Hindawi
Evidence-Based Complementary and Alternative Medicine
Volume 2021, Article ID 5587938, 23 pages
https://doi.org/10.1155/2021/5587938
Review Article
A Review on Antidiabetic Activity of Centaurea spp.: A New
Approach for Developing Herbal Remedies
Samaneh Fattaheian-Dehkordi ,1 Reza Hojjatifard ,1 Mina Saeedi ,2,3
and Mahnaz Khanavi 1,4,5
1
Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
3
Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran
4
Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute,
Tehran University of Medical Sciences, Tehran, Iran
5
Faculty of Land and Food Systems, University of British Columbia, Vancouver, Canada
2
Correspondence should be addressed to Mina Saeedi; m-saeedi@tums.ac.ir and Mahnaz Khanavi; khanavim@tums.ac.ir
Received 18 February 2021; Revised 19 May 2021; Accepted 14 June 2021; Published 5 July 2021
Academic Editor: Francesca Mancianti
Copyright © 2021 Samaneh Fattaheian-Dehkordi et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Objective. Diabetes mellitus (DM) is a long-life metabolic disorder, characterized by high blood glucose levels. The hyperglycemic
condition generally leads to irreversible nerve injury and vascular damage. Among different types of diabetes, type 2 is more
common and has spread all over the world. Although various therapeutic approaches have been developed to control type 2 DM,
regulating blood glucose levels has still remained a controversial challenge for patients. Also, most prescription drugs cause
different side effects, such as gastrointestinal disorders. Thus, developing novel and efficient antidiabetic agents possessing fewer
adverse effects is in high demand. Method. The literature was comprehensively surveyed via search engines such as Google Scholar,
PubMed, and Scopus using appropriate keywords. Results. Medicinal plants, both extracts and isolated active components, have
played a significant role in controlling the blood glucose levels. Good-to-excellent results documented in the literature have made
them a precious origin for developing and designing drugs and supplements against DM. Centaurea spp. have been traditionally
used for controlling high blood glucose levels. Also, the antidiabetic properties of different species of Centaurea have been
confirmed in recent studies through in vitro assays as well as in vivo experiments. Conclusion. Potent results encouraged us to
review their efficacy to open a new horizon for development of herbal antidiabetic agents.
1. Introduction
Diabetes mellitus (DM) is a chronic metabolic disease which
is described by hyperglycemia and high blood sugar levels in
postprandial and fasting state. It is characterized by defects
in insulin secretion, insulin action, or both of them [1]. The
total number of diabetic patients in the world has been
anticipated to rise from 171 million in 2000 to 366 million in
2030 [2]. Considering the long-term side effects of DM, it
has become one of the major causes of morbidity in the
world [3]. There are different types of diabetes based on its
pathogenesis, including insulin-dependent (type I),
noninsulin-dependent (type II), and gestational. Type 2 DM
is more common than the other types in which the body’s
insulin receptors become resistant to the normal insulin
effects. Then, β cells of the pancreas respond to the high
blood glucose levels by producing more insulin to manage
the situation. However, the insulin overproduction makes β
cells wear themselves out [4, 5].
Patients with DM may experience some complications
such as retinopathy, neuropathy, nephropathy, cataracts,
peripheral vascular insufficiencies, and damaged nerves
resulting from chronic hyperglycemia [5–7]. High blood
glucose levels in type 2 DM can be controlled by using
2
insulin or oral antidiabetic drugs [8]. Different pathways and
mechanisms are considered for preventing the progression
of the disease. They may include inhibition of intestinal
α-glucosidase and α-amylase, inhibition of aldose reductase,
insulin synthesis and secretion, inhibition of lens aldose
reductase, oxidative stress protection, inhibition of formation of advanced glycation end products, lowering plasma
glucose levels, altering enzyme activity of hexokinases and
glucose-6-phosphate, inhibition of postprandial hyperglycemia, stimulation of GLUT-4, decreasing activity of G6P,
and reducing the level of skeletal hexokinases [5].
One of the most popular approaches to the management of
blood glucose levels is the inhibition of key enzymes [9].
α-Glucosidase and α-amylase are two carbohydrate digestive
enzymes which can cause elevated postprandial hyperglycemia
(PPHG); thus, their inhibition plays a significant role in
controlling PPHG in patients with type 2 DM. Inhibition of
α-glucosidase leads to the reduction of disaccharide hydrolysis,
and inhibition of α-amylase disrupts the breakdown of starch
to simple sugars. Some of these compounds are clinically used,
and the results have shown significant reduction of blood
glucose levels in patients [10, 11]. The most important side
effect related to the approved Food and Drug Administration
(FDA) antitype 2 DM drugs, including voglibose, acarbose,
miglitol, sulphonylureas, and thiazolidine, is gastrointestinal
problems such as swelling, abdominal distraction, diarrhea,
and meteorism, which need more attention. Thus, investigation
of different therapeutic agents with lower side effects is in high
demand. Accordingly, herbal remedies have absorbed lots of
attention [12–14] and different medicinal plants such as
Abelmoschus moschatus, Alangium salvifolium, Azadirachta
indica, Bidens pilosa, Boerhaavia diffusa, Capsicum frutescens,
Cassia alata, Eclipta alba, Embellica officinalis, Ficus carica,
Gentiana olivier, Glycyrrhiza glabra, Gymnema sylvestre,
Hordeum vulgare, Ipomoea aquatic, Juniperus communis,
Mangifera indica, Momordica charantia, Ocimum sanctum,
Punica granatum, and Zingiber officinale have demonstrated
enzyme inhibitory activity possessing desirable effects on diabetes and hyperglycemia [15–33]. Furthermore, various
phytochemicals such as alkaloids, sesquiterpene and saponins,
polysaccharides, flavonoids, dietary fibers, ferulic acid, tannins,
limonene, and oleuropeoside have been studied for their inhibitory activity toward enzymes involved in the one set and
progression of type 2 DM, which deserve to be considered for
the development and production of herbal anti-DM supplements [5, 24, 34–43].
The genus Centaurea (family Asteraceae, tribe Cardueae,
subtribe Centaureinae) compromises approximately 600
species worldwide, from Asia, Europe, and tropical Africa to
North America [44]. Centaurea spp. have long been used in
traditional medicine to cure various ailments such as diabetes, diarrhea, rheumatism, malaria, hemorrhoids, and
neurological disorders. They have also been used in the
treatment of inflammation, common cold, fever, cough, and
ophthalmic disorders and their liver strengthening, wound
healing, and anti-itching effects have been important
[45–50]. A wide range of secondary metabolites, including
sesquiterpene lactones (SLs) [44, 51–53], flavonoids
[45, 46, 54, 55], lignans, and alkaloids [44, 45, 55], have been
Evidence-Based Complementary and Alternative Medicine
isolated from different Centaurea spp. The genus Centaurea
is known for possessing sesquiterpene lactones (SLs) [56, 57]
and phenolic compounds [58]. Herein, focusing on the
hypoglycemic activity of various species of Centaurea in
both folk and modern medicine [59–66], we reviewed different reports on their antidiabetic potency to develop herbal
drugs and supplements for controlling blood sugar.
2. Methods
The literature was completely searched via search engines
such as Google Scholar, Pub Med, and Scopus using keywords, including DM, Centaurea, hyperglycemia, medicinal
plants, antidiabetic plants, α-glucosidase, α-amylase, high
blood glucose levels, enzyme inhibition, plant-based diets,
folk medicine, and treatment. All results were extracted and
analyzed in a comprehensive manner.
3. Results
Antidiabetic activity of Centaurea spp. (Figure 1) has been
usually investigated through the in vitro inhibition of
α-glucosidase and α-amylase as well as in vivo studies on rats
and mice (Table 1). However, no clinical trials have been
conducted. α-Glucosidase and α-amylase are clinically responsible for glucose disorders in patients with type 2 DM.
Reported results have been summarized in Table 1.
3.1. In Vitro Assays
3.1.1. Centaurea bornmuelleri. In vitro α-amylase and
α-glucosidase, as well as antioxidant activities of Centaurea
bornmuelleri, have been reported in the literature. Among
methanolic, aqueous, and ethyl acetate extracts of aerial
parts of C. bornmuelleri, the ethyl acetate extract was found
to be more potent than the others toward α-amylase and
α-glucosidase [67] (Table 1). Other studies confirmed the
antibacterial and antioxidant activity of the methanolic
extract of the plant [80]. Also, it could inhibit the growth of
colon cancer cells under in vitro conditions [81].
3.1.2. Centaurea calcitrapa. Centaurea calcitrapa has been
used in folk medicine for the treatment of ophthalmic and
skin diseases, common fever, jaundice, and digestive disorders [82–84]. In an in vitro study, the antidiabetic activity
of methanolic extract of aerial parts of the plant was investigated. It could inhibit α-glucosidase with IC50 value
of 4.38 ± 0.31 mg/ml comparing with acarbose (IC50 =
1.41 ± 0.07 mg/ml) [68] (Table 1). It is worth mentioning that
the extract has also shown antibacterial activity against
Bacillus, Pseudomonas, Staphylococcus, Streptococcus, Salmonella, Enterobacter, Enterococcus, Acinetobacter, and
Escherichia genera [85–87]. Furthermore, C. calcitrapa has
depicted significant antioxidant activity through β-carotene/
linoleic acid bleaching assay. In vivo antioxidant assay in
mice at the doses of 50 and 100 mg/kg/day within 21 days
afforded a protective effect against erythrocytes hemolysis
[88].
Evidence-Based Complementary and Alternative Medicine
3
(a)
(b)
(c)
Figure 1: Some Centaurea species deposited in the herbarium of the Faculty Of Pharmacy, Tehran University of Medical Sciences. (a)
Centaurea bruguierana. (b) Centaurea patula. (c) Centaurea depressa.
4
Evidence-Based Complementary and Alternative Medicine
Table 1: Antidiabetic activity of Centaurea spp.
Entry
Centaurea spp.
Action
Part
Extract
C. bornmuelleri
α-Glucosidase inhibition
Aerial
parts
Ethyl acetate
2
C. bornmuelleri
α-Glucosidase inhibition
3
C. bornmuelleri
α-Glucosidase inhibition
4
C. bornmuelleri
α-Glucosidase inhibition
5
C. bornmuelleri
α-Amylase inhibition
6
C. bornmuelleri
α-Amylase inhibition
7
C. bornmuelleri
α-Amylase inhibition
8
C. bornmuelleri
α-Amylase inhibition
9
C. calcitrapa
α-Glucosidase inhibition
1
10
11
12
13
In vitro
studies
C.
C.
C.
C.
centaurium
centaurium
centaurium
centaurium
α-Amylase
α-Amylase
α-Amylase
α-Amylase
inhibition
inhibition
inhibition
inhibition
14
C. depressa
α-Glucosidase inhibition
15
C. depressa
α-Glucosidase inhibition
16
C. depressa
α-Amylase inhibition
17
C. depressa
α-Amylase inhibition
18
19
20
21
C. drabifolia
subsp. detonsa
C. drabifolia
subsp. detonsa
C. drabifolia
subsp. detonsa
C. drabifolia
subsp. detonsa
α-Glucosidase inhibition
α-Glucosidase inhibition
α-Amylase inhibition
α-Amylase inhibition
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Roots
Roots
Roots
Roots
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
MeOH
Decoction
Infusion
Ethyl acetate
MeOH
Decoction
Infusion
MeOH
MeOH
Aqueous
Polyphenol
n-Hexane
Reference
Activitya
33.12 ± 0.32 (mg
ACAEb/g
[67]
extract)
10.17 ± 0.91 (mg
[67]
ACAE/g extract)
1.95 ± 0.07 (mg
[67]
ACAE/g extract)
2.36 ± 0.25 (mg
[67]
ACAE/g extract)
19.90 ± 0.89 (mg
[67]
ACAE/g extract)
16.73 ± 0.34 (mg
[67]
ACAE/g extract)
3.98 ± 0.22 (mg
[67]
ACAE/g extract)
3.54 ± 0.66 (mg
[67]
ACAE/g extract)
4.38 ± 0.31 (mg/
[68]
ml)
32.51 ± 0.34%
[69]
—
[69]
—
[69]
158 (μg/ml)
[69]
Ethyl acetate
46.11 ± 0.97%
[70]
Chloroform
53.45 ± 1.98%
[70]
Ethyl acetate
36.93 ± 0.97%
[70]
Chloroform
43.97 ± 0.92%
[70]
Ethyl acetate
43.10 ± 2.41%
[70]
Chloroform
36.03 ± 0.24%
[70]
Ethyl acetate
25.58 ± 0.38%
[70]
Chloroform
25.28 ± 0.38%
[70]
22
C. fenzlii
α-Glucosidase inhibition
Aerial
parts
MeOH
23
C. fenzlii
α-Amylase inhibition
Aerial
parts
MeOH
24
C. hypoleuca
α-Glucosidase inhibition
Flowers
EtOH
25
C. hypoleuca
α-Glucosidase inhibition
Flowers
MeOH
26
C. hypoleuca
α-Glucosidase inhibition
Flowers
Ethyl acetate
27
C. hypoleuca
α-Glucosidase inhibition
Stems
EtOH
28
C. hypoleuca
α-Glucosidase inhibition
Stems
MeOH
0.331 (mmol
ACAE/g dry
weight)
0.354 (mmol
ACAE/g dry
weight)
10.33 ± 0.04
(mmol ACAE/g
extract)
12.77 ± 0.61
(mmol ACAE/g
extract)
19.61 ± 0.05
(mmol ACAE/g
extract)
9.10 ± 0.06
(mmol ACAE/g
extract)
8.66 ± 0.08
(mmol ACAE/g
extract)
[71]
[71]
[72]
[72]
[72]
[72]
[72]
Evidence-Based Complementary and Alternative Medicine
5
Table 1: Continued.
Entry
Centaurea spp.
Action
Part
Extract
29
C. hypoleuca
α-Glucosidase inhibition
Stems
Ethyl acetate
30
C. hypoleuca
α-Amylase inhibition
Flowers
EtOH
31
C. hypoleuca
α-Amylase inhibition
Flowers
MeOH
32
C. hypoleuca
α-Amylase inhibition
Flowers
Ethyl acetate
33
C. hypoleuca
α-Amylase inhibition
Stems
EtOH
34
C. hypoleuca
α-Amylase inhibition
Stems
MeOH
35
C. hypoleuca
α-Amylase inhibition
Stems
Ethyl acetate
36
C. karduchorum
α-Glucosidase inhibition
Roots
37
C. karduchorum
α-Glucosidase inhibition
Stems
38
C. karduchorum
α-Glucosidase inhibition
Leaves
39
C. karduchorum
α-Glucosidase inhibition
Flowers
40
C. karduchorum
α-Amylase inhibition
Roots
41
C. karduchorum
α-Amylase inhibition
Stems
42
C. karduchorum
α-Amylase inhibition
Leaves
43
C. karduchorum
α-Amylase inhibition
Flowers
44
45
46
47
C. kotschyi var.
persica
C. kotschyi var.
persica
C. kotschyi var.
persica
C. kotschyi var.
persica
α-Glucosidase inhibition
α-Glucosidase inhibition
α-Amylase inhibition
α-Amylase inhibition
48
C. papposa
α-Glucosidase inhibition
49
C. papposa
α-Glucosidase inhibition
50
C. papposa
α-Glucosidase inhibition
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Activitya
Reference
12.62 ± 0.21
(mmol ACAE/g
[72]
extract)
82.65 ± 1.31
(mmol ACAE/g
[72]
extract)
102.41 ± 1.18
(mmol ACAE/g
[72]
extract)
106.72 ± 1.10
(mmol ACAE/g
[72]
extract)
63.64 ± 1.05
(mmol ACAE/g
[72]
extract)
66.66 ± 0.67
(mmol ACAE/g
[72]
extract)
72.41 ± 0.61
(mmol ACAE/g
[72]
extract)
Hydrophilic (80%EtOH,
19% H2O, and 1% of 0.1%
trifluoroacetic acid, v/v/v)
Hydrophilic (80% ethanol,
19% H2O, and 1% of 0.1%
trifluoroacetic acid, v/v/v)
Hydrophilic (80% ethanol,
19% H2O, and 1% of 0.1%
trifluoroacetic acid, v/v/v)
Hydrophilic (80% ethanol,
19% H2O, and 1% of 0.1%
trifluoroacetic acid, v/v/v)
Hydrophilic (80% ethanol,
19% H2O, and 1% of 0.1%
trifluoroacetic acid, v/v/v)
Hydrophilic (80% ethanol,
19% H2O, and 1% of 0.1%
trifluoroacetic acid, v/v/v)
Hydrophilic (80% ethanol,
19% H2O, and 1% of 0.1%
trifluoroacetic acid, v/v/v)
Hydrophilic (80% ethanol,
19% H2O, and 1% of 0.1%
trifluoroacetic acid, v/v/v)
5.35 ± 0.08 (mg/
ml)
[73]
1.42 ± 0.10 (mg/
ml)
[73]
0.63 ± 0.00 (mg/
ml)
[73]
1.51 ± 0.22 (mg/
ml)
[73]
Not active
[73]
Not active
[73]
14.63 ± 0.67
(mg/ml)
[73]
Not active
[73]
Ethyl acetate
42.35 ± 2.22%
[70]
Chloroform
49.42 ± 0.92%
[70]
Ethyl acetate
36.16 ± 0.13%
[70]
Chloroform
42.72 ± 0.17%
[70]
Dichloromethane
Ethyl acetate
n-Butanol
227.6 ± 4.4 (μg/
ml)
791.9 ± 1.8 (μg/
ml)
Not active
[8]
[8]
[8]
6
Evidence-Based Complementary and Alternative Medicine
Table 1: Continued.
Entry
Part
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Extract
Activitya
Reference
Ethyl acetate
54.88 ± 1.11%
[70]
Chloroform
56.11 ± 0.24%
[70]
Ethyl acetate
31.70 ± 0.04%
[70]
Chloroform
33.30 ± 0.04%
[70]
Ethyl acetate
35.59 ± 0.58%
[70]
Chloroform
60.31 ± 2.13%
[70]
Ethyl acetate
21.54 ± 0.04%
[70]
Chloroform
59.54 ± 0.59%
[70]
Centaurea spp.
Action
51
C. patula
α-Glucosidase inhibition
52
C. patula
α-Glucosidase inhibition
53
C. patula
α-Amylase inhibition
54
C. patula
α-Amylase inhibition
55
C. pulchella
α-Glucosidase inhibition
56
C. pulchella
α-Glucosidase inhibition
57
C. pulchella
α-Amylase inhibition
58
C. pulchella
α-Amylase inhibition
59
C. saligna
α-Glucosidase inhibition
Leaves
Ethyl acetate
60
C. saligna
α-Glucosidase inhibition
Leaves
MeOH
61
C. saligna
α-Glucosidase inhibition
Leaves
Aqueous
62
C. saligna
α-Amylase inhibition
Leaves
Ethyl acetate
63
C. saligna
α-Amylase inhibition
Leaves
MeOH
64
C. saligna
α-Amylase inhibition
Leaves
Aqueous
65
C. tchihacheffii
α-Glucosidase inhibition
66
C. tchihacheffii
α-Glucosidase inhibition
67
C. tchihacheffii
α-Amylase inhibition
68
C. tchihacheffii
α-Amylase inhibition
69
C. triumfettii
α-Glucosidase inhibition
70
C. triumfettii
α-Glucosidase inhibition
71
C. triumfettii
α-Amylase inhibition
72
C. triumfettii
α-Amylase inhibition
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
23.80 ± 0.06
(mmol ACAE/g
extract)
12.57 ± 1.97
(mmol ACAE/g
extract)
3.32 ± 0.40
(mmol ACAE/g
extract)
0.80 ± 0.01
(mmol ACAE/g
extract)
0.59 ± 0.01
(mmol ACAE/g
extract)
0.16 ± 0.01
(mmol ACAE/g
extract)
[74]
[74]
[74]
[74]
[74]
[74]
Ethyl acetate
58.23 ± 0.53%
[70]
Chloroform
53.45 ± 1.40%
[70]
Ethyl acetate
29.89 ± 1.01%
[70]
Chloroform
40.26 ± 0.29%
[70]
Ethyl acetate
69.88 ± 1.16%
[70]
Chloroform
41.12 ± 0.77%
[70]
Ethyl acetate
42.84 ± 0.34%
[70]
Chloroform
22.40 ± 0.17%
[70]
73
C. triumfettii
α-Glucosidase inhibition
Stems
EtOH
74
C. triumfettii
α-Glucosidase inhibition
Stems
MeOH
75
C. triumfettii
α-Glucosidase inhibition
Stems
Ethyl acetate
3.74 ± 0.05
(mmol ACAE/g
extract)
3.77 ± 0.05
(mmol ACAE/g
extract)
4.13 ± 0.04
(mmol ACAE/g
extract)
[14]
[14]
[14]
Evidence-Based Complementary and Alternative Medicine
7
Table 1: Continued.
Entry
Centaurea spp.
Action
Part
Extract
76
C. triumfettii
α-Glucosidase inhibition
Flowers
EtOH
77
C. triumfettii
α-Glucosidase inhibition
Flowers
MeOH
78
C. triumfettii
α-Glucosidase inhibition
Flowers
Ethyl acetate
79
C. triumfettii
α-Amylase inhibition
Stems
EtOH
80
C. triumfettii
α-Amylase inhibition
Stems
MeOH
81
C. triumfettii
α-Amylase inhibition
Stems
Ethyl acetate
82
C. triumfettii
α-Amylase inhibition
Flowers
EtOH
83
C. triumfettii
α-Amylase inhibition
Flowers
MeOH
84
C. triumfettii
α-Amylase inhibition
Flowers
Ethyl acetate
C. urvillei subsp.
hayekiana
C. urvillei subsp.
hayekiana
C. urvillei subsp.
hayekiana
C. urvillei subsp.
hayekiana
85
86
87
88
89
90
91
C. alexanderina
In vivo
studies
C. aspera
C. bruguierana
α-Glucosidase inhibition
α-Glucosidase inhibition
α-Amylase inhibition
α-Amylase inhibition
Reduction of blood glucose
level
It exhibited an important
hypoglycemic effect by oral
route and chronic
administration in diabetic rats;
the extract obtained by
exhaustion with hot water
showed an acute hypoglycemic
activity in normal animals
The ethyl acetate extract
resulted in the best reduction
of blood glucose
The aqueous extract resulted in
the best reduction of PEPCK
activity and increment in
hepatic GP activity
Aerial
parts
Aerial
parts
Aerial
parts
Aerial
parts
Activitya
Reference
2.27 ± 0.01
(mmol ACAE/g
[14]
extract)
2.09 ± 0.03
(mmol ACAE/g
[14]
extract)
1.42 ± 0.05
(mmol ACAE/g
[14]
extract)
137.39 ± 0.76
(mmol ACAE/g
[14]
extract)
127.57 ± 0.72
(mmol ACAE/g
[14]
extract)
165.47 ± 0.72
(mmol ACAE/g
[14]
extract)
137.42 ± 0.75
(mmol ACAE/g
[14]
extract)
114.06 ± 0.50
(mmol ACAE/g
[14]
extract)
116.85 ± 0.85
(mmol ACAE/g
[14]
extract)
Ethyl acetate
67.66 ± 0.05%
[70]
Chloroform
43.65 ± 0.39%
[70]
Ethyl acetate
43.20 ± 0.59%
[70]
Chloroform
17.53 ± 0.08%
[70]
Leaves
MeOH
[75]
Flowers
Aqueous
—
[76]
Aerial
fruiting
parts
Aqueous,
dichloromethane, ethyl
acetate, and methanol
—
[77]
8
Evidence-Based Complementary and Alternative Medicine
Table 1: Continued.
Entry
92
93
Centaurea spp.
Action
Part
Consumption of aqueous
extracts of leaves and flowers at
the dose of 5 g/kg led to the
Leaves
reduction of blood glucose
and
C. corubionensis
levels; aqueous extract of
flowers
flowers (50 mg/ml) could
increase insulin release from
isolated islets of Langerhans
Reduction in blood glucose
level in chronic and acute
condition
Herb and
Using the extract significantly
C. horrida
roots
improved peripheral nerve
function of diabetic mice via
hot plate and tail flick tests
Extract
Activitya
Reference
Aqueous and EtOH
—
[78]
MeOH
—
[79]
a
IC50 values reported as mg/ml, μg/ml, mmol ACAE/g extract, or inhibition percent (%). bACAE = acarbose equivalent.
3.1.3. Centaurea centaurium. In vitro α-amylase inhibitory
activity of methanolic, aqueous, polyphenol, and nhexane extracts of Centaurea centaurium was assayed by
Conforti et al. [69]. The n-hexane extract was the most
potent extract with an IC50value of 158 μg/ml. However,
aqueous and polyphenol extracts were inactive, and the
methanolic extract was found to be weak with an inhibition percent of 32.51 ± 0.34% at the concentration of
1000 μg/ml.
3.1.4. Centaurea depressa, Centaurea drabifolia, Centaurea
kotschyi, Centaurea patula, Centaurea pulchella, Centaurea
tchihacheffii, Centaurea triumfettii, and Centaurea urvillei.
The chloroform and ethyl acetate extracts of aerial parts of
eight Centaurea spp. including C. depressa, C. drabifolia,
C. kotschyi, C. patula, C. pulchella, C. tchihacheffii,
C. triumfettii, and C. urvillei were investigated for their
α-glucosidase and α-amylase inhibitory activity by Zengin
et al. All Centaurea spp. extracts were able to inhibit both
enzymes at the concentration of 2 mg/mL (Table 1) and
compared with acarbose, inducing inhibitory activity
toward α-amylase and α-glucosidase with inhibition
percent of 50.51% and 44.16% at 1 mg/ml. The chloroform
extract of C. pulchella and C. depressa and the ethyl acetate
extract of C. urvillei showed the most potent α-amylase
inhibitory effects with inhibition percent of 59.54%,
43.97%, and 43.20%, respectively. The antiglucosidase
effect was reported in the following order: ethyl acetate
extract of C. triumfettii (69.88%) > ethyl acetate extract of
C. urvillei (67.66%) > chloroform extract of C. pulchella
(60.31%) [70].
It should be mentioned that antioxidant, antibacterial,
antinociceptive, antipyretic, and anticholinesterase activities
of these species were also proven [14, 70, 89–93].
3.1.5. Centaurea fenzlii. The methanolic extract of Centaurea fenzlii has shown α-glucosidase and α-amylase inhibitory activity as 0.331 mmol ACAE/g dry weight and
0.354 mmol ACAE/g dry weight, respectively [71]. The plant
has also shown antioxidant, antityrosinase, and anticholinesterase activities, as well as cytotoxicity against colon and
MCF-7 breast cancer cell lines [71, 94, 95].
3.1.6. Centaurea hypoleuca. Ethanolic, methanolic, and
ethyl acetate extracts of aerial parts (flower and stem) of
Centaurea hypoleuca have depicted in vitro inhibitory activity toward α-glucosidase and α-amylase. It should be
noted that the ethyl acetate extract of the plant flowers
resulted in higher activity than that of the stem as well as
other extracts (Table 1) [72]. Also, all extracts demonstrated
moderate-to-good antioxidant, antimicrobial, and anticholinesterase activities [72].
3.1.7. Centaurea karduchorum. The dried powder of Centaurea karduchorum has been traditionally used for wound
healing [96]. Also, tea prepared from aerial parts of the plant
was found to be helpful for the treatment of diabetes, which
was investigated and proven in recent studies. Among
ethanolic extracts obtained from roots, stems, leaves, and
flowers of the plant (Table 1), the leaves extract showed the
best
inhibitory
activity
against
α-glucosidase
(IC50 = 0.63 ± 0.00 mg/ml); however, it could not efficiently
inhibit the α-amylase (IC50 = 14.63 ± 0.67 mg/ml) [73].
Comparing α-glucosidase inhibitory activity of
C. karduchorum with that of cinnamon which is known for
its antidiabetic activity revealed potent efficacy of
C. karduchorum since the activity of various extracts of
cinnamon was calculated in the range of IC50 = 0.42–4.0 mg/
ml [73, 97].
Evidence-Based Complementary and Alternative Medicine
9
Table 2: Chemical compounds isolated from Centaurea spp.
Entry Centaurea spp.
1
C. alexanderina
2
C. aspera
3
C. bornmuelleri
4
C. bruguierana
5
C. calcitrapa
6
C. centaurium
7
C. corubionensis
8
C. depressa
9
C. drabifolia
10
C. fenzlii
11
C. horrida
12
C. hypoleuca
13
C. karduchorum
14
C. kotschyi
15
C. papposa
16
C. patula
17
C. pulchella
Phytochemical constituents
References
Sesquiterpene lactones and flavonoids (kaempferol 3-O-rutinoside, rutin,
apigenin 7-O-galacturonic acid methyl ester, apigenin 7-O-β-D-glucoside,
[75, 104, 115, 116]
astragalin, centaurein, vicenin, vitexin, isovitexin, kaempferol, apigenin,
quercetin, jaceosidin, and nepetin)
Sesquiterpene lactones (dehydromelitensin, melitensin, isomelitensin,
eudesmanolides, and dihydrostenophyllolide) and flavonoids (6-methoxyluteolin
[52, 116–118]
(nepetin), 6-methoxyacacetin (pectolinarigenin), 6-methoxyapigenin
(hispidulin), and 6-methoxychrisoeriol (jaceosidin)).
Flavonoids (afzelin, astragalin, isorhamnetin, apigenin, quercetin, luteolin, and
kaempferol), phenolic acids (caffeoylquinic acids and chlorogenic acid), sterol
[67, 92, 119]
(stigmast-4-en-3gamma-ol), and lignans (arctiin, arctigenin, matairesinol, and
matairesinoside)
Sesquiterpene lactones (cnicin and dehydromelitensin-8-acetate) and flavonoids
[77, 104, 112, 113, 120–123]
(kaempferol, rutin, quercetin, cirsimaritin, cirsilinelol, and eupatilin)
Sterols, sesquiterpene lactones and their closely related group of triterpenoids,
lignans, flavonoids (apigenin, luteolin, scutellarein, chrysoeriol, nepetin,
jaceosidin, eupatorin, kaempferol, kaempferide, jaceidin, and centaureidin),
[124–132]
alkaloids (stizolphine and choline), and phenolic acids (derivatives of
hydroxycinnamic acids: p-coumaric, ferulic, caffeic, and chlorogenic acid;
derivatives of hydroxybenzoic acids: p-hydroxybenzoic, protocatechuic, gallic, and
gentisic acid)
Fatty acids (11, 14-eicosadienoic acid methyl ester, 9-octadecenoic acid methyl
ester, and 9-octadecenoic acid) and terpenes (cypirene, α-zingiberene,
[69]
β-farnesene, β-santalene, β-bisabolene, β-himachalene, and azulene)
Has not been fully characterized
Phenolic compounds, condensed tannins, flavonoids (luteolin, kaempferol,
scutellarein 7-β-D-glucuronoside, scutellarein 5-β-D-glucuronoside, quercetin,
[70, 90, 92, 133–137]
isoquercitrin, quereimeritrin, and apigenin), monoterpenoid (piperitone),
sesquiterpenoid (elemol), and sesquiterpene lactones (solstitialin A and acetyl
solstitialin)
Flavonoids, sesquiterpene lactones (belonging to the guaiane class; centaurea
lactone, cynaropicrin, aguerin B, 8α-isovaleryloxyzaluzanin C, 8αacetoxyzaluzanin C, and 4β,15-dihydro-3-dehydrosolstitialin A), and phenolic
[138–142]
compounds (protocatechuic acid, 5-caffeoylquinic acid, 5-feruloylquinic acid,
orientin, vitexin, quercetin, quercetin-3-O-glucoside, patuletin-O-hexoside,
luteolin, luteolin-7-O-rutinoside, luteolin-7-O-glucoside, isovitexin, apigenin, and
hispidulin)
Flavonoids (cirsiliol, isorhamnetin, hispidulin, and cirsimaritin)
[95]
Flavonoids (horridin, apigenin, rutin, apigenin-3-Ο-glucuronide, kaempferol-3O-glucuronide, apigenin-8-C-α-L-arabinoside, apigenin-6-C-α-L-arabinoside,
apigenin-7-Ο-β-D-glucoside, apigenin6,8-di-C-β-D-glucoside, scutelarein-7-O[104, 143–146]
β-D-glucoside, kaempferol-3-O-β-D-glucoside, kaempferol-3-O-α-Lrhamnoside, vitexin, isovitexin, orientin, schaftoside, hispidulin, fisetin, quercetin,
quercetin-3-O-α-L-rhamnoside, and quercetin-3-O-β-D-galactoside), lactones,
phenolic acids, pentacyclic triterpenes, sterol glucoside, and Q acid derivatives
Sesquiterpene lactones (centaurepensin, acroptillin, cynaropicrin, janerin,
[72, 126, 147–150]
linichlorin, and repin) and phenolic compound (catechin and chlorogenic acid)
Phenolic compounds (chlorogenic acid, apigenin, and luteolin glycosides)
[73, 150, 151]
Sesquiterpene lactones (germacrene D, β-caryophyllene, β-cedrene, β-bisabolene,
and bicyclogermacrene), phenolic compounds, and flavonoid
[70, 116, 152, 153]
(patuletin-7-O-glucoside)
Phenolic acids (quinic acid, malic acid, gallic acid, protocatechuic acid,
chlorogenic acid, caffeic acid, ferulic acid, salicylic acid, vanillic acid, coumarin,
[8, 154, 155]
syringic acid, apigenin, and apigetrin), flavonoids, and terpenes
Phenolic compounds (protocatechuic acid, caffeic acid, 5-feruloylquinic acid,
orientin, vitexin, patuletin-O-hexoside, luteolin-7-O-glucoside, isovitexin,
[141, 156]
quercetin, apigenin, hispidulin, and luteolin), sesquiterpenes (spathulenol), and
diterpene alcohol (phytol)
Phenolics content, condensed tannins, and fatty acid (linoleic acid, α-linoleic acid,
[70]
and palmitic acid)
10
Evidence-Based Complementary and Alternative Medicine
Table 2: Continued.
Entry Centaurea spp.
18
19
20
21
Phytochemical constituents
Flavonoids (rutin, hesperidin, quercetin, luteolin, kaempferol, and apigenin) and
C. saligna
phenolic compounds (rosmarinic acid and p-coumaric acid)
C. tchihacheffii
Phenolic compounds
Phenolic compounds (chlorogenic acid, ferulic acid, p-coumaric acid, and caffeic
C. triumfettii
acid)
Flavonoids (naringenin-7-O-β-D glucuronopyranoside, 6-hydroxykaempferol-7O-β-D glucuronopyranoside, hispidulin-7-O-β-D-glucuronopyranoside,
apigenin-7-O-β-D-methylglucuronopyranoside, hispidulin-7-O-β-Dmethylglucuronopyranoside, hispidulin-7-O-β-D-glucopyranoside, apigenin-7C. urvillei
O-β-D-glucopyranoside, kaempferol, apigenin, luteolin, eriodictyol-7-O-β-Dglucuronopyranoside, arbutin, salidroside, and 3,5-dihydroxyphenethyl alcohol3-O-β-D-glucopyranoside)
3.1.8. Centaurea papposa. In vitro α-glucosidase inhibitory
activity of n-butanol, dichloromethane, and ethyl acetate extracts of Centaurea papposa was studied by Mawahib et al.
Among them, dichloromethane extract displayed a greater
inhibitory activity (IC50 = 227.6 ± 4.4 μg/ml) comparing with
acarbose (275.4 ± 1.6 μg/ml). The ethyl acetate extract exhibited
weak anti-α-glucosidase activity (IC50 = 791.9 ± 1.8 μg/mL),
and the n-butanol extract, however, was inactive [8].
3.1.9. Centaurea saligna. Centaurea saligna has been traditionally used as a wound healing agent, astringent, and
tonic. Moreover, its choleretic, diuretic, antibacterial, antirheumatic, and antipyretic activities have been reported
[49, 74, 98]. The plant also has demonstrated anticholinesterase, antityrosinase, antiradical, antimicrobial, and
antiproliferative properties on LNCaP, HCT-116, and MCF7 cancer cell lines [74, 99, 100].
Methanolic, aqueous, and ethyl acetate extracts of
C. saligna leaves were studied against α-glucosidase
(3.32–23.80 mmol ACAE/g extract) and α-amylase
(0.16–0.80 mmol ACAE/g extract) by Zengin et al. Among
them, the ethyl acetate extract showed the most potent antiα-glucosidase activity (23.80 mmol ACAE/g extract). It is
clear that those extracts exhibited weak inhibitory activity
toward α-amylase [74].
3.1.10. Centaurea triumfettii. Leaves of Centaurea triumfettii have been traditionally used as foodstuff [92, 101].
Biological activities of methanolic, ethanolic, and ethyl acetate extracts of stems and flowers of Centaurea triumfettii
have been reported by Acet [14]. The ethyl acetate extract of
the stems showed potent inhibitory effects on α-amylase
(165.47 ± 0.72 mmol ACAE/g extract) and α-glucosidase
(4.13 ± 0.04 mmol ACAE/g extract). The plant has also
shown the antioxidant capacity and antibacterial activity
[14, 91, 102].
3.2. In Vivo Assay
3.2.1. Centaurea alexanderina. Centaurea alexanderina has
shown different biological activities such as anti-inflammatory, analgesic, hepatoprotective, and antibacterial
References
[74]
[70]
[14, 150]
[70, 92, 157]
(against Pseudomonas aeruginosa) effects and cytotoxicity
on A-495 lung cancer cells [75, 103].
Antidiabetic properties of the 80% methanolic extract of
leaves of C. alexanderina at the doses of 300 and 600 mg/kg
have been studied under in vivo conditions in normoglycemic as well as streptozotocin- (STZ-) induced diabetic rats.
Those results were compared with glibenclamide (50 mg/kg)
as the standard drug. Administration of the extract at the
dose of 600 mg/kg led to a remarkable reduction of the
elevated blood glucose by 9.4% and 10.5% after 1 and 2 h,
respectively. However, using the dose of 300 mg/kg decreased the related item to 2.8% after 2.5 h. Using 300 and
600 mg/kg of extracts daily within two months in the STZinduced diabetic model led to the reduction of plasma
glucose levels by 2.7% and 4.9%, respectively. However, the
reduction of test days to 30 days affected the efficacy of
extract, and the corresponding levels reduced to 1.1% and
3.8%, respectively [75].
3.2.2. Centaurea aspera. Aqueous extracts of Centaurea
aspera flowers were investigated for their hypoglycemic
activity in normal and alloxan-diabetic rats. It exhibited an
important hypoglycemic effect by oral route and chronic
administration in diabetic rats comparing with glibenclamide. It should be mentioned that the extract obtained by
exhaustion with hot water showed an acute hypoglycemic
activity in normal animals [76].
3.2.3. Centaurea bruguierana. Hypoglycemic activity of
different extracts of Centaurea bruguierana and the mechanism of action was investigated in STZ-alloxan-diabetic
rats by Khanavi et al. The aqueous and dichloromethane
extracts at the dose of 400 mg/kg and the ethyl acetate and
methanol extracts at the dose of 200 mg/kg, obtained from
aerial fruiting parts of the plant, were investigated. The ethyl
acetate extract afforded the best activity to reduce the blood
glucose levels up to 50.0%, while methanol, dichloromethane, and aqueous extracts reduced that up to 45.7%,
41.7%, and 29.5%, respectively. Glibenclamide showed a
34.5% reduction. The best result from reduction of phosphoenolpyruvate carboxykinase (PEPCK) activity (84.0%)
and increasing hepatic glycogen phosphorylase (GP) activity
Evidence-Based Complementary and Alternative Medicine
11
OH
HO
OH
O
O
HO
O
HO
OH
O
O
HO
OH
O
OH
HO
OH O
OH
O
OH O
OH O
O
OH
O
HO
OH
HO
OH
OH
(a)
(b)
HO
OH
OH
HO
O
(c)
OH
OH
O
HO
O
OH
O
O
OH
OH O O
O
O
O
O
O
HO
O
OH
OH
OH
OH O
OH
OH O
OH
OH
HO
OH
OH
OH
(d)
(e)
(f )
OH
HO
O
OH
O
HO
O
HO
O
O
HO
OH
OH O
(g)
OH
(h)
OH
OH
OH
OH
OH
OH O
HO
OH
OH
(i)
OH
OH
HO
O
HO
OH
OH
O
HO
HO
HO
O
O
OH O
O
OH O
OH
HO
OH
OH O
(j)
(k)
HO
(l)
OH
OH
O
HO
O
O
HO
HO
O
O
OH
O
OH O
OH O
(m)
(n)
(o)
H
OH
HO
O
HO
OH
O
H
OH
O
HO
(p)
(q)
Figure 2: The chemical structure of constituents isolated from Centaurea spp., responsible for antidiabetic activity. (a) Kaempferol. (b)
Kaempferol 3-O-rutinoside. (c) Astragalin (kaempferol-3-glucoside). (d) Rutin. (e) Hesperidin. (f ) Quercetin. (g) Luteolin. (h) Cynaroside
(luteolin-7-O-glucoside). (i) Catechin. (j) Apigenin. (k) Vitexin. (l) Isovitexin. (m) Hispidulin. (n) Jaceosidin. (o) Caffeic acid. (p)
Cholorogenic acid. (q) β-Caryophyllene.
(134.5%) points of view was related to the aqueous extract
comparing with those of glibenclamide (62.5% and 133.0%),
respectively. C. bruguierana depicted no effect on blood
insulin, but it was able to reduce blood glucose by stimulation of hepatic glycogenolysis and inhibition of gluconeogenesis [77, 104].
12
3.2.4. Centaurea corubionensis. Chuclá et al. studied the effect
of aqueous and ethanolic extracts of leaves and flowers of
Centaurea corubionensis on normoglycemic rats, circulating
insulin levels in anesthetized rats, glucose-induced hyperglycemic rats, and alloxan-diabetic rats at different doses of 2.5, 5,
and 10 g/kg [78]. Consumption of aqueous extracts of leaves
and flowers at the dose of 5 g/kg led to the reduction of blood
glucose levels by 19 and 16%, respectively. Also, 6 h after
administration of aqueous extract of leaves (5 g/kg), the serum
glucose and insulin levels were reported to be 97.2 (mg%) and
10.2 (μU/ml) comparing with tolbutamide (75 mg/kg) with
those values of 84.4 (mg%) and 9.2 (μU/ml), respectively.
Moreover, aqueous extract of flowers (50 mg/ml) could increase insulin release from isolated islets of Langerhans to
36 μU/ml. However, no effect was observed on alloxan-diabetic
animals, and it may be associated with severe damage of the
pancreas by the alloxan. Hypoglycemic properties of
C. corubionensis can be achieved by the undamaged pancreas
via raising serum circulating insulin.
3.2.5. Centaurea horrida. Raafat et al. investigated the antidiabetic effect of the methanolic extract of Centaurea
horrida herb and roots in alloxan-induced diabetic mice
comparing with glibenclamide. All results were generally
obtained more significantly than those of glibenclamide. The
plant has been traditionally used to lower blood glucose
levels [79]. It was found that administration of the extract at
dose of 100 mg/kg led to the reduction of blood glucose
levels from 219.33 to 106.56 mg/dL. Investigation of the
subacute effect of the extract exhibited the reduction of
blood glucose levels from 121.84 mg/dL on 1th day to
105.42 mg/dL on the 8th day at the same dose. The subacute
effect of the extract on body weight in alloxan-induced
diabetic mice also revealed that using the extract at different
doses of 5, 25, 50, and 100 mg/kg did not lead to a significant
overweight in mice which was comparable to the positive
control. In vivo assessment of the antioxidant activity of the
extract demonstrated that treated mice with doses of 25, 50,
and 100 mg/kg had no remarkable increase in serum catalase
activity. However, it was clear that long-term treatment of
diabetes with all doses, particularly with a high dose of
extract, induced a reversed effect on catalase activity, which
may be associated with reduced oxidative stress. It is worth
mentioning that using the extract significantly improved
peripheral nerves function of diabetic mice via hot plate and
tail flick tests. This is an important result as uncontrolled
high blood glucose levels can damage peripheral nerves
causing diabetic neuropathy [79, 105, 106]. It has been
suggested that hypoglycemic effect of the plant is achieved by
the inhibition of the endogenous glucose production or
inhibition of intestinal glucose absorption and controlling
dietary glucose uptake in the small intestinal tract. It is
Evidence-Based Complementary and Alternative Medicine
believed that the mechanism is independent of insulin secretion [79].
The elastase and tyrosinase inhibitory effects of
C. horrida have also been reported [107].
4. Discussion
Herbal medicine has occupied a particular position in
healing purposes, and their use has grown significantly over
recent years. In this respect, there are a wide range of reports
on the antidiabetic activity of medicinal plants [108], which
can be fully considered for the development of efficient
drugs and supplements.
4.1. Toxicity. It should not be forgotten that all natural
remedies are not essentially safe, and all herbal medicine
users should be aware of the risks that they carry [93, 109].
To reach this goal, the toxicity of plants should be investigated for better knowing the range of safety. According to
the literature, there are no enough data on the toxicity of
reported Centaurea spp. in this paper, and most plant
toxicity tests should be conducted.
Orally administration of 80% methanolic extract of
C. alexanderina by different groups of mice (n = 10) in the
dose range of 50–3000 mg/kg resulted in no fatality and the
LD50 value was assumed to be greater than 3000 mg/kg [75].
LD50 value for the methanolic extract of C. urvillei was
calculated as 115.5 × 10−2 using the brine shrimp lethality
bioassay [110]; likewise, the LC50 values for methanolic and
diethyl ether extracts of C. triumfettii were obtained as 266.5
and 166.6 μg/ml, respectively [111].
Cytotoxicity of petroleum ether, chloroform, ethyl acetate, n-butanol, and remaining methanolic fractions of the
methanolic extract of C. bruguierana depicted that petroleum ether and remaining methanolic fractions were nontoxic toward NIH-3T3 cells (Swiss embryo fibroblast) [112].
However, in a study reported by Nasr et al. [113], chloroform, ethyl acetate, n-butanol, and methanol fractions of the
plant showed toxicity on HUVEC cells (a noncancerous cell
line).
As reported by Erol-Dayi et al. [114], evaluation of
cytotoxicity of methanolic and aqueous extracts of
C. calcitrapa, C. ptosimopappa, and C. spicata indicated the
lack of toxicity of aqueous extract of C. ptosimopappa and
C. spicata on Hela (human cervix adenocarcinoma) and
Vero (normal African green monkey kidney) cells
(IC50 > 1000 μg/ml). Those methanolic extracts were found
to be more toxic (IC50 > 200 μg/ml) on the same cells. The
aqueous extract of C. calcitrapa showed moderate toxicity on
both cells (IC50 > 400 μg/ml), whereas the methanolic extract
demonstrated an inhibitory effect with IC50 < 100 μg/ml on
Hela and Vero cells (92.5 and 91.7 μg/mL, respectively). It
Evidence-Based Complementary and Alternative Medicine
indicated that the methanolic extract of calcitrapa needs
more attention from the toxicity point of view.
According to the results reported by Conforti et al. [69],
based on the brine-shrimp toxicity test on the roots of
C. centaurium, the LC50value was calculated as 44.05 mg/ml
for the methanolic extract, while LC50values for the polyphenolic, lipophilic, and water fractions were found to be
157.44, 25.98, and 152.81 mg/ml, respectively.
4.2. Constituents Isolated from Centaurea spp. and Their
Antidiabetic Activity Mechanism of Action (MOA). The
antidiabetic activity of Centaurea spp. is definitely indebted
to the presence of phytochemicals. Isolated constituents
from discussed plants are listed in Table 2. In this respect,
sesquiterpenes, flavonoids, and phenolic compounds have
been generally reported in the literature (Figure 2).
4.2.1. Sesquiterpene Lactones. Sesquiterpenoids have shown
potent antidiabetic activity via various mechanisms such as
inhibition of enzymes involved in hyperglycemia, protecting
β-pancreatic cells, preventing oxidative and inflammatory
damages associated with the disease, and improving insulin
secretion. They can improve insulin sensitivity by regulating
glucose transport and key proteins of the insulin signaling
pathway. They have also exhibited lipid-lowering actions
[158].
Sesquiterpene lactones have exhibited hypoglycemic
effects in STZ-induced diabetic mice by improving the
function of pancreatic islets, increasing glycolysis, and decreasing gluconeogenesis as well as antioxidant and hypolipidemic activities, which have been assessed by using in
vitro assays. The mechanism of antidiabetic activity may
involve an antioxidant effect, improving insulin sensitivity,
and stimulation of pancreatic β-cells to secret insulin [159].
Sesquiterpene lactones have also shown in vitro inhibitory
effects on α-glucosidase and α-amylase [160]. They can be
used for the treatment of diabetes through the regulation of
nuclear factor kappa-light-chain-enhancer of activated
B cells (NF-κB) and mitogen-activated protein kinase
(MAPK) signaling pathway [158, 161]. They have also reduced the production of chemokines, such as MCP-1, TGFβ1, and FN, activate NF-κB, and inhibited sugar-induced
degradation of IκBα, confirming the efficacy of sesquiterpene lactones as drug candidates for the treatment of diabetic nephropathy [158, 162].
β-Caryophyllene, as a sesquiterpene lactone derivative,
has shown antihyperglycemic activity in STZ-induced diabetic rats. Oral administration of β-caryophyllene significantly decreased glucose and increased insulin levels.
Moreover, reversing the glycoprotein levels in plasma and
tissues of diabetic rats to near normal and decreasing
proinflammatory cytokines detected using histological and
immunohistochemical studies demonstrated the antioxidant
capacity of this compound [163, 164]. It should be noted that
chronic use of β-caryophyllene has also depicted good results in the prevention or reduction of diabetes-related
neuropathy and depressive-like behavior in mice (assessed
by marbles test) [165].
13
4.2.2. Flavonoids. Flavonoids are one of the major components of Centaurea spp. Four flavonoids including scutellarein, nepetin, apigenin, and hispidulin were evaluated
for their α-glucosidase inhibitory effects comparing with
acarbose and the order of the activity was obtained as
scutellarein > nepetin > apigenin > hispidulin > acarbose.
Also, the synergistic effects from the combination of each
flavonoid with acarbose at different concentrations were
observed. It was perceived that the best synergistic effect was
related to the combined apigenin-acarbose which acted as a
noncompetitive inhibitor [166].
The antihyperglycemic effect of apigenin may be related
to the inhibition of α-glucosidase, preventing oxidative
stress conditions, decreasing insulin resistance, decreasing
hepatic gluconeogenic enzymes activity, and increasing
serum insulin levels [167–169]. Apigenin can enhance the
metabolism of glucose via suppression of the activities of
gluconeogenic enzymes and aldose reductase. It also prevents diabetic complications such as cataracts, retinopathy,
and neuropathy due to the intracellular sorbitol accumulation. Glucose is converted to sorbitol in the polyol pathway, catalyzed by aldose reductase [170].
Vitexin and isovitexin are two apigenin isomers, and
their α-amylase inhibitory effects and antioxidant potentials
have been investigated via in vitro assays. Vitexin and
isovitexin exhibited significant anti-α-amylase activity with
IC50values of 4.6 and 13.8 μM, respectively. Also, antioxidant
activity was assayed through DPPH free radical scavenging
assay, which showed IC50 values of 92.5 and 115.4 μM, respectively [171]. Vitexin also depicted inhibitory effect on
α-glucosidase (IC50 = 52.805 μM) which was comparable
with that of acarbose (IC50 = 375 μM) [172]. In addition,
computer-aided studies of vitexin-amylase, isovitexin-amylase, and vitexin-glucosidase complexes in the active site of
related enzymes confirmed the construction of desired interactions with amino acid residues [171, 172]. Another in
vitro study using cell culture revealed that vitexin protected
pancreatic β-cells from high-glucose-induced damage,
inhibited islet β-cell apoptosis, and improved insulin release
and sensitivity. The underlying mechanism may increase the
expression of transcription factor Nrf2, resulting in increased intracellular antioxidant molecules, and suppress the
inflammatory signaling pathway. Besides, vitexin enhances
insulin production by activating insulin signaling via the
activation of phosphorylation of IR, IRS-1, and IRS-2 [173].
Hispidulin is another important flavonoid compound
inducing antidiabetic activity. Oral administration of hispidulin to STZ-induced hyperglycemia mice effectively
mitigated postprandial and fasting hyperglycemia and glucose tolerance, which was associated with a dual mechanism,
promoting β-cell function and suppressing hepatic glucose
production [174].
Kaempferol has also depicted remarkable α-glucosidase and α-amylase inhibitory activity [175, 176]. Oral
administration of kaempferol significantly improved
blood glucose control in obese mice, which was associated
with suppressing hepatic gluconeogenesis and improving
insulin sensitivity and secretion [177, 178]. It was found
that kaempferol-3-O-rutinoside was also a potent
14
inhibitor of α-glucosidase, being over 8 times more active
than the reference drug, acarbose, under in vitro conditions [179].
Astragalin has shown hypoglycemic activity on Wistar
rats (10 mg/kg) and improved insulin secretion in the glucose tolerance test. Investigation of isolated pancreatic cells
treated with astragalin (100 μM) led to Ca2+ influx stimulation via a mechanism involving ATP-dependent potassium channels, L-type voltage-dependent calcium channels,
the sarco/endoplasmic reticulum calcium transport ATPase
(SERCA), and PKC and PKA (protein kinase) [180].
Rutin is also an important flavonoid possessing antihyperglycemic effects via various mechanisms, including
decrease of carbohydrates absorption from the small intestine, inhibition of tissue gluconeogenesis, increase of
tissue glucose uptake, stimulation of insulin secretion from
β-cells, and protecting Langerhans islet against degeneration. Rutin also decreases the formation of sorbitol, reactive
oxygen species, advanced glycation end-product precursors,
and inflammatory cytokines [181].
Luteolin and luteolin 7-O-glucoside have shown good
α-glucosidase inhibitory activity. However, luteolin was
found to be more potent than acarbose by the inhibition of
36% at the concentration of 0.5 mg/ml. Although luteolin
could inhibit α-amylase effectively (IC50 in the range of 50 to
500 μg/ml), it was less potent than acarbose [182].
Jaceosidin is another flavonoid compound, and its
antihyperglycemic capacity has been assessed through
various in vivo studies. The results showed that jaceosidin
supplementation significantly lowered fasting blood glucose
levels and reduced insulin resistance. As it was also found
that jaceosidin supplementation increased antioxidant capacity by enhancement of catalase and GSH-px activities, a
relevant relationship between antioxidant and antihyperglycemic effects of jaceosidin can be concluded.
Jaceosidin could improve endoplasmic reticulum stress and
attenuate insulin resistance via SERCA2b (sarco/endoplasmic reticulum Ca2+-ATPase 2b) upregulation in mice
skeletal muscles [183, 184].
Hesperidin has shown antidiabetic activity. It has
inhibited obesity, hyperglycemia, and hyperlipidemia, and
decreased insulin resistance. These effects might be closely
related to the activation of AMPK, which regulate the insulin
signaling pathway and lipid metabolism [185]. Hesperidin
ameliorates pancreatic β-cell dysfunction and apoptosis in a
streptozotocin-induced diabetic rat model [186].
The antidiabetic activity of quercetin is also important. It
has reduced fasting and postprandial hyperglycemia in an
animal model of DM [187]. An in vivo study revealed the
hypoglycemic effects of quercetin, but no changes were
observed in the activity of lipogenic enzymes and lipoprotein
lipase. It can be concluded that the antidiabetic activity of
quercetin is comparable with that of antiobesity activity
[188]. There are different reports on the α-glucosidase inhibitory effect of quercetin, which describe its multilateral
antidiabetic activity [187, 189, 190].
Oral administration of catechin to STZ-induced diabetic
rats resulted in a potential agonist characteristic that is
capable of activating the insulin receptors and producing a
Evidence-Based Complementary and Alternative Medicine
glucose tolerance pattern. The hypoglycemic effect of catechin is associated with its insulin mimetic activity [191]. It
has been indicated that catechin significantly decreased the
different lipid parameters, hepatic, and renal function enzyme levels along with HbA1c levels in diabetic rats while
remarkably increased the high-density lipoprotein (HDL)
levels with values comparable with the glibenclamide. Also,
α-glucosidase and α-amylase inhibitory activity of catechin
have been reported with inhibition percent of 80% and 79%,
respectively [192].
4.2.3. Phenolic Compounds. Phenolic compounds have
shown versatile and attractive antidiabetic activity. Caffeic
acid, a known phenolic acid compound, could protect mice
pancreatic islets from oxidative stress induced by multiwalled carbon nanotubes (MWCNTs) [193]. Investigation of
the effect of caffeic acid and cinnamic acid on glucose uptake
in TNF-R-induced insulin-resistant hepatocytes showed that
they may eliminate insulin resistance by improving insulin
signaling and enhancing glucose uptake in insulin-resistant
cells, which described their antihyperglycemic potential
[194]. In another report, glucose uptake into the isolated
adipocytes was raised by caffeic acid. The increase of glucose
utilization by caffeic acid seems to be responsible for lowering plasma glucose [195].
Chlorogenic acid could also reduce fasting blood glucose
levels [196–198]. It has shown an inhibitory effect on
α-amylase as potent as acarbose; however, its α-glucosidase
inhibitory activity was far weaker than that of acarbose
[199, 200].
The effect of phenolic compounds, particularly in the
management of type 2 diabetes, has attracted lots of attention [201]. They are characterized by the presence of
hydroxyl group(s) on the aryl moiety and endorsed by their
antioxidant activity due to high potency of hydroxyl groups
as hydrogen donors [202]. As it has been accepted that the
formation of reactive oxygen species (ROS) is associated
with hyperglycemia [203], using antioxidants is preferred to
treat and reduce the complications of DM. Also, it has been
proven that consuming a diet low in fat and rich in antioxidants may reduce the risk of obesity and insulin resistance [204–207].
Phenolic compounds comprise a wide range of phenolic
acids and flavonoids. Flavonoids in turn contain anthocyanin pigments, flavonols, flavones, flavanols, and isoflavones. Polymerization of flavanols leads to the formation
of tannins in which the esterification of phenolic groups
affords cyclic chromenones such as ellagic acid. However,
condensed tannins known as proanthocyanidins, for example, catechin, epicatechin, and gallocatechin, are obtained
from the condensation of flavanols [208].
Centaurea spp. have been frequently reported to possess
anthocyanins [207, 209–211] and their biological activities such
as antioxidant, antiallergic, anti-inflammatory, antiviral, antiproliferative, antimutagenic, antimicrobial, and anticarcinogenic activities. Also, different properties such as improvement
of microcirculation, protection from cardiovascular damage
and allergy, prevention of peripheral capillary fragility,
Evidence-Based Complementary and Alternative Medicine
prevention of diabetes, and vision improvement are fully
considered in the literature [207, 212–222]. Also, the role of
anthocyanins is well described for their effect on the prevention
of diabetic cataracts [207, 218, 223]. The presence of apigenin in
Centaurea spp. [224] has been confirmed, and its activity against
thyroid neoplasms as well as anxiolytic, anti-inflammatory, and
antinociceptive properties has been reported [225–227]. The
presence of flavonoids in C. bornmuelleri is significant and
might be responsible for the desired activity [67]. The phytochemical analysis of C. calcitrapa proved the presence of sterols,
sesquiterpene lactones, and their closely related group of triterpenoids, bisabolenes, lignans, and flavonoids as the main
secondary metabolites [124–130]. C. hypoleuca contains higher
amounts of catechin and chlorogenic acid than the other
phenolic compounds, which are known to be responsible for
various biological activities such as antioxidant, neuroprotective, antidiabetic, hepatoprotective, and antiarthritic
properties [72, 147–149]. High levels of apigenin (2472 μg/g
extract), known as a common dietary flavonoid, has
absorbed attention in C. saligna. In silico study has confirmed the construction of H-bonding and pi-pi stacking
interactions between apigenin and the α-glucosidase active
site [74]. Chlorogenic acid has been identified as the main
phenolic compound in C. triumfettii [14]. C. karduchorum
is known to possess abundant amounts of phenolic compounds, mainly luteolin glycosides (glucoside and glucuronide) and chlorogenic acid [73]. Some studies confirmed
the activity of luteolin and/or its glycosides against diabetes
and neurodegenerative diseases through the reduction of
glucose uptake, oxidative stress, and inflammation [151].
Chlorogenic acid has chemopreventive and hypoglycemic
effects [150], and it is the main component of medicinal
plants characterized by their antioxidant, anti-inflammatory, and enzyme inhibitory activities [150, 189, 228].
C. bruguierana possessed sesquiterpene lactones and flavonoids (kaempferol, rutin, and quercetin) [77, 104, 120].
Also, the plant has been documented for its antiplasmodial
and antipeptic ulcer effects [77, 229, 230]. The antidiabetic
property of C. karduchorum as a herbal tea is directly
dependent on the high levels of bioactive phenolic derivatives profiting from synergistic interactions of those
compounds [73]. The presence of terpenes has been confirmed through qualitative analysis in C. papposa, which
may explain the favorite activity toward α-glucosidase
[154]. High total phenolic and flavonoid contents of
C. pulchella and C. urvillei, respectively, may explain their
antidiabetic activity [70]. Phytochemical examination of
aerial parts of C. horrida indicated the presence of pentacyclic triterpenes, sterol glucoside, quinic acid derivatives, phenolic acid derivatives, and flavonoids as well as
horridin [143, 144].
As mentioned above, discussed species of Centaurea are
known to possess a high content of phenolic compounds,
which explains their antitype 2 DM activity.
Inhibition of α-glucosidase and α-amylase has been
found to be a versatile tool for the treatment of type 2 diabetes [231, 232]. Apart from synthetic compounds
[233–237], a wide spectrum of medicinal plants have been
introduced to possess those enzymes inhibitory activity
15
[238], and flavonoids have been well described in this field
[239]. Amphiphilic property of phenolic moiety provides
favorite interactions with enzymes via the construction of Hbonding and hydrophobic interactions with the polar groups
of enzymes and hydrophobic amino acid residues,
respectively.
An important point comes back to side effects related to
α-amylase inhibitors. They include abdominal distention,
flatulence, meteorism, and possibly diarrhea which are
consequence of high activity of the enzyme. It seems that
extreme inhibition of pancreatic α-amylase results in the
abnormal bacterial fermentation of undigested carbohydrates in the colon [240–242]. In this respect, dual inhibitors
such as C. saligna and C. karduchorum possessing weak
inhibition of α-amylase and high inhibition of α-glucosidase
are desirable for the treatment of type 2 DM.
Finally, the efficacy of Centaurea spp. under in vivo
conditions has followed various mechanisms such as lowering blood glucose levels, stimulation of hepatic glycogenolysis, inhibition of gluconeogenesis, and insulin
secretion and circulation.
5. Conclusion
In conclusion, the antidiabetic activity of some Centaurea spp.,
which has been studied for controlling hyperglycemia, was
reviewed. The results obtained from in vitro and in vivo studies
confirmed the efficacy of Centaurea spp. for the treatment of
type 2 DM. In vitro assays generally focused on the α-glucosidase and α-amylase inhibitory activity, and the effectiveness
of C. bornmuelleri, C. calcitrapa, C. centaurium, C. drabifolia,
C. depressa, C. fenzlii, C. hypoleuca, C. karduchorum,
C. kotschyi, C. papposa, C. patula, C. pulchella, C. saligna,
C. tchihacheffii, C. triumfettii, and C. urvillei has been investigated. Among them, dichloromethane extract of C. papposa
was found to be the most potent inhibitor of α-glucosidase, and
the n-hexane extract of roots of C. centaurium showed the
highest activity toward α-amylase (Table 1). In vivo studies of
C. alexanderina, C. aspera, C. bruguierana, C. corubionensis,
and C. horrida revealed that C. horrida and C. bruguierana
were found to be more potent than glibenclamide and C.
corubionensis was comparable with tolbutamide. These results
demonstrated that Centaurea spp. deserve to be widely studied
through clinical trials to prove their antidiabetic effects. Also,
data related to the acute and chronic toxicity are in high demand to develop safe Centaurea spp.-based supplements and
drugs against type 2 DM.
Data Availability
The data supporting this review are from the previously
reported studies and data sets which have been cited. The
data used to support the findings of this study are available
from the corresponding author upon request.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
16
Evidence-Based Complementary and Alternative Medicine
Authors’ Contributions
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Samaneh Fattaheian-Dehkordi and Reza Hojjatifard contributed to the literature review and writing the manuscript.
Mina Saeedi and Mahnaz Khanavi carried out the supervision, methodology, writing, reviewing, and editing.
Acknowledgments
The authors would like to thank the partial support from
Tehran University of Medical Sciences.
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