Phytochemical and Pharmacological Profiles of Three Fagopyrum Buckwheats

Abstract

The genus Fagopyrum (Polygonaceae), currently comprising 15 species of plants, includes three important buckwheat species: Fagopyrum esculentum (F. esculentum) Moench. (common buckwheat), Fagopyrum tataricum (F. tataricum) (L.) Gaertn. (tartary buckwheat) and Fagopyrum dibotrys (F. dibotrys) (D. Don) Hara. (perennial buckwheat), which have been well explored due to their long tradition of both edible and medicinal use. This review aimed to present an up-to-date and comprehensive analysis of the phytochemistry and pharmacology of the three Fagopyrum buckwheats. In addition, the scope for future research was also discussed. All available references included in this paper were compiled from major databases, such as MEDLINE, Pubmed, Scholar, Elsevier, Springer, Wiley and CNKI. A total of 106 compounds isolated from three Fagopyrum buckwheats can be mainly divided into six classes: flavonoids, phenolics, fagopyritols, triterpenoids, steroids and fatty acids. Flavonoids and phenolic compounds were considered to be the major active components. Considerable pharmacological experiments both in vitro and in vivo have validated that Fagopyrum buckwheats possess antitumor, anti-oxidant, anti-inflammatory, hepatoprotective, anti-diabetic activities, etc. All reported data lead us to conclude that Fagopyrum buckwheats have convincing medicinal potential. However, further research is needed to explore its bioactive constituents, the relationship to their structural activities and the molecular mechanisms of action.

Full text

International Journal of
Molecular Sciences
Review
Phytochemical and Pharmacological Profiles of
Three Fagopyrum Buckwheats
Rui Jing
1,†
, Hua-Qiang Li
1,†
, Chang-Ling Hu
2
, Yi-Ping Jiang
1
, Lu-Ping Qin
1
and Cheng-Jian Zheng
1,
*
1
Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, Shanghai 200433,
China; jingruisoda@163.com (R.J.); lihuaqiang2009@126.com (H.-Q.L.); msjyp@163.com (Y.-P.J.);
qinsmmu@126.com (L.-P.Q.)
2
Department of Natural Products Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China;
changfeih@126.com
* Correspondence: zhengchengjian@smmu.edu.cn; Tel./Fax: +86-21-8187-1305
† These authors contributed equally to this work.
Academic Editor: Chang Won Choi
Received: 26 January 2016; Accepted: 11 April 2016; Published: 19 April 2016
Abstract:
The genus Fagopyrum (Polygonaceae), currently comprising 15 species of plants, includes
three important buckwheat species: Fagopyrum esculentum (F. esculentum) Moench. (common
buckwheat), Fagopyrum tataricum (F. tataricum) (L.) Gaertn. (tartary buckwheat) and Fagopyrum
dibotrys (F. dibotrys) (D. Don) Hara. (perennial buckwheat), which have been well explored due to
their long tradition of both edible and medicinal use. This review aimed to present an up-to-date and
comprehensive analysis of the phytochemistry and pharmacology of the three Fagopyrum buckwheats.
In addition, the scope for future research was also discussed. All available references included
in this paper were compiled from major databases, such as MEDLINE, Pubmed, Scholar, Elsevier,
Springer, Wiley and CNKI. A total of 106 compounds isolated from three Fagopyrum buckwheats can
be mainly divided into six classes: flavonoids, phenolics, fagopyritols, triterpenoids, steroids and
fatty acids. Flavonoids and phenolic compounds were considered to be the major active components.
Considerable pharmacological experiments both
in vitro
and
in vivo
have validated that Fagopyrum
buckwheats possess antitumor, anti-oxidant, anti-inflammatory, hepatoprotective, anti-diabetic
activities, etc. All reported data lead us to conclude that Fagopyrum buckwheats have convincing
medicinal potential. However, further research is needed to explore its bioactive constituents,
the relationship to their structural activities and the molecular mechanisms of action.
Keywords: Fagopyrum; buckwheat; phytochemistry; pharmacology
1. Introduction
The genus Fagopyrum, a member of family Polygonaceae, comprises 15 species that are mainly
distributed in the North Temperate Zone. A total of 10 species and one variety occur in China,
including three important buckwheat species: Fagopyrum esculentum (F. esculentum) Moench. (common
buckwheat), Fagopyrum tataricum (F. tataricum) (L.) Gaertn. (tartary buckwheat), and Fagopyrum dibotrys
(F. dibotrys) (D. Don) Hara. (perennial buckwheat) [
1
]. Due to their long tradition of both edible and
versatile medicinal use, more and more chemical and pharmacological studies have been carried out
on the above-mentioned three buckwheat species and little research has been performed on other
Fagopyrum species.
F. esculentum is an annual Asian herb with clusters of small pinkish or white flowers and edible
triangular seeds, while F. tataricum is also an erect annual herb but with smaller seed size. F. esculentum
and F. tataricum are two important crop plants and their seeds are consumed as the main buckwheats
Int. J. Mol. Sci. 2016, 17, 589; doi:10.3390/ijms17040589 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2016, 17, 589 2 of 20
worldwide, as a potential “functional food” material [
2
,
3
], particularly due to their high quality
protein, abundant phenolic compounds and well balanced essential amino acids and minerals [
4
,
5
].
Detailed comparisons of the seeds of F. esculentum and F. tataricum revealed that the former has
advantages of sweet taste, large seed size, and easy dehulling of seed coat. In contrast, the latter
is of bitter taste and small size with tight seed coat. Despite the above-mentioned disadvantages,
F. tataricum has been reported to contain much more phenolics content than F. esculentum [
3
,
6
–
8
], which
is therefore being increasingly favored by researchers in recent years [
9
–
11
]. Besides their edibility,
both F. esculentum and F. tataricum were also traditionally used in folk medicine for various medicinal
purposes. According to Traditional Chinese Medicine (TCM) theory, F. esculentum seeds possess the
ability of invigorating the spleen, eliminating food stagnating and descending qi-flowing. It has
also been cited as an anti-hemorrhagic and hypotensive drug in the British Herbal Pharmacopoeia
and used as therapeutics for anti-inflammation, detoxification and lowering the fever in Korean folk
medicine [
12
,
13
], whereas F. tataricum seeds have been found in wide use for antioxidant, antitumor,
hypoglycemic and hypolipidemic purposes [
14
–
18
]. In addition, F. tataricum roots were traditionally
utilized to regulate qi-flowing for relieving pain, invigorate the spleen and drain dampness, which were
commonly used to treat some chronic and incurable diseases, such as rheumatic disorders, cancers
and general debility. Its roots were therefore called “Qiao ye qi”, indicating that it might have similar
effects as “San qi” (Panax notoginseng roots) [
10
,
14
,
19
,
20
], which prompted our group to investigate the
bioactive metabolites from F. tataricum roots and subsequently revealed the abundance of cytotoxic
phenylpropanoid glycosides that have potential use in cancer therapy [
9
]. F. dibotrys, also called
F. cymosum (Trev.) Meisn, is an erect perennial herb with edible seeds and leaves that are rich in rutin,
which makes a healthy addition to the diet [
21
–
23
]. Its leaves can be boiled or steamed and used like
spinach [
24
]. In China, its rhizome was regarded as folk medicine for clearing away heat and toxic
materials, removing blood stasis and expelling pus, which was generally used for the treatment of
lung diseases, rheumatism, cancer, dysmenorrhea, inflammation, lumbago, snakebite and traumatic
injuries, especially effective for lung cancer [25–27].
To the best of our knowledge, modern pharmacological studies revealed that the above-mentioned
three Fagopyrum species possessed versatile bioactivities, including anti-tumor, anti-oxidant, anti-
inflammatory, anti-aging, hepatoprotective, hypoglycemic, anti-allergic, anti-fatigue activities,
etc. [
12
,
25
,
26
,
28
–
31
]. Several types of bioactive phenolics including flavonoids, condensed tannins,
phenylpropanoids and phenol derivatives were isolated from those buckwheat species. Flavonoids
in Fagopyrum buckwheats exhibited remarkable antioxidant and cardio-cerebral vascular protective
effects [
32
–
34
] and thus these buckwheats were considered as valuable dietary supplements. The
condensed tannins, isolated from the rhizomes of F. dibotrys, showed excellent anti-tumor and
anti-oxidant effects [
33
,
35
–
38
]. Additionally, phenylpropanoid glycosides were found to be the major
bioactive constituents in F. tataricum roots, which displayed significant cytotoxicity [9].
Due to the prominent values of these three Fagopyrum species on both edible and medicinal uses, in
this paper, we have documented an up-to-date and comprehensive retrospection of the phytochemical
and pharmacological studies on these three Fagopyrum buckwheats, which provided a scientific basis
for further studies on these species.
2. Phytochemicals
2.1. Flavonoids
Flavonoids, a group of polyphenolic compounds consisting of a 15-carbon basic skeleton
(C6–C3–C6), found widely in plants and human diet, are potent antitumor, antioxidants and
microcirculation improver [
32
]. Flavonoids have been proven to be the major active compounds
in Fagopyrum buckwheats, and the class and content of flavonoids varied in different parts of
Fagopyrum buckwheats. For example, six flavonoids (rutin (
8
), quercetin (
5
), orientin (
1
), vitexin (
3
),
isovitexin (
4
) and isoorientin (
2
)) were found in F. esculentum hulls, while only rutin (
8
) and

Int. J. Mol. Sci. 2016, 17, 589 3 of 20
isovitexin (
4
) were found in the seeds. In addition, in all tested tissues, much more content of
rutin was found in flowers than that in stems and leaves [
39
]. Since the discovery of rutin in F.
esculentum in the 20th century, more than 30 flavonoids have been isolated and identified from
these Fagopyrum buckwheats, such as aromadendrin-3-O-D-galactoside (
32
) and taxifolin-3-O-D-
xyloside (
33
) from F. esculentum [
40
] 3-methyl-gossypetin-8-O-
β
-D-glucopyranoside (
25
) and quercetin-
3-O-(2
11
-O-p-hydroxy-coumaroyl)-glucoside (
9
) from F. dibotrys [
33
] 5,7,3
1
,4
1
-tetramethylquercetine-3O-
rutinoside (
10
) and quercetine-3-O-rutinoside-7-O-galactoside (
11
) from F. tataricum [
41
] and so
on, most of which were obtained as O-glycosides (Figure 1). In addition, catechins (flavanols)
and condensed tannins (proanthocyanidins) were also found in these Fagopyrum buckwheats.
(
´
)-Epicatechin (
27
), (
´
)-epicatechin-3-O-p-hydroxybenzoate (
28
), (
´
)-epicatechin-3-O-(3,4-di-O-
methyl)-gallate (
29
), and (+)-catechin-7-O-glucoside (
31
) were found in F. esculentum [
34
] while
(+)-catechin (
30
) and (
´
)-epicatechin (
27
) were reported from F. dibotrys [
33
]. Four major condensed
tannins, dimers of catechin derivatives, including procyanidin B-1 (
65
), procyanidin B-2 (
66
),
3,3-di-O-galloyl-procyanidin B-2 (
67
), and 3-O-galloyl-procyanidin B-2 (
68
), were isolated from
the rhizomes of F. dibotrys and displayed significant radical-scavenging activities. Especially,
3,3-di-O-galloyl-procyanidin B-2 (67) and 3-O-galloyl-procyanidin B-2 (68) were the most active ones
due to their abundance of phenolic hydroxyl groups [
33
]. The chemical names and plant sources of
these compounds (1–35) are shown in Table 1 and Figures 1 and 2.
Table 1.
Chemical constitutents from Fagopyrum esculentum (F. esculentum), Fagopyrum tataricum
(F. tataricum) and Fagopyrum dibotrys (F. dibotrys).
No. Compounds Source Reference
Flavonoids
1 orientin Fe, Ft [3]
2 isoorientin Fe, Ft [3]
3 vitexin Fe, Ft [3]
4 isovitexin Fe, Ft [3]
5 quercetin Fd, Fe, Ft [33,40,42–44]
6 3-methylquercetin Fd [33]
7 3,5-dimethylquercetin Fd [33]
8 rutin Fd, Fe, Ft [33,40]
9 quercetin-3-O-(2
1 1
-O-p-hydroxy-coumaroyl)-glucoside Fd [33]
10 5,7,3
1
,4
1
-tetramethylquercetine-3-O-rutinoside Ft [41]
11 quercetin-3-O-rutinoside-7-O-galactoside Ft [41]
12 quercitrin (quercetin-3-O-rhamnoside) Fd, Ft [33,45]
13 quercetin-3-O-rutinoside-3
1
-O-β-glucopyranoside Fd, Ft [46]
14 hyperin/isoquercitrin (quercetin-3-O-glucoside) Fe [40,45,47]
15 quercetin-3-O-β-D-galactoside Ft, Fe [40,45]
16 quercetin-3-O-[β-D-xyloxyl-(1Ñ2)-α-L-rhamnoside] Ft [45]
17 myricetin Fe [47]
18 kaempferol Fd, Ft [43,44,48]
19 kaempferol-3-O-glucoside Ft [45]
20 kaempferol-3-O-galactoside Ft [45]
21 kaempferol-3-O-rutinoside Ft [42,44,49]
22 kaempferol-3-O-sophoroside Fe [40]
23 kaempferol-3-O-glucoside-7-O-glucoside Fe [40]
24 luteolin Fd [48]
25 3-methylgossypetin-8-O-β-D-glucopyranoside Fd [33]
26 3
1
,4
1
-methylenedioxy-7-hydroxy-6-isopentenyl flavone Fd [41]
27 (´)-epicatechin Fe, Fd [34]
28 (´)-epicatechin-3-O-p-hydroxybenzoate Fe [34]
29 (´)-epicatechin-3-O-(3,4-di-O-methyl)-gallate Fe [34]
30 (+)-catechin Fd [33]
31 (+)-catechin-7-O-glucoside Fe [34]
32 aromadendrin-3-O-D-galactoside Fe [40]
33 taxifolin-3-O-D-xyloside Fe [40]
34 hesperidin Fd [46]
35 rhamnetin Fd [46]

Int. J. Mol. Sci. 2016, 17, 589 4 of 20
Table 1. Cont.
No. Compounds Source Reference
Phenolics
36 tatariside A Ft [9]
37 tatariside B Ft [9]
38 tatariside C Ft [9]
39 tatariside D Ft [9]
40 tatariside E Ft [9]
41 tatariside F Ft [9]
42 tatariside G Ft [9]
43 diboside A Ft, Fd [33]
44 lapathoside A Fd [33]
45 1,3,6-tri-p-coumaroyl-6
1
-feruloyl sucrose Ft [45]
46 3,6-di-p-coumaroyl-1,6
1
-di-feruloyl sucrose Ft [45]
47 1,3,6
1
-tri-feruloyl-6-p-coumaroyl sucrose Ft [45]
48 taroside (1,3,6,6
1
-tetra-feruloyl sucrose) Ft [45]
49 1,3-dimethoxy-2-O-b-xylo-pyranosyl-5-O-β-glucopyranosyl-benzene Fd [50]
50 benzoic acid Fd [46]
51 gallic acid Fd [33]
52 p-hydroxybenzoic acid Fd [51]
53 syringic acid Ft [52]
54 vanillic acid Ft [52]
55 protocatechuic acid Fd, Fe, Ft [40,48]
56 protocatechuic acid methyl ester Fd [48]
57 6-O-galloyl-D-glucose Fd [33]
58 3,4-dihydroxybenzaldehyde Fd, Fe [40,48]
59 caffeic acid Ft [52]
60 ferulic acid Ft [52]
61 chlorogenic acid Fe, Ft [3]
62 p-coumaric acid Ft [52]
63 resveratrol Fe [40]
64 trans-p-hydroxy cinnamic methyl ester Fd [48]
Tannins
65 procyanidin B-1 Fd [33]
66 procyanidin B-2 Fd [33]
67 3,3-di-O-galloyl-procyanidinB-2 Fd [33]
68 3-O-galloyl-procyanidinB-2 Fd [33]
Cyclitol
69 fagopyritol A1 Fe [53]
70 fagopyritol A2 Fe [54]
71 fagopyritol A3 Fe [54]
72 fagopyritol B1 Fe [53]
73 fagopyritol B2 Fe [55]
74 fagopyritol B3 Fe [55]
Triterpenoids
75 ursolic acid Ft [42,43]
76 olean-12-en-3-ol Fe [56]
77 urs-12-en-3-ol Fe [56]
78 glutinone Fd [48]
79 glutinol Fd [48]
Steroids
80 β-sitosterol Ft [43,49]
81 β-sitosterol-palmitate Ft [49]
82 peroxidize-ergosterol Ft [49]
83 daucosterol Ft [43,49]
84 6-hydroxystigmasta-4,22-dien-3-one Fe [56]
85 23S-methylcholesterol Fe [56]
86 stigmast-5-en-3-ol Fe [56]
87 stigmast-5,24-dien-3-ol Fe [56]
88 trans-stigmast-5,22-dien-3-ol Fe [56]
89 stigmsat-4-en -3,6-dione Ft [49]
Fatty Acids
90 6,7-dihydroxy-3,7-dimethyl-octa-2(Z),4(E)-dienoic acid Fe [57]
91 6,7-dihydroxy-3,7-dimethyl-octa-2(E),4(E)-dienoic acid Fe [57]
92 4,7-dihydroxy-3,7-dimethyl-octa-2(E),5(E)-dienoic acid Fe [57]

Int. J. Mol. Sci. 2016, 17, 589 5 of 20
Table 1. Cont.
No. Compounds Source Reference
Others
93 uracil Ft [49]
94 (3-methoxyphenyl)-2-piperidinemethanol Fd [48]
95 N-trans-feruloyltyramine Ft [45]
96 succinic acid Fd [51]
97 3, 4-dihydroxy benzamine Fd [48]
98 emodin Fd [49]
99 emodin-8-O-β-D-glucopyranoside Fd [33]
100 5, 5
1
-di-α-furaldehyde dimethyl ester Ft [51]
101 7-hydroxycoumarin Ft [11]
102 n-butyl-β-D-fructopyranoside Fd [48]
103 γ-tocopherol Fe [56]
104 squalene Fe [56]
105 sucrose Ft [58]
106 fructose Ft [58]
Fe, Ft, Fd are Fagopyrum esculentum Moench., Fagopyrum tataricum (L. Gaertn. (tartary buckwheat) and Fagopyrum
dibotrys (D. Don) Hara., respectively.
Int. J. Mol. Sci. 2016, 17, 589 6 of 20
Figure 1. Structures of flavonoids isolated from Fagopyrum esculentum (F. esculentum),
Fagopyrum tataricum (F. tataricum) and Fagopyrum dibotrys (F. dibotrys).
Figure 2. Structures of tannin compounds isolated from F. esculentum, F. tataricum and F. diabotrys.
Figure 1.
Structures of flavonoids isolated from Fagopyrum esculentum (F. esculentum), Fagopyrum
tataricum (F. tataricum) and Fagopyrum dibotrys (F. dibotrys).

Int. J. Mol. Sci. 2016, 17, 589 6 of 20
Int. J. Mol. Sci. 2016, 17, 589 6 of 20
Figure 1. Structures of flavonoids isolated from Fagopyrum esculentum (F. esculentum),
Fagopyrum tataricum (F. tataricum) and Fagopyrum dibotrys (F. dibotrys).
Figure 2. Structures of tannin compounds isolated from F. esculentum, F. tataricum and F. diabotrys.
Figure 2. Structures of tannin compounds isolated from F. esculentum, F. tataricum and F. diabotrys.
2.2. Phenolics
Phenolic compounds are secondary metabolites derivated from the pentose phosphate, shikimate,
and phenylpropanoid pathways in plants [
59
]. This class of compounds exhibits a wide range of
physiological properties (antioxidant, antitumor, antibacterial activities, etc.), and is ubiquitous in
plants [
60
]. The major phenolic constituents in these Fagopyrum buckwheats include phenylpropanoids
and derivatives of hydroxybenzoic and hydroxycinnamic acid. Our group has recently isolated and
identified seven new phenylpropanoid glycosides, tatarisides A–G (
36
–
42
), with potent cytotoxic
activity, from the roots of F. tataricum [
9
] together with diboside A (
43
), a phenylpropanoid previously
isolated from the rhizomes of F. dibotrys along with lapathoside A (
44
) possessing the same skeleton.
More recently, 1,3,6,6
1
-tetra-feruloyl sucrose (
48
), a new phenylpropanoid glycoside named taroside,
was isolated from F. tataricum seeds together with 3,6-di-p-coumaroyl-1,6
1
-di-feruloyl sucrose (
46
),
1,3,6
1
-tri-feruloyl-6-p-coumaroyl sucrose (
47
), and 1,3,6-tri-p-coumaroyl-6
1
-feruloyl sucrose (
45
) [
45
].
More detailed information on phenolic compounds is listed in Table 1 and shown in Figure 3.
Int. J. Mol. Sci. 2016, 17, 589 7 of 20
2.2. Phenolics
Phenolic compounds are secondary metabolites derivated from the pentose phosphate,
shikimate, and phenylpropanoid pathways in plants [59]. This class of compounds exhibits a wide
range of physiological properties (antioxidant, antitumor, antibacterial activities, etc.), and is
ubiquitous in plants [60]. The major phenolic constituents in these Fagopyrum buckwheats include
phenylpropanoids and derivatives of hydroxybenzoic and hydroxycinnamic acid. Our group has
recently isolated and identified seven new phenylpropanoid glycosides, tatarisides A–G (36–42),
with potent cytotoxic activity, from the roots of F. tataricum [9] together with diboside A (43), a
phenylpropanoid previously isolated from the rhizomes of F. dibotrys along with lapathoside A (44)
possessing the same skeleton. More recently, 1,3,6,6′-tetra-feruloyl sucrose (48), a new
phenylpropanoid glycoside named taroside, was isolated from F. tataricum seeds together with
3,6-di-p-coumaroyl-1,6′-di-feruloyl sucrose (46), 1,3,6′-tri-feruloyl-6-p-coumaroyl sucrose (47), and
1,3,6-tri-p-coumaroyl-6′-feruloyl sucrose (45) [45]. More detailed information on phenolic
compounds is listed in Table 1 and shown in Figure 3.
Figure 3. Structures of phenolic compounds isolated from F. esculentum, F. tataricum and F. diabotrys.
Figure 3. Structures of phenolic compounds isolated from F. esculentum, F. tataricum and F. diabotrys.

Int. J. Mol. Sci. 2016, 17, 589 7 of 20
2.3. Fagopyritol
Fagopyritols are mono-, di-, and trigalactosyl derivatives of D-chiro-inositol that are accumulated
in embryo and aleurone tissues of buckwheat seeds and may be important for seed maturation and
as a dietary supplement. Thus far, a total of six fagopyritols (fagopyritols A1, A2, A3, B1, B2 and
B3) have been identified from F. esculentum seeds [
53
,
54
], classified into two series of fagopyritol
oligomers based on the linkage between galactopyranosyl and D-chiro-inositol moiety. Fagopyritols
A1 (
69
), A2 (
70
) and A3 (
71
) were of A-series with a 1
Ñ
3 linkage, identified as
α
-D-gal-(1
Ñ
3)-D-
chiro-inositol (
69
),
α
-D-gal-(1
Ñ
6)-
α
-D-gal-(1
Ñ
3)-D-chiro-inositol (
70
), and
α
-D-gal-(1
Ñ
6)-
α
-D-gal-
(1
Ñ
6)-
α
-D-gal-(1
Ñ
3)-D-chiro-inositol (
71
), respectively, while fagopyritols B1 (
72
), B2 (
73
) and B3
(
74
), with a 1
Ñ
2 linkage, were identified as
α
-D-gal-(1
Ñ
2)-D-chiro-inositol (
72
),
α
-D-gal-(1
Ñ
6)-
α
-D-
gal-(1
Ñ
2)-D-chiro-inositol (
73
), and
α
-D-gal-(1
Ñ
6)-
α
-D-gal-(1
Ñ
6)-
α
-D-gal-(1
Ñ
2)-D-chiro-inositol (
74
),
respectively. Fagopyritol A1 (
69
) and fagopyritol B1 (
72
) are the prominent fagopyritols accumulated
and can facilitate desiccation tolerance and storability of buckwheat seeds [
54
,
61
]. Moreover,
fagopyritols are structurally similar to a galactosamine derivative of D-chiro-inositol, a putative
insulin mediator [
62
] and therefore may be useful in the treatment for non-insulin dependent diabetes
mellitus [
61
]. More detailed information on Fagopyritols (
69
–7
4
) is listed in Table 1 and shown
in Figure 4.
Int. J. Mol. Sci. 2016, 17, 589 8 of 20
2.3. Fagopyritol
Fagopyritols are mono-, di-, and trigalactosyl derivatives of D-chiro-inositol that are
accumulated in embryo and aleurone tissues of buckwheat seeds and may be important for seed
maturation and as a dietary supplement. Thus far, a total of six fagopyritols (fagopyritols A1, A2,
A3, B1, B2 and B3) have been identified from F. esculentum seeds [53,54], classified into two series of
fagopyritol oligomers based on the linkage between galactopyranosyl and D-chiro-inositol moiety.
Fagopyritols A1 (69), A2 (70) and A3 (71) were of A-series with a 1→3 linkage, identified as
α-
D-gal-(1→3)-D-chiro-inositol (69), α-D-gal-(1→6)-α-D-gal-(1→3)-D-chiro-inositol (70), and α-D-gal-(1
→6)-α-
D-gal-(1→6)-α-D-gal-(1→3)-D-chiro-inositol (71), respectively, while fagopyritols B1 (72), B2
(73) and B3 (74), with a 1→2 linkage, were identified as α-
D-gal-(1→2)-D-chiro-inositol (72), α-D-gal-(1
→ 6)-α-
D-gal-(1 → 2)-D-chiro-inositol (73), and α-D-gal-(1 → 6)-α-D-gal-(1 → 6)-α-D-gal-(1 → 2)-D-
chiro-inositol (74), respectively. Fagopyritol A1 (69) and fagopyritol B1 (72) are the prominent
fagopyritols accumulated and can facilitate desiccation tolerance and storability of buckwheat seeds
[54,61]. Moreover, fagopyritols are structurally similar to a galactosamine derivative of
D-chiro-inositol, a
putative insulin mediator [62] and therefore may be useful in the treatment for non-insulin
dependent diabetes mellitus [61]. More detailed information on Fagopyritols (69–74) is listed in
Table 1 and shown in Figure 4.
Figure 4. Structures of cyclitol compounds isolated from F. esculentum, F. tataricum and F. diabotrys.
2.4. Triterpenoids
A few triterpenoids (75–79) have been reported from Fagopyrum buckwheats. Glutinone and
glutinol were isolated from the rhizomes of F. dibotrys [48] while olean-12-en-3-ol (76) and
urs-12-an-3-ol (77) were identified from F. esculentum seed oil that was extracted with petroleum
ether and analyzed by capillary GC/MS [56]. In addition, ursolic acid (75) was isolated from
F. dibotrys [33]. The names and structures of triterpeniods are listed in Table 1 and shown in Figure 5.
Figure 5. Structures of triterpenoids isolated from F. esculentum, F. tataricum and F. diabotrys.
Figure 4. Structures of cyclitol compounds isolated from F. esculentum, F. tataricum and F. diabotrys.
2.4. Triterpenoids
A few triterpenoids (
75
–
79
) have been reported from Fagopyrum buckwheats. Glutinone and
glutinol were isolated from the rhizomes of F. dibotrys [
48
] while olean-12-en-3-ol (
76
) and urs-12-an-3-ol
(
77
) were identified from F. esculentum seed oil that was extracted with petroleum ether and analyzed
by capillary GC/MS [
56
]. In addition, ursolic acid (
75
) was isolated from F. dibotrys [
33
]. The names
and structures of triterpeniods are listed in Table 1 and shown in Figure 5.
Int. J. Mol. Sci. 2016, 17, 589 8 of 20
2.3. Fagopyritol
Fagopyritols are mono-, di-, and trigalactosyl derivatives of D-chiro-inositol that are
accumulated in embryo and aleurone tissues of buckwheat seeds and may be important for seed
maturation and as a dietary supplement. Thus far, a total of six fagopyritols (fagopyritols A1, A2,
A3, B1, B2 and B3) have been identified from F. esculentum seeds [53,54], classified into two series of
fagopyritol oligomers based on the linkage between galactopyranosyl and D-chiro-inositol moiety.
Fagopyritols A1 (69), A2 (70) and A3 (71) were of A-series with a 1→3 linkage, identified as
α-
D-gal-(1→3)-D-chiro-inositol (69), α-D-gal-(1→6)-α-D-gal-(1→3)-D-chiro-inositol (70), and α-D-gal-(1
→6)-α-
D-gal-(1→6)-α-D-gal-(1→3)-D-chiro-inositol (71), respectively, while fagopyritols B1 (72), B2
(73) and B3 (74), with a 1→2 linkage, were identified as α-
D-gal-(1→2)-D-chiro-inositol (72), α-D-gal-(1
→ 6)-α-
D-gal-(1 → 2)-D-chiro-inositol (73), and α-D-gal-(1 → 6)-α-D-gal-(1 → 6)-α-D-gal-(1 → 2)-D-
chiro-inositol (74), respectively. Fagopyritol A1 (69) and fagopyritol B1 (72) are the prominent
fagopyritols accumulated and can facilitate desiccation tolerance and storability of buckwheat seeds
[54,61]. Moreover, fagopyritols are structurally similar to a galactosamine derivative of
D-chiro-inositol, a
putative insulin mediator [62] and therefore may be useful in the treatment for non-insulin
dependent diabetes mellitus [61]. More detailed information on Fagopyritols (69–74) is listed in
Table 1 and shown in Figure 4.
Figure 4. Structures of cyclitol compounds isolated from F. esculentum, F. tataricum and F. diabotrys.
2.4. Triterpenoids
A few triterpenoids (75–79) have been reported from Fagopyrum buckwheats. Glutinone and
glutinol were isolated from the rhizomes of F. dibotrys [48] while olean-12-en-3-ol (76) and
urs-12-an-3-ol (77) were identified from F. esculentum seed oil that was extracted with petroleum
ether and analyzed by capillary GC/MS [56]. In addition, ursolic acid (75) was isolated from
F. dibotrys [33]. The names and structures of triterpeniods are listed in Table 1 and shown in Figure 5.
Figure 5. Structures of triterpenoids isolated from F. esculentum, F. tataricum and F. diabotrys.
Figure 5. Structures of triterpenoids isolated from F. esculentum, F. tataricum and F. diabotrys.

Int. J. Mol. Sci. 2016, 17, 589 8 of 20
2.5. Steroids
A total of five steroids, including
β
-sitosterol (
80
),
β
-sitosterol palmitate (
81
), ergosterol peroxide
(
82
), daucosterol (
83
) and stigmsat-4-en-3,6-dione (
89
), were isolated from the seeds of F. tataricum [
49
].
Other steroids were identified as 6-hydroxystigmasta-4,22-dien-3-one (
84
), 23S-methylcholesterol
(
85
), stigmast-5-en-3-ol (
86
), stigmast-5,24-dien-3-ol (
87
), and trans-stigmast-5,22-dien-3-ol (
87
) in
F. esculentum seed oil by capillary GC/MS [
56
]. Hecogenin was isolated from F. dibotrys [
63
]. All steroid
compounds are listed in Table 1 and shown in Figure 6.
Int. J. Mol. Sci. 2016, 17, 589 9 of 20
2.5. Steroids
A total of five steroids, including β-sitosterol (80), β-sitosterol palmitate (81), ergosterol
peroxide (82), daucosterol (83) and stigmsat-4-en-3,6-dione (89), were isolated from the seeds of F.
tataricum [49]. Other steroids were identified as 6-hydroxystigmasta-4,22-dien-3-one (84),
23S-methylcholesterol (85), stigmast-5-en-3-ol (86), stigmast-5,24-dien-3-ol (87), and trans-stigmast-
5,22-dien-3-ol (87) in F. esculentum seed oil by capillary GC/MS [56]. Hecogenin was isolated from
F. dibotrys [63]. All steroid compounds are listed in Table 1 and shown in Figure 6.
Figure 6. Structures of steroids isolated from F. esculentum, F. tataricum and F. diabotrys.
2.6. Fatty Acid
This class of compounds is of minor polarity in plants. Fifteen fatty acids were determined in F.
esculentum seed oil analyzed by capillary GC/MS [56]. In addition, three new fatty acids,
6,7-dihydroxy-3,7-dimethyl-octa-2(Z),4(E)-dienoic acid (90), 6,7-dihydroxy-3,7-dimethyl-octa-2(E),
4(E)-dienoic acid (91) and 4,7-dihydroxy-3,7-dimethyl-octa-2(E),5(E)-dienoic acid (92) were isolated
from the methanol extract of F. esculentum hulls. These compounds, at 500 µg/mL, showed potential
antimicrobial activity against Staphylococcus aureus [57]. The names and structures of three
compounds are listed in Table 1 and shown in Figure 7.
Figure 7. Structures of fatty acids isolated from F. esculentum, F. tataricum and F. diabotrys.
2.7. Volatile Compounds
Buckwheats have a strong characteristic aroma. Volatile constituents are believed to play a
major role in the buckwheat aroma. Volatiles from ground F. esculentum flour were analyzed by
GC/MS, among which, 2,5-dimethyl-4-hydroxy-3(2H)-furanone, (E,E)-2,4-decadienal,
phenylacetaldehyde, 2-methoxy-4-vinylphenol, (E)-2-nonenal, decanal, hexanal and salicylaldehyde
were regarded as the major contributors to the buckwheat aroma compounds [64]. In addition, the
Figure 6. Structures of steroids isolated from F. esculentum, F. tataricum and F. diabotrys.
2.6. Fatty Acid
This class of compounds is of minor polarity in plants. Fifteen fatty acids were determined
in F. esculentum seed oil analyzed by capillary GC/MS [
56
]. In addition, three new fatty acids,
6,7-dihydroxy-3,7-dimethyl-octa-2(Z),4(E)-dienoic acid (
90
), 6,7-dihydroxy-3,7-dimethyl-octa-2(E),4(E)-
dienoic acid (
91
) and 4,7-dihydroxy-3,7-dimethyl-octa-2(E),5(E)-dienoic acid (
92
) were isolated from
the methanol extract of F. esculentum hulls. These compounds, at 500
µ
g/mL, showed potential
antimicrobial activity against Staphylococcus aureus [
57
]. The names and structures of three compounds
are listed in Table 1 and shown in Figure 7.
Int. J. Mol. Sci. 2016, 17, 589 9 of 20
2.5. Steroids
A total of five steroids, including β-sitosterol (80), β-sitosterol palmitate (81), ergosterol
peroxide (82), daucosterol (83) and stigmsat-4-en-3,6-dione (89), were isolated from the seeds of F.
tataricum [49]. Other steroids were identified as 6-hydroxystigmasta-4,22-dien-3-one (84),
23S-methylcholesterol (85), stigmast-5-en-3-ol (86), stigmast-5,24-dien-3-ol (87), and trans-stigmast-
5,22-dien-3-ol (87) in F. esculentum seed oil by capillary GC/MS [56]. Hecogenin was isolated from
F. dibotrys [63]. All steroid compounds are listed in Table 1 and shown in Figure 6.
Figure 6. Structures of steroids isolated from F. esculentum, F. tataricum and F. diabotrys.
2.6. Fatty Acid
This class of compounds is of minor polarity in plants. Fifteen fatty acids were determined in F.
esculentum seed oil analyzed by capillary GC/MS [56]. In addition, three new fatty acids,
6,7-dihydroxy-3,7-dimethyl-octa-2(Z),4(E)-dienoic acid (90), 6,7-dihydroxy-3,7-dimethyl-octa-2(E),
4(E)-dienoic acid (91) and 4,7-dihydroxy-3,7-dimethyl-octa-2(E),5(E)-dienoic acid (92) were isolated
from the methanol extract of F. esculentum hulls. These compounds, at 500 µg/mL, showed potential
antimicrobial activity against Staphylococcus aureus [57]. The names and structures of three
compounds are listed in Table 1 and shown in Figure 7.
Figure 7. Structures of fatty acids isolated from F. esculentum, F. tataricum and F. diabotrys.
2.7. Volatile Compounds
Buckwheats have a strong characteristic aroma. Volatile constituents are believed to play a
major role in the buckwheat aroma. Volatiles from ground F. esculentum flour were analyzed by
GC/MS, among which, 2,5-dimethyl-4-hydroxy-3(2H)-furanone, (E,E)-2,4-decadienal,
phenylacetaldehyde, 2-methoxy-4-vinylphenol, (E)-2-nonenal, decanal, hexanal and salicylaldehyde
were regarded as the major contributors to the buckwheat aroma compounds [64]. In addition, the
Figure 7. Structures of fatty acids isolated from F. esculentum, F. tataricum and F. diabotrys.
2.7. Volatile Compounds
Buckwheats have a strong characteristic aroma. Volatile constituents are believed to play a major
role in the buckwheat aroma. Volatiles from ground F. esculentum flour were analyzed by GC/MS,
among which, 2,5-dimethyl-4-hydroxy-3(2H)-furanone, (E,E)-2,4-decadienal, phenylacetaldehyde,

Int. J. Mol. Sci. 2016, 17, 589 9 of 20
2-methoxy-4-vinylphenol, (E)-2-nonenal, decanal, hexanal and salicylaldehyde were regarded as
the major contributors to the buckwheat aroma compounds [
64
]. In addition, the aroma-active
components of commercially obtained “monofloral” buckwheat honey, at least 51% the constituent
nectar or 45% of contaminant pollen were from a single floral source (F. esculentum), were identified by
Gas chromatography-olfactometry (GCO) of decreasing headspace samples, which revealed that the
most aroma-active odorants were 3-methylbutanal, 3-hydroxy-4,5-dimethyl-2(5H)-furanone (sotolon)
and (E)-
β
-damascenone, with 3-methylbutanal being primarily responsible for the distinct malty
aroma [65].
2.8. Other Compounds
Alkaloids, anthraquinones, coumarins and carbohydrate derivatives were also reported from these
three buckwheats. Uracil (
93
), 3,4-dihydroxy benzamine (
97
), 5,5
1
-di-
α
-furaldehyde dimethyl ester
(
100
), sucrose (
105
) and fructose (
106
) were isolated from seeds of F. tataricum. (3-Methoxyphenyl)-2-
piperidinemethanol (
94
), n-butyl-
β
-D-fructopyranoside (
95
),
γ
-tocopherol (
103
) and squalene (
104
)
were isolated from F. esculentum. Succinic acid (
96
), emodin (
98
), emodin-8-O-
β
-D-glucopyranoside
(
99
), and 7-hydroxycoumarin (
101
) were isolated from the rhizomes of F. dibotrys [
33
,
42
,
46
,
49
,
51
].
In addition, these three buckwheats also possess abundant nutritional protein with well-balanced
essential amino acids (glutamic acid, arginine, asparaginic acid, glycine, lysine, etc.) and minerals
(K, Mg, Na, Zn, Ca, Mn, etc.) [
27
]. More detailed information is listed in Table 1 and shown in Figure 8.
Int. J. Mol. Sci. 2016, 17, 589 10 of 20
aroma-active components of commercially obtained “monofloral” buckwheat honey, at least 51%
the constituent nectar or 45% of contaminant pollen were from a single floral source (F. esculentum),
were identified by Gas chromatography-olfactometry (GCO) of decreasing headspace samples,
which revealed that the most aroma-active odorants were 3-methylbutanal, 3-hydroxy-4,5-dimethyl-
2(5H)-furanone (sotolon) and (E)-β-damascenone, with 3-methylbutanal being primarily responsible
for the distinct malty aroma [65].
2.8. Other Compounds
Alkaloids, anthraquinones, coumarins and carbohydrate derivatives were also reported from
these three buckwheats. Uracil (93), 3,4-dihydroxy benzamine (97), 5,5′-di-α-furaldehyde dimethyl
ester (100), sucrose (105) and fructose (106) were isolated from seeds of F. tataricum.
(3-Methoxyphenyl)-2-piperidinemethanol (94), n-butyl-β-
D-fructopyranoside (95), γ-tocopherol
(103) and squalene (104) were isolated from F. esculentum. Succinic acid (96), emodin (98),
emodin-8-O-β-
D-glucopyranoside (99), and 7-hydroxycoumarin (101) were isolated from the
rhizomes of F. dibotrys [33,42,46,49,51]. In addition, these three buckwheats also possess abundant
nutritional protein with well-balanced essential amino acids (glutamic acid, arginine, asparaginic
acid, glycine, lysine, etc.) and minerals (K, Mg, Na, Zn, Ca, Mn, etc.) [27]. More detailed information
is listed in Table 1 and shown in Figure 8.
NH
H
N
O O
93
H
N
OH
OCH
3
94
OH
HO
O
O
OH
OH
H
2
N
R
3
OH
R
2
R
1
O
O
96
97
R
1
R
2
R
3
98
OH CH
3
OH
99
CH
3
OH OGlc
O OHO
102
O
HO
HO
OH
OH
O
O
O
HO
103
104
O
CHO
100
O
O
OHC
101
NH
OCH
3
OH
O
HO
95
O
O
O
OHHO
HO
OH
HO
OH
OH
OH
O
HO
OH
HO
HO
OH
106
105
Figure 8. Structures of other compounds isolated from F. esculentum, F. tataricum and F. diabotrys.
Figure 8. Structures of other compounds isolated from F. esculentum, F. tataricum and F. diabotrys.

Int. J. Mol. Sci. 2016, 17, 589 10 of 20
3. Pharmacological Properties
These three Fagopyrum buckwheats possessed versatile bioactivities, reputed for their
anti-tumor [
9
,
12
,
14
,
26
,
63
,
66
–
84
], anti-oxidant [
6
,
28
,
38
,
40
,
85
–
93
], anti-inflammatory [
94
–
97
],
hepatoprotective [
29
,
98
–
103
], anti-hyperglycemic [
30
,
104
–
112
], anti-allergic [
12
], anti-bacterial [
42
,
108
–
115
]
and anti-fatigue activities [
116
,
117
]. In this section, the available pharmacological data on F. esculentum,
F. tataricum, and F. dibotrys have been documented.
3.1. Antitumor Activity
F. dibotrys (F. cymosum) has been used in China to treat various lung ailments for a long time,
including lung tumors.
In vitro
experiments revealed that a commercial extract of F. Cymosum
obtained from the International Herbal Pharmaceuticals Inc. (Whitestone, New York, NY, USA),
exhibited broad-spectrum cytotoxicity, significantly inhibiting the growth of cancer cells from lung
(H460), liver (HepG2), colon (HCT116), leukocytes (K562) and bone (U2OS) with concentrations
that cause 50% inhibition of cell growth (G
50
) approximately in the range of 25–40
µ
g/mL, whereas
cancer cells derived from prostate (DU145), cervix (HeLa-S3), ovary (OVCAR-3) and brain (T98G)
were not sensitive to F. cymosum. Synergistic inhibition effect of F. cymosum and daunomycin
was also observed in human lung cancer cells (H460) [
25
,
26
]. Many
in vivo
and
in vitro
studies
revealed that Fr4 (the forth fraction from the extract of F. cymosum rhizomes) was responsible for
the antiproliferative activity of F. cymosum and regarded as the most promising fraction. Fr4, with more
than 50% phenolic content, significantly inhibited the growth of Lewis lung tumor on C57BL/6 mouse
at a dose of 400 mg/kg, which down-regulated the expression of matrix metalloprotease (MMP-9)
in mice [
69
]. Furthermore, Fr4 could suppress the growth of transplanted tumors of Sarcoma-180
(S180) and Hepatoma-22 (H22) in mice [
66
], which exhibited synergistic effect with cyclophosphamide
and also alleviated the myelosuppression adverse effect of cyclophosphamide [
67
,
68
]. Dimer of
5,7,3’,4’-tetrahydroxyflavan-3-ol (C4–C8 linked), named dimeric procyanidin, was recognized as the
major bioactive constituent of F. cymosum [63]. In addition, Fr4 induced HL-60 apoptosis through the
down regulation of telomerase activity [72].
The combination of extracts of F. cymosum and Rosa roxburghii showed an
in vitro
synergistic
effect on inhibiting the growth and inducing apoptosis of the human gastric carcinoma SGC-7901,
pulmonary carcinoma A549 [
75
] and esophageal carcinoma CaEs-17 [
79
] cell lines. Co-administration
of F. cymosum extracts and matrine could inhibit the expression of adhesion molecules (CD44, CD49,
ICAM-1, and E-selectin), thus reducing the adhesion ability of high metastasis lung cancer cell line
(PG) to human umbilical vein endothelial cell (HUVEC), and preventing tumor cells to adhere to vessel
wall, which could also inhibit the invasion of human hepatocellar live carcinoma cell line (HepG2)
by means of up-regulating the mRNA expression of nm23-H1 and down-regulating the expression of
Tiam-1 [74].
Extract of F. esculentum flowers and leaves (EBFL) significantly inhibited tumor cell proliferation
and induced the apoptosis of H22 cells [
83
,
84
]. Furthermore, it could alleviate cyclophosphamide
(CTX)-induced immunosupression by boosting the immune function of H22 tumor mice [
82
]. EBFL
could also inhibit the growth of S180 tumor in mice, which may be related to the increasing GSH-Px
and SOD activity and decreased malondial dehyde (MDA) content [
80
].
In vitro
, it also inhibited
the HL-60 cell growth and blocked cells from G
0
/G
1
to S phase [
83
]. The ethyl acetate and butanol
fraction of F. esculentum sprout ethanol extract, at the concentration of 1.0 mg/mL, also showed strong
cytotoxicity against A549, AGS, MCF-7, Hep3B and Colo205 cancer cell lines with growth inhibition of
70.3%, 94.8%, 79.6%, 82.3%, and 73.2%, respectively [
81
]. In addition, recombinant buckwheat trypsin
inhibitor (rBTI) possessed potent antiproliferative activity
in vitro
and its mutant (aBTI) displayed
much stronger antiproliferative efficacy
in vitro
against HL-60, EC9706 and HepG2 cells and might be
a novel candidate for cancer treatment [
77
,
78
]. A population-based case-control study revealed that
intake of buckwheat was associated with reduced risk of lung cancer [73].

Int. J. Mol. Sci. 2016, 17, 589 11 of 20
A novel cytotoxic protein, coded as TBWSP31, was isolated from the water-soluble extract of
F. tataricum. TBWSP31 significantly inhibited the growth of human mammary cancer cell Bcap37 in
time and concentration dependent manner, with IC
50
values of 43.37 (48 h) mg/mL and 19.75 mg/mL
(72 h), via induction of apoptosis, up-regulation of Fas expression and down-regulation of B cell
lymphoma 2 (Bcl-2) expression [
10
,
14
]. In addition, tartary buckwheat protein product (BWP) exhibited
in vivo
antitumor activity against 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis
by suppressing cell proliferation [
71
] and also retarded 7,12-dimethylbenz[
α
]anthracene-induced
mammary carcinogenesis in rat [
70
]. In addition, our recent work revealed that seven new
phenylpropanoid glycosides, tatarisides A–G (
36
–
42
), from the roots of F. tataricum, exhibited potent
cytotoxic activity against four human cancer cell lines (A-549, HCT116, ZR-75-30 and HL-60) with IC
50
values in the range of 2.83–55.66 µg/mL [9].
3.2. Anti-Oxidant Activity
Many phenolic compounds, including flavonoids, tannins, phenolic acids, coumarins, lignans,
stilbenes, and curcuminoids, have been reported to possess potent antioxidant activity [
86
]. The wide
use of Fagopyrum buckwheats as medicinal food largely benefits from the abundance of phenolic
compounds [
38
]. Rutin (
8
) was early found to be rich in F. esculentum and showed significant
antioxidant activity. At the concentration of 0.05 mg/mL, ascorbic acid (Vc), butylated hydroxytoluene
(BHT) and rutin (
8
) exhibited 92.8%, 58.8%, and 90.4% inhibition against 1,1-diphenyl-2-picryl-hydrazyl
(DPPH) radical, respectively, and rutin (8) also showed effective inhibition on lipid peroxidation [89].
The extracting solvents of different polarities significantly affected the yield, total phenolics and
antioxidant activity of buckwheat (F. esculentum) extracts. For example, the methanolic extracts showed
the highest antioxidant activity coefficient (AAC) of 627.0
˘
40.0 at 200 mg/L by the
β
-carotene
bleaching method and the longest induction time of 7.0
˘
0.2 h by the Rancimat method, whereas
the acetone extract showed highest scavenging activity of 78.6
˘
6.2% at 0.1 mg/mL by the DPPH
method [
28
]. The content of both rutin and total flavonoids significantly varied depending on species,
0.02% and 0.04% in F. esculentum, 0.10% and 0.35% in F. homotropicum, and 1.67% and 2.04% in
F. tataricum, respectively. The results showed that the antioxidant activity decreased in the order:
F. tataricum > F. homotropicum > F. esculentum. According to this, the contents of rutin and total
flavonoids in buckwheats play an important role in antioxidant activity [
6
]. The phenolic content
and antioxidant activity of tartary buckwheat also varied from different locations, revealing that
growing conditions and the interaction between variety and environment contributes importantly
to individual phenolics and antioxidant properties of tartary buckwheat [
92
]. However, different
processing, such as roasting or extrusion, did not cause obvious change in total phenolic content and
antioxidant activity of buckwheat flour. Roasted (200
˝
C, 10 min) buckwheat flour only exhibited an
increase both in non-polar compounds and polar compounds, whereas extrusion exhibited increase
only in polar compounds [
87
]. Besides buckwheat seeds, other parts of buckwheat also displayed
significant antioxidant activity. The ethanolic extract of buckwheat hulls inhibited lipid peroxidation
and five antioxidant compounds were isolated from its bioactive fractions, which were identified as
quercetin (
5
), hyperin (
14
), rutin (
8
), protocatechuic acid (
55
), and 3,4-dihydroxybenzaldehyde (
5
) [
40
].
The hulls, bran and protein hydrolysates of F. esculentum exhibited an excellent antioxidant effect,
including free radical scavenging ability and linoleic acid peroxidation inhibiting ability [
85
,
90
,
91
,
93
].
In addition, due to their significant antioxidant activities, both F. esculentum and F. tataricum
ethanolic extracts remarkably inhibited the non-site-specific hydroxyl radical-mediated DNA damage
and site-specific hydroxyl radical-mediated DNA strand breaks
in vitro
. The ethanolic extract of
F. tataricum possessed higher content of phenolics and therefore exhibited stronger antioxidant activity
than that of F. esculentum [88].

Int. J. Mol. Sci. 2016, 17, 589 12 of 20
3.3. Anti-Inflammatory Activity
The ethanol extract of F. esculentum sprouts (ExtBS) showed significant anti-inflammatory activity
both
in vitro
and
in vivo
. ExtBS can down-regulation IL-6 and TNF-
α
level in mice stimulated by LPS.
Besides, it directly affected the gene expression of IL-6 and IL-8 in HeLa cells. In a word, ExtBS can
be a promising candidate used to prevent the progress of various inflammatory diseases [
94
]. The
80% ethanol extract of F. dibotrys roots was suspended in water and partitioned with petroleum
ether (PE), CHCl
3
, EtOAc, and n-BuOH, successively, which were subsequently screened for
anti-inflammatory activity. The results indicated that the CHCl
3
fraction was the most effective
and significantly inhibited the auricle swelling in mice, voix pedis engorgement in rat and decrease the
PGE2 level in rat swelling foot [
96
]. The 50% ethanol extract of F. dibotrys roots, with (
´
)-epicatechin
(
27
) as the main bioactive constituent (2.18 mg/g), can also significantly restrain the mouse ear swelling
induced by dimethylbenzene compared with model control group [
95
]. In addition, the extract of
F. cymosum roots (Fag) significantly inhibited the acetic acid induced writhing in mice, and reduced
the peritoneal permeability and the exudation of Evans blue in mice, indicating that Fag possessed
antinociceptive and anti-inflammatory effects [97].
3.4. Heptoprotective Activity
The ethanol extract of germinated seeds of F. esculentum, with rutin (
8
) content increased more
than 10 times and production of quercitrin (
12
) and one newly formed flavonoid after 48 h germination,
displayed potent anti-fatty liver activities, which significantly reduced the triglyceride (TG) and total
cholesterol (TC) levels in the liver of mice with a high-fat diet, by suppressing expression of the key
adipogenic transcriptional factors, such as PPARγ and C/EBPα in hepatocytes [29].
The 60% ethanol extract of F. tartaricum seeds was shown to strikingly lower the activities of
serum aminotransferase (ALT) and aspartate aminotransferase (AST) in a dose dependent manner in
mice with acute liver injury induced by carbon tetrachloride (CCl
4
) and D-galactosamine. Significant
alleviation of the histopatholocal changes in the liver was also observed in mice pretreated with
F. tartaricum seeds extract before the induction of liver injury [
101
,
102
]. The 75% ethanol extracts
from tartary buckwheat (EEB) also showed significant heptoprotective activity against ethanol- and
CCl
4
-induced liver damage in C57BL/6 mice (ethanol induction) and Sprague-Dawley (SD) rats
(CCl
4
induction). EEB decreased the serum AST, ALT and alkaline phosphatase (ALP) levels in
liver injured animals and enhanced the activities of antioxidant enzyme, including catalase (CAT),
glutathione peroxidase (GPx), glutathione reductase (GR), and superoxide dismutase (SOD), and
inhibited the levels of hepatic inflammation. All these suggested that EEB prevent hepatic injury
via anti-oxidative and anti-inflammatory properties against oxidative liver damage. Rutin (
8
) and
quercetin (
12
) displayed the similar effects as EEB and were considered as the major active compounds
responsible for EEB’s heptoprotective activity [
103
]. In addition, F. tartaricum sprout powder exhibited
a serum cholesterol-lowering effect by enhancing fecal bile acid excretion through increased fecal
matter excretion or the up-regulation of hepatic cholesterol 7
α
-hydroxylase mRNA expression in
rats [
101
,
102
]. Tartaricum protein extract exhibited significant hypocholesterolemic effect [
98
,
99
] and
could suppressed gallstone formation in vivo [100].
3.5. Anti-Diabetic Activity
Tartary buckwheat (F. tataricum) was traditionally used to treat diabetes in China. A clinical
observation revealed that intake of tartary buckwheat obvious alleviated the symptoms of both
type I and type II diabetic patients, decreasing the levels of fasting blood glucose (FBG), glycosylated
hemoglobin (GHb) and glycosylated serum protein (GSP), and increasing the level of fasting serum
insulin [
104
]. D-chiro-inositol may be responsible for the antidiabetic activity of F. tataricum, which
markedly ameliorated FBG of both diabetic Institute of Cancer Research (ICR) mice and patients [
107
].
The total flavonoid of tartary buckwheat could also lower the blood glucose, and increase the GSH

Int. J. Mol. Sci. 2016, 17, 589 13 of 20
level and Na-K-ATPase activity, and elevate the nerve conduction velocity and the blood flow in
sciatic nerve after oral administration in streptozotocin induced diabetic rats, which indicated that
tartary buckwheat flavonoids possessed favorable neuro-protective effects in diabetic rats [
108
,
118
].
In addition, complex F. tataricum prescription (CFTP), a traditional Chinese prescription for diabetes
mellitus, significantly improved the symptoms of non-insulin-dependent diabetes mellitus (NIDDM)
induced by streptozotocin injection in rats, with blood glucose, blood lipid and MDA decreased, SOD
activities increased, and nitric oxide (NO) metabolism improved [105].
An epidemiological study revealed that intake of buckwheat (F. esculentum) in diet can lower
the blood glucose concentration (BGC) and the prevalence rate of diabetes mellitus [
106
]. Both
the ethanol and water extracts of F. esculentum seeds significantly reduced the blood glucose of
normal and type II diabetes rats [
109
]. F. esculentum flowers and leaves also exhibited significant
antidiabetic activity and rutin was considered as the main bioactive constituent, which could regulate
the metabolic disorder of glucose and lipids in fat emulsion and alloxan-induced diabetic rats and
improve insulin resistance [
111
] and possessed protective effect on liver injury at early stage in
diabetic rats by decreasing the levels of FBG, serum TBil, ALT and liver index and restoring the
histologica1 injury of hepatocytes [
112
]. In addition, buckwheat protein could lower the blood
glucose in alloxan-induced diabetic mice [
110
], whereas co-asministration of pumpkin and buckwheat
significantly reduced the blood glucose in alloxan-induced diabetic rats [119].
3.6. Antibacterial Activity
The EtOAc fraction from the ethanol extract of F. dibotrys significantly restrained the growth of beta
Hemolytic streptococcus and Pneumococcus in petri dish dilution assay, which also exhibited favorable
protection in mice infected with Streptococcus pneumoniae. Moreover, bioguided isolation of compounds
from the EtOAc fraction yielded eight compounds, including trans-p-hydroxy cinnamic methyl
ester (
64
), protocatechuic acid (
55
), protocatechuic acid methyl ester (
56
), 1uteolin (
24
), quercitrin (
12
),
rutin (
8
), and (
´
)-epicatechin (
27
). These results indicate that phenolics and flavonoids were responsible
for the bacteriostastic activity of F. dibotrys [
42
]. Recently, Dong et al. revealed that F. dibotrys possessed
protective effect against lung injury induced by Klebsiella pneumonia in rats by down-regulation the
mRNA expression of TLR2/4, MyD88 and MIP-2, and the protein expression of I
κ
B-
α
, TNF-
α
, ICAM-1
and NF
κ
B p65 in rat lung tissue [
114
,
115
]. In addition, a clinical report indicated that combination of
F. dibotrys and ciprofloxacin exhibited better anti-pneumonia effect than ciprofloxacin used alone, due
to the bacteriostastic, cough-relieving and expectorant activity of F. dibotrys [113].
3.7. Anti-Allergic Activity
Buckwheat (F. esculentum) grain extract (BGE), given orally, intraperitoneally or intradermally,
significantly inhibited compound 48/80-induced vascular permeability evidenced by Evans blue
extravasation. Oral administration of BGE displayed significant inhibition on passive cutaneous
anaphylaxis stimulated by anti-dinitrophenyl IgE. BGE also possessed inhibitory potential on
compound 48/80-induced histamine release from rat peritoneal mast cells
in vitro
. Furthermore,
BGE suppressed the IL-4 and TNF-
α
mRNA induction by phorbol myristate acetate (PMA) and A23187
in human leukemia mast cells. All these results suggest that BGE exert anti-allergic action probably by
inhibition of histamine release and cytokine gene expression in the mast cells [12].
3.8. Anti-Fatigue Activity
Tartary buckwheat (F. tataricum) protein consists of well-balanced amino acids with high biological
values, such as hypocholesterolemic and antitumor activities. In addition, tartary buckwheat protein
also possesses significant anti-fatigue ability and especially the globulin in buckwheat protein distinctly
improved the swimming time, the climbing-pole time and the content of liver hepatin, which also
reduced the content of blood lactic acid and urea. Furthermore, factor F analysis [
116
] revealed that
the globulin in buckwheat protein had a low level of factor F due to its high content of branch chain

Int. J. Mol. Sci. 2016, 17, 589 14 of 20
amino acid (BCAA), thus inhibiting the formation of 5-hydroxytryptamine (5-HT) which can suppress
the ability of movement [117].
3.9. Other Activities
Despite the above-mentioned activities, Fagopyrum buckwheats also disclaimed several other
bioactivities. It has been found that F. esculentum polysaccharide could restrain the central nervous
system, effectively inhibiting the spontaneous motion, reducing the latent period of falling asleep and
prolonging the sleep time induced by sodium pentobarbital in mice [
120
]. F. tataricum flavones showed
estrogen-like activity, which can be modified by
in vitro
simulated digestion [
121
]. The 50% ethanol
extract of F. dibotrys rhizomes exhibited significant antitussive and expectorant activities, which can
reduce the times of coughing induced by ammonia in mice, and also increase the secretion of phenol red
in mice using tracheal phenol red test [
95
]. An acute toxicity test found that maximum tolerated dose
in mice was approximately 8.0 g/kg, which was 166 times the human adult dosage, indicating high
safety [
95
]. Additionally, F. esculentum buckwheat extract showed inhibitory effect on the progression
of renal failure in nephrectomized rats by improving the state of oxidative stress and renal tissue
lesions, and enhancing renal function [122].
4. Conclusions
The seeds of F. esculentum and F. tataricum are consumed widely in many countries and contain
many beneficial ingredients for humans such as flavonoids and phenolics, commonly used to develop
functional foods [
2
]. Recently, F. tataricum is much more popular because of its abundance and
much higher content of phenolics than that of F. esculentum [
3
]. The rhizome of F. dibotrys was
used as an antitumor and anti-inflammatory herb for a long time in China [
25
]. A commercial
product, “Wei-Mai-Ning” (WMN) has already been developed from F. dibotrys, and displays significant
activity [
123
]. These three Fagopyrum buckwheats have been well explored due to their long tradition
of both edible and medicinal uses.
Herein, we documented the existing phytochemical and pharmacological studies on these three
Fagopyrum buckwheats. Almost all their traditional uses have been validated by modern pharmacological
studies, focusing on their anti-tumor, anti-oxidant, anti-inflammatory, hepatoprotective, anti-diabetic,
antibacterial, anti-allergic, anti-fatigue activities, etc. Because of their versatile pharmacological
properties, a large number of studies have been carried out on the chemical profile of these three
Fagopyrum buckwheats. More than 100 compounds including flavonoids, phenolics, fagopyritols,
triterpenoids, steroids and fatty acids have been isolated and identified. Flavonoids and phenolic
compounds were considered to be the major active components and mainly responsible for most of
their activities.
Due to the lack of clinical trials, there are few published data on clinical efficacy, toxicity or side
effects of these buckwheats and their constituents. Comprehensive well-controlled and double-blind
clinical trials are therefore urgently needed to validate the efficacy and safety. Better explanations of
the mechanisms of action of different extracts and compounds, and an exhibition of the possible
interactions between bioactive constituents and synthetic drugs are needed. Furthermore, the
structure–activity relationship and the possible synergistic action among the bioactive compounds of
this plant need to be fully elucidated before they are used in clinical practice. Additionally, limited
studies have been carried out on the other Fagopyrum species. Because of the close relationship
between Fagopyrum plants, they may produce similar secondary metabolites and thus possess similar
therapeutic potentials. Thus, the other Fagopyrum species should also be thoroughly investigated so as
to fully utilize the Fagopyrum medicinal resources.
Acknowledgments:
This study was supported by National Natural Science Foundation of China (Nos. 81102773
and 81473328), Outstanding Youth Program of Shanghai Medical System (XYQ2013100) and the National High
Technology Research and Development Program of China (2014AA020508).
Conflicts of Interest: The authors declare no conflict of interest.

Int. J. Mol. Sci. 2016, 17, 589 15 of 20
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