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From Nature - Agaricus blazei Murill

Mushrooms have a cross-cultural history of medicinal use spanning many millennia. In Asia, South America, Africa, and throughout Europe, mushrooms have been used medicinally and as food, while others were used in rituals to awaken consciousness. In traditional Chinese medicine, their legendary effects on promoting health and vitality and in fighting tumors have been extensively validated by recent studies.1, 2, 3, 4 These studies suggest that specific mushrooms are strongly immunologic and help our bodies. These mushrooms can also help us maintain physiological homeostasis, restore physical balance, and improve our natural resistance to disease. More than 270 recognized species of mushrooms are known to have specific immunotherapeutic properties.5, 6 Research demonstrates that many species are strongly immunologic and help our body maintain a natural resistance to disease. In fact, medicinal mushrooms probably hold the greatest immunological promise for the future of oncology and chronic infectious disease treatment. Most mushrooms are composed of around 90% water by weight. The remaining 10% consists of 10 to 40% protein, 2 to 8% fat, 3 to 28% carbohydrate, 3 to 32% fiber, 8 to 10% ash, and some vitamins and minerals, with potassium, calcium, phosphorus, magnesium, selenium, iron, zinc, and copper accounting for most of the mineral content. In addition to these, mushrooms contain a wide variety of bioactive molecules, such as terpenoids, steroids, phenols, nucleotides and their derivatives, glycoproteins, and polysaccharides. The low total fat content and high proportion of polyunsaturated fatty acids relative to the total fatty acids of mushrooms are considered significant contributors to the health value of mushrooms. Many mushrooms act as antioxidants, and antimicrobials, and possess antihyperlipidemic7, hypotensive and hypoglycemic properties8, in addition to improving many health conditions such as heart disease9, asthma10 and inflammation11. Research suggests that the compounds in medicinal mushrooms most responsible for up-regulating the immune system are a diverse collection of polysaccharides, particularly beta-glucans, and to a lesser extent, alpha-glucans.12 These orally-bioactive polysaccharides13 isolated from certain mushrooms have been shown to be one of the most powerful immune-enhancing substances known. Beta-glucans are known as "biological response modifiers" and their ability to activate the immune system is well documented.14, 15, 16 Specifically, beta-glucans activate the complement system and can stimulate macrophages, natural killer (NK) cells, T-cells, and immune system cytokines. Mushroom beta-glucans have the ability to directly change NK precursor cells into activated NK cells. Based on in vitro studies, beta-glucans act on several immune receptors including Dectin-1, complement receptor (CR3) and TLR-2/6, triggering a group of immune cells including macrophages, neutrophils, monocytes, natural killer cells and dendritic cells. As a consequence, beta-glucans can modulate both innate and adaptive response, and they can also enhance phagocytosis. Beta-glucans also activate the immune system by interacting with the macrophage-1 antigen (CD18) receptor on immune cells. Other cell receptors that can receive signals from beta-glucans include Toll-like receptor 2, Dectin-1, lactosylceramide, and scavenger receptors.17, 18, 19 Hence, beta-glucans contained in certain mushrooms act as strong immunomodulators and, as such, inhibit tumor growth. More than 50 mushroom species have yielded potential chemical extracts that exhibit anticancer activity in vitro or in animal models. More than half a dozen have been extensively investigated in human cancers and have been shown to be non-toxic and very well tolerated.

The medicinal mushroom Agaricus blazei Murill (AbM), originating from the Brazilian rain forest, has been long used in traditional South American medicine for the prevention and treatment of a wide range of diseases, including infection, allergy, and cancer. It was discovered in 1960 by Takatoshi Furumoto, a grower and researcher who sent it to Japan for investigation. After extensive research, it was demonstrated that this mushroom exhibited strong antitumor properties, triggering Japanese importation of AbM from Brazil and its commercial cultivation. Later, it was given the common name “Himematsutake” in Japan, while in Brazil it was named “Cogumelo Piedade.” It has been demonstrated that AbM exhibits antimutagenic, antioxidant, and immunostimulatory activities. It is now extensively commercially cultivated for its medicinal uses and exported around the world. Japan most likely has one of the greatest consumptions of AbM per capita.20 Estimates are that Japanese consumption of AbM has grown considerably since the Fukushima nuclear power plant meltdown. AbM is rich in the immunomodulating polysaccharides, specifically, beta-(1-3)-D-glucan, beta-(1-4)-a-D-glucan and beta-(1-6)-D-glucan. In addition to beta-glucans, AbM also contains derivatives of ergosterol, vitamins B1 and B2, amino acids, niacin, iron, and calcium. A major constituent of AbM, ergosterol, was found to inhibit tumor growth in mice via direct inhibition of tumor-induced angiogenesis.21 Other studies demonstrated that polysaccharides present in AbM extract caused activation of macrophages and natural killer cells22, and induced cytotoxic T-lymphocyte activity in tumor-bearing mice.23 Specifically, activation of natural killer cells was mediated through IL-12-induced IFN-gamma expression.24 AbM has been shown to have a broad spectrum of antitumor properties25, including hematological cancers such as myeloma in a mouse model26, and leukemia in a human study.27 Several studies show the antitumor and immunomodulatory effects of AbM are due to immune-potentiation, or direct inhibition of angiogenesis.28, 29, 30, 31, 32 Another proposed mechanism behind its antitumor effects is the induction of apoptosis in tumor cells, which is demonstrated in vitro.33 Its effects are also in part mediated through the mushroom's stimulation of innate immune cells, such as monocytes, natural killer cells, and dendritic cells, and the amelioration of a skewed Th1/Th2 balance and inflammation.34, 35 There are several reports from around the world of this mushroom being used successfully in late stage cancers that had been determined hopeless. Some European clinics base their entire treatment protocols on AbM mushroom extracts and other complementary botanicals. A 2004 study investigated the beneficial effects of daily consumption of an extract of AbM on immunological status and qualities of life in cancer patients undergoing chemotherapy. They observed that natural killer cell activity was significantly higher after a 6-week period compared with placebo. Additionally, chemotherapy-associated side effects such as appetite, alopecia, emotional stability and general weakness were all improved.36 Agaricus blazei Murill Dosage and Availability AbM is available as freeze-dried mushroom, as concentrated liquid extracts, or extract in capsules. Make sure the Agaricus blazei does not contain the compound agaratine. As with all medicinal mushrooms, non-extracted mushroom products (powder) cannot be digested well, and their chemicals therefore have poor bioavailability. Dosage varies for cancer patients depending on condition and GI tolerance. In Japan, the usual dosage recommended in hospitals for patients is 3 to 5 grams, three times a day, given as a hot-water extract. A trend toward integrating medicinal mushrooms with the extant cancer regimens of surgery, chemotherapy, and radiation therapy is now considerably advanced in Japan and China. These countries have taken advantage of mushroom preparation’s anticancer and immune-stimulating properties for centuries. In the West, a more comprehensive approach to cancer management is long overdue, particularly with the availability of good clinical evidence supporting mushroom products. Glucan- and proteoglycan-rich mushroom extracts offer hope for cancer patients. These substances are uniquely effective immune boosters, which pose no threat of autoimmune reactivity. As dietary supplements, mushrooms and their derivative compounds are safe, clinically proven, and exhibit near-perfect benefit-risk profiles. Medicinal mushrooms are an excellent supplement to individuals afflicted with cancer, living with impaired immunity, or merely descending into ill health with the passing of time. The following books are excellent resources for more information on medicinal mushrooms: Mycelium Running: How Mushrooms Can Help Save the World by Paul Stamets, Medicinal Mushrooms by Christopher Hobbs, Medicinal Mushrooms for Immune Enhancement: Agaricus Blazei Murill, Discover the Beta Glucan Secret by Beth M. Ley, and The Fungal Pharmacy: The Complete Guide to Medicinal Mushrooms and Lichens of North America by Robert Rogers. References ______________________ 1. Monro, Jean (2003). Treatment of Cancer with Mushroom Products. Archives of Environmental Health: an International Journal 58 (8): 533-7. 2. Hyodo I, Amano N, Eguchi K. (2005). Nationwide survey on complementary and alternative medicine in cancer patients in Japan. Journal of Clinical Oncology 23 (12): 2645-54. 3. Borchers, A. T.; Krishnamurthy, A; Keen, C. L.; Meyers, F. J.; Gershwin, M. E. (2008). The immunobiology of mushrooms. Experimental Biology and Medicine 233 (3): 259–76. 4. Xi, T; Beelman, RB; Lambert, JD; The cancer preventive effects of edible mushrooms: Anticancer Agents in Medical Chemistry (2012) Dec; 12(10): 1255-63. 5. Ooi VE, Liu F. Immunomodulation and anti-cancer activity of polysaccharide-protein complexes. Curr Med Chem. 2000;7:715–729. 6. Kidd PM. The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev. 2000;5:4–27. 7. Fukushima, M., Ohashi, T., Fugiwara, Y., Sonoyama K., Nakano, M.; Cholesterol lowering effects of Grifola frondosa fiber, Lentinus edodes fiber and Flammulina velutipes fiber in rats: Experimental Biology and Medicine (2001) Sep; 226(8): 758-765. 8. Khatoun, K.; Mahtab, H.; Kahnam, P. A.; Sayeed, M. A.; Khan, K. A.: Oyster mushroom reduced blood glucose and cholesterol in diabetic subjects. Myemsingh Medical Journal, 16, 94-99. 9. Guillamón, E; García-Lafuente, A; Lozano, M; d'Arrigo, M; Rostagno, M. A.; Villares, A; Martínez, J. A. (2010). Edible mushrooms: Role in the prevention of cardiovascular diseases. Fitoterapia 81 (7): 715–23. 10. Catalli, A, Kulka, M; Chitin and β-Glucan Polysaccharides as Immunomodulators of Airway Inflammation and Atopic Disease: Recent Patents in Endocrine, Metabolic and Immune Drug Discovery (2010) 4, 175-189. 11. Lull, C.; Wichers, J.; Savelkoul, F. (Jun 2005).Antiinflammatory and Immunomodulating Properties of Fungal Metabolites. Mediators of Inflammation (Free full text) 2005 (2): 63–80. 12. Stamets, Paul; Medicinal Polypores of the Forests of North America: Screening for Novel Antiviral Activity: International Journal of Medicinal Mushrooms, (2005), Volume 7, 362. 13. The terms glycan and polysaccharide are synonyms defined as "compounds consisting of a large number of monosaccharides linked glycosidically". Polysaccharides are composed of groups of interconnected monosaccharides (single sugars) and are a structurally diverse group that occurs widely in nature. Unlike the nucleotides in nucleic acids and amino acids in proteins that can only be interconnected in one way, polysaccharides can be interconnected at several points to form a wide variety of branched or linear structures. The number of possible permutations for four different monosaccharides can be up to 35,560 unique arrangements, while four amino acids can only form 24 different permutations. (IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997)). 14. DiLuzio, N. Immunopharmacology of Glucan: A Broad-spectrum Enhancer of Host Defense Mechanisms. Trends Pharmacol 4 (1983): 344–347. 15. Kodama N, Komuta K, Sakai N, Nanba H (December 2002). Effects of D-Fraction, a polysaccharide from Grifola frondosa on tumor growth involve activation of NK cells. Biological & Pharmaceutical Bulletin 25 (12): 1647–50. 16. Kodama N, Komuta K, Nanba H (2003). Effect of Maitake (Grifola frondosa) D-Fraction on the activation of NK cells in cancer patients. Journal of Medicinal Food 6 (4): 371–7. 17. Akramiene D, Kondrotas A, Didziapetriene J, Kevelaitis E . Effects of beta-glucans on the immune system. Department of Physiology, Kaunas University of Medicine, Kaunas, Lithuania. Medicina (Kaunas, Lithuania) [2007, 43(8):597-606]. 18. Chan GC, Chan WK, Sze DM. The effects of beta-glucan on human immune and cancer cells. Journal of hematology & oncology. 2009 Jun 10;2:25. 19. Yan J, Vetvicka V, Xia Y, Coxon A, Carroll MC, Mayadas TN, Ross GD. Beta-glucan, a "specific" biologic response modifier that uses antibodies to target tumors for cytotoxic recognition by leukocyte complement receptor type 3 (CD11b/CD18). Journal of immunology (Baltimore, Md. : 1950) [1999 Sep 15;163(6):3045-52]. 20. According to 2001 reports, 100 000–300 000 kg of the dried body of ABM is produced every year in Japan, and about 300 000–500 000 persons for the prevention or treatment of cancer assume the 3–5 g three times a day by a typical hot-water extract. 21. Takaku T, Kimura Y, and Okuda H, Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action. Journal of Nutrition, vol. 131, no. 5, pp. 1409–1413, 2001. 22. Mizuno M, Morimoto M, Minato K-I, Tsuchida H. Polysaccharides from Agaricus blazei stimulate lymphocyte T-cell subsets in mice. Bioscience, Biotechnology and Biochemistry.1998;62(3):434–437. 23. Takimoto H, Wakita D, Kawaguchi K, et al. Potentiation of cytotoxic activity in naive and tumor-bearing mice by oral administration of hot-water extracts from Agaricus blazei fruiting bodies. Biol Pharm Bull. Mar 2004;27(3):404-406. 24. Yuminamochi E, Koike T, Takeda K, et al. Interleukin-12- and interferon-gamma-mediated natural killer cell activation by Agaricus blazei Murill. Immunology. Jun 2007;121(2):197-206. 25. Itoh H, Ito H, Amano H, and Noda H, Inhibitory action of a (1→6)-β-D-glucan-protein complex (F III-2-b) isolated from Agaricus blazei Murill ('Himematsutake') on Meth A fibrosarcoma-bearing mice and its antitumor mechanism. Japanese Journal of Pharmacology, vol. 66, no. 2, pp. 265–271, 1994. 26. Murakawa K, Fukunaga K, Tanouchi M, Hosokawa M, Hossain Z, and Takahashi K, Therapy of myeloma in vivo using marine phospholipid in combination with Agaricus blazei Murill as an immune respond activator. Journal of Oleo Science, vol. 56, no. 4, pp. 179–188, 2007. 27. Endo M, Beppu H, Akiyama H et al., Agaritine purified from Agaricus blazei Murrill exerts anti-tumor activity against leukemic cells. Biochimica et Biophysica Acta, vol. 1800, no. 7, pp. 669–673, 2010. 28. Kimura Y, Kido T, Takaku T, et al. Isolation of an anti-angiogenic substance from Agaricus blazei Murill: its antitumor and antimetastatic actions. Cancer Sci. Sep 2004;95(9):758-764. 29. Lee YL, Kim HJ, Lee MS, et al. Oral administration of Agaricus blazei (H1 strain) inhibited tumor growth in a sarcoma 180 inoculation model. Exp Anim. Oct 2003;52(5):371-375. 30. Takaku T, Kimura Y, and Okuda H, Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action. Journal of Nutrition, vol. 131, no. 5, pp. 1409–1413, 2001. 31. Su ZY, Tung YC, Hwang LS, et al. Blazeispirol A from Agaricus blazei fermentation product induces cell death in human hepatoma Hep 3B cells through caspase-dependent and caspase-independent pathways. J Agric Food Chem. May 11 2011;59(9):5109-5116. 32. Akiyama H, Endo M, Matsui T, et al. Agaritine from Agaricus blazei Murrill induces apoptosis in the leukemic cell line U937. Biochim Biophysica Acta. May 2011;1810(5):519-525. 33. Fujimiya Y, Suzuki Y, Oshiman K.I. et al., Selective tumoricidal effect of soluble proteoglucan extracted from the basidiomycete, Agaricus blazei Murill, mediated via natural killer cell activation and apoptosis. Cancer Immunology Immunotherapy, vol. 46, no. 3, pp. 147–159, 1998. 34. Takaku T, Kimura Y, and Okuda H. Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action. Journal of Nutrition, vol. 131, no. 5, pp. 1409–1413, 2001. 35. Sorimachi K, Akimoto K, Ikehara Y, Inafuku K, Okubo A, and Yamazaki S, Secretion of TNF-α, IL-8 and nitric oxide by macrophages activated with Agaricus blazei Murill fractions in vitro. Cell Structure and Function, vol. 26, no. 2, pp. 103–108, 2001. 36. Ahn WS, Kim DJ, Chae GT, Lee JM, Bae SM, Sin JI, Kim YW, Namkoong SE, Lee IP. Natural killer cell activity and quality of life were improved by consumption of a mushroom extract, Agaricus blazei Murill Kyowa, in gynecological cancer patients undergoing chemotherapy. International Journal of Gynecological Cancer 2004;14(4):589-94.

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