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Submitted 15 July 2021, Accepted 22 September 2021, Published 30 September 2021
Corresponding Author: Sunil K. Deshmukh – e-mail – sunil.deshmukh1958@gmail.com 10
Hericium erinaceus - A Rich Source of Diverse Bioactive Metabolites
Deshmukh SK1*, Sridhar KR2,3, and Gupta MK4
1TERI-Deakin Nano Biotechnology Centre, The Energy and Resources Institute, Darbari Seth Block, IHC
Complex, Lodhi Road, New Delhi, India
2Department of Biosciences, Mangalore University, Mangalagangotri, Mangalore, Karnataka, India
3Centre for Environmental Studies, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
4SGT College of Pharmacy, SGT University, Gurugram, Haryana, India
Deshmukh SK, Sridhar KR, and Gupta MK 2021 – Hericium erinaceus - A Rich Source of Diverse
Bioactive Metabolites. Fungal Biotec 1(2), 10–38, Doi 10.5943/FunBiotec/1/2/2
ABSTRACT
Hericium erinaceus (commonly known as lion’s mane mushroom) is an edible mushroom
used in traditional Chinese medicine. It is a prolific producer of diverse bioactive metabolites with
neuroprotective and neuroregenerative properties (e.g. β-glucan polysaccharides, hericenones,
erinacine terpenoids, isoindolinones, sterols, and myconutrients). Because of its anti-inflammatory
properties and promotion of nerve growth factor (NGF) gene expression and neurite (axon or
dendrite) outgrowth, H. erinaceus is used for the treatment of Alzheimer's as well as Parkinson's
diseases. This review provides a comprehensive account of the bioactive compounds from H.
erinaceus (both from the fruit bodies and mycelia) and their biological activities such as
neuroprotective functions, cytotoxicity, anticarcinogenic, antidiabetic, antimicrobial, and herbicidal
activities.
Keywords – Alzheimer’s disease – anticancer agents – antidiabetic – anti-inflammatory –
antimicrobial – erinacine terpenoids – herbicidal – hericenone – neurite outgrowth –
neuroprotection – Parkinson’s disease
Introduction
In recent years, research on H. erinaceus has been focused on its antidepressant-like effects
to treat depressive disorders (Yao et al. 2015, Chiu et al. 2018, Ryu et al. 2018). This review
focuses on bioactive compounds of different strains of H. erinaceus. Primary emphasis is laid on
the pharmacological activities of various metabolites of H. erinaceus along with bioactive
compounds and their biological properties.
Hericium erinaceus (Bull.) Pers., is a macro fungus belonging to the family Hericiaceae
(Russulales, Agaricomycetes, Basidiomycota). Hericium erinaceus is an edible mushroom
possesses several medicinal properties. It has many common names: bear's head mushroom,
bearded hedgehog mushroom, bearded tooth fungus/mushroom, hog head fungus, Hou Tou Gu
(Chinese), lion's mane mushroom, monkey head mushroom, old man's beard mushroom, Pom Pom
Mushroom, Satyr's beard fungus, white beard mushroom and Yamabushitake (Japanese). It is
reported from China, Japan, Europe, and North America; found on dead oak, walnut, beech, maple,
sycamore, and other broadleaf trees. It is most frequently found on logs or stumps and has a long
Fungal Biotec 1(2):10–38 (2021) ISSN TBAXXX
www.fungalbiotec.org Article
Doi 10.5943/FunBiotec/1/2/2
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history of usage in traditional Chinese medicine (Venturella et al. 2021). Bioactive constituents of
H. erinaceus include alkaloids, fatty acids, terpenoids, phenolics, steroids, pyranones, and about 80
small compounds are isolated from H. erinaceus (Zhang 2016). Purified bioactive metabolites of
the fruit body or mycelia of H. erinaceus possess a wide range of biological activities viz.
anticancer (Wang et al. 2001, Zhang et al. 2020), antidiabetic (Yi et al. 2015), antihyperglycemic
(Liang et al. 2013), anti-inflammatory (Mori et al. 2015), antimicrobial (Zhang et al. 2015a),
antioxidant (Rahman et al. 2014), and hypolipidemic properties (Yang et al. 2003). In addition, H.
erinaceus has been investigated as a potential treatment option in cognitive impairments (Mori et
al. 2009), Alzheimer's disease (Tsai-Teng et al. 2016), Parkinson's disease (Kuo et al. 2016),
ischemic stroke (Lee et al. 2014), and presbycusis (Chan et al. 2019). In recent years, research has
been focused on its antidepressant-like effects for treating depressive disorders (Yao et al. 2015,
Chiu et al. 2018, Ryu et al. 2018). This review focuses on bioactive compounds of different strains
of H. erinaceus. This review highlights the pharmacological activities of metabolites derived from
H. erinaceus and their biological properties.
Stimulation of nerve growth factor
The nerve growth factor (NGF), a polypeptide, is a member of the neurotrophin family. NGF
is involved in the progress as well as maintenance of neurons in the peripheral nervous system and
is essential for the functions of cholinergic neurons in the central nervous system (CNS). An
optimum supply of NGF from the cortex and the hippocampus is required for proper function and
morphology of basal forebrain cholinergic neurons (BFCNs). Age-dependent degeneration BFCNs
contributes significantly to cognitive decline in AD. The agents that increase the level of NGF
showed improvement in cognitive functions and AD (Salehi et al. 2004, Aloe et al. 2012). Several
metabolites from H. erinaceus have shown significant CNS activity, such as improvement in
cognitive function and increase in NGF activity, thus investigated for the treatment of dementia and
Alzheimer’s disease (AD).
Hericenones
Hericenones (benzyl alcohol derivatives) are aromatic compounds obtained from the fruit
bodies of H. erinaceus. The fresh fruit bodies of the mushroom were extracted with acetone
followed by recurrent chromatography of chloroform-soluble fractions (chloroform, then ethyl
acetate) crude extract subject to HPLC (High-performance liquid chromatography) filled with ODS
column to yield hericenones. Hericenones A (1) and B (2) were isolated during 1990 without their
neurite outgrowth activity (Kawagishi et al. 1990). Novel compounds, hericenones C (3), D (4) and
E (5) were purified from H. erinaceus (Kawagishi et al. 1991). Compounds (3–5) displayed
stimulating activity towards the synthesis of NGF in vitro. In their presence (3–5) (33 µg/mL),
astroglial cells of mouse secreted 10.8, 23.5, and 13.9 pg/mL of NGF into the medium,
respectively. The extent of activity for (4) was comparable to the epinephrine, a potent stimulator.
Box 1 Impact of Hericium erinaceus in human health and wellbeing
▪ Improves brain health
▪ Fight anxiety and depression
▪ Supports the immune response
▪ Anti-inflammatory
▪ Supports the health and good circulation
▪ Supports fat burning and healthy metabolism
▪ Stabilizes blood sugar levels
▪ Improves digestive health
▪ Anticancer properties
▪ Improves energy levels
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However, the activity of (3) and (5) are lower than (4). Interestingly, the variation in the activity of
these compounds is rely on the length of chain and the double bond of the fatty acid (Kawagishi et
al. 1991).
Hericenone E (5) (Fig. 1) was isolated from the fruit bodies of H. erinaceus. It has the
capability to stimulate in vitro secretion of NGF in rat pheochromocytoma cells with two-fold
higher than the positive control. Neuritogenesis was partially blocked by the receptor of tyrosine
kinase (Trk) inhibitor (K252a) indicating the neuritogenic activity was not exclusively by the NGF.
Hericenone E is known to increase the phosphorylation of extracellular-signal-regulated kinases
(ERKs) as well as protein kinase B (Akt). Hericenone E (5) potentiated the NGF-induced
neuritogenesis in PC12 cells via the MEK/ERK and PI3K/Akt pathways (Phan et al. 2014). Novel
chroman, hericenone F (6), G (7), and H (8) were also purified from H. erinuceum. In the presence
of hericenones H (8) at 33 μg/mL, mouse astroglial cells secreted 45.1 pg/mL NGF into the culture
medium (Kawagishi et al. 1993, Ma et al. 2010).
Three new compounds, hericenone I (9) and hericenone J (10) 3-hydroxyhericenone F (11),
(Fig. 1) were purified from the mushroom H. erinaceus. Compounds (11) displayed significant
dose-dependent protective action against tunicamycin- and thapsigargin-toxicity at concentrations
up to 10 µg/mL in the assay against endoplasmic reticulum (ER) stress-dependent apoptosis. The
ER stress was elicited by incorporation of thapsigargin or tunicamycin into the culture medium of
Neuro-2a cells. Thapsigargin is an inhibitor of ER Ca2+-ATPase that causes depletion of Ca2+ in
the ER, while tunicamycin is one of the inhibitors of N-glycosylation to glycoproteins and it is
responsible for protein-misfolding in the ER. The results indicate that (11) could protect the
neuronal cells by attenuating the ER stress by inducing apoptotic pathways on neural cells (Ueda et
al. 2008) and may be helpful in the management of Alzheimer’s disease.
Diling et al. (2017) purified 3-hydroxyhericenone F (11) (Fig. 1), which downregulates the β-
site of β-amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) and decreases the serum
cytokines (IFN-γ, IL-1β, IL-17α) level, tumor necrosis factor (TNF-α) and production of reactive
oxygen species (ROS). Hence, it confirms that the mushrooms enriched either hericenones
ameliorate amyloid beta (Aβ) pathology as well as oxidative stress in Alzheimer's disease.
Dilinoleoyl-phosphatidylethanolamine (DLPE) (12) is a phosphatidylethanolamine bearing two
linoleic acids, and was purified from H. erinuceum. The DLPE can protect neuronal cells from ER
stress-induced cell death, and the PKC pathway is involved in the protective mechanism (Nagai et
al. 2006).
Another new compound isohericerinol A (13) (Fig. 1) along with previously reported
compounds such as hericerin (14), N-de-phenylethyl isohericerin (15) and corallocin A (16) were
extracted from the fruit bodies of H. erinaceus. The compound isohericerinol A (13) increased the
production of nerve growth factor (NGF) strongly in C6 glioma cells compared to isohericerinol A
(13) and corallocin A (16). Increase in NGF production by these compounds promote the neurite
outgrowth in N2a neuronal cells. According to Ryu et al. (2021), the Western blot analysis
confirmed increased expression of protein by NGF, synaptophysin (SYP) and brain-derived
neurotrophic factor (BDNF) in C6-N2a cells.
Erinacines
Novel diterpenoids, erinacines A (17), B (18), and C (19) (Fig. 2) were isolated from the
cultured mycelia of H. erinaceus. In the bioassay of mouse astroglia cells with erinacines A-C (17–
19) (1.0 mM), the quantity of NGF secretion into the medium was 250.1, 129.7, and 299.1 pg/mL,
respectively. These activities were much more potent (69.2 pg/mL at 1.0 mM) than known potent
stimulator epinephrine (positive control) (Kawagishi et al. 1994). The biologically active
compound erinacine A (17) has the capacity to decrease the ischemic injury in brain. Studied
carried out in vitro showed that erinacine A can decelerate the cerebral ischemic brain injuries via
inactivation of pathways: iNOS/RNS and p38 MAPK/CHOP. Erinacine A is also mediating the
antioxidative and anti-inflammatory functions during an intermittent ischemic brain injury. Thus,
compounds derived from Hericium (e.g. erinacine A) are capable to enhance the synthesis of NGF
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as well as induce neuroprotection, whereas its polysaccharides are capable to scavenge the ROS
(Lee et al. 2014).
Fig. 1 – Hericenones isolated from Hericium erinaceus.
The effects of erinacine A-enriched H. erinaceus mycelia (HE-My) on the pathological
changes in APPswe/PS1dE9 transgenic mouse model of Alzheimer’s disease were studied. After 30
days of oral administration (300 mg/kg/day) to 5-months-old female transgenic mice
(APPswe/PS1dE9), it was established that HE-My and its ethanol extracts (HE-Et) has the capacity
to attenuate the burden of cerebral Aβ plaque (Tsai-Teng et al. 2016). It is interesting to note that
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the portion of attenuated plaque is a non-compact structure. The HE-My as well as HE-Et have
increased the level of insulin-degrading enzyme in the cerebral cortex, while in the cerebral cortex
and hippocampus, the number of astrocytes and plaque-activated microglia decreased.
Administration of HE-My and HE-Et promoted hippocampal neurogenesis and increased the ratio
of NHF-NGF precursor (pro-NGF). According to Tsai-Teng et al. (2016), such administration in
APPswe/PS1dE9 transgenic mice improved the activity of daily living skills.
A novel diterpenoid, erinacine D (20) (Fig. 2), along with the previously known compounds
(erinacines A, B, and C) were isolated from the mycelia of H. erinaceus. The compound erinacine
D (20) showed stimulating activity to NGF-synthesis by rat astroglial cells; the amount of NGF
secreted into the culture medium in the presence of 4 (1.67 mM) was 141.5 pg/mL. This activity
was stronger (69.2 pg/mL at 1.0 mM) than a positive control epinephrine (Kawagishi et al. 1996a).
Compounds erinacines E (21), F (22), and G (23) were purified from the mycelia of H. erinaceus.
The compounds (21 and 22) showed powerful stimulating activity against the NGF synthesis by
astroglial cells. In the bioassay using rat astroglial cells, the amounts of NGF secreted into the
medium in the presence of (21) and (22) at 5.0 mM were 105 and 175 pg/mL, respectively. These
activities were stronger (70.2 pg/mL at 1.0 mM) than the known potent stimulator epinephrine used
as a positive control (Kawagishi et al. 1996b).
Two erinacine derivatives (24, 25) (Fig. 2) purified from the mycelia of H. erinaceus were
reported to induce the biosynthesis of NGF, which is useful to treat dementia (Shimada et al. 1996).
Similarly, the other two erinacine diterpenoids (26, 27) from the mycelia of H. erinaceus were also
reported to induce the production of NGF (Kawagishi et al. 1995). Bioactive cyatha-3, 12-diene
(28) along with its isomer (29) was purified from the mycelia of H. erinaceus serves as an
intermediate of cyathane diterpenoids (Kenmoku et al. 2001). Biotransformation capability of
erinacine E (21) was evaluated using 81 microbes. Among the tested microbes, Caladariomyces
fumago (ATCC 16373) was capable to transform erinacine E (21) into a new analog CP-412,065
(30) and the conversion rate was 29% (Saito et al. 1998).
Two new diterpenoids, erinacines H (31), and I (32) (Fig. 2), were purified from the mycelia
of H. erinaceus. The compound erinacines H (31), showed stimulating activity to synthesize NGF
using astroglial cells. The amounts of NGF (31.5 pg/mL) secreted into the medium in the presence
of 33.3 µg/mL of (31), was five times greater than those in the absence of the compound (Lee et al.
2000). According to Mori et al. (2008), the ethanol extract of H. erinaceus stimulated NGF mRNA
as well as protein levels in human astrocytoma cells (1321-N1) and stimulated neurite outgrowth in
pheochromocytoma cells (PC12) by promoting c-Jun N-terminal kinase activity. The aqueous
extract of H. erinaceus contained neuroactive compounds, which induced NGF-synthesis and
promoted neurite outgrowth in NG108-15 cells. The extract also enhanced the neurite outgrowth
stimulation activity of NGF when applied in combination. The aqueous preparation of H. erinaceus
showed neurotrophic but not neuroprotective activity (Lai et al. 2013).
A known compound 3,4-dihydro-5-methoxy-2-methyl-2-(4'-methyl-2'-oxo-3'-pentenyl)-
9(7H)-oxo-2H-furo[3,4-h]benzopyran (33) (Fig. 2), was extracted from the fruit bodies of H.
erinaceus. This compound (33) displayed activity of high neurite outgrowth-promoting in NGF-
induced cells (PC12) (Zhang et al. 2015b). Compounds such as 4-chloro-3,5-dimethoxybenzoic
methyl ester (34) (Fig. 2), and erinacine A (17) were purified from the methhanolic extract of H.
erinaceus mycelia. The compounds (17 and 34) efficient in protection of neuronally-differentiated
pheochromocytoma cells (PC12) against deprival of NGF. The compound (17) capable to mimic
the neuritogenic activity of NTs in the neurons of primary rat cortex. Similarly, the compounds (17
and 34) were also capable to potentiate the NGF-induced outgrowth of neurite devoid of the
stimulation of NGF synthesis in PC12 cells. The cellular signaling pathways disclosed that NGF-
induced neurite outgrowth is stimulated by compounds (17 and 34) fully by TrkA, while partially
Erk1/2 (Zhang et al. 2017).
Previously unknown erinacine Z1 (35) (Fig. 3), along with known compounds erinacine A
(17), erinacine B (18), erinacine C (19) were retrieved from the mycelium of H. erinaceus, while a
known compound CJ14.258 (36) was retrieved from mycelium of Hericium flagellum (Rupcic et al.
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2018). None of the tested compounds showed intrinsic neurothrophic activity, stimulating neurite
outgrowth directly from cultured PC12 cells; compounds (17–19, 35, 36) enhanced the
neurotrophin production in astrocytic cells. Promoting the effect of cyathane diterpenoid
derivatives on BDNF expression was also observed. Since erinacines can stimulate the transcription
of both investigated neurothrophins, it suggests an upstream target, which is common to upstream
events of NGF as well as BDNF induction (Rupcic et al. 2018).
Fig. 2 – Erinacines isolated from Hericium erinaceus.
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Three new cyathane diterpenes erinacines T-V (37–39) (Fig. 3), and two previously reported
cyathane diterpenes erinacine P (40) were extracted from the liquid cultures of H. erinaceus. The
compounds (37–40) showed significant neurotrophic effects in the range of 2.5-10 μM as compared
with a control group. The percentage of neurite-bearing cells for cells treated with compounds (37–
40) at 10 μM reached 43.7, 76.31, 65.3, and 48.3%, respectively. The NGF is used as a positive
control with neurite-bearing cells of 40.3% at the concentration of 40 ng/mL (Zhang et al. 2018).
The peripheral nerve injury (PNI) is one of the significant health concerns. The NGF is
known to play pivotal role in the growth, survival and maintenance of different neurons in the
nervous system. The study of neuroprotective effects (NPE) of H. erinaceus and NGF against the
mouse PNI model revealed that H. erinaceus shows a higher NPE than the NGF. The bioactive
comounds of H. erinaceus avoid the death of neurons by regeneration of their axons leading to
neuroprotection and neuro-regeneration help treating PNI. Further evaluation of bioactive
compounds of H. erinaceus as a prospective source to cure PNI are necessary (Üstün & Ayhan
2019). Trovato et al. (2016) showed evidence of the neuroprotective potential of H. erinaceus on
oral administration to the rats. In the brain of those rats treated with fungus, induction of LXA4 was
maximum in cortex and hippocampus, striatum and cerebellum.
A recent clinical trial has been performed to assess the capability of H. erinaceus various
neurological disorder (e.g. anxiety, binge eating, depression and sleep disorders) (Vigna et al.
2019). A total of 77 subjects affected by obesity with one or more mood disorders was evaluated to
receive three capsules of an H. erinaceus as dietary supplement daily up to two months with a low-
calorie diet regime. The administered fungal extract was with 80% mycelia and 20% fruit body.
Prior to treatment, after the one and two months, the above-referred ailments were assessed
(Symptom Checklist-90, Zung’s Self-Rating Depression Scale, Zung’s Self-Assessment Anxiety
Scale, and Binge Eating Scale or BES). All the studies revealed significant improvements disorders
(depression, anxiety, and sleep quality) in the H. erinaceus treated group. Further, concerning the
serum balance in brain-derived neurotrophic factor (BDNF) and its precursor pro-BDNF, increased
circulating pro-BDNF levels was evident. Still, clarifications are needed to understand whether
these neurotrophins could be used as biomarkers in mood disorders (Vigna et al. 2019).
Effects on dementia and Alzheimer's disease
Dementia is a CNS disorder characterized by severely decline in mental ability which affect
normal daily life of patients. Alzheimer’s disease (AD) is the most common cause of dementia. AD
is the fifth-leading cause of death among adults aged 65 years and older and is also a leading cause
of disability and morbidity (Alzheimer’s Association, 2019). Some of the bioactive isolated from
Hericium were found active against Alzheimer’s disease and are illustrated below.
A new sesterterpene, erinacine S (41) (Fig. 3), and, erinacine A (17) (Fig. 2), were purified
from the ethanol extract obtained from the mycelia of H. erinaceus. A 30-day oral trial of
erinacines A (17) and S (41) has attenuated the Aβ plaque burden in the brains of 5-month-old
female transgenic mice APP/PS1. In addition, erinacines A and S increased significantly the level
of insulin-degrading enzymes in the cerebral cortex (Chen et al. 2016). Compounds (17 and 41)
reduced the cortical and hippocampal amyloid plaque growth, promoted hippocampal neurogenesis
putatively by inhibition of glial cells and increased insulin-degrading enzyme (IDE) expression in
the APP/PS1 mice. However, only compound (17) was capable to decrease Aβ production as well
as the initiation of plaque formation. In addition, erinacine A recovers the behavioral deficits in the
APP/PS1 mice. These suggest that the compound (17) may possesses therapeutic potential to treat
Alzheimer's disease (Tzeng et al. 2018). Pharmacokinetics of compound (41), on oral dosing at
2.395 g/kg BW (H. erinaceus mycelial extract equivalent to 50 mg/kg body weight) of compound
(41) in the male Sprague-Dawley rats was 15.13%. The leading site of compound (41) absorption
was stomach, while the primary route of elimination of the compound (41) is the fecal excretion.
This was the first study to demonstrate that compound (41) could enter the blood-brain barrier of
rats as well as support the development of H. erinaceus mycelia to treat the neurological disorders
(Hu et al. 2019).
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A new cyathane-xyloside derivative named erinacine R (42) (Fig. 3), was isolated from the
mycelia of H. erinaceus (Ma et al. 2008). Occurrence of extract of H. erinaceus in culture media
supported the development of cerebellar neural cells (in vitro) by stimulating regulatory processes
of myelinogenesis (Kolotushkina et al. 2003), which may be helpful in degenerative neuronal
disorders such as Alzheimer's disease and peripheral nerve regeneration.
The H. erinaceus being a medicinal mushroom, which improves the recognition memory in
mice. Using the HPLC-UV-ESI/MS analyses, the quantities of erinacine A (17) and hericenones C
(3) and D (4) in the extracts of H. erinaceus were standardized to test against the animal model
towards physiological aging. Oral administration up to two-months with H. erinaceus, the age
decline of recognition memory reversed. The doublecortin (DCX) immunohistochemistry and
proliferation of cell nuclear antigen (PCNA) in the hippocampus and cerebellum in experimental
mice resulted in a positive effect of H. erinaceus of neurogenesis (Ratto et al. 2019).
Li et al. (2020) conducted a clinical trial to study the safety and efficacy of mycelia of the H.
erinaceus enriched with 5 mg/g erinacine A++. The patients with mild Alzheimer’s disease
consumed three capsules daily (lyophilized mycelia of 350 mg/capsule containing 5 mg/g erinacine
A). This study involved a 3-weeks-no-drug screening period, followed by a 49-weeks double-blind
treatment with two parallel groups where the patients were randomized either three mycelial
capsules per day or identically appearing placebo capsules. The score showed intellectual health
performance such as Cognitive Abilities Screening Instrument (CASI), Mini-Mental State
Examination (MMSE), and Instrumental Activities of Daily Living (IADL) of the patients
significantly increased by consumption of the capsules then the placebo group. This trial was
performed based on various in vivo and in vitro studies that erinacine A (17) has positive impacts
on the dementia (Li et al. 2020).
The beneficial effects of H. erinaceus have been confirmed in numerous clinical trials. For
example, Mori et al. (2009) carried out a placebo-control, parallel-group and double-blind clinical
trial on 30 patients with middle cognitive impairment by providing four 250 mg tablets consist of
96% mushroom powder or placebo thrice a day up to 16 weeks, continued the trial up to four weeks
and assessed using a cognitive function scale by Revised Hasegawa Dementia Scale (HDS-R). On
comparison to the placebo group (weeks 8, 12, and 16) treatment and four weeks of follow-up, the
yamabushitake group revealed significantly increased scores. However, in the fourth week, at the
end of ingestion the values significantly decreased. However, H. erinaceus has proved to be
valuable in the improvement of average cognitive impairment.
Hericium erinaceus stopped the impairments of visual recognition and spatial short-term
memory because of induction by Aβ25-35 peptide administered in mice intracerebroventricularly
(Mori et al. 2011). Owing to the effect of H. erinaceus on the brain function as well as autonomic
nervous, Nagano et al. (2010) studied the impacts on menopause, depression, sleep quality, and
undefined disorders (randomized, double-blind, placebo-controlled trials). Assessments were
carried out based on the Kupperman Menopausal Index (KMI), the Pittsburgh Sleep Quality Index
(PSQI), the Center for Epidemiologic Studies Depression Scale (CES-D), and the Indefinite
Complaints Index (ICI). A group of 30 females was randomly allotted to consume either cookies
four H. erinaceus (0.5 g powder carpophore/cookie) or four placebo cookies once a day up to one
month. In the treated group, after the HE intake, the CES-D and ICI scores significantly lowered
than before, on comparison with the placebo group, the "insensitive" and "palpitation" terms of the
ICI were substantially lower, and the terms "concentration", "irritating", and "anxious" tended to be
lower. This study showed that H. erinaceus is capable to alleviate the anxiety and depression
(Nagano et al. 2010).
Supplementation with erinacine A-enriched H. erinaceus mycelia extended the lifespan in
both Drosophila melanogaster and SAMP8 mice by a maximum of 32% and 23%, respectively,
compared to the untreated controls. Moreover, erinacine A-enriched H. erinaceus mycelia
decreased TBARS levels and induced the antioxidative enzyme activities of superoxide dismutase,
catalase, and glutathione peroxidase (Li et al. 2019).
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Anticancer/antitumor activities
Cancer is the second most significant cause of human mortality across the globe, which was
the reason for almost 10 million cancer deaths during 2020 (Sung et al. 2021). Extended protocols
of treatment and the severe side effects of the current anticancer drugs demand an urgent need to
explore safe and effective drugs. Mushrooms are important source of novel metabolites with unique
structural and functional traits with potent cytotoxicity. Recently, various structurally of bioactive
metabolites have been identified from Hericium and assessed for their anticancer potential.
Bioactive metabolites of Hericiumm also serve as lead molecules for the pharmacological industry
to develop new drugs. Here we summarize the anticancer impacts of natural products derived from
H. erinaceus.
The extract obtained from H. erinaceus displayed various biological activities including
anticancer one (Li et al. 2014a). Erinacine A-enriched H. erinaceus mycelia was found to be active
against the ischemic stroke, as it reduces the neuronal apoptosis plus the size of the stroke cavity in
brain by aiming iNOS/reactive nitrogen species (RNS) and p38 mitogen-activated protein kinase
(MAPK)/CCAAT enhancer-binding protein homologous protein (CHOP) pathways (Li et al. 2018).
Novel cytotoxic phenols are known as hericenone A (1) and B (2) (Fig. 1) were obtained
from the mushroom H. erinaceus. The minimum concentrations lead to complete inhibition of
growth of HeLa cells for hericenone A (1) was 100 µg/mL, for hericenone B (2) was 6.3 µg/mL,
the potent cytotoxicity of (2) may be due to -1actam and its N-substituent (Kawagishi et al. 1990).
Novel γ-pyrones, erinapyrones A (43), and B (44) (Fig. 3) have been isolated from the culture-broth
of H. erinaceus mycelia. The compound (43) and (44) exhibited cytotoxicity against HeLa cells
minimum concentration giving complete death of the cells for (43) was 0.88 and for (44) was 1.76
mM (Kawagishi et al. 1992).
Aromatic compound hericenone L (45) (Fig. 3), isolated from the fruit bodies of H. rinaceum
and displayed cytotoxic activity against the EC109 cell line with an IC50 of 46 µg/mL (Ma et al.
2012). A new isoindolinone alkaloid named isohericenone (46), together with compounds, namely
isohericerin (47), erinacerin A (48), 3,4-dihydro-5-methoxy-2-methyl-2-(4’-methyl-2’-oxo-3’-
pentenyl)-9(7H)-oxo-2H-furo[3,4-h]benzopyran (33), were extracted from the semi dried fruit
bodies of H. erinaceus. The compound (46) displayed the potent cytotoxic activity with IC50 values
of 2.6, 3.1, 1.9, and 2.9 µM against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines,
respectively. The compound (47) showed cytotoxic activity against A549, SK-OV-3, SK-MEL-2,
and HCT-15 cell lines (IC50 values of 21, 8.9, 3.1, and 19 µM, respectively). The compound (33)
was found to be active against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines (IC50 values of
17, 11, 13, and 16 µM, respectively). The compound (48) showed toxicity against A549, SK-OV-3,
SK-MEL-2, and HCT-15 cell lines (IC50 values of 11, 11, 7.7, and 14 µM, respectively).
Doxorubicin a positive control displayed cytotoxicity against A549, SK-OV-3, SK-MEL-2, and
HCT-15 cell lines (IC50 values of 0.001, 0.003, 0.002, and 0.081 µM, respectively) (Kim et al.
2012).
A new diterpene (49) (Fig. 3), was isolated from the fungal mycelia of H. erinaceus and
displayed good cytotoxicity against K562, LANCAP, HEP2 cancer cell lines with I IC50 values of
124.5, 362.3 and 198.6 µM, respectively. Positive control fluorouracil displayed cytotoxicity
against K562, LANCAP, HEP2 cell lines with IC50 values of 76.9, 61.5, and 38.5 µM, respectively
(Zhang et al. 2015a). Compounds (E)-5-(3,7-dimethylocta-2,6-dien-1-yl)-4-hydroxy-6-methoxy-2-
phenethylisoindolin-1-one (50), was purified from the solid culture of H. erinaceus. The compound
(50) also showed poor cytotoxic activity against A549 and HeLa, cells (IC50 values of 49.0 and
40.5 μM, respectively) (Wang et al. 2015a).
New alkaloids, erinacerin M (51), erinacerin N (52) (Fig. 3), erinacerin O (53), erinacerin P
(54) (Fig. 4), were extracted from the solid cultures of H. erinaceus. The compounds (51–54)
showed moderate cytotoxicity against wild K562 cells with the IC50 values of 16.3, 18.2, 15.9, and
11.4 µM, respectively (adriamycin as positive control, IC50 = 0.6 µM) (Wang et al. 2015b). Later
erinacerin O (53) and erinacerin P (54), were also isolated from H. erinaceus. The compound
erinacerin P (54) displayed good cytotoxic activity against human glioma cell line U87 with an IC50
19
value of 19.32 μg/mL. It was observed that the apoptosis of U87 cells treated with (54) increased,
and the morphology of U87 cells altered significantly. Erinacerin P (54) increases the rate of
apoptosis rate of U87 cells through Bax/capase-3 pathway and reduces DNA replication. (Zhang et
al. 2020).
Fig. 3 – Cytotoxic compounds isolated from Hericium erinaceus.
Two new aromatic compounds, hericerin A (55) and isohericenone J (56), along with five
known compounds, isoericerin (57), hericerin (58), N-De phenylethyl isohericerin (59), hericenone
J (10), and 4-[3’,7’-dimethyl-2’,6’-octadienyl]-2-formyl-3-hydroxy-5-methyoxybenzylalcohol (60),
20
were obtained from a methanol extract of the fruiting bodies of H. erinaceus. The compounds (10,
55–60) displayed cytotoxicity against HL-60 cell lines with IC50 of 4.13, 3.06, 59.74, 5.47, 62.24,
4.10, and 4.28 µM, respectively (positive control Mitoxantrone IC50 0.075 µM). The compound (10,
55, 56, 60) displayed cytotoxicity against HEL-299 cell lines with IC50 of 5.07, 64.61, 5.79, and
8.46 µM, respectively. The compounds (55) and (58) also induced apoptosis of HL-60 cells along
with time-dependent downregulation of c-myc and p-AKT levels (Li et al. 2015a). Two purified
compounds, 1-(5-chloro-2-hydroxyphenyl)-3-methyl-1-butanone (61) and 2,5-
bis(methoxycarbonyl)terephthalic acid (62), were obtained from the ethanoic extract of fruit bodies
of H. erinaceus and displayed weak cytotoxicity against K562 with IC50 <200mM (Liu et al. 2016).
Five new isoindolinones named erinaceolactams A-E (63–67) (Fig. 4), together with five
known compounds hericenone A (1), hericenone J (10), erinacerin A (48), hericerin (58), and N-De
phenylethyl isohericerin (59) were purified from the fruit bodies of H. erinaceus extracted in 70%
ethanol. These compounds (1, 10, 59, 48, 58, 63–67) exhibited significant cytotoxicity against
SMMC-7221 comparable to or more potent than 5-FU. Some compounds (1, 10, 48, 63, 65–67)
serve as growth inhibitors of SMMC-7221 in a dose-dependent manner. In MHCC-97H,
compounds (1, 59, 67), inhibited the cell growth dose-dependently. Among these compounds (1,
10, 59, 48, 58, 63–67), compound (1) (20 μg/mL) showed the most potent activity against the
growth of SMMC-7221 and MHCC-97H (Wang et al. 2016).
A new cyathane-type diterpenoids, hericinoid B (68) and known analogues erinacine Z2 (69)
(Fig. 4), erinacine Z1 (35), were isolated from fermentation broth of H. erinaceus. The compounds
(68, 35, and 69) displayed potent cytotoxicity against HL-60 cell lines with the IC50 values of 18.3,
8.9, and 0.5 μM, respectively. The compounds (35) and (69) showed moderate cytotoxicity against
MCF-7 cell lines with the IC50 values from 13.4 to 15.8 μM. Cisplatin as positive control showed
cytotoxic activity towards HL-60 MCF-7 cells (with IC50 value of 2.8 and 27.7 μM, respectively),
while paclitaxel as another positive control showed cytotoxic activity towards HL-60 MCF-7 cells
(IC50 of <0.008 μM each) (Chen et al. 2018).
A known cyathane diterpene erinacine A (17) was isolated from the liquid cultures of H.
erinaceus and displayed weak cytotoxicity against PC12 cells (IC50 of 73.7 μM) (Zhang et al.
2018). Known compounds ergosteryl stearate (70), ergosterol peroxide (71) (Fig. 5), and
hericenone I (9) were isolated from the fruiting bodies of the medicinal mushroom H. erinaceus.
The compound (9) displayed potent cytotoxic activity against SH-SY5Y, 1321N1, HCT-116, Caco-
2, OVK18, and HeLa cell lines with IC50 values of 36.69, 41.66, 7.66, 49.53, 0.99, and 25.94 µM,
respectively. The compound (71) displayed potent cytotoxic activity against SH-SY5Y, 1321N1,
HCT-116, Caco-2, OVK18, and HeLa cell lines with IC50 values of 10 8.84, 21.68, 52.73, 6.35,
8.07, and 33.04 µM, respectively. The compound (70) displayed selective cytotoxic activity against
SH-SY5Y, HCT-116, and OVK18 cell lines (IC50 values of 35.52, 2.77, and 8.1 µM, respectively)
(Ashour et al. 2019).
The peptide Lys-Ser-Pro-Leu-Tyr (KSPLY) was derived from H. erinaceus, its synthetic
peptide showed potential immunomodulatory activity at 100 μmol/l and also promoted NO, IL-1β,
IL-6 and TNF-α secretion of by the macrophages. The KSPLY also inhibited secretion of nitric
oxide (NO) as well as IL-6 by the M1 macrophages with a tendency of transformation of
macrophages M2 macrophages into M1. This peptide is an effective immunomodulation seems to
be beneficial to combat human cancer (Yu et al. 2021).
A study by Tung et al. (2021) indicated that erinacine S (41) specifically induces cell
apoptosis and increased ROS production in gastric cancer cells only. The normal cells are not
affected. Erinacine S (41) also suppressed tumor growth in a xenograft mouse model. Furthermore,
erinacine S (41) treatment significantly increases the FasL and tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL) protein. In contrast, it also decreased the levels of PCNA as
well as cyclin D1 in the gastric cancer xenograft in mice. In human gastric epithelial cell line
(AGS) the erinacine S (41) triggers the apoptosis pathways (TRAIL, Fas-L and caspase-8, -9, -3) as
well as suppresses the expression of the antiapoptotic molecules like Bcl-2 and Bcl-XL. Besides,
erinacine S (41) causes arrest of cell cycle phase G1 via inactivation of CDKs/cyclins. The data
21
also revealed that activation of AKT/FAK/PAK1 and ROS-derived pathways involved in the
erinacine S-mediated transcriptional activation of Fas-L and TRAIL by H3K4 trimethylation on
their promoters (Tung et al. 2021).
Fig. 4 – Cytotoxic compounds isolated from Hericium erinaceus (cont.).
The microwave-assisted extraction in 50% ethanol, hot water extract (HWE), acidic as well
as alkaline extracts of the fruit body of H. erinaceus showed the apoptotic ability against the U937
human monocytic leukemia cells. Assays like cell viability, cytotoxicity, chromosomal DNA
22
integrity, and expression of pro- and anti-apoptotic proteins, mitochondrial membrane potential and
activation and inhibition of caspase assays were performed to define the mechanism of apoptosis.
The aqueous as well as aqueous/ethanolic extracts were active these assays, whereas the acidic and
alkaline extracts were inactive. The results of the bioassays showed activation of mitochondria-
mediated the caspase-3 and caspase-9 but not the caspase-8 (Kim et al. 2011). Erinacine A (17) also
exhibited significant antitumor activity against TSGH 9201 cancer cell lines. It induced apoptosis
in association with increased phosphorylation of focal adhesion kinase/protein kinase
FAK/Akt/p70S6K as well as serine/threonine kinase PAK-1 pathways. It also involved in increase
of cytotoxicity, increase of ROS generation, reduction of invasiveness, activation of caspases, and
expression of tumor necrosis receptor (TRAIL) (Kuo et al. 2017).
Erinacine A is one of the major bioactive diterpenoids extracted from cultured mycelia of H.
erinaceus, which displays pronounced antitumorigenic activities. An in vitro study on two human
colon cancer cell lines: DLD-1 and HCT-116 showed that erinacine A stimulates the extrinsic
apoptosis activation pathways (TNFR, Fas, FasL and caspases) and decreases the levels of
antiapoptotic molecules Bcl-2 and Bcl-XL, suppresses of phosphorylation of Jun N-terminal kinase
JNK1/2 and responsive to stress stimuli (NF-κB p50 and p330). The in vivo assay showed that
Erinacine A increases the levels of histone H3K9K14ac, histone acetylation on Fas and FasL
including TNFR promoters (Lee et al. 2019).
Anticancer effect of extracts (HTJ5 and HTJ5A) obtained from the broth of H. erinaceus was
evaluated against many cancers by in vitro cancer cell lines and in vivo tumor xenografts (e.g.
gastrointestinal cancers: liver, colorectal and gastric). The H. erinaceus extracts HTJ5 and HTJ5A
displayed cytotoxic activity against the liver (HepG2 and Huh-7), colon (HT-29), and gastric (NCI-
87) cancer cells. In in vivo tumor xenograft studies, the HTJ5 and HTJ5A exhibited significant
antitumor activity against the four xenograft models (HepG2, Huh-7, HT-29, and NCI-87) without
the host toxicity. In addition, the HTJ5 and HTJ5A showed higher effect compared to the 5-FU
against the above-mentioned tumors with less toxicity. A total of 22 compounds were fetchd from
the fractions of HTJ5/HTJ5A with seven cyclic dipeptides, six small aromatic compounds, five
indole, three flavones, one anthraquinone, pyrimidines and amino acids derivatives. These
compounds include seven cyclic dipeptides: cyclo(Val-Tyr), cyclo(Leu-Tyr), cyclo(Phe-Tyr),
cyclo(Phe-Phe), cyclo(Leu-Leu), cyclo(Leu-Ala), and cyclo(Val-Ala); five indole, pyrimidines,
amino acids and derivative: 5-hydroxy-2-pyridinecarboxylic acid, 3-formylindole, uracil, 2,3,4,9-
tetrahydro-1Hpyrido[3,4-b]indole-3-carboxylic acid, and tryptophan; three flavones (flavonoid
glycoside): neoliquirtin, liquiritigenin, and calycosin; one anthraquinone: emodin; and six small
aromatic compounds: 4-hydroxy-3-methoxybenzoic acid, 4-hydroxy-3-methoxycinnamic acid,
hydroxy-benzaldehyde, 4-hydroxybenzoic acid, 3,4-dihydroxybenzaldehyde and syringic acid (Li
et al. 2014a).
Anticarcinogenic effects
An anticarcinogen is a carcinopreventive agent that counteracts the effects of a carcinogen on
normal cells and inhibits the development of cancer. Extract from H. erinaceus or bioactive from
H. erinaceus possess anticarcinogenic effects, and some of them are illustrated below.
The mutagenicity and genotoxicity effects of erinacine A-enriched H. erinaceus (EAHE)
mycelium were evaluated by in three standard tests (chromosomal aberration, micronuclei tests and
reverse mutation). The results showed that the EAHE mycelium has not increased the number of
revertant colonies in bacterial reverse mutation and not induced higher frequency of aberrations. In
addition, there was no significant EAHE mycelium-induced increase was seen in the incidence of
reticulocytes per 1000 RBC as well as micronucleus per 1000 reticulocytes. All these three
standard tests suggested lack of mutagenicity and genotoxicity of EAHE mycelium at test doses
under standard experimental conditions (Li et al. 2014b). Glycosphingolipid
(monoglycosylceramides cerebroside E) (72), is a new cerebroside isolated from the fruit bodies of
H. erinaceus (Fig. 5). This has alleviated cisplatin-induced nephrotoxicity (in LLC-PK1 cells) as
well as inhibited the angiogenesis in HUVECs (Lee et al. 2015).
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The H. erinaceus has been showed a protective effect on cell death of ischemia-injury-induced
neurons in rats. It has been demonstrated that pretreatment with H. erinaceus attenuated the DEHP-
induced cell death significantly. Such protective effect may be owing to its ability to reduce the
intracellular levels of ROC species, which preserves the activity of respiratory complexes to
stabilize the potential of mitochondrial membrane. In addition, H. erinaceus pre-treatment has
modulated Nrf2 and Nrf2-dependent vitagenes expression significantly, thus prevents rise of pro-
apoptotic and the fall of antiapoptotic markers. Overall, the present study provided evidence
towards new preventive nutritional strategy by H. erinaceus over DEHP-induced apoptosis (PC12
cells) (Amara et al. 2020).
Fig. 5 – Cytotoxic compounds isolated from Hericium erinaceus (cont.).
The H. erinaceus mycelium-enriched erinacine A (5 mg/g) toxicity by a 28-day oral
administration using Sprague-Dawley rats at three doses (low, 1 g; medium, 2 g; high 3 g/kg body
24
weight/day) were selected with distilled water as control showed survival of all the animals till end
of the study. No abnormality in clinical signs were observed without adverse differences were
found in haematology, serum biochemical parameters and urinalysis among the control and treated
groups. Similarly, pathologically and histopathological manner, no gross changes were evident.
Thus, the EAHE at 3g/kg body weight/day has no adverse effects on test Sprague-Dawley rats (Li
et al. 2014c).
Antidiabetic Activity (Alpha-glucosidase inhibitors)
Diabetes mellitus (DM) is one of the rapidly growing lifestyle disorders of 21st century,
affecting the health of significant population worldwide. According to recent statistical studies, it is
estimated that about 415 million people across the world are presently suffering from diabetes
(Ogurtsova et al. 2017). Some of the compounds isolated from H. erinaceus possess antidiabetic
properties and are illustrated below.
New alkaloids, erinacerins Q (73), R (74), S (75), and T (76), were purified from the cultures
of H. erinaceus (Fig. 5). These compounds (73–76) showed inhibitory activities against PTP1B
with IC50 values of 29.1, 42.1, 28.5, and 24.9 µM, respectively (positive control, sodium vanadate
IC50 = 1.2 µM). The compounds (73–76) showed inhibitory activities against a-glucosidase
inhibition with IC50 values of 12.7, 23.3, 19.5, and 20.1 µM, respectively (positive control,
acarbose IC50 = 273.1 µM) (Wang et al. 2015b).
New compounds isoindolin-1-ones designated as erinacerins D-L (77–85) along with (E)-5-
(3,7-dimethylocta-2,6-dien-1-yl)-4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one ( 50) were
obtained from the cultures of H. erinaceus. These compounds (50, 77–85) showed inhibitory effect
at IC50 ranging from 5.3–145.1 μM in α-glucosidase inhibition assay (Fig. 6). The structure-activity
relationship indicated that the presence of terpenoid side chain and phenolic hydroxy groups are
conducive for the α-glucosidase inhibitory activity of 50 and 77–85) (Wang et al. 2015a).
Four new compounds, erinacenol D (86), together with known compounds 4-[3',7'-dimethyl-
2',6'-octadienyl]-2-formyl-3-hydroxy-5-methyoxybenzylalcohol (87), hericene A (88), hericene D
(89), and known compound hericenone D (4) retrieved from the fruit bodies of H. erinaceus. These
compounds (86–89 and 4) displayed potent α-glucosidase inhibitory activity with IC50 19.6, 7.5,
6.7, 3.9, and 15.5 μM, respectively ( positive control acarbose, IC50, 71.2 μM) . The molecular
docking showed the interaction of α-glucosidase as well as isolated compounds supporting the
inhibitory activity against α-glucosidase (Lee et al. 2020).
Meroterpenoids hericenes B (90) and hericenones C(3), E(5), F(6), G(7) were purified from
the fruit body of H. erinaceus. The most potent inhibitory activities on PNPG (4-Nitrophenyl beta-
D-galactopyranoside) showed by the compound (7) and sucrose (IC50 of 15.2 and 12.6 µM,
respectively). The compound (3) possesses the strongest inhibitory activities on maltose (IC50 of
15.3 µM), while the positive control acarbose showed IC50 of 38.1, 20.5, and 17.1 µM against
PNPG, sucrose, and maltose, respectively. The compound (90) led the most potent inhibitory
activities on PNPG sucrose maltose (IC50 of 29.6, 29.1, and 65.5 µM, respectively). The compound
(3) showed the most potent inhibitory activities agaonst PNPG, sucrose and maltose with the IC50
of 21.9, 13.5, and 15.3 µM, respectively. The compound (5) possesses the strongest inhibitory
activities against PNPG, sucrose and maltose with the IC50 of 23.3, 42.5, 25.5, µM, respectively.
The compound (6) was the most potent inhibitory potential against PNPG sucrose maltose with the
IC50 of 45.3, 67.1, >100 µM, respectively. The compound (7) also showed the most potent
inhibitory potential against PNPG, sucrose and maltose with the IC50 of 15.2, 12.6 and 33.1 µM,
respectively. The positive control acarbose showed the most robust inhibition against PNPG,
sucrose, and maltose with IC50 of 45.3, 67.1, >100, 38.1, 20.5, and 17.1 µM, respectively (Chen et
al. 2020).
Antioxidant potential
Antioxidants are the substances that protects the cell organelles by reacting with highly
reactive free radicals which are produced during metabolism. Among various natural alternative
25
sources, mushrooms are identified as a major source of potent antioxidant compounds (Mishra et al.
2020). Bioactive metabolites from Hericium with antioxidant properties are illustrated below.
Lew et al. (2020) investigated the antioxidant activities of a standardized aqueous extract of
H. erinaceus in an in vitro model of FRDA (Friedreich Ataxia) involving L-Buthionine sulfoximine
(L-BSO)-induced human dermal fibroblast expressing abnormal expansion of GAA triplet repeat.
L-buthionine sulfoximine is an inhibitor of γ-glutamylcysteine synthetase, which plays a role in
GSH biogenesis (Lew et al. 2020).
Fig. 6 – Anti-diabetic compounds isolated from Hericium erinaceus.
26
Previously reported diketopiperazine alkaloids, 12b-hydroxyverruculogen TR-2 (91),
fumitremorgin C (92), and hetero-spirocyclic -lactam alkaloids, pseurotin A (93), and cerevisterol
(94) were purified from the mycelium of the H. erinaceus. These compounds (91–94) displayed
scavenging activity in DPPH assay with IC50 values of 12.56, 50.00, 12.56, and 11.38 µM,
respectively (positive control TBHQ IC50, 5.75 µM, while the ascorbic acid showed IC50, 1.95
µM) (Fig. 6). The results indicate that compounds (91, 93, and 94) exhibited better antioxidant
activity against in DPPH assay with IC50 of ca. 12 µM, compared with the tertiary
butylhydroquinone as a positive control (Lu et al. 2014).
Anti-inflammatory activity
Inflammation is one of the protective processes that can become disrupted under pathological
conditions. It can lead to many ailments such as multiple sclerosis, rheumatoid arthritis, psoriasis
and inflammatory bowel diseases. It also plays a crucial role in many complex disorders like
cancer, cardiovascular disease and AD. Many therapies could be followed to treat inflammation-
driven ailments such as antihistamines, steroids and non-steroidal anti-inflammatory drugs. In spite
of some success, still there is a gap to treat the inflammatory diseases. Various structurally diverse
bioactive metabolites are reported from Hericium with the capability to serve as a lead molecule to
develop as an anti-inflammatory drug in the future. Here we summarize the anti-inflammatory
property of bio-actives from H. erinaceus.
Erinacine C (19) is well known for antineuro-inflammatory and neuroprotective functions,
which could be accomplished by mechanisms such as inducible nitric oxide synthase (iNOS)
protein expression, activation of Nrf2/HO-1 stress-protective pathway and inhibition of IκB, p-
IκBα (involve in the upstream NF-κB signal transduction cascade) (Wang et al. 2019a). Treating
human BV2 microglial cells with lipopolysaccharide (LPS)-induced inflammation caused reduction
in levels of many constituents such as: IL-6, TNF-α, nitric oxide (NO) and iNOS; expression of the
heme oxygenase-1 (HO-1) protein; increased nuclear transcription factor erythroid 2-related factor
(Nrf2); inhibition of phosphorylation of IκBα (p-IκBα) proteins; inhibition of NF-κB expression;
inhibition of Kelch-like ECH-associated protein 1 (Keap1). Considering these data, the mechanism
of action of EC includes: expression of iNOS, activation of the Nrf2/HO-1 pathway and inhibition
of IκB, p-IκBα (Wang et al. 2019a).
Four new sterols namely erinarol G (95), erinarol H (96) (Fig. 6), erinarol I (97), erinarol J
(98), along with known sterols namely (3b,5a,22E)-ergosta-6,8(14),22-triene-3,5-diol (99),
fomentarol A (100), (3b,7a,22E)-ergosta-8(14),22-diene-3,7-diol (101), 7-ketobrassicasterol (102),
(3b,22E) ergosta-5,8(14),22-triene-7-one (103), 5a,6a-epoxy-3b-hydroxy-ergosta-22-ene-7-one
(104), 5a,6a-epoxy-(22E,24R)-ergosta-8(14),22-diene-3b,7b-diol (105), 5a,6a-epoxy-(22E,24R)-
ergosta-7,22-diene-3b-ol (106), 5a,6a;8a,9a-diepoxy-(22E,24R)-ergosta-22-ene-3b-7a-diol (107),
and 5a,6a;8a,9a-diepoxy-(22E,24R)-ergosta-22-ene-3b-7b-diol (108) were isolated from a methanol
extract of the dried fruiting bodies of H. erinaceus (Fig. 7). Anti-inflammatory functions of these
compounds were evaluated towards NO production in LPS-stimulated murine RAW264.7
macrophage cells and inhibition of TNF-α. The compounds (96, 98–100) exhibited inhibitory
activity against TNF-α secretion, with inhibition values of 37.5%, 43.3%, 36.7%, and 33.7%,
respectively, at 10 μM (positive control Celecoxib, 52.5% at 1 μM). The compounds (95, 97, 101,
and 103) exhibited moderate inhibitory activity of TNF-α secretion with inhibition ranging from
24.6–26.3% at the same concentration. Compounds (98, 102–104), exhibited significant inhibitory
effects against NO production, with inhibition values of 38.4%, 50.5%, 71.5%, and 51.6%,
respectively, while at 10 μM (positive control Celecoxib, 55.9% at 1 μM), compounds (99) and
(106–109) exhibited moderate inhibitory activities. Only compound (98), which possesses a 6,8-
dioxabicyclo[3.2.1]oct-2-ene moiety, showed strong inhibition in both the nitric oxide and TNF-a
secretion assay (Li et al. 2015b).
Oral H. erinaceus treatment showed promising efficacy in the experimental colitis model.
Biochemical indexes and microscopic and macroscopic colitis scores were analyzed. The TNF-α,
MPO, NO, MDA, and IL6 cytokines, which affect TBNS-induced colitis models, were examined,
27
and TNF-α, MPO, NO, MDA, and IL6 levels were lower in the H. erinaceus treatment group than
in the colitis groups. The less mucosal injury was detected in the H. erinaceus treatment group
than in the colitis group. The results indicate that the improvement of inflammatory bowel
disease (IBD) is due to the anti-inflammatory properties of H. erinaceus. The main disadvantage
of oral therapy with HE is the unknown dose required for the anti-inflammation effect (Durmus et
al. 2021).
Fig. 7 – Antimicrobial compounds isolated from Hericium erinaceus.
Hot water (HE-HWA) and ethanolic (HE-ETH) extracts of H. erinaceus were investigated for
anti-inflammatory and neuroprotective activities: neurotoxicity of hydrogen peroxide (H2O2)-
induced in HT22 mouse hippocampal neurons and lipopolysaccharide (LPS)-induced BV2
microglial activation. The HE-ETH revealed a potent neuroprotective action through significant
28
increase in the viability of H2O2-treated neurons. In addition, significant reduction in ROS and
improvement in the antioxidant enzyme catalase (CAT) and glutathione (GSH). The HE-ETH
showed the capacity to significantly improve the mitochondrial membrane potential (MMP) as well
as ATP production, whereas reduction in mitochondrial toxicity, nuclear apoptosis and Bcl-2-
associated X (Bax) gene expression. However, some of the functions are not affected: heme
oxygenase 1 (HO-1), gene expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and
NAD(P)H quinone dehydrogenase 1 (NQO1). The HE-ETH also showed significant reduction in
nitric oxide (NO) level in LPS-treated BV2, showed an anti-inflammatory activity in the microglia.
Thus, the HE-ETH has the potential towards neuroprotective and anti-inflammatory functions in
the neuroglia environment (Kushairi et al. 2019)
Platelet aggregation inhibitor
Platelet aggregation inhibitors prevent platelet adhesion and subsequently clot formation by
interfering different steps on clotting cascade. Platelet aggregation inhibitors are indicated in
myocardial infarction, atrial fibrillation, following coronary bypass, angioplasty, and stenting. They
are also used prophylactically to prevent myocardial infarction and stroke. The reported compounds
isolated from H. erinaceus with platelet aggregation inhibitor activity are illustrated below.
Hericenone B (2) was isolated from the ethanolic extract of H. erinaceus. Hericenone B (2)
selectively inhibited collagen-induced platelet aggregation however, did not affect the aggregation
induced by U46619 (TXA₂ analogue), ADP, thrombin, or adrenaline. Furthermore, hericenone B
(2) did not inhibit arachidonic acid- or convulxin (GPVI agonist)-induced platelet aggregation.
Therefore, it was suggested that the hericenone B blocks collagen signaling from integrin α2/β1 to
release arachidonic acid (Mori et al. 2010).
Antimicrobial activity
In the last two decades there is steady rise in the discovery of multidrug resistant bacteria
(Penicillin resistant Streptococcus pneumonia, vancomycin-resistant Enterococcus faecium and
methicillin-resistant Staphylococcus aureus) (Nannini et al. 2010). Due to acquired resistance, it is
cumbersome to diagnose and treat many diseases caused by multidrug resistant bacteria (Dheda et
al. 2018). Owing to a few alternatives against the fungal diseases, there is necessity to develop
compatible antifungal drugs to facilitate therapies like cancer, bone marrow/organ transplants
(Lockhart & Guarner. 2019). The natural products obtained from Hericium are important sources to
tune novel metabolites to facilitate the modern medicine. Following sections deal with some
developments of using Hericium-derived antimicrobials.
One new diterpene (49) and new compound 3-acetyl-4-methoylbenzoic acid (109), along
with four known compounds 1-(5-chloro-2-hydroxyphenyl)-3-methyl-1-butanone (110) 4-chloro-
3,5-dimethoxybenzyl alcohol (111) (Fig. 7) isolated from the mycelium of H. erinaceus. The
compound (110) showed potent antibacterial activity with MIC values 32.5–65 µg/mL, while
compound (49) and (109) showed moderate antibacterial activity against the growth of
Helicobacter pylori (ATCC43504) (MIC values 50-100 mg/mL), and compound (111) showed
poor antibacterial activity with MIC values 62.5–125 µg/mL (Zhang et al. 2015a).
Two compounds, 1-(5-chloro-2-hydroxyphenyl)-3-methyl-1-butanone (112) and 2,5-
bis(methoxycarbonyl)terephthalic acid (113) isolated from the ethanoic extract of fruit bodies of H.
erinaceus (Fig. 8). The fruiting bodies of H. erinaceus were obtained at Fengxian District,
Shanghai, China. The compound (112) displayed anti-Helicobacter pylori activity against H. pylori
ATCC 43504, H. pylori SS1, H. pylori 9, H. pylori 64, H. pylori 78, H. pylori 83, H. pylori W2504,
and H. pylori DXF with MIC values in the range of 12.5–50 µg/mL. In contrast, the compound
(113) was found active against the same set of H. pylori strains with minimum inhibitory
concentration (MIC) values in the range of 6.25–25 µg/mL. Positive control metronidazole
displayed anti-Helicobacter pylori activity (range, 0.78–1.5625 µg/mL), while the other positive
control tetracycline displays anti-Helicobacter pylori activity in the range of 0.78–3.125 µg/mL
29
against the same set of test strains. Both compounds showed weak cytotoxicity against K562 with
IC50 <200 mM (Liu et al. 2016).
Fig. 8 – Antimicrobial compounds isolated from Hericium erinaceus.
Known compounds CJ-14,258 (114) and erinacine C (19) isolated from cultured mycelia of
H. erinaceus. The compounds (114) and (19) displayed antimicrobial activity against Methicillin-
30
resistant Staphylococcus aureus (MRSA) with MIC of 62.5 µM each (Kawagishi et al. 2006).
A hetero-spirocyclic -lactam alkaloid called FD-838 (115) was isolated from the mycelia of the H.
erinaceus. Compound (115) inhibited the growth of two phytopathogens (Botrytis cinerea and
Glomerella cingulate), with MIC of 6.25 µM for each, similar to that of the positive fungicide
carbendazim (Lu et al. 2014).
In a growth inhibition assay on six strains H. pylori, the ethanolic extracts of H. erinaceus
showed growth inhibition of all strains with a MIC value of 2 mg/mL. Extract of H. erinaceus
inhibited adhesion capacity of (AGS) H. pylori (ATCC CRL-1739). Extract of H. erinaceus
inhibited adhesion capacity of (AGS) H. pylori (ATCC CRL-1739). Interleukin-8 (IL-8, an immune
response factor) in supernatants from AGS and 8-oxo-guanine (8-oxoG, marker for oxidative DNA
damage of the total host cell DNA) exposed to H. erinaceus extract were monitored prior to
addition of H. pylori. The result was H. pylori-mediated immune response (IL-8 production)
significantly decreased by the H. erinaceus extract, while at concentration 1.0 mg/mL, the IL-8
expression reversed to almost the background level (when no H. pylori added). Infection of AGS
by H. pylori resulted in a 3-fold increase of host’s 8-oxoG, however such increase was turndown by
addition of 2 mg/mL H. erinaceus extract. Assays were carried out on colonization of C57BL mice
on homogenized stomachs three weeks later inoculating H. pylori. The mice receiving the H.
erinaceus extract had a mean H. pylorus at 6 × 104 CFU/g in the stomach, which was one log lower
than the control (without extract) (Wang et al. 2019b).
The ethyl-acetate extract obtained from culture filtrate and mycelium of H. erinaceus
displayed potent anti-H. pylori activities with MIC (MBC) of 1.25–1.5 (5–7.5) mg/mL and
potential urease inhibitory activity with IC50 of 0.34-0.35 mg/mL. The culture filtrate extract also
displayed good antioxidant activity (IC50, 11.83 mg/mL), which was marginally better than that of
mycelium extract (IC50, 14.75 mg/mL). It was also found that the water fractions from the culture
filtrate and the mycelium exhibited noticeable inhibitory activities against bacterial urease (IC50,
1.26–1.40 mg/mL). However, they had poor or no anti-H. pylori activities with poor antioxidant
activities (Ngan et al. 2021).
Using OSMAC (One Strain, Many Active Compounds approach a new erinacerin alkaloid
erinacerin V (116), and a new aldehyde derivative of 4-hydroxy chroman, (S)-4-hydroxy-2,2-
dimethylchromane-6-carbaldehyde (117), along with four known compounds 4-chloro-3,5-
dimethoxybenzaldehyde (118), 2-chloro-1,3-dimethoxy-5-methyl benzene (119), (4-chloro-3,5-
dimethoxyphenyl)methanol (120), 3,6-bis(hydroxyl methyl)-2-methyl-4H-pyran-4-one (121), 4-
chloro-3,5-dimethoxybenzoic acid (122), 5-hydroxy-6-(1-hydroxyethyl)isobenzofuran-1(3H)-one
(123), and erinacine E (21) were isolated from a mycelial culture of Hericium sp. (Fig. 8).
Compound (119), exhibited antifungal activity against Candida such as C. albicans and C.
neoformans (MIC, 31.3–62.5 μg/mL, respectively) and also inhibited biofilm formation of C.
albicans and C. neoformans at 7.8 μg/mL (Song et al. 2020).
The related Basidiomycota Agaricus blazei Murill (AbM), H. erinaceus (HE), and Grifola
frondosa (GF) have been shown to exert antimicrobial activity against viral agents, Gram-positive
and Gram-negative bacteria, and parasites in vitro and in vivo. Since these basidiomycetes also
have anti-inflammatory potential, they may be suitable to treat lung inflammation that often caused
by COVID-19 infection.
Herbicidal activity
Herbicides are agents that are destructive to weeds or cause an alteration in their normal
growth. The global herbicide market size is expected to reach overall market revenue of $7,998.9
million by 2025 by growing at a CAGR of 4.8% during the said period. There are some reports of
herbicidal properties of bioactive metabolites. Three new compounds such as erinachromanes A
and B (124, 125) and erinaphenol A (126) with ten previously reported compounds [4-
(hydroxymethyl)-2-(3-methylbut-2-en-1-yl)phenol (127), eulatachromene (2,2-dimethyl-6-
hydroxymethylchromene) (128) (Fig. 8), 6-hydroxymethyl-2,2-dimethyl-chromanone, (129), 4-
chloro-3,5-dimethoxybenzaldehyde (130), methyl 4-chloro-3,5-dimethoxybenzoate (131) and
31
(2S,3R,4S,5R)-2,4,5-trihydroxy-3-methoxyhexanoic acid (132), 5-(hydroxymethyl)furan 2-
carboxylate (133), and 4-hydroxyphenyl acetate (134), compound (135), compound (136) were
purified from the culture broth of H. erinaceus (Fig. 9). All of these compounds significantly halted
the growth of lettuce. Some of the compounds such as (134) and (135) inhibited the growth of
hypocotyl at low doses (1 and 10 nmol/paper) and exhibited poor activity at higher doses (100 nmol
and 1 μmol/paper). Among the chromans (124, 125, 128, 129), (128) showed the potent inhibitory
activity against hypocotyl (at 1 μmol/paper). Comparison of structures among (125) and (128)
showed that the hydroxymethyl group at C-6 plays vital role in such activity. The compound (129)
significantly ceased the growth of root (at 1 μmol/paper). It suggests that the chromanone skeleton
(129) has mail role in root growth inhibition. The compound (126) also showed similar activity like
the compound (127), indicates the side chain at C-1′ did not influence the growth regulation of
plant. Among the dimethoxychlorobenzenes (130, 131, and 136), (136) exhibited the strongest
inhibition of root growth (at 1 μmol/paper). This suggests that the hydroxymethyl group is
responsible for strengthening the inhibitory activity (Wu et al. 2019).
Two unique compounds, erinaceolactones A to B (137, 138), and previously reported
compounds 2-(hydroxymethyl)-6- methyl-4H-pyran-4-one (139), erinapyrones A (140) and B (141)
and compound (142) were retrieved from the cultures of H. erinaceus (Fig. 9). Compounds such as
(139 and 142) weakly inhibited the lettuce root growth (1 μmol/paper), while the compounds like
(138, 140, and 141) showed inhibition at lower dose (100 nmol/paper). The lettuce hypocotyl
growth was inhibited by the compounds (140 and 141) 1 μmol/paper and 100 nmol/paper,
respectively. The compound (139) inhibited the growth of root as well as hypocotyl at lower doses
(1 and 10 nmol/paper, respectively), but no activity showed at the higher doses (100 nmol and 1
μmol/paper, respectively) (Wu et al. 2015).
Fig. 9 – Herbicidal compounds isolated from Hericium erinaceus
Conclusion
Hericium erinaceus is an edible mushroom with a long history of use in traditional Chinese
medicine. It has the capacity to prevent or alleviate or cure major diseases such as cancers,
diabetes, lipidemia and depression including the neurodegenerative diseases. Many bioactive
metabolites from H. erinaceus have been isolated as well as characterized by advanced techniques.
Important metabolites characterized include hericenones, erinacine terpenoids, isoindolinones, and
sterols. They possess diverse pharmacological properties such as antibiotic, anticarcinogenic,
antidiabetic, hepatoprotective, nephroprotective and neuroprotective properties such as
improvement of anxiety, cognitive function, and depression. Some of the compounds isolated from
H. erinaceus possess herbicidal activity. Erinacines have potential neuroprotective properties,
hericerins possess potent cytotoxic activity; sterols have anti-inflammatory and antiproliferative
32
properties, while erinaceolactones inhibit hypocotyl as well as root growth of lettuce at very low
concentrations. Although a large number of compounds were obtained from Hericium with
moderate to potent biological activities, rational derivatization and high-throughput screening are
warranted. Such attempts help to follow NGF, anticancer and anti-inflammatory activities, and the
molecules with superior activity profiles could be employed for various pharmaceutical
applications. It is warranted to understand their individual as well as synergistic actions, with
specific attention towards in vivo dynamics as well as in vivo and clinical experiments.
There is a great demand to use different strategies to isolate the new compounds because
conventionally used methods results in production of known compounds. Highly diverse
secondary-metabolite production could be achieved by simple approach as one strain many
compounds (OSMAC). Such approach needs varied media composition (metal ion concentration
salinity and C/N ratio) and fermentation conditions (solid/liquid, static/dynamic, pH, temperature
and oxygen level). The other methods can be co-cultivation/mixed fermentation and addition of
enzyme inhibitors including precursor/s. The approach of co-cultivation of fungi mimics the
ecological conditions, where the two or more interacting partners involve in fermentation process,
which leads to production of new metabolites (Moussa et al. 2020, Sari et al. 2020). Similarly,
another approach could be followed include incorporate of different biosynthetic precursors in to
the fermentation media, which alters the biosynthetic pathways of secondary metabolites (Ramm et
al. 2017). With the implementation of approaches like genetic engineering, metabolic engineering,
and fermentation technology help producing value added compounds from fungi. The diverse
metabolites of H. erinaceus with potential biological activities provide ample opportunities to
develop versatile compounds. Such novel compounds could be assessed for pharmacological
potential to treat dreadful diseases like Alzheimer's and cancer. In addition, a combination of
existing drugs with H. erinaceus metabolites may also provide new insights towards efficient
solutions to combat the lifestyle diseases.
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