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Bioactivities and molecular mechanisms of

Bioactivities and molecular mechanisms of
polysaccharides from Hericium erinaceus
polysaccharides from Hericium erinaceus
Jianhui Liu, Weiwei Wang, Qiuhui Hu, Xuyang Wu, Hui Xu,
Jianhui
AnxiangLiu,
Su,Weiwei
MinhaoWang, Qiuhui Yang
Xie, Wenjian Hu, Xuyang
* Wu, Hui Xu,
Anxiang Su, Minhao Xie, Wenjian Yang*
Key Laboratory of Grains and Oils Quality Control and Processing, Collaborative Innovation Center for Modern Grain Circulation and Safety,
College of Food of
Key Laboratory Science
Grainsand
andEngineering,
Oils QualityNanjing
ControlUniversity of Finance
and Processing, and Economics,
Collaborative Nanjing
Innovation 210023,
Center China Grain Circulation and Safety,
for Modern
College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing 210023, China

ARTICLE INFO ABSTRACT

ARTICLE INFO ABSTRACT
Article history: Hericium erinaceus, an edible and medicinal mushroom, has been utilized since ancient China due to its
Received 13 December 2021
Article history: Hericium taste
delicious erinaceus,
and health benefits.
an edible and The polysaccharide
medicinal mushroom, fromhasH.been
erinaceus
utilized(HEP)
since is supposed
ancient to due
China be one of
to its
Received in13revised form
December 2 January 2022
2021 the majortaste
delicious bioactive compounds,
and health benefits.which from H.
garnered widespread
The polysaccharide erinaceus
attention in seeking
(HEP) isinnovative
supposed to applications
be one of
Accepted
Received in11revised
Januaryform
20222 January 2022 for
the precision nutrition.
major bioactive Both in vitro
compounds, which in vivo studies
andgarnered haveattention
widespread shown that HEP possesses
in seeking antioxidant
innovative and
applications
Available
Accepted 11Online 1 June
January 2022
2022 anti-aging, gastrointestinal in vitro and in vivo studies
for precision nutrition. Bothprotecting, anti-tumor, hypolipidemic
have shown and that
hypoglycemic,
HEP possesses immune-enhancing,
antioxidant and
Available Online 1 June 2022 neuroprotective, and hepatoprotective
anti-aging, gastrointestinal protecting,activities, verifying
anti-tumor, its functional
hypolipidemic andbenefits to humanimmune-enhancing,
hypoglycemic, health. This review
Keywords: provides an overview
neuroprotective, of the extractionactivities,
and hepatoprotective and structure of HEP,
verifying and concluded
its functional thattoHEP
benefits had health.
human different structures
This review
Hericium
Keywords:erinaceus with different sources of H. erinaceus
of the
provides an overview extraction and
and extraction
structure of methods.
HEP, andBesides, the biochemical
concluded that HEP had and pharmacological
different structures
Hericium erinaceus
Polysaccharide properties of HEP
with different sources of H.aserinaceus
as well the relative
andmechanism
extraction were highlighted
methods. Besides,andthesummarized
biochemicalonand basis of in vivo
thepharmacological
Bioactivities
Polysaccharide and in vitroofstudies,
properties HEP aswhich
well ascould be helpful
the relative for the healthy
mechanism application and
were highlighted of HEP. Finally, on
summarized thethe
research in vivo
prospects
basis of
Mechanism
Bioactivities of in vitro
andHEP for specific
studies, populations
which couldorbeprecision nutrition
helpful for were proposed.
the healthy application of HEP. Finally, the research prospects
Mechanism 2022 Beijing
of HEP for©specific Academy
populations of Foodnutrition
or precision Sciences.were
Publishing
proposed.services by Elsevier B.V. on behalf of KeAi
©©2022
2022Beijing
Beijing Academyof
Academy
Communications of Food
Food
Co., Ltd. Sciences.
Sciences. Publishing
Publishing
This is an open access services
services by
articleby Elsevier
Elsevier
under B.V.
B.V.
the CC on behalf
on behalf of
BY-NC-ND of KeAi
KeAi
license
CommunicationsCo.,
Communications Co.,Ltd.
Ltd.This
Thisisisan
anopen
openaccess
accessarticle
articleunder
underthetheCCCCBY-NC-ND
BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/). license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction anti-aging, anti-tumor, anti-inflammation, gastrointestinal protection,

1. Introduction anti-aging, anti-tumor,
hypoglycemia, anti-inflammation,
hypolipidemia, gastrointestinal
immunoregulation, protection,
liver protection,
Hericium erinaceus belongs to Hydnaceae family and Hericium hypoglycemia, hypolipidemia, immunoregulation, liver protection,
and nerve protection. This review mainly focuses on the extraction
Hericium
genus, which erinaceus
was famous belongs
for itstodelicious
Hydnaceae family
taste, and Hericium
nutritional value, and nerve
method andprotection.
structuralThis review mainly
properties of HEP,focuses
and to on the extraction
summarizes the
genus,
and which was
medicinal famousfor
function foratitsleast
delicious taste, nutritional
two thousand years. Itvalue,
was method and structural properties of HEP, and to summarizes
biological activities of HEP and currently established mechanisms. the
and medicinal
recorded in the function
Compendium for atof least twoMedica
Materia thousandthatyears. It was
H. erinaceus biological activities of HEP and currently established mechanisms.
This will help to better understand the biological activities of
recorded
could in the
help Compendium
digestion of Materia
and nourish Medica
bodies [1]. that
There H. are
erinaceus
many Thiserinaceus
H. will helpandto better understand
its precise the biological
nutritional applicationactivities of
in specific
could helpcomponents
bioactive digestion andin H.nourish
erinaceus,bodies
such[1].
as There are many
polysaccharides, H. erinaceus
populations. and its precise nutritional application in specific
bioactive peptides,
proteins, components in H. sterols,
terpenes, erinaceus, etc such as polysaccharides,
[2]. Polysaccharide from populations.
proteins,
H. peptides,
erinaceus (HEP)terpenes,
is onesterols,
of the etc [2].studied
most Polysaccharide from
ingredients, 2. Extraction and structure of HEP
H. erinaceus
contributing (HEP) is biological
to numerous one of the most studied
activities, ingredients,
such as anti-oxidation, 2. Extraction and structure of HEP
contributing to numerous biological activities, such as anti-oxidation, With specific physicochemical properties and biochemical reaction
With specific
characteristics, thephysicochemical properties
HEP can be extracted by and biochemical
many reaction
kinds of methods
*
Corresponding author at: College of Food Science and Engineering, Nanjing University of characteristics,
such the HEP
as hot water can be[3,4],
extraction extracted
alkalibydissolution
many kindsmethod
of methods
[5],
*
Finance of
Corresponding author at: College andFood
Economics,
Science Nanjing 210023, China.
and Engineering, Nanjing University of such as hothydrolysis
enzymatic water extraction [3,4], alkali
[6], ultrasonic dissolution
extraction method [5],
[7], microwave-
E-mail address: lingwentt@163.com
Finance and(W.J. Yang) Nanjing 210023, China.
Economics,
enzymatic
assisted hydrolysis
extraction [6],[8],
method ultrasonic
etc. The extraction
sources for[7], microwave-
extraction could
E-mail address:
Peer review under responsibility of KeAi
lingwentt@163.com (W.J.Communications
Yang) Co., Ltd.
Peer review under responsibility of KeAi Communications Co., Ltd.
assisted
be extraction
fruiting method [8],
body, mycelium andetc. The sources
culture broth offor
H.extraction
erinaceus.could
The
be fruiting body, mycelium and culture broth of H. erinaceus. The

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2772-5669/© 2022 Beijing Academy of Food Sciences. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC
http://doi.org/10.1016/j.jfutfo.2022.03.007
BY-NC-ND
2772-5669/©license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
2022 Beijing Academy of Food Sciences. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC
10.1016/j.jfutfo.2022.03.007
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
2772-5669 © 2022 Beijing Academy of Food Sciences. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
104 Jianhui Liu et al. / Journal of Future Foods 2-2 (2022) 103–111

104 J.H. Liu et al. / Journal of Future Foods 2 (2022) 103-111

extraction rate of HEP can be increased by controlling the extraction and it was proposed as a β-(1→3)-linked-D-glucan with a
time, temperature, enzyme amount, and material-to-liquid ratio. (1→6)-β-linked-D- glucopyranosyl side-branching unit on every third
Besides, some new extraction methods have emerged as technical residue, as is revealed in Fig. 2B [15]. Therefore, the HEP extracted
innovations, such as the combination of extrusion and phytochemicals from different sources even with the same method had different
separation technology, the simultaneous extraction of polysaccharides structures. Furthermore, HEP from the same source by different
and proteins from H. erinaceus by flash extraction. Among them, methods exhibited different structural features.
the ultrasonic method and the microwave-assisted extraction method
A c b c
have the advantages of simple operation, saving time, saving energy,
high efficiency, and high extraction effect, which have been widely O
O O O O
O
O
applicated in the laboratory and industry. Moreover, the extraction HO HO HO
O OH
conditions should be optimized many times in the future to increase OH

HO n
the extraction rate and efficiency. HO m
OH HO
O

H. erinaceus
Fruiting bodies/Mycelia/ a m + n =3
H 3C OH
Fermented broth OH

Ultrasonic/ Hot water extraction/

Microwave assisted Alkali dissolution/
Enzyme hydrolysis B
Extracting solution OH
H
OH

Concentration H
Ethanol H
Centrifuge H c
HO O
Precipitate H
O
Deproteinization HO
H H OH
H
Decolorization H
O H O H O
HO HO HO
Crude polysaccharide O O
H OH H HO H OH
Anion exchange chromatography H H H H H H
Gel exclusion chromatography a b a

Purified polysaccharide
Fig. 1 Essential steps involved in the extraction and purification of HEP.
After deproteinization and decolorization, the extracted crude HEP
is then purified through anion exchanger column chromatography
and gel exclusion column chromatography, as shown in Fig. 1. The
obtained HEP can be determined for the structure, mainly focusing
on molecular mass, main chain and branch chain composition,
monosaccharide composition, glycosidic bond composition,
and conformation. Due to the different sources of raw materials
and extraction methods of H. erinaceus, the specific molecular
mass, monosaccharide composition and monosaccharide ratio of
polysaccharides are different. The molecular mass of HEP ranges in
13‒1 000 kDa. The high performance liquid chromatography (HPLC),
gas liquid chromatography (GLC), gas chromatography (GC), gas
chromatography-mass spectrometry (GC-MS), or high-performance
anion exchange chromatography (HPAEC) are used to determine
the composition and proportion of monosaccharides. Most HEP is
heteropolysaccharides, including two or more monosaccharides, such
as glucose (Glu), xylose (Xyl), rhamnose (Rha), mannose (Man),
fucose (Fuc), galactose (Gal), and arabinose (Ara), etc. Methylation
analysis and GC-MS are used to determine the connection type of
sugar groups. Wang et al. [9] have systematically summarized the
structure of HEP from the fruiting bodies, mycelium, and fermentation
broth. Current research showed that (1→6)-linked α-D-galactopyranose
backbone is widely present in heteropolysaccharides [10-14].
The primary structure of the heteropolysaccharide was predicted
by Li et al. [13], as shown in Fig. 2A. Recently, a water-soluble
β-D-glucan was obtained by freeze-thawing from H. erinaceus,
Fig. 2 (A) The predicted primary structure for a HEP with (1→6)-linked
α-D-galactopyranose backbone [13]; (B) The proposed structure for a
(1→3),(1→6)-β-D-glucan obtained by freeze-thawing [15].
2. Biological activities of HEP
2.1 Antioxidant and anti-aging activities of HEP
Abundant studies have shown that HEP has antioxidant and
anti-aging activities. In vitro experiments found that HEP has good
scavenging effects on hydroxyl radicals (·OH) and 1,1-diphenyl-2-
trinitrophenylhydrazine (DPPH) free radicals [16,17]. And the ability
was basically equivalent to that of vitamin C in DPPH scavenge [18].
It is well known that the antioxidant capacity is generally related to
anti-aging and anti-fatigue activities. The anti-oxidation and anti-
aging effects of HEP in cell and animal experiments are shown in
Table 1. The HEP shows anti-skin aging activity mainly through
reducing serum urea nitrogen (SUN) and malondialdehyde (MDA),
enhancing the level of collagen, and increasing tissue glycogen
content and antioxidant enzyme activity, etc.
Polysaccharides contain hydroxyl and/or amino functional
groups, which can form chelation with metals or certain non-metals
through chemical adsorption [19]. The chelating modification of
polysaccharides can not only improve its own biological activities
but also endow it with new functions [20,21]. In addition, metal
chelates are more easily absorbed by organisms [22]. Chelating
modification has become one of the most important modification
methods in the field of polysaccharides. Compared with HEP, HEP-
Zn chelate exhibited an irregular spongy structure, which provided
 Jianhui Liu et al. / Journal of Future Foods 2-2 (2022) 103–111 105

J.H. Liu et al. / Journal of Future Foods 2 (2022) 103-111 105

Table 1
Antioxidant and anti-aging effects and mechanism of action of HEP.
Subject Method Dosage Mechanism and effect Reference
IPEC-J2 cell damage model induced Protecting IPEC-J2 cells from DON-induced oxidative stress, inhibiting
IPEC-J2 cell 62.5 μg/mL [25]
by deoxynivalenol (DON) DON-induced apoptosis and reducing reactive oxygen species (ROS) production.
Reducing blood urea nitrogen (BUN), serum creatinine (Scr) and creatinine clearance
Kidney ischemia reperfusion mouse
Mouse 300 mg/kg (CrCI) levels, reducing lipid peroxidation levels and increasing activity of [16]
model
antioxidant enzyme.
Significantly reducing the activity of type I matrix metalloproteinase in the skin of
Rat Aged rat 50, 150, 250 mg/kg [17]
aged rats, enhancing the level of collagen, and showing anti-skin aging activity.
Reducing contents of blood lactic acid (BLA), serum urea nitrogen (SUN) and
Mouse Feeding 50, 100, 200 mg/kg malondialdehyde (MDA), increasing tissue glycogen content and antioxidant enzyme [26]
activity, showing significant anti-fatigue activity.
Relieving aging by scavenging free radicals, increasing enzyme activity, and reducing
Mouse D-galactose induced aging mice NA MDA content, thereby improving serum biochemical indicators and enhancing [27]
immune activity.
NA: information was not available.

a larger surface area for chelation, and showed stronger DPPH free
radical and superoxide anion scavenging activity [23]. Besides,
acetylation modification is also a common modification method for
polysaccharides. Xu et al. [24] modified HEP by acetylation and
found that its scavenging effect on DPPH and ·OH was enhanced.
These evidences insinuated that HEP was capable of elevating
the enzymatic and non-enzymatic antioxidant activity and relieving
aging both in vitro and in vivo. Besides, the polysaccharides from
H. erinaceus will be a good material for structural modification in
exerting antioxidant, anti-aging, and new functions, which can be
further studied.
2.2 Protective functions of HEP on the gastrointestinal tract
Since ancient times, the function ‘helping the internal organs and
digestion’ of H. erinaceus has been recognized, making it a stomach
nourishing food. Modern studies have confirmed that extracts with
polysaccharides as the main component in H. erinaceus have a

Table 2
Gastrointestinal protecting effects and mechanism of action of HEP.
Subject Method Dosage Mechanism and effect Reference
Human gastric mucosal Resisting cell apoptosis and oxidative damage caused by H2O2, and
In vitro NA [3]
epithelial cells GES-1 showing anti-gastritis effect.
Demonstrating anti-oxidant ability and preventing the apoptotic cell
Human gastric mucosal
In vitro 50, 100 μg/mL death induced by H2O2 through inhibiting the activation of apoptotic cell [4]
epithelial cells GES-1
signals in the mitochondrial-dependent apoptosis pathway.
Human gastric mucosal 15.625, 32.250,
In vitro Showing a good protective effect on gastric mucosa. [29]
epithelial cells GES-1 62.500 μg/mL
Significantly preventing GES-1 cells from resisting H2O2-induced
oxidative damage and effectively prevents gastric cell damage in vitro,
Human gastric mucosal GES-1 cell oxidative damage 125, 250, 500, 1 000,
mainly by promoting cell proliferation, inhibiting cell necrosis, [30]
epithelial cells GES-1 model 2 000 μg/mL
reducing ROS levels, regulating mitochondrial membrane potential and
maintaining mitochondrial membrane permeability.
Helicobacter pylori In vitro 160, 320 μg/mL Showing anti-Helicobacter pylori activity. [31]
Mouse Ethanol-induced mouse ulcer model NA Significantly reducing the area of ulcers. [32]
Ethanol induces gastric mucosal Showing the potential to prevent duodenal ulcer and promote the production
Rat injury and pyloric ligation induces 100, 200, 400 mg/kg of short-chain fatty acids (SCFAs). The mechanism of its gastroprotective [33]
gastric ulcer in SD rats activity is antioxidant and anti-inflammatory effects.
Showing gastroprotective activity with the mechanism of activating
Ethanol-induced gastric ulcer
Rat 125, 250, 500 mg/kg repair and defense systems, reducing inflammation, and reducing [34]
model in rats
oxidative damage.
Reducing the count of Escherichia coli in the cecum, lowering the pH
Broiler Feeding 0, 1, 3, 5 g/kg value, increasing the count of Lactobacillus, Bifidobacterium and the [35]
concentration of propionic acid.
Promoting the production of SCFAs in the contents of the colon and cecum,
Mouse Feeding 400 mg/kg [36]
increasing water content, lowering pH, and improving colon health.
Trinitrobenzene sulfonic acid
Decreasing the expression of NF-κB, TNF-α, and IL-17 in the colonic
Rat (TNBS) induced inflammatory 150 mg/kg [37]
mucosa, and promoting the colonization of Bifidobacteria in the colon.
bowel disease (IBD) rats
Showing antioxidant and anti-inflammatory effects and blocking the
phosphorylation of nuclear factor-κB (NF-κB) p65, NF-κB inhibitor α
Mouse DSS-induced colitis C57BL/6 mice 150, 250, 500 mg/kg (IκB-α), mitogen-activated protein kinase (MAPK) and protein kinase B [38]
(Akt), regulating the intestinal flora, and maintaining the integrity of the
intestinal barrier.
106 Jianhui Liu et al. / Journal of Future Foods 2-2 (2022) 103–111

106 J.H. Liu et al. / Journal of Future Foods 2 (2022) 103-111

particularly outstanding protective effect on the gastric mucosa,
such as restraining Helicobacter pylori, improving the nutritional
status of the gastric mucosa, enhancing the defense mechanism of
the gastric mucosa, and repairing damaged gastric mucosa [3,28].
It was confirmed in the in vitro gastric mucosal epithelial cells
that HEP promoted cell proliferation, and decreased cell apoptosis,
oxidative damage and inflammation [3,4,29,30]. Moreover, HEP has
a good protective effect on the intestinal tract, including improving
ulcerative colitis and inflammatory bowel disease (IBD), alleviating the
histological damage of the colon, reducing the infiltration of inflammatory
cells and the expression of inflammatory factors, and promoting the growth
of probiotics in the gastrointestinal tract. The mechanism and effect of HEP
in protecting the gastrointestinal tract are summarized in Fig. 3 and Table 2.
Although studies have shown that HEP has good anti-inflammatory
activity, the in-depth research and clinical application is still lacking,
and the mechanism of action is not clear. Further research on its anti-
inflammatory activity is still needed.
2.3 Anti-tumor activities of HEP
Cancer ranks as a leading cause of death and greatly threatens
human health. It has been estimated that the cancer burden would
reach 28.4 million cases in 2040 [39]. A large number of studies have
shown that HEP has good biological activity in the prevention and
treatment of cancer. The relative mechanism and effects are shown in
Table 3. Through establishing gastric cancer, liver cancer, colorectal
cancer, and breast cancer cell models, it was confirmed that HEP
could regulate the secretion of cytokines, increase the apoptosis of
cancer cells, and inhibit the growth of cancer cells. Similarly, in
mouse tumor models, HEP was confirmed to reduce tumor size and
cancer cell metastasis, increase survival time, and reduce mouse
lethality, thereby reducing the immunosuppressive effect during
tumorigenesis and exerting anti-tumor activity. With the continuous
development of science and technology, the anti-tumor activity of
HEP will be more widely applied.

HEP
2.4 Hypoglycemic and hypolipidemic activities of HEP
in virto gastricmuscosal epithelial cells

At present, the number of people with hypertension,

Duodenaluler
Oxidative damage Stomach Cell proliferation hyperglycemia, and hyperlipidemia is increasing, which is a serious
Inflammation Cell apoptosis
Oxidative damage
ROS H2O2 DPPH· ·OH
threat to human health. Hyperlipidemia is mainly manifested as
Duodenum Inflammation
high levels of cholesterol (TC), triglycerides (TG) and low-density
Helicobacter polyri lipoprotein cholesterol (LDL-C), and low levels of high-density
lipoprotein cholesterol (HDL-C), that is blood lipid metabolism
colon Echerichia coli
Lactobaccilus
disorders. Hyperglycemia is a metabolic disease characterized
Bifidobacterium
IBD
SCFAs by glucose metabolism disorders, causing vascular endothelial
Colitis
cecum
dysfunction, aggravating the development of inflammation, and
TNF-α, IL-6, IL-β, IL-17 even inducing diabetes [49]. As for the research on the function
NF-κB
MKPK of reducing blood sugar and blood lipid of HEP, some reports
Akt, IκB-α
relating to its mechanism and effect are shown in Table 4. In rodent
hyperlipidemia and diabetes models, HEP significantly reduced the
Fig. 3 The mechanism of HEP in protecting gastrointestinal tract. fasting blood glucose, serum TC, TG, and LDL-C levels, improved

Table 3
Anti-tumor effects and mechanism of action of HEP.
Subject Method Dosage Mechanism and effect Reference
As an enhancer to sensitize doxorubicin-mediated apoptosis signals. This sensitization
Human liver cancer cell line was achieved by activating c-jun N-terminal kinase (JNK) to reduce the expression of
In vitro 100 μg/mL [40]
HepG2 Cellular FLICE-inhibitory protein (c-FLIP) and by inhibiting NF-κB activity to enhance
intracellular doxorubicin accumulation.
Human gastric cancer cell Reducing cell viability and hypoxia-inducible factor 1α (HIF-1α) expression, increasing
In vitro NA [41]
SGC-7901 cell apoptosis and doxorubicin-induced ROS.
HeLa cell In vitro 2 mg/mL Inhibiting cell growth. [42]
Reducing cell proliferation and colony formation; inhibiting Caspase-8/-3 dependent
Human gastric cancer cell 25, 50, 100,
In vitro and p53 dependent mitochondrial mediated and PI3k/Akt signaling pathways, increasing [43]
SGC-7901 200 μg/mL
expression of Caspase-8, Caspase-3, p53, CDK4, Bax, and Bad.
Colon cancer cell 0, 0.2, 0.4, 0.6,
In vitro Inhibiting the growth of cancer cells. [44]
(HCT-116) 0.8, 1.0 mg/mL
Human colorectal cancer 0.2, 0.4, 0.6, 0.8， Inducing cell apoptosis through the caspase-9-dependent internal mitochondrial
In vitro [45]
cells(HCT-116 and DLD1) 1.0 mg/mL pathway, increasing ROS level in HCT-116 and DLD1 cells.
MCF-7 estrogen receptor Inducing apoptosis and G1 cell cycle arrest, increasing genes in cancer cell signaling pathways,
positive (ER+) human breast In vitro NA including tumor protein P53, Janus kinase signal transducer and activator of transcription JAK- [46]
cancer cells STAT, transforming growth factor-β, and mitogen-activated protein kinase.
ICR/Slc mice implanted with
Mouse 10 mg/kg Reducing tumor size, increasing survival time, and reducing mortality in mice. [47]
sarcoma 180 cells
BALB/c mice were inoculated with
Mouse NA Reducing lung cancer metastasis. [48]
26-M3.1 cancer cells in the colon
NA: information was not available.
 Jianhui Liu et al. / Journal of Future Foods 2-2 (2022) 103–111 107

J.H. Liu et al. / Journal of Future Foods 2 (2022) 103-111 107

glucose tolerance and serum HDL-C levels. Besides, it activated the
PI3K/Akt signal transduction pathway in diabetic rats, maintained the
balance of blood sugar in the body, inhibited lipid peroxidation, and
achieved the hypoglycemic effect. Therefore, the research of the HEP
on the mechanism of lowering blood sugar and blood lipid is of great
significance for the treatment of hyperlipidemia, obesity, and diabetes.
2.5 Immune enhancing activities of HEP
When attacked by bacteria, viruses, and other harmful substances,
the body will activate immune organs and immune cells to maintain
the stability of the internal environment [54]. Most polysaccharides
in edible fungus have immunomodulatory activity with activating T

Table 4
hypolipidemic and hypoglycemic effects and mechanism of action of HEP.
Subject Methods Dosage Mechanism and effect Reference
Mediating glycogen synthesis by activating PI3K/Akt signal transduction pathway,
Streptozocin (STZ)-induced
Rat 150, 300 mg/kg reducing liver function and serum lipid metabolism, increasing antioxidant enzyme [50]
diabetic rat model
activity, inhibiting lipid peroxidation, and relieving symptoms of diabetes.
Mouse STZ-induced diabetic mouse model 200, 400, 600 mg/kg Lowering blood sugar levels. [51]
Reducing plasma TC, LDL-C, TG, phospholipids, atherogenic index, and increasing
Rat Diet-induced hyperlipidemia rats 200 mg/kg [52]
plasma HDL-C levels.
Broiler Feeding 0, 1, 3, 5 g/kg Reducing fat deposits and promoting cholesterol metabolism. [35,53]
NA: information was not available.

Table 5
Immune Enhancing activities and mechanism of action of HEP.
Subject Methods Dosage Mechanism and effects Reference
Activating macrophages, promoting NO production, increasing the expression
RAW 264.7cell In vitro NA [58]
of TNF-α and IL-1β.
25, 50, 100, 200, Activating macrophages, promoting the production of NO, TNF-α and IL-6,
RAW 264.7cell In vitro [59]
400 μg/mL and increasing the expression of iNOS.
Lymphocytes: T and B lymphocyte proliferation, IL-2, IL-4 and IFN-γ secretion
Splenic lymphocytes 100, 250, 500, and increase; RAW 264.7 cells: pinocytosis and phagocytosis enhanced, ROS, NO,
In vitro [60]
RAW 264.7 cells 1 000 μg/mL IL-6 and TNF-α production increased, mRNA and protein expression of IL-6,
NOS and TNF-α increased.
Promoting the surface expression of MHC-II and CD86, the maturation of DCs, and
Dendritic cell 3.125, 6.25,
In vitro the production of IL-12 and IFN-γ, activating TLR4, promoting the phosphorylation [65]
（DCs） 12.5 μg/mL
of ERK, p38 and JNK, and activating NF-κB signaling pathway.
Dendritic cell 3.125, 6.25, 12.5, 25, 50， Promoting the maturation of DCs, reducing the endocytosis of DCs, promoting
In vitro [66]
（DCs） 100 μg/mL the secretion of IL-12/IFN-γ, and reducing the secretion of IL-10.
Splenic lymphocytes, 6.25, 12.5, 25, 50, 100, 200, Motivating the proliferation of lymphocytes by promoting the synthesis of
In vitro [61]
RAW 264.7 cells 400 μg/mL splenic lymphocyte DNA.
Immature DCs transforming into mature DCs with high expression of major
MODE-K/DCs histocompatibility complex (MHCII) and CD86, low antigen uptake, and
In vitro NA [67]
co-culture cell model typical morphology; increasing content of IL-12 and TNF-α and protein levels
of TLR4, MyD88 and NF-κB.
12.5, 25, 50, 100, Inducing lymphocyte proliferation and enhancing the expression of inflammatory
Mouse spleen cells In vitro [15]
200 μg/mL cytokines IL-6, TNF-α and IL-1β secreted by THP-1 macrophages.
0.97, 1.95, 3.91, 7.81, 15.63, Regulating the immune response in mouse peritoneal macrophages, promoting
Mouse peritoneal
In vitro 31.25, 62.5, 125, 250, the expression of MHCII, CD86, F4/80 and gp38, and enhancing the PCV2- [68]
macrophages
500 μg/mL specific IgG immune response and cytokine levels.
Stimulating the phagocytic activity of cells and the expression of CD40 and
0.98, 1.95, 3.91, 7.81,
Macrophages In vitro CD86, increasing the levels of NO, TNF-α, IL-1β and IL-6, and inducing a [64]
15.63 μg/mL
strong immune response.
Enhancing activities of lysozyme, complement C3 and SOD, increasing serum
Grass carp In vivo 400, 800, 1 200 mg/kg total protein, albumin and globulin concentration, up-regulating IL-1β and [69]
TNF-α, down-regulating IL-10.
Muscovy duck reovirus Reducing organ damage, improving antioxidant capacity, serum protein
Ducklings (MDRV) infected duckling 0.2 g/L drinking water level, antibody level and complement level, reducing cell apoptosis, thereby [70]
model alleviating immunosuppression.
Promoting splenic lymphocyte proliferation, increasing serum hemolysin level,
Intestinal mucosal immune
Babl/c mouse 75, 150, 300 mg/kg macrophage phagocytosis and NK cell activity, promoting SigA secretion, [71]
system
MAPK and AKT cell signaling pathway.
Cyclophosphamide-induced Enhancing immune organ index, spleen cell proliferation, NK cell activity, IL-2
Balb/c mouse 75, 150, 300 mg/kg [72]
immunosuppression in mice production and improving phagocytosis of macrophage, and showing protective effect.
16s rRNA sequencing showed that the relative abundance of Lachnospiraceae
and Akkermansiaceae increased significantly, while that of Rikenellaceae and
Adult, middle-aged and old
Mouse 1 000 mg /kg Bacteroidaceae decreased. The fermentation products of intestinal and fecal [73]
mice
microorganisms regulated immune function through NF-кB, MAPK and PI3K/
Akt signaling pathways.
NA: information was not available.
108 Jianhui Liu et al. / Journal of Future Foods 2-2 (2022) 103–111

108 J.H. Liu et al. / Journal of Future Foods 2 (2022) 103-111

cells, B cells, macrophage and other immune cells, and regulating
the immune system [55,56]. A large number of in vitro and in vivo
experiments have confirmed that HEP has immunomodulatory activity,
and its mechanism and effects are shown in Table 5. Macrophage
is a crucial member of the mononuclear phagocyte system that
plays an important role in the immune response process [57].
It has been proven that HEP possessed macrophage activation
activity, mainly via myeloid differentiation protein 88 (MyD88)/
IL-1R-associated kinase (IRAK)/TNF receptor associated factor 6
(TRAF-6)/ Nuclear factor kappa B (NF-κB), MyD88/IRAK/TRAF-
6/Jun N-terminal kinases (JNK)/Jun/activator protein-1(AP-1) or
MyD88/ROS/phosphoinositide-3-kinase (PI3K)/protein kinase
B (Akt)/mitogen-activated protein kinases (MAPKs)/NF-κB
signaling pathways (Fig. 4) [58-61]. Besides, in vivo studies
have confirmed that HEP activated splenic lymphocytes and
macrophages, regulated immune function through NF-κB, MAPK
and PI3K/Akt signaling pathways, and improved the immune
function of lymphocytes.
The molecular modification of polysaccharides is an important
means to improve its biological activity. As an effective chemical
modification method of polysaccharides, selenization has attracted
much attention due to its simple operation and benefits in improving
physiological properties. Besides, nanoparticles can encapsulate drugs
to avoid degradation or being pumped out of cells by P glycoprotein,
and distribute throughout the body through biological barriers to
enhance immune response [62]. Therefore, Ren et al. prepared Se-
HEP (selenium-HEP) and HEP-PLGA (HEP-lactic acid-glycolic
acid) nanoparticles and found that both of them enhanced the immune
response [63]. On this basis, Luo et al. [64] prepared two kinds of
nanoparticles by different combinations, namely PLGA nanoparticles
loaded with Se-HEP (Se-HEP-PLGA) and Se-modified HEP-PLGA
nanoparticles (HEP-PLGA-Se), to study the effect on macrophages
in vitro. It was found that two types of nanoparticles significantly
stimulated the phagocytic activity of cells and the expression of
CD40 and CD86, increased levels of NO, TNF-α, IL-1β and IL-6, and
induced a strong immune response [64].

HEP 2.6 Neuroprotective effects of HEP

P
HE
CD14 MR
HE HEP has a variety of pharmacological activities in the treatment
TLR2 P
MyD88 or intervention of neurodegenerative diseases such as Alzheimer’s
ROS PI3K Akt
disease, and its related protective mechanism is shown in Fig. 5 and
IRAK Table 6. To the best of our knowledge, the HEP could be served
p38 ERK
TRAF-6 MAPK as free radical scavenger, Ca2+ antagonist, nerve barrier restorer,
NF-κB
glutamate release inhibitor, as well as learning and memory function
JNK
driver in exerting neuroprotective properties. In vitro experiments
confirmed that HEP effectively delay the apoptosis of PC12 cells and
AP-1
Jun NF-κB alleviated the neurotoxicity induced by amyloid (Aβ) [74]. In vivo
Nucleus experiments have confirmed that HEP accelerated the recovery of
sensory function after peroneal nerve crush injury in Sprague-Dawley
rats [75], and displayed a neuroprotective effect on Alzheimer’s
TNF-α IL-6 iNOS NO
disease mice and optic nerve crush Wistar rats through enhancing the
Fig. 4 Signal transduction pathways involved in the immune-regulation of
concentration of acetylcholine (Ach) and choline acetyltransferase
HEP in macrophage activation. (ChAT) [76].

Table 6
Neuroprotection effects and mechanism of action of HEP.
Subject Methods Dosage Mechanism and effects Reference
Rat pheochromocytoma PC12 cells In vitro 0.8, 1.0 mg/L
Effectively delayed the apoptosis of PC12 cells. [74]
Prevent Aβ-induced cell contraction and nuclear degradation of
Rat pheochromocytoma PC12 cells Amyloid (Aβ)-induced neurotoxicity 250 μg/mL [77]
PC12 cells, alleviating neurotoxicity.
Inhibiting the accumulation of reactive oxygen species in cells,
blocking Ca2+ overload and preventing mitochondrial membrane
potential (MMP) depolarization.
L-glutamate-induced apoptosis model
Enhancing the horizontal and vertical movement in the autonomic
Rat pheochromocytoma of differentiated PC12 cells; 50, 100 μg/mL;
nerve activity test of Alzheimer’s disease mice, improving the
PC12 cells; A mouse model of Alzheimer’s 0.3, 1.0, [76]
endurance in the rotating rod test, and reducing the escape latency
Mouse disease induced by the combination of 3.0 g/kg
in the water maze test, improving the function of the central
AlCl3 and D-galactose
cholinergic system, enhancing the concentration of acetylcholine
(Ach) and choline acetyltransferase (ChAT) in serum and
hypothalamus, with neuroprotective effect.
Showing neuroprotective effects through antiapoptosis on retinal
50, 100,
Male Wistar rat Rat optic nerve crush test ganglion cells and anti-inflammatory effects by reducing the [78]
200 mg/kg
infiltration of exogenous macrophages into the optic nerve.
Accelerating the recovery of sensory function after peripheral
Sprague-Dawley rat Crush injury of peroneal nerve in rats 30 mg/(mL·kg) nerve injury, related to activating protein kinase signaling pathway [75]
and restoring blood nerve barrier.
NA: information was not available.
 Jianhui Liu et al. / Journal of Future Foods 2-2 (2022) 103–111 109
J.H. Liu et al. / Journal of Future Foods 2 (2022) 103-111
Oxidative damage
PC12
O2· ROS
Free radical
scavenger
In vivo Rentinal ganglion
Glutamate
Ca2+ release
antagonist inhibitor
Ca2+ overload
Learning &
Never barrier Neuroprotective memory
restorer polysaccharides function driver
from H. erinaceus
Recover sensory
funtion after peripheral
nerve injury
Fig. 5 Neuroprotective mechanisms of HEP in previous studies.
2.7 Liver-protecting activities of HEP
The hepatic protecting properties of HEP have been proven.
Kim et al. [79] confirmed the protective effect of HEP on liver injury
caused by Salmonella typhimurium. Cui et al. [80] established
a CCl4-induced liver injury model in mice, and found that the
intracellular and extracellular polysaccharides from H. erinaceus
mycelium reduced the levels of aspartate aminotransferase (AST) and
alanine aminotransferase (GPT) in the blood of mice, returned serum
TC, TG albumin to normal levels, increased the activity of catalase
and SOD in liver tissue, and decreased lipid peroxide and MDA
content. Besides, HEP and doxorubicin may act synergistically as an
effective tool for the treatment of drug-resistant human hepatocellular
carcinoma [40]. Therefore, HEP has the potential to help prevent and
alleviate liver damage, which can be widely used in functional foods
and nutritional products.
3. Conclusion
H. erinaceus is a kind of food and medicinal homogenous fungus.
The polysaccharide in H. erinaceus has a variety of pharmacological
activities, such as anti-oxidation, anti-inflammatory, gastrointestinal
protection, anti-tumor, hypolipidemic and hypoglycemic effects,
enhancing immune, and protecting the liver. Therefore, HEP has
great medicinal potential and broad development prospects. At this
stage, the extraction process, biological activity, and mechanism of
action of HEP have achieved a lot. However, due to the structural
complexity and the uncertainty of the molecular weight of the HEP,
the identification of the higher-level structure of the HEP has certain
limitations. In consequence, studies on the relationship between its
structural characteristics and biological activity are few. Besides, the
research and reports of HEP were mainly focused on antioxidant activity,
gastrointestinal protection and immune activity, leading to the lack of in-
depth research on other pharmacological properties of HEP.
It is recommended that future research start from the following
aspects: 1) Optimize the extraction method on the basis of traditional
methods to increase the extraction rate and the yield of HEP;
2) Clarify the high-level molecular structure of HEP, introduce
chemistry modification and other polysaccharide modification
methods to enhance the biological activity of polysaccharides, and
illustrate the relations between the specific structure and bioactivity;
3) Deeply investigate the new pharmacological activities of HEP to
determine its mechanism of action; 4) Develop various functional
109
foods and health products on HEP to serve the specific population and
precision nutrition industry.
Aβ-induced cell contraction
Cells apoptosis
Conflict of interest
Cells apoptosis
We declare that we have no known competing financial interests
or personal relationships that could have appeared to influence the
Ach ChAT work reported in this paper.
Acknowledgments
This work was financially supported by Natural Science
Foundation of the Higher Education Institutions of Jiangsu Province
(20KJB550016), Entrepreneurship and Innovation Program in
Jiangsu Province-Doctoral Program, A Project Funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions (PAPD).
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