Chaga 340 Research Papers

1. Park YK, Lee HB, Jeon EJ, Jung HS, Kang MH. Chaga mushroom extract inhibits oxidative DNA damage in human lymphocytes as assessed by comet assay. Biofactors. 2004;21:109–112.[PubMed]

2. Saar M. Fungi in Khanty folk medicine. J Ethnopharmacol. 1991;31:175–179.[PubMed]

3. Ichimura T, Otake T, Mori H, Maruyama S. HIV-1 protease inhibition and anti-HIV effect of natural and synthetic water-soluble lignin-like substances. Biosci Biotechnol Biochem. 1999;63:2202–2204.[PubMed]

4. Wasser SP, Weis AL. Therapeutic effects of substances occurring in higher Basidiomycetes mushrooms: a modern perspective. Crit Rev Immunol. 1999;19:65–96.[PubMed]

5. Kahlos K, Kangas L, Hiltunen R. Antitumor Activity of Triterpenes in Inonotus obliquus. Planta Med. 1986;52:554.[PubMed]

6. Kim YO, Park HW, Kim JH, Lee JY, Moon SH, Shin CS. Anti-cancer effect and structural characterization of endo-polysaccharide from cultivated mycelia of Inonotus obliquus. Life Sci. 2006;79:72–80.[PubMed]

7. Song HS, Lee JL, Kim SK, Moon WK, Kim DW, Kim YS, Moon KY. Downregulatory effect of AGI-1120 (α-Glucosidase inhibitor) and Chaga mushroom (Inonotus obliquus) on cellular NF-kB activation and their antioxidant activity. Kor J Pharmacogn. 2004;35:92–97.

8. Agarwal C, Singh RP, Agarwal R. Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release. Carcinogenesis. 2002;23:1869–1876.[PubMed]

9. Wang X, Jia W, Zhao A, Wang X. Anti-influenza agents from plants and traditional Chinese medicine. Phytother Res. 2006;20:335–341.[PubMed]

10. Song YS, Kim SH, Sa JH, Jin C, Lim CJ, Park EH. Anti-angiogenic, antioxidant and xanthine oxidase inhibition activities of the mushroom Phellinus linteus. J Ethnopharmacol. 2003;88:113–116.[PubMed]

11. Swanton C. Cell-cycle targeted therapies. Lancet Oncol. 2004;5:27–36.[PubMed]

12. Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 2003;36:131–149.[PubMed]

13. Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res. 1996;68:67–108.[PubMed]

14. Paschka AG, Butler R, Young CY. Induction of apoptosis in prostate cancer cell lines by the green tea component, (-)-epigallocatechin-3-gallate. Cancer Lett. 1998;130:1–7.[PubMed]

15. O'Malley KL, Liu J, Lotharius J, Holtz W. Targeted expression of BCL-2 attenuates MPP+ but not 6-OHDA induced cell death in dopaminergic neurons. Neurobiol Dis. 2003;14:43–51.[PubMed]

16. Sanchez I, Dynlacht BD. New insights into cyclins, CDKs, and cell cycle control. Semin Cell Dev Biol. 2005;16:311–321.[PubMed]

17. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science. 1998;281:1312–1316.[PubMed]

18. May P, May E. Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene. 1999;18:7621–7636.[PubMed]

19. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995;9:1149–1163.[PubMed]

20. Shah MA, Schwartz GK. Cyclin-dependent kinases as targets for cancer therapy. Cancer Chemother Biol Response Modif. 2005;22:135–162.[PubMed]

21. Borchers AT, Stern JS, Hackman RM, Keen CL, Gershwin ME. Mushrooms, tumors, and immunity. Proc Soc Exp Biol Med. 1999;221:281–293.[PubMed]

22. Park YM, Won JH, Kim YH, Choi JW, Park HJ, Lee KT. In vivo and in vitro anti-inflammatory and anti-nociceptive effects of the methanol extract of Inonotus obliquus. J Ethnopharmacol. 2005;101:120–128.[PubMed]

23. Franke TF, Kaplan DR, Cantley LC. PI3K: downstream AKTion blocks apoptosis. Cell. 1997;88:435–437.[PubMed]

24. Willis AC, Chen X. The promise and obstacle of p53 as a cancer therapeutic agent. Curr Mol Med. 2002;2:329–345.[PubMed]

25. Hofseth LJ, Hussain SP, Harris CC. p53: 25 years after its discovery. Trends Pharmacol Sci. 2004;25:177–181.[PubMed]

26. Chiu SJ, Hsu TS, Chao JI. Opposing securin and p53 protein expression in the oxaliplatin-induced cytotoxicity of human colorectal cancer cells. Toxicol Lett. 2006;167:122–130.[PubMed]

27. Bressac B, Galvin KM, Liang TJ, Isselbacher KJ, Wands JR, Ozturk M. Abnormal structure and expression of p53 gene in human hepatocellular carcinoma. Proc Natl Acad Sci USA. 1990;87:1973–1977.[PMC free article][PubMed]

28. Park YJ, Wen J, Bang S, Park SW, Song SY. [6]-Gingerol induces cell cycle arrest and cell death of mutant p53-expressing pancreatic cancer cells. Yonsei Med J. 2006;47:688–697.[PMC free article][PubMed]

29. Mantena SK, Sharma SD, Katiyar SK. Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mol Cancer Ther. 2006;5:296–308.[PubMed]

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1Sources and Composition

1.1. Sources

The mushroom Ganoderma Lucidum holds a place in a variety of Asian traditional medicine; it is most well known as Reishi, the name given to the mushroom by practitioners of Japanese medicine. In Traditional Chinese Medicine it is known as Lingzhi, and Korean medicine refers to it as Yeongji; in Taiwan it is sometimes referred to as Ling-Chih.[1] Other complimenting names given to Ganderma Lucidum include The 10,000 year Mushroom (Japanese), and the Mushroom of Immortality (Chinese).[2][3] The praise it receives is in part due to its bioactive effects, but may also be affected by the modes of distribution in the past (where, due to its rarity, only nobility or the privileged could afford it).[4][2] According to the year 2000 edition of the State Pharmacopoeia of the People’s Republic of China (an official compendium of drugs), Ganoderma Lucidum "acts to replenish Qi, ease the mind, and relieve cough and asthma, and it is recommended for dizziness, insomnia, palpitation, and shortness of breath".[2]

Traditional usage of Ganoderma Lucidum extends to as anti-cancer and anti-tumor, anti-microbial, anti-fungal, and anti-viral (specifically against herpes and HIV), as well as anti-inflammatory or immunomodulatory. Pro-longevity claims have also been made.[2]

Traditionally known as the God of Fungi, although associations with nobility may have raised it to undeserved god-like status. Used for almost everything and said to work for everything; tends to be more focused on immunity, sickness, and cancer

1.2. Comparison of Lingzhi sources

In the Chinese Pharmacopoeia (v.2000) both Ganoderma Lucidum (Red Lingzhi) and Sinensis (Purple Zingzhi) are listed as Lingzhi[5][6] Despite both being referred to as Lingzhi in Chinese medicine, these two species have some shared and differing properties. The term Ling Zhi can extend to more mushrooms, and ancient Chinese texts (ShenNong Ben Cao Jing and from the Qui/Han Dynasty and Ben Cao Gang Mu from the Ming Dynasty, the latter of which is considered the first pharmacopoeia[7]) indicated up to 6 types of Ling Zhi. The possible other Ganoderma mushrooms implicated here are atrum, luteum, tsugae, tropicum, tenue, applantum, asutrale, and capense; all other 250+ strains of Ganoderma known worldwide currently were not known during the era in China Ling Zhi was used as medicine. Ganoderma Lucidum is seen as the 'most medicinal' Ling Zhi, and is the strain that permeates into Korean and Japanese (Kampo) medicine.[3]

They (in reference to the two main strains, Purple and Red Lingzhi) differ in levels of the bioactive ergosterol and some triterpenoids[8] and the genetic influence of triterpenoids on monocytes (immune cells) shares about 26% similarity between species at best;[5] polysaccharide content does not differ as significantly.[9] In assessing their influences on the genome, it was demonstrated that 90% ethanolic extracts of the two respective mushrooms differnetially influence immunity.[5] When investigating genetic cross-over between the species, the similarities are relatively diverse with genes involved in cell development (21%), negative regulation of cellular process (16%), cellular protein metabolic process (16%), signal transduction (14%), and transcription (14%). Of the top 20 activity genes between the two species, they are most involved in immunomodulation and notable genes are the upregulation of IL-1B, IL-8, CLEC4E, BIRC3 and ADAMDEC1 with downregulation of Glycoprotein A33 and several genes with unknown actions.[5]

Beyond species, different locations that grow Ganoderma Lucidum can markedly differ in quantities of bioactives.[10] At least one study investigating over-the-counter Reishi products noted that out of 11 randomly selected products, the triterpenoids ranged from indeterminate to 7.8% and polysaccharides from 1.1-5.8%, the differences was attributed to differences in production method (with water soluble extracts possessing less triterpenoids) and growth conditions.[3] One study growin Reishi noted somewhat similar levels of triterpenoids overall, but the specific triterpenoids fluctuated wildy between samples.[11]

The triterpenoid (ethanolic extract) of these two species (Lucidum and Sinensis) markedly differs in their biological effects, but neither species is inactive in any way; the polysaccharides have more similarities between the two. There is also moderate to large differences between crops of Ganoderma Lucidum

1.3. Composition

Mushrooms in general tend to be 90% water or so, which makes a basic mushroom 'extract' dehydrated mushroom powder (and thus 1g extract, if unspecified, may be about as potent as 10g of the mushroom). Beyond that, they tend to be a good source of protein (10-40% of the non-water weight) carbohydrates (3-28%), fiber (3-32%) and then trace Essential Vitamins or Minerals.[12][3] Ganoderma is on the high end for fiber, low end for carbohydrate, moderate to high end for protein and has a relatively low ash (mineral) content.[13] Beyond the basics, Ganoderma Lucidum possesses unique bioactive molecules including:

  • A variety of Bioactive polysaccharides[14][15][16][17] that tend to be the components that interact with the immune system[18] and are subdivided into β-1,3-glucans and polysaccharide peptides like peptidoglycan.

  • Water-soluble Polysaccharide Peptides, or carbs with amino acids in the structure. They include GLPS peptide (GLPP),[19][6] GLPG,[20] GLIS,[21] PGY,[22] and F3[23]

  • β-1,3-Glucans (subset of polysaccharides) sometimes called 'Curdlan' [24] and some other Glucan molecules[25]

  • Over 120 triterpenoid compounds[26][27] which can be separated into those with a carboxylic side chain (Ganoderma Acids) and those without (Ganoderma alcohols). Some are referred to as lucidenic acids[28][29]

  • Nucleotide bases (thymine, uridine, inosine, guanosine, adenosine) the sum of all ranging from 303-1217mcg/g (in the mushroom cap) and 22-334mcg/g in the stem.[30]

  • Some bioactive proteins, such as LZ-8 (Lingzhi-8)[31] and Ganodermin[32]

  • A 114kDa hexameric lectin, a glycoprotein with 9.3% sugar[33]

  • A reversible and highly specific competitive alpha-glucosidase inhibitor known as SKG-3 with an IC50 value of 4.6mcg/mL[34]

  • Ergostane sterols[35] and ergosterol, known as pro-vitamin D2[36]

  • C19 fatty acids (nonadecenoic acid and cis-9-nonadecenoic acid)[37][38]

  • Riboflavin

  • Vitamin C

  • Copper and Zinc[39]

  • Selenium at up to 72mcg/g dry weight (best estimate of wet weight is 7.2ug/g) and can biotransform selenium into selenium-containing proteins[40][41]

  • Germanium (the ion, not to be confused with Geranium) at up to 489mcg/g[42]

There is also a large Chitin content in the Ganoderma Lucidum mushroom, which is indigestible (and for the most part, not bioactive) and makes the mushroom tough to chew.[3] The mushroom is hazel/red in color, which is due to the polysaccharide content.

Polysaccharides (the carb and fiber content), Peptidoglycans (carbs with amino acids branching off of them), and Triterpenoids (fat-soluble molecules with a structure similar to cholester) are the main reasons for the activity of Ganoderma Lucidum. Other molecules, like the C19 fatty acids, may also play a role but are less studied. The mushroom is pretty to look at and pretty hard to chew

1.4. Structure and Properties

The main bioactives of Ganoderma Lucidum tend to be seen as the triterpenoid component (broken down into Ganodermic acids, Ganodermic Alcohols, and Lucidenic Acids) and the polysaccharide content.

In regards to the differentiation between Ganoderma Acids and Alcohols (the triterpenoid compounds), acidic fractions appear to favor acid accrual and neutral fractions the alcohol fragment.[43] Triterpenoids appear to be hydrophobic, and are present in ethanolic or chrorophyll extractions; the polysaccharides are water-soluble and are the main bioactive in any Ganoderma water-soluble extract.

2Different forms of Ganoderma Lucidum

2.1. The Actual Mushroom

Traditional usage of the mushroom for its medicinal properties was in the range of 25-100g of the fruiting body (mushroom head) daily and a course of 'treatment' is 1-3 months.[44][45] The fruiting body contains a large amount of chitin, and is generally seen as touch to chew; the polysaccharides in Ganoderma Lucidum give the mushroom a reddish/hazel hue.

By weight, the fruiting body of the mushroom is about 0.5% polysaccharides.[45]

2.2. Water-soluble Extract

The water-soluble extract tends to be catered towards the polysaccharide content.

One patented blend, Ganopoly, is an extraction process yielding 98.8% content of polysaccharides by weight with no measurable triterpenoids; capsules contain 600mg total weight and 25% polysaccharides, and the recommended daily dose of 5,200mg is bioequivalent to 81g whole mushrooms based on polysaccharide content.[45]

2.3. Ethanolic Extract

The ethanolic extract of Ganoderma Lucidum tends to be catered towards the triterpenoid content, contributing little to no polysaccharides.

2.4. Antlered

The antlered form of Ganoderma (Ganoderma Lucidum AF; rokkaku-reishi) is the same species of Ganoderma Lucidum but varies in appearance, looking more like antlers than the standard mushroom.[46] It is rarely found in nature (although recently has been cultivated to higher levels), but consists of mostly the same bioactive compounds in regular Ganoderma Lucidum.[47][48] Although polysaccharide content is roughly similar at 40.1% of dry weight,[46] Triterpenoid compounds such as lucidenic acid, however, are higher in the antlered version[49][46] The specific amount of triterpene structures in the Antlered version range from 5875.8+/-80mcg/g and 7034.2+/-274.8mcg/g, whereas regular Ganoderma ranges from 2443.1+/-45.6mcg/g to 4441.2+/-328.4mcg/g; the lowest and highest recorded values being 140% and 58% higher in the Antlered version, respectively.[11]

Same as standard Ganoderma Lucidum, except with a higher triterpenoid content. Completely irrelevant if you are using a hot-water extract, but possibly beneficial to use the antlered version if consuming the entire mushroom or an ethanolic extract

2.5. Mycelium

The mycelium of a mushroom is a branching vegetable network that is seen as a growth of the mushroom, but not the stem nor the cap. Ganoderma Mycelium appears to contain many of the same bioactives that the fruiting body (cap) does,[50] and polysaccharides from the Mycelia have been used to similar efficacy as the fruiting body.[51][52][53]

A cheaper way to sell Ganoderma polysaccharides, and isn't completely inactive; can be useful for the frugal

2.6. Spores

Ganoderma Lucidum spores (Reishi Houshi) possesses a much higher content of triterpenoids on a weight basis when compared to standard Ganoderma Lucidum, but is insignificantly different or less than the antlered form of Ganoderma.[11] Whereas the total content of triterpenes in 6 strains of standard Ganoderma ranged from 2443.1+/-45.6mcg/g to 4441.2+/-328.4mcg/g, the spores averaged at 5549.2+/-317.3mcg/g (24% higher than the largest recorded Ganoderma strain). The antlered version of Ganoderma (Rokkaku-Reishi) averaged between 5875.8+/-80mcg/g and 7034.2+/-274.8mcg/g (all numbers dry weight).[11]

2.7. Jisheng Injections

Jisheng injections are injections of Ganoderma Lucidum that have been reported to aid in sleep and increase appetite for up to 2 weeks after administration.[54]

3Molecular Targets

3.1. Toll Like Receptors

Toll-Like Receptor 4 (TLR4) is a receptor that is highly expressed on cells in the immune system, such as dendritic cells[55] and macrophages;[56] polysaccharides from Ganoderma Lucidum appear to be a ligand for this receptor and activate it[56][57] which activates other pro-inflammatory proteins such as NF-kB (nuclear receptor) and TNF-α (cytokine). These effects are related to the polysaccharide and peptidoglycan content of Ganoderma Lucidum.[58]

When looking at the activation of NF-kB (correlates well with TLR4 activation in cells expressing TLR4), it appears to be activated when the pro-inflammatory stimuli LPS is not present[59][5] yet suppressed when LPS is coincubated;[60] this suggests that Ganoderma polysaccharides are a receptor modulator.

These same trends are seen with TNF-α (consequence of NF-kB activation, among other things) where Ganoderma Lucidum suppresses the increase of TNF-α induced by LPS[60] associated with less phosphorylation of Akt (Ser473)[61] and less IkB degradation and NF-kB activity.[62] When there is no proinflammatory stimuli, Ganoderma Lucidum polysaccharides reliably increase TNF-a in animal models[63][64] and isolate human cells[65][66] secondary to macrophage activation.[67] One human study on persons with breast cancer noted an improvement in immunomodulation as it pertains to cancer in response to 3g Ganoderma spores daily, suggesting the above works in humans.[68]

Ganoderma Lucidum polysaccharides appear to be a TLR4 receptor modulator, and using Lipopolysaccharide (LPS) as a proinflammatory reference Ganoderma can increase inflammation when there is no inflammatory stimuli present and attenuate inflammation when there is a stimuli present. NF-kB activation and TNF-α levels follow this same pattern, and Ganoderma appears to be a context dependent pro and anti-inflammatory (immune system modulator)

The cytokine known as Matrix metallopeptidase 9 (MMP9) is normally induced by TNF-α,[69] yet does not occur with Ganoderma-induced TNF-α;[62] a compound in Ganoderma appears to interfere with MMP9 mRNA and protein content by interfering with the promotor in the nucleus;[62] this may be related to the triterpenoids[70][71][72] and at least one peptidoglycan.[62] Another cytokine, MCP-1, is suppressed by the water soluble extract (usually polysaccharides) yet induced by the ethanolic extract (triterpenoids).[73]

Some triterpenoids (usually in ethanolic extracts) may also have immunomodulatory properties as they have been noted ot upregulate IL-2, IL-4, and IL-8 in vitro[73] while inhibiting NF-kB activation via AP-1[72] which is due to ERK phosphorylation; MEK inhibitors are synergistic in this regard with Ganoderma triterpenoids.[71]

Ganoderma may disregulate the connections between inflammation and the carcinogenic consequences of inflammation, but more research is required to assess practical relevance of this (as many compounds in Ganoderma act in different manners)

4Pharmacology

4.1. Serum

After oral administration of a blend of Reishi (13.5% polysaccharides, 6% triterpenoids) at 500mg/kg bodyweight in rats and another blend (13.4% triterpenoids) at 500mg/kg bodyweight in rats show a Tmax of around 90 minutes for Ganoderic Acid A, F, and H[74] which were similar to a previous study measuring these triterpenoids.[75] Peaks were seen quite rapidly, with a few triterpenoids appearing in plasma in relatively high quantities in under 20 minutes after ingestion.[74][75]

5Neurology

5.1. Cholinergic Neurotransmission

Numerous (18) triterpenoids from Ganoderma Lucidum have been shown to possess acetylcholinesterase inhibitory actions with an IC50 value ranging from 9.40μM to 31.03μM, potency favoring those with an n-butyl ester side chain.[76]

Some triterpenoids have shown acetylcholinesterase inhibition when tested in vitro; the practical relevance of this to oral supplementation is currently not known

5.2. Neurogenesis

Triterpenoids from Ganoderma Lucidum appear to be able to act as NGF and BDNF mimetics, and enhance neuronal survival in vitro.[77] However, Ganoderma polysaccharides have been shown in vitro to induce MAPK activation and neuronal differentiation in rat neurons and prevent NGF-induced apoptosis.[78]

5.3. Neurooxidation

Ganoderma Lucidum has been implicated in reducing neuronal loss induced by kainic-acid excitotoxicity[79] and has been demonstrated to reduce dopaminergic losses secondary to its anti-inflammatory effects on microglia, as coincubation of LPS (pro-inflammatory agent) and Ganoderma can reduce the harmful effects of LPS on microglia and dopaminergic neurons.[80][81]

5.4. Fatigue

One large study has been conducted on Ganoderma Lucidum and 'Neurasthenia', which is a term that has its diagnostic criteria to 'Chronic Fatigue Syndrome' (despite neurasthenia not being a commonly used term in the West).[45] Neurasthenia is a functional diagnosis of at least two of the following symptoms: muscular aches and pains, dizziness, headaches, sleep disturbance, inability to relax, irritability, and dyspepsia[82] and varies between affecting 0.5-2.4% of tested populations.[83][84][85]

The study found that in a sample of 132 persons with diagnosed neurasthenia (as assessed by the criteria mentioned before from the ICD-10) given Ganopoly (Ganoderma Polysaccharide at 25% by weight) at 5,400mg daily, bioequivalent to 81g of the mushroom, found that after 2 months of supplementation that there were significant improvements in measured parameters overall with more persons reporting 'significant improvement' and less reporting 'regression' of well-being.[45] Improvements in fatigue and well-being were both noted with no significant side-effects, although a pilot study done by the same research group ntoed that 4 weeks usage was insufficient in alleviating symptoms; suggesting chronic usage is needed.[45]

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