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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.
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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;
2CREA-Research Centre for Food and Nutrition, Via Ardeatina 546, 00178 Roma, Italy;
3CREA-Research Centre for Vegetable and Ornamental Crops, Via Cavalleggeri 25,
84098 Pontecagnano (Salerno), Italy;
4Department of Veterinary Sciences, University of Messina, Polo Universitario dell’Annunziata,
98168 Messina, Italy;
5Department of Endocrinology of Braga Hospital, Sete Fontes, São Victor, 4710-243 Braga, Portugal;
School of Biology and Environment, University of Tr
s-os-Montes e Alto Douro (UTAD), Quinta de Prados,
P-5001-801 Vila Real, Portugal;
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;
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;
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: (M.L.); (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
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 eects 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 eects, better ecacy, 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
in vivo
potential of this herb on human health.
hawthorn; bioactive compounds; Crataegus; biological activity; nutraceuticals; health
benefits; plant extracts
Forests 2020,11, 564; doi:10.3390/f11050564
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 [
]. 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 [
]. 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
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 eects [
], 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” [
]. This wild plant has been used
as a traditional medicine, herbal drug, and food supplement for centuries [
]. 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 eects 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.
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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, caeic), 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, caeic, and caftaric acids, were identified using HPLC-DAD and LC-MS/MS
techniques [
]. 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-
-glucoside, and quercetin [
The presence of rutin and quercetin obtained from C. oxyacantha extracts using HPLC was also
Forests 2020,11, 564 5 of 21
reported [
]. 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 [
]. The recent work of
Cao et al. [
] 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 [
], it is worth mentioning the
work of Hu et al. [
], 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 [
]. Zhao et al. [
] 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 [
]. Liu et al. [
] 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. [
], by using nuclear magnetic resonance (NMR) spectrometry,
identified chlorogenic acid and flavonoids of Crataegus species, including vitexin-2
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-eective technique
to obtain hawthorn products on an industrial scale [
]. The chemical compounds present in Crataegus
species, mainly quercetin, hyperoside, rutin, and vitexin, have been also studied using HPLC-UV and
UV-Vis spectrophotometry [
]. 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) [
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,
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)
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]
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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
Electronic circular dichroism (ECD) and
HPLC [49]
Crataegus pubescens (+)-catechin and
Micellar electrokinetic chromatography
(MEKC) and HPLC/UV [50]
Crataegus pinnatifida
Chlorogenic acid (CA),
vitexin-400-o-glucoside (VG),
(VR), orientoside (ORT), rutin
(RT), vitexin (VIT) and
hyperoside (HYP)
HPLC [51]
Crataegus pinnatifida var.
major N.E.Br.
(70S, 80R,
-glucopyranoside and
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 [
]. 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 [
], anti-HIV, anti-diabetic [
], and anticoagulant activity [
], cardioprotective
eects [
], hepatoprotective eects, antihyperglycemic and antihyperlipidemic activities,
wound healing eects [
], antimicrobial eects, gastroprotective eects, treatment of metabolic
syndrome [
], regulation of cholesterol homeostasis [
], anti-atherosclerosis eects [
], anti-aging
eects [
], ischemia protective eects [
], treatment of cognitive disorders, neuroprotective eects,
regulating gastrointestinal motility [
], anti-inflammatory activities [
], regulation of the gut–brain
axis [
], treatment of hypertension [
], antioxidant activity [
], anti-hypoxic activities [
antidepressant eects [
], anti-Alzheimer’s eects, and treatment of intestinal microbial disorder [
In the following sections, an updated snapshot of the various potential therapeutic eects 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
in vitro
studies reported dierent health-promoting eects for hawthorn extracts [
The administration of homogeneous polysaccharide (HPS) extracted from hawthorn at a concentration
of 125–1000
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 [
]. Hawthorn fruit peel extract exhibited antioxidant activity
(2,2,1-diphenyl-1-picrylhydrazyl (DPPH) IC
value of 6.72
g/mL), acetylcholinesterase inhibitory
eects (IC
value of 11.72
g/mL), and cytotoxic eects against the human tumor cells SKOV-3 and
values of 80.11
g/mL and 2.76
g/mL, respectively) [
]. 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 [
]. Table 2
reports the results of the main in vitro studies.
Table 2. In vitro reported activities for hawthorn.
Experimental Conditions: In vitro
Activity Eect 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.
Antioxidant and
Ursolic acid and oleanolic acid extracted from hawthorn showed
anti-inflammatory and antioxidative eects 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
Crataequinone A exhibited cytotoxic eects on Hep3B and HepG2 cell lines
with IC50 values of 24.90 µM and 12.24 µM, respectively.
Anticancer Quercitin 3-O-galactoside and kaempherol-3-O-glucoside inhibited the
culture of MCF-7 human breast cancer cells.
Pinnatifidanin BVI extracted from hawthorn had a preventive eect against
Mrc5 human lung cells.
Antioxidant Naturally occurring compounds from ethanolic and aqueous extracts of
C. monogyna showed antioxidant and hydrogen peroxide scavenging
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.
The use of hawthorn induced anti-inflammatory properties through the modulation of
lipopolysaccharide-induced pro-inflammatory (Interleukin-6 and Tumor necrosis factor-
) and
anti-inflammatory (Interleukin-10) cytokines [
]. 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 eect 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%) [
]. In a
study by Wyspianska et al., the procyanidins obtained from hawthorn bark extract revealed
anti-inflammatory and antioxidant properties [
]. 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-
) via the compounds 7
propanetriol and 7
-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 dierent promising activities by scavenging free radicals and inhibiting TNF-
NO production [
]. Zhao et al. observed
-glucosidase inhibitory and antioxidant activity for
Forests 2020,11, 564 8 of 21
C. pinnatifida fruit [
]. In another study, 8-O-4
neolignans extracted from C. pinnatifida seeds blocked
the activity of tyrosinase by 66.67%, in addition to exhibiting antioxidant activity [
Among the triterpenoids extracted from hawthorn berries, the compounds 3
tetrahydroxy-olean-12-en-28-oic acid, 2
-tetrahydroxy-olean-12-en-28-oic acid, and 2
,23-pentahydroxy-olean-12-en-28-oic acid had antioxidant functions and could inhibit the
proliferation of MCF-7 and HepG2 cells (EC
= <5
M) [
]. 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
M protected SH-SY5Y cells from damage
through cell apoptosis prevention due to the presence of a sesquineolignan compound, 7
-9,90,700,800 ,900-pentanol, which was found to have a neuroprotective eect [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 [
]. 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 dierent beneficial functions for hawthorn [109118].
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 eect, vascular smooth muscle cells calcium deposition, lipidosis, preventing proliferation,
lipid regulation, reducing interleukin-1
, 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 [
]. 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 [
]. 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 [
]. The co-administration of
resveratrol with hawthorn flavonoids following coronary artery bypass graft could decrease thrombotic
restenosis and endothelial cell injury [
]. 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 [
]. Anti-inflammation and
anti-oxidative stress eects for hawthorn leaf flavonoids through the suppression of PKC-
in rats with diabetes-induced cardiomyopathy has also been reported [
]. Alp et al. reported that
C. oxyacantha alcoholic extract (40
g/kg/min of digoxin) showed antiarrhythmic activity in rats [
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 [
]. Table 3reports the main studies
in animals.
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Table 3. The main studies in animals involving hawthorn.
Experimental Conditions: In Animal Model
Activity Eect 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.
Dyslipidemia therapy
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.
Anti- atherosclerosis
Oligomeric proanthocyanidins extracted from C. oxyacantha in Wistar
rats decreased the dierentiation of monocytes to macrophages via the
downregulation of inflammation and the reduction of monocyte
chemoattractant protein -1 and vascular cell adhesion molecule-1 levels.
Antibacterial eect
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 eux pumps of MRSA).
The administration of C. pinnatifida dried fruit extract reduced the
expression of hepatic cyclooxygenase-2 and nitric oxide synthase. [113]
Radioprotective eect
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.
Anti- atherosclerosis
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
Cardioprotective eect
The administration of aqueous extract of C. tanacetifolia leaf (100 mg/kg)
for 4 weeks in rats prevented hypertension. [116]
Cardioprotective eect
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.
Analgesic and central
nervous system
The administration of hawthorn seed and pulp extracts (1000 mg/kg) in
mice reduced pain, sleep disorders, nervousness and stress with low
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 [
]. Yonekubo et al. observed that the use of dierent 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 [
]. 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 [
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 [
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 [
]. In a recent study,
the use of dierent concentrations of HT048 (obtained from the extractions of Citrus unshiu peel plus
C. pinnatifida leaves) in rats resulted in an anti-obesity eect after 12 weeks by dose-dependently
suppressing the dierentiation 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
-oxidation-related gene expression, thereby indicating positive eects 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 [
]. In another study, the methanolic extract
of C.oxyacantha (100 mg/kg BW) in rats for 12 weeks treated hyperglycemia and dyslipidemia [
Aierken et al. treated rats with streptozotocin-induced type II diabetes mellitus with dierent
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 eects 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,
-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 [
]. Li et al. [
] 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 [
]. Elango et al. [
] 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 [
]. 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 [
]. 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 [
]. Rats with
Forests 2020,11, 564 11 of 21
dehydroepiandrosterone-induced polycystic ovary syndrome experienced protective eects 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 dierent health-promoting activities for hawthorn [
In a study on 2681 patients suering 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 [
]. Following the administration of hawthorn (450 mg, twice per
day) for six months, 120 ambulatory patients suering from symptomatic chronic heart showed no
positive clinical eects in inflammation, oxidative stress, neurohormones, functional capacity and
quality of life measures, but modest change in left ventricular ejection fraction was found [
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 [
]. According to the
findings of Trexler et al. [
], 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
) [
]. Similarly, in a study by Erfurt et al. [
], 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 [
]. Mildly hypertensive
patients taking hawthorn extract (500–600 mg/day) over 10 weeks caused a decrease in both diastolic
and systolic blood pressure [
]. The short-term use of camphor from Crataegus berry extract in
women enhanced mental performance and blood pressure [
]. 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
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
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]
Hypertensive patients (n=60)
received 450 mg of hawthorn
extract twice per day for three
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.
The administration of hawthorn
hydroalcoholic extract in
subjects with primary mild
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.
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.
Forests 2020,11, 564 12 of 21
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
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 ecacy [164168]. Nutraceutical science represents a great challenge for the future [169172].
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.
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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... Hawthorn (Crataegus spp.) is one of the largest genera in the predominantly woody Rosacea (Evans and Campbell 2002;Phipps et al. 2003;Campbell et al. 2007). Research on natural plant compounds has demonstrated their phar-maceutical properties (Edwards et al. 2012;Nazhand et al. 2020). The species is one of the most important edible and popular medicinal plants, with approximately 280 species found in Europe, North Africa, West Asia, and North America (Edwards et al. 2012;Nazhand et al. 2020). ...
... Research on natural plant compounds has demonstrated their phar-maceutical properties (Edwards et al. 2012;Nazhand et al. 2020). The species is one of the most important edible and popular medicinal plants, with approximately 280 species found in Europe, North Africa, West Asia, and North America (Edwards et al. 2012;Nazhand et al. 2020). However, the importance of Crataegus in terms of environment and agrosystem has also been reported (Rahmani et al. 2015;Brown et al. 2016). ...
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Rootstocks are an essential component in modern fruit production due to their ability to adapt scion cultivars to diverse environmental conditions and cultural practices. According to the present study, the effect of rootstock as well as the effect of cultivar and the rootstock/cultivar combination on mineral concentrations in flowers and leaves were significant. However, the effect of rootstock for nutrient composition of fruits (at harvest time and after 3 months of cold storage at 0°C), with the exception of K-fruit (at harvest time and after 3 months of cold storage at 0°C), was not significant. There were positive correlations between the cultivar/hawthorn combination on the one hand, and flower-Fe, leaf-Zn, and leaf-B on the other, while negative correlations were found between fruit-B with flower-B and between fruit Zn with flower Zn. There was a steady yet genotype-dependent decrease in fruit-N and fruit-K content over storage time in all genotypes or cultivar/rootstock combinations tested. The trend in terms of changes for all other mineral nutrition in fruits, at harvest time and 3 months after cold storage, differed between genotypes. This study suggests that the higher mineral nutrient uptake in the studied cultivars or genotypes favored by hawthorn (Crataegus spp.) rootstocks makes them suitable for heavy and calcareous soils.
... Vol:. (1234567890) (Dönmez 2014). Its tree form varies from shrub to single tree form and is widely found in Western Asia, North America, and Europe (Kean 2009;Nazhand et al. 2020). ...
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showed differences. Among the biochemical properties of the genotypes, the antioxidant activity, as % inhibition, ranged from 23.13 to 61.59%, the total flavonoid content ranged from 16.63 to 57.22 mg QE/100 g, and the total phenolic content ranged from 277.28 to 310.80 mg GAE/100 g. In the principal component analysis, species generally formed similar clusters. In molecular marker analysis, 101 bands were obtained from 13 ISSR (Inter Simple Sequence Repeats) primers. 76 of the bands were polymorphic and the polymorphism rate was calculated as 75.24%. The similarity index in the UPGMA (Unweighted Pair Group Method with Arithmetic Mean of Cluster analysis) dendogram because of the molecular analysis ranged between 0.71 and 0.88. In the dendrogram, genotypes did not show a dense clustering by species. The results obtained may benefit researchers in the determination and protection of genetic resources in breeding studies on hawthorn species.
... It is well known that Crataegus species (hawthorn) have been used traditionally as a drug or supplement to promote antioxidant [27], anti-inflammatory [28], antimicrobial [29], hypoglycemic [24,30], hypolipidemic [24], and hepatoprotective effects [31]. Treatment of atherosclerosis, urinary retention, hypertension, intestinal disorders, and brain and heart diseases have also been attributed to hawthorn [17,18]. Hawthorn also has shown promise in the treatment of mild-to-moderate heart failure [32]. ...
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Diabetes mellitus (DM) is one of the most important metabolic disorders associated with chronic hyperglycemia and occurs when the body cannot manage insulin secretion, insulin action, or both. Autoimmune destruction of pancreatic beta cells and insulin resistance are the major pathophysiological factors of types 1 and 2 of DM, respectively. Prolonged hyperglycemia leads to multiple organs dysfunctions, including nephropathy, neuropathy, cardiomyopathy, gastropathy, and micro- and macrovascular disorders. The basis of the metabolic abnormalities in carbohydrate, fat, and protein in diabetes is insufficient action of insulin on various target tissues. Medicinal plants are rich sources of bioactive chemical compounds with therapeutic effects. The beneficial effects of leaves, fruits, and flowers extracts of Crataegus oxyacantha, commonly called hawthorn, belonging to the Rosaceae family, are widely used as hawthorn-derived medicines. Data in this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, Web of Science, and Scientific Information Database from 2000 to 2021. Based on this review, hawthorn extracts appear both therapeutic and protective effects against diabetic-related complications in various organs through molecular mechanisms, such as decreasing triglyceride, cholesterol, very low density lipoprotein and increasing the antioxidant activity of superoxide dismutase, catalase, glutathione peroxidase, total antioxidant capacity, decreasing malondialdehyde level, and attenuating tumor necrosis factor alpha, interleukin 6 and sirtuin 1/AMP-activated protein kinase (AMPK)/nuclear factor kappa B (NF-κB) pathway and increasing the phosphorylation of glucose transporter 4, insulin receptor substrate 1, AKT and phosphoinositide 3-kinases, and attenuating blood sugar and regulation of insulin secretion, insulin resistance, and improvement of histopathological changes in pancreatic beta cells. Collectively, hawthorn can be considered as one new target for the research and development of innovative drugs for the prevention or treatment of DM and related problems.
... The Shan Zha herb has been shown to have antioxidant and antiinflammatory capacities in vitro, in vivo, and in clinical trials [31][32][33][34]. Shan Zha has many active constituents, with the main phenolics being triterpene acids, hyperoside, isoquercitrin, and chlorogenic acid [56][57][58]. Hyperoside has an antidepressant effect that may be mediated by HPA (hypothalamus-pituitary-adrenal) axis downregulation [59], reduction of the stress-induced noradrenergic response [60], and upregulation of BDNF in vitro [20]. Isoquercitrin also downregulates the HPA axis function by significantly reducing circulating adrenocorticotropic hormone and corticosterone levels in rats [59], as well as by inhibiting MAO-B activity in vitro [61]. ...
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Depression and anxiety disorders are highly prevalent. Selective serotonin reuptake inhibitors (SSRIs) are the current first-line treatment for depression, but they have pronounced limitations. Traditional Chinese medicine can serve as a safe and effective alternative to conventional drugs, particularly since many herbal remedies have already been approved for human use as food additives, making the transition from bench to bedside more efficient. We previously demonstrated that a novel herbal treatment (NHT) induces anxiolytic- and antidepressant-like effects. NHT consists of four herbs: Crataegus pinnatifida (Shan Zha), Triticum aestivum (Fu Xiao Mai), Lilium brownii (Baihe), and the fruit of Ziziphus jujuba (Da Zao). In the current study, we examined the antidepressant-like and anxiolytic-like activities of each individual herb on stressed mice and compared those to the effects of NHT and escitalopram. We show here that Shan Zha is sufficient to produce an anxiolytic and antidepressant-like effect similar to NHT or the escitalopram through activation of 5-HT1A receptor and an elevation in BDNF levels in the hippocampus and Pre-frontal cortex (PFC). Chronic treatment with Shan Zha did not alter serotonin transporter levels in the PFC, as opposed to escitalopram treatment. These results were confirmed in vitro, as none of the herbs blocked SERT activity in Xenopus oocytes. Notably, Shan Zha is sold as a nutritional supplement; thus, its transition to clinical trials can be easier. Once its efficacy and safety are substantiated, Shan Zha may serve as an alternative to conventional antidepressants.
Hawthorn (Crataegus spp.) berry has long been used in traditional Chinese medicine and as a functional food. In order to investigate the variation in metabolites in different colored hawthorn berry varieties and to identify the constituents responsible for their color trait and antioxidant activity, four different-colored hawthorn berries were analyzed and compared using LC-MS/MS based on comparative metabolomic analysis. A total of 728 metabolites were identified. The metabolic compounds differed among the samples. The differentially activated metabolic pathways included phenylpropanoid biosynthesis, phenylalanine metabolism, flavone and flavonol biosynthesis, and amino acids biosynthesis. The hawthorn berry color was caused mainly by a combination of five anthocyanins, pH (influenced by organic acids), and non-anthocyanin flavonoids present as co-pigments. Polyphenol compounds, including phenolic acids and flavonoids, were closely associated with antioxidant activity in hawthorn berry. In addition, significantly higher (P < 0.05) antioxidant activity was found in the dark red sample variety (C. pinnatifida Wulingzirou, WLZR), and may be related to the high concentration of 32 polyphenols. These findings provide valuable insight into the metabolite composition, function and the mechanism of color formation in hawthorn berry.
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Crataegus bretschneideri C. K. Schneid. is one of the species cultivated in China. Due to its unclear taxonomic classification status, the conservation and utilization of this germplasm resource have been limited. In this study, we analyzed the chloroplast genomes and nuclear sequences to reveal the taxonomic relationships among C. bretschneideri and related species. We assembled the chloroplast genomes of C. bretschneider and related species and varieties, including C. maximowiczii C. K. Schneid., C. maximowiczii var. ninganensis S. Q. Nie & B. J. Jen., C. pinnatifida Bunge, and C. pinnatifida var. major N. E. Br. The lengths of the chloroplast genomes ranged from 159,644 bp (C. bretschneideri) to 159,947 bp (C. pinnatifida var. major). The five Crataegus chloroplast genomes had similar features and possessed 86 to 88 protein-coding genes, 37 tRNA genes, and eight rRNA genes which were arranged in the same order. Eight mutation hotspot regions, including matk, psaB, accD, petA, clpP, trnD-GUC, psbH-petB, and trnN-GUU-trnR-ACG could be used as potential molecular markers for further studies of Crataegus genetic diversity. Phylogenetic analyses based on 17 chloroplast genomes of Crataegus and Amelanchier indicated that C. bretschneideri was related to C. maximowiczii and C. maximowiczii var. ninganensis. However, the phylogenetic trees constructed by nuclear sequences of 36 Crataegus accessions reflected a closer relationship between C. bretschneideri and C. pinnatifida. Furthermore, divergence time estimation suggested that C. bretschneideri and C. maximowiczii diverged in the late Miocene and that speciation of C. pinnatifida occurred during the middle to late Miocene. These findings revealed that C. bretschneideri is an independent species and may be of hybrid origin.
Conference Paper
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Medicinal plants, many of which are wildgrowing, have recently been under the the interesent of scientists due to growing requests for safe natural remedies for pathological conditions with beneficial health effects. Species of the genus Сrataegus have a wide range of biological and pharmacological activity due to a significant range of biologically active substances. In Europe, hawthorn preparations are mainly used as cardioprotective agents, however they can be used for treatment of a lot of different diseases . There are 28 species of hawthorn in the flora of Ukraine, among which one of the most common is Crataegus ucrainica Pojark. The aim of our work is to investigate the micromorphological (anatomical) features of the leaf lamina of the Pharmacopoeial species Crataegus curvisepala (C. curvisepala) and the local species Crataegus ucrainica (C. ucrainica) in order to compare them and for further standardization of C. ucrainica
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The leaves, inflorescences, and fruits of hawthorn have long been known for their therapeutic properties. A wide range of hawthorn products, including liqueurs, are manufactured, due to the technological potential of the raw material as well as the richness of its volatile compounds. This study aimed to determine the effect of the liqueur production method and various methods of fruit preservation on the quantitative and qualitative composition of volatile compounds in the liqueurs produced. Hawthorn fruits saturated with sucrose and non-saturated with sucrose, fresh or preserved through one of three methods: freezing, air-drying, and freeze-drying, were used for liqueur preparation. The samples were analyzed using a gas chromatograph–mass spectrometer. They were found to contain 54 volatile compounds classified into 12 groups of chemicals. All 54 identified volatile compounds were detected in the liqueur made from hawthorn fruits non-saturated with sucrose and preserved by freeze-drying. In this liqueur type, 12 of the identified volatile compounds occurred in the highest concentration when compared to the other treatments. Among all volatiles, the following compounds were present in the analyzed liqueurs in the highest concentrations: dodecanoic acid ethyl ester (11.782 g/100 g), lactones (6.954 g/100 g), five monoterpenes (3.18 g/100 g), two aromatic hydrocarbons (1.293 g/100 g), isobensofuran (0.67 g/100 g), alcohol—2-methyl-2-propanol (0.059 g/100 g), and malonic ester (0.055 g/100 g). Among all analyzed liqueurs, the one made from the fruits non-saturated with sucrose and frozen was characterized by the smallest diversity of volatiles, which were present in the lowest concentrations in that liqueur.
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Introduction. Commercial pectin is usually obtained from apples or citrus fruits. However, some wild fruits, such as hawthorn, are also rich in pectin with valuable nutritional and medical properties. The research objective was to study and improve the process of combined surfactant and enzyme-assisted extraction of pectin from hawthorn fruits. Study objects and methods. The study involved a 1% solution of Polysorbate-20 surfactant and a mix of two enzymes, namely cellulase and xylanase, in a ratio of 4:1. The response surface methodology with the Box-Behnken experimental design improved the extraction parameters. The experiment featured three independent variables – temperature, time, and solvent-to-material ratio. They varied at three levels: 20, 40, and 60°C; 120, 180, and 240 min; 15, 30, and 45 mL per g. Their effect on the parameters on the pectin yield was assessed using a quadratic mathematical model based on a second order polynomial equation. Results and discussion. The response surface methodology made it possible to derive a second order polynomial regression equation that illustrated the effect of extraction parameters on the yield of polyphenols. The regression coefficient (R2 = 98.14%) and the lack-of-fit test (P > 0.05) showed a good accuracy of the model. The optimal extraction conditions were found as follows: temperature = 41°C, time = 160 min, solvent-to-material ratio = 32 mL per 1 g. Under the optimal conditions, the predicted pectin yield was 14.9%, while the experimental yield was 15.2 ± 0.4%. The content of galacturonic acid in the obtained pectin was 58.5%, while the degree of esterification was 51.5%. The hawthorn pectin demonstrated a good complex-building ability in relation to ions of copper (564 mg Cu2+/g), lead (254 mg Pb2+/g), and cobalt (120 mg Co2+/g). Conclusion. Combined surfactant and enzyme-assisted extraction made improved the extraction of pectin from hawthorn fruits. The hawthorn pectin can be used to develop new functional products.
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Backround Thanks to its ecological and geographical location, Turkey is the homeland of many fruit species and allows many fruit species to be grown. Hawthorn, which is understood to be important in human health and nutrition, is one of these fruit types. This study was carried out to identify morphological, biochemical and molecular genetic variations of 22 hawthorn genotypes belonging to three different species collected from Kayseri province. Methods and Results Morphological, biochemical and molecular marker (ISSR) techniques were used to determine genetic diversity. The fruit and leaf characteristics of the genotypes showed differences. Among the biochemical properties of the genotypes, the antioxidant activity ranged from 23.13–61.59%, the total flavonoid content ranged from 16.63 to 57.22 mg QE/100 g, and the total phenolic content ranged from 277.28 to 310.80 mg GAE/100 g. Genotypes were compared with principal component analysis according to their morphological and biochemical characteristics. In the principal component analysis, species generally formed similar clusters. In molecular marker analysis, 101 bands were obtained from 13 ISSR primers. 76 of the bands are polymorphic and the polymorphism rate was calculated as 75.24%. The similarity index in the UPGMA dendogram obtained as a result of the molecular analysis ranged between 0.71 and 0.88. In the dendrogram, genotypes did not show a dense clustering by species. Conclusion The results obtained may benefit researchers in the determination and protection of gene sources in breeding studies on hawthorn species.
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Common Hawthorn has been known as a traditional remedy to relieve gastroesophageal reflux disease symptoms and to improve stomach function. This study aims to investigate the effectiveness and safety of common hawthorn fruit in patients who suffer from gastroesophageal reflux disease.Eighty male and female patients with clinically diagnosed gastroesophageal reflux disease were included in the study. The patients were randomly assigned into experimental (treatment) and control groups. Experimental group members took common hawthorn syrup and those in the control group received placebo syrup for 4 weeks (5 ml after each meal). Gastroesophageal reflux disease symptoms were assessed based on an available validated questionnaire, before and after the treatment in both groups. The side effects were monitored according to old and new medical resources. In order to assess the probable effect on hepatic or renal function, the levels of alanine transaminase, aspartate transaminase, blood urea nitrogen, and creatinine were measured before and after the treatment.After four weeks of taking the hawthorn and placebo syrups, a significant improvement was observed in two main symptoms of gastroesophageal reflux disease in the experimental group compared with the control one. Heartburn and regurgitation were alleviated by 93.5% and 94.2% respectively. The impact of the common hawthorn syrup on atypical symptoms of gastroesophageal reflux disease such as dyspnea, chest pain, cough and dysphagia was also evaluated and differences were not statically significant. Any adverse effects of the medicine on the functions of liver and kidney were not observed. Our findings suggest common hawthorn fruit as a natural source to control the main symptoms of gastroesophageal reflux disease.
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Abstract: Hawthorn belongs to Crataegus genus of the Rosaceae and is an important medicinal plant. Due to its beneficial effects on the cardiovascular system, antioxidant and antimicrobial activity hawthorn has recently become quite a popular herbal medicine in phytotherapy and food applications. In this study, physicochemical characterization (color parameters, pH, titratable acidity, total soluble solids, soluble carbohydrate, total carotenoid, total phenols and flavonoid contents), antioxidant activity (by FRAP assay) and quantification of some individual phenolic compounds of fruits of 15 samples of different hawthorn species (Crataegus spp.) collected from different regions of Iran were investigated. According to findings, the total phenols, total flavonoid content and antioxidant activity were in the range of 21.19 to 69.12 mg GAE/g dw, 2.44 to 6.08 mg QUE/g dw and 0.32 to 1.84 mmol Fe++/g dw, respectively. Hyperoside (0.87-2.94 mg/g dw), chlorogenic acid (0.06-1.16 mg/g dw) and isoquercetin (0.24-1.59 mg/g dw) were found to be the most abundant phenolic compounds in the extracts of hawthorn fruits. The considerable variation in the antioxidant activity and phenolic compounds of hawthorn species were demonstrated by our results. Hence, the evaluation of hawthorn genetic resources could supply precious data for screening genotypes with high bioactive contents for producing natural antioxidants and other phytochemical compounds valuable for food and pharma industries.
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Due the implementation of nanotechnologies in the pharmaceutical industry over the last few decades, new type of cutting-edge formulations—nanopharmaceutics—have been proposed. These comprise pharmaceutical products at the nanoscale, developed from different types of materials with the purpose to, e.g., overcome solubility problems of poorly water-soluble drugs, the pharmacokinetic and pharmacodynamic profiles of known drugs but also of new biomolecules, to modify the release profile of loaded compounds, or to decrease the risk of toxicity by providing site-specific delivery reducing the systemic distribution and thus adverse side effects. To succeed with the development of a nanopharmaceutical formulation, it is first necessary to analyze the type of drug which is to be encapsulated, select the type matrix to load it (e.g., polymers, lipids, polysaccharides, proteins, metals), followed by the production procedure. Together these elements have to be compatible with the administration route. To be launched onto the market, the selected production method has to be scaled-up, and quality assurance implemented for the product to reach clinical trials, during which in vivo performance is evaluated. Regulatory issues concerning nanopharmaceutics still require expertise for harmonizing legislation and a clear understanding of clinically compliant production methods. The first part of this study addressing “Nanopharmaceutics: Part I—Clinical trials legislation and Good Manufacturing Practices (GMP) of nanotherapeutics in the EU” has been published in Pharmaceutics. This second part complements the study with the discussion about the production scales and clinically compliant production methods of nanopharmaceutics.
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Featured Application: The loading of pharmaceuticals and cosmeceuticals into nanomaterials is discussed as new formulations for potential treatment of age-related skin problems. Topical administration of active ingredients formulated as nanopharmaceuticals and nanonutraceuticals is discussed.Abstract: Skin aging is described as dermatologic changes either naturally occurring over the course of years or as the result of the exposure to environmental factors (e.g., chemical products, pollution, infrared and ultraviolet radiations). The production of collagen and elastin, the main structural proteins responsible for skin strength and elasticity, is reduced during aging, while their role in skin rejuvenation can trigger a wrinkle reversing effect. Elasticity loss, wrinkles, dry skin, and thinning are some of the signs that can be associated with skin aging. To overcome skin aging, many strategies using natural and synthetic ingredients are being developed aiming to reduce the signs of aging and/or to treat age-related skin problems (e.g., spots, hyper- or hypopigmentation). Among the different approaches in tissue regeneration, the use of nanomaterials loaded with cosmeceuticals (e.g., phytochemicals, vitamins, hyaluronic acid, and growth factors) has become an interesting alternative. Based on their bioactivities and using different nanoformulations as efficient delivery systems, several cosmeceutical and pharmaceutical products are now available on the market aiming to mitigate the signs of aged skin. This manuscript discusses the state of the art of nanomaterials commonly used for topical administration of active ingredients formulated in nanopharmaceuticals and nanocosmeceuticals for skin anti-aging.
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Cardiovascular disease (CVD), especially atherosclerosis, is a leading cause of morbidity and mortality globally; it causes a considerable burden on families and caregivers and results in significant financial costs being incurred. Hawthorn has an extensive history of medical use in many countries. In China, the use of hawthorn for the treatment of CVD dates to 659 AD. In addition, according to the theory of traditional Chinese medicine, it acts on tonifying the spleen to promote digestion and activate blood circulation to dissipate blood stasis. This review revealed that the hawthorn extracts possess serum lipid-lowering, anti-oxidative, and cardiovascular protective properties, thus gaining popularity, especially for its anti-atherosclerotic effects. We summarize the four principal mechanisms, including blood lipid-lowering, anti-oxidative, anti-inflammatory, and vascular endothelial protection, thus providing a theoretical basis for further utilization of hawthorn.
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The latest advances in pharmaceutical technology are leading to the development of cutting edged approaches to produce what is now known as the “Holy Grail” of medicine—nanopharmaceutics. Over the latest decade, the pharmaceutical industry has made important contributions to the scale up of these new products. To ensure their quality, efficacy, and safety for human use, clinical trials are mandatory. Yet, regulation regarding nanopharmaceuticals is still limited with a set of guidelines being recently released with respect to compliance with quality and safety. For the coming years, updates on regulatory issues about nanopharmaceuticals and their use in clinical settings are expected. The use of nanopharmaceuticals in clinical trials depends on the approval of the production methods and assurance of the quality of the final product by implementation and verification of the good manufacturing practices (GMP). This review addresses the available legislation on nanopharmaceuticals within the European Union (EU), the GMP that should be followed for their production, and the current challenges encountered in clinical trials of these new formulations. The singular properties of nanopharmaceuticals over their bulk counterparts are associated with their size, matrix composition, and surface properties. To understand their relevance, four main clinical trial guidelines, namely, for intravenous iron-based nanopharmaceuticals, liposomal-based nanopharmaceuticals, block copolymer micelle-based nanopharmaceuticals, and related to surface coating requirements, are described here.
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Metal-based nanoparticles have been extensively investigated for a set of biomedical applications. According to the World Health Organization, in addition to their reduced size and selectivity for bacteria, metal-based nanoparticles have also proved to be effective against pathogens listed as a priority. Metal-based nanoparticles are known to have non-specific bacterial toxicity mechanisms (they do not bind to a specific receptor in the bacterial cell) which not only makes the development of resistance by bacteria difficult, but also broadens the spectrum of antibacterial activity. As a result, a large majority of metal-based nanoparticles efficacy studies performed so far have shown promising results in both Gram-positive and Gram-negative bacteria. The aim of this review has been a comprehensive discussion of the state of the art on the use of the most relevant types of metal nanoparticles employed as antimicrobial agents. A special emphasis to silver nanoparticles is given, while others (e.g., gold, zinc oxide, copper, and copper oxide nanoparticles) commonly used in antibiotherapy are also reviewed. The novelty of this review relies on the comparative discussion of the different types of metal nanoparticles, their production methods, physicochemical characterization, and pharmacokinetics together with the toxicological risk encountered with the use of different types of nanoparticles as antimicrobial agents. Their added-value in the development of alternative, more effective antibiotics against multi-resistant Gram-negative bacteria has been highlighted.
Diabetic gastroparesis (DGP) is a common chronic complication of diabetes mellitus. Its pathogenesis is related to many factors. Hawthorn seeds are the seeds of Crataegus pinnatifida Bunge, which has many chemical constituents and pharmacological properties. In this study, we investigated the therapeutic effect and potential mechanism of ethyl acetate extract from hawthorn seeds (HSEAE) on DGP rats. We measured their body weight, blood sugar, gastric emptying rate, and intestinal propulsion rate, as well as the effects of HSEAE on superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in gastric homogenate. The levels of ghrelin in rat plasma were determined by radioimmunoassay, while those of motilin (MTL) and gastrin (GAS) were determined by enzyme-linked immunosorbent assay. Western blot was used to detect the expression of c-kit, ghrelin, and neuronal nitric oxide synthase (nNOS) in the rats’ stomachs, and immunohistochemistry was used to detect changes in interstitial cells of Cajal (ICC). The results showed that different doses of HSEAE effectively promoted the gastric emptying and small intestinal propulsion (P < 0.05 or P < 0.01). In addition, HSEAE increased SOD and GSH-Px in the rats’ stomachs while decreasing MDA, and increased plasma ghrelin while decreasing MTL and GAS (P < 0.05 or P < 0.01). The expression of c-kit, ghrelin, and nNOS proteins and the number of ICCs in the rats’ stomachs also significantly increased (P < 0.05 or P < 0.01). Our experiments showed that HSEAE improved gastrointestinal motility in DGP rats, and its potential mechanism might be involved in the inhibition of oxidative stress injury induced by hyperglycemia, upregulating n-NOS, c-kit expression, and ICCs in their stomachs and regulating gastrointestinal hormones.
Crataegus (Rosaceae; hawthorn), are small trees that grow in the Northern Hemisphere. Plant materials of Crataegus show promising benefits in adjunctive treatment of cardiovascular disorders, primarily attributed to flavonoids and other phenolic derivatives. ¹H NMR was used in quantification of four flavonoids (naringenin, hyperoside, rutin, and vitexin-2″-O-rhamnoside) and chlorogenic acid in leaf extracts of four Crataegus species. The data were validated by comparison to HPLC-DAD. Vitexin and its derivatives were significantly more concentrated in the European (C. monogyna and C. laevigata) leaves and rutin significantly more concentrated in the North American (C. douglasii and C. okanaganensis) leaves. The concentrations of rutin and naringenin reported in this study are the highest reported for Crataegus. This work represents the first quantitative report of flavonoids in the North American hawthorns C. douglasii and C. okanaganensis and a direct comparison with the common European species.
Hawthorn including many plants from the genus Crataegus (C.) is used as traditional medicines, herbal drugs, and dietary supplements all over the world. In China, C. pimiatificia Bge. var. major N, E. Br, and C. pinnatifida Bge. are two major species that are used as hawthorn. The purpose of this study is to assay the myocardial protection of hawthorn fruit processed with honey (MSZ) and screen the chemical basis of MSZ on this effect. Firstly, ultra-performance liquid chromatography-quadrupole time of flight-mass spectrometry (UPLC/Q-TOF-MS) was used to analyze the chemical constituents of sliced dry fruit of hawthorn (SZ) and MSZ. Principal component analysis (PCA) was used to differentiate them. Orthogonal partial least squares-discriminate analysis (OPLS-DA) was applied to screen different compounds between SZ and MSZ, and 32 different compounds were selected. Then pharmacodynamic test of myocardial ischaemia protective effect was carried out. The results demonstrated that the protective effect of MSZ was better than that of SZ on the same dose. Finally, we speculated the chemical basis of MSZ on myocardial ischaemia protective effect based on correlation analysis. Taken together, all these results suggest that organic acid, flavonoids, phenylpropanoids and tannins might be the chemical basis of MSZ on protect against myocardial ischaemia.