Food Bioactives

Journal of

Food Bioactives International Society for

Nutraceuticals and Functional Foods
Review J. Food Bioact. 2018;4:69–87

Phytochemical composition and bioactivities of hawthorn

(Crataegus spp.): review of recent research advances
Petras Rimantas Venskutonis*
Department of Food Science and Technology, Kaunas University of Technology, Radvilėnų rd. 19, Kaunas, LT-50254, Lithuania
*Corresponding author: Petras Rimantas Venskutonis, Department of Food Science and Technology, Kaunas University of Technology,
Radvilėnų rd. 19, Kaunas, LT-50254, Lithuania. E-mail: [email protected]

DOI: 10.31665/JFB.2018.4163
Received: December 04, 2018; Revised received & accepted: December 23, 2018
Abbreviations: ABTS, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid; AChE, acethylcholinesterase; AMP, adenosine monophos-
phate; BchE, butyrylcholinesterase; CPT-1, carnitine palmitoyl transferase; DPPH•, stable 2,2-diphenyl-1-picrylhydrazyl radical; DW, dry
weight; eNOS, endothelial NO synthase; FRAP, ferric reducing antioxidant power; GAE, gallic acid equivalents; Gpx3, glutathione per-
oxidase 3; HDLC, high density lipoprotein cholesterol; HFD, high-fat diet; HLF, hawthorn leaf flavonoids; ICAM-1, intercellular adhesion
molecule; IL, interleukin; LDLC, low density lipoprotein cholesterols; LPS, lipopolysaccharide; MDA, malondialdehyde; NAFLD, non-
alcoholic fatty liver disease; NO, nitric oxide; ORAC, oxygen radical absorbance capacity; PKC-α, protein kinase C α; PPARα, peroxisome
proliferator activated receptor α; RAW264.7, murine macrophage cell line; RCT, reverse cholesterol transport; ROS, reactive oxygen spe-
cies; SOD, superoxide dismutase; SREBP-1c, sterol regulatory element binding protein-1c; TBARS, thiobarbituric acid reactive substances;
TC, total cholesterol; TE, trolox equivalents; TFC, total flavonoid content; TG, triacylglycerols; TNF-α, necrosis factor-α; TPC, total phe-
nolic content; VLDLC, very low density lipoprotein cholesterol.
Citation: Venskutonis, P.R. (2018). Phytochemical composition and bioactivities of hawthorn (Crataegus spp.): review of recent research
advances. J. Food Bioact. 4: 69–87.
Abstract
Hawthorn (Crataegus spp.) is one of the most famous plants which has been used as natural medicine and nutra-
ceutical. Its phytochemical composition, bioactive compounds and health benefits have been intensively studied
and hawthorn preparations may be recognized as classical natural products for cardiovascular health. Polyphe-
nolic compounds of different hawthorn anatomical parts as well as their extracts have been the focus of a ma-
jority of these studies, although various other classes of natural health promoting constituents have also been
isolated, identified and characterized. Regardless, numerous published reports have particularly focused on the
activity mechanisms which are very important for supporting various health benefits. This review summarizes the
most recent studies on hawthorn, mainly published since 2015. Search of different databases indicates that ap-
proximately 200 publications, which are relevant to phytochemistry and health benefits of Crataegus spp., have
appeared since then, most of them have not been included in the existing reviews.
Keywords: Hawthorn (Crataegus spp.); Phytochemical composition; Bioactivities; Health benefits; Toxicity.
1. Introduction cies which are native to temperate regions of the Northern Hemi-
sphere in North America, Europe and Asia (Phipps et al., 2003).
The name “hawthorn” is often used in some countries although
Hawthorns are large genus of small shrubs and trees belonging originally it was applied to the species native to northern Eu-
to Rosaceae family, Amygdaloideae subfamily, Maleae tribe, rope, especially to the common hawthorn (C. monogyna). Red
Malinae subtribe Crataegus Tourn. ex L. genus. Nowadays it is or black small pome fruits of some Crataegus spp. are edible,
agreed that the genus is represented by approximately 200 spe- e.g. fresh fruits of C. orientalis, while the fruits of other species
Copyright: © 2018 International Society for Nutraceuticals and Functional Foods. 69

All rights reserved.
Phytochemical composition and bioactivities of hawthorn (Crataegus spp.) Venskutonis
become eatable in late autumn. Their flavor has been compared 2. Bioactive constituents and antioxidant/antiinflammatory ac-
to over-ripe apples and they are mainly used for jellies or home- tivities
made wine. Picked in spring young leaves are also edible and are
tender enough to be used in salads. In Europe, the fruit, leaves,
The variations in the composition of different Crataegus spp. from
and flowers were traditionally employed for treating heart prob-
various growing regions, as well as of different anatomical parts of
lems due to their antispasmodic, cardiotonic, hypotensive, and
hawthorn have been widely studied. Acids, sugars and sugar alco-
antiatherosclerotic effects. Nowadays, hawthorn preparations
hols, minerals, vitamins, and amino acid composition were among
are mainly used as cardioprotective agents (Fong and Bauman,
the analyzed constituents, however, overwhelming number of pub-
2002); however, in traditional medicine it remains as a thera-
lished articles have been focusing on polyphenolic compounds, as
peutic agent for many other diseases including cancer, diabetes,
the most important hawthorn bioactive phytochemicals which may
cough, flu, asthma, stomach ache, rheumatic pain, nephritis, and
provide health benefits to humans. Consequently, many hawthorn-
hemorrhoids.
based preparations are standardized according to the content of
Among plant species C. pinnatifida (ten varieties of Chinese
their flavonoids and phenolic acids. The interest in phenolic and
hawthorns) have long been used in traditional Chinese and Eu-
polyphenolic compounds particularly increased in the era of func-
ropean herbal medicines, and are widely consumed in the form
tional foods (Shahidi, 2004). Besides strong antioxidant activity,
of juice, drink, jam and canned fruit, while C. monogyna is com-
phenolic compounds have demonstrated numerous protective ef-
monly cultivated in the Mediterranean countries (Çalişkan, 2015).
fects against chronic diseases, which have recently been reviewed
Chinese hawthorns comprise 18 species, however currently only
(Shahidi and Yeo, 2018). This section will review only the most
C. pinnatifida and C. pinnatifida var. major fruits are included
recent publications, which report new findings in the hawthorn
in the Chinese Pharmacopoeia. C. pinnatifida and C. scabrifolia phytochemistry. In general, the studies were performed for the iso-
fruits have also been traditionally used as peptic agents in orien- lation and purification of flavonoids, other groups of compounds,
tal medicine and recently in a various local sweet foods, mainly as well as determination of their variations among different origins
soft drinks, jams, juices, tinned foods, and wines (Jurikova et al., and other variables.
2012). Oxidative stress, which reflects an imbalance between the sys-
Several reviews summarizing numerous research findings on temic manifestations of reactive oxygen species (ROS), may in-
hawthorns are given in Table 1. Composition and health effects duce development of various diseases and disorders and, although
of phenolic compounds in Crataegus spp. of different origins was living cells possess strong endogenous antioxidant system, it is be-
reviewed by Yang and Liu (2012), while Edwards et al. (2012) lieved that under some conditions ROS-protective function might
focused their review on the chemistry of the genus. Effects of bio- be insufficient, while exogenous dietary antioxidants could assist
active natural products of Crataegus spp. on the vascular endothe- in mitigating inflammatory processes and thereby restoring home-
lium were also reviewed (Ahmad et al., 2013). More recently, poly- ostatic state in the organism. In addition, natural antioxidants have
phenolic composition and medical applications of C. monogyna attracted an increasing attention as possible alternatives to synthet-
were reviewed (Nabavi et al., 2015) by summarizing the growing ic additives in foods and cosmetics. Hawthorns are well-known as
evidence on various interesting physiological and pharmacological an excellent source of natural antioxidants as reviewed in the lit-
activities of this species due to the presence of different bioac- erature (Venskutonis, 2016). The majority of such studies applied
tive natural compounds. Nunes et al. (2017) reviewed the labeling simple and easy spectrophotometric in vitro and in situ assays such
and safety concerns of herbal products containing Crataegus spp. as DPPH• and ABTS•+ scavenging, FRAP, Folin-Ciocalteau’s reac-
among other ingredients. Rastogi et al. (2016) provided a review tion (most often considered as TPC), ORAC, β-carotene-linoleic
on the cardiovascular effects of C. oxyacantha, including ischemic acid co-oxidation, TBARS and others. Although there is an opin-
heart disease, congestive heart failure, arrhythmias and hyperten- ion that such in vitro antioxidant capacity values are not appropri-
sion and concluded that, although the mechanisms of action are ate, the experts in this area recently concluded that they, as low-
not very clear, there is enough evidence of their efficacy in various cost and high-throughput tools, cannot be ignored (Granato et al.,
cardiovascular disorders. 2018). Therefore, together with phytochemical information this
C. oxyacantha is a widely used Chinese herb for treating gas- section will also briefly reviews the most recent findings in anti-
trointestinal ailments and heart problems; it is also consumed oxidant properties of hawthorn products.
as a food. In North America, the role of treating heart problems Phytochemical studies of the most widely used C. pinnatifida
dates back to the 1800’s. Currently, the evidence is accumulating (Table 2) resulted in separation and purification of 4 new monoter-
from various in vivo and in vitro studies that hawthorn extracts pene glycosides and a new phenolic glycoside in addition to the
exert a wide range of cardiovascular and pharmacological prop- 10 previously known ones (Li et al., 2015). Furthermore, 15 triter-
erties, including antioxidant activity, positive inotropic, anti- penoids, including 4 novel acids, in hawthorn berries (Qiao et al.,
inflammatory, anticardiac remodeling, antiplatelet aggregation, 2015); 2 norditerpenoids with unique carbon skeletons, 4 sesquit-
vasodilating, and endothelial protective effects, as well as reduc- erpenoids and 9 nor-sesquiterpenoids from the ethanolic extract
tion of smooth muscle cell migration and proliferation, protec- of plant leaves (Gao et al., 2017); 8 new phenylpropanoids (cra-
tion against ischemia/reperfusion injury, antiarrhythmic, lipid- taegusoids A-F) from the fruits (Guo et al., 2018); 8 new lignans
lowering and arterial blood pressure decreasing effects (Wang (hawthornnins A-H) and 7 known analogues (Huang et al., 2015a);
et al., 2013). 2 new 8-O-4′-neolignans, huangnin A and B and four known an-
Crataegus spp. were also reviewed together with other botani- alogs (Huang et al., 2015b); 7 new lignans (crataegusnins A-G)
cals (Chen et al., 2009; Schmitt and Dirsch, 2009; Rastogi et al., and 5 known compounds from the seeds (Peng et al., 2016) and
2016; Dennehy, 2001; Bjorklund et al., 2018), Chinese Traditional from crude Crataegus Fructus drug (Kazuma et al., 2016), while 7
Medicine plants (Xie et al., 2012; Liu and Huang, 2016; Dong et known main constituents were separated from the flavonoid frac-
al., 2017), various herbal products (Ahmad et al., 2013; Nunes et tion of leaves using a combination of high-speed counter-current
al., 2017), nutraceuticals (Houston, 2005) and natural antioxidants chromatography (HSCCC) coupled with pre-HPLC (Wen et al.,
(Zhao, 2005). 2017). Crataegusins A and B, new flavanocoumarins, also showed
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Venskutonis Phytochemical composition and bioactivities of hawthorn (Crataegus spp.)
Table 1. Published review articles on Crataegus spp. bioactive compounds, pharmacological and health effects and safety
Plants or their products Topic Summary of content Reference

Standardized Treatment of Positive inotropic, chronotropic, dromotropic Loew, 1997
Crataegus extracts heart failure effects; negative bathmotropic effects; increases
coronary and myocardial perfusion, lowers
peripheral resistance, has antiarrhythmic
and economizing action with respect to
oxygen and energy consumption.
Extract from fresh Orthostatic In combination with D-camphor exerts Belz and Loew, 2003
hawthorn berries hypotension a significant effect that counteracts an
orthostatic fall in blood pressure
Hawthorn extract Clinical trials to treat A significant benefit from hawthorn extract as an Pittler et al., 2003
chronic heart failure adjunctive treatment for chronic heart failure
Hawthorn Cardiovascular disease May induce anti-ischemia/reperfusion-injury, Chang et al., 2005
anti-arrhythmic, hypolipidemic and hypotensive
effects, which may in part be due to the presence
of antioxidant flavonoid components.
Hawthorn medicinal Heart failure Improvement in patients with mild forms of heart Dahmer and
extracts (WS 1442, LI 132) failure, clinical symptoms, pressure-heart rate Scott, 2010
product, left ventricular ejection fraction; no evidence
of a notable reduction in mortality or sudden death
Standardized extracts Preclinical and clinical Cardiotonic effects, cardio- and vasoprotective Koch and Malek, 2011
from hawthorn studies mild chronic properties; may be employed in the prophylactic
leaves and flowers heart failure and therapeutic treatment of endothelial
dysfunction, atherosclerosis, coronary heart
disease, or prevention of restenosis/reocclusion
following peripheral endo-vascular treatment.
C. oxyacantha Cardiovascular A wide range of cardiovascular pharmacological Wang et al., 2013
disease prevention properties: antioxidant activity, positive
inotropic effect, anti-inflammatory effect,
anticardiac remodeling effect, antiplatelet
aggregation effect, vasodilating effect, endothelial
protective effect, reduction of smooth muscle
cell migration and proliferation, protective
effect against ischemia/reperfusion injury,
antiarrhythmic effect, lipid-lowering effect and
decrease of arterial blood pressure effect
C. pinnatifida Chemical constituents, >150 compounds (flavonoids, triterpenoids, steroids, Wu et al., 2014
pharmacology, monoterpenoids, sesquiterpenoids, lignans,
potential applications hydroxycinnamic acids, organic acids and nitrogen-
containing) have been isolated and identified;
broad pharmacological effects with low toxicity;
wide applications in pharmacological therapy
The genus Crataegus Chemical, Heart (cardiovascular disorders), central Kumar et al., 2012
pharmacological, nervous system, immune system, eyes,
health, uses aspects reproductive system, liver, kidney etc; cytotoxic,
gastroprotective, anti-inflammatory, anti-HIV and
antimicrobial activities. Bioactive phytochemicals:
oligomeric procyanidins, flavonoids, triterpenes,
polysaccharides, catecholamines; traditional
uses; the clinical trials and regulatory status.
Crataegus spp. of Composition and Epicatechin, aglycons and glycosides of B-type Yang and Liu, 2012
different origins health effects of oligomeric procyanidins and flavonols, phenolic
phenolic compounds acids and C-glycosyl flavones as he major
groups of phenolics; in vitro and animal studies
showing cardioprotective, hypolipidaemic,
hypotensive, antioxidant, radical-scavenging
and anti-inflammatory potentials
Journal of Food Bioactives | www.isnff-jfb.com 71

Table 1. Published review articles on Crataegus spp. bioactive compounds, pharmacological and health effects and safety - (continued)
Plants or their products Topic Summary of content Reference

C. oxycantha Treatment of atrial Mechanisms of cardiovascular health benefits; lack of Kanman-thareddy
fibrillation clinical studies evaluating its use in atrial fibrillation et al., 2015
C. monogyna Jacq. Polyphenolic A critical review about physiological and Nabavi et al., 2015
composition and pharmacological activities due to the presence
medical applications of different bioactive natural compounds. In
addition, scientific evidence suggests that
the toxicity of hawthorn is negligible
Hawthorn juice Various aspects Nutritional characteristics, bioactives and Venskutonis, 2016
antioxidant efficacy, phenolics, health effects,
novel products/formulations and future trends
Crataegus extract WS 1442 Benefit-risk assessment Positive inotropic and antiarrhythmic properties; Holubarsch et al., 2018
protecting from ischemic damage, reperfusion
injury, and hypertension-related hypertrophy;
improving endothelial functions (NO synthesis,
delay of endothelial senescence); favorable safety
profile (monotherapy and as add-on therapy); no
drug interactions; no specific adverse reactions
WS 1442 extract from Effects on Beneficial cardioprotective values; free radicals Zorniak et al., 2017
Crataegus spp. leaves cardiovascular system scavenger; protect the ischemic heart tissue
and flowers with 18.75% in vitro and in vivo, from neutrophile elastase action successions;
oligomeric procyanidins inc. large clinical trials vasorelaxant activity, via affecting eNOS synthase,
and prevents ischemic heart tissue swelling by
influence on calcium signaling pathways, and
thus detain hyperpermeability of endothelium.
Crataegus spp. Phenolic compounds; Beneficial effects and the mechanisms of Cervantes-Paz
their bioactivity action involved are analyzed in a critical and et al., 2018
systematic way in order to promote its use in
the treatment of various diseases considered
in Mexico as public health problems.
C. meyeri and C. pontica Antioxidant properties The advantages of using natural remedies over their Dolatkhani and
and medicinal uses synthetic equivalents, the necessity of thorough Jameie, 2015
investigations of less studied Crataegus spp
a significant DPPH• reducing activity compared with epicatechin of daytime, while most remarkable radical scavenging and reduc-
(Kazuma et al., 2016). Most of the compounds isolated from the ing power was determined for the leaves harvested in September
70% ethanolic extract of C. pinnatifida seeds showed moderate (Luo et al., 2016).
DPPH• scavenging activity and significant activities in the FRAP Several articles have reported phytochemical studies of C.
and ABTS assays. Furthermore, 6 compounds exhibited marked azarolus (Table 2). Thus, ethanolic extract of C. azarolus var. eu-
NO inhibition, 4 of them had a potent TNF-α inhibitory effect indi- azarolus Maire leaves was fractionated with different solvents and
cating that hawthorn seeds can be regarded as a potential new and it was found that ethanol extract (70%) showed the highest DPPH•
cheap source of antioxidants and inflammation inhibitors (Peng et scavenging activity compared to methanol, ethyl acetate and ac-
al., 2016). From C. pinnatifida, the isolated lignans demonstrat- etone extracts (Abu-Gharbieh and Shehab, 2017). A new ursane-
ed DPPH•/ABTS•+ scavenging efficacy, while some of them had type triterpene acid, named azarolic acid, and 8 known compounds
anti-inflammatory activities, which was assessed by detecting the were isolated from the crude ethyl acetate extract of C. azarolus
NO and TNF-α production in the LPS-induced RAW264.7 cells var. aronia (Mahmud et al., 2016). Phytochemical composition of
(Huang et al., 2015a). The fractions isolated with different polarity 20 phenolic compounds quantified in C. azarolus and C. monogyna
solvents from the crude 70% aqueous acetone extract of wood and fruits were compared (Mraihi et al., 2015). Methanol and ethanol
bark of C. pinnatifida demonstrated antioxidative and anti-inflam- extracts of C. azarolus exerted substantial antioxidant, anti-inflam-
matory activities. Thus, the n-butanol and ethyl acetate fractions matory, and antiproliferative capacities, which were evaluated by
of wood and bark, respectively, exhibited the strongest antioxidant measuring the secreted amounts of the proinflammatory mediator
effects, while all moisture-free fractions of wood showed high in- prostaglandin E2 (PGE2), and by assaying the mRNA levels of
hibitory effect on NO production (Bae and Kim, 2017). the proinflammatory cytokines (IL-α, IL-β, and Il-6), chemokines
Seasonal variations (May–October) in the yield of 7 phenolic (CCL3 and CCL4) and inflammation-sensitive COX2 and iNOS
compounds, the TPC in C. pinnatifida leaves, roots, twigs, and enzymes (Kallassy et al., 2017).
fruits were positively correlated with the temperature and length Dibenzo-p-furan derivatives and ursolic acid were isolated from

Table 2. Phytoconstituents of Crataegus spp. (recently reported; newly identified compounds are in italics)
Bioactivities, other
Sample information Name Reference
study objective
C. pinnatifida, extract of leaves 4 monoterpene glycosides, pinnatifidanosides Antithrombotic effects Li et al., 2015
A-D; phenolic glycoside, pinnatifidanoside E;
byzantionoside B, (3S,5R,6R,7E,9R)-3,6-epoxy-7-
megastigmen-5, 9-diol-9-O-β-D-glcp, (65,7Z,9R)-
roseoside, icariside B6, linalool oxide β-D-glc,
shanyenoside A, dihydrocharcone-2′-β-D-glc,
eriodectyol, vitexin, 2″-O-rhamnosyl vitexin
C. pinnatifida, ethanolic Norhawthornoids A, B; sesquiterpenoids Antithrombotic effects Gao et al., 2017
extract of leaves shnyegenin B, shnyeside B, (3S,5R,6R,7E,9S)-
megastiman-7-ene-3,5,6,9-tetrol, euodionosides
D, (6R,9R)-3-oxo-α-ionol-9-O-β-D-glucopyranoside,
(6S,7E,9R)-6,9-dihydroxy-4,7-megastiymadien-3-
one-9-O-[β-D-xylopyranosy-β-D-glucopyranoside],
linarionosides A, B, C; 3,9-dihydroxy-5-
megastigmen-3-O-[β-D-xylopyranosy-β-D-
glucopyranoside], pinnatifidanosides C, F, G.
C. pinnatifida, hydroethanolic Crataegusoids: A(−), B, C, D, E (−) and (+), F Cytotoxicity against Guo et al., 2018
extract of fruits cancer cells
C. pinnatifida, extract of seeds 8 new lignans, hawthornnins A-H Antioxidant and Huang et al., 2015a
and 7 known analogues anti-inflammatory
C. pinnatifida, extract of seeds 2 new 8-0-4′ neolignans, huangnin Tyrosinase inhibition Huang et al., 2015b
A and B; 4 known analogs
C. pinnatifida, 70% ethanol 7 Crataegusnins A-G; 3 substituted Antioxidant and Peng et al., 2016
extract of seeds propanetriols (3); leptolepisol D anti-inflammatory
Crataegus spp., 70% ethanol (7R, 8R, 8S)-, (7′S, 8′R, 8R)-, (7′R, 8′S, 8S)- Inhibition of amyloid Huang et al., 2018b
extract from seeds isolariciresinols, (7′S, 8′R, 8R)-lyoniresinol, (7′S, 8′R, Aβ1–42 aggregation
8R)-isolariciresinol-9′-β-D-glc, lyoniside, nudiposide
C. pinnatifida, flavonoid (-)-Epicatechin, quercetin-3-O-(2,6-di-α-L- Isolation and Wen et al., 2017b
extract of leaves rhamnopyranosyl)-β-D-galactopyranoside, purification of
4″-O-glucosyl and 2″-O-rhamnosylvitexins, flavonoids
vitexin, hyperoside and isoquercitrin
C. pinnatifida var. major, crude Crataegusins A and B (2) (new flavanocoumarins) DPPH reducing activity Kazuma et al., 2016
Crataegus Fructus drug
C. azarolus var. eu-azarolus EtOH: rutin, salicylic and ellagic acids; chloroform Anti-hyperglycemic Abu-Gharbieh
Maire, ethanol extract of and n-butanol fractions: ursolic, 3-β-O-acetyl activity Shehab, 2017
leaves and its fractions ursolic, and ellagic acids, quercetin-3-O-β methyl
ether, rutin and apigenin7-O-rutinoside
C. azarolus var. aronia, ethyl A new ursane-type triterpene acid, Anti-vasoconstriction Mahmud et
acetate extract of leaves azarolic acid, 4 known phenolic al., 2016
compounds; 4 known triterpene acids
C. monogyna, C. azarolus fruit 3 hydroxycinnamic and 1 hydroxybenzoic Phytochemical Mraihi et al., 2015
acid, 6 glucosylated flavonols and 2 flavones, characterization
2 cyanidin glycosides; (-)-epicatechin, a
dimer B2, two trimers, C1 and C2.
C. pycnoloba, total extract 4 dibenzofurans inc. newly discovered Melanin synthesis Agalou et al., 2018
compound 6-hydroxy-2,3,4- inhibition
trimethoxydibenzofuran; ursolic aldehyde.
C. oxyacantha, shade 2-(3, 4-dimethoxyphenyl)-2-methoxyethanol, Inhibition of acetyl and Ali, et al., 2017
dried plant twigs 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl propan- butyryl-cholinesterases
1-one, β-sitosterol-3-O-β-D-glc, lupeol, β-sitosterol,
betulin, betulinic and oleanolic acids, chrysin (9);
Crataegus spp. from Bosnia, In mg/g DW: gallic acid (0.001–0.082), chlorogenic Phytochemical Čulum et al., 2018
leaves with flowers, and berries acid (0.19–8.70, rutin (0.03 to 13.49). characterization

Table 2. Phytoconstituents of Crataegus spp. (recently reported; newly identified compounds are underlined) - (continued)
Bioactivities, other
Sample information Name Reference
study objective
C. pubescens, Fruit pulp In mg/100 mg DW: (+)-catechin Phytochemical González-Jiménez
(from Mexico) (9.17±0.20), (-)-epicatechin (4.32±0.11), characterization et al., 2018
chlorogenic acid (5.60±0.24 mg/100); total
proanthocyanidins 84.6±1.4 mg cyanidin;
total flavonoids 55.89±1.43 mg quercetin.
C. microphylla Koch. ssp. In mg/g DW: gallic acid 0.04, caffeic Phytochemical Čopra-Janićijević
malyana K. I. Chr. & Janjic, acid0.60, and hyperoside 2.61; TPC: 2.47 characterization et al., 2018
extracts of leaves with flowers to 13.35 GAE; TFC: 0.01–1.09 QE
Various Crataegus spp., TPC: 7.21–87.73 mg GAE/g DW; TFC: Flavonoids profile, Alirezalu et al., 2018
flowers and leaves of 56 2.27–17.40 mg/g DW; chlorogenic acid, antioxidant activity
samples from Iran vitexin-2-O-rhamnoside, vitexin, rutin,
hyperoside, quercetin, isoquercetin
C. almaatensis Pojark, 22 secondary metabolites (flavonoids Copmparison with Bekbolatova
leaves, flowers and fruits and phenolic acids); TPC: 218 mg/g C. oxyacantha et al., 2018
C. pinnatifida, 15 triterpenoids, inc. 4 novel hydroxy-olean- Antiproliferative and Qiao et al., 2015
commercial berries 12-en-28-oic (HOA) acids: 3-β,6 β,18 β-triHOA, antioxidant activity
3 β,6 β,18 β,23-tetra HOA, 2 α,3 β,6 β,18
β-HOA, 2 α,3 β,6 β,18 β,23-pentaHOA
Fruits, methanol, ethanol, Water (mg/g): vanillic (0.093), gallic (0.279) Effect of solvents, Miao et al., 2016
acetone (80%) water extracts acids, catechin (3.622), chlorogenic (1.457 antioxidant,
0.058) and ferulic (6.909) acid; acetone: α-glucosidase
epicatechin (2.71), protocatechuic acid (5.827) inhibitory activity
Crataegus spp., of 81 components: benzaldehyde (82.54%) Volatile, components, Ozderin et al., 2016
leaves and flowers butyraldehyde (38.27%), (E)2-hexenal (21.67%) aroma
C. pinnatifida, GC area %: Methyl acetate (4.40), n-hexane Volatile compounds, Zhong et al., 2015
(2.90), 2-methyl-furan (1.80), 3-methyl- aroma
butyraldehyde (3.64), hexanal (2.08),
furaldehyde (5.77), D-limonene (7.99)
Hawthorn, pharmaceutical Essential oil (%): 0.05 to 0.20% v/w; tricosane Essential oil, aroma Kowalski et al., 2018
forms of inflorescence (12–17), (11–16), (6–11), n-hexadecanoic
acid (1–11), nonadecane (3–7), (E,E)-α-
farnesene (1–5), caryophyllene oxide
(1–4), methyl eugenol (up to 6).
Abbreviations are: glcp,glucopyranoside; glc, glucoside; TPC,total phenolic content; TFC,total flavonoid content; GAE,gallic acid equivalents; and QE,quercetin equivalents.
C. pycnoloba extract, including the atom numbering of the newly were reported for different extracts of C. microphylla Koch subsp.
discovered compound (Agalou et al., 2018); 9 compounds were malyana K. I. Chr. and Janjic; interestingly, the Soxhlet extract of
isolated from C. oxyacantha, including 2 new natural products leaves with flowers was best in DPPH• scavenging (IC50 = 0.78
(Ali et al., 2017). Selected phytochemicals and antioxidant poten- mg/mL) while that of berries was stronger as ABTS•+ scavenger
tial were studied in the C. monogyna ethanolic extracts from bark, with IC50 of 0.39 mg/mL (Čopra-Janićijević et al., 2018). TPC in
leaves and berries: the highest TPC, radical scavenging potency methanol extracts of C. monogyna from nine different locations
as well as the levels of oleanolic acid, quercetin and lupeol were in central Spain was in the range of 117.7–204.3 mg GAE/g ex-
found in the bark extract, while the highest ursolic acid content tract, the amounts of chromatographically quantified flavonoids
was in the berries extract (Rezaei-Golmisheh et al., 2015). and phenolic acids was 23.3–143.3 mg/kg, while ORAC and IC50
The main phenolics in ethanolic extracts of leaves and berries of DPPH• scavenging values were 1.32–2.76 mol TE/mg and
of C. orientalis Pall. ex M. Bieb. from F.Y.R. Macedonia were hy- 0.82–3.76 g/mL, respectively (Abuashwashi et al., 2016). TPC and
peroside, isoquercitrin and chlorogenic acid (Šavikin et al., 2017), DPPH• scavenging activity as well as the contents of metals (Zn,
while vitexin and hyperoside, commonly found in chemotaxo- Fe, Cu, Mn, Cd, Cr, and Pb) were reported in wild C. oxyacantha
nomic investigations of Crataegus spp., were not detected in dry from Serbia (Veličković et al., 2016).
leaves with flowers, and berries of C. rhipidophylla Gand., C. × Chlorogenic acid, hyperoside, and rutin were the most abundant
subsphaericea Gand., and C. × macrocarpa Hegetschw grown in phenolics in the extracts of hawthorn flowers in most genotypes of
Bosnia (Čulum et al., 2018). The presence of polymeric polyphe- 56 studied Crataegus spp. samples collected from different geo-
nols (procyanidin dimers, trimers, and tetramers) in C. pubescens graphical regions of Iran (Alirezalu et al., 2018). The composition
fruit from Mexico was reported for the first time (González-Jimé- of 22 secondary metabolites (flavonoids and phenolic acids) in
nez et al., 2018). The composition and antioxidant activity in vitro leaves, flowers and fruits of endemic in Kazakhstan C. almaatensis

Pojark was compared with a well-known C. oxyacantha flowers. and antioxidant capacity were determined during production and
Leaf extracts were the richest sources of metabolites (TPC = 218 storage. Only six anthocyanins were detected after fermentation.
mg/g) and the most active DPPH• scavengers (IC50 = 48 μg/mL), Microwaving and heating pretreatments significantly increased the
while the flowers of the Kazakh species were as rich in polyphe- total amount of anthocyanin and antioxidant capacity values in the
nols as the C. oxyacantha (Bekbolatova et al., 2018). stored hawthorn wine while the TPC decreased (Liu et al., 2018).
Evaluation of 18 hawthorn genotypes selected from reposi- Heat and microwave pretreatments had also a significant impact on
tory collection in Malatya province (Turkey) belonging to several anthocyanins in hawthorn drink; more of them remained after heat
Crataegus spp. revealed that the genotype 44MA12 (C. monogyna treatment than after microwaving (0.745 mg/100 mL); these were
subsp. azarella) had the highest anthocyanin content (516 mg per 52.4% higher than those in the control group after storage for 7
100 g fresh fruit) and the strongest DPPH• scavenging capacity, days (Liu et al., 2016). Chemometric methods (spectrophotometry
while the genotype 44MA11 (C. meyeri) had the highest TPC, and HPLC) were successfully applied to differentiate raw and pro-
3,460 mg GAE/100 g fresh fruit (Ercisli et al., 2015). Thirty-five cessed Crataegi Fructus (Fei et al., 2018). Significant differences
compounds were isolated from C. dahurica methanol extract for in physicochemical characteristics associated with fruit quality and
the first time and their structures identified as triterpenoids and free amino acids were found during maturation of hawthorn fruits;
polyphenolics as the main components (Wang et al., 2018). Evalu- for instance, the content of moisture, total soluble sugars, soluble
ation of antioxidant activities, TPC, TPF of crude methanolic ex- pectin, reduced ascorbic acid, total ascorbic acid, fructose, and su-
tract and its fractions (ethyl acetate, diethyl ether, and chloroform) crose increased while crude protein content decreased significantly
obtained from Algerian C. azarolus showed that the aerial parts (Li et al., 2015).
extracts of this species are a good source of natural antioxidants Some studies were evaluating extraction methods. In general,
(Lakache et al., 2016). Anthocyanin composition of different wild selection of extraction solvents and procedures may have different
and cultivated berry species including Chinese hawthorn were goals, e.g. obtaining high total yields or recovery target bioactive
quantified by Veberic et al. (2015). Thirty six compounds were fractions/constituents. Ethanol and water, as the most friendly and
reported in different extracts of hawthorn fruit, 15 of them were effective polar solvents, have been most widely used for food, nat-
tentatively identified in hawthorn fruits for the first time (Miao ural pharmaceuticals and cosmetics. For instance, different ethanol
et al., 2016). TPC, condensed tannin content and DPPH•/ABTS•+ concentrations (0–100%) were applied for C. pinnatifida and the
scavenging capacities were higher for fruit extracts of C. pinnati- yields were 19.03, 33.16, 27.79, 21.88, and 21.71% at 100, 70, 50,
fida Bge. var. major N. E. Br. (Shanlihong) than for the other two 30 and 0% (water) concentration, however the highest TPC and
Chinese hawthorn varieties, namely C. pinnatifida Bge. (Shanzha) DPPH•/ABTS•+ scavenging capacity was obtained in case of 50%
and C. pinnatifida Bge. var. pinnatifida (Dou et al., 2015). The (Kang, 2015). The technical and economic advantages of pres-
advantages of Shanlihong variety, which exhibited elevated levels surized hot water (90 °C) extraction of C. monogyna compared
of TPC and TFC, including free and bond phenolics (procyanidin to traditional percolation with ethanol and water (70:30, v/v) was
B-2 epicatechin, chlorogenic acid, hyperoside, and isoquercitrin), shown by successful incorporation of natural batch variability into
were also reported by Wen et al. (2015). Among the three tested the physico-chemical process modelling concept (Sixt and Strube,
varieties, the ORAC, and hydrophilic peroxyl radical scaveng- 2018). Matrix solid-phase dispersion process was also suggested
ing capacity of the free faction were 398.3–555.8 μmol TE/g DW, as a good alternative to the classic methods for extracting poly-
and 299.1–370.9 μmol vitamin C equivalents/g DW, respectively, phenols from C. oxyacantha fruits and leaves, although phenolic
while the corresponding cellular antioxidant activity (CAA) val- profile was solvent-dependent (Benabderrahmane et al., 2018). In
ues were 678–1,200 μmol of QE/100 g DW in the no PBS wash addition, this study claimed that epicatechin gallate, caftaric acid
protocol, and 345.9–532.9 μmol of QE/100 g DW in the PBS wash and orientin were not previously reported in this species. Ultra-
protocol. Finally, the fruits of C. pinnatifida were subjected to in sonic assisted extraction (UAE) using an alkyl polyglycoside sur-
vitro digestion and it was determined that 37.41 and 31.51 mg factant and further separation and purification with commercial
GAE/g DW of TPC were released for Shanlihong and Dajinxing, macroporous resins was shown as an effective techniques for re-
respectively, while procyanidin B2, epicatechin, chlorogenic acid covery of vitexin and its 2″-O-rhamnoside from the leaves (Han et
and catechin were the major released flavonoids. ORAC and per- al., 2016a). The extract obtained by UAE from C. pinnatifida fruits
oxyl radical scavenging capacity well correlated with the released demonstrated higher TPC, TFC and DPPH• scavenging capacity
TPC or flavonoids (Zheng et al., 2018). (Park et al., 2017b). Aqueous solutions of citric acid and methanol
Some studies have reported the volatile compounds of hawthorn were compared for C. monogyna fruit; it was found that the former
although the content of essential oil in Crataegus spp. is usually was favorable in terms of total yield, TPC and ascorbic acid, while
very low. For instance, in 4 tested pharmaceutical forms of haw- DPPH• and ABTS•+ scavenging capacity was not dependent on the
thorn inflorescence it was from 0.05 to 0.20% (v/w) and composed solvent (Pliszka et al., 2016). Hawthorn seeds, as a byproduct of
mainly of long chain hydrocarbons (Kowalski et al., 2018). Zhong manufacturing hawthorn juice and jam, were evaluated as a poten-
et al. (2015) identified 46 volatile compounds in C. pinnatifida tial new and cheap source of antioxidants and inflammation inhibi-
with contents higher than 1% in the total GC area by HS-SPME tor (Huang et al., 2015).
coupled with GC-MS. The contents of furaldehyde, 5-methyl- A protocol for preparative isolation of oligomeric and poly-
furaldehyde, methyl acetate, 2-methylbutyraldehyde, D-limonene meric procyanidins from an acetone-water extract of Crataegi
and 2-methylfuraldehyde significantly changed after stir-frying folium cum fore was developed, yielding procyanidin reference
and it might be important in odor changes. Volatile components clusters with defined degree of polymerization (DP) from 2 to 10
were also reported in C. pentagyna subsp. pentagyna, C. orientalis (Hellenbrand et al., 2015). In addition, monitoring of procyanidin
subsp. orientalis, C. orientalis subsp. szovitsii, C. tanacetifolia, C. distribution during seasonal growth of fresh C. monogyna plants
azarolus var. aronia, C. monogyna var. lasiocarpa, C. monogyna showed that their contents were between 20 and 55 mg/g DW of
var. monogyna leaf and flower samples collected from different oligomeric procyanidins during the growing season in the different
provinces of Western Anatolia (Ozderin et al., 2016). plant organs with strong accumulation in the flowers and fruits (55
The changes of phytochemicals during processing and stor- mg/g DW). Regarding other components, the viscoelastic behavior
age were also studied. “Xinglongzirou” hawthorn wine bioactives and texture profile of gels, composed of the high methoxypectin in

hawthorn, were compared with commercial citrus gels (Linares- was validated in a mESC-based spontaneous differentiation assay,
Garcia et al., 2015); the homogenous polyphenolic-polysaccharide while bioassay-guided fractionation suggested that this activity
conjugates (MW > 760 × 103 and 970 × 103 g/mol) containing is exerted by specific classes of compounds (Halver et al., 2015).
some flavonoid units and rich in galacturonic acid with low es- Aerobic exercise and administration of C. oxyacantha extract re-
terification degree were isolated from flowers and fruits of C. mo- duced ICAM-1 and E-selectin in serum levels of 80 stable angina
nogyna (Pawlaczyk-Graja, 2018). pectoris patients and such combined treatment was suggested as an
effective complementary strategy for lowering the risk of athero-
sclerosis and heart problems (Jalaly et al., 2015).
3. Cardioprotective benefits The cardiac effects of hydroalcoholic extract of C. pentagyna
leaf as well as isoquercetin and vitexin were studied using car-
Cardiovascular health benefits of various Crataegus drugs and diomyocytes differentiated from healthy human embryonic stem
other preparations have been most widely studied. In addition, cells, namely long QT syndrome type 2 and catecholaminergic
polymorphic ventricular tachycardia type 1 (CPVT1) patient-spe-
the potential role of hawthorn in cardiovascular diseases was spe-
cific induced pluripotent. It was concluded that tested preparations
cifically reviewed by Chang et al. (2005). Hawthorn extracts have
may be introduced as a novel nutraceutical with antiarrhythmic
been used for this purpose in many countries, particularly against
potential for CPVT1 patients (Pahlavan et al., 2018). The effects
mild forms of chronic heart failure. For instance, search word com-
of polyphenolic extracts of C. pentagyna and C. microphylla fruits
bination Crataegus+cardiovascular in Clavirate Analytics Web of
on hypoxia, which is a state of oxygen deficiency occurring in
Science (WoS) since 1980 gave 286 records, and even during last 4
heart diseases, ischemia, bleeding and heart attack, were studied
years (since 2015) the number of publications on this topic remains
using male Swiss albino mice model. It was found that the extracts
quite high, 61 (accessed on December 7, 2018). Consequently, the
exhibited significant anti-hypoxic activity and prolonged animal
interest in hawthorn as a source of natural cardioprotective medi- survival time (Ebrahimzadeh et al., 2018). The activity of these ex-
cine, nutraceutical and functional food is evident. tracts was attributed to a high TPC, 1,136.0 and 721.1 GAE mg/g
Hawthorn extract WS 1442 containing a range of pharmaco- in C. pentagyna and C. microphylla, respectively. Polyphenolic-
logically active substances including oligomeric proanthocya- polysaccharide conjugates from flowers and fruits of C. monogyna
nidins and flavonoids is, possibly, the most famous Crataegus prolonged the plasma coagulation process in in vitro tests, even at
fruit-based drug with 89 and 14 records in WoS since 1980 and a concentration of 31.25 μg/mL; however, only the product from
2015, respectively. Moreover, two most recent articles reviewed flowers was highly selective in its action. It was mainly the indi-
WS 1442 in terms of experimental and clinical experiences (Zor- rect inhibitor of factor Xa, mediated by antithrombin, where such
niak et al., 2017) and benefit-risk assessment (Holubarsch et al., mechanism of activity is typical for highly sulfated glycosamino-
2018). Therefore, only those studies, which were not reviewed glycans (Pawlaczyk-Graja, 2018).
in these publications, will be covered briefly. Thus, Fuchs et al. Flavonoid-rich preparations of C. pinnatifida leaves (HLF) have
(2017) reported that WS 1442 protective effects against mild forms been used to treat cardiovascular diseases; however, their ability to
of chronic heart failure dysfunction may be due to the promotion attenuate atherosclerosis development and possible mechanism are
of endothelial barrier integrity and inhibition of endothelial hy- not evident. To fill this gap, Dong et al. (2017) by the large scope in
perpermeability, which are exerted by activating barrier enhanc- vivo studies using apoE knockout mice showed that administration
ing (cortactin activation) and blocking barrier disruptive (calcium of HLF resulted in the following effects: (1) reduction of the mean
signaling) pathways, respectively. Bioactivity-guided fractiona- atherosclerotic lesion area in en face aortas; (2) decrease in total
tion of WS 1442 using successive elution with water, 95% etha- cholesterol (TC) and very low density lipoprotein cholesterol plus
nol, methanol, and 70% acetone, revealed that only the ethanolic low density lipoprotein cholesterol (VLDLc+LDLc) levels; (3) in-
fraction interfered with calcium signaling and only the methanolic crease in PPARα mRNA and RCT; (4) decrease in SREBP-1c; (5)
fraction led to an activation of cortactin. Moreover, the role of induction of CPT-1 mRNA, SOD1 and SOD2, Gpx3 mRNA, LDL
phenolic compounds was excluded from the calcium active sub- receptor mRNA and protein levels; and (6) inhibition of the foam
stance, whereas cortactin activation was attributed to oligomeric cell formation. HLF also protected rats against diabetic cardiomy-
procyanidins with a distinct degree of polymerization (Fuchs et opathy and the mechanism may be involved in reducing oxidative
al., 2017). The study with human umbilical vein endothelial cells stress and inflammation via inactivation of the PKC-α signaling
(HUVECs) exposed to TNF-α, with or without simvastatin (posi- pathway (Min et al., 2017).
tive control) and WS 1442, suggested that the factors upregulat- The new norditerpenoids (Table 2) isolated from the leaves
ing miR-155 expression, which decreases eNOS expression and of C. pinnatifida exhibited exceptionally potent antithrombotic
endothelial function impairment, may be mitigated by WS 1442 activities in vitro and in vivo, pinnatifidanoside F being the most
(Wang et al., 2018). The results demonstrated that both TNF-α and potent one (Gao et al., 2017). It inhibited ADP induced platelet ag-
WS 1442 increased miR-155 expression and decreased eNOS ex- gregation, which is mediated through the response to the specific
pression, however, unlike TNF-α, WS 1442 increased phosphoryl- receptor of P2Y(12), and prolonged the time to form thrombocytes
ated eNOS expression and NO concentrations and mitigated the induced by FeCl3 in the caudal vessels of zebrafish. In vivo study
overall negative effect of miR-155. Protecting effects of total fla- with diabetic rats demonstrated that resistance training and C. oxy-
vones of hawthorn combined with resveratrol on the endothelial acantha extract can synergistically decrease ischemia-reperfusion
cells injury after artery bypass graft surgery were demonstrated in injury by oxidative stress reduction: injury indices (plasma lactate
the study with rabbits, which determined that the level of circulat- dehydrogenase, creatine kinase myocardial band isoenzyme and
ing endothelial cells, density and the expressions of albumen and infarction size) were significantly lower after sedentary diabetic
mRNA of ICAM-1 were significantly decreased (Zhu et al., 2018). group treatment with extract, whereas glutathione peroxidase and
It was also reported that WS (R) 1442 improved vascular function myeloperoxidase levels after reperfusion increased and decreased,
in diet-induced obese mice (Xia et al., 2016). The activity of WS respectively, in response to training and C. oxyacantha (Ranjbar et
1442 in stimulating cardiomyocyte differentiation from murine al., 2018). On the other hand, the study with 116 patients who un-
and human embryonic stem cells (ESC) after forming mesoderm derwent cardiac surgery showed that those who recently consumed

hawthorn extract had a significantly higher rate of postoperative weight and liver/body weight ratio; (2) improving serum param-
bleeding and overall mortality rate, which indicates that hawthorn eters and liver dysfunction; (3) decreasing hepatic lipid accumu-
extract consumption increases the potential for bleeding and the lation; (4) increasing circulating adiponectin levels and up-regu-
amount of chest tube output after cardiac surgery (Rababa’h et al., lating the expression of adiponectin receptors (AdipoR2) in the
2016). liver; and (5) activating AMP-activated protein kinase (AMPK)
C. oxyacantha alcoholic extract produced an antiarrhythmic ef- and altering AMPK-mediated SREBP-1c, PPAR-α and their
fect that was induced by digoxin in Wistar rats; however, in the downstream targets (Li et al., 2015). The inhibitory activities of C.
clinical use of this extract, the hypotensive effect should be consid- pinnatifida extract isolated with 50% ethanol were more effective
ered (Alp et al., 2015). Another in vivo study reported that adminis- against formation of advanced glycation end products (AGEs) and
tration of methanolic C. songarica extract at the dose of 300 mg/kg α-glucosidase, while water extract better inhibited aldose reduc-
body weight to albino rats with CCl4-iduced toxicity significantly tase (Kang, 2015).
decreased serum creatinine, urea, and cholesterol, malondialde- Investigation of the effects of aqueous extract of C. aronia (syn.
hyde (MDA) in kidney and heart tissues, along with recovery in azarolus L.) on sperm parameter and testicular structure in con-
antioxidant enzyme levels (Ganie et al., 2016). It was also reported trol and NAFLD-induced rats showed the improvements of the
that standardized Crataegus extract prevented DOCA-salt-induced following indicators: (1) lower hepatic TG and cholesterol con-
hypertension and alteration of cardiac, vascular and renal structure tents; (2) higher levels of testosterone, luteinizing hormone and
and function in rats (Schini-Kerth et al., 2015). One of the main follicle-stimulating hormone; (3) increased epididymis weight,
hawthorn bioactives vitexin inhibited cytochrome P450 enzyme sperm count and motility; and (4) increased testicular levels of
(CYP3A1) in a concentration-dependent and time-dependent glutathione, higher protein levels of Nrf2, γ-glutamylcysteine syn-
manner while CYP2C11 enzyme activity was induced after short thetase and SOD (Dallak, 2018).
period treatment but inhibited after long period treatment. It was The potential of novel multi-targeted herbal formula containing
concluded that vitexin can either inhibit or induce the activities Crataegus Fructus, sylimarin, Schisandrae Fructus and Momordica
of these enzymes and possible herb-drug interactions should be charantia, as a therapeutic agent for diet-induced metabolic syn-
considered when vitexin is co-administered with some CYP2C11 drome with special emphasis on NAFLD, dyslipidemia and type 2
or CYP3A1 substrates in clinic (Wang et al., 2015). diabetes, was studied using male C57Bl/6 mice. Crataegus Fructus
Some studies reported antithrombotic and anti-vasoconstriction aqueous extract inhibited differentiation of 3T3-L1 preadipocytes
effects exerted by Crataegus bioactives. Thus, among 15 from and cholesterol uptake into Caco-2 cells, while the whole herbal
C. pinnatifida leaves isolated compounds (Table 2) (65,7Z,9R)- formula exhibited mitigation of diet-induced increase of various
roseoside, eriodectyol and 2″-O-rhamnosyl vitexin exerted potent indicators in vivo, namely (1) a trend to reduce body weight and fat
antithrombotic activity in vitro, which was in agreement with the pad mass, (2) significant reduction in liver weight, liver lipid, and
in vivo results obtained in transgenic zebrafish system (Li et al., plasma lipid, (3) reduction of liver inflammation, and (4) improve-
2015). C. monogyna and C. davisii significantly inhibited the car- ment of adiponectin level (Elaine et al., 2018).
rageenan-induced mouse tail thrombosis and may potentially be The results of a number of studies support the hypothesis that
used as therapeutic agents or complementary treatments against hawthorn possesses both therapeutic and protective effect for
thrombosis (Arslan et al., 2015). Euscaphic acid isolated from the NAFLD. C. aronia extract and simvastatin significantly reduced
crude ethyl acetate extract of C. azarolus var. aronia showed high lipids and thiobarbituric acid reactive substances (TBARS), which
anti-vasoconstriction effects on aortic rings, supporting the use were increased by oxidative stress in HFD rat group, and treated
of this medicinal plant in cardiovascular disease (Mahmud et al., damage to hepatic cells, while only the extract induced GSH. C.
2016). aronia and simvastatin treatments differentially reversed hepatic
injuries (Al Humayed et al., 2017). Another in vivo study dem-
onstrated that C. aronia significantly reduced liver index (3.85%
4. Hypolipidemic and hypoglycemic activity versus 6.22% in HFD rat group), increased HDLC/LDLC and im-
proved oxidative stress biomarker and enzymes indicating liver
damage (Al Humayed, 2017). Ethanol extract of C. oxyacantha
4.1. Hypolipidemic effects administered at 10 and 20 mg/kg to HFD rats reduced the level of
some liver biomarkers, especially lactate dehydrogenase (LDH),
Lipid-lowering effects of hawthorn have been widely studied in increased GSH and FRAP and decreased lipid peroxidation, which
vivo in many cases using HFD animals. Plant preparations dem- may be beneficial in restoring the hepatocyte damage (Saeedi et
onstrated the ability to lower tricylglycerol (TG), total cholesterol al., 2018).
(TC), LDLC and VLDLC, and to increase HDLC in plasma and Polyphenols-enriched extracts from hawthorn fruit peels (HPP)
these effects have been explained by several possible mechanisms and flesh (HFP), containing chlorogenic acid, epicatechin, rutin
(Yang and Liu, 2012). Recently published articles extended exist- and hyperoside as the main polyphenolic constituents (HPP >
ing knowledge on hypolipidemic benefits of Crataegus prepara- HFP), reduced alanine aminotransferase (ALT), aspartate ami-
tions, particularly HLF, some of them carried out in in vivo stud- notransferase (AST) and alkaline phosphatase (ALP) activities, as
ies with NAFLD animals and reported beneficial effects on liver well as the ratio of pro-apoptotic protein with B-cell lymphoma-2
health, which highly depends on HFD. (Bax/Bcl-2) in mice with liver injury, which was induced by a
C. pinnatifida extract decreased the levels of serum TC, LDLC, high-fructose diet. HPP was more effective than HFP in mitigat-
hepatic TG and MDA, increased mRNA expression of nuclear ing liver inflammation and oxidative stress by inhibiting inflam-
erythroid 2-related factor (Nrf2), heme oxygenase-1 (HO-1), Gpx matory cytokine (TNF-α, IL-1 and IL-6) release, elevating anti-
and reversed the suppression of protein levels in ovariectomized oxidant enzyme activities and PPARα expression, reducing Nrf-2
rats (Yoo et al., 2016). Li et al. (2015) reported that C. pinnatifida and antioxidant response element (ARE) expression in mice. HPP-
HLF ameliorated hepatic steatosis by enhancing the adiponectin/ treated mice also had lower levels of TC, TG, LDLC, VLDLC and
AMPK pathway in the liver of HFD-induced NAFLD rats. Several apoprotein B (Apo-B), and higher levels of HDLC and Apo-A1
beneficial events were determined: (1) lowering body and liver than HFP-treated mice due to reduced expression of fatty acid syn-

thetase (FAS) (Han et al., 2016b). while the expression of glucose transporter-2 (GLUT-2) and glyc-
Hypolipidemic and antioxidant effects of aqueous and etha- erol kinase (GK) mRNA was lowered. Consequently, C. aronia
nolic extracts of C. pinnatifida fruits were compared in hyper- ameliorated type 2 diabetes mellitus by inhibiting hepatic glucose
lipidemia rats and obvious differences between extracts were ob- output. Out of six tested plants, ethanolic extract of C. monogyna
served, probably due to the existing differences in the content of leaves exhibited the best α-glucosidase inhibition activity with
phenols (Shao et al., 2016). Polyphenolic extracts of C. azarolus IC50 = 10.39 μg/mL, and was stronger inhibitor of α-amylase and
and C. monogyna leaves, fruit peel, and pulp, possessing antioxi- α-glucosidase than its traditionally made with hot water tea (Sayin
dant activity, protected against thermal-cholesterol degradation et al., 2018).
while pre-treatment with the extracts preserved liposomes and rat Complex herbal formulas with Crataegus have also been tested.
liver-homogenate from oxidative Cu2+ and Fe2+ induced damage The potential anti-obesity effects (inhibition of lipogenesis and adi-
(Belkhir et al., 2016). Synergic effects and potential mechanisms pogenesis) of HT048 (a combination of C. pinnatifida leaf and Cit-
of action of Astragalus polysaccharides combined with Crataegus rus unshiu peel extracts) was investigated in vitro and in vivo using
flavonoids were studied with diabetic mice. The mixture signifi- 3T3-L1 adipocytes and male Sprague Dawley rats, respectively
cantly reduced the fasting blood glucose, food and water intake (Lee et al., 2015). HT048 suppressed, dose-dependently, adipocyte
and restored increased serum insulin levels and islet cell function; differentiation and stimulated glycerol release and decreased the
it also increased protein expression levels of pancreatic and duo- expressions of PPAR and C/EBP mRNA in adipocytes while in
denal homeobox-1 and phosphorylated AMPK in the pancreatic rats it significantly reduced the body and fat, as well as serum li-
and liver tissue samples, respectively. The mixture significantly pid levels, decreased expression of the hepatic lipogenesis-related
increased the mRNA expression levels of neurogenin 3 (v-maf genes and increased the expression of the oxidation-related genes
musculoaponeurotic fibrosarcoma oncogene), protein A and insu- (Lee et al., 2015). The effects were supported one year later when
lin, and simultaneously decreased the expressions of IL6, TNF-α it was demonstrated that HT048 decreased body and total white
and chemokine (C-C motif) ligand 2 in the pancreatic islet cells of adipose tissue weight and serum insulin levels in HFD-fed obese
diabetic mice (Cui et al., 2016). rats, whereas at the molecular level the supplement downregulated
One of the most important Crataegus phytochemical, hypero- genes involved in lipogenesis, gluconeogenesis, and adipogenesis,
side, induced apoptosis in human hepatic stellate LX-2 cells and and up-regulated β-oxidation genes. In addition, no interactions
decreased the levels of α-smooth muscle actin (α-SMA), type I were observed between HT048 supplementation and orlistat drug,
collagen, and intracellular ROS. Remarkably, hyperoside also in- which was also used in the study (Lee et al., 2016). Orlistat and C.
hibited the DNA-binding activity of the transcription factor NF-κB monogyna ethanolic extracts significantly lowered the hypercho-
and altered expression levels of NF-κB-regulated genes related to lesterolemia-increased serum level of hepatic enzymes and lipid
apoptosis, including pro-apoptotic genes Bcl-Xs, DR4, Fas, and peroxidation level in the hypercholesterolemia-induced oxidative
FasL and anti-apoptotic genes A20, c-IAP1, Bcl-X-L and RIP1. stress in rats, protected from hepatic thiol depletion, and improved
These results suggest that hyperoside may have potential as a ther- lipid profile and hepatic damages (Rezaei-Golmisheh et al., 2015).
apeutic agent for the treatment of liver fibrosis (Wang et al., 2016). The results of Cheng et al. (2015) study with mice demonstrated
that supplementation with a formula composed of Rhizoma di-
4.2. Hypoglycemic effects oscorea, Lycium barbarum, Prunella vulgaris and hawthorn may
be a potent alternative as an anti-diabetic health-promoting diet.
Finally, hawthorn pectin pentasaccharide (HPPS) was shown to be
Enzyme inhibitory activity in vitro is a simple and widely used
method for the preliminary evaluation of hypoglycemic effects. more effective than pectin (HP) and pectin hydrolyzates (HPH)
Comparison of hawthorn extracts prepared from plant fruit using in decreasing the body weight gain, liver weight, and plasma and
80% ethanol, 80% methanol, 80% acetone and pure water revealed hepatic TC of hamsters fed by high-cholesterol diets. However,
that acetone extract had the highest α-glucosidase inhibitory activ- the HP group had higher cholesterol excretion capacities than the
ity while the highest DPPH• scavenging capacity and FRAP was HPH and HPPS groups by inhibiting cholesterol absorption in the
exhibited by the water extract. Polyphenols, triterpenoids, proto- diet (Zhu et al., 2015a). Thus, HPPS could be a promising anti-
catechuic acid and epicatechin contributed to the α-glucosidase atherogenic dietary ingredient for the development of functional
inhibitory activity, while flavonoids, polyphenols, vanillic acid, food to improve cholesterol metabolism.
gallic acid, catechin and chlorogenic acid contributed to the anti-
oxidant activity (Miao et al., 2016).
5. Anticancer effects
Antihyperglycemic (Male albino mice) and antihyperlipidem-
ic (Sprague Dawley rats) activities of the ethanolic extract of C.
azarolus var. eu-azarolus leaves and the isolated 3β-O acetyl urso- The majority of studies evaluating anticarcinogenic properties of
lic acid were proved by significantly reduced mice blood glucose plant origin products are based on cell cytotoxicity and apoptosis
level in a time-and dose-dependent manner, while ethanolic extract assays, while in vivo studies, which provide more relevant physi-
significantly reduced LDLC, VLDLC, TC and TG and increased ologically information, are rather scarce. In addition, the mecha-
HDLC. In addition, ethanolic extract and 3β-O acetyl ursolic acid nism of activity is very important issue in evaluating anticancer
reduced the activity of pancreatic lipase in vitro (Abu-Gharbieh properties. Several recent studies, which were focusing on anti-
and Shehab, 2017). C. aronia significantly improved the oral glu- cancer effects of Crataegus extracts, their fractions and purified
cose tolerance test, lowered plasma glucose, serum lipid levels and compounds, are reviewed in this section.
the hepatic glycogen content. In addition, it significantly lowered Hawthorn’s health benefits are mainly associated with the high
the levels of hepatic lipid peroxidation, TNF-α and IL-6, while the contents of polyphenolics. C. pinnatifida var. major fruits, contain-
level of reduced glutathione (GSII) was enhanced and SOD activ- ing high amounts of flavonoids and triterpenoids, showed potent
ity was increased (Mostafa et al., 2018). Regarding the mechanism antiproliferative effect against human cancer cells lines (liver, Hep
involved, it enhanced hepatic mRNA expression of the insulin G2; breast, MCF-7 and MDA-MB-231); particularly strong activ-
receptor A isoform (IR-A) and glucose 6-phosphatase (G6Pase), ity was determined for triterpenoids-enriched fraction and its main

ingredient ursolic acid, which induced restriction point G1 arrest, ited potent in vitro anticancer activity on MCF-7, HeLa, HepG2,
downregulated proliferating cell nuclear antigen (PCNA), cyclin- SF-295, SW480 and IMR-32 cancer cell lines with IC50 values of
dependent kinase (CDK4), and a protein Cyclin D1 (in humans 28.57–85.106 μg/mL, while methanol extract demonstrated protec-
encoded by the CCND1 gene) and upregulated cyclin-dependent tive activity for albino rats’ kidney and heart tissue against CCl4-
kinase inhibitor 1p21(Waf1/Cip1) in MDA-MB-231 cells (Wen et induced toxicity in vivo (Ganie et al., 2016). C. monogyna extract
al., 2017). In addition, the supplements induced MDA-MB-231 at 100–75 μg/mL concentrations exhibited better antiproliferative
apoptosis via mitochondrial death pathway induced by caspase (9 activity against C6 cell lines than 5-flurouracil drug (5-FU) and
and 3) activation. cisplatin, and also demonstrated considerable antiproliferative ac-
The studies performed by Mustapha et al. (2015, 2016a, b, c) tivity against HeLa cells (Yaglioglu et al., 2016). Ethanolic C. mey-
demonstrated various effects of C. azarolus ethyl acetate extract as eri flower extracts, which contained flavonoids and procyanidins
well as isolated from it hyperoside and vitexin-2″-O-rhamnoside. and had high in vitro antioxidant capacity in DPPH•, β-carotene–
The extract and vitexin rhamnoside exhibited anti-proliferative linoleic acid and TPC assays, also demonstrated antiproliferative
activity against B16F10 melanoma cells and the ability to reduce activity against PC3 and PC14 cells and decreased the levels of
melanin content by inhibiting the tyrosinase activities (Mustapha serum alanine aminotransferase and aspartate aminotransferase
et al., 2015); it also demonstrated significant cellular antioxidant in the blood of partially hepatectomized rats (Ozay et. al., 2015).
capacity against the ROS in B16F10 and primary human keratino- Thus, the extracts were suggested as protective agents against par-
cyte cells (Mustapha et al., 2016b). In addition, total oligomeric tial hepatectomy-induced liver injury in rats and inhibitors of the
flavonoids extract (150 mg/kg body weight, 21 days) significantly proliferation of human non-small lung cancer cells.
inhibited tumor growth volume and weight in Balb/c mice inoc- Recently isolated from the fruit of C. pinnatifida phenylpropa-
ulated with B16F10 cells and therefore was suggested as a new noids crataegusoids (Table 2) were cytotoxic against human hepa-
candidate for skin care products (Mustapha et al., 2016b). The ex- tocellular carcinoma cells HepG2 and Hep3B, while crataegusoids
tract and hyperoside also exhibited an immunomodulatory effect C and D with two methoxy groups at C-3′ most remarkably in-
by modulating macrophage lysosomal enzyme activity and NO duced apoptosis in HepG2 cells indicating on structure-activity
release in mice and anti-inflammatory activity, which was con- relationships (Guo et al., 2018). Finally, the hydroxy-olean-12-
comitant with the cellular antioxidant effect against macrophages en-28-oic acid (HOA) triterpenoids from hawthorn berry, namely
and solenocytes (Mustapha et al., 2016a). Extract-induced growth 3β,6β,18β,23-tetraHOA, 2β,3β,6β,18β-tetraHOA and 2 α,3 β,6
inhibitory effect in human colorectal cancer cell lines HCT-116 β,18 β,23-pentaHOA were potent inhibitors of HepG2 and MCF-7
and HT-29 was associated with DNA fragmentation, sub-G1 peak, cells, with the EC50 values lower than 5 μM (Qiao et al., 2015).
loss of mitochondrial potential, and poly (ADP-ribose) polymerase
(PARP) cleavage. The extract also induced the cleavage of cas-
pase-8 and had no effect on steady-state levels of total Bcl-2 pro- 6. Neuroprotective effects
tein, whereas Bax levels decreased significantly in a dose-depend-
ent manner in both tested cell lines (Mustapha et al., 2016b). It
may also be mentioned that in searching of relatively mild and safe Neuroprotective effects of sesquineolignans (Table 2) isolated
tyrosinase inhibitors, one of six isolated from C. pinnatifida seeds from the hydroethanolic (70%) extract of C. pinnatifida var. ma-
8-0-4′ neolignans, demonstrated promising tyrosinase-inhibiting jor seeds towards H2O2-induced damage in human neuroblastoma
and good antioxidant activities (Huang et al., 2015b). SH-SY5Y cells were recently reported by Huang et al. (2018a, b).
Two other studies also investigated the effects of hyperoside. All of these exhibited significant neuroprotective activity, com-
It was suggested as a candidate of concomitant treatment for leu- pared with trolox, while 6 compounds demonstrated the survival
kemia due to the ability to potentiate As2O3-dependent apoptosis rate of 90.74% at the 50 μM concentration, by inhibiting cellular
of HL-60 human acute myeloid leukemia cells by upregulating apoptosis determined by Hoechst 33258 staining and annexin V/
LC-II and inducing autophagy effects (Zhang et al., 2015). In ad- PI analysis (Huang et al., 2018a). Sesquineolignans also inhib-
dition, hyperoside inhibited Bcl-2-associated agonist of cell death ited β-amyloid aggregation; (7′S, 8′R, 8R)-isolariciresinol-9′-β-D-
BAD from phosphorylating, reactivated caspase-9, and increased glucopyranoside and lyoniside were stronger inhibitors of Aβ1–42
cell cycle regulating protein p27 levels. In another study, hypero- aggregation than curcumin (Huang et al., 2018b). Possible mecha-
side dose-dependently (0.5, 1, 2 mmol/L) increased the expression nism of interactions was investigated by molecular docking.
of LC3-II and autophagosome numbers in human non-small cell The potential of hawthorn as natural antidepressant was also
lung cancer cell line A549 cells; however, such effects in human reported. The levels of typical markers of depression in animal
bronchial epithelial cell line BEAS-2B cells were not observed. models, monoamine oxidase B and reduced spine numbers along
Moreover, hyperoside inhibited the phosphorylation of Akt, neuronal dendrites, were improved by chlorogenic acid or the ex-
mTOR, p70S6K and 4E-BP1, but increased the phosphorylation tract of C. pinnatifida both in vivo using mice model with induced
of ERK1/2 in A549 cells (Fu et al., 2016). depression-like phenotypes by daily injection of stress hormone,
The extract from hawthorn fruit peel (EPHF), rich in phenolic and in vitro using cultured astrocyte type I clone C8-D1A cells
compounds, exhibited dose-dependent cytotoxicity on MCF-7 and (Lim et al., 2018). A protective effect of vitexin, which is one of
SKOV-3 human tumor cell lines with the IC50 of 2.76 and 80.11 the most important flavonoid in hawthorn leaves, against neuro-
μg/mL, respectively (Wu et al., 2017). Polyphenolic extracts of toxicity has also been reported; however, the mechanisms of action
C. azarolus and C. monogyna leaves, fruit peel, and pulp (0.24– remain elusive. Systemic vitexin treatment significantly reduced
4.8 mg/mL) were cytotoxic to cancer Caco-2 cells, at the same neurological deficit, cerebral infarct volume and neuronal damage
time being nontoxic for differentiated Caco-2 cells (Belkhir et al., when compared with the ischemia/reperfusion (I/R) injury mice.
2016). Ethanolic extract of C. microphylla flowers and leaf buds Vitexin markedly upregulated extracellular signal-regulated kinas-
demonstrated cytotoxic and antiproliferative activity against HeLa es (p-ERK1/2), downregulated c-Jun N-terminal kinases (p-INK)
cell (IC50 = 0.871 mg/mL) and least cytotoxicity on normal hu- and p38 phosphorylation (p-p38), increased B-cell lymphoma 2
man peripheral mononuclear cells (Bura et al., 2016). Methanol, (Bcl-2) expression and suppressed the overexpression of Bax in
ethanol and ethyl acetate extracts of C. songarica K. Koch exhib- the I/R mice, thus, protecting brain against cerebral I/R injury

regulated by mitogen-activated protein kinase (MAPK) and apo- inhibitory, DPPH• scavenging capacity and protective activity
ptosis signaling pathways (Wang et al., 2015a). Vitexin presented against hydroxyl radicals-induced DNA strand scission (Renda
no cytotoxicity in RAW 264.7 cells and effectively reduced leu- et al., 2018). Macroporous resin Diaion HP-20 adsorption chro-
kocyte migration in vivo, TNF-α, IL-1β, PGE2 and NO releases matography was applied to obtain rich in phenolics extract from
and increased in IL-10 release in the LPS-challenged mice; it was hawthorn fruit peel (EPHF), which contained ideain, epicatechin
also able to regulate transcriptional factors for pro-inflammatory and chlorogenic acid as the main constituents (179.4, 40.9, and
mediators, by reducing the expression of p-p38, p-ERK1/2 and 10.0 mg/g, respectively) and exhibited strong antioxidant (ORAC
p-JNK (Rosa et al., 2016). Chen et al. (2016) also attempted to = 11.65 μM TE/mg, IC50 in DPPH• scavenging = 6.72 μg/mL) and
obtain evidence on mechanisms using Sprague Dawley rats and AChE inhibitory (IC50 = 11.72 μg/mL) activities (Wu et al., 2017).
human PC12 pheochromocytoma neurosecretory cells with iso- Methanolic extract of C. microphylla was shown as a good source
flurane-induced neurotoxicity and cytotoxicity, respectively, and of antioxidant, antimicrobial, antidiabetic, anticholinesterase, and
suggested that vitexin mediates by targeting the transient recep- anticancer agents in various in vitro assays (Aksoy-Sagirli at al.,
tor potential cation channel subfamily V member 1 gene (TRPV1) 2017).
and N-methyl D-aspartate receptor subtype 2B protein (NR2B)
signaling pathways. The study of Hu et al. (2018) demonstrated
that vitexin from C. pinnatifida protected dopaminergic neurons 7. Skin protective and other health effects
against methyl-4-phenylpyridine/1-methyl-4-phenyl-1,2,3,-6-tet-
rahydropyridine (MPP+/MPTP)-induced neurotoxicity through
The extract from the Greek hawthorn C. pycnoloba was tested as
the activation of phosphatidylinositol-4,5-bisphosphate 3-kinase/
a potent inhibitor of melanin synthesis during early zebrafish em-
protein kinase B (PI3K/Akt) signaling pathway, and these findings
bryo development. The activity based subfractionation enabled to
may facilitate the clinical application of vitexin in the Parkinson’s
identify 3 melanogenesis inhibiting dibenzofurans (Table 2), acting
disease therapy.
The combination of Radix Puerariae and hawthorn fruit tested not via inhibition of tyrosinase or interfering with neural crest dif-
with diabetic rats showed the following effects: (1) reduced ran- ferentiation or migration, but via binding to the aryl hydrocarbon
dom blood glucose, TC, TG and improved glucose tolerance; (2) receptor by activating its signaling pathway and causing the induc-
reversed the loss in body weights; (3) reduced depressive-like tion of the target genes expression (Agalou et al., 2018). Ursolic
behavior as measured by open field, the elevated plus-maze, lo- aldehyde, isolated from the active fragments of C. pycnoloba, had
comotor activity, and forced swimming tests; and (5) upregulat- no melanin synthesis inhibition activity. The assays with HaCaT
ed brain-derived neurotrophic factor and activated extracellular human keratinocytes, normal human dermal fibroblasts (HDFs),
signal-regulated protein kinase (Luo et al., 2016). Vitexin exerted and mice showed that hawthorn polyphenol extract (HPE), con-
behaviorally-specific antinociceptive effect against postoperative taining chlorogenic acid, procyanidin B2, and epicatechin (13.5,
pain using a mouse model with surgical incision on the right hind- 19.2, and 18.8% of the TPC, respectively), can prevent UVB radia-
paw, which was mediated through opioid and GABA(A) receptors tion-induced skin photo-aging by promoting human cell prolifera-
(Zhu et al., 2019). It was observed that C. pinnatifida containing tion in vitro and regulating matrix metallopeptidase expression and
Naodesheng formula could reverse most of the cerebral ischemia type I procollagen production in vivo (Liu et al., 2018). Ethanol
reperfusion induced imbalanced metabolites in brain tissue, plas- extract from C. pinnatifida fruits (TPC = 61.31 mg/g, TFC = 25.42
ma and urine, which indicates on its protective effect on ischemic mg/g) at 50 μg/mL reduced melanin contents by 8.5% while at
stroke rats by mechanisms involving multiple metabolic pathways, 1,000 μg/mL reduced intracellular tyrosinase activity by 46.83%,
including energy metabolism, amino acid metabolism, oxidative thus suggesting that the extract could be used as a whitening agent
stress and inflammatory injury (Luo et al., 2016). Most recently in cosmetics (Park et al., 2017a). The mixture of P. ginseng and
potential efficacy of Naodesheng for treating Alzheimer’s disease C. pinnatifida improved procollagen type I expression, diminished
was evaluated by combined machine learning, molecular docking, matrix metalloproteinase-1 secretion and improved various other
and pharmacophore mapping, and as a result constituent-target human skin values associated with aging, wrinkle formation and
network, constituent-target-target network and target-biological moisture (Hwang et al., 2017). Creams with 5–15% of C. pontica
pathway network was built for this formula as the virtual screen- leaf extract have a healing effect on dermal toxicity caused by T-2
ing and network pharmacology method for the first time (Pang et toxin as it was shown by the study with Iranian rabbits (Kalantari
al., 2018). C. oxyacantha extract ameliorated some seizure param- et al., 2016). The penetration of active substances into the full un-
eters in penicillin-induced epilepsy in gerbils; however, further damaged human skin from the semisolid preparations containing
and more advanced physiologic and neurochemical studies are re- C. oxyacantha extract was evaluated ex vivo. However, it was ob-
quired to determine the mechanisms involved (Cakir et al., 2016). served that, although the extract exhibited antimicrobial and anti-
The compounds from C. oxyacantha effectively inhibited AChE, radical activity, its compounds stay on the surface of the undam-
from IC50 = 5.22 μM (β-sitosterol-3-O-β-D-glucopyranoside) to aged human skin, thus only traces of hyperoside and isoquercitrin
44.47 μM, and BChE activity with IC50 = 0.55–15.36 μM. In ad- were found in the epidermis (Stelmakienė et al., 2016).
dition, docking procedures with Genetic Optimization for Ligand The effects of C. orientalis M Bieber extract on serum oxida-
Docking suit v5.4.1 were applied to study the inhibition mecha- tive status and alveolar bone loss in experimental periodontitis
nism, while software admetSAR predicted that both of the isolated was studied in vivo and showed inhibitory effect on periodontal
compounds can cross blood brain barrier (BBB+) (Ali et al., 2017). inflammation and alveolar bone loss by regulating total antioxi-
AChE catalyzes the breakdown of acetylcholine and of some oth- dant (TAS)/oxidant (TOS) status and oxidative stress index lev-
er choline esters that function as neurotransmitters, while BChE els in periodontal disease in rats when administered systemically
in plasma can be used as a liver function test in both hypercho- (Hatipoglu et al., 2015). C. azarolus extract was active against her-
linesterasemia and hypocholinesterasemia. Potential antioxidant, pes simplex virus-1 (HSV-1), and antiviral activity correlated with
hypoglycemic, and neuroprotective effects of acidified methanol TPC (R = 0.773, p < 0.001) and free radical scavenging capacity
or ethanol extracts of C. microphylla stem barks and leaves were (R = −0.684, p < 0.01) (Moradi et al., 2018). Hawthorn hyperoside
supported by evaluating their AChE, tyrosinase and α-glucosidase (10, 50, 100 μmol/L) dose-dependently inhibited LPS-induced pro-

liferation and migration of human rheumatoid fibroblast-like syn- human cells, and mutagenicity in bacterial cells (De Quadros et al.,
oviocytes (RA FLSs) in vitro. Furthermore, hyperoside decreased 2017). Previous in vitro findings were also confirmed by the study
LPS-stimulated production of TNF-α, IL-6, IL-1 and MMP-9 in of Yonekubo et al. (2018) with C. oxyacantha extract, showing that
the cells, inhibited LPS-induced phosphorylation of p65 and IκBα, in comet assay it did not markedly induce DNA damage in leuko-
and suppressed nuclear translocation of p65 and DNA biding of cytes and bone marrow cells; however, in the micronucleus test the
NF-κB in the cells. Three-week administration of hyperoside sig- extract produced a significant rise in micronucleated polychromat-
nificantly decreased the clinical scores, and alleviated synovial ic erythrocytes (PCE) in a non-dose dependent manner. The PCE/
hyperplasia, inflammatory cell infiltration and cartilage damage normochromatic erythrocytes (NCE) ratio indicated no significant
on mouse with collagen-induced arthritis. Hyperoside inhibited cytotoxicity under applied experimental conditions, however, C.
LPS-induced proliferation, migration and inflammatory responses oxyacantha fruits extract exhibited weak clastogenic and/or aneu-
in RA FLSs in vitro by suppressing activation of the NF-κB signal- genic effects in bone marrow cells of male mice (Yonekubo et al.,
ing pathway, which contributes to the therapeutic effects observed 2018). It suggests that prolonged or high dose use of such extracts
in mice with collagen-induced arthritis (Jin et al., 2016). needs to be undertaken with caution. Most recently, the electro-
In the study with male Sprague-Dawley rats hydroalcoholic cardiographic effects of hawthorn in healthy adult volunteers was
extract of C. azarolus ssp. aronia fruit significantly lowered sys- tested and it was concluded that a single dose of oral C. oxyacan-
tolic blood pressure and phenylephrine maximal response and in- tha had no effect on electrocardiographic parameters in healthy
creased acetylcholine maximal response, serum SOD, and serum volunteers (Trexler et al., 2018).
glutathione reductase in the renal artery-clipped group receiving
vehicle. It was concluded that antihypertensive effects of extract
may be partly due to antioxidant and NO releasing effects (Hay- 9. Processing, quality control and other uses
dari et al., 2017). Ethyl acetate fraction of C. dahurica methanol
extract demonstrated the greatest antioxidant activity while n-bu- Raw plant material and natural products should be carefully pre-
tanol fraction significantly accelerated the gastrointestinal transit pared, considering various aspects, e.g. protection of sensitive ac-
in mice. Thus, this plant was suggested to serve as a good source tive ingredients, convenient forms for dosing and administration,
of antioxidants and digestion-improving agents (Wang et al., standardization in terms of concentration of active ingredients and
2018). Ethanolic extracts of C. orientalis leaves and berries inhib- others. Some recent studies have focused on such issues.
ited cyclooxygenase-1 (COX-1) and 12-lipoxygenase (12-LOX), Drying is an important process for many natural ingredients for
while its leaf extract showed a concentration dependent inhibition medicines and food supplements. Aral and Bese (2016) investi-
of COX-1 pathway products, 12-HHT and TXB2 (Šavikin et al., gated convection-drying of Crataegus spp. fruit at 50, 60 70 °C
2017). with air velocities of 0.5, 0.9 and 1.3 m/s and applied different
Rhodiolae Kirliowii Radix et Rhizoma and C. pinnatifida Fruc- mathematical models for the experimental data. They observed
tus may provide sources of potential antiviral compounds that was that while the shrinkage decreased, the rehydration ratio increased
evidenced by hemagglutination inhibition activity on B human with increasing air temperature and air velocity. Microwave-dry-
polyomaviruses BK KPyV and JCPyV VLPs and reducing their ing, oven-drying at 50 and 70 °C, sun-drying and shade-drying
expression in infected cells (Chen et al., 2017). C. oxycantha buds were compared for the fresh fruits of C. azarolus and C. orienta-
fluid extract and the hydro-ethanolic macerate were active against lis. The results showed that antioxidant capacity increased, and at
thirty-due clinical strains of U. urealyticum, with MIC ranges the same time the TPC decreased with the temperature increase in
of 15.6–250 and 15.6–62.5 μg/mL, respectively. Meanwhile, oven drying, whereas in other drying methods (microwave, sun
among the major purified flavonoids luteolin 3,7-diglucoside and and shade-drying) the TPC increased; meanwhile, vitamin C con-
apigenin-7-O-glucoside were the most active compounds with tent decreased in all samples. The samples dried in a microwave
MICs 0.48–1.95 and 0.48–3.9 μg/mL, respectively (Bisignano et appeared to have the highest antioxidant capacity and it was con-
al., 2016). Ethanolic extract of C. azarolus var. eu-azarolus Maire cluded that it was the best method for preserving bioactive phyto-
leaves and its hexane, chloroform, and n-butanol fractions as well chemicals (Saadatian et al., 2016). Freeze-drying was reported to
as ursolic acid, 3β-O-acetyl ursolic acid and quercetin 3-O-methyl be better than hot air drying for hawthorn (C. pinnatifida) in terms
ether showed variable antimicrobial activities against E. coli, P. of antioxidant, α-glucosidase inhibitory potential, the TPC/TFC
aeruginosa, S. aureus, and C. albicans (Abu-Gharbieh and She- values and color (Kwon, 2016).
hab, 2017). Immersing of hawthorn fruits in a glycine betaine solution for
15 min at 20 °C effectively prevented fruit chilling injury and
improved nutritional characteristics at low-temperature storage
8. Toxicity of hawthorn preparations (Razayi et al., 2018). It significantly delayed fruit pitting develop-
ment during storage at 1 °C for 20 days, increased accumulation
Safety of Crataegus preparations has been proven by many studies of glycine betaine, proline, phenols, flavonoids, anthocyanins, and
and safe history of use. Some recent studies with C. oxyacantha ascorbic acid, which was concurrent with higher SOD, catalase
extend the knowledge on this issue. Evaluation of C. oxyacantha (CAT), ascorbate peroxidase (APX), and DPPH• scavenging ca-
fruit extract showed that it did not produce marked genotoxic ef- pacity.
fects at concentrations of 2.5 or 5 μg/mL in leukocytes and human Emulsions prepared from the extracted from hawthorn pectin
liver hepatocellular carcinoma HepG2 cultured cells; however, at and candelilla wax were used as an edible film for treating Pleu-
concentrations of 10 μg/mL or higher significant DNA damage rotus ostreatus mushroom. This process reduced weight loss, im-
and clastogenic/aneugenic responses were observed. The extract proved firmness, and lightness, compared to untreated mushroom
induced mutagenic effects in TA98 strain of S. typhimurium (Ames slices during 20 days of storage at 4 °C (Lozano-Grande et al.,
test) with metabolic activation at all tested concentrations (2.5 to 2016). The functional Ag-Fe3O4 nanocomposites, which were
500 μg/mL). Consequently, under certain experimental conditions, prepared via one-pot hydrothermal method using aqueous extract
the extract exerts genotoxic and clastogenic/aneugenic effects in of C. pinnatifida leaves as reducing and capping agent, exhibited

sustainable antibacterial activity against S. aureus and E. coli. The knowledge on Crataegus spp. in particular and natural products in
nanocomposites can be easily separated from the medium by a general. In addition, the findings of recent years provide new ideas
magnet and continues to exhibit recyclable antibacterial activity and suggest the trends for further studies of Crataegus spp.
(Li and Yang, 2016). Tonic wine was produced by maceration of
hawthorn fruits in red wine; as a result its TPC and antioxidant
capacity remarkably increased (Muresan et al., 2016). Effects of References
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