Immune Fx
References and Research Articles
GRIFOLA FRONDOSA (MAITAKE)
Mushrooms,
tumors, and immunity.
Borchers AT, Stern JS, Hackman RM, Keen CL, Gershwin
ME, Division of Rheumatology/Allergy and Clinical Immunology,
University of California at Davis School of Medicine,
Davis, California 95616-8660, USA.
Medicinal properties have been attributed to mushrooms
for thousands of years. Mushroom extracts are widely
sold as nutritional supplements and touted as beneficial
for health. Yet, there has not been a critical review
attempting to integrate their nutraceutical potential
with basic science. Relatively few studies are available
on the biologic effects of mushroom consumption, and
those have been performed exclusively in murine models.
In this paper, we review existing data on the mechanism
of whole mushrooms and isolated mushroom compounds,
in particular (1-->3)-beta-D-glucans, and the means
by which they modulate the immune system and potentially
exert tumor-inhibitory effects. We believe that the
antitumor mechanisms of several species of whole mushrooms
as well as of polysaccharides isolated from Lentinus
edodes, Schizophyllum commune, Grifola frondosa, and
Sclerotinia sclerotiorum are mediated largely by T cells
and macrophages. Despite the structural and functional
similarities of these glucans, they differ in their
effectiveness against specific tumors and in their ability
to elicit various cellular responses, particularly cytokine
expression and production. Unfortunately, our data base
on the involvement of these important mediators is still
rather limited, as are studies concerning the molecular
mechanisms of the interactions of glucans with their
target cells. As long as it remains unclear what receptors
are involved in, and what downstream events are triggered
by, the binding of these glucans to their target cells,
it will be difficult to make further progress in understanding
not only their antitumor mechanisms but also their other
biological activities.
Relationship between dendritic cells and the D-fraction-induced
Th-1 dominant response in BALB/c tumor-bearing mice.
Harada N, Kodama N, Nanba H., Cancer Lett 2003 Mar 31;192(2):181-7
Dendritic cells (DCs) are known to not only induce
the activation of T cells, but are also associated with
the differentiation of T cells. The D-fraction, a beta-glucan
extracted from maitake (Grifola frondosa) which expresses
anti-tumor effects by establishing a helper (Th)-1 dominance
in BALB/c mice, enhanced IL-12p70 production by DCs,
when the ratio of CD8alpha(+) DCs to CD8alpha(-) DCs
increased. In addition, examination of the tumor rejection
effect of D-fraction-stimulated DCs loaded with tumor
antigen revealed that tumor growth is inhibited completely
by activating CD4(+) T cells and CD8(+) T cells.
PMID: 12668282 [PubMed - in process]
Effect of beta-glucans on the nitric oxide synthesis
by peritoneal macrophage in mice.
Ohno N, Egawa Y, Hashimoto T, Adachi Y, Yadomae T School
of Pharmacy, Tokyo University Pharmacy and Life Science,
Japan.
ICR mice were treated with a carcinogen, N-butyl-N'-butanolnitrosoamine
BBN), every day for 8 consecutive weeks and the effects
of oral administration of edible mushrooms on the induction
of urinary bladder carcinoma and on the activities of
macrophages and lymphocytes were studied. Bladder carcinoma
were found in all 10 mice (100%) treated with BBN alone,
while we observed carcinoma only in 9 of 17 mice (52.9%),
in 7 of 15 mice (46.7%) and 13 of 20 mice (65.0%) treated
with Lentinus edodes, Grifola frondosa and Pleurotus
ostreatus, respectively. Chemotactic activity of macrophages
was suppressed in mice treated with BBN alone but maintained
almost the normal level in mice treated with BBN plus
Lentinus, Grifola or Pleurotus. Lymphocytes collected
from mice treated with BBN plus each mushroom showed
almost normal blastogenic response against concanavalin
A, although those from mice treated with BBN alone completely
retarded their response. Cytotoxic activity of lymphocytes
against Yac-1 cells was also maintained at a normal
level in mice treated with BBN plus each mushroom. Whereas
in mice treated with BBN alone significant depression
of NK cell activity occurred. Significantly higher cytotoxic
activity against P-815 cells was observed in lymphocytes
from mice treated with BBN plus each mushroom than that
in lymphocytes from normal mice or mice treated with
BBN alone.
Functional properties of edible mushrooms.
Chang R Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA.
Edible mushrooms such as shiitake may have important salutary effects on health or even
in treating disease. A mushroom characteristically contains many different bioactive compounds
with diverse biological activity, and the content and bioactivity of these compounds depend
on how the mushroom is prepared and consumed. It is estimated that approximately 50% of
the annual 5 million metric tons of cultivated edible mushrooms contain functional "nutraceutical" or
medicinal properties. In order of decreasing cultivated tonnage, Lentinus (shiitake), Pleurotus
(oyster), Auricularia (mu-er), Flammulina (enokitake), Tremella (yin-er), Hericium, and
Grifola (maitake) mushrooms have various degrees of immunomodulatory, lipid-lowering, antitumor,
and other beneficial or therapeutic health effects without any significant toxicity. Although
the data for this functional food class are not as strong as those for other functional
foods such as cruciferous vegetables, because of their potential usefulness in preventing
or treating serious health conditions such as cancer, acquired immune deficiency syndrome
(AIDS), and hypercholesterolemia, functional mushrooms deserve further serious investigation.
Additionally, there is a need for epidemiological evidence of the role of this functional
food class.
Structure-activity relationship of (1-->3)-beta-D-glucans in the induction of cytokine
production from macrophages, in vitro.
Okazaki M, Adachi Y, Ohno N, Yadomae T, Laboratory of Immunopharmacology of Microbial Products
School of Pharmacy, Tokyo University of Pharmacy and Life Science, Japan.
In a previous study, we reported that one of the gel-forming (1-->3)-beta-D-glucans,
grifolan (from Grifola frondosa, GRN), stimulated cytokine production from macrophages in
vitro. However, several other gel-forming (1-->3)-beta-D-glucans, such as sonifilan (SPG)
and SSG, did not induce cytokine production from macrophages. The ultrastructure of gel-forming
(1-->3)-beta-D-glucans, especially the triple- and single-helix, does not affect the
cytokine-inducing activity. The action on tumor necrosis factor alpha (TNF alpha) release
was correlated with the molecular weight of GRN, since the highest molecular weight fraction
of GRN, Mr > or = 45000, exhibited the strongest activity. Although, native SSG (Mr > or
= 2000000) did not induce cytokine production, chemical modification involving debranching
of the side chain glucosyl residues of SSG resulted in TNF alpha inducing activity. These
results suggest that the branching ratio and molecular weight of (1-->3)-beta-D-glucans
are important factors for the production of cytokines from macrophages. GRN-inducible TNF
alpha release was reduced by co-culturing with SPG, SSG, or the soluble beta-glucan, laminarin
(LAM). Pretreatment alone with SPG or LAM was not sufficient for significant inhibition
of GRN-inducible TNF alpha release. TNF alpha production induced with 50 micrograms/ml of
zymosan (ZyM) was also reduced by addition of SPG, but TNF alpha production, stimulated
with a higher concentration (100 micrograms/ml) of ZyM or with lipopolysaccharide (LPS),
was not reduced significantly. The inhibitory effect of LAM on the uptake of GRN by RAW264.7
cells was not completely correlated with TNF alpha release. These results suggest that macrophages
may incorporate beta-glucans through certain (1-->3)-beta-D-glucan-specific mechanisms
and/or other endocytosis pathways, and that the beta-glucan-specific route is partially
associated with cytokine production. In conclusion, TNF alpha release by macrophages is
induced only by beta-glucans with high molecular weights and lower branching ratios, and
the mechanism for the recognition of beta-glucans is multiple and assumed to be divided
into several parts involving various cellular functions.
Enhancement of cytokine production by macrophages stimulated with (1-->3)-beta-D-glucan,
grifolan (GRN), isolated from Grifola frondosa.
Adachi Y, Okazaki M, Ohno N, Yadomae T, Laboratory of Immunopharmacology of Microbial Products,
Tokyo University of Pharmacy and Life Science, Japan.
The ability of grifolan (GRN), a purified fungal (1-->3)-beta-D-glucan, to induce various
cytokines from macrophages was examined in vitro. Interleukin-6 (IL-6) activity in supernatants
from the culture of macrophage cell line, RAW264.7 was dependent on increasing doses of
GRN. The level of IL-6 induced with 500 micrograms/ml of GRN was comparable to that induced
with lipopolysaccharide (LPS) 10 micrograms/ml. Enhancement of the mRNA level of IL-6 by
treatment with GRN was detected by reverse transcriptase-polymerase chain reaction (RT-PCR).
The effect of GRN on production of IL-6 was also observed using peritoneal macrophages from
C3H/HeJ mice which did not respond to endotoxins. This data suggested that the ability of
GRN to activate IL-6 production of macrophages is not due to contamination of endotoxins
in the preparation. Enhanced production of cytokine by GRN was observed not only with IL-6,
but also with interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha). In the production
of TNF alpha, GRN was more effective than LPS used in this study. Other soluble or gel-forming
(1-->3)-beta-D-glucans from various sources did not enhance the production of such cytokines
although they are structurally similar to GRN. The above results indicate that GRN is a
novel macrophage activator which augments cytokine production without dependence on endotoxins.
Anti-diabetic activity present in the fruit body of Grifola frondosa (Maitake).
Kubo K, Aoki H, Nanba H, Yukiguni Maitake Co., Ltd. Niigata, Japan.
[Article in Chinese] Yang DA, Li SQ, Li XT, General Hospital of Jinan Unit of People's Liberation
Army.
The fruit body of Grifola frondosa (maitake), Basidiomycetes was confirmed to contain
substances with anti-diabetic activity. When 1 g/d of powdered fruit body of maitake was
given orally to a genetically diabetic mouse (KK-Ay), blood glucose reduction was observed,
in contrast to the control group in which the blood glucose increased with ageing. Moreover,
levels of insulin and triglyceride in plasma demonstrated a change similar to blood glucose
with feeding of maitake. Ether-ethanol-soluble (ES) and hot water-soluble (WS) fractions
were prepared from the fruit body and their hypoglycemic activity was examined. Blood glucose-lowering
activity was found when ES-fraction or WS-50% ethanol float (X) fraction was administered
orally, but other WS-fractions were inactive. These results suggest that the anti-diabetic
activity was present not only in the ES-fraction consisting of lipid but also in the X-fraction
of peptidoglycan (sugar:protein = 65:35).
Prophylactic effects of zhuling [Maitake] and BCG on postoperative recurrence of bladder
cancer.
[Article in Chinese] Yang DA, Li SQ, Li XT, General Hospital of Jinan Unit of People's Liberation
Army.
The prophylactic effects of Chinese herbal medicine Zhuling (Grifola umbellata pilat)
and BCG on bladder cancer after TURBT and partial cystectomy were evaluated. 146 patients
with bladder cancer were divided into 3 groups, Zhuling, BCG, and control group. Follow-up
for 48-124 months (average 70.8 months) showed that the tumor recurrence rate was 33.3%,
34.3% and 65.1%, respectively. Compared to the control group, the recurrence rate of Zhuling
group and BCG group was significantly decreased (P < 0.01). The effect of Zhuling was
similar to that intravesical BCG. Zhuling was cheaper and convenient in usage, and no side
effects.
Monoclonal antibody to proteoglycan derived from Grifola frondosa (Maitake).
Hirata A, Adachi Y, Itoh W, Komoda M, Tabata K, Sugawara I, Research Laboratory, Taito Co.,
Ltd., Kobe, Japan.
A murine monoclonal antibody (MAb) was prepared by immunizing BALB/c mice with a proteoglycan
fraction derived from Grifola frondosa (Maitake mushroom), followed by the hybridization
of spleen cells with mouse myeloma cells. The MAb (subclass; Ig G2b), designated MPG2, reacted
with schizophyllan (SPG), curdlan, scleroglucan, laminarin and lentinan, but not with dextran,
pullulan, mannan and xylan. Immunohistochemistry (ABC-GO method) showed that MAb MPG2 reacted
with lysosomal proteoglycan and (1-->6)-beta-branched laminaritriose taken up by rabbit
peritoneal macrophages. These results suggest that this MAb may recognize mainly (1-->3)-beta-D-glucan,
and may be useful for determining the immunological properties of Grifola frondosa-derived
proteoglycan.
Inhibitory effect of Chinese herb medicine zhuling on urinary bladder cancer. An experimental
and clinical study.
[Article in Chinese] Yang DA, General Hospital of Jian Unit of People's Liberation Army.
Inhibitory effect of Zhuling (Grifola umbellata pilat) on urinary
bladder cancer was determined experimentally and clinically.
The results showed that zhuling inhibited significantly
the induction of bladder cancer in rats exposed to N-butyl-N-(4-hydroxybutyl)
nitrosamine (BBN), decreasing from 100% (18/18) in control
group to 61.1% (11/18) in zhuling (P less than 0.01).
Zhuling was given to 22 patients with recurrent bladder
cancer after TUR or partial cystectomy. The patients
were followed up for 12 to 38 months (average 26.5 months).
Bladder cancer recurred in seven of the patients with
a longer recurrence interval (19.2 months) after medication
than before medication (P less than 0.05). The remaining
15 patients had no recurrence. The mechanism of Zhuling
is discussed.
Physiochemical properties and antitumor activities of chemically modified derivatives
of antitumor glucan "grifolan LE" from Grifola frondosa.
Adachi Y, Ohno N, Ohsawa M, Sato K, Oikawa S, Yadomae T
Antitumor glucan, grifolan LE (GRN LE), from Grifola
frondosa was chemically modified to examine the structure-function
relationship of the products. Modification by periodate,
borohydride and acid hydrolysis of side chains of GRN
LE did not alter properties such as helical conformation
and antitumor activity of GRN LE. Introduction of carboxylic
acid groups into the side chains by oxidation with periodate
and with sodium chlorite (GRN LE-PC), and substitution
with carboxymethyl (CM) or hydroxyethyl (HE) groups
abolished the gel-forming ability of GRN LE. Significant
antitumor activity was observed in all of the derivtives
having gel-forming ability as well as some derivatives
having no such ability. These results suggested that
essential factors required for antitumor activity were
(1----3)-beta-D-glucosyl linkages and high molecular
weight, and that accessory groups could be linked to
the main chain without loss of antitumor activity in
a higher ratio than that of gel-forming ability.
Antitumor and immunomodulating activities of a beta-glucan obtained from liquid-cultured
Grifola frondosa.
Suzuki I, Hashimoto K, Oikawa S, Sato K, Osawa M, Yadomae T
The effects of the beta-1,3-glucan, LELFD, obtained
from liquid-cultured mycelium of Grifola frondosa, on
the growth of syngeneic tumors and immune responses
in mice were examined. In Meth A or IMC solid tumor
systems, LELFD administered intraperitoneally (i.p.)
or intralesionally (i.l.) exhibited significant antitumor
effects. However, the growth of L1210 and P388 leukemias
was unaffected by the injection of LELFD. The injection
of LELFD i.p. enhanced the activities of natural killer
cells and macrophages in mice. LELFD also enhanced the
antibody response when it was injected i.p. with sheep
red blood cells into mice. Furthermore, it was found
that LELFD could activate the alternative complement
pathway.
Host-mediated antitumor effect of grifolan NMF-5N, a polysaccharide obtained from Grifola
frondosa.
Takeyama T, Suzuki I, Ohno N, Oikawa S, Sato K, Ohsawa M, Yadomae T, Tokyo College of Pharmacy,
Japan.
The antitumor mechanism of grifolan NMF-5N, a beta-1,3-glucan obtained from mycelia of
Grifola frondosa, was examined. Grifolan NMF-5N did not show direct cytocidal effect on
cultured tumor cells. However, intraperitoneal injection of grifolan NMF-5N increased the
number of peritoneal exudate cells and peritoneal adherent cells which showed cytostatic
activity towards syngeneic tumor cells. In an in vivo assay, the administration of carrageenan,
an inhibitor of macrophage function, reduced the antitumor activity of grifolan NMF-5N.
The delayed-type hypersensitivity reaction was augmented in the grifolan NMF-5N-administered
mice. The administration of NMF-5N augmented the induction of cytotoxic T cells but the
antitumor activity of grifolan NMF-5N was reduced in athymic nu/nu mice. In addition, the
treatment with anti-Thy 1,2 antibody and complement C' of spleen cells taken from mice which
showed regression of tumor due to grifolan NMF-5N, reduced the neutralizing effect in Winn
assay. These results suggested that grifolan NMF-5N shows antitumor activity via host-mediated
mechanisms and both macrophages and T cells play important roles in the mechanisms.
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