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Ron Steriti, ND, PhD ?2005
The Agaricus blazei Murill (ABM) mushroom, known as the sun mushroom, is native to Braziland has become known for its medicinal properties.
Immune Effects
Hemicellulase-treated Agaricus blazei activated immature bone-marrow-derived dendritic cells, inducing up-regulation of surface molecules, such as CD40, CD80 and major histocompatibility complex class I antigens, as well as inducing allogeneic T-cell proliferation and T helper type 1 cell development. However, unlike lipopolysaccharide (LPS), hemicellulase-treated Agaricus blazei did not stimulate the BMDCs to produce proinflammatory cytokines, such as interleukin-12 (IL-12) p40, tumour necrosis factor-alpha, or IL-1beta. [1]
Water-soluble proteoglycan of Agaricus blazei Murill significantly enhanced the expression of co-stimulatory molecules (CD80 and CD86) and major histocompatibility complex (MHC) II. These results indicate the immunomodulatory properties of water-soluble proteoglycan, which might be therapeutically useful in the control of cancers and immunodeficient diseases through the up-regulation of dendritic cell maturation. [2]
Treatment of tumor-bearing mice with the extracts of Agaricus blazei Murrill for 10 days restored the natural killer activity against Yac-1 target cells and the best results were observed by treatment with the n-hexane extract (21.48+/-5.26%). Treatment of the animals with the n-hexane extract for 10 days was also able to stimulate the mitogen-induced lymphoproliferative activity of spleen cells. Thirty days after the treatment, all groups presented low proliferative activity. Specific antibody production was observed to be higher in the groups treated with the dichloromethane or methanol extract 30 days after the treatment. [3]
A hemicellulase-derived extract of Agaricus blazei induced expression of IL-12, a cytokine known to be a critical regulator of cellular immune responses. IL-12 production was induced by the CD14-positive cell population, which consists of monocytes/macrophages. Oral administration enhanced natural killer (NK) activity in the spleen. [4]
Effect of Agaricus blazei Murill extract on antibody production was investigated by method of hemolytic plaque-forming cells (PFC) against sheep red blood cells antigen. Agaricus blazei Murill extracts significantly (p<0.01) increased the number of PFC in spleen with intraperitoneal administration at doses of 25 mg/kg as compared with control group. The populations of Mac-1- or CD25-positive cells significantly (p<0.01, p<0.001) increased, but in CD19-positive cells, there were no differences in Agaricus-treated mice as compared with control mice. The expressions of IL-6 and IL-1beta mRNA were augmented by Agaricus extract in both peritoneal macrophages and spleen cells. These results suggested that Agaricus blazei Murill extract might be an effective stimulator for T cell and macrophage to IL-1beta and IL-6 release, resulting in augmentation of antibody production against sheep red blood cell antigen. [5]
One study showed that a fine particle of Agaricus blazei Murill activated the human complement system via the alternative pathway in human serum. Activation of the alternative pathway was both time- and dose-dependent. When the particles from fruiting bodies of A. blazei Murill (ABP-F) were reacted with human serum, the formation of complement-opsonized ABP, iC3b-ABP-F complexes, and binding of the complexes to human peripheral blood monocytes, were demonstrated in vitro by immunofluorescence. Further, the resident human peripheral nucleated cells incubated in the presence of iC3b-ABP-F complexes inhibited the proliferation of human tumor cell line TPC-1 in vitro. [6]
Strong inhibition of cytopathic effects induced by western equine encephalitis (WEE) virus was observed in the mycelial fractions of of Agaricus blazei Murill, but not those of fruiting bodies. [7]
Ones study showed that the Agaricus blazei Murill components that activate macrophages result in the induction of cytokine- and nitric oxide secretion in vitro. Northern blot analysis showed that the increases in cytokine- and NO secretion were due to an increase in cytokine mRNAs or NO synthase mRNA. [8]
Subset analysis of splenic lymphocytes using flow cytometry showed that the percentages of Thy1.2-(pan T-cells), L3T4-(CD4, helper T-cells), and Lyt2-(CD8, cytotoxic T-cells) positive cell populations were significantly increased in mice orally administered a hot water-soluble fraction from Agaricus blazei as compared with mice treated only with saline. It seems that the polysaccharide from Agaricus blazei may be an effective prophylactic, protecting humans against cancer by stimulating lymphocytes such as cytotoxic T-cells. [9]
Anti-Cancer Effects
Water-soluble extracts from cultured medium of Ganoderma lucidum (Rei-shi) mycelia and Agaricus blazei were shown to significantly prolong the survival time of male B6C3F1 mice subjected to X-ray irradiation. [10]
An in-depth study of beta-(1-6)-D: -glucan extracted from Agaricus blazei showed that
(1) Beta-glucan had cytotoxic effect against human ovarian cancer HRA cells, but not against murine Lewis lung cancer 3LL cells, in vitro;
(2) Beta-glucan promotes p38 MAPK activity for suppressing HRA cell proliferation and amplifying the apoptosis cascade;
(3) Beta-glucan stimulates translocation of the proapoptotic protein, Bax, from the cytosol to mitochondria, cytochrome c release, and subsequent caspase-9 activation;
(4) Treatment with SB203580, a p38 MAPK-specific inhibitor, suppresses beta-glucan-induced effects, indicating that activation of p38 MAPK is involved in the suppression of cell proliferation and mitochondrial activation-mediated cell death pathway;
(5) In mice, oral supplementation with beta-glucan reduces pulmonary metastasis of 3LL cells and peritoneal disseminated metastasis of HRA cells and inhibits the growth of these metastatic tumors in lung or peritoneal cavity, in part, by suppressing uPA expression; and
(6) In an in vivo experimental metastasis assay, however, the oral supplementation with beta-glucan after i.v. tumor cell inoculation did not reduce the number of lung tumor colonies.
The authors concluded that treatment with beta-glucan may be beneficial for cancer patients with or at risk for metastasis. [11]
One hundred cervical, ovarian, and endometrial cancer patients were treated either with carboplatin (300 mg / m(2)) plus VP16 (etoposide, 100 mg / m(2)) or with carboplatin (300 mg / m(2)) plus taxol (175 mg / m(2)) every 3 weeks for at least three cycles with or without oral consumption of ABMK (Agaricus blazei Murill Kyowa). We observed that natural killer cell activity was significantly higher in ABMK-treated group (ANOVA, n = 39, P < 0.002) as compared with nontreated placebo group (n = 61). Chemotherapy-associated side effects such as appetite, alopecia, emotional stability, and general weakness were all improved by ABMK treatment. Taken together, this suggests that ABMK treatment might be beneficial for gynecological cancer patients undergoing chemotherapy. [12]
Sodium pyroglutamate isolated from Agaricus blazei was shown to be an anti-angiogenic substance that has potent antitumor and antimetastatic actions, as well as immune-modulatory activity, in tumor-bearing mice. [13]
One study found that extracts of Agaricus blazei mushroom were anticlastogenic during the G1 and S stages of the cell cycle, where chromosome breaks (of the isochromatid type) are produced by the MMS (methyl methanesulphonate) agent. [14]
The antitumor effects of biological response modifiers in an experimental mouse model using a double grafted tumor system were analyzed. The Agaricus blazei preparation cured a primary tumor and inhibited the growth of a metastatic tumor. [15]
A hot-water extract of Agaricus blazei significantly inhibited sarcoma 180 (S180) inoculated into ICR and KSN nude mice. [16]
Chemopreventive activity of the Agaricus blazei Murrill meal was observed in terms of the number of putative preneoplastic altered foci of hepatocytes, which express either the enzyme glutathione S-transferase, placental form (GST-P+) or the transforming growth factor-alpha, and on the size of GST-P+ foci. This was associated with inhibition of foci cell proliferation. The results suggest that the protective influence of the Ab meal against the diethylnitrosamine potential for rat liver carcinogenicity depends on both the strain and period of mushroom harvest. [17]
Tumor-bearing mice treated with intratumoral administration of aqueous ammonium oxalate-soluble and ethanol-insoluble derivatives of Agaricus blazei showed marked tumor regression at doses ranging from 0.1 to 2.5 mg (p < 0.05 vs. saline control; n = 7). However, oral administration of this same fraction, either prior to, simultaneously with, or after, tumor cell inoculation did not result in tumor regression (p > 0.05 vs. control). When this fraction was treated with hydrochloric acid (acid-treated fraction; ATF), intratumoral administration resulted in a marked regression of tumor growth comparable to that of the acid-untreated fraction. More importantly, parenteral administration of ATF resulted in a significantly greater regression of tumor growth than that produced by the untreated fraction (p < 0.05 vs. untreated; n = 7). When a total of 4.5 mg of ATF was given orally at varying schedules prior to, simultaneously with, or after, tumor inoculation, a significant regression was seen using a schedule starting 4 days prior to inoculation (p < 0.05 vs. all other treatments; n = 7). [18]
An aqueous extract of Agaricus blazei Murill significantly enhanced the expression of the c-Jun/activator protein-1 (AP1) in the human breast cancer cell line MCF7. Incubating the cells with 17-beta-estradiol (E2), p-nonylphenol (NP), and the aqueous extract combined, or NP plus the aqueous extract, resulted in increased cell proliferation compared to the untreated control by 93 and 67%, respectively. However, incubating the cells with the extract alone did not enhance cell division. It is suggested that the enhanced proliferation of MCF7 cells in the presence of NP and the aqueous extract may be due to the involvement of an AP1 gene regulatory complex. [19]
Results obtained from in vitro micronucleus tests showed that extracts Agaricus blazei have an antimutagenic action of the desmutagenic type. [20]
Male Swiss mice were treated with cyclophosphamide (25 or 50mg/kg i.p.) or with cyclophosphamide plus Agaricus blazei Murrill mushroom solution at three different temperatures: 4, 21, and 60 degrees C. Aqueous solution of a mixture from various lineages of the mushroom inhibited induction of micronuclei by cyclophosphamide in bone marrow and in peripheral blood of mice. The results suggest that under certain circumstances these mushrooms exhibit antimutagenic activities that might contribute to an anticarcinogenic effect. [21]
Ergosterol was identified as the substance with the antitumor activity in Agaricus blazei Murill. The oral administration of ergosterol to sarcoma 180-bearing mice significantly reduced tumor growth at doses of 400 and 800 mg/kg administered for 20 d without side effects, such as the decreases in body, epididymal adipose tissue, thymus, and spleen weights and leukocyte numbers induced by cancer chemotherapy drugs. Ergosterol had no cytotoxicity against tumor cells. Further tests suggested that either ergosterol or its metabolites may be involved in the inhibition of tumor-induced neovascularization of Lewis lung carcinoma. Female C57BL/6 mice were subcutaneously inoculated with Matrigel containing acidic fibroblast growth factor and heparin with or without ergosterol. Ergosterol inhibited the Matrigel-induced neovascularization, suggesting that ergosterol directly inhibits Matrigel-induced neovascularization. The authors concluded that it seems likely that the antitumor activity of ergosterol might be due to direct inhibition of angiogenesis induced by solid tumors. [22]
One study determined that a highly branched 1,3-beta-glucan segment forms the active center of the antitumor activity of Agaricus blazei. [23]
A study found that Agaricus blazei extracts are antimutagenic when tested in V79 cells. [24]
An anti-tumor active polysaccharide against Sarcoma 180 was isolated by chromatography from the hot-water soluble fraction of Agaricus blazei. This polysaccharide was completely different from the anti-tumor polysaccharide from fruiting body of Agaricus blazei, beta-1,6-glucan. [25]
Inoculation of the low molecule fraction extracted from Agaricus blazei Murill into the primary (MethA) tumor of a two-tumor model resulted in the marked inhibition of the tumor, not only in the right flank, but also in the non-injected left flank. [26]
Treatment with an acid-treated fraction (ATF) obtained from the fruit bodies of Agaricus blazei Murill resulted in infiltration of the distant tumor by natural killer (NK) cells with marked tumoricidal activity in mice. Cell-cycle analysis demonstrated that ATF induced the loss of S phase in MethA tumor cells, but did not affect normal splenic mononuclear cells, which were mainly in the G0G1 phase. [27]
Agaricus blazei Murill was shown to have antitumor effects on mice injected with Meth-A tumor cells. Serum levels of immunosuppressive acidic protein (IAP), produced by activated macrophages and neutrophils, increased transiently soon after intradermal injection. The effect was due to an immune reaction, involving induction of cytotoxic cells in the spleen, and the release of chemotactic factors in the distant tumor. [28]
Administration of polysaccharide-protein complex prepared from cultured mycelia of Agaricus blazei had showed antitumor activity against four kinds of established mouse tumors. The complex had no direct cytotoxic action on tumor cells in vitro. Thus the tumor growth-inhibitory effect of was apparently due to immunological host-mediated mechanisms. [29]
Antitumor effects of Agaricus blazei Murill polysaccharide were found in Meth A tumor-bearing and normal mice treated with or without 5-fluorouracil (5-FU). [30]
Extracts of Agaricus blazei were found to have an antimutagenic effect. [31]
Liver Protection
Agaricus blazei was fount to have a hepatoprotective effect on both liver toxicity and hepatocarcinogenesis process induced by a moderately toxic dose of DEN (diethylnitrosamine). [32, 33] No beneficial effect was observed in tests by the same researchers. [34]
The effects on the expression of cytochrome P450s of polysaccharides from Agaricus blazei were examined. Agaricus blazei (200 mg/kg/day) was administered to female BALB/c mice four times every other day by intraperitoneal injection. Agaricus blazei suppressed both the constitutive and 3-methylcholanthrene-induced CYP1A expression and ethoxyresorufin-O-deethylation activity in the liver. [35]
Hepatitis Vaccine Adjunct
Compared with the control mice, which received hepatitis B virus core antigen (HBcAg) alone, significant increase in not only the HBcAg-specific antibody response but also T cell proliferation was observed in mice that received HBcAg DNA vaccine plus ABM extract. These results suggest that ABM extract might represent an adjuvant to improve the efficacy of DNA vaccines in vivo. [36]
Antioxidants
Agaricus blazei Murill is an excellent source of antioxidants. [37]
Anti-Diabetic Effects
Beta-glucans prepared from Agaricus blazei Murill by repeated extraction with hot water showed anti-hyperglycemic, anti-hypertriglyceridemic, anti-hypercholesterolemic, and anti-arteriosclerotic activity indicating overall anti-diabetic activity in diabetic rats. [38]
Miscellaneous
One study showed that people with urological cancer that used complementary medicine ("Health food," in particular extract from Agaricus blazei) had significantly lower scores for social function, general health perception, and vitality domains than CAM non-users 1 year after diagnosis. CAM users, especially those who used multiple types of CAM, had lower general-health-related quality of life scores than non-users of CAM. [39]
References
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2. Kim, G.Y., et al., Effect of water-soluble proteoglycan isolated from Agaricus blazei on the maturation of murine bone marrow-derived dendritic cells. Int Immunopharmacol, 2005. 5(10): p. 1523-32.
3. Kaneno, R., et al., Effects of extracts from Brazilian sun-mushroom (Agaricus blazei) on the NK activity and lymphoproliferative responsiveness of Ehrlich tumor-bearing mice. Food Chem Toxicol, 2004. 42(6): p. 909-16.
4. Kasai, H., et al., IL-12 Production Induced by Agaricus blazei Fraction H (ABH) Involves Toll-like Receptor (TLR). Evid Based Complement Alternat Med, 2004. 1(3): p. 259-267.
5. Nakajima, A., et al., Effect of hot water extract from Agaricus blazei Murill on antibody-producing cells in mice. Int Immunopharmacol, 2002. 2(8): p. 1205-11.
6. Shimizu, S., et al., Activation of the alternative complement pathway by Agaricus blazei Murill. Phytomedicine, 2002. 9(6): p. 536-45.
7. Sorimachi, K., et al., Inhibition by Agaricus blazei Murill fractions of cytopathic effect induced by western equine encephalitis (WEE) virus on VERO cells in vitro. Biosci Biotechnol Biochem, 2001. 65(7): p. 1645-7.
8. Sorimachi, K., et al., Secretion of TNF-alpha, IL-8 and nitric oxide by macrophages activated with Agaricus blazei Murill fractions in vitro. Cell Struct Funct, 2001. 26(2): p. 103-8.
9. Mizuno, M., et al., Polysaccharides from Agaricus blazei stimulate lymphocyte T-cell subsets in mice. Biosci Biotechnol Biochem, 1998. 62(3): p. 434-7.
10. Kubo, N., et al., Protective effects of a water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia and Agaricus blazei murill against X-irradiation in B6C3F1 mice: Increased small intestinal crypt survival and prolongation of average time to animal death. Int J Mol Med, 2005. 15(3): p. 401-6.
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29. Ito, H., et al., Antitumor effects of a new polysaccharide-protein complex (ATOM) prepared from Agaricus blazei (Iwade strain 101) "Himematsutake" and its mechanisms in tumor-bearing mice. Anticancer Res, 1997. 17(1A): p. 277-84.
30. Itoh, H., et al., Inhibitory action of a (1-->6)-beta-D-glucan-protein complex (F III-2-b) isolated from Agaricus blazei Murill ("himematsutake") on Meth A fibrosarcoma-bearing mice and its antitumor mechanism. Jpn J Pharmacol, 1994. 66(2): p. 265-71.
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33. Barbisan, L.F., et al., Effects of crude extracts of Agaricus blazei on DNA damage and on rat liver carcinogenesis induced by diethylnitrosamine. Genet Mol Res, 2003. 2(3): p. 295-308.
34. Barbisan, L.F., et al., Agaricus blazei (Himematsutake) does not alter the development of rat diethylnitrosamine-initiated hepatic preneoplastic foci. Cancer Sci, 2003. 94(2): p. 188-92.
35. Hashimoto, T., et al., Suppressive effect of polysaccharides from the edible and medicinal mushrooms, Lentinus edodes and Agaricus blazei, on the expression of cytochrome P450s in mice. Biosci Biotechnol Biochem, 2002. 66(7): p. 1610-4.
36. Chen, L., H.J. Shao, and Y.B. Su, Coimmunization of Agaricus blazei Murill extract with hepatitis B virus core protein through DNA vaccine enhances cellular and humoral immune responses. Int Immunopharmacol, 2004. 4(3): p. 403-9.
37. Izawa, S. and Y. Inoue, A screening system for antioxidants using thioredoxin-deficient yeast: discovery of thermostable antioxidant activity from Agaricus blazei Murill. Appl Microbiol Biotechnol, 2004. 64(4): p. 537-42.
38. Kim, Y.W., et al., Anti-diabetic activity of beta-glucans and their enzymatically hydrolyzed oligosaccharides from Agaricus blazei. Biotechnol Lett, 2005. 27(7): p. 483-7.
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