1

The Health and Medicinal Benefits of

Ashitaba

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Table of Contents

Botantical History

Similar Plants Speices

Cultural History

Chemcial Constituients of Ashitaba

Chalcones

Medicinal Benefits of Ashitaba

Clinical Trials

Product Resources

Endnotes/References

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Botanical History

Ashitaba, which is the common name used in Japan, is botanically

known as Angelica keiskei or Angelica Keiskei Koidzumi. The

English translation of the Japanese word “Ashitaba” (アシタバ or

明日葉) is “Tomorrow's Leaf". Ashita means ‘tomorrow and ba

means ‘leaf.’ The name stems from the plant’s ability to quickly

regenerate new leaves after taking cuttings. This give an indication

of its potential for longevity of life.

Figure 1.1 Angelica keiskei (Ashitaba)

Ashitaba is from the botanical species of Angelica, which derives

from the Latin for angel. The word keiskei is named for Ito

Keisuke, the 19th century Japanese botanist called the father of

modern Japanese botany.

Angelica keiskei is the only Angelica plant that exudes yellow sap

from the stem.

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Figure 1.2 Location of the Izu Islands of Japan

Ashitaba is indigenous to a small area called the Seven Islands of

Izu. Although traditionally referred to as the "Izu Seven" (伊豆七島

), there are in fact more than a dozen islands and islets. It is

endemic to Hachijō-jima island, which lies off the southern coast of

Japan. Ashitaba is also cultivated in the islands of Izu Ōshima,

Mikura-jima, Nii-jima, To-shima and parts of Honshū. It is also

commercially cultivated and harvested in Indonesia.

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Similar Plants Species

Archangelica keiskei Miq.

Archangelica keiskei Miq. is a plant that is often confused with and

is often considered synonymous with Angelica keiskei. The name

Archangelica keiskei Miq. is unresolved by botanists. [ 1 ]

Figure 2.1 Comparison of Archangelica keiskei (left) and Angelica keiskei (right)

Angelica japonica

"Hama-udo" (Angelica japonica) belongs to the family Apiaceae

(the Carrot family). It is an evergreen perennial herb. Angelica

kiusiana Maxim. is a synonym of Angelica japonica A. Although

similarly in appearance to Ashitaba, Angelica japonica is a different

species within the Angelica family.

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Figure 2.2 Angelica japonica

Sabungai (Gynura procumbens)

Gynura procumbens (Sabuñgai) is a twining vine found in the

Philippines, the Malay Archipelago, Thailand, and Indo-China.

Sabuñgai (Gynura procumbens) is also known as “Longevity

Spinach”.

There is evidence that some Ashitaba powder being sold is actually

Sabuñgai (Gynura procumbens) rather than Ashitaba (Angelica

keiskei).

Comparison of the two plants can be seen in Figures 2.3 and 2.4.

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Figure 2.3 Sabungai (Gynura procumbens) (Notice the similarity to Ashitaba)

Figure 2.4 Angelica Kekeii (Ashitaba) (Looks similar to Sabungai (Gynura procumbens))

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Cultural History

Li Shizhen (Li Shih-chen; simplified Chinese: 李时珍; traditional

Chinese: 李時珍) was a medical doctor, scientist, pharmacologist,

herbalist and acupuncturist of the Ming dynasty. He lived from July

3, 1518 – 1593). His major contribution to clinical medicine was

his 27-year work, which is found in his scientific book Compendium

of Materia Medica (Bencao Gangmu).

The Compendium of Materia Medica is regarded as the most

complete and comprehensive medical and scientific book ever

written in the history of traditional Chinese medicine. It lists all the

plants, animals, minerals, and other items that were believed to

have medicinal properties. It is the first written record of

Ashitaba.

The Compendium of Materia Medica was introduced into Japan

and presented to the Shogun by Razan Hayashi in 1606. Hayashi

Razan, also known as Hayashi Dōshun, was a Japanese

Neo-Confucian philosopher, serving as a tutor and an advisor to the

first four shoguns of the Tokugawa bakufu.

According to Japanese folklore and medicine, the yellow sap from

stems and stalks once used for external treatment of smallpox,

whereas the roots were used as diuretic, laxative, analeptic, and

galactagogue. Other uses for medical purposes would include a

remedy for bowel disturbances, arthritis, and immune diseases.

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According to Chinese folklore and medicine, Ashitaba was believed

to activate Qi and Xue. In China it was used in the treatment of

menstrual problems, and was also believed to increase kidney yin

and yang qi. The Chinese also used it as a lactagogue to increase

mother's milk.

The Japanese Neo-Confucianist philosopher and botanist, Kaibara

Ekken wrote in 1709 the book entitled Yamato honzō (Medicinal

herbs of Japan) which was a seminal study of Japanese plants. In

this book he descried Ashitaba using the name of ashitagusa (鹹草

), as "a powerful tonic drug."

Ashitaba has been consumed as a vegetable and medicine for

many hundreds of years by inhabitants of Seven Islands of Izu . In

Japanese traditions, Ashitaba was used as a culinary staple, as it is

today. It was and is consumed as a vegetable, the leaves, roots

and stems eaten raw or cooked. Sometimes the roots are pickled.

There are many uses of Ashitaba in recipes, including in the

preparation of soba, tempura, socho, tea, and ice cream.

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Chemical Constituents

There have been numerous studies conducted to determine the

chemical compounds of Ashitaba. The results of the studies and

findings are illustrated in Table 4.1.

Table 4.1 Active Chemical Compounds of Angelica keiskei

Koidzumi (Ashitaba)

Ashitaba

Compound Sub-Compound Notes/Reference(s)

Chalcones

Ashitaba-chalcone [2]

Xanthoangelol [3]

Xanthoangelol-B

2′,4,4′-trihydroxy-3′

-[(E)-6-hydroxy-3,7-dimethyl-2,7-o

ctadienyl]chalcone [4]

Xanthoangelol-C

2′,4,4′-trihydroxy-3′

-[(E)-3-methy]-6-oxo-2-hexenyl]ch

alcone [5]

Xanthoangelol-D

2′,4-dihydroxy-4′-methoxy-3′

-(2-hydroxy-3-methyl-3-butenyl)ch

alcone [6]

Xanthoangelol-E

2′,4-dihydroxy-4′-methoxy-3′

-(2-hydroperoxy-3-methyl-3-buten

yl)chalcone [7]

Xanthoangelol H [8]

Xanthoangelol I [9]

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Xanthoangelol F

Xanthoangelol J [10]

Isobavachalcone [11]

Deoxydihydroxantho

angelol H [12]

4-Hydroxyderricin

Xanthohumol

Xanthokeismin A [13]

Coumarins

Psoralen Found in roots [14]

Imperatorin

Columbianagin

Isorhazelpitin

Rhazelpiton

Selenidin

xanthotoxin Found in roots [15]

angelicin Found in roots [16]

archangelicin furo-coumarin

8(S),9(S)-angeloylox

yl-8,9-dihydrooroselo

l

furo-coumarin

Chroman The benzopyrylium cation is the

parent of a large number of natural

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products. Chroman, or

3,4-dihydro-2 H-1-benzopyran, is

itself not found in nature, but the

chroman unit is present in many

natural products. Chroman

contained in Ashitaba can induce

nerve growth factor (NGF) [17]

Luteolin-7-glucosi

de [18]

Cynaroside [19] Cynaroside is a flavone, a

flavonoid-like chemical compound.

luteolin-7-O-α

-D-glucpyranosid

e

[20]

1-cerotol [21]

daucosterol [22]

stigmasterol [23]

quercetin-3-O-β

-D-glucopyransid

e

[24]

steviol-l3-O-β

-glucopyranoside

19-β

-glucopyranosyl

ester octaacetate

[25]

isoquercitrin

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Ruteorin

Angelic acid

Bergapten Found in roots [26]

Beta-carotene

Vitamin C

Vitamin B12 normally produced in animals and

not plants

Vitamin B2

Vitamin A

Vitamin K

Potassium

Calcium

Iron

Chlorophyll

The Japan Science and Technology Agency published a table

comparing Ashitaba with other vegetables in Table 4.2.

Table 4.2 Comparitive nutrients of Ashitaba

Source: The Japan Science and Technology Agency (JST)

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Ashitaba, compared to other vegetables, indicate a very high level

of vital nutrients, especially vitamin K and potassium. In Table 4.3,

the protein content of Ashitaba is second only to broccoli.

Table 4.3 Nutrients in Ashitaba

Source: Food Composition Database in Sugiyama Univ. Standard Tables of Food

Composition in Japan

Table 4.4 illustrates the general composition of minerals, amino

acids and other substances of Ashitaba. These substances were

discovered and evaluated in a study written in 2012 indicating the

potent antioxidants capability of Ashitaba, and its ability to induce

an enhanced antioxidant enzymes in the body.

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Table 4.4 General Composition of Ashitaba

The general composition, minerals, and high luteolin content of Ashitaba

Source: 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. Nutrition Research and Practice.

2012;6(1):9-15. doi:10.4162/nrp.2012.6.1.9.

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Table 4.5 illustrates the comparison between raw Ashitaba leaves

and dried Ashitaba powder. Apparently, the dried Ashitaba

powder contains more nutrients than the raw Ashitaba leaves.

Table 4.5 Ashitaba Nutrition Data Comparison with Ashitaba

Powder

Source: Japan Food Research Laboratories

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Chalcones

There are two separate substances (products) that are derived

from the Ashitaba plant.

The first is the hot-air dried powder of Ashitaba from the leaves

and stems. The color of this powder is bright green. The leaves of

the Ashitaba plant contain approximately 0.25% to 0.35%

chalcones.

The second is the powder made from the unique yellow sap which

is collected from the Ashitaba's stem. It is commonly called

Ashitaba Chalcone Powder which consists up to 8% chalcones.

The color of Ashitaba Chalcone Powder is bright yellow and is a

fat-soluble substance.

Although the green Ashitaba powder from the leaves and stems

provide nutritional and health benefits, it is the Ashitaba Chalcone

Powder (bright yellow powder from the sap of the stem) that is the

Figure 5.1 Young bud emerging from stem with sap

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Chalconoids are natural phenols related to chalcone. They form the

central core for a variety of important biological compounds.

Chalcones are the active factors in Angelica Keiskei Koidzumi.

At least 20 chalcones have been identified in Angelica Keiskei.

Ashitaba contains a thick, sticky yellow sap, which is not found in

other celery plants, and are unique to this strain of angelica. This

yellowish element in Ashitaba contain the chalconoids.

Figure 5.2 Yellow sap from stem contains Chalcones

The two most active chalconoids found in Angelica Keiskei are

named "Xanthoangelol" and "4-Hydroxyderricin". They are the

two chalconoids that are the subject of most of the studies,

although others have been studied.

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Figure 5.3 Chemical structure of Xanthoangelol and 4-Hydroxyderricin

Research has shown that the unique healing properties of Ashitaba

are largely due to the chalconoids as illustrated in Table 5.1.

Table 5.1 Medical Properties of Chalcones

Medical Properties

of Chalcones

Condition Properties Reference

Antibacterial Some heterocyclic chalcone

derivatives presented good

anti-microbial activities against

Gram-positive bacteria

[ 27 ]

Antifungal Sixteen chalcones were

prepared and their antifungal

activities against four common

pathogenic fungi in vitro were

examined. Some of them

[ 28 ]

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exhibited antifungal activities to

a certain extent.

Antitumor Based on the current studies,

chalcones are highly

multifunctional and their targets

cover almost all of the actions of

tumor cells, including growth,

proliferation, invasion, and

metastasis. Moreover,

researchers have discovered

several chalcones with

significant antitumor activity

both in vitro and in vivo, such as

xanthohumol, isoliquiritigenin,

and butein.

[ 29 ]

Anti-inflammatory Chalcones showed an

anti-inflammatory protective

effect when administered orally

or by the intraperitoneal route.

[ 30 ]

Aromatase inhibitor Chalcones are potent inhibitors

of aromatase

[ 31 ]

Hypertension 4-hydroxyderricin, one of the

major chalcones exerted

hypotensive and lipid regulatory

[ 32 ]

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actions in stroke-prone

spontaneously hypertensive rats

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Medicinal Benefits of Ashitaba

The medicinal benefits of Ashitaba has only recently been

discovered by science, particulary due to the discover of the many

chalcones in Ashitaba. From this discovery, a number of medical

benefits have been discussed in the medical literature. Table 6.1

is a summary of the numerous medical benefits of Ashitaba.

Table 6.1 Medical Benefits of Ashitaba

Medical Benefits

of Ashitaba

Condition Properties Reference

Alzheimer’s Memory

Impairment

One study found that Ashitaba

might be a useful agent in

preventing deficit of learning

and memory caused by

Alzheimer’s and aging.

1 study

Anti-Bacterial Two studies show evidence of

strong antibacterial action.

3 studies

Anti-Depressant

One study in 2013 points to

Ashitaba as a potent candidate

for development of combined

antidepressant drugs.

1 study

Anti-Diabetic Five studies show strong 5 studies

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evidence for the ability of

Ashitaba to decrease blood

glucose levels and to improve

insulin resistance conditions.

Anti-Inflammatory

The data demonstrates that

Angelica keiskei can suppress

inflammation and taken

together, may have efficacy as

anti-inflammatory agents.

5 studies

Antioxidant

Ashitaba can increase the

expression of antioxidant

enzymes and protect DNA from

oxidative stress

4 studies

Anti-thrombotic

Ashitaba is thought to have

anti-thrombotic properties

through the inhibition of

inflammatory-induced

plasminogen activator inhibitor

1 (PAI-1) production

1 study

Anti-tumor Agent

Angelica keiskei roots exhibited

cytotoxic activity against many

tumor cells

7 studies

Cancer Treatment Isobavachalcone induces 2 studies

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and Preventative apoptotic cell death in

neuroblastoma via the

mitochondrial pathway and has

no cytotoxicity against normal

cells.

HDL Cholesterol

(Increases)

Dietary Angelica keiskei

produces elevation of serum

HDL levels

1 study

Hypertension

4-hydroxyderricin, one of the

major chalcones in Angelica

keiskei extract, exerted

hypotensive regulatory actions

2 studies

LDL Cholesterol

(Decreases)

Dietary xanthoangelol results in

a reduction of serum LDL levels

1 study

Liver Protector Angelica keiskei extract

demonstrates hepatoprotection

3 studies

Metabolic

Syndrome

Angelica keiskei suggest

potential benefit in preventing

the metabolic syndrome.

2 studies

Neurogenesis

Angelica keiskei has an

enhancing action for NGF

production

2 studies

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Quinone Reductase

Ashitaba is considered to have

contained certain substances

that could induce Quinone

Reductase activity

1 study

Skin Cancer

An external application of the

Ashitaba extract controlled ski

cancer

1 study

Visceral Fat

(Reduces)

Clinical study showing

compelling weight loss effects

of Ashitaba Chalcone Powder

2 studies

Alzheimer’s Memory Impairment

A study was conducted in 2012 which evaluated the effects of

Ashitaba on scopolamine-induced memory impairments in mice.

The findings showed that Ashitaba significantly attenuated

scopolamine-induced cognitive impairment in mice.

Taken together, these results provide experimental evidence that

Ashitaba might be a useful agent in preventing deficit of learning

and memory caused by Alzheimer’s and aging. [ 33 ]

Antibacterial

Ashitaba shows evidence of strong antiacterial action.

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A study connducted by The Pharmaceutical Society of Japan in

1999 indicated that two chalcones, xanthoangelol (I) and

4-hydroxyderricin (II), isolated from the root of Angelica keiskei

koidzumi (Umbelliferae) showed antibacterial activity against

gram-positive pathogenic bacteria. [ 34 ]

The Kangweon National University in Korea evaluated the

pharmacological activities of nine Umbelliferae plants. Angelica

keiskei was selected and its restoring activity against

antimicrobial activity were tested and compared. [ 35 ]

Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium

that causes infections in humans. It is also called oxacillin-resistant

Staphylococcus aureus (ORSA). In a study published in 2008 in

the International Journal of Medicinal Mushrooms, the authors

discovered 2 known chalcones, xanthoangelol and

4-hydroxyderricin, in the extract of S. crispa, which have been

previously isolated from the plant Angelica keiskei. The purpose

of the study was to screen for compounds that inhibit MRSA

growth. These compounds showed anti-MRSA activity.

The result study indicates the possibility that S. crispa might be a

promising source for the production of chalcones, in addition to the

plant Angelica keiskei. [ 36 ]

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Anti-Depressant

The Journal of Applied Pharmacology published a study in May

2013 suggest that the two prenylated chalcones, xanthoangelol and

4-hydroxyderricin isolated from A. keiskei K., are expected for

potent candidates for development of combined antidepressant

drugs.

These two isolated compounds are the major active ingredients of

A. keiskei K. to inhibit MAOs activities.

A. keiskei K. will be an excellent new bio-functional food material

that has combined antidepressant effect. [ 37 ]

Anti-Diabetic

There is strong evidence for the ability of Ashitaba to decrease

blood glucose levels and to improve insulin resistance conditions.

One Chinese study from 2013 showed that Angelica keiskei

chalcones may increase the expression levels of Glut1 and Glut4 in

skeletal muscle cells, decrease fasting blood glucose and insulin of

type 2 diabetic rats and improve their insulin resistance condition. [

38 ]

A study published in 2007 in the Journal of Agricultural and Food

Chemistry found that the ethanol extract from a Japanese herb

"Ashitaba", Angelica keiskei, contained two major chalcones of

4-hydroxyderricin (4-HD) and xanthoangelol that showed strong

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insulin-like activities via a pathway independent of the peroxisome

proliferator-activated receptor-gamma activation. [ 39 ]

Ashitaba also appears to protect the endothial cells in those with

type 2 diabetes. The study that concluded these findings was

published by the Institute of Nutrition,Qingdao University Medical

College in China. Their conclusion was that Ashitaba may reduce

the levels of serum ET-1 and VE-ca and protect the endothelial

cells of rats with type 2 diabetes. [ 40 ]

A 2004 study found that ethanol extract of Angelica keiskei has

insulin mimic compounds. Their investigation revealed that there

are two insulin mimic activities of Ashitaba: (a) adipocyte

differentiation activity and (b) enhancement activity of glucose

uptake, using pre-adipocyte cell line 3T3-L1.

The two major chalcons peculiar to Angelica keiskei, xanthoangelol

(XA) and 4-hydroxyderricin (4HD) have both activities (a) and (b).

These results demonstrate that chronic ingestion of "Ashitaba"

Powder containing Chalcone (4HD) moderately reduces the blood

glucose and improved blood glucose control through increase of

adiponectin in subjects with borderline or mild hyperglycemia and

that it is also very safe. [ 41 ]

The Japan Society for Bioscience, Biotechnology, and

Agrochemistry pulished an article in 2012 investigating the effect of

A. keiskei on insulin resistance and hypertriglyceridemia in

fructose-drinking rats as a model for the metabolic syndrome. The

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results suggest that AE improved the insulin resistance and

hypertriglyceridemia of the fructose-drinking rats. [ 42 ]

Anti-Inflammatory

A new study from 2013 pulished by The Journal of Agricultural and

Food Chemistry investigated the effects and underlying molecular

mechanisms of 4-hydroxyderricin and xanthoangelol on

lipopolysaccharide (LPS)-induced inflammatory responses in

RAW264 mouse macrophages. 4-Hydroxyderricin and

xanthoangelol reduced the phosphorylation (at serine 536) level of

the p65 sub unit of NF-κB. 4-Hydroxyderricin and xanthoangelol

may be promising for the prevention of inflammatory diseases. [ 43 ]

Figure 6.1 4-hydroxyderricin and xanthoangelol suppresses only AP-1 and had no effect on NF-κB in

The Journal of Agricultural and Food Chemistry study of 2013

Source: J. Agric. Food Chem., 2014, 62 (2), pp 462–467 DOI: 10.1021/jf404175t Publication Date (Web): December 26, 2013

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The March 2011 edition of the Archives of Pharmacal Research

published a study that identified six chalcone compounds isolated

from the leaves of Angelica keiskei K (Umbelliferae). (See Table

4.1) Among the isolates, some compounds appeared to have

potent inhibitory activity of IL-6 production in TNF-α-stimulated

MG-63 cells, while some compounds did not. [ 44 ]

A research study published in the Journal of Medicinal Food in June

2010 found that the n-hexane fraction of A. keiskei (HAK)

significantly inhibited LPS-induced NO and prostaglandin E2

production and tumor necrosis factor-α secretion. A. Keiskei also

inhibited the expression of LPS-induced iNOS and COX-2 proteins

and their mRNA levels. The data suggest that the anti-inflammatory

effect of HAK is mediated through down-modulation of iNOS and

COX-2 gene products by blocking the signaling pathways of MAPKs

and NF-κB. [ 45 ]

Another later study also published in the Journal of Medicinal Food

in December 2014 indicated that the seven chalcones identified

from Ashitaba inhibited the production of NO and the expression of

pro-inflammatory cytokines, interleukin (IL)-1β and IL-6, in

LPS-activated macrophages.

The data demonstrates that four chalcones (1, 2, 4, and 5) from A.

keiskei can suppress inflammation and taken together, four

chalcones from A. keiskei may have efficacy as anti-inflammatory

agents. [ 46 ]

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A 2005 study published in the Biological & Pharmaceutical Bulletin

Journal showed the effects of xanthoangelol, xanthoangelol D, E,

and F, which isolated from the root of Angelica keiskei KOIDZUMI

(Umbelliferae), on NF-kappaB activation and ET-1 gene expression

in cultured porcine aortic endothelial cells (PAECs). The results

suggest that xanthoangelol D may be useful for the treatment of

various vascular diseases involved NF-kappaB activation. [ 47 ]

Antioxidant

Scientists in China discovered that the antioxidant activities of

Ashitaba leaves ethanol extracts were significantly higher than

stem ethanol extracts. Results showed that leaf ethanol extracts

from Angelica keiskei Koidzmi can be used as a natural antioxidant

for development and utilization in the future. [ 48 ]

It appears that Ashitaba can increase the expression of antioxidant

enzymes, including Hepatic catalase, superoxide dismutase (SOD),

glutathione reductase (GsR), glutathione peroxidase (GPx), and

glutathione transferase (GT) amRNA. [ 49 ]

Ashitaba also can protect DNA damage from oxidative stress. A

study from 2004 published in BioFactors supported the hypothesis

that Ashitaba in the form of a green vegetable drink exerts a

cancer-protective effect via a decrease in oxidative damage to DNA

in humans. [ 50 ]

33

Ashitaba chalcone appears to enhance the antioxidant capacity

and inhibit the proliferative activity of tumor cell in H22

hepatoma-bearing mice. [ 51 ]

Anti-thrombotic

Ashitaba is thought to have anti-thrombotic properties through the

inhibition of inflammatory-induced plasminogen activator inhibitor

1 (PAI-1) production. [ 52 ]

Anti-tumor Agent

A study from 2011 published in the Journal of Oleo Science found

that an extract of Angelica keiskei roots exhibited cytotoxic activity

against 4 human tumor cell lines, HL60 (leukemia), CRL1579

(melanoma), A549 (lung), and AZ521 (stomach).

4-Hydroxyderricin may therefore hold promise as an effective

antitumor agent. [ 53 ]

Study evaluated the antitumor and antimetastatic effects of various

fractions from a 50% ethanol extract of roots. Study isolated

xanthoangelol which showed inhibition of tumor growth in

LLC-bearing mice as well as lung metastases, and prolonged

survival time in carcinectomized mice. These results indicate that

the antitumor and/or antimetastatic activities of xanthoangelol may

34

be due to inhibition of DNA synthesis in LLC cells and of

tumor-induced neovascularization through inhibition of the

formation of capillary-like tubes by vascular endothelial cells and

inhibition of the binding of VEGF to vascular endothelial cells. [ 54 ]

Two chalcones, 4-hydroxyderricin and xanthoangelol were proved

to have anti-tumor-promoting activity in mouse skin carcinogenesis

induced by 7,12-dimethylbenz[a]anthracene (DMBA) plus TPA.

Both chalcones may reveal anti-tumor-promoting activity via the

modulation of calmodulin involved systems and may be useful to

develop the effective method for cancer prevention. [ 55 ]

Six chalcones from Angelica keiskei KOIDZUMI were examined for

their cytotoxicity in two human neuroblastoma cell lines (IMR-32

and NB-39) and normal cells (primary culture of rat cerebellar

granule cells). All chalcones exhibited cytotoxicity against

neuroblastoma cells, and two of them (isobavachalcone and

xanthoangelol H) had no effect on normal cells even at high

concentration (10(-4) M) exposure. [ 56 ]

A study published in the joural In Vivo in 2005 found that two

chalcone derivatives from Angelica keiskei roots also inhibited

tumor growth and metastasis in tumor-bearing mice through the

inhibition of tumor-induced neovascularization and/or the

inhibition of immune suppression caused by tumors. [ 57 ]

35

A recently study reported that the 50 % ethanol extract, the ethyl

acetate-soluble fraction and the isolated xanthoangelol, inhibited

tumor growth and metastasis to the lung in Lewis lung carcinoma

(LLC)-bearing mice. The present study examined the effects of

4-hydroxyderricin on tumor growth and metastasis to the lung or

liver in subcutaneous or intrasplenic LLC-implanted C57BL/6J

female mice. These results suggest that the antitumor and

antimetastatic activities of 4-hydroxyderricin may be modulated by

the immune system and the inhibition of angiogenesis. [ 58 ]

A 2003 study in Cancer Letters of an ethyl acetate fraction of stem

exudates yielded 17 compounds, viz., five chalcones, seven

coumarins, and three flavanones. All compounds, except for 10, 16,

ad 17, exhibited potent inhibitory effects on EBV-EA (Epstein-Barr

virus early antigen) induction in Raji cells, known to be a primary

screening test for antitumor-promoters. [ 59 ]

Cancer Treatment and Preventative

Isobavachalcone is a chalcone isolated from Angelica keiskei. A

study from 2011 published in BioFactors suggest that

isobavachalcone induces apoptotic cell death in neuroblastoma via

the mitochondrial pathway and has no cytotoxicity against normal

cells. Therefore, isobavachalcone may be applicable as an

efficacious and safe drug for the treatment of neuroblastoma. [ 60 ]

36

A study pulished in Cancer Letter in 2002 showed that Ashitaba is

considered to contain certain substances that could induce

quinone reductase (QR) activity, and such induction may play a role

in the anti-carcinogenic action of vegetables. Among 45 different

vegetable samples of the study, an extract of Ashitaba clearly

induced QR activity in Hep G2 cells. Ashitaba is therefore

considered to have contained certain substances that could induce

QR activity, and such induction may play a role in the

anti-carcinogenic action of vegetables. [ 61 ]

HDL Cholesterol (Increases)

The Journal Clinical and Experimental Pharmacology and

Physiology published an article in April 2003 that showed that

Angelica keiskei extract has a effect on serum levels of HDL.

These changes in the serum were due to increases in high-density

lipoprotein (HDL) containing ApoA-I and ApoE. 5.

In conclusion, dietary A. keiskei produces elevation of serum HDL

levels and a reduction of liver triglyceride levels in SHRSP. [ 62 ]

37

Hypertension

The inhibitory activity of angiotensin I-converting enzyme (ACE)

was extracted with 80% ethanol from the leaves of Ashitaba

(Angelica keiskei). The ACE inhibitor from Ashitaba contained in

the anti-hypertensive fraction was speculated to be very similar to

authentic nicotianamine based on a comparative study of inhibitory

activity. [ 63 ]

There is interest in using Ashitaba for hypertension. The isolated

constituent 4-hydroxyderricin, one of the major chalcones in

Angelica keiskei extract (ethyl acetate extract from the yellow

liquid of stems), exerted hypotensive regulatory actions and does

seem to lower blood pressure. [ 64 ]

LDL Cholesterol (Decreases)

In a study from 2007, the authors isolated xanthoangelol, another

major chalcone in A. keiskei extract, and examined the effect of

dietary xanthoangelol on lipid metabolism in SHRSP. In

conclusion, dietary xanthoangelol results in a reduction of serum

LDL levels and decreases in total cholesterol and triglyceride

contents in the liver of SHRSP. These beneficial effects are more

effective following consumption of a diet containing 0.10%

xanthoangelol. [ 65 ]

38

Liver Protector

Previous studies reported that the extracts of Angelica keiskei

Koidzumi (AKE) have antioxidant and anti-inflammatory properties,

suggesting that AKE could improve abnormalities associated with

alcoholic liver disease. These results suggest that AKE

supplementation might improve liver function in heavy drinkers. [ 66

]

A study evaluated the hepatoprotective effects of a methanol

extract of AK in rats with D-galactosamine and carbon tetrachloride

hepatotoxicity. Results showed AK exerted protective effects on

D-galactosamine induced hepatotoxicity. However, it exacerbated

toxicity induced by CCl4, possibly through increase in activity of

aniline hydroxylase, a cytochrome P450 isoenzyme responsible for

the metabolic activation of CCl4. [ 67 ]

The June 2011 of the Chinese-German Journal of Clinical Oncology

investigated the effect of Angelica keiskei chalcone (AC) on the

expression of Caspase-3 and Bax in mice hepatocarcinoma cells.

Study showed Angelica keiskei chalcone can increase the

expression of Caspase-3 and Bax protein in mice, and inhibit the

proliferative activity of mice hepatocarcinoma cells. [ 68 ]

Metabolic Syndrome

A study from 2012 published in the Japanese Journal of

Complementary and Alternative Medicine evaluated the efficacy

39

and safety of Ashitaba on patients and candidates with Metabolic

Syndrome (MetS).

Nine adult subjects defined as patients and candidates with MetS

ingested Ashitaba green juice (6.2 g/day of granulated powder

containing 12.3 mg chalcones) for 8 weeks. For evaluation of

efficacy, abdominal fat area, body weight, body fat and blood

parameters were measured. For evaluation of safety, blood

chemistry analysis, hematological analysis and urinalysis were

conducted.

Ingestion of Ashitaba green juice for 8 weeks significantly

decreased visceral fat area, body weight, BMI and body fat,

respectively. There were no adverse clinical changes in blood

analysis and urinary analysis, and no serious symptom was

observed.

These results indicate that it is possible that Ashitaba is a useful

and safe foodstuff for the prevention of MetS. [ 69 ]

A 2012 study pulished in the Journal of Bioscience Biotechnology

and Biochemestry investigated an ethanol extract yielding

xanthoangelol, 4-hydroxyderricin and six chalcones. The chalcones

markedly increased the expression of the adiponectin gene and

production of adiponectin in 3T3-L1 adipocytes. Results suggest

potential benefit in preventing the metabolic syndrome. [ 70 ]

40

Neurogenesis

Scientists at the Biomedical Group of TAKARA Shuzo Co Ltd have

discovered that in vivo production of Nerve Growth Factor (NGF) is

enhanced by several compounds which are contained in edible,

perennial plants such as Ashitaba (Angelica keiskei Koidzumi),

hops (Humulus luplus), edible flowers of chrysanthemum, and

Gajutsu (Curcuma zedoaria Roscoe, one strain of turmeric). Four

coumarin compounds including two novel ones and one chroman

compound were identified in the extract from Ashitaba. Rats were

fed by diet containing 1% Ashitaba dry powders (estimated dose:

750 mg/kg/day) for four days. The rats showed as high as about

20% increase of NGF concentration in the gastrocnemial muscle

compared to animals given a normal diet. [ 71 ]

Takara Bio Inc. in Japan were the assignee of a U.S. Patent on

October 10, 2003 for an “Enhancing agent for nerve growth factor

production comprising a compound having a coumarin backbone or

a compound having a 2-dimethyl chroman backbone”.

The present invention relates to a medicament, a food, a beverage

or a feed, each comprising as an effective ingredient a compound

having an enhancing action for NGF production, which is effective

for a treatment, an amelioration of symptom, prevention or the like

of a disease requiring enhancement of NGF production, wherein

the compound has a coumarin and/or chroman backbone.

41

One of the components to the enhancing agent is a root portion of

Angelica keiskei koidz, which contains chalcones.

7-β-D-glucopyranosyloxy-6-prenyl coumarin,

4′-O-angeloyl-3′-O-[6-O-(β-D-glucopyranosyl)-β-D-glucopyra

nosyl]-khellactone and

8-carboxyl-3-hydroxy-5-methoxy-2-dimethyl chroman are

compounds which are isolated from Angelica keiskei koidz. The

present invention also encompasses these compounds, of which

enhancing actions for NGF production have been also confirmed for

the first time. [ 72 ]

Quinone Reductase (Increases)

Quinone Reductase facilitates the removal of quinones from the

body.

Quinone Reductase may help to prevent many forms of cancer (by

detoxifying carcinogenic quinones) - the body naturally produces

additional Quinone Reductase in areas of the body that are afflicted

with cancer in an endogenous attempt to “fight” Cancer.

A Japanese study from 2002 idicated that Ashitaba is therefore

considered to have contained certain substances that could induce

Quinone Reductase activity, and such induction may play a role in

the anticarcinogenic action of vegetables. Among 45 different

42

vegetable samples, an extract of Ashitaba clearly induced Quinone

Reductase activity in Hep G2 cells. [ 73 ]

Skin Cancer

Dr. Toru Okuyama at Meiji University, College of Pharmacy tested

Ashitaba on mice with tobacco- induced lung cancer and skin

melanomas. In this six month study the skin cancer mice were

given an external application of the Ashitaba extract. The article

stated that the cancer was controlled-with this therapy. In the

tobacco- induced lung cancer the mice were given the extract of

Ashitaba in fluid and food form.

The article stated that the lung cancer progression stopped with

the oral Ashitaba therapy. From the active fraction of "Ashita-Ba",

Angelica keiskei, edible in Japan, five angular pyranocoumarins and

three chalcones, 4-hydroxyderricin, xanthoangelol and were

isolated.

Among these compounds, 4-hydroxyderricin and xanthoangelol

were proved to have anti-tumor-promoting activity in mouse skin

carcinogenesis [ 74 ]

43

Visceral Fat (Reduces)

In April 2010, Japan Bio Science Laboratory announced the results

of their clinical study showing compelling weight loss effects of its

Ashitaba Chalcone Powder.

Figure 6.2 Illustration from Japan Bio Science Laboratory of their randomized, double-blind, parallel

group study

In the randomized, double-blind, parallel group study, 26 slightly

obese male and female patients with BMI between 25 and 30 took

200 mg day of Ashitaba Chalcone as an active ingredient after

dinner for eight weeks. The patients were measured by CT Scan

(total, visceral and subcutaneous fat areas), weight, waist and hip.

After the eight weeks, the researchers observed a marked

reduction in the visceral and subcutaneous fat, as well as in weight,

and waist and hip ratio. The noted that the rate of change in

visceral fat was greater than that of the subcutaneous fat, and

44

attributed this to the fat-burning promotion and fat accumulation

inhibition effects of the ingredient. [ 75 ]

In another study, ingestion of Ashitaba green juice for 8 weeks

significantly decreased visceral fat area, body weight, BMI and

body fat, respectively. This was the conclusion of a 2012 study

published in the Japanese Journal of Complementary and

Alternative Medicine.

Abdominal fat area, body weight, body fat and blood parameters

were measured and Ashitaba green juice (6.2 g/day of granulated

powder containing 12.3 mg chalcones) was consumed for 8 weeks.

[ 76 ]

45

Clinical Trials

There have been two U.S. Clinical trials on Angelica Keiskei.

The first was filed on July 22, 2008 and the estimated Study

completion date was December 2010. The title of the clicial trial

was “Absorption Kinetics of Polyphenols in Angel's Plant (Angelica

Keiskei)”.

The summary of the clinical trial was “The absorption kinetics of

polyphenols in angel's plant (Angelica keiskei), which is a dark

green leafy vegetable rich in antioxidant nutrients, will be

determined in older adults in this pilot study.”

The USDA-Human Nutrition Research Center on Aging at Tufts

University was the filing and responsible party.

Unfortunately, no study results are posted on ClinicalTrials.gov for

this study. [ 77 ]

The second clinical trial was filed on August 20, 2009 and the

estimated Study completion date was July 2010. The title of the

clicial trial was “Bioactive Plant Foods: Effects on Functional

Bioavailability and Genomic Stability”.

The summary of the clinical trial was “To achieve optimal health

and to reduce the risk of age-related chronic diseases through an

easily achievable dietary modification not achievable by the limited

mixture of antioxidant supplements in older subjects, the

investigators will focus their attention on the biological functions of

46

bioactive plant food (Angelica keiskei and/or Glycine max) and its

effect on genomic stability using noble assays.

The investigators propose to study the ability of bioactive

plant-based food (Nutrition bar made from Angelica keiskei and/or

Glycine max) to 1) exert biological functions: increase total

antioxidant performance, decrease oxidative stress in vivo, and 2)

affect genomic stability: decrease DNA damage and modify DNA

methylation. The investigators hypothesize that bioactive plant

food (green leafy vegetable power, and/or black bean power) will

exert biological functions and affect genomic stability far more

efficiently than the limited mixture of purified antioxidant

supplements in the vulnerable population, older subjects (> 50

years, men and postmenopausal women) with and without

metabolic syndrome.”

Tufts University was the filing and responsible party.

Unfortunately, no study results are posted on ClinicalTrials.gov for

this study. [ 78 ]

47

Product Resources

The following resources are the existing Ashitaba products that can

be found in the United States. It is important to note that all four of

these products contain the green Ashitaba powder from the stems

and leaves of the Ashitaba plant, and not the yellow chalcone

powder from the sap of the stems.

The yellow chalcone powder does not exist at the time of this

publication (March 2015) as a finished product that can be bought

at retail. It does exist however in its raw and bulk form from Japan

Bio Science Laboratory in Japan. The name of the chalcone product

from Japan Bio Science Laboratory is called ChalCurb(TM).

Updates will be made to this e-book when the yellow chalcone

powder is made into a finished product by a nutrition company or

formulator.

Swanson's Full Spectrum Japanese Ashitaba

Sun Potion Transformational Foods Ashitaba (Organic) - 80g Jar

Percent Ashitaba

This product comes in three forms: tea, tablets and powder.

Midori Greens (Madre Labs)

This product contains a SuperGreens Blend with a core of three

traditional Japanese ingredients: Ashitaba, Japanese Matcha Green

Tea & Wildcrafted Wasabi.

48

Endnotes/References

1 http://www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?405623

2

https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact=8&ved=0CB

4QFjAA&url=http%3A%2F%2Fkitaplar.ankara.edu.tr%2Fdosyalar%2Fpdf%2F285.pdf&ei=CVD1VOiOO4i2

ogTSu4JQ&usg=AFQjCNFENmIs2qW7vsMil_fRq56ds-CD1Q&sig2=_S_MAsgeivGpkE9rBMk7KQ

3

http://www.pubfacts.com/detail/16079483/Xanthoangelol-a-major-chalcone-constituent-of-Angelica-k

eiskei-induces-apoptosis-in-neuroblastoma-an

4 Chalcones from Angelica keiskei

5 Chalcones from Angelica keiskei

6 Chalcones from Angelica keiskei

7 Chalcones from Angelica keiskei

8 http://www.ncbi.nlm.nih.gov/pubmed/17917255

9 Chalcones and Other Compounds from the Exudates of Angelica keiskeiand Their Cancer

Chemopreventive Effects

10 Chalcones and Other Compounds from the Exudates of Angelica keiskeiand Their Cancer

Chemopreventive Effects

11 http://www.ncbi.nlm.nih.gov/pubmed/17917255

12 Chalcones and Other Compounds from the Exudates of Angelica keiskeiand Their Cancer

Chemopreventive Effects

13 http://online.liebertpub.com/doi/abs/10.1089/jmf.2013.3037

14 http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201203034.htm

15 http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201203034.htm

16 http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201203034.htm

17 http://www.dbpia.co.kr/Journal/ArticleDetail/477351

18 http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201203034.htm

19 http://www.ncbi.nlm.nih.gov/pubmed/24265870

20 http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201203034.htm

49

21 http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201203034.htm

22 http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201203034.htm

23 http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201203034.htm

24 http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201203034.htm

25 http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201203034.htm

26 http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201203034.htm

27

http://onlinelibrary.wiley.com/doi/10.1002/ardp.201100005/abstract?systemMessage=Wiley+Online+L

ibrary+will+be+disrupted+on+7th+March+from+10%3A00-13%3A00+GMT+%2806%3A00-09%3A00+E

ST%29+for+essential+maintenance.++Apologies+for+the+inconvenience.

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29 http://www.hindawi.com/journals/ecam/2013/815621/

30 http://www.sciencedirect.com/science/article/pii/S0960894X13010019

31 http://www.ncbi.nlm.nih.gov/pubmed/11205867

32 http://www.ncbi.nlm.nih.gov/pubmed/17250645

33 http://www.ncbi.nlm.nih.gov/pubmed/23132631

34 Chemical Components of Angelica keiskei Koidzumi, Part VI. Antibacterial Activity of Two Chalcones,

Xanthoangelol and 4-Hydroxyderricin, Isolated from the Root of Angelica keiskei Koidumi. CHEMICAL &

PHARMACEUTICAL BULLETIN 39(6), 1604-1605, 1991 The Pharmaceutical Society of Japan, BABA

KIMIE

35 Pharmacological Activities Of Water Extracts Of Umbelliferae Plants. Kim CM, Heo MY, Kim HP, Sin

KS, Pachaly P. College of Pharmacy, Kangweon National Univ., Chuncheon, Korea. Pharm Res 1991

Mar;14(1):87-92

36

http://www.dl.begellhouse.com/journals/708ae68d64b17c52,74677e1376d0a2ef,2c29695069ad0f3c.htm

l

37 http://www.ncbi.nlm.nih.gov/pubmed/24265870

50

38 Effects of Angelica Keiskei Chalcone on Insulin Resistance of Skeletal Muscle Cells of Type 2 Diabetic

Rats

39 Anti-diabetic activities of chalcones isolated from a Japanese her, Angelica keiskei. Enoki T, Ohnogi H,

et all, J Agric Food Chem. 2007 July 25; 55 (15): 6013-7. Epub 2007 June 21.

40 THE EFFECT OF CHALCONES EXTRACTED FROM ANGELICA KEISKEI ON SERUM ET-1 AND VE-ca

IN RATS WITH TYPE 2 DIABETES

41 Anti - diabetic Activities of Ashitaba (Angelica keiskei) : Induction of Adipocyte Differentiation and

Enhancement of Glucose Uptake in Adipocyte

42 http://www.ncbi.nlm.nih.gov/pubmed/22738961

43 http://pubs.acs.org/doi/abs/10.1021/jf404175t

44 http://link.springer.com/article/10.1007%2Fs12272-011-0311-0

45 http://online.liebertpub.com/doi/abs/10.1089/jmf.2009.1271

46 http://online.liebertpub.com/doi/abs/10.1089/jmf.2013.3037

47 Sugii M., Ohkita M., Taniguchi M., Baba K., Kawai Y., Tahara C., Takaoka M. & Matsumura Y. (2005)

Xanthoangelol D isolated from the roots of Angelica keiskei inhibits endothelin-1 production through

thesuppression of nuclear factor-kappaB. Biol Pharm Bull.

48 Comparison of antioxidant content and oxidation resistance of stems and leaves from Angelica keiskei

Koidzmi

49 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296928/#B3

50 Kang M.H., Park Y.K., Kim H.Y. & Kim T.S. (2004) Green vegetable drink consumption protects

peripheral lymphocytes DNA damage in Korean smokers. Biofactors, 22(1-4): 245-247.

51 Research of Ashitaba Chalcone on the Antioxidant Effect in Tumor-Bearing Mice HOU

Fang-lin,ZHONG Jin-yi,ZHANG Yan(Haici Hospital Affiliated to Medical College of Qingdao

University,Qingdao Shandong 266033)

52 Xanthoangelols isolated from Angelica keiskei inhibit inflammatory-induced plasminogen activator

inhibitor 1 (PAI-1) production.

53 http://www.ncbi.nlm.nih.gov/pubmed/21263202

54 Antitumor and antimetastatic activities of Angelica keiskei roots, part 1: Isolation of an active

substance, xanthoangelol

51

55 http://www.ncbi.nlm.nih.gov/pubmed/1896522

56 http://www.ncbi.nlm.nih.gov/pubmed/17917255

57 Kimura Y. (2005) New anticancer agents: in vitro and in vivo evaluation of the antitumor and

antimetastatic actions of various compounds isolated from medicinal plants. In Vivo, 19(1): 37-60.

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

Kimura Y, Taniguchi M, Baba K.

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

effects

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

Pharm Bull. 2007. Biofactors. 2011.

61 http://www.ncbi.nlm.nih.gov/pubmed/11911963

62 http://www.ncbi.nlm.nih.gov/pubmed/12680848

63 http://www.ncbi.nlm.nih.gov/pubmed/10524357

64 http://www.ncbi.nlm.nih.gov/pubmed/17250645

65 Ogawa H., Ohno M. & Baba K. (2005) Hypotensive and lipid regulatory actions of 4-hydroxyderricin, a

chalcone from Angelica keiskei, in stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol

Physiol., 32(1-2): 19-23.

66 http://online.liebertpub.com/doi/abs/10.1089/jmf.2014.3222

67 Protective Effects of Angelica keiskei Extracts Against D-Galactosamine (GalN)-induced

Hepatotoxicity in Rats

68 Effect of Angelica keiskei chalcone on the expression of apoptosis-regulating proteins of mice

hepatocarcinoma cells

69

http://astp.jst.go.jp/modules/search/index.php?page=DocumentDetail&journalId=1348-7922_9_1_Effic

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70 https://www.jstage.jst.go.jp/article/bbb/76/5/76_110976/_pdf

71 Takara's Scientists Discover Compounds Enhancing in Vivo Production of Nerve Growth Factor

52

72 https://www.google.com/patents/US7078386

73 Hashimoto, K., et al. In vitro induction of the anticarcinogenic marker enzyme, quinone reductase, in

human hepatoma cells by food extracts. Cancer Lett. 180(1):1-5, 2002. Department of Bioproductive

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ogTSu4JQ&usg=AFQjCNFENmIs2qW7vsMil_fRq56ds-CD1Q&sig2=_S_MAsgeivGpkE9rBMk7KQ

75 Ashitaba Chalcones Show Efficacy in Battling Visceral Fat, Published April 6, 2010 Nutraceuticals

World

76

http://astp.jst.go.jp/modules/search/index.php?page=DocumentDetail&journalId=1348-7922_9_1_Effic

acy+and+Safety+ofi+Ashitaba%2Fi+%28iAngelica+keiskei%2Fi%29+on+the+Patients+and+Candidate

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77 https://clinicaltrials.gov/ct2/show/NCT00721643?term=Angelica+keiskei&rank=1

78 https://clinicaltrials.gov/ct2/show/NCT00963118?term=Angelica+keiskei&rank=2