; 9: 343-351
• 9 Yadav VR, Prasad S, Sung B, Aggarwal BB. The role of chalcones in suppression of NF-κB-mediated inflammation and cancer. Int Immunopharmacol 2011; 11: 295-309
• 10 Ceremuga TE, Johnson LA, Adams-Henderson J, McCall S, Johnson D. Investigation of the anxiolytic effects of xanthohumol, a component of Humulus lupulus (Hops), in the male Sprague-Dawley rat. AANA J 2013; 81: 193-198
• 11 Zhou B, Xing C. Diverse molecular targets for chalcones with varied bioactivities. Med Chem 2015; 5: 388-404
• 12 Zhang T, Yamashita Y, Yasuda M, Yamamoto N, Ashida H. Ashitaba (Angelica keiskei) extract prevents adiposity in high-fat diet-fed C57BL/6 mice. Food Funct 2015; 6: 135-145
• 13 Bourgaud F, Hehn A, Larbat R, Doerper S, Gontier E, Kellner S, Matern U. Biosynthesis of coumarins in plants: a major pathway still to be unravelled for cytochrome P450 enzymes. Phytochem Rev 2006; 5: 293-308
• 14 Fylaktakidou KC, Hadjipavlou-Litina DJ, Litinas KE, Nicolaides DN. Natural and synthetic coumarin derivatives with anti-inflammatory/antioxidant activities. Curr Pharm Des 2004; 10: 3813-3833
• 15 Musa MA, Cooperwood JS, Khan MO. A review of coumarin derivatives in pharmacotherapy of breast cancer. Curr Med Chem 2008; 15: 2664-2679
• 16 Okuyama T, Takata M, Takayasu J, Hasegawa T, Tokuda H, Nishino A, Nishino H, Iwashima A. Anti-tumor-promotion by principles obtained from Angelica keiskei . Planta Med 1991; 57: 242-246
• 17 Akihisa T, Tokuda H, Ukiya M, Iizuka M, Schneider S, Ogasawara K, Mukainaka T, Iwatsuki K, Suzuki T, Nishino H. Chalcones, coumarins, and flavanones from the exudate of Angelica keiskei and their chemopreventive effects. Cancer Lett 2003; 201: 133-137
• 18 Li J, Gao L, Meng F, Tang CL, Zhang RJ, Li JY, Luo C, Li J, Zhao WM. PTP1B inhibitors from stems of Angelica keiskei (Ashitaba). Bioorg Med Chem Lett 2015; 25: 2028-2032
• 19 Ogawa H, Nakamura R, Baba K. Beneficial effect of laserpitin, a coumarin compound from Angelica keiskei, on lipid metabolism in stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 2005; 32: 1104-1109
• 20 Wong E. The role of chalcones and flavanones in flavonoid biosynthesis. Phytochemistry 1968; 7: 1751-1758
• 21 Khan MK, Zill EH, Dangles O. A comprehensive review on flavanones, the major citrus polyphenols. J Food Comp Anal 2014; 33: 85-104
• 22 Aoki N, Ohta S. Ashitabaol A, a new antioxidative sesquiterpenoid from seeds of Angelica keiskei . Tetrahedron Lett 2010; 51: 3449-3450
• 23 Enoki T, Ohnogi H, Nagamine K, Kudo Y, Sugiyama K, Tanabe M, Kobayashi K, Sagawa H, Kato I. Antidiabetic activities of chalcones isolated from a Japanese herb, Angelica keiskei . J Agric Food Chem 2007; 55: 6013-6017
• 24 Luo L, Wang R, Wang X, Ma Z, Li N. Compounds from Angelica keiskei with NQO1 induction, DPPH scavenging and α-glucosidase inhibitory activities. Food Chem 2012; 131: 992-998
• 25 Kawabata K, Sawada K, Ikeda K, Fukuda I, Kawasaki K, Yamamoto N, Ashida H. Prenylated chalcones 4-hydroxyderricin and xanthoangelol stimulate glucose uptake in skeletal muscle cells by inducing GLUT4 translocation. Mol Nutr Food Res 2011; 55: 467-475
• 26 Zhang T, Sawada K, Yamamoto N, Ashida H. 4-Hydroxyderricin and xanthoangelol from Ashitaba (Angelica keiskei) suppress differentiation of preadipocytes to adipocytes via AMPK and MAPK pathways. Mol Nutr Food Res 2013; 57: 1729-1740
• 27 Ohnogi H, Kudo Y, Tahara K, Sugiyama K, Enoki T, Hayami S, Sagawa H, Tanimura Y, Aoi W, Naito Y, Kato I, Yoshikawa T. Six new chalcones from Angelica keiskei inducing adiponectin production in 3T3-L1 adipocytes. Biosci Biotechnol Biochem 2012; 76: 961-966
• 28 Ohnogi H, Hayami S, Kudo Y, Enoki T. Efficacy and safety of ashitaba (Angelica keiskei) on the patients and candidates with metabolic syndrome: a pilot study. JJCAM 2012; 9: 49-55
• 29 Hashimoto K, Kawamata S, Usui N, Tanaka A, Uda Y. In vitro induction of the anticarcinogenic marker enzyme, quinone reductase, in human hepatoma cells by food extracts. Cancer Lett 2002; 180: 1-5
• 30 Akihisa T, Motoi T, Seki A, Kikuchi T, Fukatsu M, Tokuda H, Suzuki N, Kimura Y. Cytotoxic activities and anti-tumor-promoting effects of microbial transformation products of prenylated chalcones from Angelica keiskei . Chem Biodivers 2012; 9: 318-330
• 31 Aoki N, Muko M, Ohta E, Ohta S. C-Geranylated chalcones from the stems of Angelica keiskei with superoxide-scavenging activity. J Nat Prod 2008; 71: 1308-1310
• 32 Yasuda M, Kawabata K, Miyashita M, Okumura M, Yamamoto N, Takahashi M, Ashida H, Ohigashi H. Inhibitory effects of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide-induced inflammatory responses in RAW264 macrophages. J Agric Food Chem 2014; 62: 462-467
• 33 Sugii M, Ohkita M, Taniguchi M, Baba K, Kawai Y, Tahara C, Takaoka M, Matsumura Y. Xanthoangelol D isolated from the roots of Angelica keiskei inhibits endothelin-1 production through the suppression of nuclear factor kappaB. Biol Pharm Bull 2005; 28: 607-610
• 34 Lee HJ, Choi TW, Kim HJ, Nam D, Jung SH, Lee EH, Lee HJ, Shin EM, Jang HJ, Ahn KS, Shim BS, Choi SH, Kim SH, Sethi G, Ahn KS. Anti-inflammatory activity of Angelica keiskei through suppression of mitogen-activated protein kinases and nuclear factor κB activation pathways. J Med Food 2010; 13: 691-699
• 35 Ohkura N, Nakakuki Y, Taniguchi M, Kanai S, Nakayama A, Ohnishi K, Sakata T, Nohira T, Matsuda J, Baba K, Atsumi G. Xanthoangelols isolated from Angelica keiskei inhibit inflammatory-induced plasminogen activator inhibitor 1 (PAI-1) production. Biofactors 2011; 37: 455-461
• 36 Nakata K, Baba K. Histamine release inhibition activity of Angelica keiskei . Nat Med 2001; 55: 32-34
• 37 Son DJ, Park YO, Yu C, Lee SE, Park YH. Bioassay-guided isolation and identification of anti-platelet-active compounds from the root of Ashitaba (Angelica keiskei Koidz.). Nat Prod Res 2014; 28: 2312-2316
• 38 Shimizu E, Hayashi A, Takahashi R, Aoyagi Y, Murakami T, Kimoto K. Effects of angiotensin I-converting enzyme inhibitor from ashitaba (Angelica keiskei) on blood pressure of spontaneously hypertensive rats. J Nutr Sci Vitaminol 1999; 45: 375-383
• 39 Park JY, Jeong HJ, Kim YM, Park SJ, Rho MC, Park KH, Ryu YB, Lee WS. Characteristic of alkylated chalcones from Angelica keiskei on influenza virus neuraminidase inhibition. Bioorg Med Chem Lett 2011; 21: 5602-5604
• 40 Inamori K, Baba K, Tsujibo H, Taniguchi M, Nakata K, Kozawa M. Antibacterial activity of two chalcones, xanthoangelol and 4-hydroxyderricin, isolated form the root of Angelica keiskei KOIDZUMI. Chem Pharm Bull 1991; 39: 1604-1605
• 41 Wesolowska O, Gasiorowska J, Petrus J, Czarnik-Matusewicz B, Michalak K. Interaction of prenylated chacones and flavaonones from common hop with phosphatidylcholine model membranes. Biochim Biophys Acta 2014; 1838: 173-184
• 42 Bolca S, Li J, Nikolic D, Roche N, Blondeel P, Possemiers S, De Keukeleire D, Bracke M, Heyerick A, van Breemen RB, Depypere H. Disposition of hop prenylflavnoids in human breast tissue. Mol Nutr Food Res 2010; 54 (Suppl. 02) S284-S294
• 43 Hanske L, Loh G, Sczensky S, Blaut M, Braune A. Recovery and metabolism of xanthohumol in germ-free and human microbiota-associated rats. Mol Nutr Food Res 2010; 52: 1405-1413
• 44 Possemiers S, Heyerick A, Robbens V, De Keukeleire D, Verstraete W. Activation of proestrogens from hops (Humulus lupulus) by intestinal microbiota; conversion of isoxanthohumol into 8-prenylnaringenin. J Agric Food Chem 2005; 53: 6281-6288
• 45 Maronpot RR. Toxicological assessment of Ashitaba Chalcone. Food Chem Toxicol 2015; 77: 111-119
• 46 Son H, Yoon E, Cha Y, Kim MA, Shin YK, Kim JM, Choi YH, Lee SH. Comparison of the toxicity of aqueous and ethanol fractions of Angelica keiskei leaf using the eye irritancy test. Exp Ther Med 2012; 4: 820-824
• 47 Vignes S, Bellanger J. Primary intestinal lymphangiectasia (Waldmannʼs disease). Orphanet J Rare Dis 2008; 3: 1-8
• 48 Messer A, Raquet N, Lohr C, Schrenk D. Major furocoumarins in grapefruit juice II: phototoxicity, photogenotoxicity, and inhibitory potency vs. cytochrome P450 3A4 activity. Food Chem Toxicol 2012; 50: 756-760
• 49 Eisenbrand G. Toxicological assessment of furocoumarins in foodstuffs, opinion of the Senate Commission on Food Safety of the German Research Foundation–shortened version. Mol Nutr Food Res 2007; 51: 367-373
• 50 Kozawa M, Morita N, Baba K, Hata K. The structure of xanthoangelol, a new chalcone from the roots of Angelica keiskei Koidzumi (Umbelliferae). Chem Pharm Bull 1977; 25: 515-516
• 51 Baba K, Nakata K, Taniguchi M, Kido T, Kozawa M. Chalcones from Angelica keiskei . Phytochemistry 1990; 29: 3907-3910
• 52 Nakata K, Taniguchi K, Baba K. Three chalcones from Angelica keiskei . Nat Med 1999; 53: 329-332
• 53 Baba K, Kido T, Yoneda Y, Taniguchi M, Kozawa M. Chemical components of Angelica keiskei Koidzumi v. components of the fruits and comparison of coumarins and chalcones in the fruits roots and leaves. Shoyakugaku Zasshi 1990; 44: 235-239
• 54 Ogawa H, Nakashima S, Baba K. Effects of dietary Angelica keiskei on lipid metabolism in stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 2003; 30: 284-288
• 55 Kim E, Choi J, Yeo I. The effects of Angelica keiskei Koidz on the expression of antioxidant enzymes related to lipid profiles in rats fed a high fat diet. Nut Res Pract 2012; 6: 9-15
• 56 Nagata J, Morino T, Saito M. Effects of dietary Angelica keiskei on serum and liver lipid profiles, and body fat accumulations in rats. J Nutr Sci Vitaminol 2007; 53: 133-137
• 57 Ohnogi H, Hayami S, Kudo Y, Deguchi S, Mizutani S, Enoki T, Tanimura Y, Aoi W, Naito Y, Kato I, Yoshikawa T. Angelica keiskei extract improves insulin resistance and hypertriglyceridemia in rats fed a high-fructose drink. Biosci Biotechnol Biochem 2012; 96: 928-932