Nutrients 2015, 7, 7708-7728; doi:10.

3390/nu7095361
OPEN ACCESS

nutrients
ISSN 2072-6643
www.mdpi.com/journal/nutrients
Review

Polyphenolic Composition of Crataegus monogyna Jacq.: From

Chemistry to Medical Applications
Seyed Fazel Nabavi 1 , Solomon Habtemariam 2 , Touqeer Ahmed 3 , Antoni Sureda 4 ,
Maria Daglia 5, *, Eduardo Sobarzo-Sánchez 6 and Seyed Mohammad Nabavi 1, *

1
Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences,
Tehran 1193653471, Iran; E-Mail: [email protected]
2
Pharmacognosy Research Laboratories, Medway School of Science, University of Greenwich,
Chatham-Maritime, Kent ME4 4TB, UK; E-Mail: [email protected]
3
Neurobiology Laboratory, Atta-ur-Rahman School of Applied Biosciences,
National University of Sciences and Technology, Sector H-12, Islamabad 44000, Pakistan;
E-Mail: [email protected]
4
Research Group on Community Nutrition and Oxidative Stress, University of Balearic Islands,
and CIBEROBN (Physiopathology of Obesity and Nutrition), Palma de Mallorca E-07122, Spain;
E-Mail: [email protected]
5
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section,
University of Pavia, Via Taramelli 12, Pavia 27100, Italy
6
Laboratory of Pharmaceutical Chemistry, Department of Organic Chemistry, Faculty of Pharmacy,
University of Santiago de Compostela, Galicia 15782, Spain; E-Mail: [email protected]

* Authors to whom correspondence should be addressed; E-Mails: [email protected] (M.D.);

[email protected] (S.M.N.); Tel.: +39-0382-987388 (M.D.); +98-21-8861-7712 (S.M.N.);
Fax: +39-0382-422975 (M.D.); +98-21-8861-7712 (S.M.N.).

Received: 21 June 2015 / Accepted: 27 August 2015 / Published: 11 September 2015

Abstract: The abundance of scientific evidence has shown that many synthetic drugs can
cause serious adverse effects in patients. Recently, the search of natural therapeutic agents
with low adverse effects has attracted much attention. In particular, considerable interest
has focused on edible and medicinal plants, which play an important role in human diet,
and have been used for disease treatment since ancient times. Crataegus monogyna Jacq.
(hawthorn) is one of the most important edible plants of the Rosaceae family and is also
used in traditional medicine. Growing evidence has shown that this plant has various
interesting physiological and pharmacological activities due to the presence of different
bioactive natural compounds. In addition, scientific evidence suggests that the toxicity of
Nutrients 2015, 7 7709

hawthorn is negligible. Therefore, the aim of this paper is to provide a critical review of the
available scientific literature about pharmacological activities as well as botanical aspects,
phytochemistry and clinical impacts of C. monogyna.

Keywords: Crataegus monogyna; hawthorn; catechins; flavones; pharmacological activities

1. Introduction
Natural products have been of great importance in disease treatment since ancient times. In fact, in
traditional medicine, medicinal plants and herbal formulations play a crucial role in the prevention and
mitigation of different human diseases. During the past two decades, herbal medicines have received
considerable attention as novel therapeutic options for human disease treatment [1–5]. It is widely accepted
that the presence of different bioactive compounds is responsible for the pharmacological effects of medicinal
plants, among which edible plants are the most promising, due to their negligible adverse effects [6–8].
Crataegus monogyna Jacq. (common hawthorn) is an endemic member of the Rosaceae family that
grows in Europe, Africa, and Asia, where is commonly found as a shrub or small tree 5–10 m tall [9].
Its small dark-red fruit (commonly called haw), which ripens in mid-autumn, is used for different
culinary purposes, such as the preparation of jellies, jams, and syrups [10]. Scientific evidence has
demonstrated that hawthorn fruit possesses potent antioxidant and free radical scavenging activities, due
to the presence of different bioactive compounds, such as epicatechin, hyperoside, and chlorogenic acid
(Figure 1) [11,12]. These compounds are reported to have many pharmacological effects, including
neuroprotective, hepatoprotective, cardioprotective, nephroprotective, etc. [13,14]. Furthermore, hawthorn
fruit possesses tonic effects on the heart [13]; several studies have shown that it could reduce some
cardiovascular risk factors, such as hypertension, hypercholesterolaemia, etc. [9,15,16]. Despite this
growing body of evidence, to date there has been little attempt towards a coherent understanding of the
potential health effects of hawthorn. Therefore, the aim of this paper is to provide a critical review of the
available literature, regarding traditional use, chemical composition, biological, pharmacological, and
toxicological Nutrients
effects 2015,
of hawthorn.
7 3

FigureFigure
1. The classes
1. The classesof C.monogyna
of C. monogyna flavonoids.
flavonoids.

2. Methods

This study consists of an up-to-date review of the literature, which contains data about chemical
Nutrients 2015, 7 7710

2. Methods

This study consists of an up-to-date review of the literature, which contains data about chemical
composition, pharmacological studies, and medical applications of C. monogyna. Criteria for selecting
the material were as follows: a search was conducted on the PubMed database [17], using the keywords
“Crataegus monogyna”. The results returned 88 papers up to 2015; these were summarized and critically
discussed to provide a consistent review. A second search was conducted on the ClinicalTrials.gov
database [18], using the keywords “hawthorn” and “Crataegus monogyna”; this returned 23 clinical
trials on this plant, which are summarized in Table 1.
In the following sections traditional uses, phytochemistry, biological and pharmacological effects,
adverse effects, drug interaction and clinical impact of C. monogyna will be discussed.

Table 1. Details of completed clinical trials according to our search with keywords
“hawthorn” and “Crataegus monogyna”.

NCT Number Study Type Conditions Study

Prehypertension; Nitric Oxide Mediated Vasodilatory

NCT01331486 Interventional
Mild Hypertension Response to Hawthorn Standardized Extract
Association of Passiflora Incarnata L; Crataegus Oxyacantha L
NCT00794456 Interventional Anxiety Disorder
and Salix Alba L. on Mild and Moderate Anxiety
Pharmacokinetic and Pharmacodynamic
NCT00006330 Interventional Heart Diseases
Interaction Study of Digoxin and Hawthorn
Hawthorn Extract Randomized Blinded
NCT00343902 Interventional Chronic Heart Failure
Chronic Heart Failure (HERB CHF) Trial
Evaluation of Daytime Corneal Swelling
NCT01482819 Interventional Myopia
During Wear of Galyfilcon A Lenses
Effect of Remifentanil on Electroencephalographic
NCT00455026 Interventional Depth of Anesthesia
BAR Index During Propofol Anesthesia
Quantifying Nitrous Oxide Effect on Depth of Anesthesia
NCT00226837 Interventional Depth of Anesthesia
Using Theoretically Based Time Series Modelling
NCT01444287 Interventional Myopia Daytime Corneal Swelling During Wear of Narafilcon B Lenses
Comparison of Senofilcon A Toric Lenses to
NCT00762502 Interventional Astigmatism
Balafilcon A Toric Lenses Over
Extended Wear Period
A Comparison of Two Ways to Manage
NCT00027352 Interventional HIV Infections
Anti-HIV Treatment (The SMART Study)

3. Traditional Uses of C. Monogyna

In both Europe and China, hawthorn fruit is commonly used for preparation of many foodstuffs, such
as jam, jelly, drink, and wine [9]. In traditional medicine, hawthorn has been widely used to treat human
diseases [11,14]. Its medical properties were first described by Dioscorides in De Materia Medica,
first century A. D., which formed the core of the European pre-modern pharmacopoeia. In Traditional
Chinese Medicine (TMC), hawthorn was mentioned in the first state-approved pharmacopoeia: the Tang
Ben Cao, 659 A.D. In Europe the most common species used for medicinal purposes are C. monogyna
and Crataegus laevigata (Poir.) DC. (which is the accepted name of Crataegus oxyacantha), while in
Nutrients 2015, 7 7711

China, Crataegus cuneata Siebold & Zucc. and Crataegus pinnatiftida Bunge are the most well-known
and used species [9,19]. In folk medicine, hawthorn has been used for the treatment of cardiac diseases,
hypertension, hyperlipidemia, and as anti-atherosclerotic agent [15,20,21]. It has been reported to be
especially effective against cardiovascular problems, such as heart failure, hypertension with myocardial
injuries, angina pectoris, arrhythmia, and atherosclerosis. In addition, it has been used for improving
blood circulation system, as well as blood stasis elimination [15]. Hawthorn has also been used for
the treatment of gastrointestinal diseases, stimulation of digestion, and promotion of stomach functions.
Moreover, hawthorn had application in the treatment of indigestion, epigastric distension, abdominal
pain, and diarrhea. In the European tradition, hawthorn is also used as an anti-spasmodic, cardiotonic,
astringent, and diuretic agent [22–24].
4. Phytochemistry of C. Monogyna
In view of the traditional medicinal uses of C. monogyna, modern scientists have extensively
investigated the chemical constituents, to which the pharmacological effects could be attributed. The
secondary metabolites, extracted from the different parts of the plant, range from simple fatty acids
to terpenoid and polyphenolic compounds. Among these latter, many polyphenols were detected in
C. monogyna, especially in the plants grown in Chile [25]. Several compounds possess antioxidant
properties; these include chlorogenic acid, epicatechin, hyperoside, quercetin, rutin, vitexin, and
procyanidins [26–28]. Generally, flavonoids, particularly flavonols and flavones, are known to be
abundant in flower buds, while proanthocyanidins are found in higher amount in unripe fruits [29].
In hawthorn, using capillary zone electrophoresis, HPLC, and spectrophotometric analyses, the highest
level of flavonoids (rutin, vitexin, vitexin-211 -O-rhamnoside, and hyperoside) was registered in the leaves
collected from the top branches of the trees [30]. In addition to the polyphenolic-based antioxidant
agents, a number of other compounds have been found, which may contribute to the nutritional value
and medicinal properties of the plant. For example, the flowers contain high levels of tocopherols,
ascorbic acid, and show a good n-6/n-3 fatty acid ratio, in comparison with ripened fruits, while unripe
fruits generally contain the highest level of polyunsaturated fatty acids [11].
In the following paragraphs, the main C. monogyna chemical classes of biological significance will
be systematically presented.
4.1. Flavonoids
Flavonoids are a class of polyphenolic compounds that are ubiquitously distributed in the plant
kingdom. Structurally, they are composed of two six-member aromatic rings (A and B) joined together
by a three-carbon chain that may cyclize to form the third ring, C (1). Depending on the position
of the B-ring bond on the three-carbon linking chain (carbon-2, 3, or 4 position) or the chemistry of
the linking chain (e.g., presence/absence of a double bond, cyclization, presence/absence of a ketone
functional group, etc.), flavonoids are further subdivided into several classes, such as flavones, flavonols,
flavanones, flavans, anthocyanidins, isoflavones, neoflavones, and chalcones. Due to their numerous
pharmacological activities, ranging from antioxidant capacity to protective activity against chronic
disease, such as cancer, diabetes, and inflammation, flavonoids are by far the most studied classes of
secondary plant metabolites [31–34]. The chemical structure of the flavonoids occurring in C. monogyna
are reported in Figure 1.
Nutrients 2015, 7 7712

4.1.1. Flavan-3-ols

The flavan-3-ol compounds, containing diorthohydroxyl (catechol) function group at ring-B, are
among the most common flavonoids known to date. Based on the C-2 and C-3 chiral centers, four
stereoisomers, (˘)-catechins, and (˘)-epicatechins (Figure 2, compound numbers 6, 7, 8, 9), are possible.
Interestingly, all these forms, either by their own or as part of complex structural components, have been
found in C. monogyna. As a monomer, (´)-epicatechin appears to be abundantly present in the plant,
Nutrients 2015, 7 6
while (+)-catechin is a minor component found both in the aerial parts and cell suspension cultures [13,35].

Figure 2. The flavan-3-ol catechin compounds of C. monogyna.

Figure 2. The flavan-3-ol catechin compounds of C. monogyna.

4.1.2. Procyanidins
4.1.2. Procyanidins

Catechins and
Catechins andepicatechins
epicatechinsoften
oftenundergo
undergooxidation
oxidation reactions
reactions in plants
in plants to form
to form dimers,
dimers, trimmers,
trimmers, and
and oligomeric structures, called procyanidins. These macromolecules are good
oligomeric structures, called procyanidins. These macromolecules are good examples of the larger examples of the larger
proanthocyanidin, or
proanthocyanidin, or condensed
condensed tannins,
tannins, formed
formed by by the
the condensation
condensation of of flavans. The list
flavans. The list of
of dimeric
dimeric
catechins(procyanidins)
catechins (procyanidins)isolated
isolatedfrom
fromvarious
various parts
parts ofof
C.C. monogyna
monogyna include
include B2B2 (compound
(compound number
number 10),10),
B4
B4 (compound
(compound number
number 11), 11),
and and B5 (compound
B5 (compound number
number 12) (Figure
12) (Figure 3), other
3), and and other catechin
catechin combinations
combinations that
could possibly be present. The (−)-epicatechin trimeric (C1, compound number 13) and tetrameric (D1,
that could possibly be present. The (´)-epicatechin trimeric (C1, compound number 13) and tetrameric
(D1, compound
compound numbernumber 14) have
14) have alsoalso
beenbeen identified
identified in in
thethe plant.ToTodate,
plant. date,the
theidentified
identified procyanidins
procyanidins
(compoundnumbers
(compound numbers10,10, 11,11,
12, 12, 13, (Figure
13, 14) 14) (Figure 4) belong
4) belong exclusively
exclusively to B-typetogroup,
B-type group,monomers
in which in which
monomers
are are linked
linked through through
single single
C-4/C-8 or C-4/C-8
C-4/C-6 or C-4/C-6 interflavanol
interflavanol linkages. Theselinkages. These compounds
compounds are also found are
also
in cellfound in cellcultures
suspension suspension
and are mainly
cultures composed
and are mainly of (−)-epicatechin
composed of (´)-epicatechin
units as a majorunits as a major
component and
component and
(+)-catechin as a(+)-catechin as a minor
minor component component [13,36].
[13,36].
 2015, 7
Nutrients 2015,
Nutrients 7713
Nutrients 2015, 77 77

Figure 3.
Figure
Figure 3. Dimeric catechins
3. Dimeric
Dimeric catechins (procyanidins)
catechins (procyanidins) isolated
(procyanidins) isolated from
isolated from various
from various parts
various parts of
parts of C.
of C. monogyna.
C. monogyna.
monogyna.

Figure 4. The (´)-epicatechin trimeric (C1, 13) and tetrameric (D1) of C. monogyna.
Figure
Figure 4.
4. The
The (−)-epicatechin
(−)-epicatechin trimeric
trimeric (C1,
(C1, 13)
13) and
and tetrameric
tetrameric (D1)
(D1) of
of C.
C. monogyna.
monogyna.
Nutrients 2015,
Nutrients 2015, 77 77148
Nutrients 2015, 7 8

4.1.3. Flavones
4.1.3. Flavones and Flavonols
Flavonols
4.1.3. Flavones and
and Flavonols
In C.
In C. monogyna,
monogyna, aa number
number of of flavones
flavones andand flavonols
flavonols with catecholic
catecholic moiety at at ring-B havehave been
In C. monogyna, a number of flavones and flavonols with
with catecholic moiety
moiety at ring-B
ring-B have been been
isolated. Quercetin-3-O-glucoside
isolated. Quercetin-3-O-glucoside (hyperoside, compound
(hyperoside, compound number
number 15,15, Figure
Figure 5), 5), aa flavonol
flavonol glucoside,
glucoside,
isolated. Quercetin-3-O-glucoside (hyperoside, compound number 15, Figure 5), a flavonol glucoside,
has been
has been isolated from
isolated from the
from the callus
thecallus cultures
calluscultures
culturesofofofthe plant
theplant [35].
plant[35]. Hyperoside
[35].Hyperoside
Hyperoside is also known to be one of
of the
has been isolated the is isalso
alsoknown
knownto to be
be one
one of the
the
major components
major components of the
componentsofofthethe flowers [36].
flowers In
[36]. addition to
In addition this compound, a rare C-glycosylated flavone derivative,
major flowers [36]. In addition to this to this compound,
compound, a rare C-glycosylated
a rare C-glycosylated flavone
flavone derivative,
linked to
derivative, glucose and
linked and rhamnose
to glucose (Figure
and(Figure
rhamnose 5, compound numbers
compound
(Figure 5, numbers 16, 18), has also been isolated from the
linked to glucose rhamnose 5, compound 16,numbers
18), has16,also18),been
has also beenfrom
isolated isolated
the
leaves the
from [37]. 8-Methoxykaempferol 3-neohesperidoside and other flavonoids (Figure 6, compound numbers
leaves [37].leaves [37]. 8-Methoxykaempferol
8-Methoxykaempferol 3-neohesperidoside
3-neohesperidoside and other flavonoids
and other flavonoids (Figure 6, (Figure
compound 6, compound
numbers
19, 20, 21)
numbers have
19,have
20, 21)been isolated
have from the bee the
been isolated pollen of C. monogyna, while Nikolov et al. [37] have
19, 20, 21) been isolated from thefrombee pollen beepollen of C. monogyna,
of C. monogyna, while while
Nikolov Nikolov
et al. et
[37] [37]
al. have
identified
have six analogues
identified six analoguesof di-C-glycosylapigenins
of di-C-glycosylapigenins (Figure 7, compounds
(Figure 7, compounds numbers
numbers 22, 22,
23, 23,
24, 24,
25, 25,
26,
identified six analogues of di-C-glycosylapigenins (Figure 7, compounds numbers 22, 23, 24, 25, 26,
27) 27)
26, from the the leaves.
27) fromfrom leaves.
the leaves.

Figure
Figure 5.
5. Isolated flavonols
flavonols with
with catecholic
catecholic moiety
moiety at
at ring-B.
ring-B.
Figure 5. Isolated flavonols with catecholic moiety at ring-B.

Figure 6. 8-Methoxykaempferol 3-neohesperidoside and other flavonoids of the bee pollen

Figure 6. 8-Methoxykaempferol 3-neohesperidoside and other flavonoids of the bee pollen
Figure 6. 8-Methoxykaempferol 3-neohesperidoside and other flavonoids of the bee pollen
of C. monogyna.
of C. monogyna.
of C. monogyna.
Nutrients 2015, 7 7715
Nutrients 2015, 7 9

Figure 7. Analogues of di-C-glycosylapigenins of C. monogyna leaves.

Figure 7. Analogues of di-C-glycosylapigenins of C. monogyna leaves.
4.1.4. Anthocyanin and Anthocyanidins
4.1.4. Anthocyanin and Anthocyanidins
Anthocyanidin glycosides (anthocyanins) are the main constituents of flowers, giving them their
Anthocyanidin glycosides (anthocyanins) are the main constituents of flowers, giving them their
distinctive colour. Therefore, the identification of cyanidin-3-O-galactoside (Figure 8, compound
distinctive colour. Therefore, the identification of cyanidin-3-O-galactoside (Figure 8, compound number 28)
number 28) as a flower pigment of C. monogyna by Froehlicher et al. [38] is not surprising.
as a flower pigment of C. monogyna by Froehlicher et al. [38] is not surprising.
Nutrients 2015, 7 10
Nutrients 2015, 7 7716
Nutrients 2015, 7 10

Figure 8. Flower
Figure pigment of C.
C. monogyna.
Figure 8. 8. Flowerpigment
Flower pigment of
of C. monogyna.
monogyna.
4.2. Chlorogenic
4.2.Chlorogenic
Chlorogenic Acids
Acids
4.2. Acids
Chlorogenic acid and its isomers (Figure 9, compound numbers 29, 30, 31) are the major components of
Chlorogenicacid
Chlorogenic acidand
anditsitsisomers
isomers(Figure
(Figure9,9, compound
compound numbers
numbers 29,29,
30,30,
31)31)
areare
thethe major
major components
components of
the flowers [38,39] and cell suspension cultures of C. monogyna [35]. An investigation on the flower
of the
the flowers
flowers [38,39]
[38,39] andandcellcell suspension
suspension cultures
cultures ofof C.monogyna
C.has monogyna[35].[35].AnAninvestigation
investigationon onthe
theflower
flower
composition, using HPLC–DAD–ESI/MS analysis, indicated the presence of other caffeoylquinic
composition,
composition, using HPLC–DAD–ESI/MS
using
acids, including HPLC–DAD–ESI/MS analysis,
analysis,
3- and 4-O-caffeoyl derivatives. has indicated
has indicated
Nevertheless, the presence
the presence
the presence of
of theseof other caffeoylquinic
other
compounds caffeoylquinic
was not
acids, including
acids, confirmed 3-
including throughand 4-O-caffeoyl
3- and 4-O-caffeoyl derivatives. Nevertheless, the presence of these compounds
isolation [36]. derivatives. Nevertheless, the presence of these compounds was wasnot
not
confirmed through
confirmed through isolation
isolation [36].
[36].

Figure 9. Chlorogenic acid and its isomers from flowers and cell suspension cultures of C.
monogyna.
Figure 9. Chlorogenic acid and its isomers from flowers and cell suspension cultures of C. monogyna.
Figure 9. Chlorogenic acid and its isomers from flowers and cell suspension cultures of C.
monogyna.
4.3. Triterpenes

By using GC-MS method, Caligiani et al. [40] have identified betulinic (compound number 37),
oleanolic (compound number 32) and ursolic acids (compound number 33) in the flower extracts of
C. monogyna. Butyrospermol (compound number 34), 24-methylen-24-dihydrolanosterol (compound
number 35) and cycloartenol (compound number 36) along with simple aliphatic alcohols have also
been isolated from the aerial parts (including twigs, stems and leaves) of the plant (Figure 10) [41].
 By using GC-MS method, Caligiani et al. [40] have identified betulinic (compound number 37),
oleanolic (compound number 32) and ursolic acids (compound number 33) in the flower extracts of
C. monogyna. Butyrospermol (compound number 34), 24-methylen-24-dihydrolanosterol (compound
number 35)
Nutrients and 7cycloartenol (compound number 36) along with simple aliphatic alcohols have also7717
2015, been
isolated from the aerial parts (including twigs, stems and leaves) of the plant (Figure 10) [41].

Figure 10. Triterpenes of the aerial parts (including twigs, stems and leaves) of C. monogyna.
Figure 10. Triterpenes of the aerial parts (including twigs, stems and leaves) of C. monogyna.

5. Biological and Pharmacological Effects of monogyna Extracts

of C. monogyna Extracts

monogyna has
C. monogyna has aa long
long history
history as medicinal plant used to treat kidney stones, digestive
digestive ailments,
ailments,
dyspnea
dyspnea and
and cardiovascular
cardiovascular disorders.
disorders. In Europe, hawthorn was first documented as a treatment for for
cardiovascular diseases in the late 1800s. Today, C. monogyna
cardiovascular diseases in the late 1800s. Today, monogyna is used primarily to treat cardiovascular
cardiovascular
conditions
conditions due to its ability to reduce important risk factors such as inflammation,
inflammation, hypertension,
hypertension, and
and
thrombosis [42]. Literature search shows that there is substantial evidence supporting the use of
hawthorn in chronic congestive heart failure [43]. Even if Chinese hawthorn (C. pinnatifida) is the
most studied [44–47] in the literature, we can also find some pharmacologic studies where C. monogyna
has been studied in in vitro and ex vivo conditions, and in animal and human studies [43].
Nutrients 2015, 7 7718

5.1. Cardiovascular Effects Registered in in Vitro and ex Vivo Experiments and in Animal Model Systems

In 2006, an in vitro study by Long et al. [48] showed that several hawthorn preparations have
negative chronotropic effects in a cultured neonatal murine cardiomyocyte assay using unpaced cells.
The hawthorn effects resulted to be different from those registered with conventional cardioactive drugs
such as epinephrine; milrinone; ouabain; and similar to that registered for propranolol; regarding its
negative chronotropic activity. Nevertheless; while propanol induced arrhythmia in the majority of the
treated cardiomyocytes; on the contrary; hawthorn extract improved rhythmicity. Moreover, in the same
research aimed at the evaluation of hawthorn extract mechanism of action; the authors showed that the
chronotropic mechanism of action is not due to beta-adrenergic receptor blockade [48]. More recently,
the same authors published the results of further investigation showing that hawthorn extract decreased
the contraction rate of cultured cardiomyocytes via muscarinic receptor activation [16].
A triterpene fraction, isolated from the hexane extract and containing cycloartenol as the main
component (80.87%), was tested for its anti-inflammatory activity in experimental animals in which
inflammation was induced by carrageenan. In rats, at the highest oral dose (40 mg¨ kg´1 ), the hind-paw
edema inhibition was 61.5% and 52.5% at 3 and 5 h of treatment, respectively. At the doses of 10, 20,
and 40 mg¨ kg´1 , peritoneal leucocyte infiltration inhibition was 41.9%, 64.7%, and 89.4%, respectively.
The same triterpene fraction was also submitted to an in vitro test to verify its capacity to inhibit
phospholipase A2 . The results showed that it had weak inhibitory capacity. These results suggest that
this C. monogyna fraction exerts in vivo anti-inflammatory activity [49].
The effects of the main flavonoids occurring in hawthorn, at concentrations ranging from 10´7 to
5 ˆ 10´4 mol/L, were tested in Langendorff perfused isolated guinea pig hearts. At the highest tested
concentration (0.5 mmol/L), O-glycosides luteolin-7-glucoside, hyperoside, and rutin increased the
coronary flow (by about 186%, 66%, and 66%, respectively), and the relaxation velocity (by about
104%, 62%, and 73%, respectively), suggesting a potential health benefit on cardiac functions [50].
More recently, Attard et al. showed the inhibitory activity of the hydroethanolic extract against
angiotensin-converting enzyme (ACE) [51]. The study of the chemical composition of this extract
showed the presence of triterpenic acids, flavonoids and coumarins. The hydroethanolic extract,
oleanolic acid (one of the main components of the extract), and captopril (used as positive control)
showed IC values of 335.00 µg/mL, 3.61 µM, and 46.9 nM, respectively. These results indicated the
anti-ACE activity of oleanolic acid extracted from C. monogyna. In 2013, Ferrugia et al. confirmed
these results showing that terpenes possess in silico predicted ligand binding affinities to ACE receptors
higher than that registered for captopril, enalaprilat and lisinopril [52].
Thrombosis is another important mechanism of development of cardiovascular disease. The ethanolic
extract obtained from C. monogyna leaves was investigated for its anti-thrombotic effect in an animal
model system in which tail thrombosis was induced by carrageenan. At the doses of 200 and 300 mg/kg,
the extract resulted to be able to reduce the lengths of tail thrombosis in comparison to heparin, used as
a positive control. The anti-thrombotic effect decreased after 48 and 72 h, nevertheless, the registered
decrease was still significant after 72 h when the highest dose (300 mg/kg) was administered. The authors
conclude that C. monogyna ethanolic extract could be used as a therapeutic agent or complementary
treatment against thrombosis [53].
Nutrients 2015, 7 7719

5.2. Effect on the Nervous System

In the Mongolian gerbil stroke model, hawthorn flavonoids decreased reactive oxygen species
production in brain homogenates in a dose-dependent manner [54]; moreover, they reduced the
inflammatory cytokines levels and showed protective effects in the ischemia/reperfusion injury model [55].
Hawthorn is known to protect the brain against ischemia-reperfusion and to improve behavior [56]. The
underlying mechanism was attributed to the reduction in lipid peroxidation and nitric oxide levels by
decreasing peroxynitrite formation [56]. On the other hand, hawthorn pulp and seed extracts caused
central nervous system (CNS) depression and decreased exploratory behavior and locomotor activity in
experimental animals [57]. In addition, hawthorn also showed analgesic effects, which were antagonized
by naloxone, suggesting that the opioid receptors mediated analgesic effects [57].

5.3. Other Beneficial Therapeutic Effects of C. Monogyna

Hawthorn extract oral administration causes anti-inflammatory effect in carrageenan-induced rat paw
edema model [39]. The same study reported that at the dose of 200 mg/kg, hawthorn extract shows
72.4% effectiveness, whereas indomethacin showed 50% reduction of rat paw edema at the given dose.
Hawthorn is also reported to possess gastro-protective activity in a rat model of ethanol-induced acute
stress ulcer, which resulted to be comparable to that of ranitidine, used as a positive control [39].
Moreover, the same study reported also the antimicrobial activity of the extract that showed moderate
bactericidal activity, especially against Gram-positive bacteria such as Micrococcus flavus, Bacillus
subtilis, and Lysteria monocytogenes, with no effect against Candida albicans [39]. Belkihir et al.,
who studied the chemical composition of the phenolic extracts prepared from leaf, fruit, and syrup also
investigated the antimicrobial activity of C. monogyna extracts. These extracts, which contain hyperoside
and procyanidins as main compounds, showed high in vitro antioxidant and antiradical activity and
weak antibacterial activity, especially against Gram-positive bacteria such as Staphylococcus aureus
and Streptococcus faecalis [58].
C. monogyna extract was also investigated to identify potential migraine therapeutic agents together
with other vegetable extracts, obtained from eighteen plants that were screened to detect plant constituents
affecting ADP induced platelet aggregation and [14C]5-hydroxytryptamine release. In in vitro conditions
C. monogyna extract inhibited ADP induced human platelet [14C]5-hydroxytryptamine release and
caused significant inhibition of ADP induced platelet aggregation. The authors conclude that further
studies elucidating the compounds responsible for these anti-platelet effects are needed to determine
their exact mechanism of action [59].
Due to the high antioxidant activity, C. monogyna leaf hydroalcoholic extract has been exploited as
an ingredient of innovative pharmaceutical formulations, such as hydrosoluble gels. Several semisolid
formulations were prepared with different hawthorn parts extracts and the hydrosoluble gels, which
presented good physico-chemical properties (consistency, color, and texture) and kept the antioxidant
activity exhibited by the extracts from which they were prepared. These results suggested that
C. monogyna extract is a good ingredient for potential dermopharmaceutical products [60].
Nutrients 2015, 7 7720

5.4. Therapeutic Effects of Drug-Derived Toxicity

Treatment of various toxicities is an important ongoing issue for humankind. Many drugs cause
various types of toxicities, and in particular antineoplastic drugs can cause multiple toxicities. Therefore,
the treatment of drug-derived toxicity is an important ongoing issue for humankind. Cyclophosphamide
is extensively used as an anti-neoplastic agent and possesses potential to cause testicular toxicity [61].
C. monogyna fruit extract has been found to reduce toxicity and improve testes and epididymis weights,
along with improvement in the spermatogenic activity C. monogyna improved cyclosporine-induced
reproductive toxicity: following treatment with fruit extract, an increase in sperm count and decrease
in DNA damage in sperm cells have been registered [62]. C. monogyna has also shown promising
results against doxorubicin toxicities, including reproductive toxicity, rescuing sperm count, and
motility [63]. Hawthorn possesses the ability to reduce the oxidative stress and genotoxicity caused
by the cyclophosphamide in mouse bone marrow cells [64]. Treatment of human subjects with hawthorn
extract protects the isolated blood lymphocytes against methyl methanesulfonate genotoxicity and
reports less binucleated cells (36% protection) in extracted and treated lymphocytes [65]. Similarly,
lymphocytes isolated from hawthorn-treated human subjects, resulted to be protected against gamma
irradiations (cobalt-60 γ irradiation) [66]. These studies suggest the huge potential of hawthorn in the
treatment of various toxicities.

6. Adverse Effects/Toxicity of C. Monogyna

Considering its culinary uses, it can be hypothesized that hawthorn causes negligible adverse
effects [67]. At therapeutic dosages, hawthorn causes very limited adverse effects, such as sweating,
headache, mild rash, palpitations, sleepiness, agitation, and gastrointestinal adverse effects [42].
A systemic review analyzing 5577 patients, to whom standardized hawthorn extracts were administered,
showed that most of the adverse effects ranged from mild to moderate [67]. Up to now, clinical studies
have shown that there are no significant adverse effects associated with hawthorn consumption [67]. The
median lethal dose (LD50 ) for oral administration of hydroalcoholic extract of leaf and fruits of hawthorn
is 18.5 mL/kg in mice and 33.8 mL/kg in rats. In addition, it has been reported that median lethal
dose (LD50 ) for intravenously-administered flavonoid-rich fractions of hawthorn is 1.56 g/kg in mice [9].
However, median lethal dose (LD50 ) for proanthocyanidins fraction is 130 mg/kg (intraperitoneal
injection) and 300 mg/kg (subcutaneous injection) in mice [68].

7. Drug Interactions

Hawthorn may have the potential to interact with vasodilator drugs. In fact, hawthorn may potentiate
or inhibit the actions of drugs used for hypertension, angina, heart failure, and arrhythmias [42].
In addition, hawthorn consumption may have some interactions with drugs, such as beta-blockers,
digitalis, and some hypotensive agents, due to its cardiotonic and hypotensive effects [68].
Nutrients 2015, 7 7721

8. Clinical Impact of C. Monogyna

Due to its minimal adverse effects, its in vitro biological properties, and its pharmacological activities
registered in experimental animals, hawthorn can be used as therapeutic agent for the treatment of various
human diseases. In clinical trials, the most studied hawthorn extracts are WS 1442 and LI 132. WS 1442
(called Crataegutt) is a leaf and flower extract that has a high content of procyanidins (standardized to
18.75%). LI 132 (called Faros) is prepared from the leaves, flowers, and berries and is standardized to
2.2% flavonoids.
The first studies on WS 1442 go back to the 1990s. More recently, Holubarsch et al. in 2000 published
the first paper on the SPICE project, which is the first, international, randomized, placebo-controlled,
double-blind study, aimed to investigate the effect Crataegus Special Extract WS 1442 on mortality of
patients suffering from congestive heart failure [69]. In 2008 [70] the same research group published
the results obtained from this multicenter study, which involved 2681 adults, with NYHA class II or
III CHF and reduced left ventricular ejection fraction (LVEF< or =35%), receiving 900 mg/day WS
1442 or placebo for 24 months (WS 1442: 1338; placebo: 1343). The results showed that WS 1442
had no significant effect on the average time to first cardiac event and on cardiac mortality reduction.
Nevertheless, WS 1442 reduced sudden cardiac death by 39.7% in the treated group in comparison with
placebo group in those patients with less compromised left ventricular function.
In 2001, Zapfe published a randomized, placebo-controlled, double-blind clinical study on the efficacy
and safety of Crataegus extract WS 1442 (standardized to 18.75% oligomeric procyanidines), performed
on 40 female and male outpatients with congestive heart failure NYHA class II, treated for 12 weeks with
either WS 1442 (3 ˆ 1 capsule) or placebo. The registered laboratory parameters and adverse events
showed that WS 1442 was safe and well tolerated. The outcomes were exercise tolerance and difference
of the double product (heart rate ˆ systolic blood pressure ˆ 10´2 ). As regards the first outcome, the
results showed that there was an increase of about 11% in the exercise tolerance (determined with bicycle
exercise testing) in the WS 1442 group and a decrease of about 17% in the placebo group. Moreover,
regarding the difference of the double product, a decrease of 27% in the WS 1442 group and 2.7% in the
placebo group, were registered. In the whole, the data showed Crataegus extract WS 1442 is active in
patients with congestive heart failure corresponding to NYHA class II [71].
In 2003, Degenring et al. showed that another registered Crataegus extract obtained from berries
(Crataegisanr ) resulted to be active and safe against patients with cardiac failure NYHA class II. In fact,
the treatment with Crataegisanr improved the exercise tolerance, without adverse effects, suggesting
that in NYHA II patients there is an improvement in heart failure conditions under long-term therapy
with this standardized extract [72].
In the last decade, other similar clinical studies were performed in which the safety and moderate
beneficial effects in the treatment of chronic heart failure (New York Heart Association classes I to III)
were described [73,74]. These clinical studies prompted Cochrane to publish a systematic review to
define benefits and harms of hawthorn leaf and flower extract for treating patients with chronic heart
failure. As regards the selection criteria, the included studies were randomized, double-blind, and
placebo-controlled. The results of selection showed that fourteen trials met the inclusion criteria, but due
to the fact that they did not all measure the same outcomes and several studies did not explain what kind
of treatments patients were receiving, the clinical trials used for meta-analysis were ten studies, including
Nutrients 2015, 7 7722

855 patients with chronic heart failure. These trials showed improvements in heart failure symptoms
and in the function of the heart. The reported adverse events (i.e., nausea, dizziness, and cardiac and
gastrointestinal complaints) were mild, sporadic and transitory. The conclusion of this meta-analysis
confirm the positive effect of hawthorn extract used in addition to conventional treatments for chronic
heart failure [75].
Moreover, a search on the ClinicalTrials.gov database [18], with keywords “hawthorn” and
“Crataegus monogyna” has shown that there are 23 clinical trials on this plant, of which 11 have been
completed. Our search has also found that there are further four recruited clinical trials and five not yet
recruited ones, while three clinical trials are of unknown status. Table 1 contains titles of completed
clinical trials, their references numbers, study type, as well as disease conditions.

9. Conclusions

In conclusion, hawthorn is both a medicinal plant, which is used in folk medicine, and a common
edible plant, which is widely used for the preparation of different foodstuff. Thus, based on the
common use as traditional medicine and food, C. monogyna can be considered safe. Moreover, clinical
trials showed no significant adverse effects. The present review has shown that hawthorn possesses a
range of pharmacological effects, due to the presence of various bioactive natural compounds, such as
flavanonoids and triterpenic compounds. In particular, hawthorn can be used in the prevention and/or
mitigation of cardiovascular diseases. In fact, it is able to reduce cardiovascular risk factors, such as
hypertension, thrombosis, etc., and has beneficial effects on cardiac functions. Therefore, due to its
multiple health-promoting effects, hawthorn can be recommended for future clinical trials aimed at
examining its beneficial effects. In addition, we recommend that future research on C. monogyna should
focus on:

(1) finding the best cultivation protocols and a way for increasing its production;
(2) finding the bioactive constituents, which are the most responsible for its pharmacological effects
and, thereafter, increasing its production through biotechnological protocols;
(3) increasing the bioavailability of its bioactive constituents;
(4) ascertaining the most effective dose for its clinical efficacy;
(5) finding the exact molecular mechanisms responsible for its pharmacological effects.

Acknowledgments

Antoni Sureda was supported by Spanish Ministry of Health and Consumer Affairs (CIBEROBN
CB12/03/30038).

Author Contributions

Seyed Fazel Nabavi and Eduardo Sobarzo-Sánchez designed the paper, Maria Daglia collected and
selected the literature data, Antoni Sureda analysed the data, Solomon Habtemariam, Touqeer Ahmed,
Maria Daglia and Seyed Mohammad Nabavi wrote the paper. All authors participated in the analysis
and interpretation of literature data, revised the paper and approved the final manuscript.
Nutrients 2015, 7 7723

Conflicts of Interest

The authors declare no conflict of interest.

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