As members of the fungal kingdom, mushrooms are more closely related to humans and other animals than plants, and provide physiologically active compounds with health benefits (particularly immunological).
These compounds are polysaccharides that help to restore healthy immune balance, up-regulating immune responses in cases of immune suppression while down-regulating overactive responses.[1]
Medicinal fungi contain a number of polysaccharide types including alpha-glucans and beta-glucans. It is the beta-glucans that have been identified as representing the primary source of medicinal activity.[2]
The structure of beta-glucans
Beta-glucans (also known as beta D-glucans) contain a glucose polymer-chain core (more specifically, a repeating structure of many D-glucose polymers). These glucose polymers are held together by what is known as a linear linkage. These can extend from the carbon 1 of one saccharide ring to the carbon 3 of the next (beta 1-3), from carbon 1 to carbon 4 (beta 1-4), from carbon 1 to carbon 6 (beta 1-6) or a mixture of these.
These branching assignments appear to be species specific. For example, beta-glucans of mushrooms have beta (1-3) and beta (1-6) side branches whereas those of bacteria have beta (1-4) side branches.[3]
Beta-glucans from different source (fungal, bacterial or cereal e.g. oat) vary in structure. For example, the core chain length of beta-glucans differ, as do the types and complexity of side chain branching. These differences in structure are believed to be what influences a beta-glucan’s function/mechanism of action and it has been suggested that a higher degree of structural complexity is associated with more potent immunomodulatory and anticancer effects.[4]
More specifically, the presence of complexes with particular proteins (polysaccharide-peptides or proteoglycans) can promote the biological efficiency of a beta-glucan. As mentioned, these compounds can be known as protein polysaccharides, polysaccharide peptides or glycoproteins and include the well known polysaccharide-krestin (PSK) from Trametes versicolor (turkey tail mushroom).
Immunological changes triggered by mushroom polysaccharides[1]
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Other examples include a glycoprotein LEM (lentinan edodes mycelia) from Lentinus edodes (shiitake mushroom), immune-stimulating glycoproteins called fungal immunomodulatory proteins (FIMs) from lingzhi mushrooms and active ganoderma polysaccharides peptide (GPP) from Ganodema lucidum (reiishi mushroom).[5] As a rule, these protein-linked glucans have greater immunopotentiation activity than the corresponding free glucans.[3]
In addition to the type and amount varying across species, the content of beta-glucans can also be influenced by the growing conditions and the degree of fruiting body maturity of mushrooms.
Mechanisms of immune activation by beta-glucans
Beta-glucans are potent immunomodulators, with effects on both innate and adaptive immunity. Beta-glucans act on a diversity of immune related receptors, in particular dectin-1 and CR3, and can trigger a wide spectrum of immune responses.
Dectin-1, which is a type II transmembrane protein receptor that binds (1-3) and (1-6)-beta-glucans, can initiate and regulate the innate immune response. It triggers effective immune responses including phagocytosis and pro-inflammatory factors production, leading to the elimination of infectious agents.[4]
The biological activities of medicinal mushrooms have been attributed to the (1-3)-beta-glucan and (1-3),(1-6)-beta-glucan,6 with the most positive effect on immune stimulation obtained with (1-3)-beta-glucan.[5]
Although the principle underlying betaglucan effect is not fully known, it seems that its biological activity is based on its interaction with specific beta-glucopyranose receptors present on leukocytes, and water-soluble glucans show better efficiency. In an acidic environment, the biological efficiency of beta-glucans is reduced, but molecules of (1-3)-beta-glucan are relatively resistant to the acid in the stomach.[5]
It is best to know the specific beta-glucan amount of the mushroom rather than the total polysaccharides, which accounts for all polysaccharides and not just the beta-glucans. For example, alpha-glucans (starch-type polysaccharides) are present in large amounts in foods such as grains, corn and rice. These foods may be used as substrates for growing mushrooms and may end up in the final mushroom product, elevating the polysaccharide levels and giving a false positive for the medicinal beta-glucans.
The many benefits of mushrooms
Mushrooms and their beta-glucans have an array of actions and benefits in many of the systems of the body.
Pleuran from Pleurotus ostreatus (oyster) mushrooms and lentinan from Lentinus erodes (shiitake) mushrooms show positive affects on the intestines; they increase the resistance of intestinal mucosa to inflammation and inhibit the development of intestinal ulcers. Lentinan also shows a positive affect on peristalsis.[5]
Fungal beta-glucans have been shown to reduce both the overall level of cholesterol and the level of LDL cholesterol in blood, as well as slightly increasing the level of HDL cholesterol, and positively influence the metabolism of fats and sugars.[5]
Beta-glucans also contribute to improved resistance against allergies by increasing the numbers of Th1 lymphocytes in the blood.[5]
Aqueous extracts of grifolan, from Grifola fondus (maitake), have been shown to increase insulin production by as much as 25%, and may be useful in the treatment of diabetes. Grifolan has been used to successfully suppress Candida albicans. The effect of grifolan is supported by simultaneous use of vitamin C.[5]
Anti-cancer effects of beta-glucans
The beta-glucans from mushrooms can have anti-cancer activity, while the same can not be said for the alpha-glucans. Six mushroom preparations have shown clinically significant efficacy against human cancers: lentinan (from shiitake), schizophyllan (from splitgill), active hexose correlated compound (AHCC) (from shiitake), maitake D-fraction (from maitake) and polysaccharide-K/polysaccharopeptide (PSK/PSP) (from turkey tail).
Extensive research in this area over the last 40 years has demonstrated that mushrooms have potent antineoplastic properties that slow the growth of tumours, regulate tumour genes, decrease tumoural angioneogensis and increase malignant-cell phagocytosis. The evidence base for using mushrooms in cancer treatment has greatly increased in the past five years.[2]
Studies have also shown that medicinal mushrooms can be used in conjunction with antineoplastic agents to increase the efficacy of chemotherapy and radiation, the mainstay treatments for most cancers. Research has shown a high safety profile for mushrooms and a lack of negative interactions.[2]
Chemotherapy must penetrate the tumour and accumulate within each cell to induce cell cycle arrest and apoptosis. PSK, reiishi, maitake and cordyceps have been shown to increase the effects of chemotherapy, usually by increasing the dose of chemotherapeutic agent that accumulates within a cell.[2]
Maitake D-fraction, extracted from Grifola frondosa (maitake), was found to decrease the size of lung, liver and breast tumours in >60% of patients when it was combined with chemotherapy, in a two-arm control study, compared with chemotherapy alone. The effects were less obvious with leukaemia, stomach and brain cancer patients.[4]
Two proteoglycans from Trametes/Coriolus versicolor (turkey tail/yun zhi) – PSK and PSP – are among the most extensively studied. PSK and PSP are protein-bound polysaccharides, so their actions are not necessarily directly equivalent to pure beta-glucans. In a series of trials from Japan (PSK) and China (PSP), PSK and PSP were found to be well tolerated without significant side-effects and prolonged the survival of some patients with carcinoma and non-lymphoid leukaemia.[4]
Ganoderma polysaccharides are beta-glucans derived from Ganoderma lucidum (lingzhi/reiishi). Used in late-stage lung cancer patients treated with 5.4g per day of a proprietary reiishi extract, IL-2, IL-6, and IFN-gamma increased but great variability in patients’ responses occurred.[2]
The immune-stimulating impact that mushrooms can exert on natural killer (NK) cells, macrophages and T cells can also provide a protective effect against chemotherapeutic myelosuppression, one of the most serious deleterious effects of chemotherapy. Maitake D-fraction and reiishi mushroom have shown results with this.[2]
Mushroom species containing biologically active beta-glucans[5]
| Fungus | Beta-glucan |
|---|---|
| Pleurotus spp. (oyster) | Pleuran |
| Lentinus edodes (shiitake) | Lentinan |
| Schizophyllum commune (splitgill) | Schizophylan |
| Ganoderma lucidum (reiishi) | GI-1 |
| Trametes versicolor (turkey tail) | PSK/PSP |
| Grifola frondosa (maitake) | Grifolan, maitake D-fraction |
| Flammulina veluptis (enoki) | Flammulin |
Maitake D-fraction
Maitake D-fraction is a mixed beta-glucan fraction prepared from the maitake mushroom.[3] In 1995, 165 patients with various cancers were treated with D-fraction plus tablets of dried crude extract of maitake. Dosages varied from patient to patient, with D-fraction doses ranging from 35-100mg per day and crude mushroom extract ranging from 4-6g. Symptomatic improvements or regression were claimed for approximately 73% of the breast cases and 67% of the lung cases, with 83% of patients experiencing less pain and 90% improvement of chemotherapyrelated symptoms such as vomiting, nausea, reduced appetite, hair loss, intestinal bleeding and lowered white cell count.[3]
Shiitake
Shiitake has a long history of traditional use for diseases involving depressed immune function (including AIDS), cancer, environmental allergies, fungal infection, frequent flu and colds, bronchial inflammation, heart disease, hyperlipidaemia (including high blood cholesterol), hypertension, infectious disease, diabetes, hepatitis, obesity, problems related to sexual dysfunction, ageing, liver ailments, respiratory diseases, exhaustion and weakness.[7]
Shiitake contains significant quantities of vitamins C, B1, B2, B12, niacin and vitamin D2 (being the highest content of vitamin D2/ergosterol of any plant food).[7]
It is a source of two well-studied and widely approved polysaccharides: LEM, a protein-bound polysaccharide derived only from the mycelium; and lentinan, a cell-wall branched beta-glucan extracted from both the fruiting body and mycelium. Both compounds are immune system enhancers that demonstrate anti-cancer activity.[7]
Vitamin D is known for its anti-inflammatory properties and extracts derived from shiitake exert an anti-inflammatory effect. Exposure to ultraviolet light increases vitamin D2 content in shiitake edible mushrooms and, following feeding of vitamin D-enriched mushroom extracts to mice with immune-mediated hepatitis, a significant decrease in liver damage was noted. The data supports its potential use as safe immunomodulatory adjuvant for the treatment of hepatitis C and nonalcoholic steatohepatitis.[8]
Polysaccharide-K (PSK) and polysaccharide-peptide (PSP)
Essentially, both PSK and PSP are the same polysaccharide from the turkey tail mushroom. PSK is a patented polysaccharide extract from Japan, known as Krestin, and PSP is a similar patented product extract from China that is considered a drug and used in Chinese hospitals. They both have demonstrated the most promise for cancer treatment.
In Japanese trials since 1970, PSK significantly extended survival at five years or beyond in cancers of the stomach, colon-rectum, oesophagus, nasopharynx and lung (non-small cell types) and in a HLA B40-positive breast cancer subset.[3]
In double-blind trials, PSP also significantly extended five-year survival in oesophageal cancer. PSP significantly improved quality of life, provided substantial pain relief and enhanced immune status in 70-97% of patients with cancers of the stomach, oesophagus, lung, ovary and cervix.[3]
PSK and PSP boost immune cell production, ameliorate chemotherapy symptoms and enhance tumour infiltration by dendritic and cytotoxic T cells. Their extremely high tolerability, proven benefits to survival and quality of life, and compatibility with chemotherapy and radiation therapy makes them well suited for cancer management regimens.[3]
PSK also helps conserve immune status in the face of toxic challenge by conventional treatments. After a quarter century of trials, indicating PSK can improve cancer survival, the cumulative human findings amount to a recommendation for its inclusion in standard anticancer protocols.[3]
PSK showed a tendency toward protecting against the immunosuppression that typically accompanies surgery and long-term chemotherapy. The use of PSK as the immuno-component of chemoimmunotherapy consistently doubled the two-year survival rate for stomach cancer.[3]
In an eight-year, double-blind trial, 111 patients with colorectal cancer were randomised into two groups, then administered PSK or placebo in decreasing doses over time. PSK of 3g per day was given until two months after surgery, followed by 2g per day until 24 months and 1g per day thereafter. PSK significantly improved both the eight-year survival rate (40% vs 25%) and the disease-free interval (25% vs 8%).[3]
The polypeptides in PSP resemble those of the closely-related proteoglycan PSK, in that they are enriched with aspartic and glutamic acids. However, PSP differs from PSK in its saccharide makeup, lacking fucose and carrying arabinose and rhamnose. PSP has been proven to be nontoxic, with marked immunopotentiation capacity sufficient to improve survival rate and quality-oflife in cancer patients.[3]
In 1992, at several hospitals in Shanghai, 274 patients with stomach, oesophageal or lung cancers were dosed with PSP, 3.1g per day before meals for two months. The benefits from PSP ranged from 90-97% for stomach, 82-87% for oesophageal and 70-86% for lung cancers. PSP alleviated symptoms commonly associated with cancer including fatigue, anorexia, nausea, thirst, cold sweat and pain. PSP also alleviated the severity of systemic toxic deterioration associated with conventional therapies, stabilised or increased body weight and significantly improved overall immune status.[3]
PSP also offers analgesic action, which can be beneficial to the cancer patient. Doses up to 15g daily have been tolerated long-term without noticeable adverse effects.[3]
Certainly, the risk-benefit and cost-benefit profiles of mushroom preparations have been proven. Besides being safe to take for periods of years, they improve energy levels in the cancer patient, speed regeneration of damaged bone marrow, support the liver, reduce side-effects of toxic anti-cancer therapies and generally raise wellbeing.[3]
References
- Powell M. Medicinal mushrooms: The essential guide. Mycology Press, 2013
- Guggenheim AG, Wright KM, Zwicky HL. Immune modulation from five major mushrooms: application of integrative oncology. Integrative Med 2014;13(1):32-44. [Full text]
- Kidd PM. The use of mushroom glucans and proteoglycans in cancer treatment. AMR 2000;5(1):4-27. [Abstract]
- Chi-Fung Chan G, Chan WK, Man-Yuen Sze D. The effects of β-glucan on human immune and cancer cells. J Hematol Oncol 2009;2:25. [Full text]
- Rop O, Vlcek J, Jurikova T. Beta-glucans in higher fungi and their health effects. Nut Rev 2009;67(11):624-631. [Abstract]
- Dalonso N, Goldman GH, Gern RMM. β-(1-3),(1-6)-glucans: medicinal activities, characterization, biosynthesis and new horizons. Apple Microbial Biotechnol 2015:DOI 10.1007 [Abstract]
- Bisen PS, Bagel RK, Sanodiya BS, et al. Lentinus edodes: a macrofungus with pharmacological activities. Cur Med Chemistry 2010;17:2419-2430. [Abstract]
- Drori A, Shabat Y, Ben Ya'acov A, et al. Extracts from Lentinula edodes (shiitake) edible mushrooms enriched with vitamin D exert an anti-inflammatory hepatoprotective effect. J Med Food 2016;19(4):383-389. [Abstract]
- Torkelson CJ, Sweet E, Marten MR, et al. Phase 1 clinical trial of Trametes versicolor in women with breast cancer. ISRN Oncology 2012 (2012):ID 251632. [Full text]
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