Trends in Food Science & Technology 41 (2015) 49e59
Review
An insight into
anti-inflammatory
effects of fungal
beta-glucans
Bin Dua,b,c, Chengyuan Lina,
Zhaoxiang Biana,* and
Baojun Xuc,*
a
School of Chinese Medicine, Hong Kong Baptist
University, Hong Kong, China (e-mails: bindufood@
aliyun.com; lincy.hkbu@gmail.com; bianzxiang@
gmail.com)
b
Analysis and Testing Center, Hebei Normal University
of Science and Technology, Qinhuangdao, Hebei,
066600, China (e-mail: bindufood@aliyun.com)
c
Food Science and Technology Program, Beijing
Normal University e Hong Kong Baptist University
United International College, Zhuhai, Guangdong,
519085, China (e-mail: baojunxu@uic.edu.hk)
b-Glucans from fungi exhibit a broad spectrum of biological
activities including anti-tumor, immune-modulating and anti-
inflammatory properties. The anti-inflammatory effect is medi-
ated through the regulation of various inflammatory cytokines,
such as nitric oxide (NO), interleukins (ILs), tumor necrosis
factor alpha (TNF)-a, interferon gamma (INF)-g as well as
non-cytokine mediator, prostaglandin E2 (PGE2). Up to now,
the anti-inflammatory activity of b-glucans has received little
attention. It is worthwhile to investigate the anti-
inflammatory properties of fungal b-glucans in a separate re-
view, discussing in vitro studies, animal studies and human
studies on anti-inflammation effects of fungal b-glucans, as
well as the structure-anti-inflammatory activity relationships.
* Corresponding authors. 28, Jinfeng Road, Tangjiawan, Zhuhai,
Guangdong, 519085, China. Tel.: þ86 756 3620636; fax: þ86 756
3620882.
http://dx.doi.org/10.1016/j.tifs.2014.09.002
0924-2244/Ó 2014 Elsevier Ltd. All rights reserved.
Introduction
Fungi are an attractive source of physiologically functional
foods and drug precursors, displaying a wide range of phar-
macological activities such as anti-inflammatory, anti-tu-
mor and immuno-modulating effects (Ruan, Su, Dai, &
Wu, 2005). Fungi are also used increasingly in food and
pharmaceutical industry (Rop, Mlcek, & Jurikova, 2009).
Fungi-derived natural products have been an excellent
source of pharmaceuticals as well (Evidente et al., 2014).
The polysaccharide b-D-glucans are components that are
found in some macrofungi (such as mushrooms), and uni-
cellular fungi such as yeast (baker’s yeast and Candida al-
bicans) (Samuelsen, Schrezenmeir, & Knutsen, 2014). All
b-glucans are glucose polymers linked together through a
1 / 3 linear b-glycosidic chain core, and they differ
from each other by their lengths and branching structures
(Stone & Clarke, 1992). The branches derived from the
glycosidic chain core are highly variable, and the two major
groups of branching are 1 / 4 or 1 / 6 glycosidic chains.
These branching assignments appear to be species specific,
fungal b-glucans have 1 / 6 side branches (Chan, Chan, &
Sze, 2009). b-Glucans such as krestin, lentinan and schizo-
phyllan from various fungi have diverse immuno-
modulatory activities both in vitro and in vivo. The interest
of researchers in mushrooms as natural sources of active
principles has noticeably increased during the past decade
and particular attentions have been paid to the polysaccha-
ride components of various mushrooms.
Inflammation is the first biological response of the im-
mune system to infection or irritation (Debnath, Kim, &
Lim, 2013). There is no clear dividing line between acute
and chronic inflammation, but the former generally refers
to a response that has an abrupt onset and is of short dura-
tion (Zamora, Vodovotz, & Billiar, 2000). Chronic inflam-
matory responses are predispose to a pathological
progression of chronic illnesses characterized by infiltration
of inflammatory cells, excessive production of cytokines,
dysregulation of cellular signaling and loss of barrier func-
tion (Pan, Lai, & Ho, 2010). In the inflammatory response,
there is an increase of permeability of endothelial lining
cells and influxes of blood leukocytes into the interstitium,
oxidative burst, and release of cytokines (Miguel, 2010). As
a matter of fact, besides infection, a number of dysregulated
immune reactivity has been associated with the fungus and/
or certain fungal components (Yoshitomi et al., 2005).
b-Glucan is known to have anti-inflammatory properties,
50 B. Du et al. / Trends in Food Science & Technology 41 (2015) 49e59

of b-glucans. It is followed by a discussion of the animal

Abbreviations and human studies in anti-inflammatory activities of b-glu-
cans. The structure-anti-inflammatory activity relationships
LPS lipopolysaccharide are also discussed. The different anti-inflammatory activ-
NO nitric oxide ities of fungal b-glucans were summarized in Table 1.
LOX lipoxygenase
COX cyclooxygenase In vitro cultured animal cell studies on anti-
TPA 12-O-tetradecanoylphorbol 13-acetate inflammatory activities of b-glucans
TNF-a tumor necrosis factor-a Effects on cytokines production
IL interleukin Cytokines are small proteins or glycoproteins that trans-
DSS dextran sulfate sodium mit information from one cell to another. Most cells in the
NF nuclear factor body secrete and respond to cytokines, and their effects
IFN-g interferon-g have been described on a myriad of cellular functions
iNOS inducible nitric oxide synthase (Vecchiarelli, 2001). Cytokines, which are produced by
MTX methotrexate cutaneous cells during inflammatory processes, represent a
CIA collagen-induced arthritis large series of regulatory proteins of the immunologic sys-
SPG schizophyllan tem. Nitric oxide (NO), an important molecule on anti-
SPG-OH alkaline-treated SPG inflammatory and antimicrobial effects of macrophages, is
NF-kB nuclear factor kappa B a chemical indicator of inflammation and inflammatory dis-
PGE2 prostaglandin E2 eases. Inducible nitric oxide synthase (iNOS) is induced in
DCs dendritic cells inflamed tissues and generates relatively large amounts of
EP E-series prostanoid receptor NO. The lipoxygenase (LOX) and cyclooxygenase (COX)
TLR Toll-like receptor are enzymes involved in the process of inflammation. Both
iNOS and COX-2 stimulate the production of large amounts
and several studies have demonstrated the beneficial effects of pro-inflammatory mediators (Mueller, Hobiger, &
of dietary b-glucans on inflammatory bowel disease (Ye Jungbauer, 2010). IL-1b and tumor necrosis factor-a
et al., 2011). Some experimental studies have reported (TNF-a) are two important pro-inflammatory cytokines
the biological properties of b-D-glucans, especially their with a relevant role in the inflammatory disorders (Miguel,
anti-inflammatory, antioxidant, and anti-tumor effects 2010). Most of the research has focused on the secretion
(Akramiene, Kondrotas, Didziapetriene, & Kevelaitis, of pro-inflammatory cytokines or mRNA expression of in-
2007; Pelizon, Kaneno, Soares, Meira, & Sartori, 2005). flammatory mediators such as IL-1, IL-6, IL-8, IL-12, IL-
In vitro experiments showed that b-glucans can directly 18, and interferon-g (IFN-g). Jo et al. (2010) determined
activate leukocytes, and further stimulate their phagocytic, the in vitro anti-inflammatory effect of hot water extract
cytotoxic, and antimicrobial activities. (mainly b-glucan) from fruiting bodies of Cordyceps milita-
Despite long-term interest and research, the mechanisms ris on lipopolysaccharide (LPS)-stimulated NO production,
on how b-D-glucan affects human health remained a mys- TNF-a and IL-6 release in RAW 264.7 cells. The treatment
tery for a long time (Vetvicka & Vetvickova, 2011). Only of macrophages with various concentrations of hot water
in the last decade, extensive research by numerous scientific extract from C. militaris significantly reduced LPS-induced
groups has helped to reveal the extraordinary effects of b- NO production as well as secretion of TNF-a and IL-6 in
glucan on the immune system and skin health. Brown and a concentration-dependent manner. These findings suggested
Gordon (2005) conducted a review about the various im- that hot water extract from C. militaris may prevent inflam-
mune responses initiated by fungal b-glucan, with reference mation by suppressing LPS-induced inflammatory media-
to fungal infection. We (Du, Bian, & Xu, 2014) reviewed tors. Splenocytes from DBA/2 mice were in vitro cultured
the skin health promotion effects of natural b-glucan with an extracellular bacterial polysaccharide (a linear b-
derived from cereals and microorganisms. Chen and 1,3-glucan). In bone marrow-derived dendritic cells, b-
Seviour (2007) summarized the medicinal importance of glucan induced productions of TNF-a and IL-6. Taken
fungal b-(1 / 3), (1 / 6)-glucans, such as immune- together, these results suggested that b-glucan stimulated
stimulating, anti-tumor, anti-diabetes, anti-infection, and mouse leukocytes to induce the productions of cytokines
blood cholesterol lowering properties. However, it is un- (Hida et al., 2009). LPS-stimulated NO production in
known that how b-glucans mediate in their anti- RAW 264.7 cells was reported to be an effective approach
inflammatory effects. What’s more, the fact that the litera- for evaluating the anti-inflammatory activity of b-glucan.
ture on b-glucan is inconsistent, and frequently contradic- In one study, Ishibashi et al. (2002) prepared 1,3-b-D-
tory, complicates delineation of underlying mechanisms. glucan from C. albicans and examined the relationship be-
Herein, this review commences with the recent insights tween leukocyte activation and the physicochemical prop-
gained on the in vitro studies on anti-inflammatory activities erties. b-Glucan in a particulate form activated leukocytes
Table 1. The different structure, conformation and anti-inflammatory activities of b-glucans.

Name Sources Solubility Primary structures Conformation Anti-inflammatory activity References

Lentinan Lentinus edodes Water-soluble b-(1,3)-glucan with one
b-(1,6)-glucose branch
every five glucose residues
b-Glucan Pleurotus pulmonarius Water-soluble (1 / 3)-linked
b-D-glucopyranosyl main-chain
substituted at O-6 of every
third unit by single
b-D-glucopyranosyl
Stiff triple helices (in water); Ameliorate DSS-induced colitis in Nishitani
random coil (in DMSO) body weight loss, shortening of et al., 2013
colon lengths, histological score,
and inflammatory cytokine mRNA
expression in inflamed tissues
e Inhibition of leukocyte migration Smiderle
to injured tissues; cause significant et al., 2008
inhibition of both the early
(neurogenic pain) and the late
phases (inflammatory pain) of

B. Du et al. / Trends in Food Science & Technology 41 (2015) 49e59

non-reducing end units formalin-induced licking
b-Glucan Pleurotus ostreatus Water-soluble b-(1 / 3), (1 / 6) glucan e Suppress secretion of TNF-a and IL-6 Jedinak
in mice challenged with LPS in vivo et al., 2011
b-Glucan Saccharomyces Water-insoluble b (1-3)-D-glucan e Inhibit anthralin-induced skin Vetvicka &
cerevisiae (Yeast) inflammation Vetvickova, 2011
b-Glucan Amanita muscaria e e e Produce potent inhibition of Ruthes
inflammatory pain et al., 2013b
b-Glucan Lactarius rufus e (1 / 3), (1 / 6)-b-D-glucans e Exhibit inhibition of inflammatory Ruthes
pain et al., 2013a
b-Glucan Geasturm saccatum Water-soluble e e Inhibit the ear edema induced by Guerra Dore
croton oil et al., 2007
b-Glucan Caripia montagnei Water-soluble e e Reduction in NO levels; decrease in Queiroz
IL-1ra, IL-10 and IFN-g in the et al., 2010
peritonitis model
b-Glucan Agrocybe chaxingu e e e Inhibit ( p < 0.01) TPA-induced ear Lee et al., 2009
edema in mice
Polysaccharide Pholiota nameko e e e Inhibit topical edema in the mouse Li et al., 2008
ear; suppress the development of
egg albumin-, carrageenan-, and
formaldehyde-induced paw
edema in the animals
b-Glucan Ganoderma lucidum e e e Show significant dose-dependent Joseph
activity in carrageenean-induced and et al., 2011
formalin-induced inflammation assays
b-Glucan Ganoderma lucidum Water-insoluble b-(1 / 3)-D-glucan with e Down regulation of iNOS and TNF-a Wang
few branches at C-6 and mRNA gene expression et al., 2014
C-2 positions
Zymosan Saccharomyces Water-insoluble e e Inhibit oxLDL-induced Wang et al.,
cerevisiae pro-inflammatory effects in 2014
(Baker’s yeast) human monocytic leukemia
macrophages via regulation
of p38 MAPK phosphorylation
Zymosan Saccharomyces Water-insoluble e e Attenuate LPS induction of Zhu et al.,
cerevisiae TLR4/MyD88/NF-kB and inhibit 2013
(Baker’s yeast) the LPS-induced inflammation
factors in mammary epithelial cells

51
(continued on next page)
 52
Table 1 (continued )
Name Sources Solubility Primary structures Conformation Anti-inflammatory activity References
b-Glucan Saccharomyces Water-insoluble e e Display a protective effect in the DSS Jawhara et al.,
cerevisiae (yeast) mouse model 2012
b-Glucan Candida albicans Water-insoluble e e Display a protective effect in the
DSS mouse model
b-Glucan Agrocybe chaxingu e e e Inhibit (p < 0.01) LPS-induced Lee et al., 2009
iNOS and COX-2 expression levels
in Raw 264.7 cells
Lentinan Lentinus edodes Water-soluble Stimulate macrophages by inducing Xu et al., 2011
phosphorylation of MAPKs ERK1/2
and JNK1/2, but not p38
b-Glucan Lingzhi (Ganoderma Water-soluble e e Induce both NO and iNOS. Batbayar

B. Du et al. / Trends in Food Science & Technology 41 (2015) 49e59

lucidum) et al., 2011
b-Glucan Candida albicans Alkali acid-insoluble e e Induce PGE2 production, which Gagliardi et al.,
has been shown to play a pivotal 2010
role in Th17 cell expansion.
Inhibition of PGE2 synthesis or
blockade of PGE2 receptors EP2
and EP4 drastically reduces IL-23
production by b-glucan-activated DCs
polysaccharide Armillariella mellea e e e Exhibit inhibition of TNF-a and IL-6 Chang et al.,
secretions 2013
Lentinan Lentinus edodes Water-soluble b-(1,3)-glucan with one Stiff triple helices (in water); Inhibit NO and TNF-a secretion and Xu et al., 2012a
b-(1,6)-glucose branch random coil (in DMSO) phosphorylation of MAP kinases
every five glucose residues JNK1/2 and ERK1/2
b-Glucan Saccharomyces Water-insoluble e e Inhibit secretion of pro-inflammatory Xu et al., 2012b
cerevisiae (bakery mediators including NO, TNF-a,
yeast) IL-1a, and IL-1ga
Lentinan Lentinus edodes Water-soluble (1 / 3)-b-d-glucans with Stiff triple helices (in water); Exhibit NO inhibition effect in Xu et al., 2012c
(1 / 6)-glucopyranoside random coil (in DMSO) LPS-stimulated RAW 264.7
side groups macrophages in a dose-dependent
manner
Lentinan Lentinus edodes Water-soluble b-(1 / 3), (1 / 6) glucan e Exhibit different suppressive effects Mizuno et al.,
on IL-8 mRNA expression in Caco-2 2009
through TNF-a production from
RAW 264.7 stimulated with LPS
b-Glucan Agaricus bisporus Water-soluble b-(1 / 3), (1 / 4) glucan e Lower NF-kB transactivation in Volman et al.,
Caco-2 cells 2010
b-Glucan Ganoderma lucidum Water-insoluble b-(1 / 3)-D-glucan with e Down regulation of iNOS and Wang et al.,
few branches at C-6 and TNF-a mRNA gene expression 2014
C-2 positions
Zymosan Saccharomyces Water-insoluble e e Inhibit oxLDL-induced Wang et al.,
cerevisiae pro-inflammatory effects in 2014
(Baker’s yeast) human monocytic leukemia
macrophages via regulation
of p38 MAPK phosphorylation
 B. Du et al. / Trends in Food Science & Technology 41 (2015) 49e59 53

more effectively than solubilized form in terms of TNF-a

NO: nitric oxide; NF-kB: nuclear factor-kB; TNF-a: tumor necrosis factor-a; DSS: dextran sulfate sodium; PGE2: prostaglandin E2; DCs: dendritic cells; EP: E-series prostanoid receptor; TLR: Toll-
production by RAW 264.7 cells, hydrogen peroxide pro-
Johnson et al.,

Johnson et al.,
Førland et al., duction by murine peritoneal exudate cells and IL-8 pro-
Zhu et al.,

duction by human peripheral blood mononuclear cell.

2013

2009

2011

2012
Therefore, it is recommended to consider the cytokines pro-
duction in anti-inflammatory activity of b-glucans.
Moreover, polysaccharides from lingzhi (Ganoderma lu-
A decline of especially pro-inflammatory

Reduced the monocyte and granulocyte

cidum), in particular b-D-glucans were reported as potent

in levels of IL-1b (97%), TNF-a (84%),
A significant reduction was observed
TLR4/MyD88/NF-kB and inhibit the

release of mainly pro-inflammatory

IL-17 (50%) and IL-2 (46%) in vivo

stimulators of murine and human macrophages in vitro

and chemotactic cytokines in vivo
LPS-induced inflammation factors

and in vivo (Han et al., 1998). It demonstrated that the

in mammary epithelial cells

anti-inflammatory activity of proteoglycan from G. lucidum

Attenuate LPS induction of

on RAW 264.7 cells. Partial removal of the protein in b-

glucan did appreciably reduce its capacity to secrete NO
in macrophages. Lee et al. (2009) examined the effects of
cytokines in vivo

the b-glucan from Agrocybe chaxingu on LPS-induced

NO and COX-2 expression in murine macrophage RAW
264.7 cells. The b-glucan significantly ( p < 0.01) inhibited
expression levels of LPS-induced iNOS and COX-2 in the
cells. Xu, Yasuda, Nakamura-Tsuruta, Mizuno, and Ashida
(2012) and Xu, Chen, Zhang, and Ashida (2012) suggested
that lentinan from shitake (Lentinus edodes) inhibited LPS-
induced NO and TNF-a production in RAW 264.7 macro-
phages partially via suppression of MAP kinases JNK1/2
and ERK1/2, and the resultant decrease the mRNA expres-
sion of iNOS and TNF-a. They also treated LPS-stimulated
RAW 264.7 macrophages with another b-glucan from
Saccharomyces cerevisiae (baker yeast). Data presented in
e

this study clearly demonstrated that b-glucan could inhibit

secretion of pro-inflammatory mediators including TNF-a,
IL-1a, IL-1ga and NO, which are important chemical mes-
sengers for the induction of many biological responses.
These results show that it is possible to use RAW 264.7
macrophages as in vitro model to investigate the anti-
inflammatory effect of b-glucan. The phosphorylation of
MAP kinases ERK1/2 and JNK1/2 was also confirmed to
be suppressed by b-glucan from baker’s yeast (Xu,
e

Yasuda, Mizuno, & Ashida, 2012). Mizuno, Nishitani,

Hashimoto, and Kanazawa (2009) developed a system for
assessing the anti-inflammatory effects of lentinan using a
Water-insoluble

co-culture system with intestinal epithelial Caco-2 cells

and macrophage RAW 264.7 cells. The results indicated
that the lentinan exhibited different suppressive effects on
mRNA expression of IL-8 in Caco-2 through TNF-a pro-
e

duction from RAW 264.7 stimulated with LPS. Addition-

ally, Smiderle et al. (2013) purified the linear (1 / 6)-b-
Agaricus blazei Murill

Agaricus blazei Murill

Agaricus blazei Murill

cerevisiae (baker’s

D-glucans from Agaricus bisporus and Agaricus brasilien-

like receptor; IFN-g: interferon-g.
Saccharomyces

sis and evaluated their effects on the innate immune system

using THP-1 macrophages. The analysis of GCeMS, HP-
SEC and 13C NMR confirmed the presence of homoge-
yeast)

neous (1 / 6)-b-D-glucans. The results showed that a sig-

nificant inhibition of the expression of IL-1b and COX-2
was observed for both treatments after 3 h of incubation
when THP-1 macrophages were incubated with LPS þ b-
b-Glucan

b-Glucan

b-Glucan
Zymosan

glucan, the reduction of TNF-a was not significant. The

mechanism by which the b-glucans act on the cells is still
argumentative.
54 B. Du et al. / Trends in Food Science & Technology 41 (2015) 49e59
Effects on non-cytokine mediator
Recent studies have shown that Th17 polarization is also
regulated by non-cytokine mediators of the inflammatory
milieu, such as prostaglandin E2 (PGE2) (Chizzolini &
Brembilla, 2009), which is one of the prostanoid lipid me-
diators derived from arachidonic acid through the activity
of COX enzymes. It is found that b-glucan purified from
yeast C. albicans stimulated human dendritic cells (DCs)
to secrete a pro-Th17 cytokine pattern. b-Glucan induces
PGE2 production, which has been shown to play a pivotal
role in Th17 cell expansion. Inhibition of PGE2 synthesis
or blockade of PGE2 receptors E-series prostanoid receptor
2 (EP2) and E-series prostanoid receptor 4 (EP4) drastically
reduced IL-23 production by b-glucan-activated DCs.
Moreover, b-glucan promoted the expansion of Th17 cells,
which was strongly decreased by EP2 and EP4 receptor
blockade on DCs (Gagliardi et al., 2010). In the context
of understanding of the non-cytokine mediator in the anti-
inflammatory effect of b-glucans, it is clear that the mech-
anism is still unclear. For instance, studies can be extended
towards detailed molecular experiments. Moreover, mRNA
and protein expression can be applied to support the
studies.
Effects on master transcription factors (NF-kB)
Nuclear factor kappa B (NF-kB) is a transcriptional
regulator that consists of homo- and heterodimers of pro-
teins. It was reported that NF-kB is maintained as a latent
form in the cytoplasm of cells where it is complexed to
IkB inhibitor protein (Miguel, 2010). The effects of poly-
saccharide from Armillariella mellea on secretions of
TNF-a and IL-6 after LPS stimulation were determined
in RAW 264.7 macrophages. Time-course study showed
that a polysaccharide from 49-day-cultured mycelia ex-
hibited maximal inhibition of TNF-a and IL-6 with respec-
tive values of 31.2% and 62.7%. The observations showed
that the suppression of NF-kB activation might be respon-
sible for their anti-inflammatory effects of polysaccharide
from mycelia of A. mellea (Chang, Lur, Lu, & Cheng,
2013). Moreover, it has been speculated that b-glucan
from A. bisporus lowered NF-kB transactivation in Caco-
2 cells (Volman et al., 2010). In a recent study, Wang,
Yuan, and Yue (2014) demonstrated that the water-
insoluble linear b-(1 / 3)-D-glucan extracted from lingzhi
(G. lucidum) exhibited significant inhibition against inflam-
mation induced by LPS in RAW 264.7 cells in a dose-
dependent manner. This linear glucan decreased the NO
production, at least partially, via blocking NF-kB and inhib-
iting the phosphorylation of JNK MAPK signal pathways.
Toll-like receptor 2 (TLR2) played a major role on anti-
inflammation activity of b-glucan. Additionally, Zhu et al.
(2013) demonstrated that b-glucan attenuated LPS induc-
tion of TLR4/MyD88/NF-kB and inhibited the LPS-
induced inflammation factors in mammary epithelial cells,
thereby providing a possibly protective effect in the preven-
tion of LPS-induced dysfunction in mammary epithelial
cells. In one study, Xu, Chen, Zhang, and Ashida (2011) re-
ported that a lentinan from L. edodes activated NF-kB p65
and triggered its nuclear translocation as determined by
Western blotting. Meanwhile, lentinan enhanced NF-kB-
luciferase activity in a Dual-Luciferase gene system assay.
Its upstream signaling molecules, MAPKs such as ERK1/2
and JNK1/2, were shown to be activated by assessing the
level of phosphorylation in time- and concentration-
dependent manners, but its downstream pro-inflammatory
enzyme, inducible NOS, was not observed.
Moreover, pustulan, linear b(1 / 6)-glucan from Lasal-
lia pustulata is recognized by the membrane-bound Dectin-
1, a C-type lectin-like pattern recognition receptor. Detec-
tion of b-glucans by Dectin-1 receptor leads to the
CARD9-dependent activation of NF-kB and MAP kinases
(Goodridge, Wolf, & Underhill, 2009).
Effects on the arachidonic acid metabolism
Arachidonic acid is oxygenated and further transformed
into a variety of products which mediate or modulate inflam-
matory reactions (Samuelsson, 1991). Castro, Ralston,
Morgenthaler, Rohrbach, and Limper (1994) examined the
roles of b-glucan components from C. albicans in mediating
the arachidonic acid metabolism. Macrophage release of
arachidonic acid was significantly inhibited. The observa-
tions indicated that macrophage arachidonic acid meta-
bolism was partly mediated by b-glucan constituents from
C. albicans. However, there are still major gaps and research
that can be pursued with regard to arachidonic acid meta-
bolism. The molecular pathway of arachidonic acid meta-
bolism was not clear.
The other factors
Blood platelets belong to principal haemostatic repre-
sentatives, but beyond hemostasis and thrombosis, they
also play a key role in inflammation. Saluk, Bijak,
Ponczek, Nowak, and Wachowicz (2013) evaluated the in-
fluence of b-D-glucan from baker’s yeast (S. cerevisiae) on
destructive activity of LPS on human blood platelets. The
in vitro results demonstrated that b-D-glucan might combat
the oxidative stress caused by LPS stroke associated with
nutritive and oxidative damages of human platelet biomol-
ecules. Moreover, Wang et al. (2014) reported that b-glucan
from yeast inhibited oxLDL-induced pro-inflammatory ef-
fects in human monocytic leukemia cells macrophages
via regulation of p38 MAPK phosphorylation. This novel
finding may provide insight for new therapeutic strategies.
Overall these reports indicate that the research in vitro
model can form the basis for anti-inflammatory activity in
the animal model and human study.
Animal studies on anti-inflammatory activities of b-
glucans
Despite in vitro studies, numerous animal studies have
been conducted to evaluate the anti-inflammatory activities
of b-glucans. Studies on anti-inflammatory properties of
 B. Du et al. / Trends in Food Science & Technology 41 (2015) 49e59
carbohydrates have led to positive results. Firstly, the intes-
tinal anti-inflammatory activity of lentinan was studied.
Dextran sulfate sodium (DSS)-induced colitis mice were
used to elucidate effects of lentinan in vivo. Oral administra-
tion of lentinan significantly ameliorated DSS-induced coli-
tis in body weight loss, shortening of colon lengths,
histological score, and mRNA expression of inflammatory
cytokine in inflamed tissues. It can be concluded that len-
tinan exhibited intestinal anti-inflammatory activity through
inhibition of IL-8 mRNA expression associated with the in-
hibition of NF-kB activation which was triggered by TNF
receptor 1 endocytosis and lowered their expression in intes-
tinal epithelial cells (Nishitani et al., 2013). In this context,
the DSS-induced mice model should be more specifically
recognized. Nevertheless, Jawhara et al. (2012) assessed
the capabilities of yeast C. albicans and yeast cell wall com-
ponents (b-glucan) to modulate intestinal inflammation in
DSS-induced mice model. It was striking that yeast b-glucan
fractions or pure b-glucans from C. albicans displayed the
most potent anti-inflammatory effect in the in vivo DSS
model. Queiroz et al. (2010) reported that b-glucan from
Caripia montagnei significantly reduced the inflammatory
infiltrate produced in the thioglycolate-induced peritonitis
model. The b-glucan at a concentration of 50 mg/kg had
good anti-inflammatory effect. They also found that b-
glucan increased the level of IL-10 concomitant with a
reduction of IFN-g. The results indicated that b-glucan
from C. montagnei had excellent anti-inflammatory activity
at a concentration of 50 mg/kg.
Experiments on mice showed that acetic acid injection
induced an inflammatory process by causing tissue injury.
A b-glucan from the basidiomycete Pleurotus pulmonarius
was tested for its effects on the acetic acid-induced writhing
reaction in mice, a typical model for quantifying inflamma-
tory pain (Smiderle et al., 2008). The b-glucan exhibited a
marked and dose-dependent anti-inflammatory response,
demonstrated by the inhibition of leukocyte migration to
injured tissues (82  6%) with an infective dose (ID50) of
1.19 (0.74e1.92) mg/kg. Furthermore, animals previously
treated with the glucan (3 mg/kg i.p.), showed a reduction
of 85  5% of writhes, after receiving the acetic acid injec-
tion. These data showed that the glucan had potent anti-
inflammatory activity. In addition, the effects of the b-glucan
from A. chaxingu on 12-O-tetradecanoylphorbol 13-acetate
(TPA)-induced ear edema in mice were examined. Topical
application of b-glucan resulted in markedly ( p < 0.01) in-
hibition against TPA-induced ear edema in mice. The study
provided evidence of the topical anti-inflammatory effects of
the polysaccharide by assessing the protective effects of
polysaccharide on TPA-induced skin inflammation (Lee
et al., 2009). The anti-inflammatory activity of polysaccha-
ride from Pholiota nameko was evaluated with mice using
xylene-induced ear edema, egg albumin-, carrageenan-,
and formaldehyde-induced paw edema. This polysaccharide
inhibited topical edema on the mice ears, and it significantly
suppressed the development of egg albumin-, carrageenan-,
55
and formaldehyde-induced paw edema in the animals. The
results indicated that this polysaccharide possessed signifi-
cant anti-inflammatory activity suggesting its potential as
an anti-inflammatory agent for use in the treatment of
various inflammatory-related diseases (Li, Lu, Zhang, Lu,
& Liu, 2008). Furthermore, Joseph, Sabulal, George,
Antony, and Janardhanan (2011) investigated the anti-
inflammatory activity of b-glucan isolated from G. lucidum
using in vivo models. b-Glucan showed significant dose-
dependent activity in carrageenan-induced inflammation
and formalin-induced inflammation. This study showed
that b-glucan of G. lucidum has marked anti-inflammatory
activity. It is also well demonstrated that b-glucan from Lac-
tarius rufus had the anti-inflammatory and antinociceptive
potential using the formalin model. Soluble b-glucan pro-
duced potent inhibition of inflammatory pain caused by
formalin when compared with the insoluble one, suggesting
that solubility or branching degree could alter the activities
of b-glucans (Ruthes, Carbonero, C
ordova, Baggio,
Santos, et al., 2013). In a similar study, Ruthes, Carbonero,
C
ordova, Baggio, Sassaki, et al. (2013) evaluated that a
(1 / 3), (1 / 6)-linked b-D-glucan from Amanita musca-
ria produced potent inhibition of inflammatory pain. In
another study, Jedinak, Dudhgaonkar, Wu, Simon, and
Sliva (2011) evaluated anti-inflammatory properties of b-
glucan from mushroom Pleurotus ostreatus in vivo. Oral
administration of b-glucan markedly suppressed secretion
of TNF-a and IL-6 in mice challenged with LPS in vivo.
Anti-inflammatory activities of b-glucans were confirmed
by the inhibition of secretion of IFN-g, IL-2, and IL-6
from concanavalin A (ConA)-stimulated mouse splenocytes.
Vetvicka and Vetvickova (2011) evaluated the potential
effects of b (1-3)-D-glucan, a yeast-derived insoluble
Glucan No. 300, using an established anthralin-induced
skin inflammation test. Results showed that Glucan No.
300 consistently inhibited the skin irritation for up to
24 h. In ear edema model induced by croton oil, Guerra
Dore et al. (2007) reported the anti-inflammatory property
of b-glucan from Geastrum saccatum. The ear edema
induced by croton oil was inhibited (60.4%) by b-glucan
(at 10 mg/kg). They concluded that the b-glucan had
anti-inflammatory properties, and its anti-inflammatory ef-
fects were mediated by inhibition of both NOS and COX.
In another study, the effects of pleuran (b-1,3 glucan) iso-
lated from P. ostreatus were studied in a model of acute co-
litis induced by intracolonic administration of acetic acid.
There was a reduction of the colonic damage score, colonic
wet weight and wet/dry weight ratio 48 h after single
luminal 2% pleuran suspension pretreatment. The results
on the protective effect of orally applied pleuran in the pre-
vention or dietetic therapy of inflammatory colon disease
are promising (Nos
al’ov
a, Bobek, Cern
a, Galbav
y, &
Stvrtina, 2001). Moreover, effects on arthritis in an animal
model have been observed after oral administration of b-
glucan. Rovensk
y, Stanc
ıkova, Sv
ık, Bauerov
a, and
Jurcovicov
a (2011) discussed the effect of b-glucan
56 B. Du et al. / Trends in Food Science & Technology 41 (2015) 49e59
isolated from P. ostreatus on prophylactic treatment of
adjuvant arthritis with methotrexate (MTX) in rats. b-
Glucan administered alone significantly decreased both
the hind paw swelling and arthritic score. The results
showed that b-glucan from P. ostreatus decreased the adju-
vant arthritis development in rats and had additional bene-
ficial effect to MTX treatment. Oral administration of
proteoglycan derived from Phellinus linteus could prevent
or treat collagen-induced arthritis (CIA) in mice as an
experimental model of autoimmune disease (Kim et al.,
2003). The inhibition of CIA by oral administration of pro-
teoglycan was associated with the decrease in anti-CII IgG
and IgG2a antibodies as well as varying kinds of cytokines
including IL-12, TNF-a, and IFN-g. The observations
showed that administration of proteoglycan was followed
by the decreases of CIA of the mice in pre- and post-
administration groups.
In the latest study, the anti-inflammatory effects of the
aqueous extracts from medicinal mushrooms (Fomes fo-
mentarius, Ganoderma applanatum and Trametes hirsuta)
were evaluated using carrageenan-induced paw edema
model. The results showed that the anti-inflammatory ef-
fects of the different doses (50, 100 and 500 mg/kg) of
the three basidiomycetes were close to the positive control
(indomethacin; 15 mg/kg) after five hours of carrageenan
injection. The considerable anti-inflammatory effects of
three basidiomycetes, may be due to polysaccharide com-
ponents (b-glucan) of the extracts (Vazirian et al., 2014).
Human studies on anti-inflammatory activities of b-
glucans
To date, very few human intervention studies have ad-
dressed the effects of b-glucans on systemic inflammation.
Further human clinical trials are required to support the hy-
potheses regarding the benefits of b-glucan for individuals
with inflammatory bowel disease.
Johnson et al. (2009) studied the effect of Agaricus
blazei Murill extract (mainly b-glucan) on release of
several cytokines in human whole blood from healthy vol-
unteers both after stimulation ex vivo and in vivo after oral
intake over several days. The in vivo results showed that the
eight volunteers who completed the daily intake (60 mL) of
this mushroom extract for 12 days, a significant reduction
in levels of IL-1b (97%), TNF-a (84%), IL-17 (50%) and
IL-2 (46%) was observed. Moreover, patients with Crohn’s
disease (n ¼ 11) and with ulcerative colitis (n ¼ 10)
consumed 60 ml/day of b-glucan from A. blazei Murill. Pa-
tient blood plasma was harvested before and after six hours
LPS (1 ng/mL) stimulation ex vivo. Plasma and faecal cal-
protectin levels were analyzed using ELISA and 17 cyto-
kines (IL-2, IFN-g, IL-12 (Th1), IL-4, IL-5, IL-13 (Th2),
IL-7, IL-17, IL-1b, IL-6, TNF-a, IL-8, MIP-1b, MCP-1,
G-CSF, GM-CSF and IL-10) by multiplex assay. Consump-
tion of an A. blazei Murill-based medicinal mushroom
extract for 12 days by patients with inflammatory bowel
disease resulted in no side-effects and a decline of
especially pro-inflammatory and chemotactic cytokines as
well as a reduction in faecal calprotectin in patients with ul-
cerative colitis. These promising results warrant further
studies on additional biological parameters and potential
improvement of clinical outcomes in these patients
(Førland et al., 2011).
In another study, oral intake (60 mL daily) an A. blazei
Murill extract over 12 days in eight healthy volunteers,
reduced the monocyte and granulocyte release of major
pro-inflammatory cytokines in vivo, suggesting an anti-
inflammatory effect. These results supported that the oral
intake of A. blazei Murill b-glucan exhibited an anti-
inflammatory effect in human in vivo (Johnson et al.,
2012). In-depth insights in the anti-inflammatory activity of
b-glucans could be gained by carrying out the double-
blind, placebo-controlled, randomized clinical trial of
human.
Structure-anti-inflammatory activity relationship
b-Glucans is the common name given to a group of
chemically heterogeneous polysaccharides (Barsanti,
Passarelli, Evangelista, Frassanito, & Gualtieri, 2011).
Viewed from the point of the structure, b-glucans vary in
molecular weight, degree of branching and conformational
structure. In fungal b-glucans, fine structure, molecular
weight, conformation and solubility have been shown to in-
fluence biological activities (Bohn & BeMiller, 1995;
Leung, Liu, Koon, & Fung, 2006; Soltanian, Stuyven,
Cox, Sorgeloos, & Bossier, 2009). b-Glucan molecular
weight and fine structure, such as 1 / 3 to 1 / 6 linkage
ratio, lengths, number and distribution of cellulosic oligo-
saccharides will together with amount and nature of co-
extracted compounds in a b-glucan preparation influence
solubility, aggregate formation and polymer conformation
(Rieder & Samuelsen, 2012). b-Glucans of different sizes,
branching patterns and conformation may have significantly
variable anti-inflammatory potency. Indeed, it has been
demonstrated that the molecular weight, conformation,
chemical modification and solubility of b-glucans signifi-
cantly affect their anti-inflammatory activities. For
example, Ohno, Hashimoto, Adachi, and Yadomae (1996)
demonstrated that NO synthesis in vivo were significantly
different between triple helical (SPG) and single helical
(alkaline-treated SPG, SPG-OH) b-glucans. It was found
that SPG-OH, but not SPG, enhanced NO synthesis
in vitro. Concentrations of IL-1a, IL-6 and TNF-a in the
culture supernatant of SPG-OH were significantly higher
than those in that of SPG. Consequently, the anti-
inflammatory activity of b-glucan may be explained by its
structure and physicochemical properties. The solubility
of b-glucans in water is dependent, above all, on their struc-
tures, and this is associated with their origins. The solubility
increases with temperature. The previous reports also
showed that an insoluble/particle glucan strongly induced
inflammatory cytokine production (Ishibashi, Miura,
Adachi, Ohno, & Yadomae, 2001). Therefore, it is thought
 B. Du et al. / Trends in Food Science & Technology 41 (2015) 49e59
that the differences in b-(1 / 6)-glucan side chain and mo-
lecular weight influenced cytokine production (Ishibashi
et al., 2004). Previous data indicated that the solubility of
b-glucan is very important for anti-tumor activity (Tao,
Zhang, & Cheung, 2006). Previous data also indicated
that the more water-soluble polymers are more active
(Bohn & BeMiller, 1995). Furthermore, Ishibashi et al.
(2002) compared the biological activities of the glucan par-
ticles oxidized under various conditions. These facts
strongly suggested that the solubility and assembly of the
components influenced the immuno-pharmacological activ-
ities of 1,3-b-D-glucans. However, the relationship between
solubility and anti-inflammatory activity of b-glucan was
not clear. Future effort should be focused on this field.
Conclusions and future perspective
b-Glucans with different mixed linkages and structures
can provide a better physiological response and have
several health promoting activities, such as, anti-cancer, im-
mune-modulating and anti-inflammatory properties. Their
promising structural characteristics favor their anti-
inflammatory properties. However, interestingly, whether
single helix or triple-helix b-(1,3)-D-glucan is the most bio-
logically active is still an unresolved issue, and the litera-
ture appears inconsistent and often contradictory. These
areas about structure-anti-inflammatory activity relation-
ship need special attention. Moreover, the limitations are
further complicated by the fact that many studies on b-
glucan related herbs often used crude extracts rather than
purified compounds. Therefore, the confounding effects
of other chemicals cannot be totally ruled out. The good
quality clinical trial data on assessing the effectiveness of
purified b-glucans on anti-inflammatory activity has to be
confirmed by future research. The anti-inflammatory effects
of b-glucans depend on the structural characteristics of the
polysaccharides. The functionality of this assumption needs
to be confirmed in studies especially designed for this
research question. Further studies elucidating the exact
mechanisms that are responsible for the anti-inflammatory
activity of b-glucan are necessary. More further study are
needed to clarify the detailed role of b-glucan played in
the NO production dependent on TLR2, and the up-
streaming and down-streaming JNK MAPK signaling path-
ways, transcription factors and the receptors involved in the
anti-inflammation mechanism need to be further studied in
future work. The current knowledge of the mechanisms of
action and pharmacokinetics remains insufficient. Fungal
b-glucan definitely deserves further study with regard to
biological activity, including studies into mechanism of ac-
tion and structureeactivity relationships. Other fungus spe-
cies should be investigated, both as a potential source of
new chemical structures and biological activity. Future
research works could focus on combining in vitro model,
animal model and human study to thoroughly achieve the
anti-inflammatory effect of b-glucans. As a final point
and to put b-glucans anti-inflammatory activity in a broader
57
perspective, research should be extended to double-blind,
placebo-controlled, randomized clinical trial.
Acknowledgments
This project is jointly supported by Natural Science
Foundation of Guangdong Province, China (Project
Code: S2012010008961), and by Beijing Normal Univer-
sity-Hong Kong Baptist University United International
College (grant number: UIC201329).
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