Dosing Principles for Medicinal Mushrooms

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Therapeutic vs maintenance dosing

Therapeutic dosing: Higher doses, often more frequently throughout the day

Maintenance: Lower doses, often less frequently throughout the day

Immune-Specific Dosing

The concept of therapeutic and maintenance dosing is based on the theory of ‘trained immunity’ (1,2). This theory suggests that ongoing, high doses of ß-glucan-rich mushrooms are not, in fact, necessary to potentiate immune modulation and protection from infections. The innate immune system, or the “first responders,” has the ability to create non-specific memory responses to a variety of subsequent infections after a primary infection or vaccination. For example, a person may become infected with a specific pathogen (virus, bacteria or fungi) and the innate immune system will mount a response to that specific pathogen. Additionally, innate memory cells will remain that can help protect against that same infection in the future, as well as other unrelated infections, i.e. a non-specific memory response. These changes in immune memory have been observed for as long as one year following initial administration of ß-glucans (3). These innate memory cells have a relatively short lifespan, and so it seems unlikely that trained immunity would last as long as it does. However, researchers have discovered that ß-glucans not only induce trained immunity in mature innate immune cells, but they also alter the cells hematopoietic progenitors (cells that will eventually differentiate into innate immune cells) within the bone marrow leading to the prolonged presence of trained monocytes and macrophages in circulation (4). The ß-glucans are essentially playing a role in your immune cells’ epigenetic purpose.

Initial higher dosing of ß-glucan-rich mushrooms is like an immune training program. Similar to building muscle, the initial training takes a little longer, and you have to train more often. Maintaining muscle is much easier than building muscle, and sometimes once a week training is all that is needed for muscle maintenance. Similarly, taking mushrooms one to two times per day, and maybe even a few times per week, is all that is needed for immune maintenance.

Initial dosing during the therapeutic phase for immune modulating effects should be done repeatedly, ideally three times per day. One study comparing the duration of the effect of oral dosing versus intravenous dosing of ß-glucans found that the repeated oral dosing “clearly resulted in stronger and longer action stimulation (5).” Intravenous dosing of ß-glucans is mostly available in clinical trials outside of the United States and is not yet common practice in the U.S. Therefore, repeated oral dosing two to three times per day is most likely to optimize initial immune benefits.

Neurocognitive-specific Dosing

When dosing mushrooms like lion’s mane, tremella and oyster mushroom for neurocognitive benefits, the idea of immune training or cellular training does not apply. In the majority of studies exploring the neurocognitive benefits of lion’s mane, researchers have found that many benefits relating to memory and mood were no longer present after discontinuation of supplementation.  It is important to note, however, that certain patterns related to mood may be a result of “negative neuroplasticity.” Negative neuroplasticity is the idea that getting stuck in a particular maladaptive pattern, like insomnia, can create neural patterns that are then primed for insomnia. Changing certain behaviors or taking certain medications and/or supplements can help to rewire negative patterns. Mushrooms with neurological actions, such as BDNF-mediated neurogenesis, may help to rewire negative plasticity, and therefore may not be needed on a daily basis as previously thought. While this may be true for mood-related disorders, it is unlikely to be the case for memory and cognitive enhancement. Either way, once daily dosing seems adequate for neurocognitive effects.

Absorption

Mushrooms are composed of many different constituents. These constituents have different physiological activities that are fully dependent on whether they are absorbed, or not absorbed, into the bloodstream from the intestines.

Immune considerations

The immune-modulating benefits of mushrooms are dependent on a healthy environment within the small intestine, where there are groups of immune cells within the gut-associated lymphoid tissue (GALT). The GALT contains pockets of immune cells called Peyer’s patches which contain M cells, and M cells present ß-glucans to innate immune cells like macrophages and dendritic cells via specific cell-surface receptors, most notably dectin-1, but also TLR2 and CR3. Mushroom ß-glucans bind to dectin-1 and stimulate an immune response throughout the bloodstream, lymphatic system, spleen, bone marrow, and lymph nodes.

It is important to note, however, that not all ß-glucans are absorbed into the bloodstream, and that some make their way to the large intestine. Mushroom ß-glucans are prebiotics, acting as food for healthy gut microbes and improving the intestinal microenvironment (6). A healthy intestinal microenvironment is fundamental to human health and research has shown that microbial fermentation of fungal ß-glucans can increase important post-biotic short chain fatty acids like butyrate (7). Improving the intestinal microenvironment does not result in trained immunity, like small intestinal absorption of ß-glucans does, so for prebiotic benefits, daily dosing seems best.

Additional Considerations

Food. If there is a lot of food in the small intestine, there will be less surface area for the ß-glucans to come into contact with M cells, and the immune response will likely be less significant than it would be on an empty stomach.

Alcohol. Chronic alcohol consumption has been shown to alter the innate immune system at the level of the Peyer’s patch (8). Frequent alcohol intake may lessen the immune benefits of mushroom ß glucans.

Tannins/polyphenols. Blending and emulsifying ß-glucans with tannin-rich substances like coffee, tea and chocolate create a tannin-polysaccharide complex. However, the bonds between polysaccharides and polyphenols are hydrogen bonds and are easily impacted by temperature and pH (acidity). Bonds can be broken at high temperatures between 68°F-104°F, so if blending mushroom powders with tannin-rich foods, blend at higher temperatures rather than cold. If polysaccharides are contained in these complexes when they reach the small intestine, they will not be available to bind immune receptors in the GALT and their immune-modulating properties will likely be nullified (9).

Work Cited

  1. Moerings, B. G. J., de Graaff, P., Furber, M., Witkamp, R. F., Debets, R., Mes, J. J., van Bergenhenegouwen, J., & Govers, C. (2021). Continuous Exposure to Non-Soluble β-Glucans Induces Trained Immunity in M-CSF-Differentiated Macrophages. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.672796
  2. Garcia-Valtanen P, Guzman-Genuino RM, Williams DL, Hayball JD, Diener KR. Evaluation of trained immunity by β-1, 3 (d)-glucan on murine monocytes in vitro and duration of response in vivo. Immunol Cell Biol. 2017 Aug;95(7):601-610. doi: 10.1038/icb.2017.13. Epub 2017 Feb 23. PMID: 28228641; PMCID: PMC5550561.
  3. Moorlag SJCFM, Khan N, Novakovic B, Kaufmann E, Jansen T, van Crevel R, Divangahi M, Netea MG. β-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1. Cell Rep. 2020 May 19;31(7):107634. doi: 10.1016/j.celrep.2020.107634. PMID: 32433977; PMCID: PMC7242907.
  4. Mitroulis I., Ruppova K., Wang B., Chen L.S., Grzybek M., Grinenko T., Eugster A., Troullinaki M., Palladini A., Kourtzelis I. Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity. Cell. 2018;172:147–161.e12.
  5. Vetvicka, Vaclav & Vetvickova, Jana & Ms,. (2008). A Comparison of Injected and Orally Administered β-glucans. 11.
  6. Nowacka-Jechalke N, Juda M, Malm A. The preliminary study of prebiotic potential of Polish wild mushroom polysaccharides: the stimulation effect on Lactobacillus strains growth. Eur J Nutr. 2018 Jun;57(4):1511-1521. doi: 10.1007/s00394-017-1436-9. Epub 2017 Mar 28. PMID: 28353071; PMCID: PMC5959981.
  7. Mitsou EK, Saxami G, Stamoulou E, Kerezoudi E, Terzi E, Koutrotsios G, Bekiaris G, Zervakis GI, Mountzouris KC, Pletsa V, Kyriacou A. Effects of Rich in Β-Glucans Edible Mushrooms on Aging Gut Microbiota Characteristics: An In Vitro Study. Molecules. 2020 Jun 18;25(12):2806. doi: 10.3390/molecules25122806. PMID: 32570735; PMCID: PMC7355846.
  8. ​​Lopez MC, Watzl B, Colombo LL, Watson RR. Alterations in mouse Peyer’s patch lymphocyte phenotype after ethanol consumption. Alcohol. 1997;14(2):107-110. doi:10.1016/s0741-8329(96)00104-8
  9. Li R, Zeng Z, Fu G, Wan Y, Liu C, McClements DJ. Formation and characterization of tannic acid/beta-glucan complexes: Influence of pH, ionic strength, and temperature. Food Res Int. 2019;120:748-755. doi:10.1016/j.foodres.2018.11.034

citations?

Ergosterol : Therapeutic constituents in medicinal mushrooms

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Photo by Pixabay on Pexels.com

Ergosterol is as ubiquitous in mushrooms as cholesterol is in humans. It is formed by an almost identical metabolic process, the mevalonate pathway. When mushrooms are exposed to ultraviolet light, ergosterol is converted to ergocalciferol, or vitamin D2. Once ingested, vitamin D2 is converted to calcidiol in the liver and eventually calcitriol, our active vitamin D3, in the kidneys. There is clinical evidence demonstrating that ergocalciferol-D2, although not as bioavailable as calcitriol, could improve vitamin D deficiency in humans (1,2,3).

Mushrooms are an excellent source of vitamin D2, particularly if they have been exposed to ample UV light (4). Researchers found that when people consumed chanterelle mushrooms containing 14 mcg of ergocalciferol with their lunch, that their serum vitamin D levels improved as much as the group who was receiving ergocalciferol supplementation (5). However, another study found that vitamin D levels decreased significantly after cooking mushrooms and serum concentrations of vitamin D after consumption of 100 g fresh sliced cooked mushrooms for 16 weeks did not show significant improvement in serum vitamin D levels. This was, notably, in a prediabetic, overweight population (6). In healthy young adults, serum vitamin D levels did improve after consumption of vitamin D2-enhanced button mushrooms via UV-B irradiation and to a similar degree as with a vitamin D2 supplement (7).

The benefits of optimal serum vitamin D levels include and are not limited to:

Bone health, kidney health, immune modulation, calcium homeostasis, and cardiovascular health (8).

  1. Vaes AMM, Tieland M, de Regt MF, Wittwer J, van Loon LJC, de Groot LCPGM. Dose-response effects of supplementation with calcifediol on serum 25-hydroxyvitamin D status and its metabolites: A randomized controlled trial in older adults. Clin Nutr. 2018;37(3):808-814. doi:10.1016/j.clnu.2017.03.029
  2. Martineau AR, Thummel KE, Wang Z, et al. Differential Effects of Oral Boluses of Vitamin D2 vs Vitamin D3 on Vitamin D Metabolism: A Randomized Controlled Trial. J Clin Endocrinol Metab. 2019;104(12):5831-5839. doi:10.1210/jc.2019-00207
  3. Seijo M, Mastaglia S, Brito G, Somoza J, Oliveri B. Es equivalente la suplementación diaria con vitamina D2 o vitamina D3 en adultos mayores? [Is daily supplementation with vitamin D2 equivalent to daily supplementation with vitamin D3 in the elderly?]. Medicina (B Aires). 2012;72(3):195-200.
  4. Kamweru PK, Tindibale EL. Vitamin D and Vitamin D from Ultraviolet-Irradiated Mushrooms (Review). Int J Med Mushrooms. 2016;18(3):205-214. doi:10.1615/IntJMedMushrooms.v18.i3.30
  5. Outila TA, Mattila PH, Piironen VI, Lamberg-Allardt CJ. Bioavailability of vitamin D from wild edible mushrooms (Cantharellus tubaeformis) as measured with a human bioassay. Am J Clin Nutr. 1999;69(1):95-98. doi:10.1093/ajcn/69.1.95
  6. Mehrotra A, Calvo MS, Beelman RB, et al. Bioavailability of vitamin D2 from enriched mushrooms in prediabetic adults: a randomized controlled trial. Eur J Clin Nutr. 2014;68(10):1154-1160. doi:10.1038/ejcn.2014.157
  7. Urbain P, Singler F, Ihorst G, Biesalski HK, Bertz H. Bioavailability of vitamin D₂ from UV-B-irradiated button mushrooms in healthy adults deficient in serum 25-hydroxyvitamin D: a randomized controlled trial. Eur J Clin Nutr. 2011;65(8):965-971. doi:10.1038/ejcn.2011.53
  8. Charoenngam N, Holick MF. Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients. 2020;12(7):2097. Published 2020 Jul 15. doi:10.3390/nu12072097

Terpenes: THERAPEUTIC CONSTITUENTS IN MEDICINAL MUSHROOMS

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Terpenes are fat- and alcohol-soluble compounds that come in many variations – monoterpenes, sesquiterpenes, diterpenes and triterpenes. The prefix indicates the number of carbons in the molecule: 10, 15, 20, and 30, respectively. As the terpene becomes bigger, it also becomes heavier and less volatile. The mushroom smell many are familiar with is in part due to low-molecular weight molecules that make their way into the nose – the monoterpenes and sesquiterpenes. These lower-weight chemicals act as attractants and deterrents to insects and other invertebrates, acting as both pheromones and defense chemicals. The most well-known terpenes in fungi are both found in lion’s mane. Erinicines, a group of diterpenoids, have nootropic properties and are found in lion’s mane mycelium, while the terpene hericenones, which are also nootropic, are found in lion’s mane fruiting body.

As the mushroom matures from primordia to fruiting body, an enzyme stimulates the synthesis of triterpenes. Because of this, there are significantly more triterpenes in the mushroom compared to the mycelium and primordia. Triterpenes in mushrooms are lanostane triterpenes, and can be referred to as “lanostanoids”. The most well-known triterpenes found in mushrooms are ganoderic acids, found in various species of reishi. These terpenes are major compounds of interest in cancer research because they have cytotoxic activity in many cancer cell lines; they also demonstrate specific antiviral activity, and are helpful in the treatment of hypersensitivity reactions.

Ganoderic acid, a triterpene isolated from Ganoderma spp. 

Anti-neoplastic

There are a significant number of in vitro and in vivo animal studies demonstrating direct anti-neoplastic activity of triterpenes. These molecules are cytotoxic to many cancer cell lines, as well as instigators of an antineoplastic immune response (1,2,3,4,5,6).

Anti-viral

Mushroom-derived triterpenes and sesquiterpenes have specific antiviral activity through the inhibition of the enzyme neuraminidase, which viruses use to leave one cell to enter another (7,8).  In addition to anti-neuraminidase activity, triterpenes stimulate an immune response that preferences cytotoxic CD8 T cells, a major component of adaptive antiviral immunity (9).

Anti-allergic

Triterpenes may be very beneficial in the treatment of hypersensitivity reactions including allergy, dermatitis and rhinitis. Ganoderic acids from reishi inhibit histamine release from mast cells, which can moderate the severity of allergic reactions (10). Ganoderic acids have also been shown to induce the release of the cytokines IL-10 and IFN-𝛾, suppressing TH2 responses in favor of TH1, and moving the immune system away from allergic responses (11).

Neuroprotective

Erinacines and hericenones, diterpenes found in lion’s mane mycelium and fruiting body, respectively, both have neuroprotective activity (12). Both molecules have demonstrated neurogenesis via nerve growth factor synthase activation, and erinacines improve plaque formation in mouse models of Alzheimer’s disease while increasing hippocampal neurogenesis (12).

Absorption

Only 10% of terpenes found in fungi are bioavailable with oral consumption, potentially due to first-pass metabolism in the liver and metabolism by intestinal bacteria (13). Raw mushrooms offer particularly poor bioavailability, as terpenes remain trapped inside fungal cells, while mushroom extracts offer improved absorption. Taking terpene-rich extracts with food impairs absorption; for best results, take terpene-rich mushrooms as extracts on an empty stomach (14). To learn more, check out my blog post on factors impacting the absorption of mushroom constituents.

DIY Extraction of Terpenes

Terpenes are alcohol- and fat-soluble and range from low- to high-molecular weight

  1. Infuse chopped mushrooms into oil and use as a base for lotion, salad dressings or flavorful drizzle
  2. Soak dried and chopped mushrooms in alcohol as part of a double extraction process.

1. Ríos JL. Effects of triterpenes on the immune system. J Ethnopharmacol. 2010;128(1):1-14. doi:10.1016/j.jep.2009.12.045.

2. Grienke U, Kaserer T, Pfluger F, et al. Accessing biological actions of Ganoderma secondary metabolites by in silico profiling. Phytochemistry. 2015;114:114-124. doi:10.1016/j.phytochem.2014.10.010.

3. Bhattarai G, Lee Y-H, Lee N-H, et al. Fomitoside-K from Fomitopsis nigra Induces Apoptosis of Human Oral Squamous Cell Carcinomas (YD-10B) via Mitochondrial Signaling Pathway. Biol Pharm Bull. 2012;35(10):1711-1719. doi:10.1248/bpb.12-00297.

4. Ren G, Liu XY, Zhu HK, Yang SZ, Fu CX. Evaluation of cytotoxic activities of some medicinal polypore fungi from China. Fitoterapia. 2006;77(5):408-410. doi:10.1016/j.fitote.2006.05.004.

5. Jin X, Ruiz Beguerie J, Sze DM-Y, Chan GCF. Ganoderma lucidum (Reishi mushroom) for cancer treatment. Cochrane database Syst Rev. 2016;4:CD007731. doi:10.1002/14651858.CD007731.pub3.

6. Zhu Q, Bang TH, Ohnuki K, Sawai T, Sawai K, Shimizu K. Inhibition of neuraminidase by Ganoderma triterpenoids and implications for neuraminidase inhibitor design. Sci Rep. 2015;5(AUGUST):13194. doi:10.1038/srep13194.

7. Teplyakova T V., Psurtseva N V., Kosogova TA, Mazurkova NA, Khanin VA, Vlasenko VA. Antiviral Activity of Polyporoid Mushrooms (Higher Basidiomycetes) from Altai Mountains (Russia). Int J Med Mushrooms. 2012;14(1):37-45. doi:10.1615/IntJMedMushr.v14.i1.40.

8. Gao L, Sun Y, Si J, et al. Cryptoporus volvatus extract inhibits influenza virus replication in vitro and in vivo. PLoS One. 2014;9(12). doi:10.1371/journal.pone.0113604.

9. Van Thu Nguyen, Nguyen The Tung, To Dao Cuong, Tran Manh Hung, Jeong Ah Kim, Mi Hee Woo, Jae Sue Choi, Jeong-Hyung Lee, Byung Sun Min, Cytotoxic and anti-angiogenic effects of lanostane triterpenoids from Ganoderma lucidum, Phytochemistry Letters, Volume 12, 2015, Pages 69-74, ISSN 1874-3900,

https://doi.org/10.1016/j.phytol.2015.02.012.

10. Bhardwaj N, Katyal P, Sharma AK. Suppression of inflammatory and allergic responses by pharmacologically potent fungus Ganoderma lucidum. Recent Pat Inflamm Allergy Drug Discov. 2014;8(2):104-17. doi: 10.2174/1872213×08666140619110657. PMID: 24948193.

11. Liu C, Cao M, Yang N, Reid-Adam J, Tversky J, Zhan J, Li XM. Time-dependent dual beneficial modulation of interferon-γ, interleukin 5, and Treg cytokines in asthma patient peripheral blood mononuclear cells by ganoderic acid B. Phytother Res. 2022 Mar;36(3):1231-1240. doi: 10.1002/ptr.7266. Epub 2022 Feb 3. PMID: 35112740.

12. Friedman M. Chemistry, Nutrition, and Health-Promoting Properties of Hericium erinaceus (Lion’s Mane) Mushroom Fruiting Bodies and Mycelia and Their Bioactive Compounds. J Agric Food Chem. 2015;63(32):7108-7123. doi:10.1021/acs.jafc.5b02914

13. Teekachunhatean, S., Sadja, S., Ampasavate, C., Chiranthanut, N., Rojanasthien, N., & Sangdee, C. (2012). Pharmacokinetics of Ganoderic Acids A and F after Oral Administration of Ling Zhi Preparation in Healthy Male Volunteers. Evidence-Based Complementary and Alternative Medicine, 2012, 780892. https://doi.org/10.1155/2012/780892

14. Verhoeven J, Keller D, Verbruggen S, Abboud KY, Venema K. A blend of 3 mushrooms dose-dependently increases butyrate production by the gut microbiota. Benef Microbes. 2021;12(6):601-612. doi:10.3920/BM2021.0015

Polysaccharides : THERAPEUTIC CONSTITUENTS IN MEDICINAL MUSHROOMS

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Polysaccharides are a major component of the fungal cell wall and possibly the most potent and abundant therapeutic constituent in mushroom medicine. They are well-touted for their immune regulatory activity, but they play a role in many other important physiologic processes including blood sugar regulation, inflammation modulation, antioxidant activity, mood support, and modulation of the intestinal microbiome and the greater intestinal environment.

Biologic Response Modifiers

The fungal cell wall is composed of many layers – mannoproteins, ß- (1,6)-glucan and ß-(1,3)-glucan, and chitin. Humans do not make chitinase, and cannot utilize chitin for anything other than non-digestible fiber. Chitin can, however, be broken down by different processing techniques, including heat, allowing the mannan and beta-glucan layers to be utilized as medicine. From an immunological perspective, these layers are considered pathogen-associated molecular patterns (PAMPs), and bind to pathogen recognition receptors (PRRs) on cells in the innate immune system – macrophages, granulocytes, dendritic cells and natural killer cells. The majority of binding occurs in the gut-associated lymphoid tissue (GALT), where Peyer’s patches contain cells of the innate immune system. Specific receptors that bind these ß-glucans include Dectin-1 and TLR-2 (1). Binding has a hormetic effect, creating a stress response in our immune system, stimulating the release of cytokines with anti-inflammatory, pro-inflammatory, and other immune-modulating actions.  These cytokines stimulate an increase in natural killer cells and cytotoxic T cells, generating a stress signal that leads to a more responsive immune system.

Blood Sugar regulation

ß-glucan polysaccharides from mushrooms inhibit the enzyme alpha-glucosidase, which is essential for carbohydrate metabolism and for generating a rise in blood sugar following a meal. They have also been shown to decrease gastric emptying, slowing the absorption of glucose, and preventing hyperglycemic episodes. Finally, polysaccharides demonstrate the ability to upregulate GLUT 4, an insulin-response glucose transporter, while down-regulating NF-κB, a nuclear transcription factor that regulates inflammation (2,3).

Antioxidant

ß-glucan polysaccharides increase the activity of hepatic oxidative enzymes such as catalase, glutathione peroxidase, and superoxide dismutase, increasing levels of glutathione and decreasing malondialdehyde levels (a marker of lipid peroxidation). Generally, these compounds support our innate antioxidant systems, relieving oxidative stress, and reducing free radical damage (4).

Prebiotic

The oligosaccharides and polysaccharides contained in mushrooms are consumed by Bifidobacterium and Lactobacilli, two important bacterial phyla in a healthy microbiome (5,6). Polysaccharides also promote production of important postbiotics like butyric acid, a short chain fatty acid, which provides colon cells with about 70% of their total energy needs (7).

Psychobiotic

Polysaccharides play a role in creating a healthy intestinal ecosystem through potentiating the growth of healthy bacteria, archaea and fungi while also supporting a more resilient gastrointestinal terrain. Healthy gut flora and intestinal mucosa are associated with better mood. Signals from the GI tract can independently relay information to the central nervous system, and the maintenance of a healthy GI tract supports a balanced central nervous system. There are a number of studies that have demonstrated increased probiotic intake associated with increased mood and diminished anxiety (8). Specifically, probiotic supplementation with Lactobacillus helveticus and Bifidobacterium longum showed less self-reported negative mood and decreased urinary cortisol. A similar effect was also observed in healthy participants who consumed a mixture of Bifidobacterium bifidum and Bifidobacterium lactis, and Lactobacillus acidophilus, Brevibacillus brevis, Brevibacterium casei, Bifidobacterium salivarius, and Lactococcus lactis (9,10).

Absorption

Raw mushroom preparations (including products labeled “mushroom powder”) have not undergone sufficient processing to break down the chitin in the cell wall, leaving ß-glucans unavailable for absorption; extractions employ heat, water, and alcohol to free ß-glucans, improving their absorption and activity. While mixing mushrooms with coffee, tea, or chocolate is increasingly popular, the tannins in these foods bind the fungal polysaccharides, diminishing bioavailability (11). For best results, take polysaccharide-rich mushroom preparation on an empty stomach, away from food. To learn more, check out my blog post on factors impacting the absorption of mushroom constituents.

DIY Extraction of Polysaccharides

Polysaccharides are water soluble and high molecular weight (heavy molecules that don’t evaporate)

  1. Boil chopped (fresh or dried) mushrooms in water for about 2 hours. Use this water as a base for creams, teas, stews, soups and concentrated extracts

References

  1. Baert K, Sonck E, Goddeeris BM, Devriendt B, Cox E. Cell type-specific differences in β glucan recognition and signalling in porcine innate immune cells. Dev Comp Immunol. 2015;48(1):192-203. doi:10.1016/j.dci.2014.10.005.
  2. Vitak T, Yurkiv B, Wasser S, Nevo E, Sybirna N. Effect of medicinal mushrooms on blood cells under conditions of diabetes mellitus. 2017;8(5):187-201. doi:10.4239/wjd.v8.i5.187.
  3. Chen Y, Liu Y, Rahman M, Yan X, Yang C. Structural characterization and antidiabetic potential of a novel heteropolysaccharide from Grifola frondosa via IRS1 / PI3K-JNK signaling pathways. Carbohydr Polym. 2018;198(15):452-461. doi:10.1016/j.carbpol.2018.06.077.
  4. Wang H, Liu YM, Qi ZM, et al. An Overview on Natural Polysaccharides with Antioxidant Properties. 2015;(February). doi:10.2174/0929867311320230006.
  5. Yu Z, Liu B, Mukherjee P, Newburg DS. Trametes versicolor Extract Modifies Human Fecal Microbiota Composition In vitro. 2013:107-112. doi:10.1007/s11130-013-0342-4.
  6. Palacios S, Losa F, Dexeus D, Cortés J. Beneficial effects of a Coriolus versicolor – based vaginal gel on cervical epithelization , vaginal microbiota and vaginal health : a pilot study in asymptomatic women. 2017:4-9. doi:10.1186/s12905-017-0374-2.
  7. Verhoeven J, Keller D, Verbruggen S, Abboud KY, Venema K. A blend of 3 mushrooms dose-dependently increases butyrate production by the gut microbiota. Benef Microbes. 2021 Nov 16;12(6):601-612. doi: 10.3920/BM2021.0015. Epub 2021 Sep 30. PMID: 34590532.
  8. Messaoudi M, Violle N, Bisson J-F, Desor D, Javelot H, Rougeot C. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes 2011;2:256– 261.
  9. Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun 2015;48:258–264.
  10. Allen AP, HutchW, Borre YE, et al. Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Transl Psychiatry 2016;6:e939.
  11. Li R, Zeng Z, Fu G, Wan Y, Liu C, McClements DJ. Formation and characterization of tannic acid/beta-glucan complexes: Influence of pH, ionic strength, and temperature. Food Res Int. 2019;120:748-755. doi:10.1016/j.foodres.2018.11.034

Fungi Parts and Medicinal Quality – Not Just Semantics

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All mushrooms are fungi, but not all fungi are mushrooms

A mushroom is the macroscopic, above-ground portion of the fungal organism. The mycelium is the root portion of the fungi that is rarely seen; it is usually found within a rotting tree trunk, or in a dense underground network. Similar to the way that humans digest and absorb nutrients, mycelia excrete enzymes that break down the waste of the forest, and use this energy to form a mushroom, or a fruit body. When the mushroom has fully matured, seed-like spores are released and wind and insects carry them to their next place of inoculation. The spores, mycelium, and mushroom are all vital aspects of the fungal organism and are, more specifically, different life stages of the fungi. A spore is not a mushroom, a mushroom is not mycelium, and mycelium is most definitely not a mushroom.

Until recently, mycelium was not used medicinally. The energy and time it would take to dig up mycelium from the earth, or separate it from a rotting tree trunk, would far outweigh the medicinal benefit from the small amount of mycelium collected. Traditionally humans, being the innately lazy animals that we are, preferred to spend a few minutes to collect the colorful mushrooms and use them as medicine rather than spend hours digging up and separating out mycelium from rotting flora. If all mushroom products were made from wild harvested fruiting bodies, there would likely be no market for mycelium. Unfortunately, this would not be sustainable, so many companies have developed sterile laboratories where they can cultivate mycelium grown on grain substrate. The same issue returns, however – the cost of the time it would take to separate all the mycelium from the grain is not economically viable. So, the mycelium is not separated from the substrate it is grown on, and the entire block of myceliated grain is dried, powdered, bottled up, and advertised as a mushroom supplement.

Mycelium as a medicine

Mycelium contains many similar medicinal compounds to mushrooms, but often to a lesser degree, with the exception of some polysaccharides. While the majority of research has focused on mushrooms, there is still a fair amount of research touting the health benefits and active compounds present in mycelium. However, these trials utilize mycelium that is grown in a liquid fermentation broth rather than the myceliated-grain that is found in many health food store and apothecary shelves. When mycelium is grown in a broth, the liquid can be strained off and pure mycelium can be processed. However, as mentioned earlier, when mycelium is grown on grain, it is not filtered out or separated and many products can contain up to 60% grain. Pure mycelium from a number of different fungal species absolutely has medicinal value, but that value is heavily diluted when 250mg of your 500mg capsule is oat or sorghum substrate.

A Comparison of Constituents

As mycelium matures into a mushroom, the organism’s energy is focused on reproduction, and there is a vast increase in production of many compounds that happen to be beneficial to humans. One study (1) compared the amount of GABA, lovastatin and ergothioneine in mycelium with that found in mushrooms. GABA, a calming neurotransmitter, was found in equal amounts in both mushroom and mycelium. Lovastatin, a compound that helps to support healthy cholesterol levels, was found to be especially high in the fruiting body of oyster mushroom in comparison to mycelium. Finally, ergothioneine, an extraordinary antioxidant, was found both in oyster mycelium and mushroom, but to a much larger extent in the mushroom.

Another study (2) compared the antioxidant activity of reishi mushroom, spores and mycelium. Reishi mushroom yielded the highest antioxidant activity via phenolic compounds in the extracts. The mycelium contained the highest total level of polysaccharides and single sugar molecules, but the free-radical scavenging properties seemed to be correlated most with the phenolic compounds found in the fruiting body. The chemical makeup of reishi mycelium, fruiting body, and spores powder was explored by another team of researchers (3). They observed the presence of polysaccharides, nucleosides, peptides, triterpenoids and alkaloids present in different fungal life stages. Triterpenoids, especially ganoderic acids, were found in all life stages of the fungal organism, but were by far most abundant in the fruit body, and least abundant in the mycelium. Triterpenoids support a healthy inflammatory response, modulate the immune system, support liver pathways and support healthy cholesterol levels. Their results demonstrated that the polysaccharide content in all parts of reishi were  almost the same, with the most upregulated in the fermentation broth.

Polysaccharides, alpha glucans and beta glucans

Polysaccharides are sugar molecules attached by different bonds, some alpha and some beta. The kind of bond determines the physiological activity of the ingested polysaccharide. When exploring the medicinal value of fungi, the beta bond, or β-glucan, is preferred. Many grains contain starch, or alpha-glucans, which can sometimes be confused in the total polysaccharide content of a mushroom supplement. If 60% of a myceliated grain powder contains a high amount of polysaccharides, it is important to differentiate between those derived from the mycelium and those derived from the grain.

β-glucans are the most comprehensively studied constituents in medicinal fungi. Scientists have determined exactly which receptors they bind to, how they bind, where they bind, and the physiological activities that take place afterwards. β-glucans help to support many body systems – a healthy immune system, blood sugar levels and microbiome, to name a few. 

The β-glucan content of shiitake fruit body and mycelium was compared by Bak in 2014 (4). Researchers presented a quantitative analysis of β-glucan levels in three sections of the mushroom: stipe (stalk), pileus (cap) and mycelium. The highest β-glucan content was observed in the stipe, or stalk, section of the shiitake fruiting bodies. β-glucan content seems to depend on the degree of fruiting body maturity – the highest level of these compounds seems to be present immediately prior to the period in which the spores begin to ripen (5). Based on this information, mushrooms are likely the best source for β-glucans.

Conclusion

While mycelium is not devoid of medicinal value, most mycelium available for purchase is diluted by grain substrate, and the medicinal value is diluted as well. For this reason, pure fruit bodies that have been extracted and dried or extracted into a quality liquid extract are preferred when using fungi as a medicine. While the ideal product would likely contain pure mycelium mixed with fruiting body, this has yet to exist on the market without grain substrate involved.

Work Cited:

  1. Lo, Y.-C., Lin, S.-Y., Ulziijargal, E., Chen, S.-Y., Chien, R.-C., Tzou, Y.-J., & Mau, J.-L. (2012). Comparative Study of Contents of Several Bioactive Components in Fruiting Bodies and Mycelia of Culinary-Medicinal Mushrooms. International Journal of Medicinal Mushrooms. International Journal of medicinal mushrooms, Volume 14,2021, issue 4 https://doi.org/10.1615/IntJMedMushr.v14.i4.30
  2. Sandrina A. Heleno, Lillian Barros, Anabela Martins, Maria João R.P. Queiroz, Celestino Santos-Buelga, Isabel C.F.R. Ferreira, Fruiting body, spores and in vitro produced mycelium of Ganoderma lucidum from Northeast Portugal: A comparative study of the antioxidant potential of phenolic and polysaccharidic extracts, Food Research International, Volume 46, Issue 1, 2012, Pages 135-140,ISSN 0963-9969 https://doi.org/10.1016/j.foodres.2011.12.009.
  3. Chunliang Xie, Shaowei Yan, Zhoumei Zhang, Wenbing Gong, Zuohua Zhu, Yingjun Zhou, Li Yan, Zhenxiu Hu, Lianzhong Ai, Yuande Peng, Mapping the metabolic signatures of fermentation broth, mycelium, fruiting body and spores powder from Ganoderma lucidum by untargeted metabolomics, LWT, Volume 129, 2020, 109494, ISSN 0023-6438, https://doi.org/10.1016/j.lwt.2020.109494.
  4. Bak WC, Park JH, Park YA, Ka KH. Determination of Glucan Contents in the Fruiting Bodies and Mycelia of Lentinula edodes Cultivars. Mycobiology. 2014 Sep;42(3):301-4. doi: 10.5941/MYCO.2014.42.3.301. Epub 2014 Sep 30. PMID: 25346611; PMCID: PMC4206800.
  5. Rop O, Mlcek J, Jurikova T. Beta-glucans in higher fungi and their health effects. Nutr Rev. 2009;67(11):624-631. doi:10.1111/j.1753-4887.2009.00230.x

Are you absorbing your mushroom supplements?

| reishiandroses

Mushroom supplements come in many varieties, and it is important to consider not only the dose form but also how they are prepared for consumption, and how they are consumed. There are a few major factors that impact optimal bioavailability of active constituents.

Let’s begin by addressing two active constituents that are responsible for the therapeutic benefits of mushrooms: polysaccharides and triterpenes.

Active constituents

Polysaccharides

Polysaccharide (1-3, 1-6) ß-glucans are ubiquitous in medicinal mushrooms. ß-glucans are an integral aspect of the mushroom cell wall, and are structurally bound within a substance called chitin, best known as the main structural component in crustacean shells. When a mushroom goes through any kind of heating process, medicinal ß-glucans are unbound from chitin, and become bioavailable.

Vega, K., & Kalkum, M. (2012). Chitin, Chitinase Responses, and Invasive Fungal Infections. International Journal of Microbiology, 2012, 920459. https://doi.org/10.1155/2012/920459

After ingestion, ß-glucans survive stomach acid, bile, and other digestive secretions essentially unchanged. The major physiological effects induced by ß-glucans occur within the small intestine, where they bind to specific receptors on immune cells present within the gut associated lymphoid tissue (GALT).

Following ß-glucan binding to the receptors, a number of different immune regulatory processes take place, including indirect immune effects via modulation of the  intestinal microbiota. ß-glucans can act as substrate for beneficial flora present in the small intestine, helping to outcompete pathogenic intestinal flora. Beneficial bacteria that consume ß-glucans excrete the short chain fatty acid butyrate (1), which is also important for immune regulation and intestinal health.

Triterpenes

The triterpenes present in medicinal mushrooms are most commonly lanostane triterpene glycosides, or lanostenoids. While ß-glucans stimulate immunoregulatory pathways via the GALT and intestinal microbiota, triterpene glycosides have exhibited direct antineoplastic and anti-viral activity both in vitro and in vivo. 

Ganoderic acid

Unfortunately, triterpenes are not well absorbed following oral consumption, and we have yet to see any mushroom supplement companies recommending injection of their products (though it goes without saying: do not inject your mushroom extracts!). Around 10% of the triterpenes present in mushroom extracts is bioavailable (2), and this relatively poor bioavailability may be due to first pass metabolism through the liver and conversion of triterpene glycosides to metabolites via intestinal bacteria. Furthermore, consuming food with mushroom extracts delays and inhibits absorption of these medicinal compounds.

Factors that interfere with absorption of Beta-glucans and triterpenes

Eating mushrooms raw 

Some supplement labels may list their mushroom ingredients as “mushroom powder”. It is safe to assume that unless the product specifically states that it contains powdered extract, the mushrooms present have been dehydrated and powdered. Typical dehydration methods do not use enough heat to break down the chitin in the cell wall, leaving the ß-glucan fraction unavailable for its immune-modulating and prebiotic effects.

Given the undigested nature of dehydrated mushroom powders, consuming powdered mushrooms is largely equivalent to consuming very expensive fiber. Choose products that state “powdered mushroom extracts” or “mushroom extracts” on their labels to ensure they contain appropriately processed ß-glucans.

Blending mushrooms with coffee, tea, or chocolate

Mushroom extracts blended with tannin-rich foods like coffee, tea and chocolate will likely not be absorbed as well as mushroom extract taken alone. When blended or emulsified, polysaccharides and tannins can bind strongly to each other, and these bonds can survive the stomach without breaking. When this tannin-ß-glucan complex reaches the small intestine, the ß-glucans will not be recognized by immune cell receptors essential for promoting immunoregulatory processes. (3)

Taking mushroom extracts with food

Consuming mushroom extracts with food can significantly alter the speed and extent of absorption of triterpene glycosides. (1). For this reason, it is not recommended to use mushroom extract powders mixed into foods. For optimal absorption of the already low bioavailable triterpenes, take triterpene-containing mushroom supplements on an empty stomach.

N.B. It has been speculated that consuming vitamin C with mushroom extracts may enhance absorption but unfortunately this seems to be a myth. (4).

Summary

For the best absorption and bioavailability, take your mushrooms extracted, plain and simple, with water, and nothing else.

Work Cited:

  1. Verhoeven J, Keller D, Verbruggen S, Abboud KY, Venema K. A blend of 3 mushrooms dose-dependently increases butyrate production by the gut microbiota. Benef Microbes. 2021;12(6):601-612. doi:10.3920/BM2021.0015
  2. Teekachunhatean, S., Sadja, S., Ampasavate, C., Chiranthanut, N., Rojanasthien, N., & Sangdee, C. (2012). Pharmacokinetics of Ganoderic Acids A and F after Oral Administration of Ling Zhi Preparation in Healthy Male Volunteers. Evidence-Based Complementary and Alternative Medicine, 2012, 780892. https://doi.org/10.1155/2012/780892
  3. Li R, Zeng Z, Fu G, Wan Y, Liu C, McClements DJ. Formation and characterization of tannic acid/beta-glucan complexes: Influence of pH, ionic strength, and temperature. Food Res Int. 2019;120:748-755. doi:10.1016/j.foodres.2018.11.034
  4. Tawasri P, Ampasavate C, Tharatha S, Chiranthanut N, Teekachunhatean S. Effect of Oral Coadministration of Ascorbic Acid with Ling Zhi Preparation on Pharmacokinetics of Ganoderic Acid A in Healthy Male Subjects: A Randomized Crossover Study. Biomed Res Int. 2016;2016:2819862. doi:10.1155/2016/2819862

coffee, tea, chocolate and mushrooms: A mismatch of mediums?

| reishiandroses

The flavor of mushrooms is not for everyone, and many ‘functional’ food companies are well aware of this. Some of these companies formulate mushrooms in teas, chocolates and coffee so that their consumers can benefit from the mushrooms without having to deal with their ‘mushroomy’ flavor. In fact, many of them claim that mushrooms in these formulations even have enhanced medicinal properties. Although I am all for getting more mushroom medicine into more people, I think it is important for people to look into the interactions between different biomolecules before making claims about the medicinal quality of their products.

The interactions between various polyphenols (like tannins), and polysaccharides, are of particular interest. Polyphenols are found in varying degrees in coffee, tea and chocolate, and are also found in many other herbs and foods, but for the purposes of this article I will keep our discussion specific to foods that mushrooms are often formulated with (1, 2).

The polyphenols present in coffee, tea and chocolate have many health benefits, including anti-oxidant, anti-inflammatory and anti-microbial activity (3). The issue is not the medicinal qualities of polyphenols, but that when blended with mushroom extracts, they create bonds with polysaccharides (4, 5).

Abstract Image
Polysaccharides (left) Polyphenols (center) Polysaccharide-Polyphenol Complex (right)
J. Agric. Food Chem. 2013, 61, 19, 4533–4538
Publication Date:April 26, 2013
https://doi.org/10.1021/jf400471u

Immune-modulating polysaccharides are the most well-researched component of mushroom medicine. In order for polysaccharides to exert an immune-modulating effect, they need to bind to specific receptors on immune cells within the gut-associated-lymphoid-tissue (GALT) (6). If the polysaccharides are bound to polyphenols, they cannot bind to these receptors, and the immune-modulating benefits that these products are touted for become obsolete.

Important caveats:

The bonds between polysaccharides and polyphenols are hydrogen bonds, and are easily affected by temperature and pH:

Temperature: Bonds become less stable as temperature increases from 68F to 104F. You may want to blend your mushroom extracts with your coffee, chocolate and tea while the temperature is high. If the temperature is too low, the bonds will remain strong, even in stomach acid.

pH: Bonds become less stable as pH increases from 2 to 9. Stronger bonds seem to be made under more acidic conditions. The pH of stomach acid is around 1.5 to 3.5. Therefore, stomach acid will NOT break these bonds, and they will remain intact as the complexes enter the small intestine. Polysaccharides contained in these complexes will NOT be available to bind immune receptors in the GALT, and their immune-modulating properties will be nullified.

But all is not lost!

Polyphenols as well as polysaccharides exert many benefits on gut microbiota, and a healthy gut microbiome is imperative to strong immunity (7, 8, 9). I suspect that if these polyphenol-polysaccharide complexes make their way to the colon, their beneficial impacts on the microbiome do enhance the immune system, but through a different pathway than in the small intestine.

Work Cited

  1. Savolainen H. Tannin content of tea and coffee. J Appl Toxicol. 1992 Jun;12(3):191-2. doi: 10.1002/jat.2550120307. PMID: 1629514.
  2. Jalil AM, Ismail A. Polyphenols in cocoa and cocoa products: is there a link between antioxidant properties and health?. Molecules. 2008;13(9):2190-2219. Published 2008 Sep 16. doi:10.3390/molecules13092190
  3. Chung KT, Wong TY, Wei CI, Huang YW, Lin Y. Tannins and human health: a review. Crit Rev Food Sci Nutr. 1998 Aug;38(6):421-64. doi: 10.1080/10408699891274273. PMID: 9759559.
  4. Wang Y, Liu J, Chen F, Zhao G. Effects of molecular structure of polyphenols on their noncovalent interactions with oat β-glucan. J Agric Food Chem. 2013 May 15;61(19):4533-8. doi: 10.1021/jf400471u. Epub 2013 May 6. PMID: 23647238.
  5. Li, R., Zeng, Z., Fu, G., Wan, Y., Liu, C., & McClements, D. J. (2019). Formation and characterization of tannic acid/beta-glucan complexes: Influence of pH, ionic strength, and temperature. Food Research International, 120, 748–755. https://doi.org/https://doi.org/10.1016/j.foodres.2018.11.034
  6. Camilli, G., Tabouret, G., & Quintin, J. (2018). The Complexity of Fungal β-Glucan in Health and Disease: Effects on the Mononuclear Phagocyte System. Frontiers in Immunology, 9, 673. https://doi.org/10.3389/fimmu.2018.00673
  7. Kumar Singh A, Cabral C, Kumar R, et al. Beneficial Effects of Dietary Polyphenols on Gut Microbiota and Strategies to Improve Delivery Efficiency. Nutrients. 2019;11(9):2216. Published 2019 Sep 13. doi:10.3390/nu11092216Ho Do M, Seo YS, Park HY. Polysaccharides: bowel health and gut microbiota. Crit Rev Food Sci Nutr. 2021;61(7):1212-1224. doi: 10.1080/10408398.2020.1755949. Epub 2020 Apr 22. PMID: 32319786.Savolainen H. Tannin content of tea and coffee. J Appl Toxicol. 1992 Jun;12(3):191-2. doi: 10.1002/jat.2550120307. PMID: 1629514.
  8. Ho Do M, Seo YS, Park HY. Polysaccharides: bowel health and gut microbiota. Crit Rev Food Sci Nutr. 2021;61(7):1212-1224. doi: 10.1080/10408398.2020.1755949. Epub 2020 Apr 22. PMID: 32319786.
  9. Zheng, D., Liwinski, T. & Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res 30, 492–506 (2020). https://doi.org/10.1038/s41422-020-0332-7

Medicinal Mushrooms – Going Viral

| reishiandroses

Mushrooms have been used as both food and medicine since antiquity. One of my favorite poems, discovered in an ancient Egyptian temple, illustrates this history: “Without leaves, without buds, without flowers, yet from fruit; as food, as tonic, as medicine: the entire creation is precious.” At a time when viral epidemics are inevitable and the current COVID-19 pandemic has presented in most of the world, antiviral therapies are possibly being investigated now more than ever before.  This paper explores the use of medicinal mushrooms as antivirals in in vivo (human and animal) and in vitro (petri dish) experiments and how these experiments may inform us on the utilization of these fungi as antiviral therapies.

Medicinal mushrooms are known as biological response modifiers. This physiologic modification is largely a result of the interaction of various mushroom constituents, primarily polysaccharides, with the immune system. Therefore, to understand the role that medicinal mushrooms play as antiviral agents, it is imperative to understand the happenings of the immune system in response to a viral pathogen and the interplay between mushrooms, their constituents, and this system. Unlike pharmaceutical antivirals, the actions of medicinal mushrooms are not straightforward, and there is no absolute rule that mushrooms stimulate or depress immunity. Mushrooms contain many constituents and are dynamic in their interplay with the human body.

Overview of anti-viral immunity 

The initial immune response to a new pathogen is facilitated by the innate immune system (innate meaning inborn or natural). This is our first response to non-self organisms, and requires no other stimulation than the pathogen itself. It is the response that is ready to go at all moments in the day and persistently protects the human body from infection. It is easy to imagine that an altered or defective innate immune response can have a detrimental effect on the ability to fight disease.

The innate immune response to a virus is multidimensional. There is a massive amount of cell-to-cell communication and different chemicals (called cytokines) are released to make this communication possible. Once an epithelial cell (cells that make up the surface of different body tissues like skin, lungs, etc) is infected with a virus, Type 1 Interferon (Interferon-α, a cytokine) is released and has three major functions: to induce resistance to viral replication in all cells, to increase expression of ligands for receptors on natural killer (NK) cells, and to activate NK cells to kill virus infected cells. NK cells are lymphocytes (a small white blood cell that is found primarily in the lymphatic system) that defend against viral infections and tumor cells via cytokine stimulation and direct killing of infected cells. NK cells provide such a vital role in antiviral immunity that people deficient in NK cells suffer from persistent viral infections. These functions of NK cells are important in regards to understanding medicinal mushrooms and their role in antiviral immunity.

Imagine the immune response to a newly inhaled viral particle. This virus enters the healthy person’s lungs and invades the lung epithelium. Once an epithelial cell is infected, it releases Type 1 Interferon, which turns circulating NK cells into cytotoxic effector NK cells (NK cells primed to seek out and kill virally infected cells). The cytotoxic effector NK cells promptly start the process of seeking out infected cells and the innate immune response commences. At the same time, there are resident macrophages in the respiratory epithelium and throughout the body. These macrophages (“big eaters”), are also major players in the innate immune response. Their role is to consume these virus particles and produce chemicals (cytokines and chemokines) that attract and engage more NK cells and also T cells. An important cytokine engaged in this process is interleukin-12 (IL-12), which stimulates NK cells to not become cytotoxic, but rather effector NK cells. Unlike cytotoxic effector NK cells, these effector NK cells stimulate an inflammatory response via Type 2 Interferon (IFN-γ), at the site of infection. This inflammatory cascade consists of IL-1, IL-6, TNF-α, and IL-12, and is essential for viral eradication. It is only when this response is out of control that it becomes problematic and detrimental to the host.1,2,3,4 If this initial response is not primed for viral combat, viral particles continue to proliferate and infect more healthy cells. It is in this phase that medicinal mushrooms can have a great impact to prevent viral infections from taking over the host.

Cytokine Source Role
IFN-α Virus infected epithelium Circulating NK cells –>Cytotoxic effector NK cells
IL-12 Macrophage post virus consumption NK cells –> effector NK cells
IFN- γ Effector NK cells Macrophages –> inflammatory cytokines (TNF-α, IL-2, IL-1, IL-6)
TNF- α Macrophages Induces blood vessels more permeable, enabling effector cells to enter infected tissue
IL-1 Macrophages Induces blood vessels more permeable, enabling effector cells to enter infected tissue
IL-6 Macrophages Induces fat and muscle cells to metabolize, make heat and raise temperature of infected tissue
IL-12 Macrophages Recruits and activates NK cells –> secrete more cytokines that strengthen macrophage response to infection
IL-10 Toxic substances secreted by macrophages–> TH2 Suppress macrophage activation
IL-4 Toxic substances secreted by macrophages–> TH2 Suppress macrophage activation

 

COVID-19 is an excellent example of these two main immune responses.5 The first stage of infection is the less severe incubation phase. The previously mentioned immune response is imperative to eliminate the virus and keep disease from progressing to later, more severe stages. It is in the incubation stage that immune-stimulating therapies are most indicated. In more severe stages, the protective immune response is impaired and the virus will spread and destroy healthy cells. Because damaged cells induce inflammation, immune stimulation is less indicated and it is more favorable to treat with anti-inflammatory therapies. It is at this stage of disease, characterized by severe lung inflammation, that life-threatening respiratory disorders occur and the feared cytokine storm is initiated. The cytokine storm is an influx of inflammatory cytokines. It is an overdramatic immune response that is harmful to the host and can often lead to acute respiratory distress syndrome. The inflammatory cytokines that are so important for stage one of the disease ( IL-1, IL6, TNF-α, and IL-12) are now abundant, destructive and out of control.6,7

The two phase division of the immune response is very important . The first immune response is protective and a response that can be altered through diet and lifestyle: our base response when initially combating infection. As mentioned previously, this is the phase where medicinal mushrooms are most indicated. They are primers of the first response to viral particles.

 

Antiviral immunity in healthy adults

The most informative studies exploring the interaction of medicinal mushrooms and the immune response are done on healthy human adults. In these studies it is ideal to see cytokine and NK cell levels before and after mushroom intake in healthy people to get a good idea of how exactly the mushrooms are priming our innate response. There are not many studies of this kind, but there are a few.

Healthy Korean men who took 1.5g/day of powdered extract of Cordyceps militaris brown rice culture for four weeks had their blood analyzed before and after treatment. Levels of NK cells, IFN-y and IL-12 were examined in blood samples before and four weeks after therapy began. There was a significant increase in NK cells and IFN-y and no difference in IL-12.8 Cordyceps sinensis mycelium extract, in combination with the endoparasitic fungus that commonly exists with C. sinensis, Paecilomyces hepialid, also had immune-stimulating activity in healthy adults. In this study, people were given 1.43g/day and after eight weeks the cytotoxic activity of NK cells was significantly higher than at baseline (before therapy.)9 Wild fruiting bodies of Cordyceps species are incredibly expensive and are therefore rarely, if ever used in research. However, It is likely that cultivated fruiting bodies have similar medicinal qualities.10,11,12

Another study with 52 healthy males and females aged 21-41 consumed either 5g or 10g of Lentinus edodes (shiitake mushroom) daily for four weeks. Eating the Shiitake for four weeks led to increased proliferation of NK cells and IgA, decreased CRP (a marker of inflammation), and an increase in IL-4, Il-10, TNF-α and IL-1. Serving size had no impact on cytokine levels, except that two servings of Shiitake increased serum IL-4.13 Shiitake is a good example of the dynamic effects that some mushrooms have on the immune system. Shiitake both increased inflammatory cytokines (IL-1, TNF-α) and anti-inflammatory cytokines (IL-10 and IL-4) simultaneously, illustrating the use of the term immunomodulatory: it is neither a pure stimulator nor a depressor of the immune system. This may mean that immune modulating mushrooms are safe and effective to take during both phases of the viral immune response, and in fact, may have inhibitory effects during the cytokine storm of acute respiratory distress syndrome.

Grifola frondosa (Maitake) also exhibits this modulating activity.  G. frondosa fruiting body extract produced both immune stimulatory IL-2, TNF-α and IFN-γ and suppressive IL-10 in breast cancer survivors taking 5-7g/kg per day of mushrooms extract for three weeks.14

The combination formula of Trametes versicolor(Turkey tail) and Salvia miltiorrhiza IMG_7864(Red sage root, or Dan Shen) given at 50mg/kg and 20mg/kg respectively for four months showed significant immunomodulatory effects in healthy adults. There was a significant increase in PBMC (peripheral blood mononuclear cells – NK, B and T cells) gene expression of IL-2 receptor, increase in T helper cells and the ratio of T helper cells to cytotoxic T cells. There is also a significant increase in IFN-γ.15 There is little information in western herbal and mycological medicine about the use of plant and mushroom combination formulas. Dan Shen is known to ‘move the qi of the blood’ and in combination with the immune stimulating activity of Turkey tail, has promise as a very useful combination for immune therapy.

Not all fungi are created equally as immune modulators. When the β-glucan isolate, lentinax, from L. edodes mycelium was administered to healthy adults, there was no difference seen in NK cells and inflammatory cytokines between treatment and control groups.16 This juxtaposes the previous Shiitake study where the subjects consumed whole mushrooms and did have immune stimulatory effects. Contrary to what has been suggested in in vitro research 17,18 a mushroom that showed no benefit in vivo was Agaricus blazeii. Healthy elderly women consumed 300mg of A. blazeii fruiting body extract three times daily for 60 days, and there was no change in levels of IFN-γ, IL-6 and TNF-α after administration.19 Perhaps the dose was too low in this study, further research is needed.

Mushroom Cytokine response Immune response (simplified) Phase of viral response most applicable
Grifola frondosa (Maitake) IL-10

IL-2, TNF-α, IFN- γ

 Anti-inflammatory

Pro-inflammatory

 Possibly severe phase

Prevention/incubation phase
Lentinus edodes (Shitake) IL-4, IL-10

TNF-α, IL-1

 Anti-inflammatory

Pro-inflammatory

 Possibly severe phase

Prevention/incubation phase
Cordyceps spp. IFN- γ Pro-inflammatory Prevention/incubation
Trametes versicolor (Turkey tail) with Salvia miltiorrhiza (Red sage) IL-2, IFN- γ Pro-inflammatory Prevention/incubation 


Mushrooms as immune-modulators

The increases seen in IL-10 and IL-4 after Maitake, Shiitake, and Cordyceps mycelium intake are important as they relate to TH2 immune responses. TH2 responses are anti-parasitic and anti-allergic, but through the lens of viral immunity and inflammation, are anti-inflammatory. In fact, IL-10 is considered an anti-inflammatory master regulator. 20,21,22,23 IL-10 is essential for defending the host from tissue destruction during acute phases of immune responses, though it is not as desirable in the initial phase of infection, where a higher TH1 (inflammatory) response is required. At this stage, IL-10 can downregulate antigen presentation in macrophages and dendritic cells and can lead to chronic infection.24 During the later stages of infection, however IL-10 levels can determine host survival and higher concentrations of IL-10 have been associated with better outcomes in patients with acute respiratory distress syndrome.25Cancer Cell Interactions

This is immune modulation. As depicted, mushrooms are neither solely inflammatory, nor anti-inflammatory, and so should be utilized as such. The safety of medicinal mushroom use at different phases of the immune response is debatable. It is most likely that if mushrooms and mushroom extracts are consumed as preventative medicine, and the immune response is primed, the host won’t succumb to infection in the first place. There is some concern that if IL-10 is too high during the initial phase, the infection will become chronic, but since the mushrooms are simultaneously stimulating inflammatory cytokines, this isn’t likely.

  TH1 TH2
Associated cytokines IL-2, IL-12, IFN-γ, TNF-α IL-4, IL-10, IL-5, IL-6, IL-13, IL-9

 

Mushroom Derived β-glucans and the Immune Response

The most studied immune-stimulating constituents derived from medicinal mushrooms are 1,3/1,6-β-glucans. β-glucans, or polysaccharides, are present in all mushrooms as they are an integral component of the mushroom cell wall. Macrophages in the gut have specific receptors for β-glucans, most significantly Dectin-1, complement receptor 3 and TLR-2.26,27 When β-glucans bind to these receptors, an immune response is initiated. Because of this, in most studies, polysaccharides have been deemed the ‘active’ constituents in regards to immune activation.  Therefore, isolation and administration of these compounds is most commonly seen in the literature.

Pleuran, a polysaccharide derived from Oyster mushrooms

There are a number of human trials exploring the use of pleuran, a polysaccharide extracted from Pleurotus ostreatus (Oyster mushroom) as a therapeutic agent in respiratory infections. As respiratory infections are most commonly of viral origin,28 it seems appropriate to discuss this research here. In a double-blinded, placebo-controlled, randomized multicentric study, 175 children treated with pleuran  experienced a significant reduction in the frequency of recurrent respiratory tract infections.29 These findings agreed with a Spanish study investigating 166 children aged one to ten years old who were also treated with pleuran for recurrent respiratory infection.30

Advantageous respiratory effects of pleuran are also observed in adult athletes. A study IMG_6690of 50 athletes treated with pleuran over a three month period found a significant reduction in the frequency of upper respiratory tract infections compared to athletes treated with placebo. Blood samples of the athletes showed significantly higher levels of circulating NK cells in the pleuran group as compared to the placebo group.31

Oyster mushrooms contain almost 33% polysaccharides,32 so we can deduce from these studies that consuming whole Oyster mushrooms and/or Oyster mushroom aqueous extracts could be beneficial for the prevention of respiratory infections.

Immune-stimulating polysaccharides in late stage cancer patients

The polysaccharides isolated from Ganoderma lucidum, also known as ‘Ganopoly’, were administered at 1800mg three times daily in late stage cancer patients, and there was a significant increase in NK cells, IL-1, IL-6 and IFN-γ after administration.33 Another isolate, polysaccharide krestin (PSK), is a protein-bound polysaccharide derived and isolated from Trametes versicolor. In a phase one clinical trial, breast cancer patients consumed 6 or 9g of PSK for six weeks, leading to an increase in CD8 T cells and NK cells.34 Another isolated polysaccharide, Maitake D fraction (derived from the fruiting body of G. frondosa), was administered to patients with stage 2-4 cancer aged 46-84 at doses between 40 and 150mg twice daily. IL-2 and NK cell activity was detected through peripheral blood draw and both were significantly increased after administration35 The research on isolated, mushroom-derived polysaccharides was intended to prove anti-cancer activity, but because of the close similarities of anti-cancer and antiviral immunity,36 it also suggests that polysaccharides support antiviral immunity in late stage cancer patients.

In vivo healthy animal trials

Polysaccharides from G. lucidum, L. edodes and G. frondosa administered to healthy mice significantly increase macrophage phagocytosis and NK cell activity.37 Other studies have demonstrated similar immune-enhancing effects on healthy mice with G. frondosa and L. edodes extracts exhibiting increases in IL-12, IL-6, and IFN-γ. In this study, the combination of the G. frondosa and L. edodes extracts have a stronger effect than either extract alone.38 Maitake D fraction increases IL-12 and IFN-γ in healthy mice along with a significant decrease in IL-4 and IL-10.39 C. militaris extract also increases IL-12 and TNF-α cell activity in H1N1 infected mice.40

In vivo animal cancer models

A number of in vivo animal trials explore different mushroom extracts with similar immune effects. Many of these animal studies are cancer models, so they will be mentioned briefly. Agaricus hot water extracts increase IFN-γ, IL-6 and IL-1,41,42 Reishi polysaccharide and triterpene extracts increase inflammatory NFkB, TNF- α, IL1-b, IL-2, IFN-γ 43,44,45,46 Maitake extract increases IL-12, IFN-γ and TNF-α, IL-147,48 and PSK increases IL-12.49 Ganoderma polysaccharides increase NK cells and cytotoxic T cells, IL-1, IL-6 and IL-1.50,51

Because these are cancer models, so it is not completely clear if the same effects would take place in healthy animal models, though we can deduct from other experiments using healthy volunteers and healthy animals that it is likely that similar immune effects would occur.

In vitro antiviral activity

There are a number of fungal constituents that have antiviral activity in-vitro, including polysaccharides, indole alkaloids, terpenoids, polyketides and lignan derivatives.  Agaricus subfruescens and Grifola frondosa act directly on viral particles, β-glucan protein from A. subfruescens inhibits viral adsorption into the cell,  polysaccharides from A. subfruescens and polysaccharopeptide from T. versicolor inhibit viral replication, and triterpenes from Ganoderma spp directly kill virus proteins.52

The fruiting body ethanol-water extract of T. versicolor extract increases the TH1-related cytokines IL-2, IL-12, IL-18 and IFN-γ.53,54 As most of the research done on T. versicolor is with an isolated constituent, PSK, it is significant that this study, which used whole fruiting body extract, exhibits immune stimulating qualities.

Maitake fruiting body extract does not show direct antiviral activity to influenza A but does exhibit antiviral activity through macrophage activation and an increase in TNF-α production. 55

L. edodes mycelium directly inhibits influenza virus growth at early phases of infection, possibly during the entry process of viral particles to host cells. The in vivo administration stimulated an increase in innate immunity as well, suggesting that Shiitake mycelium has antiviral effects through both inhibition of initial viral replication and immune stimulation.56

A little known mushroom, Cryptoporus volvatus, the Cryptic Globe Fungus, has shown cryptanti-viral activity through multiple mechanisms. Aqueous extracts of the fruiting body inhibit porcine respiratory syndrome virus infection by repressing viral entry, viral RNA expression, possibly viral protein synthesis, cell-to-cell spread, and the release of virus particles from the host cell. C. volvatus also inhibits influenza virus replication in vitro and in vivo.57,58,59

The aqueous extract of Phellinus igniarius, or Fire Sponge, shows virucidal activity against influenza A and B viruses, including 2009 pandemic H1N1, human H3N2, avian H9N2, and oseltamivir-resistant H1N1 viruses. The study concludes that this extract may interfere with one or more early events in the viral replication cycle, including viral attachment to the target cell. 60

In vitro research is what propels in vivo research forward, but it is important to take this information with a grain of salt and understand this is what may happen in the human body, and not necessarily what will happen.

Anti-neuraminidase activity

A highly valued antiviral action in pharmaceuticals is neuraminidase inhibition. This is the mechanism of the commonly known antivirals Tamilflu and Rilenza. Neuraminidase is found on the surface of influenza viruses and allows viruses to be released from the host cell so they can then infect other healthy human cells. Neuraminidase inhibitors have been shown to improve the outcome of patients with leukemia and influenza. 61 Medicinal mushrooms and their constituents have been shown to have neuraminidase phimg_7902inhibitory activity in vitro and in vivo. Ganoderic acids, triterpenes found in Ganoderma species, have broad spectrum inhibition against influenza neuraminidases, specifically H5N1 andH1N1.62,63 Both the fruiting body and mycelial extracts of Phellinus spp. have neuraminidase inhibiting actions as well. 64,65,66  While there is still more research needed in this area, it is possible that Reishi and Phellinus species could be beneficial in treating viruses that utilize neuraminidase.

This paper focuses on mushrooms as antiviral therapies for enveloped, influenza-like viruses, but there is in vitro evidence to suggest medicinal mushrooms have antiviral activity towards many different viruses.67,68 Ganoderma lucidum has shown to be active against enterovirus, 69 human papillomavirus (HPV),70,71 herpes simplex virus (HSV)72,73,74,75 hepatitis B (HBV)76 and Epstein Barr virus (EBV).77 Cordyceps militaris has anti-hepatitis C (HCV) activity.78 Trametes versicolor is active against human immunodeficiency virus HIV.79.80 Grifola frondosa is active against HSV-181 and HBV.82 Inonotus obliquus has anti-HSV, 83,84 anti-HCV 85and anti-HIV86 activity and Lentinula edodes has anti-HBV 87 and anti-HSV 88 activity. Although not explored in this paper, these antiviral actions are interesting and worth considering for further dissection in future research.

Having a basic understanding of our complex immune system is important in understanding the role that mushrooms play as antivirals. As we have seen, mushrooms are immune modulators and can stimulate inflammatory and anti-inflammatory responses simultaneously. Mushrooms are most likely to be useful as preventative medicine before infection occurs, though if there is an initial infection, Cordyceps, Maitake, Shiitake, Turkey tail and Oyster mushroom may prevent infection from becoming more severe. If infection does become severe, the mushrooms that also stimulate IL-10 – Maitake, Cordyceps and Shiitake, could also be beneficial. In the wake of the current viral pandemic, these mushrooms should be further explored and utilized as medicine. Further research is essential in elucidating their potential effects.

antiviral mechanisms of medicinal mushrooms

 

Work cited

  1. “Innate Immunity: the Induced Response to Infection.” The Immune System, by Peter Parham, Garland Science, 2015, pp. 68–78.
  2. Jost S, Altfeld M. Control of Human Viral Infections by Natural Killer Cells. Annu Rev Immunol. 2013;31(1):163-194. doi:10.1146/annurev-immunol-032712-100001
  3. Vidal, Sylvia M. Khakoo, SalminI. Biron CA. Natural Killer Cell Responses during Viral Infections: Flexibility and Conditioning of Innate Immunity by Experience. 2011;1(6):497-512. doi:10.1016/j.coviro.2011.10.017.Natural
  4. Waggoner, Stephen N. Reighard, Seth D., Gyurova IE et al. Roles of natural killer cells in antiviral immunity. Curr Opin Virol. 2016;16:15-23. doi:10.1016/j.physbeh.2017.03.040
  5. Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X. COVID-19 infection : the perspectives on immune responses. Cell Death Differ. 2020. doi:10.1038/s41418-020-0530-3
  6. Liu CH, Kuo SW, Ko WJ, et al. Early measurement of IL-10 predicts the outcomes of patients with acute respiratory distress syndrome receiving extracorporeal membrane oxygenation. Sci Rep. 2017;7(1):1-10. doi:10.1038/s41598-017-01225-1
  7. Van Erp EA, Van Kampen MR, Van Kasteren PB, De Wit J. Viral infection of human natural killer cells. Viruses. 2019;11(3):1-13. doi:10.3390/v11030243
  8. Kang, Ho Joon, Baik, Hyun Wook KSJ et al. Cordyceps militaris Enhances Cell-Mediated Immunity in Healthy Korean Men. 2015;18(October 2014):1164-1172. doi:10.1089/jmf.2014.3350
  9. Jung SJ, Jung ES, Choi EK, Sin HS, Ha KC, Chae SW. Immunomodulatory effects of a mycelium extract of Cordyceps (Paecilomyces hepiali; CBG-CS-2): A randomized and double-blind clinical trial. BMC Complement Altern Med. 2019;19(1):1-8. doi:10.1186/s12906-019-2483-y
  10. Zhu L, Tang Q, Zhou S, et al. Isolation and purification of a polysaccharide from the caterpillar medicinal mushroom Cordyceps militaris (Ascomycetes) fruit bodies and its immunomodulation of RAW 264.7 macrophages. Int J Med Mushrooms. 2014;16(3):247–257. doi:10.1615/intjmedmushr.v16.i3.50
  11. Lee JS, Hong EK. Immunostimulating activity of the polysaccharides isolated from Cordyceps militaris. Int Immunopharmacol. 2011;11(9):1226–1233. doi:10.1016/j.intimp.2011.04.001
  12. Wang M, Meng XY, Yang RL, et al. Cordyceps militaris polysaccharides can enhance the immunity and antioxidation activity in immunosuppressed mice. Carbohydr Polym. 2012;89(2):461–466. doi:10.1016/j.carbpol.2012.03.029
  13. Dai X, Stanilka JM, Rowe CA, et al. Consuming Lentinula edodes (Shiitake) Mushrooms Daily Improves Human Immunity: A Randomized Dietary Intervention in Healthy Young Adults. J Am Coll Nutr. 2015;34(6):478-487. doi:10.1080/07315724.2014.950391
  14. Deng G. A phase I/II trial of a polysaccharide extract from Grifola frondosa in breast cancer patients inmunological effects. J Cancer Res Clin Oncol. 2013;135(9):1215-1221. doi:10.1007/s00432-009-0562-z.A
  15. Wong CK, Tse PS, Wong ELY, Leung PC, Fung KP, Lam CWK. Immunomodulatory effects of Yun Zhi and Danshen capsules in health subjects – A randomized, double-blind, placebo-controlled, crossover study. Int Immunopharmacol. 2004;4(2):201-211. doi:10.1016/j.intimp.2003.12.003
  16. Gaullier J-M, Sleboda J, Øfjord ES, et al. Supplementation with a soluble β-glucan exported from Shiitake medicinal mushroom, Lentinus edodes (Berk.) singer mycelium: a crossover, placebo-controlled study in healthy elderly. Int J Med Mushrooms. 2011;13(4):319-326. http://www.ncbi.nlm.nih.gov/pubmed/22164761. Accessed June 10, 2019.
  17. Hetland G, Johnson E, Lyberg T, Kvalheim G. The mushroom Agaricus blazei murill elicits medicinal effects on tumor, infection, allergy, and inflammation through its modulation of innate immunity and amelioration of Th1/Th2 imbalance and inflammation. Adv Pharmacol Sci. 2011;2011(Figure 2). doi:10.1155/2011/157015
  18. Cui L, Sun Y, Xu H, Xu H, Cong H, Liu J. A polysaccharide isolated from Agaricus blazei Murill (ABP-AW1) as a potential Th1 immunity-stimulating adjuvant. Oncol Lett. 2013;6(4):1039-1044. doi:10.3892/ol.2013.1484
  19. Lima CUJO, Souza VC, Morita MC, Chiarello MD, Karnikowski MGDO. Agaricus blazei Murrill and Inflammatory Mediators in Elderly Women : A Randomized Clinical Trial. 2011:336-342. doi:10.1111/j.1365-3083.2011.02656.x
  20. O’Garra A, Vieira PL, Vieira P, Goldfeld AE. IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage. J Clin Invest. 2004;114(10):1372–1378
  21. Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol. 2008;180(9):5771–5777. [PubMed] [Google Scholar]
  22. Hawrylowicz CM. Regulatory T cells and IL-10 in allergic inflammation. J Exp Med. 2005;202(11):1459–1463
  23. Wu K, Bi Y, Sun K, Wang C. IL-10-producing type 1 regulatory T cells and allergy. Cell Mol Immunol. 2007;4(4):269–275
  24. Rojas JM, Avia M, Martín V, Sevilla N. IL-10: A multifunctional cytokine in viral infections. J Immunol Res. 2017;2017. doi:10.1155/2017/6104054
  25. Liu CH, Kuo SW, Ko WJ, et al. Early measurement of IL-10 predicts the outcomes of patients with acute respiratory distress syndrome receiving extracorporeal membrane oxygenation. Sci Rep. 2017;7(1):1-10. doi:10.1038/s41598-017-01225-1
  26. Fang J, Wang Y, Lv X. Structure of a β -glucan from Grifola frondosa and its antitumor effect by activating Dectin-1 / Syk / NF- κ B signaling. 2012:365-377. doi:10.1007/s10719-012-9416-z
  27. Akramienė, Dalia, Kondrotas, Anatolijus Didžiapetrienė J et al. Effects of B-glucans on the immune system. Medicina (B Aires). 2007;43(8). doi:10.4271/911515
  28. Charlton CL, Babady E, Ginocchio CC, Hatchette TF, Jerris RC, Li Y, Loeffelholz M, McCarter YS, Miller MB, Novak-Weekley S, Schuetz AN, Tang Y-W, Widen R, Drews SJ. 2019. Practical guidance for clinical microbiology laboratories: viruses causing acute respiratory tract infections. Clin Microbiol Rev 32:e00042-18. https://doi.org/10.1128/CMR .00042-18.
  29. Jesenak M, Hrubisko M, Majtan J, Rennerova Z, Banovcin P. Anti-allergic Effect of Pleuran ( b -glucan from Pleurotus ostreatus ) . Jesenak M, Urbanclkova I, Banovcin P. Respiratory Tract Infections and the Role of Biologically Active Polysaccharides in Their. Nutrients. 2017:1-12. doi:10.3390/nu9070779 in Children with Recurrent Respiratory Tract Infections. 2014;474(March 2013):471-474.
  30. Pico Sirvent L, Sapena Grau J, Morera Ingles M, Rivero Urgell M. Effect of supplementation with β–glucan from Pleurotus ostreatus in children with recurrent respiratory infections. Ann Nurr Metab. 2013; 63 (1): 1378
  31. Bergendiova K, Tibenska E. Pleuran ( b -glucan from Pleurotus ostreatus ) supplementation , cellular immune response and respiratory tract infections in athletes. 2011:2033-2040. doi:10.1007/s00421-011-1837-z.
  32. McCleary B V., Draga A. Measurement of β-Glucan in mushrooms and mycelial products. J AOAC Int. 2016;99(2):364-373. doi:10.5740/jaoacint.15-0289
  33. Gao Y, Tang W, Dai X, et al. Effects of water-soluble Ganoderma lucidum polysaccharides on the immune functions of patients with advanced lung cancer. J Med Food. 2005;8(2):159-168. doi:10.1089/jmf.2005.8.159
  34. Torkelson CJ, Sweet E, Martzen MR, et al. Phase 1 Clinical Trial of Trametes versicolor in Women with Breast Cancer. Int Sch Res Netw. 2012;2012. doi:10.5402/2012/251632
  35. Kodama N, Komuta K, Nanba H. Activation of NK Cells in Cancer Patients. 2003;6(4):371-377.
  36. Müller L, Aigner P, Stoiber D. Type I interferons and natural killer cell regulation in cancer. Front Immunol. 2017;8(MAR):1-11. doi:10.3389/fimmu.2017.00304
  37. Mb YY, Fu W, Fu M, He G, Traore L. The immune effects of edible fungus polysaccharides compounds in mice. 2007;16(Suppl l):258-260.
  38. Vetvicka V, Vetvickova J. Immune-enhancing effects of Maitake (Grifola frondosa) and Shiitake (Lentinula edodes) extracts. Ann Transl Med.2014;2(2):14. doi:10.3978/j.issn.2305-5839.2014.01.05
  39. Noriko Kodama Yukihito Murata Hiroaki Nanba. Administration of a Polysaccharide from Grifola frondosa Stimulates Immune Function of Normal Mice Noriko. 2004;7(2):141-145.
  40. Lee HH, Park H, Sung GH, et al. Anti-influenza effect of Cordyceps militaris through immunomodulation in a DBA/2 mouse model. J Microbiol. 2014;52(8):696-701. doi:10.1007/s12275-014-4300-0
  41. Takimoto H, Kato H, Kaneko M, Kumazawa Y. Amelioration of skewed Th1/ Th2 balance in tumor-bearing and asthma-induced mice by oral administra- tion of Agaricus blazei extracts. Immunopharmacol Immunotoxicol. 2008;30(4):747-760.
  42. Lin JG, Fan MJ, Tang NY, et al. An extract of Agaricus blazei Murill adminis- tered orally promotes immune responses in murine leukemia BALB/c mice in vivo. Integr Cancer Ther. 2012;11(1):29-36.
  43. Zhang S, Nie S, Huang D, Li W, Xie M. Immunomodulatory effect of Ganoderma atrum polysaccharide on CT26 tumor-bearing mice. Food Chem. 2013;136(3-4):1213-1219.
  44. Wang G, Zhao J, Liu J, Huang Y, Zhong JJ, Tang W. Enhancement of IL-2 and IFN-gamma expression and NK cells activity involved in the anti-tumor effect of ganoderic acid Me in vivo. Int Immunopharmacol. 2007;7(6):864- 870.
  45.  Wang PY, Zhu XL, Lin ZB. Antitumor and immunomodulatory effects of polysaccharides from broken-spore of Ganoderma lucidum. Front Pharmacol. July 2012;3:135.
  46. Wang G, Zhao J, Liu J, Huang Y, Zhong J-J, Tang W. Enhancement of IL-2 and IFN-γ expression and NK cells activity involved in the anti-tumor effect of ganoderic acid Me in vivo. Int Immunopharmacol. 2007;7(6):864-870. doi:10.1016/j.intimp.2007.02.006
  47. Kodama N, Mizuno S, Nanba H, Saito N. Potential antitumor activity of a low-molecular-weight protein fraction from Grifola frondosa through enhancement of cytokine production. J Med Food. 2010;13(1):20-30. doi:10.1089/jmf.2009.1029
  48. Masuda Y, Murata Y, Hayashi M, Nanba H. Inhibitory effect of MD-Fraction on tumor metastasis: involvement of NK cell activation and suppression of intercellular adhesion molecule (ICAM)-1 expression in lung vascular endothelial cells. Biol Pharm Bull. 2008;31(6):1104–1108. doi:10.1248/bpb.31.1104
  49. Lu H, Yang Y, Gad E, et al. TLR2 agonist PSK activates human NK cells and enhances the antitumor effect of HER2-targeted monoclonal antibody therapy. Clin Cancer Res. 2011;17(21):6742–6753. doi:10.1158/1078-0432.CCR-11-1142
  50. Zhu XL, Chen AF, Lin Z Bin. Ganoderma lucidum polysaccharides enhance the function of immunological effector cells in immunosuppressed mice. J Ethnopharmacol. 2007;111(2):219-226. doi:10.1016/j.jep.2006.11.013
  51. Wang C, Wang Y. Abstracts from the 2nd International Symposium on Phytochemicals in Medicine and Food (2-ISPMF). Chin Med. 2018;13(S1):1-63. doi:10.1186/s13020-018-0172-2
  52. Linnakoski R, Reshamwala D, Veteli P, Cortina-Escribano M, Vanhanen H, Marjomäki V. Antiviral agents from fungi: Diversity, mechanisms and potential applications. Front Microbiol. 2018;9(OCT). doi:10.3389/fmicb.2018.02325
  53. Ho CY, Lau CBS, Kim CF, et al. Differential effect of Coriolus versicolor (Yunzhi) extract on cytokine production by murine lymphocytes in vitro. Int Immunopharmacol. 2004;4(12):1549-1557. doi:10.1016/j.intimp.2004.07.021
  54. Jeong SC, Yang BK, Kim GN, et al. Macrophage-stimulating activity of polysaccharides extracted from fruiting bodies of Coriolus versicolor (Turkey tail mushroom). J Med Food. 2006;9(2):175-181. doi:10.1089/jmf.2006.9.175
  55. Obi N, Hayashi K, Miyahara T, et al. Inhibitory effect of TNF-α produced by macrophages stimulated with Grifola frondosa extract (ME) on the growth of influenza A/Aichi/2/68 Virus in MDCK cells. Am J Chin Med. 2008;36(6):1171-1183. doi:10.1142/S0192415X08006508
  56. Kuroki T, Lee S, Hirohama M, et al. Inhibition of Influenza Virus Infection by Lentinus edodes Mycelia Extract Through Its Direct Action and Immunopotentiating Activity. Front Microbiol. 2018;9:1164. doi:10.3389/fmicb.2018.01164
  57. Gao L, Sun Y, Si J, et al. Cryptoporus volvatus extract inhibits influenza virus replication in vitro and in vivo. PLoS One. 2014;9(12). doi:10.1371/journal.pone.0113604
  58. Gao L, Zhang W, Sun Y, et al. Cryptoporus volvatus Extract Inhibits Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) In Vitro and In Vivo. PLoS One. 2013;8(5). doi:10.1371/journal.pone.0063767
  59. Ma Z, Zhang W, Wang L, et al. A novel compound from the mushroom Cryptoporus volvatus inhibits porcine reproductive and respiratory syndrome virus (PRRSV) in vitro. PLoS One. 2013;8(11). doi:10.1371/journal.pone.0079333
  60. Lee S, Kim JI, Heo J, et al. The anti-influenza virus effect of Phellinus igniarius extract. J Microbiol. 2013;51(5):676–681. doi:10.1007/s12275-013-3384-2
  61. Chemaly RF, Torres HA, Aguilera EA, et al. Neuraminidase Inhibitors Improve Outcome of Patients with Leukemia and Influenza: An Observational Study. Clin Infect Dis. 2007;44(7):964-967. doi:10.1086/512374
  62. Zhu Q, Bang TH, Ohnuki K, Sawai T, Sawai K, Shimizu K. Inhibition of neuraminidase by Ganoderma triterpenoids and implications for neuraminidase inhibitor design. Sci Rep. 2015;5(AUGUST):13194. doi:10.1038/srep13194
  63. Zhu T, Kim S-H, Chen C-Y. A Medicinal Mushroom: Phellinus Linteus. Curr Med Chem. 2008;15(13):1330-1335. doi:10.2174/092986708784534929
  64. Kim J, Kim D, Hwang BS, et al. Mycobiology Neuraminidase Inhibitors from the Fruiting Body of Phellinus igniarius. 2016:117-120.
  65. Yeom JH, Lee IK, Ki DW, Lee MS, Seok SJ, Yun BS. Neuraminidase inhibitors from the culture broth of Phellinus linteus. Mycobiology.2012;40(2):142-144. doi:10.5941/MYCO.2012.40.2.142
  66. Song AR, Sun XL, Kong C, et al. Discovery of a new sesquiterpenoid from Phellinus ignarius with antiviral activity against influenza virus. Arch Virol. 2014;159(4):753–760. doi:10.1007/s00705-013-1857-6
  67. Teplyakova T V. antiviral activity of polyporoid mushrooms (higher basidiomycetes) from Altai Mountains (Russia). 2012:37-45.
  68. Krupodorova T, Rybalko S, Barshteyn V. Antiviral activity of Basidiomycete mycelia against influenza type A (serotype H1N1) and herpes simplex virus type 2 in cell culture. Virol Sin. 2014;29(5):284-290. doi:10.1007/s12250-014-3486-y
  69. Zheng DS, Chen LS. Triterpenoids from Ganoderma lucidum inhibit the activation of EBV antigens as telomerase inhibitors. Exp Ther Med. 2017;14(4):3273-3278. doi:10.3892/etm.2017.4883
  70. Hernández-Márquez E, Lagunas-Martínez A, Bermudez-Morales VH, et al. Inhibitory activity of Lingzhi or Reishi medicinal mushroom, Ganoderma lucidum (higher Basidiomycetes) on transformed cells by human papillomavirus. Int J Med Mushrooms. 2014;16(2):179–187. doi:10.1615/intjmedmushr.v16.i2.80
  71. Donatini B. Control of oral human papillomavirus (HPV) by medicinal mushrooms, Trametes versicolor and Ganoderma lucidum: a preliminary clinical trial. Int J Med Mushrooms. 2014;16(5):497–498. doi:10.1615/intjmedmushrooms.v16.i5.80
  72. Eo SK, Kim YS, Lee CK, Han SS. Possible mode of antiviral activity of acidic protein bound polysaccharide isolated from Ganoderma lucidum on herpes simplex viruses. J Ethnopharmacol. 2000;72(3):475–481. doi:10.1016/s0378-8741(00)00266-x
  73. Oh KW, Lee CK, Kim YS, Eo SK, Han SS. Antiherpetic activities of acidic protein bound polysacchride isolated from Ganoderma lucidum alone and in combinations with acyclovir and vidarabine. J Ethnopharmacol. 2000;72(1-2):221–227. doi:10.1016/s0378-8741(00)00254-3
  74. Hijikata Y, Yamada S, Yasuhara A. Herbal mixtures containing the mushroom Ganoderma lucidum improve recovery time in patients with herpes genitalis and labialis. J Altern Complement Med. 2007;13(9):985–987. doi:10.1089/acm.2006.6297
  75. Eo SK, Kim YS, Lee CK, Han SS. Antiherpetic activities of various protein bound polysaccharides isolated from Ganoderma lucidum. J Ethnopharmacol. 1999;68(1-3):175–181. doi:10.1016/s0378-8741(99)00086-0
  76. Li YQ, Wang SF. Anti-hepatitis B activities of ganoderic acid from Ganoderma lucidum. Biotechnol Lett. 2006;28(11):837–841. doi:10.1007/s10529-006-9007-9
  77. Iwatsuki K, Akihisa T, Tokuda H, et al. Lucidenic acids P and Q, methyl lucidenate P, and other triterpenoids from the fungus Ganoderma lucidum and their inhibitory effects on Epstein-Barr virus activation. J Nat Prod. 2003;66(12):1582–1585. doi:10.1021/np0302293
  78. Ueda Y, Mori K, Satoh S, Dansako H, Ikeda M, Kato N. Anti-HCV activity of the Chinese medicinal fungus Cordyceps militaris. Biochem Biophys Res Commun. 2014;447(2):341–345. doi:10.1016/j.bbrc.2014.03.150
  79. Rodríguez-Valentín M, López S, Rivera M, Ríos-Olivares E, Cubano L, Boukli NM. Naturally Derived Anti-HIV Polysaccharide Peptide (PSP) Triggers a Toll-Like Receptor 4-Dependent Antiviral Immune Response. J Immunol Res. 2018;2018:8741698. Published 2018 Jul 15. doi:10.1155/2018/8741698
  80. Collins RA, Ng TB. Polysaccharopeptide from Coriolus versicolor has potential for use against human immunodeficiency virus type 1 infection. Life Sci. 1997;60(25):PL383–PL387. doi:10.1016/s0024-3205(97)00294-4
  81. Gu C, Li J, Chao F, Jin M, Wang X, Shen Z. Isolation , identification and function of a novel anti-HSV-1 protein from Grifola frondosa. 2007;75:250-257. doi:10.1016/j.antiviral.2007.03.011
  82. Gu CQ, Li J, Chao FH. Inhibition of hepatitis B virus by D-fraction from Grifola frondosa: synergistic effect of combination with interferon-alpha in HepG2 2.2.15 [published correction appears in Antiviral Res. 2007 Jul;75(1):91. Li, Jun-Wen [corrected to Li, JunWen]]. Antiviral Res. 2006;72(2):162–165. doi:10.1016/j.antiviral.2006.05.011
  83. Polkovnikova MV, Nosik NN, Garaev TM, Kondrashina NG, Finogenova MP, Shibnev VA. Vopr Virusol. 2014;59(2):45–48.
  84. Pan HH, Yu XT, Li T, et al. Aqueous extract from a Chaga medicinal mushroom, Inonotus obliquus (higher Basidiomycetes), prevents herpes simplex virus entry through inhibition of viral-induced membrane fusion. Int J Med Mushrooms. 2013;15(1):29–38. doi:10.1615/intjmedmushr.v15.i1.40
  85. Shibnev VA, Mishin DV, Garaev TM, Finogenova NP, Botikov AG, Deryabin PG. Antiviral activity of Inonotus obliquus fungus extract towards infection caused by hepatitis C virus in cell cultures. Bull Exp Biol Med. 2011;151(5):612–614. doi:10.1007/s10517-011-1395-8
  86. Shibnev VA, Garaev TM, Finogenova MP, Kalnina LB, Nosik DN. Vopr Virusol. 2015;60(2):35–38.
  87. Zhao YM, Yang JM, Liu YH, Zhao M, Wang J. Ultrasound assisted extraction of polysaccharides from Lentinus edodes and its anti-hepatitis B activity in vitro. Int J Biol Macromol. 2018;107(Pt B):2217–2223. doi:10.1016/j.ijbiomac.2017.10.100
  88. Santoyo,Susana, Ramirez-Anguiana Ana, christina Aldaris-Garcia L et al. Antiviral activities of Boletus edulis, Pleurotus ostreatus and Lentinus edodes extracts and polysaccharide fractions against Herpes simplex virus type 1. Phys Rev Lett. 2002;88(12):4. doi:10.1103/PhysRevLett.88.126404