key: cord-0798201-lxup8pr2
authors: Kil, Yun-Seo; Pham, Sally T.; Seo, Eun Kyoung; Jafari, Mahtab
title: Angelica keiskei, an emerging medicinal herb with various bioactive constituents and biological activities
date: 2017-04-24
journal: Arch Pharm Res
DOI: 10.1007/s12272-017-0892-3
sha: 831037c802a882a6cae47cd231349023241e6c74
doc_id: 798201
cord_uid: lxup8pr2

Angelica keiskei (Miq.) Koidz. (Umbelliferae) has traditionally been used to treat dysuria, dyschezia, and dysgalactia as well as to restore vitality. Recently, the aerial parts of A. keiskei have been consumed as a health food. Various flavonoids, coumarins, phenolics, acetylenes, sesquiterpene, diterpene, and triterpenes were identified as the constituents of A. keiskei. The crude extracts and pure constituents were proven to inhibit tumor growth and ameliorate inflammation, obesity, diabetics, hypertension, and ulcer. The extract also showed anti-thrombotic, anti-oxidative, anti-hyperlipidemic, anti-viral, and anti-bacterial activities. This valuable herb needs to be further studied and developed not only to treat these human diseases but also to improve human health. Currently A. keiskei is commercialized as a health food and additives in health drinks. This article presents a comprehensive review of A. keiskei and its potential place in the improvement of human health.

Angelica keiskei (Miq.) Koidz. is a hardy perennial, belonging to the family Umbelliferae. A. keiskei has traditionally been used as a diuretic, mild cathartic, tonic, and galactagogue (Kimura and Baba 2003) . The herb is called 'Myeong-Il Yeob' in Korea and 'Ashitaba' in Japan, both literally meaning 'Tomorrow's Leaf' (Baba et al. 1998) . Another common name for A. keiskei is 'Shin-Sun Cho', which means 'a precious herb used by God'. A. keiskei is mainly distributed in Asian countries including Korea and Japan (Park 2013) . The aerial parts are mainly used as a source of green vegetable juice as a daily health food and the young leaves of the aerial parts are used by parboiling or deep-frying (Imai and Imai 2008). The aerial parts are also used in tea, flour, wine, and cosmetics (Bao 2014; Su 2014; Ku et al. 2014; Liu et al. 2014 ). This review paper summarizes botanical characteristics, phytochemical research, as well as biological studies on the extracts and pure constituents of A. keiskei. The extracts have been reported to have anti-inflammatory, anti-obesity, anti-oxidative, anti-coagulant, anti-tumor, anti-mutagenic, antidiabetic, anti-bacterial, and hepato-protective activities. The biological activities of each pure compounds are also separately summarized in this review.

Angelica keiskei has glossy leaves and flowers from summer to fall. The leaves are harvested from spring to fall before they lose the gloss. A yellow exudate is squeezed out of the stems when the leaves are harvested (Imai and Imai 2008) . This yellow color makes it easy to distinguish A. keiskei from A. japonica, an exudate of which shows a nearly white color . The characteristic botanical features of A. keiskei are described in Flora of Japan:

Rhizomes thick and short, with few elongate roots. Stems stout, branched above, 80-120 cm long, glabrous. Leaves radical and lower cauline, usually evergreen, 2-3-ternate-pinnate, obtusely deltoid in outline, 20-60 cm. long, glabrous; leaflets rather thick, usually deeply 2-3 cleft of parted; segments usually ovate, 5-10 cm long, 3-6 cm wide, acute, toothed, with impressed veinlets on upper side; sheaths on the upper part elliptic, inflated. Inflorescence umbels rather numerous; peduncles in upper part; the inner side of rays and pedicels puberulent; rays 10-20; pedicels 20-40; bracteoles of involucel several, linear or slightly broaden at base, caudately elongate, slightly longer or shorter than pedicels; styles short, as long as stylopodium. Fruit oblong, glabrous, 6-8 mm long, flat; dorsal ribs short and rather thick; lateral ribs winged; vittae 1 in intervals, 4 on the commissure (Oi et al. 1965 ).

Previous phytochemical investigations on A. keiskei have led to the identification of over 100 compounds including various types of flavonoids (1-31, 41-56), coumarins (57-92), phenolic (96), acetylenes (98-102), sesquiterpene (103), diterpene (104), and triterpenes (105-106). Structures of the reported constituents listed in Tables 1, 2 and 3 are shown in Fig. 1 . In our recent study on the aerial parts of A. keiskei, eight constituents, 4,2 0 ,4 0 -trihydroxy-3 0 -[(2E,5E)-7-methoxy-3,7-dimethyl-2,5-octadienyl]chalcone (32), (±)-4,2 0 ,4 0 -trihydroxy-3 0 -[(2E)-6-hydroxy-7-methoxy-3,7-dimethyl-2-octenyl]chalcone (33), 4,2 0 ,4 0 -trihydroxy-3 0 -[(2E)-3-methyl-5-(1,3-dioxolan-2-yl)-2-pentenyl] chalcone (34), 2 0 ,3 0 -furano-4-hydroxy-4 0 -methoxychalcone (35), (±)-4-hydroxy-2 0 ,3 0 -(2,3-dihydro-2-methoxyfurano)-4 0 -methoxychalcone (36), 3 0 -carboxymethyl-4,2 0 -dihydroxy-4 0 -methoxychalcone (37), (±)-4,2 0 ,4 0 -trihydroxy-3 0 -[(3-hydroxy-2,2-dimethyl-6-methylenecyclohexyl)methyl] chalcone (38), and 2 00 -hydroxyangelichalcone (39) were isolated and reported as new compounds from an ethyl acetate extract along with eight known compounds, xanthoangelol (1), xanthoangelol F (2), 4-hydroxyderricin (3), xanthoangelol G (6), xanthoangelol D (9), xanthoangelol E (10), xanthoangelol H (12), (±)-4,2 0 ,4 0 -trihydroxy-3 0 -[(6E)-2-hydroxy-7-methyl-3-methylene-6-octenyl]chalcone (27), artocarmitin A (40), (?)-cis-(3 0 R,4 0 R)-methylkhellactone (93), (-)-trans-(3 0 R,4 0 S)-methylkhellactone (94), 3,4-dihydroxanthotoxin (95), and (Z)-p-coumaryl alcohol (97) (Kil et al. 2015a (Kil et al. , 2016 . In particular, xanthoangelol (1) and 4-hydroderricin (3) were isolated in bulk (1: 5 g, 2: 1.8 g), which supported that the two chalcones are the predominant constituents in this herb. As a part of our research on the aerial parts of A. keiskei, an effective method was developed to prepare two chalcones from the crude extract using high-speed counter-current chromatography (twophase solvent system: n-hexane-ethyl acetate-methanolwater 9:5:9:4, revolution rate: 800 rpm, flow rate: 1.5 mL/ min) (Kil et al. 2015b ).

An n-hexane fraction from an ethanol extract of the aerial parts of A. keiskei showed inhibitory effects on production of lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) by downregulating inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and mRNA (Lee et al. 2010 ). An ethyl acetate fraction also inhibited production of NO in LPS-activated RAW 264.7 cells (Chang et al. 2014 ).

In a study in mice, an ethyl acetate extract was reported to prevent high-fat diet induced adiposity by modulating lipid metabolism through increasing phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in adipose tissue and liver . A patent has been filed on the anti-obesity activity of the ethanol extract of the aerial parts of A. keiskei in mice (Lee et al. 2012a ).

Dietary A. keiskei as an ethyl acetate extract from yellow exudates produced elevation of serum high-density lipoprotein (HDL) levels containing apolipoprotein A1 (ApoA1) and ApoE and reduction of liver triglyceride (TG) levels with decreased mRNA expression of hepatic Acylcoenzyme A (CoA) synthetase in stroke-prone spontaneously hypertensive rats (SHRSP) (Ogawa et al. 2003 ). An ethyl acetate fraction from a methanol extract showed inhibitory effects against 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, a crucial and rate limiting enzyme in biosynthesis of cholesterol (Park et al. 1997b ). The impact of A. keiskei was examined in rats fed a high fat diet, and it was shown that liver weight was decreased and gene expression of the anti-oxidant enzymes, catalase and glutathione-s-reductase, in the liver was increased (Kim et al. 2012 ). In addition, treatment of the ethanol extract reduced increased levels of serum insulin and triglycerides in rats after drinking fructose. The ethanol extract enhanced expression of genes related to fatty acid b-oxidation and HDL production, acyl-CoA oxidase 1 (ACO1), medium-chain acyl-CoA dehydrogenase (MCAD), ATPbinding membrane cassette transporter A1 (ABCA1), and ApoA1 genes in the fructose fed rats (Ohnogi et al. 2012a) .

The alcohol extracts of A. keiskei were evaluated for their scavenging capability against superoxide anion and 1,1diphenyl-2-picrylhydrazyl (DPPH) free radicals, and resulted in decreases of free radical formations. The scavenging effects of the leaves extract were greater than those of the stems extract (Qin et al. 2014; Guo et al. 2013) .

Exudates of A. keiskei resulted in anti-coagulation by inhibiting elevated plasma plasminogen activator inhibitor 1 (PAI-1) under inflammatory conditions induced by LPS (Ohkura et al. 2011) . A methanol extract of its roots showed anti-platelet activity when evaluated in a washed rabbit platelets model system (Son et al. 2014 ). . In these cancer cell lines studies, increasing expression level of the proapoptotic gene, Caspase-3, and apoptotic inducer gene, B cell lymphoma 2 (Bcl-2), and decreasing expression level of the apoptotic suppressor gene, Bcl-2 associated x (Bax), were presented as the mechanism of action of anti-cancer effects of A. keiskei (Jeong and Kang 2011) . The methanol extract showed an anti-mutagenic activity against aflatoxin B1 (AFB1), N-methyl-N 0 -nitro-N-nitrosoguanidine, Kozawa et al. (1977) RT Anti-ulcer activity: gastric H ? -K ? ATPase Murakami et al. (1990) RT Anti-bacterial activity: gram-positive bacteria Inamori et al. (1991) Syn (47) AP Anti-oxidative activity: DPPH radical scavenging Kim et al. (2005) Hyperoside

First isolation from the part Park et al. (1996) AP Anti-cholesterogenic activity: HMG-CoA reductase Park et al. (1997b) AP Anti-mutagenic activity (AFB1) Park et al. (1997a) AP Anti-oxidative activity: DPPH radical scavenging Kim et al. (2005) Quercitrin (49) (61) RT NGF production enhancive effect on in mouse fibroblasts (details in the patent) Ohnogi et al. (2002) Psoralen ( (2012) Angelicin (77) RT First isolation from the part Hata and Kozawa (1961) Columbianadin (78) Nucleoside and 4-nitroquinoline-1-oxide in a salmonella assay system (Park et al. 1997a ).

The ethanol extract exhibited insulin-like activities through a pathway independent of peroxisome proliferator-activated receptor-c (PPAR-c) activation ). Long-term ingestion of a powder of A. keiskei improved blood glucose control and moderately and safely reduced blood glucose . A patent is filed on the beneficial effects of A. keiskei on diabetes (Lee et al. 2013 ).

An exudate of A. keiskei showed anti-bacterial activity against Helicobacter pylori, suggesting A. keiskei as a preventive agent for gastritis (Fukuo et al. 2005) . A patent on this exudate is filed for controlling mouth odor by an anti-bacterial activity against Fusobacterium nucleatum (Saeki et al. 2013 ).

A clinical trial for habitual alcohol drinkers with abnormal liver function tests also showed that intake of the extracts significantly reduced c-glutamyl transferase (GGT) levels (Noh et al. 2015) . A patent is filed on the beneficial activity of an ethanol extract of the roots to improve liver functions and relieve fatigue (Kim et al. 2006) .

In addition to these activities, an ethanol extract also showed an anti-hypertensive activity by inhibiting angiotensin 1-converting enzyme (ACE) in spontaneously hypertensive rats, similar to nicotianamine (Shimizu et al. 1999) . Green juice of A. keiskei was proven to protect lymphocytic DNA damage of smokers, which was reported to potentially reduce the risk of lung cancer in a clinical trial (Kang et al. 2004 ). In another clinical study, consuming a drink powder of the leaves three times a day for 2 weeks alleviated mild constipation and improved defecation (Kusaba et al. 2008 ). Deficit of learning and memory caused by Alzheimer's disease and aging may be alleviated by A. keiskei since it has been shown that the plant is capable of restoring scopolamine-reduced phosphorylation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and expression of brainderived neurotrophic factor (BDNF) in the mouse hippocampus (Oh et al. 2013) . Topical uses of the extracts were shown to whiten skin with tyrosinase inhibitory effect (Higa 1985; Lee et al. 2012b ) and promote hair growth (Sakaguchi et al. 1996) in patent applications.

Isolates from A. keiskei have showed diverse biological activities. Especially two major chalcones, xanthoangelol (1) and 4-hydroxyderricin (3), have been extensively Park et al. (1996) Saccharide Sucrose (109) AP First isolation from the part Park et al. (1996) AP Anti-mutagenic activity (AFB1) Park et al. (1997a) Acids Angelic acid (110) RT First isolation from the part Hata and Kozawa (1961) Behenic acid (111) RT First isolation from the part Hata and Kozawa (1961) Others protective effects on damaged cells, and HSP-inducible agents may act as prospective agents to protect normal cells from chemotherapy induced adverse effects. (±)-4,2 0 ,4 0 -Trihydroxy-3 0 -[(6E)-2-hydroxy-7-methyl-3-methylene-6octenyl] chalcone (27) of 2 lM increased expressions of HSF1 (4.3-fold), HSP70 (1.5-fold), and HSP27 (4.6-fold) proteins at 6 h of treatment and mRNA levels of HSP70 (5.0-fold) and HSP27 (1.5-fold) at 3 h with lower cytotoxicity than celastrol, a positive control (Kil et al. 2015a ).

Xanthoangelol (1) and 4-hydroxyderricin (3) inhibited H ? , K ? -ATPase of gastric microsomal vesicles which were prepared from pig fundic mucosa. Additionally, they downregulated K ? -stimulated p-nitrophenyl phosphatase. Xanthoangelol (1) reduced the formation of stress-induced gastric lesion as well as acid secretion in rats (Murakami et al. 1990) . Xanthoangelol E (10) was also found to have the anti-ulcer activity as patented by Murakami et al. (Murakami et al. 1992) .

Xanthoangelol (1) and 4-hydroxyderricin (3) showed antibacterial activities against gram-positive bacteria, Bacillus subtilis PCI-219, B. subtilis ATCC-6633, B. cereus FDA-5, Staphylococcus aureus 209-P, S. aureus IFO-3060, S. aureus IFO-3762, and Micrococcus luteus IFO-12708, but not gram-negative bacteria. Although the antibacterial activities were lower than gentamicin for the aforementioned bacteria, the anti-bacterial activity of xanthoangelol (1) against M. luteus IFO-12708 was as strong as that of gentamicin (MIC 0.76 lg/mL) (Inamori et al. 1991) . Mechanism of anti-bacterial activity of 4-hydroxyderricin (3) against S. aureus was elucidated by utilizing a chemical cleavable linker due to its heat sensitivity, reporting that the isolate inhibits amino acylation of tRNAs catalyzed by S. aureus seryl-tRNA synthetase which is an essential enzymatic pathway for bacterial viability (Battenberg et al. 2013 ). The two chalcones exhibited antibacterial activities against plant-pathogenic bacteria, Agrobacteriu tumefaciens IFO-3058, Pseudomonas syringae pv. phaseolicola IFO-12656, P. syringae pv. tabaci IFO-3508, and P. stutzeri IFO-12510 (Inamori et al. 1991 (Sugamoto et al. 2011) .

Bioactive compounds with anti-tumor-promoter, anti-tumor-initiator, and anti-mutagenic activities may be considered as chemopreventive therapeutic agents. Two angular furanocoumarin, (8S,9R)-8-angeloxy-8,9dihydrooroseol (79, (3 0 R)-hydroxycolumbianadin) and archangelicin (81), and three chalcones, xanthoangelol (1), 4-hydroxyderricin (3), and ashitaba-chalcone (11) inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated 32 Pi-incorporation of phospholipids of cultured cells. Xanthoangelol (1) and 4-hydroxyderricin (3) showed antitumor-promoting activities in mouse skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) plus TPA via the modulation of Ca ? -calmodulin system (Okuyama et al. 1991) . Isobavachalcone (4) exhibited inhibitory effects on skin tumor promotion in in vivo twostage mouse skin carcinogenesis test (Akihisa et al. 2006) . Inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by TPA in Raji cells were found for xanthoangelol (1), xanthoangelol F (2), 4-hydroxyderricin (3), isobavachalcone (4), xanthoangelol H (12), xanthoangelol I (14), xanthoangelol J (16), munduleaflavanone A (51), munduleaflavanone B (52), isobavachin (53), prostratol F (54), 8-geranylnaringenin (55, 8-geranulnaringenin) , 4 0 -O-geranylnaringenin (56), osthenol (60), (3 0 R)-hydroxycolumbianidin (79, (8S,9R)-8-angeloxy-8,9dihydrooroseol), 3 0 -senecioyl khellactone (87), (3 0 R,4 0 R)-3 0 -angeloyl khellactone (89, miswritten as ''isolaserapitin'' in the article), 4 0 -senecioyl khellactone (90), isolemanidin (91, miswritten as ''laserapitin'' in the article), and pteryxin (92) (Akihisa et al. 2003 (Akihisa et al. , 2006 . Xanthoangelol F (2), isobavachalcone (4), xanthoangelol I (14), xanthoangelol J (16), munduleaflavanone B (52), 8-geranylnaringenin (55, sophoraflavanone A), osthenol (60), selinidin (83), 3 0senecioyl khellactone (87), (3 0 R,4 0 R)-3 0 -angeloyl khellactone (89, miswritten as ''isolaserapitin'' in the article), 4 0senecioyl khellactone (90), isolemanidin (91, miswritten as ''laserapitin'' in the article), and pteryxin (92) inhibited activation of (±)-(E)-methyl-2-[(E)-hydroxy-imino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a NO donor (Akihisa et al. 2003 (Akihisa et al. , 2006 . Cynaroside (43, luteolin-7-O-b-D-glucopyranoside), luteolin-7-O-b-D-rutinoside (44), hyperoside (48, quercetin-3-O-b-D-galactopyranoside), and sucrose (109) showed anti-mutagenic activities against aflatoxin B1 (AFB1) (Park et al. 1997a ).

In a previous study, xanthoangelol (1) and 4-hydroxyderricin (3) were identified as active compounds to inhibit tumor growth in Lewis lung carcinoma (LLC)-bearing mice and to prolong survival time and to suppress metastasis to the lung after surgical removal of primary tumors from an active ethyl acetate fraction of a 50% ethanol extract (Kimura and Baba 2003; Kimura et al. 2004 ). The anti-tumor activities of xanthoangelol (1) might be derived from its inhibitory effects on DNA synthesis in LLC cells and on tumor-induced neovascularization by reducing formation of capillary-like tubes by vascular endothelial cells and adhesion of vascular endothelial growth factor (VEGF) to human umbilical vein endothelial cells (HUVECs) (Kimura and Baba 2003) . 4-Hydroxyderricin (3) also inhibited the DNA synthesis in LLC cells and the formation of capillary-like tubes, but did not reduce adhesion of vascular endothelial growth factor (VEGF) to HUVECs. Instead, it suppressed reduction of lymphocytes, CD4 ? , CD8 ? , and natural killer (NK)-T cells in spleen of tumor-removed mice (Kimura et al. 2004) . Xanthoangelol (1) induced apoptotic cell death by activation of caspase-3 in neuroblastoma (IMR-32) and leukemia (Jurkat) cells through a mechanism, independent of Bax/Bcl-2 signal transduction (Tabata et al. 2005) . Their ongoing study revealed details of the mechanism of action of xanthoangelol (1) inducing apoptosis by triggering oxidative stress through generating reactive oxygen species and downregulating antioxidant DJ-1 protein in IMR-32 cells (Motani et al. 2008) . Xanthoangelol (1) showed cytotoxic effects on several neuroblastoma cell lines including drug-resistant LA-N-1 and NB-39 cells as well as drug-sensitive IMR-32 and SK-N-SH cells (Nishimura et al. 2007; Motani et al. 2008) . Xanthoangelol F (2), 4-hydroxyderricin (3), isobavachalcone (4), xanthoangelol H (12), and xanthoangelol I (14) were cytotoxic to the NB-39 and IMR-32 cells. Isobavachalcone (4) was found to induce apoptotic cell death in the neuroblastoma cells via the mitochondrial pathway including reduction of procaspase-3 and procaspase-9 and induction of Bax level with no cytotoxicity against normal cells (Nishimura et al. 2007 ). Xanthoangelol (1) and 4-hydroxyderricin (3) inhibited growth of human stomach cancer (KATO III) cells through induction of apoptosis by fragmenting DNA (Takaoka et al. 2008 ). 4-Hydroxyderricin (3) exhibited cytotoxic activities in human leukemia (HL60), melanoma (CRL1579), lung cancer (A549), and stomach cancer (AZ521) cells. The cytotoxicity to HL60 cells was caused by induction of apoptosis through inhibiting DNA topoisomerase and reducing procasparases-3, -8, and -9 (Akihisa et al. 2011 ).

In a genetically diabetic KK-A y mouse model, xanthoangelol (1) and 4-hydroxyderricin (3) showed insulin-like activities to enhance glucose uptake and induce preadipocyte differentiation into adipocytes without activating PPAR-c. 4-Hydroxyderricin (3) also prevented the progression of diabetes in these mice ). On the basis of the preventive effect, a clinical trial was performed with A. keiskei powder containing 4-hydroxyderricin (3), resulting in reduction of blood glucose and improvement of blood glucose control through increasing adiponectin in subjects with borderline or mild hyperglycemia after 12 weeks of consumption of A. keiskei . Xanthoangelol (1), 4-hydroxyderricin (3), isobavachalcone (4), munduleaflavanone A (51), demethylsuberosin (59), 3 0 -senecioyl khellactone (87), falcarindiol (98), and (10S,15R,Z)-10, 15-dihydroxyheptadeca-8,16-dien-11,13-diynyl acetate (100) appeared to inhibit a-glucosidase, which involved in glucose metabolism (Luo et al. 2012) . Xanthoangelol (1) and 4-hydroxyderricin (3) stimulated skeletal muscle-associated glucose uptake by inducing glucose transporter 4 (GLUT-4) translocation, resulting in normal blood glucose level (Kawabata et al. 2011) . Recently, protein tyrosine phosphatase 1B (PTP1B) has been suggested as a therapeutic target for treatment of type 2 diabetes based on its downregulating effect on insulin signaling. Li et al. evaluated isolates from the stems of A. keiskei for their PTP1B inhibitory effects using oleanolic acid as a positive control. Xanthoangelol (1), xanthoangelol F (2), 4-hydroxyderricin (3), xanthoangelol D (9), xanthoangelol E (10), xanthoangelol K (17), xanthoangelol M (20) and bergapten (63, 5-methoxypsoralen; miswritten as ''methoxsalen'' in the article) showed strong PTP1B inhibitory effect (IC 50 0.82-4.42 lg/mL), together with moderately active four compounds (selinidin, 83; 85; khellactone, 86; falcarindiol, 98, .55 lg/mL) and a weakly active one (cynaroside, 43, IC 50 17.49 lg/ mL). Furthermore, in a kinetic study, xanthoangelol (1) with IC 50 values of 0.82 lg/mL exhibited typical characteristics of the competitive PTP1B inhibitor and in molecular docking simulations, it was suggested that the ring B of the chalcone skeleton may anchor in a pocket of PTP1B (Li et al. 2015) .

Onogi et al. filed a patent application presenting angelichalcone (31) with its nerve cell protective effect (Onogi et al. 2004 ). In addition, 7-O-b-D-glucopyranosyloxy-8-prenyl coumarin (61) was reported for its enhancing effect on nerve growth factor (NGF) production in mouse fibroblast L-M cells in a patent (Ohnogi et al. 2002) .

(43, luteolin-7-O-b-D-glucopyranoside) showed hypolipidemic activity when administrated by intraperitoneal injection in rats (Park et al. 1995) . Cynaroside (43) and hyperoside (48, quercetin-3-O-b-Dgalactopyranoside) exhibited anti-cholesterogenic activity by inhibiting HMG-CoA reductase (Park et al. 1997b) . When SHRSP was fed diets containing 4-hydroxyderricin for 7 weeks, serum very low-density lipoprotein (VLDL) and hepatic triglycerides (TG) levels were significantly reduced, without any effect on serum HDL levels. It was considered that microsomal TG transfer-protein may be responsible for the decrease in serum VLDL levels and differentiation factor 1 and fatty acid synthase may induce the decrease in hepatic TG content (Ogawa et al. 2005b) . In case of isolemanidin (91, miswritten as ''laserapitin'' in the article), the serum HDL levels, especially apoE-HDL, increased and the hepatic TG content decreased, which might be relevant with a decrease in hepatic TG lipase and differentiation factor 1, respectively (Ogawa et al. 2005a) .

Ohnogi et al. isolated six new chalcones, 4,2 0 -dihydroxy-3 0 -[(2E)-6-hydroperoxy-3-methyl-7-methylene-2-octenyl]-4 0methoxychalcone (7), 2 00 -hydroxyxanthoangelol I (15), 4-hydroxy-2 0 ,3 0 -(2,3-dihydro-2-hydroxyisopropylfurano)-4 0 -methoxychalcone (21), 4,2 0 4 0 -trihydroxy-3 0 -[(2E)-6,7dihydroxy-3,7-dimethyl-2-octenyl]chalcone (29), 4,2 0 -dihydroxy-3 0 ,4 0 -{2,3-dihydro-2-[(4E)-1-hydroxy-1,5-dimethyl-4-hexenyl]furano}chalcone (30), and angelichalcone (31) together with xanthoangelol (1) and 4-hydroxyderricin (3), and evaluated their effects on adiponectin mRNA and protein levels. As a result, all isolates, except for angelichalcone (31), increased expression of adiponectin mRNA and production of adiponectin in 3T3-L1 adipocytes. The effects on adiponectin could be expected to prevent metabolic syndrome through improving insulin resistance and dyslipidemia (Ohnogi et al. 2012b) . Xanthoangelol (1) and 4-hydroxyderricin (3) suppressed adipocytes differentiation via AMPK and mitogen-activated protein kinase (MAPK) pathways, which resulted in downregulating expression of adipocyte-specific transcription factors, CCAAT/enhancer-binding protein-b (C/EBP-b), C/EBP-a, and PPAR-c. Inhibitory effects on adipocytes differentiation could provide preventive effects against obesity and obesityrelated disorders (Zhang et al. 2013) .

Xanthoangelol (1), xanthoangelol F (2), 4-hydroxyderricin (3), xanthoangelol B (5), and xanthoangelol E (10) inhibited phenylephrine-induced vasoconstriction. Among them, xanthoangelol (1), xanthoangelol F (2), 4-hydroxyderricin (3), and xanthoangelol E (10) showed the inhibitory effects through endothelium-dependent production of endothelium-derived relaxing factor (EDRF)/NO. On the other hand, xanthoangelol B (5) directly inhibited smooth muscle functions through reducing intracellular free calcium [Ca 2 ? ] i elevation induced by phenylephrine without affecting EDRF/NO production. 4-Hydroxyderricin (3) also suppressed elevation of [Ca 2 ? ] i induced by phenylephrine (Matsuura et al. 2001) . Dietary 4-hydroxyderricin (3) reduced elevation of systolic blood pressure in SHRSP, which also supported its anti-hypertensive activity (Ogawa et al. 2005b ).

Xanthoangelol B (5), xanthoangelol C (8), and xanthoangelol E (10) inhibited the compound 48/80-induced histamine release from rat peritoneal mast cells, whereas, xanthoangelol (1) and 4-hydroxyderricin (3) enhanced it. Compound 48/80 is one of immunological stimulators, which activates the mast cell to induce allergic responses by mediates (Nakata and Baba 2001) . Selinidin (83) was found to suppress degranulation, leukotriene C4 (LTC4) synthesis, and tumor necrosis factor-a (TNF-a) production without affecting binding of immunoglobulin E (IgE) with high affinity IgE receptor (FceRI) and expression of cell surface FceRI in antigen-stimulated primary mouse bone marrow-derived mast cells (BMMCs). Selinidin (83) inhibited tyrosine phosphorylation of FceRI b-chain and phospholipase C c1 (PLCc1) not FceRI c-chain in BMMCs upon FceRI stimulation, demonstrating its inhibitory effects on FceRI-dependent signaling pathway. Phosphorylation of p38 MAPK and inhibitory jB-a (IjB-a) were also downregulated by selinidin (83) (Kishiro et al. 2008 ).

Xanthoangelol D (9) inhibited activation of nuclear factor-jB (NF-jB), which was involved in attenuation of basal and TNF-a-induced endothelin-1 (ET-1), a potent vasoconstrictor peptide. Its inhibitory effect against NF-jB inflammatory signaling pathway could be useful for treating vascular and inflammatory diseases because many vascular diseases are closely related to the inflammatory processes (Sugii et al. 2005) . A patent covers the antiinflammatory activities of seven flavonoids, xanthoangelol (1), xanthoangelol F (2), 4-hydroxyderricin (3), isobavachalcone (4), deoxyxanthoangelol H (13), munduleaflavanone B (52), and sophoraflavanone A (55, 8-geranylnaringenin), and six coumarins, osthenol (60), selidinin (84), peguangxienin (88), (3 0 R,4 0 R)-3 0 -angeloyl khellactone (89), isolemandin (91), and pteryxin (92) from exudates of A. keiskei ). Shin et al. reported that xanthoangelol (1), 4-hydroxyderricin (3), xanthoangelol B (5), and 4,2 0 ,4 0 -trihydroxy-3 0 -[(6E)-2-hydroxy-7-methyl-3methylene-6-octenyl]chalcone (27) showed inhibitory activities of IL-6 production in TNF-a-stimulated MG-63 osteosarcoma cells and they have C-4 0 hydroxyl groups in common (Shin et al. 2011) . Toll-like receptors (TLRs) are essential for induction of innate immune responses against invading pathogens, however, overexpression of transcription factors and pro-inflammatory genes by activation of TLR signaling pathway might cause certain inflammatory diseases. Isobavachalcone (4) reduced overexpression of iNOS induced by TLR agonists (lipopeptide 2-kDa, polyriboinosinic polyribocytidylic acid, or LPS) in murine macrophages (Shin et al. 2013) . Xanthoangelol (1) and 4-hydroxyderricin (3) reduced production of LPS-induced NO and TNF-a, expression of iNOS and COX-2 in RAW264 mouse macrophages. Moreover, both suppressed DNA binding activities of activator protein-1 (AP-1) and NF-jB and phosphorylation level of p65 subunit of NF-jB. However, two chalcones downregulated only AP-1 not NF-jB (Yasuda et al. 2014) . Inhibitory effects on LPS-induced NO and expression of iNOS and COX-2 genes were also found for xanthoangelol B (5), xanthoangelol E (10), and xanthokeismin A (24) as well as 4-hydroxyderricin (3) and their mechanisms involved inhibition of IjB degradation and NF-jB nuclear translocation (Chang et al. 2014 ).

Cynaroside (43, luteolin-7-O-b-D-glucopyranoside) inhibited bromobenzene-induced hepatic lipid peroxidation by restoring epoxide hydrolase activity in liver of rats (Park et al. 2002) . Xanthoangelol B (5), xanthokeismin A (24), xanthokeismin B (25), and xanthokeismin C (26) showed strong superoxide-scavenging activities. Xanthoangelol (1), 4-hydroxyderricin (3), and isobavachalcone (4) induced reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H):quinone oxidoreductase 1 (NQO1) which protects against quinone-mediated oxidative damage. In addition, xanthoangelol (1), isobavachalcone (4) (107), and angelicol A (114) showed DPPH radical scavenging activities (Luo et al. 2012; Kim et al. 2005) . Ashitabaol A (103), an isolate from the seeds of A. keiskei, was found to be more abundant in the seed coat during germination through HPLC analysis. Ashitabaol A (103) exhibited 2,2 0 -azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) free radical scavenging activity and was expected to protect the seed against oxidative damage induced by free radicals during germination (Aoki and Ohta 2010) . Xanthine oxidase (XO) leads to formation of free radicals, and cause oxidative damage to living tissues. Xanthoangelol (1), xanthoangelol F (2), 4-hydroxyderricin (3), isobavachalcone (4), and xanthoangelol B (5) showed inhibitory effects on XO activity, which could be relevant with attenuation of inflammation ).

Xanthoangelol E (10) was evaluated for effects on arachidonic acid metabolism in gastric antral mucosa and platelet of rabbit. Xanthoangelol E (10) showed no significant effect on production of PGE2, PGF2a, and their metabolites in gastric antral mucosal slices, whereas, suppressed production of thromboxane B2 (TXB2) and 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) from exogenous arachidonic acid in platelets (Fujita et al. 1992 ). Ohkura et al. reported that xanthoangelol (1), xanthoangelol B (5), and xanthoangelol D (9) isolated from the exudates of A. keiskei suppressed production of TNFa-induced PAI-1, an inhibitor of fibrinolysis, in human umbilical vein endothelial cells (HUVECs) (Ohkura et al. 2011 ). Regarding to anti-thrombotic activities, xanthoangelol (1) and 4-hydroxyderricin (3) also exhibited inhibitory effects on platelet aggregation induced by collagen, platelet-activating factor, and phorbol 12-myristate 13-acetate not thrombin (Son et al. 2014 ).

Xanthoangelol (1) was compared to iproniazid, an antidepressant nonselective MAO inhibitor. Xanthoangelol (1) inhibited monoamine oxidase (MAO) in a nonselective manner and suppressed dopamine b-hydroxylase (DBH). On the other hands, 4-hydroxyderricin selectively inhibited MAO-B and mildly suppressed DBH, which was higher than deprenyl, a selective MAO-B inhibitor. Because MAO inhibitors have been widely applied for treating depression, xanthoangelol (1) and 4-hydroxyderricin (3) were suggested as candidates for developing combined antidepressant drug. Additionally, cynaroside (43, luteolin-7-O-b-Dglucopyranoside) showed strong inhibitory effect against DBH ).

Park et al. reported that xanthoangelol F (2), 4-hydroxyderricin (3), xanthoangelol B (5), xanthoangelol G (6), xanthoangelol D (9), and xanthokeistal A (28) have inhibitory effects against hydrolysis of influenza virus neuraminidase (NA) which has been an effective target to develop drugs treating patients infected with influenza virus. All active compounds showed reversible nonselective characteristics and xanthoangelol D (9) was the most potent inhibitor. Furthermore, it was suggested that the influenza virus NA inhibitory activities of the alkylated chalcones are associated with their alkyl groups (Park et al. 2011) . Because enzymatic activities of a chymotrypsin-like protease (3CL pro ) and a papain-like protease (PL pro ) are essential for a viral life cycle of severe acute respiratory syndrome corovirus (SARS-CoV), the two viral cysteine proteases are attractive targets for development of anti-SARS-CoV drugs. Xanthoangelol (1), xanthoangelol F (2), 4-hydroxyderricin (3), isobavachalcone (4), xanthoangelol B (5), xanthoangelol G (6), xanthoangelol D (9), xanthoangelol E (10), and xanthokeistal A (28) showed competitive inhibitory characteristics to 3CL pro and noncompetitive ones to PL pro , except for mixed inhibition manner of isobavachalcone (4) against PL pro . Especially, xanthoangelol E (10) exhibited the most potent inhibitory activity, and docking simulation of xanthoangelol E (10) to both protease revealed that its hydroperoxy group plays a role in enzyme binding by forming hydrogen bonding (Park et al. 2015) .

Angelichalcone (31) was presented as an osteogenesis promotive agent in a patent application (Ohnogi et al. 2004 ).

Xanthoangelol (1), 4-hydroxyderricin (3), xanthoangelol H (12), deoxyxanthoangelol H (13), and deoxydihydroxanthoangelol H (41) exhibited inhibitory effects against melanin formation in B16 melanoma cells with low cytotoxicity (Arung et al. 2012 ).

As presented in this review, the pharmacological studies on A. keiskei and its putative active compounds support a number of biological activities that can potentially impact human health. In spite of these reported biological activities and a number of filed patent applications on this plant, A. keiskei has not been developed as a pharmaceutical agent and is currently available on the market as health drinks. This review presented a summary of the studies published to date on this promising plant. Although the majority of these studies are mechanistic, but they can be used as a solid platform to design and conduct clinical studies.

Chalcones, coumarins, and flavanones from the exudate of Angelica keiskei and their chemopreventive effects

Chalcones and other compounds from the exudates of Angelica keiskei and their cancer chemopreventive effects

Antiinflammatory agents containing natural products from Angelica keiskei

4-Hydroxyderricin from Angelica keiskei roots induces caspasedependent apoptotic cell death in HL60 human leukemia cells

Ashitabaol A, a new antioxidative sesquiterpenoid from seeds of Angelica keiskei

C-Geranylated chalcones from the stems of Angelica keiskei with superoxide-scavenging activity

The inhibitory effects of representative chalcones contained in Angelica keiskei on melanin biosynthesis in B16 melanoma cells

Components of the fruits, and comparison of coumarins and chalcones in the fruits, roots and the leaves

Chemical components of Angelica keiskei. Part 7. Chalcones from Angelica keiskei

Studies on Angelica keiskei

Target profiling of 4-hydroxyderricin in S. aureus reveals seryl-tRNA synthetase binding and inhibition by covalent modification

Chalcones from Angelica keiskei attenuate the inflammatory responses by suppressing nuclear translocation of NF-jB

Antidiabetic activities of chalcones isolated from a Japanese herb, Angelica keiskei

The effects of xanthoangelol E on arachidonic acid metabolism in the gastric antral mucosa and platelet of the rabbit

Antimicrobial agent/ Antimicrobial agent against Helicobacter pylori comprising a material derived from Angelica keiskei

Pharmacognostical studies on umbelliferous plants. XVIII. Constituents of the roots of Angelica keiskei

Skin-whitening cosmetic containing Angelica keiskei Koidzumi extract and having tyrosinase inhibiting effect (Sansei Pharmaceutical Co., Ltd

Chemical components of Angelica keiskei. VI. Antibacterial activity of two chalcones, xanthoangelol and 4-hydroxyderricin, isolated from the root of Angelica keiskei Koidzumi

Effect of Angelica keiskei extract on apoptosis of MDA-MB-231 human breast cancer cells. Han'guk Sikp'um

Green vegetable drink consumption protects peripheral lymphocytes DNA damage in Korean smokers

Prenylated chalcones 4-hydroxyderricin and xanthoangelol stimulate glucose uptake in skeletal muscle cells by inducing GLUT4 translocation

Chalcones from Angelica keiskei: evaluation of their heat shock protein inducing activities

Separation of two major chalcones from Angelica keiskei by high-speed counter-current chromatography

Three new chalcones from the aerial parts of Angelica keiskei

Isolation and characterization of antioxidative compounds from the aerial parts of Angelica keiskei

Health-aid food, drink and food composition having hepato-protective effect, which comprises Angelica keiskei root extract and hydroxyderricin and xanthoangelol isolated therefrom

The effects of Angelica keiskei Koidz on the expression of antioxidant enzymes related to lipid profiles in rats fed a high fat diet

Xanthoangelol and 4-hydroxyderricin are the major active principles of the inhibitory activities against monoamine oxidases on Angelica keiskei K

Quantitative analysis of phenolic metabolites from different parts of Angelica keiskei by HPLC-ESI MS/MS and their xanthine oxidase inhibition

Antitumor and antimetastatic activities of Angelica keiskei roots, part 1: isolation of an active substance, xanthoangelol

Antitumor and antimetastatic activities of 4-hydroxyderricin isolated from Angelica keiskei roots

Anti-tumor actions of major component 3 0 -O-acetylhamaudol of Angelica japonica roots through dual actions, anti-angiogenesis and intestinal intraepithelial lymphocyte activation

Selinidin suppresses IgE-mediated mast cell activation by inhibiting multiple steps of FceRI signaling

The structure of xanthoangelol, a new chalcone from the roots of Angelica keiskei Koidzumi (Umbelliferae)

Chemical components of the roots of Angelica keiskei Koidzumi. III. The structure of a new dihydrofurocoumarin

Effects of AOJIRU drink powder of Angelica keiskei leaf containing indigestible dextrin on defecation in volunteers with constipation

Anti-inflammatory activity of Angelica keiskei through suppression of mitogen-activated protein kinases and nuclear factor-jB activation pathways

Angelica keiskei root extracts for inducing apoptosis of prostate cancer cells

inhibitors from stems of Angelica keiskei (Ashitaba)

Coix seed-Angelica keiskei nutritional health-care biscuits and production method thereof

Compounds from Angelica keiskei with NQO1 induction, DPPHÁ scavenging and a-glucosidase inhibitory activities

Artery relaxation by chalcones isolated from the roots of Angelica keiskei

Proteomic analysis of apoptosis induced by xanthoangelol, a major constituent of Angelica keiskei, in neuroblastoma

Inhibition of gastric H ? , K ? -ATPase by chalcone derivatives, xanthoangelol and 4-hydroxyderricin, from Angelica keiskei Koidzumi

Application: JP Nakata K, Baba K (2001) Histamine release-inhibiting activity of Angelica keiskei

Comparison of the characteristics and the constituents of Angelica keiskei KOIDZUMI growing in Hachijo and Oshima

Three chalcones from Angelica keiskei

Isobavachalcone, a chalcone constituent of Angelica keiskei, induces apoptosis in neuroblastoma

Angelica keiskei Koidzumi extracts improve some markers of liver function in habitual alcohol drinkers: a randomized double-blind clinical trial

Effects of dietary Angelica keiskei on lipid metabolism in stroke-prone spontaneously hypertensive rats

Beneficial effect of laserpitin, a coumarin compound from Angelica keiskei, on lipid metabolism in stroke-prone spontaneously hypertensive rats

Hypotensive and lipid regulatory actions of 4-hydroxyderricin, a chalcone from Angelica keiskei, in stroke-prone spontaneously hypertensive rats

Angelica keiskei ameliorates scopolamine-induced memory impairments in mice

Xanthoangelols isolated from Angelica keiskei inhibit inflammatory-induced plasminogen activator inhibitor 1 (PAI-1) production

Nerve growth factor enhancers for treatment of disease containing coumarin and/or chroman derivatives

Antidiabetic effect and safety of long-term ingestion of Ashitaba (Angelica keiskei) powder containing Chalcone (4HD) on borderline mild hyperglycemia

Angelica keiskei extract improves insulin resistance and hypertriglyceridemia in rats fed a high-fructose drink

Six new chalcones from Angelica keiskei inducing adiponectin production in 3T3-L1 adipocytes

Flora of Japan: in English: combined, much revised and extended translation/by the author of his Flora of Japan (1953) and Flora of Japan

Isolation of flavone-7-O-glycosides from the aerial parts of Angelica keiskei and antihyperlipidemic effects

Chemical components from the aerial parts of Angelica keiskei

Antimutagenic activity of the methanol extract and compounds of Angelica keiskei in the Salmonella assay system

Screening and characterization of anticholesterogenic substances from food plant extracts. Han'guk Sikp'um

Effects of extract from Angelica keiskei and its component, cynaroside, on the hepatic bromobenzene-metabolizing enzyme system in rats

Characteristic of alkylated chalcones from Angelica keiskei on influenza virus neuraminidase inhibition

Chalcones isolated from Angelica keiskei inhibit cysteine proteases of SARS-CoV

Determination of antioxidant compounds from leaf and stem of Angelica keiskei by gas chromatography-mass spectrometry

Deodorant composition containing extracts of Angelica keiskei for prevention of mouth odor

Hair growth promoter comprising Angelica keiskei extract, and preparation method thereof (Japan)

Effects of angiotensin 1-converting enzyme inhibitor from Ashitaba (Angelica keiskei) on blood pressure of spontaneously hypertensive rats

Chalcones isolated from Angelica keiskei and their inhibition of IL-6 production in TNF-a-stimulated MG-63 cell

Isobavachalcone suppresses expression of inducible nitric oxide synthase induced by Tolllike receptor agonists

Bioassay-guided isolation and identification of anti-platelet-active compounds from the root of Ashitaba (Angelica keiskei Koidz.)

A method for preparing Angelica keiskei wine (Nanjing Zelang Agriculture Development Co., Ltd

Isolation and analysis components of Ashitaba (Angelica keiskei koidzumi) leaves growing in Miyazaki and Korea

Isolation and analysis components of Ashitaba (Angelica keiskei Koidzumi) roots, stems and leaves

Synthesis and antibacterial activity of chalcones bearing prenyl or geranyl groups from Angelica keiskei

Xanthoangelol D isolated from the roots of Angelica keiskei inhibits endothelin-1 production through the suppression of nuclear factor-jB

Xanthoangelol, a major chalcone constituent of Angelica keiskei, induces apoptosis in neuroblastoma and leukemia cells

Chalcones from Angelica keiskei induced apoptosis in stomach cancer cells

Inhibitory effects of 4-hydroxyderricin and xanthoangelol on lipopolysaccharideinduced inflammatory responses in RAW264 macrophages

4-Hydroxyderricin and xanthoangelol from Ashitaba (Angelica keiskei) suppress differentiation of preadiopocytes to adipocytes via AMPK and MAPK pathways

Ashitaba (Angelica keiskei) extract prevents adiposity in high-fat diet-fed C57BL/6 mice

Chemical constituents of Angelica keiskei

Acknowledgements This work is supported by Ewha Womans University (collaborative research grant for Ewha-UC Irvine).

Conflict of interest The co-authors have declared no conflict of interest.