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Biomedicine & Pharmacotherapy 153 (2022) 113462
Available online 1 August 2022
0753-3322/© 2022 Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/).
Review
Comprehensive review of two groups of avonoids in Carthamus
tinctorius L.
Bin Xian
a
,
b
,
1
, Rui Wang
a
,
b
,
1
, Huajuan Jiang
a
,
b
, Yongfeng Zhou
a
,
b
, Jie Yan
a
,
b
,
c
,
Xulong Huang
a
,
b
, Jiang Chen
a
,
b
,
c
, Qinghua Wu
a
,
b
,
c
, Chao Chen
a
,
b
, Ziqing Xi
a
,
b
,
Chaoxiang Ren
a
,
b
,
*
, Jin Pei
a
,
b
,
c
,
**
a
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China
b
College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China
c
The State Bank of Chinese Drug Germplasm Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
ARTICLE INFO
Keywords:
Safower
Flavonoid
Pharmacology
Phytochemistry
Application
Biosynthetic pathway
ABSTRACT
Safower (Carthamus tinctorius L.) is cultivated in various countries for the avonoid compounds it contains.
These avonoids have been used in many industries as drugs and/or dyes. Over 60 avonoids have been isolated
from safower. These avonoids can be divided into two groups: special and common, both of which are active
pharmaceutical ingredients efcacious in the treatment of cardiovascular and cerebrovascular diseases. Gene
functions have been studied to gure out the biosynthesis of avonoids in safower. However, there is no
comprehensive summary of the avonoids in safower. Research was recognised through systematic searches of
ScienceDirect, PubMed, Web of Science, and CNKI databases by searching terms of “Carthamus tinctorius L.”,
“safower”, “avonoid”, “pharmacology”, and “gene”. More than 200 research reports were included after
eligibility checks. This study summarizes the application of avonoids in medicine and other industries.
Comprehensively collects the chemical structure information of the two groups of avonoids, and organic acids,
alkaloids, spermidine, polyacetylene, and polysaccharides. The mechanism of two groups of avonoids in
treatment of cardiovascular and cerebrovascular diseases was describe in detail, and pharmacological mecha-
nisms of protecting liver, lung and bone, and anti-cancer and anti-inammatory were also summarised. Besides,
the study updated the latest information on the molecular biology of safower avonoids. It is found that two
groups of avonoids in safower have obvious differences in application, chemical structure, pharmacological
Abbreviations: ACO, 1-aminocyclopropane carboxylic acid oxidase; AECs, arterial endothelial cells; AD, Alzheimer’s disease; ANR, anthocyanidin reductase; Ang
II, angiotensin II; ANS, anthocyanidin synthase; AT1R, angiotensin II type-1 receptor; Aβ, Amyloid β proteins; Bcl-2, B-cell lymphoma-2; Bax, Bcl-2X-associated
protein; bHLH, basic helix-loop-helix; BK
Ca
, large-Conductance Calcium-Activated Potassium; BMP-2, bone morphogenetic protein-2; CarS,, carthamin synthase; CHI,
chalcone isomerase; CHS, chalcone synthase; COVID-19, coronavirus disease 2019; COX-2, cyclooxygenase-2; C4H1, cinnamate-4-hydroxylase; DFR, dihydroavonol
4-reductase; DHI, Danhong injection; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinases; FLS, avonol synthase; FNS, avone
synthase; F3H, avanone 3-hydroxylase; F3’H, avonoid 3’-hydroxylase; F3’5’H, avonoid 3’5’-hydroxylase; GFAP, glial brillary acidic protein; GSH-Px, gluta-
thione peroxidase; GSK-3β, glycogen synthase kinase-3β; HCT, shikimate hydroxycinnamoyl transferase; HO-1, heme oxygenase-1; HSCs, hepatic stellate cells; HSYA,
Hydroxysafor yellow A; HSYC, Hydroxy saffron yellow C; HUVECs, human umbilical vein endothelial cells; ICAM-1, intercellular cell adhesion molecule-1; IFS,
isoavone synthase; IGF-IR, insulin like growth factor- I Receptor; IL-1β, interleukin1β; iNOS, inducible nitric oxide synthase; JAK2, janus kinase 2; JNK, c-Jun N-
terminal kinase; K
ATP,
, ATP-sensitive potassium channel; LPS, lipopolysaccharide; MAPK, mitogen activated protein kinases; MeJA, methyl jasmonate; miRNAs,
MicroRNAs; MMP-2, matrix metalloproteinases-2; MMP-9, matrix metalloproteinases-9; mTOR, mammalian target of rapamycin; MyD88, myeloid differentiation
factor 88; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear transcription factor-kappa B; NLRP3, NOD-like receptor family pyrin domain
containing 3; NMDARs, N-methyl-D-aspartic acid receptors; NO, nitric oxide; Nrf-2, nuclear factor erythroid2-related factor 2; PAL3, phenylalamine ammonia-lyase
3; PI3K, phosphatidylinositol-3-kinase; PLCγ, phospholipase C γ; PPARγ, peroxisome proliferator-activated receptor γ; P450, P450-monooxygenase; ROS, reactive
oxygen species; SDF-1
α
, stromal cell-derived factor-1
α
; SOD, Superoxide dismutase; STAT3, signal transducer and activator 3 of transcription; TGF-β1, transforming
growth factor-β1; TLR4, toll-like receptor-4; TNF-
α
, tumour necrosis factor-
α
; UGT, UDP-glycosyltransferase; ULK1, Unc-51-like kinase 1; VEGF-A, vascular endo-
thelial growth factor A; VSMCs, vascular smooth muscle cells; XBJ, Xue Bi Jing injection; 4CL3, 4-coumarate:coenzyme A ligase.
* Correspondence to: Chengdu University of Traditional Chinese Medicine, Liutai Avenue 1166, Chengdu, China.
** Correspondence to: Chengdu University of Traditional Chinese Medicine, Liutai Avenue 1166, Chengdu, China.
E-mail addresses: 764793950@qq.com (C. Ren), peixjin@163.com (J. Pei).
1
Equal contribution.
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
https://doi.org/10.1016/j.biopha.2022.113462
Received 7 June 2022; Received in revised form 11 July 2022; Accepted 21 July 2022
Biomedicine & Pharmacotherapy 153 (2022) 113462
2
mechanism, and biosynthetic pathway. It is hoped that this summative research will provide a new insight to
avonoids research in safower.
1. Introduction
Carthamus tinctorius L. (safower) is an annual herbaceous plant,
belonging to the genus Carthamus of the Asteraceae family (Fig. 1).
Safower originated from ‘New Crescent’ on the east coast of the
Mediterranean and has been cultivated by humans for at least 4500
years [1]. Safower is a multipurpose economic crop. The seed oil of
safower is rich in unsaturated fatty acids and is consumed in Iran,
India, Japan [2], Turkey, Pakistan, France, and China, among others,
making its distribution worldwide. In addition to the seed oil, avonoids
contained in safower have great economic value. These avonoids give
safower the ability to alleviate cardiovascular and cerebrovascular
diseases, and protect cardiomyocyte and brain cell functions. Addi-
tionally, these compounds can protect the lung, liver, and bone, and
exert anti-cancer and anti-inammatory effects. Among them, hydrox-
ysafor yellow A (HSYA) has been most detailed in pharmacological
research. HSYA has signicant biological activity in the treatment of
coronary heart disease, myocardial infarction, ischaemic encephalopa-
thy, cerebral thrombosis, and stroke. Moreover, some avonoids in
safower are natural dyes widely used in food, cosmetics, and industrial
products [3].
Flavonoids in safower are of can be divided into two categories:
special and common. The special group exists in safower has a unique
structure and signicant activity in the treatment of cardiovascular and
cerebrovascular diseases, which almost are quinochalcone compounds,
such as HSYA, safor yellow A, and carthamin, exist only in safower,
mainly belonging to C-glycosides [4]. Thus, the special avonoid
biosynthesis pathway in safower has attracted research attention, and
some avonoid biosynthesis genes and transcription factors in safower
have been successfully cloned. Flavonoids in safower belong to com-
mon group are exists in many species, also possess a variety of activities,
which are represented by kaempferol, hyperoside, naringenin, quer-
cetin, and luteolin [5].
The present review aims to summarise the information on the
application, phytochemistry, pharmacology, and synthesis of the com-
mon and special avonoids in safower. This paper could provide new
insights into the applications of safower and help explore the full po-
tential of its values.
2. Applications of safower
2.1. Medicine
Safower is recorded in the pharmacopoeias of various countries and
regions, such as China, Europe, Japan, Hong Kong, and Taiwan, with
avonoids as the main active ingredients. In China, safower, named
‘honghua’ in Chinese, has been used to treat various gynaecological
diseases for thousands of years, and it is an important raw material in
some preparations. In Chinese Pharmacopoeia 2020, the actions of saf-
ower are described as activating the blood and unblocking the me-
ridian, dissipating stasis, and relieving pain. Thus, safower is used to
treat heart pain, abdominal pain caused by stasis and stagnation, sores,
ulcers, amenorrhoea, dysmenorrhoea, and retention of lochia, among
others. The ancient Chinese created many efcacious formulae, such as
Taohong Siwu decoction and Xuefu Zhuyu decoction, in which safower
is the key medicine. These formulae can be applied in some cardiovas-
cular and cerebrovascular diseases [6,7].
With the combination of the basic theory of Chinese medicine and
modern preparation technology, safower is made into new medical
products combined with other Chinese herbal medicines, such as Xuefu
Zhuyu capsules [8], and Xuefu Zhuyu oral liquids. In recent decades,
safower extracts have been made into injections such as Danhong in-
jection (DHI), and Xue Bi Jing injection (XBJ). DHI is widely used to
treat stroke, coronary heart disease, angina pectoris, and protect endo-
thelial cells [9,10]. XBJ is widely employed in sepsis in China and plays
an important role in ghting coronavirus disease (COVID-19), as XBJ
ameliorates the clinical symptoms and increase the survival rate [11,
12]. In these injections, HSYA was the main contributor from safower.
As an ethnic medicine in China, safower has been used to treat liver
diseases in Tibet [13]. In Japan, safower is used to treat various
gynaecological diseases and plays a crucial role in some Kampo prepa-
rations. For example, a Japanese prescription, Kangen-karyu, which
contains safower is used to promote blood circulation and remove
blood stasis [14]. Safower is also an essential element in Iranian
medical folklore and is used against constipation, rheumatic paralysis,
psoriasis, and oral ulcers [15]. Safower has also been recorded to have
contraceptive effects in some region [16]. In Turkey, safower is applied
as aphrodisiac [17]. Safower are rich in protein, calcium, magnesium,
iron, and potassium, which makes safower used as a tea in India [18].
Fig. 1. Pictures (A) and simple strokes (B) of safower plants.
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
3
2.2. Natural dye
The pigments contained in safower are also avonoids and can be
divided into yellow and red pigments. The main compounds contained
in yellow pigment are HSYA, anhydrosafor yellow B, safomin C,
isosafomin C, safor yellow A, safor yellow B, and et al., and the red
pigment mainly contains carthamine, and these pigments are chalcones
[18]. Safower is a traditional dye with a long history. Archaeological
research found that safower was used to dye clothes yellow or red in
ancient Egypt [19,20]. The red dye from safower, known as ‘beni’ in
Japan, is used to dye traditional Japanese kimonos [21]. The red
pigment can show different colour hues after processing and has the
advantageous feature of being fat-soluble, making it widely used in the
cosmetics industry [22]. The yellow pigment is water-soluble and used
in wooden furniture and medicine colouring. The pigments extracted
from safower are also used for natural food colouring [23]. Therefore,
they are extensively used to colour bread, cakes, biscuits, sweets, and
drinks. Furthermore, bovine sperm clouds have been found to be dyed
by safower, indicating that safower has the potential to be developed
into a biological stain [24].
3. Phytochemistry
To date, more than 200 compounds have been isolated from saf-
ower. These compounds can be divided into subgroups of avonoids,
fatty acids, phenylethanoid glycosides, coumarins, steroids, and poly-
saccharides (Table 1). To obtain an overview of the compounds in saf-
ower, we collected information on all compounds isolated from
safower. The isolated compounds and their chemical structures are as
follows.
Flavonoids are considered the active ingredients of safower that
promote cardiovascular and cerebrovascular health. 67 avonoid de-
rivatives have been summarised in this article. The avonoids of saf-
ower can be divided into two groups, the special one, which
represented by quinochalcones (24 compounds), and the common one
(43 compounds), which including avonoids, avonols, and dihydro-
avonoids. Quinochalcones in safower including HSYA, hydroxysafor
yellow B, and cartormin, which mostly belong to C-glycosylated. The
common groups of avanoids are represented by kaempferol, hypero-
side, and naringenin, and the avonoid glycosylation products belong to
O-glycosides (Fig. 2).
Safower seeds are rich in fatty acids, including linoleic acid
(40–80%) (66), oleic acid (20–50%) (67), palmitic acid (6–10%) (68),
and stearic acid (2–3%) (69). The content of linoleic acid in safower
seed oil is close to 80%, which is why it is called ‘king of linoleic acid’
[25]. It also contains other organic acids in small amounts, all of which
are listed below [26,27] (Fig. 3).
Alkaloids isolated from safower are serotonin derivatives, which
are mainly present in the seeds and can be used as natural antioxidants
[28–31]. (Fig. 4).
Spermidine components containing three coumarinyl groups were
also extracted and isolated from safower orets. Jiang et al. isolated
safospermidine A (121) and safospermidine B (122), N
1
,N
5
,N
10
-(E)-
tri-p-coumaroyl spermidine(123) and N
1
,N
5
,N
10
-(Z)-tri-p-coumaroyl
spermidine (124). Furthermore, Zhao et al. [32] isolated one cis-trans
isomers (125) (Fig. 5).
Polyacetylene compounds have been found in many parts of the
safower, such as roots, owers, immature seeds, and tissues of Phy-
tophthora infestations [33]. However, little research has been conducted
on polyacetylene compounds in safower. The polyacetylene com-
pounds distributed in the safower were based on ten-carbon and
thirteen-carbon compounds (Fig. 6).
Safowers contain glycosides and polysaccharides. Most poly-
saccharides in safower are connected by β-bonds with glucose, xylose,
arabinose, and lactose. Wakabayashi et al. [34] puried active fractions
named SF1 and SF2 from dried petals of safower. Yao et al. [35]
puried HH1–1 from safower, the backbone of which is a 1,3-linked
Galp side chain branching at C-3, and the branches mainly include 1,
5-linked, 1,3,5 linked terminal arabinose, and terminal galactose. Cui
et al. puried two water-soluble polysaccharides from safower and
identied the backbones using GC-MS,
1
H,
13
C, and HSQC NMR ana-
lyses. SPS was found to have a repeating backbone of 1,4,6-β-Glcp that
was attached to T-β-Glcp at its C6 position along the main chain at a
molar ratio of 1:1. SPAW is composed of repeating units of (1→3)-linked
β-D-Glcp [36] (Fig. 7).
In addition to these compounds, many other components have been
isolated from safower, such as syringin, esters, lignans, and alkyl glycol
compounds [37]. Akihisa et al. [38] successively isolated many alkyl
diol compounds (Fig. 7).
4. Pharmacology
The owers of C. tinctorius L. contain a high content of avonoids,
including HSYA, kaempferol, hyperoside, quercetin, naringenin, luteo-
lin, which have the ability to alleviate diseases of the heart or brain. For
example, the standardised avonoid extract of safower can inuence
conglomeration of platelets, transaminases, and blood glucose [76] and
has the potential to treat Parkinson’s disease [77]. In addition, these
active substances can relieve and/or treat diseases of the lung, liver, and
bone. The activities and related mechanisms of avonoids in safower
are shown in Fig. 8.
The avonoids in safower can be divided into two groups, with
different pharmacological effects and mechanisms of action. HSYA
represents quinochalcone compounds, and kaempferol and hypericin
represent the other category of avonoids. The pharmacology and
mechanisms of these three components to reect the difference between
the two kinds of avonoids in safower are summarised and discussed
below.
4.1. Effects on cardiovascular and cerebrovascular diseases
Cardiovascular and cerebrovascular diseases are two closely related
diseases with major threats to human life. For example, these diseases
have the same or similar causes, such as ischaemia, diabetes, hyper-
tension, and dyslipidaemia. Moreover, patients with cardiovascular
diseases are more likely to have cerebrovascular diseases [78]. Safower
can ameliorate ischaemia in the heart and brain, reduce inammation,
and cell apoptosis, and therefore, maintain the normal shape of the heart
and function of the brain. The related signalling pathways are shown in
Fig. 9.
4.1.1. Anti-ischaemic effect in heart and brain
Ischaemia of the heart and brain can cause oxidative stress,
apoptosis, and inammation, which may induce stroke, coronary heart
disease, and psychiatric disorders [79,80]. By reducing inammation
and oxidative stress, avonoids in safower can protect cardiomyocytes
from damage and apoptosis through different signalling pathways. By
suppressing the toll-like receptor-4 (TLR4) signalling pathway, HSYA
has been shown to reduce the secretion of inammatory factors and
protect the myocardium from I/R damage in hypertensive mice [81].
Kaempferol has been reported to reduce cardiomyocyte apoptosis and
myocardial infarct size by mediating the mitogen-activated protein ki-
nase (MAPK) signalling pathway and inhibiting total glycogen synthase
kinase-3β (GSK-3β) activity [82,83]. By activating the extracellular
signal-regulated kinase (ERK) signalling pathway, hyperoside can
reduce creatine kinase and lactate dehydrogenase leakage, thus signif-
icantly improving heart contraction and limiting infarct size [84].
Research has shown that in ischaemic brain tissue, safower avo-
noid extracts can treat cerebral infarction [85]. This effect may be
contributed to quinochalcones. HSYA can protect nerves by restraining
inammation, reducing apoptosis, and releasing inducible nitric oxide
synthase (iNOS) [86–88]. Furthermore, HSYA can inhibit
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
4
Table 1
The compounds isolated from safower.
No. Compounds Molecular
formula
Type Part Extraction Ref.
1 Acacetin C
16
H
12
O
5
Flavonoid Floret &
seed
methanol [39]
2 Acacetin-7-O-β-D-glucuronide (Tilianin) C
22
H
22
O
10
Flavonoid leave 90% methanol [40]
3 Acacetin-7-O-alpha-L-rhamnopyranoside C
22
H
22
O
9
Flavonoid seed ethanol [41]
4 Acacetin-7-O-β-D-apiofuranosyl (1→6)-O-β-D-glucoside C
27
H
30
O
14
Flavonoid seed ethanol [41]
5 Apigenin C
15
H
10
O
5
Flavonoid oret methanol [39]
6 Apigenin-6,8-di-C-β-D-glucopyranoside C
27
H
30
O
15
Flavonoid oret &
leave
90% methanol [40]
7 6-Hydroxyapigenin (Scutellarein) C
15
H
10
O
6
Flavonoid oret 95% ethanol [42]
8 Luteolin C
15
H
10
O
6
Flavonoid oret &
leave
methanol [40]
9 Cynaroside C
21
H
20
O
11
Flavonoid oret &
leave
90% methanol [40]
10 Luteolin-7-O-(6’’-O-acetyl)-β-glucopyranoside C
23
H
22
O
12
Flavonoid oret ethanol [41]
11 Naringenin C
15
H
12
O
5
Flavonoid oret 80% ethanol [43]
12 Naringin C
27
H
32
O
14
Flavonoid oret 80% ethanol [43]
13 Scutellarin C
21
H
18
O
12
Flavonoid oret methanol [39]
14 Kaempferol C
15
H
10
O
6
Flavonol oret 80% ethanol [43]
15 Kaempferide C
16
H
12
O
6
Flavonol oret 80% ethanol [43]
16 Kaempferol-3-O-β-D-glucoside (Astragalin) C
21
H
20
O
11
Flavonol oret 80% ethanol [43]
17 Kaempferol-3-O-β-D-rutinoside C
27
H
30
O
15
Flavonol oret 95% ethanol [44]
18 kaempferol-3-O-β-D-glucopyranosyl-7-O-β-D-glucopyranoside C
27
H
30
O
16
Flavonol oret 95% ethanol [44]
19 Kaempferol-3-O-β-sophoroside (Sophoraavonoloside) C
27
H
30
O
16
Flavonol oret 50% methanol [45]
20 6-Hydroxykaempferol C
15
H
10
O
7
Flavonol oret methanol [39]
21 6-Hydroxykaempferol-3-O-β- glucoside C
21
H
20
O
12
Flavonol oret 95% ethanol [46]
22 6-Hydroxykaempferol-7-O-β-glucoside C
21
H
20
O
12
Flavonol oret 95% ethanol [46]
23 6-Hydroxykaempferol-3,6-di-O-β- glucoside C
27
H
30
O
17
Flavonol oret methanol [39]
24 6-Hydroxykaempferol-3,7-di-O-β- glucoside C
27
H
30
O
17
Flavonol oret methanol [39]
25 6-Hydroxykaempferol-6,7-di-O-β-glucoside C
27
H
30
O
17
Flavonol oret water [47]
26 6-Hydroxykaempferol-3,6,7-tri-O-β-glucoside C
33
H
40
O
22
Flavonol oret methanol [39]
27 6-Hydroxykaempferol-3,6-di-O-β-glucoside-7-O-β-glucuronide C
33
H
38
O
23
Flavonol oret 95% ethanol [44]
28 6-Hydroxykaempferol-3-O-β-rutinoside-6-O-β-glucoside C
33
H
40
O
21
Flavonol oret 95% ethanol [44]
29 6-Hydroxykaempferol-3-O-β-rutinoside C
27
H
30
O
16
Flavonol oret 95% ethanol [44]
30 Quercetin C
15
H
14
O
9
Flavonol oret 80% ethanol [43]
31 Quercetin-3-O-β-D-glucoside (Isoquercetin) C
21
H
20
O
12
Flavonol oret 80% ethanol [43]
32 Quercetin-3-O-β-D-galactosid (Hyperoside) C
21
H
20
O
12
Flavonol oret 80% ethanol [43]
33 Quercetin-7-O-β-glucoside C
21
H
20
O
12
Flavonol oret methanol [39]
34 Quercetin-3,7-di-O-β-glucoside C
27
H
30
O
17
Flavonol oret methanol [39]
35 Quercetin-3-O-
α
-L-rhamnoside-7-O-β-glucuronide C
27
H
30
O
16
Flavonol oret 80% ethanol [43]
36 Rutin C
27
H
30
O
16
Flavonol oret 60% ethanol [48]
37 Myricetin C
15
H
10
O
8
Flavonol oret 95% ethanol [49]
38 Eriodictyol C
15
H
12
O
6
Flavanone oret methanol [39]
39 (2 S)−4’,5,6,7-tetrahydroxy avanone 6-O-β-D-glucoside C
21
H
27
O
10
avanone oret water [26]
40 (2 R)−5,6,7,4’-tetrahydroxyavanone-6,7-diglucoside C
27
H
32
O
16
avanone oret water [47]
41 (2 S)−5,6,7,4’-tetrahydroxyavanone-6,7-diglucoside C
27
H
32
O
16
avanone oret 95% ethanol [50]
42 Safoavonesides A C
21
H
18
O
9
avanone oret water [51]
43 Safoavonesides B C
21
H
18
O
9
avanone oret water [51]
44 Hydroxysafor yellow A (Safomin A) C
27
H
32
O
16
Quinochalcones oret 60% acetone [52]
45 Hydroxysafor yellow B (Safomin B) C
27
H
32
O
16
Quinochalcones oret 95% ethanol and 70%
ethanol
[53]
46 Hydroxysafor yellow A-4’-O-β-D-glucopyranosid C
33
H
42
O
21
Quinochalcones oret water [54]
47 3’-hydroxyhydroxysafor yellow A C
27
H
32
O
17
Quinochalcones oret water [54]
48 Safomin C C
30
H
30
O
14
Quinochalcones oret polyamide [55]
49 Isosafomin C C
27
H
29
O
15
Quinochalcones oret 95% ethanol and 70%
ethanol
[53]
50 Methylsafomin C C
28
H
31
O
15
Quinochalcones oret 80% methanol [56]
51 Methylisosafomin C C
28
H
31
O
15
Quinochalcones oret 80% methanol [56]
52 Anhydrosafor yellow B C
48
H
52
O
26
Quinochalcones oret 50% methanol [45]
53 Safor yellow A C
27
H
30
O
15
Quinochalcones oret 60% acetone [52]
54 Safor yellow B C
48
H
54
O
27
Quinochalcones oret pyridine [57]
55 Cartormin C
27
H
29
O
13
N Quinochalcones oret methanol [58]
56 Isocartormin C
27
H
29
O
13
N Quinochalcones oret water & ethyl acetate [59]
57 Tinctormine C
27
H
31
O
14
N Quinochalcones oret 60% acetone [52]
58 Safoquinoside A C
27
H
29
O
15
Quinochalcones oret water [60]
59 Safoquinoside B C
34
H
38
O
17
Quinochalcones oret water [60]
60 Safoquinoside C C
27
H
30
O
15
Quinochalcones oret 95% ethanol [42]
61 Safoquinoside D C
27
H
31
O
16
Quinochalcones oret 95% ethanol [42]
62 Safoquinoside E C
30
H
29
O
14
Quinochalcones oret 95% ethanol [42]
63 Carthamine C
43
H
42
O
22
Quinochalcones oret 50% methanol [45]
64 Hydroxyethylcarthamin C
45
H
46
O
23
Quinochalcones oret methanol [61]
65 Precarthamin C
44
H
43
O
23
Quinochalcones oret 50% methanol [45]
66 Neocarthamin C
21
H
22
O
11
Quinochalcones oret 80% ethanol [62]
67 Carthamone C
21
H
20
O
11
Quinochalcones oret 50% methanol [45]
(continued on next page)
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
5
Table 1 (continued )
No. Compounds Molecular
formula
Type Part Extraction Ref.
68 Linoleic acid C
18
H
32
O
2
Organic acids oret petroleum ether [25,
63]
69 Oleic acid C
18
H
34
O
2
Organic acids oret petroleum ether [25,
63]
70 Palmitic acid C
16
H
32
O
2
Organic acids oret petroleum ether [25,
63]
71 Stearic acid C
18
H
36
O
2
Organic acids oret petroleum ether [25,
63]
72 Lauric acid C
12
H
24
O
2
Organic acids oret petroleum ether [25,
63]
73 Myristic acid C
14
H
28
O
2
Organic acids oret hexane [25]
74 Palmitoleic acid C
16
H
30
O
2
Organic acids oret hexane [25]
75 Linolenic acid C
18
H
30
O
2
Organic acids oret hexane [25]
76 Arachidic acid C
20
H
40
O
2
Organic acids oret hexane [25]
77 Erucic acid C
22
H
42
O
2
Organic acids oret methanol [64]
78 Succinic acid C
4
H
6
O
4
Organic acids oret 95% ethanol [42]
79 Chlorogenic acid C
16
H
18
O
9
Organic acids seed water [27]
80 Syringic acid C
9
H
10
O
5
Organic acids seed water [27]
81 p-coumaric acid C
9
H
8
O
3
Organic acids seed water [27]
82 Ferulic acid C
10
H
10
O
4
Organic acids oret methanol [64]
83 Trans-ferulic acid C
10
H
10
O
4
Organic acids seed water [27]
84 Caffeic acid C
9
H
8
O
4
Organic acids oret methanol [64]
85 p-hydroxybenzoic acid C
7
H
6
O
3
Organic acids oret 95% ethanol [42]
86 Isovaleric acid C
5
H
10
O
2
Organic acids oret 95% ethanol [42]
87 p-hydroxybenzoyl coumaric anhydride C
16
H
12
O
5
Organic acids oret 95% ethanol [42]
88 Isovanillic acid C
8
H
8
O
4
Organic acids oret water [65]
89 (-)-Epigallocatechin C
15
H
14
O
7
Organic acids seed water [27]
90 4-O-β-D-glucopyranosyl oxy-benzoic acid C
13
H
16
O
8
Organic acids oret 95% ethanol [42]
91 4-O-β-D-glucosyl trans-p-Coumar ic acid C
15
H
18
O
8
Organic acids oret 95% ethanol [50]
92 4-O-β-D-glucosyl-cis-p-coumaric acid C
15
H
18
O
8
Organic acids oret 95% ethanol [50]
93 4-Hydroxybenzoyl hydrazide C
7
H
8
N
2
O
2
Alkaloid oret 95% ethanol [42]
94 2-amino-3,4-dimethylbenzoic acid C
9
H
11
NO
2
Alkaloid oret 95% ethanol [42]
95 Uridine C
9
H
12
N
2
O
6
Alkaloid oret 95% ethanol [42]
96 Adenosine C
10
H
13
N
5
O
4
Alkaloid oret 95% ethanol [42]
97 Adenine C
5
H
7
N
5
Alkaloid oret 95% ethanol [42]
98 Thymine C
5
H
6
N
2
O
2
Alkaloid oret 95% ethanol [42]
99 Uracil C
4
H
4
N
2
O
2
Alkaloid oret 95% ethanol [42]
100 7,8-dimethyl pyrazino [2,3-g] quinazoline-2,4-(1 H,3 H) dione C
13
H
11
O
2
N
3
Alkaloid oret 95% ethanol [42]
101 Serotobenine C
20
H
18
N
2
O
4
Alkaloid oret 70% ethanol [66]
102 N-feruloyl serotonin C
20
H
20
N
2
O
4
Alkaloid oret ethyl acetate [29]
103 N-(p-coumaroyl) serotonin C
19
H
18
N
2
O
3
Alkaloid oret ethyl acetate [29]
104 N-(p-coumaroyl)serotonin-β-D-glucopyranoside C
35
H
38
N
2
O
13
Alkaloid oret ethyl acetate [29]
105 N-[2-(5-hydroxy-1 H-indol-3-yl)ethyl]-ferulamide C
20
H
20
N
2
O
4
Alkaloid oret methanol [28]
106 N-[2-(5-hydroxy-1 H-indol-3-yl)ethyl]-p-coumaramide C
19
H
18
N
2
O
3
Alkaloid oret methanol [28]
107 N,N’-[2,2’-(5,5’-dihydroxy-4,4’-bi-1 H-indol-3,3’-yl)diethyl]- di-p-
coumaramide
C
38
H
34
N
4
O
6
Alkaloid oret methanol [28]
108 N-[2-[3’-[2-(p-coumaramido)ethyl]−5,5’ihydroxy-4,4’-bi-1 H-indol-3-yl]
ethyl]ferulamide
C
39
H
36
N
4
O
7
Alkaloid oret methanol [28]
109 N,N’-[2,2’-(5,5’ihydroxy-4,4’-bi-1 H-indol-3,3’-yl)diethyl]-diferulamide C
40
H
38
N
4
O
8
Alkaloid oret methanol [28]
110 N-[2-[5-(β-glucosyloxy)−1 H-indol-3-yl) ethyl]-p- coumaramide C
19
H
18
N
2
O
3
Alkaloid oret methanol [28]
111 N-[2-[5-(β-glucosyloxy)−1 H-indol-3-yl)ethyl]ferulamide C
19
H
18
N
2
O
3
Alkaloid oret methanol [28]
112 Carthamine A C
19
H
18
N
2
O
3
Alkaloid oret water [30]
113 Carthamine B C
19
H
18
N
2
O
3
Alkaloid oret water [30]
114 (1 R,3 S)1-methyl-2,3,4,9-tetrahydro-1 H-pyrido[3.4-b]indole-3-carboxylic
acid
C
13
H
11
N
2
O
2
Alkaloid oret water [30]
115 (1 R,3 S)1-methyl-2,3,4,9-tetrahydro-1 H-pyrido[3.4-b]in-dole-3-carboxylic
acid ethylester
C
14
H
11
N
2
O
2
Alkaloid oret water [30]
116 (1 R,3 S)1-propyl-2,3,4,9-tetrahydro-1 H-pyrido[3.4-b]indole-3-carboxylic
acid
C
15
H
16
N
2
O
2
Alkaloid oret water [30]
117 4,9-dimethoxy-1-ethyl-β-carboline C
15
H
16
N
2
O
2
Alkaloid leave methanol [31]
118 4-methoxy-1-ethyl-β-carboline C
14
H
14
N
2
O Alkaloid leave methanol [31]
119 (3 S)−1-methyl-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]indole-3-carboxylic
acid
C
13
H
14
N
2
O
2
Alkaloid oret water [30]
120 Thymidine C
10
H
14
N
2
O
5
Alkaloid oret 95% ethanol [42]
121 Safospermidine A C
34
H
38
N
3
O
6
Spermidine oret 95% ethanol [42]
122 Safospermidine B C
34
H
38
N
3
O
6
Spermidine oret 95% ethanol [42]
123 N
1
,N
5
,N
10
-(E)-tri-p-coumaroyl spermidine C
34
H
38
N
3
O
6
Spermidine oret 95% ethanol [42]
124 N
1
,N
5
,N
10
-(Z)-tri-p-coumaroyl spermidine C
34
H
38
N
3
O
6
Spermidine oret 95% ethanol [42]
125 N
1
,N
5
-(Z)-N
10
-(E)-tri-p-coumaroyl spermidine C
34
H
38
N
3
O
6
Spermidine oret ethanol [32]
126 11Z-trideca-1,11-diene-3,5,7,9-tetrayne C
13
H
8
Polyacetylene seed chloroform-
methanol (1:1）
[67,
68]
127 11E-trideca-1,11-diene-3,5,7,9-tetrayne C
13
H
8
Polyacetylene seed chloroform-
methanol (1: 1)
[67,
68]
128 3E-trideca-1,3-diene-5,7,9,11-tetrayne C
13
H
8
Polyacetylene seed water [68]
129 3Z,5Z-trideca-1,3,5-triene-7,9,11-triyne C
13
H
10
Polyacetylene seed water [68]
(continued on next page)
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
6
Table 1 (continued )
No. Compounds Molecular
formula
Type Part Extraction Ref.
130 3Z,5E-trideca-1,3,5-triene-7,9,11-triyne C
13
H
10
Polyacetylene seed water [68]
131 3E,5E-trideca-1,3,5-triene-7,9,11-triyne C
13
H
10
Polyacetylene seed water [68]
132 3Z,11Z-trideca-1,3,11-triene-5,7,9-triyne C
13
H
10
Polyacetylene seed water [68]
133 3Z,11E-trideca-1,3,11-triene-5,7,9-triyne C
13
H
10
Polyacetylene seed water [68]
134 3E,11E-trideca-1,3,11-triene-5,7,9-triyne C
13
H
10
Polyacetylene seed water [68]
135 3E,5Z,1lE-trideca-1,3,5,11-tetraene-7,9-diyne C
13
H
12
Polyacetylene seed water [68]
136 3Z,5E,1lE-trideca-1,3,5,11-tetraene-7,9-diyne C
13
H
12
Polyacetylene seed water [68]
137 3E,5E,1lE-trideca-1,3,5,11-tetraene-7,9-diyne C
13
H
12
Polyacetylene seed water [68]
138 Trans-3-tridecene-5,7,9,11-tetrayne-1,2-diol C
13
H
12
O
2
Polyacetylene seed ether [69]
139 Trans, trans-3,11-tridecene-5,7,9-triyne-1,2-diol C
13
H
12
O
2
Polyacetylene seed ether [69]
140 2Z-decaene-4,6-diyne-1-O-β-d- glucopyranoside C
16
H
22
O
6
Polyacetylene seed 50% methanol [45]
141 8Z-decaene-4,6-diyne-l-O-β-D-glucopyranoside C
16
H
22
O
6
Polyacetylene oret 90% ethanol [37]
142 8E-decaene-4,6-diyne-l-O-β-D-glucopyranoside C
16
H
22
O
6
Polyacetylene seed water [70]
143 8Z-decaene-4,6-diyne-1-ol-1-O-β-D-glucuronyl- (1”−2’)-β-D-glucopyranoside C
22
H
30
O
12
Polyacetylene seed water [70]
144 (2E,8E)-teteradecadiene-4,6-diyne-1,11,14-triol C
14
H
18
O
3
Polyacetylene seed water [70]
145 (2E,8E)-teteradecadiene-4,6-diyne-1,12,14-triol-1-O-β-D-glucopyranoside C
20
H
28
O
8
Polyacetylene seed water [70]
146 (2Z,8Z)-teteradecadiene-4,6-diyne-1,12,14-triol-1-O-β-D-glucopyranoside C
20
H
28
O
8
Polyacetylene seed water [70]
147 (2Z,8E)-teteradecadiene-4,6-diyne-1,12,14-triol-1-O-β-D-glucopyranoside C
20
H
28
O
8
Polyacetylene seed water [70]
148 (2E,8Z)-teteradecadiene-4,6-diyne-1,12,14-triol-l-O-β-D-glucopyranoside C
20
H
28
O
8
Polyacetylene seed water [70]
149 (2E,8E)-tetradecadiene-4,6-diyne-1,12,14-triol C
14
H
18
O
3
Polyacetylene seed water [70]
150 (2E,8Z)-decadiene-4,6-diyne-1-ol-1-O-β-D-glucopyranoside C
16
H
20
O
6
Polyacetylene seed water [70]
151 (2Z,8Z,10Z)-tridecatriene-4,6-diyne-1,12,13-triol-1-O-β-D-glucopyranoside C
19
H
24
O
8
Polyacetylene seed water [70]
152 (2E)-tetradecaene-4,6-diyne-1,10,14-triol-1-O-β-D-glucopyranoside C
20
H
30
O
8
Polyacetylene seed water [70]
153 (2E,8E)−11S-teteradecadiene-4,6-diyne-1,11,14-triol-1-O-β-D-gluco-
pyranoside
C
20
H
30
O
8
Polyacetylene seed water [65]
154 (2E,8E)−11S-teteradeca-diene-4,6-diyne-1,11,14-triol C
14
H
18
O
3
Polyacetylene seed water [65]
155 (2Z,8Z)−11S-teteradecadiene-4,6-diyne-1,11,14-triol-1-O-β-D-
glucopyranoside
C
20
H
30
O
8
Polyacetylene seed water [65]
156 (2Z,8E)−11S-teteradecadiene-4,6-diyne-1,11,14-triol-1-O-β-D-
glucopyranoside
C
20
H
30
O
8
Polyacetylene seed water [65]
157 (2E,8Z)−11S-teteradeca-diene-4,6-diyne-1,11,14-triol-l-O-β-D-
glucopyranoside
C
20
H
30
O
8
Polyacetylene seed water [65]
158 4,6-decadiyne-1-O-β-D-glucopyranoside C
16
H
26
O
6
Polyacetylene oret 90% ethanol [37]
159 4’,6’-acetonide-8Z-decaene-4,6-diyne-1-O-β-D-glucopyranoside C
19
H
26
O
6
Polyacetylene oret 90% ethanol [37]
160 Roseoside C
19
H
30
O
8
Other oret 95% ethanol [42]
161 Sitosterol C
29
H
50
O Other oret 95% ethanol [42]
162 Stigmasterol C
29
H
48
O Other oret 95% ethanol [42]
163 Campesterol C
28
H
48
O Other oret 95% ethanol [42]
164 Carotene C
40
H
56
Other oret 95% ethanol [42]
165 Progesterone C
21
H
30
O
2
Other oret 95% ethanol [42]
166 Syringin C
17
H
24
O
9
Other oret 95% ethanol [42]
167 Ethylsyringin C
19
H
28
O
9
Other oret 95% ethanol [71]
168 Methylsyringin C
18
H
26
O
9
Other oret 95% ethanol [71]
169 Arctigenin C
21
H
24
O
6
Other oret methanol [64]
170 Trachelogenin C
21
H
24
O
7
Other oret methanol [64]
171 Coniferyol C
10
H
12
O
3
Other oret methanol [64]
172 Sinapyl alcohol C
11
H
14
O
4
Other oret methanol [64]
173 Matairesinol C
20
H
22
O
6
Other oret methanol [64]
174 (-)- secoisolariciresinol C
20
H
26
O
6
Other oret methanol [64]
175 Methyl-3-(4-O-β-D-glucopyranosyl-3-methoxyphenyl) propionate C
18
H
26
O
9
Other oret 95% ethanol [50]
176 Ethyl-3-(4-O-β-D-glucopyranosyl-3-methoxyphenyl) propionate C
19
H
28
O
9
Other oret 95% ethanol [71]
177 Dihydrosaforic acid-4′-O-β-D-glucoside methyl ester C
22
H
34
O
10
Other oret 95% ethanol [42]
178 3-(3’, 4’-dimethoxyphenyl)−7-hydroxy-8-(3-methylbutyl)- coumarin C
22
H
24
O
5
Other oret 75% ethanol [72]
179 1-(2-Pyridinyl)−3-pentanone C
10
H
13
NO Other oret 75% ethanol [72]
180
α
- Methoxyphenylacetic acid-1-undecyldodecyl ester C
32
H
56
O
3
Other oret 75% ethanol [72]
181 Icosane-6,8-diol C
20
H
42
O
2
Other oret methanol [38]
182 Tricosane-6,8-diol C
23
H
48
O
2
Other oret methanol [38]
183 Pentacosane-6,8-diol C
25
H
52
O
2
Other oret methanol [38]
184 Heptacosane-6,8-diol C
27
H
56
O
2
Other oret methanol [38]
185 Octacosane-6,8-diol C
28
H
58
O
2
Other oret methanol [38]
186 Nonacosane-6,8-diol C
29
H
60
O
2
Other oret methanol [38]
187 Triacontane-6,8-diol C
30
H
62
O
2
Other oret methanol [38]
188 Hentriacontane-6,8-diol C
31
H
64
O
2
Other oret methanol [38]
189 Dotriacontane-6,8-diol C
32
H
66
O
2
Other oret methanol [38]
190 Tritriacontane-6,8-diol C
33
H
68
O
2
Other oret methanol [38]
191 Tetratriacontane-6,8-diol C
34
H
70
O
2
Other oret methanol [38]
192 Pentatriacontane-6,8-diol C
35
H
72
O
2
Other oret methanol [38]
193 Hexatriacontane-6,8-diol C
36
H
74
O
2
Other oret methanol [38]
194 Octacosane-7,9-doil C
28
H
58
O
2
Other oret methanol [38]
195 Triacontane-7,9-diol C
30
H
62
O
2
Other oret methanol [38]
196 Dotriacontane-7,9-diol C
32
H
66
O
2
Other oret methanol [38]
197 Tetratriacontane-7,9-doil C
34
H
70
O
2
Other oret methanol [38]
198 Hexatriacontane-7,9-diol C
36
H
74
O
2
Other oret methanol [38]
199 Heptacosane-8,10-doil C
25
H
52
O
2
Other oret methanol [38]
200 Nonacosane-8,10-diol C
29
H
60
O
2
Other oret methanol [38]
(continued on next page)
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
7
lipopolysaccharides (LPS)-induced TLR4 activation and inammatory
cytokine release, including myeloid differentiation factor 88 (MyD88),
nuclear transcription factor-kappa B (NF-κB), c-Jun N-terminal kinase
(JNK), ERK1/2, tumour necrosis factor-
α
(TNF-
α
), and interleukin 1β
(IL-1β) [89,90]. A large amount of HSYA is present in safower yellow.
HSYA can signicantly decrease platelet aggregation, blood viscosity,
and thrombogenesis. Moreover, it can protect against ischaemic stroke
by dilating cerebral vessels and improving cerebrovascular permeability
[91]. Therefore, safower yellow can change haemodynamic parame-
ters and treat stroke caused by acute cerebral ischaemia [92].
4.1.2. Hypertension and cardiovascular remodelling ameliorating effect
In addition to reducing the damage caused by ischaemia, safower
avonoids protect cardiomyocytes from many other harmful conditions.
Safower extracts have been found to alleviate hypertension by
increasing endothelial nitric oxide synthase (eNOS) protein expression,
reducing oxidative stress, and inhibiting sarcoma activation in rats [93,
94]. Safower extract contains a variety of avonoids, but only the
mechanism by which HSYA can relieve hypertension has been studied in
detail. The expression and activity of large-Conductance Calcium-Acti-
vated Potassium (BK
Ca
) are closely related to cardiovascular, muscular,
and neurological defects [95]. ATP-sensitive potassium (K
ATP
) channels
can inuence blood vessel tone and blood pressure, and potassium
channels can regulate apoptosis, proliferation, and survival of pulmo-
nary artery smooth muscle cells [96]. Therefore, by targeting these
channels, HSYA can regulate the mean arterial pressure, heart rate, and
mean right ventricular systolic pressure, and inhibit the proliferation
and hypertrophy of pulmonary artery smooth muscle cells to alleviate
hypertension [97,98]. Haemodynamic changes, right ventricular hy-
pertrophy, and morphological changes caused by pulmonary arterial
hypertension can also be alleviated by HSYA [99].
Hypertension can cause cardiac brosis and apoptosis, which can
induce cardiovascular remodelling [100]. Safower not only improves
hypertension but also reduces cardiac brosis and apoptosis. This in-
dicates that safower has a great potential to treat cardiovascular
remodelling. The extracts of safower can improve cardiovascular
remodelling by activating the insulin-like growth factor-I receptor
(IGF-IR) to inhibit the IGF-IIR signalling pathway, and by restraining the
transforming growth factor-β1 (TGF-β1), MMP-9, and angiotensin
II-angiotensin II type-1 receptor-nicotinamide adenine dinucleotide
phosphate (Ang II-AT1R-NADPH) oxidase pathways [101,102]. Saf-
ower prevents cardiac brosis and reduces apoptosis. Research has
shown that safower extract can inhibit ERK 1/2 and decrease the
expression of matrix metalloproteinases-2 (MMP-2) and matrix
metalloproteinases-9 （MMP-9) in brotic cardiomyocytes [103].
Among these extracts, HSYA can upregulate haem oxygenase-1 (HO-1)
expression in the PI3K/Akt/Nrf2 signalling pathway and
heme-oxygenase-1/ vascular endothelial growth factor A/ stromal
cell-derived factor-1
α
(HO-1/VEGF-A/SDF-1
α
) signalling cascade,
which can protect H9c2 cardiomyocytes from apoptosis and improve the
cardiac function [104,105]. Moreover, kaempferol can inhibit NF-κB,
p53, and ERK signalling pathways, and activate nuclear factor
erythroid2-related factor 2 (Nrf-2) to protect the cardiac function [106,
107].
4.1.3. Brain protective effect
Various avonoids in safower can play a protective role on brain
tissues. HSYA works primarily by virtue of its anti-inammatory activ-
ity, which can alleviate neurotoxicity and neuroinammation by
reducing the secretion of IL-1β, TNF-
α
, p65, p38, MyD88, ERE1/2, and
JNK through NF-κB, TLR4, and MAPK signalling pathway [89,108–110].
Additionally, HSYA can protect neurones from excitotoxic death
through the inhibition of N-methyl-D-aspartic acid receptors (NMDARs)
[111]. Kaempferol can ameliorate CdCl
2
-induced oxidative stress,
inammation, and apoptosis in the brain by increasing the activity of
silent information regulator 1 and decreasing the activity of poly
(ADP-ribose) polymerase-1 [112]. The anti-oxidant ability makes
hyperoside have a protective effect to nerve cell. For example, hypero-
side can protect the hippocampal CA3 region from epilepsy-induced
neuronal damage by promoting anti-oxidant effect through the
PI3K/Akt and MAPK pathways [113]. Furthermore, hyperoside can
improve neurotoxicity in neurons by activating nuclear factor-erythroid
2-related factor 2 (Nrf2) dependent HO-1 to reduce the excessive
accumulation of reactive oxygen species (ROS) [114].
The protective effect on nerves can improve brain function, which
makes these avonoids have the potential to treat Alzheimer’s disease
(AD) and/or Parkinson’s disease. Amyloid β (Aβ) proteins and neuro-
brillary tangles of hyperphosphorylated tau are markers of AD. Saf-
ower yellow can increase the levels of superoxide dismutase (SOD) and
glutathione peroxidase (GSH-Px), decrease Aβ1–42 deposition, decrease
the levels of glial brillary acidic protein (GFAP), iNOS, IL-1β, IL-6, TNF-
α
, malondialdehyde, and acetylcholinesterase, ameliorate the disorder
of glutamate circulation, and reduce tau hyperphosphorylation at
Ser199, Thr205, Ser396, and Ser404 sites in the brain. Therefore, vastly
ameliorate learning and memory decits [115–119]. HSYA can inhibit
the NF-κB signalling pathway, reduce the inammatory response and
activate the JAK2/ signal transducer and activator 3 of transcription
(STAT3) pathway to protect nerves, which allows HSYA to treat AD
[120,121]. Kaempferol works by reducing oxidative stress, which can
exert neuroprotective effects in Aβ1–42-induced mice [122], and by
inhibiting the nucleotide-binding domain, leucine-rich repeat, and pyrin
domain-containing protein 3 (NLRP3) inammasome. Therefore,
kaempferol can be used in the treatment of neurodegenerative disorders
[123]. Research has shown that hyperoside can be used to treat and/or
prevent occlusive vascular diseases, causing it to target Nur77 in
vascular smooth muscle cells (VSMCs). Thereby signicantly inhibiting
the proliferation of VSMCs and the formation of new intima [124].
4.1.4. Endothelial cell protective effect
Endothelial cells can inuence vascular relaxation and constriction.
Blood molecules and cells and angiogenesis, play a very important role
in the normal function of the heart and brain. Both inammation and
Table 1 (continued )
No. Compounds Molecular
formula
Type Part Extraction Ref.
201 Hentriacontane-8,10-diol C
31
H
64
O
2
Other oret methanol [38]
202 Tritriacontane-8,10-diol C
33
H
68
O
2
Other oret methanol [38]
203 Pentatriacontane-8,10-diol C
35
H
72
O
2
Other oret methanol [38]
204 Dihydrophaseic acid 3-O-β-d- glucopyranoside C
21
H
32
O
10
Other oret 95% ethanol [42]
205 (-)−4-hydroxybenzoic acid-4-O-[6’-O-(2’’-methylbutyryl)-β-d-
glucopyranoside]
C
18
H
24
O
9
Other oret water [73]
206 2,3-dimethoxy-5-methylphenyl-1-O-β-D-glucopyranoside C
15
H
22
O
8
Other oret 95% ethanol [71]
207 2,6-dimethoxy-4-methylphenyl-1-O-β-D-glucopyranoside C
15
H
22
O
8
Other oret 95% ethanol [71]
208 (15
α
,20 R)-Dihydroxypregn-4-en-3-one 6’-O-acetyl-20- β-cellobioside C
35
H
54
O
14
Other seed methanol [74]
209 Matairesinol 4’-O-β-D-apiofuranosyl(1–2)- β-d- glucopyranoside C
31
H
45
O
15
Other seed methanol [74]
210 (2E,4E)-dihydrophaseic acid methyl ester-3-O-β-D-glucopyranoside C
22
H
34
O
10
Other orets 80% methanol [75]
211 (2Z,4E)-dihydrophaseic acid methyl ester-3-O-β-d- glucopyranoside C
22
H
34
O
10
Other orets 80% methanol [75]
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8
oxidative stress are key factors that promote functional loss of endo-
thelial cells [125], which can cause atherosclerosis, thrombosis, and
neurodegenerative diseases such as AD [126,127]. The avonoids in
safower can protect various endothelial cells. However, the different
avonoids protect different types of endothelial cells. Their protective
mechanism may depend on the expression of 77 kinds of proteins and
Fig. 2. The avonoid, avonol, avanone and quinochalcones present in safower.
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
9
their anti-inammatory and anti-oxidant effects [128,129].
HSYA protects endothelial cells primarily through its anti-
inammatory effects. For example, HSYA could restrain the TNF
α
-induced upregulation of intercellular cell adhesion molecule-1(ICAM-
1) in arterial endothelial cells (AECs) and reduce the adhesion of
RAW264.7 cells to AECs [130]. By upregulating the Bcl-2/Bax ratio and
downregulating p53 protein expression in the nucleus and increasing the
NO content of cell supernatant, HSYA can protect human umbilical vein
Fig. 2. (continued).
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
10
endothelial cells (HUVECs) from hypoxia-induced apoptosis [131].
Additionally, HSYA protects brain microvascular endothelial cells by
restraining the class I PI3K /Akt/ mTOR signalling pathway [132].
Kaempferol also works by inhibiting inammatory pathways, such as
MAPK, NF-κB and TLR4 signalling pathways, to protect human AECs
[133,134]. In addition to the anti-inammatory effect, by upregulating
the expression of 14–3–3γ and reducing oxidative stress, kaempferol can
protected the HUVECs from doxorubicin-induced damage [135].
Hyperoside could also protect HUVECs, while playing a role in amelio-
rating inammation [136].
Fig. 2. (continued).
B. Xian et al.
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11
4.2. Lung protective effect
Safower avonoids can be used to improve lung inammation
[137]. Both types of avonoids in safower improve lung disease by
virtue of this effect. HSYA can inhibit p38 MAPK, NF-κB, and TLR-4
signalling pathways and the expression of downstream inammatory
factors (MYD 88, ICAM-1, TNF
α
, IL-1β, and IL-6), which can reduce the
adhesion of leucocytes to human alveolar epithelial A549 cells [138].
Research has shown that small airway remodelling can be attenuated
through the suppression of TGF-β1 expression [139]. HSYA can improve
the morphological changes and brosis in lung tissue by inhibiting the
increase in
α
-smooth muscle actin (
α
-SMA) expression, smad 3 phos-
phorylation and TGF-β1 type II receptor [140,141].
Kaempferol can also restrain the activation of the NF-κB signalling
Fig. 3. The organic acids present in safower.
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
12
pathway and regulate the polyubiquitination of TNF receptor-associated
factor-6. Thereby, reducing lung inammation and improving acute
lung injury [142]. COVID-19 is a global pandemic, and the virus can
cause serious inammation in the lungs. The avonoids in safower can
inhibit NF-κB, MAPK, and TNF signalling pathways and TGF-β, which
means that safower may have the potential to be used in the treatment
of COVID-19 [143,144].
4.3. Liver protection effect
Regarding the protective effects on the liver, HSYA has been the
subject of more research than other avonoids. Inammation-induced
Fig. 4. The alkaloids present in safower.
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
13
liver injury can activate hepatic stellate cells (HSCs), leading to liver
brosis and cirrhosis. Restraining activation and inducing apoptosis by
decreasing the level of inammation is one way to block HSC activation.
HYSA can block HSC activation by inhibiting TGF-β1 and myocyte
enhancer factor 2 [145–147]. Furthermore, HSYA can induce HSC
apoptosis by suppressing the activation of ERK1/2 and its regulated gene
expression [148]. In addition, the hepatoprotective effects of HSYA and
hydroxy saffron yellow C (HSYC) are better than those of acetylcysteine,
which is more robust than aspirin. HSYA and HSYC can enhance blood
circulation and reduce liver toxicity [149]. HSYA has been shown to
protect against ischaemic liver in mice by attenuating inammation and
necrosis, reducing serum transaminase levels, inammatory cytokine
expression, and macrophage recruitment [150]. Kaempferol can inhibit
hepatocyte apoptosis, and hyperoside has anti-inammatory and
anti-oxidative effects, which contribute to alleviation of acute liver
injury [151,152].
4.4. Anti-cancer effect
Flavonoids in safower can exert anti-cancer effect in many human
organs, such as the skin, liver, colon, ovary, prostate, cervix, pancreas,
stomach, and bladder [153]. The quinochalcones mainly act against
liver cancer. For example, safower yellow can inhibit liver cancer by
stimulating collagen degradation and regulating the gut microbiota
[154]. HSYA can inhibit the viability, proliferation, and migration of
HepG2 liver cancer cells through suppressing p38 MAPK phosphoryla-
tion [155]. Recent research has shown that HSYA can inhibit prolifer-
ation and stimulate apoptosis of liver cancer cells via blocking
autophagic ux [156]. In addition to attenuating liver cancer, HSYA can
inhibit glioma [157], colorectal cancer [158], and lung cancer [159].
Moreover, HSYB can induce breast cancer cell apoptosis [160]. How-
ever, research on the underlying mechanisms is not comprehensive.
Other safower avonoids may also help improve the treatment of
multiple cancers. Kaempferol and hyperoside have anti-breast cancer
effects. Kaempferol can regulate the MAPK pathway and the ratio of
Bax/Bcl-2, inhibiting proliferation, promoting apoptosis, and alleviating
DNA damage and cell cycle arrest at the G2/M phase in breast cancer
cells [161,162]. Hyperoside can inhibit activation of NF-κB signalling
pathway and reduce the production of ROS [163]. Hyperoside can also
suppress proliferation and induce apoptosis in non-small cell lung cancer
cells [164,165] and inhibit liver cancer [166].
Kaempferol also inhibits cancer cell resistance. Resistance is one of
the difculties in cancer treatment. Research has shown that there are
many clues related to resistance, such as claudins [167], genes related to
apoptosis (PI3K, Akt, Bcl2, Bax, etc.), and multi-drug resistance genes
(Abcb1 and Abcc1). Kaempferol reduces claudin mRNA levels and pro-
motes activity in human lung adenocarcinoma A549 cell spheroids to
prevent lung adenocarcinoma chemoresistance [168]. In resistant EJ
bladder cancer cells and leukaemic cells, kaempferol can inhibit pro-
liferation by inhibiting the function of resistance-related genes [169,
170]. Kaempferol overcomes 5-uorouracil resistance in human resis-
tant LS174 colon cancer cells and activates peroxisome
proliferator-activated receptor γ (PPARγ) [171].
4.5. Bone protection effect
Osteoporosis is a systemic bone disease, accompanied by osteopenia
and fracture. Women at menopausal age have higher risk of osteoporosis
[172]. Oestrogen inuences bone cells such as osteoblasts and osteo-
clasts [173]. Phytoestrogens have an effect similar to that of oestrogen.
Some chalcones, avones, avanones, and isoavones belong to phy-
toestrogens [174,175]. This may be the reason that kaempferol,
hyperoside, and HSYA can treat several bone diseases conditions such as
osteopenia, osteoporosis, and osteoarthritis. Therefore, these avonoids
inuence the apoptosis or differentiation of osteoblasts and osteoclasts,
exert anti-inammatory and anti-oxidant effects.
In ovariectomy-induced osteoporotic models, HSYA, kaempferol,
and hyperoside have been shown to have anti-osteoporotic activities.
HSYA acts by inhibiting carbonic anhydrase 2 activity and osteoclast
differentiation [176]. Kaempferol and hyperoside act by inhibiting
NF-κB, MAPK, and mammalian target of rapamycin (mTOR) signalling
pathways and regulating oestrogen receptor and bone morphogenetic
protein-2 (BMP-2) [177,178]. HSYA can ameliorate the development of
osteoarthritis by inhibiting NF-κB and MAPK signalling pathways [179],
and by regulating the expression of miR-146a. Kaempferol can also
improve osteoarthritis [180]. Kaempferol can inhibit the gene expres-
sion and differentiation of osteoclasts and promote the proliferation,
migration, and differentiation of osteoblasts, which allows kaempferol
to be used in the treatment of calvarial osteolysis and fractures
[181–183]. Hyperoside can inhibit H
2
O
2
-induced apoptosis of
Fig. 5. The spermidine present in safower.
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
14
Fig. 6. The polyacetylene present in safower.
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Biomedicine & Pharmacotherapy 153 (2022) 113462
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Fig. 7. The other compounds present in safower.
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
16
Fig. 7. (continued).
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
17
MC3T3-E1 cells by inhibiting the MAPK signalling pathway and exerting
an anti-oxidant effect [184]. Therefore, safower extract also has
anti-oxidative and anti-inammatory effects, which can protect osteo-
blasts from ROS-induced damage [185], osteopenia, and microstructural
changes in ovariectomised rats [186].
4.6. Anti-inammatory effect
HSYA, kaempferol, and hyperoside have anti-inammatory effects in
different organs and tissues, such as the heart, liver, brain, lung, muscle,
and soft tissues. The anti-inammatory effects were reected by the
inhibition of NF-κB and P38 MAPK signalling pathways and reduction in
the secretion of inammatory factors (TNF-
α
, IL-1β, IL-6, VCAM-1, COX-
2) [187–189]. In this way, HSYA can inhibit apoptosis in the kidney
[190], improve renal brosis [191], and improve ovalbumin-induced
asthma [192]. Hyperoside can reduce TNF-
α
-induced vascular inam-
mation and inammation in BV2 microglia [193–195]. Coupled with
anti-oxidant effects, kaempferol can be used to treat skin brosis and
inammation [196,197]. In addition, via the protein kinase C-phos-
pholipase Cγ1-inositol 1,4,5-trisphosphate receptor (PKC-PLCγ-IP3R)
signalling pathway, HSYA can signicantly inhibit mast cell degranu-
lation to suppress drug-induced anaphylactoid reactions [198].
Kaempferol can reduce the release of inammatory cytokines (such as
IL-17, IL-21, and TNF-
α
), and inhibit the proliferation, migration, and
activation of broblast-like synoviocytes [199].
4.7. Other effects
Studies have shown that HSYA can ameliorate diabetes. HSYA can
enhance angiogenesis, granulation tissue formation, collagen content
Fig. 7. (continued).
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
18
increase, and re-epithelialisation to promote diabetic wound healing
[200,201]. By improving the expression of PPARγ 2, HSYA can improve
insulin sensitivity [202]. Furthermore, HSYA can protect pancreatic
β-cells via the JNK signalling pathway [203]. The anti-inammatory and
anti-oxidative effects of kaempferol help attenuate diabetic nephropathy
[204]. Hyperoside can inhibit JNK activation in ECV304 cells to prevent
diabetes [205] and inhibit AMPK-Unc-51-like kinase 1 (ULK1)-mediated
autophagy to attenuate renal ageing and injury [206].
In addition to the pharmacological activities mentioned above, there
are other activities of safower. The ethanol extract of safower can
stimulate hair growth [207] and exert an antidepressant effect through
the interaction of dopaminergic and serotonergic systems [208]. Saf-
ower yellow can inhibit the accumulation of fat, decrease the glucose
level, and increase the sensitivity to insulin [202,209]. HSYA and
kaempferol can also reduce fat accumulation and formation [210–212].
Additionally, HSYA can ameliorate skin ageing in mice which results
from ultraviolet irradiation [213]. Research has demonstrated that at a
high concentration, HSYA may exert a pro-oxidant effect [214].
Kaempferol can be used to prevent ethanol/HCl-induced ulcer [215].
Kaempferol can inhibit retinal pigment epithelium cell damage and
apoptosis by upregulating the Bax/Bcl-2 and caspase-3 molecular acti-
vation pathways and reducing oxidative stress [216]. Hyperoside which
is present in many plants, still has many activities, such as a cytochrome
P450 inhibition [217], improvement of H
2
O
2
-induced apoptosis and
oxidative stress in rat ovarian granulosa cells [218], and antidepressant
effect [219].
5. Biomolecular research
Flavonoids are the main active compounds responsible for the
pharmacological activity of safower. Clarifying the avonoid meta-
bolism pathway is conducive to regulating the biosynthesis and prop-
erties of avonoids in safower. Research progress on avonoids is
shown in two parts, genes that directly regulate avonoid synthesis and
genes that could inuence avonoid synthesis.
Fig. 8. Pharmacological activities and molecular mechanism of avonoids in safower Note:ABCB, ATP-binding cassette B; ABCC1, ATP-binding cassette C1; Akt,
protein kinase B; AMPK, AMP-activated protein kinase; AP-1, activator protein-1; ASC, apoptosis-associated speck-like protein containing a CARD; ATM, ataxia
telangiectasia mutated; Bad, Bcl-2-antagonist of cell death; Bax, Bcl-2X-associated protein; Bcl-2, B-cell lymphoma-2; BDNF,brain-derived neurotrophic factor; Bid,
BH3 interacting domain death agonist; BMP, bone morphogenetic protein; BRCA1, breast cancer type 1 susceptibility protein; CASP, caspase; CD14, cluster of
dierentiation 14; CDK5,cyclin-dependent kinase 5; CHOP, CCAAT/enhancer-binding protein homologous protein; COX2, cyclooxygenase-2; CREB, cyclic adenosine
monophosphate response element binding protein; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinases; FGFR3, broblast growth
factor receptor 3; FoxO1, forkhead box protein O1; GFAP, glial brillary acidic protein; GRB2, growth factor receptor-bound protein 2; GSH, glutathione; GSK-3β,
Glycogen synthase kinase-3beta; HO-1, heme oxygenase 1; ICAM-1, intercellular adhesion molecule 1; IGF-IR, insulin-like growth factor 1 receptor; IGF-IIR, insulin-
like growth factor 2 receptor; IKK, inhibitor of κ B kinase; IL, interleukin; iNOS, inductible nitric oxide synthase; IκB
α
: Inhibitor of NF-κB; JNK, c-Jun N-terminal
kinase; JAK2, janus kinase 2; MAPK, mitogen-activated protein kinases; MCP-1, monocyte chemoattractant protein 1; MEF2C, MADS-box transcription enhancer
factor 2 C; MEKK3, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3; MEK, mitogen-activated protein kinase kinase; MKK,
mitogen-activated protein kinase kinase; MK-2, mitogen-activated protein kinase-activated protein kinase 2; Mmp9, matrix metalloproteinases-9; mPTP; MSK1,
mitogen- and stress-activated protein kinase 1; MyD88, myeloid differentiation factor 88; NFATc1, nuclear factor of activated T-cells cytoplasmic 1; NF-κB, nuclear
factor-κB; NGF, nerve growth factor; NIK, NF-κB-Inducing kinase; NLRP3, NOD-like receptor family pyrin domain containing 3; NO, nitric oxide; NQO1, NAD(P)H
dehydrogenase, quinone 1; Nrf2, nuclear factor erythroid 2-like 2; P:PEG2,prostaglandin E2; PDGF, platelet derived growth factor; PIP3, phosphatidylinositol 3,4,5-
trisphosphate; PI3K, phosphatidylinositol-3-kinase; PSD95; p90RSK, ribosomal protein S6 kinase alpha; Rac, Ras-related C3 botulinum toxin substrate; RIP1,
receptor-interacting serine/threonine-protein kinase 1; RSK2, ribosomal protein S6 kinase 2; SDF-1
α
, stromal cell-derived factor-1
α
SIRT1, silent mating type in-
formation regulation 2 homologue- 1.; SOD, superoxide dismutase; SOS, son of sevenless; STAT3, signal transducer and activator of transcription 3; TAB, TAK binding
protein; TAK1, Tgf-β-activatedkinase1; TGF-β1, transforming growth factor beta 1; TIMP-1, tissue inhibitors of metalloproteinase 1; TLR4, toll-like receptor-4; TNF-
R1, tumour necrosis factor-receptor 1; TNF-
α
, tumour necrosis factor-
α
Tpl2, tumour progression locus 2; TRAF, TNF receptor-associated factor; TrkB, tropomysin
related kinase B; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; Wnt,
wingless-type MMTV integration site family;
α
SMA,
α
-smooth muscle actin. Green indicate up-regulation, red indicate down-regulation, and black words indicate
pathways involved.
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
19
5.1. Genes directly regulating avonoid synthesis
Flavonoid metabolism is an important component of the phenyl-
propanoid metabolism. In Arabidopsis, chalcone synthase (CHS), one of
the key enzymes in avonoid biosynthesis, catalyses p-coumaroyl CoA
to tetrahydroxychalcone. In turn, tetrahydroxychalcone is then trans-
formed into naringenin via chalcone isomerase (CHI). Naringenin can
generate genistein under the action of isoavone synthase (IFS). While
genistein is catalysed into apigenin by avone synthase (FNS), and can
also produce dihydroavonol under the effect of avanone 3-hydroxy-
lase (F3H). Flavonoid 3’-hydroxylase (F3’H), and avonoid 3’5’-hy-
droxylase (F3’5’H). Dihydroavonol can yield quercetin or
leucoanthocyanidins through the catalysis of avonol synthase (FLS) or
dihydroavonol 4-reductase (DFR). Leucoanthocyanidins are substrates
of anthocyanidins and catechin [220–223].
Many avonoid synthesis genes were successfully cloned. Their
expression patterns and functions were analysed ( Fig. 10). In safower,
the differential expression of CHS gene can inuence the avonoid type,
content, and colour of owers [224,225]. A CHS gene in safower was
cloned and named CHS1, which shared 86.94% conserved residues with
CHSs in other plants [226]. Overexpression of CtCHS1 in safower can
upregulate the expression of CtPAL3 and CtC4H1 while downregulating
the expression of Ct4CL3, CtF3H, and CtDFR2 [227].
Two CHI genes were cloned in safower. One had a full-length of
696 bp, while the other was 1161 bp. Further research found that the
accumulation of HSYA and the gene expression of 696 bp-CHI had a
similar tendency during the owering stages [228]. The transient
expression in tobacco mesophyll cells showed that the 1162 bp-CHI gene
may inuence avonoid accumulation at different owering stages of
safower [229,230].
A avanone 3-hydroxylase gene (F3H) containing a 1086 bp open
reading frame was obtained from safower. Under the stimulation of
methyl jasmonate (MeJA), CtF3H was expressed at higher levels, which
is related to the accumulation of quinochalcones and avonols [231].
The avonol synthase (FLS) gene was obtained from the ower of saf-
ower, with an open reading frame of 1011 bp. Phylogenetic analysis
Fig. 9. Related signalling pathways of avonoids in safower in the treatment of cardiovascular and cerebrovascular diseases Note: Akt, protein kinase B; AP-1,
activator protein-1; ASC, apoptosis-associated speck-like protein containing a CARD; Bad, Bcl-2-antagonist of cell death; Bax, Bcl-2X-associated protein; Bcl-2, B-
cell lymphoma-2; BDNF,brain-derived neurotrophic factor; CASP1, caspase-1; CASP3, caspase-3; CASP9, caspase-9; CD14, cluster of dierentiation 14; COX2,
cyclooxygenase-2; CREB, cyclic adenosine monophosphate response element binding protein; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-
regulated kinases; GRB2, growth factor receptor-bound protein 2; IKK, IkappaB kinase; IL-1
α
, interleukin1
α
IL-1β, interleukin1β IL-18, interleukin18; IL-6, inter-
leukin 6; IκB
α
: Inhibitor of NF-κB; JNK, c-Jun N-terminal kinase; LBP, lipopolysaccharide binding protein; LPS, lipopolysaccharide; MEKK3, mitogen-activated
protein kinase/extracellular signal-regulated kinase kinase kinase 3; MEK, mitogen-activated protein kinase kinase; MKK, mitogen-activated protein kinase ki-
nase; MK-2, mitogen-activated protein kinase-activated protein kinase 2; Mmp9, matrix metalloproteinases-9; MSK1, mitogen- and stress-activated protein kinase 1;
MyD88, myeloid differentiation factor 88; NIK, NF-κB-inducing kinase; NLRP3, NOD-like receptor family pyrin domain containing 3; NO, nitric oxide; Nur77, nuclear
receptor subfamily 4 group A member 1; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PI3K, phosphatidylinositol-3-kinase; p90RSK, ribosomal protein S6 kinase
alpha; Rac, Ras-related C3 botulinum toxin substrate; RADD, repair assisted damage detection; RIP1, receptor-interacting serine/threonine-protein kinase 1; SDF-1
α
,
stromal cell-derived factor-1
α
SOS, son of sevenless; TAB, TAK binding protein; TAK1, Tgf-β-activatedkinase1; TLR4, toll-like receptor-4; TNF-R1, tumour necrosis
factor-receptor 1; TNF-
α
, tumour necrosis factor-
α
Tpl2, tumour progression locus 2; TRAF2/5, TNF receptor-associated factor 2/5; TrkB, tropomysin related kinase
B; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
20
revealed that CtFLS has relatively high homology with the FLS of
Rudbeckia laciniata L. [232]. A full-length-1226 bp anthocyanidin syn-
thase (ANS) gene was cloned. The ANS gene had three functional do-
mains of ANS protein, containing 2-oxoglutarate and iron ion
combination sites [229].
The chalcone glycosides in safower consist of yellow and red pig-
ments. Thus, the chalcone glycoside content could change the colour of
the safower. A study found that the expression of CHS, CHI, and ANS in
different owering periods is involved in the synthesis and content of the
safower yellow pigment [233]. Apart from this, a gene named car-
thamin synthase (CarS) also determines the colour of safower, because
CarS can catalyse the composition and decomposition of carthamin
[234]. Some compounds can also alter the colour of safower by regu-
lating gene expression. Based on transcriptome data, research has shown
that under the treatment of MeJA, the upstream genes (CHSs, CHIs, and
HCTs) in the avonoid biosynthesis pathway were upregulated, and the
downstream genes (F3Ms, ANRs, and ANSs) were downregulated [235,
236].
Safower contains many avonoid glycoside compounds. Glycosyl-
transferases can transfer glycosyl moieties from the activated sugar
donors to certain acceptors. Forty-ve UDP-glycosyltransferase (UGT)
genes were screened from safower, CtUGT3 and CtUGT25 were posi-
tively related to kaempferol-3-O-β-D-glucoside, and CtUGT16 was
positively related to quercetin-3-O-β-D-glucoside in the yellow safower
variety. Furthermore, CtUGT3 and CtUGT25 were positively related to
quercetin-3-O-β-D-glucosidein of the white safower variety [237].
Moreover, a study reported a new glycosyltransferase gene from saf-
ower named UGT73AE1. UGT73AE1 can act on acceptors of different
structures, form O-, S-, and N-glycosidic bonds, and catalyse the reverse
reaction, which can be used in a deglucosylation reaction and an aglycon
exchange reaction [238].
5.2. Genes inuencing avonoid synthesis
In addition to the genes in the avonoid metabolic pathway that can
directly regulate avonoid synthesis, genes that can inuence avonoid
synthesis have also been found in safower. 1-aminocyclopropane car-
boxylic acid oxidase (ACO) catalyses the conversion of 1-
aminocyclopropane carboxylic acid into ethylene. It can also inuence
genes and metabolites in the avonoid biosynthetic pathway. Yanhua Tu
et al. [239] cloned 2 ACO genes from safower. The safower plant with
overexpressed CtACO1 had a higher accumulation of quercetin and its
glycosylated derivatives (quercetin 3-β-D-glucoside and rutin), and a
lower accumulation of kaempferol glycosylated derivatives (kaempfer-
ol-3-O-β-rutinoside and kaempferol-3-O-β-D-glucoside), apigenin, and
luteolin.
Transcription factors are important proteins which can affect gene
expression in higher plants. MYB transcription factors comprise one of
the largest families of transcriptional regulators in plants. They can in-
uence plant development, stress responses, and metabolism. Three
MYB genes in safower were cloned, named CtFRMYB1, CtFRMYB2, and
CtFRMYB3, with full-lengths of 1223 bp, 1080 bp, and 1 348 bp,
respectively. Furthermore, expression analysis showed that CtFRMYB1
and CtFRMYB2 were only expressed in owers, and their expression
levels were higher on the third day of owering [182]. The basic
helix-loop-helix (bHLH) family is the second-largest transcription factor
family. Hong et al. [240] screened 41 bHLH genes related to avonoid
synthesis and found that those genes were clustered into two groups.
One group was highly expressed in the petals, while the other was highly
expressed in the roots.
Transcriptome sequencing is an effective method for screening target
genes and studying gene metabolomic and transcriptome patterns.
MicroRNAs (miRNAs) are 20–24 nucleotide noncoding RNAs that are
widely present in the biological kingdom and play an irreplaceable role
in developmental plasticity, abiotic/biotic responses, and symbiotic/
parasitic interactions [241]. High-throughput sequencing discovered
236 known and 13 novel miRNAs in safower. These miRNAs have been
found to vary greatly in different tissues [242].
6. Conclusions and future perspectives
Safower is an important plant with a variety of applications. It is
widely distributed across Europe, Asia, and North America, showing
signicant regional distribution. Except for owers, which can be used
as medicine and dye, more than 80% of the safower (seed residue, leaf,
and stem) is considered an agricultural waste, while this part also
Fig. 10. Flavonoid synthesis pathway in safower Note: CHI, chalcone isomerase; CHS, chalcone synthase; HSYA, hydroxysafor yellow A; FLS, avonol synthase;
F3H, avanone 3-hydroxylase.
B. Xian et al.
Biomedicine & Pharmacotherapy 153 (2022) 113462
21
contains benecial compounds, mainly avonoid-type phenolic com-
pounds [243]. Safower has strong cold and barren resistance, which
makes it suitable for cultivation in dry regions and marginal areas.
More than 60 avonoids have been isolated from safower. Based on
their structure, these avonoids can be divided into the special and the
common. The special group belongs to C-glycosides, while the common
group belongs to O-glycosides. Glycosylation can alter the stability and
solubility of avonoids, and can also affect the cellular activities that
these compounds are involved in, such as angiogenesis, apoptosis,
migration, and inammation [244]. The difference in the structure may
be one of the reasons for the difference in the pharmacological effects of
these two types of avonoids. HSYA is the main active ingredient of
safower, and was used in various industries and in different countries
and regions. However, ensuring its stability is challenging. Light, tem-
perature, and metal ions can oxidise, hydrolyse, or polymerise HSYA
[245]. Therefore, future studies should be conducted to enhance the
stability of HSYA.
The many pharmacological effects of safower compounds were
summarised in this review. However, compared with the recommended
therapeutic usage recorded in ancient Chinese materia medica, there are
still several traditional uses of safower that are not estimated by
modern pharmacological research. These include amenorrhoea, dys-
menorrhoea, retention of lochia, and aggregation-accumulation masses.
Although animal and cell experiments have been conducted to verify the
pharmacological ability, further clinical experiments, pharmacokinetics,
and toxicological studies are required. In addition to traditional prepa-
rations, safower should also try to develop new preparations. For
example, study found that safower extract nanoparticles produced by
Ag and Cu
2+
through a green synthesis pathway had a strong inhibitory
effect to human colon adenocarcinoma cells, human liver cancer cells,
and Human breast ductal carcinoma cells [246]. Cardiovascular dis-
eases, cerebrovascular diseases, and some cancers have a close relation
with oestrogen. The therapeutic effect of safower is related to certain
avonoids that belong to phytoestrogens, which worth further research.
In case of relevance to the occurrence of diabetes, obesity, and liver
inammation, safower might synergistically may enhance the effect of
single compounds.
Additionally, HSYA has attracted the most pharmacological research
attention, whereas other compounds, such as safoavonesides A,
hydroxysafor yellow B, and cartormin, are mostly ignored causing the
low content in safower and lacking of compounds control. Therefore,
the pharmacological potential of safower has not been fully developed.
In addition, the structural characteristics of HSYA make transmembrane
transport difcult, which leads to low bioavailability. Furthermore, red
pigment compounds are fat-soluble, making it difcult to induce phar-
macological effects through the general routes of administration.
CHS, CHI, F3H, and FLS, the key enzymes in the synthesis of saf-
ower avonoids, have been successfully cloned. However, these genes
are related to the biosynthesis of avonoids, avonols, and dihydro-
avonoids, and a few gene function verication studies have been car-
ried out. The synthesis pathway of quinochalcones remains unknown.
Studying the C-glycosylated cyclohexanonedienol gene in safower may
provide a breakthrough in determining the synthesis mechanism of
quinolones. Further investigations are needed to fully reveal the huge
potential of safower.
Funding
This work was supported by grants from the National Natural Science
Foundation of China (81803669, U19A2010), Key R&D Plan of Science
and Technology Department of Sichuan Province (2021YFYZ0012-5,
2020YFN0152), Sichuan Provincial Central Guiding Local Science and
Technology Development Special Project (2020ZYD058), Xinglin Talent
Program of Chengdu University of TCM (0300510007).
CRediT authorship contribution statement
Bin Xian: Formal analysis, Data curation, Writing - original draft,
Writing - review & editing. Rui Wang: Data curation, Writing - original
draft. Huajuan Jiang: Supervision, Methodology, Writing - review &
editing. Yongfeng Zhou: Supervision, Methodology. Jie Yan: Formal
analysis. Xulong Huang: Formal analysis, Supervision. Jiang Chen:
Supervision, Methodology. Qinghua Wu: Supervision. Chao Chen:
Supervision. Ziqing Xi: Supervision. Chaoxiang Ren: Conceptualiza-
tion, Supervision, Project administration. Jin Pei: Conceptualization,
Funding acquisition, Project administration.
Conict of interest statement
The authors declare that they have no known competing nancial
interests or personal relationships that could have appeared to inuence
the work reported in this paper.
Data availability
The data that has been used is condential.
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