IMMUNE DEFENCEIN THE CORNONA ERA

MEDICINAL MUSHROOMSThe use of natural medicines

to support the immune systemDr Michael McMullen

(Ph.D. Univerity of Westminster, UK)

UK

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TRADITIONAL MEDICINE

• Medicinal mushrooms play a role in traditional medicine in East Asia, perhaps the best known are Cordyceps, Maitake, Rieshi and Shitake. Today they used extensively in cancer treatments in Japan.

• For example: 68 lung cancer patients were recruited and randomized into a Ganopoly (Reishi extract) group of 37 patients and a placebo group of 31 patients.

• For the Ganopoly treatment group, 32 of 37 patients were assessable at the end of 12 weeks’ treatment.

• CD3 percentage and NK cell activity were significantly increased, whereas there were no significant changes for the other parameters.

• This is only one of many studies and the review concluded that Coriolus versicolor and Ganoderma lucidum showed immunomodulatory effects in both innate and adaptive immunity arms.(1)

• In Western medicine there is little interest in the use of medical mushrooms, even though both antibiotics and cholesterol-reducing medicines are based on mushrooms/ fungi.

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HIGH QUALITY PRODUCTION

• The overwhelming majority of mushrooms used for medicines are cultivated commercially rather than gathered in the wild. This guarantees proper identification of species and pure, unadulterated products. In many cases, it also means genetic uniformity as mushrooms are easily propagated vegetatively and limited to a single genetic form.

• The mycelium can be stored for a long time, and the genetic and biochemical consistency may be checked after considerable time.(2)

• Typically, medicinal mushrooms are grown and harvested under controlled conditions in eastern Asia. Some mushroom farms have very stringent standards and are internationally registered as Organic farms.

• In Europe, high quality mushrooms from organic farms are tested for contaminants and quality before being processed into standardised powder for use in capsules.

• Typically there are the same 10 – 15 mushrooms available in various forms. The author prefers capsules with a standardised polysaccharide content. At recommended dosages there is little evidence of side effects, apart from intestinal gas.

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WHY MUSHROOMS?/1

• Mushrooms possess medicinal properties because of the presence of several types of secondary metabolites.

• These secondary metabolites are bioactive, low molecular weight compounds which are produced in response to stress. They help survival by signaling, part of the defense against attack, but are generally not required for normal growth or reproduction.

• The most important secondary metabolites are polysaccharides belonging to the 1,3-β-glucans family. These possess antitumor activities which are achieved by enhancing and blocking cellular immunity pathways.

• Generally, these polysaccharides are not soluble in alcohol and are extracted using hot water. (3)

• Alcoholic extractions of mushrooms such as tinctures contain phenols, terpenes etc. but not β-glucans.

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WHY MUSHROOMS?/2

• Bioactive compounds can be found in mushrooms as cell wall components such as polysaccharides (e.g. β -glucans) and proteins, as well as secondary metabolites such as phenolic compounds, terpenes, and steroids. These latter substances provide mushrooms with secondary activity.

• The concentration and efficacy of the bioactive compounds are varied and depend on the type of mushroom, substrate, fruiting conditions (if cultivated), stage of development, age of the fresh mushroom, storage conditions and cooking procedures.

• The medicinal properties of mushrooms include anti-inflammatory, antioxidant, immunomodulatory, anticarcinogenic, antiviral, antibacterial, antifungal, hepatoprotective, antineurodegenerative, antidiabetic, antiangiogenic and hypoglycemic.(3)

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IMMUNMODULATION/1

• The immunomodulating activity is mainly caused by β-glucans, the main components of the fungal cell wall.

• These molecules are glucose polymers of a linear ß(1,3) -glucan backbone with ß(1,6)-linked side chains.

• They are unknown to the human body and belong to the so-called PAMPs (pathogen associated molecular pattern).

• Following peroral administration, the β-glucans are recognized by PRR (pattern recognition receptors) on the surface of dendritic cells and macrophages in the gastrointestinal tract (M cells of Peyer’s patches).

• After recognition by PRR, the glucan molecules are internalized into the cells and fragmented within.

• The fragments are taken up by the lymph and transported to other parts of the immune system in the body.

• They bind to specific receptors of the complement system (CR3 receptors) on the surface of immune cells, e.g. neutrophil granulocytes and NK (natural killer) cells, and activate them. These immune cells are now primed.(2)

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IMMUNMODULATION/2

• This is followed by the secretion of cytokines, such as TNFα (tumor necrosis factor α), IFN-γ (interferon-gamma) and several interleukins (IL-6, IL-8, IL-12), leading to the activation of cytotoxic T lymphocytes, T helper cells and B cells.

• Increased phagocytic activity, production of nitrite monoxide (NO) and antibody formation occur.

• Altogether, innate and adaptive immunity are activated, reacting fast and strongly against invading micro-organisms and abnormal cells, e.g. tumor cells.

• The effects depend strongly on the basic conditions of the organism. An immuno-compromised organism will react much stronger on an immunomodulating drug than an organism with an intact immune system.

• Thus, it is recommended to use the term “immunomodulator” or “biological response modifier (BRM)” instead of “immunostimulator”.

• The extent of activity is also influenced by dosage, mode of application, time of application and pharmaceutical formulation.(2)

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IMMUNMODULATION/3

• The immunomodulating effects of β-glucans may also useful for the prevention of viral infections.

• A two-week feeding of influenza virus-infected mice with a mixture of glucans from fruit bodies of G. frondosa and mycelium from L. edodes, A. brasiliensis and I. obliquus significantly reduced the symptoms of infection, of application, time of application and pharmaceutical formulation.

• The influence of medicinal mushrooms and β-glucans on the immune system can also result in antiallergic effects.

• Such activities have been shown in vitro and in animal assays for A. brasiliensis (syn: A. blazei), Ganoderma sp., G. frondosa, Phellinus ssp., and various others. The effect is explained by an influence on the balance between Th1/Th2 cells in the immune system.

• The stimulation of a patient’s immune defense against tumorcells by fungal β-glucans can be used in the adjunct treatment of cancer patients in an integrative concept with surgery, chemotherapy and radiation.(2)

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ALMOND MUSHROOM/1 AGARICUS BLAZEI / BRASILIENSIS

• In vitro and animal research suggests it might enhance the production of cytokines such as interferon and interleukin.

• Fractions of agaricus also seem to stimulate monocyte production of interleukin-12 and result in antitumor activity in vitro.

• Extracts of agaricus mushroom, particularly beta-glucan extracts, also have antitumor and immunostimulant effects in animal models

• There is interest in using agaricus mushroom as a biologic response modifier (such as interferon or interleukin-2) as an adjunct to chemotherapy.

• Agaricus mushroom is thought to enhance natural killer cell activity and potentially reduce some side effects of chemotherapy.(4)

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ALMOND MUSHROOM/2 AGARICUS BLAZEI/ BRASILIENSIS

• Natural killer cell activity and quality of life were improved by consumption of a mushroom extract, Agaricus blazei

• We investigated the beneficial effects of ABMK consumption on immunological status and qualities of life in cancer patients undergoing chemotherapy.

• 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 three weeks for at least three cycles, with or without oral consumption of ABMK.

• We observed that natural killer cell activity was significantly higher in the ABMK-treated group (ANOVA, n = 39, P < 0.002) compared to the non-treated placebo group (n = 61). However, no significant difference in lymphokine-activated killer and monocyte activities was observed in a manner similar to the count of specific immune cell populations between ABMK-treated and nontreated groups.

• 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.(5)

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CHAGAINONOTUS OBLIQUUS

• Evidence from in vitro research suggests that the mycelial endopolysaccharide of chaga can enhance the proliferation and polyclonal IgM antibody production in B cells and nitrite production and expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) in macrophages.

• Chaga can increase catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, as well as decrease malondialdehyde (MDA) levels in diabetic mice.

• Evidence from in vitro research suggests that chaga can reduce hydrogen peroxide-induced DNA damage in human lymphocytes.

• Chaga also has a high oxalate content — between 2.8 and 11.2 grams per 100 grams of chaga powder.

• One case of nephropathy with renal failure, thought to be due to the high oxalate content of chaga, has been reported.(4)

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CORDYCEPSCORDYCEPS SINENSIS

• Cordyceps sinensis is a fungus; for commercial purposes, the cordyceps cells (Cs-4 strain) are usually propagated in a laboratory setting.

• Active constituents of cordyceps are polysaccharides, adenosine, cordycepin, cordycepic acid, and ergosterol.

• Preliminary studies suggest cordyceps might stimulate immune function by:

1. increasing the number of T helper cells increasing the natural killer cell activity

2. stimulating the blood mononuclear cells 3. increasing the levels of interferon-gamma, tumor necrosis factor-

alpha, and interleukin-1 4. prolonging the survival of lymphocytes.

• In cases of chronic kidney disease, pooled analysis of results from clinical research shows that taking cordyceps 0.6-2 grams orally three times daily, along with standard treatment, does not reduce the risk of chronic kidney disease progression but seems to modestly improve kidney function. Cordyceps treatment decreases serum creatinine levels by 0.6 mg/dL and increases creatinine clearance by 9.2 mL/min compared to standard treatment alone.(4)

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CORIOLUS / TURKEY TAIL CORIOLUS VERSICOLOR

• Also known as Trametes versicolor, its record of application in China can be traced back to The Compendium of Materia Medica written by Li Shizhen during the Ming Dynasty.

• There are two well-known commercial preparations of polysaccharide of Coriolus versicolor — polysaccharide peptide (PSP, produced in China) and polysaccharide Krestin (PSK, produced in Japan).

• Coriolus versicolor has been extensively investigated in phase I, II and III randomized clinical trials in esophageal, breast, colorectal and stomach cancer patients in Asia. Since 1970, many large-scale clinical research studies have been conducted, mainly in Japan. Coriolus is used in combination with standard therapy.

• Among the 35 randomized control trials on Coriolus versicolor conducted in Asia, more than half of these, with 13,948 patients participating, were gastric cancer (n=19) cases.

• In summary, the use of Coriolus versicolor, in either the processed form of PSK or the freeze-dried mycelial powder of the medicinal mushroom, has shown itself to be related to increases in both the numbers and functional activities of the blood NK cells.(1)

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LION’S MANEHERICIUM ERINACEUS

• Evidence from animal research shows that extracts from Hericiumerinaceus can protect mice against Salmonella typhimurium-induced liver damage by activating innate immune cells

• In vitro research shows that polysaccharides from the fruiting body of Hericium erinaceus can activate macrophages to increase the production of NO and the expression of cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha.

• In an animal model of colon cancer, Hericium erinaceus extract has been shown to reduce tumour size by stimulating the immune system, inhibiting angiogenesis, and inducing apoptosis.

• In vitro research shows that the antiangiogenic effect of Hericiumerinaceus extract may relate to its ability to downregulate TNF-alpha-induced activation of nuclear factor kappaB (NF-kB) and matrix metalloproteinase (MMP)-9.

• Other in vitro research shows that extracts from Hericiumerinaceus can promote apoptosis by activating caspase-3 and -9. (1)

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MAITAKEGRIFOLA FRONDOSA

• Laboratory research suggests that maitake mushroom possesses immunomodulating activities.

• The relatively low-molecular-mass polysaccharides isolated from mycelia of maitake mushroom may enhance innate immunity by enhancing phagocytosis and increasing natural killer cell cytotoxicity, and therefore may serve as biological response modifiers.

• Activation of helper T cells, decreased activation of B cells, and increased production of Interferon-gamma, interleukin (IL)-12 p70 and IL-18. Suppression of IL-4 have also been observed.

• In human research, increasing doses of maitake mushroom resulted in increases in some immunologic parameters and decreases in others for many of the endpoints measured.

• The optimal dose with the largest immunological effect varied for different parameters tested, but positive effects were most often seen with doses between 5-7 mg/kg daily.

• No dose-limiting toxicities were noticed.(1)

• Used together, maitake and shiitake have been reported to have a synergistc effect in the immunsystem.(6)

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REISHIGANODERMA LUCIDUM

• Extracts of Reishi commonly combine a water-based extract and an alcohol extract, so the final product contains both polysaccahrides and non-water soluble terpenes.

• In humans, reishi mushroom extract prevented white blood cell depletion and improved T cell counts.

• The immune effects of reishi mushroom polysaccharides may play a role in their anti-cancer effects. They seem to stimulate cytokine production from macrophages and T lymphocytes.

• These polysaccharides increase interleukin-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-alpha) in macrophage cultures.

• They also seem to increase release of interferon-gamma from T-lymphocytes.

• Triterpenoids from reishi mushroom are also thought to have potential antitumor and immunomodulatory effects.

• In clinical research, reishi mushroom extract has been used to reduce lower urinary tract symptoms (LUTS). It is possible that these benefits are related to the inhibition of 5-alpha-reductase enzymes responsible for the synthesis of dihydrotestosterone.(4)

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SHITAKELENTINUS EDODES

• Fresh shiitake is available in Scandavia and is frequently found in East Asian restaurants and markets.

• Laboratory research suggests that shiitake extract has antiviral activity, possibly by inhibiting the initial stages of replication.

• Shiitake contains lentinan (0.02%) which has known immunostimulatory effects. Lentinan appears to enhance T-helper cells and stimulate interferon and various cytokines. It also increases the activity of natural killer cells and macrophages.

• In human research, eating shiitake mushrooms increased signs of immune stimulation in laboratory research, including natural killer cell and T cell activity. Based on saliva immunoglobulin levels, gut immunity was enhanced. In laboratory research these same effects may be seen with shiitake extract.(1)

• Used together, maitake and shiitake have been reported to have a synergistc effect in the immunsystem.(6)

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WHICH ONE?

• Medical mushrooms have benefical effects on the immune system due to their β-glucan content and this is similar for all types.

• Medicinal mushrooms have secondary effects, listed below, due to their content of other chemical groups. These are:

➢ Almond – together with standard treatment cancer

➢ Chaga – avoid with kidney problems

➢ Cordyceps – kidney and pancreas (endocrine) problems

➢ Coriolus – well tolerated with poor digestion

➢ Lion’s Mane – stomach problems

➢ Maitake – very safe

➢ Reishi – prostate problems

➢ Shiitake – depressed immunity, well tolerated; use in soups

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DOSAGES?• The author’s clinical experience with medicinal mushrooms is limited to

5 years. It is the author’s view that capsules of concentrated extractsare particularly convenient for several reasons: controlled dosage; no taste; convenient to swallow and convenient for travel.

• Recommded dosage is generally 1 capsule twice daily, but for severeproblems alternative doses may include:

o 1 capsule twice daily of 2 types: tex. Shiitake and Maitake, or

o 1 capsule twice daliy of Almond mushroom and 1 Shiitake and 1 Maitake.

▪ Agricus / Almond - 1400mg (350mg 4:1 extract), 30% polysaccahrides

▪ Chaga – 2400mg (300mg 8:1 extract), 25% polysaccahrides.

▪ Cordyceps – 2100mg (350mg 6:1 extract), 30% polysaccahrides

▪ Coriolus – 2400mg (300mg 8:1 extract), 30% polysaccahrides

▪ Lion’s Mane – 2100mg (300mg 7:1 extract), 30% polysaccahrides

▪ Maitake – 2400mg (300mg 8:1 extract), 30% polysaccahrides

▪ Reishi – 4500mg (300mg 15:1 extract), 20% polysaccahrides + 5% triterpenes. Polar and nonpolar extracts combined.

➢ Shiitake – 1400mg (350mg 4:1 extract), 30% polysaccahrides

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REFERENCES

1. Ng, J.W., W.C. Cho, and D.M. Sze, The Use of Medicinal Mushroom or Herb as

Effective Immunomodulatory Agent. Herb Med. 2016,, 2016. 2(1).

2. Gargano, M.L., et al., Medicinal mushrooms: Valuable biological resources of high

exploitation potential. Plant Biosystems - An International Journal Dealing with all

Aspects of Plant Biology, 2017. 151(3): p. 548-565.

3. Chaturvedi, V.K., et al., Medicinal mushroom: boon for therapeutic applications. 3 Biotech, 2018. 8(8): p. 334.

4. Therapeutic Research Center, Natural Medicines Database. 2020.

https://naturalmedicines.therapeuticresearch.com/.

5. Ahn, W.-S., et al., Natural killer cell activity and quality of life were improved by

consumption of a mushroom extract, <em>Agaricus blazei Murill</em> Kyowa, in

gynecological cancer patients undergoing chemotherapy. International Journal of

Gynecologic Cancer, 2004. 14(4): p. 589-594.6. Vetvicka, V. and J. Vetvickova, Immune-enhancing effects of Maitake (Grifola

frondosa) and Shiitake (Lentinula edodes) extracts. Annals of translational medicine, 2014. 2(2): p. 14-14.

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