Journal of Functional Foods 90 (2022) 104988

Contents lists available at ScienceDirect

Journal of Functional Foods

journal homepage: www.elsevier.com/locate/jff

Biological properties and potential application of hawthorn and its major

functional components: A review
Tuoping Li, Siyu Fu, Xin Huang, Xiushan Zhang, Yanmin Cui, Zuoyi Zhang, Yue Ma,
Xuan Zhang, Qianhui Yu, Shuning Yang, Suhong Li *
College of Food Science, Shenyang Agricultural University, Shenyang 110866, China

A R T I C L E I N F O A B S T R A C T

Keywords: Hawthorn (Crataegus) widely distribute in the world, and is known as an excellent fruit resource commonly
Hawthorn planted in China. It has been used for food and medicine for thousands of years in China. This paper surmised the
Antioxidant up-to-date literatures on the functional properties of flavonoids, phenols, terpenoids and polysaccharides of
Glucose and lipid metabolism
hawthorn. Meanwhile, the application prospects of hawthorn in functional foods are also prospected. These will
Inflammation
Memory
be helpful for the developments of functional foods or deep-processing technologies of hawthorn.

1. Introduction 2. Antioxidant of hawthorn

Hawthorn belong to the rose family, hawthorn genus (Yang & Liu, Antioxidant is any substance that can act on free radicals directly or
2012). There are more than 280 varieties in hawthorn genus, such as indirectly to delays, prevents or eliminates oxidative damage to target
Crataegus pinnatifida is the commonly distributed in China and Asia, and molecules (Halliwell, 2020). The bioactive components with antioxidant
the C. monogyna and C. laevigata are mainly distributed in Europe effects reported in recent years are mainly phenolics, polysaccharides,
(Caliskan, 2015; Chen et al., 2019). In China, hawthorn is cultured as a and alkaloids (Kołodziej et al., 2019). It has been verified that hawthorn
traditional edible fruit. The major cultivar are C. pinnatifida Bge, is rich in phenolics, which are recognized as strong antioxidants (Keser
C. brettschneideri Scheneid, C. scabrifolia Recd and C. hupehensis Sarg et al., 2014). Researchers have reported that there is a linear correlation
(Dong, 2015). It is not only used for direct consumption, but also is between the release of total phenols or total flavonoids from hawthorn
processed as jam or jelly due to its rich pectin content (Li et al., 2021), or and the ability to scavenge free radicals (Zheng et al., 2018). It is seemed
used as snack food processing because of its sweet and sour taste and that the antioxidant capacity of free phenol in hawthorn is depended on
rich nutrients (Liu et al., 2019). Besides, hawthorn also has been used in its organs, that the antioxidant activity of peels was significantly higher
Chinese herb for centuries, to possess the therapeutic effects on tonifying than that of pulps (Lou et al., 2020). The antioxidant activity of haw­
spleen (Rocchetti et al., 2020), prompting appetite (Zuo et al., 2006), thorn extracts also differed with different extraction methods that the
regulating blood glucose and lipid metabolism (Lin et al., 2011), etc., methanol and ethanol extracts represented good anti-oxidative effects to
because it contains a lot of biologically active substances, such as fla­ protect the protein and DAN from damages of free radicals, while
vonoids (Dai et al., 2021), phenolics, terpenoids, and pectin. Therefore, chloroform and petroleum ether extracts basically had no protective
hawthorn also is considered as a medicinal and food homologous fruit in effects (Zhang et al., 2020), indicated that phenolics are the antioxidant
China. Through the existing literatures and research contents, this paper components in hawthorn. Besides, the strength of antioxidant activity
tries to sunrise the functional characteristics and application of haw­ also varies with the varieties of hawthorn, which may be due to the great
thorn and fills the gap of comprehensive content, which can help more difference of compounds composition in hawthorn, especially, the total
systematic research on the functional application of hawthorn in the phenolic and individual phenolic compounds were the main contribu­
future, and promote the development of deep-processing technologies of tors to the antioxidant activity of hawthorn (Alirezalu et al., 2020).
hawthorn in food industry. In order to consider the metabolism and bioavailability of antioxi­
dants, Wen et al. explored the intracellular antioxidation of hawthorn.

* Corresponding author.
E-mail address: [email protected] (S. Li).

https://doi.org/10.1016/j.jff.2022.104988
Received 21 November 2021; Received in revised form 28 January 2022; Accepted 3 February 2022
Available online 7 February 2022
1756-4646/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
T. Li et al. Journal of Functional Foods 90 (2022) 104988

As the results, a large number of phenolic substances in hawthorn pro­ diet (Li et al., 2014), which is mainly reflected in improving the hepatic
vided sufficient hydrogen atoms for scavenging peroxy free radicals, and fatty acid oxidation (Yu et al., 2021), and suppressing the TG and fatty
the antioxidant activity was significantly related to total phenols and acid synthesis in the liver (Li et al., 2014; Li et al., 2017). Meanwhile,
total flavonoids (Wen et al., 2015). The possible antioxidant mechanism cholesterol accumulation in the liver is also reduced with the treatment
of hawthorn in vivo may be realized by increasing endogenous antiox­ of POS by promoting bile acid biosynthesis and excretion (Zhu et al.,
idant enzymes (Zhang et al., 2014). The treatment of 80% ethanol 2013). One of the possible mechanisms is suggested that POS treatment
extract from hawthorn containing the procyanidin B2, epicatechin, facilitated the synthesis of adiponectin in the white adipose tissue and
chlorogenic acid, hyperoside, and isoquercitrin significantly increased improve activation of adiponectin in the liver, leading to improve the
the activities and mRNA levels of CuZn-SOD and CAT, but decreased the hepatic lipid metabolism (Yu et al., 2021; Fig. 2). Besides, the ethanol
level of peroxide product MDA. Similar results were also demonstrated extract of hawthorn also has been found to have lipid lowering activity
by Wang et al. that hawthorn ethanol extracts increased the activities (Shao et al., 2016), which may be partly due to the existence of flavo­
and the gene expression levels of SOD, CAT and GSHPX in brain, liver noids of hawthorn (Chang et al., 2005), since hawthorn flavanone has
and serum, but decreased the MDA content in senescence-accelerated been confirmed to reduce blood lipid concentration and regulate lipid
mice (Wang et al., 2011). metabolism by regulating the gene expressions of FAS, HSL, TGH, and
A large number of studies indicated that cancer, aging or neurode­ SREBP-1c (Xie et al., 2009). However, more research and in-depth
generative diseases are mostly associated with the production of excavation are needed to justify the relevant mechanisms of haw­
excessive free radicals. It is worth noting that once the oxidative injury thorn, especially the impact and the cross-talk of intestinal flora and
begins, antioxidant treatment often cannot inhibit the progress of tissue hawthorn pectin and its derivatives with the lipid metabolism regulating
damage, because other factors dominated the pathology (Forman & functions.
Zhang, 2021). Therefore, it is important to prevent oxidative damage
happening through natural foodborne products. As a rich source of 4. Anti-inflammatory activity of hawthorn
phenols and flavonoids, hawthorn is expected to be widely used as di­
etary supplements to prevent or improve oxidative related diseases Chronic inflammation is often accompanied with obesity and
(Fig. 1). abnormal lipid metabolism with increased proinflammatory cytokines
(Rodríguez-Hernández et al., 2013; Lackey & Olefsky, 2016). Inflam­
3. Improvement of hawthorn on lipid metabolism disorders mation is the body’s response to destructive stimulus, microbial path­
ogens and inflammatory factors for the pathological activities caused by
Disorders of lipid metabolism and associated nonalcoholic fatty liver, stimulation, thereby harm the organ or tissue of body (Turner et al.,
obesity, and cardiovascular disease arising therefrom have become a 2014). Hawthorn contains a large number bioactive compounds with
serious health and social problem in recent year worldwide. It is char­ multiple pharmacological activities and functions. These components
acterized by the increase of total cholesterol (TC) or low-density lipo­ have been used to treat inflammatory diseases and enhance human
protein cholesterol (LDL-C) and total triglyceride (TG) levels in the immunity. For example, maslinic acid (MA), a pentacyclic triterpene
blood, or the decrease of high-density lipoprotein cholesterol (HDL-C) acid, is an important quality index of hawthorn as herbal medicine, has
(Hunter & Hegele, 2017). Dietary hawthorn extract has been reported to been found great significance in inhibiting inflammation (Zhong et al.,
reduce blood lipid by reducing the contents of plasma TC, TG, and LDL 2012). Huang et al. (2011) using LPS-stimulated rat astrocyte cultures to
(Kwok et al., 2010). Considering the soluble dietary fiber pectin is very investigate the anti-inflammatory effects of MA, and found that MA
rich in hawthorn that we previously confirmed (Wang et al., 2007), could reduce inflammatory mediator release through NF-κB signaling
hawthorn pectin and its hydrolysates are supplemented to the high-fat pathway (Fig. 3), clearly validated the role of MA in suppressing
diet fed mice, and the significant anti-hyperlipidemia effects are neuroinflammation.
observed (Li et al., 2010). Because of the hardly handing of high- Polyphenol and flavonoids are the other rich bioactive compounds in
molecular pectin with the high viscosity, we further prepared haw­ hawthorn, are also proved to have significant effects on preventing and
thorn pectin oligosaccharide (POS) by pectinase hydrolysate and DEAE treating inflammation. Liu et al. (2020) reported the flavonoids
Sephadex A-25 column chromatography (Li et al., 2011), and found that extracted from hawthorn by 70% ethanol could act as anti-inflammatory
POS also obviously ameliorated the hyperlipidemia caused by a high-fat role to alleviate TNF-α evoked intestinal epithelial barrier deficit in

Fig. 1. Diseases caused by oxidative damage and the preventive actions of hawthorn.

2
T. Li et al. Journal of Functional Foods 90 (2022) 104988

Fig. 2. Role of POS in improvement of fatty

acid oxidation mediated by adiponectin.
Adiponectin is a cytokine secreted by adi­
pocytes, is very important in regulating lipid
metabolism and plays its function by binding
with receptors. POS promotes adiponectin
synthesis in adipose tissue through PKA/
ERK/CREB and cAMP/PPARγ two pathways,
that POS increased the cAMP content, the
gene and protein expressions of C/EBPα,
RXR, PPARγ, PKA and Rap1, along with
enhancing the mRNA and phosphorylated
protein levels of Src, ERK and CREB. In
response to increased circulation adipo­
nectin, phosphorylation of AMPK is stimu­
lated by POS, along with the downregulated
expression of ACC, and upregulated expres­
sions of PPARα and its target gene ACO and
CPT-I, thus improved hepatic fatty acid
oxidation of high-fat fed mice. ACC, acetyl
CoA carboxylase; AMPK, AMP-activated
protein kinase; CREB, cAMP-response
element binding protein; C/EBPα, CCAAT/
enhancer binding protein; CPT-I, carnitine
palmitoyl transterase-1; LKB1, Liver kinase
B1; PKA, protein kinase A; WAT, white adi­
pose tissue; Rap1, Ras approximate protein
1; RXR, Retinoid X receptor; PPARα, peroxi­
some proliferator-activated receptor α;
PPARγ, peroxisome proliferator-activated
receptor γ; Src, Src tyrosine kinase.

Fig. 3. POS and polyphenols significantly

down-regulated gene and protein expression
of NF-κB with concomitant decreased mRNA
levels of receptor interacting protein kinase 1
(RIP1), NF-κB-inducing kinase (NIK), TNFα
and its receptors 1 (TNFR1), receptor-
associated factor 2 (TRAF2). Expressions of
AMP-activated protein kinase (AMPK) and
silent information regulator T1 (SIRT1) were
also upregulated by POS and polyphenols.
MA treatment attenuated LPS-induced
translocation of NF-κB p65 subunit to the
nucleus and prevented LPS-induced IκBα
phosphorylation in a concentration-
dependent manner.

Caco-2 cells, presenting as the improvement of epithelium permeability extract regulates AMPK/SIRT1/NF-κB signaling to reduce the gene and/
(Fig. 3). Oligomeric proanthocyanidins extracted from hawthorn also or protein expressions of inflammatory related factors (Liu et al., 2021;
has been found to reduce the gene expressions of proinflammatory Fig. 3).
factors IL-1β, IL-6, and TNF-α, and finally helped to alleviate pro- Likewise, our studies have confirmed that as well as the properties of
inflammatory immune responses in rats (Elango & Devaraj, 2010). improving lipid metabolism, hawthorn pectin oligosaccharide (POS)
Echoes aforementioned antioxidant property of polyphenols, Han et al. also possesses the anti-inflammatory properties (Li et al., 2019).
(2016) investigated the effects of polyphenol from hawthorn in high- Administration of POS decreased the pro-inflammatory factor levels,
fructose diet-induced liver injury mice, and found that polyphenols and finally inhibited the liver inflammation in high fat diet-induced
had both protective effects against inflammation and oxidative stress mice. This inhibitive effect is concerned with the inactivation of NF-
with the reduced production of IL-6 and TNF-α. The possible mecha­ κB, that POS may be acts through the AMPK/SIRT1/NF-κB and NIK/
nisms of thus functions have been suggested that hawthorn polyphenol IKK/NF-κB pathways, to block the progression of inflammatory response

3
T. Li et al. Journal of Functional Foods 90 (2022) 104988

and reduce the production of pro-inflammatory factors (Fig. 3). promising resource for cancer treatments. The effective anti-cancer
component and the mechanisms is worth further research in the future.
5. Anti-diabetic effects of hawthorn
7. Improvement of cognitive dysfunction and learning and
Diabetes is a metabolic disorder characterized by abnormal increase memory
in blood glucose levels and accompanied by complications of multiple
systems (Dehghani et al., 2019; Hua, 2020). Polyphenols and flavonoids The aging of the population is often concomitant with the cognitive
of hawthorn are recognized as important active substances to act on the impairment. The disease is usually caused by the neurodegeneration of
hypoglycemic effects. Researchers have reported that 80% methanol neurons in the hippocampal and cortical etc., in which, the nicotinic and
extracts of hawthorn were able to reduce the blood glucose level and muscarinic receptors of acetylcholine are reduced, and the activities of
increase plasma insulin release from pancreas, to attenuate diabetic acetylcholinesterase and butyrylcholinesterase are damaged, leading to
symptom in high-fat diet induced dyslipidemia mice (Aierken et al., serious learning and memory impairment (Reeta et al., 2017). MA, an
2017; Shih et al., 2013). Human α-glucosidase is the main enzyme that important terpenoid in hawthorn is not only widely used in the field of
catalyzes the last step of carbohydrate hydrolysis in the digestive system. anti-inflammatory, but also is expected to improve cognitive dysfunc­
In this case, inhibition of the enzyme and the associated reduction in tion. Bae et al. (2020) used Y-maze, passive avoidance and Morris water
glucose release and absorption is an attractive method to reduce blood maze tests to prove the effects of MA in improving cognitive function,
glucose levels and hyperglycemia (Aierken et al., 2017). Xin et al. (2021) and found that MA can ameliorate scopolamine-induced memory
found that hawthorn polyphenols mainly contained quercetin (74.58%) impairment, and increase the expression level of brain-derived neuro­
and hyperoside (9.58%), which were the important source of biological trophic factor in the hippocampus. An animal experiment has observed
activity to inhibit α-glucosidase. Further researches have suggested that that feeding of MA increased the phosphorylation levels of extracellular-
SIRT1/AMPK/NF-κB signaling pathway was a critical mechanism of signal-regulated kinase-cAMP response element-binding protein, phos­
hawthorn polyphenols for reducing inflammation and further to alle­ phoinositide 3-kinase, and protein kinase B in the hippocampus of mice
viate hyperglycemic, insulin resistance responses and ameliorate aortic (Ahn et al., 2005; Ishii et al., 2010). These neuroprotective effects
injury in T2DM rats (Liu et al., 2021). Wang et al. (2011) have found that perhaps act through the Akt-GSK3β signal pathway (Jeon et al., 2017).
the increase of postprandial glucose was also inhibited by hawthorn Therefore, MA is potential to be a promising dietary component to delay
flavonoids in sucrose loaded rats. Moreover, there is a piece of evidence the development of cognitive impairment by modulating the Akt-GSK3β
that flavonoids extracted from hawthorn possessed the protective effect signaling pathway.
on diabetic cardiomyopathy in rats induced by streptozotocin and the Furthermore, the prevalence of diabetes as a common chronic
mechanism may be related to protein kinase C-α inactivation of metabolic disease continues to increase recent years. Besides its com­
signaling pathway to reduce oxidative stress and inflammation (Min mon complications, diabetes-related cognitive dysfunction has gained
et al., 2017). Vitexin is a natural flavonoid from hawthorn and also has growing attention (El Batsh et al., 2015). It has been reported that
been demonstrated to improve high-fat diet triggered insulin resistance diabetes accelerates mild cognitive impairment of dementia in the
in HepG2 cells and C57BL/6J mice (Xu et al., 2021). Currently, insulin elderly (Xu et al., 2010). Animal experiments have shown that insulin
injection and oral hypoglycemic agents are the main effective methods deficiency can lead to a decrease in neurons in the cerebral cortex, which
for the treatment of diabetes, but there are many problems in the in turn leads to memory loss in the cerebral cortex (Kumari et al., 2000;
treatment of insulin, such as needles phobia, allergic reactions, and the Redish & Touretzky, 1997). Increased production of free radicals and
pressure caused by the long-term difficult treatment of insulin therapy oxidative stress induced by hyperglycemia are the main causes of
(Shi et al., 2019). Hawthorn is one of the popular herbs in Traditional cognitive dysfunction in diabetic patients (Kucukatay et al., 2007). A
Chinese Medicine and has been used for the treatment of hyperglycemia recent study by Zarrinkalam et al. (2018) explored the positive effects of
for a long time. However, its active ingredients and specific mechanism natural antioxidants on learning and memory in type 1 diabetic rats. Its
of action remains further to study. principle of action is to increase total antioxidant capacity and reduce
lipid peroxidation. Considering the rich content of flavonoids and
6. Anti-cancer function of hawthorn polyphenols with strong antioxidant activities in hawthorn, it is also
expected to applied in the development of functional foods with
It is well known that regularly eating of fruits, vegetables and whole improvement of memory related dysfunctions.
grains are beneficial to reduce the probability of cancer (Tariq et al.,
2015). To data, there are few reports about the anticancer effects of 8. Gastrointestinal effects of hawthorn
hawthorn. However, hawthorn fruits contain a mass of biologically
active substances, which are expected to have an anti-proliferative ef­ Traditional Chinese medicine recorded hawthorn as the method of
fects on human cancer cells (Vanden Berghe, 2012). Li et al. (2013) entering medicine for the cure of gastroenteric disease (Chinese Phar­
pointed out that triterpenoids in hawthorn may be responsible for the macopoeia Commission, 2020), because intake of hawthorn can act as a
anti-cancer function. Qiao et al. (2015) reported that triterpenoids prebiotics to improve the intestinal flora and gastrointestinal function
extracted from hawthorn with acetone had inhibitory activity on the (Sammari et al., 2020; Míguez et al., 2016). Haw1-1 is a polysaccharide
proliferation of human breast cancer and liver cancer cells. Ursolic acid, with the backbone of α-1,4-glucan and α-1,4,6-glucan, isolated from
an important triterpene component from hawthorn has been demon­ hawthorn by hot-water and fractionated by DEAE-Sepharose and
strated to exhibit antiproliferative activity through cell cycle arrest and Sephacryl S-100HR column chromatograph, which has been found to
apoptosis induction in cancer cells. Ursolic acid induce apoptosis in promote the growth of Bacteroidetes, such as B. thetaiotamicron, B. ovatus,
MDA-MB-231 cancer cells through the mitochondrial death pathway and B. fragilis, and to maintaine the intestinal environment stability,
(Wen et al., 2017). Besides, polysaccharide from hawthorn also has been thereby contributed to the treatment of intestinal microbial related
found to exhibit the inhibitory effects on the proliferation of human diseases (Zhang et al., 2019). Similarly, the another hetero­
colon cancer cells, that it can arrest the cell cycle in the S and G2/M polysaccharide Haw1-2, which is composed of glucose, galactose, and
phases and increase the apoptosis rate (Ma et al., 2020). Another similar arabinose with the backbone of linear α-1,4-D-Glc, obtained by water
study by Li et al. (2021) further confirmed that a hawthorn poly­ extraction, and DEAE-cellulose and Sephacryl S-100 HR chromatog­
saccharide exhibited the inhibitory effect against gastric cancer cell raphy, was also considered to be a beneficial prebiotic, to modulate
proliferation by regulating miR-146a-5p expression and Wnt/β-catenin intestinal bacteria with promotion of the growth of B. theaiotamicron,
signaling activation. The above results suggest that hawthorn is a B. ovatus and Bifidobacterium longum, and to increase the production of

4
T. Li et al. Journal of Functional Foods 90 (2022) 104988

short-chain fatty acid (Guo et al., 2020). Aierken, A., Buchholz, T., Chen, C., Zhang, X., & Melzig, M. F. (2017). Hypoglycemic
effect of hawthorn in type II diabetes mellitus rat model. Journal of the Science of
In addition to polysaccharides, studies have shown that the intake of
Food and Agriculture, 97(13), 4557–4561. https://doi.org/10.1002/jsfa.8323
processed hawthorn products (charred hawthorn and mixed hawthorn Alirezalu, A., Ahmadi, N., Salehi, P., Sonboli, A., Alirezalu, K., Mousavi Khaneghah, A.,
juice) represented a positive effect on the gastrointestinal tract, that it Barba, F. J., Munekata, P. E. S., & Lorenzo, J. M. (2020). Physicochemical
reduced the ratio of Bacteroides and Firmicutes, but, Oscillibacter, Holde­ characterization, antioxidant activity, and phenolic compounds of hawthorn
(Crataegus spp.) fruits species for potential use in food applications. Foods, 9(4), 436.
mania, and Bilophila have been recovered to varying degrees in high- https://doi.org/10.3390/foods9040436
calorie diet induced dyspepsia rats (Wang et al., 2019). Meanwhile, Bae, H. J., Kim, J., Kim, J., Goo, N., Cai, M., Cho, K., Jung, S. Y., Kwon, H. Y., Kim, D. H.,
the intestinal flora also has been modulated with increased numbers of Jang, D. S., & Ryu, J. H. (2020). The effect of maslinic acid on cognitive dysfunction
induced by cholinergic blockade in mice. British Journal of Pharmacology, 177(14),
Bacteroides, Coprococcus, Sporobacter, and Subdoligranulum and a low­ 3197–3209. https://doi.org/10.1111/bph.15042
ered level of Akkermansia (Wang et al., 2019). Wei et al (2018) used Caliskan, O. (2015). Mediterranean hawthorn fruit (Crataegus) species and potential
functional dyspepsia rat model to evaluate the functionalities of raw or usage. The Mediterranean Diet, 621–628. https://doi.org/10.1016/B978-0-12-
407849-9.00055-5
charred hawthorn, and found that both raw or charred hawthorn Chang, W. T., Dao, J., & Shao, Z. H. (2005). Hawthorn: Potential roles in cardiovascular
ameliorated the gastric emptying and intestinal propulsion. the relative disease. American Journal of Chinese Medicine, 33(1), 1–10. https://doi.org/10.1142/
abundance of all dysregulated microflora including Lactobacillus and S0192415X05002606
Chen, X. W., Qi, Y. J., Zhu, C. H., & Wang, Q. (2019). Effect of ultrasound on the
Bacteroides are recovered to those in the normal control levels, indi­ properties and antioxidant activity of hawthorn pectin. International Journal of
cating its ability to improve dyspepsia and regulate intestinal microflora Biological Macromolecules, 131(15), 273–281. https://doi.org/10.1016/j.
dysfunction. Although there is a lack of deep-researches about the ijbiomac.2019.03.077
Chinese Pharmacopoeia Commission (2020). Chinese Pharmacopoeia. China Medical
functionality of hawthorn on the gastrointestinal tract, considering the
Science Press (In Chinese).
fact that hawthorn contains abundant pectin, flavonoids and poly­ Dai, H. J., Lv, Z. P., Huang, Z. W., Ye, N. W., Li, S. M., Jiang, J. L., Cheng, Y., & Shi, F. X.
phenols, it can be predicted and expected that hawthorn with these (2021). Dietary hawthorn-leaves flavonoids improves ovarian function and liver
components is able to play a positive role in health benefits mediated by lipid metabolism in aged breeder hens. Poultry Science, 100(12), 101499. https://doi.
org/10.1016/j.psj.2021.101499
gut microbiota. Dehghani, S., Mehri, S., & Hosseinzadeh, H. (2019). The effects of Crataegus pinnatifida
(Chinese hawthorn) on metabolic syndrome: A review. Iranian Journal of Basic
9. Conclusion Medical Sciences, 22(5), 460–468. https://doi.org/10.22038/IJBMS.2019.31
964.7678.
Dong, W. X. (2015). Hawthorn. Chinese Fruit Tree Science and Practice, 38–40 (In
The substantial studies revealed that hawthorn has various health Chinese).
benefit functions. Dozens of biologically active substances in hawthorn Elango, C., & Devaraj, S. (2010). Immunomodulatory effect of Hawthorn extract in an
experimental stroke model. Journal of Neuroinflammation, 7(1), 97. https://doi.org/
can be extracted for a health-care food. However, owing to the intricate 10.1186/1742-2094-7-97
composition of hawthorn, the massive samples and numerous experi­ El Batsh, M. M., El Batsh, M. M., Shafik, N. M., & Younos, I. H. (2015). Favorable effects
ments are required for certifying their effectiveness and safety. The of vildagliptin on metabolic and cognitive dysfunctions in streptozotocin-induced
diabetic rats. European Journal of Pharmacology, 769(15), 297–305. https://doi.org/
specific type and underlying mechanism of activities and functions also 10.1016/j.ejphar.2015.11.033
need further investigations. At present, the traditional and emerging Forman, H. J., & Zhang, H. Q. (2021). Author Correction: Targeting oxidative stress in
processing technology of hawthorn food is extensive and attaching great disease: Promise and limitations of antioxidant therapy. Nature Reviews Drug
Discovery, 20(8), 652. https://doi.org/10.1038/s41573-021-00267-5
importance, which is like hawthorn coil, hawthorn fruit wine, inspis­
Guo, C. L., Zhang, S. H., Wang, Y. Q., Li, M. X., & Ding, K. (2020). Isolation and structure
sated juice, fruit vinegar, etc. Some enterprises also began to pay characterization of a polysaccharide from Crataegus pinnatifida and its bioactivity on
attention to the development of hawthorn health food. Nevertheless, gut microbiota. International Journal of Biological Macromolecules, 154, 82–91.
https://doi.org/10.1016/j.ijbiomac.2020.03.058
there still are few functional foods with hawthorn as raw material on the
Halliwell, B. (2020). Reflections of an aging free radical. Free Radical Biology and
market. In the future, the advanced functional food applying to various Medicine, 161, 234–245. https://doi.org/10.1016/j.freeradbiomed.2020.10.010
consumers can be exploited, which are based on hawthorn extracts and Han, X., Li, W. F., Huang, D., & Yang, X. B. (2016). Polyphenols from hawthorn peels and
bioactive substance from other parts. The exploration on hawthorn fleshes differently mitigate dyslipidemia, inflammation and oxidative stress in
association with modulation of liver injury in high fructose diet-fed mice. Chemico-
functional food represents a large challenge for the future. Biological Interactions, 257, 132–140. https://doi.org/10.1016/j.cbi.2016.08.002
Hua, F. (2020). New insights into diabetes mellitus and its complications: A narrative
Declaration of Competing Interest review. Annals of Translational Medicine, 8(24), 1689. https://doi.org/10.21037/at
m-20-7243.
Huang, L. F., Guan, T., Qian, Y. S., Huang, M. H., Tang, X. Z., Li, Y. M., & Sun, H. B.
The authors declare that they have no known competing financial (2011). Anti-inflammatory effects of maslinic acid, a natural triterpene, in cultured
interests or personal relationships that could have appeared to influence cortical astrocytes via suppression of nuclear factor-kappa B. European Journal of
Pharmacology, 672(1), 169–174. https://doi.org/10.1016/j.ejphar.2011.09.175
the work reported in this paper. Hunter, P. M., & Hegele, R. A. (2017). Functional foods and dietary supplements for the
management of dyslipidemia. Nature Reviews Endocrinology, 13(5), 278–288. https://
Acknowledgements doi.org/10.1038/nrendo.2016.210
Ishii, D., Matsuzawa, D., Kanahara, N., Matsuda, S., Sutoh, C., Ohtsuka, H.,
Nakazawa, K., Kohno, M., Hashimoto, K., Iyo, M., & Shimizu, E. (2010). Effects of
This work was supported by the National Natural Science Foundation aripiprazole on MK-801-induced prepulse inhibition deficits and mitogen-activated
of China (32072225), the Applied Basic Research Program of Shenyang protein kinase signal transduction pathway. Neuroscience Letters, 471(1), 53–57.
https://doi.org/10.1016/j.neulet.2010.01.010
(F16-205-1-52) and the scientific research foundation of Shenyang Jeon, S. J., Kim, E., Lee, J. S., Oh, H. K., Zhang, J., Kwon, Y., Jang, D. S., & Ryu, J. H.
Agricultural University. (2017). Maslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-
like behaviors in mice. Neuropharmacology, 126, 168–178. https://doi.org/10.1016/
j.neuropharm.2017.09.014
Ethics statement Keser, S., Celik, S., Turkoglu, S., Yilmaz, O., & Turkoglu, I. (2014). The Investigation of
Some Bioactive Compounds and Antioxidant Properties of Hawthorn (Crataegus
The review in the manuscript did not involve any human subjects monogyna subsp. monogyna Jacq). Journal of Intercultural Ethnopharmacology, 3(2),
51–55. https://doi.org/10.5455/jice.20140120103320
and animal experiments. Kołodziej, B., Sęczyk, Ł., Sugier, D., Kędzia, B., Chernetskyy, M., Gevrenova, R., &
Henrye, M. (2019). Determination of the yield, saponin content and profile,
References antimicrobial and antioxidant activities of three Gypsophila species. Industrial Crops
and Products, 138(5), 111422. https://doi.org/10.1016/j.indcrop.2019.05.071
Kucukatay, V., Ağar, A., Gumuslu, S., & Yargiçoğlu, P. (2007). Effect of sulfur dioxide on
Ahn, Y. M., Seo, M. S., Kim, S. H., Kim, Y., Yoon, S. C., Juhnn, Y. S., & Kim, Y. S. (2005).
active and passive avoidance in experimental diabetes mellitus: Relation to oxidant
Increased phosphorylation of Ser473-Akt, Ser9-GSK-3beta and Ser133-CREB in the
stress and antioxidant enzymes. International Journal of Neuroscience, 117(8),
rat frontal cortex after MK-801 intraperitoneal injection. International Journal of
1091–1107. https://doi.org/10.1080/00207450600934531
Neuropsychopharmacology, 8(4), 607–613. https://doi.org/10.1017/
S1461145705005353

5
T. Li et al. Journal of Functional Foods 90 (2022) 104988

Kumari, M., Brunner, E., & Fuhrer, R. (2000). Minireview: Mechanisms by Which the (hawthorn) and their in vitro biological activities. Journal of the Science of Food and
Metabolic Syndrome and Diabetes Impair Memory. The Journals of Gerontology Series Agriculture, 100(5), 1998–2006. https://doi.org/10.1002/jsfa.10216
A: Biological Sciences and Medical Sciences, 55(5), B228–B232. https://doi.org/ Rodríguez-Hernández, H., Simental-Mendía, L. E., Rodríguez-Ramírez, G., & Reyes-
10.1093/gerona/55.5.B228 Romero, M. A. (2013). Obesity and inflammation: Epidemiology, risk factors, and
Kwok, C.-Y., Wong, C. N.-Y., Yau, M. Y.-C., Yu, P. H.-F., Au, A. L. S., Poon, C. C.-W., markers of inflammation. International Journal of Endocrinology, 2013, 1–11. https://
Seto, S.-W., Lam, T.-Y., Kwan, Y.-W., & Chan, S.-W. (2010). Consumption of dried doi.org/10.1155/2013/678159
fruit of Crataegus pinnatifida (hawthorn) suppresses high-cholesterol diet-induced Sammari, H., Jedidi, S., Selmi, H., Rtibi, K., Jabri, M. A., Jridi, M., Zouari, N., Toumi, L.,
hypercholesterolemia in rats. Journal of Functional Foods, 2(3), 179–186. https://doi. & Sebai, H. (2020). Protective effects of Crataegus azarolus L. berries aqueous extract
org/10.1016/j.jff.2010.04.006 against castor oil–induced diarrhea, oxidative stress, and inflammation in rat.
Lackey, D. E., & Olefsky, J. M. (2016). Regulation of metabolism by the innate immune Neurogastroenterology & Motility, 33(6), e14065. https://doi.org/10.1111/
system. Nature Reviews Endocrinology, 12(1), 15–28. https://doi.org/10.1038/ nmo.14065
nrendo.2015.189 Shao, F., Gu, L. F., Chen, H. J., Liu, R. H., Huang, H. L., & Ren, G. (2016). Comparation of
Li, L., Gao, X. L., Liu, J. G., Chitrakar, B., Wang, B., & Wang, Y. C. (2021). Hawthorn hypolipidemic and antioxidant effects of aqueous and ethanol extracts of Crataegus
pectin: Extraction, function and utilization. Current Research in Food Science, 4, pinnatifida fruit in high-fat emulsion-induced hyperlipidemia rats. Pharmacognosy
429–435. https://doi.org/10.1016/j.crfs.2021.06.002 Magazine, 12(45), 64–69. https://doi.org/10.4103/0973-1296.176049
Li, S. H., Huang, Z., Dong, Y. P., Zhu, R. G., & Li, T. P. (2017). Haw pectin Shi, G.-J., Li, Y., Cao, Q.-H., Wu, H.-X., Tang, X.-Y., Gao, X.-H., Yu, J.-Q., Chen, Z., &
pentaglaracturonide inhibits the fatty acid synthesis and improves insulin sensitivity Yang, Y. (2019). In vitro and in vivo evidence that quercetin protects against
in high-fat-fed mice. Journal of Functional Foods, 34, 440–446. https://doi.org/ diabetes and its complications: A systematic review of the literature. Biomedicine &
10.1016/j.jff.2017.04.030 Pharmacotherapy, 109, 1085–1099. https://doi.org/10.1016/j.biopha.2018.10.130
Li, S. H., Li, T. P., Jia, Y. F., Zhu, R. G., Wang, N., Jin, S., & Guo, M. (2011). Fractionation Shih, C.-C., Lin, C.-H., Lin, Y.-J., & Wu, J.-B. (2013). Validation of the antidiabetic and
and structural characterization of haw pectin oligosaccharides. European Food hypolipidemic effects of hawthorn by assessment of gluconeogenesis and lipogenesis
Research and Technology, 233(5), 731–734. https://doi.org/10.1007/s00217-011- related genes and AMP-activated protein kinase phosphorylation. Evidence-Based
1568-8 Complementary and Alternative Medicine, 2013, 597067. https://doi.org/10.1155/
Li, T., Zhu, J., Guo, L., Shi, X. L., Liu, Y. F., & Yang, X. B. (2013). Differential effects of 2013/597067
polyphenols-enriched extracts from hawthorn fruit peels and fleshes on cell cycle Tariq, A., Mussarat, S., & Adnan, M. (2015). Review on ethnomedicinal, phytochemical
and apoptosis in human MCF-7 breast carcinoma cells. Food Chemistry, 141(2), and pharmacological evidence of Himalayan anticancer plants. Journal of
1008–1018. https://doi.org/10.1016/j.foodchem.2013.04.050 Ethnopharmacology, 164, 96–119. https://doi.org/10.1016/j.jep.2015.02.003
Li, T. P., Chen, X. J., Huang, Z., Xie, W. Y., Tong, C. N., Bao, R. W., Sun, X., Li, W. J., & Turner, M. D., Nedjai, B., Hurst, T., & Pennington, D. J. (2014). Cytokines and
Li, S. H. (2019). Pectin oligosaccharide from hawthorn fruit ameliorates hepatic chemokines: At the crossroads of cell signalling and inflammatory disease.
inflammation via NF-κB inactivation in high-fat diet fed mice. Journal of Functional Biochimica et Biophysica Acta- Molecular Cell Research, 1843(11), 2563–2582. https://
Foods, 57, 345–350. https://doi.org/10.1016/j.jff.2019.04.027 doi.org/10.1016/j.bbamcr.2014.05.014
Li, T. P., Li, S. H., Du, L. J., Wang, N., Guo, M., Zhang, J. W., Yan, F. W., & Zhang, H. L. Vanden Berghe, W. (2012). Epigenetic impact of dietary polyphenols in cancer
(2010). Effects of haw pectic oligosaccharide on lipid metabolism and oxidative chemoprevention: Lifelong remodeling of our epigenomes. Pharmacological Research,
stress in experimental hyperlipidemia mice induced by the high-fat diet. Food 65(6), 565–576. https://doi.org/10.1016/j.phrs.2012.03.007
Chemistry, 121(4), 1010–1013. https://doi.org/10.1016/j.foodchem.2010.01.039 Wang, H., Zhang, Z. S., Guo, Y., Sun, P., Lv, X. L., & Zuo, Y. B. (2011). Hawthorn fruit
Li, T. P., Liu, Y. H., Dong, Y. P., Li, S. H., & Zhu, R. G. (2014). Anti-fat deposition and increases the antioxidant capacity and reduces lipid peroxidation in senescence-
antioxidant effects of haw pectic oligosaccharide in the liver of high-fat-fed mice. accelerated mice. European Food Research and Technology, 232(5), 743–751. https://
CyTA-Journal of Food, 12(1), 27–31. https://doi.org/10.1080/ doi.org/10.1007/s00217-011-1435-7
19476337.2013.783625 Wang, N., Zhang, C. Y., Qi, Y. D., & Li, T. P. (2007). Extraction and food chemical
Li, X. P., Li, W., Gao, F. F., Huang, C. G., He, T. Y., & Sun, Z. J. (2021). Hawthorn characterizations of haw pectins. Science and Technology of Food Industry, 28(11),
polysaccharide extract up-regulates miR-146a-5p and inhibits Wnt. Anhui Medicine, 87–92. https://doi.org/10.3969/j.issn.1002-0306.2007.11.024. (In Chinese)
25(2), 326–330 (In Chinese). Wang, T., An, Y. T., Zhao, C. F., Han, L. F., Boakye-Yiadom, M., Wang, W., & Zhang, Y.
Lin, Y. G., Vermeer, M. A., & Trautwein, E. A. (2011). Triterpenic acids present in (2011). Regulation effects of Crataegus pinnatifida leaf on glucose and lipids
hawthorn lower plasma cholesterol by inhibiting intestinal ACAT activity in metabolism. Journal of Agricultural and Food Chemistry, 59(9), 4987–4994. https://
hamsters. Evidence-Based Complementary and Alternative Medicine, 2011, 1–9. https:// doi.org/10.1021/jf1049062
doi.org/10.1093/ecam/nep007 Wang, Y., Lv, M., Wang, T., Sun, J. Y., Wang, Y. X., Xia, M. Q., Jiang, Y., Zhou, X., &
Liu, F., Zhang, X. S., & Ji, Y. (2020). Total flavonoid extract from hawthorn (Crataegus Wan, J. (2019). Research on mechanism of charred hawthorn on digestive through
pinnatifida) improves inflammatory cytokines-evoked epithelial barrier deficit. modulating “brain-gut” axis and gut flora. Journal of Ethnopharmacology, 245,
Medical Science Monitor, 26, e920170. https://doi.org/10.12659/MSM.920170. 112166. https://doi.org/10.1016/j.jep.2019.112166
Liu, H., Liu, J. C., Lv, Z. Z., Yang, W. B., Zhang, C. L., Chen, D. L., & Jiao, Z. G. (2019). Wei, Z. Q., Ai, L., Chen, X., Li, L., Wang, L., Fan, W. X., Tang, X. K., Liang, F., & Wu, C. J.
Effect of dehydration techniques on bioactive compounds in hawthorn slices and (2018). Comparative studies on the regulatory effects of raw and charred hawthorn
their correlations with antioxidant properties. Journal of Food Science and Technology, on functional dyspepsia and intestinal flora. Tropical Journal of Pharmaceutical
56(5), 2446–2457. https://doi.org/10.1007/s13197-019-03720-x Research, 18(2), 333–339. https://doi.org/10.4314/tjpr.v18i2.16
Liu, S. W., Yu, J. C., Fu, M. F., Wang, X. F., & Chang, X. D. (2021). Regulatory effects of Wen, L. R., Guo, R. X., You, L. J., Abbasi, A. M., Li, T., Fu, X., & Liu, R. H. (2017). Major
hawthorn polyphenols on hyperglycemic, inflammatory, insulin resistance triterpenoids in Chinese hawthorn “Crataegus pinnatifida” and their effects on cell
responses, and alleviation of aortic injury in type 2 diabetic rats. Food Research proliferation and apoptosis induction in MDA-MB-231 cancer cells. Food and
International, 142, 110239. https://doi.org/10.1016/j.foodres.2021.110239 Chemical Toxicology, 100, 149–160. https://doi.org/10.1016/j.fct.2016.12.032
Lou, X. M., Xu, H. D., Hanna, M., & Yuan, L. (2020). Identification and quantification of Wen, L. R., Guo, X. B., Liu, R. H., You, L. J., Abbasi, A. M., & Fu, X. (2015). Phenolic
free, esterified, glycosylated and insoluble-bound phenolic compounds in hawthorn contents and cellular antioxidant activity of Chinese hawthorn “Crataegus
berry fruit (Crataegus pinnatifida) and antioxidant activity evaluation. LWT-Food pinnatifida”. Food Chemistry, 186, 54–62. https://doi.org/10.1016/j.
Science and Technology, 130, 109643. https://doi.org/10.1016/j.lwt.2020.109643 foodchem.2015.03.017
Ma, L., Xu, G. B., Tang, X. Y., Zhang, C., Zhao, W., Wang, J., & Chen, H. (2020). Anti- Xie, W. H., Sun, C., & Liu, S. M. (2009). Effect of hawthorn flavanone on blood-fat and
cancer potential of polysaccharide extracted from hawthorn (Crataegus.) on human expression of lipogenesis and lipolysis genes of hyperlipidemia model mouse. China
colon cancer cell line HCT116 via cell cycle arrest and apoptosis. Journal of Journal of Chinese Materia Medica, 34(2), 224–229. https://doi.org/10.3321/j.issn:
Functional Foods, 64, 103677. https://doi.org/10.1016/j.jff.2019.103677 1001-5302.2009.02.026
Míguez, B., Gómez, B., Gullón, P., Gullón, B., & Alonso, J. L. (2016). Pectic Xin, C., Zhao, M. Y., Wang, J. H., & Wang, Z. Y. (2021). Hawthorn polyphenols, D-chiro-
oligosaccharides and other emerging prebiotics. Probiotics and Prebiotics in Human inositol, and epigallocatechin gallate exert a synergistic hypoglycemic effect. Journal
Nutrition and Health, 301–330. of Food Biochemistry, 45(7), e13771. https://doi.org/10.1111/jfbc.13771
Min, Q., Bai, Y. T., Zhang, Y. C., Yu, W., Zhang, M. L., Liu, D. Y., Diao, T. T., & Lv, W. Xu, W. D., Li, J. Y., Qi, W. P., & Peng, Y. (2021). Hypoglycemic effect of vitexin in
(2017). Hawthorn leaf flavonoids protect against diabetes-induced cardiomyopathy C57BL/6J mice and HepG2 models. Journal of Food Quality, 2021, 5535476. https://
in Rats via PKC-α signaling pathway. Evidence-Based Complementary and Alternative doi.org/10.1155/2021/5535476
Medicine, 2017, 1–8. https://doi.org/10.1155/2017/2071952 Xu, W. L., Caracciolo, B., Wang, H.-X., Winblad, B., Bäckman, L., Qiu, C. X., &
Qiao, A. M., Wang, Y. H., Xiang, L. M., Zhang, Z. X., & He, X. J. (2015). Novel Fratiglioni, L. (2010). Accelerated progression from mild cognitive impairment to
triterpenoids isolated from hawthorn berries functioned as antioxidant and dementia in people with diabetes. Diabetes, 59(11), 2928–2935. https://doi.org/
antiproliferative activities. Journal of Functional Foods, 13, 308–313. https://doi.org/ 10.2337/db10-0539
10.1016/j.jff.2014.12.047 Yang, B. R., & Liu, P. Z. (2012). Composition and health effects of phenolic compounds in
Redish, A. D., & Touretzky, D. S. (1997). Cognitive maps beyond the hippocampus. hawthorn (Crataegus spp.) of different origins. Journal of the Science of Food and
Hippocampus, 7(1), 15–35. https://doi.org/10.1002/(SICI)1098-1063(1997)7: Agriculture, 92(8), 1578–1590. https://doi.org/10.1002/jsfa.5671
1<15::AID-HIPO3>3.0. CO;2-6 Yu, Q. H., Chen, X. J., Sun, X., Li, W. J., Liu, T. Z., Zhang, X. Z., Li, Y. Q., Li, T. P., &
Reeta, K. H., Singh, D., & Gupta, Y. K. (2017). Chronic treatment with taurine after Li, S. H. (2021). Pectic oligogalacturonide facilitates the synthesis and activation of
intracerebroventricular streptozotocin injection improves cognitive dysfunction in adiponectin to improve hepatic lipid oxidation. Molecular Nutrition & Food Research,
rats by modulating oxidative stress, cholinergic functions and neuroinflammation. 60(20), 2100167. https://doi.org/10.1002/mnfr.202100167
Neurochemistry International, 108, 146–156. https://doi.org/10.1016/j. Zarrinkalam, E., Ranjbar, K., Salehi, I., Kheiripour, N., & Komaki, A. (2018). Resistance
neuint.2017.03.006 training and hawthorn extract ameliorate cognitive deficits in streptozotocin-
Rocchetti, G., Senizza, B., Zengin, G., Mahomodally, M. F., Senkardes, I., Lobine, D., & induced diabetic rats. Biomedicine & Pharmacotherapy, 97, 503–510. https://doi.org/
Lucini, L. (2020). Untargeted metabolomic profiling of three Crataegus species 10.1016/j.biopha.2017.10.138

6
T. Li et al. Journal of Functional Foods 90 (2022) 104988

Zhang, L. L., Zhang, Z. N., Yan, K. J., Erihemu, Zhang, L. F., & Xu, J. G. (2020). pinnatifida” during in vitro digestion. Journal of Functional Foods, 40, 76–85. https://
Antioxidant activity and protective effects on oxidative DNA and protein damage of doi.org/10.1016/j.jff.2017.10.039
different solvent extracts from hawthorn (Crataegus pinnatifida Bunge). Food Zhong, X. L., Guo, J., Wang, L. Y., Luo, D. S., Bei, W. J., Chen, Y., Yan, K. Q., & Peng, J. H.
Research and Development, 41(7), 63–68. https://doi.org/10.12161/j.issn.1005-6521 (2012). Analysis of the constituents in rat serum after oral administration of Fufang
.2020.07.012. Zhenzhu Tiaozhi capsule by UPLC-Q-TOF-MS/MS. Chromatographia, 75(3–4),
Zhang, S. H., Zhang, C. Q., Li, M. X., Chen, X., & Ding, K. (2019). Structural elucidation of 111–129. https://doi.org/10.1007/s10337-011-2164-6
a glucan from Crataegus pinnatifida and its bioactivity on intestinal bacteria strains. Zhu, R. G., Li, T. P., Dong, Y. P., Liu, Y. H., Li, S. H., Chen, G., Zhao, Z. S., & Jia, Y. F.
International Journal of Biological Macromolecules, 128(1), 435–443. https://doi.org/ (2013). Pectin pentasaccharide from hawthorn (Crataegus pinnatifida Bunge. Var.
10.1016/j.ijbiomac.2019.01.158 major) ameliorates disorders of cholesterol metabolism in high-fat diet fed mice.
Zhang, Y., Shen, T. T., Liu, S. W., Zhao, J., Chen, W., & Wang, H. (2014). Effect of Food Research International, 54(1), 262–268. https://doi.org/10.1016/j.
hawthorn on drosophila melanogaster antioxidant-related gene expression. Tropical foodres.2013.07.010
Journal of Pharmaceutical Research, 13(3), 353–357. https://doi.org/10.4314/tjpr. Zuo, Z., Zhang, L., Zhou, L. M., Chang, Q., & Chow, M. (2006). Intestinal absorption of
v13i3.6 hawthorn flavonoids-in vitro, in situ and in vivo correlations. Life Sciences, 79(26),
Zheng, G. Q., Deng, J., Wen, L. R., You, L. J., Zhao, Z. G., & Zhou, L. (2018). Release of 2455–2462. https://doi.org/10.1016/j.lfs.2006.08.014
phenolic compounds and antioxidant capacity of Chinese hawthorn “Crataegus