Hawthorn (Crataegus spp.): An Updated Overview on Its Beneficial Properties

Abstract

Medicinal plants, many of which are wild, have recently been under the spotlight worldwide due to growing requests for natural and sustainable eco-compatible remedies for pathological conditions with beneficial health effects that are able to support/supplement a daily diet or to support and/or replace conventional pharmacological therapy. The main requests for these products are: safety, minimum adverse unwanted effects, better efficacy, greater bioavailability, and lower cost when compared with synthetic medications available on the market. One of these popular herbs is hawthorn (Crataegus spp.), belonging to the Rosaceae family, with about 280 species present in Europe, North Africa, West Asia, and North America. Various parts of this herb, including the berries, flowers, and leaves, are rich in nutrients and beneficial bioactive compounds. Its chemical composition has been reported to have many health benefits, including medicinal and nutraceutical properties. Accordingly, the present review gives a snapshot of the in vitro and in vivo therapeutic potential of this herb on human health.

Full text

Perspective
Hawthorn (Crataegus spp.): An Updated Overview on
Its Beneficial Properties
Amirhossein Nazhand 1, Massimo Lucarini 2, *, Alessandra Durazzo 2, Massimo Zaccardelli 3,
Santo Cristarella 4, Selma B. Souto 5, Amélia M. Silva 6,7 , Patrícia Severino 8, 9, 10 ,
Eliana B. Souto 11, 12 and Antonello Santini 13, *
1Department of Biotechnology, Sari Agricultural Science and Natural Resource University,
9th km of Farah Abad Road, Sari 48181 68984, Mazandaran, Iran; nazhand.ah@gmail.com
2CREA-Research Centre for Food and Nutrition, Via Ardeatina 546, 00178 Roma, Italy;
alessandra.durazzo@crea.gov.it
3CREA-Research Centre for Vegetable and Ornamental Crops, Via Cavalleggeri 25,
84098 Pontecagnano (Salerno), Italy; massimo.zaccardelli@crea.gov.it
4Department of Veterinary Sciences, University of Messina, Polo Universitario dell’Annunziata,
98168 Messina, Italy; scristarella@unime.it
5Department of Endocrinology of Braga Hospital, Sete Fontes, São Victor, 4710-243 Braga, Portugal;
sbsouto.md@gmail.com
6
School of Biology and Environment, University of Tr
á
s-os-Montes e Alto Douro (UTAD), Quinta de Prados,
P-5001-801 Vila Real, Portugal; amsilva@utad.pt
7Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB),
University of Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5001-801 Vila Real, Portugal
8Industrial Biotechnology Program, University of Tiradentes (UNIT), Av. Murilo Dantas 300,
Aracaju 49032-490, Brazil; pattypharma@gmail.com
9Tiradentes Institute, 150 Mt Vernon St., Dorchester, MA 02125, USA
10 Laboratory of Nanotechnology and Nanomedicine (LNMED), Institute of Technology and Research (ITP),
Av. Murilo Dantas, 300, Aracaju 49010-390, Brazil
11 Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra,
Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; souto.eliana@gmail.com
12 CEB-Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
13 Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy
*Correspondence: massimo.lucarini@crea.gov.it (M.L.); asantini@unina.it (A.S.);
Tel.: +39-06-51494446 (M.L.); +39-081-253-9317 (A.S.)
Received: 20 April 2020; Accepted: 12 May 2020; Published: 18 May 2020


Abstract:
Medicinal plants, many of which are wild, have recently been under the spotlight worldwide
due to growing requests for natural and sustainable eco-compatible remedies for pathological
conditions with beneficial health effects that are able to support/supplement a daily diet or to support
and/or replace conventional pharmacological therapy. The main requests for these products are:
safety, minimum adverse unwanted effects, better efficacy, greater bioavailability, and lower cost
when compared with synthetic medications available on the market. One of these popular herbs
is hawthorn (Crataegus spp.), belonging to the Rosaceae family, with about 280 species present in
Europe, North Africa, West Asia, and North America. Various parts of this herb, including the
berries, flowers, and leaves, are rich in nutrients and beneficial bioactive compounds. Its chemical
composition has been reported to have many health benefits, including medicinal and nutraceutical
properties. Accordingly, the present review gives a snapshot of the
in vitro
and
in vivo
therapeutic
potential of this herb on human health.
Keywords:
hawthorn; bioactive compounds; Crataegus; biological activity; nutraceuticals; health
benefits; plant extracts
Forests 2020,11, 564; doi:10.3390/f11050564 www.mdpi.com/journal/forests

Forests 2020,11, 564 2 of 21
1. Introduction
Medicinal wild plants and herbs have recently received increased interest worldwide since they
are rich sources of bioactive compounds and for their potential beneficial health properties, which have
often been well known for centuries [
1
–
18
]. The World Health Organization (WHO) reported that about
80% of the world’s population uses traditional drugs, including herbal medicine, for the treatment of
diseases before considering conventional drugs when available [
19
]. One of these interesting popular
medicinal plants is hawthorn (Crataegus spp.), a deciduous branched shrub/small tree that is twisted
and thorny, belonging to the Rosaceae family and Maloideae sub-family. Hawthorn is present worldwide
with about 280 species, among which the most common are: C. monogyna,C. laevigata,C. mexicana and
C. douglasii, grown in Europe, North Africa, West Asia, and North America. The scientific name of
hawthorn comes from the Greek word “kr
à
taigos” which means “strength and robustness” due to its
hard and durable wood. Natural habitats of hawthorn are wooded and sunny areas on predominantly
limestone soils up to 1500 m above sea level. This species is very rustic and is not very water demanding.
C. monogyna has leaves that are 20–60 mm long with a rhomboidal shape that are deeply engraved
and have notched lobes; the flowers are white/pink and form blooms of 5–35 units; the fruits are red
berries of 10 mm when ripened, and contain one seed. Flowering takes place between April and
May, and fruit ripening between September and October. Various parts of this plant—in particular,
the berries, flowers, and leaves—are rich in nutrients, and have been traditionally associated with many
health, medicinal or nutraceutical beneficial health effects [
20
], e.g., anti-microbial, anti-inflammatory,
antioxidant, anti-cancer, and anticoagulant properties. Some of the most relevant properties associated
to this plant are reported in Figure 1. According to its traditional use, and since it is generally recognized
as safe (GRAS), the Committee for Herbal Medicinal Products of the European Medicines Agency
classified hawthorn as a “traditional herbal medicinal product” [
21
,
22
]. This wild plant has been used
as a traditional medicine, herbal drug, and food supplement for centuries [
23
,
24
]. According to the
holistic and traditional approach, hawthorn leaves and flowers are used to prepare infusions that
can be used to control palpitations, tachycardia, and nervousness. Away from meals, hawthorn has
been used against hypertension and, before sleeping, for its relaxing and sedative actions. The berries
promote cardiovascular health, protecting from angina, hypertension, heart failure, cardiac arrhythmias,
myocarditis, arteriosclerosis, insomnia, and anxiety. Moreover, the berries are astringents and diuretics,
and can act against diarrhea, urinary retention, and intestinal cramps. Indigenous peoples from Latin
America use the berries for the preparation of a highly energetic drink called “Pennican”, and, in many
parts of the world, the berries are used to prepare jams and as flavoring for dishes like white meats.
Hawthorn, however, can also have a few collateral effects and contraindications; in particular, it is
not recommended when blood pressure is low. Considering the multiple health properties of this
medicinal wild herb, this review describes the potential use of hawthorn in therapy and as a support
of some human health conditions.

Forests 2020,11, 564 3 of 21
Forests 2020, 11, x FOR PEER REVIEW 3 of 21
Figure 1. Scheme of the hawthorn therapeutic properties.
2. Phytochemical Composition of Hawthorn
Chemical analysis has allowed for the identification of more than 150 bioactive molecules in
hawthorn, including phenolic acids (ferulic, gallic, p-coumaric, syringic, chlorogenic, caffeic),
quercetin, pyrocatechin, phlorodizin, terpenoids, lignans, steroids, organic acids (fumaric, tartaric,
succinic, citric, malic), and sugars (maltose, sucrose, glucose, fructose). These are represented in
Figure 2 [25,26].
Figure 1. Scheme of the hawthorn therapeutic properties.
2. Phytochemical Composition of Hawthorn
Chemical analysis has allowed for the identification of more than 150 bioactive molecules in
hawthorn, including phenolic acids (ferulic, gallic, p-coumaric, syringic, chlorogenic, caffeic), quercetin,
pyrocatechin, phlorodizin, terpenoids, lignans, steroids, organic acids (fumaric, tartaric, succinic, citric,
malic), and sugars (maltose, sucrose, glucose, fructose). These are represented in Figure 2[25,26].

Forests 2020,11, 564 4 of 21
Forests 2020, 11, x FOR PEER REVIEW 4 of 21
Figure 2. Overview of the main compounds found in hawthorn.
Polyphenol compounds from C. oxyacantha extracts, including epicatechin, epicatechin gallate
(ECG), rutin, caffeic, and caftaric acids, were identified using HPLC-DAD and LC-MS/MS
techniques [27]. In a study, UV/MS analysis coupled with 1D/2D nuclear magnetic resonance (NMR)
spectroscopy was used to detect the compounds extracted from the ethyl acetate extract of C.
oxyacantha, which included naringenin, epicatechin, quercetin-3-O-β-glucoside, and quercetin [28].
The presence of rutin and quercetin obtained from C. oxyacantha extracts using HPLC was also
reported [29]. The work of Nabavi et al. focused on the polyphenolic composition of C. monogyna
Figure 2. Overview of the main compounds found in hawthorn.
Polyphenol compounds from C. oxyacantha extracts, including epicatechin, epicatechin gallate
(ECG), rutin, caffeic, and caftaric acids, were identified using HPLC-DAD and LC-MS/MS
techniques [
27
]. In a study, UV/MS analysis coupled with 1D/2D nuclear magnetic resonance
(NMR) spectroscopy was used to detect the compounds extracted from the ethyl acetate extract of
C. oxyacantha, which included naringenin, epicatechin, quercetin-3-O-
β
-glucoside, and quercetin [
28
].
The presence of rutin and quercetin obtained from C. oxyacantha extracts using HPLC was also

Forests 2020,11, 564 5 of 21
reported [
29
]. The work of Nabavi et al. focused on the polyphenolic composition of C. monogyna
Jacq., ranging from its chemistry and composition to its medical applications [
30
]. The recent work of
Cao et al. [
31
] gives an updated snapshot of the water-based extraction of the bioactive principles of
hawthorn, describing the current experimental laboratory research and further valuable information.
In this study, attention has been addressed to the quantitative and qualitative aspects of the extraction,
as well as to the kinetics of the extraction according to the part of the plant (flowers or leaves),
their state (fresh or dried), and the granulometry of the dry plant, also taking into account parameters
like stirring speed, temperature, extraction time, volume of the container (cup, mug or bowl) and
the use of infusion bags. In agreement with green technologies [
32
,
33
], it is worth mentioning the
work of Hu et al. [
34
], which proposed an eco-friendly microwave-assisted extraction of bioactive
compounds from hawthorn leaf combined with ultra-high-performance liquid chromatography
coupled with an ultraviolet detector for the identification and quantification of compounds. In a
recent study, mannose, glucose and fructose were extracted from hawthorn fruits by acid hydrolysis
using 2 M trifluoroacetic acid, and then identified and characterized by gas chromatography/mass
spectrometry [
35
]. Zhao et al. [
36
] used headspace/solid phase microextraction (HS/SPME) coupled with
gas chromatography/mass spectrometry (GC/MS) to determine the chemical composition of hawthorn
fruits, reporting that alcohols and esters are the main compounds present. Salmanian et al. detected
the phenolic acids contained in the hawthorn pulp and seed extract using RP-HPLC and reported that
chlorogenic acid is the main one [
37
]. Liu et al. [
38
] applied HPLC-UV/ESI-MS to determine the phenolic
constituents of hawthorn, which was found to contain C-glycosyl flavones, hyperoside, procyanidins
B2/C1, and epicatechin. Lund et al. [
39
], by using nuclear magnetic resonance (NMR) spectrometry,
identified chlorogenic acid and flavonoids of Crataegus species, including vitexin-2
00
-O-rhamnoside,
rutin, hyperoside, and naringenin. In their study, HPLC-DAD analysis was also used to confirm the
obtained results. The hawthorn seed extract distillation at the optimum temperature (in the range of
211 to 230
◦
C) was analyzed by gas chromatography coupled with a mass spectrometer (GC-MS) to
determine the chemical composition, with the aim of proposing this method as a cost-effective technique
to obtain hawthorn products on an industrial scale [
40
]. The chemical compounds present in Crataegus
species, mainly quercetin, hyperoside, rutin, and vitexin, have been also studied using HPLC-UV and
UV-Vis spectrophotometry [
41
]. The hawthorn fruit examined by spectrophotometry at a wavelength of
285 ±2 nm
revealed the presence of hyperoside flavonoid in an amount up to 0.112–0.183% (w/w) [
42
].
Table 1reports the main compounds found in hawthorn and the methodological and analytical
approach used in their characterization.
Table 1. Identified compounds from hawthorn.
Species Compound Identified Methodological and Analytical
Approach Reference
Crataegus oxyacantha
Epicatechin, epicatechin
gallate (ECG), rutin, cafeic and
caftaric acids
HPLC-DAD and LC-MS/MS [27]
Crataegus oxyacantha
Naringenin, epicatechin,
quercetin-3-O-β-glucoside,
and quercetin
Nuclear magnetic resonance (NMR)
spectroscopy [28]
Crataegus oxyacantha Rutin and Quercetin HPLC [29]
Crataegus pinnatifida Crataequinone A
Nuclear magnetic resonance (NMR)
spectroscopy and electronic circular
dichroism (ECD)
[43]
Crataegus songarica Quercitin 3-O-galactoside and
kaempherol-3-O-glucoside HPLC-DAD-ESI/MS [44]
Crataegus pinnatifida Pinnatifidanin BVI Nuclear magnetic resonance (NMR)
spectroscopy [45]

Forests 2020,11, 564 6 of 21
Table 1. Cont.
Species Compound Identified Methodological and Analytical
Approach Reference
Crataegus pinnatifida Pinnatifidanoside F Nuclear magnetic resonance (NMR)
spectroscopy [46]
Crataegus azarolus var Quercetin 3-O-methyl ether,
3-β-O acetyl ursolic acid Reversed phase HPLC (RP-HPLC) [47]
Crataegus pinnatifida (+)-(7S,8R)-crataegusin A and
(−)-(7R,8S)-crataegusin A Electronic circular dichroism (ECD) [48]
Crataegus pinnatifida Bge
(−)-7S,8R-4,7,9,90-
tetrahydroxy-3,5,30,50-
tetramethoxy-8-O-4
0
-neolignan
Electronic circular dichroism (ECD) and
HPLC [49]
Crataegus pubescens (+)-catechin and
(−)-epicatechin
Micellar electrokinetic chromatography
(MEKC) and HPLC/UV [50]
Crataegus pinnatifida
Chlorogenic acid (CA),
vitexin-400-o-glucoside (VG),
vitexin-200-o-rhamnoside
(VR), orientoside (ORT), rutin
(RT), vitexin (VIT) and
hyperoside (HYP)
HPLC [51]
Crataegus pinnatifida var.
major N.E.Br.
(70S, 80R,
8R)-isolariciresinol-90-β-D
-glucopyranoside and
lyoniside
Nuclear magnetic resonance (NMR)
spectroscopy and LC-MS [52]
3. In Vitro and In Vivo Therapeutic Potentials of Hawthorn: An Updated Snapshot
The evaluation of phytochemical composition can be considered as the first step for the
determination of the beneficial health properties of a plant [
53
,
54
]. Figure 1summarizes the health
properties as reported in the literature from in vitro and in vivo studies.
As indicated above, many beneficial properties have been attributed to hawthorn,
including anticancer [
55
], anti-HIV, anti-diabetic [
56
], and anticoagulant activity [
57
], cardioprotective
effects [
58
–
65
], hepatoprotective effects, antihyperglycemic and antihyperlipidemic activities,
wound healing effects [
66
], antimicrobial effects, gastroprotective effects, treatment of metabolic
syndrome [
67
], regulation of cholesterol homeostasis [
68
], anti-atherosclerosis effects [
69
–
72
], anti-aging
effects [
73
], ischemia protective effects [
74
], treatment of cognitive disorders, neuroprotective effects,
regulating gastrointestinal motility [
75
], anti-inflammatory activities [
76
,
77
], regulation of the gut–brain
axis [
78
], treatment of hypertension [
79
], antioxidant activity [
80
–
85
], anti-hypoxic activities [
86
],
antidepressant effects [
87
], anti-Alzheimer’s effects, and treatment of intestinal microbial disorder [
88
].
In the following sections, an updated snapshot of the various potential therapeutic effects of
hawthorn in vitro and in vivo are described, as well as its beneficial properties for human health.
3.1. Health-Promoting Activities of Hawthorn In Vitro
Many
in vitro
studies reported different health-promoting effects for hawthorn extracts [
89
–
92
].
The administration of homogeneous polysaccharide (HPS) extracted from hawthorn at a concentration
of 125–1000
µ
g/mL showed anticancer activity against a human colon cancer cell line HCT116, after 12 h
by arresting the cell cycle and inducing cell apoptosis through extrinsic and intrinsic mechanisms
using P38 mitogen-activated protein kinase and the phosphatidylinositol-3-kinase/AKT/mammalian
target of rapamycin signaling pathway [
93
]. Hawthorn fruit peel extract exhibited antioxidant activity
(2,2,1-diphenyl-1-picrylhydrazyl (DPPH) IC
50
value of 6.72
µ
g/mL), acetylcholinesterase inhibitory
effects (IC
50
value of 11.72
µ
g/mL), and cytotoxic effects against the human tumor cells SKOV-3 and
MCF-7 (IC
50
values of 80.11
µ
g/mL and 2.76
µ
g/mL, respectively) [
94
]. A recent study concluded
that hawthorn extract-Selenium nano particles caused mitochondrial dysfunction and intracellular

Forests 2020,11, 564 7 of 21
oxidative stress to start the apoptosis of HepG2 cells via the mitochondrial pathway [
95
]. Table 2
reports the results of the main in vitro studies.
Table 2. In vitro reported activities for hawthorn.
Experimental Conditions: In vitro
Activity Effect Reference
Antimicrobial Apigenin-7-O-glucoside and luteolin 3,7-diglucoside extracted from
hawthorn were the most potent chemicals to eliminate
Ureaplasma urealyticum with minimum inhibitory concentration value
ranges of 0.48–3.9 µg/mL and 0.48–1.95 µg/mL, respectively.
[89]
Antioxidant and
anti-inflammatory
Ursolic acid and oleanolic acid extracted from hawthorn showed
anti-inflammatory and antioxidative effects in PC12 cells by decreasing the
cell death induced by 1-methyl-4-phenylpyridinium ions (MPP+) and
hydrogen peroxide (H2O2) as well as reducing lactate dehydrogenase
leakage.
[90]
Anticancer
Crataequinone A exhibited cytotoxic effects on Hep3B and HepG2 cell lines
with IC50 values of 24.90 µM and 12.24 µM, respectively.
[43]
Anticancer Quercitin 3-O-galactoside and kaempherol-3-O-glucoside inhibited the
culture of MCF-7 human breast cancer cells.
[44]
Anticancer
Pinnatifidanin BVI extracted from hawthorn had a preventive effect against
Mrc5 human lung cells.
[45]
Antioxidant Naturally occurring compounds from ethanolic and aqueous extracts of
C. monogyna showed antioxidant and hydrogen peroxide scavenging
properties.
[91]
Anti-inflammatory
Aqueous hawthorn fruit extract inhibited the expression of ILInterleukin-6,
Interleukin-1β, Tumor necrosis factor-αand cyclooxygenase-2 genes,
and prevented NO formation in RAW 264.7 cells.
[92]
The use of hawthorn induced anti-inflammatory properties through the modulation of
lipopolysaccharide-induced pro-inflammatory (Interleukin-6 and Tumor necrosis factor-
α
) and
anti-inflammatory (Interleukin-10) cytokines [
96
]. The flavonoids extracted from hawthorn could treat
inflammatory bowel disease via the prevention of the nuclear factor kappa-light-chain-enhancer of
activated B cells and extra cellular signal-regulated kinase 1/2 activity, the suppression of myosin light
chain kinase and phosphorylatedmyosin light chain upregulation, the suppression of the production of
inflammatory cytokines in Caco-2 cells, and the alleviation of inflammatory cytokine-induced intestinal
barrier deficit [97].
The administration of C. orientalis berries and leaves at the concentration of 0.4 mg/mL
displayed a DPPH radical scavenging effect and anti-inflammatory activity via the inhibition of
12- lipoxygenase (12-LOX) and cyclooxygenase-1 (COX-1), thereby impeding the generation of
thromboxane B2 (up to 55.2%) and 12-Hydroxyheptadecatrienoic acid (up to 68.9%) [
98
]. In a
study by Wyspianska et al., the procyanidins obtained from hawthorn bark extract revealed
anti-inflammatory and antioxidant properties [
99
]. Furthermore, neolignans obtained from the
ethanolic extract of hawthorn seeds exhibited anti-inflammatory and antioxidant properties,
most likely due to the prevention of tumor necrosis factor-
α
) via the compounds 7
0
,8
0
-threo,7S,8R-1-
[4-[(2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-1-(hydroxymethyl)ethoxy]-3-methoxyphenyl]-1,2,3-
propanetriol and 7
0
,8
0
-threo,7R, 8R-1-[4-[(2-hydroxy-2-(4-hydroxyl-3-methoxyphenyl)-1-(hydro-
xymethyl)ethoxy]-3-methoxyphenyl]-1,2,3-propanetriol, and the inhibition of NO production via
leptolepisol D [100].
The antioxidant and anti-inflammatory bioassay-guided fractionation of the seed extract of
mountain hawthorn, C. pinnatifida, led to the isolation of eight new lignans called hawthornnins,
which showed different promising activities by scavenging free radicals and inhibiting TNF-
α
and
NO production [
101
]. Zhao et al. observed
α
-glucosidase inhibitory and antioxidant activity for

Forests 2020,11, 564 8 of 21
C. pinnatifida fruit [
102
]. In another study, 8-O-4
0
neolignans extracted from C. pinnatifida seeds blocked
the activity of tyrosinase by 66.67%, in addition to exhibiting antioxidant activity [
103
].
Among the triterpenoids extracted from hawthorn berries, the compounds 3
β
,6
β
,18
β
,23-
tetrahydroxy-olean-12-en-28-oic acid, 2
α
,3
β
,6
β
,18
β
-tetrahydroxy-olean-12-en-28-oic acid, and 2
α
,3
β
,
6
β
,18
β
,23-pentahydroxy-olean-12-en-28-oic acid had antioxidant functions and could inhibit the
proliferation of MCF-7 and HepG2 cells (EC
50
= <5
µ
M) [
104
]. In a study by Chai et al. the proanthocyanidin
compounds extracted from Chinese hawthorn fruits were characterized by HPLC-ESI-MS and
MALDI-TOF-MS and examined for their bioactivities. The results showed anti-tyrosinase properties
by preventing tyrosinases such as diphenolase and monophenolase and antioxidant activity [105].
Hawthorn seed extract at a concentration of 50
µ
M protected SH-SY5Y cells from damage
through cell apoptosis prevention due to the presence of a sesquineolignan compound, 7
00
,8
00
-
erythro;7R,8R,7
0
R,8
0
S)-3,7,3
0
,5
0
,3
00
-pentamethoxy-4-hydroxy-4
0
,8-oxy-4
00
,7
0
-epoxy-8
0
,5
00
sesquineolignan
-9,90,700,800 ,900-pentanol, which was found to have a neuroprotective effect [106].
The extractions of C. pinnatifida fructus and Rhodiolae kirliowii radix and rhizome showed antiviral
potential towards infection by the human polyomaviruses BK (BKPyV) and JC (JCPyV) by reducing
the expression of viral proteins in the infected cells [
107
]. The growth of pathogenic S. aureus and E. coli
was inhibited by gold and silver chloride nanoparticles functionalized by fruit extract of C. pinnatifida,
which also scavenged DPPH free radicals and showed anti-inflammatory function via a reduction in
the levels of inflammatory cytokines such as prostaglandin E2 (PGE2) and NO [108].
3.2. Health-Promoting Activities of Hawthorn in Animals
Many in vivo investigations have reported different beneficial functions for hawthorn [109–118].
The administration of hawthorn extract could attenuate atherosclerosis through the prevention of
factors related to apoptosis and inflammation signaling pathways, by an apoptosis and inflammation
resistance effect, vascular smooth muscle cells calcium deposition, lipidosis, preventing proliferation,
lipid regulation, reducing interleukin-1
β
, hypersensitive C-reactive protein, monocyte chemoattractant
protein-1, Bax mRNA expression and protein levels, as well as the enhancement of adiponectin
level in serum and Bcl-2 (mRNA and protein expression) in the aorta [
119
]. In another study,
the administration of hawthorn leaf flavonoids (20 mg/kg) to apo-lipoprotein E (apoE) knock-out
mice for 16 weeks showed an improvement in atherosclerosis via the
in vivo
promotion of reverse
cholesterol transport, the inhibition of foam cell synthesis, and the induction of antioxidant-related
gene expression [
120
]. In a recent study, ethanolic hawthorn fruit extract in hypocholesterolemic rats
exposed vascular protective activities due to the phenolic compounds with reactive oxygen species
scavenging and cholesterol-lowering activities, resulting in high cholesterol intake and bile acid
production via the upregulation of hepatic CYP7A1 mRNA expression [
121
]. The co-administration of
resveratrol with hawthorn flavonoids following coronary artery bypass graft could decrease thrombotic
restenosis and endothelial cell injury [
122
]. The cardioprotective role of hawthorn leaf extract in
rats was attributed to some functions, including the enhancement of the antioxidant defense system,
the improvement of heart antioxidant biomarkers, the elevation of inflammatory cytokine biomarkers,
and the enhancement of serum parameters related to heart function [
123
]. Anti-inflammation and
anti-oxidative stress effects for hawthorn leaf flavonoids through the suppression of PKC-
α
activation
in rats with diabetes-induced cardiomyopathy has also been reported [
124
]. Alp et al. reported that
C. oxyacantha alcoholic extract (40
µ
g/kg/min of digoxin) showed antiarrhythmic activity in rats [
125
].
The alcoholic extract of C. oxyacantha berries was given to rats with isoproterenol-induced myocardial
infarction, and anti-apoptotic and anti-inflammatory functions were found as a result of reducing
nitritive stress, lipid peroxidation and apoptotic processes [
126
]. Table 3reports the main studies
in animals.

Forests 2020,11, 564 9 of 21
Table 3. The main studies in animals involving hawthorn.
Experimental Conditions: In Animal Model
Activity Effect Reference
Anticataract potential
C. pinnatifida leaf extracts used three times a day reduced the level of
malondialdehyde and increased serum levels of catalase and
superoxide dismutase in rats with selenite-induced cataracts.
[109]
Dyslipidemia therapy
effect
C. pinnatifi fruit extract (250 mg/kg) for 7 days in high-fat-diet-fed mice
with hyperlipidemia reduced blood lipid and lipid degradation by
enhancing the hepatic expression of peroxisome proliferator-activated
receptor α.
[110]
Anti- atherosclerosis
effect
Oligomeric proanthocyanidins extracted from C. oxyacantha in Wistar
rats decreased the differentiation of monocytes to macrophages via the
downregulation of inflammation and the reduction of monocyte
chemoattractant protein -1 and vascular cell adhesion molecule-1 levels.
[111]
Antibacterial effect
Hawthorn fruit extract (including monomers of (+)-catechin,
(−)-epicatechin gallate and (−)-epigallocatechin) could control
methicillin-resistant Staphylococcus aureus (MRSA) in septic mice by
enhancing the accumulation of daunomycin inside MRSA cells and by
downregulating the expression of norA,norC and abcA mRNAs (the
main efflux pumps of MRSA).
[112]
Anti-inflammatory
effect
The administration of C. pinnatifida dried fruit extract reduced the
expression of hepatic cyclooxygenase-2 and nitric oxide synthase. [113]
Radioprotective effect
The treatment of mouse bone marrow cells with phenolic compounds
extracted from hawthorn (200 mg/kg) caused a reduction in 2-Gy
γ-radiation-induced stress and genotoxicity.
[114]
Anti- atherosclerosis
effect
The administration of sugar-free C. pinnatifida aqueous extract in
atherosclerosis-induced rats resulted in the regulation of endothelial
function and reduction of inflammatory responses and serum lipid
levels.
[115]
Cardioprotective effect
The administration of aqueous extract of C. tanacetifolia leaf (100 mg/kg)
for 4 weeks in rats prevented hypertension. [116]
Cardioprotective effect
The administration of alcoholic extract of C. oxycantha (0.5 mL/100 g
body weight/day) for a month prevented isoproterenol-induced
myocardial infarction through a reduction in enzymes involved in the
Krebs cycle. It also prevented peroxidative injury of mitochondrial
lipids and preserved the mitochondrial antioxidant balance.
[117]
Analgesic and central
nervous system
activities
The administration of hawthorn seed and pulp extracts (1000 mg/kg) in
mice reduced pain, sleep disorders, nervousness and stress with low
toxicity.
[118]
A study reported anti-melanogenesis, antioxidant and antitumor roles for hawthorn extract.
The treatment of tumor-implanted mice with total oligomer flavonoids from hawthorn extract
(150 mg/kg body weight) for 21 days reduced the tumor weight and volume, prevented intracellular
free radical scavenging activity, decreased the melanin production and blocked the tyrosinase in
melanoma cells [
127
]. Yonekubo et al. observed that the use of different concentrations of C. oxyacantha
fruit extracts for a week in mice induced genotoxicity activity [128].
The co-treatment of type I diabetes-induced rats by hawthorn extract (100 mg/kg per day),
plus resistance training for five days/week for 10 consecutive weeks, improved memory and learning
by decreasing lipid peroxidation and increasing total antioxidant capacity [
129
]. In another study,
the administration of C. oxyacantha leaves (200 mg/kg and 400 mg/kg) improved memory and learning in
rats with scopolamine-induced amnesia through the inhibition of dementia and oxidative damage [
130
].
Lee et al. observed that the administration of ethanol extract of C. pinnatifida fruits could treat
Alzheimer’s disease by inhibiting amyloid βaccumulation [131].
The treatment of high-fat-diet-fed rats with L. plantarum grade A pasteurized milk ordinance
-fermented hawthorn juice for 28 days showed hypolipidemic activity through the regulation of
adipose tissues and liver morphology, the restoration of liver tissue and the reduction in low-density
lipoprotein cholesterol, serum total cholesterol, lipid vacuolization and lipid metabolism levels [
132
].
The administration of C. pinnatifida with high-fat-diet-induced obese mice modulated the gut microbiota

Forests 2020,11, 564 10 of 21
activity by reducing serum triglyceride, decreasing fat and body weight, inhibiting adipogenesis
and inflammation, and altering gut microbial abundance and diversity [
133
]. In a recent study,
the use of different concentrations of HT048 (obtained from the extractions of Citrus unshiu peel plus
C. pinnatifida leaves) in rats resulted in an anti-obesity effect after 12 weeks by dose-dependently
suppressing the differentiation of adipocytes and the release of stimulated glycerol, reducing peroxisome
proliferator-activated receptor-gamma and CCAAT/enhancer binding protein-alpha mRNA expression,
decreasing body weight, lowering the serum lipid content, reducing hepatic lipogenesis-related gene
expression and increasing
β
-oxidation-related gene expression, thereby indicating positive effects of
HT048 to prevent obesity by blocking adipogenesis and lipogenesis [134].
Diabetic nephropathy was improved in rats treated with hawthorn leaf flavonoids through the
improvement of renal function and the reduction of renal damage via a decrease in oxidative stress injury
and the regulation of the p38/MAPK signaling pathway [
135
]. In another study, the methanolic extract
of C.oxyacantha (100 mg/kg BW) in rats for 12 weeks treated hyperglycemia and dyslipidemia [
136
].
Aierken et al. treated rats with streptozotocin-induced type II diabetes mellitus with different
concentrations of hawthorn extracts and reported hypoglycemic activity in the treatment animals via
the elevation of pancreatic-released plasma insulin and by the reduction of total cholesterol, triglyceride
and glucose levels in the blood [137].
Hawthorn showed hepatoprotective effects in rats with alcoholic liver damage via the reduction
of LDL and total cholesterol levels, the regulation of serum lipids as triglycerides, the reduction of
sinusoidal distension, congestion, necrosis, steatosis and fibrosis, as well as the reduction of cell
damage markers (acid phosphatase,
γ
-glutamyltranspeptidase, alanine aminotransferase and aspartate
aminotransferase). Furthermore, hawthorn exhibited antioxidant activity via the elimination of
bilirubin, the regulation of glycogen levels in liver tissue, the elevation of serum total antioxidant
capacity levels and the reduction of lipid peroxidation [
138
]. Li et al. [
139
] reported that the daily
administration of flavonoids extracted from hawthorn leaf (50 mg/kg/day and 100 mg/kg/day) for
three months reduced hepatic steatosis in rats with non-alcoholic fatty liver disease induced by a
high fat diet due to the activation of the adiponectin/AMPK pathway. The use of hawthorn pectin
pentaglaracturonide (150 mg/kg/day and 300 mg/kg/day) for 10 weeks in high-fat-diet-fed mice
inhibited hepatic lipid accumulation and prevented hepatic fatty acid synthesis by reducing the
gene expression of high-fat-diet-induced sterol regulatory element binding factor-1c, pyruvate kinase,
acetyl-CoA carboxylase and fatty acid synthase [140].
In a study by Mustafa et al., the antioxidant activity and the immunomodulatory potential were
seen for the hyperoside and ethyl acetate extractions of C. azarolus leaves on macrophages, cytotoxic T
lymphocytes and natural killer cells [
141
]. Elango et al. [
142
] reported an immunomodulatory role
for the ethanolic extract of hawthorn (100 mg/kg) in stroke rats over 15 days due to diminished
brain apoptosis during reperfusion through the expression of Bcl-xL, the phosphorylation of signal
transducer and activator of transcription 3, the elevation of the regulatory T cell (Treg) population and
the prevention of activated inflammatory cells via increased levels of Foxp3-positive Tregs and IL-10,
and reduced pro-inflammatory immune responses to ischemia and reperfusion-induced damage.
The daily use of hawthorn extract (100 mg/kg/day) for 11 days prevented alveolar bone loss in rats
with periodontal disease via the regulation of oxidative stress, total oxidant and serum total antioxidant
levels [
143
]. Others observed that the methanol extract of C. dahurica fruit caused an acceleration of the
gastrointestinal tract and activation of the antioxidant system [144].
The polyphenol extract of hawthorn controlled the skin damage induced by UVB radiation via the
suppression of p53, the reduction of DNA damage, the elimination of excess ROS, the downregulation
of pro-apoptotic BAX and the upregulation of anti-apoptotic BCL-2, thereby preventing apoptosis and
suppressing caspase-3/9 activation [
145
]. In another study, mice experienced the promotion of hair
growth by taking C. pinnatifida extract through the induction of anagen phase, by mediating cellular
signaling activation resulting in high proliferation and survival rate of human dermal papilla cells,
as well as by increasing the Bcl-2/Bax ratio, resulting in protection from cell death [
146
]. Rats with

Forests 2020,11, 564 11 of 21
dehydroepiandrosterone-induced polycystic ovary syndrome experienced protective effects due to the
consumption of hawthorn leaf flavonoids [147].
3.3. Health-Promoting Activities of Hawthorn Reported in Clinical Trials
Many clinical trials have reported different health-promoting activities for hawthorn [
148
–
154
].
In a study on 2681 patients suffering from congestive heart failure, the administration of hawthorn
extract (900 mg/day) for 620 days reduced the odds ratio of sudden cardiac death in patients with
lower left ventricular function [
155
]. Following the administration of hawthorn (450 mg, twice per
day) for six months, 120 ambulatory patients suffering from symptomatic chronic heart showed no
positive clinical effects in inflammation, oxidative stress, neurohormones, functional capacity and
quality of life measures, but modest change in left ventricular ejection fraction was found [
156
].
Moeini et al. showed that 5 mL of hawthorn fruit extract after each meal in male and female patients
with gastroesophageal reflux disease controlled the main symptoms over four weeks, as well as causing
a 94.2% and 93.5% alleviation in regurgitation and heartburn, respectively [
157
]. According to the
findings of Trexler et al. [
158
], 160 mg of hawthorn supplementation in adult subjects for a week
could not influence electrocardiographic indices. In another study, adolescent subjects experienced
hypertension following the supplementation of ethanolic extract of fresh Crataegus berries and natural
D-camphor (Korodin
®
) [
159
]. Similarly, in a study by Erfurt et al. [
160
], sphygmomanometric blood
pressure measurements before and after intervention confirmed the hypertension. In a recent clinical
trial, a greater reduction was observed in the diastolic blood pressure in patients with type 2 diabetes
over 16 weeks following daily consumption of 1200 mg of hawthorn extract [
161
]. Mildly hypertensive
patients taking hawthorn extract (500–600 mg/day) over 10 weeks caused a decrease in both diastolic
and systolic blood pressure [
162
]. The short-term use of camphor from Crataegus berry extract in
women enhanced mental performance and blood pressure [
163
]. In Table 4, we list the reported
examples of studies in humans involving hawthorn.
Table 4. Examples of studies in humans involving hawthorn.
Experimental Conditions: Clinical Trials
Activity Administration Main Findings Reference
Anti-inflammatory
effect
Patients with diabetes (n=37)
received hawthorn vinegar (20
mL) diluted with water (40 mL)
after meals for a month.
The treatment reduced serum levels of
triglyceride, LDL, cholesterol and
glucose, as well as decreased glycated
hemoglobin, blood pressure and body
weight.
[149]
Anti-hypertensive
effect
Patients (n=21) randomly
received 1000 mg, 1500 mg and
2500 mg of hawthorn extract
twice per day for four days.
The treatment lowered blood
pressure. [150]
Anti-hypertensive
effect
Hypertensive patients (n=60)
received 450 mg of hawthorn
extract twice per day for three
months.
The treatment elevated the level of
high-density lipoprotein and reduced
the level of low-density lipoprotein,
total cholesterol, diastolic blood
pressure and systolic blood pressure.
[151]
Antihypertensive
effect
The administration of hawthorn
hydroalcoholic extract in
subjects with primary mild
hypertension.
A reduction in diastolic and systolic
blood pressure after four months. [152]
Treatment of patient
with New York Heart
Association class II
heart failure
The administration of Crataegus
berry extracts (30 drops, three
times per day) in subjects with
NYHA class II heart failure.
An improvement of confirmed
tolerability and an enhancement of
exercise tolerance after eight weeks.
[153]
Treatment of patient
with New York Heart
Association class II
heart failure
The administration of Crataegus
extract in subjects with
congestive heart failure (NYHA
class II).
A confirmation of the well-tolerated
nature and safety of Crataegus extract
based on in vitro parameters and
treatment of congestive heart failure
(NYHA class II) after 12 weeks.
[154]

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4. Conclusions and Future Remarks
Medicinal herbs, including hawthorn, are rich sources of high market impact medicines around the
world due to the presence of significant amounts of naturally occurring bioactive chemical compounds
with therapeutic properties. However, further
in vivo
and
in vitro
research and clinical trials are needed
to evaluate the link between the chemical compositions of such plants, particularly hawthorn, and their
mechanisms of action in the treatment of various diseases. An emerging direction is suggested by the
possible use of nanonutraceuticals, assuring their nutraceutical value at a nano level as well as safety
and efficacy [164–168]. Nutraceutical science represents a great challenge for the future [169–172].
Author Contributions:
A.N., M.L. and A.S. conceived and designed the work. A.N., M.L., A.D., M.Z., E.B.S. and
A.S. wrote the work. A.N., A.D., S.C., S.B.S., A.M.S. and P.S. validated and elaborated data information and
figures. A.N., M.L., A.D., M.Z., S.C., S.B.S., A.M.S., P.S., E.B.S., and A.S. have made a substantial contribution to
the revision of work and approved it for publication. All authors have read and agreed to the published version of
the manuscript.
Funding:
The authors acknowledge the support of the research project: Nutraceutica come supporto nutrizionale
nel paziente oncologico, CUP: B83D18000140007. E. B. Souto acknowledges the sponsorship of the projects
M-ERA-NET-0004/2015-PAIRED and UIDB/04469/2020 (strategic fund), receiving support from the Portuguese
Science and Technology Foundation, Ministry of Science and Education (FCT/MEC) through national funds,
and co-financed by FEDER, under the Partnership Agreement PT2020.
Conflicts of Interest: The authors declare no conflict of interest.
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