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The Chemistry, Nutritional Value, Immunopharmacology, and Safety of the Traditional Food of Medicinal Split-Gill Fugus Schizophyllum commune Fr.:Fr. (Schizophyllaceae). A Literature Review

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The cosmopolitan wood-loving mushroom, Schizophyllum commune, is used as a traditional food throughout Southeast Asia and India. Researchers have intensively studied a (1→3)-β-D-glucan from the mycelium extract, schizophyllan (SPG) since the 1970s, and today it is used as a biological response modifier (BRM) in combination with chemo- and radiation therapy, especially for cervical and gastric cancers. Based on an abundance of preliminary evidence showing binding of its (1→3)-β-D-glucan to dectin-1 receptors of macrophages and other cells, activation of a T-cell cascade with subsequent increased production of cytokines, such as interleukins and tumor necrosis factor (TNF-α), reduction of tumor size and growth, increased survival of tumor-bearing animals, and a few controlled human trials of varying methodologies and quality, it continues to be used in clinical practice. Larger, well-designed clinical trials are needed to secure its place in modern medical practice in other countries. Fundamental questions such as whether oral application is effective, determination of proper dose, frequency and length of administration, and whether SPG is effective with other types of cancer still need to be answered.
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International Journal of Medicinal Mushrooms, Vol. 7, pp. 127–139 (2005)
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© 2005 by Begell House, Inc. 127
The Chemistry, Nutritional Value, Immunopharmacology,
and Safety of the Traditional Food of Medicinal
Split-Gill Fugus Schizophyllum commune Fr.:Fr.
(Schizophyllaceae). A Literature Review
Christopher R. Hobbs
Institute for Natural Products Research, Davis, California, USA
Address all correspondence to Christopher R. Hobbs, Institute for Natural Products Research, 2543 Overhill Ln, Davis, CA
95616; ch@christopherhobbs.com
ABSTRACT: e cosmopolitan wood-loving mushroom, Schizophyllum commune, is used as a tra-
ditional food throughout Southeast Asia and India. Researchers have intensively studied a (13)-
β--glucan from the mycelium extract, schizophyllan (SPG) since the 1970s, and today it is used as
a biological response modifi er (BRM) in combination with chemo- and radiation therapy, especially
for cervical and gastric cancers. Based on an abundance of preliminary evidence showing binding of
its (13)-β--glucan to dectin-1 receptors of macrophages and other cells, activation of a T-cell cas-
cade with subsequent increased production of cytokines, such as interleukins and tumor necrosis factor
(TNF-α), reduction of tumor size and growth, increased survival of tumor-bearing animals, and a few
controlled human trials of varying methodologies and quality, it continues to be used in clinical practice.
Larger, well-designed clinical trials are needed to secure its place in modern medical practice in other
countries. Fundamental questions such as whether oral application is eff ective, determination of proper
dose, frequency and length of administration, and whether SPG is eff ective with other types of cancer
still need to be answered.
KEY WORDS: biological response modifi er, SPG, schizophyllan, sizofi ran, Schizophyllum commune,
medicinal mushrooms, polysaccharides, (13)-β--glucan
ABBREVIATIONS
5-FU: 5-fl uorouracil; CMG: carboxymethlylglucan; CR3: complement receptor 3; DC-SIGN: dendritic cell-specifi c
ICAM-3-grabbing nonintegrin; IFN-: interferon-γ; IL-x: interleukin-x; i.m.: intramusculare; i.p.: intraperitoneal;
i.v.: intravenale; LAK cells: lymphokine activated killer cells; MR: mannose receptor; NK cells: natural killer cells;
NO: nitric oxide; PBMC: peripheral blood mononuclear cells; PMN: polymorphonucleocyte; SCEs: sister chromatid
exchanges; SPG: schizophyllan (triple xelix); SPG-OH: schizophyllan (single strand); TDP: true digestibility of protein;
TNF-: tumor necrosis factor-α; WBC: white blood cell
INTRODUCTION
Split-gill Fungus Schizophyllum commune Fr.:Fr.
(Schizophyllaceae, Agaricomycetideae) is also
known as the “split-fold” mushroom. It has been
renowned in Far Eastern countries as medicine for
hundreds of years. S. commune one of the most eas-
ily identifi able species. S. commune grows inside and
outside forests, commonly in light, sunny, dry places,
such as clear cuts, forest edges, and street sides, on
128 International Journal of Medicinal Mushrooms
C. R. HOBBS
dead, fallen, or standing wood of broadleaved trees,
and, more rarely, of conifers. ese small, thin, ex-
ible, whitish fungi grow in overlapping layers. ey
have dense whitish hairs, no stalks, and buff to
brownish gills that fork regularly (hence the name
“split-gill”). ey appear most of the year. ey may
be distinguished from look-alikes by their split gills
and in-rolled margins.
S. commune grows worldwide, on every continent
except Antarctica, being one of the most common
mushrooms known. e species name, commune,
means “common” or “widespread.” Large intra- and
interpopulation genetic variation occurs by long-
distance spore dispersal and genetic drift ( James et
al., 1999; Chang and Miles, 2004).
Split-gill fungus is one of the most potent and
best studied of all medicinal mushrooms (Hobbs,
1995; Mizuno, 1999; Chang and Miles, 2004).
CHEMISTRY
Besides nutrient substances such as protein, ber,
and minerals, analysis of S. commune samples show
that it produces at least three identifi able biopoly-
mers in an aqueous culture medium—a 24 kDa
hydrophobin, a 17 kDa protein, and schizophyllan
(Martin et al., 1999), a gel-forming (13)-β--
glucan with a mean molecular weight (MW) of
100,000 (Tabata et al., 1988) to 150,000 (Sakurai
and Shinkai, 2000). Hydrophobins are small pro-
teins composed of eight conserved cysteine residues,
with a typical hydropathic pattern that aff ects the
hydrophobicity of surfaces by self-assembly at
hydrophilic/hydrophobic interfaces.
By far the most widely researched glucan in S.
commune is a water-soluble triple-stranded helix
known as schizophyllan, or its various trade names
SPG, sizofi ran, Sonifi lan, and Sizofi lan. In DMSO
and other organic solvents, the three strands sepa-
rate and, in DMSO at least, are not recoverable
(Norisuye et al., 1980).
Schizophyllan forms a gel in water (intrinsic vis-
cosity [η] dL/g = 7.32) and is composed of glucose
polymers of diff erent sizes and degree of branch-
ing, but often consisting of (13)-β-D-glucan
main chains with 1,6-β--glucosyl side groups (β-
-glucoside links at position 6 and often repeating)
that form triple helix structures for cell structural
rigidity, with a melting point between 5 and 20 °C
(Mueller et al., 2000). Glucose concentration of the
solvent (0–50%) was the main determinant factor
in the range (Bot et al., 2001). e (13)-β--
glucans are similar to ones found in the cell walls
of other fungi, algae, lichens, and some plants. ey
can exist as an unbranched backbone, or with (1
6)-β-branches.
e triple helix is rigid up to M = 5 × 10⁵ g/mol
(Yanaki et al., 1980) and stiff er than collagen, which
also has a triple helix structure, although the mol-
ecule is more fl exible, and the diameter and pitch
is similar to the similar β-glucan lentinan from
shiitake mushroom Lentinus edodes.
e immunomodulating properties of schizo-
phyllan and other (13)-β--glucans (scleroglucan
and lentinan) depend upon their branching patterns,
molecular weight, and structural conformation, such
as the triple helix. More branching was often seen
to confer higher activity, and the relation of size to
activity is fairly predictable. Compared with linear
and macrocyclic structures, monocyte activation
to production of cytokines was greater in higher
order structures with MW less than 60 × 10⁴ g/mol
or larger than 110 × 10⁴ g/mol (Falch et al., 2000).
e antitumor eff ects were present only with MW
>50,000 (Tabata et al., 1988).
Branched (13)-β--glucans, as opposed to
those with nonlinear or particulate structures, have
stronger biological response modifi er activity in
cancer patients (Tateishi et al., 1997).
e comparative eff ects of single or triple he-
lix conformations are more unpredictable, and
results of a number of studies is equivocal. e
hematopoietic response in mice was independent
of single or triple helix conformation (Tateishi et
al., 1997), and IL-6 mRNA synthesis, gene expres-
sion of NK1.1, stem cell factor gene expression,
and macrophage-colony stimulating factor were
all increased with either SPG (triple helix)- or
SPG-OH (single strand)-treated mice (Tsuzuki et
al., 1999). Both SPG and SPG-OH demonstrated
Volume 7, Issues 1&2, 2005 129
MEDICINAL SPLITGILL FUGUS SCHIZOPHYLLUM COMMUNE
equal antitumor eff ects and cyclophophamide-in-
duced leucopenia hematopoietic response in mice,
but SPG had greater zymosan-mediated hydrogen
peroxide synthesis on peritoneal macrophages, and
SPG-OH demonstrated stronger lipopolysaccaride
priming of tumor necrosis factor synthesis, nitric
oxide synthesis, and hydrogen peroxide synthesis in
mice (Ohno et al., 1995). NO synthesis and IFN-γ
gene expression from mice peritoneal macrophages
was higher in vitro with SPG-OH than with SPG
(Ohno et al., 1996), and the triple helix conforma-
tion of SPG activated the alternative complement
pathway (Suzuki et al., 1992). Hirata et al. (1998)
found that an SPG monomer, but not the trimer,
could stimulate gene expression and production of
the cytokines IL-8, IL-12 p 70, and TNF-α from
monocyte-like human cell lines.
However, Falch et al. (2000) found that the native,
linear triple helix may be necessary for maximum
immunological stimulation in vivo with human
monocyte cultures, which was also confi rmed by other
groups (Tabata et al., 1981; Maeda et al., 1988).
When schizophyllan was heated excessively, the
triple helix degraded, and the molecular weight
was reduced. Cooling could not cause the triple
helix to reform, but an aggregation of the strands
formed (Tabata et al., 1988). Most or all (13)-
β--glucans are likely to be sensitive to heat and
various solvents. e immunological activity of the
related scleroglucan was reduced after treatment
with a strong base or heating (>133 °C) with
subsequent loss of the triple helix conformation
and was not regained after cooling or neutralization
of the base.
Schizophyllan is unusually stable to heat, but
the three strands will separate above 135 °C (Brant
et al., 1997), which may have implications for the
heat stability of similar molecules in other mush-
rooms when extracts are made for oral application
by boiling down the fruiting bodies or mycelium to
make a tea or powder concentrate. e triple helix
conformation will slowly reaggregate after cooling
and may not reform the triple helix. However, the
antitumor activity was the same in these large ag-
gregates as in the pure triple helix conformation
(Yanaki et al., 1986).
e strain of S. commune infl uences the activity
of the (13)-β--glucans (Tateishi et al., 1997), so
the activity of wild populations can be assumed to
vary, depending on the strain, as well as the time of
year it is harvested, the extraction process, and the
length of storage.
Schizocommunin, an indole derivative, indigotin
(indigo), indirubin, isatin, and tryptanthrin were all
isolated from an aqueous culture medium of S. com-
mune. Schizocommunin showed cytotoxicity with
murine lymphoma cells (Hosoe et al., 2000).
NUTRITIONAL VALUE
In many tropical countries, Schizophyllum commune
is commonly eaten as a food—fresh or dried, from
wild-harvested sources, and from cultivation (FAO
review). Longvah and Deosthale (1998) found the
average protein content was 16% and fat content
2% from samples purchased at local markets in
northeast India. e essential amino acid content
of S. commune is 34% lower than whole egg protein,
with methionine the limiting amino acid. e true
digestibility of protein (TDP) was about 91% for
casein, 76% for Lentinus edodes, and 53% for S. com-
mune. Oleic and linoleic acids made up 72–77% of
the total fat (Table 1). Mineral content varies, likely
depending on the habitat and strain. Fat and protein
content in two analyses were in agreement (Parent
and  oen, 1997).
TABLE 1. Nutritional Content of Schizophyllum
commune
Nutrient /100g Nutrient /100g
Protein 15.9 g Phosphorus 408 mg
Fat 2.0 g Magnesium 227 mg
Carbohydrates,
ber
68.0 g Calcium 188 mg
Energy (Kcal) 399 Iron 12.3 mg
Zinc 5.7 mg
Magnesium 8.8 mg
Copper 0.9 mg
Chromium 133 µg
130 International Journal of Medicinal Mushrooms
C. R. HOBBS
BIOLOGICAL EFFECTS
Structure/Functions of (13)--D-glucans
Pharmacokinetics and Pharmacodynamics
A number of researchers have theorized that animal
immune system recognition of (13)-β--glucans
and other heteropolysaccharides evolved because
they are highly conserved constituents of the cell
walls and membranes of fungi and yeasts, not pro-
duced by animals, which alert the organism to poten-
tial local or systemic infection by pathogenic fungi
(Stahl, 1992; Fearon and Locksley, 1996; Mueller et
al., 2000). Most animals—including horseshoe crabs
and earthworms and other insects—have specifi c
β--glucan receptors (Adachi et al., 2004).
Complex carbohydrates are well known to be
useful to cells in recognition and identifi cation.
High concentrations of glucans have been found
in the serum of patients with systemic fungemia
and deep tissue mycoses (Obayashi et al., 1992;
Obayashi, 1997), as well as Pneumocystis carinii
infections (Okamoto et al., 1998).
e large variation among (13)-β--glucans in
whole mushrooms, commercial extracts, and prepa-
rations, and among species makes generalizations
about structure/function relationships diffi cult at
best. More work needs to be done to compare the
activity of extracts and mixtures of glucans from
various species. For a review of some of the work
so far, see Mueller et al. (2000) and Kubala et al.
(2003). Although schizophyllan is administered by
i.v. or i.m., at least two studies demonstrated im-
munomodulation in murine tumor models with oral
doses of (13)-β--glucans. Větvička et al. (2002)
showed increased cytokine production such as IL-2,
IFN-γ, and TNF-α; and Hong et al. (2004) showed
heightened protection against anthrax infection and
cancer in mice.
Uptake of (13)-β--glucans from yeast in
the guts of mice after oral administration was
accomplished by macrophages that transported
them to the spleen, lymph nodes, and bone
marrow. e macrophages reduced the large
(13)-β--glucans to smaller soluble fragments in
the bone marrow, which were subsequently bound
by CR3 of granulocytes. Radiolabeled SPG was
found to accumulate in reticuloendothelial cells,
Kupff er’s cells in the liver, and reticulum cells and
macrophages in the spleen, bone marrow, lymph
nodes, and thymus in sarcoma 180-bearing mice
(Mizuhira et al., 1985). Macrophages strongly ac-
cumulated in cells of the capsular belt area of the
tumors in the DBA mice strain, but not the ICR
strain, leading to widespread tumor cell degenera-
tion. Diff ering immunological responses between
the two strains were thought to be a possible cause.
Based on this observation, it is possible to propose
that the effi cacy of SPG treatments may vary be-
tween humans, based on genotypic variation.
With i.v. administration of a radiolabeled prepa-
ration SPG to rats, most of the label was excreted
from the urine as small metabolites with molecular
weight <10,000, and less from the feces and breath.
After 24 hours, the label was also found concentrated
in the reticuloendothelial tissues, macrophages, the
liver, spleen, mesenteric lymph nodes, and bone
marrow (Horiba et al., 1988), and tissues next to
tumors (Mizuhira et al., 1985). β-glucans with a
single helix were eliminated more rapidly than those
with a triple helix conformation (Mura et al., 1995).
SPG degraded slowly in the liver to lower molecular
weight SPG-like substances, and was metabolized
even more slowly in the spleen and mesenteric
lymph nodes (Tanji et al., 1990a).
e (13)-β--glucans also potentiated the ac-
tivity of antitumor mAb which primed inactivated
iC3b (CR3) receptors with subsequent deposition
on cancer cells, leading to increased cancer cell kill-
ing and tumor regression (Hong et al., 2004).
e molecular mechanisms of action for SPG and
(13)-β--glucans in general is still being worked
out and is likely to be complex. Early studies on SPG
focused on its macrophage-activating eff ects, or the
cooperative role of macrophages and T lymphocytes
as the major antitumor mechanism (Suzuki et al.,
1982; Sugawara et al., 1984), but more recent lit-
erature shows more far-reaching eff ects.
Because large glucans cannot penetrate the cel-
lular plasma membrane, one crucial step seems to
be binding of the (13)-β--glucans to B or T
lymphocytes, polymorphonucleocytes, neutrophils,
or macrophage cell surface receptors, as well as ac-
Volume 7, Issues 1&2, 2005 131
MEDICINAL SPLITGILL FUGUS SCHIZOPHYLLUM COMMUNE
tivation of NK cells (Kubala et al., 2003). What
cell type or types play the most important role for
the overall antitumor and immunoprotective eff ects
of various mushroom glucans is still under discus-
sion. Key cell-surface receptors were proposed to
include Toll-like receptors (TLR), complement
integrin receptor CR3, mannose receptor, scaven-
ger receptors, and DC-SIGN, which are variously
expressed on neutrophils, monocytes, macrophages,
T-cells, dendritic, and NK cells ( ornton et al.,
1996; Herre et al., 2004; Rice et al., 2004). Besides
(13)-β--glucan binding to CR3 receptors,
upregulated PMN chemotactic migration toward
complement C5a (Tsikitis et al., 2004) and binding
to scavenger receptors on human monocytes (Rice
et al., 2002) has also been noted. Recently, Brown
and Gordon (2001) reported binding of zymosan
β-glucans to the dectin-1 receptor on macrophages.
Dectin-1 is a C-type lectin with a carbohydrate
recognition domain consisting of six highly con-
served cysteine residues. It is a widely-expressed
type II transmembrane receptor on a variety of
mammalian immune cells, including neutrophils
and macrophages, initiating gene expression and
subsequent cytokine production. Dectin-1 also
binds to endogenous T-lymphocytes (Willment et
al., 2001). Brown et al. (2002) postulated that dec-
tin-1 is the major (13)-β--glucan receptor on
macrophages, and thus a major player in antifungal
immune recognition in animals, including hu-
mans—a contention that is supported by other
researchers (Herre et al., 2004). Using specifi c car-
bohydrate inhibitors, Brown et al. (2002) concluded
that neither the widely studied macrophage man-
nose receptor (MR), nor the complement receptor
3 (CR3) was the β-glucan receptor responsible for
the nonopsonic recognition of zymosan β-glucan
by primary macrophages. Recently, SPG has been
shown to bind to dectin-1 (Adachi et al., 2004), a
likely initial step in the immunomodulating and
antitumor eff ects of therapeutic products from S.
commune (Table 2).
TABLE 2. Cellular Mechanisms for (13)--D-glucan Pattern Recognition and Host
Immunomodulation
Cell surface
binding
Cell type Activity, effectors SPG
binding
Ref.
Toll-like
receptors
(TLR)-2
Macrophages,
NK cells
TNF-αno data Brown et al., 2003
Scavenger
receptors
Monocytes TNF-αno data Rice et al., 2002
Complement
receptor (CR3)
PMN,
macrophages
Upregulation of chemotaxis toward C5a,
suppression towards IL-8; priming of
inactivated iC3b receptors with deposition
onto neoplastic cells; CR3 activated by
(13)-β-D-glucans trigger killing of iC3b-
target cancer cells otherwise resistant
to cytotoxicity through potentiation of
antitumor mAb
no data Tsikitis et al., 2004;
Hong et al., 2004;
Yan et al., 1999;
Vetvicka et al., 1996;
Thorton et al., 1996
P-selectin Platelets Peripheral blood mononuclear cells (PBMC)
and polymorphonucleocytes (PMNs)
showed enhanced IL-8 production when in
the presence of platelets and SPG, and the
maximum was reached at 18 hours
Yes Suzuki et al., 2002
Dectin-1
(C-type lectin)
Dendritic
cells,
macrophages,
neutrophils
Gene expression, cytokine production
(esp. TNF-α), superoxide production by
macrophages; ITAM signaling motif
Yes Brown et al., 2003;
Adachi et al., 2004
132 International Journal of Medicinal Mushrooms
C. R. HOBBS
IMMUNOMODULATING EFFECTS
After binding to various immune cells, such as
PMNs and peripheral blood mononuclear cells,
SPG stimulates the synthesis of cytokines such as
IL-8 (Suzuki et al., 2002; Kubala et al., 2003).
Macrophage activation has been widely discussed
as being among the most important mediators of
systemic immunomodulation. Schizophyllan binds
nonselectively but specifi cally to two non-CR3
receptors on promonocytic U937 cells (Mueller et
al., 2000).
Schizophyllan (SPG) activates macrophages in
vitro and in vivo, which results in augmentation of
T-cell activities and increased sensitivity of cytotoxic
LAK and NK cells to IL-2 (Kano et al., 1996). Peri-
toneal exudate macrophages from littermate mice
activated by i.m. and i.v. administration of sizofi ran
had no eff ect in athymic mice, emphasizing the T-
cell and macrophage collaboration (Numasaki et al.,
1990). Further studies by the same group showed
other distinct T cell-activating eff ects dependent on
the collaboration, but Shimizu et al. (1991) found
that SPG did not directly activate T cells.
SPG i.m. was able to increase levels of peri-
toneal macrophages and subsequent production
of IFN-γ after one day in a group of 62 patients
with intraperitoneal recurrence of ovarian cancer
undergoing laparotomy (Chen et al., 1990). Con-
comitant administration of recombinant IFN-γ
extended the PM production and increased IL-1
production (Table 2).
Cell-Mediated Immunity
SPG administered at 2.5 mg/kg to aged immuno-
defi cient mice enhanced the Con A-induced lym-
phocyte proliferation to about 162% (Xia et al.,
1990). Lymphokine-activated killer (LAK) cells are
white blood cells (WBC) that mediate the identifi -
cation and destruction of cancer cells. SPG-induced
LAK cells in mice after sensitization from exposure
to lymphoma tumor antigen in vivo increased the
survival period over animals in a control group with
no prior SPG treatment (Kano et al., 1998).
Both SPG and carboxymethylglucan (CMG)
added to cultured human blood leukocytes acti-
vated phagocytes and lyphocytes, increasing levels
of IL-6, IL-8, TNF-α, lymphocyte CD62L, PMN
leukocyte/monocyte CD11β, and CD62L surface
receptor expression. e authors suggest that the
heightened phagocytic stimulation from SPG may
refl ect on its greater branching frequencies, polymer
charge, or varied solution conformation (Kubala et
al., 2003).
Cytokine Modulation
IL-12 and IFN-γ, but not TNF-α, production from
mouse spleen cell cultures was increased when the
mice were pretreated with SPC orally, as part of
the diet, compared with those from a control group
(p < 0.05). e levels of IFN-γ were dose dependent
(Kawaguchi et al., 2004). IL-1α and IL-1β mRNA
expression was stimulated by administration of
schizophyllan in vivo in mice (Nemoto et al.,
1993). Either single (SPG-OH) or triple helix
conformations of SPG, when administered with
cyclophosphamide to mice, could induce gene
expression of stem cell factor and colony-stimulating
factor and increase production of IL-6, compared
with mice given only cyclophosphamide (Tsuzuki
et al., 1999). Polymorphonucleocytes exposed to (10
µg/mL) SPG enhanced superoxide generation and
enhanced protein kinase C activity did not stimu-
late production of any of the cytokines measured—
interleukin-1β, -3, -4, -6; tumor necrosis factor-α;
granulocyte-macrophage colony stimulating factor;
or IFN-γ (Yoneda et al., 1991).
Exposure of murine alveolar macrophages (AM)
to IFN-γ after priming with SPG had a much
greater eff ect on cytokine and NO production than
cells exposed to either single agent, or with pretreat-
ment with SPG, than INF-γ, due to enhancement
of (13)-β--glucan binding site affi nity by INF-γ
(Sakurai et al., 1996).
Protective Effects
In bone marrow cells of mice, SPG inhibited
chromosomal damage caused by chemotherapeu-
Volume 7, Issues 1&2, 2005 133
MEDICINAL SPLITGILL FUGUS SCHIZOPHYLLUM COMMUNE
tic agents (cyclophosphamide, adriamycin, and
mitomycin C) and by radiation. e best results
against radiation damage were found when SPG
was administered shortly after or at the same time
as radiation, and SPG restored mitosis of bone
marrow cells previously suppressed by anticancer
drugs (Yang et al., 1993). Sizofi ran increased the
rate of recovery of bone marrow cells and NK
activity when administered to mice at 200 µg
i.m. after 5-FU treatment, compared with 5-FU
alone (Tsuchiya et al., 1991). Sizofi ran alone had
no eff ect.
ANTICANCER AND ANTITUMOR EFFECTS
A number of preliminary studies have shown that
SPG administered by injection can increase sur-
vival time and reduce tumor growth and metastatic
foci in squamous-cell innoculated mice, compared
with control groups given conventional treatment
alone, especially after radiotherapy (Arika et al.,
1992), with ACI/N tumor and AMC-60 fi brosar-
coma and BC-47 bladder cancer in rats (Mitani
et al., 1984) and with lymphoma-innoculated
mice after pretreatment with macrophage colony-
stimulating factor (Kakuta, 1998) or IL-2 (Kano
et al., 1996). SPG was also eff ective for reducing
tumor growth when combined with cisplatin in
chemically- induced rat ovarian adenocarcinoma
(Sugiyama et al., 1995) and when given prior to,
but not after, photodynamic therapy in mice with
squamous cell carcinoma (Krosl and Korbelik,
1994). Either one dose at 100 or 200 mg/kg or
daily injections of SPG at 20 or 50 mg/kg could
inhibit pulmonary metastasis in mice, while com-
bined therapy with cyclophosphamide signifi cantly
prolonged the survival of mice with pulmonary
metastases (Yamamoto et al., 1981). SPG admin-
istration to mice with hepatomas, either alone or in
combination with mitomycin C, led to an increased
antibody-dependent, cell- mediated cytotoxicity of
spleen cells, accompanied by increased survival time
(Oka, 1985).
Schizophyllan showed antitumor activity and
prolonged life expectancy in both solid (Tabata et
al., 1981) and ascites (Komatsu et al., 1969) forms
of Sarcoma 180 (Komatsu et al., 1969), Lewis lung
carcinoma (Yamamoto et al., 1981), and syngeneic
tumors, adenocarcinoma, and MM46 mammary
carcinoma (Matsuo et al., 1982), but not the solid
form of Sarcoma 180 or solid or ascites form of
sarcoma 37, Ehrlich carcinoma, Yoshida sarcoma in
mice, or spontaneous mammary carcinoma in Swiss
mice (Komatsu et al., 1969). Schizophyllan also in-
creased cellular immunity in mice with implanted
tumors by restoring suppressed killer-cell activity to
normal levels (Oka, 1985).
e antitumor eff ects in mice with bladder
cancer were mediated by increased production of
lysosomal enzymes by macrophages (Kinoshita,
1986); with combination IL-2 and SPG therapy in
mice, more tumor infi ltrating lymphocytes, stimula-
tion of NK cell activity, and longer survival times
were seen than with therapy alone (Ikeuchi, 1991).
Syngeneic murine tumor, adenocarcinoma, MM 46
mammary carcinoma, and sarcoma 180 inhibition
was mediated by enhanced T-cell, macrophage
functions, NK cell activity, and RES stimulation
(Matsuo et al., 1982). Miura et al. (2000) found
that administration of SPG to mice could increase
vascular permeability, TNF-α production, and
anti-sarcoma 180 antibody production in vivo and
macrophage adherence in vitro, but TNF-α pro-
duction declined when excessive doses were given
(Miura et al., 2000).
Combined administration of rIL-2 and SPG
could increase lymphocytic infi ltration, cytotoxic
T cells, NK cells, macrophages, and helper T-cells
(Kano et al., 1997) and produce a marked reduc-
tion in Lyt2+ lymphocytes and an elevation of
L3T4+ lymphocytes in mice, leading to a stronger
antitumor immune response at tumor sites (Hashi-
moto, 1994).
e demonstrated antitumor activity of SPG
against Sarcoma 180 in vivo was reversed when
the T-cell suppressor cyclosporin A was fi rst
administered, suggesting the necessity of T-cell
signaling in the antitumor eff ect (Kraus and
Franz, 1992).
Miura et al. (2000) found the cytokine production
and antitumor eff ects of SPG were dose dependent
and became inactive when administered in an exces-
sive dose.
134 International Journal of Medicinal Mushrooms
C. R. HOBBS
Protective Effects Against Chemo- and
Radiation Therapy
Sizofi ran restored cell mitosis and reduced sister
chromatid exchanges (SCEs) in bone marrow of
mice after treatment with radio- and chemotherapy
(Yang et al., 1993) and could partially protect the
NK activity of bone marrow cells in mice after treat-
ment with 5-FU (Tsuchiya et al., 1991).
Protection Against Infections
Schizophyllan could protect mice against Pseudomo-
nas aeruginosa infection, reducing bacterial growth
and increasing the bactericidal activity of the peri-
toneal exudate cells (Koike, 1976). Schizophyllan
treatment also demonstrated protective eff ects
against Pseudomonas aeruginosa, Staphylococcus aureus,
Escherichia coli, and Klebsiella pneumoniae infections
in mice (Komatsu et al., 1973).
Antiviral Effects
Preliminary studies with SPG showed a protective
eff ect against viral infections in mice, but no hu-
man studies have been performed so far. Mice with
Sendai virus infection and Kuruma shrimp with
Penaeus japonicus virus infection showed increased
survival rates and higher phagocytic activity with
i.p. and oral administration of SPG, suggesting a
protective eff ect against viral infection in animals
and invertebrates (Hotta et al., 1993; Itoh, 1998).
SPG was associated with an increased production
of IFN-γ and the proliferation of peripheral blood
mononuclear cells in blood taken from six patients
with chronic hepatitis B, compared with four con-
trols, in response to recombinant HbcAg in vitro
(Kakumu et al., 1991).
Antifungal Effects
Clinically, the question has arisen about the possibil-
ity of allergic reactions to mushroom preparations,
especially in people who may already be sensitive to
molds or yeasts such as Candida albicans. Ohno et al.
(1986) showed that schizophyllan could stimulate
the candidastatic activity of a mouse macrophage
line in vitro (Ohno et al., 1986).
Hepatoprotective Effects
ere are also indications (in vitro) that chronic
hepatitis B patients could benefi t f rom SPG, because
SPG can enhance immunological responsiveness to
the virus, particularly in IFN-γ production (Kakumu
et al., 1991).
TOXICITY AND CONTRAINDICATIONS
e idea that the (13)-β--glucans of higher
fungi, being similar to ones found in bacteria, molds,
yeasts, and other potential human pathogens, yet
with minimal potential for causing infections in
themselves, and so might be taken safely as immu-
noadjuvants is appealing. Cooking mushrooms to
make extracts further reduces any harmful potential,
as does using purifi ed mushroom isolates, similar to
the idea of giving a vaccination with an attenuated
virus or a viral protein with the idea of conferring
immunity against the pathogen.
While ingesting crude fungal extracts or fungal
compounds does not seem to be a potential health
hazard in itself, Schizophyllum commune (and other
species, such as Lentinus edodes), are known to cause
a variety of health problems in some individuals
who inhale the spores. Among the disease condi-
tions caused by the spores of S. commune, the medical
literature documents a case of pulmonary infection
that disseminated to the brain of a 58-year-old man
in Pittsburgh. After weeks of misdiagnosis and mis-
treatment with immunosuppressing corticosteroids,
cultures of lung tissue fi nally revealed S. commune.
However, antibacterial and antifungal agents were
of no avail, and the patient died from progressive
pulmonary failure and bacterial pneumonia (Rihs
et al., 1996).
Researchers suspect that S. commune may be
an emerging pathogen, because there have been
an increasing number of reports of illness traced
Volume 7, Issues 1&2, 2005 135
MEDICINAL SPLITGILL FUGUS SCHIZOPHYLLUM COMMUNE
to the fungus (Lacaz et al., 1996). ese include
chronic lung disorder, sinusitis with chronic and
acute infl ammation (Rihs et al., 1996) even in im-
munocompetent persons (Shaw et al., 2000), allergic
fungal sinusitis (Clark et al., 1996), allergic broncho-
pulmonary mycosis (Kamei et al., 1994), bronchial
asthma (Kawano et al., 2003), atypical meningitis,
and onychomycosis of the toenails (Rihs et al., 1996).
In the case of sinusitis, treatment with the antifungal
agent intraconazol appears to be eff ective (Sigler et
al., 1997).
No changes in hepatic enzymes, such as ami-
nopyrine, N-demethylase (APD), and aniline hy-
droxylase, and in cytochrome P-450 could be seen
in rats given a single dose of SPG i.v. at 0.5 or 10
mg/kg, or subcutaneous treatment of animals with
either 10 or 40 mg/kg dose for 3 and 6 months.
APD activity was decreased by 34% at 200 mg/kg
(Tanji et al., 1990b). However, when four repeated
doses of SPG were given to rats at 3 mg/kg every
12 hours, hepatic cytochrome P-450 content and
the activities of aminopyrine N-demethylase and
aniline hydroxylase were depressed (Yomogida et
al., 1989).
Morita and Ueda (2002) report on the possible
triggering of Graves disease in a single patient,
possibly through activation of proinfl ammatory
cytokines.
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... It grows on the dead, fallen, or standing wood of broadleaved trees. Its characteristic is dense white hairs, no stalks, and pale yellow to brown gills (Hobbs, 2005). Cell wall composition is composed of β-glucans cross-linked with chitin (Leung et al., 2006), and the conformation of β-glucans in the mushroom (schizophyllan) is a triple-stranded helix. ...
... Furthermore, there are significant nutritional values, incredibly high fiber, protein, and low lipid (Hobbs, 2005), including phenolic compounds in its ethanolic extract (Yelithao et al., 2019;Saetang et al., 2022c). It is a medicinal mushroom with various biological properties (Klaus et al., 2011), for instance, antioxidant, anti-inflammatory, immune-enhancing, anticancer (Chandrawanshi et al., 2017Du et al., 2017;Smirnou et al., 2017;Yelithao et al., 2019;Lee and Ki, 2020), antiviral and antifungal properties (Hobbs, 2005). ...
... Furthermore, there are significant nutritional values, incredibly high fiber, protein, and low lipid (Hobbs, 2005), including phenolic compounds in its ethanolic extract (Yelithao et al., 2019;Saetang et al., 2022c). It is a medicinal mushroom with various biological properties (Klaus et al., 2011), for instance, antioxidant, anti-inflammatory, immune-enhancing, anticancer (Chandrawanshi et al., 2017Du et al., 2017;Smirnou et al., 2017;Yelithao et al., 2019;Lee and Ki, 2020), antiviral and antifungal properties (Hobbs, 2005). In addition, the schizophyllan plays the leading role in preventing oxidative damage in the human body against free radicals (Yelithao et al., 2019). ...
Article
The nutritional value of routinely used synthetic antioxidants is being reemphasized in today's preventative medicine and food sector. The split gill mushroom is a pharmaceutical mushroom distinguished by its high nutritional content and biological activity. It contains schizophyllan and a polysaccharide made up of β-glucan. The β-glucan has a significant level of antioxidant activity. Therefore, this is an investigation into producing split gill mushroom essence rich in bioactive components. This study examined the total phenolic content and antioxidant capacity (radical scavenging activity) of the schizophyllan (the hot water combined with ethanolic extraction of polysaccharide), supernatant from the separation of the extraction of the polysaccharide, and the mushroom essence (the production of split gill mushroom essence steamed in an electric pressure cooker). From this research, split gill mushroom essence (using an electric pressure cooker) showed more great total phenolic content (14.07 mg of gallic acid equivalent [GAE]/g of dry extract) compared to the supernatant and ethanolic schizophyllan (12.85 and 6.22 mg of GAE/g of dry extract). Furthermore, this mushroom essence revealed more potential for antioxidant activity (IC50 value) for inhibition of free radical (0.73 mg of dry extract/ml), compared to other extracts (IC50 values of the supernatant and the schizophyllan extract as 0.76 and 2.64 mg of dry extract/ml). Therefore, split gill mushroom essence is probably developed as an innovative antioxidant functional food product with beneficial compounds to human health.
... This mushroom grows on a broadleaved tree, dead, fallen, or standing wood. It is distinguished by light yellow to brown gills, dense white hairs, and the absence of stalks [5]. The mushroom composes of β-glucans cross-linked with chitin in its cell wall [6]. ...
... Additionally, this mushroom contains peptides formed during protein hydrolysis by a protease enzyme that exhibits antioxidant properties [13], hydrophobin protein with anticancer activity in S180 mouse sarcoma and B16-F10 mouse melanoma [14], lectin protein with inhibition of cancer cell growth and proliferation [15], both hydrophobin and lectin protein via possibly immunomodulatory [14,16], and schizolysin (hemolysin) with antiviral activity due to inhibition of HIV-1 reverse transcriptase [15]. Besides, this mushroom is abundant schizophyllan, which is distinguished by a variety of biological properties [8], for instance, antioxidant [4,17], anti-inflammatory [7,18], immunomodulatory in immune cells from whole human blood [19] and macrophage cells [4], anticancer activity in lung, gastric, cervical, breast carcinoma cells [20] and tumor-bearing mouse [21], antiviral, antifungal [5], along with prebiotic properties [22]. ...
... Aside from that, β-glucan has a critical role in protecting the body from the oxidative damage caused by free radicals [4]. As a result, the mushroom is used in a wide variety of industrial applications, including pharmaceuticals [7], vaccines, cosmetics, functional food [19][20][21], and traditional food widely in Southeast Asia and India [5]. In addition, β-glucan is a prebiotic oligosaccharide or polysaccharide indigestible in the human digestive system [23]. ...
Article
Full-text available
Schizophyllum commune or split gill mushroom is a pharmaceutical mushroom. Its cell wall contains abundant schizophyllan (β-glucan or polysaccharide from S. commune) distinguished by various biological activities. This experiment focused on studying the optimized ethanol precipitation process of the schizophyllan on the maximum degree of polymerization (DP), highest total sugar, and optimal reducing sugar concentration using response surface methodology (RSM) on central composite design (CCD). The experimental design examined the factors, including the split gill mushroom content (5–15% w/v) and ethanol concentration (49–74% v/v). From this experiment, it could be concluded that the optimized condition of this cost-effective extraction was the low mushroom content 5–8% (w/v) and optimal ethanol concentration 62–65% (v/v) with the highest DP value around 5, along with efficient immunomodulatory and anticancer effects. Thus, further research will develop the pharmaceutical schizophyllan extract as nutraceutical products or drugs.
... This mushroom grows on a broadleaved tree, dead, fallen, or standing wood. It is distinguished by light yellow to brown gills, dense white hairs, and the absence of stalks [4]. The fruiting body is small and fan-shaped with a white spore. ...
... Furthermore, the split gill mushroom is a medicinal mushroom [8] with a variety of nutritional values, including higher phosphorus, magnesium, calcium, iron, zinc, manganese, copper, and chromium, as well as high carbohydrate, fiber, protein, and low lipid, as well as various mineral components, such as higher phosphorus, magnesium, calcium, iron, zinc, manganese, copper, and chromium [4,9]. This mushroom is abundant in schizophyllan, which is distinguished by a variety of biological properties [8], for instance, antioxidant [3,5], anti-inflammatory [7,10], immunomodulatory [3,11], anticancer activity [12,13], antiviral, and antifungal [4], along with prebiotic properties [14]. ...
... Furthermore, the split gill mushroom is a medicinal mushroom [8] with a variety of nutritional values, including higher phosphorus, magnesium, calcium, iron, zinc, manganese, copper, and chromium, as well as high carbohydrate, fiber, protein, and low lipid, as well as various mineral components, such as higher phosphorus, magnesium, calcium, iron, zinc, manganese, copper, and chromium [4,9]. This mushroom is abundant in schizophyllan, which is distinguished by a variety of biological properties [8], for instance, antioxidant [3,5], anti-inflammatory [7,10], immunomodulatory [3,11], anticancer activity [12,13], antiviral, and antifungal [4], along with prebiotic properties [14]. As a result, the mushroom is used in a wide variety of industrial applications, including pharmaceuticals [7], vaccines, cosmetic, functional food [11][12][13], and traditional food widely in Southeast Asia and India [4]. ...
Article
Full-text available
The split gill mushroom or Schizophyllum commune (S. commune) is a therapeutic mushroom. For cell wall composition, it consists of rich β-glucans (schizophyllan). This mushroom is high in nutritional content and has a wide range of biological properties. In this research, it is interesting to study hot water extraction of this functional schizophyllan. Central composite design (CCD) of response surface methodology (RSM) was applied to optimize these extraction parameters, namely, temperature (80-121 °C) and time (1-3 h) of schizophyllan extract (polysaccharide from S. commune) with a greater degree of polymerization (DP), maximum total sugar content, minimum reducing sugar content, and appropriate extraction yield. The results revealed the highest yield obtained from polysaccharide and supernatant extract (from the separation of poly-saccharide extraction) at an extraction temperature of 121 °C for 2-3 h. Moreover, the optimal extraction temperature and time of polysaccharide extracts were 106.5 °C and 126.7 min (total sugar content); 103.1 °C and 177.0 min (reducing sugar content); and 104.1 °C and 175.5 min (DP value). This research shows that the optimum condition of schizophyllan extraction was around 100-110 °C for 2-3 h with the highest DP of about 6, including potential immune-enhancing and anticancer properties. As a result, the schizophyllan from the split gill mushroom is probably utilized as a functional ingredient with nutraceutical compounds and developed as other high value-added functional food products in further study.
... Trametes versicolor (L.) Lloyd and β-(1-6) -d-glucan from A. subrufescens (Ikekawa et al. 2001;Hobbs et al. 2005;Angeli et al. 2009;Yao et al. 2011;Ziaja-Sołtys et al. 2020). Studies on fungal polysaccharides at this concern are mostly focused on their immunomodulant properties (Chakraborty et al. 2019); lentinan in particular is a model since it stimulates immune response and it is also applied in creams for external use (Bisen et al. 2010). ...
Chapter
Medicinal mushrooms are a rich source of bioactive molecules, nutraceutic products, as well as natural co-formulants and excipients. The fungal cell wall is rich in branched polysaccharides (mainly β-glucans), peptidic residues, and chitin or chitosan. A plethora of secondary metabolites with current or potential application includes e.g. terpenoids, polyketides, ceramides, polyphenolics, l-ergothioneine and others. Mushroom application in cosmeticsCosmetics has been explored for a few decades only, but the increasing demand for bio-based products has stimulated this research field. Strategies against skinSkin aging are the main target of cosmeticCosmetics and cosmeceutic applications. Based on an integrated approach that pursues psycho-physical wellness, Systemic Aesthetic MedicineSystemic aesthetic medicine focuses on both external (creams, lotions) and internal (foodFoods supplements) uses of fungal molecules and extracts, besides the introduction in the diet of bulk fungal biomass (nutritional strategy). Far beyond the pure cosmetology, Systemic Aesthetic MedicineSystemic aesthetic medicine in fact focuses on prevention and treatment of skinSkin diseases and cutaneous symptoms. Main properties reported from mushrooms at this concern include: hydration, anti-oxidant, acceleration of skinSkin cells turnover, stimulation of skinSkin bio-reparation, antiseptic, and immunomodulant.
... It grows on the broadleaved trees, standing, dead, or fallen woods. Its characteristic has pale yellow to brown gills, dense white hairs, and an absence of stalks (Hobbs, 2005). Additionally, this mushroom is a medicinal mushroom (Klaus et al., 2011) with abundant nutritional values, especially in terms of high carbohydrate, protein, and low lipid (Basso et al., 2020). ...
Conference Paper
Schizophyllum commune (split gill mushroom) is the alternative protein source. This mushroom comprises of nutritive mycoprotein (mushroom protein) with essential amino acids, including pharmaceutical schizophyllan (β-glucan), and so on. It also has plentiful nutritional values and various biological properties. This research focused on studying the influence of hot water treatment on this alternative mycoprotein. The factorial experiment in complete randomized design (CRD) was applied to investigate these response variables, namely temperature (80-121°C) and time (1-3 hr) of hot water extraction of mycoprotein. This experiment noticed that the maximum protein content (10.47 mg/g extract) was obtained from 80°C and 1 hr extraction temperatures. However, in order to extract the schizophyllan with biologically pharmaceutical activities, the optimized extraction conditions of the polysaccharide extracts were around 100°C for 2 hr with the highest degree of polymerization (DP value about 6), along with immunomodulatory and anticancer properties. However, the protein content of this extract was not greater (7.10 mg/g extract) due to the denaturation of some protein at a higher extraction temperature. Therefore, the actual commercial extraction of bioactive mycoprotein should consider both lower extraction temperature to sustain this mycoprotein's nutritional and pharmaceutical values, including the optimal yield of the protein extract. Additionally, the mycoprotein extract from S. commune is probably utilized as an alternative protein ingredient in functional food, snack or beverage products in further study.
Chapter
Mushrooms are among the few natural products that have been relied upon for prophylactic and therapeutic applications in human diseases. They have been referred to as forest gems since they can be picked in the wild or better domesticated for appropriate use. Several scientific studies have been conducted to establish claimed potentials or further probe new areas into which mushrooms can find application. Many disciplines, including mycology, microbiology, physiology, chemistry, genetics, and medicine, among others, conduct research on mushrooms. These enable broad and in-depth studies of mushrooms, to include in vitro and in vivo demonstrations of their bioactivity, structural characterization, and isolation of bioactive components. This chapter highlights the bioactive composition of mushrooms by relating structure to bioactivity and demonstrating therapeutic effects on some human diseases using existing literature. The potentials of mushrooms or their products for the treatment or management of diseases, such as tropical illnesses and COVID-19 pandemic, among other issues, have been discussed. Chemistry of bioactive compounds, structure–activity relationships, patents, and analyses of data obtained have been reported and studied for interpretation of results.
Chapter
The survival of Homo sapiens is continually under threat from agencies capable of inflicting calamitous damage to the overall health and well-being of humankind. One strategy aimed at combatting this threat is focused on medicinal mushrooms and derivatives thereof. Mushrooms themselves have been consumed as part of the human diet for centuries, whereas 'mushroom nutriceuticals' is a more recently adopted term describing mushroom-derived products taken as dietary supplements to enhance general health and fitness. Among the most extensively studied pharmacologically active components of mushrooms are polysaccharides and polysaccharide-protein complexes, triterpenes, lectins, and fungal immunomodulatory proteins. Medicinal mushrooms have been credited with a wide range of therapeutic properties including antitumour/anti-cancer, antioxidant, hepatoprotective, anti-diabetic, antimicrobial, cholesterol-lowering and genoprotective activities as well as protection against atherosclerosis, cardiovascular, chronic inflammatory and autoimmune diseases, and neurodegenerative conditions. This review examines the past, present and future of medicinal mushroom development including the two legs concept for the mushroom industry and the pyramid model summarizing the various human applications of mushrooms. It considers numerous issues the industry needs to address to exploit fully the opportunities presented by the continued increasing demand for medicinal mushrooms, and by the future overall expansion of the medicinal mushroom movement.
Book
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Coffee agroecosystems are a farmer-designed environment, which designed by the producers, and they are postulated as a biodiversity reservoir of the original forest, as many species that once used to live in the forest remain in the coffee plantation, including wild mushrooms. Fungi are sensitive to the use of agrochemicals that favour coffee cultivation, their diversity and productivity decrease if their habitat is drastically modified. The presence of fungi is an indicator of good practices. The following is information on seven edible species that were the most common species that inhabit coffee plantations in the central region of Veracruz. Morphological descriptions are provided, photographs and a brief review of their nutraceutical* properties, i.e. nutraceutical* properties*, i.e. they have a beneficial effect on human health. At the end of the book a section of recommendations for increasing the natural production of edible mushrooms on coffee farms. In addition to recipes to prepare them, and a glossary of terms that define some technical terms that help to distinguish the species and their species and their technical studies
Book
Since the publication of the first edition, important developments have emerged in modern mushroom biology and world mushroom production and products. The relationship of mushrooms with human welfare and the environment, medicinal properties of mushrooms, and the global marketing value of mushrooms and their products have all garnered great attention, identifying the need for an updated, authoritative reference. Mushrooms: Cultivation, Nutritional Value, Medicinal Effect, and Environmental Impact, Second Edition presents the latest cultivation and biotechnological advances that contribute to the modernization of mushroom farming and the mushroom industry. It describes the individual steps of the complex mushroom cultivation process, along with comprehensive coverage of mushroom breeding, efficient cultivation practices, nutritional value, medicinal utility, and environmental impact. Maintaining the format, organization, and focus of the previous edition, this thoroughly revised edition includes the most recent research findings and many new references. It features new chapters on medicinal mushrooms and the effects of pests and diseases on mushroom cultivation. There are also updated chapters on specific edible mushrooms, and an expanded chapter on technology and mushrooms. Rather than providing an encyclopedic review, this book emphasizes worldwide trends and developments in mushroom biology from an international perspective. It takes an interdisciplinary approach that will appeal to industrial and medical mycologists, mushroom growers, botanists, plant pathologists, and professionals and scientists in related fields. This book illustrates that mushroom cultivation has and will continue to have a positive global impact on long-term food nutrition, health care, environmental conservation and regeneration, and economic and social change.
Article
Antitumor activities and effects on cellular immunity of Schizophyllan (SPG), a highly purified polysaccharide extracted from the culture filtrate of Schizophyllum commune Fries, and Bestatin (NK-421), an inhibitor of aminopeptidase B discovered in the culture broth of Streptomyces olivoreticuli, were investigated. The optimal dose of SPG monotherapy to manifest an antitumor effect on MH-134 hepatomas transplanted into C3H/He mice was 10mg/kg, both intraperitoneally (i.p.) and subcutaneously (S.C.). The optimal timing of SPG monotherapy was observed in the group which was treated from 1 day after tumor transplantation, resulting in the most prolonged mean survival (MS) and the highest survival rate. In combined therapy with SPG and mitomycin C (MMC), the most prolonged MS was observed in the group which was treated with MMC on day 3 after tumor transplantation and combined with SPG from day 5. Moreover, the effectiveness continued when the same combined therapy was conducted after the removal of transplanted tumors. The highest ADCC activity by spleen cells harvested from the mice in the SPG monotherapy group was obtained on day 12 after tumor transplantation. The ADCC activity tended to become lower in the MMC monotherapy group, but in the combined therapy group with optimal timing, the highest ADCC activity mediated by non-adherent cells was observed on day 14 after tumor transplantation. Suppressed NK cell activity in tumor-bearing mice was increased to normal levels by SPG monotherapy. On the other hand, NK 421 monotherapy did not manifest a satisfactory antitumor effect regarding survival rate, although it potentiated ADCC activity over a wide range of doses, particularly 5 and 10mg/kg. The main cellular component exhibiting ADCC activity induced by NK 421 therapy seemed to be non-T-cells. By NK-421 monotherapy, the suppressed NK cell activity in tumor-bearing mice was restored up to the normal level.
Article
The anti-tumor effect of the combination of sizofiran (SPG) and macrophage colony-stimulating factor (M-CSF) was studied in C 57 BL/6 mice intraperitoneally inoculated with the syngeneic tumor, EL-4 lymphoma. The effect was evaluated by examining the survival time (1), Giemsa-stained specimens (2), surface markers of peritoneal exudative cells (3), the cytotoxic effect of these cells on autologous tumor and Yac-1 lymphoma (4), and the cytokines in ascites (5). The results showed (1) significant prolongation of the survival time, (2) reduction in the number of lymphoma cells in Giemsa-stained specimens, (3) increase in the number of anti-tumor effector cells, (4) increased cytotoxic action of peritoneal exudative cells on autologous tumor and the NK (natural killer) activity, and (5) increased concentrations of TNF-α, IL-6 and IL-1 β in the mice given both SPG and M- CSF, as compared with either single administration. These results demonstrated the effectiveness of a combination of SPG and M-CSF in treating EL-4 lymphoma.
Article
The culture product of Suehirotake (Schizophyllum commune Fries) mycelium (SCP) is supposed to stimulate cellular immunity. In fact, Schizophyllan (β-1,6-branched β-1,3-glucan) contained in SCP has anti-tumor activity. In the present study, we investigated the effects of SCP feeding on cytokine production in mice in order to clarify the immunological effects of SCP as a dietary component. The levels of interleukin (IL)-12 and interferon (IFN)-γ produced in the culture supernatant of spleen cells from SCP-fed mice were significantly high compared to those in control group (P < 0.05). Furthermore, the level of IFN-γ was dependent on the dose of SCP. The level of tumor necrosis factor (TNF)-α was not changed by SCP-feeding. These results suggest that SCP could be useful food with immunomodulating activities by promoting Th 1 immune response via oral route.
Article
Effect of schizophyllan (SPG), a simple glucan produced bySchizophyllumcommune, and other immunostimulants on candidastatic activity of murine macrophage cell line J774.1 was examinedin vitro. The J774.1 cells treated with each immunostimulant were seeded in 96-multiwell tissue culture plates and infected with serially (2-fold) dilutedCandida parapsilosiscells. Fungistatic index (FI) was estimated after 24 hours incubation. (1) When J774.1 cells were cultivated in the presence of SPG at the concentrations of 10⁻⁴-10²μg/ml, the candidastatic activity proved to be augmented, showing diphasic pattern. The first peak was observed at one hour cultivation (FI: 2.5-9.0), and the second between 24 and 72 hours (FI: 2.12-7.25) . (2) In the case of LPS, increase of candidastatic activity (FI: 4-8) was recognized after one hour cultivation at the concentrations of 10⁻⁵-10⁻¹μg/ml, and maintained for 24 hours. (3) The activation of macrophage with krestin (FI: 4-32) could be observed at the higher concentrations (10-500μg/ml) . (4) Lentinan showed weak activation (FI: 2-4) at the concentrations of 10⁻¹-10⁻³μg/ml after 24 hours cultivation. (5) Corynebacterium parvum, BCG-CWS and picibanil activated J774.1 cells at the very narrow range of concentrations after 48 hours cultivation. (6) No enhancement of candidastatic activity could be detected in the cases of lipid A, MDP, MDP-Lys (L18), DMG and levamisole.
Article
We have already demonstrated that various activities including NO (nitric oxide) synthesis in vivo were significantly different between triple helical (SPG) and single helical (alkaline-treated SPG, SPG-OH) beta-glucans, and that beta-glucan-mediated NO synthesis was associated with increased gene expression of IFN-gamma. In this study, we analyzed beta-glucan-mediated NO production in vitro with the concomitant use of IFN-gamma. Proteose peptone-elicited peritoneal macrophages (PM) were collected from male C3H/HeJ mice and cultured with beta-glucans in the presence or absence of IFN-gamma for 24 h. It was found that SPG-OH, but not SPG, enhanced NO synthesis in vitro, especially in the presence of IFN-gamma. Concentrations of interleukin-1 alpha, -6 and TNF-alpha in the culture supernatant of SPG-OH were significantly higher than those in that of SPG. Membrane-associated IL-1 alpha was also high with SPG-OH. Cytokine productivity of PMs, as well as NO synthesis, was elevated in the presence of IFN-gamma. These facts intensely suggest that the single helical conformer of beta-glucan (SPG-OH) is dominant in cytokine production and subsequent NO synthesis.
Article
The immunologic characteristics of a glucan, sizofiran (formerly referred to as schizophyllan), were investigated by determining its effect on various parameters of immune responses in normal, T cell-deficient or Ehrlich ascites fluid-treated mice. Peritoneal exudate macrophages were rendered cytotoxicity to tumorigenic targets by i.m. and i.v. administration of sizofiran to normal and littermate nu/+ mice but sizofiran was without effect in athymic nu/nu and neonatal thymectomized mice. These results suggest that the collaboration between T cells and macrophages take part in the antitumor activity of sizofiran. In normal mice, moreover, sizofiran augmented alloreactive cytotoxic T lymphocyte generation and lymphoblastogenesis but suppressed production of antibodies against sheep red blood cells and decreased helper T cell activity. Sizofiran prevented and restored the suppression of immune responses such as alloreactive cytotoxic T lymphocyte induction, lymphoblastogenesis, antibody production and helper T cell development in mice treated with Ehrlich ascites fluid. Thus, it is concluded that sizofiran has a distinct property as a T cell adjuvant and it is also suggested that collaborative T lymphocytes and macrophages play an important role in the mechanism of antitumor action of sizofiran.
Article
Purified schizophyllan (SPG), which was not labeled with radioactive isotopes, was administered intraperitoneally or intramuscularly to female mice of the ICR and DBA strains every third day from the 13th day after sarcoma-180 inoculation to the 28th day. Four days after the last SPG administration, 400 µCi/head of ³H-SPG was injected intravenously. The liver, spleen, bone marrow, lymph nodes, thymus, and tumor were studied with whole-body, microscope, and electron microscope (EM) autoradiography I ARG). Anesthetized animals were used for whole-body ARG after tissue pieces were removed and fixed for micro-ARG and EM-ARG. In whole-body ARG, ³H-SPG was mainly accumulated in the liver, spleen, lymph nodes, thymus, bone marrow, and a capsular belt area of the tumor. In the tumor capsular belt area, a very strong accumulation was observed in ICR mice, but the accumulation was very weak in DBA mice. In micro-ARG, ³H-SPG was incorporated in the reticuloendothelial cells; Kupffer's cells in the liver, and reticulum cells and macrophages in the spleen, bone marrow, lymph nodes, and thymus. A large number of macrophages in the tumor capsular belt area were observed migrating between the tumor cells and ³H-SPG was strongly incorporated in their cytoplasm in ICR mice. But only a few macrophages were observed there in DBA mice. In EM-ARG, ³H-SPG was accumulated in special lysosomal granules in the reticuloendothelial cells, including Kupffer's cells and macrophages. The special granules were enveloped with a limiting membrane, and were composed of a compact fine filamentous substance and an electron opaque lysosomal cap structure (filamentous ball, Fb). The nature of these fine Fbs was exactly the same as that of SPG macromolecules observed in the negatively stained samples. There were no great differences on the observations by ARG and histology between the SPG-treated ICR and DBA mice, except in the tumor region. A large number of macrophages with many intracytoplasmic Fbs were migrating into the sarcoma nest in the capsular area, and many sarcoma cells were rapidly degenerating or had disappeared in the SPG-treated ICR mice. In DBA mice, however, there were no significant changes in the cancer nests; the cancer cells were growing and increasing rapidly, and the animals died within a month. These autoradiographic data suggest that the SPG granules (Fbs) containing activated macrophages in the ICR tumor nests play an important role in destroying the growing sarcoma cells, but there was no evidence of active macrophages in the DBA sarcoma nests. The Fbs in the macrophages in ICR mice probably produce a large amount of various lysosomal enzymes and act as activators of the destruction of sarcoma cells, but did not act in DBA mice. The reason for such a big difference between the two mouse strains was not clear, but some immunogenomic factors could be concerned. © 1985, JAPAN SOCIETY OF HISTOCHEMISTRY AND CYTOCHEMISTRY. All rights reserved.